Pyrrolobenzodiazepines

1. A compound of formula (S):

wherein:

SEM is 2-(trimethylsilyl)ethoxymethyl;

R 2 is CHR 2A , and R 2A is independently selected from H, R, CO 2 R, COR, CHO, CO 2 H, and halo;

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

or the adjacent groups R 6 and R 7 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2; and

R is independently selected from optionally substituted C 1-12 alkyl, C 3-7 heterocyclyl and C 5-20 aryl groups, wherein the optional substituents are selected from C 1-7 alkyl, C 3-7 heterocyclyl, C 5-20 aryl, halo, hydroxy, C 1-7 alkoxy, C 3-7 heterocyclyloxy, and C 5-20 aryloxy;

R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S and N(H); and/or aromatic rings;

each X is independently selected from O, S, or N(H); and

R 2 ′, R 6 ′, R 7 ′, R 9 ′, and X′ are independently selected from the same groups as R 2 , R 6 , R 7 , R 9 , and X respectively; and

wherein C 3-7 heterocyclyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms, selected from N, O and S.

2. The compound according to claim 1 , wherein R 2A is independently selected from H and R.

3. The compound according to claim 2 , wherein R 2A is independently H.

4. The compound according to claim 1 , wherein R 7 and R 7 ′ are each independently OR.

5. The compound according to claim 4 , wherein R 7 and R 7 ′ are each independently OMe.

6. The compound according to claim 1 , wherein R 6 and R 6 ′ are each independently H.

7. The compound according to claim 1 , wherein R 9 and R 9 ′ are each independently H.

8. The compound according to claim 1 , wherein X and X′ are each independently O.

9. The compound according to claim 1 , wherein R″ is a C 3-12 alkylene group.

10. The compound according to claim 9 , wherein R″ is selected from a C 3 alkylene group and a C 5 alkylene group.

11. The compound according to claim 10 , wherein R″ is a C 3 alkylene group.

12. The compound according to claim 1 of formula (8):

13. A process for the preparation of a compound of formula (A), the process comprising the step of reacting a compound of formula (S) with a reducing agent, wherein the compound of formula (S) is:

wherein:

SEM is 2-(trimethylsilyl)ethoxymethyl;

R 2 is CHR 2A , and R 2A is independently selected from H, R, CO 2 R, COR, CHO, CO 2 H, and halo;

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

or the adjacent groups R 6 and R 7 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2; and

R is independently selected from optionally substituted C 1-12 alkyl, C 3-7 heterocyclyl and C 5-20 aryl groups, wherein the optional substituents are selected from C 1-7 alkyl, C 3-7 heterocyclyl, C 5-20 aryl, halo, hydroxy, C 1-7 alkoxy, C 3-20 heterocyclyloxy, and C 5-20 aryloxy;

R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S and N(H) and/or aromatic rings;

each X is independently selected from O, S, or N(H); and

R 2 ′, R 6 ′, R 7 ′, R 9 ′, and X′ are independently selected from the same groups as R 2 , R 6 , R 7 , R 9 , and X respectively; and

wherein C 3-7 heterocyclyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms, selected from N, O and S; and (A) is a compound:

where R 2 ′, R 6 ′, R 7 ′, R 9 ′, X′, R″, R 2 , R 6 , R 7 , R 9 , and X are as defined for the compounds of formula (S).

14. The process according to claim 13 , wherein the reducing agent is a borohydride salt.

15. A process for the preparation of a compound of formula (S), the process comprising the step of protecting the amide nitrogens of (B) with SEM, wherein the compound of formula (S) is:

wherein:

SEM is 2-(trimethylsilyl)ethoxymethyl;

R 2 is CHR 2A , and R 2A is independently selected from H, R, CO 2 R, COR, CHO, CO 2 H, and halo;

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

or the adjacent groups R 6 and R 7 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2; and

R is independently selected from optionally substituted C 1-12 alkyl, C 3-7 heterocyclyl and C 5-20 aryl groups, wherein the optional substituents are selected from C 1-7 alkyl, C 3-7 heterocyclyl, C 5-20 aryl, halo, hydroxy, C 1-7 alkoxy, C 3-20 heterocyclyloxy, and C 5-20 aryloxy; R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S and N(H) and/or aromatic rings;

each X is independently selected from O, S, or N(H); and

R 2 ′, R 6 ′, R 7 ′, R 9 ′, and X′ are independently selected from the same groups as R 2 , R 6 , R 7 , R 9 , and X respectively; and

wherein C 3-7 heterocyclyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms, selected from N, O and S; and B is a compound:

where R 2 ′, R 6 ′, R 7 ′, R 9 ′, X′, R″, R 2 , R 6 , R 7 , R 9 , and X are as defined for the compound of formula (S).

16. The process according to claim 15 , wherein (B) is reacted with SEM-CI thereby to form (S).

17. A process for the preparation of a compound formula (B)

wherein:

R 2 is CHR 2A , and R 2A is independently selected from H, R, CO 2 R, COR, CHO, CO 2 H, and halo;

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

or the adjacent groups R 6 and R 7 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2; and

R is independently selected from optionally substituted C 1-12 alkyl, C 3-7 heterocyclyl and C 5-20 aryl groups, wherein the optional substituents are selected from C 1-7 alkyl, C 3-7 heterocyclyl, C 5-20 aryl, halo, hydroxy, C 1-7 alkoxy, C 3-20 heterocyclyloxy, and C 5-20 aryloxy;

R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S and N(H) and/or aromatic rings;

each X is independently selected from O, S, or N(H); and

R 2 ′, R 6 ′, R 7 ′, R 9 ′, and X′ are independently selected from the same groups as R 2 , R 6 , R 7 , R 9 , and X respectively; and

wherein C 3-7 heterocyclyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms, selected from N, O and S;

the process comprising the step of reacting a compound of formula (X) with a compound of formula (C), and (X) and (C) are:

where R b , R′, R 9 , X′, R″, R′, R b , R′, R 9 , and X are as defined for the compounds of formula (B).

18. The process according claim 17 , wherein (C) is compound (6):

19. The process according to claim 17 , wherein (X) is compound (3):

20. The process according to claim 15 further comprising the preceding step of reacting a compound of formula (X) with a compound of formula (C), wherein (B) is as defined in claim 15 , and (X) and (C) are:

and R 6 ′, R 7 ′, R 9 ′, X′, R″, R 2 , R 6 , R 7 , R 9 , and X are as defined for the compounds of formula (B).

21. The process according to claim 13 , further comprising the preceding step of protecting the amide nitrogens of (B) with SEM,

wherein B is a compound:

wherein R 2 ′, R 6 ′, R 7 ′, R 9 ′, X′, R″, R 2 , R 6 , R 7 , R 9 , and X are as defined for the compound of formula (S);

and optionally the preceding step of reacting a compound of formula (X) with a compound of formula (C), and (X) and (C) are:

and R 6 ′, R 7 ′, R 9 ′, X′, R″, R 2 , R 6 , R 7 , R 9 , and X are as defined above.

22. A process for the preparation of a compound of formula (S), the process comprising the step of reacting (W) with an alkene forming reagent comprising a group R 2 , wherein the compound of formula (S) is:

wherein:

SEM is 2-(trimethylsilyl)ethoxymethyl;

R 2 is CHR 2A , and R 2A is independently selected from H, R, CO 2 R, COR, CHO, CO 2 H, and halo;

R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', NO 2 , Me 3 Sn and halo;

or the adjacent groups R 6 and R 7 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2; and

R is independently selected from optionally substituted C 1-12 alkyl, C 3-7 heterocyclyl and C 5-20 aryl groups, wherein the optional substituents are selected from C 1-7 alkyl, C 3-7 heterocyclyl, C 5-20 aryl, halo, hydroxy, C 1-7 alkoxy, C 3-20 heterocyclyloxy, and C 5-20 aryloxy;

R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S and N(H) and/or aromatic rings;

each X is independently selected from O, S, or N(H); and

R 2 ′, R 6 ′, R 7 ′, R 9 ′, and X′ are independently selected from the same groups as R 2 , R 6 , R 7 , R 9 , and X respectively; and

wherein C 3-7 heterocyclyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms, selected from N, O and S;

and (W) is a compound:

where R 2 , R 6 ′, R 7 ′, R 9 ′, X′, R″, R 6 , R 7 , R 9 , and X are as defined for the compound of formula (S).

23. The process according to claim 22 , wherein the alkene forming reagent is a phosphonium methylene ylide, and R 2 and R 2 ′ are each H.