JPH0551359A - Phenoxyalkylcarboxylic acid derivative and its production - Google Patents
Phenoxyalkylcarboxylic acid derivative and its productionInfo
- Publication number
- JPH0551359A JPH0551359A JP3359460A JP35946091A JPH0551359A JP H0551359 A JPH0551359 A JP H0551359A JP 3359460 A JP3359460 A JP 3359460A JP 35946091 A JP35946091 A JP 35946091A JP H0551359 A JPH0551359 A JP H0551359A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- general formula
- compound
- ethyl
- compound represented
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、強力な選択的ロイコト
リエン拮抗作用を有し、喘息のようなアレルギー疾患の
予防及び治療に有用である新規なフェノキシアルキルカ
ルボン酸誘導体及びそれらの製造法に関する。TECHNICAL FIELD The present invention relates to novel phenoxyalkylcarboxylic acid derivatives having a strong selective leukotriene antagonism and useful for the prevention and treatment of allergic diseases such as asthma, and a process for producing them.
【０００２】[0002]
【従来の技術】アラキドン酸の５−リポキシゲナーゼ系
の代謝物であるロイコトリエン類（ロイコトリエン
Ｃ4 、Ｄ4 、Ｅ4 ）は気管支喘息等の即時型アレルギー
疾患の主要な原因物質と考えられているＳＲＳ−Ａ（ s
low reacting substance of anaphylaxis ）の構成成分
である。したがって、ロイコトリエン類に拮抗する薬物
は、有用な抗アレルギー剤として期待される。2. Description of the Related Art Leukotrienes (leukotrienes C 4 , D 4 and E 4 ), which are metabolites of the 5-lipoxygenase system of arachidonic acid, are considered to be major causative agents of immediate allergic diseases such as bronchial asthma. -A (s
low reacting substance of anaphylaxis). Therefore, drugs that antagonize leukotrienes are expected as useful antiallergic agents.
【０００３】[0003]
【発明が解決しようとする課題】本発明者は、フェノキ
シアルキルカルボン酸誘導体の一部の化合部がロイコト
リエン類に拮抗する薬物であることを先に見出したが
（特開平２−１４５９号公報）、更に生体内で活性有る
化合物の創製が望まれていた。The present inventor has previously found that a part of the compound part of the phenoxyalkylcarboxylic acid derivative is a drug that antagonizes leukotrienes (Japanese Patent Laid-Open No. 2-1459). Furthermore, it has been desired to create compounds that are active in vivo.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、ロイコト
リエン類に拮抗する薬物に関して鋭意研究を重ねた結
果、下記一般式（１）で示されるフェノキシアルキルカ
ルボン酸誘導体が、強力で選択的なロイコトリエン拮抗
作用を有することを見出し、本発明を完成した。 （１）〔式中、Ｒ1 は水素原子、メチル基又はエチル基
を表す〕Means for Solving the Problems As a result of intensive studies on drugs that antagonize leukotrienes, the present inventors have found that a phenoxyalkylcarboxylic acid derivative represented by the following general formula (1) is potent and selective. The inventors have found that they have a leukotriene antagonism and completed the present invention. (1) [In the formula, R 1 represents a hydrogen atom, a methyl group or an ethyl group]
【０００５】本発明によれば、一般式（１）の化合物は
以下に述べる経路により製造することができる。According to the present invention, the compound of the general formula (1) can be produced by the route described below.
【０００６】（イ）下記の一般式（１ａ）である化合物
は下記の一般式（２）の化合物に一般式（３）の化合物
を作用させることにより製造することができる。 （１ａ）〔式中、Ｒ2 はメチル基又はエチル基を表す〕(A) The compound represented by the following general formula (1a) can be produced by reacting the compound represented by the following general formula (2) with the compound represented by the general formula (3). (1a) [in the formula, R 2 represents a methyl group or an ethyl group]
【０００７】反応は、有機溶媒、例えばアセトン、メチ
ルエチルケトン、ジエチルケトン又はジメチルホルムア
ミド等中で、反応温度としては室温〜溶媒還流温度で行
うことが好ましい。また無機塩基例えば炭酸カリウム又
は炭酸ナトリウム等の存在、更にヨウ化カリウムの添加
も好ましい。 （２）〔式中、Ｒ2 はメチル基又はエチル基を表す〕 （３）〔式中、Ｙはハロゲン原子を表す〕上記の一般式
（１ａ）の化合物は、常法により対応するカルボン酸体
に変換できる。The reaction is preferably carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide at a reaction temperature of room temperature to solvent reflux temperature. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide. (2) [In the formula, R 2 represents a methyl group or an ethyl group] (3) [wherein Y represents a halogen atom] The compound of the above general formula (1a) can be converted into the corresponding carboxylic acid compound by a conventional method.
【０００８】（ロ）一般式（１）で表される化合物は下
記の一般式（４）の化合物に式（５）の化合物を作用さ
せ、要すれば加水分解することにより製造することがで
きる。反応は、上記（イ）の方法に準じて行われ、有機
溶媒、例えばアセトン、メチルエチルケトン、ジエチル
ケトン又はジメチルホルムアミド等中で、反応温度とし
ては室温〜溶媒還流温度で行うことが好ましい。また無
機塩基例えば炭酸カリウム又は炭酸ナトリウム等の存
在、更にヨウ化カリウムの添加も好ましい。 （４）〔式中、Ｙはハロゲン原子を表し、Ｒ1 は水素原
子、メチル基又はエチル基を表す〕 （５）(B) The compound represented by the general formula (1) can be produced by reacting the compound of the following general formula (4) with the compound of the formula (5) and, if necessary, hydrolyzing the compound. .. The reaction is carried out according to the above method (a), and is preferably carried out in an organic solvent such as acetone, methyl ethyl ketone, diethyl ketone or dimethylformamide at a reaction temperature of room temperature to solvent reflux temperature. It is also preferable to add an inorganic base such as potassium carbonate or sodium carbonate, and to add potassium iodide. (4) [In the formula, Y represents a halogen atom and R 1 represents a hydrogen atom, a methyl group or an ethyl group] (5)
【０００９】（ハ）下記の一般式（７）で表される化合
物は一般式（６）の化合物を水素接触還元するか、また
は還元剤と反応させることにより製造することができ
る。水素接触還元反応は、常圧あるいは加圧下に、メタ
ノール、エタノール、テトラヒドロフラン、又はジメチ
ルホルムアミド等中で、反応温度としては０℃〜溶媒還
流温度で行うことが好ましい。触媒としては、不均一系
あるいは均一系のパラジウム、ニッケル、ロジウム、ル
テニウム等が好ましい。また、不斉触媒の使用も好まし
い。(C) The compound represented by the following general formula (7) can be produced by subjecting the compound of the general formula (6) to hydrogen-catalyzed reduction or by reacting with a reducing agent. The hydrogen catalytic reduction reaction is preferably carried out under normal pressure or under pressure in methanol, ethanol, tetrahydrofuran, dimethylformamide or the like at a reaction temperature of 0 ° C. to a solvent reflux temperature. The catalyst is preferably heterogeneous or homogeneous palladium, nickel, rhodium, ruthenium or the like. It is also preferable to use an asymmetric catalyst.
【００１０】還元剤と反応させる場合は、メタノール、
エタノール、テトラヒドロフラン、又はジメチルホルム
アミド等中で、反応温度としては氷冷下〜溶媒還流温度
に、還元剤、例えば水素化ホウ素ナトリウム、水素化リ
チウムアルミニウム等を作用させることが好ましい。 （６）〔式中、Ｒは水素原子又はハロゲノプロピル基を
表し、Ｒ1 は水素原子、メチル基又はエチルを表す〕 （７）〔式中、Ｒ及びＲ1 は前述の通り〕一般式（７）
においてＲ1 がメチル基又はエチル基を表す場合は、常
法により対応するカルボン酸体に変換できる。When reacting with a reducing agent, methanol,
In ethanol, tetrahydrofuran, dimethylformamide or the like, it is preferable that a reducing agent such as sodium borohydride or lithium aluminum hydride is allowed to act at a reaction temperature of ice cooling to solvent reflux temperature. (6) [In the formula, R represents a hydrogen atom or a halogenopropyl group, and R 1 represents a hydrogen atom, a methyl group or ethyl] (7) [wherein R and R 1 are as described above] General formula (7)
In the case where R 1 represents a methyl group or an ethyl group, it can be converted into the corresponding carboxylic acid by a conventional method.
【００１１】なお、一般式（１）で表される化合物は、
１−ヒドロキシエチル基の１位に不斉炭素を有し、その
不斉炭素に基づく２種の光学異性体が存在するが、その
各々、あるいはそれらの混合物のいずれも本発明に包含
される。The compound represented by the general formula (1) is
There is an asymmetric carbon atom at the 1-position of the 1-hydroxyethyl group, and there are two kinds of optical isomers based on the asymmetric carbon atom, and each of them or a mixture thereof is included in the present invention.
【００１２】２種の光学異性体は、例えば、（Ｓ）−
（−）−１−（１−ナフチル）エチルアミン等の塩基と
対応するカルボン酸体とのジアステレオマー塩を形成す
るか、光学活性カラムを用いた分取により光学分割でき
る。この光学分割は、一般式（１）の化合物において
も、一般式（７）の化合物においても可能である。The two kinds of optical isomers are, for example, (S)-
It can be optically resolved by forming a diastereomeric salt of a base such as (−)-1- (1-naphthyl) ethylamine and the corresponding carboxylic acid derivative or by preparative separation using an optically active column. This optical resolution is possible for both the compound of general formula (1) and the compound of general formula (7).
【００１３】さらに一般式（１）で表される化合物は所
望ならばその塩に常法に従って変換することができる。
塩としては、例えばナトリウム、カリウム、カルシウ
ム、アルミニウム等の塩が挙げられる。Further, if desired, the compound represented by the general formula (1) can be converted into its salt according to a conventional method.
Examples of the salt include salts of sodium, potassium, calcium, aluminum and the like.
【００１４】[0014]
【実施例】次に本発明を具体例によって説明するがこれ
らの例によって発明が限定されるものではない。EXAMPLES The present invention will now be described by way of specific examples, but the invention is not limited to these examples.
【００１５】（実施例１）4-[3-[3-(4- アセチル-3- ヒ
ドロキシ-2- プロピルフェニルチオ）プロポキシ]-6-(1
- ヒドロキシエチル)-2-プロピルフェノキシ] 酪酸Example 1 4- [3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -6- (1
-Hydroxyethyl) -2-propylphenoxy] butyric acid
【００１６】（ｉ）4-(3- ヒドロキシ-6-(1-ヒドロキシ
エチル)-2-プロピルフェノキシ）酪酸エチル 8.7ｇ、(4
-(3-ブロモプロピルチオ)-2-ヒドロキシ-3- プロピルフ
ェニル）エタノン10.21 ｇ、炭酸カリウム7.79ｇ及びア
セトン70mlの混合物を攪拌下に加熱還流した。(4-(3-ブ
ロモプロピルチオ)-2-ヒドロキシ-3- プロピルフェニ
ル）エタノン2.79ｇを９時間後に、炭酸カリウム3.87ｇ
を９時間後、11時間後及び16時間後にそれぞれ加え、合
計18時間攪拌下加熱還流した後、無機物を濾過し、溶媒
を減圧濃縮した。残渣を中圧シリカゲルカラムクロマト
グラフィー（ベンゼン：酢酸エチル＝９：１）で精製し
て、油伏物として粗製の4-[3-[3-(4- アセチル-3- ヒド
ロキシ-2- プロピルフェニルチオ）プロポキシ]-6-(1-
ヒドロキシエチル)-2-プロピルフェノキシ] 酪酸エチル
13.6ｇ（86.5％）を得た。(I) Ethyl 4- (3-hydroxy-6- (1-hydroxyethyl) -2-propylphenoxy) butyrate 8.7 g, (4
A mixture of 10.21 g of-(3-bromopropylthio) -2-hydroxy-3-propylphenyl) ethanone, 7.79 g of potassium carbonate and 70 ml of acetone was heated to reflux with stirring. 2.79 g of (4- (3-bromopropylthio) -2-hydroxy-3-propylphenyl) ethanone was added 9 hours later, and 3.87 g of potassium carbonate was added.
Was added after 9 hours, 11 hours, and 16 hours, and the mixture was heated under reflux for 18 hours with stirring, the inorganic matter was filtered, and the solvent was concentrated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (benzene: ethyl acetate = 9: 1) to give crude 4- [3- [3- (4-acetyl-3-hydroxy-2-propylphenyl) as an oily residue. Thio) propoxy] -6- (1-
(Hydroxyethyl) -2-propylphenoxy] ethyl butyrate
13.6 g (86.5%) was obtained.
【００１７】（ii）4-[3-[3-(4- アセチル-3- ヒドロキ
シ-2- プロピルフェニルチオ）プロポキシ]-6-(1- ヒド
ロキシエチル)-2-プロピルフェノキシ] 酪酸エチル6.60
ｇをエタノール10mlに溶解し水酸化ナトリウム1.41ｇを
水10mlに溶解した溶液を加えた。室温で５分間攪拌した
のち、氷水を加え冷却し、エーテル洗浄した。水層に塩
酸を加え酸性とし酢酸エチルで抽出した。有機層を水
洗、硫酸ナトリウムで乾燥し、濃縮した。残渣を中圧シ
リカゲルカラムクロマトグラフィー（順相塩化メチレ
ン：エタノール＝ 100：３、次いで逆相メタノール：水
＝19：１）で分離精製したのち、メタノール−水より再
結晶して無色結晶として目的物1.98ｇ（31.6％）を得
た。(Ii) 4- [3- [3- (4-acetyl-3-hydroxy-2-propylphenylthio) propoxy] -6- (1-hydroxyethyl) -2-propylphenoxy] ethyl butyrate 6.60
g was dissolved in 10 ml of ethanol and a solution of 1.41 g of sodium hydroxide in 10 ml of water was added. After stirring at room temperature for 5 minutes, ice water was added and the mixture was cooled and washed with ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated. The residue was separated and purified by medium pressure silica gel column chromatography (normal phase methylene chloride: ethanol = 100: 3, then reverse phase methanol: water = 19: 1) and then recrystallized from methanol-water to give the desired product as colorless crystals. 1.98 g (31.6%) was obtained.
【００１８】融点 85〜86℃ 元素分析値（％） Ｃ29Ｈ40Ｏ7 Ｓとして 計算値（実測値） Ｃ：65.39 （65.20 ） Ｈ：7.57
（7.63）Melting point 85 to 86 ° C. Elemental analysis value (%) Calculated value as C 29 H 40 O 7 S (actual value) C: 65.39 (65.20) H: 7.57
(7.63)
【００１９】（実施例２）4-(3- ヒドロキシ-6-(1-ヒド
ロキシエチル)-2-プロピルフェノキシ）酪酸エチル(Example 2) Ethyl 4- (3-hydroxy-6- (1-hydroxyethyl) -2-propylphenoxy) butyrate
【００２０】4-(6- アセチル-3- ヒドロキシ-2- プロピ
ルフェノキシ）酪酸エチル16.4ｇをエタノール90mlに溶
解し、５％パラジウム炭素1.2 ｇを加え水冷常圧下で水
素接触還元を行った。反応終了後触媒を濾去し、濾液を
濃縮した。残渣を中圧シリカゲルカラムクロマトグラフ
ィー（ベンゼン：酢酸エチル＝７：３）で分離精製し、
淡黄色油伏物である目的物14.0ｇ（84.8％）を得た。16.4 g of ethyl 4- (6-acetyl-3-hydroxy-2-propylphenoxy) butyrate was dissolved in 90 ml of ethanol, 1.2 g of 5% palladium carbon was added, and hydrogen catalytic reduction was carried out under water cooling and atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated. The residue is separated and purified by medium pressure silica gel column chromatography (benzene: ethyl acetate = 7: 3),
14.0 g (84.8%) of the target product, which was a pale yellow oily residue, was obtained.
【００２１】 1Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ：0.98
（３Ｈ，ｔ，Ｊ＝７Ｈｚ）、1.28 （３Ｈ，ｔ，Ｊ＝７
Ｈｚ）、1.48 （３Ｈ，ｄ，Ｊ＝６Ｈｚ）、1.58 （２
Ｈ，ｍ）、2.14 （２Ｈ，ｍ）、2.4 〜 2.6 （５Ｈ、
ｍ）、3.8 〜 3.9 （２Ｈ，ｍ）、4.17 （２Ｈ，
ｑ）、〜5.1 （１Ｈ，ｍ）、５．６５（１Ｈ，ｓ）、
６．５６（１Ｈ，ｄ，Ｊ＝９Ｈｚ）、７．１１（１Ｈ，
ｄ，Ｊ＝９Ｈｚ） 1 H-NMR (CDCl 3 ) δ: 0.98
(3H, t, J = 7Hz), 1.28 (3H, t, J = 7)
Hz), 1.48 (3H, d, J = 6Hz), 1.58 (2
H, m), 2.14 (2H, m), 2.4-2.6 (5H,
m), 3.8 to 3.9 (2H, m), 4.17 (2H, m
q), ~ 5.1 (1H, m), 5.65 (1H, s),
6.56 (1H, d, J = 9Hz), 7.11 (1H,
d, J = 9Hz)
【００２２】（実施例３）4-[3-(3-クロロプロポキシ)-
6-(1- ヒドロキシエチル)-2-プロピルフェノキシ] 酪酸
エチル。(Example 3) 4- [3- (3-chloropropoxy)-
6- (1-hydroxyethyl) -2-propylphenoxy] ethyl butyrate.
【００２３】4-[6- アセチル-3-(3-クロロプロポキシ)-
2-プロピルフェノキシ] 酪酸エチル15.0ｇのメタノール
195ml 溶液に、氷冷下水素化ホウ素ナトリウム2.9 ｇを
少量ずつ加え、同温度で２時間攪拌した。反応液に水10
0ml を加え、溶媒を減圧留去後、氷冷下２Ｎ−塩酸を加
え酸性とし、酢酸エチルで抽出した。有機層を水、飽和
食塩水で洗浄し、無水芒硝で乾燥した。溶媒を減圧留去
すると淡黄色油伏物として目的物14.6ｇ（96.8％）を得
た。4- [6-acetyl-3- (3-chloropropoxy)-
2-Propylphenoxy] Ethyl butyrate 15.0 g of methanol
To the 195 ml solution, 2.9 g of sodium borohydride was added little by little under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Water in the reaction solution 10
0 ml was added, the solvent was evaporated under reduced pressure, 2N-hydrochloric acid was added under ice-cooling to acidify, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 14.6 g (96.8%) of the desired product as a pale yellow oily substance.
【００２４】ＮＭＲ（ＣＤＣｌ3 ）δ：0.96（３Ｈ，
ｔ，Ｊ＝７Ｈｚ）、1.27（３Ｈ，ｔ，Ｊ＝７Ｈｚ）、1.
40〜1.80（２Ｈ，ｍ）、1.47（３Ｈ，ｄ，Ｊ＝6.6 Ｈ
ｚ）、2.00〜2.40（４Ｈ，ｍ）、2.40〜2.70（５Ｈ，
ｍ）、3.70〜4.00（４Ｈ，ｍ）、4.00〜4.30（４Ｈ，
ｍ）5.10（１Ｈ，ｑ，Ｊ＝6.6 Ｈｚ）、6.70（１Ｈ，
ｄ，Ｊ＝8.4 Ｈｚ）、7.20（１Ｈ，ｄ，Ｊ＝8.8 Ｈｚ）NMR (CDCl 3 ) δ: 0.96 (3H,
t, J = 7 Hz), 1.27 (3H, t, J = 7 Hz), 1.
40-1.80 (2H, m), 1.47 (3H, d, J = 6.6H
z), 2.00 to 2.40 (4H, m), 2.40 to 2.70 (5H,
m), 3.70 to 4.00 (4H, m), 4.00 to 4.30 (4H,
m) 5.10 (1H, q, J = 6.6 Hz), 6.70 (1H,
d, J = 8.4 Hz), 7.20 (1H, d, J = 8.8 Hz)
【００２５】（実施例４）4-[3-(3-クロロプロポキシ)-
6-(1- ヒドロキシエチル)-2-プロピルフェノキシ] 酪酸(Example 4) 4- [3- (3-chloropropoxy)-
6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid
【００２６】4-[3-(3-クロロプロポキシ)-6-(1- ヒドロ
キシエチル)-2-プロピルフェノキシ]酪酸エチル14.6ｇ
のエタノール85ml溶液に、氷冷下、水酸化ナトリウム 1.67ｇの33.3ml水溶液を滴下した。そのまま１時間攪拌
後、室温にて４時間反応させた後、１時間間隔で２回水
酸化ナトリウム250mgの5ml 水溶液を追加し反応させ
た。氷冷下、１Ｎ塩酸を加えて中和し、溶媒を減圧留去
後、５％水酸化ナトリウム水溶液を加え、アルカリ性と
し、酢酸エチルで洗浄後、水層を１Ｎ塩酸で酸性とし、
酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄
後、無水芒硝で乾燥した。溶媒を減圧留去し、淡黄色油
状物として目的物12.9ｇ（収率95.1％）を得た。Ethyl 4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyrate 14.6 g
A solution of 1.67 g of sodium hydroxide in 33.3 ml of water was added dropwise to the solution of ethanol in 85 ml of ice under ice cooling. After stirring for 1 hour as it was, the mixture was reacted at room temperature for 4 hours, and then, twice at 1 hour intervals, a 5 ml aqueous solution of 250 mg of sodium hydroxide was added and reacted. Under ice-cooling, 1N hydrochloric acid was added to neutralize, the solvent was distilled off under reduced pressure, 5% aqueous sodium hydroxide solution was added to make the mixture alkaline, washed with ethyl acetate, and the aqueous layer was acidified with 1N hydrochloric acid.
The mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 12.9 g (yield 95.1%) of the desired product as a pale yellow oily substance.
【００２７】ＮＭＲ（ＣＤＣｌ3 ）δ：0.95（３Ｈ，
ｔ，Ｊ＝7.3 Ｈｚ）、1.38〜1.80（２Ｈ，ｍ）、1.47
（３Ｈ，ｄ，Ｊ＝6.6 Ｈｚ）、2.00〜2.40（４Ｈ，
ｍ）、2.40〜2.75（４Ｈ，ｍ）、3.62〜3.94（４Ｈ，
ｍ）、4.08（２Ｈ，ｔ，Ｊ＝5.7 Ｈｚ）、5.12（１Ｈ，
ｑ，Ｊ＝6.6 Ｈｚ）、6.66（１Ｈ，ｄ，Ｊ＝8.8 Ｈ
ｚ）、7.22（１Ｈ，ｄ，Ｊ＝8.8 Ｈｚ）NMR (CDCl 3 ) δ: 0.95 (3H,
t, J = 7.3 Hz), 1.38 to 1.80 (2H, m), 1.47
(3H, d, J = 6.6 Hz), 2.00 to 2.40 (4H,
m), 2.40 to 2.75 (4H, m), 3.62 to 3.94 (4H,
m), 4.08 (2H, t, J = 5.7 Hz), 5.12 (1H,
q, J = 6.6 Hz), 6.66 (1 H, d, J = 8.8 H)
z), 7.22 (1H, d, J = 8.8 Hz)
【００２８】（実施例５）(+)-4-[3-(3-クロロプロポキ
シ)-6-(1- ヒドロキシエチル)-2-プロピルフェノキシ]
酪酸及び(-)-4-[3-(3 クロロプロポキシ)-6-(1- ヒドロ
キシエチル)-2-プロピルフェノキシ] 酪酸(Example 5) (+)-4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy]
Butyric acid and (-)-4- [3- (3 Chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid
【００２９】4-[3-(3-クロロプロポキシ)-6-(1- ヒドロ
キシエチル)-2-プロピルフェノキシ] 酪酸（5.0 ｇ）の
酢酸エチル7ml 溶液に(S)-(-)-1-(1- ナフチル）エチル
アミン（2.15ml）を加え、４℃にて一夜静置した。析出
した結晶を濾取し、冷酢酸エチルで洗浄後乾燥し、粗塩
1.07ｇを得た。4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid (5.0 g) in a solution of 7 ml in ethyl acetate (S)-(-)-1- (1-Naphthyl) ethylamine (2.15 ml) was added and the mixture was allowed to stand overnight at 4 ° C. The precipitated crystals were collected by filtration, washed with cold ethyl acetate and dried to give crude salt.
1.07 g was obtained.
【００３０】粗塩を酢酸エチルにて３回再結晶し(+)-4-
[3-(3-クロロプロポキシ)-6-(1- ヒドロキシエチル)-2-
プロピルフェノキシ] 酪酸の(S)-(-)-1-(1- ナフチル）
エチルアミン塩の無色針状晶68.0mg（融点124.0 〜125.
0℃、［α］20 D ＋4.1 °（ｃ＝1.05、エタノール )）
を得た。この塩に氷冷下、１Ｎ塩酸を加え酸性とし、酢
酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後
・無水芒硝で乾燥し、溶媒を減圧留去することにより、
(+)-4-[3-(3-クロロプロポキシ)-6-(1- ヒドロキシエチ
ル）-2- プロピルフェノキシ] 酪酸42.6mgを微黄色油状
物として得た。［α］20 D ＋19.0°(c=0.852、エタノー
ル）The crude salt was recrystallized from ethyl acetate three times (+)-4-
[3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-
Propylphenoxy] butyric acid (S)-(-)-1- (1-naphthyl)
Colorless needle-like crystals of ethylamine salt 68.0 mg (melting point 124.0-125.
0 ° C, [α] 20 D + 4.1 ° (c = 1.05, ethanol))
Got The salt was acidified with 1N hydrochloric acid under ice cooling, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
42.6 mg of (+)-4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid was obtained as a pale yellow oil. [Α] 20 D + 19.0 ° (c = 0.852, ethanol)
【００３１】粗塩を得た濾液に氷冷下１Ｎ塩酸を加えて
酸性とし、酢酸エチルで抽出した。有機層を水、飽和食
塩水で洗浄後、無水芒硝で乾燥し、溶媒を減圧留去して
得た残渣4.45ｇを酢酸エチル7ml に溶解し、(R)-(+)-1-
(1- ナフチル）エチルアミン(1.92ml)を加え、室温で一
夜静置した。析出した結晶を濾取し、冷酢酸エチルで洗
浄後乾燥し、粗塩1.53ｇを得た。The filtrate from which the crude salt was obtained was acidified by adding 1N hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.45 g of a residue, which was dissolved in 7 ml of ethyl acetate, and then (R)-(+)-1-
(1-Naphthyl) ethylamine (1.92 ml) was added, and the mixture was left at room temperature overnight. The precipitated crystals were collected by filtration, washed with cold ethyl acetate and then dried to obtain 1.53 g of crude salt.
【００３２】粗塩酢酸エチルにて再結晶を３回行ない、
(-)-4-[3-(3-クロロプロポキシ)-6-(1- ヒドロキシエチ
ル)-2-プロピルフェノキシ] 酪酸の(R)-(+)-1-(1- ナフ
チル）エチルアミン塩の無色針状晶141.4mg(融点123.0
〜124.5 ℃、［α］20 D -4.1°(c=1.084、エタノール
)）を得た。この塩に氷冷下１Ｎ塩酸を加え酸性とし、
酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄
後、無水芒硝で乾燥し、溶媒を減圧留去することによ
り、(-)-4-[3-(3-クロロプロポキシ)-6-(1- ヒドロキシ
エチル)-2-プロピルフェノキシ] 酪酸55.9mgを微黄色油
状物として得た。［α］20 D −19.1°（ｃ＝1.034 、エ
タノール）Recrystallization with crude salt ethyl acetate was performed 3 times,
(-)-4- [3- (3-Chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid (R)-(+)-1- (1-naphthyl) ethylamine salt Colorless needles 141.4 mg (melting point 123.0
~ 124.5 ° C, [α] 20 D -4.1 ° (c = 1.084, ethanol
)) Got. To this salt, add 1N hydrochloric acid under ice cooling to make it acidic,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give (-)-4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl). ) -2-Propylphenoxy] butyric acid (55.9 mg) was obtained as a pale yellow oil. [Α] 20 D -19.1 ° (c = 1.034, ethanol)
【００３３】（実施例６）(-)-4-[3-(3-(4- アセチル-3
- ヒドロキシ-2- プロピルフェニルチオ）プロポキシ)-
6-(1- ヒドロキシエチル)-2-プロピルフェノキシ] 酪酸(Example 6) (-)-4- [3- (3- (4-acetyl-3
-Hydroxy-2-propylphenylthio) propoxy)-
6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid
【００３４】(-)-4-[3-(3-クロロプロポキシ)-6-(1-ヒ
ドロキシエチル)-2-プロピルフェノキシ] 酪酸55.9mg、
(2- ヒドロキシ-4- メルカプト-3- プロピルフェニル）
エタノン39.3mg、炭酸カリウム51.7mg及びジメチルホル
ムアミド1ml の混合液を室温で６時間攪拌した。反応液
を氷水中に注加し、１Ｎ塩酸で酸性とし、酢酸エチルで
抽出した。有機層を水、飽和食塩水で洗浄後、無水芒硝
で乾燥し、溶媒を減圧留去して残留物をシリカゲルカラ
ムクロマト（塩化メチレン：メタノール＝20：１）にて
精製後、さらに分取用薄層クロマト（塩化メチレン：メ
タノール＝15：１）にて精製し、表題化合物として黄色
油状物29.8mg(35.9 ％）を得た。［α］20 D −13.8°
（ｃ＝2.98、エタノール）(-)-4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid 55.9 mg,
(2-hydroxy-4-mercapto-3-propylphenyl)
A mixed solution of 39.3 mg of ethanone, 51.7 mg of potassium carbonate and 1 ml of dimethylformamide was stirred at room temperature for 6 hours. The reaction solution was poured into ice water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, the residue is purified by silica gel column chromatography (methylene chloride: methanol = 20: 1), and then preparative. Purification by thin layer chromatography (methylene chloride: methanol = 15: 1) gave 29.8 mg (35.9%) of a yellow oil as the title compound. [Α] 20 D -13.8 °
(C = 2.98, ethanol)
【００３５】ＮＭＲ（ＣＤＣｌ3 ）δ：0.84〜1.17（６
Ｈ，ｍ）、1.37〜1.75（４Ｈ，ｍ）、1.49（３Ｈ，ｄ，
Ｊ＝6.6 Ｈｚ）、2.09〜2.36（４Ｈ，ｍ）、2.40〜2.78
（６Ｈ，ｍ）、2.58（３Ｈ，ｓ）、3.19（２Ｈ，ｔ，Ｊ
＝7.5 Ｈｚ）、3.74〜4.13（６Ｈ，ｍ）、5.12（１Ｈ，
ｑ，Ｊ＝6.2 Ｈｚ）、6.64（１Ｈ，ｄ，Ｊ＝8.8 Ｈ
ｚ）、6.76（１Ｈ，ｄ，Ｊ＝8.4 Ｈｚ）、7.23（１Ｈ，
ｄ，Ｊ＝8.4 Ｈｚ）、7.50（１Ｈ，ｄ，Ｊ＝8.4 Ｈ
ｚ）、12.73 （１Ｈ，ｓ）NMR (CDCl 3 ) δ: 0.84 to 1.17 (6
H, m), 1.37 to 1.75 (4H, m), 1.49 (3H, d,
J = 6.6 Hz), 2.09 to 2.36 (4H, m), 2.40 to 2.78
(6H, m), 2.58 (3H, s), 3.19 (2H, t, J
= 7.5 Hz), 3.74 to 4.13 (6H, m), 5.12 (1H,
q, J = 6.2 Hz, 6.64 (1 H, d, J = 8.8 H)
z), 6.76 (1H, d, J = 8.4 Hz), 7.23 (1H,
d, J = 8.4 Hz), 7.50 (1H, d, J = 8.4 H)
z), 12.73 (1H, s)
【００３６】（実施例７）(+)-4-[3-(3-(4- アセチル-3
- ヒドロキシ-2- プロピルフェニルチオ）プロポキシ)-
6-(1- ヒドロキシエチル)-2-プロピルフェノキシ] 酪酸(Example 7) (+)-4- [3- (3- (4-acetyl-3
-Hydroxy-2-propylphenylthio) propoxy)-
6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid
【００３７】(+)-4-[3-(3-クロロプロポキシ)-6-(1-ヒ
ドロキシエチル)-2-プロピルフェノキシ] 酪酸42.6mg、
(2- ヒドロキシ-4- メルカプト-3- プロピルフェニル）
エタノン30.0mg、炭酸カリウム39.4mg及びジメチルホル
ムアミド(1ml) の混合液を室温で４時間攪拌した。反応
液を氷水中に注ぎ、１Ｎ塩酸で酸性とし、酢酸エチルで
抽出し、有機層を水、飽和食塩水で洗浄後、無水芒硝で
乾燥し、溶媒を減圧留去して、残留物をシリカゲルカラ
ムクロマト（塩化メチレン：エタノール＝20：１）で精
製後、さらに分取用薄層クロマト（塩化メチレン：メタ
ノール＝15：１）にて精製し、表題化合物として黄色油
状物16.1mg( 収率25.4％）を得た。［α］20 D ＋13.3°
（ｃ＝1.56、エタノール）(+)-4- [3- (3-chloropropoxy) -6- (1-hydroxyethyl) -2-propylphenoxy] butyric acid 42.6 mg,
(2-hydroxy-4-mercapto-3-propylphenyl)
A mixture of ethanone 30.0 mg, potassium carbonate 39.4 mg and dimethylformamide (1 ml) was stirred at room temperature for 4 hours. The reaction solution was poured into ice water, acidified with 1N hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was silica gel. After purification by column chromatography (methylene chloride: ethanol = 20: 1), further purification by preparative thin-layer chromatography (methylene chloride: methanol = 15: 1) gave 16.1 mg of yellow oil as the title compound (yield 25.4 %) Was obtained. [Α] 20 D + 13.3 °
(C = 1.56, ethanol)
【００３８】ＮＭＲ（ＣＤＣｌ3 ）δ：0.84〜1.17（６
Ｈ，ｍ）、1.37〜1.75（４Ｈ，ｍ）、1.48（３Ｈ，ｄ，
Ｊ＝6.6 Ｈｚ）、2.09〜2.36（４Ｈ，ｍ）、2.40〜2.78
（６Ｈ，ｍ）、2.58（３Ｈ，ｓ）、3.19（２Ｈ，ｔ，Ｊ
＝7.5 Ｈｚ）、3.56( ２Ｈ，brs ）、3.81〜4.07（４
Ｈ，ｍ）、5.12（１Ｈ，ｑ，Ｊ＝6.6 Ｈｚ）、6.64（１
Ｈ，ｄ，Ｊ＝8.8 Ｈｚ）、6.76（１Ｈ，ｄ，Ｊ＝8.8 Ｈ
ｚ）、7.23（１Ｈ，ｄ，Ｊ＝8.4 Ｈｚ）、7.50（１Ｈ，
ｄ，Ｊ＝8.4 Ｈｚ）、12.74（１Ｈ，ｓ）NMR (CDCl 3 ) δ: 0.84 to 1.17 (6
H, m), 1.37 to 1.75 (4H, m), 1.48 (3H, d,
J = 6.6 Hz), 2.09 to 2.36 (4H, m), 2.40 to 2.78
(6H, m), 2.58 (3H, s), 3.19 (2H, t, J
= 7.5 Hz), 3.56 (2H, brs), 3.81 to 4.07 (4
H, m), 5.12 (1H, q, J = 6.6 Hz), 6.64 (1
H, d, J = 8.8 Hz), 6.76 (1H, d, J = 8.8 H)
z), 7.23 (1H, d, J = 8.4 Hz), 7.50 (1H,
d, J = 8.4 Hz), 12.74 (1H, s)
【００３９】[0039]
【発明の効果】実験例１ モルモット気道狭窄抑制試験 体重450 ｇ前後のハートレー（Hartley ）系雄性モルモ
ットをペントバルビタールナトリウム30mg/kg （腹腔
内）で麻酔し、気道内圧の変化をコンツェットーレスラ
ー変法（Konzett-Roessler:J.Harvery,et al.,J.Pharma
col.Method, 9,147-155,1983)に従って測定した。気道
狭窄反応は、ロイコトリエンＤ4 （３μｇ／kg）を左外
頚静脈に挿入したカニューレより投与することにより惹
起した。なお、ロイコトリエンＤ4 投与に先立ち、動物
にはインドメタシン及びプロブラノロールを静脈内投与
した。実施例１の化合物はナトリウム塩溶液とし、ロイ
コトリエンＤ4 投与３分前に静脈内投与した。実験結果
を表１に示した。EFFECTS OF THE INVENTION Experimental Example 1 Suppression Test of Guinea Pig Airway Stenosis A male Hartley strain guinea pig weighing about 450 g was anesthetized with sodium pentobarbital sodium 30 mg / kg (intraperitoneal), and changes in airway pressure were changed by the Kontzet-Wrestler change. Law (Konzett-Roessler: J.Harvery, et al., J.Pharma
col. Method, 9, 147-155 , 1983). The airway narrowing reaction was induced by administering leukotriene D 4 (3 μg / kg) from a cannula inserted into the left external jugular vein. Prior to administration of leukotriene D 4 , animals were intravenously administered indomethacin and probranolol. The compound of Example 1 was prepared as a sodium salt solution and administered intravenously 3 minutes before the administration of leukotriene D 4 . The experimental results are shown in Table 1.
【００４０】本発明化合物は、モルモットの摘出気管平
滑筋標本において強力なロイコトリエンＤ4 拮抗作用を
示し、更に低用量の静脈内投与で気道狭窄抑制効果を示
した。The compound of the present invention showed a strong leukotriene D 4 antagonism in the isolated tracheal smooth muscle specimen of guinea pig, and further showed an inhibitory effect on airway stenosis even when administered at a low dose intravenously.
【００４１】以上の成績から明らかなように、一般式
（１）で表される本発明化合物はロイコトリエン類が原
因である疾病、例えば、気管支喘息、目、鼻及び胃腸の
アレルギー性疾患やアレルギー性皮膚炎、更に循環障害
等の治療に有用である。As is apparent from the above results, the compound of the present invention represented by the general formula (1) is a disease caused by leukotrienes, such as bronchial asthma, eye, nose and gastrointestinal allergic diseases and allergic diseases. It is useful for treating dermatitis and circulatory disorders.
【００４２】[0042]
【表１】 [Table 1]
Claims (5)
を表す〕で表されるフェノキシアルキルカルボン酸誘導
体又はそれらのアルカリ塩。1. The general formula (1) (1) [wherein R 1 represents a hydrogen atom, a methyl group or an ethyl group] or a phenoxyalkylcarboxylic acid derivative or an alkali salt thereof.
表される化合物に下記一般式（３） （３）〔式中、Ｙはハロゲン原子を表す〕で表される化
合物を作用させ一般式（１ａ） （１ａ）〔式中、Ｒ2 はメチル基又はエチル基を表す〕
としたのち、加水分解することを特徴とする、一般式
（１）でＲ1 が水素原子である化合物の製造方法。2. The general formula (2) (2) [in the formula, R 2 represents a methyl group or an ethyl group] and a compound represented by the following general formula (3) (3) by reacting a compound represented by the formula (wherein Y represents a halogen atom) with the general formula (1a) (1a) [in the formula, R 2 represents a methyl group or an ethyl group]
And then hydrolyzing the compound, wherein R 1 is a hydrogen atom in the general formula (1).
子、メチル基又はエチル基を表す〕で表される化合物に
下記式（５） （５）で表される化合物を作用させ、要すれば加水分解
することを特徴とする一般式（１） （１）〔式中、Ｒ1 は前述の通り〕で表される化合物の
製造方法。3. The general formula (4) (4) [wherein Y represents a halogen atom and R 1 represents a hydrogen atom, a methyl group or an ethyl group] and a compound represented by the following formula (5) A compound represented by the general formula (1), characterized in that the compound represented by the formula (5) is caused to act and, if necessary, is hydrolyzed. (1) A method for producing a compound represented by the formula (wherein R 1 is as described above).
表し、Ｒ1 は水素原子、メチル基又はエチル基を表す〕
で表される化合物を還元することを特徴とする一般式
（７） （７）〔式中、Ｒは水素原子又はハロゲノプロピル基を
表し、Ｒ1 は水素原子、メチル基又はエチル基を表す〕
で表される化合物の製造方法。4. The general formula (6) (6) [In the formula, R represents a hydrogen atom or a halogenopropyl group, and R 1 represents a hydrogen atom, a methyl group or an ethyl group]
A general formula (7) characterized by reducing a compound represented by (7) [In the formula, R represents a hydrogen atom or a halogenopropyl group, and R 1 represents a hydrogen atom, a methyl group or an ethyl group]
The manufacturing method of the compound represented by.
を表す〕で表されるフェノキシアルキルカルボン酸誘導
体又はそれらのアルカリ塩の少なくとも１種以上を有効
成分とする抗アレルギー剤。5. The general formula (1) (1) An antiallergic agent comprising, as an active ingredient, at least one or more of a phenoxyalkylcarboxylic acid derivative represented by the formula [wherein R 1 represents a hydrogen atom, a methyl group or an ethyl group] or an alkali salt thereof.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/814,477 US5290812A (en) | 1991-01-18 | 1991-12-30 | Phenoxyalkylcarboxylic acid derivatives and process of preparing the same |
| HU9200008A HU214714B (en) | 1991-01-18 | 1992-01-02 | Process for producing phenylthiopropoxy substituted phenoxyalkylcarboxylic acid derivatives |
| CA002058888A CA2058888C (en) | 1991-01-18 | 1992-01-07 | Phenoxyalkylcarboxylic acid derivatives and process of preparing the same |
| KR1019920000340A KR950014597B1 (en) | 1991-01-18 | 1992-01-13 | Phenoxyalkyl carboxylic acid derivatives process of preparing the same |
| DE69201964T DE69201964T2 (en) | 1991-01-18 | 1992-01-15 | Phenoxyalkylcarboxylic acid derivatives, process for their preparation and anti-allergic agents. |
| EP92100614A EP0495485B1 (en) | 1991-01-18 | 1992-01-15 | Phenoxyalkylcarboxylic acid derivatives, process of preparing the same and anti-allergic agents |
| ES92100614T ES2073189T3 (en) | 1991-01-18 | 1992-01-15 | DERIVATIVES OF PHENOXIAL ACID CARBOXYLIC ACID, PROCEDURE FOR ITS PREPARATION AND ANTI-ALLERGIC AGENTS. |
| AU10288/92A AU638626B2 (en) | 1991-01-18 | 1992-01-16 | Phenoxyalkylcarboxylic acid derivatives and process of preparing the same |
| CN92100324A CN1063487A (en) | 1991-01-18 | 1992-01-16 | Phenoxyalkylcarboxylacid acid derivatives and preparation method thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5420791 | 1991-01-18 | ||
| JP3-54207 | 1991-01-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0551359A true JPH0551359A (en) | 1993-03-02 |
Family
ID=12964110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3359460A Pending JPH0551359A (en) | 1991-01-18 | 1991-12-26 | Phenoxyalkylcarboxylic acid derivative and its production |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPH0551359A (en) |
| KR (1) | KR950014597B1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007534771A (en) * | 2004-04-27 | 2007-11-29 | メディシノバ，インコーポレーテッド | Phenoxyalkylcarboxylic acid derivatives in the treatment of inflammatory diseases |
| JP2017516812A (en) * | 2014-06-02 | 2017-06-22 | メディシノバ・インコーポレイテッドＭｅｄｉｃｉＮｏｖａ， Ｉｎｃ． | Method for inhibiting or treating fibrosis |
-
1991
- 1991-12-26 JP JP3359460A patent/JPH0551359A/en active Pending
-
1992
- 1992-01-13 KR KR1019920000340A patent/KR950014597B1/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007534771A (en) * | 2004-04-27 | 2007-11-29 | メディシノバ，インコーポレーテッド | Phenoxyalkylcarboxylic acid derivatives in the treatment of inflammatory diseases |
| JP2017516812A (en) * | 2014-06-02 | 2017-06-22 | メディシノバ・インコーポレイテッドＭｅｄｉｃｉＮｏｖａ， Ｉｎｃ． | Method for inhibiting or treating fibrosis |
Also Published As
| Publication number | Publication date |
|---|---|
| KR920014774A (en) | 1992-08-25 |
| KR950014597B1 (en) | 1995-12-11 |
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