Pyrrolobenzodiazepines

• US 8,487,092 B2
• Filed: 10/16/2009
• Issued: 07/16/2013
• Est. Priority Date: 10/17/2008
• Status: Expired due to Fees

• Current Assignee: MedImmune Ltd. (Astrazeneca PLC)
• Original Assignee: Spirogen Developments SARL (Astrazeneca PLC)
• Inventors: Howard, Philip Wilson, Gregson, Stephen John, Tiberghien, Arnaud Charles, Masterson, Luke, Chen, ZhiZhi
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US13/124,232
• Publication Number:
  US 20110201803A1
• Time in Patent Office: 1,369 Days
• Field of Search: 540/496
• US Class Current: 540/496
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention relates to certain pyrrolobenzodiazepines (PBDs), and in particular pyrrolobenzodiazepine dimers bearing C2 substitutions, including compounds of formula (T): wherein: R² is CHR^2A, and R^2A is independently selected from H, R, CO₂R, COR, CHO, CO₂H, and halo; R⁶ and R⁹ are independently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, NO₂, Me₃Sn and halo; R⁷ is independently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, NO₂, Me₃Sn and halo; R⁸ is independently selected from H, R, OH, OR, SH, SR, NH₂, NHR, NRR′, NO₂, Me₃Sn and halo; R is independently selected from optionally substituted C_1-12 alkyl, C_3-20 heterocyclyl and C_5-20 aryl groups; or the compound is a dimer with each monomer being of formula (M), where the R⁷ groups or R⁸ groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers; wherein R″ is a C_3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), and/or aromatic rings, e.g. benzene or pyridine; and each X is independently selected from O, S, or N(H); or any pair of adjacent groups from R⁶ to R⁹ together form a group —O—(CH₂)_p—O—, where p is 1 or 2, and salts and solvates thereof, and their use as intermediates for the preparation of other PBD compounds.

Claims

1. A compound of formula (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 R⁷ and R⁷′

are each independently OR.

5. The compound according to claim 4, wherein R⁷ and R⁷′

are each independently OMe.

6. The compound according to claim 1, wherein R⁶ and R⁶′

are each independently H.

7. The compound according to claim 1, wherein R⁹ and R⁹′

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 C₃ alkylene group and a C₅ alkylene group.

11. The compound according to claim 10, wherein R″

is a C₃ 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:

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

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:

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:

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

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:

17. A process for the preparation of a compound 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):

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 R², wherein the compound of formula (S) is:

23. The process according to claim 22, wherein the alkene forming reagent is a phosphonium methylene ylide, and R² and R²′

are each H.