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Tricyclic compounds and preparation method thereof, and medicinal composition containing compounds and application thereof

A compound and tricyclic technology, applied in the field of condensed tricyclic compounds and their preparation

Inactive Publication Date: 2012-06-20
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] As mentioned above, c-Met tyrosine kinase inhibitors have been reported in many literatures, and some monoclonal antibodies and synthetic small molecule compounds against c-Met or HGF are in phase 1-3 clinical trials. However, due to the well-known Uncertainty in clinical trials, no c-Met or HGF inhibitors have been approved as drugs yet

Method used

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  • Tricyclic compounds and preparation method thereof, and medicinal composition containing compounds and application thereof
  • Tricyclic compounds and preparation method thereof, and medicinal composition containing compounds and application thereof
  • Tricyclic compounds and preparation method thereof, and medicinal composition containing compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0190] 8-[1-(6-quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]-2,3,4,5-tetra Synthesis of Hydrogen-1H-pyridin[4,3-b]indole

[0191]

[0192] Step 1: Synthesis of 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0193]

[0194] The synthesis method described in this step is slightly improved with reference to the Fischer indole synthesis method (J.-P.Hénichart et al J.Heterocycl.Chem.2006, 43, 571-578), and the specific process is as follows: 4-bromophenylhydrazine Hydrochloride (224 mg or 1 mmol) and N-tert-butoxycarbonyl-4-piperidone (199 mg or 1 mmol) were dissolved in 10 ml of saturated ethanol solution of HCl (prepared by drying HCl gas in absolute ethanol) , the solution was refluxed for 3 hours with stirring, and LC-MS showed that the reaction was complete. After cooling to room temperature, the solvent was removed by rotary evaporation, and the crude product was washed with 10 mL of saturated NaHCO 3 The aqueous solution was worked up and extracted w...

Embodiment 2

[0201] 2-methyl-8-[1-(6-quinolylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]-2,3, Synthesis of 4,5-tetrahydro-1H-pyridin[4,3-b]indole

[0202]

[0203] Step 1: Synthesis of {2-methyl-2,3,4,5-tetrahydro-1H-pyridin[4,3-b]indol-8-yl}boronic acid pinacol ester

[0204]

[0205] {2,3,4,5-tetrahydro-1H-pyridin[4,3-b]indol-8-yl}pinacol borate (1.788 g or 6 mmol) was suspended in 15 mL THF and cooled to -78°C, add dropwise 1M NaN(SiMe 3 ) 2 THF solution (30mL or 30mmol). After the addition was complete, it was stirred at -78°C for 30 minutes, and then 2-chloro-N-(2-chloroethyl)-N-methylethylamine hydrochloride solid (1.155 g or 6 mmol) was added. Stirring was continued for 30 minutes after the addition was complete, then raised to room temperature and stirred for two days. TLC showed that the reaction was complete, and 10 mL of 4M hydrochloric acid aqueous solution was carefully added to the pink suspension, then adjusted to pH ≈ 9 with concentrated ammonia, and extracted ...

Embodiment 3

[0209] 8-[1-(6-quinolinylmethyl)-1H-[1,2,3]triazol[4,5-b]pyrazin-6-yl]-3,4-dihydro-1H- Synthesis of pyridin[4,3-b]indole-2(5H)-carbaldehyde

[0210]

[0211] Step 1: 8-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-pyrido[4, Synthesis of 3-b]indole-2(5H)-carbaldehyde

[0212]

[0213] Formic acid (69 mg or 1.5 mmol) and EDC.HCl (288 mg or 1.5 mmol) were suspended in 20 mL of DCM, and diisopropylethylamine (129 mg or 1 mmol) was added dropwise with stirring. After the addition, stir at room temperature for half an hour, add {2,3,4,5-tetrahydro-1H-pyridin[4,3-b]indol-8-yl}pinacol borate (432mg or 1mmol), Stirring was continued for 2 hours. The solvent was removed by rotary evaporation, and the crude product obtained by concentration was chromatographed on a silica gel column (7M NH 3 methanol solution / DCM: 5 / 95) to obtain 280.4 mg of the target product (yield: 86%). Mass Spectrum m / z: 327.08 [M+H + ].

[0214] Step 2: 8-[1-(6-Quinolinylmethyl)-1H-[1,2,...

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Abstract

The invention provides tricyclic compounds shown as a formula (I), and also discloses a preparation method and application for the compounds and a medicinal composition containing the compounds. The compounds are protein kinase inhibitors and can be used for treating diseases caused by abnormality of protein kinase activity, such as tumors and the like.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a condensed tricyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound and an application thereof. Background technique [0002] Cancer and cardiovascular disease are two major diseases that seriously threaten human health and life. In particular, the incidence and mortality of cancer have been rising rapidly in recent years, surpassing cardiovascular disease to become the number one killer of human health. [0003] The proliferation, apoptosis, and metastasis of tumors are closely related to the abnormality of a certain link in a series of signal transduction pathways inside and outside cells. An important class of molecules in these signal transduction pathways are protein kinases. The abnormality of protein kinase activity is not only directly related to tumors, but also the main cause of a series of other h...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D471/04A61K31/4985A61K31/5025A61K31/519A61K31/52A61K31/4709A61P35/00A61P35/02A61P17/06A61P1/16A61P3/10A61P9/00A61P27/02A61P29/00A61P19/02A61P37/00A61P13/12
Inventor 张嘉杰朱正光李中皇王广发金宏田元新万山河叶连宝游文玮吴曙光
Owner SOUTHERN MEDICAL UNIVERSITY
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