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Combination therapy for the treatment of prostate cancer

A technology for prostate cancer, therapy, applied in the field of combination therapy for the treatment of prostate cancer, which can solve the problem of unpredictable overall profile, etc.

Active Publication Date: 2021-06-04
NEWSOARA BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, it is impossible to predict which combination will present the best overall profile

Method used

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  • Combination therapy for the treatment of prostate cancer
  • Combination therapy for the treatment of prostate cancer
  • Combination therapy for the treatment of prostate cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Embodiment 1: the synthesis of compound I

[0168] Step A: 5-Bromo-N 3 Synthesis of -(phenylmethylene)pyridine-2,3-diamine (compound B)

[0169]

[0170] Starting material A was dissolved in methanol and acetic acid. The solution was cooled to 0°C to 5°C and benzaldehyde was added dropwise. Once the reaction is complete, add treated water and NaHCO dropwise 3 solution, kept at low temperature (0°C to 5°C). The solid was filtered off and washed with methanol / water (1:1) followed by drying to give compound B in 94% yield and +99% purity (by HPLC). 1 H-NMR (DMSO-d 6 ): δ8.75(1H), 8.04(2H), 7.93(1H), 7.65(1H), 7.50-7.60(3H).

[0171] Step B: N 3 -Synthesis of benzyl-5-bromopyridine-2,3-diamine (compound C)

[0172]

[0173] Compound B was dissolved in ethanol and NaHB was added portionwise 4 , keeping the temperature between 15°C and 25°C. The reaction mixture was stirred for 8 to 15 hours until completion as monitored by HPLC. The HCl solution was added to...

Embodiment 2

[0186] Example 2: Crystalline Mesylate Salt of Compound I

[0187] About 5 g of compound I was dissolved in ethanol (115 mL) and a solution of methanesulfonic acid in ethanol (10 mL, 158.7 mg / mL) was added according to a 1:1 molar ratio. The mixture was shaken at 50°C for 2 hours, then concentrated to half volume and stirred overnight. The solid formed (mesylate salt of compound I / co-crystal Form I) was isolated, dried and characterized.

[0188] The mesylate salt / co-crystal Form I of Compound I was also obtained from other solvents and solvent mixtures including acetone and acetonitrile.

[0189] The mesylate / co-crystal form I of Compound 1 was characterized by XRPD as comprising the following peaks in 2Θ: 8.4±0.2, 10.6±0.2, 11.7±0.2, 14.5±0.2, 15.3±0.2, 16.9±0.2, 18.2±0.2 0.2, 19.0±0.2, 19.9±0.2, 20.5±0.2, 22.6±0.2, 23.8±0.2, 24.5±0.2 and 27.6±0.2, such as using Cu-K α The radiation tube was measured on a diffractometer ( Figure 4 ).

[0190] The mesylate / co-crystal fo...

Embodiment 3

[0192] Example 3: Synergistic inhibition of VCaP cell viability by combining Compound I with Enzalutamide

[0193] VCaP cells (CRL-2876) were plated at a density of 10,000 cells per well on a 96-well flat-bottomed plate with D-MEM medium (containing 10% charcoal-removed FBS and penicillin / streptomycin), and incubated at 37°C for 5 %CO 2 Incubate for 24 hours. The medium was replaced with D-MEM and incubated at 37°C, 5% CO 2 For 3 to 7 days under incubation, the D-MEM contained 10% charcoal-depleted FBS, and had a constant ratio of Compound I or enzalutamide as a single agent or at four different concentrations (2×IC50, 1×IC50, 0.5×IC50, 0.25×IC50) of 0.1 nM R1881 treated with the combination of the two drugs. If cells were grown for 7 days, they were reprocessed on day 3 or 4 as described above. If cells were grown for 7 days, they were reprocessed on day 3 or 4 as described above. Triplicate wells were used for each concentration and wells containing only medium with 0.1...

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PUM

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Abstract

The invention provides methods for treating prostate cancer, including metastatic castration-resistant prostate cancer, comprising administering to a subject in need thereof a BET faromadomain inhibitor in combination with a second agent.

Description

[0001] field of invention [0002] The present invention relates to a combination therapy for the treatment of prostate cancer. Background technique [0003] Metastatic castration-resistant prostate cancer ("mCRPC") is often characterized by androgen receptor ("AR") signaling that continues to drive cancer proliferation, tumor invasion, and metastasis (Wyatt and Gleave, 2015 ). Initial treatment for prostate cancer consists of surgery or chemical castration, followed by androgen ablation therapy. In many cases, further progression of the cancer and metastases are observed, hence the term metastatic castration-resistant prostate cancer. First-line standard-of-care therapies for mCRPC include the AR antagonist enzalutamide, androgen synthesis inhibitors such as the cytochrome steroid 17-alpha-hydroxylase / 17,20 dissociating enzyme (CYP17A1) inhibitor abiraterone (abiraterone), and in some cases, chemotherapy. However, recent studies have shown that over time individuals becom...

Claims

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Application Information

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IPC IPC(8): A61K31/41A61K31/422C07D413/04C07D471/04
CPCC07D471/04A61P13/08A61P35/04A61K31/437A61K31/4439A61K31/58A61K31/4166A61K2300/00A61K31/41A61K31/422C07D413/04A61K45/06A61P35/00
Inventor 莎拉·克里斯汀·艾特维艾立克·坎珀桑杰·拉霍堤
Owner NEWSOARA BIOPHARMA CO LTD
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