11-hydroxy-5h-pyrrolo[2,1-c][1,4] benzodiazepin-5-one derivatives as key intermediates for the preparation of c2 substituted pyrrolobenzodiazepines

1. A compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

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 and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;

the compound being a dimer with each monomer being of formula (III), where the R 8 of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S, or NH, and R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, or any pair of adjacent groups from R 6 to R 9 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2;

either R 10 and R 16 together form a double bond between N10 and C11, or R 10 is H and R 16 is OH;

R 15 is an optionally substituted C 5-20 aryl group,

wherein the optional substituents are independently selected from the group consisting of C 1-12 alkyl, C 3-12 cycloalkyl, C 3-20 heterocyclyl, C 5-20 aryl, halo, hydroxyl, —OR 1 wherein R 1 is a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group, alkoxy, —CH(OR 1 )(OR 2 ) wherein R 1 is as defined above and R 2 is independently a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group or R 1 and R 2 together with the two oxygen atoms to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms, —CH(OH)(OR 1 ) wherein R 1 is as defined above, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR 1 wherein R 1 is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido, acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone, —S(═O)OH, —SO 2 H, —S(═O) 2 OH, —SO 3 H, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino, sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR 17 ) 2 wherein R 17 is —H or C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-20 aryl group, phosphonooxy, —PO(═O)(OR 17 ) 2 wherein R 17 is as defined above, —OP(OH) 2 , phosphate, phosphoramidite, and phosphoramidate; and wherein heteroatoms of the heterocyclyl groups and the optional heteroatoms of the alkylene groups are independently selected from the group consisting of N, S, and O.

2. A compound according to claim 1 , wherein the dimer bridge has the formula —O—(CH 2 ) n —O— linking the monomers, where n is from 3 to 12.

3. A compound according to claim 2 , wherein n is from 3 to 7.

4. A compound according to claim 1 , wherein R 10 and R 16 together form a double bond between N10 and C11.

5. A compound according to claim 1 , wherein R 9 is H.

6. A compound according to claim 1 , wherein R 7 and R 8 are independently selected from H, OH, OR, SH, NH 2 , NHR, NRR′ and halo.

7. A pharmaceutical composition containing a compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.

8. A method of treatment of chronic myeloid leukemia, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of claim 1 .

9. A method of synthesizing a compound of formula III:

comprising reacting a compound of formula I:

with a compound of formula z-R 15 in a coupling reaction, wherein

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 and R′ are independently selected from optionally substituted

C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;

R 7 and R 8 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo,

or the compound is a dimer with each monomer being of formula (I), where the R 7 groups or R 8 groups of each monomers form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S, or NH;

or any pair of adjacent groups from R 6 to R 9 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2;

R 10 is a carbamate-based nitrogen protecting group;

R 2 is a labile leaving group;

R 16 is either O—R 11 , where R 11 is an oxygen protecting group, or OH, or R 10 and R 16 together form a double bond between N10 and C11;

z-R 15 is any reactant suitable for a coupling reaction;

R 15 is an optionally substituted C 5-20 aryl group,

wherein the optional substituents are independently selected from the group consisting of C 1-12 alkyl, C 3-12 cycloalkyl, C 3-20 heterocyclyl, C 5-20 aryl, halo, hydroxyl, —OR wherein R is a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group, alkoxy, —CH(OR 1 )(OR 2 ) wherein R 1 is as defined above and R 2 is independently a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group or R 1 and R 2 together with the two oxygen atoms to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms, —CH(OH)(OR 1 ) wherein R 1 is as defined above, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR 1 wherein R 1 is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido, acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone, —S(═O)OH, SO 2 H, —S(═O) 2 OH, —SO 3 H, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino, sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR 17 ) 2 wherein R 17 is —H or C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-20 aryl group, phosphonooxy, —PO(═O)(OR 17 ) 2 wherein R 17 is as defined above, —OP(OH) 2 , phosphate, phosphoramidite, and phosphoramidate; and wherein heteroatoms of the heterocyclyl groups and the optional heteroatoms of the alkylene groups are independently selected from the group consisting of N, S, and O.

10. A method according to claim 9 , wherein the synthesis of said compound of formula III uses a palladium catalysed coupling step.

11. A method according to claim 10 , wherein the palladium catalyst is Pd(PPh 3 ) 4 , Pd(OCOCH 3 ) 2 , PdCl 2 or Pd(dba) 3 .

12. A method according to claim 10 , wherein the coupling reaction is performed under microwave conditions.

13. A method according to claim 10 , wherein the palladium catalyst is solid supported.

14. A compound of formula III

and salts and solvates thereof, wherein:

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 and R′ are independently selected from optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups;

the compound being a dimer with each monomer being of formula (III), where the R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S, or NH, and

R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo; or any pair of adjacent groups from R 6 to R 9 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2;

R 10 is a carbamate-based nitrogen protecting group;

R 16 is —O—R 11 , where R 11 is an oxygen protecting group or H;

R 15 is an optionally substituted C 5-20 aryl group,

wherein the optional substituents are independently selected from the group consisting of C 1-12 alkyl, C 3-12 cycloalkyl, C 3-20 heterocyclyl, C 5-20 aryl, halo, hydroxyl, —OR wherein R is a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group, alkoxy, —CH(OR 1 )(OR 2 ) wherein R 1 is as defined above and R 2 is independently a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group or R 1 and R 2 together with the two oxygen atoms to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms, —CH(OH)(OR 1 ) wherein R 1 is as defined above, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR 1 wherein R 1 is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido, acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone, —S(═O)OH, SO 2 H, —S(═O) 2 OH, —SO 3 H, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino, sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR 17 ) 2 wherein R 17 is H or C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-20 aryl group, phosphonooxy, —PO(═O)(OR 17 ) 2 wherein R 17 is as defined above, —OP(OH) 2 , phosphate, phosphoramidite, and phosphoramidate; and wherein heteroatoms of the heterocyclyl groups and the optional heteroatoms of the alkylene groups are independently selected from the group consisting of N, S, and O.

15. A compound according to claim 14 , wherein R 10 is Troc.

16. A compound according to claim 14 , wherein R 11 is a silyl oxygen protecting group or THP.

17. A compound of formula I:

for use in the synthesis of a compound of formula III:

wherein:

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 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, NRR′, nitro, Me 3 Sn and halo, the compound of formula III being dimer with each monomer being of formula III, where the R 8 groups of each monomer form together a dimer bridge having the formula —X—R″—X— linking the monomers, where R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings, and each X is independently selected from O, S, or NH;

or any pair of adjacent groups from R 6 to R 9 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2;

R 10 is a carbamate-based nitrogen protecting group, or either R 10 and R 16 together form a double bond between N10 and C11, or R 10 is H and R 16 is OH;

R 11 is an oxygen protecting group or H;

R 2 is a labile leaving group;

R 15 is an optionally substituted C 5-20 aryl group,

wherein the optional substituents are independently selected from the group consisting of C 1-12 alkyl, C 3-12 cycloalkyl, C 3-20 heterocyclyl, C 5-20 aryl, halo, hydroxyl, —OR wherein R is a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group, alkoxy, —CH(OR 1 )(OR 2 ) wherein R 1 is as defined above and R 2 is independently a C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-10 aryl group or R 1 and R 2 together with the two oxygen atoms to which they are attached form a heterocyclic ring having from 4 to 8 ring atoms, —CH(OH)(OR 1 ) wherein R 1 is as defined above, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolocarboxy, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR 1 wherein R 1 is as defined above, acyloxy, oxycarboyloxy, amino, amido, thioamido, acylamido, aminocarbonyloxy, ureido, guanidine, tetrazolyl, amindino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone, —S(═O)OH, SO 2 H, —S(═O) 2 OH, —SO 3 H, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamide, sulfamino, sulfonamino, sulfinamino, phosphino, phosphor, phosphinyl, phosphono, —P(═O)(OR 17 ) 2 wherein R 17 is —H or C 1-7 alkyl group or C 3-20 heterocyclyl group or C 5-20 aryl group, phosphonooxy, —PO(═O)(OR 17 ) 2 wherein R 17 is as defined above, —OP(OH) 2 , phosphate, phosphoramidite, and phosphoramidate; and wherein heteroatoms of the heterocyclyl groups and the optional heteroatoms of the alkylene groups are independently selected from the group consisting of N, S, and O.

18. A compound according to claim 6 , wherein R 7 is OR.

19. A compound according to claim 6 , wherein R 7 is OMe.

20. A compound according to claims 1 wherein R 15 is a C 5-20 aryl group optionally substituted with a substituent selected from the group consisting of R, OH, OR, NH 2 , NHR, NRR′, ON, C(═O)H, C(═O)OH and halo.

21. A compound according to claim 1 , wherein R 15 is a C 5-20 aryl group substituted by OR.

22. A compound according to claim 1 , wherein R 15 is a C 5-20 aryl group substituted by OMe.

23. A compound according to claim 1 , wherein R 6 is H, R 7 is OMe, X is O, R″ is (CH 2 ) 3 , R 9 is H, R 10 and R 16 together form a double bond between N10 and C11, and R 15 is para-methoxyphenyl.

24. The compound of claim 1 , wherein R″ is a C 3-12 alkylene group interrupted by one or more heteroatoms, wherein the one or more heteroatoms are independently selected from the group consisting of O, S, and N.

25. A compound of the following formula:

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein R and R′ are unsubstituted.

27. The compound of claim 1 , wherein R 15 is an unsubstituted C 5-20 aryl group.

28. The compound of claim 1 , wherein R 15 is a singly substituted C 5-20 aryl group.