WO2011067348A2 - Sels d'inhibiteurs de mek et leurs solvates - Google Patents

Sels d'inhibiteurs de mek et leurs solvates Download PDF

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Publication number
WO2011067348A2
WO2011067348A2 PCT/EP2010/068763 EP2010068763W WO2011067348A2 WO 2011067348 A2 WO2011067348 A2 WO 2011067348A2 EP 2010068763 W EP2010068763 W EP 2010068763W WO 2011067348 A2 WO2011067348 A2 WO 2011067348A2
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Prior art keywords
oxo
bromo
methyl
sodium salt
fluorophenylamino
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PCT/EP2010/068763
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English (en)
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WO2011067348A3 (fr
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Liladhar Murlidhar Waykole
Piotr H. Karpinski
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Novartis Ag
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Publication of WO2011067348A3 publication Critical patent/WO2011067348A3/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 salt forms of 7-(4-Bromo-2-fluoro-phenylamino)-6- methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxyethoxy) -amide and 7- (4-Br omo - 2-fluor o-phenyl mino)-5-oxo-l,2,3,5 -tetrahydr o-indoliz ine- 8 - carboxyl ic acid cyclopropylmethoxy-amide and their corresponding solvates and polymorphs, 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-hydroxyethoxy)-amide (referred to herein as "Compound 1") and 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo- 1,2,3, 5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide (referred to herein as "Compound 2”) are potent MEK inhibitors.
  • the crystallinity, polymorphic behavior, and hygroscopicity of the compound and its pharmaceutical salt can have a significant effect on both stability and solubility of the compound or salt.
  • the toxicological considerations, crystallinity, monomorphism, melting point, stiochiometry, hydgroscopicity, stability in bulk, compatibility with excipients, pH of aqueous solutions, solubility in water and aqueous media, formation of solvates, morphology, handling, polymorphism behavior are all taken into consideration which is unique to a particular form of the compound and the mode of administration to a patient. Not all forms of the compound provide useful formulations, thus there is a need to identify specific forms of Compound 1 and 2 which can be used to provide a useful and stable pharmaceutical composition for use in treating diseases, conditions or disorders associated with MEK inhibition.
  • the present invention provides sodium salts of 7-(4-Bromo-2-fluoro-phenylamino)-6- methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxyethoxy) -amide and 7- (4-Br omo - 2-fluor o-phenyl amino)-5-oxo-l,2,3,5 -tetrahydr o-indoliz ine- 8 - carboxyl ic acid cyclopropylmethoxy-amide which have higher aqueous solubility, higher dissolution rate and good photo stability as compared to their corresponding free form.
  • a sodium salt of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxyethoxy)-amide is provided.
  • the salt is a 1 : 1 ratio of sodium to Compound 1.
  • a crystalline form of 7-(4-Bromo-2-fluoro- phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxyethoxy)-amide, sodium salt (“Form 1 A") is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 1.
  • a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl- 5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxyethoxy)-amide, sodium salt (“Form 1 A") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2(9) of 7.5°, 10.5°, 14.2°, 15.2°, 16. P, 17.8°, 19.9°, 20.3°, 22.8°, 23.8°, 24.2°, 24.8°, 25.9°, 27.0°, 28.6°, and 30.1°.
  • the crystalline form is substantially pure.
  • the sodium to Compound 1 ratio is preferably 1: 1.
  • 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-hydroxyethoxy)-amide, sodium salt ("Form 1 A") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 7.5°, 10.5°, 14.2°, 15.2°, 16. 1°, 17.8°, 19.9°, 20.3°, 22.8°, 23.8°, 24.2°, 24.8°, 25.9°, 27.0°, 28.6°, and 30.
  • the pharmaceutical composition may optionally comprise at least one additional pharmaceutical agent described herein below (preferably, the additional pharmaceutical agent is selected from an anti-tumor or an anti-proliferative agent).
  • a preferred additional pharmaceutical agent is a mTOR inhibitor or a PI3K inhibitor.
  • 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-hydroxyethoxy)-amide, sodium salt ("Form 1 A”) having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 7.5°, 10.5°, 14.2°, 15.2°, 16.1°, 17.8°, 19.9°, 20.3°, 22.8°, 23.8°, 24.2°, 24.8°, 25.9°, 27.0°, 28.6°, and 30.1°, or a pharmaceutical composition thereof.
  • the sodium salt may be administered either simultaneously or sequentially with at least one additional pharmaceutical agent described herein below (preferably, a mTOR inhibitor or
  • a crystalline form of 7-(4-Bromo-2- fluoro-phenylamino)-6-methyl-5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2- hydroxyethoxy)-amide, sodium salt (“Form IB") is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 3.
  • a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl- 5-oxo- l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxyethoxy)-amide, sodium salt (“Form IB") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 10.5°, 14.3°, 15. 1°, 18.5°, 19.0°, 20.2°, 21.3°, 23.1°, 24.3°, 24.8°, 25.3°, 25.8°, 26.4°, 27.2°, 28.2°, 28.4°, 29.2°, 30.0°, 31.1°, 32. P, 33.1°, 33.7°, 34.9°, and 36.3°.
  • the crystalline form is substantially pure.
  • the sodium to Compound 1 ratio is preferably 1: 1.
  • 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-hydroxyethoxy)-amide, sodium salt ("Form IB") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 10.5°, 14.3°, 15. 1°, 18.5°, 19.0°, 20.2°, 21.3°, 23.
  • the pharmaceutical composition may optionally comprise at least one additional pharmaceutical agent described herein below (preferably, the additional pharmaceutical agent is selected from an anti-tumor or an antiproliferative agent).
  • a preferred additional pharmaceutical agent is a mTOR inhibitor or a PI3K inhibitor.
  • 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-hydroxyethoxy)-amide, sodium salt ("Form IB”) having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2(9) of 10.5°, 14.3°, 15.
  • the sodium salt may be administered either simultaneously or sequentially with at least one additional pharmaceutical agent described herein below (preferably, a mTOR inhibitor or a PI3K inhibitor).
  • the present invention also provides a sodium salt of 7-(4-Bromo-2-fluoro- phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy- amide.
  • the salt is a 1 : 1 ratio of sodium to Compound 2.
  • cyclopropylmethoxy-amide, sodium salt having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 5.
  • a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide, sodium salt (“Form 2A") having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2(9) of 6.3°, 6.9°, 7.6°, 10.2°, 13.2°, 20.7°, 21.6°, 23.8°, 24.7°, 26.8°, 27.9°, 30.0°, and 32.6°.
  • the crystalline form is substantially pure.
  • the sodium to Compound 2 ratio is preferably 1 : 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo- l,2,3, 5- tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide, sodium salt having a powder X-ray diffraction pattern comprising peaks at diffraction angles (26?) of 6.3°, 6.9°, 7.6°, 10.2°, 13.2°, 20.7°, 21.6°, 23.8°, 24.7°, 26.8°, 27.9°, 30.0°, and 32.6°; and a
  • the pharmaceutical composition may optionally comprise at least one additional pharmaceutical agent described herein below (preferably, the additional pharmaceutical agent is selected from an anti-tumor or an anti- proliferative agent).
  • a preferred additional pharmaceutical agent is a mTOR inhibitor or a PI3K inhibitor.
  • 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)-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide, sodium salt having a powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 6.3°, 6.9°, 7.6°, 10.2°, 13.2°, 20.7°, 21.6°, 23.8°, 24.7°, 26.8°, 27.9°, 30.0°, and 32.6°, or a pharmaceutical composition thereof.
  • the sodium salt may be administered either simultaneously or sequentially with at least one additional pharmaceutical agent described herein below (preferably, a mTOR inhibitor or a PI3K inhibitor).
  • an acetone solvate of (7-(4-bromo-2- fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 7.
  • an acetonitrile solvate of (7-(4-bromo-2- fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt (“2A-ACN”) is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 9.
  • an ethanol solvate of (7-(4-bromo-2- fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt (“2A-ETH") is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 11.
  • an isopropyl acetate solvate of 7-(4-bromo- 2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8- carbonyl)(cyclopropylmethoxy)amide, sodium salt (“2A-I AC") is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 13.
  • an isopropanol solvate of -(4-bromo-2- fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8- carbonyl)(cyclopropylmethoxy)amide, sodium salt (“2A-ISO”)having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 15.
  • a tetrahydrofuran solvate of -(4-bromo-2- fluorophenylamino)-6-methyl-5-oxo- 1,2,3, -tetrahydroindolizine-8- carbonyl)(cyclopropylmethoxy)amide, sodium salt is provided having a X-ray diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in FIG. 17.
  • the crystalline form is substantially pure.
  • the sodium to Compound 2 ratio is preferably 1 : 1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a sodium salt of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo-l, 2,3,5- tetrahydroindolizine-8-carbonyl)(cyclopropylmethoxy)amide or any one of the solvates thereof (i.e., 2 A- ACT, 2A-ACN, 2A-ETH, 2A-IAC. 2A-ISO or 2A-THF) and a
  • the pharmaceutical composition may optionally comprise at least one additional pharmaceutical agent described herein below (preferably, the additional pharmaceutical agent is selected from an anti-tumor or an antiproliferative agent).
  • a preferred additional pharmaceutical agent is a mTOR inhibitor or a PI3K inhibitor.
  • 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 sodium salt of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- l,2,3,5-tetrahydroindolizine-8-carbonyl)(cyclopropylmethoxy)amide or any one of the solvates thereof (i.e., 2 A- ACT, 2A-ACN, 2A-ETH, 2A-IAC. 2A-ISO or 2A-THF) or a pharmaceutical composition thereof.
  • the sodium salt may be administered either simultaneously or sequentially with at least one additional pharmaceutical agent described herein below (preferably, a mTOR inhibitor or a PI3K inhibitor).
  • 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.
  • peak positions 26
  • peak positions 26
  • peak positions 26
  • 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).
  • solvate refers to a molecular complex of the compound with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, acetone, acetonitrile, ethanol, isopropanol, isopropyl acetate, tetrahydrofuran, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • compounds of the present invention refers to the sodium salts of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro- indolizine-8-carboxylic acid (2-hydroxyethoxy)-amide and (7-(4-bromo-2- fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)-
  • 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-hydroxyethoxy)-amide, sodium salt ("Form 1 A").
  • Figure 2 shows a TGA-DTA thermogram of the "Form 1A" crystalline form of 7-(4- Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxyethoxy)-amide, sodium salt.
  • 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-hydroxyethoxy)-amide, sodium salt ("Form IB").
  • Figure 4 shows a TGA-DTA thermogram of the "Form IB" crystalline form of 7-(4-
  • Figure 5 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt ("Form 2 A").
  • Figure 6 shows a TGA-DTA thermogram of the "Form 2A" crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt.
  • Figure 7 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, acetone solvate ("Form 2A-ACT").
  • Figure 8 shows a TGA-DTA thermogram of the "Form 2A- ACT" crystalline form of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, acetone solvate.
  • Figure 9 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, acetonitrile solvate ("Form 2A-ACN").
  • Figure 10 shows a TGA-DTA thermogram of the "Form 2A-ACN” crystalline form of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, acetonitrile solvate.
  • Figure 11 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, ethanol solvate ("Form 2A-ETFF ').
  • Figure 12 shows a TGA-DTA thermogram of the "Form 2A-ETH” crystalline form of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, ethanol solvate.
  • Figure 13 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, isopropyl acetate solvate ("Form 2A-IAC").
  • Figure 14 shows a TGA-DTA thermogram of the "Form 2A-IAC" crystalline form of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, isopropyl acetate solvate.
  • Figure 15 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, isopropanol solvate ("Form 2A-ISO").
  • Figure 16 shows a TGA-DTA thermogram of the "Form 2A-ISO” crystalline form of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, Isopropanol solvate.
  • Figure 17 shows a powder X-ray diffraction pattern of the crystalline form of (7-(4- bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, tetrahydofuran solvate ("Form 2A-THF").
  • Figure 18 shows a TGA-DTA thermogram of the "Form 2A-THF" crystalline form of (7-(4-bromo-2-fluorophenylamino)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carbonyl)- (cyclopropylmethoxy)amide, sodium salt, tetrahydrofuran solvate.
  • thermogram for the crystalline Form 1 A and Form IB of 7-(4-Bromo-2-fluoro-phenylamino)- 6-methyl-5-oxo-l,3,5-tetrahydro-indolizine-8-carboxylic acid (2-hydroxyethoxy)-amide, sodium salt (Compound 1) are shown in FIG. 2 and FIG. 4, respectively.
  • 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] yrimidin-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-Morpholiny
  • dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • a compound of the present invention or a combination of a compound of the present invention and at least one additional
  • 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 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.
  • Thermogravimetric analysis/differential thermal analysis (TGA)fDTA) TA
  • X-ray powder diffraction : Bruker AXS Discover D8, Madison, WI, USA
  • Hyproscopicity Sorption/desorption isotherms were measured at 25 °C using Surface Measurement Systems Ltd's dynamic vapor sorption instrument (DVS-HT).
  • Step 1 Preparation of Intermediate 7-Hydroxy-6-methyl-5-oxo- 1,2,3, 5-tetrahydro- indolizine-8-carboxylic acid ethyl ester (1-1 a):
  • Step 2 Preparation of Intermediate 6-Methyl-5-oxo-7-trifluoromethanesulfonyloxy-l ,2,3,5- tetrahydro-indolizine-8-carboxylic acid ethyl ester (1-1 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-indo!izine-8-carboxyiic acid fl-ld):
  • Step 5 Preparation of Intermediate 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1 ,2,3,5-tetrahvdro-indolizine-8-carboxylic acid (2-vinyloxy-ethoxy) -amide (1-le): To a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1,2,3,5- tetrahydro-indolizine-8-carboxylic acid (I-ld: 300 mg, 0.787 mmol) in 6 mL of dry dimethylformamide(DMF) and 2 mL of dichloromethane was added l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI) (165 mg, 0.865 mmol) and HOBt ( 116 mg, 0.865 mmol) at 0°C. The resulting reaction
  • 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).
  • Compound 1 was also prepared using the following synthesis.
  • Step 1 Preparation of Intermediate Ethyl 7-chloro-6-methyl-5-oxo-l,2,3, 5-tetrahydro- indolizine-8-carboxylate (I-2a).
  • Step 2 Preparation of Intermediate 7-C loro-6- ethyl-5-oxo-l,2,3,5-tetrahydro-indolizine- 8-carboxylic acid (I-2b).
  • Step 3 Preparation of Intermediate 7-(4-Bromo-2-fluoro-phenylamino)-6-methyl-5-oxo- 1 ,2,3,5-tetrahydro-indoli ⁇ ine-8-carboxylic acid (I-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).
  • 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 1).
  • Triethylamine is added to a mixture of 5 -methoxy-3,4-dihydro-2H- pyrrole (SM-2: 73 g, 0.73 mmol) and 3-oxopentanedioic acid diethyl ester (200 g, 0.99 mmol) at room temperature.
  • SM-2 5 -methoxy-3,4-dihydro-2H- pyrrole
  • 3-oxopentanedioic acid diethyl ester 200 g, 0.99 mmol
  • the reaction is monitored by the TLC (9: 1 CHCl 3 -MeOH v/v).
  • the reaction mixture is diluted with ethyl acetate (60ml) and filtered.
  • the filtrate is washed with water (100ml) and the aqueous layer is re-extracted with ethyl acetate (30ml).
  • the combined organic extracts are dried (anhydrous Na 2 S0 4 ), concentrated, and the crude product is purified by column chromatography on silica gel (60- 120 mesh) using 0.1-0.5% MeOH in chloroform to afford 336 mg (13% yield) of the title compound.
  • the reaction mixture is diluted with ethyl acetate (20ml) and washed with saturated aqueous NH 4 CI solution (25ml), saturated aqueous NaHCOs solution (25ml), and brine (25ml).
  • the combined organic extracts are dried (anhydrous a 2 S0 4 ) and concentrated.
  • the residual material is purified by column chromatography on silica gel (1% MeOH in CHC1 3 ) to afford the title compound in 36% yield.
  • Example 1 illustrates the preparation of 7-(4-bromo-2-fluorophenylamino)-N-(2- hydroxyethoxy)-6-methyl-5-oxo- 1,2,3, 5-tetrahydroindolizine-8-carboxamide, sodium salt in its crystalline form.
  • the solid was collected by suction filtration and washed with approximately 5 mL of propan-2-ol and then dried at 55°C for 16 hours to obtain 4.68 g (yield 92.1%) of colorless crystalline salt.
  • the salt is a crystalline solid having >99% purity and a 1: 1 acid:base stoichiometry (N:Na).
  • the salt ( 1A) has a very high solubility in aqueous media as well as in alcohols and aqueous-organic solvent mixtures.
  • the crystalline sodium salt exhibited polymorphic behavior: two polymorphic forms (Forms A and B) were identified (see, FIG. 1 and FIG. 3).
  • the crystalline salt is non- hygroscopic: absorbs 1.6% moisture at 85% relative humidity and retained up to 10% moisture upon desorption to 25% relative humidity with loss of crystallinity.
  • the salt form lost crystallinity upon compression but retained crystallinity upon grinding.
  • the crystalline salt had very high solubility in the aqueous media as well as in alcohols and aqueous-organic solvent mixtures. It had only 0.37% of residual solvent/moisture content.
  • Step time 180 seconds
  • Step time 60 seconds
  • Example 2 illustrates the preparation of 7-(4-Bromo-2-fluoro-phenylamino)-5-oxo- l,2,3,5-tetrahydro-indolizine-8-carboxylic acid cyclopropylmethoxy-amide, sodium salt in its crystalline form.
  • Salt (2A) is a crystalline solid having > 99% purity and has a 1: 1 acid:base stiochiometry (N-Na). The TGA data indicated that it decomposes at approximately 232°C. Unlike the corresponding free form, the salt has a very high solubility in aqueous media as well as in alcohols and aqueous- organic solvent mixtures.
  • Step time 180 seconds
  • Salt (2A) formed an amorphous solvate with acetonitrile. It also formed crystalline solvates with acetone, absolute ethanol, isopropyl acetate, propan-2-ol, and tetrahydrofuran.
  • the crystalline solvates of the sodium salt (2A) were prepared with acetone, ethanol, isopropyl acetate, isopropanol, and tetrahydrofuran using the following general procedure. A suspension of—50 mg of salt in 1 mL of solvent was agitated for 24 hours at 25°C and filtered. The solids were air dried and tested by XRPD and TGA-DTA.
  • Step time 60 seconds
  • Step time 60 seconds
  • Step time 60 seconds
  • Step time 60 seconds
  • Step time 60 seconds

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Abstract

La présente invention a pour objet des formes de sels de sodium du (2-hydroxyéthoxy)-amide de l'acide 7-(4-bromo-2-fluoro-phénylamino)-6-méthyl-5-oxo-1,3,5-tétrahydro- indolizine-8-carboxylique et du cyclopropylméthoxy-amide de l'acide 7-(4-bromo-2-fluoro-phénylamino)-5-oxo-1,2,3,5-tétrahydro-indolizine-8- carboxylique et leurs solvates et polymorphes correspondants, 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.
PCT/EP2010/068763 2009-12-03 2010-12-02 Sels d'inhibiteurs de mek et leurs solvates WO2011067348A2 (fr)

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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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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
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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

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