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Thienopyrimidine diaromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof

A technology of epidermal growth factor and pyrimidine, which is applied in the field of thienopyrimidine bisaromatic ring derivatives, can solve the problems of cancer recurrence in patients

Inactive Publication Date: 2019-11-05
YA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, patients who develop secondary drug mutations to these drugs suffer from cancer recurrence within a few months

Method used

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  • Thienopyrimidine diaromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof
  • Thienopyrimidine diaromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof
  • Thienopyrimidine diaromatic ring derivative epidermal growth factor inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: 2-{1'-N,N-dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro- 6'-quinoxaline}-4-(1"-methyl-1H-3"-indole)thiophene[2,3-D]pyrimidine (Compound 501)

[0034]

[0035] Preparation of 2-chloro-4-(1'-methyl-1H-3'-indole)thiophene[2,3-D]pyrimidine:

[0036]

[0037] Dissolve 2,4-dichlorothiophene[2,3-D]pyrimidine (0.82g, 4mmol) in ethylene glycol dimethyl ether (20mL), stir under ice bath, add ferric chloride (0.77 g, 4.59mmol), followed by stirring the reaction at room temperature for 15 minutes. Then N-methylindole (0.68 g, 5.2 mmol) was added dropwise, followed by heating to 60° C. and stirring the reaction for 24 hours. Stop the reaction, lower to 0°C, add 3.5mL of methanol and 9mL of water, and then stir the reaction at room temperature for 3 hours. A large amount of solid precipitated, filtered, washed the filter cake with methanol, and dried to obtain 0.81 g of yellow solid, yield: 68%. LC / MS (ESI): m / z 300 (M+H) + .

[0038] Prepa...

Embodiment 2

[0062] Example 2: 2-{1'-N,N-Dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro-6 '-quinoxaline}-4-(1"-methyl-4-aza-3"-indole)thiophene[3,2-D]pyrimidine (Compound 502)

[0063]

[0064] Preparation of 2-chloro-4-(1'-methyl-1H-3'-indole)thiophene[3,2-D]pyrimidine:

[0065]

[0066]Dissolve 2,4-dichlorothieno[3,2-D]pyrimidine (0.82g, 4mmol) in ethylene glycol dimethyl ether (20mL), stir under ice bath, add ferric chloride (0.77 g, 4.59 mmol), followed by stirring the reaction at room temperature for 15 minutes. Then N-methylindole (0.68 g, 5.2 mmol) was added dropwise, followed by heating to 60° C. and stirring the reaction for 24 hours. Stop the reaction, lower to 0°C, add 3.5mL of methanol and 9mL of water, and then stir the reaction at room temperature for 3 hours. A large amount of solid precipitated, filtered, washed the filter cake with methanol, and dried to obtain a yellow solid, 0.86 g, yield: 72%. LC / MS (ESI): m / z 300 (M+H) + .

[0067] 2-[1'...

Embodiment 3

[0073] Example 3: 2-{1'-N,N-dimethylaminoethyl-4'-butenamido-7'-methoxy-1',2',3',4'-tetrahydro- 6'-quinoxaline}-4-(3"-pyrazol[1,5-a]pyridine)thiophene[2,3-D]pyrimidine (Compound 503)

[0074]

[0075] 2-{1'-N,N-Dimethylaminoethyl-4'-acrylamido-7'-methoxy-1',2',3',4'-tetrahydro-6'-quinoxa Preparation of morpholine}-4-(3"-pyrazol[1,5-a]pyridine)thiophene[2,3-D]pyrimidine (compound 503):

[0076]

[0077] 2-[1'-N,N-Dimethylaminoethyl-7'-methoxy-1',2',3',4'-tetrahydro-6'-quinoxaline]-4-( 3"-pyrazolo[1,5-a]pyridine)thienopyrimidine (390mg, 0.76mmol) and DIPEA (0.146mL, 0.84mmol) were dissolved in dichloromethane (10mL), stirred at 0°C, and then dropped Add crotonoyl chloride (79 mg, 0.76 mmol) dissolved in DCM (2 mL) solution, then stir the reaction for 2 hours. The reaction is complete as detected by TLC. Stop the reaction, add DCM (50 mL), and then use 100 mL of saturated NaHCO 3 Washed with water, the aqueous layer was extracted with DCM (2*50mL), anhydrous MgSO 4 Afte...

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Abstract

The invention discloses a selective inhibitor of a clinical mutant of EGFR protein tyrosine kinase, a diaromatic ring template compound containing thienopyrimidine having the structure shown in formulas (I and II) and a preparation method and application of the compound as the selective inhibitor of the clinical mutant of the EGFR protein tyrosine kinase. The selective inhibitor particularly has an inhibiting effect on an epidermal growth factor receptor EGFR of T790M mutation, and treats the diseases associated with the overexpression of the epidermal growth factor receptor EGFR such as the kidney cancer, the lung cancer, the prostate cancer, the pancreatic cancer, the breast cancer and glioma.

Description

technical field [0001] The present invention relates to thienopyrimidine bisaromatic ring derivatives. Background technique [0002] Epithelial growth factor EGFR (epithelial growth factor receptor) is a 170kDa transmembrane glycoprotein receptor tyrosine kinase, which is activated by epidermal growth factor and affects cell growth and differentiation. Binding of EGF or TGF[alpha] to EGFR activates the receptor's tyrosine kinase activity. The tyrosine residues Tyr1068, Tyr1148, and Tyr1173 at the carboxy-terminus of EGFR are the main sites for autophosphorylation following EGF binding. Once activated, phosphorylated tyrosine residues at positions 1068 and 1173 of EGFR mediate the binding of Grb2 to EGFR. In addition, the phosphorylated tyrosine residue at position 1173 is the main binding site of SHC on EGFR. EGFR is widely distributed in many normal and malignant epithelial cells, and its overexpression and self-activation may be related to the occurrence and development...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D519/00A61K31/519A61P35/00
CPCA61P35/00C07D495/04C07D519/00
Inventor 梁永宏曾兆森凌苑
Owner YA THERAPEUTICS INC
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