EP0805818A1 - Nouveaux peptides, leur preparation et leur utilisation - Google Patents

Nouveaux peptides, leur preparation et leur utilisation

Info

Publication number
EP0805818A1
EP0805818A1 EP96900898A EP96900898A EP0805818A1 EP 0805818 A1 EP0805818 A1 EP 0805818A1 EP 96900898 A EP96900898 A EP 96900898A EP 96900898 A EP96900898 A EP 96900898A EP 0805818 A1 EP0805818 A1 EP 0805818A1
Authority
EP
European Patent Office
Prior art keywords
gly
ala
new
pro
peptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96900898A
Other languages
German (de)
English (en)
Inventor
Stefan Dhein
Tatjana Tudyka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP0805818A1 publication Critical patent/EP0805818A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new peptides, processes for their preparation and their use in combating diseases.
  • ion channel blockers have been used as antiarrhythmics which block transmembrane ion channels (sodium channels, calcium channels and / or potassium channels) which are suitable for therapy of acute cardiac arrhythmias which already exist.
  • a new principle is the improvement of cellular coupling.
  • An antiarrhythmic peptide AAP10 was proposed as a new principle (Naunyn Schmiedeberg's Arch. Pharmacol. 350, 174 (1994)), which leads to improved cellular coupling, local differences in the action potential duration reduced and the epicardial excitation patterns stabilized.
  • this substance shows practically no proarrhythmic risk, but it is effective against ischemia-associated arrhythmias.
  • the primary effect of the substance is to reduce the dispersion of the potential duration.
  • the invention relates to the compounds of the formula I.
  • X preferably denotes a glycine residue.
  • Y is preferably a proline residue.
  • Z is in particular a halogen atom, preferably iodine, which is in the 2- and preferably in the 3-position.
  • the compounds I can be prepared by the methods customary in peptide chemistry. The following processes are particularly suitable for the production thereof:
  • Solid phase synthesis on insoluble resins by a modified Merrifield method according to E. Atherston & R.C. Streppard (1989; "Solid phase peptide synthesis, IRL-Press, Oxford) using the Fmoc strategy.
  • the amino acid activation can take place via the formation of acid anhydrides, 1-hydroxybenzotriazole esters or pentafluorophenyl esters.
  • the invention allows prophylactic therapy of ischemia-associated and age-associated cardiac arrhythmias.
  • the substances have no significant proarrhythmic risk in an in vitro experiment.
  • the new peptides show a higher potency and a higher achievable maximum effect.
  • tyrosine and phthalic anhydride were reacted with one another in glacial acetic acid for 20 h, and the reaction product was reacted with iodine and Hg (II) acetate to give N-phthalyl-L-monoiodtyrosine.
  • the protective group was then cleaved off with phenylhydrazine.
  • the reaction product was reacted with fluorenylmethoxycarbonyl-N-hydroxysuccinimide in the presence of Na 2 CO 3 , water and acetone. After acidification with HC1, the desired Fmoc iodine tyrosine was obtained.
  • Fmoc-proline-OH was combined with 0- ((1H-benzotriazole-1-yD-NNNN-tetramethyluromi- num-tetrafluoroborate (TBTU), 1-hydroxybenzotriazole (HOBT), diisopropylethylamine (DIPEA) in DMF with the peptide
  • the protective group was again split off with piperidine, DMF and, after further rinsing, the reaction product was reacted with Fmoc-hydroxyproline-OH as described above.
  • OH and Fmoc-Glycino-OH were coupled in.
  • the protective group was cleaved with 20% piperidine in DMF, rinsed and added for 6 h
  • the peptide (1) was intracoronary to isolated rabbit hearts perfused with constant pressure (70 cm H 2 O) perfused with Tyrode's solution using the Langendorff technique (10 ⁇ 10 ,
  • Table 1 Concentration-dependent effect on the dispersion of the epicardial potential duration under the antiarrhythmic peptide AAP10 and the new peptide.
  • the better effect of the new peptide becomes particularly clear when one considers the number of values for the epicardial potential duration (ARI) which deviate from the mean value by less than 5 ms.
  • the new peptide under control conditions was 54%, on the other hand already 10 " 10 mol / 1 71%, 10" 9 mol / 1 73%, 10 " ⁇ mol / 1 75% 10 " 7 mol / 1 up to 90% of the ARI values in the interval + 5 ms around the mean.
  • AAP10 values were achieved over 70% only at concentrations above 10 "8 mol / 1, wherein a maximum of 74% was not th überschrit ⁇ .
  • the new substance shows an effect compared to AAP10 even at a lower concentration and a greater maximum achievable effect of up to 90% compared to 74% with AAP10 (% values: n% of epicardial action potentials showed a duration which scattered around the mean value in the range of ⁇ 5 ms, which corresponds to a decrease in the dispersion).
  • the new peptide is thus not only more potent, but also more effective than AAPIO with regard to the maximum effect and therefore represents an advance over AAPIO.
  • lidocaine belongs to those with a recognized relatively low proarrhythmic risk, while flecainide is generally considered to have a very high proarrhythmic risk.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des composés de la formule (I) dans laquelle R, X, Y et Z ont la notation mentionnée dans la description, ainsi que leur préparation. Ces composés s'utilisent pour lutter contre des maladies.
EP96900898A 1995-01-14 1996-01-04 Nouveaux peptides, leur preparation et leur utilisation Withdrawn EP0805818A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19500990 1995-01-14
DE19500990A DE19500990A1 (de) 1995-01-14 1995-01-14 Neues Peptid, seine Herstellung und Verwendung
PCT/EP1996/000009 WO1996021674A1 (fr) 1995-01-14 1996-01-04 Nouveaux peptides, leur preparation et leur utilisation

Publications (1)

Publication Number Publication Date
EP0805818A1 true EP0805818A1 (fr) 1997-11-12

Family

ID=7751510

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96900898A Withdrawn EP0805818A1 (fr) 1995-01-14 1996-01-04 Nouveaux peptides, leur preparation et leur utilisation

Country Status (14)

Country Link
EP (1) EP0805818A1 (fr)
JP (1) JPH11511727A (fr)
KR (1) KR19980701397A (fr)
CN (1) CN1168142A (fr)
AU (1) AU4483696A (fr)
BR (1) BR9606756A (fr)
CA (1) CA2209496A1 (fr)
CZ (1) CZ204897A3 (fr)
DE (1) DE19500990A1 (fr)
FI (1) FI972965A0 (fr)
IL (1) IL116658A0 (fr)
NO (1) NO973230L (fr)
WO (1) WO1996021674A1 (fr)
ZA (1) ZA96239B (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7585839B2 (en) 2000-02-23 2009-09-08 Zealand Pharma A/S Medical uses of intercellular communication facilitating compounds
ES2228807T3 (es) * 2000-02-23 2005-04-16 Zealand Pharma A/S Nuevo peptidos antiarritmicos.
US7250397B2 (en) 2000-02-23 2007-07-31 Zealand Pharma A/S Antiarrhythmic peptides
JP2005506295A (ja) * 2001-02-22 2005-03-03 ジーランド ファーマ アクティーゼルスカブ 細胞間連絡促進化合物の新規医薬使用
EA007792B1 (ru) * 2001-02-22 2007-02-27 Зеаланд Фарма А/С Новое медицинское применение соединений, способствующих межклеточным связям
EA006860B1 (ru) * 2002-01-29 2006-04-28 Уайт Композиции и способы модулирования гемиканалов коннексина
CN111303249B (zh) * 2020-01-02 2020-12-18 兰州大学 一种特异性检测病变胶原蛋白的探针、制备方法及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9621674A1 *

Also Published As

Publication number Publication date
IL116658A0 (en) 1996-05-14
AU4483696A (en) 1996-07-31
WO1996021674A1 (fr) 1996-07-18
KR19980701397A (ko) 1998-05-15
JPH11511727A (ja) 1999-10-12
ZA96239B (en) 1997-07-14
FI972965A (fi) 1997-07-11
BR9606756A (pt) 1998-01-06
CZ204897A3 (en) 1997-12-17
DE19500990A1 (de) 1996-07-18
NO973230D0 (no) 1997-07-11
CA2209496A1 (fr) 1996-07-18
FI972965A0 (fi) 1997-07-11
MX9704796A (es) 1997-10-31
CN1168142A (zh) 1997-12-17
NO973230L (no) 1997-07-11

Similar Documents

Publication Publication Date Title
DE3200812C2 (de) D-Phenylalanyl-L-prolyl-L-arginin-aldehyd-sulfat, Verfahren zu seiner Herstellung und diese Verbindung enthaltende Arzneimittel
DE69015671T2 (de) Peptide und deren Benützung in der Therapie.
EP0017760B1 (fr) Peptides analogues à la somatostatine, leur préparation et leur utilisation, compositions pharmaceutiques les contenant et leur préparation
DE2647843A1 (de) Neue peptide, ihre herstellung sowie verfahren zur herstellung cyclischer peptide
DE2705514C3 (de) Nonapeptide und diese enthaltende Arzneimittel
EP0805818A1 (fr) Nouveaux peptides, leur preparation et leur utilisation
DE3506992A1 (de) Modifizierte hirudine, verfahren zu deren herstellung und pharmazeutische mittel, die diese wirkstoffe enthalten
DE69028692T2 (de) Substance P Antagoniste
DE2635558A1 (de) Somatostatinanaloge
DE3314357A1 (de) Vasopressin-analoga, ihre herstellung und pharmazeutische mittel
DE2708125A1 (de) Mittel fuer die verhinderung der fortpflanzung von weiblichen warmbluetern
DE69119409T2 (de) Vasoaktive derivate des vasotocins
DE3586793T2 (de) Verwendung von vollsynthetischem alpha-hanap.
DE60020939T2 (de) Salze von pharmakologisch aktiven peptiden mit verzögerter wirkstofffreigabe und deren herstellung
DE19707854A1 (de) Neue Cyclopeptide, deren Herstellung und Verwendung
DE3239710C2 (de) Peptid mit Nerven-regenerierenden Eigenschaften
EP0028716B1 (fr) Peptides augmentant l'effet de motilité et leur utilisation
DE3882233T2 (de) Gefässaktive peptide.
CH667994A5 (de) Pharmazeutische zusammensetzungen mit polypeptid-wirkstoffen.
DE3781691T2 (de) Tetrapeptid-hemmstoff zum eintritt in den kreislauf von hemopoietischen stammzellen, verfahren zu deren herstellung und deren anwendungen.
EP0188629A1 (fr) Hexapeptide
DE3205991A1 (de) Polypeptide, verfahren zu ihrer herstellung, deren verwendung und verfahren zum reinigen von polypeptiden
DE3689850T2 (de) Peptide und deren Verwendung in der Therapie.
DE3633651A1 (de) Verwendung von fraktionen aus thymus- und milzextrakten zur behandlung der psoriasis
EP0054514A1 (fr) Dérivés d'aminopapulacandin à activité antibiotique

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19970702

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE ES FR GB IT LI NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 19980318