N1-And N7-Substituted Sibiriline Derivatives And Their Use As Inhibitor Of Cellular Necroptosis

• US 20180312502A1
• Filed: 10/13/2016
• Published: 11/01/2018
• Est. Priority Date: 10/13/2015
• Status: Active Grant

• Current Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Centre National De La Recherche Scientifique, Sorbonne Universite, Université Claude Bernard Lyon 1
• Original Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Centre National De La Recherche Scientifique, Sorbonne Universite, Université Claude Bernard Lyon 1
• Inventors: Dimanche-Boitrel, Marie-Therese, Bach, Stephane, Delehouze, Claire, Goekjian, Peter, Comte, Arnaud
• Granted Patent: US 10,457,678 B2
• Time in Patent Office: Days
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to new N1- and N7-substituted sibiriline derivatives of the following general formula (I): (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as drug, in particular for use as inhibitor of cellular necroptosis. The present invention also relates to a pharmaceutical composition comprising such a compound and processes to prepare such a compound. The present invention also encompasses the use of a compound of the general formula (I) for organs preservation.

Claims

1. A compound of the following general formula (I):

2. The compound according to claim 1, wherein Z is (C₁-C₃)alkyl.

3. The compound according to claim 1, wherein R₁ to R₄ are, independently of one another, H, halo, (C₁-C₆)alkyl or —

OR₅₁.

4. The compound according to claim 1, wherein R₅ is H.

5. The compound according to claim 1, wherein R₆ to R₈ are, independently of one another, H;

halo;

—

OR₅₆;

—

NR₅₇R₅₈;

or a group selected from (C₁-C₆)alkyl, heterocycloalkyl, aryl, heteroaryl, —

(C₁-C₆)alkyl-aryl and —

(C₁-C₆)alkyl-heterocycloalkyl, said group being optionally substituted with one or several groups selected from halo, —

OR₇₉, —

NR₈₀R₈₁, —

SR₈₂, —

S(O)R₈₃, —

SO₂R₈₄, —

SO₂NR₈₅R₈₆, —

OCOR₈₇, —

NR₈₈COR₈₉, —

NR₉₀C(O)OR₉₁, —

CO₂R₉₂, —

CONR₉₃R₉₄, —

CO₂R₉₅, —

OCONR₉₆R₉₇, —

COR₉₈, nitro (—

NO₂), cyano (—

CN) and oxo (═

O).

6. The compound according to claim 1, wherein R₁₀ to R₁₂, R₂₅, R₂₉ to R₃₁ and R₅₁ to R₉₈ are, independently of one another, H;

halo;

or a group selected from (C₁-C₆)alkyl, phenyl, benzyl, heterocycloalkyl, said group being optionally substituted with one or several groups selected from halo, (C₁-C₆)alkyl, —

C(O)R_alk, —

C(O)OR_alk, —

SO₂R_alk, —

OR_alk, —

COR_alkR_alk′

, oxo (═

O), and SO₂-R_alk, wherein R_alk and R_alk′

are, independently of each other, (C₁-C₆)alkyl.

7. The compound according to any claim 1, wherein it is selected from the following compounds:

8. (canceled)

A method for preventing and/or treating disorders associated with cellular necroptosis comprising the administration to a patient in need thereof of an effective amount of a compound according to claim 1.

12. A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable excipient.

13. A method for the preservation and/or protection of biological materials comprising placing said biological materials in a medium containing a compound as defined in claim 1.

14. A process to prepare a compound according to claim 1, wherein Z is (C₁-C₆)alkyl, comprising the following steps:

i) reacting a 3-picoline with a 4-ethoxybenzonitrile to give a compound of following formula (II);

15. A process to prepare a compound according to claim 1, or a pharmaceutically acceptable salt and/or solvate thereof,

wherein

16. The compound according to claim 2, wherein Z is ethyl.

17. The compound according to claim 3, wherein R₁ to R₄ are, independently of one another, H, halo, methyl or OMe.

18. The compound according to claim 5, wherein R₆ to R₈ are, independently of one another, H, halo, —

OR₅₆, —

NR₅₇R₅₈;

or a group selected from (C₁-C₆)alkyl, heterocycloalkyl, aryl and heteroaryl.

19. The compound according to claim 6, wherein R₁₀ to R₁₂, R₂₅, R₂₉ to R₃₁ and R₅₁ to R₉₈ are, independently of one another, H;

halo;

or a group selected from (C₁-C₆)alkyl, phenyl, benzyl, heterocycloalkyl, said group being optionally substituted with one or several groups selected from halo, methyl, oxo (═

O), and SO₂—

CH₃.

20. A method for inhibiting cellular necroptosis comprising the administration of an effective amount of a compound according to claim 1.

22. The method according to claim 13, wherein the biological materials are cells, tissues, body fluids, organs or microorganisms.

23. The process according to claim 14, wherein Z is ethyl.

24. The process according to claim 15, wherein Z is ethyl.

10. The method according to claim 9, wherein said disorders associated with cellular necroptosis are trauma in brain, hepatitis, alcoholic and non-alcoholic steatohepatitis, acute pancreatitis and acute tubular necrosis, heart or kidney transplantation, atherosclerosis, bone marrow failure, viral infection, Crohn'"'"'s and ulcerative colitis, terminal ileitis, chronic obstructive pulmonary disease or ischemia reperfusion injury.

21. The method according to claim 10, wherein the disorder associated with cellular necroptosis is an ischemia reperfusion injury and is a myocardial infarction or a stroke.

11. The method according to claim 9, wherein said cellular necroptosis is tumour-cell-induced endothelial cell necroptosis and said disorders associated with it are tumour cells extravasation or metastasis.