Tricyclic analogues, preparation method and uses thereof

Patent metadata

Field	Value
Publication number	US-10278962-B2
Application number	US-201615556932-A
Country	US
Kind code	B2
Filing date	Mar 3, 2016
Priority date	Mar 19, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

The present invention relates to a series of analogs of natural product Pyripyropene A represented by general formula I and a preparation method and use thereof. More particularly, the present invention relates to analogs of the natural product Pyripyropene A, a preparation method and use thereof as the acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors for the treatment of cardiovascular diseases such as atherosclerosis and the like.

First claim

The invention claimed is:

1. Analogues of Pyripyropene A, which are represented by the following formula (I):

wherein:
n=0, 1 or 2;
R 1 is hydrogen or C1 to C6 alkyl;
R 2 and R 3 are each independently hydrogen, hydroxy, C1 to C6 alkylcarbonyloxy group, C1 to C6 alkylcarbonylthio group, C1 to C6 alkylcarbonylamine group, 3- to 8-membered cycloalkylcarbonyloxy group, 3- to 8-membered cycloalkylcarbonylthio group, 3- to 8-membered cycloalkylcarbonylamine group, substituted or unsubstituted 5- to 8-membered arylcarbonyloxy group, or substituted or unsubstituted heteroarylcarbonyloxy group, wherein the term of “substituted” means to be substituted with halogen, hydroxy, alkyl, alkoxy, amino, cyano, wherein one of R 2 and R 3 is hydrogen and the other is selected from hydroxy, acetoxy or para-cyano-substituted phenylcarbonyloxy groups;
R 4 and R 5 are each independently hydrogen, wherein one of R 4 and R 5 is hydrogen and the other is selected from

wherein R 7 , R 8 and R 9 are each independently hydrogen, hydroxy, halogen, methyl, C1 to C6 alkylcarbonyloxy group, C1 to C6 alkylcarbonylthio group, C1 to C6 alkylcarbonylamine group, 3- to 8-membered cycloalkylcarbonyloxy group, 3- to 8-membered cycloalkylcarbonylthio group, 3- to 8-membered cycloalkylcarbonylamine group, C1 to C6 alkylcarbonyloxy methylene group, 3- to 8-membered cycloalkylcarbonyloxy methylene group, substituted or unsubstituted 5- to 8-membered heteroarylcarbonyloxy group, substituted or unsubstituted 5- to 8-membered heteroarylcarbonyloxy methylene group, substituted or unsubstituted 5- to 8-membered arylcarbonyloxy group, substituted or unsubstituted 5- to 8-membered arylcarbonyloxy methylene group, wherein the term of “substituted” means to be substituted with halogen, hydroxy, alkyl, alkoxy, amino, cyano;
R 6 is substituted or unsubstituted 5- to 8-membered heteroaryl;
X is an oxygen atom, a sulfur atom, an amino group or a C1 to C6 alkyl;
Y is hydrogen;
W is halogen, oxo (═O), ═N—OH, substituted or unsubstituted 5- to 8-membered aryl or heteroarylcarbonyloxy group, C1 to C6 alkylcarbonyloxy group or 3- to 8-membered cycloalkylcarbonyloxy group;
represents a single bond or a double bond.

2. The analogues of Pyripyropene A according to claim 1 , wherein
n=1;
R 1 is hydrogen or methyl;
R 2 and R 3 are each independently hydrogen, hydroxy, acetoxy or para-cyano-substituted phenylcarbonyloxy group, wherein one of R 2 and R 3 is hydrogen and the other is selected from hydroxyl, acetoxy or para-cyano-substituted phenylcarbonyloxy groups;
R 4 and R 5 are each independently hydrogen, wherein one of R 4 and R 5 is hydrogen and the other is selected from

R 7 , R 8 and R 9 are each independently hydrogen, hydroxy, halogen, methyl, C1 to C6 alkylcarbonyloxy group, substituted or unsubstituted phenylcarbonyloxy group, wherein said substitution means to be substituted with halogen, hydroxy, alkyl, alkoxy, amino, cyano;
R 6 is substituted or unsubstituted 5- to 8-membered heteroaryl;
X is an oxygen atom;
Y is hydrogen;
W is halogen, oxo (═O), ═N—OH, substituted or unsubstituted 5- to 8-membered aryl or heteroarylcarbonyloxy group, C1 to C6 alkylcarbonyloxy group or 3- to 8-membered cycloalkylcarbonyloxy group;
represents a single bond or a double bond.

3. The analogues of Pyripyropene A according to claim 1 , wherein
n=1;
R 1 is methyl;
R 2 and R 3 are each independently hydrogen, hydroxy, acetoxy or para-cyano-substituted phenylcarbonyloxy group, wherein one of R 2 and R 3 is hydrogen and the other is selected from hydroxyl, acetoxy or para-cyano-substituted phenylcarbonyloxy groups;
R 4 and R 5 are each independently hydrogen, wherein one of R 4 and R 5 is hydrogen and the other is selected from

R 7 , R 8 and R 9 are each independently hydrogen, hydroxy, halogen, methyl, C1 to C6 alkylcarbonyloxy group, substituted or unsubstituted phenylcarbonyloxy group, wherein the term of “substituted” means to be substituted with cyano;
R 6 is substituted or unsubstituted 5- to 8-membered heteroaryl;
X is an oxygen atom, a sulfur atom, an amino group or a C1 to C6 alkyl;
Y is hydrogen;
W is oxo (═O) or para-halogen-substituted phenylcarbonyloxy;
is a single bond.

4. The analogues of Pyripyropene A according to claim 1 , wherein Y is hydrogen, n=1, X is oxygen, R 1 is methyl, is a single bond, R 3 and R 5 are hydrogen, and the configurations of W and Y are the same, the configurations of R 2 , R 4 and R 1 are the absolute steric configurations represented by the following formula (IV):

wherein in formula (IV), the definitions of other substituents are the same as those in formula (I) of claim 1 .

5. The analogues of Pyripyropene A according to claim 1 , which are selected from the following compounds:

6. The analogues of Pyripyropene A according to claim 1 , wherein one of R 2 and R 3 is hydrogen and the other is selected from hydroxy, acetoxy or para-cyano-substituted phenylcarbonyloxy groups;
one of R 4 and R 5 is hydrogen and the other is

R 6 is a 3-pyridyl group;
X an oxygen atom.

Assignees

• Shanghai Inst Materia Medica Cas

Inventors

• Nan Fajun
• Li Boliang
• Zhan Yang
• Zhang Xiaowei
• Xiong Ying
• Hu Xichan
• Zhang Yangming

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D493/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4433 Primary

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title