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Inhibitor of nedd8-activating enzyme

A technology of compounds, chemical entities, applied in the field of cell proliferation disorders, active compounds

Inactive Publication Date: 2018-05-04
MILLENNIUM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] At this time, no inhibitors of E1-activating enzymes have been approved by the government health administration as a treatment

Method used

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  • Inhibitor of nedd8-activating enzyme
  • Inhibitor of nedd8-activating enzyme
  • Inhibitor of nedd8-activating enzyme

Examples

Experimental program
Comparison scheme
Effect test

example

[0140] abbreviation

[0141] AcOH acetic acid

[0142] ACN acetonitrile

[0143] DABCO Triethylenediamine

[0144] DCM dichloromethane

[0145] DCP 4,6-Dichloropyrimidine

[0146] DEA diethylamine

[0147] DIPEA N,N-Diisopropylethylamine

[0148] DMSO Dimethyl Sulfoxide

[0149] Et 2 O diethyl ether

[0150] EtOAc ethyl acetate

[0151] EtOH ethanol

[0152] Et 3 N triethylamine

[0153] FA formic acid

[0154] h 2 O water

[0155] hours

[0156] IPA isopropyl alcohol

[0157] IPAc isopropyl acetate

[0158] LC / MS liquid chromatography mass spectrometry

[0159] LDA lithium diisopropylamide

[0160] MTBE methyl tert-butyl ether

[0161] MeOH Methanol

[0162] min minutes

[0163] MS mass spectrometry

[0164] NMP N-methyl-2-pyrrolidone

[0165] rt room temperature

[0166] P 3 NO 4-Phenylpropylpyridine-N-oxide

[0167] TBS tert-butyldimethylsilyl

[0168] TFA trifluoroacetic acid

[0169] THF Tetrahydrofuran

[0170] TLC thin layer chromatograph...

example 1

[0177] Example 1. Synthesis of (1R,2S)-5-chloro-2-methoxyindan-1-amine (8)

[0178] Step 1: rel-(1aR,6aS)-4-Chloro-6,6a-dihydro-1aH-indeno[1,2-b]oxirane (2).

[0179]To a stirred solution of 4-phenylpropylpyridine-N-oxide (278 mg, 1.31 mmol) in dichloromethane (20 mL) at 0°C was added (R,R)-Jacobson's catalyst (237.0 mg, 0.3732mmol) and sodium hypochlorite solution (2.0M aqueous solution; 16mL, 32mmol). The resulting brown suspension was stirred at 0 °C for 15 minutes, then a solution of 6-chloro-1H-indene (1) (2.81 g, 18.6 mmol) in dichloromethane (20 mL) was added via syringe along with additional sodium hypochlorite (2.0 M in water; 16 mL, 32 mmol). The reaction was stirred at 0 °C for 1 hour, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. An aliquot was taken and TLC on silica gel (hexanes) showed that all starting material was consumed. The reaction was poured into brine and extracted with dichloromethane. The combined extr...

example 2

[0191] Example 2. Sulfamic acid {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-indene- Synthesis of 1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl ester (I-216)

[0192] Step 1: rel-(1R,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopent-2-en-1-ol (10).

[0193] rel-(1R,5R)-5-(hydroxymethyl)cyclopent-2-en-1-ol (47.20g, 0.4135mol), N,N-dimethylamino To a solution of pyridine (2.52 g, 0.0207 mol) and 1H-imidazole (30.97 g, 0.4549 mol) in dichloromethane (800 mL, 10 mol) was added tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol). The reaction was stirred at 0 °C for 2.5 h at which time tert-butyldimethylsilyl chloride (28.0 g, 0.186 mol) was added. The reaction was stirred for another 2 hours. The reaction was quenched by adding saturated aqueous NaCl (200 mL) and water (200 mL). The layers were separated and the organic layer was washed with water (3×200 mL) and brine (1×200 mL), washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. ...

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Abstract

The present invention discloses chemical entities that are inhibitors of Nedd8-activating enzyme NAE, namely, the compound sulfamic acid {(1S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2 -Methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl ester and pharmaceutically acceptable salts thereof ; solid state forms thereof; and prodrugs thereof. Also disclosed are methods of using the chemical entities to treat conditions such as cancer.

Description

technical field [0001] The present invention relates to compounds, compositions and methods for the treatment of various disorders, particularly cell proliferative disorders, including cancer and inflammatory disorders. In particular, the present invention provides compounds that inhibit the activity of NEDD8-activating enzyme. Background technique [0002] Post-translational modification of proteins by ubiquitin-like molecules (ubls) is an important regulatory process in cells, playing a key role in the control of many biological processes, including cell division, cell signaling, and immune responses. Ubl is a small protein that is covalently linked to a lysine on the target protein via linkage of an isopeptide to the C-terminal glycine of ubl. Ubiquitin-like molecules alter the molecular surface of target proteins and can affect properties such as protein-protein interactions, enzyme activity, target stability and cellular localization. [0003] Ubiquitin and other ubls...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D487/02A61K31/519A61K31/505A61P35/00
CPCC07D239/47C07D473/34C07D239/46C07D473/02A61P35/00
Inventor 阿什利·苏·麦卡伦托德·B·塞尔斯马修·史提灵斯蒂芬·G·斯特劳德
Owner MILLENNIUM PHARMA INC