JP6911197B2 - ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体、その調製方法及びそれを含む光増感薬 - Google Patents
ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体、その調製方法及びそれを含む光増感薬 Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明の第2の目的は、ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体の調製方法を提供することである。
本発明の第3の目的は、ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体の使用を提供することである。
ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体であって、構造一般式が式I−a〜I−dに示されることを特徴とする。
置換基R1、R2は、各々独立してアミノ基に連結され、R1及びR2は、同じであってもよく、異なってもよく、R1及びR2の構造一般式は、各々独立して式IIに示され、
式II中、連結基X、Yは、各々独立して−NH−、−O−、−S−、カルボキシレート基、アミド基、スルホカルボキシレート基、スルホンアミド基、カルボニル基、フォスフェート基、C3−12不飽和炭化水素基、C3−12環状炭化水素基、C6−12アリール基又はC3−12ヘテロシクリル基であり、
前記C3−12不飽和炭化水素基は、置換又は非置換又はヘテロ原子含有のオレフィン又はアルキンであり、前記C3−12環状炭化水素基は、置換又は非置換又はヘテロ原子含有のナフテン、シクロオレフィン又はシクロアルキンであり、前記ヘテロ原子は、酸素、窒素又は硫黄原子であり、前記C6−12アリール基は、置換又は非置換アリール基であり、ここで置換アリール基は単置換又は多置換アリール基であり、置換位置がアリール基のオルト位、メタ位又はパラ位であり、前記C3−12ヘテロシクリル基は、置換又は非置換ヘテロシクリル基であり、置換ヘテロシクリル基は単置換又は多置換であり、置換位置が複素環のオルト位、メタ位又はパラ位であり、前記ヘテロシクリル基は、フラン、ピロール、チオフェン、ピラゾール、イミダゾール、オキサゾール、チアゾール、ピリジン、ピペリジン、ピリミジン、ピラジン、ピペラジン、インドール、キノリン、イソキノリン、プリン、ピリミジン又はアクリジンであり、
上記シクロアルキル基、シクロアルケニル基、アリール基又はヘテロシクリル基上の置換基は、各々独立してC1−8アルキル基、C2−8アルケニル基、C2−8アルキニル基、C3−8シクロアルキル基、アリール基、C6−12アラルキル基、若しくは、末端基としてヒドロキシ基、カルボン酸基、スルホン酸基又はカルボキシレートを含有するアルキル基であり、
式II中、末端基Zは、水素、C1−8アルキル基、C1−8アルコキシ基、C3−8シクロアルキル基、フェニル基、ピリジル基、ヒドロキシ基、アミノ基、メルカプト基、カルボン酸基、カルボキシレート、スルホン酸基、スルホン酸エステル、リン酸基、フォスフェート、アミノ酸、トリフェニルホスフィン、四級アンモニウム塩、ピリジン塩、薬物製剤により許容されるカチオンで形成されるカルボン酸塩、スルホン酸塩及びアミノ酸塩から選ばれる1種であり、
式II中、前記末端基Zが四級アンモニウム塩である場合、四級アンモニウム塩の3つの置換基は、それぞれ独立して、C1−8アルキル基、C2−8アルケニル基、C2−8アルキニル基、C3−8シクロアルキル基、C3−8シクロアルケニル基、アリール基、C6−12アラルキル基、若しくは、末端基としてヒドロキシ基、カルボン酸基、スルホン酸基、カルボキシレートを含有するアルキル基であり、四級アンモニウム塩におけるアニオンは、薬物製剤により許容されるアニオンであり、
式II中、前記末端基Zがピリジン塩である場合、前記ピリジン塩におけるピリジン環上の置換基は、オルト位、メタ位又はパラ位にあり、前記ピリジン塩は、ピリジンと1−8個の炭素原子を含む鎖長の異なるハロゲン化炭化水素とを四級化したものであり、ピリジン塩におけるアニオンは、薬物製剤により許容されるアニオンである。)
好ましくは、式II中、前記置換基R1及びR2は、各々独立して、メチレンシクロヘキサン酸と鎖長の異なるポリエチレングリコールとをカルボキシレート結合で連結したものであって、末端基がヒドロキシ基である、たとえば、
好ましくは、前記反応は、アルカリ性条件で行われてもよく、前記アルカリ性条件はpH=9〜14である。
より好ましくは、反応は、1%水酸化ナトリウム水溶液又は5%炭酸カリウム水溶液又はpH=11程度のアンモニア水溶液にて行われる。
脱アセチル化ヒポクレリンBとアミノ酪酸とを反応させる場合、ペリ位及び2−位の両方がアミノ置換された脱アセチル化ヒポクレリン誘導体HC−8a〜HC−8dが主に生成され、得られた生成物はヒドロキシ基を持つポリエチレングリコールとエステル化してHC−8a−PEGn〜HC−8d−PEGnを得て、その合成方法及び対応する生成物は、図4及び実施例22、実施例23に示される。
以下、図面を参照しながら本発明の具体的な実施形態をさらに詳細に説明する。
ヒポクレリンA(HA)の抽出
ヒポクレリンB(HB)の調製
ジエタノールアミン置換のヒポクレリンB誘導体(R1=R2=−CH2CH2−OCH2CH2−OH、R3=−COCH3、R4=−H)の調製
ジエタノールアミン−鎖長の異なるポリエチレングリコール置換のヒポクレリン誘導体(R1=R2=−CH2CH2−OCH2CH2−OCO−PEGn−OCH3、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールのユニット数、n=1、6、16)の調製
ジエタノールアミン−四級アンモニウム塩置換のヒポクレリン誘導体(R1=R2=−CH2CH2−OCH2CH2−OCO−(CH2)n−N+(CH3)3、R3=−COCH3、R4=−H)(n=2、4、6)の調製
ジエタノールアミン置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2CH2−OCH2CH2−OH、R3=R4=−H)の調製
ジエタノールアミン−鎖長の異なるポリエチレングリコール置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2CH2−OCO−PEGn−OCH3、R3=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノエタノール置換ヒポクレリン誘導体(R1=R2=−CH2CH2−OH、R3=−COCH3、R4=−H)の調製
アミノエタノール−鎖長の異なるポリエチレングリコール置換のヒポクレリン誘導体(R1=R2=−CH2CH2−OCO−PEGn−OCH3、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノエタノール置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2CH2−OH、R3=R4=−H)の調製
アミノエタノール−鎖長の異なるポリエチレングリコール置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2CH2−OCO−PEGn−OCH3、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
ジアミノエチル−鎖長の異なるポリエチレングリコールメチルエーテル置換のヒポクレリン誘導体(R1=R2=−CH2CH2−PEGn−OH、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=4、8、12)の調製
ジアミノエチル−鎖長の異なるポリエチレングリコールメチルエーテル置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2CH2−PEGn−OH、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=4、8、12)の調製
ジアミノエチル−鎖長の異なるポリエチレングリコールメチルエーテル置換ヒポクレリン誘導体(R1=R2=−CH2CH2−PEGn−OCH3、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=4、8、16)の調製
エチレンジアミン−鎖長の異なるポリエチレングリコール置換のヒポクレリン誘導体(R1=R2=−CH2CH2−NH−CH2CH2−PEGn−OH、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4)の調製
エチレンジアミン−鎖長の異なるポリエチレングリコール置換のブロモヒポクレリン誘導体(R1=R2=−CH2CH2−NH−CH2CH2−PEGn−OH、R3=−H、R4=−Br)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4)の調製
ジアミノチアポリエチレングリコール置換ヒポクレリンB誘導体(R1=R2=−CH2CH2−SCH2CH2−PEGn−OH、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4)の調製
ジアミノ酢酸置換のヒポクレリン誘導体(R1=R2=−CH2COOH、R3=−COCH3、R4=−H)の調製
ジアミノ酢酸置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2COOH、R3=R4=−H)の調製
ジアミノ酪酸置換のヒポクレリンB誘導体(R1=R2=−CH2CH2CH2COOH、R3=−COCH3、R4=−H)の調製
アミノ酪酸−鎖長の異なるポリエチレングリコール置換ヒポクレリン誘導体(R1=R2=−CH2CH2CH2COO−PEGn、R3=−COCH3、R4=−H)の調製
ジアミノ酪酸−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−(CH2)3CO−NH−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
ジアミノ酪酸置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2(CH2)2COOH、R3=R4=−H)の調製
アミノ酪酸−鎖長の異なるポリエチレングリコール置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2CH2CH2COO−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノ酪酸−鎖長の異なるアミノPEG置換の脱アセチル化ヒポクレリンB誘導体(R1=R2=−CH2(CH2)4CO−NH−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノ酪酸−鎖長の異なるスルホン酸置換の脱アセチル化ヒポクレリンB誘導体(R1=R2=−(CH2)3CO−NH−(CH2)n−SO3H、R3=R4=−H)(n=2、4、6)の調製
アミノ酪酸−鎖長の異なる四級アンモニウム塩置換の脱アセチル化ヒポクレリンB誘導体(R1=R2=−(CH2)3COO−(CH2)n−N+(CH3)3、R3=R4=−H)(n=2、4、6)の調製
アミノ酪酸−鎖長の異なるアミノ四級アンモニウム塩置換の脱アセチル化ヒポクレリンB誘導体(R1=R2=−(CH2)3CO−NH−(CH2)n−N+(CH3)3、R3=R4=−H)(n=2、4、6)の調製
アミノカプロン酸置換の脱アセチル化ヒポクレリン誘導体(R1=R2=−CH2(CH2)4COOH、R3=R4=−H)の調製
アミノカプロン酸−鎖長の異なるPEG置換のヒポクレリンB誘導体(R1=R2=−CH2(CH2)4COO−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノカプロン酸−鎖長の異なる四級アンモニウム塩置換のヒポクレリン誘導体(R1=R2=−(CH2)5COO−(CH2)n−N+(CH3)3、R3=R4=−H)(n=2、4、6)の調製
アラニン置換のヒポクレリンB誘導体(R1=R2=−CH2CH2COOH、R3=−COCH3、R4=−H)の調製
アラニン−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−CH2CH2CO−NH−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
スルファミン酸置換のヒポクレリンB誘導体(R1=R2=−(CH2)m−SO3H、R3=−COCH3、R4=−H)の調製
タウリン酸メチル置換のヒポクレリンB誘導体(R1=R2=−CH2CH2SO3CH3、R3=−COCH3、R4=−H)の調製
4−アミノメチルシクロヘキサン酸置換のヒポクレリンB誘導体(R1=R2=−CH2C6H10COOH、R3=−COCH3、R4=−H)の調製
4−(アミノメチル)シクロヘキサンカルボン酸メチル置換のヒポクレリンB誘導体(R1=R2=−CH2C6H10COOCH3、R3=−COCH3、R4=−H)の調製
4−アミノメチルシクロヘキサン酸−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−CH2C6H10COO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4、8、16)の調製
4−アミノメチルシクロヘキサン酸−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−CH2C6H10CO−NH−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4、8、16)の調製
4−アミノメチルシクロヘキサン酸−鎖長の異なるPEG置換のヒポクレリンB誘導体(R1=R2=−CH2C6H10COO−PEGn−OH、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4、8)の調製
4−アミノメチルシクロヘキサン酸−鎖長の異なるアミノPEG置換の脱アセチル化ヒポクレリンB誘導体(R1=R2=−CH2C6H10 COO−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4、8)の調製
4−アミノメチルシクロヘキサン酸−鎖長の異なるアミノPEG置換の脱アセチル化ヒポクレリンB誘導体(R1=R2=−CH2C6H10CO−NH−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、4、8)の調製
4−(アミノメチル)シクロヘキサンカルボン酸−鎖長の異なる四級アンモニウム塩置換ヒポクレリンB誘導体(R1=R2=−CH2C6H10COO−Cn−N(CH3)3、R3=R4=−H)(n 四級アンモニウム塩の炭素数、n=2、4、6)の調製
4−(アミノメチル)シクロヘキサンカルボン酸−鎖長の異なるスルホン酸基置換のヒポクレリンB誘導体(R1=R2=−CH2C6H10CO−NH−Cn−SO3H、R3=R4=−H)(n スルホン酸塩の炭素数、n=2、4、6)の調製
4−(アミノメチル)シクロヘキサンカルボン酸−鎖長の異なるアミノトリフェニルホスフィン置換ヒポクレリン誘導体(R1=R2=−CH2C6H10CO−NH−Cn−PPh3 +、R3=R4=−H)(n アミノトリフェニルホスフィン上の炭素数、n=2、4、6)の調製
4−アミノシクロヘキサンカルボン酸置換ヒポクレリンB誘導体(R1=R2=−C6H10COOCH3、R3=−COCH3、R4=−H)の調製
4−アミノシクロヘキサンカルボン酸−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−C6H10COO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
3−アミノシクロヘキサンカルボン酸置換ヒポクレリン誘導体(R1=R2=−C6H10COOCH3、R3=−COCH3、R4=−H)の調製
3−アミノシクロヘキサンカルボン酸−鎖長の異なるPEG置換のヒポクレリンB誘導体(R1=R2=−C6H10COO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
2−アミノシクロヘキサンカルボン酸置換ヒポクレリンB誘導体(R1=R2=−C6H10COOCH3、R3=−COCH3、R4=−H)の調製
2−アミノシクロヘキサンカルボン酸−鎖長の異なるPEG置換のヒポクレリンB誘導体(R1=R2=−C6H10CO−NH−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
2−アミノシクロヘキサンカルボン酸−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−C6H10CO−NH−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
4−ヒドロキシシクロヘキシルアミン置換のヒポクレリンB誘導体(R1=R2=−C6H10OH、R3=−COCH3、R4=−H)の調製
4−アミノシクロヘキサノール−鎖長の異なるカルボキシ基PEG置換のヒポクレリンB誘導体(R1=R2=−C6H10O−CO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
4−アミノエチルシクロヘキサノール置換のヒポクレリンB誘導体(R1=R2=−CH2CH2C6H9(OH)、R3=−COCH3、R4=−H)の調製
3−アミノシクロペンタン酸置換のヒポクレリンB誘導体(R1=R2=−C5H8COOH、R3=−COCH3、R4=−H)の調製
3−アミノシクロペンタン酸−鎖長の異なるPEG置換のヒポクレリンB誘導体(R1=R2=−C5H8COO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
3−アミノシクロペンタン酸−鎖長の異なるアミノPEG置換ヒポクレリンB誘導体(R1=R2=−C5H8CO−NH−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
3−アミノシクロペンタノール置換のヒポクレリンB誘導体(R1=R2=−C5H8OH、R3=−COCH3、R4=−H)の調製
3−アミノシクロペンタノール−鎖長の異なるカルボキシ基PEG置換のヒポクレリンB誘導体(R1=R2=−C5H8−O−CO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
2−アミノシクロカルボン酸置換のヒポクレリンB誘導体(R1=R2=−C5H8COOH、R3=−COCH3、R4=−H)の調製
2−アミノシクロペンタンカルボン酸−鎖長の異なるPEG置換のヒポクレリンB誘導体(R1=R2=−C5H8−COO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
2−アミノシクロカルボン酸−鎖長の異なるアミノPEG置換のヒポクレリンB誘導体(R1=R2=−C5H8−COO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
ジバリン置換のヒポクレリンB誘導体(R1=R2=−CH(CH(CH3)2)−COOH、R3=−COCH3、R4=−H)の調製
ジセリン置換ヒポクレリンB誘導体(R1=R2=−CH(CH2OH)−COOH、R3=−COCH3、R4=−H)の調製
セリンメチルエステル置換ヒポクレリンB誘導体(R1=R2=−CH(CH2OH)−COOCH3、R3=−COCH3、R4=−H)の調製
システイン置換脱アセチル化ヒポクレリン誘導体(R1=R2=−CH(CH2SH)−COOH、R3=−COCH3、R4=−H)の調製
アスパラギン置換ヒポクレリンB誘導体(R1=R2=−CH(CH2CONH2)−COOH、R3=−COCH3、R4=−H)の調製
アスパラギン酸置換のヒポクレリンB誘導体(R1=R2=−CH(COOH)−CH2COOH、R3=−COCH3、R4=−H)の調製
ジグルタミン酸置換ヒポクレリンB誘導体(R1=R2=−CH(COOH)−CH2CH2COOH、R3=−COCH3、R4=−H)の調製
ジスルファミン酸置換のヒポクレリンB誘導体(R1=R2=−(CH2)n−SO3H、R3=R4=−H)の調製
4−(アミノメチル)シクロヘキサンカルボン酸−鎖長の異なるトリフェニルホスフィン塩置換ヒポクレリンB誘導体(R1=R2=−CH2C6H10COO−Cn−N(CH3)3、R3=R4=−H)(n 四級アンモニウム塩の炭素数、n=2、4、6)の調製
4−(アミノメチル)シクロヘキサンカルボン酸−鎖長の異なるトリフェニルホスフィン塩置換ヒポクレリン誘導体(R1=R2=−CH2C6H10CO−NH−Cn−N(CH3)3、R3=−COCH3、R4=−H)(n 四級アンモニウム塩の炭素数、n=2、4、6)の調製
4−アミノメチルピペリジン−鎖長の異なるPEG置換ヒポクレリン誘導体(R1=R2=−CH2C5H9N−CO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n=1、6、12)の調製
4−アミノメチルピペリジン−鎖長の異なるPEG置換ブロモヒポクレリン誘導体(R1=R2=−CH2C5H9N−CO−PEGn、R3=−COCH3、R4=−Br)(PEG ポリエチレングリコール、n=1、6、12)の調製
4−アミノメチルピペリジン−鎖長の異なるPEG置換ヒポクレリン誘導体(R1=R2=−CH2C5H9N−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n=1、6、12)の調製
ジ−n−プロピルアミン置換のヒポクレリンB誘導体(R1=R2=−CH2CH2CH3、R3=−COCH3、R4=−H)の調製
ジヘキシルアミノ置換のヒポクレリンB誘導体(R1=R2=−C6H13、R3=R4=−H)の調製
ヒドロキシメチルシクロプロピルアミン−置換のジシクロプロピルアミン置換ヒポクレリン誘導体(R1=R2=−C3H4CH2OH、R3=−COCH3、R4=−H)の調製
ヒドロキシメチルシクロプロピルアミン−鎖長の異なるポリエチレングリコール置換ヒポクレリン誘導体(R1=R2=−C3H4CH2O−CO−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n=1、6、12)の調製
ヒドロキシメチルシクロプロピルアミン−鎖長の異なるポリエチレングリコール置換ヒポクレリン誘導体(R1=R2=−C3H4CH2−COO−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n=1、6、12)の調製
ジアミノエチル置換のヒポクレリン誘導体(R1=R2=−NHC2H5、R3=−COCH3、R4=−H)の調製
ジヒドロキシアミノ置換のヒポクレリン誘導体(R1=R2=−NHC6H4CH3、R3=R4=−H)の調製
ベンジルアミノピリジン置換ヒポクレリンB誘導体(R1=R2=−CH2C5H4N、R3=−COCH3、R4=−H)の調製
ジベンジルアミノメチルピリジン塩置換のヒポクレリンB誘導体(R1=R2=−CH2C5H4N+(CH3)、R3=−COCH3、R4=−H)の調製
ジピペラジン置換のヒポクレリンB誘導体(R1=R2=、R3=−COCH3、R4=−H)の調製
置換アミノ原料はNH2−であり、その合成スキームは実施例17におけるジアミノ酪酸置換−ポリエチレングリコール修飾のヒポクレリンB誘導体の調製と類似し、4種類の青黒色の固体生成物HB−39a〜HB−39dはそれぞれ得られた。HB−39a:収率6.4%、Rf 0.35;MS (ESI+):878.8;最大吸収波長622nm;モル吸光係数22,500M-1cm-1;一重項酸素収率20%。HB−39b:収率9.2%、Rf 0.32;MS (ESI+):878.8;最大吸収波長620nm;モル吸光係数23,500M-1cm-1;一重項酸素収率21%。HB−39c:収率8.4%、Rf 0.26;MS (ESI+):878.8;最大吸収波長628nm;モル吸光係数21,000M-1cm-1;一重項酸素収率29%。HB−39d:収率6.6%、Rf 0.25;MS (ESI+):878.8;最大吸収波長626nm。モル吸光係数21,000M-1cm-1;一重項酸素収率22%。上記アミノ置換生成物構造式は、下記に示される。
アミノエチルピペラジンジオン置換のヒポクレリン誘導体(R1=R2=−CH2CH2O−CO−piperazine、R3=−COCH3、R4=−H)の調製
ピペラジンジオン−ポリエチレングリコール置換のヒポクレリン誘導体(R1=R2=−CH2CH2O−CO−piperazine−PEGn、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n=1、6、12)の調製
DABACO置換のヒポクレリン誘導体の調製
アミノモルホリンアミン置換のヒポクレリンB誘導体(R1=R2=,R3=−COCH3、R4=−H)の調製
グリシン/アミノ酪酸置換のヒポクレリンB誘導体(R1=−CH2COOH、R2=−CH2(CH2)2COOH、R3=−COCH3、R4=−H)の調製
エチルアミン/シクロペンチルアミン置換のヒポクレリンB誘導体(R1=−C2H5、R2=−C5H9、R3=−COCH3、R4=−H)の調製
エチルアミン/シクロペンチルアミン置換のヒポクレリン誘導体(R1=−C2H5、R2=−C5H9、R3=−COCH3、R4=−SCH2CH2OH)の調製
エタンスルホン酸/プロパンスルホン酸置換の脱アセチル化ヒポクレリン誘導体(R1=−CH2SO3H、R2=−CH2(CH2)2SO3H、R3=R4=−H)の調製
エチルヒドラジン/アスパラギン酸置換のヒポクレリンB誘導体(R1=−NHC2H5、R2=−CH(COOH)−CH2COOH、R3=R4=−H)の調製
アミノ酪酸/アミノポリエチレングリコール置換のヒポクレリン誘導体(R1=−CH2CH2−PEGn−OCH3、R2=−CH2(CH2)2COOH、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノ酪酸/エタノールアミン−ポリエチレングリコール置換のヒポクレリン誘導体(R1=−CH2(CH2)2COOH、R1=−CH2CH2−O−CH2CH2−O−CO−PEGn−OCH3、R3=−COCH3、R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
アミノ酪酸/4−アミノメチルシクロヘキサン酸−ポリエチレングリコール置換のヒポクレリン誘導体(R1=−CH2(CH2)2COOH、R2=−CH2C6H10COO−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
グリシン/4−アミノメチルシクロヘキサン酸−ポリエチレングリコール置換のヒポクレリンB誘導体(R1=−CH2COOH、R2=−CH2C6H10COO−PEGn、R3=R4=−H)(PEG ポリエチレングリコール、n エチレングリコールユニット数、n=1、6、12)の調製
細胞暗毒性実験
細胞光毒性実験
細胞暗毒性実験
細胞光毒性実験
細胞光毒性実験
Claims (8)
- ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体であって、構造一般式が式I−a〜I−dに示されることを特徴とする誘導体。
置換基R3は、−COCH3又は−Hであり、置換基R4は、−H、−F、−Cl、−Br、−I又は−S−R5であり、ここでR5はC2−12アルキル基、末端基がヒドロキシ基のC2−12アルキル基、末端基がカルボキシ基のC2−12アルキル基であり、
置換基R1及びR2の構造一般式は、各々独立して式IIに示され、
式II中、連結基X、Yは、各々独立して−NH−、−O−、−S−、カルボキシレート基、アミド基、スルホカルボキシレート基、スルホンアミド基、カルボニル基、フォスフェート基、C3−12不飽和炭化水素基、C3−12環状炭化水素基、C6−12アリール基又はC3−12ヘテロシクリル基であり、
前記C3−12不飽和炭化水素基は、置換又は非置換又はヘテロ原子含有のオレフィン又はアルキンであり、前記C3−12環状炭化水素基は、置換又は非置換又はヘテロ原子含有のナフテン、シクロオレフィン又はシクロアルキンであり、前記ヘテロ原子は、酸素、窒素又は硫黄原子であり、前記C6−12アリール基は、置換又は非置換のアリール基であり、そのうち、置換アリール基は、単置換又は多置換アリール基であり、置換位置がアリール基のオルト位、メタ位又はパラ位であり、前記C3−12ヘテロシクリル基は、置換又は非置換ヘテロシクリル基であり、置換ヘテロシクリル基は、単置換又は多置換であり、置換位置が複素環のオルト位、メタ位又はパラ位であり、前記ヘテロシクリル基は、フラン、ピロール、チオフェン、ピラゾール、イミダゾール、オキサゾール、チアゾール、ピリジン、ピペリジン、ピリミジン、ピラジン、ピペラジン、インドール、キノリン、イソキノリン、プリン、ピリミジン又はアクリジンであり、
上記シクロアルキル基、シクロアルケニル基、アリール基又はヘテロシクリル基上の置換基は、各々独立してC1−8アルキル基、C2−8アルケニル基、C2−8アルキニル基、C3−8シクロアルキル基、アリール基、C6−12アラルキル基であり、若しくは、末端基としてヒドロキシ基、カルボン酸基、スルホン酸基又はカルボキシレートを含有するアルキル基であり、
式II中、末端基Zは、水素、C1−8アルキル基、C1−8アルコキシ基、C3−8シクロアルキル基、フェニル基、ピリジル基、ヒドロキシ基、アミノ基、メルカプト基、カルボン酸基、カルボキシレート、スルホン酸基、スルホン酸エステル、リン酸基、フォスフェート、アミノ酸、トリフェニルホスフィン、四級アンモニウム塩及びピリジン塩から選ばれ、
式II中、前記末端基Zが四級アンモニウム塩である場合、四級アンモニウム塩の3つの置換基は、それぞれ独立して、C1−8アルキル基、C2−8アルケニル基、C2−8アルキニル基、C3−8シクロアルキル基、C3−8シクロアルケニル基、アリール基、C6−12アラルキル基、若しくは、末端基としてヒドロキシ基、カルボン酸基、スルホン酸基、カルボキシレートを含有するアルキル基であり、
式II中、前記末端基Zがピリジン塩である場合、前記ピリジン塩におけるピリジン環上の置換基は、オルト位、メタ位又はパラ位にあり、前記ピリジン塩は、ピリジンと1−8個の炭素原子を含む鎖長の異なるハロゲン化炭化水素とを四級化したものである。) - 式II中、前記連結基X、Yは、各々独立して、−NH−、−O−、−S−、−COO−、−OC(=O)−、−CONH−、−NHC(=O)−、−SO3−、−SO2NH−、−C(=O)−、−PO3−、−CH=CH−、−C(CH3)=CH−、−C(CH3)=C(CH3)−、−C(COOH)=CH−、−C(CH2COOH)=CH−、−C≡C−、シクロプロピル基、メチルシクロプロピル基、ヒドロキシシクロプロピル基、ヒドロキシメチルシクロプロピル基、カルボキシシクロプロピル基、シクロブチル基、メチルシクロブチル基、ヒドロキシシクロブチル基、カルボキシシクロブチル基、シクロペンチル基、メチルシクロペンチル基、ヒドロキシシクロペンチル基、カルボキシシクロペンチル基、アミノシクロペンチル基、シクロヘキシル基、メチルシクロヘキシル基、エチルシクロヘキシル基、プロピルシクロヘキシル基、ヒドロキシシクロヘキシル基、アミノシクロヘキシル基、カルボキシシクロヘキシル基、カルボキシメチルシクロヘキシル基、ジカルボキシシクロヘキシル基、シクロヘプチル基、カルボキシシクロヘプチル基、ヒドロキシシクロヘプチル基、メチルシクロヘプチル基、−C6H4−、−C6H3(CH3)−、−C6H3(C2H5)−、−C6H2(CH3)2−、−C6H3(OH)−、−C6H3(OCH3)−、−C6H3(OC2H5)−、−C6H3(CH2OH)−、−C6H3(NH2)−、−C6H3(CH2NH2)−、−C6H3(F)−、−C6H3(Cl)−、−C6H3(Br)−、−C6H3(I)−、−C6H3(COOH)−、−C6H2(COOH)2−、−C6H3(SO3H)−、−C6H3(CH2COOH)−、−C5H3N−、−C5H2N(CH3)−、−C5H2N(OH)−、−C5H2N(NH2)−、−C5H2N(CH2NH2)−、−C5H2N(COOH)−、−C5H9N−、
ことを特徴とする請求項1に記載の誘導体。 - 式II中、前記末端基Zは、−H、−CH3、−C2H5、−C3H7、−C4H9、−C5H11、−C6H13、−C12H25、−OCH3、−OC2H5、−OC3H7、−OC4H9、−OC5H11、−OC6H13、−OC12H25、−C3H5、−C4H7、−C5H9、−C6H11、−C7H13、−C6H5、−OH、−NH2、−SH、−COOH、−COOCH3、−COOC2H5、−SO3H、−SO3CH3、−SO3C2H5、グリシン基、アラニン基、バリン基、ロイシン基、イソロイシン基、フェニルアラニン基、プロリン基、トリプトファン基、チロシン基、セリン基、システイン基、メチオニン基、アスパラギン酸基、グルタミン酸基、トレオニン基、リジン基、アルギニン基、ヒスチジン基、シスチン基、グルタチオン基、−PPh3 +、−C5H4N+、−C5H4N+(CH3)、−C5H4N+(C2H5)、−C5H4N+(C12H25)、−N+(CH3)3、−N+(C2H5)3、−N+(C3H7)3、−N+(C4H9)3、−N+(C6H13)3、−N+(CH3)2(C2H5)、−N+(CH3)2(C3H7)、−N+(CH3)2(C4H9)、−N+(CH3)2(C6H13)、−N+(CH3)2(C12H25)、−N+(C2H5)2(C3H7)、−N+(C2H5)2(C6H13)、−N+(C2H5)2(C12H25)、又は末端基としてヒドロキシ基、カルボン酸基、スルホン酸基又はカルボキシレートを含有する四級アンモニウム塩である、
ことを特徴とする請求項1に記載の誘導体。 - 前記R1、R2は、各々独立して、−H、−CH3、−C2H5、−C3H7、−C4H9、−C5H11、−C6H13、−C12H25、−C6H5、−CH2C6H5、−CH2CH2C6H5、−CH2(CH2)5C6H5、−C6H4(COOH)、−CH2C6H4(COOH)、−CH2C6H4(OH)、−C6H4(CH2COOH)、−CH2C6H4(CH2COOH)、シクロプロピル基、メチルシクロプロピル基、ヒドロキシシクロプロピル基、ヒドロキシメチルシクロプロピル基、カルボキシシクロプロピル基、シクロブチル基、メチルシクロブチル基、ヒドロキシシクロブチル基、カルボキシシクロブチル基、−CH2C4H6(COOH)、シクロペンチル基、メチルシクロペンチル基、ヒドロキシシクロペンチル基、アミノシクロペンチル基、カルボキシシクロペンチル基、シクロヘキシル基、メチルシクロヘキシル基、エチルシクロヘキシル基、プロピルシクロヘキシル基、ヒドロキシシクロヘキシル基、アミノシクロヘキシル基、カルボキシシクロヘキシル基、カルボキシメチルシクロヘキシル基、ジカルボキシシクロヘキシル基、−CH2C6H10(COOH)、−CH2C6H10(OH)、シクロヘプチル基、カルボキシシクロヘプチル基、ヒドロキシシクロヘプチル基、メチルシクロヘプチル基、−CH2COOH、−CH2CH2COOH、−CH2(CH2)2COOH、−CH2(CH2)3COOH、−CH2(CH2)4COOH、−CH2(CH2)5COOH、−CH2(CH2)6COOH、−CH2(CH2)10COOH、−CH2COOCH3、−CH2CH2COOC6H13、−CH2(CH2)2COOCH3、−CH2(CH2)2COOC2H5、−CH2(CH2)2COOC6H13、−CH2(CH2)4COOCH3、−CH2(CH2)6COOC6H13、−CH2COONa+、−CH2(CH2)2COONa+、−CH2(CH2)4COONa+、−CH2SO3H、−CH2CH2SO3H、−CH2(CH2)2SO3H、−CH2(CH2)3SO3H、−CH2(CH2)4SO3H、−CH2(CH2)5SO3H、−CH2(CH2)11SO3H、−CH2SO3CH3、−CH2SO3C6H13、−CH2CH2SO3CH3、−CH2(CH2)2SO3CH3、−CH2(CH2)2SO3C6H13、−CH2(CH2)4SO3C4H9、−CH2(CH2)11SO3C6H13、−CH2SO3Na、−CH2CH2SO3K、−OH、−OCH3、−OC2H5、−OC6H13、−NH2、−NHC2H5、−NHC6H13、−NHC12H25、−NHC6H5、−NHC5H4N、−C5H4N、−CH2C5H4N、−(CH2)2C5H4N、−(CH2)6C5H4N、−C5H3N(CH3)、−C5H3N(OH)、−C5H3N(NH2)、−C5H3N(COOH)、−C5H3N(CH2COOH)、−CH2C5H3N(CH2COOH)、−CH2CH2−(OCH2CH2)n−OH、−CH2CH2−(OCH2CH2)n−OCH3、−CH2CH2−(OCH2CH2)n−OC6H13、−CH2CH2−(OCH2CH2)n−OC12H25、−CH2CH2−(OCH2CH2)n−O−COCH3、−CH2CH2−(OCH2CH2)n−O−COC6H13、−CH2CH2−O−CO−CH2CH2−(OCH2CH2)n−OH、−CH2CH2−O−CO−CH2CH2−(OCH2CH2)n−OCH3、−CH2CH2−OCH2CH2−O−CO−CH2CH2−(OCH2CH2)n−OH、−CH2CH2−OCH2CH2−O−CO−CH2CH2−(OCH2CH2)n−OCH3、−CH2CH2−OCH2CH2−OCH2CH2−O−CO−CH2CH2−(OCH2CH2)n−OH、−CH2CH2−OCH2CH2−OCH2CH2−O−CO−CH2CH2−(OCH2CH2)n−OCH3、−CH2CH2−O−CO−CH2CH2−PPh3 +、−CH2CH2−O−CO−(CH2)3−PPh3 +、−CH2CH2−O−CO−(CH2)5−PPh3 +、−CH2CH2−OCH2CH2−O−CO−CH2CH2−PPh3 +、−CH2CH2−OCH2CH2−O−CO−(CH2)3−PPh3 +、−CH2CH2−OCH2CH2−O−CO−(CH2)5−PPh3 +;−(CH2)3−OH、−(CH2)3−OCH3、−(CH2)3−OC2H5、−(CH2)3−OCOCH3、−(CH2)3−OCOC2H5、−(CH2)3−O−COCH2CH2−(OCH2CH2)n−OCH3、−(CH2)4−OH、−(CH2)4−OCH3、−(CH2)4−OCOCH3、−(CH2)4−OCOC2H5、−(CH2)4−O−COCH2CH2−(OCH2CH2)n−OCH3、−(CH2)6−OH、−(CH2)6−OCH3、−(CH2)6−OCOCH3、−(CH2)6−O−COCH2CH2−(OCH2CH2)n−OCH3;−CH2CH2−NH−CH2CH2−(OCH2CH2)n−OH、−CH2CH2−NH−CH2CH2−(OCH2CH2)n−OCH3、−CH2CH2−(NHCH2CH2)n−NH2、−CH2CH2−(NHCH2CH2)n−N(CH3)2、−CH2CH2−NHCH2CH2−NH−COCH2CH2−(OCH2CH2)n−OCH3、−CH2CH2−S−CH2CH2−(OCH2CH2)n−OH、−CH(CH3)−COOH、−CH(CH(CH3)2)−COOH、−CHCH2(CH(CH3)2)−COOH、−CH(CH2CH2SCH3)−COOH、−CHCH(CH3)(C2H5)−COOH、−CH(CH2OH)−COOH、−CHCH(OH)(CH3)−COOH、−CH(CH2SH)−COOH、−CH(CH2CONH2)−COOH、−CH(CH2CH2CONH2)−COOH、−CH(CH2C6H5)−COOH、−CH(CH2C6H5OH)−COOH、−CH(CH2CH2CH2CH2NH3 +)−COOH、−CH(COOH)−CH2COOH、−CH(COOH)−CH2CH2COOH、
CONH−(CH2)3−N+(CH3)3、−CH2CONH−(CH2)4−N+(CH3)3、−CH2CH2CONH−(CH2)4−N+(CH3)3、−CH2(CH2)4CONH−(CH2)4−N+(CH3)3、−CH2CONH−(CH2)5−N+(CH3)3、−CH2CH2CONH−(CH2)5−N+(CH3)3、−CH2(CH2)4CONH−(CH2)5−N+(CH3)3、−CH2CONH−(CH2)6−N+(CH3)3、−CH2CH2CONH−(CH2)6−N+(CH3)3、−CH2(CH2)4CONH−(CH2)6−N+(CH3)3、−CH2CONH−CH2CH2−N+(CH3)2(C6H13)、−CH2CONH−CH2CH2−N+(CH3)2(C12H25);−C5H4N+(CH3)、−CH2C5H4N+(CH3)、−CH2C5H4N+(C6H13)、−CH2C5H4N+(CH2COOH)、−CH2CH2C5H4N+(CH3)、−CH2CH2C5H4N+(C6H13)、−CH2CH2C5H4N+(CH2COOH)、
ことを特徴とする請求項1に記載の誘導体。 - 請求項1〜5のいずれか1項に記載の誘導体の調製方法であって、
ヒポクレリン原料と対応する置換アミノ誘導体とを溶剤中に混合して、保護ガスの保護、遮光下、温度20〜150℃で4〜24時間反応させ、生成物を分離して精製し、ヒポクレリンのペリ位及び2−位の両方がアミノ置換された誘導体を得るステップを含む、
ことを特徴とする調製方法。 - 前記ヒポクレリン原料は、ヒポクレリンB又は脱アセチル化ヒポクレリンであり、前記置換アミノ誘導体の構造一般式がR1−NH2又はR2−NH2であり、前記ヒポクレリン原料と対応する置換アミノ誘導体との投入モル比が1:10〜1:100であり、前記溶剤は、有機溶剤、又は有機溶剤と水との混合溶剤であり、前記有機溶剤は、ジクロロメタン、アセトニトリル、テトラヒドロフラン、ピリジン、メタノール、エタノールのうちの1種又は複数種の組み合わせである、
ことを特徴とする請求項6に記載の方法。 - 光線力学療法における光増感薬であって、
請求項1〜5のいずれか1項に記載の誘導体を含む光増感薬。
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