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WO1997010214A1 - Nouveaux derives d'acide phenylacetique et compositions medicinales les contenant - Google Patents

Nouveaux derives d'acide phenylacetique et compositions medicinales les contenant Download PDF

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Publication number
WO1997010214A1
WO1997010214A1 PCT/JP1996/002607 JP9602607W WO9710214A1 WO 1997010214 A1 WO1997010214 A1 WO 1997010214A1 JP 9602607 W JP9602607 W JP 9602607W WO 9710214 A1 WO9710214 A1 WO 9710214A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituent
lower alkyl
optionally
compound
optionally substituted
Prior art date
Application number
PCT/JP1996/002607
Other languages
English (en)
Japanese (ja)
Inventor
Kunio Hayashi
Teruo Yamamori
Yasuhiko Kanda
Original Assignee
Shionogi & 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 Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU69446/96A priority Critical patent/AU6944696A/en
Publication of WO1997010214A1 publication Critical patent/WO1997010214A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

  • R 1 is a lower alkyl which may have a substituent, a cycloalkyl which may have a substituent, an aryl or a substituent which may have a substituent.
  • R 2 and R 3 are each independently hydrogen or a lower alkyl optionally having substituent (s), and R 4 is hydrogen or a substituent having lower substituent (s).
  • R 5 , R 6, and R 7 are each independently hydrogen, halogen, or a lower alkyl which may have a substituent.
  • R 2 and R 3 are each independently hydrogen or a lower alkyl optionally having a substituent, More preferably compounds each being hydrogen,
  • R 4 is hydrogen, lower alkyl optionally having substituent (s), or aryl which may have substituent (s),
  • R 1 is hydrogen, lower alkyl optionally having substituent (s), cycloalkyl optionally having substituent (s), aryl (s) optionally having substituent (s), Lower alkoxy optionally having, lower alkylthio optionally having a substituent, lower acyl optionally having a substituent, amino optionally having a substituent, having a substituent Ri good force Rubamoiru or single NHS ⁇ 2 R 8 der also be, and R 2 and R 3 have each independently hydrogen or a substituent is also optionally substituted lower alkyl, R 4 is hydrogen, substituted A lower alkyl which may have a group or an aryl which may have a substituent, wherein X is —O—,
  • Reference to the "compound of the present invention” includes, where possible, pharmaceutically acceptable salts thereof.
  • alkali metals sodium, calcium, lithium, etc.
  • alkaline earth metals calcium, magnesium, etc.
  • ammonium or organic bases salts with amino acids, etc., and inorganic acids (hydrochloric acid, etc.)
  • Hydrobromic acid, phosphoric acid, sulfuric acid, etc. or salts with organic acids (acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).
  • These salts can be formed by a commonly used method.
  • the compounds of the present invention also include the aminoxides.
  • the compound (III) is obtained by hydrolyzing the compound (I) in a usual manner.
  • the condensation reaction is carried out, for example, in a solvent such as dimethylformamide, acetonitril, and aceton, in a solvent such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, or the like.
  • the reaction may be carried out in the presence of a base at room temperature to under heating, preferably around room temperature, for several hours to 24 hours, preferably for about 2 to 5 hours.
  • the compound (XI) is dissolved in a lower alcohol such as methanol or ethanol, and a suitable concentration, for example, a base such as 1 N sodium hydroxide or an aqueous solution of potassium hydroxide is dissolved.
  • the compound (III) can be obtained by reacting the mixture under cooling to heating, preferably at about room temperature for about 1 to 24 hours.
  • the compound (II) is activated by activating the carboxyl group of the compound (III) dissolved in the solvent and condensing with the sulfonamide compound (XII) in the presence of a base under cooling to warming, preferably around room temperature. obtain.
  • the solvent for example, tetrahydrofuran, getyl ether, dimethoxyethane, methylene chloride, 1,2-dichloroethane, or the like may be used.
  • 1,1′-carbonyldiimidazole is used.
  • 1,8-diazabicyclo [5.4.0] indene-17-ene can be suitably used.
  • the compound (III) of the present invention obtained by the above method is in a racemic form, if necessary, it can be converted to a quaternary salt with a chiral amine and then dissociated with an acid to obtain an optically active compound. it can.
  • racemic compound of the present invention (III) and (R)-(+) I-methylbenzylamine, (1S, 2R) -1-(+)-norephedrine, (1S, 2S) -(+) — 2 — Amino 1 — Phenyl 1, 3, 3-propanediol, D — Threo (one) 1-2 — Amino 1-1 (412 trophenyl) 1-1,3 — Pronondiol Is dissolved in an organic solvent such as ethyl acetate, acetonitril, methanol, ethanol, or isopropanol, and then the solvent is distilled off, and recrystallization is repeated with the above solvent.
  • an organic solvent such as ethyl acetate, acetonitril, methanol, ethanol, or isopropanol
  • Compound (VI) can be obtained, for example, by the following method.
  • a known compound or a compound (IV) obtained by a known method is prepared for several hours to several days at 0 t: to 100 t :, preferably 40: to 60, preferably for 1 hour to 24 hours.
  • the reaction is followed by acylation to obtain compound (V).
  • the compound (V) is mixed with a suitable alcohol containing ammonia or ammonium hydroxide or the like at room temperature to under heating, preferably at 150: or more, for several hours to several days, preferably for 10 hours to 48 hours.
  • the compound (VI) in which X ′ OH is obtained by reacting to a certain degree.
  • compound (IV) is converted to an acid anhydride (eg, n-butyric anhydride, propionic anhydride) or an acid chloride (eg, 4-tert-butylbutylsulfonyl chloride, acetyl chloride) corresponding to the target compound
  • the compound (V) is obtained by reacting with an acylating agent such as amide, propionyl chloride or the like at 0 to under heating, preferably at 40: to 6O: to obtain the compound (V).
  • a buffer such as phosphoric acid may be used.
  • a rearrangement reaction is carried out at a high temperature of 20 O: or higher with a high boiling point solvent such as diphenyl ether, dougham, etc., to form carbamoylthio, and further, a solvent such as tetrahydrofuran, getyl ether, dimethoxane, etc.
  • a high boiling point solvent such as diphenyl ether, dougham, etc.
  • the substituents R 1 ′ to R 4 ′ of the compound (IV) and the compound (V) are finally converted to the substituents 1 to! Of the target compound (VI) by a usual method. ? Any group can be used as long as it can be converted to 4 .
  • the substituents R i ′ to R 4 ′ can be converted into the substituents R 1 to R 4 at an appropriate stage using a commonly used chemical reaction, for example, the following reaction.
  • the compound (VI) in which any substituent is lower alkylthio is prepared in a solvent such as acetonitrile and tetrahydrofuran.
  • a solvent such as acetonitrile and tetrahydrofuran.
  • the reaction may be carried out with an alkylating agent such as acetyl iodide or propyl bromide at room temperature to under heating, preferably at around 80, for a few minutes to several hours.
  • the compound (VI) in which either group is lower alkyl may be added to the compound (VI) having metaclo-peroxybenzoic acid, hydrogen peroxide, acetic acid, peracetic acid, or acetic acid.
  • An oxidizing agent such as trifluoroperacetic acid, perbenzoic acid, or dimethyldioxysilane is reacted to obtain an aminoxide compound, which is usually used at room temperature to under heating for several tens of minutes to several hours, for example, acetic anhydride, trifluoric anhydride, etc. May be reacted with the acylating agent.
  • the reaction is carried out under ice-cooling to 0X: preferably under ice-cooling for several hours, and the reaction is carried out in a solvent such as toluene, benzene, chloroform, methylene chloride or the like, in the presence of a base such as sodium metal.
  • the reaction may be carried out with an alcohol such as ethanol, ethanol, or the like according to the purpose.
  • the compound (VI) in which either group is an aldehyde is prepared by dissolving the compound (VI) in a solvent such as dichloromethane or tetrahydrofuran. 0 to room temperature for acetic anhydride, anhydrous Application Benefits Furuoro acetate, S_ ⁇ 3 - using Bok Riechiruami down, DCC-Application Benefits Furuoro ⁇ , as an activator of P 2 0 5, etc. - pyridinium Jin, (COC 1) 2 DM SO oxidation may be performed.
  • PCC PDC, may be oxidized using an oxidizing agent such as M N_ ⁇ 2, KM n 0 4.
  • the compound (VI) in which either group is lower alkyl substituted with imino or hydrazone is obtained, the compound (VI) in which either group has an aldehyde is converted to an alcohol such as methanol or ethanol.
  • the reaction may be performed by mixing with an amino compound such as hydroxyaluminum, dimethylhydroxylamine, hydrazine or the like in an ice-cooled room temperature at room temperature for several minutes to several hours.
  • a compound (VI) in which any of the groups is cyano is converted into an aminoxide compound in the same manner as described above.
  • the compound is reacted with a methylating agent such as dimethyl sulfate or methyl iodide to form a methoxypyridinium compound, which is heated at room temperature to under heating for several hours to several tens of hours, and is treated with sodium cyanide or potassium cyanide.
  • the reaction may be carried out with a cyanating agent such as chromium to form a cyanogen.
  • a cyanating agent such as chromium
  • the substitution reaction between hydroxy and halogen (H a1: for example, bromine, chlorine, iodine, etc.) is performed.
  • the substitution reaction for halogen is, for example, ethylene chloride, 1,2-dichloroethane, chloroform, ethyl acetate.
  • Solution of a compound (IX) dissolved in a suitable solvent such as thiocyanyl chloride, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, phosphorous trichloride, etc.
  • a suitable solvent such as thiocyanyl chloride, phosphorous trichloride, phosphorous oxychloride, phosphorous pentachloride, phosphorous trichloride, etc.
  • the reaction may be carried out at ⁇ 5 "C for several hours to several tens of hours, preferably 10 to 20 hours.
  • the compound (X) can be obtained by extracting the reaction product obtained here.
  • the dose of the compound of the present invention as a medicament is desirably determined in consideration of the patient's age, body weight, administration route, type and degree of disease, and the like. It is in the range of 0.01 to 1000 mg / kg / day, preferably in the range of 0.01 to 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the route of administration, but it is usually 0.001 to 10011 1 ⁇ / day, preferably 0.01 to 10 mg / kg / day. Within range. It may be administered once or several times a day.
  • the compound (II-3a) was fractionated on a column of Chiralpak AD (CHIRALP AKAD, manufactured by Daicel Chemical Co., Ltd.) (solvent: n-hexane-ethanol-ethanol-trifluoroacetic acid); 90: 10: 0.
  • Chiralpak AD CHIRALP AKAD, manufactured by Daicel Chemical Co., Ltd.
  • solvent n-hexane-ethanol-ethanol-trifluoroacetic acid
  • the compound (II-8a) is fractionated on a column of CHIRALPAKAD (manufactured by Daicel Chemical Co., Ltd.) (solvent; n-hexane-ethanol-trifluoroacetic acid; 90: 10: 0.1).
  • COS - 7 was determined from 1 2 5 I-labeled ene Doseri down one 3 strength to inhibit binding to the cells. More specifically, A plasmid vector incorporating the B-receptor gene was introduced into COS-7 cells by the lipofectin method.
  • Table 6 shows the results of the test examples.
  • the compound (I) of the present invention antagonizes the binding of endoselin in the endoselin receptor and strongly suppresses the action of endoselin. Therefore, these compounds are useful as therapeutic and / or prophylactic agents for diseases caused by endoselin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Composés représentés par la formule générale (I), leurs oxydes d'amine, leurs sels pharmaceutiquement acceptables ou leurs hydrates, et compositions médicinales les contenant. Dans ladite formule R1 à R7 représentent chacun hydrogène, halogéno, alkyle inférieur facultativement substitué, etc; et X représente -O-, -S- ou -NR?15 où R15¿ représente hydrogène ou alkyle inférieur facultivement substitué. Les composés constituent un antagoniste puissant des récepteurs à l'endothéline, et, par conséquent, ils sont très utiles dans le traitement ou dans la prévention de maladies provoquées par l'endothéline.
PCT/JP1996/002607 1995-09-14 1996-09-12 Nouveaux derives d'acide phenylacetique et compositions medicinales les contenant WO1997010214A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69446/96A AU6944696A (en) 1995-09-14 1996-09-12 Novel phenylacetic acid derivatives and medicinal composition containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP7/262337 1995-09-14
JP26233795 1995-09-14

Publications (1)

Publication Number Publication Date
WO1997010214A1 true WO1997010214A1 (fr) 1997-03-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/002607 WO1997010214A1 (fr) 1995-09-14 1996-09-12 Nouveaux derives d'acide phenylacetique et compositions medicinales les contenant

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AU (1) AU6944696A (fr)
WO (1) WO1997010214A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122559B2 (en) 2003-02-11 2006-10-17 Bristol-Myers Squibb Company Phenylglycine derivatives useful as serine protease inhibitors
US7144895B2 (en) 2003-02-11 2006-12-05 Bristol-Myers Squibb Co. Benzene acetamide compounds useful as serine protease inhibitors
US7622585B2 (en) 2005-01-10 2009-11-24 Bristol-Myers Squibb Company Phenylglycinamide derivatives useful as anticoagulants
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US20160115158A1 (en) * 2013-05-14 2016-04-28 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as s100-inhibitors
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
WO2017150704A1 (fr) * 2016-03-04 2017-09-08 国立大学法人新潟大学 Activateur de la fonction de l'aquaporine 4 et composition pharmaceutique pour troubles neurologiques

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2637911A1 (de) * 1975-08-25 1977-03-10 Ciba Geigy Ag Das pflanzenwachstum regulierende 3-pyridinol-verbindungen
US4197302A (en) * 1976-03-04 1980-04-08 Ciba-Geigy Corporation 2-Pyridinecarboxylic acids
US4202901A (en) * 1976-03-04 1980-05-13 Ciba-Geigy Corporation 2-Pyridinecarbonitrile compounds
JPH08183786A (ja) * 1994-08-26 1996-07-16 Bristol Myers Squibb Co 置換ビフェニルイソキサゾールスルホンアミド類

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2637911A1 (de) * 1975-08-25 1977-03-10 Ciba Geigy Ag Das pflanzenwachstum regulierende 3-pyridinol-verbindungen
US4197302A (en) * 1976-03-04 1980-04-08 Ciba-Geigy Corporation 2-Pyridinecarboxylic acids
US4202901A (en) * 1976-03-04 1980-05-13 Ciba-Geigy Corporation 2-Pyridinecarbonitrile compounds
JPH08183786A (ja) * 1994-08-26 1996-07-16 Bristol Myers Squibb Co 置換ビフェニルイソキサゾールスルホンアミド類

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BULL. CHEM. SOC. JPN., (1977), Vol. 50, No. 12, INOUE, S., ASAI, N., YASUDA, G., HORI, T., "Sydnones. Synthesis and Photochemic Behavior of 3-(3-Pyridyl) Sydnone Derivatives and a 4-Alkyl-3-Phenylsydnone", p. 3268-3270. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122559B2 (en) 2003-02-11 2006-10-17 Bristol-Myers Squibb Company Phenylglycine derivatives useful as serine protease inhibitors
US7144895B2 (en) 2003-02-11 2006-12-05 Bristol-Myers Squibb Co. Benzene acetamide compounds useful as serine protease inhibitors
US7622585B2 (en) 2005-01-10 2009-11-24 Bristol-Myers Squibb Company Phenylglycinamide derivatives useful as anticoagulants
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
US9394285B2 (en) 2013-03-15 2016-07-19 Pfizer Inc. Indole and indazole compounds that activate AMPK
US20160115158A1 (en) * 2013-05-14 2016-04-28 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as s100-inhibitors
US9873687B2 (en) * 2013-05-14 2018-01-23 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as S100-inhibitors
US10125125B2 (en) 2013-05-14 2018-11-13 Active Biotech Ab N-(heteroaryl)-sulfonamide derivatives useful as S100-inhibitors
WO2017150704A1 (fr) * 2016-03-04 2017-09-08 国立大学法人新潟大学 Activateur de la fonction de l'aquaporine 4 et composition pharmaceutique pour troubles neurologiques
US10632084B2 (en) 2016-03-04 2020-04-28 Niigata University Aquaporin 4 function promotor and pharmaceutical composition for neurological disorders

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Publication number Publication date
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