(1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof

A compound, triazolo technology, applied in the field of [1,2,4]triazolo[4,3-b][1,2,4]triazine compounds, their preparation and application, to achieve easy raw materials obtained, the reaction conditions are mild, and the raw materials are abundant

Inactive Publication Date: 2012-07-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many compounds that can effectively block the HGF / c-Met signaling pathway have been discovered. A series of small molecule compounds developed by Sugen can inhibit the kinase activity of Met at the nanomolar level (WO2005004607, WO2005004808, WO2005005378 and WO2005010005), But so far there are no reports of the in vivo activity data of these compounds. The SGX126 developed by SGX Company was discontinued due to nephrotoxic phase I clinical research (WO2008051808), the triazolopyridazine compound JNJ-38877605 of Johnson & Johnson (WO2007075567) and the PF-04217903 (US2007265272) has entered the first phase of clinical research. In addition, there are multiple multi-target tyrosine kinase inhibitors that can effectively block the HGF / c-Met signal transduction pathway and have entered clinical research. However, there is still no such Small molecule c-Met tyrosine kinase inhibitors are on the market, so it is necessary to find more safe and effective inhibitors

Method used

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  • (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof
  • (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof
  • (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] 3-(6-Quinolinylmethyl)-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine (I-1)

[0065]

[0066] Step 1: 2-oxo-2-phenylacetaldehyde (Ⅲ-1)

[0067] Add 14 grams of selenium dioxide, 62 milliliters of dioxane and 2.5 milliliters of water into a 100 milliliter round bottom flask, heat and stir at 50° C. until the selenium dioxide dissolves, add 15 grams of acetophenone, and cool the reaction solution after reflux for 4 hours. After filtration, the solvent was removed under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate:petroleum ether=1:5) to obtain a white solid product III-1, weighing 9.8 g, with a yield of 58.5%. Mp 120-122°C. 1 H-NMR (300Hz, CDCl 3 -d 6 )δ: 9.67 (s, 1H), 8.04-8.15 (m, 2H), 7.53-7.66 (m, 3H).

[0068] Step 2: 2,2-diethoxyacetophenone (IV-1)

[0069] Dissolve 5.58 g of 2-oxo-2-phenylacetaldehyde (Ⅲ-1), 12.34 g of triethyl orthoformate, and 400 mg of p-toluenesulfonic acid in 40 ml of dichloromethane, stir and ...

Embodiment 2

[0082] 3-(6-quinolinemethyl)-6-(4-benzyloxyphenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (Ⅰ -2)

[0083]

[0084] Step 1: 2-oxo-2-(4-benzyloxyphenyl)acetaldehyde (Ⅲ-2)

[0085] Dissolve 21.82 g of 4-benzyloxyacetophenone in 200 ml of DMSO, slowly drop into 33 ml of 48% hydrobromic acid with stirring at room temperature, heat and stir at 70°C for 8 hours after dropping, cool the reaction solution, and pour it into 200 ml Suction filter in ice water, wash the filter cake with water, and dry to obtain the white solid product III-2, weighing 21.47 g, with a yield of 92.7%. 1 H-NMR (300Hz, DMSO-d 6 )δ: 8.05(d, J=9.0Hz, 2H), 7.34-7.48(m, 5H), 7.13(d, J=9.0Hz, 2H), 5.22(s, 2H).

[0086] Step 2: 2,2-diethoxy-1-(4-benzyloxyphenyl)ethanone (IV-2)

[0087] Replace 2-oxo-2-phenylacetaldehyde (Ⅲ-1) with 2-oxo-2-(4-benzyloxyphenyl)acetaldehyde (Ⅲ-2), and the remaining raw materials, reagents and preparation The method is the same as step 2 in Example 1 to obtain pale yellow oily liq...

Embodiment 3

[0099] 3-(6-quinolinemethyl)-6-(2-thienyl)[1,2,4]triazolo[4,3-b][1,2,4]triazine (I-3)

[0100]

[0101] Step 1: 2-oxo-2-(2-thienyl)acetaldehyde (Ⅲ-3)

[0102] Acetophenone is replaced with 2-thienyl ethyl ketone, and all the other required raw materials, reagents and preparation methods are the same as step 1 in Example 1 to obtain yellow solid product 2-oxo-2-(2-thienyl)acetaldehyde ( III-3).

[0103] Step 2: 2,2-diethoxy-1-(2-thienyl)ethanone (IV-3)

[0104] Replace 2-oxo-2-phenylacetaldehyde (Ⅲ-1) with 2-oxo-2-(2-thienyl)acetaldehyde (Ⅲ-3), and the rest of the required raw materials, reagents and preparation methods are implemented in the same way Step 2 in Example 1 gave the product IV-3 as a pale yellow oily liquid. 1 H-NMR (300Hz, CDCl 3 -d 6 )δ: 8.06(d, J=5.4Hz, 1H), 7.66(dd, J=0.9, 4.8Hz, 1H), 7.14(m, 1H), 5.12(s, 1H), 3.63-3.78(m, 4H ), 1.23-1.28(m, 6H).

[0105] Step 3: 3-Methylthio-6-(2-thienyl)-1,2,4-triazine (V-3)

[0106] Replace 2,2-diethoxyacetophen...

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Abstract

The invention relates to (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds which are of a novel structure and are shown in a formula (I) or formula (II), and a pharmaceutical salt, a prodrug, a hydrate or a solvate thereof, a preparation method of the compounds, a pharmaceutical composition containing the treatment effective dose of the compound and an application of the compound as a protein tyrosine kinase inhibitor, especially as a c-Met inhibitor, in the preparation of medicaments for preventing and / or treating c-Met abnormality-related diseases.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to [1,2,4]triazolo[4,3-b][1,2,4]triazine compounds, pharmaceutically acceptable salts thereof, and prodrugs thereof And its hydrate or solvate, also relates to the preparation method of said compound, the pharmaceutical composition containing said compound and its as protein tyrosine kinase inhibitor, especially as c-Met inhibitor, in the preparation prevention and / or use in medicines for treating diseases related to c-Met abnormality. Background technique [0002] The treatment of malignant tumors has been a worldwide problem for a long time and has been a serious threat to human life. Although the diagnosis and treatment level has been improved, the survival rate of many tumor patients has been very low. Several new anti-tumor targets have been discovered in recent years, among which protein tyrosine kinase has become a new promising anti-tumo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/53A61P35/00A61P35/02
CPCC07D401/14C07D401/12C07D487/04A61K31/4196C07D401/06C07D403/14C07D409/14C07D403/06A61P35/00A61P35/02A61P43/00A61K31/53
Inventor 段文虎耿美玉陈方艾菁陈奕詹正生吕永聪王英丁健
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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