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US 5,672,584 AGranted
Cyclic prodrugs of peptides and peptide nucleic acids having improved metabolic stability and cell membrane permeability
AssigneeUniversity of Kansas
InventorsRonald T. Borchardt, Teruna Siahaan, Sanjeev Gangwar, Valentino J. Stella, Binghe Wang
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Abstract
Provided are cyclic prodrugs of biologically active peptides and peptide nucleic acids exhibiting improved cell membrane permeability and enzymatic stability, containing 3-(2'-hydroxy-4',6'-dimethyl phenyl)-3,3-dimethyl propionic acid and its deriveatives and acyloxyalkoxy linkers. Also provided are pharmaceutical compositions containing effective amounts of these cyclic prodrugs in combination with pharmaceutically acceptable carriers, excipients, or diluents.
Claims5
A cyclic prodrug of a biologically active peptide or peptide nucleic acid, wherein the N-terminal amino group and the C-terminal carboxyl group of said biologically active peptide or peptide nucleic acid are linked via a linker, or
- wherein the C-terminal carboxyl group of said peptide is linked to a side chain amino group or a side chain hydroxyl group via a linker, or
- wherein a side chain carboxyl group of said peptide is linked to a side chain amino group or a side chain hydroxyl group via a linker, and wherein said linker is selected from the group consisting of compounds of the formula:
- ##STR24## wherein R.sub.1 =CH.sub.3, alkyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, phenyl, benzyl, halogen
- R.sub.3 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- R.sub.5 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen;
- ##STR25## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.5 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen,
- Ring B can be aliphatic or aromatic
- n=1,2,3,4 . . . 10
- m=can be 1 or 2 depending if ring B is aliphatic, has double bond(s) or aromatic
- X=O, S, NH, N-alkyl;
- ##STR26## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.3 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen,
- Ring B can be aliphatic or aromatic
- n=1,2,3,4 . . . 10
- m=can be 1 or 2 depending if ring B is aliphatic or contains double bond(s) or aromatic
- X=O, S, NH, N-alkyl;
- ##STR27## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.3 =CH.sub.3, alkyl, alkenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- Ring B can be aliphatic or aromatic
- n=1,2,3,4 . . . 10
- m=can be 1 or 2 depending if ring B is aliphatic or contains double bond(s) or aromatic;
- ##STR28## wherein R.sub.3 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- R.sub.5 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- n=1,2,3,4 . . . 10;
- ##STR29## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.3 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- R.sub.5 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen;
- ##STR30## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- R.sub.5 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen;
- ##STR31## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.3 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- R.sub.5 =H, CH.sub.3, alkyl, phenyl, benzyl, halogen
- R.sub.6 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen;
- ##STR32## wherein R.sub.1 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.2 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.3 =CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.4 =OH, H, NO.sub.2
- R.sub.5 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen
- R.sub.6 H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl, halogen;
- ##STR33## wherein R.sub.2 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl
- R.sub.3 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl;
- ##STR34## wherein n=0, 1, . . . 15
- Y=S, O
- Z=S, O;
- and ##STR35## wherein R.sub.2 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl
- R.sub.3 =H, CH.sub.3, alkyl, alkenyl, phenyl, benzyl,
- Y=S, O
- Z=S, O.
66 more elements
Dependencies are inferred from the claim text.