Hydroxyindalpine derivatives and their medical use

Patent metadata

Field	Value
Publication number	US-9637471-B2
Application number	US-201414768037-A
Country	US
Kind code	B2
Filing date	Feb 14, 2014
Priority date	Feb 14, 2013
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The present invention relates to hydroxyindalpine derivatives of formula (I) as defined herein and pharmaceutical compositions comprising these compounds, as well as their medical use, particularly in the treatment or prevention of gastrointestinal diseases/disorders, such as constipation and functional dyspepsia.

First claim

The invention claimed is:

1. A compound of formula (I-1)

wherein:
L 1 is C 1-4 alkylene;
L 2 is C 2-4 alkylene;
R 1 is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
each R 2 is independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
R 4 is selected from the group consisting of hydrogen, C 1-4 alkyl, and —CO(C 1-4 alkyl);
R 5 is selected from the group consisting of hydrogen, C 1-4 alkyl, and —CO(C 1-4 alkyl); and
n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , wherein L 1 is —CH 2 — or —CH 2 CH 2 —.

3. The compound of claim 1 , wherein L 2 is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —.

4. The compound of claim 1 , wherein L 2 is —CH 2 CH 2 —.

5. The compound of claim 1 , wherein R 1 is phenyl optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl).

6. The compound of claim 1 , wherein R 1 is phenyl.

7. The compound of claim 1 , wherein R 3 , R 4 and R 5 are each hydrogen.

8. The compound of claim 1 , wherein the moiety —O-L 1 -R 1 is bound to position 5 or 6 of the indole ring of the compound of formula (I).

9. The compound of claim 1 , wherein said compound is a compound of formula (II-1)

wherein:
L 1 is —(CH 2 ) 1-4 —;
L 2 is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —; and
R 1 is phenyl optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);

or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 1 , wherein said compound has one of the following structures:

or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient:

wherein:
L 1 is C 1-4 alkylene;
L 2 is C 2-4 alkylene;
R 1 is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
each R 2 is independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
R 4 is selected from the group consisting of hydrogen, C 1-4 alkyl, and —CO(C 1-4 alkyl);
R 5 is selected from the group consisting of hydrogen, C 1-4 alkyl, and —CO(C 1-4 alkyl); and
n is 0, 1, 2 or 3.

12. The pharmaceutical composition of claim 11 , wherein said compound of formula (I) is a compound of formula (II)

wherein:
L 1 is —(CH 2 ) 1-4 —;
L 2 is —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —; and
R 1 is phenyl optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);

or a pharmaceutically acceptable salt or solvate thereof.

13. A method of treating a gastrointestinal disease or disorder, the method comprising the administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a subject in need thereof:

wherein:
L 1 is C 1-4 alkylene;
L 2 is C 2-4 alkylene;
R 1 is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
each R 2 is independently selected from the group consisting of C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogen, —CF 3 , —CN, —OH, —O(C 1-4 alkyl), —SH, —S(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl)(C 1-4 alkyl);
R 4 is selected from the group consisting of hydrogen, C 1-4 alkyl, and —CO(C 1-4 alkyl);
R 5 is selected from the group consisting of hydrogen, C 1-4 alkyl, and —CO(C 1-4 alkyl); and
n is 0, 1, 2 or 3.

14. The method of claim 13 , wherein said gastrointestinal disease or disorder is selected from the group consisting of constipation, dyspepsia and/or associated dyspeptic symptoms, irritable bowel syndrome, gastroparesis, intestinal pseudo-obstruction, obstructed defecation, abdominal bloating, abdominal distension, fecal impaction, and abdominal pain.

15. The method of claim 13 , wherein the subject is a human.

16. A process of preparing a compound of formula (I-1) as defined in claim 1 , the process comprising a step of reacting a compound of formula (Ib), either with hydrazine and a base or with lithium aluminum hydride, to obtain the compound of formula (I-1):

wherein R 1 , R 2 , R 3 , R 4 , R 5 , L 1 and n in formula (Ib) have the same meanings as the corresponding groups or variables in the compound of formula (I-1).

Assignees

• Univ Muenchen Tech

Inventors

• Skerra Arne
• Muller Michael
• Schemann Michael
• Berger Thomas

Classifications

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title