 Method of treatment of parkinson's disease |
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| 4-aminoethoxy indolone derivatives |
| What is claimed is: 1. A compound of the formula I: ##STR5## in which: Y is hydrogen, halogen or ... |
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| Genetically engineered cells that produce produce L. Dopa |
| In one aspect, the present invention provides a process of increasing the production of dopamine in ... |
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| C. elegans deletion mutants |
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| Feline hepatocyte growth factor |
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| ppRB.sup.110 -phosphoprotein the retinoblastoma susceptibility gene product |
| OF FIGURES FIG. 1 is the chromatogram illustrating the identification of RB proteins by ... |
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| Mutants of the RB and P53 genes |
| OF THE INVENTION Definitions The term "functional expression of the gene" meant to include the ... |
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| Oncolytic virus therapy |
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| Covalently cross-linked oligonucleotides |
| OF THE INVENTION In accordance with the objects of this invention novel, covalently cross-linked ... |
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Terminally-branched polymeric linkers and polymeric conjugates containing the same
| Details |
Inventors: Martinez, Anthony J.; Pendri, Annapurna; Greenwald, Richard B.; Choe, Yun H.;
Assignee: Enzon, Inc. (Piscataway, NJ)
Primary Examiner: Page; Thurman K.
Assistant Examiner: Fubara; Blessing M.
Attorney, Agent or Firm: Roberts & Mercanti, LLP
The present invention is directed to polymeric-prodrug transport forms of the formula: ##STR1## wherein: ##STR2## E.sub.1-4 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.3-12 branched alkyls, C.sub.3-8 cycloalkyls, C.sub.1-6 substituted alkyls, C.sub.3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.sub.1-6 heteroalkyls, substituted C.sub.1-6 heteroalkyls, C.sub.1-6 alkoxy, phenoxy, C.sub.1-6 heteroalkoxy, ##STR3## and at least one of E.sub.1-4 includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl-or amino-containing moiety or ##STR4## wherein J.sub.1 is the same as J, or another member of the group defining J and E.sub.5 is the same as E.sub.1-4, or another member of the group defining E.sub.1-4 ; Y.sub.1-2 are independently O, S or NR.sub.9 ; M is a heteroatom selected from either 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(=Y.sub.2); R.sub.2-5 and R.sub.7-9 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.3-12 branched alkyls, C.sub.3-8 cycloalkyls, C.sub.1-6 substituted alkyls, C.sub.3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.sub.1-16 heteroalkyls, substituted C.sub.1-6 heteroalkyls, C.sub.1-6 alkoxy, phenoxy and C.sub.1-6 heteroalkoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer, Z is an electron withdrawing group; and R.sub.1 is a polymeric residue. which is optionally capped with a moiety of the formula: ##STR5## |
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DETAILED DESCRIPTION In one aspect of the invention, compounds of Formula (I) are provided: ##STR6## wherein: J is ##STR7## E.
sub.
1-4 are independently selected from the group consisting of hydrogen, C.
sub.
1-6 alkyls, C.
sub.
3-12 branched alkyls, C.
sub.
3-8 cycloalkyls, C.
sub.
1-6 substituted alkyls, C.
sub.
3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.
sub.
1-6 heteroalkyls, substituted C.
sub.
1-6 heteroalkyls, C.
sub.
1-6 alkoxy, phenoxy, C.
sub.
1-6 heteroalkoxy, ##STR8## and at least one of E.
sub.
1-4 includes a B moiety, wherein B is a leaving group, OH, a residue of a hydroxyl- or amine- containing moiety or ##STR9## wherein J.
sub.
1 is the same as J, or another member of the group defining J and E.
sub.
5 is the same as E.
sub.
1-4, or another member of the group defining E.
sub.
1-4 ; Y.
sub.
1-2 are independently O or S; M is a heteroatom selected from either 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(=Y.
sub.
2); R.
sub.
2-5 and R.
sub.
7-8 are independently selected from the group consisting of hydrogen, C.
sub.
1-6 alkyls, C.
sub.
3-12 branched alkyls, C.
sub.
3-8 cycloalkyls, C.
sub.
1-6 substituted alkyls, C.
sub.
3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C.
sub.
1-6 heteroalkyls, substituted C.
sub.
1-6 heteroalkyls, C.
sub.
1-6 alkoxy, phenoxy and C.
sub.
1-6 heteroakoxy; (m1) and (m2) are independently zero or one; (n1), (n2), (p1), (p2) and (q) are independently zero or a positive integer; Z is an electron withdrawing group; and R.
sub.
1 is a polymeric residue such as a water-soluble polyalkylene oxide, preferably having a molecular weight of at least about 20,000 Daltons.
In preferred aspects of the invention, the polymeric residue is also substituted on the distal portion with another branching group to provide compounds of the formula (I'): ##STR10## where all variables are as previously defined.
The bifunctional compounds are thus formed when the polymeric residue (R.
sub.
1) includes both an alpha and an omega terminal linking group so that two, four or more equivalents of a biologically active agent, drug or protein, designated herein as B, can be delivered
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Gene Therapy 
