WO2015018520A1 - Inhibiteur bet-brd représentant un nouvel agent pour un lymphome anaplasique à grandes cellules alk positif - Google Patents

Inhibiteur bet-brd représentant un nouvel agent pour un lymphome anaplasique à grandes cellules alk positif Download PDF

Info

Publication number
WO2015018520A1
WO2015018520A1 PCT/EP2014/002163 EP2014002163W WO2015018520A1 WO 2015018520 A1 WO2015018520 A1 WO 2015018520A1 EP 2014002163 W EP2014002163 W EP 2014002163W WO 2015018520 A1 WO2015018520 A1 WO 2015018520A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
carbon number
cell lymphoma
anaplastic large
large cell
Prior art date
Application number
PCT/EP2014/002163
Other languages
English (en)
Inventor
Francesco Bertoni
Giorgio Inghirami
Original Assignee
Oncoethix Sa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oncoethix Sa filed Critical Oncoethix Sa
Publication of WO2015018520A1 publication Critical patent/WO2015018520A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam

Definitions

  • the present invention relates to pharmaceutical compositions and methods of using the same to treat ALK positive anaplastic large cell lymphoma. More particularly, the present invention relates to compositions comprising dispersions of thienotriazolodiazepine compounds which have improved solubility and bioavailability and methods for treating ALK positive anaplastic large cell lymphoma.
  • the compound of Formula (1) has been shown to inhibit the binding of acetylated histone H4 to the tandem bromodomain (BRD)-containing family of transcriptional regulators known as the BET (bromodomains and extraterminal) proteins, which include BRD2, BRD3, and BRD4.
  • BET tandem bromodomain
  • BET bromodomains and extraterminal proteins
  • the BET proteins have emerged as major epigenetic regulators of proliferation and differentiation and also have been associated with predisposition to dyslipidemia or improper regulation of adipogenesis, elevated inflammatory profile and risk for cardiovascular disease and type 2 diabetes, and increased susceptibility to autoimmine diseases such as rheumatoid arthritis and systemic lupus erythematosus as reported by Denis, G.V. "Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation," Discov Med 2010; 10:489-499, which is incorporated herein by reference in its entirety. Accordingly, the compound of formula (II) may be useful for treatment of various cancers, cardiovascular disease, type 2 diabetes, and autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus.
  • Anaplastic large cell lymphoma is a rare type of non-Hodgkin lymphoma, but one of the more common subtypes of T-cell lymphoma.
  • Anaplastic large cell lymphoma comprises about three percent of all non-Hodgkin lymphoma and 10 percent to 30 percent of all non-Hodgkin lymphoma in children.
  • a subset of patients with systemic anaplastic large cell lymphoma may have an abnormal form of a protein on their surface called "anaplastic lymphoma kinase" (ALK).
  • ALK anaplastic lymphoma kinase
  • Anaplastic large cell lymphoma is typically refractory to available therapies with poor overall survival.
  • the present invention provides for a method of treating ALK positive anaplastic large cell lymphoma.
  • the present invention provides for a method of treating ALK positive anaplastic large cell lymphoma comprising: administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient, wherein the combination includes a first compound and a second compound; the first compound being an ALK inhibitor, and the second compound being a thienotriazolodiazepine compound having the structure of Formula (1) below:
  • R 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
  • R 3 is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon
  • n 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 wherein R 7 is a hydrogen atom or alkyl having a carbon number of 1-4,
  • n is an integer of 0-2
  • R 8 is phenyl or pyridyl optionally substituted by a halogen atom
  • 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 )t,— COOR 10 wherein b is an integer of 1 -4, and
  • R 10 is alkyl having a carbon number of 1 -4,
  • the gene expression profile of the patient's cancer cells is positive for genes associated with sensitivity to the thienotriazolodiazepine compound of Formula
  • the first compound is selected from the group consisting CEP28122, Crizotinib, AP261 13, LDK378 and combinations thereof.
  • the thienotriazolodiazepine compound having Formula (1 ) is independently selected from the group consisting of: (i) (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- fJ[l,2,4]triazolo- [4,3-a][ l ,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide or a dihydrate thereof, (ii) methyl (S)- ⁇ 4-(3'-cyanobiphenyl-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]tri-azolo[4,3- a][l ,4]diazepin-6-yl ⁇ acetate, (iii) methyl (S)- ⁇ 2,3,9-trimethyl-4-
  • the thienotriazolodiazepine compound having Formula (1) is (5 -2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- ][l ,2,4]triazolo[4,3- a][l , 4]diazepin-6-yl)-N-(4-hydroxyphenyl)acetamide dihydrate.
  • the thienotriazolodiazepine compound having Formula (1) causes cell cycle arrest and/or c-MYC down-regulation in a malignant lymphocyte.
  • the thienotriazolodiazepine compound having Formula (1 ) causes cell cycle arrest and/or c-MYC down-regulation in a malignant T-cell.
  • the MYC down-regulation is associated with a concomitant down-regulation c-MYC regulated gene CAD.
  • MYC down-regulation is associated with a concomitant down-regulation c-MYC regulated gene NUC.
  • the present invention provides for a method of treating ALK positive anaplastic large cell lymphoma in a mammal, comprising: administering to the patient a
  • composition comprising a thienotriazolodiazepine compound having the structure of Formula (1) below:
  • R 1 is alkyl having a carbon number of 1-4
  • R 2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group,
  • R 3 is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4 or cyano;— NR 5 — (CH2) 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
  • R 7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R 8 is 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
  • 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
  • thienotriazolodiazepine compound 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 gene expression profile of the patient's cancer cells is positive for genes associated with sensitivity to the thienotriazolodiazepine compound of Formula (1) ⁇
  • the thienotriazolodiazepine compound having Formula (1) is independently selected from the group consisting of: (i) (S)-2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- fJ[l,2,4]triazolo- [4,3-a][l,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide or a dihydrate thereof, (ii) methyl (S)- ⁇ 4-(3'-cyanobiphenyl-4-yl)-2,3,9-trimethyl-6H-thieno[3,2-f][l,2,4]tri-azolo[4,3- a][l,4]diazepin-6-yl ⁇ acetate, (iii) methyl (S)- ⁇ 2,3,9-trimethyl-4-(4-phenylamin
  • the thienotriazolodiazepine compound having Formula (1) is (5)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-/J[l ,2,4]triazolo[4,3- a][l ,4]diazepin-6-yl)-7V-(4-hydroxyphenyl)acetamide dihydrate.
  • 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 thienotriazolodiazepine compound having Formula (1) causes cell cycle arrest and/or c-MYC down-regulation in a malignant lymphocyte.
  • the thienotriazolodiazepine compound having Formula (1) causes cell cycle arrest and/or c-MYC down-regulation in a malignant T-cell.
  • the MYC down-regulation is associated with a concomitant down-regulation c-MYC regulated gene CAD. In some embodiments of the method of treating ALK positive anaplastic large cell lymphoma, MYC down-regulation is associated with a concomitant down-regulation c-MYC regulated gene NUC.
  • 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 1 F illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound (1-1) and PVP-VA.
  • Figure 1 G illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1 -1) and hypromellose acetate succinate (HPMCAS-M).
  • Figure 1 H illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 50% compound ( 1 -1) and HPMCAS-M.
  • Figure II illustrates dissolution profile of an exemplary formulation comprising a solid dispersion comprising 25% compound (1-1) and hypromellose phthalate (HPMCP-HP55).
  • Figure 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-
  • Figure 4A illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1-1) and PVP equilibrated under ambient conditions.
  • Figure 4B illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1 -1) and HPMCAS-M equilibrated under ambient conditions.
  • Figure 4C illustrates modified differential scanning calorimetry trace for a solid dispersion of 50% compound (1-1) and HPMCAS-M equilibrated under ambient conditions.
  • Figure 5 illustrates plot of glass transition temperature (Tg) versus relative humidity (PvH) for solid dispersions of 25% compound (1-1) and PVP or HMPCAS-M and 50% compound (1-1) and HPMCAS-MG.
  • Figure 6 illustrates modified differential scanning calorimetry trace for a solid dispersion of 25% compound (1 -1) and PVP equilibrated under 75% relative humidity.
  • Figures 7A and 7B illustrate plasma concentration versus time curves for Compound (1-1) after 1 mg/kg intravenous dosing (solid rectangles) and 3 mg/kg oral dosing as 25% Compound (1 - 1):PVP (open circles), 25% Compound (1-1):HPMCAS-MG (open triangles), and 50% Compound (1-1 ):HPMCAS-MG (open inverted triangles).
  • the inset depicts the same data plotted on a semilogarithmic scale.
  • Figures 8 A and 8B illustrate plasma concentration versus time curves for Compound (1-1) after 3 mg/kg oral dosing as 25% Compound (1-1):PVP (open circles), 25% Compound (1- 1):HPMCAS-MG (open triangles), and 50% Compound (1-1):HPMCAS-MG (open inverted triangles). The inset depicts the same data plotted on a semi-logarithmic scale.
  • Figure 9 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1- 1) in HPMCAS-MG at time zero of a stability test.
  • Figure 10 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 1 month at 40 °C and 75 % relative humidity.
  • Figure 1 1 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 2 months at 40 °C and 75 % relative humidity.
  • Figure 12 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG after 3 month at 40 °C and 75 % relative humidity.
  • Figure 13 illustrates dose curve response of ALK postive anaplastic large-cell lymphoma (ALCL) cell lines, L82, JB6, Karpas 299, TS-Supm2, SUDHL1, treated with increasing doses of thienotriazolodiazepine compound (1-1), also referred to as OTX015.
  • ALK postive anaplastic large-cell lymphoma (ALCL) cell lines L82, JB6, Karpas 299, TS-Supm2, SUDHL1, treated with increasing doses of thienotriazolodiazepine compound (1-1), also referred to as OTX015.
  • Anti-proliferative activity of OTX015 was evaluated through MTT assay after 72 hours of drug exposure on a panel of five ALK- positive anaplastic large-cell lymphoma (ALK-pos ALCL) cell lines (GI50 values for the cell lines shown). Cellular viability revealed that OTX015 has anti-proliferative activity in a dose-dependent manner in all the
  • Figures 14A-14D illustrate effects of different doses of OTX015 on the cell cycle of different cell lines.
  • the cell lines were treated with two different doses, 250 nM and 500 nM, and differences among these treatments in terms of Gl cell cycle arrest ( Figure 14A), c-MYC
  • Figure 15 shows show that a 24-hour treatment with OTX015 is sufficient to induce a Gl cell cycle arrest in the SUDHLl cell line.
  • Figures 16 shows that a 24-hour treatment with OTX015 is sufficient to induce a Gl cell cycle arrest the L82 cell line.
  • L82 cell line presented an increase of percentage of dead cells after OTX015 treatment. This phenotypic effect is observable after 24 hours of treatment, but the effect is more marked after 48 or 72 hours of drug exposure.
  • Figures 17 and 18 show that different exposure schedules and time kinetic of OTX015 are equally efficacious against the SUDHL1 cell line.
  • Cells were treated according to two different strategies: (1) cells were treated with a single dose of OTX015 and read-out evaluated after 72 hours of single drug exposure; and (2) cells were treated with OTX015 with a refill of the drug every 24 hours and read-out evaluated after 72 hours of drug exposure.
  • c-MYC downregulation and Gl cell cycle arrest results were comparable among the two different strategies, suggesting that OTX015 small molecule possess a long half life in the in vitro treatments.
  • Figure 19 shows that OTX015 efficiently downregulates c-MYC expression in Karpas 299 cell line, after a short drug exposure. After 12 hours of drug exposure, medium with OTX015 was replaced with fresh medium without the drug (Wash Out) and c-MYC mRNA expression was evaluated at different time points (after 6, 12, 24 and 48 hours from Wash Out). c-MYC levels remained downregulated till 24 hours from the Wash Out. They started to restore after 48 hours from Wash Out suggesting that at this time point the drug is not more active.
  • Figure 20 illustrates synergy of the combination of OTX015 and anti-ALK.
  • OTX015 and anti-ALK can synergize and efficiently dowregulate c-MYC expression in TS-Sypm2 cell line.
  • the combination of treatments with OTX015 (250 nM) and the AL inhibitor CEP28122 (25-50 nM) led to a more marked decrease of c-MYC protein levels starting from 6 hours of treatments. After 24 hours of drugs exposure we observed also a more marked Gl cell cycle arrest suggesting a synergistic action of the two drugs.
  • the present invention provides for a method of treating ALK positive anaplastic large cell lymphoma comprising: administering a pharmaceutical acceptable amount of a combination of anti-cancer drugs to a patient, wherein the combination includes a first compound and a second compound; the first compound being an ALK inhibitor, and the second compound being a thienotriazolodiazepine compound according to the various embodiments described herein.
  • the thienotriazolodiazepine compound is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • a solid dispersion comprising an amorphous thienotriazolodiazepine compound and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • the gene expression profile of the patient's cancer cells is positive for genes associated with sensitivity to the thienotriazolodiazepine compound of Formula (1) described herein.
  • the thienotriazolodiazepine compound having Formula ( 1 ) causes cell cycle arrest and/or c-MYC down-regulation in a malignant lymphocyte.
  • the thienotriazolodiazepine compound having Formula (1) causes cell cycle arrest and/or c-MYC down-regulation in a malignant T-cell.
  • the MYC down-regulation is associated with a concomitant down-regulation c- MYC regulated gene CAD. In some such embodiments of the method of treating ALK positive anaplastic large cell lymphoma, MYC down-regulation is associated with a concomitant down- regulation c-MYC regulated gene NUC.
  • the present invention provides a method of treating ALK positive anaplastic large cell lymphoma comprising the step of administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound, as described herein, is formed as a solid dispersion comprising an amorphous thienotriazolodiazepine compound and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • a solid dispersion comprising an amorphous thienotriazolodiazepine compound and a pharmaceutically acceptable salt thereof or a hydrate thereof; and a pharmaceutically acceptable polymer.
  • the gene expression profile of the patient's cancer cells is positive for genes associated with sensitivity to the thienotriazolodiazepine compound of Formula (1) described herein.
  • the thienotriazolodiazepine compound having Formula (1) causes cell cycle arrest and/or c-MYC down-regulation in a malignant lymphocyte.
  • the thienotriazolodiazepine compound having Formula (1) causes cell cycle arrest and/or c-MYC down-regulation in a malignant T-cell.
  • the MYC down-regulation is associated with a concomitant down-regulation c- MYC regulated gene CAD. In some such embodiments of the method of treating ALK positive anaplastic large cell lymphoma, MYC down-regulation is associated with a concomitant down- regulation c-MYC regulated gene NUC.
  • thienotriazolodiazepine compounds used in the formulations of the present invention, are represented by Formula (1):
  • R 1 is alkyl having a carbon number of 1-4
  • R 2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydro xyl group
  • R 3 is a halogen atom
  • — NR 5 — (CH 2 ) m — R 6 wherein R 5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R 6 is phenyl or pyridyl optionally substituted by a halogen atom; or -NR 7 — CO— (CH 2 ) n — R 8 wherein R 7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of
  • a suitable alkyl group includes linear or branched akyl radicals including from 1 carbon atom up to 4 carbon atoms. In one embodiment, a suitable alkyl group includes linear or branched akyl radicals including from 1 carbon atom up to 3 carbon atoms. In one embodiment, a suitable alkyl group includes linear or branched akyl radicals include from 1 carbon atom up to 2 carbon atoms. In one embodiment, exemplary alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. In one embodiment, exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -propyl, and 2 -methyl -2-propyl.
  • the present invention provides pharmaceutically acceptable salts, solvates, including hydrates, and isotopically-labeled forms of the thienotriazolodiazepine compounds described herein.
  • pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with inorganic acids.
  • thienotriazolodiazepine include salts of hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids.
  • pharmaceutically acceptable salts of the thienotriazolodiazepine compounds include acid addition salts formed with organic acids.
  • pharmaceutically acceptable organic acid addition salts of the thienotriazolodiazepine include salts of tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfuric, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example benzenesulfonic and 4-methyl benzenesulfonic acids.
  • Representative thienotriazolodiazepine compounds of Formula (1) include,
  • Compound (1-1), of Table A, will be referred to herein as OTX-015, OTX015 or Y803.
  • thienotriazolodiazepine compounds of Formula (1) include (i) (S)- 2-[4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f [l,2,4]triazolo 4,3-a][l,4]diazep
  • thienotriazolodiazepine compounds of Formula (1) include (S)-2- [4-(4-chlorophenyl)-2,3,9 rimethyl-6H W
  • thienotriazolodiazepine compounds of Formula (1) include (S)-2-
  • ALK Inhibitors [0076] Suitable ALK inhibitors for use in combinations with the thienopyrazolodiazapine of Formula (1) in the methods of the present invention include, but are not limited to, the ALK inhibitors listed in Table B below.
  • suitable pyrimidine compounds useful as ALK inhibitors are described United States Patent No. 7,910,585.
  • suitable pyrimidine and pyridine compoundss useful as ALK inhibitors are described United States Patent No. 8,399,450.
  • suitable pyridopyrazine compounds useful as ALK inhibitors are described United States Patent No. 8,080,561.
  • suitable pyrrolotriazine compounds useful as ALK inhibitors are described United States Patent 8,471,005.
  • the compound of Formula (1) presents highly specific difficulties in relation to administration generally and the preparation of galenic compositions in particular, including the particular problems of drug bioavailability and variability in inter- and intra-patient dose response, necessitating development of a non-conventional dosage form with respect to the practically water- insoluble properties of the compound.
  • the compound of Formula (1) could be formulated as a solid dispersion with the carrier ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer (Eudragit RS, manufactured by Rohm) to provide an oral formulation that preferentially released the pharmaceutical ingredient in the lower intestine for treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (US Patent Application 20090012064 Al, published Jan 8, 2009). It was found, through various experiments, including animal tests, that in inflammatory bowel diseases drug release in a lesion and a direct action thereof on the inflammatory lesion were more important than the absorption of the drug into circulation from the gastrointestinal tract.
  • the carrier ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer Eudragit RS, manufactured by Rohm
  • thienotriazolodiazepine compounds according to Formula (1), pharmaceutically acceptable salts, solvates, including hydrates, racemates, enantiomers isomers, and isotopically-labeled forms thereof, can be formulated as a solid dispersion with pharmaceutically acceptable polymers to provide an oral formulation that provides high absorption of the pharmaceutical ingredient into the circulation from the gastrointestinal tract for treatment of diseases other than inflammatory bowel diseases.
  • pharmaceutically acceptable polymers can be formulated as a solid dispersion with pharmaceutically acceptable polymers to provide an oral formulation that provides high absorption of the pharmaceutical ingredient into the circulation from the gastrointestinal tract for treatment of diseases other than inflammatory bowel diseases.
  • Studies in both dogs and humans have confirmed high oral bioavailability of these solid dispersions compared with the Eudragit solid dispersion formulation previously developed for the treatment of inflammatory bowel disease.
  • Solid dispersions are a strategy to improve the oral bioavailability of poorly water soluble drugs.
  • the term "solid dispersion" as used herein refers to a group of solid products including at least two different components, generally a hydrophilic carrier and a hydrophobic drug, the thienotriazolodiazepine compounds, according to Formula (1). Based on the drug's molecular arrangement within the dispersion, six different types of solid dispersions can be distinguished. Commonly, solid dispersions are classified as simple eutectic mixtures, solid solutions, glass solution and suspension, and amorphous precipitations in a crystalline carrier. Moreover, certain combinations can be encountered, for example, in the same sample some molecules may be present in clusters while some are molecularly dispersed.
  • the thienotriazolodiazepine compounds, according to Formula (1) can be dispersed molecularly, in amorphous particles (clusters).
  • the thienotriazolodiazepine compounds, according to Formula (1) can be dispersed molecularly, in amorphous particles (clusters).
  • thienotriazolodiazepine compounds, according to Formula (1) can be dispersed as crystalline particles.
  • the carrier can be crystalline.
  • the carrier can be amorphous.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion of a thienotriazolodiazepine compound, in accordance with Formula (1), or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof; and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate (also called hydroxypropylmethylcellulose acetate succinate or HPMCAS).
  • the dispersion has a thienotriazolodiazepine compound to hydroxypropylmethylcellulose acetate succinate (HPMCAS) weight ratio of 1:3 to 1 :1.
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C. In other such embodiments, the single Tg occurs at about 135 °C. In some such
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • the hydroxypropylmethyl cellulose acetate succinates may include M grade having 9% acetyl/ 1 1% succinoyl (e.g., HPMCAS having a mean particle size of 5 ⁇ (i.e., HPMCAS-MF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-MG, granular grade)), H grade having 12% acetyl/6% succinoyl (e.g., HPMCAS having a mean particle size of 5 ⁇ (i.e., HPMCAS-HF, fine powder grade) or having a mean particle size of 1 mm (i.e., HPMCAS-HG, granular grade)), and L grade having 8% acetyl/15% succinoyl (e.g., HPMCAS having a mean particle size of 5 ⁇ (i.e., HPMCAS-LF, fine powder grade) or having a mean particle size of 1 mm (i.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion of a thienotriazolodiazepine compound of Formula (1) or a
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone (also called povidone or PVP).
  • the dispersion has a thienotriazolodiazepine compound to PVP weight ratio of 1 :3 to 1 :1. In one embodiment, at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion. In another embodiment, the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to about 185 °C. In other such embodiments, the single Tg occurs at about 179 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • the polyvinyl pyrrolidones may have molecular weights of about 2,500 (Kollidon ®12 PF, weight-average molecular weight between 2,000 to 3,000), about 9,000 (Kollidon® 17 PF, weight-average molecular weight between 7,000 to 1 1 ,000), about 25,000 (Kollidon® 25, weight-average molecular weight between 28,000 to 34,000), about 50,000 (Kollidon® 30, weight-average molecular weight between 44,000 to 54,000), and about 1 ,250,000 (Kollidon® 90 or Kollidon® 90F, weight-average molecular weight between 1 ,000,000 to 1 ,500,000).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion. In another embodiment, the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion. In some embodiments, the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 130 °C to 140 °C. In other such embodiments, the single Tg occurs at about 135 °C. In some such
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21 ° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an iso
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to about 185 °C. In other such embodiments, the single Tg occurs at about 179 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21 ° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to hypromellose acetate succinate ranges from 1 :3 to 1 :1.
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
  • a pharmaceutical composition comprising a solid dispersion is prepared by spray drying.
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a thienotriazolodiazepine compound of Formula ( 1 ) or a
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of compound (1) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion exhibits a single inflection for the glass transition
  • 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. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a thienotriazolodiazepine compound of Formula (1) or a
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of compound (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 : 1. In one
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to 185 °C. In other such embodiments, the single Tg occurs at about 179 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • Tg glass transition temperature
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is hypromellose acetate succinate.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1 ) to hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 130 °C to 140 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In other such embodiments, the single Tg occurs at about 135 °C. In some embodiments, the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline
  • thienotriazolodiazepine compound of Formula (1) for the purpose of this application “substantially free” shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound of Formula (1).
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of an amorphous form of a thienotriazolodiazepine compound of Formula ( 1 ) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • the weight ratio of thienotriazolodiazepine compound of Formula (1) to polyvinylpyrrolidone ranges from 1 :3 to 1 :1.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg). In some embodiments, the single Tg occurs between 175 °C to 185 °C. In some such embodiments, the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month. In other such embodiments, the single Tg occurs at about 179 °C.
  • 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.
  • hypromellose acetate succinate ranges from 1 :3 to 1 : 1.
  • a pharmaceutical composition of the present invention comprises a spray dried solid dispersion of a crystalline form of a thienotriazolodiazepine compound of Formula (1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is polyvinylpyrrolidone.
  • polyvinylpyrrolidone ranges from 1 :3 to 1 : 1.
  • the present invention provides a pharmaceutical
  • composition comprising a solid dispersion of 2-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thienol[3,2-fJ-[l ,2,4]triazolo[4,3-a][l,4]diazepin-6-yl]-N-(4-hydroxyphenyl)acetamide dihydrate, compound (1-1):
  • the pharmaceutically acceptable polymer is HPMCAS.
  • the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C.
  • the single Tg occurs at about 135 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound ( 1 - 1).
  • 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.
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to 185 °C.
  • the single Tg occurs at about 179 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound ( 1 - 1 ) or a
  • the pharmaceutically acceptable polymer is HPMCAS.
  • the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 130 °C to 140 °C.
  • the single Tg occurs at about 135 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound ( 1 - 1 ).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21 ° 2-theta associated with crystalline thienotriazolodiazepine compound (1-1).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of an amorphous form of a thienotriazolodiazepine compound (1-1) or a pharmaceutically acceptable salt, a solvate, including a hydrate, a racemate, an enantiomer, an isomer, or an isotopically-labeled form thereof; and a pharmaceutically acceptable polymer.
  • the pharmaceutically acceptable polymer is PVP.
  • the dispersion has compound (1-1) and PVP in a weight ratio 1 :3 to 1 : 1.
  • at least some portion of the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the thienotriazolodiazepine compound is homogeneously dispersed throughout the solid dispersion.
  • the solid dispersion is spray dried.
  • the solid dispersion exhibits a single inflection for the glass transition temperature (Tg).
  • Tg glass transition temperature
  • the single Tg occurs between 175 °C to 185 °C.
  • the single Tg occurs at about 189 °C.
  • the solid dispersion was exposed to a relative humidity of 75 % at 40 °C for at least one month.
  • the solid dispersion exhibits an X-ray powder diffraction pattern substantially free of diffraction lines associated with crystalline thienotriazolodiazepine compound (1-1).
  • substantially free shall mean the absence of a diffraction line, above the amorphous halo, at about 21 ° 2-theta associated with crystalline thienotriazolodiazepine compound ( 1 - 1 ).
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound (1-1) or a
  • the pharmaceutically acceptable polymer is HPMCAS.
  • the dispersion has compound (1-1) and HPMCAS in a weight ratio of 1 :3 to 1 : 1.
  • the solid dispersion is spray dried.
  • a pharmaceutical composition of the present invention comprises a solid dispersion of a crystalline form of a thienotriazolodiazepine compound (1 -1 ) or a
  • the pharmaceutically acceptable polymer is PVP.
  • the dispersion has compound (1-1) and PVP in a weight ratio 1 :3 to 1 : 1.
  • the solid dispersion is spray dried.
  • the solid dispersions of the invention exhibit especially advantageous properties when administered orally.
  • advantageous properties of the solid dispersions include, but are not limited to, consistent and high level of bioavailability when administered in standard bioavailability trials in animals or humans.
  • the solid dispersions of the invention can include a solid dispersion comprising thienotriazolodiazepine compound of Formula (1) and a polymer and additives.
  • the solid dispersions can achieve absorption of the thienotriazolodiazepine compound of Formula (1) into the bloodstream that cannot be obtained by merely admixing the thienotriazolodiazepine compound of Formula ( 1 ) with additives since the thienotriazolodiazepine compound of Formula (1) drug has negligible solubility in water and most aqueous media.
  • the bioavailability, of thienotriazolodiazepine compound of Formula (1) or of thienotriazolodiazepine compound (1-1) may be measured using a variety of in vitro and/or in vivo studies. The in vivo studies may be performed, for example, using rats, dogs or humans.
  • the bioavailability may be measured by the area under the curve (AUC) value obtained by plotting a serum or plasma concentration, of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1), along the ordinate (Y-axis) against time along the abscissa (X-axis).
  • AUC value of the thienotriazolodiazepine compound of Formula (1) or thienotriazolodiazepine compound (1-1) from the solid dispersion is then compared to the AUC value of an equivalent concentration of crystalline thienotriazolodiazepine compound of Formula (1) or crystalline thienotriazolodiazepine compound (1 -1) without polymer.
  • the solid dispersion provides an area under the curve (AUC) value, when administered orally to a dog, that is selected from: at least 0.4 times, 0.5 times, 0.6 time, 0.8 time, 1.0 times, a corresponding AUC value provided by a control composition administered intravenously to a dog, wherein the control composition comprises an equivalent quantity of a crystalline thienotriazolodiazepine compound of Formula I.
  • AUC area under the curve
  • the bioavailability may be measured by in vitro tests simulating the pH values of a gastric environment and an intestine environment.
  • the measurements may be made by suspending a solid dispersion of the thienotriazolodiazepine compound of Formula ( 1 ) or thienotriazolodiazepine compound (1-1), in an aqueous in vitro test medium having a pH between 1.0 to 2.0, and the pH is then adjusted to a pH between 5.0 and 7.0, in a control in vitro test medium.
  • thienotriazolodiazepine compound (1-1 ) may be measured at any time during the first two hours following the pH adjustment.
  • the solid dispersion provides a concentration, of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous
  • thienotriazolodiazepine compound (1-1) in an aqueous in vitro test medium at pH between 5.0 to 7.0 that is selected from: at least 5-fold greater, at least 6 fold greater, at least 7 fold greater, at least 8 fold greater, at least 9 fold greater or at least 10 fold greater, compared to a concentration of a crystalline thienotriazolodiazepine compound of Formula (1) or crystalline thienotriazolodiazepine compound (1-1), without polymer.
  • the concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous thienotriazolodiazepine compound (1-1), from the solid dispersion placed in an aqueous in vitro test medium having a pH of 1.0 to 2.0 is: at least 40%, at least 50% higher, at least 60 %, at least 70 %; at least 80 %, than a concentration of a crystalline thienotriazolodiazepine compound of Formula (1 ) without polymer.
  • the polymer of the solid dispersion is HPMCAS.
  • the polymer of the solid dispersion is PVP.
  • a concentration of the amorphous thienotriazolodiazepine compound of Formula (1) or amorphous thienotriazolodiazepine compound (1-1), from the solid dispersion is: at least 40%, at least 50% higher, at least 60 %, at least 70 %; at least 80 %, compared to a concentration of thienotriazolodiazepine compound of Formula (1), from a solid dispersion of thienotriazolodiazepine compound of the Formula (1) and a pharmaceutically acceptable polymer selected from the group consisting of: hypromellose phthalate and ethyl acrylate-mefhyl
  • 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,
  • HPMC hydroxypropylmethylcellulose
  • phthalate hydroxypropylmethylcellulose phthalate
  • HPMCAS hydroxylpropylmethylcellulose acetate succinate
  • the solid dispersions of the invention may be formulated as tablets, caplets, or capsules. In one some embodiments, the solid dispersions of the invention may be formulated as mini-tablets or pour-into-mouth granules, or oral powders for constitution. In some embodiments, the solid dispersions of the invention are dispersed in a suitable diluent in
  • the solid dispersions of the invention may be formulated for pediatric treatment.
  • the pharmaceutical composition of the present invention is 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 thienotriazolodiazepme 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), (1-1 1), (1-12), (1-13), (1-14), (1-15), (1-16), (1-17), and (1-18), in a dosage amount selected from the group consisting of about 1 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, and about 150 mg, and in a dosage form selected from the group consisting
  • 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
  • the thienotriazolodiazepine compounds disclosed herein can exist as free base or as acid addition salt can be obtained according to the procedures described in US Patent Application Publication No. 2010/0286127, incorporated by reference in its entirety herein, or in the present application.
  • Individual enantiomers and diastereomers of the thienotriazolodiazepine compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.
  • a one or more of the various embodiments for the formulation of the thienotriazolodiazepine, according to Formula (1), is prepared by a solvent evaporation method.
  • the solvent evaporation method comprises solubilization of a
  • the volatile solvent may one or more excipients.
  • the one or more excipients include, but are not limited to anti-sticking agents, inert fillers, surfactants wetting agents, pH modifiers and additives.
  • the excipients may dissolved or in suspended or swollen state in the volatile solvent.
  • preparation of solid dispersions in accordance with the present invention includes drying one or more excipients suspended in a volatile solvent.
  • the drying includes vacuum drying, slow evaporation of the volatile solvent at low temperature, use of a rotary evaporator, spray-drying, spray granulation, freeze-drying, or use of supercritical fluids.
  • thienotriazolodiazepine composition according to Formula (1), which involves atomization of a suspension or a solution of the composition into small droplets, followed by rapid removal solvent from the formulation.
  • preparation of a formulation in accordance with the present invention involves spray granulation in which a solution or a suspension of the composition in a solvent is sprayed onto a suitable chemically and/or physically inert filler, such as lactose or mannitol.
  • spray granulation of the solution or the suspension of the composition is achieved via two-way or three-way nozzles.
  • the half maximal inhibitory concentration (IC-50 value) of a compound is a measure of the effectiveness of the compound in inhibiting a biological or a biochemical function. IC-50 value, therefore, can be considered a quantitative measure indicating how much of a particular drug or any chemical substance is requiredd to inhibit a given biological process by half (50%).
  • GI-50 is used to symbolize the value for the concentration that causes 50% growth inhibition. The use of GI-50 indicates that a correction for the cell count at time zero has been made.
  • An example of one formula for calculating GI-50 value defines GI-50 as the
  • T the optical density of the test well after a 48 hour period of exposure to test drug is T, for example; TO is the optical density the test well at time zero.
  • 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 Euragit LI 00-55, at both 25% and 50% of compound (1-1) loading, for each polymer.
  • Solid dispersions were prepared by a solvent evaporation method, using spray-drying followed by secondary drying in a low-temperature convection oven. The performance was assessed, for each solid dispersion, 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 raM sodium taurocholate, 0.75 raM lechithin, 0.174 g NaOH pellets, 1.977 g NaH 2 P VH 2 0, 3.093 g NaCl, and purified water qs 500 raL.
  • the amount of dissolved drug was quantified using a high-performance liquid chromatography (HPLC) method and an Agilent 1 100 series HPLC.
  • HPLC high-performance liquid chromatography
  • Agilent 1 100 series HPLC The dissolution profiles of the formulations ( Figures 1A-1 J) showed large increases in drug solubility in all dispersion candidates relative to the unformulated compound in the same media.
  • the 25% compound ( 1 -1) in PVP, 25% compound (1-1) in HPMCAS-M, and 50% compound (1-1) in HPMCAS-M dispersions were the most promising candidates for enhanced oral absorption as compared to the unformulated compound, based on finding higher levels of free drug released at intestinal pH.
  • Example 2 in vivo screening of solid dispersions of compound (1-1)
  • the area under the plasma concentration-time curve was determined by use of the linear trapezoidal rule up to the last measurable concentration without extrapolation of the terminal elimination phase to infinity.
  • the elimination half-life (ti /2 ) was calculated by least-squares regression analysis of the terminal linear part of the log concentration-ime curve.
  • the maximum plasma concentration (C max ) and the time to C max (t 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 (%).
  • Table 1 pharmacokinetic parameters of compound (1-1) after oral (po) and intravenous (iv) administrations to dogs (the values are averages from three dogs)
  • AUC area under the plasma concentration-time curve
  • C max maximum plasma concentration
  • F bioavailability
  • HPMCAS hypromellose acetate sodium
  • IV intravenous
  • PEG polyethylene glycon
  • PO per os, oral
  • PVP polyvinylpyrrolidone
  • 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.
  • 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):
  • composition containing Eudragit L100-55solid dispersion of compound (1-1): 10 mg strength, size 2 hard gelatin capsule
  • AUC 0 - 2 4h area under the OTX015 plasma concentration vs. time curve over 24 hours
  • HPMCAS hypromellose acetate succinate
  • Example 4 Oral exposure in the rat
  • the oral bioavailability of three formulations of solid dispersions of compound (1-1) was determined in rats.
  • the three dispersions chosen were the 25% dispersion of compound (1-1) in PVP, the 25% dispersion of compound (1-1) in HPMCAS-MG, and the 50% dispersion of compound (1-1) in HPMCAS-MG.
  • the animals used in the study were Specific Pathogen Free (SPF) Hsd:Sprague Dawley rats obtained from the Central Animal Laboratory at the University of Turku, Finland.
  • the rats were originally purchased from Harlan, The Netherlands.
  • the rats were female and were ten weeks of age, and 12 rats were used in the study.
  • the animals were housed in polycarbonate Makrolon II cages (three animals per cage), the animal room temperature was 21 +/- 3 °C, the animal room relative humidity was 55 +/- 15%, and the animal room lighting was artificial and was cycled for 12 hour light and dark periods (with the dark period between 18:00 and 06:00 hours). Aspen chips (Tapvei Oy, Estonia) were used for bedding, and bedding was changed at least once per week. Food and water was provided prior to dosing the animals but was removed during the first two hours after dosing.
  • the oral dosing solutions containing the 25% dispersion of compound (1-1) in PVP, the 25% dispersion of compound (1-1) in HPMCAS-MG, and the 50% dispersion of compound (1-1) in HPMCAS-MG were prepared by adding a pre-calculated amount of sterile water for injection to containers holding the dispersion using appropriate quantities to obtain a concentration of 0.75 mg/mL of compound (1-1).
  • the oral dosing solutions were subjected to vortex mixing for 20 seconds prior to each dose.
  • the dosing solution for intravenous administration contained 0.25 mg/mL of compound (1-1) and was prepared by dissolving 5 mg of compound (1-1) in a mixture containing 4 mL of polyethylene glycol with an average molecular weight of 400 Da (PEG400), 4 mL of ethanol (96% purity), and 12 mL of sterile water for injection.
  • the dosing solution containing the 25% dispersion of compound (1-1) in PVP was used within 30 minutes after the addition of water.
  • the dosing solutions containing the 25% dispersion of compound (1-1) in HPMCAS-MG and the 50% dispersion of compound (1-1) in HPMCAS-MG were used within 60 minutes of after the addition of water.
  • a dosing volume of 4 mL/kg was used to give dose levels of compound (1-1) of 1 mg/kg for intravenous administration and 3 mg/kg for oral administration.
  • the dosing scheme is given in Table 4.
  • Pharmacokinetic parameters were calculated with the Phoenix WinNonlin software package (version 6.2.1 , Pharsight Corp., CA, USA) with standard noncompartmental methods.
  • the elimination phase half-life ( a) 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.
  • the tentative oral bioavailability (F) was calculated by dividing the dose normalised AUC after oral administration by the dose normalised AUC after intravenous
  • F (AUC(oral)/Dose(oral))/(AUC(intravenous) / Dose(intravenous))] and is reported as percentage (%).
  • Example 5 Preparation of spray dried dispersions.
  • 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 L 100-55 (Evonik Industries AG). All spray dried solutions were prepared at 25% and 50% by weight with each polymer. All solutions were prepared in acetone, with the exception of the PVP solutions, which were prepared in ethanol. For each solution, 1.0 g of solids (polymer and compound (1-1)) were prepared in 10 g of solvent.
  • the solutions were spray dried using a Buchi B-290, PE-024 spray dryer with a 1.5 mm nozzle and a Buchi B-295, P-002 condenser.
  • the spray dryer nozzle pressure was set to 80 psi
  • the target outlet temperature was set to 40 °C
  • the chiller temperature was set to -20 °C
  • the pump speed was set to 100%
  • the aspirator setting was 100%.
  • the solid dispersions were collected and dried overnight in a low temperature convection oven to remove residual solvents.
  • Example 6 Stability with humidity and temperature.
  • Spray dried dispersions of compound (1-1) in HPMCAS-MG were assessed for stability by exposure to moisture at elevated temperature.
  • the glass transition temperature (Tg) as a function of relative humidity was determined at 75% relative humidity, 40 °C for 1 , 2 and 3 months.
  • the spray dried dispersion was stored in an LDPE bag inside a HDPE bottle to simulate bulk product packaging.
  • the data is summarized in Table 6. At time zero, the Tg was 134 °C, at 1 month the Tg was 134 °C, at 2 months the Tg was 135 °C and at 3 months the Tg was 134 °C and only a single inflection point was observed for each measurement. X-ray diffraction patterns were also obtained for each sample.
  • Figure 9 illustrates a powder X-ray diffraction profile of solid dispersions of compound (1-1) in HPMCAS-MG at time zero of a stability test.
  • Figures 10, 1 1 and 12 illustrate powder X-ray diffraction profiles of solid dispersions of compound (1-1) in HPMCAS-MG
  • Example 7 Human cell lines derived from ALKpos ALCL (SUPM2/TS. SU-DHL-L
  • thienopyrazolodiazepine compound (1 -1) (ranging from ⁇ to ⁇ ⁇ ) underwent to a
  • Example 8 Effects of BRD-inhibitor OTX015 on anaplastic large T-cell
  • ACL lymphoma
  • ALK+ and ALK- anaplastic large cell lymphoma were treated with increasing doses of OTX015 (OncoEthix SA) and MTT assays were performed after 72 hour exposure.
  • OTX015 OncoEthix SA
  • MTT assays were performed after 72 hour exposure.
  • cells were treated and stained with Click-iT Edu Flow Cytometry Assay Kits (Invitrogen) and 7-AAD and analyzed for DNA content using a FACScan flow cytometer. Results were analyzed with FlowJo 7.6.3 software.
  • Figures 13-20 illustrate results of Examples 7 and 8. As shown in Figures 13-20, the majority (5/8) of the cell lines tested were sensitive to OTX015, with IC50 between 36 and 546 nM. Cell cycle analyses revealed Gl arrest and a concomitant decrease of the S phase after 24 hour OTX015 exposure in 4/4 ALCL cell lines, without an increase in cell death, suggesting a cytostatic effect of OTX015. An increase in the percentage of senescent cells after treatment with the BRD- inhibitor was observed in the most sensitive ALK+ALCL cell line.
  • OTX015 Mechanism of action of OTX015 was investigated by assessment of MYC mRNA levels before and after treatment. OTX015 suppressed the transcription of MYC gene and some of its downstream target genes (such as NCL and CAD) in 4/4 ALCL cell lines, with less efficacy in the most resistant one. Thus, OTX015 exhibits anti-proliferative activity in several ALCL cell lines. The down-regulation of MYC gene, followed by cell cycle Gl arrest and increase of cellular senescence, observed after OTX015 treatment, suggest one possible mechanism of action of OTX015.
  • Figure 13 illustrates a dose curve response of anaplastic large-cell lymphoma (ALCL) cell lines treated with increasing doses of thienotriazolodiazepine compound (1-1) (also referred to as OTX015).
  • ACL anaplastic large-cell lymphoma
  • OTX015 thienotriazolodiazepine compound
  • Anti-proliferative activity of OTX015 was evaluated through MTT assay after 72 hours of drug exposure on a panel of five ALK-positive anaplastic large-cell lymphoma (ALK-pos ALCL) cell lines (GI50 values for the cell lines shown). Cellular viability revealed that OTX015 has antiproliferative activity in a dose-dependent manner in all the cell lines analyzed.
  • Figures 14A-14D illustrate effects of different doses of OTX015 on the cell cycle of different cell lines.
  • the cell lines were with two different doses, 250 nM and 500 nM, and differences among these treatments in terms of Gl cell cycle arrest ( Figure 14A), c-MYC
  • Figures 15 and 16 show that a 24-hour treatment with OTX015 is sufficient to induce a Gl cell cycle arrest in all the cell lines analyzed.
  • L82 cell line presented an increase of percentage of dead cells after OTX015 treatment. This phenotypic effect is observable after 24 hours of treatment, but the effect is more marked after 48 or 72 hours of drug exposure.
  • Figures 17 and 18 show that different exposure schedules and time kinetic of OTX015 are equally efficacious against the tested cell line.
  • Cells were treated according to two different strategies: (1) cells were treated with a single dose of OTX015 and read-out evaluated after 72 hours of single drug exposure; and (2) cells were treated with OTX015 with a refill of the drug every 24 hours and read-out evaluated after 72 hours of drug exposure.
  • c-MYC downregulation and Gl cell cycle arrest results were comparable among the two different strategies, suggesting that OTX015 small molecule possess a long half life in the in vitro treatments.
  • Figure 19 shows that OTX015 efficiently downregulates c-MYC expression after a short drug exposure. After 12 hours of drug exposure, medium with OTX015 was replaced with fresh medium without the drug (Wash Out) and c-MYC mRNA expression was evaluated at different time points (after 6, 12, 24 and 48 hours from Wash Out). c-MYC levels remained downregulated till 24 hours from the Wash Out. They started to restore after 48 hours from Wash Out suggesting that at this time point the drug is not more active.
  • Figure 20 illustrates synergy of the combination of OTX015 and anti-ALK.
  • OTX015 and anti-ALK can synergize and efficiently dowregulte c-MYC expression in ALCL lines.
  • the combination of treatments with OTX015 (250 nM) and the ALK inhibitor CEP28122 (25-50 nM) led to a more marked decrease of c-MYC protein levels starting from 6h of treatments. After 24 hours of drugs exposure we observed also a more marked Gl cell cycle arrest suggesting a synergistic action of the two drugs.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de manière générale une méthode de traitement de lymphome anaplasique à grandes cellules ALK positif et en particulier une méthode de traitement de lymphome anaplasique à grandes cellules qui est positif pour les gènes associés à une sensibilité à une thiéno-triazolo-diazépine ayant la structure représentée par la formule (1) ci-dessous, qui, dans certains modes de réalisation, consiste à administrer à un patient une quantité pharmaceutiquement acceptable d'une composition comprenant le composé thiéno-triazolo-diazépine ayant la structure représentée par la formule (1) sous forme de dispersion solide, formule dans laquelle X représente un halogène, R1 représente alkyle en C1-C4, R2 représente alkyle en C1-C4, a représente un nombre entier compris entre 1 et 4, R3 représente alkyle en C1-C4, hydroxyalkyle en C1-C4, alcoxy en C1-C4, phényle ayant éventuellement un (des) substituant(s), ou hétéroaryle ayant éventuellement un (des) substituant(s), un sel pharmaceutiquement acceptable de celui-ci ou un hydrate de celui-ci; et un polymère pharmaceutiquement acceptable. Dans un mode de réalisation, le polymère pharmaceutiquement acceptable est HPMCAS.
PCT/EP2014/002163 2013-08-06 2014-08-06 Inhibiteur bet-brd représentant un nouvel agent pour un lymphome anaplasique à grandes cellules alk positif WO2015018520A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361862754P 2013-08-06 2013-08-06
US61/862,754 2013-08-06

Publications (1)

Publication Number Publication Date
WO2015018520A1 true WO2015018520A1 (fr) 2015-02-12

Family

ID=51298705

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/002163 WO2015018520A1 (fr) 2013-08-06 2014-08-06 Inhibiteur bet-brd représentant un nouvel agent pour un lymphome anaplasique à grandes cellules alk positif

Country Status (1)

Country Link
WO (1) WO2015018520A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016026912A1 (fr) * 2014-08-19 2016-02-25 Oncoethix Gmbh Méthode de traitement de lymphomes à l'aide de composés thiénotriazolodiazépine
CN105801603A (zh) * 2016-04-13 2016-07-27 成都倍特药业有限公司 一种具有大环结构的alk抑制剂及其制备方法
WO2016176335A1 (fr) 2015-04-27 2016-11-03 Concert Pharmaceuticals, Inc. Otx-015 deutéré
EP3137086A4 (fr) * 2014-05-02 2017-12-27 Oncoethix GmbH Methode de traitement de lymphome non hodgkinien resistant, de medulloblastome et/ou de cancer bronchopulmonaire non a petites cellules alk+ a l'aide de composes de thienotriazolodiazepine
WO2019052519A1 (fr) * 2017-09-14 2019-03-21 成都海创药业有限公司 Inhibiteur de brd4
WO2019056950A1 (fr) * 2017-09-22 2019-03-28 南京明德新药研发股份有限公司 Dérivés de thiénodiazépine et leur application
RU2721120C2 (ru) * 2015-03-30 2020-05-15 Джубилант Байосис Лимитед Новые гетероциклические соединения как ингибиторы brd4
WO2020192637A1 (fr) * 2019-03-22 2020-10-01 石药集团中奇制药技术（石家庄）有限公司 Composé inhibiteur de brd4 sous forme solide, son procédé de préparation et son application
RU2793346C1 (ru) * 2019-03-22 2023-03-31 СиЭсПиСи ЧЖУНЦИ ФАРМАСЬЮТИКАЛ ТЕКНОЛОДЖИ (ШИЦЗЯЧЖУАН) КО., ЛТД. Соединение ингибитора brd4 в твердой форме, способ его получения и применение

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1297836A1 (fr) * 2000-06-16 2003-04-02 Mitsubishi Pharma Corporation Compositions permettant de reguler la plage et/ou la vitesse de liberation du ph
EP2239264A1 (fr) * 2007-12-28 2010-10-13 Mitsubishi Tanabe Pharma Corporation Agent antitumoral
WO2012075456A1 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals Inhibiteurs de bromodomaines et leurs utilisations
WO2014001356A1 (fr) * 2012-06-25 2014-01-03 Oncoethix Sa Méthode de traitement d'un lymphome à l'aide de composés thiénotriazolodiazépine
WO2014068402A2 (fr) * 2012-09-28 2014-05-08 Oncoethix Sa Formulation pharmaceutique contenant des composés thienotriazolodiazepine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1297836A1 (fr) * 2000-06-16 2003-04-02 Mitsubishi Pharma Corporation Compositions permettant de reguler la plage et/ou la vitesse de liberation du ph
EP2239264A1 (fr) * 2007-12-28 2010-10-13 Mitsubishi Tanabe Pharma Corporation Agent antitumoral
WO2012075456A1 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals Inhibiteurs de bromodomaines et leurs utilisations
WO2014001356A1 (fr) * 2012-06-25 2014-01-03 Oncoethix Sa Méthode de traitement d'un lymphome à l'aide de composés thiénotriazolodiazépine
WO2014068402A2 (fr) * 2012-09-28 2014-05-08 Oncoethix Sa Formulation pharmaceutique contenant des composés thienotriazolodiazepine

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3137086A4 (fr) * 2014-05-02 2017-12-27 Oncoethix GmbH Methode de traitement de lymphome non hodgkinien resistant, de medulloblastome et/ou de cancer bronchopulmonaire non a petites cellules alk+ a l'aide de composes de thienotriazolodiazepine
WO2016026912A1 (fr) * 2014-08-19 2016-02-25 Oncoethix Gmbh Méthode de traitement de lymphomes à l'aide de composés thiénotriazolodiazépine
US9968620B2 (en) 2014-08-19 2018-05-15 Oncoethix Gmbh Methods of treating lymphoma using thienotriazolodiazepine compounds
CN107073011A (zh) * 2014-08-19 2017-08-18 翁科埃斯克斯有限公司 利用噻吩并三唑并二氮杂*化合物治疗淋巴瘤的方法
RU2721120C2 (ru) * 2015-03-30 2020-05-15 Джубилант Байосис Лимитед Новые гетероциклические соединения как ингибиторы brd4
US10689390B2 (en) 2015-03-30 2020-06-23 Jubilant Biosys Limited Tricyclic fused derivatives of 1-(cyclo)alkyl pyridin-2-one useful for the treatment of cancer
US11319326B2 (en) 2015-03-30 2022-05-03 Jubilant Biosys Limited Tricyclic fused derivatives of 1-(cyclo)alkyl pyrtdin-2-one useful for the treatment of cancer
WO2016176335A1 (fr) 2015-04-27 2016-11-03 Concert Pharmaceuticals, Inc. Otx-015 deutéré
CN105801603A (zh) * 2016-04-13 2016-07-27 成都倍特药业有限公司 一种具有大环结构的alk抑制剂及其制备方法
WO2019052519A1 (fr) * 2017-09-14 2019-03-21 成都海创药业有限公司 Inhibiteur de brd4
US11572371B2 (en) 2017-09-14 2023-02-07 Hinova Pharmaceuticals Inc. BRD4 inhibitor
US11312726B2 (en) 2017-09-22 2022-04-26 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Thienodiazepine derivatives and application thereof
CN111372937B (zh) * 2017-09-22 2021-10-01 石药集团中奇制药技术（石家庄）有限公司 噻吩并二氮杂卓衍生物及其应用
CN111372937A (zh) * 2017-09-22 2020-07-03 石药集团中奇制药技术（石家庄）有限公司 噻吩并二氮杂卓衍生物及其应用
WO2019056950A1 (fr) * 2017-09-22 2019-03-28 南京明德新药研发股份有限公司 Dérivés de thiénodiazépine et leur application
CN113646312A (zh) * 2019-03-22 2021-11-12 石药集团中奇制药技术（石家庄）有限公司 固体形式的brd4抑制剂化合物及其制备方法与应用
WO2020192637A1 (fr) * 2019-03-22 2020-10-01 石药集团中奇制药技术（石家庄）有限公司 Composé inhibiteur de brd4 sous forme solide, son procédé de préparation et son application
CN113646312B (zh) * 2019-03-22 2022-12-06 石药集团中奇制药技术（石家庄）有限公司 固体形式的brd4抑制剂化合物及其制备方法与应用
RU2793346C1 (ru) * 2019-03-22 2023-03-31 СиЭсПиСи ЧЖУНЦИ ФАРМАСЬЮТИКАЛ ТЕКНОЛОДЖИ (ШИЦЗЯЧЖУАН) КО., ЛТД. Соединение ингибитора brd4 в твердой форме, способ его получения и применение

Similar Documents

Publication Publication Date Title
US20140107107A1 (en) Pharmaceutical formulation containing thienotriazolodiazepine compounds
WO2015018522A1 (fr) Inhibiteur de bromodomaine bet présentant une synergie avec plusieurs agents anti-cancéreux dans des modèles cliniques de lymphome diffus de cellule b de grande taille (dlbcl)
WO2015018520A1 (fr) Inhibiteur bet-brd représentant un nouvel agent pour un lymphome anaplasique à grandes cellules alk positif
KR20160037201A (ko) Bet-브로모도메인 억제제를 사용한 미만성 거대 b-세포 림프종 (dlbcl)의 치료 방법
US9968619B2 (en) Method of treating triple-negative breast cancer using thienotriazolodiazepine compounds
US9757385B2 (en) Method of treating leukemia using pharmaceutical formulation containing thienotriazolodiazepine compounds
WO2015169953A1 (fr) Méthode de traitement d'un gliome à l'aide de composés thiénotriazolodiazépine
EP3137086A1 (fr) Methode de traitement de lymphome non hodgkinien resistant, de medulloblastome et/ou de cancer bronchopulmonaire non a petites cellules alk+ a l'aide de composes de thienotriazolodiazepine
WO2015168621A1 (fr) Procédé de traitement de leucémie myéloïde aiguë et/ou de leucémie lymphoblastique aiguë à l'aide de composés de thiénotriazolodiazépine
US9901583B2 (en) Method of treating non-small cell lung cancer and/or small cell lung cancer using thienotriazolodiazepine compounds
US9795612B2 (en) Pharmaceutical formulation containing thienotriazolodiazepine compounds
EP3185871A1 (fr) Méthodes de traitement de la leucémie myéloïde aiguë, ou de la leucémie lymphoïde aiguë à l'aide de compositions pharmaceutiques contenant des composés de thiénotriazolodiazépine
US9820992B2 (en) Method of treating non-small-cell lung cancer using pharmaceutical formulation containing thienotriazolodiazepine compounds
WO2015018523A1 (fr) Nouvel inhibiteur de bet-brd pour le traitement de tumeurs solides
WO2015168587A1 (fr) Procédé de traitement de myélome multiple résistant et de lymphome des cellules du manteau à l'aide de composés de thiénotriazolodiazépine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14748125

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14748125

Country of ref document: EP

Kind code of ref document: A1