Pyrrolobenzodiazepines

#This patent application is a national stage filing under 35 U.S.C. 371 of International Application No. PCT/GB2005/000915, filed on Mar. 9, 2005, which claims foreign priority benefits to United Kingdom Application No. 0405319.5, filed Mar. 9, 2004 and United Kingdom Application No. 0412409.5, filed Jun. 3, 2004.

#The present invention relates to a specific pyrrolobenzodiazepine (PBD) dimer with C2-exo unsaturation.

#Pyrrolobenzodiazepines

#FIG. 1 shows the distribution of MICs of different MRSA strains for compound 1;

#FIG. 2 shows the distribution of MICs of different VRE strains for compound 1;

#FIGS. 3a and 3b show the antibacterial activity of compound 1 on MRSA strain P1 at different time points, where the bacterial counts were calculated from 20 μL drops and 100 μL drops of the bacterial suspensions respectively.

#The compounds of formula I may be made by two alternative routes which are similar to those described in WO 00/12508. An important step is the formation of the C2-exo double bond. This may proceed by the methods described in schemes 8 and 9 of WO 00/12508.

#One method involves the synthesis of the compound to provide the C-ring before coupling to the remainder of the molecule.

#Commercially available trans-4-hydroxy-L-proline A can be N-alloc protected (or with any other suitable nitrogen protecting group) to give the protected compound B which can then be esterified using standard conditions. Hydride reduction of the ester C furnishes the diol D. Selective TBDMS protection of the diol gives a silyl ether E, which can then be oxidised, using, for example, Swern or TPAP oxidation, to provide the ketone F.