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Carbamate and urea compounds as multikinase inhibitors

A compound and hydrocarbon-based technology, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve the problems of increased kinase-specific activity, overexpression or loss of negative regulation

Pending Publication Date: 2020-08-07
ANGEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These changes result in increased specific activity, overexpression, or loss of negative regulation of the kinase itself

Method used

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  • Carbamate and urea compounds as multikinase inhibitors
  • Carbamate and urea compounds as multikinase inhibitors
  • Carbamate and urea compounds as multikinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example

[0303] Example: Ex. or ex.

[0304] Formic acid: FA

[0305] Gram: g

[0306] High Performance Liquid Chromatography: HPLC

[0307] Inhibition: Inh.

[0308] Liquid Chromatography Mass Spectrometry: LCMS or LC-MS

[0309] Methanol: MeOH

[0310] Microliter: μL

[0311] Micrometer: μm

[0312] milligram: mg

[0313] Milliliter: mL

[0314] millimole: mmol

[0315] Nuclear magnetic resonance spectroscopy (Nuclear magnetic resonance spectroscopy): NMR

[0316] Phosphoryl chloride: POCl 3

[0317] Preparative HPLC: Prep-HPLC

[0318] Preparative TLC: Prep-TLC

[0319] Retention time: t R

[0320] Room temperature (ambient temperature, ~25°C): rt or RT

[0321] Potassium tert-butoxide: t-BuOK

[0322] Preparative HPLC: Prep-HPLC

[0323] Preparative TLC: Prep-TLC

[0324] Sodium methoxide: NaOMe

[0325] Supercritical Fluid Chromatography: SFC

[0326] temperature: temp.

[0327] Tetrahydrofuran (Tetrahydrofuran): THF

[0328] Thin layer chromatography: TLC ...

example 1

[0340] Example 1: 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)phenoxy)-6-methoxy Quinolin-7-yl 4-methylpiperazine-1-carboxylate (4-(4-(1-((-fluorophenyl)carbamoyl)cyclopropane- 1-carboxamido)phenoxy)-6-methoxyquinolin-7-yl4-methylpiperazine-1- carboxylate) synthetic scheme 1

[0341]

[0342] step 1:

[0343] Add 12.5g (90.5mmol) K 2 CO 3 and 11.3g (66.07mmol) bromotoluene (benzyl bromide) to 10.0g (60.2mmol) 1-(4-hydroxyl-3-methoxyphenyl) ethane-1-ketone (1-( 4-hydroxy-3-methoxyphenyl)ethan-1-one) stirred solution. The reaction mixture was stirred at 40 °C under N2 atmosphere for 1 h. Diluted with 500 mL of water, and filtered; the filter cake was washed with water to obtain compound 1-1, which was used in the next step without further purification. LC-MS: m / e=257[M+H] + .

[0344] Step 2:

[0345] Add 10.6 mL (238.1 mmol) HNO dropwise at 0 °C 3 To a stirred solution of 26.0 g (101.6 mmol) of compound 1-1 in 400 mL of dichloromethane. Aft...

example 2

[0367] Example 2: 4-(4-(1-((-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)phenoxy)-6-methoxyquin Lin-7-yl (R)-3,4-methoxyquinoline 1-carboxylate (4-(4-(1-((-fluorophenyl)carbamoyl) cyclopropane-1-carboxamido)phenoxy)-6-methoxyquinolin-7-yl(R)-3,4- Synthetic Scheme 2 of dimethylpiperazine-1-carboxylate)

[0368]

[0369] step 1:

[0370] Add 0.40 g (3.1 mmol) DIEA and 0.46 g (2.3 mmol) 4-nitrophenyl carbonochloridate in 2 mL THF to 1.0 g ( 2.1 mmol) stirred solution of compound 1-9. The mixture was stirred at room temperature for 2 hours and then quenched with water. Extract with three 50 mL portions of ethyl acetate; the combined organic extracts were washed with brine and washed with anhydrous Na 2 SO 4 dry. After filtration, the filtrate was concentrated under vacuum to provide compound 2-1. LC-MS: m / e=653[M+H] + .

[0371] Step 2:

[0372] At room temperature, add 0.078g (0.77mmol) Et 3 N and 0.068g (0.46mmol) (R)-1,2-dimethylpiperazine hydrochlorid...

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Abstract

The present disclosure describes carbamate and urea compounds as novel multikinase inhibitors and methods for preparing them. The pharmaceutical compositions comprising such multikinase inhibitors andmethods of using them for treating cancer, infectious diseases, and other disorders associated with kinases are also described.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 608,375, filed December 20, 2017, the entire contents of which are hereby incorporated by reference. technical field [0003] The disclosure relates to heterocyclic compounds comprising aminocarbonate or urea, such as 4-(4-(1-((4-fluorophenyl)carbamoyl)cyclopropane as multikinase inhibitors -1-formamido)phenoxy)-6-methoxyquinolin-7-yl(R)-2,4-dimethylpiperazine-1-carboxylate (4-(4-(1 -((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxamido)phenoxy)-6-methoxyquinolin-7-yl(R)-2,4-dimethylpiperazine-1-carboxylate)(1-11) and medicines containing this compound combination. The present disclosure also relates to the use of these compounds and pharmaceutical compositions containing these compounds for the treatment of cancer, infectious diseases and other conditions. Background technique [0004] Cancer occurs when normal cells lose their ability to co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/16A61K31/50C07D239/70C07D239/72C07D239/88
CPCC07D215/233C07D401/04C07D401/12C07D239/88C07D487/04C07D487/08A61K31/496A61K31/4709A61K31/5377A61P35/00A61P31/00C07D215/22C07D403/12
Inventor 吴文连杨志强李煜辉谭强
Owner ANGEX PHARMA INC
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