Drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases

Patent metadata

Field	Value
Publication number	US-10071966-B2
Application number	US-201514978964-A
Country	US
Kind code	B2
Filing date	Dec 22, 2015
Priority date	Jun 9, 2008
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present invention relates to a compound represented by formula (E). The present invention also relates to a compound represented by the formula (E) for use in the treatment or prevention of diseases linked to protein aggregation and/or neurodegenerative diseases. Moreover, the present invention relates to pharmaceutical and diagnostic compositions comprising the compound of the invention as well as to a kit. Furthermore, the present invention relates to a method of imaging deposits of aggregated protein. A kit for preparing a detectably labelled compound of the present invention is also disclosed.

First claim

The invention claimed is:

1. A method of treating a disease of protein aggregation in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (E),

wherein
the ring D is directionally selected from the following structures:

wherein
R 8 and R 9 are independently selected from hydrogen; C 1-4 alkyl; —C 1-4 alkylene-halogen; —C 1-4 alkylene-OH; —C 1-4 alkylene-C 1-4 alkoxy; —C(O)—C 1-4 alkyl; and C 6-10 aryl, wherein the aryl ring can be optionally substituted by C 1-4 alkyl or halogen;
Hal is selected from F, Cl, Br, and I;
R E5 and R E6 are independently selected from hydrogen and C 1-6 alkyl;
R E7 and R E8 are independently H or F;
R E9 and R E10 are independently H or F;
n is 1 to 3;
R E3 is a C 1-6 alkyl group or a C 5-10 aryl group;
m is 0 to 2;
R E4 is a halogen atom, a C 1-6 alkyl group or a C 5-10 aryl group;
p is 0 to 2;
wherein
(i) R E1 and R E2 are attached to adjacent carbon atoms and R E1 and R E2 together form a structure -T-(CR E7 R E8 ) n —V—, wherein T is selected from CR E9 R E10 m NH and O and V is selected from CR E9 R 10 , NH and O, as well as corresponding structures in which a double bond is present;
(ii) R E is —NR E5 R E6 and is attached in para-position compared to the carbon atom which binds the phenyl ring to ring D and R E2 is selected from hydrogen, halogen, hydroxy, C 1-6 alkoxy, and —NR E5 R E6 ; or
(iii) R E1 and R E2 are independently selected from C 1-6 alkoxy and hydroxy and are attached meta and para compared to the carbon atom which binds the phenyl ring to ring D;
as well as an ester, solvate or salt of the compound represented by formula (E); wherein the disease of protein aggregation is selected from the group consisting of scrapie, Parkinson's disease, Alzheimer's disease, Creutzfeldt-Jakob disease, multiple system atrophy, dementia with Lewy bodies, and type II diabetes.

2. The method according to claim 1 , wherein the disease of protein aggregation is selected from the group consisting of Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies.

3. The method according to claim 1 , wherein the disease of protein aggregation is selected from the group consisting of Alzheimer's disease, Creutzfeldt-Jakob disease; and scrapie.

4. The method according to claim 1 , wherein the disease of protein aggregation is type II diabetes.

5. The method of claim 1 , wherein the compound represented by formula (E) is a compound represented by formula (A)

wherein
R A1 and R A2 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkoxy, and —NR A5 R A6 , with the proviso that at least one of R A1 and R A2 is hydroxy, C 1-6 alkoxy, or —NR A5 R A6 ;
alternatively R A1 and R A2 can together form a structure -T-(CR E7 R E8 ) n —V—;
R A3 is a C 1-6 alkyl group or a C 5-10 aryl group;
R A4 is a halogen atom, a C 1-6 alkyl group or a C 5-10 aryl group; and
R A5 and R A6 are independently selected from hydrogen and C 1-6 alkyl;
as well as an ester, solvate or salt of the compound represented by formula (A).

6. The method of claim 1 wherein R 8 and R 9 are selected from hydrogen; C 1-4 alkyl; —C 1-4 alkylene-halogen; and C 6-10 aryl, wherein the aryl ring can be optionally substituted by C 1-4 alkyl or halogen.

7. The method of claim 1 , wherein ring D is directionally selected from the following structures:

wherein R 9 is H.

8. The method of claim 1 , wherein the compound is selected from the group consisting of:

wherein Hal is Cl or Br;
as well as an ester, solvate or salt of these compounds.

9. The method of claim 1 , wherein the compound is

wherein Hal is Cl or Br;
or an ester, solvate or salt thereof.

10. The method of claim 1 , wherein the compound is

wherein Hal is Cl or Br;
or an ester, solvate or salt thereof.

11. The method of claim 1 , wherein the compound is

wherein Hal is Cl or Br;
or an ester, solvate or salt thereof.

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

wherein Hal is Cl or Br;
or an ester, solvate or salt thereof.

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

wherein Hal is Cl or Br;
or an ester, solvate or salt thereof.

Assignees

• Univ Muenchen Ludwig Maximilians
• Max Planck Gesellschaft
• Ludwig Maximalians Univ Munchen
• Max Planck Gesellschaft

Inventors

• Giese Armin
• Bertsch Uwe
• Kretzschmar Hans
• Habeck Matthias
• Hirschberger Thomas
• Tavan Paul
• Griesinger Christian
• Leonov Andrei
• Ryazanov Sergey
• Frick Petra
• Geissen Markus
• Groschup Martin H
• Wagner Jens

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title