Indole derivatives

Patent metadata

Field	Value
Publication number	US-10329296-B2
Application number	US-201615563259-A
Country	US
Kind code	B2
Filing date	Apr 14, 2016
Priority date	Apr 15, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present invention relates to compounds of the general form (I). The present invention relates to new substituted diazepino-indole derivatives of the general formula (I), and to pharmaceutically acceptable salts thereof, as well as to pharmaceutical compositions comprising such compounds, to new intermediate thereof, as well as to the use of such compounds in treatment or prevention of disorders associated with melanin-concentrating hormone receptor 1 activity.

First claim

The invention claimed is:

1. A compound of the formula (I)

wherein
A is CH or nitrogen;
R is hydrogen or halogen or C 1 -C 6 straight or branched chain alkyl group;
R 1 is hydrogen or halogen, or
C 1 -C 6 straight or branched chain alkyl group, or
C 1 -C 6 straight or branched chain alkoxy group, or
mono- or polyhalogenated C 1 -C 6 straight or branched chain haloalkyl group;

R 2 is hydrogen or halogen, or
C 1 -C 6 straight or branched chain alkyl group, or
C 1 -C 6 straight or branched chain alkoxy group, or
mono- or polyhalogenated C 1 -C 4 straight or branched chain haloalkyl group;

R 3 is hydrogen, or
C 1 -C 6 straight or branched chain alkyl group, optionally substituted with C 3 -C 6 cycloalkyl group, or
mono- or polyhalogenated C 1 -C 6 straight or branched chain haloalkyl group, or
C 3 -C 6 cycloalkyl group, or
(C 1 -C 6 straight or branched chain alkyl)-C(O)-group;

or salts, geometric isomers, stereoisomers, diastereomers, or hydrates thereof.

2. The compound of claim 1 , wherein R 3 is:
hydrogen, or
C 1 -C 4 straight or branched chain alkyl group, optionally substituted with C 3 -C 6 cycloalkyl group, or
C 3 -C 6 cycloalkyl group, or
(C 1 -C 4 straight or branched chain alkyl)-C(O)-group.

3. The compound of claim 1 , wherein R 3 is:
hydrogen, or
C 1 -C 4 straight or branched chain alkyl group, optionally substituted with C 3 -C 4 cycloalkyl group or fluorine, or
C 3 -C 4 cycloalkyl group, or
acetyl.

4. The compound of claim 1 , wherein R 3 is methyl, ethyl, isopropyl, cyclopropylmethyl, cyclobutyl or fluoroethyl.

5. The compound of claim 1 , wherein R 3 is isopropyl or cyclopropylmethyl.

6. The compound of claim 1 , wherein R 2 is hydrogen, halogen, trifluoromethyl, or C 1 -C 3 alkyl group.

7. The compound of claim 1 , wherein R 2 is hydrogen, fluorine, chlorine, or methyl.

8. The compound of claim 1 , wherein R 2 is hydrogen.

9. The compound of claim 1 , wherein R 1 is:
hydrogen or halogen, or
C 1 -C 4 straight or branched chain alkyl group, optionally mono- or polyhalogenated, or
C 1 -C 3 alkoxy group.

10. The compound of claim 1 , wherein R 1 is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl.

11. The compound of claim 1 , wherein R 1 is hydrogen, fluorine, or chlorine.

12. The compound of claim 1 , wherein R is hydrogen.

13. The compound of claim 1 , wherein R is hydrogen and R 1 is chlorine.

14. The compound of claim 1 , wherein A is nitrogen.

15. The compound of claim 1 , wherein A is CH.

16. The compound of claim 1 , selected from the group consisting of:
4-[(5-chloro-pyridin-2-yl)methoxy]-1-{1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1-{3-methyl-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1-{3-ethyl-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one;
4-[(5-fluoro-pyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-(benzyloxy)-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-[(4-fluoro-phenyl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-[(4-chloro-phenyl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-[(2-fluoro-phenyl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
1-[11-chloro-3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-4-[(5-chloro-pyridin-2-yl)methoxy]-1,2-dihydropyridin-2-one;
4-(benzyloxy)-1-[11-chloro-3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1[3-(cyclopropylmethyl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1-{3-cyclopropyl-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1-{3-cyclobutyl-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl}-1,2-dihydropyridin-2-one;
4-[(5-chloro-pyridin-2-yl)methoxy]-1-[11-methyl-3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one;
and pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition, comprising a compound of claim 1 , and one or more pharmaceutically acceptable excipients, carriers or combination thereof.

18. A method of treating obesity, obesity related comorbid conditions and complications, diabetes, psychiatric diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfunctions, anxiety disorders, or sleep-wake cycle disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 17 .

19. A method of treating obesity, obesity related comorbid conditions and complications, diabetes, psychiatric diseases accompanied by weight gain, inflammatory bowel diseases, affective dysfunctions, anxiety disorders, or sleep-wake cycle disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .

20. A compound of formula (II), tert-butyl 9-bromo-1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indol-3-carboxylate,

21. The compound of claim 1 , in the form of a pharmaceutically acceptable salt.

Assignees

• Richter Gedeon Nyrt

Inventors

• Beke Gyula
• Éles János
• Boros András
• Farkas Sándor
• Keserü György Miklós

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/22

  Anxiolytics · CPC title