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Substituted muramyl dipeptide compound and preparation method and applications thereof

A compound and composition technology, applied in the direction of dipeptide components, medical preparations containing active ingredients, peptides, etc., can solve the problems of unclear relationship between tumors and the need for further research on NOD1/2 receptors

Active Publication Date: 2017-04-26
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few studies on the function of NLRs to promote or suppress tumors, and the relationship between NOD1 or NOD2 and tumors is still unclear.
[0004] Therefore, the research on NOD1 / 2 receptors still needs to be in-depth

Method used

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  • Substituted muramyl dipeptide compound and preparation method and applications thereof
  • Substituted muramyl dipeptide compound and preparation method and applications thereof
  • Substituted muramyl dipeptide compound and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0269] Synthesis of Compound 1 (No. ZLT-03-14)

[0270]

[0271] Paclitaxel (1mmol, 853mg) was dissolved in 10mL of dichloromethane, and 1.05 equivalents, 110μL of N-methylmorpholine and 160mg of benzyl propiolate were added at room temperature. After 4 hours of reaction at room temperature, LC-Ms detected that the reaction was complete. Purified by chromatography to obtain 912 mg of intermediate 1-2a (white solid powder), yield: 90%.

[0272] Dissolve 507mg of intermediate 1-2a in 10mL of ethyl acetate, add 507mg of Pd / C, and react at 50°C under an atmosphere of hydrogen. The progress of the reaction was monitored by LC-Ms. After the reaction was complete, Pd / C was filtered, and the filter cake was washed twice with ethyl acetate. The filtrates were combined and concentrated to obtain 460 mg of intermediate 1-3a (white solid powder), with a yield of 99%. It was directly used in subsequent reactions without further purification.

[0273] Weigh 1g (1.0mmol) Wang resin int...

Embodiment 2

[0276] Synthesis of Compound 2 (No. ZLT-03-15)

[0277]

[0278] According to the method described in Example 1, the title compound 2 was prepared by reacting the intermediate 1-3a with the carboxy-terminal MDP derivative substituted with p-methylcinnamic acid. 1HNMR(400MHz,DMSO-d6)δ1.00(s,3H),1.02(s,3H),1.20-1.33(m,7H),1.44-1.52(m,6H),1.61-1.66(m,1H) ,1.66-1.78(m,2H),1.80(s,3H),1.91-2.02(m,1H),2.07-2.20(m,8H),2.26-2.35(m,4H),2.35-2.42(m, 2H), 2.84-2.96(m, 2H), 3.60(d, 1H, J=6.7Hz), 3.70-3.85(m, 2H), 3.95-4.18(m, 5H), 4.38-4.45(m, 2H) ,4.66(s,1H),4.90(d,J=9.3Hz,1H),4.95(1H,brs),5.30(t,1H,J=8.7Hz),5.40(d,1H,J=6.9Hz) ,5.88(t,1H,J=8.5Hz),6.31(s,1H),6.70(d,1H,J=15.7Hz),7.09(s,1H),7.17-7.25(m,3H),7.32( s,1H),7.37-7.42(m,4H),7.42-7.52(m,4H),7.52-7.58(m,1H),7.62-7.68(m,2H),7.74(t,J=7.1Hz, 1H), 7.86(d, J=7.5Hz, 3H), 7.94(d, J=7.5Hz, 3H), 8.22(d, J=7.8Hz, 1H), 8.32(d, J=6.2Hz, 1H) ,9.02(d,J=7.4Hz,1H).

Embodiment 3

[0280] Synthesis of Compound 3 (No. ZLT-03-18)

[0281]

[0282] According to the method described in Example 1, the title compound 3 was prepared by reacting the intermediate 1-3a with the carboxy-terminal MDP derivative substituted with 3-4-difluorocinnamic acid. 1 HNMR(400MHz,DMSO-d6)δ1.01(s,3H),1.03(s,3H),1.21-1.31(m,7H),1.42-1.55(m,6H),1.58-1.65(m,1H) ,1.70-1.82(m,5H),1.91-2.03(m,1H),2.11-2.20(m,8H),2.26-2.35(m,1H),2.35-2.42(m,2H),2.87-2.94( m,2H),3.60(d,1H,J=6.8Hz),3.72-3.84(m,2H),3.88-4.05(m,3H),4.06-4.19(m,2H),4.37-4.52(m, 2H), 4.68(s, 1H), 4.91(d, J=9.0Hz, 1H), 4.95-5.15(brs, 1H), 5.32(t, 1H, J=8.6Hz), 5.40(d, 1H, J =6.7Hz), 5.88(t,1H,J=8.5Hz),6.32(s,1H),6.83(d,1H,J=15.6Hz),7.02(s,1H),7.17-7.25(m,1H ),7.35-7.52(m,9H),7.53-7.58(m,1H),7.60-7.80(m,5H),7.88(d,J=7.2Hz,3H),7.95(d,J=7.5Hz, 3H), 8.31(d, J=6.2Hz, 1H), 8.52(d, J=6.5Hz, 1H), 9.16(d, J=7.2Hz, 1H).

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Abstract

The invention discloses a substituted muramyl dipeptide compound and a preparation method and applications thereof, and further discloses a pharmaceutical composition of the compound and applications of the pharmaceutical composition. The substituted muramyl dipeptide compound can antagonize human derived or mouse derived immune cell NOD1 and / or NOD2 mediated inflammation NF-[kappa]B and MAPKs signal transduction pathway and inhibit the growth and metastasis of tumors.

Description

technical field [0001] The present invention relates to the field of medicine, specifically, the present invention relates to substituted cytoacyl dipeptide compounds, their preparation method and use, and the use of antagonists in the preparation of medicines, more specifically, the present invention relates to paclitaxel or docetaxel and A compound obtained by linking its analogue with muramyl dipeptide through an ether bond, its preparation method and application, and the application of the antagonist comprising the above-mentioned compound in the preparation of medicaments. Background technique [0002] Pattern recognition receptors NOD1 and NOD2 belong to the NOD-like receptors (NLRs) family, which is an important class of intrinsic pattern recognition receptors (pattern recognition receptors, PPRs) in the body, similar to Toll-like receptors (TLRs), by recognizing exogenous Pathogen-associated molecular pattern (pathogen associated molecular pattern, PAMP) or endogenou...

Claims

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Application Information

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IPC IPC(8): C07K5/065C07K5/078A61K38/05A61K45/06A61P29/00A61P37/02A61P35/00
CPCA61K38/00A61K38/05A61K45/06C07K5/06078C07K5/06139
Inventor 刘刚马瑶董毅王素华王春廷刘子节
Owner TSINGHUA UNIV
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