US 12,577,219 B2Granted

Macrolide brefeldin a ester derivatives and use thereof

AssigneeOcean University of China

InventorsChanglun Shao, Yaoyao Jiang, Ming Liu, Changyun Wang, Meiyan Wei, Cuifang Wang

Life of this patent

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Abstract

The ester derivatives of brefeldin A represented by Formula (I) in the inhibition of tumor proliferation. The compounds are prominent in the prevention or treatment of hyperproliferative diseases, including liver cancer, leukemia, breast cancer, colon adenocarcinoma, gastric cancer, lung cancer, Bart's esophageal cancer, cervical cancer, pancreatic cancer, endometrial cancer, bone cancer, lymphoma, kidney cancer, brain cancer, nerve cancer, nasopharyngeal cancer, oral cancer and colorectal cancer, and have the potential to be developed as antitumor agents.

Claims10

Dependent claims

An ester derivative of brefeldin A, wherein the ester derivative of brefeldin A is a compound represented by Formula (I), or a stereoisomer, a tautomer, a solvate, or a pharmaceutical acceptable salt of the compound represented by Formula (I),

wherein R1 and R2 are each independently H or
R1 and R2 are not H simultaneously;
Y is selected from the group consisting of benzene ring having at least one substituent, pyridine ring optionally having a substituent, quinoline ring optionally having a substituent and isoquinoline ring optionally having a substituent;
when Y is benzene ring, the at least one substituent is optionally fused to the benzene ring, and the at least one substituent is selected from
F
Cl
Br
OH
CN
CF3
NH2
COOH
NHOCH3
COOC2H5
NHOC2H5
CONH2
CH(CH3)OH
C(CH3)3
CH2Br
2,3-2OH
2,4-2OH
2,5-2OH
2,3,4-3OH
2,3,5-3OH
2,3,6-3OH
3,4,5-3OH
3,4,6-3OH
3,5,6-3OH
2,3-2F
2,3-2Cl
2,3-2Br
2,4-2F
2,4-2Cl
2,4-2Br
2,5-2F
2,5-2Cl
2,5-2Br
2,6-2F
2,6-2Cl
2,6-2Br
3,4-2F
3,4-2Cl
3,4-2Br
3,5-2F
3,5-2Cl
3,5-2Br
2,3,4-3F
2,3,4-3Cl
2,3,4-3Br
2,3,5-3F
2,3,5-3Cl
2,3,5-3Br
2,3,6-3F
2,3,6-3Cl
2,3,6-3Br
2,4,5-3F
2,4,5-3Cl
2,4,5-3Br
2,4,6-3F
2,4,6-3Cl
2,4,6-3Br
2,5,6-3F
2,5,6-3Cl
2,5,6-3Br
3,4,5-3F
3,4,5-3Cl
3,4,5-3Br
3,4,6-3F
3,4,6-3Cl
3,4,6-3Br
3,5,6-3F
3,5,6-3Cl
3,5,6-3Br
2,3,4,5-4F
2,3,4,5-4Cl
2,3,4,5-4Br
2,3,4,6-4F
2,3,4,6-4Cl
2,3,4,6-4 Br
2,3,4,5,6-5F
2,3,4,5,6-5Cl
2,3,4,5,6-5Br
2,3-2CF3
2,3,4-3CF3
3,4,5-3CF3
2,4-2CF3
2,3,5-3CF3
3,4,6-3CF3
2,5-2CF3
2,3,6-3CF3
3,5,6-3CF3
2,6-2CF3
2,4,5-3CF3
2,3,4,5-4CF3
3,4-2CF3
2,4,6-3CF3
2,3,4,6-4 CF3
3,5-2CF3
2,5,6-3CF3
2,3,4,5,6-5 CF3
I
CH3
OCH3
OCF3
NO2
SO2CH3
COOCH3
N(CH3)2
C2H5
CONHCH3
CON(CH3)2
CH2CH2OH
2,6-2OH
3,4-2OH
3,5-2OH
2,4,5-3OH
2,4,6-3OH
2,5,6-3OH
2,3,4,5-4OH
2,3,4,6-4OH
2,3,4,5,6-5OH
2,3-2I
2,3-2CH3
2,3-2OCH3
2,4-2I
2,4-2CH3
2,4-2OCH3
2,5-2I
2,5-2CH3
2,5-2OCH3
2,6-2I
2,6-2CH3
2,6-2OCH3
3,4-2I
3,4-2CH3
3,4-2OCH3
3,5-2I
3,5-2CH3
3,5-2OCH3
2,3,4-3I
2,3,4-3CH3
2,3,4-3OCH3
2,3,5-3I
2,3,5-3CH3
2,3,5-3OCH3
2,3,6-3I
2,3,6-3CH3
2,3,6-3OCH3
2,4,5-3I
2,4,5-3CH3
2,4,5-3OCH3
2,4,6-3I
2,4,6-3CH3
2,4,6-3OCH3
2,5,6-3I
2,5,6-3CH3
2,5,6-3OCH3
3,4,5-3I
3,4,5-3CH3
3,4,5-3OCH3
3,4,6-3I
3,4,6-3CH3
3,4,6-3OCH3
3,5,6-3I
3,5,6-3CH3
3,5,6-3OCH3
2,3,4,5-4I
2,3,4,5-4CH3
2,3,4,5-4OCH3
2,3,4,6-4I
2,3,4,6-4 CH3
2,3,4,6-4 OCH3
2,3,4,5,6-5I
2,3,4,5,6-5 CH3
2,3,4,5,6-5 OCH3
2,3-2OCF3
2,3,4-3OCF3
3,4,5-3OCF3
2,4-2OCF3
2,3,5-3OCF3
3,4,6-3OCF3
2,5-2OCF3
2,3,6-3OCF3
3,5,6-3OCF3
2,6-2OCF3
2,4,5-3OCF3
2,3,4,5-4 OCF3
3,4-2OCF3
2,4,6-3OCF3
2,3,4,6-4 OCF3
3,5-2OCF3
2,5,6-3OCF3
2,3,4,5,6-5 OCF3.
when Y is pyridine ring optionally having a substituent, quinoline ring optionally having a substituent or isoquinoline ring optionally having a substituent, the substituent is selected from:
F
Cl
Br
I
CH3
OCH3
OH
CN
CF3
OCF3
NO2
SO2CH3
NH2
COOH
NHOCH3
COOCH3
N(CH3)2
C2H5
COOC2H5
NHOC2H5
CONH2
CONHCH3
CON(CH3)2
CH2CH2OH
CH(CH3)OH
C(CH3)3
CH2Br

218 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/523,459Filed 10 Nov 2021 · continuation in part
Priority: CN 201911188758.128 Nov 2019
Published: US 2022/0064138 A13 Mar 2022
Granted: 17 Mar 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 313/00
Heterocyclic compounds containing rings of more than six members having one oxygen
A61K 31/365
Having oxygen as the only ring hetero atom, e.g. fungichromin: lactones
A61K 31/443
Containing further heterocyclic ring systems: containing a five-membered ring with oxygen as a ring hetero atom
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone

Family

PCT/CN2020/137696Parent of this continuation-in-part · filed 18 Dec 2020
US 2022/0064138 A1Pre-grant publication · published 3 Mar 2022
US 12,577,219 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

wherein R1 and R2 are each independently H or
R1 and R2 are not H simultaneously;
Y is selected from the group consisting of benzene ring having at least one substituent, pyridine ring optionally having a substituent, quinoline ring optionally having a substituent and isoquinoline ring optionally having a substituent;
when Y is benzene ring, the at least one substituent is optionally fused to the benzene ring, and the at least one substituent is selected from
F
Cl
Br
OH
CN
CF3
NH2
COOH
NHOCH3
COOC2H5
NHOC2H5
CONH2
CH(CH3)OH
C(CH3)3
CH2Br
2,3-2OH
2,4-2OH
2,5-2OH
2,3,4-3OH
2,3,5-3OH
2,3,6-3OH
3,4,5-3OH
3,4,6-3OH
3,5,6-3OH
2,3-2F
2,3-2Cl
2,3-2Br
2,4-2F
2,4-2Cl
2,4-2Br
2,5-2F
2,5-2Cl
2,5-2Br
2,6-2F
2,6-2Cl
2,6-2Br
3,4-2F
3,4-2Cl
3,4-2Br
3,5-2F
3,5-2Cl
3,5-2Br
2,3,4-3F
2,3,4-3Cl
2,3,4-3Br
2,3,5-3F
2,3,5-3Cl
2,3,5-3Br
2,3,6-3F
2,3,6-3Cl
2,3,6-3Br
2,4,5-3F
2,4,5-3Cl
2,4,5-3Br
2,4,6-3F
2,4,6-3Cl
2,4,6-3Br
2,5,6-3F
2,5,6-3Cl
2,5,6-3Br
3,4,5-3F
3,4,5-3Cl
3,4,5-3Br
3,4,6-3F
3,4,6-3Cl
3,4,6-3Br
3,5,6-3F
3,5,6-3Cl
3,5,6-3Br
2,3,4,5-4F
2,3,4,5-4Cl
2,3,4,5-4Br
2,3,4,6-4F
2,3,4,6-4Cl
2,3,4,6-4 Br
2,3,4,5,6-5F
2,3,4,5,6-5Cl
2,3,4,5,6-5Br
2,3-2CF3
2,3,4-3CF3
3,4,5-3CF3
2,4-2CF3
2,3,5-3CF3
3,4,6-3CF3
2,5-2CF3
2,3,6-3CF3
3,5,6-3CF3
2,6-2CF3
2,4,5-3CF3
2,3,4,5-4CF3
3,4-2CF3
2,4,6-3CF3
2,3,4,6-4 CF3
3,5-2CF3
2,5,6-3CF3
2,3,4,5,6-5 CF3
I
CH3
OCH3
OCF3
NO2
SO2CH3
COOCH3
N(CH3)2
C2H5
CONHCH3
CON(CH3)2
CH2CH2OH
2,6-2OH
3,4-2OH
3,5-2OH
2,4,5-3OH
2,4,6-3OH
2,5,6-3OH
2,3,4,5-4OH
2,3,4,6-4OH
2,3,4,5,6-5OH
2,3-2I
2,3-2CH3
2,3-2OCH3
2,4-2I
2,4-2CH3
2,4-2OCH3
2,5-2I
2,5-2CH3
2,5-2OCH3
2,6-2I
2,6-2CH3
2,6-2OCH3
3,4-2I
3,4-2CH3
3,4-2OCH3
3,5-2I
3,5-2CH3
3,5-2OCH3
2,3,4-3I
2,3,4-3CH3
2,3,4-3OCH3
2,3,5-3I
2,3,5-3CH3
2,3,5-3OCH3
2,3,6-3I
2,3,6-3CH3
2,3,6-3OCH3
2,4,5-3I
2,4,5-3CH3
2,4,5-3OCH3
2,4,6-3I
2,4,6-3CH3
2,4,6-3OCH3
2,5,6-3I
2,5,6-3CH3
2,5,6-3OCH3
3,4,5-3I
3,4,5-3CH3
3,4,5-3OCH3
3,4,6-3I
3,4,6-3CH3
3,4,6-3OCH3
3,5,6-3I
3,5,6-3CH3
3,5,6-3OCH3
2,3,4,5-4I
2,3,4,5-4CH3
2,3,4,5-4OCH3
2,3,4,6-4I
2,3,4,6-4 CH3
2,3,4,6-4 OCH3
2,3,4,5,6-5I
2,3,4,5,6-5 CH3
2,3,4,5,6-5 OCH3
2,3-2OCF3
2,3,4-3OCF3
3,4,5-3OCF3
2,4-2OCF3
2,3,5-3OCF3
3,4,6-3OCF3
2,5-2OCF3
2,3,6-3OCF3
3,5,6-3OCF3
2,6-2OCF3
2,4,5-3OCF3
2,3,4,5-4 OCF3
3,4-2OCF3
2,4,6-3OCF3
2,3,4,6-4 OCF3
3,5-2OCF3
2,5,6-3OCF3
2,3,4,5,6-5 OCF3.
when Y is pyridine ring optionally having a substituent, quinoline ring optionally having a substituent or isoquinoline ring optionally having a substituent, the substituent is selected from:
F
Cl
Br
I
CH3
OCH3
OH
CN
CF3
OCF3
NO2
SO2CH3
NH2
COOH
NHOCH3
COOCH3
N(CH3)2
C2H5
COOC2H5
NHOC2H5
CONH2
CONHCH3
CON(CH3)2
CH2CH2OH
CH(CH3)OH
C(CH3)3
CH2Br

218 more elements

Facts

Application

17/523,459Filed 10 Nov 2021 · continuation in part

Priority

CN 201911188758.128 Nov 2019

Published

US 2022/0064138 A13 Mar 2022

Granted

17 Mar 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 313/00
Heterocyclic compounds containing rings of more than six members having one oxygen
A61K 31/365
Having oxygen as the only ring hetero atom, e.g. fungichromin: lactones
A61K 31/443
Containing further heterocyclic ring systems: containing a five-membered ring with oxygen as a ring hetero atom
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone