Sibiriline derivatives for use for preventing and/or treating disorders associated with cellular necroptosis

• US 10,426,758 B2
• Filed: 10/13/2016
• Issued: 10/01/2019
• 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, Universite de Poitiers
• Original Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Inventors: Dimanche-Boitrel, Marie-Therese, Bach, Stephane, Delehouze, Claire, Mettey, Yvette, Goekjian, Peter, Comte, Arnaud
• Primary Examiner(s): Carcanague, Daniel R
• Application Number:
  US15/768,388
• Publication Number:
  US 20180325876A1
• Time in Patent Office: 1,083 Days
• Field of Search: 514300
• CPC Class Codes: A01N 1/0226 Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to a compound of the following general formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, for use as inhibitor of cellular necroptosis. The present invention also relates to a pharmaceutical composition comprising a compound of general formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use for preventing and/or treating disorders associated with cellular necroptosis. The present invention also encompasses the use of a compound of the general formula (I) for organs preservation.

Claims

1. A method for inhibiting cellular necroptosis comprising the administration to a patient in need thereof of an effective amount of a compound of the following general formula (I)

2. The method according to claim 1, wherein:

R₁ is H, a (C₁-C₆)alkyl or a (C₃-C₆)cycloalkyl, or R₁ forms together with R₂ or R₄ a heterocycloalkyl;

R₂ and R₃ are H;

R₂ to R₆ are, independently of one another, H or OR₁₀;

R₁₀ is H or (C₁-C₆)alkyl;

R₇ is H or halo;

R₈ is H;

halo;

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

(C₁-C₆)alkyl-aryl, and —

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

OR₃₆, —

NR₃₇R₃₈, —

SR₃₉, —

S(O)R₄₀, —

SO₂R₄₁, —

SO₂NR₄₂R₄₃, —

OCOR₄₄, —

NR₄₅COR₄₆, —

NR₄₇C(O)OR₄₈, —

CO₂R₄₉, —

CONR₅₀R₅₁, —

OCONR₅₃R₅₄, —

COR₅₅, nitro (—

NO₂), cyano (—

CN), oxo (═

O), and a group selected from aryl, heterocycle and —

(C₁-C₆)alkyl-heterocycle, said group being optionally substituted with one or several-more (C₁-C₆)-alkyl;

R₉ is H;

halo;

or a group selected from (C₁-C₆)alkyl, aryl and heteroaryl, said group being optionally substituted with one or more groups selected from halo, —

OR₃₆, —

NR₃₇R₃₈, —

SR₃₉, —

S(O)R₄₀, —

SO₂R₄₁, —

SO₂NR₄₂R₄₃, —

OCOR₄₄, —

NR₄₅COR₄₆, —

NR₄₇C(O)OR₄₈, —

CO₂R₄₉, —

CONR₅₀R₅₁, —

OCONR₅₃R₅₄, —

COR₅₅, nitro (—

NO₂), cyano (—

CN), oxo (═

O), and a group selected from aryl, heterocycle and —

(C₁-C₆)alkyl-heterocycle, said group being optionally substituted with one or more (C₁-C₆)-alkyl;

R₃₆ to R₅₅ are, independently of one another, H, halo, benzoylbenzyl, or a group selected from (C₁-C₆)alkyl, aryl, heteroaryl, heterocycle, —

(C₁-C₆)alkyl-heterocycle, and —

(C₁-C₆)alkyl-aryl, said group being optionally substituted with one or more groups selected from halo, CF₃ or (C₁-C₆)alkyl;

or R₃₇-R₃₈, R₄₂-R₄₃, R₅₀-R₅₁, and/or R₅₃-R₅₄ may together respectively form a heterocycloalkyl.

3. The method according to claim 1, wherein R₈ to R₉ are, independently of one another, H;

halo;

or a group selected from (C₁-C₆)alkyl, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, benzyl, thiophenyl, benzimidazolyl or imidazolyl, said group being optionally substituted with one or two groups selected from halo, —

OR₃₆, —

NR₃₇R₃₈, —

SR₃₉, —

S(O)R₄₀, —

SO₂R₄₁, —

SO₂NR₄₂R₄₃, —

OCOR₄₄, —

NR₄₅COR₄₆, —

NR₄₇C(O)OR₄₈, —

CO₂R₄₉, —

CONR₅₀R₅₁, —

OCONR₅₃R₅₄, —

COR₅₅, nitro (—

NO₂), cyano (—

CN), oxo (═

O), —

(C₁-C₆)alkyl-heterocycle, and an heterocycle group.

4. The method according to claim 1, wherein R₈ to R₉ are, independently of one another, H, halo, or a phenyl group, said phenyl group being optionally substituted with one or two groups selected from halo, —

OR₃₆ and —

(C₁-C₆)alkyl-heterocycle.

5. The method according to claim 1, wherein:

R₇ is H or halo;

R₈ and R₉ are, independently of one another, H, halo, or a phenyl group, said phenyl group being optionally substituted with one or two groups selected from halo or —

OR₃₆.

6. The method according to claim 1, wherein R₃, R₅ and R₆ are H.

7. The method according to claim 1, wherein R₃₆ to R₅₅ are, independently of one another, H, halo, or a group selected from (C₁-C₆)alkyl, aryl, heteroaryl, said group being optionally substituted with one or more groups selected from halo, CF₃ or methyl.

8. The method according to claim 1, wherein the compound is selected from the following compounds:

9. The method according to claim 1, wherein the compound is selected from the following compounds:

10. The method according to claim 1, wherein said pharmaceutically acceptable salts of the compound of general formula (I) are hydrobromic acid addition salts.

11. The method according to claim 1, wherein the patient has a disorder selected from 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.

12. The method according to claim 1, wherein the patient has a disorder selected from tumour cells extravasation or metastasis.

13. The method according to claim 1 wherein said compound of formula (I) is administered to said patient as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

14. The method according to claim 13, wherein the patient has a disorder selected from 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.

16. The method according to claim 2, wherein R₁ is H, a (C₁-C₃)alkyl or R₁ forms together with R₂ or R₄ a heterocycloalkyl.

17. The method according to claim 3, wherein R₈ to R₉ are, independently of one another, H;

halo;

or a group selected from (C₁-C₆)alkyl, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, benzyl, thiophenyl, benzimidazolyl or imidazolyl, said group being optionally substituted with one or two groups selected from —

OR₃₆, —

NR₃₇R₃₈, —

OCOR₄₄, —

NR₄₅COR₄₆, —

NR₄₇C(O)OR₄₈, —

CO₂R₄₉, —

CONR₅₀R₅₁, —

OCONR₅₃R₅₄, —

COR₅₅, —

(C₁-C₆)alkyl-heterocycle or an heterocycle group.

18. The method according to claim 3, wherein R₈ to R₉ are, independently of one another, H;

halo;

or a group selected from (C₁-C₆)alkyl, piperidinyl, morpholinyl, pyrrolidinyl, phenyl, benzyl, thiophenyl, benzimidazolyl or imidazolyl, said group being optionally substituted with one or two groups selected from —

OR₃₆ or an —

(C₁-C₆)alkyl-heterocycle group.

19. The method according to claim 11, wherein the ischemia reperfusion injury is associated with a myocardial infarction or a stroke.

20. The method according to claim 14, wherein the ischemia reperfusion injury is associated with a myocardial infarction or a stroke.

15. A method for the preservation and/or protection of biological materials comprising placing said biological materials in a medium containing a compound of the following general formula (I)

21. The method according to claim 15, wherein the biological materials are cells, tissues, body fluids, organs or microorganisms.