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Antiproliferative compounds and second active agents for use in treating multiple myeloma

A multiple myeloma, active agent 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: 2021-10-22
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 use in treating multiple myeloma
  • Antiproliferative compounds and second active agents for use in treating multiple myeloma
  • Antiproliferative compounds and second active agents for use in treating multiple myeloma

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0329] 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)

[0330]

[0331] (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), Dried over anhydrous sodium sulfate, filtered and concentrated to give crude (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid tert-butyl ester (450 g, crude material) as white Solid, which was ...

Embodiment 2

[0341] Example 2: Anti-proliferative effect on multiple myeloma

[0342] 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).

[0343] Table 1: Multiple myeloma cell lines tested

[0344]

[0345] 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

[0350] Example 3: Off-target effects and impact of compound 1 / compound 2

[0351] 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.

[0352] 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.

[0353] 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-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-l-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof, in combination with a second active agent for treating, preventing or managing multiple myeloma. 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 claims the benefit of U.S. Provisional Application No. 62 / 790,326, filed January 9, 2019, which is incorporated herein by reference in its entirety. 1. Technical field [0002] Provided herein is the use of 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methanol Base) benzyl) piperazin-1-yl) -3-fluorobenzonitrile or its enantiomers, mixtures of enantiomers, tautomers or pharmaceutically acceptable salts with a second active agent Methods of treating, preventing or managing multiple myeloma in combination. 2. Background technology [0003] Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, the uncontrolled growth of these cells can lead to bone pain and fractures, anemia, infection and other complications. Multiple myeloma is the second most common hematological malignancy, but the exact cause of multiple myeloma is unkn...

Claims

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Application Information

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