.alpha.-Aminoboronic acid peptides

• US 4,499,082 A
• Filed: 12/05/1983
• Issued: 02/12/1985
• Est. Priority Date: 12/05/1983
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Inventors: Kettner, Charles A., Shenvi, Ashokkumar B.
• Primary Examiner(s): NOT, DEFINED
• Application Number:
  US06/558,362
• Time in Patent Office: 435 Days
• Field of Search: 424/263, 424/177, 260/112.5 R
• US Class Current: 514/20.4
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N

Abstract

Peptides comprising C-terminal α-aminoboronic acid residues are potent, reversible inhibitors of proteolytic enzymes.

Claims

1. A compound of the formula ##STR16## or a physiologically acceptable salt thereof, wherein A¹ is an amino acid of L-configuration selected from the group consisting of Ala, Pro, Gly, Glu, Leu, Lys, Phe, Ser, Val, Ile, Arg, Tyr, Thr, Asp, Asn or Gln;

A² and A³ are, independently, amino acids of D or L-configuration selected from the group consisting of Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val;

n is 1 and o is 0 or 1;

R¹ is --H or an N-terminal protecting group;

R² is an alkyl group of one to six carbons, optionally comprising an aromatic substituent, or one or more in-chain bivalent groups selected from the group consisting of --O--, --CO--, --S--, --NH--, --CONH--, --CH═

CH-- or --SO₂ --; and

Y¹ and Y² are each --H, or taken together form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms, and optionally, a heteroatom or heteroatoms which can be N, S, or O;

with the proviso that where is O, R¹ cannot be --H.

2. A compound according to claim 1 wherein A¹ is Ala, Pro, Gly, Glu, Leu, Lys, Phe or Ser;

and o is 1.

3. A compound according to claim 2 wherein R² is ##STR17##

4. A compound according to claim 3 wherein R¹ is MeOSuc, Suc, Boc, Z, Ac or Bz.

5. A compound according to claim 4 wherein Y¹ and Y² are each --H, or a moiety derived from pinacol or diethanolamine.

6. A compound according to claim 5 wherein A¹ is Pro, Ala, Leu, Lys, Gly or Ser.

7. A compound according to claim 6 wherein A² and A³ are, independently, Ala, Pro, Gly, Phe, or Lys.

8. A compound according to claim 7 wherein A¹ is Pro;

and A² and A³ are each Ala.

9. A compound according to claim 8 wherein R² is --CH(CH₃)₂.

10. A compound according to claim 8 wherein R² is --CH₃.

11. A compound according to claim 8 wherein R² is --CH₂ CH(CH₃)₂.

12. A compound according to claim 8 wherein R² is --CH(CH₃)CH₂ CH₃.

13. A compound according to claim 8 wherein R² is ##STR18##

14. A compound according to claim 9 wherein R¹ is MeOSuc.

15. A compound according to claim 14 wherein Y¹ and Y² are each --H.

16. A composition for inhibiting proteolysis in a mammal, comprising an amount of a compound of claim 1 effective to inhibit proteolysis, and a physiologically acceptable carrier or diluent.

17. A composition for inhibiting proteolysis in a mammal, comprising an amount of a compound of claim 3 effective to inhibit proteolysis, and a physiologically acceptable carrier or diluent.

18. A method of inhibiting proteolysis in a mammal, comprising administering to the mammal a composition of claim 16.

19. A method of inhibiting proteolysis in a mammal, comprising administering to the mammal a composition of claim 17.