EP0276014A2
Expired / Lapsed
EP
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Anticoagulant peptides
Assignee: Aventis Pharmaceuticals Inc
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Filing: 1988-01-22
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Granted: —
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Expires: 2008-01-22
Abstract
Abstract This invention relates to peptide derivatives which are useful anticoagulant agents. These peptides have the formula X-A₁-A₂-A₃-A₄-A₅-A₆-A₇-A₈-A₉-A₁₀-Y wherein X is an amino terminal residue selected from hydrogen, one or two alkyl groups of from 1 to 6 carbon atoms, one or two acyl groups of from 2 to 10 carbon atoms, carbobenzyloxy or t-butyloxy carbonyl; A₁ is a bond or is a peptide containing from 1 to 5 residues of any amino acid; A₂ is Phe, SubPhe, β-(2- and 3-thienyl)alanine, β-(2-and 3-furanyl)alanine, β-(2-, 3-, and 4-pyridyl)alanine, β-(benzothienyl-2- and 3-yl)alanine, β-(1- and 2-naphthyl)alanine, Tyr or Trp;. A₃ is Glu or Asp; A₄ is any amino acid; A₅ is Ile, Val, Leu, Nle, or Thr; A₆ is Pro, Hyp, 3,4-dehydroPro, thiazolidine-4-carboxylate, Sar, NMePgl or any amino acids having a D-configuration; A₇ is any amino acid; A₈ is Glu or Asp; A₉ is a lipophilic amino acid selected from Tyr, Tyr(SO₃H), Trp, Phe, Leu, Nle, Ile, Val, His and Pro or is a dipeptide containing at least one of these lipophilic amino acids; A₁₀ is a bond or is a peptide fragment containing from one to five residues of any amino acid; and Y is a carboxy terminal residue selected from OH, C₁-C₆ alkoxy, amino, mono- or di(C₁-C₄) alkyl substituted amino, or benzylamino; and are useful anticoagulant agents.
Inventors
- 👤 John L. Krstenansky
- 👤 Simon J. T. Mao
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 22:28
CPC Classifications
C; C07; C07K; C07K14/00; C07K14/435; C07K14/745; C07K14/81; C07K14/815; A; A61; A61P; A61P7/00; A61P7/02; A61K; A61K38/00
Claims Analysis
Total Claims: 34
Claim 1
Independent Claim
195 words
A peptide derivative of the formula X-A₁-A₂-A₃-A₄-A₅-A₆-A₇-A₈-A₉-A₁₀-Y wherein X is a hydrogen, one or two alkyl groups of from 1 to 6 carbon atoms, or one or two acyl groups of from 2 to 10 carbon atoms; A₁ is a bond or is a peptide fragment containing from one to eleven residues of any amino acid; A₂ is Phe, SubPhe, β-(2- and 3-thienyl)alanine, β-(2- and 3-furanyl)alanine, β-(2-, and 3-, and 4-pyridyl)alanine, β-(benzothienyl-2- and 3-yl)alanine, β-(1- and 2-naphthyl)alanine, Tyr, or Trp; A₃ is Glu or Asp; A₄ is any amino acid; A₅ is Ile, Val, Leu, Nle, or Phe; A₆ is Pro, Hyp, 3,4-dehydroPro, thiazolidine-4-carboxylate, Sar, NMePgl, or D-Ala; A₇ is any amino acid; A₈ is any amino acid; A₉ is a lipophilic amino acid selected from Tyr, Trp, Phe, Leu, Nle, Ile, Val, Cha and Pro or is a dipeptide containing at least one of these lipophilic amino acids; A₁₀ is a bond or is a peptide fragment containing from one to five residues of any amino acid of; and Y is a carboxy terminal residue selected from OH, (C₁-C₆) alkoxy, amino, mono or di (C₁-C₄) alkyl substituted amino, and the pharmaceutically acceptable salts thereof.
Claim 2
Dependent Claim
195 words
A peptide derivative of the formula X-A₁-A₂-A₃-A₄-A₅-A₆-A₇-A₈-A₉-A₁₀-Y wherein X is a hydrogen, one or two alkyl groups of from 1 to 6 carbon atoms, or one or two acyl groups of from 2 to 10 carbon atoms; A₁ is a bond or is a peptide fragment containing from one to eleven residues of any amino acid; A₂ is Phe, SubPhe, β-(2- and 3-thienyl)alanine, β-(2- and 3-furanyl)alanine, β-(2-, and 3-, and 4-pyridyl)alanine, β-(benzothienyl-2- and 3-yl)alanine, β-(1- and 2-naphthyl)alanine, Tyr, or Trp; A₃ is Glu or Asp; A₄ is any amino acid; A₅ is Ile, Val, Leu, Nle, or Phe; A₆ is Pro, Hyp, 3,4-dehydroPro, thiazolidine-4-carboxylate, Sar, NMePgl, or D-Ala; A₇ is any amino acid; A₈ is any amino acid; A₉ is a lipophilic amino acid selected from Tyr, Trp, Phe, Leu, Nle, Ile, Val, Cha and Pro or is a dipeptide containing at least one of these lipophilic amino acids; A₁₀ is a bond or is a peptide fragment containing from one to five residues of any amino acid of; and Y is a carboxy terminal residue selected from OH, (C₁-C₆) alkoxy, amino, mono or di (C₁-C₄) alkyl substituted amino, and the pharmaceutically acceptable salts thereof.
Claim 3
Dependent Claim
15 words
A peptide derivative of claim 1 wherein A₂ is Phe, β-(2- or 3-thienyl)alanine, or Tyr.
Claim 4
Dependent Claim
10 words
A peptide derivative of claim 1 wherein A₃ is Glu.
Claim 5
Dependent Claim
13 words
A peptide derivative of claim 1 wherein A₄ is Glu, Ala, or Pro.
Claim 6
Dependent Claim
10 words
A peptide derivative of claim 1 wherein A₅ is Ile.
Claim 7
Dependent Claim
10 words
A peptide derivative of claim 1 wherein A₆ is Pro.
Claim 8
Dependent Claim
12 words
A peptide derivative of claim 1 wherein A₇ is Glu or Ala.
Claim 9
Dependent Claim
12 words
A peptide derivative of claim 1 wherein A₈ is Glu or Asp.
Claim 10
Dependent Claim
13 words
A peptide derivative of claim 1 wherein A₉ is Tyr-Leu, Ala-Tyr, or Ala-Cha.
Claim 11
Dependent Claim
24 words
A peptide derivative of claim 1 wherein A₁₀ is Gln, Asp, Pro, a bond, Asn, Asp-Glu, Glu, Ala, D-Lys, Lys, D-Asp, D-Glu or Orn.
Claim 12
Dependent Claim
13 words
A peptide derivative of claim 1 wherein X is H, acetyl, or succinyl.
Claim 13
Dependent Claim
12 words
A peptide derivative of claim 1 wherein Y is OH pr NH₂.
Claim 14
Dependent Claim
17 words
A peptide derivative of claim 1 wherein A₁ is -Ser-His-Asn-Asp-Gly-Asp, Asn-Asp-Gly-Asp, Asp-Gly-Asp, Gly-Asp, Asp, or a bond.
Claim 15
Dependent Claim
10 words
A peptide derivative of claim 1 wherein A₁ is Thr-Pro-Lys-Pro-Gln-Ser-His-Asn-Asp-Gly-Asp.
Claim 16
Dependent Claim
10 words
A peptide derivative of claim 1 wherein A₁ is Thr-Pro-Asn-Pro-Glu-Ser-His-Asn-Asn-Gly-Asp.
Claim 17
Dependent Claim
44 words
A peptide derivative of claim 1 wherein X is H, A₁ is -Gly-Asp-, A₂ is Phe, A₃ is Glu, A₄ is Glu, A₅ is Ile, A₆ is Pro, A₇ is Glu, A₈ is Glu, A₉ is Tyr-Leu, A₁₀ is Gln, and Y is OH.
Claim 18
Dependent Claim
45 words
A peptide derivative of Claim 1 wherein X is Suc, A₁ is a bond, A₂ is Phe, A₃ is Gly, A₄ is Glu, A₅ is Ile, A₆ is Pro, A₇ is Glu, A₈ is Glu, A₉ is Tyr-Leu, A₁₀ is Gln, and Y is OH.
Claim 19
Dependent Claim
44 words
A peptide derivative of Claim 1 wherein X is H A₁ is Gly-Asp, A₂ is Phe, A₃ is Glu, A₄ is Pro, A₅ is Ile, A₆ is Pro, A₇ is Glu, A₈ is Asp, A₉ is Ala-Tyr, A₁₀ is Asp-Glu, and Y is OH.
Claim 20
Dependent Claim
45 words
A peptide derivative of Claim 1 wherein X is Suc, A₁ is a bond, A₂ is Phe, A₃ is Glu, A₄ is Pro, A₅ is Ile, A₆ is Pro, A₇ is Glu, A₈ is Glu, A₉ is Tyr-Leu, A₁₀ is Pro, and Y is NH₂.
Claim 21
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-Gln-OH
Claim 22
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Phe-Glu-Pro-Ile-Pro-Glu-Glu-Tyr-Leu-Gln-OH.
Claim 23
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Phe-D-Lys-NH₂.
Claim 24
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Tyr-Lys-NH₂.
Claim 25
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-Lys-NH₂.
Claim 26
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-Lys-NH₂.
Claim 27
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Phe-Glu-OH.
Claim 28
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Phe-Gln-OH.
Claim 29
Dependent Claim
9 words
A peptide derivative of claim 1 which is Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-Asp-OH.
Claim 30
Dependent Claim
12 words
A compound of claims 1 to 28 for use as a medicine.
Claim 31
Dependent Claim
18 words
A pharmaceutical formulation comprising a compound of claims 1 to 28 in admixture with a pharmaceutically acceptable carrier.
Claim 32
Dependent Claim
17 words
Use of a compound of claims 1 to 28 for preparing a medicament for reducing blood coagulation.
Claim 33
Dependent Claim
21 words
A process for preparing a compound of claims 1 to 28 by solid phase block synthesis, gene cloning or combinations thereof.
Claim 34
Dependent Claim
67 words
A solid phase sequential and block synthesis process for preparing a compound of claims 1 to 28 which comprises binding a suitably protected aminoacid of formula A₁ to an activated resin support, and subsequently binding the other alpha amino protected amino acids from A₂ to A₁₀ to the terminal amino group of the growing peptidic chain which has meanwhile been exposed by removing its amino protecting group.
References Cited (Backward Citations)
No citation records indexed.
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