3,5-diarylazaindoles as DYRK1A protein inhibitors for the treatment of cognitive deficiencies associated with Down's syndrome and with Alzheimer's disease

Patent metadata

Field	Value
Publication number	US-9447093-B2
Application number	US-201314653570-A
Country	US
Kind code	B2
Filing date	Dec 18, 2013
Priority date	Dec 18, 2012
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

The present invention discloses compositions of novel DYRK1A protein inhibitors based on a 3,5-diarylazaindole motif and their preparation and use as medications in the treatment of cognitive disorders associated with dysfunction of DYRK1A protein, with Down's syndrome and with Alzheimer's disease.

First claim

The invention claimed is:

1. A compound of formula (I′) or one of the pharmaceutically acceptable salts, solvates and hydrates thereof:

wherein:
X 3 is F, OH or SH,
Y 3 is F, OH or SH,
X 1 , X 2 , X 4 , X 5 , Y 1 , Y 2 , Y 4 and Y 5 independently of one another are H, F, Cl, Br, OH or SH, and
one to two groups among radicals X 1 , X 2 , X 4 and X 5 are different from H and/or one to two groups among radicals Y 1 , Y 2 , Y 4 and Y 5 are different from H.

2. The compound of formula (I′) according to claim 1 wherein radicals X 1 -X 5 and Y 1 -Y 5 independently of one another are H, F, OH or SH.

3. The compound of formula (I′) according to claim 1 wherein Y 2 is different from H.

4. The compound of formula (I′) according to claim 1 wherein X 1 is different from H.

5. The compound of formula (I′) according to claim 1 wherein X 2 is different from H.

6. The compound of formula (I′) according to claim 1 wherein X 1 and Y 2 are different from H.

7. The compound of formula (I′) according to claim 1 wherein X 2 and Y 2 are different from H.

8. The compound of formula (I′) according to claim 1 wherein at least one radical among X 1 -X 5 and Y 1 -Y 5 is OH.

9. The compound of formula (I′) according to claim 1 wherein at least one radical among X 1 -X 5 is OH and at least one radical among Y 1 -Y 5 is OH.

10. A method for the treatment and/or reduction of cognitive disorders associated with dysfunction of DYRK1A protein, with Alzheimer's disease or with Down's syndrome comprising administering a compound of formula (I′) according to claim 1 to a patient in need thereof.

11. A pharmaceutical composition comprising at least one compound of formula (I′) according to claim 1 and at least one pharmaceutically acceptable excipient.

12. A method for the treatment and/or reduction of cognitive disorders associated with Down's syndrome comprising administering to a patient in need thereof a compound of formula (I):

wherein:
X 1 -X 5 independently of one another are H, F, Cl, Br, OR 1 or SR 2 ,
Y 1 -Y 5 independently of one another are H, F, Cl, Br, OR 3 or SR 4 , where
R 1 and R 3 independently of one another represent (C 1 -C 6 )-alkyl; acyl; optionally substituted aralkyl or optionally substituted aryl,
R 2 and R 4 independently of one another represent (C 1 -C 6 )-alkyl; acyl; optionally substituted aralkyl or optionally substituted aryl,

one to three radicals among X 1 -X 5 are different from H,
one to three radicals among Y 1 -Y 5 are different from H,
and at least one radical among radicals X 1 -X 5 and Y 1 -Y 5 different from H is F, OH or SH.

13. The method according to claim 12 wherein radicals X 1 -X 5 and Y 1 -Y 5 represent H, F, OH, SH, OR 1 , SR 2 , OR 3 or SR 4 .

14. The method according to claim 12 wherein at least one radical among X 1 -X 5 is F, OH or SH, and at least one radical among Y 1 -Y 5 is F, OH or SH.

15. The method according to claim 12 wherein X 3 and Y 3 are different from H.

16. The method according to claim wherein X 1 , Y 2 and Y 3 are different from H.

17. The method according to claim 12 wherein X 3 , Y 2 and Y 3 are different from H.

18. The method according to claim 12 wherein X 2 , X 3 and Y 3 are different from H.

19. The method according to claim 12 wherein X 1 , X 3 , Y 2 and Y 3 are different from H.

20. The method according to claim 12 wherein X 2 , X 3 , Y 2 and Y 3 are different from H.

21. The method of claim 12 wherein the compound is administered as a pharmaceutical composition.

22. A method for the preparation of a compound of formula (I′) according to claim 1 or one of the pharmaceutically acceptable salts, solvates and hydrates thereof comprising the steps of:
(a) reaction between a compound of formula (II′):

and a compound of formula (III′):
wherein:
PG represents an N-protecting group,
Hal represents a halogen atom, in particular bromine, or an OSO 2 CF 3 group,
E 2 represents a boronic acid B(OH) 2 or a derivative thereof,
radicals X 3′ and Y 3′ are F, OPG 1 or SPG 2 , where PG 1 represents an O-protecting group and PG 2 represents an S-protecting group,
radicals X 1 , X 2 , X 4 , X 5 , Y 1 , Y 2 , Y 4 and Y 5 independently of one another are H, F, Cl, Br, OPG 1 or SPG 2 ,
PG 1 represents an O-protecting group and PG 2 represents an S-protecting group, to yield a compound of formula (IV′):

(b) deprotection of the N-PG group of the compound of formula (IV′) and the OPG 1 and SPG 2 groups to yield a compound of formula (I′),
(c) optionally salification, solvation or hydration to yield a pharmaceutically acceptable salt, solvate or hydrate of a compound of formula (I′).

23. A method for inhibiting DYRK1A protein activity in a patient with cognitive disorders associated with dysfunction of DYRK1A protein, with Alzheimer's disease or with Down's syndrome comprising administering a compound of formula (I′) according to claim 1 to the patient.

24. A method for inhibiting DYRK1A protein activity in a patient with cognitive disorders associated with Down's syndrome comprising administering a compound of formula (I) according to claim 12 to the patient.

Assignees

• Centre Nat Rech Scient
• Univ De Reims Champagne-Ardenne
• Univ Paris Diderot Paris 7
• Centre Nat De La Rech Scient (Cnrs)

Inventors

• Dobb Robert
• Cariou Kevin
• Gourdain Stephanie
• Delabar Jean Maurice
• Janel Nathalie
• Rodrigues Lima Fernando
• Dairou Julien
• Denhez Clement

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• 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