Aromatic dihydrazide type PLK1 (Polo-like Kinase 1) inhibitor and applications thereof

Abstract

The invention relates to the field of the pharmaceutical chemistry, in particular to aromatic dihydrazide compounds, a preparation method of the compounds, pharmaceutical composites with the compounds and medical applications of the compounds, especially the applications of the compounds used as Polo like kinase 1 inhibitor.

Description

technical field

[0001] The present invention relates to the field of medicinal chemistry, in particular to aromatic bishydrazide derivatives, their preparation method, pharmaceutical composition containing these compounds and their medical application, especially the application as polo-like kinase 1 inhibitor. Background technique

[0002] In recent years, tumors have surpassed cardiovascular diseases and become the world's leading cause of death. The research on anti-tumor drugs has important academic and practical significance.

[0003] Studies have found that almost all tumors are related to uncontrolled cell growth, blocked differentiation, and abnormal apoptosis caused by the disorder of cell cycle regulation mechanism. The frequency of tumor cell division is faster than that of normal cells, and various proteins that regulate microtubule polymerization, centrosome duplication, spindle formation, and cytokinesis are often overexpressed and their activities are enhanced...

Examples

Embodiment 1

[0197] 3,4,5-Trimethoxybenzohydrazide (I'-1)

[0198] Add 15.15g (0.1mol) of 3,4,5-trimethoxybenzoic acid and 30ml of methanol into a 100ml three-necked flask, stir at room temperature, and slowly add excess SOCl dropwise 2 (20ml), then heated to 70 ° C, reflux for 4h, and then evaporated under reduced pressure to remove unreacted SOCl 2 And methanol, after cooling, a white solid precipitates out, add saturated Na 2 500ml of CO3 solution, filtered by suction and dried by infrared, directly proceeded to the next step without purification.

[0199] Dissolve 8.0 g of the solid obtained in the previous step in 15 ml of methanol, slowly add 15 ml of hydrazine hydrate, and a white solid precipitates out during the dropwise addition. After the addition, 5ml of methanol was added to dilute the reaction solution. After stirring at 100°C for 1 h, TLC detected that new substances were formed, and the raw material ester basically disappeared. After cooling to room temperature, filter ...

Embodiment 2

[0201] p-Tolylhydrazide (I'-2)

[0202] The preparation method was similar to (I'-1), and 6.0 g of the sample was obtained, with a yield of 90%, mp.116-118°C (literature value 116-118°C).

Embodiment 3

[0204] 4-hydrazinobenzoic acid (I'-3)

[0205] The preparation method was similar to (I'-1), and 1.68 g of the sample was obtained, with a yield of 93%, and mp.230-232°C.

technical field

[0001] The present invention relates to the field of medicinal chemistry, in particular to aromatic bishydrazide derivatives, their preparation method, pharmaceutical composition containing these compounds and their medical application, especially the application as polo-like kinase 1 inhibitor. Background technique

[0002] In recent years, tumors have surpassed cardiovascular diseases and become the world's leading cause of death. The research on anti-tumor drugs has important academic and practical significance.

[0003] Studies have found that almost all tumors are related to uncontrolled cell growth, blocked differentiation, and abnormal apoptosis caused by the disorder of cell cycle regulation mechanism. The frequency of tumor cell division is faster than that of normal cells, and various proteins that regulate microtubule polymerization, centrosome duplication, spindle formation, and cytokinesis are often overexpressed and their activities are enhanced...

Examples

Embodiment 1

[0197] 3,4,5-Trimethoxybenzohydrazide (I'-1)

[0198] Add 15.15g (0.1mol) of 3,4,5-trimethoxybenzoic acid and 30ml of methanol into a 100ml three-necked flask, stir at room temperature, and slowly add excess SOCl dropwise 2 (20ml), then heated to 70 ° C, reflux for 4h, and then evaporated under reduced pressure to remove unreacted SOCl 2 And methanol, after cooling, a white solid precipitates out, add saturated Na 2 500ml of CO3 solution, filtered by suction and dried by infrared, directly proceeded to the next step without purification.

[0199] Dissolve 8.0 g of the solid obtained in the previous step in 15 ml of methanol, slowly add 15 ml of hydrazine hydrate, and a white solid precipitates out during the dropwise addition. After the addition, 5ml of methanol was added to dilute the reaction solution. After stirring at 100°C for 1 h, TLC detected that new substances were formed, and the raw material ester basically disappeared. After cooling to room temperature, filter ...

Embodiment 2

[0201] p-Tolylhydrazide (I'-2)

[0202] The preparation method was similar to (I'-1), and 6.0 g of the sample was obtained, with a yield of 90%, mp.116-118°C (literature value 116-118°C).

Embodiment 3

[0204] 4-hydrazinobenzoic acid (I'-3)

[0205] The preparation method was similar to (I'-1), and 1.68 g of the sample was obtained, with a yield of 93%, and mp.230-232°C.

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