Unsymmetrical pyrrolobenzodiazepine-dimers for treatment of proliferative diseases
View Patent ↗Claimed are unsymmetrical Pyrrolobenzodiazepine-dimers (PBD-dimers) of formula (I), that are unsymmetrical due at least to the values that the variables R 12 and R 2 represent. Formula (I), wherein: R 2 is of formula (II), where A is a C 5-7 aryl group, X is selected from the group comprising: OH, SH, CO 2 H, COH, N═C═O, NHR N , wherein R N is selected from the group comprising H and C 1-4 alkyl, and (OC 2 H 4 ) m OCH 3 , where m is 1 to 3, and either: (i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from a single bond, O, S and NH and n is from 1 to 3; or (ii) Q 1 is —CH═CH—, and Q 2 is a single bond; R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene. The other variables are as defined in the claims. The compounds are useful for the treatment of proliferative diseases.
1. A compound with the formula I:
wherein:
R 2 is of formula II:
where A is a C 5-7 aryl group, X is selected from the group consisting of: OH, SH, CO 2 H, COH, N═C═O, NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl, and (OC 2 H 4 ) m OCH 3 , where m is 1 to 3, and either:
(i) Q 1 is a single bond, and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, where Z is selected from the group consisting of a single bond, O, S and NH and n is from 1 to 3; or
(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, ether, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
either:
(a) R 10 is H, and R 11 is OH, or OR A , where R A is C 1-4 alkyl;
(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 10 is H and R 11 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from the group consisting of O, S, and NH, and/or aromatic rings selected from benzene or pyridine;
Y and Y′ are independently selected from the group consisting of O, S, or NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively and R 10′ and R 11′ are the same as R 10 and R 11 , wherein if R 11 and R 11′ are SO z M, M represents a divalent pharmaceutically acceptable cation selected from Ca 2+ and Mg 2+ .
2. A compound according to claim 1 , wherein R 7 is selected from H, OH and OR.
3. A compound according to claim 2 , wherein R 7 is a C 1-4 alkyloxy group.
4. A compound according to claim 1 , wherein Y is O.
5. A compound according to claim 1 , wherein R″ is C 3-7 alkylene.
6. A compound according to claim 1 , wherein R 9 is H.
7. A compound according to claim 1 , wherein R 6 is selected from H and halo.
8. A compound according to claim 1 , wherein A is phenyl.
9. A compound according to claim 1 , wherein X is selected from OH, SH, or NH 2 .
10. A compound according to claim 1 , wherein Q 1 is a single bond.
11. A compound according to claim 10 , wherein Q 2 is a single bond.
12. A compound according to claim 10 , wherein Q 2 is —Z—(CH 2 ) n —, Z is O or S and n is 1 or 2.
13. A compound according to claim 1 , wherein Q 1 is —CH═CH—.
14. A compound according to claim 1 , wherein R 12 is a C 5-7 aryl group.
15. A compound according to claim 14 , wherein R 12 is phenyl.
16. A compound according to claim 1 , wherein R 12 is a C 8-10 aryl group.
17. A compound according to claim 1 , wherein R 12 bears one to three substituent groups.
18. A compound according to claim 1 , wherein R 10 and R 11 and form a nitrogen-carbon double bond.
19. A compound according to claim 1 , wherein R 6′ , R 7′ , R 9′ , R 10′ , R 11′ and Y′ are the same as R 6 , R 7 , R 9 , R 10 , R 11 and Y respectively.
20. A compound of formula II:
wherein:
R 2 is
where A is a C 5-7 aryl group, X is selected from the group consisting of: OH, SH, CO 2 H, COH, N═C═O, NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl, and (OC 2 H 4 ) m OCH 3 , where m is 1 to 3, and either:
(i) Q 1 is a single bond, and Q 2 is selected from a single bond or —Z—(CH 2 ) n —, where Z is selected from a single bond, O, S or NH and is from 1 to 3; or
(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, ether, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo; either:
(a) R 10 is carbamate nitrogen protecting group, and R 11 is O-Prot o , wherein Prot o is an oxygen protecting group;
(b) R 10 is a hemi-aminal nitrogen protecting group and R 11 is an oxo group;
R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, selected from the group consisting of O, S, and NR N2 (where R N2 is H or C 1-4 alkyl), and/or aromatic rings, e.g. benzene or pyridine;
Y and Y′ are selected from O, S, or NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively and R 10′ and R 11′ are the same as R 10 and R 11 .
21. A compound according to claim 20 , wherein R 7 is selected from H, OH or OR.
22. A compound according to claim 21 , wherein R 7 is a C 1-4 alkyloxy group.
23. A compound according to claim 20 , wherein Y is O.
24. A compound according to claim 20 , wherein R″ is C 3-7 alkylene.
25. A compound according to claim 20 , wherein R 9 is H.
26. A compound according to claim 20 , wherein R 6 is selected from H or halo.
27. A compound according to claim 20 , wherein A is phenyl.
28. A compound according to claim 20 , wherein X is selected from OH, SH, or NH 2 .
29. A compound according to claim 20 , wherein Q 1 is a single bond.
30. A compound according to claim 29 , wherein Q 2 is a single bond.
31. A compound according to claim 29 , wherein Q 2 is —Z—(CH 2 ) n —, Z is O or S and n is 1 or 2.
32. A compound according to claim 20 , wherein Q 1 is —CH═CH—.
33. A compound according to claim 20 , wherein R 12 is a C 5-7 aryl group.
34. A compound according to claim 33 , wherein R 12 is phenyl.
35. A compound according to claim 20 , wherein R 12 is a C 8-10 aryl group.
36. A compound according to claim 20 , wherein R 12 bears one to three substituent groups.
37. A compound according to claim 20 , wherein R 10 is Troc.
38. A compound according to claim 20 , wherein R 11 is OTBS.
39. A compound according to claim 20 , wherein R 11 is oxo and R 10 is SEM.
40. A compound according to claim 20 , wherein R 6′ , R 7′ , R 9′ , R 10′ , R 11′ and Y′ are the same as R 6 , R 7 , R 9 , R 10 , R 11 and Y respectively.
41. A compound of the formula:
42. A compound of the formula: