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WO2011058179A1 - 5-(4-(n-(2,3-diméthyl-2h-indazol-6-yl)-n-méthylamino)pyrimidin-2-ylamino)-2-méthylbenzènesulfonamide - Google Patents

5-(4-(n-(2,3-diméthyl-2h-indazol-6-yl)-n-méthylamino)pyrimidin-2-ylamino)-2-méthylbenzènesulfonamide Download PDF

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Publication number
WO2011058179A1
WO2011058179A1 PCT/EP2010/067504 EP2010067504W WO2011058179A1 WO 2011058179 A1 WO2011058179 A1 WO 2011058179A1 EP 2010067504 W EP2010067504 W EP 2010067504W WO 2011058179 A1 WO2011058179 A1 WO 2011058179A1
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WO
WIPO (PCT)
Prior art keywords
pazopanib
polymorph
free base
theta
characteristic peaks
Prior art date
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Ceased
Application number
PCT/EP2010/067504
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English (en)
Inventor
Ramesh Matioram Gidwani
Channaveerayya Hiremath
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ratiopharm GmbH
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Ratiopharm GmbH
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Filing date
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Application filed by Ratiopharm GmbH filed Critical Ratiopharm GmbH
Publication of WO2011058179A1 publication Critical patent/WO2011058179A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • C07D403/12—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 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 relates to a novel forms of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)- N-methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide as active pharmaceutical ingredient and to a process of preparing them.
  • Pazopanib The compound 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino)pyrimidine-2- ylamino)-2-methylbenzenesulfonamide, also known as Pazopanib, is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals.
  • Pazopanib has the following formula (I):
  • this compound is an inhibitor of tyrosine kinase enzymes, namely vascular endothelial growth factor receptors, and can be used for the treatment and/or prevention of diseases which are associated with tyrosine kinase enzymes such as vascular endothelial growth factor receptors, such as cancer, particularly breast cancer and colon cancer.
  • WO 2007/064752 the use of Pazopanib for the treatment of age related macula degeneration is disclosed.
  • WO 2007/064753 further discloses Pazopanib for the treatment of various types of cancer, e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.
  • cancer e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.
  • Pazopanib is administered orally, as this route provides great comfort and convenience of dosing.
  • hydrochloride form of Pazopanib is known in the art, as described above, this form is not optimal in regard to bioavailability, inter-patient variability, and safety.
  • the known form of Pazopanib hydrochloride is not optimal with regard to mechanical and chemical stability, which is in particular necessary for manufacturing tablets, as well as not optimal in regard to flow properties, compressibility, dissolution rate. Additionally, it is at least to some extent hygroscopic and shows electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions.
  • the provided forms show improved bioavailability, reduced inter-patient variability, improved overall therapeutic efficacy, good mechanical and/or chemical stability, excellent flow properties, good compressibility, improved dissolution profiles.
  • the new forms are non-hygroscopic and/or do not electrostatically charge.
  • the forms of Pazopanib according to the invention are advantageous in at least one aspect of the above-mentioned properties.
  • the present invention relates to the free base of Pazopanib.
  • the present invention relates to the free base of Pazopanib in crystalline form.
  • crystalline refers to any non-amorphous form of the substance including hydrates, solvates and different polymorphic forms of the crystalline form.
  • amorphous form refers to a form of the substance which has no long-range order like crystalline structures. The atoms or molecules of a material present in amorphous form are arranged in a non-uniform array. It is for example possible to distinguish amorphous forms from crystalline forms of a substance by powder X-ray diffraction.
  • the present invention relates to the free base of Pazopanib in the polymorphic form I (also referred to as "polymorph I").
  • Polymorph I of Pazopanib is characterized by an XRPD pattern having characteristic peaks at 7.3 +/- 0.2, 13.6 +/- 0.2, 21.6 +/- 0.2 and 26.7 +/- 0.2 degree 2-theta.
  • polymorph I of Pazopanib can be characterized by an XRPD pattern with characteristic peaks at 7.3 +/- 0.2, 12.3 +/- 0.2, 13.6 +/- 0.2, 14.5 +/- 0.2, 16.0 +/- 0.2, 18.6 +/- 0.2, 21.6 +/- 0.2, 25.8 +/- 0.2, 26.7 +/- 0.2 and 28.1 +/- 0.2 degree 2-theta.
  • Polymorph I of Pazopanib shows an IR spectrum exhibiting characteristic peaks at 3338 +/- 2 cm '1 , 3266 +/- 2 cm '1 , 3098 +/- 2 cm '1 , 1616 +/- 2 cm “1 , 1581 +/- 2 cm "1 , 1551 +/- 2 cm ' 1 and 1523 +/- 2 cm "1 .
  • Polymorph I of Pazopanib is further characterized by a melting point of 310 +/- 4°C.
  • the DSC thermogram is shown in figure 3.
  • the present invention relates to the free base of Pazopanib in the polymorphic form II (also referred to as "polymorph II").
  • Polymorph II of Pazopanib is characterized by an XRPD pattern having characteristic peaks at 13.1 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.
  • polymorph II of Pazopanib can be characterized by an XRPD pattern with characteristic peaks at 7.8 +/- 0.2, 9.3 +/- 0.2, 12.8 +/- 0.2, 13.1 +/- 0.2, 14.7 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2, 22.5 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.
  • Polymorph II of Pazopanib can further be characterized by an XRPD pattern with characteristic peaks at 6.5 +/- 0.2, 7.8 +/- 0.2, 9.3 +/- 0.2, 11.2 +/- 0.2, 12.8 +/- 0.2, 13.1 +/- 0.2, 14.7 +/- 0.2, 15.6 +/- 0.2, 18.1 +/- 0.2, 19.0 +/- 0.2, 22.5 +/- 0.2 and 24.0 +/- 0.2 degrees 2-theta.
  • the free base of Pazopanib according to the present invention may be obtained by:
  • suitable inert solvents are water, aliphatic and aromatic hydrocarbons (preferably hexane, benzene, toluene or xylene), aliphatic alcohols (preferably methanol, ethanol, propanol, iso-propanol), ethers (preferably diethyl ether, diisopropyl ether or dimethoxyethane), cyclic ethers (preferably tetrahydrofuran or dioxane), ketones (preferably acetone, methylisobutylketone or methylethylketone), esters (preferably ethyl acetate), chlorinated hydrocarbons (preferably dichloromethane or chloroform) or nitrogen containing organic solvents (preferably N-methyl pyrollidone, dimethylformamide or acetonitrile). Water is especially preferred.
  • aliphatic and aromatic hydrocarbons preferably hexane, benzene, toluene or xylene
  • Bronsted bases are metal hydroxides, metal carbonates or amines, preferably alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, ammonia, or organic amines, such as, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, ammonia, diethylamine, triethylamine, diisopropylamine or pyridine.
  • Sodium hydroxide and sodium bicarbonate are preferred.
  • the base is used in an amount sufficient to obtain the free base of Pazopanib from its salt.
  • the present invention further relates to pharmaceutical compositions comprising the above mentioned new forms of Pazopanib.
  • pharmaceutical composition refers to single dosage forms, such as tablets, capsules, pellets, etc., as well as powders or granules which are used in the preparation of single dosage forms. Where it is referred to the total weight of the pharmaceutical composition and the pharmaceutical composition in a single dosage form the total weight is the weight of the single dosage form excluding, if applicable, the weight of any coating or capsule shell.
  • the active pharmaceutical ingredient i.e. the Pazopanib in its forms as described herein, e.g. its amorphous or crystalline form, can be present in the pharmaceutical composition in an amount of 5 to 80 % by weight, preferably 10 to 70 % by weight of the total weight of the composition.
  • the pharmaceutical composition of the present invention has a mean particle size of 1 to 800 m, preferably 5 to 600 ⁇ , more preferably 10 to 400 ⁇ .
  • a bulk density of the pharmaceutical composition ranging from of 0.3 to 0.9 g/ml, preferably of 0.4 to 0.8 g/ml is advantageous.
  • the pharmaceutical composition of the invention preferably possesses a Hausner factor in the range of 1.05 to 1.65, more preferably of 1.10 to 1.50.
  • the Hausner factor is the ratio of bulk density to tapped density.
  • the pharmaceutical composition of the present invention can further comprise one or more pharmaceutically acceptable excipients, such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers.
  • pharmaceutically acceptable excipients such as fillers, binding agents, lubricants, flow enhancers, antisticking agents, disintegrating agents and solubilizers.
  • conventional excipients known to the person skilled in the art may be used. See for example "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre", edited by H. P. Fiedler, 4th Edition, Edito Cantor, Aulendorf and earlier editions, and "Handbook of Pharmaceutical Excipients", Third Edition, edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.
  • the fillers are lactose, mannitol, sorbitol and microcrystalline cellulose.
  • the filler is suitably present in an amount of 0 to 90 % by weight, preferably of 30 to 80 % by weight of the total weight of the composition.
  • the binding agent can for example be microcrystalline cellulose (MCC) or hydroxypropylmethyl cellulose (HPMC).
  • MCC microcrystalline cellulose
  • HPMC hydroxypropylmethyl cellulose
  • the binding agent is present in an amount of 1 to 25 % by weight, more preferably at 2 to 10 % by weight of the total weight of the composition.
  • the lubricant is preferably a stearate, more preferably an earth alkali metal stearate, such as magnesium stearate.
  • the lubricant is suitably present in an amount of 0.1 to 2 % by weight, preferably about 1 % by weight of the total weight of the composition.
  • Preferred disintegrating agents are croscarmellose sodium, sodium carboxymethyl starch or cross-linked polyvinylpyrrolidone (crospovidone).
  • the disintegrating agent is suitably present in an amount of 0.1 to 20 % by weight, more preferably at 0.5 to 7 % by weight of the total weight of the composition.
  • the flow enhancer can for example be colloidal silicon dioxide.
  • the flow enhancer is present in an amount of 0.5 to 8 % by weight, more preferably at 0.5 to 3 % by weight of the total weight of the composition.
  • the antisticking agent is for example talcum and may be present in an amount of 1 to 5 % by weight, more preferably in an amount of 1.5 to 3 % by weight of the total weight of the composition.
  • an improvement of the solubility of the active pharmaceutical ingredient can for example be achieved by the addition of complex forming agents/compounds (e.g. sodium benzoate, sodium salicylate or cyclodextrins), alternation of solvent properties (e.g. by adding PVP or polyethylene glycols) or the addition of solubilizers which form tenside micelles (e.g. surfactants).
  • complex forming agents/compounds e.g. sodium benzoate, sodium salicylate or cyclodextrins
  • alternation of solvent properties e.g. by adding PVP or polyethylene glycols
  • solubilizers which form tenside micelles e.g. surfactants.
  • Suitable solubilizers are for example surfactants such as polyoxyethylene alcohol ethers (e.g. Brij®), polysorbates (e.g. Tween®) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic®) and may be present in amounts of 0.5 to 7 % by weight, more preferably 1 to 5 % by weight of the total weight of the composition.
  • surfactants such as polyoxyethylene alcohol ethers (e.g. Brij®), polysorbates (e.g. Tween®) or polyoxypropylene polyoxyethylene copolymers (poloxamer; e.g. Pluronic®) and may be present in amounts of 0.5 to 7 % by weight, more preferably 1 to 5 % by weight of the total weight of the composition.
  • pseudo-emulsifier can be used. Its mechanism of action mainly relies on an enhancement of viscosity. However, pseudo-emulsifiers also possess emulsifying properties.
  • Preferred pseudo-emulsifiers of the present invention are for example cellulose ethers, gum Arabic or tragacanth and may be present in amounts of 1 to 10 % by weight, more preferably 3 to 7 % by weight of the total weight of the composition.
  • the pharmaceutical composition of the present invention can be formulated in any known form, preferably as tablets, capsules, granules, pellets or sachets.
  • a particularly preferred pharmaceutical composition is in the form of capsules.
  • the pharmaceutical composition may contain dosage amounts of 12.5, 25 and 50 mg of the active pharmaceutical ingredient.
  • the administered amount can be readily varied according to individual tolerance and safety warranting more flexible dosing than the standard dose of 50 mg once daily.
  • the pharmaceutical composition of the present invention can be manufactured according to standard methods known in the art.
  • Granulates according to the invention can be obtained by dry compaction or wet granulation. These granulates can subsequently be mixed with e.g. suitable disintegrating agents, glidants and lubricants and compressed into tablets or filled into sachets or capsules of suitable size. Tablets can also be obtained by direct compression of a suitable powder mixture, i.e. without any preceding granulation of the excipients.
  • Suitable powder or granulate mixtures according to the invention are further obtainable by spray drying, lyophilization, melt extrusion, pellet layering, coating of the active pharmaceutical ingredient or any other suitable method provided that the conditions are chosen such as to prevent amorphization of the active pharmaceutical ingredient.
  • the so obtained powders or granulates can be mixed with one or more suitable ingredients and the resulting mixtures can either be compressed to form tablets or filled into sachets or capsules.
  • Figure 1 is an XRPD pattern of polymorph I of Pazopanib.
  • Figure 2 is an IR spectrum of polymorph I of Pazopanib.
  • Figure 3 is a DSC thermogram of polymorph I of Pazopanib.
  • IR spectra were obtained using a Perkin Elmer, Model "Spectrum one", DFR mode.
  • DSC thermograms were obtained using a Mettler Toledo Model DSC 822 e :
  • Heating range 30 to 360°C

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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

La présente invention porte sur de nouvelles formes de Pazopanib et sur un procédé pour leur préparation.
PCT/EP2010/067504 2009-11-16 2010-11-15 5-(4-(n-(2,3-diméthyl-2h-indazol-6-yl)-n-méthylamino)pyrimidin-2-ylamino)-2-méthylbenzènesulfonamide Ceased WO2011058179A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2360DE2009 2009-11-16
IN2360DEL2009 2009-11-16

Publications (1)

Publication Number Publication Date
WO2011058179A1 true WO2011058179A1 (fr) 2011-05-19

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PCT/EP2010/067504 Ceased WO2011058179A1 (fr) 2009-11-16 2010-11-15 5-(4-(n-(2,3-diméthyl-2h-indazol-6-yl)-n-méthylamino)pyrimidin-2-ylamino)-2-méthylbenzènesulfonamide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104130245A (zh) * 2014-05-23 2014-11-05 南京威诺德医药技术有限公司 盐酸帕唑帕尼n晶型及其制备
US10626110B2 (en) 2018-08-07 2020-04-21 Formosa Laboratories, Inc. Polymorph of pazopanib hydrochloride and preparation process thereof
US10730859B2 (en) 2013-11-05 2020-08-04 Laurus Labs Limited Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059110A1 (fr) 2000-12-21 2002-08-01 Glaxo Group Limited Composes chimiques
WO2003106416A2 (fr) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Processus chimique
WO2006020564A1 (fr) * 2004-08-09 2006-02-23 Smithkline Beecham Corporation Derives de pyrimidine pour le traitement du myelome multiple
WO2007064752A2 (fr) 2005-11-29 2007-06-07 Smithkline Beecham Corporation Procede de traitement
WO2007064753A2 (fr) 2005-11-29 2007-06-07 Smithkline Beecham Corporation Procede de traitement du cancer
WO2007143483A2 (fr) * 2006-06-01 2007-12-13 Smithkline Beecham Corporation Procédé de traitement du cancer
EP2058307A1 (fr) * 2007-11-12 2009-05-13 Cellzome Ag Procédés d'identification des molécules d'interaction JAK kinase et de purification de JAK kinases

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002059110A1 (fr) 2000-12-21 2002-08-01 Glaxo Group Limited Composes chimiques
WO2003106416A2 (fr) 2002-06-17 2003-12-24 Smithkline Beecham Corporation Processus chimique
WO2006020564A1 (fr) * 2004-08-09 2006-02-23 Smithkline Beecham Corporation Derives de pyrimidine pour le traitement du myelome multiple
WO2007064752A2 (fr) 2005-11-29 2007-06-07 Smithkline Beecham Corporation Procede de traitement
WO2007064753A2 (fr) 2005-11-29 2007-06-07 Smithkline Beecham Corporation Procede de traitement du cancer
WO2007143483A2 (fr) * 2006-06-01 2007-12-13 Smithkline Beecham Corporation Procédé de traitement du cancer
EP2058307A1 (fr) * 2007-11-12 2009-05-13 Cellzome Ag Procédés d'identification des molécules d'interaction JAK kinase et de purification de JAK kinases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Excipients", AMERICAN PHARMACEUTICAL ASSOCIATION
"Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", AULENDORF AND EARLIER EDITIONS

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10730859B2 (en) 2013-11-05 2020-08-04 Laurus Labs Limited Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof
US11299477B2 (en) 2013-11-05 2022-04-12 Laurus Labs Limited Process for the preparation of Pazopanib or a pharmaceutically acceptable salt thereof
US11427570B2 (en) 2013-11-05 2022-08-30 Laurus Labs Limited Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof
CN104130245A (zh) * 2014-05-23 2014-11-05 南京威诺德医药技术有限公司 盐酸帕唑帕尼n晶型及其制备
US10626110B2 (en) 2018-08-07 2020-04-21 Formosa Laboratories, Inc. Polymorph of pazopanib hydrochloride and preparation process thereof

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