Luciferin amides

Patent metadata

Field	Value
Publication number	US-9370588-B2
Application number	US-201313839791-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Jan 4, 2013
Publication date	Jun 21, 2016
Grant date	Jun 21, 2016

Abstract

This disclosure relates to luciferin amides of formula (I) shown below:

Each variable in formula (I) is defined in the specification. These compounds can be used to detect fatty acid amide hydrolase activities in vitro, in live cells, or in vivo.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
n is 0;
is deleted;
each of X 1 and X 2 is S;
each of Y 1 and Y 2 is N;
Z is C(R c ) or C(R c R c′ ), in which each of R c and R c′ , independently, is H or C 1 -C 10 alkyl; provided that, when is a single bond, Z is C(R c R c′ ) and that, when is a double bond, Z is C(R c );
each of R 1 , R 4 , R 5 , and R 6 , independently, is H, halo, CN, OR e , SR e , NO 2 , N(R e R e′ ), C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, aryl, heteroaryl, in which each of R e and R e′ , independently, is H or C 1 -C 10 alkyl;
R 2 and R 3 , together with the carbon atoms to which they are attached, are a 5 or 6-membered ring, each of which is optionally substituted with C 1 -C 10 alkyl or optionally fused with a 5 or 6-membered ring; and
each of R 7 and R 8 , independently, is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, aryl, or heteroaryl.

2. The compound of claim 1 , wherein R 2 and R 3 , together with the carbon atoms to which they are attached, are a 5-membered ring optionally substituted with CH 3 , or a 6-membered ring optionally substituted with CH 3 or optionally fused with a 5-membered ring.

3. The compound of claim 2 , wherein each of R 1 and R 4 , independently, is H, OH, or C 1 -C 10 alkyl.

4. The compound of claim 3 , wherein each of R 5 and R 6 is H and each of R 7 and R 8 , independently, is H or C 1 -C 10 alkyl.

5. The compound of claim 4 , wherein the compound is

6. The compound of claim 1 , wherein the compound is a D-isomer.

7. An imaging method, comprising:
contacting a cell comprising a luciferase and a fatty acid amide hydrolase with the compound of claim 1 ; and
detecting bioluminescent emission from the cell.

8. The method of claim 7 , wherein the luciferase is a wild-type luciferase.

9. The method of claim 8 , wherein the wild-type luciferase is a beetle luciferase.

10. The method of claim 9 , wherein the beetle luciferase is a firefly, click beetle, or railroad worm luciferase.

11. The method of claim 7 , wherein the luciferase is a mutated luciferase.

12. The method of claim 7 , wherein the contacting step is performed in a brain of a subject.

13. An imaging method, comprising:
contacting a cell comprising a fatty acid amide hydrolase with the compound of claim 1 ;
introducing a luciferase; and
detecting bioluminescent emission.

14. A compound of formula (I):

wherein
n is 0;
is deleted;
each of X 1 and X 2 is S;
each of Y 1 and Y 2 is N;
Z is C(R c ) or C(R c R c′ ), in which each of R c and R c′ , independently, is H or C 1 -C 10 alkyl; provided that, when is a single bond, Z is C(R c R c′ ) and that, when is a double bond, Z is C(R c );
each of R 1 , R 4 , R 5 , and R 6 , independently, is H, halo, CN, OR e , SR e , NO 2 , N(R e R e′ ), C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, aryl, heteroaryl, in which each of R e and R e′ , independently, is H or C 1 -C 10 alkyl;
R 2 and R 3 , together with the carbon atoms to which they are attached, are a 5 or 6-membered ring, each of which is optionally substituted with C 1 -C 10 alkyl or optionally fused with a 5 or 6-membered ring;
R 7 is H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, aryl, or heteroaryl; and
R 8 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 -C 20 heterocycloalkenyl, aryl, or heteroaryl.

15. An imaging method, comprising:
contacting a cell comprising a luciferase and a fatty acid amide hydrolase with the compound of claim 14 ; and
detecting bioluminescent emission from the cell.

16. An imaging method, comprising:
contacting a cell comprising a fatty acid amide hydrolase with the compound of claim 14 ;
introducing a luciferase; and
detecting bioluminescent emission.

Assignees

• Univ Massachusetts

Inventors

• Miller Stephen C

Classifications

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K49/0045 Primary

  the fluorescent agent being a peptide or protein used for imaging or diagnosis in vivo · CPC title

• C07D513/06

  Peri-condensed systems · CPC title

• A61K49/0021 Primary

  the fluorescent group being a small organic molecule · CPC title

• A61K49/0017

  Fluorescence in vivo · CPC title