Piperidinyl targeting compounds that selectively bind integrins
First Claim
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1. A targeting ligand having a formula selected from the group consisting of Formula (I):
1 Assignment
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Abstract
The present invention relates to the synthesis and biological application of piperidinoyl carboxylic acid integrin antagonists affinity moiety of IFormula (I):
and Formula (II):
These affinity moieties maybe used with imaging agents or liposomes to target cells that express the αvβ3, αvβ5, or αvβ6 integrin receptors.
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Citations
90 Claims
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1. A targeting ligand having a formula selected from the group consisting of Formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
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2. The targeting ligand of claim 1 wherein W is selected from the group consisting of —
- C0-4alkyl(R1) and —
C0-4alkyl-aryl(R1,R8).
- C0-4alkyl(R1) and —
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3. The targeting ligand of claim 1 wherein W is —
- C0-4alkyl(R1) or —
C0-4alkyl-phenyl(R1,R8).
- C0-4alkyl(R1) or —
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4. The targeting ligand of claim 1 wherein R1 is selected from the group consisting of —
- N(R4)(R6), -heterocyclyl(R8) and -heteroaryl(R8).
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5. The targeting ligand of claim 1 wherein R1 is selected from the group consisting of —
- N(R4)(R6), -dihydro-1H-pyrrolo[2,3-b]pyridinyl(R8), -tetrahydropyrimidinyl(R8), -tetrahydro-1,8-naphthyridinyl(R8), -tetrahydro-1H-azepino[2,3-b]pyridinyl(R8) and -pyridinyl(R8).
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6. The targeting ligand of claim 1 wherein R1 is selected from the group consisting of —
- N(R4)(R6), -tetrahydropyrimidinyl(R8) and -tetrahydro-1,8-naphthyridinyl(R8).
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7. The targeting ligand of claim 1 wherein R1a is selected from the group consisting of —
- C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7) and —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2.
- C(R4)(═
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8. The targeting ligand of claim 1 wherein R4 is selected from the group consisting of hydrogen and —
- C1-4alkyl(R7).
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9. The targeting ligand of claim 1 wherein R4 is hydrogen.
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10. The targeting ligand of claim 1 wherein R5 is selected from the group consisting of —
- C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
C(═
O)-cycloalkyl(R8), —
C(═
O)-heterocyclyl(R8), —
C(═
O)-aryl(R8), —
C(═
O)-heteroaryl(R8), —
C(═
O)—
N(R4)-cycloalkyl(R8), —
C(═
O)—
N(R4)-aryl(R8), —
CO2—
R4, —
CO2-cycloalkyl(R9), —
CO2-aryl(R8), —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
SO2—
C1-4alkyl(R7), —
SO2—
N(R4)2, —
SO2-cycloalkyl(R8) and —
SO2-aryl(R8).
- C(═
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11. The targeting ligand of claim 1 wherein R5 is selected from the group consisting of —
- C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
CO2—
R4, —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
SO2—
C1-4alkyl(R7) and —
SO2—
N(R4)2.
- C(═
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12. The targeting ligand of claim 1 wherein R6 is selected from the group consisting of -heterocyclyl(R8) and -heteroaryl(R8).
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13. The targeting ligand of claim 1 wherein R6 is selected from the group consisting of -dihydroimidazolyl(R8), -tetrahydropyridinyl(R8), -tetrahydropyrimidinyl(R8) and -pyridinyl(R8).
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14. The targeting ligand of claim 1 wherein R7 is one to two substituents independently selected from the group consisting of hydrogen, —
- C1-4alkoxy(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SH, —
S—
C1-4alkyl(R9), —
S—
C1-4alkyl-S—
C1-4alkyl(R9), —
S—
C1-4alkyl-C1-4alkoxy(R9), —
S—
C1-4alkyl-NH—
C1-4alkyl(R9), —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C4alkyl(R9))2, —
SO2-aryl(R10), cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl(R10), -heterocyclyl(R10), -aryl(R10) and -heteroaryl(R10).
- C1-4alkoxy(R9), —
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15. The targeting ligand of claim 1 wherein R7 is one to two substituents independently selected from the group consisting of hydrogen, —
- C1-4alkoxy(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, (halo)1-3, hydroxy and oxo.
- C1-4alkoxy(R9), —
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16. The targeting ligand of claim 1 wherein R7 is hydrogen.
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17. The targeting ligand of claim 1 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl(R9), —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), -cycloalkyl(R10) and -aryl(R10) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-cycloalkyl(R10), —
O-aryl(R10), —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl-R11)2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), —
SH, —
S—
C1-4alkyl(R9), —
S—
C1-4alkyl-S—
C1-4alkyl(R9), —
S—
C1-4alkyl-C1-4alkoxy(R9), —
S—
C1-4alkyl-NH—
C1-4alkyl(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R10), -heterocyclyl(R10), -aryl(R10) and -heteroaryl(R10) when attached to a carbon atom.
- C1-4alkyl(R9), —
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18. The targeting ligand of claim 1 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl(R9), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9) and —
SO2—
NH2 when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9), —
SO2—
NH2, —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, cyano, halo, hydroxy, nitro and oxo when attached to a carbon atom.
- C1-4alkyl(R9), —
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19. The targeting ligand of claim 1 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen and —
- C1-4alkyl(R9) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, halo, hydroxy and oxo when attached to a carbon atom.
- C1-4alkyl(R9) when attached to a nitrogen atom; and
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20. The targeting ligand of claim 1 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen and —
- C1-4alkyl(R9) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10) and hydroxy when attached to a carbon atom.
- C1-4alkyl(R9) when attached to a nitrogen atom; and
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21. The targeting ligand of claim 1 wherein R9 is selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo.
- C1-4alkoxy, —
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22. The targeting ligand of claim 1 wherein R9 is selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, —
C(═
O)H, —
CO2H, —
C(═
O)—
C1-4alkoxy, (halo)1-3, hydroxy and oxo.
- C1-4alkoxy, —
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23. The targeting ligand of claim 1 wherein R9 is selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, (halo)1-3 and hydroxy.
- C1-4alkoxy, —
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24. The targeting ligand claim 1 wherein R10 is one to four substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl and —
SO2—
N(C1-4alkyl)2 when attached to a nitrogen atom; and
, wherein R10 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl, —
C1-4alkoxy, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, cyano, halo, hydroxy, nitro and oxo when attached to a carbon atom.
- C1-4alkyl, —
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25. The targeting ligand of claim 1 wherein (R10)14 is selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C1-4alkoxy, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
CO2H, —
CO2—
C1-4alkyl, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, halo, hydroxy, nitro and oxo when attached to a carbon atom.
- C1-4alkyl, —
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26. The targeting ligand of claim 1 wherein R10 is hydrogen.
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27. The targeting ligand of claim 1 wherein R2a is selected from the group consisting of —
- C1-4alkyl (R7)(R11), —
C2-4alkenyl(R7)(R11), —
C2-4alkynyl(R7)(R11), -cycloalkyl(R7)(R11), -heterocyclyl(R8)(R12), -aryl(R8)(R12), and -heteroaryl(R8)(R12).
- C1-4alkyl (R7)(R11), —
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28. The targeting ligand of claim 1 wherein R2a is selected from the group consisting of -cycloalkyl(R7)(R11), -heterocyclyl(R8)(R12), -aryl(R8)(R12), and -heteroaryl(R8)(R11).
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29. The targeting ligand of claim 1 wherein R2a is selected from the group consisting of -cycloalkyl(R7)(R11), -heterocyclyl(R8)(R12), -phenyl(R8)(R12), -naphthalenyl(R8)(R12), and -heteroaryl(R8)(R11).
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30. The targeting ligand claim 1 wherein R2a is selected from the group consisting of -tetrahydropyrimidinyl(R8)(R12), -1,3-benzodioxolyl(R8)(R12), -dihydrobenzofuranyl(R8)(R12), -tetrahydroquinolinyl(R8)(R12), -phenyl(R8)(R12), -naphthalenyl(R8)(R12), -pyridinyl(R8)(R12), -pyrimidinyl(R8)(R12), and -quinolinyl(R8)(R12).
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31. The targeting ligand of claim 1 wherein R11 is selected from the group consisting of —
- C1-8alkyl(R14), —
O—
C1-8alkyl(R14), —
NH—
C1-8alkyl(R14), —
S—
C1-8alkyl(R14), —
C(═
O)C1-8alkyl(R14), —
O—
C(═
O)C1-8alkyl(R14), —
NH—
C(═
O)C1-8alkyl(R14), —
C(═
O)OC1-8alkyl(R14), —
C(═
O)NHC1-8alkyl(R14), —
O—
C(═
O)OC1-8alkyl(R14), —
O—
C(═
O)NHC1-8alkyl(R14), —
O—
C(═
O)C1-8alkylC(═
O)(R14), —
NH—
C(═
O)C1-8alkylC(═
O)(R14), —
C(═
O)OC1-8alkylC(═
O)(R14), —
O—
C(═
O)OC1-8alkylC(═
O)(R14), —
NH—
C(═
O)OC1-8alkylC(═
O)(R14), —
C(═
O)NHC1-8alkylC(═
O)(R14), —
O—
C(═
O)NHC1-8alkylC(═
O)(R14), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R14), —
SCH2CH2O(CH2CH2O)rCH2CH2(R14), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R14), —
C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R14), —
OC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), and —
SO2NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14).
- C1-8alkyl(R14), —
-
32. The targeting ligand of claim 1 wherein R11 is selected from the group consisting of —
- C1-8alkyl(R14), —
O—
C1-8alkyl(R14), —
NH—
C1-8alkyl(R14), —
S—
C1-8alkyl(R14), —
C(═
O)C1-8alkyl(R14), —
O—
C(═
O)C1-8alkyl(R14), —
NH—
C(═
O)C1-8alkyl(R14), —
C(═
O)OC1-8alkyl(R14), —
C(═
O)NHC1-8alkyl(R14), —
O—
C(═
O)OC1-8alkyl(R14), —
O—
C(═
O)NHC1-8alkyl(R14), —
O—
C(═
O)C1-8alkylC(═
O)(R14), —
NH—
C(═
O)C1-8alkylC(═
O)(R14), —
C(═
O)OC1-8alkylC(═
O)(R14), —
O—
C(═
O)OC1-8alkylC(═
O)(R14), —
NH—
C(═
O)OC1-8alkylC(═
O)(R14), —
C(═
O)NHC1-8alkylC(═
O)(R14), —
O—
C(═
O)NHC1-8alkylC(═
O)(R14), and —
NH—
C(═
O)NHC1-8alkylC(═
O)(R14).
- C1-8alkyl(R14), —
-
33. The targeting ligand of claim 1 wherein R12 is selected from the group consisting of —
- C1-6alkyl(R14), —
O—
C1-6alkyl(R14), —
NH—
C4alkyl(R14), —
S—
C1-6alkyl(R14), —
CH2O—
C1-6alkyl(R14), —
CH2NH—
C1-6alkyl(R14), —
CH2S—
C1-6alkyl(R14), —
C(═
O)C1-6alkyl(R14), —
O—
C(═
O)C1-6alkyl(R14), —
NH—
C(═
O)C1-8alkyl(R14), —
CH2O—
C(═
O)C1-8alkyl(R14), —
CH2NH—
C(═
O)C1-6alkyl(R14), —
C(═
O)OC1-6alkyl(R14), —
C(═
O)NHC1-6alkyl(R14), —
O—
C(═
O)OC1-6alkyl(R14), —
O—
C(═
O)NHC1-6alkyl(R14), —
NH—
C(═
O)OC1-6alkyl(R14), —
NH—
C(═
O)NHC1-6alkyl(R14), —
NH—
C(═
O)C1-6alkylC(═
O)(R14), —
CH2O—
C(═
O)C1-8alkylC(═
O)(R14), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R14), —
CH2O—
C(═
O)NHC1-8alkylC(═
O)(R14), —
CH2NH—
C(═
O)NHC1-8alkylC(═
O)(R14), —
OCH2CH2O(CH2CH2O)rCH2CH2(R14), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R14), —
SCH2CH2O(CH2CH2O)rCH2CH2(R14), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R14), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R14), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2CH2(R14), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R14), —
SO2CH2CH2O(CH2CH2O)rCH2CH2(R14), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R14), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R14), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R14), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R14), —
CH2OCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R14), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), —
CH2C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R14), —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R14), —
CH2NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R14), and —
CH2NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R14).
- C1-6alkyl(R14), —
-
34. The targeting ligand of claim 1 wherein q is 1, 2 or 3.
-
35. The targeting ligand claim 1 wherein Z is selected from the group consisting of hydroxy, —
- NH2, —
NH—
C1-8alkyl, —
N(C1-8alkyl)2, —
O—
C1-8alkyl, —
O—
C1-8alkyl-OH, —
O—
C1-8alkylC1-4alkoxy, —
O—
C1-8alkylcarbonylC1-4alkyl, —
O—
C1-8alkyl-CO2H, —
O—
C1-8alkyl-C(O)O—
C1-6alkyl, C1-8alkyl-OC(O)—
C1-6alkyl, —
O—
C1-8alkyl-NH2, —
O—
C1-8alkyl-NH—
C1-8alkyl, —
O—
C1-8alkyl-N(C1-8alkyl)2, —
O—
C1-8alkylamide, C1-8alkyl-C(O)—
NH—
C1-8alkyl, —
O—
C1-8alkyl-C(O)—
N(C1-8alkyl)2 and —
NHC(O)C1-8alkyl.
- NH2, —
-
36. The targeting ligand of claim 1 wherein the targeting ligand is conjugated to an radioactive element.
-
37. The targeting ligand of claim 1 wherein the targeting ligand is conjugated to an imagining agent.
-
38. The targeting ligand of claim 37 wherein the imagining agent is selected from the group consisting of 99Tc, 125I, 18F, 11C, and 64Cu.
-
2. The targeting ligand of claim 1 wherein W is selected from the group consisting of —
-
39. A targeting ligand of Formula (I):
-
40. A targeting conjugate having a formula selected from the group consisting of
- View Dependent Claims (41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)
-
41. The targeting conjugate of claim 40 wherein W is selected from the group consisting of —
- C0-4alkyl(R1) and —
C0-4alkyl-aryl(R1,R8).
- C0-4alkyl(R1) and —
-
42. The targeting conjugate of claim 40 wherein W is —
- C0-4alkyl(R1) or —
C0-4alkyl-phenyl(R1,R8).
- C0-4alkyl(R1) or —
-
43. The targeting conjugate of claim 40 wherein R1 is selected from the group consisting of —
- N(R4)(R6), -heterocyclyl(R8) and -heteroaryl(R9).
-
44. The targeting conjugate of claim 40 wherein R1 is selected from the group consisting of —
- N(R4)(R6), -dihydro-1H-pyrrolo[2,3-b]pyridinyl(R8), -tetrahydropyrimidinyl(R8), -tetrahydro-1,8-naphthyridinyl(R8), -tetrahydro-1H-azepino[2,3-b]pyridinyl(R8) and -pyridinyl(R8).
-
45. The targeting conjugate of claim 40 wherein R1 is selected from the group consisting of —
- N(R4)(R6), -tetrahydropyrimidinyl(R8) and -tetrahydro-1,8-naphthyridinyl(R8).
-
46. The targeting conjugate of claim 40 wherein R1a is selected from the group consisting of —
- C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7) and —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2.
- C(R4)(═
-
47. The targeting conjugate of claim 40 wherein R4 is selected from the group consisting of hydrogen and —
- C1-4alkyl(R7).
-
48. The targeting conjugate of claim 40 wherein R4 is hydrogen.
-
49. The targeting conjugate of claim 40 wherein R5 is selected from the group consisting of —
- C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
C(═
O)-cycloalkyl(R8), —
C(═
O)-heterocyclyl(R9), —
C(═
O)-aryl(R8), —
C(═
O)-heteroaryl(R8), —
C(═
O)—
N(R4)-cycloalkyl(R8), —
C(═
O)—
N(R4)-aryl(R9), —
CO2—
R4, —
CO2-cycloalkyl(R8), —
CO2-aryl(R8), —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
SO2—
C1-4alkyl(R7), —
SO2—
N(R4)2, —
SO2-cycloalkyl(R8) and —
SO2-aryl(R8).
- C(═
-
50. The targeting conjugate of claim 40 wherein R5 is selected from the group consisting of —
- C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
CO2—
R4, —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
SO2—
C1-4alkyl(R7) and —
SO2—
N(R4)2.
- C(═
-
51. The targeting conjugate of claim 40 wherein R6 is selected from the group consisting of -heterocyclyl(R8) and -heteroaryl(R8).
-
52. The targeting conjugate of claim 40 wherein R6 is selected from the group consisting of -dihydroimidazolyl(R8), -tetrahydropyridinyl(R8), -tetrahydropyrimidinyl(R8) and -pyridinyl(R8).
-
53. The targeting conjugate of claim 40 wherein R7 is one to two substituents independently selected from the group consisting of hydrogen, —
- C1-4alkoxy(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SH, —
S—
C1-4alkyl(R9), —
S—
C1-4alkyl-S—
C1-4alkyl(R9), —
S—
C1-4alkyl-C1-4alkoxy(R9), —
S—
C1-4alkyl-NH—
C1-4alkyl(R9), —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl(R10), -heterocyclyl(R10), -aryl(R10) and -heteroaryl(R10).
- C1-4alkoxy(R9), —
-
54. The targeting conjugate of claim 40 wherein R7 is one to two substituents independently selected from the group consisting of hydrogen, —
- C1-4alkoxy(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, (halo)13, hydroxy and oxo.
- C1-4alkoxy(R9), —
-
55. The targeting conjugate of claim 40 wherein R7 is hydrogen.
-
56. The targeting conjugate of claim 40 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl(R9), —
C(═
O)H, —
C(═
O)—
C4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), -cycloalkyl(R10) and -aryl(R10) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-cycloalkyl(R10), —
O-aryl(R10), —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl-R11)2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R1a), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), —
SH, —
S—
C1-4alkyl(R9), —
S—
C1-4alkyl-S—
C1-4alkyl(R9), —
S—
C1-4alkyl-C1-4alkoxy(R9), —
S—
C1-4alkyl-NH—
C1-4alkyl(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, cyano, halo, hydroxy, nitro, oxo, -cycloalkyl(R10), -heterocyclyl(R10), -aryl(R10) and -heteroaryl(R10) when attached to a carbon atom.
- C1-4alkyl(R9), —
-
57. The targeting conjugate of claim 40 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl(R9), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9) and —
SO2—
NH2 when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9), —
SO2—
NH2, —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, cyano, halo, hydroxy, nitro and oxo when attached to a carbon atom.
- C1-4alkyl(R9), —
-
58. The targeting conjugate of claim 40 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen and —
- C1-4alkyl(R9) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R1a), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, halo, hydroxy and oxo when attached to a carbon atom.
- C1-4alkyl(R9) when attached to a nitrogen atom; and
-
59. The targeting conjugate of claim 40 wherein R8 is one to four substituents independently selected from the group consisting of hydrogen and —
- C1-4alkyl(R9) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10) and hydroxy when attached to a carbon atom.
- C1-4alkyl(R9) when attached to a nitrogen atom; and
-
60. The targeting conjugate of claim 40 wherein R9 is selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo.
- C1-4alkoxy, —
-
61. The targeting conjugate of claim 40 wherein R9 is selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, —
C(═
O)H, —
CO2H, —
C(═
O)—
C1-4alkoxy, (halo)1-3, hydroxy and oxo.
- C1-4alkoxy, —
-
62. The targeting conjugate of claim 40 wherein R9 is selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, (halo)1-3 and hydroxy.
- C1-4alkoxy, —
-
63. The targeting conjugate claim 40 wherein R10 is one to four substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl and —
SO2—
N(C1-4alkyl)2 when attached to a nitrogen atom; and
, wherein R10 is one to four substituents independently selected from the group consisting of hydrogen, —
C1-4alkyl, —
C1-4alkoxy, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, cyano, halo, hydroxy, nitro and oxo when attached to a carbon atom.
- C1-4alkyl, —
-
64. The targeting conjugate of claim 40 wherein (R10)1-4 is selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C1-4alkoxy, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
CO2H, —
CO2—
C1-4alkyl, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, halo, hydroxy, nitro and oxo when attached to a carbon atom.
- C1-4alkyl, —
-
65. The targeting conjugate of claim 40 wherein R10 is hydrogen.
-
66. The targeting conjugate of claim 40 wherein R2a is selected from the group consisting of —
- C1-4alkyl (R7)(R11), —
C2-4alkenyl(R7)(R11), —
C2-4alkynyl(R7)(R11), -cycloalkyl(R7)(R11), -heterocyclyl(R8)(R12), -aryl(R8)(R12), and -heteroaryl(R8)(R12).
- C1-4alkyl (R7)(R11), —
-
67. The targeting conjugate of claim 40 wherein R2a is selected from the group consisting of -cycloalkyl(R7)(R11), -heterocyclyl(R8)(R12), -aryl(R8)(R12), and -heteroaryl(R8)(R11).
-
68. The targeting conjugate of claim 40 wherein R2a is selected from the group consisting of -cycloalkyl(R7)(R11), -heterocyclyl(R8)(R12), -phenyl(R8)(R12), -naphthalenyl(R8)(R12), and -heteroaryl(R8)(R11).
-
69. The targeting conjugate claim 40 wherein R2a is selected from the group consisting of -tetrahydropyrimidinyl(R8)(R12), -1,3-benzodioxolyl(R8)(R12), -dihydrobenzofuranyl(R8)(R12), -tetrahydroquinolinyl(R8)(R12), -phenyl(R8)(R12), -naphthalenyl(R8)(R12), -pyridinyl(R8)(R12), -pyrimidinyl(R8)(R12), and -quinolinyl(R8)(R12).
-
70. The targeting conjugate of claim 40 wherein R11 is selected from the group consisting of —
- C1-8alkyl(R13), —
O—
C1-8alkyl(R13), —
NH—
C1-8alkyl(R13), —
S—
C1-8alkyl(R13), —
C(═
O)C1-8alkyl(R13), —
O—
C(═
O)C1-8alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
C(═
O)OC1-8alkyl(R13), —
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)OC1-8alkyl(R13), —
O—
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)C1-8alkylC(═
O)(R13), —
C(═
O)OC1-8alkylC(═
O)(R13), —
O—
C(═
O)OC1-8alkylC(═
O)(R13), —
NH—
C(═
O)OC1-8alkylC(═
O)(R13), —
C(═
O)NHC1-8alkylC(═
O)(R13), —
O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2H2O)rCH2C(═
O)(R13), and —
SO2NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13).
- C1-8alkyl(R13), —
-
71. The targeting conjugate of claim 40 wherein R11 is selected from the group consisting of —
- C1-8alkyl(R13), —
O—
C1-8alkyl(R13), —
NH—
C1-8alkyl(R13), —
S—
C1-8alkyl(R13), —
C(═
O)C1-8alkyl(R13), —
O—
C(═
O)C1-8alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
C(═
O)OC1-8alkyl(R13), —
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)OC1-8alkyl(R13), —
O—
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)C1-8alkylC(═
O)(R13), —
C(═
O)OC1-8alkylC(═
O)(R13), —
O—
C(═
O)OC1-8alkylC(═
O)(R13), —
NH—
C(═
O)OC1-8alkylC(═
O)(R13), —
C(═
O)NHC1-8alkylC(═
O)(R13), —
O—
C(═
O)NHC1-8alkylC(═
O)(R13), and —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13).
- C1-8alkyl(R13), —
-
72. The targeting conjugate of claim 40 wherein R12 is selected from the group consisting of —
- C1-6alkyl(R13), —
O—
C1-6alkyl(R13), —
NH—
C1-4alkyl(R13), —
S—
C1-6alkyl(R13), —
CH2O—
C1-8alkyl(R13), —
CH2NH—
C1-6alkyl(R13), —
CH2S—
C1-6alkyl(R13), —
C(═
O)C1-6alkyl(R13), —
O—
C(═
O)C1-6alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
CH2O—
C(═
O)C1-8alkyl(R13), —
CH2NH—
C(═
O)C1-6alkyl(R13), —
C(═
O)OC1-6alkyl(R13), —
C(═
O)NHC1-6alkyl(R13), —
O—
C(═
O)OC1-6alkyl(R13), —
O—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)OC1-6alkyl(R13), —
NH—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)C1-6alkylC(═
O)(R13), —
CH2O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2CH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NH(C═
O)CH2O(CH2CH22O)rCH2C(═
O)(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
CH2NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13);
wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting of
- C1-6alkyl(R13), —
-
73. The targeting conjugate of claim 40 wherein R12 is selected from the group consisting of —
- CH2O—
C1-6alkyl(R13), —
CH2NH—
C1-6alkyl(R13), —
CH2S—
C1-6alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
CH2NH—
C(═
O)C1-6alkyl(R13), —
NH—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)C1-6alkylC(═
O)(R13), —
OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13).wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting of
- CH2O—
-
74. The targeting conjugate of claim 40 wherein said —
- O—
(CH2CH2O—
)p—
or
- O—
-
75. The targeting conjugate of claim 40 wherein wherein Q and Q1 of substituents R12 and R13 are the same within a given compound and are selected from the group consisting of the C1-5 saturated chain of palmitoic acid,
the C1-7 saturated chain of stearoic acid, and the C17 mono-unsaturated chain of oleoic acid. -
76. The targeting conjugate of claim 40 wherein
W is preferably is selected from the group consisting of — - C0-4alkyl(R1), —
C1-4alkyl(R1a), —
C0-4alkyl-aryl(R1,R8), —
C0-4alkyl-heterocyclyl(R1,R8), —
C0-4alkoxy(R1), —
C0-4alkoxy-aryl(R1,R8), and —
C0-4alkoxy-heterocyclyl(R1,R8);
R1 is —
N(R4)(R6), -heterocyclyl(R8) or -heteroaryl(R8);
R1a is —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7) or —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2;
R4 is hydrogen or —
C1-4alkyl(R7);
R5 is —
C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
C(═
O)-cycloalkyl(R8), —
C(═
O)-heterocyclyl(R8), —
C(═
O)-aryl(R8), —
C(═
O)-heteroaryl(R8), —
C(═
O)—
N(R4)-cycloalkyl(R8), —
C(═
O)—
N(R4)-aryl(R8), —
CO2—
R4, —
CO2-cycloalkyl(R8), —
CO2-aryl(R8), —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
SO2—
C1-4alkyl(R7), —
SO2—
N(R4)2, —
SO2-cycloalkyl(R8) or —
SO2-aryl(R8);
R6 is -heterocyclyl(R8) or -heteroaryl(R8);
R7 is one to two substituents independently selected from hydrogen, —
C1-4alkoxy(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SH, —
S—
C1-4alkyl(R9), —
S—
C1-4alkyl-S—
C1-4alkyl(R9), —
S—
C1-4alkyl-C1-4alkoxy(R9), —
S—
C1-4alkyl-NH—
C1-4alkyl(R9), —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), cyano, (halo)-3, hydroxy, nitro, oxo, -cycloalkyl(R10), -heterocyclyl(R10), -aryl(R10) or -heteroaryl(R10);
R8 is one to four substituents independently selected from hydrogen, —
C1-4alkyl(R9), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9) or —
SO2—
NH2 when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9), —
SO2—
NH2, —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, cyano, halo, hydroxy, nitro or oxo when attached to a carbon atom;
R9 is hydrogen, —
C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro or oxo;
R10 is one to four substituents independently selected from hydrogen, —
C1-4alkyl, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl or —
SO2—
N(C1-4alkyl)2 when attached to a nitrogen atom; and
, wherein R10 is one to four substituents independently selected from hydrogen, —
C1-4alkyl, —
C1-4alkoxy, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, cyano, halo, hydroxy, nitro or oxo when attached to a carbon atom;
R2a is -cycloalkyl(R8)(R11), -heterocyclyl(R8)(R12), -aryl(R8)(R12) or -heteroaryl(R8)(R12);
q is 1, 2 or 3. R11 is selected from the group consisting of —
C1-8alkyl(R13), —
O—
C1-8alkyl(R13), —
NH—
C1-8alkyl(R13), —
S—
C1-8alkyl(R13), —
C(═
O)C1-8alkyl(R13), —
O—
C(═
O)C1-8alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
C(═
O)OC1-8alkyl(R13), —
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)OC1-8alkyl(R13), —
O—
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)C1-8alkylC(═
O)(R13), —
C(═
O)OC1-8alkylC(═
O)(R13), —
O—
C(═
O)OC1-8alkylC(═
O)(R13), —
NH—
C(═
O)OC1-8alkylC(═
O)(R13), —
C(═
O)NHC1-8alkylC(═
O)(R13), —
O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
SO2NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13);
R12 is selected from the group consisting of —
C1-6alkyl(R13), —
O—
C1-6alkyl(R13), —
NH—
C1-4alkyl(R13), —
S—
C1-6alkyl(R13), —
CH2O—
C1-6alkyl(R13), —
CH2NH—
C1-6alkyl(R13), —
CH2S—
C1-6alkyl(R13), —
C(═
O)C16alkyl(R13), —
O—
C(═
O)C1-6alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
CH2O—
C(═
O)C1-8alkyl(R13), —
CH2NH—
C(═
O)C1-6alkyl(R13), —
C(═
O)OC1-6alkyl(R13), —
C(═
O)NHC1-6alkyl(R13), —
O—
C(═
O)OC1-6alkyl(R13), —
O—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)OC1-6alkyl(R13), —
NH—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)C1-6alkylC(═
O)(R13), —
CH2O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R)
3), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2CH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
CH2NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13);
wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting of
and when R11 or R12 does not terminate with a —
C(═
O)—
, R13 is selected from the group consisting ofsaid —
O—
(CH2CH2O—
)p—
or
of R12 and R13 is a polyethylene glycol (PEG) polymer ranging in molecular weight from 750 to 5000 daltons;
r is an integer from 0 to 8;
Q and Q1 of substituents R12 and R13 are the same within a given compound and are selected from the group consisting of the C11 saturated chain of lauric acid, the C15 saturated chain of palmitoic acid, the C17 saturated chain of stearoic acid, the C17 mono-unsaturated chain of oleoic acid, and the C17 di-unsaturated chain of linoleic acid;
Z is selected from the group consisting of hydroxy, —
NH2, —
NH—
C1-8alkyl, —
N(C1-8alkyl)2, —
O—
C1-8alkyl, —
O—
C1-8alkyl-OH, —
O—
C1-8alkylC1-4alkoxy, —
O—
C1-8alkylcarbonylC1-4alkyl, —
O—
C1-8alkyl-CO2H, —
O—
C1-8alkyl-C(O)O—
C1-6alkyl, —
O—
C1-8alkyl-O—
C(O)C1-8alkyl, —
O—
C1-8alkyl-NH2, —
O—
C1-8alkyl-NH—
C1-8alkyl, —
O—
C1-8alkyl-N(C1-8alkyl)2, —
O—
C1-8alkylamide —
O—
C1-8alkyl-C(O)—
NH—
C1-8alkyl, —
O—
C1-8alkyl-C(O)—
N(C1-8alkyl)2 and —
NHC(O)C1-8alkyl.
- C0-4alkyl(R1), —
-
77. The targeting conjugate of claim 40 wherein
W is preferably — - C0-4alkyl(R1) or —
C0-4alkyl-phenyl(R1,R8);
R1 is —
N(R4)(R6), -tetrahydropyrimidinyl(R8) or -tetrahydro-1,8-naphthyridinyl(R8);
R1a is —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7) or —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2;
R4 is hydrogen;
R5 is —
C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
CO2—
R4, —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
SO2—
C1-4alkyl(R7) or —
SO2—
N(R4)2;
R6 is -dihydroimidazolyl(R8), -tetrahydropyridinyl(R8), -tetrahydropyrimidinyl(R8) or -pyridinyl(R8);
R7 is hydrogen;
R8 is one to four substituents independently selected from hydrogen or —
C1-4alkyl(R9) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9)-O-aryl(R10) or hydroxy when attached to a carbon atom;
R9 is hydrogen, —
C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, (halo)1-3 or hydroxy;
R10 is hydrogen;
R2a is -tetrahydropyrimidinyl(R8)(R12), -1,3-benzodioxolyl(R8)(R12), -dihydrobenzofuranyl(R8)(R12), -tetrahydroquinolinyl(R8)(R12), -phenyl(R8)(R12), -naphthalenyl(R8)(R12), -pyridinyl(R8)(R12), -pyrimidinyl(R8)(R12) or -quinolinyl(R8)(R12);
q is 1 or 2;
R12 is selected from the group consisting of —
CH2—
O—
(CH2)4(R13)—
,—
CH2—
NH—
(CH2)4(R13)—
,—
CH2—
S—
(CH2)4(R13)—
,—
CH2—
O—
(CH2)6(R13)—
,—
CH2—
NH—
(CH2)6(R13)—
,—
CH2—
S—
(CH2)6(R13)—
,—
NH—
C(═
O)—
(CH2)4(R13)—
,—
NH—
C(═
O)—
(CH2)7(R13)—
,—
NH—
C(═
O)NH—
(CH2)3(R13)—
,—
NH—
C(═
O)NH—
(CH2)6(R13)—
,—
CH2NH—
C(═
O)NH—
(CH2)2(R13)—
,—
CH2NH—
C(═
O)NH—
(CH2)5(R13)—
,—
NHC(═
O)—
(CH2)2—
C(═
O)(R13)—
,—
NHC(═
O)—
(CH2)3—
C(═
O)(R13)—
,—
NHC(═
O)—
(CH2)4—
C(═
O)(R13)—
,—
OCH2CH2OCH2CH2(R13)—
,—
NHCH2CH2OCH2CH2(R13)—
,—
OCH2CH2OCH2CH2OCH2CH2(R13)—
,—
NHCH2CH2OCH2CH2OCH2CH2(R13)—
,—
OCH2CH2OCH2C(═
O)(R13)—
,—
OCH2CH2OCH2CH2OCH2C(═
O)(R13)—
,—
NHC(═
O)CH2OCH2CH2(R13)—
,—
NHC(═
O)CH2OCH2CH2OCH2CH2(R13)—
,—
CH2OCH2CH2OCH2CH2(R13)—
,—
CH2NHCH2CH2OCH2CH2(R13)—
,—
CH2SCH2CH2OCH2CH2(R13)—
,—
CH2OCH2CH2OCH2CH2OCH2CH2(R13)—
,—
CH2NHCH2CH2OCH2CH2OCH2CH2(R13)—
,—
CH2SCH2CH2OCH2CH2OCH2CH2(R13)—
,—
CH2NHC(═
O)CH2OCH2C(═
O)(R13)—
, and—
NHC(═
O)CH2OCH2C(═
O)(R13)—
;
wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting ofand when R11 or R12 does not terminate with a —
C(═
O)—
, R13 is selected from the group consisting ofwherein said —
O—
(CH2CH2O—
)p—
or
of R12 and R13 is a polyethylene glycol (PEG) polymer selected from 2000 (PEG
2000), 3400 (PEG 3400), or 5000 (PEG
5000) Daltons;
r is an integer from 0 to 8;
Q and Q1 of substituents R12 and R13 are the same within a given compound and is the C1-7 saturated chain of stearoic acid;
Z is selected from the group consisting of hydroxy, —
NH2, —
NH—
C1-8alkyl, —
N(C1-8alkyl)2, —
O—
C1-8alkyl, —
O—
C1-8alkyl-OH, —
O—
C1-8alkylC1-4alkoxy, —
O—
C1-8alkylcarbonylC1-4alkyl, —
O—
C1-8alkyl-CO2H, —
O—
C1-8alkyl-C(O)O—
C1-6alkyl, —
O—
C1-8alkyl-O—
C(O)C1-8alkyl, —
O—
C1-8alkyl-NH2, —
O—
C1-8alkyl-NH—
C1-8alkyl, —
O—
C1-8alkyl-N(C1-8alkyl)2, —
O—
C1-8alkylamide —
O—
C1-8alkyl-C(O)—
NH—
C1-8alkyl, —
O—
C1-8alkyl-C(O)—
N(C1-8alkyl)2 and —
NHC(O)C1-8alkyl.
- C0-4alkyl(R1) or —
-
41. The targeting conjugate of claim 40 wherein W is selected from the group consisting of —
-
78. A therapeutic liposome composition sensitized to a target cell, comprising
(i) a liposomal composition composed of pre-formed liposomes having an entrapped therapeutic agent; - and
(ii) a plurality of targeting conjugates, each conjugate composed of (a) a lipid having a polar head group and a hydrophobic tail, (b) a hydrophilic polymer having a proximal end and a distal end, where the polymer is attached at its proximal end to the head group of the lipid, and (c) a targeting ligand attached to the distal end of the polymer. - View Dependent Claims (79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90)
-
79. The liposome of claim 78 wherein the targeting conjugate has a formula selected from the group consisting of Formula (I):
-
80. The liposome of claim 79 wherein R12 is selected from the group consisting of —
- C1-6alkyl(R13), —
O—
C1-6alkyl(R13), —
NH—
C1-4alkyl(R13), —
S—
C1-6alkyl(R13), —
CH2O—
C1-6alkyl(R13), —
CH2NH—
C1-6alkyl(R13), —
CH2S—
C1-6alkyl(R13), —
C(═
O)C1-6alkyl(R13), —
O—
C(═
O)C1-6alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
CH2O—
C(═
O)C1-8alkyl(R13), —
CH2NH—
C(═
O)C1-6alkyl(R13), —
C(═
O)OC1-6alkyl(R13), —
C(═
O)NHC1-6alkyl(R13), —
O—
C(═
O)OC1-6alkyl(R13), —
O—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)OC1-6alkyl(R13), —
NH—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)C1-6alkylC(═
O)(R13), —
CH2O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2CH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2OC(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
CH2NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13);
wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting ofand when R11 or R12 does not terminate with a —
C(═
O)—
, R13 is selected from the group consisting of
- C1-6alkyl(R13), —
-
81. The liposome of claim 79 wherein R12 is selected from the group consisting of —
- CH2O—
C1-6alkyl(R13), —
CH2NH—
C1-6akyl(R13), —
CH2S—
C1-6alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
CH2NH—
C(═
O)C1-6alkyl(R13), —
NH—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)C1-6alkylC(═
O)(R13), —
OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13).wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting ofand when R11 or R12 does not terminate with a —
C(═
O)—
, R13 is selected from the group consisting of
- CH2O—
-
82. The liposome of claim 79 wherein said —
- O—
(CH2CH2O—
)p—
or
- O—
-
83. The liposome of claim 79 wherein wherein Q and Q1 of substituents R12 and R13 are the same within a given compound and are selected from the group consisting of the C15 saturated chain of palmitoic acid, the C17 saturated chain of stearoic acid, and the C17 mono-unsaturated chain of oleoic acid.
-
84. The liposome of claim 79 wherein
W is preferably is selected from the group consisting of — - C0-4alkyl(R1), —
C1-4alkyl(R1a), —
C0-4alkyl-aryl(R1,R8), —
C0-4alkyl-heterocyclyl(R1,R8), —
C0-4alkoxy(R1), —
C0-4alkoxy-aryl(R1,R8), and —
C0-4alkoxy-heterocyclyl(R1,R8);
R1 is —
N(R4)(R6), -heterocyclyl(R8) or -heteroaryl(R8);
R1a is —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7) or —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2;
R4 is hydrogen or —
C1-4alkyl(R7);
R5 is —
C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
C(═
O)-cycloalkyl(R8), —
C(═
O)-heterocyclyl(R8), —
C(═
O)-aryl(R8), —
C(═
O)-heteroaryl(R8), —
C(═
O)—
N(R4)-cycloalkyl(R8), —
C(═
O)—
N(R4)-aryl(R8), —
CO2—
R4, —
CO2-cycloalkyl(R8), —
CO2-aryl(R8), —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7), —
N(R4)—
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2, —
SO2—
C1-4alkyl(R7), —
SO2—
N(R4)2, —
SO2-cycloalkyl(R8) or —
SO2-aryl(R8);
R6 is -heterocyclyl(R8) or -heteroaryl(R8);
R7 is one to two substituents independently selected from hydrogen, —
C1-4alkoxy(R9), —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, —
C(═
O)H, —
C(═
O)—
C1-4alkyl(R9), —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
C(═
O)—
NH-aryl(R10), —
C(═
O)-cycloalkyl(R10), —
C(═
O)-heterocyclyl(R10), —
C(═
O)-aryl(R10), —
C(═
O)-heteroaryl(R10), —
CO2H, —
CO2—
C1-4alkyl(R9), —
CO2-aryl(R10), —
C(═
NH)—
NH2, —
SH, —
S—
C1-4alkyl(R9), —
S—
C1-4alkyl—
S—
C1-4alkyl(R9), —
S—
C1-4alkyl—
C1-4alkoxy(R9), —
S—
C1-4alkyl—
NH—
C1-4alkyl(R9), —
SO2—
C1-4alkyl(R9), —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl(R9), —
SO2—
N(C1-4alkyl(R9))2, —
SO2-aryl(R10), cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl(R10), -heterocyclyl(R10), -aryl(R10) or -heteroaryl(R10);
R8 is one to four substituents independently selected from hydrogen, —
C1-4alkyl(R9), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9) or —
SO2—
NH2 when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9), —
O-aryl(R10), —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl(R9), —
C(═
O)—
N(C1-4alkyl(R9))2, —
CO2H, —
CO2—
C1-4alkyl(R9), —
SO2—
NH2, —
NH2, —
NH—
C1-4alkyl(R9), —
N(C1-4alkyl(R9))2, cyano, halo, hydroxy, nitro or oxo when attached to a carbon atom;
R9 is hydrogen, —
C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, —
C(═
O)H, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro or oxo;
R10 is one to four substituents independently selected from hydrogen, —
C1-4alkyl, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl or —
SO2—
N(C1-4alkyl)2 when attached to a nitrogen atom; and
, wherein R10 is one to four substituents independently selected from hydrogen, —
C1-4alkyl, —
C1-4alkoxy, —
C(═
O)H, —
C(═
O)—
C1-4alkyl, —
C(═
O)—
NH2, —
C(═
O)—
NH—
C1-4alkyl, —
C(═
O)—
N(C1-4alkyl)2, —
CO2H, —
CO2—
C1-4alkyl, —
SO2—
C1-4alkyl, —
SO2—
NH2, —
SO2—
NH—
C1-4alkyl, —
SO2—
N(C1-4alkyl)2, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, cyano, halo, hydroxy, nitro or oxo when attached to a carbon atom;
R2a is -cycloalkyl(R8)(R11), -heterocyclyl(R8)(R12), -aryl(R8)(R12) or -heteroaryl(R8)(R12);
q is 1, 2 or 3. R11 is selected from the group consisting of —
C1-8alkyl(R13), —
O—
C1-8alkyl(R13), —
NH—
C1-8alkyl(R13), —
S—
C1-8alkyl(R13), —
C(═
O)C1-8alkyl(R13), —
O—
C(═
O)C1-8alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
C(═
O)OC1-8alkyl(R13), —
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)OC1-8alkyl(R13), —
O—
C(═
O)NHC1-8alkyl(R13), —
O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)C1-8alkylC(═
O)(R13), —
C(═
O)OC1-8alkylC(═
O)(R13), —
O—
C(═
O)OC1-8alkylC(═
O)(R13), —
NH—
C(═
O)OC1-8alkylC(═
O)(R13), —
C(═
O)NHC1-8alkylC(═
O)(R13), —
O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
C(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
SO2NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13);
R12 is selected from the group consisting of —
C1-6alkyl(R13), —
O—
C1-6alkyl(R13), —
NH—
C1-4alkyl(R13), —
S1-6alkyl(R13), —
CH2O—
C1-6alkyl(R13), —
CH2NH—
C1-6alkyl(R13), —
CH2S—
C1-6alkyl(R13), —
C(═
O)C1-6alkyl(R13), —
O—
C(═
O)C1-6alkyl(R13), —
NH—
C(═
O)C1-8alkyl(R13), —
CH2O—
C(═
O)C1-8alkyl(R13), —
CH2NH—
C(═
O)C1-6alkyl(R13), —
C(═
O)OC1-6alkyl(R13), —
C(═
O)NHC1-6alkyl(R13), —
O—
C(═
O)OC1-6alkyl(R13), —
O—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)OC1-6alkyl(R13), —
NH—
C(═
O)NHC1-6alkyl(R13), —
NH—
C(═
O)C1-6alkylC(═
O)(R13), —
CH2O—
C(═
O)C1-8alkylC(═
O)(R13), —
NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2O—
C(═
O)NHC1-8alkylC(═
O)(R13), —
CH2NH—
C(═
O)NHC1-8alkylC(═
O)(R13), —
OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2CH2CH2O(CH2CH2O)rCH2CH2(R13), —
SO2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2NHCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2SCH2CH2O(CH2CH2O)rCH2CH2(R13), —
CH2OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
OC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2OC(═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NH(C═
O)CH2O(CH2CH2O)rCH2C(═
O)(R13), —
CH2NHC(═
O)OCH2CH2O(CH2CH2O)rCH2C(═
O)(R13), and —
CH2NHC(═
O)NHCH2CH2O(CH2CH2O)rCH2C(═
O)(R13);
wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting ofand when R11 or R12 does not terminate with a —
C(═
O)—
, R13 is selected from the group consisting ofsaid —
O—
(CH2CH2O—
)p—
or
of R12 and R13 is a polyethylene glycol (PEG) polymer ranging in molecular weight from 750 to 5000 daltons;
r is an integer from 0 to 8;
Q and Q1 of substituents R12 and R13 are the same within a given compound and are selected from the group consisting of the C11 saturated chain of lauric acid, the C15 saturated chain of palmitoic acid, the C17 saturated chain of stearoic acid, the C17 mono-unsaturated chain of oleoic acid, and the C17 di-unsaturated chain of linoleic acid;
Z is selected from the group consisting of hydroxy, —
NH2, —
NH—
C1-8alkyl, —
N(C1-8alkyl)2, —
O—
C1-8alkyl, —
O—
C1-8alkyl—
OH, —
O—
C1-8alkyl1-4alkoxy, —
O—
C1-8alkylcarbonylC1-4alkyl, —
O—
C1-8alkyl—
CO2H, —
O—
C1-8alkyl—
C(O)O—
C1-6alkyl, —
O—
C1-8alkyl—
O—
C(O)C1-8alkyl, —
O—
C1-8alkyl—
NH2, —
O—
C1-8alkyl—
NH—
C1-8alkyl, —
O—
C1-8alkyl—
N(C1-8alkyl)2, —
O—
C1-8alkylamide—
O—
C1-8alkyl—
C(O)—
NH—
C1-8alkyl, —
O—
C1-8alkyl—
C(O)—
N(C1-8alkyl)2 and —
NHC(O)C1-8alkyl.
- C0-4alkyl(R1), —
-
85. The liposome of claim 79 wherein
W is preferably — - C0-4alkyl(R1) or —
C0-4alkyl—
phenyl(R1,R8);
R1 is —
N(R4)(R6), -tetrahydropyrimidinyl(R8) or -tetrahydro-1,8-naphthyridinyl(R8);
R1a is —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
C(═
N—
R4)—
N(R4)—
C(═
O)—
R4, —
C(═
N—
R4)—
N(R4)—
C(═
O)—
N(R4)2, —
C(═
N—
R4)—
N(R4)—
CO2—
R4, —
C(═
N—
R4)—
N(R4)—
SO2—
C1-4alkyl(R7) or —
C(═
N—
R4)—
N(R4)—
SO2—
N(R4)2;
R4 is hydrogen;
R5 is —
C(═
O)—
R4, —
C(═
O)—
N(R4)2, —
CO2—
R4, —
C(R4)(═
N—
R4), —
C(═
N—
R4)—
N(R4)2, —
C(═
N—
R4)—
N(R4)(R6), —
N(R4)—
C(R4)(═
N—
R4), —
N(R4)—
C(═
N—
R4)—
N(R4)2, —
N(R4)—
C(═
N—
R4)—
N(R4)(R6), —
SO2—
C1-4alkyl(R7) or —
SO2—
N(R4)2;
R6 is -dihydroimidazolyl(R8), -tetrahydropyridinyl(R8), -tetrahydropyrimidinyl(R8) or -pyridinyl(R8);
R7 is hydrogen;
R8 is one to four substituents independently selected from hydrogen or —
C1-4alkyl(R9) when attached to a nitrogen atom; and
, wherein R8 is one to four substituents independently selected from hydrogen, —
C1-4alkyl(R9), —
C1-4alkoxy(R9)—
O-aryl(R10) or hydroxy when attached to a carbon atom;
R9 is hydrogen, —
C1-4alkoxy, —
NH2, —
NH—
C1-4alkyl, —
N(C1-4alkyl)2, (halo)1-3, or hydroxy;
R10 is hydrogen;
R2a is -tetrahydropyrimidinyl(R8)(R12), -1,3-benzodioxolyl(R8)(R12), -dihydrobenzofuranyl(R8)(R12), -tetrahydroquinolinyl(R8)(R12), -phenyl(R8)(R12), -naphthalenyl(R8)(R12), -pyridinyl(R8)(R12), -pyrimidinyl(R8)(R12) or -quinolinyl(R8)(R12);
q is 1 or 2;
R12 is selected from the group consisting of —
CH2—
O—
(CH2)4(R13)—
, —
CH2—
NH—
(CH2)4(R13)—
, —
CH2—
S—
(CH2)4(R13)—
, —
CH2—
O—
(CH2)6(R13)—
, —
CH2—
NH—
(CH2)6(R13)—
, —
CH2—
S—
(CH2)6(R13)—
, —
NH—
C(═
O)—
(CH2)4(R13)—
, —
NH—
C(═
O)—
(CH2)7(R13)—
, —
NH—
C(═
O)NH—
(CH2)3(R13)—
, —
NH—
C(═
O)NH—
(CH2)6(R13)—
, —
CH2NH—
C(═
O)NH—
(CH2)2(R13)—
, —
CH2NH—
C(═
O)NH—
((CH2)5(R13)—
, —
NHC(═
O)—
(CH2)2—
C(═
O)(R13)—
, —
NHC(═
O)—
(CH2)3—
C(═
O)(R13)—
, —
NHC(═
O)—
(CH2)4—
C(═
O)(R13)—
, —
OCH2CH2OCH2CH2(R13)—
, —
NHCH2CH2OCH2CH2(R13)—
, —
OCH2CH2OCH2CH2OCH2CH2(R13)—
, —
NHCH2CH2OCH2CH2OCH2CH2(R13)—
, —
OCH2CH2OCH2C(═
O)(R13)—
, —
OCH2CH2OCH2CH2OCH2C(═
O)(R13)—
, —
NHC(═
O)CH2OCH2CH2(R13)—
, —
NHC(═
O)CH2OCH2CH2OCH2CH2(R13)—
, —
CH2OCH2CH2OCH2CH2(R13)—
, —
CH2NHCH2CH2OCH2CH2(R13)—
, —
CH2SCH2CH2OCH2CH2(R13)—
, —
CH2OCH2CH2OCH2CH2OCH2CH2(R13)—
, —
CH2NHCH2CH2OCH2CH2OCH2CH2(R13)—
, —
CH2SCH2CH2OCH2CH2OCH2CH2(R13)—
, —
CH2NHC(═
O)CH2OCH2C(═
O)(R13)—
, and —
NHC(═
O)CH2OCH2C(═
O)(R13)—
;
wherein when R11 or R12 terminates with a —
C(═
O)—
, R13 is selected from the group consisting ofand when R11 or R12 does not terminate with a —
C(═
O)—
, R13 is selected from the group consisting ofwherein said —
O—
(CH2CH2O—
)p—
or
of R12 and R13 is a polyethylene glycol (PEG) polymer selected from 2000 (PEG
2000), 3400 (PEG
3400), or 5000 (PEG
5000) Daltons;
r is an integer from 0 to 8;
Q and Q1 of substituents R12 and R13 are the same within a given compound and is the C17 saturated chain of stearoic acid;
Z is selected from the group consisting of hydroxy, —
NH2, —
NH—
C1-8alkyl, —
N(C1-8alkyl)2, —
O—
C1-8alkyl, —
O—
C1-8alkyl—
OH, —
O—
C1-8alkylC1-4alkoxy, —
O—
C1-8alkylcarbonylC1-4alkyl, —
O—
C1-8alkyl—
CO2H, —
O—
C1-8alkyl—
C(O)O—
C1-6alkyl, —
O—
C1-8alkyl—
O—
C(O)C1-8alkyl, —
O—
C1-8alkyl—
NH2, —
O—
C1-8alkyl—
NH—
C1-8alkyl, —
O—
C1-8alkyl—
N(C1-8alkyl)2, —
O—
C1-8alkylamide—
O—
C1-8alkyl—
C(O)—
NH—
C1-8alkyl, —
O—
C1-8alkyl—
C(O)—
N(C1-8alkyl)2 and —
NHC(O)C1-8alkyl.
- C0-4alkyl(R1) or —
-
86. The therapeutic liposome composition of claim 78 wherein the therapeutic agent is selected from the group consisting of steroids, immunosuppressants, antihistamines, non-steroidal anti-asthamtics, non-steroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors, cytotoxic agents, gene therapy agents, radiotherapy agents, and imaging agents.
-
87. The therapeutic liposome composition of claim 78 wherein the therapeutic agent is a cytotoxic drug.
-
88. The therapeutic liposome composition of claim 87 wherein the cytotoxic drug is selected from the group consisting of anthracycline antibiotics, platinum compounds, topoisomerase 1 inhibitors, and vinca alkaloids.
-
89. The therapeutic liposome composition of claim 87 wherein the cytotoxic agent is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, cisplatin, carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin, lobaplatin, spiroplatin, ((-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutane dicarboxylato)platinum), (SP-4-3(R)1,1-cyclobutane-dicarboxylato(2-)-(2-methyl-1,4-butanediamine-N,N′
- )platinum), nedaplatin, (bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV), topotecan, irinotecan, (7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin), 7-(2-(N-isopropylamino)ethyl)-(20S)-camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine, and vindesine.
-
90. The therapeutic liposome composition of claim 87 wherein the cytotoxic agent is selected from the group consisting of doxorubicin, daunorubicin, epirubicin, idarubicin, cisplatin, including salts.
-
79. The liposome of claim 78 wherein the targeting conjugate has a formula selected from the group consisting of Formula (I):
- and
Specification
- Resources
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-
Current AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
-
Original AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
-
InventorsLiu, Li, Ghosh, Shyamali, Maryanoff, Bruce E., De Corte, Bart, Kinney, William A.
-
Application NumberUS10/782,060Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/326CPC Class CodesA61K 2300/00 Mixtures or combinations of...A61K 31/4523 containing further heterocy...A61K 45/06 Mixtures of active ingredie...A61K 51/0455 having six-membered rings w...A61K 51/0459 having six-membered rings w...A61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 19/00 Drugs for skeletal disordersA61P 19/02 for joint disorders, e.g. a...A61P 19/10 for osteoporosisA61P 27/00 Drugs for disorders of the ...A61P 35/00 Antineoplastic agentsC07D 401/12 linked by a chain containin...C07D 401/14 containing three or more he...C07D 405/14 containing three or more he...C07D 471/04 Ortho-condensed systemsY02P 20/582 Recycling of unreacted star...