Hycanthone derivatives and Primaquine derivatives for use in the prevention and/or the treatment of disorders associated to gammaherpesvirus

Patent metadata

Field	Value
Publication number	US-10842776-B2
Application number	US-201716312459-A
Country	US
Kind code	B2
Filing date	Jun 28, 2017
Priority date	Jun 28, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

The present invention relates to compounds of the following general formula (I) or (II) or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prevention and/or the treatment of disorders associated to gammaherpesvirinae, in particular to the human herpesvirus 8 (HHV8) or the human herpes virus 4 (HHV4), and pharmaceutical compositions containing such compounds.

First claim

The invention claimed is:

1. A method for preventing and/or treating disorders associated with the human herpesvirus 8 (HHV8) or the human herpes virus 4 (HHV4), comprising administering to a subject in need thereof, an effective amount of a compound of following general formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, wherein:
X is an oxygen or a sulfur atom;
Y is a (C 1 -C 10 )alkyl group;
R 1 to R 4 are, independently of one another, hydrogen atom, halo, —CF 3 , —CN, —CO 2 R 10 , —CONR 12 R 13 , —NO 2 , or a group selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;
R 5 to R 7 are, independently of one another, hydrogen atom or a group selected from (C 1 -C 6 )alkyl, —OR 14 , —NR 15 R 16 , —CONR 17 R 18 , —CO(NR 10 R 20 ), —SR 21 , —COR 22 , —COOR 23 , —SO 2 R 24 , —NO 2 and —NO + , said (C 1 -C 6 )alkyl group being optionally substituted with one or several groups selected from halo, —OR 25 , —NR 26 R 27 , —CONR 28 R 20 , —CO(NR 30 R 31 ), —SR 32 , —COR 33 , —COOR 34 , —SO 2 R 35 , —NO 2 and —NO + ;
R 8 and R 9 are, independently of one another, hydrogen atom or a (C 1 -C 10 )alkyl group optionally substituted with OH, or R 8 and R 9 form together with the nitrogen atom to which they are chemically linked, an heterocycle;
R 10 to R 35 are, independently of one another, hydrogen atom, halo or a (C 1 -C 6 )alkyl group.

2. The method of claim 1 , wherein X is a sulfur atom.

3. The method of claim 1 , wherein Y is a (C 1 -C 6 )alkyl group.

4. The method of claim 1 , wherein said compound is a compound of the following general formula (Ia):

5. The method of claim 1 , wherein R 8 and R 9 are, independently of one another, a (C 1 -C 10 )alkyl group.

6. The method of claim 1 , wherein R 1 to R 4 are, independently of one another, hydrogen atom, halo, or a group selected from (C 1 -C 6 )alkyl and (C 2 -C 6 )alkenyl.

7. The method of claim 1 , wherein R 5 to R 7 are, independently of one another, hydrogen atom or a (C 1 -C 6 )alkyl group optionally substituted with one or several groups selected from, halo, —OR 25 , —NR 26 R 27 , —CONR 28 R 29 , —CO(NR 30 R 31 ), —SR 32 , —COR 33 , —COOR 34 , —SO 2 R 35 , —NO 2 and —NO + ; R 25 to R 35 being as defined in claim 1 .

8. The method of claim 1 , wherein R 6 and R 7 are hydrogen atom and R 5 is a (C 1 -C 6 )alkyl group substituted with OH.

9. The method of claim 1 , wherein said compound is a compound of the following formula (Ib):

10. A method for preventing and/or treating disorders associated with the human herpesvirus 8 (HHV8), comprising administering to a subject in need thereof, an effective amount of a compound of following general formula (II):

or a pharmaceutically acceptable salt and/or solvate thereof, wherein:
X is a (C 1 -C 10 )alkyl group;
R′ 1 to R′ 3 are, independently of one another, hydrogen atom, halo, —OR′ 9 , —R′ 10 R′ 11 , —SR′ 12 , —COSR′ 13 , —NR′ 14 R′ 15 , —COR′ 16 , —COOR′ 17 or a (C 1 -C 6 )alkyl group;
R′ 4 to R′ 6 are, independently of one another, hydrogen atom, halo, —OR′ 18 , —R′ 19 OR′ 20 , —SR′ 21 or —NR′ 22 R′ 23 ;
R′ 7 and R′ 8 are, independently of one another, hydrogen atom or a (C 1 -C 10 )alkyl group, or R′ 7 and R′ 8 form together with the nitrogen atom to which they are chemically linked, an heterocycle;
R′ 9 to R′ 23 are, independently of one another, hydrogen atom, halo or a group selected from (C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkylaryl group.

11. The method of claim 10 , wherein X is a (C 1 -C 6 )alkyl group.

12. The method of claim 10 , wherein said compound is a compound of the following general formula (IIa):

13. The method of claim 10 , wherein R′ 7 and R′ 8 are, independently of one another, an hydrogen atom or a (C 1 -C 10 )alkyl group.

14. The method of claim 10 , wherein R′ 1 to R′ 3 are, independently of one another, hydrogen atom, —OR′ 9 , —SR′ 12 , —COSR′ 13 , —NR′ 14 R′ 15 or a (C 1 -C 6 )alkyl group; R′ 9 to R′ 15 being as defined in claim 10 .

15. The method of claim 10 , wherein R′ 4 to R′ 6 are, independently of one another, hydrogen atom, halo, —OR′ 18 or —R′ 19 OR′ 20 , R′ 18 to R′ 20 being as defined in claim 10 .

16. The method of claim 10 , wherein said compound is a compound of the following formula (IIb):

17. A method for preventing and/or treating disorders associated with the human herpesvirus 8 (HHV8) or the human herpes virus 4 (HHV4), comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition comprising at least one compound of claim 1 and at least one pharmaceutically acceptable excipient.

18. The method of claim 17 , wherein said composition further comprises another active principle selected from the group consisting of Bleomycine, Vinblastine, paclitaxel and docetaxel, daunorubicine liposomiale, adriamycine, vincristine, navelbine, gemcitabine, interferon α, all-transretinoic acid, thalidomide, IL-12, IL-4, Panretin, Revlimid, lenalinomide, rituximab, etoposide, cyclophosphamide, doxorubicin, vincristin, prednisone, cidofovir, foscarnet, ganciclovir, valganciclovir, Tocilizumab, siltuximab, bortezomib, RNAi against LANA and/or vFlip, Hydroxyurea, and Rapamycin.

19. The method of claim 1 ,
wherein said disorders associated with the human herpesvirus 8 (HHV8) are selected from human Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD);
and wherein said disorders associated with the human herpes virus 4 (HHV4) are selected from:
infectious mononucleosis (glandular fever);
lymproliferative disorders;
non lymphoid malignancies; and
autoimmune diseases.

20. The method of claim 10 ,
wherein said disorders associated with the human herpesvirus 8 (HHV8) are selected from human Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD).

21. The method of claim 17 ,
wherein said disorders associated with the human herpesvirus 8 (HHV8) are selected from human Kaposi sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD);
and wherein said disorders associated with the human herpes virus 4 (HHV4) are selected from:
infectious mononucleosis (glandular fever);
lymproliferative disorders;
non lymphoid malignancies; and
autoimmune diseases.

22. A method for preventing and/or treating disorders associated with the human herpesvirus 8 (HHV8), comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising at least one compound of claim 10 and at least one pharmaceutically acceptable excipient.

23. The method of claim 22 , wherein said composition further comprises another active principle selected from the group consisting of Bleomycine, Vinblastine, paclitaxel, docetaxel, daunorubicine liposom

Assignees

• Assist Publique—Hopitaux De Paris
• Inst Nat Sante Rech Med
• Univ Sorbonne
• Univ Paris Descartes
• Centre Nat Rech Scient
• Assist Publique—Hopitaua De Paris
• Sorbonne Unicersite

Inventors

• Dupin Nicolas
• Marcelin Anne-Geneviève
• Calvez Vincent
• Grange Philippe

Classifications

• A61K45/06

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

• A61K31/4706

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title

• A61K31/382 Primary

  having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61K31/352

  condensed with carbocyclic rings, e.g. methantheline  {(cannabinoids A61K31/658)} · CPC title