Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-04-02
1998-07-28
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514822, 530326, A61K 3800
Patent
active
057863300
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to new peptide compounds which are therapeutically active in the cascade of blood coagulation.
PRIOR ART
It is now widely known that when the balance between procoagulant and anticoagulant factors in the blood is disrupted, it may lead to the formation of a thrombus or blood clot. The development of a thrombosis is essentially favored by three principal pathogenic factors which are stasis or decrease in blood flow, hypercoagulatability states and lesions of the endothelium of the vascular wall. Against these pathogeneses, it is therefore advisable to establish a treatment of which one of the principal bases is the anticoagulant drug.
Anticoagulants can indeed be used in the treatment of acute venous thromboses, pulmonary embolism, arterial embolism of the extremities, arterial thromboses such as myocardial infarction, atherosclerosis, all the other thromboembolic manifestations as well as for maintaining blood homeostasis, in particular in extracorporeal circulation.
Among the known anticoagulant agents, hirudin, which is a polypeptide comprising 65 amino acids, is a specific thrombin inhibitor isolated from the salivary glands of medicinal leeches (Biochemistry 25, 4622-28, 1986).
Variants of hirudin which can be used as thrombin inhibitor have already been described. This is the case, for example, for the compounds described in Patents EP 209061 or EP 332523. Furthermore, synthetic analogues of hirudin fragments with anticoagulant properties have also been described; this is the case, for example, for the compounds claimed in Patents EP 276014, EP 291981, EP 291982 and EP 333356. Compared with the natural model, these shorter fragments (10 to 20 amino acids) offer the advantage of being "easier to handle": in particular their synthesis is simpler. More recently, the European Patent Application EP 0,372,503 claimed peptides which are analogues of hirudin in which a natural amino acid was replaced by a synthetic amino acid. Application EP 0,443,598 claims peptides which are analogues of hirudin in which a natural amino acid is replaced by a sulfonated or phosphonated derivative.
Applications PCT 91/01328, EP 443429 and EP 552999 claim analogues of hirudin in which the modifications affect both the introduction non-natural amino acids but also the introduction of sulfono-oxo or phosphono-oxo-amino-acids.
Finally, P. Bourdon et al. (FEBS Letters, 294(3), 163-166, 1991) have presented a structure-activity study relating to the interactions of peptides with thrombin.
DESCRIPTION OF THE INVENTION
The present invention relates more particularly to the compounds of formula (I): -Asn-Gly-Asp-Phe-Glu-Abo-Ile-Pro-Glu-Glu-A.sub.2 -Leu-glu-OH(I) (SEQ ID NO: 1) by a group PO.sub.3 H.sub.2 (Phe(pPO.sub.3 H.sub.2), Phe(mPO.sub.3 H.sub.2)), amino acid of the peptide sequence being optically pure and the carbon of each amino acid having the D or L configuration.
Among the pharmaceutically acceptable acids there may be mentioned, with no limitation being implied, hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic and camphoric acids and the like. Among the pharmaceutically acceptable bases there may be mentioned,with no limitation being implied, sodium hydroxide, potassium hydroxide, triethylamine, tertbutyl- amine and the like.
The invention also extends to the process for preparing derivatives of formula (I) which can be obtained by various methods such as sequential solid phase synthesis, synthesis of fragments and their coupling in solution, enzymatic synthesis, genetic synthesis by cloning and expression of genes in transformed bacteria or by various combinations of these techniques.
The general methods for solid phase peptide synthesis have been described by B. W. ERICKSON and R. B. MERRIFIELD ("The Proteins", Solid-phase Peptide Synthesis, 3rd edition, 257-527, 1976).
The solid phase synthesis can be carried out in an automatic m
REFERENCES:
patent: 5371071 (1994-12-01), Fauchere et al.
Maraganore, et al., "Design and Characterization of Hirulogs: A Novel Class of Bivalent Peptide Inhibitors of Thrombin Biochemistry", vol. 29, No. 30, 7095-7101 Jul. 31, (1990).
Bourdon, et al., "Structure-function relationships of hirulog peptide interactions with thrombin", FEBS Letters, vol. 294, No. 3, 163-166, (Dec. 1991).
Krstenansky, et al., "Development of MDL 28,050, a Small Stable Antithrombin Agent Based on a Functional Domain of the Leech Protein, Hirudin", Thrombosis & Haemostasis, vol. 63, No. 2, 208-214, (1990).
Thurieau, et al., "Synthesis of a New Bivalent Hirudin Analog (Hirufos), which Includes a Stable 4'-Phosphono-L-phenylalanine Mimic of (L-Tyrosine O.sup.4 -Sulfate)-63", Helvetica Chimica ACTA, vol. 77, No. 3, 679-684 (May 11, 1994).
Fauchere Jean-Luc
Rupin Alain
Simonet Serge
Thurieau Christophe
Verbeuren Tony
Adir et Compagnie
Delacroix-Muirheid C.
Tsang Cecilia J.
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