Polymer conjugates of ara-C and ara-C derivatives
First Claim
Patent Images
1. A compound comprising the formula:
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wherein;
G is a linear or branched, terminally functionalized polymer residue;
Y1 is O, S, or NR1;
M 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(═
Y1);
R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, a C1-6 alkyl, a C3-12 branched alkyl, a C3-8 cycloalkyl, a C1-6 substituted alkyl, a C3-8 substituted cycloalkyl, an aryl, a substituted aryl, an aralkyl, a C1-6 heteroalkyl or a substituted C1-6 heteroalkyl;
R6 is OR7 or N3, NH2, NO2 or CN, where R7 is selected from the same group which defines R1-5;
R8-9 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, or R6; and
a and n are each independently zero or a positive integer.
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Abstract
The present invention is directed to polymeric-prodrug transport forms of the formula:
wherein:
G is a linear or branched, terminally functionalized polymer residue;
Y1 is O, S, or NR1;
M 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(═Y1);
R1-5 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;
R6 is OR7 or N3, NH2, NO2 or CN, where R7 is selected from the same group which defines R1-5;
R8-9 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, or R6; and
a and n are each independently zero or a positive integer.
Methods of forming and methods of treating using the polymeric-prodrug transport forms disclosed herein are also disclosed.
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Citations
19 Claims
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1. A compound comprising the formula:
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wherein; G is a linear or branched, terminally functionalized polymer residue;
Y1 is O, S, or NR1;
M 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(═
Y1);
R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, a C1-6 alkyl, a C3-12 branched alkyl, a C3-8 cycloalkyl, a C1-6 substituted alkyl, a C3-8 substituted cycloalkyl, an aryl, a substituted aryl, an aralkyl, a C1-6 heteroalkyl or a substituted C1-6 heteroalkyl;
R6 is OR7 or N3, NH2, NO2 or CN, where R7 is selected from the same group which defines R1-5;
R8-9 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, or R6; and
a and n are each independently zero or a positive integer. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
wherein x is a positive integer selected so that the number average molecular weight is at least about 20,000 Daltons.
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17. A compound of claim 1, selected from the group consisting of:
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wherein x is a positive integer selected so that the number average molecular weight is at least about 20,000 Daltons.
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18. A method of treating neoplastic disease in mammals comprising administering to a mammal in need of such treatment an effective amount of a composition of claim 1.
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19. A method of preparing polymeric conjugates, comprising reacting a compound selected from the group consisting of:
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wherein R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, a C1-6 alkyl, a C3-12 branched alkyl, a C3-8 cycloalkyl, a C1-6 substituted alkyl, a C3-8 substituted cycloalkyl, an aryl, a substituted aryl, an aralkyl, a C1-6 heteroalkyl or a substituted C1-6 heteroalkyl;
R6 is OR7 or N3, NH2 , NO2 or CN, where R7 is selected from the same group as that which defines R1-5;
R8-9 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, or R6;
with a bis terminally activated polymer of the formula (IV);
wherein G is a linear or branched, terminally functionalized polymer residue;
Y1 is O, S, or NR1;
M 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(═
Y1);
Z is a leaving group; and
a and n are each independently zero or a positive integer, whereby a polymeric conjugate is formed.
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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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InventorsChoe, Yun Hwang, Greenwald, Richard B.
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Primary Examiner(s)Wilson, James O.
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Application NumberUS09/404,075Time in Patent Office943 DaysField of Search514/42, 514/43, 514/44, 514/49, 514/50, 536/27.4, 536/28.1, 536/28.4, 536/28.5US Class Current514/43CPC Class CodesA61K 47/60 the organic macromolecular ...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemia
