WO2020075196A1 - Polymorphes de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (s)-malate, leurs procédés de production et leurs utilisations pharmaceutiques - Google Patents

Polymorphes de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (s)-malate, leurs procédés de production et leurs utilisations pharmaceutiques Download PDF

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WO2020075196A1
WO2020075196A1 PCT/IN2019/050754 IN2019050754W WO2020075196A1 WO 2020075196 A1 WO2020075196 A1 WO 2020075196A1 IN 2019050754 W IN2019050754 W IN 2019050754W WO 2020075196 A1 WO2020075196 A1 WO 2020075196A1
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dimethoxyquinolin
yloxy
cyclopropane
fluorophenyl
phenyl
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PCT/IN2019/050754
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English (en)
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Srinivas Laxminarayan Pathi
Venkata Srinivas Pullela
Ramanaiah CHENNURU
Ravikumar Puppala
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Cipla Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Present invention relates to polymorphic forms of N-(4-(6,7-dimethoxyquinolin-4- yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide, (S)-malate, methods of preparation, pharmaceutical compositions and methods of therapeutic treatment involving polymorphic forms thereof.
  • Formula- is a inhibitor of tyrosine kinases c-Met and VEGFR2, indicated for the treatment of patients with progressive, unresectable locally advanced or metastatic medullary thyroid carcinoma and advanced renal cell carcinoma (RCC) in people who have received prior anti-angiogenic therapy.
  • US 9815789 B2 discloses crystalline forms Mi, M2, M3, M4 of (L)- malate salt of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)- N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide and crystalline forms Mi, M2, M 3 of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, 1 -dicarboxamide and a processes of preparation thereof .
  • WO 2018/10 4954 Al discloses crystalline forms M and S of (L)- malate salt of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'- (4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide; crystalline forms M, S, N, and R of hydrochloride salt of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, 1 -dicarboxamide and a processes of preparation thereof.
  • CN104961680 A discloses crystal A and crystal B of hydrochloride salt of N-(4- (6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1- dicarboxamide and process for its preparation.
  • CN104961681 A discloses various acid addition salts of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide and process for
  • the solid state physical properties of crystalline forms of a pharmaceutically useful salt can be influenced by controlling the conditions under which the salt is obtained in solid form.
  • Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
  • Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
  • the rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
  • the solid-state form of a compound may also affect its behaviour on compaction and its storage stability.
  • the present invention relates to novel polymorphic forms of the kinases inhibitor N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1, l-di carboxamide (S)-malate of Formula I.
  • N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate may be in anhydrous form or a pseudopolymorphic form. Accordingly, pseudopolymorphs provided include hydrates, solvates, and/or hydrated solvates thereof.
  • the polymorphic forms of the present invention are designated herein as “Form C2”,“Form C3”,“Form C4” and“ Form C5” .
  • the novel polymorphic forms of the present invention are characterized by unique XRD patterns.
  • the novel polymorphic forms of the present invention possess certain physical and chemical properties which render them particularly suitable for pharmaceutical development, such as good solubility, permeability and bioavailability. In addition, they are suitable for bulk handling and formulation.
  • the present invention relates to process for preparing novel polymorphic forms of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate.
  • the present invention also relates to pharmaceutical composition containing novel polymorphic forms of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, l-di carboxamide (S)-malate, optionally comprising one or more pharmaceutically acceptable excipients.
  • the invention also provides methods of treatment of carcinoma wherein N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate is useful.
  • method for the prevention or treatment of carcinoma comprises administering novel polymorphic forms of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate to a patient in need thereof.
  • novel polymorphic forms of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, l-di carboxamide (S)-malate for use in the prevention or treatment of carcinoma.
  • FIG. l is an X-ray powder diffraction pattern of crystalline Form C2 of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate of formula I.
  • FIG.2 is a Solid State 13 C NMR of crystalline Form C2 of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate of formula I.
  • FIG.3 is a DVS thermogram of crystalline Form C2 of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate of formula I.
  • FIG.4 is an X-ray powder diffraction pattern of crystalline Form C3 of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate of formula I.
  • FIG.5 is an X-ray powder diffraction pattern of crystalline Form C4 of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate of formula I.
  • FIG.6 is an X-ray powder diffraction pattern of crystalline Form C5 of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate of formula I.
  • solvated is understood to mean formation of a complex of variable stoichiometry comprising N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l-di carboxamide (S)-malate of Formula (I) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • the solvent used is a pharmaceutically acceptable solvent.
  • Suitable pharmaceutically acceptable solvents include C1-C4 alcohol solvents, benzyl alcohol, methyl isobutyl ketone, propylene glycol, acetonitrile and dimethylsulfoxide (DMSO), and solvates of more than 1%.
  • the solvate can be isolated either as an amorphous form or in a crystalline form, preferably in a crystalline form.
  • the solvate can be further isolated either in anhydrous form or hydrated form.
  • hydrate is understood as a substance that is formed by adding water molecules.
  • the skilled person will appreciate that the water molecules are absorbed, adsorbed or contained within a crystal lattice of the solid compounds, usually in defined stoichiometric ratio.
  • the notation for a hydrated compound may be nFhO, where n is the number of water molecules per formula unit of the compound. For example, in a hemihydrate, n is 0.5; in a monohydrate n is one; in a sesquihydrate, n is 1.5; in a dihydrate, n is 2; and so on.
  • the term "substantially the same X-ray powder diffraction pattern" is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2Q values within ⁇ 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.
  • the polymorphs of the present invention have been characterized by powder X-ray diffraction spectroscopy which produces a fingerprint of the particular crystalline form. Measurements of 2Q values are accurate to within ⁇ 0.2 degrees. All the powder diffraction patterns were measured on a PANalytical X’Pert 3 X-ray powder diffractometer using a Cu K a radiation source.
  • the present invention provides novel polymorphic form of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate, wherein the said malate is referred to as“Form C2”.
  • the malate may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.
  • the crystalline Form C2 is relatively stable towards moisture and humidity, thereby representing a crystalline form of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)- N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate, thus enhancing the efficacy of the parent molecule in lower doses.
  • Crystalline Form C2 may be characterized by having an XRPD diffractogram comprising peaks at 7.9, 9.8, 10.6, 14.8, 15.9 and 18.3 ⁇ 0.2°2Q.
  • the XRD pattern may have further peaks at 6.6, 13.4, 22.7, 27.0 and 28.0 ⁇ 0.2°20.
  • the XRPD diffractogram may be as depicted in Figure 1.
  • Crystalline Form C2 may also be characterized by the Solid-state 13 C nuclear magnetic resonance (SS 13 C NMR) spectrum wherein chemical shift is expressed in parts per million.
  • SS 13 C NMR Solid-state 13 C nuclear magnetic resonance
  • crystalline Form C2 is characterized by having a SS 13 CNMR spectrum as shown in Figure 2.
  • Crystalline Form C2 may also be characterized as having a DVS spectrum.
  • automated vapor sorption data were collected on a SMS DVS Intrinsic vapor sorption analyzer. Adsorption and desorption data were collected at 25°C, over a range from 5 to 95%RH, at l0%RH increments under a nitrogen purge. Samples were held at the corresponding RH for 1 hour prior to moving to the next RH range.
  • crystalline Form C2 is characterized by having a DVS spectrum as shown in Figure 3.
  • Form C2 may be further characterized by other methods including, but not limited to IR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.
  • the present invention encompasses a process for preparing the crystalline Form C2 of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate by crystallizing it from a mixture of solvent and water.
  • the crystallization comprises: a) combining N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl) cyclopropane- 1, 1 -di carboxamide (S)-malate in a suitable first solvent or mixture of first solvent and water thereof, at a temperature ranging from 25°C to -lO°C to form a mixture; b) stirring the mixture at a temperature and for a sufficient period.
  • stirring is for a period of about 30 minutes to about 10 hours, preferably of about 1 hour to about 5 hours.
  • stirring is done at about at about 25°C to about -l0°C, more preferably at 5°C to about -5°C; c) optionally, mixing the reaction mass with a second solvent or mixture of second solvent and water.
  • a suspension is obtained.
  • the suspension may be stirred, optionally, for at about 2 hours to about 24 hours; preferably for about 4 hours to about 24 hours; preferably, at about at about -l0°C to about l5°C, more preferably at -5°C to about l0°C; and; d) isolating the precipitated crystalline Form C2 and drying under reduced pressure at 25-60°C, preferably at 30-50°C for at about 5 hours to about 10 hours.
  • first and second solvents are selected from C1-C5 alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; halogenated solvent such as methylene dichloride, ethylene chloride, chloroform and carbon tetrachloride; ketone such as acetone, MIBK, ethyl isopropyl ketone; nitriles such as acetonitrile, propionitrile, butyronitrile; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert- butyl acetate, amyl acetate; ethers such as MTBE, diisoproyl ether, diethyl ether, cyclopentyl methyl ether; hydrocarbon
  • amount of water is based on the solvent used and varies from about 0.1% to about 0.5% v/v.
  • crystallization may be accelerated by cooling the solution, adding an antisolvent or seeding the solution with a crystal of Form C2.
  • crystal seeding may be used to control the crystal form obtained.
  • the crystal form is controlled primarily by choosing the appropriate seed crystals and the batch temperature, and secondarily through control of solubility/supersaturation (via adjusting the solvent composition) and the supersaturation relief rate (via adjusting solvent charge rate or batch cooldown rate).
  • Physical properties such as particle size may be controlled by manipulation of the seed size and seed amount, and also by dry or wet milling processes.
  • the process comprises: a) Dissolving N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl) cyclopropane- 1, l-di carboxamide base in a suitable solvent or solvent mixture;
  • Base used as a starting material can be in any form, e.g. it can be in anhydrous, hydrated, solvated or amorphous form.
  • Steps b and c may be performed one after another or simultaneously.
  • solvents are selected from water, C1-C5 alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; halogenated solvent such as methylene dichloride, ethylene chloride, chloroform and carbon tetrachloride; ketone such as acetone, MIBK, ethyl isopropyl ketone; nitriles such as acetonitrile, propionitrile, butyronitrile; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert- butyl acetate, amyl acetate; ethers such as THF, MTBE, diisopropyl ether, diethyl ether, cyclopentyl methyl ether;
  • a preferred solvent is selected from water, C1-C5 alcohol, ethers and halogenated solvent or mixture thereof.
  • the dissolution may be performed at a temperature of about 20°C to about 80°C, more preferably, of about 25°C to about 65°C, depending upon the solvent used.
  • the solution is clarified by filtration.
  • the solution is cooled.
  • cooling is done to a temperature of about lO°C to about -lO°C, more preferably, cooling is done to a temperature of about 5 °C to about -5°C.
  • Crystalline Form C2 can be generated in a variety of solvent mixtures such as MDC-Methanol and THF- water, by a variety of methods.
  • base is dissolved in a mixture of MDC-methanol and water is charged to the clear solution to reach a suitable seeding composition.
  • Form C2 solids are introduced as seed, L-malic acid is added under stirring.
  • more MDC is charged over time to complete the crystallization.
  • the Form C2 seed solids are charged to a mixture of heptane and L-malic acid to form the seed slurry. Then, base dissolved in a mixture of THF- water are simultaneously charged to the seed slurry, while maintaining the appropriate solvent composition. Optionally, more water may be charged to drive crystalline Form C2 out of solution to improve the yield.
  • a stirring step is performed.
  • the stirring is performed for about 1 hour to about 30 hours, more preferably, for about 2 hours to about 25 hours.
  • the stirring is done at temperature of about -lO°C to about 30°C, more preferably, at about -5°C to about 25 °C.
  • the obtained crystalline Form C2 is further isolated.
  • the isolation is done by filtration.
  • the drying may be done under reduced pressure at 25-60°C, preferably at 30-50°C for at about 4 hours to about 10 hours.
  • the dried material may be further exposed to the humidity at 25-30°C, 60-75% RH for about 1 hour to about 20 hours.
  • the present invention provides novel polymorphic form of N-(4- (6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1- dicarboxamide (S)-malate, wherein the said malate is referred to as“Form C3”.
  • the malate may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.
  • the crystalline Form C3 is relatively stable towards moisture and humidity, thereby representing a crystalline form of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)- N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate, thus enhancing the efficacy of the parent molecule in lower doses.
  • Crystalline Form C3 may be characterized by having an XRPD diffractogram comprising peaks at 5.02, 6.69, 10.15, 13.53, 15.23, 23.47 and 24.8l ⁇ 0.2°20.
  • the XRPD diffractogram may be as depicted in Figure 4.
  • Form C3 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.
  • the present invention encompasses a process for preparing the crystalline Form C3 of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate by drying Form C2 for a sufficient time.
  • drying is for a period of about 30 minutes to about 10 hours, preferably of about 2 hour to about 5 hours.
  • drying is done at about at about 20°C to about 40°C, more preferably at 25°C to about 35°C.
  • the present invention provides novel polymorphic form of N-(4- (6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1- dicarboxamide (S)-malate, wherein the said malate is referred to as“Form C4”.
  • the malate may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.
  • the crystalline Form C4 is relatively stable towards moisture and humidity, thereby representing a crystalline form of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)- N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate, thus enhancing the efficacy of the parent molecule in lower doses.
  • Crystalline Form C4 may be characterized by having an XRPD diffractogram comprising peaks at 4.5, 6.7, 9.1, 10.2, 12.1, 15.2, 18.3, 22.2 and 24.0 ⁇ 0.2°20.
  • the XRPD pattern may further peaks at 13.6, 16.5, 21.2 and 23.1 ⁇ 0.2°20.
  • the XRPD diffractogram may be as depicted in Figure 5.
  • Form C4 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.
  • the present invention encompasses a process for preparing the crystalline Form C4 of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl) cyclopropane- 1, l-di carboxamide (S)-malate, the process comprising; a) combining N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl) cyclopropane- 1, l-di carboxamide and L-malic acid in a solvent or mixture of solvents at a temperature ranging from 0°C to lO°C to form a mixture.
  • stirring is for a period of about 30 minutes to about 30 hours, preferably of about 1 hour to about 25 hours.
  • stirring is done at about at about 0°C to about l0°C, more preferably at 2°C to about 8°C for about 2 hour to about 10 hours.
  • the temperature of the reaction mixture is then raised to about 20°C to about 30°C, more preferably at 25°C to about 30°C and then stirring is done for a period of about 10 hours to about 30 hours, preferably for about 20 hours to about 25 hours, and d) isolating the precipitated crystalline Form C4 and drying under reduced pressure at 25-60°C, preferably at 30-50°C for at about 2 hours to about 10 hours.
  • solvents are selected from C1-C5 alcohol solvent such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol; halogenated solvent such as methylene dichloride, ethylene chloride, chloroform and carbon tetrachloride; ketone such as acetone, MIBK, ethyl isopropyl ketone; nitriles such as acetonitrile, propionitrile, butyronitrile; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate; carbonate esters such as dimethyl carbonate, diethyl carbonate, diphenyl carbonate, ethylene carbonate, propylene carbonate; ethers such as
  • the present invention provides novel polymorphic form of N-(4- (6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1- dicarboxamide (S)-malate, wherein the said malate is referred to as“Form C5”.
  • the malate may be isolated in pseudo polymorphic form as a solvate optionally in hydrated form, or as a non-hydrated solvate.
  • the crystalline Form C5 is relatively stable towards moisture and humidity, thereby representing a crystalline form of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)- N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate, thus enhancing the efficacy of the parent molecule in lower doses.
  • Crystalline Form C5 may be characterized by having an XRPD diffractogram comprising peaks at: 7.5, 8.2, 10.3, 12.5, 16.5, 17.8, and 25.6 ⁇ 0.2°20.
  • the XRPD diffractogram may be as depicted in Figure 6.
  • Form C5 may be further characterized by other methods including, but not limited to IR, solid state NMR, DSC, TGA, intrinsic dissolution and Raman spectroscopy.
  • the present invention encompasses a process for preparing the crystalline Form C5 of N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate by drying Form C4 for a sufficient time.
  • drying is for a period of about 1 hour to about 10 hours, preferably of about 2 hours to about 8 hours. Preferably, drying is done at about at about 50°C to about l00°C, more preferably at 70°C to about 90°C.
  • the N-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4- fluorophenyl)cyclopropane-l, 1 -dicarboxamide (S)-malate may be in any polymorphic form or in a mixture of any polymorphic forms.
  • the starting material can be obtained by any method known in the art, such as the one described in U.S. Pat. No. US 7579473B2 which is incorporated herein by reference.
  • the process of invention may be used as a method for purifying any form of N-(4- (6,7-dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane-l, 1- dicarboxamide (S)-malate, as well as for the preparation of the new polymorphic forms.
  • a pharmaceutical composition comprising polymorphic forms of N-(4-(6,7- dimethoxyquinolin-4-yloxy) phenyl)-N'-(4-fluorophenyl)cyclopropane- 1 , 1 - dicarboxamide (S)-malate as described above, together with one or more pharmaceutically acceptable excipients.
  • the clear filtrate was added to the L-malic acid slurry at 0°C to 5°C over a period of 15-30 min. Added 1 ml of water to the reaction mass at 0°C to 5°C and stirred further for 1-2 hr at 0°C to 5°C. The temperature of the reaction mass was slowly raised to 20°C to 25°C and the stirring continued further for 15-24 hr. The solids were isolated by filtration, washed with n-Heptane (2X40 ml) and then dried under vacuum at 40°C for 4-6 hr. The resulting solids were kept in the humidification chamber at 30°C, 60% RH for 1-5 hr. Crystalline Form C2 was analysed by XRD.

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Abstract

La présente invention concerne de nouvelles formes cristallines de (N-(4-(6,7-diméthoxyquinolin-4-yloxy)phényl)-N'-(4-fluorophényl) cyclopropane-1, 1-dicarboxamide, (S)-malate, des compositions pharmaceutiques contenant lesdites formes cristallines et l'utilisation desdites formes cristallines dans le traitement d'un carcinome médullaire de la thyroïde progressif, avancé non résécable localement ou métastatique et un carcinome à cellules rénales (RCC) avancé chez des personnes qui ont reçu auparavant une thérapie anti-angiogénique. La présente invention concerne en outre un procédé de préparation des nouvelles formes cristallines.
PCT/IN2019/050754 2018-10-11 2019-10-10 Polymorphes de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophényl)cyclopropane-1, 1-dicarboxamide, (s)-malate, leurs procédés de production et leurs utilisations pharmaceutiques WO2020075196A1 (fr)

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IN201821038634 2018-10-11
IN201821038634 2018-10-11
IN201921003678 2019-01-30
IN201921003678 2019-01-30

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IT202000027678A1 (it) 2020-11-18 2022-05-18 Indena Spa Dispersioni solide amorfe di cabozantinib-(s)-malato e processi per la loro preparazione
US11814356B1 (en) 2023-03-29 2023-11-14 Apotex Inc. Salt of cabozantinib

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Publication number Priority date Publication date Assignee Title
IT202000027678A1 (it) 2020-11-18 2022-05-18 Indena Spa Dispersioni solide amorfe di cabozantinib-(s)-malato e processi per la loro preparazione
US11814356B1 (en) 2023-03-29 2023-11-14 Apotex Inc. Salt of cabozantinib

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