Hydrazone derivatives for preventing or treating EBV-related cancers
The present invention relates to novel bis-hydrazone derivatives of formula (I): wherein Ar 1 and Ar 2 may be identical or different and are each independently selected from the group consisting of groups of formula (II) and (III): Y 1 and Z 1 are independently CH or NR c + , provided that al least one of Y 1 and Z 1 is NR c + and at least one of Y 1 and Z 1 is CH, and R a , R b , R c , X 2− and L as defined in the claims, or a hydrate or a solvate thereof. Compositions and kits comprising same are also described. Said bis-hydrazone derivatives of formula (I), compositions and kits are useful as drugs, in particular for treating or preventing cancers associated with the Epstein-Barr Virus.
1. A compound of formula (I), or a hydrate or a solvate thereof:
wherein
Ar 1 and Ar 2 may be identical or different and are each independently selected from the group consisting of groups of formula (II) and (III):
R a is C 1 -C 6 alkyl, optionally substituted with a OH group, a O—(C 1 -C 4 )alkyl group or a monocyclic or bicyclic 5- to 10-membered aromatic or heteroaromatic group,
R b is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl optionally substituted with a OH group, or a O—(C 1 -C 4 )alkyl group,
Y 1 and Z 1 are independently CH or N + —R c , provided that at least one of Y 1 and Z 1 is N + —R c + and at least one of Y 1 and Z 1 is CH,
R c is C 1 -C 6 alkyl, optionally substituted with a OH group, a O—(C 1 -C 4 )alkyl group, or a monocyclic or bicyclic 5- to 10-membered aromatic or heteroaromatic group,
X 2− is one or a plurality of pharmaceutically acceptable anion(s), selected so as to obtain an overall electrically neutral salt,
L is (A), (C) or (E):
provided that Ar 1 and Ar 2 are not groups of formula (II) when L is (C) or (E),
m, n, p, u and v may be identical or different and are each independently an integer selected from 0 to 2;
s is an integer selected from 0 to 3;
R 1 , R 2 , R 3 , R 6 , R 8 and R 9 may be identical or different and are each independently a halogen atom, a C 1 -C 6 alkyl group, a C 3 -C 8 cycloalkyl group, a O(C 1 -C 6 )alkyl group, a NR 10 R 11 group, a C 2 -C 6 alkenyl group, or a C 5 -C 8 cycloalkenyl group,
said C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, O(C 1 -C 6 )alkyl group, C 2 -C 6 alkenyl group, or C 5 -C 8 cycloalkenyl group being optionally substituted with one to three halogen atoms, a OH group, a O—(C 1 -C 6 )alkyl group, a NH—(C 1 -C 6 )alkyl group or a NHC(O)—R′;
R 10 and R 11 may be identical or different and are each independently:
a hydrogen atom,
a C 1 -C 6 alkyl group optionally substituted with a OH group, a O—(C 1 -C 6 )alkyl group, a NH—(C 1 -C 6 )alkyl group or a NHC(O)—R′, or NR 10 R 11 , taken together, form a 3- to 8-membered heterocycloalkyl or 5- to 8-membered heterocycloalkenyl,
R′ is a (C 1 -C 6 )alkyl group optionally substituted with a C 5 -C 10 aryl group, wherein said C 5 -C 10 aryl group is optionally substituted with a halogen atom, a C 1 -C 6 alkyl group, a O(C 1 -C 6 )alkyl group, a C 2 -C 6 alkenyl group, a C 5 -C 8 cycloalkenyl group, a 3- to 8-membered heterocycloalkyl, a 5- to 8-membered heterocycloalkenyl, a N((C 1 -C 6 )alkyl) 2 group or a N((C 1 -C 6 )haloalkyl) 2 group.
2. The compound of claim 1 , wherein Ar 1 and Ar 2 may be identical or different and are each independently selected from the group consisting of groups of formula (II′), (III′) and (III″):
With R a , R b and R c as defined in claim 1 .
3. The compound of claim 1 or a hydrate or a solvate thereof, wherein Ar 1 and Ar 2 are identical.
4. The compound of claim 1 , or a hydrate or a solvate thereof, wherein Ar 1 and/or Ar 2 is of formula (II), R a is a linear C 1 -C 4 alkyl optionally substituted with a phenyl group, and R b is a hydrogen or halogen atom;
or wherein Ar 1 and/or Ar 2 are of formula (III), and R c is a linear C 1 -C 4 alkyl optionally substituted with a phenyl group.
5. The compound of claim 1 , or a hydrate or a solvate thereof, wherein X 2− represents two anions selected from the group consisting of a halogenide, a carboxylate, a C 1 -C 6 alkylsulfonate, a C 1 -C 6 haloalkylsulfonate and an alkylarylsulfonate.
6. The compound of claim 1 , or a hydrate or a solvate thereof, wherein L is (C), s is 0, and Ar 1 and Ar 2 are identical and of formula (III).
7. The compound of claim 1 , or a hydrate or a solvate thereof, wherein L is (A), Ar 1 and Ar 2 are identical and of formula (II) or (III), and
m and p are 0, and n is 0 or 1, or
m and n are 0, and p is 0 or 1, or
n is 0, and m and p are identical and are 0 or 1, or
m, n and p are 0.
8. The compound of claim 1 , or a hydrate or a solvate thereof, wherein L is (E) and u and v are 0.
9. The compound of claim 1 , or a hydrate or a solvate thereof, wherein it is:
10. A composition comprising:
as active ingredient, the compound of formula (I) as defined in claim 1 , or a hydrate or a solvate thereof, and optionally another therapeutic agent selected from antibiotics, anticancer agents, and steroidal and non-steroidal anti-inflammatory drugs, and
a pharmaceutically acceptable excipient.
11. The composition of claim 10 , wherein the pharmaceutically acceptable excipient is suitable for injection.
12. A method for treating an Epstein-Barr-Virus (EBV)-related cancer, comprising the administration of an effective amount of the compound of claim 1 .
13. A method for treating an Epstein-Barr-Virus (EBV)-related cancer, comprising the simultaneous, staggered or sequential administration as a combination product of a kit comprising at least:
a first composition comprising the compound of formula (I) as defined in claim 1 , or a hydrate or a solvate thereof, and a pharmaceutically acceptable excipient, and
a second composition comprising another therapeutic agent.
14. The method of claim 12 , wherein the EBV-related cancer is a Hodgkin's lymphoma, a Burkitt's lymphoma, a nasopharyngeal carcinoma, a gastric cancer, lymphomas in immunosuppressed patients, or T/NK cell lymphomas.
15. The compound of claim 4 , or a hydrate or a solvate thereof, wherein R a is an ethyl, a methyl group or a benzyl group.
16. The compound of claim 4 , or a hydrate or a solvate thereof, wherein R c is an ethyl, a methyl group or a benzyl group.
17. The compound of claim 6 , or a hydrate or a solvate thereof, wherein Ar 1 and Ar 2 are identical and of formula
18. The compound of claim 7 , or a hydrate or a solvate thereof, wherein Ar 1 and Ar 2 are identical and of formula
19. The compound of claim 1 , or a hydrate or a solvate thereof, wherein it is:
20. A method for treating an Epstein-Barr-Virus (EBV)-related cancer, comprising the administration of an effective amount of the composition of claim 10 .
21. The method of claim 13 , wherein the other therapeutic agent is selected from antibiotics, anticancer agents, and steroidal and non-steroidal anti-inflammatory drugs.
22. The method of claim 13 , wherein the EBV-related cancer is a Hodgkin's lymphoma, a Burkitt's lymphoma, a nasopharyngeal carcinoma, a gastric cancer, lymphomas in immunosuppressed patients, or T/NK cell lymphomas.
23. The method of claim 20 , wherein the EBV-related cancer is a Hodgkin's lymphoma, a Burkitt's lymphoma, a nasopharyngeal carcinoma, a gastric cancer, lymphomas in immunosuppressed patients, or T/NK cell lymphomas.