JP5009459B2 - Amino alcohol derivatives and pharmaceuticals containing the same - Google Patents

Description

【０００９】
式中、*は不斉炭素を示し、Ｒは下記▲１▼若しくは▲２▼で示されるモノカルボン酸誘導体の残基、又は▲３▼で示されるジカルボン酸またはその誘導体の残基を表す。
▲１▼ （ＣＯＣＨ₂ＮＨ)mＺで示されるグリシンまたはポリグリシンの残基（ただし、mは１〜３の整数を、Zはアミノ基の保護基またはアルカノイル基を示す）
▲２▼ ＣＯ−Ｗ−Ｙで示されるカルボン酸誘導体の残基（ただし、Ｗはアルキレン基またはシクロアルキレン基、Ｙはヒドロキシル基、単糖残基、置換基を有し得るアリール基、またはアルキル鎖中に酸素原子を含み得るアルコキシ基を示す）
▲３▼ ＣＯ−Ｗ−ＣＯ−Ｘで示されるジカルボン酸またはその誘導体の残基［ただし、Ｗはアルキレン基またはシクロアルキレン基、Ｘはヒドロキシル基、鎖状若しくは環状のアルコキシ基、アルキル基、α-アミノ酸残基、またはＮＲ¹Ｒ²（Ｒ¹，Ｒ²はそれぞれ同一または異なる水素原子、アルキル鎖中に酸素原子を含み得る鎖状若しくは環状のアルキル基、アルキル鎖中に酸素原子を含み得る鎖状若しくは環状のヒドロキシアルキル基を表す）を示す］。
【００１０】
本発明の第２の要旨は、
（２）上記式（Ｉ）で示されるアミノアルコール誘導体又は薬学的に許容されるその塩を有効成分として含有する医薬に存する。
なお、一般式（Ｉ）の化合物には４種類の立体配置(1S,2S)、(1S,2R)、(1R,2S),(1R,2R)が存在するが、神経疾患の治療剤または脳保護剤の有効成分としては、立体配置が（１Ｓ，２Ｓ）であるL-トレオ体が好ましい。
【００１１】
本発明の好適な態様として以下のアミノアルコール誘導体又は薬学的に許容されるその塩を挙げることが出来る。
（ａ）上記式（Ｉ）において、Ｒが下記▲１▼乃至▲３▼のいずれかで表されることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
▲１▼ （ＣＯＣＨ₂ＮＨ）mＺ（Ｚは炭素数８〜１５のアラルキルオキシカルボニル基および炭素数５〜７のアルコキシカルボニル基から選ばれるアミノ保護基または炭素数４〜８のアルカノイル基を示す）
▲２▼ ＣＯ−Ｗ−Ｙ（Ｗは炭素数１〜１２のアルキレン基または炭素数４〜８のシクロアルキレン基であり、Ｙはヒドロキシル基、グルコース残基、ガラクトース残基、N-アセチルグルコサミン残基、N-アセチルガラクトサミン残基、マンノース残基、フコース残基、シアル酸残基、置換基を有し得るフェニル基、炭素数１〜６のアルコキシ基またはアルキル鎖中に１〜３個の酸素原子を含む炭素数４〜１２のアルコキシ基を示す）
▲３▼ ＣＯ−Ｗ−ＣＯ−Ｘ［Ｗは炭素数１〜１２のアルキレン基または炭素数４〜８のシクロアルキレン基であり、Ｘはヒドロキシル基、炭素数１〜８のアルコキシ基、炭素数５〜８のシクロアルコキシ基、炭素数１〜６のアルキル基、側鎖に反応性の官能基を有するα-アミノ酸残基またはＮＲ¹Ｒ²（Ｒ¹，Ｒ²はそれぞれ同一または異なる水素原子、炭素数１〜６のアルキル基、シクロヘキシル基または炭素数２〜４のヒドロキシアルキル基を示す）を示す］。
【００１２】
（ｂ）上記式（Ｉ）において、Ｒが下記▲１▼乃至▲３▼のいずれかで表されることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
▲１▼ （ＣＯＣＨ₂ＮＨ)mＺ（Ｚはベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基またはヘキサノイル基を示す）
▲２▼ ＣＯ−Ｗ−Ｙ（Ｗは炭素数１〜９のアルキレン基、Ｙはヒドロキシル基、グルコース残基、ガラクトース残基、N-アセチルグルコサミン残基、N-アセチルガラクトサミン残基、シアル酸残基、炭素数１〜３のアルコキシ基で置換されたフェニル基、炭素数１〜４のアルコキシ基またはアルキル鎖中に１個の酸素原子を含む炭素数６〜８のアルコキシ基を示す）
▲３▼ ＣＯ−Ｗ−ＣＯ−Ｘ［Ｗは炭素数２〜８のアルキレン基またはシクロヘキシレン基であり、Ｘはヒドロキシル基；炭素数１〜４のアルコキシ基；シクロヘキシルオキシ基；メチル基；リジン、アルギニン、ヒスチジン、アスパラギン酸、グルタミン酸、オルニチン、システイン、セリン、トレオニンおよびチロシンから選ばれるアミノ酸残基、あるいはＮＲ¹Ｒ²（Ｒ¹，Ｒ²はそれぞれ同一または異なる水素原子、炭素数１〜６の直鎖アルキル基、シクロヘキシル基またはヒドロキシエチル基を示す）を示す］
【００１３】
（ｃ）上記式（Ｉ）において、ＲはＣＯ−Ｗ−ＣＯ−Ｘで表され、且つ、Ｗは炭素数２〜８のアルキレン基であり、Ｘはヒドロキシル基、炭素数１〜４のアルコキシ基またはメチル基であることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
（ｄ）上記式（Ｉ）において、ＲはＣＯ−Ｗ−ＣＯ−Ｘで表され、且つ、Ｗは炭素数４〜８のアルキレン基であり、Ｘはリジン残基またはオルニチン残基であることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
【００１４】
（ｅ）上記式（Ｉ）において、ＲはＣＯ−Ｗ−ＣＯ−Ｘで表され、且つ、Ｗは炭素数４〜８のアルキレン基またはシクロヘキシレン基であり、ＸはＮＲ¹Ｒ²（Ｒ¹、Ｒ²はそれぞれ同一または異なる水素原子、メチル基、エチル基、プロピル基、ｎ−ブチル基、ｎ−ヘキシル基、シクロヘキシル基またはヒドロキシエチル基）であることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
【００１５】
（ｆ）上記式（Ｉ）において、ＲはＣＯ−Ｗ−Ｙで表され、且つ、Ｗはノニレン基であり、Ｙはヒドロキシル基であることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
（ｇ）上記式（Ｉ）において、ＲはＣＯ−Ｗ−Ｙで表され、且つ、Ｗはメチレン基であり、Ｙはｎ−ブトキシ基またはアルキル鎖中に１個の酸素原子を含む炭素数６〜８のアルコキシ基であることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
【００１６】
（ｈ）上記式（Ｉ）において、ＲはＣＯ−Ｗ−Ｙで表され、且つ、Ｗはオクチレン基であり、Ｙはシアル酸残基であることよりなる上記式（１）に記載のアミノアルコール誘導体又は薬学的に許容されるその塩。
【００１７】
更に、本発明の好適な医薬の態様として上記の（１）、（ａ）〜（ｈ）のいずれかに記載のアミノアルコール誘導体又は薬学的に許容されるその塩を有効成分とする神経疾患の治療剤又は脳保護剤を挙げることが出来る。
【００１８】
【発明の実施の形態】
以下、本発明を具体的に説明する。
本発明の化合物は式（Ｉ）で示されるアミノアルコール誘導体又は薬学的に許容されるその塩（以下、「本発明化合物」ということもある。）であり、式中における置換基Ｒの定義▲１▼〜▲３▼は上記に示したとおりであるが、置換基▲１▼〜▲３▼に相応するこれらの具体例を以下に示す。
式（Ｉ）において、Ｒが（ＣＯＣＨ₂ＮＨ）mＺである本発明化合物としては、mは１〜３，好ましくは１または２であり、Ｚは炭素数８〜１５のアラルキルオキシカルボニル基および炭素数５〜７のアルコキシカルボニル基から選ばれるアミノ保護基または炭素数４〜８のアルカノイル基であるアミノアルコール誘導体又は薬学的に許容されるその塩が挙げられる。
【００１９】
アミノ保護基としては、ウレタン型の保護基が挙げられ、具体的にはベンジルオキシカルボニル基、ｐ−ニトロベンジルオキシカルボニル基、ｐ−ブロモベンジルオキシカルボニル基、ｐ−メトキシベンジルオキシカルボニル基、ｐ−メトキシフェニルアゾベンジルオキシカルボニル基、ｐ−フェニルアゾベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基またはシクロペンチルオキシカルボニル基が挙げられ、好ましくはベンジルオキシカルボニル基またはｔ−ブトキシカルボニル基である。アルカノイル基としては好ましくはヘキサノイル基が挙げられる。
Ｒが（ＣＯＣＨ₂ＮＨ）mＺである式（Ｉ）で示されるより具体的な化合物としては、（１Ｓ，２Ｓ）−２−ベンジルオキシカルボニルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−ベンジルオキシカルボニルグリシルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(n-ブトキシ)カルボニルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(n-ヘキサノイル)グリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノールが挙げられる。
【００２０】
式（Ｉ）において、ＲがＣＯ−Ｗ−ＣＯ−Ｘである本発明化合物としては、Ｗは炭素数１〜１２のアルキレン基または炭素数４〜８のシクロアルキレン基であり、Ｘはヒドロキシル基、炭素数１〜８のアルコキシ基、炭素数５〜８のシクロアルコキシ基、炭素数１〜６のアルキル基、側鎖に反応性の官能基（例えば、アミノ基、グアニジノ基、カルボキシル基、ヒドロキシル基）を有するα-アミノ酸残基またはＮＲ¹Ｒ²（Ｒ¹，Ｒ²はそれぞれ同一または異なる水素原子、炭素数１〜６のアルキル基、シクロヘキシル基または炭素数２〜４のヒドロキシアルキル基を示す）であるアミノアルコール誘導体又は薬学的に許容されるその塩が挙げられる。これらの中より具体的には、Ｗは炭素数２〜８のアルキレン基またはシクロヘキシレン基であり、Ｘはヒドロキシル基、炭素数１〜４のアルコキシ基、シクロヘキシルオキシ基、メチル基、またはリジン、アルギニン、ヒスチジン、アスパラギン酸、グルタミン酸、オルニチン、システイン、セリン、トレオニンおよびチロシンから選ばれるアミノ酸残基あるいはＮＲ¹Ｒ²（Ｒ¹，Ｒ²はそれぞれ同一または異なる水素原子、炭素数１〜６の直鎖アルキル基、シクロヘキシル基またはヒドロキシエチル基を示す）である化合物が挙げられる。
【００２１】
ＲがＣＯ−Ｗ−ＣＯ−Ｘである式（Ｉ）の具体的な化合物としては、（１Ｓ，２Ｓ）−２−(n-ブトキシ)ブタンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−エトキシヘキサンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−イソプロポキシヘキサンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(n-ブトキシヘキサンジオイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−メトキシデカンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(9-カルボキシノナノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−（7-オキソオクタノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ,12Ｓ）−２−(12-アミノ-7-アザ-6-オキソ-12-カルボキシドデカノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ,16Ｓ）−２−(16-アミノ-11-アザ-10-オキソ-16-カルボキシヘキサデカノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノールが挙げられる。
【００２２】
更に、（１Ｓ，２Ｓ）−２−(3-ブチルカルバモイル)プロピオニルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(N-ブチル-N-メチルアミノ)ブタンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−（5-エチルカルバモイル)ペンタノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−（5-シクロヘキシルカルバモイル)ペンタノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−（5-ヘキシルカルバモイル)ペンタノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(9-ブチルカルバモイル)ノナノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(9-ヘキシルカルバモイル)ノナノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(N,N-ジエタノールアミノ)デカンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(シクロヘキサン−4−ヘキシルカルバモイル−1−カルボニル)アミノ−３−モルホリノ−１−フェニル−１−プロパノールも挙げられる。
【００２３】
更に式（Ｉ）において、ＲがＣＯ−Ｗ−Ｙである本発明化合物としては、Ｗは炭素数１〜１２のアルキレン基または炭素数４〜８のシクロアルキレン基であり、Ｙはヒドロキシル基、グルコース残基、ガラクトース残基、N-アセチルグルコサミン残基、N-アセチルガラクトサミン残基、マンノース残基、フコース残基、シアル酸残基、置換基を有し得るフェニル基、炭素数１〜６のアルコキシ基またはアルキル鎖中に１〜３個の酸素原子を含む炭素数４〜１２のアルコキシ基であるアミノアルコール誘導体又は薬学的に許容されるその塩が挙げられる。これらの中より具体的には、Ｗは炭素数１〜９のアルキレン基、Ｙはヒドロキシル基、グルコース残基、ガラクトース残基、N-アセチルグルコサミン残基、N-アセチルガラクトサミン残基、シアル酸残基、炭素数１〜３のアルコキシ基で置換されたフェニル基、炭素数１〜４のアルコキシル基またはアルキル鎖中に１個の酸素原子を含む炭素数６〜８のアルコキシル基である化合物が例示される。
【００２４】
ＲがＣＯ−Ｗ−Ｙである一般式（Ｉ）の具体的な化合物としては、（１Ｓ，２Ｓ）−２−(10-ヒドロキシデカノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(9-シアリルノナノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−[4-(4-メトキシフェニル)ブチリル]アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(3-オキサヘプタノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(3,6-ジオキサデカノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール、（１Ｓ，２Ｓ）−２−(3,6-ジオキサドデカノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノールが挙げられる。
【００２５】
本発明化合物中、毒性が低く、シナプス形成活性が高い化合物の具体例としては特に、上記式（Ｉ）において、ＲがＣＯ−Ｗ−ＣＯ−Ｘで示される化合物又はＲがＣＯ−Ｗ−Ｙで示される化合物であり、ＷおよびＸ若しくはＹで示される基がそれぞれ表−１に示す以下の組合せからなる化合物が挙げられる。
【００２６】
【表１】

【００２７】
式（Ｉ）で示される本発明のアミノアルコール誘導体は、式（II）で示されるアミノアルコール誘導体のアミノ基に、置換基Ｒに対応するカルボン酸又はその反応性誘導体を用い、自体既知の方法であるペプチド結合生成反応によりＲを導入することによって得られるが、このような方法に限定されるものではない。
【化２】

【００２８】
Ｒに対応するカルボン酸誘導体に、反応性の高い官能基が含まれる場合は、この官能基をあらかじめ適当な保護基で保護し、所望のペプチド結合生成反応を行った後、脱保護させてもよい。また、脱保護により得られた反応性官能基（例えばアミノ基、カルボキシル基）に自体既知の方法であるペプチド結合生成反応またはエステル化反応を繰り返すことにより、所望の化合物を得ることができる。
【００２９】
ペプチド結合生成方法としては、上記Ｒに対応するカルボン酸と縮合剤を用いる方法、酸無水物を用いる方法、酸ハロゲン化物を用いる方法等が例示される。
具体的には、式（II）で示されるアミノアルコール誘導体又はその酸付加塩（例、塩酸塩）を水、塩化メチレン、ピリジン、エタノール等の溶媒中、上記カルボン酸と縮合剤［例えば、ジシクロヘキシルカルボジイミド（ＤＣＣ）や水溶性カルボジイミド(WSC)、より具体的には1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩（EDC）］と必要に応じてN-ヒドロキシスクシンイミド等の活性化剤を用いて反応させる方法、酸無水物又は酸ハロゲン化物（例えば、酸塩化物）と塩基（例えば、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ−メチルモルホリン等の有機塩基、炭酸水素ナトリウムのような無機塩基）を用いて反応させる方法等が例示される。なお、反応の際に使用する溶媒は、ペプチド結合生成反応を阻害せず、上記アミノアルコール誘導体およびカルボン酸誘導体を溶解するものであれば、特に限定されるものではない。
【００３０】
ペプチド結合生成反応は、通常約０〜５０℃、好ましくは室温下（５〜３５℃（ＪＩＳ Ｋ００５０））、数時間〜数日間、好ましくは１０時間〜２日間行われるが、反応条件は当業者であれば予備実験によって適宜に設定することができる。
ペプチド結合生成反応の後、酢酸エチル、クロロホルム等による溶媒抽出、各種クロマトグラフィー（吸着クロマトグラフィー、イオン交換クロマトグラフィー等）、結晶化等の自体既知の精製手段を適宜に組み合わせて式（Ｉ）で表される本発明化合物を精製・単離することができる。
【００３１】
本発明化合物の出発物質である式（II）の化合物の製法としては、特開平９−２１６８５６号公報に記載されているような公知の方法を適宜採用することができる。具体的には次に示すように、式（III）で表されるキラル化合物を出発物質として使用し、下記工程の反応式に従い順次反応させることにより所望の立体配置を有する化合物として得られる。
【００３２】
【化３】

【００３３】
（工程式中、*は不斉炭素を表し、Ｐ₁ はアミノ基の保護基であり、例えばベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基、ベンゼンスルホニル基、フルオレニルメトキシカルボニル基等が挙げられる。Ｙはメタンスルホニル、トリハロゲノメタンスルホニル、Ｐ−トルエンスルホニル、ベンゼンスルホニル、Ｐ−ブロモベンゼンスルホニル基等の脱離基を表す）
【００３４】
すなわち、式（III）で示されるアミノアルコール誘導体の１級水酸基のみに脱離基（Ｙ）を導入して式（IV）で示される化合物とした後、該化合物にモルホリンを反応させて式（V）で示されるアミノアルコール誘導体となし、該化合物よりＰ₁を脱離させることにより、式（II）で示されるキラルなアミノアルコール誘導体を得ることができる。
このようにして得られた式（II）の化合物は、上記の反応に従い式（Ｉ）の化合物に誘導される。
【００３５】
本発明の式（Ｉ）で示される化合物の薬学的に許容される塩としては、塩酸、リン酸、硫酸、硝酸等の無機酸塩、ギ酸、酢酸、クエン酸、乳酸、リンゴ酸、シュウ酸、マレイン酸、フマル酸、コハク酸、トリフルオロ酢酸、メタンスルホン酸（メシル酸）、Ｐ−トルエンスルホン酸（トシル酸）等の有機酸の塩をあげることができる。このような塩の製造は自体既知の方法によって行うことができ、例えば式（Ｉ）で示される化合物（遊離型）をアルコール等の適宜な溶媒に溶解し、通常等モル程度の上記の酸を添加して反応させ、所望により溶媒を留去すればよい。
【００３６】
本発明化合物の式（Ｉ）で示されるアミノアルコール誘導体又は薬学的に許容されるその塩は、糖脂質の生合成の制御作用に関与する特性を有し、該特性に基づく医薬としての有用性を有している。
式（Ｉ）で示される化合物のうちシナプス形成促進効果及び／又は糖脂質（ガングリオシド等）生合成促進作用を有する化合物は、神経突起伸展促進効果、神経細胞死防止効果、MAPキナーゼ活性化効果を有すると予想され、このような効果に基づく神経疾患治療剤として有用である。したがって、本発明化合物の有効量を、末梢神経又は中枢神経の障害に起因する神経疾患に罹患したヒトを含む哺乳動物に投与することによって、該動物を治療することができる。代表的な疾患として、例えば脳卒中、脳梗塞、脳血管障害後遺症、脳出血、脳外傷、記憶障害、老年痴呆、アルツハイマー病やパーキンソン氏病等の、神経繊維が再生されることによって治療効果が期待される種々の中枢神経系疾患；並びに、例えば代謝障害性多発性神経障害、機械的神経障害、毒性神経障害等の種々の末梢神経系疾患が挙げられる。特にシナプス形成促進活性を有する本発明化合物は、中枢神経系疾患治療剤、特に脳保護剤若しくは脳神経賦活・保護剤として、例えば脳血管障害後遺症の治療に有効である。
【００３７】
〔製剤化〕
本発明の式（Ｉ）で示される化合物およびその薬学的に許容される塩は、ヒトを含む哺乳動物の各種疾患（例えば神経疾患）の治療に用いることができ、該化合物およびその塩を、担体、賦形剤、その他の添加物と共に、経口又は非経口的に投与する製剤とすることができる。
経口製剤としては、散剤、顆粒剤、カプセル剤、錠剤等の固形製剤；シロップ剤、エリキシル剤、乳剤等の液状製剤を挙げることができる。散剤は、例えば乳糖、デンプン、結晶セルロース、乳酸カルシウム、リン酸水素カルシウム、メタケイ酸アルミン酸マグネシウム、無水ケイ酸等の賦形剤と混合して得ることができる。顆粒剤は、上記賦形剤のほか、必要に応じて、例えば白糖、ヒドロキシプロピルセルロース、ポリビニルピロリドン等の結合剤や、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム等の崩壊剤を更に加え、湿式又は乾式で造粒して得ることができる。錠剤は、上記散剤又は顆粒剤をそのまま、又はステアリン酸マグネシウム、タルク等の滑沢剤を加えて打錠して得ることができる。また、上記錠剤又は顆粒剤は、ヒドロキシプロピルメチルセルロースフタレート、メタクリル酸メチルコポリマー、ヒドロキシプロピルメチルセルロースアセテート、ヒドロキシプロピルメチルセルロースサクシネート等の腸溶性基剤で被覆し、あるいはエチルセルロース、カルナウバロウ、硬化油、白色セラック等で被覆し、これらを腸溶性又は持続性製剤にすることができる。
【００３８】
硬カプセル剤は、上記散剤又は顆粒剤を硬カプセルに充填して得ることができる。また軟カプセル剤は、本発明化合物を、グリセリン、ポリエチレングリコール、ゴマ油、オリーブ油等に溶解し、これをゼラチン膜で被覆して得ることができる。
シロップ剤は、白糖、ソルビトール、グリセリン等の甘味剤と本発明化合物とを、水に溶解して得ることができる。また、甘味剤及び水のほかに、精油、エタノール等を加えてエリキシル剤とするか、あるいはアラビヤゴム、トラガント、ポリソルベート類（ポリソルベート２０、ポリソルベート６０、ポリソルベート８０（トウィーン８０）等）、カルボキシメチルセルロースナトリウム等を加えて乳剤又は懸濁剤にすることもできる。またこれらの液状製剤には必要に応じ、矯味剤、着色剤、保存剤等を加えることができる。
【００３９】
非経口製剤としては、注射剤、直腸投与剤、ペッサリー、皮膚外用剤、吸入剤、エアゾール剤、点眼剤等を挙げることができる。注射剤は、本発明化合物に、必要に応じてポリソルベート類等の非イオン界面活性剤；塩酸、水酸化ナトリウム、乳酸、乳酸ナトリウム、リン酸一水素ナトリウム、リン酸二水素ナトリウム等のpH調整剤；塩化ナトリウム、ブドウ糖等の等張化剤；アミノ酸類等の安定化剤；及び注射用蒸留水又は生理食塩水を加え、滅菌濾過した後、アンプルに充填して得ることができる。また更にマンニトール、デキストラン、ゼラチン等を加えて真空凍結乾燥し、用時溶解型の注射剤とすることができる。その他、粉末充填型の注射剤とすることもできる。また本発明化合物に、レシチン、ポリソルベート類、ポリオキシエチレン硬化ヒマシ油、マクロゴール等の乳化剤を加えた後、水中で乳化させた注射用乳剤にすることもできる。
【００４０】
また、注射剤としては、溶解性、目標臓器への移行速度の改善が可能なリポソーム製剤やリピッドマイクロスフェア等が挙げられる。特にナノスフェア−リポソーム（脂質超微粒子）は網内系組織に取り込まれることなく血中濃度を高め、薬効発現に必要な最小有効投与量を低下させることができるだけでなく、脳血管関門を１０倍程度通過しやすくするので、脳の神経疾患の治療に使用する場合に好適である。リポソーム製剤は公知のリポソーム調製法（C.G. Knight, Liposomes: From Physical Structure to Therapeutic Applications, pp. 51-82, Elsevier, Amsterdam (1981); Proc. Natl. Acad. Sci., U.S.A., Vol.75, 4194(1978)）に従って調製することができる。
【００４１】
すなわち、リポソーム膜を形成する両親媒性物質としては、天然リン脂質（卵黄レシチン、大豆レシチン、スフィンゴミエリン、ホスファチジルセリン、ホスファチジルグリセロール、ホスファチジルイノシトール、ジホスファチジルグリセロール、ホスファチジルエタノールアミン、カルジオリピン等）、合成リン脂質（ジステアロイルホスファチジルコリン、ジパルミトイルホスファチジルコリン、ジパルミトイルホスファチジルエタノールアミン等）等のリン脂質が使用される。また、膜の安定性、流動性、薬剤の膜透過性を改善するために、コレステロール類（コレステロール、エルゴステロール、フィトステロール、シトステロール、スチグマステロール等）、リポソームに負電荷を付与することが知られている物質（ホスファチジン酸、ジセチルホスフェート等）、正電荷を付与することが知られている物質（ステアリルアミン、ステアリルアミンアセテート等）、酸化防止剤（トコフェロール等）、油性物質（大豆油、綿実油、ゴマ油、肝油等）等、公知の種々の添加剤を使用してもよい。
【００４２】
リポソームの製造は、例えば、以下の方法で行うことができる。上記両親媒性物質及び添加剤と、本発明化合物を、有機溶媒（クロロホルム、ジクロロメタン、エタノール、メタノール、ヘキサン等の単独又は混合溶媒）にそれぞれ溶解し、両溶液を混合し、フラスコ等の容器中において不活性ガス（窒素ガス、アルゴンガス等）の存在下で有機溶媒を除去し、器壁に薄膜を付着させる。次いで、この薄膜を適当な水性媒体（生理食塩水、緩衝液、リン酸緩衝生理食塩水等）に加え、攪拌機で攪拌する。小粒径のリポソームを得るためには、超音波乳化機、加圧型乳化機、フレンチプレス細胞破砕機等を用いて更に分散させる。このようにリポソーム化に必要な両親媒性物質等と本発明誘導体が水性媒体に分散した液をメンブランフィルター処理することによってリポソーム化が進行し、粒径分布が制御されたナノスフェア−リポソーム（脂質超微粒子；粒径２５〜５０nm程度）を得ることができる。また、リポソームを限外濾過、遠心分離、ゲル濾過等の分画処理に付し、担持されなかった薬剤を除去してもよい。
【００４３】
また、膜形成物質として、上記両親媒性物質、添加剤の他に、β−オクチルグルコシド、Ｌ−チロシン−７−アミド−４−メチルクマリン、フェニルアミノマンノシド又はスルファチドを添加することによって得られる、グルコース残基、チロシン残基、マンノース残基又はスルファチドを膜上に有するリポソームに本発明化合物である式（Ｉ）のアミノアルコール誘導体を担持させることによって、脳血管関門を通過しやすくすることもできる（方法自体は、特開平４−６９３３２号参照）。
リピッドマイクロスフェアは、本発明化合物を大豆油、ゴマ油等に溶解し、天然リン脂質、グリセリン、水等を加え攪拌機で攪拌し、更に超音波乳化機、加圧型乳化機、フレンチプレス細胞破砕機等を用いて分散させることにより得られる。
【００４４】
直腸投与剤は、本発明化合物に、カカオ脂肪酸のモノ、ジ又はトリグリセリド、ポリエチレングリコール等の坐剤用基剤を加えた後、加温して溶融し、これを型に流し込んで冷却するか、あるいは本発明化合物を、ポリエチレングリコール、大豆油等に溶解した後、ゼラチン膜で被覆して得ることができる。
皮膚外用剤は、本発明化合物に、白色ワセリン、ミツロウ、流動パラフィン、ポリエチレングリコール等を加え、必要に応じ加温し、混練して得ることができる。
【００４５】
テープ剤は、本発明化合物に、ロジン、アクリル酸アルキルエステル重合体等の粘着剤を混練し、これを不織布等に展延して得ることができる。
吸入剤は、例えば薬学的に許容される不活性ガス等の噴射剤に、本発明化合物を溶解又は分散し、これを耐圧容器に充填して得ることができる。
本発明化合物を神経疾患の治療剤、特に脳保護剤若しくは脳神経賦活・保護剤として使用する場合は、注射剤が好ましく、静脈注射剤がより好ましい。このような注射剤は本発明化合物の脳内移行性を考慮して、リピッドマイクロスフェア製剤、界面活性剤を含む製剤としてもよい。
【００４６】
〔投与方法〕
本発明化合物を有効成分として含有する薬剤の投与方法は、特に限定されないが、中枢神経系の障害に起因する神経疾患の治療に使用する場合、筋肉内注射、静脈内注射、皮下注射又は腹腔内注射等の注射、経直腸投与、経肺投与、点眼、経口投与などが好ましい。また、末梢神経系の障害に起因する神経疾患の治療に使用する場合、筋肉内注射、経皮投与、点眼、経口投与などが好ましい。
投与量は、患者の年令、健康状態、体重等に応じ適宜決定するが、一般には、本発明化合物を０．２５〜２００mg/kg 、好ましくは０．５〜１００mg/kg を一日１回あるいはそれ以上に分けて投与する。
【００４７】
【実施例】
次に本発明を実施例により更に詳細に説明するが、本発明はその要旨を越えない限り、以下の実施例に限定されるものではない。
＜合成例＞
本発明化合物の合成例を実施例１〜２８に示す。
なお、本発明化合物の中間体の合成例は、調製例として示し、又反応温度について特に記載のないものは、室温下にて反応を行った。
更に、実施例および調製例における生成物質の同定は核磁気共鳴吸収により行った。
本発明実施例で合成した化合物は全てＬ−トレオ体であり、下記式(I)'で表される。なお、式中*、Ｒは上記と同義である。
【００４８】
【化４】

【００４９】
下記実施例中における略号は、それぞれ下記を意味する。
EDC ：1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
Z ：ベンジルオキシカルボニル基
L-PDMP ：(1S,2S)-1-フェニル-2-デカノイルアミノ-3-モルホリノ-1-プロパノール
¹⁴C-GaL：D-[1-¹⁴C]ガラクトース
EDTA ：エチレンジアミン四酢酸
PBS ：ダルベッコりん酸緩衝塩類溶液
DMSO ：ジメチルスルホキシド
【００５０】
実施例１
（１Ｓ，２Ｓ）−２−ベンジルオキシカルボニルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール716.5mg（3.04mmol）に塩化メチレン（25ml）、Z-グリシン 635.4mg（3.04mmol）、N-ヒドロキシスクシンイミド 699.3mg（6.08mmol）、EDC 582.3mg（3.04mmol）を加え、18時間攪拌した後、Z-グリシン 635.3mg（3.04mmol）、トリエチルアミン 846μl（6.08mmol）を加え、さらに16時間攪拌した。反応溶液に飽和炭酸水素ナトリウム溶液 70mlを加え、酢酸エチル 100mlで抽出し、有機層を水 70ml、飽和食塩水 70mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質494.0mg（収率38.1%）を得た。
¹H-NMR(CDCl₃) δ: 7.39-7.25(10H,m,aromatic)，6.43(1H,brs,NH), 5.34(1H,brs,NH), 5.11(2H,m,COOCH₂),4.96(1H,d,J=2.93Hz,H-1)，4.29(1H,m,H-2)，3.76(2H,m,COCH ₂ -NH), 3.69(4H,m,(CH₂)₂O), 2.55(6H,m,CH₂N(CH₂)₂)
¹³C-NMR(CDCl₃)δ: 169.2, 156.5，140.6, 136.0, 129.1, 129.0, 128.6, 128.4, 128.3, 128.1, 127.8, 126.6, 126.0, 75.1, 67.3, 66.9, 59.7, 54.4, 51.2, 44.7
【００５１】
実施例２
（１Ｓ，２Ｓ）−２−ベンジルオキシカルボニルグリシルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール232mg（0.98mmol）に塩化メチレン：メタノール＝1：1（5ml）、トリエチルアミン 274μl（1.97mmol）を加え、溶液A2とした。一方、Z-グリシルグリシン 262.0mg（0.98mmol）に、塩化メチレン：メタノール＝1：1（5ml）、1-ヒドロキシベンゾトリアゾール263.9mg（0.99mmol）を加え、溶液B2とした。溶液A2と溶液B2を混合し、EDC 189.8mg（0.99mmol）を加え、18時間攪拌した後、Z-グリシルグリシン 260.0mg（0.98mmol）、1-ヒドロキシベンゾトリアゾール264.6mg（1.00mmol）を追加し、さらに３時間攪拌した。反応溶液に飽和炭酸水素ナトリウム溶液 70mlを加え、酢酸エチル 100mlで抽出し、有機層を水 70ml、飽和食塩水 70mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 90.0mg（収率19.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.33-7.20(10H,m,aromatic)，6.94(1H,brs,NH), 6.05(1H,brs,NH), 5.04(2H,m,COOCH₂),4.88(1H,d,J=3.42Hz,H-1)，4.28(1H,m,H-2)，3.8(4H,m,COCH ₂ -NH), 3.62(4H,brs,(CH₂)₂O), 2.45(6H,m,CH₂N(CH₂)₂)
¹³C-NMR(CDCl₃)δ: 169.8, 169.0, 156.7，141.0, 136.0, 128.5, 128.2, 127.9, 127.6, 126.1, 74.2, 67.1, 66.7, 59.4, 54.0, 51.5, 44.3, 42.9
【００５２】
実施例３
（１Ｓ，２Ｓ）−２− (n- ブトキシ ) カルボニルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
下記調製例１で得た（１Ｓ，２Ｓ）−２−グリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、188.7mg (0.64mmol)にメタノール 3ml、トリエチルアミン178μl （1.28 mmol）、クロロギ酸n-ブチル 100μl （0.77 mmol）を加え、15時間攪拌した。反応溶液に飽和炭酸水素ナトリウム溶液 35mlを加え、酢酸エチル 50mlで抽出し、有機層を水 35ml、飽和食塩水 35mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル、酢酸エチル：メタノール＝20：1）で精製し、無色油状の標記物質 160.9mg（収率 64.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.33-7.23(5H,m,aromatic)，6.67(1H,brs,NH), 5.61(1H,brs,NH), 4.91(1H,s,H-1)，4.26(1H,m,H-2)，4.03(2H,t,COOCH₂),3.70-3.66(6H,m,COCH ₂ -NH及び(CH₂)₂O), 2.58-2.39(6H,m,CH₂N(CH₂)₂), 1.58(2H,m,COOCH₂CH ₂ ), 1.36(2H,m,CH ₂ -CH₃), 0.92(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 169.5, 156.8，140.8, 128.2, 127.5, 126.0, 74.3, 66.7, 65.2, 59.3, 54.0, 51.1, 44.3, 30.8, 18.8, 13.6
【００５３】
調製例１
（１Ｓ，２Ｓ）−２−グリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの調製
実施例１で調製した（１Ｓ，２Ｓ）−２−ベンジルオキシカルボニルグリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノール 478.7mg（1.12mmol）をメタノール１０mlに溶かし、１０％パラジウム炭素119.2mg（10.0 mol%）を加え、水素雰囲気下、６時間攪拌した。パラジウム炭素をろ過除去し、ろ液を濃縮して標記化合物を得た。
【００５４】
実施例４
（１Ｓ，２Ｓ）−２− (n- ヘキサノイル ) グリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
調製例１で得た（１Ｓ，２Ｓ）−２−グリシルアミノ−３−モルホリノ−１−フェニル−１−プロパノール、201.8mg (0.69mmol)にメタノール 3ml、トリエチルアミン115μl （0.83 mmol）、n-ヘキサノイルクロリド 114μl （0.83 mmol）を加え、3時間攪拌した。反応溶液に飽和炭酸水素ナトリウム溶液 35mlを加え、酢酸エチル 50mlで抽出し、有機層を水 35ml、飽和食塩水 35mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 120.9mg（収率 44.8%）を得た。
¹H-NMR(CDCl₃) δ: 7.35-7.24(5H,m,aromatic)，6.68(1H,brs,NH), 6.39(1H,brs,NH), 4.97(1H,d,J=2.93Hz,H-1)，4.31(1H,m,H-2)，3.79(2H,m,COCH ₂ -NH),3.71(4H,m,(CH₂)₂O), 2.66-2.47(6H,m,CH₂N(CH₂)₂), 2.18(2H,t,COCH ₂ CH₂), 1.59(2H,m,COCH₂CH ₂ ), 1.30(4H,m,(CH ₂ )₂-CH₃), 0.89(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 173.8, 169.1, 140.9, 128.3, 127.6, 126.0, 74.5, 66.9, 59.8, 54.3, 51.3, 43.2, 36.2, 31.4, 25.2, 22.3, 13.9
【００５５】
実施例５
（１Ｓ，２Ｓ）−２− (n- ブトキシ ) ブタンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 255.2mg（1.08mmol）に塩化メチレン 5ml、トリエチルアミン300μl（2.16mmol）を加え、溶液A5とした。一方、コハク酸モノ(n-ブチル)エステル196.0mg（1.13mmol）に、塩化メチレン 5ml、N-ヒドロキシスクシンイミド 263.9mg（2.16mmol）を加え、溶液B5とした。溶液A5と溶液B5を混合し、EDC 207.5mg（1.08mmol）を加え、18時間攪拌した。反応溶液に飽和炭酸水素ナトリウム溶液 70mlを加え、酢酸エチル 100mlで抽出し、有機層を水 70ml、飽和食塩水 70mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 70.7mg（収率16.7%）を得た。
¹H-NMR(CDCl₃) δ: 7.37-7.26(5H,m,aromatic)，6.06(1H,d,J=7.32Hz,NH), 4.95(1H,d,J=3.90Hz,H-1)，4.30(1H,m,H-2)，4.05(2H,t,COOCH ₂ ), 3.73(4H,m,(CH₂)₂O), 2.66-2.35(10H,m,CH₂N(CH₂)₂及びCOCH ₂ ), 1.59(2H,m,COOCH₂CH ₂ ), 1.36(2H,m,CH ₂ -CH₃), 0.93(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 172.9, 171.9, 140.8, 128.4, 127.7, 126.1, 75.3, 66.9, 64.7, 59.7, 54.3, 51.1, 31.0, 30.6, 29.4, 19.1, 13.7
【００５６】
実施例６
（１Ｓ，２Ｓ）−２−エトキシヘキサンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 2.858g（11.13mmol）に塩化メチレン 40ml、アジピン酸モノエチルエステル1.986g（11.40mmol）、EDC 2.227g（11.62mmol）を加え16時間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 90mlを加え、酢酸エチル 150mlで抽出し、有機層を水 90ml、飽和食塩水 90mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 3.855g（収率88.4%）を得た。
¹H-NMR(CDCl₃) δ: 7.36-7.25(5H,m,aromatic)，5.94(1H,d,J=7.81Hz,NH),4.95(1H,d,J=3.42Hz,H-1)，4.29(1H,m,H-2)， 4.11(2H,m,COO-CH₂), 3.71(4H,m,(CH₂)₂O), 2.61-2.45(6H,m,N(CH₂)₃), 2.25(2H,t,O-CO-CH₂), 2.11(2H,t,NHCO-CH₂), 1.53(4H,m,COCH₂-CH ₂ ), 1.25(3H,t,CH₃)
【００５７】
実施例７
（１Ｓ，２Ｓ）−２−イソプロポキシヘキサンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）にアジピン酸モノイソプロピルエステル 530.0mg（2.0mmol）、塩化メチレン 10ml、トリエチルアミン 700μl（5.0mmol）、EDC 580mg（3.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝20：1）で精製し、無色油状の標記物質 416.0mg（収率51.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，5.90(1H,d,J=7.33Hz,NH),4.99(1H,m,CO-O-CH), 4.97(1H,d,J=3.42Hz,H-1)，4.30(1H,m,H-2)， 3.72(4H,m,(CH₂)₂O), 2.61および2.50(2H,dd,H-3), 2.57(4H,m,N(CH₂)₂), 2.22(2H,m,O-CO-CH₂), 2.12(2H,m,CO-CH₂), 1.54(4H,m,CO-CH₂-CH ₂ ), 1.22(6H,d,J=6.35,CH₃)
¹³C-NMR(CDCl₃)δ: 173.1, 172.9, 140.9, 128.4, 127.7, 126.0, 75.4, 67.6, 66.9, 59.8, 54.4, 51.2, 36.2, 34.2, 24.9, 24.3, 21.8
【００５８】
実施例８
（１Ｓ，２Ｓ）−２− (n- ブトキシヘキサンジオイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）にアジピン酸モノ(n-ブチル)エステル 405mg（2.0mmol）、塩化メチレン 12ml、トリエチルアミン 420μl（3.0mmol）、EDC 580mg（3.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝20：1）で精製し、無色油状の標記物質 308mg（収率37.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，5.90(1H,d,J=7.33Hz,NH),4.97(1H,d,J=3.90Hz,H-1)，4.30(1H,m,H-2)， 4.06(2H,m,COO-CH₂), 3.73(4H,m,(CH₂)₂O), 2.61および2.50(2H,dd,H-3), 2.57(4H,m,N(CH₂)₂), 2.26(2H,t,O-CO-CH₂), 2.13(2H,t,NHCO-CH₂), 1.60(2H,m,COO-CH₂-CH ₂ ), 1.55(4H,m,CO-CH₂-CH ₂ ), 1.37(2H,m,CH ₂ -CH₃), 0.93(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 173.5, 173.1, 140.9, 128.4, 127.7, 126.0, 75.4, 67.0, 64.3, 59.8, 54.4, 51.2, 36.2, 33.9, 30.7, 25.0, 24.3, 19.1, 13.2
【００５９】
実施例９
（１Ｓ，２Ｓ）−２− (3- ブチルカルバモイル ) プロピオニルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 802.4mg（3.4mmol）に3-ブチルカルバモイルプロピオン酸 600mg（3.4mmol）、塩化メチレン 25ml、トリエチルアミン 1.7ml（12.0mmol）、EDC 1.0g（5.1mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 962mg（収率71.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，6.28(1H,d,J=7.81Hz,NH), 5.81(1H,brs,NH), 4.95(1H,d,J=3.42Hz,H-1)，4.30(1H,m,H-2)，3.73(4H,m,(CH₂)₂O), 3.19(2H,m,CONH-CH ₂ ), 2.6-2.5(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.6-2.4(4H,m,CO-CH₂),1.45(2H,m,CH ₂ -CH₂-CH₃), 1.32(2H,m,CH ₂ -CH₃),0.91(3H,t,CH₃)
【００６０】
実施例１０
（１Ｓ，２Ｓ）−２− (N- ブチル -N- メチルアミノ ) ブタンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）にコハク酸モノ(N-ブチル-N-メチル)アミド 370mg（2.0mmol）、塩化メチレン 10ml、トリエチルアミン 0.7ml（5.0mmol）、EDC 580.0mg（3.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝20：1）で精製し、無色油状の標記物質 532.9mg（収率66.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，6.49(1H,d,J=6.84Hz,NH), 4.93(1H,d,J=3.91Hz,H-1)，4.30(1H,m,H-2)， 3.73(4H,m,(CH₂)₂O), 3.4-3.2(2H,m,CONH-CH ₂ ), 2.94および2.89(3H,s,N-CH₃), 2.6-2.5(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.6-2.4(4H,m,CO-CH₂), 1.6-1.4(2H,m,CH ₂ -CH₂-CH₃), 1.4-1.2(2H,m,CH ₂ -CH₃), 0.94および0.92(3H,m,CH₂-CH ₃ )
¹³C-NMR(CDCl₃)δ: 173.1, 171.4, 141.0, 128.2, 127.5, 126.2, 75.6, 66.9, 59.6, 54.3, 51.1, 49.6, 47.7, 35.1, 33.5, 31.6, 31.5, 30.3, 29.4, 29.2, 28.5, 19.9, 13.8
【００６１】
実施例１１
（１Ｓ，２Ｓ）−２−（ 5- エチルカルバモイル ) ペンタノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 4.72g（20.0mmol）に5-エチルカルバモイルペンタン酸 3.46g（20.0mmol）、塩化メチレン 160ml、トリエチルアミン 6.4ml（46.0mmol）、EDC 4.98g（26.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 350mlを加え、有機層を飽和炭酸水素ナトリウム溶液 250ml、水 250ml、飽和食塩水 250mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 1.02g（収率13.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，6.03(1H,d,J=7.33Hz,NH), 5.57(1H,brs,NH), 4.97(1H,d,J=3.90Hz,H-1)，4.31(1H,m,H-2)， 3.73(4H,m,(CH₂)₂O), 3.26(2H,m,CH ₂ -CH₃), 2.61および2.50(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.1(4H,m,CO-CH₂), 1.54(4H,m,CO-CH₂-CH ₂ ), 1.13(3H,t,CH₃)
【００６２】
実施例１２
（１Ｓ，２Ｓ）−２−（ 5- シクロヘキシルカルバモイル ) ペンタノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）に5-シクロヘキシルカルバモイルペンタン酸 546.0mg（2.4mmol）、塩化メチレン：メタノール＝４：１の混合溶媒 10ml、トリエチルアミン 620μl（4.4mmol）、EDC 460mg（2.4mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝10：1）で精製し、無色油状の標記物質 607mg（収率68.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，6.04(1H,d,J=7.81Hz,NH), 5.42(1H,d,J=7.81,NH), 4.97(1H,d,J=3.91Hz,H-1)，4.32(1H,m,H-2)， 3.70(4H,m,(CH₂)₂O), 2.61および2.50(2H,dd,H-3), 2.58(4H,m,N(CH₂)₂), 2.1(4H,m,CO-CH₂), 1.6-1.5(4H,m,CO-CH₂-CH ₂ ), 1.4-1.3(4H,m,CH-CH ₂ ), 1.2-1.0(6H,m,(CH₂)₃)¹³C-NMR(CDCl₃)δ: 173.3, 171.6, 141.0, 128.4, 127.7, 126.1, 75.4, 67.0, 59.8, 54.4, 51.2, 48.2, 36.3, 36.1, 33.2, 25.5, 24.9, 24.8
【００６３】
実施例１３
（１Ｓ，２Ｓ）−２−（ 5- ヘキシルカルバモイル ) ペンタノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 703.1mg（2.979mmol）に塩化メチレン 20ml、5-ヘキシルカルバモイルペンタン酸 708.6mg（3.094mmol）、EDC 621.7mg（3.243mmol）を加え18時間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 30mlを加え、酢酸エチル 50mlで抽出し、有機層を水 30ml、飽和食塩水 30mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 292.2mg（収率21.9%）を得た。
¹H-NMR(CDCl₃) δ: 7.36-7.25(5H,m,aromatic)，6.07(1H,d,J=7.33Hz,NH), 5.65(1H,brs,NH), 4.96(1H,d,J=3.41Hz,H-1),4.31(1H,m,H-2)，3.72(4H,m,(CH₂)₂O), 3.21(2H,m,NH-CH ₂ ), 2.62-2.47(6H,m,CH₂N(CH₂)₂), 2.13-2.08(4H,m,COCH₂), 1.55-1.44(6H,m,COCH₂-CH ₂ , NH-CH₂CH ₂ ), 1.29(6H,m,CH₂(CH ₂ )₃CH₂), 0.89(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 173.2, 172.5, 141.0, 128.3, 127.6, 126.0, 75.2, 66.9, 59.7, 54.3, 51.2, 39.5, 36.0, 31.4, 29.5, 26.6, 24.8, 22.5, 14.0
【００６４】
実施例１４
（１Ｓ，２Ｓ）−２− (9- ブチルカルバモイル ) ノナノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 920.8mg（3.901mmol）に塩化メチレン 20ml、9-(n-ブチル)カルバモイルノナン酸 1063.1mg（4.136mmol）、EDC 1546.1mg（8.065mmol）を加え21時間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 100mlを加え、酢酸エチル 100mlで抽出し、有機層を水 100ml、飽和食塩水 100mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 442.3mg（収率23.9%）を得た。
¹H-NMR(CDCl₃) δ: 7.37-7.26(5H,m,aromatic)，5.91(1H,d,J=6.84Hz,NH), 5.50(1H,brs,NH), 4.96(1H,d,J=3.42Hz,H-1),4.28(1H,m,H-2)，3.72(4H,m,(CH₂)₂O), 3.23(2H,m,NH-CH ₂ ), 2.62-2.46(6H,m,CH₂N(CH₂)₂), 2.11(4H,m,COCH₂), 1.60(2H,m,COCH₂-CH ₂ ), 1.47(4H,m,COCH₂-CH ₂ , NH-CH₂CH ₂ ), 1.34及び1.26(10H,m,CH₂(CH ₂ )₄CH₂, CH ₂ -CH₃), 0.92(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 173.7, 173.0, 141.0, 128.4, 127.6, 126.0, 75.5, 66.9, 59.8, 54.3, 51.2, 39.2, 36.8, 36.7, 31.7, 29.1, 29.0, 25.7, 25.6, 25.5, 20.1, 13.7
【００６５】
実施例１５
（１Ｓ，２Ｓ）−２− (9- ヘキシルカルバモイル ) ノナノイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 732.1mg（3.102mmol）に塩化メチレン 25ml、9-(n-ヘキシル)カルバモイルノナン酸 908.2mg（3.187mmol）、エタノール 3ml、EDC 628.5mg（3.278mmol）を加え、17時間攪拌した後、EDC 765.8mg（3.995mmol）、トリエチルアミン 0.90ml（6.469mmol）を追加し、14時間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 100mlを加え、酢酸エチル 100mlで抽出し、有機層を水 100ml、飽和食塩水 100mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、無色油状の標記物質 468.1mg（収率30.0%）を得た。
¹H-NMR(CDCl₃) δ: 7.37-7.26(5H,m,aromatic)，5.91(1H,d,J=7.32Hz,NH), 5.49(1H,brs,NH), 4.96(1H,d,J=3.91Hz,H-1),4.29(1H,m,H-2)，3.73(4H,m,(CH₂)₂O), 3.22(2H,m,NH-CH ₂ ), 2.62-2.47(6H,m,CH₂N(CH₂)₂), 2.15-2.08(4H,m,COCH₂), 1.60(2H,m,NHCH₂-CH ₂ ), 1.48(4H,m,COCH₂-CH ₂ ), 1.29-1.24(14H,m,CH₂(CH ₂ )₄CH₂,(CH ₂ )₃-CH₃), 0.88(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 173.7, 173.0, 140.9, 128.4, 127.6, 126.0, 75.4, 66.9, 59.8, 54.3, 51.2, 39.5, 36.8, 36.7, 31.5, 29.6, 29.1, 29.0, 28.9, 26.6, 25.7, 25.5, 22.5, 14.0
【００６６】
実施例１６
（１Ｓ，２Ｓ）−２− (N,N- ジエタノールアミノ ) デカンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
セバシン酸モノ(ジエタノール)アミド 969.2mg（3.354mmol）に塩化メチレン 5ml、エタノール 5ml、N-ヒドロキシスクシンイミド 394.8mg（3.433mmol）を加え、溶液A16とした。一方、（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 735.1mg（3.115mmol）にエタノール 10mlを加え、溶液B16とした。溶液A16と溶液B16を混合し、EDC 760.8mg（3.969mmol）を加え、90分間攪拌した後、EDC 362.8mg（1.893mmol）を追加し、17時間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 20mlを加え、酢酸エチル 50mlで抽出し、有機層を水 20ml、飽和食塩水 20mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル：メタノール＝9：10：1 および クロロホルム：メタノール＝20：1）で精製し、無色油状の標記物質 193.9mg（収率12.3%）を得た。
¹H-NMR(CDCl₃) δ: 7.36-7.25(5H,m,aromatic)，5.27(1H,brs,NH), 5.06(1H,d,J=5.86Hz,NH),4.82(1H,d,J=4.88Hz,H-1)，4.16-4.07(1H,m,H-2)，3.83(1H,t,CH ₂ -OH),3.77(1H,t,CH ₂ -OH),3.70(4H,m,(CH₂)₂O), 3.55-3.35(6H,m,CH ₂ -OH,CH ₂ CH₂-OH), 2.57-2.26(10H,m,CH₂N(CH₂)₂及びCOCH ₂ ), 1.61(4H,m,COCH₂CH ₂ ), 1.30-1.23(8H,m,CH₂(CH ₂ )₄CH₂)
¹³C-NMR(CDCl₃)δ: 175.6, 172.9, 141.2, 128.3, 127.6, 126.4, 76.5, 66.8, 61.7, 60.8, 60.7, 60.2, 59.8, 54.0, 52.1, 52.0, 50.5, 35.9, 34.6, 29.0, 25.1, 24.8
【００６７】
実施例１７
（１Ｓ，２Ｓ）−２− ( シクロヘキサン− 4- ヘキシルカルバモイル−１−カルボニル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）にシクロヘキサンジカルボン酸 1.72g（10.0mmol）、トリエチルアミン 1.60ml（11.0mmol）、EDC 420mg（2.2mmol）を加え、一夜攪拌した。反応溶媒を濃縮した後、飽和炭酸水素ナトリウム溶液 50mlを加え濃縮し、クロロホルム：メタノール＝5：1の混合溶媒 60mlを加え、不溶物をろ過除去した後、ろ液を濃縮し、シリカゲルクロマトグラフィー（クロロホルム：メタノール＝9：1および5：1）で精製し、中間生成物 152mgを得た。次に、中間生成物 135mg（0.35mmol）にヘキシルアミン 350mg（3.5mmol）、トリエチルアミン 0.24ml（1.7mmol）、EDC 330mg（1.7mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝9：1）で精製し、無色油状の標記物質 32.6mg（収率 19.7%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，5.97(1H,d,J=7.32Hz,NH), 5.53(1H,t,NH), 4.96(1H,d,J=3.42Hz,H-1)，4.28(1H,m,H-2)， 3.72(4H,m,(CH₂)₂O), 3.2(2H,q,CONH-CH ₂ ), 2.60および2.49(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.0(2H,m,CO-CH), 1.9-1.7(8H,m,CH-CH ₂ ), 1.6-1.2(8H,m,CONH-CH₂(CH ₂ )₄), 0.88(3H,t,(CH₂)₃)
¹³C-NMR(CDCl₃)δ: 176.0, 175.3, 141.0, 128.4, 127.7, 126.1, 75.3, 67.0, 59.8, 54.4, 51.1, 44.7, 44.6, 39.4, 31.5, 29.6, 28.7, 28.6, 26.6, 22.6, 14.0
【００６８】
実施例１８
（１Ｓ，２Ｓ）−２− (3- オキサヘプタノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 944.0mg（4.0mmol）に3-オキサヘプタン酸 529.0mg（4.0mmol）、塩化メチレン 20ml、トリエチルアミン 1.40ml（10.0mmol）、EDC 1.15g（6.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝30：1）で精製し、無色油状の標記物質 825mg（収率59%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，6.95(1H,d,J=7.81Hz,NH),4.99(1H,d,J=3.91Hz,H-1)，4.35(1H,m,H-2)， 3.88および3.82(2H,d,CO-CH₂), 3.74(4H,m,(CH₂)₂O), 3.40(2H,t,O-CH ₂ -(CH₂)₂-CH₃), 2.63および2.50(2H,dd,H-3), 2.59(4H,m,N(CH₂)₂), 1.55(2H,m,CH ₂ -CH₂CH₃), 1.35(2H,m,CH ₂ -CH₃), 0.93(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 170.3, 140.7, 128.4, 127.7, 126.2, 75.6, 71.5, 70.1, 67.0, 59.8, 54.4, 50.3, 31.6, 19.2, 13.9
【００６９】
実施例１９
（１Ｓ，２Ｓ）−２− (3,6- ジオキサデカノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 944.0mg（4.0mmol）に3,6-ジオキサデカン酸 705.0mg（4.0mmol）、塩化メチレン 20ml、トリエチルアミン 1.40ml（10.0mmol）、EDC 1.15g（6.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝30：1）で精製し、無色油状の標記物質 815mg（収率52%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，7.06(1H,d,J=7.82Hz,NH),4.99(1H,d,J=3.91Hz, H-1)，4.38(1H,m,H-2)， 3.96および3.89(2H,d,CO-CH₂), 3.73(4H,m,(CH₂)₂O), 3.52(4H,m,O-CH₂-CH₂-O), 3.42(2H,t,O-CH ₂ -(CH₂)₂-CH₃), 2.63および2.50(2H,dd,H-3), 2.58(4H,m,N(CH₂)₂), 1.54(2H,m,CH ₂ -(CH₂)₂-CH₃), 1.34(2H,m,CH ₂ -CH₃), 0.92(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 170.2, 140.9, 128.3, 127.6, 126.2, 75.2, 71.3, 70.9, 70.3, 69.7, 66.9, 59.6, 54.3, 50.4, 31.6, 19.2, 13.9
【００７０】
実施例２０
（１Ｓ，２Ｓ）−２− [4-(4- メトキシフェニル ) ブチリル ] アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）に4-(4-メトキシフェニル)ブタン酸 388.0mg（2.0mmol）、塩化メチレン 10ml、トリエチルアミン 0.70ml（5.0mmol）、EDC 580mg（3.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝20：1）で精製し、無色油状の標記物質 549mg（収率66%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，7.02(2H,d,J=8.79Hz,aromatic), 6.81(2H,m,aromatic), 5.80(1H,d,J=7.32Hz,NH), 4.97(1H,d,J=3.41Hz,H-1)，4.31(1H,m,H-2)， 3.79(3H,s,O-CH₃), 3.72(4H,m,(CH₂)₂O), 2.61および2.49(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.48(2H,m,CO-CH₂), 2.10(2H,m,CO(CH₂)₂CH ₂ ), 1.82(2H,m,COCH₂-CH ₂ )
¹³C-NMR(CDCl₃)δ: 173.3, 157.9, 140.8, 133.3, 129.3, 128.4, 127.7, 126.0, 113.8, 75.4, 66.9, 59.9, 55.3, 54.4, 51.2, 35.7, 34.0, 27.2
【００７１】
実施例２１
（１Ｓ，２Ｓ）−２− (3,6- ジオキサドデカノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 959.1mg（4.064mmol）に塩化メチレン 40ml、3,6-ジオキサドデカン酸 1.086g（5.325mmol）、EDC 1.167g（6.090mmol）を加え3時間攪拌した後、EDC 719.3mg（3.752mmol）を追加し、3日間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 70mlを加え、酢酸エチル 100mlで抽出し、有機層を水 70ml、飽和食塩水 70mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝30：1）で精製し、無色油状の標記物質 812.3mg（収率47.4%）を得た。
¹H-NMR(CDCl₃) δ: 7.37-7.25(5H,m,aromatic)，7.05(1H,d,J=8.31Hz,NH), 4.98(1H,d,J=3.91Hz,H-1),4.38(1H,m,H-2)，3.92(2H,m,CO-CH₂-O), 3.73(4H,m,(CH₂)₂O), 3.52(4H,m,O(CH ₂ )₂O), 3.41(2H,t,OCH ₂ (CH₂)₄), 2.66-2.47(6H,m,CH₂N(CH₂)₂), 1.53(2H,m,CH ₂ (CH₂)₃CH₃), 1.29(6H,m,CH₂(CH ₂ )₃CH₃),0.89(3H,t,CH₃)
¹³C-NMR(CDCl₃)δ: 170.2, 140.9, 128.3, 127.5, 126.2, 75.2, 71.6, 71.0, 70.4, 69.6, 66.9, 59.6, 54.3, 50.4, 31.6, 29.5, 25.7, 22.6, 14.1
【００７２】
実施例２２
（１Ｓ，２Ｓ）−２−（ 7- オキソオクタノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 944.0mg（4.0mmol）に7-オキソオクタン酸 700mg（4.4mmol）、塩化メチレン：メタノール＝９：１の混合溶媒 20ml、トリエチルアミン 1.40ml（10.0mmol）、EDC 1.15g（6.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝20：1）で精製し、無色油状の標記物質 890mg（収率59%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，5.88(1H,d,J=7.33Hz,NH),4.96(1H,d,J=3.42Hz,H-1)，4.28(1H,m,H-2)， 3.72(4H,m,(CH₂)₂O), 2.61および2.49(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.38(2H,t,CO-CH₂), 2.12(3H,s,CO-CH₃), 2.10(2H,dt,CH₃COCH ₂ ), 1.52(4H,m,COCH₂CH ₂ ), 1.18(2H,m,CO(CH₂)₂CH ₂ )
¹³C-NMR(CDCl₃)δ: 209.4, 173.4, 141.0, 128.4, 127.6, 126.0, 75.3, 67.0, 59.8, 54.4, 51.2, 43.3, 36.4, 29.9, 28.4, 25.4, 23.2
【００７３】
実施例２３
（１Ｓ，２Ｓ）−２− (10- ヒドロキシデカノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 472.0mg（2.0mmol）に10-ヒドロキシデカン酸 377mg（2.0mmol）、塩化メチレン 20ml、トリエチルアミン 0.70ml（5.0mmol）、EDC 580mg（3.0mmol）を加え、一夜攪拌した。反応溶媒に塩化メチレン 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：エタノール＝20：1）で精製し、無色油状の標記物質 508mg（収率62%）を得た。
¹H-NMR(CDCl₃) δ: 7.38-7.26(5H,m,aromatic)，5.88(1H,d,J=7.32Hz,NH), 4.96(1H,d,J=3.42Hz,H-1)，4.29(1H,m,H-2)， 3.73(4H,m,(CH₂)₂O), 3.62(2H,m,CH ₂ -OH), 2.60および2.49(2H,dd,H-3), 2.56(4H,m,N(CH₂)₂), 2.10(2H,m,CO-CH₂), 1.6-1.4(4H,m,CH ₂ -CH₂-OH,CO-CH₂-CH ₂ ), 1.4-1.2(10H,m,(CH₂)₅)
¹³C-NMR(CDCl₃)δ: 173.7, 140.9, 128.4, 127.7, 126.0, 75.5, 66.9, 63.0, 59.8, 54.4, 51.2, 36.4, 32.7, 29.3, 29.1, 29.0, 25.6
【００７４】
実施例２４
（１Ｓ，２Ｓ）−２−メトキシデカンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 1.244g（5.27mmol）に塩化メチレン 40ml、セバシン酸モノメチルエステル 1.13g（5.23mmol）、EDC 1.51g（7.88mmol）を加え15時間攪拌し、EDC 1.10g（5.73mmol）、トリエチルアミン1.0ml（7.19mmol）を加え、22時間攪拌した。溶媒を減圧留去した後、飽和炭酸水素ナトリウム溶液 70mlを加え、酢酸エチル 100mlで抽出し、有機層を水 70ml、飽和食塩水 70mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル：メタノール＝9：10：1）で精製し、無色油状の標記物質 1.89g（収率82.7%）を得た。
¹H-NMR(CDCl₃) δ: 7.37-7.25(5H,m,aromatic)，5.85(1H,d,J=7.32Hz,NH), 4.96(1H,d,J=3.42Hz,H-1),4.28(1H,m,H-2)，3.72(4H,m,(CH₂)₂O), 3.67(3H,s,OCH₃), 2.63-2.47(6H,m,CH₂N(CH₂)₂), 2.30(2H,m,COCH₂), 2.09(2H,m,COCH₂), 1.60(2H,m,COCH₂-CH ₂ ), 1.50(2H,m,COCH₂-CH ₂ ), 1.26(8H,m,CH₂(CH ₂ )₄CH₂)
【００７５】
実施例２５
（１Ｓ，２Ｓ）−２− (9- カルボキシノナノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 316.2mg（1.34mmol）に塩化メチレン 10ml、トリエチルアミン 190μl（1.37mmol）、無水セバシン酸 292.4mg（1.59mmol）を加え5時間攪拌した後、溶媒を減圧留去した。得られた粗生成物を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＝20：1 およびクロロホルム：メタノール＝9：1）で精製し、無色油状の標記物質 171.1mg（収率30.4%）を得た。
¹H-NMR(CDCl₃) δ: 7.36-7.25(5H,m,aromatic)，6.50(1H,d,J=7.82Hz,NH), 4.94(1H,d,J=3.91Hz,H-1),4.37(1H,m,H-2)，3.80-3.69(4H,m,(CH₂)₂O), 2.77-2.63(6H,m,CH₂N(CH₂)₂), 2.30(2H,m,COCH₂), 2.09(2H,m,COCH₂), 1.61(2H,m,COCH₂-CH ₂ ), 1.48(2H,m,COCH₂-CH ₂ ), 1.30-1.16(8H,m,CH₂(CH ₂ )₄CH₂)
¹³C-NMR(CDCl₃)δ: 178.3, 174.1, 140.7, 128.4, 127.7, 126.0, 75.1, 66.2, 59.3, 53.9, 51.0, 36.5, 34.4, 28.9, 28.8, 25.4, 24.9, 24.8
【００７６】
実施例２６
（１Ｓ，２Ｓ ,12S ）−２− (12- アミノ -7- アザ -6- オキソ -12- カルボキシドデカノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
実施例６で得た（１Ｓ，２Ｓ）−２−エトキシヘキサンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノールのエステル結合を加水分解し、（１Ｓ，２Ｓ）−２−(5-カルボキシペンタノイル)アミノ−３−モルホリノ−１−フェニル−１−プロパノール［中間生成物(26-1)］とした後、該化合物のカルボキシル基とN_α-ベンジルオキシカルボニル-L-リジンメチルエステルのアミノ基を常法にて縮合させ、最後に保護基を外すことにより標記化合物を得た。
具体的には、（１Ｓ，２Ｓ）−２−エトキシヘキサンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール 230.6mg(0.588mmol)にメタノール 6ml、２Ｎ−水酸化ナトリウム溶液 588μl(1.176mmol)を加えた後、40℃で一昼夜攪拌した。
【００７７】
次に、２Ｎ−塩酸 で中和した後、溶媒を減圧留去し、ゲル濾過クロマトグラフィーで脱塩操作を行った。得られた中間生成物（26-1）212.4mg(0.583mmol)に、N_α-ベンジルオキシカルボニル-L-リジンメチルエステル 202.9mg(0.690mmol)、塩化メチレン 9ml、エタノール 2ml、EDC 389.0mg(2.029mmol)を加え一昼夜攪拌した。次に、反応溶媒を減圧留去し、酢酸エチル 70mlを加え、有機層を飽和炭酸水素ナトリウム溶液 30ml、水 30ml、飽和食塩水 30mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、中間生成物26-2を得た。次に中間生成物(26-2) 198.6mg(0.310mmol)にメタノール 3ml、２Ｎ−水酸化ナトリウム溶液 320μl(0.64mmol)を加え、40℃で3時間攪拌した後、２Ｎ−塩酸 320μl(0.64mmol)を加え、一夜攪拌後、２Ｎ−塩酸 320μl(0.64mmol)、10%パラジウム炭素 47.3mgを加え水素雰囲気下、一昼夜攪拌した。最後に溶媒を減圧留去し、得られた粗生成物をゲル濾過クロマトグラフィー（Sephadex LH-20(アマシャム ファルマシア バイオテク株式会社)、クロロホルム：メタノール＝2：1）で精製し、無色無晶状の標記物質 160.6mgを得た。
【００７８】
ＮＭＲ（中間生成物 26-2）
¹H-NMR(CDCl₃) δ: 7.38-7.24(10H,m,aromatic)，6.01(1H,d,J=7.82Hz,NH),5.78(1H,brs,NH), 5.54(1H,d,J=8.30Hz,NH), 5.09(2H,s,COOCH₂), 4.96(1H,d,J=3.91Hz,H-1),4.38-4.32(2H,m,H-2及びNH₂-CH-CO),3.74-3.70(7H,m,(CH₂)₂O,OCH₃), 3.22(2H,m,CONHCH ₂ ), 2.61-2.45(6H,m,CH₂N(CH₂)₂), 2.10(4H,m,COCH ₂ ), 1.83(1H,m,CH₂),1.69(1H,m,CH₂),1.52(8H,m,CH₂),1.37(2H,m,CH₂)
ＮＭＲ（実施例２６の標記化合物）
¹H-NMR(CD₃OD) δ: 7.42(2H,d,J=7.32Hz,aromatic),7.33(2H,m,aromatic)，7.25(1H,m,aromatic), 4.93(1H,d,J=2.93Hz,H-1),4.62(1H,m,NH₂-CH-CO),4.06-3.92(4H,m)，3.82-3.76(2H,m), 3.54-3.46(3H,m), 3.35-3.16(4H,m), 2.23-2.12(4H,m,COCH₂), 2.02-1.86(2H,m,NH₂CHCH ₂ ), 1.61-1.30(8H,m,CH₂)
¹³C-NMR(CD₃OD)δ: 176.8, 176.0, 171.8, 142.5, 129.3, 128.8, 127.3, 73.9, 64.8, 60.9, 58.3, 54.8, 53.9, 53.8, 52.9, 51.2, 51.1, 39.9, 36.5, 36.4, 31.1, 29.9, 26.2, 25.8, 23.4
【００７９】
実施例２７
（１Ｓ，２Ｓ ,16S ）−２− (16- アミノ -11- アザ -10- オキソ -16- カルボキシヘキサデカノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
実施例２４で得た（１Ｓ，２Ｓ）−２−メトキシデカンジオイルアミノ−３−モルホリノ−１−フェニル−１−プロパノール 579.6mg(1.335mmol)にメタノール 14ml、２Ｎ−水酸化ナトリウム溶液1335μl(2.670mmol)を加えた後、40℃で16時間攪拌した。次に、２Ｎ−塩酸 1335μl(2.670mmol)を加え10分間攪拌した後、溶媒を減圧濃縮し、ゲル濾過クロマトグラフィーで脱塩操作を行った。得られた中間生成物(27-1) 475.2mg(1.131mmol)に、N_α-ベンジルオキシカルボニル-L-リジンメチルエステル 394.2mg(1.341mmol)、塩化メチレン 12ml、EDC 491.0mg(2.562mmol)を加え、14時間攪拌した。次に、反応溶媒を減圧留去し、酢酸エチル 80mlを加え、有機層を飽和炭酸水素ナトリウム溶液 50ml、水 50ml、飽和食塩水 50mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、中間生成物(27-2)を得た。次に中間生成物(27-2) 441.7mg(0.635mmol)にメタノール 6ml、２Ｎ−水酸化ナトリウム溶液 640μl(1.28mmol)を加え、40℃で3時間攪拌した後、２Ｎ−塩酸 640μl(1.28mmol)を加え一昼夜攪拌した。次に、２Ｎ−塩酸 640μl(1.28mmol)、10%パラジウム炭素 64.9mgを加え水素雰囲気下、一昼夜攪拌した。最後に溶媒を減圧留去し、得られた粗生成物をゲル濾過クロマトグラフィー（Sephadex LH-20(アマシャム ファルマシア バイオテク株式会社)、クロロホルム：メタノール＝2：1）で精製し、無色無晶状の標記物質 366.7mgを得た。
【００８０】
ＮＭＲ（中間生成物 27-2）
¹H-NMR(CDCl₃) δ: 7.53-7.25(10H,m,aromatic)，5.91(1H,d,J=7.33Hz,NH),5.64(1H,brs,NH), 5.46(1H,d,J=7.81Hz,NH), 5.10(2H,s,COOCH₂), 4.95(1H,d,J=3.90Hz,H-1),4.35(1H,m), 4.28(1H,m),3.73(3H,s,OCH₃), 3.72(4H,m,(CH₂)₂O), 3.21(2H,m,CONHCH ₂ ), 2.61-2.45(6H,m,CH₂N(CH₂)₂), 2.10(4H,m,COCH ₂ ), 1.83(1H,m,CH₂),1.68(1H,m,CH₂),1.59(2H,m,CH₂),1.50(4H,m,CH₂), 1.36(2H,m,CH₂), 1.24(8H,m,CH₂)
【００８１】
ＮＭＲ（実施例２７の標記化合物）
¹H-NMR(CD₃OD) δ: 7.43(2H,d,J=7.33Hz,aromatic),7.33(2H,m,aromatic)，7.25(1H,m,aromatic), 4.94(1H,d,J=2.93Hz,H-1),4.61(1H,m,NH₂-CH-CO),4.06-3.90(4H,m)，3.81-3.74(2H,m), 3.57-3.46(3H,m), 3.31-3.16(4H,m), 2.22-2.13(4H,m,COCH₂), 2.02-1.86(2H,m,NH₂CHCH ₂ ), 1.61-1.41(6H,m,COCH₂CH ₂ ,CONHCH₂CH ₂ ), 1.37-1.21(8H,m,CH₂), 1.08(2H,m,CH₂)
¹³C-NMR(CD₃OD)δ: 177.3, 176.6, 171.8, 142.5, 129.3, 128.7, 127.3, 73.8, 64.8, 61.1, 58.4, 54.8, 53.9, 53.0, 51.2, 40.0, 37.1, 31.2, 30.3, 30.2, 30.1, 30.0, 29.9, 27.1, 26.5, 23.4
【００８２】
実施例２８
（１Ｓ，２Ｓ）−２− (9- シアリルノナノイル ) アミノ−３−モルホリノ−１−フェニル−１−プロパノールの合成
（１Ｓ，２Ｓ）−２−アミノ−３−モルホリノ−１−フェニル−１−プロパノール 358.0mg（1.517mmol）に 9-(1-メトキシ-4,5,7,8,9-ペンタアセチルシアリル)ノナン酸 976.4mg(1.508mmol)、塩化メチレン 15ml、EDC 348.4mg(1.817mmol)を加え、17時間攪拌した。次に、反応溶媒を減圧留去し、酢酸エチル 100mlを加え、有機層を飽和炭酸水素ナトリウム溶液 40ml、水 40ml、飽和食塩水 40mlで順次洗浄後、硫酸ナトリウム上で乾燥、ろ過し、溶媒を減圧留去した。得られた粗生成物を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＝20：1）で精製し、中間生成物(28-1)を得た。次に中間生成物(28-1) 1.00g(1.155mmol)にメタノール 5ml、テトラヒドロフラン 5ml、ナトリウムメトキシド 112.4mg(2.081mmol)を加え、室温で3.5時間攪拌した後、水 40μl(2.22mmol)、４Ｎ−水酸化ナトリウム 1156μl(4.62mmol)を加え一夜攪拌した。最後に溶媒を減圧留去し、得られた粗生成物をゲル濾過クロマトグラフィー[Sephadex LH-20(アマシャム ファルマシア バイオテク株式会社)、クロロホルム：メタノール＝2：1]で精製し、無色無晶状の標記物質 759.4mgを得た。
【００８３】
ＮＭＲ（中間生成物 28-1）
¹H-NMR(CDCl₃) δ:7.37-7.26(5H,m,aromatic),5.87(1H,d,J=7.33Hz,NH),5,41-5.37(1H,m),5.34及び5.32(1H,m),5.18(1H,d,J=8.79Hz),4.97(1H,d,J=3.90Hz,H-1),4.84(1H,m),4.32-4.26(2H,m),4.12-4.02(3H,m),3.79(3H,s,O-CH₃),3.73(4H,m,(CH₂)₂O),3.20(1H,m),2.62-2.48(7H,m,N(CH₂)₃,H-3'eq), 2.14, 2.13, 2.04, 2.02(3HX4,sx4,OCOCH₃又はNHCOCH ₃ ), 2.1(2H,m,COCH₂),1.95(1H,t,J=12.2Hz,H-3'ax), 1.88(3H,s,NHCOCH ₃ 又はOCOCH₃), 1.51(4H,m,CH ₂ (CH₂)₄CH ₂ ), 1.25(8H,m,CH₂(CH ₂ )₄CH₂)
¹³C-NMR(CDCl₃)δ: 173.6, 171.0, 170.7, 170.2, 170.1, 170.0, 168.5, 140.9, 128.4, 127.6, 126.0, 98.7, 76.5, 75.5, 72.4, 69.2, 69.1, 68.6, 67.4, 66.9, 65.0, 62.4, 62.3, 62.2, 59.8, 54.4, 52.6, 51.1, 49.5, 38.1, 36.7, 29.5, 29.2, 29.1, 29.0, 25.8, 25.6, 23.2, 21.1, 20.8
【００８４】
ＮＭＲ（実施例２８の標記化合物）
¹H-NMR(CDCl₃:CD₃OD = 1:1) δ: 7.35-7.20(5H,m,aromatic), 4.90(1H,d,J=2.93Hz,H-1),4.28(1H,m,H-2),3.90-3.43(13H,m),2.84(1H,dd,J=4.2,12.2Hz,H-3'eq),2.62-2.42(6H,m,N(CH₂)₃), 2.11(2H,m,COCH₂), 2.02(3H,s,NHCOCH ₃ ), 1.62-1.41(4H,m,CH ₂ (CH₂)₄CH ₂ ), 1.59(1H,t,J=12.2Hz,H-3'ax), 1.37-1.22(8H,m,CH₂(CH ₂ )₄CH₂)
¹³C-NMR(CDCl₃:CD₃OD = 1:1)δ: 175.9, 175.4, 174.3, 143.3, 128.9, 128.1, 127.1, 101.7, 79.3, 78.9, 78.6, 74.1, 73.9, 70.2, 69.3, 67.8, 65.1, 60.6, 54.9, 54.0, 42.6, 37.0, 30.8, 30.3, 30.2, 29.9, 27.0, 26.8, 22.6
【００８５】
＜in vitro活性＞
試験例 １
ラット胎児大脳皮質培養神経細胞に対するシナプス形成促進活性測定
〔原理〕シナプス活動を示すと考えられる同期した自発的な神経細胞の発火に伴う細胞内カルシウムイオンレベルの変動を、カルシウムイオン蛍光指示薬fura-2を用いた細胞内カルシウムイオン多点観察システムで測定することにより、シナプス形成促進活性を測定した。
【００８６】
〔方法〕
(1) 初代培養
ラット胎児大脳皮質神経細胞の初代培養は、BankerとCowmanの方法（Brain Res.,126(1977),p397-425）を改変して行った。具体的には、妊娠１８日目のWister系ラット（日本ＳＬＣ）より胎児を取り出した後、胎児の大脳皮質を切り出し小片にした。次に、パパイン（Worthington Biochemical社）で30分間（37℃）処理した後、5%牛新生仔血清/5%馬血清含有Dulbecco改変Eagle培地に懸濁し、Cell Striner(70μm,FALCON社)で単一細胞に解離した。次に、0.5%ポリエチレンイミンでコートしたフレキシパームプレートに播種し（1.0 x 10⁶cells／500μl/well）、37℃、7%CO₂インキュベーター内で培養し、培地交換を培養２日目、５日目、８日目に行った。この初代培養系を用い、本発明化合物の活性測定を行った。化合物の添加は培地交換時に行い、化合物の濃度が20μMに保たれるようにした。アッセイは培養開始後１０日目に行った。
【００８７】
(2) シナプス形成促進活性測定
シナプス形成促進活性測定は、工藤らの方法（Br.J.Pharmacol.,89(1986)p191-198）に従って行った。具体的には、細胞を培養した各ウェルの培地を基礎塩類溶液（BSS）で置き換えた後、カルシウムイオン蛍光指示薬fura-2のDMSO溶液（1mg/ml）を3μl加え、37℃で１時間保温した。次に、各ウェルをBSSで数回洗浄した後、BSSの入った状態（37℃）で細胞内カルシウムイオンモニター装置を用いて細胞内カルシウムイオンの変動を観察した。
〔結果〕 本発明化合物及びコントロール（供試化合物無添加群）の値を、Ｌ−ＰＤＭＰを１００とした場合の相対数値に変換して下記表−２に示した。なお、化合物No.は、実施例番号に対応する。
【００８８】
【表２】

【００８９】
試験例２
ガングリオシド GM3 合成酵素促進活性測定
〔原理〕マウスB16メラノーマ細胞が産生するガングリオシドは、ほとんどがガングリオシドGM3である。従って、液層分配法により、総脂質抽出画分に取り込まれた¹⁴C-Galの量を測定すれば、簡便的にガングリオシドGM3合成酵素活性を測定することができる。
【００９０】
〔方法〕マウスB16メラノーマ細胞の細胞浮遊液を10%牛胎児血清含有Dulbecco改変Eagle培地で調製し、１２穴プレートに2.0 x 10⁵cells/ml/well播種し、37℃、5%CO₂インキュベーター内で培養した。培養開始２４時間後に培地を全量交換することにより、供試化合物処理（24μM）および¹⁴C-Galの添加（22.2kBq/11.7nmol/6μl/well）を開始した。供試化合物処理開始24時間後に0.02%EDTA含有PBSおよび0.25%トリプシン含有PBSで順次処理を行い、細胞を回収した。
次に、細胞ペレットにクロロホルム：メタノール＝２：１の混合溶媒（3ml）を加え、30分間超音波処理した後、遠心上清を回収した。さらに上清回収後の残ペレットにクロロホルム：メタノール＝１：１の混合溶媒（3ml）を加え、同様の操作を行い１回目の上清と合わせ、窒素気流下で乾固させた。この総脂質画分に脱塩水（1.0ml）を加え、１分間超音波処理を行った後、透析チューブに移し、水に対して２日間透析を行った。透析の済んだサンプルを液シンバイアルに移し、シンチレーターを加えシンチレーションカウンターで¹⁴C-Galの取り込み活性を測定した。
〔結果〕表−３に本発明化合物の活性をコントロール（供試化合物無添加群）の値を100とした場合の相対数値で示した。
【００９１】
試験例３
ガングリオシド GM3 合成量測定
〔方法〕マウスB16メラノーマ細胞の細胞浮遊液を10%牛胎児血清含有Dulbecco改変Eagle培地で調製し、カルチャーフラスコ（175cm²）に0.8 x 10⁷cells/20ml播種し、37℃、5%CO₂インキュベーター内で培養した。培養開始２４時間後に培地を3/4量交換することにより、供試化合物処理（25μM）を開始した。供試化合物処理開始24時間後に0.02%EDTA含有PBSおよび0.25%トリプシン含有PBSで順次処理を行い、細胞を回収した。
次に、細胞ペレットにクロロホルム：メタノール＝２：１の混合溶媒（4ml）を加え、30分間超音波処理した後、一夜室温放置し、遠心上清を回収した。さらに上清回収後の残ペレットにクロロホルム：メタノール＝１：１の混合溶媒（4ml）を加え、同様の操作を行い１回目の上清と合わせ、窒素気流下で乾固させた。この総脂質画分に0.1Nメタノール性水酸化ナトリウム溶液（2.0ml）を加え、40℃で２時間放置した後、1N-塩酸（0.2ml）を加え、1.5時間放置した。
【００９２】
次にn-ヘキサン（2ml×2）で洗浄し、洗浄後の下層を窒素気流下で乾固させた後、クロロホルム：メタノール＝２：１を流出溶媒としたゲル濾過クロマトグラフィー[Sephadex LH-20(アマシャム ファルマシア バイオテク株式会社),直径10mm,高さ120mm]で脱塩を行った。脱塩された溶出画分を窒素気流下で乾固させた後、クロロホルム：メタノール：水＝30:60:8で平衡化した陰イオン交換樹脂カラム（DEAE-Sephadex,直径10mm,高さ40mm）にアプライし、溶出溶媒をクロロホルム：メタノール：1M酢酸ナトリウム溶液＝30:60:8として酸性脂質画分を得た。次に、酸性脂質画分を樹脂カラムで同様に脱塩した後、HPTLC（縦200mm×横100mm、展開溶媒；クロロホルム：メタノール：水＝60:35:8）を行った。オルシノール硫酸試薬をプレートに噴霧した後、110℃で5分間加熱し、発色したガングリオシドGM3のスポットをデンシトメーター（測定波長505nm）で定量化した。
〔結果〕表−３に本発明化合物の値をコントロール（供試化合物無添加群）の値を100とした場合の相対数値で示した。
【００９３】
【表３】

【００９４】
以上の結果より、本発明化合物はコントロールに比し、シナプス形成活性が高いことが証明された。さらに本発明化合物中の何例かは、Ｌ−ＰＤＭＰに比し糖脂質生合成促進活性が優れていることが確認された。
【００９５】
＜安全性＞
試験例 ４
マウス静脈内単回投与による安全性試験
５週齢の Crjマウスを用い、実施例の本発明化合物及びＬ−ＰＤＭＰの安全性を検討した。具体的には、供試薬物濃度を20mg/mlとし、薬液媒体に5.0％Tween80 含有生理食塩水を使用した。この条件で調製した薬液を尾静脈より注入速度1ml/minで200mg/kg投与し、一般状態を観察した。
その結果、本発明化合物はＬ−ＰＤＭＰに比し安全性が高いことが確認された。
【００９６】
試験例 ５
ラットによる組織移行性試験
６〜８週齢のWistar系ラット（雄性）を用い、本発明化合物（実施例１９の化合物）とＬ−ＰＤＭＰの組織移行性を比較した。
＜試験方法＞
薬液投与方法；
経口投与は、被検物質濃度２０ｍｇ／ｍｌの生理食塩水溶液を１００ｍｇ／５ｍｌ／ｋｇで行い、また静脈内投与は、被検物質濃度１．２５ｍｇ／ｍｌの生理食塩水溶液を５ｍｇ／４ｍｌ／ｋｇで頸静脈内に投与することにより行った。
試料採取；
薬液投与から所定の時間経過後、ラット頸静脈から採取した血液に、３．８％クエン酸ナトリウム溶液を１／１０容量添加した後、遠心分離（3000ｒｐｍ、１５分間）し、上清を血漿試料とした。また、薬液投与から所定の時間経過後、骨格筋を両足大腿部より採取し、氷冷水を添加（４ｍｌ／ｇ骨格筋）後、ホモジナイズし、更に同容量のアセトニトリルを加え激しく撹拌した後、遠心分離（4000ｒｐｍ、１０分間）し、上清を骨格筋試料とした。
【００９７】
組織中濃度測定；
血漿試料または骨格筋試料をOASIS HLB固相抽出カラム（ウォーターズ社）で抽出した後、ＨＰＬＣで定量した。ＨＰＬＣ分析条件は下記の通りである。

【００９８】
＜結果＞
実施例１９の化合物及びＬ−ＰＤＭＰの薬液投与から所定時間経過した後の、両化合物の血漿中及び骨格筋内濃度を以下の表−４〜表−６に示す。測定値は検体数２以上の平均値である。
【表４】

【００９９】
【表５】

【０１００】
【表６】

以上の結果から、本発明化合物（実施例１９の化合物）はＬ−ＰＤＭＰに比し血漿中濃度及び骨格筋内濃度が高く、従って組織移行性が高いことが判明した。
【０１０１】
【発明の効果】
本発明化合物の式（Ｉ）で示されるアミノアルコール誘導体又は薬学的に許容されるその塩は、糖脂質の生合成の制御作用に関与する特性を有し、該特性に基づく医薬としての有用性を有するので、本発明化合物を含有する有効な医薬を提供することが出来る。特に本発明化合物のうちシナプス形成促進効果及び／又は糖脂質生合成促進作用を有する化合物は、神経突起伸展促進効果、神経細胞死防止効果、MAPキナーゼ活性化効果を有すると予想され、神経疾患治療剤として有望であり、中枢神経系疾患治療剤、特に脳保護剤若しくは脳神経賦活・保護剤として、例えば脳血管障害後遺症の治療に、また、末梢神経系疾患治療剤として、例えば代謝障害性多発性神経障害、機械的神経障害、毒性神経障害等の治療に有効である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an aminoalcohol derivative that is a ceramide analog and a medicament containing the same, particularly a therapeutic agent for neurological diseases and a brain protective agent.
[0002]
[Prior art]
Glycosphingolipid (hereinafter referred to as GSL) exists as a component of the cell surface membrane of mammalian cells, and is generated and proliferated through the receptor function of biologically active substances, the mutual recognition function between cells, and the interaction between cells. It plays an important role in cell functions such as differentiation, canceration and immune response.
Among them, ganglioside is a GSL containing sialic acid, and is said to be active in the recovery of neurological diseases such as peripheral nerve damage and central nervous disorder, that is, promotion of nerve regeneration and neurotransmission processes. The efficacy of exogenous gangliosides for pathological models has been studied. Already, Clonassial (Cronassial) has been used in Italy^TM) Is marketed and related patents are also known (Japanese Examined Patent Publication No. 62-50450).
[0003]
Currently, the most frequently used method for exploring the function of ganglioside is the type of adding ganglioside from the outside to the experimental system, but in that case, the relationship with endogenous ganglioside becomes a problem. In other words, the endogenous ganglioside present in the cell membrane has already formed a complex with various cell surface receptors, etc., and the result derived by adding further ganglioside is the true cell physiology of endogenous ganglioside. This is because it may not always reflect the meaning of the profession. Therefore, in order to know the original role of ganglioside in cell physiology, a method for specifically changing the biosynthesis of endogenous GSL was required.
[0004]
By the way, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP), which is an analog of ceramide, specifically inhibits glucosylceramide biosynthetic enzyme to produce glucosylceramide. (J. Lipid. Res., 28, p565-571, 1987). Furthermore, D-threo-PDMP promotes neurite outgrowth. It has also been reported to be suppressed (J. Biochem., 110, p96-103, 1991). It has also been found that D-threo-PDMP suppresses synaptic function, and this suppression is specifically released by GQ1b among various gangliosides (Biochem. Biophys. Res. Commun., 222, p494-498, 1996). From these results, it is suggested that ganglioside GQ1b is an active molecule essential for synaptic function, and the importance of endogenous ganglioside on nerve function is recognized.
[0005]
On the other hand, it is suggested that L-threo-PDMP (which may be simply referred to as “L-PDMP”), which is an optical enantiomer of D-threo-PDMP, may promote biosynthesis of GSL (J. Cell. Physiol., 141, p573-583, 1989).
In addition, 2-acylaminopropanol derivatives such as L-threo-PDMP promote ganglioside biosynthesis in nerve cells, promote neurite outgrowth (J. Neurochem., 67, p1821-1830, 1996) and promote synapse formation. It has also been shown to be effective as a therapeutic agent for neurological diseases (PCT International Publication WO95 / 05177).
[0006]
Furthermore, with the aim of elucidating the mechanism of action of the neurotrophic factor-like activity of L-threo-PDMP, N-methyl-D-aspartate (NMDA), brain-derived neurotrophic factor (BDNF), etc. As a result of examining the influence of these substances on MAP kinase (MAPkinase; mitogen-activated proteinkinase) activated when synaptic transmission is continuously enhanced, L-threo-PDMP is proportional to the effect of promoting synapse formation. It has been found to activate MAP kinase for a long time, and L-threo-PDMP has also been found to increase GQ1b synthase activity (Biochem. Biophys. Res. Commun., 237, p595-600, 1997).
However, L-threo-PDMP has been determined to have room for further improvement in terms of drug-to-toxicity ratio and tissue transferability in order to exert its efficacy in vivo.
[0007]
[Problems to be solved by the invention]
The present inventors modified the acylamino group of 2-acylaminopropanol derivatives such as L-threo-PDMP, so that when the derivative was administered to a mammal, the toxicity was low and the tissue migration of the derivative was remarkably improved. And the present invention has been completed based on these findings.
An object of the present invention is to provide an amino alcohol derivative or a pharmaceutically acceptable salt thereof having synapse formation promoting activity and / or glycolipid biosynthesis promoting activity, low toxicity and improved tissue migration. It is.
Another object of the present invention is to provide a medicament containing the amino alcohol derivative, particularly a therapeutic agent for neurological diseases or a brain protective agent.
[0008]
[Means for Solving the Problems]
The present invention relates to an amino alcohol derivative which is a ceramide analog and a pharmaceutical containing the same, particularly a therapeutic agent and a brain protective agent for neurological diseases. The first gist of the present invention is as follows.
(1) An amino alcohol derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
[Chemical 1]

[0009]
In the formula, * represents an asymmetric carbon, and R represents a residue of a monocarboxylic acid derivative represented by the following (1) or (2), or a residue of a dicarboxylic acid or a derivative thereof represented by (3).
▲ 1 ▼ (COCH₂NH) mZ glycine or polyglycine residue (where m is an integer of 1 to 3, Z is an amino-protecting group or alkanoyl group)
(2) Residue of a carboxylic acid derivative represented by CO—W—Y (W is an alkylene group or cycloalkylene group, Y is a hydroxyl group, a monosaccharide residue, an aryl group which may have a substituent, or an alkyl group) Represents an alkoxy group that may contain an oxygen atom in the chain)
(3) Residue of dicarboxylic acid represented by CO-W-CO-X or a derivative thereof [W is an alkylene group or a cycloalkylene group, X is a hydroxyl group, a chain or cyclic alkoxy group, an alkyl group, α -Amino acid residues, or NR¹R²(R¹, R²Each represents the same or different hydrogen atom, a chain or cyclic alkyl group that can contain an oxygen atom in the alkyl chain, and a chain or cyclic hydroxyalkyl group that can contain an oxygen atom in the alkyl chain).
[0010]
The second gist of the present invention is as follows:
(2) It exists in the pharmaceutical which contains the amino alcohol derivative or its pharmaceutically acceptable salt shown by the said formula (I) as an active ingredient.
In addition, the compound of the general formula (I) has four types of configuration (1S, 2S), (1S, 2R), (1R, 2S), (1R, 2R), As an active ingredient of the brain protective agent, an L-threo form having a configuration of (1S, 2S) is preferable.
[0011]
As preferred embodiments of the present invention, the following amino alcohol derivatives or pharmaceutically acceptable salts thereof can be mentioned.
(A) The amino alcohol derivative or the pharmaceutically acceptable salt thereof according to the above formula (1), wherein R is represented by any one of the following (1) to (3) in the above formula (I): .
▲ 1 ▼ (COCH₂NH) mZ (Z represents an amino protecting group selected from an aralkyloxycarbonyl group having 8 to 15 carbon atoms and an alkoxycarbonyl group having 5 to 7 carbon atoms or an alkanoyl group having 4 to 8 carbon atoms)
(2) CO-W-Y (W is an alkylene group having 1 to 12 carbon atoms or a cycloalkylene group having 4 to 8 carbon atoms, and Y is a hydroxyl group, glucose residue, galactose residue, N-acetylglucosamine residue Group, N-acetylgalactosamine residue, mannose residue, fucose residue, sialic acid residue, phenyl group which may have a substituent, alkoxy group having 1 to 6 carbon atoms or 1 to 3 oxygen atoms in the alkyl chain An alkoxy group having 4 to 12 carbon atoms containing an atom)
(3) CO-W-CO-X [W is an alkylene group having 1 to 12 carbon atoms or a cycloalkylene group having 4 to 8 carbon atoms, X is a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, a carbon number Α-amino acid residue or NR having a 5-8 cycloalkoxy group, an alkyl group having 1-6 carbon atoms, a reactive functional group in the side chain¹R²(R¹, R²Each represents the same or different hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cyclohexyl group, or a hydroxyalkyl group having 2 to 4 carbon atoms.
[0012]
(B) The amino alcohol derivative according to the above formula (1) or a pharmaceutically acceptable salt thereof, wherein, in the above formula (I), R is represented by any one of the following (1) to (3): .
▲ 1 ▼ (COCH₂NH) mZ (Z represents a benzyloxycarbonyl group, a t-butoxycarbonyl group or a hexanoyl group)
(2) CO-W-Y (W is an alkylene group having 1 to 9 carbon atoms, Y is a hydroxyl group, glucose residue, galactose residue, N-acetylglucosamine residue, N-acetylgalactosamine residue, sialic acid residue A phenyl group substituted with an alkoxy group having 1 to 3 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or an alkoxy group having 6 to 8 carbon atoms containing one oxygen atom in the alkyl chain)
(3) CO-W-CO-X [W is an alkylene group having 2 to 8 carbon atoms or cyclohexylene group, X is a hydroxyl group; an alkoxy group having 1 to 4 carbon atoms; a cyclohexyloxy group; a methyl group; Amino acid residue selected from arginine, histidine, aspartic acid, glutamic acid, ornithine, cysteine, serine, threonine and tyrosine, or NR¹R²(R¹, R²Each represents the same or different hydrogen atom, a straight-chain alkyl group having 1 to 6 carbon atoms, a cyclohexyl group or a hydroxyethyl group)
[0013]
(C) In the above formula (I), R is represented by CO—W—CO—X, W is an alkylene group having 2 to 8 carbon atoms, X is a hydroxyl group, and alkoxy having 1 to 4 carbon atoms. An amino alcohol derivative according to the above formula (1) or a pharmaceutically acceptable salt thereof, which is a group or a methyl group.
(D) In the above formula (I), R is represented by CO—W—CO—X, W is an alkylene group having 4 to 8 carbon atoms, and X is a lysine residue or ornithine residue. An amino alcohol derivative according to the above formula (1) or a pharmaceutically acceptable salt thereof.
[0014]
(E) In the above formula (I), R is represented by CO—W—CO—X, W is an alkylene group having 4 to 8 carbon atoms or a cyclohexylene group, and X is NR.¹R²(R¹, R²Are the same or different hydrogen atoms, methyl groups, ethyl groups, propyl groups, n-butyl groups, n-hexyl groups, cyclohexyl groups or hydroxyethyl groups, respectively, and the amino alcohol derivatives according to the above formula (1) Or a pharmaceutically acceptable salt thereof.
[0015]
(F) In the formula (I), R is represented by CO—W—Y, W is a nonylene group, and Y is a hydroxyl group. Or a pharmaceutically acceptable salt thereof.
(G) In the above formula (I), R is represented by CO—W—Y, W is a methylene group, and Y is an n-butoxy group or a carbon number containing one oxygen atom in the alkyl chain. The amino alcohol derivative according to the above formula (1) or a pharmaceutically acceptable salt thereof, which is an alkoxy group of 6 to 8.
[0016]
(H) In the above formula (I), R is represented by CO—W—Y, W is an octylene group, and Y is a sialic acid residue. Alcohol derivatives or pharmaceutically acceptable salts thereof.
[0017]
Furthermore, as a preferred pharmaceutical aspect of the present invention, a neurological disease comprising the amino alcohol derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1), (a) to (h) as an active ingredient. A therapeutic agent or a brain protective agent can be mentioned.
[0018]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be specifically described.
The compound of the present invention is an amino alcohol derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”), and the definition of the substituent R in the formula ▲ 1 to 3 are as described above, and specific examples corresponding to the substituents 1 to 3 are shown below.
In formula (I), R is (COCH₂NH) mZ As the compound of the present invention, m is 1 to 3, preferably 1 or 2, and Z is selected from an aralkyloxycarbonyl group having 8 to 15 carbon atoms and an alkoxycarbonyl group having 5 to 7 carbon atoms. Examples thereof include amino alcohol derivatives which are amino protecting groups or alkanoyl groups having 4 to 8 carbon atoms, or pharmaceutically acceptable salts thereof.
[0019]
Examples of the amino protecting group include urethane type protecting groups, and specifically include benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-bromobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p- A methoxyphenylazobenzyloxycarbonyl group, a p-phenylazobenzyloxycarbonyl group, a t-butoxycarbonyl group or a cyclopentyloxycarbonyl group can be mentioned, and a benzyloxycarbonyl group or a t-butoxycarbonyl group is preferred. The alkanoyl group is preferably a hexanoyl group.
R is (COCH₂More specific compounds of formula (I) which are NH) mZ include (1S, 2S) -2-benzyloxycarbonylglycylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2-Benzyloxycarbonylglycylglycylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (n-butoxy) carbonylglycylamino-3-morpholino-1-phenyl Examples include -1-propanol and (1S, 2S) -2- (n-hexanoyl) glycylamino-3-morpholino-1-phenyl-1-propanol.
[0020]
In the formula (I), the compound of the present invention in which R is CO—W—CO—X, W is an alkylene group having 1 to 12 carbon atoms or a cycloalkylene group having 4 to 8 carbon atoms, and X is a hydroxyl group. , An alkoxy group having 1 to 8 carbon atoms, a cycloalkoxy group having 5 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, a functional group reactive to the side chain (for example, amino group, guanidino group, carboxyl group, hydroxyl group) Α-amino acid residues having a group) or NR¹R²(R¹, R²Each represents the same or different hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cyclohexyl group or a hydroxyalkyl group having 2 to 4 carbon atoms) or a pharmaceutically acceptable salt thereof. More specifically, W is an alkylene group having 2 to 8 carbon atoms or a cyclohexylene group, and X is a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms, a cyclohexyloxy group, a methyl group, or lysine, Amino acid residue or NR selected from arginine, histidine, aspartic acid, glutamic acid, ornithine, cysteine, serine, threonine and tyrosine¹R²(R¹, R²Are the same or different hydrogen atoms, straight-chain alkyl groups having 1 to 6 carbon atoms, cyclohexyl groups or hydroxyethyl groups).
[0021]
Specific compounds of formula (I) wherein R is CO—W—CO—X include (1S, 2S) -2- (n-butoxy) butanedioylamino-3-morpholino-1-phenyl-1 -Propanol, (1S, 2S) -2-ethoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2-isopropoxyhexanedioylamino-3-morpholino-1- Phenyl-1-propanol, (1S, 2S) -2- (n-butoxyhexanedioyl) amino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2-methoxydecandioylamino- 3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (9-carboxynonanoyl) amino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2- (7-oxooctanoyl) amino-3-morpholino-1-phenyl-1-propanol, (1S, 2S, 12S) -2- (12-amino-7-aza-6- Oxo-12-carboxydodecanoyl) amino-3-morpholino-1-phenyl-1-propanol, (1S, 2S, 16S) -2- (16-amino-11-aza-10-oxo-16-carboxyhexadeca Noyl) amino-3-morpholino-1-phenyl-1-propanol.
[0022]
Further, (1S, 2S) -2- (3-butylcarbamoyl) propionylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (N-butyl-N-methylamino) butane Dioylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (5-ethylcarbamoyl) pentanoylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S ) -2- (5-cyclohexylcarbamoyl) pentanoylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (5-hexylcarbamoyl) pentanoylamino-3-morpholino-1- Phenyl-1-propanol, (1S, 2S) -2- (9-butylcarbamoyl) nonanoylamino-3-morpholino-1-phenyl-1-prop (1S, 2S) -2- (9-hexylcarbamoyl) nonanoylamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (N, N-diethanolamino) de Candioilamino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (cyclohexane-4-hexylcarbamoyl-1-carbonyl) amino-3-morpholino-1-phenyl-1-propanol Can be mentioned.
[0023]
Further, in the formula (I), as the compound of the present invention in which R is CO—W—Y, W is an alkylene group having 1 to 12 carbon atoms or a cycloalkylene group having 4 to 8 carbon atoms, Y is a hydroxyl group, Glucose residue, galactose residue, N-acetylglucosamine residue, N-acetylgalactosamine residue, mannose residue, fucose residue, sialic acid residue, phenyl group which may have a substituent, 1 to 6 carbon atoms An amino alcohol derivative which is an alkoxy group having 4 to 12 carbon atoms and containing 1 to 3 oxygen atoms in the alkyl chain or a pharmaceutically acceptable salt thereof. More specifically, W is an alkylene group having 1 to 9 carbon atoms, Y is a hydroxyl group, glucose residue, galactose residue, N-acetylglucosamine residue, N-acetylgalactosamine residue, sialic acid residue. Group, a phenyl group substituted with an alkoxy group having 1 to 3 carbon atoms, an alkoxyl group having 1 to 4 carbon atoms or an alkoxyl group having 6 to 8 carbon atoms containing one oxygen atom in the alkyl chain. Is done.
[0024]
Specific compounds of the general formula (I) in which R is CO—W—Y include (1S, 2S) -2- (10-hydroxydecanoyl) amino-3-morpholino-1-phenyl-1-propanol , (1S, 2S) -2- (9-sialylnonanoyl) amino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- [4- (4-methoxyphenyl) butyryl] amino -3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (3-oxaheptanoyl) amino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (3,6-Dioxadecanoyl) amino-3-morpholino-1-phenyl-1-propanol, (1S, 2S) -2- (3,6-dioxadodecanoyl) amino-3-morpholino-1- And phenyl-1-propanol
[0025]
Among the compounds of the present invention, specific examples of the compound having low toxicity and high synapse forming activity include compounds in which R is represented by CO-W-CO-X or R is CO-W-Y in the above formula (I). In which the groups represented by W and X or Y are each shown in Table 1 below.
[0026]
[Table 1]

[0027]
The amino alcohol derivative of the present invention represented by the formula (I) uses a carboxylic acid corresponding to the substituent R or a reactive derivative thereof as the amino group of the amino alcohol derivative represented by the formula (II), and is a method known per se. However, the present invention is not limited to such a method.
[Chemical 2]

[0028]
When the carboxylic acid derivative corresponding to R contains a highly reactive functional group, this functional group may be protected with an appropriate protecting group in advance, and after the desired peptide bond forming reaction has been performed, it may be deprotected. Good. Moreover, a desired compound can be obtained by repeating the peptide bond formation reaction or esterification reaction which is a method known per se to the reactive functional group (for example, amino group, carboxyl group) obtained by deprotection.
[0029]
Examples of the peptide bond generation method include a method using a carboxylic acid corresponding to R and a condensing agent, a method using an acid anhydride, a method using an acid halide, and the like.
Specifically, an amino alcohol derivative represented by the formula (II) or an acid addition salt thereof (eg, hydrochloride) is mixed with a carboxylic acid and a condensing agent [for example, dicyclohexyl] in a solvent such as water, methylene chloride, pyridine or ethanol. Carbodiimide (DCC), water-soluble carbodiimide (WSC), more specifically 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)] and N-hydroxysuccinimide as necessary A method of reacting with an agent, an acid anhydride or an acid halide (for example, acid chloride) and a base (for example, an organic base such as pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, inorganic such as sodium hydrogen carbonate) And a method of reacting with a base). The solvent used in the reaction is not particularly limited as long as it does not inhibit the peptide bond formation reaction and dissolves the amino alcohol derivative and the carboxylic acid derivative.
[0030]
The peptide bond-forming reaction is usually performed at about 0 to 50 ° C., preferably at room temperature (5-35 ° C. (JIS K0050)) for several hours to several days, preferably 10 hours to 2 days. If so, it can be appropriately set by a preliminary experiment.
After the peptide bond formation reaction, formula (I) can be used by appropriately combining known purification means such as solvent extraction with ethyl acetate, chloroform, etc., various chromatography (adsorption chromatography, ion exchange chromatography, etc.), crystallization and the like. The represented compound of the present invention can be purified and isolated.
[0031]
As a method for producing the compound of the formula (II) which is the starting material of the compound of the present invention, a known method as described in JP-A-9-216856 can be appropriately employed. Specifically, as shown below, a chiral compound represented by the formula (III) is used as a starting material, and sequentially reacted according to the reaction formula of the following steps to obtain a compound having a desired configuration.
[0032]
[Chemical Formula 3]

[0033]
(In the process formula, * represents an asymmetric carbon and P₁ Is an amino-protecting group, and examples thereof include benzyloxycarbonyl group, t-butoxycarbonyl group, benzenesulfonyl group, fluorenylmethoxycarbonyl group and the like. Y represents a leaving group such as methanesulfonyl, trihalogenomethanesulfonyl, P-toluenesulfonyl, benzenesulfonyl, P-bromobenzenesulfonyl group)
[0034]
That is, a leaving group (Y) is introduced only into the primary hydroxyl group of the amino alcohol derivative represented by the formula (III) to form a compound represented by the formula (IV), and then the compound is reacted with morpholine to form the formula (IV). V) An amino alcohol derivative represented by₁Can be obtained to obtain a chiral amino alcohol derivative represented by the formula (II).
The compound of formula (II) thus obtained is derived into the compound of formula (I) according to the above reaction.
[0035]
Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) of the present invention include inorganic acid salts such as hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid, formic acid, acetic acid, citric acid, lactic acid, malic acid and oxalic acid. And salts of organic acids such as maleic acid, fumaric acid, succinic acid, trifluoroacetic acid, methanesulfonic acid (mesyl acid), and P-toluenesulfonic acid (tosylic acid). Such a salt can be produced by a method known per se. For example, the compound represented by the formula (I) (free form) is dissolved in an appropriate solvent such as alcohol, and usually about equimolar amount of the above acid is obtained. The solvent may be distilled off if desired.
[0036]
The amino alcohol derivative represented by the formula (I) of the compound of the present invention or a pharmaceutically acceptable salt thereof has characteristics involved in the control action of biosynthesis of glycolipids, and is useful as a medicine based on the characteristics. have.
Among the compounds represented by formula (I), a compound having a synapse formation promoting effect and / or a glycolipid (ganglioside etc.) biosynthesis promoting effect has a neurite outgrowth promoting effect, a neuronal cell death preventing effect, and a MAP kinase activation effect. Therefore, it is useful as a therapeutic agent for neurological diseases based on such effects. Therefore, the animal can be treated by administering an effective amount of the compound of the present invention to mammals including humans suffering from neurological diseases caused by peripheral nerve or central nerve disorders. Representative diseases such as stroke, cerebral infarction, cerebrovascular disorder sequelae, cerebral hemorrhage, brain trauma, memory impairment, senile dementia, Alzheimer's disease and Parkinson's disease are expected to have a therapeutic effect due to regeneration of nerve fibers. And various peripheral nervous system diseases such as metabolic disorder neuropathy, mechanical neuropathy, toxic neuropathy and the like. In particular, the compound of the present invention having synapse formation promoting activity is effective for treating, for example, sequelae of cerebrovascular disorders as a therapeutic agent for central nervous system diseases, particularly a brain protective agent or a cranial nerve activation / protection agent.
[0037]
[Formulation]
The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof can be used for the treatment of various diseases (for example, neurological diseases) of mammals including humans. It can be made into the formulation administered orally or parenterally with a carrier, an excipient | filler, and another additive.
Examples of oral preparations include solid preparations such as powders, granules, capsules and tablets; liquid preparations such as syrups, elixirs and emulsions. The powder can be obtained by mixing with excipients such as lactose, starch, crystalline cellulose, calcium lactate, calcium hydrogen phosphate, magnesium aluminate metasilicate, and silicic anhydride. In addition to the above-mentioned excipients, granules may be prepared in a wet or dry manner by further adding, for example, a binder such as sucrose, hydroxypropylcellulose, polyvinylpyrrolidone, or a disintegrant such as carboxymethylcellulose or carboxymethylcellulose calcium. Can be obtained by granulation. Tablets can be obtained by compressing the powder or granules as described above or by adding a lubricant such as magnesium stearate or talc. The tablet or granule is coated with an enteric base such as hydroxypropylmethylcellulose phthalate, methyl methacrylate copolymer, hydroxypropylmethylcellulose acetate, hydroxypropylmethylcellulose succinate, or ethylcellulose, carnauba wax, hydrogenated oil, white shellac, etc. These can be made into enteric or persistent formulations.
[0038]
The hard capsule can be obtained by filling the above powder or granule into a hard capsule. Soft capsules can be obtained by dissolving the compound of the present invention in glycerin, polyethylene glycol, sesame oil, olive oil or the like and coating it with a gelatin film.
A syrup can be obtained by dissolving a sweetener such as sucrose, sorbitol, glycerin and the compound of the present invention in water. In addition to sweeteners and water, essential oils, ethanol, etc. are added to make elixirs, or Arabia gum, tragacanth, polysorbates (polysorbate 20, polysorbate 60, polysorbate 80 (Tween 80), etc.), sodium carboxymethylcellulose, etc. Can be added to form an emulsion or suspension. Moreover, a corrigent, a coloring agent, a preservative, etc. can be added to these liquid preparations as needed.
[0039]
Examples of parenteral preparations include injections, rectal administration agents, pessaries, external preparations for skin, inhalants, aerosols, eye drops and the like. Injections include compounds of the present invention and nonionic surfactants such as polysorbates as necessary; pH adjusters such as hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium monohydrogen phosphate, sodium dihydrogen phosphate An isotonic agent such as sodium chloride and glucose; a stabilizer such as amino acids; and distilled water for injection or physiological saline; Further, mannitol, dextran, gelatin and the like can be added and lyophilized in vacuum to obtain a dissolution type injection for use. In addition, it can be a powder-filled injection. Moreover, after adding an emulsifier, such as a lecithin, polysorbates, polyoxyethylene hydrogenated castor oil, macrogol, to this invention compound, it can also be set as the emulsion for injection emulsified in water.
[0040]
Examples of injections include liposome preparations and lipid microspheres that can improve solubility and the rate of transfer to target organs. In particular, nanosphere-liposomes (lipid ultrafine particles) can not only be taken up into the reticuloendothelial system, but can increase the blood concentration and reduce the minimum effective dose required for the expression of the drug effect, and the brain blood vessel barrier is about 10 times higher. It is suitable for use in the treatment of neurological diseases of the brain because it is easy to pass. Liposome preparation is a known method for preparing liposomes (CG Knight, Liposomes: From Physical Structure to Therapeutic Applications, pp. 51-82, Elsevier, Amsterdam (1981); Proc. Natl. Acad. Sci., USA, Vol. 75, 4194. (1978)).
[0041]
That is, examples of amphipathic substances that form liposome membranes include natural phospholipids (egg yolk lecithin, soybean lecithin, sphingomyelin, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidylethanolamine, cardiolipin). Phospholipids such as lipids (distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, etc.) are used. It is also known to impart negative charges to cholesterols (cholesterol, ergosterol, phytosterol, sitosterol, stigmasterol, etc.) and liposomes in order to improve membrane stability, fluidity, and drug membrane permeability. Substances (phosphatidic acid, dicetyl phosphate, etc.), substances known to impart a positive charge (stearylamine, stearylamine acetate, etc.), antioxidants (tocopherol, etc.), oily substances (soybean oil, cottonseed oil) , Sesame oil, liver oil, etc.) may be used.
[0042]
The liposome can be produced, for example, by the following method. The above amphiphile and additive and the compound of the present invention are each dissolved in an organic solvent (single or mixed solvent such as chloroform, dichloromethane, ethanol, methanol, hexane, etc.), and both solutions are mixed together in a container such as a flask. The organic solvent is removed in the presence of an inert gas (nitrogen gas, argon gas, etc.) to deposit a thin film on the vessel wall. Next, this thin film is added to an appropriate aqueous medium (physiological saline, buffer solution, phosphate buffered physiological saline, etc.) and stirred with a stirrer. In order to obtain a liposome having a small particle size, it is further dispersed using an ultrasonic emulsifier, a pressure emulsifier, a French press cell crusher, or the like. In this way, a solution in which an amphiphile necessary for liposome formation and the derivative of the present invention is dispersed in an aqueous medium is subjected to membrane filter treatment, whereby liposome formation proceeds, and nanosphere-liposomes (lipid Fine particles; particle size of about 25 to 50 nm) can be obtained. Further, the liposome may be subjected to fractionation treatment such as ultrafiltration, centrifugation, and gel filtration to remove the unsupported drug.
[0043]
Moreover, it is obtained by adding β-octylglucoside, L-tyrosine-7-amido-4-methylcoumarin, phenylamino mannoside or sulfatide as a film-forming substance in addition to the above amphiphilic substance and additives. To facilitate passage through the cerebrovascular barrier by supporting the aminoalcohol derivative of formula (I), which is a compound of the present invention, in a liposome having a glucose residue, a tyrosine residue, a mannose residue or a sulfatide on the membrane. (For the method itself, see JP-A-4-69332).
Lipid microspheres dissolve the compound of the present invention in soybean oil, sesame oil, etc., add natural phospholipids, glycerin, water, etc., stir with a stirrer, and further, ultrasonic emulsifier, pressure emulsifier, French press cell crusher, etc. It is obtained by dispersing using.
[0044]
For rectal administration, a suppository base such as mono-, di- or triglyceride of cacao fatty acid, polyethylene glycol, etc. is added to the compound of the present invention, and then heated and melted, poured into a mold and cooled, Alternatively, the compound of the present invention can be obtained by dissolving in polyethylene glycol, soybean oil or the like and then coating with a gelatin film.
The external preparation for skin can be obtained by adding white petrolatum, beeswax, liquid paraffin, polyethylene glycol or the like to the compound of the present invention, heating as necessary, and kneading.
[0045]
The tape agent can be obtained by kneading a pressure-sensitive adhesive such as rosin or alkyl acrylate polymer in the compound of the present invention and spreading it on a nonwoven fabric or the like.
The inhalant can be obtained by, for example, dissolving or dispersing the compound of the present invention in a propellant such as a pharmaceutically acceptable inert gas and filling it in a pressure resistant container.
When the compound of the present invention is used as a therapeutic agent for neurological diseases, particularly as a brain protecting agent or a cranial nerve activation / protecting agent, an injection is preferable, and an intravenous injection is more preferable. Such an injection may be a lipid microsphere preparation or a preparation containing a surfactant in consideration of the ability of the compound of the present invention to enter the brain.
[0046]
[Method of administration]
The administration method of the drug containing the compound of the present invention as an active ingredient is not particularly limited, but when used for the treatment of neurological diseases caused by central nervous system disorders, intramuscular injection, intravenous injection, subcutaneous injection or intraperitoneal injection Injection such as injection, transrectal administration, pulmonary administration, eye drops, oral administration and the like are preferable. In addition, when used for the treatment of neurological diseases caused by peripheral nervous system disorders, intramuscular injection, transdermal administration, eye drops, oral administration and the like are preferable.
The dose is appropriately determined according to the age, health condition, body weight, etc. of the patient. In general, the compound of the present invention is 0.25 to 200 mg / kg, preferably 0.5 to 100 mg / kg once a day. Or it is divided and administered in more than that.
[0047]
【Example】
EXAMPLES Next, although an Example demonstrates this invention still in detail, this invention is not limited to a following example, unless the summary is exceeded.
<Synthesis example>
Synthesis examples of the compounds of the present invention are shown in Examples 1 to 28.
In addition, the synthesis example of the intermediate body of this invention compound is shown as a preparation example, and it reacted at room temperature for the thing which is not described in particular about reaction temperature.
Further, the product substances in Examples and Preparation Examples were identified by nuclear magnetic resonance absorption.
The compounds synthesized in the examples of the present invention are all L-threo forms and are represented by the following formula (I) ′. In the formula, * and R are as defined above.
[0048]
[Formula 4]

[0049]
The abbreviations in the following examples mean the following.
EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
Z: benzyloxycarbonyl group
L-PDMP: (1S, 2S) -1-phenyl-2-decanoylamino-3-morpholino-1-propanol
¹⁴C-GaL: D- [1-¹⁴C] Galactose
EDTA: Ethylenediaminetetraacetic acid
PBS: Dulbecco's phosphate buffered saline
DMSO: Dimethyl sulfoxide
[0050]
Example 1
(Synthesis of 1S, 2S) -2-benzyloxycarbonylglycylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 716.5 mg (3.04 mmol), methylene chloride (25 ml), Z-glycine 635.4 mg (3.04 mmol), N-hydroxysuccinimide 699.3 mg (6.08 mmol) and 582.3 mg (3.04 mmol) of EDC were added and stirred for 18 hours, and then 63-5.3 mg (3.04 mmol) of Z-glycine and 846 μl (6.08 mmol) of triethylamine were added, followed by further stirring for 16 hours. To the reaction solution was added 70 ml of saturated sodium hydrogen carbonate solution, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 70 ml of water and 70 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 494.0 mg (yield 38.1%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.39-7.25 (10H, m, aromatic), 6.43 (1H, brs, NH), 5.34 (1H, brs, NH), 5.11 (2H, m, COOCH₂), 4.96 (1H, d, J = 2.93Hz, H-1), 4.29 (1H, m, H-2), 3.76 (2H, m, COCH ₂ -NH), 3.69 (4H, m, (CH₂)₂O), 2.55 (6H, m, CH₂N (CH₂)₂)
¹³C-NMR (CDCl_Three) δ: 169.2, 156.5, 140.6, 136.0, 129.1, 129.0, 128.6, 128.4, 128.3, 128.1, 127.8, 126.6, 126.0, 75.1, 67.3, 66.9, 59.7, 54.4, 51.2, 44.7
[0051]
Example 2
Synthesis of (1S, 2S) -2-benzyloxycarbonylglycylglycylamino-3-morpholino-1-phenyl-1-propanol
To 232 mg (0.98 mmol) of (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol was added methylene chloride: methanol = 1: 1 (5 ml), 274 μl (1.97 mmol) of triethylamine, and solution A2 It was. On the other hand, methylene chloride: methanol = 1: 1 (5 ml) and 1-hydroxybenzotriazole 263.9 mg (0.99 mmol) were added to 262.0 mg (0.98 mmol) of Z-glycylglycine to prepare a solution B2. Mix solution A2 and solution B2, add 189.8 mg (0.99 mmol) of EDC, stir for 18 hours, then add 260.0 mg (0.98 mmol) of Z-glycylglycine and 264.6 mg (1.00 mmol) of 1-hydroxybenzotriazole The mixture was further stirred for 3 hours. To the reaction solution was added 70 ml of saturated sodium hydrogen carbonate solution, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 70 ml of water and 70 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 90.0 mg (yield 19.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.33-7.20 (10H, m, aromatic), 6.94 (1H, brs, NH), 6.05 (1H, brs, NH), 5.04 (2H, m, COOCH₂), 4.88 (1H, d, J = 3.42Hz, H-1), 4.28 (1H, m, H-2), 3.8 (4H, m, COCH ₂ -NH), 3.62 (4H, brs, (CH₂)₂O), 2.45 (6H, m, CH₂N (CH₂)₂)
¹³C-NMR (CDCl_Three) δ: 169.8, 169.0, 156.7, 141.0, 136.0, 128.5, 128.2, 127.9, 127.6, 126.1, 74.2, 67.1, 66.7, 59.4, 54.0, 51.5, 44.3, 42.9
[0052]
Example 3
(1S, 2S) -2- (n- Butoxy ) Synthesis of carbonyl glycylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-glycylamino-3-morpholino-1-phenyl-1-propanol obtained in Preparation Example 1 below, 188.7 mg (0.64 mmol) in methanol 3 ml, triethylamine 178 μl (1.28 mmol), chloroformate n- 100 μl (0.77 mmol) of butyl was added and stirred for 15 hours. To the reaction solution was added 35 ml of saturated sodium hydrogen carbonate solution, followed by extraction with 50 ml of ethyl acetate. The organic layer was washed successively with 35 ml of water and 35 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate, ethyl acetate: methanol = 20: 1) to obtain 160.9 mg (yield 64.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.33-7.23 (5H, m, aromatic), 6.67 (1H, brs, NH), 5.61 (1H, brs, NH), 4.91 (1H, s, H-1), 4.26 (1H, m, H -2), 4.03 (2H, t, COOCH₂), 3.70-3.66 (6H, m, COCH ₂ -NH and (CH₂)₂O), 2.58-2.39 (6H, m, CH₂N (CH₂)₂), 1.58 (2H, m, COOCH₂CH ₂ ), 1.36 (2H, m, CH ₂ -CH_Three), 0.92 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 169.5, 156.8, 140.8, 128.2, 127.5, 126.0, 74.3, 66.7, 65.2, 59.3, 54.0, 51.1, 44.3, 30.8, 18.8, 13.6
[0053]
Preparation Example 1
Preparation of (1S, 2S) -2-glycylamino-3-morpholino-1-phenyl-1-propanol
478.7 mg (1.12 mmol) of (1S, 2S) -2-benzyloxycarbonylglycylamino-3-morpholino-1-phenyl-1-propanol prepared in Example 1 was dissolved in 10 ml of methanol, and 119.2 mg of 10% palladium carbon. (10.0 mol%) was added, and the mixture was stirred for 6 hours under a hydrogen atmosphere. Palladium carbon was removed by filtration, and the filtrate was concentrated to obtain the title compound.
[0054]
Example 4
(1S, 2S) -2- (n- Hexanoyl ) Synthesis of glycylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-glycylamino-3-morpholino-1-phenyl-1-propanol obtained in Preparation Example 1, 201.8 mg (0.69 mmol) in 3 ml of methanol, 115 μl (0.83 mmol) of triethylamine, n-hexanoyl chloride 114 μl (0.83 mmol) was added and stirred for 3 hours. To the reaction solution was added 35 ml of saturated sodium hydrogen carbonate solution, followed by extraction with 50 ml of ethyl acetate. The organic layer was washed successively with 35 ml of water and 35 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 120.9 mg (yield 44.8%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.35-7.24 (5H, m, aromatic), 6.68 (1H, brs, NH), 6.39 (1H, brs, NH), 4.97 (1H, d, J = 2.93Hz, H-1), 4.31 ( 1H, m, H-2), 3.79 (2H, m, COCH ₂ -NH), 3.71 (4H, m, (CH₂)₂O), 2.66-2.47 (6H, m, CH₂N (CH₂)₂), 2.18 (2H, t, COCH ₂ CH₂), 1.59 (2H, m, COCH₂CH ₂ ), 1.30 (4H, m, (CH ₂ )₂-CH_Three), 0.89 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 173.8, 169.1, 140.9, 128.3, 127.6, 126.0, 74.5, 66.9, 59.8, 54.3, 51.3, 43.2, 36.2, 31.4, 25.2, 22.3, 13.9
[0055]
Example 5
(1S, 2S) -2- (n- Butoxy ) Synthesis of butanedioylamino-3-morpholino-1-phenyl-1-propanol
To 255.2 mg (1.08 mmol) of (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol was added 5 ml of methylene chloride and 300 μl (2.16 mmol) of triethylamine to obtain a solution A5. On the other hand, to 196.0 mg (1.13 mmol) of succinic acid mono (n-butyl) ester, 5 ml of methylene chloride and 263.9 mg (2.16 mmol) of N-hydroxysuccinimide were added to obtain a solution B5. Solution A5 and solution B5 were mixed, 207.5 mg (1.08 mmol) of EDC was added, and the mixture was stirred for 18 hours. To the reaction solution was added 70 ml of saturated sodium hydrogen carbonate solution, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 70 ml of water and 70 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 70.7 mg (yield 16.7%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.37-7.26 (5H, m, aromatic), 6.06 (1H, d, J = 7.32Hz, NH), 4.95 (1H, d, J = 3.90Hz, H-1), 4.30 (1H, m, H-2), 4.05 (2H, t, COOCH ₂ ), 3.73 (4H, m, (CH₂)₂O), 2.66-2.35 (10H, m, CH₂N (CH₂)₂And COCH ₂ ), 1.59 (2H, m, COOCH₂CH ₂ ), 1.36 (2H, m, CH ₂ -CH_Three), 0.93 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 172.9, 171.9, 140.8, 128.4, 127.7, 126.1, 75.3, 66.9, 64.7, 59.7, 54.3, 51.1, 31.0, 30.6, 29.4, 19.1, 13.7
[0056]
Example 6
(Synthesis of 1S, 2S) -2-ethoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 2.858 g (11.13 mmol), methylene chloride 40 ml, adipic acid monoethyl ester 1.986 g (11.40 mmol), EDC 2.227 g (11.62 mmol) ) And stirred for 16 hours. After distilling off the solvent under reduced pressure, 90 ml of saturated sodium hydrogen carbonate solution was added and extracted with 150 ml of ethyl acetate. The organic layer was washed successively with 90 ml of water and 90 ml of saturated brine, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 3.855 g (yield: 88.4%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.36-7.25 (5H, m, aromatic), 5.94 (1H, d, J = 7.81Hz, NH), 4.95 (1H, d, J = 3.42Hz, H-1), 4.29 (1H, m, H-2), 4.11 (2H, m, COO-CH₂), 3.71 (4H, m, (CH₂)₂O), 2.61-2.45 (6H, m, N (CH₂)_Three), 2.25 (2H, t, O-CO-CH₂), 2.11 (2H, t, NHCO-CH₂), 1.53 (4H, m, COCH₂-CH ₂ ), 1.25 (3H, t, CH_Three)
[0057]
Example 7
Synthesis of (1S, 2S) -2-isopropoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol) adipic acid monoisopropyl ester 530.0 mg (2.0 mmol), methylene chloride 10 ml, triethylamine 700 μl (5.0 mmol) , EDC 580 mg (3.0 mmol) was added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to obtain 416.0 mg (yield 51.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 5.90 (1H, d, J = 7.33Hz, NH), 4.99 (1H, m, CO-O-CH), 4.97 (1H, d, J = 3.42) Hz, H-1), 4.30 (1H, m, H-2), 3.72 (4H, m, (CH₂)₂O), 2.61 and 2.50 (2H, dd, H-3), 2.57 (4H, m, N (CH₂)₂), 2.22 (2H, m, O-CO-CH₂), 2.12 (2H, m, CO-CH₂), 1.54 (4H, m, CO-CH₂-CH ₂ ), 1.22 (6H, d, J = 6.35, CH_Three)
¹³C-NMR (CDCl_Three) δ: 173.1, 172.9, 140.9, 128.4, 127.7, 126.0, 75.4, 67.6, 66.9, 59.8, 54.4, 51.2, 36.2, 34.2, 24.9, 24.3, 21.8
[0058]
Example 8
(1S, 2S) -2- (n- Butoxyhexane dioil ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol) to adipic acid mono (n-butyl) ester 405 mg (2.0 mmol), methylene chloride 12 ml, triethylamine 420 μl ( 3.0 mmol) and 580 mg (3.0 mmol) of EDC were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to obtain 308 mg (yield 37.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 5.90 (1H, d, J = 7.33Hz, NH), 4.97 (1H, d, J = 3.90Hz, H-1), 4.30 (1H, m, H-2), 4.06 (2H, m, COO-CH₂), 3.73 (4H, m, (CH₂)₂O), 2.61 and 2.50 (2H, dd, H-3), 2.57 (4H, m, N (CH₂)₂), 2.26 (2H, t, O-CO-CH₂), 2.13 (2H, t, NHCO-CH₂), 1.60 (2H, m, COO-CH₂-CH ₂ ), 1.55 (4H, m, CO-CH₂-CH ₂ ), 1.37 (2H, m, CH ₂ -CH_Three), 0.93 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 173.5, 173.1, 140.9, 128.4, 127.7, 126.0, 75.4, 67.0, 64.3, 59.8, 54.4, 51.2, 36.2, 33.9, 30.7, 25.0, 24.3, 19.1, 13.2
[0059]
Example 9
(1S, 2S) -2- (3- Butylcarbamoyl ) Synthesis of propionylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 802.4 mg (3.4 mmol) to 3-butylcarbamoylpropionic acid 600 mg (3.4 mmol), methylene chloride 25 ml, triethylamine 1.7 ml (12.0 mmol) ), 1.0 g (5.1 mmol) of EDC was added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 962 mg (yield 71.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 6.28 (1H, d, J = 7.81Hz, NH), 5.81 (1H, brs, NH), 4.95 (1H, d, J = 3.42Hz, H- 1), 4.30 (1H, m, H-2), 3.73 (4H, m, (CH₂)₂O), 3.19 (2H, m, CONH-CH ₂ ), 2.6-2.5 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.6-2.4 (4H, m, CO-CH₂), 1.45 (2H, m, CH ₂ -CH₂-CH_Three), 1.32 (2H, m, CH ₂ -CH_Three), 0.91 (3H, t, CH_Three)
[0060]
Example 10
(1S, 2S) -2- (N- Butyl -N- Methylamino ) Synthesis of butanedioylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol) to succinic acid mono (N-butyl-N-methyl) amide 370 mg (2.0 mmol), methylene chloride 10 ml , 0.7 ml (5.0 mmol) of triethylamine and 580.0 mg (3.0 mmol) of EDC were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to obtain 532.9 mg (yield 66.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 6.49 (1H, d, J = 6.84Hz, NH), 4.93 (1H, d, J = 3.91Hz, H-1), 4.30 (1H, m, H-2), 3.73 (4H, m, (CH₂)₂O), 3.4-3.2 (2H, m, CONH-CH ₂ ), 2.94 and 2.89 (3H, s, N-CH_Three), 2.6-2.5 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.6-2.4 (4H, m, CO-CH₂), 1.6-1.4 (2H, m, CH ₂ -CH₂-CH_Three), 1.4-1.2 (2H, m, CH ₂ -CH_Three), 0.94 and 0.92 (3H, m, CH₂-CH _Three )
¹³C-NMR (CDCl_Three) δ: 173.1, 171.4, 141.0, 128.2, 127.5, 126.2, 75.6, 66.9, 59.6, 54.3, 51.1, 49.6, 47.7, 35.1, 33.5, 31.6, 31.5, 30.3, 29.4, 29.2, 28.5, 19.9, 13.8
[0061]
Example 11
(1S, 2S) -2- ( Five- Ethylcarbamoyl ) Synthesis of pentanoylamino-3-morpholino-1-phenyl-1-propanol
4.71 g (20.0 mmol) of (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol, 3.46 g (20.0 mmol) of 5-ethylcarbamoylpentanoic acid, 160 ml of methylene chloride, 6.4 ml of triethylamine (46.0 mmol) and 4.98 g (26.0 mmol) of EDC were added and stirred overnight. 350 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 250 ml of saturated sodium bicarbonate solution, 250 ml of water and 250 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 1.02 g (yield 13.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 6.03 (1H, d, J = 7.33Hz, NH), 5.57 (1H, brs, NH), 4.97 (1H, d, J = 3.90Hz, H- 1), 4.31 (1H, m, H-2), 3.73 (4H, m, (CH₂)₂O), 3.26 (2H, m, CH ₂ -CH_Three), 2.61 and 2.50 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.1 (4H, m, CO-CH₂), 1.54 (4H, m, CO-CH₂-CH ₂ ), 1.13 (3H, t, CH_Three)
[0062]
Example 12
(1S, 2S) -2- ( Five- Cyclohexylcarbamoyl ) Synthesis of pentanoylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol) and 5-cyclohexylcarbamoylpentanoic acid 546.0 mg (2.4 mmol), methylene chloride: methanol = 4: 1 10 ml of a mixed solvent, 620 μl (4.4 mmol) of triethylamine and 460 mg (2.4 mmol) of EDC were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 607 mg (yield 68.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 6.04 (1H, d, J = 7.81Hz, NH), 5.42 (1H, d, J = 7.81, NH), 4.97 (1H, d, J = 3.91 Hz, H-1), 4.32 (1H, m, H-2), 3.70 (4H, m, (CH₂)₂O), 2.61 and 2.50 (2H, dd, H-3), 2.58 (4H, m, N (CH₂)₂), 2.1 (4H, m, CO-CH₂), 1.6-1.5 (4H, m, CO-CH₂-CH ₂ ), 1.4-1.3 (4H, m, CH-CH ₂ ), 1.2-1.0 (6H, m, (CH₂)_Three)¹³C-NMR (CDCl_Three) δ: 173.3, 171.6, 141.0, 128.4, 127.7, 126.1, 75.4, 67.0, 59.8, 54.4, 51.2, 48.2, 36.3, 36.1, 33.2, 25.5, 24.9, 24.8
[0063]
Example 13
(1S, 2S) -2- ( Five- Hexylcarbamoyl ) Synthesis of pentanoylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 703.1 mg (2.979 mmol) to methylene chloride 20 ml, 5-hexylcarbamoylpentanoic acid 708.6 mg (3.094 mmol), EDC 621.7 mg (3.243 mmol) was added and stirred for 18 hours. After distilling off the solvent under reduced pressure, 30 ml of saturated sodium hydrogen carbonate solution was added and extracted with 50 ml of ethyl acetate. The organic layer was washed with 30 ml of water and 30 ml of saturated brine successively, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 292.2 mg (yield 21.9%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.36-7.25 (5H, m, aromatic), 6.07 (1H, d, J = 7.33Hz, NH), 5.65 (1H, brs, NH), 4.96 (1H, d, J = 3.41Hz, H- 1), 4.31 (1H, m, H-2), 3.72 (4H, m, (CH₂)₂O), 3.21 (2H, m, NH-CH ₂ ), 2.62-2.47 (6H, m, CH₂N (CH₂)₂), 2.13-2.08 (4H, m, COCH₂), 1.55-1.44 (6H, m, COCH₂-CH ₂ , NH-CH₂CH ₂ ), 1.29 (6H, m, CH₂(CH ₂ )_ThreeCH₂), 0.89 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 173.2, 172.5, 141.0, 128.3, 127.6, 126.0, 75.2, 66.9, 59.7, 54.3, 51.2, 39.5, 36.0, 31.4, 29.5, 26.6, 24.8, 22.5, 14.0
[0064]
Example 14
(1S, 2S) -2- (9- Butylcarbamoyl ) Synthesis of nonanoylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 920.8 mg (3.901 mmol) to methylene chloride 20 ml, 9- (n-butyl) carbamoylnonanoic acid 1063.1 mg (4.136 mmol), EDC 1546.1 mg (8.065 mmol) was added and stirred for 21 hours. After distilling off the solvent under reduced pressure, 100 ml of saturated sodium hydrogen carbonate solution was added and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 100 ml of water and 100 ml of saturated brine, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 442.3 mg (yield 23.9%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.37-7.26 (5H, m, aromatic), 5.91 (1H, d, J = 6.84Hz, NH), 5.50 (1H, brs, NH), 4.96 (1H, d, J = 3.42Hz, H- 1), 4.28 (1H, m, H-2), 3.72 (4H, m, (CH₂)₂O), 3.23 (2H, m, NH-CH ₂ ), 2.62-2.46 (6H, m, CH₂N (CH₂)₂), 2.11 (4H, m, COCH₂), 1.60 (2H, m, COCH₂-CH ₂ ), 1.47 (4H, m, COCH₂-CH ₂ , NH-CH₂CH ₂ ), 1.34 and 1.26 (10H, m, CH₂(CH ₂ )_FourCH₂, CH ₂ -CH_Three), 0.92 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 173.7, 173.0, 141.0, 128.4, 127.6, 126.0, 75.5, 66.9, 59.8, 54.3, 51.2, 39.2, 36.8, 36.7, 31.7, 29.1, 29.0, 25.7, 25.6, 25.5, 20.1, 13.7
[0065]
Example 15
(1S, 2S) -2- (9- Hexylcarbamoyl ) Synthesis of nonanoylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 732.1 mg (3.102 mmol) to methylene chloride 25 ml, 9- (n-hexyl) carbamoylnonanoic acid 908.2 mg (3.187 mmol), ethanol 3 ml and 628.5 mg (3.278 mmol) of EDC were added and stirred for 17 hours, and then 765.8 mg (3.995 mmol) of EDC and 0.90 ml (6.469 mmol) of triethylamine were added and stirred for 14 hours. After distilling off the solvent under reduced pressure, 100 ml of saturated sodium hydrogen carbonate solution was added and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 100 ml of water and 100 ml of saturated brine, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 468.1 mg (yield 30.0%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.37-7.26 (5H, m, aromatic), 5.91 (1H, d, J = 7.32Hz, NH), 5.49 (1H, brs, NH), 4.96 (1H, d, J = 3.91Hz, H- 1), 4.29 (1H, m, H-2), 3.73 (4H, m, (CH₂)₂O), 3.22 (2H, m, NH-CH ₂ ), 2.62-2.47 (6H, m, CH₂N (CH₂)₂), 2.15-2.08 (4H, m, COCH₂), 1.60 (2H, m, NHCH₂-CH ₂ ), 1.48 (4H, m, COCH₂-CH ₂ ), 1.29-1.24 (14H, m, CH₂(CH ₂ )_FourCH₂, (CH ₂ )_Three-CH_Three), 0.88 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 173.7, 173.0, 140.9, 128.4, 127.6, 126.0, 75.4, 66.9, 59.8, 54.3, 51.2, 39.5, 36.8, 36.7, 31.5, 29.6, 29.1, 29.0, 28.9, 26.6, 25.7, 25.5, 22.5, 14.0
[0066]
Example 16
(1S, 2S) -2- (N, N- Diethanolamino ) Synthesis of decandioylamino-3-morpholino-1-phenyl-1-propanol
To 969.2 mg (3.354 mmol) of sebacic acid mono (diethanol) amide was added 5 ml of methylene chloride, 5 ml of ethanol, and 394.8 mg (3.433 mmol) of N-hydroxysuccinimide to obtain a solution A16. On the other hand, 10 ml of ethanol was added to 735.1 mg (3.115 mmol) of (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol to obtain a solution B16. Solution A16 and Solution B16 were mixed, 760.8 mg (3.969 mmol) of EDC was added and stirred for 90 minutes, and then 362.8 mg (1.893 mmol) of EDC was added and stirred for 17 hours. After distilling off the solvent under reduced pressure, 20 ml of saturated sodium hydrogen carbonate solution was added and extracted with 50 ml of ethyl acetate. The organic layer was washed successively with 20 ml of water and 20 ml of saturated brine, dried over sodium sulfate, filtered and the solvent was removed. Distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethyl acetate: methanol = 9: 10: 1 and chloroform: methanol = 20: 1) to give 193.9 mg (yield 12.3%) of the title material as a colorless oil. Got.
¹H-NMR (CDCl_Three) δ: 7.36-7.25 (5H, m, aromatic), 5.27 (1H, brs, NH), 5.06 (1H, d, J = 5.86Hz, NH), 4.82 (1H, d, J = 4.88Hz, H- 1), 4.16-4.07 (1H, m, H-2), 3.83 (1H, t, CH ₂ -OH), 3.77 (1H, t, CH ₂ -OH), 3.70 (4H, m, (CH₂)₂O), 3.55-3.35 (6H, m, CH ₂ -OH, CH ₂ CH₂-OH), 2.57-2.26 (10H, m, CH₂N (CH₂)₂And COCH ₂ ), 1.61 (4H, m, COCH₂CH ₂ ), 1.30-1.23 (8H, m, CH₂(CH ₂ )_FourCH₂)
¹³C-NMR (CDCl_Three) δ: 175.6, 172.9, 141.2, 128.3, 127.6, 126.4, 76.5, 66.8, 61.7, 60.8, 60.7, 60.2, 59.8, 54.0, 52.1, 52.0, 50.5, 35.9, 34.6, 29.0, 25.1, 24.8
[0067]
Example 17
(1S, 2S) -2- ( Cyclohexane Four- Hexylcarbamoyl-1-carbonyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol), cyclohexanedicarboxylic acid 1.72 g (10.0 mmol), triethylamine 1.60 ml (11.0 mmol), EDC 420 mg (2.2 mg) mmol) was added and stirred overnight. After concentrating the reaction solvent, 50 ml of a saturated sodium hydrogen carbonate solution was added and concentrated. After adding 60 ml of a mixed solvent of chloroform: methanol = 5: 1, insolubles were removed by filtration, the filtrate was concentrated and purified by silica gel chromatography ( Purification by chloroform: methanol = 9: 1 and 5: 1) gave 152 mg of an intermediate product. Next, 350 mg (3.5 mmol) of hexylamine, 0.24 ml (1.7 mmol) of triethylamine and 330 mg (1.7 mmol) of EDC were added to 135 mg (0.35 mmol) of the intermediate product, and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain 32.6 mg (yield 19.7%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 5.97 (1H, d, J = 7.32Hz, NH), 5.53 (1H, t, NH), 4.96 (1H, d, J = 3.42Hz, H- 1), 4.28 (1H, m, H-2), 3.72 (4H, m, (CH₂)₂O), 3.2 (2H, q, CONH-CH ₂ ), 2.60 and 2.49 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.0 (2H, m, CO-CH), 1.9-1.7 (8H, m, CH-CH ₂ ), 1.6-1.2 (8H, m, CONH-CH₂(CH ₂ )_Four), 0.88 (3H, t, (CH₂)_Three)
¹³C-NMR (CDCl_Three) δ: 176.0, 175.3, 141.0, 128.4, 127.7, 126.1, 75.3, 67.0, 59.8, 54.4, 51.1, 44.7, 44.6, 39.4, 31.5, 29.6, 28.7, 28.6, 26.6, 22.6, 14.0
[0068]
Example 18
(1S, 2S) -2- (3- Oxaheptanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 944.0 mg (4.0 mmol), 3-oxaheptanoic acid 529.0 mg (4.0 mmol), methylene chloride 20 ml, triethylamine 1.40 ml (10.0 mmol) ) And 1.15 g (6.0 mmol) of EDC were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 30: 1) to obtain 825 mg (yield 59%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 6.95 (1H, d, J = 7.81Hz, NH), 4.99 (1H, d, J = 3.91Hz, H-1), 4.35 (1H, m, H-2), 3.88 and 3.82 (2H, d, CO-CH₂), 3.74 (4H, m, (CH₂)₂O), 3.40 (2H, t, O-CH ₂ -(CH₂)₂-CH_Three), 2.63 and 2.50 (2H, dd, H-3), 2.59 (4H, m, N (CH₂)₂), 1.55 (2H, m, CH ₂ -CH₂CH_Three), 1.35 (2H, m, CH ₂ -CH_Three), 0.93 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 170.3, 140.7, 128.4, 127.7, 126.2, 75.6, 71.5, 70.1, 67.0, 59.8, 54.4, 50.3, 31.6, 19.2, 13.9
[0069]
Example 19
(1S, 2S) -2- (3,6- Dioxadecanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 944.0 mg (4.0 mmol) to 3,6-dioxadecanoic acid 705.0 mg (4.0 mmol), methylene chloride 20 ml, triethylamine 1.40 ml (10.0 mmol) and 1.15 g (6.0 mmol) of EDC were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: ethanol = 30: 1) to obtain 815 mg (yield 52%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 7.06 (1H, d, J = 7.82Hz, NH), 4.99 (1H, d, J = 3.91Hz, H-1), 4.38 (1H, m, H-2), 3.96 and 3.89 (2H, d, CO-CH₂), 3.73 (4H, m, (CH₂)₂O), 3.52 (4H, m, O-CH₂-CH₂-O), 3.42 (2H, t, O-CH ₂ -(CH₂)₂-CH_Three), 2.63 and 2.50 (2H, dd, H-3), 2.58 (4H, m, N (CH₂)₂), 1.54 (2H, m, CH ₂ -(CH₂)₂-CH_Three), 1.34 (2H, m, CH ₂ -CH_Three), 0.92 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 170.2, 140.9, 128.3, 127.6, 126.2, 75.2, 71.3, 70.9, 70.3, 69.7, 66.9, 59.6, 54.3, 50.4, 31.6, 19.2, 13.9
[0070]
Example 20
(1S, 2S) -2- [4- (4- Methoxyphenyl ) Butyryl ] Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol) and 4- (4-methoxyphenyl) butanoic acid 388.0 mg (2.0 mmol), methylene chloride 10 ml, triethylamine 0.70 ml (5.0 mmol) and EDC 580 mg (3.0 mmol) were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to obtain 549 mg (yield 66%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 7.02 (2H, d, J = 8.79Hz, aromatic), 6.81 (2H, m, aromatic), 5.80 (1H, d, J = 7.32Hz, NH) , 4.97 (1H, d, J = 3.41Hz, H-1), 4.31 (1H, m, H-2), 3.79 (3H, s, O-CH_Three), 3.72 (4H, m, (CH₂)₂O), 2.61 and 2.49 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.48 (2H, m, CO-CH₂), 2.10 (2H, m, CO (CH₂)₂CH ₂ ), 1.82 (2H, m, COCH₂-CH ₂ )
¹³C-NMR (CDCl_Three) δ: 173.3, 157.9, 140.8, 133.3, 129.3, 128.4, 127.7, 126.0, 113.8, 75.4, 66.9, 59.9, 55.3, 54.4, 51.2, 35.7, 34.0, 27.2
[0071]
Example 21
(1S, 2S) -2- (3,6- Dioxadodecanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 959.1 mg (4.064 mmol) to methylene chloride 40 ml, 3,6-dioxadodecanoic acid 1.086 g (5.325 mmol), EDC 1.167 g (6.090 mmol) was added and stirred for 3 hours, and 719.3 mg (3.752 mmol) of EDC was added, followed by stirring for 3 days. After distilling off the solvent under reduced pressure, 70 ml of saturated sodium hydrogen carbonate solution was added and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 70 ml of water and 70 ml of saturated brine, dried over sodium sulfate, filtered, Distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain 812.3 mg (yield 47.4%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.37-7.25 (5H, m, aromatic), 7.05 (1H, d, J = 8.31Hz, NH), 4.98 (1H, d, J = 3.91Hz, H-1), 4.38 (1H, m, H-2), 3.92 (2H, m, CO-CH₂-O), 3.73 (4H, m, (CH₂)₂O), 3.52 (4H, m, O (CH ₂ )₂O), 3.41 (2H, t, OCH ₂ (CH₂)_Four), 2.66-2.47 (6H, m, CH₂N (CH₂)₂), 1.53 (2H, m, CH ₂ (CH₂)_ThreeCH_Three), 1.29 (6H, m, CH₂(CH ₂ )_ThreeCH_Three), 0.89 (3H, t, CH_Three)
¹³C-NMR (CDCl_Three) δ: 170.2, 140.9, 128.3, 127.5, 126.2, 75.2, 71.6, 71.0, 70.4, 69.6, 66.9, 59.6, 54.3, 50.4, 31.6, 29.5, 25.7, 22.6, 14.1
[0072]
Example 22
(1S, 2S) -2- ( 7- Oxooctanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 944.0 mg (4.0 mmol), 7-oxooctanoic acid 700 mg (4.4 mmol), methylene chloride: methanol = 9: 1 mixed solvent 20 ml, triethylamine 1.40 ml (10.0 mmol) and EDC 1.15 g (6.0 mmol) were added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to obtain 890 mg (yield 59%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 5.88 (1H, d, J = 7.33Hz, NH), 4.96 (1H, d, J = 3.42Hz, H-1), 4.28 (1H, m, H-2), 3.72 (4H, m, (CH₂)₂O), 2.61 and 2.49 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.38 (2H, t, CO-CH₂), 2.12 (3H, s, CO-CH_Three), 2.10 (2H, dt, CH_ThreeCOCH ₂ ), 1.52 (4H, m, COCH₂CH ₂ ), 1.18 (2H, m, CO (CH₂)₂CH ₂ )
¹³C-NMR (CDCl_Three) δ: 209.4, 173.4, 141.0, 128.4, 127.6, 126.0, 75.3, 67.0, 59.8, 54.4, 51.2, 43.3, 36.4, 29.9, 28.4, 25.4, 23.2
[0073]
Example 23
(1S, 2S) -2- (Ten- Hydroxydecanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 472.0 mg (2.0 mmol) to 10-hydroxydecanoic acid 377 mg (2.0 mmol), methylene chloride 20 ml, triethylamine 0.70 ml (5.0 mmol) , EDC 580 mg (3.0 mmol) was added and stirred overnight. 100 ml of methylene chloride was added to the reaction solvent, and the organic layer was washed successively with 50 ml of saturated sodium bicarbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to obtain 508 mg (yield 62%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.38-7.26 (5H, m, aromatic), 5.88 (1H, d, J = 7.32Hz, NH), 4.96 (1H, d, J = 3.42Hz, H-1), 4.29 (1H, m, H-2), 3.73 (4H, m, (CH₂)₂O), 3.62 (2H, m, CH ₂ -OH), 2.60 and 2.49 (2H, dd, H-3), 2.56 (4H, m, N (CH₂)₂), 2.10 (2H, m, CO-CH₂), 1.6-1.4 (4H, m, CH ₂ -CH₂-OH, CO-CH₂-CH ₂ ), 1.4-1.2 (10H, m, (CH₂)_Five)
¹³C-NMR (CDCl_Three) δ: 173.7, 140.9, 128.4, 127.7, 126.0, 75.5, 66.9, 63.0, 59.8, 54.4, 51.2, 36.4, 32.7, 29.3, 29.1, 29.0, 25.6
[0074]
Example 24
Synthesis of (1S, 2S) -2-methoxydecandioylamino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 1.244 g (5.27 mmol), methylene chloride 40 ml, sebacic acid monomethyl ester 1.13 g (5.23 mmol), EDC 1.51 g (7.88 mmol) The mixture was stirred for 15 hours, and 1.10 g (5.73 mmol) of EDC and 1.0 ml (7.19 mmol) of triethylamine were added, followed by stirring for 22 hours. After distilling off the solvent under reduced pressure, 70 ml of saturated sodium hydrogen carbonate solution was added and extracted with 100 ml of ethyl acetate. The organic layer was washed successively with 70 ml of water and 70 ml of saturated brine, dried over sodium sulfate, filtered, Distilled under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: ethyl acetate: methanol = 9: 10: 1) to obtain 1.89 g (yield 82.7%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.37-7.25 (5H, m, aromatic), 5.85 (1H, d, J = 7.32Hz, NH), 4.96 (1H, d, J = 3.42Hz, H-1), 4.28 (1H, m, H-2), 3.72 (4H, m, (CH₂)₂O), 3.67 (3H, s, OCH_Three), 2.63-2.47 (6H, m, CH₂N (CH₂)₂), 2.30 (2H, m, COCH₂), 2.09 (2H, m, COCH₂), 1.60 (2H, m, COCH₂-CH ₂ ), 1.50 (2H, m, COCH₂-CH ₂ ), 1.26 (8H, m, CH₂(CH ₂ )_FourCH₂)
[0075]
Example 25
(1S, 2S) -2- (9- Carboxonanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
To (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 316.2 mg (1.34 mmol) was added 10 ml of methylene chloride, 190 μl (1.37 mmol) of triethylamine, and 292.4 mg (1.59 mmol) of sebacic anhydride. After stirring for 5 hours, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1 and chloroform: methanol = 9: 1) to obtain 171.1 mg (yield 30.4%) of the title material as a colorless oil.
¹H-NMR (CDCl_Three) δ: 7.36-7.25 (5H, m, aromatic), 6.50 (1H, d, J = 7.82Hz, NH), 4.94 (1H, d, J = 3.91Hz, H-1), 4.37 (1H, m, H-2), 3.80-3.69 (4H, m, (CH₂)₂O), 2.77-2.63 (6H, m, CH₂N (CH₂)₂), 2.30 (2H, m, COCH₂), 2.09 (2H, m, COCH₂), 1.61 (2H, m, COCH₂-CH ₂ ), 1.48 (2H, m, COCH₂-CH ₂ ), 1.30-1.16 (8H, m, CH₂(CH ₂ )_FourCH₂)
¹³C-NMR (CDCl_Three) δ: 178.3, 174.1, 140.7, 128.4, 127.7, 126.0, 75.1, 66.2, 59.3, 53.9, 51.0, 36.5, 34.4, 28.9, 28.8, 25.4, 24.9, 24.8
[0076]
Example 26
(1S, 2S , 12S ) -2- (12- amino -7- Aza -6- Oxo -12- Carboxydodecanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
Hydrolysis of the ester bond of (1S, 2S) -2-ethoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol obtained in Example 6 gave (1S, 2S) -2- (5- Carboxypentanoyl) amino-3-morpholino-1-phenyl-1-propanol [intermediate product (26-1)], then the carboxyl group of the compound and N_αThe title compound was obtained by condensing the amino group of -benzyloxycarbonyl-L-lysine methyl ester by a conventional method and finally removing the protecting group.
Specifically, (1S, 2S) -2-ethoxyhexanedioylamino-3-morpholino-1-phenyl-1-propanol 230.6 mg (0.588 mmol) in methanol 6 ml, 2N sodium hydroxide solution 588 μl (1.176 mmol) ) Was added, and the mixture was stirred at 40 ° C overnight.
[0077]
Next, after neutralizing with 2N hydrochloric acid, the solvent was distilled off under reduced pressure, and desalting operation was performed by gel filtration chromatography. The intermediate product (26-1) 212.4 mg (0.583 mmol) was added to N_α-Benzyloxycarbonyl-L-lysine methyl ester 202.9 mg (0.690 mmol), methylene chloride 9 ml, ethanol 2 ml, EDC 389.0 mg (2.029 mmol) were added and stirred overnight. Next, the reaction solvent was distilled off under reduced pressure, 70 ml of ethyl acetate was added, and the organic layer was washed successively with 30 ml of saturated sodium bicarbonate solution, 30 ml of water and 30 ml of saturated brine, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain an intermediate product 26-2. Next, methanol (3 ml) and 2N-sodium hydroxide solution (320 μl, 0.64 mmol) were added to 198.6 mg (0.310 mmol) of the intermediate product (26-2), and the mixture was stirred at 40 ° C. for 3 hours, and then 2N-hydrochloric acid (320 μl, 0.64 mmol). ) And stirred overnight, 320 μl of 2N hydrochloric acid (0.64 mmol) and 47.3 mg of 10% palladium carbon were added and stirred overnight in a hydrogen atmosphere. Finally, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by gel filtration chromatography (Sephadex LH-20 (Amersham Pharmacia Biotech Co., Ltd., chloroform: methanol = 2: 1)) 160.6 mg of the title material was obtained.
[0078]
NMR (intermediate product 26-2)
¹H-NMR (CDCl_Three) δ: 7.38-7.24 (10H, m, aromatic), 6.01 (1H, d, J = 7.82Hz, NH), 5.78 (1H, brs, NH), 5.54 (1H, d, J = 8.30Hz, NH) , 5.09 (2H, s, COOCH₂), 4.96 (1H, d, J = 3.91Hz, H-1), 4.38-4.32 (2H, m, H-2 and NH₂-CH-CO), 3.74-3.70 (7H, m, (CH₂)₂O, OCH_Three), 3.22 (2H, m, CONHCH ₂ ), 2.61-2.45 (6H, m, CH₂N (CH₂)₂), 2.10 (4H, m, COCH ₂ ), 1.83 (1H, m, CH₂), 1.69 (1H, m, CH₂), 1.52 (8H, m, CH₂), 1.37 (2H, m, CH₂)
NMR (title compound of Example 26)
¹H-NMR (CD_ThreeOD) δ: 7.42 (2H, d, J = 7.32Hz, aromatic), 7.33 (2H, m, aromatic), 7.25 (1H, m, aromatic), 4.93 (1H, d, J = 2.93Hz, H-1 ), 4.62 (1H, m, NH₂-CH-CO), 4.06-3.92 (4H, m), 3.82-3.76 (2H, m), 3.54-3.46 (3H, m), 3.35-3.16 (4H, m), 2.23-2.12 (4H, m, COCH₂), 2.02-1.86 (2H, m, NH₂CHCH ₂ ), 1.61-1.30 (8H, m, CH₂)
¹³C-NMR (CD_ThreeOD) δ: 176.8, 176.0, 171.8, 142.5, 129.3, 128.8, 127.3, 73.9, 64.8, 60.9, 58.3, 54.8, 53.9, 53.8, 52.9, 51.2, 51.1, 39.9, 36.5, 36.4, 31.1, 29.9, 26.2, 25.8, 23.4
[0079]
Example 27
(1S, 2S , 16S ) -2- (16- amino -11- Aza -Ten- Oxo -16- Carboxyhexadecanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-methoxydecandioylamino-3-morpholino-1-phenyl-1-propanol obtained in Example 24 was mixed with 579.6 mg (1.335 mmol) of methanol 14 ml, 2N sodium hydroxide solution 1335 μl (2.670). mmol) and then stirred at 40 ° C. for 16 hours. Next, 1335 μl (2.670 mmol) of 2N-hydrochloric acid was added and stirred for 10 minutes, and then the solvent was concentrated under reduced pressure and desalted by gel filtration chromatography. The intermediate product (27-1) 475.2 mg (1.131 mmol) was added to N_α-Benzyloxycarbonyl-L-lysine methyl ester 394.2 mg (1.341 mmol), methylene chloride 12 ml, EDC 491.0 mg (2.562 mmol) were added, and the mixture was stirred for 14 hours. Next, the reaction solvent was distilled off under reduced pressure, 80 ml of ethyl acetate was added, and the organic layer was washed successively with 50 ml of saturated sodium hydrogen carbonate solution, 50 ml of water and 50 ml of saturated brine, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain an intermediate product (27-2). Next, 6 ml of methanol and 640 μl (1.28 mmol) of 2N-sodium hydroxide solution were added to 441.7 mg (0.635 mmol) of the intermediate product (27-2), followed by stirring at 40 ° C. for 3 hours, and then 640 μl of 2N hydrochloric acid (1.28 mmol). ) Was added and stirred overnight. Next, 640 μl (1.28 mmol) of 2N hydrochloric acid and 64.9 mg of 10% palladium carbon were added, and the mixture was stirred overnight under a hydrogen atmosphere. Finally, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by gel filtration chromatography (Sephadex LH-20 (Amersham Pharmacia Biotech Co., Ltd., chloroform: methanol = 2: 1)) 366.7 mg of the title material were obtained.
[0080]
NMR (Intermediate product 27-2)
¹H-NMR (CDCl_Three) δ: 7.53-7.25 (10H, m, aromatic), 5.91 (1H, d, J = 7.33Hz, NH), 5.64 (1H, brs, NH), 5.46 (1H, d, J = 7.81Hz, NH) , 5.10 (2H, s, COOCH₂), 4.95 (1H, d, J = 3.90Hz, H-1), 4.35 (1H, m), 4.28 (1H, m), 3.73 (3H, s, OCH_Three), 3.72 (4H, m, (CH₂)₂O), 3.21 (2H, m, CONHCH ₂ ), 2.61-2.45 (6H, m, CH₂N (CH₂)₂), 2.10 (4H, m, COCH ₂ ), 1.83 (1H, m, CH₂), 1.68 (1H, m, CH₂), 1.59 (2H, m, CH₂), 1.50 (4H, m, CH₂), 1.36 (2H, m, CH₂), 1.24 (8H, m, CH₂)
[0081]
NMR (title compound of Example 27)
¹H-NMR (CD_ThreeOD) δ: 7.43 (2H, d, J = 7.33Hz, aromatic), 7.33 (2H, m, aromatic), 7.25 (1H, m, aromatic), 4.94 (1H, d, J = 2.93Hz, H-1 ), 4.61 (1H, m, NH₂-CH-CO), 4.06-3.90 (4H, m), 3.81-3.74 (2H, m), 3.57-3.46 (3H, m), 3.31-3.16 (4H, m), 2.22-2.13 (4H, m, COCH₂), 2.02-1.86 (2H, m, NH₂CHCH ₂ ), 1.61-1.41 (6H, m, COCH₂CH ₂ , CONHCH₂CH ₂ ), 1.37-1.21 (8H, m, CH₂), 1.08 (2H, m, CH₂)
¹³C-NMR (CD_ThreeOD) δ: 177.3, 176.6, 171.8, 142.5, 129.3, 128.7, 127.3, 73.8, 64.8, 61.1, 58.4, 54.8, 53.9, 53.0, 51.2, 40.0, 37.1, 31.2, 30.3, 30.2, 30.1, 30.0, 29.9, 27.1, 26.5, 23.4
[0082]
Example 28
(1S, 2S) -2- (9- Sialylnonanoyl ) Synthesis of amino-3-morpholino-1-phenyl-1-propanol
(1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol 358.0 mg (1.517 mmol) to 9- (1-methoxy-4,5,7,8,9-pentaacetylsialyl) nonane 976.4 mg (1.508 mmol) of acid, 15 ml of methylene chloride and 348.4 mg (1.817 mmol) of EDC were added and stirred for 17 hours. Next, the reaction solvent was distilled off under reduced pressure, 100 ml of ethyl acetate was added, and the organic layer was washed successively with 40 ml of saturated sodium bicarbonate solution, 40 ml of water and 40 ml of saturated brine, dried over sodium sulfate, filtered, and the solvent was removed. Distilled under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain an intermediate product (28-1). Next, to 1.00 g (1.155 mmol) of the intermediate product (28-1), 5 ml of methanol, 5 ml of tetrahydrofuran and 112.4 mg (2.081 mmol) of sodium methoxide were added and stirred at room temperature for 3.5 hours, and then 40 μl (2.22 mmol) of water, 4N-sodium hydroxide 1156 μl (4.62 mmol) was added and stirred overnight. Finally, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by gel filtration chromatography [Sephadex LH-20 (Amersham Pharmacia Biotech Co., Ltd., chloroform: methanol = 2: 1)] 759.4 mg of the title material was obtained.
[0083]
NMR (intermediate product 28-1)
¹H-NMR (CDCl_Three) δ: 7.37-7.26 (5H, m, aromatic), 5.87 (1H, d, J = 7.33Hz, NH), 5,41-5.37 (1H, m), 5.34 and 5.32 (1H, m), 5.18 ( 1H, d, J = 8.79Hz), 4.97 (1H, d, J = 3.90Hz, H-1), 4.84 (1H, m), 4.32-4.26 (2H, m), 4.12-4.02 (3H, m) , 3.79 (3H, s, O-CH_Three), 3.73 (4H, m, (CH₂)₂O), 3.20 (1H, m), 2.62-2.48 (7H, m, N (CH₂)_Three, H-3'eq), 2.14, 2.13, 2.04, 2.02 (3HX4, sx4, OCOCH_ThreeOr NHCOCH _Three ), 2.1 (2H, m, COCH₂), 1.95 (1H, t, J = 12.2Hz, H-3'ax), 1.88 (3H, s, NHCOCH _Three Or OCOCH_Three), 1.51 (4H, m, CH ₂ (CH₂)_FourCH ₂ ), 1.25 (8H, m, CH₂(CH ₂ )_FourCH₂)
¹³C-NMR (CDCl_Three) δ: 173.6, 171.0, 170.7, 170.2, 170.1, 170.0, 168.5, 140.9, 128.4, 127.6, 126.0, 98.7, 76.5, 75.5, 72.4, 69.2, 69.1, 68.6, 67.4, 66.9, 65.0, 62.4, 62.3, 62.2 , 59.8, 54.4, 52.6, 51.1, 49.5, 38.1, 36.7, 29.5, 29.2, 29.1, 29.0, 25.8, 25.6, 23.2, 21.1, 20.8
[0084]
NMR (title compound of Example 28)
¹H-NMR (CDCl_Three: CD_Three(OD = 1: 1) δ: 7.35-7.20 (5H, m, aromatic), 4.90 (1H, d, J = 2.93Hz, H-1), 4.28 (1H, m, H-2), 3.90-3.43 ( 13H, m), 2.84 (1H, dd, J = 4.2,12.2Hz, H-3'eq), 2.62-2.42 (6H, m, N (CH₂)_Three), 2.11 (2H, m, COCH₂), 2.02 (3H, s, NHCOCH _Three ), 1.62-1.41 (4H, m, CH ₂ (CH₂)_FourCH ₂ ), 1.59 (1H, t, J = 12.2Hz, H-3'ax), 1.37-1.22 (8H, m, CH₂(CH ₂ )_FourCH₂)
¹³C-NMR (CDCl_Three: CD_Three(OD = 1: 1) δ: 175.9, 175.4, 174.3, 143.3, 128.9, 128.1, 127.1, 101.7, 79.3, 78.9, 78.6, 74.1, 73.9, 70.2, 69.3, 67.8, 65.1, 60.6, 54.9, 54.0, 42.6, 37.0, 30.8, 30.3, 30.2, 29.9, 27.0, 26.8, 22.6
[0085]
<In vitro activity>
Test example 1
Measurement of synapse-promoting activity on cultured rat fetal cerebral cortex neurons
[Principle] Changes in intracellular calcium ion levels associated with synchronized spontaneous neuronal firing, which is thought to indicate synaptic activity, are measured with an intracellular calcium ion multipoint observation system using the calcium ion fluorescent indicator fura-2. The synapse formation promoting activity was measured.
[0086]
〔Method〕
(1) Primary culture
Primary culture of rat fetal cerebral cortical neurons was performed by modifying Banker and Cowman's method (Brain Res., 126 (1977), p397-425). Specifically, after removing a fetus from a Wister rat (Japan SLC) on the 18th day of pregnancy, the fetal cerebral cortex was cut into small pieces. Next, after treatment with papain (Worthington Biochemical) for 30 minutes (37 ° C.), the suspension was suspended in Dulbecco's modified Eagle medium containing 5% newborn calf serum / 5% horse serum, and simply treated with Cell Striner (70 μm, FALCON). Dissociated into one cell. Next, seeded on 0.5 mm polyethyleneimine coated flexi palm plates (1.0 x 10⁶cells / 500μl / well), 37 ℃, 7% CO₂The cells were cultured in an incubator, and medium exchange was performed on the 2nd, 5th, and 8th days of culture. Using this primary culture system, the activity of the compound of the present invention was measured. The compound was added at the time of medium exchange so that the concentration of the compound was kept at 20 μM. The assay was performed on the 10th day after the start of culture.
[0087]
(2) Measurement of synapse formation promoting activity
The synapse formation promoting activity was measured according to the method of Kudo et al. (Br. J. Pharmacol., 89 (1986) p191-198). Specifically, the medium in each well in which cells were cultured was replaced with a basic salt solution (BSS), 3 μl of DMSO solution (1 mg / ml) of the calcium ion fluorescent indicator fura-2 was added, and incubated at 37 ° C. for 1 hour. did. Next, after each well was washed several times with BSS, the change of intracellular calcium ion was observed using an intracellular calcium ion monitor in a state containing BSS (37 ° C.).
[Results] The values of the compound of the present invention and the control (no test compound added group) were converted into relative values when L-PDMP was set to 100, and are shown in Table 2 below. Compound No. corresponds to the example number.
[0088]
[Table 2]

[0089]
Test example 2
Ganglioside GM3 Synthetic enzyme measurement
[Principle] Most gangliosides produced by mouse B16 melanoma cells are ganglioside GM3. Therefore, it was incorporated into the total lipid extraction fraction by liquid layer partitioning.¹⁴If the amount of C-Gal is measured, ganglioside GM3 synthase activity can be easily measured.
[0090]
[Method] A cell suspension of mouse B16 melanoma cells was prepared in Dulbecco's modified Eagle medium containing 10% fetal bovine serum, and 2.0 x 10 in a 12-well plate.^FiveCells / ml / well seeded, 37 ° C, 5% CO₂Cultured in an incubator. By exchanging the whole medium 24 hours after the start of the culture, the test compound treatment (24 μM) and¹⁴C-Gal addition (22.2 kBq / 11.7 nmol / 6 μl / well) was started. Twenty-four hours after the start of the treatment with the test compound, cells were collected by sequential treatment with PBS containing 0.02% EDTA and PBS containing 0.25% trypsin.
Next, a mixed solvent (3 ml) of chloroform: methanol = 2: 1 was added to the cell pellet, and after ultrasonic treatment for 30 minutes, the centrifugal supernatant was recovered. Furthermore, a mixed solvent (3 ml) of chloroform: methanol = 1: 1 was added to the remaining pellet after the supernatant was recovered, and the same operation was performed to combine with the first supernatant and dried under a nitrogen stream. Demineralized water (1.0 ml) was added to the total lipid fraction, sonicated for 1 minute, transferred to a dialysis tube, and dialyzed against water for 2 days. Transfer the dialyzed sample to a liquid scintillation vial, add a scintillator and use a scintillation counter.¹⁴C-Gal uptake activity was measured.
[Results] Table 3 shows the activity of the compounds of the present invention as relative values when the value of the control (no test compound added group) is 100.
[0091]
Test example 3
Ganglioside GM3 Synthesis amount measurement
[Method] A cell suspension of mouse B16 melanoma cells was prepared in Dulbecco's modified Eagle medium containing 10% fetal bovine serum and cultured in a culture flask (175 cm²) 0.8 x 10⁷cells / 20ml seeded, 37 ℃, 5% CO₂Cultured in an incubator. The test compound treatment (25 μM) was started by exchanging 3/4 volume of the medium 24 hours after the start of the culture. Twenty-four hours after the start of the treatment with the test compound, cells were collected by sequential treatment with PBS containing 0.02% EDTA and PBS containing 0.25% trypsin.
Next, a mixed solvent (4 ml) of chloroform: methanol = 2: 1 was added to the cell pellet, subjected to ultrasonic treatment for 30 minutes, and then allowed to stand overnight at room temperature, and the centrifugal supernatant was collected. Further, a mixed solvent (4 ml) of chloroform: methanol = 1: 1 was added to the remaining pellet after the supernatant was recovered, and the same operation was performed to combine with the first supernatant and dried under a nitrogen stream. To this total lipid fraction, 0.1N methanolic sodium hydroxide solution (2.0 ml) was added and allowed to stand at 40 ° C. for 2 hours, and then 1N-hydrochloric acid (0.2 ml) was added and left for 1.5 hours.
[0092]
Next, after washing with n-hexane (2 ml × 2), the lower layer after washing was dried under a nitrogen stream, followed by gel filtration chromatography using chloroform: methanol = 2: 1 as an effluent solvent [Sephadex LH-20 (Amersham Pharmacia Biotech Co., Ltd.), diameter 10 mm, height 120 mm]. After desalting the desalted elution fraction under a nitrogen stream, an anion exchange resin column equilibrated with chloroform: methanol: water = 30: 60: 8 (DEAE-Sephadex, diameter 10 mm, height 40 mm) The elution solvent was chloroform: methanol: 1M sodium acetate solution = 30: 60: 8 to obtain an acidic lipid fraction. Next, the acidic lipid fraction was similarly desalted with a resin column and then subjected to HPTLC (length 200 mm × width 100 mm, developing solvent; chloroform: methanol: water = 60: 35: 8). After spraying orcinol sulfate reagent on the plate, the plate was heated at 110 ° C. for 5 minutes, and the colored ganglioside GM3 spot was quantified with a densitometer (measurement wavelength: 505 nm).
[Results] Table 3 shows the values of the compounds of the present invention as relative values when the value of the control (no test compound added group) is 100.
[0093]
[Table 3]

[0094]
From the above results, it was proved that the compound of the present invention has higher synapse forming activity than the control. Furthermore, some of the compounds of the present invention were confirmed to have superior glycolipid biosynthesis promoting activity compared to L-PDMP.
[0095]
<Safety>
Test example 4
Safety test by single intravenous administration in mice
Using 5-week-old Crj mice, the safety of the compounds of the present invention and L-PDMP in Examples was examined. Specifically, the reagent product concentration was 20 mg / ml, and 5.0% Tween80-containing physiological saline was used as the chemical solution medium. The drug solution prepared under these conditions was administered through the tail vein at an injection rate of 1 ml / min at 200 mg / kg, and the general condition was observed.
As a result, it was confirmed that the compound of the present invention has higher safety than L-PDMP.
[0096]
Test example 5
Rat tissue transferability test
Using 6 to 8 week-old Wistar rats (male), the tissue transferability of the compound of the present invention (the compound of Example 19) and L-PDMP was compared.
<Test method>
Method of administering the drug solution;
Oral administration is performed with a physiological saline solution having a test substance concentration of 20 mg / ml at 100 mg / 5 ml / kg, and intravenous administration is conducted with a physiological saline solution having a test substance concentration of 1.25 mg / ml at 5 mg / 4 ml / kg. It was performed by administering into the jugular vein.
Sampling;
After a predetermined time has elapsed since drug administration, 1/10 volume of 3.8% sodium citrate solution was added to blood collected from the rat jugular vein, and then centrifuged (3000 rpm, 15 minutes), and the supernatant was plasma sample It was. In addition, after a predetermined time has elapsed from the administration of the drug solution, skeletal muscles were collected from both thighs, ice-cold water was added (4 ml / g skeletal muscle), homogenized, and the same volume of acetonitrile was added and stirred vigorously. Centrifugation (4000 rpm, 10 minutes) was performed, and the supernatant was used as a skeletal muscle sample.
[0097]
Tissue concentration measurement;
Plasma samples or skeletal muscle samples were extracted with an OASIS HLB solid phase extraction column (Waters) and then quantified by HPLC. The HPLC analysis conditions are as follows.

[0098]
<Result>
The concentrations of both compounds in plasma and skeletal muscle after a lapse of a predetermined time from administration of the compound of Example 19 and L-PDMP are shown in Tables 4 to 6 below. The measured value is an average value of 2 or more samples.
[Table 4]

[0099]
[Table 5]

[0100]
[Table 6]

From the above results, it was found that the compound of the present invention (the compound of Example 19) had higher plasma concentration and higher skeletal muscle concentration than L-PDMP, and therefore higher tissue migration.
[0101]
【The invention's effect】
The amino alcohol derivative represented by the formula (I) of the compound of the present invention or a pharmaceutically acceptable salt thereof has characteristics involved in the control action of biosynthesis of glycolipids, and is useful as a medicine based on the characteristics. Therefore, an effective medicine containing the compound of the present invention can be provided. In particular, among the compounds of the present invention, a compound having a synapse formation promoting effect and / or a glycolipid biosynthesis promoting effect is expected to have a neurite outgrowth promoting effect, a neuronal cell death preventing effect, and a MAP kinase activation effect. It is promising as a therapeutic agent, particularly as a therapeutic agent for central nervous system diseases, particularly as a brain protective agent or activation / protective agent for cranial nerves, for example, for treatment of sequelae of cerebrovascular disorders, and as a therapeutic agent for peripheral nervous system diseases, for example, metabolic disorder multiple It is effective for the treatment of neuropathy, mechanical neuropathy, toxic neuropathy and the like.

Claims (14)

An amino alcohol derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

In the formula, * represents an asymmetric carbon, R represents a dicarboxylic acid residue represented by CO-W-CO-X, W represents an alkylene group having 2 to 8 carbon atoms, and X represents a hydroxyl group. , An alkoxy group having 1 to 4 carbon atoms or a methyl group. Represented by formula (I), wherein * represents an asymmetric carbon, R represents a residue of a dicarboxylic acid represented by CO-W-CO-X, and W represents an alkylene having 4 to 8 carbon atoms. An amino alcohol derivative or a pharmaceutically acceptable salt thereof, wherein X is a lysine residue or ornithine residue. Represented by formula (I), wherein * represents an asymmetric carbon, R represents a residue of a dicarboxylic acid represented by CO-W-CO-X, and W represents an alkylene having 4 to 8 carbon atoms. X is NR ¹ R ² (R ¹ and R ² are the same or different hydrogen atom, methyl group, ethyl group, propyl group, n-butyl group, n-hexyl group, cyclohexyl group or An amino alcohol derivative or a pharmaceutically acceptable salt thereof.       Represented by formula (I), wherein * represents an asymmetric carbon, R represents a residue of a carboxylic acid derivative represented by CO—W—Y, W represents a nonylene group, and Y represents a hydroxyl group. An amino alcohol derivative or a pharmaceutically acceptable salt thereof.       Represented by formula (I), wherein * represents an asymmetric carbon, R represents a residue of a carboxylic acid derivative represented by CO—W—Y, W represents a methylene group, and Y represents n -An amino alcohol derivative or a pharmaceutically acceptable salt thereof comprising a butoxy group or an alkoxy group having 6 to 8 carbon atoms containing one oxygen atom in the alkyl chain.       Represented by formula (I), wherein * represents an asymmetric carbon, R represents a residue of a carboxylic acid derivative represented by CO—W—Y, W represents an octylene group, and Y represents a sial. An amino alcohol derivative consisting of an acid residue or a pharmaceutically acceptable salt thereof.       A pharmaceutical comprising the amino alcohol derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient. Represented by the formula (I), wherein * represents an asymmetric carbon, R represents a residue of glycine or polyglycine represented by (COCH ₂ NH) mZ (where m represents an integer of 1 to 3, Is a protective group for an amino group selected from an aralkyloxycarbonyl group having 8 to 15 carbon atoms and an alkoxycarbonyl group having 5 to 7 carbon atoms or an alkanoyl group having 4 to 8 carbon atoms) A pharmaceutical comprising a pharmaceutically acceptable salt thereof as an active ingredient.       The pharmaceutical according to claim 8, wherein Z represents benzyloxycarbonyl group, t-butoxycarbonyl group or hexanoyl group. Represented by formula (I), wherein * represents an asymmetric carbon, R represents a residue of a dicarboxylic acid represented by CO—W—CO—X, wherein W is an alkylene group having 2 to 8 carbon atoms or A cyclohexylene group, wherein X is a hydroxyl group; an alkoxy group having 1 to 4 carbon atoms; a cyclohexyloxy group; a methyl group; lysine, arginine, histidine, aspartic acid, glutamic acid, ornithine, cysteine, serine, threonine and tyrosine An amino alcohol comprising an amino acid residue or NR ¹ R ² (R ¹ and R ² each represent the same or different hydrogen atom, a linear alkyl group having 1 to 6 carbon atoms, a cyclohexyl group or a hydroxyethyl group) A medicament comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.       The medicament according to claim 7, comprising the amino alcohol derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.       The pharmaceutical according to claim 7, comprising the amino alcohol derivative according to any one of claims 4 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.       The medicament according to any one of claims 7 to 12, which is a therapeutic agent for neurological diseases.       The medicament according to any one of claims 7 to 12, which is a brain protective agent.