Certain chemical entities, compositions, and methods

Patent metadata

Field	Value
Publication number	US-9707202-B2
Application number	US-201615044424-A
Country	US
Kind code	B2
Filing date	Feb 16, 2016
Priority date	Sep 1, 2011
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Chemical entities that are curcumin derivatives, pharmaceutical compositions and methods of treatment of cancer are described.

First claim

What is claimed is:

1. A method of inhibiting growth of a cancer cell selected from the group consisting of a colorectal cancer cell, a liver cancer cell, a lung cancer cell, a breast cancer cell and an oral cancer cell, the method comprising administering to the cell a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
or R 1 and R 2 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and
R 3 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted alkoxycarbonyl, and optionally substituted phosphato.

2. The method of claim 1 , wherein R 1 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

3. The method of claim 1 , wherein R 2 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

4. The method of claim 1 , wherein R 1 and R 2 are independently chosen from optionally substituted alkyl.

5. The method of claim 1 , wherein R 1 and R 2 are joined together to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

6. The method of claim 5 , wherein R 1 and R 2 are joined together to form an optionally substituted pyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, 1,4-diazepan-1-yl, and 1,4-diazocan-1-yl.

7. The method of claim 1 , wherein R 3 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aminocarbonyl, and optionally substituted phosphato.

8. The method of claim 7 , wherein R 3 is chosen from hydrogen, optionally substituted lower alkyl, and optionally substituted aminocarbonyl.

9. The method of claim 8 , wherein R 3 is hydrogen.

10. The method of claim 8 , wherein R 3 is optionally substituted lower alkyl.

11. The method of claim 10 , wherein R 3 is lower alkyl substituted with hydroxyl or amino.

12. The method of claim 8 , wherein R 3 is optionally substituted aminocarbonyl.

13. The method of claim 1 , wherein the compound is chosen from:
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-hydroxypiperidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-aminopiperidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-hydroxypiperidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopiperidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(hydroxymethyl)piperazine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-(hydroxymethyl)morpholine-4-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-(aminomethyl)morpholine-4-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl pyrrolidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-hydroxypyrrolidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-(aminomethyl)pyrrolidine-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 1,4-diazepam-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methyl-1,4-diazepane-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl (2-aminoethyl)(methyl)carbamate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl (2-(dimethylamino)ethyl)(methyl)carbamate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl dimethylcarbamate,
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopiperidine-1-carboxylate,
4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopiperidine-1-carboxylate,
4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-aminopiperidine-1-carboxylate,
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate,
4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate,
4-((1E,6E)-7-(4-((dimethylcarbamoyl)oxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperazine-1-carboxylate,
((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2-methoxy-4, 1-phenylene)bis(piperazine-1-carboxylate),
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 4-methylpiperazine-1-carboxylate,
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate,
4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 3-aminopyrrolidine-1-carboxylate,
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 1,4-diazepane-1-carboxylate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl methyl (2-(pyrrolidin-1-yl)ethyl)carbamate,
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl methyl (2-morpholinoethyl)carbamate,
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate,
4-((1E,6E)-7-(3,4-dimethoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl morpholine-4-carboxylate,
4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl piperidine-1-carboxylate,
4-((1E,6E)-7-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping

Classifications

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D295/192

  from aromatic carboxylic acids · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/535

  having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines · CPC title

• A61K31/4453

  only substituted in position 1, e.g. propipocaine, diperodon · CPC title