JP3958391B2 - Drugs for eye diseases - Google Patents
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- JP3958391B2 JP3958391B2 JP28211596A JP28211596A JP3958391B2 JP 3958391 B2 JP3958391 B2 JP 3958391B2 JP 28211596 A JP28211596 A JP 28211596A JP 28211596 A JP28211596 A JP 28211596A JP 3958391 B2 JP3958391 B2 JP 3958391B2
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Description
【０００１】
【発明の属する技術分野】
本発明は眼疾患用薬剤に関し、さらに詳しくは特定構造のセロトニン受容体１Ａリガンドを有効成分とする眼疾患用薬剤、例えば緑内障治療剤及び眼圧降下剤に関する。
緑内障等の眼疾患は、特に超高齢化社会を迎えている先進諸国における成人病の一つとして社会的重要性が益々増大している。
【０００２】
【従来の技術】
眼疾患、例えば緑内障は眼圧異常を起こす病変に基づいて眼内組織、特に視神経機能が障害される疾患群である。一般に病変を惹起する機構については、眼圧の上昇を起因とする視神経乳頭における循環障害による虚血症状および視神経軸索流障害が主因であると考えられており、眼圧の調整を目的として諸種の薬物療法が試みられ成果をあげている（例えば、眼科Ｍｏｏｋ Ｎｏ．９，１９７９．緑内障の治療、金原出版株式会社参照）。しかしながら、眼圧上昇のメカニズムについては未だ不明であり、さらに良好な治療薬の開発が強く望まれている。
【０００３】
一方、セロトニン受容体のリガンドは、血管収縮作用、交感神経興奮様作用、抗うつ作用、降圧作用、血小板凝集抑制作用等諸種の薬理作用を示すことが知られており、抗うつ剤、抗不安剤、抗高血圧剤等として疾患の治療に用いられている。また、これらのセロトニン受容体リガンドの中で、ある種のアルキレンジオキシベンゼン誘導体は、セロトニン受容体１Ａ（以下これを「５−ＨＴ1A受容体」と略称することがある）の選択的リガンドであり、血圧降下作用、抗不安作用等を有することが知られている（特開昭５７−１０８０８８号公報、特開平３−２６４５２８号公報、特開平４−２８８０７２号公報参照）。
【０００４】
【発明が解決しようとする課題】
本発明は、さらに優れた眼疾患用薬剤、例えば緑内障治療剤及び眼圧降下剤の提供を目的としてなされたものである。
【０００５】
【課題を解決するための手段】
本発明者等は、上記課題を解決すべく鋭意研究を重ねた結果、セロトニン受容体１Ａリガンド、例えば特定構造のアルキレンジオキシべンゼン誘導体が、優れた眼圧降下作用を有し、緑内障等の眼疾患の治療薬剤となり得ることを見い出し、本発明を完成するに至った。
即ち、本発明は、セロトニン受容体１Ａ（５−ＨＴ1A受容体）リガンドを有効成分とする眼疾患用薬剤を提供するものである。
さらに、この発明の好ましい態様によれば、５−ＨＴ1A受容体リガンドが下記式（Ｉ）
【０００６】
【化３】
（式中、ｍは２〜５の整数を示し、ｎは１〜３の整数を示す。）
で表されるアルキレンジオキシベンゼン誘導体、そのラセミ体またはそれらの酸付加塩である上記薬剤；該アルキレンジオキシベンゼン誘導体が下記式（II）
【０００８】
【化４】
で表される化合物である上記薬剤；該眼疾患用薬剤が緑内障治療剤である上記薬剤；該眼疾患用薬剤が眼圧降下剤である上記薬剤；該眼疾患用薬剤が経口剤である上記薬剤；該眼疾患用薬剤が注射剤である上記薬剤；該眼疾患用薬剤が点眼剤である上記薬剤が提供される。
【００１０】
【発明の実施の形態】
以下、本発明の実施の形態について説明する。
本発明の眼疾患用薬剤の有効成分として使用される５−ＨＴ1A受容体リガンドとしては、５−ＨＴ1A受容体に特異的に結合する化合物であって、眼圧の降下作用を有するものであれば、いかなる化合物であっても良い。具体的には、例えばＮｅｕｒｏｐｈａｒｍａｃｏｌｏｇｙ Ｖｏｌ．２６，Ｎｏ２／３，ｐｐ．１３９−１４６（１９８７）に記載されている８−ヒドロキシ−２−（Ｎ，Ｎ−ジプロピルアミノ）−テトラリン（以下これを「８−ＯＨ−ＤＰＡＴ」と称することがある）、２−（４−（４−（２−ピリミジニル）−１−ピペラジニル）ブチル）−１，２−ベンズイソチアゾール−３−（２Ｈ）オン−１，１−ジオキサイド−ハイドロクロライド（以下これを「ＴＶＸ Ｑ ７８２１」と称することがある）；前記式（Ｉ）で表されるアルキレンジオキシベンゼン誘導体、そのラセミ体、それらの酸付加塩またはそれらの任意の水和物を挙げることができる。これら５−ＨＴ1A受容体リガンドの中で上記式（Ｉ）で表される化合物、そのラセミ体、それらの酸付加塩またはそれらの任意の水和物が好ましい。
【００１１】
上記式（Ｉ）のアルキレンジオキシベンゼン誘導体において、ｍは２〜５の整数を示し、ｍは１〜３の整数を示すが、これらの中で、ｍが３または４の整数を示し、且つｎが１〜３の整数を示す化合物がより好ましく、ｍが３でありｎが１である化合物が最も好ましい。
本発明で使用される化合物のうち好ましい化合物の具体例を下記表１及び表２に示す。
【００１２】
【表１】
【表２】
上記式（Ｉ）で表される化合物又はそのラセミ体の酸付加塩における酸としては、塩酸、シュウ化水素酸、硫酸、リン酸、硝酸等の無機酸；酢酸、コハク酸、アジピン酸、プロピオン酸、酒石酸、フマル酸、マレイン酸、シュウ酸、クエン酸、安息香酸、トルエンスルホン酸、メタンスルホン酸等の有機酸が挙げられる。これらのうち、上記した化合物の塩酸塩を用いるのが好ましい。
上記した化合物の中で、表１の化合物Ｎｏ．１、すなわち前記式（II）の化合物が最も好ましく、この化合物の塩酸付加塩を本明細書においてＭＫＣ−２４２と称することがある。
【００１５】
本発明で使用される前記一般式（Ｉ）のアルキレンジオキシベンゼン誘導体、そのラセミ体及びそれらの酸付加塩は、公知の化合物であり、例えば特開昭５７−１０８０８８号公報、特開平４−２８８０７２号公報に記載の方法またはそれに準じた方法より容易に合成することができる。
本発明の眼疾患用薬剤は、前記５−ＨＴ1A受容体リガンドを有効成分として含有するものであり、それ自体既知の通常用いられる方法により経口剤、注射剤、点眼剤または軟膏剤等の諸種の製剤形態とすることができる。経口剤の場合は、錠剤、カプセル剤、粉剤、液剤、エリキシル剤等の形態で用いられる。この様な形態で用いられる場合、固体あるいは液体の毒性のない製剤的担体が組成に含まれ得る。
【００１６】
固体担体としては、例えばセルロース、マニトール、ラクトース、でん粉、ポリビニルピロリドン、ナトリウムでん粉グリコラート等のでん粉誘導体、ラウリル硫酸ナトリウム等が用いられる。有効成分を補助剤と共に、或いはそれなしにゼラチンタイプのカプセルに充填、打錠等による錠剤化、または粉末包装する。
これらのカプセル、錠剤、粉末は一般的に５〜９５％、好ましくは２５〜９０％重量の有効成分を含む。
即ち、これらの投与形式では１回の投与につき５〜５００ｍｇ、好ましくは２５〜２５０ｍｇの有効成分を含有することができる。
液状担体としては、例えば水あるいは石油、ピーナツ油、大豆油、ミネラル油、ゴマ油等の動植物起原の、又は合成の油が用いられる。
【００１７】
また、一般に生理食塩水、デキストロースあるいは類似のショ糖溶液、プロピレングリコール、ポリエチレングリコール等のグルコール類が液状担体として好ましく、特に生理食塩水を用いた注射液の場合には通常０．５〜２０％、好ましくは１〜１０％重量の有効成分を含むようにする。
経口投与の薬剤の場合、０．５〜１０％重量の有効成分を含む懸濁液あるいはシロップが良い。この場合の担体としては香料、シロップ、製剤学的ミセル体等の水様賦形剤を用いる。
点眼剤の調製には、前記５−ＨＴ1A受容体リガンドを水に溶解したものに以下のような各種の添加剤を適宜添加すればよい。
【００１８】
緩衝剤としては、例えばリン酸緩衝剤、ホウ酸緩衝剤、クエン酸塩緩衝剤、酒石酸緩衝剤、酢酸塩緩衝剤、アミノ酸などが用いられる。等張化剤としては、例えばソルビトール、グルコース、マンニトールなどの糖類、グリセリン、プロピレングリコールなどの多価アルコール類、塩化ナトリウムなどの塩類なとが用いられる。防腐剤としては、たとえば塩化ベンザルコニウム、塩化ベンゼトニウムなどの第四級アンモニウム塩、パラオキシ安息香酸メチル、パラオキシ安息香酸エチルなどのパラオキシ安息香酸エステル類、ベンジルアルコール、フェネチルアルコール、ソルビン酸およびそれらの塩、チメロサール、クロロブタノールなどが用いられる。粘稠剤としては、たとえばヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースおよびそれらの塩などが用いられる。
【００１９】
軟膏剤は、前記５−ＨＴ1A受容体リガンドをワセリン等の適当な基剤と均等に混和し、必要に応じて保存剤、安定剤、またはその他の適当な添加剤を加えて調製される。
その他の形態の医薬組成物も当業者に周知の方法で調製でき、本発明の医薬の一態様である薬剤の形態は上記のものに限定されることはない。
【００２０】
本発明の眼疾患用薬剤に含有される５−ＨＴ1A受容体リガンドの投与量は、患者の年令、体重、症状、疾患の重篤度等により変動し、最終的には臨床医によって決定されるべきものであるが、一般には０．００１〜１０．０ｍｇ／ｋｇ体重／日、一日あるいはそれ以上投与される。具体的には、５−ＨＴ1A受容体リガンドが前記式（Ｉ）のアルキレンジオキシベンゼン誘導体である場合の投与量は通常０．０５〜３ｍｇ／ｋｇ／体重／日が好ましく、経口剤の場合にはアルキレンジオキシベンゼン誘導体を通常０．５〜５００ｍｇ、好ましくは１〜１００ｍｇ含有させて単位投与剤型とし、それを、例えば１回５ｍｇとして通常一日１〜３回服用させる。注射剤の場合にはアルキレンジオキシベンゼン誘導体を通常０．５〜２０％、好ましくは１〜１０％重量含有させて単位投与剤型とし、それを、例えば、０．０３〜３ｍｇ／回、通常一日１〜４回投与させる。点眼剤の場合には、アルキレンジオキシベンゼン誘導体の濃度が０．１〜１％である点眼剤を調製し、それを１日１〜４回適用させる。
【００２１】
本発明の眼疾患用薬剤は前記した５−ＨＴ1A受容体リガンドの眼圧降下作用等に基づき、広く眼科領域の疾患に適用できる。５−ＨＴ1A受容体リガンドを有効成分とする本発明の薬剤は、例えば緑内障、高眼圧症等の眼疾患の予防および治療に有用である。なお、緑内障には高眼圧緑内障と、正常眼圧を示しながら緑内障性の乳頭異常や視野変化がみられる低眼圧緑内障とがあり、本発明の薬剤はこの両者に有効であるが、特に高眼圧緑内障に有効である。
【００２２】
【実施例】
以下、実施例を挙げて本発明を更に詳細に説明する。しかしながら、下記の実施例は本発明の具体的な認識を得る一助とみなすべきものであり、本発明の範囲を何ら制限するものではない。
製造例１
５−〔３−｛（２Ｓ）−（１，４−ベンゾジオキサン−２−イルメチル）アミノ｝プロポキシ〕−１，３−ベンゾジオキソール塩酸塩（表１の化合物Ｎｏ．１ の塩酸塩；ＭＫＣ−２４２）の合成
５−（３−アミノプロポキシ）−１，３−ベンゾジオキソール５．８６ｇと（２Ｒ）−２−トシロキシメチル−１，４−ベンゾジオキサン（Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ，２０，８８０，１９７７に従って合成した）３．２０ｇをアセトニトリル１００ｍｌに溶解し、トリエチルアミン２．７７ｍｌを加え、加熱還流下１２時間撹拌した。反応終了後、水を加え、クロロホルムで抽出した。抽出液を水で洗浄後、無水硫酸ナトリウムで乾燥した。クロロホルム層を濃縮し、シリカゲルカラムクロマトグラフィー（クロロホルム−メタノール）で精製し、５−〔３−｛（２ｓ）−（１，４−ベンゾジオキキサン−２−イルメチル）アミノ｝プロポキシ〕−１，３−ベンゾジオキソール２．６８ｇを得た。
これを酢酸エチルに溶解し、２６％塩酸／イソプロパノールを加えた。生成した結晶をろ取し、標題化合物２．３７ｇを得た。
【００２３】
融点２１２−２１８℃。
1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6 ）δ９．１６（２Ｈ，ｍ）、６．８９（５Ｈ，ｍ）、６．６３（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）、６．３７（１Ｈ，ｄｄ，Ｊ＝７．５、２．５Ｈｚ）、５．９５（２Ｈ，ｓ）、４．６５（１Ｈ，ｍ）、４．３７（１Ｈ，ｄｄ，Ｊ＝１２．５，２．３Ｈｚ）、４．０２（３Ｈ，ｍ）、３．２５（４Ｈ，ｍ）、２．１０（２Ｈ，ｍ）。
上記で得られた光学活性体と、別に合成したラセミ体（特開昭５７−１０８０８８号公報記載の方法に従って合成）を、それぞれピリジン中、（Ｓ）−メトキシトリフルオロメチルフェニル酢酸クロリドでアミド化したのち、高速液体クロマトグラフィー（カラム：ウォータース ノバパックＣ１８）で分析し、その比較によって光学純度を求めたところ、合成した光学活性体は、９９％ｅ．ｅ以上であった。
【００２４】
実施例１
体重約２ｋｇの雄性日本白色家兎８匹を保定缶に入れ約１時間の馴化後、試験に使用した。馴化後、初期眼圧を測定し、４匹の家兎の左眼に０．２％ＭＫＣ−２４２水溶液を、他の４匹の家兎の左眼に蒸留水をそれぞれ５０μｌ点眼した。薬剤点眼の０．５、１、２、３および４時間後に眼圧の測定を行った。眼圧の測定はアルコン（Ａｌｃｏｎ）社製のアプラネーション・ニューマトノグラフ（Ａｐｐｌａｎａｔｉｏｎ Ｐｎｅｕｍａｔｏｎｏｇｒａｐｈ）を用いて行った。同様の試験を５日後に行い、最初の試験で０．２％ＭＫＣ−２４２溶液を点眼した家兎には蒸留水を、蒸留水を点眼した家兎には０．２％ＭＫＣ−２４２をそれぞれ左眼に５０μｌ点眼した。なお、ＭＫＣ−２４２は超音波処理と試験管ミキサーを用いて、０．２％になるように蒸留水に溶解した。
【００２５】
その結果を図１に示す。図１から明らかなとおり、対照として蒸留水を点眼した家兎（ｃｏｎｔｒｏｌ）では初期眼圧２０．８ｍｍＨｇ、点眼４時間後の眼圧２２．８ｍｍＨｇと経時的に上昇した。これに対して、０．２％ＭＫＣ−２４２溶液を点眼した眼では、点眼３０分後より眼圧は降下し、点眼１〜２時間後に１８．０ｍｍＨｇの最低眼圧を示し、初期眼圧２０．８ｍｍＨｇに比較して２．８ｍｍＨｇ（点眼１および２時間後）、ｃｏｎｔｒｏｌの家兎の眼圧に比較して４．９ｍｍＨｇ（点眼２時間後）の最大眼圧降下作用が認められた。また、何ら点眼を行わなかった反対眼（右眼）に比較して、３．９ｍｍＨｇ（点眼２時間後）の最大眼圧降下作用が認められた。
【００２６】
実施例２
体重約３ｋｇの雄性日本白色家兎８匹を保定缶に入れ約１時間の馴化後、試験に使用した。馴化後、初期眼圧を測定し、４匹の家兎に０．５％ＣＭＣ（カルボキシメチルセルロース）に懸濁したＭＫＣ−２４２を３０ｍｇ／５ｍｌ／ｋｇ体重、他の４匹の家兎には０．５％ＣＭＣをそれぞれ５ｍｌ／ｋｇ体重経口投与した。経口投与の０．５時間後、１〜７時間後の１時間毎および２４時間後に眼圧の測定を行った。なお、眼圧の測定は実施例１と同様の方法で行い、ＭＫＣ−２４２は０．６％（３０ｍｇ／５ｍｌ）となるように撹拌と超音波処理により０．５％ＣＭＣ溶液に懸濁した。
【００２７】
その結果を図２に示す。図２から明らかなとおり、対照として０．５％ＣＭＣ溶液を経口投与した家兎（ｃｏｎｔｒｏｌ）では、初期眼圧２１．９ｍｍＨｇ、その後測定時間中１９．８〜２３．０の範囲で変動した。これに対して、ＭＫＣ−２４２を３０ｍｇ／ｋｇ経口投与した家兎では投与３０分後より眼圧は降下し、投与２時間後に１０．５ｍｍＨｇの最低眼圧を示した。投与３時間後より、眼圧は徐々に上昇していったが、投与７時間後においても、１４．３ｍｍＨｇと初期眼圧およびｃｏｎｔｒｏｌに比較して低眼圧を維持していた。投与２４時間後では、初期眼圧とほぼ同等になった。
【００２８】
実施例３
体重約２〜２．５ｋｇの雄性白色家兎を保定缶に入れ約１時間の馴化後、試験に使用した。馴化後、初期眼圧を測定し、５匹の家兎の片眼に１％８−ＯＨ−ＤＰＡＴ（フナコシ社製）水溶液を、反対眼に蒸留水をそれぞれ５０μｌ点眼し、点眼の０．５、１、２および３時間後に眼圧を測定した。眼圧の測定は実施例１と同様の方法で行った。
その結果を図３に示した。図３から明らかなとおり、８−ＯＨ−ＤＰＡＴは１％の点眼投与で家兎眼圧を有意に降下させた。
【図面の簡単な説明】
【図１】ＭＫＣ−２４２の点眼による眼圧降下作用を示す図である。図中、測定点及びバーは、８匹の眼圧の平均値＋／−Ｓ．Ｅ．を示し、＃は初期眼圧との有意差（Ｐ＜０．０１）を示し、＊はｃｏｎｔｒｏｌ群の眼圧との有意差（Ｐ＜０．０１）を示す。
【図２】ＭＫＣ−２４２経口投与による眼圧降下作用を示す図である。図中、測定点及びバーは、４匹の眼圧の平均値＋／−Ｓ．Ｅ．を示し、＃は初期眼圧との有意差（Ｐ＜０．０５）を示し、＊はｃｏｎｔｒｏｌ群との有意差（Ｐ＜０．０１）を示す。
【図３】８−ＯＨ−ＤＰＡＴの点眼による眼圧降下作用を示す図である。図中、測定点及びバーは、５匹の眼圧の平均値＋／−Ｓ．Ｅ．を示し、＊及び＊＊は初期眼圧との有意差（それぞれＰ＜０．０５及びＰ＜０．０１）を示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a drug for eye diseases, and more particularly to a drug for eye diseases containing a serotonin receptor 1A ligand having a specific structure as an active ingredient, such as a glaucoma therapeutic agent and an intraocular pressure-lowering agent.
Eye diseases such as glaucoma are becoming more and more socially important as one of the adult diseases in developed countries, especially in the aging society.
[0002]
[Prior art]
Ocular diseases, such as glaucoma, are a group of diseases in which intraocular tissues, particularly optic nerve functions, are impaired based on lesions that cause abnormal intraocular pressure. In general, the mechanism causing lesions is thought to be mainly caused by ischemic symptoms and optic nerve axonal flow disorders due to circulatory disturbances in the optic nerve head caused by increased intraocular pressure. (See, for example, Ophthalmology Mook No. 9, 1979. Treatment of glaucoma, Kanehara Publishing Co., Ltd.). However, the mechanism of the increase in intraocular pressure is still unclear, and the development of a better therapeutic agent is strongly desired.
[0003]
On the other hand, ligands of serotonin receptors are known to exhibit various pharmacological actions such as vasoconstriction, sympathomimetic action, antidepressant action, antihypertensive action, and platelet aggregation inhibitory action. It is used to treat diseases as an agent, an antihypertensive agent and the like. Among these serotonin receptor ligands, certain alkylenedioxybenzene derivatives are selective ligands of serotonin receptor 1A (hereinafter sometimes referred to as “5-HT 1A receptor”). It is known to have a blood pressure lowering action, an anxiolytic action, and the like (see JP-A-57-108088, JP-A-3-264528, JP-A-4-288072).
[0004]
[Problems to be solved by the invention]
The present invention has been made for the purpose of providing more excellent drugs for ophthalmic diseases, such as a glaucoma therapeutic agent and an intraocular pressure-lowering agent.
[0005]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventors have found that serotonin receptor 1A ligands such as alkylenedioxybenzene derivatives having a specific structure have an excellent intraocular pressure-lowering action, such as glaucoma. The present inventors have found that it can be a therapeutic drug for eye diseases and have completed the present invention.
That is, the present invention provides a drug for eye diseases comprising a serotonin receptor 1A (5-HT 1A receptor) ligand as an active ingredient.
Furthermore, according to a preferred embodiment of the present invention, the 5-HT 1A receptor ligand is represented by the following formula (I):
[0006]
[Chemical 3]
(In the formula, m represents an integer of 2 to 5, and n represents an integer of 1 to 3.)
The above-mentioned drug which is an alkylenedioxybenzene derivative represented by the following formula, a racemate thereof or an acid addition salt thereof; the alkylenedioxybenzene derivative represented by the following formula (II)
[0008]
[Formula 4]
The above-mentioned drug which is a compound represented by the above; the above-mentioned drug wherein the ophthalmic disease drug is a glaucoma therapeutic agent; the above-mentioned drug wherein the ophthalmic disease drug is an intraocular pressure-lowering agent; Provided is the above drug, wherein the eye disease drug is an injection; and the eye drug is an eye drop.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention will be described below.
The 5-HT 1A receptor ligand used as an active ingredient of the drug for eye diseases of the present invention is a compound that specifically binds to the 5-HT 1A receptor and has a function of lowering intraocular pressure. Any compound may be used as long as it is present. Specifically, for example, Neuropharmacology Vol. 26, No2 / 3, pp. 139-146 (1987), 8-hydroxy-2- (N, N-dipropylamino) -tetralin (hereinafter sometimes referred to as “8-OH-DPAT”), 2- (4 -(4- (2-pyrimidinyl) -1-piperazinyl) butyl) -1,2-benzisothiazole-3- (2H) one-1,1-dioxide-hydrochloride (hereinafter referred to as “TVX Q 7821”) An alkylenedioxybenzene derivative represented by the above formula (I), a racemate thereof, an acid addition salt thereof, or an arbitrary hydrate thereof. Among these 5-HT 1A receptor ligands, compounds represented by the above formula (I), racemates thereof, acid addition salts thereof, or arbitrary hydrates thereof are preferable.
[0011]
In the alkylenedioxybenzene derivative of the above formula (I), m represents an integer of 2 to 5, m represents an integer of 1 to 3, and in these, m represents an integer of 3 or 4, and A compound in which n is an integer of 1 to 3 is more preferable, and a compound in which m is 3 and n is 1 is most preferable.
Specific examples of preferable compounds among the compounds used in the present invention are shown in Tables 1 and 2 below.
[0012]
[Table 1]
[Table 2]
Examples of the acid in the compound represented by the above formula (I) or a racemic acid addition salt thereof include inorganic acids such as hydrochloric acid, oxalic acid, sulfuric acid, phosphoric acid, nitric acid; acetic acid, succinic acid, adipic acid, propion Examples thereof include organic acids such as acid, tartaric acid, fumaric acid, maleic acid, oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, and methanesulfonic acid. Of these, it is preferable to use hydrochlorides of the above-described compounds.
Among the compounds described above, compound No. 1 in Table 1 was used. 1, ie, the compound of formula (II) is most preferred, and the hydrochloric acid addition salt of this compound is sometimes referred to herein as MKC-242.
[0015]
The alkylenedioxybenzene derivatives of the above general formula (I), their racemates and their acid addition salts used in the present invention are known compounds, such as JP-A 57-108088 and JP-A 4- It can be easily synthesized by the method described in Japanese Patent No. 288072 or a method analogous thereto.
The drug for ophthalmic diseases of the present invention contains the 5-HT 1A receptor ligand as an active ingredient, and various kinds such as oral preparations, injection preparations, eye drops, ointments and the like according to commonly used methods known per se. It can be set as the formulation form. In the case of oral preparations, it is used in the form of tablets, capsules, powders, liquids, elixirs and the like. When used in such a form, the composition may include a solid or liquid non-toxic pharmaceutical carrier.
[0016]
As the solid carrier, for example, cellulose, mannitol, lactose, starch, polyvinyl pyrrolidone, starch derivatives such as sodium starch glycolate, sodium lauryl sulfate and the like are used. The active ingredient is filled into gelatin-type capsules with or without auxiliaries, tableted by tableting, or powder-packed.
These capsules, tablets and powders generally contain 5 to 95%, preferably 25 to 90% by weight of active ingredient.
That is, these dosage forms can contain 5 to 500 mg, preferably 25 to 250 mg of active ingredient per administration.
As the liquid carrier, for example, water or petroleum, peanut oil, soybean oil, mineral oil, sesame oil or other animal or plant origin or synthetic oil is used.
[0017]
In general, physiological saline, dextrose or similar sucrose solution, and glycols such as propylene glycol and polyethylene glycol are preferred as the liquid carrier, and in the case of an injection solution using physiological saline, usually 0.5 to 20%. The active ingredient is preferably contained in an amount of 1 to 10% by weight.
In the case of a drug for oral administration, a suspension or syrup containing 0.5 to 10% by weight of the active ingredient is preferable. In this case, water-based excipients such as fragrances, syrups and pharmaceutical micelles are used as carriers.
For the preparation of eye drops, various additives such as those described below may be appropriately added to the 5-HT 1A receptor ligand dissolved in water.
[0018]
As the buffer, for example, phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer, amino acid and the like are used. As the isotonic agent, for example, sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin and propylene glycol, and salts such as sodium chloride are used. Examples of preservatives include quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride, paraoxybenzoates such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and their salts. , Thimerosal, chlorobutanol and the like are used. As the thickener, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof are used.
[0019]
Ointments, said 5-HT 1A receptor ligands uniformly mixed with a suitable base such as vaseline, preservatives if necessary, be stabilizers, or in addition to other suitable additives prepared.
Other forms of the pharmaceutical composition can be prepared by methods well known to those skilled in the art, and the form of the drug which is one embodiment of the medicament of the present invention is not limited to the above.
[0020]
The dose of 5-HT 1A receptor ligand contained in the drug for eye diseases of the present invention varies depending on the patient's age, weight, symptoms, disease severity, etc., and is ultimately determined by a clinician Generally, it is administered at 0.001 to 10.0 mg / kg body weight / day, one day or more. Specifically, when the 5-HT 1A receptor ligand is an alkylenedioxybenzene derivative of the above formula (I), the dose is usually preferably 0.05 to 3 mg / kg / body weight / day. In general, 0.5 to 500 mg, preferably 1 to 100 mg, of an alkylenedioxybenzene derivative is contained in a unit dosage form, and it is usually taken 1 to 3 times a day, for example, 5 mg at a time. In the case of injections, an alkylenedioxybenzene derivative is usually contained in an amount of 0.5 to 20%, preferably 1 to 10% in a unit dosage form, for example, 0.03 to 3 mg / dose, usually Administer 1 to 4 times a day. In the case of eye drops, eye drops having a concentration of the alkylenedioxybenzene derivative of 0.1 to 1% are prepared and applied 1 to 4 times a day.
[0021]
The drug for ophthalmic diseases of the present invention can be widely applied to diseases in the ophthalmic field based on the above-described intraocular pressure lowering action of 5-HT 1A receptor ligand. The agent of the present invention containing a 5-HT 1A receptor ligand as an active ingredient is useful for the prevention and treatment of eye diseases such as glaucoma and ocular hypertension. Note that glaucoma includes high-tension glaucoma and low-tension glaucoma in which glaucomatous nipple abnormalities and visual field changes are observed while showing normal intraocular pressure, and the drug of the present invention is effective for both. Effective for high-tension glaucoma.
[0022]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples should be regarded as an aid for obtaining specific recognition of the present invention, and do not limit the scope of the present invention.
Production Example 1
5- [3-{(2S)-(1,4-benzodioxan-2-ylmethyl) amino} propoxy] -1,3-benzodioxole hydrochloride (hydrochloride of compound No. 1 in Table 1 ; MKC -242) 5- (3-aminopropoxy) -1,3-benzodioxole 5.86 g and (2R) -2-tosyloxymethyl-1,4-benzodioxan (Journal of Medicinal Chemistry, 20 , 3.20 g (synthesized according to 880, 1977) was dissolved in 100 ml of acetonitrile, 2.77 ml of triethylamine was added, and the mixture was stirred for 12 hours with heating under reflux. After completion of the reaction, water was added and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The chloroform layer was concentrated and purified by silica gel column chromatography (chloroform-methanol) to give 5- [3-{(2s)-(1,4-benzodioxan-2-ylmethyl) amino} propoxy] -1, 2.68 g of 3-benzodioxole was obtained.
This was dissolved in ethyl acetate and 26% hydrochloric acid / isopropanol was added. The generated crystals were collected by filtration to give 2.37 g of the title compound.
[0023]
Mp 212-218 ° C.
1 H-NMR (DMSO-d 6 ) δ 9.16 (2H, m), 6.89 (5H, m), 6.63 (1H, d, J = 2.4 Hz), 6.37 (1H, dd , J = 7.5, 2.5 Hz), 5.95 (2H, s), 4.65 (1H, m), 4.37 (1H, dd, J = 12.5, 2.3 Hz), 4 .02 (3H, m), 3.25 (4H, m), 2.10 (2H, m).
The optically active form obtained above and a racemic form synthesized separately (synthesized according to the method described in JP-A-57-108088) are each amidated with (S) -methoxytrifluoromethylphenylacetic acid chloride in pyridine. After that, when analyzed by high-performance liquid chromatography (column: Watersnova Pack C18) and optical purity was determined by comparison, 99% e.e. It was more than e.
[0024]
Example 1
Eight male Japanese white rabbits weighing about 2 kg were placed in a holding can and used for the test after acclimatization for about 1 hour. After acclimatization, the initial intraocular pressure was measured, and 0.2 μM MKC-242 aqueous solution was applied to the left eye of 4 rabbits, and 50 μl of distilled water was applied to the left eye of the other 4 rabbits. Intraocular pressure was measured 0.5, 1, 2, 3 and 4 hours after drug instillation. Measurement of intraocular pressure was performed using an application Pneumatograph made by Alcon. A similar test was conducted 5 days later. In the first test, the rabbits instilled with 0.2% MKC-242 solution were distilled water, and the rabbits instilled with distilled water were 0.2% MKC-242. The left eye was instilled with 50 μl. MKC-242 was dissolved in distilled water so as to be 0.2% using ultrasonic treatment and a test tube mixer.
[0025]
The result is shown in FIG. As is clear from FIG. 1, the control of the rabbits instilled with distilled water as the control increased with an initial intraocular pressure of 20.8 mmHg and an intraocular pressure of 22.8 mmHg after 4 hours of instillation. On the other hand, in the eye instilled with 0.2% MKC-242 solution, the intraocular pressure dropped from 30 minutes after instillation, and showed a minimum intraocular pressure of 18.0 mmHg after 1 to 2 hours of instillation. The maximum intraocular pressure-lowering effect of 2.8 mmHg (1 and 2 hours after instillation) compared to 0.8 mmHg and 4.9 mmHg (2 hours after instillation) compared to the intraocular pressure of control rabbits was observed. In addition, the maximum intraocular pressure-lowering effect of 3.9 mmHg (after 2 hours of instillation) was observed compared to the opposite eye (right eye) in which no instillation was performed.
[0026]
Example 2
Eight male Japanese white rabbits weighing about 3 kg were placed in a holding can and used for the test after acclimatization for about 1 hour. After habituation, the initial intraocular pressure was measured, and MKC-242 suspended in 0.5% CMC (carboxymethylcellulose) in 4 rabbits was 30 mg / 5 ml / kg body weight, and 0 in the other 4 rabbits. 5% CMC was orally administered at 5 ml / kg body weight. Intraocular pressure was measured 0.5 hours after oral administration, every hour after 1 to 7 hours, and 24 hours later. The intraocular pressure was measured in the same manner as in Example 1. MKC-242 was suspended in a 0.5% CMC solution by stirring and sonication so that the concentration was 0.6% (30 mg / 5 ml). .
[0027]
The result is shown in FIG. As is clear from FIG. 2, in the rabbits orally administered with a 0.5% CMC solution as a control, the initial intraocular pressure was 21.9 mmHg, and thereafter varied in the range of 19.8 to 23.0 during the measurement time. On the other hand, in the rabbits to which MKC-242 was orally administered at 30 mg / kg, the intraocular pressure dropped from 30 minutes after administration, and showed a minimum intraocular pressure of 10.5 mmHg 2 hours after administration. The intraocular pressure gradually increased from 3 hours after the administration, but even after 7 hours from the administration, the intraocular pressure was maintained at 14.3 mmHg and lower than the initial intraocular pressure and control. At 24 hours after administration, the pressure was almost equal to the initial intraocular pressure.
[0028]
Example 3
A male white rabbit weighing about 2 to 2.5 kg was placed in a holding can and used for the test after acclimation for about 1 hour. After acclimatization, the initial intraocular pressure was measured, 50 μl of 1% 8-OH-DPAT (Funakoshi) aqueous solution was applied to one eye of 5 rabbits, and 50 μl of distilled water was applied to the opposite eye. Intraocular pressure was measured after 1, 2 and 3 hours. Intraocular pressure was measured in the same manner as in Example 1.
The results are shown in FIG. As is apparent from FIG. 3, 8-OH-DPAT significantly reduced rabbit intraocular pressure with 1% ophthalmic administration.
[Brief description of the drawings]
FIG. 1 is a diagram showing an intraocular pressure lowering effect by instillation of MKC-242. In the figure, the measurement points and bars are the mean values of the intraocular pressure of 8 animals +/− S. E. # Indicates a significant difference (P <0.01) from the initial intraocular pressure, and * indicates a significant difference (P <0.01) from the intraocular pressure of the control group.
FIG. 2 is a view showing an intraocular pressure lowering effect by oral administration of MKC-242. In the figure, the measurement points and bars are the mean values of the intraocular pressure of 4 animals +/− S. E. # Indicates a significant difference (P <0.05) from the initial intraocular pressure, and * indicates a significant difference (P <0.01) from the control group.
FIG. 3 is a diagram showing an intraocular pressure lowering effect by instillation of 8-OH-DPAT. In the figure, the measurement points and bars are the mean values of the intraocular pressure of 5 animals +/− S. E. * And ** indicate significant differences from the initial intraocular pressure (P <0.05 and P <0.01, respectively).
Claims (6)
で表されるアルキレンジオキシベンゼン誘導体、そのラセミ体またはそれらの酸付加塩から選ばれるセロトニン受容体１Ａリガンドを有効成分とする緑内障治療剤である眼疾患用薬剤。 8-Hydroxy-2- (N, N-dipropylamino) -tetralin and formula (I)
A drug for ophthalmic diseases, which is a glaucoma therapeutic agent comprising a serotonin receptor 1A ligand selected from an alkylenedioxybenzene derivative represented by the following formula, a racemate thereof, or an acid addition salt thereof:
で表されるアルキレンジオキシベンゼン誘導体、そのラセミ体またはそれらの酸付加塩から選ばれるセロトニン受容体１Ａリガンドを有効成分とする眼圧降下剤である眼疾患用薬剤。 8-Hydroxy-2- (N, N-dipropylamino) -tetralin and formula (I)
A drug for ophthalmic diseases which is an intraocular pressure-lowering agent comprising a serotonin receptor 1A ligand selected from an alkylenedioxybenzene derivative represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28211596A JP3958391B2 (en) | 1995-10-25 | 1996-10-24 | Drugs for eye diseases |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27811995 | 1995-10-25 | ||
| JP7-278119 | 1995-10-25 | ||
| JP7582496 | 1996-03-29 | ||
| JP8-75824 | 1996-03-29 | ||
| JP28211596A JP3958391B2 (en) | 1995-10-25 | 1996-10-24 | Drugs for eye diseases |
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| Publication Number | Publication Date |
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| JPH09316002A JPH09316002A (en) | 1997-12-09 |
| JP3958391B2 true JP3958391B2 (en) | 2007-08-15 |
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| JP28211596A Expired - Fee Related JP3958391B2 (en) | 1995-10-25 | 1996-10-24 | Drugs for eye diseases |
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| EP1263434A1 (en) * | 2000-03-17 | 2002-12-11 | Alcon, Inc | Compounds with 5-ht 2 and 5-ht 1a agonist activity for treating glaucoma |
| JP2022059092A (en) * | 2019-02-15 | 2022-04-13 | アステラス製薬株式会社 | Pharmaceutical composition for lowering intraocular pressure |
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