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no 2 -Substituted alkoxy aromatic ring-2-aminopyrimidine derivatives and their application

An aminopyrimidine and derivative technology, applied in the application of antitumor drugs, N2-substituted alkoxy aromatic ring-2-aminopyrimidine derivatives and optical isomers or salts thereof, can solve the problem of secondary resistance Drugs, off-targets, side effects and other problems, to overcome drug resistance and reduce toxic side effects

Active Publication Date: 2021-12-21
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main problems facing FLT3 small molecule inhibitors are drug resistance and toxic side effects
The first-generation FLT3 inhibitors were originally developed for other targets and indications, which are prone to off-targets, which will cause some side effects, and because of dose-limiting toxicity, monotherapy is not effective
These inhibitors generally show good inhibitory activity in the pre-clinical phase, but are not effective when used in AML patients in the clinical phase I / II
The second-generation FLT3 inhibitors are obtained through rational drug design, and their selectivity is better than that of the first-generation FLT3 inhibitors. At present, there are few second-generation FLT3 inhibitors that have entered the clinic. The main problems encountered are drug resistance caused by mutations. Drug resistance and some toxic side effects, such as quizartinib has the disadvantages of myelosuppression, QTc interval prolongation, and drug resistance due to mutations such as D835 and F691 after medication

Method used

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  • no <sup>2</sup> -Substituted alkoxy aromatic ring-2-aminopyrimidine derivatives and their application
  • no <sup>2</sup> -Substituted alkoxy aromatic ring-2-aminopyrimidine derivatives and their application
  • no <sup>2</sup> -Substituted alkoxy aromatic ring-2-aminopyrimidine derivatives and their application

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0107] Preparation Example 1 N 4 -(piperidin-4-ylmethyl)-N 2 -(6-(2-(pyrrol-1-yl)ethoxy)pyridin-3-yl)-5-trifluoromethylpyrimidine-2,4-diamine (compound 1)

[0108]

[0109] Step 1. 4-Chloro-5-trifluoromethyl-2-aminopyrimidine (1-2)

[0110]

[0111] Dissolve 2,4-dichloro-5-trifluoromethylpyrimidine (6.5g, 30.0mmol) in acetonitrile (30mL), slowly add ammonia water (20mL) dropwise under ice-cooling, after the dropwise completion, move to room temperature to react for 40min, reduce The solvent was recovered by pressure distillation to obtain a residue. Purified by silica gel column chromatography using PE:EA (6:1) as the eluent to obtain white solid 1-2. Yield: 46%; 1 H NMR (500MHz, CDCl 3 )δ8.47 (s, Ar-H, 1H), 5.57 (s, NH, 2H); ESI-MS: m / z=217[M+H] + .

[0112] Step 2. 1-Boc-4-(((2-Amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)piperidine (1-3)

[0113]

[0114] Intermediate 1-2 (593mg, 3.0mmol) was dissolved in anhydrous methanol (12mL), followed by addin...

preparation Embodiment 2

[0121] Preparative Example 2N 4 -Methyl-N 2 -(6-(2-(pyrrol-1-yl)ethoxy)pyridin-3-yl)-5-trifluoromethylpyrimidine-2,4-diamine (compound 2)

[0122]

[0123] Step 1.N 4 Synthesis of -methyl-5-trifluoromethylpyrimidine-2,4-diamine(1-6)

[0124] Synthetic steps Referring to step 2 of Example 1, compound 1-6 was prepared by replacing 1-Boc-4-aminomethylpiperidine with methylamine hydrochloride salt. Yield: 73%; 1 H NMR (500MHz, DMSO-d 6 )δ7.95(s,Ar-H,1H),6.75–6.74(m,NH×3,3H),2.82 (d,J=4.5Hz,CH 3 ,3H); ESI-MS: m / z=193[M+1] + .

[0125] Step 2.N 4 -Methyl-N 2 Synthesis of -(6-(2-(pyrrol-1-yl)ethoxy)pyridin-3-yl)-5-trifluoromethylpyrimidine-2,4-diamine (compound 2)

[0126]

[0127] Synthetic steps Referring to Step 4 of Example 1, compound 2 was prepared by substituting 1-3 for 1-6. Yield: 35%; 1 H NMR (500 MHz, DMSO-d 6 )δ9.49(s,NH,1H),8.54–8.43(m,Ar-H,1H),8.14(s,Ar-H,1H),8.01(dd,J=9.0,3.0Hz,Ar-H ,1H),7.08(d,J=5.5Hz,NH,1H),6.76(d,J=9.0Hz,Ar-H,1H),4.30(t,J=6.0Hz,C...

preparation Embodiment 3

[0128] Preparation Example 3N 2- (6-(2-(pyrrol-1-yl)ethoxy)pyridin-3-yl)-N 4 -((tetrahydropyran-4-yl)methyl)-5-trifluoromethylpyrimidine-2,4-diamine (compound 3)

[0129]

[0130] Step 1.N 4 Synthesis of -((tetrahydropyran-4-yl)methyl-5-5-trifluoromethylpyrimidine-2,4-diamine(1-7)

[0131]

[0132] Synthetic steps Referring to step 2 of Example 1, compound 1-7 was prepared by replacing 1-Boc-4-aminomethylpiperidine with 4-aminomethyltetrahydropyran. Yield: 75%; 1 H NMR (500MHz, CDCl 3 )δ8.05(s,Ar-H,1H),5.35–4.99(m,s,NH×3,3H),4.00–3.97(m,CH 2 ,2H),3.42–3.34(m,CH 2 ×2,4H),1.91–1.82(m,CH,1H),1.65–1.60(m,CH 2 ,2H),1.38–1.30(m,CH 2 ,2H); ESI-MS: m / z=277[M+1] + .

[0133] Step 2.N 2- (6-(2-(pyrrol-1-yl)ethoxy)pyridin-3-yl)-N 4 Synthesis of -((tetrahydropyran-4-yl)methyl)-5-trifluoromethylpyrimidine-2,4-diamine (Compound 3)

[0134]

[0135] Synthetic steps Referring to Step 4 of Example 1, compound 3 was prepared by substituting 1-7 for 1-3. Yield: 35%; 1 H N...

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Abstract

The present invention provides a kind of N 2 ‑Substituted alkoxyaromatic ring‑2‑aminopyrimidine derivatives and their applications, including their optical isomers and pharmaceutically acceptable salts. Preliminary drug efficacy shows that the compound of the present invention has FLT3 inhibitory activity, has proliferation inhibitory activity on various leukemia cell lines, and has anti-AML multiple mutations such as the internal tandem repeat mutation of the juxtamembrane domain and the D835 activation loop in the kinase domain. The point mutation is effective, has almost no inhibitory effect on c-KIT, can overcome the clinical drug resistance brought by the point mutation, can reduce the side effects of myelosuppression, and can be used in the preparation of anti-tumor drugs. The general structural formula of the derivative is:

Description

technical field [0001] The present invention relates to the field of medicine, relates to N 2 -Substituted alkoxyaromatic ring-2-aminopyrimidine derivatives and their applications, mainly N 2 - Substituted alkoxy aromatic ring-2-aminopyrimidine derivatives and their optical isomers or salts, and their application in the preparation of antitumor drugs as Fms-like tyrosine kinase 3 (FLT3) inhibitors. Background technique [0002] Fms-like tyrosine kinase 3 (Fms-like tyrosine kinase, FLT3), also known as fetal liver kinase 2 (Fetal Liver Kinase-2, FLK2) and stem cell kinase-1 (Stem Cell Kinase-1, STK1) in mice ), which belong to type III receptor tyrosine kinases together with stem cell growth factor receptor (c-Kit), macrophage colony-stimulating factor receptor (Fms) and platelet-derived growth factor receptor (PDGFR). FLT3 is mainly distributed in hematopoietic cells and nerve tissues, and also exists in placenta, gonads and brain tissues, and plays a key role in the proli...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D405/14C07D401/12C07D403/12C07D239/48C07D405/12A61P35/00A61P35/02
CPCC07D401/14C07D405/14C07D401/12C07D403/12C07D239/48C07D405/12A61P35/00A61P35/02
Inventor 刘滔李佳童乐仙周宇波董晓武王培培徐高亚米田宋宁
Owner ZHEJIANG UNIV
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