Dipeptide linked medicinal agents

Patent metadata

Field	Value
Publication number	US-2016158375-A1
Application number	US-201615016959-A
Country	US
Kind code	A1
Filing date	Feb 5, 2016
Priority date	Jun 24, 2010
Publication date	Jun 9, 2016
Grant date	—

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.

First claim

What is claimed:

1 . A prodrug comprising the structure:
A-B-Q; wherein Q is an amine bearing medicinal agent, A is an amino acid and B is an N-alkylated amino acid; wherein A-B comprises the structure:

wherein
R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 18 alkyl, C 2 -C 18 alkenyl, (C 1 -C 18 alkyl)OH, (C 1 -C 18 alkyl)SH, (C 2 -C 3 alkyl)SCH 3 , (C 1 -C 4 alkyl)CONH 2 , (C 1 -C 4 alkyl)COOH, (C 1 -C 4 alkyl)NH 2 , (C 1 -C 4 alkyl)NHC(NH 2 + )NH 2 , (C 0 -C 4 alkyl)(C 3 -C 6 cycloalkyl), (C 0 -C 4 alkyl)(C 2 -C 5 heterocyclic), (C 0 -C 4 alkyl)(C 6 -C 10 aryl)R 7 , (C 1 -C 4 alkyl)(C 3 -C 9 heteroaryl), and C 1 -C 12 alkyl(W 1 )C 1 -C 12 alkyl, wherein W 1 is a heteroatom selected from the group consisting of N, S and O, or R 1 and R 2 together with the atoms to which they are attached form a C 3 -C 12 cycloalkyl;
R 3 is C 1 -C 18 alkyl;
R 4 is H, C 1 -C 4 alkyl, or (C 1 -C 4 alkyl)NH 2 ;
R 5 is NH 2 ;
R 8 is H; and,
R 7 is selected from the group consisting of H and OH;
wherein A-B is linked to Q through an amide bond between A-B and an aliphatic amino group of Q;
wherein the chemical cleavage half-life (t 1/2 ) of A-B from Q is at least about 1 hour to about 1 week in PBS under physiological conditions;
with the proviso that when both R 1 and R 2 are H, R 3 is C 5 -C 18 alkyl;

2 . The prodrug of claim 1 , wherein B is selected from the group consisting of glycine(N-methyl), glycine(N-ethyl), glycine(N-propyl), glycine(N-butyl), glycine(N-pentyl), glycine(N-hexyl), glycine(N-heptyl), and glycine(N-octyl).

3 . The prodrug of claim 2 wherein
R 1 is H or C 1 -C 8 alkyl; and
R 2 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 OH, (C 1 -C 4 alkyl)NH 2 , and CH 2 (C 6 aryl)R 7 .

4 . The prodrug of claim 2 wherein
R 1 is H;
R 2 is (C 1 -C 4 alkyl)NH 2 .

5 . The prodrug of claim 1 wherein A-B is glycine-glycine(N-hexyl).

6 . The prodrug of claim 1 , wherein A has d-stereochemistry.

7 . The prodrug of claim 1 , wherein A-B is selected from the group consisting of dLys-Gly(N-Hexyl), dCys-Gly(N-Hexyl), dLys-Gly(N-Methyl), dCys-Gly(N-Methyl), dAla-Gly(N-Hexyl), dLys-Phe(N-Methyl), or dCys-Phe(N-Methyl).

8 . A prodrug comprising the structure:
A-B-Q; wherein Q is an amine bearing medicinal agent, A is an amino acid and B is an N-alkylated amino acid; wherein A-B comprises the structure:

wherein
R 1 is C 1 -C 8 alkyl;
R 2 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 OH, (C 1 -C 4 alkyl)NH 2 , and CH 2 (C 6 aryl)R 7 ,
R 3 and R 4 together with the atoms to which they are attached form a pyrrolidine ring;
R 5 is NH 2 ;
R 8 is H; and,
R 7 is selected from the group consisting of H and OH; wherein the chemical cleavage half-life (t 1/2 ) of A-B from Q is at least about 1 hour to about 1 week in PBS under physiological conditions.

9 . The prodrug of claim 8 , wherein A is aminoisobutyric acid.

10 . The prodrug of claim 1 , further comprising a hydrophilic moiety covalently linked to the prodrug.

11 . The prodrug of claim 1 , further comprising an acyl group or alkyl group covalently linked to the prodrug.

12 . A prodrug comprising the structure of Formula II;

wherein
R 1 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 2 and R 4 are independently selected from the group consisting of H, C 1 -C 8 alkyl, and (C 1 -C 4 alkyl)NH 2 ;
R 3 is C 1 -C 6 alkyl, or R 4 and R 3 together with the atoms to which they are attached form a pyrrolidine ring;
R 5 is NH 2 ;
R 7 is selected from the group consisting of H and OH; and
R 8 is H, with the proviso that when R 4 and R 3 together with the atoms to which they are attached form a pyrrolidine ring, both R 1 and R 2 are other than H, and
R 15 and R 16 are independently selected from hydrogen and iodine.

13 . The complex of claim 12 wherein
R 1 is H;
R 2 is (C 1 -C 4 alkyl)NH 2 ;
R 3 is C 1 -C 8 alkyl;
R 4 and R 8 are each hydrogen; and
R 5 is an NH 2 .

14 . The complex of claim 12 wherein
R 1 and R 2 are each CH 3 ;
R 3 and R 4 together with the atoms to which they are attached form a pyrrolidine ring;
R 8 is H; and
R 5 is an NH 2 .

Assignees

• Univ Indiana Res & Tech Corp

Inventors

• Dimarchi Richard D

Classifications

• C07K5/0606

  the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title

• C07K5/06113

  Asp- or Asn-amino acid · CPC title

• C07K5/06165

  and Pro-amino acid; Derivatives thereof · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title