CN1771032B - Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors - Google Patents
Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors Download PDFInfo
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- CN1771032B CN1771032B CN2004800050217A CN200480005021A CN1771032B CN 1771032 B CN1771032 B CN 1771032B CN 2004800050217 A CN2004800050217 A CN 2004800050217A CN 200480005021 A CN200480005021 A CN 200480005021A CN 1771032 B CN1771032 B CN 1771032B
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Classifications
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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
- C07D403/14—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 three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to polymorphs of the 3-pyrrole substituted 2-indolinone compound 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
Description
Cross reference
The application is claimed to meet U.S. Provisional Application No.60/448 35U.S.C.119 (e), that on February 24th, 2003 submitted to, 863 priority, and its disclosure is incorporated herein by reference in full.
Background of invention
Invention field
The present invention relates to the 2-indolinone compounds 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2 that 3-pyrroles replaces, the polymorphic of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide.
Prior art
5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is the chemical compound of a kind of performance protein kinase (PK) ability of regulation and control.Therefore this chemical compound can be used for treatment and relates to the active obstacle of unusual PK.
In brief, PK is the enzyme of hydroxyl phosphorylation on catalytic proteins tyrosine, serine and the threonine residues.This to seem simple active consequence be complicated, because in fact all aspects of cell life (for example growth of cell, differentiation and propagation) all depends on the PK activity to a certain extent.In addition, unusual PK activity has related to host's obstacle, the disease that existing relative no life threatens, and for example psoriasis also has very fatal diseases, for example glioblastoma (brain cancer).
5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is the inhibitor of receptor tyrosine kinase (RTK), this kinases is a kind of of PK.Neovascularization in RTK and their part VEGF, PDGF and the FGF mediation entity tumor claims angiogenesis again.So,, can suppress neovascularity and in tumor, grow by suppressing RTK.In theory, this novel molecular that is called as anti-angiogenic agent is significantly less than conventional anticarcinogen to the toxicity of body.5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-ylmethyl]-2, amide is developed and is used for the treatment of the house pet cancer 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) at present, mainly is Canis familiaris L., especially also can be used for treatment except other factor, human cancer.This class cancer includes but not limited to leukemia, the brain cancer, nonsmall-cell lung cancer, squamous cell carcinoma, astrocytoma, Kaposi, glioblastoma, pulmonary carcinoma, bladder cancer, head and neck cancer, melanoma, ovarian cancer, carcinoma of prostate, breast carcinoma, small cell lung cancer, glioma, colorectal carcinoma, urogenital cancer and gastrointestinal stromal cancer.The overexpression of mastocyte, include but not limited to that mastocytosis also is encompassed in.
Summary of the invention
The inventor has been found that, chemical compound 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2, there are two kinds of polymorphics in 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide, be polymorphic I and polymorphic II, have visibly different physical property separately.
Therefore in the first embodiment, the present invention relates to not contain substantially the formula I chemical compound of polymorphic I:
In second embodiment, the present invention relates to not contain substantially the formula I chemical compound of polymorphic II:
In preferred embodiment, the first embodiment chemical compound has PXRD pattern shown in Fig. 1 II type, and the second embodiment chemical compound has PXRD pattern shown in Fig. 1 I type.
In the 3rd embodiment, the present invention relates to compositions, comprise the polymorphic I of formula I chemical compound:
Wherein polymorphic I accounts for more than about 85 percentage by weights of compositions; Perhaps more than about 90 percentage by weights of compositions; Perhaps more than about 95 percentage by weights of compositions; Perhaps more than about 99 percentage by weights of compositions.
In the 4th embodiment, the present invention relates to compositions, comprise the polymorphic II of formula I chemical compound:
Wherein polymorphic II accounts for more than about 85 percentage by weights of compositions; Perhaps more than about 90 percentage by weights of compositions; Perhaps more than about 95 percentage by weights of compositions; Perhaps more than about 99 percentage by weights of compositions.
In the 5th embodiment, the present invention relates to the polymorphic of formula I chemical compound:
Wherein said polymorphic is preparation like this:
(a) described chemical compound is dissolved in acidic aqueous solution;
(b) the described aqueous solution that alkalizes is settled out the described chemical compound that does not contain polymorphic II substantially thus; With
(c) separate the polymorphic I of sedimentary described chemical compound.
In the 6th embodiment, the present invention relates to the polymorphic of formula I chemical compound:
Wherein said polymorphic is preparation like this:
(a) described chemical compound is dissolved in the polar organic solvent that does not generate hydrogen bond;
(b) evaporate described polar organic solvent, be settled out the described chemical compound that does not contain polymorphic II substantially thus; With
(c) separate the polymorphic I of sedimentary described chemical compound.
In the 7th embodiment, the present invention relates to the polymorphic of formula I chemical compound:
Wherein said polymorphic is preparation like this:
(a) described chemical compound is dissolved in the polar organic solvent that generates hydrogen bond;
(b) evaporate described polar organic solvent, be settled out the described chemical compound that does not contain polymorphic I substantially thus; With
(c) separate the polymorphic II of sedimentary described chemical compound.
In preferred implementation of the present invention, the polar organic solvent that does not generate hydrogen bond of the 6th embodiment is THF.Another preferred embodiment in, the polar organic solvent of the generation hydrogen bond of the 7th embodiment is a methanol.
In the 8th embodiment, the present invention relates to pharmaceutical composition, comprise chemical compound and the pharmaceutically acceptable carrier or the excipient of first or second embodiment.
In the 9th embodiment, the present invention relates to the kinase catalytic active method of modulin, comprise described protein kinase is contacted with the chemical compound of first or second embodiment.In preferred embodiment, protein kinase is selected from the group of being made up of receptor tyrosine kinase, nonreceptor tyrosine kinase and serine-threonine kinase.
In the tenth embodiment, the present invention relates to treat or prevent the method for organism protein kinase associated disorders, comprise the pharmaceutical composition of this organism being given to treat effective dose, described compositions comprises chemical compound and the pharmaceutically acceptable carrier or the excipient of first or second embodiment.In preferred embodiment, the protein kinase associated disorders is selected from the group of being made up of receptor tyrosine kinase associated disorders, non-receptor tyrosine associated disorders and serine-threonine kinase associated disorders.Another preferred embodiment in, the protein kinase associated disorders is selected from the group of being made up of EGFR associated disorders, PDGFR associated disorders, IGFR associated disorders, c-kit associated disorders and flk associated disorders.Another preferred embodiment in, the protein kinase associated disorders is a cancer, is selected from the group of being made up of leukemia, the brain cancer, nonsmall-cell lung cancer, squamous cell carcinoma, astrocytoma, Kaposi, glioblastoma, pulmonary carcinoma, bladder cancer, a cancer, neck cancer, melanoma, ovarian cancer, carcinoma of prostate, breast carcinoma, small cell lung cancer, glioma, colorectal carcinoma, urogenital cancer and gastrointestinal stromal cancer.The overexpression of mastocyte, include but not limited to that mastocytosis also is encompassed in.Another preferred embodiment in, the protein kinase associated disorders is selected from the group of being made up of diabetes, autoimmune obstacle, hyper-proliferative obstacle, restenosis, fibre modification, psoriasis, hippel-Lindau disease (Heppel-Lindau disease), osteoarthritis, rheumatoid arthritis, angiogenesis, inflammatory disorder, immunology obstacle and cardiovascular disorder.Another preferred embodiment in, organism is the people.
In the 11 embodiment, the present invention relates to treat the house pet method for cancer, comprise and give pharmaceutical composition, described compositions comprises chemical compound and the pharmaceutically acceptable carrier or the excipient of first or second embodiment.In preferred embodiment, house pet is cat or Canis familiaris L..
Brief description of drawings
Fig. 1 is 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) the polymorphic I (I type) of amide and powder x-ray diffraction (PXRD) pattern of polymorphic II (II type).
Fig. 2 is a 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) the polymorphic I (top spectrum) of amide and infrared (IR) transmitted spectrum of polymorphic II (bottom spectrum) are at the spectrographic height of IR, medium frequency region measurement.
Fig. 3 is a 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) the polymorphic I (top spectrum) of amide and the Raman spectrum of polymorphic II (bottom spectrum) are at height, the medium frequency region measurement of Raman spectrum.
Detailed description of the invention
Unless otherwise stated, the following term that is used in description and claims has following implication:
The solid phase of " polymorphic " expression material, there are some different forms in it because of the difference arrangement and/or the configuration of molecule in the lattice.
The difference that polymorphic also can be defined as chemical compound is the solvation crystal formation not.
Polymorphic has different chemistry and physical property usually.Term " polymorphic " also comprises solvate (form that just contains solvent or water), amorphous (just noncrystalline form) and desolvated solvate (just only can by remove the form of the preparation of desolvating from solvate) in the context of the preferred embodiment for the present invention.
In preferred implementation of the present invention, pure single polymorphic and comprising in two or more different polymorphous mixture all are encompassed in.Pure single polymorphic can not contain other polymorphics substantially." do not contain substantially " and mean that other polymorphous content less than about 15 percentage by weights, are more preferably less than about 10 percentage by weights, and then be more preferably less than about 5 percentage by weights, most preferably less than about 1 percentage by weight.Those skilled in the art will appreciate that wording " content is less than about 15 percentage by weights ", this means that relevant polymorphous content is greater than about 85 percentage by weights.Equally, wording " less than about 10 percentage by weights " will mean relevant polymorphous content greater than about 90 percentage by weights, or the like.
The polymorphic of the chemical compound of the preferred embodiment for the present invention is desirable, because the specific polymorphic of chemical compound can have better physics of other polymorphics and chemical property than same compound.For example, a kind of polymorphic can have the dissolubility that has increased in some solvent.The dissolubility that this class has increased can help the preparation or the administration of the chemical compound of the preferred embodiment for the present invention.Different polymorphics also can have different mechanical property (for example different compressibilityes, the compatibility, tabletting ability), and these can influence the tabletting performance of medicine, thereby influences the preparation of medicine.Specific polymorphic also can show in same solvent and be different from another kind of polymorphous rate of dissolution.Different polymorphics also can have different physics (from metastable polymorphic to more stable polymorphous solid-state conversion) and chemistry (reactivity) stability.
Preferred implementation of the present invention contains pharmaceutical composition, comprises polymorphic and the pharmaceutically acceptable carrier or the excipient of the preferred embodiment for the present invention.The polymorphous pharmaceutically acceptable composite preparation that comprises the preferred embodiment for the present invention is well known in the art with carrier and excipient, for example is disclosed in the U.S. Patent application No.09/783 that submits to February 15 calendar year 2001,264, be combined in this in full.Referring to WO 01/60814.
Preferred implementation of the present invention also contains the kinase catalytic active method of modulin, comprises described protein kinase is contacted with the polymorphic of the preferred embodiment for the present invention.In preferred implementation of the present invention, protein kinase is selected from the group of being made up of receptor tyrosine kinase, nonreceptor tyrosine kinase and serine-threonine kinase.
Preferred implementation of the present invention contains the method for treatment or prevention organism (for example people) protein kinase associated disorders, comprise the pharmaceutical composition of this organism being given to treat effective dose, described compositions comprises polymorphic and the pharmaceutically acceptable carrier or the excipient of the preferred embodiment for the present invention.In preferred implementation of the present invention, the protein kinase associated disorders is selected from the group of being made up of receptor tyrosine kinase associated disorders, non-receptor tyrosine associated disorders and serine-threonine kinase associated disorders.In another preferred implementation of the present invention, the protein kinase associated disorders is selected from the group of being made up of EGFR associated disorders, PDGFR associated disorders, IGFR associated disorders and flk associated disorders.In another preferred implementation of the present invention, the protein kinase associated disorders is a cancer, is selected from the group of being made up of squamous cell carcinoma, astrocytoma, Kaposi, glioblastoma, pulmonary carcinoma, bladder cancer, head and neck cancer, melanoma, ovarian cancer, carcinoma of prostate, breast carcinoma, small cell lung cancer, glioma, colorectal carcinoma, urogenital cancer and human primary gastrointestinal cancers.In a preferred embodiment of the present invention, the protein kinase associated disorders is selected from the group of being made up of diabetes, autoimmune obstacle, hyper-proliferative obstacle, restenosis, fibre modification, psoriasis, hippel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, inflammatory disorder, immunology obstacle and cardiovascular disorder.
Preferred implementation of the present invention also contains treatment house pet method for cancer, comprises and gives pharmaceutical composition, and described compositions comprises polymorphic and the pharmaceutically acceptable carrier or the excipient of the preferred embodiment for the present invention.Term used herein " house pet " includes but not limited to cat and Canis familiaris L..
Embodiment
The following example makes those skilled in the art can more be expressly understood and implement the present invention.They should not be regarded as limiting invention scope, and only are its illustration and representative.
5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide synthetic
Make 5-fluoro-1,3-Indolin-2-one and 5-formoxyl-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) is amide condensed, obtains title compound.
MS+ve APCI 397[M
++1].
Amplification technique in proportion:
With 5-formoxyl-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (61g), 5-fluoro-1,3-Indolin-2-one (79g), ethanol (300ml) and pyrrolidine (32ml) refluxed 4.5 hours.Add acetic acid (24ml) to mixture, continue to reflux 30 minutes.Mixture is cooled to Xuan Wen, and vacuum filtration is collected solid, uses twice of washing with alcohol.Solid was stirred 130 minutes in containing 40% aqueous acetone solution (400ml) of 12N hydrochloric acid (6.5ml).Vacuum filtration is collected solid, with 40% aqueous acetone solution washed twice.Drying solid under vacuum obtains 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (86g, 79% yield) is orange solids.
1H-NMR (dimethyl sulfoxide-d
6) δ 2.48,2.50 (2xs, 6H, 2xCH
3), 6.80,6.88,7.68,7.72 (4xm, 4H, aromatics and vinyls), 10.88 (s, 1H, CONH), 12.12 (s, 1H, COOH), 13.82 (s, 1H, pyrroles NH) .MSm/z 299[M-1].
Stir 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (100g) and dimethyl formamide (500ml) add benzotriazole-1-base oxygen base three (dimethylamino) Phosphonium hexafluorophosphate (221g), 1-(2-amino-ethyl) pyrrolidine (45.6g) and triethylamines (93ml).Mixture was stirred 2 hours at ambient temperature.Vacuum filtration is collected solid product, uses washing with alcohol.Solid was washed and starched by stirring in 64 ℃ of ethanol (500ml) in 1 hour, be cooled to room temperature.Vacuum filtration is collected solid, uses washing with alcohol, and is dry under vacuum, obtains 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide (101.5g, 77% yield).
1H-NMR (dimethyl sulfoxide-d
6) δ 1.60 (m, 4H, 2xCH
2), 2.40,2.44 (2xs, 6H, 2xCH
3), 2.50 (m, 4H, 2xCH
2), 2.57,3.35 (2xm, 4H, 2xCH
2), 7.53,7.70,7.73,7.76 (4xm, 4H, aromatics and vinyls), 10.88 (s, 1H, CONH), 13.67 (s, 1H, pyrroles NH) .MS m/z 396[M+1].
Polymorphic is differentiated the general analysis method with determination of physical appearance
The dissolubility of polymorphic in all kinds of solvents estimated
About 1.5mg polymorphic is transferred to 10ml vial (weighing), weigh (being accurate to 0.1mg).In a step-wise fashion add solvent (every a kind of solvent of bottle) to bottle.After each the adding, bottle is covered, shake.The solid dissolving of perusal.If do not observe tangible dissolving, add more solvent immediately.If dissolving obviously, before solvent adds next time, bottle placed on the platform at least 30 minutes.Repeat this step, until before the black and white background, there not being visible crystal.Represent dissolubility with weight divided by final volume and the volume classification before last the adding then.If the solid residue is arranged after adding the 10ml solvent, dissolubility is represented as less than weight divided by final volume.If solid dissolves fully after the first time, solvent added, dissolubility is represented as greater than weight divided by solvent volume.Solubility values is represented with mg/ml.All experiments are all at room temperature carried out.
The mensuration of polymorphic pH-solubility curve
With the HCl or the NaOH of various concentration, about 3ml aqueous solution of pH 1-13 is transferred to the 10ml vial.Add the capacity polymorphic.Bottle is wrapped up with aluminium foil, with hand moving.Before further handling, place them in the fuming cupboard and spend the night.
Powder x-ray diffraction (PXRD)
Utilize Scintag X2 Advanced Diffraction System to carry out powder x-ray diffraction, under Scintag DMS/NT 1.30a and Microsoft Windows NT 4.0 softwares, operate.System adopts and provides 1.5406
(45kV is 40mA) with solid-state Peltier cooling detector for the copper X-ray light source of CuK α 1 emission.Utilize pipe disperse with 2 with the anti-scatter slit of 4mm and 0.5 with the wide anti-scattering of detector of 0.2mm with receive slit and control light beam hole.Collect the data of 2 to 352 θ, adopt the step-scan in 0.03/ step, per step gate time is 1 second.The rustless steel specimen cup that utilizes the Scintag circular top to load experimentizes internal diameter 9mm.With the powder anchor clamps of packing into, use the sheet glass applying light, to guarantee the coplanarity between sample surfaces and the chucking surface.
Differential scanning calorimetry (DSC)
Utilize DSC calorimeter (TA Instruments 2920) to obtain differential scanning calorimetry (DSC) data.With pack into aluminum DSC dish of 1-10mg powder.Aluminium lid is placed on the dish top, curls.The dish that curls is placed sample cell, with blank panel as reference.Make temperature rise to 300 ℃ from 30 ℃, speed is 10 ℃/min.
PLM
On Olympus BHSP micropolariscope, carry out microscopy.Powder is encapsulated in the silicone oil, is dispersed between microslide and the cover plate.Before observing, cover plate and slide are rubbed gently, to give the fine dispersion of powder sample.Utilize the microscopy assessment to pulverize particle diameter, shape and the degree of crystallinity of sample.When warm table is connected with microscope, also can perusal by the observed calorifics incident of other technologies (for example DSC, thermogravimetry (TGA)).
The infrared spectroscopy art (FTIR) that Fourier transforms
The polymorphic sample is made the KBr granule that supplies infrared analysis.Collect from 4000 to 400cm being equipped with on the Nicolet 760FTIR of TGS detector
-1The infrared transmission data.Sensitivity is represented with instrument gain, is 4.Utilize Happ-Genzel apodization process data, transform for Fourier.Final FT-IR spectrum is represented 200 independent scanning.
The raman spectroscopy art that Fourier transforms
The 1.7mm capillary glass tube of will about 2mg polymorphic packing into is exposed to 1.00WT 1064nm laser.Acquisition from 3800 to 100cm
-1Raman spectrum.The Nicolet 960FT-raman spectroscopy that the INGAS detector is equipped with in utilization collects the collection data.Sensitivity is represented with instrument gain, is 8.Still utilize Happ-Genzel apodization process data, transform for Fourier.Final FT-IR spectrum is represented 200 independent scanning.
The intrinsic rate of dissolution of rotating disc type (IDR) is measured
Utilize the automatic dissolution system of optical fiber UV to measure IDR.In some situation, utilize fiber optics probe continuous monitoring course of dissolution under 426.2nm, per minute is gathered 10 data points.For the compact disk that preparing experiment is used, utilize high-speed steel (HSS) drift (diameter 3/16 ", long by 3
1/
2") with powder by be pressed on rustless steel (SS) punch die (1 1/4 " dia x 1 ", ID 3/16 ").The HSS drift is inserted punch die to about 3/4 " distance, reserve about 1/4 " for placing about 10mg medicine to die cavity.(diameter 1/4 ") covers die cavity to place the SS substrate.Then complete assemblies is fixed with 2-screw anchor clamps.Utilize the Carver tablet machine that powder was pushed 3 minutes, pressure is～1, and 0001bs (～37,000psi).From the Carver tablet machine, take out punch die and anchor clamps, retract some drifts, so that loose particles/distending.With hold-down screw the punch die type tightly is connected with the HSS drift then.From anchor clamps, take out the complete drift contain drug particles and die assembly as a unit, drug particles have simultaneously be exposed to outside, be connected with motor.Began back 3 minutes in data collection program, punch die is rotated under 300rpm, drop in the dissolve medium.Make the dissolve medium degassing, place 500ml water leg beaker (Pyrex, No.1000).Pro-was collected data during 3 minutes, and the baseline value of each dissolution experiment is provided.Dissolve medium is made up of pH=2 solution (0.01N HCl and 0.05M KCl).Punch die is positioned like this, and the bottom upward about 2.5 " is located, approximately equated with the distance of liquid surface so that medicine is crushed on the 500ml dissolution vessel.
Utilize Microsoft Excel to make intrinsic solubility curve, calculate intrinsic rate of dissolution according to equation (1) Automatic Program.
The volume of dissolve medium is 300ml.The granule surface area that is exposed to dissolve medium is 0.177cm
2The time that dissolving is carried out is generally 15 minutes, can depend on the needs.
5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) the polymorphous determination of physical appearance of amide
Differentiate 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2, two kinds of polymorphics of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide.During active pharmaceutical ingredient (API) was made, thermodynamic relation, their solubility behavior and their solid state properties between two kinds of polymorphics of chemical compound obviously can be used for solid form selection and suitably process control immediately.Therefore, for understanding the stability relation between two kinds of polymorphics of chemical compound and utilizing multiple technologies (for example dissolubility, IDR, PXRD, IR/ raman spectroscopy art, PLM and DSC) to differentiate that their solid state properties makes an effort.
Dissolubility
Estimated 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) dissolubility of amide in all kinds of solvents is listed in the Table A.At room temperature use polymorphic I to experimentize.Dissolubility can be divided into three groups.
Group I
5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is at isopropyl alcohol, CH
2Cl
2, the dissolubility in ethyl acetate, acetonitrile, acetone, chloroform, toluene, hexane and pH＞6 water: dissolubility be low-down (＜＜0.3mg/ml).
Group II
Dissolubility in methanol, ethanol, diox and THF: dissolubility still very low (0.1-0.4mg/ml) still is significantly higher than the dissolubility in group I solvent.
Group III
5-[5-fluoro-2-oxo-1,2-indylidene-(3Z)-ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) dissolubility of amide in dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and pH＜=2 water: dissolubility be quite high (＞1mg/ml).
Table A: estimated 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) dissolubility of amide polymorphic I in 23 ℃ of all kinds of solvents
| Solvent | Dissolubility (mg/ml) | |
| 1 | Water (pH=2) | 3.11 |
| Water (pH=6) | 0.005 | |
| 2 | DMSO | 1.5-3.0 |
| 3 | DMF | ＞1.5 |
| 4 | Methanol | 0.21-0.31 |
| 5 | Ethanol | 0.17-0.19 |
| 6 | Diox | 0.18-0.20 |
| 7 | THF | 0.32-0.4 |
| 8 | Isopropyl alcohol | ＜0.14 |
| 9 | CH 2Cl 2 | ＜0.12 |
| 10 | Ethyl acetate | ＜＜0.28 |
| Solvent | Dissolubility (mg/ml) | |
| 11 | Acetonitrile | ＜＜0.08 |
| 12 | Acetone | ＜＜0.16 |
| 13 | Chloroform | ＜0.11 |
| 14 | Toluene | ＜＜0.13 |
| 15 | Hexane | ＜＜＜0.13 |
| 16 | PEG 400 | 0.30-0.43 |
5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2, the pKa of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is 8.50.Just as expected, the equilbrium solubility of this chemical compound higher under lower pH value of solution (Table A).But, the dissolving of granule in dissolve medium depends on the pH of diffusion layer.PH value (the pH of the diffusion layer that closely contacts with solid
H=0) can obtain from the balance pH of solution, the latter measures with pH meter.The results are shown among the table B.When initial pH is higher than 10,5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2, the dissolubility of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is low-down.Therefore, be in the almost not change of pH of equilibrated solution.On the other hand, if initial pH＜10, more 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide enters solution, and balance solution pH is higher than initial pH (table B).Therefore, Notes of Key Data pH
H=0Keeping quite high (＞5), also is like this even the body dissolve medium has low 1.4 the pH of reaching.
Table B:5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide does not cushion the influence of the balance solution pH value of aqueous medium to room temperature
| Initial soln pH | To 2ml not buffered water add 5-[5-fluoro-2-oxo-1,2-indylidene-(3Z)-ylmethyl]-2, the amount (mg) of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide | Balance solution pH |
| 1.43 | 322.5 | 5.36 |
| 2.19 | 333.2 | 5.20 |
| 3.22 | 280.7 | 6.98 |
| 5.47 | 209.7 | 8.13 |
| 6.73 | 143.0 | 8.31 |
| Initial soln pH | To 2ml not buffered water add 5-[5-fluoro-2-oxo-1,2-indylidene-(3Z)-ylmethyl]-2, the amount (mg) of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide | Balance solution pH |
| 7.24 | 141.5 | 8.49 |
| 7.61 | 95.4 | 8.87 |
| 10.07 | 95.1 | 9.86 |
| 11.53 | 96.2 | 11.61 |
| 12.50 | 88.0 | 12.52 |
| 13.20 | 98 | 13.18 |
Measure 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2, the trial of the pH-solubility curve of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is unsuccessful.In pH＜2.2 time, initial drug dissolving back forms very fine granule.These subparticles pass 0.45 μ m filter membrane, obtain muddy filtrate.Do not test the more filter membrane of aperture (0.1 μ m), because obviously these class data do not have immediately use.
IDR
The intrinsic rate of dissolution (IDR) of many crystal form IIs and polymorphic I.Discovery is in 23 ℃ of pH2 buffer, and the IDR of polymorphic II is about three times (the table C) of the apparent IDR of polymorphic I.This result contradicts with early stage observed result, and promptly polymorphic II less stable estimates to have lower dissolubility, therefore has lower IDR under uniform temp He in the same solvent.Do not limit although do not wish to accept opinion, under experiment condition, experience solid-state conversion but a kind of explanation of this contradiction is a medicine.So, IDR can not be compared with original two kinds of polymorphous thermodynamic relations.The microscopic examination of polymorphic I drug particles has shown the admissible evidence of solid-state conversion hypothesis.The color that is exposed to granule one side of dissolve medium is orange-redness, and primary granule is yellow.Might contact with dissolve medium (0.05M KCl, pH 2 buffer) by granule one, polymorphic just has been converted into HCl salt.Because common-ion effect, the dissolubility of newly-generated HCl salt, therefore also have IDR to be significantly less than the expection of polymorphic II.After polymorphic II granule is exposed to identical dissolve medium, does not observe obvious color and change.
Hypothesis in order further to check HCl salt to generate is suspended in polymorphic I and II in the above-mentioned dissolve medium.But, after making suspension, do not observe the color change of particle at least in 15 minutes.This result is consistent with viewed polymorphic II solid-state stability in the dissolution experiment process, but does not support the rapid conversion of polymorphic I granule to HCl salt.After one day, in two bottles, occur orange-red needle-shaped crystals at the preparation suspension, be assumed to HCl salt crystal.This result confirms that HCl salt is lower than the dissolubility of polymorphic I and II at the dissolubility of the medium that is used for solubility test.Also might revise the crystal of polymorphic I in the compression before the IDR experiment, give the ability that it transforms rapidly.Shown amorphous composition to a certain degree in the particulate XRD figure case of the polymorphic I of various pressure lower compression, this may generate relevant with the rapid salt of IDR experimental session.
Powder x-ray diffraction (PXRD)
Observed two batches of 5-[5-fluoro-2-oxos-1, the 2-indylidene-(3Z)-and ylmethyl]-2, visibly different powder x-ray diffraction (PXRD) pattern (Fig. 1) of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide.A kind of like this observed result has been pointed out the existence of this medicine polytropism.Therefore, utilize FTIR and raman spectroscopy art to confirm 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-and ylmethyl]-2, the polytropism of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide.
IR and raman spectroscopy art
IR and Raman spectrum are respectively shown in Fig. 2 and 3.Two kinds of 5-[5-fluoro-2-oxos-1, the 2-indylidene-(3Z)-and ylmethyl]-2, obviously observed SPECTRAL DIVERSITY in 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) the amide crystal formation data.Generally speaking, these differences involve the variation of vibration mode, and are relevant with C=O functional group with the N-H of molecule.In the C-H of two kinds of crystal formations stretching mode, also observe some variations.5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-ylmethyl]-2, the solution NMR data (in DMSO) of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide polymorphic I and II are equal to, confirmed 5-[5-fluoro-2-oxo-1, the 2-indylidene-(3Z)-ylmethyl]-2, two kinds of polymorphics of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide are chemical equivalence.Therefore, any vibrational spectrum difference between two kinds of samples may be by two kinds of 5-[5-fluoro-2-oxos-1, the 2-indylidene-(3Z)-ylmethyl]-2, the crystal packing of 4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide crystal formation is caused.
The IR data of close examination polymorphic II are presented at 3198cm
-1Wide shuttle belt occurs, it is not present in the spectrum of polymorphic I.The wide shuttle belt of this frequency may be stretched caused by O-H.The IR data of polymorphic II also lack and see polymorphic I spectrum 1631cm
-1The C=O amidocarbonylation stretch.On the contrary, the IR data of polymorphic II are at 1589cm
-1Show powerful peak, it is not present in the data of polymorphic I.The vibration of this frequency is that the C=N stretching, extension is peculiar.Existence and the disappearance of C=O vibration and the class likelihood data of polymorphic I of C=N and O-H stretching mode in many crystal form II IR data have pointed out the ketoenol tautomerization between two kinds of crystal formations to distinguish.The position of this variation in three amidocarbonylations is unknown.But, polymorphic I IR data 2798cm
-1CH
2Vibration is split into polymorphic II data 2798 and 2776cm
-1Two shuttle belts, pointed out enolization may occur in the amide moieties adjacent, and may be subjected to the promotion of C-N amido link rotation with methylene.Two kinds of polymorphous FTIR spectrum as shown in Figure 2.Raman spectrum (Fig. 3) also shows the similar difference between two kinds of polymorphic powder.
PLM
Two kinds of polymorphics all show birefringence under micropolariscope.Therefore, two kinds of polymorphics all are crystalline, and are consistent with strong diffraction maximum in the PXRD pattern.Particle among the polymorphic I is significantly smaller than polymorphic II.
Thermodynamic stability
Differential scanning calorimetry (DSC)
Two kinds of polymorphous DSC scannings show different fusing points and different fusion enthalpies (table C).The fusing point of polymorphic II is higher about 3 ℃ than polymorphic I.Therefore, polymorphic II is the more stable polymorphic of thermodynamics near fusing point.The polymorphic II of higher melt also has higher fusion enthalpy.Therefore, these two kinds of solid crystal formations of " melting heat " rule prediction are monotropic relevant.Shown similar difference (about 3 ℃) by the observed fusing point of warm table microscopy.DSC and warm table microscopy are not all observed the calorifics incident under the temperature that is lower than every kind of polymorphic fusing point.
Table C: two kinds of polymorphous fusing point (T
m), fusion enthalpy (H
f) and intrinsic rate of dissolution (IDR)
| Physical property | Polymorphic I | Polymorphic II |
| T m(℃) a | 256.3 | 259.4 |
| H f(J/g) a | 55.78 | 85.44 |
| IDR(n＝3) b(mg/min/cm 2) | 1.08±0.09 c | 3.54±0.15 |
aUtilize dsc measurement fusing point and fusion enthalpy.Fusing point is regarded as initial temperature.
bPH=2 buffer (0.01N HCl, 0.05M KCl), 23 ℃
cThe inversion of phases of polymorphic I experience solution mediation.Measured IDR value is not represented the true IDR of polymorphic I.
PXRD
In order to measure two kinds of relatively hot mechanical stability relations between the polymorphic, also utilize PXRD at room temperature to study the serosity transformation experiment.The result is shown in table D.
The technical staff will recognize, relevant polymorphous thermodynamic stability will depend on a large amount of factors, include but not limited to sample size, stir speed (S.S.) (if stirred sample), whether use relative scale, solvent for use and temperature between crystal seed, the existing polymorphic.
Table D: suspension crystallization condition and by gained solid polymorphic attribute that PXRD differentiated
| Solvent | Initial solid a | PXRD gained solid |
| Methanol | The crystal seed of I+II | II |
| Ethanol | The crystal seed of I+II | ND b |
| Acetonitrile | The crystal seed of I+II | ND b |
| Acetone | The crystal seed of I+II | II |
| THF | The crystal seed of I+II | I |
| DMSO+H 2O(1∶1，v∶v) | The crystal seed of I+II | ND b |
| Methanol | I+II(2∶1，w/w) | II |
aHere used polymorphic I is 2008 batches.Here used polymorphic II is 35282-CS-11.
bMost solid is passed through filter paper.Not collecting enough materials analyzes for PXRD.
In the 10ml vial, polymorphic I that 20mg is independent and trace polymorphic II crystal seed are suspended in all kinds of solvents.Stir suspension with the magnetic puddler and reached for 2 weeks, cross filter solid then, analyze with PXRD.The result shows that methanol and acetone suspension obtain pure polymorphic II, that is to say the mediation that is subjected to two kinds of solvents, and polymorphic I is converted into polymorphic II.Therefore, the Notes of Key Data, polymorphic II is that thermodynamics is more stable than polymorphic I at room temperature.Because polymorphic II also is more stable near fusing point, two kinds of polymorphics are monotropic relevant, that is to say that polymorphic II is more stable from the room temperature to the fusing point.But, as if polymorphic I is stable in oxolane (THF) suspension.Because the dissolubility in THF is higher than in acetone (Table A), low solubility is not the dynamic (dynamical) reason of slow-speedization.
Although not wishing to accept opinion limits, but might in solution, interact uniquely in 5-[5-fluoro-2-oxo-1 by the THF molecule, the 2-indylidene-(3Z)-ylmethyl]-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide molecule, suppress nucleation and the crystal growth of polymorphic II, causing polymorphic I subsequently is dynamic stabilization in THF.
The preparation of polymorphic I and II is described below.
The preparation of polymorphic I: method 1
With 24.8mg 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is dissolved in (6ml at least) pH2 buffer (0.01N HCl, 0.04M KCl) in right amount fully, heats on hot plate simultaneously.Solution was cooled off in fuming cupboard 5 minutes.Add 1N NaOH solution, bring out from solution and precipitate.Solid does not contain polymorphic II, mainly is made of polymorphic I, has certain amorphous feature.
The preparation of polymorphic I: method 2
With 41.3mg 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide mixes with 25ml oxolane (THF) and 5ml water.With the mixture slightly heated, with dissolved solid.The gained settled solution is collected in the vial of uncapping, so that evaporating solvent.Precipitation betides in an amount of solvent evaporation.Precipitation is made of needle-shaped crystals, shown in microscopic examination.Leach precipitation, the slight grinding used XRD analysis then.Grind and reduce the solid particle diameter of gained, reduce the crystal preferred orientation effect on the PXRD pattern.PXRD result shows that solid is pure polymorphic I.
The preparation of polymorphic II
Will about 6mg 5-(5-fluoro-2-oxo-1,2-indylidene-3-ylmethyl)-2,4-dimethyl-1H-pyrroles-3-carboxylic acid (2-pyrrolidine-1-base ethyl) amide is dissolved in 20ml methanol at least, obtains settled solution.Slightly heated can promote solid dissolving.With this methanol solution cooling, slowly be evaporated to dried at ambient temperature.Add then small amount of methanol (～2ml), with dissolving part solid.The residue crystal is polymorphic II.
Those skilled in the art can easily determine not deviate from its spirit and scope by inner characteristic of the present invention from above-mentioned explanation, can carry out variations and modifications of the present invention, to adapt to various uses and condition, need not extra experiment.
Claims (26)
1. formula I chemical compound:
It has PXRD pattern shown in Fig. 1 II type.
2. formula I chemical compound:
It has PXRD pattern shown in Fig. 1 I type.
3. compositions comprises the formula I chemical compound of claim 2:
Wherein said chemical compound accounts for more than about 85 percentage by weights of compositions.
4. the compositions of claim 3, wherein said chemical compound accounts for more than about 90 percentage by weights of compositions.
5. the compositions of claim 3, wherein said chemical compound accounts for more than about 95 percentage by weights of compositions.
6. the compositions of claim 3, wherein said chemical compound accounts for more than about 99 percentage by weights of compositions.
7. compositions comprises the formula I chemical compound of claim 1:
Wherein said chemical compound accounts for more than about 85 percentage by weights of compositions.
8. the compositions of claim 7, wherein said chemical compound accounts for more than about 90 percentage by weights of compositions.
9. the compositions of claim 7, wherein said chemical compound accounts for more than about 95 percentage by weights of compositions.
10. the compositions of claim 7, wherein said chemical compound accounts for more than about 99 percentage by weights of compositions.
11. the polymorphic of the formula I chemical compound of claim 2:
Wherein said polymorphic prepares by following process:
(a) described chemical compound is dissolved in acidic aqueous solution;
(b) the described aqueous solution that alkalizes is settled out described chemical compound thus; With
(c) separate sedimentary described chemical compound.
12. the polymorphic of the formula I chemical compound of claim 2:
Wherein said polymorphic prepares by following process:
(a) described chemical compound is dissolved in the polar organic solvent that does not generate hydrogen bond;
(b) evaporate described polar organic solvent, be settled out described chemical compound thus; With
(c) separate sedimentary described chemical compound.
13. the polymorphic of the formula I chemical compound of claim 1:
Wherein said polymorphic prepares by following process:
(a) described chemical compound is dissolved in the polar organic solvent that generates hydrogen bond;
(b) evaporate described polar organic solvent, be settled out described chemical compound thus; With
(c) separate sedimentary described chemical compound.
14. by the prepared polymorphic of the method for claim 12, the wherein said polar organic solvent that does not generate hydrogen bond is THF.
15. by the prepared polymorphic of the method for claim 13, the polar organic solvent of wherein said generation hydrogen bond is a methanol.
16. pharmaceutical composition comprises chemical compound and the pharmaceutically acceptable carrier or the excipient of one of claim 1 or 2.
17. the purposes of the chemical compound of one of claim 1 or 2 in producing the kinase catalytic active compositions of modulin.
18. the purposes of claim 17, wherein said protein kinase is selected from the group of being made up of receptor tyrosine kinase, nonreceptor tyrosine kinase and serine-threonine kinase.
19. chemical compound of one of the claim 1 of treatment effective dose or 2 and pharmaceutically acceptable carrier or the excipient purposes in the pharmaceutical composition of production for treating or prevention organism protein kinase associated disorders.
20. the purposes of claim 19, wherein said protein kinase associated disorders is selected from the group of being made up of receptor tyrosine kinase associated disorders, nonreceptor tyrosine kinase associated disorders and serine-threonine kinase associated disorders.
21. the purposes of claim 19, wherein said protein kinase associated disorders is selected from the group of being made up of EGFR associated disorders, PDGFR associated disorders, IGFR associated disorders, c-kit associated disorders and flk associated disorders.
22. the purposes of claim 19, wherein said protein kinase associated disorders is a cancer, is selected from the group of being made up of leukemia, the brain cancer, nonsmall-cell lung cancer, squamous cell carcinoma, astrocytoma, Kaposi, glioblastoma, pulmonary carcinoma, bladder cancer, a cancer, neck cancer, melanoma, ovarian cancer, carcinoma of prostate, breast carcinoma, small cell lung cancer, glioma, mastocytosis, mastocyte overexpression, colorectal carcinoma, urogenital cancer and gastrointestinal stromal cancer.
23. the purposes of claim 19, wherein said protein kinase associated disorders is selected from the group of being made up of diabetes, autoimmune obstacle, hyper-proliferative obstacle, restenosis, fibre modification, psoriasis, hippel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogenesis, inflammatory disorder, immunology obstacle and cardiovascular disorder.
24. the purposes of claim 19, wherein said organism is the people.
25. chemical compound of one of claim 1 or 2 and pharmaceutically acceptable carrier or the purposes of excipient in the pharmaceutical composition of production for treating house pet cancer.
26. the purposes of claim 25, wherein said house pet are cat or Canis familiaris L..
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US44886303P | 2003-02-24 | 2003-02-24 | |
| US60/448,863 | 2003-02-24 | ||
| US10/776,337 | 2004-02-12 | ||
| US10/776,337 US7452913B2 (en) | 2003-02-24 | 2004-02-12 | Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors |
| PCT/US2004/005281 WO2004076410A2 (en) | 2003-02-24 | 2004-02-23 | Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors |
Publications (2)
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| CN1771032A CN1771032A (en) | 2006-05-10 |
| CN1771032B true CN1771032B (en) | 2010-06-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2004800050217A Expired - Lifetime CN1771032B (en) | 2003-02-24 | 2004-02-23 | Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors |
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| Country | Link |
|---|---|
| CN (1) | CN1771032B (en) |
| AR (1) | AR043230A1 (en) |
| GT (1) | GT200400024A (en) |
| NL (1) | NL1025551C2 (en) |
| PA (1) | PA8596301A1 (en) |
| PE (1) | PE20050225A1 (en) |
| TW (1) | TW200505853A (en) |
| UY (1) | UY28204A1 (en) |
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2004
- 2004-02-18 TW TW093103939A patent/TW200505853A/en unknown
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- 2004-02-20 UY UY28204A patent/UY28204A1/en not_active Application Discontinuation
- 2004-02-20 PE PE2004000177A patent/PE20050225A1/en not_active Application Discontinuation
- 2004-02-23 CN CN2004800050217A patent/CN1771032B/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| UY28204A1 (en) | 2004-09-30 |
| CN1771032A (en) | 2006-05-10 |
| TW200505853A (en) | 2005-02-16 |
| AR043230A1 (en) | 2005-07-20 |
| GT200400024A (en) | 2004-10-04 |
| NL1025551A1 (en) | 2004-08-26 |
| PE20050225A1 (en) | 2005-04-19 |
| PA8596301A1 (en) | 2005-08-04 |
| NL1025551C2 (en) | 2005-03-14 |
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