Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto

1. A compound of Formula I:

wherein X is a substituent selected from the group consisting of an OH, an alkoxy, a silyloxy, a trialkylsilyloxy, an alkylcarbonyloxy, an alkyloxycarbonyloxy, a carbamoyl, a thiocarbamoyl, a cyclic carbamoyl, a cyclic thiocarbamoyl, SH, SR, a sulfoxy, a sulfonyl, a sulfito, a bisulfito, a sulphonamido, an amino, an amido, an azido, a cyano, a halo, a triphenyl phosphonium ion with a counter ion, a silyl, a trialkyl silyl, an amino acid-derived group having an amine fragment and a carboxyl fragment of an amino acid, and a phosphorus-containing group selected from the group consisting of a phosphoric acid group, a phosphorus acid group, a phosphonic group, or a phosphonous acid group; wherein R is a C 1 -C 24 alkyl optionally substituted with amino, hydroxyl, or sulfhydryl, a cycloalkyl, a C 2 -C 24 alkenyl, a C 3 -C 26 alkoxyacetyl, or a group of structure:

wherein each of Y and Y′ is independently hydrogen, C 1 -C 24 alkyl, aryl alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 alkoxy, or halogen, or Y and Y′ together form 3,4-methylenedioxy, and Y″ is hydrogen, C 1 -C 24 alkyl, C 1 -C 24 alkoxy, halogen, a naphthalenalkyl optionally substituted by methyl or halogen, a phenyl (C 2 -C 24 alkenyl) wherein the phenyl is optionally substituted with methyl or halogen, or cinnamyl;

wherein the bond between the carbon to which Y is attached and the N of NR 7 to which the carbon is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 7 is absent and Y is H, and, when the bond is a single bond, R 7 is H and Y is a substituent selected from the group defined for X, wherein Y is optionally the same as X;

wherein each of T 1 and T 2 is independently O, S, or NR 8 ;

wherein Z is a divalent radical of an alkane, an alkene, or an alkyne, any of which optionally contains a carbonyl and any of which is substituted with a substituent selected from the group consisting of halo, nitro, amino, alkoxy, hydroxyl, aryloxy, arylalkoxy, alkylcarbonyloxy, amido, sulfhydryl, alkylthio, arylthio, alkylsulfoxy, arylsulfoxy, alkylsulfonyl, aryl sulfonyl, keto, thioketo, alkyl, and a cyano, or unsubstituted;

wherein p is an integer that is greater than or equal to 2;

wherein each of R 3 , R 4 , and R 8 is independently a hydrogen; a C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl, optionally substituted with a group selected from the group consisting of an aryl and an amine; or an aryl optionally substituted with an alkyl, an aryl, an alkoxy, a halo, an amine, a hydroxy, or a trifluoromethyl;

wherein the bond between R 1 and the carbon to which R 1 is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 2 is absent and R 1 is a divalent radical derived from an alkane or an aromatic hydrocarbon, and when the bond is a single bond, R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 8 alkyl, and aryl; and

wherein the bond between R 5 and the carbon to which R 5 is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 6 is absent and R 5 is a divalent radical derived from an alkane or an aromatic hydrocarbon, and when the bond is a single bond, R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 8 alkyl, and aryl;

or a salt thereof,

wherein the compound is a solid.

2. A compound of Formula I:

wherein X is a substituent selected from the group consisting of an OH, an alkoxy, a silyloxy, a trialkylsilyloxy, an alkylcarbonyloxy, an alkyloxycarbonyloxy, a carbamoyl, a thiocarbamoyl, a cyclic carbamoyl, a cyclic thiocarbamoyl, SH, SR, a sulfoxy, a sulfonyl, a sulfito, a bisulfito, a sulphonamido, an amino, an amido, an azido, a cyano, a halo, a triphenyl phosphonium ion with a counter ion, a silyl, a trialkyl silyl, an amino acid-derived group having an amine fragment and a carboxyl fragment of an amino acid, and a phosphorus-containing group selected from the group consisting of a phosphoric acid group, a phosphorus acid group, a phosphonic acid group, or a phosphonous acid group; wherein R is a C 1 -C 24 alkyl optionally substituted with amino, hydroxyl, or sulfhydryl, a cycloalkyl, a C 2 -C 24 alkenyl, a C 3 -C 26 alkoxyacetyl, or a group of structure:

wherein each of Y and Y′ is independently hydrogen, C 1 -C 24 alkyl, aryl alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 alkoxy, or halogen, or Y and Y′ together form 3,4-methylenedioxy, and Y″ is hydrogen, C 1 -C 24 alkyl, C 1 -C 24 alkoxy, halogen, a naphthalenalkyl optionally substituted by methyl or halogen, a phenyl (C 2 -C 24 alkenyl) wherein the phenyl is optionally substituted with methyl or halogen, or cinnamyl;

wherein the bond between the carbon to which Y is attached and the N of NR 7 to which the carbon is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 7 is absent and Y is H, and, when the bond is a single bond, R 7 is H and Y is a substituent selected from the group defined for X, wherein Y is optionally the same as X;

wherein each of T 1 and T 2 is independently O, S, or NR 8 ;

wherein Z is a divalent radical of an alkane, an alkene, or an alkyne, any of which optionally contains a carbonyl and any of which is substituted with a substituent selected from the group consisting of halo, nitro, amino, alkoxy, hydroxyl, aryloxy, arylalkoxy, alkylcarbonyloxy, amido, sulfhydryl, alkylthio, arylthio, alkylsulfoxy, arylsulfoxy, alkylsulfonyl, aryl sulfonyl, keto, thioketo, alkyl, and a cyano, or unsubstituted;

wherein p is an integer that is greater than or equal to 2;

wherein each of R 3 , R 4 , and R 8 is independently a hydrogen; a C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl, optionally substituted with a group selected from the group consisting of an aryl and an amine; or an aryl optionally substituted with an alkyl, an aryl, an alkoxy, a halo, an amine, a hydroxy, or a trifluoromethyl;

wherein the bond between R 1 and the carbon to which R 1 is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 2 is absent and R 1 is a divalent radical derived from an alkane or an aromatic hydrocarbon, and when the bond is a single bond, R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 8 alkyl, and aryl; and

wherein the bond between R 5 and the carbon to which R 5 is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 6 is absent and R 5 is a divalent radical derived from an alkane or an aromatic hydrocarbon, and when the bond is a single bond, R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 8 alkyl, and aryl;

or a salt thereof,

provided that, when each of R 1 and R 5 is CH 2 attached by a double-bond, R 2 and R 6 are absent, R 3 and R 4 are CH 3 , R 7 is H, T 1 and T 2 are both O, Z is CH 2 , and p is 3, then X and Y are not both methoxy, both ethoxy, or both hydroxyl; and when each of R 1 , R 2 , R 5 , and R 6 are H, then X and Y are not both SR where R is an alkyl or both alkoxy.

3. A compound of Formula I:

wherein X is a substituent selected from the group consisting of an alkoxy, a silyloxy, a trialkylsilyloxy, an alkylcarbonyloxy, an alkyloxycarbonyloxy, a carbamoyl, a thiocarbamoyl, a cyclic carbamoyl, a cyclic thiocarbamoyl, SH, SR a sulfoxy, a sulfonyl, a sulfito, a bisulfito, a sulphonamido, an amino, an amido, an azido, a cyano, a halo, a triphenyl phosphonium ion with a counter ion, a silyl, a trialkyl silyl, an amino acid-derived group having an amine fragment and a carboxyl fragment of an amino acid, and a phosphorus-containing group selected from the group consisting of a phosphoric acid group, a phosphorus acid group, a phosphonic acid group, or a phosphonous acid group; wherein R is a C 1 -C 24 alkyl optionally substituted with amino, hydroxyl, or sulfhydryl, a cycloalkyl, a C 2 C 24 alkenyl, a C 3 -C 26 alkoxyacetyl, or a group of structure:

wherein each of Y and Y′ is independently hydrogen, C 1 -C 24 alkyl, aryl alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 alkoxy, or halogen, or Y and Y′ together form 3,4-methylenedioxy, and Y″ is hydrogen, C 1 -C, 4 alkyl, C 1 -C 74 alkoxy, halogen, a naphthalenalkyl optionally substituted by methyl or halogen, a phenyl (C 2 -C 24 alkenyl) wherein the phenyl is optionally substituted with methyl or halogen, or cinnamyl;

wherein the bond between the carbon to which Y is attached and the N of NR 7 to which the carbon is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 7 is absent and Y is H, and, when the bond is a single bond, R 7 is H and Y is a substituent selected from the group defined for X, wherein Y is optionally the same as X;

wherein each of T 1 and T 2 is independently O, S, or NR 8 ;

wherein Z is a divalent radical of an alkane, an alkene, or an alkyne, any of which optionally contains a carbonyl and any of which is substituted with a substituent selected from the group consisting of halo, nitro, amino, alkoxy, hydroxyl, aryloxy, arylalkoxy, alkylcarbonyloxy, amido, sulfhydryl, alkylthio, arylthio, alkylsulfoxy, arylsulfoxy, alkylsulfonyl, aryl sulfonyl, keto, thioketo, alkyl, and a cyano, or unsubstituted;

wherein p is an integer that is greater than or equal to 2;

wherein each of R 3 , R 4 , and R 8 is independently a hydrogen; a C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl, optionally substituted with a group selected from the group consisting of an aryl and an amine; or an aryl optionally substituted with an alkyl, an aryl, an alkoxy, a halo, an amine, a hydroxy, or a trifluoromethyl;

wherein the bond between R 1 and the carbon to which R 1 is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 2 is absent and R 1 is a divalent radical derived from an alkane or an aromatic hydrocarbon, and when the bond is a single bond, R 1 and R 2 are independently selected from the group consisting of a C 1 -C 8 alkyl, and an aryl; and

wherein the bond between R 5 and the carbon to which R 5 is attached is a single bond or a double bond, wherein, when the bond is a double bond, R 6 is absent and R 5 is a divalent radical derived from an alkane or an aromatic hydrocarbon, and when the bond is a single bond, R 5 and R 6 are independently selected from the group consisting of C 1 -C 8 alkyl, and aryl;

or a salt thereof.

4. The compound or salt of claim 1 , wherein the amino acid-derived group has the structure:

wherein each of R, R′, and R″ is independently selected from the group consisting of H, a C 1 -C 8 alkyl optionally substituted with an amine or a carboxylate; an aryl; or an aryl alkyl.

5. The compound or salt of claim 4 , wherein R is H, CH 3 , benzyl, (CH 2 ) 4 —NH 2 , or CH 2 COOH.

6. The compound or salt of claim 1 , wherein the phosphoric acid group has the structure:

7. The compound or salt of claim 1 , wherein the phosphonic acid group has the structure:

8. The compound or salt of claim 1 , wherein the phosphonic acid group has the structure:

wherein R is C 1 -C 8 alkyl optionally substituted with an aryl, an alkoxy, a halo, an amine, or carboxylate; or an aryl.

9. The compound or salt of claim 1 , wherein the phosphonous acid group has the structure

wherein R is C 1 -C 8 alkyl optionally substituted with an aryl, an alkoxy, a halo, an amine, or carboxylate; or an aryl.

10. The compound or salt of claim 1 , wherein X is selected from the group consisting of:

wherein each of R, R′, and R″ is independently selected from the group consisting of H; C 1 -C 8 alkyl optionally substituted with an aryl, an alkoxy, a halo, an amine, or carboxylate; and an aryl; and wherein u is 1 to about 16.

11. The compound or salt of claim 1 , wherein X is an amide having the structure:

—NHCOR or —NR′COR,

wherein each of R and R′ is independently H; C 1 -C 8 alkyl optionally substituted with an aryl, an alkoxy, a halo, an amine, or carboxylate; or an aryl.

12. The compound or salt of claim 1 , wherein X is a monohydroxylic or a polyhydroxylic group.

13. The compound or salt of claim 12 , wherein the monohydroxylic group or polyhydroxylic group is derived from a diol, a polyol, a sorbitol, a polyethylene glycol (PEG), a polymer, or a sugar.

14. The compound or salt of claim 12 , wherein the monohydroxylic group or polyhydroxylic group has the structure:

wherein B is O, B is attached to the pyranose ring at any carbon of the ring, at the carbon to which B is attached, A is H, and, at the carbons where B is not attached, A is —OH; or

wherein B is O, B is attached to any carbon of PEG, at the carbon to which B is attached, A is H, and, at the carbons where B is not attached, A is —OH.

15. The compound or salt of claim 1 , wherein each of T 1 and T 2 is O, p is 3 and Z is —CH 2 —.

16. The compound or salt of claim 1 wherein R 1 and R 2 are not both H.

17. A pharmaceutical composition comprising a compound or salt of claim 1 and a pharmaceutically acceptable carrier.

18. A method of treating a parasitic or bacterial infection in a host, which method comprises administering to the host an amount effective to treat the parasitic or bacterial infection a compound or salt of claim 1 .

19. A method of treating cancer in a host comprising administering to the host a compound or salt of claim 1 in an amount effective to treat said cancer in the host, wherein the cancer is leukemia, non-small cell lung cancer, colon cancer, cancer of the central nervous system, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

20. A method of treating cancer in a host comprising administering to the host a compound or salt of claim 2 in an amount effective to treat said cancer in the host, wherein the cancer is leukemia, non-small cell lung cancer, colon cancer, cancer of the central nervous system, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

21. A method of treating cancer in a host comprising administering to the host a compound or salt of claim 3 in an amount effective to treat said cancer in the host, wherein the cancer is leukemia, non-small cell lung cancer, colon cancer, cancer of the central nervous system, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.

22. A method of treating a parasitic or bacterial infection in a host, which method comprises administering to the host an amount effective to treat the parasitic or bacterial infection a compound or salt of claim 2 .

23. A method of treating a parasitic or bacterial infection in a host, which method comprises administering to the host an amount effective to treat the parasitic or bacterial infection a compound or salt of claim 3 .

24. A pharmaceutical composition comprising a compound or salt of claim 2 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a compound or salt of claim 3 and a pharmaceutically acceptable carrier.