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Antiproliferative compounds and methods of use thereof

A technology of compounds and compositions, applied in the fields of active ingredients of boron compounds, drug combinations, organic chemistry, etc.

Active Publication Date: 2020-03-06
CELGENE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

10 -4 The MRD thresholds were originally based on technical capability, but are now possible by flow cytometry at 10 -5 Quantitative MRD detection under , and through high-throughput sequencing is possible in 10 -6 Quantitative MRD detection under

Method used

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  • Antiproliferative compounds and methods of use thereof
  • Antiproliferative compounds and methods of use thereof
  • Antiproliferative compounds and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0396] Example 1: 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)methanol yl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 1).

[0397]

[0398] 2-Amino-5-methoxy-5-oxopentanoic acid. To a suspension of 2-aminoglutaric acid (250 g, 1.70 mol) in dry methanol (2.5 L) was added trimethylsilyl chloride (277 g, 2.55 mol) under nitrogen over 30 minutes. The resulting clear solution was stirred at room temperature (20° C.) for 30 minutes. 1 H NMR indicated complete consumption of starting material. The reaction mixture was used in the next step without further work-up. 1 H NMR: 400MHz CD 3 ODδ: 4.17-4.15 (m, 1H), 3.71 (s, 3H), 2.70-2.60 (m, 2H), 2.33-2.25 (m, 2H).

[0399] 2-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid. To the above solution was added triethylamine (275 g, 2.72 mol) and di-tert-butyl dicarbonate (447.35 g, 2.05 mol). The mixture was stirred at 25°C for 2 hours. The solution was concentrated to dryness, then water (2....

Embodiment 2

[0410] Example 2: (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl) Oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 2)

[0411]

[0412] (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), washed over Drying over anhydrous sodium sulfate, filtration and concentration afforded crude (4S)-5-amino-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid tert-butyl ester (450 g, crude) as a white solid, It was used i...

Embodiment 3

[0422] Example 3: (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl) Oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (compound 2)

[0423]

[0424]4-(4-(4-(Chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile hydrochloride. To a solution of 3-fluoro-4-(piperazin-1-yl)benzonitrile (100 g) in toluene (1400 mL) was charged acetic acid (28 mL) at 25 °C and the reaction mixture was maintained for 30 min. 4-(Chloromethyl)benzaldehyde (79 g) was charged at 25°C and the mixture was maintained for 2 hours. Sodium triacetoxyborohydride (52 g each) was charged 3 times every 30 minutes at 25°C. The mixture was stirred at 25°C for about 10 hours. Water (600 mL) was charged over 1 hour while maintaining the batch temperature below 30°C. Most of the lower layer was separated. The mixture was filtered, and the lower layer was separated. The organic layer was washed with water (200 mL). To the organic layer was charged IPA (75 mL), added 5-6N HCl in IPA (8 m...

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Abstract

Provided herein is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof, and methods for treating, preventing or managing multiple myeloma using such compounds. Also provided are pharmaceutical compositions comprising the compounds, and methods of use of the compositions.

Description

[0001] This application claims U.S. Provisional Application Serial No. 62 / 530,778 filed July 10, 2017, U.S. Provisional Application Serial No. 62 / 593,185 filed November 30, 2017, and U.S. Provisional Application Serial No. 62 / 593,185 filed May 23, 2018 62 / 675,581, said US Provisional Application Serial No. is hereby incorporated by reference in its entirety. [0002] 1. Technical field [0003] Provided herein is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl )benzyl)piperazin-1-yl)-3-fluorobenzonitrile or its enantiomers, mixtures of enantiomers, tautomers or pharmaceutically acceptable salts, and the use of such Compounds for treating, preventing or managing multiple myeloma. Also provided are pharmaceutical compositions comprising the compounds, and methods of using the compositions, including combination therapy. [0004] 2. Background of the invention [0005] Multiple myeloma (MM) is a cancer of the plasma cells in the bone marrow. Normally, pl...

Claims

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Application Information

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IPC IPC(8): A61K31/496C07D241/02A61K38/05A61K31/573A61P35/00
CPCA61K38/05C07D401/04A61P35/00A61K31/496A61P35/02A61K31/69A61K31/573A61K2300/00C07D401/14A61K31/454A61K45/06
Inventor 马修·D·亚历山大杰拉尔德·D·阿特曼三世戈登·L·布雷詹姆斯·卡迈克尔索拉雅·卡兰西奥布莱恩·E·卡瑟斯马修·D·科雷亚约书亚·汉森考特尼·G·黑文斯蒂莫西·S·克尔彻安东尼娅·洛佩兹-吉罗纳陆小玲汉华·曼马克·A·纳吉拉玛·K·娜尔拉约瑟夫·R·皮科蒂丹尼尔·W·皮尔斯保拉·A·塔瓦雷斯-格雷科布兰登·W·怀特菲尔德莉莉·L·王邹难非
Owner CELGENE CORP
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