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WO1996023773A1 - Derives d'acide 4-oxo-2-butenoique - Google Patents

Derives d'acide 4-oxo-2-butenoique Download PDF

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Publication number
WO1996023773A1
WO1996023773A1 PCT/JP1996/000195 JP9600195W WO9623773A1 WO 1996023773 A1 WO1996023773 A1 WO 1996023773A1 JP 9600195 W JP9600195 W JP 9600195W WO 9623773 A1 WO9623773 A1 WO 9623773A1
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WO
WIPO (PCT)
Prior art keywords
group
methylenedioxyphenyl
methoxyphenyl
oxo
butenoic acid
Prior art date
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Ceased
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PCT/JP1996/000195
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English (en)
Japanese (ja)
Inventor
Kiyofumi Ishikawa
Toshio Nagase
Masaki Ihara
Masaru Nishikibe
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MSD KK
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Banyu Phamaceutical Co Ltd
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Priority to AU45478/96A priority Critical patent/AU4547896A/en
Publication of WO1996023773A1 publication Critical patent/WO1996023773A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present invention is useful in the field of medicine, and more specifically, has an antagonistic effect on three types of endoselins (endothelin-1, endoselin-12 and endoselin-13), which are endogenous potent bioactive peptides.
  • the present invention relates to a novel compound having the formula, a method for producing the compound, and a use thereof.
  • Endothelin is a polypeptide consisting of 21 amino acids and is produced by human and butter endothelial cells and has a strong vasoconstrictive action and a sustained and strong pressor action [Nature, 332, pp. 411—p. 415 (1988)].
  • Endothelin is also known to contain three types of endothelin (endothelin-1, endoselin-1 and endothelin-3) in animals including humans as 5-family peptides with similar structures. It is known that all of these peptides have a vasoconstrictive action and a pressor action [Proceding National 'Academy of Sciences (Proc. Nat 1. Acad. Sci. USA), 86, 0 2863 -2867 (1 989)].
  • Endothelin is clinically present in patients with essential hypertension, patients with acute myocardial infarction, patients with pulmonary hypertension, patients with Reino's disease, patients with diabetes mellitus, patients with atherosclerosis, blood in patients with asthma, or airway lavage fluid.
  • Japan it has been reported that the number is clearly higher than that in normal subjects [Japn. J.5 Hypertension, Vol. 12, p. 79 (1989), Journal Biological Medicine 'and' Biology (J. Vascular Medicine Bioloy, Vol. 2, pp. 207 (1991)), Diabetologia (Diabetologia) 306, p. 306—p. 310 (1990), Journal of Ob. American Medical Medical Assoc. J. Am. Ed. As sociation, Vol. 264, pp. 2868 (1990) and The Lancet, Vol. 2, 747-748. 1989) and Vol. 2, pp. 1144-1-1147 (1990)].
  • endothelin is considered as one of the causative agents of cerebral vasospasm and acute gastric insufficiency after subarachnoid hemorrhage.
  • Endothelin is an endogenous bioactive peptide, renin and atrial natriuretic diuretic hormone, as well as endothelial cell-derived vasorelaxant (EDRF), umbo boxane A2, proscine cyclin, noradrenaline, and angiotensin. It has also been found that it regulates the release of physiologically active substances such as II and substance P [Biochemical and Biophysical Research Communication (Biochem. Biophysis. Res. Commun.), Vol. 157, pp. 1164-1-1168 (1988), Biochemical 'and' Biophysical Research 'Communications (Biochems. Biohys) Commun.), Vol. 155, pp.
  • II and substance P Biochemical and Biophysical Research Communication (Biochem. Biophysis. Res. Commun.), Vol. 157, pp. 1164-1-1168 (1988), Biochemical 'and' Biophysical Research 'Communications (Biochems. Biohys) Comm
  • Endothelin has also been found to promote the proliferation of rat vascular smooth muscle cells, suggesting a relationship with arterial hypertrophy [A therosc erosis, Vol. 78, No. 225]. Page 228 (1 989)]. 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 have an important role in regulation [see Neuroscience Letters, 97, 276-279 (11989)]. In particular, endothelin has been suggested to be a type of mediator of pain sensation [Life's Sciences, Vol. 49, PL-61, PL-65 (1991) )].
  • endotoxin is one of the potential candidates for promoting endogenous endoselin release. It has been found that when endotoxin is administered exogenously to animals or when added to cultured vascular endothelial cells, the endocrine port in blood or culture supernatant is significantly increased. Endothelin is considered to be one of the important mediators involved in endotoxin-induced diseases [Biochemical & Biophysical Research Communications (Biochem. Biophysis. Res. O mm un.)
  • Endoserine receptors have at least two subtypes from previous studies, and it is known that vasoconstriction by endoselin is also induced through these two subtypes [Journal ⁇ ' ⁇ ⁇ ''io io io
  • ETJ endothelin receptor
  • ET B Endoserin receptor having substantially the same activity at 3
  • tissue ⁇ cloth two Endoserin receptor subtypes with different selectivity between these Endoseri Nfami Li one base peptide are different, whereas ET A receptors often the cardiovascular system, ET B receptors
  • the body is known to be distributed in a wide range of tissues, such as the brain, kidney, lung, heart, and blood vessels.
  • Endothelin is an endogenous bioactive substance that directly or indirectly (regulates release of various endogenous substances) continuously contracts or relaxes vascular and non-vascular smooth muscle, and its excess Production and hypersecretion include hypertension, pulmonary hypertension, Reino's disease, bronchial asthma, gastric drought, diabetes, arteriosclerosis, acute insufficiency, heart failure, myocardial infarction, angina, cerebral vasoconstriction and cerebral infarction. It is thought to be one of the causes.
  • endoselin acts as an important mediator for diseases such as restenosis, benign prostatic hyperplasia, endotoxin shock or endotoxin-induced multiple organ failure, disseminated intravascular coagulation, cyclosporine-induced renal impairment, and high Jfilffi.
  • diseases such as restenosis, benign prostatic hyperplasia, endotoxin shock or endotoxin-induced multiple organ failure, disseminated intravascular coagulation, cyclosporine-induced renal impairment, and high Jfilffi.
  • the Endoseri down receptors are known E TA receptor ⁇ beauty E T beta receptor, with E T Alpha receptor antagonist, E T beta receptor antagonists, are useful as pharmaceuticals.
  • non-peptidic compounds having an antagonistic action on endoselin receptor have already been disclosed in the art (for example, EP 0526708 A1 and WO9308799A1), the present invention , they a have a different new structures, ET a receptors, the invention of the non-base peptide compound having at least one strongly antagonistic activity against one of the ET B receptor, the various diseases of the upper Symbol On the other hand, it seeks to provide new treatments that have never existed before.
  • the present inventors synthesized various derivatives and examined their endocerin antagonistic activity.
  • a 5-hydroxy-2 (5 () monofuranone derivative or a pharmaceutically acceptable salt thereof [wherein, in the general formulas [I] and [II], Ar ′ and Ar 3 are each independently Any hydrogen atom on the aryl ring may be a halogen atom, a hydroxyl group, an amino group, a carboxy group, a C, monoalkoxycarbonyl group, a mono- or di-, mono-alkylaminocarbonyl group, a carbamoyl group, Lazo rule 5 I group, Mechirenjiokishi groups, C, - C fi alkoxy groups, C 2 - C 6 ⁇ Rukeniruokishi group, Ji mono- or di-one C 6 alkylamino groups, C, -C 6 7 alkyl groups, C 2 — C «alkenyl group and C 2 — C fi alkynyl group (provided that the C, — C « alkoxy group, C 2 — C 6 alkenyloxy group, mono or
  • the compound of the present invention has a high affinity for end serine receptor subtype ET, and at least one of ET and at least one receptor, and inhibits end serine binding.
  • has a smooth muscle relaxing action such as vasodilatory action, bronchodilator action, etc., in the field of medicine, especially hypertension, pulmonary hypertension, Reino's disease, acute renal failure, heart failure, myocardial infarction, angina, cerebral infarction, brain Multiple organ failure or disseminated intravascular coagulation due to vasospasm, arteriosclerosis, bronchial asthma, gastric pouch, diabetes, restenosis, prostatic hypertrophy, endotoxin shock, endotoxin, and renal disorder induced by Z or cyclosporine And therapeutic agents for hypertension and the like.
  • a halogen atom means fluorine, chlorine, bromine and iodine. means.
  • the C, 1 alkoxyl propyl group means an alkoxycarbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.
  • alkylaminocarbonyl group means an alkylaminocarbonyl group having 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms on N, For example, a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, an isopropylaminocarbonyl group, a butylaminocarbonyl group, an isobutylaminocarbonyl group, a tert-butylaminocarbonyl group, a pentylaminocarbonyl group, a Soventilaminocarbonyl, hexylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, ethylaminocarbonyl, isopropylmethylaminocarbonyl, dipropylaminocarbonyl, Tyl isopropylaminocarbonyl group Propyla
  • the C, -C s alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group. And butoxy groups, isobutoxy groups, sec-butoxy groups, tert-butoxy groups, pentyloxy groups, hexyloxy groups and the like.
  • alkenyloxy group means an alkenyloxy group having a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyloxy group, aryloxy group, and 1-propenyloxy group.
  • Group, isopropenyloxy group examples thereof include a 2-butenyloxy group, a 3-butenyloxy group, a 2-pentenyloxy group, a 3-methyl-3-butenyloxy group, and a 2-hexenyloxy group.
  • a mono- or di-C 1, 1 C 6 alkylamino group means an alkylamino group having 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms, such as a methylamino group and an ethylamino group.
  • C - The C K alkyl group, carbon number means the 1-6 linear or branched alkyl group, specifically, methyl group, Echiru group, propyl group, isopropyl group, Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-1 Ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1.1 I-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl Group, 1-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group, 1-eth
  • the C one C K alkenyl group, carbon atoms means a 2-6 straight-chain or branched an alkenyl group include a vinyl group, Ariru group, 1 one propenyl group, isopropenyl Benzyl group, 3-butenyl group, 2-butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1 1-ethenyl group, 2 —Methyl-2-propenyl group, 2-methyl-1-propenyl group, 4-pentenyl group and the like.
  • the C 2 -C 6 alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, specifically, an ethynyl group, a 1-propynyl group, a 2-propynyl group , 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-12-propynyl, and 1-pentynyl.
  • the hydroxy C, -C 6 alkylcarbonyl group means a linear or branched hydroxyalkyl carbonyl group having 2 to 7 carbon atoms, such as a hydroquinone methylcarbonyl group and a 1-hydroquinethyl carbonyl group.
  • Anrokishi CC fi alkylcarbonyl groups, C having aliphatic or aromatic en port alkoxy groups, one C s Anrokishi C means a single C 6 alkylcarbonyl group, e.g., ⁇ cetyl O Kin methylcarbonyl Group, 1-acetyloxy acetyl group, 2-acetyl oxyethyl carbonyl group, 1-acetyl oxypropyl carbonyl group, 1-acetyl oxy butyl carbonyl group, 1-acetyl oxy pentyl carbonyl group, 1-acetyloquinecarbonylcarbonyl, 2-acetyloquinepropylcarbonyl, propionyloxymethylcarbonyl, 1-propionyloxyshetylcarbonyl, butyryloxymethylcarbonyl, pentanoyloxymethylcarbonyl , Hexanoyloxymethylcarbonyl group, benzoyloxime Rucarbon
  • a carboxy CC fi alkoxycarbonyl group means a straight-chain or branched carboquin C 3, 1C 6 alkoxycarbonyl group having 3 to 10 carbon atoms.
  • a carboxy C, 1 CB alkoxycarbonyl C, 1 Ce alkoxycarbonyl group is a straight or branched carboxy C—alkoxycarbonyl C, — C alkoxycarbonyl group having 6 to 16 carbon atoms.
  • the C 1, C «alkylsulfonylaminocarbonyl group means an alkylsulfonylaminocarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methylsulfonylaminocarbonyl group.
  • any of the hydrogen atoms on the aryl ring may be substituted with a C 1, -C alkyl group [the aryl C 1, 1 c «alkylsulfonylaminocarbonyl group may be a C 1, 1, alkylsulfonyla as defined above.
  • a r 'and A r 3 are each independently any of a hydrogen atom on Ariru ring, a halogen atom, a hydroxyl group, an amino group, a carboxy group, C, one C B alkoxy carbonyl group, mono- or di, -Ce alkyl aminocarbonyl group, Cal Bamoiru group, Tetorazoru 5 I group, Mechirenjiokishi group, C, one C 6 7 alkoxy group, C 2 -C 3 Arukeniruokishi group, mono- or di - C 6 alkyl Ruamino group, C, one C 6 alkyl group, Ji 2 - Ji Arukeniru groups and 2 - Ji 6 ⁇ Le Kiniru group (with the proviso that the C, one C 6 alkoxy groups, C 2 - C «Arukeniruokishi group, a mono- or di-C, - C « Alkylamino group, C 1, 1C B alkyl group
  • 5-year old It may be substituted with 1 to 3 substituents selected from the group consisting of a Satidiazol-41-yl group and a 5-oxo-l-4 ⁇ -1.2,4-oxosaziazol-3-yl group (however, And when a hydroxyl group and a carboxyl group are selected as the substituent, they may be combined to form a lactone ring)) and are substituted with 1 to 4 substituents selected from the group consisting of may also show a full group, a thienyl group or a dihydric Dorobenzofura two Le group; a r 2 represents a hydrogen atom arbitrary on the heterocyclic ring, C, one C H alkyl, or C, one C «alkyl amino group Represents a pyridyl group, an imidazolyl group, a thiazolyl group, a pyrimidinyl group, a pyridazinyl group or a virazinyl group which
  • the halogen atom means fluorine, chlorine, bromine and iodine.
  • the C, C 6 alkoxyl alkoxyl group means an alkoxycarbonyl group having a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxycarbonyl group and ethoxycarbonyl group.
  • a mono- or di-C 1, 6 -C 6 alkylaminocarbonyl group means an alkylaminocarboxy group having 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms on N.
  • the C 1, C «alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxyquinone group, an ethoxy group, a propoxy group, an isopropoxy group.
  • the C 2 -C ( , alkenyloxy group means an alkenyloxy group having a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyloxy group, an aryloxy group, and a 1-propyl group.
  • Niloxy group, isopropenyloxy group examples thereof include a 2-butenyloxy group, a 3-butenyloxy group, a 2-pentenyloxy group, a 3-methyl-3-butenyloxy group, a 2-hexenyloxy group, and the like.
  • the mono- or di-, 1 C 6 alkylamino group means an alkylamino group having 1 or 2 linear or branched alkyl groups having 1 to 6 carbon atoms on N, such as methylamino group, ethylamino group.
  • the C, -Cb alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1- Ethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1.2-dimethylbutyl group, 2, 2 — Dimethylbutyl group, 1-ethylbutyl group, 1.1,2—trimethylpropyl group, 1,2,2—trimethyl propyl group, 1-eth
  • the C 2 -C b alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, Isopropenyl group, 3-butenyl group, 2-butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl_1-propenyl group, 1-ethyl-1-ethenyl group, 2 —Methyl-2-propenyl group, 2-methyl-1-propenyl group, 4-pentenyl group and the like.
  • alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, specifically, ethynyl group, 1-propynyl group, 2-propynyl group , 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-12-propynyl group, 1-pentynyl group and the like.
  • the hydroxy C, 1 C 6 alkylcarbonyl group means a linear or branched hydroxyalkyl carbonyl group having 2 to 7 carbon atoms, such as a hydroxymethylcarbonyl group and a 1-hydroxyethylcarbonyl group.
  • acyloxy C,-CK alkylcarbonyl group means a C, 1 C 6 -anhydroquinone C, monoalkylcarbonyl group having an aliphatic or aromatic amino group, for example, acetyl Oxymethyl carbonyl group, 1-acetyloxy acetyl group, 2-acetyl oxyethyl carbonyl group, 1-acetyl oxy propyl carbonyl group, 1-acetyl oxy butyl carbonyl group, 1-acetyl oxy carbonyl group Pentylcarbonyl group, 1-acetyloxyhexylcarbonyl group, 2-acetyloxypropylcarbonyl group, propionyloxymethylcarbonyl group, 1-propionyloxyshetylcarbonyl group, butyryloxymethylmethylcarbonyl group, pentanoyloxy Methylcarbonyl group, hexanoyloxymethylcarbonyl group, benzoyloxime Ty
  • Karubokin C, and one C B alkoxycarbonyl group, charcoal Shu number 3-1 0 straight-chain or branched carboxy C means a single C 6 alkoxycarbonyl two group, Kiyoshi
  • a carboxy C, 1 C ⁇ alkoxycarbonyl C, 1 C 6 alkoxycarbonyl group means a linear or branched carboquine C 6, 1 C ⁇ , alkoxycarbonyl c, 1 c ft having 6 to 16 carbon atoms.
  • An alkoxycarbonyl group means, for example, carboxymethoxycarbonylcarbonyl, 1-carboxyethoxyquinoxycarbonyl, 1-carboxypropoxycarbonylmethoxycarbonyl, 1-carboxybutoxycarbonylmethoxycarbonyl.
  • the C 1, C «alkylsulfonylaminocarbonyl group means an alkylsulfonylaminocarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methylsulfonylaminocarbonyl.
  • Any hydrogen atom on the aryl ring may be replaced by a C, 1C ⁇ alkyl group, and the arylC, 1alkylsulfonylaminocarbonyl group is a C, 1C alkyl as defined above.
  • Aminocarbonyl group 1-methyl-2-phenylethylsulfonylaminocarbonyl group, phenylbutylsulfonylaminocarbonyl group, phenylpentylsulfo Ruminocarbonyl group, phenylhexylsulfonylaminocarbonyl group, naphthylmethylsulphonylaminocarbonyl group, naphthylethylsulphonylaminocarbonyl group, naphthylbutylpyrusulfonylaminocarbonyl group, cetylmethylsulphonylaminocarbonyl group, Pyridylmethylsulfonylaminocarbonyl group, furylmethylsulfonylaminocarbonyl group, ceenylethylsulfonylaminocarbonyl group, pyridylethylsulfonylaminocarbonyl group, furylethylsulfony
  • Ar ′ and Ar 3 are each independently an aromatic Any hydrogen atom on the ring a halogen atom, a hydroxyl group, an amino group, Mechirenjio alkoxy group, C, - C 6 alkoxy groups, C 2 - C 6 Arukeniruokishi group, mono Wakashi Ku di.
  • a r 2 is any hydrogen atom on the heterocyclic ring, C, - C 6 alkyl group or a C, - C,> alkylamino Bruno pyridyl group which may be substituted with a group, Lee imidazolyl group, Ji Azoriru group, pyridinium Represents a midinyl group, a pyridazinyl group or a birazinyl group, and specific examples of the C, 1Cb alkyl group include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl, Hexyl group and the like.
  • Examples of the C, -C alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a sec-butylamino group, a pentylamino group, and a phenylamino group.
  • the compound represented by the general formula [I] has a general formula [I]
  • a r ', A r 2, and A r 3 are as defined above] exists isomers represented by the compounds represented by the Among the general formula [I a] is more preferable.
  • the novel 4-oxo-12-butenoic acid derivatives and 5-hydroxy-2 (5H) monofuranone derivatives represented by the general formulas [I] and [II] of the present invention can be produced by the methods described below. it can.
  • a r 11 denotes an A r 1 or its synthetic equivalent] the Mechiruke Bok emissions derivative represented by methanol, ethanol, in a solvent and propanol, - at 20 ° C ⁇ solvent boiling point temperature , In the presence of a base such as sodium hydroxide, potassium hydroxide, etc.
  • Ar 31 represents Ar 3 or a synthetic equivalent thereof] with an aldehyde derivative represented by the general formula: Ar 31 — CH-CH— CO— Ar 11 [V]
  • the ⁇ , —unsaturated ketone [V] is reacted with sodium cyanide, potassium cyanide, etc. in a solvent such as ethanol or 2-ethoxyethanol in the presence of an acid such as acetic acid.
  • reaction temperature is preferably from room temperature to the boiling point of the solvent.
  • the nitrile derivative [VI] is reacted with an alcohol such as methanol or ethanol in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, etc.
  • the reaction temperature is preferably from room temperature to the boiling point of the solvent.
  • the compound of the present invention represented by the general formulas [I] and Z or [II] can be produced by combining the reaction and ii) reactions such as deprotection of the protecting group.
  • the base used in the reaction between the aldehyde [VIII] and the compound [VII] includes sodium methoxide and potassium tert-butoxide. And sodium hydride.
  • the reaction solvent is selected from methanol, tert-butanol, DMF, THF and the like according to the base used.
  • the reaction temperature is preferably from room temperature to the boiling point of the solvent.
  • the reaction intermediate and the target compound in the above-mentioned production method can be purified by a purification method known per se (for example, recrystallization, reprecipitation, partitioning operation, normal or reverse phase chromatography, ion exchange chromatography, etc.).
  • a purification method known per se for example, recrystallization, reprecipitation, partitioning operation, normal or reverse phase chromatography, ion exchange chromatography, etc.
  • a human neuroblast cell line (SK-N-MC cells) (purchased from Dainippon Pharmaceutical Co., Ltd.) was cultured in a minimum essential medium containing fetal bovine serum. Collect the cultured cells and use a polytron homogenizer at 4 ° C containing 154 mM NaCl, 10 mM KC1, 0.8 mM CaC and 20% sucrose. The mixture was homogenized in OmJVI OPS buffer (pH 7.4), and the homogenate was centrifuged at 1,000 ⁇ g for 15 minutes. The supernatant was further centrifuged at 100 ° C, xg at 4 ° C for 1 hour.
  • the obtained precipitate was washed with 5 mM HEPES / Tris buffer (PH 7.4) to obtain a membrane fraction.
  • This membrane fraction was purified using 0.1 mM PMS F, 11 VI capstatin, leptin, 1 mM 1, 10—phenanthine, 1 mM EDTA, I 0 CaCl 2 , ⁇ (: In a total of 0.4 ml of 50 mM TrisZHC1 buffer (pH 7.4) containing 12 and 0.1% bovine serum albumin, test compound or solvent (1
  • Compound of Example 2 and Example 8 is the representative compound of the present invention compounds, the binding of the '25 I- endothelin one 1 for ⁇ receptors were impaired respectively 9 9.5% inhibitory.
  • 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 end serine-11.
  • the compounds of Examples 2 and 8, which are representative compounds of the present invention significantly shift the end-serine-1 dose-response curve to the right at a concentration of 0.1 M to 10 zM, and show the maximum response. Had no effect. In addition, this compound alone did not show any action on the above-mentioned vascular specimen. As described above, the compound of the present invention showed a remarkable antagonistic effect on endoselin contraction in the above-mentioned blood vessel specimen.
  • the effect of the compound of the present invention on sudden death induced by administration of ET-1 (5 nmo 1 / kg) into the tail vein using male ddY mice was examined.
  • the test compound was administered intravenously 5 minutes before the administration of ET-1 to determine the mortality.
  • the compound of Example 8 which is a representative compound of the present invention, inhibited ET-1-induced sudden death by 80% by intravenous administration of 3 mg / kg.
  • the compound of the present invention was effective against ET-1-induced sudden death.
  • the compound of the present invention has excellent endoselin antagonism to the endoselin receptor, and is useful as a vasodilator and a bronchodilator in the field of pharmaceuticals.
  • the compound 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.
  • Pharmaceutical preparations include, for example, liquid preparations such as injections, inhalants, syrups or emulsions, solid preparations such as tablets, capsules or granules, and external preparations such as sound, suppositories and the like.
  • these preparations may optionally contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants.
  • the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.
  • the dose of the compound of the present invention as an endoselin 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.
  • Cesium fluoride (4.10 g, 0.027 Omo 1) and molecular sieve 4 A powder (1 g) were heated and dried under reduced pressure, allowed to cool, and suspended in 1,2-dichloroethane (5 ml). Then, a solution of 3- (tricholoquinemethyl) pyridine-N-oxide (20 Omg, 0.544 mmol) in 1,2-dichloroethane (2.5 m 1) obtained in (2), N —Isopropylbenzene power Add a solution of ruboximidoyl chloride (495 mg, 2.72 mol) in 1.2-dichloroethane (2.5 ml), and place in an argon atmosphere at room temperature for 2 hours at 50 ° C. Stirred for hours.
  • the reaction solution was filtered through celite, washed with chloroform, and the filtrate and the washing solution were combined and partitioned with water-cold form.
  • the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and dried over Na 2 SO.
  • the obtained crude product 35 Omg was dissolved in trifluoroacetic acid (3 ml), and the mixture was stirred at 0 ° C for 1 hour and then at room temperature for 30 minutes.
  • the reaction solution was partitioned between water and a black hole form, and the organic layer was washed with a saturated sodium bicarbonate solution and a saturated saline solution, and dried over Na 2 SO ⁇ .
  • the 1 mmo mixture was stirred and heated to 158 ° C over 45 minutes after cooling to room temperature, the reaction solution was allowed to cool to room temperature, then dropped into ice water, and extracted with isopropyl ether. After washing with saturated aqueous sodium hydrogen carbonate and saturated brine, drying over MgSO 4 and distilling off the solvent under reduced pressure, the obtained residue was distilled under reduced pressure to give 2-bromo-1-n-butyl-3-.
  • the cyano pyridine (1.20 g) was obtained.
  • the 2-promo 6-n-butyl-3-cyanopyridine (1.00 g, 418 mmol) obtained in (2) is dissolved in toluene (20 ml), and 2,2'-azobis (isopropane) is dissolved.
  • Tyronitrile) (34 mg, 0.21 mmo 1) and tri-n-butyltin hydride (1.46 ml, 5.44 mmo 1) were added, and the mixture was stirred at 110 for 2 hours.

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Abstract

Dérivé d'acide 4-oxo-2-buténoïque représenté par la formule générale (I) ou un sel ou ester pharmaceutiquement acceptable de celui-ci, formule dans laquelle Ar?1 et Ar3¿ représentent chacun phényle, thiényle ou dihydrobenzofuranyle présentant facultativement 1 à 4 substituants; et Ar2 représente pyridyle, imidazolyle, thiazolyle, pyrimidinyle, pyridazinyle ou pyrazinyle dans lequel un atome d'hydrogène arbitraire sur son hétérocycle peut être substitué par alkyle C¿1-6? ou alkylamino C1-6. Etant donné qu'il présente un antagonisme puissant vis-à-vis de l'endothéline, laquelle est un peptide endogène physiologiquement actif, le composé est utile en tant que médicament contre les contractions de vaisseaux sanguins et de muscles de la trachée auxquelles participent l'endothéline et, à son tour, en tant que remède contre l'hypertension humaine, l'hypertension artérielle pulmonaire, la maladie de Raynaud, l'asthme bronchique, l'artériosclérose, l'insuffisance rénale aiguë, l'insuffisance cardiaque, l'infarctus du myocarde, l'angine de poitrine, l'infarctus cérébral, le spasme cérébrovasculaire, l'ulcère gastrique et le diabète. Il est également utile en tant que remède contre la reconstriction, l'hypertrophie prostatique, le choc endotoxinique, l'insuffisance organique multiple ou la coagulation intravasculaire disséminée provoquée par des endotoxines, des dérèglements rénaux induits par la ciclosporine, et l'hypertension.
PCT/JP1996/000195 1995-02-03 1996-02-01 Derives d'acide 4-oxo-2-butenoique Ceased WO1996023773A1 (fr)

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AU45478/96A AU4547896A (en) 1995-02-03 1996-02-01 4-oxo-2-butenoic acid derivatives

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JP7/39357 1995-02-03
JP3935795 1995-02-03

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997030017A1 (fr) * 1996-02-19 1997-08-21 Japan Tobacco Inc. Agent therapeutique contre le diabete
US5691373A (en) * 1993-08-19 1997-11-25 Warner-Lambert Company Nonpeptide endothelin antagonists I
WO1998027077A1 (fr) * 1996-12-19 1998-06-25 Merck Patent Gmbh Derives de 2,1,3-benzothia(oxa)diazole et leur utilisation comme antagonistes des recepteurs d'endotheline
WO1998037070A1 (fr) * 1997-02-21 1998-08-27 Takeda Chemical Industries, Ltd. Composes a anneaux condenses, leur procede de production et leur utilisation
US5891892A (en) * 1996-10-29 1999-04-06 Warner-Lambert Company Small molecule biaryl compounds as inhibitors of endothelin converting enzyme
US5922759A (en) * 1996-06-21 1999-07-13 Warner-Lambert Company Butenolide endothelin antagonists
US5998468A (en) * 1995-08-24 1999-12-07 Warner-Lambert Company Furanone endothelin antagonists
RU2325157C2 (ru) * 2006-04-11 2008-05-27 Общество с ограниченной ответственностью "Экофарминвест" Применение мексикора для ускорения физической реабилитации больных хронической сердечной недостаточностью

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0597819A (ja) * 1990-10-26 1993-04-20 Sankyo Co Ltd Ｎ−（３，３−ジ置換アクリロイル）ピペラジン誘導体
JPH0647575A (ja) * 1992-08-03 1994-02-22 Fanuc Ltd 光走査型レーザ加工機
JPH06157520A (ja) * 1992-11-13 1994-06-03 Kirin Brewery Co Ltd 新規物質ｈｑ２４
JPH0776575A (ja) * 1993-08-11 1995-03-20 Bayer Ag １−チオカルバモイル−５−ヒドロキシピラゾールを含む医薬品及び細菌性シヨツクの防除のための薬剤としてのその利用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0597819A (ja) * 1990-10-26 1993-04-20 Sankyo Co Ltd Ｎ−（３，３−ジ置換アクリロイル）ピペラジン誘導体
JPH0647575A (ja) * 1992-08-03 1994-02-22 Fanuc Ltd 光走査型レーザ加工機
JPH06157520A (ja) * 1992-11-13 1994-06-03 Kirin Brewery Co Ltd 新規物質ｈｑ２４
JPH0776575A (ja) * 1993-08-11 1995-03-20 Bayer Ag １−チオカルバモイル−５−ヒドロキシピラゾールを含む医薬品及び細菌性シヨツクの防除のための薬剤としてのその利用

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5691373A (en) * 1993-08-19 1997-11-25 Warner-Lambert Company Nonpeptide endothelin antagonists I
US6017916A (en) * 1993-08-19 2000-01-25 Warner-Lambert Company Nonpeptide endothelin antagonists I
US6017951A (en) * 1995-07-06 2000-01-25 Warner-Lambert Company Butenolide endothelin antagonists
US5998468A (en) * 1995-08-24 1999-12-07 Warner-Lambert Company Furanone endothelin antagonists
WO1997030017A1 (fr) * 1996-02-19 1997-08-21 Japan Tobacco Inc. Agent therapeutique contre le diabete
US5922759A (en) * 1996-06-21 1999-07-13 Warner-Lambert Company Butenolide endothelin antagonists
US5891892A (en) * 1996-10-29 1999-04-06 Warner-Lambert Company Small molecule biaryl compounds as inhibitors of endothelin converting enzyme
WO1998027077A1 (fr) * 1996-12-19 1998-06-25 Merck Patent Gmbh Derives de 2,1,3-benzothia(oxa)diazole et leur utilisation comme antagonistes des recepteurs d'endotheline
WO1998037070A1 (fr) * 1997-02-21 1998-08-27 Takeda Chemical Industries, Ltd. Composes a anneaux condenses, leur procede de production et leur utilisation
US6420375B1 (en) 1997-02-21 2002-07-16 Takeda Chemical Industries, Ltd. Fused ring compounds, process for producing the same and use thereof
RU2325157C2 (ru) * 2006-04-11 2008-05-27 Общество с ограниченной ответственностью "Экофарминвест" Применение мексикора для ускорения физической реабилитации больных хронической сердечной недостаточностью

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