Amyloid targeting agents and methods of using the same

Patent metadata

Field	Value
Publication number	US-10370345-B2
Application number	US-201815969328-A
Country	US
Kind code	B2
Filing date	May 2, 2018
Priority date	Mar 19, 2014
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

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 methods for treating diseases associated with amyloid or amyloid like proteins.

First claim

What is claimed is:

1. A method for monitoring response to a treatment of a patient having a disease or condition characterized by amyloid deposit in a body part or a body area of the patient, comprising:
(i) forming a detectable complex in the body part or the body area following the treatment by contacting an effective amount of a compound of Formula Ic, or a salt or solvate thereof, or a pharmaceutical composition thereof, with the amyloid deposit; and
(ii) detecting the detectable complex, wherein a decrease of detectable complex as compared to before the treatment indicates that the patient is responsive to the treatment;
wherein the compound of Formula Ic has the structure:

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 ;
each R 1 is independently halogen, —OR 2 , —NR 3 R 4 , C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl,
each of R 2 , R 3 and R 4 is independently hydrogen, C 1 -C 10 alkyl, C 1 -C 10 heteroalkyl;

R 84 is hydrogen or C 1 -C 10 alkyl;
EWG is halogen, —CN, —NO 2 , or methyl;
WSG is:

wherein n is an integer from 2-50, and R 81 is hydrogen, a 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, aryl of no more than 10 carbon atoms, or heteroaryl of no more than 10 carbon atoms;
each R 82 is independently hydrogen or C 1 -C 10 alkyl;
X is C═O or SO 2 ; and
Y is NH or S.

2. The method of claim 1 , in which the amyloid deposit comprises an amyloid or amyloid like protein, wherein the amyloid or amyloid like protein is Aβ peptide, prion peptide, alpha-synuclein, or superoxide dismutase.

3. The method of claim 2 , wherein the amyloid or amyloid like protein is beta amyloid (1-42) (Aβ(1-42)).

4. The method of claim 1 , wherein EDG is

5. The method of claim 1 , wherein EDG is

6. The method of claim 1 , wherein EWG is —CN.

7. The method of claim 1 , wherein R 84 is hydrogen or methyl.

8. The method of claim 1 , wherein WSG is:

wherein R 81 is methyl or CH 2 —C≡CH,
wherein n is 2, 3, 4, 5, 6, 7, 8, 9, or 10;

9. The method of claim 1 , wherein WSG is

wherein n is an integer from 2-50 and R 81 is C 1 -C 10 alkyl.

10. The method of claim 1 , wherein R 81 is methyl.

11. The method of claim 1 , wherein n is 3 or 6.

12. The method of claim 1 , wherein the compound of Formula Ic is:

wherein n is an integer from 2 to 10, and n′ is an integer from 2 to 10.

13. The method of claim 1 , wherein the compound of Formula Ic is:

14. The method of claim 1 , wherein the compound of Formula Ic is:

15. The method of claim 1 , wherein the disease or condition is Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Lewy body dementia, or Down's syndrome.

16. The method of claim 1 , wherein the disease or condition is a prion disease or condition.

17. The method of claim 1 , wherein the disease or condition is Creutzfeldt-Jakob disease.

18. A method for monitoring response to a treatment of a patient having a disease or condition characterized by amyloid deposit in a body part or a body area of the patient, comprising
(i) forming a detectable complex in the body part or the body area following the treatment by contacting an effective amount of a compound of the formula:

 or a salt or solvate thereof, or a pharmaceutical composition thereof, with the amyloid deposit; and
(ii) detecting the detectable complex, wherein a decrease of detectable complex as compared to before the treatment indicates that the patient is responsive to the treatment.

19. A method of detecting an amyloid or amyloid like protein comprising
(i) contacting a compound of Formula Ic, or a salt or solvate thereof, with a body part or a body area of a patient potentially comprising the amyloid or amyloid like protein;
(ii) forming a detectable complex of the amyloid or amyloid like protein; and
(iii) detecting the detectable complex such that the presence or absence of the detectable complex correlates with the presence or absence of the amyloid or amyloid like protein;
wherein the compound of Formula Ic has the structure:

wherein
EDG is heterocycloalkyl of no more than 10 carbons optionally substituted with one or more R 17 ;
wherein 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 carbo

Assignees

• Univ California
• Amydis Inc
• Amydis Diagnostics Inc

Inventors

• Yang Jerry
• Theodorakis Emmanuel A
• Sarraf Stella

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D407/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D295/155 Primary

  with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• A61B5/0075

  by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy (A61B5/0071 takes precedence) · CPC title