Peptide derivatives usable as zinc endopeptidase 24-15 inhibitors

• US 5,776,903 A
• Filed: 01/24/1996
• Issued: 07/07/1998
• Est. Priority Date: 02/06/1995
• Status: Expired due to Fees

• Current Assignee: Commissariat a L'Energie Atomique (AES Corporation)
• Original Assignee: Commissariat a L'Energie Atomique (AES Corporation)
• Inventors: Dive, Vincent, Jiracek, Jiri, Yiotakis, Athanasios
• Primary Examiner(s): Achutamurthy, Ponnathapura
• Assistant Examiner(s): WESSENDORF, TERESA D
• Application Number:
  US08/590,483
• Time in Patent Office: 895 Days
• Field of Search: 514/7, 514/18, 530/330, 530/304, 530/302, 530/300, 435/212
• US Class Current: 514/20.1
• 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 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 5/0207 containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids

Abstract

Peptide derivatives usable as zinc endopeptidase 24-15 inhibitors.

These peptide derivatives have the following amino acid sequence:

-Pheψ(PO.sub.2 CH.sub.2)-.sub.(L,D) Xaa'"'"'-Yaa'"'"'-Zaa'"'"'-

in which ψ(PO₂ CH₂) indicates that the peptide bond (CONH) has been replaced by the phosphine bond (PO₂ CH₂), Xaa'"'"' and Zaa'"'"', which can be the same or different, in each case represent a natural amino acid or an amino pseudo-acid and Yaa'"'"' represents Arg or Lys.

As examples of such derivatives, reference can be made to those of formula:

Z-.sub.(L,D) Pheψ(PO.sub.2 CH.sub.2)-.sub.(L,D) -Gly-Arg-MetOH

Z-.sub.(L,D) Pheψ(PO.sub.2 CH.sub.2)-.sub.(L,D) -Ala-Arg-MetOH

Z-.sub.(L,D) Pheψ(PO.sub.2 CH.sub.2)-.sub.(L,D) -Ala-Arg-PheOH

with Z representing the benzyloxycarbonyl group.

Claims

1. Peptide derivative according to the formula:

space="preserve" listing-type="equation">Z-.sub.(L,D) Pheψ

(PO.sub.2 CH.sub.2)-.sub.(L,D) Xaa'"'"'Lys Zaa'"'"'OR.sup.1 (II)

in which

Z represents the benzyloxycarbonyl group,

ψ

(PO₂ CH₂) indicates that the peptide bond (CO--NH) has been replaced by the phosphine bond (PO₂ --CH₂),

Xaa'"'"' represents Gly, Ala or Leu,

Zaa'"'"' represents Met, Nle, Phe, Leu or Ile, and

R¹ represents a hydrogen atom, NH₄⁺ or a pharmaceutically acceptable metal.

2. Peptide derivative according to claim 1, characterized in that Xaa'"'"' represents Ala, Zaa'"'"' represents Met and R¹ represents a hydrogen atom.

3. Peptide derivative of formula

4. Peptide derivative of formula

5. A pharmaceutical composition which inhibits endopeptidase 24-15, consisting essentially of a pharmaceutically effective quantity of a peptide derivative having the formula:

space="preserve" listing-type="equation">Z-.sub.(L,D) Pheψ

(PO.sub.2 CH.sub.2)-.sub.(L,D) Xaa'"'"' Lys Zaa'"'"'OR.sub.1(II),

or

space="preserve" listing-type="equation">Z-.sub.(L,D) Pheψ

(PO.sub.2 CH.sub.2)-.sub.(L,D) Ala-Arg-Zaa'"'"'OH(III)

wherein

Z represents a benzyloxycarbonyl group;

Pheψ

(PO₂ CH₂) indicates that the peptide bond (CO--NH) has been replaced by the phosphine bond (PO₂ CH₂);

Xaa'"'"' represents Gly, Ala or Leu;

Zaa'"'"' represents Met, Nle, Phe, Leu or Ile in formula (II), and Met or Phe in formula (III); and

R¹ represents a hydrogen atom, NH₄⁺ or a pharmaceutically acceptable metal.

6. The pharmaceutical composition of claim 5, wherein the polypeptide derivative is a polypeptide derivative of formula (II) with Xaa'"'"' representing Ala, Zaa'"'"' representing Met and R¹ representing a hydrogen atom.