Diazacarbazole derivatives as tau-PET-ligands

Patent metadata

Field	Value
Publication number	US-10004817-B2
Application number	US-201615093366-A
Country	US
Kind code	B2
Filing date	Apr 7, 2016
Priority date	Oct 8, 2013
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

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

First claim

The invention claimed is:

1. A compound of Formula I

wherein
R is hydrogen or tritium;
F is fluoro or 18 fluoro;
or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of Formula I according to claim 1 , selected from the group consisting of
2-(6-fluoro-pyridin-3-yl)-9H-dipyrido[2,3-b;3′,4′-d]pyrrole,
3 H-2-(6-fluoro-pyridin-3-yl)-9H-dipyrido[2,3-b;3′,4′-d]pyrrole and
and [18F]-2-(6-fluoro-pyridin-3-yl)-9H-dipyrido[2,3-b;3′,4′-d]pyrrole.
or a pharmaceutically acceptable acid addition salt thereof.

3. A process for the manufacture of a compound of Formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, comprising one of the following three methods, a)-c):
a) coupling a compound of Formula 2 (X=Cl, Br)

with a boronic acid or boronic acid ester of Formula 3

wherein R′ is hydrogen or lower alkyl,
thus producing the following compound of Formula I, called Compound A

wherein R is hydrogen,
and, optionally, converting Compound A into a pharmaceutically acceptable acid addition salt or into a compound of Formula I, wherein R is tritium by bombarding Compound A with tritium gas in the presence of a catalyst selected from iridium, ruthenium, rhodium and palladium containing complexes, in a solvent selected from dichloromethane, chlorobenzene, DMF and DMSO or mixtures thereof;
or
b) coupling a compound of Formula 4

with a fluorinating reagent selected from potassium fluoride and tetrabutylammonium fluoride,
thus producing Compound A of Formula I

wherein R is hydrogen,
and, optionally, converting Compound A into a pharmaceutically acceptable acid addition salt or into a compound of Formula I, wherein R is tritium by bombarding Compound A with tritium gas in the presence of a catalyst selected from iridium, ruthenium, rhodium and palladium containing complexes, in a solvent selected from dichloromethane, chlorobenzene, DMF and DMSO or mixtures thereof;
or
c) reacting a compound of Formula I

wherein R is hydrogen, with tritium gas in the presence of a catalyst selected from iridium, ruthenium, rhodium and palladium containing complexes, in a solvent selected from dichloromethane, chlorobenzene, DMF and DMSO or mixtures thereof, thus producing the following compound of Formula I, called Compound B

wherein R is tritium, and, optionally, converting Compound B into a pharmaceutically acceptable acid addition salt.

4. A pharmaceutical preparation comprising a compound of Formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical acceptable carrier.

5. A method of diagnostic imaging tau-aggregate deposits, beta-amyloid aggregate deposits, or alpha-synuclein aggregate deposits, comprising
introducing into a mammal a detectable quantity of the preparation according to claim 4 ;
and
detecting the compound bound to one or more deposits selected from tau-aggregate deposits, beta-amyloid aggregate deposits, or alpha-synuclein aggregate deposits via diagnostic imaging.

6. The method of claim 5 , wherein the deposits are tau-aggregate deposits.

Assignees

• Hoffmann La Roche

Inventors

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

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• G01N33/58

  involving labelled substances (G01N33/53 takes precedence) · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title