US 8,557,837 B2Granted

Sinomenine derivatives, synthetic methods and uses thereof

AssigneesShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

InventorsZhujun Yao, Bing Sun, Yangtong Lou, Zhenyu Yang, Aizhong Chen, Zhao Ma

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Abstract

The invention relates to sinomenine derivatives, methods for their synthesis and their applications. The sinomenine derivatives include oxidation derivatives, and C-10 substituted sinomenine derivatives. Based on the readily oxidizable phenol group on sinomenine structure, using oxidation, oxidative dearomatization, or conjugated addition aromatization, one can introduce C-10 substitutions to synthesize the sinomenine derivatives. The sinomenine derivatives of the invention have the following structures: Using in vitro TNF-α inhibition assay, the activities of the synthetic compounds are assessed. Results from these assays shown that most compounds have anti-inflammatory effects, and some compounds have better activities than that of sinomenine. These compounds may be used in treating immune diseases such as rheumatoid arthritis (RA).

A sinomenine derivative, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein the sinomenine derivative has the following structure:

wherein R1=H or R10CO;
R2=H or R10CO;
R3=R11O, R12S, R13R14N, OH, R10COO, or
R4=H or R16R17R18Si;
R5=R11O, OH, or CH3COO;
R6=H or R11O;
or R5 and R6 together form an oxo group;
R7=H, halogen, or hydroxymethyl;
R8=hydroxyl or H;
R9=hydroxyl or H;
or R8 and R9 together form an oxo group;
R10=C1-4 hydrocarbyl;
R11=C1-10 hydrocarbyl;
R12=C1-10 hydrocarbyl, a 5-membered or 6-membered aromatic ring that is unsubstituted or contains 1-3 substituents, a 5-membered or 6-membered nitrogen-containing heterocycle that is unsubstituted or contains 1-3 substituents, a 5-membered or 6-membered oxygen-containing heterocycle that is unsubstituted or contains 1-3 substituents, or a 5-membered or 6-membered sulfur-containing heterocycle that is unsubstituted or contains 1-3 substituents, wherein the substituent is C1-10 hydrocarbyl, halogen, C1-4 alkyl, or C1-4 fluoroalkyl, nitro, cyano, methoxy, or hydroxyl group;
R13=C1-10 hydrocarbyl, a 5-membered or 6-membered aromatic ring that is unsubstituted or contains 1-3 substituents, a 5-membered or 6-membered nitrogen-containing heterocycle that is unsubstituted or contains 1-3 substituents, a 5-membered or 6-membered oxygen-containing heterocycle that is unsubstituted or contains 1-3 substituents, or a 5-membered or 6-membered sulfur-containing heterocycle that is unsubstituted or contains 1-3 substituents, wherein the substituent is C1-10 hydrocarbyl, halogen, C1-4 alkyl, or C1-4 fluoroalkyl, nitro, cyano, C1-4 alkoxy, or hydroxyl group;
R14H or C1-10 hydrocarbyl;
or R13 and R14 together with the N atom, to which they are attached, form a 5-membered or 6-membered nitrogen-containing heterocycle that is unsubstituted or contains 1-3 substituents, wherein the substituent is halogen, C1-4 alkyl, or C1-4 fluoroalkyl, nitro, cyano, C1-4 alkoxy, or hydroxyl group;
R15=H or C1-10 alkyl;
R16=C1-10 hydrocarbyl or phenyl;
R17=C1-10 hydrocarbyl or phenyl;
R18=C1-10 hydrocarbyl or phenyl.

18 more elements

Abstract

Claims16