Triazolo-azepine derivatives

Patent metadata

Field	Value
Publication number	US-11370802-B2
Application number	US-201916963398-A
Country	US
Kind code	B2
Filing date	Jan 21, 2019
Priority date	Jan 22, 2018
Publication date	Jun 28, 2022
Grant date	Jun 28, 2022

Abstract

The present invention relates to a compound of formula (I) wherein Ar is (II) or (II); R is CH3 or OCH3; or a pharmaceutically acceptable acid addition salt or a corresponding enantiomer thereof. The compounds are modulators of γ-secretase (A β42) and may be useful for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome.

First claim

The invention claimed is:

1. A compound of formula I

wherein:
Ar is

and
R is CH 3 or OCH 3 ;
or a pharmaceutically acceptable acid addition salt or a corresponding enantiomer thereof.

2. A compound of formula IA-1 or IA-2,

which have the following respective formulae:
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine; and
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methylpyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;

or a pharmaceutically acceptable acid addition salt thereof.

3. A compound of formula IB-1, IB-2, IB-3 or IB-4,

which have the following respective formulae:
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine; and
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine; or
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[(1S,5R,8S)-3-(6-methoxypyridazin-4-yl)-3-azabicyclo[3.2.1]octan-8-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine;

or a pharmaceutically acceptable acid addition salt thereof.

4. A process for preparing a compound of formula I, which process comprises:
1) reacting a compound of formula 2

with a compound of formula 3

to form a compound of formula I

wherein Ar is

and optionally converting the compound of formula I into a pharmaceutically acceptable acid addition salt, and
2) optionally separating a racemic mixture of compounds of formula I by a chiral HPLC separation.

5. A compound prepared by a process as in claim 4 .

6. A pharmaceutical preparation containing one or more compounds of claim 1 and one or more pharmaceutically acceptable excipients.

7. A method for treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to a subject in need thereof a pharmaceutical preparation according to claim 6 .

8. A method for treating of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-Dutch type, multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to a subject in need thereof an effective amount of a compound as defined in claim 1 .

9. The pharmaceutical preparation of claim 6 in a form selected from: tablet, coated tablet, dragée, hard gelatin capsule, soft gelatin capsule, emulsion, suspension, suppository, eye drop, and ear drop.

10. The pharmaceutical preparation of claim 6 , wherein the one or more pharmaceutically acceptable excipients include one or more of:
a preservative, solubilizer, stabilizer, wetting agent, emulsifier, sweetener, colorant, flavorant, salt, buffer, masking agent, antioxidant, and a carrier selected from lactose, corn starch, talc, stearic acid, vegetable oil, wax, glycerol, and a polyol.

11. The process of claim 4 , wherein the reacting a compound of formula 2 with a compound of formula 3 is accompanied by a palladium catalyst selected from: dibromo-bis-(tritert-butyl)-phosphine palladium or tri(dibenzylideneacetone) dipalladium(0), in the presence of 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl and NaOt-Bu.

Assignees

• Hoffmann La Roche

Inventors

• Ratni Hasane

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

• 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title