Polyal drug conjugates comprising variable rate-releasing linkers

A conjugate of the Formula (II):

• wherein
• X is —CH2—, —OCH2—, or —CH2CH2—, wherein one or more of the CH2 is optionally substituted;
• R1 is H or CH3;
• R2 is —CH(Y)—C(O)—, wherein Y is a non-hydrogen side chain of a naturally occurring amino acid;
• or Tether is alanine, β-alanine, sarcosine, or proline;
• Polyal is a polyacetal or polyketal;
• Drug is any organic compound with a molecular weight of between about 200 daltons and 1000 daltons, capable of covalent attachment to Tether;
• wherein
• when Linker is a dicarboxylic acid with two atoms between the carbonyls and Tether contains a nitrogen with no reactive hydrogen, the release half-life of Drug is from about 10 h to more than about 300 h;
• when Linker is a dicarboxylic acid with at least three atoms between the carbonyls and contains a heteroatom alpha to the carbonyl forming the ester, the release half-life is less than about 10 hours;
• when Linker is a dicarboxylic acid with at least three atoms between the carbonyls with no heteroatom alpha to the carbonyl forming the ester, the release half-life is more than about 100 hours;
• when Linker is a dicarboxylic acid with two atoms between the carbonyls and Tether contains a nitrogen with a reactive hydrogen, the release half-life of Drug is from about 0.1 hours to about 24 hours;
• and
• wherein
• the release half-life being measured in 0.05M phosphate buffer, 0.9% saline, pH 7.4, at 37° C.

A conjugate of the Formula (III):

• or a pharmaceutically acceptable salt thereof;
• wherein
• Polyal is a polyacetal or polyketal;
• X is —CH2—, —OCH2—, or —CH2CH2—, wherein one or more of —CH2— is optionally substituted;
• R1 is H or CH3;
• R2 is —CH(Y)—C(O)—, wherein Y is a non-hydrogen side chain of a naturally occurring amino acid or —NR1R2— is alanine, β-alanine, sarcosine, or proline;
• R7 is —CH3 or —CHO;
• and
• R8 is —OCOCH3 or OH.

A conjugate of the Formula (IV):

• or a pharmaceutically acceptable salt;
• wherein
• Polyal is a polyacetal or polyketal;
• X is —CH2—, —OCH2—, or —CH2CH2—, wherein one or more of —CH2— is optionally substituted;
• R1 is H or CH3;
• R2 is —CH(Y)—C(O)—, wherein Y is a non-hydrogen side chain of a naturally occurring amino acid;
• or —NR1R2— is alanine, β-alanine, sarcosine, or proline;
• R3 is —H, —Cl, —F, —OH or alkyl;
• or R3 and R4, may be taken together to form a five- or six-membered ring;
• R4 is —H, —F, —OH, —CH3, —CH═N—O-t-Butyl, —CH2CH2Si(CH3)3, or —Si((CH3)2)-t-Butyl;
• R5 is —CH2—N(CH3)2, NH2, or NO2;
• R6 is ethyl, N-methyl piperidine, cycloalkyl, —CH2CH2NHCH(CH3)2, or —N-4-methylcyclohexylamine;
• or R5 and R6, may be taken together to form a six-membered optionally substituted ring;
• p is 0 or 1;
• and
• q is 0 or 1.

A pharmaceutical composition comprising a conjugate of the Formula (III):

• or a pharmaceutically acceptable salt thereof;
• wherein
• Polyal is a polyacetal or polyketal;
• X is —CH2—, —OCH2—, or —CH2CH2—, wherein one or more of —CH2— is optionally substituted;
• R1 is H or CH3;
• R2 is —CH(Y)—C(O)—, wherein Y is a non-hydrogen side chain of a naturally occurring amino acid;
• or —NR1R2— is alanine, β-alanine, sarcosine, or proline;
• R7 is —CH3 or —CHO;
• and
• R8 is —OCOCH3 or OH;
• and a pharmaceutically acceptable carrier.

A pharmaceutical composition comprising a conjugate of Formula (IV):

• or a pharmaceutically acceptable salt;
• wherein
• Polyal is a polyacetal or polyketal;
• X is —CH2—, —OCH2—, or —CH2CH2—, wherein one or more of —CH2— is optionally substituted;
• R1 is H or CH3;
• R2 is —CH(Y)—C(O)—, wherein Y is a non-hydrogen side chain of a naturally occurring amino acid;
• or —NR1R2— is alanine, β-alanine, sarcosine, or proline;
• R3 is —H, —Cl, —F, —OH or alkyl;
• or R3 and R4, may be taken together to form a five- or six-membered ring;
• R4 is —H, —F, —OH, —CH3, —CH═N—O-t-Butyl, —CH2CH2Si(CH3)3, or —Si((CH3)2)-t-Butyl;
• R5 is —CH2—N(CH3)2, NH2, or NO2;
• R6 is ethyl, N-methyl piperidine, cycloalkyl, —CH2CH2NHCH(CH3)2, or —N-4-methylcyclohexylamine;
• or R5 and R6, may be taken together to form a six-membered optionally substituted ring;
• p is 0 or 1;
• and
• q is 0 or 1;
• and a pharmaceutically acceptable carrier.