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Cytarabine analogue and preparation method and application thereof

A cytarabine, a technology similar in structure, applied in the field of cytarabine structural analogs and their preparation, can solve the problems of limiting the clinical use of cytarabine, not significantly improving the survival rate, organ toxicity and side effects, etc. Effective blood drug concentration, preparation method is simple and easy to operate, high bioavailability effect

Active Publication Date: 2021-02-26
武汉伯瑞恒医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

From a clinical point of view, high-dose cytarabine treatment is better than ordinary dose long-term treatment, but it has toxic side effects on the blood, nervous system and organs, and is prone to drug resistance, and the survival rate within five years has not significantly improved
The side effects of cytarabine are positively correlated with the dosage, which also limits the clinical use of cytarabine

Method used

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  • Cytarabine analogue and preparation method and application thereof
  • Cytarabine analogue and preparation method and application thereof
  • Cytarabine analogue and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Synthesis of Cytarabine Structural Analogue P1

[0073] The synthetic route is shown in the following formula:

[0074]

[0075] Method: Cytarabine (compound 1, 5.0g, 20.56mmol) and compound 2 (10.72g, 30.84mmol, 1.5eq.) were dissolved in anhydrous THF (tetrahydrofuran, 50mL), N 2 The temperature was lowered to -78°C under protection, and 1-methylimidazole (4.39g, 53.46mmol, 2.6eq.) was slowly added dropwise, then stirred at -78°C for 2 hours and then naturally warmed to room temperature (20°C) for 12 hours. The reaction solution was concentrated under reduced pressure at 40°C, diluted with DCM (dichloromethane), washed successively with dilute hydrochloric acid (0.5mol / L), water, and saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and reduced to 40°C. After concentration under reduced pressure, it was purified by column chromatography (DCM / MeOH=20 / 1-10 / 1, V / V, MeOH is methanol) to obtain a white p...

Embodiment 2

[0076] Example 2 Synthesis of Cytarabine Structural Analogue P2

[0077] The synthetic route is shown in the following formula:

[0078]

[0079] Method: Compound P1 (3.0 g, 5.41 mmol) and compound 3 (2.32 g, 6.49 mmol, 1.2 eq.) were dissolved in anhydrous DCM (tetrahydrofuran, 50 mL), N 2 The temperature was lowered to 0°C under protection, and 1-propylphosphoric anhydride (50% ethyl acetate solution) (6.88g, 1-propylphosphoric anhydride T 3 P 10.82mmol, 2.0eq.), then naturally warmed to room temperature (20°C) for 1 hour reaction. The reaction solution was saturated NaHCO 3 The solution was quenched, the aqueous phase was extracted with DCM (dichloromethane, 50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure at 40°C, and column chromatography (PE / EA=20 / 1~1 / 1, PE is petroleum ether, EA is ethyl acetate) and purified to obtain intermediate P1a. Dissolve the intermediate P1a in methanol (50 mL), add Pd / C (...

Embodiment 3

[0080] Example 3 Synthesis of Cytarabine Structural Analogue P3

[0081] The synthetic route is shown in the following formula:

[0082]

[0083] Method: Cytarabine (compound 1, 5.0g, 20.56mmol) and compound 4 (16.16g, 30.84mmol, 1.5eq.) were dissolved in anhydrous THF (tetrahydrofuran, 50mL), N 2 The temperature was lowered to -78°C under protection, and 1-methylimidazole (4.39g, 53.46mmol, 2.6eq.) was slowly added dropwise, then stirred at -78°C for 2 hours and then naturally warmed to room temperature (20°C) for 12 hours. The reaction solution was concentrated under reduced pressure at 40°C, diluted with DCM (dichloromethane), washed successively with dilute hydrochloric acid (0.5mol / L), water, and saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, and reduced to 40°C. After concentrated under reduced pressure, it was purified by column chromatography (DCM / MeOH=20 / 1-10 / 1, V / V) to obtain a white powdery compound. L...

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Abstract

The invention discloses a cytarabine analogue and a preparation method and application thereof. The cytarabine structural analogues P1-P4 are synthesized for the first time and can inhibit proliferation of leukemia cells HL60, and particularly, compared with Ara-C, the cytarabine structural analogues P4 are higher in leukemia cell proliferation inhibition capacity and cell penetration capacity, the concentration of the drug entering the cells and the concentration of the active metabolite cytarabine triphosphate generated in the cells are higher, and the bioavailability is higher; the cytosinearabinoside can be converted into a parent drug cytosine arabinoside in cells, so that the blood concentration of target cells in vivo is remarkably improved, and toxic and side effects and drug resistance caused by large-dose medication can be avoided; and the half-life period of cytarabine is remarkably prolonged, the effective blood concentration is maintained for a long time, oral administration can be achieved, and inconvenience caused by injection medication can be avoided. The preparation method is simple, easy to operate and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and specifically relates to a structural analog of cytarabine, a preparation method and application thereof. Background technique [0002] Cytosine arabinoside (Ara-C) chemical name: 1-β-D-arabinofuranosyl-4-amino-2(1H)-cytosine, CAS registration number is [147-94-4] , molecular formula: C 9 h 13 N 3 o 5 , its structural formula is as follows: [0003] [0004] Cytarabine belongs to pyrimidine anti-metabolite drugs and is mainly used for the treatment of acute myeloid leukemia (AML). Ara-C must go through three steps in the body to be converted into cytarabine triphosphate (Ara-CTp) in order to exert its anticancer effect. First, cytarabine monophosphate (Ara-CMp) is catalyzed by deoxycytidine kinase in the cytoplasm, and then converted into cytarabine diphosphate (Ara-CDp) and Active cytarabine triphosphate (Ara-CTp), cytarabine triphosphate inhibits DNA polymerase, affects DNA synthes...

Claims

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Application Information

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IPC IPC(8): C07H19/10C07H1/00A61P35/02
CPCC07H19/10C07H1/00A61P35/02
Inventor 付瑞新黎维勇周媛
Owner 武汉伯瑞恒医药科技有限公司
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