Hycanthone derivatives and Primaquine derivatives for use in the prevention and/or the treatment of disorders associated to gammaherpesvirus
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.
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 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.
24. The method of claim 22 , wherein said disorders associated with the human herpesvirus 8 (HHV8) are selected from the group consisting of human Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD).