LEPTOMYCIN DERIVATIVES
Leptomycin derivatives having a moiety, such as a sulfide or a disulfide, that can conjugate to a cell binding reagent such as an antibody are disclosed. The therapeutic use of such leptomycin derivative conjugates is also described; such conjugates have therapeutic use because they can deliver cytotoxic leptomycin derivatives to a specific cell population in a targeted fashion.
1 . A therapeutic agent for inhibiting the growth of selected cell population comprising:
(a) a cytotoxic amount of a leptomycin derivative of formula (I) linked to a cell binding agent,
wherein:
Ra and R′a are independently H or a linear or branched C 1 -C 20 alkyl;
R17 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl;
R9 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl;
X is —NR—;
Y is a linear or branched C 1 -C 20 alkyl;
T represents H or a thiol protecting group or T represents
where:
Ra, R′a, R17, R9, X, and Y are defined as above; and
R and R′, which may be identical or different, are H or a linear or branched C 1 -C 20 alkyl; or a pharmaceutically acceptable salt thereof;
and
(b) a pharmaceutically acceptable carrier, diluent or excipient
2 . The therapeutic agent according to claim 1 , wherein the thiol protecting group is Ac, R 1 or SR 1 , where R 1 is H, methyl or a linear or branched C 1 -C 20 alkyl.
3 . The therapeutic agent according to claim 1 , wherein Ra is a linear or branched C 1 -C 20 alkyl and R′a is H.
4 . The therapeutic agent according to claim 1 . wherein Ra is a linear or branched C 1 -C 20 alkyl and R′a is H.
5 . The therapeutic agent according to claim 1 , wherein R17 is a linear or branched C 1 -C 20 alkyl.
6 . The therapeutic agent according to claim 1 , wherein R17 is a linear or branched C 1 -C 20 alkyl.
7 . The therapeutic agent according to claim 1 , wherein R9 is a linear or branched C 1 -C 20 alkyl.
8 . The therapeutic agent according to claim 1 , wherein R9 is a linear or branched C 1 -C 20 alkyl.
9 . The therapeutic agent according to claim 1 , wherein T is H or SR 1 where R 1 is a linear or branched C 1 -C 20 alkyl.
10 . The therapeutic agent according to claim 1 , wherein:
Ra is a linear or branched C 1 -C 20 alkyl;
R′a is H;
R17 is a linear or branched C 1 -C 20 alkyl;
R9 is a linear or branched C 1 -C 20 alkyl; and
T is H or SR 1 where R 1 is a linear or branched C 1 -C 20 alkyl.
11 . The therapeutic agent according to claim 1 , wherein the leptomycin derivative is:
(2-Methylsulfanyl-ethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-Hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;
Bis-[(2-mercaptoethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid];
(2-Mercapto-ethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;
(2-Methyldisulfanyl-ethyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;
(2-Methyl-2-methyldisulfanyl-propyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid; or
(2-Mercapto-2-methyl-propyl)-amide of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid;
or a pharmaceutically acceptable salt thereof.
12 . The therapeutic agent according to claim 1 , wherein the selected cell population is a malignancy.
13 . The therapeutic agent according to claim 12 , wherein the malignancy is cancer of lung, breast, colon, prostate, kidney, pancreas, ovary, lymphatic organ or melanoma.
14 . The therapeutic agent according to claim 1 , wherein the cell binding agent is a modified cell binding agent comprising a function reactive towards the linking group of the leptomycin derivative, so that the derivative and the cell binding agent are linked together via said linker comprising said linking group.
15 . The therapeutic agent according to claim 14 , wherein the cell binding agent is modified with SMCC, SSNPB, LC-SMCC, STAB, SIA, SBA or SBAP.
16 . The therapeutic agent according to claim 14 , wherein the cell binding agent is an antibody or peptide.
17 . The therapeutic agent according to claim 16 , wherein the cell binding agent is modified by SPP, SMPT, SDPB, SPDP, SMCC, SSNPB, 2-iminothiolate, or S-acetylsuccinic anhydride.
18 . A leptomycin derivative of formula (I) linked to a cell binding agent,
wherein:
Ra and R′a are independently H or a linear or branched C 1 -C 20 alkyl;
R17 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl;
R9 is alkyl optionally substituted by OR, CN, NRR′, or perfluoroalkyl;
X is —NR—;
Y is a linear or branched C 1 -C 20 alkyl;
T represents H or a thiol protecting group or T represents
where:
Ra, R′a, R17, R9, X, and Y are defined as above; and
R and R′, which may be identical or different, are H or a linear or branched C 1 -C 20 alkyl; or a pharmaceutically acceptable salt thereof.