Triazolotetrazine compound containing morpholine and quinoline rings as well as preparation method and application thereof

A compound and quinoline ring technology, applied in the field of drug synthesis, can solve the problems of less anti-tumor activity and unpredictable drug activity of unknown compounds, and achieve the effects of easy availability of reaction reagents, excellent biological activity, and fewer by-products.

Active Publication Date: 2021-12-14
TAIZHOU VOCATIONAL & TECHN COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Another example is the triazole-tetrazine derivative compound disclosed in the patent document (publication number: CN103012410B), which also exhibits certain in vitro antitumor activity. Active ones are still less, and the drug activity of unknown compounds cannot be predicted

Method used

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  • Triazolotetrazine compound containing morpholine and quinoline rings as well as preparation method and application thereof
  • Triazolotetrazine compound containing morpholine and quinoline rings as well as preparation method and application thereof
  • Triazolotetrazine compound containing morpholine and quinoline rings as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The triazolotetrazine compound containing morpholine and quinoline rings of the present invention is characterized in that the structural formula of the compound is as shown in formula I below:

[0034]

[0035] In the above formula I, the substituent R is selected from hydrogen, halogen, alkoxy, benzyloxy or trihaloalkyl, where the halogen can be chlorine, bromine or fluorine, preferably substituted by fluorine, alkoxy long-chain alkoxy A group such as an alkoxy group with more than 5 C atoms or a short-chain alkoxy group is good C 1 -C 4 Alkoxy groups, such as methoxy, ethoxy or propoxy groups; trihaloalkyl groups are preferably trifluoromethyl, trifluoroethyl and other groups. The compounds screened above all have good anti-tumor activity and inhibit the activity of tumor cells, so as to achieve the expected goal of prevention or treatment. Compared with the antitumor activity of cisplatin, it can also achieve comparable or better activity performance. For abov...

Embodiment 2

[0045] The compound of this example is 4-(3-((quinoline-4-oxyl)methyl)-1,2,4]triazol[4,3-b][1,2,4,5]tetra Oxyzin-6-yl) morpholine, its structural formula is shown in following formula I-1:

[0046]

[0047] The synthesis of the above compounds is shown below:

[0048] Synthesis of intermediate 2-(quinoline-4-propoxy)acetic acid:

[0049] Add 2.47g (32.5mmol) of glycolic acid and 2.52g (45mmol) of potassium hydroxide into a 100mL three-necked flask, heat up to 170°C for sufficient reflux reaction, and then pre-dissolve 2.13g (13mmol) of 4-chloroquinoline in anhydrous After DMSO, the corresponding DMSO solution containing 4-chloroquinoline was formulated, and the DMSO solution containing 4-chloroquinoline was slowly added dropwise to the reaction solution. During the dropping process, the temperature of the reaction system was controlled at 165°C to 170°C. Finally, keep the temperature for heat preservation reaction for 2.5 hours. After the reaction, remove the reaction sol...

Embodiment 3

[0067] The compound of this example is 4-(3-((6-methoxyquinolin-4-yl)oxy)methyl)-[1,2,4]triazol[4,3-b][1 , 2,4,5] tetrazin-6-yl) morpholine, its structural formula is as shown in the following formula I-2:

[0068]

[0069] The synthesis of above-mentioned corresponding compound is as follows:

[0070] Synthesis of intermediate product 2-((6-methoxyquinolin-4-yl)oxy)acetic acid:

[0071] Add 24.7g (325mmol) of glycolic acid and 25.2g (450mmol) of potassium hydroxide into a 1000mL three-necked flask, heat up to about 170°C for sufficient reflux reaction, and then add 25.2g of 4-chloro-6-methoxyquinoline (130mmol) was dissolved in anhydrous DMSO in advance to form a DMSO solution containing 4-chloro-6-methoxyquinoline, and the solution was slowly added dropwise to the reaction solution, and the dropwise process controlled the temperature of the reaction system at 165° C. 170°C. After the dropwise addition, keep the temperature for heat preservation reaction for 2.5 hours. A...

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Abstract

The invention relates to a triazolotetrazine compound containing morpholine and quinoline rings as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The invention aims to provide a novel anti-tumor compound, and provides a triazolotetrazine compound containing morpholine and quinoline rings as well as a preparation method and application thereof. The preparation method of the triazolotetrazine compound comprises the steps that inorganic strong base, glycollic acid and 4-chloroquinoline are subjected to a reaction, and after the reaction is finished, the reaction system is adjusted to be acidic; and a reaction is carried out on an intermediate and 4-(6-hydrazino-1, 2, 4, 5-tetrazine-3-yl) morpholine under the action of a condensing agent, and then a cyclization reaction is carried out under the action of phosphorus oxychloride to obtain the triazolo tetrazine compound containing morpholine and quinoline rings, wherein the triazolo tetrazine compound can be used for preparing drugs or functional foods for treating and resisting tumors. The compound has the advantages of inhibition activity on c-Met kinase, in-vitro anti-tumor activity, short reaction route and easiness in operation.

Description

technical field [0001] The invention relates to a triazolotetrazine compound containing morpholine and quinoline rings, a preparation method and application thereof, and belongs to the technical field of drug synthesis. Background technique [0002] Receptor protein tyrosine kinase c-Met is a high-affinity receptor for hepatocyte growth factor (HGF), encoded by the Met proto-oncogene. After c-Met specifically binds to HGF, the signaling pathway is activated, c-Met first undergoes autophosphorylation at the tyrosine residues near the four phosphorylation sites in the intracellular region, recruits downstream adapter proteins, and then passes through a A series of phosphorylation reactions activate phosphatidylinositol-3 kinase (PI-3K), extracellular regulated protein kinase (ERK1 / 2), phospholipase (PLC-γ), luciferase (STAT) and focal adhesion kinase (FAK) and other important signaling molecules and corresponding signaling pathways, thereby regulating the proliferation, diffe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/00A23L33/10
CPCC07D487/04A61P35/00A23L33/10A23V2002/00A23V2200/308
Inventor 裴天运张轩赫施情宋毛晴晴徐子航张汉卿丁吉翔杨珍珍徐峰柯中炉
Owner TAIZHOU VOCATIONAL & TECHN COLLEGE
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