Phosphonate derivatives and methods of use thereof in the treatment of Alzheimer's disease

Patent metadata

Field	Value
Publication number	US-9346839-B2
Application number	US-201414539050-A
Country	US
Kind code	B2
Filing date	Nov 12, 2014
Priority date	May 14, 2012
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

Benzothiazole phosphonate analogs and methods of using the same to inhibit the activity of Amyloid Binding Alcohol Dehydrogenase and in the amelioration or treatment of Alzheimer's disease are provided.

First claim

What is claimed is:

1. An Amyloid Binding Alcohol Dehydrogenase (ABAD) inhibitor of Formula III, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof

wherein
X is S or O;
the dashed bonds are independently present or absent;
R 1 and R 2 are each independently a hydrogen, hydroxyl, halo, alkoxy, or methylcarboxylate group;
R 4 and R 6 are each independently a hydrogen or phosphonate group; and
R 5 is a substituted or unsubstituted aryl or heteroaryl group;
with the proviso that at least one of R 4 or R 6 is a phosphonate group having the structure —PO(OR 7 ) 2 , wherein each R 7 is independently a methyl or ethyl group.

2. A method for ameliorating or treating Alzheimer's Disease comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an Amyloid Binding Alcohol Dehydrogenase inhibitor having the structure of Formula II

wherein
X is S or O;
R 1 and R 2 are each independently a hydrogen, hydroxyl, halo, alkoxy, or methylcarboxylate group;
R 4 is a phosphonate group; and
R 5 is a substituted or unsubstituted aryl or heteroaryl group, wherein said substituted aryl comprises one or more substituents selected from the group of —NO 2 , —CN, —NH 2 , —COOH, —OH, —OCH 3 , —OCF 3 , —CONH 2 , -alkyl, -alkoxy or a methylcarboxylate group thereby ameliorating or treating the subject's Alzheimer's Disease.

3. A pharmaceutical composition comprising the ABAD inhibitor of claim 1 and a pharmaceutically acceptable carrier.

4. A method for inhibiting the activity of Amyloid Binding Alcohol Dehydrogenase (ABAD) comprising contacting ABAD with an inhibitor of claim 1 thereby inhibiting the activity of ABAD.

5. A method for ameliorating or treating Alzheimer's Disease comprising administering to a subject in need thereof the pharmaceutical composition of claim 3 thereby ameliorating or treating the subject's Alzheimer's Disease.

Assignees

• Univ Kansas

Inventors

• Yan Shidu
• Valasani Koteswara Rao

Classifications

• C07F9/6541 Primary

  condensed with carbocyclic rings or {carbocyclic} ring systems · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• C07F9/65586

  at least one of the hetero rings does not contain nitrogen as ring hetero atom · CPC title

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07F9/4056

  Esters of arylalkanephosphonic acids (C07F9/4025 takes precedence) · CPC title