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WO2010057430A1 - Forme polymorphe l de l'erlotinib, procédés de préparation et utilisations associées - Google Patents

Forme polymorphe l de l'erlotinib, procédés de préparation et utilisations associées Download PDF

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Publication number
WO2010057430A1
WO2010057430A1 PCT/CN2009/075015 CN2009075015W WO2010057430A1 WO 2010057430 A1 WO2010057430 A1 WO 2010057430A1 CN 2009075015 W CN2009075015 W CN 2009075015W WO 2010057430 A1 WO2010057430 A1 WO 2010057430A1
Authority
WO
WIPO (PCT)
Prior art keywords
polymorph
ethynylphenylamino
decyloxyethoxy
bis
cancer
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.)
Ceased
Application number
PCT/CN2009/075015
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English (en)
Chinese (zh)
Inventor
王胡博
张小敏
张鹏
杨玉雷
袁哲东
俞雄
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.)
Shanghai Institute of Pharmaceutical Industry
Original Assignee
Shanghai Institute of Pharmaceutical Industry
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 Shanghai Institute of Pharmaceutical Industry filed Critical Shanghai Institute of Pharmaceutical Industry
Publication of WO2010057430A1 publication Critical patent/WO2010057430A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen 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 present invention relates to novel N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride (erlotinib hydrochloride)
  • erlotinib hydrochloride A method of preparing a polymorph thereof and its use in the manufacture of a medicament for treating an over-value-added disease in a mammal.
  • the compound of the formula (1) is N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride (general name erlotidine) Nicotinate) is indicated for the treatment of excessively prevalent diseases in mammals, such as cancer.
  • the compound is an inhibitor of a tyrosine kinase such as an epidermal growth factor receptor and can be used to treat or prevent diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, brain tumor or neck cancer.
  • a tyrosine kinase such as an epidermal growth factor receptor
  • diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, brain tumor or neck cancer.
  • polymorph A Two different polymorphs of N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride are disclosed in WO 01/34574 , referred to as polymorph A and polymorph B, which is incorporated herein by reference. Specifically disclosed in the polymorph A is shown to have 2 ⁇ . X-ray powder diffraction patterns of the characteristic peaks represented by 5.58, 9.84, 11.25, 18.86, 22.70, 23.50, 24.18, 24.59, 25.40 and 29.24 are shown in Fig. 3; polymorph B is shown to have 2 ⁇ .
  • polymorph B is thermodynamically more stable than polymorph A, while polymorph A has better solubility and dissolution rate than polymorph B.
  • polymorph E N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride is disclosed in WO2004/072049 , referred to as polymorph E, which is incorporated herein by reference. Specifically, the polymorph E is shown to have 2 ⁇ . X-ray powder diffraction patterns of characteristic peaks represented by 5.7, 9.7, 10.1, 11.3, 17.0, 17.4, 18.9, 19.6, 21.3, 22.8, 23.6, 24.2, 24.7, 25.4, 26.2, 26.7 and 29.3, as shown in FIG. . It is also disclosed that the melting point of polymorph E is 211-214 °C. Polymorph E is thermodynamically more stable than polymorph A and has better solubility and dissolution rate than polymorph B. Summary of the invention
  • a first object of the present invention is to provide a novel N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride.
  • the polymorph L is characterized in that the polymorph L is shown to have 2 ⁇ . 5.6 ⁇ 0.2, 10.8 ⁇ 0.2, 12.2 ⁇ 0.2, 12.9 ⁇ 0.2, 16.1 ⁇ 0.2, 16.7 ⁇ 0.2, 18.3 ⁇ 0.2, 20.8 ⁇ 0.2, 21.2 ⁇ 0.2, 21.4 ⁇ 0.2, 22.3 ⁇ 0.2, 23.2 ⁇ 0.2 and 24.8 X-ray powder diffraction pattern of the characteristic peak represented by ⁇ 0.2.
  • the polymorph L of the N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride of the present invention is characterized by X-rays thereof.
  • the powder diffraction pattern has the above 2 ⁇ .
  • the characteristic peaks represented are close to the following values:
  • the term "proximity” as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative strength is highly dependent on the measurement conditions.
  • the relative intensity value can vary, for example, within a range of ⁇ 30% or preferably within a range of ⁇ 10%.
  • the above crystal polymorph L has an X-ray powder diffraction pattern as shown in Fig. 1.
  • the above crystal polymorph L can be characterized by its melting point. Therefore, the polymorphic form L of N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride of the present invention is characterized It has a melting point of 250 ° C - 253 ° C.
  • a second object of the present invention is to provide a process for the preparation of the above crystalline polymorph L, which comprises N-(3-ethynylphenylamino)-6,7-di(2- in an aqueous hydrochloric acid solution The step of recrystallization of the quinoxyethoxy)- 4-quinazolinamine hydrochloride.
  • the pH of the aqueous hydrochloric acid solution is preferably between 1-5.
  • the method can include the following steps:
  • a third object of the present invention is to provide a plurality of the N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride.
  • the excessive value-adding disease is cancer.
  • the cancer is non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer, pancreatic Adenocarcinoma, ovarian cancer, breast cancer, glioma, brain tumor or neck cancer.
  • the polymorphic form L of the N-(3-ethynylphenylamino)-6,7-bis(2-decyloxyethoxy)-4-quinazolinamine hydrochloride of the present invention has a higher melting point than High, therefore thermodynamically more stable than known polymorphs A, B and E. DRAWINGS
  • Figure 1 is an X-ray diffraction pattern of polymorph L obtained in Example 1 of the present invention.
  • Figure 2 is a DSC spectrum of the polymorph L obtained in Example 1 of the present invention.
  • Figure 3 is an X-ray diffraction pattern of polymorph A disclosed in WO 01/34574;
  • Figure 4 is an X-ray diffraction pattern of polymorph B disclosed in WO 01/34574;
  • Figure 5 is an X-ray diffraction pattern of polymorph E disclosed in WO2004/072049. detailed description
  • the specific measurement conditions of the X-ray powder diffraction in the following examples are as follows: ⁇ Measured by a Bmker D8 ADVANCE meter.
  • the measurement conditions were as follows: CuKa 40Kv 40 mA was a light source with a step size of 0.02. , Scanning speed: 8 min, scanning range: 3° ⁇ 80°, room temperature.
  • Example 1
  • X-ray powder diffraction patterns of characteristic peaks represented by about 5.6, 10.8, 12.2, 12.9, 16.1, 16.7, 18.3, 20.8, 21.2, 21.4, 22.3, 23.2 and 24.8 are shown in Fig. 1.
  • the polymorphic form L has a melting point of 250 ° C - 253 ° C.
  • Polymorph B 227-231 Experimental Example 2: Studying the stability of polymorphs L, E, A and B
  • Polymorph A, polymorph B, polymorph E and polymorph L were placed in an incubator at 60 ° C for 10 days, and the stability of these crystal forms was studied by high performance liquid chromatography. .
  • Chromatographic conditions octadecylsilane bonded silica as a filler; 50 mM / L of acid buffer salt (pH adjusted to 7.5 with sodium hydroxide) and sterol volume ratio of 3: 7 mixed solution as mobile phase
  • the column temperature is 40 ° C; the detection wavelength is 254 nm.
  • the purity was determined by an internal standard method.
  • Polymorph A, polymorph B, polymorph E, and polymorph L were each placed in a 2 mg/mL solution using a mobile phase, and 8 L each was injected into a liquid chromatograph to record a chromatogram.
  • the measurement method is determined by the method of measuring the purity of the sample by an external standard method.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une nouvelle forme polymorphe L du chlorhydrate de N-(3-éthynylphényl)-6,7-bis(2-méthoxyéthoxy)quinazolin-4-amine (chlorhydrate d'erlotinib). Cette nouvelle forme polymorphe L présente un profil de diffraction des rayons X sur poudre affichant des pics caractéristiques exprimés en degrés 2-thêta à 5,6 ± 0,2, 10,8 ± 0,2, 12,2 ± 0,2, 12,9 ± 0,2, 16,1 ± 0,2, 16,7 ± 0,2, 18,3 ± 0,2, 20,8 ± 0,2, 21,2 ± 0,2, 21,4 ± 0,2, 22,3 ± 0,2, 23,2 ± 0,2 et 24,8 ± 0,2. L'invention concerne également les procédés de préparation de la forme polymorphe L et ses utilisations pour produire le médicament permettant de traiter des maladies hyperprolifératives chez un mammifère.
PCT/CN2009/075015 2008-11-20 2009-11-18 Forme polymorphe l de l'erlotinib, procédés de préparation et utilisations associées Ceased WO2010057430A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200810203067XA CN101735156B (zh) 2008-11-20 2008-11-20 厄罗替尼盐酸盐的多晶型l、其制备方法及其应用
CN200810203067.X 2008-11-20

Publications (1)

Publication Number Publication Date
WO2010057430A1 true WO2010057430A1 (fr) 2010-05-27

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CN (1) CN101735156B (fr)
WO (1) WO2010057430A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118737A1 (fr) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Sels d'erlotinib

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101914068A (zh) * 2010-08-14 2010-12-15 浙江华海药业股份有限公司 一种厄洛替尼碱的新晶型及其制备方法
CN103772298A (zh) * 2012-10-25 2014-05-07 鲁南制药集团股份有限公司 一种盐酸厄罗替尼多晶型物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060154941A1 (en) * 2005-01-12 2006-07-13 Mai De Ltd. Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion
WO2007060691A2 (fr) * 2005-11-23 2007-05-31 Natco Pharma Limited Nouveau procede pour la preparation d'erlotinib
WO2008122776A2 (fr) * 2007-04-04 2008-10-16 Cipla Limited Procédé de préparation de l'erlotinib et de ses sels pharmaceutiquement acceptables

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060154941A1 (en) * 2005-01-12 2006-07-13 Mai De Ltd. Novel amorphous form of erlotinib hydrochloride and its solid amorphous dispersion
WO2007060691A2 (fr) * 2005-11-23 2007-05-31 Natco Pharma Limited Nouveau procede pour la preparation d'erlotinib
WO2008122776A2 (fr) * 2007-04-04 2008-10-16 Cipla Limited Procédé de préparation de l'erlotinib et de ses sels pharmaceutiquement acceptables

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014118737A1 (fr) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Sels d'erlotinib

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CN101735156B (zh) 2012-07-04
CN101735156A (zh) 2010-06-16

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