WO2005077401A1 - Cardiotonique contenant un tripeptide ou un derive de celui-ci en tant qu'ingredient actif - Google Patents

Cardiotonique contenant un tripeptide ou un derive de celui-ci en tant qu'ingredient actif Download PDF

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Publication number
WO2005077401A1
WO2005077401A1 PCT/CN2004/000107 CN2004000107W WO2005077401A1 WO 2005077401 A1 WO2005077401 A1 WO 2005077401A1 CN 2004000107 W CN2004000107 W CN 2004000107W WO 2005077401 A1 WO2005077401 A1 WO 2005077401A1
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WO
WIPO (PCT)
Prior art keywords
tripeptide
asn
trp
active ingredient
phe
Prior art date
Application number
PCT/CN2004/000107
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English (en)
Chinese (zh)
Inventor
Jianrong Miao
Original Assignee
Jianrong Miao
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 Jianrong Miao filed Critical Jianrong Miao
Priority to PCT/CN2004/000107 priority Critical patent/WO2005077401A1/fr
Publication of WO2005077401A1 publication Critical patent/WO2005077401A1/fr

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Classifications

    • 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
    • A61K38/06—Tripeptides
    • 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

Definitions

  • the present invention relates to a medicine containing a tripeptide or a derivative thereof having an enhanced myocardial function as an active ingredient. Background technique
  • medicines used to enhance myocardial function, improve insufficient heart strength, or be used as cardiotonic drugs are mainly digitalis drugs. Although such drugs can play a certain role, they are caused by high toxicity or even serious. Death due to abnormal heart rate.
  • the object of the present invention is to provide a cardiotonic medicine using tripeptide or a derivative thereof as an active ingredient, which has strong action, good therapeutic effect, and does not affect the normal heart rate of the human body without any side effects.
  • R1, R2, and R3 are independent functional groups, and the independent functional groups may be H atoms, C1-C5 fluorene hydrocarbon groups, halogen atoms, amino groups, primary or secondary alkyl chain amino groups.
  • the active ingredients of the medicament of the present invention also include the above-mentioned tripeptides which can be used as medicines.
  • the medicine according to the present invention includes the tripeptide of the following three active ingredients:
  • the tripeptide according to the present invention may be an endogenous peptide extracted from an animal body.
  • Sample preparation The biological tissue samples were ground with 10 mM phosphate buffer solution at 0 ° C, separated by centrifugation, the upper supernatant was added with 30% trichloroacetic acid to remove protein, centrifuged, and the supernatant 20 ⁇ 1 was injected and analyzed by HPLC-MS. The test results are shown in Figure 1 and Figure 2.
  • the tripeptide of the present invention can be obtained by a synthetic method.
  • the synthesis of Asn-D-Trp-Ptie-NH 2 is:
  • Boc-Asn (tert-butoxycarbonyl asparagine) is reacted with a chloromethylated resin, and the resin is connected to the resin through a benzyl ester bond to obtain a Boc-Asn benzyl ester resin.
  • the Boc-protecting group was removed and washed with water and ethanol.
  • the Asn benzyl ester resin was integrated with Boc-D- ⁇ under the action of a DCCI condensing agent to obtain a Boc-dipeptide benzyl ester resin, which was washed with water and ethanol alternately to remove unreacted Boc-D-Trp. Click here to relink Boc-Phe-NH2.
  • the peptide-linked resin is suspended in anhydrous trifluoroacetic acid, and dried hydrogen bromide or dry ammonia in methanol is used for ammonolysis to dissociate the peptide chain from the resin and remove the protective group.
  • Asn-D-Trp-Phe-NH 2 is obtained.
  • Figure 6 shows a control chromatogram of two isomers of the tripeptide.
  • the substance (tripeptide) of the present invention can be used to enhance myocardial function and improve insufficient heart strength, and is used for cardiac strengthening medicine and health care medicine.
  • the animal experiments of Asn-D-Trp-Hie-NH2 to enhance cardiac function are explained. Two animal experimental methods were used: 1. STRAUB isolated frog heart method; 2. Changes in left ventricular pressure (LVP) of awake rats before and after administration.
  • LVP left ventricular pressure
  • the isolated frog heart method experiments (three cases) all showed that the contraction amplitude of the frog heart increased by more than 20% after giving Asn-D-Trp-Plie-NH 2 without changing the heart rate.
  • LVP left ventricular pressure
  • the present invention is a cardiotonic medicine using a tripeptide or a derivative thereof as an active ingredient, and can also be used as a health medicine, which can be used to enhance myocardial function, improve heart failure, and the like. It has strong effects and good effects; because it is an endogenous peptide, it is non-toxic, does not affect heart rate, and has low production costs.
  • Figure 1 is a HPLC chromatogram of two foreign bodies in a biological sample (California sea rabbit brain knot);
  • Figure 2 is a HPLC measurement chart of two foreign bodies in a biological sample (rat heart);
  • Figure 3 is a high performance liquid chromatography (HPLC) chart of a synthetic sample;
  • Figure 4 is a mass spectrum (MS) chart of a synthetic sample
  • Figure 5 is a nuclear magnetic resonance (NMR) chart of the synthesized sample
  • Figure 6 is a HPLC separation chromatogram of two isomers
  • Figure 7 shows rat heart rate and left ventricular pressure (LVP) before and after administration (Asn-D-Trp-e-H 2 ) Wave chart of the change.
  • Example: Asn-D-Tip-Phe-NH 2 was obtained according to the aforementioned synthetic method, and water (for example, physiological saline) was added to prepare an injection solution with a certain concentration.
  • water for example, physiological saline
  • the salts of the general formula (1) that can be used as medicines are: hydrochloride, sulfate, phosphate, nitrate, acetate, mesylate, maleate, citrate, tartrate .

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

Abstract

L'invention concerne un médicament dont l'ingrédient actif se compose de tripeptides et de dérivés de ceux-ci, le tripeptide utilisé étant représenté par une des formules générales suivantes : (a)(L)Asn-(D)Trp-(L)Phe-NH2 ou formule (A), dans laquelle R1, R2 et R3 représentent des groupes fonctionnels indépendants, et peuvent être un atome d'hydrogène, un groupe alkyle C1-C5, un atome d'halogène, un groupe amino, un p-alcane-amide. De tels médicaments possèdent une action puissante, et une bonne efficacité, ne modifient pas la fréquence cardiaque normale, et ne produisent pas d'effets nocifs ou d'effets secondaires, et conviennent pour la préparation de tous les types de formes galéniques, ainsi que de produits de soins.
PCT/CN2004/000107 2004-02-09 2004-02-09 Cardiotonique contenant un tripeptide ou un derive de celui-ci en tant qu'ingredient actif WO2005077401A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2004/000107 WO2005077401A1 (fr) 2004-02-09 2004-02-09 Cardiotonique contenant un tripeptide ou un derive de celui-ci en tant qu'ingredient actif

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2004/000107 WO2005077401A1 (fr) 2004-02-09 2004-02-09 Cardiotonique contenant un tripeptide ou un derive de celui-ci en tant qu'ingredient actif

Publications (1)

Publication Number Publication Date
WO2005077401A1 true WO2005077401A1 (fr) 2005-08-25

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PCT/CN2004/000107 WO2005077401A1 (fr) 2004-02-09 2004-02-09 Cardiotonique contenant un tripeptide ou un derive de celui-ci en tant qu'ingredient actif

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WO (1) WO2005077401A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000169499A (ja) * 1998-12-04 2000-06-20 Suetsuna Yoko 新規なトリペプチドおよび活性化酸素阻害剤
US6107489A (en) * 1998-03-17 2000-08-22 Conjuchem, Inc. Extended lifetimes in vivo renin inhibitors
US20020061840A1 (en) * 1999-01-20 2002-05-23 Bernard Roques Tripeptide compounds useful as selective inhibitors of aminopeptidase A and corresponding pharmaceutical compositions
CN1475274A (zh) * 2002-08-14 2004-02-18 缪建荣 三肽或其衍生物为有效成份的强心药

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6107489A (en) * 1998-03-17 2000-08-22 Conjuchem, Inc. Extended lifetimes in vivo renin inhibitors
JP2000169499A (ja) * 1998-12-04 2000-06-20 Suetsuna Yoko 新規なトリペプチドおよび活性化酸素阻害剤
US20020061840A1 (en) * 1999-01-20 2002-05-23 Bernard Roques Tripeptide compounds useful as selective inhibitors of aminopeptidase A and corresponding pharmaceutical compositions
CN1475274A (zh) * 2002-08-14 2004-02-18 缪建荣 三肽或其衍生物为有效成份的强心药

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