JP2016535760A - 炎症性疾患および/または免疫疾患の治療のためのコルチスタチンアナログ - Google Patents
炎症性疾患および/または免疫疾患の治療のためのコルチスタチンアナログ Download PDFInfo
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Abstract
Description
コルチスタチンおよびソマトスタチンの配列
H2N−Pc[CKNFFWKTFSSC]K−OH コルチスタチン−14(ラット/マウス)
H2N−DRMPc[CRNFFWKTFSSC]K−OH コルチスタチン−17(ヒト)
H2N−AGc[CKNFFWKTFTSC]−OH ソマトスタチン−14(ヒト/ラット/マウス)
ここでは、本発明の文脈の中で使用されている、いくつかの用語および表現の意味を、その理解を助ける目的で記載する。
Ala(A):アラニン
Asn(N):アスパラギン
Asp(D):アスパラギン酸
Arg(R):アルギニン
Cys(C):システイン
Gly(g):グリシン
Lys(K):リシン
Met(M):メチオニン
Phe(F):フェニルアラニン
Pro(P):プロリン
Ser(S):セリン
Thr(T):スレオニン
Trp(W):トリプトファン
Phg:フェニルグリシン
本発明の第1の態様は、式(I)で定義される化合物、
(式中、
AA1は、Aspまたは結合であり、
AA2は、Argまたは結合であり、
AA3は、Met、Alaまたは結合であり、
AA4は、ProまたはGlyであり、
AA5は、LysまたはArgであり、
AA6は、SerまたはThrであり、
AA7は、Lysまたは結合であり、
X、Y、Zは、アミノ酸Phe、Phg、Msa、3,4,5−トリメチルフェニルアラニン、Msg、3,4,5−トリメチルフェニルグリシン、および/またはジハロゲノフェニルアラニン(diW−Phe)であり、
Wは、F、Cl、BrおよびIからなる群から選択され、
R1は、H、置換または非置換の非環状脂肪族基、置換または非置換の脂環式基、置換または非置換の複素環基、置換または非置換のヘテロアリールアルキル基、置換または非置換のアリール基、置換または非置換のアラルキル基、ポリエチレングリコールから誘導されるポリマー、キレート剤およびR5−CO−からなる群から選択され、
R2は、−NR3R4、−OR3および−SR3からなる群から選択され、
R3およびR4は、独立に、H、置換または非置換の非環状脂肪族基、置換または非置換の脂環式基、置換または非置換の複素環基、置換または非置換のヘテロアリールアルキル基、置換または非置換のアリール基、置換または非置換のアラルキル基、およびポリマーからなる群から選択され、
R5は、H、置換または非置換の非環状脂肪族基、置換または非置換の脂環式基、置換または非置換のヘテロアリールアルキル基、置換または非置換のアリール基、置換または非置換のアラルキル基、置換または非置換の複素環基、および置換または非置換のヘテロアリールアルキル基からなる群から選択され、
但し、
−アミノ酸X、YまたはZの少なくとも1つは、Msa、3,4,5−トリメチルフェニルアラニン、Msg、3,4,5−トリメチルフェニルグリシン、および/またはジハロゲノフェニルアラニン(diW−Phe)であり、
−AA1およびAA2が結合で、AA3がAlaで、AA4がGlyで、AA5がLysで、AA6がThrで、かつAA7が結合であるとき、アミノ酸X、YまたはZの少なくとも1つは、ジハロゲノフェニルアラニン(diW−Phe)である
という条件を有する)
である。
本発明の化合物、その立体異性体、または薬学的に許容されるその塩の合成は、この分野の技術水準で知られる従来方法により実施することができる。
1.固相合成
2.ペプチドのポリマー担体からの切出し
3.溶液中でのペプチドの環化
4.保護基の脱離
または
1.固相合成
2.固相環化
3.ペプチドのポリマー担体からの切出し、および好ましくはトリフルオロ酢酸での処理による、保護基の同時脱離
本発明の化合物は、その化合物と、哺乳動物の体、好ましくはヒトの体の作用部位とを接触させることができる任意の方法で、またそれらの化合物を含む組成物の形態で、投与することができる。
他の態様に関し、本発明は、薬剤に使用するための、一般式(I)の化合物、その立体異性体、それらの混合物、および/または薬学的に許容される塩である。
本明細書において使用される略語は以下の意味を有する。
Ac2O、無水酢酸;AcOH、酢酸;Adpoc、1−(1−アダマンチル)−1−メチルエトキシ−カルボニル基;All、アリル基;Alloc、アリルオキシカルボニル基;Boc、tert−ブチルオキシカルボニル基;Bzl、ベンジル基;Cbz、ベンジルオキシカルボニル基;cHx、シクロヘキシル基;ClZ、2−クロロベンジル基;CST、コルチスタチン;DCM、ジクロロメタン;Dde、N−[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];DMEM、ダルベッコ変法イーグル培地;Dfp、3,5−ジフルオロフェニルアラニン;DIEA、N,N−ジイソプロピルエチルアミン;DIPCDI、ジイソプロピルカルボジイミド;Dmab、4−(N−[1−(4,4−ジメチル−2,6−ジオキソシクロヘキシリデン)−3−メチルブチル]アミノ)ベンジル;DMF、N,N−ジメチルホルムアミド;Dnp、2,4−ジニトロフェニル基;DOTA、1,4,7,10−テトラアザシクロドデカン−1,4,7,10−テトラ酢酸;DTPA、ジエチレントリアミンペンタ酢酸;ESI−MS、エレクトロスプレーイオン化質量分析;Fm、フルオレニルメチル;Fmoc、9−フルオレニルメチルオキシカルボニル基;HF、フッ化水素酸;HOBT、N−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;IC50、半数阻害濃度;ivDde、1−(4,4−ジメチル−2,6−ジオキソシクロヘキシリデン)−3−メチル−ブチル基;Ki、薬物の阻害定数;LPS、リポ多糖体;M、分子量;Mtt、メトキシトリチル基;μL、マイクロリットル;μmol、マイクロモル;pNZ、p−ニトロベンジルオキシカルボニル基;RP−HPLC、逆相HPLC;SST、ソマトスタチン;sstr、ソマトスタチン受容体;tBu、tert−ブチル基;Teoc、2−(トリメチルシリル)エチルオキシカルボニル基;TFA、トリフルオロ酢酸;TFE、2,2,2−トリフルオロエタノール;TIS、トリイソプロピルシラン;tr、保持時間;Trt、トリチル基;Troc、2,2,2−トリクロロエチルオキシカルボニル基;Z、ベンジルオキシカルボニル基。
H−L−Pro−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Msa−D−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys−]−L−Lys−OH
樹脂をフィルタープレートおよびキーを備えた合成反応容器に入れた。2−クロロトリチル樹脂0.25g(1.6mmol/g)上にC末端残基を導入した。最初のアミノ酸、Fmoc−Lys(Boc)−OH(1当量)を1.25mLのDCMおよび75μLのDMFに溶解した。DIEA(3当量)を加えた。アミノ酸および塩基を含む溶液を反応容器に移し、45分間撹拌した。この後、MeOH0.2mLを加え、10分間反応させた。濾過し、濾液を廃棄した。樹脂をDCMおよびDMFで洗浄した。1回の洗浄毎に濾過処理を行い、濾液を廃棄した。次のアミノ酸を導入するために、2.5当量のFmoc−アミノ酸、2.5当量のHOBTおよび2.5当量のDIPCDIを使用した。カップリング反応のために、40〜60分間反応させ、アミノ酸導入をニンヒドリンテストで調節した。ニンヒドリンテストが陽性であれば、再活性化ステージを15〜30分間、0.83当量のHOBTおよび0.83当量のDIPCDIを用いて実施した。ニンヒドリンテストがまだ陽性であれば、リカップリングを1.25当量のFmoc−アミノ酸、HOBTおよびDIPCDIを用いて行った。ニンヒドリンテストが陰性であれば、20%ピペリジン・DMF溶液を用いた2回の処理によるFmoc基の脱保護工程に合成を進めた。ペプチジル樹脂をDMFで5回洗浄し、濾過し、フィルタは毎回廃棄し、その後、次のアミノ酸を導入した。N末端アミノ酸をBoc−Pro−OHの形態で導入した。1.03gのペプチド樹脂が得られた。
特色:ESI−MS:理論値M=1777.1g/mol、実験値M:(m/z):[M+2H]+/2=889.3,[M+3H]+/3=593.1
オクタノイル−L−Pro−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Msa−D−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys−]−L−Lys−OH
実施例1に記載の方法により化合物を調製した。最初に0.25gの樹脂を使用し、同じ当量比を使用した。N末端アミノ酸をFmoc−Pro−OHの形態で加えた。オクタノイル酸を5当量の酸、5当量のHOBTおよび5当量のDIPCDIを用いて配列に導入した。0.5gの粗生成物が得られた。
特色:ESI−MS:理論値M=1903.35g/mol、実験値M:(m/z):[M+2H]+/2=952.4,[M+3H]+/2=635.2
H−L−Pro−c[L−Cys−L−Lys−L−Asn−L−Msa−L−Phe−D−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−L−Lys−OH
実施例1に記載の方法により化合物を調製した。0.25gの樹脂および同じ当量比を使用した。N末端アミノ酸をBoc−Pro−OHの形態で加えた。0.53gの粗生成物が得られた。
特色:ESI−MS:理論値M=1777.15g/mol、実験値M:(m/z):[M+2H]+/2=889.3,[M+3H]+/2=593.1
オクタノイル−L−Pro−c[L−Cys−L−Lys−L−Asn−L−Msa−L−Phe−D−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys−]−L−Lys−OH
実施例1に記載の方法により化合物を調製した。0.25gの樹脂および同じ当量比を使用した。N末端アミノ酸をFmoc−Pro−OHの形態で加えた。オクタノイル酸を5当量の酸、5当量のHOBTおよび5当量のDIPCDIを用いて配列に導入した。0.55gの粗生成物が得られた。
特色:ESI−MS:理論値M=1903.35g/mol、実験値M:(m/z):[M+2H]+/2=952.4,[M+3H]+/2=635.2
オクタノイル−L−Pro−c[L−Cys−L−Lys−L−Asn−L−Msa−L−Phe−D−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−OH
実施例1に記載の方法により化合物を調製した。0.4gの樹脂および同じ当量比を使用した。N末端アミノ酸をFmoc−Pro−OHの形態で加えた。オクタノイル酸を5当量の酸、5当量のHOBTおよび5当量のDIPCDIを用いて配列に導入した。0.53gの粗生成物が得られた。
特色:ESI−MS:理論値M=1775.18g/mol、実験値M:(m/z):[M+2H]+/2=888.6,[M+3H]+/2=592.7
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Dfp−D−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−OH
実施例1に記載の方法および同じ当量比を用いて化合物を調製した。N末端アミノ酸をBoc−Ala−OHの形態で加えた。0.53gの粗生成物が得られた。
特色:ESI−MS:理論値M=1673.9g/mol、実験値M:(m/z):[M+H]+=1674.8;[M+2H]+/2=837.9
実施例1に記載の方法により、MBHA樹脂および同じ当量比を用いて、化合物を調製した。N末端アミノ酸をFmoc−Pro−OHの形態で加えた。アセチル化を固相で5当量の無水酢酸、10当量のDIEAを用いて行った。0.48gの粗生成物が得られた。
特色:ESI−MS:理論値M=1812.15g/mol、実験値M:(m/z):[M+2H]+/2=907.07,[M+3H]+/3=605.05
実施例1に記載の方法により、MBHA樹脂および同じ当量比を用いて、化合物を調製した。N末端アミノ酸をBoc−Pro−OHの形態で加えた。0.5gの粗生成物が得られた。
特色:ESI−MS:理論値M=1798.15g/mol、実験値M:(m/z):[M+2H]+/2=900.1,[M+3H]+/3=600.3
実施例1に記載の方法および同じ当量比を用いて、化合物を調製した。N末端アミノ酸をFmoc−Asp(OtBu)−OHの形態で加えた。Fmocの脱保護および最後の酸分解の後、0.54gの粗生成物が得られた。
特色:ESI−MS:理論値M=2207.54g/mol、実験値M:(m/z):[M+2H]+/2=1104.7,[M+3H]+/3=736.8
実施例1に記載の方法および同じ当量比を用いて、化合物を調製した。N末端アミノ酸をFmoc−Asp(OtBu)−OHの形態で加えた。ミリスチン酸を5当量の酸、5当量のHOBTおよび5当量のDIPCDIを用いて導入した。0.52gの粗生成物が得られた。
特色:ESI−MS:理論値M=2411.5g/mol、実験値M:(m/z):[M+2H]+/2=1206.8;[M+3H]+/3=804.8
5種のソマトスタチン受容体(sstr1〜sstr5)のそれぞれが独立して発現するCHO−K1細胞を使用した。細胞を、0.1nM〜10μmの濃度範囲の新規コルチスタチンアナログ(化合物1〜10)とともに、pH7.4のHEPES緩衝液中で2〜4時間インキュベートし、125I−Tyr11−ソマトスタチン14を放射性リガンドとして使用し、ソマトスタチン−14を冷リガンドとして使用した。ソマトスタチン−14の非存在下で得られた放射能は全結合と見なし、1μMのソマトスタチン−14存在下で得られた放射能は非特異的結合として見なした。特異的結合は、完全な結合と非特異的結合との差と見なした。0.1nM〜10μMの試験濃度範囲で、評価した新規コルチスタチンアナログは、特異的結合に対し、50%を超える阻害率を示した。前記値は、新規コルチスタチンアナログのIC50値と、すべてナノモル範囲の次の範囲、(IC50(sstr1)=1nM〜50nM;IC50(sstr2)=1nM〜50nM;IC50(sstr3,sstr4およびsstr5)=0.5nM〜5nM)、コルチスタチンについて公表されている範囲[Spier et al.,Brain Research Reviews 2000,33,228−241]IC50(sstr1)=1〜5nM;IC50(sstr2,sstr3,sstr5)=0.1nM〜5nM;IC50(sstr4)=0.1nM〜20nM)で相関していた。この結果は、評価した新規コルチスタチンアナログがソマトスタチン受容体sstr1〜sstr5とナノモルアフィニティで相互作用することを示している。
Raw264細胞を完全DMEM培地で、コンフルエンス80%に達するまで培養した。細胞を、リポ多糖体(LPS、1μg/mL、大腸菌(E.coli)血清型055:B5より)の非存在下または存在下でインキュベートした。リポ多糖体の非存在下でインキュベートした細胞をリファレンス(基準)として使用した。新規コルチスタチンアナログを、培養開始時に100nMで加えた。24時間後、上清を集め、サイトカインおよび酸化窒素濃度を測定した。サイトカイン濃度(TNFアルファおよびIL−6)は、ELISA試験で測定した。酸化窒素(NO)はGriess試験により測定した。培養液の上清(90μl)とGriess試薬を同容量混合し、吸光度を550nmで測定した。亜硝酸塩の量をNaNo2標準曲線から算出した。
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Msa−L−Phe−L−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−OH(化合物11)
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Msa−L−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−OH(化合物12)
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Phe−L−Trp−L−Lys−L−Thr−L−Msa−LThr−L−Ser−L−Cys]−OH(化合物13)
8週齢のオスのC57BI/6マウスからの脾細胞を、細胞の機械的分離、ナイロンメッシュによる濾過、および赤血球の溶解の後、得た。脾細胞を完全DMEM培地で、106細胞/mLの密度になるまでインキュベートした。非接着性細胞(T細胞により80%で生成)をサイトカインの測定および増殖分析のために使用した。T細胞を完全DMEM培地で培養し、100nM濃度の種々のコルチスタチンアナログの存在下に抗CD3抗体(2μg/mL)で刺激した。48時間後、培養物の上清を分離し、サイトカイン(IFNγおよびIL−2)の濃度をELISA試験で測定した。種々のコルチスタチンアナログの増殖に対する効果を調べるために、細胞を72時間培養し、培養の最後の8時間の間に[3H]−チミジンを0.5μCi(0.0185MBq)/well加え、膜を集め、そして加えた[3H]−チミジンをシンチレーションカウンターで測定した。
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Msa−L−Phe−L−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−OH(化合物11)
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Msa−L−Trp−L−Lys−L−Thr−L−Phe−L−Thr−L−Ser−L−Cys]−OH(化合物12)
H−L−Ala−Gly−c[L−Cys−L−Lys−L−Asn−L−Phe−L−Phe−L−Trp−L−Lys−L−Thr−L−Msa−LThr−L−Ser−L−Cys]−OH(化合物13)
新規化合物を37℃で90%ヒト血清とともにインキュベートした。インキュベーション時間を変えて一定分量を抽出した。メタノールを添加し、血清からタンパク質を沈澱させ、遠心分離し、上清をRP−HPLC(勾配:20〜80%B、30分、B=アセトニトリル中、0.07%TFA)によるクロマトグラフィー分析に供した。初期生成物の消失を、初期生成物に対応する面積により解析し、半減期を算出した。
H−Pro−c[Cys−Lys−Asn−Phe−Phe−Trp−Lys−Thr−Phe−Ser−Ser−Cys]−OH(化合物14)
DBA/1マウスに、完全フロイントアジュバント中のニワトリII型コラーゲンおよびマイコバクテリウム・ツベルクローシス(M.tuberculosis)を0日目および21日目に注射した。25日目から29日目の間、マウスの皮下に生理食塩水(対照)または0.4mg/kgの化合物4、5もしくは6を、1日1回投与した。リファレンス処理として、抗−TNFアルファ抗体を使用し、25日目および32日目に静脈注射した。関節炎の臨床的重篤度を毎日、損傷の程度にしたがい0〜10の数で解析した。肢の腫脹を、研究期間を通して5日毎にキャリパーにより厚みを測定することによって評価した(20、25、30、35、40、45、50日目)。
6〜8週齢のオスのBALB/cマウスを使用した。大腸炎を誘発するために、それらに、50%エタノールに溶解したトリニトロベンゼンスルホン酸(TBNS)を直腸内投与した。疾患がすでに確立した3、4および5日目に、マウスの皮下に緩衝液(PBS)または種々のコルチスタチンアナログ(0.4mg/kg)を投与した。
7〜8週齢のオスのC57BI/6マウスを使用した。急性結腸炎を誘発するために、研究の0日目および7日目に、それらに、5%デキストラン硫酸ナトリウム(DSS)を含む自発的飲料水を与えた。対照群の動物には、標準の水を与えた。研究の1、2および3日目に、マウスの皮下に(PBS)緩衝液、または種々のコルチスタチンアナログ(0.4mg/kg)を投与した。CSTをリファレンスとして使用した。結腸炎の重症度を毎日、便の硬さ、血便の有無および体重の減少を考慮した臨床疾患活性係数を示す0〜4の尺度で評価した。研究の8日目にマウスを処分し、剖検後、結腸のマクロ的損傷の程度を0〜8の尺度で確立した。5%DSSに経口投与により、疾患活性係数(0〜4)は大きく増大し、疾患群で基準値の0から3.7に上昇した。CSTおよびコルチスタチンアナログで処理した病気のマウスは、はるかに低く、それらの中では類似した、1〜1.5の範囲の臨床疾患活性係数を得た。さらに、研究の1〜3日目の新規コルチスタチンアナログによる処理では、病気の動物の生存率が50%から100%に大きく上昇した。マクロ的レベルでは、病気のマウスの結腸炎の重篤度は6.6であり、CSTで処理した病気のマウスでは0.87、新規コルチスタチンアナログで処理した病気のマウスでは0.74〜1.5であった。病気のマウスの結腸の平均重量は763mg、CSTで処理した病気のマウスの結腸の平均重量は621mg、そして新規コルチスタチンアナログで処理した病気のマウスの結腸のそれは614〜621mgであり、これは結腸の炎症の減少を示している。これらのすべての結果は、この結腸炎の実験モデルにおける、新規コルチスタチンアナログの有効性を示している。
Claims (19)
- 一般式(I)で示されるコルチスタチンアナログ化合物、
その立体異性体、それらの混合物、および/または薬学的に許容されるその塩
(式中、
AA1は、Aspまたは結合であり、
AA2は、Argまたは結合であり、
AA3は、Met、Alaまたは結合であり、
AA4は、ProまたはGlyであり、
AA5は、LysまたはArgであり、
AA6は、SerまたはThrであり、
AA7は、Lysまたは結合であり、
X、Y、Zは、アミノ酸Phe、Phg、Msa、3,4,5−トリメチルフェニルアラニン、Msg、3,4,5−トリメチルフェニルグリシン、および/またはジハロゲノフェニルアラニン(diW−Phe)であり、
Wは、F、Cl、BrおよびIからなる群から選択され、
R1は、H、置換または非置換の非環状脂肪族基、置換または非置換の脂環式基、置換または非置換の複素環基、置換または非置換のヘテロアリールアルキル基、置換または非置換のアリール基、置換または非置換のアラルキル基、ポリエチレングリコールから誘導されるポリマー、キレート剤およびR5−CO−からなる群から選択され、
R2は、−NR3R4、−OR3および−SR3からなる群から選択され、
R3およびR4は、独立に、H、置換または非置換の非環状脂肪族基、置換または非置換の脂環式基、置換または非置換の複素環基、置換または非置換のヘテロアリールアルキル基、置換または非置換のアリール基、置換または非置換のアラルキル基、およびポリマーからなる群から選択され、
R5は、H、置換または非置換の非環状脂肪族基、置換または非置換の脂環式基、置換または非置換のアリール基、置換または非置換のアラルキル基、置換または非置換の複素環基、および置換または非置換のヘテロアリールアルキル基からなる群から選択され、
但し、
−アミノ酸X、YまたはZの少なくとも1つは、Msa、3,4,5−トリメチルフェニルアラニン、Msg、3,4,5−トリメチルフェニルグリシン、および/またはジハロゲノフェニルアラニン(diW−Phe)であり、
−AA1およびAA2が結合で、AA3がAlaで、AA4がGlyで、AA5がLysで、AA6がThrで、かつAA7が結合であるとき、アミノ酸X、YまたはZの少なくとも1つは、ジハロゲノフェニルアラニン(diW−Phe)である
という条件を有する)。 - AA3は、Metまたは結合であり、AA4は、Proである請求項1に記載の化合物。
- アミノ酸X、YまたはZの少なくとも1つは、ジハロゲノフェニルアラニン(diW−Phe)である請求項1または2に記載の化合物。
- アミノ酸X、YまたはZの少なくとも1つは、3,5−ジフルオロフェニルアラニン(Dfp)である請求項1〜3のいずれか一項に記載の化合物。
- R5は、置換または非置換のC1〜C24アルキル基、置換または非置換のC2〜C24アルケニル基、置換または非置換のC2〜C24アルキニル基、置換または非置換のC3〜C24シクロアルキル基、置換または非置換のC5〜C24シクロアルケニル基、置換または非置換のC8〜C24シクロアルキニル基、置換または非置換のC6〜C30アリール基、置換または非置換のC7〜C24アラルキル基、置換または非置換の3〜10員複素環、および置換または非置換の、2〜24個の炭素原子と炭素以外の原子1〜3個からなるヘテロアリールアルキル基(ここで、アルキル鎖は1〜6個の炭素原子からなる)からなる群から選択される請求項1〜4のいずれか一項に記載の化合物。
- R1は、H、分子量が200〜35000ダルトンのポリエチレングリコールから誘導されるポリマー、アセチル基、tert−ブタノイル基、プレニル基、ヘキサノイル基、2−メチルヘキサノイル基、シクヘキサンカルボキシル基、オクタノイル基、デカノイル基、ラウロイル基、ミリストイル基、パルミトイル基、ステアロイル基、ベヘニル基、オレオイル基およびリノレオイル基からなる群から選択される請求項1〜5のいずれか一項に記載の化合物。
- R3およびR4は、独立に、H、置換または非置換のC1〜C24アルキル基、置換または非置換のC2〜C24アルケニル基、置換または非置換のC2〜C24アルキニル基、置換または非置換のC3〜C24シクロアルキル基、置換または非置換のC5〜C24シクロアルケニル基、置換または非置換のC8〜C24シクロアルキニル基、置換または非置換のC6〜C30アリール基、置換または非置換のC7〜C24アラルキル基、置換または非置換の3〜10員複素環、および置換または非置換の、2〜24個の炭素原子と炭素以外の原子1〜3個からなるヘテロアリールアルキル基(ここで、アルキル鎖は1〜6個の炭素原子からなる)、およびポリエチレングリコールから誘導されるポリマーからなる群から選択される請求項1〜6のいずれか一項に記載の化合物。
- R3およびR4は、H、メチル基、エチル基、ヘキシル基、ドデシル基またはヘキサデシル基からなる群から選択される請求項7に記載の化合物。
- 下記からなる群から選択される配列を含む請求項1に記載の化合物。
- 下記からなる群から選択される請求項1に記載の化合物。
- 請求項1〜10のいずれか一項の一般式(I)で示される化合物、その立体異性体、それらの混合物、または化粧料もしくは薬学的に許容されるその塩の調製方法であって、固相合成または溶液合成により行われる調製方法。
- 1.固相合成
2.ペプチドのポリマー担体からの切出し
3.溶液中でのペプチドの環化
4.保護基の脱離
または
1.固相合成
2.固相環化
3.ペプチドのポリマー担体からの切出し、および好ましくはトリフオロ酢酸での処理による、保護基の同時脱離
を含む請求項11に記載の方法。 - 請求項1〜10のいずれか一項に記載の一般式(I)で示される少なくとも1種の化合物、その立体異性体、それらの混合物、および/または薬学的に許容される塩を、薬学的に有効な量含む医薬組成物。
- 一般式(I)で示される化合物、その立体異性体、それらの混合物、および/または薬学的に許容される塩は、リポソーム、混合リポソーム、オレオソーム、ニオソーム、エトソーム、ミリ粒子、マイクロ粒子、ナノ粒子および固体脂質ナノ粒子、ナノ構造脂質担体、スポンジ、シクロデキストリン、ベシクル、ミセル、界面活性剤の混合ミセル、界面活性剤−リン脂質混合ミセル、ミリ球状粒子、マイクロ球状粒子およびナノ球状粒子、リポ球状粒子、ミリカプセル、マイクロカプセルおよびナノカプセル、マイクロエマルション、ならびにナノエマルションからなる群から選択される送達システム、および/または医薬徐放性送達システムに組み込まれる請求項13に医薬組成物。
- 他の抗炎症剤、免疫抑制剤、代謝および酵素阻害剤、非ステロイド性抗炎症剤、イブプロフェン、テニダップ、ナプロキセン、メロキシカム、メサラジン、ピロキシカム、ジクロフェナック、インドメタシン、スルファサラジン、コルチコステロイド、プレドニソロン、ヒドロコルチゾン、ベクロメタゾン、ブデソニド、サイトカイン抑制抗炎症薬、ヌクレオチド合成阻害剤、メトトレキサート、レフルノミド、免疫抑制剤、シクロスポリン、タクロリムス、mTOR阻害剤、シロリムスまたはラパマイシン、およびその誘導体、腫瘍壊死因子TNFα阻害剤、インフリキシマブ、アダリムマブ、エタネルセプト、セルトリズマブ、ゴリムマブ、COX−2阻害剤、セレコキシブ、ロフェコキシブ、バルデコキシブ、およびそれらの変異体、ホスホジエステラーゼ阻害剤、ホスホリパーゼ阻害剤、トリフルオロメチルケトンアナログ、血管内皮成長因子阻害剤、成長因子受容体阻害剤、血管形成阻害剤、ナタリズマブ、リツキシマブ、アバタセプト、フォスタマチニブ、トシリズマブ)、アナキンラ、トファシチニブ、6−メルカプトプリン、アザチオプリン、バルサラジド、スルファサラジン、メサラジン、オルサラジン、クロロキン、ヒドロキシクロロキン、ペニシラミン、オーラノフィン、金チオリンゴ酸塩、アザチオプリン、コルヒチン、ベータ−2アドレナリン受容体作動薬、サルブタモール、テルブタリンおよびサルメチロール、キサンチン、テオフィリン、アミノフィリン、クロモグリケート、ネドクロミル、ケトチフェン、イプラトピウム、オキシトロピウム、ミコフェノール酸モフェチル、アデノシン作動薬、抗血栓症薬、ペニシリン、補体阻害剤、ならびにアドレナリン剤からなる群から選択される他の治療薬をさらに含む請求項13または14に記載の医薬組成物。
- 局所経路、腸内経路または非経口経路で投与される請求項13〜15のいずれか一項に記載の医薬組成物。
- 薬剤に使用するための請求項1〜10のいずれか一項に記載の化合物。
- ソマトスタチン受容体(sstr1、sstr2、sstr3、sstr4、および/またはsstr5)、および/またはグレリン受容体、および/または特定のコルチスタチン受容体、あるいはこれらの組み合わせを発現する病態、疾患および/または病変の治療、予防および/または診断のための請求項1〜10のいずれか一項に記載の化合物。
- 前記病態、疾患および/または病変は、免疫系疾患、炎症性病変、腫瘍、癌、神経変性疾患、眼疾患、呼吸器疾患、感染症、痛み、回復期創傷、組織再生、敗血症、および移植/臓器もしくは組織の移植に関連する疾患、内毒素血症、敗血性ショック、毒素ショック症候群、敗血症、炎症性腸疾患、クローン病、慢性大腸炎、潰瘍性結腸炎、自己免疫性胃炎、関節炎、リウマチ性関節炎、変形性関節症、乾癬性関節炎、多発性硬化症、末端肥大症、膵・消化管神経内分泌腫瘍の対症療法、下痢、グレード3−4の下痢、放射線治療および/または化学療治療に関連する下痢、カルチノイド症候群またはビポーマの対症療法、内分泌癌、膵臓癌、慢性膵炎、末端肥大症、膵・消化管神経内分泌腫瘍の対症療法、食道静脈瘤、肥大性肺性骨関節症および甲状腺種(thyrotropic adenoma)、結腸直腸癌、乳癌、卵巣癌、前立腺癌、甲状腺癌、肺癌、胃癌、肝細胞癌、アルツハイマー病、関節炎、アレルギー、狼瘡、紅斑性狼瘡、リンパ増殖性疾患、糖尿病性網膜症、黄斑浮腫、グレーブス眼症、クッシング症候群、神経障害性疼痛、再狭窄、血管新生、甲状腺機能亢進症、甲状腺機能低下症、高インスリン血症、乾癬、低カルシウム血症、ページェット病、カヘキシーおよびゾリンジャー・エリソン症候群、壊疽性膿皮症、甲状腺障害、一型インスリン依存性糖尿病、橋本甲状腺炎、グレーブス病、自己免疫性肝炎、アレルギー性脳脊髄炎、網膜ブドウ膜炎、ブドウ膜炎、移植片拒絶(transplant rejection)、移植片拒絶(graft rejection)、移植片対宿主病、リブマン・サックス心内膜炎、混合性結合組織病、強皮症、多発性筋炎・皮膚筋炎、ウェゲナー肉芽腫症、シェーグレン症候群、肉芽腫、硬化性苔癬、原発性胆汁性肝硬変、角膜炎、糸球体腎炎、反応性関節炎、sinovialitis、ライター症候群、ライム病、乾癬性関節炎、誘発関節炎、強直性脊椎炎、重症筋無力症、血管炎、自己免疫性甲状腺炎、アレルギー、皮膚炎または湿疹、乾癬、乾癬、皮膚炎、繊維症、慢性閉塞性疾患(COPD)、脳脊髄炎、自己免疫性甲状腺炎、老人性潰瘍(aged ulcer)、虹彩炎、結膜炎、角結膜炎、脊椎関節症、膣炎、直腸炎、薬疹、ハンセン病逆転反応(leprosy reversal reaction)、癩性結節性紅斑、急性壊死性出血性脳症、特発性進行性両側性感音難聴、再生不良性貧血、純赤血球貧血、特発性血小板減少症、多発性軟骨炎、慢性活動性肝炎、スティーブンス・ジョンソン症候群、特発性スプルー、扁平苔癬およびサルコイドーシスからなる群から選択される請求項18に記載の化合物。
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MY180383A (en) | 2013-12-24 | 2020-11-28 | Harvard College | Cortistatin analogues and syntheses and uses thereof |
EP3294298A4 (en) | 2015-05-08 | 2018-10-17 | President and Fellows of Harvard College | Cortistatin analogues, syntheses, and uses thereof |
EP3316889A4 (en) | 2015-07-01 | 2018-11-14 | President and Fellows of Harvard College | Cortistatin analogues and syntheses and uses thereof |
CA3068917A1 (en) | 2017-07-05 | 2019-01-10 | Wisconsin Alumni Research Foundation | Mineral coated microparticles for co-delivery of anti-inflammatory molecules with nucleic acids to improve gene delivery outcomes |
WO2019152232A1 (en) * | 2018-01-31 | 2019-08-08 | Twi Pharmaceuticals, Inc. | Topical formulations comprising tofacitinib |
AU2019240773B2 (en) | 2018-03-29 | 2024-05-16 | Lateral IP Pty Ltd | Cyclic peptides and uses thereof |
RU2698451C1 (ru) * | 2018-07-02 | 2019-08-27 | Павел Александрович Храмов | Средство и способ для лечения нейросенсорной тугоухости |
ES2780274A1 (es) * | 2019-02-15 | 2020-08-24 | Consejo Superior De Investig Científicas (Csic) | Cortistatina o un análogo de la misma como agente farmacéuticamente activo en forma latente |
CA3163483A1 (en) * | 2019-12-05 | 2021-06-10 | Bcn Peptides, S.A. | Peptides for the treatment of cancer and/or metastasis |
CN111297876B (zh) * | 2020-01-16 | 2021-04-27 | 武汉理工大学 | 一种塞来昔布胶束和和厚朴酚胶束药物联用控释系统及其制备方法 |
CN113797314B (zh) * | 2021-09-29 | 2023-08-22 | 山东大学齐鲁医院 | Cst多肽在制备股骨头坏死治疗药物中的应用 |
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WO2007082980A1 (es) * | 2006-01-23 | 2007-07-26 | Consejo Superior De Investigaciones Científicas | Composiciones y procedimientos para tratar trastornos inflamatorios e inmunitarios con cortistatina |
JP2012526081A (ja) * | 2009-05-07 | 2012-10-25 | ベーセーエネ ペプティデス,エセ.ア. | ソマトスタチン受容体のペプチドリガンド |
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US6660843B1 (en) * | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
EP1040837A3 (en) | 1999-02-26 | 2002-01-02 | Erasmus Universiteit Rotterdam | Medicaments for the treatment of a choroidal neovascularization (CNV) related disorder |
JP2009523129A (ja) | 2006-01-05 | 2009-06-18 | ユニバーシティ オブ ユタ リサーチ ファウンデーション | 神経系を標的する薬理学的物質の性質を改善することに関連する方法および組成物 |
WO2009043523A2 (en) | 2007-09-11 | 2009-04-09 | Mondobiotech Laboratories Ag | Cortistatin 17 and neuropeptide 1 for use as therapeutic agent |
EP2168983A1 (fr) * | 2008-09-30 | 2010-03-31 | Ipsen Pharma | Nouveaux composés octapeptidiques et leur utilisation thérapeutique |
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