WO2015018523A1 - Nouvel inhibiteur de bet-brd pour le traitement de tumeurs solides - Google Patents

Nouvel inhibiteur de bet-brd pour le traitement de tumeurs solides Download PDF

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WO2015018523A1
WO2015018523A1 PCT/EP2014/002166 EP2014002166W WO2015018523A1 WO 2015018523 A1 WO2015018523 A1 WO 2015018523A1 EP 2014002166 W EP2014002166 W EP 2014002166W WO 2015018523 A1 WO2015018523 A1 WO 2015018523A1
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compound
carbon number
solid dispersion
thienotriazolodiazepine
pharmaceutically acceptable
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PCT/EP2014/002166
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English (en)
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Eric Raymond
Maria E. RIVEIRO
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Oncoethix Sa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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 disclosure relates to a method of treating solid tumors using a
  • the human BET family bromodomains which consists of BRD2, BRD3, BRD4 and BRDT proteins has become a druggable target for the development of specific gene transcription inhibitors.
  • BRD2, BRD3, BRD4 and BRDT proteins has become a druggable target for the development of specific gene transcription inhibitors.
  • anti-proliferative activity of an orally bioavailable small-molecule BRD-inhibitor which displays high potency and specificity to BRDs 2, 3, and 4, across a large panel of human solid tumor cell lines.
  • the present invention provides for a method of treating solid tumors comprising the step of administering a pharmaceutical acceptable amount of a
  • thienotriazolodiazepine compound being represented by the thienotriazolodiazepine compound of
  • R 1 is alkyl having a carbon number of 1-4
  • R 2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1 - 4, alkoxy having a carbon number of 1-4 or cyano; ⁇ NR 5 ⁇ (CH 2 ) m — R 6 wherein R 5 is a hydrogen atom or alkyl having a carbon number of 1 -4, m is an integer of 0-4, and R 6 is phenyl or pyridyl optionally substituted by a halogen atom; or— NR 7 — CO— (CH 2 )n— R 8 wherein R 7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R 8 is
  • the solid tumor independently includes colon cancer, renal cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, liver cancer, triple negative breast cancer, and ovarian cancer. In some embodiments, the solid tumor is independently selected from head and neck cancer and triple negative breast cancer.
  • the thienotriazolodiazepine compound represented by Formula (1) is selected from the group consisting of: (a) (S)-2-[4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-fJ[l,2,4]triazolo- [4,3-a][l ,4]diazepin-6-yl]-N-(4- hydroxyphenyl)acetamide or a dihydrate thereof, (b) methyl (S)- ⁇ 4-(3'-cyanobiphenyl-4-yl)-2,3,9- trimethyl-6H-thieno[3,2-fj[l,2,4]tri- azolo[4,3 -a] [l,4]diazepin-6-yl ⁇ acetate, (c) methyl (S)- ⁇ 2,3,9- trimethyl-4-(4-phenylaminophenyl)-6H-thieno
  • the thienotriazolodiazepine compound is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-fJ[l,2,- 4]triazolo[4,3- a][l,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate.
  • the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion.
  • the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion.
  • thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1) and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate having a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate (HPMCAS), weight ratio of 1 :3 to 1 : 1.
  • the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
  • Figure 1A illustrates dissolution profile of a comparator formulation comprising a solid dispersion comprising 25% compound (1-1) and Eudragit L100-55.
  • Figure IB illustrates dissolution profile of a comparator formulation comprising a solid dispersion comprising 50% compound (1-1) and Eudragit L100-55.
  • Figure 1C illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • Figure ID illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and PVP.
  • Figure IE illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and PVP -vinyl acetate (PVP-VA).
  • Figure I F illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and PVP-VA.
  • Figure 1G illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose acetate succinate (HPMCAS-M).
  • Figure 1H illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HPMCAS-M.
  • Figure I I illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound ( 1-1) and hypromellose phthalate (HPMCP-HP55).
  • Figure 1J illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HMCP-HP55.
  • Figure 2A illustrates results of in vivo screening of an exemplary formulation comprising a solid dispersion of 25% compound (1-1) and PVP.
  • Figure 2B illustrates results of an in vivo screening of an exemplary formulation comprising a solid dispersion of 25% compound (1-1) and HPMCAS-M.
  • Figure 2C illustrates results of an in vivo screening of an exemplary formulation comprising a solid dispersion of 50% compound (1-1) and HPMCAS-M.
  • Figure 3 illustrates powder X-ray diffraction profiles of solid dispersions of compound (1 - 1) ⁇
  • Figure 4A illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under ambient conditions.
  • Figure 4B illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and HPMCAS-M equilibrated under ambient conditions.
  • Figure 4C illustrates modified differential scanning calorimetry trace for a solid dispersion of 50% compound (1-1) and HPMCAS-M equilibrated under ambient conditions.
  • FIG. 5 illustrates plot of glass transition temperature (Tg) versus relative hunidity (RH) for solid dispersions of 25% compound (1-1) and PVP or HMPCAS-M and 50% compound (1 -1) and HPMCAS-MG.
  • Figure 6 illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under 75% relative humidity.
  • Figures 7A and 7B illustrate plasma concentration versus time curves for Compound (1-1) after 1 mg/kg intravenous dosing (solid rectangles) and 3 mg/kg oral dosing as 25% Compound (1 - 1):PVP (open circles), 25% Compound (1-1):HPMCAS-MG (open triangles), and 50% Compound (1-1):HPMCAS-MG (open inverted triangles).
  • the inset depicts the same data plotted on a semilogarithmic scale.
  • Figures 8A and 8B illustrate plasma concentration versus time curves for Compound (1-1 ) after 3 mg/kg oral dosing as 25% Compound (1-1): PVP (open circles), 25% Compound (1- 1):HPMCAS-MG (open triangles), and 50% Compound (1-1):HPMCAS-MG (open inverted triangles).
  • the inset depicts the same data plotted on a semi-logarithmic scale.
  • Figure 9 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1 - 1) in HPMCAS-MG at time zero of a stability test.
  • Figure 10 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 1 month at 40 °C and 75 % relative humidity.
  • Figure 11 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 2 months at 40 °C and 75 % relative humidity.
  • Figure 12 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 3 month at 40 °C and 75 % relative humidity.
  • Figure 13 illustrates mRNA levels of BRD2 for cell lines SKHEP1, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels of BRD2.
  • Figure 14 illustrates mRNA levels of BRD3 for cell lines SKHEP1 , HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels of BRD3.
  • Figure 15 illustrates mRNA levels of BRD4 for cell lines SKHEP 1 , HEP2, C AKI- 1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels of BRD4.
  • Figure 16 illustrates mRNA levels of c-MYC for cell lines SKHEP 1 , HEP2, C AKI- 1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels c-MYC for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2.
  • Figure 17 illustrates mRNA levels of BCL2 for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels BCL2 for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2.
  • Figure 18 illustrates mRNA levels of P21 for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels P21for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2.
  • Figure 19 illustrates the GI50 for cell lines SKHEP 1 , HEP2, CAKI- 1 and MiaPaca2 when treated with Compound (1-1).
  • Figures 20A and 20B illustrate cell cycle alterations induced by Compound (1 -1) in SKHEP 1 cell line and concentration of ⁇ -galactosidase positive cells, y-axis, verus concentration of Compound (1-1), x-axis, respectively. Cells were incubated with PI prior to cell cycle analysis.
  • Figures 21 A and 21B illustrate cell cycle alterations induced by Compound (1-1) in
  • HEP2 cell line and concentration of Anexin V Positive, y-axis, verus concentration of Compound (1-1), x-axis, respectively. Cells were incubated with PI prior to cell cycle analysis.
  • Figures 22A- 22D illustrate cell cycle alterations induced by Compound (1 -1) in CAKI- 1 cell line and the induction of senescence for ⁇ ⁇ Compound (1-1) verus a control after 72 hours.
  • Figure 23 illustrates cell cycle alterations induced by Compound (1 - 1) in MiaPaca2 cell lines verus concentration of Compound (1 - 1 ), x-axis, respectively.
  • Figure 24 illustrates mRNA levels of c-MYC for cell lines SKHEP 1 , HEP2, C AKI- 1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels of C-MYC.
  • Figure 25 illustrates mRNA levels of BRD2 for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels of BRD2.
  • Figure 26 illustrates mRNA levels of BRD3 for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels BRD3.
  • Figure 27 illustrates mRNA levels of BRD4 for cell lines SKHEP 1, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels BRD4.
  • Figure 28 illustrates effects of Compound (1-1) at the protein level for BRD2, BRD4, c- MYC, p-ERK, Bcl2 and Actin at times of 0, 6, 24, 48 and 72 hours exposure to 500 ⁇ Compound (1-1) for cell lines SKHEP 1, HEP2 and MiaPaca2.
  • the data shown is a representativ result of three independent experiments.
  • alkyl group refers to a saturated straight or branched hydrocarbon.
  • substituted alkyl group refers to an alkyl moiety having one or more substituents replacing a hydrogen or one or more carbons of the hydrocarbon backbone.
  • alkenyl group whether used alone or as part of a substituent group, for example, "C alkenyl(aryl),” refers to a partially unsaturated branched or straight chain monovalent hydrocarbon radical having at least one carbon— carbon double bond, whereby the double bond is derived by the removal of one hydrogen atom from each of two adjacent carbon atoms of a parent alkyl molecule and the radical is derived by the removal of one hydrogen atom from a single carbon atom.
  • Atoms may be oriented about the double bond in either the cis (Z) or trans (E) conformation.
  • Typical alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl(2-propenyl), butenyl and the like. Examples include Q ⁇ alkenyl or C 2-4 alkenyl groups.
  • Cy. k (where j and k are integers referring to a designated number of carbon atoms) refers to an alkyl, alkenyl, alkynyl, alkoxy or cycloalkyl radical or to the alkyl portion of a radical in which alkyl appears as the prefix root containing from j to k carbon atoms inclusive.
  • C( ⁇ A) denotes a radical containing 1 , 2, 3 or 4 carbon atoms.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts, or inorganic or organic base addition salts of compounds, including, for example, those contained in compositions of the present invention.
  • chiral is art-recognized and refers to molecules That have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • a "prochiral molecule” is a molecule that has the potential to be converted to a chiral molecule in a particular process.
  • enantiomer as it used herein, and structural formulas depicting an enantiomer are meant to include the “pure” enantiomer free from its optical isomer as well as mixtures of the enantiomer and its optical isomer in which the enantiomer is present in an enantiomeric excess, e.g., at least 10%, 25%, 50%, 75%, 90%, 95%, 98%, or 99% enantiomeric excess.
  • stereoisomers when used herein consist of all geometric isomers, enantiomers or diastereomers.
  • the present invention encompasses various stereoisomers of these compounds and mixtures thereof. Conformational isomers and rotamers of disclosed compounds are also contemplated.
  • stereoselective synthesis denotes a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, and are well known in the art.
  • Stereoselective syntheses encompass both enantioselective and diastereoselective transformations. For examples, see Carreira, E. M. and Kvaerno, L., Classics in Stereoselective Synthesis, Wiley- VCH: Weinheim, 2009.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts, or inorganic or organic base addition salts of compounds, including, for example, those contained in compositions of the present invention.
  • spray drying refers to processes which involve the atomization of the feed suspension or solution into small droplets and rapidly removing solvent from the mixture in a processor chamber where there is a strong driving force for the evaporation (i.e., hot dry gas or partial vacuum or combinations thereof).
  • the term "effective amount” refers to an amount of a
  • the term "effective amount" is used to refer any amount of a thienotriazolodiazapine of the present invention or any other pharmaceutically active agent which is effective at enhancing a normal physiological function.
  • terapéuticaally effective amount refers to any amount of a thienotriazolodiazapine of the present invention or any other pharmaceutically active agent which, as compared to a corresponding a patient who has not received such an amount of the
  • thienotriazolodiazapine or the other pharmaceutically active agent results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the present inventions described herein provide for methods of treating a solid tumor.
  • the detailed description sets forth the disclosure in various parts: III. Thienotriazolodiazepine Compounds; IV. Formulations; V. Dosage Forms; VI. Dosage; VII. Process; and VIII. Examples.
  • One of skill in the art would understand that each of the various embodiments of methods of treatment include the various embodiments of thienotriazolodiazepine compounds, formulations, dosage forms, dosage and processes described herein.
  • the present invention provides a method of treating a solid tumor in a mammal, wherein the method comprises the step of: administering thienotriazolodiazepine compound being represented by the compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, a racemate, an enantomer, an isomer, or an isotopically-labeled form thereof.
  • the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound of Formula (1) and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • a solid dispersion comprising an amorphous thienotriazolodiazepine compound of Formula (1) and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • the solid tumor independently includes colon cancer, renal cancer, pancreatic cancer, head and neck cancer, non-small cell lung cancer, liver cancer, triple negative breast cancer, and ovarian cancer. In some embodiments, the solid tumor is independently selected from head and neck cancer and triple negative breast cancer.
  • the solid tumor is head and neck cancer.
  • the solid tumor is head and neck cancer which contains cells that express wild type KRAS protein.
  • the solid tumor is head and neck cancer which contains cells that express wild type BRAF protein.
  • the solid tumor is head and neck cancer which contains cells that have a mutation in the EGFR gene.
  • the solid tumor is head and neck cancer which contains cells that have P1KCA wild type gene.
  • the solid tumor is head and neck cancer which contains cells that have a mutation in the P1KCA gene.
  • the solid tumor is head and neck cancer which contains cells that are wildtype for the p53 gene.
  • the solid tumor is head and neck cancer which contains cells that have a mutant the p53 gene.
  • the solid tumor is non-small cell lung cancer.
  • the solid tumor is non-small cell lung cancer which contains cells that express wild type KRAS protein.
  • the solid tumor is non-small cell lung which contains cells that express wild type BRAF protein.
  • the solid tumor is non-small cell lung cancer which contains cells that have a mutation in the EGFR gene.
  • the solid tumor is non-small cell lung cancer which contains cells that have P1KCA wild type gene.
  • the solid tumor is non-small cell lung cancer which contains cells that have a mutation in the P1KCA gene.
  • the solid tumor is non-small cell lung cancer which contains cells that are wildtype for the p53 gene.
  • the solid tumor is non-small cell lung cancer which contains cells that have a mutant the p53 gene.
  • the solid tumor is liver cancer.
  • the solid tumor is liver cancer which contains cells that express wild type KRAS protein.
  • the solid tumor is liver cancer which contains cells that express wild type BRAF protein.
  • the solid tumor is liver cancer which contains cells that have a mutation in the EGFR gene.
  • the solid tumor is liver cancer which contains cells that have P1KCA wild type gene.
  • the solid tumor is liver cancer which contains cells that have a mutation in the P1KCA gene.
  • the solid tumor is liver cancer which contains cells that are wildtype for the p53 gene.
  • the solid tumor is liver cancer which contains cells that have a mutant the p53 gene.
  • the solid tumor is colon cancer.
  • the solid tumor is colon cancer which contains cells that express wild type KRAS protein.
  • the solid tumor is colon cancer which contains cells that express wild type BRAF protein.
  • the solid tumor is colon cancer which contains cells that have a mutation in the EGFR gene.
  • the solid tumor is colon cancer which contains cells that have P1KCA wild type gene.
  • the solid tumor is colon cancer which contains cells that have a mutation in the P1KCA gene.
  • the solid tumor is colon cancer which contains cells that are wildtype for the p53 gene.
  • the solid tumor is colon cancer which contains cells that have a mutant the p53 gene.
  • the solid tumor is renal cancer.
  • the solid tumor is renal cancer which contains cells that express wild type KRAS protein.
  • the solid tumor is renal cancer which contains cells that express wild type BRAF protein.
  • the solid tumor is renal cancer which contains cells that have a mutation in the EGFR gene.
  • the solid tumor is renal cancer which contains cells that have P1KCA wild type gene.
  • the solid tumor is renal cancer which contains cells that have a mutation in the P1 KCA gene.
  • the solid tumor is renal cancer which contains cells that are wildtype for the p53 gene.
  • the solid tumor is renal cancer which contains cells that have a mutant the p53 gene.
  • the solid tumor is pancreatic cancer.
  • the solid tumor is pancreatic cancer which contains cells that express wild type KRAS protein. In one embodiment the solid tumor is pancreatic cancer which contains cells that express wild type BRAF protein. In one embodiment the solid tumor is pancreatic cancer which contains cells that have a mutation in the EGFR gene. In one embodiment the solid tumor is pancreatic cancer which contains cells that have PIKCA wild type gene. In one embodiment the solid tumor is pancreatic cancer which contains cells that have a mutation in the PI CA gene. In one embodiment the solid tumor is pancreatic cancer which contains cells that are wildtype for the p53 gene. In one embodiment the solid tumor is pancreatic cancer which contains cells that have a mutant the p53 gene. [0078] In one embodiment, the solid tumor is triple negative breast cancer.
  • the solid tumor is triple negative breast cancer which contains cells that express wild type KRAS protein. In one embodiment the solid tumor is triple negative breast cancer which contains cells that express wild type BRAF protein. In one embodiment the solid tumor is triple negative breast cancer which contains cells that have a mutation in the EGFR gene. In one embodiment the solid tumor is triple negative breast cancer which contains cells that have PIKCA wild type gene. In one embodiment the solid tumor is triple negative breast cancer which contains cells that have a mutation in the P 1 KCA gene. In one embodiment the solid tumor is triple negative breast cancer which contains cells that are wildtype for the p53 gene. In one embodiment the solid tumor is triple negative breast cancer which contains cells that have a mutant the p53 gene. [0079] In one embodiment, the solid tumor is ovarian cancer.
  • the solid tumor is ovarian cancer which contains cells that express wild type KRAS protein. In one embodiment the solid tumor is ovarian cancer which contains cells that express wild type BRAF protein. In one embodiment the solid tumor is ovarian cancer which contains cells that have a mutation in the EGFR gene. In one embodiment the solid tumor is ovarian cancer which contains cells that have PIKCA wild type gene. In one embodiment the solid tumor is ovarian cancer which contains cells that have a mutation in the PIKCA gene. In one embodiment the solid tumor is ovarian cancer which contains cells that are wildtype for the p53 gene. In one embodiment the solid tumor is ovarian cancer which contains cells that have a mutant the p53 gene.
  • a mammalian subject as used herein can be any mammal.
  • the mammalian subject includes, but is not limited to, a human; a non-human primate; a rodent such as a mouse, rat, or guinea pig; a domesticated pet such as a cat or dog; a horse, cow, pig, sheep, goat, or rabbit.
  • the mammalian subject includes, but is not limited to, a bird such as a duck, goose, chicken, or turkey.
  • the mammalian subject is a human.
  • the mammalian subject can be either gender and can be any age.
  • R 1 is alkyl having a carbon number of 1-4
  • R 2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1 - 4, alkoxy having a carbon number of 1-4 or cyano;— NR 5 — (CH 2 ) m — R 6 wherein R 5 is a hydrogen atom or alkyl having a carbon number of 1 -4, m is an integer of 0-4, and R 6 is phenyl or pyridyl optionally substituted by a halogen atom; or -NR 7 — CO— (CH 2 ) n — R 8 wherein R 7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R 8
  • a suitable alkyl group includes linear or branched akyl radicals including from 1 carbon atom up to 4 carbon atoms. In one embodiment, a suitable alkyl group includes linear or branched akyl radicals including from 1 carbon atom up to 3 carbon atoms. In one embodiment, a suitable alkyl group includes linear or branched akyl radicals include from 1 carbon atom up to 2 carbon atoms. In one embodiment, exemplary alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. In one embodiment, exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, and 2-methyl-2-propyl.
  • the present invention provides pharmaceutically acceptable salts, solvates, including hydrates, and isotopically-labeled forms of the thienotriazolodiazepine compounds described herein.
  • pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with inorganic acids.
  • thienotriazolodiazepine include salts of hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids.
  • pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with organic acids.
  • pharmaceutically acceptable organic acid addition salts of the thienotriazolodiazepine include salts of tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and 4-methyl benzenesulfonic acids.
  • Representative thienotriazolodiazepine compounds of Formula (1) include, but are not limited to, the thienotriazolodiazepine compounds (1 -1 ) to (1-18), which are listed in the following Table A.
  • thienotriazolodiazepine compounds of Formula (1) include (i) (S)- 2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]triazolo-[4,3-a][l ,4]diazepin-6-yl]-N- (4-hydroxyphenyl)acetamide or a dihydrate thereof, (ii) methyl (S)- ⁇ 4-(3'-cyanobiphenyl-4-yl)- 2,3,9-trimethyl-6H-thieno[3,2-fj[l,2,4]tri- azolo[4,3-a][l,4]diazepin-6-yl ⁇ acetate, (iii) methyl (S)- ⁇ 2,3,9-trimethyl-4-(4-phenylaminophenyl)-6H-thieno[3,2-fJ[l,2,4]triaz-
  • thienotriazolodiazepine compounds of Formula (1 ) include (S)-2- [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-i][l,2,-4]triazolo[4,3-a][l,4]diazepin-6-yl]-N-(4- hydroxyphenyl)acetamide dihydrate.
  • thienotriazolodiazepine compounds of Formula (1) include (S)-2- [4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-i][l,2,-4]triazolo[4,3-a][l,4]diazepin-6-yl]-N-(4- hydroxyphenyl)acetamide dihydrate.
  • thienotriazolodiazepine compounds of Formula (1) include (S)-2-
  • the compound of Formula (1) could be formulated as a solid dispersion with the carrier ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer (Eudragit RS, manufactured by Rohm) to provide an oral formulation that preferentially released the pharmaceutical ingredient in the lower intestine for treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (US Patent Application 20090012064 Al, published Jan 8, 2009). It was found, through various experiments, including animal tests, that in inflammatory bowel diseases drug release in a lesion and a direct action thereof on the inflammatory lesion were more important than the absorption of the drug into circulation from the gastrointestinal tract.
  • the carrier ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer Eudragit RS, manufactured by Rohm
  • thienotriazolodiazepine compounds according to Formula (1), pharmaceutically acceptable salts, solvates, including hydrates, racemates, enantiomers isomers, and isotopically-labeled forms thereof, can be formulated as a solid dispersion with pharmaceutically acceptable polymers to provide an oral formulation that provides high absorption of the pharmaceutical ingredient into the circulation from the gastrointestinal tract for treatment of diseases other than inflammatory bowel diseases.
  • pharmaceutically acceptable polymers can be formulated as a solid dispersion with pharmaceutically acceptable polymers to provide an oral formulation that provides high absorption of the pharmaceutical ingredient into the circulation from the gastrointestinal tract for treatment of diseases other than inflammatory bowel diseases.
  • Studies in both dogs and humans have confirmed high oral bioavailability of these solid dispersions compared with the Eudragit solid dispersion formulation previously developed for the treatment of inflammatory bowel disease.
  • Solid dispersions are a strategy to improve the oral bioavailability of poorly water soluble drugs.
  • solid dispersion refers to a group of solid products including at least two different components, generally a hydrophilic carrier and a hydrophobic drug, the thienotriazolodiazepine compounds, according to Formula (1). Based on the drug's molecular arrangement within the dispersion, six different types of solid dispersions can be distinguished. Commonly, solid dispersions are classified as simple eutectic mixtures, solid solutions, glass solution and suspension, and amorphous precipitations in a crystalline carrier. Moreover, certain combinations can be encountered, for example, in the same sample some molecules may be present in clusters while some are molecularly dispersed.
  • the thienotriazolodiazepine compounds, according to Formula (1) can be dispersed molecularly, in amorphous particles (clusters).
  • the thienotriazolodiazepine compounds, according to Formula (1) can be dispersed molecularly, in amorphous particles (clusters).
  • thienotriazolodiazepine compounds, according to Formula (1) can be dispersed as crystalline particles.
  • the carrier can be crystalline.
  • the carrier can be amorphous.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion of a thienotriazolodiazepine compound, in accordance with Formula (1), or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof; and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate (also called hydroxypropylmethylcellulose acetate succinate or HPMCAS).
  • the dispersion has a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate (HPMCAS) weight ratio of 1 :3 to 1 : 1.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C. In other such embodiments, the single Tg occurs at about 135 °C. In some such
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • the hydroxypropylmethyl cellulose acetate succinates may include M grade having 9% acetyl/ 1 1% succinoyl (e.g., HPMCAS having a mean particle size of 5 ⁇ (i.e., HPMCAS-MF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-MG, granular grade)), H grade having 12% acetyl/6% succinoyl (e.g., HPMCAS having a mean particle size of 5 ⁇ (i.e., HPMCAS-HF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-HG, granular grade)), and L grade having 8% acetyl/15% succinoyl (e.g., HPMCAS having a mean particle size of 5 ⁇ (i.e., HPMCAS-LF, fine powder grade) or having a mean particle size of 1 mm (i.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion of a thienotriazolodiazepine compound of Formula (1) or a
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone (also called povidone or PVP).
  • the dispersion has a thienotriazolodiazepine compound to PVP weight ratio of 1 :3 to 1 : 1. In one embodiment, at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion. In another embodiment, the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to about 185 °C. In other such embodiments, the single Tg occurs at about 179 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • the polyvinyl pyrrolidones may have molecular weights of about 2,500 (Kollidon ® 12 PF, weight-average molecular weight between 2,000 to 3,000), about 9,000 (Kollidon® 17 PF, weight-average molecular weight between 7,000 to 1 1,000), about 25,000 (Kollidon® 25, weight-average molecular weight between 28,000 to 34,000), about 50,000 (Kollidon® 30, weight-average molecular weight between 44,000 to 54,000), and about 1 ,250,000 (Kollidon® 90 or Kollidon® 90F, weight-average molecular weight between 1 ,000,000 to 1,500,000).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion. In another embodiment, the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion. In some embodiments, the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 130 °C to 140 °C. In other such embodiments, the single Tg occurs at about 135 °C. In some such
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an iso
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to about 185 °C. In other such embodiments, the single Tg occurs at about 179 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
  • a pharmaceutical composition comprising a solid dispersion is prepared by spray drying.
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a thienotriazolodiazepine compound of Formula (1) or a
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of compound (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C. In other such embodiments, the single Tg occurs at about 135 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a thienotriazolodiazepine compound of Formula ( 1 ) or a
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of compound (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1. In one
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to 185 °C. In other such embodiments, the single Tg occurs at about 179 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • Tg glass transition temperature
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula ( 1 ) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 130 °C to 140 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In other such embodiments, the single Tg occurs at about 135 °C.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1: 1.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to 185 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In other such embodiments, the single Tg occurs at about 179 °C.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21 ° 2-theta associated with crystalline
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
  • the present invention provides a pharmaceutical
  • composition comprising a solid dispersion of 2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thienol[3,2-fJ-[l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate, compound (1-1):
  • the pharmaceutically acceptable polymer is HPMCAS.
  • the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C.
  • the single Tg occurs at about 135 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
  • the pharmaceutical composition comprises a solid dispersion compound (1-1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form; and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is PVP.
  • the dispersion has compound (1-1) and PVP in a weight ratio 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to 185 °C.
  • the single Tg occurs at about 179 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound (1-1) or a
  • the pharmaceutically acceptable polymer is HPMCAS.
  • the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C.
  • the single Tg occurs at about 135 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound (1-1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof; and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is PVP.
  • the dispersion has compound (1-1) and PVP in a weight ratio 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to 185 °C.
  • the single Tg occurs at about 189 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound (1-1) or a
  • the pharmaceutically acceptable polymer is HPMCAS.
  • the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1.
  • the solid dispersion is spray dried.
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound (1-1) or a
  • the pharmaceutically acceptable polymer is PVP.
  • the dispersion has compound (1-1) and PVP in a weight ratio 1 :3 to 1 : 1.
  • the solid dispersion is spray dried.
  • the solid dispersions of the invention exhibit especially advantageous properties when administered orally.
  • advantageous properties of the solid dispersions include, but are not limited to, consistent and high level of bioavailability when administered in standard bioavailability trials in animals or humans.
  • the solid dispersions of the invention can include a solid dispersion comprising thienotriazolodiazepine compound of Formula (1) and a polymer and additives.
  • the solid dispersions can achieve absorption of the thienotriazolodiazepine compound of Formula (1) into the bloodstream that cannot be obtained by merely admixing the thienotriazolodiazepine compound of Formula (1) with additives since the thienotriazolodiazepine compound of Formula (1) drug has negligible solubility in water and most aqueous media.
  • the bioavailability, of thienotriazolodiazepine compound of Formula (1) or of thienotriazolodiazepine compound (1-1) may be measured using a variety of in vitro and/or in vivo studies. The in vivo studies may be performed, for example, using rats, dogs or humans.
  • the bioavailability may be measured by the area under the curve (AUC) value obtained by plotting a serum or plasma concentration, of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1), along the ordinate (Y-axis) against time along the abscissa (X-axis).
  • AUC value of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1) from the solid dispersion is then compared to the AUC value of an equivalent concentration of crystalline thienotriazolodiazepine compound of Formula (1) or crystalline thienotriazolodiazepine compound (1-1) without polymer.
  • the solid dispersion provides an area under the curve (AUC) value, when administered orally to a dog, that is selected from: at least 0.4 times, 0.5 times, 0.6 time, 0.8 time, 1.0 times, a corresponding AUC value provided by a control composition administered intravenously to a dog, wherein the control composition comprises an equivalent quantity of a crystalline thienotriazolodiazepine compound of Formula I.
  • AUC area under the curve
  • the bioavailability may be measured by in vitro tests simulating the pH values of a gastric environment and an intestine environment.
  • the measurements may be made by suspending a solid dispersion of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1), in an aqueous in vitro test medium having a pH between 1.0 to 2.0, and the pH is then adjusted to a pH between 5.0 and 7.0, in a control in vitro test medium.
  • thienotriazolodiazepine compound (1-1) may be measured at any time during the first two hours following the pH adjustment.
  • the solid dispersion provides a concentration, of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous
  • thienotriazolodiazepine compound (1-1) in an aqueous in vitro test medium at pH between 5.0 to 7.0 that is selected from: at least 5-fold greater, at least 6 fold greater, at least 7 fold greater, at least 8 fold greater, at least 9 fold greater or at least 10 fold greater, compared to a concentration of a crystalline thienotriazolodiazepine compound of Formula (1) or crystalline thienotriazolodiazepine compound ( 1 - 1 ), without polymer.
  • the concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous thienotriazolodiazepine compound (1-1), from the solid dispersion placed in an aqueous in vitro test medium having a pH of 1.0 to 2.0 is: at least 40%, at least 50% higher, at least 60 %, at least 70 %; at least 80 %, than a concentration of a crystalline thienotriazolodiazepine compound of Formula (1) without polymer.
  • the polymer of the solid dispersion is HPMCAS.
  • the polymer of the solid dispersion is PVP.
  • a concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous thienotriazolodiazepine compound (1-1), from the solid dispersion is: at least 40%, at least 50% higher, at least 60 %, at least 70 %; at least 80 %, compared to a concentration of thienotriazolodiazepine compound of Formula (1), from a solid dispersion of thienotriazolodiazepine compound of the Formula (1) and a pharmaceutically acceptable polymer selected from the group consisting of: hypromellose phthalate and ethyl acrylate-methyl
  • methacrylate-trimethylammonioethyl methacrylate chloride copolymer wherein each solid dispersion was placed in an aqueous in vitro test medium having a pH of 1.0 to 2.0.
  • the polymer of the solid dispersion is HPMCAS.
  • the polymer of the solid dispersion is PVP.
  • the solid dispersions, described herein exhibit stability against recrystallization of the thienotriazolodiazepine compound of the Formula ( 1 ) or the
  • the concentration of the amorphous thienotriazolodiazepine compound of the Formula (1) or the thienotriazolodiazepine compound (1-1) which remains amorphous is selected from: at least 90 %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% and at least 99%.
  • Suitable dosage forms that can be used with the solid dispersions of the present invention include, but are not limited to, capsules, tablets, mini-tablets, beads, beadlets, pellets, granules, granulates, and powder.
  • Suitable dosage forms may be coated, for example using an enteric coating.
  • Suitable coatings may comprise but are not limited to cellulose acetate phthalate, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, a
  • HPMCAS hydroxylpropylmethylcellulose acetate succinate
  • the solid dispersions of the invention may be formulated as tablets, caplets, or capsules. In one some embodiments, the solid dispersions of the invention may be formulated as mini-tablets or pour-into-mouth granules, or oral powders for constitution. In some embodiments, the solid dispersions of the invention are dispersed in a suitable diluent in
  • the solid dispersions of the invention may be formulated for pediatric treatment.
  • the pharmaceutical composition of the present invention is formulated for oral administration.
  • the pharmaceutical composition comprises a solid dispersion, according to the various embodiments described herein, comprising a
  • the pharmaceutical composition further includes one or more additives such as disintegrants, lubricants, glidants, binders, and fillers.
  • Suitable pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants for use with the pharmaceutical composition include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and sodium stearyl fumarate.
  • Suitable pharmaceutically acceptable binders for use with the pharmaceutical composition include, but are not limited to starches; celluloses and derivatives thereof, e.g., microcrystalline cellulose (e.g., AVICEL PH from FMC), hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxylpropylmethylcellulose (HPMC, e.g., METHOCEL from Dow Chemical); sucrose, dextrose, corn syrup; polysaccharides; and gelatin.
  • suitable pharmaceutically acceptable fillers and pharmaceutically acceptable diluents for use with the pharmaceutical composition include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose (MCC), powdered cellulose, sorbitol, sucrose, and talc.
  • excipients may serve more than one function in the pharmaceutical composition.
  • fillers or binders may also be disintegrants, glidants, anti-adherents, lubricants, sweeteners and the like.
  • the pharmaceutical compositions of the present invention may further include additives or ingredients, such as antioxidants (e.g., ascorbyl palmitate, butylated hydroxylanisole (BHA), butylated hydroxytoluene (BHT), cc-tocopherols, propyl gallate, and fumaric acid), antimicrobial agents, enzyme inhibitors, stabilizers (e.g., malonic acid), and/or preserving agents.
  • antioxidants e.g., ascorbyl palmitate, butylated hydroxylanisole (BHA), butylated hydroxytoluene (BHT), cc-tocopherols, propyl gallate, and fumaric acid
  • antioxidants e.g., ascorbyl palmitate, butylated hydroxylanisole (BHA), butylated hydroxytoluene (BHT), cc-tocopherols, propyl gallate, and fumaric acid
  • antimicrobial agents e.g
  • the pharmaceutical compositions of the present invention may be formulated into any suitable solid dosage form.
  • the solid dispersions of the invention are compounded in unit dosage form, e.g., as a capsule, or tablet, or a multi-particulate system such as granules or granulates or a powder, for administration.
  • a pharmaceutical compositions includes a solid dispersion of a thienotriazolodiazepine compound of Formula (1), according to the various embodiments of solid dispersions described herein, and hydroxypropylmethylcellulose acetate succinate (HPMCAS), wherein the thienotriazolodiazepine compound is amorphous in the solid dispersion and has a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate (HPMCAS), weight ratio of 1 :3 to 1 : 1; 45 -50 wt. % of lactose monohydrate; 35-40 wt. % of microcrystalline cellulose; 4-6 wt. % of croscarmellose sodium; 0.8-1.5 wt. % of colloidal silicon dioxide; and 0.8- 1.5 wt. % of magnesium stearate.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • the present invention provides a pharmaceutical composition that maybe formulated into any suitable solid dosage form.
  • a pharmaceutical composition in accordance with the present invention comprises one or more of the various embodiments of the thienotriazolodiazepine of Formula (1) as described herein in a dosage amount ranging from about 10 mg to about 100 mg.
  • the pharmaceutical composition of the present invention includes one or more of the various embodiments of the
  • the pharmaceutical composition of the present invention includes one or more of the various embodiments of the thienotriazolodiazepine of Formula ( 1 ) as described herein in a dosage amount selected from the group consisting of about 10 mg, about 50 mg, about 75 mg, about 100 mg.
  • the methods of the present invention includes administering to a subject in need thereof one or more of the various embodiments of the thienotriazolodiazepine of Formula (I) as described herein in a dosage amount selected from the group consisting of about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, and about 150 mg, and in a dosage form selected from the group consisting of once weekly, once daily every sixth day, once daily every fifth day, once daily every fourth day, once daily every third day, once daily every other day, once daily, twice daily, three times daily, four times daily, and
  • the methods of the present invention includes administering to a subject in need thereof a thienotriazolodiazepine selected from the group consisting of compounds (1-1), (1-2), (1-3), (1-4), (1-5), (1-6), (1-7), (1-8), (1-9), (1-10), (1-1 1), (1-12), (1-13), (1-14), (1- 15), (1-16), (1-17), and (1-18), in a dosage amount selected from the group consisting of about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, and about 150 mg, and in a dosage form selected from the group consisting of
  • any of the foregoing dosage amounts or dosage forms is decreased periodically or increased periodically.
  • Such unit dosage forms are suitable for administration 1 to 5 times daily depending on the particular purpose of therapy, the phase of therapy, and the like.
  • the dosage form may be administered to a subject in need thereof at least once daily for at least two successive days.
  • the dosage form may be administered to a subject in need thereof at least once daily on alternative days.
  • the dosage form may be administered to a subject in need thereof at least weekly and divided into equal and/or unequal doses.
  • the dosage form may be administered to a subject in need thereof weekly, given either on three alternate days and/or 6 times per week.
  • the dosage form may be administered to a subject in need thereof in divided doses on alternate days, every third day, every fourth day, every fifth day, every sixth day and/or weekly. In one embodiment, the dosage form may be administered to a subject in need thereof two or more equally or unequally divided doses per month.
  • the dosage form used e.g., in a capsule, tablet, mini-tablet, beads, beadlets, pellets, granules, granulates, or powder may be coated, for example using an enteric coating.
  • Suitable coatings may comprise but are not limited to cellulose acetate phthalate,
  • HPMC hydroxypropylmethylcellulose
  • phthalate hydroxypropylmethylcellulose phthalate
  • polymethylacrylic acid copolymer or hydroxylpropylmethylcellulose acetate succinate (HPMC AS).
  • a one or more of the various embodiments for the formulation of the thienotriazolodiazepine, according to Formula (1), is prepared by a solvent evaporation method.
  • the solvent evaporation method comprises solubilization of a
  • the volatile solvent may one or more excipients.
  • the one or more excipients include, but are not limited to anti-sticking agents, inert fillers, surfactants wetting agents, pH modifiers and additives.
  • the excipients may dissolved or in suspended or swollen state in the volatile solvent.
  • preparation of solid dispersions in accordance with the present invention includes drying one or more excipients suspended in a volatile solvent.
  • the drying includes vacuum drying, slow evaporation of the volatile solvent at low temperature, use of a rotary evaporator, spray-drying, spray granulation, freeze-drying, or use of supercritical fluids.
  • thienotriazolodiazepine composition according to Formula (1), which involves atomization of a suspension or a solution of the composition into small droplets, followed by rapid removal solvent from the formulation.
  • preparation of a formulation in accordance with the present invention involves spray granulation in which a solution or a suspension of the composition in a solvent is sprayed onto a suitable chemically and/or physically inert filler, such as lactose or mannitol.
  • spray granulation of the solution or the suspension of the composition is achieved via two-way or three-way nozzles.
  • Example 1 In vitro screening of solid dispersions of compound (1 -1)
  • Solid dispersions were prepared using compound (1 -1) and one of five polymers, including hypromellose acetate succinate (HPMCAS-M), hypromellose phthalate (HPMCP-HP55), polyvinylpyrrolidone (PVP), PVP-vinyl acetate (PVP-VA), and Eudragit LI 00-55, at both 25% and 50% of compound (1-1) loading, for each polymer.
  • Solid dispersions were prepared by a solvent evaporation method, using spray-drying followed by secondary drying in a low-temperature convection oven. The performance of each solid dispersion was assessed via a non-sink dissolution performance test which measured both the total amount of drug and the amount of free drug present in solution over time.
  • Non-sink dissolution was chosen because it best represents the in vivo situation for low soluble compounds.
  • This test included a "gastric transfer" of dispersion from gastric pH (0.1N NaCl, pH 1.0) to intestinal pH (FaFSSIF, pH 6.5) approximately 30 to 40 minutes after the introduction of dispersion to the test medium, simulating in vivo conditions.
  • FaFSSIF Fasted State Simulated Intestinal Fluid, comprised of 3 mM sodium taurocholate, 0.75 mM lechithin, 0.174 g NaOH pellets, 1.977 g NaH 2 P0 4 *H 2 0, 3.093 g NaCl, and purified water qs 500 mL.
  • the amount of dissolved drug was quantified using a high-performance liquid
  • Example 2 In vivo screening of solid dispersions of compound (1 -1)
  • the area under the plasma concentration- time curve was determined by use of the linear trapezoidal rule up to the last measurable concentration without extrapolation of the terminal elimination phase to infinity.
  • the elimination half-life (ti /2 ) was calculated by least-squares regression analysis of the terminal linear part of the log concentration-ime curve.
  • the maximum plasma concentration (C max ) and the time to C raax (t raax ) were derived directly from the plasma concentration data.
  • bioavailability (F) was calculated by dividing the dose normalized AUC after oral administration by the dose normalized AUC after intravenous administration and reported as percentages (%).
  • AUC area under the plasma concentration-time curve
  • C max maximum plasma concentration
  • F bioavailability
  • HPMCAS hypromellose acetate sodium
  • IV intravenous
  • PEG polyethylene glycon
  • PO per os, oral
  • PVP polyvinylpyrrolidone
  • Example 3 Preparation and clincial use of capsules containing a solid dispersion of compound (1-1)
  • a gelatin capsule of 10 mg strength was prepared for initial clinical studies in patients with hematologic malignancies. Based on results of in vitro and in vivo testing of solid dispersions of compound (1-1), as described in Examples 1 and 2, a 50% compound ( 1-1) in HPMCAS-M solid dispersion was selected for capsule development. Capsule development was initiated targeting a fill weight of 190 mg in a size 3 hard gelatin capsule, as this configuration would potentially allow increasing the capsule strength by filling a larger size capsule while maintaining the pharmaceutical composition. Based on experience, four capsule formulations were designed with different amounts of disintegrant and with and without wetting agent.
  • the 50% compound (1-1) in HPMCAS-M solid dispersion (1000 g) and excipients, including microcrystalline cellulose filler-binder (4428 g), croscarmellose sodium disintegrant (636 g), colloidal silicon dioxide dispersant/lubricant 156 g), magnesium stearate dispersant/lubricant (156 g), and lactose monohydrate filler (5364 g) were blended in stages in a V-blender. The blend was them compacted and granulated to obtain a bulk density of approximately 0.6 g/mL. The blend was dispensed into size 3 hard gelatin capsules (target fill weight: 190 mg) using an automated filling machine and finished capsules were polished using a capsule polisher machine.
  • the Eudragit solid dispersion formulation was made by dissolving and/or dispersing the thienotriazolodiazepine of formula (A) and coating excipients, including ammonio methacrylate copolymer type B (Eudragit RS), methacrylic acid copolymer type C (Eudragit LI 00-55), talc, and magnesium aluminosilicate, in a mixture of water and ethanol.
  • This heterogeneous mixture then was applied to microcrystalline cellulose spheres (Nonpareil 101, Freund) using a centrifugal fluidizing bed granulator to produce granules that were dispensed into size 2 hydroxypropyl methylcellulose capsules.
  • HPMCAS-M solid dispersion formulation is unexpected.
  • Table 2A solid dispersion capsules of compound (1-1) for clinical use pharmaceutical composition containing 50% HPMCAS solid dispersion of compound (1-1):
  • Table 2B pharmaceutical composition containing Eudragit L100-55solid dispersion of compound (1-1 ): 10 mg strength, size 2 hard gelatin capsule Core:
  • Ammonio methacrylate copolymer type B (NF. PhEur)
  • coating agent 10.8 4.2 (Edragit RS, Evonik)
  • Methacrylic acid copolymer type C (NF)/
  • coating agent 20.0 7.7 (Neuslin, Fuji Chemical)
  • Triethyl citrate plasticizer 5.0 1.9
  • AUC 0 - 2 4i area under the OTX015 plasma concentration vs. time curve over 24 hours
  • HPMCAS hypromellose acetate succinate
  • the oral bioavailability of three formulations of solid dispersions of compound (1-1) was determined in rats.
  • the three dispersions chosen were the 25% dispersion of compound (1-1) in PVP, the 25% dispersion of compound (1-1) in HPMCAS-MG, and the 50% dispersion of compound (1-1) in HPMCAS-MG.
  • the animals used in the study were Specific Pathogen Free (SPF) Hsd:Sprague Dawley rats obtained from the Central Animal Laboratory at the University of Turku, Finland.
  • the rats were originally purchased from Harlan, The Netherlands.
  • the rats were female and were ten weeks of age, and 12 rats were used in the study.
  • the animals were housed in polycarbonate Makrolon II cages (three animals per cage), the animal room temperature was 21 +/- 3 °C, the animal room relative humidity was 55 +/- 15%, and the animal room lighting was artificial and was cycled for 12 hour light and dark periods (with the dark period between 18:00 and 06:00 hours). Aspen chips (Tapvei Oy, Estonia) were used for bedding, and bedding was changed at least once per week. Food and water was provided prior to dosing the animals but was removed during the first two hours after dosing.
  • the oral dosing solutions containing the 25% dispersion of compound (1-1) in PVP, the 25% dispersion of compound (1-1) in HPMCAS-MG, and the 50% dispersion of compound (1-1) in HPMCAS-MG were prepared by adding a pre-calculated amount of sterile water for injection to containers holding the dispersion using appropriate quantities to obtain a concentration of 0.75 mg/mL of compound (1-1).
  • the oral dosing solutions were subjected to vortex mixing for 20 seconds prior to each dose.
  • the dosing solution for intravenous administration contained 0.25 mg/mL of compound (1-1) and was prepared by dissolving 5 mg of compound (1-1) in a mixture containing 4 mL of polyethylene glycol with an average molecular weight of 400 Da (PEG400), 4 mL of ethanol (96% purity), and 12 mL of sterile water for injection.
  • the dosing solution containing the 25% dispersion of compound (1-1) in PVP was used within 30 minutes after the addition of water.
  • the dosing solutions containing the 25% dispersion of compound (1-1) in HPMCAS-MG and the 50% dispersion of compound (1 -1) in HPMCAS-MG were used within 60 minutes of after the addition of water.
  • a dosing volume of 4 mL/kg was used to give dose levels of compound (1-1) of 1 mg/kg for intravenous administration and 3 mg/kg for oral administration.
  • the dosing scheme is given in Table 4.
  • Pharmacokinetic parameters were calculated with the Phoenix WinNonlin software package (version 6.2.1 , Pharsight Corp., CA, USA) with standard noncompartmental methods.
  • the elimination phase half-life (ti /2 ) was calculated by least-squares regression analysis of the terminal linear part of the log concentration-time curve.
  • the area under the plasma concentration-time curve (AUC) was determined by use of the linear trapezoidal rule up to the last measurable concentration and thereafter by extrapolation of the terminal elimination phase to infinity.
  • the maximum plasma concentration (C max ) and the time to C max (t max ) were derived directly from the plasma concentration data.
  • the tentative oral bioavailability (F) was calculated by dividing the dose normalised AUC after oral administration by the dose normalised AUC after intravenous
  • Spray dried dispersions of compound (1- 1) were prepared using five selected polymers: HPMCAS-MG (Shin Etsu Chemical Co., Ltd.), HPMCP-HP55 (Shin Etsu Chemical Co., Ltd.), PVP (ISP, a division of Ashland, Inc.), PVP-VA (BASF Corp.), and Eudragit LI 00-55 (Evonik Industries AG). All spray dried solutions were prepared at 25% and 50% by weight with each polymer. All solutions were prepared in acetone, with the exception of the PVP solutions, which were prepared in ethanol. For each solution, 1.0 g of solids (polymer and compound (1-1)) were prepared in 10 g of solvent.
  • the solutions were spray dried using a Biichi B-290, PE-024 spray dryer with a 1.5 mm nozzle and a Biichi B-295, P-002 condenser.
  • the spray dryer nozzle pressure was set to 80 psi
  • the target outlet temperature was set to 40 °C
  • the chiller temperature was set to -20 °C
  • the pump speed was set to 100%
  • the aspirator setting was 100%.
  • the solid dispersions were collected and dried overnight in a low temperature convection oven to remove residual solvents
  • Example 6 Stability with humidity and temperature.
  • Spray dried dispersions of compound (1-1) in HPMCAS-MG were assessed for stability by exposure to moisture at elevated temperature.
  • the glass transition temperature (Tg) as a function of relative humidity was determined at 75% relative humidity, 40 °C for 1, 2 and 3 months.
  • the spray dried dispersion was stored in an LDPE bag inside a HDPE bottle to simulate bulk product packaging.
  • the data is summarized in Table 6. At time zero, the Tg was 134 °C, at 1 month the Tg was 134 °C, at 2 months the Tg was 135 °C and at 3 months the Tg was 134 °C and only a single inflection point was observed for each measurement. X-ray diffraction patterns were also obtained for each sample.
  • Figure 9 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS- MG at time zero of a stability test.
  • Figures 10, 1 1 and 12 illustrate powder X-ray diffraction profiles of solid dispersions of compound (1-1) in HPMCAS-MG after 1 month, 2 months and 3 months, respectively, after exposure at 40 °C and 75 % relative humidity. The patterns did not show any diffraction lines associated with compound (1-1).
  • HNSCC head and neck squamous cell carcinoma
  • LA lung adenocarcinoma
  • HCC hepatocarcinoma
  • CRC colorectal carcinoma
  • RC renal
  • PC pancreatic
  • BC triple-negative breast cancer
  • Hepatocarcinoma HEPG2 Heterozygous Snp heterozygote WT WT mutation WT .261 G>A
  • MTT assays were performed after 72 hours exposure.
  • GI50 (CI95%) values were estimated using GraphPad Prism 3.0. Cell lines displaying GI50 values ⁇ 500nM were considered sensitive to thienopyrazolodiazepine compound (1-1), while those displaying GI50 >500nM were considered insensitive.
  • Genomic DNA from the cell lines was PCR-amplified, sequenced, and assessed for potential sequence alterations (ABI BigDye Terminator Sequencing kit) in the genes KRAS (exon 2 and 3); BRAF (exon 11 and 15); EGFR (exon 20) and PI3KCA (exon 20). Protein levels were analyzed by Western Blot using commercial antibodies.
  • Example 7 The results of Example 7 are illustrated in Figures 13-28 as described below.
  • Figure 13 illustrates mRNA levels of BRD2 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels of BRD2.
  • Figure 14 illustrates mRNA levels of BRD3 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels of BRD3.
  • Figure 15 illustrates mRNA levels of BRD4 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels of BRD4.
  • Figure 16 illustrates mRNA levels of c-MYC for cell lines SKHEPl , HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels c-MYC for cell lines SKHEPl , HEP2, CAKI-1 and MiaPaca2.
  • Figure 17 illustrates mRNA levels of BCL2 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels BCL2 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2.
  • Figure 18 illustrates mRNA levels of P21 for cell lines SKHEPl , HEP2, CAKI-1 and MiaPaca2.
  • the x-axis depicts the cell line and the y-axis depicts the nRNA levels P21for cell lines SKHEPl , HEP2, CAKI-1 and MiaPaca2.
  • Figure 19 illustrates the GI50 for cell lines SKHEP l , HEP2, CAKI-1 and MiaPaca2 when treated with Compound (1-1).
  • Figures 20A and 20B illustrate cell cycle alterations induced by Compound (1-1) in SKHEPl cell line and concentration of ⁇ -galactosidase positive cells, y-axis, verus concentration of Compound (1-1), x-axis, respectively. Cells were incubated with PI prior to cell cycle analysis.
  • Figures 21A and 21B illustrate cell cycle alterations induced by Compound (1-1) in HEP2 cell line and concentration of Anexin V Positive, y-axis, verus concentration of
  • Figures 22A- 22D illustrate cell cycle alterations induced by Compound (1 -1) in CAKI-1 cell line and the induction of senescence for ⁇ ⁇ Compound (1-1) verus a control after 72 hours.
  • Figure 23 illustrates cell cycle alterations induced by Compound (1-1) in MiaPaca2 cell lines verus concentration of Compound (1-1), x-axis, respectively.
  • Figure 24 illustrates mRNA levels of c-MYC for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels of C-MYC.
  • Figure 25 illustrates mRNA levels of BRD2 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels of BRD2.
  • Figure 26 illustrates mRNA levels of BRD3 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line and the y-axis depicts the nRNA levels BRD3.
  • Figure 27 illustrates mRNA levels of BRD4 for cell lines SKHEPl, HEP2, CAKI-1 and MiaPaca2 at 0.5 ⁇ Compound (1-1) after 4 hours and 24 hours relative to a control exposed to DMSO.
  • the x-axis depicts the time and cell line arid the y-axis depicts the nRNA levels BRD4.
  • Figure 28 illustrates effects of Compound (1-1) at the protein level for BRD2, BRD4, c- MYC, p-ERK, Be 12 and Actin at times of 0, 6, 24, 48 and 72 hours exposure to 500 ⁇
  • Baseline BRD4/2, c-MYC, BCL-2, CyclinDl protein levels are well characterized in our panel of cell lines and no difference in BRD4/2, c-MYC or BCL-2 basal levels was observed between thienopyrazolodiazepine compound (1-1) sensitive or resistant cell lines.
  • thienopyrazolodiazepine compound (1-1) anti-proliferative activity was found in sensitive cell lines.
  • OTX105 caused a cell cycle arrest in Gl in a dose-dependent manner without an increase in cell death (sub-GO increased).
  • thienopyrazolodiazepine compound (1-1) treated cells compared to vehicle treated group.

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Abstract

La présente invention concerne un procédé permettant de traiter une tumeur solide chez un mammifère comprenant les étapes consistant à : administrer une quantité pharmaceutiquement acceptable d'un composé thiénotriazolodiazépine réprésenté par la formule suivante (1) : dans laquelle R1 est un groupe alkyle ayant 1 à 4 atomes de carbone, R2 est un atome d'hydrogène, un atome d'halogène ou un groupe alkyle ayant 1 à 4 atomes de carbone facultativement substitué par un atome d'halogène ou un groupe hydroxyle, R3 est un atome d'halogène, un groupe phényle facultativement substitué par un atome d'halogène, un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe alkoxy ayant 1 à 4 atomes de carbone ou un groupe cyano;— NR5— (CH2)m— R6 où R5 est un atome d'hydrogène ou un groupe alkyle ayant 1 à 4 atomes de carbone, m est un nombre entier de 0 à 4, et R6 est un groupe phényle ou pyridyle facultativement substitué par un atome d'halogène; ou -NR 7— CO— (CH2)n— R8 où R7 est un atome d'hydrogène ou un groupe alkyle ayant 1 à 4 atomes de carbone, n est un nombre entier de 0 à 2, et R8 est un groupe phényle ou pyridyle facultativement substitué par un atome d'halogène, et R4 est — (CH2)a— CO— NH— R9 où a est un nombre entier de 1 à 4, et R9 est un groupe alkyle ayant 1 à 4 atomes de carbone; un groupe hydroxyalkyle ayant 1 à 4 atomes de carbone; un groupe alkoxy ayant 1 à 4 atomes carbone; ou un groupe phényle ou pyridyle facultativement substitué par un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe alcoxy ayant 1 à 4 atomes de carbone, un groupe amino ou hydroxyle ou— (CH2)b— COOR10 où b est un nombre entier de 1 à 4, et R10 est un groupe alkyle ayant 1 à 4 atomes de carbone, ou son sel pharmaceutiquement acceptable ou leur hydrate ou leur solvat.
PCT/EP2014/002166 2013-08-06 2014-08-06 Nouvel inhibiteur de bet-brd pour le traitement de tumeurs solides WO2015018523A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015169951A1 (fr) * 2014-05-08 2015-11-12 Oncoethix Gmbh Méthode de traitement du cancer du sein triple négatif à l'aide de composés de thiénotriazolodiazépine
WO2016176335A1 (fr) 2015-04-27 2016-11-03 Concert Pharmaceuticals, Inc. Otx-015 deutéré
CN111259788A (zh) * 2020-01-14 2020-06-09 华志微创医疗科技（北京）有限公司 头颈拐点的检测方法、装置以及计算机设备

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