Pyrrolobenzodiazepines as unsymmetrical dimeric PBD compounds for inclusion in targeted conjugates
View Patent ↗A compound with the formula I wherein: R 2 is of formula II where Q is selected from OH, SH and NR N , and R N is selected from H, methyl and ethyl, as well as drug-linkers and drug-conjugates made from this compound.
1. A compound with the formula I:
wherein:
R 2 is of formula II:
where Q is selected from OH, SH and NHR N , and R N is selected from H, methyl and ethyl;
when there is a double bond present between C2′ and C3′, R 12 is selected from:
(ia) 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;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;and
where R 24 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 12 is
where R 26a and R 26b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from 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 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, and/or aromatic rings;
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 , wherein if R 11 and R 11′ are SO Z M, M may represent a divalent pharmaceutically acceptable cation.
2. A compound according to any 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 Q is NHR N .
9. A compound according to claim 8 , wherein R N is H or methyl.
10. A compound according to claim 1 , wherein Q is OH or SH.
11. A compound according to claim 1 , wherein there is a single bond between C2′ and C3′, R 12 is
and R 26a and R 26b are both H.
12. A compound according to claim 1 , wherein there is a single bond between C2′ and C3′, R 12 is
and R 26a and R 26b are both methyl.
13. A compound according to claim 1 , wherein there is a single bond between C2′ and C3′, R 12 is
one of R 26a and R 26b is H, and the other is selected from C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.
14. A compound according to claim 1 , wherein there is a double bond between C2′ and C3′, and 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 there is a double bond between C2′ and C3′, and 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 there is a double bond between C2′ and C3′, and R 12 is a C 1-5 saturated aliphatic alkyl group.
19. A compound according to claim 18 , wherein R 12 is methyl, ethyl or propyl.
20. A compound according to claim 1 , wherein there is a double bond between C2′ and C3′, and R 12 is a C 3-6 saturated cycloalkyl group.
21. A compound according to claim 20 , wherein R 12 is cyclopropyl.
22. A compound according to claim 1 , wherein there is a double bond between C2′ and C3′, and R 12 is a group of formula:
23. A compound according to claim 22 , wherein the total number of carbon atoms in the R 12 group is no more than 4.
24. A compound according to claim 23 , wherein the total number of carbon atoms in the R 12 group is no more than 3.
25. A compound according to claim 22 , wherein one of R 21 , R 22 and R 23 is H, with the other two groups being selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl.
26. A compound according to claim 22 , wherein two of R 21 , R 22 and R 23 are H, with the other group being selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl.
27. A compound according to claim 1 , wherein there is a double bond between C2′ and C3′, and R 12 is a group of formula:
28. A compound according to claim 27 , wherein R 12 is the group:
29. A compound according to claim 1 , wherein there is a double bond between C2′ and C3′, and R 12 is a group of formula:
30. A compound according to claim 29 , wherein R 24 is selected from H, methyl, ethyl, ethenyl and ethynyl.
31. A compound according to claim 30 , wherein R 24 is selected from H and methyl.
32. A compound according to claim 1 , wherein R 10 and R 11 and form a nitrogen-carbon double bond.
33. 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.
34. The use of a compound according to claim 1 in the manufacture of a medicament for treating a proliferative disease.
35. A compound according to claim 1 for use in the treatment of a proliferative disease.
36. A compound of formula II:
wherein:
R 2 is of formula II:
where Q is selected from OH, SH and NHR N , and R N is selected from H, methyl and ethyl;
when there is a double bond present between C2′ and C3′, R 12 is selected from:
(ia) 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;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;and
where R 24 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 12 is
where R 26a and R 26b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from 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, and/or aromatic rings;
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 .
37. A compound according to any claim 36 , wherein R 7 is selected from H, OH and OR.
38. A compound according to claim 37 , wherein R 7 is a C 1-4 alkyloxy group.
39. A compound according to claim 3 , wherein Y is O.
40. A compound according to claim 36 , wherein R″ is C 3-7 alkylene.
41. A compound according to claim 36 , wherein R 9 is H.
42. A compound according to claim 36 , wherein R 6 is selected from H and halo.
43. A compound according to claim 36 , wherein Q is NHR N .
44. A compound according to claim 43 , wherein R N is H or methyl.
45. A compound according to claim 36 , wherein Q is OH or SH.
46. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a C 5-7 aryl group.
47. A compound according to claim 46 , wherein R 12 is phenyl.
48. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a C 8-10 aryl group.
49. A compound according to claim 46 , wherein R 12 bears one to three substituent groups.
50. A compound according to claim 36 , wherein there is a single bond between C2′ and C3′, R 12 is
and R 26a and R 26b are both H.
51. A compound according to claim 36 , wherein there is a single bond between C2′ and C3′, R 12 is
and R 26a and R 26b are both methyl.
52. A compound according to claim 36 , wherein there is a single bond between C2′ and C3′, R 12 is
one of R 26a and R 26b is H, and the other is selected from C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted.
53. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a C 1-5 saturated aliphatic alkyl group.
54. A compound according to claim 53 , wherein R 12 is methyl, ethyl or propyl.
55. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a C 3-6 saturated cycloalkyl group.
56. A compound according to claim 55 , wherein R 12 is cyclopropyl.
57. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a group of formula:
58. A compound according to claim 57 , wherein the total number of carbon atoms in the R 12 group is no more than 4.
59. A compound according to claim 58 , wherein the total number of carbon atoms in the R 12 group is no more than 3.
60. A compound according to claim 57 , wherein one of R 21 , R 22 and R 23 is H, with the other two groups being selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl.
61. A compound according to claim 57 , wherein two of R 21 , R 22 and R 23 are H, with the other group being selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl.
62. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a group of formula:
63. A compound according to claim 62 , wherein R 12 is the group:
64. A compound according to claim 36 , wherein there is a double bond between C2′ and C3′, and R 12 is a group of formula:
65. A compound according to claim 64 wherein R 24 is selected from H, methyl, ethyl, ethenyl and ethynyl.
66. A compound according to claim 65 , wherein R 24 is selected from H and methyl.
67. A compound according to claim 36 , wherein R 10 is Troc.
68. A compound according to claim 36 , wherein R 11 is OTBS.
69. A compound according to claim 36 , wherein R 11 is oxo and R 10 is SEM.
70. A compound according to claim 36 , wherein R6′, R7′, R9′, R 10′ , R 11′ and Y′ are the same as R 6 , R 7 , R 9 ,R 10 , R 11 and Y respectively.
71. A Conjugate having formula III:
L-(LU-D) p (I)
wherein L is a Ligand unit which is a cell binding agent that specifically binds to a target molecule on the surface of a target cell, LU is a Linker unit of formula -A 1 -L 1 -, wherein L 1 is a dipeptide and A 1 is selected from:
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6;
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1 and m is 0 to 30; or
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1 and m is 0 to 30,
p is 1 to 20; and
D is a Drug unit which is a compound with the formula I:
wherein:
R 2 is of formula II:
where Q is selected from —O—, —S— and —NR N and R N is selected from H, methyl and ethyl;
when there is a double bond present between C2′ and C3′, R 12 is selected from:
(ia) 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;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 saturated alkyl C 2-3 alkenyl and cyclopropyl, where the total number of carbon atoms in the R 12 group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl; which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 12 is
where R 26a and R 26b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH ,OR SH, SR, NH 2 NHR, NRR′ nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;
R 7 is selected from 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 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 and/or aromatic rings;
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 wherein if R 11 and R 11′ are SO z M, M may represent a divalent pharmaceutically acceptable cation,
wherein LU is connected to D via the Q substituent of R 2 .
72. The Conjugate of claim 71 , wherein A 1 is
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1 and m is 0 to 30.
73. The Conjugate of claim 71 , wherein A 1 is:
where the asterisk indicates the point of attachment to L 1 , the wavy line indicates the point of attachment to the Ligand unit, and n is 0 to 6.
74. The Conjugate of claim 73 , wherein n is 5.
75. The Conjugate of claim 71 , wherein L 1 is selected from the group consisting of valine-alanine, valine-citrulline and phenyalanine-lysine.
76. A method of treating a mammal having a proliferative disease or an autoimmune disease, comprising administering an effective amount of the Conjugate of claim 71 .