WO2015018522A1 - Bet-bromodomain inhibitor shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (dlbcl) - Google Patents

Bet-bromodomain inhibitor shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (dlbcl) Download PDF

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WO2015018522A1
WO2015018522A1 PCT/EP2014/002165 EP2014002165W WO2015018522A1 WO 2015018522 A1 WO2015018522 A1 WO 2015018522A1 EP 2014002165 W EP2014002165 W EP 2014002165W WO 2015018522 A1 WO2015018522 A1 WO 2015018522A1
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compound
carbon number
solid dispersion
thienotriazolodiazepine
alkyl
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PCT/EP2014/002165
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French (fr)
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Francesco Bertoni
Giorgio Inghirami
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Oncoethix Sa
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • 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
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    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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Definitions

  • the present disclosure is concerned with methods of treatment, particularly methods of treating diffuse large B-cell lymphoma in a mammal.
  • BET Bromodomain inhibitors have shown promising pre-clinical activity in hematological and solid tumors and are currently investigated in early clinical trials.
  • the present invention provides a method of treating diffuse large B-cell lymphoma in a mammal.
  • the method of treating diffuse large B-cell lymphoma in a mammal comprises the step of: (i) administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound being represented by the thienotriazolodiazepine compound of Formula (1)
  • 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 3 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
  • 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-phenylaminophen
  • the thienotriazolodiazepine compound is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-tmeno[3,2- fj[l,2,- 4]triazolo[4,3-a][l ,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate.
  • the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where said combination of the first compound and the second compound produces a synergistic effect.
  • the thienotriazolodiazepine compound the first compound is selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
  • the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion.
  • the 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.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
  • the present invention provides methods of treating diffuse large B- cell lymphoma comprising administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound, said thienotriazolodiazepine compound being represented by the following Formula (1):
  • Ri 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 3 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 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,
  • thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound of the Formula (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable polymer.
  • the patient has activated B-cell diffuse large B-cell lymphoma.
  • the thienotriazolodiazepine compound represented by Formula 1 is independently selected from the group consisting of: (i) (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, (ii) methyl (S)- ⁇ 4-(3'-cyanobiphenyl-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][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-
  • the thienotriazolodiazepine compound is (5)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- J[l ,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
  • the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where said combination of the first compound and the second compound produces a synergistic effect.
  • the thienotriazolodiazepine compound the first compound is selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
  • 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.
  • 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 LI 00-55.
  • Figure 1 C illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1 - 1 ) and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • Figure I D 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 1 H illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HPMCAS-M.
  • Figure II illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose phthalate (HPMCP-HP55).
  • Figure 1 J 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.
  • Figure 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 7 A 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 8 A 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 1 1 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 additive and synergistic effects of combinations of compound (1-1) with everolimus, lenalidomide, rituximab, decitabine, and vorinostat (Y-axis: confidence interval (CI) ⁇ 0.3, strong synergism; 0.3-0.9, synergism; 0.9-1.1 additive effect) in germinal center B celllike (GCB) cell lines (1 : DOHH2; 2: Karpas422; 3: SUDHL6) and activated B cell-like (ABC) type of diffuse large B cell lymphoma (DLBCL) cell lines (4: U2932; and 5: TMD8).
  • GCB germinal center B celllike
  • 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, "Ci. 4 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 or C 2-4 alkenyl groups.
  • C ⁇ 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 ( i_4) denotes a radical containing 1, 2, 3 or 4 carbon atoms.
  • compositions of the present invention 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 invention provides a method of treating diffuse large B cell lymphoma in a mammal, wherein the method comprises the step of: (i) administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a mammal, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HD AC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound being represented by the compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, a racemate, an
  • first compound and the second compound can be administered simultaneously, while in other embodiments the first compound and the second compound can be administered sequentially. In some embodiments the combination produces a synergistic effect.
  • 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 first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where the combination of the first compound and the second compound produces a synergistic effect.
  • the first compound being selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
  • the present invention provides a method of treating diffuse large B cell lymphoma in a mammal, wherein the method comprises the step of: (i) administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a mammal, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound being represented by the compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, a racemate, an
  • thienotriazolodiazepine compound of Formula (1) and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • Various embodiments of such a solid dispersion are described herein and can be used accordingly.
  • the first compound and the second compound can be administered simultaneously, while in other embodiments the first compound and the second compound can be administered sequentially. In some embodiments the combination produces a synergistic effect.
  • the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where the combination of the first compound and the second compound produces a synergistic effect.
  • the first compound being selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
  • 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.
  • Suitable mammalian target of rapamycin (mTOR) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the mTOR inhibitors listed in the below Table A. [0068] Table A:
  • Suitable phosohoinositide 3 -kinase (PI3K) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the PI3K inhibitors listed in the below Table B.
  • Suitable histone deacetylase (HDAC) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but limited to, the HDAC inhibitors listed in the below Table C.
  • HDAC6 inhibitor with IC50 of 5 nM.
  • Suitable Bruton's tyrosine kinase (BKT) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the BKT inhibitors listed in the below Table D. [00741 Table D:
  • Suitable Anti-CD20 monoclonal antibodies for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the Anti-CD20 monoclonal antibodies listed in the below Table E.
  • thienotriazolodiazepine compounds used in the formulations of the present invention, are represented by Formula (1):
  • 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 hydro xyl group
  • R 3 is a halogen atom
  • — 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,
  • 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.
  • exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -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 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-fJ[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-f][l,2,4]triaz-
  • thienotriazolodiazepine compounds of Formula (1) include (S)-2- [4-(4-chlorophenyl)-2,3,9-trimethyl-6 ⁇
  • thienotriazolodiazepine compounds of Formula (1) include (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.
  • the compound of Formula (1) presents highly specific difficulties in relation to administration generally and the preparation of galenic compositions in particular, including the particular problems of drug bioavailability and variability in inter- and intra-patient dose response, necessitating development of a non-conventional dosage form with respect to the practically water- insoluble properties of the compound.
  • 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/ 11% 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.e., M grade having 9% ace
  • 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 salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof in a pharmaceutically acceptable polymer is polyvinylpyrrolidone (also called povidone or PVP).
  • the dispersion has a thienotriazolodiazepine compound to P VP weight ratio of 1 : 3 to 1 : 1. In one embodiment, at least some portion of the
  • 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 175 °C to about 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).
  • 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 11,000), 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.
  • 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).
  • 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 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline
  • thienotriazolodiazepine compound of Formula (1) for the purpose of this application “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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern
  • 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 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
  • 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 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 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
  • 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. In other such embodiments, 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 HPMCAS.
  • 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,
  • HPMC hydroxypropylmethylcellulose
  • phthalate hydroxypropylmethylcellulose phthalate
  • 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
  • the pharmaceutical composition comprises a solid dispersion, according to the various embodiments described herein, comprising 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 polymer carrier.
  • 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), a-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), a-tocopherols, propyl gallate, and fumaric acid
  • antioxidants e.g., ascorbyl palmitate, butylated hydroxylanisole (BHA), butylated hydroxytoluene (BHT), a-tocopherols, propyl gallate, and fumaric acid
  • antimicrobial agents e.g., as
  • 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 macrocrystalline 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
  • any of the foregoing dosage amounts or dosage forms is decreased periodically or increased periodically.
  • 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
  • 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
  • HPMCAS hydroxylpropylmethylcellulose acetate succinate
  • the thienotriazolodiazepine compounds disclosed herein can exist as free base or as acid addition salt can be obtained according to the procedures described in US Patent Application Publication No. 2010/0286127, incorporated by reference in its entirety herein, or in the present application.
  • Individual enantiomers and diastereomers of the thienotriazolodiazepine compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • 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 LlOO-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 )
  • HPMCAS-M dispersions were prepared at larger scale for in vivo studies. Each formulation was assessed in the in vitro dissolution test described in Example 1. To ensure that these dispersions were both amorphous and homogeneous, each dispersion was assessed by powder x-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Additionally, to understand the effect of water on the glass transition temperature (Tg) for each dispersion, mDSC was performed on samples first equilibrated at a set relative humidity (i.e., 25%, 50%, and 75% RH) for at least 18 hours. [Water can act as a plasticizer for solid dispersions and the hygroscopicity of the system due to the active compound or polymer can affect the amount of water uptake by these systems.]
  • PXRD powder x-ray diffraction
  • mDSC modulated differential scanning calorimetry
  • 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 (t] /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 Cmax (tmax) were derived directly from the plasma concentration data.
  • bioavailability was calculated by dividing the dose noiTnalized AUC after oral administration by the dose normalized AUC after intravenous administration and reported as percentages (%). Results, summarized in Table 1 below, gave mean oral bioavailabilities of the 25% compound (1 - 1) in PVP, 25% compound (1- 1) in HPMCAS-M, and 50% compound (1 -1 ) in HPMCAS-M solid dispersions of 58%, 49%, and 74%, respectively.
  • Table 1 pharmacokinetic parameters of compound (1 - 1) after oral (po) and intravenous (iv) administrations to dogs (the values are averages from three dogs)
  • 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
  • t max time of C max ; n- plasma elimination half-life
  • Example 3 Preparation and clincial use of capsules containing a solid dispersion of compound (1 - I)
  • 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 SDI was shown by PXRD analysis to be amorphous and by mDSC analysis to be homogeneous (i.e., single Tg under ambient conditions).
  • 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.
  • 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): 10 mg strength, size 3 hard gelatin capsule
  • Table 2B pharmaceutical composition containing Eudragit L100-55solid dispersion
  • Table 3 pharmacokinetic parameters following oral administration of solid dispersions of compound ( 1 -1 ) to humans
  • 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
  • F (AUC(oral)/Dose(oral))/(AUC(intravenous) / Dose(intravenous))] and is reported as percentage (%).
  • 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 L100-55 (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 Buchi B-290, PE-024 spray dryer with a 1.5 mm nozzle and a Buchi 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, 11 and 12 illustrate powder X-ray diffraction profiles of solid dispersions of compound (1-1) in HPMCAS-MG
  • Example 7 Compound (1-1) shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (DLBCL)
  • SUDHL6) and 2 activated B cell (ABC) DLBCL cell lines were exposed to increasing doses of thienotriazolodiazepine compound (1- 1) alone or in combination with increasing doses of other drugs.
  • the MTT assay was performed after 72 hours of exposure.
  • Synergy was assessed by Chou-Talalay combination index (CI) with the Synergy R package: confidence interval (CI) ⁇ 0.3, strong synergism; 0.3-0.9, synergism; 0.9-1.1, additive effect.
  • Example 8 Compound ( 1-1) shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (DLBCL)
  • Example 9 Compound ( 1 -1) shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (DLBCL) [00162] Methods: Synergy was assessed in cells (2-5 cell lines) exposed for 72 hours to increasing doses of Compound (1-1) alone or in combination with increasing doses of other agents. MTT assays were performed and Chou-Talalay combination index (CI) calculated.
  • CI Chou-Talalay combination index

Abstract

A method of treating diffuse large B cell lymphoma in a mammal comprising the step of: administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound being represented by the following Formula (1): wherein R1 is alkyl having a carbon number of 1-4, R2 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, R3 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;— NR5— (CH2)m— R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R6 is phenyl or pyridyl optionally substituted by a halogen atom; or -NR7— CO— (CH2)n— R8 wherein R7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R8 is phenyl or pyridyl optionally substituted by a halogen atom, and R4 is— (CH2)a— CO— NH— R9 wherein a is an integer of 1-4, and R9 is alkyl having a carbon number of 1 -4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1 -4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1 -4, amino or a hydroxyl group or— (CH2)b— COOR10 wherein b is an integer of 1 -4, and R10 is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof.

Description

TITLE OF THE INVENTION
BET-BROMODOMAIN INHIBITOR SHOWS SYNERGISM WITH SEVERAL ANTI-CANCER AGENTS IN PRE-CLINICAL MODELS OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application Serial No.
61/862,752, filed August 6, 2013, U.S. Provisional Application Serial No. 61/862,772, filed August 6, 2013, and U.S. Provisional Application Serial No. 61/909,703, filed November 27, 2013, each of which is incorporated herein by reference in its entirety.
FIELD OF INVENTION
[0002] The present disclosure is concerned with methods of treatment, particularly methods of treating diffuse large B-cell lymphoma in a mammal.
SEQUENCE LISTING
[0003] Incorporated by reference in its entirety herein is a computer- readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: one xxx Bytes ASCII (Text) file named "filename.txt," created on August 4, 2014.
BACKGROUND OF THE INVENTION
[0004] Relapsed/refractory DLBCL is still the cause of death in a portion of patients; hence novel active therapies are needed. BET Bromodomain inhibitors have shown promising pre-clinical activity in hematological and solid tumors and are currently investigated in early clinical trials. We have shown preclinical single-agent activity of the BET Bromodomain OTX015 on mature lymphoid tumors, including DLBCL.
BRIEF SUMMARY OF THE INVENTION
[0005] In an aspect, the present invention provides a method of treating diffuse large B-cell lymphoma in a mammal. In some embodiments, the method of treating diffuse large B-cell lymphoma in a mammal comprises the step of: (i) administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound being represented by the thienotriazolodiazepine compound of Formula (1)
Figure imgf000004_0001
wherein R1 is alkyl having a carbon number of 1-4, R2 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, R3 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;— NR5— (CH2)m— R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1 -4, m is an integer of 0-4, and R6 is phenyl or pyridyl optionally substituted by a halogen atom; or— NR7— CO— (CH2)n— R8 wherein R7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R8 is phenyl or pyridyl optionally substituted by a halogen atom, and R4 is— (CH2)a— CO— NH— R9 wherein a is an integer of 1-4, and R9 is alkyl having a carbon number of 1-4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1-4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4, amino or a hydroxyl group or— (CH2)b— COOR10 wherein b is an integer of 1-4, and R10 is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof.
[0006] In one embodiment of the methods of treating diffuse large B-cell lymphoma, 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[3,2-fJ[ l ,2,4]triaz- olo[4,3-a][l,4]diazepin-6-yI} acetate; and (d) methyl (S)- {2,3,9-trimethyl-4-[4-(3- phenylpropionylamino)phenyl]-6H-thieno[3,2-f- ][l,2,4]triazolo[4,3-a][l ,4]diazepin-6-yl} acetate.
[0007] In one embodiment of the methods of treating diffuse large B-cell lymphoma, the thienotriazolodiazepine compound is (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-tmeno[3,2- fj[l,2,- 4]triazolo[4,3-a][l ,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate.
[0008] In one embodiment of the methods of treating diffuse large B-cell lymphoma, the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where said combination of the first compound and the second compound produces a synergistic effect. In one embodiment of the methods of treating diffuse large B-cell lymphoma, the thienotriazolodiazepine compound, the first compound is selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
[0009] In one embodiment of the methods of treating diffuse large B-cell lymphoma, the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion. In one such embodiment, the 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. In one such embodiment, 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. In still yet another embodiment, the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
[0010] In some embodiments, the present invention provides methods of treating diffuse large B- cell lymphoma comprising administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound, said thienotriazolodiazepine compound being represented by the following Formula (1):
Figure imgf000006_0001
wherein Ri is alkyl having a carbon number of 1 -4, R2 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, R3 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; ~NR5~(CH2)m~R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R is phenyl or pyridyl optionally substituted by a halogen atom; or— NR7— CO~(CH2)n— R8 wherein R7 is a hydrogen atom or alkyl having a carbon number of 1 -4, n is an integer of 0-2, and R is phenyl or pyridyl optionally substituted by a halogen atom, and R4 is— (CH2)a— CO— NH--R9 wherein a is an integer of 1-4, and R9 is alkyl having a carbon number of 1 -4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1-4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1 -4, alkoxy having a carbon number of 1 -4, amino or a hydroxyl group or— (CH2)b— COOR10 wherein b is an integer of 1-4, and Rio is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, wherein the
thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound of the Formula (1) or a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable polymer. In some embodiments, the patient has activated B-cell diffuse large B-cell lymphoma.
[0011] In some embodiments, the thienotriazolodiazepine compound represented by Formula 1 is independently selected from the group consisting of: (i) (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, (ii) methyl (S)- {4-(3'-cyanobiphenyl-4-yl)-2,3,9-trimethyl-6H-thieno[3,2- f][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-f][ 1 ,2,4]triaz-olo[4,3-a][ 1 ,4]diazepin-6-yl} acetate; and (iv) methyl (S)- {2,3,9-trimethy]-4-[4-(3-phenylpropionylamino)phenyl]-6H-thieno[3,2-f- ][ l ,2,4]triazolo[4,3-a][l ,4]diazepin-6-yl} acetate. In some embodiments, the thienotriazolodiazepine compound is (5)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- J[l ,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
[0012] In one embodiment of the methods of treating diffuse large B-cell lymphoma, the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where said combination of the first compound and the second compound produces a synergistic effect. In one embodiment of the methods of treating diffuse large B-cell lymphoma, the thienotriazolodiazepine compound, the first compound is selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
[0013] In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). In some embodiments, the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C. In some embodiments, 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The foregoing summary, as well as the following detailed description of embodiments of the methods of the present invention, will be better understood when read in conjunction with the appended drawings of exemplary embodiments. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.
[0015] In the drawings:
[0016] Figure 1A illustrates dissolution profile of a comparator formulation comprising a solid dispersion comprising 25% compound (1 -1 ) and Eudragit L100-55.
[0017] Figure IB illustrates dissolution profile of a comparator formulation comprising a solid dispersion comprising 50% compound (1 - 1 ) and Eudragit LI 00-55.
[0018] Figure 1 C illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1 - 1 ) and polyvinylpyrrolidone (PVP).
[0019] Figure I D illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound ( 1 - 1 ) and PVP. [0020] Figure IE illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and PVP-vinyl acetate (PVP-VA).
[0021] Figure I F illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and PVP-VA.
[0022] Figure 1G illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose acetate succinate (HPMCAS-M).
[0023] Figure 1 H illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HPMCAS-M.
[0024] Figure II illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose phthalate (HPMCP-HP55).
[0025] Figure 1 J illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HMCP-HP55.
[0026] Figure 2A illustrates results of in vivo screening of an exemplary formulation comprising a solid dispersion of 25% compound (1 -1 ) and PVP.
[0027] 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.
[0028] 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.
[0029] Figure 3 illustrates powder X-ray diffraction profiles of solid dispersions of compound (1- 1).
[0030] Figure 4A illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under ambient conditions.
[0031] Figure 4B illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1 -1) and HPMCAS-M equilibrated under ambient conditions.
[0032] Figure 4C illustrates modified differential scanning calorimetry trace for a solid dispersion of 50% compound (1-1) and HPMCAS-M equilibrated under ambient conditions.
[0033] Figure 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.
[0034] Figure 6 illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under 75% relative humidity.
[0035] Figures 7 A 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.
[0036] Figures 8 A 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.
[0037] 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.
[0038] 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.
[0039] Figure 1 1 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.
[0040] 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.
[0041] Figure 13 illustrates additive and synergistic effects of combinations of compound (1-1) with everolimus, lenalidomide, rituximab, decitabine, and vorinostat (Y-axis: confidence interval (CI) <0.3, strong synergism; 0.3-0.9, synergism; 0.9-1.1 additive effect) in germinal center B celllike (GCB) cell lines (1 : DOHH2; 2: Karpas422; 3: SUDHL6) and activated B cell-like (ABC) type of diffuse large B cell lymphoma (DLBCL) cell lines (4: U2932; and 5: TMD8).
DETAILED DESCRIPTION OF THE INVENTION
[0042] The present subject matter will now be described more fully hereinafter with reference to the accompanying Figures and Examples, in which representative embodiments are shown. The present subject matter can, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided to describe and enable one of skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entireties. I. Definitions: [0043] The term "alkyl group" as used herein refers to a saturated straight or branched hydrocarbon.
[0044] The term "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.
[0045] The term "alkenyl group" whether used alone or as part of a substituent group, for example, "Ci.4alkenyl(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
Figure imgf000010_0001
or C2-4alkenyl groups.
[0046] The term "C^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. For example, C(i_4) denotes a radical containing 1, 2, 3 or 4 carbon atoms.
[0047] The term "pharmaceutically acceptable salts" is art -recognized and 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.
[0048] The term "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.
[0049] The symbol " " is used to denote a bond that may be a single, a double or a triple bond.
[0050] The term "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.
[0051] The term "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. [0052] The term "stereoselective synthesis" as it is used herein 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.
[0053] The term "pharmaceutically acceptable salts" is art-recognized and 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.
[0054] The term "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).
[0055] As used herein, the term "effective amount" refers to an amount of a
hienopyrazolodiazapine of the present invention or any other pharmaceutically active agent that will elicit a targeted biological or amedical response of a tissue, a biological system, an animal or a human, for instance, intended by a researcher or clinician or a healthcare provider. In some embodiments, 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.
[0056] The term "therapeutically effective amount" as used herein 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.
[0057] Throughout this application and in the claims that follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", should be understood to imply the inclusion of a stated integer step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
II. Method of Use: [0058] The present inventions described herein provide for methods of treating diffuse large B cell lymphoma. 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.
[0059] In some embodiments, the present invention provides a method of treating diffuse large B cell lymphoma in a mammal, wherein the method comprises the step of: (i) administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a mammal, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HD AC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a 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.
[0060] In some embodiments the first compound and the second compound can be administered simultaneously, while in other embodiments the first compound and the second compound can be administered sequentially. In some embodiments the combination produces a synergistic effect.
[0061] In some embodiments, 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. Various embodiments of such a solid dispersion are described herein and can be used accordingly.
[0062] In one embodiment of the method of treating diffuse large B-cell lymphoma in a mammal, the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where the combination of the first compound and the second compound produces a synergistic effect. In one embodiment of the method of treating diffuse large B-cell lymphoma in a mammal, the first compound being selected from the group consisting of: romodepsin, bendamustine and doxorubicin. [0063] In some embodiments, the present invention provides a method of treating diffuse large B cell lymphoma in a mammal, wherein the method comprises the step of: (i) administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a mammal, wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a 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 wherein 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. Various embodiments of such a solid dispersion are described herein and can be used accordingly.
[0064] In some embodiments the first compound and the second compound can be administered simultaneously, while in other embodiments the first compound and the second compound can be administered sequentially. In some embodiments the combination produces a synergistic effect. [0065] In one embodiment of the method of treating diffuse large B-cell lymphoma in a mammal, the first compound is selected from the group consisting of: ibrutinib, idelalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and where the combination of the first compound and the second compound produces a synergistic effect. In one embodiment of the method of treating diffuse large B-cell lymphoma in a mammal, the first compound being selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
[0066] A mammalian subject as used herein can be any mammal. In one embodiment, 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. In one embodiment, the mammalian subject includes, but is not limited to, a bird such as a duck, goose, chicken, or turkey. In one embodiment, the mammalian subject is a human. In one embodiment, the mammalian subject can be either gender and can be any age.
[0067] Suitable mammalian target of rapamycin (mTOR) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the mTOR inhibitors listed in the below Table A. [0068] Table A:
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
[0069] Suitable phosohoinositide 3 -kinase (PI3K) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the PI3K inhibitors listed in the below Table B.
[0070] Table B:
Figure imgf000021_0001
Figure imgf000022_0001
20
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
[0071] Suitable histone deacetylase (HDAC) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but limited to, the HDAC inhibitors listed in the below Table C.
[0072] Table C:
Figure imgf000026_0002
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
HDAC6 inhibitor with IC50 of 5 nM.
Figure imgf000030_0001
[0073] Suitable Bruton's tyrosine kinase (BKT) inhibitors for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the BKT inhibitors listed in the below Table D. [00741 Table D:
Figure imgf000031_0001
[0075] Suitable Anti-CD20 monoclonal antibodies for use in combinations with the thienotriazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the Anti-CD20 monoclonal antibodies listed in the below Table E.
[0076] Table E:
Figure imgf000032_0001
Thienotriazolodiazepine Compounds:
[0077] In one embodiment, the thienotriazolodiazepine compounds, used in the formulations of the present invention, are represented by Formula (1):
Figure imgf000033_0001
wherein R1 is alkyl having a carbon number of 1-4, R2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydro xyl group, R3 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;— NR5— (CH2)m— R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1 -4, m is an integer of 0-4, and R6 is phenyl or pyridyl optionally substituted by a halogen atom; or -NR7— CO— (CH2)n— R8 wherein R7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R8 is phenyl or pyridyl optionally substituted by a halogen atom, and R4 is— (CH2)a— CO— NH— R9 wherein a is an integer of 1-4, and R9 is alkyl having a carbon number of 1-4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1-4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4, amino or a hydroxyl group or
— (CH2)b— COOR10 wherein b is an integer of 1-4, and R10 is alkyl having a carbon number of 1-4, including any salts, isomers, enantiomers, racemates, hydrates, solvates, metabolites, and
polymorphs thereof.
[0078] In one embodiment, 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-l -propyl, and 2-methyl-2-propyl. [0079] In some embodiments, the present invention provides pharmaceutically acceptable salts, solvates, including hydrates, and isotopically-labeled forms of the thienotriazolodiazepine compounds described herein. In one embodiment, pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with inorganic acids. In one embodiment, pharmaceutically acceptable inorganic acid addition salts of the
thienotriazolodiazepine include salts of hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids. In one embodiment, pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with organic acids. In one embodiment, 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.
[0080] 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.
[0081] Compound (1-1), of Table F, will be referred to herein as OTX-015 or Y-803.
[0082] Table F: Exemplary compounds of the invention:
Figure imgf000034_0001
Figure imgf000035_0001
33
Figure imgf000036_0001
 )
Figure imgf000037_0001
[0083] In some embodiments, thienotriazolodiazepine compounds of Formula (1) include (i) (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, (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-f][l,2,4]triaz- olo[4,3-a][l ,4]diazepin-6- yl} acetate; and (iv) methyl (S)- {2,3,9-trimethyl-4-[4-(3-phenylpropionylamino)phenyl]-6H- thieno[3,2-f- ][ l ,2,4]triazolo[4,3-a][l,4]diazepin-6-yl} acetate.
[0084] In some embodiments, thienotriazolodiazepine compounds of Formula (1) include (S)-2- [4-(4-chlorophenyl)-2,3,9-trimethyl-6^
hydroxyphenyl)acetamide dihydrate.
[0085] In some embodiments, thienotriazolodiazepine compounds of Formula (1) include (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. IV. Formulations:
[0086] The compound of Formula (1) presents highly specific difficulties in relation to administration generally and the preparation of galenic compositions in particular, including the particular problems of drug bioavailability and variability in inter- and intra-patient dose response, necessitating development of a non-conventional dosage form with respect to the practically water- insoluble properties of the compound.
[0087] Previously, it had been found that 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.
[0088] It has now been unexpectedly found that 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. 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.
[0089] Solid dispersions are a strategy to improve the oral bioavailability of poorly water soluble drugs.
[0090] The term "solid dispersion" as used herein 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.
[0091] In one embodiment, the thienotriazolodiazepine compounds, according to Formula (1) can be dispersed molecularly, in amorphous particles (clusters). In another embodiment, the
thienotriazolodiazepine compounds, according to Formula (1) can be dispersed as crystalline particles. In one embodiment, the carrier can be crystalline. In another embodiment, the carrier can be amorphous.
[0092] In one embodiment, the present invention provides 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. In one embodiment, the pharmaceutically acceptable polymer is hypromellose acetate succinate (also called hydroxypropylmethylcellulose acetate succinate or HPMCAS). In one embodiment, the dispersion has a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate (HPMCAS) 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. 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
embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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). In some embodiments, the hydroxypropylmethyl cellulose acetate succinates (HPMCAS), may include M grade having 9% acetyl/ 11% succinoyl (e.g., HPMCAS having a mean particle size of 5 μιτι (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 μηι (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 μπι (i.e., HPMCAS-LF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-LG, granular grade).
[0093] In one embodiment, the present invention provides a pharmaceutical composition comprising a solid dispersion 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 in a pharmaceutically acceptable polymer. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone (also called povidone or PVP). In one embodiment, the dispersion has a thienotriazolodiazepine compound to P VP 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. In some embodiments, the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to about 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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). In some embodiments, 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 11,000), 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).
[0094] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is hypromellose acetate succinate. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 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. 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
embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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).
[0095] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 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. In some embodiments, the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to about 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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).
[0096] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is hypromellose acetate succinate. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
[0097] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
[0098] In some embodiments, a pharmaceutical composition comprising a solid dispersion is prepared by spray drying. [0099] In one embodiment, a pharmaceutical composition of the present invention comprises a spray dried solid dispersion 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. In one embodiment, the pharmaceutically acceptable polymer is hypromellose acetate succinate. In one embodiment, the weight ratio of compound (1) to hypromellose acetate succinate ranges from 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. 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 embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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).
[00100] In one embodiment, a pharmaceutical composition of the present invention comprises a spray dried solid dispersion 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. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone. In one embodiment, the weight ratio of compound (1) to polyvinylpyrrolidone ranges from 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. In some embodiments, 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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).
[00101] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is hypromellose acetate succinate. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 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. 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 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline
thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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).
[00102] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 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. In some embodiments, 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern
substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1). For the purpose of this application "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).
[00103] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is hypromellose acetate succinate. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
[00104] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is polyvinylpyrrolidone. In one embodiment, the weight ratio of thienotriazolodiazepine compound of Formula ( 1 ) to
polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
[00105] In one preferred embodiment, 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):
Figure imgf000044_0001
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. In one embodiment, the pharmaceutically acceptable polymer is HPMCAS. In one embodiment, the dispersion has compound (1-1) and HPMCAS in a 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. In one embodiment, the solid dispersion is spray dried. 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 embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1). For the purpose of this application "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).
[00106] In another embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is PVP. In one embodiment, the dispersion has compound (1-1) and PVP in a weight ratio 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. In one embodiment, the solid dispersion is spray dried. In some embodiments, 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1). For the purpose of this application "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).
[00107] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is HPMCAS. In one embodiment, the dispersion has compound (1-1) and HPMCAS in a 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. In one embodiment, the solid dispersion is spray dried. 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 embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1). For the purpose of this application "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).
[00108] In one embodiment, 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. In one embodiment, the pharmaceutically acceptable polymer is PVP. In one embodiment, the dispersion has compound (1-1) and PVP in a weight ratio 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. In one embodiment, the solid dispersion is spray dried. In some embodiments, 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 189 °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 some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1). For the purpose of this application "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).
[00109] In one embodiment, a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline 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. In one embodiment, the pharmaceutically acceptable polymer is HPMCAS. In one embodiment, the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1. In one embodiment, the solid dispersion is spray dried.
[00110] In one embodiment, a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline 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. In one embodiment, the pharmaceutically acceptable polymer is PVP. In one embodiment, the dispersion has compound (1-1) and PVP in a weight ratio 1 :3 to 1 : 1. In one embodiment, the solid dispersion is spray dried.
[00111] The solid dispersions of the invention, described herein, exhibit especially advantageous properties when administered orally. Examples of 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. In some embodiments, 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.
[00112] 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). The 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. In some embodiments, 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.
[00113] 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. The concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous
thienotriazolodiazepine compound (1-1) may be measured at any time during the first two hours following the pH adjustment. In some embodiments, 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.
[00114] In other embodiments, 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. In some such embodiments, the polymer of the solid dispersion is HPMCAS. In some such embodiments, the polymer of the solid dispersion is PVP.
[00115] In other embodiments, 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. In some such embodiments, the polymer of the solid dispersion is HPMCAS. In some such embodiments, the polymer of the solid dispersion is PVP.
[00116] In some embodiments, the solid dispersions, described herein, exhibit stability against recrystallization of the thienotriazolodiazepine compound of the Formula (1) or the
thienotriazolodiazepine compound ( 1 - 1 ) when exposed to humidity and temperature over time. In one embodiment, 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%.
V. Dosage Forms:
[00117] 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
polymethylacrylic acid copolymer, or hydroxylpropylmethylcellulose acetate succinate (HPMCAS). In some embodiments, certain combinations can be encountered, for example, in the same sample some molecules of the thienotriazolodiazepine of the present invention may be present in clusters while some are molecularly dispersed with a carrier.
[00118] In some embodiments, 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
combination with other excipients (e.g., re-crystallization/precipitation inhibiting polymers, taste- masking components, etc) to give a ready-to-use suspension formulation. In some embodiments, the solid dispersions of the invention may be formulated for pediatric treatment.
[00119] In one embodiment, the pharmaceutical composition of the present invention is
foimulated for oral administration. In one embodiment, the pharmaceutical composition comprises a solid dispersion, according to the various embodiments described herein, comprising 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 polymer carrier. In one embodiment, the pharmaceutical composition further includes one or more additives such as disintegrants, lubricants, glidants, binders, and fillers.
[00120] Examples of 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.
[00121] Examples of 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.
[00122] Examples of 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.
[00123] In some embodiments, excipients may serve more than one function in the pharmaceutical composition. For example, fillers or binders may also be disintegrants, glidants, anti-adherents, lubricants, sweeteners and the like.
[00124] In some embodiments, 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), a-tocopherols, propyl gallate, and fumaric acid), antimicrobial agents, enzyme inhibitors, stabilizers (e.g., malonic acid), and/or preserving agents.
[00125] Generally, the pharmaceutical compositions of the present invention may be formulated into any suitable solid dosage form. In some embodiments, 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. [00126] In one embodiment, 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 macrocrystalline 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.
VI. Dosage: [00127] In one embodiment, the present invention provides a pharmaceutical composition that maybe formulated into any suitable solid dosage form. In one embodiment, 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. In one embodiment, 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 from about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 40 mg, about 10 mg to about 30 mg, and about 10 mg to about 20 mg. In one embodiment, 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.
[00128] In some embodiments, 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 five times daily. In another embodiment, any of the foregoing dosage amounts or dosage forms is decreased periodically or increased periodically. [00129] In some embodiments, 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 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 five times daily. In another embodiment, any of the foregoing dosage amounts or dosage forms is decreased periodically or increased periodically.
[00130] 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. In one embodiment, the dosage form may be administered to a subject in need thereof at least once daily for at least two successive days. In one embodiment, the dosage form may be administered to a subject in need thereof at least once daily on alternative days. In one embodiment, the dosage form may be administered to a subject in need thereof at least weekly and divided into equal and/or unequal doses. In one embodiment, 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. In one embodiment, 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. [00131] 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,
hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, a
polymethylacrylic acid copolymer, or hydroxylpropylmethylcellulose acetate succinate (HPMCAS).
VII. Process: [00132] The thienotriazolodiazepine compounds disclosed herein can exist as free base or as acid addition salt can be obtained according to the procedures described in US Patent Application Publication No. 2010/0286127, incorporated by reference in its entirety herein, or in the present application. Individual enantiomers and diastereomers of the thienotriazolodiazepine compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
[00133] In some embodiments, 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. In one embodiment, the solvent evaporation method comprises solubilization of a
thienotriazolodiazepine compound, according to Formula (1), carrier in a volatile solvent that is subsequently evaporated. In one embodiment, the volatile solvent may one or more excipients. In one embodiment, the one or more excipients include, but are not limited to anti-sticking agents, inert fillers, surfactants wetting agents, pH modifiers and additives. In one embodiment, the excipients may dissolved or in suspended or swollen state in the volatile solvent. [00134] In one embodiment, preparation of solid dispersions in accordance with the present invention includes drying one or more excipients suspended in a volatile solvent. In one
embodiment, 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. [00135] In one embodiment, spray drying preparation of a formulation for the
thienotriazolodiazepine composition, according to Formula (1 ), is used which involves atomization of a suspension or a solution of the composition into small droplets, followed by rapid removal solvent from the formulation. In one embodiment, 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. In one embodiment, spray granulation of the solution or the suspension of the composition is achieved via two-way or three-way nozzles.
[00136] The invention is illustrated in the following non-limiting examples.
VIII. Examples: Example 1 : In vitro screening of solid dispersions of compound (1-1 )
[00137] Ten 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 LlOO-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 is Fasted State Simulated Intestinal Fluid, comprised of 3 mM sodium taurocholate, 0.75 mM lechithin, 0.174 g NaOH pellets, 1.977 g NaH2P04*H20, 3.093 g NaCl, and purified water qs 500 mL.] The amount of dissolved drug was quantified using a high-performance liquid
chromatrography (HPLC) method and an Agilent 1100 series HPLC. The dissolution profiles of the formulations (Figures 1A-1J) showed large increases in drug solubility in all dispersion candidates relative to the unformulated compound in the same media. Of the solid dispersions, the 25% compound (1-1) in PVP, 25% compound (1-1) in HPMCAS-M, and 50% compound (1-1) in HPMCAS-M dispersions were the most promising candidates for enhanced oral absorption as compared to the unformulated compound, based on finding higher levels of free drug released at intestinal pH.
Example 2: In vivo screening of solid dispersions of compound ( 1 -1 )
[00138] The three most promising solid dispersions of compound (1-1), namely the 25% compound (1-1) in PVP, 25% compound (1-1) in HPMCAS-MG, and 50% compound ( 1-1 ) in
HPMCAS-M dispersions, were prepared at larger scale for in vivo studies. Each formulation was assessed in the in vitro dissolution test described in Example 1. To ensure that these dispersions were both amorphous and homogeneous, each dispersion was assessed by powder x-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Additionally, to understand the effect of water on the glass transition temperature (Tg) for each dispersion, mDSC was performed on samples first equilibrated at a set relative humidity (i.e., 25%, 50%, and 75% RH) for at least 18 hours. [Water can act as a plasticizer for solid dispersions and the hygroscopicity of the system due to the active compound or polymer can affect the amount of water uptake by these systems.]
[00139] The non-sink dissolution results (Figures 2A-2C) were comparable to those found for the dispersions in Example 1. PXRD results (Figure 3) showed no evidence of crystalline compound in any of the dispersions and mDSC results (Figures 4A-4C) showed a single glass transition temperature (Tg) for each dispersion, indicating that each dispersion was homogeneous. The x-ray diffractomer was a Bruker D-2 Phaser. An inverse relationship between Tg and relative humidity was observed for each (Figure 5). Notably, for the 25% compound (1 -1) in PVP solid dispersion equilibrated at 75% RH, there appeared to be two Tgs, indicating that phase separation was occurring, and this dispersion also showed a melt event at 75% RH, suggesting that crystallization occurred during the RH equilibration (Figure 6). This finding suggests that the 25% compound (1- 1) in PVP dispersion may be less stable than the HPMCAS-M dispersions.
[00140] To assess the bioavailability of the three dispersions, groups of male beagle dogs (three per group) were given a 3 mg/kg dose of an aqueous suspension of solid dispersion of compound (1- 1) administered by oral gavage or a 1 mg/kg dose of compound (1-1) dissolved in
water:ethanol:polyethylene glycol (PEG) 400 (60:20:20) and administered as an intravenous bolus into the cephalic vein. Blood samples were collected from the jugular vein of each animal at 0 (pre- dose), 5, 15, and 30 minutes and 1, 2, 4, 8, 12, and 24 hours following intravenous administration and at 0 (pre-dose), 15 and 30 minutes and 1 , 2, 4, 8, 12, and 24 hours following oral gavage administration. The amount of compound (1 -1) present in each sample was detected using a qualified LC-MS/MS method with a lower limit of quantification of 0.5 ng/mL. The area under the plasma concentration-time curve (AUC) 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 (t]/2) was calculated by least-squares regression analysis of the terminal linear part of the log concentration-ime curve. The maximum plasma concentration (Cmax) and the time to Cmax (tmax) were derived directly from the plasma concentration data. The oral
bioavailability (F) was calculated by dividing the dose noiTnalized AUC after oral administration by the dose normalized AUC after intravenous administration and reported as percentages (%). Results, summarized in Table 1 below, gave mean oral bioavailabilities of the 25% compound (1 - 1) in PVP, 25% compound (1- 1) in HPMCAS-M, and 50% compound (1 -1 ) in HPMCAS-M solid dispersions of 58%, 49%, and 74%, respectively.
Table 1 : pharmacokinetic parameters of compound (1 - 1) after oral (po) and intravenous (iv) administrations to dogs (the values are averages from three dogs)
Figure imgf000056_0001
AUC: area under the plasma concentration-time curve; Cmax: maximum plasma concentration; F: bioavailability; HPMCAS: hypromellose acetate sodium; IV: intravenous; PEG: polyethylene glycon; PO; per os, oral; PVP: polyvinylpyrrolidone; tmax: time of Cmax; n- plasma elimination half-life
Example 3: Preparation and clincial use of capsules containing a solid dispersion of compound (1 - I)
[00141] 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. Since all four formulations showed similar disintegration test and dissolution test results, the simplest formulation (without wetting agent and minimum disintegrant) was selected for manufacturing. Manufacturing process development and scale-up studies were performed to confirm the spray drying process and post-drying times for the solid dispersion; blending parameters; roller compaction and milling of the blend to achieve target bulk density of approximately 0.60 g/cc; and capsule filling conditions. [00142] Crystalline compound (1 -1) and the polymer hypromellose actate succinate (HPMCAS- M) were dissolved in acetone and spray-dried to produce solid dispersion intermediate (SDI) granules containing a 50% compound (1-1) loading. The SDI was shown by PXRD analysis to be amorphous and by mDSC analysis to be homogeneous (i.e., single Tg under ambient conditions). 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.
[00143] Pharmacokinetic assessments were performed following oral dosing of 10 mg capsules containing the 50% compound (1-1) in HPMCAS solid dispersion and results were compared with pharmacokinetic assessments performed following oral dosing of administration of 4 x 10 mg capsules containing the Eudragit solid dispersion of compound (1-1) to healthy volunteers
[00144] A comparison of the two pharmaceutical compositions is provided in Tables 2A and 2B below. The Eudragit formulation previously was described in Example 5 in US Patent Application 2009/0012064 Al, published January 8, 2009. That application noted that 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 L100-55), 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.
[00145] In both clinical studies, blood levels of compound ( 1 - 1 ) were determined using validated LC-MS/MS methods and pharmacokinetic analyses were perfoiTned based on plasma concentrations of compound (1-1) measured at various time points over 24 hours after capsule administration. Results, summarized in Table 3 below, showed that the HPMCAS-M solid dispersion formulation had over 3 -fold higher bioavailability in humans than the Eudragit solid dispersion formulation based on AUCs (924*4 / 1 140, adjusting for difference in doses administered). Additionally, based on the observed Tmax, the HPMCAS formulation is more rapidly absorbed than the Eudragit formulation (Tmax of 1 h vs 4-6 h). The marked improvement in systemic exposure with the
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): 10 mg strength, size 3 hard gelatin capsule
Figure imgf000058_0001
Table 2B: pharmaceutical composition containing Eudragit L100-55solid dispersion
of compound ( 1 -1): 10 mg strength, size 2 hard gelatin capsule
Figure imgf000058_0002
* as anhydrate
Table 3 : pharmacokinetic parameters following oral administration of solid dispersions of compound ( 1 -1 ) to humans
Figure imgf000058_0003
AUCo-24h: area under the OTX015 plasma concentration vs. time curve over 24 hours
Cmax: maximum concentration in plasma
hr: hour
HPMCAS: hypromellose acetate succinate
mL: milliliter
ng: nanogram
PO: per os, oral
1 max : time of Cmax Example 4. Oral exposure in the rat
[00146] 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.
[00147] 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.
[00148] Table 4. Dosing scheme for rat oral exposure study.
Figure imgf000060_0001
[00149] Blood samples of approximately 50 were collected into Eppendorf tubes containing 5 \iL of ethylenediaminetetraacetic acid (EDTA) solution at time points of 0.25, 0.5, 1 , 2, 4, 8, 12, and 24 hours after dosing, with each sample collected within a window of 5 minutes from the prescribed time point. From each sample, 20 of plasma was obtained and stored at dry ice temperatures for analysis. Analysis of each sample for the concentration of compound ( 1- 1) was performed using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantitation of 0.5 ng/mL.
[00150] 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 mean residence time (MRT), representing the average amount of time a compound remains in a compartment or system, was calculated by extrapolating the drug concentration profile to infinity. The maximum plasma concentration (Cmax) and the time to Cmax (tmax) 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
administration, i.e. F = (AUC(oral)/Dose(oral))/(AUC(intravenous) / Dose(intravenous))] and is reported as percentage (%).
[00151] The pharmacokinetic parameters are given in Table 5, and the plasma concentration versus time plots are shown in Figures 7 and 8.
[00152] Table 5. Pharmacokinetic parameters of compound (1-1) after oral and intravenous administrations. The values are an average from three animals.
Figure imgf000061_0001
Figure imgf000062_0001
Example 5. Preparation of spray dried dispersions.
[00153] 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 L100-55 (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 Buchi B-290, PE-024 spray dryer with a 1.5 mm nozzle and a Buchi 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%, and the aspirator setting was 100%. After spray drying, 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.
[00154] Table 6
Figure imgf000063_0001
[00155] 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, 11 and 12 illustrate powder X-ray diffraction profiles of solid dispersions of compound (1-1) in HPMCAS-MG
[00156] 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)·
[00157] The patterns did not show any diffraction lines associated with compound (1-1).
Example 7: Compound (1-1) shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (DLBCL)
[00158] Methods: 3 germinal center B cell (GCB) DLBCL (DOHH2; Karpas422; and
SUDHL6) and 2 activated B cell (ABC) DLBCL cell lines (U2932 and TMD8) were exposed to increasing doses of thienotriazolodiazepine compound (1- 1) alone or in combination with increasing doses of other drugs. The MTT assay was performed after 72 hours of exposure. Synergy was assessed by Chou-Talalay combination index (CI) with the Synergy R package: confidence interval (CI) <0.3, strong synergism; 0.3-0.9, synergism; 0.9-1.1, additive effect.
[00159] Results: Strong synergism was observed with thienotriazolodiazepine compound (1- 1) combined with the mTOR inhibitor everolimus (median CI, 0.1 1 ; range 0.1-0.17) and with the BTK-inhibitor ibrutinib in ABC-cells (0=0.04; 0.02-0.1). A synergistic effect was estimated for thienotriazolodiazepine compound ( 1-1) in combinations with the class I and II HDAC-inhibitor vorinostat (CI=0.45; 0.31 -0.56), the anti-CD20 moAb rituximab (CI=0.47; 0.37-0.54), the hypomethylating agent decitabine (CI=0.62; 0.56-0.66), and the immunomodulant lenalidomide (0=0.66; 0.59-0.72). Thienotriazolodiazepine compound (1 -1 ) combinations with the class I HDAC inhibitor romidepsin (0=1.08; 1-1.22) and with the chemotherapy agents bendamustine (CI=0.92; 0.83-1.1) and doxorubicin (CI=0.83; 0.71-0.96) presented a moderate additive effect. A stronger synergism was observed in ABC than in GCB DLBCL cells for ibrutinib (P<0.0001 ), lenalidomide (P=0.0001), and rituximab (P=0.007).
Example 8. Compound ( 1-1) shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (DLBCL)
[00160] Methods: For combination studies, 3 germinal center B-cell (GCB), namely
(DOHH2; Karpas422; SUDHL6), and 2 activated B-cell (ABC) DLBCL, namely U2932; and TMD8, were exposed to increasing doses of compound (1-1) alone or in combination with increasing doses of targeted agents for 72 hours, followed by MTT assay. Synergy was assessed by Chou-Talalay combination index (CI) with Synergy R package.
[00161] Results: We evaluated compound (1 - 1 ) combination with the BTK inhibitor ibrutinib. Synergy was observed in particular in ABC-DLBCL with a median CI of .04 (range 0.02-0.1 ). Other targeted agents (everolimus, lenalidomide, rituximab, decitabine, vorinostat) appeared to synergize with compound ( 1- 1) (Figure 13). The mTOR inhibitor everolimus presented a very strong synergism with a median CI of 0.1 1 (0.1-0.2), in accordance with the association between compound (1-1) sensitivity to high glucose metabolism and high levels of SG 1 in cells undergoing apoptosis.
Example 9. Compound ( 1 -1) shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (DLBCL) [00162] Methods: Synergy was assessed in cells (2-5 cell lines) exposed for 72 hours to increasing doses of Compound (1-1) alone or in combination with increasing doses of other agents. MTT assays were performed and Chou-Talalay combination index (CI) calculated.
[00163] Results: Synergy was observed with everolimus (median CI=0.1 ; range 0. 1-0.2), ibrutinib in ABC-DLBCL (CI=0.04; 0.02-0.1), idelalisib (CALl Ol) (CI-0.5; 0.04-2.4), corinostat (CI=0.5; 0.3-0.6); rituximab (CI=0.5; 0.4-0.5), decitabine (CI=0.6; 0.6-0.7), lenalidomide
(CI=0.7; 0.6-0.7), and all-trans retinoic acid (CI=0.4; 0.1 -1.6). Additive effects were observed for combinations with romidepsin (CI=1.08; 1 - 1.22), bendamustine (0=0.92; 0.83- 1.1), and doxorubicin (0=0.83; 0.71 -0.96)
[00164] It will be appreciated by those skilled in the art that changes could be made to the exemplary embodiments shown and described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the exemplary embodiments shown and described, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the claims. For example, specific features of the exemplary embodiments may or may not be part of the claimed invention and features of the disclosed embodiments may be combined. Unless specifically set forth herein, the terms "a", "an" and "the" are not limited to one element but instead should be read as meaning "at least one".
[00165] It is to be understood that at least some of the figures and descriptions of the invention have been simplified to focus on elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the invention. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.
[00166] Further, to the extent that the method does not rely on the particular order of steps set forth herein, the particular order of the steps should not be construed as limitation on the claims. The claims directed to the method of the present invention should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be varied and still remain within the spirit and scope of the present invention.

Claims

CLAIMS I/we claim:
1. A method of treating diffuse large B cell lymphoma in a mammal comprising the step of: administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient wherein the combination includes a first compound and a second compound; the first compound being selected from the group consisting of an mTOR inhibitor, a PI3K inhibitor, a BTK inhibitor, an HDAC inhibitor, an anti-CD20 monoclonal antibody, a hypomethylating agent and an immunomodulant, and the second compound being a thienotriazolodiazepine compound being represented by the following Formula (1):
wherein R1 is alkyl having a
Figure imgf000067_0001
halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R3 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;— NR5— (CH2)m— R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4,
7 8 and R6 is phenyl or pyridyl optionally substituted by a halogen atom; or -NR— CO— (CH2)n— R wherein R7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R8 is phenyl or pyridyl optionally substituted by a halogen atom, and R4 is— (CH2)a— O— NH— R9 wherein a is an integer of 1-4, and R9 is alkyl having a carbon number of 1-4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1-4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4, amino or a hydroxyl group or— (CH2)b— COOR10 wherein b is an integer of 1-4, and R10 is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof.
2. The method according to claim 1 , wherein the thienotriazolodiazepine compound represented by formula I is selected from the group consisting of:
(i) (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, (ii) methyl (S)- {4- (3'-cyanobiphenyl-4-yl)-2,3,9 rimethyl-6H hieno[3,2-f][l ,2,4]triazolo[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- olo[4,3 -a] [l,4]diazepin-6-yl} acetate; and (iv) methyl (S)-{2,3,9-trimethyl-4-[4-(3- phenylpropionylamino)phenyl]-6H-thieno[3,2-f- ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl} acetate.
3. The method according to claim 2, wherein the thienotriazolodiazepine compound represented by formula I 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.
4. The method according to claim 2, wherein the thienotriazolodiazepine compound represented by formula I 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.
5. The method according to any one of claims 1-4, wherein the first compound being selected from the group consisting of: ibrutinib, idelaalisib, vorinostat, rituximab, lenalidomide, decitabine, and everolimus, and wherein the combination of the first compound and the second compound produces a synergistic effect.
6. The method according to any one of claims 1-4, wherein the first compound being selected from the group consisting of: romodepsin, bendamustine and doxorubicin.
7. The method according to any one of claims 1-6, wherein the thienotriazolodiazepine compound is formed as a solid dispersion.
8. The method according to claim 7, wherein the solid dispersion comprises an amorphous thienotriazolodiazepine compound of the Formula (1) and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
9. The method according to claim 8, wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline
thienotriazolodiazepine compound of Formula (1).
10. The method according to claim 9, wherein 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.
1 1. The method according to claim 10, wherein the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
12. The method according to claim 7, wherein the solid dispersion comprises an amorphous thienotriazolodiazepine compound of (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 and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
13. The method according to claim 12, wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline
thienotriazolodiazepine compound of (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 dihydrate.
14. The method according to claim 13, wherein 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.
15. The method according to claim 14, wherein the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
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