Substance with protein kinase inhibiting activity and preparation method therefor and application thereof

Abstract

The present invention discloses a substance with protein kinase inhibiting activity and a preparation method therefor and an application thereof. The substance is a benzamide derivative and is specifically N-(2,4-dimethylphenyl)-4-[(7-chlorine-4-quinoline)amino]benzamide. The compound can be used as a protein kinase inhibitor and a histone deacetylase inhibitor, and used for treating a tumor; and a preparation reaction of the substance is low in cost and high in yield, and a reaction process is simple and easy to control, so that the preparation method is applicable to industrial production.

Description

technical field

[0001] The present invention belongs to the field of medicine, and relates to a class of new compounds, in particular to a class of benzamide derivatives (general formula I), a preparation method of the compound and its use in the preparation of drugs for treating some diseases caused by protein kinase regulation abnormalities. application. Background technique

[0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins, particularly on specific tyrosine, serine, and threonine residues in proteins. Protein kinases play key roles in regulating many cellular physiological processes, including metabolism, cell proliferation, cell differentiation, cell survival, immune response, and angiogenesis.

[0003] Protein kinases are generally divided into two classes, namely protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). Among them, protein tyrosine kinases can be divided into two categories, namely non-transmembr...

Examples

preparation example Construction

[0028] The preparation method of the benzamide derivatives involved in the present invention is as follows:

[0029] The following room temperature refers to 25°C, and ice bath refers to 0-4°C.

[0030] Step (1), Dissolving Compound II (4,7-dichloroquinoline) (5-20mmol) and Compound III (p-aminobenzoic acid) (5-20mmol) in isopropanol (20-50mL), stirred and refluxed (75-95°C), after 5-7 hours, a pale yellow precipitate precipitated, after the reaction solution was cooled to room temperature, evaporated to dryness under reduced pressure, the residual solid was washed 3 times with dichloromethane, the filter cake was collected, and dried to obtain a pale yellow solid Powder IV (4-(7-chloroquinoline-4-amino)benzoic acid).

[0031] The reaction equation is as follows:

[0032]

[0033] Step (2), dissolve the compound IV obtained in step (1) in dry dichloromethane, stir, slowly add thionyl chloride (25-100mmol) dropwise to the reaction system under ice bath, and reflux after th...

Embodiment 1

[0042] Add 4,7-dichloroquinoline (0.985g, 5mmol), p-aminobenzoic acid (0.685g, 5mmol) and 20mL of isopropanol into a dry 100mL round-bottomed flask, and stir to fully dissolve it. Slowly raise the temperature to 85°C, stir and reflux for 5 hours, the reaction solution precipitates a light yellow precipitate, TLC detects that the reaction has been balanced, and the reaction is terminated. After the reaction solution was cooled to room temperature, it was evaporated to dryness under reduced pressure, the residual solid was washed 3 times with 10 mL of dichloromethane, the filter cake was collected, and dried to obtain 1.40 g of light yellow solid powder 4-(7-chloroquinoline-4-amino)benzoic acid , yield 95%.

[0043] Add 10 mL of dichloromethane solution containing 4-(7-chloroquinoline-4-amino)benzoic acid (1.491 g, 5 mmol) into a 100 mL dry round bottom flask, stir, and slowly add Add thionyl chloride (2.974g, 25mmol) dropwise, reflux (80°C) for 4 hours after the dropwise addit...

Embodiment 2

[0051] Add 4,7-dichloroquinoline (1.970g, 10mmol), p-aminobenzoic acid (1.372g, 10mmol) and 20mL of isopropanol into a dry 100mL round-bottomed flask, and stir to fully dissolve it. Slowly raise the temperature to 85°C, stir and reflux for 5 hours, the reaction solution precipitates a light yellow precipitate, TLC detects that the reaction has been balanced, and the reaction is terminated. After the reaction solution was cooled to room temperature, it was evaporated to dryness under reduced pressure, the residual solid was washed 3 times with 15 mL of dichloromethane, the filter cake was collected, and dried to obtain 2.751 g of light yellow solid powder 4-(7-chloroquinoline-4-amino)benzoic acid , yield 92%.

[0052] Add 15 mL of dry methylene chloride solution containing 4-(7-chloroquinoline-4-amino)benzoic acid (2.982 g, 10 mmol) into a 100 mL dry round bottom flask, stir, and pour into the reaction system under an ice bath at 0°C Slowly add thionyl chloride (5.948g, 50mmol...

technical field

[0001] The present invention belongs to the field of medicine, and relates to a class of new compounds, in particular to a class of benzamide derivatives (general formula I), a preparation method of the compound and its use in the preparation of drugs for treating some diseases caused by protein kinase regulation abnormalities. application. Background technique

[0002] Protein kinases are a class of enzymes that catalyze the phosphorylation of proteins, particularly on specific tyrosine, serine, and threonine residues in proteins. Protein kinases play key roles in regulating many cellular physiological processes, including metabolism, cell proliferation, cell differentiation, cell survival, immune response, and angiogenesis.

[0003] Protein kinases are generally divided into two classes, namely protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). Among them, protein tyrosine kinases can be divided into two categories, namely non-transmembr...

Examples

preparation example Construction

[0028] The preparation method of the benzamide derivatives involved in the present invention is as follows:

[0029] The following room temperature refers to 25°C, and ice bath refers to 0-4°C.

[0030] Step (1), Dissolving Compound II (4,7-dichloroquinoline) (5-20mmol) and Compound III (p-aminobenzoic acid) (5-20mmol) in isopropanol (20-50mL), stirred and refluxed (75-95°C), after 5-7 hours, a pale yellow precipitate precipitated, after the reaction solution was cooled to room temperature, evaporated to dryness under reduced pressure, the residual solid was washed 3 times with dichloromethane, the filter cake was collected, and dried to obtain a pale yellow solid Powder IV (4-(7-chloroquinoline-4-amino)benzoic acid).

[0031] The reaction equation is as follows:

[0032]

[0033] Step (2), dissolve the compound IV obtained in step (1) in dry dichloromethane, stir, slowly add thionyl chloride (25-100mmol) dropwise to the reaction system under ice bath, and reflux after th...

Embodiment 1

[0042] Add 4,7-dichloroquinoline (0.985g, 5mmol), p-aminobenzoic acid (0.685g, 5mmol) and 20mL of isopropanol into a dry 100mL round-bottomed flask, and stir to fully dissolve it. Slowly raise the temperature to 85°C, stir and reflux for 5 hours, the reaction solution precipitates a light yellow precipitate, TLC detects that the reaction has been balanced, and the reaction is terminated. After the reaction solution was cooled to room temperature, it was evaporated to dryness under reduced pressure, the residual solid was washed 3 times with 10 mL of dichloromethane, the filter cake was collected, and dried to obtain 1.40 g of light yellow solid powder 4-(7-chloroquinoline-4-amino)benzoic acid , yield 95%.

[0043] Add 10 mL of dichloromethane solution containing 4-(7-chloroquinoline-4-amino)benzoic acid (1.491 g, 5 mmol) into a 100 mL dry round bottom flask, stir, and slowly add Add thionyl chloride (2.974g, 25mmol) dropwise, reflux (80°C) for 4 hours after the dropwise addit...

Embodiment 2

[0051] Add 4,7-dichloroquinoline (1.970g, 10mmol), p-aminobenzoic acid (1.372g, 10mmol) and 20mL of isopropanol into a dry 100mL round-bottomed flask, and stir to fully dissolve it. Slowly raise the temperature to 85°C, stir and reflux for 5 hours, the reaction solution precipitates a light yellow precipitate, TLC detects that the reaction has been balanced, and the reaction is terminated. After the reaction solution was cooled to room temperature, it was evaporated to dryness under reduced pressure, the residual solid was washed 3 times with 15 mL of dichloromethane, the filter cake was collected, and dried to obtain 2.751 g of light yellow solid powder 4-(7-chloroquinoline-4-amino)benzoic acid , yield 92%.

[0052] Add 15 mL of dry methylene chloride solution containing 4-(7-chloroquinoline-4-amino)benzoic acid (2.982 g, 10 mmol) into a 100 mL dry round bottom flask, stir, and pour into the reaction system under an ice bath at 0°C Slowly add thionyl chloride (5.948g, 50mmol...

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