JPS6041664A - Benzoic acid derivative - Google Patents

Abstract

NEW MATERIAL:A benzoic acid derivative shown by the formula I (X is group shown by the formula II, formula III, or formula IV) and its salt. EXAMPLE:p-(3-Pyridylmethoxymethyl)benzoate hydrochloride. USE:An inhibitor against an enzyme synthesizing thromboxane A2. Useful for remedying various kinds of disease such as thrombosis, myocardial infarction, diabetic vascular complication, asthma, etc. resulting from thromboxane A2. PREPARATION:Nicotinic aldehyde is condensed with malonic acid to give a reaction product, which is converted in HCl-containing methanol by heating to give a compound shown by the formula V. This compound is hydrogenated in a solvent in the presence of Pd/C catalyst at normal pressure, which is subjected to Grignard reaction with p-diethoxymethylphenylmagnesium bromide, and treated with a mineral acid to give a compound(novel compound) shown by the formula VI, which is oxidized with an oxidizing agent in a mixed solvent to give a compound shown by the formula I where X is a group shown by the formula II.

Description

【発明の詳細な説明】 本発明は、一般式 ％式％） る新規な安息香酸誘導体およびこれらの薬学的に許容さ
れる非毒性塩に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel benzoic acid derivatives having the general formula %) and pharmaceutically acceptable non-toxic salts thereof.

本発明の一般式（Ｄで表わされる安息香酸誘導体はトロ
ンボキサンＡ２の生合成を特異的に阻害するために、ト
ロンボキサンＡ２に起因する種々の疾患、たとえば血除
症、心筋］す↓塞、ｌ＞、ｌ＋尿尿性性血管合併症ぜん
息などの治療に有用である。Since the benzoic acid derivative represented by the general formula (D) of the present invention specifically inhibits the biosynthesis of thromboxane A2, it can be used to treat various diseases caused by thromboxane A2, such as hematopoiesis, myocardial obstruction, l>, l+It is useful in the treatment of urinary vascular complications such as asthma.

イミダソールがトロンホキサンＡ２の生合成を阻害する
（　Ｐｒｏｃ、　Ｎａ１１．　Ａｃａｄ、　Ｓｃｉ、　
ＵＳＡ。Imidazole inhibits the biosynthesis of tromphoxane A2 (Proc, Na11. Acad, Sci.
USA.

７４、１７１６（１９７７）、　Ｐｒｏｓｔａｇｌａｎ
ｃｌｉｎｓ、　Ｃ３，６１１（１９７７））ことが見出
されて以来、トロンホキサンＡ２合成酵素阻害剤に関す
る研究は盛んに行なわれ、イミダゾール誘導体（たとえ
は特開１１百　５４−１１２８６２　、１１２８６３　
、１４４３６９　、　■６：う５７３；特開昭５５−：
３１３．２８９２７．８５５７２．１００３６８）、ピ
リジン誘導体（たとえば、特開昭５５−４７６７６．８
９２６６　；特開昭５６−２５１６１）などの特許出願
がなされている。しかし、これらの化合物は治療効果、
消化管よりの薬物の吸収あるいは７１Ｊ性などの点で幾
多の検問の余地を残している。74, 1716 (1977), Prostaglan
Since the discovery of thromboxane A2 synthetase inhibitors (Clins, C3, 611 (1977)), research on thromboxane A2 synthase inhibitors has been actively conducted, and imidazole derivatives (for example,
, 144369, ■6: U573; JP-A-1983-:
313.28927.85572.100368), pyridine derivatives (for example, JP-A-55-47676.8
Patent applications such as No. 9266; Japanese Unexamined Patent Publication No. 56-25161) have been filed. However, these compounds have therapeutic effects,
There are still many questions to be investigated regarding the absorption of drugs from the gastrointestinal tract and the nature of 71J.

本発明者らは、強いトロンホキサンＡ２合成酵素阻害剤
用を有する化合物を１（するへく、ピリジン誘導体に関
し特許出願した（特願昭５７−２８３９２　）。今回、
さらに鋭意研究を重ねた結果、優れた薬理作用を有する
一般式（１）で表わされる安息香酸誘導体を得ることに
成功し、本発明を完結するに至った。The present inventors have filed a patent application for a pyridine derivative (Japanese Patent Application No. 57-28392), which has a strong thromboxane A2 synthetase inhibitory effect.
As a result of further extensive research, we succeeded in obtaining a benzoic acid derivative represented by general formula (1) that has excellent pharmacological effects, and completed the present invention.

本発明化合物（Ｉ）は、次のようにして製造することが
できる。すなわち、 ニコチンアルデヒドとマロン酸とを、ピペリジン存在下
、ベンゼン中にて縮合反応させて公知化合物■を得、つ
いで塩化水素含有メタノール中、加熱反応により公知化
合物σ尋とし、これをメタノール、エタノール、または
酢酸溶媒中パラジウム−炭素触媒存在下で常圧水素添加
により公知化合物（ＩＶ）を得、このエステル体を、無
水のエーテルまたはテトラヒドロフラン中、Ｐ−ジェト
キシメチルフェニルマグネシウムプロミドとグリニヤー
ル反応さ′ｉだ後、塩酸または硫酸などの鉱酸処理して
保護基アセタール基を除き新規化合物（Ｖ）を得る。こ
こに得られたアルデヒド体（功を、メタノール、エタノ
ール、アセトンなどの溶媒と水との混液中、−Ｊ当な酸
化剤、たとえば過マンガン酸カリウム、次亜塩素酸ナト
リウムなどで酸化反応させることにより容易にＩＥＩ的
化金化合物）を得ることができる。Compound (I) of the present invention can be produced as follows. That is, nicotinaldehyde and malonic acid are subjected to a condensation reaction in benzene in the presence of piperidine to obtain the known compound (1), which is then subjected to a heating reaction in methanol containing hydrogen chloride to form the known compound σ, which is mixed with methanol, ethanol, Alternatively, the known compound (IV) is obtained by hydrogenation at normal pressure in the presence of a palladium-carbon catalyst in an acetic acid solvent, and this ester is subjected to a Grignard reaction with P-jethoxymethylphenylmagnesium bromide in anhydrous ether or tetrahydrofuran. After that, the protective acetal group is removed by treatment with a mineral acid such as hydrochloric acid or sulfuric acid to obtain a new compound (V). The aldehyde obtained here is subjected to an oxidation reaction with a suitable oxidizing agent such as potassium permanganate or sodium hypochlorite in a mixture of water and a solvent such as methanol, ethanol, or acetone. IEI-like gold compounds) can be easily obtained.

次に、Ｘが　■−ＣＨ（ＯＨ）ＣＨ２０−の場合、下３
−アセチルピリジンを酢酸中またはこれとクロロホルム
、イソプロピルエーテルなどの混液中、臭素を反応させ
て公知化合物α■）を得、ついで、炭酸カリウム、ｍ　
１７．１７などの塩基存在下、Ｎ、　Ｎ−ジメチルホル
ムアミド、ジメチルホキシト、ヘキサメチルホスホルア
ミドなどの溶媒中、Ｐ−ヒドロキシ安息香酸メチルを反
応させて化合物α■）とし、これを、メタノール、エタ
ノール、イソプロピルアルコールなどの溶媒中、水素化
ホウ素ナトリウムを反応させて化合物α■）を得る。こ
のエステル体を水酸化ナトリウム、水酸化カリウムなど
のアルカリ水溶液中加水分解した後、適当な酸、たとえ
ば酢酸などで中和すれば目的化合物（Ｉ）の遊離体を得
ることができる。Next, if X is -CH(OH)CH20-, lower 3
- Acetylpyridine is reacted with bromine in acetic acid or a mixture of chloroform, isopropyl ether, etc. to obtain the known compound α■), and then potassium carbonate, m
In the presence of a base such as 17.17, methyl P-hydroxybenzoate is reacted in a solvent such as N,N-dimethylformamide, dimethyl phosoxide, hexamethylphosphoramide, etc. to form a compound α■), which is mixed with methanol, ethanol , react with sodium borohydride in a solvent such as isopropyl alcohol to obtain compound α■). By hydrolyzing this ester in an aqueous alkali solution such as sodium hydroxide or potassium hydroxide, and then neutralizing it with an appropriate acid such as acetic acid, the free form of the target compound (I) can be obtained.

Ｑ−ＣＨ２０ＣＨ２つ−ＣＯ２Ｍｅ−→Ｉ■ ３−ピリジンメタノールとＰ−ブロモメチル安息香酸メ
チルエステルとを、水素化ナトリウム存在下Ｎ、　Ｎ−
ジメチルホルムアミド、テトラヒドロフランなどの溶媒
中で反応させて化合物（ＩＸ）を得、ついて前記同様に
アルカリ加水分解により１」的化合物（Ｉ）を得ること
ができる。Q-CH20CH2-CO2Me-→I■ 3-Pyridinemethanol and P-bromomethylbenzoic acid methyl ester were combined with N, N- in the presence of sodium hydride.
Compound (IX) can be obtained by reacting in a solvent such as dimethylformamide or tetrahydrofuran, followed by alkaline hydrolysis in the same manner as described above to obtain 1'-like compound (I).

このようにして得られる本発明化合物「Ｓ■）は強いト
ロンボキサンＡ２合成酵素阻害作用を有している。この
ようないわゆる抗血栓剤のｉｉＪ能性のある化合物の評
価方法の一つとし゛て、１１１・ｉｖ。The compound of the present invention "S■" thus obtained has a strong thromboxane A2 synthase inhibitory effect.As one of the methods for evaluating compounds with such so-called antithrombotic iiJ activity, , 111・iv.

で行なうところの、アラキドン酸によるウサギの急性致
死を防御する試験方法が多数報告され仁 ている（たとえば、Ａｇｅｎｔｓ　ａｎｄ　Ａｃｔ％（
ｏｎｓ、　７゜４８１（１９７７）；　円＋ａｒｍａｃ
ｏｌｏｇｙ、１４，５２２（１９７６）；　５ｃｉｅｎ
ｃｅ、　１８３　、１０８５（１９７４）など。）。す
なイつち、アラキドン酸のすトリウム塩を１．４１１ｒ
グ／　Ｋｇ、ウサギの静脈内に投与すると血小板凝集や
肺塞栓がおこり、ウサギは数分以内に死亡する。本発明
化合物（１）はこのウサギのアラキドン酸急性致死を強
く抑制するので、トロンボキサンＡ２に起因すると考え
られる前述の疾患を予防あるいは治療する医薬品として
産業上有用である。Many test methods have been reported to protect rabbits from acute lethality caused by arachidonic acid (for example, Agents and Act%).
ons, 7°481 (1977); yen + armac
ology, 14, 522 (1976);
ce, 183, 1085 (1974), etc. ). 1.411r of thorium salt of arachidonic acid
When administered intravenously to rabbits, platelet aggregation and pulmonary embolism occur, and the rabbits die within a few minutes. Since the compound (1) of the present invention strongly suppresses the acute lethality of arachidonic acid in rabbits, it is industrially useful as a pharmaceutical for preventing or treating the above-mentioned diseases thought to be caused by thromboxane A2.

本発明化合物（Ｉ）および原料化合物の合成について、
実施例および参考例をあげて詳述する。Regarding the synthesis of the compound (I) of the present invention and the raw material compounds,
This will be explained in detail by giving examples and reference examples.

参考例１ ニコチンアルデヒド４３．５ｆ、マロン酸４３　ｙ、ピ
ロリジノ１　ｍｌおよびベンゼン２００−を４時間攪拌
還流する。析出した結晶をろ取、エーテルにて洗い、メ
タノールより再結晶し無色針状晶の３−（３−ピリジル
）プロペン酸＠６７ｙを得た。次に、これの６０１を塩
化水素飽和、メタノール１５０ｍ／！と共に３時間還流
する。ついで減圧濃縮し、残渣に水を加え、炭酸カリウ
ムアルカリ性とし、エーテル抽出、水洗し、乾燥（ＭＶ
ＳＯ４）、溶媒を留去し、淡黄色油状物のメチル３−（
３−ピリジル）プロペネート［相］５６．６ｆを得た。Reference Example 1 43.5f of nicotinaldehyde, 43y of malonic acid, 1ml of pyrrolidino and 200ml of benzene are stirred and refluxed for 4 hours. The precipitated crystals were collected by filtration, washed with ether, and recrystallized from methanol to obtain colorless needle-like crystals of 3-(3-pyridyl)propenoic acid @67y. Next, 601 of this was saturated with hydrogen chloride and methanol 150m/! Reflux for 3 hours. Then, it was concentrated under reduced pressure, water was added to the residue to make it alkaline with potassium carbonate, extraction with ether, washing with water, and drying (MV
SO4), the solvent was distilled off, and a pale yellow oil, methyl 3-(
3-Pyridyl)propenate [phase] 56.6f was obtained.

次に、これの２０７をエタノール１００ｍ１にとかし、
パラジウム−炭素触媒２２を加え、常圧にて接触水素化
する。６時間反応させた後、触媒をろ過して除き、ろ液
を減圧濃縮、淡黄色油状物のメチル３−（３−ピリジル
）プロパネート（ＩＶ）１９グを得た。次に、これの４
７をとり、Ｐ−プロモベンズアルデヒドシエチルア士タ
ール２４２と金属マグネシウム２．２４１および乾燥テ
トラヒドロフラン８０ｍ１より周知の方法にて調製した
グリニヤール試薬中に、水冷下で滴下する。室温にして
３時間攪拌後、溶液を約３分の１程度まで減圧濃縮、水
を加えて分解し、濃塩酸５ｄおよびジクロルメタン７０
ｍ１を加えて３０分而面する。水層を分取し、炭酸カリ
ウムアルカリ性とし、ジクロルメタン抽出、水洗し、乾
燥（Ｍグｓｏ４　）　、溶媒を留去し、得られた残渣を
シリカゲルカラムクロマトグラフィー（エーテル）にて
精製し、Ｐ−〔１−オキソ−３−（３−ピリジル）プロ
ピル〕ベンズアルデヒドω２．５ｇを得た。融点５５−
６０℃。ＮＭＲ（ＣＩ）ｃｌｌｓ　）δ　２．６４（４
Ｈ，ｓ　）、７．１８（ＬＨ，ｍ）。Next, dissolve 207 of this in 100ml of ethanol,
A palladium-carbon catalyst 22 is added and catalytic hydrogenation is carried out at normal pressure. After reacting for 6 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 19 g of methyl 3-(3-pyridyl)propanate (IV) as a pale yellow oil. Next, this 4
7 was added dropwise under water cooling into a Grignard reagent prepared by a known method from 242 ml of P-promobenzaldehyde ethyl acetate, 2.241 ml of metallic magnesium and 80 ml of dry tetrahydrofuran. After bringing the solution to room temperature and stirring for 3 hours, the solution was concentrated under reduced pressure to about one-third, water was added to decompose it, and 5d of concentrated hydrochloric acid and 70% of dichloromethane were added.
Add m1 and wait for 30 minutes. The aqueous layer was separated, made alkaline with potassium carbonate, extracted with dichloromethane, washed with water, dried (MGSO4), the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ether). 2.5 g of [1-oxo-3-(3-pyridyl)propyl]benzaldehyde ω was obtained. Melting point 55-
60℃. NMR (CI) clls ) δ 2.64 (4
H,s), 7.18 (LH,m).

７．４６　（ＩＨ，ｍ　）、　７．６５　（２Ｈ，Ａ２
Ｂ２　ｔｙｐｅ　ｄ。7.46 (IH, m), 7.65 (2H, A2
B2 type d.

Ｊ＝９．０Ｉ４ｚ　）、　７．８９　（２１−１，Ａ２
Ｂ２　ｔｙｐｅ　（１，Ｊ−９，０Ｈｚ）、８．３０（
ＩＨ，ｍ）、８．３８（ｌＨ，ｍ）。J=9.0I4z), 7.89 (21-1, A2
B2 type (1, J-9,0Hz), 8.30 (
IH, m), 8.38 (lH, m).

１０．０９　（Ｌ　Ｈ，ｓ　）。10.09 (LH,s).

参考例２ ３−アセチルピリジン３０２を、イソプロピルエーテル
１５０ｍ！！および酢酸１５ｒｎ１．の混液にとかし、
水冷下にて臭素４２２を滴下する。２時間攪拌後、析出
した結晶をろ取、イソプロピルニー−チルにて洗い、ｎ
−ブタノール−イソプロピルエーテル混液より再結晶し
、３−ブロムアセチルピリジン・臭化水素酸塩（ＶＩ）
６２ｒを得た。Reference example 2 3-acetylpyridine 302, isopropyl ether 150m! ! and acetic acid 15rn1. Dissolve in a mixture of
Bromine 422 is added dropwise under water cooling. After stirring for 2 hours, the precipitated crystals were collected by filtration, washed with isopropyl dichloromethane, and
- Recrystallized from a butanol-isopropyl ether mixture to produce 3-bromoacetylpyridine hydrobromide (VI)
I got 62r.

次に、これの２８．１　ｆを取り、Ｐ−ヒドロキシ安息
香酸メチル１５．７１、炭酸カリウム３５２およびＮ、
Ｎ−ジメチルホルムアミド８ｏ−と共に室温にて５時間
攪拌する。析出した結晶をろ過して除き、ろ液を減圧濃
縮、残渣を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−３：１）にて精製した。得られた結
晶を、ジクロルメタン−〇−ヘキサン混液より再結晶し
、無色針状晶のメチルＰ−〔２−オキソ−２−（３−ピ
リジル）エトキシ〕ベンゾエート（ｖｎ）１０７を得た
。融点１０６−７℃。ＮＭＲ（ＣＤ娶ｉｓ）δ：　３．
８９　（３Ｈ，ｓ　）、５．３１　（２Ｈ，ｓ　）、６
．９７（２Ｈ，Ａ２Ｂ２　ｔｙｐｅ　ｄ、Ｊ＝８．５Ｈ
ｚ　）、７．．４８　（ＩＨ。Next, take 28.1 f of this, 15.71 methyl P-hydroxybenzoate, 352 potassium carbonate and N,
Stir with N-dimethylformamide 8o- at room temperature for 5 hours. The precipitated crystals were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (benzene-ethyl acetate-3:1). The obtained crystals were recrystallized from a dichloromethane-0-hexane mixture to obtain methyl P-[2-oxo-2-(3-pyridyl)ethoxy]benzoate (vn) 107 as colorless needles. Melting point 106-7°C. NMR (CD is) δ: 3.
89 (3H,s), 5.31 (2H,s), 6
．． 97 (2H, A2B2 type d, J=8.5H
z), 7. ．． 48 (IH.

ｎｌ）、８．０２　（２Ｈ，Ａ２Ｂ２　ｔｙｐｅ　ｄ、
Ｊ　＝３．５Ｈｚ　）。nl), 8.02 (2H, A2B2 type d,
J = 3.5Hz).

８．３０　（ＩＨ，ｍ　）、８．８５　（’　ＩＨ＋　
ｍ　Ｌ　９．２５（ＩＨ，ｍ）。次に、これの８．５ｆ
をメタノール５０ｍ１にとかし、水素化ホウ素ナトリウ
ム１７を室温にて添加し、１時間撹拌。後、減圧濃縮、
水を加えてジクロルメタン抽出、水洗、有機層を塩酸酸
性とし、水層分取、炭酸カリウムアルカリ性にてジクロ
ルメタン抽出、水洗し乾燥（Ｍ２ＳＯ４）、溶媒を留去
し、ｎ−ヘキサンにて結晶化、酢酸エチル−〇−ヘキサ
ンより＋Ｉｊ結晶し、無色プリズム品のメチルＰ−〔２
−ヒドロキシ−２−（３−ピリジル）エトキシ〕ベンゾ
エート（ＶＩＩＩ）　７．３ｙを得た。融点９０−２℃
ｏＮＭＲ（ＣＤＭａ）δ：　３．８０　（３Ｈ，Ｓ　）
、　４．１０（２Ｈ。8.30 (IH,m), 8.85 ('IH+
m L 9.25 (IH, m). Next, this 8.5f
was dissolved in 50 ml of methanol, 17 ml of sodium borohydride was added at room temperature, and the mixture was stirred for 1 hour. After that, vacuum concentration,
Add water and extract with dichloromethane, wash with water, acidify the organic layer with hydrochloric acid, separate the aqueous layer, extract with dichloromethane with alkaline potassium carbonate, wash with water and dry (M2SO4), distill off the solvent, crystallize with n-hexane, +Ij crystallized from ethyl acetate-〇-hexane to give colorless prism methyl P-
-Hydroxy-2-(3-pyridyl)ethoxy]benzoate (VIII) 7.3y was obtained. Melting point 90-2℃
oNMR (CDMa) δ: 3.80 (3H,S)
, 4.10 (2H.

ｄ、　Ｊ＝５．７Ｈ２Ｌ　５．１２（ＩＨ，ｔ、　Ｊ＝
５．７Ｈ２）１６．８９（２Ｈ，Ａ２Ｂ２　ｔ３’ｐｅ
　ｄ、　Ｊ＝８．０Ｈｚ　）、　７．２８（ＩＨ，ｍ）
、　７．６６−８．１０（３Ｈ，ｍ　）、　８．３８−
８．７５　（２Ｈ，ｍ　）。d, J=5.7H2L 5.12 (IH, t, J=
5.7H2) 16.89(2H, A2B2 t3'pe
d, J=8.0Hz), 7.28 (IH, m)
, 7.66-8.10 (3H, m), 8.38-
8.75 (2H, m).

実施例１ ５０％含イ１水素化ナトリウム６．３２をＮ、Ｎ−ジメ
チルホルムアミド５０ｍ１！に懸濁し、水冷下にてピリ
ジンメタノール１０．４　ｒを滴下、１時間ｂｙ拌。つ
いでメチルＰ−ブロモメチルベンゾニー１−１３．４Ｍ
を滴下し、２４時間攪拌。溶媒を減圧留去し、粗製のメ
チルＰ−（３−ピリジルメトキシメチル）ベンゾニー１
−　（ＩＸ）を得た。これをエタノール１５０　ｍ７！
にとかじ、水酸化カリウム５．６ｇおよび水４　ｍｌ、
を加え２時間還流。ついで減圧濃縮し、希塩酸酸性にて
エーテル洗浄、水酸化すｌ・リウムアルカリ性とし、水
層分取後酢酸酸性にてクロロホルム抽出、水洗し、乾燥
（Ｍ７ＳＯ４）、溶媒を留去し、残渣をエーテルにて結
晶化し、目的化合物Ｐ−（３−ピリジルメトキシメチル
）安息香酸１．７２を得た。Example 1 6.32 ml of 50% sodium hydride was added to 50 ml of N,N-dimethylformamide! 10.4 r of pyridine methanol was added dropwise under water cooling, and stirred for 1 hour. Then methyl P-bromomethylbenzony 1-13.4M
was added dropwise and stirred for 24 hours. The solvent was distilled off under reduced pressure to obtain crude methyl P-(3-pyridylmethoxymethyl)benzony 1.
- (IX) was obtained. This is 150 m7 of ethanol!
Nitokaji, 5.6 g of potassium hydroxide and 4 ml of water,
was added and refluxed for 2 hours. Then, it was concentrated under reduced pressure, washed with ether with dilute hydrochloric acid acidity, made alkaline with sulfur and lithium hydroxide, separated the aqueous layer, extracted with chloroform with acetic acid acidity, washed with water, dried (M7SO4), the solvent was distilled off, and the residue was diluted with ether. The mixture was crystallized to obtain 1.72 of the target compound P-(3-pyridylmethoxymethyl)benzoic acid.

ＮＭＲ（ＤＭＳＯ−（１６）δ：　４．５５（２Ｈ，Ｓ
　）。NMR (DMSO-(16)δ: 4.55(2H,S
).

４．５８　（２Ｈ，ｓ　）、　７．１８−７．４５　（
ＬＨ，ｍ　）、　７．３３（２Ｈ，Ａ２　Ｂ２　ｔｙｐ
ｅ　ｄ、　Ｊ＝８．０Ｈｚ　）、　７．６３−７．９５
（Ｉ　Ｈ，ｍ　）、　７．８７　（２Ｈ，Ａ２　Ｂ２　
ｔｙｐｅ　ｄ、　Ｊ＝８．０Ｈｚ）。4.58 (2H,s), 7.18-7.45 (
LH, m), 7.33 (2H, A2 B2 typ.
ed, J=8.0Hz), 7.63-7.95
(I H, m), 7.87 (2H, A2 B2
type d, J=8.0Hz).

８．２０−８．５３（２Ｈ，ｍ）。8.20-8.53 (2H, m).

次に、この遊離体１．５ｇを酢酸３　ｍｌに熱時溶解し
、冷浸濃塩酸０．２ｔｎ１２を加え、減圧留去する。Next, 1.5 g of this educt was dissolved in 3 ml of acetic acid while hot, 0.2 tn12 of cold concentrated hydrochloric acid was added, and the mixture was distilled off under reduced pressure.

エーテルにて固化させ、酢酸−メタノール混液中脱色処
理をした後留去し、残渣を酢酸−酢酸エチル混液より再
結晶し、無色剣状晶のＰ−（３−ピリジルメトキシメチ
ル）安息香酸・塩酸塩０．１８９を拐だ。融点１４３−
６℃。It was solidified with ether, decolorized in an acetic acid-methanol mixture, and then evaporated. The residue was recrystallized from an acetic acid-ethyl acetate mixture to give colorless sword crystals of P-(3-pyridylmethoxymethyl)benzoic acid and hydrochloric acid. The salt is 0.189. Melting point 143-
6℃.

実施例２ 参考例１で得られたＰ〜〔１−オキソ−３−（３−ピリ
ジル）プロピル〕ベンズアルデヒド（Ｖ１２．ｌｌを、
過マンガン酸カリウム１．５ｆ、エタノール５−および
水１５ｍ１！の混合物を外浴８０℃で１時間加熱攪拌す
る。無機物をろ過して除き、エタノールで洗い、ろ液を
濃縮、残渣に水酸化すＩ・リウム水溶液を加えてとかし
、エーテルａし浄、水層を分取し、酢酸酸性とし酢酸エ
チル抽出、乾燥（Ｍｇ３０４　）　、溶媒留去し、淡黄
色結晶を得た。これをシリカゲルカラムクロマトグラフ
ィー（ジクロルメタン−メタノール）で精製した後メタ
ノール−ｎ−ヘキサン混液より再結晶し、無色針状晶の
１」釣札合物Ｐ−〔１−オキソ−３−（３−ピリジル）
プロピル〕安息香酸１．３グを得た。融点２２２−７℃
。ＮＭＲ（ＣＤ３０Ｄ）δ：２．６５　（４Ｈ，ｂｒｓ
　）、　７．２８　（ＬＨ，ｍ）、　７．４６−７．８
７　（Ｉ　８９ｍ）　＋　７．６２　（２Ｈ＋　Ａ　２
　Ｂ　２　ｔ　ｙｐｅ　ｄ　ｔ　Ｊ　−３、ＱＨｚ　）
、　７．９８　（２Ｈ，Ａ２Ｂ２　ｔｙｐｅ　ｄ、　Ｊ
　＝３．ＱＨｚ）８．２０−８．４５　（２Ｈ，ｍ　）
、　９．９５　（ＩＨ，ｓ　）。Example 2 P~[1-oxo-3-(3-pyridyl)propyl]benzaldehyde (V12.ll) obtained in Reference Example 1 was
1.5 f potassium permanganate, 5 ml of ethanol and 15 ml of water! The mixture was heated and stirred in an external bath at 80°C for 1 hour. Remove inorganic substances by filtration, wash with ethanol, concentrate the filtrate, add an aqueous solution of I.lium hydroxide to the residue, dissolve, filter with ether, separate the aqueous layer, acidify with acetic acid, extract with ethyl acetate, and dry. (Mg304), the solvent was distilled off to obtain pale yellow crystals. This was purified by silica gel column chromatography (dichloromethane-methanol) and then recrystallized from a methanol-n-hexane mixture to form a colorless needle-shaped compound P-[1-oxo-3-(3-pyridyl). )
1.3 g of propyl]benzoic acid was obtained. Melting point 222-7℃
. NMR (CD30D) δ: 2.65 (4H, brs
), 7.28 (LH, m), 7.46-7.8
7 (I 89m) + 7.62 (2H+ A 2
B 2 type d t J-3, QHz)
, 7.98 (2H, A2B2 type d, J
=3. QHz) 8.20-8.45 (2H, m)
, 9.95 (IH,s).

実施例３ 参考例２で得られたメチルＰ−〔２−ヒドロキシ−２−
（３−ピリジル）エトキシ〕ベンゾエート４７を、１０
％水酸化ナトリウム１５０　ｍｌにとかし、室温にて５
時間攪拌する。ついで酢酸エチル洗浄し、水層を酢酸酸
性とし、析出した結晶をろ取、エタノールより再結晶し
、無色針状晶のＰ−〔２−ヒドロキシ−２−（３−ピリ
ジル）エトキシ〕安息香酸３７を得た。融点２２１−３
℃ｏＮＭＲ（ＣＤ８０Ｄ）δ：４．３３（２Ｈ。Example 3 Methyl P-[2-hydroxy-2- obtained in Reference Example 2
(3-pyridyl)ethoxy]benzoate 47, 10
Dissolve in 150 ml of % sodium hydroxide and add 5% at room temperature.
Stir for an hour. The aqueous layer was then washed with ethyl acetate, the aqueous layer was made acidic with acetic acid, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give P-[2-hydroxy-2-(3-pyridyl)ethoxy]benzoic acid 37 as colorless needle-like crystals. I got it. Melting point 221-3
°C o NMR (CD80D) δ: 4.33 (2H.

ｄ、Ｊ−５，５Ｈ２）、５，３６（ＩＨ９ｔ、Ｊ−５，
５Ｈ２）。d, J-5, 5H2), 5,36 (IH9t, J-5,
5H2).

６．９７　（２Ｈ，’Ａ２Ｂ２　ｔｙｐｅ　ｄ、　Ｊ　
＝１３．５Ｈｚ　）、　７．９３（２ＨＩ　Ａ２Ｂ２　
ｔｙｐｅ　ｄ、　Ｊ＝８．５Ｈｚ　）、　８．３０　（
１１−１゜ｍ）、８．６６−９．１０（３Ｈ，ｍ）。　
ＦＪ　ら　オｔｔコ　カ　ルＪ１ン酸の遊離体を塩化水
素含有メタノール１；１（ごて塩酸塩とする。メタノー
ル−エーテル 再結晶し、無色針状晶のＰ−（２−ヒドロキシ−２−（
３−ピリジン）エトキシ〕安，ｅ、香酸・塩酸塩を得た
。融点１８４−７℃。6.97 (2H,'A2B2 type d, J
=13.5Hz), 7.93(2HI A2B2
type d, J=8.5Hz), 8.30 (
11-1°m), 8.66-9.10 (3H, m).
FJ et al. The educt of cocaric acid was converted into hydrochloride using hydrogen chloride-containing methanol 1; (
3-Pyridine)ethoxy]an,e, fragrant acid hydrochloride was obtained. Melting point 184-7°C.

次に、このようにして得られた本発明化合１勿につき、
薬理試験の結果を例示する。Next, for the compound 1 of the present invention obtained in this way,
The results of pharmacological tests are illustrated.

化合物Ａ　：　ｐ　−　（３−ピリジルメトキシメチル
化合物Ｂ：ＰーＣＩーオキソ−３−（３−ピリジル）プ
ロピル〕安息香酸（実施例２の化合物） 化合物Ｃ：Ｐ−［２−ヒドロキシ−２−（３−ピリジル
）エトキシ〕安息香酸・ＪｉｌＸ酸Ｊｉｌｌｉ（実施例
３の化合物） ’／　ＪＬ／　ｔ＜−らの方法（　Ｓｃｉｅｎｃｅ，　
１８３．　１０８５（１９７４）　）に準じて次のよう
に行なった。被検体を２０　ｍｑ　／　Ｋｇ腹腔内投与
（ｌｒｎｌ／Ｋｖ）シ、その２時間後に、アラキドン酸
ナトリウム１．５ｍり７Ｋｇを静脈内投与（１ｒｎｌ／
に７）シた。そして、致死の有無をアラキドン耐ナトリ
ウム投与後３０分間観察した。なお、本発明化合物（Ｉ
）は、水に６！？Ｅ溶のため、ポリエチレングリコール
（ＰＥＧエタノール（ＥｔＯＨ）で溶解した後精製水で
調整した（化合物Ａ、Ｃでは、ＰＥＧ、ＥｔＯＨは各２
５％含有）。ＰＥＧ、ＥｔＯＨで不溶のもの（化合物Ｂ
）は、Ｑ、５　Ｎ　−Ｎａ　ＯＨ溶液を加えた（ＰＥＧ
、ＥｔＯＨは各２５％、Ｑ、５　Ｎ　−ＮａＯＨは１５
％含有）。Compound A: p-(3-pyridylmethoxymethyl Compound B: P-CI-oxo-3-(3-pyridyl)propyl]benzoic acid (compound of Example 2) Compound C: P-[2-hydroxy-2-( 3-Pyridyl)ethoxy]benzoic acid JilliX acid Jilli (compound of Example 3) '/JL/t<- method of et al. (Science,
183. 1085 (1974)) as follows. The subject was administered 20 mq/Kg intraperitoneally (lrnl/Kv), and 2 hours later, 7 kg of sodium arachidonate was administered intravenously (1rnl/Kv) via 1.5 m.
7) It was. Then, the presence or absence of mortality was observed for 30 minutes after administration of arachidone sodium tolerance. In addition, the compound of the present invention (I
) is 6 in water! ? To dissolve in E, polyethylene glycol (PEG) was dissolved in ethanol (EtOH) and then adjusted with purified water (for compounds A and C, PEG and EtOH were each
(contains 5%). PEG, insoluble in EtOH (compound B
) was added with Q,5N-NaOH solution (PEG
, EtOH is 25% each, Q,5N-NaOH is 15%
%).

急性毒性試験 ｃｌｃｌＹ系雄性マウスに被検共を腹腔内投与（１ケ。acute toxicity test The test substance was intraperitoneally administered to male clclY mice (1 mouse).

ｐ、）し、−週間後の生死数よりＬＤ５ｏ値を、べ−レ
ンスーケルバー法にてめた。p, ), and the LD5o value was determined from the number of live and dead animals after - weeks using the Behrens-Kerber method.

ウサギには２％溶液を、マウスには０．２ｍｌ！／１０
ｇとなるよう調整した。それぞれ試験の結果を表に示す
。2% solution for rabbits, 0.2ml for mice! /10
It was adjusted so that it was g. The results of each test are shown in the table.

コントロール　１／９　− Ａ　３／４　３１０ ）、　Ｂ　１／４　４８０ Ｃ１／４　７９０ 特許出願人　マルコ製薬林式会社　、 代表者小島茂雄゛、□　□１Control 1/9 - A 3/4 310 ), B 1/4 480 C1/4 790 Patent applicant: Marco Pharmaceutical Forest Company, Representative Shigeo Kojima゛、□　□１

Claims (1)

【特許請求の範囲】 一般式 る新規な安息香酸誘導体およびこれらの薬学的に許容さ
れる非毒性塩[Claims] Novel benzoic acid derivatives of the general formula and pharmaceutically acceptable non-toxic salts thereof