Unsymmetrical pyrrolobenzodiazepines-dimers for use in the treatment of proliferative and autoimmune diseases
View Patent ↗A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof.
1. A compound of formula III:
or a pharmaceutically acceptable salt thereof,
wherein:
R 22 is selected from:
(a) formula IVa:
where A is a phenyl group, 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;
(b) formula IVb:
where R C1 , R C2 and R C3 are independently selected from H and unsubstituted C 1-2 alkyl;
(c) formula IVc:
where Q is selected from OH, SH and NR N , and R N is selected from H, methyl and ethyl
X is selected from the group consisting of: OH, SH, CO 2 H, COH, N═C═O, NHNH 2 , CONHNH 2 ,
and NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl;
L 4 is selected from a single bond and a group of:
wherein n is 0 to 3;
wherein n is as defined above;
wherein n is as defined above; and
wherein n is as defined above, E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;
L3 is:
where X is such that L3 is an amino-acid residue, a dipeptide residue or a tripeptide residue;
Prot is selected from Fmoc (fluorenylmethyloxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) and Boc (t-butoxycarbonyl);
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;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
when there is a double bond present between C2′ and C3′, R 12 is selected from the group consisting of:
(ia) phenyl, naphthyl or azulenyl group or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, carboxy, —C(═O)OC 1-7 alkyl, —C(═O)OC 3-20 heterocyclyl, —C(═O)OC 5-20 aryl, 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 H or
where R 26a and R 26b are independently selected form 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″ is a C 3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from benzene or pyridine;
Y and Y′ are selected from O, S, or NH;
either:
(A) R 20 is H or Me and R 21a and R 21b are both H or together form ═O and either:
(i) R 10 is H, R 11a is H and R 11b is OH or OR A , where R A is C 1-4 alkyl; or
(ii) R 10 and R 11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H; or
(iii) R 10 is H, R 11a is H and R 11b is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or
(B) R 10 is H or Me and R 11a and R 11b are both H or together form ═O and either:
(i) R 20 is H, R 21a is H and R 21b is OH or OR A , where R A is C 1-4 alkyl; or
(ii) R 20 and R 21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H; or
(iii) R 20 is H, R 21a is H and R 21b is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
wherein the C 3-20 heterocyclyloxy group and —C(═O)OC 3-20 heterocyclyl group independently contain 1 to 10 ring heteroatoms selected from N, O and S;
the C 3-7 heterocyclyl group contains 1 to 4 ring heteroatoms selected from N, O and S.
2. A Conjugate having formula V:
L-(LU-D) p (V)
wherein L is an antibody or antibody fragment,
LU is a Linker unit,
p is 1 to 20; and
D is a Drug unit which is a PBD dimer according to formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 2 is of formula IIa, formula IIb or formula IIc:
where A is a phenyl group, 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;
where;
R C1 , R C2 and R C3 are independently selected from H and unsubstituted C 1-2 alkyl;
where Q is selected from OH, SH and NR N , and R N is selected from H, methyl and ethyl X is selected from the group consisting of: OH, SH, CO 2 H, COH, N═C═O, NHNH 2 , CONHNH 2 ,
and NHR N , wherein R N is selected from the group consisting of H and C 1-4 alkyl;
and either:
when there is a double bond present between C2′ and C3′, R 12 is selected from the group consisting of:
(ia) phenyl, naphthyl or azulenyl group or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, carboxy, —C(═O)OC 1-7 alkyl, —C(═)OC 3-20 heterocycyl, —C(═O)OC 5-20 aryl, 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 H or
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 with 1 to 10 ring heteroatoms selected from N, O, and S, 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;
R″ is a C 3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from 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;
either:
(A) R 20 is H or Me and R 21a and R 21b are both H or together form ═O and either:
(i) R 10 is H, R 11a is H and R 11b is OH or OR A , where R A is C 1-4 alkyl; or
(ii) R 10 and R 11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H; or
(iii) R 10 is H, R 11a is H and R 11b is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or
(B) R 10 is H or Me and R 11a and R 11b are both H or together form ═O and either:
(i) R 20 is H, R 21a is H and R 21b is OH or OR A , where R A is C 1-4 alkyl; or
(ii) R 20 and R 21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H; or
(iii) R 20 is H, R 21a is H and R 21b is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
wherein LU is connected to D via the X substituent of R 2 wherein the Linker unit (LU) has the formula (Va):
-A 1 -L 3 -L 4 -, (Va)
wherein:
-A 1 - is a Stretcher unit,
p is from 1-20;
L 4 is selected from a single bond and a group of:
wherein n is 0 to 3;
wherein n is as defined above;
wherein n is as defined above; and
wherein n is as defined above, E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;
L 3 is:
where X is such that L 3 is an amino-acid residue, a dipeptide residue or a tripeptide residue;
wherein -A 1 - is selected from
where the asterisk indicates the point of attachment to L 3 , 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 3 , 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 3 , 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 3 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30;
wherein the C 3-20 heterocyclyloxy group and —C(═O)OC 3-20 heterocyclyl group independently contain 1 to 10 ring heteroatoms selected from N, O and S;
the C 3-7 heterocyclyl group contains 1 to 4 ring heteroatoms selected from N, O and S.
3. The Conjugate of claim 2 , wherein the Linker unit (LU) has formula (Va), L 3 is a dipeptide, L 4 is a single bond, and wherein A 1 is selected from:
where the asterisk indicates the point of attachment to L 3 , 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 3 , 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 3 , 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 3 , the wavy line indicates the point of attachment to the Ligand unit, n is 0 or 1, and m is 0 to 30.
4. A drug linker of formula VI:
LU-D (VI)
or a pharmaceutically acceptable salt thereof, wherein LU is a Linker unit and where D is a Drug unit which is a PBD dimer according to formula I:
wherein:
R 2 is of formula IIa, formula IIb or formula IIc:
where A is a phenyl group, 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;
where;
R C1 , R C2 and R C3 are independently selected from H and unsubstituted C 1-2 alkyl;
where X is selected from *—O— q , *—S— q , *—CO 2 — q , *—CO— q , *—NH(C═O)— q , *—NHNH— q , *—CONHNH— q ,
wherein R N is selected from the group consisting of H and C 1-4 alkyl, and the asterix indicates the point of attachment to the remainder of the Drug unit and the wavy line or q indicates the point of attachment to the Linker Unit;
and either:
when there is a double bond present between C2′ and C3′, R 12 is selected from the group consisting of:
(ia) phenyl, naphthyl or azulenyl group or C 5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, C 5-20 aryloxy, carboxy, —C(═O)OC 1-7 alkyl, —C(═O)OC 3-20 heterocyclyl, —C(═O)OC 5-20 aryl, 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 is 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 H or
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; wherein R and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl with 1 to 10 ring heteroatoms selected from N, O and S 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;
R″ is a C 3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from 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;
either:
(A) R 20 is H or Me and R 21a and R 21b are both H or together form ═O and either:
(i) R 10 is H, R 11a is H and R 11b is OH or OR A , where R A is C 1-4 alkyl; or
(ii) R 10 and R 11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H; or
(iii) R 10 is H, R 11a is H and R 11b is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or
(B) R 10 is H or Me and R 11a and R 11b are both H or together form ═O and either:
(i) R 20 is H, R 21a is H and R 21b is OH or OR A , where R A is C 1-4 alkyl; or
(ii) R 20 and R 21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H; or
(iii) R 20 is H, R 21a is H and R 21b is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
wherein the C 3-20 heterocyclyloxy group and —C(═O)OC 3-20 heterocyclyl group independently contain 1 to 10 ring heteroatoms selected from N, O and S;
the C 3-7 heterocyclyl group contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein the Linker unit (LU) has the formula (Va):
G 1 -L 3 -L 4 -, (Va)
wherein:
-G 1 - is a Stretcher unit,
p is from 1-20;
L 4 is selected from a single bond and a group of:
wherein n is 0 to 3;
wherein n is as defined above;
wherein n is as defined above; and
wherein n is as defined above E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;
L 3 is:
where X is such that L 3 is an amino-acid residue, a dipeptide residue or a tripeptide residue;
wherein -G 1 - is selected from
where the asterisk indicates the point of attachment to L 3 and n is 0 to 6;
where the asterisk indicates the point of attachment to L 3 and n is 0 to 6;
where the asterisk indicates the point of attachment to L 3 , n is 0 or 1, and m is 0 to 30; or
where the asterisk indicates the point of attachment to L 3 , n is 0 or 1 and m is 0 to 30.
5. A conjugate according to claim 2 , wherein R 7 is a C 1-4 alkyloxy group.
6. A conjugate according to claim 2 , wherein Y is O and R″ is C 3-7 alkylene which chain is interrupted by one or more aromatic rings selected from benzene or pyridine.
7. A conjugate according to claim 2 , wherein R 6 and R 9 are H.
8. A conjugate according to claim 2 , wherein there is a double bond between C2′ and C3′, and R 12 is:
(a) a C 5-7 aryl group, which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or
(b) methyl, ethyl or propyl; or
(c) cyclopropyl; or
(d) a group of formula:
wherein the total number of carbon atoms in the R 12 group is no more than 4; or
(e) the group:
or
(f) a group of formula:
wherein R 24 is selected from H and methyl.
9. A conjugate according to claim 2 , wherein there is a single bond between C2′ and C3′, R 12 is
and:
(a) R 26a and R 26b are both H; or
(b) R 26a and R 26b are both methyl; or
(c) 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.
10. A conjugate according to claim 2 , wherein R 2 is of formula IIa, and A is phenyl, Q 1 is a single bond, and Q 2 is a single bond.
11. A compound according to claim 2 , wherein R 2 is of formula IIb, and R C1 , R C2 and R C3 are all H.
12. A conjugate according to claim 10 , wherein X is NH 2 .
13. A conjugate according to claim 2 , wherein R 2 is of formula IIc, and Q is NR N , wherein R N is H or methyl.
14. A conjugate according to claim 2 , wherein R 6′ , R 7′ , R 9′ and Y′ are the same as R 6 , R 7 , R 9 , and Y respectively.
15. A conjugate according to claim 2 , wherein R 20 is H or Me and R 21a and R 21b are both H.
16. A conjugate according to claim 2 , wherein R 20 is H or Me and R 21a and R 21b together form ═O.
17. A conjugate according to claim 15 , wherein R 10 and R 11b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H.
18. A conjugate according to claim 2 , wherein R 10 is H or Me and R 11a and R 11b are both H.
19. A conjugate according to claim 2 , wherein R 10 is H or Me and R 11a and R 11b together form ═O.
20. A conjugate according to claim 18 , wherein R 20 and R 21b form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound and R 11a is H.