WO2001053293A1 - Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one - Google Patents

Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one Download PDF

Info

Publication number
WO2001053293A1
WO2001053293A1 PCT/US2001/000519 US0100519W WO0153293A1 WO 2001053293 A1 WO2001053293 A1 WO 2001053293A1 US 0100519 W US0100519 W US 0100519W WO 0153293 A1 WO0153293 A1 WO 0153293A1
Authority
WO
WIPO (PCT)
Prior art keywords
flavopiridol
medium
essentially free
methyl
forms
Prior art date
Application number
PCT/US2001/000519
Other languages
French (fr)
Inventor
Gary L. Bafus
Christine M. Harrison-Bowman
Gary L. Silvey
Original Assignee
Aventis Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE60104822T priority Critical patent/DE60104822T2/en
Priority to EA200200775A priority patent/EA005247B1/en
Priority to PL356165A priority patent/PL200696B1/en
Priority to EP01900939A priority patent/EP1259507B1/en
Priority to SI200130201T priority patent/SI1259507T1/en
Priority to MXPA02007005A priority patent/MXPA02007005A/en
Priority to BR0107726-0A priority patent/BR0107726A/en
Application filed by Aventis Pharmaceuticals Inc. filed Critical Aventis Pharmaceuticals Inc.
Priority to HU0204126A priority patent/HUP0204126A3/en
Priority to CA002397593A priority patent/CA2397593C/en
Priority to IL15063801A priority patent/IL150638A0/en
Priority to AT01900939T priority patent/ATE273303T1/en
Priority to NZ520280A priority patent/NZ520280A/en
Priority to JP2001553767A priority patent/JP2003520797A/en
Priority to AU2001226346A priority patent/AU2001226346A1/en
Priority to DK01900939T priority patent/DK1259507T3/en
Priority to SK1036-2002A priority patent/SK287404B6/en
Publication of WO2001053293A1 publication Critical patent/WO2001053293A1/en
Priority to IL150638A priority patent/IL150638A/en
Priority to NO20023386A priority patent/NO322572B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the compound (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1- methyl)piperidinyl]-4H-1-benzopyran-4-one or one of its pharmaceutically acceptable salt forms is an immunomodulator and antiinflammatory agent (U. S. Patent no. 4,900,727), and inhibitor of oncogene-encoded kinases or growth factor receptor tyrosine kinases (US Patent no. 5,284,856).
  • Flavopiridol is a strong inhibitor of cyclin dependent kinases (CDKs) including CDK1 , CDK2, CDK4, CDK6 and CDK7, (cdk1/clyclin B; cdk2/cyclin A; cdk2/cyclin E; cdk4/cyclinD; cdk ⁇ /cyclinD; cdk7/cyclin H) with the potential to cause inhibition of cell cycle progression in G ⁇ and G 2 by multiple mechanisms relatable to cdk inhibition.
  • CDKs cyclin dependent kinases
  • Flavopiridol has been j shown to inhibit the EGF receptor family, the receptor associated SRC family kinases, and signal transducing kinases. In vitro and in vivo experiments have shown that
  • Flavopiridol is able to inhibit a broad type range of human tumors, leukemias and lymphomas.
  • Form II meets pharmaceutical standards, it has a tendency to absorb water if not packaged in water impermeable packaging, which increases cost of production. It is also desirable to have as much stability as possible in the crystalline structure for handling purposes and for approvals through different pharmaceutical regulatory agencies throughout the world. It is an object of the present invention to provide a form of Flavopiridol as Form I which has superior physical characteristics for use as a pharmaceutical composition.
  • Form is prepared by combining a sufficient quantity of Form II with a sufficient amount of an appropriate azeotropic solvent thus forming an azeotropic mixture; submitting the azeotropic mixture to azeotropic distillation sufficient to form Form I; and optionally recovering Form I therefrom.
  • Figure 1 Estimated Limit of Detection of Form II in Form I by X-ray Powder Diffraction (XRPD)
  • Form II in Form I To estimate the limit of detection of Form II in Form I, varying quantities of Form II were accurately weighed and carefully mixed (unmilled) with Form I. The entire mixture was transferred to a platinum sample holder and leveled using glass microscope slide. All samples were scanned at 0.2 min. from 12° - 16° 2Q. At a minimum, duplicate determinations were made at each spike level, the XRPD patterns averaged, and the peak height at ⁇ 13.8° 2Q measured to the nearest 0.1 mm. The estimated detection limit of Form II in Form I is ⁇ 3%. DETAILED DESCRIPTION OF THE INVENTION
  • Form I is identified by x-ray diffraction patterns expressed in terms of "d" spacing using Cu K-alpha radiation as follows: D space- A
  • Form I is identified by x-ray diffraction patterns expressed in terms of "d" spacing using Cu K-alpha radiation and the Relative Intensities thereof:
  • Form I is identified x-ray diffraction patterns expressed in terms of "d" spacing using Cu K-alpha radiation and the Relative Intensities (Rl) percentages thereof:
  • Form I is preferably essentially free of Form II and/or other forms of Flavopiridol.
  • "Essentially free" of Form II and/or other forms of Flavopiridol means that Form II and/or other forms of Flavopiridol are present in less than 10%, 9%, 8%, 7%, 6%, 5%, 4% and 3% as shown by x-ray powder diffraction or Nuclear Magnetic Resonance (NMR).
  • Flavopiridol include base and salt forms as is appropriate, and which include hydrates, solvates or solvate hydrates, but does not include Form I or Form II.
  • Form II means the solvate/hydrate of ethanol/water of (-)-cis-2-(2- chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1- benzopyran-4-one hydrochloride as described by x-ray powder diffraction in Table 2, obtained using Cu K-alpha radiation.
  • Form I is made by combining a sufficient quantity of Form II with a sufficient amount of an appropriate azeotropic solvent to form an azeotropic mixture; submitting the azeotropic mixture to azeotropic distillation sufficient to form Form I; and optionally recovering Form I.
  • a “sufficient quantity of Form II” is an amount to form crystals of Form I in the reaction mixture which can be recovered. One skilled in the art may experimentally determine this quantity.
  • a "sufficient quantity of a suitable solvent” is enough suitable solvent to at least partially dissolve Form II thus forming a reaction mixture and can be experimentally determined by one skilled in the art. The experiments described hereafter give examples of quantities that could be used.
  • Appropriate conditions in large part depend upon the suitable solvent selected. For example, if the appropriate conditions comprise azeoptropic distillation, an appropriate azeoptropic solvent will be selected.
  • a “suitable solvent” is a solvent that at least partially dissolves Form II, and permits the formation of crystals of Form I.
  • the suitable solvent can be an "appropriate azeotropic solvent” or as otherwise described herein.
  • “Azeotropic mixture” refers to a liquid mixture of two or more substances which behaves like a single substance in that the vapor produced by partial evaporation of liquid has the same composition as the liquid.
  • the constant boiling mixture exhibits either a maximum or minimum boiling point as compared with that of other mixtures of the same substance.
  • Azeotropic distillation refers to a type of distillation in which a substance is added to the mixture to be separated in order to form an azeotropic mixture with one or more of the constituents of the original mixture. Typically, the azeotropic mixture is heated to a temperature at which the solvate/water is driven off of Form II. The azeotropes thus formed will have boiling points different from the boiling points of the original mixture.
  • Appropriate azeotropic solvent comprise ketone solvents such as acetone, methyl ethyl ketone and the like; aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like; mixtures of ketone solvents and aliphatic ester solvents; C 5 -C 8 aliphatic solvents such as pentane, hexane and the like; aliphatic nitriles, such as acetonitrile; benzene, toluene, pyridine, and so on.
  • ketone solvents such as acetone, methyl ethyl ketone and the like
  • aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like
  • suitable temperature refers to that temperature which is permit the crystallization of Form I without substantial damage to the Form I thus formed. In the azeotropic distillation, it will be the boiling point at which the solvate and/or water has been driven off.
  • the Form I is in the form of a crystal which has precipitated and which may be recovered by isolating the crystal. Typically, this may be accomplished by filtering the crystal or evaporating the solvent or otherwise removing the solvent from the crystal, or the crystal from the solvent. Drying of the solvent, e.g. evaporation at ambient temperature or upon heating, may also be appropriate.
  • Flavopiridol which has a weight gain due to water of less than 5%, including 4%, 3%, 2%, 1% and less than 1% in fractions (normally about 1-2%) with a Relative Humidity of about 75% and even up to a Relative Humidity of about 90% (weight gain of about 3.5%).
  • Form II as a solvate/hydrate, showed a slow but continual weight gain of about 4% through about 60% Relative Humidity. Above 60%, Form II showed a weight gain of about 15-20%.
  • Flavopiridol Form I Approximately 6 g of Flavopiridol Form II was placed in a 600 mL beaker. 300 mL of Methyl ethyl ketone (MEK) was added slowly, with stirring, to obtain a slurry. The solution was heated slowly to 50°C until cloudy. The temperature was increased to about 73°C with stirring and the addition of 100 ml of solvent. As the solution was brought to a strong boil it began to precipitate out and settle to the bottom. The temperature was increased and monitored to 80°C (boiling point of MEK), for a few minutes to obtain additional precipitate, then removed and allowed to cool to about 55°C.
  • MEK Methyl ethyl ketone
  • X-Ray Powder Diffraction Methodology X-ray powder diffraction (XRPD) patterns were obtained on a Scintag XDS 2000 QIQ diffractometer operating with copper radiation at 45kV and 40mA , using a Kevex Psi Peltier-cooled silicon detector. The source slits of 2 and 4 mm, and detector slits of 0.5 and 0.3 mm were used for data collection. Sample obtained was gently milled using an agate mortar and pestle for approximately one minute, placed in a platinum sample holder, and leveled using a glass microscope slide. Powder diffraction patterns of the samples were obtained from 2° to 42° 2Q at 1 min. Calibration of the XDS 2000 is verified annually using a silicon powder standard.
  • Form II was studied at 25°C using a Surface Measurement Systems Dynamic Vapor Sorption DVS-1 analyzer.
  • a sample in the range of about 14.8 mg was placed in a tared quartz sample holder at an initial ambient room humidity setting of about 48% Relative Humidity (RH).
  • RH Relative Humidity
  • a total wet/dry nitrogen flow rate of 200 cc/min was used throughout the study.
  • the following full cycle program was initiated: 30 min at the initial ambient RH, followed by settings of 0, 20, 40, 60, 80, 90, 95 and 98%RH, with exposure time at each humidity set point dependent upon dm/dt being less than 0.001 % for 60 min.
  • the maximum time allowed at any one humidity set point was 24 hours.
  • data collection took about 4 days to complete. After the full cycle the sample was maintained at the same RH as the initial ambient starting RH.
  • Form I was studied at 25°C and 40°C using the DVS-1 analyzer. Data was collected over two full cycles. Samples of 10.4 and 16.7 mg were placed into respective tared quartz sample holders at an initial ambient room humidity setting of about 46%RH and 33%RH, respectively. For this study, an additional 75%RH set point was used. For 2 full cycles, data collection took about 7 days at 25°C and about17 days at 40°C to complete. After completion of each 2 cycle study, the samples were maintained at the same RH as the initial ambient starting RH.
  • X-ray Powder Diffraction (XRPD) patterns were taken on a Scintag XDS 2000 e/ ⁇ diffractometer operating with copper radiation at 45kV and 40 mA, using a Kevex Psi Peltier-cooled silicon detector. Source slits of 2 and 4 mm, and detector slits of 0.5 and 0.3 mm were used for data collection. Form II samples were gently milled using an agate mortar and pestle for approximately one minute, placed in a platinum sample pan, and leveled using a glass microscope slide. Samples taken during or post hygroscopicity testing were not milled due to the limited amount of sample available. In each case, powder diffraction patterns were scanned from 2° to 42° 2Q at 1 minute. Calibration of the XDS 2000 was verified using Silicon powder.
  • Form II showed a slow but continual weight gain through about 60%RH of approximately 4%, and above 60% relative humidity an additional 15 - 20% weight gain was observed. In contrast, Form I showed an approximate weight gain of 1 - 2% through about 75%RH, plus an additional estimated 3.5% weight gain through about 90%RH. Above 90%RH, a weight gain of about 30% was observed. Thus, Form II would be considered hygroscopic, while Form I would be considered hygroscopic above 75%RH.
  • Variable humidity x-ray powder diffraction showed, that, as the humidity is increased there is an apparent decrease in crystallinity in Form II, and a significant change in the XRPD pattern which is presumably due to the loss of ethanol. Whereas Form I apparently retains its crystallinity until extremely high relative humidity is reached, (i.e., >98%) at which point it loses crystallinity and becomes amorphous. Based upon these results, Form I has superior physical properties for relative to Form II for use as a pharmaceutical composition.
  • a reactor is charged under nitrogen atmosphere with (-)-cis-1-methyl-4R- (2,4,6-trimethoxyphenyl)-3S-piperidinol) and acetic anhydride.
  • Boron trifluoride etherate is added at a constant rate while stirring and cooling the resulting solution to 8-20°C. After the addition is complete the resulting mixture is stirred at 20-30°C for 3- 5 hours.
  • the reaction mixture is cooled to 8-12°C and ice-water is added while stirring followed by addition of aqueous sodium hydroxide until pH 10-11 is attained.
  • the mixture is extracted with ethyl acetate.
  • the ethyl acetate extracts are pooled and concentrated under vacuum. The residue is taken up in methanol and water.
  • (+)-cis-2-(2-chloropheny)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1- methyl)piperidinyl]-4H-1-benzopyran-4-one crude, acetone is added. The resulting mixture is stirred at 55-60°C for 30-60 minute, then cooled to 15-20°C and stirred for another 1-2 hours. The precipitated solid is isolated by filtration, washed twice with acetone and dried under reduced pressure to give (+)-cis-2-(2-chloropheny)-5,7- dihydroxy-8-[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one in a purified form.
  • the free base from the previous step is suspended in ethanol and acidified using concentrated hydrochloric acid at such a rate that the temperature does not exceed 30°C. During this process initially all of the solid dissolves and then the hydrochloride precipitates. The suspension is cooled to 0-10°C and stirred for 1 hour while maintaining the temperature. The crystals are isolated by filtration and washed with cold ethanol to yield (-)-cis-2-(2-chloropheyl)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1- methyl)piperidinyI]-4-H-1-benzopyran-4-one hydrochloride, crude.
  • composition means a therapeutically effective amount of Form I with a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” is an agent which is non-toxic, does not interfere with the therapeutic profile of Form I and is appropriate to the method of administration.
  • Form I is preferably administered by the intravenous route over an appropriate period of time for cancer chemotherapy.
  • Form I is mixed with one or more pharmaceutically acceptable carriers.
  • Form I may be mixed with iso-ismotic and pH controlled liquids such as water, dextrose/water or saline/water for injection intravenously into the patient.
  • an “effective amount” includes a “therapeutically effective amount”, “an effective protein kinase inhibiting amount”, “an effective cyclin dependent kinase amount” and an effective tumor-inhibiting amount of Form I and will vary with the individual, concomitant therapy, the disease, and other variable factors.
  • An effective amount for Form I will be about the same as for Form II.
  • the dosage of Form I will be 0.001 mg/kg to 100 mg/kg per day.
  • Flavopiridol is useful in treating a number of conditions or diseases that benefit from inhibition of protein kinases, and more particularly cyclin dependent kinases as previously described herein. Flavopiridol is expected to be useful in treating a broad range of cancers including, for example, leukemia, mesothelioma and cancers of the lung (large cell, small, cell and non-small cell), colorectal, breast, ovarian, prostate melanoma, renal, uterine body and central nervous system.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Stereophonic System (AREA)
  • Inorganic Insulating Materials (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The present invention comprises a pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride, a method of making same, a pharmaceutical composition and methods of using the pseudopolymorph.

Description

Pseudopolymorph of (-)-cis-2-(2-ch[orophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy- 1 -methyl)piperidinyl]-4H-1 -benzopyran-4-one
BACKGROUND OF THE INVENTION
The compound (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1- methyl)piperidinyl]-4H-1-benzopyran-4-one or one of its pharmaceutically acceptable salt forms (known as "Flavopiridol") is an immunomodulator and antiinflammatory agent (U. S. Patent no. 4,900,727), and inhibitor of oncogene-encoded kinases or growth factor receptor tyrosine kinases (US Patent no. 5,284,856). Flavopiridol is a strong inhibitor of cyclin dependent kinases (CDKs) including CDK1 , CDK2, CDK4, CDK6 and CDK7, (cdk1/clyclin B; cdk2/cyclin A; cdk2/cyclin E; cdk4/cyclinD; cdkβ/cyclinD; cdk7/cyclin H) with the potential to cause inhibition of cell cycle progression in G^ and G2 by multiple mechanisms relatable to cdk inhibition. See
International Journal of Oncology 9: 1143-1168 (1996). Also, Flavopiridol has been j shown to inhibit the EGF receptor family, the receptor associated SRC family kinases, and signal transducing kinases. In vitro and in vivo experiments have shown that
Flavopiridol is able to inhibit a broad type range of human tumors, leukemias and lymphomas.
(-)-cis-2-(2-ch lorophenyl)-5, 7-dihyd roxy-8[4R-(3S-hyd roxy- 1 - methyl)piperidinyl]-4H-1-benzopyran-4-one or a pharmaceutically acceptable salt thereof crystallizes into numerous solvates with solvents such as ethanol, DMSO, methanol, acetonitrile/isopropanol, ethanol/isopropanol, and isopropanol and solvate hydrates such as ethanol/ and isopropanol/water combinations. The preferred form is the Flavopiridol hydrochlonde ethanol/water solvate form (hereafter "Form II").
Although Form II meets pharmaceutical standards, it has a tendency to absorb water if not packaged in water impermeable packaging, which increases cost of production. It is also desirable to have as much stability as possible in the crystalline structure for handling purposes and for approvals through different pharmaceutical regulatory agencies throughout the world. It is an object of the present invention to provide a form of Flavopiridol as Form I which has superior physical characteristics for use as a pharmaceutical composition.
SUMMARY OF THE INVENTION The present invention comprises pseudopolymorph Form I as defined by x-ray powder diffraction. Preferably, Form I is essentially free of Form II and/or other Flavopiridol forms. It is useful in a pharmaceutical composition comprising an effective amount of Form I and a pharmaceutically acceptable carrier. Form I is useful as a protein kinase inhibitor, cyclin dependent kinase inhibitor, and in the treatment for various forms of cancer.
Form I is further characterized by its ability of being less hydroscopic than Form II e.g., has less weight gain due in comparative relative humidities.
Form is prepared by combining a sufficient quantity of Form II with a sufficient amount of an appropriate azeotropic solvent thus forming an azeotropic mixture; submitting the azeotropic mixture to azeotropic distillation sufficient to form Form I; and optionally recovering Form I therefrom.
DESCRIPTION OF DRAWING
Figure 1 : Estimated Limit of Detection of Form II in Form I by X-ray Powder Diffraction (XRPD)
To estimate the limit of detection of Form II in Form I, varying quantities of Form II were accurately weighed and carefully mixed (unmilled) with Form I. The entire mixture was transferred to a platinum sample holder and leveled using glass microscope slide. All samples were scanned at 0.2 min. from 12° - 16° 2Q. At a minimum, duplicate determinations were made at each spike level, the XRPD patterns averaged, and the peak height at ~13.8° 2Q measured to the nearest 0.1 mm. The estimated detection limit of Form II in Form I is ~ 3%. DETAILED DESCRIPTION OF THE INVENTION
"Form I" means (-)-cis-2-(2-chIorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1- methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride. It has the same active ingredient as Flavopiridol but differs from known crystals of Flavopiridol in that it is anhydrous and/or solvate free, i.e., a pseudopolymorph of known forms of Flavopiridol.
Form I is identified by x-ray diffraction patterns expressed in terms of "d" spacing using Cu K-alpha radiation as follows: D space- A
12.708
4.323
5.594
5.349 3.590, and more preferably as:
D space- A
12.708
4.323 5.594
5.349
3.590
3.366
4.209 3.395
3.438
4.839.
Also, Form I is identified by x-ray diffraction patterns expressed in terms of "d" spacing using Cu K-alpha radiation and the Relative Intensities thereof:
D space- A Relative Intensities
12.708 Strong
4.323 Strong
5.594 Strong 5.349 Medium
3.590 Medium
3.366 Medium
4.209 Medium
3.395 Medium 3.438 Medium
4.839 Medium. More preferably, Form I is identified x-ray diffraction patterns expressed in terms of "d" spacing using Cu K-alpha radiation and the Relative Intensities (Rl) percentages thereof:
D space- A Relative Intensity %
12.708 100.0
4.323 75.9
5.594 58.5
5.349 49.5
3.590 46.6
3.366 42.0
4.209 40.7
3.395 39.5
3.438 38.8
4.839 37.1.
Form I X-ray powder diffraction is more fully described in Table 1.
Table 1
Figure imgf000006_0001
Form I is preferably essentially free of Form II and/or other forms of Flavopiridol. "Essentially free" of Form II and/or other forms of Flavopiridol means that Form II and/or other forms of Flavopiridol are present in less than 10%, 9%, 8%, 7%, 6%, 5%, 4% and 3% as shown by x-ray powder diffraction or Nuclear Magnetic Resonance (NMR).
"Other forms of Flavopiridol" include base and salt forms as is appropriate, and which include hydrates, solvates or solvate hydrates, but does not include Form I or Form II.
"Form II" means the solvate/hydrate of ethanol/water of (-)-cis-2-(2- chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1- benzopyran-4-one hydrochloride as described by x-ray powder diffraction in Table 2, obtained using Cu K-alpha radiation.
Table 2
Figure imgf000007_0001
Preferably, Form I is made by combining a sufficient quantity of Form II with a sufficient amount of an appropriate azeotropic solvent to form an azeotropic mixture; submitting the azeotropic mixture to azeotropic distillation sufficient to form Form I; and optionally recovering Form I.
A "sufficient quantity of Form II" is an amount to form crystals of Form I in the reaction mixture which can be recovered. One skilled in the art may experimentally determine this quantity. A "sufficient quantity of a suitable solvent" is enough suitable solvent to at least partially dissolve Form II thus forming a reaction mixture and can be experimentally determined by one skilled in the art. The experiments described hereafter give examples of quantities that could be used.
"Appropriate conditions" in large part depend upon the suitable solvent selected. For example, if the appropriate conditions comprise azeoptropic distillation, an appropriate azeoptropic solvent will be selected.
A "suitable solvent" is a solvent that at least partially dissolves Form II, and permits the formation of crystals of Form I. The suitable solvent can be an "appropriate azeotropic solvent" or as otherwise described herein.
"Azeotropic mixture" refers to a liquid mixture of two or more substances which behaves like a single substance in that the vapor produced by partial evaporation of liquid has the same composition as the liquid. The constant boiling mixture exhibits either a maximum or minimum boiling point as compared with that of other mixtures of the same substance.
"Azeotropic distillation" refers to a type of distillation in which a substance is added to the mixture to be separated in order to form an azeotropic mixture with one or more of the constituents of the original mixture. Typically, the azeotropic mixture is heated to a temperature at which the solvate/water is driven off of Form II. The azeotropes thus formed will have boiling points different from the boiling points of the original mixture.
"Appropriate azeotropic solvent"(s), comprise ketone solvents such as acetone, methyl ethyl ketone and the like; aliphatic ester solvents such as ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl acetate and the like; mixtures of ketone solvents and aliphatic ester solvents; C5-C8 aliphatic solvents such as pentane, hexane and the like; aliphatic nitriles, such as acetonitrile; benzene, toluene, pyridine, and so on. See for example Practical Organic Chemistry, 3rd ed., John Wiley &Sons, 1956 e.g., pp. 10-1 1 , incorporated herein by reference. As used herein, the term "suitable temperature" refers to that temperature which is permit the crystallization of Form I without substantial damage to the Form I thus formed. In the azeotropic distillation, it will be the boiling point at which the solvate and/or water has been driven off.
At this point, the Form I is in the form of a crystal which has precipitated and which may be recovered by isolating the crystal. Typically, this may be accomplished by filtering the crystal or evaporating the solvent or otherwise removing the solvent from the crystal, or the crystal from the solvent. Drying of the solvent, e.g. evaporation at ambient temperature or upon heating, may also be appropriate.
An important feature of Form I over Form II is the ability of Form I not to absorb water readily from the atmosphere. The present invention provides a form of
Flavopiridol which has a weight gain due to water of less than 5%, including 4%, 3%, 2%, 1% and less than 1% in fractions (normally about 1-2%) with a Relative Humidity of about 75% and even up to a Relative Humidity of about 90% (weight gain of about 3.5%). Form II, as a solvate/hydrate, showed a slow but continual weight gain of about 4% through about 60% Relative Humidity. Above 60%, Form II showed a weight gain of about 15-20%.
EXAMPLE 1
Preparation of Flavopiridol Form I Approximately 6 g of Flavopiridol Form II was placed in a 600 mL beaker. 300 mL of Methyl ethyl ketone (MEK) was added slowly, with stirring, to obtain a slurry. The solution was heated slowly to 50°C until cloudy. The temperature was increased to about 73°C with stirring and the addition of 100 ml of solvent. As the solution was brought to a strong boil it began to precipitate out and settle to the bottom. The temperature was increased and monitored to 80°C (boiling point of MEK), for a few minutes to obtain additional precipitate, then removed and allowed to cool to about 55°C. The final volume of 325 mL of solution required filtering through a Buchner funnel, under vacuum, using Whatman #1 filter paper, until dry; resulting in a dense yellow and flocculent chunk-like powder. The structure was confirmed by Mass Spectrometry, Nuclear Magnetic Resonance and Fourier Transform Infra Red, and X- Ray powder diffraction performed on the sample.
EXAMPLE 2
X-Ray Powder Diffraction Methodology X-ray powder diffraction (XRPD) patterns were obtained on a Scintag XDS 2000 QIQ diffractometer operating with copper radiation at 45kV and 40mA , using a Kevex Psi Peltier-cooled silicon detector. The source slits of 2 and 4 mm, and detector slits of 0.5 and 0.3 mm were used for data collection. Sample obtained was gently milled using an agate mortar and pestle for approximately one minute, placed in a platinum sample holder, and leveled using a glass microscope slide. Powder diffraction patterns of the samples were obtained from 2° to 42° 2Q at 1 min. Calibration of the XDS 2000 is verified annually using a silicon powder standard.
EXAMPLE 3
Hygroscopicity screening - Comparison of Form I and Form II Dynamic Vapor Sorption (DVS) analysis studies were conducted on Form II versus Form I. Dynamic Water Vapor Sorption Analysis (DVS)
Form II was studied at 25°C using a Surface Measurement Systems Dynamic Vapor Sorption DVS-1 analyzer. A sample in the range of about 14.8 mg was placed in a tared quartz sample holder at an initial ambient room humidity setting of about 48% Relative Humidity (RH). A total wet/dry nitrogen flow rate of 200 cc/min was used throughout the study. The following full cycle program was initiated: 30 min at the initial ambient RH, followed by settings of 0, 20, 40, 60, 80, 90, 95 and 98%RH, with exposure time at each humidity set point dependent upon dm/dt being less than 0.001 % for 60 min. The maximum time allowed at any one humidity set point was 24 hours. For a full cycle, data collection took about 4 days to complete. After the full cycle the sample was maintained at the same RH as the initial ambient starting RH.
Form I was studied at 25°C and 40°C using the DVS-1 analyzer. Data was collected over two full cycles. Samples of 10.4 and 16.7 mg were placed into respective tared quartz sample holders at an initial ambient room humidity setting of about 46%RH and 33%RH, respectively. For this study, an additional 75%RH set point was used. For 2 full cycles, data collection took about 7 days at 25°C and about17 days at 40°C to complete. After completion of each 2 cycle study, the samples were maintained at the same RH as the initial ambient starting RH.
X-ray Powder Diffraction (XRPD) patterns were taken on a Scintag XDS 2000 e/θ diffractometer operating with copper radiation at 45kV and 40 mA, using a Kevex Psi Peltier-cooled silicon detector. Source slits of 2 and 4 mm, and detector slits of 0.5 and 0.3 mm were used for data collection. Form II samples were gently milled using an agate mortar and pestle for approximately one minute, placed in a platinum sample pan, and leveled using a glass microscope slide. Samples taken during or post hygroscopicity testing were not milled due to the limited amount of sample available. In each case, powder diffraction patterns were scanned from 2° to 42° 2Q at 1 minute. Calibration of the XDS 2000 was verified using Silicon powder.
For variable relative humidity experiments, the larger capacity DVS-2 Surface Measurement Systems Dynamic Vapor Sorption analyzer was used. Using a flow rate of 500cc/min, Form II was held at desired RH settings and sampled periodically for XRPD analysis. Unmilled material was placed in the platinum sample pan and leveled using a glass microscope slide prior to analysis using the above conditions.
Form II showed a slow but continual weight gain through about 60%RH of approximately 4%, and above 60% relative humidity an additional 15 - 20% weight gain was observed. In contrast, Form I showed an approximate weight gain of 1 - 2% through about 75%RH, plus an additional estimated 3.5% weight gain through about 90%RH. Above 90%RH, a weight gain of about 30% was observed. Thus, Form II would be considered hygroscopic, while Form I would be considered hygroscopic above 75%RH.
Variable humidity x-ray powder diffraction showed, that, as the humidity is increased there is an apparent decrease in crystallinity in Form II, and a significant change in the XRPD pattern which is presumably due to the loss of ethanol. Whereas Form I apparently retains its crystallinity until extremely high relative humidity is reached, (i.e., >98%) at which point it loses crystallinity and becomes amorphous. Based upon these results, Form I has superior physical properties for relative to Form II for use as a pharmaceutical composition.
EXAMPLE 4 Form II
A reactor is charged under nitrogen atmosphere with (-)-cis-1-methyl-4R- (2,4,6-trimethoxyphenyl)-3S-piperidinol) and acetic anhydride. Boron trifluoride etherate is added at a constant rate while stirring and cooling the resulting solution to 8-20°C. After the addition is complete the resulting mixture is stirred at 20-30°C for 3- 5 hours. The reaction mixture is cooled to 8-12°C and ice-water is added while stirring followed by addition of aqueous sodium hydroxide until pH 10-11 is attained. The mixture is extracted with ethyl acetate. The ethyl acetate extracts are pooled and concentrated under vacuum. The residue is taken up in methanol and water. Then sodium hydroxide (about 50% aqueous solution) is added. The reaction mixture is stirred at 20-30°C for 2-3 hours. The mixture is evaporated under reduced pressure at < 80°C. The residue is cooled to 15-20°C and brought to pH 8.5-9.5 using concentrated hydrochloric acid. A solid precipitates, which is collected by filtration washed with demineralized water and dried under reduced pressure to give ((-)-cis-1- methyl-4-(3-acetyl-4,6-dimethoxy-2-hydroxy)phenyl-3-piperidinol).
((-)-cis-1-methyl-4-(3-acetyl-4,6-dimethoxy-2-hydroxy)phenyl-3-piperidinol) is then added portionwise to a stirred suspension of potassium tert. butoxide in dry N,N-dimethylforamide at such a rate that the temperature does not exceed 20°C. After the addition is complete the resulting mixture is stirred for one hour at <30°C. Methyl 2-chlorobenzoate is added at such a rate, that the temperature does not exceed 30°C. the resulting mixture is stirred at 20-30°C for 4-6 hours. Demineralized water is added, followed by concentrated hydrochloric acid until the pH of the mixture reaches 6-8. The mixture is extracted two times using chloroform. The chloroform extracts are pooled together and concentrated under reduced pressure.
After cooling the remaining oil to <40°C, concentrated hydrochloric acid is added. The mixture is then stirred at <40°C for < 2 hours or overnight is necessary. After cooling the reaction mixture to 15-30°C, water and chloroform are added. The resulting mixture is basified to pH 8.5-10.5 using sodium hydroxide solution (50%). The phases are separated. The aqueous layer is then extracted with chloroform. The combined organic extracts are evaporated under reduced pressure to yield (-)- cis-2-(2-Chlorophenyl)-5,7-dimethoxy-8-[4R-(3S-hydroxy-1-methyl)-piperidinyl]-4H-1- benzopyran-4-one as an oil, which is directly used in the next step without purification.
To (-)-cis-2-(2-Chlorophenyl)-5,7-dimethoxy-8-[4R-(3S-hydroxy-1-methyl)- piperidinyl]-4H-1-benzopyran-4-one, quinoline and pyridine hydrochloride are added. The resulting mixture is heated to 160-190°C while stirring. Stirring is continued while maintaining the temperature at 160-190°C for 2 hours. After cooling the reaction mixture to 90-110°C water is added. The resulting mixture is basified to pH 7.5-8.5 using saturated sodium carbonate solution. A mixture of ethanol twice with a mixture of ethanol and chloroform. The combined extracts are evaporated to dryness to obtain (+)-cis-2-(2-chloropheny)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1 - methyl)piperidinyl]-4H-1-benzopyran-4-one crude as a brown gum, which is purified as follows.
To (+)-cis-2-(2-chloropheny)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1- methyl)piperidinyl]-4H-1-benzopyran-4-one crude, acetone is added. The resulting mixture is stirred at 55-60°C for 30-60 minute, then cooled to 15-20°C and stirred for another 1-2 hours. The precipitated solid is isolated by filtration, washed twice with acetone and dried under reduced pressure to give (+)-cis-2-(2-chloropheny)-5,7- dihydroxy-8-[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one in a purified form.
The free base from the previous step is suspended in ethanol and acidified using concentrated hydrochloric acid at such a rate that the temperature does not exceed 30°C. During this process initially all of the solid dissolves and then the hydrochloride precipitates. The suspension is cooled to 0-10°C and stirred for 1 hour while maintaining the temperature. The crystals are isolated by filtration and washed with cold ethanol to yield (-)-cis-2-(2-chloropheyl)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1- methyl)piperidinyI]-4-H-1-benzopyran-4-one hydrochloride, crude. To (-)-cis-2-(2-chloropheyl)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1- methyl)piperidinyl]-4-H-1-benzopyran-4-one hydrochloride, crude, ethanol is added. The resulting mixture is heated to 70-79°C, stirred for 1 hour while maintaining the temperature and then filtered while still hot. The filter is rinsed with hot ethanol. The filtrate is concentrated by atmospheric distillation, until 60-80% of the volatives have been removed. The remaining suspension is then cooled to 0-10°C while isolated by filtration and dried under reduced pressure to give (-)-cis-2-(2-chloropheyl)-5,7- dihydroxy-8-[4R-(3S-hydroxy-1-methyl)piperidinyl]-4-H-1-benzopyran-4-one hydrochloride, purified as a yellow solid.
After the Form I is recovered, a pharmaceutical composition can be prepared. As used herein, "pharmaceutical composition" means a therapeutically effective amount of Form I with a pharmaceutically acceptable carrier.
A "pharmaceutically acceptable carrier" is an agent which is non-toxic, does not interfere with the therapeutic profile of Form I and is appropriate to the method of administration. Form I is preferably administered by the intravenous route over an appropriate period of time for cancer chemotherapy. Preferably, Form I is mixed with one or more pharmaceutically acceptable carriers. For example, Form I may be mixed with iso-ismotic and pH controlled liquids such as water, dextrose/water or saline/water for injection intravenously into the patient.
An "effective amount" includes a "therapeutically effective amount", "an effective protein kinase inhibiting amount", "an effective cyclin dependent kinase amount" and an effective tumor-inhibiting amount of Form I and will vary with the individual, concomitant therapy, the disease, and other variable factors. An effective amount for Form I will be about the same as for Form II. Typically, the dosage of Form I will be 0.001 mg/kg to 100 mg/kg per day.
Flavopiridol is useful in treating a number of conditions or diseases that benefit from inhibition of protein kinases, and more particularly cyclin dependent kinases as previously described herein. Flavopiridol is expected to be useful in treating a broad range of cancers including, for example, leukemia, mesothelioma and cancers of the lung (large cell, small, cell and non-small cell), colorectal, breast, ovarian, prostate melanoma, renal, uterine body and central nervous system.
All articles and patents cited herein are hereby incorporated herein by reference.

Claims

What is claimed is:
1. Pseudopolymorph Form I having an x-ray powder diffraction pattern expressed in terms of "D" spacing:
D space- A
12.708 4.323 5.594 5.349
3.590.
2. A pseudopolymorph Form I having an x-ray powder diffraction pattern expressed in terms of "D" spacing and relative intensities thereof: D space- A Relative Intensity
12.708 Strong
4.323 Strong
5.594 Strong
5.349 Medium 3.590 Medium
3.366 Medium
4.209 Medium
3.395 Medium
3.438 Medium 4.839 Medium.
3. A pseudopolymorph Form I having an x-ray powder diffraction pattern expressed in terms of "D" spacing and percentage of relative intensities thereof:
D space- A Relative Intensity % 12.708 100.0
4.323 75.9
5.594 58.5
5.349 49.5
3.590 46.6 3.366 42.0
4.209 40.7
3.395 39.5
3.438 38.8
4.839 37.1.
4. A pseudopolymorph Form I having an x-ray powder diffraction pattern as defined in Table 1 :
Table 1
Figure imgf000018_0001
The Form I of claims 1 , 2, 3 or 4 wherein the Form I is essentially free of Form
6. The Form I of claims 1 , 2, 3 or 4 wherein the Form I is essentially free of Form II and other Forms of Flavopiridol.
7. The Form I of claims 1 , 2,3 or 4 wherein Form II and other forms of Flavopiridol are present in less than 4%.
8. A pharmaceutical composition comprising a therapeutically effective amount of Form I of claim 1 ,2,3 or 4 and a pharmaceutical acceptable carrier.
9. A pharmaceutical composition comprising a therapeutically effective amount of the Form I of claim 1 ,2,3 or 4, which is essentially free of Form II, and a pharmaceutical acceptable carrier.
10. A pharmaceutical composition comprising a therapeutically effective amount of the Form I of claim 1 ,2,3 or 4, which is essentially free of Form II and other forms of Flavopiridol, and a pharmaceutical acceptable carrier.
11. A method of treating a patient for cancer by administering to the patient a therapeutically effective amount of Form I of claim 1 , 2, 3 or 4.
12. The method of claim 11 wherein the Form I is essentially free from Form II or other Flavopiridol forms.
13. A method of inhibiting protein kinases in a patient by administering to the patient in need thereof an effective protein kinase inhibiting amount of the Form 1 of claims 1 , 2, 3 or 4.
14. The method of claim 13 wherein the Form I is essentially free from Form II or other forms of Flavopiridol.
15. A method of inhibiting cyclin dependent kinases in a patient by administering to the patient in need thereof an effective cyclin dependent kinase inhibiting amount of Form I of claims 1 , 2, 3 or 4.
16. The method of claim 15 wherein the Form I is essentially free from Form II or other forms of Flavopiridol.
17. A method of making the Form I of claims 1 , 2,3 or 4 comprising (a) combining a sufficient quantity of Form II with a sufficient amount of an apropriate azeotropic solvent, thus forming an azeotropic mixture;
(b) submitting the azeotropic mixture to azeotropic distillation sufficient to form Form 1 ; and
(c) optionally recovering Form I therefrom.
18. The method of claim 17 wherein the solvent is a ketone solvent.
19. The method of claim 17 wherein the solvent is methyl ethyl ketone.
20. The method of claim 15 wherein the crystallized Form I is recovered by filtering Form I.
21. The method of claim 15 wherein the temperature of the azeotropic distillation is about 73 ° C to about 80 ° C.
22. A form of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1 - methyl)piperidinyl]-4H-1-benzopyran-4-one or one of its pharmaceutically acceptable salts characterized by a weight gain due to water of less than five percent at a relative humidity of about 75%.
23. A form of (-)-cis-2-(2-ch!orophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1 - methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride characterized by a weight gain due to water of less than five percent at a relative humidity of about 75%.
24. The Form I of claims 1 , 2,3 or 4 for use as a pharmaceutically active compound.
PCT/US2001/000519 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one WO2001053293A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
JP2001553767A JP2003520797A (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2- (2-chlorophenyl) -5,7-dihydroxy-8 [4R- (3S-hydroxy-1-methyl) piperidinyl] -4H-1-benzopyran-4-one ( pseudopolymorph)
PL356165A PL200696B1 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (−)−cis−2−(2−chlorophenyl)−5,7−dihydroxy−8[4r−(3s−hydroxy−1−methyl)piperidinyl]−4h−1−benzopyran−4−one
EP01900939A EP1259507B1 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8 4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one hydrochloride
SI200130201T SI1259507T1 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8 4r-(3s-hydroxy-1-methyl)piperidinyl)-4h-1-benzopyran-4-one hydrochloride
MXPA02007005A MXPA02007005A (en) 2000-01-18 2001-01-08 PSEUDOPOLYMORPH OF ()CIS2(2CHLOROPHENYL)5, 7DIHYDROXY8[4R(3SHYDROXY1METHYL)PIPERIDINYL]4Hminu s;1BENZOPYRAN4ONE.
BR0107726-0A BR0107726A (en) 2000-01-18 2001-01-08 Compound, pharmaceutical composition, and methods of treating a cancer patient, inhibiting protein kinases in a patient, inhibiting cyclin-dependent kinases in a patient, and preparing the compound
IL15063801A IL150638A0 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8 [4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one
HU0204126A HUP0204126A3 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one, process for their preparation and pharmaceutical compositions containing them
CA002397593A CA2397593C (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one
DE60104822T DE60104822T2 (en) 2000-01-18 2001-01-08 PSEUDOPOLYMORPH OF (-) - CIS-2- (2-CHLOROPHENYL) -5,7-DIHYDROXY-8 [4R- (3S-HYDROXY-1-METHYL) PIPERIDINYL] -4H-1-BENZOPYRAN-4-ON HYDROCHLORIDE
AT01900939T ATE273303T1 (en) 2000-01-18 2001-01-08 PSEUDOPOLYMORPH OF (-)-CIS-2-(2-CHLORPHENYL)-5,7-DIHYDROXY-8(4R-(3-HYDROXY-1-METHYL)PIPERIDINYL)- 4H-1-BENZOPYRAN-4-ONE HYDROCHLORIDE
NZ520280A NZ520280A (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-CIS-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one
EA200200775A EA005247B1 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2(2-chlorrophenyl)-5,7-dihydroxy-8[4r-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one
AU2001226346A AU2001226346A1 (en) 2000-01-18 2001-01-08 Pseudopolymorph of
DK01900939T DK1259507T3 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-) - cis-2- (2-chlorophenyl) -5,7-dihydroxy-8 [4R- (3S-hydroxy-1-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride
SK1036-2002A SK287404B6 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R- (3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one hydrochloride, method of preparation and pharmaceutical composition comprising the same
IL150638A IL150638A (en) 2000-01-18 2002-07-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7- dihydroxy-8[4r- (3s - hydroxy-1-methyl)piperidinyl]- 4h-1-benzopyran - 4 - one, its preparation and pharmaceutical compositions comprising it
NO20023386A NO322572B1 (en) 2000-01-18 2002-07-12 Pseudopolymorph of (-) - cis-2- (2-chlorophenyl) -5,7-dihydroxy-8 [4R- (3S-hydroxy-1-methyl) piperidinyl] -4H-1-benzopyran-4-one hydrochloride, Methods for the preparation thereof, its use in cancer treatment, and the pharmaceutical composition including the pseudopolymorph.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48471700A 2000-01-18 2000-01-18
US09/484,717 2000-01-18

Publications (1)

Publication Number Publication Date
WO2001053293A1 true WO2001053293A1 (en) 2001-07-26

Family

ID=23925305

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/000519 WO2001053293A1 (en) 2000-01-18 2001-01-08 Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one

Country Status (26)

Country Link
EP (1) EP1259507B1 (en)
JP (1) JP2003520797A (en)
KR (1) KR100806464B1 (en)
CN (1) CN1174977C (en)
AT (1) ATE273303T1 (en)
AU (1) AU2001226346A1 (en)
BR (1) BR0107726A (en)
CA (1) CA2397593C (en)
CZ (1) CZ301195B6 (en)
DE (1) DE60104822T2 (en)
DK (1) DK1259507T3 (en)
EA (1) EA005247B1 (en)
ES (1) ES2222332T3 (en)
HU (1) HUP0204126A3 (en)
IL (2) IL150638A0 (en)
MX (1) MXPA02007005A (en)
NO (1) NO322572B1 (en)
NZ (1) NZ520280A (en)
PL (1) PL200696B1 (en)
PT (1) PT1259507E (en)
SI (1) SI1259507T1 (en)
SK (1) SK287404B6 (en)
TR (1) TR200402036T4 (en)
TW (1) TWI284129B (en)
WO (1) WO2001053293A1 (en)
ZA (1) ZA200205639B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039324A1 (en) 2016-08-23 2018-03-01 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of hepatocellular carcinoma
WO2018170447A1 (en) 2017-03-16 2018-09-20 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
WO2020130125A1 (en) 2018-12-21 2020-06-25 第一三共株式会社 Combination of antibody-drug conjugate and kinase inhibitor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284856A (en) * 1988-10-28 1994-02-08 Hoechst Aktiengesellschaft Oncogene-encoded kinases inhibition using 4-H-1-benzopyran-4-one derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN164232B (en) * 1986-04-11 1989-02-04 Hoechst India
US5908934A (en) * 1996-09-26 1999-06-01 Bristol-Myers Squibb Company Process for the preparation of chiral ketone intermediates useful for the preparation of flavopiridol and analogs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284856A (en) * 1988-10-28 1994-02-08 Hoechst Aktiengesellschaft Oncogene-encoded kinases inhibition using 4-H-1-benzopyran-4-one derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI, PING ET AL: "Evaluation of intravenous flavopiridol formulations", PDA J. PHARM. SCI. TECHNOL. (1999), 53(3), 137-140, XP000995938 *
SEDLACEK ET AL.: "Flavopiridol, a new kinase inhibitor for tumor therapy", INT. J. ONCOLOGY, vol. 9, pages 1143 - 1168, XP002103774 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039324A1 (en) 2016-08-23 2018-03-01 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of hepatocellular carcinoma
WO2018170447A1 (en) 2017-03-16 2018-09-20 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
US11083722B2 (en) 2017-03-16 2021-08-10 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
EP4218820A2 (en) 2017-03-16 2023-08-02 Eisai R&D Management Co., Ltd. Combination therapies for the treatment of breast cancer
WO2020130125A1 (en) 2018-12-21 2020-06-25 第一三共株式会社 Combination of antibody-drug conjugate and kinase inhibitor

Also Published As

Publication number Publication date
NZ520280A (en) 2004-04-30
MXPA02007005A (en) 2004-09-06
DE60104822D1 (en) 2004-09-16
NO20023386D0 (en) 2002-07-12
CN1174977C (en) 2004-11-10
SK10362002A3 (en) 2003-01-09
PT1259507E (en) 2004-12-31
BR0107726A (en) 2002-10-01
CA2397593A1 (en) 2001-07-26
SK287404B6 (en) 2010-09-07
EP1259507B1 (en) 2004-08-11
NO20023386L (en) 2002-09-12
PL356165A1 (en) 2004-06-14
HUP0204126A3 (en) 2006-02-28
TWI284129B (en) 2007-07-21
ATE273303T1 (en) 2004-08-15
CN1395576A (en) 2003-02-05
EP1259507A1 (en) 2002-11-27
JP2003520797A (en) 2003-07-08
EA200200775A1 (en) 2002-12-26
IL150638A0 (en) 2003-02-12
DK1259507T3 (en) 2004-11-01
EA005247B1 (en) 2004-12-30
TR200402036T4 (en) 2004-10-21
CA2397593C (en) 2009-11-10
SI1259507T1 (en) 2005-02-28
HUP0204126A2 (en) 2003-04-28
CZ20022466A3 (en) 2002-11-13
CZ301195B6 (en) 2009-12-02
KR100806464B1 (en) 2008-02-21
NO322572B1 (en) 2006-10-30
KR20020069361A (en) 2002-08-30
ES2222332T3 (en) 2005-02-01
DE60104822T2 (en) 2005-09-01
IL150638A (en) 2009-06-15
ZA200205639B (en) 2003-10-15
AU2001226346A1 (en) 2001-07-31
PL200696B1 (en) 2009-01-30

Similar Documents

Publication Publication Date Title
JP5119153B2 (en) A new crystal form of irinotecan hydrochloride
US20080108657A1 (en) Ethanol Solvate of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8-[4R-(3S-hydroxy-1-methyl)piperidinyl]-4H-1-benzopyran-4-one
US6576647B2 (en) Pseudopolymorph of (—)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4R-(3S-hydroxy -1-methyl)piperidinyl]-4H-1-benzopyran-4-one
EP1259507B1 (en) Pseudopolymorph of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8 4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one hydrochloride
WO2023174400A1 (en) Salt of substituted amino six-membered nitric heterocyclic compound, crystal form thereof, method for preparing same, and use thereof
CA2397594C (en) Ethanol solvate of (-)-cis-2-(2-chlorophenyl)-5,7-dihydroxy-8[4r-(3s-hydroxy-1-methyl)piperidinyl]-4h-1-benzopyran-4-one
CN111601791A (en) EZH2 inhibitor and pharmaceutically acceptable salt and polymorph thereof and application thereof
TWI826013B (en) Crystal forms of imidazolinone derivatives

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1200200736

Country of ref document: VN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 150638

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2001 553767

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2001900939

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2002/05639

Country of ref document: ZA

Ref document number: 10362002

Country of ref document: SK

Ref document number: 200205639

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: PV2002-2466

Country of ref document: CZ

Ref document number: IN/PCT/2002/00701/DE

Country of ref document: IN

Ref document number: 1020027009215

Country of ref document: KR

Ref document number: 2397593

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2002/007005

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 018038476

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 520280

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 200200775

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 1020027009215

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2002-2466

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 2001900939

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 520280

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2001900939

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 520280

Country of ref document: NZ