WO1994018235A1 - Nouveau pentapeptide cyclique - Google Patents

Nouveau pentapeptide cyclique Download PDF

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Publication number
WO1994018235A1
WO1994018235A1 PCT/JP1994/000151 JP9400151W WO9418235A1 WO 1994018235 A1 WO1994018235 A1 WO 1994018235A1 JP 9400151 W JP9400151 W JP 9400151W WO 9418235 A1 WO9418235 A1 WO 9418235A1
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Prior art keywords
dtrp
group
dasp
acid
leu
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PCT/JP1994/000151
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English (en)
Japanese (ja)
Inventor
Kiyofumi Ishikawa
Takehiro Fukami
Masaki Ihara
Masaru Nishikibe
Mitsuo Yano
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Banyu Pharmaceutical Co., Ltd.
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Priority to AU59785/94A priority Critical patent/AU5978594A/en
Publication of WO1994018235A1 publication Critical patent/WO1994018235A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • 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 a novel compound having an antagonistic activity against three types of endoselins (endoselin-1, endoselin-12 and endoselin-3), which are endogenous powerful bioactive peptides, a process for producing the same, and a use thereof. .
  • the compounds of the invention have a high affinity for both receptors Endoserin receptor subtypes ET A and ET B, Ri by the inhibiting action of Endoserin, vasodilatory activity and bronchodilator
  • a high affinity for both receptors Endoserin receptor subtypes ET A and ET B, Ri by the inhibiting action of Endoserin, vasodilatory activity and bronchodilator
  • hypertension especially hypertension, pulmonary hypertension, Reino's disease, acute renal failure, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, It can be used as a therapeutic agent for multi-organ failure, disseminated intravascular coagulation, and no or cyclosporine-induced renal impairment and hypertension caused by endotoxin.
  • Endothelin is a polypeptide consisting of 21 amino acids and is produced by human and human endothelial cells and has a strong vasoconstrictor action and a sustained and strong pressor action [Nature, vol. 332, no. Pp. 411-415 (1988)].
  • endothelin has a family peptide with similar structure,
  • Endothelin is clinically present in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Reino's disease, diabetes, atherosclerosis, asthma, and airway lavage fluid
  • J. Hypertension vol. 12, p. 79 (1989), Journal of Vascular. Medicine. J. Vascular Medicine Biology, Vol. 2, p. 207 (1990), Diabetology (01 & 1 ⁇ 1: 01 ( ⁇ &), Vol. 33, p. 306-p. 310 (1990) J. Am. Med. Association, Vol. 264, p. 2868 (1990), and The Lancet, Vol. 2, 747-748 (1989) and 2, pp. 1144--1147 (1990)].
  • endothelin has been found to be released not only from vascular endothelial cells but also from tracheal epithelial cells or renal parenchymal cells [Fubes Letters]
  • Endoserin the renin and atrial sodium ⁇ beam diuretic hormone endogenous physiologically active base peptide, more vascular relaxing factor derived endothelial cells (EDRF), thromboxane A 2, prostacyclin Zai prostacyclin, noradrenaline, Angi O tensin II ⁇ And the release of physiologically active substances such as substance P [Biochemical 'and' Biophysical 'Research' Communications (Biochem. Biophys. Res. Commun.), Vol. 157, Vol.
  • Endothelin has also been found to promote the proliferation of rat vascular smooth muscle cells, suggesting a relationship with arterial hyperplasia [Atherosclerosis, Vol. 78, pp. 225- 228 (1989)]. Furthermore, it is known that endothelin receptors are present in high concentrations not only in peripheral tissues but also in central tissues.Endothelin administered in the brain causes changes in animal behavior. It is also thought to play an important role in the field of neuroscience (see Neuroscience Letters. Vol. 97, pp. 276-279 (1989)). In particular, endothelin has been suggested to be a kind of mediator of pain sensation [Life Sciences. Vol. 49, PL-61-PL-65 (1991)].
  • Endotoxin is one of the potential candidates for endogenous endoselin release. It has been found that when endotoxin is exogenously administered to animals or added to cultured vascular endothelial cells, the endothelin concentration in blood or culture supernatant is significantly increased. Is considered to be one of the important mediators involved in endotoxin-induced diseases [Biochemical's and Biophysical Research Communications (Biochem. Biophys. Res. Commun.), Vol. 161, P. 1220 (1989) and Acta PhysioL Scand., Vol. 137, p. 317 (1989)].
  • Endothelin receptors have at least two subtypes from previous studies, and it is known that vasoconstriction by endothelin is also induced through these two endothelin receptor subtypes [Journal of See “Cardiovasquila Pharmaceuticals (J. Cardiovas Pharmacol.), Vol. 17 (Suppl. 7), S119-S121 (1991)].
  • One of these endoselin receptor subtypes is the endoselin receptor peptide.
  • ET A The endothelin receptor (ET A ) has selectivity for ET-1 over ET-3, and the other is the endothelin receptor (ET B ), which has almost the same activity as ET-1 and ET-3. It has been shown that each of these receptor proteins is different [see Nature, Vol. 348, pp. 730-735 (1990)].
  • tissue distribution of the two Endoserin receptor subtypes with different selectivity between these endothelin Fuamiri peptides are different, whereas ET A receptors often the cardiovascular system, ET B receptors brain It is known to be distributed in a wide range of tissues such as kidney, lung, heart, and blood vessels.
  • Endothelin is an endogenous bioactive substance that directly or indirectly (regulates the release of various endogenous substances) and continuously contracts vascular and non-vascular smooth muscles. Secretion is considered to be one of the causes of hypertension, pulmonary hypertension, Reino's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, acute renal failure, myocardial infarction, angina, cerebral vasospasm and cerebral infarction Can be In addition, it has been suggested that endoselin acts as an important mediator for diseases such as endotoxin shock or endotoxin-induced multiple organ failure, disseminated intravascular coagulation, cyclosporine-induced renal impairment, and hypertension. .
  • the receptor of Endoserin are known ET A receptor and ET B receptors, with ET A receptor antagonists, ET B receptor antagonists are useful as pharmaceuticals.
  • ET A receptors, Ri by the invention of a substance having a strongly antagonistic activity against both ET B receptors, it is intended to'll provide novel therapies unprecedented for various conditions described above.
  • the present inventors have synthesized various cyclic pentapeptides in order to solve the above-mentioned problems, and have investigated the endothelin antagonist activity thereof.
  • X 1 is DTrp (2- F)
  • X 2 represents DASP, the DGlu or DCys (0 3 H),
  • X 3 is Pro , Hyp Pip, Thz or -.
  • X 5 may be substituted with a hydrogen atom is ⁇ ⁇ alkyl groups on Amino groups, Ala, Aba, Val , Nva, Leu, Ile, alle, Nle, ⁇ MeLeu, Met, Phg ⁇ Thg, Fug, Tzg, Itg ⁇ Phe, Tyr ⁇ Tha, Trp, Tza, Cprg, Cpeg, Chg, Cpra, Cpea or Cha] in cyclic pentapeptide or its pharmaceutically acceptable salt is a strong ET a receptors expressed, found to have a strong antagonistic activity against both ET B receptors, and completed the present invention.
  • DAsp D aspartic acid
  • DAsp (OMe) D-aspartic acid
  • DCpeg D 2—open mouth pentyl glycine
  • Chg L-1 2 Hexyl hexylglycine
  • the cyclic pentapeptide of the present invention may be, if necessary, a corresponding linear pentapeptide having a protected amino acid side chain functional group or a linear pentapeptide having the amino acid residue X 1 of DTrp in the general formula [I]. Cyclization of the peptide or, if necessary, the corresponding linear pentapeptide with its amino acid side chain functional group protected, followed by 1) removal of the side chain protecting group, 2) indole ring of tributofan, if necessary Halogenation at the 2-position, 3) Formylation of the amino group on the side chain of lysine or ordinine, 4) Oxidation of methionine to methionine sulfoxide or methionine sulfone.
  • the linear pentapeptide can be produced by a method of condensing amino acids one by one, a method of condensing condensates composed of a plurality of amino acids, or a method of combining these.
  • Such condensation can be carried out by known methods such as, for example, the azide method, the mixed anhydride method, the DCC method and the active ester method [for example, by M. Bodansky and MA Ondetti, Peptide Synthesis, Interscience, New York, 1966; FMFinn and K. Hofmann, The Proteins, 2nd ed. Volume, edited by H. Nenrath and R. Hill, Academic Press Inc. New York, 1976; Nobuo Izumiya et al., Peptides Syntheses, described by Maruzen Co., Ltd., 1975] can be carried out in a liquid phase or a solid phase.
  • the compound of the present invention can be produced by the solid phase method as follows.
  • the linear pentapeptide is, for example, chloromethyl resin [Biochemistry
  • the amino protected derivative may be used in the form of a carboxyl-activated amino acid such as pentafluorophenyl ester, acid azide and the like. By repeating such deprotection and condensation, the desired linear pentapeptide is obtained.
  • the amino protecting group are those well known in the art, such as Z group, Boc group, Fmoc group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and the like. 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 a relatively mild action of a base, for example, with a 20% piperidine in DMF solution, while the Boc group can be removed by a relatively mild action of an acid, such as TFA. It can be easily removed.
  • carboxylic acid groups such as aspartic acid and glutamic acid are used as tert-butyl esters or trityl esters, and hydroxyl groups such as tyrosine, serine and threonine are used as tert-butyl ether.
  • Amino groups such as lysine and ordinine, and imidazolyl group of histidine are Boc group, mercapto group of cysteine is trityl group, and guanidino group of arginine is protected by pentamethylchromansulfonyl group. It is stable under Fmoc removal conditions and can remove all protecting groups simultaneously by mild acid action, eg TFA, after cyclization of the linear pentapeptide.
  • a Boc group is used to protect an ⁇ -amino group
  • a carboxyl group such as aspartic acid and glutamic acid is used as a benzyl ester
  • a hydroxyl group such as tyrosine, serine and threonine is used as a benzyl ether
  • lysine and oleic acid are used. If the amino group of ditin or the like and the imidazolyl group of histidine are protected with the Z group, these protecting groups are stable under the condition of removing the Boc group, and after the linear pentapeptide cyclization, contact hydrogenation treatment and hydrofluorination are carried out.
  • Removal of the linear pentapeptide from the resin after removal of the N-terminal protecting group can be performed by various methods well known to those skilled in the art. For example, cleavage of the peptide from the resin with hydrazine yields the corresponding hydrazide, which can then be cyclized via the azide to the desired cyclic pentapeptide. The hydrazide is converted to the corresponding azide by reaction with a reagent that supplies nitrous acid in the system. Reagents suitable for this purpose include strong reagents such as hydrochloric acid and sulfuric acid.
  • Examples include lower alkyl nitrite in the presence of an acid (eg, tert-butyl nitrite, isoamyl nitrite) or alkali metal nitrite (eg, sodium nitrite, potassium nitrite).
  • an acid eg, tert-butyl nitrite, isoamyl nitrite
  • alkali metal nitrite eg, sodium nitrite, potassium nitrite
  • linear pentapeptides can be prepared, for example, in the presence of a solvent such as DMF, THF, 1,4-dioxane, acetonitrile, dichloromethane, and chloroform at a temperature between about 140 ° C and 20 ° C.
  • a solvent such as DMF, THF, 1,4-dioxane, acetonitrile, dichloromethane, and chloroform at a temperature between about 140 ° C and 20 ° C.
  • DCC (or EDC Les HC1) - HOBT ⁇ H 2 0 , can be cyclized to the diphenyl We sulfonyl phosphorylase Rua condensing agent by Ri cyclic penta peptide to the action of such disilazide.
  • a cyclization reaction is desirably carried out under highly diluted conditions, because the intermolecular reaction may compete with the intramolecular reaction.
  • the cyclic pentapeptide obtained as described above has a protective group in the side chain, the protective group can be removed by an appropriate method.
  • the cyclic pentapeptide thus obtained may further optionally contain, for example, salts of alkali or alkaline earth metals such as sodium, potassium and calcium, addition salts with basic amino acids such as lysine and arginine, for example, hydrochloric acid, Acid addition salts with mineral acids such as sulfuric acid, for example, acid addition salts with acidic amino acids, such as aspartic acid and glutamic acid, and acids with organic acids such as maleic acid, fumaric acid, tartaric acid, malic acid, and citric acid Can lead to addition salts.
  • alkali or alkaline earth metals such as sodium, potassium and calcium
  • addition salts with basic amino acids such as lysine and arginine
  • hydrochloric acid for example, hydrochloric acid
  • Acid addition salts with mineral acids such as sulfuric acid
  • acid addition salts with acidic amino acids such as aspartic acid and glutamic acid
  • acids with organic acids such as maleic acid, fumaric acid, tartaric acid
  • linear pentapeptides can also be produced by a method of condensing amino acids one by one by a liquid phase method, a method of condensing condensates composed of a plurality of amino acids, or a method of combining these. .
  • the protecting groups for the «-carboxyl group and the side chain reactive functional group should be selected in consideration of the method of cyclizing the linear pentapeptide.
  • esther Ethil Este And benzyl ester, etc.
  • side chain reactive functional groups such as carboxyl group such as aspartic acid and glutamic acid as tert-butyl ester or trityl ester, and hydroxyl group such as tyrosine, serine and threonine as tert-butyl ether.
  • amino groups such as lysine and ordinine are protected by Boc groups
  • imidazolyl groups of histidine and mercapto groups of cystine are trityl groups
  • guanidino groups of arginine are protected by pentamethylchromansulfonyl groups.
  • a Boc group can be selected as a protecting group for the —amino group of the N-terminal amino acid in the present azide method.
  • the linear pentapeptide hydrazide obtained by the liquid phase method, from which the N-terminal protecting group has been removed, can be subjected to a cyclization reaction via an azide in the same manner as that obtained by the solid phase method to obtain a cyclic pentapeptide. it can.
  • the side-chain reactive functional group is a carboxyl group such as aspartic acid and glutamic acid as a lower alkyl ester such as methyl ester and ethyl ester or a benzyl ester; a hydroxyl group such as tyrosine, serine and threonine as a benzyl ether; and lysine.
  • Amino groups such as and ordinine, imidazolyl groups of histidine and indori of tributophan Groups it is preferable to protect z group.
  • the N-terminal of the protected linear pentapeptide obtained after the condensation is a tert-butyl ester
  • the N-terminal is removed without removing the side-chain protecting group by the action of a mild acid such as TFA.
  • Boc group and C Both terminal tert-butyl esters can be removed simultaneously.
  • the C-terminal is a funinasyl ester
  • the N-terminal Boc group is removed by the action of a mild acid such as TFA without removing the side-chain protecting group
  • the C-terminal phenacyl ester is removed by the action of zinc monoacetic acid. Can be removed.
  • all of these side chain protecting groups can be removed simultaneously or stepwise, for example, by a method such as alkali hydrolysis, catalytic hydrogenation, or a combination thereof.
  • a method such as alkali hydrolysis, catalytic hydrogenation, or a combination thereof.
  • the side chain-reactive functional groups are aspartic acid and glutamic acid.
  • Carboxyl groups such as tert-butyl ester or trityl ester, hydroxyl groups such as thiocyanine, serine and threonine as tert-butyl ether, and amino groups such as lysine and ornithine and imidazolyl groups of histidine are protected by Boc group.
  • Boc group Under conditions where the protecting group for the ⁇ -amino group of the terminal amino acid and the protecting group for the monocarboxyl group of the C-terminal amino acid are removed, these side-chain protecting groups are not removed. All of these side chain protecting groups can be removed by the action of a mild acid.
  • the linear vent peptide obtained in this manner is subjected to a cyclization reaction by the action of a condensing agent in the same manner as that obtained by the solid phase method to obtain a cyclic vent peptide.
  • a condensing agent in the same manner as that obtained by the solid phase method to obtain a cyclic vent peptide.
  • the linear pentapeptide is converted into an active ester such as ⁇ -ditrophenyl ester or ⁇ ⁇ ⁇ ⁇ ⁇ -hydroxysuccinimide ester in a state where the ⁇ -amino group of the ⁇ -terminal amino acid is protected. Cyclization can also be carried out by removing the protecting group of the group.
  • the cyclic pentapeptide which may be protected, or a salt thereof, obtained as described above may further contain, if necessary, a side chain amino group of halogen, lysine or ordinine at the 2-position of the indole ring of tryptophan.
  • Formylation, oxidation of methionine to methionine sulfoxide or methionine sulfone, and the like can also be performed.
  • Halogenation of the 2-position of the tryptophan ring can be performed in a solvent such as acetic acid or carbon tetrachloride, for example, in a solvent such as acetic acid, carbon tetrachloride, or ⁇ -halosuccinic acid imide, such as ⁇ -bromosuccinic acid imide or ⁇ -chlorosuccinic acid imide. And 2,2'-a as needed By acting in the presence of zobis (isobutyronitrile) or the like, the 2-position of the indole ring can be halogenated.
  • Formylation of the amino group at the side chain of lysine or ordinine can be performed, for example, by subjecting a cyclic pentapeptide containing lysine or ordinine to a solvent such as DMF, acetonitrile, etc., under ice-cooling to room temperature, for 1 to 1 hour. It can be carried out by treating with 10 equivalents of vivaric formate anhydride.
  • the conversion of methionine to methionine sulfoxide or methionine sulfone is carried out, for example, by using a cyclic pentapeptide containing methionine (however, when it contains an amino acid residue having a side chain functional group susceptible to oxidation other than methionine, these compounds may be used).
  • the side chain functional group is preferably protected with an appropriate protecting group) by treating with hydrogen peroxide or a peracid such as peracetic acid in a solvent such as acetic acid at 0 to 85 ° C. Can be performed.
  • methionine sulfoxide or methionine sulfone can be selectively obtained by appropriately controlling the amount of the oxidizing agent, the reaction temperature, and the reaction time. Further, methionine sulfone can be obtained by further treating methionine sulfoxide under the above reaction conditions.
  • the cyclic pentapeptide thus obtained is further subjected to removal of a protecting group, if necessary, and optionally salt formation or salt exchange, thereby obtaining the cyclic pentapeptide of the present invention or a pharmaceutically acceptable salt thereof.
  • the reaction intermediate and the target substance in the above-mentioned production method can be purified by a known purification method (for example, recrystallization, reprecipitation, distribution operation, normal-phase or reverse-phase chromatography, or ion-exchange chromatography). .
  • a known purification method for example, recrystallization, reprecipitation, distribution operation, normal-phase or reverse-phase chromatography, or ion-exchange chromatography.
  • the raw material compounds used in the above-mentioned production methods commercially available compounds can be used, and the following raw material compounds were each produced by a known method.
  • Busan aortic smooth muscle tissue was homogenized with 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 minutes. The supernatant was further centrifuged at 90,000 ⁇ g for 40 minutes, and the obtained precipitate was suspended in 5 mM HEPES / Tris pH 7.4 buffer to prepare a membrane fraction so as to have a concentration of 25 mg / ml.
  • This membrane fraction 16 1 was treated with 50 mM TrisZHCl pH 7.4 buffer A (10 ⁇ chloride, 10 ⁇ magnesium chloride, O.lmM PMSF, 1 fiM ⁇ pstati, ⁇ 2 ⁇ M leuptin, ImM 1,10-Phenanthroline, containing 0.1% bovine serum albumin).
  • the suspension may contain (A) unlabeled endoselin-1 (for non-specific binding) to a final concentration of 0.2 ⁇ , ( ⁇ ) buffer A (for total binding), or (C) a final concentration of 1.1 M. 4 / l of each of the test compounds to be added, and 125 / 1-endoserine-1 (12000 to 18000 cpm) 40/1 were further added to each.
  • the compound of the present invention showed extremely strong inhibitory activity on endothelin binding to the £ 1 receptor.
  • the test compound was expressed in Example No. c Table 1 Test compound 1.1
  • Porcine cerebellum was 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 lOOOXg for 15 minutes, and the supernatant was further centrifuged at 10,000 Xg for 15 minutes. The supernatant was further centrifuged at 90,000 ⁇ g for 40 minutes, and the obtained precipitate was suspended in 5 mM HEPES / Tris pH 7.4 buffer, and the membrane fraction was adjusted to 3.3 mg / ml. Prepared.
  • This membrane fraction (16 il) was added to 50 mM Tris / HCl pH 7.4 buffer A (10 / z M chloride chloride, 10 // M magnesium chloride, O.lmM PMSF, 1 ⁇ . Leptin, ImM 1,10-Phenanthroline, 0.1% bovine serum albumin).
  • the suspension may contain (A) unlabeled endoselin-1 with a final concentration of 0.2 M (for non-specific binding), (B) buffer A (for total binding), or (C) a final concentration of 1.1 / M. 4/1 of each test compound was added, and 125 1-endothelin-1 (12000 to 18000 cpm) 40 ⁇ 1 was further added to each.
  • the compounds of the present invention exhibited very strong inhibitory activity against the Endoserin binding to ET B receptors.
  • the test compound was shown by the example number.
  • Reference Compound 1 cyclo (- DTrp - DAsp - Pro - DVal - Leu -)
  • Reference Compound 2 obtain cyclo (one DTrp - DCys (0 3 Na) - Pro - DVal - Leu -)
  • Reference Compound 3 cyclo (- DTrp - DAsp - Pro - DThg - Leu -) action on Endoserin contraction in porcine isolated coronary artery specimen (ET a contraction receptor-mediated)
  • the effect of the compound of the present invention on a dose-response curve obtained by cumulatively adding endoselin-1 to a Magnus tube was examined.
  • the compound of the present invention was applied to a Magnus tube 20 minutes before the addition of endoselin-1 so that the final concentration was 10 / zM.
  • the compound of Example 9 significantly shifted the dose-response curve of endoserin-1 to the right, and did not affect its maximum response. Further, the compound of the present invention alone did not show any action on the above-mentioned blood vessel specimen. As described above, the compound of the present invention showed a remarkable antagonistic effect on the contraction of endoselin in the above-mentioned blood vessel specimen.
  • the effect of the compound of the present invention on the dose-response curve obtained by cumulatively adding endoselin-1 to the Magnus tube was examined.
  • the compound of the present invention was added to the Magnus tube 20 minutes before the addition of endoselin so that the final concentration was 10 / M.
  • the compound of Example 9 significantly shifted the dose-response curve of endoselin-1 in the isolated bronchial muscle preparation to the right.
  • the compound of the present invention alone did not show any action on the above specimen.
  • the compound of the present invention showed a remarkable antagonistic effect on the contraction of endoselin in the above specimen.
  • Endothelin-a product obtained by cumulatively adding 1 into a Magnus tube The effect of the compound of the present invention on the dose-response curve was examined.
  • the compound of the present invention was added to a Magnus tube 20 minutes before the addition of endoselin.
  • the compound of Example 9 significantly shifted the dose-response curve of endoselin-11 in the isolated pulmonary artery specimen to the right. Further, the compound of the present invention alone did not show any action on the above-mentioned blood vessel specimen. As described above, the compound of the present invention has a remarkable antagonistic effect on endoselin contraction in the above-mentioned vascular sample.
  • the present invention compounds ET A has excellent Endoseri emissions antagonism against ET B both receptors, are useful as vasodilators and bronchodilators in the field of pharmaceuticals, hypertension, pulmonary hypertension , Reino's disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, multiple organ failure and dissemination due to endotoxin It can be used as a therapeutic drug for intravascular coagulation and renal damage or hypertension induced by no- or cyclosporine. When used as a therapeutic agent for such diseases, the compounds of the present invention can be used alone or in combination with other therapeutic agents.
  • 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.
  • a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration.
  • the pharmaceutical preparation include liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories.
  • these preparations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants, if necessary.
  • the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol corn, sucrose, corn starch, magnesium stearate, and talc.
  • the dosage of the compound of the present invention as an endothelin antagonist varies depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, and the like.
  • a typical administration method for an adult is oral administration or parenteral administration.
  • Yes, for oral administration to adult patients, the dose is OlOOmgZKg body weight per day, and for parenteral administration, 0.01-10mg / Kg body weight per day.
  • FIG. 1 shows the effects of the compound of Example 9 (10 zM) and endocerin-1 contraction on isolated porcine coronary artery specimens in the absence of a drug ( ⁇ ).
  • FIG. 2 shows the effects of the compound of Example 9 (10 M) and endocerin-11 contraction on a guinea pig isolated bronchial specimen in the absence of a drug ( ⁇ ).
  • FIG. 3 shows the effects of compound 10 ( ⁇ ) of Example 9 and the absence of the drug ( ⁇ ) on endoselin-1 contraction in a rabbit heron pulmonary artery specimen.
  • Boc-Pro-DtertLeu-Leu-OBzl 869 g of Boc-DtertLeu-Leu-OBzl obtained in (1-e) was dissolved in 20 ml of TFA and stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMF (40 ml), and N-methylmorpholine was added under ice cooling to neutralize TFA.
  • Boc- Pro- OH 4.74g 1 hour under ice-cooling by adding ⁇ ⁇ ⁇ 2 0 3.37g and EDCI * HC1 4.22 g, was stirred at room temperature overnight.
  • Example (1-1h) The compounds of Examples 2 and 3 below were replaced with Boc-Pro-DtertLeu-Leu-OH in Example (1-1h), and the corresponding N-terminal was protected with a Boc group. It was obtained by performing the same operation as in Examples (1-1h) and (l-i) using the peptide.
  • Example 1 A—N—Trifluo synthesized according to the method of (RS Phillips) et al. [Journal 'ob' the 'American' chemical 'Society (J. Am. Chem. Soc.), 108, 2023 (1986)] The same operation as in Example 1 was performed using roacetyl-2-bromo-D-tryptophan methyl ester as a starting material to obtain the title compound. Melting point: 196.5-200 ° C
  • Example 4 Each of the compounds of the following Examples 5 to 9 was replaced with Boc-Pro-DtertLeu-Leu-OH in Example 4, and the corresponding N-terminal protected peptide was protected by a Boc group. And obtained in the same manner as in Example 4.
  • the mixture was washed successively with a 30% aqueous solution of citric acid (30 ml) and a saturated saline solution (30 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • the residue was dissolved in methanol (10 ml), 10% Pd / C (37 mg) was added, and the mixture was stirred overnight at room temperature under 1 atm of hydrogen pressure.
  • the catalyst was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure to obtain 114 mg of the desired product.
  • Example 13 Each of the compounds of the following Examples 13 to 15 was the same as Example 12 except that the corresponding N-protected or carboxyl-protected amino acid was used instead of Boc-DCpeg-OH or H-Leu-OBzl in Example 12. Obtained by performing the operation.
  • Example 13
  • the aqueous layer was acidified by adding a 10% aqueous solution of cunic acid, and extracted with ethyl acetate (10 ml ⁇ 3).
  • the ethyl acetate extract layer was washed with a saturated saline solution (10 ml), dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.47 g of the title compound.
  • Dioxane was distilled off under reduced pressure, water (150 ml) was added to the residue, and a 10% aqueous solution of citric acid was added to make the residue acidic, followed by extraction with ethyl acetate (80 ml ⁇ 3). The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.91 g of the title compound.
  • the cyclic pentapeptide of the present invention has a strong antagonistic activity against endogen, which is an endogenous bioactive peptide, it is useful as a drug which antagonizes the blood vessel and tracheal muscle contractile action involving endoselin, and furthermore, Animal hypertension, pulmonary hypertension, Reino's disease, bronchial asthma, arteriosclerosis, acute renal failure, myocardial infarction, narrowing It is useful as a therapeutic agent for heart disease, cerebral infarction, cerebral vasospasm, gastric ulcer and diabetes. It is also useful as a therapeutic agent for endotoxin shock, endotocin-induced multi-organ failure or disseminated intravascular coagulation, and cyclosporine-induced renal damage and hypertension.

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  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Pentapeptide cyclique représenté par la formule générale (I) et sel pharmaceutiquement acceptable de cette substance: cyclo (-X?1-X2-X3-X4-X5¿-), dans laquelle chaque Xn (n = 1-5) représente un résidu acide aminé, c'est-à-dire X1 DTrp(2-Br), etc.; X2 DAsp, etc.; X3 Pro1, etc.; X4 DVal, etc.; et X5 Ala, etc. Ce peptide présente un effet antagoniste à l'endothéline et se révèle utile à la prévention et au traitement de diverses maladies dans lesquelles d'endothéline est en cause.
PCT/JP1994/000151 1993-02-04 1994-02-02 Nouveau pentapeptide cyclique WO1994018235A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU59785/94A AU5978594A (en) 1993-02-04 1994-02-02 Novel cyclic pentapeptide

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP4045093 1993-02-04
JP5/40450 1993-02-04
JP16863893 1993-06-15
JP5/168638 1993-06-15

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WO1994018235A1 true WO1994018235A1 (fr) 1994-08-18

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AU (1) AU5978594A (fr)
WO (1) WO1994018235A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03130299A (ja) * 1989-08-31 1991-06-04 Fujisawa Pharmaceut Co Ltd ペプチド化合物とその製造法および用途
JPH04261198A (ja) * 1989-12-28 1992-09-17 Banyu Pharmaceut Co Ltd エンドセリン拮抗性環状ペンタペプチド
JPH0559098A (ja) * 1991-08-30 1993-03-09 Takeda Chem Ind Ltd 環状ペプチドおよびその用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03130299A (ja) * 1989-08-31 1991-06-04 Fujisawa Pharmaceut Co Ltd ペプチド化合物とその製造法および用途
JPH04261198A (ja) * 1989-12-28 1992-09-17 Banyu Pharmaceut Co Ltd エンドセリン拮抗性環状ペンタペプチド
JPH0559098A (ja) * 1991-08-30 1993-03-09 Takeda Chem Ind Ltd 環状ペプチドおよびその用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, Vol. 20, No. 6, (1992), M.K. BAZIL et al., "Pharmacologic Characterization of an Endothelin A (ET A) Receptor Antagonist in Conscious Rats", p. 940-948. *

Also Published As

Publication number Publication date
AU5978594A (en) 1994-08-29

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