WO2009156837A2 - Forme amorphe d'un sel de malate de 2-indolinone à substitution 3-pyrrole - Google Patents

Forme amorphe d'un sel de malate de 2-indolinone à substitution 3-pyrrole Download PDF

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Publication number
WO2009156837A2
WO2009156837A2 PCT/IB2009/006056 IB2009006056W WO2009156837A2 WO 2009156837 A2 WO2009156837 A2 WO 2009156837A2 IB 2009006056 W IB2009006056 W IB 2009006056W WO 2009156837 A2 WO2009156837 A2 WO 2009156837A2
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WO
WIPO (PCT)
Prior art keywords
sunitinib
sunitinib malate
amorphous form
malic acid
malate
Prior art date
Application number
PCT/IB2009/006056
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English (en)
Other versions
WO2009156837A3 (fr
Inventor
Stephen Benedict David Winter
Monica Benito Velez
Original Assignee
Medichem, S.A.
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 Medichem, S.A. filed Critical Medichem, S.A.
Publication of WO2009156837A2 publication Critical patent/WO2009156837A2/fr
Publication of WO2009156837A3 publication Critical patent/WO2009156837A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol

Definitions

  • Sunitinib (compound I) is the international commonly accepted name for (Z)-N- [2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-yliden)methyl]-2,4- dimethyl-lH-pyrrole-3-carboxamide, and has an empirical formula Of C 22 H 27 N 4 O 2 F, and a molecular weight of 398.47 g/mol. Sunitinib is an active pharmaceutical substance indicated for the treatment of abnormal cell growth, such as cancer, in mammals, particularly in humans.
  • the malic acid salt of sunitinib has been selected for medical purpose and is commercially marketed under the trade name of SUTENTTM for the treatment of renal cell carcinoma and gastrointestinal stromal tumor.
  • '158 publication discloses a number of preparations of sunitinib malate.
  • the crystalline forms of sunitinib obtained from processes disclosed in the '158 publication are characterized by powder X-ray diffraction (XRD) and thermal techniques and are referred to as crystalline Form I and Form II.
  • compositions include sunitinib racemic malate (Form A and Form B), polymorphs of sunitinib hemi-L-malate (Form E and Form U), and a number of compositions containing sunitinib and either L-malic acid (Compositions: C, F to R, V-A to V-C, and V-S) or racemic malic acid (Composition V-T), and processes for the preparation thereof.
  • Polymorphism is defined as the ability of a substance to crystallize in more than one crystal lattice arrangement and as such, polymorphism influences many aspects of solid state properties of a drug. For example, physical properties such as solubility, dissolution rate, and bioavailability can differ between different polymorphic forms of a drug substance due to the differences in the crystal structure.
  • Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is much higher than the energy required for escaping from an amorphous form.
  • amorphous forms of a number of drugs exhibit different solubility properties, and in some cases also exhibit different bioavailability patterns, as compared to their crystalline form. For some therapeutic indications, one bioavailability pattern may be favored with respect to another. Therefore, it is desirable to have amorphous forms of drugs and processes for their preparation.
  • new forms of sunitinib and pharmaceutically acceptable salts thereof including amorphous form sunitinib malate and processes therefor, as well as processes for preparing crystalline forms of sunitinib and pharmaceutically acceptable salts thereof using amorphous form sunitinib and/or salts thereof.
  • improved pharmaceutical compositions comprising amorphous form sunitinib and pharmaceutically acceptable salts thereof.
  • the invention provides new forms of sunitinib and salts thereof, including amorphous form sunitinib malate and sunitinib malate Form III.
  • the invention provides amorphous form sunitinib of formula (I): including pharmaceutically acceptable salts thereof (e.g., amorphous form sunitinib malate).
  • the invention also provides a process for preparing amorphous form sunitinib and pharmaceutically acceptable salts thereof.
  • the invention provides a process for preparing a crystalline form sunitinib, including pharmaceutically acceptable salts thereof, using amorphous form sunitinib.
  • the invention further provides pharmaceutical compositions comprising amorphous form sunitinib and pharmaceutically acceptable salts thereof.
  • Figure 1 is a powder X-ray diffractogram (XRD) of sunitinib malate Form I obtained as described in Example 1.
  • Figure 2 is an Infrared (IR) spectrum of sunitinib malate Form I obtained as described in Example 1.
  • Figure 3 is an XRD of amorphous form sunitinib malate obtained as described in Example 2.
  • Figure 4 is an IR spectrum of amorphous sunitinib malate obtained as described in Example 2.
  • Figure 5 is an XRD of sunitinib malate Form III obtained as described in Example 3.
  • the present invention provides new forms of sunitinib of formula (I), that is, (Z)-iV-[2-(diethylamino)ethyl]-5-[(5-fluoro-l,2-dihydro-2-oxo-3H-indol- 3-yliden)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide, and pharmaceutically acceptable salts thereof including, for example, amorphous form malic acid salts of sunitinib, such as amorphous form sunitinib malates) and sunitinib malate Form III.
  • illustrative salts suitable for forming pharmaceutically acceptable salts of sunitnib include salts of malic acid. Malic acid exists as
  • malic acid salts of the invention can be formed from one or more of D-malic acid, L-malic acid, or D,L-malic acid.
  • a particularly preferred malic acid is L-malic acid.
  • the present invention provides amorphous form sunitinib L-malate.
  • amorphous form sunitinib malate has a powder XRD pattern (2 ⁇ ) ( ⁇ 0.2°) as depicted herein at Figure 3.
  • amorphous form sunitinib malate has an IR spectrum as depicted herein at Figure 4, having characteristic absorption bands at approximately 3417, 1680, 1576, 1516, 1479, 1443, 1403, 1330, 1302, 1260, 1233, 1200,
  • the present invention provides a process for preparing new forms of sunitinib and pharmaceutically acceptable salts thereof, such as, for example, a process for preparing amorphous form sunitinib malate.
  • amorphous form sunitinib malate can be prepared by a process comprising preparing a solution of sunitinib malate in a solvent and thereafter removing the solvent.
  • a process for preparing amorphous sunitinib malate comprises forming a suspension of amorphous sunitinib malate.
  • amorphous form sunitinib malate is precipitated from a solution to form a suspension of amorphous sunitinib malate, which is then isolated from the solvent by a suitable method, such as, for example, by filtration.
  • An illustrative solvent suitable for a process for preparing amorphous form sunitinib malate in accordance with the invention is iV-methyl-2-pyrrolidone (NMP).
  • a solution of sunitinib malate is formed at a suitable temperature.
  • a process for preparing amorphous form sunitinib malate comprises preparing a solution of sunitinib malate at a temperature of between about 0 0 C and to about 200 0 C.
  • the solvent is removed from a solution, or suspension if present, of sunitinib malate by a suitable method.
  • solvent is removed by a method selected from the group consisting of filtration, evaporation, spray drying, or lyophilization.
  • sunitinib malate is dissolved in NMP with heating to form a solution, cooled, stirred for a period of time (e.g., 24 h), and the mixture concentrated, to yield amorphous form sunitinib malate.
  • sunitinib malate is used to prepare amorphous form sunitinib malate.
  • the physical form of sunitinib malate used in the process is not critical.
  • sunitinib malate used to prepare amorphous form sunitinib malate is crystalline Form I, Form II, Form
  • Form III and mixtures of Form II and Form III, in any proportion.
  • amorphous form sunitinib malate can be used to prepare any suitable crystalline form of sunitinib malate.
  • the present invention provides a process for preparing crystalline forms of sunitinib malate from amorphous form sunitinib malate.
  • the crystalline form of sunitinib malate that is made from amorphous form sunitinib malate is Form I, Form II, Form III, or mixures thereof, such as mixtures of Form I and Form II, mixtures of Form I and Form III, and mixtures of Form II and Form III, in any proportion.
  • the present invention further provides a process for preparing sunitinib malate Form III (e.g., see Example 3).
  • sunitinib malate is dissolved in a suitable solvent, stirred for a period of time (e.g., 24 h), after which period the solvent is removed.
  • Illustrative solvents suitable for a process for preparing sunitinib malate Form III in accordance with the invention include water.
  • the solvent comprises water.
  • the present invention provides a pharmaceutical composition comprising amorphous form sunitinib, including amorphous form sunitinib malate and a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition comprising amorphous form of sunitinib L-malate.
  • This example describes a process for preparing sunitinib malate Form I.
  • Sunitinib base 13 g was suspended in 2 L of methanol at ambient temperature and L-malic acid (4.7 g) was added. The mixture was stirred for 30 minutes and then concentrated under vacuum to dryness. Acetonitrile (500 mL) was added and the mixture stirred at 70 0 C for 1 hour. After cooling to ambient temperature, the solid was collected by filtration and dried under vacuum at 40 0 C for 48 hours.
  • Analytical data XRD: Form I, see Figure 1 ; IR: see Figure 2.
  • This example describes a process for preparing amorphous form sunitinib malate in accordance with an embodiment of the invention.
  • This example describes a process for preparing sunitinib malate Form III.
  • Sunitinib malate 100 mg was dissolved in water with heating. After cooling to ambient temperature the mixture was stirred for 24 hours and then concentrated under vacuum at 40 0 C.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouvelles formes de l'agent anticancéreux sunitinib de formule (I) ainsi que des sels pharmaceutiquement acceptables correspondants, et notamment du malate de sunitinib sous forme amorphe et du malate de sunitinib de forme III. L'invention concerne également un procédé de préparation correspondant et des compositions pharmaceutiques comprenant du malate de sunitinib sous forme amorphe.
PCT/IB2009/006056 2008-06-26 2009-06-26 Forme amorphe d'un sel de malate de 2-indolinone à substitution 3-pyrrole WO2009156837A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7603108P 2008-06-26 2008-06-26
US61/076,031 2008-06-26

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WO2009156837A2 true WO2009156837A2 (fr) 2009-12-30
WO2009156837A3 WO2009156837A3 (fr) 2010-08-05

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011092664A1 (fr) 2010-01-29 2011-08-04 Ranbaxy Laboratories Limited Formes cristallines du sel d'acide l-malique du sunitinib
WO2011100325A2 (fr) 2010-02-09 2011-08-18 Sicor Inc. Polymorphes de sels de sunitinib
WO2013160916A1 (fr) * 2012-04-25 2013-10-31 Hetero Research Foundation Dispersion solide de malate de sunitinib
WO2015056247A1 (fr) * 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Forme cristalline ii pure de sel d'acide l-malique du sunitinib et procédés pour sa préparation
CN104693187A (zh) * 2013-12-10 2015-06-10 安杰世纪生物科技（北京）有限公司 一种舒尼替尼L-苹果酸盐晶型λ及其制备方法
CN105085490A (zh) * 2014-05-09 2015-11-25 上海科胜药物研发有限公司 新的舒尼替尼苹果酸盐晶型及其制备方法
EP2332934B1 (fr) 2001-08-15 2017-03-01 Pharmacia & Upjohn Company LLC Procédés der préparation des cristaux comprenant un sel d'acide malique de n- [2-(diethylamino)ethyl] -5- [(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl] -2,4-dimethyl-1h-pyrrole-3-carboxamide.
WO2020216450A1 (fr) 2019-04-25 2020-10-29 Synthon B.V. Composition pharmaceutique comprenant du sunitinib amorphe
RU2774382C1 (ru) * 2021-03-19 2022-06-20 Общество с ограниченной ответственностью «АксельФарм» Способ получения аморфной формы n-[2-(диэтиламино)этил]-5-[(z)-(5-фтор-1,2-дигидро-2-оксо-3h-индол-3-илиден)метил]-2,4-диметил-1h-пиррол-3-карбоксамида малата, продукт и его применение для лечения онкологических и иммунологических заболеваний
WO2024039213A1 (fr) * 2022-08-19 2024-02-22 주식회사 스카이테라퓨틱스 Sunitinib amorphe, son procédé de production et composition pharmaceutique le comprenant

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020156292A1 (en) * 2000-02-15 2002-10-24 Tang Peng Cho Pyrrole substituted 2-indolinone protein kinase inhibitors
US20030069298A1 (en) * 2001-08-15 2003-04-10 Pharmacia & Upjohn Company Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof
US20030229229A1 (en) * 2002-02-15 2003-12-11 Qingwu Jin Process for preparing indolinone derivatives
US20060009510A1 (en) * 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2009067674A2 (fr) * 2007-11-21 2009-05-28 Teva Pharmaceutical Industries Ltd. Polymorphes de base de sunitinib et procédés pour les préparer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020156292A1 (en) * 2000-02-15 2002-10-24 Tang Peng Cho Pyrrole substituted 2-indolinone protein kinase inhibitors
US20030069298A1 (en) * 2001-08-15 2003-04-10 Pharmacia & Upjohn Company Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof
US20030229229A1 (en) * 2002-02-15 2003-12-11 Qingwu Jin Process for preparing indolinone derivatives
US20060009510A1 (en) * 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2009067674A2 (fr) * 2007-11-21 2009-05-28 Teva Pharmaceutical Industries Ltd. Polymorphes de base de sunitinib et procédés pour les préparer

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2332934B1 (fr) 2001-08-15 2017-03-01 Pharmacia & Upjohn Company LLC Procédés der préparation des cristaux comprenant un sel d'acide malique de n- [2-(diethylamino)ethyl] -5- [(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl] -2,4-dimethyl-1h-pyrrole-3-carboxamide.
WO2011092664A1 (fr) 2010-01-29 2011-08-04 Ranbaxy Laboratories Limited Formes cristallines du sel d'acide l-malique du sunitinib
WO2011100325A2 (fr) 2010-02-09 2011-08-18 Sicor Inc. Polymorphes de sels de sunitinib
WO2013160916A1 (fr) * 2012-04-25 2013-10-31 Hetero Research Foundation Dispersion solide de malate de sunitinib
WO2015056247A1 (fr) * 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Forme cristalline ii pure de sel d'acide l-malique du sunitinib et procédés pour sa préparation
US9604968B2 (en) 2013-10-18 2017-03-28 Sun Pharmaceutical Industries Limited Pure crystalline Form II of L-malic acid salt of sunitinib and processes for its preparation
CN104693187A (zh) * 2013-12-10 2015-06-10 安杰世纪生物科技（北京）有限公司 一种舒尼替尼L-苹果酸盐晶型λ及其制备方法
CN105085490A (zh) * 2014-05-09 2015-11-25 上海科胜药物研发有限公司 新的舒尼替尼苹果酸盐晶型及其制备方法
WO2020216450A1 (fr) 2019-04-25 2020-10-29 Synthon B.V. Composition pharmaceutique comprenant du sunitinib amorphe
RU2774382C1 (ru) * 2021-03-19 2022-06-20 Общество с ограниченной ответственностью «АксельФарм» Способ получения аморфной формы n-[2-(диэтиламино)этил]-5-[(z)-(5-фтор-1,2-дигидро-2-оксо-3h-индол-3-илиден)метил]-2,4-диметил-1h-пиррол-3-карбоксамида малата, продукт и его применение для лечения онкологических и иммунологических заболеваний
WO2024039213A1 (fr) * 2022-08-19 2024-02-22 주식회사 스카이테라퓨틱스 Sunitinib amorphe, son procédé de production et composition pharmaceutique le comprenant

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