Dipeptide linked medicinal agents
AssigneeIndiana University Research and Technology Corporation
InventorRichard D. DiMarchi
Life of this patent
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Abstract
A non-enzymatically self cleaving dipeptide element is provided that can be linked to known medicinal agents via an amide bond. The dipeptide will spontaneously be cleaved from the medicinal agent under physiological conditions through a reaction driven by chemical instability. Accordingly, the dipeptide element provides a means of linking various compounds to known medicinal agents wherein the compounds are subsequently released from the medicinal agent after a predetermined time of exposure to physiological conditions. For example, the dipeptide can be linked to an active site of a drug to form a prodrug and/or the dipeptide may comprise a depot polymer to sequester an injectable composition comprising the complex at the point of administration.
Claims62
A non-enzymatic self cleaving moiety covalently bound to a medicinal agent, said self cleaving moiety comprising the general structure
- A-B—;
- wherein
- A is an amino acid or a hydroxyl acid;
- B is an N-alkylated amino acid;
- wherein said self cleaving moiety is linked to said medicinal agent through formation of an amide bond between B and an amine of said medicinal agent, wherein the chemical cleavage half life (t1/2) of A-B from said medicinal agent is at least about 1 hour to about 1 week in standard PBS solution under physiological conditions.
A prodrug comprising the structure:
- A-B-Q;
- wherein Q is a medicinal agent;
- A is an amino acid or a hydroxyl acid;
- B is an N-alkylated amino acid;
- and A-B is a dipeptide that is linked to Q through formation of an amide bond between B and an amine of Q, wherein chemical cleavage half life (t1/2) of A-B from Q is at least about 1 hour to about 1 week in standard PBS solution under physiological conditions and wherein said prodrug has only 10% or less activity relative to free Q.
A prodrug comprising the structure
- wherein
- R1, R2, R4 and R8 are independently selected from the group consisting of H, C1-C18 alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or aryl;
- or R4 and R8 together with the atoms to which they are attached form a C3-C6 cycloalkyl;
- R3 is selected from the group consisting of C1-C18 alkyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)NH2, (C1-C18 alkyl)SH, (C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, and (C1-C4 alkyl)(C3-C9 heteroaryl) or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
- R5 is NHR6 or OH;
- R6 is H, C1-C8 alkyl or R6 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
- R7 is selected from the group consisting of H and OH;
- R15 and R16 are independently selected from hydrogen and iodine.
A prodrug comprising the structure
- wherein R1, R2, R4 and R8 are independently selected from the group consisting of H, C1-C18 alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl;
- or R4 and R8 together with the atoms to which they are attached form a C3-C6 cycloalkyl;
- R3 is selected from the group consisting of C1-C18 alkyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)NH2, (C1-C18 alkyl)SH, (C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, and (C1-C4 alkyl)(C3-C9 heteroaryl) or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
- R5 is NHR6 or OH;
- R6 is H, C1-C8 alkyl or R6 and R1 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, C1-C18 alkyl, C2-C18 alkenyl, (C0-C4 alkyl)CONH2, (C0-C4 alkyl)COOH, (C0-C4 alkyl)NH2, (C0-C4 alkyl)OH, and halo;
- and
- R15 and R16 are independently selected from hydrogen and iodine.
The prodrug of any of the preceding claims, wherein A is an amino acid in the D-stereochemical configuration.
Dependencies are inferred from the claim text.