JP6220180B2 - 合成ペプチドアミドおよびその二量体 - Google Patents
合成ペプチドアミドおよびその二量体 Download PDFInfo
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- JP6220180B2 JP6220180B2 JP2013160295A JP2013160295A JP6220180B2 JP 6220180 B2 JP6220180 B2 JP 6220180B2 JP 2013160295 A JP2013160295 A JP 2013160295A JP 2013160295 A JP2013160295 A JP 2013160295A JP 6220180 B2 JP6220180 B2 JP 6220180B2
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- synthetic peptide
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Description
本出願は、2006年11月10日に出願された米国仮特許出願第60/858,120号、同第60/858,121号、同第60/858,123号ならびに、2007年5月10日に出願された米国仮特許出願第60/928,527号、同第60/928,551号、同第60/928,557号の優先権の利益を主張するものであり、その内容全体を明示的に本明細書に援用する。
本発明は、D−アミノ酸をペプチド鎖に導入した合成ペプチドアミドに関し、特に、κオピオイド受容体アゴニストである合成ペプチドアミドならびに、予防薬および治療薬としてのその使用方法に関する。
κオピオイド受容体アゴニストを投与することで、多種多様な疾患および症状の治療または予防に介入するための標的として、κオピオイド受容体が提案されている。たとえば、齧歯類の糖尿病性神経障害におけるκ受容体アゴニストであるアシマドリンの薬効について説明している、Jolivalt et al., Diabetologia, 49(11):2775-85;Epub Aug. 19, 2006)ならびに、ラットにおける神経因性疼痛の絞扼性神経損傷(CCI)モデルでのκアゴニストU-50,488の薬効と、その作用をオピオイドアンタゴニストであるナロキソンで遮断することについて説明している、Bileviciute-Ljungar et al., Eur. J. Pharm. 494:139-46 (2004)を参照のこと。これらの観察結果は、糖尿病性神経因性疼痛、ウイルスによる神経因性疼痛、化学療法後神経因性疼痛の治療に、κオピオイド受容体アゴニストを用いることを裏付けるものである。月経困難症の生理痛や子宮内膜症などの婦人科領域での症状をはじめとする内臓痛の治療または予防にκ受容体アゴニストを用いることが、概説されている。たとえば、Riviere, Br. J. Pharmacol. 141:1331-4 (2004)を参照のこと。
本発明は、式I
の合成ペプチドアミドならびに、その立体異性体、立体異性体混合物、プロドラッグ、薬学的に許容される塩、水和物、溶媒和物、酸性塩水和物N−オキシドおよび同形結晶形態を提供するものである。
(i)Gが、
であり、
式中、p、q、r、sおよびtは各々独立に、0または1であり、ただし、sおよびtのうちの少なくとも1つが1である。部分Lは、ε−D−Lys、ε−Lys、δ−D−Orn、δ−Orn、γ−アミノ酪酸、8−アミノオクタン酸、11−アミノ−ウンデカン酸、8−アミノ−3,6−ジオキサオクタン酸、4−アミノ−4−カルボン酸ピペリジン、(D−Lys−Glyラクタム)2から選択されるリンカーであり、
(ii)Gが、
であり、
式中、pは1であり、Xaa3−Xaa4−は、D−ノルロイシン−(B)2D−アルギニン−、D−ロイシン−δ−(B)2α−(B’)D−オルニチン−、α−メチル−D−ロイシン−δ(B)2−α(B’)D−オルニチン−から選択され、部分
は、置換されていてもよい4から8員環の複素環部分であり、式中、前記環部分の環ヘテロ原子はいずれも窒素原子であり、式中、YおよびZは各々独立に、炭素または窒素原子であり、ただし、当該環部分が、6員環、7員環または8員環である場合、YとZとは少なくとも2個の環原子で隔てられ、ただし、当該環部分が窒素である単一のヘテロ原子を有する場合、当該環部分が非芳香族である。
(iii)Gが、
であり、
式中、pは1であり、部分
は、置換されていてもよい4から8員環の複素環部分であり、式中、Yは炭素または窒素原子であり、Zは、炭素、窒素、酸素、イオウ、スルホキシドまたはスルホニルであり、ただし、当該環部分が、6員環、7員環または8員環である場合、YとZとは少なくとも2つの環原子で隔てられ、ただし、当該環部分が非芳香族であり、かつ、Zが炭素または窒素原子である場合、当該環部分は少なくとも1つのイオウまたは酸素の環ヘテロ原子を含み、ただし、当該環部分が芳香族である場合、Yは炭素原子である。
(iv)Gが、
であり、
式中、Jは、環に、1個、2個または3個のヘテロ原子を含む、5員環、6員環または7員環の複素環部分であり、式中、R3およびR4は各々、C1〜C3アルキル、ハロ、−OH、−CF3、−NH2、−COOH、アミジノから独立に選択され、R5およびR6は各々、C1〜C3アルキル、オキソ、ハロ、−OH、−CF3、−NH2、−COOH、アミジノから独立に選択される。
(a)R1が、H、OH、ハロ、CF3、−NH2、−COOH、C1〜C6アルキル、アミジノ、C1〜C6アルキル置換アミジノ、アリール、置換されていてもよいヘテロシクリル、Pro−アミド、Pro、Gly、Ala、Val、Leu、Ile、Lys、Arg、Orn、Ser、Thr、CN、CONH2、COR’、SO2R’、CONR’R’’、NHCOR’、OR’またはSO2NR’R’’であり、前記置換されていてもよいヘテロシクリルは、C1〜C6アルキル、−C1〜C6アルコキシ、オキソ、−OH、−Cl、−F、−NH2、−NO2、−CN、−COOH、アミジノからなる群から独立に選択される置換基で単一置換または二重置換されていてもよく、式中、R’およびR’’は各々独立に、H、C1〜C8アルキル、アリール、ヘテロシクリルであるか、R’とR’’の組み合わせで、4員環から8員環の環を形成し、この環は、C1〜C6アルキル、−C1〜C6アルコキシ、−OH、−Cl、−F、−NH2、−NO2、−CN、−COOH、アミジノからなる群から独立に選択される置換基で単一置換または二重置換されていてもよく、R2が、H、アミジノ、単一または二重のC1〜C6アルキル置換アミジノ、−CN、−CONH2、−CONR’R’’、−NHCOR’、−SO2NR’R’’または−COOHであるか、
(b)R1およびR2が一緒になって、Y・Z含有環部分の単一の環原子に結合された、置換されていてもよい4員環から9員環の複素単環式または二環式の環部分を形成可能であるか、
(c)R1およびR2が、Y・Z含有環部分の単一の環原子と一緒になって、置換されていてもよい4員環から8員環の複素環部分を形成してスピロ構造を形成可能であるか、
(d)R1およびR2が、Y・Z含有環部分の2個またはそれよりも多くの隣接する環原子と一緒になって、Y・Z含有環部分に融合された、置換されていてもよい4員環から9員環の複素単環式または二環式の環部分を形成可能である。
(1)Y・Z含有環部分が単一の環ヘテロ原子を含む6員環または7員環であり、かつ、YおよびZのうちの一方がCであり、YおよびZのうちの他方がNであり、かつ、eが0である場合、R1はOHではなく、R1およびR2はともにHであることはない。
(2)Y・Z含有環部分が2個の環ヘテロ原子を有する6員環であり、YおよびZがともに窒素原子であり、Wが空であり、部分−Ve(R1)(R2)がZに結合される場合、−Ve(R1)(R2)は、アミジノ、C1〜C6アルキル置換アミジノ、ジヒドロイミダゾール、−CH2COOH、−CH2C(O)NH2から選択される。
(3)Y・Z含有環部分がイオウまたは酸素の環ヘテロ原子を有する6員環であるか、Y・Z含有環部分が2個の環ヘテロ原子を有する非芳香族の6員環である(YおよびZがともに窒素原子であり、Wは空である)か、Y・Z含有環部分が単一の環ヘテロ原子を有する6員環の芳香環(ヘテロ原子は窒素原子である)であれば、eが0である場合、R1およびR2がともに水素であることはない。
本明細書全体で使用する場合、「合成ペプチドアミド」という用語は、式Iに一致する本発明の化合物あるいは、その立体異性体、立体異性体混合物、プロドラッグ、薬学的に許容される塩、水和物、溶媒和物、酸性塩水和物、N−オキシドまたは同形結晶形態を意味する。Xaa1、Xaa2、Xaa3、Xaa4という表記は、本発明の合成ペプチドアミドのD−アミノ酸を示す。式Iに一致する本発明の合成ペプチドアミドの立体異性体は、D−配置にアミノ酸を有する化合物に限定される(式Iにそのように指定される場合)。本発明の合成ペプチドアミドの立体異性体は、Xaa1、Xaa2、Xaa3およびXaa4の4つのアミノ酸のα炭素以外のキラル中心にD−配置またはL−配置のいずれかを有する化合物を含む。「立体異性体混合物」という用語は、このような本発明の立体異性体同士の混合物を示す。本明細書で使用する場合、「ラセミ酸塩」とは、Xaa1、Xaa2、Xaa3、Xaa4のα炭素の対掌性が変わることなくXaa1、Xaa2、Xaa3、Xaa4のα炭素以外の1以上のキラル中心にD−配置の化合物とL−配置の化合物とを同じ割合で持つ立体異性体同士の混合物のことである。
で表される合成ペプチドアミドおよびその立体異性体、立体異性体混合物、プロドラッグ、薬学的に許容される塩、水和物、溶媒和物、酸性塩水和物、N−オキシドおよび同形結晶形態を提供するものであり、式中、各Xaa1は、(A)(A’)D−フェニルアラニン、(A)(A’)(α−Me)D−フェニルアラニン、D−チロシン、D−1,2,3,4−テトラヒドロイソキノリン−3カルボン酸、D−フェニルグリシン、D−ネオペンチルグリシン、D−フェニルグリシン、D−ホモフェニルアラニン、β−(E)D−Alaから独立に選択され、式中、(A)および(A’)は各々、−H、−F、−Cl、−NO2、−CH3、−CF3、−CN、−CONH2から独立に選択されるフェニル環置換基であり、式中、各(E)は、シクロブチル、シクロペンチル、シクロヘキシル、ピリジル、チエニルおよびチアゾリルから独立に選択される。各Xaa2は、(A)(A’)D−フェニルアラニン、(A)(A’)(α−Me)D−フェニルアラニン、ナフチル−1−D−アラニン、ナフチル−2−D−アラニン、D−チロシン、(E)D−アラニン、D−トリプトファンから独立に選択される。各Xaa3は、D−ノルロイシン、D−フェニルアラニン、(E)D−アラニン、D−ロイシン、(α−Me)D−ロイシン、D−ホモロイシン、D−バリン、D−メチオニンから独立に選択される。各Xaa4は、(B)2D−アルギニン、(B)2D−ノルアルギニン、(B)2D−ホモアルギニン、ζ−(B)D−ホモリジン、D−2,3−ジアミノプロピオン酸、ε−(B)D−リジン、ε−(B)2−D−リジン、D−(NH2CH2−)フェニルアラニン、アミジノ−D−(NH2CH2−)フェニルアラニン、γ−(B)2D−ジアミノ酪酸、δ−(B)2α−(B’)D−オルニチン、D−2−アミノ−3(4−ピペリジル)プロピオン酸、D−2−アミノ−3(2−アミノピロリジル)プロピオン酸、D−α−アミノ−β−アミジノ−プロピオン酸、α−アミノ−4−ピペリジン酢酸、cis−α,4−ジアミノシクロヘキサン酢酸、trans−α,4−ジアミノシクロヘキサン酢酸、cis−α−アミノ−4−メチル−アミノシクロ−ヘキサン酢酸、trans−α−アミノ−4−メチルアミノシクロヘキサン酢酸、α−アミノ−1−アミジノ−4−ピペリジン酢酸、cis−α−アミノ−4−グアニジノ−シクロヘキサン酢酸、trans−α−アミノ−4−グアニジノシクロヘキサン酢酸から独立に選択され、式中、各(B)は、−HおよびC1〜C4アルキルからなる群から独立に選択され、(B’)は、−Hまたは(α−Me)であり、pは0または1である。
(i)Gは、
であり、
式中、p、q、r、sおよびtは各々独立に、0または1であり、ただし、sおよびtのうちの少なくとも1つが1であり、Lは、ε−D−リジン、ε−リジン、δ−D−オルニチン、δ−オルニチン、γ−アミノ−酪酸、8−アミノオクタン酸、11−アミノ−ウンデカン酸、8−アミノ−3,6−ジオキサ−オクタン酸、4−アミノ−4−カルボン酸ピペリジン、(D−Lys−Glyラクタム)2から選択されるリンカーである。また、本実施形態の合成ペプチドアミドは、結合部分Lによって結合された2個の合成ペプチドアミド成分を含むことから、本明細書では「二量体」、「二量体構造」または「合成ペプチドアミド二量体」と同義に用いられる。
(ii)Gは、
であり、
式中、pは1であり、Xaa3−Xaa4−は、D−Nle−(B)2D−アルギニン−、D−ロイシン−δ−(B)2α−(B’)D−オルニチン−、(α−Me)D−ロイシン−δ(B)2−α(B’)D−オルニチン−から選択され、Y・Z含有環部分
は、置換されていてもよい4から8員環の複素環部分であり、式中、前記環部分の環ヘテロ原子はいずれも窒素原子であり、式中、YおよびZは各々独立に、炭素原子または窒素原子であり、ただし、当該環部分が、6員環、7員環または8員環である場合、YとZとは少なくとも2個の環原子で隔てられ、ただし、当該環部分が窒素である単一のヘテロ原子を有する場合は、当該環部分が非芳香族である。
(iii)Gは、
であり、
式中、pは1であり、部分
は、置換されていてもよい4から8員環の複素環部分であり、式中、YはCまたはNであり、Zは、炭素原子、窒素原子、酸素原子、イオウ原子、スルホキシド基またはスルホニル基であり、ただし、当該環部分が、6員環、7員環または8員環である場合、YとZとは少なくとも2つの環原子で隔てられ、ただし、当該環部分が非芳香族であり、かつ、Zが炭素原子または窒素原子である場合、当該環部分は少なくとも1つのイオウまたは酸素の環ヘテロ原子を含み、ただし、当該環部分が芳香族である場合、Yは炭素原子であり、
(iv)Gは、
であり、
式中、Jは、環に、1個、2個または3個のヘテロ原子を含む、5員環、6員環または7員環の複素環部分であり、式中、R3およびR4は各々、C1〜C3アルキル、ハロ、−OH、−CF3、−NH2、−COOH、アミジノから独立に選択され、R5およびR6は各々、C1〜C3アルキル、オキソ、ハロ、−OH、−CF3、−NH2、−COOH、アミジノから独立に選択され、式中、W’は、
空、
bが0、1、2、3、4、5または6である−NH−(CH2)b−、
cが2または3である−NH−(CH2)c−O−
から選択される。
(a)R1は、−H、−OH、ハロ、CF3、−NH2、−COOH、C1〜C6アルキル、アミジノ、C1〜C6アルキル置換アミジノ、アリール、置換されていてもよいヘテロシクリル、Pro−アミド、Pro、Gly、Ala、Val、Leu、Ile、Lys、Arg、Orn、Ser、Thr、CN、CONH2、COR’、SO2R’、CONR’R’’、NHCOR’、OR’またはSO2NR’R’’であり、前記置換されていてもよいヘテロシクリルは、C1〜C6アルキル、−C1〜C6アルコキシ、オキソ、−OH、−Cl、−F、−NH2、−NO2、−CN、−COOH、アミジノからなる群から独立に選択される置換基で単一置換または二重置換されていてもよく、式中、R’およびR’’は各々独立に、−H、C1〜C8アルキル、アリール、ヘテロシクリルであるか、R’とR’’の組み合わせで、4員環から8員環の環を形成し、この環は、C1〜C6アルキル、−C1〜C6アルコキシ、−OH、−Cl、−F、−NH2、−NO2、−CN、−COOH、アミジノからなる群から独立に選択される置換基で単一置換または二重置換されていてもよく、R2が、H、アミジノ、単一または二重のC1〜C6アルキル置換アミジノ、−CN、−CONH2、−CONR’R’’、−NHCOR’、−SO2NR’R’’または−COOHであるか、
(b)R1およびR2が一緒になって、Y・Z含有環部分の単一の環原子に結合された、置換されていてもよい4員環から9員環の複素単環式または二環式の環部分を形成可能であるか、
(c)R1およびR2がY・Z含有環部分の単一の環原子と一緒になって、置換されていてもよい4員環から8員環の複素環部分を形成してスピロ構造を形成可能であるか、
(d)R1およびR2が、Y・Z含有環部分の2個またはそれよりも多くの隣接する環原子と一緒になって、Y・Z含有環部分に融合された、置換されていてもよい4員環から9員環の複素単環式または二環式の環部分を形成可能であり、式中、R1およびR2を含む前記置換されていてもよい4員環から9員環の複素環部分は各々、C1〜C6アルキル、−C1〜C6アルコキシ、置換されていてもよいフェニル、オキソ、−OH、−Cl、−F、−NH2、−NO2、−CN、−COOH、アミジノからなる群から独立に選択される置換基で単一置換または二重置換されていてもよく、
ただし、Y・Z含有環部分が単一の環ヘテロ原子を含む6員環または7員環であり、かつ、YおよびZのうちの一方がCであり、YおよびZのうちの他方がNであり、かつ、eが0である場合、R1は−OHではなく、R1およびR2はいずれも−Hではなく、さらに、Y・Z含有環部分が2個の環ヘテロ原子を有する非芳香族6員環である場合、YおよびZがともにNであり、Wが空であり、−Ve(R1)(R2)がZに結合される場合、−Ve(R1)(R2)は、アミジノ、C1〜C6アルキル置換アミジノ、ジヒドロイミダゾール、−CH2COOH、−CH2C(O)NH2からなる群から選択され、最後に、Y・Z含有環部分がSまたはOの環ヘテロ原子を有する6員環であるか、Y・Z含有環部分が2個の環ヘテロ原子を有する6員環である(YおよびZがともにNであり、Wは空である)か、Y・Z含有環部分が単一の環ヘテロ原子を有する6員環の芳香環(ヘテロ原子はNである)であれば、eが0である場合、R1およびR2はともに−Hであることはない。
の合成ペプチドアミドおよびその立体異性体、立体異性体混合物、ラセミ酸塩、プロドラッグ、薬学的に許容される塩、水和物、溶媒和物、酸性塩水和物、N−オキシドおよび同形結晶形態が得られ、式中、
Xaa1は、(A)(A’)D−Phe、(α−Me)D−Phe、D−Tyr、D−Tic、D−フェニルグリシン、D ホモフェニルアラニン、β−(E)D−Alaから選択され、式中(A)および(A’)は各々、−H、−F、−Cl、−NO2、−CH3、−CF3、−CN、CONH2から独立に選択されるフェニル環置換基であり、(E)は、シクロブチル、シクロペンチル、シクロヘキシル、ピリジル、チエニルおよびチアゾリルから選択される。Xaa2は、(A)(A’)D−Phe、(α−Me)D−Phe、D−1Nal、D−2Nal、D−Tyr、(E)D−Ala、D−Trpから選択され、Xaa3−Xaa4−は、f D−Nle−(B)2D−Arg−、D−Leu−δ−(B)2α−(B’)D−Orn−、(α−Me)D−Leu−δ(B)2−α(B’)D−Orn−から選択され、式中、各(B)は、−HおよびC1〜C4アルキルから独立に選択され、(B’)は、−Hまたは(α−Me)である。上記の式のWは、以下の3とおりの選択肢のうちの1つから選択される。
(i)空(Wが空であり、YはNである)であるか、
(ii)bが0、1、2、3、4、5または6である−N−(CH2)bであるか、
(iii)cが2または3である−N−(CH2)c−O−(ただし、Yは炭素原子である)である。
で表され、式中、Xaa1は、(A)(A’)D−Phe、(α−Me)D−Phe、D−Tyr、D−Tic、(E)D−Alaから選択され、式中、AおよびA’は各々、−H、−F、−Cl、−NO2、−CH3、−CF3、−CN、−CONH2から独立に選択されるフェニル環置換基であり、式中、Eは、シクロペンチル、ピリジル、チエニルおよびチアゾリルからなる群から選択される。Xaa2は、(A)(A’)D−Phe、(α−Me)D−Phe、D−1Nal、D−2Nal、D−Tyr、(E)D−Ala、D−Trpから選択される。Xaa3は、D−Nle、D−Phe、シクロペンチル−D−Ala、D−Leu、(α−Me)D−Leu、D−Hle、D−Val、D−Metから選択される。Xaa4は、(B)2D−Arg、(B)2D−nArg、(B)2D−Har、ζ−(B)D−Hlys、D−Dap、ε−(B)D−Lys、ε−(B)2−D−Lys、D−Amf、アミジノ−D−Amf、γ−(B)2D−Dbu、δ−(B)2α−(B’)D−Orn、D−2−アミノ−3(4−ピペリジル)プロピオン酸、D−2−アミノ−3(2−アミノピロリジル)プロピオン酸、D−α−アミノ−β−アミジノプロピオン酸、(R)−α−アミノ−4−ピペリジン酢酸、cis−α,4−ジアミノシクロヘキサン酢酸、trans−α,4−ジアミノシクロヘキサン酢酸、cis−α−アミノ−4−メチルアミノシクロヘキサン酢酸、trans−α−アミノ−4−メチルアミノ−シクロヘキサン酢酸、α−アミノ−1−アミジノ−4−ピペリジン酢酸、cis−α−アミノ−4−グアニジノシクロヘキサン酢酸、trans−α−アミノ−4−グアニジノシクロヘキサン酢酸から選択され、式中、各(B)は、HおよびC1〜C4アルキルからなる群から独立に選択され、(B’)は、Hまたは(α−Me)である。部分Wは、以下の3とおりの選択肢のうちの1つから選択される。(i)空;(ii)bが0、1、2、3、4、5または6に等しい−N−(CH2)bおよび
(iii)cが2または3である−N−(CH2)c−O−(ただし、Yは炭素原子である)。
は、置換されていてもよい6〜8員環の飽和複素環部分であり、式中、YおよびZ以外の環原子がヘテロ原子ではなく、YおよびZは少なくとも2個の炭素環原子で隔てられ、YはCまたはNであり、ZはS、OまたはNである。
で表される。
の合成ペプチドアミドを提供するものであり、式中、Gは、
であり、式中、qは0または1であり、rは0または1であり、sは0または1であり、pおよびtは各々独立に、0または1であり、ただし、q、r、s、tのうちの少なくとも1つが1であり、Lは、ε−D−Lys、ε−Lys、δ−D−Orn、δ−Orn、γ−アミノ酪酸、8−アミノ−オクタン酸、11−アミノ−ウンデカン酸、8−アミノ−3,6−ジオキサオクタン酸、4−アミノ−4−カルボン酸ピペリジン、(D−Lys−Glyラクタム)2から選択されるリンカーである。
で表される合成ペプチドアミドを提供するものであり、式中、Gは、
であり、
式中、Jは、1、2または3個のヘテロ原子を環に含む、5員環、6員環または7員環の複素環部分であり、式中、R3およびR4は各々独立に、C1〜C3アルキル、ハロ、−OH、−CF3、−NH2、−COOH、アミジノから選択され、R5およびR6は各々独立に、C1〜C3アルキル、オキソ、ハロ、−OH、−CF3、−NH2、−COOH、アミジノから選択される。
の合成ペプチドアミドを提供するものであり、式中、Gは、
であり、Wは空であり、YはNであり、ZはCである。一態様では、Y・Z含有環部分は、単一の環ヘテロ原子を含む6員環の飽和環である。
であり、YおよびZはともにNであり、Y・Z含有環部分の唯一の環ヘテロ原子である。別の実施形態では、eが0であり、置換基R1およびR2が、Y・Z含有環部分の0個、1個または2個の環原子と一緒になって、単環式または二環式の4〜9員環の複素環部分を構成する。本実施形態の一態様では、R1およびR2が、Y・Z含有環部分の1個の環原子と一緒になって、4員環から8員環の複素環部分を構成し、これによってY・Z含有環部分がスピロ構造を形成し、Wは空である。
であり、eが0であり、R1およびR2が直接に同一の環原子に結合される。あるいは、別の実施形態では、R1が、H、OH、−NH2、−COOH、−CH2COOH、C1〜C3アルキル、アミジノ、C1〜C3アルキル置換アミジノ、ジヒドロイミダゾール、D−Pro、D−ProアミドまたはCONH2であり、式中、R2が、H、−COOHまたはC1〜C3アルキルである。
から選択される。
であり、ジペプチドXaa3−Xaa4が、D−Leu−D−OrnおよびD−Nle−D−Argから選択される。別の実施形態では、Xaa1−Xaa2がD−Phe−D−Pheである。別の実施形態では、Xaa1がD−(4−F)Pheであり、Xaa2がD−(4−Cl)Pheである。
であり、Xaa1が、D−Phe、D−(4−F)Phe、D−(2−F)Phe、シクロペンチルD−Ala、2−チエニルD−Alaから選択され、Xaa2が、D−(4−F)Phe、D−(4−Cl)Phe、D−1Nal、D−2Nal、D−Trpから選択され、Xaa3−Xaa4が、D−Nle−D−ArgおよびD−Leu−D−Ornから選択される。
であり、Wが空である。
であり、Wが−N−(CH2)b(bは、0、1、2、3または4と等しい)である。一態様では、bが0であり、Yが炭素原子である。別の態様では、bが1または2であり、Yが窒素原子である。別の実施形態では、Wが−N−(CH2)c−O−である。一態様では、cが1または2である。別の態様では、Y・Z含有環部分が4員環または5員環であり、Yが窒素原子である。別の実施形態では、Y・Z含有環部分が4員環または5員環であり、Yが炭素原子である。
であり、Xaa1がD−Pheであり、Xaa2がD−Pheであり、Xaa3がD−Leuであり、Xaa4がδ−(B)2D−Ornであり、式中、(B)は、−H、メチルまたはイソプロピルであり、さらに式中、Wは空であり、Y・Z含有環部分は6員環または7員環であり、Yは窒素原子であり、eは0であり、R1は、−NH2、アミジノ、C1〜C3アルキル、C1〜C3アルキル置換アミジノ、ジヒドロイミダゾール、D−ProまたはD−Proアミドであり、R2はHまたは−COOHである。
の実施形態(式中、Gが
であり、q、r、sのうちの1つまたは複数が1であるか、pとtの両方が1である)では、Xaa1、Xaa2、Xaa3およびXaa4がそれぞれ2か所含まれる。このような実施形態では、残基Xaa1、Xaa2、Xaa3およびXaa4各々の各例が同一であってもよい。よって、どちらのXaa1も、たとえばD−フェニルアラニンなど同一であってもよい。同様に、Xaa2、Xaa3およびXaa4の各例が同一であってもよい。このため、たとえば、各Xaa2がD−(4−F)フェニルアラニンであってもよく、各Xaa3がD−ロイシンであってもよく、各Xaa2がD−アルギニンであってもよい。
で表され、式中、Gは、
であり、bは0であり、Yは炭素原子である。別の実施形態では、bが1または2であり、Yが窒素原子である。本発明の特定の態様では、bが2である。
であり、Y・Z含有部分が[ω(4−アミノピペリジン−4−カルボン酸)]−OHである。
化合物(1):D−Phe−D−Phe−D−Leu−D−Orn−[4−(2−アミノエチル)−1−カルボキシメチル−ピペラジン]−OH(配列番号1):
アミノ酸誘導体とレジンとを事業者(Novabiochem, Bachem, Peptide InternationalおよびPepTech Corporation)から購入した。他の化学薬品と溶媒は、Sigma-Aldrich, Fisher ScientificおよびVWRから購入した。本明細書の化合物については、Fmoc法とBoc法の両方を利用して、固相ペプチド化学分野の標準的な方法で合成した。特に明記しないかぎり、反応はいずれも室温にて実施した。
ACN:アセトニトリル
Aloc:アリルオキシカルボニル
Boc:tert−ブトキシカルボニル
BOP:ベンゾトリアゾール−1−イル−オキシ−トリス(ジメチルアミノ)−ホスホニウムヘキサフルオロホスフェート
Cbz:ベンジルオキシカルボニル。
Cbz−OSu:Nα−(ベンジルオキシカルボニルオキシ)スクシンイミド
DBU:1,8−ジアザビシクロ[5.4.0]ウンデセン−7
DCM:ジクロロメタン
Dde:1−(4,4−ジメチル−2,6−ジオキソシクロヘキサ−1−イリデン)エチル
DIC:N,N’−ジイソプロピルカルボジイミド
DIEA:N,N−ジイソプロピルエチルアミン
DMF:N,N−ジメチルホルムアミド
Fmoc:9−フルオレニルメトキシカルボニル
HATU:2−(1H−9−アザベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルアミニウムヘキサフルオロホスフェート
HBTU:2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルアミニウムヘキサフルオロホスフェート
HOBt:1−ヒドロキシベンゾトリアゾール
HPLC:高速液体クロマトグラフィ
i:イソ
ivDde:1−(4,4−ジメチル−2,6−ジオキソシクロヘキサ−1−イリデン)−3−メチルブチル
NMM:4−メチルモルホリノ
NMP:N−メチルピロリジノン
All:アリル
o−NBS−Cl:o−ニトロベンゼンスルホニルクロリド
Pbf:2,2,4,6,7−ペンタメチルジヒドロ−ベンゾフラン−5−スルホニル
PyBOP:ベンゾトリアゾール−1−イルオキシ−トリス−ピロリジノ−ホスホニウムヘキサフルオロホスフェート
RP:逆相
TBTU:2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムテトラフルオロボーレート
TEAP:リン酸トリエチルアンモニウム
TFA:トリフルオロ酢酸
TIS:トリイソプロピルシラン
TMOF:オルトギ酸トリメチル
TMSOTf:トリフルオロメタンスルホン酸トリメチルシリル
Trt:トリチル
化合物(1)の合成に用いられる一般的なスキームについては、図1を参照のこと。アミノ酸誘導体には、Boc−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Leu−OH、Fmoc−D−Orn(Boc)−OHおよびFmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドを使用した。SYMPHONY Multiple Synthesizer (Protein Technology Inc.)で、2−クロロトリチルクロライドレジン(0.4mmol;Novabiochem)から開始して、完全保護レジン結合ペプチドを合成した。DIEA(0.35mL、2mmol)およびFmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライド(0.24g、0.5mmol;Chem-Impex International Inc.)のDMF(7ml)混合溶液で室温にて4時間処理して、第1のアミノ酸をレジンに結合した。このレジンを3×DCM/MeOH/DIEA(v/v/v=17:2:1)で洗浄し、さらに3×DCMで洗浄した。続いて、3倍過剰のアミノ酸誘導体を用いるHBTU/DIEAでのシングルカップリングによって、ペプチド鎖を伸長させた。25%ピペリジン/DMF溶液でFmoc基を除去した。切断のために、最終的なペプチドレジンをTFA/TIS/H2O(15ml、v/v/v=95:2.5:2.5)混合物で室温にて90分間処理した。レジンを濾過し、TFAで洗浄した。濾液をin vacuoにて蒸発させ、粗ペプチド(0.2g、D−Phe−D−Phe−D−Leu−D−Orn−[4−(2−アミノエチル)−1−カルボキシメチル−ピペラジン]−OH)(配列番号1)をジエチルエーテルで沈殿させた。
D−Phe−D−Phe−D−Leu−D−Orn−[4−カルボキシメチル−ピペリジン]−OH(配列番号1)。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、Fmoc−4−カルボキシメチル−ピペリジン(Chem-Impex International Inc.)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.4mmolで収率123mg。HPLC分析:tR=15.36分間、純度100%、20分かけて15%Bから35%Bまでの勾配;MS(M+H+):予測分子イオン質量665.4、実測値665.3。
D−Phe−D−Phe−D−Nle−D−Arg−D−Pro−OH(配列番号2):
化合物(1)の合成で説明した手法で、化合物を調製した。アミノ酸誘導体には、Boc−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Nle−OH、Fmoc−D−Arg(Pbf)−OH、Fmoc−D−Pro−OHを使用した。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率140mg。HPLC分析:tR=20.23分間、純度99.7%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量679.4、実測値679.5。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えてFmoc−(2S,4R)−4−アミノ−1−Boc−ピロリジン−2−カルボン酸(Chem-Impex International Inc.)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率294mg。HPLC分析:tR=16.65分間、純度99.4%、20分かけて5%Bから25%Bまでの勾配;MS(M+H+):予測分子イオン質量652.4、実測値652.4。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、Fmoc−(2S,4S)−4−アミノ−1−Boc−ピロリジン−2−カルボン酸(Chem-Impex International Inc.)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率285mg。HPLC分析:tR=17.42分間、純度99.5%、20分かけて5%Bから25%Bまでの勾配;MS(M+H+):予測分子イオン質量652.4、実測値652.4。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、N−Boc−アミノ−(4−N−Fmoc−ピペリジニル)カルボン酸(PharmaCore)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率343mg。HPLC分析:tR=16.82分間、純度99.7%、20分かけて5%Bから25%Bまでの勾配;MS(M+H+):予測分子イオン質量664.4、実測値664.3。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、2−N−Boc−アミノ−3−(N−Fmoc−4−ピペリジル)プロピオン酸(PharmaCore)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率343mg。HPLC分析:tR=16.82分間、純度99.7%、20分かけて5%Bから25%Bまでの勾配;MS(M+H+):予測分子イオン質量664.4、実測値664.3。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、N1−Boc−N4−Fmoc−ピペラジン−2−カルボン酸(Chem-Impex International Inc.)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率200mg。HPLC分析:tR=17.78分間、純度99.9%、20分かけて5%Bから25%Bまでの勾配;MS(M+H+):予測分子イオン質量652.4、実測値652.4。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、Fmoc−イソニペコチン酸(NeoMPS)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.4mmolで収率125mg。HPLC分析:tR=18.74分間、純度99.3%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量651.4、実測値651.3。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、N−(1−Fmoc−ピペリジン−4−イル)−L−プロリン(NeoMPS)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.4mmolで収率18mg。HPLC分析:tR=14.59分間、純度100%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量720.4、実測値720.3。
化合物(19)の合成時に調製した、ペプチド中間体であるCbz−D−Phe−D−Phe−D−Leu−D−Orn(Cbz)−[ホモピペラジンアミド]0.3mmolから合成を開始した。このペプチドを、TMSOTf/TFA/m−クレゾール混合物(10ml、v/v/v=2:7:1)で加水分解し、化合物(19)の合成で説明した手法を用いて、分取HPLCで粗生成物を精製した。最終精製ペプチド:非晶質粉末、収率225mg。HPLC分析:tR=16.43分間、純度100%、20分かけて2%Bから22%Bまでの勾配;MS(M+H+):予測分子イオン質量622.4、実測値622.4。
化合物(1)の合成で説明した手法で、化合物を調製した。違いは、2−Cl−Trtレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、4−(1−Fmoc−ピペリジン−4−イル)−ブタン酸(NeoMPS)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.4mmolで収率474mg。HPLC分析:tR=17.91分間、純度100%、20分かけて15%Bから35%Bまでの勾配;MS(M+H+):予測分子イオン質量693.4、実測値693.3。
図2に示すようにして合成を実施した。アミノ酸誘導体には、Boc−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Leu−OH、Fmoc−D−Orn(Boc)−OH、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドを使用した。SYMPHONY Multiple Synthesizer (Protein Technology Inc.)で、Rink Amide AMレジン(0.3mmol;Novabiochem)から開始して、完全保護レジン結合ペプチドを合成した。Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライド(0.48g、1mmol;Chem-Impex International Inc.)と、HBTU(0.38g、1mmol)と、DIEA(0.53mL、3mmol)とのDMF(7ml)混合溶液で室温にて3時間処理して、第1のアミノ酸をレジンに結合した。レジンを3×DMFで洗浄した。
化合物(13)の合成で説明した手法で、化合物を調製した。違いは、Rink Amide AMレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、N−(1−Fmoc−ピペリジン−4−イル)−L−プロリン(NeoMPS)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率14mg。HPLC分析:tR=18.13分間、純度91.7%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量719.5、実測値719.3。
化合物(13)の合成で説明した手法で、化合物を調製した。違いは、Rink Amide AMレジンへの結合時に、Fmoc−4−(2−アミノエチル)−1−カルボキシメチル−ピペラジンジヒドロクロライドに代えて、Fmoc−4−アミノ−1−カルボキシメチル−ピペリジン(NeoMPS)を用いたことである。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率65mg。HPLC分析:tR=16.74分間、純度99.7%、20分かけて2%Bから22%Bまでの勾配;MS(M+H+):予測分子イオン質量679.4、実測値679.3。
化合物(19)の合成時に調製した、ペプチド中間体であるCbz−D−Phe−D−Phe−D−Leu−D−Orn(Cbz)−[ホモピペラジンアミド]0.2mmolから合成を開始した。C末端でのホモピペラジンのグアニル化のために、1H−ピラゾール−1−カルボキサミジン塩酸塩(0.4g、3.0mmol)およびDIEA(0.5ml、6mmol)のDMF(3ml)溶液で室温にて一晩、ペプチドを処理した。酢酸とH2Oを加えて反応を停止させ、この溶液を冷凍し、凍結乾燥機で乾燥させて、所望の保護ペプチドであるCbz−DPhe−DPhe−DLeu−DOrn(Cbz)−[4−アミジノホモピペラジンアミド](0.2mmol)を得た。続いて、化合物(19)の合成で説明した手法を用いて、脱保護/加水分解とHPLC精製を実施した。最終精製ペプチド:非晶質粉末、収率74mg。HPLC分析:tR=10.10分間、純度98.7%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量664.4、実測値664.5。
化合物(19)の合成時に調製した、ペプチド中間体であるCbz−D−Phe−D−Phe−D−Leu−D−Orn(Cbz)−[ホモピペラジンアミド]0.2mmolから合成を開始した。C末端でのホモピペラジンのグアニル化のために、2−メチルチオ−2−イミダゾリンヨウ化水素酸塩(730mg、3.0mmol;Aldrich)およびDIEA(0.5ml、6mmol)のDMF(3ml)溶液で室温にて4日間、ペプチドを処理した。酢酸とH2Oを加えて反応を停止させ、この溶液を冷凍し、凍結乾燥機で乾燥させて、所望の保護ペプチドであるCbz−D−Phe−D−Phe−D−Leu−D−Orn(Cbz)−[4−(4,5−ジヒドロ−1H−イミダゾール−2−イル)ホモピペラジンアミド](0.2mmol)を得た。続いて、化合物(19)の合成で説明した手法を用いて、脱保護/加水分解とHPLC精製を実施した。最終精製ペプチド:非晶質粉末、収率46mg。HPLC分析:tR=10.89分間、純度100%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量690.4、実測値690.5。
化合物(19)の合成時に調製した、ペプチド中間体であるCbz−D−Phe−D−Phe−D−Leu−D−Orn(Cbz)−[ホモピペラジンアミド]0.3mmolから合成を開始した。C末端でのホモピペラジンのエチル化のために、ヨードエタン(0.4mmol;Aldrich)およびDIEA(0.5ml、6mmol)のDMF(3ml)溶液で室温にて1日間、ペプチドを処理した。続いて、化合物(19)の合成で説明した手法を用いて、脱保護/加水分解とHPLC精製を実施した。最終精製ペプチド:非晶質粉末、収率75mg。HPLC分析:tR=10.43分間、純度98.4%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量650.4、実測値650.3。
化合物(19)の調製に用いられる一般的な合成スキームについては、図3を参照のこと。後述する手法を用いて合成したCbz−D−Phe−D−Phe−D−Leu−D−Orn(Cbz)−[ホモピペラジンアミド]のC末端でホモピペラジンをグアニル化することで、化合物を調製した。
D−Phe−D−Phe−D−Leu−(δ−iPr)D−Orn−[ω(4−アミノピペリジン−4−カルボン酸)]−OH
アミノ酸誘導体には、Boc−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Leu−OH、Fmoc−D−Orn(Aloc)−OH、N−Boc−アミノ−(4−N−Fmoc−ピペリジニル)カルボン酸を使用した。2−クロロトリチルクロライドレジン(0.8mmol)から開始して、完全保護レジン結合ペプチドを手作業で合成した。レジンへのN−Boc−アミノ−(4−N−Fmoc−ピペリジニル)カルボン酸の結合と、これに続くカップリングについては、化合物(1)の合成で説明した手法を用いて実施した。アセンブル後のペプチドレジンであるBoc−D−Phe−D−Phe−D−Leu−D−Orn−ω(4−アミノピペリジン−4−カルボン酸)−[2−Cl−Trtレジン]を、CHCl3/AcOH/NMM(80ml、v/v/v=37:2:1)混合物中、アルゴン雰囲気下で室温にて3時間Pd(PPh3)4(4.5mmol;Aldrich)で処理し、Alocを除去した。続いて、化合物(22)の合成で説明する手法を用いて、N−イソプロピル化を実施した。最終的な切断と分取HPLCによる精製については、化合物(1)の合成で説明した手法を用いておこなった。最終精製ペプチド:非晶質粉末、収率336mg。HPLC分析:tR=18.88分間、純度98.9%、20分かけて5%Bから25%Bまでの勾配;MS(M+H+):予測分子イオン質量708.4、実測値708.4。
図3に示すスキームを参照のこと。アミノ酸誘導体には、Z−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Leu−OH、Fmoc−D−Orn(Aloc)−OHを使用した。p−ニトロフェニルカーボネートWangレジン(5.0g、4.4mmol;Novabiochem)から開始して、完全保護レジン結合ペプチドを手作業で合成した。これをホモピペラジン(8.7g、87mmol;Acros Organics)のDCM(100mL)溶液と室温にて一晩混合することで、ホモピペラジンをレジンに結合した。レジンをDMFおよびDCMで洗浄し、in vacuoにて乾燥させた。得られたホモピペラジンカルバメートWangレジン(5.1g;ホモピペラジン−[カルバメートWangレジン])をいくつかに分け、このうち1.1g(1mmol)を用いてペプチド合成を継続した。3倍過剰のアミノ酸誘導体を用いて、DIC/HOBtによるシングルカップリングを実施した。25%ピペリジン/DMF溶液でFmoc基を除去した。ペプチド鎖伸長の完了時、CHCl3/AcOH/NMM(60ml、v/v/v=37:2:1)混合物中、アルゴン雰囲気下で室温にて3時間レジンをPd(PPh3)4(3.5g、3.0mmol;Aldrich)で処理し、Alocを除去した。レジンをDMFおよびDCMで洗浄し、in vacuoにて乾燥させた。得られたペプチドレジン(1.8g;Z−D−Phe−D−Phe−D−Leu−D−Orn−ホモピペラジン−[カルバメートWangレジン])を再度分けて、0.9g(0.5mmol)を以後の誘導体化(N−メチル化)に利用した。
上述した化合物(21)の合成時に調製した、ペプチド−レジン:Z−D−Phe−D−Phe−D−Leu−D−Orn−ホモピペラジン−[カルバメートWangレジン]0.9g(0.5mmol)から合成を開始した。
化合物(21)の合成時に調製した、ペプチド中間体であるZ−D−Phe−D−Phe−D−Leu−D−Orn(Me,Z)−[ホモピペラジンアミド]0.2mmolから合成を開始した。このペプチドを、TMSOTf/TFA/m−クレゾール混合物(10ml、v/v/v=2:7:1)で加水分解し、化合物(19)の合成で説明した手法を用いて、分取HPLCで粗生成物を精製した。最終精製ペプチド:非晶質粉末、収率98mg。HPLC分析:tR=16.38分間、純度99.6%、20分かけて2%Bから22%Bまでの勾配;MS(M+H+):予測分子イオン質量636.4、実測値636.5。
化合物(22)の合成時に調製した、ペプチド中間体であるZ−D−Phe−D−Phe−D−Leu−D−Orn(iPr,Z)−[ホモピペラジンアミド]0.2mmolから合成を開始した。このペプチドを、TMSOTf/TFA/m−クレゾール混合物(10ml、v/v/v=2:7:1)で加水分解し、化合物(19)の合成で説明した手法を用いて、分取HPLCで粗生成物を精製した。最終精製ペプチド:非晶質粉末、収率87mg。HPLC分析:tR=18.41分間、純度100%、20分かけて2%Bから22%Bまでの勾配;MS(M+H+):予測分子イオン質量664.5、実測値664.5。
表Iに、各化合物の分子イオンの計算で求めた分子量MH+と、質量分析で測定した実際の分子量を示す。また、各化合物の合成で用いた合成相のタイプ(固相または混合)と、合成で用いたレジンのタイプ(2−クロロトリチル「2−Cl−Trt」レジン、ヒドラジノベンゾイル「ヒドラジン」レジン、Rink AMまたはp−ニトロフェニル−カーボネート(Wang)「カーボネート」レジンのいずれか)も示す。各化合物を合成するための関連の合成スキームを示す図を一番右の欄に示す。
これらの合成については、図4に示すスキームを用いて実施した。後述する中間体が、図4に示す中間体に相当する。Boc−D−Phe−OH中間体I−1(7.96g、30.0mmol)、D−Leu−OBn p−TsOH中間体I−2(11.80g、30.0mmol)、HOBt一水和物(4.46g、33.0mmol)およびDIEA(8.53g、66.0mmol)の無水THF(250mL)懸濁液を氷水浴で冷却した中に、EDCI(6.33g、33.0mmol)を4回に分けて5分間隔で20分かけて添加した。この懸濁液を開始温度である0℃から室温まで一晩攪拌した。THFを蒸発させた後、残渣を酢酸エチルに溶解させ、10%クエン酸、飽和NaHCO3、水で順次洗浄した。有機相を硫酸ナトリウム上で乾燥させ、減圧下にて蒸発させた。残渣をDCMに溶解させ、シリカゲルプラグに通し、20%酢酸エチル/ヘキサンで溶出した。溶離液を蒸発させ、純粋な生成物であるBoc−D−Phe−D−Leu−OBnすなわち中間体I−3(12.40g、88%)を、透明な油として得た。LC−MS:m/z=469(M+H)。
アミドカップリングステップで2−(ピペラジン−1−イル)ピリミジンを用いたこと以外、基本的には実施例25で説明したようにして、化合物(26)を調製した。LC−MS:m/z=700(M+H)。
アミドカップリングステップで2−(ピペラジン−1−イル)ピラジンを用いたこと以外、基本的には実施例25で説明したようにして、化合物27を調製した。LC−MS:m/z=700(M+H)。
アミドカップリングステップで1−(ピリジン−2−イル)ピペラジンを用いたこと以外、基本的には実施例25で説明したようにして、化合物(28)を調製した。LC−MS:m/z=699(M+H)。
アミドカップリングステップで2−(ピペラジン−1−イル)チアゾールを用いたこと以外、基本的には実施例25で説明したようにして、化合物29を調製した。LC−MS:m/z=705(M+H)。
アミドカップリングステップでN,N−ジメチル−ピペラジン−1−スルホンアミドを用いたこと以外、基本的には実施例25で説明したようにして、化合物30を調製した。LC−MS:m/z=729(M+H)。
アミドカップリングステップで1−(メチルスルホニル)ピペラジンを用いたこと以外、基本的には実施例25で説明したようにして、化合物31を調製した。LC−MS:m/z=700(M+H)。
アミドカップリングステップで1−(フェニルスルホニル)ピペラジンを用いたこと以外、基本的には実施例25で説明したようにして、化合物32を調製した。LC−MS:m/z=762(M+H)。
アミドカップリングステップでフェニル(ピペラジン−1−イル)メタノンを用いたこと以外、基本的には実施例25で説明したようにして、化合物33を調製した。LC−MS:m/z=726(M+H)。
アミドカップリングステップでチオールモルホリン−1,1−ジオキシドを用いたこと以外、基本的には実施例25で説明したようにして、化合物34を調製した。LC−MS:m/z=671(M+H)。
アミドカップリングステップで6−トリフルオロメチル−3−アミノメチルピリジンを用いたこと以外、基本的には実施例25で説明したようにして、化合物35を調製した。LC−MS:m/z=712(M+H)。
アミドカップリングステップで(テトラヒドロ−2H−ピラン−4−イル)メタナミンを用いたこと以外、基本的には実施例25で説明したようにして、化合物36を調製した。LC−MS:m/z=651(M+H)。
アミドカップリングステップで5−(アミノメチル)−1H−ベンゾ[d]イミダゾール−2(3H)−オンを用いたこと以外、基本的には実施例25で説明したようにして、化合物(37)を調製した。LC−MS:m/z=699(M+H)。
アミドカップリングステップで(5−メチル−ピラジン−2−イル)−メタナミンを用いたこと以外、基本的には実施例25で説明したようにして、化合物38を調製した。LC−MS:m/z=659(M+H)。
化合物(40)の合成については、図5の一般的なスキームを参照のこと。アミノ酸誘導体には、Boc−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Leu−OH、Boc−D−Leu−OH、Fmoc−D−Orn(Boc)−OH、Fmoc−Lys(Dde)−OHを使用した。2−クロロトリチルクロライドレジン(0.3mmol;Peptide International)から開始して、完全保護レジン結合ペプチドを手作業で合成した。Fmoc−Lys(Dde)−OH(0.29g、0.5mmol;Novabiochem)およびDIEA(0.35mL、2mmol)のDCM(7ml)混合溶液で室温にて4時間処理して、第1のアミノ酸をレジンに結合した。このレジンを3×DCM/MeOH/DIEA(v/v/v=17:2:1)で洗浄した後、25%ピペリジン/DMF溶液で処理してFmocを除去した。続いて、3倍過剰のアミノ酸誘導体、Fmoc−D−Orn(Boc)−OHおよびBoc−D−Leu−OHを用いるPyBOP/DIEAでのシングルカップリングによって、ペプチド鎖を伸長させた。得られたペプチドレジン、Boc−D−Leu−D−Orn(Boc)−Lys(Dde)−[2−Cl−Trtレジン]を4%ヒドラジン/DMF溶液で3分間ずつ3回処理し、Ddeを除去した。続いて、3倍過剰のアミノ酸誘導体、Fmoc−D−Orn(Boc)−OH、Fmoc−D−Leu−OH、Fmoc−D−Phe−OHおよびBoc−D−Phe−OHを用いるPyBOP/DIEAでのシングルカップリングによって、ペプチド鎖を伸長させた。25%ピペリジン/DMF溶液でFmoc基を除去した。完全にアセンブルされたペプチドを、TFA/TIS/H2O(15ml、v/v/v=95:2.5:2.5)混合物で室温にて90分間処理してレジンから切断した。このレジンを濾過し、TFAで洗浄した。濾液をin vacuoにて蒸発させ、粗ペプチド(0.3mmol;D−Phe−D−Phe−D−Leu−D−Orn−[eLys(D−Orn−D−Leu−H)]−OH)をジエチルエーテルで沈殿させた。
上記化合物(39)の合成で説明した手法で、化合物を調製した。違いは、ペプチドレジン中間体Boc−D−Phe−D−Leu−D−Orn(Boc)−Lys(Dde)−[2−Cl−Trtレジン]における別のアミノ酸残渣D−Pheであり、Fmoc−Lys(Dde)−OHを2−クロロトリチルクロライドレジンに結合した上でFmocを除去し、アミノ酸誘導体Fmoc−D−Orn(Boc)−OH、Fmoc−D−Leu−OH、Boc−D−Phe−OHのカップリングを行ってレジン中間体を調製した。最終精製ペプチド:非晶質粉末、合成スケール0.3mmolで収率508mg。HPLC分析:tR=18.90分間、純度100%、20分かけて10%Bから30%Bまでの勾配;MS(M+H+):予測分子イオン質量1042.4、実測値1042.7。
化合物(41):
化合物(42):
化合物(43):
化合物(44):
化合物(45):
化合物(46):
化合物(47):
化合物(48):
化合物(49):1N,4N−ビス−[D−Phe−D−Phe−D−Leu−(iPr)D−Orn]−4−アミノ−4−カルボン酸−ピペリジン
化合物(50):1N,4N−ビス−[D−Phe−D−Phe−D−Leu−D−Dap(アミジノ)]−4−アミノ−4−カルボン酸ピペリジン
化合物(51):1N,4N−ビス−(D−Phe−D−Phe−D−Leu−D−Nar)−4−アミノ−4−カルボン酸ピペリジン
化合物(52):
図8のスキームを参照のこと。アミノ酸誘導体には、Boc−D−Phe−OH、Fmoc−D−Phe−OH、Fmoc−D−Leu−OH、Fmoc−D−Orn(Boc)−OH、(R,S)−Fmoc−2−カルボキシモルホリンを使用した。SYMPHONY Multiple Synthesizer(Protein Technology Inc.)で、2−クロロトリチルクロライドレジン(0.4mmol;Novabiochem)から開始して、完全保護レジン結合ペプチドを合成した。(R,S)−Fmoc−2−カルボキシモルホリン(0.18g、0.5mmol;NeoMPS)およびDIEA(0.35mL、2mmol)のDCM(7ml)混合溶液で室温にて4時間処理して、第1のアミノ酸をレジンに結合した。このレジンを3×DCM/MeOH/DIEA(v/v/v=17:2:1)で洗浄し、さらに3×DCMで洗浄した。続いて、3倍過剰のアミノ酸誘導体を用いるHBTU/DIEAでのシングルカップリングによって、ペプチド鎖を伸長させた。25%ピペリジン/DMF溶液でFmoc基を除去した。切断のために、最終的なペプチドレジンをTFA/TIS/H2O(15ml、v/v/v=95:2.5:2.5)混合物で室温にて90分間処理した。レジンを濾過し、TFAで洗浄した。濾液をin vacuoにて蒸発させ、粗ペプチド(0.15g、DPhe−DPhe−DLeu−DOrn−[R/S−2−カルボキシモルホリン]−OH)をジエチルエーテルで沈殿させた。
化合物(53):D−Phe−D−Phe−D−Leu−D−Orn−[R/S−2−カルボキシモルホリン]−OH(配列番号1):
化合物(54)〜(66)を周知の合成方法で調製することが可能である。たとえば、化合物(40)(下記参照)は、図9の化学合成スキームを用いて調製可能なものである。
ホルスコリン刺激アデニル酸シクラーゼ活性の阻害を測定し、合成ペプチドアミドのκ−オピオイド受容体アゴニストとしての力価を求めた。R1.G1細胞(κ−オピオイド受容体のみを発現し、他のオピオイド受容体サブタイプは発現しないマウス胸腺腫細胞系)をまず、ホルスコリン(cAMP誘導用)プラス合成ペプチドアミドに試験濃度で曝露した。インキュベーション後、曝露R1.G1細胞のcAMP濃度を時間分解蛍光共鳴エネルギ移動(TR−FRET)ベースのcAMPイムノアッセイ(LANCE(商標)、Perkin Elmer)で求めた。詳しい方法は、下記のとおりである。
Fugene6 (Roche Molecular Biochemicals)トランスフェクション試薬とDNAコンストラクトとを3.3対1の比で用いて、100mmのシャーレに入れたヒト胎児由来腎臓細胞(HEK−293細胞、ATCC, Manassas, VA)をトランスフェクトした。トランスフェクションには、以下のDNAコンストラクトを使用した。(i)ヒトκオピオイド受容体用の発現ベクター、(ii)ヒトキメラG−タンパク質用の発現ベクター、(iii)カルシウム感受性転写因子NFATによってルシフェラーゼ発現が誘導されるルシフェラーゼレポーターコンストラクト。
培養内で分化するヒト結腸腺癌細胞系に、Caco−2細胞系があり、ヒト小腸の上皮層のモデル化に用いられている。標準アッセイでCaco−2のTC7サブクローンを用いる膜透過アッセイで本発明の化合物を試験することが可能である(Cerep, Seattle, WA)。簡単に説明すると、96ウェルのポリカーボネート膜フィルタで培養した細胞単層膜で頂側膜側から側底膜側へ(A−B)の方向で、見かけの透過係数(Papp)を求めることが可能である。
本発明の合成ペプチドアミド化合物(17)による、シトクロムP450オキシダーゼアイソザイムCYP1A、CYP2C9、CYP2C19、CYP2D6およびCYP3A4の阻害を、Cerep (Seattle, WA)によって実施される以下の方法で判断した。
合成ペプチドアミド化合物を静脈注射でカニクイザル(n=オス4匹、体重3〜5kg、SNBL USA, Ltd., Everett, WA)に単回ボーラス投与し、注射の5分後、10分後、15分後、20分後、30分後、60分後、90分後、120分後、180分後に血漿試料を得た。最大血漿濃度に達した後に血漿濃度が50%落ちるまでに必要な時間として、「半減期」を求めた。カニクイザルには、実施例19で詳しく説明したプロトコールに従って、単回静脈用量の合成ペプチドアミド化合物(19)を注射し、血漿濃度の半減期を求めた。結果を表Vに示す。
この試験では、内臓痛またはpH感受性侵害受容器の活性化に関連する痛みに対して鎮痛活性を呈する化合物を特定する[Barber and Gottschlich (1986) Med. Res. Rev. 12: 525-562;Ramabadran and Bansinath (1986) Pharm. Res. 3: 263-270を参照のこと]。希酢酸溶液を腹腔内投与すると、マウスにライジング挙動が生じる。ライジングとは、前肢の伸びと体の伸びを伴う腹筋の収縮として定義される。被験化合物が存在する場合と存在しない場合とで観察されたライジング数をカウントし、化合物の鎮痛活性を求める。
式中、Wvは溶媒剤処理した群での平均ライジング数であり、Wcは化合物処理したマウスでのライジング数である。2パラメータでのヒルの方程式(別名Emaxモデル)を用いてデータを分析した。ここで、Emaxを100%抗痛覚(すなわち、酢酸投与後15分間ライジングが生じない)と仮定する。
鎮静活性を呈する化合物は、試験チャンバ内のマウスの自然な歩行運動を阻害する。被験化合物の潜在的な鎮静作用を求めるには、被験化合物または溶媒対照の投与後の歩行運動の度合いを判断し、この目的で設計された特別な装置(Opto-Varimex Activity Meter)と比較すればよい。各実験の開始時、各々のマウスの体重を計測し、検査をして健康状態が良好であると判断した。被験化合物の活性および力価を求めるため、データ収集を開始する15分前または180分前に、用量の異なる化合物溶液または溶媒剤を皮下注射した。皮下注射はマウスの頸背部に対して行い、注射針が正しく入るように「テント」形につまんだ。注射後、Opto-Varimex Activity Meter装置内のPlexiglasボックス(43cm×43cm)にマウスを個々に入れた。マウスを装置に入れる前に、SANI-CHIPS齧歯類用床敷をPlexiglasボックスの底に薄く敷き、快適な環境を用意しておいた。続いて、各Opto-Varimex Activity Meter装置の電源を入れ、ATM3 Auto-Track Systemによるデータの取得を開始した。データを処理し、上記のライジングアッセイのデータについて説明したものと同じようにして結果を表した。
酢酸ライジングの阻害は、鎮痛作用(抗侵害受容作用とも呼ばれる)を示す1つの指標である。同様に、歩行運動の減少を、一般的な鎮静作用を示す尺度として利用することができる。IRCマウスでの酢酸ライジングアッセイで求めたED50は、合成ペプチドアミド(17)を皮下送達した場合で74ug/kgであった[95%信頼区間49〜99ug/kg]。歩行運動アッセイの阻害時に求めたED50値は、同一の合成ペプチドアミドを皮下送達した場合で3172ug/kgであった[95%信頼区間1810〜4534ug/kg]。図10を参照のこと。鎮静作用に対する鎮痛作用の治療可能比は、鎮静作用を得るのに必要なED50のほうが鎮痛作用を得るのに必要なED50よりも何倍も高い。よって、化合物(17)は、割合が(3172/74)すなわち、42.86倍になる。よって、化合物(17)の治療可能比は約43倍である。
3〜7歳で体重3〜5キログラムのオスのサルすなわち、Macaca fascicularis (SNBL USA, Ltd., Everett, WA、研究目的で繁殖したカニクイザル。系統発生学的および生理学的の両方で人間の近縁種である)に試料を投与した。試料の投与は、腕または脚の表在静脈(上腕または伏在静脈など)に対して、0.9%注射用生理食塩水USP(Baxter Healthcare, Deerfield, Ill.)にて以下のようにして実施した。本発明の化合物(19)0.4mgと他の9種類の化合物各々0.4mgとを含有(合計用量4mg)するカセット試料を、10種類の化合物各々の濃度が0.2mg/mlになるように0.9%注射用生理食塩水2mlで調製した。厳密に2mlを被験動物に静脈内ボーラス投与し、個々の動物の体重に応じて総用量レベルが0.8〜1.3mg/kgになるようにした。静脈注射に続いて、0.9%注射用生理食塩水を1mlフラッシュした。注射の2分後、5分後、10分後、15分後、30分後、さらには1時間後、2時間後、4時間後に、末梢静脈からの静脈穿刺により血液試料0.6mlを採取した。リチウムヘパリンを入れて事前に冷却しておいたガラス製試験管に試料を入れ、すみやかに氷冷した。2〜8℃にて2,000gで15分間の遠心処理後に血漿を回収した。各試料の血漿層をポリプロピレン管に移し、アッセイを行うまで−60℃以下で冷凍保存した。解凍血漿のアリコート100マイクロリットルを、適切な内部標準(この場合、周知の合成ペプチドアミド化合物)を0.1%TFAに入れた400ng/mlの溶液5マイクロリットルでスパイクし、100マイクロリットルの0.1%TFA/アセトニトリル溶液でタンパク質を沈殿させた。試料を1000×gで5分間遠心処理し、上清をLC−MSで分析した。このLC−MS分析については、Surveyor HPLCシステム(Thermo Electron Corporation, Waltham, Massachusetts, USA)にインタフェースしたFinnigan LCQ Deca質量分析計で実施した。HPLC分析については、2.1×150mmのC18逆相カラムで、0.01%TFA/水溶液での0.01%TFA/アセトニトリル溶液の勾配を用いて実施した。質量検出については、選択反応検出モード(SRM)で実施した。同一の内部標準を用いて、ブランクのカニクイザル血漿分析物の較正曲線に対して定量化を行った。データ解析と薬物動態学的パラメータの抽出は、PK Solution 2.0プログラム(Summit Research Services, Ashland, Ohio, USA)を使って行った。化合物(19):D−Phe−D−Phe−D−Leu−D−Orn−[4−(N−メチル)アミジノ−ホモピペラジンアミド](配列番号1)での結果を図11に示す。
本発明の合成ペプチドアミドで誘導する眼の痛覚消失を、ウサギのin vivo試験で以下のようにして評価することが可能である。5容量の被験化合物を試験濃度で50マイクロリットルずつ生理食塩水に入れたものを、20分以内に未処理のNew Zealand系アルビノウサギの右眼に点眼する。被験化合物を最後に点眼してから15分後、各ウサギの処理眼に10mg/mlカプサイシン(33mM)30マイクロリットルを単回点眼投与する。カプサイシンは、角膜痛を誘導することが知られている。透明定規を利用して、処理眼と未処理眼についてミリメートル単位で測定される眼裂を測定することで、角膜痛を評価する。この動物モデルでは、カプサイシン点眼後の眼裂の大きさの減少が、誘導した痛みの度合いを示す指標となる。よって、被験化合物での処理後に眼裂の大きさの回復が観察された場合は、これをカプサイシンによる眼の痛みが軽減されている尺度とする。
試験対象となる合成ペプチドアミドを何通りかの濃度で未処理のNew Zealand系アルビノウサギの右眼に点眼して誘導した眼の痛覚消失を、上記実施例31で説明したようにして評価する。モルヒネ(非選択的オピオイドアゴニスト)10mg/mlで誘導した痛覚消失ならびに、同一実験にて同一条件下での対照としての10mMのジルチアゼムと、結果を比較する。
Claims (10)
- 式
(式中、
Xaa1は、(A)(A’)D−Phe、(α−Me)D−Phe、D−Tyr、D−Tic、D−ネオペンチルグリシン、D−フェニルグリシン、D−ホモフェニルアラニン、β−(E)D−Alaからなる群から独立に選択され、式中、各(A)および各(A’)は、−H、−F、−Cl、−NO2、−CH3、−CF3、−CN、−CONH2からなる群から独立に選択されるフェニル環置換基であり、式中、各(E)は、シクロブチル、シクロペンチル、シクロヘキシル、ピリジル、チエニルおよびチアゾリルからなる群から独立に選択され、
Xaa2は、(A)(A’)D−Phe、(α−Me)D−Phe、D−1−ナフチルアラニン(D−1Nal)、D−2−ナフチルアラニン(D−2Nal)、D−Tyr、(E)D−Ala、D−Trpからなる群から独立に選択され、
Xaa3は、D−ノルロイシン(D−Nle)、D−Phe、シクロペンチル−D−Ala、D−Leu、(α−Me)D−Leu、D−ホモロイシン(D−Hle)、D−Val、およびD−Metからなる群から独立に選択され、
Xaa4はD−Lysであり、
pは1であり、
Gが、
から成る群から選択される)
で表される合成ペプチドアミドあるいは、その立体異性体、立体異性体混合物、薬学的に許容される塩、水和物、溶媒和物、酸性塩水和物またはN−オキシド。 - 各Xaa2がD−Pheである、請求項1に記載の合成ペプチド。
- 各Xaa3がD−NleおよびD−Leuからなる群から選択される、請求項1に記載の合成ペプチド。
- R1が、H、OH、−NH2、−COOH、C1〜C3アルキル、アミジノ、C1〜C3アルキル置換アミジノ、ジヒドロイミダゾール、D−Pro、D−ProアミドまたはCONH2であり、式中、R2が、H、−COOHまたはC1〜C3アルキルである、請求項1〜3のいずれか1項に記載の合成ペプチドアミド。
- 請求項1〜4のいずれか1項に記載の合成ペプチドアミドと、薬学的に許容される賦形剤または担体とを含む、医薬組成物。
- 哺乳動物のκオピオイド受容体関連疾患または症状を治療または予防のための医薬の製造のための、請求項1〜4のいずれか1項に記載の合成ペプチドの使用。
- κオピオイド受容体関連症状が、痛み、炎症、掻痒症、浮腫、低ナトリウム血症、低カリウム血症、腸閉塞、咳および緑内障からなる群から選択される、請求項6に記載の使用。
- 痛みが、神経因性疼痛、体性痛、内臓痛および皮膚痛からなる群から選択される、請求項7に記載の使用。
- 痛みが、関節痛、腎臓結石痛、子宮痙攣、月経困難症、子宮内膜症、消化不良、術後の痛み、医療処置後の痛み、眼の痛み、耳の痛み、癌の突出痛およびGI機能障害に関連した痛みからなる群から選択される、請求項7に記載の使用。
- 痛みが骨盤腹腔鏡手術、卵管結紮、子宮摘出または胆嚢摘出に起因する、請求項7に記載の使用。
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