Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents

A method for preparing a trialkyl lock based prodrug transport form, comprising:

• a. providing an intermediate compound (III) ##STR18## where M.sub.2 is a cleavable or reversible protecting group
• B is H, OH, OSiR.sub.13 or a residue of an amine-containing target moiety;
• G is ##STR19## or CH.sub.2 ;
• Y.sub.1-2 are independently O or S;
• 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 C(.dbd.Y.sub.2);
• R.sub.1, R.sub.4, R.sub.7, R.sub.8, and R.sub.13 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 and substituted C.sub.1-6 heteroalkyls;
• R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.1-6 alkoxy, phenoxy, C.sub.1-8 heteroalkyls, C.sub.1-8 heteroalkoxy, substituted C.sub.1-6 alkyls, C.sub.3-8 cycloalkyls, C.sub.3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-;
• carboxy-, C.sub.1-6 carboxyalkyls and C.sub.1-6 alkyl carbonyls;
• (n) is zero or a positive integer;
• (p) is zero, one or two;
• and
• b. treating the intermediate compound (III) with an acid;
• and
• c. reacting the unprotected intermediate with a compound capable of reacting with an M and forming a compound of Formula (IV):
• ##STR20## where B.sub.2 is a leaving group;
• R.sub.9, and R.sub.10 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 and substituted C.sub.1-6 heteroalkyls;
• R.sub.11 is a substantially non-antigenic polymer;
• and
• all other variables are as set forth above.

A method for preparing a trialkyl lock based prodrug transport form, comprising:

• a. providing an intermediate compound (III) ##STR21## where M.sub.2 is a cleavable or reversible protecting group
• B is H, OH, OSiR.sub.13 or a residue of an amine-containing target moiety;
• G is ##STR22## or CH.sub.2 ;
• Y.sub.1-2 are independently O or S;
• 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 C(.dbd.Y.sub.2);
• R.sub.1, R.sub.4, R.sub.7, R.sub.8, and R.sub.13 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 and substituted C.sub.1-6 heteroalkyls;
• R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, C.sub.1-6 alkyls, C.sub.1-6 alkoxy, phenoxy, C.sub.1-8 heteroalkyls, C.sub.1-8 heteroalkoxy, substituted C.sub.1-6 alkyls, C.sub.3-8 cycloalkyls, C.sub.3-8 substituted cycloalkyls, aralkyls, aryls, substituted aryls, such as aryls substituted with halo-, nitro- and cyano-;
• carboxy-, C.sub.1-6 carboxyalkyls and C.sub.1-6 alkyl carbonyls;
• (n) is zero or a positive integer;
• (p) is zero, one or two;
• and
• b. coupling the intermediate compound (III) to an amine-containing compound to form a trialkyl lock-based intermediate;
• c. deprotecting the trialkyl lock-based intermediate with an acid;
• and
• d. reacting the unprotected trialkyl lock-based intermediate intermediate with an activated polymer to form a compound of the formula(I):
• ##STR23## R.sub.9, R.sub.10, 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 and substituted C.sub.1-6 heteroalkyls;
• R.sub.11 is a substantially non-antigenic polymer;
• and
• all other variables are as set forth above.