Imidazo[1,2-a]pyridin-7-amine

Patent metadata

Field	Value
Publication number	US-9957266-B2
Application number	US-201615081002-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Sep 26, 2013
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

The present invention relates to compounds that may be used for binding and imaging tau aggregates and related beta-sheet aggregates including, for example, beta-amyloid aggregates or alpha-synuclein aggregates.

First claim

The invention claimed is:

1. A compound of Formula I

wherein
R 1 is lower alkyl or lower alkyl substituted by halogen;
R 2 , R 3 are hydrogen or tritium;
or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of Formula I according to claim 1 , wherein R 1 is lower alkyl and R 2 and R 3 are as described in claim 1 .

3. The compound of Formula I according to claim 1 , which is
2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-amine or
[ 3 H]-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-amine.

4. The compound of Formula I according to claim 1 , wherein R 1 is lower alkyl substituted by halogen and R 2 and R 3 are as described in claim 1 .

5. The compound of Formula I according to claim 1 , which compound is
2-(4-(fluoromethoxy)phenyl)imidazo[1,2-a]pyridin-7-amine,
2-[4-(3-fluoropropoxy)phenyl]imidazo[1,2-a]pyri din-7-amine,
2-[4-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-7-amine, or
[ 3 H]-2-[4-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-7-amine.

6. The compound of Formula I according to claim 1 , wherein R 2 and R 3 are tritium and R 1 is as described in claim 1 .

7. The compound of Formula I according to claim 1 , which compound is
[ 3 H]-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-amine or
[ 3 H]-2-[4-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyridin-7-amine.

8. A process for the manufacture of a compound of Formula I as defined in claim 1 , which process comprises one of the following a)-d)
a) amination of a compound of Formula 2 (X=Cl, Br)

wherein R 1 is as in claim 1 , and R 2 and R 3 are each hydrogen, with NH 4 OH,
thus producing the following compound of Formula I, called Compound A

wherein R 1 is as defined in claim 1 , and R 2 and R 3 are hydrogen, and, optionally, converting Compound A into a pharmaceutically acceptable acid addition salt,
or
b) coupling a compound of Formula 4

with a corresponding α-activated ketone of Formula 3 (X is a leaving group)

wherein R 1 is as in claim 1 , and R 2 and R 3 are each hydrogen, thus producing Compound A of Formula I

wherein R 1 is as defined in claim 1 , and R 2 and R 3 are hydrogen, and, optionally, converting the compound obtained into a pharmaceutically acceptable acid addition salt, or
c) reacting a compound of Formula 5

wherein R 2 and R 3 are each hydrogen, with a alkylation agent R 1 —X (X is halogen or sulfonate)
thus producing the following compound of Formula I, called Compound B

wherein R 1 is as defined in claim 1 , and R 2 and R 3 are hydrogen, and, optionally, converting Compound B into a pharmaceutically acceptable acid addition salt,
or
d) reacting Compound C

wherein R 1 is as in claim 1 , and R 2 and R 3 are hydrogen,
with tritium gas in the presence of a catalyst selected from the group consisting of iridium, ruthenium, rhodium and palladium containing complexes, in a solvent selected from the group consisting of dichloromethane, chlorobenzene, DMF, and DMSO or mixtures thereof,
thus producing the following compound of Formula I, called Compound D

wherein R 1 is as defined in claim 1 and R 2 and R 3 are tritium, and, optionally, converting the compound obtained into a pharmaceutically acceptable acid addition salt.

9. A pharmaceutical composition comprising a compound of Formula I according to claim 1 , and a pharmaceutical acceptable carrier.

10. A method of imaging tau-aggregate deposits, beta-amyloid aggregate deposits, or alpha-synuclein aggregate deposits, comprising
introducing into a mammal a detectable quantity of the composition according claim 9 ; and
detecting the compound bound to one or more deposits selected from tau-aggregate, beta-amyloid aggregate, or alpha-synuclein aggregate via diagnostic imaging.

11. The method of claim 10 , wherein the deposits are tau-aggregate deposits.

Assignees

• Hoffmann La Roche

Inventors

• Gobbi Luca
• Knust Henner
• Koerner Matthias
• Muri Dieter

Classifications

• G01N33/52

  Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper {and including single- and multilayer analytical elements (immunological elements G01N33/54386; involving labelled immunochemicals G01N33/58; for haemoglobin or occult blood G01N33/72)} · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · 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

• G01N33/53

  Immunoassay; Biospecific binding assay; Materials therefor · CPC title