Piperlongumine analogues and uses thereof

Patent metadata

Field	Value
Publication number	US-12084423-B2
Application number	US-201817056705-A
Country	US
Kind code	B2
Filing date	May 18, 2018
Priority date	May 18, 2018
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders.

First claim

What is claimed is:

1. A compound, the compound of Formula (I):

wherein:
R is selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , NO 2 , and CN;
X is selected from the group consisting of CH 2 , O, NH, S, C(O), and S(O) 2 ;
n is an integer from 0-2;
A is S(O) 2 ;
B is selected from the group consisting of

wherein:
R 1 is selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR′, SR′, NR′R′, NR′COR′, NR′CONR′R′, NR′CO 2 R′, COR′, CO 2 R′, NOR′, NO 2 , CONR′R′, OC(O)NR′R′, SO 2 R′, SO 2 NR′R′, NR′SO 2 R′, NR′SO 2 NR′R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 1 -C 6 alkenyl, a substituted or unsubstituted C 1 -C 6 alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl;
R′ is independently selected from the group consisting of hydrogen, substituted C 1 -C 4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R′ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a β-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
C is hydrogen or

wherein:
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR″, SR″, NR″R″, NR″COR″, NR″CONR″R″, NR″CO 2 R″, COR″, CO 2 R″, NOR″, NO 2 , CONR″R″, OC(O)NR″R″, SO 2 R″, SO 2 NR″R″, NR″SO 2 R″, NR″SO 2 NR″R″, C(O)C(O)R″, and C(O)CH 2 C(O)R″, a substituted or unsubstituted C 1 to C 6 alkyl, a substituted or unsubstituted C 1 to C 6 alkenyl, a substituted or unsubstituted C 1 to C 6 alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl;
R″ is independently selected from the group consisting of hydrogen, substituted C 1 -C 4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R″ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a β-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
Optionally, R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 4-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
m is an integer from 0-6; and
Optionally, the phenyl ring in C or R′ and C taken together may be replaced by the following one or more monocyclic aryl, one or more heteroaryl, a β-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 6-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur.

2. The compound of claim 1 , wherein R is selected from the group consisting of hydrogen, F, Cl, Br, I, and CF 3 .

3. The compound of claim 1 , wherein X is selected from the group consisting of CH 2 and O.

4. The compound of claim 1 , wherein n is an integer from 1-2.

5. The compound of claim 1 , wherein B is

6. The compound of claim 1 , wherein C is

7. The compound of claim 6 , wherein R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, OCH 3 , and O(CH 2 )N(CH 3 ) 2 .

8. The compound of claim 7 , wherein R 2 and R 6 are hydrogen and R 3 , R 4 , and R 5 are OCH 3 .

9. A method of selectively killing one or more senescent cells in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I):

wherein:
R is selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , NO 2 , and CN;
X is selected from the group consisting of CH 2 , O, NH, S, C(O), and S(O) 2 ;
n is an integer from 0-2;
A is S(O) 2 ;
B is selected from the group consisting of

wherein:
R 1 is selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR′, SR′, NR′R′, NR′COR′, NR′CONR′R′, NR′CO 2 R′, COR′, CO 2 R′, NOR′, NO 2 , CONR′R′, OC(O)NR′R′, SO 2 R′, SO 2 NR′R′, NR′SO 2 R′, NR′SO 2 NR′R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 1 -C 6 alkenyl, a substituted or unsubstituted C 1 -C 6 alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl;
R′ is independently selected from the group consisting of hydrogen, substituted C 1 -C 4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R′ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a β-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
C is hydrogen or

wherein:
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR″, SR″, NR″R″, NR″COR″, NR″CONR″R″, NR″CO 2 R″, COR″, CO 2 R″, NOR″, NO 2 , CONR″R″, OC(O)NR″R″, SO 2 R″, SO 2 NR″R″, NR″SO 2 R″, NR″SO 2 NR″R″, C(O)C(O)R″, and C(O)CH 2 C(O)R″, a substituted or unsubstituted C 1 to C 6 alkyl, a substituted or unsubstituted C 1 to C 6 alkenyl, a substituted or unsubstituted C 1 to C 6 alkynyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl;
R″ is independently selected from the group consisting of hydrogen, substituted C 1 -C 4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R″ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a β-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;
Optionally, R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , and R 5 and R 6 are taken together to form a 4-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen,

Assignees

• Bioventures Llc

Inventors

• Zheng Guangrong
• Zhou Daohong
• Zhang Xuan

Classifications

• C07D265/02

  1,2-Oxazines; Hydrogenated 1,2-oxazines · CPC title

• C07D211/88

  attached in positions 2 and 6, e.g. glutarimide · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D223/10 Primary

  attached in position 2 · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title