Terminally-branched polymeric linkers containing extension moieties and polymeric conjugates containing the same
First Claim
Patent Images
1. A compound comprising the formula:
-
wherein;
E1-4 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy,
and at least one of E1-4 includes a B moiety;
B is a leaving group, OH, a residue of a hydroxyl-containing moiety, a residue of an amine-containing moiety orwherein E5 is independently selected from the same group which defines E1-4;
E10-30 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy,
wherein B1 is a leaving group, OH, a residue of a hydroxyl-containing moiety or a residue of an amine-containing moiety or
wherein E6 is independently selected from the same group which defines E1-4;
wherein E1b-3b 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy,
wherein B2 is a leaving group, OH, a residue of a hydroxyl-containing moiety or a residue of an amine-containing moiety;
G is a polymeric residue;
Y1-3, Y2a-d and Y3a-d are each independently O, S or NR11a M1-4, M2a-2d, M3a-3d, and M4a-4d are each independently O, S or NR11b;
M5 and M5a-d are each independently X or Q, wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y3) or C(═
Y3a-d);
R1-10, R1a-11a, R1b-11b, R1c-10c and R1d-10d are each 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, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
a, b, c, d1-d6, e1-e6, f1-f6, g1-g6, h1-h6, i1-i6, m1-m6 are each independently zero or a positive integer; and
i1-i6, j1-j6 and k1-k6 are each independently selected positive integers.
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Abstract
The present invention is directed to polymeric prodrug transport forms and methods of making and using the same. In one preferred aspect, the prodrugs are of the formula:
wherein
G is a polymeric residue;
Z is one of:
and B is a residue of a biologically active amine-containing moiety or a hydroxyl-containing moiety.
60 Citations
18 Claims
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1. A compound comprising the formula:
-
wherein;
E1-4 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy, and at least one of E1-4 includes a B moiety; B is a leaving group, OH, a residue of a hydroxyl-containing moiety, a residue of an amine-containing moiety or wherein E5 is independently selected from the same group which defines E1-4;
E10-30 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy, wherein B1 is a leaving group, OH, a residue of a hydroxyl-containing moiety or a residue of an amine-containing moiety or wherein E6 is independently selected from the same group which defines E1-4;
wherein E1b-3b 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy, wherein B2 is a leaving group, OH, a residue of a hydroxyl-containing moiety or a residue of an amine-containing moiety; G is a polymeric residue;
Y1-3, Y2a-d and Y3a-d are each independently O, S or NR11a M1-4, M2a-2d, M3a-3d, and M4a-4d are each independently O, S or NR11b;
M5 and M5a-d are each independently X or Q, wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y3) or C(═
Y3a-d);
R1-10, R1a-11a, R1b-11b, R1c-10c and R1d-10d are each 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, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
a, b, c, d1-d6, e1-e6, f1-f6, g1-g6, h1-h6, i1-i6, m1-m6 are each independently zero or a positive integer; and
i1-i6, j1-j6 and k1-k6 are each independently selected positive integers. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18)
wherein a, b, c, R1-2, M1, Y1, E4 and J are the same as set forth in claim 1. -
3. A compound of claim 2, of the formula:
-
4. The compound of claim 1, where a, b, c, d1-d6, e1-e6, f1-f6, g1-g6, h1-h6, l1-l6, and m1-m6 are independently zero, one or two;
- and i1-i6, j1-j6, and k1-k6 are independently one or two.
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5. The compound of claim 1, wherein R1 and R2 are both H, a and c are one, Y1 is O and both and E1 and E4 are H.
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6. The compound of claim 1, wherein G is polyalkylene oxide residue.
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7. The compound of claim 6, wherein G is a polyethylene glycol residue.
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8. The compound of claim 1, wherein G is —
- O—
(CH2CH2O)x or —
O—
(CH(CH3)CH2O)x.wherein x is the degree of polymerization.
- O—
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9. The compound of claim 8, wherein G is —
- O—
(C2CH2O)x and x is a positive integer so that the weight average molecular weight is at least about 20,000 daltons.
- O—
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10. The compound of claim 9, wherein G has a weight average molecular weight of from about 20,000 to about 100,000 daltons.
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11. The compound of claim 10, wherein G has a weight average molecular weight of from about 25,000 to about 60,000 daltons.
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12. The compound of claim 1, wherein B is a residue of an amine-containing moiety.
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13. The compound of claim 12, wherein said amine-containing moiety is
wherein R12-13 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, halo, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls; R14-18 are independently selected from alkoxy, e.g. OR19 or, in the alternative, H, OH, N3, NHR20, NO2 or CN, fluoro, chloro, bromo, iodo, where R19-20 are independently selected from the same group which defines R12-13.
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14. A compound of claim 3, selected from the group consisting of:
-
wherein Z is one of;
-
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17. A method of treatment, comprising:
administering to a mammal in need of such treatment an effective amount of a compound of claim 1, wherein B is a residue of a biologically active moiety.
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18. A method of treatment, comprising:
administering to a mammal in need of such treatment an effective amount of a compound of claim 3, wherein B is a residue of a biologically active moiety.
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15. A method of preparing a polymeric transport system, comprising
a) reacting compound of the formula: -
wherein B is a residue of a biologically active amine-containing moiety or a hydroxyl-containing moiety;
B3 is a cleavable protecting group;
Y3 is O, S, or NR11m;
M3 and M4 are independently O, S, or NR11h;
M5 is X or Q;
wherein X is an electron withdrawing group and Q is a moiety containing a free electron pair positioned three to six atoms from C(═
Y3);
R7-10 and R11u-b 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;
h1, i1, j1, l1 and m1 are each independently zero or a positive integer;
k1 is a positive integer;
b) cleaving the cleavable protecting group B3; and
c) reacting the resultant compound with a compound of the formula wherein H′
1-4 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, C1-6 alkoxy, phenoxy, C1-6 heteroalkoxy,wherein B4 is a leaving group;
G is a polymer residue;
Y1-2 are independently O, S, or NR11a;
M1-2 are independently O, S, or NR11b;
R1-6, R9 and R10 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;
a, b, c, d1-g1 and d2-g2 are each independently zero or a positive integer, whereby a polymeric conjugate is formed.
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16. A method of preparing a polymeric transport system, comprising:
-
reacting a biologically active moiety containing an unprotected amino or hydroxyl group with polymeric residue containing a terminal moiety of the formula;
wherein; Y3 is O, S, or NR11a;
R7-10 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;
M4-5 are independently O, S, or NR11b;
R11a and R11b are independently selected from the group consisting of hydrogen, C1-6alkyls, 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, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy;
B5 is a leaving group capable of reacting with an unprotected amino or hydroxyl group of a biologically active moiety;
i1, j1, l1 and m1 are each independently zero or a positive integer, k1 is a positive integer; and
whereby a polymeric conjugate is formed.
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Specification
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Current AssigneeBelrose Pharma, Inc.
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Original AssigneeEnzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
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InventorsGreenwald, Richard B., Choe, Yun H.
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Primary Examiner(s)Carlson, Karen Cochrane
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Assistant Examiner(s)Desai, Anand U
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Application NumberUS09/823,296Publication NumberTime in Patent Office1,237 DaysField of Search514/8, 514/49, 514/616, 514/43, 536/28.5, 424/9.4, 424/78.17, 564/152, 564/153, 564/159US Class Current530/350CPC Class CodesC08G 73/02 Polyamines
