WO1992004343A1 - Nouveau derive de tetrahydrobenzazole - Google Patents

Nouveau derive de tetrahydrobenzazole Download PDF

Info

Publication number
WO1992004343A1
WO1992004343A1 PCT/JP1991/001155 JP9101155W WO9204343A1 WO 1992004343 A1 WO1992004343 A1 WO 1992004343A1 JP 9101155 W JP9101155 W JP 9101155W WO 9204343 A1 WO9204343 A1 WO 9204343A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
methyl
lower alkyl
alkyl group
hydrogen atom
Prior art date
Application number
PCT/JP1991/001155
Other languages
English (en)
Japanese (ja)
Inventor
Isao Yanagisawa
Toshihiro Watanabe
Kazumi Kikuchi
Akihiro Tanaka
Toshio Okazaki
Osamu Inagaki
Minoru Okada
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Publication of WO1992004343A1 publication Critical patent/WO1992004343A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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

Definitions

  • the present invention relates to a novel tetrahydrobenzazole derivative having angiotensin ⁇ ( ⁇ ) antagonism, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and a method for producing them.
  • ⁇ is a bioactive peptide that exhibits a strong pressor action, and has been considered as a causative agent of hypertension in various mammalian species.
  • a typical pathway is the production of angiotensin I from angiotensinogen by the action of the enzyme renin. Then, angiotensin converting enzyme (ACE) acts on this to convert it to ⁇ .
  • ACE angiotensin converting enzyme
  • Examples of conventionally known compounds having anti-bacterial activity include, for example, 1-aralkyl imidazole derivatives described in European Patent Publication No. 253,310 (representative compound: Dup7 5 3 (quoted in Table 1 below))). Disclosure of the invention
  • the present inventors have created various compounds and proceeded with screening.
  • the tetrahydrobenzazole derivative represented by the following general formula (I) and a salt thereof have been compared with the above-mentioned known compounds in anti-angiotensin activity. It has been found that it has an antihypertensive effect based on its activity, Completed the invention,
  • R 1 represents a hydrogen atom, an alkyl group, a cycloalkyl lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl alkyl group or a hydroxy lower alkyl group,
  • R 2 is a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group, a hydroxyl group, a hydroxy lower alkyl group, a morpholinocarbonyl R 6
  • R 8 represents a hydrogen atom or a lower alkyl group
  • R 3 and R 4 are the same or different and are a hydrogen atom, a hydroxyl group, or carbonyl oxygen together with R 5
  • a tetrazo represented by the formula X represents N or a group represented by the formula CR 1 Q (where R 1 represents a hydrogen atom or an aralkyl group), wherein R 9 represents a hydrogen atom or an aralkyl group. Means) respectively.
  • an object of the present invention is to provide a compound represented by the above general formula (I).
  • An object of the present invention is to provide a drovenzazole derivative or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above derivative or a salt thereof and a pharmaceutically acceptable carrier.
  • Still another object of the present invention is to provide a method for producing the above derivative or a salt thereof.
  • lower means a linear or skin-like hydrocarbon chain having 1 to 6 carbon atoms.
  • the “lower alkyl group” specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group Group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl 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, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethyl :: -Butyl, 1-e
  • alkyl group a linear or branched one having 1 to 20 carbon atoms is preferable.
  • lower alkyl group butyl, 5-methylhexyl, octyl, 6-methylheptyl, nonyl, 7-methyloctyl, decyl, 8-methylnonyl undecyl, 9-methyldecyl, dodecyl, 10- Methylpentadecyl, tridecyl, 11-methyldodecyl, tetradecyl, 12-methyltridecyl, Pentadecyl, 13-methyltetradecyl, hexadecyl, 14-methylpentadecyl, heptadecyl, 15-methylhexadecyl, octadecyl, 16-methylheptadecyl, nonadecyl, Examples include a 17-methyl
  • cycloalkyl lower alkyl group is a cycloalkyl group substituted at any position of the above lower alkyl group.
  • cycloalkyl group means a group derived from a monocyclic hydrocarbon having 3 to 7 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group. And a cycloheptyl group.
  • hydroxy lower alkyl group refers to a group in which any hydrogen atom of the above “lower alkyl group” is substituted with a hydroxyl group. Specifically, a hydroxymethyl group, a 1-hydroxyl group, —Hydroxyshethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxy Examples thereof include a hydroxybutyl group and a 1,2-dihydroxyl group.
  • lower alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-carbonyl group.
  • the “lower alkoxycarbonyl bottom alkyl group” means the above “lower alkyl group” substituted by the above “lower alkoxycarbonyl group”.
  • the “aralkyl group” means a group in which any hydrogen atom of the above “lower alkyl group” is substituted with 1 to 3 aryl groups.
  • examples of the aryl group include a phenyl group and a tolyl group.
  • the compound of the present invention has a double bond, and may contain an oxygen atom depending on the type of the substituent. Therefore, the compound of the present invention includes a mixture of various isomers such as geometric isomers, tautomers, and optical isomers, and an isolated isomer.
  • the compound (I) of the present invention may form an acid addition salt.
  • a salt with a base may be formed.
  • Specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, drunk acid, propionic acid, oxalic acid, malonic acid, and succinic acid.
  • Acid fumaric acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, methanesulfonic acid, organic acid such as ethanesulfonic acid, and acid addition salt with acidic amino acid such as aspartic acid and glutamic acid;
  • inorganic bases such as sodium, lithium, potassium, magnesium and calcium aluminum
  • organic bases such as methylamine, ethylamine, and ethanolamine
  • salts with basic amino acids such as lysine and ordinamide
  • ammonium salts include inorganic bases such as sodium, lithium, potassium, magnesium and calcium aluminum, organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ordinamide; and ammonium salts.
  • the compounds of the present invention and salts thereof can be produced by applying various synthetic methods, utilizing characteristics based on the basic skeleton or types of substituents.
  • the typical production method is illustrated below.
  • R 9 ′ represents an aralkyl group
  • R e represents a hydrogen atom
  • Y represents a halogen atom.
  • the compound represented by the formula (Ia) is suitably a tetrahydrobenzazole derivative represented by the general formula (I) and a biphenylmethyl halide derivative represented by the general formula (m).
  • the reaction can be carried out in a suitable solvent at room temperature or under heating (first step).
  • Solvents include alcohols such as methanol and ethanol, acetone, toluene, benzene, dimethylformamide (DMF), Tetrahydrofuran (THF), dioxane, ether, dimethyl sulfoxide and the like are appropriately used.
  • a base such as, for example, potassium carbonate, sodium hydride, metallic sodium, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
  • the compound (lb) in which R 9 ′′ is a hydrogen atom can be obtained by subjecting the compound (I a) in which R 9 ′ is an aralkyl group to catalytic reduction, reduction reaction such as liquid reduction, This can be obtained by treating with an acid (second step)
  • the acid for example, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, HBr-acetic acid, etc. are used.
  • the reaction is performed in an organic solvent such as ethanol, ethanol, acetone, or the like, or in distilled water at room temperature to under heating (under reflux).
  • the compounds of the present invention include target compounds having various substituents, and these can be produced by further changing the substituents according to the types. Although the conversion of the substituents of R 2 to R 4 is not described in detail, it can be carried out using the following conventional methods.
  • the target compound having a hydroxy lower alkyl group is obtained by subjecting a known compound having a lower alkoxycarbonyl group to a known ester reduction reaction or a carboxylic acid known from a target compound having a carboxyl group.
  • a known compound having a lower alkoxycarbonyl group is obtained by subjecting a known compound having a lower alkoxycarbonyl group to a known ester reduction reaction or a carboxylic acid known from a target compound having a carboxyl group.
  • the target compound having a carboxyl group is
  • the compound can be produced from a target compound having a lower alkoxycarbonyl group by a known ester hydrolysis reaction.
  • a morpholinocarbonyl group in the compound of the present invention, a morpholinocarbonyl group; A group represented by the formula (wherein, R 6 and R 7 have the above-mentioned meanings);
  • the target compound having a group represented by CON ⁇ N-Re (wherein R 8 has the meaning described above) can be produced from the target compound having a carboxyl group by a known amide bond formation reaction. .
  • ⁇ stimulates ⁇ receptors on cell membranes, causing vasoconstriction and consequently blood pressure.
  • the compound of the present invention Since the compound of the present invention has an antagonistic action, various diseases caused by the physiological action of All (hypertension, chronic heart failure, early nephropathy of diabetic nephropathy (urine microalbumin), urine of chronic glomerulonephritis It is useful for the treatment or suppression of proteins. Further, since the compound of the present invention also exhibits an antagonistic effect on renin, which is formed without mediated by ACE, a wider antihypertensive spectrum can be expected as compared with an ACE inhibitor or a renin antagonist. .
  • the efficacy of the compound of the present invention for the ⁇ receptor blocking effect was examined based on the antagonism (in vitro) of All vasoconstriction in the isolated ⁇ s aorta and the inhibitory effect (in vivo) on All pressor response of spinal cord destruction rats.
  • the aorta of the heron was excised, a spiral strip specimen was prepared, and suspended in Krebs-Henseleit solution. This spiral strip specimen undergoes a dose-dependent contraction when All is added to the Krebs-Henseleit solution. Since the drug having a blocking effect on the All receptor shifts the dose-response curve of the contraction caused by All to the higher concentration side, the movement width of the dose-response curve before and after the addition of the test drug was calculated. The efficacy of the All receptor blocking activity was expressed as pA2 value (negative logarithm of the concentration of the blocking agent required to shift the dose-response curve to a two-fold higher concentration).
  • the spinal cord was destroyed in the rat under artificial respiration, and force neurons were inserted into arteries and veins to use for blood pressure measurement and drug administration, respectively.
  • This spinal cord destruction rat shows a continuous increase in blood pressure of 50 to 7 OmmHg by continuous intravenous administration of All (100 ng / kg / min).
  • Drugs having a blocking effect on All receptors suppress the continuous increase in blood pressure due to ⁇ in a dose-dependent manner. Therefore, all antagonistic effects were examined based on the decrease in blood pressure after administration of the test drug.
  • the efficacy of the All receptor blocking action is IC 3 . It was expressed as a value (a dose that lowered the blood pressure after All administration by 3 OmmHg).
  • compositions containing one or more of the compounds represented by the general formula (I) or salts thereof as an active ingredient are prepared using carriers, excipients and other additives commonly used in pharmaceutical preparations. It is prepared by
  • Examples of carriers and excipients for pharmaceuticals include solid or liquid non-toxic pharmaceutical substances. Examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like, and other commonly used ones.
  • the administration may be in the form of tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous or intramuscular injections, suppositories, transdermals, etc. You may.
  • the dosage is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject of administration, gender, etc.In general, the oral dose is about 10 to 10 mg / adult for adults. Is administered once or in 2-4 divided doses.
  • the starting material compound of the present invention also contains a novel substance, and its production method is shown in Reference Examples.
  • the extract was washed sequentially with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Tr means a triphenylmethyl group.
  • Tritrifluoromethyl-4,5,6,7-tetrahydrobenzimidazole 2 g of tetrahydrofuran in 60 ml of ice-cooled solution of 1.58 M hexane solution of n-butyllithium 3.8 2 ml was added dropwise, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Under ice cooling, 0.58 ml of ethyl ethyl carbonate was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to this under ice cooling, and the mixture was extracted with black-mouthed form. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
  • Ethyl 1-triphenylmethyl-4,5,6,7-tetrahydridobenzimidazole-2-carboxylate 427 mg of a 5% acetic acid / ethanol 10 ml solution was heated to reflux for 3 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (form: methanol: 50: 1), and ethyl 4,5,6,7-tetrahydrobenzimidazole-2-carboxylate 14 was added. 9 mg was obtained as a solid.
  • 2-butyl-4,5,6,7-tetrahydrobenzimidazole 1.5- or 16-potassium sulfonate 2.0 g was stirred in 30 ml of thionyl chloride at 65 ° C for 1 hour, and then excess thionyl chloride was added.
  • thionyl chloride was added to the residue to form a suspension, which was added dropwise to a methylene chloride solution (30 ml) containing morpholine (3 g) under ice-cooling.
  • Example 2 The following compounds of Examples 2 to 18 were produced in the same manner as in Example 1.
  • Methyl 1 [[2 '— (N-triphenylmethyl-1H-tetrazol-5-yl) biphenyl 41-yl] methyl] 1,4,5,6,7-tetrahydro 1H-benz Mixture of imidazole-5- and 1-6-carboxylate

Abstract

L'invention se rapporte à un composé représenté par la formule générale (I), et possédant une action d'inhibition de l'angiotensine II. Dans la formule (I), R1 représente hydrogène, alkyle, alkyle inférieur cycloalkyle, carboxyle, alcoxycarbonyle, alcoxycarbonylalkyle ou hydroxyalkyle; R2 représente hydrogène, alkyle, alcoxycarbonyle, carboxyle, hydroxyalkyle, α, -CONR6R7 ou β; R3 et R4 représentent chacun hydrogène ou hydroxyle ou forment ensemble un groupe OXO; R5 représente tétrazolyle; et X représente N ou CR10.
PCT/JP1991/001155 1990-09-04 1991-08-30 Nouveau derive de tetrahydrobenzazole WO1992004343A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/233867 1990-09-04
JP23386790 1990-09-04

Publications (1)

Publication Number Publication Date
WO1992004343A1 true WO1992004343A1 (fr) 1992-03-19

Family

ID=16961815

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/001155 WO1992004343A1 (fr) 1990-09-04 1991-08-30 Nouveau derive de tetrahydrobenzazole

Country Status (2)

Country Link
AU (1) AU8405691A (fr)
WO (1) WO1992004343A1 (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0622077A1 (fr) * 1993-04-22 1994-11-02 Takeda Chemical Industries, Ltd. Antagonistes de l'angiotensine II comme agent prophylactique et thérapeutique des maladies rénales
US5594003A (en) * 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5602127A (en) * 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5614519A (en) * 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
US5663187A (en) * 1994-03-29 1997-09-02 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
US6437147B1 (en) 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
US6569888B1 (en) 1999-02-05 2003-05-27 Astrazeneca Ab Anti-inflammatory indole derivatives
US6613760B1 (en) 1999-02-05 2003-09-02 Astrazeneca Ab Indole derivatives and their use as MCP-1 receptor antagonists
US6833387B1 (en) 1999-02-05 2004-12-21 Astrazeneca Ab Chemical compounds
US6911465B1 (en) 1999-02-05 2005-06-28 Astrazeneca Ab Anti-inflammatory indole derivatives
US6984657B1 (en) 2000-01-13 2006-01-10 Astrazeneca Ab Indole derivatives as MCP-1 receptor antagonists
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP1785134A3 (fr) * 2000-01-19 2009-02-18 Synvista Therapeutics, Inc. Utilisation de composés thiazole, imidazole et oxazole pour le traitement des désordres associés à la protéine de vieillissement
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
US20110245310A1 (en) * 2008-12-18 2011-10-06 Ian Baxter Campbell Novel Compounds
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
JP2016539978A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのテトラヒドロベンゾイミダゾール誘導体
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
CN111201229A (zh) * 2017-10-11 2020-05-26 豪夫迈·罗氏有限公司 用作rip1激酶抑制剂的二环化合物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01117876A (ja) * 1987-05-22 1989-05-10 E I Du Pont De Nemours & Co 抗高血圧化合物のためのテトラゾール中間体
JPH035464A (ja) * 1989-05-23 1991-01-11 Imperial Chem Ind Plc <Ici> ベンズイミダゾール誘導体、その製造方法、高血圧およびうっ血性心不全を治療するための製薬組成物、および中間生成物
JPH035480A (ja) * 1989-05-23 1991-01-11 Imperial Chem Ind Plc <Ici> アザインデン、その製法、これを含有する高血圧及びうつ血性心臓疾患の治療剤及び中間体
JPH0395181A (ja) * 1989-05-30 1991-04-19 Merck & Co Inc アンギオテンシン２拮抗剤としての置換イミダゾ縮合六員ヘテロ環
JPH03106879A (ja) * 1989-08-30 1991-05-07 Ciba Geigy Ag アザベンズイミダゾール化合物
JPH03184976A (ja) * 1989-10-31 1991-08-12 Fujisawa Pharmaceut Co Ltd ベンズイミダゾール誘導体およびその製造法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01117876A (ja) * 1987-05-22 1989-05-10 E I Du Pont De Nemours & Co 抗高血圧化合物のためのテトラゾール中間体
JPH035464A (ja) * 1989-05-23 1991-01-11 Imperial Chem Ind Plc <Ici> ベンズイミダゾール誘導体、その製造方法、高血圧およびうっ血性心不全を治療するための製薬組成物、および中間生成物
JPH035480A (ja) * 1989-05-23 1991-01-11 Imperial Chem Ind Plc <Ici> アザインデン、その製法、これを含有する高血圧及びうつ血性心臓疾患の治療剤及び中間体
JPH0395181A (ja) * 1989-05-30 1991-04-19 Merck & Co Inc アンギオテンシン２拮抗剤としての置換イミダゾ縮合六員ヘテロ環
JPH03106879A (ja) * 1989-08-30 1991-05-07 Ciba Geigy Ag アザベンズイミダゾール化合物
JPH03184976A (ja) * 1989-10-31 1991-08-12 Fujisawa Pharmaceut Co Ltd ベンズイミダゾール誘導体およびその製造法

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594003A (en) * 1991-02-06 1997-01-14 Dr. Karl Thomae Gmbh Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5602127A (en) * 1991-02-06 1997-02-11 Karl Thomae Gmbh (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
US5614519A (en) * 1991-02-06 1997-03-25 Karl Thomae Gmbh (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
US6469037B2 (en) 1993-04-22 2002-10-22 Takeda Chemical Industries, Ltd. Prophylactic or therapeutic drug for renal diseases
US7135490B2 (en) 1993-04-22 2006-11-14 Takeda Pharmaceutical Company, Limited Method for the treatment of glomerulonephritis
EP0622077A1 (fr) * 1993-04-22 1994-11-02 Takeda Chemical Industries, Ltd. Antagonistes de l'angiotensine II comme agent prophylactique et thérapeutique des maladies rénales
US5719173A (en) * 1993-04-22 1998-02-17 Takeda Chemical Industries, Ltd. Method for the treatment of sclerosis of the glomeruli
US5889036A (en) * 1993-04-22 1999-03-30 Takeda Chemical Industries, Ltd. Prophylactic or therapeutic drug for renal diseases
US6040324A (en) * 1993-04-22 2000-03-21 Takeda Chemical Industries, Inc. Prophylactic or therapeutic drug for renal diseases
US6319938B1 (en) 1993-04-22 2001-11-20 Takeda Chemical Industries, Ltd. Prophylactic or therapeutic drug for renal diseases
US6686383B2 (en) 1993-04-22 2004-02-03 Takeda Chemical Industries, Ltd Prophylactic or therapeutic drug for renal diseases
US5663187A (en) * 1994-03-29 1997-09-02 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
US5663186A (en) * 1994-03-29 1997-09-02 Merck & Co., Inc. Treatment of atherosclerosis with angiotensin II receptor blocking imidazoles
US6569888B1 (en) 1999-02-05 2003-05-27 Astrazeneca Ab Anti-inflammatory indole derivatives
US6613760B1 (en) 1999-02-05 2003-09-02 Astrazeneca Ab Indole derivatives and their use as MCP-1 receptor antagonists
US6833387B1 (en) 1999-02-05 2004-12-21 Astrazeneca Ab Chemical compounds
US6911465B1 (en) 1999-02-05 2005-06-28 Astrazeneca Ab Anti-inflammatory indole derivatives
EP2277519A2 (fr) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
US6984657B1 (en) 2000-01-13 2006-01-10 Astrazeneca Ab Indole derivatives as MCP-1 receptor antagonists
EP1785134A3 (fr) * 2000-01-19 2009-02-18 Synvista Therapeutics, Inc. Utilisation de composés thiazole, imidazole et oxazole pour le traitement des désordres associés à la protéine de vieillissement
US6437147B1 (en) 2000-03-17 2002-08-20 Novo Nordisk Imidazole compounds
US6756384B2 (en) 2000-03-17 2004-06-29 Novo Nordisk A/S Imidazole compounds
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
US20110245310A1 (en) * 2008-12-18 2011-10-06 Ian Baxter Campbell Novel Compounds
US8399444B2 (en) * 2008-12-18 2013-03-19 GlaxoSmithKline Intellectual Property Development Ltd. Bicyclic imidazole as DP1 receptor antagonists
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
JP2016539978A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのテトラヒドロベンゾイミダゾール誘導体
CN111201229A (zh) * 2017-10-11 2020-05-26 豪夫迈·罗氏有限公司 用作rip1激酶抑制剂的二环化合物
JP2020536915A (ja) * 2017-10-11 2020-12-17 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｒｉｐ１キナーゼ阻害剤として使用するための二環式化合物

Also Published As

Publication number Publication date
AU8405691A (en) 1992-03-30

Similar Documents

Publication Publication Date Title
WO1992004343A1 (fr) Nouveau derive de tetrahydrobenzazole
EP0459136B1 (fr) Dérivés de benzimidazole, leur préparation et utilisation
EP0420237B1 (fr) Dérivés du diphénylméthane, utilisation et compositions pharmaceutiques les contenant
US5650414A (en) Method of inhibiting angiotensin effects
JPH0625181A (ja) 縮合５員複素環式化合物、それらの調製法およびこれらの化合物を含む製薬製剤
US5210211A (en) 4-(1h-pyrrol-1-yl) imidazoles with angiotension ii antagonist activity
CZ281937B6 (cs) Substituované bifenylpyridony
RO109735B1 (ro) Derivati de imidazol, substituiti cu indol si benzimidazol
US5510354A (en) Imidazopyridine derivatives
CZ16994A3 (en) Heterocyclic compounds and pharmaceutical preparations in which they are comprised
US5281615A (en) Cycloheptimidazolone compounds as angiotensin II antagonists for control of hypertension
CZ297692A3 (en) Substituted derivatives of imidazolyl-propenoic acid
CZ297792A3 (en) Cyclically substituted derivatives of imidazolyl-propenoic acid
JPH07500336A (ja) イミダゾール誘導体およびこれを有効成分とする医薬組成物
US5234923A (en) Substitute indole and benzimidazole derivatives
FI98369C (fi) Menetelmä valmistaa farmaseuttisesti aktiivista 1- tai 3-difenyylimetyyli-imidatsoindolitsiinijohdannaista
US5284661A (en) Fused thiophene derivatives, their production and use
CA2119095A1 (fr) Derives de substitution heterotricycliques d&#39;acide phenylcyclohexanecarboxylique
EP0669333A1 (fr) Dérivés d&#39;imidazopyridine comme antagonistes de l&#39;angiotensine II
US5627285A (en) Sulphonylbenzyl-substituted imidazolylpropenoic acid derivatives
US5442062A (en) Imidazole derivatives and pharmaceutical compositions containing the same
US9371311B2 (en) Benzoimidazol-2-yl pyrimidine derivatives
US5364942A (en) Sulphonylbenzyl-substituted imidazopyridines
US5475114A (en) Pyrazolotriazole derivatives
JP3466694B2 (ja) ピラゾロ〔１，５−ａ〕ピリミジン−７（４Ｈ）−オン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

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

NENP Non-entry into the national phase

Ref country code: CA