WO1986002636A1 - Derives de l'acide benzoique et procede de preparation - Google Patents

Derives de l'acide benzoique et procede de preparation Download PDF

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Publication number
WO1986002636A1
WO1986002636A1 PCT/JP1984/000520 JP8400520W WO8602636A1 WO 1986002636 A1 WO1986002636 A1 WO 1986002636A1 JP 8400520 W JP8400520 W JP 8400520W WO 8602636 A1 WO8602636 A1 WO 8602636A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
formula
general formula
salt
Prior art date
Application number
PCT/JP1984/000520
Other languages
English (en)
Japanese (ja)
Inventor
Akira Nohara
Yoshitaka Maki
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/JP1984/000520 priority Critical patent/WO1986002636A1/fr
Priority to JP60213578A priority patent/JPS61267539A/ja
Priority to NO854219A priority patent/NO854219L/no
Priority to AU49000/85A priority patent/AU4900085A/en
Priority to EP85307684A priority patent/EP0181125A3/fr
Priority to DK491785A priority patent/DK491785A/da
Priority to US06/791,543 priority patent/US4714774A/en
Priority to GR852604A priority patent/GR852604B/el
Priority to HU854162A priority patent/HU195179B/hu
Priority to KR1019850008050A priority patent/KR870003047A/ko
Priority to SU853969758A priority patent/SU1454247A3/ru
Priority to ZA858341A priority patent/ZA858341B/xx
Priority to ES548360A priority patent/ES8702877A1/es
Priority to CN85107954A priority patent/CN85107954A/zh
Publication of WO1986002636A1 publication Critical patent/WO1986002636A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups

Definitions

  • the present invention shows antagonistic action against a chemical messenger [Slow Reacting Substance of Anaphylaxis (SRS-A)] that causes contraction of bronchial smooth muscle and the like, and a benzoic acid derivative or a derivative thereof useful as a therapeutic agent for asthma or the like.
  • SRS-A Small Reacting Substance of Anaphylaxis
  • the present invention relates to a salt and a method for producing the salt.
  • the present inventors have conducted intensive studies with the aim of obtaining a compound having a sufficient SRS-A antagonistic action, and have found that certain benzoic acid derivatives meet this purpose. completed. -The present invention is-
  • R 1 represents a lower alkyl group
  • f- 2 represents a carboxy group which may be protected
  • X represents a halogen.
  • FT has the same meaning as described above, and Y represents a group which is eliminated during the acylation reaction. Reacting with the vulcanizing agent (V :) represented by
  • R 1 and X have the same meanings as described above, and R 2 ′ represents a protected carboxy group.
  • X has the same meaning as described above, and R 2 ′′ represents a carboxy group protected by a protecting group represented by R 5 ′.
  • R- (de) By reacting the acylating agent represented by the general formula R- (de)
  • the lower alkyl represented by R 1 has 1 to 3 carbon atoms
  • Mouth pill isopropyl and the like. Above all, methyl and ethyl
  • the protecting group for the protected carbonyl group represented by R 2 ′ is represented by R 5 , and a specific example of the protecting group represented by the formula is (-(CH 2 ) 3 ⁇ 4 / V ⁇ 3 + (W) (In the formula, n is an integer of 2 to 4, R 3 and R 4 are the same or different and each represents hydrogen or carbon.
  • R 2 A protecting group (R 5 ') which is protected by a carboxy group protected by a protecting group represented by R 5 ' represented by the formula — (CH 2 ) n H ⁇ (formula
  • a protecting group for example, tetrahydro sigma bilanyl, t-butyl,
  • Trityl benzyl, benzyloxymethyl, phenacyl group, etc.
  • heterocyclic groups may have a substituent, and as the substituent;
  • OMPI '' For example, lower alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, 11-propyl.
  • examples of the halogen represented by X include bromine, chlorine, fluorine and iodine.
  • the group which is eliminated during the acylation reaction represented by Y include an acyloxy group such as acethoxy and propionyloxy and a halogen atom such as chlorine and bromine.
  • 1 X is preferably in the ortho position, and -COOH, -R 2 ,-'and -R 2 "are each preferably in the para position.
  • the reaction of producing the compound (I) or a salt thereof by reacting the compound (II) or a salt thereof with the acylating agent (V) is carried out in an amount of about 2 to 30 equivalents of the acyl compound to 1 equivalent of the compound (II).
  • Activator (V). The reaction is preferably performed in the presence of a base such as pyridine, 4-dimethylmethylaminopyridine, or triethylamine.
  • a base such as pyridine, 4-dimethylmethylaminopyridine, or triethylamine.
  • the solvent to be used include chloroform, dichloromethane, dimethylformamide, tetrahydrofuran, and dioxane. In general, an excess of pyridine or the like is often used as the solvent.
  • the reaction time is about 1 to 48 hours.
  • the anti-t & temperature usually ranges from under ice-cooling to around the boiling point of the reagents and solvents used.
  • the compound (1Y) is subjected to a protecting group-introducing reaction of the carboxy group to produce the compound ( ⁇ ) by reacting the compound (17) or a salt thereof with a halogenating agent, and reacting the compound (IV ') with an acid halide. And then reacting this with an alcohol derivative of a protecting group.
  • compound (IV ') is converted to a halogenating agent (eg, thionyl chloride, phosphoryl chloride, thionyl bromide, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride). , Phosphorus tribromide, etc.).
  • Solvents used in the reaction include, for example, chloroform, dimethylformamide, dimethylformamide, tetrahydrofuran, and dihydrofuran.
  • the reaction temperature is about 80 to 120 ° C, and the reaction time is about 0.5 to 4 hours.
  • the reaction for producing the compound (II) by subjecting the compound to a reaction for introducing a protecting group for a carboxy group can be carried out by reacting the compound with a compound having a protecting group.
  • halide of the protecting group include, for example, those represented by the general formula
  • ⁇ represents halogen.
  • R 5 has the same meaning as described above.
  • halogen represented by ⁇ include chlorine, bromine, and iodine.
  • reaction about 1 to 4 equivalents of compound 1) is used per 1 equivalent of compound ().
  • the reaction is preferably performed in the presence of a base.
  • the base include: for example, triethylamine, pyridine, dimethylaniline and the like.
  • examples of the reaction include: for example, dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, dioxane, acetate.
  • a solvent such as nitrile is used.
  • the reaction temperature is about 70 to 150 ° C, and the reaction time is about 1 to 6 hours.
  • compound ( ⁇ ⁇ ′′) can be produced by reacting the mixture under ice cooling or at room temperature for about 0 minutes to 5 hours.
  • the solvent used for example, methylene chloride, chloroform, acetonitrile, tetrahydrofuran and the like are used, and as the acid, p-toluenesulfonic acid, sulfuric acid and the like are used.
  • the compound ( ⁇ ′) is subjected to the same reaction as that used to convert the compound (ff) into an acid halide as described above.
  • a base such as pyridine
  • R 5 ′ is a trityl group or a benzyloxymethyl group
  • the compound ( ⁇ ′) is converted to a salt such as sodium, potassium, silver, or the like, and the salt is mixed with tritium bromide or Compound ( ⁇ ") can be derived by reacting benzyloxymethyl chloride, etc.
  • a phenacyl group phenacyl bromide can be added to compound ( ⁇ ') in the presence of triethylamine, etc.
  • the compound (′′) can be led by reacting
  • the solvent used in the reaction Retsue if benzene, hexane, black hole Holm, dichloroethane port methane, acetic Echiru child Jewishi Dorofuran, c ⁇ cell Tonito Lil and the like
  • reaction temperature is appropriately selected from conditions under ice-cooling or around the boiling point of the solvent.
  • the reaction time is about 1 to 5 hours.
  • the reaction can be carried out in the same manner as in the acylation reaction.
  • the elimination reaction of R 5 ′ is the reaction of the protecting group R 5 ′
  • R 5 ′ is a tetrahydrobiranyl group
  • it is about 30 at room temperature in the presence of an acid such as hydrochloric acid or ⁇ -toluenesulfonic acid in tetrahydrofuran-water or acetic acid.
  • an acid such as hydrochloric acid or ⁇ -toluenesulfonic acid in tetrahydrofuran-water or acetic acid.
  • c R 5 ′ is benzyloxymethyl or phenacyl
  • the reaction can be carried out for about 1 to 10 hours at about room temperature by catalytic reduction using palladium or the like as a catalyst. Can be.
  • R 5 ′ is t-butyl or trityl
  • the reaction is carried out in the presence of an acid such as hydrochloric acid, trifluoroacetic acid, formic acid and P-toluenesulfonic acid under ice cooling or about 50 hours for about 1 to 5 hours. Can do it.
  • an acid such as hydrochloric acid, trifluoroacetic acid, formic acid and P-toluenesulfonic acid under ice cooling or about 50 hours for about 1 to 5 hours. Can do it.
  • the target compound obtained by the above method can be separated and purified from the anti-mixture by a means known per se, for example, recrystallization or chromatography.
  • a pharmacologically acceptable salt is preferable, and examples thereof include alkali metal salts such as sodium salt and potassium salt, hydrochloride, Inorganic and organic acid salts, such as sulfates, phosphates, fumarate maleates, and oxalates.
  • R 2 is a carboxy group in the starting compound ( ⁇ ) of the method of the present invention
  • R 2 is a carboxy group in the starting compound ( ⁇ ) of the method of the present invention
  • R 2 is -C00H or a compound of the formula
  • compound () Certain compound [hereinafter referred to as compound (). Is a chemical mediator that causes the contraction of bronchial smooth muscle, etc.
  • SRS-A slow reacting substance of anaphylaxis
  • SRS-A is produced by various stimuli such as the immune response and is considered to be an immediate mediator of allergic reactions, such as bronchospasm in allergic asthma.
  • SRS-A includes leukotriene C (LTC), leukotriene D (LTD), etc., and its effect on human tracheal muscle: LTD and LTC are almost equal.
  • LTC leukotriene C
  • LTD leukotriene D
  • LTD human tracheal muscle
  • Antagonism of drugs against SRS-A can be determined using the ileum of a perm or LR.
  • Guinea pigs were treated with urethane (nrethane) a.5gAg, ip (peritoneal cavity) Intra-administration)) Fix the dorsal position under anesthesia, and connect the incised trachea to the artificial respirator mouth dent respirator model 680 [Herbert Apparatus • Power amp; did.
  • the side branch of the tracheal force neura was connected to a bronchospasm transducer 7020 [ ⁇ Gobasil 'Biological' Research-Apara-Tas (Italian-)].
  • the test drug was suspended in 5% gum arabic solution or dissolved in water, and orally administered 1 hour before L.TD + administration in a volume of 0.2 ml per 100 g of guinea pig body weight. LTD + was administered via a force neuron previously placed in the jugular vein. LTD + was used by diluting inig / methanol (iml) stored at -70 ° C with physiological saline.
  • Control compound (A) a compound represented by the following formula in European Patent Application Publication No. 80, 371
  • mice The results of the acute toxicity test of the compound (I ′)-11 in mice were as follows.
  • J cl Five male J cl: ICR mice (5 weeks old) weighing about 3 Og per group were used. Compound (J) -1 was suspended in a 5% gum arabic solution, and 0.2 ml per body weight i Og was orally administered.
  • the compound (I ')-11 was orally administered to mice at 50 Omg / Kg each, and the toxicity thereof was examined. At this dose, no significant drug-related symptoms were observed. At necropsy, one day after administration, no abnormalities were observed and no hearing was observed.
  • compound (1 ') is a disease caused by SRS-A, such as asthma, hay fever, chronic bronchitis, eye allergic diseases, gastrointestinal allergic diseases and circulatory disorders, allergic dermatitis. It can be used as a therapeutic agent for other inflammations.
  • compound (1 ') or a salt thereof can be administered orally to mammals (size, mouse, rat, guinea pig, human, etc.) at a daily dose of about 2 to 2 mg as an anti-inflammatory drug or as an anti-inflammatory agent.
  • Compound (1 ') or Compound (1') or a salt thereof may be converted into a pharmacologically acceptable carrier, excipient, diluent (eg, milk, starch, cellulose derivative, Stearate, magnesium stearate, silver, gelatin, ara
  • OMPI Compound (1 ') or a salt thereof is pharmacologically acceptable for parenteral administration together with beer gum, for example, as tablets, capsules, granules, troches, solutions, syrups, etc. Ointments, suppositories, aerosols, inhalants, injections, etc. together with carriers, excipients, and diluents (eg, white cellulose, II ointment, oily ointment, glyceride, polyethylene dalicol, etc.) Each of them can be formulated and administered in the usual manner.
  • R 2 is a protecting group other than a group represented by the formula (CH 2 ) nN; ⁇ , wherein n, R 3 and R + have the same meanings as described above.
  • (R 5 ') protected carboxy group (R 2 ") is a compound [compound (I")] is had example, if a compound useful as the treatment of asthma agents (Ji) synthetic intermediate for the production of Useful as
  • Tetrahydroviranil 4-1 3- (4-acetyl-3-hydr ⁇ -xy 2-prop ⁇ -pyruphenoxy) propoxy: 13-bromobenzoate (1.2 g of methylene chloride) 0 ml), triethylamine (6 ml) and 4-dimethylaminopyridine (15 mg) were added, and ice anhydride (5 ml) was added dropwise under ice cooling. After stirring for 30 minutes under ice-cooling, methanol (5 ml) was added, and the mixture was allowed to stand for a while. Then, ⁇ -mouthed form (50 ml) was added, and the mixture was washed with a 5% aqueous sodium hydrogencarbonate solution and then with water.
  • Compound (I) or a salt thereof has excellent anti-asthmatic and anti-inflammatory effects, and can be used as a therapeutic or anti-inflammatory agent for asthma in mammals.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dérivés de l'acide benzoïque représentés par la formule générale (I) (où R1 représente alkyle inférieur, R2 représente carboxy éventuellement protégé et X représente halogène) et leurs sels, notamment ceux où R2 représente un groupe carboxy protégé par un groupe représenté par (II) (où n représente un nombre entier compris entre 2 et 4, R3 et R4 peuvent être identiques ou différents et représentent chacun hydrogène ou alkyle ou, lorsqu'ils sont pris ensemble avec l'atome d'azote adjacent, R3 et R4 peuvent former un groupe hétérocyclique). Ces composés ou leurs sels présentent d'excellents effets anti-asthmatiques et anti-inflammatoires, ce qui permet de les utiliser comme agents anti-asthmatiques et anti-inflammatoires pour les mammifères.
PCT/JP1984/000520 1984-10-30 1984-10-30 Derives de l'acide benzoique et procede de preparation WO1986002636A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
PCT/JP1984/000520 WO1986002636A1 (fr) 1984-10-30 1984-10-30 Derives de l'acide benzoique et procede de preparation
JP60213578A JPS61267539A (ja) 1984-10-30 1985-09-25 安息香酸誘導体およびその製造法
NO854219A NO854219L (no) 1984-10-30 1985-10-22 Benzosyrederivater og fremstilling derav.
AU49000/85A AU4900085A (en) 1984-10-30 1985-10-23 Etherified hydroxy- halo- benzoic acid
EP85307684A EP0181125A3 (fr) 1984-10-30 1985-10-24 Dérivés de l'acide benzoique et leur production
DK491785A DK491785A (da) 1984-10-30 1985-10-25 Benzoesyrederivater og fremstilling deraf
US06/791,543 US4714774A (en) 1984-10-30 1985-10-25 Benzoic acid derivatives and their production
GR852604A GR852604B (fr) 1984-10-30 1985-10-29
HU854162A HU195179B (en) 1984-10-30 1985-10-30 Process for producing benzoic acid derivatives and pharmaceutical preparations comprising these compounds as active substance
KR1019850008050A KR870003047A (ko) 1984-10-30 1985-10-30 벤조산 유도체의 제조방법
SU853969758A SU1454247A3 (ru) 1984-10-30 1985-10-30 Способ получени производных бензойной кислоты или их монооксалатов
ZA858341A ZA858341B (en) 1984-10-30 1985-10-30 Benzoic acid derivatives and their production
ES548360A ES8702877A1 (es) 1984-10-30 1985-10-30 Un metodo para producir un derivado de acido benzoico.
CN85107954A CN85107954A (zh) 1984-10-30 1985-10-30 苯甲酸衍生物及其制备

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1984/000520 WO1986002636A1 (fr) 1984-10-30 1984-10-30 Derives de l'acide benzoique et procede de preparation

Publications (1)

Publication Number Publication Date
WO1986002636A1 true WO1986002636A1 (fr) 1986-05-09

Family

ID=13818454

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1984/000520 WO1986002636A1 (fr) 1984-10-30 1984-10-30 Derives de l'acide benzoique et procede de preparation

Country Status (7)

Country Link
JP (1) JPS61267539A (fr)
KR (1) KR870003047A (fr)
AU (1) AU4900085A (fr)
ES (1) ES8702877A1 (fr)
SU (1) SU1454247A3 (fr)
WO (1) WO1986002636A1 (fr)
ZA (1) ZA858341B (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4683242A (en) * 1985-10-28 1987-07-28 A. H. Robins Company, Incorporated Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
No relevant documents have been disclosed. *

Also Published As

Publication number Publication date
JPS61267539A (ja) 1986-11-27
ES548360A0 (es) 1987-01-16
ZA858341B (en) 1987-06-24
SU1454247A3 (ru) 1989-01-23
AU4900085A (en) 1986-05-08
KR870003047A (ko) 1987-04-14
ES8702877A1 (es) 1987-01-16

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