Naphthalene diimide compounds
The invention relates to novel compounds which are naphthalene diimides of general formula (I). The compounds are used in therapy, particularly in cancer treatment.
1. A pharmaceutical composition comprising a compound that is of general formula (I) or is a salt, solvate, or prodrug thereof,
wherein R 1 and R 2 are each independently divalent radicals selected from C 1-20 alkyl, C 2-20 alkenyl, C 7-20 alkaryl, C 2-10 alkynyl, C 7-20 aralkyl, C 2-20 heteroaralkyl, C 3-30 heterocyclylalkyl, C 3-30 alkylheterocyclyl, C 3-20 cycloalkyl, C 3-20 heterocyclyl, C 2-20 heteroaryl, C 5-20 aryl and C 1-10 alkoxy;
R is H or A 2 X 4 ;
wherein X 1 -X 4 are each independently selected from halo, OH, OR 3 , COH, NH 2 , NHR 3 , NR 3 R 4 , COOH, CONH 2 , COOR 3 , CONHR 3 , CONR 3 R 4 , SH, SR 3 , COR 3 and cyano, provided that at least one of groups X 1 -X 4 is a tertiary amine;
wherein R 3 and R 4 are independently selected from C 1-6 alkyl, C 6-20 aryl, and C 7-20 aralkyl or R 3 and R 4 together with the nitrogen atom to which they are attached form a 3-8 membered ring, which is optionally substituted and optionally comprises other hetero atoms;
A 1 and A 2 are each independently selected from NHR 5 ;
wherein R 5 is a divalent radical selected from C 1-20 alkyl, C 6-20 aryl, C 7-20 alkaryl and C 7-20 aralkyl;
wherein any of the groups R 1 -R 5 , A 1 and A 2 may be substituted with C 1-20 alkyl, C 2-20 alkenyl, C 7-20 alkaryl, C 2-10 alkynyl, C 7-20 aralkyl, C 2-20 heteroaralkyl, C 3-30 heterocyclylalkyl, C 3-30 alkylheterocyclyl, C 3-20 cycloalkyl, C 3-20 heterocyclyl, C 2-20 heteroaryl, C 5-20 aryl or C 1-10 alkoxy, halo, OH, OR 3 , COH, NH 2 , NHR 3 , NR 3 R 4 , COOH, CONH 2 , COOR 3 , CONHR 3 , CONR 3 R 4 , SH, SR 3 , COR 3 or cyano; and
wherein the pharmaceutical composition also comprises a pharmaceutically acceptable carrier.
2. The pharmaceutical composition according to claim 1 wherein R is H.
3. The pharmaceutical composition according to claim 1 wherein R is A 2 X 4 .
4. The pharmaceutical composition according to claim 1 wherein R 1 x 1 ═R 2 X 2 .
5. The pharmaceutical composition according to claim 3 wherein X 1 -X 4 are selected from NH 2 , NR 3 R 4 , OH, OR 3 and NHR 3 .
6. The pharmaceutical composition according to claim 5 wherein X 1 -X 4 are NR 3 R 4 , wherein R 3 and R 4 are independently methyl or ethyl.
7. The pharmaceutical composition according to claim 5 wherein X 1 -X 4 are NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen-atom to which they are attached form a 5 or 6 membered ring.
8. The pharmaceutical composition according to claim 7 wherein the group NR 3 R 4 is pyrrolidine, piperidine or morpholine.
9. The pharmaceutical composition according to claim 1 comprising a prodrug of a compound of formula (I), wherein groups X 1 -X 4 of the prodrug are N-oxides or N + (—O − ) R 3 R 4 .
10. The pharmaceutical composition according to claim 1 wherein R 1 and R 2 are divalent radicals selected from C 1-10 alkyl.
11. The pharmaceutical composition according to claim 1 wherein R 5 is a divalent radical selected from C 1-10 alkyl.
12. The pharmaceutical composition according to claim 3 wherein at least one of A 1 X 3 and A 2 X 4 has the structure
wherein n is 1-4 and p is 2-6.
13. A compound that is of general formula (I) or is a salt, solvate, or prodrug thereof
wherein R 1 and R 2 are each independently divalent radicals selected from C 1-20 alkyl, C 2-20 alkenyl, C 7-20 alkaryl, C 2-10 alkynyl, C 7-20 aralkyl, C 2-20 heteroaralkyl, C 3-30 heterocyclylalkyl, C 3-30 alkylheterocyclyl, C 3-20 cycloalkyl, C 3-20 heterocyclyl, C 2-20 heteroaryl, C 5-20 aryl and C 1-10 alkoxy;
R is H or A 2 X 4 ;
wherein X 1 -X 4 are each independently selected from halo, OH, OR 3 , COH, NH 2 , NHR 3 , NR 3 R 4 , COOH, CONH 2 , COOR 3 , CONHR 3 , CONR 3 R 4 , SH, SR 3 , COR 3 and cyano, provided that at least one of groups X 1 -X 4 is a tertiary amine;
wherein R 3 and R 4 are independently selected from C 1-6 alkyl, C 6-20 aryl, and C 7-20 aralkyl or R 3 and R 4 together with the nitrogen atom to which they are attached form a 3-8 membered ring, which is optionally substituted and optionally comprises other hetero atoms;
A 1 and A 2 are each independently selected from NHR 5 ;
wherein R 5 is a divalent radical seleced from C 1-20 alkyl, C 6-20 aryl, C 7-20 alkaryl and C 7-20 aralkyl;
wherein any of the groups R 1 -R 5 , A l and A 2 may be substituted with C 1-20 alkyl, C 2-20 alkenyl, C 7-20 alkaryl, C 2-10 alkynyl, C 7-20 aralkyl, C 2-20 heteroaralkyl, C 3-30 heterocyclylalkyl, C 3-30 alkylheterocyclyl, C 3-20 cycloalkyl, C 3-20 heterocyclyl, C 2-20 heteroaryl, C 5-20 aryl or C 1-10 alkoxy, halo, OH, OR 3 , COH, NH 2 , NHR 3 , NR 3 R 4 , COOH, CONH 2 , COOR 3 , CONHR 3 , CONR 3 R 4 , SH, SR 3 , COR 3 or cyano.
14. A compound according to claim 13 wherein R is H.
15. A compound according to claim 13 wherein R is A 2 X 4 .
16. A compound according to claim 13 wherein R 1 X 1 ═R 2 X 2 .
17. A compound according to claim 15 wherein X 1 -X 4 are selected from NH 2 , NR 3 R 4 , OH, OR 3 and NHR 3 .
18. A compound according to claim 17 wherein X 1 -X 4 are NR 3 R 4 , wherein R 3 and R 4 are independently methyl or ethyl.
19. A compound according to claim 17 wherein X 1 -X 4 are NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen-atom to which they are attached form a 5 or 6 membered ring.
20. A compound according to claim 19 wherein the group NR 3 R 4 is pyrrolidine, piperidine or morpholine.
21. A compound according to claim 13 which is a prodrug of a compound of formula (I), wherein groups X 1 -X 4 of the prodrug are N-oxides or N + (—O − ) R 3 R 4 .
22. A compound according to claim 13 wherein R 1 and R 2 are divalent radicals selected from C 1-10 alkyl.
23. A compound according to claim 13 wherein R 5 is a divalent radical selected from C 1-10 alkyl.
24. A compound according to claim 15 wherein at least one of A 1 X 3 and A 2 X 4 the structure
wherein n is 1-4 and p is 2-6.
25. The pharmaceutical composition according to claim 7 wherein the 5 or 6 membered ring contains an oxygen atom.
26. The pharmaceutical composition according to claim 10 wherein R 1 and R 2 are divalent radicals selected from C 2-4 alkyl.
27. The pharmaceutical composition according to claim 11 wherein R 5 is a divalent radical selected from C 2-4 alkyl.
28. A compound according to claim 19 wherein the 5 or 6 membered ring contains an oxygen atom.
29. A compound according to claim 22 wherein R 1 and R 2 are divalent radicals selected from C 2-4 alkyl.
30. A compound according to claim 23 wherein R 5 is a divalent radical selected from C 2-4 alkyl.