WO2015078931A1 - Méthode de traitement de neuroblastomes à l'aide de composés thiénotriazolodiazépine - Google Patents
Méthode de traitement de neuroblastomes à l'aide de composés thiénotriazolodiazépine Download PDFInfo
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- WO2015078931A1 WO2015078931A1 PCT/EP2014/075711 EP2014075711W WO2015078931A1 WO 2015078931 A1 WO2015078931 A1 WO 2015078931A1 EP 2014075711 W EP2014075711 W EP 2014075711W WO 2015078931 A1 WO2015078931 A1 WO 2015078931A1
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- thienotriazolodiazepine
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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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
- A61K9/1605—Excipients; Inactive ingredients
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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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- A61K9/16—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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Definitions
- the present disclosure relates to a method of treating neuroblastoma, in particular MYCN- amplified neuroblastoma, using a thienotriazolodiazepine compound as the active ingredient wherein the thienotriazolodiazepine compounds have improved solubility and bioavailability and may be provided in the form of solid dispersions.
- Neuroblastomas harboring MYCN amplifications are highly lethal tumors. The disease frequently occurs principally in children of five years old or younger, and of which the frequency is the highest among solid tumors in infants. Although the relationship between the amplification of MYCN oncogene (found in about 20% of the disease cases) and neuroblastoma was suggested in the mid-1980s, there has been no report on a molecule that surely has an important function specific for neuroblastoma since then, and almost nothing has been elucidated concerning the molecular mechanism of the tumor. Although there is an urgent need for establishment of a method of treating neuroblastoma, targeted therapies development has been hampered by a lack of compounds targeting MYCN.
- the present invention provides for a method of treating neuroblastoma comprising the step of administering a pharmaceutical acceptable amount of 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 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 7 8 7
- R 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 R 4 is — (CH 2 ) a — CO— NH— R 9 wherein a is an integer of 1-4, and R 9 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— (CH 2 ) b — COOR 10 wherein b is an integer of 1-4, and R 10 is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate
- 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-f][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-f][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-
- the neuroblastoma is MYCN amplified.
- the neuroblastoma is characterized by one or more regions of super- enhancer gene, said super-enhancer gene having higher amounts of H3K27Ac compared to an amount of H3K27Ac associated with an average gene.
- the super-enhancer gene is selected from the group consisting of MYCN, NCOR2, GLI2 and combinations thereof.
- the super-enhancer gene is characterized as being down regulated following administration of the thienotriazolodiazepine compound being represented by Formula (1).
- the thienotriazolodiazepine compound is (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.
- the neuroblastoma is MYCN amplified.
- the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion.
- the thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion.
- thienotriazolodiazepine compound of Formula (1) is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound wherein the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1) and a pharmaceutically acceptable polymer.
- the pharmaceutically acceptable polymer is hydroxypropylmethylcellulose acetate succinate having a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate (HPMCAS), weight ratio of 1:3 to 1: 1.
- the solid dispersion exhibits a single glass transition temperature (Tg) inflection point ranging from about 130 °C to about 140 °C.
- Tg glass transition temperature
- the neuroblastoma is MYCN amplified.
- Figure 1A illustrates dissolution profile of a comparator formulation comprising a solid dispersion comprising 25% compound (1-1) and Eudragit L100-55.
- Figure IB illustrates dissolution profile of a comparator formulation comprising a solid dispersion comprising 50% compound (1-1) and Eudragit L100-55.
- Figure 1C illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and polyvinylpyrrolidone (PVP).
- PVP polyvinylpyrrolidone
- Figure ID illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and PVP.
- Figure IE illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and PVP- vinyl acetate (PVP-VA).
- Figure IF illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and PVP-VA.
- Figure 1G illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose acetate succinate (HPMCAS-M).
- Figure 1H illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HPMCAS-M.
- Figure II illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose phthalate (HPMCP-HP55).
- Figure 1J illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and HMCP-HP55.
- Figure 2A illustrates results of in vivo screening of an exemplary formulation comprising a solid dispersion of 25% compound (1-1) and PVP.
- Figure 2B illustrates results of an in vivo screening of an exemplary formulation comprising a solid dispersion of 25% compound (1-1) and HPMCAS-M.
- Figure 2C illustrates results of an in vivo screening of an exemplary formulation comprising a solid dispersion of 50% compound (1-1) and HPMCAS-M.
- Figure 3 illustrates powder X-ray diffraction profiles of solid dispersions of compound (1- 1).
- Figure 4A illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under ambient conditions.
- Figure 4B illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and HPMCAS-M equilibrated under ambient conditions.
- Figure 4C illustrates modified differential scanning calorimetry trace for a solid dispersion of 50% compound (1-1) and HPMCAS-M equilibrated under ambient conditions.
- FIG. 5 illustrates plot of glass transition temperature (Tg) versus relative hunidity (RH) for solid dispersions of 25% compound (1-1) and PVP or HMPCAS-M and 50% compound (1-1) and HPMCAS-MG.
- Figure 6 illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under 75% relative humidity.
- Figures 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 11 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 2 months at 40 °C and 75 % relative humidity.
- Figure 12 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 3 month at 40 °C and 75 % relative humidity.
- Figure 13A illustrates event free survival, months, versus % survival for high and low expression of BRD4 expression in MYCN single copy neuroblastoma.
- Figure 13B illustrates the overall survival, months, versus % survival for high and low expression of BRD4 expression in MYCN-amplified neuroblastoma.
- Figure 13C illustrates Kaplan-Meier plots for event free survival, months, versus % survival for high expression of BRD4 expression in MYCN single copy neuroblastoma.
- Figure 13D illustrates Kaplan-Meier plots for event free survival, months, versus % survival for high expression of BRD4 expression in MYCN-amplified neuroblastoma.
- Figure 13E illustrates the log-rank test results for event free survival, months, versus % survival for high expression of BRD4 expression in MYCN single copy neuroblastoma.
- Figure 13F illustrates the log-rank test results for event free survival, months, versus % survival for high expression of BRD4 expression in MYCN-amplified neuroblastoma.
- Figure 13G illustrates a comparision of relative BRD4 expression for stages 3 and 4 versus stages 1, 2 and 4 neuroblastomas.
- Figure 14 illustrates the effect of compound (1-1) on cell viability of non-malignant fibroblasts, as shown in a MTT assay after 72 h treatment.
- Figure 15A illustrates relative cell viability of IMR-5 cells after 72 hours of treatment with compound (1-1).
- Figure 15B illustrates illustrates relative cell viability of SK-N-AS cells after 72 hours of treatment with compound (1-1).
- Figure 15C illustrates that compound (1-1) reduced cell proliferation compared to DMSO controls in IMR-5 cells after 72 hours of treatment.
- Figure 15D illustrates that compound (1-1) induced cell death in IMR5 cells compared to DMSO controls in IMR-5 cells after 72 hours of treatment.
- Figure 15E illustrates that compound (1-1) induced the fraction of cells in the subGl phase of the cell cycle in IMR-5 cells after 72 hours of treatment compared to DMSO controls.
- Figure 15F illustrates images of IMR-5 and SK-N-AS cells in culture after 72 hours treatment with compound (1-1) compared to DMSO controls.
- Figure 16 illustrates relative MYCN mRNA expression of IMR-5 cells after 8 hours of treatment with DMSO control or compound (1-1).
- Figure 17 illustrates relative CCNDl mRNA expression of IMR-5 and SK-N-AScells after 48 hours of treatment with DMSO control or compound (1-1).
- Figure 18 illustrates Brd4, Cyclin Dl, MYCN and Actin protein expression levels in EVIR- 5 cells and CCNDl expression in SK-N-AS cells after 72 hours of treatment with DMSO control or compound (1-1).
- Figure 19A illustrates illustrates images of mice bearing xenografts established from IMR- 5 cells treated with H 2 0 control or compound (1-1).
- Figure 19B illustrates relative cell proliferation of mice bearing xenografts established from IMR-5 cells treated with H 2 0 control or compound (1-1).
- Figure 19C illustrates relative apoptosis of mice bearing xenografts established from IMR- 5 cells treated with H 2 0 control or compound (1-1).
- Figure 19D illustrates tumor volume versus treatment time using compound (1-1) at different concentrations and postive control cyclophosphamide and water.
- Figure 19E illustrates mice survival time versus treatment time using compound (1-1) at different concentrations and postive control cyclophosphamide and water.
- Figure 20 illustrates a dose-response curve of human foreskin fibroblasts treated with increasing doses of compound (1-1) for 72 hours and measured using MTT cell viability assay.
- Figure 21A illustrates cell index over time for foreskin fibroblast tissue treated with compound (1-1) and DMSO.
- Figure 21B illustrates relative cell viability for foreskin fibroblast tissue treated with compound (1-1) and DMSO.
- Figure 22 illustrates cell viability dose response of neuroblastoma cell lines, IMR 5, Chp 134, Chp 212, SK N-BE(2), IMR-32 SK-N-BE, NB69, SK N AS and GI-M-EN treated with increased compound (1-1) concentrations for 72 h.
- Figure 23A illustrates IC50 values for IMR-5, Chp 212, Chp-134, SK-N-BE2, IMR 32, SK-N-BE, NB69, SK-N-AS and Gimen neuroblastoma cell lines treated with compound (1-1).
- Figure 23B illustrates E max values for IMR-5, Chp 212, Chp-134, SK-N-BE2, IMR 32, SK- N-BE, NB69, SK-N-AS and Gimen neuroblastoma cell lines treated with compound (1-1).
- Figure 23C illustrates MYCN mRNA expression for IMR-5, IMR-32, SK-N-AS, SK-N- BE, SK-N-BE2, NB69, Gimen, Chp-134 and Chp 212 neuroblastoma cell lines treated with compound (1-1).
- Figure 23D illustrates MYCN mRNA expression, % relative to SK-N-BE, versus IC50 value.
- Figure 23E shows the Western blot profie of MYCN and Actin values for IMR-5, IMR-32, SK-N-AS, SK-N-BE, SK-N-BE2, NB69, Gimen, Chp-134 and Chp 212 treated with compound (1- 1).
- Figure 23F llustrates MYCN protein expression, % relative to Chp-134, versus IC50 value.
- Figure 25A illustrates cell proliferation over time course of 120 hours for IMR-5 neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 25B illustrates cell proliferation over time course of 120 hours for Chp-134 neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 25C illustrates cell proliferation over time course of 120 hours for Chp-212 neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 25D illustrates cell proliferation over time course of 120 hours for SK-N-BE neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 25E illustrates cell proliferation over time course of 120 hours for SK-N-AS neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 26A illustrates IMR-5, Chp-134, Chp-212, SK-N-BE and SK-N-AS neuroblastoma cell lines in culture after treatment with either DMSO (control) or 500 nM compound (1-1).
- Figure 26B illustrates relative cell viability for IMR-5, Chp-134, Chp-212, SK-N-BE and SK-N-AS neuroblastoma cell lines after treatment with either DMSO (control) or 500 nM compound (1-1).
- Figure 26C illustrates relative cell viability for Chp-134 neuroblastoma cell line after treatment with either DMSO (control) or 500 nM compound (1-1).
- Figure 26D illustrates relative cell viability for Chp-212 neuroblastoma cell line after treatment with either DMSO (control) or 500 nM compound (1-1).
- Figure 26E illustrates relative cell viability for SK-N-BE neuroblastoma cell line after treatment with either DMSO (control) or 500 nM compound (1-1).
- Figure 26F illustrates relative cell viability for SK-N-AS neuroblastoma cell line after treatment with either DMSO (control) or 500 nM compound (1-1).
- Figure 27A illustrates fraction of cells in different stages of cell cycle for IMR-5 neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 27B illustrates fraction of cells in different stages of cell cycle for Chp-134 neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 27C illustrates fraction of cells in different stages of cell cycle for Chp-212 neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 27D illustrates fraction of cells in different stages of cell cycle for SK-N-BE neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 27E illustrates fraction of cells in different stages of cell cycle for SK-N-AS neuroblastoma cell line treated with compound (1-1) (500 nM) or DMSO control.
- Figure 28A illustrates fraction of apoptotic cells measured using cell death ELISA after 72 hours treatment for IMR-5 neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 28B illustrates fraction of apoptotic cells measured using cell death ELISA after 72 hours treatment for Chp-134 neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 28C illustrates fraction of apoptotic cells measured using cell death ELISA after 72 hours treatment for Chp-212 neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 28D illustrates of apoptotic cells measured using cell death ELISA after 72 hours treatment for SK-N-BE neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 28E illustrates of apoptotic cells measured using cell death ELISA after 72 hours treatment for SK-N-AS neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 29A illustrates cell proliferation measured using BrdU ELISA after 72 hours treatment for IMR-5 neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 29B illustrates cell proliferation measured using BrdU ELISA after 72 hours treatment for Chp-134 neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 29C illustrates cell proliferation measured using BrdU ELISA after 72 hours treatment for Chp-212 neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 29D illustrates cell proliferation measured using BrdU ELISA after 72 hours treatment for SK-N-BE neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 29E illustrates cell proliferation measured using BrdU ELISA after 72 hours treatment for SK-N-AS neuroblastoma cell line treated with compound (1-1) (250 nM or 500 nM) or DMSO control.
- Figure 30 illustrates IMR 5 xenograft tumor volumes after treatment with compound (1-1) per oral gavage at 25 mg / kg body weight (BW) per day, 2 x 25 mg / kg BW per day, and 50 mg / kg BW per day, with cyclophosphamide 150 mg / kg BW per day as a positive control or with water (H20) 200 ⁇ / d as negative control.
- the average tumor volume was significantly smaller in the compound (1-1) treated groups compared to vehicle group from day 9 onward to day 23 (Student's t-test, p ⁇ 0.05).
- Figure 31 illustrates Kaplan-Meier of mouse survival treated with compound (1-1) showing that compound (1-1) treatment significantly increases mouse survival with established xenograft tumors (Log -rank test, p ⁇ 0.02).
- Figure 33A illustrates the relative fraction of positively stained cells for cleaved caspase 3 (d) and Mib-1 (e) showing an significant increase in apoptotic cells in neuroblastoma xenografts following treatment of mice with OTX015 compared to H 2 0 treated.
- Figure 33B illustrates the relative fraction of positively stained cells for cleaved caspase 3 (d) and Mib-1 (e) showing a decrease of proliferating cells in neuroblastoma xenografts following treatment of mice with OTX015 compared to H 2 0 treated.
- Figure 34A illustrates tumor volumes of LSL MYCN;Dbh iCre murine neuroblastoma grafts grown in nude mice and orally treated with 25 mg / kg body weight (BW) per day compound (1-1) or water alone.
- Figure 34B illustrates Kaplan-Meier analysis showing the survival of nude mice harboring LSL-MYCN;Dbh iCre tumor grafts treated with compound (1-1) or H20 alone.
- Figure 34D illustrates relative fraction of positively stained cells for cleaved caspase and Mib-1 (e) showing an significant increase in apoptotic cells following murine neuroblastoma grafts following treatment of mice with compound (1-1) compared to H20 treated.
- Figure 35E illustrates relative fraction of positively stained cells for Mib-1 and a decrease of proliferating cells in murine neuroblastoma grafts following treatment of mice with OTX015 compared to H 2 0 treated.
- Figure 35A illustrates chromatin immuno-precipitation of BRD4 and PCR at the MYCN promotor region after treatment of IMR5 cells with compound (1-1).
- Figure 35B illustrates the relative chromatin immuno-precipitation of BRD4 at the MYCN promotor region after treatment of IMR5 cells with compound (1-1), JQ1 and control.
- Figure 35C illustrates chromatin immuno-precipitation of BRD4 and PCR at the CCNDl promotor region after treatment of IMR5 cells with compound (1-1).
- Figure 35D illustrates the relative chromatin immuno-precipitation of BRD4 at the CCNDl promotor region after treatment of IMR5 cells with compound (1-1), JQ1 and control.
- Figure 36A illustrates MYCN mRNA expression after treatment of IMR-5, Chp-134, Chp212, SK-N-BE neuroblastoma cell lines with 500 nM compound (1-1) relative to respective DMSO control for 4 hours, 8 hours, 24 hours, 48 hours and 72 hours.
- Figure 36B illustrates CCND1 mRNA expression after treatment of IMR-5, Chp-134, Chp212, SK-N-BE neuroblastoma cell lines treated with 500 nM compound (1-1) relative to respective DMSO control for 4 hours, 8 hours, 24 hours, 48 hours and 72 hours.
- Figure 37 illustrates Western blot profile for BRD4, E2F1, CMYC, Cyclin Dl, MYCN and Actin for IMR-5, Chp-134, Chp212, SK-N-BE neuroblastoma cell lines treated with 500 nM compound (1-1).
- Figure 38 illustrates relative MYCN mRNA expression for in vivo treatment by compound (1-1) and H 2 0.
- Figure 39 illustrates the Western blot profile of E2F1, Cyclin Dl, MYCN and Actin for in vivo treatment by compound (1-1) and H 2 0.
- Figure 40 illustrates a heatmap of the top 50 differentially expressed genes showing distinct gene-expression changes following compound (1-1) treatment in IMR 5 cells measured using Affymetrix gene-expression arrays.
- Figure 41A illustrates a venn diagram comparing differentially expressed genes after compound (1-1) treatment and after JQl treatment showing a high overlap in up-regulated genes after treatment.
- Figure 41B illustrates a venn diagram comparing differentially expressed genes after compound (1-1) treatment and after JQl treatment showing a high overlap in down -regulated genes after treatment.
- Figure 42 illustrates a gene set enrichment analysis of differentially expressed genes after treatment with compound (1-1) or JQl using C6 gene sets that represent signatures of cellular pathways, which are often dis-regulated in cancer.
- Figure 43A illustrates the differentially expressed genes after treatment of IMR5 with JQl to known gene signature of Stegmaier.
- Figure 43B illustrates the differentially expressed genes after treatment of IMR5 with compound (1-1) to known gene signature of MYCN targets of Dang.
- Figure 43C illustrates the differentially expressed genes after treatment of IMR5 with compound (1-1) to known gene signature of MYCN targets of Westermann.
- Figure 44 illustrates H3K27ac signal across enhancer regions for all enhancers in MYCN- amplified cell line IMR5. Super enhancers were defined as surpassing the threshold oflOOO. In IMR5 cells, 4.6% of the enhancers were classed as SEs
- Figure 45 illustrates Fisher Exact test for enrichment of genes associated with super- enhancers in the genes down-regulated (logFC ⁇ 0 and q ⁇ 0.05) upon compound (1-1) or JQ1 treatment.
- Figure 46A illustrates a cumulative distribution plot of the top 200 super-enhancer associated genes and their FC measured using gene-expression arrays after treatment with JQ1.
- Figure 46B illustrates a cumulative distribution plot of the top 200 super-enhancer associated genes and their FC measured using gene-expression arrays after treatment with compound (1-1).
- Figure 46C illustrates the overlap in cumulative distribution plot of the top 200 super- enhancer associated genes and their FC measured using gene-expression arrays after treatment with JQ1 and compound (1-1).
- Figure 47 A illustrates a box plots of log2 fold changes in the top 200 genes associated with SEs and regular enhancers (RE) in MYCN-amplified cells treated with JQ1 versus DMSO (two- sided Mann-Whitney test).
- Figure 47B illustrats a box plots of log2 fold changes in the top 200 genes associated with SEs and regular enhancers (RE) in MYCN-amplified cells treated with compound (1-1) versus DMSO (two-sided Mann- Whitney test).
- Figure 47C illustrates a box plots of log2 fold changes in the top 200 genes associated with SEs and regular enhancers (RE) in MYCN-amplified cells treated with compound (1-1) and JQ1 versus DMSO (two-sided Mann- Whitney test).
- alkyl group refers to a saturated straight or branched hydrocarbon.
- substituted alkyl group refers to an alkyl moiety having one or more substituents replacing a hydrogen or one or more carbons of the hydrocarbon backbone.
- alkenyl group whether used alone or as part of a substituent group, for example, "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 Ci_ 4 alkenyl or C 2 - 4 alkenyl groups.
- C . ⁇ (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 (1-4) 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 enantio selective and diastereo selective 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 disclosure demonstrates that targeting BET bromodomain proteins disrupts the epigenetic regulation of MYCN and its targets in neuroblastoma.
- the expression of BRD4 in 101 primary neuroblastomas was assessed and evaulated for correlations with event-free survival (EFS) and overall- survival (OS) through a reanalysis of microarray data previously published by (REF: Schramm et al., BJC 2012)). Both EFS and OS were negatively correlated with BRD4 expression suggesting that high expression of BRD4 may suggest an adverse outcome of patients with neuroblastoma, Figures 13A-13F. Furthermore, BRD4 expression was significantly upregulated in high (stage 3 and 4) versus low (stage 1, 2 and 4s) stage neuroblastomas, Figure 13G.
- the present inventions described herein provide for methods of treating neuroblastoma.
- the neuroblastoma is MYCN amplified.
- the detailed description sets forth the disclosure in various parts: III. Thienotriazolodiazepine Compounds; IV.
- the present invention provides a method of treating neuroblastoma in a mammal, wherein the method comprises the step of: administering thienotriazolodiazepine compound being represented by the compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, a racemate, an enantomer, an isomer, or an isotopically-labeled form thereof.
- the neuroblastoma is MYCN amplified.
- the neuroblastoma is characterized by one or more regions of super- enhancer gene, said super-enhancer gene having higher amounts of H3K27Ac compared to an amount of H3K27Ac associated with an average gene.
- the super-enhancer gene is selected from the group consisting of MYCN, NCOR2, GLI2 and combinations thereof.
- the super-enhancer gene is characterized as being down regulated following administration of the thienotriazolodiazepine compound being represented by Formula (1).
- 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.
- a mammalian subject as used herein can be any mammal.
- the mammalian subject includes, but is not limited to, a human; a non-human primate; a rodent such as a mouse, rat, or guinea pig; a domesticated pet such as a cat or dog; a horse, cow, pig, sheep, goat, or rabbit.
- the mammalian subject includes, but is not limited to, a bird such as a duck, goose, chicken, or turkey.
- the mammalian subject is a human.
- the mammalian subject can be either gender and can be any age.
- R 1 is alkyl having a carbon number of 1-4
- R 2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1- 4, alkoxy having a carbon number of 1-4 or cyano;— NR 5 — (CH 2 ) m — R 6 wherein R 5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R 6 is phenyl or pyridyl optionally substituted by a halogen atom; or -NR 7 — CO— (CH 2 ) n — R 8 wherein R 7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R is pheny
- 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.
- the present invention provides pharmaceutically acceptable salts, solvates, including hydrates, and isotopically-labeled forms of the thienotriazolodiazepine compounds described herein.
- pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with inorganic acids.
- thienotriazolodiazepine include salts of hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids.
- pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with organic acids.
- pharmaceutically acceptable organic acid addition salts of the thienotriazolodiazepine include salts of tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and 4-methyl benzenesulfonic acids.
- Representative thienotriazolodiazepine compounds of Formula (1) include,
- thienotriazolodiazepine compounds of Formula (1) include (i) (S)- 2-[4-(4-cMorophenyl)-2,3,9-trme
- thienotriazolodiazepine compounds of Formula (1) include (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 .
- thienotriazolodiazepine compounds of Formula (1) include (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 ⁇ hydroxyphenyl) acetamide .
- 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.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a solid dispersion of a thienotriazolodiazepine compound of Formula (1) or a
- the pharmaceutically acceptable polymer is polyvinylpyrrolidone (also called povidone or PVP).
- the dispersion has a thienotriazolodiazepine compound to PVP weight ratio of 1:3 to 1: 1.
- 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 175 °C to about 185 °C. In other such embodiments, the single Tg occurs at about 179 °C.
- the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
- the polyvinyl pyrrolidones may have molecular weights of about 2,500 (KoUidon ®12 PF, weight- average molecular weight between 2,000 to 3,000), about 9,000 (KoUidon® 17 PF, weight- average molecular weight between 7,000 to 11,000), about 25,000 (KoUidon® 25, weight-average molecular weight between 28,000 to 34,000), about 50,000 (KoUidon® 30, weight- average molecular weight between 44,000 to 54,000), and about 1,250,000 (KoUidon® 90 or KoUidon® 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.
- 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).
- 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 thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
- the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
- Tg glass transition temperature
- the single Tg occurs between 130 °C to 140 °C. In other such embodiments, the single Tg occurs at about 135 °C.
- the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
- a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a thienotriazolodiazepine compound of Formula (1) or a
- the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
- the weight ratio of compound (1) to polyvinylpyrrolidone ranges from 1:3 to 1: 1.
- the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to 185 °C. In other such embodiments, the single Tg occurs at about 179 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
- Tg glass transition temperature
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
- substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
- a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
- the pharmaceutically acceptable polymer is hypromellose acetate succinate.
- the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1:3 to 1: 1.
- the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 130 °C to 140 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In other such embodiments, the single Tg occurs at about 135 °C.
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
- substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
- a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
- the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
- the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1:3 to 1: 1.
- the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to 185 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In other such embodiments, the single Tg occurs at about 179 °C.
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
- substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline
- a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
- the pharmaceutically acceptable polymer is hypromellose acetate succinate.
- the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1:3 to 1: 1.
- a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
- the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
- the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1:3 to 1: 1.
- the present invention provides a pharmaceutical
- composition comprising a solid dispersion of 2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thienol[3,2-f]-[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. 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 (1-1).
- substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
- a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound (1-1) or a
- the pharmaceutically acceptable polymer is HPMCAS.
- the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1:3 to 1: 1.
- at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
- the thienotriazolodiazepine compound is
- the solid dispersion is spray dried.
- the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
- Tg glass transition temperature
- the single Tg occurs between 130 °C to 140 °C.
- the single Tg occurs at about 135 °C.
- the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
- substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
- a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound (1-1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof; and a pharmaceutically acceptable polymer.
- the pharmaceutically acceptable polymer is PVP.
- the dispersion has compound (1-1) and PVP in a weight ratio 1:3 to 1: 1.
- at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
- the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
- the solid dispersion is spray dried.
- the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
- Tg glass transition temperature
- the single Tg occurs between 175 °C to 185 °C.
- the single Tg occurs at about 189 °C.
- the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
- the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
- substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
- a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound (1-1) or a
- the pharmaceutically acceptable polymer is HPMCAS.
- the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1:3 to 1: 1.
- the solid dispersion is spray dried.
- a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound (1-1) or a
- the pharmaceutically acceptable polymer is PVP.
- the dispersion has compound (1-1) and PVP in a weight ratio 1:3 to 1: 1.
- the solid dispersion is spray dried.
- the solid dispersions of the invention exhibit especially advantageous properties when administered orally.
- advantageous properties of the solid dispersions include, but are not limited to, consistent and high level of bioavailability when administered in standard bioavailability trials in animals or humans.
- the solid dispersions of the invention can include a solid dispersion comprising thienotriazolodiazepine compound of Formula (1) and a polymer and additives.
- the solid dispersions can achieve absorption of the thienotriazolodiazepine compound of Formula (1) into the bloodstream that cannot be obtained by merely admixing the thienotriazolodiazepine compound of Formula (1) with additives since the thienotriazolodiazepine compound of Formula (1) drug has negligible solubility in water and most aqueous media.
- the bioavailability, of thienotriazolodiazepine compound of Formula (1) or of thienotriazolodiazepine compound (1-1) may be measured using a variety of in vitro and/or in vivo studies. The in vivo studies may be performed, for example, using rats, dogs or humans.
- the bioavailability may be measured by the area under the curve (AUC) value obtained by plotting a serum or plasma concentration, of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1), along the ordinate (Y-axis) against time along the abscissa (X-axis).
- AUC value of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1) from the solid dispersion is then compared to the AUC value of an equivalent concentration of crystalline thienotriazolodiazepine compound of Formula (1) or crystalline thienotriazolodiazepine compound (1-1) without polymer.
- the solid dispersion provides an area under the curve (AUC) value, when administered orally to a dog, that is selected from: at least 0.4 times, 0.5 times, 0.6 time, 0.8 time, 1.0 times, a corresponding AUC value provided by a control composition administered intravenously to a dog, wherein the control composition comprises an equivalent quantity of a crystalline thienotriazolodiazepine compound of Formula I.
- AUC area under the curve
- the bioavailability may be measured by in vitro tests simulating the pH values of a gastric environment and an intestine environment.
- the measurements may be made by suspending a solid dispersion of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1), in an aqueous in vitro test medium having a pH between 1.0 to 2.0, and the pH is then adjusted to a pH between 5.0 and 7.0, in a control in vitro test medium.
- thienotriazolodiazepine compound (1-1) may be measured at any time during the first two hours following the pH adjustment.
- the solid dispersion provides a concentration, of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous
- thienotriazolodiazepine compound (1-1) in an aqueous in vitro test medium at pH between 5.0 to 7.0 that is selected from: at least 5-fold greater, at least 6 fold greater, at least 7 fold greater, at least 8 fold greater, at least 9 fold greater or at least 10 fold greater, compared to a concentration of a crystalline thienotriazolodiazepine compound of Formula (1) or crystalline thienotriazolodiazepine compound (1-1), without polymer.
- the concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous thienotriazolodiazepine compound (1-1), from the solid dispersion placed in an aqueous in vitro test medium having a pH of 1.0 to 2.0 is: at least 40%, at least 50% higher, at least 60 %, at least 70 %; at least 80 %, than a concentration of a crystalline thienotriazolodiazepine compound of Formula (1) without polymer.
- the polymer of the solid dispersion is HPMCAS.
- the polymer of the solid dispersion is PVP.
- a concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous thienotriazolodiazepine compound (1-1), from the solid dispersion is: at least 40%, at least 50% higher, at least 60 %, at least 70 %; at least 80 %, compared to a concentration of thienotriazolodiazepine compound of Formula (1), from a solid dispersion of thienotriazolodiazepine compound of the Formula (1) and a pharmaceutically acceptable polymer selected from the group consisting of: hypromellose phthalate and ethyl acrylate-methyl
- methacrylate-trimethylammonioethyl methacrylate chloride copolymer wherein each solid dispersion was placed in an aqueous in vitro test medium having a pH of 1.0 to 2.0.
- the polymer of the solid dispersion is HPMCAS.
- the polymer of the solid dispersion is PVP.
- the solid dispersions, described herein exhibit stability against recrystallization of the thienotriazolodiazepine compound of the Formula (1) or the
- the concentration of the amorphous thienotriazolodiazepine compound of the Formula (1) or the thienotriazolodiazepine compound (1-1) which remains amorphous is selected from: at least 90 %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% and at least 99%.
- Suitable dosage forms that can be used with the solid dispersions of the present invention include, but are not limited to, capsules, tablets, mini-tablets, beads, beadlets, pellets, granules, granulates, and powder.
- Suitable dosage forms may be coated, for example using an enteric coating.
- Suitable coatings may comprise but are not limited to cellulose acetate phthalate, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, a polymethylacrylic acid copolymer, or hydroxylpropylmethylcellulose acetate succinate (HPMCAS).
- HPMC hydroxypropylmethylcellulose
- HPMC hydroxypropylmethylcellulose
- HPMCAS hydroxylpropylmethylcellulose acetate succinate
- 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.
- the solid dispersions of the invention may be formulated as tablets, caplets, or capsules. In one some embodiments, the solid dispersions of the invention may be formulated as mini-tablets or pour-into-mouth granules, or oral powders for constitution. In some embodiments, the solid dispersions of the invention are dispersed in a suitable diluent in
- the solid dispersions of the invention may be formulated for pediatric treatment.
- the pharmaceutical composition of the present invention is formulated for oral administration.
- the pharmaceutical composition comprises a solid dispersion, according to the various embodiments described herein, comprising a
- the pharmaceutical composition further includes one or more additives such as disintegrants, lubricants, glidants, binders, and fillers.
- Suitable pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants for use with the pharmaceutical composition include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose, glyceryl behenate, stearic acid, hydrogenated castor oil, glyceryl monostearate, and sodium stearyl fumarate.
- Suitable pharmaceutically acceptable binders for use with the pharmaceutical composition include, but are not limited to starches; celluloses and derivatives thereof, e.g., microcrystalline cellulose (e.g., AVICEL PH from FMC), hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxylpropylmethylcellulose (HPMC, e.g., METHOCEL from Dow Chemical); sucrose, dextrose, corn syrup; polysaccharides; and gelatin.
- suitable pharmaceutically acceptable fillers and pharmaceutically acceptable diluents for use with the pharmaceutical composition include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose (MCC), powdered cellulose, sorbitol, sucrose, and talc.
- excipients may serve more than one function in the pharmaceutical composition.
- fillers or binders may also be disintegrants, glidants, anti-adherents, lubricants, sweeteners and the like.
- the pharmaceutical compositions of the present invention may further include additives or ingredients, such as antioxidants (e.g., ascorbyl palmitate, butylated hydroxylanisole (BHA), butylated hydroxytoluene (BHT), 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 microcrystalline cellulose; 4-6 wt. % of croscarmellose sodium; 0.8-1.5 wt. % of colloidal silicon dioxide; and 0.8- 1.5 wt. % of magnesium stearate.
- HPMCAS hydroxypropylmethylcellulose acetate succinate
- the present invention provides a pharmaceutical composition that maybe formulated into any suitable solid dosage form.
- a pharmaceutical composition in accordance with the present invention comprises one or more of the various embodiments of the thienotriazolodiazepine of Formula (1) as described herein in a dosage amount ranging from about 10 mg to about 100 mg.
- the pharmaceutical composition of the present invention includes one or more of the various embodiments of the
- the pharmaceutical composition of the present invention includes one or more of the various embodiments of the thienotriazolodiazepine of Formula (1) as described herein in a dosage amount selected from the group consisting of about 10 mg, about 50 mg, about 75 mg, about 100 mg.
- the methods of the present invention includes administering to a subject in need thereof one or more of the various embodiments of the thienotriazolodiazepine of Formula (I) as described herein in a dosage amount selected from the group consisting of about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 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
- 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), (1-11), (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 110 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,
- any of the foregoing dosage amounts or dosage forms is decreased periodically or increased periodically.
- Such unit dosage forms are suitable for administration 1 to 5 times daily depending on the particular purpose of therapy, the phase of therapy, and the like.
- the dosage form may be administered to a subject in need thereof at least once daily for at least two successive days.
- the dosage form may be administered to a subject in need thereof at least once daily on alternative days.
- the dosage form may be administered to a subject in need thereof at least weekly and divided into equal and/or unequal doses.
- the dosage form may be administered to a subject in need thereof weekly, given either on three alternate days and/or 6 times per week.
- the dosage form may be administered to a subject in need thereof in divided doses on alternate days, every third day, every fourth day, every fifth day, every sixth day and/or weekly. In one embodiment, the dosage form may be administered to a subject in need thereof two or more equally or unequally divided doses per month.
- the dosage form used e.g., in a capsule, tablet, mini-tablet, beads, beadlets, pellets, granules, granulates, or powder may be coated, for example using an enteric coating.
- Suitable coatings may comprise but are not limited to cellulose acetate phthalate,
- HPMC hydroxypropylmethylcellulose
- phthalate hydroxypropylmethylcellulose phthalate
- HPMCAS hydroxylpropylmethylcellulose acetate succinate
- 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 L100-55, at both 25% and 50% of compound (1-1) loading, for each polymer.
- Solid dispersions were prepared by a solvent evaporation method, using spray-drying followed by secondary drying in a low-temperature convection oven. The performance of each solid dispersion was assessed via a non-sink dissolution performance test which measured both the total amount of drug and the amount of free drug present in solution over time.
- Non-sink dissolution was chosen because it best represents the in vivo situation for low soluble compounds.
- This test included a "gastric transfer" of dispersion from gastric pH (0.1N NaCl, pH 1.0) to intestinal pH (FaFSSIF, pH 6.5) approximately 30 to 40 minutes after the introduction of dispersion to the test medium, simulating in vivo conditions.
- FaFSSIF Fasted State Simulated Intestinal Fluid, comprised of 3 mM sodium taurocholate, 0.75 mM lechithin, 0.174 g NaOH pellets, 1.977 g NaH 2 P0 4 'H 2 0, 3.093 g NaCl, and purified water qs 500 mL.
- the amount of dissolved drug was quantified using a high-performance liquid
- Example 2 In vivo screening of solid dispersions of compound (1-1)
- the elimination half-life (ti /2 ) was calculated by least- squares regression analysis of the terminal linear part of the log concentration-ime curve.
- the maximum plasma concentration (C max ) and the time to C max ( ) were derived directly from the plasma concentration data.
- bioavailability (F) was calculated by dividing the dose normalized AUC after oral administration by the dose normalized AUC after intravenous administration and reported as percentages (%).
- AUC area under the plasma concentration-time curve
- C max maximum plasma concentration
- F bioavailability
- HPMCAS hypromellose acetate sodium
- IV intravenous
- PEG polyethylene glycon
- PO per os, oral
- PVP polyvinylpyrrolidone
- Example 3 Preparation and clincial use of capsules containing a solid dispersion of compound (1-1)
- a gelatin capsule of 10 mg strength was prepared for initial clinical studies in patients with hematologic malignancies. Based on results of in vitro and in vivo testing of solid dispersions of compound (1-1), as described in Examples 1 and 2, a 50% compound (1-1) in HPMCAS-M solid dispersion was selected for capsule development. Capsule development was initiated targeting a fill weight of 190 mg in a size 3 hard gelatin capsule, as this configuration would potentially allow increasing the capsule strength by filling a larger size capsule while maintaining the pharmaceutical composition. Based on experience, four capsule formulations were designed with different amounts of disintegrant and with and without wetting agent.
- the 50% compound (1-1) in HPMCAS-M solid dispersion (1000 g) and excipients, including microcrystalline cellulose filler-binder (4428 g), croscarmellose sodium disintegrant (636 g), colloidal silicon dioxide dispersant/lubricant 156 g), magnesium stearate dispersant/lubricant (156 g), and lactose monohydrate filler (5364 g) were blended in stages in a V-blender. The blend was them compacted and granulated to obtain a bulk density of approximately 0.6 g/mL. The blend was dispensed into size 3 hard gelatin capsules (target fill weight: 190 mg) using an automated filling machine and finished capsules were polished using a capsule polisher machine.
- the Eudragit solid dispersion formulation was made by dissolving and/or dispersing the thienotriazolodiazepine of formula (A) and coating excipients, including ammonio methacrylate copolymer type B (Eudragit RS), methacrylic acid copolymer type C (Eudragit L100-55), talc, and magnesium alumino silicate, in a mixture of water and ethanol.
- This heterogeneous mixture then was applied to microcrystalline cellulose spheres (Nonpareil 101, Freund) using a centrifugal fluidizing bed granulator to produce granules that were dispensed into size 2 hydroxypropyl methylcellulose capsules.
- HPMCAS-M solid dispersion formulation is unexpected.
- Table 2A solid dispersion capsules of compound (1-1) for clinical use pharmaceutical composition containing 50% HPMCAS solid dispersion of compound (1-1):
- Table 2B pharmaceutical composition containing Eudragit L100-55solid dispersion of compound (1-1): 10 mg strength, size 2 hard gelatin capsule
- 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.
- 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. [00223] Table 4. Dosing scheme for rat oral exposure study.
- 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 (t ) 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 (C max ) and the time to C max (t max ) were derived directly from the plasma concentration data.
- Table 5 Pharmacokinetic parameters of compound (1-1) after oral and intravenous administrations. The values are an average from three animals.
- 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 Biichi B-290, PE-024 spray dryer with a 1.5 mm nozzle and a Biichi B-295, P-002 condenser.
- the spray dryer nozzle pressure was set to 80 psi
- the target outlet temperature was set to 40 °C
- the chiller temperature was set to -20 °C
- the pump speed was set to 100%
- the aspirator setting was 100%.
- the solid dispersions were collected and dried overnight in a low temperature convection oven to remove residual solvents.
- Example 6 Stability with humidity and temperature.
- Spray dried dispersions of compound (1-1) in HPMCAS-MG were assessed for stability by exposure to moisture at elevated temperature.
- the glass transition temperature (Tg) as a function of relative humidity was determined at 75% relative humidity, 40 °C for 1, 2 and 3 months.
- the spray dried dispersion was stored in an LDPE bag inside a HDPE bottle to simulate bulk product packaging.
- the data is summarized in Table 6. At time zero, the Tg was 134 °C, at 1 month the Tg was 134 °C, at 2 months the Tg was 135 °C and at 3 months the Tg was 134 °C and only a single inflection point was observed for each measurement. X-ray diffraction patterns were also obtained for each sample.
- Figure 9 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG at time zero of a stability test.
- Figures 10, 11 and 12 illustrate powder X-ray diffraction profiles of solid dispersions of compound (1-1) in HPMCAS-MG after 1 month, 2 months and 3 months, respectively, after exposure at 40 °C and 75 % relative humidity. The patterns did not show any diffraction lines associated with compound (1-1).
- Example 7 In Vitro and in vivo Treatment of Neuroblastoma Cell Lines and
- Example 8 an analysis of gene expression profiles before and after exposure to BET bromodomain inhibitors
- Example 9 Compound (1-1) efficacy in treatment of MYCN amplified
- Example 9a IC50 and cell cycle profile:
- Compound (1-1) efficacy was tested in four established neuroblastoma cell lines (IMR-5, SK-N-AS, SK-N-BE and SY5Y) and determined the 50% inhibition concentration (IC50) in vitro using MTT assays.
- Cell cycle profiling was performed and analyzed markers for apoptosis and proliferation after 72 h treatment with 250 or 500 nM compound (1-1) using Cell Death and BrdU Incorporation ELISA assays.
- the effect of compound (1-1) on MYCN expression and global MYCN-associated transcriptional activity was assessed by quantitative real-time PCR, Western blot, and Affymetrix U133 plus 2.0 Arrays, respectively.
- the effect of oral compound (1-1) was assessed in mice engrafted with the MYCN-driven
- Figs. 15A and 15B the IC50 observed in the MYCN-amplified cell line IMR-5 was lower than that observed in SK-N-AS, which does not harbor amplified MYCN or express MYCN after 72 hours of treatment with compound (1-1).
- Treatment of MYCN- amplified neuroblastoma cells with compound (1-1) resulted in reduced cell proliferation (Fig. 15C) compared to DMSO contrals in IMR-5 cells after 72 hours of treatment.
- Compound (1-1) also induced apoptosis (Fig. 15D) compared to DMSO controls.
- Compound (1-1) treatment also resulted in an increased percent of cells in sub-Gl fraction compared to DMSO contrals in IMR- 5 cells after 72 hours of treatment (Fig. 15E).
- Fig. 15F illustrates images of cells in culture after 72 hours of treatment with compound (1-1).
- Example 9b MYCN expression and transscriptional activity
- Affymetrix U133 plus 2.0 Arrays were assessed in mice engrafted with the MYCN-driven neuroblastoma cell line, IMR-5, using different treatment schedules (25 and 50 mg/kg/day versus 25 mg/kg twice daily
- Fig. 16 corresponds to the down-regulation of MYCN mRNA (Fig. 16) and MYCN protein levels (Fig. 18).
- Fig. 16 illustrates that compound (1-1) significantly decreased MYCN mRNA expression in IMR-5 cells after 8 hours of treatment. Expression levels (including those of SK-NA-S) are shown relative to DMSO-treated IMR-5 cells. Note, that SK-N-AS expresses very low MYCN levels.
- Figs. 17 and 18 illustrate the known MYCN target Cyclin Dl.
- Fig. 17 illustrates that compound (1-1) significantly decreased CCND1 mRNA expression in IMR-5 and SK-N-AS cells after 48 h of treatment. Expression levels are shown relative to DMSO-treated IMR-5 cells.
- Fig. 18 illustrates that compound (1-1) reduced protein expression levels of MYCN and Cyclin Dl in IMR-5 cells and
- Example 10 Neuroblastoma Xenografts
- mice bearing xenografts established from IMR-5 cells were treated with vehicle control (H20), compound (1-1) or positive control (cyclophosphamide; CPM).
- Immunohistochemical analysis of IMR-5 xenografts from mice treated with compound (1-1) revealed a significant increase in the level of cleaved caspase 3, indicating the induction of apoptosis (Figs. 19A,C), and decreased Ki-67 expression, indicating reduced cell proliferation (Figs. 19A,B).
- Tumors from compound (1-1) treated mice showed significantly increased apoptosis (cleaved caspase 3) and reduced numbers of proliferating cells (Ki-67) as illustrated in Fig. 19D.
- Tumor growth was significantly reduced in mice treated with compound (1-1) after 23 days with all doses and schedules compared to negative controls (significance levels compared to H 2 0 are shown) as illustrated in Fig. 19E.
- Mice survival was significantly prolonged after OTX015 treatment compared to vehicle control (significance levels compared to H 2 0 are shown).
- Example 11 Effect of compound (1-1) on non-malignant primary human cells
- Compound (1-1), as described in Example 9 inhibits the binding of BRD2, BRD3, and BRD4 to acetylated histones with IC50 values from 92 to 112 nM.
- the putative effects of compound (1-1) on non-malignant primary human cells were assessed by treating foreskin fibroblast with compound (1-1) and measured the cell viability after 72 hours, Figures 20, 21A and 2 IB.
- Compound (1-1) insignificantly decreased cell viability of human fibroblasts with a maximal reduction of less than 30% at high micromolar concentrations.
- Example 12 Reduction of neuroblastoma cell viability
- the human neuroblastoma cell lines Chp 212, Chp-134, Gimen, IMR 32, NB69, SKIN- AS, SK-N-BE, and SK N BE2 were obtained from the German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany) or the American Type Culture Collection (ATCC, Manassas, Virginia, USA), respectively.
- the human neuroblastoma cell line, IMR 5 was provided by Frank Westermann (DKFZ, Heidelberg, Germany). The identity of all cell lines was verified by comparison of alleles for 16 different markers reported for the respective cell line. Furthermore, cell lines were confirmed to be of human origin and neither mammalian interspecies nor Mycoplasma sp.
- Cell lines were cultured under standard conditions (37 °C in a humidified atmosphere, with 5% C0 2 ) in RPMI 1640 supplemented with 10% FCS and antibiotics (100 U / ml penicillin and 100 ⁇ g / ml streptomycin). Cells were passaged if at a confluence of 80% using 0.2% trypsin / EDTA and seeded at a dilution of 1:5 to 1: 10. Cell lines were maintained in culture for a maximum of 12 weeks.
- Example 13 Apoptosis and cell proliferation
- Example 14 Compound (1-1) antitumor activity agsint MYCN- amplified
- IMR 5 cells were cultured to 80% confluence, harvested and 2 x 10 7 cells were suspended in 200 ⁇ MatrigelTM (BD Bioscience, Heidelberg, Germany) per mouse for subcutaneous inoculation into the left flank of 6-week-old female athymic (nu/nu) mice. Mice were randomly assigned to vehicle control, compound (1-1) or positive control
- Compound (1-1) was provided as a solid dispersion ("compound (l-l)-SD") containing 50% compound (1-1) and used to prepare a suspension.
- Compound (1-1)- SD was administered by oral gavage at the following final doses: 25 mg / kg body weight (BW) daily (concentration of suspension was 7.5 mg compound (l-l)-SD per ml), 50 mg / kg BW daily (concentration of suspension was 15 mg compound (l-l)-SD per ml) or 25 mg / kg BW twice daily at 7 days per week.
- Vehicle controls were treated with water alone (100 ⁇ daily) and positive controls with cyclophosphamide (150 mg / kg BW daily) per os. Tumor growth was monitored using calipers and tumor volume was calculated using the formula (width x length x height) / 2. Mice were sacrificed by cervical dislocation after 42 days of treatment or when tumor size exceeded 2,500 mm .
- tissues obtained from tumors treated with vehicle or compound (1-1) were fixed overnight in 4% formalin solution and embedded in paraffin. Briefly, 3 ⁇ thick sections of FFPE tumors were deparaffinized and antigen retrieval was performed by boiling the sections in citrate buffer at pH 6, or EDTA at pH 9 for 20 min.
- Ki-67 (1:50; pH 6; #275R 16, Cell Marque)
- cleaved caspase 3 (1: 100; pH 6; #9661, Cell Signaling
- corresponding secondary antibody detection kits for reduced background were used (Histofine Simple Stain MAX PO, Medac, Hamburg, Germany) and stained on an automated stainer (Lab Vision Autostainer 480S, Thermo Scientific). All slides were scanned with a Pannoramic 250 slide scanner (3D Histech.com).
- neuroblastoma cells dependent on MYCN status.
- Example 15 Compound (1-1) treatment of murine tumors grown as grafts in nude mice
- Murine tumors (-1,000 mm 3 ) derived from the genetically engineered mouse model LSL MYCN;Dbh-iCre [12] were minced manually with scissors and digested with 2 mg / ml collagenase in PBS for 30 min at 37°C. Tumor pieces were passed through a sieve with 400 ⁇ pore size to obtain a cell suspension.
- Tumor growth was monitored using calipers and tumor volume was calculated using the formula (width x length x height) / 2.
- Mice were sacrificed by cervical dislocation after 24 days treatment or when tumor size exceeded 2,500 mm .
- six doses of 75 mg compound per kg BW were administered twice daily over a 3-day course.
- Mice were sacrificed by cervical dislocation 4 h after the last compound (1-1) dose.
- Blood samples were taken from the tail vein and stored in lithium-heparin tubes on ice. Plasma was separated by centrifugation (15 min at 4,000 rpm), snap-frozen in liquid nitrogen and stored at -80 °C. Grafted tumors were excised and divided into halves.
- FIGs. 34A and 34B A delay in tumor progression resulting in significantly prolonged mouse survival (Figs. 34A and 34B) was observed. These tumors showed increased fractions of apoptotic cells and decreased fractions of proliferating cells measured by IHC of cleaved caspase 3 and Ki-67 (Figs. 34C, 34D and 34E).
- the results show that inhibition of BRD4 after oral treatment with compound (1-1) is effective in reducing tumor burden in human neuroblastoma models with amplified MYCN locus as well as in murine neuroblastoma GEMM ectopically expressing MYCN, where MYCN transcription is not coupled to endogenous regulation. This suggests that effects of BRD4 inhibition with compound (1-1) might be independent on the downregulation of MYCN itself and shows how powerful anti-tumoral effects of BRD4 inhibition are in MYCN driven neuroblastoma models.
- Example 16 Compound (1-1) treatment and BRD4 chromatin interaction
- HRP Horseradish peroxidase
- ChIP Chromatin immunoprecipitation pull-downs were then prepared by Zymo Research (Irving, CA, USA) using frozen cross-linked cells.
- H3K27Ac ChIP DNA enriched from 3 independent ChIP assays were verified by qPCR using positive control primers for human RPL10 promoter. ChlP-Seq libraries were quantified using 2200 Tape Station before being run on Next-Gen Sequencing platform HiSeq.
- Compound (1-1) treatment reduced MYCN transcript levels in all MYCN amplified cell lines after 4 hours up to 72 hours of compound (1-1) treatment (Fig. 36).
- CCND1 mRNA was measured and showed similarly significant reduction over time (Fig. 36).
- the reduction in transcript levels in IMR-5, Chp-134, Chp-212, SK-N-AS and SK-N-BE neuroblastoma cell lines treated with compound (1-1) was also recapitulated at protein level for MYCN and other BRD4 targets (Fig. 37).
- Example 17 Effect of BRD4 inhibition by compound (1-1) on gene transcription of MYCN target genes
- Affymetrix microarray analysis IMR 5 cells were plated at 1 x 10 5 cells per well in 6-well plates, left over night to attach, then treated in triplicate with 0.2% DMSO (control) or 500 nM compound (1-1) or 500 nM JQ1 for 24 h. Total RNA was extracted using the
- Affymetrix Human Gene Expression Array (HG-U133 Plus 2.0, Affymetrix, Santa Clara, CA, USA) using established protocols.
- Microarray CEL files were normalized and summarized to gene level, using the Bioconductor repository of the statistical language R to do gcRMA normalization.
- a Ward-Manhattan clustering was performed. The 50 probes with the highest standard deviation over all selected samples were used.
- Differential expression analysis was performed using the Rank Product analysis using R (v 2.13, RankProd package). Hierarchical clustering on Manhattan distance of log2 expression values of the 50 most differentially expressed genes was applied to visualize differential gene expression on treatment.
- Gene set enrichment analysis was performed with GSEA v2.0 software. Genes were rank-ordered using a signal-to-noise ranking metric (the difference of the means of the comparator populations scaled by the standard deviation).
- the c2.cgp.v3.1.symbols.gmt gene set was used (broadinstitute.org/gsea). Gene signature scores were calculated with adaptation of a previously reported algorithm.
- MYC-regulated genes as previously defined by Westermann
- JQ1 responsive genes as previously defined by Puissant
- MYC(N) signatures retrieved from curated gene sets (c2) from version 3.1 of the
- R2 visualization and analysis platform http://hgserverl.amc.nl/cgi-bin/r2/main.cgi
- SPSS version 18.0 (IBM SPSS) was used for further statistical analysis.
- the student's two-sided t-test was used to compare all interval variables and the chi-square test was used for the comparison for all categorical variables.
- Graph Pad Prism 5.0 (GraphPad Software Inc.) was used to perform Kaplan-Meier survival analysis with log-rank statistics on compund (1-1) treated and control mouse cohorts.
- GSEA Gene set enrichement analysis
- Fig. 43A illustrates the differentially expressed genes after treatment of IMR5 with JQl to known gene signature of Stegmaier.
- Figure 43B illustrates the differentially expressed genes after treatment of IMR5 with compound (1-1) to known gene signature of MYCN targets of Dang. (See, C. V. Dang, "MYC on the Path to Cancer," Cell. Mar 30, 2012; 149(1): 22-35).
- Fig. 43C illustrates the differentially expressed genes after treatment of IMR5 with compound (1-1) to known gene signature of MYCN targets of Westermann.
- BRD4 can bind to acetylated histones at so called super-enhancer sites, regulating transcriptional pause release of oncogenes such as MYC. No super-enhancers have yet been identified in neuroblastoma.
- ChlP-seq was used for H3K27Ac to identify super-enhancers in the MYCN amplified neuroblastoma cell line IMR 5. Using an algorithm proposed by Whyte, 1335 super-enhancers in IMR-5 were found, (Fig. 44).
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Abstract
La présente invention concerne une méthode permettant de traiter un neuroblastome chez un mammifère, comprenant une étape qui consiste à administrer une quantité pharmaceutiquement acceptable d'un composé thiènotriazolodiazépine de formule (1) dans laquelle R1 désigne un groupe alkyle ayant 1 à 4 atomes de carbone; R2 désigne un atome d'hydrogène, un atome d'halogène ou un groupe alkyle ayant 1 à 4 atomes de carbone facultativement substitués par un atome d'halogène ou un groupe hydroxyle; R3 désigne un atome d'halogène, un groupe phényle facultativement substitué par un atome d'halogène, un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe alkoxy ayant 1 à 4 atomes de carbone ou un groupe cyano, ou — NR5— (CH2)m— R6, R5 désignant un atome d'hydrogène ou un groupe alkyle ayant 1 à 4 atomes de carbone, m désigne un nombre entier compris entre 0 et 4, et R6 désigne un groupe phényle ou pyridyle facultativement substitué par un atome d'halogène, ou -NR7— CO— (CH2)n— R8, R7désignant un atome d'hydrogène ou un groupe alkyle ayant 1 à 4 atomes de carbone, n désigne un nombre entier compris entre 0 et 2, et R8 désigne un groupe phényle ou pyridyle facultativement substitué par un atome d'halogène; et R4 désigne — (CH2)a— CO— NH— R9, a désignant un nombre entier compris entre1 et 4, et R9 désigne un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe hydroxyalkyle ayant 1 à 4 atomes de carbone, un groupe alkoxy ayant 1 à 4 atomes carbone, ou un groupe phényle ou pyridyle facultativement substitué par un groupe alkyle ayant 1 à 4 atomes de carbone, un groupe alcoxy ayant 1 à 4 atomes de carbone, un groupe amino ou hydroxyle ou— (CH2)b— COOR10, b désignant un nombre entier compris entre 1 et 4, et R10 désigne un groupe alkyle ayant 1 à 4 atomes de carbone, ou son sel, hydrate ou solvate pharmaceutiquement acceptable.
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CN110538179B (zh) * | 2018-05-29 | 2021-08-17 | 中国人民解放军陆军军医大学第一附属医院 | Yg1702在制备aldh18a1特异性抑制剂中的应用 |
US10906917B2 (en) | 2018-06-13 | 2021-02-02 | Dybly Ag | Preparation of condensed triazepine derivatives and their use as BET inhibitors |
US11708374B2 (en) | 2018-06-13 | 2023-07-25 | Worg Pharmaceuticals (Zhejiang) Co., Ltd. | Preparation of condensed triazepine derivatives and their use as BET inhibitors |
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