WO2017029584A1 - Forme amorphe du bosutinib - Google Patents

Forme amorphe du bosutinib Download PDF

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Publication number
WO2017029584A1
WO2017029584A1 PCT/IB2016/054820 IB2016054820W WO2017029584A1 WO 2017029584 A1 WO2017029584 A1 WO 2017029584A1 IB 2016054820 W IB2016054820 W IB 2016054820W WO 2017029584 A1 WO2017029584 A1 WO 2017029584A1
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WO
WIPO (PCT)
Prior art keywords
bosutinib
amorphous form
process according
acid
aqueous layer
Prior art date
Application number
PCT/IB2016/054820
Other languages
English (en)
Inventor
Sourav HANDIQUE
Ashok Kumar
Amit Kumar Jain
Satish Manohar Bhoge
Kaptan Singh
Mohan Prasad
Original Assignee
Sun Pharmaceutical Industries Limited
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 Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2017029584A1 publication Critical patent/WO2017029584A1/fr

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention provides an amorphous form of bosutinib, a process for its preparation, its pharmaceutical composition, and a method of use thereof.
  • Bosutinib monohydrate is chemically designated as 3-quinolinecarbonitrile, 4- [(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-l- piperazinyl)propoxy]-, hydrate (1 : 1), as depicted by Formula I.
  • Chinese Patent Publication No. 104447542 discloses crystalline bosutinib monohydrate with particular XRD peaks.
  • the present invention provides an amorphous form of bosutinib.
  • the present invention provides an amorphous form of bosutinib.
  • the present invention also provides a process for the preparation of an amorphous form of bosutinib.
  • the present invention also provides a pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients.
  • the present invention also provides use of an amorphous form of bosutinib for treating cancer, for example, chronic myelogenous leukemia (CML).
  • CML chronic myelogenous leukemia
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of an amorphous form of bosutinib.
  • Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of an amorphous form of bosutinib.
  • treating refers to adding, dissolving, slurrying, stirring, reacting, condensing, or combinations thereof.
  • base includes sodium hydroxide, potassium hydroxide, magnesium hydroxide, ammonia solution, dipotassium hydrogen orthophosphate, magnesium carbonate, sodium carbonate, and sodium bicarbonate.
  • polar aprotic solvent includes polar solvents insoluble in water, for example, dichloromethane, methyl acetate, ethyl acetate, propyl acetate, and dichloroethane.
  • acid includes hydrochloric acid, sulfuric acid, nitric acid, acetic acid, and phosphoric acid.
  • isolated refers to precipitation, crystallization, filtration, concentration, centrifugation, or combinations thereof, followed by drying. Drying may be carried out under reduced pressure, vacuum tray drying, spray drying, or air drying.
  • a first aspect of the present invention provides an amorphous form of bosutinib.
  • the amorphous form of bosutinib is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
  • XRPD X-ray powder diffraction
  • the amorphous form of bosutinib is characterized by a differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2.
  • DSC differential scanning calorimetry
  • the amorphous form of bosutinib is further characterized by a DSC thermogram having an endothermic peak at about 79.9°C.
  • a second aspect of the present invention provides a process for the preparation of an amorphous form of bosutinib comprising the steps of:
  • step ii) stirring the product of step i) with water, a polar aprotic solvent, and an acid; iii) separating the reaction mixture of step ii) into an organic layer and an aqueous layer;
  • 7-(3-chloropropoxy)-4-((2,4- dichloro-5-methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile is treated with N- methyl piperazine in the presence of triethylamine and dimethyl sulfoxide.
  • 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile is treated with N-methyl piperazine at a temperature of about 95°C to about 120°C.
  • the polar aprotic solvent is selected from the group consisting of ethyl acetate, methyl acetate, and propyl acetate.
  • the acid is concentrated hydrochloric acid.
  • the concentrated hydrochloric acid is added to adjust the pH of the reaction mixture to about 0.7 to about 1.0.
  • the base is an aqueous sodium bicarbonate solution.
  • the aqueous sodium bicarbonate solution is added to adjust the pH of the aqueous layer to about 7.5 to about 8.0.
  • the isolation of the amorphous bosutinib can be carried out by precipitation, cooling, filtration, concentration, centrifugation, or combinations thereof, followed by drying. Drying can be carried out by drying under reduced pressure, vacuum tray drying, spray drying or air drying. Drying can be carried out at a temperature of about 40°C to about 45°C for about 12 hours to about 16 hours.
  • the isolation of the amorphous bosutinib is carried out by filtration, followed by washing with water, and then drying at a temperature of about 40°C to about 45 °C for about 14 hours.
  • the pH of the reaction mixture is adjusted to 0.8 with concentrated hydrochloric acid at 25°C to 30°C, and then the mixture is stirred for 5 minutes. On standing, the reaction mixture separates into organic and aqueous layers, which are separated. The pH of the aqueous layer is adjusted to 7.8 with the addition of an aqueous sodium bicarbonate solution. The reaction mixture is cooled to 10°C to 15°C, and then stirred for 2 hours. The obtained solid is filtered, then washed with deionized water, and then dried under reduced pressure at 40°C to 45°C for 14 hours to obtain the amorphous form of bosutinib.
  • a third aspect of the present invention provides a pharmaceutical composition comprising an amorphous form of bosutinib and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is in the form of tablets, capsules, powder, solution, or suspension.
  • composition comprising mixing the amorphous form of bosutinib together with pharmaceutically acceptable carriers, excipients, and/or diluents.
  • pharmaceutical composition comprising the amorphous form of bosutinib as a solid dispersion or as nanoparticles with at least one polymeric component.
  • a fourth aspect of the present invention provides the use of an amorphous form of bosutinib for treating cancer, for example, CML.
  • the starting material, 7-(3-chloropropoxy)-4-((2,4-dichloro-5- methoxyphenyl)amino)-6-methoxyquinoline-3-carbonitrile can be prepared by any method known in the art, such as the processes described in U.S. Patent No. 6,002,008 and Journal of Medicinal Chemistry 44(23):3965-3977 (2001).
  • X-ray diffraction patterns were recorded using a PANalytical ® X'pert PRO with X'celerator ® as the detector, 0.02 as step size, and 3-40° 2 ⁇ as range, using CuKa radiation.
  • DSC endotherms were recorded using a Mettler Toledo ® Star 6 , SW 11.0, with Temperature range 30°C to 300°C, Heating rate: 10°C/min., and Nitrogen flow: 20.0 mL/min.
  • the reaction mass was cooled, and then deionized water (50 mL) was added at 25 °C to 30°C, and then the mixture was stirred for 70 minutes.
  • the solid material obtained was filtered, and then washed with deionized water (20 mL).
  • the wet solid obtained was added to deionized water (25 mL), followed by the addition of ethyl acetate (25 mL).
  • the pH of the reaction mass was adjusted to 0.8 with concentrated hydrochloric acid ( ⁇ 2 mL) within 5 minutes at 25 °C to 30°C.
  • the reaction mass was stirred at 25°C to 30°C for 5 minutes ,and then the layers were separated.
  • the product was isolated in an aqueous layer.
  • the pH of the aqueous layer was adjusted to 7.8 within 10 minutes with an aqueous sodium bicarbonate solution (3.5 g sodium bicarbonate in 52 mL of water).
  • the reaction mass was cooled to 10°C to 15°C, and then stirred for 2 hours, followed by filtration, and then washing with deionized water (20 mL).
  • the wet material obtained was dried under reduced pressure at 40°C to 45 °C for 14 hours to obtain the title product.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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

La présente invention concerne une forme amorphe du bosutinib, un procédé pour sa préparation, sa composition pharmaceutique, et un procédé d'utilisation associé.
PCT/IB2016/054820 2015-08-19 2016-08-10 Forme amorphe du bosutinib WO2017029584A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2559DE2015 2015-08-19
IN2559/DEL/2015 2015-08-19

Publications (1)

Publication Number Publication Date
WO2017029584A1 true WO2017029584A1 (fr) 2017-02-23

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Application Number Title Priority Date Filing Date
PCT/IB2016/054820 WO2017029584A1 (fr) 2015-08-19 2016-08-10 Forme amorphe du bosutinib

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WO (1) WO2017029584A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321505A (zh) * 2019-10-25 2021-02-05 杭州中美华东制药有限公司 一种伯舒替尼晶型及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075898A1 (fr) * 2003-02-21 2004-09-10 Wyeth 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alcoxy-3-quinolinecarbonitriles pour le traitement des lesions ischemiques
WO2005047259A1 (fr) * 2003-11-06 2005-05-26 Wyeth 4-anilino-3-quinolinecarbonitriles destines au traitement de leucemie myelogene chronique (cml)
WO2007005462A1 (fr) * 2005-07-01 2007-01-11 Wyeth Formes cristallines de 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile, et leurs procedes de preparation
WO2015123758A1 (fr) * 2014-02-20 2015-08-27 Apotex Inc. Formes du bosutinib et procédés de synthèse de celles-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004075898A1 (fr) * 2003-02-21 2004-09-10 Wyeth 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-alcoxy-3-quinolinecarbonitriles pour le traitement des lesions ischemiques
WO2005047259A1 (fr) * 2003-11-06 2005-05-26 Wyeth 4-anilino-3-quinolinecarbonitriles destines au traitement de leucemie myelogene chronique (cml)
WO2007005462A1 (fr) * 2005-07-01 2007-01-11 Wyeth Formes cristallines de 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile, et leurs procedes de preparation
WO2015123758A1 (fr) * 2014-02-20 2015-08-27 Apotex Inc. Formes du bosutinib et procédés de synthèse de celles-ci

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BOSCHELLI, DH ET AL.: "Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 44, no. Issue 23, 2001, pages 3965 - 3977 *
WITHBROE, GJ ET AL.: "A Robust, Streamlined Approach to Bosutinib Monohydrate", ORGANIC PROCESS RESEARCH & DEVELOPMENT;, vol. 17, no. 3, 15 March 2013 (2013-03-15), pages 500 - 504, XP055133427 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112321505A (zh) * 2019-10-25 2021-02-05 杭州中美华东制药有限公司 一种伯舒替尼晶型及其制备方法

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