JPS61129153A - Benzoic acid derivative and preparation thereof - Google Patents

Benzoic acid derivative and preparation thereof

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Publication number
JPS61129153A
JPS61129153A JP60213579A JP21357985A JPS61129153A JP S61129153 A JPS61129153 A JP S61129153A JP 60213579 A JP60213579 A JP 60213579A JP 21357985 A JP21357985 A JP 21357985A JP S61129153 A JPS61129153 A JP S61129153A
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JP
Japan
Prior art keywords
compound
formula
formulas
tables
salt
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.)
Pending
Application number
JP60213579A
Other languages
Japanese (ja)
Inventor
Akira Nohara
野原　昭
Yoshitaka Maki
牧　良孝
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 EP85307685A priority Critical patent/EP0180416A3/en
Priority to KR1019850008051A priority patent/KR870003060A/en
Publication of JPS61129153A publication Critical patent/JPS61129153A/en
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07C65/32—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 keto groups
    • C07C65/40—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 keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain

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

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are H, lower alkyl or together with adjuacent N form a 5- or 6-membered heterocyclic group; n is 2-4; X is halogen) and its salt. EXAMPLE:2-(N,N-dimethylamino)ethyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy) propoxy]-3-bromobenzoate. USE:Remedy for asthma and anti-inflammatory agent. It has antagonistic activity against the chemotransmitter SRS-A causing the constriction of bronchial smooth muscle, and is useful for the remedy of asthma and hay fever, etc. caused by SRS-A. PREPARATION:The compound of formula I can be prepared by reacting the reactive derivative of the compound of formula II with the reactive derivative of formula II.

Description

【発明の詳細な説明】 産業上の利用分野 本発明は、気管支平滑筋等の収縮をひき起こす化学伝達
物質Ｓｌｏｗ　　Ｒｅａｃｔｉｎｇ　　５ｕｂｓｔａｎ
ｃｅ　　ｏｆＡ　ｎａｐｈｙｌａｘｉｓ　　（Ｓ　ＲＳ
　−Ａ　）に対し拮抗作用を示し、喘息治療剤などとし
て有用な安息香酸誘導体またはその塩、およびその製造
法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a chemical mediator, Slow Reacting 5ubstan, which causes contraction of bronchial smooth muscle, etc.
ce of A naphylaxis (S RS
The present invention relates to a benzoic acid derivative or a salt thereof that exhibits an antagonistic effect on -A) and is useful as a therapeutic agent for asthma, and a method for producing the same.

従来の技術 気管支平滑筋の収縮作用を示す化学伝達物質ＳＲＳ−Ａ
に拮抗する化合物として、イギリス特許出願公開第１，
３８４，５３０号公報、ヨーロッパ特許出願公開第２８
．０６３号公報およびヨーロッパ特許出願公開第８０，
３７１号公報に記載された化合物が挙げられる。Conventional technologySRS-A, a chemical messenger that exhibits the contractile action of bronchial smooth muscle
As a compound that antagonizes
Publication No. 384,530, European Patent Application Publication No. 28
．． Publication No. 063 and European Patent Application Publication No. 80,
Examples include the compounds described in Japanese Patent No. 371.

発明が解決しようとする問題点 イギリス特許出願公開第１．３８４．５３０号公報およ
びヨーロッパ特許出願公開第２８，０６３号公報の実施
例として具体的に記載された化合物の５Ｒ９−Ａ拮抗作
用は充分とは言えず、作用の改善が望まれていた。また
ヨーロッパ特許出願公開第８０．３７１号公報に記載さ
れた化合物については、経口吸収の改善および作用の持
続性を増強することが、より望まれていた。Problems to be Solved by the Invention The 5R9-A antagonism of the compounds specifically described as examples in GB 1.384.530 and EP 28,063 is sufficient. However, it was hoped that the effect would be improved. Furthermore, with respect to the compounds described in European Patent Application Publication No. 80.371, it has been desired to improve oral absorption and enhance the duration of action.

問題点を解決するための手段 本発明者らは、充分な５ＲＩ−Ａ拮抗作用を有する化合
物を得る目的で鋭意研究したところ、ある種の安息香酸
誘導体が該目的に合致することを見い出だし、さらに研
究した結果、本発明を完成した。Means for Solving the Problems The present inventors conducted intensive research with the aim of obtaining a compound having sufficient 5RI-A antagonistic activity, and found that a certain type of benzoic acid derivative met the objective. As a result of further research, the present invention was completed.

本発明は、（１）　　一般式 Ｅ式中、Ｒ１およびＲ２は、同一または異なって、水素
、低級アルキルまたは隣接する窒素原子と共に５もしく
は６員異項環基を形成している場合を、ｎは２ないし４
の整数を、Ｘはハロゲンをそれぞれ示す。］で表わされ
る安息香酸誘導体（１）またはその塩７ （２）一般式 ［式中、Ｘはハロゲンを示す。］て表わされる化合物（
ＩＩ）の反応性誘導体と一般式 ［式中、Ｒ１，Ｒ２およびｎは前記と同意義を何する。(1) In the general formula E, R1 and R2 are the same or different and form a 5- or 6-membered heterocyclic group together with hydrogen, lower alkyl, or an adjacent nitrogen atom, n is 2 to 4
and X represents a halogen, respectively. ] Benzoic acid derivative (1) or its salt 7 (2) General formula [wherein, X represents a halogen. ] Compound (
II) Reactive derivatives of the general formula [wherein R1, R2 and n have the same meanings as above.

］で表わされる反応性誘導体（ＩＩ／）とを反応させる
ことを特徴とする安息香酸誘導体（１）またはその塩の
製造法、および （３）化合物（ＩＩ）またはその塩と一般式［式中、Ｚ
はエステル化反応の際に脱離する基を示す。Ｒ１、Ｒ１
およびｎは前記と同意義を有する。］て表わされる反応
性誘導体とを反応させることを特徴とする化合物（１）
またはその塩の製造法である。], and (3) a method for producing a benzoic acid derivative (1) or a salt thereof, which is characterized by reacting the compound (II) or a salt thereof with a reactive derivative (II/) represented by the general formula [in the formula ,Z
represents a group that leaves during the esterification reaction. R1, R1
and n have the same meanings as above. ] Compound (1) characterized by reacting with a reactive derivative represented by
or a method for producing its salt.

」二記式中、Ｒ１およびＲ２における低級アルキルとし
ては、炭素数１ないし３のものが好ましく、その例とし
ては、たとえばメチル、エチル、ｎ−プロピル、イソプ
ロピルなどが挙げられる。In the two notation formulas, the lower alkyl in R1 and R2 preferably has 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, and the like.

Ｒ１およびＲ１が隣接する窒素原子と共に形成している
５もしくは６員異項環基としては、酸素原子１個を含む
もの、窒素原子を１〜２個含むものなどが挙げられ、そ
の具体例としてはたとえばモルホリノ、ピペラジノ、ピ
ペリジノ、ピロリジノなどが挙げられる。Examples of the 5- or 6-membered heterocyclic group formed by R1 and R1 together with the adjacent nitrogen atom include those containing one oxygen atom and those containing 1 to 2 nitrogen atoms. Examples include morpholino, piperazino, piperidino, and pyrrolidino.

上記異項環基は、置換基を有していてらよく、該置換基
としてはたとえば炭素数１〜３の低級アルキル（例、メ
チル、エチル、ｎ−プロピル）などが挙げられる。The above-mentioned heterocyclic group may have a substituent, and examples of the substituent include lower alkyl having 1 to 3 carbon atoms (eg, methyl, ethyl, n-propyl).

上記式中、Ｘで表わされるハロゲンとしては、たとえば
臭素、塩素、フッ素、ヨウ素が挙げられる。In the above formula, examples of the halogen represented by X include bromine, chlorine, fluorine, and iodine.

化合物（１）、（ｎ）におけるＸはオルト位であること
が、−ＣＯＯＨ基および が好ましい。In compounds (1) and (n), X is preferably at the ortho position, and is preferably a -COOH group.

化合物（ＩＩ）の反応性誘導体としては、たとえば酸ハ
ロゲン化物が挙げられる。該酸ハロゲン化物におけるハ
ロゲンとしては、たとえば塩素、臭素１ヨウ素等が挙げ
られる。Examples of reactive derivatives of compound (II) include acid halides. Examples of the halogen in the acid halide include chlorine, bromine-1-iodine, and the like.

化合物（Ｖ）におけるＺで表わされるエステル化反応の
際に脱離する基としては、たとえばハロゲン（例、塩素
、臭素、ヨウ素など）、ｐ−ｔ−ルエノスルホニルオキ
シ、メタンスルホニルオキン、水酸基などが挙げられる
。Examples of the group that is eliminated during the esterification reaction represented by Z in compound (V) include halogen (e.g., chlorine, bromine, iodine, etc.), pt-luenosulfonyloxy, methanesulfonyluoquine, and hydroxyl group. Examples include.

化合物（ｎ）の反応性誘導体か酸ハロゲン化物である場
合の該酸ハロゲン化物は、化合物（ｎ）またはその塩に
ハロゲン化剤を作用させることにより得られる。When the reactive derivative of compound (n) is an acid halide, the acid halide can be obtained by reacting compound (n) or a salt thereof with a halogenating agent.

化合物（ｎ）またはその塩にハロゲン化剤を作用　　　
　−させる反応におけるハロゲン化剤としては、たとえ
ば塩化チオニル、塩化ホスホリル、臭化チオニル。Action of a halogenating agent on compound (n) or its salt
Examples of the halogenating agent in the reaction include thionyl chloride, phosphoryl chloride, and thionyl bromide.

五塩化リン、三塩化リン、オキシ塩化リン、三臭化リン
などが挙げられる。化合物（ＩＩ）と該ハロゲン化剤と
を、たとえばクロロホルム、ジクロルメタン。テトラク
ロロエタン、テトラヒドロフラン、ジオキサンなどの溶
媒中で、反応温度約８０−１２０℃で、約０．５〜１２
時間程時間芯させる。Examples include phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, and phosphorus tribromide. Compound (II) and the halogenating agent, for example, chloroform or dichloromethane. In a solvent such as tetrachloroethane, tetrahydrofuran, dioxane, etc., at a reaction temperature of about 80-120°C, about 0.5-12
Let it stand for about an hour.

上記酸ハロゲン化物（ＩＩ［）と反応性誘導体（Ｉｔ／
）とを反応させるには、酸ハロゲン化物（［Ｎ当量に対
し、化合物（ＩＶ）約ｌ〜３当量を作用させる。使用さ
れる溶媒としては、たとえばアセトン１クロロホルム、
ジクロルメタン。ジメチルホルムアミド。The above acid halide (II[) and the reactive derivative (It/
), about 1 to 3 equivalents of compound (IV) is reacted with the acid halide (N equivalent. Examples of the solvent used include acetone, 1 chloroform,
Dichloromethane. Dimethylformamide.

テトラヒドロフラン、ジオキサンなどが挙げられる。反
応は塩基の存在下に行なうのが好ましく、該塩基として
はたとえばトリエチルアミン、ピリジン、４−ツメチル
アミノビ１ノノン、ジメチルアニリンなどが挙げられる
。反応温度は、約１５〜８０℃であり、反応時間は約１
−１０時間である。Examples include tetrahydrofuran and dioxane. The reaction is preferably carried out in the presence of a base, and examples of the base include triethylamine, pyridine, 4-methylaminobi-1-nonone, and dimethylaniline. The reaction temperature is about 15-80°C, and the reaction time is about 1
-10 hours.

化合物（ＴＩ）またはその塩と化合物（Ｖ）とを反応さ
せる工程において、化合物（Ｖ）のＺかハロゲンあるい
はｐ−）ルエンスルホニルオキノやメタンスルホニルオ
キン基である化合物を用いるエステル化反応においては
、化合物（ｎ）の塩として、ナトリウム、カリウム、銀
、トリブチルアンモニウム塩等が用いられ、化合物（ｎ
）１当量に対し、化合物（Ｖ）は約１−１０当量が使用
される。該反応においては、塩基の存在下に行なうのが
好ましい。In the step of reacting compound (TI) or a salt thereof with compound (V), in an esterification reaction using a compound that is Z or halogen or p-) luenesulfonyloquino or methanesulfonyloquine group of compound (V), , sodium, potassium, silver, tributylammonium salts, etc. are used as the salt of the compound (n).
) Compound (V) is used in an amount of about 1-10 equivalents. The reaction is preferably carried out in the presence of a base.

該塩基としては、たとえばトリエチルアミン。ピリノン
、ジメチルアニリン、４−ジメチルアミノピリジンなど
が挙げられる。該反応は、たとえばジメチルホルムアミ
ド、ヘキサメチルリン酸トリアミド、アセトン、メチル
エチルケトン、テトラヒドロフラン、ジオキサンなどの
溶媒が用いられる。As the base, for example, triethylamine. Examples include pyrinone, dimethylaniline, 4-dimethylaminopyridine, and the like. In this reaction, a solvent such as dimethylformamide, hexamethylphosphoric triamide, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, etc. is used.

反応温度は約ｔｏｏ−１５０℃であり、反応時間は約１
〜６時間である。The reaction temperature is about too-150°C, and the reaction time is about 1
~6 hours.

化合物（ｎ）と化合物（■）とのエステル化反応は、常
法に従って行なイっれる。たとえば、化合物（ｎ）１当
量に対し、化合物（ＩＶ）を約１〜３当量用い、これに
対し触媒として硫酸、ｐ−トルエンスルホン酸、塩酸、
三フッ化ホウ素エーテラート、トリエチルオキソニウム
フロロホウ酸塩−ノイソプロピルエチルアミン等の過剰
ｍが用いられる。反応温度は約５０〜１２０℃付近が一
般的である。反応は無溶媒のまま、もしくは、溶媒とし
てトルエン。The esterification reaction between compound (n) and compound (■) is carried out according to a conventional method. For example, about 1 to 3 equivalents of compound (IV) are used per 1 equivalent of compound (n), and sulfuric acid, p-toluenesulfonic acid, hydrochloric acid,
An excess of boron trifluoride etherate, triethyloxonium fluoroborate-noisopropylethylamine, etc. is used. The reaction temperature is generally around 50 to 120°C. The reaction was carried out without solvent or with toluene as a solvent.

ジクロルエタン、テトラヒドロフラン等が用いられる 上記方法で得られた目的化合物は、自体公知の手段たと
えば、クロマトグラフィーや再結晶などにより、反応混
合物から分離、精製することができる。The target compound obtained by the above method using dichloroethane, tetrahydrofuran, etc. can be separated and purified from the reaction mixture by means known per se, such as chromatography or recrystallization.

本発明の原料化合物および目的物における塩としては、
薬理的に許容され得る塩が好ましく、その例としては、
たとえばナトリウム塩、カリウム塩のようなアルカリ金
属塩、塩酸塩、硫酸塩、リン酸塩、フマール酸塩、マレ
イン酸塩、シュウ酸塩のような無機酸塩および有機酸塩
が挙げられる。Salts in the raw material compound and target product of the present invention include:
Pharmaceutically acceptable salts are preferred, examples of which include:
Examples include alkali metal salts such as sodium salts and potassium salts, inorganic and organic acid salts such as hydrochlorides, sulfates, phosphates, fumarates, maleates, oxalates.

本発明方法の原料化合物（ｎ）は、たとえばヨーロッパ
特許出願公開第８０，３７１号公報に記載の方法あるい
はこれと同様の方法で製造することができる。The starting compound (n) for the method of the present invention can be produced, for example, by the method described in European Patent Application Publication No. 80,371 or a method similar thereto.

本発明の化合物（１）は、気管支平滑筋等の収縮をひき
起こす化学伝達物質（ｃｈｅｍｉｃａｌ　　ｍｅｄｉａ
ｔｏｒ）である５Ｒ８−Ａに対し顕著な拮抗作用を有す
る。Compound (1) of the present invention is a chemical mediator that causes contraction of bronchial smooth muscle, etc.
tor) has a significant antagonistic effect on 5R8-A.

５Ｒ９−Ａは免疫反応等の種々の刺激により生成し、即
時型アレルギー例えばアレルギー性喘息における気管支
重縮の重要なメディエータ−と考えられる。５ＲＳ−Ａ
にはロイコトリエンＣ（ｌｅｕ。5R9-A is produced by various stimuli such as immune reactions, and is considered to be an important mediator of bronchial condensation in immediate-type allergies, such as allergic asthma. 5RS-A
contains leukotriene C (leu).

ｋｏｔｒｉｅｎｅ　　Ｃ）（Ｌ　Ｔ　Ｃ）、ロイコトリ
エンＤ　（ｌｅｕｋｏ−ｔｒｉｅｎｅ　　Ｄ　ＸＬ　Ｔ
　Ｄ　）等があり、ヒトの気管筋に対する作用は、ＬＴ
ＤとＬＴＣではほぼ等しく、モルモットの回腸に対する
収縮作用は、ＬＴＤの方がＬＴＣよりも強い［Ｓ　、　
Ｅ、　Ｄａｈｌｅｎ　ｅｔ　ａｌ、ネイチ＋−（Ｎａｔ
ｕｒｅ）、　　２８８４８４（１９８０）；Ｒ，Ａ、　
Ｌｅｗｉｓ　　ｅｔ　　ａＬ、バイオケミカル・アンド
・バイオフィジカル・リサーチ・コミュニケーソヨンズ
（Ｂｉｏｃｈｅｍｉｃａｌ　ａｎｄ　Ｂｉｏｐｈｙｓｉ
ｃａｌ　Ｒｅ５ｅａｒｃｈＣｏｎ＋ｍｕｎｉｃａｔｉｏ
ｎｓ）、９６．２７１　（１９８０）］。kotriene C) (LTC), leukotriene D (leuko-triene DXL T
D), etc., and the effect on human tracheal muscles is LT.
D and LTC are almost equal, and LTD has a stronger contractile effect on the guinea pig ileum than LTC [S,
E, Dahlen et al.
ure), 288484 (1980); R,A,
Lewis et aL, Biochemical and Biophysical Research Communications.
cal Re5earchCon+munication
ns), 96.271 (1980)].

５Ｒ３−Ａに対する薬物の拮抗作用はモルモットの回腸
を用いて調べることが出来る［　Ｒ，Ａ、Ａｐｐ−１ｅ
ｔｏｎ　　ｅｔ　　ａｌ、ツヤ−ナル・オブ・メゾイノ
ナル・ケミストリー（Ｊｏｕｒｎａｌ　ｏｒ　Ｍｅｄｉ
ｃｉｎａｌ　Ｃｈｅｍｉ−ｓｔｒｙ）、　２０，３７１
（１９７７）］が、５ＲＳ−ＡはＬＴＣ，ＬＴＤ等の混
合物であり、その生成比も一定していないので、合成品
を用いて拮抗作用を調べることが望ましい。そこで、本
発明音らは合成したＬＴＤ、を用いて化合物（１）の抗
５Ｒ８−Ａ作用を、以下に述べる方法で調べたところ、
合成ロイコトリエンＤ、（ＬＴＤ、）の静脈内投与に基
づくモルモットの気道狭窄反応に対し、化合物（Ｄ−１
〜（１）−４はともにＬＴＤ４投与１時間前の経口投与
により対照化合物（Ａ）に勝る著明な抑制効果を示した
。The antagonistic effect of drugs on 5R3-A can be investigated using guinea pig ileum [R, A, App-1e
ton et al., Journal or Medi.
cinal Chemi-stry), 20,371
(1977)], but since 5RS-A is a mixture of LTC, LTD, etc., and the production ratio thereof is not constant, it is desirable to investigate the antagonistic effects using a synthetic product. Therefore, the anti-5R8-A effect of compound (1) was investigated using the synthesized LTD by the method described below.
Compound (D-1
-(1)-4 both showed remarkable suppressive effects superior to control compound (A) when administered orally 1 hour before administration of LTD4.

（１）実験方法 体重約４００ｇ前後の雌雄のＨａｒｔｌｅｙ系モルモッ
トを１群６〜１０匹として用い、ＬＴＤ、に基づく気道
狭窄反応をＫ　ｏｎｚｅｔ　ｔ　−ＲＯｓｓ　ｌｅｒ法
［Ｋｏ　ｎｚｅｔｔ。(1) Experimental method Using 6 to 10 male and female Hartley guinea pigs weighing approximately 400 g per group, the airway constriction response based on LTD was measured using the Konzert-Rossler method [Konzett.

Ｈ，ａｎｄ　Ｒｏｓｓｌｅｒ、　Ｒ，：ナウニンーノユ
ミーダーヘルグス・アルヒーフ・フユア・エクスペリメ
ンテレ・パトロキー・ラント・ファーマコロノー（Ｎａ
ｕｎｙｎ−Ｓ　ｃｈｍｉｅｄｅｒｂｅｒｇｓ　　　Ａ　
ｒｃｈｉｖ　　　ｆｕｒ　　　Ｅ　ｘｐｅｒｉｍｅ−ｎ
ｔｅｌｌｅ　　　Ｐａｔｈｏｌｏｇｉｅ　　　ｕｎｄ　
　Ｐｈａｒｍａｋｏｌｏｇｉｅ）　　　　ｌ　　９−５
．７１−４１１（１９４０）］に従って測定した。モル
モットをウレタン（ｕｒｅｔｈａｎｅ）　　（１，５８
／Ｋｇ、　　ｉ。H, and Rossler, R.
unyn-S chmiederbergs A
rchiv fur Experime-n
Telle Pathology and
Pharmacology) l 9-5
．． 71-411 (1940)]. Guinea pig with urethane (1,58
/Kg, i.

ｐ　（腹腔内投与））麻酔下で背位固定し、切開した気
管をカニユーレを介して人工呼吸器ロープント・レスビ
レ−ター・モデル　６８０［バーバード・アパラータス
・カンパニー（米国）］に連結した。p (Intraperitoneal administration)) The patient was fixed in the dorsal position under anesthesia, and the incised trachea was connected to a mechanical ventilator Ropent Resurrector Model 680 [Barbard Apparatus Company (USA)] via a cannula.

また、気管カニユーレの側枝をｂｒａｎｃｈｏｓｐａｓ
ｍ　ｔｒａ−ｎｓｄｕｃｅｒ　７０２０型［ウゴバシル
・バイオロジカル・リサーチ・アパラータス社（イタリ
ー）］に連結しに一１ｒ；：１１．’Ｗ、’＝Ｉ！コ％
Ａ−７ｑｌ’、”ｈ’Ｍ１層’；１１閂−乙Ｔ７０１Ｔ
ＦＩ／’５１Ｌｌｉへの負荷圧１０ｃｍＨｚｏとし、オ
ーバーフロー　（ｏｖｅｒＮｏｗ）する空気量を　ｔ　
ｒａｎｓｄｕｃｅｒを介してＲｅｃｔｉ−ｇｒａｐｈ　
−８９（三栄測器）上に記録した。ガラメン・トリエチ
オダイト（１ｍｇ／Ｋｇ、ｉ、　ｖ、　（静脈投与））
処置後、生理食塩水に溶解したＬＴＤ、（ｔｏμｇ／Ｋ
ｇ）を静脈内投与して惹起する気道狭窄反応を１５分間
記録した。被検薬物は、５％アラビアゴム溶液に懸濁す
るか、または水に溶解し、ＬＴＤ、投与１時間面に、モ
ルモットの体重１００ｇ当たり０．２ｍｌの容量で経口
投与した。ＬＴＤ、は、あらかじめ頚静脈内に装着した
カニユーレを介して投与しｌ゛二。またＬＴＤ、は、１
ｍｇ／メタノール（１ｍｌ）を−７０℃に保存したもの
を生理食塩水で希釈して使用した。Also branchospas the side branches of the tracheal cannula.
m tra-nsducer type 7020 [Ugobasil Biological Research Apparatus S.A. (Italy)] 1r;:11. 'W,'=I! Ko%
A-7ql', "h'M1 layer"; 11 bar - Otsu T701T
The load pressure to FI/'51Lli is 10 cmHz, and the amount of air that overflows (overNow) is t.
Recti-graph via transducer
-89 (Sanei Sokki). Garamen triethiodite (1mg/Kg, i, v, (intravenous administration))
After treatment, LTD dissolved in saline, (to μg/K
g) was administered intravenously and the airway constriction reaction induced was recorded for 15 minutes. The test drug was suspended in a 5% gum arabic solution or dissolved in water, and orally administered in a volume of 0.2 ml per 100 g of body weight of the guinea pig at 1 hour after administration. LTD was administered via a cannula previously placed in the jugular vein. Also, LTD is 1
mg/methanol (1 ml) stored at -70°C was diluted with physiological saline and used.

（２）実験成績 （以下余白少 組　ＩＤ、。（５０％抑制用ｆｆ１）：Ｌ、ＴＤ、投与
３０秒後の最大反応における気道からオーバーフローす
る空気量（百分率）に対する抑制率と投与ｍｍとの関係
から算出した。(2) Experimental results (small margin ID, below. (50% suppression ff1): L, TD, suppression rate against the amount of air overflowing from the airway (percentage) at the maximum response 30 seconds after administration and administration mm Calculated from the relationship.

″　塩酸塩・１水和物 ３２塩酸塩・ｌ水和物 ハ　対照化合物（Ａ）、ヨーロッパ特許出願公開第８０
．３７１号公報に、ｉｃ、載の下式で示される化合物化
合物（１）−２および（＋）７４のマウスにおける急性
毒性試験の成績は以下の通りであった。″ Hydrochloride monohydrate 32 Hydrochloride monohydrate C Control compound (A), European Patent Application Publication No. 80
．． The results of an acute toxicity test in mice of compounds (1)-2 and (+)74, which are listed in Publication No. 371 as ic, are as follows.

（１）　　実験方法 体重約３０８の１群５匹の雄性Ｊｃｌ：ＩＣＲ系マウス
（５週令）を使用した。化合物（Ｉ）−２または（Ｉ　
）−４を５％アラビアゴム溶液に懸濁し、体重１０ｇ当
たり０．２酎を経口投与した。(1) Experimental Method Male Jcl:ICR mice (5 weeks old) with a body weight of approximately 308 yen and 5 mice per group were used. Compound (I)-2 or (I
)-4 was suspended in a 5% gum arabic solution and administered orally at 0.2 doses per 10 g of body weight.

（２）実験成績 化合物（［）−２または（［）−４を各々２０００ｍｇ
／Ｋｇをマウスに経口投与して、その毒性を検討した。(2) Experimental results 2000 mg each of compound ([)-2 or ([)-4]
/Kg was orally administered to mice to examine its toxicity.

本用量においては薬物に起因する顕著な症状は観察され
なかった。また投与７日後の剖検においてら何ら異常所
見はなかった。No significant drug-induced symptoms were observed at this dose. Further, there were no abnormal findings at autopsy 7 days after administration.

以上のことから、化合物（Ｉ）の毒性はきわめて低いと
考えられる。From the above, it is considered that the toxicity of compound (I) is extremely low.

したがって化合物（１）は、５Ｒ９−Ａが原因である疾
病、例えば、喘息、枯草熱、慢性気管支炎。Therefore, compound (1) is useful for diseases caused by 5R9-A, such as asthma, hay fever, and chronic bronchitis.

眼のアレルギー性疾咀、胃腸のアレルギー性疾患。Eye allergic diseases, gastrointestinal allergic diseases.

循環器系障害、アレルギー性皮膚炎、その他の炎症の治
療剤として用いることができる。たとえば、化合物（［
）またはその塩は喘息治療剤または抗炎症剤として１日
投与量約１〜２０ｍｇ／Ｋｇを哺乳動物（例、マウス、
ラット、モルモット、人など）に経口的にまたは非経口
的に投与される。　経口的に投与するには、化合物（＋
）またはその塩を薬理学上許容され得る担体、賦形剤、
稀釈剤（これらの例、乳糖、てんぶん、セルロース誘導
体、ステアリノ酸、ステアリン酸マグネンウム、し上糖
、ゼラチン、アラビアゴムなど）と共にたとえば錠剤、
カプセル剤、Ｗｔ粒剤、トローチ剤、液剤、シロップ剤
などとして、非経口的に投与するには、化合物（［）ま
たはその塩を薬理学上許容され得る担体、賦形剤。It can be used as a therapeutic agent for circulatory system disorders, allergic dermatitis, and other inflammations. For example, the compound ([
) or a salt thereof is administered to mammals (e.g., mice,
It is administered orally or parenterally to rats, guinea pigs, humans, etc. To be administered orally, the compound (+
) or a salt thereof in a pharmacologically acceptable carrier, excipient,
Tablets, for example, along with diluents (such as lactose, protein, cellulose derivatives, stearinoic acid, magnesium stearate, sucrose, gelatin, gum arabic, etc.)
For parenteral administration in the form of capsules, Wt granules, troches, liquids, syrups, etc., the compound ([) or a salt thereof may be administered as a pharmacologically acceptable carrier or excipient.

稀釈剤（これらの例、白色ワセリン、親水軟膏、油性軟
膏、グリセライド、ポリエチレングリコールなと）と共
に軟膏剤、坐剤、エーロゾル剤、吸入剤、注ｑ、１剤な
どとしてそれぞれ通兇用いられる方法で製剤化して投与
することがてきろ。Commonly used with diluents (such as white petrolatum, hydrophilic ointment, oily ointment, glyceride, and polyethylene glycol) as ointments, suppositories, aerosols, inhalers, injections, single preparations, etc. It should be possible to formulate and administer it.

実施例 以下に参考例および実施例を挙げて、本発明をさらに具
体的に説明する。EXAMPLES The present invention will be explained in more detail by referring to Reference Examples and Examples below.

参考例１ ヨーロッパ特許出願公開第８０．３７１号公報に記載の
方法と同様の方法により、下記の化合物を製造した。Reference Example 1 The following compound was produced by a method similar to that described in European Patent Application Publication No. 80.371.

（１）　　３−［３−（４−アセチル−３−ヒドロキシ
−２−プロピルフェノキノ）プロポキシ］−４−ブロモ
安息香酸メヂルエステル　融点　１０８〜１１０℃（再
結晶溶媒：アセトン−エーテル）（２）　　３−［３−
（４−アセチル−３−ヒドロキシ−２−プロピルフェノ
キノ）プロポキシ］−４−ブロモ安息香酸　融点　１４
６〜１４９°Ｃ（再結晶溶媒・含水アルコール） 参考例２ （１）３−フルオロ−４−ヒドロキシ安息香酸（１゜２
ｇ）、エタノール（２０ｍ１２）および濃硫酸＜　ｌ　
ＩＱ）の混合物を１３時間加熱還流した後、ａ縮し、残
留物をクロロホルムて抽出し、炭酸水素ナトリウム水で
洗浄した。乾燥後、クロロホルムを留去し、エチル　３
−フルオロ−４−ヒドロキシヘンシアート（１，３ｇ）
を得た。融点７９〜８０°Ｃ（２）　　エチル　３−フ
ルオロ−４−ヒドロキノヘンシアート（（ｉ　００　ｍ
ｇ）、　４〜（３−クロロプロポキノ）−２−ヒドロキ
シ−３−プロピルアセトフェノン（１，１５ｇ）、　　
炭酸カリウム（４５０ｍｇ）、　　ヨウ化カリウム（５
５０ｍｇ）、　　ジメチルホルムアミド（２ｍＱ、）の
混合物を８０〜９０℃で４５時間かきまぜたのち、酢酸
エチルを加えて不溶物をろ去した。(1) 3-[3-(4-acetyl-3-hydroxy-2-propylphenoquino)propoxy]-4-bromobenzoic acid methyl ester Melting point 108-110°C (recrystallization solvent: acetone-ether) (2) 3 -[3-
(4-acetyl-3-hydroxy-2-propylphenoquino)propoxy]-4-bromobenzoic acid Melting point 14
6 to 149°C (recrystallization solvent/hydrous alcohol) Reference example 2 (1) 3-fluoro-4-hydroxybenzoic acid (1°2
g), ethanol (20 m12) and concentrated sulfuric acid < l
The mixture of IQ) was heated under reflux for 13 hours, then condensed, and the residue was extracted with chloroform and washed with aqueous sodium bicarbonate. After drying, chloroform was distilled off and ethyl 3
-Fluoro-4-hydroxyhenthiate (1,3g)
I got it. Melting point 79-80°C (2) Ethyl 3-fluoro-4-hydroquinohensiate ((i 00 m
g), 4-(3-chloropropoquino)-2-hydroxy-3-propylacetophenone (1,15 g),
Potassium carbonate (450 mg), potassium iodide (5
After stirring a mixture of 50 mg) and dimethylformamide (2 mQ) at 80 to 90°C for 45 hours, ethyl acetate was added and insoluble materials were filtered off.

ろ夜を濃縮し、メタノールから再結晶し、エチル４−［
３−（４−アセチル−３−ヒドロキノ−２−プロピルフ
ェノキシ）プロポキシ］−３−フルオロベンゾアートの
結晶（１，３ｇ）を得た。　融点８７〜８８℃ （３）エチル４−［３−（４−アセチル−３−ヒドロキ
シ−２−プロピルフェノキノ）プロボキシコ＝３−フル
オロベンゾアート（１、３ｇ）、エタノール（８ｍσ）
、水酸化ナトリウム（Ｉｇ）、水（５＋＋＋Ｑ）の混合
物を４０分加熱還流したのち、エタノールを留去した。The filter residue was concentrated, recrystallized from methanol, and ethyl 4-[
Crystals (1.3 g) of 3-(4-acetyl-3-hydroquino-2-propylphenoxy)propoxy]-3-fluorobenzoate were obtained. Melting point 87-88°C (3) Ethyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoquino)proboxyco=3-fluorobenzoate (1,3 g), ethanol (8 mσ)
, sodium hydroxide (Ig), and water (5+++Q) was heated under reflux for 40 minutes, and then ethanol was distilled off.

残留物を水に溶かし、希塩酸で酸性にし、析出する結晶
をろ取し、エタノールから再結晶し、４−［３−（４−
アセチル−３−ヒドロキン−２−プロピルフェノキノ）
プロポキノ１−３−フルオロ安息香酸（１，０６ｇ）を
得た。The residue was dissolved in water, acidified with dilute hydrochloric acid, the precipitated crystals were collected by filtration, and recrystallized from ethanol to give 4-[3-(4-
acetyl-3-hydroquine-2-propylphenoquino)
Propoquino 1-3-fluorobenzoic acid (1,06 g) was obtained.

融点１６５〜１６６°Ｃ 実施例１ （１）　　４−［３−（４−アセチル−３−ヒドロキノ
−２−プロピルフェノキノ）プロポキノ１−３−ブロモ
安息香酸（２ｇ）、クロロホルム（２０ｍ１）、および
塩化チオニル（６ｍｌ）の混合物を３０分間加熱還流し
たのち濃縮した。残留物をアセトノ（４０ｍｌ）に溶か
し、Ｎ、Ｎ−ツメチルエタノールアミノ（・ｔｏｏｍｇ
）を加え、トリエチルアミン（２ｍｌ）を滴下したのち
室温でかきまぜた。２時間後、析出物をろ去し、ろ液を
濃縮後ノリカゲル力ラムにかけ、酢酸エチルで溶出した
。溶媒を留去後、残留する油状物をエーテルに溶かし、
エーテル性塩酸を加えたのち、エーテルを留去した。残
留物をイソプロパツールから結晶化させ、ろ取し、イソ
プロピルエーテルで洗浄後、乾燥し、２−（Ｎ、Ｎ−ジ
メチルアミノ）エチル　４−４３−（４−アセチル−３
−ヒドロキノ−２−プロピルフェノキノ）プロポキノコ
−３−ブロモベンゾアート・塩酸塩・ｌ水和物（２，１
ｇ）の結晶を得た。Melting point 165-166°C Example 1 (1) 4-[3-(4-acetyl-3-hydroquino-2-propylphenoquino)propoquino 1-3-bromobenzoic acid (2 g), chloroform (20 ml), and A mixture of thionyl chloride (6 ml) was heated under reflux for 30 minutes and then concentrated. The residue was dissolved in acetonate (40 ml) and diluted with N,N-methylethanolamino (.toomg
), triethylamine (2 ml) was added dropwise, and the mixture was stirred at room temperature. After 2 hours, the precipitate was filtered off, and the filtrate was concentrated, applied to a Norica gel ram, and eluted with ethyl acetate. After distilling off the solvent, the remaining oil was dissolved in ether,
After adding ethereal hydrochloric acid, the ether was distilled off. The residue was crystallized from isopropanol, filtered, washed with isopropyl ether and dried to give 2-(N,N-dimethylamino)ethyl 4-43-(4-acetyl-3
-Hydroquino-2-propylphenoquino)propo mushroom-3-bromobenzoate hydrochloride l-hydrate (2,1
Crystals of g) were obtained.

融点　３８〜４０℃（吸湿性） （２）上記と同様の方法で、２−（４−メチル−１−ピ
ペラジニル）エチル　４−［３−（４−アセチル−３−
ヒドロキノ−２−プロピルフェノキン）プロポキノコ−
３−ブロモベンゾアート・２塩酸塩・１永和物（イソプ
ロパツールより再結晶）を得た。融点　１４２〜【４４
°Ｃ （３）上記と同様の方法で、２−モルホリノエチル　３
−［３−（４−アセチル−３−ヒドロキノ−２−プロピ
ルフェノキシ）プロポキノコ−４−ブロモベンゾアート
・１修酸塩を得た。Melting point: 38-40°C (hygroscopic) (2) In the same manner as above, 2-(4-methyl-1-piperazinyl)ethyl 4-[3-(4-acetyl-3-
Hydroquino-2-propylphenoquine) propomushroom
3-Bromobenzoate dihydrochloride monoeternal hydrate (recrystallized from isopropanol) was obtained. Melting point 142~[44
°C (3) In the same manner as above, 2-morpholinoethyl 3
-[3-(4-acetyl-3-hydroquino-2-propylphenoxy)propo mushroom-4-bromobenzoate mono-oxalate was obtained.

融点　１４５〜１４８℃ 実施例２ （１）　　４−［３−（４−アセデル−３−ヒドロキノ
−２−プロピルフェノキノ）プロポキノコ−３−プロ七
安、ω、香酸（２ｇ）、クロロホルム（２０ｍｌ）、お
よび塩化チオニル（５ｍｌ）の混合物を３０分間加熱還
流したのち、クロロポルムを留去し、残留物をアセトン
（４０ｍｌ）に溶かし、３−（Ｎ、Ｎ−ツメチルアミノ
）−１−プロパツール（５００ｍｇ）１次いてトリエチ
ルアミン（４ｍｌ）を加え、室温で２時間かきまぜた。Melting point 145-148°C Example 2 (1) 4-[3-(4-acedel-3-hydroquino-2-propylphenoquino)propo mushroom-3-pro7iann, ω, folic acid (2 g), chloroform ( After heating and refluxing a mixture of 20 ml) and thionyl chloride (5 ml) for 30 minutes, chloroporm was distilled off, the residue was dissolved in acetone (40 ml), and 3-(N,N-tumethylamino)-1-propatol ( 500 mg), then triethylamine (4 ml) was added and stirred at room temperature for 2 hours.

析出物をろ去し、ろ液を濃縮後ンリカゲルのカラムにか
け、酢酸エチル１次いで酢酸エチル−トリエチルアミン
（ｉｏｆｌ）で溶出し、溶媒を留去後残留物をヘキサン
から再結晶し、３−（Ｎ、Ｎ−ジメチルアミノ）プロピ
ル　４−［３−（ｌｌ−アセチル−３−ヒドロキン−２
−プロピルフェノキン）プロポキノコ−３−ブロモヘン
シアートの結晶（１，８ｇ）を得た。　融点　７１〜７
２°Ｃ（２）　と記と同様の方法て、２−モルホリノエ
チル　４−［３−（４−アセチ−ルー３−ヒドロキノ−
２−プロピルフェノキノ）プロボギノ］−３−ブロモベ
ンゾアートの結晶（ヘキサノ−クロロホルムより再結晶
）か得られた。融点　９８〜９９℃（３）上記（１）と
同様の方法て、２−（ピロリノン−１−イル）エチル　
４−［３−（４−アセチル−３−ヒドロキノ−２−プロ
ピルフェノキノ）プロポキノコ−３−ブロモヘノシアー
トか得られた。The precipitate was filtered off, the filtrate was concentrated, applied to a column of 3-(N , N-dimethylamino)propyl 4-[3-(ll-acetyl-3-hydroquine-2
Crystals (1.8 g) of propomushroom-3-bromohenthiate (propylphenoquine) were obtained. Melting point 71~7
2°C (2) 2-morpholinoethyl 4-[3-(4-acetyl-3-hydroquino-
Crystals of 2-propylphenoquino)probogino]-3-bromobenzoate (recrystallized from hexano-chloroform) were obtained. Melting point: 98-99°C (3) In the same manner as in (1) above, 2-(pyrrolinon-1-yl)ethyl
4-[3-(4-acetyl-3-hydroquino-2-propylphenoquino)propo mushroom-3-bromohenocyate was obtained.

融点７９〜８０℃ （４）上記（１）と同様の方法で４−ジメチルアミノブ
チル　４−［３−（４−アセチル−３−ヒドロキノ−２
−プロピルフェノキン）プロボキソ］−３−ブロモベン
ゾアートが得られた。Melting point: 79-80°C (4) 4-dimethylaminobutyl 4-[3-(4-acetyl-3-hydroquino-2) was prepared in the same manner as in (1) above.
-propylphenoquine)proboxo]-3-bromobenzoate was obtained.

融点　６９〜７０°Ｃ 実施例３ ４−［３−（４−アセチル−３−ヒドロキシ−２−プロ
ビルフェノキノ）プロポキノコ−３−ブロモ安息香酸（
Ｉｇ）、ジメチルホルムアミド（２０ｍｌ）。Melting point 69-70°C Example 3 4-[3-(4-acetyl-3-hydroxy-2-propylphenoquino)propo mushroom-3-bromobenzoic acid (
Ig), dimethylformamide (20ml).

トリエチルアミン（５ｍｌ）、ツメチルアミノエチルク
ロリドの塩酸塩（１ｇ）の混合物を１５０℃で１時間加
熱後、溶媒を留去し、残留物を酢酸エチルに溶かし、炭
酸ナトリウム水溶液で洗浄した。硫酸ナトリウムで乾燥
後、シリカゲルのカラムにかけ、酢酸エチルで溶出後、
実施例２と同様にして塩酸塩に変え、２−ツメチルアミ
ノエチル　４−［３−（４−アセチル−３−ヒドロキン
−２−プロピルフェノキノ）プロポキン］−３−ブロモ
ヘンシアート・塩酸塩・１水和物の結晶を得た。融点　
３８〜４０°Ｃ（吸湿性） 実施例４ ４、−［３−（４−アセチル−３−ヒドロキシ−２−プ
ロピルフェノキシ）プロポキシコー３−クロロ安息香酸
（Ｉｇ）、クロロホルム（１０ｍｌ）、塩化チオニル（
３ｍｌ）の混合物を１時間加熱還流したのち、溶媒を留
去し、さらに減圧下、水酸化ナトリウムを用い揮発性の
酸を除去した。得られた酸クロリドをアセトン（２０ｍ
ｌ）に溶解し、３−ジメチルアミツブロバノール（３０
０ｍｇ）、　トリエチルアミン（２ｍｌ）を加え、室温
で１時間かきまぜたのち、析出物をろ去し、ろ液を濃縮
した。残留物をシリカゲルのカラムクロマトグラフィー
（酢酸エチルエステル）により精製し、得た油状物をヘ
キサンより結晶化させることにより、３−（ジメチルア
ミノ）−１−プロピル　４−［３−（４−アセチル−３
−ヒドロキン−２−プロピルフェノキン）プロポキノコ
−３−クロロベンゾアートの結晶１．０３ｇを得た。After heating a mixture of triethylamine (5 ml) and trimethylaminoethyl chloride hydrochloride (1 g) at 150°C for 1 hour, the solvent was distilled off, the residue was dissolved in ethyl acetate, and washed with an aqueous sodium carbonate solution. After drying with sodium sulfate, it was applied to a silica gel column and eluted with ethyl acetate.
In the same manner as in Example 2, the hydrochloride was changed to 2-trimethylaminoethyl 4-[3-(4-acetyl-3-hydroquine-2-propylphenoquino)propoquine]-3-bromohensiate hydrochloride. Crystals of monohydrate were obtained. melting point
38-40°C (hygroscopic) Example 4 4,-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy-3-chlorobenzoic acid (Ig), chloroform (10 ml), thionyl chloride (
After heating the mixture (3 ml) under reflux for 1 hour, the solvent was distilled off, and the volatile acid was further removed under reduced pressure using sodium hydroxide. The obtained acid chloride was mixed with acetone (20 m
l) and 3-dimethylamitubrobanol (30
After adding triethylamine (2 ml) and stirring at room temperature for 1 hour, the precipitate was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate), and the resulting oil was crystallized from hexane to give 3-(dimethylamino)-1-propyl 4-[3-(4-acetyl- 3
-Hydroquine-2-propylphenoquine) 1.03 g of crystals of propomushroom-3-chlorobenzoate were obtained.

融点　７２〜７３℃ 実施例５ ４４３−（４−アセチル−３−ヒドロキノ−２−プロ、
ピルフェノキノ）プロポキノコ−３−フルオロ安息香酸
（２２０ｍｇ）、クロロホルム（２ｍＱ）、塩化チオニ
ル（０４ｍσ）の溶液を２０分間加熱還流したのち減圧
下に留去し、残留物にトルエンを加えて再び留去した。Melting point 72-73°C Example 5 443-(4-acetyl-3-hydroquino-2-pro,
A solution of pyrufenoquino)propo mushroom-3-fluorobenzoic acid (220 mg), chloroform (2 mQ), and thionyl chloride (04 mσ) was heated under reflux for 20 minutes, then evaporated under reduced pressure, toluene was added to the residue, and evaporated again. did.

　残留物にアセトン（５ｍＱ）。Add acetone (5mQ) to the residue.

３−ツメチルアミツブロバノール（７０ｍｇ）、　トリ
エチルアミン（０，２５ｍσ）を加え、０５時間加熱還
流したのち、針山した無色結晶をろ去し、濃縮した。残
留物をクロロホルムに溶かし、飽和炭酸水素ナトリウム
水溶液で１回洗浄後乾燥（硫酸ナトリウム）し、クロロ
ホルムを留去し７こ。残留物を冷却し、ヘキサンを加え
結晶化させ、３−ジメチルアミノプロピル　４−［１（
４−アセチル−３−ヒドロキノ−２−プロピルフェノキ
ノ）プロポキンロー３−フルオロヘンシアートの無色結
晶（＋４０ｍｇ）を得た。After adding 3-trimethylamitubrobanol (70 mg) and triethylamine (0.25 mσ) and heating under reflux for 05 hours, colorless crystals with needles were filtered off and concentrated. The residue was dissolved in chloroform, washed once with a saturated aqueous sodium bicarbonate solution, dried (sodium sulfate), and the chloroform was distilled off. The residue was cooled and crystallized by adding hexane to give 3-dimethylaminopropyl 4-[1(
Colorless crystals (+40 mg) of 4-acetyl-3-hydroquino-2-propylphenoquino)propoquine 3-fluorohensiate were obtained.

融点　５５〜５６°Ｃ 発明の効果 本発明の化合物（１）またはその塩は、優れた抗喘息作
用および抗炎症作用を有するので、哺乳動物の喘息治療
剤あるいは抗炎症剤として利用し得る。Melting point: 55-56°C Effects of the Invention The compound (1) of the present invention or a salt thereof has excellent anti-asthmatic and anti-inflammatory effects, and therefore can be used as a therapeutic agent for asthma or an anti-inflammatory agent for mammals.

Claims (3)

【特許請求の範囲】[Claims] （１）一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＾１およびＲ＾２は、同一または異なって、
水素、低級アルキルまたは隣接する窒素原子と共に５も
しくは６員異項環基を形成している場合を、ｎは２ない
し４の整数を、Ｘはハロゲンをそれぞれ示す。］で表わ
される安息香酸誘導体またはその塩。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different,
When a 5- or 6-membered heterocyclic group is formed together with hydrogen, lower alkyl, or an adjacent nitrogen atom, n represents an integer of 2 to 4, and X represents a halogen. ] A benzoic acid derivative or a salt thereof. （２）一般式 ▲数式、化学式、表等があります▼ ［式中、Ｘはハロゲンを示す。］で表わされる化合物の
反応性誘導体と一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＾１およびＲ＾２は、同一または異なって、
水素、低級アルキルまたは隣接する窒素原子とともに５
もしくは６員異項環基を形成している場合を、ｎは２な
いし４の整数をそれぞれ示す。］で表わされる反応性誘
導体とを反応させることを特徴とする一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＾１、Ｒ＾２およびＸは前記と同意義を有す
る。 ］で表わされる安息香酸誘導体またはその塩の製造法。(2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X represents halogen. ] Reactive derivatives of compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different,
5 with hydrogen, lower alkyl or adjacent nitrogen atom
Alternatively, when a 6-membered heterocyclic group is formed, n represents an integer of 2 to 4, respectively. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ where R^1, R^2 and X have the same meanings as above. ] A method for producing a benzoic acid derivative or a salt thereof. （３）一般式 ▲数式、化学式、表等があります▼ ［式中、Ｘはハロゲンを示す。］で表わされる化合物ま
たはその塩と一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＾１およびＲ＾２は、同一または異なって、
水素、低級アルキルまたは隣接する窒素原子と共に５も
しくは６員異項環基を形成している場合を、ｎは２ない
し４の整数をそれぞれ示す。］で表わされる基を、Ｚは
エステル化反応の際に脱離する基をそれぞれ示す。］で
表わされる反応性誘導体とを反応させることを特徴とす
る一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＾１、Ｒ＾２、ｎおよびＸは前記と同意義を
有する。］で表わされる安息香酸誘導体またはその塩の
製造法。(3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X represents halogen. ] Compounds or salts thereof and general formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different,
When a 5- or 6-membered heterocyclic group is formed together with hydrogen, lower alkyl, or an adjacent nitrogen atom, n represents an integer of 2 to 4, respectively. ], and Z represents a group that is eliminated during the esterification reaction. ] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, n and X have the same meanings as above. . ] A method for producing a benzoic acid derivative or a salt thereof.
JP60213579A 1984-10-30 1985-09-25 Benzoic acid derivative and preparation thereof Pending JPS61129153A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP85307685A EP0180416A3 (en) 1984-10-30 1985-10-24 Benzoic acid analogues and their production
KR1019850008051A KR870003060A (en) 1984-10-30 1985-10-30 Method for producing benzoic acid derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/JP1984/000521 WO1986002637A1 (en) 1984-10-30 1984-10-30 Benzoic acid derivatives and process for their preparation
WO84/00521 1984-10-30

Publications (1)

Publication Number Publication Date
JPS61129153A true JPS61129153A (en) 1986-06-17

Family

ID=13818455

Family Applications (1)

Application Number Title Priority Date Filing Date
JP60213579A Pending JPS61129153A (en) 1984-10-30 1985-09-25 Benzoic acid derivative and preparation thereof

Country Status (3)

Country Link
JP (1) JPS61129153A (en)
KR (1) KR870003060A (en)
WO (1) WO1986002637A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05154776A (en) * 1991-04-05 1993-06-22 Fukushima Seiko Kk Rotational inclination positioner

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05154776A (en) * 1991-04-05 1993-06-22 Fukushima Seiko Kk Rotational inclination positioner

Also Published As

Publication number Publication date
WO1986002637A1 (en) 1986-05-09
KR870003060A (en) 1987-04-14

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