Delivery systems for controlled drug release
The present invention provides a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, for the controlled delivery and release of Agent.
1. A compound having the structure of Formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereo;
wherein:
Agent is selected from the group consisting of a cytostatic agent, a cytotoxic agent, a cytokine, an immunosuppressive agent, an antirheumatic, an antiphlogistic, an antibiotic, an analgesic, a virostatic agent, an anti-inflammatory agent, an antimicotic agent, a transcription factor inhibitor, a cell cycle modulator, an MDR modulator, a proteasome or protease inhibitor, an apoptosis modulator, an enzyme inhibitor, a signal transduction inhibitor, a protease inhibitor, an angiogenesis inhibitor, a hormone or hormone derivative, an antibody or a fragment thereof, a therapeutically or diagnostically active peptide, a radioactive substance, a light emitting substance, a light absorbing substance, and a derivative of any of the foregoing;
Spacer is absent, or is selected from the group consisting of
n is 0 or 1;
X is selected from the group consisting of optionally substituted C 1 -C 18 alkyl wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-NH—C(O)—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-C(O)—NH—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted aryl; optionally substituted heteroaryl; and optionally substituted cycloalkyl;
R 5 is selected from the group consisting of an optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;
Y is absent or selected from the group consisting of optionally substituted C 1 -C 6 alkyl, —NH—C(O)—, —C(O)—NH—, —C(O)—O—, and —O—C(O)—;
R 1 is absent or selected from the group consisting of optionally substituted C 1 -C 18 alkyl wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-NH—C(O)R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; and optionally substituted C 1 -C 18 alkyl-C(O)—NH—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —,
or R 1 is a naturally or non-naturally occurring amino acid,
or R 1 has the following formula:
wherein:
is absent, or is selected from the group consisting of:
R is: OPO 3 M 1 wherein M 1 =Mg 2+ , 2Na + , 2K + and/or 2NH 4 + , or
OSO 3 M 2 wherein M 2 =Na + , K + , H + , and/or NH 4 + ;
R 2 is selected from the group consisting of —H, optionally substituted C 1 -C 12 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
Z 1 , Z 2 , Z 3 and Z 4 are each independently —H, an electron-withdrawing group, and/or a water-soluble group; wherein at least one of Z 1 , Z 2 , Z 3 and Z 4 is an electron-withdrawing group;
PBG is
which may be optionally substituted; and
wherein when Spacer is absent, Agent is linked to the nitrogen adjacent to Spacer by a double bond.
2. The compound according to claim 1 , wherein said compound has a structure of Formula (II):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein Agent, PBG, Y, R 1 , Z 1 , Z 2 , Z 3 and Z 4 are as defined in claim 1 .
3. The compound according to claim 1 , said compound having the structure of Formula (III):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein Agent, Spacer, Z 1 , Z 2 , Z 3 , Z 4 , Y, R 1 and PBG are as defined in claim 1 ; and
wherein Z 1 is an electron withdrawing group.
4. The compound according to claim 1 , said compound having the structure of Formula (IV):
or pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein Agent, PBG, Y, R 1 , Z 1 , Z 2 , Z 3 and Z 4 are as defined in claim 1 ; and
wherein Z 1 is an electron withdrawing group.
5. The compound according to claim 1 , said compound having the structure of Formula (V):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein Agent, n, X, R 1 , R 2 , Z 1 , Z 2 , Z 3 , Z 4 , Y, R 1 , and PBG are as defined in claim 1 .
6. The compound according to claim 5 , said compound-having the structure of Formula (VI):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein:
M is a pyrimidine or purine group that contains at least one primary or secondary amino group and optionally contains one or more substituents selected from halogen;
X 1 and X 2 are each independently selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
X 3 and X 4 are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
R′ is —R 3 or —CH 2 R 3 ;
wherein each occurrence of R 3 is independently selected from the group consisting of —OH, —CH 3 , —OP(O)(OH) 2 , —P(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)(NH 2 ), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and
wherein X, n, Z 1 , Z 2 , Z 3 , Z 4 , Y, R 1 , R 2 and PBG are as defined in claim 5 .
7. The compound according to claim 5 , said compound having the structure of Formula (VI):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein
M is a pyrimidine or purine group that contains at least one primary or secondary amino group;
X 1 and X 2 are each independently selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
X 3 and X 4 are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
R 3 is selected from the group consisting of —H, —OH, —OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)(NH 2 ), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and
wherein X, n, Z 1 , Z 2 , Z 3 , Z 4 , Y, R 1 , R 2 and PBG are as defined in claim 5 .
8. The compound according to claim 6 , said compound having the structure of Formula (VII):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein R′ is —R 3 or —CH 2 R 3 ; and X, X 1 , X 2 , X 3 , X 4 , n, Y, R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 , Z 4 and PBG are as defined in claim 6 .
9. The compound according to claim 7 , said compound having the structure of Formula (VII):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein X, X 1 , X 2 , X 3 , X 4 , n, Y, R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 , Z 4 and PBG are as defined in claim 7 .
10. The compound of claim 5 , said compound having the structure of formula (VIII):
or pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein Agent, X, n, R 2 , PBG, Y, R 1 , Z 1 , Z 2 , Z 3 and Z 4 are as defined in claim 5 , and
wherein Z 1 is an electron withdrawing group.
11. The compound according to claim 10 , said compound having the structure of Formula (IX):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein:
M is a pyrimidine or purine group that contains at least one primary or secondary amino group and optionally contains one or more substituents selected from halogen;
X 1 and X 2 are each independently selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
X 3 and X 4 are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
R′ is —R 3 or —CH 2 R 3 ;
wherein each occurrence of R 3 is independently selected from the group consisting of —OH, —CH 3 , —OP(O)(OH) 2 , —P(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)(NH 2 ), an amino acid, an acyl group, and a pharmaceutically acceptable salt thereof; wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and
wherein X, n, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 2 and PBG are as defined in claim 10 .
12. The compound according to claim 10 , said compound having the structure of Formula (IX):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein
M is a pyrimidine or purine group that contains at least one primary or secondary amino group;
X 1 and X 2 are each independently selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
X 3 and X 4 are each independently, as valence permits, absent or selected from the group consisting of —H, —OH, C 1 -C 6 alkyl, halogen, and —N 3 ;
R 3 is selected from the group consisting of —H, —OH, —OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)(NH 2 ), an amino acid or an acyl group, and a pharmaceutically acceptable salt thereof, wherein the salt contains an alkali metal ion, an alkaline metal ion, an ammonium or an alkyl substituted ammonium ion; and
wherein X, n, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 , R 2 and PBG are as defined in claim 10 .
13. The compound according to claim 11 , said compound having the structure of Formula (X):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein R′ is —R 3 or —CH 2 R 3 ; and X 1 , X 2 , X 3 , X 4 , R 3 , X, n, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 and R 2 are as defined in claim 11 .
14. The compound according to claim 12 , said compound having the structure of Formula (X):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof; and
wherein X 1 , X 2 , X 3 , X 4 , R 3 , X, n, Y, Z 1 , Z 2 , Z 3 , Z 4 , R 1 and R 2 are as defined in claim 12 .
15. The compound according to claim 1 , wherein Agent is selected from the group consisting of N-nitrosoureas; doxorubicin, 2-pyrrolpyrrolinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, nemorubicin, PNU-159682, mitoxantrone; ametantrone; chlorambucil, bendamustine, melphalan, oxazaphosphorines; 5-fluorouracil, 5′-deoxy-5-fluorocytidine, 2′-deoxy-5-fluoridine, cytarabine, cladribine, fludarabine, pentostatine, gemcitabine, 4-amino-1-(((2S,3R,4S,5R)-3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)methyl)-5-fluoropyrimidin-2(1H)-one, thioguanine; methotrexate, raltitrexed, pemetrexed, plevitrexed; paclitaxel, docetaxel; topotecan, irinotecan, SN-38, 10-hydroxycamptothecin, GG211, lurtotecan, 9-aminocamptothecin, camptothecin, 7-formylcamptothecin, 7-acetylcamptothecin, 9-formylcamptothecin, 9-acetylcamptothecin, 9-formyl-10-hydroxycamptothecin, 10-formylcamptothecin, 10-acetylcamptothecin, 7-butyl-10-aminocamptothecin, 7-butyl-9-amino-10,11-methylenedioxocamptothecin; vinblastine, vincristine, vindesine, vinorelbine; calicheamicins; maytansine, maytansinol; an auristatin selected from the group consisting of auristatin D, auristatin E, auristatin F, monomethyl auristatin D, monomethyl auristatin E, monomethyl auristatin F, monomethyl auristatin F nethylester, auristatin PYE, auristatin PHE, the related natural product dolastatin 10, and derivatives thereof; an amatoxin selected from the group consisting of α-amanitin, β-amanitin, γ-amanitin, F-amanitin, amanin, amaninamide, ainanullin, and amanullinic acid and derivatives thereof; duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C, duocarmycin SA, CC1065, adozelesin, bizelesin, carzelesin; eribulin; trabectedin; pyrrolobenzodiazepine, anthramycin, tomaymycin, sibiromycin, DC-81, DSB-120; epothilones; bleomycin; dactinomycin; plicamycin, mitomycin C and cis-configured platinum(II) complexes; or a derivative of any of the foregoing.
16. The compound according to claim 1 , wherein:
(a) Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —H, halogen, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —NO 2 , haloalkyl, —S(O) 2 —C 1 -C 6 alkyl, and —CN, wherein at least one of Z 1 , Z 2 , Z 3 and Z 4 is not —H;
(b) Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO 2 , —CF 3 , and —CN;
(c) Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —H, —Cl, —F, —NO 2 , and —CF 3 ;
(d) Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —OP(O)(OH) 2 , —P(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)(NH 2 ), —P(O)(OH) 2 , —SO 3 H, and a pharmaceutically acceptable salt thereof;
(e) Z 1 is selected from the group consisting of halogen, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —NO 2 , haloalkyl, —S(O) 2 —C 1 -C 6 alkyl, and —CN; and Z 2 , Z 3 and Z 4 are each independently selected from —H, halogen, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —NO 2 , haloalkyl, —S(O) 2 —C 1 -C 6 alkyl, and —CN;
(f) Z 1 is selected from the group consisting of —Cl, —Br, —I, —F, —C(O)OH, —NO 2 , —CF 3 , and —CN; and Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO 2 , —CF 3 , and —CN; or
(g) Z 1 is selected from the group consisting of —Cl, —F, and —NO 2 ; and Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —H, —Cl, —F, —NO 2 , and —CF 3 .
17. A compound having a structure according to Formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof;
wherein:
Agent is selected from the group consisting of a cytostatic agent, a cytotoxic agent, a cytokine, an immunosuppressive agent, an antirheumatic, an antiphlogistic, an antibiotic, an analgesic, a virostatic agent, an anti-inflammatory agent, an antimicotic agent, a transcription factor inhibitor, a cell cycle modulator, an MDR modulator, a proteasome or protease inhibitor, an apoptosis modulator, an enzyme inhibitor, a signal transduction inhibitor, a protease inhibitor, an angiogenesis inhibitor, a hormone or hormone derivative, an antibody or a fragment thereof, a therapeutically or diagnostically active peptide, a radioactive substance, a light emitting substance, a light absorbing substance, and a derivative of any of the foregoing;
Spacer is absent, or is selected from the group consisting of
n is 0 or 1;
X is selected from the group consisting of optionally substituted C 1 -C 18 alkyl wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-NH—C(O)—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-C(O)—NH—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted aryl; optionally substituted heteroaryl; and optionally substituted cycloalkyl;
R 5 is selected from the group consisting of an optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl;
is:
(a) selected from the group consisting of:
(b) selected from the group consisting of:
or
(c) selected from the group consisting of:
wherein Y is absent or selected from the group consisting of optionally substituted C 1 -C 6 alkyl, —NH—C(O)—, —C(O)—NH—, —C(O)—O—, and —O—C(O)—;
R 1 is absent or selected from the group consisting of optionally substituted C 1 -C 18 alkyl wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-NH—C(O)R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; and optionally substituted C 1 -C 18 alkyl-C(O)—NH—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —,
or R 1 is a naturally or non-naturally occurring amino acid,
or R 1 has the following formula:
wherein:
is absent, or is selected from the group consisting of:
R is: OPO 3 M 1 wherein M 1 =Mg 2+ , 2Na + , 2K + and/or 2NH 4 + , or
OSO 3 M 2 wherein M 2 =Na + , K + , H + , and/or NH 4 + ; and
PBG is
which may be optionally substituted.
18. The compound according to claim 1 , wherein Y is:
(a) —C(O)—NH—;
(b) —C(O)—O—; or
(c) absent.
19. The compound according to claim 1 , wherein R 1 is:
(a) selected from the group consisting of optionally substituted C 1 -C 18 alkyl wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted C 1 -C 18 alkyl-NH—C(O)—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; and optionally substituted C 1 -C 18 alkyl-C(O)—NH—R 5 — wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —;
(b)
(c) absent;
(d) a naturally or non-naturally occurring amino acid; or
(e)
wherein:
is absent, or is selected from the group consisting of:
R is: OPO 3 M 1 wherein M 1 =Mg 2+ , 2Na + , 2K + and/or 2NH 4 + , or
OSO 3 M 2 wherein M 2 =Na + , K + , H + , and/or NH 4 + .
20. The compound according to claim 1 , wherein Spacer is:
(a)
n is 0 or 1;
X is a selected from the group consisting of optionally substituted C 1 -C 18 alkyl wherein optionally up to six carbon atoms in said C 1 -C 18 alkyl are each independently replaced with —OCH 2 CH 2 —; optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted cycloalkyl; and
R 2 is as defined in claim 1 ;
(b)
wherein R 2 is selected from the group consisting of —H, optionally substituted C 1 -C 12 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W 1 , W 2 , W 3 and W 4 are each independently selected from the group consisting of —H, halogen, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —NO 2 , haloalkyl, —S(O) 2 —C 1 -C 6 alkyl, and —CN;
(c)
wherein R 2 is selected from the group consisting of —H, optionally substituted C 1 -C 12 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W 1 , W 2 , W 3 and W 4 are each independently selected from a phenoxy group, a primary, secondary or tertiary amine group, an ether group, a phenol group, an amide group, an ester group, an alkyl group, a substituted alkyl group, a phenyl group, and a vinyl group;
(d)
wherein R 2 is selected from the group consisting of —H, optionally substituted C 1 -C 12 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and W 1 , W 2 , W 3 and W 4 are each independently selected from —OP(O)(OH) 2 , —P(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)OP(O)(OH)OP(O)(OH) 2 , —OP(O)(OH)(NH 2 ), —P(O)(OH) 2 , —SO 3 H, and a pharmaceutically acceptable salt thereof;
(e)
wherein R 2 is selected from the group consisting of —H, optionally substituted C 1 -C 12 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; W 1 is selected from the group consisting of halogen, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —NO 2 , haloalkyl, —S(O) 2 —C 1 -C 6 alkyl, and —CN; and
W 2 , W 3 and W 4 are each independently selected from the group consisting of —H, halogen, —C(O)OH, —C(O)O—C 1 -C 6 alkyl, —NO 2 , haloalkyl, —S(O) 2 —C 1 -C 6 alkyl, and —CN;
(f)
wherein R 2 is selected from the group consisting of —H, optionally substituted C 1 -C 12 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
(g)
(h) is
wherein m is 1, 2, 3, 4, 5, or 6; or
(i)
21. The compound according to claim 20 , wherein W 1 , W 2 , W 3 and W 4 in subpart (b) are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO 2 , —CF 3 , and —CN.
22. The compound according to claim 21 , wherein W 1 , W 2 , W 3 and W 4 are each independently selected from the group consisting of —H, —Cl, —F, —NO 2 , and —CF 3 .
23. The compound according to claim 20 , wherein W 1 in subpart (e) is selected from the group consisting of —Cl, —Br, —I, —F, —C(O)OH, —NO 2 , —CF 3 , and —CN; and W 2 , W 3 and W 4 in subpart (e) are each independently selected from the group consisting of —H, —Cl, —Br, —I, —F, —C(O)OH, —NO 2 , —CF 3 , and —CN.
24. The compound according to claim 23 , wherein W 1 is selected from the group consisting of —Cl, —F, and —NO 2 ; and Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of —H, —Cl, —F, —NO 2 , and —CF 3 .
25. The compound according to claim 6 , wherein X 1 , X 2 , X 3 , and X 4 are each independently selected from the group consisting of —H, —OH, —CH, —F, —Cl, —Br, —I, and —N 3 .
26. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof,
wherein:
is absent, or is selected from the group consisting of:
R is OPO 3 M 1 wherein M 1 =Mg 2+ , 2Na + , 2K + , 2H + , 2NH 4 + , Na + , K + , NH 4 + , and/or H + or
SO 3 M 2 wherein M 2 =Na + , K + , H + , and/or NH 4 + .
27. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
28. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
29. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof.
30. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.
31. The compound according to claim 15 , wherein Agent is selected from the group consisting of doxorubicin, 2-pyrrolpyrrolinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, nemorubicin, PNU-159682, mitoxantrone or ametantrone, or a derivative of any of the foregoing.
32. The compound according to claim 15 , wherein Agent is doxorubicin or a derivative thereof.
33. The compound according to claim 15 , wherein Agent is selected from the group consisting of a maytansinoid, an auristatin, an epothilones, a bleomycin, dactinomycin, plicamycin, mitomycin C, a cis-configured platinum(II) complex, or a derivative of any of the foregoing.
34. A pharmaceutical composition comprising a compound according to claim 31 , and a pharmaceutically acceptable carrier.
35. A pharmaceutical composition comprising a compound according to claim 32 , and a pharmaceutically acceptable carrier.
36. A pharmaceutical composition comprising a compound according to claim 33 , and a pharmaceutically acceptable carrier.