MALEATE SALTS OF A QUINAZOLINE DERIVATIVE USEFUL AS AN ANTIANGIOGENIC AGENT

Abstract

The present invention relates to AZD2171 maleate salt, to particular crystalline forms of AZD2171 maleate salt, to processes for their preparation, to pharmaceutical compositions containing them as active ingredient, to their use in the manufacture of medicaments for use in the production of antiangiogenic and/or vascular permeability reducing effects in warm-blooded animals such as humans, and to their use in methods for the treatment of disease states associated with angiogenesis and/or increased vascular permeability.

Claims

1-20. (canceled)

21. A method for inhibiting VEGF receptor tyrosine kinase in a warm-blooded animal in need of such treatment which comprises orally administering to said animal an effective amount of a pharmaceutical composition comprising crystalline Form A of 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline maleate, wherein said warm-blooded animal in need of such treatment has a solid tumor cancer that is recurrent, and optionally administering at least one additional treatment chosen from surgery, radiotherapy, and chemotherapy.

22. The method according to claim 21, herein said cancer is a female reproductive cancer.

23. The method according to claim 21, wherein the daily dose of Form A of 4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline maleate administered to said animal ranges from 0.03 mg/kg to 0.5 mg/kg.

24. The method according to claim 21, wherein said chemotherapy comprises at least one therapeutic agent chosen from (i) other antiangiogenic agents; (ii) cytostatic agents; and (iii) antiproliferative/antineoplastic drugs.

25. The method according to claim 24, herein said antiproliferative/antineoplastic drugs are chosen from platinum derivatives.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0144] FIG. 1: DSC and TGA Thermograms for AZD2171 Free base Monohydratewith temperature in C. plotted on the horizontal axis and heat flow/% weight loss on the vertical axis

[0145] FIG. 2: X-Ray Powder Diffraction Pattern for AZD2171 free basewith the 20 values plotted on the horizontal axis and the relative line intensity (count) plotted on the vertical axis.

[0146] FIG. 3: X-Ray Powder Diffraction Pattern for AZD2171 Free base Monohydrate Heated to 100 C.with the 20 values plotted on the horizontal axis and the relative line intensity (count) plotted on the vertical axis.

[0147] FIG. 4: X-Ray Powder Diffraction Pattern for AZD2171 Free base Micronisedwith the 20 values plotted on the horizontal axis and the relative line intensity (count) plotted on the vertical axis.

[0148] FIG. 5: X-Ray Powder Diffraction Pattern for AZD2171 Maleate Salt Form Awith the 20 values plotted on the horizontal axis and the relative line intensity (count) plotted on the vertical axis.

[0149] FIG. 6: DSC Thermogram for AZD2171 Maleate Form Awith temperature in C. plotted on the horizontal axis and endothermic heat flow (milliWatts (mW)) plotted on the vertical axis.

[0150] FIG. 7: AZD2171 Maleate Form A Vapour Sorption Isotherm at 25 C.with target relative humidity (RH) (%) plotted on the horizontal axis and change in dry mass (%) plotted on the vertical axis.

[0151] FIG. 8: X-Ray Powder Diffraction Pattern AZD2171 Maleate Salt Form Bwith the 20 values plotted on the horizontal axis and the relative line intensity (count) plotted on the vertical axis.

[0152] FIG. 9: DSC Thermogram for AZD2171 Maleate Form Bwith temperature in C. plotted on the horizontal axis and endothermic heat flow (milliWatts (mW)) plotted on the vertical axis.

[0153] FIG. 10: X-Ray Powder Diffraction Patterns for AZD2171 Maleate Slurry Experiment with the 2 values plotted on the horizontal axis and the relative line intensity (count) plotted on the vertical axis.

DETAILS OF TECHNIQUES USED

[0154] X-Ray Powder Diffraction

TABLE-US-00005 TABLE 5 % Relative Intensity* Definition 25-100 vs (very strong) 10-25 s (strong) 3-10 m (medium) 1-3 w (weak) *The relative intensities are derived from diffractograms measured with fixed slits Analytical Instrument: Siemens D5000

[0155] The X-ray powder diffraction spectra were determined by mounting a sample of the crystalline salt on Siemens single silicon crystal (SSC) wafer mounts and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 40 kV and 40 mA with a wavelength of 1.5406 angstroms. The collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 2 mm antiscatter slit and a 0.2 mm detector slit. The sample was exposed for 1 second per 0.02 degree 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode. The running time was 31 minutes and 41 seconds. The instrument was equipped with a scintillation counter as detector. Control and data capture was by means of a Dell Optiplex 686 NT 4.0 Workstation operating with Diffract+ software. Persons skilled in the art of X-ray powder diffraction will realise that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios which may affect analysis of samples. The skilled person will also realise that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values.

[0156] Sieving/Micronisation

[0157] AZD2171 free base was sieved prior to Micronising using al mm stainless steel sieve, the base being used for product collection and for manual feeding directly into the microniser. Approximately 7.5 g of AZD2171 free base was sieved.

[0158] A clean S/S lined 2 Microniser was used.

[0159] Manual feed rate: approximately g per minute.

[0160] Grind air pressure range 10/20 psi (0.67/1.33 atmospheres).

[0161] Venturi air pressure range 20/25 psi (1.33/1.67 atmospheres).

[0162] Dynamic Vapour Sorption

[0163] Analytical Instrument: Surface Measurements Systems Dynamic Vapour Sorption Analyser. About 5 mg of material contained in a quartz holder at 25 C. was subjected to humidified nitrogen at the following relative humidities (RH): 0, 20, 40, 60, 80, 95, 80, 60, 40, 20, 0% RH in duplicate.

[0164] Differential Scanning Calorimetry

[0165] Analytical Instrument: Mettler DSC820e.

[0166] Typically less than 5 mg of material contained in a 40 l aluminium pan fitted with a pierced lid was heated over the temperature range 25 C. to 325 C. at a constant heating rate of 10 C. per minute. A purge gas using nitrogen was usedflow rate 100 ml per minute.

[0167] Thermogravimetric Analysis

[0168] Analytical Instrument: Mettler TG851.

[0169] Typically between 3 and 12 mg of material contained in a 70 l alox (aluminium oxide) crucible was heated over the temperature range 25 C. to 325 C. at a constant heating rate of 10 C. per minute. A purge gas using helium was usedflow rate 50 ml per minute.

[0170] Karl Fischer Water Content

[0171] Analytical Instrument: Mitsubishi Moisture Meter CA-05.

[0172] Typically approximately 50 mg of material was used.