# US 2008/0188463 A1 · 6-oxo-6,7-dihydro-5h-dibenzo[b,d]azepin-7-yl derivatives

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- Number: US 2008/0188463 A1
- Document ID: US20080188463A1
- Status: Published application
- Kind: A1
- Application number: 12/019,667
- Filed: 2008-01-25
- Published: 2008-08-07
- Earliest claimed: 2007-02-02
- Assignees: Hoffman-La Roche Inc.
- Inventors: Alexander Flohr; Roland Jakob-Roetne; Wolfgang Wostl
- Web page: https://patentgrep.com/patent/US20080188463A1

## CPC

- C07D 223/18: Dibenzazepines; Hydrogenated dibenzazepines
- A61P 25/28: 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
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to 6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl derivatives of formula I wherein R1, R2 and R3 are as defined herein. The compounds are γ-secretase inhibitors useful in the treatment of Alzheimer's disease or common cancer, including, but not limited to, cervical carcinomas and breast carcinomas and malignancies of the hematopoietic system.

## Claims

### Claim 1

A compound of formula I
wherein
R1 is hydrogen or lower alkyl substituted by halogen;
R2 is lower alkyl;
R3 is lower alkyl substituted by halogen, —(CH2)n-cycloalkyl or —(CH2)n-phenyl, wherein the phenyl ring is unsubstituted or substituted by halogen;
n is 0, 1 or 2;
or a pharmaceutically suitable optically pure epimer or mixture thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen and R3 is lower alkyl substituted by halogen.

### Claim 3 (depends on 2)

The compound of claim 2, selected from the group consisting of
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(R)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide,
(R/S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,3-trifluoro-propyl)-malonamide,
(S)-2-hydroxy-2-methyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,3-trifluoro-propyl)-malonamide,
(R)-2-ethyl-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,2-trifluoro-ethyl)-malonamide,
(R/S)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-2-propyl-malonamide,
(R)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-2-propyl-malonamide and
(S)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N-(2,2,3,3,3-pentafluoro-propyl)-2-propyl-malonamide.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is lower alkyl substituted by halogen and R3 is lower alkyl substituted by halogen.

### Claim 5 (depends on 4)

The compound of claim 4, selected from the group consisting of
(R)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide and
(S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,2-trifluoro-ethyl)-malonamide.

### Claim 6

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
R1 is hydrogen or lower alkyl substituted by halogen;
R2 is lower alkyl;
R3 is lower alkyl substituted by halogen, —(CH2)n-cycloalkyl or —(CH2)n-phenyl, wherein the phenyl ring is unsubstituted or substituted by halogen;
n is 0, 1 or 2;
or a pharmaceutically suitable optically pure epimer or mixture thereof and a pharmaceutically acceptable carrier.