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Dolutegravir derivative with biological activity as well as preparation method and application thereof

A technology of biological activity and derivatives, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problems of reducing human immunity and susceptibility of patients to various tumors, so as to achieve method optimization, increase yield, and expand application range effect

Active Publication Date: 2021-10-22
NANKAI UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because HIV will reduce the body's immunity, which in turn will cause patients to be prone to various tumors, and the current research on dolutegravir is mainly in the anti-HIV aspect, and it has not been found that it can be applied to treat other diseases

Method used

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  • Dolutegravir derivative with biological activity as well as preparation method and application thereof
  • Dolutegravir derivative with biological activity as well as preparation method and application thereof
  • Dolutegravir derivative with biological activity as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068]

[0069] Add compound 1 (30g) into 100mL of anhydrous formic acid, and heat to 65°C under the protection of argon; after reacting for about 3 hours, add 150mL of acetonitrile after concentration, stir to dissolve, add 12.5g of R-3-aminobutanol, Stir for 10 minutes; raise the temperature to reflux and stir for 2 hours; add 200 mL of dichloromethane after vacuum concentration and steaming, add 100 mL of water while stirring, then add 2N hydrochloric acid to adjust the pH of the reaction solution to 1-2, separate the lower organic phase after stirring for 10 minutes, and separate the upper layer of water The phase was extracted three times with 50 mL of dichloromethane, and the combined organic phases were concentrated to obtain compound 2 (25.5 g); 1 H NMR (400MHz, CDCl 3 ):δ8.43(s,1H),5.30(t,J 1 =4.0Hz,J 2 =4.0Hz,1H),5.02(t,J 1 =4.0Hz,J 2 =8.0Hz,1H),4.41(dd,J 1 =4.0Hz,J 2 =4.0Hz,1H),4.27(dd,J 1 =8.0Hz,J 2 =4.0Hz,1H),4.08(s,3H),4.03-3.99(m,2H),2.25-2.16(m,1H),1...

Embodiment 2

[0071]

[0072] Add compound 1 (30g) into a mixture of 70mL of anhydrous formic acid and 40mL of anhydrous acetic acid, and heat to 65°C under the protection of argon; -12.5g of 3-aminobutanol, stirred for 10min; heated to 80°C and stirred for 8h; after vacuum concentration and steaming, 200mL of dichloromethane was added, and 100mL of water was added under stirring, and the lower organic phase was separated after stirring for 10min, and the upper aqueous phase was washed with distilled water Extracted three times with 50 mL of methyl chloride, combined the organic phases, and concentrated to obtain pure compound 2 (23.1 g); 1 H NMR (400MHz, CDCl 3 ):δ8.43(s,1H),5.30(t,J 1 =4.0Hz,J 2 =4.0Hz,1H),5.02(t,J 1 =4.0Hz,J 2 =8.0Hz,1H),4.41(dd,J 1 =4.0Hz,J 2 =4.0Hz,1H),4.27(dd,J 1 =8.0Hz,J 2=4.0Hz,1H),4.08(s,3H),4.03-3.99(m,2H),2.25-2.16(m,1H),1.56(d,J=12.0Hz,1H),1.39(d,J= 8.0Hz, 3H).

Embodiment 3

[0074]

[0075] Add compound 1 (30g) and 24g of benzenesulfonic acid into 300mL of acetonitrile, heat to 70°C under the protection of argon; after reacting for about 5h, add 18g of R-3-aminobutanol, stir for 10min; heat up to 80°C and stir the reaction 3.5h; add 200mL of dichloromethane after vacuum concentration and steaming, add 150mL of water under stirring, separate the lower organic phase after stirring for 10min, extract the upper layer of water phase with 50mL of dichloromethane three times, combine the organic phases, wash with 40mL of saturated saline for 3 Then concentrated to obtain the crude product, finally recrystallized and purified in methanol to obtain pure compound 2 (19.1g); 1 H NMR (400MHz, CDCl 3 ):δ8.43(s,1H),5.30(t,J 1 =4.0Hz,J 2 =4.0Hz,1H),5.02(t,J 1 =4.0Hz,J 2 =8.0Hz,1H),4.41(dd,J 1 =4.0Hz,J 2 =4.0Hz,1H),4.27(dd,J 1 =8.0Hz,J 2 =4.0Hz,1H),4.08(s,3H),4.03-3.99(m,2H),2.25-2.16(m,1H),1.56(d,J=12.0Hz,1H),1.39(d,J= 8.0Hz, 3H).

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Abstract

The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a dolutegravir derivative with biological activity and a preparation method thereof. The structural formula of the derivative is shown in the specification, wherein R1 is methyl or hydrogen; R2 is methyl, isopropyl, phenyl, benzyl, a nitrogen-containing heterocyclic ring, a sulfur-containing heterocyclic ring or an oxygen-containing heterocyclic ring; and R3 is hydrogen, methyl, ethyl, phenyl, benzyl, a nitrogen-containing heterocyclic ring, a sulfur-containing heterocyclic ring or an oxygen-containing heterocyclic ring. The preparation method comprises the following steps of: deprotecting 1-(2, 2-dimethoxyethyl)-1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester to obtain aldehyde, cyclizing the aldehyde with aminobutanol, then carrying out acylation reaction on the cyclized aldehyde and an amino compound, and finally carrying out click reaction with azide to obtain a target compound. The derivative provided by the invention has proliferation inhibition activity on human tumor cells.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a biologically active dolutegravir derivative and a preparation method and application thereof. Background technique [0002] Human immunodeficiency virus (HIV) was first discovered in the United States in 1981. It is a lentivirus that infects cells of the human immune system and belongs to the category of retroviruses. The virus destroys the immune ability of the human body, causing the immune system to lose its resistance, which leads to the survival of various diseases and cancers in the human body, and finally leads to AIDS, that is, acquired immunodeficiency syndrome. So far, there is no effective cure. Highly Active Antiretroviral Therapy (HAART) is a routine treatment for AIDS, which uses a combination of a basic drug and two nucleoside reverse transcriptase inhibitors. Integrase inhibitors exert anti-HIV activity by inhibiting the integration of...

Claims

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Application Information

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IPC IPC(8): C07D498/14A61P35/00
CPCC07D498/14A61P35/00
Inventor 李月明毛龙飞吴琼汪贞贞孙秀伟刘晓斐姚小军王文君王育伟
Owner NANKAI UNIV
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