Tetrapartate prodrugs
First Claim
1. A compound of formula I:
-
wherein;
L1 is a bifunctional linking moiety;
D is a moiety that is a leaving group, or a residue of a compound to be delivered into a cell;
Z is covalently linked to [D]y, wherein Z is selected from the group consisting of;
a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
Y1, Y2, Y3 and Y4 are each independently O, S, or NR12;
R11 is a mono- or divalent polymer residue;
R1, R4, R9, R10 and R12 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, and substituted C1-6 hetoroalkyls;
R2, R3, R5 and R6, are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkylcarbonyls;
Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(m), (r), (s), (t), and (u) are independently zero or one;
(p) is zero or a positive integer; and
(y) is 1 or 2;
wherein Z[D]y is capable of crossing the membrane of the target cell and is capable of being hydrolyzed therein to release D.
1 Assignment
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Accused Products
Abstract
A compound of Formula I, providing tetrapartate prodrugs is provided
wherein:
L1 is a bifunctional linking moiety;
D is a moiety that is a leaving group, or a residue of a compound to be delivered into a cell;
Z is covalently linked to [D]y, wherein Z is selected from the group consisting of: a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof,
Y1, Y2, Y3 and Y4 are each independently O, S, or NR12;
R11 is a mono- or divalent polymer residue;
R1, R4, R9, R10 and R12 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls and substituted C1-6 heteroalkyls;
R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro- and cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkylcarbonyls;
Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(m), (r), (s), (t), and (u) are independently zero or one;
(p) is zero or a positive integer; and (y) is 1 or 2;
together with methods of preparing and using these new tetrapartate prodrugs.
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Citations
35 Claims
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1. A compound of formula I:
-
wherein; L1 is a bifunctional linking moiety;
D is a moiety that is a leaving group, or a residue of a compound to be delivered into a cell;
Z is covalently linked to [D]y, wherein Z is selected from the group consisting of;
a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
Y1, Y2, Y3 and Y4 are each independently O, S, or NR12;
R11 is a mono- or divalent polymer residue;
R1, R4, R9, R10 and R12 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, and substituted C1-6 hetoroalkyls;
R2, R3, R5 and R6, are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkylcarbonyls;
Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(m), (r), (s), (t), and (u) are independently zero or one;
(p) is zero or a positive integer; and
(y) is 1 or 2;
wherein Z[D]y is capable of crossing the membrane of the target cell and is capable of being hydrolyzed therein to release D.- 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)
wherein; M is X or Q;
where X is an electron withdrawing group;
Q is a moiety containing a free electron pair positioned three to six atoms from (a) and (n) are independently zero or a positive integer;
(b) is zero or one;
(g) is a positive integer;
(q) is three or four;
R7, R8, R14, R15 and R18 are independently selected from the group which defines R9; and
Y5 and Y6 are independently O, S, or NR12.
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3. The compound of claim 1 wherein when y is 2, each of the two D moieties is the same or different.
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4. The compound of claim 1 wherein Z is selected from the group consisting of an amino acid residue, a sugar residue a fatty acid residue, a peptide residue, a C6-18 alkyl, a substituted aryl, a heteroaryl, —
- C(═
O), —
C(═
S), and —
C(═
NR16), wherein R16 is selected from the same group as R12.
- C(═
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5. The compound of claim 4 wherein the amino acid residue is selected from the group consisting of alanine, valine, leucine, isoleucine, glycine, serine, threonine, methionine, cysteine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine and proline.
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6. The compound of claim 4 wherein the peptide ranges in size from 2 to about 10 amino acid residues.
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7. The compound of claim 6 wherein the peptide is Gly-Phe-Leu-Gly (SEQ ID NO:
- 1) or Gly-Phe-Leu.
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8. The compound of claim 1 wherein each D moiety is independently a residue of an active biological material.
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9. The compound of claim 1 wherein at least one D moiety is a leaving group selected from the group consisting of N-hydroxybenzotriazolyl, halogen, N-hydroxyphthal-imidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thione, and combinations thereof.
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10. The compound of claim 1 wherein Ar is selected from the group consisting of
wherein J is selected from the group consisting of O, S, and N— - R19, B and Z are independently CR19 or N—
R19 and R19 is selected from the group consisting of hydrogen, C1-6 alkyl, C3-12 branched alkyl, C3-8 cycloalkyl, C1-6 substituted alkyl, C3-8 substituted cyoloalkyl, aryls, substituted aryl, aralkyl, C1-6 heteroalkyl, and substituted C1-6 heteroalkyls.
- R19, B and Z are independently CR19 or N—
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11. The compound of claim 1, wherein
comprises an amino acid residue. -
12. The compound of claim 11, wherein said amino acid residue is selected from the group consisting of naturally occurring and non-naturally occurring amino acid residues.
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13. The compound of claim 1, wherein (p) is one.
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14. The compound of claim 2, wherein X is selected from the group consisting of O and NR12.
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15. The compound of claim 2, wherein Q is selected from the group consisting of C2-4 alkyls, cycloalkyls, aryls, and aralkyl groups substituted with a member of the group consisting of NH, O, S, —
- CH2—
C(O)—
N(H)—
, and ortho-substituted phenyls.
- CH2—
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16. The compound of claim 2, wherein (n) is 1 or 2.
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17. The compound of claim 1, wherein (m) is 0.
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18. The compound of claim 1, wherein Y1, Y2, Y3 and Y4 are O.
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19. The compound of claim 1, wherein R11 comprises a polyalkylene oxide residue.
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20. The compound of claim 19, wherein said polyalkylene oxide residue comprises polyethylene glycol.
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21. The compound of claim 1 wherein said polymer residue has a number average molecular weight of from about 2000 to about 100,000 daltons.
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22. The compound of claim 1, wherein said polymer residue has a number average molecular weight of from about 20,000 to about 40,000 daltons.
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23. The compound of claim 10, wherein Ar is
wherein r and t are both 1, R2 and R6 are independently H or methyl. -
24. The compound of claim 1 that is selected from the group consisting of:
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25. The compound of claim 24 wherein the polyethylene glycol (PEG) has a number average molecular weight of from about 20,000 to about 40,000 daltons.
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26. A composition comprising a pharmaceutically or diagnostically effective amount of the compound of claim 1, where D is a residue of a compound to be delivered into a cell, together with a carrier acceptable for in vivo administration to an animal in need thereof.
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27. A method of treating a disease or disorder in an animal, that comprises administering a pharmaceutically acceptable composition comprising an effective amount of a compound of claim 1, where D is a moiety that is a residue of a compound to be delivered into a cell;
- to an animal in need thereof.
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28. A method of delivering a biologically active material D into a cell in need of treatment therewith, comprising the process of administering a compound of claim 1 to an animal comprising said cell, wherein Formula I is hydrolyzed in vivo extracellularly to yield:
-
wherein Y* is the remainder of Y2, and is independently selected from the group consisting of HO—
, HS—
, or HNR12;and Formula I-(i) then spontaneously hydrolyzes to and CO2, and a compound of Formula I-(iii) Z—
[D]y is released;wherein Y** is the remainder of Y*, and is independently selected from the group consisting of O, S, or NR12; and
Z—
[D]y crosses the membrane of the cell, and is hydrolyzed therein to release D.
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29. The compound of claim 2, wherein X is selected from the group consisting of O, NR12,
S, SO and SO2 where R17 is independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, and substituted C1-6 heteroalkyls.
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30. A compound of Formula I:
-
wherein; L1 is a bifunctional linking moiety;
each D moiety is independently a residue of an anticancer agent, an anticancer prodrug, a detectable tag, or combinations thereof;
Z is covalently linked to [D]y, wherein Z is selected from the group consisting of;
a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
Y1, Y2, and Y4 are each independently O, S, or NR12;
R11 is a mono- or divalent polymer residue;
R1, R4, R9, R10 and R12 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, and substituted C1-6 heteroalkyls;
R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cyoloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkylcarbonyls;
Ar is a moiety which when included in Formula (V) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(m), (r), (s), (t), and (u) are independently zero or one;
(p) is zero or a positive integer; - View Dependent Claims (31, 32)
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33. A method of preparing a tetrapartate prodrug comprising reacting a compound of formula:
-
with a compound of formula;
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34. A method of preparing a tetrapartate prodrug comprising reacting a compound of formula
with at least one biologically active material; - wherein
L1 is a bifunctional linking moiety;
La is a leaving group for Formula V;
Z is covalently linked to La and wherein Z is selected from the group consisting of;
a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
R1, R4, R9, R10 and R12 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cyoloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, and substituted C1-6 heteroalkyls;
R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, Y1, Y2, Y3 and Y4 are independently O, S, or NR12; and
R11 is a monovalent or divalent polymer residue wherein after the reaction Z is covalently linked to the at least one biologically active material.
- wherein
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35. A compound of Formula I:
-
wherein; L1 —
C(═
Y3) comprises an amino acid residue;
D is a moiety that is a leaving group, or a residue of a compound to be delivered into a cell;
Z is covalently linked to [D]y, wherein Z is selected from the group consisting of;
a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof;
Y1, Y2 and Y4 are each independently O, S, or NR12;
R11 is a mono- or divalent polymer residue;
R1, R4, R9, R10 and R12 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cyoloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, and substituted C1-6 heteroalkyls;
R2, R3, R5 and R6 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C1-6 alkoxy, phenoxy, C1-8 heteroalkyls, C1-8 heteroalkoxy, substituted C1-6 alkyls, C3-8 cycloalkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkylcarbonyls;
Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(m), (r), (s), (t), and (u) are independently zero or one; and
(p) is zero or a positive integer; and
(y) is 1 or 2.
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Specification