Certain chemical entities, compositions, and methods

Patent metadata

Field	Value
Publication number	US-9328081-B2
Application number	US-201214342348-A
Country	US
Kind code	B2
Filing date	Aug 29, 2012
Priority date	Sep 1, 2011
Publication date	May 3, 2016
Grant date	May 3, 2016

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 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 compound or salt of claim 1 wherein R 1 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl.

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

4. The compound or salt of claim 1 wherein R 1 and R 2 are independently chosen from optionally substituted alkyl.

5. The compound or salt 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 compound or salt 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 compound or salt of any one of claims 1 to 6 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 compound or salt of claim 7 wherein R 3 is chosen from hydrogen, optionally substituted lower alkyl, and optionally substituted aminocarbonyl.

9. The compound or salt of claim 8 wherein R 3 is hydrogen.

10. The compound or salt of claim 8 wherein R 3 is optionally substituted lower alkyl.

11. The compound or salt of claim 10 wherein R 3 is methyl.

12. The compound or salt of claim 10 wherein R 3 is lower alkyl substituted with hydroxyl or amino.

13. The compound or salt of claim 8 wherein R 3 is optionally substituted aminocarbonyl.

14. A compound 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-diazepane-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-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-m

Assignees

• Qian Xiangping
• Neupharma Inc

Inventors

• Qian Xiangping

Classifications

• C07D295/192 Primary

  from aromatic carboxylic acids · CPC title

• C07D295/205

  Radicals derived from carbonic acid · 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

• A61P35/00

  Antineoplastic agents · CPC title

• 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