JP4783967B2 - Pharmaceuticals containing fluorine-containing amino acid derivatives as active ingredients - Google Patents

Description

【００１０】
［式中、Ｘ¹は水素原子又はフッ素原子を示し、Ｒ¹及びＲ²は同一又は異なって水素原子又は炭素数１−１０のアルキル基を示す。］で表される含フッ素アミノ酸誘導体又はその医薬上許容される塩を有効成分とする、例えばグループ２メタボトロピックグルタミン酸受容体に作用する医薬である。
本発明において、炭素数１−１０のアルキル基とは直鎖状又は分岐鎖状のアルキル基を示し、直鎖状又は分岐鎖状アルキル基としては、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、ペンチル基、イソペンチル基、１−エチルプロピル基、ヘキシル基、イソヘキシル基、１−エチルブチル基、ヘプチル基、イソヘプチル基、オクチル基、ノニル基、デシル基などを挙げることができる。
また、本発明における医薬上許容される塩とは、例えば硫酸、塩酸、燐酸などの鉱酸との塩、酢酸、シュウ酸、乳酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸、ベンゼンスルホン酸などの有機酸との塩、トリメチルアミン、メチルアミンなどのアミンとの塩、又はナトリウムイオン、カリウムイオン、カルシウムイオンなどの金属イオンとの塩などである。なお、本発明に係る化合物は各種の溶媒和物として存在し得るが、医薬としての適用性の面からは水和物が好ましい。
【００１１】
式［１］で示される化合物の中でＸ¹が水素原子の場合、１、２、３、５及び６位に５つの不斉炭素原子が存在する。従って、Ｘ¹が水素原子である本発明に係る化合物は、光学活性体、ラセミ体等の２種のエナンチオマー混合物及びジアステレオマーの混合物として存在できる。更に、Ｘ¹がフッ素原子の場合、１、２、５及び６位に４つの不斉炭素原子が存在する。従って、Ｘ¹がフッ素原子である本発明に係る化合物は、光学活性体、ラセミ体等の２種のエナンチオマー混合物及びジアステレオマーの混合物として存在できる。
【００１２】
式［１］で示される化合物において好ましいＸ¹は水素原子である。更に、Ｘ¹が水素原子である場合には、式［１］で示される化合物は下記の相対的立体化学配置を有することがより好ましい。
【００１３】
【化４】

【００１４】
また、Ｘ¹、Ｒ¹及びＲ²が水素原子の場合、本化合物の光学異性体の中で最も好ましい光学活性体は正の旋光性を有しており、この絶対立体化学配置は、本化合物の合成前駆体である２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸 (Ｒ)−(＋)−1−フェニルエチルアミン塩のＸ線単結晶構造解析により、１Ｓ,２Ｓ,３Ｓ,５Ｒ,６Ｓと決定された。
【００１５】
一方、式［１］においてＲ¹とＲ²の片方又は両方が水素以外を示す場合、すなわちエステル体はグループ２メタボトロピックグルタミン酸受容体に影響を及ぼさない。しかし、このエステル体は生体内でカルボン酸に加水分解され、グループ２メタボトロピックグルタミン酸受容体に影響を及ぼすカルボン酸に変化する。従って、エステル体はプロドラッグとして機能するため、極めて有用な化合物である。
【００１６】
【発明の実施の形態】
式［１］の化合物は、以下に示す製造法により供給される。以下の反応式中、Ｒ¹、Ｒ²、Ｘ¹は前記と同様であり、Ｒ³とＲ⁴は同一又は異なって炭素数１−１０のアルキル基を示し、Ｙは一般的なアミノ基の保護基（PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,THEODORA W. GREENE and PETER G. M. WUTS著 参照）を示す。
【００１７】
【化５】

【００１８】
光学活性体、ラセミ体等の２種のエナンチオマー混合物又はジアステレオマーの混合物であるモノフッ化化合物（２）は、対応する光学活性体、ラセミ体等の２種のエナンチオマー混合物又はジアステレオマーの混合物であるケトン体（１）を一旦エノールシリルエーテル体又はエノールエステル体とした後フッ素化試薬と反応するか、或いはケトン体（１）に直接フッ素化試薬を反応することによって得られる。また、光学活性体、ラセミ体等の２種のエナンチオマー混合物又はジアステレオマーの混合物であるジフッ化化合物（３）は、モノフッ化化合物（２）を一旦エノールシリルエーテル体とした後フッ化試薬と反応するか、モノフッ化化合物（２）に直接フッ化試薬と反応するか、或いはケトン体（１）に２当量以上のフッ素化試薬を反応することによって得られる。
【００１９】
ここで、エノールシリルエーテル体の製造は、ケトン体（１）に、例えばテトラヒドロフラン、ジエチルエーテルなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、メタノール、ｔ−ブタノールなどのアルコール類、Ｎ,Ｎ−ジメチルホルムアミド等の不活性溶媒中、例えばｎ−ブチルリチウム、ｓ−ブチルリチウムなどのアルキルリチウム類、例えばリチウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミド、ナトリウムアミドなどの金属アミド類、例えば水素化ナトリウムなどの水素化金属類、又は、例えばトリエチルアミン等のアミン類等の塩基の存在下、例えばクロロトリメチルシラン、クロロｔ−ブチルジメチルシラン等のシリル化剤を反応することによって得られる。ここでの反応温度は１００℃以下が好ましく、更に−７８℃から室温が最適である。
【００２０】
エノールエステル体の製造は、シリル化剤を例えば無水酢酸等の酸無水物、例えばプロピオニルクロライド等の酸ハライド、又は例えば酢酸等のカルボン酸とエトキシカルボニルクロライド等のアルコキシカルボニルハライドから調製される混合酸無水物等に変え、エノールシリルエーテル体の製造と同様に反応し得られる。
フッ素化試薬とは、例えばＮ−フルオロピリジニウムトリフラート、Ｎ−フルオロ−Ｎ−ｔ−ブチルベンゼンスルホンアミド、Ｎ−フルオロサッカリンスルタム、Ｎ−フルオロビス（ベンゼンスルホン）イミド、Ｎ−フルオロ−ｏ−ベンゼンスルホンイミドなどのＮ−フルオロ型フッ素化剤、フッ素、ＣｌＯ₃Ｆ、又はＣＦ₃ＣＯＯＦ等である。ここで、直接フッ素化試薬を反応させる態様としては、ケトン体（１）に、例えばテトラヒドロフラン、ジエチルエーテルなどのエーテル類、トルエン、ベンゼンなどの炭化水素類、メタノール、ｔ−ブタノールなどのアルコール類、Ｎ,Ｎ−ジメチルホルムアミド等の不活性溶媒中、例えばｎ−ブチルリチウム、ｓ−ブチルリチウムなどのアルキルリチウム類、例えばリチウムビストリメチルシリルアミド、ナトリウムアミドなどの金属アミド類、例えば水素化ナトリウムなどの水素化金属類、又は例えばトリエチルアミン等のアミン類等の塩基の存在下、反応温度を１００℃以下で、好ましくは−７８℃から室温で、上記のようなフッ素化試薬を反応させる態様が好ましい。
【００２１】
このようにして得られた光学活性体、ラセミ体等の２種のエナンチオマー混合物又はジアステレオマーの混合物であるモノ又はジフッ素化化合物（４）は、ストレッカーアミノ酸合成（Strecker Amino Acid Synthesis）（Ann.,75,27(1850);91,349(1850)）、ブッヘラー−ベルグス反応（Bucherer-Bergs Reaction）（J.Prakt.Chem.,140,69(1934)）又はこれらの変法によって得られたアミノシアニド誘導体又はヒダントイン誘導体等を加水分解することによって本発明に係る化合物である対応する光学活性体、ラセミ体等の２種のエナンチオマー混合物又はジアステレオマーの混合物である含フッ素アミノ酸誘導体（５）とすることができる。
【００２２】
具体的には、モノ又はジフッ化合物（４）を、シアン化ナトリウム又はシアン化カリウム及び炭酸アンモニウムと、例えばエタノールなどのアルコール類又はアルコール類と水の混合溶媒中、好ましくは３０℃〜５０℃で１日〜２日反応し、合成中間体であるヒダントインに導く。続いて、例えば水酸化ナトリウムなどの塩基、或いは塩酸、硫酸等の酸によって、例えばエタノールなどのアルコール類、ジオキサンなどのエーテル類、又はアセトンなどのケトン類などの不活性溶媒中加水分解することによって、本発明化合物である含フッ素アミノ酸誘導体（５）が得られる。
【００２３】
【化６】

【００２４】
下記式化７に示すように、(1SR,5RS,6SR)−（１）で示されるケトン体に１つのフッ素原子が導入されたモノフッ化化合物（前出の（２）参照）のブッヘラー−ベルグス反応によって得られる、(1SR,5RS,6SR)−（６）で示されるヒダントイン誘導体は、例えばシリカゲル等を用いたカラムクロマトグラフィーや再結晶などの一般的な手法によって４つのシアステレオマーに分離することができる。
【００２５】
更に４つのジアステレオマーのエステルをそれぞれ加水分解後、例えば塩基性キラル分割剤を用いた分割等の一般的な分割方法によって８つのエナンチオマー（８）に分割できる。続いて、ヒダントイン部位を加水分解することによって本発明化合物である８つの光学活性な含フッ素アミノ酸誘導体（９）が得られる。
【００２６】
ここで、塩基性キラル分割剤としては、例えば（＋）又は（−）−１−フェニルエチルアミン、（＋）又は（−）−２−アミノ−１−ブタノール、（＋）又は（−）−アラニノール、ブルシン、シンコニジン、シンコニン、キニン、キニジン、デヒドロアビエチルアミン等の光学活性なアミン類を使用することができる。
【００２７】
【化７】

【００２８】
一方、本発明化合物の一つである２つのフッ素原子を含有する４つの光学活性なアミノ酸誘導体（１２）は、下記化８に示すように、(1SR,5RS,6SR)−（１）を出発原料にしてフッ素化、ヒダントイン化、ジアステレオマーの分離、エステルの加水分解、分割及びヒダントイン部位の加水分解によて合成することができる。
【００２９】
【化８】

【００３０】
１つのフッ素原子を有する式(1SR,5RS,6SR)−（２）で示されるケトン体は、下記化９に示すように、ジアステレオマーの分離、エステルの加水分解及び分割により式（１３）で示される４つの光学活性なケトカルボン酸に導かれる。従って、４つの光学活性なケトカルボン酸（１３）を直接、或いはエステル化後に、式（５）に示した化合物の合成の場合と同様の操作を行い、また更にジアステレオマーの分離を行うことによっても、光学活性な本発明化合物である含フッ素アミノ酸誘導体を製造することができる。
【００３１】
【化９】

【００３２】
式（１４）で示される２つのフッ素原子を有する２つの光学活性なケトカルボン酸は、２つのフッ素原子を有する式(1SR,5RS,6SR)−（３）で示されるケトン体より、化９と同様の方法、すなわち、エステルの加水分解及び分割によって得ることができる。従って、２つの光学活性なケトカルボン酸（１４）を直接、或いはエステル化後に、化６で示したアミノ酸合成法と同様な操作を行い、また、更にジアステレオマーの分離を行うことによって、光学活性な本発明化合物である含フッ素アミノ酸誘導体（１５）を製造することができる。
【００３３】
【化１０】

【００３４】
ところで、下記化１１に示すように、式（６）で示される光学活性体、ラセミ体等の２種のエナンチオマー混合物又はジアステレオマーの混合物の本発明化合物である含フッ素アミノ酸は、アミノ基をＹで示される保護基で保護した後、Ｒ³−Ｘ²又はＲ⁴−Ｘ²で示されるアルキルハライド、もしくはＲ³−ＯＨ又はＲ⁴−ＯＨで示されるアルコールを用い一般的な方法にてエステル化し、アミノ基の保護基を除去することによって、式（１５）で示される本発明化合物である含フッ素アミノ酸エステルに誘導される。
【００３５】
【化１１】

【００３６】
ここで、アミノ基の保護、エステル化及びアミノ基の脱保護は、一般的方法（PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,THEODORA W. GREENE and PETER G. M.WUTS著 参照）で実施される。
【００３７】
更に、式（１５）で示される含フッ素アミノ酸エステル又は式（１７）で示されるＮ−保護含フッ素アミノ酸エステルの各ジアステレオマーは、例えばシリカゲル等を用いたカラムクロマトグラフィーや再結晶などの一般的な手法によって分離することができる。式（１５）の各ジアステレオマーは、例えば酸性キラル分割剤を用いた分割等の一般的な分割方法によって各エナンチオマーに分割できる。
ここで、酸性キラル分割剤としては、（＋）又は（−）−ジ−ｐ−トルオルイル酒石酸、（＋）又は（−）−ジベンゾイル酒石酸、（＋）又は（−）−酒石酸、（＋）又は（−）−マンデル酸、（＋）又は（−）−しょうのう酸、又は（＋）又は（−）−しょうのうスルホン酸等の光学活性な有機酸類を使用することができる。
【００３８】
本発明に係る化合物は、１つ又はそれ以上の医薬的に許容される担体、賦形剤又は希釈剤と組み合わされて医薬的製剤とすることができる。前記担体、賦形剤及び希釈剤の例には、水、糖乳、デキストロース、フラクトース、ショ糖、ソルビトール、マンニトール、ポリエチレングリコール、プロピレングリコール、でんぷん、ガム、ゼラチン、アルギネート、ケイ酸カルシウム、リン酸カルシウム、セルロース、水シロップ、メチルセルロース、ポリビニルピロリドン、アルキルパラヒドロキシベンゾエート、タルク、ステアリン酸マグネシウム、ステアリン酸、グリセリン、ゴマ油、オリーブ油、大豆油などが含まれる。
【００３９】
本発明に係る化合物は、これらの担体、賦形剤又は希釈剤、そして、必要に応じて一般に使用される増量剤、結合剤、崩壊剤、ｐＨ調整剤、溶解剤などの添加剤が混合された上で、常用の製剤技術によって錠剤、丸剤、カプセル剤、顆粒剤、粉剤、液剤、乳剤、懸濁剤、軟膏剤、注射剤、皮膚貼付剤などの経口又は非経口用医薬、特にグロープ２メタボトロピックグルタミン酸受容体作用薬として調製されることができる。本発明に係る化合物は、成人患者に対して０.０１〜５００ｍｇを１日１回又は数回に分けて経口又は非経口で投与することが可能である。なお、この投与量は治療対象となる疾病の種類、患者の年齢、体重、症状などにより適宜増減することが可能である。
【００４０】
【発明の効果】
本発明により、医薬として有用な薬物、特にメタボトロピックなグルタミン酸受容体の作動薬が提供された。従って、例えば精神分裂病、不安及びその関連疾患、うつ病、二極性障害、てんかん等の精神医学的障害、例えば薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患に有用な治療薬及び予防薬として使用できる。
【００４１】
【実施例】
以下に製造例及び試験例を示し本発明を具体的に説明する。
製造例１
(1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレート、及び(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートの合成
窒素雰囲気下、ｎ−ブチルリチウム３０.９ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキサメチルジシラザン７.５０ｇから調製したリチウムビストリメチルシリルアミドのテトラヒドロフラン１５０ｍｌ中に、−７５℃でテトラヒドロフラン１５０ｍｌに溶解した(1SR,5RS,6SR)エチル ２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレート６.６０ｇを滴下した。この温度で１時間攪拌した後、クロロトリメチルシラン７.５ｍｌを加え、室温で１時間攪拌した。反応溶液を減圧下濃縮後、残渣に無水ヘキサンを加え、生じた無機塩を濾別し、濃縮した。
【００４２】
残渣を塩化メチレン６６ｍｌに溶解し、Ｎ−フルオロベンゼンスルホンイミド１５.００ｇを加え、室温で１６.５時間攪拌した。反応溶液を水で２回洗浄後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、減圧下、濃縮した。残渣をクロマトグラフィー（シリカゲル：ワコウゲル（和光純薬製）、展開溶媒：ヘキサン−塩化メチレン−酢酸エチル＝６０：４：１）で精製し、(1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートと(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートの混合物を４.３０ｇ得た。
¹Ｈ−ＮＭＲ(CDCl₃)δ(ppm)；1.28(3Hx3/4,t,J=7.2Hz),1.29(3Hx1/4,t,J=7.2Hz),2.11-2.79(5H,m),4.18(2H,q,J=7.2Hz),4.51(1Hx1/4,dd,J=51Hz,8.1Hz),4.58(1Hx3/4,dt,J=51Hz,8.1Hz)
ＭＳ(FAB)(Pos)ｍ／ｅ；１８７（Ｍ⁺＋１）
【００４３】
製造例２
(1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレート、及び(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートの合成
窒素雰囲気下、ｎ−ブチルリチウム１.５ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキサメチルジシラザン０.３８ｇから調製したリチウムビストリメチルシリルアミドのテトラヒドロフラン６ｍｌ中に、−７５℃でテトラヒドロフラン６ｍｌに溶解した（1SR,5RS,6SR)エチル ２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレート０.２０ｇを滴下した。この温度で４５分間攪拌した後、Ｎ−フルオロベンゼンスルホンイミド０.７５ｇを加え、室温で２時間攪拌した。反応溶液を水で２回洗浄後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、減圧下、濃縮した。残渣をクロマトグラフィー（シリカゲル：ワコウゲル（和光純薬製）、展開溶媒：ヘキサン−塩化メチレン−酢酸エチル＝６０：４：１）で精製し、(1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートと(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートの混合物を０.０８ｇ得た。
¹Ｈ−ＮＭＲ(CDCl₃)δ(ppm)；1.28(3Hx3/4,t,J=7.2Hz),1.29(3Hx1/4,t,J=7.2Hz),2.11-2.79(5H,m),4.18(2H,q,J=7.2Hz),4.51(1Hx1/4,dd,J=51Hz,8.1Hz),4.58(1Hx3/4,dt,J=51Hz,8.1Hz)
ＭＳ(FAB)(Pos)ｍ／ｅ；１８７（Ｍ⁺＋１）
【００４４】
製造例３
(1SR,5RS,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートの合成
窒素雰囲気下、ｎ−ブチルリチウム３０.９ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキサメチルジシラザン７.５０ｇから調製したリチウムビストリメチルシリルアミドのテトラヒドロフラン１５０ｍｌ中に、−７５℃でテトラヒドロフラン１５０ｍｌに溶解した(1SR,5RS,6SR)エチル ２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレート６.６０ｇを滴下した。この温度で１時間攪拌した後、クロロトリメチルシラン７.５ｍｌを加え、室温で１時間攪拌した。反応溶液を減圧下濃縮後、残渣に無水ヘキサンを加え、生じた無機塩を濾別し、濃縮した。残渣を塩化メチレン６６ｍｌに溶解し、Ｎ−フルオロベンゼンスルホンイミド１５.００ｇを加え、室温で１６.５時間攪拌した。反応溶液を水で２回洗浄後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、減圧下、濃縮した。残渣をクロマトグラフィー（シリカゲル：ワコウゲル（和光純薬製）、展開溶媒：ヘキサン−塩化メチレン−酢酸エチル＝６０：４：１）で精製し、(1SR,5RS,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートを０.０２ｇ得た。
¹Ｈ−ＮＭＲ(CDCl₃)δ(ppm)；1.30(3H,t,J=7.1Hz),2.42-2.80(5H,m),4.20(2H,q,J=7.1Hz)
ＭＳ(Ion Spray)(Nega)ｍ／ｅ；２０３（Ｍ⁺−１）
【００４５】
製造例４
(1SR,5RS,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートの合成
窒素雰囲気下、ｎ−ブチルリチウム５.０ｍｌ（１.５４Ｍヘキサン溶液）と1,1,1,3,3,3−ヘキサメチルジシラザン１.４０ｇから調製したリチウムビストリメチルシリルアミドのテトラヒドロフラン２６ｍｌ中に、−７５℃でテトラヒドロフラン６.５ｍｌに溶解した製造例１で合成した化合物１.３ｇを滴下した。この温度で１時間攪拌した後、クロロトリメチルシラン１.３ｍｌを加え、室温で１時間攪拌した。反応溶液を減圧下濃縮後、残渣に無水ヘキサンを加え、生じた無機塩を濾別し、濃縮した。
【００４６】
残渣を塩化メチレン１３ｍｌに溶解し、Ｎ−フルオロベンゼンスルホンイミド３.３０ｇを加え、室温で５時間攪拌した。反応溶液を水で２回洗浄後、無水硫酸ナトリウムで乾燥し、乾燥剤を濾別後、減圧下、濃縮した。残渣をクロマトグラフィー（シリカゲル：ワコウゲル（和光純薬製）、展開溶媒：ヘキサン−塩化メチレン−酢酸エチル＝６０：４：１）で精製し、(1SR,5RS,6SR)エチル 3,3−ジフルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートを０.３４ｇ得た。
¹Ｈ−ＮＭＲ(CDCl₃)δ(ppm)；1.30(3H,t,J=7.1Hz),2.42-2.80(5H,m),4.20(2H,q,J=7.1Hz)
ＭＳ(Ion Spray)(Nega)ｍ／ｅ；２０３（Ｍ⁺−１）
【００４７】
製造例５
(1SR,2SR,3SR,5RS,6SR)エチル ２−スピロ−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート、(1SR,2SR,3RS,5RS,6SR)エチル ２−スピロ−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート、及び(1SR,2RS,3RS,5RS,6SR)エチル ２−スピロ−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートの合成
(1SR,3RS,5RS,6SR)エチル ３−フルオロ−２−オキソビシクロ[3.1.0]ヘキサン−６−カルボキシレートと(1SR,3SR,5RS,6SR)エチル ３−フルオロ−２−オキソビロビシクロ[3.1.0]ヘキサン−６−カルボキシレートの混合物４.８４ｇを、水２６ｍｌとエタノール３８ｍｌの混合溶液に溶解し、炭酸アンモニウム６.２５ｇとシアン化カリウム１.８６ｇを加え３５℃で３７時間攪拌した。反応混合物を室温まで冷却後水３１ｍｌを加え、更に氷冷下２.５時間攪拌し生じた結晶を濾取し、２.１０ｇの第１結晶を得た。濾液に氷冷下濃塩酸を加えｐＨを１.０に調整し、生成した結晶を濾取し、２.００ｇの第２結晶を得た。
【００４８】
第１結晶をクロマトグラフィー（シリカゲル：ワコウゲル（和光純薬製）、展開溶媒：クロロホルム−メタノール＝１００：１）に付し、低極性ジアステレオマーを０.６１ｇと極性ジアステレオマーＡ（極性ジアステレオマーＢを約２５％を含む、極性ジアステレオマーＡと極性ジアステレオマーＢのＲｆ値は同じ）０.５５ｇに分離した。
低極性ジアステレオマー０.６１ｇを水−エタノール＝１：１の混合溶液より再結晶し、(1SR,2SR,3SR,5RS,6SR)エチル ２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートを０.５２ｇを得た。
¹Ｈ−ＮＭＲ(DMSO-d₆)δ(ppm)；1.19(3H,t,J=7.0Hz),1.95-2.46(5H,m),4.06(2H,q,J=7.0Hz),4.81(1H,dd,J=52Hz,5.1Hz),8.44(1H,s),10.91(1H,s)
ＭＳ(EI)ｍ／ｅ；２５６（Ｍ⁺）
【００４９】
極性ジアステレオマーＡ０.５５ｇを水−エタノール＝１：１の混合溶液より再結晶し、(1SR,2SR,3RS,5RS,6SR)エチル ２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート０.３７ｇを得た。
¹Ｈ−ＮＭＲ(DMSO-d₆)δ(ppm)；1.18(3H,t,J=7.1Hz),1.85-2.43(5H,m),4.05(2H,q,J=7.1Hz),4.70(1H,dt,J=52Hz,8.0Hz),8.21(1H,s),10.83(1H,s)
ＭＳ(EI)ｍ／ｅ；２５６（Ｍ⁺）
【００５０】
第２結晶を酢酸エチルで洗浄し不溶物を濾別後濾液を減圧下濃縮し、残渣を水−エタノール＝１：１で２回再結晶した。この２回の再結晶濾液を減圧下濃縮し、残渣をクロマトグラフィー（シリカゲル：ワコウゲル（和光純薬製）、展開溶媒：クロロホルム−メタノール＝１００：１）に付し前記低極性ジアステレオマーを完全に除去した。得られた極性ジアステレオマーＢ（極性ジアステレオマーＡを約１０％を含む）の結晶０.２５ｇを水−エタノール＝１：１で再結晶を行い、、(1SR,2RS,3RS,5RS,6SR)エチル ２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレートを０.１８ｇ得た。
¹Ｈ−ＮＭＲ(DMSO-d₆)δ(ppm)；1.18(3H,t,J=7.1Hz),1.81-2.17(4H,m),2.36(1H,dd,J=13Hz,7.2Hz),3.95-4.11(2H,m),4.90(1H,ddd,J=51Hz,8.9Hz,7.2Hz),8.54(1H,s),10.87(1H,s)
ＭＳ(EI)ｍ／ｅ；２５６（Ｍ⁺）
【００５１】
同様にして下記の化合物を合成した。
(1SR,2SR,5RS,6SR)エチル ２−スピロ−５'−ヒダントイン−3,3−ジフルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート
¹Ｈ−ＮＭＲ(DMSO-d₆)δ(ppm)；1.19(3H,t,J=7.0Hz),1.85-1.89(1H,m),2.00-2.08(1H,m),2.15-2.27(1H,m),2.33-2.50(1H,m),2.55-2.86(1H,m),4.07(2H,q,J=7.0Hz),8.49(1H,m)
ＭＳ(EI)ｍ／ｅ；２７４（Ｍ⁺）
【００５２】
製造例６
(1SR,2SR,3RS,5RS,6SR)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の合成
(1SR,2SR,3RS,5RS,6SR)エチル ２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート３００ｍｇを３Ｍ水酸化ナトリウム水溶液２.５ｍｌに溶解し、１６時間加熱還流した。反応溶液を室温まで冷却後、ガラスフィルターで濾過し、濾液を濃塩酸でｐＨ３にした後、イオン交換クロマトグラフィー（ＡＧ１−Ｘ８ 陰イオン交換樹脂(Bio-Rad)、展開溶媒：０.１Ｍ酢酸〜３Ｍ酢酸）で精製し、(1SR,2SR,3RS,5RS,6SR)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−２,６−ジカルボン酸を５１ｍｇ得た。
¹Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.23-2.24(1H,m),2.56-2.96(4H,m),5.15(1H,dt,J=52Hz,7.5Hz)
ＭＳ(CI)ｍ／ｅ；２０４（Ｍ⁺＋１）
【００５３】
同様にして下記の化合物を合成した。
(1SR,2SR,5RS,6SR)−２−アミノ−3,3−ジフルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
¹Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.46(1H,brs),2.63-2.90(3H,m),3.01-3.12(1H,m)
ＭＳ(CI)ｍ／ｅ；２２２（Ｍ⁺＋１）
【００５４】
製造例７
(1SR,2SR,3SR,5RS,6SR)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−２,６−ジカルボン酸の合成
(1SR,2SR,3SR,5RS,6SR)エチル ２−スピロ−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート１００ｍｇを６０％硫酸水溶液１.５ｍｌに溶解し、１４０℃で１２時間加熱した。反応溶液を室温まで冷却後、５Ｍ水酸化ナトリウム水溶液でｐＨ８にした後、イオン交換クロマトグラフィー（ＡＧ１−Ｘ８ 陰イオン交換樹脂(Bio-Rad)、展開溶媒：０.１Ｍ酢酸〜２Ｍ酢酸）で精製し、(1SR,2SR,3SR,5RS,6SR)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸を２０ｍｇ得た。
¹Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.49(1H,brs),2.59-3.06(4H,m),5.40(1H,dd,J=52Hz,5.3Hz)
ＭＳ(CI)ｍ／ｅ；２０４（Ｍ⁺＋１）
【００５５】
同様にして下記の化合物を合成した。
(1SR,2RS,3RS,5RS,6SR)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
¹Ｈ−ＮＭＲ(TFA-d)δ(ppm)；2.33(1H,brs),2.54-2.89(4H,m),5.42-5,59(1H,m)
ＭＳ(CI)ｍ／ｅ；２０４（Ｍ⁺＋１）
【００５６】
製造例８
(1S,2S,3S,5R,6S)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸の合成
（１）(1SR,2SR,3SR,5RS,6SR)エチル ２−スピロ−５´−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボキシレート２.２０ｇと２Ｍ水酸化ナトリウム１７ｍｌの混合物を室温で攪拌した。２時間後、濃塩酸を加えｐＨを１.０に調整した。生成した結晶を濾過により単離し、乾燥して(1SR,2SR,3SR,5RS,6SR)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸を１.８１ｇ得た。
¹Ｈ−ＮＭＲ(DMSO-d₆)δ(ppm)；1.85-2.44(5H,m),4.80(1H,dd,J=52Hz,5.3Hz),8.44(1H,s),10.88(1H,s),12.30(1H,brs)
ＭＳ(FAB)(Nega)ｍ／ｅ；２２７（Ｍ⁺−１）
【００５７】
（２）(1SR,2SR,3SR,5RS,6SR)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸１.８０ｇをアセトン：水＝８：５の混合溶液２６ｍｌ中５５℃で攪拌し、（Ｒ）−（＋）−1−フェニルエチルアミン０.９６ｇを加えた後、室温で１５時間 攪拌した。生成した結晶を濾過し、（Ｒ）−(＋)−1−フェニルエチルアミン塩１.３０ｇを得た。濾液は製造例９に使用した。
この塩１.２０ｇを水１５ｍｌに懸濁し、１Ｍ塩酸を用いてｐＨを１.０に調整し、室温で１４時間攪拌した。生成した結晶を濾過により単離し(1S,2S,3S,5R,6S)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸０.６５ｇを得た。更に濾液はイオン交換クロマトグラフィー（ＡＧ５０Ｗ−Ｘ８ 陽イオン交換樹脂(Bio-Rad)、展開溶媒：１Ｍ酢酸）で精製し、(1S,2S,3S,5R,6S)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸を０.０６ｇ得た。
_D［α］²²＝３６.８４（ｃ＝０.２０,ＭｅＯＨ）
【００５８】
（３）(1S,2S,3S,5R,6S)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸０.６０ｇを６０％硫酸水溶液１０ｍｌに溶解し、１４０℃で２日間攪拌した。反応溶液を室温まで冷却後、５Ｍ水酸化ナトリウム水溶液でｐＨ８にした後、イオン交換クロマトグラフィー（ＡＧ１−Ｘ８ 陰イオン交換樹脂(Bio-Rad)、展開溶媒：０.１Ｍ酢酸〜２Ｍ酢酸）で精製し、(1S,2S,3S,5R,6S)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−２,６−ジカルボン酸を０.３４ｇ得た。
_D［α］²²＝５８.６１（ｃ＝０.２０,１Ｍ ＨＣｌ）
【００５９】
製造例９
(1R,2R,3R,5S,6R)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−２,６−ジカルボン酸の合成
（１）製造例８（２）の濾液を減圧下、濃縮した。得られた結晶１.３ｇと水１７ｍｌの混合物を１Ｍ塩酸を用いてｐＨを１.０に調整し、室温で攪拌した。４時間後、生成した結晶を濾取し０.８１ｇの結晶を得た。濾液はイオン交換クロマトグラフィー（ＡＧ５０Ｗ−Ｘ８ 陽イオン交換樹脂(Bio-Rad)、展開溶媒：１Ｍ酢酸）で精製し、０.０８ｇの結晶を得た。
【００６０】
（２）前記２つの結晶を合わせ（０.８９ｇ）、アセトン：水=８：５の混合溶液１３ｍｌを加え、５５℃で攪拌した。この溶液に（Ｓ）−（−）−1−フェニルエチルアミン０.４７ｇを加えた後、室温で１５時間攪拌した。生成した結晶を濾過し、（Ｒ）−(−)−1−フェニルエチルアミン塩を１.１０ｇ得た。
この塩を製造例８の（２）と同様に１Ｍ塩酸を用いてフリー体とし、(1R,2R,3R,5S,6R)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸０.５８ｇを得た。濾液をイオン交換クロマトグラフィー（ＡＧ５０Ｗ−Ｘ８ 陽イオン交換樹脂(Bio-Rad)、展開溶媒：１Ｍ酢酸）で精製し、(1R,2R,3R,5S,6R)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸を０.０７ｇ得た。
_D［α］²²＝−３７.５２（ｃ＝０.２０,ＭｅＯＨ）
【００６１】
（３）(1R,2R,3R,5S,6R)２−スピロ−５'−ヒダントイン−３−フルオロビシクロ[3.1.0]ヘキサン−６−カルボン酸０.５８ｇを製造例８の（３）と同様に反応し、(1R,2R,3R,5S,6R)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−２,６−ジカルボン酸０.３７ｇを得た。
_D［α］²²＝−５９.３６（ｃ＝０.２０,１Ｍ ＨＣｌ）
【００６２】
試験例１［被検薬のcＡＭＰ蓄積に及ぼす効果］
代謝型グルタメ−ト受容体 ｍＧｌｕＲ２安定発現ＣＨＯ細胞を、１０％透析馬胎児血清含有ダルベッコ改変イ−グル培地［１％Proline 50units/ml,Penicillin 50μg/ml,Streptomycin 2mM,L-glutamine（用時添加）］を用いて１.２６×１０４cells/well/0.32cm²/150μlの割合で９６穴プレ−トに播種し、３７℃、５％ＣＯ₂下で２日間培養を行った。その後、L-Glutamine free培地に交換し、４時間後に上清を吸引除去し、１５０μｌ ＰＢＳ（＋）−ＩＢＭＸ（10mM PBS(-),1mM MgCl₂,1mM CaCl₂,1mM IBMX）を添加して、２０分間、３７℃、５％ＣＯ₂存在下でインキュベ−ションを行った。再び上清を吸引除去し、６０μｌ １０−５Ｍ Forskolin、１０−１０〜１０−４Ｍの被検体を含有したＰＢＳ（＋）−ＩＢＭＸを添加して１５分間、３７℃で５％ＣＯ₂存在下インキュベ−ションを行い、Forskolin刺激ｃＡＭＰ蓄積量に対するアゴニストの抑制効果の検討を行った（コントロ−ルは,Forskolinと化合物無添加の条件とした。（Tanabe et al,Neuron,8,169-179(1992)））。１００μｌの氷冷エタノールを添加して反応停止し、上清を別のプレ−トに全量回収した後、エバポレーターで常温乾固し、−２０℃で保存した。乾固したサンプルは、ｃＡＭＰ EIA kit（アマシャム社）を用いてｃＡＭＰ量を定量した。各ｃＡＭＰ量からコントロ−ルの値を差し引いた。１０−５Ｍ Forskolinで刺激を行ったときのｃＡＭＰ蓄積を５０％抑制する被検薬の濃度をＥＤ₅₀値を求め、結果を表１に示した。
【００６３】
【表１】

【００６４】
Ｃｏｍｐ.１：(1S,2S,3S,5R,6S)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
Ｃｏｍｐ.２：(1SR,2SR,3SR,5RS,6SR)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
ＬＹ３５４７４０：（＋）−(1S,2S,5R,6S)−２−アミノビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
ＤＣＧIV：(2S,2'R,3'R)−２−（2',3'−ジカルボキシシクロプロピル）グリシン
(1S,3R)ＡＣＰＤ：(1S,3R)−１−アミノシクロペンタン−1,3−ジカルボン酸
Ｌ−ＣＣＧ−Ｉ：(2S,1'S,2'S)−２−（カルボキシシクロプロピル）グリシン。
【００６５】
試験例２［マウスのメタンフェタミン運動過多に及ぼす効果］
雄性ＩＣＲ系マウス（体重２３−３２ｇ、日本チャールスリバー）を１群１１〜１２匹用いた。動物は塩化ビニール製円筒透明測定ケージ（直径３０ｃｍ、高さ３０ｃｍ）に動物を入れ９０分間環境順化させた。動物に各薬物を経口投与３０分後にメタンフェタミンを１ｍｇ／ｋｇ腹腔内投与した。その１５分後に自動活動量測定装置（ＳＣＡＮＥＴ／ＳＶ−１０、東洋産業株式会社）を用いて３０分間の運動量を測定した。薬物は０.３％tween80−生理食塩水に懸濁した。溶媒投与群のカウント数と各用量のカウント数より抑制率を求め、ＥＤ₅₀値を算出し、結果を表２に示した。また、統計処理は分散分析（ＡＮＯＶＡ）後、ダンネット検定を行った。
ＬＹ−３５４７４０は０.０１ｍｇ／ｋｇ経口投与群を除き、用量依存的にメタンフェタミン運動過多を抑制［Ｆ（４,５４）＝３.２４２,Ｐ＜０.０５］し、ＥＤ₅₀値は０.８７ｍｇ／ｋｇであった。ＭＧＳ０００８も同様な作用が認められ［Ｆ（３,４３）＝３.３０６,Ｐ＜０.０５］、ＥＤ₅₀値は０.０５ｍｇ／ｋｇとなり、ＬＹ−３７４７４０の１７.４倍の強度であった。
【００６６】
【表２】

【００６７】
Ｎ：１群の動物数。*P<0.01 溶媒投与群との比較
Ｃｏｍｐ.１：(1S,2S,3S,5R,6S)−２−アミノ−３−フルオロビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸
ＬＹ３５４７４０：（＋）−(1S,2S,5R,6S)−２−アミノビシクロ[3.1.0]ヘキサン−2,6−ジカルボン酸[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical comprising a novel compound as an active ingredient, and more specifically, acts on a group 2 metabotropic glutamate receptor, such as schizophrenia, anxiety and related diseases, depression, bipolar disorder, epilepsy and the like. For psychiatric disorders and neurological diseases such as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, head disorder The present invention relates to a medicine showing a therapeutic effect and a preventive effect.
[0002]
[Prior art]
Recently, the glutamate receptor gene has been cloned one after another, and it has been revealed that there are a surprising number of subtypes of glutamate receptors. At present, glutamate receptors are broadly classified into two types: “ionotropic type in which the receptor has an ion channel type structure” and “metabolic type in which the receptor is coupled to G-protein”. Furthermore, ionotropic receptors are pharmacologically classified into three types: NMDA, α-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA), and kinetics (Science, 258 , 597-603, 1992), metabotropic receptors are classified into eight types of type 1 to type 8 (J. Neurosci., 13 , 1372-1378, 1993; Neuropharmacol., 34, 1-26, 1995).
[0003]
Metabotropic glutamate receptors are pharmacologically classified into three groups. Among them, group 2 (mGluR2 / mGluR3) binds to adenyl cyclase and suppresses forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Trends Pharmacol. Sci., 14 , 13 (1993)), compounds that act on metabotropic glutamate receptors should be effective in the treatment or prevention of acute and chronic psychiatric and neurological diseases. JP-A-8-188561 discloses (+)-(1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-2 as a substance acting on the group 2 metabotropic glutamate receptor. 1,6-dicarboxylic acid is disclosed.
[0004]
By the way, the fluorine atom has a tendency to impart strong electron withdrawing property and high fat solubility, and the compound into which the fluorine atom is introduced greatly changes the physical properties. For this reason, introduction of a fluorine atom may greatly affect the absorbability, metabolic stability and pharmacological action of the compound. However, it is not easy to introduce fluorine atoms. Actually, in JP-A-8-188561, introduction of a fluorine atom into (+)-(1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid is It has not been studied at all.
[0005]
[Problems to be solved by the invention]
The object of the present invention is, for example, psychiatric disorders such as schizophrenia, anxiety and related diseases, depression, bipolar disorder, epilepsy, and drug dependence, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, A therapeutic or prophylactic agent for diseases associated with group 2 metabotropic glutamate receptors, such as neurological diseases such as movement disorders associated with muscular rigidity, cerebral ischemia, brain failure, spinal cord disorder, and head disorders As a group 2 metabotropic glutamate receptor antagonist effective as an oral administration.
[0006]
[Means for Solving the Problems]
The present inventors have earnestly studied about a fluorine-containing amino acid derivative in which a fluorine atom is introduced into ((+)-(1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid. As a result of the study, a novel fluorine-containing amino acid derivative that has an effect on oral administration to a group 2 metabotropic glutamate receptor was found, and the present invention was completed.
[0007]
The present invention will be described below.
[0008]
The present invention provides formula [1]
[0009]
[Chemical 3]

[0010]
[Where X ¹ Represents a hydrogen atom or a fluorine atom, R ¹ And R ² Are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. ] Or a pharmaceutically acceptable salt thereof, for example, a drug that acts on a group 2 metabotropic glutamate receptor.
In the present invention, the alkyl group having 1 to 10 carbon atoms is linear Or Represents a branched alkyl group, and examples of the linear or branched alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, and 1-ethylpropyl. Group, hexyl group, isohexyl group, 1-ethylbutyl group, heptyl group, isoheptyl group, octyl group, nonyl group, decyl group and the like.
Further, the pharmaceutically acceptable salt in the present invention is, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid. A salt with an organic acid such as trimethylamine or methylamine, or a salt with a metal ion such as sodium ion, potassium ion or calcium ion. The compounds according to the present invention can exist as various solvates, but hydrates are preferable from the viewpoint of applicability as pharmaceuticals.
[0011]
Among the compounds represented by the formula [1], X ¹ When is a hydrogen atom, there are five asymmetric carbon atoms at positions 1, 2, 3, 5 and 6. Therefore, X ¹ The compound according to the present invention in which is a hydrogen atom can exist as a mixture of two enantiomers such as an optically active substance and a racemate and a mixture of diastereomers. In addition, X ¹ When is a fluorine atom, there are four asymmetric carbon atoms at the 1, 2, 5 and 6 positions. Therefore, X ¹ The compound according to the present invention in which is a fluorine atom can exist as a mixture of two enantiomers such as an optically active substance and a racemate and a mixture of diastereomers.
[0012]
Preferred X in the compound represented by the formula [1] ¹ Is a hydrogen atom. In addition, X ¹ When is a hydrogen atom, the compound represented by the formula [1] more preferably has the following relative stereochemical configuration.
[0013]
[Formula 4]

[0014]
X ¹ , R ¹ And R ² Is a hydrogen atom, the most preferred optically active isomer among the optical isomers of this compound has a positive optical rotation, and this absolute stereochemical configuration is determined by 2-spiro-, a synthetic precursor of this compound. X-ray single crystal structure analysis of 5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid (R)-(+)-1-phenylethylamine salt revealed that 1S, 2S, 3S, 5R, 6S was determined.
[0015]
On the other hand, R in the formula [1] ¹ And R ² When one or both of them represent other than hydrogen, that is, the ester does not affect the group 2 metabotropic glutamate receptor. However, this ester is hydrolyzed to a carboxylic acid in vivo and converted to a carboxylic acid that affects the group 2 metabotropic glutamate receptor. Therefore, the ester form functions as a prodrug and is therefore a very useful compound.
[0016]
DETAILED DESCRIPTION OF THE INVENTION
The compound of the formula [1] is supplied by the following production method. In the following reaction formula, R ¹ , R ² , X ¹ Is the same as above, R ^Three And R ^Four Are the same or different and each represent an alkyl group having 1 to 10 carbon atoms, and Y represents a general amino protecting group (see PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE and PETER GM WUTS).
[0017]
[Chemical formula 5]

[0018]
The monofluorinated compound (2) which is a mixture of two enantiomers such as an optically active substance, a racemate or a mixture of diastereomers is a mixture of two enantiomers such as a corresponding optically active substance, a racemate or a mixture of diastereomers. The ketone body (1) is once converted into an enol silyl ether body or enol ester body and then reacted with a fluorination reagent, or by directly reacting the ketone body (1) with a fluorination reagent. Further, a difluoride compound (3) which is a mixture of two enantiomers such as an optically active substance and a racemate or a mixture of diastereomers is obtained by converting a monofluoride compound (2) once into an enolsilyl ether form, It is obtained by reacting, reacting monofluorinated compound (2) directly with a fluorinating reagent, or reacting ketone body (1) with 2 or more equivalents of fluorinating reagent.
[0019]
Here, the enol silyl ether is produced by adding the ketone (1) to ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, alcohols such as methanol and t-butanol, N, N In an inert solvent such as dimethylformamide, for example, alkyllithiums such as n-butyllithium and s-butyllithium, for example, metal amides such as lithium bistrimethylsilylamide, potassium bistrimethylsilylamide, and sodium amide, such as sodium hydride It can be obtained by reacting a silylating agent such as chlorotrimethylsilane and chlorot-butyldimethylsilane in the presence of a metal hydride or a base such as an amine such as triethylamine. The reaction temperature here is preferably 100 ° C. or lower, more preferably from −78 ° C. to room temperature.
[0020]
The enol ester is produced by preparing a silylating agent from an acid anhydride such as acetic anhydride, an acid halide such as propionyl chloride, or a mixed acid prepared from a carboxylic acid such as acetic acid and an alkoxycarbonyl halide such as ethoxycarbonyl chloride. The reaction can be carried out in the same manner as in the production of an enol silyl ether, instead of an anhydride.
Examples of the fluorinating reagent include N-fluoropyridinium triflate, N-fluoro-Nt-butylbenzenesulfonamide, N-fluorosaccharin sultam, N-fluorobis (benzenesulfone) imide, and N-fluoro-o-benzene. N-fluoro type fluorinating agents such as sulfonimide, fluorine, ClO _Three F or CF _Three COOF and the like. Here, as a mode in which the fluorinating reagent is directly reacted, the ketone body (1) is subjected to, for example, ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as toluene and benzene, alcohols such as methanol and t-butanol, In an inert solvent such as N, N-dimethylformamide, for example, alkyllithiums such as n-butyllithium and s-butyllithium, metal amides such as lithium bistrimethylsilylamide, sodium amide, and hydrogen such as sodium hydride In a preferred embodiment, the fluorination reagent is reacted in the presence of a metal fluoride or a base such as an amine such as triethylamine at a reaction temperature of 100 ° C. or lower, preferably from −78 ° C. to room temperature.
[0021]
The mono- or difluorinated compound (4), which is a mixture of two enantiomers such as optically active substance, racemate and the like, or a mixture of diastereomers (4) thus obtained is obtained by using Strecker Amino Acid Synthesis ( Ann., 75 , 27 (1850); 91 349 (1850)), Bucherer-Bergs Reaction (J. Prakt. Chem., 140 , 69 (1934)) or an amino cyanide derivative or a hydantoin derivative obtained by a modification thereof, or a mixture of two enantiomers such as the corresponding optically active compound, racemate, etc., which are the compounds according to the present invention, or It can be set as the fluorine-containing amino acid derivative (5) which is a mixture of diastereomers.
[0022]
Specifically, the mono- or difluoride compound (4) is mixed with sodium cyanide or potassium cyanide and ammonium carbonate in an alcohol such as ethanol or a mixed solvent of water and water, preferably at 30 ° C to 50 ° C for 1 day. It reacts for ~ 2 days and leads to hydantoin which is a synthetic intermediate. Subsequently, by hydrolysis in an inert solvent such as an alcohol such as ethanol, an ether such as dioxane, or a ketone such as acetone with a base such as sodium hydroxide or an acid such as hydrochloric acid or sulfuric acid. The fluorine-containing amino acid derivative (5) which is the compound of the present invention is obtained.
[0023]
[Chemical 6]

[0024]
As shown in the following formula 7, Buchler-Bergs of a monofluoride compound (see (2) above) in which one fluorine atom is introduced into the ketone body represented by (1SR, 5RS, 6SR)-(1) The hydantoin derivative represented by (1SR, 5RS, 6SR)-(6) obtained by the reaction is separated into four shear stereomers by a general technique such as column chromatography using silica gel or recrystallization, for example. be able to.
[0025]
Furthermore, after each of the four diastereomeric esters is hydrolyzed, it can be resolved into eight enantiomers (8) by a general resolution method such as resolution using a basic chiral resolving agent. Then, eight optically active fluorine-containing amino acid derivatives (9) which are the compounds of the present invention are obtained by hydrolyzing the hydantoin site.
[0026]
Here, as the basic chiral resolving agent, for example, (+) or (−)-1-phenylethylamine, (+) or (−)-2-amino-1-butanol, (+) or (−)-alaninol , Optically active amines such as brucine, cinchonidine, cinchonine, quinine, quinidine, dehydroabiethylamine and the like can be used.
[0027]
[Chemical 7]

[0028]
On the other hand, four optically active amino acid derivatives (12) containing two fluorine atoms which are one of the compounds of the present invention start from (1SR, 5RS, 6SR)-(1) as shown in the following chemical formula 8. The raw material can be synthesized by fluorination, hydantoinization, diastereomer separation, ester hydrolysis, resolution, and hydantoin site hydrolysis.
[0029]
[Chemical 8]

[0030]
The ketone body represented by the formula (1SR, 5RS, 6SR)-(2) having one fluorine atom has the formula (13) by separation of diastereomers, hydrolysis of the ester and resolution as shown in the following chemical formula 9. To four optically active ketocarboxylic acids. Accordingly, by directly or after esterifying the four optically active ketocarboxylic acids (13), the same operation as in the synthesis of the compound represented by formula (5) is performed, and further diastereomers are separated. In addition, a fluorine-containing amino acid derivative which is an optically active compound of the present invention can be produced.
[0031]
[Chemical 9]

[0032]
Two optically active ketocarboxylic acids having two fluorine atoms represented by the formula (14) are represented by the following chemical formula 9 from the ketone body represented by the formula (1SR, 5RS, 6SR)-(3) having two fluorine atoms. It can be obtained in a similar manner, ie hydrolysis and resolution of the ester. Therefore, the optically active ketocarboxylic acid (14) can be directly or after esterification by performing the same operation as the amino acid synthesis method shown in Chemical formula 6 and further separating the diastereomers. Thus, a fluorine-containing amino acid derivative (15) which is a compound of the present invention can be produced.
[0033]
[Chemical Formula 10]

[0034]
By the way, as shown in the following chemical formula 11, the fluorine-containing amino acid which is the compound of the present invention in a mixture of two enantiomers such as an optically active substance and a racemate represented by the formula (6) or a mixture of diastereomers has an amino group. After protecting with a protecting group represented by Y, R ^Three -X ² Or R ^Four -X ² Or an alkyl halide represented by R ^Three -OH or R ^Four Esterification is performed by a general method using an alcohol represented by —OH, and the amino-protecting group is removed to derive a fluorine-containing amino acid ester which is a compound of the present invention represented by the formula (15).
[0035]
Embedded image

[0036]
Here, protection of the amino group, esterification and deprotection of the amino group are carried out by general methods (see PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, THEODORA W. GREENE and PETER GMWUTS).
[0037]
Furthermore, each diastereomer of the fluorine-containing amino acid ester represented by the formula (15) or the N-protected fluorine-containing amino acid ester represented by the formula (17) can be used in general such as column chromatography using silica gel or the like, recrystallization, etc. Can be separated by conventional techniques. Each diastereomer of formula (15) can be resolved into each enantiomer by a general resolution method such as resolution using an acidic chiral resolving agent.
Here, as the acidic chiral resolving agent, (+) or (−)-di-p-toluoyl tartaric acid, (+) or (−)-dibenzoyl tartaric acid, (+) or (−)-tartaric acid, (+) or Optically active organic acids such as (−)-mandelic acid, (+) or (−)-camphoric acid, or (+) or (−)-camphor sulfonic acid can be used.
[0038]
The compounds according to the invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents into pharmaceutical preparations. Examples of the carriers, excipients and diluents include water, sugar milk, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, Cellulose, water syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like are included.
[0039]
The compound according to the present invention is mixed with these carriers, excipients or diluents, and additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary. In addition, tablets or pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, skin patches, etc., such as tablets, pills, capsules, granules, powders, and oral patches, especially groups It can be prepared as a 2 metabotropic glutamate receptor agonist. The compound according to the present invention can be orally or parenterally administered to an adult patient in an amount of 0.01 to 500 mg once or several times a day. This dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
[0040]
【The invention's effect】
According to the present invention, there are provided drugs useful as pharmaceuticals, in particular, metabotropic glutamate receptor agonists. Therefore, it is associated with psychiatric disorders such as schizophrenia, anxiety and related diseases, depression, bipolar disorder, epilepsy, such as drug dependence, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, muscle rigidity It can be used as a therapeutic and prophylactic agent useful for neurological diseases such as movement disorders, cerebral ischemia, brain failure, spinal cord disorders, and head disorders.
[0041]
【Example】
The present invention will be specifically described below with reference to production examples and test examples.
Production Example 1
(1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [ 3.1.0] Synthesis of hexane-6-carboxylate
In a nitrogen atmosphere, in 150 ml of tetrahydrofuran, lithium bistrimethylsilylamide prepared from 30.9 ml of n-butyllithium (1.54 M hexane solution) and 7.50 g of 1,1,1,3,3,3-hexamethyldisilazane. 6.60 g of (1SR, 5RS, 6SR) ethyl 2-oxobicyclo [3.1.0] hexane-6-carboxylate dissolved in 150 ml of tetrahydrofuran at −75 ° C. was added dropwise. After stirring at this temperature for 1 hour, 7.5 ml of chlorotrimethylsilane was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, anhydrous hexane was added to the residue, and the resulting inorganic salt was filtered off and concentrated.
[0042]
The residue was dissolved in 66 ml of methylene chloride, 15.00 g of N-fluorobenzenesulfonimide was added, and the mixture was stirred at room temperature for 16.5 hours. The reaction solution was washed twice with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro- A mixture of 2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate is used. 30 g was obtained.
¹ H-NMR (CDCl _Three ) δ (ppm); 1.28 (3Hx3 / 4, t, J = 7.2Hz), 1.29 (3Hx1 / 4, t, J = 7.2Hz), 2.11-2.79 (5H, m), 4.18 (2H, q, J = 7.2Hz), 4.51 (1Hx1 / 4, dd, J = 51Hz, 8.1Hz), 4.58 (1Hx3 / 4, dt, J = 51Hz, 8.1Hz)
MS (FAB) (Pos) m / e; 187 (M ⁺ +1)
[0043]
Production Example 2
(1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [ 3.1.0] Synthesis of hexane-6-carboxylate
In a nitrogen atmosphere, in 1.5 ml of lithium bistrimethylsilylamide prepared from 1.5 ml of n-butyllithium (1.54 M hexane solution) and 0.38 g of 1,1,1,3,3,3-hexamethyldisilazane in tetrahydrofuran. Then, 0.20 g of (1SR, 5RS, 6SR) ethyl 2-oxobicyclo [3.1.0] hexane-6-carboxylate dissolved in 6 ml of tetrahydrofuran at −75 ° C. was added dropwise. After stirring at this temperature for 45 minutes, 0.75 g of N-fluorobenzenesulfonimide was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed twice with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro- A mixture of 2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate is reduced to 0. 08 g was obtained.
¹ H-NMR (CDCl _Three ) δ (ppm); 1.28 (3Hx3 / 4, t, J = 7.2Hz), 1.29 (3Hx1 / 4, t, J = 7.2Hz), 2.11-2.79 (5H, m), 4.18 (2H, q, J = 7.2Hz), 4.51 (1Hx1 / 4, dd, J = 51Hz, 8.1Hz), 4.58 (1Hx3 / 4, dt, J = 51Hz, 8.1Hz)
MS (FAB) (Pos) m / e; 187 (M ⁺ +1)
[0044]
Production Example 3
Synthesis of (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo [3.1.0] hexane-6-carboxylate
In a nitrogen atmosphere, in 150 ml of tetrahydrofuran, lithium bistrimethylsilylamide prepared from 30.9 ml of n-butyllithium (1.54 M hexane solution) and 7.50 g of 1,1,1,3,3,3-hexamethyldisilazane. 6.60 g of (1SR, 5RS, 6SR) ethyl 2-oxobicyclo [3.1.0] hexane-6-carboxylate dissolved in 150 ml of tetrahydrofuran at −75 ° C. was added dropwise. After stirring at this temperature for 1 hour, 7.5 ml of chlorotrimethylsilane was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, anhydrous hexane was added to the residue, and the resulting inorganic salt was filtered off and concentrated. The residue was dissolved in 66 ml of methylene chloride, 15.00 g of N-fluorobenzenesulfonimide was added, and the mixture was stirred at room temperature for 16.5 hours. The reaction solution was washed twice with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo 0.03 g of [3.1.0] hexane-6-carboxylate was obtained.
¹ H-NMR (CDCl _Three ) δ (ppm): 1.30 (3H, t, J = 7.1Hz), 2.42-2.80 (5H, m), 4.20 (2H, q, J = 7.1Hz)
MS (Ion Spray) (Nega) m / e; 203 (M ⁺ -1)
[0045]
Production Example 4
Synthesis of (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo [3.1.0] hexane-6-carboxylate
In a nitrogen atmosphere, 5.0 ml of n-butyllithium (1.54 M in hexane) and 26 ml of lithium bistrimethylsilylamide prepared from 1.40 g of 1,1,1,3,3,3-hexamethyldisilazane in tetrahydrofuran Then, 1.3 g of the compound synthesized in Production Example 1 dissolved in 6.5 ml of tetrahydrofuran at −75 ° C. was added dropwise. After stirring at this temperature for 1 hour, 1.3 ml of chlorotrimethylsilane was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, anhydrous hexane was added to the residue, and the resulting inorganic salt was filtered off and concentrated.
[0046]
The residue was dissolved in 13 ml of methylene chloride, 3.30 g of N-fluorobenzenesulfonimide was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was washed twice with water and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-methylene chloride-ethyl acetate = 60: 4: 1), and (1SR, 5RS, 6SR) ethyl 3,3-difluorobicyclo 0.34 g of [3.1.0] hexane-6-carboxylate was obtained.
¹ H-NMR (CDCl _Three ) δ (ppm): 1.30 (3H, t, J = 7.1Hz), 2.42-2.80 (5H, m), 4.20 (2H, q, J = 7.1Hz)
MS (Ion Spray) (Nega) m / e; 203 (M ⁺ -1)
[0047]
Production Example 5
(1SR, 2SR, 3SR, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate, (1SR, 2SR, 3RS, 5RS, 6SR) ethyl 2 -Spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 2RS, 3RS, 5RS, 6SR) ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo Synthesis of [3.1.0] hexane-6-carboxylate
(1SR, 3RS, 5RS, 6SR) ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate and (1SR, 3SR, 5RS, 6SR) ethyl 3-fluoro-2-oxobibicyclo [ 3.1.0] A mixture of hexane-6-carboxylate (4.84 g) was dissolved in a mixed solution of 26 ml of water and 38 ml of ethanol, 6.25 g of ammonium carbonate and 1.86 g of potassium cyanide were added, and the mixture was stirred at 35 ° C for 37 hours. The reaction mixture was cooled to room temperature, 31 ml of water was added, and the mixture was further stirred for 2.5 hours under ice cooling, and the resulting crystals were collected by filtration to obtain 2.10 g of first crystals. Concentrated hydrochloric acid was added to the filtrate under ice-cooling to adjust the pH to 1.0, and the produced crystals were collected by filtration to obtain 2.00 g of second crystals.
[0048]
The first crystal was subjected to chromatography (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries), developing solvent: chloroform-methanol = 100: 1), 0.61 g of low-polar diastereomer and polar diastereomer A (polar diastereomer A) The diastereomer A and polar diastereomer B, which contain about 25% of stereomer B, have the same Rf value).
0.61 g of low-polar diastereomer was recrystallized from a mixed solution of water-ethanol = 1: 1 and (1SR, 2SR, 3SR, 5RS, 6SR) ethyl 2-spiro-5′-hydantoin-3-fluorobicyclo [ 3.1.0] 0.52 g of hexane-6-carboxylate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.19 (3H, t, J = 7.0Hz), 1.95-2.46 (5H, m), 4.06 (2H, q, J = 7.0Hz), 4.81 (1H, dd, J = 52Hz, 5.1) Hz), 8.44 (1H, s), 10.91 (1H, s)
MS (EI) m / e; 256 (M ⁺ )
[0049]
0.55 g of polar diastereomer A was recrystallized from a mixed solution of water-ethanol = 1: 1 and (1SR, 2SR, 3RS, 5RS, 6SR) ethyl 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1 .0] 0.37 g of hexane-6-carboxylate was obtained.
¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.18 (3H, t, J = 7.1Hz), 1.85-2.43 (5H, m), 4.05 (2H, q, J = 7.1Hz), 4.70 (1H, dt, J = 52Hz, 8.0) Hz), 8.21 (1H, s), 10.83 (1H, s)
MS (EI) m / e; 256 (M ⁺ )
[0050]
The second crystals were washed with ethyl acetate, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized twice with water-ethanol = 1: 1. The two recrystallized filtrates were concentrated under reduced pressure, and the residue was chromatographed (silica gel: Wako gel (manufactured by Wako Pure Chemical Industries), developing solvent: chloroform-methanol = 100: 1) to complete the low-polar diastereomer. Removed. 0.25 g of the obtained polar diastereomer B crystal (including about 10% of polar diastereomer A) was recrystallized with water-ethanol = 1: 1, and (1SR, 2RS, 3RS, 5RS, 6SR) Ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate was obtained in an amount of 0.18 g.
¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.18 (3H, t, J = 7.1Hz), 1.81-2.17 (4H, m), 2.36 (1H, dd, J = 13Hz, 7.2Hz), 3.95-4.11 (2H, m), 4.90 (1H, ddd, J = 51Hz, 8.9Hz, 7.2Hz), 8.54 (1H, s), 10.87 (1H, s)
MS (EI) m / e; 256 (M ⁺ )
[0051]
The following compounds were synthesized in the same manner.
(1SR, 2SR, 5RS, 6SR) Ethyl 2-spiro-5′-hydantoin-3,3-difluorobicyclo [3.1.0] hexane-6-carboxylate
¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.19 (3H, t, J = 7.0Hz), 1.85-1.89 (1H, m), 2.00-2.08 (1H, m), 2.15-2.27 (1H, m), 2.33-2.50 (1H) , m), 2.55-2.86 (1H, m), 4.07 (2H, q, J = 7.0Hz), 8.49 (1H, m)
MS (EI) m / e; 274 (M ⁺ )
[0052]
Production Example 6
Synthesis of (1SR, 2SR, 3RS, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
(1SR, 2SR, 3RS, 5RS, 6SR) Dissolve 300 mg of ethyl 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate in 2.5 ml of 3M aqueous sodium hydroxide, Heated to reflux for 16 hours. The reaction solution was cooled to room temperature, filtered through a glass filter, and the filtrate was adjusted to pH 3 with concentrated hydrochloric acid, followed by ion exchange chromatography (AG1-X8 anion exchange resin (Bio-Rad), developing solvent: 0.1 M acetic acid). 3M acetic acid) to obtain 51 mg of (1SR, 2SR, 3RS, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid.
¹ H-NMR (TFA-d) δ (ppm); 2.23-2.24 (1H, m), 2.56-2.96 (4H, m), 5.15 (1H, dt, J = 52Hz, 7.5Hz)
MS (CI) m / e; 204 (M ⁺ +1)
[0053]
The following compounds were synthesized in the same manner.
(1SR, 2SR, 5RS, 6SR) -2-Amino-3,3-difluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
¹ 1 H-NMR (TFA-d) δ (ppm); 2.46 (1H, brs), 2.63-2.90 (3H, m), 3.01-3.12 (1H, m)
MS (CI) m / e; 222 (M ⁺ +1)
[0054]
Production Example 7
Synthesis of (1SR, 2SR, 3SR, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
(1SR, 2SR, 3SR, 5RS, 6SR) Ethyl 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate (100 mg) was dissolved in 1.5 ml of 60% aqueous sulfuric acid solution. Heat at 12 ° C. for 12 hours. The reaction solution is cooled to room temperature, adjusted to pH 8 with 5M aqueous sodium hydroxide solution, and purified by ion exchange chromatography (AG1-X8 anion exchange resin (Bio-Rad), developing solvent: 0.1 M acetic acid to 2 M acetic acid). 20 mg of (1SR, 2SR, 3SR, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (TFA-d) δ (ppm); 2.49 (1H, brs), 2.59-3.06 (4H, m), 5.40 (1H, dd, J = 52Hz, 5.3Hz)
MS (CI) m / e; 204 (M ⁺ +1)
[0055]
The following compounds were synthesized in the same manner.
(1SR, 2RS, 3RS, 5RS, 6SR) -2-Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
¹ H-NMR (TFA-d) δ (ppm); 2.33 (1H, brs), 2.54-2.89 (4H, m), 5.42-5,59 (1H, m)
MS (CI) m / e; 204 (M ⁺ +1)
[0056]
Production Example 8
Synthesis of (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
(1) (1SR, 2SR, 3SR, 5RS, 6SR) ethyl 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylate 2.20 g and 2M sodium hydroxide 17 ml mixture Was stirred at room temperature. After 2 hours, concentrated hydrochloric acid was added to adjust the pH to 1.0. The resulting crystals were isolated by filtration and dried (1SR, 2SR, 3SR, 5RS, 6SR) to give 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid as 1. 81 g was obtained.
¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.85-2.44 (5H, m), 4.80 (1H, dd, J = 52Hz, 5.3Hz), 8.44 (1H, s), 10.88 (1H, s), 12.30 (1H, brs)
MS (FAB) (Nega) m / e; 227 (M ⁺ -1)
[0057]
(2) (1SR, 2SR, 3SR, 5RS, 6SR) 1.80 g of 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was added to acetone: water = 8: 5 The mixture was stirred in 26 ml of the mixed solution at 55 ° C., 0.96 g of (R)-(+)-1-phenylethylamine was added, and the mixture was stirred at room temperature for 15 hours. The produced crystal was filtered to obtain 1.30 g of (R)-(+)-1-phenylethylamine salt. The filtrate was used in Production Example 9.
1.20 g of this salt was suspended in 15 ml of water, the pH was adjusted to 1.0 with 1M hydrochloric acid, and the mixture was stirred at room temperature for 14 hours. The produced crystals were isolated by filtration (1S, 2S, 3S, 5R, 6S) to give 0.65 g of 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid. Further, the filtrate was purified by ion exchange chromatography (AG50W-X8 cation exchange resin (Bio-Rad), developing solvent: 1M acetic acid), and (1S, 2S, 3S, 5R, 6S) 2-spiro-5'-hydantoin. 0.06 g of -3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was obtained.
_D [Α] ^{twenty two} = 36.84 (c = 0.20, MeOH)
[0058]
(3) 0.61 g of (1S, 2S, 3S, 5R, 6S) 2-spiro-5'-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was dissolved in 10 ml of 60% sulfuric acid aqueous solution. , And stirred at 140 ° C. for 2 days. The reaction solution is cooled to room temperature, adjusted to pH 8 with 5M aqueous sodium hydroxide solution, and purified by ion exchange chromatography (AG1-X8 anion exchange resin (Bio-Rad), developing solvent: 0.1 M acetic acid to 2 M acetic acid). 0.34 g of (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
_D [Α] ^{twenty two} = 58.61 (c = 0.20, 1M HCl)
[0059]
Production Example 9
Synthesis of (1R, 2R, 3R, 5S, 6R) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
(1) The filtrate of Production Example 8 (2) was concentrated under reduced pressure. A mixture of 1.3 g of the obtained crystals and 17 ml of water was adjusted to pH 1.0 with 1M hydrochloric acid and stirred at room temperature. After 4 hours, the produced crystals were collected by filtration to obtain 0.81 g of crystals. The filtrate was purified by ion exchange chromatography (AG50W-X8 cation exchange resin (Bio-Rad), developing solvent: 1M acetic acid) to obtain 0.08 g of crystals.
[0060]
(2) The two crystals were combined (0.89 g), 13 ml of a mixed solution of acetone: water = 8: 5 was added, and the mixture was stirred at 55 ° C. To this solution was added 0.47 g of (S)-(−)-1-phenylethylamine, and the mixture was stirred at room temperature for 15 hours. The produced crystal was filtered to obtain 1.10 g of (R)-(−)-1-phenylethylamine salt.
This salt was made free using 1M hydrochloric acid in the same manner as in Production Example 8 (2), and (1R, 2R, 3R, 5S, 6R) 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] was obtained. 0.58 g of hexane-6-carboxylic acid was obtained. The filtrate was purified by ion exchange chromatography (AG50W-X8 cation exchange resin (Bio-Rad), developing solvent: 1M acetic acid), and (1R, 2R, 3R, 5S, 6R) 2-spiro-5'-hydantoin- 0.07 g of 3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was obtained.
_D [Α] ^{twenty two} = -37.52 (c = 0.20, MeOH)
[0061]
(3) 0.58 g of (1R, 2R, 3R, 5S, 6R) 2-spiro-5′-hydantoin-3-fluorobicyclo [3.1.0] hexane-6-carboxylic acid was added to (3) of Production Example 8 The same reaction was performed to obtain 0.37 g of (1R, 2R, 3R, 5S, 6R) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid.
_D [Α] ^{twenty two} = -59.36 (c = 0.20, 1M HCl)
[0062]
Test Example 1 [Effect of test drug on cAMP accumulation]
Metabotropic glutamate receptor mGluR2 stably expressing CHO cells in 10% dialyzed fetal bovine serum-containing Dulbecco's modified Eagle medium [1% Proline 50 units / ml, Penicillin 50 μg / ml, Streptomycin 2 mM, L-glutamine (added when used) )] 1.26 × 104cells / well / 0.32cm ² / 150 μl in 96-well plates, 37 ° C., 5% CO ₂ Cultivation was carried out for 2 days. Thereafter, the medium was replaced with L-Glutamine free medium, and after 4 hours, the supernatant was removed by aspiration. 150 μl PBS (+)-IBMX (10 mM PBS (−), 1 mM MgCl ₂ , 1mM CaCl ₂ , 1 mM IBMX) for 20 minutes at 37 ° C., 5% CO ₂ Incubation was performed in the presence. The supernatant was aspirated again, and PBS (+)-IBMX containing 60 μl of 10-5M Forskolin, 10-10 to 10-4M of the sample was added, and 5% CO at 37 ° C. for 15 minutes. ₂ Incubation was carried out in the presence, and the inhibitory effect of the agonist on the amount of Forskolin-stimulated cAMP accumulation was examined (the control was performed under the condition that no Forskolin and a compound were added. 8 169-179 (1992))). The reaction was stopped by adding 100 μl of ice-cold ethanol, and the whole supernatant was collected in another plate, dried at room temperature with an evaporator, and stored at −20 ° C. The amount of cAMP in the dried sample was quantified using cAMP EIA kit (Amersham). The control value was subtracted from each cAMP amount. The concentration of the test drug that suppresses cAMP accumulation by 50% when stimulated with 10-5M Forskolin is ED. ₅₀ Values were determined and the results are shown in Table 1.
[0063]
[Table 1]

[0064]
Comp. 1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
Comp. 2: (1SR, 2SR, 3SR, 5RS, 6SR) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
LY354740: (+)-(1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
DCGIV: (2S, 2′R, 3′R) -2- (2 ′, 3′-dicarboxycyclopropyl) glycine
(1S, 3R) ACPD: (1S, 3R) -1-aminocyclopentane-1,3-dicarboxylic acid
L-CCG-I: (2S, 1 ′S, 2 ′S) -2- (carboxycyclopropyl) glycine.
[0065]
Test Example 2 [Effect on excessive methamphetamine exercise in mice]
11 to 12 male ICR mice (weight 23-32 g, Nippon Charles River) were used. The animal was placed in a cylindrical transparent measuring cage made of vinyl chloride (diameter 30 cm, height 30 cm) and acclimatized for 90 minutes. 30 minutes after oral administration of each drug to the animals, 1 mg / kg of methamphetamine was intraperitoneally administered. 15 minutes later, the amount of exercise for 30 minutes was measured using an automatic activity meter (SCANET / SV-10, Toyo Sangyo Co., Ltd.). The drug was suspended in 0.3% tween 80-saline. The inhibition rate is calculated from the count number of the solvent administration group and the count number of each dose, and ED ₅₀ Values were calculated and the results are shown in Table 2. In addition, statistical processing was performed with Dunnett's test after analysis of variance (ANOVA).
LY-354740 suppresses methamphetamine hyperactivity in a dose-dependent manner except in the 0.01 mg / kg oral administration group [F (4,54) = 3.242, P <0.05], and ED ₅₀ The value was 0.87 mg / kg. MGS0008 has a similar effect [F (3,43) = 3.306, P <0.05], ED ₅₀ The value was 0.05 mg / kg, which was 17.4 times the strength of LY-374740.
[0066]
[Table 2]

[0067]
N: Number of animals in group. * P <0.01 Comparison with vehicle administration group
Comp. 1: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid
LY354740: (+)-(1S, 2S, 5R, 6S) -2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid

Claims (3)

formula

[Wherein, X ¹ represents a hydrogen atom or a fluorine atom, and R ¹ and R ² are the same or different and represent a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. ] The therapeutic agent or preventive agent of schizophrenia which uses the fluorine-containing amino acid derivative represented by this, or its pharmaceutically acceptable salt as an active ingredient. formula

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. ] The therapeutic agent or preventive agent of schizophrenia which uses the fluorine-containing amino acid derivative which has the relative stereochemical configuration represented by this, or its pharmaceutically acceptable salt as an active ingredient. (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient A therapeutic or prophylactic agent for schizophrenia .