WO1992019644A1 - Peptide vasodilatateur - Google Patents

Peptide vasodilatateur Download PDF

Info

Publication number
WO1992019644A1
WO1992019644A1 PCT/JP1992/000520 JP9200520W WO9219644A1 WO 1992019644 A1 WO1992019644 A1 WO 1992019644A1 JP 9200520 W JP9200520 W JP 9200520W WO 9219644 A1 WO9219644 A1 WO 9219644A1
Authority
WO
WIPO (PCT)
Prior art keywords
ala
leu
asp
lie
fmoc
Prior art date
Application number
PCT/JP1992/000520
Other languages
English (en)
Japanese (ja)
Inventor
Masaki Ihara
Toshihiko Saeki
Takahiro Fukuroda
Kyoko Nakamichi
Mitsuo Yano
Original Assignee
Banyu Pharmaceutical Co., Ltd.
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 Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Publication of WO1992019644A1 publication Critical patent/WO1992019644A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to bioactive peptides having a strong vasorelaxant activity and their uses.
  • the compounds of the present invention among endothelin receptor located on vascular smooth muscle, does not act on receptor subtype involved in vascular contractions (ET A), Ri vascular endothelium on near, involved in vasorelaxation Has strong vasorelaxant activity by acting on the receptor subtype ( ⁇ ⁇ ), which is active in the pharmaceutical field, especially in hypertension, myocardial infarction, angina, acute renal failure, cerebral infarction, cerebral vasospasm It can be used as a therapeutic agent for
  • Endothelin is a 21 amino acid polypeptide that is produced by human and porcine endothelial cells, has a strong vasoconstrictor action, and is persistent and strong when administered intravenously to animals. Has a pressurizing effect.
  • endothelin is known to have three types of endoselins (endoselin-1, endoselin-2, and endoselin-3) in animals including humans as family peptides with similar structures [Naturia (Nature), 332, 411-415 (1988), Tubes 'Letters (FEBS Letters), 231, 440-444 (1988), Nobiochemical' and * Biophysical Research Communications (Biochem. Biophys. Res. Commun.), 154, 868-875 (1988), 164, 74-80 (1989), and Proceeding. National Academy of Sciences (Proc. Natl. Acad. Sci. USA), 86, 2863. -2867 (1989)].
  • endoselin-1 has an endothelium-dependent vasorelaxation activity in addition to a vasoconstrictor activity, and it is known that vasoconstriction and relaxation actions are caused by activating different endoselin receptor subtypes.
  • Endothelin-induced vasoconstriction is mainly caused by activation of the endothelin receptor ( ⁇ ⁇ ) on vascular smooth muscle, and the activity of ⁇ -1 is higher than that of 3-3.
  • vasorelaxation is caused by the activation of endoselin receptor ( ⁇ ⁇ ) on the vascular endothelium.
  • EDRF EDRF Quality
  • Endose Endoserin receptor subtype selectivity is different among phosphorus receptors have different tissue distribution, ET A receptors in the cardiovascular system excluding the vascular endothelium are many, ET B in the vascular endothelium and their other tissues It has been shown that there are many receptors and that each receptor protein is different [Japanese 'Journal' of 'Pharma collage-supplement' First (Jap. J. Pharmacol.), 52 (suppl. I), 203 (1990), Nature, 348, 730-735 (1990)].
  • LLC-Pkt cells from kidney proximal tubule it forces ⁇ et al to promote more cyclic GMP production in Endoserin have the ET B receptor, the activation of ET B receptors also diuretic [Jap. J. Pharmacol, 55 (suppl. I), 70 (1991)].
  • selectively substance activating only ET B receptors represents a diuretic vasorelaxant activity and kidney is considered to be useful as pharmaceuticals.
  • X I -X 2 -Ala-X 3 -Tyr-Phe-AIa-X ' , -Leu-Asp-X 5 -Ile-Trp [I]
  • X' represents a hydrogen atom, an acyl group, or an amino group. Represents any amino acid residue which may have an acyl group or any peptide residue having an arbitrary sequence consisting of 2 to 4 amino acids, which may have an amino group at the end.
  • X 2 represents Glu or D-Giu
  • X 3 represents Val or Ala
  • X 4 represents His or Ala
  • X 5 represents lie or Ala] or a pharmaceutically acceptable peptide represented by The present inventors have found that a salt which can be used has a vasorelaxant action, and completed the present invention.
  • the compound according to the present invention has a strong vasorelaxant effect.
  • the present invention provides hypertension, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, It is expected as a therapeutic and / or prophylactic agent.
  • any amino acid or any amino acid residue means alanine, arginine, asparagine, aspartic acid, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylanilanine.
  • acyl group means an acetyl group, a propanoyl group, an isopropanol group, a butanol group, an isobutanol group, a tert-butanol group, It means an aliphatic acyl group having 2 to 5 carbon atoms such as a pennoyl group or an isopentanoyl group or an aromatic acyl group such as a benzoyl group or a naphthoyl group, and various abbreviations described in this specification. The meaning is as follows. Abbreviations Abbreviations Abbreviations
  • the compound of the present invention can be produced by performing a condensation reaction of amino acids by a usual solid phase method or liquid phase method in the field of peptide chemistry.
  • the target peptide derivative was obtained using a commercially available peptide synthesizer, for example, Model 431A manufactured by Applied Biosystems, Inc., using chloromethyl resin [Biochemistry, 3, 1385 (1964)], oxymethyl resin [chemistry]. Chem. Ind. (London), 1966, 1597], p-alkoxybenzyl alcohol resin [J. Am. Chem. Soc. , 95. 1328 (1973)], and functionalized polyamide resin [Bioorganic Chemistry, 8, 351-370 (1979)], etc. to perform a sequential condensation reaction on an insoluble carrier.
  • a commercially available peptide synthesizer for example, Model 431A manufactured by Applied Biosystems, Inc., using chloromethyl resin [Biochemistry, 3, 1385 (1964)], oxymethyl resin [chemistry]. Chem. Ind. (London), 1966, 1597], p-alkoxybenzyl alcohol resin [J. Am. Chem. Soc. , 95. 1328 (1973)], and functionalized polyamide resin [Bioorgan
  • the ⁇ -amino group of the amino acid selected as the C-terminal amino acid in the peptide derivative is protected, and if a reactive functional group is present in the side chain, the side chain functional group is also protected. Is covalently bonded to the insoluble carrier in the form of a carboxylic acid ester. Then, the amino protecting group is o one
  • the amino-protected derivative in the following sequence (which also protects the side chain functional group if necessary) is added simultaneously with a condensing agent such as DCC or DIPC and an additive such as ⁇ ⁇ 3 ⁇ 40 if necessary.
  • a condensing agent such as DCC or DIPC
  • an additive such as ⁇ ⁇ 3 ⁇ 40 if necessary.
  • the amino protected derivative may be used in the form of a carboxy activated amino acid such as pentafluorophenyl ester, acid azide and the like. Such deprotection and condensation are repeated to obtain the desired peptide derivative.
  • Amino protecting groups are commonly known in the art, such as ⁇ ⁇ ⁇ , Boc, Fmoc, p-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl groups. ⁇ Selected from urethane-type protecting groups.
  • an Fmoc group or a Boc group is preferred.
  • the Fmoc group can be easily removed after the condensation reaction by the action of a relatively mild base, for example, piperidin N-methylpyrrolidone solution, piperidine / DMF solution, while the Boc group is relatively mild. It can be easily removed by the action of acids, such as TFA.
  • the power of aspartic acid is tert-butyl ester or trityl ester
  • the hydroxyl group of serine, isoserine and tyrosine is tert-butyl ether
  • the imidazolyl group of histidine May be protected with a Trt group. Since these protecting groups are stable under Fmoc group removal conditions, after the completion of peptide chain elongation, all protecting groups of the peptide derivative cleaved from the resin are simultaneously removed by treating with a mild acid such as TFA. be able to.
  • the hydroxyl group of serine and tyrosine may be used as benzyl ether
  • the imidazolinole group of histidine may be protected by a Tos group
  • the indolyl group of tributofan may be protected by a forminole group.
  • Removal of the peptide derivative from the resin after completion of peptide chain extension can be performed by various methods well known to those skilled in the art.
  • a mild acid such as TFA is preferably used to prepare a peptide derivative having a carboxy group at the C-terminus with a solution of TFAZm-creso-monoethaneethanedithionole. Obtainable.
  • the carrier resin To remove the carrier resin from the reaction mixture, suspend the mixture in a solvent capable of dissolving the peptide component and then filter the resin, or separate the resin and peptide components from the reagents by sedimentation, and then The resin may be filtered by dissolving only the peptide component in acetic acid or the like.
  • the solution is concentrated, and the residue is subjected to a method known per se (for example, recrystallization, reprecipitation, distribution operation, normal phase or reverse phase chromatography). Chromatography or ion exchange chromatography).
  • the peptide of the present invention can also be produced by a general liquid phase method of a peptide derivative. That is, by condensing amino acids one by one, by condensing condensates composed of a plurality of amino acids, or by combining these, if necessary, after the condensation reaction, the C-terminal and Z
  • the compound can be produced by removing the protecting group by hydrolysis with hydrogen or catalytic hydrogenolysis.
  • the condensation reaction is carried out by known methods such as the DCC method, the azide method, the active ester method and the mixed anhydride method [for example, by M. Bodansky and MA Ondetti, Peptide Synthesis, Interscience, New York (Peptide synthesis. Interscience, New York), 1966; FM Finn and K.
  • Examples of the monoamino protecting group include those commonly known to those skilled in the art, for example, urethane type such as Z group, Boc group, p-methoxybenzyloxycarbinole group and p-nitrobenzyloxycarbonyl group. Selected from protecting groups.
  • ⁇ -force ruboxyl protecting groups include methyl, ethyl, benzinole and tert-butyl ester. Etc., but should be selected according to the i 'terminal protecting group so that each protecting group after condensation can be selectively removed.
  • the N-terminal protecting group is a Boc group
  • the C-terminal side is preferably protected as methyl, ethyl or benzyl ester.
  • Boc groups are easily removed by the action of relatively mild acids, such as TFA. Under these conditions, these carboxine protecting groups are stable.
  • methyl and ethyl esters are easily removed by alkaline hydrolysis, and benzyl esters are easily removed by catalytic hydrogenolysis.
  • the N-terminal acylated peptide derivative can be obtained by reacting the produced peptide derivative with an acid anhydride or an acid halide in the presence of a base, if necessary.
  • a salt of an alkali metal such as sodium, potassium, calcium or the like, or a salt with a non-toxic organic amine such as dimethylamine, triethylamine, benzylamine, dicyclohexylamine, etc.
  • addition salts with basic amino acids such as lysine and arginine
  • addition salts with amide derivatives of amino acids such as fujyulananamide and leucine amide
  • acid addition salts with mineral acids such as hydrochloric acid and sulfuric acid
  • An acid addition salt with an acidic amino acid such as aspartic acid or glutamic acid
  • an acid addition salt with an organic acid such as maleic acid, fumaric acid, tartaric acid, malic acid or citric acid can be derived.
  • Porcine aortic smooth muscle and cerebellum were homogenized with a polytron at 4 ° C. in 10 mM MOPS pH 7.4 buffer. Sucrose was added to the homogenate to a concentration of 20%, centrifuged at 1000 ⁇ g for 15 minutes, and the supernatant was further centrifuged at 10,000 ⁇ g for 15 minutes. The supernatant was further centrifuged at 90,000 xg for 40 minutes, and the obtained precipitate was suspended in 5 mM HEPES / Tris pH 7.4 buffer to prepare a membrane fraction so that the concentration became 25 mgZml.
  • test compound 41 (For whole packing) or (C) Various concentrations of test compound 41 were added, and 125 1-endothelin-11 (12000-: L8000 cpm) 401 was added to each. Incubate these mixtures at 25 ° C for 4 hours, and use a glass filter GFZ.
  • each test compound was found to have a vasorelaxant effect.
  • the compound of the present invention had an effect of increasing the intracellular calcium concentration of cells derived from renal proximal tubule.
  • Such an effect of increasing the intracellular calcium concentration in the renal proximal tubule cells causes activation of the guanylate cyclase, resulting in a diuretic effect.
  • the compound of the present invention has an excellent vasorelaxant effect and is useful as a vasodilator in the field of pharmaceuticals, such as hypertension, acute renal failure, myocardial infarction, angina, m infarction, cerebral vasospasm, etc.
  • the compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.
  • Pharmaceutical preparations include, for example, liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and wisteria.
  • these preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants, if necessary.
  • Additives include distilled water for injection, physiological saline, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, hydroxypropylcellulose, lactose, sucrose, and corn starch. , Magnesium stearate or talc.
  • the dose of the compound of the present invention as a vasorelaxant varies depending on the administration method, the age and body weight of the patient, and the condition of the patient to be treated.A typical administration method for adults is oral or parenteral. Orally administered to adult patients
  • 0.05 to 10 mgZ per day kg body weight.
  • parenteral administration 0.1 to 5 mg kg per day.
  • Fmoc-Trp, Fmoc-He.Fmoc applied to p-alkoxybenzyl alcohol resin 256 mg: 0.25 mmo equivalent
  • Fmoc-Asp 0.25 mmo equivalent
  • Fmoc-Leu Fmoc-Leu
  • Fmoc-His Trt
  • Fmoc-Ala were sequentially subjected to force coupling (298 mg: Intermediate 13).
  • Fmoc—Val, Fmoc—Ala ⁇ Fmoc—Glu ( ⁇ 3 ⁇ 4 ⁇ ), Fmoc—Ala, Fmoc—Asp (0 ⁇ ), Fmoc—Met and Fmoc—Leu were sequentially coupled under the same conditions as in Example 1. (108 mg). 108 mg of the obtained coupled resin was taken, a mixed solution of 9.5 ml of TFA, 0.5 ml of m-cresol and 0.25 ml of ethanedithiol was added, and the mixture was stirred at room temperature for 90 minutes.
  • Fmoc-Met. Fmoc-Leu were sequentially coupled under the same conditions as in Example 1 (105 mg). A mixed solution of 9.5 ml of TFA, 0.5 ml of m-cresol and 0.25 ml of ethanedithiol was added to 105 mg of the obtained coupled resin, and the mixture was stirred at room temperature for 90 minutes.
  • Fmoc—Trp, Fmoc—Ile, Fmoc—Peptide synthesizer model 431A manufactured by Applied Biosystems, and p-alkoxybenzyl alcohol resin (311 mg: equivalent to 0.3 mmoI) were applied to the p-alkoxybenzyl alcohol resin by the standard Fmoc method.
  • Fmoc-Trp, Fmoc-Ile, Fmoc were applied to p-alkoxybenzyl alcohol resin (316 mg: equivalent to 0.3 mmol) by the standard Fmoc method using a peptide synthesizer model 431A manufactured by Applied Biosystems.
  • Ile, Fmoc-Asp (OtBu 8 Fmoc—Leu, Fmoc—His (Trt), Fmoc-Ala ⁇ Fmoc—Phe, Fmoc-Tyr CBu) were sequentially coupled (804 mg: intermediate-14). This coupling reaction was carried out in N-methylpyrrolidone at room temperature, Fmoc was eliminated using a piperidine / N-methylpiperidone solution, and DCC-HOBt was used as a condensing agent.
  • tmoc- Asp (O'Bu) Fmoc-] Leu, Fmoc- His (Trt), Fmoc- Ala, Fmoc- Phe, Fmoc- Tyr CBu) N Fmoc- Ala, Fmoc- Ala, Fmoc- Glu (O l Bu ) was sequentially force coupled (665 mg).
  • the compound according to the present invention has a strong vasorelaxant effect, it can be useful as a therapeutic agent for hypertension in humans, acute renal failure, myocardial infarction, angina, cerebral infarction and cerebral vasospasm. [Sequence List]
  • Distribution system ij Leu Met Asp Ala Glu Ala Val Tyr Phe Ala His Leu 1 5 10

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Reproductive Health (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Vasodilatateur contenant un peptide représenté par la formule générale (I) X?1-X2-Ala-X3¿-Tyr-Phe-Ala-X4-Leu-Asp-X5-Ile-Trp ou sel de ce composé acceptable en pharmacologie. Dans la formule, X1 représente hydrogène, acyle, un quelconque résidu d'aminoacide présentant un groupe amino éventuellement acylé, ou un résidu peptidique présentant une séquence quelconque comprenant de 2 à 4 résidus d'aminoacides quelconques et une terminaison N éventuellement acylée; X2 représente Glu ou D-Glu; X3 représente Val ou Ala; X4 représente His ou Ala; X5 représente Ile ou Ala.
PCT/JP1992/000520 1991-04-24 1992-04-22 Peptide vasodilatateur WO1992019644A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP3/122084 1991-04-24
JP12208491 1991-04-24
JP13836291 1991-05-14
JP3/138362 1991-05-14
JP22946191 1991-08-15
JP3/229461 1991-08-15

Publications (1)

Publication Number Publication Date
WO1992019644A1 true WO1992019644A1 (fr) 1992-11-12

Family

ID=27314386

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/000520 WO1992019644A1 (fr) 1991-04-24 1992-04-22 Peptide vasodilatateur

Country Status (2)

Country Link
JP (1) JPH0597891A (fr)
WO (1) WO1992019644A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024482A2 (fr) * 1996-12-04 1998-06-11 Schering Aktiengesellschaft Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production
WO2019213558A1 (fr) 2018-05-03 2019-11-07 Midwestern University Altérations des récepteurs de l'endothéline suite à une hémorragie et une réanimation par centhaquine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOCHEM. BIOPHYS. RES. COMMUN., Vol. 179, no. 1, (1991), TOSHIHIKO SAEKI et al., "Ala 1, 3, 11, 15), Endothelin - 1 Analogs with ETB Agonistic Activity", pp. 286-292. *
BR. J. PHARMACOL., Vol. 104, No. 2, (1991), STEPHEN A. DOUGLAS et al., "Endothelium - Dependent Mesenteric Vasorelaxant Effects and Systemic Actions of Endothelin (16- 21) and other Endotherin - Related Peptides in the Rat", pp. 311-320. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024482A2 (fr) * 1996-12-04 1998-06-11 Schering Aktiengesellschaft Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production
WO1998024482A3 (fr) * 1996-12-04 1999-04-01 Schering Ag Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production
WO2019213558A1 (fr) 2018-05-03 2019-11-07 Midwestern University Altérations des récepteurs de l'endothéline suite à une hémorragie et une réanimation par centhaquine
JP2021523125A (ja) * 2018-05-03 2021-09-02 ミッドウェスタン ユニバーシティ 出血およびセンタキンによる蘇生後のエンドセリン受容体の変化
EP3813942A4 (fr) * 2018-05-03 2022-01-19 Midwestern University Altérations des récepteurs de l'endothéline suite à une hémorragie et une réanimation par centhaquine
JP7458032B2 (ja) 2018-05-03 2024-03-29 ミッドウェスタン ユニバーシティ 出血およびセンタキンによる蘇生後のエンドセリン受容体の変化
EP4364811A3 (fr) * 2018-05-03 2024-07-10 Midwestern University Altérations des récepteurs de l'endothéline suite à une hémorragie et une réanimation par centhaquine

Also Published As

Publication number Publication date
JPH0597891A (ja) 1993-04-20

Similar Documents

Publication Publication Date Title
JP2000256397A (ja) 新規な環状テトラペプチド誘導体とその医薬用途
JP2002530430A (ja) Ｃ型肝炎ウイルスｎｓ３プロテアーゼ阻害用の医薬組成物
EP0298820A1 (fr) Nouveaux dérivés peptidiques et leur application notamment en thérapeutique
CN114269775A (zh) 肠促胰岛素类似物的制备方法
JPWO2018052002A1 (ja) Ｔｈｒｏｍｂｏｓｐｏｎｄｉｎ １結合ペプチド
JP2837352B2 (ja) 胃腸運動活性を抑制するモチリン類似ポリペプチド
JP3178835B2 (ja) 新規ポリペプチドおよびこれを用いる抗ｈｉｖ剤
CN114585637A (zh) Masp抑制化合物及其用途
CH637111A5 (fr) Composes polypeptidiques a activite thymique ou antagoniste et leurs procedes de synthese.
WO2002020561A1 (fr) Nouveaux polypeptides et medicaments anti-vih contenant lesdits polypeptides
EP0448099A2 (fr) Peptides nouveaux
US5786335A (en) Sulfhydryl containing peptides for treating vascular disease
CA2173939C (fr) Oligopeptides derives de fragments de proteines c-reactives
WO1992019644A1 (fr) Peptide vasodilatateur
WO1997049724A1 (fr) Depsipeptides cycliques et medicaments contenant ces composes comme ingredient actif
JPH051798B2 (fr)
JPH1160598A (ja) オピオイド様ペプチド
JP2005082489A (ja) 新規な摂食促進ペプチド、新規な成長ホルモン分泌促進ペプチド
JP2005082489A6 (ja) 新規な摂食促進ペプチド、新規な成長ホルモン分泌促進ペプチド
JP4332618B2 (ja) 抗ｈｉｖ剤
US6342481B1 (en) Oligopeptides derived from C-reactive protein fragments
JPH10182479A (ja) ペプチド誘導体類からなる薬剤
JP2002265497A (ja) 生理活性ペプチドニューロメジンｕの高活性誘導体
WO2024094685A1 (fr) Inhibiteurs de ccr2 et procédés d'utilisation
JP2922247B2 (ja) アンギオテンシン変換酵素阻害剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

NENP Non-entry into the national phase

Ref country code: CA