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Antiproliferative compounds and second active agents for treatment of multiple myeloma

A multiple myeloma, compound technology, applied in the direction of active ingredients of boron compounds, active ingredients of heterocyclic compounds, organic active ingredients, etc., can solve problems such as disease recurrence

Pending Publication Date: 2022-04-29
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, persistent levels of residual disease below the sensitivity of bone marrow (BM) morphology, immunofixed protein electrophoresis, and light chain quantification persist in many patients with multiple myeloma, even after these patients have achieved a complete response ( CR) persists and will eventually lead to disease relapse

Method used

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  • Antiproliferative compounds and second active agents for treatment of multiple myeloma
  • Antiproliferative compounds and second active agents for treatment of multiple myeloma
  • Antiproliferative compounds and second active agents for treatment of multiple myeloma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0387] Example 1: (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl) Synthesis of oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (compound 2)

[0388]

[0389] (4S)-5-Amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid tert-butyl ester. To a solution of (2S)-2-(benzyloxycarbonylamino)-5-tert-butoxy-5-oxo-pentanoic acid (150g, 445mmol) in 1,4-dioxane (1.50L) Di-tert-butyl dicarbonate (155 g, 711 mmol), pyridine (70.3 g, 889 mmol) and ammonium bicarbonate (105 g, 1.33 mol) were added. The reaction mixture was stirred at 18°C ​​for 16 hours, then concentrated. The residue was dissolved in ethyl acetate (5.0 L) and water (5.0 L), the organic layer was separated and washed with HCl (3.0 mL, 1 N), saturated sodium bicarbonate (3.0 L), brine (3.0 L), Drying over anhydrous sodium sulfate, filtration and concentration gave crude (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid tert-butyl ester (450 g, crude material) as white Solid, which was...

Embodiment 2

[0399] Example 2: Anti-proliferative effect on multiple myeloma

[0400] Cell culture material: Human multiple myeloma cell lines were purchased from suppliers and cultured at 37 °C with 5% CO in the medium 2 ,As shown in Table 1. Lenalidomide- and pomalidomide-resistant cell lines were obtained as previously described (Lopez-Girona et al. Leukemia 2012;26(11):2335). All cell lines were maintained in log phase, and cell density and viability were monitored by trypan blue exclusion using a Vi-cell XR cell viability analyzer (Beckman Coulter, Brea, CA).

[0401] Table 1: Multiple myeloma cell lines tested

[0402]

[0403] Preparation of test article solutions: Assuming a maximum volume of 50 μL, compounds were plated into black 384-well plates (Corning Inc.) to a final DMSO volume of 0.1%. A 10-point dose-response starting at 10 μM with a dilution ratio of 1:3 was printed in duplicate by acoustic dispense using the EDC ATS-100 platform. Alternatively, use a 10-point dose...

Embodiment 3

[0408] Example 3: Off-target effects and impact of compound 1 / compound 2

[0409] α1 adrenergic and dopamine D2 receptors. METHODS: Binding and functional assays of α1 adrenergic and dopamine D2 receptors were performed by Eurofins Cerep according to their method.

[0410] α1 adrenergic receptors. Binding at 10 μM. Binding assays evaluate the affinity of the test articles for non-selective alpha 1 adrenergic receptors in the rat cerebral cortex. Membrane homogenates of the cerebral cortex were mixed with 0.25 nM [ 3 H] Prazosin was incubated with prazosin in duplicate at room temperature for 60 minutes. After the incubation period, samples were filtered through glass fiber filters, the filters were dried, and radioactivity was counted using a scintillation counter. Results are expressed as mean percent inhibition of control radioligand binding.

[0411] combined IC 50 . To determine the binding IC of nonselective α1-adrenergic receptors 50 , with different concentrati...

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Abstract

Provided herein are methods of using 4-(4-(4-((2-(2, 4-difluorophenyl)-1, 2 The present invention relates to a method of treating, preventing or managing multiple myeloma in combination with a first active agent, a second active agent, or an enantiomer, enantiomer mixture, tautomer, or pharmaceutically acceptable salt thereof. The present invention also relates to a method of treating, preventing or managing multiple myeloma in combination with a first active agent and an enantiomer, enantiomer mixture, tautomer, or pharmaceutically acceptable salt thereof, or an enantiomer, enantiomer mixture, tautomer, or pharmaceutically acceptable salt thereof. The second active agent is one or more of a BTK inhibitor, an mTOR inhibitor, a PIM inhibitor, an IGF-1R inhibitor, an MEK inhibitor, an XPO1 inhibitor, a DOT1L inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a BRD4 inhibitor, a PLK1 inhibitor, an NEK2 inhibitor, an AURKB inhibitor, a BIRC5 inhibitor, a BET inhibitor or a DNA methyltransferase inhibitor.

Description

[0001] This application is a divisional application of the Chinese invention patent application filed on January 8, 2020 with the invention title of "Antiproliferative Compounds and Second Active Agents for the Treatment of Multiple Myeloma" and the application number of 202080018980.1. [0002] This application claims the benefit of US Provisional Application No. 62 / 790,326, filed January 9, 2019, the entire contents of which are incorporated herein by reference. 1. Technical field [0003] Provided herein is the use of 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methan yl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile or an enantiomer, mixture of enantiomers, tautomer or pharmaceutically acceptable salt thereof and a second active agent The combination therapy, prevention or management of multiple myeloma. 2. Background technology [0004] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/496A61K31/519A61K31/436A61P35/00A61P7/00
CPCA61K45/06A61K31/496A61K31/519A61K31/436A61P35/00A61P7/00A61K31/454A61K31/497A61K31/416A61K31/517A61K31/4178A61K31/5025A61K31/7076A61K31/4184A61K31/4188A61K31/551A61K31/573A61K31/444A61K31/5517A61K31/4704A61K31/506A61K31/706A61K31/5377A61K31/52A61K31/4985A61K31/4523A61K31/4545A61K31/69A61K2300/00
Inventor 莉莉·L·王
Owner CELGENE CORP
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