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2,8,9-trisubstituted-9h-purine compound and its salt and application

A technology of purines and compounds, applied in the field of anticancer drugs, can solve the problem of decreased effect of osimertinib and achieve significant antitumor activity in vivo

Active Publication Date: 2020-04-28
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, after osimertinib was used for about 10 months, it was found that the third site of EGFR had a mutation, namely C797S, resulting in acquired drug resistance, which significantly reduced the effect of osimertinib

Method used

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  • 2,8,9-trisubstituted-9h-purine compound and its salt and application
  • 2,8,9-trisubstituted-9h-purine compound and its salt and application
  • 2,8,9-trisubstituted-9h-purine compound and its salt and application

Examples

Experimental program
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preparation example Construction

[0034] The synthetic method of 2,8,9-trisubstituted-9H-purine compounds, the synthetic route is as follows figure 1 shown, including the following steps:

[0035] Step 1: Reference (J.Med.Chem.2012,55,10685-10699) to synthesize compound A, A was refluxed together with carbon disulfide and potassium hydroxide in ethanol / water (10:1) to obtain intermediate B;

[0036] Step 2: Under the catalysis of ketone iodide, intermediate B and iodobenzene were stirred in dimethyl sulfoxide at 140°C for 24 hours to obtain product C, namely 8-phenylthio-2,9-disubstituted-9H -purine compounds; or, in the presence of potassium carbonate, intermediate B and benzyl bromide are stirred and refluxed in acetone for 4h to obtain product D, that is, 8-benzylthio-2,9-disubstituted-9H-purines compound;

[0037] Step 3: C is oxidized by m-chloroperoxybenzoic acid in dichloromethane to obtain product D, namely 8-benzenesulfinyl-2,9-disubstituted-9H-purine compound.

Embodiment 1

[0039] Example 1: 2-(4-(4-methyl-1-piperazinyl)anilino)-8-phenylthio-9-(2H-4-tetrahydropyranyl)-9H-purine (structural formula 1) Synthesis of:

[0040] Step 1: Synthesis of 2-(4-(4-methyl-1-piperazinyl)anilino)-8-mercapto-9-(2H-4-tetrahydropyranyl)-9H-purine (B1)

[0041]

[0042] Reference J. Med. Chem. 2012, 55, 10685-10699 to prepare A1. A1 (0.40g), carbon disulfide (95mg), potassium hydroxide (70mg), ethanol (20mL) and water (2mL) were added to a 100mL eggplant-shaped bottle, the mixture was heated to reflux for 3h, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography Separation (dichloromethane:methanol=20:1) gave intermediate B1 (0.40g) with a yield of 90.3%.

[0043] Step 2: 2-(4-(4-methyl-1-piperazinyl)anilino)-8-phenylthio-9-(2H-4-tetrahydropyranyl)-9H-purine (structural formula 1 )Synthesis

[0044]

[0045]Add B1 (0.20 g), iodobenzene (80 μL), cuprous iodide (6.7 mg), potassium carbonate (0.20 g)...

Embodiment 2

[0046] Example 2: 2-(4-(N-methyl-2-dimethylaminoethylamino)anilino)-8-phenylthio-9-(2H-4-tetrahydropyranyl)-9H-purine (Structural formula 2) synthesis:

[0047]

[0048] Reference J. Med. Chem. 2012, 55, 10685-10699 to prepare A2. The synthesis of B2 is the same as that of B1. Compound 2 was synthesized by replacing B1 with B2, and the process was the same as that of compound 1. Yield 55.3%. 1 H NMR (400MHz, CDCl 3 )δ8.69(s,1H,Ar-H),7.52(s,1H,Ar-H),7.50(d,J=2.3Hz,2H,Ar-H),7.49–7.47(m,1H,Ar-H) -H),7.41–7.34(m,3H,Ar-H),6.77(d,J=9.0Hz,2H,Ar-H),4.71–4.62(m,1H,CH),4.11(dd,J= 11.5, 4.2Hz, 2H, CH×2), 3.48–3.45(m, 2H, CH 2 ), 3.42(d, J=11.7Hz, 2H, CH×2), 2.96(s, 3H, CH 3 ),2.95–2.86(m,2H,),2.55–2.47(m,2H,CH 2 ),2.31(s,6H,CH 3 ×2), 1.55(dd, J=12.4, 2.5Hz, 2H, CH×2).

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Abstract

The invention provides 2,8,9-trisubstituted-9H-purine compounds, and salts and application thereof, belonging to the technical field of anticancer drugs. The compounds have novel structures and the activity of inhibiting epidermal growth factor receptor (EGFR) tyrosine kinase; the compounds have significant inhibitory activity against single-mutation (L858R) EGFR and show obvious in-vivo and in-vitro antitumor activity; the compounds can be used for treatment of cancers associated with EGFR mutations; raw materials for synthesis of the compounds are easily available, and synthesis methods forthe compounds are easy to implement.

Description

technical field [0001] The invention belongs to the technical field of anticancer drugs, and in particular relates to a 2,8,9-trisubstituted-9H-purine compound and its salt and application. Background technique [0002] Cancer is one of the malignant diseases that seriously threaten human health. In the past 30 years, the incidence of cancer in my country has been in a period of rapid rise. The incidence of cancer is about 2 million per 100,000 people. Every year, there are more than 3.2 million new cases, about 2.7 million deaths, and more than 7 million patients under treatment. [0003] At present, the main treatment methods for cancer are still surgical treatment, radiotherapy and drug treatment, but to a large extent, drug treatment is still the main treatment. Therefore, it is of great significance to research and develop new anticancer drugs. [0004] Traditional antitumor drugs have strong activity, but lack of selectivity and high toxicity. In recent years, with ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/32A61K31/52A61P35/00
CPCC07D473/32
Inventor 张三奇黑媛媛张浩王瑾曹永孝辛敏行吕社民
Owner XI AN JIAOTONG UNIV
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