IGF-1R signaling pathway inhibitors useful in the treatment of neurodegenerative diseases

Patent metadata

Field	Value
Publication number	US-9770454-B2
Application number	US-201414904787-A
Country	US
Kind code	B2
Filing date	Jul 13, 2014
Priority date	Jul 14, 2013
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present invention provides compounds acting as Insulin/IGF signaling modulators useful in the treatment of neurodegenerative diseases and disorders. The invention provides pharmaceutical compositions including such compounds, and methods of using these compounds and compositions for the treatment of neurodegenerative diseases, in particular neurodegenerative diseases caused by proteotoxicity such as Alzheimer's disease.

First claim

The invention claimed is:

1. A method of inhibiting toxic protein aggregation in a subject having a neurodegenerative disease selected from the group consisting of Amyloidosis, Prion disorders, Motor Neuron disease, Alzheimer's disease, Fronto temporal dementia 17 (FTD17), Huntington disease and Parkinson's disease, the method comprising the step of administering to the subject a therapeutically effective amount of a compound represented by the structure of formula IV:

wherein
R 1 , R 2 , R 5 and R 6 are independently selected from the group consisting of H, (CH 2 CH 2 O) n , wherein n is an integer of 1 to 20, acyl and a functional group that gives rise to hydroxyl upon hydrolysis;
R 3 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, haloalkyl and OR 16 wherein R 16 is H, C 1 -C 4 alkyl, (CH 2 CH 2 O) n , acyl or a functional group that gives rise to hydroxyl upon hydrolysis; and
R 4 is H or CN;

and salts, hydrates and solvates thereof.

2. The method of claim 1 , wherein the compound is represented by the structure of formula III:

wherein
R 1 , R 2 , R 5 and R 6 are independently selected from the group consisting of H, (CH 2 CH 2 O) n , wherein n is an integer of 1 to 20, acyl and a functional group that gives rise to hydroxyl upon hydrolysis;
R 3 and R 7 are independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, haloalkyl and OR 16 wherein R 16 is H, C 1 -C 4 alkyl, (CH 2 CH 2 O) n , acyl or a functional group that gives rise to hydroxyl upon hydrolysis; and
R 4 is H or CN;

and salts, hydrates and solvates thereof.

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

and salts, hydrates and solvates thereof.

4. The method of claim 3 , comprising administering to the subject a therapeutically effective amount of compound no. 39 or salts, hydrates or solvates thereof.

5. The method of claim 3 , comprising administering to the subject a therapeutically effective amount of compound no. 29 or salts, hydrates or solvates thereof.

6. The method of claim 1 , wherein Amyloidosis is selected from the group consisting of AL amyloidosis, AA amyloidosis, familial amyloid polyneuropathies, senile systemic amyloidosis, Leptomeningeal amyloidosis, Haemodialysis-associated amyloidosis, Finnish type amyloidosis, Cerebral amyloid angiopathy; Familial visceral amyloidosis; Familial corneal amyloidosis; Primary cutaneous amyloidosis and Senile amyloid of atria of heart.

7. The method of claim 1 , wherein the prion disorders are selected from the group consisting of Finnish type amyloidosis; Creutzfeldt-Jakob disease, fatal familial insomnia (FFI) and Gerstmann-Straussler-Scheinker syndrome (GSS).

8. The method of claim 1 , wherein the neurodegenerative disease is caused by toxic amyloid beta (Aβ) aggregation.

9. The method of claim 8 , wherein the neurodegenerative disease is Alzheimer's disease.

10. The method of claim 1 , wherein the compound inhibits Insulin/IGF signaling cascade (IIS).

11. The method of claim 1 , wherein the compound is compound no. 39 or salts, hydrates and solvates thereof, and wherein the neurodegenerative disease is Alzheimer's disease.

12. The method of claim 1 , wherein the compound is compound no. 39 or salts, hydrates and solvates thereof, and wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, and Prion disorders.

Assignees

• Yissum Res Dev Co

Inventors

• Reuveni Hadas
• Cohen Ehud
• Levitzki Alexander
• Ben-Sasson Shmuel

Classifications

• 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

• A61K31/165

  having aromatic rings, e.g. colchicine, atenolol, progabide · CPC title

• A61K31/5415 Primary

  ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title