MX2008007436A - Lestaurtinib crystalline form 1, crystalline lestaurimib anhydrate and amorphous lestaurimib - Google Patents
Lestaurtinib crystalline form 1, crystalline lestaurimib anhydrate and amorphous lestaurimibInfo
- Publication number
- MX2008007436A MX2008007436A MXMX/A/2008/007436A MX2008007436A MX2008007436A MX 2008007436 A MX2008007436 A MX 2008007436A MX 2008007436 A MX2008007436 A MX 2008007436A MX 2008007436 A MX2008007436 A MX 2008007436A
- Authority
- MX
- Mexico
- Prior art keywords
- crystalline
- lestaurtinib
- lestaurtmib
- approximately
- solvent
- Prior art date
Links
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Abstract
Lestaurtinib Crystalline Form 1, isolated crystalline lestaurtinib anhydrate and amorphous lestaurtinib, processes to reproducibly make them and methods of treating patients using them.
Description
of the same. Lestaurtinib of different crystalline forms can have different melting points, solubilities or ranges of solubility, whose physical properties, either alone or in combination, can affect its bioavailability. Due to the knowledge of crystallinity, or high cost thereof, of the lestaurtinib a guidance can be provided during the clinical development, there is an existing need for the identification of different crystalline forms of lestaurtinib, processes to effect reproducibility of these and methods to treat patients using these .
Brief Description of the Invention One embodiment of this invention, therefore, relates to Lestaurtinib Crystalline Form 1, when measured at approximately 25 ° C with Cu-Ka radiation, by a powder diffraction pattern with at least three peaks. which have respective 2T values of approximately 6.8 °, 8.5 °, 9.7 °, 12.0 °, 13.2 °, 14.2 °, 14.7 °, 15.0 °, 15.5 °, 16.9 °, 17.5 °, 17.9 °, 19.3 °, 20.0 °, 20.4 °, 25.1 °, 25.6 °, 25.8 °, 26.3 ° or 26.6 °. Another embodiment refers to Form 1 Crystalline Lestaurtinib characterized in the triclinic crystal system and space group P1, when it is measured at approximately -100 ° C with Mo-Ka radiation, by means of reticular parameters a, b and c of 11.235 ± 0.002. , 13,317 ± 0.004Á, 7,095? ± 0.003Á, respectively, and a, ß y y of 92.33 ° ± 0.03 °, 107.78 ± 0.02 ° and 100.95 ° ± 0.02 °, respectively.
Another embodiment refers to compositions comprising or being made from Form 1 Crystalline Lestaurtinib and an excipient. Another embodiment relates to a method for treating patients having a condition caused or exacerbated by unregulated or overexpressed tyrosine kinase receptor comprising administering to them a therapeutically acceptable amount of a
Form 1 Crystalline of Lestaurtinib. Another embodiment relates to a method for treating patients having acute myeloid leukemia comprising administering to them a therapeutically acceptable amount of Form 1 Crystalline Lestaurtinib. Another embodiment relates to a method for treating patients having chronic myeloid leukemia comprising administering to them a therapeutically acceptable amount of Form 1 Crystalline Lestaurtinib. Another embodiment relates to a method for treating patients having acute lymphocytic leukemia comprising administering to them a therapeutically acceptable amount of Form 1 Crystalline Lestaurtinib. Another embodiment relates to a method for treating patients having chronic lymphocytic leukemia comprising administering to them a therapeutically acceptable amount of Form 1 Crystalline Lestaurtinib. Another modality refers to a process to elaborate Form 1
Crystalline Lestaurtinib comprising: making lestaurtinib, or a solvate thereof, and isolating or not isolating lestaurtinib, or the solvate thereof; providing a mixture comprising lestaurtinib, or the solvate thereof, and solvent, wherein the lestaurtinib, or the solvate thereof, is completely dissolved in the solvent; cause Form 1 Crystalline Lestaurtinib to exist in the mixture, Crystalline Form 1 of Lestaurtinib, when isolated and characterized in the triclinic crystal system and space group P1 at approximately -100 ° C with o-Ka radiation, by reticular parameters a, b and c of 11.235Á ± 0.002Á, 13.317 ± 0.004Á, 7.095 Á ± 0.003Á, respectively, ya, ß yy of 92.33 ° ± 0.03 °, 107.78 ± 0.02 ° and 100.95 ° ± 0.02 °, respectively; and isolate Crystalline Form 1 from Lestaurtinib. Another embodiment refers to a process for making Lestaurtinib Crystalline Form 1 comprising: making lestaurtinib, or a solvate thereof, and isolating or not isolating lestaurtinib, or the solvate thereof; providing a mixture comprising lestaurtinib, or the solvate thereof, and solvent, wherein the lestaurtinib is completely dissolved and the solvent is supersaturated with lestaurtinib; cause Form 1 Crystalline Lestaurtinib to exist in the mixture, Form 1 Crystalline Lestaurtinib, when isolated and
characterized in the tpclinic crystal system and space group P1 at approximately -100 ° C with Mo-Ka radiation, by means of lattice parameters a, b and c of 11 235A ± 0002Á, 13317 ± 0004Á, 7095 A ± 0003Á, respectively, ya, ß yy of 9233 ° ± 003 °, 10778 ± 002 ° and 10095 ° ± 002 °, respectively, and isolate Lestaurtinib Crystalline Form 1 Another modality refers to a process to elaborate Lestaurtmib Crystalline Form 1 which comprises making and isolating or not isolate lestaurtmib or a solvate thereof, provide a mixture comprising the lestaurtmib and solvent, wherein the lestaurtinib is partially soluble in the solvent, allow Lestaurtinib Crystalline Form 1 to develop in the mixture, and isolate Form 1 Crystalline from Lestaurtinib. "modality" refers to a process of making Lestaurtinib Crystalline Form 1 comprising, preparing and isolating or not isolating lestaurtinib or a solvate thereof, providing a mixture comprising e lestaurtinib and ethanol, in which lestaurtmib is partially soluble in ethanol, allow Form 1 Crystalline of Lestaurtinib to develop in the mixture, and isolate Crystalline Form 1 of Lestaurtmib Another modality refers to a process to elaborate Crystalline Form 1 of Lestaurtinib comprising
providing a mixture comprising lestaurtinib and ethanol at about 0 ° C to about 33 ° C, wherein lestaurtinib is partially soluble in ethanol; allow Form 1 Crystalline Lestaurtinib to develop in the mixture; and isolate Crystalline Form 1 from Lestaurtinib. Another embodiment refers to isolated crystalline lestaurtinib anhydrate. Another embodiment refers to compositions comprising or being made from isolated crystalline lestaurtinib anhydrate and an excipient. Another embodiment refers to treating patients having a condition caused or exacerbated by unregulated or overexpressed tyrosine kinase receptor comprising administering to them a therapeutically acceptable amount of isolated crystalline lestaurtinib anhydrate. Another embodiment relates to a method for treating patients having acute myeloid leukemia comprising administering to them a therapeutically acceptable amount of crystalline lestaurtinib anhydrate isolated. Another embodiment relates to a method for treating patients having chronic myeloid leukemia comprising administering to them a therapeutically acceptable amount of crystalline lestaurtinib anhydrate isolated. Another embodiment refers to a method for treating patients
having acute nphocytic leukemia comprising administering to them a therapeutically acceptable amount of crystalline Lestaurtmib anhydrate isolated Another embodiment relates to a method of treating patients having chronic lymphocytic leukemia comprising administering to them a therapeutically acceptable amount of crystalline lestaurtmib anhydrate isolated Another embodiment relates to a process for making isolated crystalline lestaurtmib anhydrate comprising making crystalline lestaurtmib anhydrate or a mixture of crystalline lestaurtmib hydrates, removing water from crystalline lestaurtmib hydrate or mixtures of crystalline lestaurtinib hydrates, and isolating crystalline lestaurtinib anhydrate Another embodiment refers to a process for making isolated crystalline lestaurtinib anhydrate which comprises making a crystalline lestaurtmib anhydrate or the mixture of crystalline lestaurtinib hydrates, heating the hydrate of crystalline lestaurtmib or the mixture of crystalline lestaurtmib hydrates above about 40 ° C, with or without a desiccant and under an aspiration of less than 760 mm Hg or at approximately 760 mm Hg, and isolating the crystalline lestaurtmib anhydrate
Another embodiment refers to a process for making crystalline lestaurtmib anhydrate isolated which comprises making crystalline lestaurtinib anhydrate or a mixture of crystalline lestaurtinib hydrates, heating the crystalline lestaurtmib hydrate or the mixture of crystalline lestaurtmib hydrates between about 80 ° C and 100 ° C, with or without a desiccant and under an aspiration of less than 760 mm Hg or approximately 760 mm Hg, isolate the crystalline lestaurtinib anhydrate Another modality refers to a process to elaborate Form 1
Crystalline of Lestaurtmib comprising treatment of a carboxyl intermediate protected in said process with a reducing agent and then refining or recutting said lestaurtinib for said Crystalline Form 1 of Lestaurtmib, wherein said process comprises direct crystallization of Form 1 Crystalline Lestaurtmib from a solid, semi-base or honey having therewith one or more than one solvent from said reduction of protected carboxylic acid intermediate Another embodiment refers to a process for making Form 1 Crystalline Lestaurtmib comprising treatment of an intermediate of carboxyl protected in said process with a reducing agent and subsequently depstable or recrystallized said lestaurtinib for said Lestaurtmib Crystalline Form 1, said process comprising direct crystallization of Form 1 Crystalline Lestaurtmib from a solid having thereby one or more from
a solvent from the group consisting of water, tetrahydrofuran, toluene, methanol and ethanol from said carboxylic acid deprotection reaction. Another embodiment refers to a process for making Lestaurtinib Crystalline Form 1 comprising treatment of a carboxyl intermediate. protected in said process with a lithium aluminum hydride or sodium borohydride and subsequently cpstalinizing or recrystallizing said lestaurtinib for said Lestaurtinib Crystalline Form 1, wherein said process comprising direct crystallisation of Form 1 Crystalline Lestaurtmib from a solid which it has therewith one or more than one solvent from the group consisting of water, tetrahydrofuran, toluene, methanol and ethanol from said deprotection reaction of carboxylic acid Another embodiment refers to a process for making Form 1
Crystalline Lestaurtmib comprising treatment of methyl (9S-9a, 10β, 12a)) - 2,3,9,10,11,12-hexahydro-10-hydroxyl-10- (carboxylate) - 9-met? L-9,12-epoxy-1H-dnndol [1,2,3-fg 3 ', 2, 1-kl] p? Rrol [3,4-?] [1,6] benzod? Azoc n-1-one with a reducing agent, and subsequently rectally recrystallize said lestaurtinib for said Lestaurtmib Crystalline Form 1, wherein said process comprises direct crystallisation of Form 1 Crystalline Lestaurtmib from a solid, semi-solid or honey that has with it one or more than one solvent from said reduction of protected carboxylic acid intermediate
Another embodiment refers to a process to make Lestaurtmib Crystalline Form 1 comprising treatment of methyl (9S-9a, 10β, 12a)) - 2,3,9,10,11,12-hexahydr-10-h? drox? -10- (carboxylate) -9-methyl-9,12-epoxy-1H-dnndol [, 2,3-fg 3, 2, 1-kl] pyrrole [3,4-?] [1, 6] benzod? Azoc? N-1-one with a reducing agent and subsequent cisplatin or rectallyseed said lestaurtmib for said Lestaurtmib Crystalline Form 1, wherein said process comprising direct crystallization of Form 1 Crystalline Lestaurtmib from a solid having therewith one or more than one solvent from the group consisting of water, tetrahydrofuran, toluene, methanol and ethanol from said carboxylic acid deprotection reaction. Another embodiment refers to a process for making Form 1 Crystalline from Lestaurtmib comprising treatment of methyl (9S-9a, 10β, 12a)) - 2,3,9,10,11,12-hexahydro-10-hydroxyl-10- (carboxylate) -9- methyl - 9,12 - epoxy - 1 H - dnndol [1,2,3 - fg 3 ', 2, 1 - k l] pyrrole [3,4-?] [1,6] benzod? azoc? n-1-one with a lithium aluminum hydride or sodium borohydride and cpstammize or subsequently recrystallize said lestaurtinib for said Crystalline Form 1 from Lestaurtinib, wherein said process comprising direct crystallisation of Form 1 Crystalline Lestaurtinib from a solid, semi-solid or honey having therewith one or more than one solvent from the group consisting of water, tetrahydrofuran, toluene, methanol and ethanol from said carboxylic acid deprotection reaction. Another embodiment refers to a process for making Form 1
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Crystalline Lestaurtmib comprising treatment of (9S-9a, 10β, 12a)) -2,3,9,10,11, 12-hexah id ro-10-h? Drox? -10- (carbox?) - 9- methyl-9,12-epox? -1H-dnndol [1,2,3-fg 3 ', 2, 1"-kl] pyrrole [3,4-?] [1,6] benzod? azoc? n-1 -one with a reducing agent and subsequently cpstahnizing or recpstablishing said lestaurtmib for said Lestaurtmib Crystalline Form 1, wherein said process comprising direct crystallization of Form 1 Crystalline Lestaurtmib from a solid, semi-solid or honey that has thereby one or more of a solvent from said reduction of protected carboxylic acid intermediate. Another embodiment refers to a process for making Lestaurtinib Crystalline Form 1 comprising treatment of (9S-9a, 10β, 12a)) -2.3, 9,10,11, 12-hexah id ro-10-h? Drox? -10- (carbox?) - 9-methyl-9,12-epoxy -1H-d? Ddol [1,2,3-fg 3, 2, 1-kl] pyrrole [3,4-?] [1,6] benzod? Azoc? N-1-one with a reducing agent and subsequently cpstalinize or recptalize ho lestaurtmib for said Lestaurtmib Crystalline Form 1, wherein said process comprising direct cstastalisation of Lestaurtmib from a solid having therewith one or more than one solvent from the group consisting of water, tetrahydrofuran, toluene, methanol and Ethanol from said carboxylic acid deprotection reaction Another embodiment relates to a process for making Form 1 Crystalline Lestaurtmib comprising (9S-9a, 10β, 12a)) -2,3,9,10,11 treatment, 12 - hexahydro-10-hydroxy? -10- (carbox?) - 9-methyl-9,12-epoxy-1 H-dundol [1,2,3-fg 3, 2 ', 1-kl] pyrrolo [3,4-?] [1,6]
12
benzod? azoc? n-1-one with a lithium aluminum hydride or sodium borohydride and subsequently cystestamize or reclassify said lestaurtinib for said Lestaurtmib Crystalline Form 1, wherein said process comprises direct crystallization of Form 1 Crystalline Lestaurtmib from of a solid which has therewith one or more than one solvent from the group consisting of water, tetrahydrofuran, toluene, methanol and ethanol from said carboxylic acid deprotection reaction. Another embodiment refers to amorphous lestaurtmib. Another embodiment refers to to compositions comprising or made from amorphous lestaurtinib and an excipient. Another embodiment refers to treating patients having a condition caused or exacerbated by unregulated or overexpressed tyrosine kinase receptor comprising administering to them a therapeutically acceptable amount. of amorphous lestaurtmib Another modality refers to a method to treat patients who in acute myeloid leukemia comprising administering to them a therapeutically acceptable amount of amorphous lestaurtmib. Another embodiment refers to a method of treating patients having chronic myeloid leukemia comprising administering to them a therapeutically acceptable amount of amorphous lestaurtmib. Another modality refers to a method to treat patients who have acute lymphocytic leukemia which comprises administering
these a therapeutically acceptable amount of amorphous lestaurtinib. Another embodiment refers to a method of treating patients having chronic lymphocytic leukemia comprising administering to them a therapeutically acceptable amount of amorphous lestaurtmib.
Detailed Description of the Invention Crystalline forms different from a given drug have physical, pharutical, physiological and biological properties that can differ markedly from one to another. This invention relates to crystalline forms of lestaurtmib and amorphous lestaurtmib It is intended that it be understood that the term "lestaurtinib", as used herein, without a cpstahnity designation or lack thereof, means a particular or amorphous crystalline form of lestaurtmib, lestaurtinib in solution or a mixture thereof. Lestaurtmib Crystalline Form 1 is the form crystalline more thermodynamically stable of lestaurtinib at room temperature (approximately 25 ° C) It is a non-hygroscopic crystalline form that has less than 005% humidity, as determined by thermogravimetric analysis (TGA) Additionally, it is not known that Form 1 undergoes conversion of solid state despite the temperature or relative humidity (RH)
Crystalline lestaurtmib tphidrate is stable at RH from about 45% to about 95% at room temperature. Crystalline lestaurtmib monohydrate is stable at about 10% to 40% RH at about 25 ° C at room temperature and above RH at 40 ° C. %, the monohydrate quickly becomes tphidrate When it is ground by hand and with a mortar, the ability of the relative lestaurtmib monohydrate to absorb water is reduced by a factor of about 6 Thus it takes approximately 6 times more to absorb water amounts when it is ground that when it is not ground Lestaurtinib monohydrate can be made by exposing the tphidrate to RH levels of 40% or less at room temperature or by heating the tphidrate between 80 ° C and 200 ° C, followed by exposure to Environmental conditions for approximately 10 minutes After the exposure period, the sample should be stored in a container The crystalline lestaurtmib anhydrate is stable at room temperature between RH of about 0% and about 5% to form crystalline lestaurtmib monohydrate The existence of crystalline lestaurtinib anhydrate was demonstrated by dynamic moisture sorption gravimetry (DMSG) which showed, at 25 ° C, a phase of solid state between RH of 0% and 5% with less than 05% of water Because the crystallization of humidity
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mediated was not observed during the levels of RH between 5% and 10%, it was concluded that the solid at RH of 5% was crystalline, and due to the solid content less than 05% of water, it was also determined that it was an anhydrate The anhydrate of crystalline lestaurtinib can be produced by either exposing a crystalline lestaurtmib anhydrate to RH levels of 5% or less at room temperature or by heating the tphidrate between 80 ° C and 200 ° C and storing the product under moisture-free conditions The sample can absorb water from the atmosphere during the transfer period The hemiacetonitpleate of crystalline lestaurtinib hemihydrate is a crystalline mixed solvate with approximately V = - mol equivalent of water and approximately A mol equivalent of acetonitoplo The solvents are entrapped within the lattice crystal and can be removed by heating a sample between 130 ° C and 220 ° C The data of the X-ray diffraction (PXRD) of powder obtained with a model unit X1 Scintag with a copper target (radiation of wavelength Á1 54060, 45 Kv and 40 ma) scanning speed 1 ° per continuous minute, and a scanning speed of 2-40 ° 20T at temperature environment using a Peltier cooled detector tuned for copper radiation All XRPD samples were gently ground to obtain a fine powder by hand and in mortar before analysis
16
The differential scanning calorimetry (DSC) data were obtained using a Model 3100 Thermal Analysis of TA Instruments with a Model 2910 DCS Module. The samples were prepared in a closed non-compressed aluminum mold. Typical DSC sample weights were approximately 1-4 mg. The thermograms were acquired at a heat range of 5 ° C per minute under nitrogen purge with a flow range of approximately 40 mL per minute. Thermograms of crystalline Form 1 of Lestaurtinib and amorphous lestaurtinib were obtained between room temperature and approximately 330 ° C. Form 1
Crystalline Lestaurtinib exhibited an endotherm with onset at 268.2 ° C and peak temperature at 277.4 ° C. Amorphous lestaurtinib exhibited a broad endotherm with onset at 26.6 ° C and peak temperature at 57.0 ° C.
The TGA data were obtained using a Thermal Analysis 5200 and Model 3100 of TA Instruments with a TGA Hi Res Model 2950 module. The thermograms were acquired at a heating range of 5 ° C per minute, under nitrogen purge with a degree of flow of approximately 40 mL per minute. Crystalline Form 1 of Lestaurtinib exhibited weight loss of 0.04% at approximately 100 ° C. Amorphous lestaurtinib exhibited weight loss of 5.56% at approximately 184 ° C. Dynamic moisture sorption gravimetry (DMSG) data (hygroscopicity ) were obtained in a sorption microbalance Model MB 300 G from Corporation VTI using aspirate to control RH. The automatic system controlled the HR and the temperature
17
to which each sample was exposed, while the weight of the samples recorded changed continuously The sorption and desorption isotherms were made at RH of 25 ± 0 1 ° C with intervals of the RH step of 5 ± 1% from RH of 0-95% Samples of approximately 30 mg were dried under vacuum for up to 3 hours (approximate RH = RH of 01%) before each experiment The weight loss observed during the drying period was used to estimate how well it was sustained each sample in the water After the drying period, the sorption osoterms started at 5% RH. An equilibrium of the critical weight of less than the 5 mg weight change during three periods of 5 minutes was used to continue to the next step. equilibrium conditions were reached by the passage of RH of 95%, the isotherm of desorption was initiated. The crystalline Form 1 of Lestaurtmib exhibited moisture taken up to approximately 04% with an equilibrium moisture content (EMC or mol of water per mole of drug) of approximately 01 and a nominal moisture taken up to approximately 02% (w / w) with an EMC of approximately 005 This means that any water present in the sample was surface water and not water from the reticule The solubility of crystalline Form 1 of Lestaurtmib and anhydrous lestaurtmib at 26 ° C and 28 ° C was determined using HPLC The saturated solutions of the solid state phase in ethanol (200 proof) were obtained by stirring a sample in ethanol for two days at 26 ° C and at 2-8 ° C After shaking, each solution was
filtered through a micro filter of 0.45 μm and the level of CEP-701 was determined by HPLC. The solubility data are presented in Table 1.
Tal) I a 1 Solubility of Form 1 Crystalline of Lestauítinib and Anhydrous Lestaurtinib in Proot'200 Ethanol
These data demonstrate differences in a particular physical property (i.e. solubility) of lestaurtinib. To determine the more stable crystalline form of lestaurtinib, the forms of lestaurtinib were agitated with Proof 200 ethanol for 48 hours at 26 ° C and at 2-8 ° C. The forms of lestaurtinib that remained were analyzed by PXRD to determine if any crystal shape conversion. The results, in Table 2, show that each form of lestaurtinib tested was converted to Crystalline Form I of Lestaurtinib, indicating that Crystalline Form 1 of Lestaurtinib is the most stable crystalline form of lestaurtinib at room temperature and at 2-8 ° C.
Tibia 2 Crystalline Form of Lestaurtmib After Contact with Ethanol Proof 200 by 43 Hours Form Before Ezclar with Shape After Use with Ethanol by Rtannl 48 H "ir s 2- 8 ° C 26 ° C 1 1 1 hydrated 1 1 hemi hydrate / acetonitrileate 1 1 amorphous 1 1
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The term "amorphous" as used herein means a supercooled liquid or a viscous liquid which looks like a solid but does not have a regularly repeated placement of molecules that is maintained over a range and does not have a melting point but rather is softens or softens above its transition temperature. The term "anti-solvent", as used herein, means a solvent in which a compound is substantially insoluble. The term "Crystalline Form 1 of Lestaurtinib", as used herein, means the Thermodynamically more stable crystalline form of lestaurtmib at 25 ° C The term "crystalline", as used herein, means that it has a regularly repeated placement of molecules or planes of external face. The term "isolated" as used herein, means to separate a compound of a solvent, anti-solvent, or a mixture of solvent and anti-solvent to provide a semi-solid solid or honey This is typically accompanied by means such as centrifugation, filtration with or without aspiration, filtration under positive pressure, distillation, evaporation or a combination thereof Isolating may or may not be accompanied by purification during which the purity of the chemical, chiral or chemical and chiral isolate is increased The purification is typically conducted by means such as crystallization, distillation, extraction, filtration through basic or neutral acidic alumina, filtration through acidic, basic or neutral carbon, chromatography column in a
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column packed with a chiral stationary phase, filtration through a porous glass or glass barrier, silica gel column chromatography, ion exchange chromatography, recrystallization, normal phase high resolution liquid chromatography, high performance liquid chromatography reverse phase resolution, grinding and the like The term "miscible" as used herein means capable of combining without phase separation. The term "solvate" as used herein means that it has a surface, a lattice or a surface and in a grid, a solvent such as water, acetic acid, acetone acetone, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-d-oxane, ethanol, ethyl acetate, butanol, tert-butanol, N , Nd? Mettaltam? Da, N, Nd? Met? Lformam formamide, formic acid, heptane, hexane, isopropanol, methanol, ethyl methyl ketone, 1-met? L-2-p? Rrol? D? Nona , mesitylene, nitromethane, po eti glycol, propanol, 2-propanone, pipdin, tetrahydrofuran, toluene, xylene, mixtures thereof and the like A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or on the surface and in the the grid is water Hydrates may or may not have other solvents than water on the surface, in the grid or on the surface and in the grid of the substance The term "solvent", as used herein, means a substance, typically a liquid, which is capable of partially or completely dissolving another substance, typically a solid Solvents
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for the practice of this invention include water, acetic acid, acetone, acetonitop, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1,4-d-oxane, ethanol, ethyl acetate, butanol, tert-butanol, N, Nd? Met? Lacetam? Da, N, Nd? Metformal? Da, formamide, formic acid, heptane, hexane, isopropanol, methanol, ethyl methyl ketone, 1-met? L-2-p? Rrol? D? None , mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pipdin, tetrahydrofuran, toluene, xylene, mixtures thereof and the like The term "supersaturated" as used herein, means having a compound in a solvent in which it is completely dissolved at a certain temperature but at which the solubility of the compound in the solvent at that certain temperature is exceeded. Unless stated otherwise, the percentages established through this specification are percentages of weight / weight (w / w). which comprise lestaurtmib and solvent may or may not have im Diastereopropic and chemical purities, which, if present, may be completely soluble, partially soluble or essentially insoluble in the solvent. The level of diastereomeric or chemical impurity in the mixture may be lower before or during the Lestaurtmib Crystalline Form isolation by means of such as distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral carbon, column chromatography on a column packed with a chiral stationary phase, filtration at
22
Through a barrier of porous plastic or glass paper, gel column chromatography, ion exchange chromatography, recrystallization, normal phase high resolution liquid chromatography, reverse phase high performance liquid chromatography, grinding and the like Causing the crystalline Form 1 of Lestaurtmib to exist in a mixture comprising lestaurtmib and solvent, wherein the lestaurtinib is completely dissolved in the solvent, is nucleation In a preferred embodiment for the practice of this invention the nucleation of crystalline Form 1 Lestaurtmib is made to occur in a solvent that is supersaturated with lestaurtinib Lestaurtmib mixtures and the solvent, where the lestaurtinib is completely dissolved in the solvent can be prepared from a crystalline lestaurtmib, amorphous lestaurtmib, a lestaurtinib solvate or a mixture thereof. For the practice of this invention, nucleation can be elaborated to occur in a solution by techniques that are well known to those skilled in the art such as solvent removal, temperature, addition solvent solvent solvent miscible solvent, non-miscible solvent anti-solvent addition, addition of Lestaurtinib Crystalline Form 1 seed crystal, wear or scratching the inside of the container, preferably a glass container with a glass rod or a glass bed or beds or by a combination of
2. 3
It is intended that it be understood that, because several solvents and anti-solvents contain impurities, the level of impurities in the solvents and anti-solvents for the practice of this invention, if present, is at sufficiently low concentration. so that it does not interfere with the intended use of the solvent when the impurities are present. The solvents used were HPLC, reagent or USP grade and were used as received. The term "alkyl of 1 carbon atom" as it is here used, means methyl The term "2 carbon atom" as used herein means ethyl The term "3 carbon atom" as used herein means prop-1? and prop-2-? (isopropyl) The term "4-carbon-alkyl" as used herein, means but-1-? l, but-2-? l, 2-met? lprop-1-? ly. 2-methoprop-2? (Tert-butyl) The term "5-carbon atom" as used herein means 2,2-d? Met? Lprop-1-? (Neo-pentyl) , 2-met? Lbut-1-? L, 2-met? Lbut-2-? L, 3-met? Lbut-1-? L, 3-met? Lbut-2-? L, pent-l? The term "6 carbon atom" as used herein means 2,2-d? met? lbut-1-? l, 2,3-d? met L-but-1-yl, 2,3-d? met? lbut-2-? l, 3,3-d? met? lbut-1-? l, 3,3-d? met? lbut-2-? l, 2-et? lbut-1-? l, hex-1-? l, hex-
24
2-? L, hex-3-? L, 2-met? Lpent-1-yl, 2-met? Lpent-2-? L, 2-met? Lpent-3? L, 2-met? Lpent- 3-? L, 3-met? Lpent-1-? L, 3-met? Lpent-2-? L, 3-met? Lpent-3-? L, 4-met? Lpent-1-? Ly 4- met? lpent-2-? The term "protected carboxyl intermediate", as used herein, means an intermediate having a carboxyl C (O) OH ratio to which a carboxyl protecting group is attached. "carboxyl protection", as used herein, means a ratio that can be bound to a C (O) OH ratio to make it less susceptible to unwanted reactions during synthesis. Specific examples of carboxyl protection groups include, but are not limited to, phenyl, naphthyl, furanyl, imidazole, isothiazolyl, isoxazole, 1,2,3-oxadiazoyl, 1, 2,5-oxadidozol, oxazolyl, pyrazyl, pyrazolyl, pipdazmyl, pipdinyl, pipm id inyl, pyrrolyl, tetrazo it, thiazole, thiophenyl, thiazyl, 1,2,3-tr? azol? acetomethyl, a, benzoylmethyl, benzyloxymethyl, tert- butyldiphenylsilyl, diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, d-ifen-1-ylmethyl-1, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, para-nitrobenzyl, phenyl, 2,2,2-tr? -chloroetyl, t-phenylsilo, 2- (tr? met? l? l) et? l, 2- (tmetmet? l? l?) ethoxy? methole, tpphenylmethyl or alkyl of 1 carbon atom, alkyl of 2 carbon atoms, 3 carbon atoms, alkyl of 4 carbon atoms, alkyl of 5 carbon atoms or alkyl of 6 carbon atoms, each of which is unsubstituted or substituted by phenyl, naphthyl, furanyl, imidazolyl, isothiazolyl, isoxazole, 1, 2,3-oxad? Azole, 1, 2,5-oxad? Azole,
oxazolyl, pyrazinyl, pyrazolyl, pipdazinyl, pipdinyl, pipmidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, tpazinyl, 1,2,3-trolol and the like The invention provides methods for treating conditions and conditions in a patient comprising administer to it a therapeutically acceptable amount of lestaurtmib Accordingly, lestaurtmib is useful for treating a variety of therapeutic indications. For example, lestaurtinib is useful for the treatment of cancers such as carcinomas of the pancreas, prostate, breast, thyroid, colon and lung. , malignant melanomas, glioblastomas, derived neuroectodermal tumors including Wilm's tumor, neuroblastomas and medulloblastomas, and leukemias such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute hnfocytic leukemia (ALL), chronic nfocitic leukemia (CLL), pathological conditions of the prostate such as prostate cancer or hypertrophy, carcinomas of the pancreas, such omo pancreatic ductal adenocarcinoma (PDAC), hyperprophylactic disorders such as pro-therapeutic skin disorders including actinic keratosis, basal cell carcinoma, squamous cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberances, hamangioma, wine stain, xanthoma, Kaposi's sarcoma, mastocytosis, mycosis fungoides, lentigo, Nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, and various forms of psoriasis, including psoriasis vulgaps and psoriasis eosmophilia, myelosproductive disorders and
26
related disorders associated with JAK2 activation and myeloprotective disorders and related disorders including, but not limited to, febrile myelopic disorders such as, for example, polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MM), also called chronic idiopathic myelofibrosis (ICPM), unclassified myeloproliferative disorders (uMPDs), hypereosinophilic syndrome (HES), and systemic mastocytosis (SM). Lestaurtmib can be administered by any means that results in contact of the active agent with the site of the agent. action in the patient's body Lestaurtmib can be administered by any conventional means available, either as individual therapeutic agents or in combination with other therapeutic agents Lestaurtmib is preferably administered to patients who need it in therapeutically effective amounts for the treatment of padecim and The disorders described here Therapeutically effective amounts of lestaurtmib can be rapidly determined by a diagnosis of care through the use of conventional techniques. The effective dose may vary depending on a number of factors, including type and extent of disease progression or disorder, especially of the health of a particular patient, biological efficacy of lestaurtinib, formulation of lestaurtinib, and route of administration of lestaurtinib forms Lestaurtinib can
27
also be administered at lower dosage levels with gradual increase until the desired effect is obtained. As used herein, the term "approximately" refers to a range of values of ± 10% of a specified value. For example, the phrase "about 50 mg" includes ± 10% of 50 or from 45 to 55 mg. Typical dose ranges of lestaurtinib comprise from about 001 mg / kg to about 100 mg / kg of body weight per day or from about 001 mg / kg to 10 mg / kg of body weight per day Daily doses for human adults include approximately 20, 25 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 90, 100, 120, 140, 160 and 200 mg and an equivalent dose for a human child Lestaurtmib can be administered in one or more dosage unit forms and can also be administered one to four times a day, including twice daily (BID). Dosage ranges of lestaurtinib unit comprise approximately 1 to apr Approximately 400 mg administered one to four times a day, or approximately 10 mg to approximately 200 mg BID, or 20-80 mg BID, or 60-100 mg BID or approximately 40, 60, 80 or 100 mg BID Dosage forms of lestaurtmib may also be in the form of liquids or suspensions in a concentration of between 15 to 25 mg / mL, 16 mg / mL or 25 mg / mL. The liquid or suspension dosage forms of lestaurtmib may include
28
equivalent of the doses (mg) described above For example, dosages of lestarutinib may include 1 to 5 mL of the 25 mg / mL solution, or 1, 1 2, 1 4, 1 6, 1 8, 2, 22, 24, 26, 28, 3, 3.2, 34, 36, 38, or 4 mL of the 25 mg / mL solution, wherein a dose of 60 mg of lestaurtmib can be provided in 24 mL of solution, a dose of 80 mg of lestaurtmib can be provided in 32 mL of solution and a dose of 100 mg of lestaurtmib can be provided in 4 mL of solution Additionally, a dose of 20 mg of lestaurtmib can be provided with 1 25 mL of a solution of 16 mg / mL The daily dose of lestaurtmib can range from 1 mg to 5 mg / kg (normalization based on an average body weight of about 65 kg) For example, a daily dose of a form of lestaurtmib is approximately 1 to 3 mg / kg or approximately 1 2 to 25 mg / kg, or approximately 1 2, 1 4, 1 6, 1 8, 2, 22, 24, 26, 28, or 3 mg / kg In an alternative method of describing a effective dose, an oral unit dose of lestaurtmib is one that is necessary to obtain a serum level in the blood of approximately 005 to 20 μg / mL or 1 to 20 μg / mL in a patient. Lestaurtmib can be formulated in compositions pharmaceutical compositions by mixing the forms with one or more pharmaceutically acceptable excipients It is intended that it be understood that the pharmaceutical compositions include any form of lestaurtmib or any combination thereof
29
The term "pharmaceutically acceptable excipients" as used herein, includes any and all solvents, dispersion media, coatings, antifungal and antibacterial agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances. it is well known in the art, such as in Remington The Science and Practice of Pharmacy, 20th ed, Gennaro, AR, Ed, Lippmcott Williams & Wilkins Philadelphia, PA, 2000 Except where conventional means or agent is compatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplemental active ingredients may also be incorporated into the compositions. The excipients for the preparation of compositions comprising forms of lestaurtmib to be administered orally include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butyl glycol, carbomers, castor oil, cellulose, cellulose acetate, butter cocoa, corn starch, corn oil, cottonseed oil, povidone cross, diglypepdos, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, ground walnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, ma nitol, monoglyceptes, olive oil, peanut oil, potassium phosphate salts, potato starches, povidone, propylene glycol, Rmger's solution,
sunflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium laupl sulfate, sodium sorbitol, soybean oil, stearic acids, stearate fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuployl alcohol , tpglicépdos, water and mixtures thereof The excipients for the preparation of compositions comprising forms of lestaurtmib to be orally or orally administered include, for example, 1,3-butylene glycol, castor oil, corn oil, oil of cottonseed, ethanol, sorbitan fatty acid esters, germ oil, ground walnut oil, g cerol, isopropanol, olive oil, glycerol glycerol, propylene glycol, sesame oil, water mixtures thereof Excipients for Preparation of compositions comprising forms of lestaurtmib to be osmotically administered include, for example, chlorofluoro-hydrocarbons, ethanol, water and mixtures thereof The excipie Methods for the preparation of compositions comprising forms of lestaurtinib to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, oil ground walnut, posomes, oleic acid, olive oil, peanut oil, Ringer's solution, sunflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water and mixtures thereof Excipients for preparation of compositions comprising forms of lestaurtmib to be administered rectally or vaginally
include, for example, cocoa butter, polyethylene glycol, wax and mixtures thereof. Lestaurtmib dosage forms depend on the route of administration. Any route of administration is contemplated, including oral, mucosal (eg ocular, intranasal, pulmonary). , gastric, intestinal, rectal, vaginal and urethral) or parenteral (eg subcutaneous, intradermal, intramuscular, intravenous or mtrapeptoneal) The pharmaceutical compositions are more preferably administered orally, preferably in forms such as tablets, capsules, powders, pills, liquids / suspensions or gels / suspensions, or emulsions, syrups and all other forms described in patents and applications mentioned herein, more preferably as tablets, capsules and liquids / suspensions or gels / suspensions The administration vehicle may comprise one or more carriers pharmaceutically acceptable that are similar to ensure the solid state or stability of Crystalline form (e g suspension in oil) Lestaurtmib can be formulated as a variety of pharmaceutical compositions and dosage forms such as those described in U.S. Pat., 200,968 and 6,660,729 and PCT Publication No. 04/037928, each of which is incorporated herein by reference. In particular, lestaurtinib can be formulated as microemulsions or dispersions. In some embodiments, the compositions comprise
32
lestaurtinib, propylene glycol and a fatty acid ester by oxyethylene sorbitan, examples of which include TWEEN® 20 (polyoxyethylene sorbitan monolaurate 20), TWEEN® 40 (polyoxyethylene sorbitan monopalmitate 20), and TWEEN® 80 (polyoxyethylene monoolaceate 20). sorbitan) In a particular embodiment, lestaurtmib is present at a concentration of 25 mg / mL In another embodiment, the ratio of propylene glycol to polyoxyethylene sorbitan fatty acid ester has a range of 5050 to 8020 or 5050 or 8020. other embodiments, the compositions comprise lestaurtmib, a po-oxy stearate and polyethylene glycol ("PEG"), examples which include PEG of 300-8000, 400-3350 or 400-1500 Daltons or PEG-400, PEG- 600, PEG-1000, PEG-1450, PEG-1500, PEG-400 / PEG-1000, PEG-400 / PEG-1450, PEG-600 / PEG-1000 or PEG-600 / PEG-1450 In other embodiments, the Pooxil stearate is polyoxyl 40 stearate (MYRJ 52®) In particular embodiments, lestaurtinib is present in a concentration of 25 mg / mL In other embodiments, the ratio of polyethylene glycol to polyoxyl stearate has a range of 5050 to 8020 or proportions of 5050 or 8020. In some embodiments, the compositions comprise PEG-400, PEG-1000 and stearate of oxoyl in a proportion of 252550 or PEG-400, PEG-1450 and polyoxyl stearate in a proportion of 252550 or PEG-600, PEG 1000 and polyoxyl stearate in a proportion of 252550 or PEG-600 PEG-
33
1450 polyoxyl stearate in a proportion of 252550 In other embodiments, the composition comprises PEG-400 PEG-1000, and polyoxyl stearate in a ratio of 404020 or PEG-400, PEG-1450 and polyoxyl stearate in a ratio of 404020 or PEG-600, PEG-1000 and polyoxyl stearate in a proportion of 404020 or PEG-600, PEG-1450 and polyoxyl stearate in a proportion of 404020. In another embodiment of this invention, the composition includes an antioxidant therein. The term " "antioxidant" as used herein, refers to a substance that retards detection by oxidation or inhibits reactions promoted by oxygen or peroxides Antioxidants include, but are not limited to ascorbic acid, fatty acid esters or ascorbic acid, hydroxytoluene butylated ( BHT), propyl gallate, butylated hydroxyanisole, mixtures thereof and the like In some embodiments of this invention, microemulsions or solution compositions are only Lidas comprising lestaurtmib also comprise BHT, and in particular BHT 002% p / p Lestaurtmib can be made by synthetic chemical processes, examples of which are shown hereafter. It is intended that it be understood that the order of the steps in the processes it can vary, that the reagents, solvents and reaction conditions can be replaced by those specifically mentioned, and that the portions susceptible to unwanted reactions can be protected and unprotected,
as necessary The following examples are presented to provide what is considered to be the most easily understood and useful description of the procedures and conceptual aspects of this invention.
Preparative Example 1 Lestaurtinib and methanolate thereof was prepared as described in U.S. Patent No. 4,932,986
Example 1 Form 1 Crystalline Lestaurtmib A mixture of lestarutinib methanolate in methanol and acetone was filtered for cleaning. The filtrate was distilled at constant volume with the addition of isopropyl acetate. When the boiling point of the solvent was stabilized at 82 ° C, the mixture It was cooled and poured.
Example 2 Lestaurtinib Hydrated Crystalline A mixture of lestaurtmib (400 mg) in refluxing acetone (200 mL), in which lestaurtmib was completely soluble, was treated with water until turbid, cooled, stored in the dark at room temperature for 3 hours. days and filtered through an agglomerated glass funnel of medium porosity. The filtrate was washed with water and dried with air. The exposure of the product to humidity
relative to less than 40% provided crystalline lestaurtmib monohydrate Exposure of the product to relative humidity of 40% or more provided crystalline lestaurtmib tphidrate
Example 2A Crystalline Hydrated Lestaurtinib A mixture of lestaurtinib (1 2 g) at reflux 1 3-d-oxolane, in which the lestaurtmib was completely soluble (120 mL), was poured into water (600 mL), stored in the dark a ambient temperature for 6 days and filtered through an agglomerated glass funnel of medium porosity. The filtrate was washed with water (10 mL) and air dried. Exposure of the product at relative humidity less than 40% provided crystalline lestaurtinib monohydrate. of the product at a relative humidity of 40% or more provide crystalline lestaurtmib tphidrate
Example 3 Hemiacetonitpleate of Crystalline Lestaurtmib Hemihydrate A solution of lestaurtinib (300 mg) in refluxing acetonitide (150 mL), in which lestaurtmib was completely soluble, was treated with water until cloudy, cooled stored in the dark at room temperature for 24 hours and filtered
Example 4 Amorphous Lestaurtinib
36
A mixture of lestaurtmib (1.6 g) in isopropanol (350 mL) and 1,3-d? Oxolane (50 mL) at 80 ° C and in which the lestaurtinib was completely soluble, was concentrated under vacuum The concentrate was washed with isopropanol (10 mL) and air drying
Example 4A Amorphous Lestaurtinib A mixture of lestaurtinib in acetone, in which lestaurtinib was completely soluble, was concentrated at 65 ° C under suction. The concentrate was washed with isopropanol (10 mL) and air dried. Additional modes for preparing amorphous lestaurtmib were shown in Table 3 The concentrations were carried out at about the temperature indicated in Table 3 at about 0.5 atm
TABLE 3
Example 5 Crystalline Lestaurtinib Anhydrate Crystalline hydrated lestaurtinib was heated between about 80 ° C and 100 ° C at about 760 pressure
mm Hg (1 atm) The product was stored in an environment that has less than approximately 5% relative humidity
Example 6 Form 1 Crystalline Lestaurtinib A mixture of EXAMPLE 2, EXAMPLE 2A, EXAMPLE 4, EXAMPLE 4A or a mixture thereof in ethanol, in which the example, or mixture thereof, was partially soluble, was left to chain , with or without agitation, until the crystalline form 1 of Lestaurtmib was formed
Example 7 Hemitetrafudrofuranate of Lestaurtinib Hemihydrate Crystalline A solution of lestaurtmib in THF refluxing, in which lestaurtmib was completely soluble, was treated with water until turbid, cooled, stored in the dark at room temperature for 24 hours and filtered. It is intended that it be understood that peak heights in a PXRD spectrum may vary and will depend on variables such as temperature, size of crystal size or morphology, sample preparation, or sample height in the analysis well of the Standard System. Diffraction Sc? ntagx2 It is also intended to be understood that peak positions can vary when measured with different radiation sources. For example Cu-Ka radiation, Mo-Ka, Co-Ka and
Fe-Ka, which have wavelengths of 1 54060Á, 07107 A, 1 7902 A and 1 9373 Á, respectively, can provide peak positions that differ from those measured with Cu-Ka radiation. The term "approximately" preceding a series of peak positions means that it includes all the peak positions of the group it precedes The term "approximately" that precedes a series of peak positions means that all peaks of the group it precedes are reported in terms of angular positions with a variable of ± 01 ° For example, the phrase approximately 68 °, 85 °, 97 °, 120 °,
132 °, 142 °, 147 °, 150 °, 155 °, 169 °, 175 °, 179 °, 193 ° 200 °, 204 °, 251 °, 256 °, 258 ° 263 °, or 266 ° means approximately 68 ° approximately 85 °, approximately 97 °, approximately 120 °, approximately 132 °, approximately
142 °, about 147 °, about 150 °, about 155 °, about 169 °, about 175 °, about 179 ° about 193 °, about 200 °, about 204 °, about 251 °, about 256 °, about 258 °, approximately 263 °, or approximately 266 ° v also 68 ° ± 01 °, 85 ° ± 01 °, 97 ° ± 0 1 °, 120 ° ± 0 1 ° 132 ° ± 0 1 ° 142 ° ± 01 °, 147 ° ± 01 °, 150 ° ± 01 ° 155 ° ± 0 1 °, 169 ° ± 0 1 °, 175 ° ± 01 °, 179 ° ± 01 °, 193 ° ± 0 1 °, 200 ° ± 0 1 °, 204 ° ± 0 1 °, 251 ° ± 01 °, 256 ° ± 01 °, 258 ° ± 01 °, 263 ° ± 01 °, or 266 ° ± 01 °
39
As those skilled in the art will appreciate, numerous modifications and variations of the invention are possible in view of the foregoing teachings. It is therefore understood that within the scope of the appended claims, the invention can be practiced in other ways than those which are here. specifically described, and the field of the invention is intended to include all these variations
Claims (1)
- 40 CLAIMS 1 A Crystalline Form 1 of Lestaurtinib characterized, when measured at about 25 ° C with Cu-Ka radiation, by a powder diffraction pattern with at least three peaks having respective 2T values of approximately 68 °, 85 °, 97 ° , 120, 132, 142, 147, 150, 155, 169, 175, 179, 193, 200, 204, 251, 256, 258, 263 or 266. ° 2 The crystalline Form 1 of Lestaurtmib characterized, in a typical tpc crystal system and space group P1, when measured at approximately -100 ° C with Mo-Ka radiation, by reticular parameters a, b and c of 11 253A ± 0002A, 13317 ± 0004Á, 7095 Á ± 0003Á, respectively ya, ß yy of 9233 ° ± 003 °, 10778 ± 002 ° and 10095 ° ± 002 °, respectively 3 A composition comprising Form 1 Crystalline of Lestaurtinib and an excipient 4 A method for treating a patient having acute myeloid leukemia comprising administering to it a therapeutically acceptable amount of a Form 1 crystalline hydrate of Lestaurtmib 5 A method of treating a patient having chronic myeloid leukemia comprising administering to this a therapeutically acceptable amount of a crystalline Form 1 hydrate of Lestaurtinib 6 A method for treating a patient having acute lymphocytic leukemia comprising administering to it a therapeutically acceptable amount of Form 1 Crystalline Lestaurtmib 7 A method of treating a patient having chronic lymphocytic leukemia comprising administering to it a therapeutically acceptable amount of 1 Lestaurtmib Crystalline 8 A process for making Crystalline Form 1 of Lestaurtinib which comprises providing a mixture comprising the lestaurtmib, or the solvate thereof, and solvent, wherein the lestaurtinib, or the solvate thereof is completely dissolved in the solvent and which causes Form 1 Crystalline Lestaurtmib in the mixture, Crystalline Form 1 of Lestaurtinib when isolated and measured at approximately -100 ° C with Mo-Ka radiation characterizes the tpchnico crystal system and the space group P1 by reticular parameters to , b and c of 11 253Á ± 0002Á 13317 ± 0004Á, 7095 A ± 0003A, respectively ß y y of 9233 ° ± 003 °, 10778 ± 002 ° and 10095 ° ± 002 ° respectively 9 The process according to claim 8 which further comprises isolating the crystalline Form 1 from Lestaurtmib 10 In a process for making Form 1 Crystalline from Lestaurtmib comprising treatment of a carboxyl intermediary protected in said process with a reducing agent and subsequently synthesizing or rectalizing said lestaurtinib or said Crystalline Form 1 of Lestaurtinib, said process comprising direct crystallization of Form 1 Crystalline of 42 Lestaurtinib from a solid, semi-solid or honey having therewith one or more than one solvent from said reduction of protected carboxylic acid intermediate.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/748,855 | 2005-12-09 |
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