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Synthesis and medical application of pyrrolo-[2,1-f] [1,2,4] triazine mother nucleus compound

A compound, pyrrole technology, applied in the field of medicinal chemistry, can solve problems such as the incomplete development of BTK inhibitors and narrow clinical indications

Inactive Publication Date: 2017-02-22
NINGBO WESDON POWDER PHARMA COATINGS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the value of BTK inhibitors has not been fully developed at present, and the clinical indications are relatively narrow, so it is necessary to continue to develop BTK inhibitors with high selectivity, high biological activity and low toxicity

Method used

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  • Synthesis and medical application of pyrrolo-[2,1-f] [1,2,4] triazine mother nucleus compound
  • Synthesis and medical application of pyrrolo-[2,1-f] [1,2,4] triazine mother nucleus compound
  • Synthesis and medical application of pyrrolo-[2,1-f] [1,2,4] triazine mother nucleus compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of pyrrolo[2,1-f][1,2,4]triazine core compound BTK irreversible inhibitor compound (1)

[0033]

[0034] White crystalline powder, M.P.186-188℃. 1 H-NMR (400MHz, DMSO-d 6 )δ:10.17(1H,s),9.02(1H,s),8.67(1H,s),7.15-7.34(2H,m),6.45-6.96(6H,m),6.64(1H,d),6.51 (1H,m),6.17-6.25(2H,m),6.02(1H,d,J=15.6Hz),5.51(1H,d,J=6.8Hz),4.43(2H,t),3.39(2H, t),2.38(2H,t),2.27(3H,s),1.64(2H,m); 13 C-NMR (100MHz, DMSO-d 6 )δ: 166.8, 161.6, 149.5, 142.8, 139.7, 136.8, 131.2, 129.9, 128.6, 126.9, 122.8, 118.2, 113.7, 111.9, 110.3, 108.2, 100.8, 86.6, 58.5, 57.8, 42.4 )calcd.for C 26 h 28 N 8 O[M+H] + ,468.2386; found, 468.2392.

Embodiment 2

[0036] Preparation of Pyrrolo[2,1-f][1,2,4]triazine Core Compound BTK Irreversible Inhibitor Compound (2)

[0037]

[0038] White crystalline powder, M.P.165-167℃. 1 H-NMR (400MHz, DMSO-d 6 )δ:10.33(1H,s),9.25(1H,s),8.79(1H,s),7.19-7.38(2H,m),6.44-6.95(6H,m),6.66(1H,d),6.53 (1H,m),6.16-6.25(2H,m),6.02(1H,d,J=12.5Hz),5.50(1H,d,J=8.7Hz),3.46(4H,t),2.38(4H, t),2.26(3H,s); 13 C-NMR (100MHz, DMSO-d 6 )δ: 166.8, 161.6, 149.5, 142.8, 139.7, 136.8, 131.2, 129.9, 128.6, 126.9, 122.8, 118.2, 113.7, 111.9, 110.3, 108.2, 101.1, 57.4, 52.1, 46.8; C 26 h 28 N 8 O[M+H] +,468.2386; found, 468.2392.

Embodiment 3

[0040] Preparation of pyrrolo[2,1-f][1,2,4]triazine core compound BTK irreversible inhibitor compound (3)

[0041]

[0042] White crystalline powder, M.P.170-172℃. 1 H-NMR (400MHz, DMSO-d 6 )δ:10.29(1H,s),9.18(1H,s),8.82(1H,s),7.18-7.37(2H,m),6.44-6.95(6H,m),6.65(1H,d),6.53 (1H,m),6.16-6.25(2H,m),6.04(1H,d,J=14.4Hz),5.53(1H,d,J=9.8Hz),3.47(4H,t),2.80(4H, t),1.93(1H,s); 13 C-NMR (100MHz, DMSO-d 6 )δ: 166.8, 161.6, 149.5, 142.8, 139.7, 136.8, 131.2, 129.9, 128.6, 126.9, 122.8, 118.2, 113.7, 111.9, 110.3, 108.2, 101.1, 53.8, 45.9; HRMS (ESI) calcd. 25 h 26 N 8 O[M+H] + ,454.2230; found, 454.2235.

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Abstract

The invention discloses a synthesis and medical application of pyrrolo-[2,1-f] [1,2,4] triazine mother nucleus compound. The compound belongs to a novel-structure compound. The synthesis method is high in operating safety, mild in reaction condition and suitable for industrial production. The activity and the selectivity of BTK kinase and the in-vitro proliferation activity of a leukemia cell line are test, it is verified that the compound has the selective and irreversible inhibition effect on the BTK kinase, and has the different-degree inhibition effect on leukemia cells. According to measurement, the compound also has the good anti-arthritic activity on a collagen-induced arthritis (rCIA) model. The pyrrolo-[2,1-f] [1,2,4] triazine mother nucleus compound can be used for preparing medicine for treating arthritis and leukemia.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of pyrrolo[2,1-f][1,2,4]triazine core compounds and their medical applications. Background technique [0002] Bruton Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase, which belongs to the Tec family member and is mainly expressed in B cells. It is an important factor in the B cell signaling pathway and affects the development of B cells in the body. with maturity. In the immune system, B cells can recognize antigens, present antigens to T cells, and assist T cell activation; B cells can also produce autoantibodies (RF, CCP) and secrete inflammatory factors (IL-6, IFN, TNF) to accelerate disease process. BTK is a key factor for B cells to perform immune functions, and is extremely important for the differentiation, development, proliferation, and apoptosis of B cells. Inhibiting BTK can effectively block the migration and adhesion of malignant B cells, and lead ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P35/02A61P19/02A61P29/00
CPCC07D487/04
Inventor 梁承远贾敏一田丹妮孙涵
Owner NINGBO WESDON POWDER PHARMA COATINGS CO LTD