Tricyclic pyrone compounds reduce amyloid beta aggregates

Patent metadata

Field	Value
Publication number	US-9802962-B2
Application number	US-201414503262-A
Country	US
Kind code	B2
Filing date	Sep 30, 2014
Priority date	Sep 30, 2013
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

Tricyclic pyrone compounds having high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity are presented. Administration of the compounds to Alzheimer's Disease transgenic models resulted in substantially reduced soluble and insoluble Aβ species in the brain without affecting general behavior and motor coordination. Furthermore, in addition to blocking the toxicity and formation of both intraneuronal and extracellular Aβ aggregates, the compounds also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic plasticity.

First claim

What is claimed is:

1. A method for reducing cerebral amyloid load and toxic Ab dimer level in a subject in need thereof, comprising orally administering to said subject a therapeutically effective amount of a compound of the formula

wherein,
R 1 , R 2 , and R 3 are independently selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl; and
R 4 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
wherein R 4 is other than adenine joined to the remainder of the compound through an endocyclic nitrogen atom of said adenine,
wherein said therapeutically effective amount is sufficient to achieve therapeutic brain concentration of said compound and reduce cerebral amyloid load and toxic Aβ dimer level, and said compound protects MC65 neuroblastoma cells from death caused by Aβ in a medium-throughput cell-based MC65 protection assay.

2. The method according to claim 1 , wherein said compound is of the formula:

3. The method according to claim 1 , said compound having the structure:

wherein R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halogen, CN, CF 3 , acyl, —SO 2 NR 10 R 11 , —NR 10 R 11 , —OR 10 , —S(O) 2 R 10 , —C(O)R 10 , —COOR 10 , —CONR 10 R 11 , —S(O) 2 OR 10 , —OC(O)R 10 , —C(O)NR 10 R 11, —NR 10 C(O)R 11 , —NR 10 SO 2 R 11 and —NO 2 ,
wherein two or more of R 5 , R 6 , R 7 , R 8 , and R 9 , together with the atoms to which they are bonded, are optionally joined to form a ring system which is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and
R 10 and R 11 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl,
wherein R 10 and R 11 , together with the atoms to which they are bonded, are optionally joined to form a 5- to 7-membered ring which is a member selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

4. The method according to claim 3 , wherein at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is selected from OH, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl or a combination thereof.

5. The method according to claim 3 , wherein at least one of R 5 and R 6 ; R 6 and R 7 ; R 7 and R 8 , or R 8 and R 9 ,together with the atoms to which they are bonded, are joined to form a phenyl ring, such that moiety A is substituted or unsubstituted napthyl.

6. The method according to claim 3 , in which moiety A is napthyl or phenyl, which is substituted with a member selected from OH, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl or a combination thereof.

7. The method according to claim 1 , wherein said compound is a component of a pharmaceutical formulation further comprising a pharmaceutically acceptable carrier.

Assignees

• Afasci Inc
• Univ Kansas State
• Univ California
• The Regents Of The Univ Of California A California Corp

Inventors

• Hua Duy H
• Jin Lee-Way
• Maezawa Izumi
• Xie Xinmin

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title