Pyrrolobenzodiazepines
View Patent ↗Compounds of the formula: (I) or solvate thereof, wherein: R 2 is an optionally substituted C 5-20 aryl group; 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 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 may be interrupted by one or more heteroatoms and/or aromatic rings; X is selected from O, S, or NH; z is 2 or 3; M is a monovalent pharmaceutically acceptable cation; R 2 ′, R 6 ′, R 7 ′, R 9 ′, X′ and M′ are selected from the same groups as R 2 , R 6 , R 7 , R 9 , X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
1. A compound of the formula I:
wherein:
R 2 is an optionally substituted aryl or heteroaryl group having 5 to 20 ring atoms, the heteroaryl groups having one or more heteroatoms independently selected from the group consisting of N, O and S, wherein the optional substituents are independently selected from C 1 -C 12 alkyl, heterocyclyl groups having 3 to 20 ring atoms of which 1 to 10 are heteroatoms independently selected from the group consisting of N, O and S, aryl groups having 5 to 20 ring atoms, halo, hydroxy, alkoxy, acetal, hemiacetal, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolcarboxy, imidic acid, hydroxamic acid, ester, acyloxy, oxycaroyloxy, amino, amido, thioamido, acylamido, aminocaronyloxy, ureido, guanidino, tetrazolyl, imino, amidino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone, sulfinic acid, sulfonic acid, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamido, sulfamino, sulfinamino, phosphino, phospho, phosphinyl, phosphonic acid, phosphonate, phosphoric acid, phosphate, phosphorous acid, phosphite, phosphoramidite, phosphoramidate or bisoxyalkylene;
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, heterocyclyl groups having 3 to 20 ring atoms of which 1 to 10 are heteroatoms independently selected from the group consisting of N, O and S and aryl groups having 5 to 20 ring atoms wherein the optional substituents are independently selected from C 1 -C 12 alkyl, heterocyclyl groups having 3 to 20 ring atoms of which 1 to 10 are heteroatoms independently selected from the group consisting of N, O and S, aryl groups having 5 to 20 ring atoms, halo, hydroxy, alkoxy, acetal, hemiacetal, ketal, hemiketal, oxo, thione, imino, formyl, acyl, carboxy, thiocarboxy, thiolcarboxy, imidic acid, hydroxamic acid, ester, acyloxy, oxycaroyloxy, amino, amido, thioamido, acylamido, aminocaronyloxy, ureido, guanidino, tetrazolyl, imino, amidino, nitro, nitroso, azido, cyano, isocyano, cyanato, isocyanato, thiocyano, isothiocyano, sulfhydryl, thioether, disulfide, sulfine, sulfone, sulfinic acid, sulfonic acid, sulfinate, sulfonate, sulfinyloxy, sulfonyloxy, sulfate, sulfamyl, sulfonamido, sulfamino, sulfinamino, phosphino, phospho, phosphinyl, phosphonic acid, phosphonate, phosphoric acid, phosphate, phosphorous acid, phosphite, phosphoramidite, phosphoramidate or bisoxyalkylene;
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 may be interrupted by one or more heteroatoms and/or aromatic rings;
X is selected from O, S, or NH;
z is 2 or 3;
M is a monovalent pharmaceutically acceptable cation;
R 2′ , R 6′ , R 7′ , R 9′ , X′ and M′ are selected from the same groups as R 2 , R 6 , R 7 , R 9 , X and M respectively, or M and M′ may together represent a divalent pharmaceutically acceptable cation.
2. A compound according to claim 1 , wherein X is O.
3. A compound according to claim 1 , wherein R″ represents a linear saturated C 3-12 alkylene group.
4. A compound according to claim 1 , wherein R 9 is H.
5. A compound according to claim 1 , wherein R 6 is H.
6. A compound according to claim 1 , wherein R 7 is selected from H, OH and OR, where R is selected from optionally substituted C 1-7 alkyl, heterocyclyl groups having 3 to 10 ring atoms of which 1 to 5 are heteroatoms independently selected from the group consisting of N, O and S, or aryl groups having 5 to 10 ring atoms.
7. A compound according to claim 6 , wherein R 7 is OMe or OCH 2 Ph.
8. A compound according to claim 1 , wherein R 2 is an optionally substituted aryl group having 5 to 7 ring atoms.
9. A compound according to claim 8 , wherein R 2 is an optionally substituted phenyl group.
10. A compound according to claim 1 , wherein R 2 is the same as R 2′ ;
R 6 is the same as R 6′ ;
R 7 is the same as R 7′ ;
R 9 is the same as R 9′ ;
M is the same as M′; and
X is the same as X′.
11. A compound according to claim 1 , wherein M and M 40 are monovalent pharmaceutically acceptable cations.
12. A compound according to claim 11 , wherein M and M′ are Na + .
13. A compound according to claim 1 wherein z is 3.
14. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutical excipient.
15. A compound according to claim 1 , wherein the optional substituents on R 2 are independently selected from C 1 -C 12 alkyl, aryl groups having 5 to 20 ring atoms, halo, hydroxy, alkoxy, formyl, amino, acylamido, nitro, cyano, sulfhydryl, thioether or bisoxyalkylene.
16. A compound according to claim 15 , wherein the optional substituents on R 2 are independently selected from halo, C 1 -C 7 alkoxy, C 1 -C 7 alkyl or bis-oxy-alkylene.
17. A compound according to claim 1 , wherein R and R′ are unsubstituted.