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WO1986003742A1 - Procede de preparation de derives d'acide benzoique - Google Patents

Procede de preparation de derives d'acide benzoique Download PDF

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Publication number
WO1986003742A1
WO1986003742A1 PCT/JP1984/000617 JP8400617W WO8603742A1 WO 1986003742 A1 WO1986003742 A1 WO 1986003742A1 JP 8400617 W JP8400617 W JP 8400617W WO 8603742 A1 WO8603742 A1 WO 8603742A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
general formula
formula
reaction
benzoic acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1984/000617
Other languages
English (en)
Japanese (ja)
Inventor
Akira Nohara
Yoshitaka Maki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries 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 Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Priority to PCT/JP1984/000617 priority Critical patent/WO1986003742A1/fr
Priority to NO855138A priority patent/NO855138L/no
Priority to EP85309258A priority patent/EP0186440A3/fr
Priority to GR853120A priority patent/GR853120B/el
Priority to AU51541/85A priority patent/AU5154185A/en
Priority to DK596285A priority patent/DK596285A/da
Priority to HU855080A priority patent/HUT40608A/hu
Priority to ES550389A priority patent/ES8802296A1/es
Priority to CN85109332A priority patent/CN85109332A/zh
Publication of WO1986003742A1 publication Critical patent/WO1986003742A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups

Definitions

  • the present invention exhibits an antagonistic effect on a chemical mediator [Slow Reacting S ubstance of Anaphy xis (SRS-A)] that causes contraction of bronchial smooth muscle and the like, and is useful as a therapeutic agent for asthma and the like. It relates to the manufacturing method of the.
  • SRS-A Slow Reacting S ubstance of Anaphy xis
  • the present inventors have conducted intensive studies with the aim of obtaining a compound having a sufficient SRS-A antagonism, and found that certain benzoic acid derivatives are suitable for the purpose.
  • the present inventors have found a production method that is advantageous for the present invention, and have further studied, and as a result, completed the present invention.
  • the present invention provides: )
  • R 1 has the same meaning as described above.
  • Y represents a group which is eliminated during the condensation reaction.
  • n is an integer of 2 to 4, and R 2 and R 3 are the same or different and form a 5- or 6-membered heterocyclic ring with hydrogen or lower alkyl or an adjacent nitrogen atom.
  • Show. X has the same meaning as described above.
  • n, R 2 , R 3 and X have the same meaning as described above.
  • IE benzoic acid derivative
  • the lower alkyl represented by R 1 is preferably one having 1 to 3 carbon atoms, and specific examples thereof include methyl, ethyl, ⁇ -propyl, and isopropyl. Of these, methyl and ethyl are particularly preferred.
  • examples of the alkyl having 1 to 3 carbon atoms in R 2 and R 3 include: methyl, ethyl, ⁇ -propyl, isopropyl and the like.
  • examples of the 5- or 6-membered heterocyclic group include those containing one oxygen atom and those containing one or two nitrogen atoms. Specific examples thereof include morpholino, piperazino, piperidino, And pyrrolidino.
  • heterocyclic groups may have a substituent, and examples of the substituent include lower alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, l-propyl, isopyl pill) and the like.
  • substituent include lower alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, l-propyl, isopyl pill) and the like.
  • halogen represented by X examples include bromine, chlorine, fluorine, and iodine. It is.
  • R 2 In the present invention: — CHO, — CO OH, one CO 0 (CH 2 ) n ⁇ ,
  • R 3 One CO OR + described later is preferably in the para position, and X is preferably in the ortho position.
  • the group leaving during the condensation reaction represented by Y includes, for example, a halogen atom (eg, chlorine, bromine, iodine), ⁇ -toluenesulfonyloxy, methanesulfonyloxy, etc. Is mentioned.
  • Examples of the reagent used in the reaction for obtaining the compound (I) by subjecting the compound () to an oxidation reaction include potassium permanganate, chromate, hydrogen peroxide, silver (I) oxide, silver (II) oxide, oxygen and the like.
  • No. In the reaction about 1 to 4 equivalents of the oxidizing agent is used for 1 equivalent of the compound (1V), and a common organic solvent can be used as a solvent for the reaction. Particularly, acetic acid, acetate, benzene, acetonitrile and the like, or a mixed solvent thereof and the like can be mentioned. Sometimes it can also be carried out by a two-layer reaction with water.
  • the reaction temperature is preferably room temperature, but a temperature up to the boiling point of the solvent is appropriately selected.
  • the reaction time varies depending on the oxidizing agent, but is about 0.5 to 5 hours.
  • the solvent used in the reaction may be dimethylformamide, hexamethylphosphoric triamide, acetate, methylethylketone, tetrachloride.
  • the reaction temperature is about 50 to 150 ° C, and the reaction temperature time is about 1 to 6 hours.
  • the target compound obtained by the above method can be separated and purified from the reaction mixture by a means known per se, for example, recrystallization or chromatography.
  • a starting compound in the form of a salt of each compound may be used.
  • the target object may be searched for in the form of salt.
  • a pharmacologically acceptable salt is preferable, and examples thereof include metal salts such as sodium salts and potassium salts, and hydrochlorides, sulfates, and salts.
  • Inorganic and organic acid salts such as oxalate, fumarate, maleate and oxalate.
  • the raw material compound of the present invention (RO is a raw material compound (V) described later)
  • the substance compound (V) can be obtained by converting the known raw material compound (IX) into a compound represented by the general formula FTCO—Z (2), wherein R 1 has the same meaning as described above, and Z is removed during the acylation reaction.
  • the leaving groups are shown.
  • the reaction can be carried out by reacting with an acylating agent represented by the formula Examples of the group leaving during the acylation reaction represented by Z include acyloxy groups such as acetooxy and propionyloxy groups and halogen atoms such as chlorine and bromine.
  • the reaction for producing the compound (V) by reacting the compound (IX) with the acylating agent (H) is carried out by reacting about 2 to 30 equivalents of the acylating agent (XI) with respect to 1 equivalent of the compound (IX). Let it.
  • the reaction is preferably performed in the presence of a base such as pyridine, 4-dimethylaminopyridine, and triethylamine.
  • a base such as pyridine, 4-dimethylaminopyridine, and triethylamine.
  • a base such as pyridine, 4-dimethylaminopyridine, and triethylamine.
  • the solvent used For example, there may be mentioned form-form, dichloromethane, dimethylformamide, tetrahydrofuran, dioxane and the like. In general, ': is often used in excess of pyridine or the like without using a solvent.
  • the reaction time is about 1 to 48 hours.
  • the reaction temperature is usually from ice
  • the starting compound (VI) can be produced by the following production steps.
  • Formula (XI) In the formula, X has the same meaning as described above, and R + represents lower alkyl such as methyl and ethyl.
  • R + represents lower alkyl such as methyl and ethyl.
  • Y represents lower alkyl such as methyl and ethyl.
  • Y represents lower alkyl such as methyl and ethyl.
  • Y represents lower alkyl such as methyl and ethyl.
  • Y CH 2 ) 3 Y (Xni): wherein Y has the same meaning as described above, and two Ys represent the same or different cases.
  • the reaction conditions used in this case are compound (VI) and compound (VI) or compound (IX) and compound (W) to compound (II). Then, the reaction conditions are used to produce the compound (X is led to a compound of the general formula (XV) by a hydrolysis reaction.
  • the reaction is carried out using an excess amount of sodium hydroxide, hydroxylating water, etc.
  • the solvent a mixed solution with water such as methanol, ethanol, etc. is used
  • the reaction temperature is from room temperature to the boiling point of the solvent.
  • a reaction time of about 0.5 to 5 hours is usually used.
  • R 3 and n have the same meaning as described above, and T represents a group which is eliminated upon esterification. And the compound represented by the general formula (VI) can be produced.
  • Examples of the reactive derivative of the compound (XV) include an acid halide.
  • Examples of the halogen in the acid halide include chlorine, bromine and iodine.
  • Examples of the group leaving during the esterification reaction represented by T in compound (XW) include, for example, halogen (eg, chlorine, bromine, iodine, etc.), di-toluenesulfonyloxy, methansulfonyloxy, hydroxyl group And the like.
  • halogen eg, chlorine, bromine, iodine, etc.
  • di-toluenesulfonyloxy methansulfonyloxy, hydroxyl group And the like.
  • the reactive derivative of compound (XV) is an acid halide
  • the acid halide can be obtained by reacting compound (XV) or a salt thereof with a halogenating agent.
  • the compound (XV) and the ⁇ -genizing agent are reacted at a reaction temperature of about 80 to 120, for example, in a solvent such as chloroform, dichloromethane, tetrax-roethane, tetrahydrofuran, and dioxane. And react for about 0.5 to 12 hours.
  • an esterification reaction using a compound in which T of compound (XW) is a halogen or a p-toluenesulfonyloxy-methanesulfonyloxy group In the above, as a salt of the compound (XV), titanium, potassium, silver, tributylammonium salt or the like is used, and about 1 to 0 equivalent of the compound (XVI) is used for 1 equivalent of the compound (XV). .
  • the reaction is preferably performed in the presence of a base. Examples of the base include triethylamine, pyridine, dimethylaniline, 4-dimethylaminopyridine and the like.
  • reaction temperature is about 100 to 150 ° C, and the reaction time is about 1 to 6 hours.
  • the starting compound ( ⁇ ) can be produced by the following production steps.
  • the target compound (I). ( ⁇ ), ( ⁇ ) of the method of the present invention is directed against the slow reacting substance of anaphylaxis (SRS-A) which is a chemical ftAchemical mediator that causes the contraction of bronchial smooth muscle.
  • SRS-A anaphylaxis
  • SRS-A Produced by various stimuli such as immune responses, and is considered to be an immediate mediator of allergic diseases such as bronchospasm in allergic asthma.
  • SRS-A includes leukotriene C (LTC) and leukotriene D (LTD), etc.
  • LTC leukotriene C
  • LTD leukotriene D
  • the contractile action on the ileum is stronger in LTD than in LTC [S.E Dahlen et al. Ature, 288, 484 (1800); RALewis et al. Biochemical and Biophysical Research Communicat ions, 96, 2 7 1 (1 980).
  • the antagonism of drugs against SRS-A can be examined using the guinea pig ileum [R. A. Appleton et al. Journal of Medicinal Chemistry, 20, 371 (1977)].
  • the airway constriction response based on LTD + was determined by the Konzett-RGssler method (Konzett, H. and Rossler, R: Measured according to aunyn-Schmieder bergs Archiviur Experimen-telle Pathologie and Pharmakologie 1995, 71-74 (1940).
  • the guinea pig was fixed in a dorsal position under anesthesia with Lirethane (l. 5 g / g, i.p. (intraperitoneal administration)), and the incised trachea was passed through a forcepneumatic neurorespirator.
  • Control compound a compound represented by the following formula described in European Patent Application Publication No. 80, 371
  • mice of Compound A, Compound C or Compound E are as follows.
  • the compound C or E 200 Omg / Kg and the compound A 50 Omg / Kg were orally administered to mice, respectively, and the toxicity was examined. No significant symptoms attributable to the drug were observed at this dose. Necropsy 7 days after administration showed no abnormal findings.
  • Compounds (I) to (! II) can be used for diseases caused by SRS-A, such as asthma, hay fever, chronic bronchitis, allergic diseases of the eye, allergic diseases of the gastrointestinal tract and circulatory disorders, It can be used as a treatment for allergic dermatitis and other inflammations.
  • Compounds (I)-(II) or a salt thereof can be administered to a mammal (eg, mouse, rat, guinea pig, human, etc.) at a daily dose of about 1-2 Omg / Kg as an asthma therapeutic or anti-inflammatory. ) Is administered orally or parenterally.
  • compounds (I) to (! C) or a salt thereof can be converted into a pharmacologically acceptable carrier, excipient, diluent (eg, lactose, starch, cell sigma derivative).
  • a pharmacologically acceptable carrier e.g, lactose, starch, cell sigma derivative.
  • Parenteral administration for example, as tablets, capsules, granules, troches, solutions, syrups, etc., together with stearylate, magnesium stearate, sucrose, gelatin, gum arabic, etc.
  • a salt thereof is a pharmacologically acceptable carrier, vehicle, diluent (eg, white cellulose, hydrophilic plaster, oily plaster, glyceride, polyethylene glycol, etc.)
  • diluent eg, white cellulose, hydrophilic plaster, oily plaster, glyceride, polyethylene glycol, etc.
  • they can be formulated and administered as ointments, suppositories, aerosols, inhalants, injections, etc. in the usual manner.
  • the method of the present invention is a method capable of industrially and advantageously producing the compounds (I) to (!) Which have remarkably excellent effects.
  • Compounds (I) to (! ⁇ ) or salts thereof have excellent anti-asthmatic and anti-inflammatory effects, and can be used as therapeutic or anti-inflammatory agents for mammals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des dérivés d'acide benzoïque sont représentés par la formule (I) où R1 représente un alkyle inférieur, R2' représente -COOH ou la formule (II), dans laquelle n représente un entier compris entre 2 et 4, R2 et R3 peuvent être identiques ou différents et chacun représente de l'hydrogène ou un alkyle, ou bien R2 et R3 se combinenet pour former un anneau hétérocyclique de concert avec l'atome d'azote adjacent, et x représente un halogène, ou par la formule (III) dans laquelle X, n, R2 et R3 sont tels que définis ci-dessus. Ces dérivés qui possèdent une excellente action anti-asthmatique et ani-inflammatoire et sont utilisés comme agents anti-asthamatique ou anti-inflammatoires, sont judicieusement préparés par oxydation des dérivés d'aldéhyde correspondants ou par condensation des produits de départ correspondants.
PCT/JP1984/000617 1984-12-26 1984-12-26 Procede de preparation de derives d'acide benzoique Ceased WO1986003742A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
PCT/JP1984/000617 WO1986003742A1 (fr) 1984-12-26 1984-12-26 Procede de preparation de derives d'acide benzoique
NO855138A NO855138L (no) 1984-12-26 1985-12-18 Fremgangsmaate for fremstilling av benzosyrederivater.
EP85309258A EP0186440A3 (fr) 1984-12-26 1985-12-19 Méthode de préparation de dérivés d'acide benzoique
GR853120A GR853120B (fr) 1984-12-26 1985-12-20
AU51541/85A AU5154185A (en) 1984-12-26 1985-12-20 Benzoic acid derivatives
DK596285A DK596285A (da) 1984-12-26 1985-12-20 Fremgangsmaade til fremstilling af benzoesyrederivater
HU855080A HUT40608A (en) 1984-12-26 1985-12-23 Process for preparing benzoic acid derivatives and pharmaceutical preparations containing these compounds as active substance
ES550389A ES8802296A1 (es) 1984-12-26 1985-12-24 Un metodo para preparar un derivado de acido benzoico
CN85109332A CN85109332A (zh) 1984-12-26 1985-12-25 制备苯甲酸衍生物的方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1984/000617 WO1986003742A1 (fr) 1984-12-26 1984-12-26 Procede de preparation de derives d'acide benzoique

Publications (1)

Publication Number Publication Date
WO1986003742A1 true WO1986003742A1 (fr) 1986-07-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1984/000617 Ceased WO1986003742A1 (fr) 1984-12-26 1984-12-26 Procede de preparation de derives d'acide benzoique

Country Status (1)

Country Link
WO (1) WO1986003742A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1384530A (en) * 1971-07-29 1975-02-19 Fisons Ltd Chromone derivatives
US4200577A (en) * 1975-09-23 1980-04-29 Beecham Group Limited Coumarin derivatives
US4211791A (en) * 1975-09-23 1980-07-08 Beecham Group Limited Indanediones
GB2058785A (en) * 1979-09-05 1981-04-15 Glaxo Group Ltd Phenol Derivatives
EP0080371A1 (fr) * 1981-11-25 1983-06-01 Takeda Chemical Industries, Ltd. Dérivés du diphénoxypropane, leur production et leur application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1384530A (en) * 1971-07-29 1975-02-19 Fisons Ltd Chromone derivatives
US4200577A (en) * 1975-09-23 1980-04-29 Beecham Group Limited Coumarin derivatives
US4211791A (en) * 1975-09-23 1980-07-08 Beecham Group Limited Indanediones
GB2058785A (en) * 1979-09-05 1981-04-15 Glaxo Group Ltd Phenol Derivatives
EP0080371A1 (fr) * 1981-11-25 1983-06-01 Takeda Chemical Industries, Ltd. Dérivés du diphénoxypropane, leur production et leur application

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