WO2011067356A2 - Polymorphes d'un inhibiteur de mek - Google Patents

Polymorphes d'un inhibiteur de mek Download PDF

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Publication number
WO2011067356A2
WO2011067356A2 PCT/EP2010/068776 EP2010068776W WO2011067356A2 WO 2011067356 A2 WO2011067356 A2 WO 2011067356A2 EP 2010068776 W EP2010068776 W EP 2010068776W WO 2011067356 A2 WO2011067356 A2 WO 2011067356A2
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Prior art keywords
oxo
methyl
bromo
fluoro
phenylamino
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PCT/EP2010/068776
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English (en)
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WO2011067356A3 (fr
Inventor
Liladhar Murlidhar Waykole
Piotr H. Karpinski
Song Xue
Karen Beltz
Frank Hans Seiler
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Novartis Ag
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Publication of WO2011067356A3 publication Critical patent/WO2011067356A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to polymorphic forms of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide which are useful in the treatment of a disease, disorder or syndrome associated with MEK inhibition, such as cancer, in mammals.
  • the invention also relates to
  • compositions thereof and to methods of using such compositions in the treatment of cancer in mammals, especially humans.
  • Compound 1 The compound 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (referred to herein as "Compound 1") is a potent MEK inhibitor.
  • the crystallinity, polymorphic behavior, and hygroscopicity of the compound or its pharmaceutical salt can have a significant effect on both stability and solubility of the compound or salt. In the development of a useful and effective
  • compositions for use in treating diseases, conditions or disorders associated with MEK inhibition.
  • the present invention provides a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1 (referred to herein as "Form 1- A").
  • the present invention also provides a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide ("Form 1-A") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2(9) of 5.2°, 7.4°, 8.6°, 13.3°, 14.7°, 15. ⁇ , 17.3°, 18.8°, 20.0°, 20.8°, 22.3°, 23.7°, and 26. ⁇ .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 5.2°, 7.4°, 8.6°, 13.3°, 14.7°, 15. 1°, 17.3°, 18.8°, 20.0°, 20.8°, 22.3°, 23.7°, and 26. 1°; and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of treating cancer in a mammal comprising administering to a mammal (preferably a human) in need thereof a therapeutic amount of a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5- oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 5.2°, 7.4°, 8.6°, 13.3°, 14.7°, 15. P, 17.3°, 18.8°, 20.0°, 20.8°, 22.3°, 23.7°, and 26. P, or a
  • the present invention provides a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3 (referred to herein as "Form 1-B").
  • a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide (“Form 1-B") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2(9) of 7.7°, 20.3°, 22.5°, 23.5°, 24.8°, 27.9° and 31.9° is provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 7.7°, 20.3°, 22.5°, 23.5°, 24.8°, 27.9° and 3 1.9°; and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of treating cancer in a mammal comprising administering to a mammal (preferably a human) in need thereof a therapeutic amount of a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5- oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (29) of 7.7°, 20.3°, 22.5°, 23.5°, 24.8°, 27.9° and 3 1.9°, or a pharmaceutical composition thereof.
  • a crystalline form of 7-(4-Bromo-2- fluoro-phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxy-ethoxy)-amide is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 5 (referred to herein as "Form 2").
  • a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl- 5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (“Form 2") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 7.7°, 15.4°, 15.8°, 21. 1°, 21.5°, 21.9°, 23. 1°, 23.5°, 26.4° and 36.6°.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 7.7°, 15.4°, 15.8°, 21.1°, 21.5°, 21.9°, 23. 1°, 23.5°, 26.4° and 36.6°; and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of treating cancer in a mammal comprising administering to a mammal (preferably a human) in need thereof a therapeutic amount of a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5- oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 7.7°, 15.4°, 15.8°, 21.1°, 21.5°, 21.9°, 23.1°, 23.5°, 26.4° and 36.6°, or a pharmaceutical composition thereof.
  • a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 7 (referred to herein as "Form 3").
  • a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl- 5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (“Form 3") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 7.3°, 8.5°, 13.2°, 14.6°, 19.8°, 22.6°, 23.6°, 26.2°, 31.0° and 34.8°.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 7.3°, 8.5°, 13.2°, 14.6°, 19.8°, 22.6°, 23.6°, 26.2°, 31.0° and 34.8°; and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of treating cancer in a mammal comprising administering to a mammal (preferably a human) in need thereof a therapeutic amount of a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5- oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 7.3°, 8.5°, 13.2°, 14.6°, 19.8°, 22.6°, 23.6°, 26.2°, 31.0° and 34.8°, or a pharmaceutical composition thereof.
  • a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy- ethoxy)-amide is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 9 (referred to herein as "Form 4").
  • a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl- 5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (“Form 4") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 13.0°, 13.7°, 14.5°, 23.7°, 24. F, 26.0°, 31.3°, and 32.8°.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 13.0°, 13.7°, 14.5°, 23.6°, 24.1°, 26.0°, 31.3°, and 32.8°; and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of treating cancer in a mammal comprising administering to a mammal (preferably a human) in need thereof a therapeutic amount of a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5- oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 13.0°, 13.7°, 14.5°, 23.6°, 24. 1°, 26.0°, 31.3°, and 32.8°, or a pharmaceutical composition thereof.
  • a crystalline hydrate of 7-(4-bromo-2- fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxy-ethoxy)-amide is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 11 (referred to herein as "Hydrate").
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5- tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 3.7°, 10.9°, 14.3°, 15.2°, 17.0°, 17.8°, 19.0°, 19.3°, 20.6°, 21.4°, 21.9°, 22.4, 23.0°, 23.3°, 24.6°, 25.1°, 25.9°, 26.6°, 27.7°, 28.8°, 30.3°, 30.7°, and 32.0°; and a pharmaceutically acceptable excipient, diluent or carrier.
  • the present invention provides a method of treating cancer in a mammal comprising administering to a mammal (preferably a human) in need thereof a therapeutic amount of a crystalline form of 7-(4-bromo-2-fluoro-phenylamino)-6-mefhyl-5- oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2(9) of 3.7°, 10.9°, 14.3°, 15.2°, 17.0°, 17.8°, 19.0°, 19.3°, 20.6°, 21.4°, 21.9°, 22.4, 23.0°, 23.3°, 24.6°, 25. P, 25.9°, 26.6°, 27.7°, 28.8°, 30.3°, 30.7°, and 32.0°, or a pharmaceutical composition thereof.
  • a mammal preferably a
  • Form 3 Form 4 and Hydrate are substantially pure.
  • the term "substantially pure" with reference to a particular polymorphic form means that the polymorphic form includes less than 10%, preferably less than 5%, more preferably less than 3%, most preferably less than 1% by weight of any other physical forms of the compound.
  • X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account.
  • peak positions (2 ⁇ ) will show some inter- apparatus variability, typically as much as 0.2°.
  • relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measure only.
  • free form refers to the compound per se without salt formation or association with a solvent (e.g., solvate).
  • Figure 1 shows a powder X-ray diffraction pattern of the crystalline form of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1 "Form 1-A").
  • Figure 2 shows a TGA-DT A thermogram of the "Form 1-A" polymorph of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
  • Figure 3 shows a powder X-ray diffraction pattern of the crystalline form of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1 "Form 1-B").
  • Figure 4 shows a differential scanning calorimetry (DSC) thermogram of the "Form 1-B" polymorph of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
  • DSC differential scanning calorimetry
  • Figure 5 shows a powder X-ray diffraction pattern of a crystalline form of 7-(4-
  • Figure 6 shows a differential scanning calorimetry (DSC) thermogram for the "Form 2" polymorph of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
  • DSC differential scanning calorimetry
  • Figure 7 shows a powder X-ray diffraction pattern of the crystalline form of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1 - "Form 3").
  • Figure 8 shows a differential scanning calorimetry (DSC) thermogram of the "Form 3" polymorph of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
  • Figure 9 shows a powder X-ray diffraction pattern of the crystalline form of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1 - "Form 4").
  • Figure 10 shows a differential scanning calorimetry (DSC) thermogram of the "Form 4" polymorph of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
  • DSC differential scanning calorimetry
  • Figure 11 shows a powder X-ray diffraction pattern of the crystalline hydrate form of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide (Compound 1 "Hydrate").
  • Figure 12 shows a TGA-DTA thermogram of the crystalline hydrate form of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide.
  • thermogram for the "Hydrate” crystalline form of 7-(4-Bromo- 2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxy-ethoxy)-amide is shown in FIG 12.
  • Compound 1 (7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxy-ethoxy)-amide) can be synthesized using the procedures outlined in Schemes I or 2 below or by the methods disclosed in PCT Publication No. WO 2008/082846 or US Publication No. 2009/0275606, incorporated herein by reference.
  • Compound 1 may be prepared using the synthesis outlined in Scheme II below.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.
  • the pharmaceutical formulations may be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention is dissolved in a suitable solvent in the presence of one or more of the excipients described below.
  • the compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • compositions comprising a compound of the present invention in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or
  • binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/ or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds of the invention in combination with one or more therapeutic agents (pharmaceutical combinations).
  • therapeutic agents for example, synergistic effects can occur with other anti-tumor or anti-proliferative agents, for example, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors (e.g., trastuzumab, panitumumab, cetuximab, gefitinib, erlotinib, lapatinib, sorafenib, etc.), cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, anti-androgens, an anti- angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor.
  • mitotic inhibitors for example, mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors (e.g., trastuzumab, panitum
  • Suitable therapeutic agents include erlotinib, docetaxel, gemcitabine, cisplatin, carboplatin, paclitaxel, bevacizumab, trastuzumab, pertuzumab, temozolomide, taxoxifen, doxorubicin, rapamycin and lapatnib. Other suitable therapeutic agents are listed in the Physicians Desk Reference.
  • Preferred therapeutic agents for combination therapy include mTOR inhibitors (e.g., Rapamycin (sirolimus), TORISELTM(temsirolimus), RADOOl (everolimus),
  • mTOR inhibitors e.g., Rapamycin (sirolimus), TORISELTM(temsirolimus), RADOOl (everolimus)
  • PI3K inhibitors e.g., wortmannin, 17-hydroxywortmannin analogs described in WO 06/044453, 4-(2-(lH-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-l-yl)methyl)thieno- [3,2- d]pyrimidin-4-yl)morpholine, (S)- l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- mo holinothieno[3,2-d]pyrirrlidin-6-yl)methyl)piperazin-l-yl)-2-hydroxypropan-l-one, 4- (2-(lH-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin- l-yl)methyl)thieno- [2,3-d]pyrimidin- 4-yl)morpholine, LY294002(2-(4-Morpholin
  • the pharmaceutical agent is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.
  • the compound of the present invention and at least one other pharmaceutical agent may be administered either separately or in the pharmaceutical composition comprising both. It is generally preferred that such administration be oral. However, if the subject being treated is unable to swallow, or oral administration is otherwise impaired or undesirable, parenteral or transdermal administration may be appropriate.
  • a combination of a compound of the present invention and at least one other pharmaceutical agent when administered together, such administration can be sequential in time or simultaneous with the simultaneous method being generally preferred.
  • a compound of the present invention and the additional pharmaceutical agent can be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous.
  • the administration of each can be by the same or by different methods.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container has deposited thereon a label that describes the contents of the container.
  • the label may also include appropriate warnings.
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, and b) at least one additional therapeutic agent.
  • the kit may also include instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of the present invention and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of the present invention and a co-agent are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • DSC Differential scanning calorimetry
  • X-ray powder diffraction : Bruker AXS Discover D8, Madison, WI, USA
  • Examples 1 through 4 illustrate crystalline forms of 7-(4-bromo-2- fluorophenyl amino )-N-( 2-hydroxyethoxy )- 6 -methyl- 5-oxo-l,2,3,5 -tetrahydroindol izine- 8- carboxamide.
  • Step l Preparation of Intermediate 7-Hydroxy-6-methyl-5-oxo-l,2,3,5-tetrahydro- indolizine-8-carboxylic acid ethyl ester (I- la):
  • Step 2 Preparation of Intermediate 6-Methyl-5-oxo-7-trifluoromethanesulfonyloxy-l ,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester (I-l b):
  • Step 3 Preparation of Intermediate 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1 ,2,3,5-tetrahydro-indolizine-8-carboxylic acid ethyl ester (I-lc):
  • Step 4 Preparation of Intermediate 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1 ,2,3,5-tetrahydro-indoli ⁇ ine-8-carboxylic acid (I- Id):
  • Step 6 Preparation of 7-(4-bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-6-methyl-5- oxo-1,2,3, 5-tetrahydroindolizine-8-carboxamide (Compound 1).
  • Step time 60 seconds
  • the crystalline form may be prepared by substituting ethyl acetate with 2-butanone or absolute ethanol.
  • Step 1 Preparation of Intermediate Ethyl 7-chloro-6-methyl-5-oxo-l,2,3, 5-tetrahydro- indolizine-8-carboxylate (I-2a).
  • Step 3 Preparation of Intermediate 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1 ,2,3,5-tetrahvdro-indolizine-8-carboxylic acid (l-2c).
  • Lithium bis(trimethylsilyl)amide (0.4 L, 1M in tetrahydrofuran, 0.4 mol) was added over 1 hour while maintaining an internal batch temperature below 10 °C throughout the addition.
  • the resulting suspension was warmed to 22°C over 1 hour and stirred at 22°C for 4 hours till the remaining intermediate carboxylic acid (I-2b) was fully consumed as determined by HPLC analysis.
  • the reaction mixture was cooled to 12°C and 3N hydrochloric acid (0.4 L) was added over 30 minutes while maintaining a batch temperature ⁇ 22 °C.
  • Heptane (0.6 L) was added over 30 minutes and the mixture was stirred at room temperature over 10 hours.
  • the suspension was filtered and the solid cake was rinsed with water (0.6 L). The solid cake was collected and slurried in
  • Step 4 Preparation of 7-f (4-Bromo-2-fluorophenyl) amino] -1 ,2,3, 5-tetrahydro-N-(2- hydroxyethoxy)-6-methyl-5-oxo-8-indolizinecarboxamide (Compound I).
  • Step 5 Recrystallization and isolation of Form 3 crystalline material:
  • the mixture was filtered while hot through a Celite ® pad and the filter cake was rinsed with hot (> 60 °C) 200 proof ethanol (1.2 L).
  • the filtrate was heated to 78°C and stirred at 78°C for another 10 minutes.
  • the mixture was allowed to cool to 40°C over a minimum of 30 minutes.
  • After seeding with 7-(4-bromo-2-fluorophenylamino)-N-(2-hydroxyethoxy)-6- methyl-5-oxo- l,2,3,5-tetrahydroindolizine-8-carboxamide (0.5 g) the mixture was stirred gently for 6 hours at 40°C during which precipitation occurs.
  • Step time 60 seconds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention a pour objet des formes polymorphes du (2-hydroxy-éthoxy)-amide de l'acide 7-(4-bromo-2-fluoro-phénylamino)-6-méthyl-5-oxo-1,3,5-tétrahydro- indolizine-8-carboxylique et son hydrate qui sont utiles dans le traitement d'une maladie, d'un trouble ou d'un syndrome associé à l'inhibition de MEK, tel qu'un cancer, chez les mammifères. L'invention concerne également leurs compositions et des méthodes d'utilisation de ces compositions dans le traitement d'un cancer chez les mammifères, spécialement chez l'homme.
PCT/EP2010/068776 2009-12-03 2010-12-02 Polymorphes d'un inhibiteur de mek WO2011067356A2 (fr)

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US61/266,391 2009-12-03
US26683809P 2009-12-04 2009-12-04
US61/266,838 2009-12-04

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109142A1 (fr) 2012-01-16 2013-07-25 Stichting Het Nederlands Kanker Instituut Inhibition de la voie des mapk/erk et pdk combinée dans des cas de néoplasie
WO2015041533A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut Association de rock et de la voie mapk
WO2015041534A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut P90rsk en combinaison avec raf/erk/mek
WO2015156674A2 (fr) 2014-04-10 2015-10-15 Stichting Het Nederlands Kanker Instituut Méthode de traitement du cancer
WO2015178770A1 (fr) 2014-05-19 2015-11-26 Stichting Het Nederlands Kanker Instituut Compositions pour le traitement du cancer

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044453A1 (fr) 2004-10-13 2006-04-27 Wyeth Analogues de la 17-hydroxywortmannine employés en tant qu’inhibiteurs de pi3k
WO2006090167A2 (fr) 2005-02-25 2006-08-31 Kudos Pharmaceuticals Limited Composes
WO2006090169A1 (fr) 2005-02-25 2006-08-31 Kudos Pharmaceuticals Limited Derives de 2 , 4-diamino-pyridopyrimidine et leur utilisation comme inhibiteurs mtor
WO2007060404A1 (fr) 2005-11-22 2007-05-31 Kudos Pharmaceuticals Limited Dérivés de pyrido-, pyrazo- et pyrimido-pyrimidine en tant qu'inhibiteurs de mtor
WO2007080382A1 (fr) 2006-01-11 2007-07-19 Astrazeneca Ab Dérivés de morpholinopyrimidine et leur utilisation thérapeutique
WO2008023161A1 (fr) 2006-08-23 2008-02-28 Kudos Pharmaceuticals Limited Dérivés de la 2-méthylmorpholine pyrido-, pyrazo- et pyrimido-pyrimidine en tant qu'inhibiteurs de mtor
WO2008082846A1 (fr) 2006-12-29 2008-07-10 3M Innovative Properties Company Appareil pour monter des structures de film, et procédés
US20090275606A1 (en) 2008-04-21 2009-11-05 Novartis Ag Heterocyclic Compounds as MEK Inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044453A1 (fr) 2004-10-13 2006-04-27 Wyeth Analogues de la 17-hydroxywortmannine employés en tant qu’inhibiteurs de pi3k
WO2006090167A2 (fr) 2005-02-25 2006-08-31 Kudos Pharmaceuticals Limited Composes
WO2006090169A1 (fr) 2005-02-25 2006-08-31 Kudos Pharmaceuticals Limited Derives de 2 , 4-diamino-pyridopyrimidine et leur utilisation comme inhibiteurs mtor
WO2007060404A1 (fr) 2005-11-22 2007-05-31 Kudos Pharmaceuticals Limited Dérivés de pyrido-, pyrazo- et pyrimido-pyrimidine en tant qu'inhibiteurs de mtor
WO2007080382A1 (fr) 2006-01-11 2007-07-19 Astrazeneca Ab Dérivés de morpholinopyrimidine et leur utilisation thérapeutique
WO2008023161A1 (fr) 2006-08-23 2008-02-28 Kudos Pharmaceuticals Limited Dérivés de la 2-méthylmorpholine pyrido-, pyrazo- et pyrimido-pyrimidine en tant qu'inhibiteurs de mtor
WO2008082846A1 (fr) 2006-12-29 2008-07-10 3M Innovative Properties Company Appareil pour monter des structures de film, et procédés
US20090275606A1 (en) 2008-04-21 2009-11-05 Novartis Ag Heterocyclic Compounds as MEK Inhibitors

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109142A1 (fr) 2012-01-16 2013-07-25 Stichting Het Nederlands Kanker Instituut Inhibition de la voie des mapk/erk et pdk combinée dans des cas de néoplasie
WO2015041533A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut Association de rock et de la voie mapk
WO2015041534A1 (fr) 2013-09-20 2015-03-26 Stichting Het Nederlands Kanker Instituut P90rsk en combinaison avec raf/erk/mek
WO2015156674A2 (fr) 2014-04-10 2015-10-15 Stichting Het Nederlands Kanker Instituut Méthode de traitement du cancer
WO2015178770A1 (fr) 2014-05-19 2015-11-26 Stichting Het Nederlands Kanker Instituut Compositions pour le traitement du cancer

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