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A kind of amide compound and composition comprising the same and use thereof

A technology of compounds and compositions, applied in the field of medicine, can solve problems such as acquired drug resistance

Active Publication Date: 2020-09-18
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients taking AZD9291 still develop symptoms of acquired resistance

Method used

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  • A kind of amide compound and composition comprising the same and use thereof
  • A kind of amide compound and composition comprising the same and use thereof
  • A kind of amide compound and composition comprising the same and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] The following synthetic route was used to prepare 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindoline-2-yl)-N-(thiazol-2-yl-5-d)ethyl Amide (compound 11), comprising the following steps:

[0116]

[0117] Step 1: Synthesis of compound 3.

[0118] Add 4mL of methanesulfonic acid to the reaction flask, cool to 0°C, add α-hydroxyhippuric acid (compound 1, 1g, 5.12mmol), add 4-fluoroanisole (646mg, 5.12mmol) at 0°C, and Under stirring for 1 hour, the reactant was slowly added dropwise to ice water, a white solid was washed out, filtered, the filter cake was washed with water, and vacuum-dried to obtain compound 3 (1.3 mg, yield 86.6%), LC-MS (APCI ):m / z=302(M-1) - .

[0119] Step 2: Synthesis of compound 4.

[0120]Add compound 3 (1g, 3.3mmol) to the reaction flask, add 60mL of 6N hydrochloric acid, heat up to 100°C, react for 36 hours, TLC (thin layer chromatography) detects that the raw materials have reacted completely, cool to room temperature, filter, and the filtr...

Embodiment 2

[0134] The following synthetic route was used to prepare 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindoline-2-yl-3-d)-N-(thiazol-2-yl)ethyl Amide (compound 21), comprising the following steps:

[0135]

[0136] Step 1: Synthesis of Compound 12.

[0137] Add compound 4 (2.08g, 1045mmol) to the reaction flask, add methanol 30mL, cool to 0°C, dropwise add thionyl chloride (1.5mL, 20.9mmol) and raise to 75°C after the dropwise addition, react for 3 hours, the raw material After the reaction was complete, concentrated to remove methanol and excess thionyl chloride, added 20 mL of methyl tert-butyl ether to make a slurry to obtain compound 12 (2.15 g, yield 98.4%), LC-MS (APCI): m / z=214 (M +1) + .

[0138] Step 2: Synthesis of Compound 14.

[0139] Add compound 13 (2g, 12mmol) to the reaction flask, add thionyl chloride 10mL at 0°C, reflux for 3 hours, concentrate to remove excess thionyl chloride to obtain compound 14 (2.74g, yield 100%).

[0140] Step 3: Synthesis of Compoun...

Embodiment 3

[0155] The following synthetic route was used to prepare 2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxoisoindoline-2-y-yl-3,3-d 2 )-N-(thiazol-2-yl)acetamide (compound 25), comprising the following steps:

[0156]

[0157] Step 1: Synthesis of compound 22.

[0158] Add compound 16 (1g, 2.91mmol) to the reaction flask, add zinc powder (10g, 152mmol) in 5 times, add deuterated acetic acid 10mL, heat up to 110°C and react for 7 hours, TLC detects that the reaction of the raw materials is complete, filter to remove excess Zinc powder, concentrated to remove acetic acid, added ethyl acetate 40mL, washed with saturated sodium bicarbonate solution, concentrated organic phase, and purified by column chromatography to obtain compound 22 (315mg, yield 26.1%), LC-MS (APCI):m / z=332(M+1) + .

[0159] Step 2: Synthesis of Compound 23.

[0160] Add compound 22 (252mg, 0.76mmol) to the reaction flask, add lithium hydroxide (159mg, 3.8mmol), add water (1mL), tetrahydrofuran (5mL), and react at ...

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Abstract

An amide compound of formula (I), a polymorph, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant, a hydrate, or a solvate thereof, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof. The compound and the pharmaceutical composition have excellent protein kinase inhibitory activity and good pharmacokinetic properties, can increase drug concentrations of the compound in animals, and improve the efficacy and safety of the drug.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an amide compound, a composition containing the compound and its application. Background technique [0002] Protein tyrosine kinases play important roles in cellular regulation and their aberrant expression or mutations have been observed in cancer cells or autoimmune diseases. Protein tyrosine kinases are enzymes that catalyze the transport of phosphate groups from ATP to tyrosine located on protein substrates. Many growth factor receptor proteins function as tyrosine kinases to transmit cellular signals. Interactions between growth factors and their receptors normally control cell growth, but aberrant signaling caused by mutation or overexpression of any of the receptors often induces a variety of cancers or autoimmune diseases (such as rheumatoid arthritis inflammation). [0003] EGFR tyrosine kinase inhibitor (EGFR-TKI) is a molecularly targeted drug against E...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12A61P29/00A61P31/00A61P37/00A61P31/12A61P9/00A61P3/00A61P35/00A61P19/02A61P19/06A61P11/06A61P11/02A61P11/08A61P11/00A61K31/426
CPCA61P3/00A61P9/00A61P11/00A61P11/02A61P11/06A61P11/08A61P19/02A61P19/06A61P29/00A61P31/00A61P31/12A61P35/00A61P37/00C07B2200/05C07D417/12A61K31/4035A61K31/426A61K31/427C07D209/34
Inventor 王义汉赵九洋
Owner SHENZHEN TARGETRX INC
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