Inhibitors of trypsin-like enzymes

• US 5,856,306 A
• Filed: 06/02/1995
• Issued: 01/05/1999
• Est. Priority Date: 04/28/1988
• Status: Expired due to Fees

• Current Assignee: Thrombosis Research Institute
• Original Assignee: Trigen Limited
• Inventors: Metternich, Rainer, Claeson, Goran, Philipp, Manfred Hans Wilhelm
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): CELSA, BENNETT M
• Application Number:
  US08/459,177
• Time in Patent Office: 1,313 Days
• Field of Search: 530/328, 530/329, 530/330, 530/331, 514/15, 514/16, 514/17, 514/18, 514/19
• US Class Current: 514/13.7
• 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: 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
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Pharmaceutical compositions comprising compounds of the formula: ##STR1## in which X═H or is an N-protecting group; Y is 1-10 α-amino acids; Q1 and Q2 taken together represent the residue or a diol; R is C_1-4 alkyl; and the asymmetric carbon atom marked * may have the D- or L-configuration, are useful in therapeutic methods of inhibiting thrombin.

Claims

1. A method of inhibiting thrombin in the treatment of disease comprising administering to a mammal a therapeutically effective amount of a compound of the formula:

##STR19## in which X═

H or is an N-protecting group;

Y is a sequence of 2-10 α

-amino acids, wherein D-Phe-Pro is attached to --NH;

Q1 and Q2 taken together represent the residue of a diol;

R is C_1-4 alkyl; and

the asymmetric carbon atom marked * may have the D- or L- configuration, wherein the compound has affinity for the active site of thrombin.

2. The method of claim 1 wherein Y is a sequence of 2-4 α

-amino acids.

3. The method of claim 1 wherein Q₁ and Q₂ together represent 2,3-dimethylbutandiol-2,3.

4. The method of claim 1 wherein Q₁ and Q₂ together represent OPin.

5. The method of claim 1 wherein X is benzyloxycarbonyl.

6. The method of claim 1 wherein R is CH₃.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the formula:

##STR20## in which X═

H or is an N-protecting group;

Y is a sequence of 1-10 α

-amino acids;

Q1 and Q2 taken together represent the residue of a diol;

R is C_1-4 alkyl; and

the asymmetric carbon atom marked * may have the D- or L- configuration, wherein the compound has affinity for the active site of thrombin.

8. The pharmaceutical composition of claim 7 wherein Y is a sequence of 2-4 α

-amino acids.

9. The pharmaceutical composition of claim 7 wherein Q₁ and Q₂ together represent 2,3-dimethylbutandiol-2,3.

10. The pharmaceutical composition of claim 7 wherein Q₁ and Q₂ together represent OPin.

11. The pharmaceutical composition of claim 7 wherein X is benzyloxycarbonyl.

12. The pharmaceutical composition of claim 7 wherein R is CH₃.