EP2220071A2 - Hémi-l-malate de sunitinib, polymorphes et leur préparation, polymorphes de malate de sunitinib racémique, compositions contenant une base de sunitinib et de l'acide malique et leur préparation - Google Patents
Hémi-l-malate de sunitinib, polymorphes et leur préparation, polymorphes de malate de sunitinib racémique, compositions contenant une base de sunitinib et de l'acide malique et leur préparationInfo
- Publication number
- EP2220071A2 EP2220071A2 EP08851719A EP08851719A EP2220071A2 EP 2220071 A2 EP2220071 A2 EP 2220071A2 EP 08851719 A EP08851719 A EP 08851719A EP 08851719 A EP08851719 A EP 08851719A EP 2220071 A2 EP2220071 A2 EP 2220071A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- sunitinib
- malate
- theta
- pxrd pattern
- degrees
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention encompasses Sunitinib hemi-L-malate. In one embodiment, the invention encompasses a crystalline form of sunitinib hemi-
- Figure 8 illustrates a powder X-ray diffraction pattern of composition I containing Sunitinib base and L-malic acid.
- Figure 8a illustrates a powder X-ray diffraction pattern of composition I containing
- Figure lla illustrates a powder X-ray diffraction pattern of composition L containing Sunitinib base and L-malic acid (zoomed).
- Figure 21 illustrates a DSC thermogram of of sunitinib hemi-L-malate form U.
- Figure 37 illustrate a powder XRD pattern of crystalline Sunitinib base Form II.
- Sunitinib base characterized by crystalline Sunitinib base characterized by data selected from a group consisting of a PXRD pattern having any 5 peaks selected from the list consisting of: 3.8, 7.8, 9.0, 10.2, 11.8, 15.8, 17.9, 20.3, 26.1 and 26.8 deg ⁇ 0.2 degrees 2-theta, a PXRD pattern having peaks at about 9.0 and 26.1 ⁇ 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of 3.8, 7.8, 10.2, 11.8, 15.8, 17.9, 20.3 and 26.8 deg ⁇ 0.2 degrees 2-thetaa PXRD pattern as depicted in Figure 37 and combination thereof.
- the crystalline racemic sunitinib malate Form A can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 5.7, 8.0, 12.5, 14.7 and 18.3 ⁇ 0.2 degrees 2-theta; a PXRD pattern having peaks at about 5.7, 8.0, 9.3, 24.7 and 18.3 ⁇ 0.2 degrees 2-theta; and a PXRD pattern having a single peak at about 27.4 ⁇ 0.2 degrees 2-theta.
- the crystalline racemic sunitinib malate Form A can be prepared by a process comprising reacting Sunitinib base and racemic malic acid in ethanol to obtain a suspension comprising the said crystalline form.
- the said solution is maintained at the said temperature for a period of about 15 minutes to about 2 hours. More preferably, the said solution is maintained at the said temperature for a period of about 30 minutes.
- the present inventions encompasses crystalline sunitinib hemi-L-malate designated form E characterized by a PXRD pattern having peaks at about 6.8 and 11.3 ⁇ 0.2 degrees 2-theta and any 3 peaks at positions selected from the group consisting of: 3.7, 11.9, 15.1, 25.9 and 26.6 ⁇ 0.2 degrees 2-theta.
- Crystalline sunitinib hemi-L-malate can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 3.7, 6.8, 11.3, 11.9 and 25.9 ⁇ 0.2 degrees 2-theta.
- the aqueous solution is provided by combining sunitinib base, water and L- malic acid, and heating the combination.
- the heating is done to a temperature of about 100 0 C.
- L-malic acid in water to obtain a solution, and lyophilizing the solution; wherein the ratio of L-malic acid to water is about 34:1 w/v, respectively.
- the invention encompasses a composition containing Sunitinib base and L-malic acid characterized by data selected from a group consisting of a PXRD pattern having any 5 peaks at positions selected from the group consisting of: 6.0, 7.7, 9.2, 12.3, 14.5, 23.0 and 27.3 ⁇ 0.2 degrees 2-theta, a PXRD pattern as depicted in Figure 12, a PXRD pattern as depicted in Figure 12a and combination thereof.
- This composition can be designated as composition M.
- composition M can be further characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 6.0, 9.2, 14.5, 23.0 and 27.3 ⁇ 0.2 degrees 2-theta; and a PXRD pattern having peaks at about 7.7, 9.2, 12.3, 14.5 and 23.0 ⁇ 0.2 degrees 2-theta.
- Composition M can be prepared by a process comprising heating Sunitinib malate to a temperature of about 50°C to 100°C. Preferably, heating is done to a temperature of about 8O 0 C. Preferably, heating is done for a period of about 30 minutes to about 4 hours. More preferably, heating is done for a period of about 2 hours.
- Composition N can be prepared by a process comprising dissolving sunitinib malate in a mixture of dioxane and water, and lyophilizing the solution. In the lyophilization process, the said solution is subjected to a pressure of less than about one atmosphere, to remove solvent.
- composition O can be further characterized by a PXRD pattern having four peaks at about 6.0, 7.4, 8.9 and 11.9 ⁇ 0.2 degrees 2-theta.
- the composition O can be prepared by a process comprising combining sunitinib base, L-malic acid, and a mixture of water, and tetrahydrofuran and evaporating the solvent.
- the solution is provided by combining sunitinib base, L-malic acid and a mixture of water and dioxane, and heating the said combination to obtain a solution.
- the invention encompasses a composition containing Sunitinib base and L-malic acid characterized by data selected from a group consisting of a PXRD pattern any 5 peaks at positions selected from the group consisting of: 3.4, 5.6, 9.6, 10.3,
- the invention encompasses a composition containing Sunitinib base and L-malic acid, characterized by a PXRD pattern having peaks at about 8.5 and 11.3 ⁇ 0.2 degrees 2-theta and any 3 peaks selected from a group consisting of 14.2, 23.2, 24.0 and 26.9 ⁇ 0.2 degrees 2-theta.
- Example 10 Preparation of composition H containing sunitinib base and L-malic acid. To sunitinib base (form VII, 300 mg) and L-malic acid (101 mg) was added TBME 10 ml) and the slurry was heated 10 min to reflux temperature facilitating formation of the titled composition (368 mg).
- Example 13 Preparation of composition O containing sunitinib base and L-malic acid.
- Sunitinib base (form X, dried 70°C, 2 h, 1 mBar, 150 mg)
- L-malic acid 50 mg in 3 ml of water, 1:1 molar
- THF 8 ml
- boiling to dissolution allowed to evaporate at 20°C to dryness in an open baker.
- Sunitinib base was dissolved in water (250 g) at about 40° by adjusting the pH to 1.5 with IN HCl. The solution was extracted with methyl isobutyl ketone (100 g), the phases were separated and to the aqueous phase dimethylacetamide (20 g) was added. Under strong stirring, the solution was adjusted to pH 8.5 by addition of 25% ammonium hydroxide solution. After one hour the suspension was filtered and the cake was rinsed with 200 g of water. The product was dried at 70° under vacuum overnight to give 12.6 g (56%) of Sunitinib base Form II.
- Sunitinib Base obtained by reaction of Sunitinib activated carboxylic acid derivative with excess of N,N'-diethylaminoethylamine in tetrahydrofuran, were dissolved with 150g of water and 5Og of HCl IM. The solution was washed with methyl isobutyl ketone at 50°C and then precipitated with ammonia 30% in water to pH 9, the product was filtered and dried in oven under vacuum at 60 0 C for 16 hours.
- the stirred suspension was cooled at room temperature for 2 hours and filtered; the cake was washed with 5O g of toluene and dried at 50° under vacuum overnight.
Abstract
L'invention concerne l'hémi-L-malate de sunitinib, ses polymorphes, des polymorphes de malate de sunitinib racémique, des compositions contenant une base de sunitinib et de l'acide malique L ou racémique, des procédés pour leur préparation et des compositions pharmaceutiques les contenant.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10166182A EP2253629A1 (fr) | 2007-11-21 | 2008-11-21 | Polymorphes de malate de sunitinib racémique, compositions les contenant et leur préparation |
Applications Claiming Priority (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98956007P | 2007-11-21 | 2007-11-21 | |
US3016708P | 2008-02-20 | 2008-02-20 | |
US3177308P | 2008-02-27 | 2008-02-27 | |
US4143908P | 2008-04-01 | 2008-04-01 | |
US4213808P | 2008-04-03 | 2008-04-03 | |
US4519608P | 2008-04-15 | 2008-04-15 | |
US4846008P | 2008-04-28 | 2008-04-28 | |
US4846708P | 2008-04-28 | 2008-04-28 | |
US5805308P | 2008-06-02 | 2008-06-02 | |
US5841708P | 2008-06-03 | 2008-06-03 | |
US5922208P | 2008-06-05 | 2008-06-05 | |
US5908808P | 2008-06-05 | 2008-06-05 | |
US6106908P | 2008-06-12 | 2008-06-12 | |
US6192008P | 2008-06-16 | 2008-06-16 | |
US7865008P | 2008-07-07 | 2008-07-07 | |
US8240508P | 2008-07-21 | 2008-07-21 | |
US8415608P | 2008-07-28 | 2008-07-28 | |
US8599108P | 2008-08-04 | 2008-08-04 | |
US8785908P | 2008-08-11 | 2008-08-11 | |
US8855408P | 2008-08-13 | 2008-08-13 | |
US10152708P | 2008-09-30 | 2008-09-30 | |
US10807808P | 2008-10-24 | 2008-10-24 | |
PCT/US2008/084386 WO2009067686A2 (fr) | 2007-11-21 | 2008-11-21 | Hémi-l-malate de sunitinib, polymorphes et leur préparation, polymorphes de malate de sunitinib racémique, compositions contenant une base de sunitinib et de l'acide malique et leur préparation |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10166182.5 Division-Into | 2010-06-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2220071A2 true EP2220071A2 (fr) | 2010-08-25 |
Family
ID=40668097
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08851719A Withdrawn EP2220071A2 (fr) | 2007-11-21 | 2008-11-21 | Hémi-l-malate de sunitinib, polymorphes et leur préparation, polymorphes de malate de sunitinib racémique, compositions contenant une base de sunitinib et de l'acide malique et leur préparation |
EP10166182A Withdrawn EP2253629A1 (fr) | 2007-11-21 | 2008-11-21 | Polymorphes de malate de sunitinib racémique, compositions les contenant et leur préparation |
EP08852503A Withdrawn EP2220072A2 (fr) | 2007-11-21 | 2008-11-21 | Polymorphes de base de sunitinib et procédés pour les préparer |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10166182A Withdrawn EP2253629A1 (fr) | 2007-11-21 | 2008-11-21 | Polymorphes de malate de sunitinib racémique, compositions les contenant et leur préparation |
EP08852503A Withdrawn EP2220072A2 (fr) | 2007-11-21 | 2008-11-21 | Polymorphes de base de sunitinib et procédés pour les préparer |
Country Status (4)
Country | Link |
---|---|
EP (3) | EP2220071A2 (fr) |
KR (1) | KR20100069705A (fr) |
CA (2) | CA2699305A1 (fr) |
WO (2) | WO2009067674A2 (fr) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2274303B1 (fr) * | 2008-03-31 | 2012-08-29 | Teva Pharmaceutical Industries Ltd. | Procédés de préparation de sunitinib et de sels de ce dernier |
CA2720943A1 (fr) | 2008-04-16 | 2009-10-22 | Natco Pharma Limited | Nouvelles formes polymorphes du sunitinib base |
WO2009156837A2 (fr) * | 2008-06-26 | 2009-12-30 | Medichem, S.A. | Forme amorphe d'un sel de malate de 2-indolinone à substitution 3-pyrrole |
EP2297138A1 (fr) * | 2008-07-10 | 2011-03-23 | Generics [UK] Limited | Procédés de préparation de formes cristallines de malate de sunitinib |
EP2342195B1 (fr) | 2008-07-24 | 2014-09-10 | Medichem, S.A. | Formes cristallines d un sel de malate de 2-indolinone à substitution 3-pyrrole |
WO2010011834A2 (fr) * | 2008-07-24 | 2010-01-28 | Teva Pharmaceutical Industries Ltd. | Sunitinib et ses sels et leurs polymorphes |
US20120029046A1 (en) * | 2008-08-25 | 2012-02-02 | Generics (Uk) Limited | Crystalline form of sunitinib and processes for its preparation |
AU2009286521A1 (en) * | 2008-08-25 | 2010-03-04 | Generics [Uk] Limited | Novel polymorphs of sunitinib and processes for their preparation |
EP2181991A1 (fr) | 2008-10-28 | 2010-05-05 | LEK Pharmaceuticals D.D. | Nouveaux sels de sunitinib |
EP2186809A1 (fr) | 2008-11-13 | 2010-05-19 | LEK Pharmaceuticals D.D. | Nouvelle forme cristalline du malate de sunitinib |
AU2010296849A1 (en) | 2009-09-16 | 2012-05-03 | Ranbaxy Laboratories Limited | Salts of sunitinib |
EP2499133A2 (fr) | 2009-11-12 | 2012-09-19 | Ranbaxy Laboratories Limited | Procédé de préparation de la forme cristalline i du sel d'acide l-malique de sunitinib |
US8916716B2 (en) | 2009-11-19 | 2014-12-23 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline form II of L-malic acid salt of sunitinib |
EP2528913A1 (fr) | 2010-01-29 | 2012-12-05 | 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 |
WO2011107919A1 (fr) | 2010-03-04 | 2011-09-09 | Ranbaxy Laboratories Limited | Procédé de préparation directe de sel d'acide malique de sunitinib |
AU2011228765A1 (en) | 2010-03-18 | 2012-10-11 | Ranbaxy Laboratories Limited | Process for the preparation of malic acid salt of sunitinib |
CN103833733B (zh) * | 2012-11-21 | 2017-08-25 | 广东东阳光药业有限公司 | 一种替尼类药物新晶型 |
DK3039424T3 (da) | 2013-08-28 | 2020-08-31 | Crown Bioscience Inc Taicang | Genekspressionssignaturer, der er prædiktive for et individs respons på en multikinaseinhibitor, og fremgangsmåder til anvendelse af disse |
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 |
RU2567535C1 (ru) * | 2014-10-01 | 2015-11-10 | Олег Ростиславович Михайлов | КРИСТАЛЛИЧЕСКАЯ ε-МОДИФИКАЦИЯ N-[2-(ДИЭТИЛАМИНО)ЭТИЛ]-5-[(Z)-(5-ФТОР-1,2-ДИГИДРО-2-ОКСО-3Н-ИНДОЛ-3-ИЛИДЕН)МЕТИЛ]-2,4-ДИМЕТИЛ-1Н-ПИРРОЛ-3-КАРБОКСАМИД МАЛАТА, СПОСОБ ЕЕ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЕ ОСНОВЕ |
WO2020216450A1 (fr) | 2019-04-25 | 2020-10-29 | Synthon B.V. | Composition pharmaceutique comprenant du sunitinib amorphe |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001060814A2 (fr) * | 2000-02-15 | 2001-08-23 | Sugen, Inc. | Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole |
CA2455050C (fr) | 2001-08-15 | 2007-02-20 | Pharmacia & Upjohn Company | 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, procedes de preparation associes et compositions correspondantes |
CN1308326C (zh) * | 2002-02-15 | 2007-04-04 | 法马西亚和厄普乔恩公司 | 吲哚满酮衍生物的制备方法 |
TW200418836A (en) * | 2002-09-10 | 2004-10-01 | Pharmacia Italia Spa | Formulations comprising an indolinone compound |
US20060009510A1 (en) * | 2004-07-09 | 2006-01-12 | Pharmacia & Upjohn Company Llc | Method of synthesizing indolinone compounds |
BRPI0609957A2 (pt) * | 2005-05-12 | 2010-05-11 | Pfizer | uso de malato de sunitinib na preparação de um medicamento para o tratamento de cáncer |
US8389562B2 (en) * | 2007-12-12 | 2013-03-05 | Medichem, S.A. | Polymorphic forms of a 3-pyrrole substituted 2-indolinone |
EP2098521A1 (fr) * | 2008-03-06 | 2009-09-09 | Ratiopharm GmbH | Formules cristallines de N-[2-(diéthylamino)éthyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidène)méthyl]-2,4-diméthyl-1H-pyrrole-3-carboxamide |
CA2720943A1 (fr) * | 2008-04-16 | 2009-10-22 | Natco Pharma Limited | Nouvelles formes polymorphes du sunitinib base |
EP2313396A1 (fr) * | 2008-06-23 | 2011-04-27 | Natco Pharma Limited | Procédé de préparation de sunitinib de haute pureté et de ses sels pharmaceutiquement acceptables |
JP2011526615A (ja) * | 2008-07-02 | 2011-10-13 | ジェネリクス・(ユーケー)・リミテッド | 3−ピロール置換2−インドリノン誘導体の調製 |
-
2008
- 2008-11-21 EP EP08851719A patent/EP2220071A2/fr not_active Withdrawn
- 2008-11-21 WO PCT/US2008/084366 patent/WO2009067674A2/fr active Application Filing
- 2008-11-21 KR KR1020107010188A patent/KR20100069705A/ko not_active Application Discontinuation
- 2008-11-21 EP EP10166182A patent/EP2253629A1/fr not_active Withdrawn
- 2008-11-21 CA CA2699305A patent/CA2699305A1/fr not_active Abandoned
- 2008-11-21 CA CA2699306A patent/CA2699306A1/fr not_active Abandoned
- 2008-11-21 WO PCT/US2008/084386 patent/WO2009067686A2/fr active Application Filing
- 2008-11-21 EP EP08852503A patent/EP2220072A2/fr not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO2009067686A2 * |
Also Published As
Publication number | Publication date |
---|---|
CA2699305A1 (fr) | 2009-05-28 |
EP2220072A2 (fr) | 2010-08-25 |
KR20100069705A (ko) | 2010-06-24 |
WO2009067674A2 (fr) | 2009-05-28 |
WO2009067686A3 (fr) | 2009-11-12 |
EP2253629A1 (fr) | 2010-11-24 |
WO2009067686A8 (fr) | 2009-07-16 |
CA2699306A1 (fr) | 2009-05-28 |
WO2009067686A2 (fr) | 2009-05-28 |
WO2009067674A3 (fr) | 2009-08-27 |
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