JPH05310724A - Coumarone derivative or dihydrobenzofuran derivative - Google Patents

Coumarone derivative or dihydrobenzofuran derivative

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Publication number
JPH05310724A
JPH05310724A JP11349792A JP11349792A JPH05310724A JP H05310724 A JPH05310724 A JP H05310724A JP 11349792 A JP11349792 A JP 11349792A JP 11349792 A JP11349792 A JP 11349792A JP H05310724 A JPH05310724 A JP H05310724A
Authority
JP
Japan
Prior art keywords
formula
dihydro
group
chemical
compound
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.)
Granted
Application number
JP11349792A
Other languages
Japanese (ja)
Other versions
JP3162175B2 (en
Inventor
Shigeki Hibi
滋樹 日比
Naoki Kobayashi
小林  直樹
Yasushi Okamoto
康 岡本
Katsuya Tagami
克也 田上
Hirotoshi Numata
博敏 沼田
Masanobu Shinoda
昌信 篠田
Tetsuya Kawahara
哲也 川原
Isao Yamatsu
功 山津
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.)
Eisai Co Ltd
Original Assignee
Eisai Co Ltd
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Filing date
Publication date
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Priority to JP11349792A priority Critical patent/JP3162175B2/en
Publication of JPH05310724A publication Critical patent/JPH05310724A/en
Application granted granted Critical
Publication of JP3162175B2 publication Critical patent/JP3162175B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

PURPOSE:To provide a coumarone derivative or a dihydrobenzofuran derivative having a combination of leukotriene production-inhibitory activity and thromboxane synthesis-inhibitory activity, thus useful for preventing or curing asthema or hepatopathy. CONSTITUTION:The compound of formula I {R<1> to R<3> are each H, OH or of formula IV [A is H or heteroarylalkyl; B is H, carboxyl or protected carboxyl; Y is of formula VII, VIII or IX (p and q are each 0-6)]; X is OH or protected OH; n is 2 or 3} or a salt thereof, e.g. 3,4-dihydro-7- hydroxy-6-(methoxymethoxy)-5-(3-pyridylmethyl-2H-1-benzopyrane. The compound of the formula I [where, R<1> is of formula X (R<1a>) and R<2> is of formula XI (R<2a>)] (a compound of formula V) can be obtained by the following process: a compound of formula II is put to addition reaction, acetylation, catalytic reduction, etc., to produce a compound of formula III, which is then put to de-t-butyldimethylsilylation and oxidation with MnO2 into a compound of formula IV, which is, in turn, subjected to Wittig-Honer reaction.

Description

【発明の詳細な説明】Detailed Description of the Invention

【0001】[0001]

【産業上の利用分野】本発明は、医薬として優れた作用
を有するクロマン誘導体若しくはジヒドロベンゾフラン
誘導体に関する。
TECHNICAL FIELD The present invention relates to a chroman derivative or a dihydrobenzofuran derivative having an excellent action as a medicine.

【0002】[0002]

【発明の背景及び先行技術】近年、気管支喘息は著しい
増大傾向を示しており、抗喘息薬としてのアプローチも
キサンチン製剤やβ刺激剤などの気管支拡張剤、ヒスタ
ミンに代表されるメディエーターの遊離あるいは産生抑
制剤など多面的な試みがなされている。特に近年、喘息
におけるメディエーターの役割が急速に解明され、ヒス
タミンに加えロイコトリエン(以下LTsと略す)、P
AF、トロンボキサン(以下TXsと略す)などが知ら
れるようになり、ことにアラキドン酸カスケード系代謝
物であるLTs、TXsについてはあらゆる方向から研
究されているようになった。これらメディエーターは複
雑に相互作用することも知られており、喘息の多様な病
態を考えた場合、単一のメディエーターの阻害剤だけで
は有効率、改善度の向上に限界があることが容易に考え
られる。
Background of the Invention and Prior Art In recent years, bronchial asthma has shown a marked increase tendency, and an approach as an anti-asthma drug is also a bronchodilator such as a xanthine preparation or a β-stimulant, and release or production of a mediator represented by histamine. Multifaceted trials such as inhibitors have been made. Particularly in recent years, the role of mediators in asthma has been rapidly elucidated, and in addition to histamine, leukotrienes (hereinafter abbreviated as LTs), P
AF, thromboxane (hereinafter abbreviated as TXs), etc. have come to be known, and in particular, arachidonic acid cascade metabolites LTs and TXs have been studied from all directions. It is also known that these mediators interact in a complex manner, and when considering various pathological conditions of asthma, it is easy to conclude that there is a limit to the improvement of the efficacy rate and improvement rate with only a single mediator inhibitor. Be done.

【0003】また、LTs、TXsを研究するにつれ
て、肝疾患の発症及び進展にも関与することがわかって
きた。即ち、アルコール性肝炎や慢性肝炎患者の血中L
Ts、TXs濃度が健常人に比べ著しく上昇している、
培養細胞系でLTsが低酸素状態で肝障害をひきおこす
等の報告がされている。このように、LTs、TXsは
もちろん単独でも作用するが、相互に作用して疾患の発
症・進展に関与することも多く、これら両メディエータ
ーの産生を抑制する薬剤が渇望されているが、未だ市場
に現れてないのが実情である。
Also, as LTs and TXs have been studied, it has been found that they are involved in the onset and progression of liver diseases. That is, blood L in patients with alcoholic hepatitis and chronic hepatitis
Ts and TXs concentrations are significantly higher than those of healthy people,
It has been reported that LTs cause hepatic disorder in hypoxia in cultured cell lines. Thus, although LTs and TXs act not only by themselves, but they often interact with each other and are involved in the onset / progression of diseases, and a drug that suppresses the production of both mediators has been craved, but it is still in the market. The reality is that it doesn't appear.

【0004】以上のような状況に鑑み、本発明者等は、
ロイコトリエン産生抑制作用、トロンボキサン合成阻害
作用の2つの作用を兼ね備えている薬剤の探索研究に着
手した。その結果、下記に示すクロマン誘導体若しくは
ジヒドロベンゾフラン誘導体がこれら2つの作用を同時
にバランスよく持ち、しかも粘膜保護作用を持つことが
知られるプロスタグランジンE2 など、炎症の発生・進
展を阻止するアラキドン酸カスケード系代謝物の産生を
抑制しないということを見出し、本発明を完成した。
In view of the above situation, the present inventors have
We have started research on a drug that has both the leukotriene production inhibitory action and the thromboxane synthesis inhibitory action. As a result, the following chroman derivatives or dihydrobenzofuran derivatives have these two actions at the same time in a well-balanced manner, and are known to have a mucosal protective action, such as prostaglandin E 2 and the like. They have found that they do not suppress the production of cascade metabolites and completed the present invention.

【0005】[0005]

【発明の構成】本発明化合物は、次の一般式(I)で表
されるクロマン誘導体若しくはジヒドロベンゾフラン誘
導体及びそれらの薬理学的に許容できる塩である。
The compound of the present invention is a chroman derivative or dihydrobenzofuran derivative represented by the following general formula (I) and a pharmacologically acceptable salt thereof.

【0006】[0006]

【化6】 [Chemical 6]

【0007】{式中、 R1,R2及びR3は同一又は相異なる
水素原子、水酸基又は式
[Wherein R 1 , R 2 and R 3 are the same or different hydrogen atoms, hydroxyl groups or formulas

【0008】[0008]

【化7】 [Chemical 7]

【0009】〔式中 Aは水素原子又はヘテロアリールア
ルキル基を意味する。 Bは水素原子又はカルボキシル基
又は保護されたカルボキシル基を意味する。 Yは式
[In the formula, A means a hydrogen atom or a heteroarylalkyl group. B means a hydrogen atom, a carboxyl group or a protected carboxyl group. Y is an expression

【0010】[0010]

【化8】 [Chemical 8]

【0011】(式中 pは0又は1〜6の整数を意味す
る。)で示される基、式
(Wherein p represents 0 or an integer of 1 to 6), a group represented by the formula:

【0012】[0012]

【化9】 [Chemical 9]

【0013】(式中 qは0又は1〜6の整数を意味す
る。)で示される基、又は式
(Wherein q represents 0 or an integer of 1 to 6), or a group represented by the formula:

【0014】[0014]

【化10】 [Chemical 10]

【0015】で示される基を意味する。〕で示される基
を意味する。Xは水酸基又は保護された水酸基を意味す
る。nは2又は3の整数を意味する。} 一般式(I)において、 Xにみられる保護された水酸基
として例を挙げると、炭素数1〜6の直鎖もしくは分枝
状のアルキル基、例えばメチル基、エチル基、プロピル
基、イソプロピル基、ブチル基、イソブチル基、 sec−
ブチル基、tert−ブチル基、ペンチル基(アミル基)、
イソペンチル基、ネオペンチル基、1−メチルブチル
基、1,2−ジメチルプロピル基、イソヘキシル基、2
−メチルペンチル基、1,2,2−トリメチルプロピル
基、1−エチル−2−メチルプロピル基などで保護され
た基、即ちアルコキシ基である場合、アセチル基、プロ
ピオニル基、ブチロイル基、ピバロイル基、ニコチノイ
ル基などのアシル基で保護された基、即ちエステルを形
成している場合などを挙げることができるが、要する
に、生体内で何らかの手段で分解されて水酸基となり得
るものであればよい。
Means a group represented by: ] It means the group shown by. X means a hydroxyl group or a protected hydroxyl group. n means an integer of 2 or 3. } In the general formula (I), examples of the protected hydroxyl group represented by X include a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group. , Butyl group, isobutyl group, sec-
Butyl group, tert-butyl group, pentyl group (amyl group),
Isopentyl group, neopentyl group, 1-methylbutyl group, 1,2-dimethylpropyl group, isohexyl group, 2
-A group protected with a methylpentyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-2-methylpropyl group or the like, that is, when it is an alkoxy group, an acetyl group, a propionyl group, a butyroyl group, a pivaloyl group, Examples thereof include a group protected by an acyl group such as a nicotinoyl group, that is, a case where an ester is formed. In short, any group that can be decomposed into a hydroxyl group by some means in the living body may be used.

【0016】Aの定義にみられるヘテロアリールアルキ
ル基においてヘテロアリールとは、窒素原子、硫黄原子
又は酸素原子を1〜2個含む5〜6員環を意味し、例を
挙げればピリジル、イミダゾリル、フリル、チエニル、
ピラジルなどを挙げることができる。また、この場合の
アルキル基、即ちアルキレン鎖の炭素数は1〜10であ
り、好ましくは2〜8、更に好ましくは4〜6である。
The term "heteroaryl" in the heteroarylalkyl group in the definition of A means a 5- or 6-membered ring containing 1 to 2 nitrogen atoms, sulfur atoms or oxygen atoms, and examples thereof include pyridyl, imidazolyl, Ruffles, thienyl,
Examples thereof include pyrazyl. In this case, the alkyl group, that is, the alkylene chain has 1 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 4 to 6 carbon atoms.

【0017】Bの定義にみられる「保護されたカルボキ
シル基」において保護基とは、メチル、エチル、t−ブ
チルなどの低級アルキル基;p−メトキシベンジル、p
−ニトロベンジル、3,4−ジメトキシベンジル、ジフ
ェニルメチル、トリチル、フェネチルなどの置換基を有
していても良いフェニル基で置換された低級アルキル
基;2,2,2−トリクロロエチル、2−ヨードエチル
などのハロゲン化低級アルキル基;ピバロイルオキシメ
チル、アセトキシメチル、プロピオニルオキシメチル、
ブチリルオキシメチル、バレリルオキシメチル、1−ア
セトキシエチル、2−アセトキシエチル、1−ピバロイ
ルオキシエチル、2−ピバロイルオキシエチルなどの低
級アルカノイルオキシ低級アルキル基;パルミトイルオ
キシエチル、ヘプタデカノイルオキシメチル、1−パル
ミトイルオキシエチルなどの高級アルカノイルオキシ低
級アルキル基;メトキシカルボニルオキシメチル、1−
ブトキカルボニルオキシエチル、1−(イソプロポキシ
カルボニルオキシ)エチル等の低級アルコキシカルボニ
ルオキシ低級アルキル基;カルボキシメチル、2−カル
ボキシエチル等のカルボキシ低級アルキル基;3−フタ
リジル等の複素環基;4−グリシルオキシベンゾイルオ
キシメチル、4−〔N−(t−ブトキシカルボニル)グ
リシルオキシ〕ベンゾイルオキシメチル等の置換基を有
していても良いベンゾイルオキシ低級アルキル基;(5
−メチル−2−オキソ−1,3−ジオキソレン−4−イ
ル)メチル等の(置換ジオキソレン)低級アルキル基;
1−シクロヘキシルアセチルオキシエチル等のシクロア
ルキル置換低級アルカノイルオキシ低級アルキル基、1
−シクロヘキシルオキシカルボニルオキシエチル等のシ
クロアルキルオキシカルボニルオキシ低級アルキル基な
どが挙げられる。更に、種々の酸アミドとなっていても
良い。要するに、生体内で何らかの手段で分解されて、
カルボン酸となり得る保護基であればいかなる基でも良
い。
In the "protected carboxyl group" in the definition of B, the protecting group means a lower alkyl group such as methyl, ethyl, t-butyl; p-methoxybenzyl, p.
-Lower alkyl group substituted with a phenyl group which may have a substituent such as nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; 2,2,2-trichloroethyl, 2-iodoethyl Halogenated lower alkyl groups such as; pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,
Lower alkanoyloxy lower alkyl groups such as butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl, 2-pivaloyloxyethyl; palmitoyloxyethyl, heptadeca Higher alkanoyloxy lower alkyl groups such as noyloxymethyl, 1-palmitoyloxyethyl; methoxycarbonyloxymethyl, 1-
Lower alkoxycarbonyloxy lower alkyl groups such as butoxycarbonyloxyethyl and 1- (isopropoxycarbonyloxy) ethyl; carboxy lower alkyl groups such as carboxymethyl and 2-carboxyethyl; heterocyclic groups such as 3-phthalidyl; 4- Benzoyloxy lower alkyl group optionally having substituents such as glycyloxybenzoyloxymethyl, 4- [N- (t-butoxycarbonyl) glycyloxy] benzoyloxymethyl; (5
A (substituted dioxolene) lower alkyl group such as -methyl-2-oxo-1,3-dioxolen-4-yl) methyl;
Cycloalkyl-substituted lower alkanoyloxy lower alkyl groups such as 1-cyclohexylacetyloxyethyl, 1
And cycloalkyloxycarbonyloxy lower alkyl groups such as cyclohexyloxycarbonyloxyethyl and the like. Further, various acid amides may be used. In short, it is decomposed by some means in vivo,
Any protective group may be used as long as it can be a carboxylic acid.

【0018】pは0又は1〜6の整数を意味する。qは
0又は1〜6の整数を意味する。nは2又は3の整数を
意味する。
P means 0 or an integer of 1 to 6. q means 0 or an integer of 1 to 6. n means an integer of 2 or 3.

【0019】薬理学的に許容できる塩とは、塩酸塩、臭
化水素酸塩、硫酸塩、燐酸塩などの無機酸塩、例えば酢
酸塩、マレイン酸塩、酒石酸塩、メタンスルホン酸塩、
ベンゼンスルホン酸塩、トルエンスルホン酸塩などの有
機酸塩、又は例えばアルギニン、アスパラギン酸、グル
タミン酸などのアミノ酸との塩などを挙げることができ
る。
The pharmacologically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, such as acetate, maleate, tartrate and methanesulfonate.
Examples thereof include organic acid salts such as benzene sulfonate and toluene sulfonate, and salts with amino acids such as arginine, aspartic acid and glutamic acid.

【0020】更に化合物によっては、Na、K、Ca、
Mgなどの金属塩をとることがあり、本発明の薬理学的
に許容できる塩に包含される。また、本発明化合物は、
例えばその化学構造から明らかな如く、幾何異性体(シ
ス体、トランス体)が存在しうるが、いかなる異性体も
本発明の範囲に包含されることは言うまでもない。
Further, depending on the compound, Na, K, Ca,
It may take a metal salt such as Mg and is included in the pharmacologically acceptable salt of the present invention. Further, the compound of the present invention is
For example, as is clear from its chemical structure, geometric isomers (cis isomer, trans isomer) may exist, but it goes without saying that any isomer is included in the scope of the present invention.

【0021】以下に本発明化合物の代表的な製造方法を
掲げる。製造方法1 一般式(I)において、R1が式
Typical methods for producing the compound of the present invention are listed below. Production Method 1 In the general formula (I), R 1 is a formula

【0022】[0022]

【化11】 [Chemical 11]

【0023】(式中 A,B,pは前記の意味を有する)で示
される基であり、R2が式
(Wherein A, B and p have the above-mentioned meanings), R 2 is a group represented by the formula

【0024】[0024]

【化12】 [Chemical formula 12]

【0025】(式中 A,Bは前記の意味を有する)で示さ
れる基である時、以下の方法で製造することができる。
When the group is represented by (wherein A and B have the above meanings), they can be produced by the following method.

【0026】[0026]

【化13】 [Chemical 13]

【0027】〔一連の式中、R3,X,nは前記の意味を有す
る。R1a は式
[Wherein R 3 , X, and n have the above-mentioned meanings. R 1a is the formula

【0028】[0028]

【化14】 [Chemical 14]

【0029】(式中 A,B,pは前記の意味を有する)で示
される基を意味する。R2a は式
(Wherein A, B and p have the above-mentioned meanings). R 2a is the formula

【0030】[0030]

【化15】 [Chemical 15]

【0031】(式中 A,Bは前記の意味を有する)で示さ
れる基を意味する。〕即ち、第1工程で化合物(II)に通
常の方法で付加反応、アセチル化、接触還元などを行い
化合物(III) を得、得られた化合物(III) を第2工程で
脱tert−ブチルジメチルシリル化、次いでMnO2酸化する
ことによって化合物(IV)を得、更にウィティッヒ−ホー
ナー反応を行って、目的化合物である一般式(V)で示
される物質を得る方法である。尚、上記一連の式ではR1
が式
(In the formula, A and B have the above-mentioned meanings). That is, in the first step, the compound (II) is subjected to an addition reaction, acetylation, catalytic reduction, etc. by a conventional method to obtain a compound (III), and the obtained compound (III) is detert-butylated in the second step. In this method, the compound (IV) is obtained by dimethylsilylation and then MnO 2 oxidation, and the Wittig-Horner reaction is further carried out to obtain the target compound represented by the general formula (V). In the above series of equations, R 1
Is the expression

【0032】[0032]

【化16】 [Chemical 16]

【0033】(式中 A,B,pは前記の意味を有する)で示
される基であり、R2が式
(Wherein A, B and p have the above-mentioned meanings), R 2 is a group represented by the formula

【0034】[0034]

【化17】 [Chemical 17]

【0035】(式中 A,Bは前記の意味を有する)で示さ
れる基の場合を示したが、実際にはその他の位置に上記
置換基が結合している場合も、上記の方法に準じて製造
することができる。
Although the case where the group represented by the formula (A and B have the above-mentioned meanings) is shown, the case where the above-mentioned substituents are actually bonded to other positions is also the same as the above-mentioned method. Can be manufactured.

【0036】製造方法2 一般式(I)において、R1が式 Production Method 2 In the general formula (I), R 1 is a formula

【0037】[0037]

【化18】 [Chemical 18]

【0038】(式中 A,B,qは前記の意味を有する)で示
される基であり、R2が式
(Wherein A, B and q have the above-mentioned meanings), R 2 is a group represented by the formula

【0039】[0039]

【化19】 [Chemical 19]

【0040】(式中 A,Bは前記の意味を有する)で示さ
れる基である時、以下の方法で製造することができる。
When the group is represented by (wherein A and B have the above meanings), they can be produced by the following method.

【0041】[0041]

【化20】 [Chemical 20]

【0042】[0042]

【化21】 [Chemical 21]

【0043】〔一連の式中、R3,X,nは前記の意味を有す
る。R1b は式
[In the series of formulas, R 3 , X, and n have the above-mentioned meanings. R 1b is the formula

【0044】[0044]

【化22】 [Chemical formula 22]

【0045】(式中 A,B,qは前記の意味を有する)で示
される基であり、R2b は式
(Wherein A, B and q have the above-mentioned meanings), R 2b is a group represented by the formula:

【0046】[0046]

【化23】 [Chemical formula 23]

【0047】(式中 A,Bは前記の意味を有する)で示さ
れる基を意味する。〕即ち、第1工程において通常の方
法で化合物(II)をホルミル化し、得られた化合物(VI)に
第2工程においてバイヤー・ビリガー反応、ホルメート
の加水分解、次いでアルキル化反応を行うことにより化
合物(VII) を得、更に第3工程で脱tert−ブチルジメチ
ルシリル化、酸化を行い化合物(VIII)を得、第4工程で
ウィティッヒ−ホーナー反応又はウィティッヒ反応を行
うことにより、目的化合物(IX)を得る方法である。尚、
上記一連の式では、R1が式
(Wherein A and B have the above-mentioned meanings). That is, the compound (II) is formylated by a usual method in the first step, and the obtained compound (VI) is subjected to the Bayer-Villiger reaction, the formate hydrolysis and the alkylation reaction in the second step. Compound (VIII) is obtained by detert-butyldimethylsilylation and oxidation in the third step, and then the Wittig-Horner reaction or Wittig reaction is performed in the fourth step to obtain the target compound (IX). Is a way to get. still,
In the above series of equations, R 1 is

【0048】[0048]

【化24】 [Chemical formula 24]

【0049】(式中 A,B,qは前記の意味を有する)で示
される基であり、R2が式
(Wherein A, B and q have the above-mentioned meanings), R 2 is a group represented by the formula

【0050】[0050]

【化25】 [Chemical 25]

【0051】(式中 A,Bは前記の意味を有する)で示さ
れる基である時の製造方法を示したが、その他の位置に
上記置換基が結合している場合も、上記の方法に準じて
製造することができる。
The production method when the group is represented by the formula (A and B have the above meanings) is shown. However, when the above substituents are bonded to other positions, the above method is also applicable. It can be manufactured in a similar manner.

【0052】製造方法3 一般式(I)において、 Xが水酸基であるものは以下の
方法で脱保護して得ることができる。
Production Method 3 In the general formula (I), those in which X is a hydroxyl group can be obtained by deprotection by the following method.

【0053】[0053]

【化26】 [Chemical formula 26]

【0054】(一連の式中、R1,R2,R3,nは前記の意味を
有する。X'は水酸基の保護基を意味する。)即ち、通常
用いられる方法で化合物(X)の保護基を除いて目的化
合物(XI)を得る方法である。
(In the series of formulas, R 1 , R 2 , R 3 and n have the above-mentioned meanings. X'means a hydroxyl-protecting group.) That is, the compound (X) can be prepared by a commonly used method. This is a method of obtaining the target compound (XI) by removing the protecting group.

【0055】製造方法4 一般式(I)において、R2が式 Production Method 4 In the general formula (I), R 2 is of the formula

【0056】[0056]

【化27】 [Chemical 27]

【0057】(式中 A,Bは前記の意味を有する)で示さ
れる基の時、以下の方法でも製造することができる。
When the group is represented by the formula (A and B have the above-mentioned meanings), they can also be produced by the following method.

【0058】[0058]

【化28】 [Chemical 28]

【0059】(一連の式中、R1,R3,A,B,n,X は前記の意
味を有する。) 即ち、通常の方法で化合物(XII) に接触水素添加を行
い、目的化合物(XIII)を得る方法である。
(In the series of formulas, R 1 , R 3 , A, B, n and X have the above-mentioned meanings.) That is, the compound (XII) is subjected to catalytic hydrogenation in the usual manner to obtain the target compound ( XIII) is obtained.

【0060】出発物質の製造方法 上述した製造方法の出発物質の代表的製造方法を以下に
示す。製造方法1及び2の出発物質となった一般式(II)
で表される化合物は、以下の方法で製造することができ
る。
[0060] shown below a representative method for producing a starting material for the production method described above manufacturing method of the starting materials. The general formula (II) used as the starting material in the production methods 1 and 2
The compound represented by can be produced by the following method.

【0061】[0061]

【化29】 [Chemical 29]

【0062】(一連の式中、R3,X,X',n は前記の意味を
有する。) 即ち、第1工程で通常の方法で化合物(XIV) をブロム化
して化合物(XV)を得、第2工程で通常の方法により化合
物(XV)の水酸基を保護して化合物(XVI) を得、第3工程
で通常の方法により化合物(XVI) の還元を行い、次いで
tert−ブチルジメチルシリル化を行って化合物(II)を
得る方法である。
(In the series of formulas, R 3 , X, X ', n has the above-mentioned meanings.) That is, in the first step, the compound (XIV) is brominated by a conventional method to obtain the compound (XV). In the second step, the hydroxyl group of the compound (XV) is protected by a conventional method to obtain a compound (XVI), and in the third step, the compound (XVI) is reduced by a conventional method.
In this method, compound (II) is obtained by carrying out tert-butyldimethylsilylation.

【0063】tert−ブチルジメチルシリル化において、
好ましい反応溶媒としてはN,N−ジメチルホルムアミ
ドなどを挙げることができる。好ましい反応温度は約0
℃から25℃である。水酸基に保護基を結合する反応は、
通常行われるあらゆる方法が行い得るが、水素化ナトリ
ウム存在下クロロメチルメチルエーテルと反応させるな
どの方法が好ましい。この場合、反応溶媒はN,N−ジ
メチルホルムアミドなどが好ましい。また、反応温度は
約0℃から10℃が好ましい。
In tert-butyldimethylsilylation,
Examples of preferable reaction solvent include N, N-dimethylformamide. The preferred reaction temperature is about 0.
℃ to 25 ℃. The reaction of attaching a protective group to a hydroxyl group is
Although any commonly used method can be performed, a method such as reaction with chloromethyl methyl ether in the presence of sodium hydride is preferable. In this case, the reaction solvent is preferably N, N-dimethylformamide or the like. The reaction temperature is preferably about 0 ° C to 10 ° C.

【0064】第3工程の還元は通常行われるあらゆる方
法で行うことができるが、好ましくは水素化ホウ素ナト
リウム還元を挙げることができる。この場合、反応溶媒
はエタノールなどが好ましい。また、反応は室温で十分
進行しうる。また、還元して得られた化合物をN,N−
ジメチルホルムアミドなどに溶解させ、tert−ブチルジ
メチルシリルクロライドと反応させることにより、目的
とする原料化合物(II)を得ることができる。尚、ブロム
基、t−ブチルジメチルシリルオキシメチル基が上記の
位置とは異なる化合物も、上記の方法に準じて製造する
ことができる。
The reduction in the third step can be carried out by any conventional method, but sodium borohydride reduction is preferred. In this case, the reaction solvent is preferably ethanol or the like. Further, the reaction can proceed sufficiently at room temperature. In addition, the compound obtained by reduction is treated with N, N-
The target raw material compound (II) can be obtained by dissolving it in dimethylformamide or the like and reacting it with tert-butyldimethylsilyl chloride. A compound having a bromine group or a t-butyldimethylsilyloxymethyl group different from the above position can also be produced according to the above method.

【0065】[0065]

【発明の効果】次に本発明化合物の効果を詳述するため
に実験例を掲げる。実験例 ラット腹腔浸潤細胞からのロイコトリエンB4 (LTB
4)、トロンボキサンB2(TxB2)産生抑制作用 <実験方法>体重 150〜 200gのフィッシャー系雄性ラ
ットの腹腔内に6% w/vグリコーゲン(Type II from Oy
ster, Sigma)生理食塩水溶液を10ml注入する。20〜24時
間後、このラットより腹腔浸出細胞を回収し、洗浄後ハ
ンクの平衡塩溶液(HBSS)に5×106/mlの濃度で懸
濁する。所定の濃度に希釈した被験薬を10μl/wellで分
注しておいた96穴カルチャープレート(Costar
(登録商標))中にこの細胞懸濁液を 100μl/well分注
する。このプレートを5分間37℃でインキュベートした
後、A−23187(カルシウムイオノフォア,CAL
BIOCHEM(登録商標))を最終2μg/mlとなるよ
うに添加する。更に10分間37℃で反応させた後、プレー
トを氷上に移し、BW755C溶液を最終 100μMとな
るように加える。このプレートを15000rpm×10分間遠心
分離させた後、上清を回収し、上清中のLTB4 、Tx
2 をケイマン社製EIAキットを用いた酸素免疫測定
法にて測定した。
[Embodiment of the Invention] Next, experimental examples will be given in order to describe the effect of the compound of the present invention in detail. Experimental example Leukotriene B 4 (LTB from rat peritoneal infiltrating cells
4 ), thromboxane B 2 (TxB 2 ) production inhibitory action <Experimental method> 6% w / v glycogen (Type II from Oy) was intraperitoneally administered to Fischer male rats weighing 150 to 200 g.
(ster, Sigma) 10 ml of physiological saline solution is injected. After 20 to 24 hours, peritoneal exudate cells are collected from the rat, washed, and then suspended in Hank's balanced salt solution (HBSS) at a concentration of 5 × 10 6 / ml. 96-well culture plate (Costar) in which the test drug diluted to the specified concentration was dispensed at 10 μl / well
(Registered trademark)), 100 μl / well of this cell suspension is dispensed. After incubating the plate for 5 minutes at 37 ° C, A-23187 (calcium ionophore, CAL
BIOCHEM®) is added to a final 2 μg / ml. After reacting for another 10 minutes at 37 ° C., the plate is transferred to ice and BW755C solution is added to a final concentration of 100 μM. After centrifuging this plate at 15000 rpm for 10 minutes, the supernatant was recovered and LTB 4 , Tx in the supernatant was collected.
B 2 was measured by an oxygen immunoassay using an EIA kit manufactured by Cayman.

【0066】<結果>各化合物(後述の実施例における
実施例No. で示した)のロイコトリエンB4、トロンボ
キサンB2 の産生抑制作用をIC50で次の表1に示し
た。
<Results> The inhibitory action on leukotriene B 4 and thromboxane B 2 production of each compound (shown in Example No. in Examples described later) is shown in the following Table 1 by IC 50 .

【0067】[0067]

【表1】 [Table 1]

【0068】上記薬理実験例から本発明化合物はロイコ
トリエン(LTs)産生抑制作用及びトロンボキサン
(TXs)合成阻害作用のいずれの作用をも有するとい
うことが明らかである。よって本発明化合物は、LTs
産生抑制作用又はTXs合成阻害作用が有効な疾患の予
防・治療剤として有効である。
From the above-mentioned pharmacological experimental examples, it is clear that the compound of the present invention has both the leukotriene (LTs) production inhibitory action and the thromboxane (TXs) synthesis inhibitory action. Therefore, the compound of the present invention is
It is effective as a prophylactic / therapeutic agent for diseases for which production suppression or TXs synthesis inhibition is effective.

【0069】これらの作用が有効な疾患の例を挙げれ
ば、喘息、各種肝疾患(慢性肝炎、急性肝炎、薬物中毒
性肝障害、ウイルス性肝炎、アルコール性肝炎、黄疸、
肝硬変など)、虚血性心疾患(心筋梗塞、狭心症な
ど)、虚血性脳疾患(脳塞栓症、脳血栓症など)、各種
腎疾患(腎不全、ネフローゼ、腎炎など)が挙げられ
る。更に本発明化合物は安全性が高く、この意味でも本
発明の価値は高い。
Examples of diseases for which these effects are effective include asthma, various liver diseases (chronic hepatitis, acute hepatitis, drug-toxic liver injury, viral hepatitis, alcoholic hepatitis, jaundice,
Cirrhosis), ischemic heart disease (myocardial infarction, angina, etc.), ischemic brain disease (cerebral embolism, cerebral thrombosis, etc.), and various renal diseases (renal failure, nephrosis, nephritis, etc.). Furthermore, the compound of the present invention is highly safe, and in this sense, the value of the present invention is high.

【0070】本発明化合物をこれらの疾患の治療・予防
剤として投与する場合、錠剤、散剤、顆粒剤、カプセル
剤、シロップ剤、吸入剤として投与する。投与量は症状
の程度、年齢、疾患の種類などにより著しく異なるが、
通常成人1日当たり約0.1mg〜1,000mg 、
好ましくは約1mg〜500mg を1日1〜数回にわけて投与
する。注射の場合は、通常1μg/kg〜 3,000μg/kgであ
り、好ましくは約3μg/kg〜1,000μg/kgである。
When the compound of the present invention is administered as a therapeutic / preventive agent for these diseases, it is administered as tablets, powders, granules, capsules, syrups and inhalants. The dose varies significantly depending on the degree of symptoms, age, type of disease, etc.
Usually about 0.1 mg to 1,000 mg per day for adults,
Preferably, about 1 mg to 500 mg is administered once or several times a day. In the case of injection, it is usually 1 μg / kg to 3,000 μg / kg, preferably about 3 μg / kg to 1,000 μg / kg.

【0071】製剤化の際は通常の製剤担体を用い、常法
により製造する。即ち、経口用固形製剤を調製する場合
は、主薬に賦形剤、更に必要に応じて結合剤、崩壊剤、
滑沢剤、着色剤、矯味矯臭剤などを加えた後、常法によ
り錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤などとす
る。
In formulating, a usual pharmaceutical carrier is used, and it is manufactured by a conventional method. That is, when preparing a solid preparation for oral use, the main ingredient is an excipient, and if necessary, a binder, a disintegrant,
After adding a lubricant, a coloring agent, a flavoring agent and the like, tablets, coated tablets, granules, powders, capsules and the like are prepared by a conventional method.

【0072】賦形剤としては、例えば乳糖、コーンスタ
ーチ、白糖、ブドウ糖、ソルビット、結晶セルロース、
二酸化ケイ素などが、結合剤としては、例えばポリビニ
ルアルコール、ポリビニルエーテル、エチルセルロー
ス、メチルセルロース、アラビアゴム、トラガント、ゼ
ラチン、シェラック、ヒドロキシプロピルセルロース、
ヒドロキシプロピルメチルセルロース、クエン酸カルシ
ウム、デキストリン、ペクチン等が、滑沢剤としては、
例えばステアリン酸マグネシウム、タルク、ポリエチレ
ングリコール、シリカ、硬化植物油等が、着色剤として
は医薬品に添加することが許可されているものが、矯味
矯臭剤としては、ココア末、ハッカ脳、芳香酸、ハッカ
油、龍脳、桂皮末等が用いられる。これらの錠剤、顆粒
剤には糖衣、ゼラチン衣、その他必要により適宜コーテ
ィングすることは勿論差支えない。注射剤を調製する場
合には、主薬に必要によりpH調整剤、緩衝剤、安定化
剤、可溶化剤などを添加し、常法により皮下、筋肉内、
静脈内用注射剤とする。
As the excipient, for example, lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose,
Silicon dioxide or the like, as the binder, for example, polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose,
Hydroxypropyl methylcellulose, calcium citrate, dextrin, pectin, etc. are lubricants.
For example, magnesium stearate, talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc. are permitted to be added to pharmaceuticals as coloring agents, but as flavoring agents, cocoa powder, peppermint, aromatic acid, peppermint Oil, Borneolum, cinnamon powder, etc. are used. Needless to say, these tablets and granules may be sugar-coated, gelatin-coated or any other suitable coating. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, a solubilizing agent, etc. are added to the main drug as necessary, and subcutaneous, intramuscular,
It will be an intravenous injection.

【0073】[0073]

【実施例】次に本発明の実施例を掲げるが、本発明がこ
れらのみに限定されることがないことはいうまでもな
い。また、本発明の目的物質を製造する際に用いられる
原料化合物の製造例も以下に示した。尚、例中のMeはメ
チル基、Etはエチル基を示す。
EXAMPLES Examples of the present invention will be given below, but it goes without saying that the present invention is not limited thereto. In addition, Production Examples of raw material compounds used in producing the target substance of the present invention are also shown below. In the examples, Me represents a methyl group and Et represents an ethyl group.

【0074】製造例1 3,4−ジヒドロ−6−(メトキシメトキシ)−2H−
1−ベンゾピラン−7−カルバルデヒド
Production Example 1 3,4-dihydro-6- (methoxymethoxy) -2H-
1-benzopyran-7-carbaldehyde

【0075】[0075]

【化30】 [Chemical 30]

【0076】3,4−ジヒドロ−6−ヒドロキシ−2H
−1−ベンゾピラン−7−カルバルデヒド12.7gをN,
N−ジメチルホルムアミド 100mlに溶かし、0℃に冷却
した。60%水素化ナトリウム 4.0gを10℃以下で加え
た。続けてクロロメチルメチルエーテル 6.9gを加え30
分間攪拌した。反応液を氷水に加え、酢酸エチルで抽出
した。有機層を飽和食塩水で洗浄した後、無水硫酸マグ
ネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲル
カラムクロマトグラフィー(30%酢酸エチル/ヘキサ
ン)にて精製すると、標記化合物 1.9gが黄色油状物と
して得られた。
3,4-dihydro-6-hydroxy-2H
-1-benzopyran-7-carbaldehyde 12.7 g was added to N,
It was dissolved in 100 ml of N-dimethylformamide and cooled to 0 ° C. 4.0 g of 60% sodium hydride was added below 10 ° C. Continuously add 6.9 g of chloromethyl methyl ether to 30
Stir for minutes. The reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give the title compound (1.9 g) as a yellow oil.

【0077】・ 1H−NMR(400MHz, CDCl3) δ ppm;
2.00(tt,J=6.0,6.0Hz,2H), 2.83(t,J=6.0Hz,2H), 3.52
(s,3H),4.16(t,J=6.0Hz,2H), 5.21(s,2H), 6.91(s,1H),
7.24(s,1H),10.38(s,1H)製造例2 7−ブロモ−3,4−ジヒドロ−5−メトキシ−6−
(メトキシメトキシ)−2H−1−ベンゾピラン
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
2.00 (tt, J = 6.0,6.0Hz, 2H), 2.83 (t, J = 6.0Hz, 2H), 3.52
(s, 3H), 4.16 (t, J = 6.0Hz, 2H), 5.21 (s, 2H), 6.91 (s, 1H),
7.24 (s, 1H), 10.38 (s, 1H) Production Example 2 7-Bromo-3,4-dihydro-5-methoxy-6-
(Methoxymethoxy) -2H-1-benzopyran

【0078】[0078]

【化31】 [Chemical 31]

【0079】(1) 7−ブロモ−3,4−ジヒドロ−6−
(メトキシメトキシ)−2H−1−ベンゾピラン−5−
カルバルデヒド1.37gをジクロロメタン50mlに溶かし、
80%m−クロロ過安息香酸1.28gを少量ずつ加えた。反
応液は穏やかに発熱還流した。そのまま加熱して30分間
還流した。反応液を氷冷し、飽和チオ硫酸ナトリウム水
溶液30mlを加えた。析出する不溶物を濾去し、ジクロロ
メタンで洗浄した。濾液を飽和炭酸水素ナトリウム水溶
液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥
し、溶媒を減圧下留去した。 (2) 得られた残渣 1.3gをエタノール30mlに溶かし、5
N水酸化ナトリウム水溶液を加え、30分間還流した。反
応液を冷却し、2N塩酸でpHを5に調整し、酢酸エチル
で抽出した。有機層を飽和食塩水で洗浄した後、無水硫
酸マグネシウムで乾燥し、減圧下濃縮した。 (3) 得られた残渣 1.2gをN,N−ジメチルホルムアミ
ド20mlに溶かし、0℃に冷却した。60%水素化ナトリウ
ム360mg を、10℃以下で加えた。室温で30分間攪拌した
後、ヨウ化メチル1.29gを加え、室温で1時間攪拌し
た。反応液を氷水に注ぎ、酢酸エチルで抽出した。有機
層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで
乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロ
マトグラフィー(10%酢酸エチル/ヘキサン)にて精製
すると、標記化合物 1.1gが淡黄色油状物として得られ
た。
(1) 7-Bromo-3,4-dihydro-6-
(Methoxymethoxy) -2H-1-benzopyran-5-
Dissolve 1.37 g carbaldehyde in 50 ml dichloromethane,
1.28 g of 80% m-chloroperbenzoic acid was added in small portions. The reaction solution was gently heated to reflux. It was heated as it was and refluxed for 30 minutes. The reaction mixture was ice-cooled, and 30 ml of saturated aqueous sodium thiosulfate solution was added. The precipitated insoluble material was filtered off and washed with dichloromethane. The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. (2) Dissolve 1.3 g of the obtained residue in 30 ml of ethanol,
An aqueous solution of sodium hydroxide N was added, and the mixture was refluxed for 30 minutes. The reaction solution was cooled, adjusted to pH 5 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. (3) 1.2 g of the obtained residue was dissolved in 20 ml of N, N-dimethylformamide and cooled to 0 ° C. 360 mg of 60% sodium hydride was added below 10 ° C. After stirring at room temperature for 30 minutes, 1.29 g of methyl iodide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate / hexane) to give 1.1 g of the title compound as a pale yellow oil.

【0080】・ 1H−NMR(400MHz, CDCl3) δ ppm;
1.94(tt,J=7.0,7.0Hz,2H), 2.68(t,J=7.0Hz,2H), 3.65
(s,3H),3.81(s,3H), 4.09(t,J=7.0Hz,2H), 5.06(s,2H),
6.80(s,1H)実施例1 3,4−ジヒドロ−7−ヒドロキシ−6−(メトキシメ
トキシ)−5−(3−ピリジルメチル)−2H−1−ベ
ンゾピラン
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.94 (tt, J = 7.0,7.0Hz, 2H), 2.68 (t, J = 7.0Hz, 2H), 3.65
(s, 3H), 3.81 (s, 3H), 4.09 (t, J = 7.0Hz, 2H), 5.06 (s, 2H),
6.80 (s, 1H) Example 1 3,4-dihydro-7-hydroxy-6- (methoxymeth)
Toxy) -5- (3-pyridylmethyl) -2H-1-be
Nzopyran

【0081】[0081]

【化32】 [Chemical 32]

【0082】(1) 5−ブロモ−3,4−ジヒドロ−6−
(メトキシメトキシ)−7−(フェニルメトキシ)−2
H−1−ベンゾピラン 1.3gを無水テトラヒドロフラン
30mlに溶かし、窒素気流下−70℃に冷却した。これに
1.6M n−ブチルリチウムヘキサン溶液 2.7mlを−65
℃以下で加え、その温度で30分間攪拌した。この中に、
3−ピリジンカルボキシアルデヒド 470mgを一気に加え
た。ゆっくりと室温に戻し、50mlの水を加え、酢酸エチ
ルで抽出し、有機層を飽和食塩水で洗浄した後、無水硫
酸マグネシウムで乾燥し、減圧下濃縮した。 (2) (1)で得られた残渣 2.0gをピリジン5mlに溶か
し、無水酢酸5mlを加え、室温で 2.5時間攪拌した。溶
媒を減圧下留去した。 (3) (2)で得られた残渣2gをエタノール 200mlに溶か
し、10%パラジウム炭素(50%含水品)1.3 gを加え、
6時間常温常圧で水素添加を行った。パラジウム炭素を
セライトを用いて濾去した後、溶媒を減圧下留去した。
析出した結晶をイソプロピルエーテル−エタノール(5
%)混合溶液で洗浄すると、標記化合物 800mgが白色結
晶として得られた。
(1) 5-Bromo-3,4-dihydro-6-
(Methoxymethoxy) -7- (phenylmethoxy) -2
1.3 g of H-1-benzopyran was added to anhydrous tetrahydrofuran
It was dissolved in 30 ml and cooled to -70 ° C under a nitrogen stream. to this
2.7M of 1.6M n-butyllithium hexane solution is -65
The mixture was added below ℃ and stirred at that temperature for 30 minutes. In this
470 mg of 3-pyridinecarboxaldehyde was added all at once. The temperature was slowly returned to room temperature, 50 ml of water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. (2) 2.0 g of the residue obtained in (1) was dissolved in 5 ml of pyridine, 5 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure. (3) Dissolve 2 g of the residue obtained in (2) in 200 ml of ethanol, add 1.3 g of 10% palladium-carbon (50% hydrous product),
Hydrogenation was carried out at room temperature and atmospheric pressure for 6 hours. The palladium carbon was filtered off using Celite, and the solvent was evaporated under reduced pressure.
The precipitated crystals were washed with isopropyl ether-ethanol (5
%) When washed with a mixed solution, 800 mg of the title compound was obtained as white crystals.

【0083】・ 1H−NMR(400MHz, CDCl3) δ ppm;
1.94(tt,J=7.0,7.0Hz,2H), 2.51(t,J=7.0Hz,2H), 3.58
(s,3H),3.95(s,2H), 4.07(t,J=7.0Hz,2H), 4.75(s,2H),
6.43(s,1H),7.18(dd,J=5.0,8.0Hz,1H), 7.34(dt,J=1.
5,8.0Hz,1H),8.41(dd,J=1.5,5.0Hz,1H), 8.44(d,J=1.5H
z,1H)実施例2 2,3−ジヒドロ−6−ヒドロキシ−5−(メトキシメ
トキシ)−4−(3−ピリジルメチル)ベンゾフラン
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.94 (tt, J = 7.0,7.0Hz, 2H), 2.51 (t, J = 7.0Hz, 2H), 3.58
(s, 3H), 3.95 (s, 2H), 4.07 (t, J = 7.0Hz, 2H), 4.75 (s, 2H),
6.43 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.34 (dt, J = 1.
5,8.0Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1H), 8.44 (d, J = 1.5H
z, 1H) Example 2 2,3-dihydro-6-hydroxy-5- (methoxymeth)
Toxy) -4- (3-pyridylmethyl) benzofuran

【0084】[0084]

【化33】 [Chemical 33]

【0085】4−ブロモ−2,3−ジヒドロ−5−(メ
トキシメトキシ)−6−(フェニルメトキシ)ベンゾフ
ランから、実施例1と同様の方法により標記化合物を白
色結晶として得た。
The title compound was obtained as white crystals from 4-bromo-2,3-dihydro-5- (methoxymethoxy) -6- (phenylmethoxy) benzofuran in the same manner as in Example 1.

【0086】・ 1H−NMR(400MHz, CDCl3) δ ppm;
2.98(t,J=8.5Hz,2H), 3.58(s,3H), 3.90(s,2H), 4.53
(t,J=8.5Hz,2H),4.71(s,2H), 6.40(s,1H), 7.19(dd,J=
5.0,8.0Hz,1H),7.41(dt,J=1.5,8.0Hz,1H), 8.44(dd,J=
1.5,5.0Hz,1H),8.48(d,J=1.5Hz,1H)実施例3 4−{〔3,4−ジヒドロ−6−(メトキシメトキシ)
−5−(3−ピリジルメチル)−2H−1−ベンゾピラ
ン−7−イル〕オキシ}酪酸エチル
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
2.98 (t, J = 8.5Hz, 2H), 3.58 (s, 3H), 3.90 (s, 2H), 4.53
(t, J = 8.5Hz, 2H), 4.71 (s, 2H), 6.40 (s, 1H), 7.19 (dd, J =
5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 8.44 (dd, J =
1.5,5.0Hz, 1H), 8.48 (d, J = 1.5Hz, 1H) Example 3 4-{[3,4-dihydro-6- (methoxymethoxy)
-5- (3-pyridylmethyl) -2H-1-benzopyra
Nethyl-7-yl] oxy} butyrate ethyl

【0087】[0087]

【化34】 [Chemical 34]

【0088】製造例2の(3) と同様の方法で、実施例1
で得られた3,4−ジヒドロ−7−ヒドロキシ−6−
(メトキシメトキシ)−5−(3−ピリジルメチル)−
2H−1−ベンゾピランを4−ブロモ酪酸エチルと反応
させることにより標題化合物を得た。
Example 1 was carried out in the same manner as in (3) of Production Example 2.
3,4-dihydro-7-hydroxy-6-obtained in
(Methoxymethoxy) -5- (3-pyridylmethyl)-
The title compound was obtained by reacting 2H-1-benzopyran with ethyl 4-bromobutyrate.

【0089】・ 1H−NMR(400MHz, CDCl3) δ ppm;
1.25(t,J=7.0Hz,2H), 1.89(tt,J=7.0,7.0Hz,2H),2.13(t
t,J=7.5,7.5Hz,2H), 2.44(t,J=7.5Hz,2H), 2.50(t,J=7.
0Hz,2H),3.97(t,J=7.5Hz,2H), 4.03(t,J=7.0Hz,2H), 4.
13(q,J=7.0Hz,2H),5.00(s,2H), 6.48(s,1H), 7.15(dd,J
=5.0,8.0Hz,1H),7.41(dt,J=1.5,8.0Hz,1H), 8.39(dd,J=
1.5,5.0Hz,1H),8.46(d,J=1.5Hz,1H)実施例4 (E)−3−〔3,4−ジヒドロ−6−(メトキシメト
キシ)−2H−1−ベンゾピラン−7−イル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.25 (t, J = 7.0Hz, 2H), 1.89 (tt, J = 7.0,7.0Hz, 2H), 2.13 (t
t, J = 7.5,7.5Hz, 2H), 2.44 (t, J = 7.5Hz, 2H), 2.50 (t, J = 7.
0Hz, 2H), 3.97 (t, J = 7.5Hz, 2H), 4.03 (t, J = 7.0Hz, 2H), 4.
13 (q, J = 7.0Hz, 2H), 5.00 (s, 2H), 6.48 (s, 1H), 7.15 (dd, J
= 5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 8.39 (dd, J =
1.5,5.0Hz, 1H), 8.46 (d, J = 1.5Hz, 1H) Example 4 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -2H-1-benzopyran-7-yl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0090】[0090]

【化35】 [Chemical 35]

【0091】60%水素化ナトリウム 340mgをN,N−ジ
メチルホルムアミド20mlに懸濁させた中に、2−ジエチ
ルホスホノ−7−(3−ピリジル)ヘプタン酸エチル
(ウィティッヒ−ホーナー試薬)3.4gを室温下滴下し、
20分間攪拌した。得られた透明溶液に製造例1で得られ
た3,4−ジヒドロ−6−(メトキシメトキシ)−2H
−1−ベンゾピラン−7−カルバルデヒド 1.9gのN,
N−ジメチルホルムアミド5ml溶液を滴下した後、室温
で2時間攪拌した。反応液を氷水 300mlに加え、酢酸エ
チルで2回抽出し、有機層を硫酸マグネシウムで乾燥し
た。溶媒を留去後、シリカゲルカラムクロマトグラフィ
ー(50%酢酸エチル/ヘキサン)にて精製し、標題化合
物 900mgを褐色油状物として得た。
While 340 mg of 60% sodium hydride was suspended in 20 ml of N, N-dimethylformamide, 3.4 g of ethyl 2-diethylphosphono-7- (3-pyridyl) heptanoate (Wittig-Horner reagent) was added. Drop at room temperature,
Stir for 20 minutes. 3,4-dihydro-6- (methoxymethoxy) -2H obtained in Production Example 1 was added to the obtained transparent solution.
-1-benzopyran-7-carbaldehyde 1.9 g N,
After a 5 ml solution of N-dimethylformamide was added dropwise, the mixture was stirred at room temperature for 2 hours. The reaction solution was added to 300 ml of ice water, extracted twice with ethyl acetate, and the organic layer was dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (50% ethyl acetate / hexane) to give the title compound (900 mg) as a brown oil.

【0092】・1H−NMR(400MHz, CDCl3) δ ppm;
1.33(t,J=7.0Hz,3H), 1.39(tt,J=7.5,7.5Hz,2H), 1.51
〜1.61(m,4H),1.98(tt,J=6.0,6.0Hz,2H), 2.46(t,J=7.5
Hz,2H), 2.58(t,J=7.5Hz,2H),2.76(t,J=6.0Hz,2H), 3.4
6(s,3H), 4.13(t,J=6.0Hz,2H),4.26(q,J=7.0Hz,2H), 5.
10(s,2H), 6.72(s,1H), 6.82(s,1H),7.19(dd,J=5.5,8.0
Hz,1H), 7.47(dt,J=1.5,8.0Hz,1H), 7.73(s,1H),8.41
(d,J=1.5Hz,1H), 8.44(dd,J=1.5,5.5Hz,1H)実施例5 (E)−3−〔2,3−ジヒドロ−5−(メトキシメト
キシ)−6−ベンゾフラニル〕−2−〔5−(3−ピリ
ジル)ペンチル〕アクリル酸エチル
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.33 (t, J = 7.0Hz, 3H), 1.39 (tt, J = 7.5,7.5Hz, 2H), 1.51
~ 1.61 (m, 4H), 1.98 (tt, J = 6.0,6.0Hz, 2H), 2.46 (t, J = 7.5
Hz, 2H), 2.58 (t, J = 7.5Hz, 2H), 2.76 (t, J = 6.0Hz, 2H), 3.4
6 (s, 3H), 4.13 (t, J = 6.0Hz, 2H), 4.26 (q, J = 7.0Hz, 2H), 5.
10 (s, 2H), 6.72 (s, 1H), 6.82 (s, 1H), 7.19 (dd, J = 5.5,8.0
Hz, 1H), 7.47 (dt, J = 1.5,8.0Hz, 1H), 7.73 (s, 1H), 8.41
(d, J = 1.5Hz, 1H), 8.44 (dd, J = 1.5,5.5Hz, 1H) Example 5 (E) -3- [2,3-dihydro-5- (methoxymeth)
Xy) -6-benzofuranyl] -2- [5- (3-pyri
Dill) pentyl] ethyl acrylate

【0093】[0093]

【化36】 [Chemical 36]

【0094】2,3−ジヒドロ−5−(メトキシメトキ
シ)−ベンゾフラン−6−カルバルデヒドから、実施例
4と同様の方法により標題化合物を得た。
The title compound was obtained in the same manner as in Example 4 from 2,3-dihydro-5- (methoxymethoxy) -benzofuran-6-carbaldehyde.

【0095】・1H−NMR(400MHz, CDCl3) δ ppm;
1.33(t,J=7.0Hz,3H), 1.35〜1.43(m,2H), 1.50〜1.63
(m,4H),1.70〜1.80(m,2H), 2.46(t,J=7.5Hz,2H), 2.56
(t,J=7.5Hz,2H),3.21(t,J=8.5Hz,2H), 3.48(s,3H), 4.2
5(q,J=7.0Hz,2H),4.54(t,J=8.5Hz,2H), 5.08(s,2H), 6.
68(s,1H), 7.03(s,1H),7.18(dd,J=5.0,8.0Hz,1H), 7.46
(dt,J=1.5,8.0Hz,1H), 7.73(s,1H),8.34(d,J=1.5Hz,1
H), 8.41(dd,J=1.5,5.0Hz,1H)実施例6 (E)−3−〔3,4−ジヒドロ−5−メトキシ−6−
(メトキシメトキシ)−2H−1−ベンゾピラン−7−
イル〕−2−〔5−(3−ピリジル)ペンチル〕アクリ
ル酸エチル
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.33 (t, J = 7.0Hz, 3H), 1.35 ~ 1.43 (m, 2H), 1.50 ~ 1.63
(m, 4H), 1.70 to 1.80 (m, 2H), 2.46 (t, J = 7.5Hz, 2H), 2.56
(t, J = 7.5Hz, 2H), 3.21 (t, J = 8.5Hz, 2H), 3.48 (s, 3H), 4.2
5 (q, J = 7.0Hz, 2H), 4.54 (t, J = 8.5Hz, 2H), 5.08 (s, 2H), 6.
68 (s, 1H), 7.03 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.46
(dt, J = 1.5,8.0Hz, 1H), 7.73 (s, 1H), 8.34 (d, J = 1.5Hz, 1
H), 8.41 (dd, J = 1.5,5.0Hz, 1H) Example 6 (E) -3- [3,4-dihydro-5-methoxy-6-
(Methoxymethoxy) -2H-1-benzopyran-7-
Il] -2- [5- (3-pyridyl) pentyl] acryl
Ethyl acetate

【0096】[0096]

【化37】 [Chemical 37]

【0097】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.31(t,J=7.0H
z,3H), 1.40(tt,J=7.5,7.5Hz,2H), 1.53〜1.65(m,4H),
1.96(tt,J=7.0,7.0Hz,2H), 2.46(t,J=7.5Hz,2H), 2.58
(t,J=7.5Hz,2H),2.73(t,J=7.0Hz,2H), 3.55(s,3H), 3.8
0(s,3H), 4.10(t,J=7.0Hz,2H),4.24(q,J=7.0Hz,2H), 4.
98(s,2H), 6.53(s,1H),7.18(dd,J=5.0,8.0Hz,1H), 7.46
(dt,J=1.5,8.0Hz,1H),8.40〜8.43(m,2H)実施例7 (E)−3−〔2,3−ジヒドロ−4−メトキシ−5−
(メトキシメトキシ)−6−ベンゾフラニル)〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
By a method similar to that in Example 4, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 1.31 (t, J = 7.0H
z, 3H), 1.40 (tt, J = 7.5,7.5Hz, 2H), 1.53 to 1.65 (m, 4H),
1.96 (tt, J = 7.0,7.0Hz, 2H), 2.46 (t, J = 7.5Hz, 2H), 2.58
(t, J = 7.5Hz, 2H), 2.73 (t, J = 7.0Hz, 2H), 3.55 (s, 3H), 3.8
0 (s, 3H), 4.10 (t, J = 7.0Hz, 2H), 4.24 (q, J = 7.0Hz, 2H), 4.
98 (s, 2H), 6.53 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.46
(dt, J = 1.5,8.0Hz, 1H), 8.40-8.43 (m, 2H) Example 7 (E) -3- [2,3-dihydro-4-methoxy-5-
(Methoxymethoxy) -6-benzofuranyl)]-2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0098】[0098]

【化38】 [Chemical 38]

【0099】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.33(t,J=7.0H
z,3H), 1.36〜1.41(m,2H), 2.26〜1.62(m,4H),2.45(t,J
=7.5Hz,2H), 2.56(t,J=7.5Hz,2H), 3.29(t,J=8.5Hz,2
H),3.54(s,3H), 3.89(s,3H), 4.24(q,J=7.0Hz,2H), 4.5
6(t,J=8.5Hz,2H),4.96(s,2H), 6.43(s,1H), 7.20(dd,J=
5.0,8.0Hz,1H),7.46(dt,J=1.5,8.0Hz,1H), 7.77(s,1H),
8.41(d,J=1.5Hz,1H),8.44(dd,J=1.5,5.0Hz,1H)実施例8 (E)−3−〔2,3−ジヒドロ−5−(メトキシメト
キシ)−4−メチル−6−ベンゾフラニル〕−2−〔5
−(3−ピリジル)ペンチル〕アクリル酸エチル
By a method similar to that in Example 4, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 1.33 (t, J = 7.0H
z, 3H), 1.36 ~ 1.41 (m, 2H), 2.26 ~ 1.62 (m, 4H), 2.45 (t, J
= 7.5Hz, 2H), 2.56 (t, J = 7.5Hz, 2H), 3.29 (t, J = 8.5Hz, 2
H), 3.54 (s, 3H), 3.89 (s, 3H), 4.24 (q, J = 7.0Hz, 2H), 4.5
6 (t, J = 8.5Hz, 2H), 4.96 (s, 2H), 6.43 (s, 1H), 7.20 (dd, J =
5.0,8.0Hz, 1H), 7.46 (dt, J = 1.5,8.0Hz, 1H), 7.77 (s, 1H),
8.41 (d, J = 1.5Hz, 1H), 8.44 (dd, J = 1.5,5.0Hz, 1H) Example 8 (E) -3- [2,3-dihydro-5- (methoxymeth)
Xy) -4-methyl-6-benzofuranyl] -2- [5
-(3-Pyridyl) pentyl] ethyl acrylate

【0100】[0100]

【化39】 [Chemical Formula 39]

【0101】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.32(t,J=7.0H
z,3H), 1.33〜1.60(m,6H), 2.21(s,3H),2.46(t,J=7.0H
z,2H), 2.57(t,J=7.0Hz,2H), 3.13(t,J=8.5Hz,2H),3.59
(s,3H), 4.25(q,J=7.0Hz,2H), 4.59(t,J=8.5Hz,2H), 4.
84(s,2H),6.54(s,1H), 7.19(dd,J=5.0,8.0Hz,1H), 7.46
(dt,J=1.5,8.0Hz,1H),7.75(s,1H), 8.40(d,J=1.5Hz,1
H), 8.41(dd,J=1.5,5.0Hz,1H)実施例9 (E)−3−〔2,3−ジヒドロ−4−メトキシ−5−
(メトキシメトキシ)−7−メチル−6−ベンゾフラニ
ル〕−2−〔5−(3−ピリジル)−ペンチル〕アクリ
ル酸エチル
By a method similar to that in Example 4, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 1.32 (t, J = 7.0H
z, 3H), 1.33 to 1.60 (m, 6H), 2.21 (s, 3H), 2.46 (t, J = 7.0H
z, 2H), 2.57 (t, J = 7.0Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.59
(s, 3H), 4.25 (q, J = 7.0Hz, 2H), 4.59 (t, J = 8.5Hz, 2H), 4.
84 (s, 2H), 6.54 (s, 1H), 7.19 (dd, J = 5.0,8.0Hz, 1H), 7.46
(dt, J = 1.5,8.0Hz, 1H), 7.75 (s, 1H), 8.40 (d, J = 1.5Hz, 1
H), 8.41 (dd, J = 1.5,5.0Hz, 1H) Example 9 (E) -3- [2,3-dihydro-4-methoxy-5-
(Methoxymethoxy) -7-methyl-6-benzofurani
L] -2- [5- (3-pyridyl) -pentyl] acryl
Ethyl acetate

【0102】[0102]

【化40】 [Chemical 40]

【0103】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.24(tt,J=7.
5,7.5Hz,2H), 1.32(t,J=7.0Hz,3H),1.41(tt,J=7.5,7.5H
z,2H), 1.47(tt,J=7.5,7.5Hz,2H), 1.98(s,3H),2.18(t,
J=7.5Hz,2H), 2.48(t,J=7.5Hz,2H), 3.27(t,J=8.5Hz,2
H),3.48(s,1H), 3.82(s,3H), 4.25(q,J=7.5Hz,2H), 4.5
5(t,J=8.5Hz,2H),4.88(s,2H), 7.16(dd,J=5.0,8.0Hz,1
H), 7.40(dt,J=1.5,8.0Hz,1H),7.45(s,1H), 8.35(d,J=
1.5Hz,1H), 8.41(dd,J=1.5,5.0Hz,1H)実施例10 (E)−3−〔2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−7−ベンゾフラニル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
By a method similar to that in Example 4, the title compound was obtained. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.24 (tt, J = 7.
5,7.5Hz, 2H), 1.32 (t, J = 7.0Hz, 3H), 1.41 (tt, J = 7.5,7.5H
z, 2H), 1.47 (tt, J = 7.5,7.5Hz, 2H), 1.98 (s, 3H), 2.18 (t,
J = 7.5Hz, 2H), 2.48 (t, J = 7.5Hz, 2H), 3.27 (t, J = 8.5Hz, 2
H), 3.48 (s, 1H), 3.82 (s, 3H), 4.25 (q, J = 7.5Hz, 2H), 4.5
5 (t, J = 8.5Hz, 2H), 4.88 (s, 2H), 7.16 (dd, J = 5.0,8.0Hz, 1
H), 7.40 (dt, J = 1.5,8.0Hz, 1H), 7.45 (s, 1H), 8.35 (d, J =
1.5Hz, 1H), 8.41 (dd, J = 1.5, 5.0Hz, 1H) Example 10 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0104】[0104]

【化41】 [Chemical 41]

【0105】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.25〜1.37(m,
5H), 1.48(tt,J=7.5,7.5Hz,2H),1.53(tt,J=7.5,7.5Hz,2
H), 2.31(t,J=7.5Hz,2H), 2.53(t,J=7.5Hz,2H),3.15(t,
J=8.5Hz,2H), 3.53(s,3H), 3.74(s,3H), 4.25(q,J=7Hz,
2H),4.51(t,J=8.5Hz,2H), 5.11(s,2H), 7.00(s,1H),7.1
8(dd,J=5.0,8.0Hz,1H), 7.41(dt,J=1.5,8.0Hz,1H), 7.4
4(s,1H),8.38(d,J=1.5Hz,1H), 8.41(dd,J=1.5,5.0Hz,1
H)実施例11 (Z)−3−〔2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−7−ベンゾフラニル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
By a method similar to that in Example 4, the title compound was obtained. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.25 to 1.37 (m,
5H), 1.48 (tt, J = 7.5,7.5Hz, 2H), 1.53 (tt, J = 7.5,7.5Hz, 2
H), 2.31 (t, J = 7.5Hz, 2H), 2.53 (t, J = 7.5Hz, 2H), 3.15 (t,
J = 8.5Hz, 2H), 3.53 (s, 3H), 3.74 (s, 3H), 4.25 (q, J = 7Hz,
2H), 4.51 (t, J = 8.5Hz, 2H), 5.11 (s, 2H), 7.00 (s, 1H), 7.1
8 (dd, J = 5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 7.4
4 (s, 1H), 8.38 (d, J = 1.5Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1
H) Example 11 (Z) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0106】[0106]

【化42】 [Chemical 42]

【0107】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.09(t,J=7.0H
z,3H), 1.42(tt,J=7.0,7.0Hz,2H),1.57(tt,J=7.0,7.0H
z,2H), 1.66(tt,J=7.0,7.0Hz,2H),2.46(t,J=7.0Hz,2H),
2.61(t,J=7.0Hz,2H), 3.13(t,J=8.5Hz,2H),3.53(s,3
H), 3.71(s,3H), 4.13(q,J=7.0Hz,2H), 4.51(t,J=8.5H
z,2H),5.10(s,2H), 6.56(s,1H), 6.93(s,1H), 7.19(dd,
J=5.0,8.0Hz,1H),7.49(dt,J=1.5,8.0Hz,1H), 8.43(dd,J
=1.5,5.0Hz,1H),8.44(d,J=1.5Hz,1H)実施例12 (E)−3−〔6−エトキシ−2,3−ジヒドロ−5−
(メトキシメトキシ)−7−ベンゾフラニル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
By a method similar to that in Example 4, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 1.09 (t, J = 7.0H
z, 3H), 1.42 (tt, J = 7.0,7.0Hz, 2H), 1.57 (tt, J = 7.0,7.0H
z, 2H), 1.66 (tt, J = 7.0,7.0Hz, 2H), 2.46 (t, J = 7.0Hz, 2H),
2.61 (t, J = 7.0Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.53 (s, 3
H), 3.71 (s, 3H), 4.13 (q, J = 7.0Hz, 2H), 4.51 (t, J = 8.5H
z, 2H), 5.10 (s, 2H), 6.56 (s, 1H), 6.93 (s, 1H), 7.19 (dd,
J = 5.0,8.0Hz, 1H), 7.49 (dt, J = 1.5,8.0Hz, 1H), 8.43 (dd, J
= 1.5,5.0Hz, 1H), 8.44 (d, J = 1.5Hz, 1H) Example 12 (E) -3- [6-ethoxy-2,3-dihydro-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0108】[0108]

【化43】 [Chemical 43]

【0109】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.24〜1.38(m,
8H), 1.40〜1.58(m,4H), 2.31(t,J=7.5Hz,2H),2.53(t,J
=7.5Hz,2H), 3.15(t,J=8.5Hz,2H), 3.53(s,3H),3.94(q,
J=7.0Hz,2H), 4.24(q,J=7.0Hz,2H), 4.50(t,J=8.5Hz,2
H),5.09(s,2H), 7.00(s,1H), 7.18(dd,J=5.0,8.0Hz,1
H),7.43(dt,J=1.5,8.0Hz,1H), 7.46(s,1H), 8.38〜8.45
(m,2H)実施例13 (E)−3−〔2,3−ジヒドロ−5−(メトキシメト
キシ)−6−プロポキシ−7−ベンゾフラニル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
By a method similar to that in Example 4, the title compound was obtained. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.24 to 1.38 (m,
8H), 1.40 to 1.58 (m, 4H), 2.31 (t, J = 7.5Hz, 2H), 2.53 (t, J
= 7.5Hz, 2H), 3.15 (t, J = 8.5Hz, 2H), 3.53 (s, 3H), 3.94 (q,
J = 7.0Hz, 2H), 4.24 (q, J = 7.0Hz, 2H), 4.50 (t, J = 8.5Hz, 2
H), 5.09 (s, 2H), 7.00 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1
H), 7.43 (dt, J = 1.5,8.0Hz, 1H), 7.46 (s, 1H), 8.38 ~ 8.45
(m, 2H) Example 13 (E) -3- [2,3-dihydro-5- (methoxymeth)
Xy) -6-Propoxy-7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0110】[0110]

【化44】 [Chemical 44]

【0111】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.98(t,J=7.0H
z,3H), 1.24〜1.34(m,5H), 1.43〜1.58(m,4H),1.70(tt,
J=7.5,7.5Hz,2H), 2.31(t,J=7.0Hz,2H), 2.53(t,J=7.0H
z,2H),3.15(t,J=8.5Hz,2H), 3.52(s,3H), 3.83(t,J=7.5
Hz,2H),4.25(q,J=7.0Hz,2H), 4.50(t,J=8.5Hz,2H), 5.0
9(s,2H), 6.99(s,1H),7.18(dd,J=5.0,8.0Hz,1H), 7.43
(dt,J=1.5,8.0Hz,1H), 7.48(s,1H),8.38(d,J=1.5Hz,1
H), 8.41(dd,J=1.5,5.0Hz,1H)実施例14 (E)−3−〔6−ヘプチルオキシ−2,3−ジヒドロ
−5−(メトキシメトキシ)−7−ベンゾフラニル〕−
2−〔5−(3−ピリジル)ペンチル〕アクリル酸エチ
By a method similar to that in Example 4, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 1.98 (t, J = 7.0H
z, 3H), 1.24 to 1.34 (m, 5H), 1.43 to 1.58 (m, 4H), 1.70 (tt,
J = 7.5,7.5Hz, 2H), 2.31 (t, J = 7.0Hz, 2H), 2.53 (t, J = 7.0H
z, 2H), 3.15 (t, J = 8.5Hz, 2H), 3.52 (s, 3H), 3.83 (t, J = 7.5
Hz, 2H), 4.25 (q, J = 7.0Hz, 2H), 4.50 (t, J = 8.5Hz, 2H), 5.0
9 (s, 2H), 6.99 (s, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.43
(dt, J = 1.5,8.0Hz, 1H), 7.48 (s, 1H), 8.38 (d, J = 1.5Hz, 1
H), 8.41 (dd, J = 1.5,5.0Hz, 1H) Example 14 (E) -3- [6-heptyloxy-2,3-dihydro
-5- (Methoxymethoxy) -7-benzofuranyl]-
2- [5- (3-pyridyl) pentyl] ethyiacrylic acid
Le

【0112】[0112]

【化45】 [Chemical 45]

【0113】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;0.86(t,J=7.0H
z,3H), 1.25〜1.58(m,17H), 1.60〜1.70(m,2H),2.30(t,
J=7.5Hz,2H), 2.50(t,J=7.5Hz,2H), 3.14(t,J=8.5Hz,2
H),3.52(s,3H), 3.85(t,J=7.0Hz,2H), 4.24(q,J=7.0Hz,
2H),4.51(t,J=8.5Hz,2H), 5.09(s,2H), 6.99(s,1H),7.1
8(dd,J=5.0,8.0Hz,1H), 7.42(dt,J=1.5,8.0Hz,1H), 7.4
7(s,1H),8.38(d,J=1.5Hz,1H), 8.41(dd,J=1.5,5.0Hz,1
H)実施例15 (E)−3−〔2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−4−メチル−7−ベンゾフラニ
ル〕−2−〔5−(3−ピリジル)ペンチル〕アクリル
酸エチル
By a method similar to that in Example 4, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 0.86 (t, J = 7.0H
z, 3H), 1.25 to 1.58 (m, 17H), 1.60 to 1.70 (m, 2H), 2.30 (t,
J = 7.5Hz, 2H), 2.50 (t, J = 7.5Hz, 2H), 3.14 (t, J = 8.5Hz, 2
H), 3.52 (s, 3H), 3.85 (t, J = 7.0Hz, 2H), 4.24 (q, J = 7.0Hz,
2H), 4.51 (t, J = 8.5Hz, 2H), 5.09 (s, 2H), 6.99 (s, 1H), 7.1
8 (dd, J = 5.0,8.0Hz, 1H), 7.42 (dt, J = 1.5,8.0Hz, 1H), 7.4
7 (s, 1H), 8.38 (d, J = 1.5Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1
H) Example 15 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-7-benzofurani
] -2- [5- (3-pyridyl) pentyl] acrylic
Ethyl acid

【0114】[0114]

【化46】 [Chemical 46]

【0115】実施例4と同様の方法により標題化合物を
得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.19〜1.27(m,
2H), 1.31(t,J=8Hz,3H), 1.42〜1.60(m,4H), 2.21(s,3
H),2.30(t,J=7.5Hz,2H), 2.54(t,J=7.5Hz,2H), 3.08
(t,J=8.5Hz,2H),3.58(s,3H), 3.70(s,3H), 4.24(q,J=7.
5Hz,2H), 4.51(t,J=8.5Hz,2H),5.00(s,2H), 7.17(dd,J=
5.0,8.0Hz,1H), 7.43(dt,J=1.5,8.0Hz,1H),7.44(s,1H),
8.39(dd,J=1.5,5.0Hz,1H), 8.41(d,J=1.5Hz,1H)実施例16 (E)−3−〔2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−4−メチル−7−ベンゾフラニ
ル〕−2−〔6−(3−ピリジル)ヘキシル〕アクリル
酸エチル
The title compound was obtained in the same manner as in Example 4. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.19 to 1.27 (m,
2H), 1.31 (t, J = 8Hz, 3H), 1.42 ~ 1.60 (m, 4H), 2.21 (s, 3
H), 2.30 (t, J = 7.5Hz, 2H), 2.54 (t, J = 7.5Hz, 2H), 3.08
(t, J = 8.5Hz, 2H), 3.58 (s, 3H), 3.70 (s, 3H), 4.24 (q, J = 7.
5Hz, 2H), 4.51 (t, J = 8.5Hz, 2H), 5.00 (s, 2H), 7.17 (dd, J =
5.0,8.0Hz, 1H), 7.43 (dt, J = 1.5,8.0Hz, 1H), 7.44 (s, 1H),
8.39 (dd, J = 1.5,5.0Hz, 1H), 8.41 (d, J = 1.5Hz, 1H) Example 16 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-7-benzofurani
] -2- [6- (3-pyridyl) hexyl] acryl
Ethyl acid

【0116】[0116]

【化47】 [Chemical 47]

【0117】2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−4−メチル−ベンゾフラン−7
−カルバルデヒドと2−ジエチルホスホノ−8−(3−
ピリジル)オクチル酸エチルとを実施例4の方法に従い
反応させることにより、標題化合物を得た。
2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-benzofuran-7
-Carbaldehyde and 2-diethylphosphono-8- (3-
The title compound was obtained by reacting with pyridyl) ethyl octylate according to the method of Example 4.

【0118】・1H−NMR(400MHz, CDCl3) δ ppm;
1.23〜1.29(m,4H), 1.33(t,J=7.0Hz,3H), 1.37〜1.48
(m,2H),1.49〜1.58(m,2H), 2.23(s,3H), 2.29(t,J=7.0H
z,2H),2.55(t,J=7.0Hz,2H), 3.09(t,J=8.5Hz,2H), 3.60
(s,3H), 3.71(s,3H),4.24(q,J=7.0Hz,2H), 4.54(t,J=8.
5Hz,2H), 5.02(s,2H),7.18(dd,J=5.0,8.0Hz,1H), 7.43
(s,1H), 7.45(dt,J=1.5,8.0Hz,1H),8.39〜8.44(m,2H)実施例17 4−{〔3,4−ジヒドロ−6−(メトキシメトキシ)
−7−〔(E)−2−(3−ピリジル)−1−ビニル〕
−2H−1−ベンゾピラン−5−イル〕オキシ}酪酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.23 to 1.29 (m, 4H), 1.33 (t, J = 7.0Hz, 3H), 1.37 to 1.48
(m, 2H), 1.49 to 1.58 (m, 2H), 2.23 (s, 3H), 2.29 (t, J = 7.0H
z, 2H), 2.55 (t, J = 7.0Hz, 2H), 3.09 (t, J = 8.5Hz, 2H), 3.60
(s, 3H), 3.71 (s, 3H), 4.24 (q, J = 7.0Hz, 2H), 4.54 (t, J = 8.
5Hz, 2H), 5.02 (s, 2H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.43
(s, 1H), 7.45 (dt, J = 1.5,8.0Hz, 1H), 8.39 to 8.44 (m, 2H) Example 17 4-{[3,4-dihydro-6- (methoxymethoxy)
-7-[(E) -2- (3-pyridyl) -1-vinyl]
-2H-1-benzopyran-5-yl] oxy} butyric acid

【0119】[0119]

【化48】 [Chemical 48]

【0120】3−ピリジルメチルトリフェニルホスホニ
ウムクロライド塩酸塩970mg をN,N−ジメチルホルム
アミド20mlに懸濁させ、氷冷下60%水素化ナトリウム
180mgを加えた。4−{〔7−ホルミル−3,4−
ジヒドロ−6−(メトキシメトキシ)−2H−1−ベン
ゾピラン−5−イル〕オキシ}酪酸エチル 400mg
を室温で加え、1時間半攪拌した。反応混合物に氷水を
加え、2N塩酸でpH6にし、酢酸エチルで抽出した。有
機層を水で洗い、無水硫酸マグネシウムで乾燥し、減圧
下濃縮し、標記化合物 560mgを褐色油状物として得た。
970 mg of 3-pyridylmethyltriphenylphosphonium chloride hydrochloride was suspended in 20 ml of N, N-dimethylformamide, and 60% sodium hydride under ice cooling.
180 mg was added. 4-{[7-formyl-3,4-
Ethyl dihydro-6- (methoxymethoxy) -2H-1-benzopyran-5-yl] oxy} butyrate 400 mg
Was added at room temperature and stirred for 1 hour and a half. Ice water was added to the reaction mixture, the pH was adjusted to 6 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (560 mg) as a brown oil.

【0121】・ 1H−NMR(400MHz, CDCl3) δ ppm;
1.93(tt,J=7.0,7.0Hz,2H), 2.05(t,J=7.5Hz,2H), 2.51
(t,J=7.5Hz,2H),2.71(t,J=7.0Hz,2H), 3.48(s,3H), 4.0
0(t,J=7.5Hz,2H),4.05(t,J=7.0Hz,2H), 4.96(s,2H), 6.
35(s,1H), 6.55(d,J=13.0Hz,1H),6.76(d,J=13.0Hz,1H),
7.20(dd,J=5.0,8.0Hz,1H),7.59(dt,J=1.5,8.0Hz,1H),
8.38(dd,J=1.5,5.0Hz,1H),8.44(d,J=1.5Hz,1H)実施例18 (E)−3−(3,4−ジヒドロ−6−ヒドロキシ−2
H−1−ベンゾピラン−7−イル)−2−〔5−(3−
ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.93 (tt, J = 7.0,7.0Hz, 2H), 2.05 (t, J = 7.5Hz, 2H), 2.51
(t, J = 7.5Hz, 2H), 2.71 (t, J = 7.0Hz, 2H), 3.48 (s, 3H), 4.0
0 (t, J = 7.5Hz, 2H), 4.05 (t, J = 7.0Hz, 2H), 4.96 (s, 2H), 6.
35 (s, 1H), 6.55 (d, J = 13.0Hz, 1H), 6.76 (d, J = 13.0Hz, 1H),
7.20 (dd, J = 5.0,8.0Hz, 1H), 7.59 (dt, J = 1.5,8.0Hz, 1H),
8.38 (dd, J = 1.5,5.0Hz, 1H), 8.44 (d, J = 1.5Hz, 1H) Example 18 (E) -3- (3,4-dihydro-6-hydroxy-2)
H-1-benzopyran-7-yl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

【0122】[0122]

【化49】 [Chemical 49]

【0123】(1) (E)−3−(3,4−ジヒドロ−6
−(メトキシメトキシ)−2H−1−ベンゾピラン−7
−イル〕−2−〔5−(3−ピリジル)ペンチル〕アク
リル酸エチル900mg をエタノール50mlに溶かし、5M水
酸化ナトリウム水溶液2mlを加え、1時間加熱還流し
た。反応混合物を氷冷下2M塩酸でpH6にし、酢酸エチ
ルで抽出した。有機層と無水硫酸マグネシウムで乾燥
し、減圧下濃縮した。
(1) (E) -3- (3,4-dihydro-6)
-(Methoxymethoxy) -2H-1-benzopyran-7
Ethyl (2-yl) -2- [5- (3-pyridyl) pentyl] acrylate (900 mg) was dissolved in ethanol (50 ml), 5 M aqueous sodium hydroxide solution (2 ml) was added, and the mixture was heated under reflux for 1 hr. The reaction mixture was adjusted to pH 6 with 2M hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

【0124】(2) (1) で得られた残渣をアセトン30mlに
溶かし、濃塩酸 1.5mlを加え、室温で3時間攪拌した。
水10mlを加え、飽和炭酸水素ナトリウム水溶液を加え、
pHを6にした。酢酸エチルで抽出し、有機層を飽和食塩
水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧
下濃縮した。残渣にクロロホルム−イソプロピルエーテ
ルを加えて結晶化させることにより、標題化合物360mg
を淡黄色結晶として得た。
(2) The residue obtained in (1) was dissolved in 30 ml of acetone, 1.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours.
Add 10 ml of water, add saturated aqueous sodium hydrogen carbonate solution,
The pH was set to 6. The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Chloroform-isopropyl ether was added to the residue for crystallization to give 360 mg of the title compound.
Was obtained as pale yellow crystals.

【0125】・1H−NMR(400MHz, CDCl3) δ ppm;
1.39(tt,J=7.5,7.5Hz,2H), 1.59(tt,J=7.5,7.5Hz,2H),
1.61(tt,J=7.5,7.5Hz,2H), 1.95(tt,J=6.0,6.0Hz,2H),
2.48(t,J=7.5Hz,2H), 2.59(t,J=7.5Hz,2H), 2.72(t,J=
6.0Hz,2H),4.10(t,J=6.0Hz,2H), 6.59(s,1H), 6.68(s,1
H),7.21(dd,J=5.5,8.0Hz,1H), 7.50(dt,J=1.5,8.0Hz,1
H),7.91(s,1H), 8.41(bs,2H)実施例19 4−{〔2,3−ジヒドロ−5−ヒドロキシ−4−(3
−ピリジルメチル)−ベンゾフラン−6−イル〕オキ
シ}酪酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.39 (tt, J = 7.5,7.5Hz, 2H), 1.59 (tt, J = 7.5,7.5Hz, 2H),
1.61 (tt, J = 7.5,7.5Hz, 2H), 1.95 (tt, J = 6.0,6.0Hz, 2H),
2.48 (t, J = 7.5Hz, 2H), 2.59 (t, J = 7.5Hz, 2H), 2.72 (t, J =
6.0Hz, 2H), 4.10 (t, J = 6.0Hz, 2H), 6.59 (s, 1H), 6.68 (s, 1
H), 7.21 (dd, J = 5.5,8.0Hz, 1H), 7.50 (dt, J = 1.5,8.0Hz, 1
H), 7.91 (s, 1H), 8.41 (bs, 2H) Example 19 4-{[2,3-dihydro-5-hydroxy-4- (3
-Pyridylmethyl) -benzofuran-6-yl] oxy
Si} butyric acid

【0126】[0126]

【化50】 [Chemical 50]

【0127】実施例2で製造された2,3−ジヒドロ−
6−ヒドロキシ−5−(メトキシメトキシ)−4−(3
−ピリジルメチル)ベンゾフラン600mg から実施例3次
いで実施例18(1)(2)と同様の方法により標題化合物28
0mg を白色結晶として得た。
2,3-dihydro-prepared in Example 2
6-hydroxy-5- (methoxymethoxy) -4- (3
-Pyridylmethyl) benzofuran from 600 mg of the title compound 28 in the same manner as in Example 3 and then in Example 18 (1) (2).
0 mg was obtained as white crystals.

【0128】・融点;134〜136℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.90(tt,J=
7.0,7.0Hz,2H), 2.42(t,J=7.0Hz,2H), 2.97(t,J=8.5Hz,
2H),3.85(s,2H), 3.90(t,J=7.0Hz,2H), 4.40(t,J=8.5H
z,2H), 6.35(s,1H),7.25(dd,J=5.0,8.0Hz,1H), 7.54(d
t,J=1.5,8.0Hz,1H),8.35(dd,J=1.5,5.0Hz,1H), 8.44(d,
J=1.5Hz,1H)実施例20 (E)−3−〔3,4−ジヒドロ−6−(メトキシメト
キシ)−5−(3−ピリジルメチル)−2H−1−ベン
ゾピラン−7−イル〕アクリル酸エチル
Melting point: 134 to 136 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.90 (tt, J =
7.0,7.0Hz, 2H), 2.42 (t, J = 7.0Hz, 2H), 2.97 (t, J = 8.5Hz,
2H), 3.85 (s, 2H), 3.90 (t, J = 7.0Hz, 2H), 4.40 (t, J = 8.5H
z, 2H), 6.35 (s, 1H), 7.25 (dd, J = 5.0,8.0Hz, 1H), 7.54 (d
t, J = 1.5,8.0Hz, 1H), 8.35 (dd, J = 1.5,5.0Hz, 1H), 8.44 (d,
J = 1.5 Hz, 1H) Example 20 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -5- (3-pyridylmethyl) -2H-1-ben
Zopyran-7-yl] ethyl acrylate

【0129】[0129]

【化51】 [Chemical 51]

【0130】3,4−ジヒドロ−6−(メトキシメトキ
シ)−5−(3−ピリジルメチル)−2H−1−ベンゾ
ピラン−7−カルバルデヒドとジエチルホスホノ酸エチ
ルを用いて実施例4と同様にウィティッヒ−ホーナー反
応を行うことにより標題化合物を得た。
As in Example 4, using 3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethyl) -2H-1-benzopyran-7-carbaldehyde and ethyl diethylphosphonoate. The title compound was obtained by performing a Wittig-Horner reaction.

【0131】・1H−NMR(400MHz, CDCl3) δ ppm;
1.32(t,J=7.0Hz,3H), 1.91(tt,J=7.0,7.0Hz,2H), 2.52
(t,J=7.0Hz,2H),3.50(s,3H), 4.04(s,2H), 4.06(t,J=7.
0Hz,2H), 4.23(q,J=7.0Hz,2H),4.85(s,2H), 6.36(d,J=1
5.0Hz,1H), 6.97(s,1H),7.15(dd,J=5.0,8.0Hz,1H), 7.3
5(dt,J=1.5,8.0Hz,1H),7.92(d,J=15.0Hz,1H), 8.39(dd,
J=1.5,5.0Hz,1H),8.43(d,J=1.5Hz,1H)実施例21 (E)−3−〔3,4−ジヒドロ−6−ヒドロキシ−8
−メチル−5−(3−ピリジルメチル)−2H−1−ベ
ンゾピラン−7−イル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.32 (t, J = 7.0Hz, 3H), 1.91 (tt, J = 7.0,7.0Hz, 2H), 2.52
(t, J = 7.0Hz, 2H), 3.50 (s, 3H), 4.04 (s, 2H), 4.06 (t, J = 7.
0Hz, 2H), 4.23 (q, J = 7.0Hz, 2H), 4.85 (s, 2H), 6.36 (d, J = 1
5.0Hz, 1H), 6.97 (s, 1H), 7.15 (dd, J = 5.0,8.0Hz, 1H), 7.3
5 (dt, J = 1.5,8.0Hz, 1H), 7.92 (d, J = 15.0Hz, 1H), 8.39 (dd,
J = 1.5,5.0Hz, 1H), 8.43 (d, J = 1.5Hz, 1H) Example 21 (E) -3- [3,4-dihydro-6-hydroxy-8]
-Methyl-5- (3-pyridylmethyl) -2H-1-be
Nzopyran-7-yl] acrylic acid

【0132】[0132]

【化52】 [Chemical 52]

【0133】3,4−ジヒドロ−6−(メトキシメトキ
シ)−8−メチル−5−(3−ピリジルメチル)−2H
−1−ベンゾピラン−7−カルバルデヒド 900mgを用い
て実施例20及び実施例18と同様の方法により標題化
合物 1.0gを黄色結晶として得た。
3,4-Dihydro-6- (methoxymethoxy) -8-methyl-5- (3-pyridylmethyl) -2H
1.0 g of the title compound was obtained as yellow crystals in the same manner as in Example 20 and Example 18 using 900 mg of -1-benzopyran-7-carbaldehyde.

【0134】・融点;198〜200℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.80(tt,J=
7.0,7.0Hz,2H), 2.11(s,3H), 2.52(t,J=7.0Hz,2H),3.96
(s,2H), 3.98(t,J=7.0Hz,2H), 6.34(d,J=15.0Hz,1H),7.
23(dd,J=5.0,8.0Hz,1H), 7.41(dt,J=1.5,8.0Hz,1H),7.7
4(d,J=15.0Hz,1H), 8.31(dd,J=1.5,5.0Hz,1H),8.36(d,J
=1.5Hz,1H)実施例22 3−〔3,4−ジヒドロ−6−ヒドロキシ−8−メチル
−5−(3−ピリジルメチル)−2H−1−ベンゾピラ
ン−7−イル〕プロピオン酸
Melting point: 198 to 200 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.80 (tt, J =
7.0,7.0Hz, 2H), 2.11 (s, 3H), 2.52 (t, J = 7.0Hz, 2H), 3.96
(s, 2H), 3.98 (t, J = 7.0Hz, 2H), 6.34 (d, J = 15.0Hz, 1H), 7.
23 (dd, J = 5.0,8.0Hz, 1H), 7.41 (dt, J = 1.5,8.0Hz, 1H), 7.7
4 (d, J = 15.0Hz, 1H), 8.31 (dd, J = 1.5,5.0Hz, 1H), 8.36 (d, J
= 1.5 Hz, 1H) Example 22 3- [3,4-dihydro-6-hydroxy-8-methyl
-5- (3-pyridylmethyl) -2H-1-benzopyra
N-7-yl] propionic acid

【0135】[0135]

【化53】 [Chemical 53]

【0136】実施例21で得られた化合物 500mgをエタ
ノール 200mlに溶かし、10%パラジウム炭素(50%含水
品)150mgを加え、2時間常温常圧で水素添加を行った。
パラジウム炭素をセライトを用いて濾去した後、溶媒を
減圧下留去した。析出した結晶をエタノールで洗浄する
ことにより、標題化合物 200mgを白色結晶として得た。
500 mg of the compound obtained in Example 21 was dissolved in 200 ml of ethanol, 150 mg of 10% palladium carbon (50% water-containing product) was added, and hydrogenation was carried out at room temperature and atmospheric pressure for 2 hours.
The palladium carbon was filtered off using Celite, and the solvent was evaporated under reduced pressure. The precipitated crystals were washed with ethanol to give the title compound (200 mg) as white crystals.

【0137】・融点;190〜191℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.78(tt,J=
7.0,7.0Hz,2H), 2.02(s,3H), 2.35(t,J=7.5Hz,2H),2.47
(t,J=7.5Hz,2H), 2.82(t,J=7.5Hz,2H), 3.92(s,2H),3.9
6(t,J=7.0Hz,2H), 7.22(dd,J=5.0,8.0Hz,1H),7.41(dt,J
=1.5,8.0Hz,1H), 8.32(dd,J=1.5,5.0Hz,1H),8.35(d,J=
1.5Hz,1H)実施例23 (E)−3−〔3,4−ジヒドロ−6−(メトキシメト
キシ)−7−メチル−5−(3−ピリジルメチル)−2
H−1−ベンゾピラン−8−イル〕アクリル酸エチル
Melting point: 190 to 191 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.78 (tt, J =
7.0,7.0Hz, 2H), 2.02 (s, 3H), 2.35 (t, J = 7.5Hz, 2H), 2.47
(t, J = 7.5Hz, 2H), 2.82 (t, J = 7.5Hz, 2H), 3.92 (s, 2H), 3.9
6 (t, J = 7.0Hz, 2H), 7.22 (dd, J = 5.0,8.0Hz, 1H), 7.41 (dt, J
= 1.5,8.0Hz, 1H), 8.32 (dd, J = 1.5,5.0Hz, 1H), 8.35 (d, J =
1.5 Hz, 1H) Example 23 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -7-methyl-5- (3-pyridylmethyl) -2
H-1-benzopyran-8-yl] ethyl acrylate

【0138】[0138]

【化54】 [Chemical 54]

【0139】実施例20と同様の方法により標題化合物
を得た。 ・1H−NMR(400MHz, CDCl3) δ ppm;1.32(t,J=7.0H
z,3H), 1.91(tt,J=7.0,7.0Hz,2H), 2.38(s,3H),2.53(t,
J=7.0Hz,2H), 3.48(s,3H), 4.06(s,2H), 4.24(q,J=7.0H
z,2H),4.85(s,2H), 6.59(d,J=15.0Hz,1H), 7.16(dd,J=
5.0,8.0Hz,1H),7.36(dt,J=1.5,8.0Hz,1H), 7.87(d,J=1
5.0Hz,1H),8.41(dd,J=1.5,5.0Hz,1H), 8.45(d,J=1.5Hz,
1H)実施例24 3−〔3,4−ジヒドロ−6−ヒドロキシ−5−(3−
ピリジルメトキシ)−2H−1−ベンゾピラン−7−イ
ル〕アクリル酸
By a method similar to that in Example 20, the title compound was obtained.・1 H-NMR (400MHz, CDCl 3 ) δ ppm; 1.32 (t, J = 7.0H
z, 3H), 1.91 (tt, J = 7.0,7.0Hz, 2H), 2.38 (s, 3H), 2.53 (t,
J = 7.0Hz, 2H), 3.48 (s, 3H), 4.06 (s, 2H), 4.24 (q, J = 7.0H
z, 2H), 4.85 (s, 2H), 6.59 (d, J = 15.0Hz, 1H), 7.16 (dd, J =
5.0,8.0Hz, 1H), 7.36 (dt, J = 1.5,8.0Hz, 1H), 7.87 (d, J = 1
5.0Hz, 1H), 8.41 (dd, J = 1.5,5.0Hz, 1H), 8.45 (d, J = 1.5Hz,
1H) Example 24 3- [3,4-dihydro-6-hydroxy-5- (3-
Pyridylmethoxy) -2H-1-benzopyran-7-i
] Acrylic acid

【0140】[0140]

【化55】 [Chemical 55]

【0141】3,4−ジヒドロ−6−(メトキシメトキ
シ)−5−(3−ピリジルメトキシ)−2H−1−ベン
ゾピラン−7−カルバルデヒド 150mgから実施例18及
び実施例20と同様の方法により標題化合物 130mgを微
黄色結晶として得た。
By a method similar to that in Example 18 and Example 20, from 150 mg of 3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethoxy) -2H-1-benzopyran-7-carbaldehyde. 130 mg of the compound was obtained as pale yellow crystals.

【0142】・融点;228〜230℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.80(tt,J=
7.0,7.0Hz,2H), 2.61(t,J=7.0Hz,2H), 4.00(t,J=7.0Hz,
2H),4.91(s,2H), 6.41(d,J=15.0Hz,1H), 6.80(s,1H),7.
41(dd,J=5.0,8.0Hz,1H), 7.79(d,J=15.0Hz,1H),7.90(d
t,J=1.5,8.0Hz,1H), 8.53(dd,J=1.5,5.0Hz,1H),8.66(d,
J=1.5Hz,1H), 8.96(bs,1H)実施例25 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−6
−ベンゾフラニル)−2−〔5−(3−ピリジル)ペン
チル〕アクリル酸
Melting point: 228 to 230 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.80 (tt, J =
7.0,7.0Hz, 2H), 2.61 (t, J = 7.0Hz, 2H), 4.00 (t, J = 7.0Hz,
2H), 4.91 (s, 2H), 6.41 (d, J = 15.0Hz, 1H), 6.80 (s, 1H), 7.
41 (dd, J = 5.0,8.0Hz, 1H), 7.79 (d, J = 15.0Hz, 1H), 7.90 (d
t, J = 1.5,8.0Hz, 1H), 8.53 (dd, J = 1.5,5.0Hz, 1H), 8.66 (d,
J = 1.5 Hz, 1H), 8.96 (bs, 1H) Example 25 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Benzofuranyl) -2- [5- (3-pyridyl) pen
Chill] acrylic acid

【0143】[0143]

【化56】 [Chemical 56]

【0144】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−6−ベンゾフラニル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
1.0gから、実施例18と同様の方法により標題化合物
270mgを黄色結晶として得た。
(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -6-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] ethyl acrylate
From 1.0 g of the title compound by the same method as in Example 18.
270 mg were obtained as yellow crystals.

【0145】・融点;205〜206℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.22〜1.32
(m,2H), 1.42〜1.58(m,4H), 2.34(t,J=7.5Hz,2H),2.53
(t,J=7.5Hz,2H), 3.09(t,J=8.5Hz,2H), 4.41(t,J=8.5H
z,2H),6.56(s,1H), 6.78(s,1H), 7.26(dd,J=5.0,8.0Hz,
1H),7.56(dt,J=1.5,8.0Hz,1H), 7.64(s,1H), 8.35(dd,J
=1.5,5.0Hz,1H),8.36(d,J=1.5Hz,1H), 9.29(bs,1H)実施例26 (E)−3−(3,4−ジヒドロ−6−ヒドロキシ−5
−メトキシ−2H−1−ベンゾピラン−7−イル)−2
−〔5−(3−ピリジル)ペンチル〕アクリル酸
Melting point: 205 to 206 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.22 to 1.32
(m, 2H), 1.42 to 1.58 (m, 4H), 2.34 (t, J = 7.5Hz, 2H), 2.53
(t, J = 7.5Hz, 2H), 3.09 (t, J = 8.5Hz, 2H), 4.41 (t, J = 8.5H
z, 2H), 6.56 (s, 1H), 6.78 (s, 1H), 7.26 (dd, J = 5.0,8.0Hz,
1H), 7.56 (dt, J = 1.5,8.0Hz, 1H), 7.64 (s, 1H), 8.35 (dd, J
= 1.5,5.0Hz, 1H), 8.36 (d, J = 1.5Hz, 1H), 9.29 (bs, 1H) Example 26 (E) -3- (3,4-dihydro-6-hydroxy-5)
-Methoxy-2H-1-benzopyran-7-yl) -2
-[5- (3-Pyridyl) pentyl] acrylic acid

【0146】[0146]

【化57】 [Chemical 57]

【0147】(E)−3−〔3,4−ジヒドロ−6−
(メトキシメトキシ)−5−メトキシ−2H−1−ベン
ゾピラン−7−イル〕−2−〔5−(3−ピリジル)ペ
ンチル〕アクリル酸エチル 420mgから、実施例18と同
様の方法により標題化合物 140mgを黄色結晶として得
た。
(E) -3- [3,4-dihydro-6-
140 mg of the title compound was obtained from 420 mg of ethyl (methoxymethoxy) -5-methoxy-2H-1-benzopyran-7-yl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18. Obtained as yellow crystals.

【0148】・融点;168〜170℃ ・1H−NMR(400MHz, CDCl3+DMSO-d6) δ ppm;1.40
(tt,J=7.5,7.5Hz,2H), 1.54〜1.65(m,4H),1.96(tt,J=7.
0,7.0Hz,2H), 2.47(t,J=7.5Hz,2H), 2.58(t,J=7.5Hz,2
H),2.77(t,J=7.0Hz,2H), 3.78(s,3H), 4.09(t,J=7.0Hz,
2H), 6.53(s,1H),7.20(dd,J=5.5,8.0Hz,1H), 7.49(dt,J
=1.5,8.0Hz,1H), 7.79(s,1H),8.40(bs,2H)実施例27 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−4
−メトキシ−6−ベンゾフラニル)−2−〔5−(3−
ピリジル)ペンチル〕アクリル酸
Melting point: 168 to 170 ° C. 1 H-NMR (400 MHz, CDCl 3 + DMSO-d 6 ) δ ppm; 1.40
(tt, J = 7.5,7.5Hz, 2H), 1.54 to 1.65 (m, 4H), 1.96 (tt, J = 7.
0,7.0Hz, 2H), 2.47 (t, J = 7.5Hz, 2H), 2.58 (t, J = 7.5Hz, 2
H), 2.77 (t, J = 7.0Hz, 2H), 3.78 (s, 3H), 4.09 (t, J = 7.0Hz,
2H), 6.53 (s, 1H), 7.20 (dd, J = 5.5,8.0Hz, 1H), 7.49 (dt, J
= 1.5,8.0Hz, 1H), 7.79 (s, 1H), 8.40 (bs, 2H) Example 27 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methoxy-6-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

【0149】[0149]

【化58】 [Chemical 58]

【0150】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−4−メトキシ−6−ベンゾフラ
ニル〕−2−〔5−(3−ピリジル)ペンチル〕アクリ
ル酸エチル 1.0gから、実施例18と同様の方法により
標題化合物 230mgを微黄色結晶として得た。
(E) -3- [2,3-dihydro-5-
From 1.0 g of ethyl (methoxymethoxy) -4-methoxy-6-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate, 230 mg of the title compound was obtained as slightly yellow crystals in the same manner as in Example 18. It was

【0151】・融点;157〜159℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.26(tt,J=
7.5,7.5Hz,2H), 1.45(tt,J=7.5,7.5Hz,2H),1.51(tt,J=
7.5,7.5Hz,2H), 2.35(t,J=7.5Hz,2H),1.53(t,J=7.5Hz,2
H), 3.27(t,J=8.5Hz,2H), 3.78(s,3H),4.44(t,J=8.5Hz,
2H), 6.31(s,1H), 7.26(dd,J=5.0,8.0Hz,1H),7.56(dt,J
=1.5,8.0Hz,1H), 7.63(s,1H), 8.36(bs,1H), 8.48(bs,1
H)実施例28 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−4
−メチル−6−ベンゾフラニル)−2−〔5−(3−ピ
リジル)ペンチル〕アクリル酸
Melting point: 157 to 159 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.26 (tt, J =
7.5,7.5Hz, 2H), 1.45 (tt, J = 7.5,7.5Hz, 2H), 1.51 (tt, J =
7.5,7.5Hz, 2H), 2.35 (t, J = 7.5Hz, 2H), 1.53 (t, J = 7.5Hz, 2
H), 3.27 (t, J = 8.5Hz, 2H), 3.78 (s, 3H), 4.44 (t, J = 8.5Hz,
2H), 6.31 (s, 1H), 7.26 (dd, J = 5.0,8.0Hz, 1H), 7.56 (dt, J
= 1.5,8.0Hz, 1H), 7.63 (s, 1H), 8.36 (bs, 1H), 8.48 (bs, 1
H) Example 28 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methyl-6-benzofuranyl) -2- [5- (3-pi
Lysyl) pentyl] acrylic acid

【0152】[0152]

【化59】 [Chemical 59]

【0153】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−4−メチル−6−ベンゾフラニ
ル〕−2−〔5−(3−ピリジル)ペンチル〕アクリル
酸エチル500mg から、実施例18と同様の方法により標
題化合物100mg を褐色油状物として得た。
(E) -3- [2,3-dihydro-5-
100 mg of the title compound was obtained as a brown oil from 500 mg of ethyl (methoxymethoxy) -4-methyl-6-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18. ..

【0154】・1H−NMR(400MHz, CDCl3) δ ppm;
1.31(tt,J=7.0,7.0Hz,2H), 1.50〜1.65(m,4H), 2.18(s,
3H),2.46(t,J=7.0Hz,2H), 2.59(t,J=7.0Hz,2H), 3.14
(t,J=8.5Hz,2H),4.56(t,J=8.5Hz,2H), 6.48(s,1H), 7.2
0〜7.28(m,1H),7.53(bd,J=8.0Hz,1H), 7.74(s,1H), 8.3
8〜8.45(m,2H)実施例29 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−4
−メトキシ−7−メチル−6−ベンゾフラニル)−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸エチル
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.31 (tt, J = 7.0,7.0Hz, 2H), 1.50 ~ 1.65 (m, 4H), 2.18 (s,
3H), 2.46 (t, J = 7.0Hz, 2H), 2.59 (t, J = 7.0Hz, 2H), 3.14
(t, J = 8.5Hz, 2H), 4.56 (t, J = 8.5Hz, 2H), 6.48 (s, 1H), 7.2
0 ~ 7.28 (m, 1H), 7.53 (bd, J = 8.0Hz, 1H), 7.74 (s, 1H), 8.3
8 to 8.45 (m, 2H) Example 29 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methoxy-7-methyl-6-benzofuranyl) -2-
[5- (3-pyridyl) pentyl] ethyl acrylate

【0155】[0155]

【化60】 [Chemical 60]

【0156】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−4−メトキシ−7−メチル−6
−ベンゾフラニル〕−2−〔5−(3−ピリジル)ペン
チル〕アクリル酸エチル200mg から、実施例18の(2)
と同様の方法により標題化合物140mg を褐色油状物とし
て得た。
(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -4-methoxy-7-methyl-6
-Benzofuranyl] -2- [5- (3-pyridyl) pentyl] ethyl acrylate (200 mg) to (18) of Example 18
By a method similar to the above, 140 mg of the title compound was obtained as a brown oil.

【0157】・1H−NMR(400MHz, CDCl3) δ ppm;
1.26(tt,J=7.5,7.5Hz,2H), 1.34(t,J=7.5Hz,3H), 1.40
〜1.49(m,4H),1.99(s,3H), 2.21(t,J=7.5Hz,2H), 2.47
(t,J=7.5Hz,2H),3.33(t,J=8.5Hz,2H), 3.88(s,3H), 4.2
6(q,J=7.5Hz,2H),4.52(t,J=8.5Hz,2H), 7.17(dd,J=5.0,
8.0Hz,1H),7.40(dt,J=1.5,8.0Hz,1H), 7.42(s,1H), 8.3
5(d,J=1.5Hz,1H),8.34(dd,J=1.5,5.0Hz,1H)実施例30 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−4
−メトキシ−7−メチル−6−ベンゾフラニル)−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.26 (tt, J = 7.5,7.5Hz, 2H), 1.34 (t, J = 7.5Hz, 3H), 1.40
~ 1.49 (m, 4H), 1.99 (s, 3H), 2.21 (t, J = 7.5Hz, 2H), 2.47
(t, J = 7.5Hz, 2H), 3.33 (t, J = 8.5Hz, 2H), 3.88 (s, 3H), 4.2
6 (q, J = 7.5Hz, 2H), 4.52 (t, J = 8.5Hz, 2H), 7.17 (dd, J = 5.0,
8.0Hz, 1H), 7.40 (dt, J = 1.5,8.0Hz, 1H), 7.42 (s, 1H), 8.3
5 (d, J = 1.5Hz, 1H), 8.34 (dd, J = 1.5,5.0Hz, 1H) Example 30 (E) -3- (2,3-dihydro-5-hydroxy-4)
-Methoxy-7-methyl-6-benzofuranyl) -2-
[5- (3-pyridyl) pentyl] acrylic acid

【0158】[0158]

【化61】 [Chemical formula 61]

【0159】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−4−メトキシ−7−メチル−6
−ベンゾフラニル〕−2−〔5−(3−ピリジル)ペン
チル〕アクリル酸エチル500mg から、実施例18と同様
の方法により標題化合物350mgを褐色油状物として得
た。
(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -4-methoxy-7-methyl-6
350 mg of the title compound was obtained as a brown oil from 500 mg of ethyl-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18.

【0160】・1H−NMR(400MHz, CDCl3) δ ppm;
1.20〜1.28(m,2H), 1.40〜1.50(m,4H), 2.00(s,3H),2.2
4(t,J=7.5Hz,2H), 2.49(t,J=7.5Hz,2H), 3.29(t,J=8.5H
z,2H),3.84(s,3H), 4.49(t,J=8.5Hz,2H), 7.24(bs,1H),
7.48(d,J=8.0Hz,1H),7.52(s,1H), 8.45(bs,2H)実施例31 (E)−3−〔2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−7−ベンゾフラニル〕−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.20 ~ 1.28 (m, 2H), 1.40 ~ 1.50 (m, 4H), 2.00 (s, 3H), 2.2
4 (t, J = 7.5Hz, 2H), 2.49 (t, J = 7.5Hz, 2H), 3.29 (t, J = 8.5H
z, 2H), 3.84 (s, 3H), 4.49 (t, J = 8.5Hz, 2H), 7.24 (bs, 1H),
7.48 (d, J = 8.0Hz, 1H), 7.52 (s, 1H), 8.45 (bs, 2H) Example 31 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -7-benzofuranyl] -2-
[5- (3-pyridyl) pentyl] acrylic acid

【0161】[0161]

【化62】 [Chemical formula 62]

【0162】(E)−3−〔2,3−ジヒドロ−6−メ
トキシ−5−(メトキシメトキシ)−7−ベンゾフラニ
ル〕−2−〔5−(3−ピリジル)ペンチル〕アクリル
酸エチル 1.1gから、実施例18の(1) と同様の方法に
より標題化合物 1.0gを得た。
From 1.1 g of ethyl (E) -3- [2,3-dihydro-6-methoxy-5- (methoxymethoxy) -7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate. By a method similar to that of Example 18, (1), 1.0 g of the title compound was obtained.

【0163】・1H−NMR(400MHz, CDCl3) δ ppm;
1.24〜1.33(m,2H), 1.49〜1.60(m,4H), 2.33(t,J=7.5H
z,2H),2.55(t,J=7.5Hz,2H), 3.16(t,J=8.5Hz,2H), 3.53
(s,3H), 3.75(s,3H),4.52(t,J=8.5Hz,2H), 5.12(s,2H),
7.02(s,1H),7.21(dd,J=5.0,8.0Hz,1H), 7.48(dt,J=1.
5,8.0Hz,1H), 7.57(s,1H),8.43(dd,J=1.5,5.0Hz,1H),
8.44(d,J=1.5Hz,1H)実施例32 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−6
−メトキシ−7−ベンゾフラニル)−2−〔5−(3−
ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.24 to 1.33 (m, 2H), 1.49 to 1.60 (m, 4H), 2.33 (t, J = 7.5H
z, 2H), 2.55 (t, J = 7.5Hz, 2H), 3.16 (t, J = 8.5Hz, 2H), 3.53
(s, 3H), 3.75 (s, 3H), 4.52 (t, J = 8.5Hz, 2H), 5.12 (s, 2H),
7.02 (s, 1H), 7.21 (dd, J = 5.0,8.0Hz, 1H), 7.48 (dt, J = 1.
5,8.0Hz, 1H), 7.57 (s, 1H), 8.43 (dd, J = 1.5,5.0Hz, 1H),
8.44 (d, J = 1.5Hz, 1H) Example 32 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-7-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

【0164】[0164]

【化63】 [Chemical 63]

【0165】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−6−メトキシ−7−ベンゾフラ
ニル)−2−〔5−(3−ピリジル)ペンチル〕アクリ
ル酸1.0 gから、実施例18の(2) と同様の方法により
標題化合物800mg を乳白色結晶として得た。
(E) -3- [2,3-dihydro-5-
800 mg of the title compound was obtained as milk-white crystals from 1.0 g of (methoxymethoxy) -6-methoxy-7-benzofuranyl) -2- [5- (3-pyridyl) pentyl] acrylic acid in the same manner as in Example 18, (2). Got as.

【0166】・融点;115〜117℃ ・1H−NMR(400MHz, CDCl3) δ ppm;1.19〜1.27(m,
2H), 1.49〜1.59(m,4H), 2.35(t,J=7.5Hz,2H),2.56(t,J
=7.5Hz,2H), 3.14(t,J=8.5Hz,2H), 3.72(s,3H),4.50(t,
J=8.5Hz,2H), 6.83(s,1H), 7.23(dd,J=5.0,8.0Hz,1H),
7.49(dt,J=1.5,8.0Hz,1H), 7.59(s,1H), 8.43(dd,J=1.
5,5.0Hz,1H),8.45(d,J=1.5Hz,1H)実施例33 (Z)−3−(2,3−ジヒドロ−5−ヒドロキシ−6
−メトキシ−7−ベンゾフラニル)−2−〔5−(3−
ピリジル)ペンチル〕アクリル酸
Melting point: 115 to 117 ° C. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.19 to 1.27 (m,
2H), 1.49 ~ 1.59 (m, 4H), 2.35 (t, J = 7.5Hz, 2H), 2.56 (t, J
= 7.5Hz, 2H), 3.14 (t, J = 8.5Hz, 2H), 3.72 (s, 3H), 4.50 (t,
J = 8.5Hz, 2H), 6.83 (s, 1H), 7.23 (dd, J = 5.0,8.0Hz, 1H),
7.49 (dt, J = 1.5,8.0Hz, 1H), 7.59 (s, 1H), 8.43 (dd, J = 1.
5,5.0Hz, 1H), 8.45 (d, J = 1.5Hz, 1H) Example 33 (Z) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-7-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

【0167】[0167]

【化64】 [Chemical 64]

【0168】(Z)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−6−メトキシ−7−ベンゾフラ
ニル〕−2−〔5−(3−ピリジル)ペンチル〕アクリ
ル酸エチルから、実施例18と同様の方法により標題化
合物を白色結晶として得た。
(Z) -3- [2,3-dihydro-5-
The title compound was obtained as white crystals from ethyl (methoxymethoxy) -6-methoxy-7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18.

【0169】・融点;150〜151℃ ・1H−NMR(400MHz, CDCl3) δ ppm;1.42〜1.44(m,
2H), 1.60〜1.70(m,4H), 2.48(t,J=7.5Hz,2H),2.63(t,J
=7.5Hz,2H), 3.09(t,J=8.5Hz,2H), 3.68(s,3H),4.47(t,
J=8.5Hz,2H), 6.58(s,1H), 6.75(s,1H),7.24(dd,J=5.0,
8.0Hz,1H), 7.55(bd,J=8.0Hz),8.42(dd,J=1.5,5.0Hz,1
H), 8.45(d,J=1.5Hz,1H)実施例34 (E)−3−(6−エトキシ−2,3−ジヒドロ−5−
ヒドロキシ−7−ベンゾフラニル)−2−〔5−(3−
ピリジル)ペンチル〕アクリル酸
Melting point: 150 to 151 ° C. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.42 to 1.44 (m,
2H), 1.60 to 1.70 (m, 4H), 2.48 (t, J = 7.5Hz, 2H), 2.63 (t, J
= 7.5Hz, 2H), 3.09 (t, J = 8.5Hz, 2H), 3.68 (s, 3H), 4.47 (t,
J = 8.5Hz, 2H), 6.58 (s, 1H), 6.75 (s, 1H), 7.24 (dd, J = 5.0,
8.0Hz, 1H), 7.55 (bd, J = 8.0Hz), 8.42 (dd, J = 1.5,5.0Hz, 1
H), 8.45 (d, J = 1.5Hz, 1H) Example 34 (E) -3- (6-ethoxy-2,3-dihydro-5-
Hydroxy-7-benzofuranyl) -2- [5- (3-
Pyridyl) pentyl] acrylic acid

【0170】[0170]

【化65】 [Chemical 65]

【0171】(E)−3−〔6−エトキシ−2,3−ジ
ヒドロ−5−(メトキシメトキシ)−7−ベンゾフラニ
ル〕−2−〔5−(3−ピリジル)ペンチル〕アクリル
酸エチル 6.5gから、実施例18と同様の方法により標
題化合物 1.7gを黄色アモルファスとして得た。
From 6.5 g of ethyl (E) -3- [6-ethoxy-2,3-dihydro-5- (methoxymethoxy) -7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate. By a method similar to that in Example 18, 1.7 g of the title compound was obtained as a yellow amorphous substance.

【0172】・1H−NMR(400MHz, CDCl3) δ ppm;
1.23〜1.33(m,5H), 1.49〜1.56(m,4H), 2.36(t,J=7.0H
z,2H),2.55(t,J=7.0Hz,2H), 3.13(t,J=8.5Hz,2H), 3.92
(q,J=7.0Hz,2H),4.50(t,J=8.5Hz,2H), 6.83(s,1H), 7.2
5(dd,J=5.0,8.0Hz,1H),7.49(bd,J=8.0Hz,1H), 7.60(s,1
H), 8.43〜8.45(m,2H)実施例35 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−6
−プロポキシ−7−ベンゾフラニル)−2−〔5−(3
−ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.23 to 1.33 (m, 5H), 1.49 to 1.56 (m, 4H), 2.36 (t, J = 7.0H
z, 2H), 2.55 (t, J = 7.0Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.92
(q, J = 7.0Hz, 2H), 4.50 (t, J = 8.5Hz, 2H), 6.83 (s, 1H), 7.2
5 (dd, J = 5.0,8.0Hz, 1H), 7.49 (bd, J = 8.0Hz, 1H), 7.60 (s, 1
H), 8.43 to 8.45 (m, 2H) Example 35 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Propoxy-7-benzofuranyl) -2- [5- (3
-Pyridyl) pentyl] acrylic acid

【0173】[0173]

【化66】 [Chemical 66]

【0174】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−6−プロポキシ−7−ベンゾフ
ラニル〕−2−〔5−(3−ピリジル)ペンチル〕アク
リル酸エチル 7.1gから、実施例18と同様の方法によ
り標題化合物 1.5gを黄色油状物として得た。
(E) -3- [2,3-dihydro-5-
From 7.1 g of ethyl (methoxymethoxy) -6-propoxy-7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate, 1.5 g of the title compound was obtained as a yellow oil in the same manner as in Example 18. Obtained.

【0175】・1H−NMR(400MHz, CDCl3) δ ppm;
0.98(t,J=7.5Hz,3H), 1.23〜1.27(m,2H), 1.50〜1.55
(m,4H),1.72(tt,J=7.5,7.5Hz,2H), 2.37(t,J=7.5Hz,2
H), 2.55(t,J=7.5Hz,2H),3.13(t,J=8.5Hz,2H), 3.80(t,
J=7.5Hz,2H), 4.50(t,J=8.5Hz,2H),6.82(s,1H), 7.24(d
d,J=5.0,8.0Hz,1H), 7.50(bd,J=8.0Hz,1H),7.61(s,1H),
8.43〜8.45(m,2H)実施例36 (E)−3−(6−ヘプチルオキシ−2,3−ジヒドロ
−5−ヒドロキシ−7−ベンゾフラニル)−2−〔5−
(3−ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
0.98 (t, J = 7.5Hz, 3H), 1.23〜1.27 (m, 2H), 1.50〜1.55
(m, 4H), 1.72 (tt, J = 7.5,7.5Hz, 2H), 2.37 (t, J = 7.5Hz, 2
H), 2.55 (t, J = 7.5Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.80 (t,
J = 7.5Hz, 2H), 4.50 (t, J = 8.5Hz, 2H), 6.82 (s, 1H), 7.24 (d
d, J = 5.0,8.0Hz, 1H), 7.50 (bd, J = 8.0Hz, 1H), 7.61 (s, 1H),
8.43-8.45 (m, 2H) Example 36 (E) -3- (6-heptyloxy-2,3-dihydro
-5-Hydroxy-7-benzofuranyl) -2- [5-
(3-Pyridyl) pentyl] acrylic acid

【0176】[0176]

【化67】 [Chemical 67]

【0177】(E)−3−〔6−ヘプチルオキシ−2,
3−ジヒドロ−5−(メトキシメトキシ)−7−ベンゾ
フラニル〕−2−〔5−(3−ピリジル)ペンチル〕ア
クリル酸エチル 1.5gから、実施例18と同様の方法に
より標題化合物 1.1gを黄色油状物として得た。
(E) -3- [6-heptyloxy-2,
1.1 g of the title compound was obtained as a yellow oil from 1.5 g of ethyl 3-dihydro-5- (methoxymethoxy) -7-benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18. I got it as a thing.

【0178】・1H−NMR(400MHz, CDCl3) δ ppm;
0.86(t,J=7.0Hz,3H), 1.20〜1.42(m,10H), 1.46〜1.58
(m,4H),1.69(tt,J=7.5,7.5Hz,2H), 2.36(t,J=7.5Hz,2
H), 2.55(t,J=7.5Hz,2H),3.13(t,J=8.5Hz,2H), 3.83(t,
J=7.0Hz,2H), 4.49(t,J=8.5Hz,2H),6.83(s,1H), 7.22(d
d,J=5.0,8.0Hz,1H), 7.48(dt,J=1.5,8.0Hz,1H),7.60(s,
1H), 8.43(dd,J=1.5,5.0Hz,1H), 8.45(d,J=1.5Hz,1H)実施例37 (E)−3−〔2,3−ジヒドロ−6−メトキシ−5−
(メトキシメトキシ)−4−メチル−7−ベンゾフラニ
ル〕−2−〔5−(3−ピリジル)ペンチル〕アクリル
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
0.86 (t, J = 7.0Hz, 3H), 1.20〜1.42 (m, 10H), 1.46〜1.58
(m, 4H), 1.69 (tt, J = 7.5,7.5Hz, 2H), 2.36 (t, J = 7.5Hz, 2
H), 2.55 (t, J = 7.5Hz, 2H), 3.13 (t, J = 8.5Hz, 2H), 3.83 (t,
J = 7.0Hz, 2H), 4.49 (t, J = 8.5Hz, 2H), 6.83 (s, 1H), 7.22 (d
d, J = 5.0,8.0Hz, 1H), 7.48 (dt, J = 1.5,8.0Hz, 1H), 7.60 (s,
1H), 8.43 (dd, J = 1.5,5.0Hz, 1H), 8.45 (d, J = 1.5Hz, 1H) Example 37 (E) -3- [2,3-dihydro-6-methoxy-5-
(Methoxymethoxy) -4-methyl-7-benzofurani
] -2- [5- (3-pyridyl) pentyl] acrylic
acid

【0179】[0179]

【化68】 [Chemical 68]

【0180】(E)−3−〔2,3−ジヒドロ−6−メ
トキシ−5−(メトキシメトキシ)−4−メチル−7−
ベンゾフラニル〕−2−〔5−(3−ピリジル)ペンチ
ル〕アクリル酸エチルから、実施例18の(1) と同様の
方法により標題化合物を得た。
(E) -3- [2,3-Dihydro-6-methoxy-5- (methoxymethoxy) -4-methyl-7-
The title compound was obtained from ethyl benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylate by the same method as in Example 18, (1).

【0181】・1H−NMR(400MHz, CDCl3) δ ppm;
1.24〜1.33(m,2H), 1.45〜1.65(m,4H), 2.23(s,3H),2.3
3(t,J=7.5Hz,2H), 2.56(t,J=7.5Hz,2H), 3.09(t,J=8.5H
z,2H),3.59(s,3H), 3.71(s,3H), 4.54(t,J=8.5Hz,2H),
5.01(s,2H),7.23(bs,1H), 7.48(d,J=9.0Hz,1H), 7.57
(s,1H), 8.45(bs,2H)実施例38 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−6
−メトキシ−4−メチル−7−ベンゾフラニル)−2−
〔5−(3−ピリジル)ペンチル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.24 to 1.33 (m, 2H), 1.45 to 1.65 (m, 4H), 2.23 (s, 3H), 2.3
3 (t, J = 7.5Hz, 2H), 2.56 (t, J = 7.5Hz, 2H), 3.09 (t, J = 8.5H
z, 2H), 3.59 (s, 3H), 3.71 (s, 3H), 4.54 (t, J = 8.5Hz, 2H),
5.01 (s, 2H), 7.23 (bs, 1H), 7.48 (d, J = 9.0Hz, 1H), 7.57
(s, 1H), 8.45 (bs, 2H) Example 38 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-4-methyl-7-benzofuranyl) -2-
[5- (3-pyridyl) pentyl] acrylic acid

【0182】[0182]

【化69】 [Chemical 69]

【0183】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−6−メトキシ−4−メチル−7
−ベンゾフラニル〕−2−〔5−(3−ピリジル)ペン
チル〕アクリル酸から、実施例18の(2) と同様の方法
により標題化合物を得た。
(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -6-methoxy-4-methyl-7
The title compound was obtained from -benzofuranyl] -2- [5- (3-pyridyl) pentyl] acrylic acid in the same manner as in Example 18, (2).

【0184】・1H−NMR(400MHz, CDCl3) δ ppm;
1.21〜1.31(m,2H), 1.44〜1.64(m,4H), 2.19(s,3H),2.3
7(t,J=7.5Hz,2H), 2.56(t,J=7.5Hz,2H), 3.09(t,J=7.5H
z,2H),3.70(s,3H), 4.51(t,J=8.5Hz,2H), 7.22(dd,J=5.
0,7.5Hz,1H),7.48(bd,J=7.5Hz,1H), 7.60(s,1H), 8.42
〜8.46(m,2H)実施例39 (E)−3−(2,3−ジヒドロ−5−ヒドロキシ−6
−メトキシ−4−メチル−7−ベンゾフラニル)−2−
〔5−(3−ピリジル)ヘキシル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.21 to 1.31 (m, 2H), 1.44 to 1.64 (m, 4H), 2.19 (s, 3H), 2.3
7 (t, J = 7.5Hz, 2H), 2.56 (t, J = 7.5Hz, 2H), 3.09 (t, J = 7.5H
z, 2H), 3.70 (s, 3H), 4.51 (t, J = 8.5Hz, 2H), 7.22 (dd, J = 5.
0,7.5Hz, 1H), 7.48 (bd, J = 7.5Hz, 1H), 7.60 (s, 1H), 8.42
~ 8.46 (m, 2H) Example 39 (E) -3- (2,3-dihydro-5-hydroxy-6)
-Methoxy-4-methyl-7-benzofuranyl) -2-
[5- (3-pyridyl) hexyl] acrylic acid

【0185】[0185]

【化70】 [Chemical 70]

【0186】(E)−3−〔2,3−ジヒドロ−5−
(メトキシメトキシ)−6−メトキシ−4−メチル−7
−ベンゾフラニル〕−2−〔5−(3−ピリジル)ヘキ
シル〕アクリル酸エチル 1.5gから、実施例18と同様
の方法により標題化合物410mgを黄色結晶として得た。
(E) -3- [2,3-dihydro-5-
(Methoxymethoxy) -6-methoxy-4-methyl-7
In the same manner as in Example 18, the title compound (410 mg) was obtained as yellow crystals from 1.5 g of ethyl -benzofuranyl] -2- [5- (3-pyridyl) hexyl] acrylate.

【0187】・融点;145〜146℃ ・1H−NMR(400MHz, CDCl3) δ ppm;1.23〜1.29(m,
4H), 1.43〜1.60(m,4H), 2.20(s,3H),2.36(t,J=7.0Hz,2
H), 2.57(t,J=7.0Hz,2H), 3.10(t,J=8.5Hz,2H),3.69(s,
3H), 4.52(t,J=8.5Hz,2H), 7.24(dd,J=5.0,8.0Hz,1H),
7.50(dt,J=1.5,8.0Hz,1H), 7.59(s,1H), 8.44〜8.46(m,
2H)実施例40 4−{〔3,4−ジヒドロ−6−(メトキシメトキシ)
−5−(3−ピリジルメチル)−2H−1−ベンゾピラ
ン−7−イル〕オキシ}酪酸
Melting point: 145 to 146 ° C. 1 H-NMR (400 MHz, CDCl 3 ) δ ppm; 1.23 to 1.29 (m,
4H), 1.43 to 1.60 (m, 4H), 2.20 (s, 3H), 2.36 (t, J = 7.0Hz, 2
H), 2.57 (t, J = 7.0Hz, 2H), 3.10 (t, J = 8.5Hz, 2H), 3.69 (s,
3H), 4.52 (t, J = 8.5Hz, 2H), 7.24 (dd, J = 5.0,8.0Hz, 1H),
7.50 (dt, J = 1.5,8.0Hz, 1H), 7.59 (s, 1H), 8.44 ~ 8.46 (m,
2H) Example 40 4-{[3,4-dihydro-6- (methoxymethoxy)
-5- (3-pyridylmethyl) -2H-1-benzopyra
N-7-yl] oxy} butyric acid

【0188】[0188]

【化71】 [Chemical 71]

【0189】実施例3で製造された4−{〔3,4−ジ
ヒドロ−6−(メトキシメトキシ)−5−(3−ピリジ
ルメチル)−2H−1−ベンゾピラン−7−イル〕オキ
シ}酪酸エチル 1.4gから、実施例18の(1) と同様の
方法により標題化合物860mgを白色結晶として得た。
Ethyl 4-{[3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethyl) -2H-1-benzopyran-7-yl] oxy} butyrate prepared in Example 3 From 1.4 g, 860 mg of the title compound was obtained as white crystals by a method similar to that in Example 18, (1).

【0190】・1H−NMR(400MHz, CDCl3) δ ppm;
1.89(tt,J=7.0,7.0Hz,2H), 2.16(tt,J=7.5,7.5Hz,2H),
2.41(t,J=7.5Hz,2H), 2.57(t,J=7.0Hz,2H), 3.44(s,3
H),4.00〜4.05(m,4H), 4.08(s,2H), 5.01(s,2H), 6.37
(s,1H), 7.24(bs,1H),7.5(bd,J=8.0Hz,1H), 8.45(bs,2
H)実施例41 4−{〔3,4−ジヒドロ−6−ヒドロキシ−5−(3
−ピリジルメチル)−2H−1−ベンゾピラン−7−イ
ル〕オキシ}酪酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.89 (tt, J = 7.0,7.0Hz, 2H), 2.16 (tt, J = 7.5,7.5Hz, 2H),
2.41 (t, J = 7.5Hz, 2H), 2.57 (t, J = 7.0Hz, 2H), 3.44 (s, 3
H), 4.00 ~ 4.05 (m, 4H), 4.08 (s, 2H), 5.01 (s, 2H), 6.37
(s, 1H), 7.24 (bs, 1H), 7.5 (bd, J = 8.0Hz, 1H), 8.45 (bs, 2
H) Example 41 4-{[3,4-dihydro-6-hydroxy-5- (3
-Pyridylmethyl) -2H-1-benzopyran-7-i
[Oxy] butyric acid

【0191】[0191]

【化72】 [Chemical 72]

【0192】4−{〔3,4−ジヒドロ−6−(メトキ
シメトキシ)−5−(3−ピリジルメチル)−2H−1
−ベンゾピラン−7−イル〕オキシ}酪酸860mg から、
実施例18の(2) と同様の方法により標題化合物320mg
を白色結晶として得た。
4-{[3,4-dihydro-6- (methoxymethoxy) -5- (3-pyridylmethyl) -2H-1
From 860 mg of -benzopyran-7-yl] oxy} butyric acid,
320 mg of the title compound was prepared in the same manner as in Example 18, (2)
Was obtained as white crystals.

【0193】・融点;140〜142℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.80(tt,J=
7.0,7.0Hz,2H), 1.91(tt,J=7.5,7.5Hz,2H),2.41〜2.53
(m,4H), 3.89〜3.93(m,6H), 6.28(s,1H), 7.20〜7.28
(m,1H),7.46(bd,J=8.0Hz,1H), 8.28 〜8.44(m,2H)実施例42 (E)−3−〔3,4−ジヒドロ−6−(メトキシメト
キシ)−5−(3−ピリジルメチル)−2H−1−ベン
ゾピラン−7−イル〕アクリル酸
Melting point: 140 to 142 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.80 (tt, J =
7.0,7.0Hz, 2H), 1.91 (tt, J = 7.5,7.5Hz, 2H), 2.41 ~ 2.53
(m, 4H), 3.89 ~ 3.93 (m, 6H), 6.28 (s, 1H), 7.20 ~ 7.28
(m, 1H), 7.46 (bd, J = 8.0Hz, 1H), 8.28 to 8.44 (m, 2H) Example 42 (E) -3- [3,4-dihydro-6- (methoxymeth)
Xy) -5- (3-pyridylmethyl) -2H-1-ben
Zopyran-7-yl] acrylic acid

【0194】[0194]

【化73】 [Chemical 73]

【0195】(E)−3−〔3,4−ジヒドロ−6−
(メトキシメトキシ)−5−(3−ピリジルメチル)−
2H−1−ベンゾピラン−7−イル〕アクリル酸エチル
1.0gから、実施例18の(1) と同様の方法により標題
化合物900mg を白色結晶として得た。
(E) -3- [3,4-dihydro-6-
(Methoxymethoxy) -5- (3-pyridylmethyl)-
2H-1-benzopyran-7-yl] ethyl acrylate
From 1.0 g, the title compound (900 mg) was obtained as white crystals by a method similar to that in Example 18 (1).

【0196】・1H−NMR(400MHz, CDCl3) δ ppm;
1.94(tt,J=7.0,7.0Hz,2H), 2.55(t,J=7.0Hz,2H), 3.52
(s,3H),4.09(t,J=7.0Hz,2H), 4.09(s,2H), 4.89(s,2H),
6.41(d,J=15.0Hz,1H),7.03(s,1H), 7.22(dd,J=5.0,8.0
Hz,1H), 7.42(dt,J=1.5,8.0Hz,1H),8.02(d,J=15.0Hz,1
H), 8.45(dd,J=1.5,5.0Hz,1H), 8.49(d,J=1.5Hz,1H)実施例43 (E)−3−〔3,4−ジヒドロ−6−ヒドロキシ−5
−(3−ピリジルメチル)−2H−1−ベンゾピラン−
7−イル〕アクリル酸
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.94 (tt, J = 7.0,7.0Hz, 2H), 2.55 (t, J = 7.0Hz, 2H), 3.52
(s, 3H), 4.09 (t, J = 7.0Hz, 2H), 4.09 (s, 2H), 4.89 (s, 2H),
6.41 (d, J = 15.0Hz, 1H), 7.03 (s, 1H), 7.22 (dd, J = 5.0,8.0
Hz, 1H), 7.42 (dt, J = 1.5,8.0Hz, 1H), 8.02 (d, J = 15.0Hz, 1
H), 8.45 (dd, J = 1.5,5.0Hz, 1H), 8.49 (d, J = 1.5Hz, 1H) Example 43 (E) -3- [3,4-dihydro-6-hydroxy-5
-(3-Pyridylmethyl) -2H-1-benzopyran-
7-yl] acrylic acid

【0197】[0197]

【化74】 [Chemical 74]

【0198】(E)−3−〔3,4−ジヒドロ−6−
(メトキシメトキシ)−5−(3−ピリジルメチル)−
2H−1−ベンゾピラン−7−イル〕アクリル酸から、
実施例18の(2) と同様の方法により標題化合物を白色
結晶として得た。
(E) -3- [3,4-dihydro-6-
(Methoxymethoxy) -5- (3-pyridylmethyl)-
2H-1-benzopyran-7-yl] acrylic acid,
The title compound was obtained as white crystals by a method similar to that in Example 18, (2).

【0199】・融点;195〜197℃ ・1H−NMR(400MHz, DMSO-d6) δ ppm;1.82(tt,J=
7.0,7.0Hz,2H), 2.54(t,J=7.0Hz,2H),3.95(t,J=7.0Hz,2
H), 3.98(s,2H), 6.36(d,J=15.0Hz,1H), 6.96(s,1H),7.
25(dd,J=5.0,8.0Hz,1H), 7.43(dt,J=1.5,8.0Hz,1H),7.9
0(d,J=15.0Hz,1H), 8.34(dd,J=1.5,5.0Hz,1H), 8.37(d,
J=1.5Hz,1H),8.73(bs,1H)実施例44 (E)−3−〔3,4−ジヒドロ−6−ヒドロキシ−7
−メチル−5−(3−ピリジルメチル)−2H−1−ベ
ンゾピラン−8−イル〕アクリル酸
Melting point: 195 to 197 ° C. 1 H-NMR (400 MHz, DMSO-d 6 ) δ ppm; 1.82 (tt, J =
7.0,7.0Hz, 2H), 2.54 (t, J = 7.0Hz, 2H), 3.95 (t, J = 7.0Hz, 2
H), 3.98 (s, 2H), 6.36 (d, J = 15.0Hz, 1H), 6.96 (s, 1H), 7.
25 (dd, J = 5.0,8.0Hz, 1H), 7.43 (dt, J = 1.5,8.0Hz, 1H), 7.9
0 (d, J = 15.0Hz, 1H), 8.34 (dd, J = 1.5,5.0Hz, 1H), 8.37 (d,
J = 1.5 Hz, 1H), 8.73 (bs, 1H) Example 44 (E) -3- [3,4-dihydro-6-hydroxy-7
-Methyl-5- (3-pyridylmethyl) -2H-1-be
Nzopyran-8-yl] acrylic acid

【0200】[0200]

【化75】 [Chemical 75]

【0201】(E)−3−〔3,4−ジヒドロ−6−
(メトキシメトキシ)−7−メチル−5−(3−ピリジ
ルメチル)−2H−1−ベンゾピラン−8−イル〕アク
リル酸エチル 1.7gから、実施例18と同様の方法によ
り標題化合物200mg を白色結晶として得た。
(E) -3- [3,4-dihydro-6-
In the same manner as in Example 18, from 200 g of ethyl (methoxymethoxy) -7-methyl-5- (3-pyridylmethyl) -2H-1-benzopyran-8-yl] acrylate, 200 mg of the title compound was obtained as white crystals. Obtained.

【0202】・融点;259〜261℃ ・1H−NMR(400MHz, CDCl3+DMSO-d6) δ ppm;1.95
(tt,J=7.0,7.0Hz,2H), 2.33(s,3H), 2.60(t,J=7.0Hz,2
H),4.06(s,2H), 4.11(t,J=7.0Hz,2H), 6.50(d,J=15.0H
z,1H),7.18(dd,J=5.0,8.0Hz,1H), 7.45(dt,J=1.5,8.0H
z,1H),7.86(d,J=15.0Hz,1H), 8.37(dd,J=1.5,5.0Hz,1
H), 8.45(d,J=1.5Hz,1H)実施例45 4−{〔3,4−ジヒドロ−6−ヒドロキシ−7−
〔(E)−2−(3−ピリジル)−1−ビニル〕−2H
−1−ベンゾピラン−5−イル〕オキシ}酪酸
Melting point: 259 to 261 ° C. 1 H-NMR (400 MHz, CDCl 3 + DMSO-d 6 ) δ ppm; 1.95
(tt, J = 7.0,7.0Hz, 2H), 2.33 (s, 3H), 2.60 (t, J = 7.0Hz, 2
H), 4.06 (s, 2H), 4.11 (t, J = 7.0Hz, 2H), 6.50 (d, J = 15.0H
z, 1H), 7.18 (dd, J = 5.0,8.0Hz, 1H), 7.45 (dt, J = 1.5,8.0H
z, 1H), 7.86 (d, J = 15.0Hz, 1H), 8.37 (dd, J = 1.5,5.0Hz, 1
H), 8.45 (d, J = 1.5Hz, 1H) Example 45 4-{[3,4-dihydro-6-hydroxy-7-
[(E) -2- (3-pyridyl) -1-vinyl] -2H
-1-Benzopyran-5-yl] oxy} butyric acid

【0203】[0203]

【化76】 [Chemical 76]

【0204】4−{〔3,4−ジヒドロ−6−(メトキ
シメトキシ)−7−〔(E)−2−(3−ピリジル)−
1−ビニル〕−2H−1−ベンゾピラン−5−イル〕オ
キシ}酪酸エチル560mg から、実施例18と同様の方法
により標題化合物260mg を黄色無晶形質として得た。
4-{[3,4-dihydro-6- (methoxymethoxy) -7-[(E) -2- (3-pyridyl)-]
260 mg of the title compound was obtained as a yellow amorphous phenotype from 560 mg of ethyl 1-vinyl] -2H-1-benzopyran-5-yl] oxy} butyrate in the same manner as in Example 18.

【0205】・1H−NMR(400MHz, CDCl3) δ ppm;
1.94(tt,J=7.0,7.0Hz,2H),
2.10(tt,J=7.5,7.5Hz,2H),
2.54(t,J=7.5Hz,2H), 2.74
(t,J=7.0Hz,2H), 3.96(t,J=
7.5Hz,2H),4.08(t,J=7.0Hz,
2H), 6.38(s,1H), 6.54(d,J
=13.0Hz,1H),6.72(d,J=13.0
Hz,1H), 7.21(dd,J=5.0,8.0
Hz,1H),7.63(dt,J=1.5,8.0H
z,1H), 8.34(dd,J=1.5,5.0H
z,1H),8.45(d,J=1.5Hz,1H)
1 H-NMR (400 MHz, CDCl 3 ) δ ppm;
1.94 (tt, J = 7.0, 7.0 Hz, 2H),
2.10 (tt, J = 7.5, 7.5 Hz, 2H),
2.54 (t, J = 7.5 Hz, 2H), 2.74
(T, J = 7.0 Hz, 2H), 3.96 (t, J =
7.5 Hz, 2 H), 4.08 (t, J = 7.0 Hz,
2H), 6.38 (s, 1H), 6.54 (d, J
= 13.0 Hz, 1H), 6.72 (d, J = 13.0)
Hz, 1H), 7.21 (dd, J = 5.0, 8.0
Hz, 1H), 7.63 (dt, J = 1.5, 8.0H
z, 1H), 8.34 (dd, J = 1.5, 5.0H
z, 1H), 8.45 (d, J = 1.5Hz, 1H)

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 FI 技術表示箇所 C07D 405/06 213 8829−4C 405/12 213 8829−4C //(C07D 405/06 213:00 6701−4C 311:00) 7729−4C (C07D 405/06 213:00 6701−4C 307:00) 7729−4C (C07D 405/12 213:00 6701−4C 311:00) 7729−4C (72)発明者 田上 克也 茨城県つくば市梅園2−20−12 MKハイ ツ203 (72)発明者 沼田 博敏 茨城県つくば市並木3−18−7 イースト アベニューB201 (72)発明者 篠田 昌信 茨城県つくば市春日4−19−13 紫山寮 203 (72)発明者 川原 哲也 茨城県つくば市天久保2−23−5 メゾン 学園304 (72)発明者 山津 功 茨城県牛久市柏田3605−669─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Office reference number FI technical display location C07D 405/06 213 8829-4C 405/12 213 8829-4C // (C07D 405/06 213: 00 6701-4C 311: 00) 7729-4C (C07D 405/06 213: 00 6701-4C 307: 00) 7729-4C (C07D 405/12 213: 00 6701-4C 311: 00) 7729-4C (72) Invention Katsuya Tagami 2-20-12 Umezono Tsukuba, Ibaraki Prefecture MK Heights 203 (72) Inventor Hirotoshi Numata 3-18-7 Namiki, Tsukuba City, Ibaraki Prefecture East Avenue B201 (72) Masanobu Shinoda 4 Kasuga, Tsukuba City, Ibaraki Prefecture −19−13 Shiyama Dormitory 203 (72) Inventor Tetsuya Kawahara 2-23-5 Amakubo, Tsukuba City, Ibaraki Prefecture 304 Maison Gakuen 304 (72) Isao Yamazu 3605-669 Kashida, Ushiku City, Ibaraki

Claims (9)

【特許請求の範囲】[Claims] 【請求項1】 一般式(I) 【化1】 {式中、 R1,R2及びR3は同一又は相異なる水素原子、水
酸基又は式 【化2】 〔式中 Aは水素原子又はヘテロアリールアルキル基を意
味する。 Bは水素原子又はカルボキシル基又は保護され
たカルボキシル基を意味する。 Yは式 【化3】 (式中 pは0又は1〜6の整数を意味する。)で示され
る基、式 【化4】 (式中 qは0又は1〜6の整数を意味する。)で示され
る基、又は式 【化5】 で示される基を意味する。〕で示される基を意味する。
Xは水酸基又は保護された水酸基を意味する。nは2又は
3の整数を意味する。}で示されるクロマン誘導体若し
くはジヒドロベンゾフラン誘導体又はそれらの薬理学的
に許容できる塩。
1. A compound represented by the general formula (I): {In the formula, R 1 , R 2 and R 3 are the same or different hydrogen atom, hydroxyl group or the formula: [In the formula, A represents a hydrogen atom or a heteroarylalkyl group. B means a hydrogen atom, a carboxyl group or a protected carboxyl group. Y is the formula (In the formula, p means 0 or an integer of 1 to 6), a group represented by the formula: (Wherein q represents 0 or an integer of 1 to 6) or a group represented by the formula: Means a group represented by. ] It means the group shown by.
X means a hydroxyl group or a protected hydroxyl group. n means an integer of 2 or 3. } The chroman derivative or dihydrobenzofuran derivative shown by these, or those pharmacologically acceptable salts.
【請求項2】 請求項1記載のクロマン誘導体若しくは
ジヒドロベンゾフラン誘導体又はそれらの薬理学的に許
容できる塩を有効成分とする5−リポキシゲナーゼ阻害
剤。
2. A 5-lipoxygenase inhibitor comprising the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
【請求項3】 請求項1記載のクロマン誘導体若しくは
ジヒドロベンゾフラン誘導体又はそれらの薬理学的に許
容できる塩を有効成分とするトロンボキサン合成酵素阻
害剤。
3. A thromboxane synthase inhibitor containing the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.
【請求項4】 ロイコトリエン産生抑制剤である請求項
2記載の5−リポキシゲナーゼ阻害剤。
4. The 5-lipoxygenase inhibitor according to claim 2, which is a leukotriene production inhibitor.
【請求項5】 トロンボキサン合成阻害剤である請求項
3記載のトロンボキサン合成酵素阻害剤。
5. The thromboxane synthase inhibitor according to claim 3, which is a thromboxane synthase inhibitor.
【請求項6】 請求項1記載のクロマン誘導体若しくは
ジヒドロベンゾフラン誘導体又はそれらの薬理学的に許
容できる塩を有効成分とするロイコトリエン産生抑制剤
が有効な疾患の予防・治療剤。
6. A preventive / therapeutic agent for a disease for which a leukotriene production inhibitor containing the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient is effective.
【請求項7】 請求項1記載のクロマン誘導体若しくは
ジヒドロベンゾフラン誘導体又はそれらの薬理学的に許
容できる塩を有効成分とするトロンボキサン合成阻害剤
が有効な疾患の予防・治療剤。
7. A prophylactic / therapeutic agent for diseases for which a thromboxane synthesis inhibitor containing the chroman derivative or dihydrobenzofuran derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient is effective.
【請求項8】 ロイコトリエン産生抑制剤が有効な疾患
が、喘息又は肝疾患である請求項6記載の予防・治療
剤。
8. The preventive / therapeutic agent according to claim 6, wherein the disease for which the leukotriene production inhibitor is effective is asthma or liver disease.
【請求項9】 トロンボキサン合成阻害剤が有効な疾患
が、喘息又は肝疾患である請求項7記載の予防・治療
剤。
9. The preventive / therapeutic agent according to claim 7, wherein the disease for which the thromboxane synthesis inhibitor is effective is asthma or liver disease.
JP11349792A 1992-05-06 1992-05-06 Chromane derivative or dihydrobenzofuran derivative Expired - Fee Related JP3162175B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP11349792A JP3162175B2 (en) 1992-05-06 1992-05-06 Chromane derivative or dihydrobenzofuran derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP11349792A JP3162175B2 (en) 1992-05-06 1992-05-06 Chromane derivative or dihydrobenzofuran derivative

Publications (2)

Publication Number Publication Date
JPH05310724A true JPH05310724A (en) 1993-11-22
JP3162175B2 JP3162175B2 (en) 2001-04-25

Family

ID=14613819

Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Link
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0640609A1 (en) * 1993-08-24 1995-03-01 Ono Pharmaceutical Co., Ltd. Fused phenol derivatives having inhibitory activity on TXA2 synthetase, and 5-lipoxygenase and scavenging activity on oxygen species
WO1998009956A1 (en) * 1996-09-09 1998-03-12 Dainippon Pharmaceutical Co., Ltd. 2,3-dihydrobenzofuran derivative and hepatopathy remedy comprising the same as active ingredient
WO2004092153A1 (en) * 2003-04-14 2004-10-28 Nippon Soda Co. Ltd. Diamine derivative, production process, and antioxidizing drug
JP2005008631A (en) * 2003-05-29 2005-01-13 New Industry Research Organization Benzofuran compound and pharmaceutical composition containing the same

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0640609A1 (en) * 1993-08-24 1995-03-01 Ono Pharmaceutical Co., Ltd. Fused phenol derivatives having inhibitory activity on TXA2 synthetase, and 5-lipoxygenase and scavenging activity on oxygen species
US5534536A (en) * 1993-08-24 1996-07-09 Ono Pharmaceuticals Co. Ltd. Fused phenol derivatives
US5750544A (en) * 1993-08-24 1998-05-12 Ono Pharmaceuticals Co., Ltd. Fused phenol derivatives
WO1998009956A1 (en) * 1996-09-09 1998-03-12 Dainippon Pharmaceutical Co., Ltd. 2,3-dihydrobenzofuran derivative and hepatopathy remedy comprising the same as active ingredient
WO2004092153A1 (en) * 2003-04-14 2004-10-28 Nippon Soda Co. Ltd. Diamine derivative, production process, and antioxidizing drug
US7652155B2 (en) 2003-04-14 2010-01-26 Nippon Soda Co., Ltd. Diamine derivative, production process therefor and antioxidant
JP2005008631A (en) * 2003-05-29 2005-01-13 New Industry Research Organization Benzofuran compound and pharmaceutical composition containing the same

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