Indole guanidine compound as well as preparation method and application thereof

A compound, the technology of indoguanidine, applied in the field of preparation of indoguanidine compounds

Active Publication Date: 2021-12-28
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, hybrids containing both an indole skeleton and a guanidine group have rarely been reported.

Method used

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  • Indole guanidine compound as well as preparation method and application thereof
  • Indole guanidine compound as well as preparation method and application thereof
  • Indole guanidine compound as well as preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0035] see figure 1 , the preparation method of the indoguanidine compound containing fatty acid ester of above-mentioned structure, comprises the following steps:

[0036] 1) thiosemicarbazide reacts with ethyl bromide to prepare thiobarbituric acid ethyl hydrazide;

[0037] 2) N-valeryl hydrazide carboxyxime amide is prepared by reacting ethyl thiobarbituryl hydrazide with pentylamine;

[0038] 3) Preparation of (E)-2-((5-hydroxy-1H-indol-3-yl)methylene)-N - Amylhydrazine-1-carboxamide;

[0039] 4) Condensation of (E)-2-((5-hydroxy-1H-indol-3-yl)methylene)-N-pentylhydrazine-1-carboxamide with fatty acid to generate indoguanidine containing fatty acid ester class of compounds.

[0040] The specific process of the step 1) is: add thiosemicarbazide and absolute ethanol into an eggplant-shaped bottle, heat up the oil bath to 55-65°C, then add bromoethane to react for 5-7h, after the reaction is completed, the reaction system Cool to room temperature, wait for a large amount...

Embodiment 1

[0046] A kind of indoguanidine compound, R is , the preparation method is as follows:

[0047] 1) Synthesis of ethyl thiobarbiturohydrazide: 2g of thiosemicarbazide (21.95mmol) and 40mL of absolute ethanol were added to a 100mL eggplant-shaped bottle, the oil bath was heated to 60°C, and 3.588g of bromoethane ( 32.925mmol) for 6h. After the reaction was completed, the reaction system was cooled to room temperature, and a large amount of white solid was precipitated in the bottle, filtered, and the filter cake was washed with anhydrous ether and dried to constant weight to obtain white crystal ethyl thiobarbiturohydrazide with a yield of 97%. EI-MS(m / z):120[M] - .

[0048] 2) Synthesis of N-valeryl hydrazide carboximide: add 1 g of ethyl thiobarbituryl hydrazide (8.390 mmol) and 20 mL of methanol into a 100 mL eggplant-shaped bottle, heat the oil bath to 65°C, and add 0.878 g of n-pentyl hydrazide Amine (10.068mmol), reflux for 5h. After the reaction was completed, the so...

Embodiment 2

[0052] A kind of indoguanidine compound, R is , the preparation method is as follows:

[0053] 1) Step 1) to step 4) are the same as in Example 1, except that 5-hexynoic acid is replaced by 6-heptynoic acid to obtain white solid compound 2 ((E)-3-((2-(N -Verylcarbamoyl)hydrazone)methyl)-1H-indol-5-ylhept-6-ynoate, yield 40%; EI-MS(m / z):396[M] - ;394[M] + . Purity: 97.560%. 1 H NMR(400MHz,DMSO)δ11.85(s,1H),11.35(s,1H),8.38(s,1H),7.95(d,J=3.7Hz,1H),7.77(s,1H),7.67 (s,1H),7.45(d,J=8.7Hz,1H),6.94(dd,J=8.7,2.2Hz,1H),3.28(d,J=4.9Hz,2H),2.80(t,J= 2.6Hz, 1H), 2.61(t, J=7.4Hz, 2H), 2.50(s, 1H), 2.23(td, J=6.9, 2.6Hz, 2H), 1.76(dt, J=15.2, 7.4Hz, 2H),1.61–1.57(m,2H),1.55(d,J=2.8Hz,2H),1.36–1.29(m,4H),0.89(t,J=6.5Hz,3H).

[0054] The synthesis steps of compound 3 are the same as those in Example 1, except that 5-hexynoic acid is replaced by levulinic acid.

[0055] Compound 3, white solid, yield 42%. EI-MS(m / z):386[M] - ;384[M] + . Purity: 95.996%; 1 HNMR(400MHz,DMSO)δ11.85...

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Abstract

The invention relates to an indole guanidine compound as well as a preparation method and application thereof. The preparation method comprises the following steps: (1) subjecting N-valeryl hydrazide carboxyoxime amide to reacting with 5-hydroxyindole-3-formaldehyde to prepare (E)-2-((5-hydroxy-1H-indol-3-yl)methylene)-N-pentylhydrazine-1-carboxamide; and (2) carrying out condensation on the (E)-2-((5-hydroxy-1H-indol-3-yl)methylene)-N-pentylhydrazine-1-carboxamide and fatty acid to generate the indole guanidine compound. According to the invention, 5-hydroxyindole-3-formaldehyde is used as a basic skeleton, a 3-site aldehyde group is converted into imine, a pentylguanidine side chain is introduced, a 5-site hydroxyl group and fatty acids with different structure types are subjected to esterification, and a series of fatty acid ester-containing indole guanidine compounds are synthesized through nucleophilic substitution, condensation and other reactions. The compound can be applied to preparation of antitumor drugs and has inhibitory activity.

Description

technical field [0001] The invention belongs to the technical field of preparation of indoguanidine compounds, and relates to an indoguanidine compound and its preparation method and application. Background technique [0002] Indole is an important class of drug skeletons with a wide range of pharmacological activities, such as antitumor, antihistamine, antibacterial, antioxidant, anticonvulsant, anti-inflammatory and analgesic, etc. Guanidine group is an important class of pharmacophore, which widely exists in various drug structures, such as antihypertensive drug clonidine hydrochloride, hypoglycemic drug metformin hydrochloride, antiviral drug morpholine hydrochloride, etc. However, hybrids containing both indole skeleton and guanidine group are rarely reported. Therefore, based on the drug design strategy of hybrid molecules, the design and synthesis of indoguanidine hybrid molecules is expected to discover new drug candidates with significant anti-tumor activity and ex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14A61K31/404A61P35/00
CPCC07D209/14A61P35/00
Inventor 张杰卢闻潘晓艳李靖
Owner XI AN JIAOTONG UNIV
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