Amyloid targeting agents and methods of using the same

Patent metadata

Field	Value
Publication number	US-10005745-B2
Application number	US-201514915883-A
Country	US
Kind code	B2
Filing date	Mar 19, 2015
Priority date	Mar 19, 2014
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

Provided herein is the design and synthesis of novel molecular rotor fluorophores useful for detection of amyloid or amyloid like proteins. The fluorophores are designed to exhibit enhanced fluorescence emission upon associating with amyloid or amyloid like proteins as compared to unbound compound. Also disclosed herein are the methods for treating of diseases associated with an amyloid or amyloid like proteins.

First claim

What is claimed is:

1. A compound of Formula Ic:

wherein:
EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R 17 ;
each R 17 is independently halogen, —OR 18 , —NR 19 R 20 , C 1 -C 10 alkyl, or C 1 -C 10 heteroalkyl;
each of R 18 , R 19 , and R 20 is independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl, or cycloalkyl of no more than 10 carbon atoms, each of which except for hydrogen is optionally substituted with one or more R 21 ;
each R 21 is independently halogen, —OR 22 , —NR 23 R 24 , C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, or heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each of R 22 , R 23 and R 24 is independently hydrogen or C 1 -C 10 alkyl;
Ar is arylene of no more than 14 carbon atoms optionally substituted with one or more R 1 ;
each R 1 is independently halogen, —OR 2 , —NR 3 R 4 , C 1 -C 10 alkyl, or C 1 -C 10 heteroalkyl
each of R 2 , R 3 , R 4 is independently hydrogen, C 1 -C 10 alkyl, or C 1 -C 10 heteroalkyl
R 84 is hydrogen or C 1 -C 10 alkyl;
EWG is halogen, —CN, NO 2 or CR 26 R 27 R 28 ;
each of R 26 , R 27 and R 28 is hydrogen;
WSG is selected from the group consisting of:

n is an integer from 2 to 50;
R 81 is hydrogen, C 1 -C 10 alkyl, a C 2 -C 10 alkenyl, or a C 2 -C 10 alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, arylene of no more than 10 carbon atoms, and heteroarylene of no more than 10 carbon atoms;
R 82 is hydrogen or C 1 -C 10 alkyl;
X is C═O or SO 2 ; and
Y is NH, or S;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein EDG is selected from a group consisting of

3. The compound claim 1 , wherein EDG is

4. The compound of claim 1 , wherein EWG is selected from the group consisting of halogen, —NO 2 , and —CN.

5. The compound of claim 4 , wherein EWG is —CN.

6. The compound of claim 1 , wherein R 81 is methyl.

7. The compound of claim 1 , wherein n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

8. The compound of claim 1 , wherein n is 3 or 6.

9. The compound of claim 1 , wherein R 84 is hydrogen.

10. The compound of claim 1 , wherein R 84 is methyl.

11. The compound of claim 1 , wherein X is SO 2 and Y is NH.

12. The compound of claim 1 , wherein X is C═O and Y is NH.

13. A compound selected from a group consisting of

or a pharmaceutically acceptable salt thereof.

14. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein Ar is phenyl or naphthyl.

16. The compound of claim 1 , wherein WSG is

17. The compound of claim 1 , wherein WSG is

18. A pharmaceutical composition comprising a compound according to claim 1 .

19. The pharmaceutical composition of claim 18 , further comprising one or more pharmaceutically acceptable additive, carrier, or excipient selected from the group consisting of ethanol, DMSO, polyethylene glycol, polypropylene glycol, an aqueous acetate buffer, an aqueous citrate buffer, an aqueous phosphate buffer, an aqueous carbonate buffer, cyclodextrin, corn oil, vitamin E, a polysorbate, solutol, and a bile acid.

20. A compound of Formula Ic:

wherein
EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R 17 ,
each R 17 is independently halogen, —OR 18 , —NR 19 R 20 , C 1 -C 10 alkyl, or C 1 -C 10 heteroalkyl
each of R 18 , R 19 , and R 20 is independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl, or cycloalkyl of no more than 10 carbon atoms, each of which except for hydrogen is optionally substituted with one or more R 21 ;
each R 21 is independently halogen, —OR 22 , —NR 23 R 24 , C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl, cycloalkyl of no more than 10 carbon atoms, heterocycloalkyl of no more than 10 carbon atoms, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each of R 22 , R 23 and R 24 is independently hydrogen or C 1 -C 10 alkyl;
Ar is arylene of no more than 14 carbon atoms optionally substituted with one or more R 1 ;
R 1 is independently halogen, —OR 2 , —NR 3 R 4 , C 1 -C 10 alkyl, or C 1 -C 10 heteroalkyl;
each of R 2 , R 3 , R 4 is independently hydrogen, C 1 -C 10 alkyl, or C 1 -C 10 heteroalkyl;
R 84 is hydrogen or C 1 -C 10 alkyl;
EWG is halogen, —CN, NO 2 or —CR 26 R 27 R 28 ;
each of R 26 , R 27 , and R 28 is hydrogen;
X is C═O or SO 2
Y is NH or S;
WSG is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

21. A compound selected from a group consisting of

or a pharmaceutically acceptable salt thereof, wherein n is an integer having a value from 1-10 and n′ is an integer from 2-10.

22. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignees

• Amydis Diagnostics Inc
• Univ California
• Amydis Inc

Inventors

• Yang Jerry
• Theodorakis Emmanuel A
• Sarraf Stella

Classifications

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D405/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07H13/04

  having the esterifying carboxyl radicals attached to acyclic carbon atoms · CPC title

• A61B5/4082

  Diagnosing or monitoring movement diseases, e.g. Parkinson, Huntington or Tourette · CPC title

• C07C255/58

  containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton · CPC title