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N2-carbamylaryl-2-aminopyrimidine derivative and medical application thereof

A carbamoyl aromatic ring and aminopyrimidine technology, applied in the application field of anti-tumor drugs, can solve the problems of secondary drug resistance, drug resistance, side effects, etc.

Active Publication Date: 2020-10-02
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 bone marrow suppression, QTc interval prolongation, and drug resistance due to mutations such as D835 and F691 after medication

Method used

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  • N2-carbamylaryl-2-aminopyrimidine derivative and medical application thereof
  • N2-carbamylaryl-2-aminopyrimidine derivative and medical application thereof
  • N2-carbamylaryl-2-aminopyrimidine derivative and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0145] Preparation Example 1 Compound 1~7 Preparation

[0146]

[0147] Step 1. 4-Chloro-5-trifluoromethyl-2-aminopyrimidine (1-2)

[0148]

[0149] 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 intermediate 1-2 as a white solid. 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] + .

[0150] Step 2. 1-Boc-4-(((2-Amino-5-(trifluoromethyl)pyrimidin-4-yl)amino)methyl)piperidine (1-3)

[0151]

[0152] Intermediate 1-2 (593mg, 3.0mmol) was dissolved in anhydrous methanol (12mL), followed by adding triethylamine (303mg, 3.0mmol), 1-Boc-4-aminomethylpiperidine (771mg, 3.6mmol) , Heated t...

preparation Embodiment 2

[0171] The preparation of preparation example 2 compound 8~16

[0172]

[0173] Step 1. Synthesis of Compounds 1-12~1-19

[0174] Synthetic procedure Referring to step 2 of Example 1, compounds 1-12 to 1-19 were prepared by substituting corresponding amines for 1-Boc-4-aminomethylpiperidine.

[0175] 1.1N 4 -(tetrahydropyran-4-ylmethyl)-5-trifluoromethylpyrimidine-2,4-diamine (1-12) 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] + .

[0176] 1.2 1-Boc-N 4 -(1r,4r)-4-Aminocyclohexyl-5-trifluoromethylpyrimidine-2,4-diamine (1-13) 1 H NMR (500MHz, DMSO-d 6 )δ7.96(s,Ar-H,1H),6.76(d,J=8.5Hz,NH 2 ,NH 2 -a,3H),6.05(d,J=8.5Hz,NH 2 -b,1H),4.19–3.94(m,CH,1H),3.22–3.15(m,CH,1H),1.78–1.73(m,CH 2 ×2,4H),1.55–1.42(m,CH 2 ,2H),1.37(s,CH 3 ×3,9H),1.24–1.16(m,CH 2 ,2H); ESI-MS: m / z=376[M+1] + .

[0177] 1.3 1-Boc-N 4 -(1s,4...

preparation Embodiment 3

[0194] Preparation of Example 3 Compounds 17-19

[0195]

[0196] Step 1. Preparation of Intermediates 1-21~1-22

[0197] Synthesis steps Referring to step 3 of Example 1, compounds 1-21 to 1-22 were prepared using corresponding amines.

[0198] 1.1 5-bromo-N-methylpicolinamide (intermediate 1-21) 1 H NMR (500MHz, CDCl 3 )δ8.58(d, J=2.0Hz, Ar-H, 1H), 8.08(d, J=8.5Hz, Ar-H, 1H), 7.96(dd, J=8.5, 2.0Hz, Ar-H, 1H), 7.93–7.84(m, NH, 1H), 3.02(d, J=5.0Hz, CH 3 ,3H).ESI-MS: m / z=215[M+1] + .

[0199] 1.2 5-bromo-N,N-lutidine amide (intermediate 1-22) 1 H NMR (500MHz, CDCl 3 )δ8.63 (d, J=2.0Hz, Ar-H, 1H), 7.92 (dd, J=8.5, 2.0Hz, Ar-H, 1H), 7.57 (dd, J=8.5, 2.0Hz, Ar- H,1H),3.12(s,CH 3 ,3H),3.09(s,CH 3 ,3H).ESI-MS: m / z=229[M+1] + .

[0200] Step 2. Preparation of Compounds 17-19

[0201] For the synthesis steps, refer to step 4 of Preparation Example 1, replace 1-3 with 1-13 / 1-14, replace 1-5~1-11 with 1-21~1-22 / 1-9, and prepare compounds 17~19 .

[0202] 2.1N-(5-((4-(...

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Abstract

The invention provides an N2-carbamylaryl-2-aminopyrimidine derivative and a medical application thereof. The N2-carbamylaryl-2-aminopyrimidine derivative provided by the invention comprises an optical isomer of the N2-carbamylaryl-2-aminopyrimidine derivative and pharmaceutically acceptable salt thereof. Pharmacodynamic research shows that the traditional Chinese medicine composition has no toxicor side effect, the compound has an FLT3 inhibitory activity. The proliferation inhibition activity is realized on various leukemia cell strains; a medium inhibition effect is achieved on breast cancer cells; moreover, the polypeptide is effective for multiple mutations of AML, such as internal tandem repeat mutation of a near-membrane structural domain and D835 point mutation of an activated ring in a kinase structural domain, almost has no inhibition effect on c-KIT, can overcome drug resistance brought by clinical point mutation, can reduce toxic and side effects of bone marrow inhibition,and can be applied to preparation of antitumor drugs. The structures of the general formulas Ia and Ib of the N2-carbamylaryl-2-aminopyrimidine derivative are shown in the specification,

Description

technical field [0001] The present invention relates to the field of medicines, in particular to N 2 -Carbamoyl aromatic ring-2-aminopyrimidine derivatives and their medicinal uses, mainly N 2 - Optical isomers or salts or solvates of carbamoyl aromatic ring-2-aminopyrimidine derivatives 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 (FLT3), also known as 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 proliferation of hematopoietic cells and lymphocytes. Ab...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D239/47C07D239/48C07D401/04C07D401/12C07D401/14C07D403/04C07D405/14A61P35/00A61P35/02
CPCC07D401/14C07D405/14C07D401/12C07D401/04C07D239/48C07D239/42C07D403/04C07D239/47A61P35/02A61P35/00
Inventor 刘滔李佳童乐仙周宇波董晓武王培培徐高亚李佳楠
Owner ZHEJIANG UNIV
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