Polyal Drug Conjugates Comprising Variable Rate-Releasing Linkers

Conjugates 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 one of the side chains of the naturally occurring amino acids, an aryl group, a heteroaryl group, a cycloalkyl, an alkyl group attached to both the N—R1 and the Drug, or a heterocycle;
• or R1 and R2 when taken together with nitrogen to which they are attached form a ring;
• 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 the 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;
• wherein
• the release half-life being measured in 0.05M phosphate buffer, 0.9% saline, pH 7.4, at 37° C.;
• with the proviso that the conjugate of Formula II is not PHF-SA-Gly-CPT, PHF-(methyl)SA-Gly-CPT, PHF-(2,2-dimethyl)SA-Gly-CPT, PHF-(2-nonen-2-yl)SA-Gly-CPT, PHF-SA-Gly-Taxol, or PHF-SA-Gly-Illudin.

A method of identifying a Polyal-Drug conjugate having a drug release half-life of between less than about 1 hour and greater than 300 hours as measured in PBS buffer at 37° C., the method comprising:

• selecting a dicarboxylic acid linker;
• obtaining a conjugate with said linker the conjugate comprising a polyal, a Drug, and said linker;
• and
• determining the release half-life of Drug from the conjugate.

Conjugates of the Formula III:

• and pharmaceutically acceptable salts thereof;
• wherein
• Polyal is a polyacetal or polyketal derived from cyclodextran;
• 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 one of the side chains of the naturally occurring amino acids, an aryl group, a heteroaryl group, a cycloalkyl, an alkyl group attached to both the N—R1 and the —NHC(O)— of the vinca alkaloid derivative, or a heterocycle;
• or R1 and R2, when taken together with nitrogen to which they are attached, form a ring;
• R7 is —CH3 or —CHO;
• and
• R8 is —OCOCH3 or OH.

Conjugates of the Formula IV:

• and pharmaceutically acceptable salts 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 one of the side chains of the naturally occurring amino acids, an aryl group, a heteroaryl group, a cycloalkyl, an alkyl group attached to both the N—R1 and the —O— of the non-natural camptothecin derivative, or a heterocycle;
• or R1 and R2 when taken together with nitrogen to which they are attached form a ring;
• 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;
• with the proviso that the conjugate is not PHF-SA-Gly-CPT, PHF-(methyl)SA-Gly-CPT, PHF-(2,2-dimethyl)SA-Gly-CPT, or PHF-(2-nonen-2-yl)SA-Gly-CPT.

A pharmaceutical composition comprising a conjugate of the Formula III:

• or a pharmaceutically acceptable salts 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 one of the side chains of the naturally occurring amino acids, an aryl group, a heteroaryl group, a cycloalkyl, an alkyl group attached to both the N—R1 and the —NHC(O)— of the vinca alkaloid derivative, or a heterocycle;
• or R1 and R2, when taken together with nitrogen to which they are attached, form a ring;
• 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:

• and pharmaceutically acceptable salts 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 one of the side chains of the naturally occurring amino acids, an aryl group, a heteroaryl group, a cycloalkyl, an alkyl group attached to both the N—R1 and the —O— of the non-natural camptothecin derivative, or a heterocycle;
• or R1 and R2 when taken together with nitrogen to which they are attached form a ring;
• 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;
• with the proviso that the conjugate is not PHF-SA-Gly-CPT, PHF-(methyl)SA-Gly-CPT, PHF-(2,2-dimethyl)SA-Gly-CPT, or PHF-(2-nonen-2-yl)SA-Gly-CPT.