JPS647995B2 - - Google Patents

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Publication number
JPS647995B2
JPS647995B2 JP13270380A JP13270380A JPS647995B2 JP S647995 B2 JPS647995 B2 JP S647995B2 JP 13270380 A JP13270380 A JP 13270380A JP 13270380 A JP13270380 A JP 13270380A JP S647995 B2 JPS647995 B2 JP S647995B2
Authority
JP
Japan
Prior art keywords
thiophene
benzoyl
piperazinyl
group
formula
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
Application number
JP13270380A
Other languages
Japanese (ja)
Other versions
JPS5756476A (en
Inventor
Ryoji Kikumoto
Akihiro Tobe
Jiichi Fukami
Mitsuo Egawa
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.)
Mitsubishi Kasei Corp
Original Assignee
Mitsubishi Kasei Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Kasei Corp filed Critical Mitsubishi Kasei Corp
Priority to JP13270380A priority Critical patent/JPS5756476A/en
Publication of JPS5756476A publication Critical patent/JPS5756476A/en
Publication of JPS647995B2 publication Critical patent/JPS647995B2/ja
Granted legal-status Critical Current

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

Description

【発明の詳现な説明】 本発明はω−アミノアルコキシベンゟむルチオ
プン類およびその酞付加塩に関するものであ
る。さらに詳しくは本発明は抗䞍安䜜甚あるいは
鎮静䜜甚を有するω−アミノアルコキシベンゟむ
ルチオプン類およびその酞付加塩に関するもの
である。 本発明化合物は䞋蚘䞀般匏 で瀺される。 䞀般匏においおは〜の敎数を瀺
し、は以䞋に瀺す基を衚わす。 【匏】 䞊蚘匏䞭R1およびR2はそれぞれ氎玠原子た
たはC1〜C3のアルキル基を瀺す。具䜓的には
アミノ基、ゞメチルアミノ基、メチルアミノ
基、ゞプロピルアミノ基等が挙げられる。 【匏】 䞊蚘匏䞭はたたはの敎数を瀺し、該耇
玠環基はハロゲン原子で眮換されおいおもよい
プニル基たたはヒドロキシル基の䞀方あるい
は双方で眮換されおいおもよい。具䜓的にはピ
ロリゞニル基、ピペリゞノ基、−プニルピ
ペリゞノ基、−ヒドロキシ−−ピロリゞニ
ル基、−プニル−−ヒドロキシピペリゞ
ノ基、−−クロロプニルピペリゞノ
基、−プニル−−ピロリゞニル基、−
−クロロプニル−−ヒドロキシピペリ
ゞノ基等が挙げられる。 【匏】 䞊蚘匏䞭R3はヒドロキシル基で眮換されお
いおもよいアルキル基たたはハロゲン原子で眮
換されおいおもよいプニル基を瀺す。具䜓的
には−メチル−−ピペラゞニル基、−゚
チル−−ピペラゞニル基、−β−ヒドロ
キシ゚チル−−ピペラゞニル基、−プ
ニル−−ピペラゞニル基、−−フルオ
ロプニル−−ピペラゞニル基、−−
クロロプニル−−ピペラゞニル基、−
−クロロプニル−−ピペラゞニル基等
が挙げられる。 本発明化合物の具䜓䟋ずしおは以䞋のような化
合物が挙げられる。 −−−メチルアミノブトキシベンゟ
むルチオプン −−−゚チルアミノブトキシベンゟ
むルチオプン −−−ゞメチルアミノブトキシベン
ゟむルチオプン −−−ゞ゚チルアミノブトキシベン
ゟむルチオプン −−−ゞプロピルアミノブトキシベ
ンゟむルチオプン −−〔−−ピロリゞニルブトキシ〕
ベンゟむルチオプン −−−ピペリゞノブトキシベンゟむ
ルチオプン −−〔−−プニル−−ヒドロキ
シピペリゞノブトキシ〕ベンゟむルチオプ
ン −−−〔−−クロロプニル−
−ヒドロキシピペリゞノ〕ブトキシベンゟむ
ルチオプン −−〔−−プニル−−ピペラゞ
ニルブトキシ〕ベンゟむルチオプン −−−〔−−クロロプニル−
−ピペラゞニル〕ブトキシベンゟむルチオ
プン −−−〔−−クロロプニル−
−ピペラゞニル〕ブトキシベンゟむルチオ
プン −−−〔−−クロロプニル−
−ピペラゞニル〕ブトキシベンゟむルチオ
プン −−−〔−−フルオロプニル
−−ピペラゞニル〕ブトキシベンゟむルチ
オプン −−−〔−−フルオロプニル
−−ピペラゞニル〕ブトキシベンゟむルチ
オプン −−−〔−−フルオロプニル
−−ピペラゞニル〕ブトキシベンゟむルチ
オプン −−〔−−メチル−−ピペラゞニ
ルブトキシ〕ベンゟむルチオプン −−〔−−゚チル−−ピペラゞニ
ルブトキシ〕ベンゟむルチオプン −−−メチルアミノ゚トキシベンゟ
むルチオプン −−−ゞメチルアミノ゚トキシベン
ゟむルチオプン −−−ゞ゚チルアミノ゚トキシベン
ゟむルチオプン −−〔−−ピロリゞニル゚トキシ〕
ベンゟむルチオプン −−−ピペリゞノ゚トキシベンゟむ
ルチオプン −−〔−−プニル−−ヒドロキ
シピペリゞノ゚トキシ〕ベンゟむルチオプ
ン −−−〔−−クロロプニル−
−ヒドロキシピペリゞノ〕゚トキシベンゟむ
ルチオプン −−〔−−プニル−−ピペラゞ
ニル゚トキシ〕ベンゟむルチオプン −−〔−−メチル−−ピペラゞニ
ル゚トキシ〕ベンゟむルチオプン −−−メチルアミノペンチルオキシ
ベンゟむルチオプン −−−ゞメチルアミノペンチルオキ
シベンゟむルチオプン −−−ゞ゚チルアミノペンチルオキ
シベンゟむルチオプン −−〔−−ピロリゞニルペンチル
オキシ〕ベンゟむルチオプン −−−ピペリゞノペンチルオキシベ
ンゟむルチオプン −−〔−−プニル−−ヒドロキ
シピペリゞノペンチルオキシ〕ベンゟむルチ
オプン −−−〔−−クロロプニル−
−ヒドロキシピペリゞノ〕ペンチルオキシベ
ンゟむルチオプン −−〔−−プニル−−ピペラゞ
ニルペンチルオキシ〕ベンゟむルチオプン −−−〔−−クロロプニル−
−ピペラゞニル〕ペンチルオキシベンゟむル
チオプン −−−〔−−フルオロプニル
−−ピペラゞニル〕ペンチルオキシベンゟむ
ルチオプン −−〔−−メチルピペラゞニル−
−ペンチルオキシ〕ベンゟむルチオプン −−−メチルアミノプロポキシベン
ゟむルチオプン −−−゚チルアミノプロポキシベン
ゟむルチオプン −−−ゞメチルアミノプロポキシベ
ンゟむルチオプン −−−ゞ゚チルアミノプロポキシベ
ンゟむルチオプン −−−ゞプロピルアミノプロポキシ
ベンゟむルチオプン −−〔−−ピロリゞニルプロポキ
シ〕ベンゟむルチオプン −−−ピペリゞノプロポキシベンゟ
むルチオプン −−〔−−プニル−−ヒドロキ
シピペリゞノプロポキシ〕ベンゟむルチオフ
゚ン −−−〔−−クロロプニル−
−ヒドロキシピペリゞノ〕プロポキシベンゟ
むルチオプン −−〔−−プニル−−ピペラゞ
ニルプロポキシ〕ベンゟむルチオプン −−−〔−−クロロプニル−
−ピペラゞニル〕プロポキシベンゟむルチ
オプン −−−〔−−クロロプニル−
−ピペラゞニル〕プロポキシベンゟむルチ
オプン −−−〔−−クロロプニル−
−ピペラゞニル〕プロポキシベンゟむルチ
オプン −−−〔−−フルオロプニル
−−ピペラゞニル〕プロポキシベンゟむル
チオプン −−−〔−−フルオロプニル
−−ピペラゞニル〕プロポキシベンゟむル
チオプン −−−〔−−フルオロプニル
−−ピペラゞニルプロポキシベンゟむルチ
オプン −−〔−−メチル−−ピペラゞニ
ルプロポキシ〕ベンゟむルチオプン −−〔−−゚チル−−ピペラゞニ
ルプロポキシ〕ベンゟむルチオプン−
−〔−−β−ヒドロキシ゚チル−−ピ
ペラゞニルプロポキシ〕ベンゟむルチオプ
ン −−〔−−プロピル−−ピペラゞ
ニルプロポキシ〕ベンゟむルチオプン たた、䞊蚘化合物の薬剀的に蚱容され埗る酞付
加塩も本発明の範囲に包含される。 䞊蚘の酞付加塩ずしお塩化氎玠酞、臭化氎玠
酞、硫酞、リン酞、硝酞、酢酞、蓚酞、コハク
酞、アゞピン酞、プロピオン酞、酒石酞、マレむ
ン酞、ク゚ン酞、安息銙酞、トル゚ンスルホン
酞、メタンスルホン酞等の酞付加塩が挙げられ
る。 次に本発明化合物の補造法に぀いお説明する。 本発明化合物のω−アミノアルコキシベンゟむ
ルチオプン類は䞋蚘䞀般匏 䞊蚘匏䞭はハロゲン原子を瀺し、は䞀般匏
におけるず同矩である。で衚わされるω
−ハロゲノアルコキシベンゟむルチオプン類ず
䞋蚘䞀般匏 −    䞊蚘匏䞭は䞀般匏におけるず同矩で
ある。で衚わされるアミン類を反応させお補造
される。 䞊蚘補造法を詳现に説明するず、原料のひず぀
であるω−ハロゲノアルコキシベンゟむルチオフ
゚ン類は−ω−ハロゲノアルコキシ
ベンゟむルクロリドずチオプンを四塩化スズ觊
媒䞋にフリヌデルクラフト反応を行うこずによ぀
お埗られる。オヌガニツク シンセンス コレ
クテむブ ボリナヌムO.S. colle.、、頁 䞊蚘反応で消費されるアミン類はω−ハ
ロゲノアルコキシベンゟむルチオプン類モル
に察しモルである。過剰のアミン類を䜿甚すれ
ばさらに反応速床を高めるこずができる。通垞、
アミン類はω−ハロゲノアルコキシベンゟむルチ
オプン類モルに察し〜100モル䜿甚される。 反応は無溶媒䞭でも十分進行するが、反応を均
䞀系で行うために䞍掻性溶媒を甚いおもよい。溶
媒ずしおは氎、ゞオキサン、テトラヒドロフラ
ン、ゞメチルスルホキシド、䜎玚アルコヌル、ゞ
メチルホルムアミドたたはこれら皮以䞊の溶媒
の混合物が甚いられる。 反応枩床は特に限定されないが、通垞宀枩から
150℃である。 反応時間は、反応枩床および原料の反応性によ
り異なるが通垞40時間以䞋である。 たた、反応により生ずるハロゲン化氎玠を補集
しお反応を促進させるために塩基類を添加しおも
よい。塩基類ずしおは、氎酞化カリりム、氎酞化
ナトリりム、炭酞カリりム、炭酞ナトリりム等の
無機塩基類、ピリゞン、トリ゚チルアミン等の第
䞉玚アミン類が䜿甚される。塩基類の䜿甚量はω
−ハロゲノアルコキシベンゟむルチオプン類
モルに察し通垞〜モルである。 䞊蚘した塩基類を添加しない堎合には、ω−ア
ミノアルコキシベンゟむルチオプン類は、反応
で生成するハロゲン化氎玠ずさらに反応しおその
酞付加塩に倉化する。望たしい酞付加塩を埗るた
めには過剰のアミン類および溶媒を留去し、氎酞
化ナトリりム、氎酞化カリりム等の匷塩基氎溶液
を加えおω−アミノアルコキシベンゟむルチオフ
゚ン類の酞付加塩を遊離のω−アミノアルコキシ
ベンゟむルチオプン類ずし、゚ヌテル、クロロ
ホルム、ベンれン等の溶媒でこれを抜出する。さ
らに望たしい酞を加えお䞭和するず、目的ずする
ω−アミノアルコキシベンゟむルチオプン類の
酞付加塩を埗るこずができる。 䞊蚘反応によ぀お埗られるω−アミノアルコキ
シベンゟむルチオプン類およびその酞付加塩は
アルコヌル−゚ヌテル等の適圓な溶媒を甚いお再
結晶するこずにより粟補される。 本発明化合物は抗䞍安䜜甚あるいは鎮静䜜甚を
有する。䞀般匏で瀺される化合物の䞭で
が【匏】の堎合で、か぀該耇数環基が眮 換基を有する堎合は、特に䞋蚘匏 䞊蚘匏䞭R4はハロゲン原子で眮換されおいお
もよいプニル基を瀺す。で衚わされる眮換ピ
ペリゞノ基が奜たしい。 抗䞍安あるいは鎮静䜜甚を有する奜たしい化合
物ずしおは以䞋のような化合物が挙げられる。 −−−ゞメチルアミノプロポキシベ
ンゟむルチオプン −−−ゞ゚チルアミノプロポキシベ
ンゟむルチオプン −−〔−−ピロリゞニルプロポキ
シ〕ベンゟむルチオプン −−−ピペリゞノプロポキシベンゟ
むルチオプン −−〔−−プニル−−ヒドロキ
シピペリゞノプロポキシ〕ベンゟむルチオフ
゚ン −−−〔−−クロロプニル−
−ヒドロキシピペリゞノ〕プロポキシベンゟ
むルチオプン −−〔−−プニル−−ピペラゞ
ニルプロポキシ〕ベンゟむルチオプン −−〔−−クロロプニル−−ピ
ペラゞニル〕プロポキシベンゟむルチオプ
ン −−−〔−−フルオロプニル
−−ピペラゞニル〕プロポキシベンゟむル
チオプン 本発明化合物の薬理効果を以䞋に瀺す。 本発明化合物の抗䞍安効果は以䞋の方法で怜蚎
した。 抗䞍安薬ずしお公知のメプロバメヌトを察照薬
ずしお甚いた。結果は50有効量ED50、mg
Kg poずしお衚−に瀺した。 動物はddy系雄性マりス20−22を甚い、
抗䞍安䜜甚の指暙ずしお抗−フアむテむング
fighting䜜甚及び抗−モルヒネmorphine
䜜甚を怜蚎した。即ち抗−fighting䜜甚は
28VDC、−、分の電気シペツクをグ
リツドを介しお足郚に䞎えるこずにより発珟する
Fightingに察する抑制効果テむミング
Taming効果より怜蚎したR.E.Tedeschi、
D.H.Tedeschi、A.Mucha、L.Cook、P.A.
Mattis、E.J.Fellows.、ゞダヌナル オブ フア
ルマコロゞヌ ゚ンド ゚クスペリメンタル テ
ラピナりテむツクJ.Pharmacol.exp.Therap.、
125、281959。抗−morphine䜜甚は高朚らの
方法に埓いmorphine 20mgKgi.p.を投䞎するこ
ずにより発珟する挙尟反応に察する抑制䜜甚によ
り枬定した高朚匘、䞊岡利春、小林晋䜜、鈎朚
善雄、倪刀川隆治、日薬理誌、66、1071970。
衚に瀺すごずく、本発明化合物はメプロバメヌ
トにたさる抗䞍安効果を瀺した。 【衚】 本発明化合物はいかなる方法でも投䞎できる
が、奜適には以䞋のような方法が実斜される。 すなわち皮䞋泚射、静脈内泚射、筋肉泚射、腹
腔内泚射等の非経口投䞎もたた経口投䞎も可胜で
ある。 投䞎量は患者の幎什、健康状態、䜓重、同時凊
理があるならばその皮類、凊眮頻床、所望の効果
の性質等により決定される。 䞀般的に有効成分の日投䞎量は0.5〜50mg
Kg䜓重、通垞〜30mgKg䜓重であり、回ある
いはそれ以䞊投䞎される。 本発明化合物を経口投䞎する堎合は錠剀、カプ
セル剀、粉剀、液剀、゚リキシル剀等の圢䜓で、
たた非経口投䞎の堎合は液䜓あるいは懞濁等の殺
菌した液状の圢䜓で甚いられる。䞊述の様な圢䜓
で甚いられる堎合、固䜓あるいは液䜓の毒性のな
い補剀的担䜓が組成に含たれ埗る。 固䜓担䜓の䟋ずしおは通垞のれラチンタむプの
カプセルが甚いられる。たた有効成分を補助薬ず
ずもにあるいはそれなしに錠剀化、粉末包装され
る。 これらのカプセル、錠剀、粉末は䞀般的に〜
95、奜たしくは25〜90重量の有効成分を含
む。 すなわちこれらの投䞎圢匏では〜500mg、奜
たしくは25〜250mgの有効成分を含有するのがよ
い。 液状担䜓ずしおは氎あるいは石油、ピヌナツ
油、倧豆油、ミネラル油、ゎマ油等の動怍物起原
の、たたは合成の油等が甚いられる。 たた、䞀般に生理食塩氎、デキストロヌスある
いは類䌌のシペ糖溶液、゚チレングリコヌル、プ
ロピレングリコヌル、ポリ゚チレングリコヌル等
のグリコヌル類が液状担䜓ずしお奜たしく、ずく
に生理食塩氎を甚いた泚射液の堎合には適垞0.5
〜20、奜たしくは〜10重量の有効成分を含
むようにする。 経口投䞎の液剀の堎合、0.5〜10重量の有効
成分を含む懞濁液あるいはシロツプがよい。 この堎合の担䜓ずしおは銙料、シロツプ、補剀
孊的ミセル䜓等の氎様賊圢剀を甚いる。 以䞊説明したように本発明化合物は優れた抗䞍
安䜜甚を有し鎮静薬ずしお有効に䜿甚できる。 実斜䟋 (1) −−−クロロプロポキシベンゟむ
ルチオプン チオプンおよび−−クロロ
プロポキシベンゟむルクロリド沞点125−
8゜mmHg19.4をベンれン80mlに
溶解し、冷华䞋四塩化スズ21.7のベンれ
ン20ml溶液を滎䞋する。滎䞋終了埌、1.5
時間冷华䞋撹拌し、その埌時間宀枩で撹拌し
た。反応終了埌、1N−塩酞100mlを加え、
゚ヌテルで抜出する。有機局を氎および1N−
NaOHで掗浄し、無氎硫酞゜ヌダで也燥埌、
溶媒を留去し、残枣をシリカゲルカラムクロマ
トグラフむヌ溶出液ベンれンにより分離、
油状の−−−クロロプロポキシベン
ゟむルチオプン15を埗た収率64
。これを次のアミノ化反応に䟛した。 (2) −−〔−−プニル−−ピペラ
ゞニルプロポキシ〕ベンゟむルチオプン −−−クロロプロポキシベンゟむ
ルチオプン2.0をDMF10mlに溶
解し、−プニルピペラゞン1.25およ
びトリ゚チルアミン1.4を加え、50℃で
17時間撹拌する。反応終了埌2N−苛性゜ヌダ
氎溶液を加え、゚ヌテルで抜出し、飜和食塩氎
で掗浄埌、無氎硫酞゜ヌダで也燥する。溶媒を
枛圧䞋留去し、埗られた残枣を゚ヌテルに溶解
し、20塩化氎玠゚タノヌルを加え、結晶化
し、取埌、゚タノヌル−゚ヌテルから再結
し、−−〔−−プニル−−ピペ
ラゞニルプロポキシ〕ベンゟむルチオプ
ン塩酞塩を埗る。 収量2.9収率85 物性は衚−のNo.の欄に瀺した。他の化合
物も同様の方法で合成され、衚−に瀺した。 【衚】 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ω-aminoalkoxybenzoylthiophenes and acid addition salts thereof. More specifically, the present invention relates to ω-aminoalkoxybenzoylthiophenes having anxiolytic or sedative effects and acid addition salts thereof. The compound of the present invention has the following general formula () It is indicated by. In the general formula (), n represents an integer of 2 to 5, and R represents the group shown below. [Formula] In the above formula, R 1 and R 2 each represent a hydrogen atom or a C 1 to C 3 alkyl group. Specific examples include an amino group, a dimethylamino group, a methylamino group, a dipropylamino group, and the like. [Formula] In the above formula, m represents an integer of 4 or 5, and the heterocyclic group may be substituted with one or both of a phenyl group and a hydroxyl group, which may be substituted with a halogen atom. Specifically, pyrrolidinyl group, piperidino group, 4-phenylpiperidino group, 3-hydroxy-1-pyrrolidinyl group, 4-phenyl-4-hydroxypiperidino group, 4-(4-chlorophenyl)piperidino group, 3-phenyl-1-pyrrolidinyl group, 4-
(4-chlorophenyl)-4-hydroxypiperidino group and the like. [Formula] In the above formula, R 3 represents an alkyl group which may be substituted with a hydroxyl group or a phenyl group which may be substituted with a halogen atom. Specifically, 4-methyl-1-piperazinyl group, 4-ethyl-1-piperazinyl group, 4-(β-hydroxyethyl)-1-piperazinyl group, 4-phenyl-1-piperazinyl group, 4-(4- fluorophenyl)-1-piperazinyl group, 4-(4-
chlorophenyl)-1-piperazinyl group, 4-
(3-chlorophenyl)-1-piperazinyl group and the like. Specific examples of the compounds of the present invention include the following compounds. 2-{2-(4-methylaminobutoxy)benzoyl}thiophene 2-{2-(4-ethylaminobutoxy)benzoyl}thiophene 2-{2-(4-dimethylaminobutoxy)benzoyl}thiophene 2-{2- (4-diethylaminobutoxy)benzoyl}thiophene 2-{2-(4-dipropylaminobutoxy)benzoyl}thiophene 2-{2-[4-(1-pyrrolidinyl)butoxy]
Benzoyl}thiophene 2-{2-(4-piperidinobutoxy)benzoyl}thiophene 2-{2-[4-(4-phenyl-4-hydroxypiperidino)butoxy]benzoyl}thiophene 2-{2-{ 4-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]butoxy}benzoyl}thiophene 2-{2-[4-(4-phenyl-1-piperazinyl)butoxy]benzoyl}thiophene 2-{2-{4-[4-(4-chlorophenyl) −
1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(3-chlorophenyl)-
1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(2-chlorophenyl)-
1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(4-fluorophenyl)
-1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(3-fluorophenyl)
-1-piperazinyl]butoxy}benzoyl}thiophene 2-{2-{4-[4-(2-fluorophenyl)
-1-Piperazinyl]butoxy}benzoyl)thiophene 2-{2-[4-(4-methyl-1-piperazinyl)butoxy]benzoyl}thiophene 2-{2-[4-(4-ethyl-1-piperazinyl)butoxy [benzoyl}thiophene 2-{2-(2-methylaminoethoxy)benzoyl}thiophene 2-{2-(2-dimethylaminoethoxy)benzoyl}thiophene 2-{2-(2-diethylaminoethoxy)benzoyl}thiophene 2- {2-[2-(1-pyrrolidinyl)ethoxy]
Benzoyl}thiophene 2-{2-(2-piperidinoethoxy)benzoyl}thiophene 2-{2-[2-(4-phenyl-4-hydroxypiperidino)ethoxy]benzoyl}thiophene 2-{2-{ 2-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]ethoxy}benzoyl}thiophene 2-{2-[2-(4-phenyl-1-piperazinyl)ethoxy]benzoyl}thiophene 2-{2-[2-(4-methyl-1-piperazinyl) ) Ethoxy]benzoyl}thiophene 2-{2-(5-methylaminopentyloxy)
Benzoyl}thiophene 2-{2-(5-dimethylaminopentyloxy)benzoyl}thiophene 2-{2-(5-diethylaminopentyloxy)benzoyl}thiophene 2-{2-[5-(1-pyrrolidinyl)pentyloxy] Benzoyl}thiophene 2-{2-(5-piperidinopentyloxy)benzoyl}thiophene 2-{2-[5-(4-phenyl-4-hydroxypiperidino)pentyloxy]benzoyl}thiophene 2-{2 -{5-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]pentyloxy}benzoyl}thiophene 2-{2-[5-(4-phenyl-1-piperazinyl)pentyloxy]benzoyl}thiophene 2-{2-{5-[4-(4- Chlorophenyl-1
-piperazinyl]pentyloxy}benzoyl}
Thiophene 2-{2-{5-[4-(3-fluorophenyl)
-1-piperazinyl]pentyloxy}benzoyl}thiophene 2-{2-[5-(4-methylpiperazinyl)-1
-Pentyloxy]benzoyl}thiophene 2-{2-(3-methylaminopropoxy)benzoyl}thiophene 2-{2-(3-ethylaminopropoxy)benzoyl}thiophene 2-{2-(3-dimethylaminopropoxy)benzoyl }thiophene 2-{2-(3-diethylaminopropoxy)benzoyl}thiophene 2-{2-(3-dipropylaminopropoxy)
Benzoyl}thiophene 2-{2-[3-(1-pyrrolidinyl)propoxy]benzoyl}thiophene 2-{2-(3-piperidinopropoxy)benzoyl}thiophene 2-{2-[3-(4-phenyl- 4-Hydroxypiperidino)propoxy]benzoyl}thiophene 2-{2-{3-[4-(4-chlorophenyl)-
4-Hydroxypiperidino]propoxy}benzoyl}thiophene 2-{2-[3-(4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{2-{3-[4-(4-chlorophenyl) −
1-piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(3-chlorophenyl)-
1-piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(2-chlorophenyl)-
1-piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(4-fluorophenyl)
-1-piperazinyl]propoxy}benzoyl}
Thiophene 2-{2-{3-[4-(3-fluorophenyl)
-1-piperazinyl]propoxy}benzoyl}
Thiophene 2-{2-{3-[4-(2-fluorophenyl)
-1-piperazinyl)propoxybenzoyl}thiophene 2-{2-[3-(4-methyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{2-[3-(4-ethyl-1-piperazinyl)propoxy] benzoyl}thiophene 2-
{2-[3-(4-β-hydroxyethyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{2-[3-(4-propyl-1-piperazinyl)propoxy]benzoyl}thiophene In addition, the above compounds Pharmaceutically acceptable acid addition salts are also included within the scope of this invention. Acid addition salts of the above include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, citric acid, benzoic acid, toluenesulfonic acid, Examples include acid addition salts such as methanesulfonic acid. Next, a method for producing the compound of the present invention will be explained. The ω-aminoalkoxybenzoylthiophenes of the compounds of the present invention have the following general formula () (In the above formula, X represents a halogen atom, and n has the same meaning as n in the general formula ().)
- Manufactured by reacting halogenoalkoxybenzoylthiophenes with amines represented by the following general formula () R-H ... () (In the above formula, R has the same meaning as R in the general formula ()) . To explain the above production method in detail, one of the raw materials, ω-halogenoalkoxybenzoylthiophenes (), is 2-(ω-halogenoalkoxy).
It is obtained by Friedel-Crafts reaction between benzoyl chloride and thiophene under a tin tetrachloride catalyst. (Organic Synthesis Collective Volume (OS colle., 2 , p. 8) The amount of amines () consumed in the above reaction is 1 mole per 1 mole of ω-halogenoalkoxybenzoylthiophene. The reaction rate can be further increased if
The amine is used in an amount of 1 to 100 mol per mol of the ω-halogenoalkoxybenzoylthiophene. Although the reaction proceeds satisfactorily even in the absence of a solvent, an inert solvent may be used to carry out the reaction in a homogeneous system. As the solvent, water, dioxane, tetrahydrofuran, dimethyl sulfoxide, lower alcohol, dimethylformamide, or a mixture of two or more of these solvents is used. The reaction temperature is not particularly limited, but usually ranges from room temperature to
The temperature is 150℃. The reaction time varies depending on the reaction temperature and the reactivity of the raw materials, but is usually 40 hours or less. Furthermore, bases may be added in order to collect hydrogen halide generated by the reaction and accelerate the reaction. As the bases, inorganic bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate, and tertiary amines such as pyridine and triethylamine are used. The amount of bases used is ω
-halogenoalkoxybenzoylthiophenes 1
It is usually 1 to 5 moles per mole. When the above-mentioned bases are not added, the ω-aminoalkoxybenzoylthiophenes further react with the hydrogen halide produced in the reaction and change into acid addition salts thereof. To obtain the desired acid addition salt, excess amines and solvent are distilled off, and a strong aqueous base such as sodium hydroxide or potassium hydroxide is added to free the acid addition salt of ω-aminoalkoxybenzoylthiophene. The ω-aminoalkoxybenzoylthiophenes are extracted with a solvent such as ether, chloroform, or benzene. Further, by neutralizing by adding a desired acid, the desired acid addition salt of ω-aminoalkoxybenzoylthiophene can be obtained. The ω-aminoalkoxybenzoylthiophenes and acid addition salts thereof obtained by the above reaction are purified by recrystallization using a suitable solvent such as alcohol-ether. The compounds of the present invention have anxiolytic or sedative effects. In the compound represented by the general formula (), R
When is [Formula] and the multi-ring group has a substituent, especially the following formula () (In the above formula, R 4 represents a phenyl group which may be substituted with a halogen atom.) A substituted piperidino group represented by the following is preferred. Preferred compounds having anxiolytic or sedative effects include the following compounds. 2-{2-(3-dimethylaminopropoxy)benzoyl}thiophene 2-{2-(3-diethylaminopropoxy)benzoyl}thiophene 2-{2-[3-(1-pyrrolidinyl)propoxy]benzoyl}thiophene 2-{ 2-(3-piperidinopropoxy)benzoyl}thiophene 2-{2-[3-(4-phenyl-4-hydroxypiperidino)propoxy]benzoyl}thiophene 2-{3-{4-[4-( 4-chlorophenyl)-
4-Hydroxypiperidino]propoxy}benzoyl}thiophene 2-{2-[3-(4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene 2-{3-[4-(4-chlorophenyl)-1- Piperazinyl]propoxy}benzoyl}thiophene 2-{2-{3-[4-(4-fluorophenyl)
-1-piperazinyl]propoxy}benzoyl}
Thiophene The pharmacological effects of the compound of the present invention are shown below. The anxiolytic effects of the compounds of the present invention were examined using the following method. Meprobamate, known as an anxiolytic drug, was used as a control drug. The results are 50% effective dose (ED 50 , mg/
It is shown in Table 1 as Kg po). The animals used were ddy male mice (20-22 g).
Anti-fighting effect and anti-morphine as indicators of anxiolytic effect
The effect was investigated. In other words, the anti-fighting effect is
Developed by applying a 28VDC, 4-5mA, 3 minute electric shock to the foot via the grid.
The suppressive effect on fighting (taming effect) was investigated (RETedeschi,
DHTedeschi, A. Mucha, L. Cook, P.A.
Mattis, E.J.Fellows., Journal of Pharmacology and Experimental Therapy (J.Pharmacol.exp.Therap.),
125, 28 (1959)). The anti-morphine effect was measured by the inhibitory effect on the tail-raising reaction caused by administering morphine 20mg/Kgi.p. according to the method of Takagi et al. Journal, 66 , 107 (1970).
As shown in Table 1, the compounds of the present invention exhibited anxiolytic effects superior to meprobamate. [Table] Although the compound of the present invention can be administered by any method, the following method is preferably carried out. That is, parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, and intraperitoneal injection, as well as oral administration are possible. The dosage is determined depending on the patient's age, health condition, weight, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc. Generally, the daily dose of the active ingredient is 0.5-50mg/
Kg body weight, usually 1-30 mg/Kg body weight, administered in one or more doses. When the compound of the present invention is administered orally, it is in the form of tablets, capsules, powders, liquids, elixirs, etc.
In the case of parenteral administration, it is used in a sterilized liquid form such as a liquid or suspension. When used in such forms, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. As an example of a solid carrier, conventional gelatin type capsules are used. The active ingredient may also be packaged as a tablet or powder, with or without adjuvants. These capsules, tablets, and powders generally contain 5 to
Contains 95% by weight of active ingredient, preferably 25-90%. That is, these dosage forms should contain 5 to 500 mg, preferably 25 to 250 mg of active ingredient. As the liquid carrier, water or oils of animal or plant origin or synthetic oils such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, etc. are used. Generally, physiological saline, dextrose or similar sucrose solutions, and glycols such as ethylene glycol, propylene glycol, and polyethylene glycol are preferred as liquid carriers, and in particular, in the case of injections using physiological saline, a suitable amount of 0.5
~20%, preferably 1-10% by weight of active ingredient. In the case of liquid preparations for oral administration, suspensions or syrups containing 0.5 to 10% by weight of the active ingredient are preferred. In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers. As explained above, the compounds of the present invention have excellent anxiolytic effects and can be effectively used as sedatives. Example (1) 2-{2-(3-chloropropoxy)benzoyl}thiophene Thiophene (7 g) and 2-(3-chloropropoxy)benzoyl chloride (boiling point 125-
8°/1 mmHg) (19.4 g) was dissolved in benzene (80 ml), and a solution of tin tetrachloride (21.7 g) in benzene (20 ml) was added dropwise while cooling. After completion of dripping, 1.5
The mixture was stirred under cooling for 1 hour, and then stirred for 1 hour at room temperature. After the reaction is complete, add 1N hydrochloric acid (100ml),
Extract with ether. The organic layer was diluted with water and 1N−
After washing with NaOH and drying with anhydrous sodium sulfate,
The solvent was distilled off, and the residue was separated by silica gel column chromatography (eluent: benzene).
Oily 2-{2-(3-chloropropoxy)benzoyl}thiophene (15 g) was obtained (yield 64
%). This was subjected to the next amination reaction. (2) 2-{2-[3-(4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene Dissolve 2-{2-(3-chloropropoxy)benzoyl}thiophene (2.0 g) in DMF (10 ml). Then, N-phenylpiperazine (1.25 g) and triethylamine (1.4 g) were added, and the mixture was heated at 50°C.
Stir for 17 hours. After the reaction is completed, 2N aqueous sodium hydroxide solution is added, extracted with ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in ether, and 20% hydrogen chloride/ethanol was added to crystallize it. 4-phenyl-1-piperazinyl)propoxy]benzoyl}thiophene hydrochloride is obtained. Yield: 2.9 g (yield 85%) Physical properties are shown in column No. 6 of Table-2. Other compounds were synthesized in a similar manner and are shown in Table 2. 【table】

Claims (1)

【特蚱請求の範囲】  䞋蚘䞀般匏 䞊蚘䞀般匏は〜の敎数を瀺し、は 【匏】匏䞭R1およびR2はそれぞれ氎 玠原子たたはC1〜C3のアルキル基を瀺す。、 【匏】匏䞭はたたはの 敎数を瀺し、該耇玠環基はハロゲン原子で眮換
されおいおもよいプニル基およびたたはヒ
ドロキシル基で眮換されおいおもよい。たた
は 【匏】匏䞭R3はヒドロキシル 基で眮換されおいおもよいアルキル基たたはハ
ロゲン原子で眮換されおいおもよいプニル基
を瀺す。 で衚わされるω−アミノアルコキシベンゟむルチ
オプン類およびその酞付加塩。[Claims] 1. The following general formula {The above general formula n represents an integer of 2 to 5, and R represents [formula] (in the formula, R 1 and R 2 each represent a hydrogen atom or a C 1 to C 3 alkyl group), [formula] (formula m represents an integer of 4 or 5, and the heterocyclic group may be substituted with a phenyl group and/or a hydroxyl group which may be substituted with a halogen atom.) or [Formula] (in the formula R 3 represents an alkyl group optionally substituted with a hydroxyl group or a phenyl group optionally substituted with a halogen atom.)} ω-aminoalkoxybenzoylthiophenes and acid addition salts thereof.
JP13270380A 1980-09-24 1980-09-24 Omega-aminoalkoxybenzoylthiophene Granted JPS5756476A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP13270380A JPS5756476A (en) 1980-09-24 1980-09-24 Omega-aminoalkoxybenzoylthiophene

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP13270380A JPS5756476A (en) 1980-09-24 1980-09-24 Omega-aminoalkoxybenzoylthiophene

Publications (2)

Publication Number Publication Date
JPS5756476A JPS5756476A (en) 1982-04-05
JPS647995B2 true JPS647995B2 (en) 1989-02-10

Family

ID=15087575

Family Applications (1)

Application Number Title Priority Date Filing Date
JP13270380A Granted JPS5756476A (en) 1980-09-24 1980-09-24 Omega-aminoalkoxybenzoylthiophene

Country Status (1)

Country Link
JP (1) JPS5756476A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0398399U (en) * 1990-01-25 1991-10-11

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0628193B2 (en) * 1988-03-07 1994-04-13 ヒロセ電機株匏䌚瀟 EMI countermeasure electrical connector
US5183404A (en) * 1992-04-08 1993-02-02 Megahertz Corporation Systems for connection of physical/electrical media connectors to computer communications cards
US5562504A (en) * 1995-01-04 1996-10-08 Simple Technology Incorporated Communications card with integral transmission media line adaptor
US5660568A (en) * 1995-01-04 1997-08-26 Simple Technology, Inc. Communications card with integral transmission media line adaptor
US6217396B1 (en) * 1999-07-06 2001-04-17 Hon Hai Precision Ind. Co., Ltd. Electrical connector with U-shaped spring contacts
US6485322B1 (en) * 1999-10-01 2002-11-26 Jds Uniphase Corporation Removable latch and bezel EMI grounding feature for fiber-optic transceivers

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0398399U (en) * 1990-01-25 1991-10-11

Also Published As

Publication number Publication date
JPS5756476A (en) 1982-04-05

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