JPH0649700B2 - Benzofuran compound - Google Patents
Benzofuran compoundInfo
- Publication number
- JPH0649700B2 JPH0649700B2 JP63181374A JP18137488A JPH0649700B2 JP H0649700 B2 JPH0649700 B2 JP H0649700B2 JP 63181374 A JP63181374 A JP 63181374A JP 18137488 A JP18137488 A JP 18137488A JP H0649700 B2 JPH0649700 B2 JP H0649700B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- acid
- room temperature
- inert solvent
- present
- 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.)
- Expired - Lifetime
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、胃の運動性亢進、抗嘔吐活性および／または
５−ＨＴ３受容体拮抗作用を有し、医薬として有用であ
る新規なベンゾフラン化合物、その医薬上許容される塩
類または光学活性体に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention has a novel benzofuran having gastric motility, antiemetic activity and / or 5-HT 3 receptor antagonism, which is useful as a medicine. It relates to a compound, a pharmaceutically acceptable salt thereof or an optically active substance.
ネイチャー(Nature)第３１６巻第１１号第２１６頁（１
９８５年）にセロトニン−Ｍ受容体拮抗作用を有する８
−メチル−８−アザビシクロ〔３，２，１〕オクタン−
３−イル・インドール−３−カルボキシレートが記載さ
れている。最近、このセロトニン−Ｍ受容体は５−ＨＴ
３受容体と同一であることが判明した。Nature Vol. 316, No. 11, p. 216 (1
985) has serotonin-M receptor antagonism 8
-Methyl-8-azabicyclo [3,2,1] octane-
3-yl indole-3-carboxylates have been described. Recently, this serotonin-M receptor is 5-HT
It was found to be identical to the 3 receptor.
一方、特公昭６１−１９６３０号公報にはドパミン拮抗
作用を有する一群のベンゾフラン−およびベンゾピラン
カルボキサミド類が開示されている。On the other hand, Japanese Examined Patent Publication No. 61-19630 discloses a group of benzofuran- and benzopyrancarboxamides having a dopamine antagonistic action.
本発明者らは、胃の運動性亢進作用、抗嘔吐活性および
／または５−ＨＴ３受容体拮抗作用を有する新規な化合
物を開発することを目的として、鋭意研究を重ねてき
た。The present inventors have conducted intensive studies for the purpose of developing a novel compound having a gastric motility action, an antiemetic activity, and / or a 5-HT 3 receptor antagonistic action.
〔課題を解決するための手段〕 本発明者らの一連の研究の結果、ある種のベンゾフラン
化合物が上記目的に合致することを見出し、本発明を完
成した。[Means for Solving the Problems] As a result of a series of studies conducted by the present inventors, the inventors have found that a certain benzofuran compound meets the above object, and completed the present invention.
すなわち、本発明は式 で表わされるベンゾフラン化合物、その医薬上許容され
る塩または光学異性体に関する。That is, the invention has the formula And a pharmaceutically acceptable salt or optical isomer thereof.
本発明化合物は、式 で表わされるカルボン酸またはその反応性誘導体と、式 で表わされる化合物とを反応させることにより製造され
る。The compound of the present invention has the formula A carboxylic acid represented by It is produced by reacting with a compound represented by
(1)式（II）の化合物が遊離のカルボン酸である場合、
反応は、ジシクロヘキシルカルボジイミド、四塩化チタ
ン、ハロゲン化リン（三塩化リン、オキシ塩化リンな
ど）、ジエチルクロロホスファイト、ｏ−フェニレンク
ロロホスファイト、エチルジクロロホスファイトなどの
縮合剤の存在下に不活性溶媒中、冷却下、室温下または
加温下に行なわれる。なお、化合物（III）にあらかじ
めハロゲン化リンを不活性溶媒中で作用させた後、化合
物（II）と縮合させることもできる。たとえば、ハロゲ
ン化リンが三塩化リンである場合には、化合物（III）
にあらかじめ約1/2モルの三塩化リンを不活性溶媒中、
トリエチルアミン、ピリジン、Ｎ，Ｎ−ジメチルアニリ
ンなどの三級塩基の存在下に冷却下または室温下で作用
させた後、不活性溶媒中で化合物（II）と室温または加
温下好ましくは、加熱還流下に反応させる。(1) When the compound of formula (II) is a free carboxylic acid,
The reaction is inert in the presence of a condensing agent such as dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halides (phosphorus trichloride, phosphorus oxychloride, etc.), diethylchlorophosphite, o-phenylenechlorophosphite, ethyldichlorophosphite, etc. It is carried out in a solvent under cooling, at room temperature or under heating. The compound (III) may be reacted with phosphorus halide in an inert solvent in advance and then condensed with the compound (II). For example, when the phosphorus halide is phosphorus trichloride, the compound (III)
In advance about 1/2 mol of phosphorus trichloride in an inert solvent,
After reacting in the presence of a tertiary base such as triethylamine, pyridine, N, N-dimethylaniline under cooling or at room temperature, the compound (II) is reacted with an inert solvent at room temperature or under heating, preferably under heating under reflux. React below.
(2)式（II）のカルボン酸の反応性誘導体として酸クロ
リド、酸プロミドなどの酸ハライドを用いる場合、反応
は不活性の溶媒中でトリエチルアミン、ピリジン、Ｎ，
Ｎ−ジメチルアニリンなどの三級塩基の存在下に冷却下
または室温下で行なわれるか、または水酸化ナトリウ
ム、水酸化カリウムなどのアルカリの存在下、水中で冷
却下あるいは室温下に行なわれる。(2) When an acid halide such as acid chloride or acid bromide is used as the reactive derivative of the carboxylic acid of the formula (II), the reaction is carried out in an inert solvent with triethylamine, pyridine, N,
It is carried out in the presence of a tertiary base such as N-dimethylaniline under cooling or at room temperature, or in the presence of an alkali such as sodium hydroxide or potassium hydroxide in water under cooling or at room temperature.
(3)化合物（II）の反応性誘導体として対称型酸無水物
またはアルキル炭酸混合酸無水物、アルキルリン酸混酸
無水物、アルキル亜リン酸混合酸無水物、硫酸混合酸無
水物などの混合酸無水物を用いる場合、反応は不活性溶
媒中でトリエチルアミン、ピリジン、Ｎ，Ｎ−ジメチル
アニリンなどの三級塩基の存在下、冷却下、室温または
加温下に行なわれる。(3) As a reactive derivative of compound (II), a symmetrical acid anhydride or a mixed acid such as an alkyl carbonic acid mixed acid anhydride, an alkyl phosphoric acid mixed acid anhydride, an alkyl phosphorous acid mixed acid anhydride, and a sulfuric acid mixed acid anhydride. When the anhydride is used, the reaction is carried out in an inert solvent in the presence of a tertiary base such as triethylamine, pyridine and N, N-dimethylaniline, under cooling, at room temperature or under heating.
(4)化合物（II）の反応性誘導体として酸イミダゾリ
ド、酸ピロリジド、２．４−ジメチルピラゾリドなどの
活性アミドを用いる場合、反応は不活性溶媒中で室温ま
たは加温下に行なわれる。(4) When an active amide such as acid imidazolide, acid pyrrolidide or 2.4-dimethylpyrazolide is used as a reactive derivative of compound (II), the reaction is carried out in an inert solvent at room temperature or under heating.
(5)式（III）の化合物は、さらに化合物（II）の反応性
誘導体としてメチルエステル、エチルエステル、ｐ−ニ
トロフェニルエステル、ｐ−クロロフェニルエステルな
どのエステルと反応させることもでき、その反応は不活
性溶媒（化合物（III）を過剰に用いて溶媒を兼ねさせ
ることができる）中、室温または加温下に、好ましくは
加熱還流下に行なわれる。(5) The compound of the formula (III) can be further reacted with an ester such as methyl ester, ethyl ester, p-nitrophenyl ester or p-chlorophenyl ester as a reactive derivative of the compound (II). The reaction is carried out in an inert solvent (compound (III) can be used in excess to serve also as a solvent) at room temperature or under heating, preferably under heating under reflux.
前記の各縮合反応で使用される不活性溶媒としては、ベ
ンゼン、トルエン、キシレン、メタノール、エタノー
ル、イソプロピルアルコール、エチルエーテル、ジオキ
サン、テトラヒドロフラン、クロロホルム、ジクロロメ
タン、ジクロロエタン、ヘキサメチルホスホリックトリ
アミド、ジエチレングリコール、ジメチルホルムアミド
などまたはこれらの混合溶媒であるか、反応性誘導体で
あるが、反応性誘導体の種類により適当に選択される。As the inert solvent used in each condensation reaction, benzene, toluene, xylene, methanol, ethanol, isopropyl alcohol, ethyl ether, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, hexamethylphosphoric triamide, diethylene glycol, It may be dimethylformamide or the like or a mixed solvent thereof, or a reactive derivative, which is appropriately selected depending on the kind of the reactive derivative.
本発明化合物は、ラセミ混合物として得られるが、本発
明には、それぞれの光学異性体も包含される。ラセミ混
合物は所望により、その塩基性を利用して光学活性な酸
（酒石酸、ジベンゾイル酒石酸、マンデル酸、１０−カ
ンファースルホン酸など）を用いて常法により光学分割
することができる。また、ラセミ体（II）を光学活性な
塩基（シンコニン、シンコニジン、ブルシン、キニー
ネ、α−メチルベンジルアミンなど）を用いて光学分割
して得た光学活性カルボン酸またはその反応性誘導体
と、別途に、光学活性な酸（酒石酸、ジベンゾイル酒石
酸、マンデル酸、１０−カンファースルホン酸など）で
分割して調製した光学活性な化合物（III）とを、前述
の縮合反応に付することにより、所望する立体配置を有
する目的化合物（Ｉ）を立体選択的に製造することがで
きる。The compound of the present invention is obtained as a racemic mixture, but the present invention also includes each optical isomer. If desired, the racemic mixture can be optically resolved by a conventional method using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by utilizing its basicity. Separately, an optically active carboxylic acid or a reactive derivative thereof obtained by optically resolving the racemate (II) using an optically active base (cinchonine, cinchonidine, brucine, quinine, α-methylbenzylamine, etc.) , An optically active compound (III) prepared by resolution with an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) is subjected to the above-mentioned condensation reaction to give a desired stereoisomer. The target compound (I) having a configuration can be stereoselectively produced.
式（Ｉ）の化合物は、塩酸塩、臭化水素酸塩、リン酸
塩、硫酸塩、トルエンスルホン酸塩、クエン酸塩、乳酸
塩、マレイン酸塩、フマール酸塩、酒石酸塩などの医薬
上許容しうる酸付加塩とすることができる。The compound of formula (I) is a pharmaceutical compound such as hydrochloride, hydrobromide, phosphate, sulfate, toluenesulfonate, citrate, lactate, maleate, fumarate or tartrate. It can be an acceptable acid addition salt.
本発明の化合物は、胃の運動性亢進作用、抗嘔吐活性お
よび／または５−ＨＴ３受容体拮抗活性を有し、消化不
良、遅延性胃内容排出、消化性潰瘍などの消化器系諸疾
患の予防、治療などおよび／または偏頭痛、群発性頭
痛、不整脈、またはシスプラチンなどの制癌剤投与によ
り誘発される嘔吐、放射線治療により誘発される悪心も
しくは嘔吐、あるいは不安、精神病などの中枢神経系の
障害などの治療に有用である。本発明の化合物のこれら
薬理作用は標準的な薬理実験方法により確認されてお
り、また、５−ＨＴ３受容体に対する拮抗作用はベゾル
ト−ジャーリッシュ(Bezold−Jarisch)試験により確か
められている。The compound of the present invention has gastric hypermotility, antiemetic activity and / or 5-HT 3 receptor antagonistic activity, and digestive system diseases such as dyspepsia, delayed gastric emptying and peptic ulcer. , Treatment and / or vomiting induced by migraine, cluster headache, arrhythmia, or administration of anticancer drugs such as cisplatin, nausea or vomiting induced by radiation therapy, or central nervous system disorders such as anxiety or psychosis It is useful for treatment such as. These pharmacological actions of the compounds of the present invention have been confirmed by standard pharmacological experimental methods, and their antagonism to the 5-HT 3 receptor has been confirmed by the Bezold-Jarisch test.
本発明の化合物を医薬として用いる場合、通常医薬とし
て許容しうる担体、賦形剤、希釈剤などの添加剤と混合
して錠剤（糖衣錠、フィルムコート錠も含む）、顆粒、
散剤、注射剤などの剤型として患者に安全に投与され
る。投与量は患者の症状、体重、年齢などにより変わり
うるが、通常経口投与の場合、成人１日当たり0.1〜１
００mg／kg程度であり、これを１回または数回に分けて
投与するのが好ましい。When the compound of the present invention is used as a medicine, it is usually mixed with a pharmaceutically acceptable carrier, an excipient, an additive such as a diluent, to obtain tablets (including sugar-coated tablets and film-coated tablets), granules,
It is safely administered to patients in dosage forms such as powders and injections. The dose may vary depending on the patient's symptoms, body weight, age, etc., but usually, in the case of oral administration, 0.1 to 1 per adult day
It is about 00 mg / kg, and it is preferable to administer this once or divided into several times.
以下、実施例により本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described with reference to examples.
実施例１ ５−クロロ−２−メチル−２，３−ジヒドロベンゾフラ
ン−７−カルボン酸クロライド2.5ｇおよびトリエチル
アミン1.09ｇを含有するジクロロメタン８０mの溶液
に０〜３℃で３−アミノキヌクリジン1.24ｇをジクロロ
メタン２０mに溶かした溶液を攪拌下加えた。反応混
合物を４時間室温で攪拌し、次に１０％水酸化ナトリウ
ム水溶液を加え、有機層を分離し、水洗後無水硫酸マグ
ネシウムで乾燥した。溶媒を留去後、シリカゲルクロマ
トグラフィーに付し、１０％メタノール含有クロロホル
ムで溶出して精製し、塩酸塩とした後、エタノール−イ
ソプロピルエーテル混液から再結晶すると、５−クロロ
−２−メチル−Ｎ−（３−キヌクリジニル）−２，３−
ジヒドロベンゾフラン−７−カルボキサミド・塩酸塩・
２／３水和物が得られた。融点２６７〜２６９℃Example 1 A solution of 2.5 g of 5-chloro-2-methyl-2,3-dihydrobenzofuran-7-carboxylic acid chloride and 1.09 g of triethylamine in 80 m of dichloromethane at 0-3 ° C. 1.24 g of 3-aminoquinuclidine. Was dissolved in 20 m of dichloromethane, and the solution was added with stirring. The reaction mixture was stirred at room temperature for 4 hours, 10% aqueous sodium hydroxide solution was then added, the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel chromatography, eluted with 10% methanol-containing chloroform for purification, and converted to a hydrochloride, which was then recrystallized from an ethanol-isopropyl ether mixed solution to give 5-chloro-2-methyl-N. -(3-quinuclidinyl) -2,3-
Dihydrobenzofuran-7-carboxamide / hydrochloride /
A 2/3 hydrate was obtained. Melting point 267-269 ° C
Claims (1)
る塩または光学異性体。1. A formula The benzofuran compound represented by, a pharmaceutically acceptable salt or optical isomer thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63181374A JPH0649700B2 (en) | 1987-07-21 | 1988-07-20 | Benzofuran compound |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18259187 | 1987-07-21 | ||
| JP62-182591 | 1987-07-21 | ||
| JP63181374A JPH0649700B2 (en) | 1987-07-21 | 1988-07-20 | Benzofuran compound |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15424489A Division JPH0232077A (en) | 1989-06-16 | 1989-06-16 | Benzofuran and benzopyran compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01104072A JPH01104072A (en) | 1989-04-21 |
| JPH0649700B2 true JPH0649700B2 (en) | 1994-06-29 |
Family
ID=26500587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63181374A Expired - Lifetime JPH0649700B2 (en) | 1987-07-21 | 1988-07-20 | Benzofuran compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0649700B2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5122528A (en) * | 1983-12-22 | 1992-06-16 | Erbamont, Inc. | Analgesic use of benzobicyclic carboxamides |
| IL87674A (en) * | 1987-09-08 | 1993-08-18 | Lilly Co Eli | Azabicycloalkyl esters and amides of heterocyclic acids, their preparation and pharmaceutical compositions containing them |
| JPH05310732A (en) * | 1992-03-12 | 1993-11-22 | Mitsubishi Kasei Corp | Cinnoline-3-carboxylic acid derivative |
| JP2999669B2 (en) * | 1993-08-24 | 2000-01-17 | 株式会社三和化学研究所 | Benzo [b] furancarboxamide derivatives, their preparation and use |
| JPH0820586A (en) | 1994-07-05 | 1996-01-23 | Sanwa Kagaku Kenkyusho Co Ltd | 1-azbicyclo(octane derivative, its salt, production and use |
| JPH0873463A (en) | 1994-07-05 | 1996-03-19 | Sanwa Kagaku Kenkyusho Co Ltd | Benzopyrane carboxamide derivative, its salt and production method and use |
| GB9507882D0 (en) * | 1995-04-18 | 1995-05-31 | Pharmacia Spa | Substituted dihydrobenzofuran derivatives as 5-ht4 agonists |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62234083A (en) * | 1986-02-28 | 1987-10-14 | アーバモント インク ディビーエイ アドリヤ ラボラトリーズ | Carboxamides useful as antiemetic and mental disease remedy |
-
1988
- 1988-07-20 JP JP63181374A patent/JPH0649700B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01104072A (en) | 1989-04-21 |
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