초록

Jorumycin, renieramycin, safracin and saframycin related compounds formulations, methods of preparing the same, articles of manufacture and kits with such formulations, and methods of treating proliferative diseases with the same formulations are provided.

대표청구항 ▼

1. A pharmaceutical composition comprising a disaccharide and a compound of general formula (I): wherein R1 is selected from the group consisting of —CH2—N(Ra)2 and —CH2—ORa, where each Ra is independently selected from the group consisting of H, alkyl-CO—, haloalkyl-CO—, cycloalkylalkyl-CO—, haloal

1. A pharmaceutical composition comprising a disaccharide and a compound of general formula (I): wherein R1 is selected from the group consisting of —CH2—N(Ra)2 and —CH2—ORa, where each Ra is independently selected from the group consisting of H, alkyl-CO—, haloalkyl-CO—, cycloalkylalkyl-CO—, haloalkyl-O—CO—, arylalkyl-CO—, arylalkenyl-CO—, heteroaryl-CO—, alkenyl-CO—, alkyl, alkenyl and amino acid acyl, or the two Ra groups together with the N atom of —CH2—N(Ra)2 form a heterocyclic group;R2 is selected from alkyl-CO—, cycloalkyl-CO— and haloalkyl-CO—; andR3 is OH or CN; or a pharmaceutically acceptable salt or stereoisomer thereof; and wherein said R1 and R2 independently, are unsubstituted or substituted at one or more available positions by one or more groups selected from R′, OR′, ═O, SR′, SOR′, SO2R′, NO2, NHR′, N(R′)2, ═N—R′, NHCOR′, N(COR′)2, NHSO2R′, CN, halogen, C(═O)R′, CO2R′, OC(═O)R′, wherein each of the R′ groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, ═O, C(═O)H, C(═O)alkyl, CO2H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl and substituted or unsubstituted aryl, where, when such R′ groups are themselves substituted, the substituents of R′ are independently selected from the group consisting of R″, OR″, ═O, SR″, SOR″, SO2R″, NO2, NHR″, N(R″)2, ═N—R″, NHCOR″, N(COR″)2, NHSO2R″, CN, halogen, C(═O)R″, CO2R″, OC(═O)R″, wherein each R″ groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, ═O, C(═O)H, C(═O)alkyl, CO2H, unsubstituted C1-C12 alkyl, unsubstituted C2-C12 alkenyl, unsubstituted C2-C12 alkynyl and unsubstituted aryl. 2. A composition according to claim 1, wherein said compound is the compound of formula (II) (PM00104) or formula (III) (PM00121): 3. A composition according to claim 1, wherein said disaccharide is selected from the group consisting of lactose, trehalose, sucrose, and mixtures thereof. 4. A composition according to claim 3, wherein said disaccharide is sucrose. 5. A composition according to claim 1, wherein the ratio (w/w) of compound to disaccharide is from about 1:80 to about 1:1500. 6. A composition according to claim 5, wherein the ratio (w/w) of compound to disaccharide is from about 1:100 to about 1:400. 7. A composition according to claim 6, wherein the ratio (w/w) of compound to disaccharide is about 1:200. 8. A composition according to claim 1, which further comprises a buffering agent. 9. A composition according to claim 8, wherein said buffering agent is a phosphate buffer. 10. A composition according to claim 1 which further comprises a surface-active agent. 11. A composition according to claim 10, wherein the surface-active agent is a polyoxyethylene sorbitan monooleate. 12. A composition according to claim 1, wherein the composition is in the form of a lyophilised formulation. 13. A composition according to claim 1, wherein the composition is in the form of a lyophilised formulation. 14. A composition according to claim 13, wherein said PM00104 is in present in said composition an amount of about 2.5 mg. 15. A composition according to claim 14, wherein said disaccharide is sucrose, wherein said sucrose is present in said composition in an amount of about 500 mg and wherein said formulation further comprises about 34 mg phosphate, wherein said 34 mg phosphate is calculated as potassium dihydrogen phosphate. 16. A composition according to claim 3, wherein said disaccharide is selected from the group consisting of lactose, trehalose, sucrose, and mixtures thereof. 17. A composition according to claim 16, wherein said disaccharide is sucrose. 18. A composition according to claim 3, wherein the ratio (w/w) of compound to disaccharide is from about 1:80 to about 1:1500. 19. A composition according to claim 18, wherein the ratio (w/w) of compound to disaccharide is from about 1:100 to about 1:400. 20. A composition according to claim 19, wherein the ratio (w/w) of compound to disaccharide is about 1:200. 21. A composition according to claim 3, which further comprises a buffering agent. 22. A composition according to claim 21, wherein said buffering agent is a phosphate buffer. 23. A composition according to claim 3 which further comprises a surface-active agent. 24. A composition according to claim 23, wherein the surface-active agent is a polyoxyethylene sorbitan monooleate. 25. A composition according to claim 3, wherein said composition does not include a surface-active agent. 26. A pharmaceutical composition comprising a disaccharide and a compound of general formula (I): wherein R1 is selected from the group consisting of —CH2—N(Ra)2 and —CH2—ORa, where each Ra is independently selected from the group consisting of H, alkyl-CO—, haloalkyl-CO—, cycloalkylalkyl-CO—, haloalkyl-O—CO—, arylalkyl-CO—, arylalkenyl-CO—, heteroaryl-CO—, alkenyl-CO—, alkyl, alkenyl and amino acid acyl, or the two Ra groups together with the N atom of —CH2—N(Ra)2 form a heterocyclic group;R2 is selected from alkyl-CO—, cycloalkyl-CO—and haloalkyl-CO—; andR3 is OH or CN; ora pharmaceutically acceptable salt or stereoisomer thereof. 27. A pharmaceutical composition comprising a disaccharide and a single active anti-tumor agent selected from compounds of general formula (I): wherein R1 is selected from the group consisting of —CH2—N(Ra)2 and —CH2—ORa, where each Ra is independently selected from the group consisting of H, alkyl-CO—, haloalkyl-CO—, cycloalkylalkyl-CO—, haloalkyl-O—CO—, arylalkyl-CO—, arylalkenyl-CO—, heteroaryl-CO—, alkenyl-CO—, alkyl, alkenyl and amino acid acyl, or the two Ra groups together with the N atom of —CH2—N(Ra)2 form a heterocyclic group;R2 is selected from alkyl-CO—, cycloalkyl-CO— and haloalkyl-CO—; andR3 is OH or CN; or a pharmaceutically acceptable salt or stereoisomer thereof; and wherein said R1 and R2 independently, are unsubstituted or substituted at one or more available positions by one or more groups selected from R′, OR′, ═O, SR′, SOR′, SO2R′, NO2, NHR′, N(R′)2, ═N—R′, NHCOR′, N(COR′)2, NHSO2R′, CN, halogen, C(═O)R′, CO2R′, OC(═O)R′, wherein each of the R′ groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, ═O, C(═O)H, C(═O)alkyl, CO2H, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl and substituted or unsubstituted aryl, where, when such R′ groups are themselves substituted, the substituents of R′ are independently selected from the group consisting of R″, OR″, ═O, SR″, SOR″, SO2R″, NO2, NHR″, N(R″)2, ═N—R″, NHCOR″, N(COR″)2, NHSO2R″, CN, halogen, C(═O)R″, CO2R″, OC(═O)R″, wherein each R″ groups is independently selected from the group consisting of hydrogen, OH, NO2, NH2, SH, CN, halogen, ═O, C(═O)H, C(═O)alkyl, CO2H, unsubstituted C1-C12 alkyl, unsubstituted C2-C12 alkenyl, unsubstituted C2-C12 alkynyl and unsubstituted aryl. 28. The composition according to claim 1, wherein said composition has improved stability compared to a formulation using mannitol instead of the disaccharide. 29. The composition according to claim 2, wherein said composition has improved stability compared to a formulation using mannitol instead of the disaccharide. 30. The composition according to claim 1, wherein said disaccharide is present in an amount sufficient to inhibit degradation of the anti-tumor agent after storage at 5° C. for 1 month compared to the same composition comprising mannitol instead of the disaccharide. 31. The composition according to claim 1, wherein said disaccharide is present in an amount sufficient to inhibit degradation of the anti-tumor agent after storage at 25° C. for 1 month compared to a composition comprising mannitol instead of the disaccharide. 32. The composition according to claim 1, wherein said disaccharide is present in an amount sufficient to inhibit degradation of the anti-tumor agent after storage of at 40° C. for 1 month compared to a composition comprising mannitol instead of the disaccharide. 33. A method of making a lyophilised formulation according to claim 12, comprising freeze-drying a bulk solution that comprises said compound and said disaccharide. 34. A method according to claim 33, wherein the compound is the compound of formula (II) (PM00104): 35. A method of reducing the formation of impurities in said lyophilised formulation according to claim 12, comprising freeze-drying a bulk solution that comprises said compound and said disaccharide. 36. A method according to claim 35, wherein the compound is the compound of formula (II) (PM00104): 37. A method of preparing a solution for intravenous infusion, comprising: providing a lyophilised formulation according to claim 12, adding water to form a reconstituted solution, and diluting said reconstituted solution with an aqueous system. 38. A method according to claim 37, wherein the compound is the compound of formula (II) (PM00104): 39. A method of treating cancer, which comprises intravenous infusion of a solution prepared by a method according to claim 37 or 38.