WO1997011942A1 - Nouveaux composes de sulfonamide et composition medicinale - Google Patents

Nouveaux composes de sulfonamide et composition medicinale Download PDF

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Publication number
WO1997011942A1
WO1997011942A1 PCT/JP1996/002764 JP9602764W WO9711942A1 WO 1997011942 A1 WO1997011942 A1 WO 1997011942A1 JP 9602764 W JP9602764 W JP 9602764W WO 9711942 A1 WO9711942 A1 WO 9711942A1
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Prior art keywords
compound
optionally substituted
pharmaceutically acceptable
acceptable salt
hydrate
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PCT/JP1996/002764
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English (en)
Japanese (ja)
Inventor
Yoshitaka Araki
Tadashi Takahashi
Toshiro Konoike
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Shionogi & Co., Ltd.
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Priority to AU70949/96A priority Critical patent/AU7094996A/en
Publication of WO1997011942A1 publication Critical patent/WO1997011942A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C07D261/16—Benzene-sulfonamido isoxazoles

Definitions

  • the present invention relates to compounds useful as medicaments and uses thereof. More specifically, the present invention relates to a novel sulfonamide derivative which has a selective antagonistic activity of endoselin B receptor and is useful for prevention and / or treatment of endoselin or a disease involving endoselin B.
  • Endothelin is a vasoconstrictor peptide derived from vascular endothelial cells consisting of 21 amino acids, and is involved in vascular homeostasis.
  • endothelin is high in blood pressure and cerebral vasoconstriction.
  • endoselin receptors There are two types of sub-ends of endoselin receptors, endoselin A and endoselin B, and A-selective, B-selective and AB-nonselective receptor antagonists. There are three types. It is becoming increasingly clear which diseases each type of receptor antagonist is involved in. Endothelin A receptor selective antagonists are expected to be effective in the acute phase of cardiovascular disease, but satisfactory results have not been obtained. This suggests that not only endocerin A receptor but also endocerin B receptor may be involved in the development and progression of cardiovascular lesions. The body is also thought to be involved in the metabolism of endocrine in blood, intimal thickening of blood vessels, and the development and differentiation of certain cells.
  • WO 94/27979 also discloses sulfonamide compounds, some of which are described as having endocelin B-selective receptor-selective antagonism.
  • the present inventors have conducted intensive studies with the aim of developing an endoselin B receptor selective antagonist. As a result, it has been found that the compound represented by the following formula (I) has a high activity as an antagonist. And completed the present invention. That is, the present invention provides a compound represented by the formula (I):
  • R 1 and R 2 are each independently halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted X is a lower alkylene or a lower alkenylene, m and n are each independently an integer of 0 to 5, and m or ⁇ is 2 or more.
  • the present invention also provides a pharmaceutical composition containing these compounds and a selective antagonist of endoselin B receptor.
  • the present invention relates to a method for preventing and / or treating a disease associated with endothelin B, which comprises administering compound (I). Furthermore, the present invention relates to the use of the compound (I) for the manufacture of a medicament for preventing and / or treating a disease involving endoselin B.
  • Halogen represents fluorine, chlorine, bromine or iodine.
  • “Lower alkyl” means a straight or branched alkyl having 1 to 6 carbon atoms, and specifically, tyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec— It includes butyl, t-butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like, and is preferably t-butyl. These groups may have one or more substituents at arbitrary positions, and examples of the substituents include halogen and hydroxy.
  • “Lower alkenyl” means straight or branched alkenyl having 2 to 7 carbon atoms, specifically, vinyl, probenyl, isoprobenyl, aryl, butenyl, pentenyl, hexenyl , Heptenyl and the like. These may have one or more double bonds at any position, and may have one or more substituents at any position. The substituent is the same as the above “lower alkyl” substituent.
  • “Lower alkynyl” means straight-chain or branched alkynyl having 2 to 7 carbon atoms, and specifically includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and the like. . These triple bonds may be in any position, and may have one or more substituents in any position. The substituent is the same as the above "lower alkyl” substituent. “Aryl” specifically includes phenyl, naphthyl and the like, and is preferably phenyl. These may have one or more lower alkyl, lower alkoxy, halogen, hydroxy, etc. at any position as a substituent.
  • “Lower alkoxy” means a straight or branched alkoxy having 1 to 6 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like. And is preferably methoxy. These may have one or more substituents at arbitrary positions, and the substituents are the same as the above-mentioned "lower alkyl” substituents.
  • the “lower alkylene” is a linear or branched alkylene having 1 to 6 carbon atoms, specifically, methylene, ethylene, propylene, ethylethylene, trimethylene, methyltrimethylene, methyl. It includes trimethylene, tetramethylene, methyltetramethylene, ethyltetramethylene, pentamethylene, methylpentamethylene, hexamethylene, and the like, and is preferably trimethylene or tetramethylene.
  • the “lower alkenylene” is a straight-chain or branched alkenylene having at least one double bond and having 2 to 7 carbon atoms, specifically, vinylene, probenylene, Methylprobenylene, ethylpropylenylene, butenylene, methylbutenylene, ethylbutenylene, butagenylene, pentenylene, methylpentenylene, ethylpentenylene, pentagenenylene, hexenylene, methylhexenylene, hexenenylene, hexatorenie It includes len, heptenylene, heptangen, heptatrienylene and the like, and is preferably butenylene. The positions of these double bonds may be arbitrary.
  • the compound (I) of the present invention also includes pharmaceutically acceptable salts thereof.
  • salts with alkali metals sodium, calcium, lithium, etc.
  • alkaline earth metals calcium, magnesium, etc.
  • ammonium or organic bases triethylamine, pyridine, etc.
  • the compound (I) of the present invention also includes a hydrate thereof, and the compound (I) has one molecule per compound (I). However, it may form a hydrate with one or more water molecules.
  • a structural feature of the compounds of the present invention is the combination of benzenesulfonamide, isoxazolyl, phenylthio, and aldehyde-substituted lower alkyl or aldehyde-substituted lower alkenyl.
  • Compounds (I) represented by the above formula having this combination all exhibit endocerin B receptor antagonistic activity.
  • R 1 is optionally substituted lower alkyl, optionally substituted aryl or optionally substituted lower alkoxy
  • R 2 is an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted lower alkoxy
  • n 1 and R 2 is lower alkoxy substituted at the meta position
  • the compound has n force 1 and R 2 is methoxy substituted at the meta position.
  • RR 2 is independently lower alkyl which may be substituted, aryl which may be substituted or lower alkoxy which may be substituted, and further preferably R 1 is A compound wherein R 2 is lower alkyl or aryl, and R 2 is lower alkoxy;
  • R 1 is para-substituted t-butyl or phenyl and R 2 Is methoxy converted to the meta position,
  • R 1 and R 2 are each independently an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted lower alkoxy, and X is a lower alkylene or A compound which is lower alkenylene, wherein m and n are each independently 1 or 2,
  • R is an optionally substituted lower alkyl or an optionally substituted aryl
  • R 2 is an optionally substituted lower alkoxy
  • X is a lower alkylene or A lower alkenylene compound wherein m and n are each 1;
  • R 1 is lower alkyl substituted at the para position
  • R 2 is lower alkoxy substituted at the meta position
  • X is alkylene or alkenylene having 3 or 4 carbon atoms
  • m and n are Compounds each being 1;
  • R 1 is t-butyl substituted at the para position
  • R 2 is methoxy substituted at the meta position
  • X is alkylene or alkenylene having 3 or 4 carbon atoms
  • R 3 and R 4 are each independently hydrogen, halogen, optionally substituted lower alkyl, optionally substituted A lower alkenyl, an optionally substituted lower alkynyl, an optionally substituted aryl or an optionally substituted lower alkoxy, and X is a lower alkylene or a lower alkenylene.
  • R 1 'R 1 compound' is hydrogen
  • R 1 't been substituted at the para-position - butyl or phenyl, R 1' compound 'is hydrogen,
  • R 2 ′ and R 2 ′′ are each independently hydrogen, an optionally substituted lower alkyl or an optionally substituted lower alkoxy
  • R 2' R 2 compound ' is hydrogen
  • R 2 ′ is a methoxy substituted at the meta position
  • R 2 ′′ is hydrogen
  • R 1 ′ and R ′ are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aryl, and R 2 ′ and R 2 ′′ are each independently A compound which is hydrogen, optionally substituted lower alkyl or optionally substituted lower alkoxy,
  • R 1 ′ is an optionally substituted lower alkyl or an optionally substituted aryl
  • R 2 ′ is an optionally substituted lower alkoxy
  • R 1 ′ and R 2 ′′ are Compounds each being hydrogen
  • a compound wherein R 1 ′ is lower alkyl or aryl substituted at the para position, R 2 ′ is lower alkoxy substituted at the meta position, and R 1 ′′ and R 2 ′ are each hydrogen.
  • a compound wherein R 1 ′ is t-butyl or phenyl substituted at the para position, R 2 ′ is methoxy substituted at the meta position, and R 1 , ′ and R ′ are each hydrogen; (5) R 1 ′ and R ⁇ ′′ are each independently hydrogen, optionally substituted lower alkyl or optionally substituted aryl, and R 2 ′ and R 2 ′′ are each independently hydrogen.
  • R 1 ′ is an optionally substituted lower alkyl or an optionally substituted aryl
  • R 2 ′ is an optionally substituted lower alkoxy
  • R 1 ′′ and R 1 ′ 2 '' is each hydrogen and R 3 and R 4 are each hydrogen, particularly preferably R 1 ′ is lower alkyl or aryl substituted at the para position, and R 2 ′ is substituted at the meta position A compound wherein R ′ ′′, R 2 ′ R 3 and R 4 are each hydrogen,
  • R 1 ′ is t-butyl or phenyl substituted at the para position
  • R 2 ′ is methoxy substituted at the meta position
  • R 1 ”, R 2 R 3 and R 4 are each hydrogen.
  • R 1 ′ and R ′ are each independently hydrogen, an optionally substituted lower alkyl or an optionally substituted aryl, and R 2 ′ and R 2 ′ are each independently A compound wherein hydrogen, optionally substituted lower alkyl or optionally substituted lower alkoxy, wherein R 3 and R 4 are each hydrogen and X is alkylene or alkenylene having 3 or 4 carbon atoms,
  • R 1 ′ is an optionally substituted lower alkyl or an optionally substituted aryl
  • R 2 ′ is an optionally substituted lower alkoxy
  • R 1 ′′ and R 1 ′ Compounds wherein 2 "is each hydrogen and X is alkylene or alkenylene having 3 or 4 carbon atoms
  • R 1 ′ is lower alkyl or aryl substituted at the para position
  • R 2 ′ is lower alkoxy substituted at the meta position
  • R 1 ”, R 2 ′ R 3 and R 4 are each hydrogen.
  • X is alkylene or alkenylene having 3 or 4 carbon atoms
  • R 1 ′ is t-butyl or phenyl substituted at the para-position
  • R 2 ′ is methoxy substituted at the meta-position
  • R ′, R 2 ′′, R 3 and R 4 are each With hydrogen
  • X is alkylene or alkenylene having 3 or 4 carbon atoms.
  • R 1 ′ is t-butyl substituted at the para position
  • R 2 ′ is methoxy substituted at the meta position
  • R 1 ”, R 2 R 3 and R 4 are each hydrogen
  • X is Methylene compound (I_1)
  • R 1 ' is t one-butyl substituted at the para-position
  • R 2' is a main butoxy which are substituted in the meta position
  • R 1 '', R 2 ⁇ R 3 and R 4 are each hydrogens
  • X A compound that is tetramethylene (I—2)
  • R 1 ′ is para-substituted t-butyl
  • R 2 ′ is meta-substituted methoxy
  • R 1 ′′, R 2 , R 3 and R 4 are each hydrogen
  • X is 3 —Butenylene compounds (I-3) and
  • R 1 ′ is phenyl substituted at the para position
  • R 2 ′ is methoxy substituted at the meta position
  • R 1 ′′, R 2 R 3 and R 4 are each hydrogen
  • X is trimethylene.
  • endoselin ⁇ selective antagonistic activity and endoselin ⁇ selectivity are strongly preferred. Among them,
  • R 1 ′ is para-substituted t-butyl
  • R 2 ′ is meta-substituted methoxy
  • R 1 ′′, R 2 R 3 and R 4 are each hydrogen
  • X is tri Methylene compound (I-1)
  • R 1 ′ is t-butyl substituted at the para position
  • R 2 ′ is methoxy substituted at the meta position
  • R 1 ′′, R 2 R 3 and R 4 are each hydrogen
  • X is tetramethylene.
  • R 1 ′ is phenyl substituted at the para position
  • R 2 ′ is methoxy substituted at the meta position
  • R ′ ′′, R 2 ′′, R 3 and R 4 are each hydrogen
  • X is tri Compounds that are methylene (I-IV)
  • R 1 ' is t-butyl substituted at the para-position
  • R 2 ' is methoxy substituted at the meta-position.
  • R 1 ′′, R 2 ′′, R 3 and R 4 are each hydrogen and X is trimethylene (I-11)
  • the compound of the present invention can be synthesized, for example, by the following steps.
  • X of the target compound is a lower alkylene
  • a known compound for example, a compound ⁇ _ (X is trimethylene, Y is protected by t-butyloxycarbonyl) as described in JP-A-7-304756
  • the amino and Z are introduced with a phenylthio group at the 4-position under appropriate conditions, starting from t-butyldiylsilyl-protected hydroxy) and the like.
  • the desired phenylthione Compound b can be obtained by reacting with a reagent for introducing a group (for example, disulfide, sulfenyl halide, etc.).
  • a reagent for introducing a group for example, disulfide, sulfenyl halide, etc.
  • the solvent include tetrahydrofuran, getyl ether, 1, 2-Dimethoxetane, Dichloroethane, 1.2-Dichloroethane, benzene, toluene, etc.
  • the reaction may be performed for up to several tens of hours, preferably for about 1 to 3 hours.
  • ⁇ of the compound ⁇ _ is sulfonylated under appropriate conditions.
  • Y is a protected amino
  • a deprotection reaction is performed, if necessary, prior to sulfonylation.
  • Any protecting group may be used as long as it is generally used, and examples thereof include lower alkoxycarbonyl, lower alkenyloxycarbonyl, halogenoalkoxycarbonyl, arylalkoxycarbonyl, trialkylsilyl and the like.
  • t-butyroxyl-ponyl is preferred.
  • Deprotection may be performed according to a treatment method according to the nature of each protecting group. For example, when the protecting group is t-butyloxycarbonyl, it can be removed by using trifluoroacetic acid.
  • the sulfonylation of amino is carried out by using an organic base such as pyridine, 41 N, N-dimethylaminopyridin, triethylamine, diisopropylethylamine, sodium hydride, hydrogenation.
  • an organic base such as pyridine, 41 N, N-dimethylaminopyridin, triethylamine, diisopropylethylamine, sodium hydride, hydrogenation.
  • a solvent such as dichloromethane, dimethylformamide, and toluene
  • a compound having a sulfonyl group corresponding to the target compound is preferably used under ice-cooling to heating. After reacting at room temperature for several hours to several tens of hours, compound c can be obtained.
  • Pyridines can be used in the same solvent amount as the base and the solvent. Examples of the compound having a sulfonyl group include 4-t-butylbenzenesulfonyl chloride,
  • the hydroxy is first sulfonylated using a sulfonylating agent, and then cyanated using a cyanating agent.
  • a sulfonylating agent for example, methanesulfonyl chloride, toluenesulfonyl chloride, methanesulfonic anhydride, toluenesulfonic anhydride, or the like may be used, such as pyridine, triethylamine, diisoprom. Pyruethylamine, 4-N, N-dimethylaminopyridine, 1,4 diazabicyclo [2.2.
  • the reaction may be carried out under ice cooling to room temperature, preferably under ice cooling for several hours to several tens of hours in the presence of a base such as 2-octane.
  • a base such as 2-octane.
  • the cyanating agent include sodium cyanide, potassium cyanide, and the like. Dimethylformamide and dimethylsulfoxyl as solvents at room temperature to under heating, preferably around 50 to 90. And dimethylacetamide for several hours.
  • Z is a protected hydroxy or hydroxymethyl, it is subjected to a deprotection reaction prior to this reaction.
  • the protecting group for hydroxy for example, lower alkylsulfonyl, lower alkanol, aroyl, lower alkoxycarbonyl, lower alkoxyalkyl and the like may be used, and particularly, t-butyldimethylsilyl and acetyl are preferable.
  • Deprotection may be carried out according to a general treatment method according to the nature of each protecting group. For example, when the protecting group is t-butyldimethylsilyl, tetra-n-butylammonium fluoride is protected.
  • the group is acetyl, elimination may be carried out using a base such as sodium hydroxide or potassium hydroxide.
  • the obtained cyano compound is reacted with a reducing agent such as diisobutylaluminum hydride and the obtained imino compound is hydrolyzed to obtain the desired compound (I).
  • a reducing agent such as diisobutylaluminum hydride
  • the reaction may be carried out at around 110 O: to O :, preferably around 180, for several hours.
  • the target compound (I) can be obtained by directly subjecting the compound to the above reaction.
  • Z of compound _ is hydroxymethyl which may be protected, when protected, the protecting group is first eliminated, and then dimethylsulfoxide, anhydrous chromic acid, and pyridinium chromate chloride are removed.
  • the compound (I) can be suitably obtained by subjecting it to an oxidation reaction according to a conventional method using a commonly used oxidizing agent such as pyridinium chromate.
  • a commonly used oxidizing agent such as pyridinium chromate.
  • the solvent is dichloroethane, dichloromethane?
  • (Z is hydroxyl in the presence of an activating agent such as oxalyl chloride, trifluoric anhydride, anhydride, or dipentoxide using tan, dimethoxetane, getyl ether, tetrahydrofuran, etc.
  • an activating agent such as oxalyl chloride, trifluoric anhydride, anhydride, or dipentoxide using tan, dimethoxetane, getyl ether, tetrahydrofuran, etc.
  • an activating agent such as oxalyl chloride, trifluoric anhydride, anhydride, or dipentoxide using tan, dimethoxetane, getyl ether, tetrahydrofuran, etc.
  • One compound c The reaction may be carried out at 0 to room temperature, preferably at around 180 for several hours, and then with an amine such as triethylamine.
  • X of the target compound (I) is lower alkenylene
  • compound (I) in which X is lower alkylene is synthesized, and dimethylformamide, dimethylsulfoxide, acetonitride is synthesized.
  • trityl or the like as a solvent, the compound and dimethyl cyanomethylphosphonate, dimethyl cyanomethylphosphonate, etc. are converted into sodium hydride,
  • the reaction is carried out in the presence of a base such as DBU at 0 ° C. to under heating, preferably at about room temperature for several hours to several tens hours to obtain a compound wherein X is lower alkenylene and the terminal is cyano. Then, when the cyano of the compound obtained in the same manner as described above is converted into an aldehyde, the target compound (I) in which X is lower alkenylene is obtained.
  • a base such as DBU at 0 ° C.
  • All of the compounds of the present invention have a strong endothelin B receptor antagonistic activity and can be used as a medicament.
  • Endothelin B together with endothelin A, is thought to be involved in the development of cardiovascular diseases such as hypertension, acute renal failure, heart failure, renal ischemia, cerebral ischemia, cerebral infarction, cerebral edema, etc. Therefore, it is very useful as an agent for preventing and / or treating these diseases.
  • the compound (I) of the present invention When the compound (I) of the present invention is administered as a medicament, it can be administered orally or parenterally. Oral administration may be carried out in a conventional manner by preparing tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals in a commonly used form.
  • any commonly used dosage form such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorption agents, and inhalants, can be suitably administered.
  • oral administration is preferred.
  • the preparation may be prepared by sterilizing with an appropriate carrier
  • the excipients include lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose
  • the binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and the like.
  • Disintegrants such as gelatin or polyvinylpyrrolidone, carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate, etc. Examples include talc, magnesium stearate or macrogol. As a suppository base, cocoa butter, macrogol or methylcellulose can be used.
  • a solubilizing agent, a suspending agent, an emulsifier, a stabilizer, a preservative, an isotonic agent, etc. which are usually used, are appropriately used. It may be added, and in the case of oral administration, a flavoring agent, a fragrance and the like may be added.
  • the dose of the compound of the present invention as an endothelin receptor antagonist is desirably set in consideration of the age, body weight, type and degree of disease, administration route, etc. of the patient, but is orally administered to an adult. In this case, it is usually in the range of 0.05 to 100 mgZkg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, the force varies greatly depending on the route of administration.It is usually between 0.001 and 1000 mgZ kg / day, preferably between 0.Oll O mgZ and kgZ day. is there. It may be administered once or several times a day.
  • a 1 L eggplant-shaped flask was charged with 17.5 g (35.3 mmo 1) of the compound and 75 mL of THF, and cooled to 0 in an ice bath.
  • a THF solution (1 M) of tetra-n-butylammonium fluoride (1 M) (141 ml) was added dropwise, and after completion of the dropwise addition, the mixture was stirred for 2 hours while warming to room temperature.
  • the mixture was cooled again to 0, and 35 ml (35 mmol) of a THF solution (1 M) of tetra-n-butylammonium fluoride was added dropwise.
  • the concentrated residue is purified by silica gel chromatography, and 5-(3-acetooxypropyl) 13-amino-41-(3-methoxyphenylthio) isoxazole (9.3 g of compound (from compound _ 86%).
  • the compound 10.4 g (14.5 mmo 1), methanol 160 ml and THF 40 ml were put into a 500 ml eggplant-shaped flask. 2.9 ml (58 mmo 1) of a 2 N aqueous sodium hydroxide solution was added dropwise, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was poured into IN hydrochloric acid and extracted twice with ethyl acetate.
  • the extract layer was washed once with a saturated saline solution, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude concentrated residue of the compound (corresponding to compound II 2.10 mO1) and 12 mL of DMF were placed in a 200 m1 eggplant-shaped flask. Under a nitrogen atmosphere, sodium cyanide (226 mg, 4.61 mmo 1) was added, and the mixture was heated to 80 in an oil bath. After stirring at 80 for 2.5 'hours, the mixture was allowed to cool, then cooled to 0 in a water bath, and 1N hydrochloric acid was added until the solution became neutral. The reaction solution was poured into a saturated saline solution, extracted twice with ethyl acetate, and the extracted layer was washed once with dilute hydrochloric acid and twice with a saturated saline solution.
  • Oxalyl chloride 20 ⁇ ul (29 mg, 0, 23 mmo 1) and dichloromethane 1 ml were added to a 20 ml eggplant-shaped flask.
  • the mixture was cooled to 178 in a dry ice / acetone bath, and DMS0321 (35 mg, 0.45 mmol) was added under a nitrogen atmosphere.
  • DMS0321 35 mg, 0.45 mmol
  • a solution of compound 100 mg (0.21 mmol) in dichloromethane (1 ml) was added.
  • triethylamine 1441 105 mg, 1.04 mmol
  • the reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted twice with ethyl sulphate.
  • the extract layer was washed once with a saturated saline solution, and the extract layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the concentrated residue is purified by silica gel chromatography and purified by using 4-t-butyl-N— [4- (3—methoxyphenylthio) —5— (3—oxopropyl) isoxazole—3—yl] benzenesulfonamide (Compound 10) was obtained in an amount of 61 mg (61%).
  • the reaction solution was poured into a solution prepared by diluting 30 ml of 1 N hydrochloric acid with 500 ml of water, extracted twice with ethyl acetate, and the extracted layer was extracted once with an aqueous solution of sodium hydrogen carbonate and saturated saline. Was washed once.
  • the extract layer is dried over magnesium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the concentrated residue is purified by silica gel chromatography to obtain 5- (3-tert-butyldimethylsilyloxypropyl) -3—ethoxycarbonitrile.
  • ruisoxazole Compound 1 (75.8% from ethyl chloroimidyl acetate).
  • Compound J_ White (or pale yellow) crystal
  • ETA- affinity to R was determined from 1 2 5 I-labeled E down Doseri down one 1 strength to inhibit binding to rat Bok aortic smooth muscle A 7 r 5 cells. Specifically, 4 8 After washing the cells cultured in the hole plates with buffer, 8 3 X 1 0 -. 1 2 M of 1 2 5 I-labeled end-cell Li down one 1 and various proteolytic enzymes HEPES-buffered Hanks' solution (0.3 ml) containing an inhibitor was added, and the mixture was incubated at 37 with or without the compound of the present invention for 1 hour. After the reaction is completed, the reaction solution is removed by suction, and the cells are washed.
  • Table 3 shows the results of Test Examples 1 and 2.
  • the compound of the present invention selectively exerts an antagonistic activity on the endoselin B receptor. Therefore, the compound of the present invention can be expected as a very useful pharmaceutical for diseases considered to be caused by the action of endoselin B receptor.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I), des sels ou des hydrates de ces composés acceptables en pharmacie et une composition médicinale, plus particulièrement un antagoniste sélectif du récepteur de l'endothéline B contenant ces substances. X représente un alkylène ou un alkénylène inférieurs.
PCT/JP1996/002764 1995-09-26 1996-09-25 Nouveaux composes de sulfonamide et composition medicinale WO1997011942A1 (fr)

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JP7/273600 1995-09-26

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387915B2 (en) 2000-05-31 2002-05-14 Pfizer Inc. Isoxazole-sulfonamide endothelin antagonists
US6962923B2 (en) 1999-07-29 2005-11-08 Pfizer Inc. Pyrazole compositions

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JPH0859635A (ja) * 1994-08-17 1996-03-05 Shionogi & Co Ltd エンドセリン受容体拮抗作用を有するスルホンアミド誘導体

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JPH0649046A (ja) * 1992-05-06 1994-02-22 E R Squibb & Sons Inc フェニルスルホンアミドエンドセリンアンタゴニスト
JPH0859635A (ja) * 1994-08-17 1996-03-05 Shionogi & Co Ltd エンドセリン受容体拮抗作用を有するスルホンアミド誘導体

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962923B2 (en) 1999-07-29 2005-11-08 Pfizer Inc. Pyrazole compositions
US6387915B2 (en) 2000-05-31 2002-05-14 Pfizer Inc. Isoxazole-sulfonamide endothelin antagonists

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