WO1997011960A1 - Antagonistes des recepteurs de l'endotheline - Google Patents

Antagonistes des recepteurs de l'endotheline Download PDF

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Publication number
WO1997011960A1
WO1997011960A1 PCT/EP1996/004063 EP9604063W WO9711960A1 WO 1997011960 A1 WO1997011960 A1 WO 1997011960A1 EP 9604063 W EP9604063 W EP 9604063W WO 9711960 A1 WO9711960 A1 WO 9711960A1
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WIPO (PCT)
Prior art keywords
methyl
phenyl
acid
triazol
butanesulfonyl
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PCT/EP1996/004063
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English (en)
Inventor
Junichi Sakaki
Toshiki Murata
Yoko Yuumoto
Ikushi Nakamura
Toshikazu Okada
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Japat Ltd.
Novartis Ag
Ciba-Geigy Japan Limited
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Application filed by Japat Ltd., Novartis Ag, Ciba-Geigy Japan Limited filed Critical Japat Ltd.
Priority to JP9513117A priority Critical patent/JPH11512702A/ja
Priority to AU71302/96A priority patent/AU7130296A/en
Publication of WO1997011960A1 publication Critical patent/WO1997011960A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/10—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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 novel compounds as antagonists of endothelin (ET) receptors, processes for their preparation, their use and pharmaceutical compositions.
  • ET endothelin
  • ETs are a family of vasoactive peptides with 21 amino acid residues and two intramolecular disulfide bonds. They comprise ET-1 , the original ET isolated from the culture media of porcine endothelial cells, ET-2 and ET-3.
  • ETs of which biosynthesis is enhanced by many biological and pathological factors, are widely distributed in both peripheral and brain tissues of mammalians, and elicit a number of biological responses by binding to at least two distinct ET receptor subtypes, ET A and ET B receptors.
  • ET receptors are present in cardiovascular, renal, hepatic and neural tissues. ET receptors are also found in the respiratory, gastro-intestinal, endocrine, central nervous and genito-urinary systems, the blood and blood forming organs, the sensory organs, and other tissues in the body.
  • ETs are the most potent and longest acting endogeneous constrictors of blood vessels identified to date. ETs also cause contraction of various non-vascular smooth muscles including the air-way, and the cardiac muscle. In addition, ETs are mitogenic ulcerogenic and pro-inflammatory. ETs have regulatory functions on hormone- or peptide- secretion, neurotransmission, ion-transport and metabolism.
  • the present invention provides novel compounds represented by the general formula I
  • R represents 1 ,2,4-triazoM -yl
  • R 2 represents methyl or hydroxy
  • R 3 represents methyl or hydroxy
  • the asterix means that the chiral carbon atom to which said asterix is attached has the (D) or (D,L) configuration
  • Ri represents isoxazol-5-yl
  • R 2 is methyl
  • R 3 is methyl
  • the asterix means that the chiral carbon atom to which said asterix is attached has the (D) configuration
  • salts thereof processes for the manufacture, pharmaceutical compositions and the use of the compounds of formula I and salts thereof.
  • All of the compounds of the present invention possess two or more chiral centers which may exist e.g. in the (D), (L), or (D,L) configuration which means that the corresponding structural features are derhved from corresponding (D), (L), or (D,L) amino acids.
  • the compounds of the present invention exist in an essentially pure diasteromeric and enantiomerical form.
  • the compounds represented by the formula (I) are capable of forming pharma ⁇ ceutically acceptable acid addition salts and/or base addition salts.
  • Pharmaceutically acceptable acid addition salts of the compounds (I) include those of inorganic acids, for example, hydrohalic acids such as hydrochloric acid, hydrodromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; organic acids, for example, lower alkanoic acids such as formic acid, acetic acid, propionic acid, butylic acid, hydroxy acids such as lactic acid, citric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, sulfonic acids, for example, lower alkanesulfonic acids such as methanesulfonic acid, or benzenesulfonic acid.
  • hydrohalic acids such as hydrochloric acid, hydrodromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid
  • organic acids for example,
  • Salts of the present compounds (I) with bases are, for example, those with bases, for example, inorganic bases such as ammonium hydroxide or metal hydroxide, such as lithium hydroxide, such as alkaline metal hydroxide such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxide, such as calcium hydroxide; or those with organic bases, for example, amines, for example, mono-, di- or tri-lower alkylamines, such as mono- , di- or tri-methyl-amine or -ethyl-amine.
  • inorganic bases such as ammonium hydroxide or metal hydroxide, such as lithium hydroxide, such as alkaline metal hydroxide such as sodium hydroxide, potassium hydroxide, alkaline earth metal hydroxide, such as calcium hydroxide
  • organic bases for example, amines, for example, mono-, di- or tri-lower alkylamines, such as mono- , di- or tri-methyl-amine or -ethy
  • lower alkyl means an alkyl having 1 up to and including 7 carbon atoms, preferably 1 up to and including 4 carbon atoms, and for example, is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, straight or branched pentyl, straight or branched hexyl, or straight or branched heptyl.
  • Lower alkoxy is in particular d-C 7 alkoxy and is, for example, methoxy, ethoxy, n- propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.
  • C C 4 aikoxy is preferred.
  • Lower alkylene is, for example, C ⁇ -C 7 alkylene, and is straight-chain or branched and is in particular methylene, ethylene, propylene and butylene and also 1 ,2-propylene, 2- methyl-1 ,3-propylene and 2,2-dimethyl-1 ,3-propylene.
  • d-Csalkylene is preferred.
  • Halogen is in particular halogen of atomic number not more than 35, such as fluorine, chlorine or bromine, and also includes iodine.
  • the compounds I and their pharmaceutically acceptable salts for example, have pronounced pharmaceutical, for example, endothelin receptor antagonistic, properties and a beneficial pharmacological profile.
  • the compounds of the present invention bind to both the ET A and ET B receptors.
  • the compounds according to the present invention comprise at most two peptidic bonds. Furthermore, they are distinguished from prior art compounds not only by their unexpected and favorable stability as well as by the pharmacological profile.
  • the ET receptor antagonists of the present invention are useful for various human diseases caused by ETs, either directly or in concert with other factors.
  • they are useful for various cardiovascular diseases such as cerebral and coronary vasospasm, cerebral and cardiac ischemia, subarachnoidal haemorrhage, various types of hypertension, pulmonary hypertention, cardiac failure, Raynand-syndrome, diabetes, benign prostatic hyperplasia, atherosclerosis or restenosis due to denudation following angioplasty.
  • the compounds of the present invention also provide a new therapeutic potential for asthma, renal failure, dialysis, glomerular injury, hepatic failure, stomach and duodenal ulcer, ulcus cruris, various brain dysfunctions including migraine and delayed neuronal death, various cancers including prostate cancer, and occular diseases, glaucoma in particular.
  • the compounds of the formula I and their pharmaceutically acceptable salts can therefore be used, for example, as pharmaceutical active ingredients which are employed, for example, for the treatment of various cardiovascular diseases such as cerebral and coronary vasospasm, cerebral and cardiac ischemia, subarachnoidal haemorrhage, various types of hypertension, pulmonary hypertention, cardiac failure, Raynand-syndrome, diabetes, benign prostatic hyperplasia, atherosclerosis or restenosis due to denudation following angioplasty and also for the treatment of asthma, renal failure, dialysis, glomerular injury, hepatic failure, stomach and duodenal ulcer, ulcus cruris, various brain dysfunctions including migraine and delayed neuronal death, various cancers including prostate cancer, and occular diseases, glaucoma in particular.
  • cardiovascular diseases such as cerebral and coronary vasospasm, cerebral and cardiac ischemia, subarachnoidal haemorrhage, various types of hypertension, pulmonary hypertention, cardiac failure, Raynand-s
  • the invention thus relates to the use of the compounds according to the invention and their pharmaceutically acceptable salts for the production of appropriate medicaments and to the therapeutic treatment of various cardiovascular diseases such as cerebral and coronary vasospasm, cerebral and cardiac ischemia, subarachnoidal haemorrhage, various types of hypertension, pulmonary hypertention, cardiac failure, Raynand-syndrome, diabetes, benign prostatic hyperplasia, atherosclerosis or restenosis due to denudation following angioplastyalso for the treatment of asthma, renal failure, dialysis, glomerular injury, hepatic failure, stomach and duodenal ulcer, ulcus cruris, various brain dysfunctions including migraine and delayed neuronal death, various cancers including prostate cancer, and occular diseases, glaucoma in particular.
  • the industrial production of the active substances is also included in the production of the pharmaceuticals.
  • the invention relates in particular to compounds of the formula (la)
  • R represents 1 ,2,4-triazol-1 -yl or isoxazol-5-yl, and salts, especially pharmaceutically acceptable salts thereof.
  • the invention relates in particular to the novel compounds shown in the examples and to the methodes for their preparation described therein.
  • the invention relates to processes for the preparation of the compounds according to the invention.
  • the preparation of compounds of the formula I or la, respectively, and their salts comprises, for example,
  • R 1 R 3 and the asterix are as definied above, or a salt or a reactive acid derivative thereof with a compound of formula (lib)
  • R 2 is as defined above, or a salt thereof; or, b) for the manufacture of a compound of formula (I) or a salt thereof, wherein the asterix means that the chiral carbon atom to which said asterix is attached has the (D) configuration, separating a mixture of isomers of formula (I), wherein the asterix means that the chiral carbon atom to which said asterix is attached has the (D,L) configuration and isolating the desired isomer,
  • reaction described above and below in the variants are carried out, for example in the absence or, customarily, in the presence of a suitable solvent or diluent or a mixture thereof, the reaction, as required, being carried out with cooling, at room temperature or with warming, for example in a temperature range from about -80°C up to the boiling point of the reaction medium, preferably from about -10° to about +200°C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.
  • Reactive acid derivatives of compounds of formula (lla) are for example derived activated esters or reactive anhydrides, and also reactive cyclic amides.
  • the reactive acid derivatives can be formed in situ.
  • esters of compounds of formula (lla) having a carboxy group are especially esters unsaturated at the linking carbon atom of the esterifying radical, for example of the vinyl ester type, such as vinyl esters (obtainable, for example, by trans ⁇ esterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium reagent; 1 ,2-oxazolium or Woodward method), or 1 -lower alkoxyvinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxy- acetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N'-disub- stituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N '-disubstituted carbodiimide, for example N,N'-d
  • Anhydrides of acids may be symmetric or preferably mixed anhydrides of those acids, for example anhydrides with inorganic acids, such as acid halides, especially acid fluorides (obtainable, for example by treatment of the corresponding acid with suitable fluorinating agents such as 1 ,1-difluoro-3-trifluoro-propyleneoxide, 2-fluoro-1 ,3-dimethyl- pyridinium benzenesulfonate, dimethyl-difluoromethyl-amine, benzoylfluoride, perfluoro- 2methyl-pentene, hexafluoropropane, thfluorotuoluene/BF 3 and especially cyanuric fluioride), acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride, phosgene or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via
  • Suitable cyclic amides are especially amides having five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • imidazole obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method
  • pyrazole for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).
  • condensation for forming an amide bond can be carried out in a manner known per se, for example, as described in:
  • condensation of a free carboxylic acid (lla) with the corresponding amine (lib) can be carried out preferably in the presence of one of the customary condensation agents, or using as a corresponding reactive acid derivative carboxylic acid anhydrides or carboxylic acid halides, such as chlorides, or activated carboxylic acid esters, such as p-nitrophenyl esters.
  • Customary condensation agents are, for example, carbodiimides, for example diethyl-, dipropyl-, 1-(3-dimetylaminopropyl)-3-ethyl-carbodiimide or especially dicyclohexylcarbodiimide, also suitable carbonyl compounds, for example carbonylimidazole, 1 ,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1 ,2-oxazolium 3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline, N,N,N',N'-- tetraalkyluronium compounds, such as O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, also activated
  • an organic base is added, preferably a tertiary amine, for example a tri- lower alkylamine having bulky radicals, for example ethyl diisopropylamine or triethylamine, and/or a heterocyclic base, for example 4-d ⁇ methylam ⁇ nopyr ⁇ d ⁇ ne or preferably N-methyl- morpholine or pyridine.
  • a tertiary amine for example a tri- lower alkylamine having bulky radicals, for example ethyl diisopropylamine or triethylamine
  • a heterocyclic base for example 4-d ⁇ methylam ⁇ nopyr ⁇ d ⁇ ne or preferably N-methyl- morpholine or pyridine.
  • the condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines (lib) is customarily carried out in the presence of an organic base, for example simple tri-lower alkylamines, for example triethylamine or tributylamine, or one of the above-mentioned organic bases.
  • an organic base for example simple tri-lower alkylamines, for example triethylamine or tributylamine, or one of the above-mentioned organic bases.
  • a condensation agent is additionally used, for example as described for free carboxylic acids.
  • the condensation of acid anhydrides with amines (lib) can be effected, for example, in the presence of inorganic carbonates, for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (if desired together with a sulfate).
  • inorganic carbonates for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (if desired together with a sulfate).
  • Carboxylic acid chlorides for example the chlorocarbonic acid derivatives, derived from the acid of formula (lla).
  • the condensation of a free carboxylic acid with the corresponding amine (lib) can be carried out preferably in the presence of one of the customary condensation agents, or using carboxylic acid anhydrides or carboxylic acid halides, such as chlorides, or activated carboxylic acid esters, such as p-nitrophenyl esters.
  • Customary condensation agents are, for example, carbodiimi ⁇ es, for example diethyl-, dipropyl-, 1-(3-dimethylam ⁇ nopropyl)-3-ethyl-carbod ⁇ m ⁇ de or especially dicyclohexylcarbo ⁇ diimide, also suitable carbonyl compounds, for example carbonylimidazole, 1 ,2-oxazol ⁇ um compounds, for example 2-ethyl-5-phenyl-1 ,2-oxazol ⁇ um 3'-sulfonate and 2-tert-butyl-5- methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy-1- ethoxycarbonyl-1 ,2-dihydro ⁇ u ⁇ nol ⁇ ne, N,N,N',N'-tetraalkyluron ⁇ um compounds, such as O- benzot ⁇ azol-1-yl-N,N,N',N'-tetramethylur
  • an organic base is added, preferably a tertiary amine, for example a tri- lower alkylamine having bulky radicals, for example ethyl diisopropylamine or triethylamine, and/or a heterocyclic base, for example 4-dimethylaminopyridine or preferably N-methyl- morpholine or pyridine.
  • a tertiary amine for example a tri- lower alkylamine having bulky radicals, for example ethyl diisopropylamine or triethylamine
  • a heterocyclic base for example 4-dimethylaminopyridine or preferably N-methyl- morpholine or pyridine.
  • condensation reactions when starting from an essentially pure isomeric carboxylic acid fluoride surprisingly result in essentially pure isomeric condensation products without inversion of the optical center.
  • the condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines (lib) is customarily carried out in the presence of an organic base, for example simple tri-lower alkylamines, for example triethylamine or tributylamine, or one of the above-mentioned organic bases.
  • an organic base for example simple tri-lower alkylamines, for example triethylamine or tributylamine, or one of the above-mentioned organic bases.
  • a condensation agent is additionally used, for example as described for free carboxylic acids.
  • the condensation of acid anhydrides with amines can be effected, for example, in the presence of inorganic carbonates, for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (if desired together with a sulfate).
  • inorganic carbonates for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (if desired together with a sulfate).
  • Carboxylic acid chlorides for example the chlorocarbonic acid derivatives derived from the acid of formula (lla) are condensed with the corresponding amines preferably in the presence of an organic amine (Mb), for example the above-mentioned tri-lower alkylamines or heterocyclic bases, where appropriate in the presence of a hydrogen sulfate.
  • Mb organic amine
  • the condensation is preferably carried out in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in a mixture thereof, as appropriate at reduced or elevated temperature, for example in a temperature range of from approximately -40°C to approximately +100°C, preferably from approximately -10°C to approximately +50°C, and in the case where arylsulfonyl esters are used also at approximately from +100°C to +200°C, and where appropriate under an inert gas atmosphere, for example a nitrogen or argon atmosphere.
  • Aqueous for example alcoholic, solvents, for example ethanol, or aromatic solvents, for example benzene or toluene, may also be used.
  • solvents for example ethanol
  • aromatic solvents for example benzene or toluene
  • acetone can also be added where appropriate.
  • the condensation can also be carried out in accordance with the technique known as solid phase synthesis which originates from R. Merrifield and is described, for example, in Angew. Chem. 97, 801 - 812 (1985), Naturwissenschaften 71, 252 - 258 (1984) or in R. A. Houghten, Proc. Natl. Acad. Sci. USA 82, 5131 - 5135 (1985).
  • Reactive acid derivatives can also be formed in situ.
  • sulfonamides may be used in form of an alkali metal salt such as a sodium or potassium salt, whereas if an hydoxylamine derivative is used it may be used as hydrohalide such as hydrochloride.
  • Diastereomer mixtures can be separated into the pure isomers in a known manner on the basis of the physicochemical differences of the components, for example by fractional crystallization. Diastereomers may furthermore be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, e.g.
  • protecting groups may already be present in the precursors and are intended to protect the relevant functional groups against undesired secondary reactions, such as acylation, esterification, or solvolysis, etc.. In certain cases the protecting groups can additionally cause the reactions to proceed selectively, for example stereoselectively. It is a characteristic of protecting groups that they can be removed easily, i.e. without undesired secondary reactions, for example by solvolysis, reduction, photolysis, and also enzymat ⁇ ically, for example also under physiological conditions. Radicals analogous to protecting groups may, however, also be present in the end products. Hereinbefore and hereinafter, it is protecting groups in the narrower sense that are referred to unless the relevant radicals are present in the end products.
  • a carboxy group protected in esterified form is esterified especially by a lower alkyl group that is preferably branched in the 1 -position of the lower alkyl group or substituted in the 1- or 2-position of the lower alkyl group by suit ⁇ able substituents.
  • a protected carboxy group esterified by a lower alkyl group is, for example, methoxy ⁇ carbonyl or ethoxycarbonyl.
  • a protected carboxy group esterified by a lower alkyl group that is branched in the 1 - position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, for example tert- butoxycarbonyl.
  • a protected carboxy group esterified by a lower alkyl group that is substituted in the 1 - or 2-position of the lower alkyl group by suitable substituents is, for example, aryl- methoxycarbonyl having one or two aryl radicals, wherein aryl is phenyl that is unsubstituted or mono-, di- or tri-substituted, for example, by lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the mentioned substituents, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxy- carbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by the mentioned substituents, for example di(4-methoxyphenyl)
  • a carboxy group can also be protected in the form of an organic silyloxycarbonyl group.
  • An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, for example tnmethylsilyloxycarbonyl.
  • the silicon atom of the silyloxycarbonylgroup can also be substituted by two lower alkyl groups, for example methyl groups, and the amino group or the carboxy group of a second molecule of formulal.
  • Compounds having such protecting groups can be prepared, for example, using dimethylchlorosilane as silylating agent.
  • a protected carboxy group is preferably lower alkoxycarbonyl, for example methoxy-, ethoxy- or tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9- fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.
  • protecting groups that are not constituents of the desired end product of formulal for example the carboxy-protecting groups
  • the removal of the protecting groups is described, for example, in the standard works mentioned above in the section relating to "Protecting groups".
  • protected carboxy for example lower alkoxycarbonyl, tert-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by a trisubstituted silyl group or in the 1 -position by lower alkoxy or lower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonyl can be converted into free carboxy by treatment with a suitable acid, such as formic acid, hydrogen chloride or trifluoroacetic acid, where appropriate with the addition of a nucleophilic compound, such as phenol or anisole.
  • a suitable acid such as formic acid, hydrogen chloride or trifluoroacetic acid
  • Carboxy can also be freed from lower alkoxycarbonyl by means of bases, such as hydroxides, for example alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • bases such as hydroxides, for example alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • Unsubstituted or substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst.
  • suitably substituted benzyloxycarbonyl such as 4-n ⁇ trobenzyloxycarbonyl
  • 2-halo-lower alkoxy ⁇ carbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2- ⁇ odo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into free carboxy.
  • Aroylmethoxycarbonyl can also be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide 2-(tr ⁇ -substituted silyl)-lower alkoxycarbonyl, such as 2-tr ⁇ -lower alkylsilyl-lower alkoxycarbonyl, can also be converted into free carboxy by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, where appropriate in the presence of a macrocyclic polyether ("Crown ether"), or with a fluoride of an organic quaternary base, such as tetra-lower alkyl- ammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, for example tetra- ethylammonium fluoride or tetrabut
  • Carboxy protected in the form of organic silyloxycarbonyl such as tri-lower alkylsilyloxycarbonyl, for example tnmethylsilyloxycarbonyl
  • solvolysis for example by treatment with water, an alcohol or an acid, or, furthermore, a fluoride, as described above
  • Esterified carboxy can also be freed enzymatically, for example by means of esterases or suitable peptidases, for example esterified arginine or lysine, such as lysine methyl ester, using trypsin
  • the invention relates in particular to the processes described in the examples.
  • Salts of compounds of the formula I can be prepared in a manner known per se.
  • acid addition salts of compounds of the formula I are obtained by treating with an acid or a suitable ion exchange reagent Salts can be converted into the free compounds in a customary manner, and acid addition salts can be converted, for example, by treating with a suitable basic agent.
  • the compounds according to the invention having salt-forming, in particular basic properties can be obtained in free form or preferably in the form of salts.
  • novel compounds including their salts of salt-forming compounds can also be obtained in the form of their hydrates or can include other solvents used for crystallization.
  • novel compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures, depending on the number of asymmetric carbon atoms.
  • Acid addition salts can be prepared by neutralizing a compound of the formula (I) having a basic group with an acid or an acidic ion exchanger.
  • Salts with a base can be prepared by neutralizing a compound of the formula (I) having an acidic group with a base compound.
  • the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material and the missing steps are carried out or a starting material in the form of a derivative or salt and/or its racemates or antipodes is used or, in particular, formed under the reaction conditions.
  • those starting materials are preferably used which lead to the compounds described as particularly useful at the beginning.
  • the invention likewise relates to novel starting materials which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation.
  • the invention especially relates to novel starting materials their manufacture and use, e.g. as starting material.
  • the invention likewise relates to pharmaceutical preparations which contain the compounds according to the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for their preparation.
  • the pharmaceutical preparations according to the invention which contain the compound according to the invention or pharmaceutically acceptable salts thereof are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) warm ⁇ blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • the daily dose of the active ingredient depends on the age and the individual condition and also on the manner of administration.
  • the novel pharmaceutical preparations contain, for example, from about 10 % to about 80%, preferably from about 20 % to about 60 %, of the active ingredient.
  • the pharmacologically active compounds of the invention can be used in the manufacture of pharmaceutical compositions that comprise an effective amount of the same on its own or in conjunction or admixture with excipients or carriers that are suitable for enteral or parenteral administration.
  • Preferred are tablets and gelatin capsules that comprise the active constituent together with a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, b) glidants, for example silica, talc, stearic acid, the magnesium or calcium salt thereof and/or polyethylene glycol, for tablets also c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired d) dispersing or disintegrating agents, for example starches, agar, alginic acid or the sodium salt thereof, or foaming mixtures and
  • Injectable preparations are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously produced from fatty emulsions or suspensions.
  • These compositions may be sterilised and/or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. In addition they may also contain other therapeutically valuable substances.
  • These preparations are manufactured according to conventional mixing, granulating or coating methods and contain approximately from 0.1 to 100%, preferably approximately from 1 to 50%, of the active constituent.
  • a unit dose for a mammal weighing approximately from 50 to 70 kg may contain between approximately 0.2 and 2000 mg, preferably between approximately 1 and 200 mg, of active constituent.
  • N-butanesulfonyl-(t-butoxycarbonyl)-valineamide (0.70 g, 2.08 mmol) in 1 ,4- dioxane (25 ml) is added 4N HCI/1 ,4-dioxane (30 ml) at room temperature under nitrogen atmosphere and the mixture is stirred for 8 hours.
  • the reaction mixture is concentrated in vacuo and the solid residue is washed with diethyl diethyl ether and dried to give N- butanesulfonyl-valineamide hydrochloride.
  • the material can be purified by flash chromatography on silica gel, using hexane/ethyl acetate (4:1) as eluent.
  • hexane/ethyl acetate (4:1) as eluent.
  • bis benzoyl peroxide (0.43 g, 1.78 mol) is added, and the mixture is heated on reflux over night.
  • the solvent is evaporated, and the residue is purified by flash chromatography (silica gel, hexane/ethyl acetate 4:1) to give pure 5-(4-bromomethylphenyl)-isoxazole.
  • N-(3,5-dimethylbenzoyl)-3-[4-(5-isoxazolyl)-phenyl]-(D,L)-alanine ethyl ester (3.8 g, 9.7 mmol) and iodomethane (1.8 ml, 28.9 mmol) in dry N
  • N-dimethylformamide 40 ml
  • sodium hydride 60 % in oil, 390 mg, 9.8 mmol
  • the mixture is allowed to warm to room temperature during 5 hours, then poured into water, extracted with ethyl acetate. The organic phase is washed with water, and with brine, dried and evaporated.
  • N-(3,5-Dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D,L)-alanine ethyl ester (44 mg, 0.11 mmol) is treated with lithium hydroxide monohydrate (5 mg, 0.12 mmol) in methanol (0.5 ml), tetrahydrofurane (0.25ml), and water (0.25 ml) for 3 hours at room temperature. The mixture is then extracted with ether and water, the aqueous phase is acidified with 1 N hydrochloric acid, and subsequently extracted with ethyl acetate.
  • the diastereomeric mixture is separated by HPLC [Shim-pack PREP-SIL (L), hexane/isopropanol (95:5)] into a less polar isomer N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanine [(R)-(-)-2,2-dimethyl-1 ,3-dioxolane-4-yl]-methyl ester (16) and a more polar isomer N-(3,5- dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(L)-alanine [(R)-(-)-2,2-dimethyl-1 ,3- dioxolane-4-yl]-methyl ester.
  • reaction mixture is condensed in vacuo and the residue is diluted with water and washed with ethyl acetate three times.
  • the aqueous layer is acidified with 1 N HCl and extracted with ethyl acetate.
  • the organic layer is dried over magnesium sulfate and concentrated in vacuo to give N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanine.
  • N-(3.5-Dimethylbenzoyl)-N-methyl-3-r4-n .2.4-triazol-1-yl)-phenvn-(D.L ⁇ -alanine A mixture of 3,5-dimethylbenzamide (22.6g, 0.15mol) and glyoxylic acid monohydrate (15.3g, 0.17mol) in acetone (120ml) is heated under nitrogen atmosphere at reflux for 6h. The solvent is evaporated in vacuo to give 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine. To a solution of 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine in methanol (350ml) is added concentrated sulfuric acid (4.6ml) at room temperature.
  • the crude material is purified by column chromatography on silica with hexane/ethyl acetate (1 :2) to give 4-(1 ,2,4-triazol-1-yl)-benzaldehyde and with ethyl acetate/methanol (19:1) to give 4-(1 ,3,4-triazol-1-yl)-benzaldehyde.
  • the prepicipates are filtered, washed with diethyl ether and water successively, and dried in vacuo to give methyl 2-(3,5-dimethylbenzoyl)amino-3- [4-(1 ,2,4-triazol-1 -yl)phenyl]acrylate.
  • the crude material is purified by column chromatography on silica with hexane/ethyl acetate (1 :5) to give N-(3,5-dimethylbenzoyl)-N-methyl-3-[4- (1 ,2,4-triazol-1-yl)-phenyl]-(D,L)-alanine methyl ester.
  • N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(1 ,2,4-triazol-1 -yl)-phenyl]-(D,L)-alanine methyl ester (1 ,24g, 3.15mmol) is treated with lithium hydroxide (0.16g, 3.77mmol) in methanol ⁇ etra- hydrofuran/water (1 :1 :1) (30ml) at 0°C. After 2h, the mixture is slowly warmed to room temperature and stirred overnight. The reaction mixture is acidified with 1 N hydrochloric acid (3.8ml), diluted with water, and extracted with chloroform.
  • N-butanesulfonyl-(t-butoxycarbonyl-O-t-butyl)-(L)-threonineamide (759 mg, 2.29 mmol) is treated with trifluoroacetic acid (5 ml) at 0°C under nitrogen atmosphere and the stirring is continued for 2.5 hours.
  • reaction mixture is concentrated in vacuo and 4N HCl in 1 ,4- dioxane (4 ml) and diethyl ether is added to the residue.
  • the white precipitates are filtered and washed with diethyl ether.
  • the solid is recrystallized from ethanol to give N- butanesulfonyl-(L)-theronineamide hydrochloride.
  • Methyl 3-benzyloxy-5-methyl-benzoate (1.77 g, 6.90 mmol) is treated with lithium hydroxide (0.323 g, 7.70 mmol) in methanol ⁇ etrahydrofuran/water (2:1 :1) at 50°C. After 2.5 hours, the mixture is cooled to room temperature, acidified with 1 N hydrochloric acid, diluted with water, and extracted with ethyl acetate The organic layer is washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 3-benzyloxy-5-methyl-benzoic acid.
  • N-(3-Hydroxy-5-methyl-benzoyl)-N-methyl-3-[4-(1 ,2,4-triazol-1-yl)-phenyl]-(D,L)-alanine methyl ester (0.397g, 1.01 mmol) is treated with lithium hydroxide (0.118 g, 2.81 mmol) in methanol/tetrahydrofuran/water (2.5:2.5:1) (6 ml) at room temperature. After being stirred for 4 hours, the mixture is concentrated in vacuo. The residue is diluted with water and washed with 2 portions of diethyl ether.
  • the aqueous layer is acidified with 1 N hydrochloric acid (2.85 ml), diluted with brine, and extracted twice with ethyl acetate.
  • the organic layer is dried over sodium sulfate and concentrated in vacuo to give N-(3-hydroxy-5-methyl- benzoyl)-N-methyl-3-[4-(1 ,2,4-triazol-1-yl)-phenyl]-(D,L)-alanine.
  • N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(1 ,2,4-triazol-1-yl)-phenyl]- (D.L)-alanine (213 mg, 0.56 mmol) in N.N'-dimethylformamide (7.0 ml) under nitrogen atmosphere are added N-butanesulfonyl-(L)-valineamide hydrochloride (159 mg, 0.58 mmol) and 1 -hydroxybenzotriazole (150 mg, 1.11 mmol).
  • N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(1 ,2,4- triazol-1-yl)-phenyl]-(D,L)-alanyl]-(L)-valineamide is separated by preparative HPLC (Ultron silica) with hexane/ethanol/trifluoroacetic acid (90:10.0.5) to give N-butanesulfonyl- [N-(3,5- d ⁇ methylbenzoyl)-N-methyl-3-[4-(1 ,2,4-tr ⁇ azol-1-yl)-phenyl]-(D)-alanyl]-(L)-val ⁇ neam ⁇ de trifluoroacetic acid salt
  • N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(1 ,2,4-t ⁇ azol-1-yl)-phenyl]- (D.L)-alanine 350 mg, 0.92 mmol
  • N,N'-dimethylformam ⁇ de 5.0 ml
  • N-butanesulfonyl-(L)-threon ⁇ neam ⁇ de hydrochloride 280 mg, 1.02 mmol
  • 1 -hydroxybenzotriazole 250 mg, 1.85 mmol
  • the crude material is purified by preparative thin layer chromato ⁇ graphy with chloroform/methanol/acetic acid (100:10:1) to give N-butanesulfonyl-[N-(3,5- dimethylbenzoyl)-N-methyl-3-[4-(1 ,2,4-triazol-1-yl)-phenyl-(D,L)-alanyl]-(L)-threonineamide.
  • N-butanesulfonyl-[N-(3-hydroxy-5-methylbenzoyl)-N-methyl-3-[4- (1 ,2,4-triazol-1 -yl)-phenyl]-(D,L)-alanine (272 mg, 0.72 mmol) in N.N'-dimethylformamide (10 ml) under nitrogen atmosphere are added N-butanesulfonyl-(L)-valineamide hydrochloride (253 mg, 0.93 mmol) and 1 -hydroxybenzotriazole (208 mg, 1.54 mmol).
  • composition for 10,000 tablets
  • the active ingredient e.g. N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5- isoxazolyl)-phenyl]-(D)-alanyl]-(L)-valineamide
  • the active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened using an alcoholic solution of the gelatin and granulated by means of a sieve.
  • the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of weight 145.0 mg each and active ingredient content 50.0 mg which, if desired, can be provided with breaking notches for finer adjustment of the dose.
  • Coated tablets each containing 100 mg of active ingredient, for example, N-butanesulfonyl-
  • Composition for 1000 tablets:
  • the active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste prepared from 15 g of corn starch and water (with warming).
  • the granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules.
  • the mixture is compressed to give tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the coated tablet: 283 mg).
  • Example 12 Tablets and coated tablets containing another compound of the formula I or a pharmaceutically acceptable salt of a compound of the formula I, for example as in one of Examples 1 to 9, can also be prepared in an analogous manner to that described in Examples 10 and 11. Pharmacological Experiments
  • the binding affinity to the ET receptor of the compounds of the present invention is determined according to the method described below (published in Takagi et al. (1995) J. Biol. Chem., 270, 10072-10078).
  • ET-1 and ET-3 were purchased from Peptide Institute Inc. (Osaka, Japan), and [ 125 I]ET-1 (-74 TBq/mmol) was from Amersham International (Buckinghamshire, U.K.).
  • Human ETA or ET ⁇ receptors are stably expressed in CHO (Chinese hamster ovary) cells, and plasma membranes having the ETA or ET ⁇ receptor are prepared from these cells.
  • the membranes (-0.04 mg ⁇ ube, for ETA receptor binding and -0.3 mg/tube for ET ⁇ receptor binding) are incubated at 37°C for 4 hours and 2 hours for ETA and ET ⁇ , respectively, with 10 pM [ 125 I]ET-1 in the absence or presence of various amounts of nonlabeled ligands in a total volume of 1 ml of 20 mM HEPES (pH 7.4), containing 145 mM NaCI, 5 mM KCl, 3 mM MgCl2, 1 mM EGTA, 1 mg/ml bovine serum albumin, and 0.2 mg/ml bacitracin.
  • the ETA receptor shows an apparant dissociation constant (Kd) of 5.9 pM and maximum binding sites (Bmax) of 33.3 pmol/mg of protein, while the ET ⁇ receptor has a Kd of 3.5 pM and Bmax of 1.0 pmol/mg of protein.
  • Kd apparant dissociation constant
  • Bmax maximum binding sites

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Abstract

L'invention concerne de nouveaux composés, représentés par la formule générale (I). Dans cette formule, (i) R1 représente un 1,2,4-triazol-1-yle, R2 représente un méthyle ou hydroxy, R3 représente un méthyle ou hydroxy et l'astérisque signifie que l'atome de carbone chiral indiqué a la configuration (D) ou (D,L), ou (ii) R1 représente un isoxazol-5-yl, R2 est un méthyle, R3 est un méthyle et l'astérisque signifie que l'atome de carbone chiral indiqué a la configuration (D). L'invention concerne également les sels de ces composés, des procédés permettant leur fabrication, des compositions pharmaceutiques les contenant et l'utilisation des composés de la formule (I) et de leurs sels.
PCT/EP1996/004063 1995-09-28 1996-09-17 Antagonistes des recepteurs de l'endotheline WO1997011960A1 (fr)

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JP9513117A JPH11512702A (ja) 1995-09-28 1996-09-17 エンドセリンレセプターのアンタゴニスト
AU71302/96A AU7130296A (en) 1995-09-28 1996-09-17 Antagonists of endothelin receptors

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6855843B2 (en) 1998-01-20 2005-02-15 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7476758B2 (en) 2002-02-28 2009-01-13 Mitsubishi Tanbe Pharma Corporation Process for preparing a phenylalanine derivative and intermediates thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline
WO1995012611A1 (fr) * 1993-11-01 1995-05-11 Japat Ltd. Antagonistes de recepteur d'endotheline
WO1995026360A1 (fr) * 1994-03-28 1995-10-05 Japat Ltd. Antagonistes des recepteurs de l'endotheline

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0460679A2 (fr) * 1990-06-07 1991-12-11 Banyu Pharmaceutical Co., Ltd. Dérivés peptidiques ayant une activité antagoniste d'endothéline
WO1995012611A1 (fr) * 1993-11-01 1995-05-11 Japat Ltd. Antagonistes de recepteur d'endotheline
WO1995026360A1 (fr) * 1994-03-28 1995-10-05 Japat Ltd. Antagonistes des recepteurs de l'endotheline

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6855843B2 (en) 1998-01-20 2005-02-15 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7476758B2 (en) 2002-02-28 2009-01-13 Mitsubishi Tanbe Pharma Corporation Process for preparing a phenylalanine derivative and intermediates thereof

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