Amino acids containing dihydropyridine ring systems for site-specific delivery of peptides to the brain

• US 4,888,427 A
• Filed: 04/07/1987
• Issued: 12/19/1989
• Est. Priority Date: 04/07/1987
• Status: Expired due to Term

• Current Assignee: Rodob Drug Research Inc.
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Bodor, Nicholas S.
• Primary Examiner(s): Fan, Jane T.
• Application Number:
  US07/035,648
• Time in Patent Office: 987 Days
• Field of Search: 546/316, 546/287, 546/286, 546/288, 546/321, 546/318, 546/323, 546/328, 546/335
• US Class Current: 546/316
• CPC Class Codes: A61K 38/00 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 Class Codes: A61K 47/559 Redox delivery systems, e.g. dihydropyridine pyridinium salt redox systems
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07D 211/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 215/20 Oxygen atoms
• CPC Class Codes: C07D 215/233 only one oxygen atom which is attached in position 4
• CPC Class Codes: C07D 215/48 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06086 with the first amino acid being basic
• CPC Class Codes: C07K 5/06139 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0815 with the first amino acid being basic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

The invention provides novel amino acids and peptides containing them which comprise a dihydropyridine⃡pyridinium salt-type redox system and which provide site-specific and sustained delivery of pharmacologically active peptides to the brain. These new amino acids contain a redox system appended directly or via an alkylene bridge to the carbon atom adjacent to the carboxyl carbon and may be incorporated into a peptide chain at a variety of positions, including non-terminal positions.

Claims

1. A compound of the formula ##STR140## or a non-toxic pharmaceutically acceptable salt thereof, wherein Z is either a direct bond or C₁ -C₆ alkylene and can be attached to the heterocyclic ring via a ring carbon atom or via the ring nitrogen atom;

R₁ is C₁ -C₇ alkyl, C₁ -C₇ haloalkyl or C₇ -C₁₂ aralkyl when Z is attached to a ring carbon atom;

R₁ is a direct bond when Z is attached to the ring nitrogen atom;

R₂ and R₃, which can be the same or different, are selected from the group consisting of hydrogen, halo, cyano, C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₂ -C₈ alkoxycarbonyl, C₂ -C₈ alkanoyloxy, C₁ -C₇ haloalkyl, C₁ -C₇ alkylthio, C₁ -C₇ alkylsulfinyl, C₁ -C₇ alkylsulfonyl, --CH═

NOR'"'"'" wherein R'"'"'" is hydrogen or C₁ -C₇ alkyl, and --CONR'"'"'R" wherein R'"'"' and R", which can be the same or different, are each hydrogen or C₁ -C₇ alkyl;

R₄ is hydrogen or a carboxyl protective group and R₅ is hydrogen or an amino protective group, said carboxyl protective group and said amino protective group being designed to protect the carboxyl and amino functions during synthesis or to improve lipoidal characteristics and prevent premature metabolism of said functions in vivo; and

the dotted lines indicate that the compound of formula (I) contains a 1,4- or 1,6-dihydropyridine ring system.

2. A compound according to claim 1 wherein Z is --CH₂ --.

3. A compound according to claim 1 wherein Z is --(CH₂)₄ --.

4. A compound according to claim 1 wherein R₁ is a direct bond and Z is attached to the ring nitrogen atom.

5. A compound according to claim 4 wherein one of R₂ and R₃ is hydrogen.

6. A compound according to claim 5 wherein the other of R₂ and R₃ is --CONH₂.

7. A compound according to claim 1 wherein R₁ is methyl.

8. A compound according to claim 1 wherein Z is attached to a ring carbon atom.

9. A compound according to claim 8 wherein R₁ is methyl.

10. A compound according to claim 8 wherein at least one of R₂ and R₃ is hydrogen.

11. A compound according to claim 10 wherein both R₂ and R₃ are hydrogen.

12. A compound according to claim 1 wherein R₄ is a carboxyl protective group.

13. A compound according to claim 1 wherein R₅ is an amino protective group.

14. A compound according to claim 1 containing a 1,4-dihydropyridine ring system.

15. A compound according to claim 1 containing a 1,6-dihydropyridine ring system.

16. A compound according to claim 1 wherein ##STR141##

17. A compound according to claim 1 wherein ##STR142##

18. A compound according to claim 1 wherein ##STR143##

19. A compound according to claim 1 wherein ##STR144##

20. A compound according to claim 1 having the formula ##STR145##