Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents
First Claim
Patent Images
1. A compound comprising the formula:
-
wherein;
L1 is a bifunctional linking moiety;
G is H orwhereB is H, a leaving group, a residue of an amine-containing moiety, or a residue of a hydroxyl-containing moiety;
Y1-4 are independently O, S, or NR12;
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-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;
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), (u) and (v) are independently zero or one;
(p) is zero or a positive integer; and
R11 is a substantially non-antigenic polymer, except that(1) G is not H when (v) is 0;
(2) R11 is not —
C(═
Y)-(CH2)n-O-(CH2CH2O)x-CH3 when m=0, p=0 and Y3=NH and (3) R11 is not CH3-O-(CH2CH2O)x-CH2)n when m=0, p=1, L1=OCH2, Y4=O and Y3=NH wherein (n) is zero or a positive integer;
Y is O, S or NR12; and
(x) represents the degree of polymerization.
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Abstract
The present invention is directed to double prodrugs containing polymeric-based transport forms. These polymeric prodrugs are preferably of the formula:
wherein:
L1 is a bifunctional linking moiety;
G is H or
where
B is H, a leaving group, a residue of an amine-containing moiety, or a residue of a hydroxyl-containing moiety;
Y1-4 are independently, O, S, or NR12;
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, 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 alkyl carbonyls;
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), (u) and (v) are independently zero or one;
(p) is zero or a positive integer; and
R11 is a substantially non-antigenic polymer.
The first prodrug is generated when the polymeric portion of the double prodrug is cleaved and the parent molecule is generated rapidly thereafter in vivo, preferably as a result of 1,6 or 1,4 benzyl elimination-reaction. Methods of preparing the compounds and methods of treatment are also disclosed.
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Citations
56 Claims
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1. A compound comprising the formula:
-
wherein; L1 is a bifunctional linking moiety;
G is H or where B is H, a leaving group, a residue of an amine-containing moiety, or a residue of a hydroxyl-containing moiety;
Y1-4 are independently O, S, or NR12;
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-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls;
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), (u) and (v) are independently zero or one;
(p) is zero or a positive integer; and
R11 is a substantially non-antigenic polymer, except that (1) G is not H when (v) is 0;
(2) R11 is not —
C(═
Y)-(CH2)n-O-(CH2CH2O)x-CH3 when m=0, p=0 and Y3=NH and(3) R11 is not CH3-O-(CH2CH2O)x-CH2)n when m=0, p=1, L1=OCH2, Y4=O and Y3=NH wherein (n) is zero or a positive integer;
Y is O, S or NR12; and
(x) represents the degree of polymerization.- 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, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52)
L1 is selected from the group consisting of wherein;
M is X or Q;
whereX 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;
(q) is three or four;
R7, R8, R14, and R15 are independently selected from the group which defines R9; and
Y5 is O, S, or NR12.
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3. The compound of claim 1, wherein Ar is selected from the group consisting of:
-
wherein J is O, S, or NR13, E and Z are independently CR13 or NR13; and
R13 is independently selected from the same group as that which defines R9.
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4. A compound of claim 1, having the formula
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5. The compound of claim 1, wherein R1, R4, R9 and R10 are all H.
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6. The compound of claim 1, having the formula:
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7. The compound of claim 2, wherein
comprises an amino acid residue. -
8. The compound of claim 7, 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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9. The compound of claim 1, wherein (p) is one.
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10. The compound of claim 1, wherein R11 includes a capping group A.
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11. The compound of claim 10, wherein A is selected from the group consisting of hydrogen, CO2H, C1-6 alkyl moieties, dialkyl acyl urea alkyls and
wherein G′ - is the same as G or another member of the group defined as G.
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12. The compound of claim 2, wherein X is selected from the group consisting of O, NR12, S, SO and SO2.
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13. The compound of claim 12, wherein X is selected from the group consisting of O and NR12.
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14. 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-C(O)-N(H)—
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15. The compound of claim 2, wherein (n) is 1 or 2.
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16. The compound of claim 1, wherein (m) is 0.
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17. The compound of claim 1, wherein Y1-4 are O.
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18. The compound of claim 1, wherein R11 comprises a polyalkylene oxide.
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19. The compound of claim 18, wherein said polyalkylene oxide comprises polyethylene glycol.
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20. The compound of claim 1 wherein said polymer has a number average molecular weight of from about 2,000 to about 100,000 daltons.
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21. The compound of claim 1, wherein said polymer has a number average molecular weight of from about 5,000 to about 40,000 daltons.
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22. The compound of claim 1, wherein R11 is selected from the group consisting of —
- C(═
Y)-(CH2)n-O-(CH2CH2O)x-A, —
C(═
Y)-Y-(CH2)n-O-(CH2CH2O)x-A and —
C(═
Y)-NR12-(CH2)n-O-(CH2CH2O)x-A, where(n) is zero or a positive integer;
Y is O, S or NR12;
A is a capping group; and
(x) represents the degree of polymerization.
- C(═
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23. The compound of claim 1 wherein B is a leaving group selected from the group consisting of N-hydroxybenzotriazolyl, halogen, N-hydroxyphthalimidyl, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidinyl thioine, and an acid activating group.
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24. The compound of claim 1 wherein B is a residue of a hydroxyl-containing compound.
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25. The compound of claim 1, wherein B is a residue of an amine containing compound.
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26. The compound of claim 1, wherein B includes a second polymeric transport system.
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27. The compound of claim 4 wherein:
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L1 is M is X or Q;
X is an electron withdrawing group;
Q is a moiety containing a free electron pair positioned three to six atoms from Y3;
R7 and R8, 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;
(n) is zero or a positive integer;
r, s, t, u, p and v are all equal to 1; and
G is except that R2, R3, R5 and R6 are not all H when (m) and (n) are both zero.
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28. The compound of claim 27, wherein R2 and R6 are C1-6 alkyls.
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29. The compound of claim 27, wherein R2 and R6 are methyl.
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30. The compound of claim 27, wherein R2 and R6 are independently C1-6.
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31. The compound of claim 27, wherein R2 and R6 are methoxy.
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32. The compound of claim 27, wherein R3 and R5 are hydrogen.
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33. The compound of claim 27, wherein R1 and R4 are independently selected from the group consisting of hydrogen, CH3 and CH2CH3.
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34. The compound of claim 27, wherein said substituted C1-6 alkyl is selected from the group consisting of carboxyalkyls, aminoalkyls, dialkylaminos, hydroxyalkyls and mercaptoalkyls.
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35. The compound of claim 27, wherein X is selected from the group consisting of O, NR12, S, SO and SO2.
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36. The compound of claim 35, wherein X is selected from the group consisting of O and NR12.
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37. The compound of claim 27, wherein Q is selected from the group consisting of C2-4 alkyls, cycloalkyls, aryls, and aralkyl groups, and Q is substituted with a member of the group consisting of NH, NR12, O, S, —
- CH2-CH(O)-N(H)—
, and ortho-substituted phenyls.
- CH2-CH(O)-N(H)—
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38. The compound of claim 27, wherein (n) is an integer from 1 to about 12.
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39. The compound of claim 38, wherein (n) is 1 or 2.
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40. The compound of claim 27, wherein B is a residue of a member of the group consisting of anthracyclins, daunorubicin, doxorubicin, p-hydroxyaniline mustard, cytosine arabinoside and gemcitabine.
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41. The compound of claim 27, wherein B is a residue of an amine containing compound selected from the group consisting of cardiovascular agents, anti-neoplastics, anti-infectives, anti-fungals, anti-anxiety agents, gastrointestinal agents, central nervous system-activating agents, analgesics, fertility agents, contraceptive agents, anti-inflammatory agents, steroidal agents, anti-urecemic agents, vasodilating agents, and vasoconstricting agents.
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42. The compound of claim 26, wherein B includes an attachment moiety for said second polymeric transport system selected from the group consisting of alpha amino, epsilon amino, histidine nitrogen, carboxyl, reactive carbonyl, mercapto, sulfhydryl and hydroxyl.
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43. The compound of claim 42, wherein B is a member of the group consisting of proteins, polypeptides, peptides and enzymes.
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44. The compound of claim 43, wherein B is a cytokine or an interferon.
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45. The compound of claim 44, wherein said cytokine is an interleukin.
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46. The compound of claim 45, wherein said interleukin is selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12 and IL-13.
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47. The compound of claim 44, wherein said interferon is selected from the group consisting of α
- -interferons, β
-interferons and γ
-interferons.
- -interferons, β
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48. The compound of claim 1, wherein v=1.
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49. The compound of claim 1, wherein (p) is four and
comprises Gly-Phe-Leu-Gly (SEQ ID NO: - 1).
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50. A compound of claim 1, selected from the group consisting of:
-
wherein J is O, S, or NR13, E and Z are independently CR13 or NR13, and R13 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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52. A method of treating a mammal with prodrugs, comprising:
administering to a mammal in need of such treatment an effective amount of a pharmaceutically acceptable composition comprising the compound of claim 1, wherein B is a residue of an amine-containing or hydroxyl-containing biologically active moiety.
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51. A composition comprising a compound of the formula:
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wherein B is a leaving group or a residue of an amine-containing target moiety.
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53. A method for preparing a prodrug transport form comprising:
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a. providing an intermediate compound (III) wherein M2 is a cleavable or reversible protecting group;
L1 is a bifunctional linking moiety;
B2 is selected from the group consisting of H, OH, and leaving groups; Y1-4 are independently O, S, or NR12;
(r), (s), (t), (u) and (v) are independently zero or one;
(p) is zero or a positive integer;
R1, R4, 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-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls; and
Ar is a moiety which forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
except that G is not H when (v) is 0;
b. removing the protecting group;
c. reacting the resultant unprotected intermediate compound with an activated polymer capable of reacting with L1 to form an intermediate activated double prodrug transport form; and
d. reacting the intermediate activated double prodrug transport form with an activating moiety donor. - View Dependent Claims (54, 55)
e. reacting the prodrug transport form of step d with an amine-containing or hydroxyl-containing compound residue to form a conjugate.
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55. The method of claim 53 further comprising reacting the compound of formula (I) with an activating polymer to form a hybrid transport system.
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56. A method for preparing a prodrug transport form comprising:
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a. providing an intermediate compound (III) wherein M2 is a cleavable or reversible protecting group;
L1 is a bifunctional linking moiety;
B2 is selected from the group consisting of H, OH, and leaving groups; Y1-4 are independently O, S, or NR12;
(r), (s), (t), (u) and (v) are independently zero or one;
(p) is zero or a positive integer;
R1, R4, 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-, cyano-, carboxy-, C1-6 carboxyalkyls and C1-6 alkyl carbonyls; and
Ar is a moiety which forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group when compound III is reacted with an activating moiety donor except that G is not H when (v) is 0;
b. reacting intermediate compound III with an activating moiety donor and then reacting the resultant activated product with an amine-containing or hydroxyl-containing compound;
c. removing the protecting group from the last product of step b, to form an unprotected intermediate; and
d. reacting the unprotected intermediate of step c with an activated polymer to form the prodrug transport form.
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Specification
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Current AssigneeEnzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
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Original AssigneeEnzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
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InventorsGreenwald, Richard B., Pendri, Annapurna, Choe, Yun H.
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Primary Examiner(s)Russel, Jeffrey E.
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Application NumberUS09/183,557Time in Patent Office823 DaysField of Search526/332, 528/421, 536/4.1, 536/6.4, 536/16.8, 536/17.2, 536/18.1, 536/28.5, 514/34, 514/49, 514/247, 514/345, 514/351, 514/352, 514/424, 514/425, 514/426, 514/432, 514/445, 514/447, 514/459, 514/460, 514/471, 514/472, 514/473, 514/480, 514/512, 514/547, 514/2, 514/13, 514/18, 424/85.1, 424/85.2, 424/85.4, 424/94.3, 530/326, 530/330, 530/345, 530/351, 530/408, 530/409, 530/410, 435/188US Class Current424/85.1CPC Class CodesA61K 47/60 the organic macromolecular ...A61P 35/00 Antineoplastic agentsA61P 43/00 Drugs for specific purposes...
