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A kind of preparation method of novel anti-tumor IDO inhibitor

A technology of intermediates and compounds, applied in the field of preparation of novel anti-tumor IDO inhibitors, can solve the problems of toxic and side effects, poor biological activity of NLG919, limited clinical data, etc.

Active Publication Date: 2021-02-26
XIAMEN BIOTIME BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the toxicity and side effects of INCB024360, the existing clinical research dose (50mg bid, or 100mg bid) is about 30% of the optimal dose (300mg bid, 600mg bid), and the clinical activity is greatly limited; at the same time, the toxic groups of INCB024360 Another pharmacophore, INCB024360 and its derivatives have a problem of high toxicity
The safety of NLG919 is better, but the biological activity of NLG919 is poor
BMS-986205 has also entered the clinic, but the clinical data is limited

Method used

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  • A kind of preparation method of novel anti-tumor IDO inhibitor
  • A kind of preparation method of novel anti-tumor IDO inhibitor
  • A kind of preparation method of novel anti-tumor IDO inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: Compound 1

[0069]

[0070] Compound 1 was prepared from intermediate F (20 mg) and 4-chloro-1,2-phenylenediamine via general route 1 and general route 3. Compound 1 (10.05 mg) was obtained as a white solid with a yield of 37%. MS(ESI):m / z 408.3(M+H) + . 1 HNMR (500MHz, d 6 -DMSO)δ12.40(s,1H),8.79(d,J=4.5Hz,1H),8.11–8.04(m,1H),7.97(d,J=10.5Hz,1H),7.65(t,J =8.5Hz,1H),7.60–7.45(m,2H),7.42(d,J=4.0Hz,1H),7.15(d,J=8.5Hz,1H),3.30–3.24(m,1H),2.95 –2.88(m,1H),1.95(t,J=10.5Hz,2H),1.90–1.79(m,2H),1.61–1.47(m,3H),1.45–1.32(m,5H).

Embodiment 2

[0071] Example 2: Compound 17 and Compound 18

[0072]

[0073] Compound 17 (trans, rac) and Compound 18 (cis, rac) proceed from intermediate F (40 mg) and 4-fluoro-1,2-phenylenediamine via general route 1 and general route 3 prepared.

[0074] Compound 17 (8.49 mg), the first eluting isomer, was obtained as a white solid in 16% yield. MS(ESI):m / z392.5(M+H) + . 1 H NMR (500MHz, d 6 -DMSO)δ12.28(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J=10.5Hz,1H),7.65(t,J=8.5Hz,1H ),7.45–7.39(m,2H),7.34(d,J=10.0Hz,1H),7.02–6.92(m,1H),3.29–3.23(m,1H),2.93–2.87(m,1H), 2.00–1.91(m,2H),1.89–1.79(m,2H),1.61–1.46(m,3H),1.45–1.33(m,5H).

[0075] Compound 18 was obtained (9.24 mg), the second eluting isomer, as a white solid in 18% yield. MS(ESI):m / z392.5(M+H) + . 1 H NMR (500MHz, d 6 -DMSO)δ12.31(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J=11.0Hz,1H),7.66(t,J=8.5Hz,1H ),7.58(s,1H),7.44–7.39(m,1H),7.23(d,J=9.0Hz,1H),7.01–6.92(m,1H),3.45–3.35(m,2H),2.15– 2.09(m,1H),2.06–1.99(m,1H),1.93–1.8...

Embodiment 3

[0076] Embodiment 3: Compound 21 and Compound 22

[0077]

[0078] Compound 21 (trans, rac) and Compound 22 (cis, rac) starting from intermediate F (40 mg) and 4-methyl-1,2-phenylenediamine via general route 1 and general route Three prepared.

[0079] Compound 21 (11.40 mg), the first eluting isomer, was obtained as a white solid in 22% yield. MS(ESI):m / z 388.5(M+H) + . 1 H NMR (500MHz, d 6 -DMSO)δ11.98(s,1H),8.79(s,1H),8.11–8.04(m,1H),7.97(d,J=10.5Hz,1H),7.65(t,J=8.5Hz,1H ),7.44–7.38(m,2H),7.20(s,1H),6.93(t,J=9.5Hz,1H),3.30–3.23(m,1H),2.91–2.83(m,1H),2.39( s,3H),2.00–1.91(m,2H),1.89–1.78(m,2H),1.61–1.46(m,3H),1.44–1.33(m,5H).

[0080] Compound 22 (13.51 mg), the second eluting isomer, was obtained as a white solid in 26% yield. MS(ESI):m / z 388.5(M+H) + . 1 H NMR (500MHz, d 6 -DMSO)δ12.02(s,1H),8.86(s,1H),8.13–8.06(m,1H),7.97(d,J=11.0Hz,1H),7.66(t,J=9.0Hz,1H ),7.58(s,1H),7.39(d,J=8.5Hz,1H),7.20(s,1H),6.93(t,J=10.0Hz,1H),3.46–3.34(m,2H),2.38 (s,3H),2.16–2.09(m,1...

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Abstract

The invention relates to a preparation method of a novel anti-tumor IDO inhibitor formula (I). The compound prepared by the method has obvious inhibitory activity on tryptophan metabolism.

Description

[0001] This application is a divisional application, the Chinese application number of its parent case is: 201980004340.2, the international application number is PCT / CN2019 / 071704, and the international application date is January 15, 2019. [0002] The present invention claims the priority of the Chinese patent application CN201810044798.8, and the content described in the specification, drawings and claims of the priority document is incorporated into the specification of the present invention in its entirety and is regarded as a part of the original description of the specification of the present invention. The applicant further declares that the applicant has the right to amend the description and claims of the present invention based on the priority document. technical field [0003] The invention relates to the field of medicines, in particular to a preparation method of a novel anti-tumor IDO inhibitor. Background technique [0004] Tryptophan (TRP) is an α-amino aci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/08C07D471/04C07D413/08A61K31/4709A61K45/06A61P35/00A61P31/12A61P37/06A61P37/02
CPCC07D401/08C07D471/04C07D413/08A61K45/06A61K31/4709A61P31/12A61P35/00A61P37/02A61P37/06
Inventor 李磐温俏冬王骥甘泉路杨杨东晖
Owner XIAMEN BIOTIME BIOTECHNOLOGY CO LTD