Substituted purrocoline compound and preparation method and application thereof

A compound, C3-C7 technology, applied to substituted indolizine compounds and preparation thereof, in the field of pharmaceutical compositions of the compounds, can solve the problems of not developing antiviral drugs and the like, achieve effective drugs, inhibit virus replication Effect

Inactive Publication Date: 2013-05-08
PEKING UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] For the HIV-1 regulatory protein, people have carried out a series of anti-HIV virus research, but so far no antiviral drugs targeting the regulatory protein have been developed

Method used

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  • Substituted purrocoline compound and preparation method and application thereof
  • Substituted purrocoline compound and preparation method and application thereof
  • Substituted purrocoline compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1, Synthesis of 7-(2-pyridineformyl)-3-(pyridin-2-yl-methylcarbamoyl)-indolizine-1-carboxylic acid ethyl ester (1)

[0058] The compound 7-(2-pyridinecarbonyl)-3-benzyl carboxylate-indolizine-1-carboxylate ethyl ester (0.8g, 1.8mmol) was dissolved in tetrahydrofuran (THF) (20mL), ethanol (20mL) and In the mixed solution of water (5mL), add lithium hydroxide monohydrate (LiOH·H 2 O) (0.23g, 0.54mmol) react overnight at room temperature, evaporate the solvent under reduced pressure, add 1N hydrochloric acid solution, precipitate a solid, filter, and wash with water to give a yellow solid 7-(2-pyridineformyl)-1-carboethoxy-3 -Carboxylic acid indolizine 0.54g; yield: 88.5%; directly used in the next step without purification.

[0059] Dissolve the product 7-(2-pyridineformyl)-1-carbocarboxylate-3-indolizine (101mg, 0.3mmol) in THF (20mL), add EDC (86mg, 0.45mmol) successively, HOBt (61mg, 0.45mmol), DIPEA (77mg, 0.6mmol) and 2-aminomethylpyridine (39mg, 0.36mmol),...

Embodiment 2

[0060] Example 2, Synthesis of 7-(2-pyridineformyl)-3-(pyridin-3-yl-methylcarbamoyl)-indolizine-1-carboxylic acid ethyl ester (2)

[0061] Using 7-(2-pyridineformyl)-3-carbocarboxylate-indolizine-1-carboxylic acid ethyl ester and 3-aminomethylpyridine as starting materials, according to the similar method of Example 1, the compound was synthesized 2. Yield: 78.1%; Mp: 135-137°C; 1 H NMR (400MHz, CDCl3 )δ9.72(d,J=7.4Hz,1H),9.18(s,1H),8.76(d,J=3.1Hz,1H),8.63(s,1H),8.54(d,J=2.8Hz, 1H), 8.11(d, J=7.8Hz, 1H), 7.95(t, J=7.7Hz, 1H), 7.81(s, 1H), 7.75(d, J=7.8Hz, 1H), 7.61(d, J=7.3Hz,1H),7.54(t,J=5.9Hz,1H),7.30(t,J=5.5Hz,1H),6.90(d,J=4.3Hz,1H),4.69(d,J= 5.1Hz, 2H), 4.33(q, J=6.8Hz, 2H), 1.34(t, J=7.0Hz, 3H); 13 C NMR (100MHz, CDCl 3 )δ191.2, 164.0, 161.3, 154.7, 149.5, 149.3, 148.7, 137.5, 136.4, 135.9, 134.1, 131.6, 127.8, 126.8, 125.2, 125.0, 123.9, 120.1, 118.9, 110.4, 10.5, IES -MS m / z:429.0[M+H] + ;Anal.Calcd.for C 24 h 20 N 4 o 4 :C,67.00;H,4.692;N,12.93;Found:C,67.28;...

Embodiment 3

[0062] Example 3, Synthesis of 7-(2-pyridineformyl)-3-(benzylcarbamoyl)-indolizine-1-carboxylic acid ethyl ester (3)

[0063] Using 7-(2-pyridineformyl)-3-benzyl carboxylate-indolizine-1-carboxylate ethyl ester and benzylamine as starting materials, according to the similar method of Example 1, compound 3 was synthesized, and the yield : 78.1%; Mp: 170-173°C; 1 H NMR (400MHz, CDCl 3 )δ9.74(d,J=7.3Hz,1H),9.18(s,1H),8.77(s,1H),8.10(d,J=7.8Hz,1H),7.94(t,J=7.8Hz, 1H),7.74(s,1H),7.60(d,J=7.4Hz,1H),7.56–7.48(m,1H),7.41-7.28(m,5H),6.51(s,1H),4.66(d ,J=4.9Hz,2H),4.33(q,J=6.7Hz,2H),1.34(t,J=7.0Hz,3H); 13 C NMR (100MHz, CDCl 3 )δ191.2, 164.0, 161.1, 154.8, 148.7, 138.2, 137.5, 136.3, 131.4, 129.1, 128.1, 127.9, 127.9, 126.8, 125.3, 125.0, 119.7, 119.2, 113.6, 109, 43.6, IES, 60.5; m / z:428.0[M+H] + ;Anal.Calcd.for C 25 h 21 N 3 o 4 : C, 70.09; H, 4.936; N, 9.755; Found: C, 70.25; H, 4.95; N, 9.83.

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Abstract

The invention discloses a substituted purrocoline compound shown as a formula (I) and a preparation method and application thereof. The definition of each substituent group in the formula (I) is detailed in the specification. The experimental data proves that the compound has the function of inhibiting the VIF (virus infection factor) activity due to the interaction of inhibiting VIF / ElonginC and has the function of inhibiting virus replication. The compound with the acting mechanism is expected to reduce the tolerance problem in the HIV (human Immunodeficiency virus) treatment process, and a novel medicine is provided for treatment of a HIV patient.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a substituted indolizine compound, a preparation method thereof and an antiviral application thereof. Furthermore, the invention also relates to pharmaceutical compositions of said compounds. Background technique [0002] At present, the anti-HIV drugs approved by the FDA all target the structural proteins encoded by Pol and Env. The application of these drugs causes virus mutation and drug resistance to become more and more serious, which leads to the failure of treatment. The invention of highly active antiretroviral therapy (HAATR) has greatly improved the effectiveness of treatment and significantly reduced AIDS morbidity and mortality. But so far none of the drugs, either alone or in combination, can completely clear the virus from a patient's body. If the targets of HIV treatment can be expanded, the development of drugs targeting HIV-1 regulatory proteins and accessory...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/444A61K31/437A61K31/551A61K31/496A61K31/5377A61P31/18
Inventor 张亮仁于湘晖黄文林左陶杨振军张礼和
Owner PEKING UNIV
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