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Method of treating diffuse large B-cell lymphoma (DLBCL) using a beta-bromodomain inhibitor

A B-cell, diffuse technology for the treatment of lymphoma in mammals that addresses the lack of well-established, insufficiently characterized response predictors

Inactive Publication Date: 2016-08-24
ONCOETHIX
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Mechanism of action and associated genes affected have not been fully characterized and response predictors have not been established

Method used

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  • Method of treating diffuse large B-cell lymphoma (DLBCL) using a beta-bromodomain inhibitor
  • Method of treating diffuse large B-cell lymphoma (DLBCL) using a beta-bromodomain inhibitor
  • Method of treating diffuse large B-cell lymphoma (DLBCL) using a beta-bromodomain inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Example 1: In Vitro Screening of Solid Dispersion of Compound (1-1)

[0177] Ten solid dispersions were prepared using compound (1-1) and one of five polymers, including hydroxypropylmethylcellulose acetate succinate (HPMCAS-M), hydroxypropyl Methylcellulose phthalate (HPMCP-HP55), polyvinylpyrrolidone (PVP), PVP-vinyl acetate (PVP-VA) and Eudragit L100-55, and for each polymer, compound (1- 1) The load factor is 25% and 50%. Solid dispersions were prepared by solvent evaporation using spray drying followed by secondary drying in a low temperature convection oven. The performance of each solid dispersion was evaluated by a non-sink dissolution performance test, which measures the total amount of drug and the amount of free drug present in solution over time. Non-sedimenting dissolution was chosen because it best represents the in vivo situation of low solubility compounds. The test involves "stomach shift" of the dispersion from gastric pH (0.1 N NaCl, pH 1.0) to i...

Embodiment 2

[0178] Example 2: In Vivo Screening of Solid Dispersion of Compound (1-1)

[0179] Solid dispersions of the three most promising compounds (1-1) were prepared on a larger scale, namely 25% compound (1-1) in PVP, 25% compound (1-1) in HPMCAS- Dispersions in MG, and 50% compound (1-1) in HPMCAS-M for in vivo studies. Each formulation was evaluated in the in vitro dissolution test described in Example 1. To ensure that these dispersions were amorphous and homogeneous, each dispersion was evaluated by X-ray powder diffraction (PXRD) and modified differential scanning calorimetry (mDSC). Additionally, to understand the effect of water on the glass transition temperature (Tg) of various dispersions, samples first equilibrated at a set relative humidity (i.e., 25%, 50%, and 75% RH) for at least 18 hours were tested. mDSC. [Water can be used as a plasticizer for solid dispersions, and the hygroscopicity of systems caused by active compounds or polymers can affect the amount of wa...

Embodiment 3

[0185] Example 3: Preparation and Clinical Application of Capsules Comprising Solid Dispersion of Compound (1-1)

[0186] A 10 mg strength gelatin capsule was prepared for a preliminary clinical study in patients with hematologic malignancies. Based on the in vitro and in vivo test results of the solid dispersion of compound (1-1) described in Examples 1 and 2, the solid dispersion of 50% compound (1-1) in HPMCAS-M was selected for the development of capsules . Capsule development was initiated with a size 3 hard gelatin capsule targeting a fill weight of 190 mg, as this configuration could potentially increase capsule strength by filling larger sized capsules while maintaining the pharmaceutical composition. Empirically, 4 capsule formulations were designed with different amounts of disintegrant and with or without wetting agent. Since all 4 formulations showed similar disintegration and dissolution test results, the simplest formulation (with no wetting agent, and with t...

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Abstract

A method of treating diffuse large B-cell lymphoma comprising administering to a patient a pharmaceutically acceptable amount of a composition comprising a thienotriazolodiazepine compound, said thienotriazolodiazepine compound being represented by Formula (I), wherein R1 is alkyl having a carbon number of 1-4, R2 is a hydrogen atom; a halogen atom; or alkyl having a carbon number of 1-4 optionally substituted by a halogen atom or a hydroxyl group, R3 is a halogen atom; phenyl optionally substituted by a halogen atom, alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4 or cyano; --NR5--(CH2)m--R6 wherein R5 is a hydrogen atom or alkyl having a carbon number of 1-4, m is an integer of 0-4, and R6 is phenyl or pyridyl optionally substituted by a halogen atom; or --NR7--CO--(CH2)n-- R8 wherein R7 is a hydrogen atom or alkyl having a carbon number of 1-4, n is an integer of 0-2, and R8 is phenyl or pyridyl optionally substituted by a halogen atom, and R4 is --(CH2)a--CO--NH--R9 wherein a is an integer of 1-4, and R9 is alkyl having a carbon number of 1-4; hydroxyalkyl having a carbon number of 1-4; alkoxy having a carbon number of 1-4; or phenyl or pyridyl optionally substituted by alkyl having a carbon number of 1-4, alkoxy having a carbon number of 1-4, amino or a hydroxyl group or --(CH2)b--COOR10 wherein b is an integer of 1-4, and R10 is alkyl having a carbon number of 1-4, or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof, wherein the patient has activated B-cell diffuse large B-cell lymphoma.

Description

[0001] Cross references to related patent applications [0002] This patent application claims U.S. Provisional Application No. 61 / 862,752, filed August 6, 2013, U.S. Provisional Application No. 61 / 862,772, filed August 6, 2013, and U.S. Provisional Application No. 61 / 862,772, filed November 27, 2013 Priority No. 61 / 909,703, all of which are hereby incorporated by reference in their entirety. technical field [0003] In some aspects, the invention relates to methods of treatment, particularly methods of treating lymphoma in mammals. Background technique [0004] Downregulation of the epigenome in cancer cells affects the transcription of oncogenes and tumor suppressor genes. BET bromodomain proteins recognize chromatin modifications and act as epigenetic recognition proteins to promote gene transcription. BET bromodomain inhibitors have shown promising preclinical activity in hematological and solid tumors and are currently in Phase I clinical studies. The mechanism of ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517A61P35/00
CPCA61K9/1652A61K9/146A61K31/551A61P35/00A61P43/00A61K9/4808A61K9/1635A61K31/5517A61K47/38
Inventor 弗朗切斯科·贝尔托尼乔治·因吉拉米
Owner ONCOETHIX
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