WO2009079541A1 - Formes d'anhydrate de quinazoline ditosylate - Google Patents

Formes d'anhydrate de quinazoline ditosylate Download PDF

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WO2009079541A1
WO2009079541A1 PCT/US2008/087118 US2008087118W WO2009079541A1 WO 2009079541 A1 WO2009079541 A1 WO 2009079541A1 US 2008087118 W US2008087118 W US 2008087118W WO 2009079541 A1 WO2009079541 A1 WO 2009079541A1
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methyl
fluorobenzyl
oxy
methanesulphonyl
chloro
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PCT/US2008/087118
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English (en)
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Andrew Simon Craig
David M. Crowe
Michael Millan
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Smithkline Beecham (Cork) Limited
Smithkline Beecham Corporation
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Publication of WO2009079541A1 publication Critical patent/WO2009079541A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to anhydrate forms of quinazoline ditosylate salt compounds.
  • the invention relates to ditosylate salts of 4-quinazolineamines in anhydrate form.
  • These compounds are inhibitors of various protein tyrosine kinases (PTKs) of the erbB family and consequently are useful in the treatment of disorders mediated by aberrant activity of such kinases.
  • PTKs protein tyrosine kinases
  • PTKs catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation.
  • A. F. Wilks Progress in Growth Factor Research, 1990, 2, 97-111 ; S.A. Courtneidge, Dev. Supp.l, 1993, 57-64; J.A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R.F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A.C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401).
  • Inappropriate or uncontrolled activation of many PTKs i.e. aberrant PTK activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
  • PTK protein tyrosine kinase
  • Ditosylate salts including anhydrate form 1 and monohydrate, of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine are disclosed in International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002.
  • the ditosylate salts of International Patent Application WO 02/02552 may be prepared in crystalline form and possess good moisture sorption properties (low hygroscopicity) and good physical stability.
  • Specific ditosylate salts disclosed were crystalline forms of a monohydrate ditosylate and an anhydrate ditosylate (Form 1).
  • Figure 1 (a) depicts an X-ray powder diffraction pattern of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate anhydrate in crystalline Form 2.
  • Figure 1 (b) depicts an infrared spectrum of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate in crystalline Form 2.
  • Figure 2(a) depicts an X-ray powder diffraction pattern of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate anhydrate in crystalline Form 3.
  • Figure 2(b) depicts an infrared spectrum of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -
  • Figure 3(a) depicts an X-ray powder diffraction pattern of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate anhydrate in crystalline Form 4.
  • Figure 3(b) depicts an infrared spectrum of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxyjphenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate in crystalline Form 4.
  • Figure 4(a) depicts an X-ray powder diffraction pattern of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate anhydrate in crystalline Form 5.
  • Figure 4(b) depicts an infrared spectrum of N- ⁇ 3-ChIoro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate in crystalline Form 5.
  • Figure 5(a) depicts an X-ray powder diffraction pattern of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate anhydrate in crystalline Form 6.
  • Figure 5(b) depicts an infrared spectrum of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxyjphenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate in crystalline Form 6.
  • Figure 6 depicts a simulated X-ray powder diffraction pattern of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine ditosylate anhydrate in crystalline Form 7.
  • Figure 7 depicts a simulated X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate in crystalline Form 8.
  • Figure 8 depicts a simulated X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ crystalline N-methyl-2-pyrrolidinone solvate (Class 1).
  • Figure 9 depicts an X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -
  • Figure 10 depicts a simulated X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ crystalline dioxane solvate (Class 1).
  • Figure 11 depicts a simulated X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ crystalline methanol solvate (Class 1).
  • Figure 12 depicts a simulated X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ crystalline acetonitrile solvate (Class 1).
  • Figure 13 depicts a simulated X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ crystalline N,N-dimethylformamide solvate (Class 1).
  • Figure 14 depicts an X-ray powder pattern of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ crystalline nitrobenzene solvate (Class D-
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • pharmaceutically acceptable salts means those salts which are non-toxic and that are suitable for manufacturing and formulation as a pharmaceutical entity.
  • Class 1 solvates means those crystalline solvates of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2- furyl]-4-quinazolinamine having similar XRPD (isostructural) and are useful intermediates for generating other N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine crystalline forms.
  • Suitable solvents useful to prepare Class 1 solvates include, but are not limited to, N-methyl-2-pyrrolidinone, dioxane, methanol, acetonitrile, dimethylformamide, and nitrobenzene. As will be apparent to those skilled in the art, said solvents may also be useful as mixtures or in mixture with water.
  • the term "substantially the same X-ray powder diffraction pattern” is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2 theta values within plus or minus 0.2° of the diffraction pattern referred to herein are within the scope of the referred to diffraction pattern.
  • the term "at least substantially includes peaks of Table X" (where X is one of Tables 1-15) is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2 theta values within plus or minus 0.2° of the subject Table are within the scope of the diffraction pattern referenced to the Table X.
  • the term "at least substantially includes the X-ray powder diffraction (XRPD) °2 ⁇ peaks Q1 , Q2, Q3, " (where Q1 , Q2, Q3, ... represent specific listed peak two theta values) is understood to mean that those X-ray powder diffraction patterns having diffraction peaks with 2 theta values within plus or minus 0.2° of the subject listed peak two theta values are within the scope of the subject listed peak 2 theta values.
  • the term "substantially the same infrared spectrum” is understood to mean that those infrared spectrum (run according to the method described) having infrared peaks with cm “1 values within plus or minus 2 cm “1 of the spectrum referred to herein are within the scope of the referred to infrared spectrum.
  • the present invention includes anhydrate ditosylate salts of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4- quinazolinamine in crystalline forms 2, 3, 4, 5, 6, 7, and 8.
  • the present invention includes anhydrate ditosylate salts of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6- [5-( ⁇ [2-(methanesulphonyl)ethyl] amino ⁇ methyl)-2-furyl]-4-quinazolinamine in crystalline forms 2, 3, 4, 5, and 6.
  • the intermediates, free base, and hydrochloride salt of the compound of Formula (I) may be prepared according to procedures similar to those of International Patent Application No. PCT/EP99/00048, filed January 8, 1999, and published as WO 99/35146 on July 15, 1999.
  • the ditosylate salts of the compound of Formula (I) may be prepared according to procedures similar to those of International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002, or according to the procedures of International Patent Application No.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4- quinazolinamine is form 2.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2- furyI]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 1 (a).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by substantially the same infrared spectrum shown in Figure 1 (b).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by an X- ray powder diffraction pattern which at least substantially includes the peaks of Table I.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]pheny! ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl) ⁇ 2- furyl]-4-quinazolinamine is characterized by an X-ray powder diffraction pattern which at least substantially includes the X-ray powder diffraction (XRPD) °2 ⁇ peaks 6.0, 9.4, 11.9, 16.9 and 24.2.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-ChIoro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4- quinazolinamine is form 3.
  • the crystalline form of the anhydrate ditosyiate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 2(a).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyI) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by substantially the same infrared spectrum shown in Figure 2(b).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by an X- ray powder diffraction pattern which at least substantially includes the peaks of Table II.
  • Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphony!) ethyljamino ⁇ methy!)-2- furyI]-4-quinazolinamine is characterized by an X-ray powder diffraction pattern which at least substantially includes the X-ray powder diffraction (XRPD) °2 ⁇ peaks 6.4, 7.2, 11.6 and 19.3.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyI]-4- quinazolinamine is form 4.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 3(a).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furylJ-4-quinazolinamine is characterized by substantially the same infrared spectrum shown in Figure 3(b).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyljamino ⁇ methyl)-2-furylJ-4-quinazolinamine is characterized by an X- ray powder diffraction pattern which at least substantially includes the peaks of Table III.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyI ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by an X-ray powder diffraction pattern which at least substantially includes the X-ray powder diffraction (XRPD) °2 ⁇ peaks 6.8, 8.9, 12.3 and 20.0.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4- quinazolinamine is form 5.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 4(a).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by substantially the same infrared spectrum shown in Figure 4(b).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by an X- ray powder diffraction pattern which at least substantially includes the peaks of Table IV.
  • Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by an X-ray powder diffraction pattern which at least substantially includes the X-ray powder diffraction (XRPD) °2 ⁇ peaks 4.3, 5.5, 8.0 and 16.4.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesuIphonyl) ethyljamino ⁇ methyl)-2-furyl]-4- quinazolinamine is form 6.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 5(a).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyI) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by substantially the same infrared spectrum shown in Figure 5(b).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine is characterized by an X- ray powder diffraction pattern which at least substantially includes the peaks of Table V.
  • Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by an X-ray powder diffraction pattern which at least substantially includes the X-ray powder diffraction (XRPD) °2 ⁇ peaks 4.0, 5.4, 8.1 , 14.0 and 19.3.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4- quinazolinamine is form 7.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 6(a).
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro- 4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4- quinazolinamine is form 8.
  • the crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2- furyl]-4-quinazolinamine is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 7(a).
  • each of the anhydrate ditosylate salts of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4- quinazolinamine described above are pharmaceutically acceptable salts.
  • N- ⁇ 3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl)ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine crystalline dioxane solvate (Class 1) is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 10.
  • N- ⁇ 3-ChIoro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl)ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine crystalline methanol solvate (Class 1 ) is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 11.
  • N- ⁇ 3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl)ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine crystalline acetonitrile solvate (Class 1) is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 12.
  • N- ⁇ 3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl)ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine crystalline N 1 N- dimethylformamide solvate (Class 1 ) is characterized by substantially the same X-ray powder diffraction pattern shown in Figure 13.
  • each of crystalline forms 2 to 8 of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine may be administered as the raw chemical, it is possible to present each active ingredient in crystalline form as a pharmaceutical composition.
  • compositions which include a therapeutically effective amount of a crystalline anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-
  • a process for the preparation of a pharmaceutical formulation including admixing a crystalline anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine selected from form 2, 3, 4, 5, 6, 7, and 8, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the crystalline anhydrate ditosylate salts of of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine described herein may be formulated for administration by any route, and the appropriate route will depend on the disease being treated as well as the subjects to be treated.
  • Suitable pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal, sublingual, and transdermal), vaginal or parenteral (including intramuscular, sub-cutaneous, intravenous, and directly into the affected tissue) administration or in a form suitable for administration by inhalation or insufflation.
  • the formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well know in the pharmacy art.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the crystalline anhydrate ditosylate salts of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine, described herein, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the crystalline anhydrate ditosylate salts of N- ⁇ 3-Chloro-4-[(3-fluorobenzyI) oxyjphenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine, as described herein, may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in- water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation, through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • a pharmaceutical composition including a therapeutically effective amount of a crystalline anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4- quinazolinamine selected wherein said crystalline salt is selected from forms 2, 3, 4, 5, 6, 7, and 8.
  • the pharmaceutical composition further includes one or more pharmaceutically acceptable, carriers, diluents and excipients.
  • a method for treating a disorder in a mammal characterized by aberrant activity of at least one erbB family protein tyrosine kinase which includes administering a therapeutically effective amount of a crystalline anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine selected wherein said crystalline salt is selected from forms 2, 3, 4, 5, 6, 7, and 8 to the mammal.
  • a crystalline anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine selected where
  • the crystalline forms of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine are as described above.
  • the aberrant PTK activity referred to herein is any erbB family PTK activity that deviates from the normal erbB family protein kinase activity expected in a particular mammalian subject.
  • Aberrant erbB family PTK activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of PTK activity.
  • aberrant activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.
  • unwanted PTK activity may reside in an abnormal source, such as a malignancy. That is, the level of PTK activity does not have to be abnormal to be considered aberrant, rather the activity derives from an abnormal source.
  • the crystalline forms of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine are inhibitors of one or more erbB family PTKs and as such have utility in the treatment of disorders in mammals which are characterized by aberrant PTK activity, particularly humans.
  • the disorder treated is characterized by at least one erbB family PTK, selected from EGFr, erbB-2 and erbB-4, exhibiting aberrant activity.
  • the disorder treated is characterized by at least two erbB family PTKs, selected from EGFr, erbB-2 and erbB-4, exhibiting aberrant activity.
  • a crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3- fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4- quinazolinamine inhibit at least one erbB family PTK, selected from EGFr, erbB-2 and erbB-4, wherein said crystalline form is selected from form 2, 3, 4, 5, 6, 7, and 8.
  • a crystalline form of the anhydrate ditosylate salt of N- ⁇ 3- Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2- furyl]-4-quinazoIinamine inhibit at least two erbB family PTKs selected from EGFr, c-erb-B2 and c-erb-B4, wherein said crystalline form is selected from form 2, 3, 4, 5, 6, 7, and 8.
  • a method of inhibiting at least one of EGFr, erbB-2 and erbB-4 in a mammal including administering a therapeutically effective amount of a crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxyjphenyl ⁇ - 6-[5-( ⁇ [2-(methanesulphonyI) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine wherein said form is selected from forms 2, 3, 4, 5, 6, 7, and 8.
  • a method of inhibiting at least two of EGFr, erbB-2 and erbB-4 in a mammal including administering a therapeutically effective amount of a crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine wherein said form is selected from forms 2, 3, 4, 5, 6, 7, and 8.
  • the disorders referred to may be any disorder which is characterized by aberrant PTK activity.
  • disorders include, but are not limited to, cancer and psoriasis.
  • the disorder is cancer.
  • the cancer is non-small cell lung, colo-rectal, bladder, prostate, liver, brain, head and neck, breast, renal, cervical, ovarian, gastric, esophageal, colorectal, or pancreatic cancers.
  • a method of treating a cancer in a mammal comprising: administering to said mammal a therapeutically effective amount of a crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methanesulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine wherein said form is selected from forms 2, 3, 4, 5, 6, 7, and 8.
  • a method of treating a cancer in a mammal comprising: administering to said mammal a therapeutically effective amount of a crystalline form of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-
  • the mammal is a human.
  • the crystalline forms of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-flUorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)-2-furyl]-4-quinazolinamine are useful in therapy and in the preparation of medicaments for treating a disorder in a mammal, which is characterized by aberrant activity of at least one erbB family PTK.
  • the medicament prepared is useful in treating a disorder characterized by at least one erbB family PTK, selected from EGFr, c-erb-B2 and c-erb-B4, exhibiting aberrant activity.
  • the medicament prepared is useful in treating a disorder characterized by at least two erbB family PTKs, selected from EGFr, c-erb-B2 and c- erb-B4, exhibiting aberrant activity.
  • a therapeutically effective amount of crystalline forms of the anhydrate ditosylate salt of N- ⁇ 3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl ⁇ -6-[5-( ⁇ [2-(methanesulphonyl) ethyljamino ⁇ methyl)- 2-furyl]-4-quinazolinamine will depend on a number of factors including, but not limited to, the age and weight of the mammal, the precise disorder requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veternarian.
  • Tr retention time
  • RP reverse phase
  • EtOAc ethyl acetate
  • DME 1,2-dimethoxyethane
  • DCM diichloromethane
  • DCE diichloroethane
  • the X-Ray Powder Diffraction (XRPD) analysis shown in the Figures were performed on a Phillips X'pert Pro powder diffractometer, Model PW3040/60, serial number DY1379 using an X'Celerator detector.
  • the acquisition conditions were; radiation: Cu Ka, generator tension: 45 kV, generator current: 4OmA, start angle: 2.0 °2 ⁇ , end angle: 40.0 °2 ⁇ , step size: 0.0167 °2 ⁇ , time per step: 31.75 seconds.
  • the sample was prepared using silicon wafer technique. The 20 or so most intense peaks plus low angle peaks have been included in the preceding Tables I-XVI.
  • Example 10 Fig 9
  • Example 15 Fig. 14
  • the data collection was carried out at room temperature using monochromatic CuKa radiation in the region of 2 ⁇ between 1.5 and 41.5°.
  • the diffraction pattern was collected in two 2 ⁇ ranges with an exposure time of 90s for each frame. No background subtraction or curve smoothing is applied to the XRPD patterns.
  • IR analyses were performed on a Perkin Elmer infrared spectrometer, model Spectrum One, using a diamond ATR attachment.
  • the acquisition conditions were; number of scans: 16, resolution: 2 cm "1 .
  • the free base N- ⁇ 3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl ⁇ -6-[5-( ⁇ [2- (methane sulphonyl) ethyl]amino ⁇ methyl)-2-furyl]-4-quinazolinamine is also know as GW572016X or lapatinib.
  • Lapatinib ditosylate anhydrate (form 1) and monohydrate were prepared according to methods similar to those disclosed in International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002,
  • Single crystal of crystalline anhydrate form 1 was obtained by evaporating a drop of a solution of crystalline anhydrate form 1 in DMSO. Crystal structure data for lapatinib ditosylate anhydrate form 1 was collected on a Bruker Smart CCD 6000 X-ray diffractometer
  • Lapatinib free base was prepared as follows. A suspension of lapatinib ditosylate and ethyl acetate was stirred at 22+3°C. An aqueous sodium carbonate solution (10%w/v) was added and the mixture stirred for at least 60 min. The layers were separated and the upper organic layer stirred with water (x 2) at 52+3°C. The layers were separated and the upper organic layer clarified. The contents were cooled to 22 ⁇ 3°C and the bottom aqueous layer is removed. The contents were then concentrated by atmospheric distillation to 9vol. The solution was cooled to 68-70° and seeded with lapatinib free base.
  • the mixture was stirred at 68-70° for at least 15 min to allow crystallisation to establish, then concentrated by atmospheric distillation to 4vol.
  • the mixture was cooled to 22+5° over at least 1h and aged for at least 1h.
  • the product was isolated by filtration and washed with ethyl acetate.
  • the product was dried in vacuo at 45 ⁇ 3°C to give lapatinib free base as a cream solid.
  • Expected yield 90% theory; 56% w/w.
  • Lapatinib ditosylate monohydrate (1.0 g) was dissolved in 2,2,2-trifluoroethanol (50 ml) at ambient temperature. The solution was concentrated using a rotary evaporator to give a solid residue which was dried in the vacuum oven at 40 0 C for 3 hours. An X-ray powder diffraction was run which indicated the sample was mostly non-crystalline.
  • Single crystal of crystalline anhydrate form 2 was obtained by recrystallisation of the monohydrate form prepared by methods similar to those disclosed in International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002, from DMF containing a small amount of acetonitrile as an antisolvent.
  • Crystal structure data for anhydrate Form 2 was collected on a Bruker Smart CCD 6000 X-ray diffractometer
  • Amorphous lapatinib ditosylate (1.0 g), prepared according to methods similar to those of Example 1 , was slurried in acetonitrile (10 ml) under argon for 2 hours at ambient temperature. More acetonitrile (5 ml) was added to mobilise and the solid was filtered, washed with acetonitrile and dried under vacuum for 24 hours. An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 4(a) and Figure 4(b) respectively.
  • Amorphous lapatinib ditosylate (0.6 g) was slurried in acetic acid (2 ml) for 2 hours at ambient temperature. More acetic acid (2 ml) was added to mobilise and the solid was filtered, washed with acetic acid and dried in the vacuum oven at 50°C for 24 hours. An X-ray powder diffraction pattern and an infrared spectrum were obtained and are depicted in Figure 5(a) and Figure 5(b) respectively.
  • a single crystal of anhydrate form 2 was mounted on a Bruker Smart CCD 6000 X-ray diffractometer equipped with an Oxford cryosystems cryostream LT device and cooled to - 103 0 C.
  • Single crystal data were collected and a simulated X-ray powder pattern is depicted in Figure 6 and single crystal structure data follows.
  • a single crystal of anhydrate form 1 prepared by methods similar to those disclosed in International Patent Application No. PCT/US01 /20706, filed June 28, 2001 , and published as WO 02/02552 on January 10, 2002, was mounted on a Bruker Smart CCD 6000 X-ray diffractometer equipped with an Oxford cryosystems cryostream LT device and heated to 137°C. Single crystal data were collected and a simulated X-ray powder pattern is depicted in Figure 7.
  • Lapatinib ditosylate monohydrate (445.9 mg) was slurried in N-methyl-2-pyrrolidinone (1.4 ml) to give Lapatinib ditosylate N-methyl-2-pyrrolidinone solvate.
  • An X-ray powder diffraction pattern was obtained and is depicted in Figure 9.
  • GW572016X has been tested for erbB family protein tyrosine kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays. See International Patent Application PCT/EP99/00048 filed January 8, 1999, and published as WO 99/35146 on July 15, 1999.
  • the salts of the present invention may be tested for erbB family protein tyrosine kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays as follows.
  • the substrate phosphorylation assays use baculovirus expressed, recombinant constructs of the intracellular domains of c-erbB-2 and c-erbB-4 that are constitutively active and EGFr isolated from solubilised A431 cell membranes.
  • the method measures the ability of the isolated enzymes to catalyse the transfer of the g-phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide (Biotin-GluGluGluGluTyrPheGluLeuVal).
  • Substrate phosphorylation was detected following either of the following two procedures: a.) c-ErbB-2, c-ErbB4 or EGFr were incubated for 30 minutes, at room temperature, with 10mM MnCl2, 10mM ATP, 5 mM peptide, and test compound (diluted from a 5mM stock in DMSO, final DMSO concentration is 2%) in 4OmM HEPES buffer, pH 7.4. The reaction was stopped by the addition of EDTA (final concentration 0.15mM) and a sample was transferred to a streptavidin-coated 96-well plate.
  • Results for GW572016X are shown in Table XVIII for EGFR, erbB2, and erbB4 tyrosine kinase inhibition.
  • the structure of the free base (GW572016X) is given.
  • HFF human foreskin Fibroblasts
  • HB4a clones were cultured in RPMI containing 10% FBS, insulin (5 ⁇ g/ml), hydrocortisone (5 ⁇ g/ml), supplemented with the selection agent hygromycin B (50 ⁇ g/ml).
  • Cells were harvested using trypsin/EDTA, counted using a haemocytometer, and plated in 100 ml of the appropriate media, at the following densities, in a 96-well tissue culture plate (Falcon 3075): BT474 10,000 cells/well, HN5 3,000 cells/well, N87 10,000 ceils/well, HB4a c5.2 3,000 cells/well, HB4a r4.2 3,000 cells/well, HFF 2500 cells/well.
  • DMSO DMSO
  • the final concentration of DMSO in all wells was 0.3%.
  • Cells were incubated at 37 0 C, 10% CO 2 for 3 days. Medium was removed by aspiration.
  • Cell biomass was estimated by staining cells with 100 ⁇ l per well methylene blue (Sigma M9140, 0.5% in 50:50 ethanol:water), and incubation at room temperature for at least 30 minutes. Stain was removed, and the plates rinsed under a gentle stream of water, and air-dried. To release stain from the cells 100 ⁇ l of solubilization solution was added (1% N-lauroyl sarcosine, Sodium salt, Sigma L5125, in PBS), and plates were shaken gently for about 30 minutes.
  • solubilization solution 1% N-lauroyl sarcosine, Sodium salt, Sigma L5125, in PBS
  • Table XIX illustrates the inhibitory activity of GW572016X as IC 50 values in ⁇ M against a range of tumor cell lines. Using HFF as a representative human normal cell line, values for cytotoxicity are supplied as IC50 values in micromolar. A measure of selectivity between normal and tumor lines is provided as well. Table XIX

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Abstract

La présente invention concerne les formes cristallines de sels d'anhydrate de ditosylate de 4-quinazolineamines ainsi que leurs procédés d'utilisation dans le traitement de troubles caractérisés par une activité PTK aberrante de la famille erbB.
PCT/US2008/087118 2007-12-18 2008-12-17 Formes d'anhydrate de quinazoline ditosylate WO2009079541A1 (fr)

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Cited By (12)

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WO2009137714A2 (fr) * 2008-05-07 2009-11-12 Teva Pharmaceutical Industries Ltd. Formes de ditosylate de lapatinib et procédés pour leur préparation
WO2009140144A1 (fr) * 2008-05-15 2009-11-19 Teva Pharmaceutical Industries Ltd. Formes du lapatinib cristallin et leurs procédés de préparation
WO2010017387A2 (fr) * 2008-08-06 2010-02-11 Teva Pharmaceutical Industries Ltd. Intermédiaires de lapatinib
WO2011116634A1 (fr) 2010-03-23 2011-09-29 Scinopharm Taiwan Ltd. Procédé et intermédiaires pour la préparation du lapatinib
WO2011130831A1 (fr) * 2010-04-22 2011-10-27 Apotex Pharmachem Inc. Formes polymorphes du ditosylate de lapatinib et leurs procédés de préparation
US8710221B2 (en) 2010-03-23 2014-04-29 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
CN103896926A (zh) * 2012-12-27 2014-07-02 上海创诺医药集团有限公司 二对甲苯磺酸拉帕替尼溶剂化物多晶型物及其制法和用途
WO2014170910A1 (fr) 2013-04-04 2014-10-23 Natco Pharma Limited Procédé de préparation du lapatinib
US20160096826A1 (en) * 2014-04-24 2016-04-07 F.I.S. - Fabrica Italiana Sintetici S.P.A. Co-crystals of lapatinib monoacid salts
EP3266773A1 (fr) 2016-07-04 2018-01-10 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé de préparation de lapatinib ditosylate monohydrate par un procédé de cristallisation amélioré
WO2018139626A1 (fr) 2017-01-30 2018-08-02 塩野義製薬株式会社 Préparation solide comprenant un dérivé de quinazoline
US10329285B2 (en) 2015-07-29 2019-06-25 Shionogi & Co., Ltd. Salts of quinazoline derivative or crystals thereof, and the process for producing thereof

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US7141576B2 (en) * 2001-01-16 2006-11-28 Smithkline Beecham (Cork) Limited Cancer treatment method

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009137714A3 (fr) * 2008-05-07 2010-03-18 Teva Pharmaceutical Industries Ltd. Formes de ditosylate de lapatinib et procédés pour leur préparation
US8252805B2 (en) 2008-05-07 2012-08-28 Teva Pharmaceutical Industries Ltd. Forms of lapatinib ditosylate and processes for preparation thereof
WO2009137714A2 (fr) * 2008-05-07 2009-11-12 Teva Pharmaceutical Industries Ltd. Formes de ditosylate de lapatinib et procédés pour leur préparation
WO2009140144A1 (fr) * 2008-05-15 2009-11-19 Teva Pharmaceutical Industries Ltd. Formes du lapatinib cristallin et leurs procédés de préparation
WO2010017387A2 (fr) * 2008-08-06 2010-02-11 Teva Pharmaceutical Industries Ltd. Intermédiaires de lapatinib
WO2010017387A3 (fr) * 2008-08-06 2010-05-14 Teva Pharmaceutical Industries Ltd. Intermédiaires de lapatinib
TWI453202B (zh) * 2010-03-23 2014-09-21 Scinopharm Taiwan Ltd 製備拉帕替尼之方法及中間體
WO2011116634A1 (fr) 2010-03-23 2011-09-29 Scinopharm Taiwan Ltd. Procédé et intermédiaires pour la préparation du lapatinib
US8563719B2 (en) 2010-03-23 2013-10-22 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
US8710221B2 (en) 2010-03-23 2014-04-29 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
WO2011130831A1 (fr) * 2010-04-22 2011-10-27 Apotex Pharmachem Inc. Formes polymorphes du ditosylate de lapatinib et leurs procédés de préparation
CN103896926A (zh) * 2012-12-27 2014-07-02 上海创诺医药集团有限公司 二对甲苯磺酸拉帕替尼溶剂化物多晶型物及其制法和用途
WO2014170910A1 (fr) 2013-04-04 2014-10-23 Natco Pharma Limited Procédé de préparation du lapatinib
US20160096826A1 (en) * 2014-04-24 2016-04-07 F.I.S. - Fabrica Italiana Sintetici S.P.A. Co-crystals of lapatinib monoacid salts
US10329285B2 (en) 2015-07-29 2019-06-25 Shionogi & Co., Ltd. Salts of quinazoline derivative or crystals thereof, and the process for producing thereof
US10513513B2 (en) 2015-07-29 2019-12-24 Shionogi & Co., Ltd. Salts of quinazoline derivative or crystals thereof, and the process for producing thereof
EP3266773A1 (fr) 2016-07-04 2018-01-10 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé de préparation de lapatinib ditosylate monohydrate par un procédé de cristallisation amélioré
WO2018139626A1 (fr) 2017-01-30 2018-08-02 塩野義製薬株式会社 Préparation solide comprenant un dérivé de quinazoline
KR20190108606A (ko) 2017-01-30 2019-09-24 시오노기세이야쿠가부시키가이샤 퀴나졸린 유도체를 함유하는 고형 제제
US10953016B2 (en) 2017-01-30 2021-03-23 Shionogi & Co., Ltd. Solid dosage form containing quinazoline derivative

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