JP2022539076A - 分岐連結体を有する細胞結合分子と細胞毒性剤との共役体 - Google Patents
分岐連結体を有する細胞結合分子と細胞毒性剤との共役体 Download PDFInfo
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- YCXHPBHFOLIYEB-AABGKKOBSA-N vincaminol Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(CO)N5C2=C1 YCXHPBHFOLIYEB-AABGKKOBSA-N 0.000 description 1
- CXBGOBGJHGGWIE-IYJDUVQVSA-N vindoline Chemical compound CN([C@H]1[C@](O)([C@@H]2OC(C)=O)C(=O)OC)C3=CC(OC)=CC=C3[C@]11CCN3CC=C[C@]2(CC)[C@@H]13 CXBGOBGJHGGWIE-IYJDUVQVSA-N 0.000 description 1
- 229960000744 vinpocetine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229960005502 α-amanitin Drugs 0.000 description 1
- OFILNAORONITPV-ZUROAWGWSA-N ε-amanitin Chemical compound O=C1N[C@@H](CC(O)=O)C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H]([C@@H](C)[C@H](C)O)C(=O)N[C@@H](C2)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@H]1CS(=O)C1=C2C2=CC=C(O)C=C2N1 OFILNAORONITPV-ZUROAWGWSA-N 0.000 description 1
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Abstract
Description
は、L1又はL2との結合部位である;G1及びG2はそれぞれ独立して、OC(O)、NHC(O)、C(O)、CH2、NH、OC(O)NH、NHC(O)NH、O、S、B、P(O)(OH)、NHP(O)(OH)、NHP(O)(OH)NH、CH2P(O)(OH)NH、OP(O)(OH)O、CH2P(O)(OH)O、NHS(O)2、NHS(O)2NH、CH2S(O)2NH、OS(O)2O、CH2S(O)2O、Ar、ArCH2、ArO、ArNH、ArS、ArNR1、又は(Aa)q1;G3は、OH、SH、OR12、SR12、OC(O)R12、NHC(O)R12、C(O)R12、CH3、NH2、NR12、+NH(R12)、+N(R12)(R12’)、C(O)OH、C(O)NH2、NHC(O)NH2、BH2、BR12R12’、P(O)(OH)2、NHP(O)(OH)2、NHP(O)(NH2)2、S(O)2(OH)、(CH2)q1C(O)OH、(CH2)q1P(O)(OH)2、C(O)(CH2)q1C(O)OH、OC(O)(CH2)q1C(O)OH、NHC(O)(CH2)q1C(O)OH、CO(CH2)q1P(O)(OH)2、NHC(O)O(CH2)q1C(O)OH、OC(O)NH(CH2)q1C(O)OH、NHCO(CH2)q1-P(O)(OH)2、NHC(O)(NH)(CH2)q1C(O)OH、CONH(CH2)q1P(O)(OH)2、NHS(O)2(CH2)q1C(O)OH、CO(CH2)q1S(O)2(OH)、NHS(O)2NH(CH2)q1C(O)OH、OS(O)2NH(CH2)q1C(O)OH、NHCO(CH2)q1S(O)2(OH)、NHP(O)(OH)(NH)(CH2)q1C(O)OH、CONH(CH2)q1S(O)(OH)、OP(O)(OH)2、(CH2)q1P(O)(NH)2、NHS(O)2(OH)、NHS(O)2NH2、CH2S(O)2NH2、OS(O)2OH、OS(O)2OR1、CH2S(O)2OR12、Ar、ArR12、ArOH、ArNH2、ArSH、ArNHR12、又は(Aa)q1である;p1、p2、及びp3は独立して0~100であるが、同時に0ではない;q1及びq2は独立して0~24である;Q1及びQ2は独立して、線状又は分岐の、C2-C90ポリカルボン酸、C2-C90ポリアルキルアミン、C6-C90オリゴ糖類若しくは多糖類、四級アンモニウムカチオン及び/若しくはスルフォネートアニオンからなるC6-C90双性イオン性ベタイン若しくは双性イオン性ポリ(スルホベタイン))(PSB)、又はポリ(乳酸/グリコール酸)(PLGA)、ポリ(アクリレート)、キトサン、N-(2-(2-ヒドロキシプロピル)メタクリルアミドの共重合体、ポリ[2-(メタクリロイルオキシ)エチルホスホリルコリン](PMPC)、ポリ-L-グルタミン酸、ポリ(ラクチド-co-グリコリド)(PLG)、ポリ(ラクチド-co-グリコリド)、ポリ(エチレングリコール)(PEG)、ポリ(プロピレングリコール)(PPG)、ポリ(ラクチド-co-グリコリド)、ポリ(エチレングリコール)修飾ペプチド、ポリ(エチレングリコール)-アミノ酸又はペプチドを含む、ポリ(エチレングリコール)-修飾脂質、ポリ-グリシン、ポリ-N-メチル-グリシン、ポリ(エチレングリコール)-修飾アルキルカルボン酸、ポリ(エチレングリコール)-修飾アルキルアミン、ポリ(ラクチド-co-グリコリド、ヒアルロン酸(HA)(グリコサミノグリカン)、ヘパリン/ヘパラン硫酸(HSGAG)、コンドロイチン硫酸/デルマタン硫酸(CSGAG)、ポリ(エチレングリコール)修飾アルキル硫酸塩、ポリ(エチレングリコール)修飾アルキルリン酸、又はポリ(エチレングリコール)-修飾アルキル四級アンモニウム等で構成される、生分解性ポリマーである;Dは、カリケアマイシン類、カンプトテシン類、メイタンシノイド類、タキサン類、ダウノルビシン/ドキソルビシン、ビンカアルカロイド類、オーリスタチン類、エリブリン類、ピロロベンゾジアゼピン類(PBD)、デュオカルマイシン類、キナーゼ阻害剤、MEK阻害剤、KSP阻害剤、ニコチンアミドホスホリボシルトランスフェラーゼ(NAMPT)阻害剤、免疫毒素、これらの化合物の類縁体又はプロドラッグから独立して選択される、細胞毒性剤である。
は、単結合、二重結合、又は不存在であり、D1及びD2は同一又は異なり、且つDと同じ定義である。
は、L1又はL2との結合部位である;G1及びG2はそれぞれ独立して、OC(O)、NHC(O)、C(O)、CH2、NH、OC(O)NH、NHC(O)NH、O、S、B、P(O)(OH)、NHP(O)(OH)、NHP(O)(OH)NH、CH2P(O)(OH)NH、OP(O)(OH)O、CH2P(O)(OH)O、NHS(O)2、NHS(O)2NH、CH2S(O)2NH、OS(O)2O、CH2S(O)2O、Ar、ArCH2、ArO、ArNH、ArS、ArNR1、又は(Aa)q1;G3は、OH、SH、OR12、SR12、OC(O)R12、NHC(O)R12、C(O)R12、CH3、NH2、NR12、+NH(R12)、+N(R12)(R12’)、C(O)OH、C(O)NH2、NHC(O)NH2、BH2、BR12R12’、P(O)(OH)2、NHP(O)(OH)2、NHP(O)(NH2)2、S(O)2(OH)、(CH2)q1C(O)OH、(CH2)q1P(O)(OH)2、C(O)(CH2)q1C(O)OH、OC(O)(CH2)q1C(O)OH、NHC(O)(CH2)q1C(O)OH、CO(CH2)q1P(O)(OH)2、NHC(O)O(CH2)q1C(O)OH、OC(O)NH(CH2)q1C(O)OH、NHCO(CH2)q1-P(O)(OH)2、NHC(O)(NH)(CH2)q1C(O)OH、CONH(CH2)q1P(O)(OH)2、NHS(O)2(CH2)q1C(O)OH、CO(CH2)q1S(O)2(OH)、NHS(O)2NH(CH2)q1C(O)OH、OS(O)2NH(CH2)q1C(O)OH、NHCO(CH2)q1S(O)2(OH)、NHP(O)(OH)(NH)(CH2)q1C(O)OH、CONH(CH2)q1S(O)(OH)、OP(O)(OH)2、(CH2)q1P(O)(NH)2、NHS(O)2(OH)、NHS(O)2NH2、CH2S(O)2NH2、OS(O)2OH、OS(O)2OR1、CH2S(O)2OR12、Ar、ArR12、ArOH、ArNH2、ArSH、ArNHR12、又は(Aa)q1である;(Aa)q1は、同一の又は異なる天然又は非天然アミノ酸を含むペプチドである;X1及びX2は独立して、O、CH2、S、S(O)、NHNH、NH、N(R12)、+NH(R12)、+N(R12)(R12’)、C(O)、OC(O)、OC(O)O、OC(O)NH、NHC(O)NHである;Y2はO、NH、NR12、CH2、S、NHNH、Arである;p1、p2、及びp3は独立して0~100であるが、同時に0ではない;q1及びq2は独立して0~24である;R12、R12’、R13、及びR13’は独立して、H、C1~C8アルキル;C2~C8ヘテロアルキル、又は複素環;C3~C8アリール、Ar-アルキル、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、炭素環、又はアルキルカルボニルである;
は、Wとの接続部位である;P1は H、OH、NH2、COOH、C(O)NH2、OCH2OP(O)(OR18)2、OC(O)OP(O)(OR18)2、OPO(OR18)2、NHPO(OR18)2、OC(O)R18、OP(O)(OR18)OP(O)(OR18)2、OC(O)NHR18、OC(O)N(C2H4)2NCH3、OSO2(OR18)、O-(C4-C12-配糖体)、OC(O)N(C2H4)2CH2N(C2H4)2CH3、C1-C8の直鎖又は分岐アルキル又はヘテロアルキル;C2-C8の直鎖又は分岐アルケニル、アルキニル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8の直鎖又は分岐アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;カーボネート(-C(O)OR17)、カルバメート(-C(O)NR17R18)である;R17及びR18は独立して、H、直鎖又は分岐アルキル又はヘテロアルキル;C2-C8の直鎖又は分岐アルケニル、アルキニル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8の直鎖又は分岐アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;カーボネート(-C(O)OR17)、カルバメート(-C(O)NR17R18)である。
と結合している場合、独立して、O、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R2)、C(O)NHNHC(O)、及びC(O)NR1であり、また、接続部位
と結合していない場合、独立して、OH、NH2、NHNH2、NHR5、SH、C(O)OH、C(O)NH2、OC(O)NH2、OC(O)OH、NHC(O)NH2、NHC(O)SH、OC(O)NH(R1)、N(R1)C(O)NH(R2)、C(O)NHNHC(O)OH、及びC(O)NHR1である;R12は、OH、NH2、NHR1、NHNH2、NHNHCOOH、O-R1-COOH、NH-R1-COOH、NH-(Aa)nCOOH、O(CH2CH2O)pCH2CH2OH、O(CH2CH2O)pCH2CH2NH2、NH(CH2CH2O)pCH2CH2NH2、NR1R1’、NHOH、NHOR1、O(CH2CH2O)pCH2CH2COOH、NH(CH2CH2O)pCH2CH2COOH、NH-Ar-COOH、NH-Ar-NH2、O(CH2CH2O)pCH2CH2NH-SO3H、NH(CH2CH2O)pCH2CH2NHSO3H、R1-NHSO3H、NH-R1-NHSO3H、O(CH2CH2O)pCH2-CH2NHPO3H2、NH(CH2CH2O)pCH2CH2NHPO3H2、OR1、R1-NHPO3H2、R1-OPO3H2、O(CH2CH2O)pCH2CH2OPO3H2、OR1-NHPO3H2、NH-R1-NHPO3H2、NH(CH2CH2NH)pCH2-CH2NH2、NH(CH2CH2S)pCH2CH2NH2、NH(CH2CH2NH)pCH2CH2OH、NH(CH2CH2S)pCH2-CH2OH、NH-R1-NH2、又はNH(CH2CH2O)pCH2CH2NHPO3H2であり、ここで、Aaは1~8個の同一の又は異なるアミノ酸である;pは1-5000である;R1、R2、R3、R4、R5、R5’、Z1、Z2、及びnは、上記と同じ定義である。
と結合している場合、独立して、O、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R2)、C(O)NHNHC(O)、及びC(O)NR1であり、また、接続部位
と結合していない場合、独立して、OH、NH2、NHNH2、NHR1、SH、C(O)OH、C(O)NH2、OC(O)NH2、OC(O)OH、NHC(O)NH2、NHC(O)SH、OC(O)NH(R1)、N(R1)C(O)NH(R2)、C(O)NHNHC(O)OH、及びC(O)NHR1である;Z3は、H、PO(O)(OM1)(OM2)、SO3M1、CH2PO(O)(OM1)(OM2)、CH3N(CH2CH2)2NC(O)-、O(CH2CH2)2NC(O)-、R1、又はグリコシドである;R1、R2、R3、M1、M2、及びnは、上記と同じ定義である。
は連結部位である;好ましくは、X2、X3、X4、X5、又はX6は独立して、NH;NHNH;N(R12);N(R12)N(R12’);O;S;C1-C6アルキル;C2-C6ヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;CH2OR12、CH2SR12、CH2NHR12、又は1~8アミノ酸から選択される;式中、R12及びR12’は独立して、H;C1-C8アルキル;C2-C8ヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;又は、炭素原子数1~8のエステル、エーテル、若しくはアミド;又は式(OCH2CH2)p若しくは(OCH2CH(CH3))pのポリエチレンオキシ単位(pは0から約1000までの整数)、あるいはそれらの組み合わせである。
-(CR15R16)m(Aa)r(CR17R18)n(OCH2CH2)t-、-(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t-、-(Aa)r-(CR15R16)m(CR17R18)n(OCH2CH2)t-、-(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t-、-(CR15R16)m(CR17=CR18)(CR19R20)n(Aa)t(OCH2CH2)r-、-(CR15R16)m(NR11CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(CO)(Aa)t-(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(OCO)(Aa)t(CR19R20)n-(OCH2CH2)r-、-(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m-フェニル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-フリル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-オキサゾリル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-チアゾリル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)t-チエニル-(CO)(CR17R18)n-、-(CR15R16)t-イミダゾリル-(CO)(CR17R18)n-、-(CR15R16)t-モルホリノ-(CO)(Aa)t(CR17R18)n-、-(CR15R16)t-ピペラジノ-(CO)(Aa)t(CR17R18)n-、-(CR15R16)t-N-メチルピペラジン-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-(Aa)tフェニル-、-(CR15R16)m-(Aa)tフリル-、-(CR15R16)m-オキサゾリル(Aa)t-、-(CR15R16)m-チアゾリル(Aa)t-、-(CR15R16)m-チエニル(Aa)t-、-(CR15R16)m-イミダゾリル(Aa)t-、-(CR15R16)m-モルホリノ-(Aa)t-、-(CR15R16)m-ピペラジノ-(Aa)t-、-(CR15R16)m-N-メチルピペラジノ-(Aa)t-、-K(CR15R16)m(Aa)r(CR17R18)n(OCH2CH2)t-、-K(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t-、-K(Aa)r(CR15R16)m(CR17R18)n(OCH2CH2)t-、-K(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t-、-K(CR15R16)m(CR17=R18)(CR19R20)n(Aa)t(OCH2CH2)r-、-K(CR15R16)m(NR11CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m-フェニル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-フリル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-オキサゾリル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-チアゾリル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)t-チエニル-(CO)(CR17R18)n-、-K(CR15R16)t-イミダゾリル-(CO)(CR17R18)n-、-K(CR15R16)t-モルホリノ-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)t-ピペラジノ-(CO)(Aa)t(CR17R8)n-、-K(CR15R16)t-N-メチルピペラジン-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-(Aa)tフェニル-、-K(CR15R16)m-(Aa)tフリル-、-K(CR15R16)m-オキサゾリル(Aa)t-、-K(CR15R16)m-チアゾリル(Aa)t-、-K(CR15R16)m-チエニル(Aa)t-、-K(CR15R16)m-イミダゾリル(Aa)t-、-K(CR15R16)m-モルホリノ-(Aa)t-、-K(CR15R16)m-ピペラジノ-(Aa)tG-、-K(CR15R16)m-N-メチルピペラジノ-(Aa)t;式中、m、Aa、m、n、R13、R14、及びR15の定義は上記の通りである;t及びrは独立して0~100で
ある;R16、R17、R18、R19、及びR20は独立して、H;ハロゲン化物;C1~C8アルキル若しくはヘテロアルキル;C2~C8アリール、アルケニル、アルキニル、エーテル、エステル、アミン、若しくはアミド;又は1以上のハロゲン化物、CN、NR12R12’、CF3、OR12、アリール、複素環、S(O)R12、SO2R12、-CO2H、-SO3H、-OR12、-CO2R12、-CONR12、-PO2R12R13、-PO3H、又はP(O)R12R12’R13’で任意に置換されていてもよいC3~C8アリールから選択される;KはNR12、-SS-、-C(=O)-、-C(=O)NH-、-C(=O)O-、-C=NH-O-、-C=N-NH-、-C(=O)NH-NH-、O、S、Se、B、Het(C3~C12の複素環又は複素芳香環)、又は同一の若しくは異なる1~20個のアミノ酸を含むペプチドである。
抗β-アミロイド抗体)、ソネプシズマブ(Sonepcizumab)(抗スフィンゴシン-1-リン酸抗体)、ソンツズマブ(Sontuzumab)(抗エピシアリン抗体)、スタムルマブ(Stamulumab)(抗ミオスタチン抗体)、スレソマブ(sulesomab)(別名:LeukoScan、(抗NCA-90(顆粒球抗原)抗体)))、タカツズマブ(Tacatuzumab)(抗α-フェトプロテイン抗体)、タドシズマブ(tadocizumab)(抗インテグリンαIIbβ3抗体)、タリズマブ(抗IgE抗体)、タネズマブ(tanezumab)(抗NGF抗体)、タプリツモマブ(taplitumomab)(抗CD19抗体)、テフィバズマブ(Tefibazumab)(別名:Aurexis、抗クランピング因子A抗体)、テリモマブ(Telimomab)、テナツモマブ(Tenatumomab)(抗テネイシンC抗体)、テネリキシマブ(Teneliximab)(抗CD40抗体)、テプリズマブ(Teplizumab)(抗CD3抗体)、TGN1412(抗CD28抗体)、チシリムマブ(別名:Tremelimumab、抗CTLA-4抗体)、ティガツズマブ(Tigatuzumab)(抗TRAIL-R2抗体)、TNX-650(抗IL-13抗体)、トシリズマブ(別名Atlizumab、Actemra、RoActemra、(抗IL-6受容体抗体)、トラリズマブ(Toralizumab)(抗CD154(CD40L)抗体)、トシツモマブ(抗CD20抗体)、トラスツズマブ(別名:Herceptin、抗HER2/neu抗体)、トレメリムマブ(Tremelimumab)(抗CTLA-4抗体)、ツコツズマブセルモロイキン(Tucotuzumab celmoleukin)(抗EpCAM抗体)、ツビルマブ(tuvirumab)(抗B型肝炎抗体)、ウルトキサズマブ(Urtoxazumab)(抗大腸菌抗体)、ウステキヌマブ(Ustekinumab)(別名:Stelara、抗IL-12、IL-23抗体)、バパリキシマブ(Vapaliximab)(抗AOC3(VAP-1)抗体)、ベドリズマブ(Vedolizumab)、(抗インテグリンα4β7抗体)、ベルツズマブ(抗CD20抗体)、ベパリモマブ(Vepalimomab)(抗AOC3(VAP-1))抗体)、ビシリズマブ(別名:Nuvion、抗CD3抗体)、ビタキシン(抗血管新生インテグリンavb3抗体)、ボロシキシマブ(Volociximab)(抗インテグリンα5β1)、ボツムマブ(Votumumab)(別名:HumaSPECT、抗腫瘍抗原CTAA16.88抗体)、ザルツムマブ(別名:HuMax-EGFr、(抗EGFR抗体)、ザノリムマブ(別名:HuMax-CD4、抗CD4抗体)、ジラリムマブ(Ziralimumab)(抗CD147(基本免疫グロブリン)抗体)、ゾリモマブ(zolimomab)(抗CD5抗体)、エタネルセプト(登録商標「Enbrel」)、アレファセプト(Alefacept)(登録商標「Amevive」)、アバタセプト(登録商標「Orencia」)、リロナセプト(Rilonacept)(Arcalyst)、14F7[抗IRP-2(鉄調節タンパク質2)抗体]、14G2a(Nat.Cancer Inst.から黒色腫及び固形腫瘍のための抗ガングリオシドGD2抗体)、J591(Weill Cornell Medical Schoolから前立腺癌を治療するための抗PSMA抗体、)、225.28S[黒色腫のための抗HMW-MAA(高分子量黒色腫関連抗原)抗体、Sorin Radiofarmaci S.R.L.(ミラノ、イタリア)]、COL-1(Nat. Cancer Inst.から大腸癌及び胃癌のための抗CEACAM3抗体、CGM1)、CYT-356(登録商標「Oncoltad」、前立腺癌)、HNK20(Ora Vax Inc.からRSウイルスのための)、ImmuRAIT(IMMUNOMEDICSから非ホジキンリンパ腫のための)、Lym-1(抗HLA-DR10抗体、Peregrine Pharmから腫瘍のため)、MAK-195F[Abbott/Knollから敗血症、毒素ショックのための抗TNF(腫瘍壊死因子;TNFA、TNF-α;TNFSF2)抗体]、MEDI-500[別名:T10B9、MedImmune Incから移植片対宿主病のための抗CD3抗体、TRαβ(T細胞受容体α/β)、]、RING SCAN[Neoprobe Corp.から乳癌、結腸癌及び結腸直腸癌のための抗TAG72(腫瘍関連糖タンパク質72)抗体)]、Avicidin(抗EPCAM(上皮細胞接着分子)抗体)、抗TACSTD1(腫瘍関連カルシウムシグナルトランスデューサー1)抗体、抗GA733-2(胃腸腫瘍関連タンパク質2)抗体、抗EGP-2(上皮糖タンパク質2)抗体;抗KSA抗体;KS1/4抗原;M4S;腫瘍抗原17-1A;NeoRx Corp.から結腸癌、卵巣癌、前立腺癌、及び非ホジキンリンパ腫のためのCD326;LYMPHOCIDE(IMMUNOMEDICS、NJ)、スマートID10(Protein Design Labs)、Oncolym(Techniclone Inc、CA)、Allomune(BioTransplant、CA)、抗VEGF抗体(ジェネンテック、CA);CEAcide(Immunomedics、NJ)、IMC-1C11(ImClone Systems、NJ)、並びにセツキシマブ(ImClone、NJ)。
、α5β1、α6β4、α7β7、αIIβ3、α5β5、αvβ5)、インターフェロンγ誘導タンパク質、ITAGA2、ITGB2、KIR2D、Kappa Ig、LCK、Le、レグマイン、ルイス-Y抗原、LFA-1(リンパ球機能関連抗原1、CD11a)、LHRH、LINGO-1、リポタイコ酸、LIV1A、LMP2、LTA、MAD-CT-1、MAD-CT-2、MAGE-1、MAGE-2、MAGE-3、MAGEA1、MAGEA3、MAGE4、MART1、MCP-1、MIF(マクロファージ遊走阻止因子又はグリコシル化阻害因子(GIF))、MS4A1(膜貫通4ドメインサブファミリーAメンバー1)、MSLN(メソテリン)、MUC1(ムチン1、細胞表面関連(MUC1)又はPolymorphic epithelial mucin(PEM))、MUC1-KLH、MUC16(CA125)、MCP1(単球走化性タンパク質1)、MelanA/MART1、ML-IAP、MPG、MS4A1(膜貫通型4ドメインサブファミリーA)、MYCN、ミエリン関連糖タンパク質、ミオスタチン、NA17、NARP-1、NCA-90(顆粒球抗原)、Nectin-4(ASG-22ME)、NGF、神経アポトーシス制御プロテイナーゼ1、NOGO-A、Notch受容体、ヌクレオリン、Neu癌遺伝子産物、NY-BR-1、NY-ESO-1、OX-40、OxLDL(酸化低密度リポタンパク質)、OY-TES1、P21、p53非変異体、P97、Page4、PAP、抗(N-グリコリルノイラミン酸)のパラトープ、PAX3、PAX5、PCSK9、PDCD1(PD-1、プログラムされた細胞死タンパク質1)、PDGF-Rα、(血小板由来成長因子受容体α)、PDGFR-β、PDL-1、PLAC1、PLAP様精巣アルカリホスファターゼ、血小板由来成長因子受容体β、リン酸ナトリウム共輸送体、PMEL17、ポリシアル酸、プロテイナーゼ3(PR1)、前立腺癌、PS(ホスファチジルセリン)、前立腺癌細胞、緑膿菌、PSMA、PSA、PSCA、狂犬病ウイルス糖タンパク質、RHD(Rhポリペプチド1(RhPI))、アカゲザル因子(Rhesus factor)、RANKL、PhoC,Ras変異体、RGS5、ROBO4、RSウイルス、RON、ROR1、肉腫転移ブレイクポイント、SART3、スクレロスチン、SLAMF7(SLAMファミリーメンバー7)、セレクチンP、SDC1(シンデカン1)、sLe(a)、ソマトメジンC、SIP(スフィンゴシン-1-ホスフェート)、ソマトスタチン、精子タンパク質17、SSX2、STEAP1(前立腺1の6回膜貫通上皮抗原)、STEAP2、STn、TAG-72(腫瘍関連糖タンパク質72)、サバイビン、T細胞受容体、T細胞膜貫通タンパク質、TEM1(腫瘍上皮マーカー1)、TENB2、テナスシンC(TN-C)、TGF-α、TGF-β(トランスフォーミング増殖因子β)、TGF-β1、TGF-β2(トランスフォーミング増殖因子β2)、Tie(CD202b)、Tie2、TIM-1(CDX-014)、TN、TNF、TNF-α、TNFRSF8、TNFRSF10B(腫瘍壊死因子受容体スーパーファミリーメンバー10B)、TNFRSF13B(腫瘍壊死因子受容体スーパーファミリーメンバー13B)、TPBG(栄養膜糖タンパク質)、TRAIL-R1(腫瘍壊死アポトーシス誘導リガンド受容体1)、TRAILR2(細胞死受容体5(DR5))、腫瘍関連カルシウムシグナルトランスデューサー2、MUC1の腫瘍特異的グリコシル化、TWEAK受容体、TYRP1(糖タンパク質75)、TRP-1(Trop1)、TRP-2(Trop2)、チロシナーゼ、VCAM-1、VEGF、VEGF-A、VEGF-2、VEGFR-1、VEGFR2、又はビメンチン、WT1、XAGE1、又は任意のインスリン成長因子受容体を発現する細胞、又は任意の上皮増殖因子受容体。
は、本特許の側鎖連結体との連結部位である;X4及びY1は独立して、O、NH、NHNH、NR1、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH2、C(O)NHNHC(O)、及びC(O)NR1である;X1は、H、CH2、OH、O、C(O)、C(O)NH、C(O)N(R1)、R1、NHR1、NR1、C(O)R1、又はC(O)Oである;X5は、H、CH3、F、又はClである;M1及びM2は独立して、H、Na、K、Ca、Mg、NH4、N(R12R12’R13R13’)である;R12、R12’、R13、及びR13’は、式(I)で定義されている。
は、式(I)又は上記で定義されているものと同じである;
は、一本鎖又は二本鎖のDNA、RNA、mRNA、siRNA、miRNA、又はpiRNAである;Yは好ましくは、O、S、NH、又はCH2である。
a)アルキル化剤:ナイトロジェンマスタード:クロラムブシル、クロルナファジン、シクロホスファミド、ダカルバジン、エストラムスチン、イホスファミド、メクロレタミン、塩酸メクロレタミンオキサイド、マンノムスチン、ミトブロニトール、メルファラン、ミトラクトール、ピポブロマン、ノベンビチン、フェネステリン、プレドニムスチン、チオテパ、トロホスファミド、ウラシルマスタード;CC-1065並びにアドゼレシン、カルゼレシン及びビゼレシンの合成類似体;デュオカルマイシン並びにその合成類似体であるKW-2189及びCBI-TMI;ベンゾジアゼピン二量体又はピロロベンゾジアゼピン(PBD)二量体、トマイマイシン二量体、インドリノベンゾジアゼピン二量体、イミダゾベンゾチアヂアゼピン二量体、又はオキサゾリジノベンゾジアゼピン二量体;カルムスチン、ロムスチン、クロロゾトシン、フォテムスチン、ニムスチン、ラニムスチンを含むニトロソ尿素化合物;ブスルファン、トレオスルファン、イムプロスルファン、及びピポスルファンを含むアルキルスルホネート;トリアゼン又はダカルバジン;カルボプラチン、シスプラチン、及びオキサリプラチンを含む白金含有化合物;アジリジン類、ベンゾドパ、カルボクオン、メツレドパ、及びウレドパ;エチレンイミン類、並びにアルトレタミン、トリエチレンメラミン、トリエチレンホスホルアミド、トリエチレンチオホスホルアミン、トリメチロロメラミン(trimethylolomelamine)を含むメチラメラミン類等;
b)植物アルカロイド:ビンクリスチン、ビンブラスチン、ビンデシン、ビノレルビン、ナベルビンを含むビンカアルカロイド類;パクリタキセル及びドセタキセルを含むタキソイド類並びにこれらの類似体;DM1、DM2、DM3、DM4、DM5、DM6、DM7、メイタンシン、アンサマイトシンを含むメイタンシノイド類並びにこれらの類似体;クリプトフィシン1及びクリプトフィシン8等のクリプトフィシン類;エポチロン類、エリュテロビン、ディスコデルモライド、ブリオスタチン類、ドロスタチン類、オーリスタチン類、チューブリシン類、セファロスタチン類;パンクラチスタチン;サルコジクチイン;スポンジスタチン糖;
c)DNAトポイソメラーゼ阻害剤:9-アミノカンプトテシン、カンプトテシン、クリスナトール、ダウノマイシン、エトポシド、リン酸エトポシド、イリノテカン、ミトキサントロン、ノバントロン、レチノイン酸(レチノール類)、テニポシド、トポテカン、9-ニトロカンプトテシン又はRFS 2000を含むエピポドフィリン類;及びマイトマイシン類、並びにそれらの類縁体等;
d)代謝拮抗剤:{[抗葉酸:(例えば、DHFR阻害剤:メトトレキサート、トリメトレキサート、デノプテリン、プテロプテリン、アミノプテリン(4-アミノプテロイン酸)、又はその他の葉酸類縁体);IMPデヒドロゲナーゼ阻害剤(例えば、ミコフェノール酸、チアゾフリン、リバビリン、EICAR);リボヌクレオチド還元酵素阻害薬(例えば、ヒドロキシウレア、デフェロキサミン)];[ピリミジン類縁体:ウラシル類縁体(例えば、アンシタビン、アザシチジン、6-アザウリジン、カペシタビン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、5-フルオロウラシル、フロクスウリジン、ラルチトレキセド。);シトシン類似体:(例えば、シタラビン、シトシンアラビノシド、フルダラビン);プリン類縁体:(例えば、アザチオプリン、フルダラビン、メルカプトプリン、チアミプリン、チオグアニン)];フォリン酸等の葉酸補充剤}等;
e)ホルモン療法剤:受容体拮抗薬:[抗エストロゲン:(例えば、メゲストロール、ラロキシフェン、タモキシフェン);LHRHアゴニスト:(ゴセレリン、酢酸リュープロリドを含む);抗アンドロゲン:(例えば、ビカルタミド、フルタミド、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、ゴセレリン、リュープロリド、メピチオスタン、ニルタミド、テストラクトン、トリロスタン、及び他の類似のアンドロゲン阻害剤)];レチノイド類/三角筋:[例えば、ビタミンD3類縁体:(CB1093、EB1089、KH1060、コレカルシフェロール、エルゴカルシフェロール);光線力学的療法剤:(例えば、ベルテポルフィン、フタロシアニン、光増感剤Pc4、デメトキシヒポクレリンA);サイトカイン類:(例えば、インターフェロンα、インターフェロンγ、腫瘍壊死因子(TNF)、TNFドメイン含有ヒトタンパク質)]}等;
f)キナーゼ阻害剤:BIBW2992(抗EGFR/Erb2)、イマチニブ、ゲフィチニブ、ペガプタニブ、ソラフェニブ、ダサチニブ、スニチニブ、エルロチニブ、ニロチニブ、ラパチニブ、アキシチニブ、パゾパニブ、バンデタニブ、E7080(抗VEGFR2)、ムブリチニブ、ポナチニブ、バフェチニブ、ボスチニブ、カボザンチニブ、ビスモデギブ、イニパリブ、ルキソリチニブ、CYT387、アキシチニブ、チボザニブ、ソラフェニブ、ベバシズマブ、セツキシマブ、トラスツズマブ、ラニビズマブ、パニツムマブ、イスピネシブ等;
g)オラパリブ、ニラパリブ、イニパリブ、タラゾパリブ、ベリパリブ、CEP9722(セファロン)、E7016(エーザイ)、BGB-290(ベイジーン)、又は3-アミノベンズアミド等のポリ(ADP-リボース)ポリメラーゼ(PARP)阻害剤;
h)エンジイン系抗生物質(例えば、カリケアマイシン類、特にカリケアマイシンγ1、δ1、α1、又はβ1(J.Med.Chem.,39(11),2103-2117(1996)、Angew Chem Intl.Ed.Engl.33:183-186(1994)参照);ダイネミシンA及びデオキシダイネミシンを含むダイネミシン;エスペラミシン、ケダルシジン、C-1027、マズロペプチン、又はネオカルジノスタチンクロモフォア及び関連する色素タンパク質エンジイン抗生物質クロモフォアから選択される。)、アクラシノマイシン類、アクチノマイシン、アンスラマイシン(authramycin)、アザセリン、ブレオマイシン類、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン、カルジノフィリン;クロモマイシン類、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、ドキソルビシン、モルホリノ-ドキソルビシン、シアノモルホリノ-ドキソルビシン、2-ピロリノ-ドキソルビシン及びデオキシドキソルビシン、エピルビシン、エリブリン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン類(nitomycins)、ミコフェノール酸、ノガラマイシン、オリボマイシン類、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン(streptonigrin)、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシン等の抗生物質;
i)その他:ポリケチド(アセトゲニン類)等、特にブラタシン及びブラタシノン;ゲムシタビン、エポキソミシン類(例えば、カルフィルゾミブ)、ボルテゾミブ、サリドマイド、レナリドミド、ポマリドマイド、トセドスタット、ザイブレスタット、PLX4032、STA-9090、スチムバックス(Stimuvax)、アロベクチン-7、ザイゲバ、プロベンジ、エルボイ、イソプレニル化阻害剤(例えば、ロバスタチン)、ドーパミン作動性神経毒(例えば、1-メチル-4-フェニルピリジンイオン)、細胞周期阻害剤(例えば、スタウロスポリン)、アクチノマイシン類(例えば、アクチノマイシンD、ダクチノマイシン)、アマニチン類、ブレオマイシン類(例えば、ブレオマイシンA2、ブレオマイシンB2、ペプロマイシン)、アントラサイクリン類(例えば、ダウノルビシン、ドキソルビシン(アドリアマイシン)、イダルビシン、エピルビシン、ピラルビシン、ゾルビシン)、ミトキサントロン、MDR阻害剤(例えば、ベラパミル)、Ca2+ATP阻害剤(例えば、タプシガルギン)、ヒストン脱アセチル化酵素阻害剤(ボリノスタット、ロミデプシン、パノビノスタット、バルプロ酸、モセチノスタット(MGCD0103)、ベリノスタット、PCI-24781、エンチノスタット、SB939、レスミノスタット、ギビノスタット、AR-42、CUDC-101、スルフォラファン、トリコスタチンAを含む。);タプシガルギン、セレコキシブ、グリタゾン類、エピガロカテキンガレート、ジスルフィラム、サリノスポラミドA、抗副腎薬(アミノグルテチミド、ミトタン、トリロスタンカからなる群から選択される);アセグラトン;アルドホスファミドクリコシド;アミノレブリン酸;アムサクリン(amsacrine);アラビノシド、ベストラブシル;ビサントレン;エダトレキサート;デフォファミン;デメコルシン;ジアジコン;エルフォルニチン(DFMO)、エルフォミチン;酢酸エリプチニウム;エトクルシド、硝酸ガリウム、ガシトシン、ヒドロキシ尿素;イバンドロネート、レンチナン;ロニダミン;ミトグアゾン;モピダモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テニュアゾン酸;トリアジコン;2,2’,2’’-トリクロロトリエチルアミン;トリコテセン類(特に、T2トキシン、ベルカリンA、ロリジンA、及びアングイジンを含む。);ウレタン、siRNA、アンチセンス医薬、及び核酸分解酵素;
a)アミノグリコシド類:アミカシン、アストロマイシン、ゲンタマイシン(ネチルマイシン、シソマイシン、イセパマイシン)、ハイグロマイシンB、カナマイシン(アミカシン、アルベカシン、ベカナマイシン、ジベカシン、トブラマイシン)、ネオマイシン(フラマイシン、パロモマイシン、リボスタマイシン)、ネチルマイシン, スペクチノマイシン、ストレプトマイシン、トブラマイシン、ベルダミシン;
b)アンフェニコール類:アジダムフェニコール、クロラムフェニコール、フロルフェニコール、チアンフェニコール;
c)アンサマイシン類:ゲルダナマイシン、ハービマイシン;
d)カルバペネム類:ビアペネム、ドリペネム、エルタペネム、イミペネム、シラスタチン、メロペネム、パニペネム;
e)セフェム類:カルバセフェム(ロラカルベフ)、セファセトリル、セファクロル、セフラジン、セファドロキシル、セファロニウム、セファロリジン、セファロチン又はセファロチン、セファレキシン、セファログリシン、セファマンドール、セファピリン、セファトリジン、セファザフル、セファゼドン、セファゾリン、セフブペラゾン、セフカペン、セフダロキシム、セフェピム、セフミノックス、セフォキシチン、セフプロジル、セフロキサジン、セフテゾル、セフロキシム、セフィキシム、セフジニル、セフジトレン、セフェピム、セフェタメト、セフメノキシム、セフォジジム、セフォニシド、セフォペラゾン、セフォラニド、セフォタキシム、セフォチアム、セフォゾプラン、セファレキシン、セフピミゾール、セフピラミド、セフピロム、セフポドキシム、セフプロジル、セフキノム、セフスロジン、セフタジジム、セフテラム、セフチブテン、セフチオレン、セフチゾキシム、セフトビプロル、セフトリアキソン、セフロキシム、セフゾナム、セファマイシン(セフォキシチン、セフォテタン、セフメタゾールを含む。)、オキサセフェム(フロモキセフ、ラタモキセフ);
f)糖ペプチド類:ブレオマイシン、バンコマイシン(オリタバンシン、テラバンシンを含む。)、テイコプラニン(ダルババンシン)、ラモプラニン;
g)グリシルサイクリン類:例えば、チゲサイクリン;
h)β-ラクタマーゼ阻害剤:ペナム(スルバクタム、タゾバクタム)、クラバム(クラブラン酸);
i)リンコサミド類:クリンダマイシン、リンコマイシン;
j)リポペプチド類:ダプトマイシン、A54145、カルシウム依存性抗生物質(CDA);
k)マクロライド類:アジスロマイシン、セスロマイシン、クラリスロマイシン、ジリスロマイシン、エリスロマイシン、フルリスロマイシン、ジョサマイシン、ケトライド(テリスロマイシン、セスロマイシン)、ミデカマイシン、ミオカマイシン、オレアンドマイシン、リファマイシン(リファンピシンン、リファンピン、リファブチン、リファペンチン)、ロキタマイシン、ロキシスロマイシン、スペクチノマイシン、スピラマイシン、タクロリムス(FK506)、トロレアンドマイシン、テリスロマイシンン;
l)モノバクタム類:アズトレオナム、チゲモナム;
m)オキサゾリジノン類:リネゾリド;
n)ペニシリン類:アモキシシリン、アンピシリン、ピバンピシリン、ヘタシリン、バカンピシリン、メタンピシリン、タランピシリン、アジドシリン、アズロシリン、ベンジルペニシリン、ベンザチンベンジルペニシリン、ベンザチンフェノキシメチルペニシリン、クロメトシリン、プロカインベンジルペニシリン、カルベニシリン(カリンダシリン)、クロキサシリン、ジクロキサシリン、エピシリン、フルクロキサシリン、メシリナム(ピブメシリナム)、メズロシリン、メチシリン、ナフシリン、オキサシリン、ペナメシリン、ペニシリン、フェネチシリン、フェノキシメチルペニシリン、ピペラシリン、プロピシリン、スルベニシリン、テモシリン、チカルシリン;
o)ポリペプチド類:バシトラシン、コリスチン、ポリミキシンB;
p)キノロン類:アラトロフロキサシン、バロフロキサシン、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、ジフロキサシン、エノキサシン、エンロフロキサシン、フロキシン、ガレノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、カノトロバフロキサシン、レボフロキサシン、ロメフロキサシン、マルボフロキサシン、モキシフロキサシン、ナジフロキサシン、ノルフロキサシン、オルビフロキサシン、オフロキサシン、ペフロキサシン、トロバフロキサシン、グレパフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン;
q)ストレプトグラミン類:プリスチナマイシン、キヌプリスチン/ダルフォプリスチン;
r)スルホンアミド類:マフェニド、プロントジル、スルファセタミド、スルファメチゾール、スルファニルアミド、スルファサラジン、スルフィソキサゾール、トリメトプリム、トリメトプリム-スルファメトキサゾール(コ-トリモキサゾール);
s)ステロイド系抗菌薬:フシジン酸から選択される;
t)テトラサイクリン類:ドキシサイクリン、クロルテトラサイクリン、クロモサイクリン、デメクロサイクリン、リメサイクリン、メクロサイクリン、メタサイクリン、ミノサイクリン、オキシテトラサイクリン、ペニメピサイクリン、ロリテトラサイクリン、テトラサイクリン、グリシルサイクリン(例えば、チゲサイクリン);
u)その他の抗生物質:アンノナシン、アルスフェナミン、バクトプレノール阻害剤(バシトラシン)、DADAL/AR阻害剤(サイクロセリン)、ジクチオスタチン、ディスコデルモライド、エレウテロビン、エポチロン、エタンブトール、エトポシド、ファロペネム、フシジン酸、フラゾリドン、イソニアジド、ラウリマリド、メトロニダゾール、ムピロシン、マイコラクトン、NAM合成阻害剤(例えば、ホスホマイシン)、ニトロフラントイン、パクリタキセル、プラテンシマイシン、ピラジナミド、キヌプリスチン/ダルホプリスチン、リファンピシン(リファンピン)、タゾバクタムチニダゾール、ウバリシン;
a)侵入/融合阻害剤:アプラビロック、マラビロク、ビクリビロック、gp41(エンフビルチド)、PRO140、CD4(イバリズマブ);
b)インテグラーゼ阻害剤:ラルテグラビル、エルビテグラビル、グロボイドナンA;
c)成熟阻害剤:ベビリマット、ヴィヴェコン;
d)ノイラミニダーゼ阻害剤:オセルタミビル、ザナミビル、ペラミビル;
e)ヌクレオシド及びヌクレオチド:アバカビル、アシクロビル、アデフォビル、アムドキソビル、アプリシタビン、ブリブジン、シドフォビル、クレブジン、デキセルブシタビン、ジダノシン(DDI)、エルブシタビン、エムトリシタビン(FTC)、エンテカビル、ファムシクロビル、フルオロウラシル(5-FU)、3’-フルオロ置換2’,3’-デオキシヌクレオシド類似体(3’-フルオロ-2’,3’-ジデオキシチミジン(FLT)及び3’-フルオロ-2’,3’-ジデオキシグアノシン(FLG)からなる群を含む)、ホミビルセン、ガンシクロビル、イドクスウリジン、ラミブジン(3TC)、L-ヌクレオシド(β-L-チミジン及びβ-L-2’-デオキシシチジンからなる群を含む)、ペンシクロビル、ラシビル、リバビリン、スタンピジン、スタブジンセット(d4T)、タリバビリン(ビラミジン)、テルビブジン、テノホビル、トリフルリジン、バラシクロビル、バルガンシクロビル、ザルシタビン(ddC)、ジドブジン(AZT);
f)非ヌクレオシド:アマンタジン、アテビリジン、カプラビリン、ジアリルピリミジン(エトラビリン、リルピビリン)、デラビルジン、ドコサノール、エミビリン、エファビレンツ、ホスカルネット(ホスホリルギ酸)、イミキモド、インターフェロンα、ロビリド、ロデノシン、メチサゾン、ネビラピン、NOV-205、ペグインターフェロンα、ポドフィロトキシン、リファンピシン、リマンタジン、レシキモド(R-848)、トロマンタジン;
g)プロテアーゼ阻害剤:アンプレナビル、アタザナビル、ボセプレビル、ダルナビル、ホスアンプレナビル、インジナビル、ロピナビル、ネルフィナビル、プレコナリル、リトナビル、サキナビル、テラプレビル(VX-950)、チプラナビル;
h)その他の抗ウイルス薬:アブザイム、アルビドール、カラノリドA、セラゲニン、シアノビリン-N、ジアリルピリミジン、没食子酸エピガロカテキン(EGCG)、ホスカルネット、グリフィスシン、タリバビリン(ビラミジン)、ヒドロキシウレア、KP-1461、ミルテフォシン、プレコナリル、ポートマントー阻害剤、リバビリン、セリシクリブ。
Claims (21)
- 式(I)の側鎖連結共役体化合物:
式中、
は単結合を表す;nは1~30である;
Tは、抗体;一本鎖抗体;標的細胞に結合する抗体断片;モノクローナル抗体;一本鎖モノクローナル抗体;又は標的細胞に結合するモノクローナル抗体断片;キメラ抗体;標的細胞に結合するキメラ抗体断片;ドメイン抗体;標的細胞に結合するドメイン抗体断面;抗体を模倣したアドネクチン;DARPins;リンホカイン;ホルモン;ビタミン;成長因子;コロニー刺激因子;又は栄養輸送分子;トランスフェリン;結合ペプチド、又はタンパク質、又は抗体、又はアルブミンに結合した小分子、ポリマー、デンドリマー、リポソーム、ナノ粒子、小胞、又は(ウイルス)カプシドからなる群から選択される細胞結合剤/分子である;
L1及びL2は独立して、同一の又は異なる、O、NH、N、S、P、NNH、NHNH、N(R3)、N(R12)、N(R12)N(R12’)、CH、CO、C(O)NH、C(O)O、NHC(O)NH、NHC(O)O、式(OCH2CH2)pOR12、(OCH2CH-(CH3))pOR12、NH(CH2CH2O)pR12、NH(CH2CH(CH3)O)pR12、N[(CH2CH2O)pR12]-[(CH2CH2O)p’R12’]、(OCH2CH2)pCOOR12、若しくはCH2CH2(OCH2CH2)pCOOR12のポリエチレンオキシ単位(p及びp’は独立して、0から約1000から選択される整数である)、又はそれらの組み合わせ;C1-C8アルキル;C2-C8ヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;又は(Aa)r(r=1-12(1~12アミノ酸単位)であり、天然又は非天然アミノ酸、あるいは同一又は異なるジペプチド、トリペプチド、テトラペプチド、ペンタペプチド、ヘキサペプチド、ヘプタペプチド、オクタペプチド、ノナペプチド、デカペプチド、ウンデカペプチド、若しくはドデカペプチド単位から構成される。)から選択される;
WはC1-C8の拡張単位であり、通常は自壊性スペーサー、ペプチド単位、ヒドラゾン、ジスルフィド、チオエーテル、エステル、又はアミド結合である;wは1、2、又は3である;
V1及びV2は独立してスペーサー単位であり、O、NH、S、C1-C8アルキル、C2-C8ヘテロアルキル、アルケニル、若しくはアルキニル、C3-C8アリール、複素環、炭素環、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、ヘテロアルキルシクロアルキル、若しくはアルキルカルボニル、又は(Aa)r(r=1-12(1~12アミノ酸単位)であり、天然又は非天然アミノ酸、あるいは同一又は異なるジペプチド、トリペプチド、テトラペプチド、ペンタペプチド、ヘキサペプチド、ヘプタペプチド、オクタペプチド、ノナペプチド、デカペプチド、ウンデカペプチド、若しくはドデカペプチド単位から構成される。);又は(CH2CH2O)p(p;0-1000);並びにv1及びv2は独立して0、1、又は2であるが、v1及びv2は同時に0である;v1又はv2が0の場合、側鎖Q1又はQ2フラグメントの一方が存在しないことを意味する;
Q1及びQ2は独立して、式(I-q1)で表される:
式中、
は、L1又はL2との結合部位である;G1及びG2はそれぞれ独立して、OC(O)、NHC(O)、C(O)、CH2、NH、OC(O)NH、NHC(O)NH、O、S、B、P(O)(OH)、NHP(O)(OH)、NHP(O)(OH)NH、CH2P(O)(OH)NH、OP(O)(OH)O、CH2P(O)(OH)O、NHS(O)2、NHS(O)2NH、CH2S(O)2NH、OS(O)2O、CH2S(O)2O、Ar、ArCH2、ArO、ArNH、ArS、ArNR1、又は(Aa)q1;G3は、OH、SH、OR12、SR12、OC(O)R12、NHC(O)R12、C(O)R12、CH3、NH2、NR12、+NH(R12)、+N(R12)(R12’)、C(O)OH、C(O)NH2、NHC(O)NH2、BH2、BR12R12’、P(O)(OH)2、NHP(O)(OH)2、NHP(O)(NH2)2、S(O)2(OH)、(CH2)q1C(O)OH、(CH2)q1P(O)(OH)2、C(O)(CH2)q1C(O)OH、OC(O)(CH2)q1C(O)OH、NHC(O)(CH2)q1C(O)OH、CO(CH2)q1P(O)(OH)2、NHC(O)O(CH2)q1C(O)OH、OC(O)NH(CH2)q1C(O)OH、NHCO(CH2)q1-P(O)(OH)2、NHC(O)(NH)(CH2)q1C(O)OH、CONH(CH2)q1P(O)(OH)2、NHS(O)2(CH2)q1C(O)OH、CO(CH2)q1S(O)2(OH)、NHS(O)2NH(CH2)q1C(O)OH、OS(O)2NH(CH2)q1C(O)OH、NHCO(CH2)q1S(O)2(OH)、NHP(O)(OH)(NH)(CH2)q1C(O)OH、CONH(CH2)q1S(O)(OH)、OP(O)(OH)2、(CH2)q1P(O)(NH)2、NHS(O)2(OH)、NHS(O)2NH2、CH2S(O)2NH2、OS(O)2OH、OS(O)2OR1、CH2S(O)2OR12、Ar、ArR12、ArOH、ArNH2、ArSH、ArNHR12、又は(Aa)q1である;(Aa)q1は、同一の又は異なる天然又は非天然アミノ酸を含むペプチドである;X1及びX2は独立して、O、CH2、S、S(O)、NHNH、NH、N(R12)、+NH(R12)、+N(R12)(R12’)、C(O)、OC(O)、OC(O)O、OC(O)NH、NHC(O)NHである;Y2はO、NH、NR12、CH2、S、NHNH、Arである;p1、p2、及びp3は独立して0~100であるが、同時に0ではない;q1及びq2は独立して0~24である;R12、R12’、R13、及びR13’は独立して、H、C1~C8アルキル;C2~C8ヘテロアルキル、又は複素環;C3~C8アリール、Ar-アルキル、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、炭素環、又はアルキルカルボニルである;
Y2は O、NH、NR1、CH2、S、NHNH、Arである;
p1、p2、及びp3は独立して0~100であるが、同時に0ではない;
q1及びq2は独立して0~24である;
あるいは、Q1及びQ2は独立して、線状又は分岐の、C2-C100ポリカルボン酸、C2-C90ポリアルキルアミン、C6-C90オリゴ糖類若しくは多糖類、四級アンモニウムカチオン及び/若しくはスルフォネートアニオンからなるC6-C100双性イオン性ベタイン若しくは双性イオン性ポリ(スルホベタイン))(PSB)、又はポリ(乳酸/グリコール酸)(PLGA)、ポリ(アクリレート)、キトサン、N-(2-(2-ヒドロキシプロピル)メタクリルアミドの共重合体、ポリ[2-(メタクリロイルオキシ)エチルホスホリルコリン](PMPC)、ポリ-L-グルタミン酸、ポリ(ラクチド-co-グリコリド)(PLG)、ポリ(ラクチド-co-グリコリド)、ポリ(エチレングリコール)(PEG)、ポリ(プロピレングリコール)(PPG)、ポリ(ラクチド-co-グリコリド)、ポリ(エチレングリコール)修飾ペプチド、ポリ(エチレングリコール)-アミノ酸又はペプチドを含む、ポリ(エチレングリコール)-修飾脂質、ポリ-グリシン、ポリ-N-メチル-グリシン、ポリ(エチレングリコール)-修飾アルキルカルボン酸、ポリ(エチレングリコール)-修飾アルキルアミン、ポリ(ラクチド-co-グリコリド、ヒアルロン酸(HA)(グリコサミノグリカン)、ヘパリン/ヘパラン硫酸(HSGAG)、コンドロイチン硫酸/デルマタン硫酸(CSGAG)、ポリ(エチレングリコール)修飾アルキル硫酸塩、ポリ(エチレングリコール)修飾アルキルリン酸、又はポリ(エチレングリコール)-修飾アルキル四級アンモニウム等で構成される、C6-C100生分解性ポリマーである;
あるいは、W、Q1、Q2、L1、L2、V1、又はV2のいずれか1以上は独立して不存在でもよいが、Q1及びQ2が同時に不存在ではない;
Dは、カリケアマイシン類、メイタンシノイド類、カンプトテシン類、タキサン類、アントラサイクリン類(ダウノルビシン/ドキソルビシン)、ビンカアルカロイド類、オーリスタチン類、エリブリン類、(ピロロ)ベンゾジアゼピン類(PBD)、CC-106/デュオカルマイシン類、チューブリシン類、アマトキシン類(アマニチン等)、プロテインキナーゼ阻害剤、MEK阻害剤、KSP阻害剤、ニコチンアミドホスホリボシルトランスフェラーゼ(NAMPT)阻害剤、免疫毒素、これらの化合物の類縁体又はプロドラッグから独立して選択される、細胞毒性剤である。 - 細胞結合分子Tと容易に反応して、請求項1に記載の式(I)の共役体を形成することができる、式(IV)の側鎖連結化合物:
式中、
D、W、w、L1、L2、Q1、Q2、V1、V2、v1、v2、及びnは、請求項1と同じ定義である;
Lv1は、細胞結合分子上のチオール、アミン、カルボン酸、セレノール、フェノール、又はヒドロキシル基と反応することができる脱離基を表し、Lv1は、OH;F;Cl;Br;I;ニトロフェノール;N-ヒドロキシスクシンイミド(NHS);フェノール、ジニトロフェノール、ペンタフルオロフェノール、テトラフルオロフェノール;ジフルオロフェノール;モノフルオロフェノール;ペンタクロロフェノール;トリフレート;イミダゾール;ジクロロフェノール;テトラクロロフェノール;1-ヒドロキシベンゾトリアゾール;トシレート;メシレート;2-エチル-5-フェニルイソキサゾリウム-3’-スルホネート、自己で若しくは無水酢酸、無水ホルミル等の他の無水物とで形成される無水物:又はペプチドカップリング反応若しくはミツノブ反応のための縮合試薬で生成された中間体分子から選択され;前記縮合試薬は、EDC(N-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド)、DCC(ジシクロヘキシル-カルボジイミド)、N,N’-ジイソプロピルカルボジイミド(DIC)、N-シクロヘキシル-N’-(2-モルホリノエチル)カルボジイミドメソ-p-トルエンスルホナート(CMC、又はCME-CDI)、1,1’-カルボニルジイミダゾール(CDI)、TBTU(O-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボラート)、N,N,N’,N’-テトラメチル-O-(1H-ベンゾトリアゾール-1-イル)ウロニウムヘキサフルオロホスファート(HBTU)、(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ァート(BOP)、(ベンゾトリアゾール-1-イルオキシ)トリピロリジノホスホニウムヘキサフルオロホスファート(PyBOP)、ジエチルシアノホスホネート(DEPC)、クロロ-N,N,N’,N’-テトラメチルホルムアミジニウムヘキサフルオロホスファート、1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム-3-オキシドヘキサフルオロホスファート(HATU)、1-[(ジメチルアミノ)(モルホリノ)メチレン]-1H-[1,2,3]トリアゾロ[4,5-b]ピリジン-1-イウム-3-オキシドヘキサフルオロホスファート(HDMA)、2-クロロ-1,3-ジメチルイミダゾリジニウムヘキサフルオロホスファート(CIP)、クロロトリピロリジノホスホニウムヘキサフルオロホスファート(PyCloP)、フルオロ-N,N,N’,N’-ビス(テトラメチレン)ホルムアミジニウムヘキサフルオロホスフェート(BTFFH)、N,N,N’,N’-テトラメチル-S-(1-オキシド-2-ピリジル)チウロニウムヘキサフルオロホスフェート、O-(2-オキソ-1(2H)ピリジル)-N,N,N’,N’-テトラメチルチウロニウムテトラフルオロボラート(TPTU)、S-(1-オキシド-2-ピリジル)-N,N,N’,N’-テトラメチルチウロニウムテトラフルオロボラート、O-[(エトキシカルボニル)シアノメチレンアミノ]-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロホスファート(HOTU)、(1-シアノ-2-エトキシ-2-オキソエチリデンアミノオキシ)ジメチルアミノ-モルホリノ-カルベニウムヘキサフルオロホスファート(COMU)、O-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-ビス(テトラメチレン)ウロニウムヘキサフルオロホスファート(HBPyU)、N-ベンジル-N’-シクロヘキシルカルボジイミド(重合体結合と共に、あるいはなし)、ジピロリジノ(N-スクシンイミジルオキシ)-カルベニウムヘキサフルオロホスファート(HSPyU)、クロロジピロリジノカルベニウムヘキサフルオロホスファート(PyCIU)、2-クロロ-1,3-ジメチルイミダゾリニウムテトラフルオロボレート(CIB)、(ベンゾトリアゾール-1-イルオキシ)ジピペリジノカルベニウムヘキサフルオロホスファート(HBPipU)、O-(6-クロロベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート(TCTU)、ブロモトリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスファート(BroP)、プロピルホスホン酸無水物(PPACA、T3P(登録商標))、2-モルホリノエチルイソシアニド(MEI)、N,N,N’,N’-テトラメチル-O-(N-スクシンイミジル)ウロニウムヘキサフルオロホスファート(HSTU)、2-ブロモ-1-エチル-ピリジニウムテトラフルオロボレート(BEP)、O-[(エトキシカルボニル)シアノメチレンアミノ]-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート(TOTU)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド(MMTM,DMTMM)、N,N,N’,N’-テトラメチル-O-(N-スクシンイミジル)ウロニウムテトラフルオロボレート(TSTU)、O-(3,4-ジヒドロ-4-オキソ-1,2,3-ベンゾトリアジン-3-イル)-N,N,N’,N’-テトラメチルウロニウムテトラフルオロボレート(TDBTU)、1,1’-(アゾジカルボニル)ジピペリジン(ADD)、ジ-(4-クロロベンジル)アゾジカルボキシレート(DCAD)、ジ-tert-ブチル アゾジカルボキシレート(DBAD)、ジイソプロピル アゾジカルボキシレート(DIAD)、若しくはジエチルアゾジカルボキシレート(DEAD)から選択され;Lv1は、それ自身により又は他のC1-C8酸無水物と共に形成される無水物とすることができる;Lv1は好ましくは以下から選択される:
式中、X1’は、F、Cl、Br、I、又はLv3である;X2’は、O、NH、N(R1)、又はCH2である;R3は独立して、H、芳香族、複素芳香族、又は1若しくは複数のH原子が独立して-R1、-ハロゲン、-OR1、-SR1、-NR1R2、-NO2、-S(O)R1、-S(O)2R1、又は-COOR1により置換されている芳香族基である;Lv3は、F、Cl、Br、I、ニトロフェノール;N-ヒドロキシスクシンイミド(NHS);フェノール;ジニトロフェノール;ペンタフルオロフェノール;テトラフルオロフェノール;ジフルオロフェノール;モノフルオロフェノール;ペンタクロロフェノール;トリフレート;イミダゾール;ジクロロフェノール;テトラクロロフェノール;1-ヒドロキシベンゾトリアゾール;トシレート;メシレート;2-エチル-5-フェニルイソオキサゾリウム-3’-スルホン酸塩、自己で形成された、若しくは他の無水物、例えば無水酢酸若しくはギ酸無水物と共に形成された無水物から選択される脱離基;あるいは、ペプチドカップリング反応のための、又はミツノブ反応のための縮合試薬により生成された中間体分子である。 - 請求項1、2、3、又は4に記載の側鎖Q1及びQ2は独立して、以下のIq-01からIq-36から選択される:
式中、R25及びR25’は独立して、H;HC(O)、CH3C(O)、CH3C(NH)、NHCH3、COOH、CONH2、CONHCH3、C1-C18アルキル、C1-C18アルキル、アルキル-Y1-SO3H、C1-C18アルキル-Y1-PO3H2、C1-C18アルキル-Y1-CO2H、C1-C18アルキル-Y1-N+R12R13R13’R14、C1-C18アルキル-Y1-CONH2、C2-C18アルキレン、C2-C18エステル、C2-C18エーテル、C2-C18アミン、C2-C18アルキルカルボキシルアミド、C3-C18アリール、C3-C18環状アルキル、C3-C18複素環、1~24アミノ酸; C2-C18脂質、C2-C18脂肪酸、又はC2-C18脂肪アンモニウム脂質;X1及びX2は独立して、NH、N(R12’)、O、CH2、S、C(O)、S(O)、S(O2)、P(O)(OH)、NHNH、CH=CH、Ar、又は(Aa)q1(q1=0~24(0~24アミノ酸、q1=0は不存在を意味する))から選択される;X1、X2、X3、X4、Y1、Y2、及びY3は独立して、NH、N(R12’)、O、C(O)、CH2、S、S(O)、NHNH、C(O)、OC(O)、OC(O)O、OC(O)NH、NHC(O)NH、Ar、又は(Aa)q1から選択され、但し、X1、X2、X3、X4、Y1、Y2、及びY3は独立して不存在でもよい;p1、p2、及びp3は独立して0~100であるが、同時に0ではない;q1、q2、及びq3は独立して0~24である。R12、R13、R13’、及びR14’は独立して、H及びC1-C6アルキルから選択される;Aaは天然又は非天然のアミノ酸である;Ar又は(Aa)q1は、同一の又は異なる配列のペプチドである;q1=0は、(Aa)q1が不存在であることを意味する。 - D、D1、及びD2が以下の式、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマーから独立して選択される、請求項1、2、3、又は4に記載の化合物:
(A)カリケアマイシン類縁体:
(B)メイタンシノイド:
(C)カンプトテシン(CPT)及びその誘導体:
式中、
は接続部位である;R1、R2、及びR4は独立して、H、F、Cl、Br、CN、NO2、C1~C8アルキル;O-C1~C8アルキル;NH-C1~C8アルキル;C2-C8のヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8のアリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;又は炭素数2~8のエステル、エーテル、アミド、カーボネート、尿素、又はカルバメートから選択される;R3はH、OH、NH2、C1~C8アルキル;O-C1~C8アルキル;NH-C1~C8アルキル;C2-C8のヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;又は炭素数2~8のエステル、エーテル、アミド、カーボネート、尿素、又はカルバメートである;あるいは、R1R2、R2R3、及びR3R4は独立して、5~7員の炭素環、複素環、ヘテロシクロアルキル、芳香族、又はヘテロ芳香族環系を形成する;P1はH、OH、NH2、COOH、C(O)NH2、OCH2OP(O)(OR18)2、OC(O)OP(O)(OR18)2、OPO(OR18)2、NHPO(OR18)2、OC(O)R18、OP(O)(OR18)OP(O)(OR18)2、OC(O)NHR18、OC(O)N(C2H4)2NCH3、OSO2(OR18)、O-(C4-C12-配糖体)、OC(O)N(C2H4)2CH2N(C2H4)2CH3、C1-C8の直鎖又は分岐アルキル又はヘテロアルキル;C2-C8の直鎖又は分岐アルケニル、アルキニル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8の直鎖又は分岐アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;カーボネート(-C(O)OR17)、カルバメート(-C(O)NR17R18)である;R17及びR18は独立して、H、直鎖又は分岐アルキル又はヘテロアルキル;C2-C8の直鎖又は分岐アルケニル、アルキニル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8の直鎖又は分岐アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;カーボネート(-C(O)OR17)、カルバメート(-C(O)NR17R18)である。
(D)タキサン及びその類縁体:
(E)アントラサイクリン及びその類縁体:
(F)ビンカアルカロイド:
(G)オーリスタンチン類若しくはドラスタチン類縁体、又は1以上の化学元素の同位体、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマー:
式中、R1、R2、R3、R4、及びR5は独立して、H;C1-C8直鎖若しくは分岐アルキル、アリール、ヘテロアリール、ヘテロアルキル、アルキルシクロアルキル、エステル、エーテル、アミド、アミン、ヘテロシクロアルキル、若しくはアシルオキシルアミン;又は1~8アミノ酸を含むペプチド、又は式(OCH2CH2)p又は(OCH2CH(CH3))pを有するポリエチレンオキシ単位(pは1から約5000までの整数)である。2つのR:R1R2、R2R3、R1R3、又はR3R4は、アルキル、アリール、ヘテロアリール、ヘテロアルキル、又はアルキルシクロアルキル基の3~8員環を形成できる。X3は、H、CH3、又はX1’R1’であり、ここで X1’はNH、N(CH3)、NHNH、O、又はSであり、R1’は、H又はC1-C8の直鎖若しくは分岐のアルキル、アリール、ヘテロアリール、ヘテロアルキル、アルキルシクロアルキル、アシルオキシルアミンである;R3’はH又はC1-C6の直鎖若しくは分岐アルキルである;Z3’は、H、COOR1、NH2、NHR1、OR1、CONHR1、NHCOR1、OCOR1、OP(O)(OM1)(OM2)、OCH2OP(O)(OM1)(OM2)、OSO3M1、R1、又はO-グリコシド(グルコシド、ガラクトシド、マンノシド、グルクロノシド/グルクロニド、アロシド、フルクトシド等)、NH-グリコシド、S-グリコシド、若しくはCH2-グリコシドである;M1及びM2は独立して、H、Na、K、Ca、Mg、NH4、NR1R2R3である;Y1及びY2は、接続部位
と結合している場合、独立して、O、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R2)、C(O)NHNHC(O)、及びC(O)NR1であり、また、接続部位
と結合していない場合、独立して、OH、NH2、NHNH2、NHR5、SH、C(O)OH、C(O)NH2、OC(O)NH2、OC(O)OH、NHC(O)NH2、NHC(O)SH、OC(O)NH(R1)、N(R1)C(O)NH(R2)、C(O)NHNHC(O)OH、及びC(O)NHR1である;R12は、OH、NH2、NHR1、NHNH2、NHNHCOOH、O-R1-COOH、NH-R1-COOH、NH-(Aa)nCOOH、O(CH2CH2O)pCH2CH2OH、O(CH2CH2O)pCH2CH2NH2、NH(CH2CH2O)pCH2CH2NH2、NR1R1’、NHOH、NHOR1、O(CH2CH2O)pCH2CH2COOH、NH(CH2CH2O)pCH2CH2COOH、NH-Ar-COOH、NH-Ar-NH2、O(CH2CH2O)pCH2CH2NH-SO3H、NH(CH2CH2O)pCH2CH2NHSO3H、R1-NHSO3H、NH-R1-NHSO3H、O(CH2CH2O)pCH2-CH2NHPO3H2、NH(CH2CH2O)pCH2CH2NHPO3H2、OR1、R1-NHPO3H2、R1-OPO3H2、O(CH2CH2O)pCH2CH2OPO3H2、OR1-NHPO3H2、NH-R1-NHPO3H2、NH(CH2CH2NH)pCH2-CH2NH2、NH(CH2CH2S)pCH2CH2NH2、NH(CH2CH2NH)pCH2CH2OH、NH(CH2CH2S)pCH2-CH2OH、NH-R1-NH2、又はNH(CH2CH2O)pCH2CH2NHPO3H2であり、ここで、Aaは1~8個の同一の又は異なるアミノ酸である;pは1-5000である;R1、R2、R3、R4、R5、R5’、Z1、Z2、及びnは、上記と同じ定義である。
(H)エリブリン:
(I)ニコチンアミドホスホリボシルトランスフェラーゼ(NAMPT)阻害剤、又は1以上の化学元素の同位体、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマー:
式中、
及びX1は、請求項5と同じ定義である。X5はF、Cl、Br、I、OH、OR1、R1、OPO3H2、OSO3H、NHR1、OCOR1、NHCOR1である;
(J)ベンゾジアゼピン二量体及びその類縁体、又は1以上の化学元素の同位体、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマー:
式中、X1、X2、Y1、及びY2は独立して、O、N、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH、C(O)NHNHC(O)、又はC(O)NR1である;R1、R2、R3、R1’、R2’、及びR3’は独立して、H;F;Cl;=O;=S;OH;SH;C1-C8直鎖又は分岐アルキル、アリール、アルケニル、ヘテロアリール、ヘテロアルキル、アルキルシクロアルキル、エステル(COOR5又は-OC(O)R5)、エーテル(OR5)、アミド(CONR5)、カルバメート(OCONR5)、アミン(NHR5、NR5R5’)、ヘテロシクロアルキル、又はアシルオキシルアミン(-C(O)NHOH、-ONHC(O)R5);又は1~20個の天然若しくは非天然アミノ酸を含むペプチド、又は式(OCH2CH2)p若しくは(OCH2CH(CH3))pのポリオキシエチレン単位(pは1から約5000までの整数)である;2つのR:R1R2、R2R3、R1R3、R1’R2’、R2’R3’、又はR1’R3’は独立して、アルキル、アリール、ヘテロアリール、ヘテロアルキル、又はアルキルシクロアルキル基の3~8員環を形成できる。;X3及びY3は独立して、N、NH、CH2、又はCR5であり、ここでR4、R5、R6、R12、及びR12’は独立して、H、OH、NH2、NH(CH3)、NHNH2、COOH、SH、OZ3、SZ3、F、Cl、又はC1-C8直鎖又は分岐アルキル、アリール、ヘテロアリール、ヘテロアルキル、アルキルシクロアルキル、アシルオキシルアミンである;Z3は、H、OP(O)(OM1)(OM2)、OCH2OP(O)(OM1)(OM2)、OSO3M1、又はO-グリコシド(グルコシド、ガラクトシド、マンノシド、グルクロノシド/グルクロニド、アロシド、フルクトシド等)、NH-グリコシド、S-グリコシド、若しくはCH2-グリコシドである;M1及びM2は独立して、H、Na、K、Ca、Mg、NH4、NR1R2R3である。
(K)CC-1065類縁体及びデュオカルマイシン類縁体:
CC02,
CC03,
CC04,
CC05,
CC06,
CC07,
式中、X1、X2、Y1、及びY2は、接続部位
と結合している場合、独立して、O、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R2)、C(O)NHNHC(O)、及びC(O)NR1であり、また、接続部位
と結合していない場合、独立して、OH、NH2、NHNH2、NHR1、SH、C(O)OH、C(O)NH2、OC(O)NH2、OC(O)OH、NHC(O)NH2、NHC(O)SH、OC(O)NH(R1)、N(R1)C(O)NH(R2)、C(O)NHNHC(O)OH、及びC(O)NHR1である;Z3は、H、PO(O)(OM1)(OM2)、SO3M1、CH2PO(O)(OM1)(OM2)、CH3N(CH2CH2)2NC(O)-、O(CH2CH2)2NC(O)-、R1、又はグリコシドである;R1、R2、R3、M1、M2、及びnは、上記と同じ定義である。
(L)チューブリシン及びその類縁体、又は1以上の化学元素の同位体、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマー:
式中、X1及びY1は独立して、O、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH、C(O)NHNHC(O)、及びC(O)NR1である;mAbは抗体、好ましくはモノクローナル抗体である;R12はOH、NH2、NHR1、NHNH2、NHNHCOOH、O-R1-COOH、NH-R1-COOH、NH-(Aa)nCOOH、O(CH2CH2O)pCH2CH2OH、O(CH2CH2O)pCH2CH2NH2、NH(CH2CH2O)pCH2CH2NH2、NR1R1’、NHOH、NHOR1、O(CH2CH2O)pCH2CH2COOH、NH(CH2CH2O)pCH2CH2COOH、NH-Ar-COOH、NH-Ar-NH2、O(CH2CH2O)pCH2CH2NH-SO3H、NH(CH2CH2O)pCH2CH2NHSO3H、R1-NHSO3H、NH-R1-NHSO3H、O(CH2CH2O)pCH2-CH2NHPO3H2、NH(CH2CH2O)pCH2CH2NHPO3H2、OR1、R1-NHPO3H2、R1-OPO3H2、O(CH2CH2O)pCH2CH2OPO3H2、OR1-NHPO3H2、NH-R1-NHPO3H2、NH(CH2CH2NH)pCH2-CH2NH2、NH(CH2CH2S)pCH2CH2NH2、NH(CH2CH2NH)pCH2CH2OH、NH(CH2CH2S)pCH2-CH2OH、NH-R1-NH2、又はNH(CH2CH2O)pCH2CH2NHPO3H2であり、ここで、Aaは1~8個のアミノ酸である;n及びm1は独立して、1-20である;pは1-5000である;R1、R1’、R2、R3、及びR4は独立して、H、C1-C8の直鎖又は分岐アルキル、アミド、又はアミン;C2-C8アリール、アルケニル、アルキニル、ヘテロアリール、ヘテロアルキル、アルキルシクロアルキル、エステル、エーテル、ヘテロシクロアルキル、又はアシルオキシルアミン;又は1~8アミノ酸を含むペプチド、若しくは式(OCH2CH2)p又は(OCH2CH(CH3))pを有するポリエチレンオキシ単位(pは1から約5000までの整数);2つのR:R1R2、R2R3、R1R3、又はR3R4は独立して、アルキル、アリール、ヘテロアリール、ヘテロアルキル、又はアルキルシクロアルキル基の3~8員環を形成できる;X3は、H、CH3、CH2CH3、C3H7、又はX1’R1’であり、ここで X1’はNH、N(CH3)、NHNH、O、又はSである;R1’は、H又はC1-C8の直鎖若しくは分岐のアルキル、アリール、ヘテロアリール、ヘテロアルキル、アルキルシクロアルキル、アシルオキシルアミンである;R3’はH又はC1-C6の直鎖若しくは分岐アルキルである;Z3は、H、COOR1、NH2、NHR1、OR1、CONHR1、NHCOR1、OCOR1、OP(O)(OM1)(OM2)、OCH2OP(O)(OM1)(OM2)、OSO3M1、R1、又はO-グリコシド(グルコシド、ガラクトシド、マンノシド、グルクロノシド/グルクロニド、アロシド、フルクトシド等)、NH-グリコシド、S-グリコシド、若しくはCH2-グリコシドである;M1及びM2は独立して、H、Na、K、Ca、Mg、NH4、NR1R2R3である。
(M)アマトキシン及びその類縁体、又は1以上の化学元素の同位体、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマー:
式中、X1及びY1は独立して、O、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH、C(O)NHNHC(O)、及びC(O)NR1である;R7、R8、及びR9は独立して、H、OH、OR1、NH2、NHR1、C1-C6アルキル、又は不存在である;Y2はO、O2、NR1、NH、又は不存在である;R10は、CH2、O、NH、NR1、NHC(O)、NHC(O)NH、NHC(O)O、OC(O)O、C(O)、OC(O)、OC(O)(NR1)、(NR1)C(O)(NR1)、C(O)R1、又は不存在である;R11は、OH、NH2、NHR1、NHNH2、NHNHCOOH、O-R1-COOH、NH-R1-COOH、NH-(Aa)nCOOH、O(CH2CH2O)pCH2CH2OH、O(CH2CH2O)pCH2CH2NH2、NH(CH2CH2O)pCH2CH2NH2、NR1R1’、NHOH、NHOR1、O(CH2CH2O)pCH2CH2COOH、NH(CH2CH2O)pCH2CH2COOH、NH-Ar-COOH、NH-Ar-NH2、O(CH2CH2O)pCH2CH2NH-SO3H、NH(CH2CH2O)pCH2CH2NHSO3H、R1-NHSO3H、NH-R1-NHSO3H、O(CH2CH2O)pCH2-CH2NHPO3H2、NH(CH2CH2O)pCH2CH2NHPO3H2、OR1、R1-NHPO3H2、R1-OPO3H2、O(CH2CH2O)pCH2CH2OPO3H2、OR1-NHPO3H2、NH-R1-NHPO3H2、NH(CH2CH2NH)pCH2-CH2NH2、NH(CH2CH2S)pCH2CH2NH2、NH(CH2CH2NH)pCH2CH2OH、NH(CH2CH2S)pCH2-CH2OH、NH-R1-NH2、又はNH(CH2CH2O)pCH2CH2NHPO3H2であり、ここで、Aaは1~8個のアミノ酸である;n及びm1は独立して、1-20である;pは1-5000である;R1及びArは、請求項1と同じ定義である。
(N)プロテインキナーゼ阻害剤:
(O)MEK阻害剤:
式中、Z5はO、NH、NHNH、NR5、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R2)、C(O)NHNHC(O)、及びC(O)NR1から選択される;
(P)プロテイナーゼ阻害剤:
(Q)通常、細菌又は植物タンパク質に由来する細胞毒性タンパク質である高分子薬物であり、ジフテリア毒素(DT)、コレラ毒素(CT)、トリコサンチン(TCS)、ジアンチン、シュードモナス外毒素A(ETA’)、発赤毒素、ジフテリア毒素、AB毒素、III型外毒素、プロエロリジン、及びトプサリシンから選択され、アミン、チオール、又はカルボン酸基を有するアミノ酸によって、側鎖連結体を介して結合する、免疫毒素。 - W、L1、L2、V1、及びV2は独立して以下の構造の連結体成分の1以上を含む、請求項1、2、3、又は4に記載の化合物:
式中、
は連結部位である;X2、X3、X4、X5、又はX6は独立して、NH;NHNH;N(R12);N(R12)N(R12’);O;S;C1-C6アルキル;C2-C6ヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;CH2OR12、CH2SR12、CH2NHR12、又は1~8アミノ酸から選択される;式中、R12及びR12’は独立して、H;C1-C8アルキル;C2-C8ヘテロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル;C3-C8アリール、Ar-アルキル、複素環、炭素環、シクロアルキル、ヘテロアルキルシクロアルキル、アルキルカルボニル、ヘテロアリール;又は、炭素原子数1~8のエステル、エーテル、若しくはアミド;又は式(OCH2CH2)p若しくは(OCH2CH(CH3))pのポリエチレンオキシ単位(pは0から約1000までの整数)、あるいはそれらの組み合わせである; - W、L1、L2、V1、及びV2は独立して以下の構造を含む、請求項1、2、3、又は4に記載の化合物:
(A)自壊性成分、ペプチド単位、ヒドラゾン結合、ジスルフィド、エステル、オキシム、アミド、又はチオエーテル結合。前記自壊性ユニットは、パラアミノベンジルカルバモイル(PAB)基と電子的に類似する芳香族化合物、2-アミノイミダゾール-5-メタノール誘導体、複素環PAB類縁体、β-グルクロニド、及びo-又はp-アミノベンジルアセタール;又は以下の構造のいずれかを含む:
式中、(*)で標識された原子は、他の成分との結合点である;X1、Y1、Z2、及びZ3は独立して、NH、O又はSである;Z1は独立して、H、NHR1、OR1、SR1、COX1R1であり、ここでX1及びR1は上記で定義されたとおりである;vは0又は1である;U1は独立して、H、OH、C1-C6アルキル、(OCH2CH2)n、F、Cl、Br、I、OR5、SR5、NR5R5’、N=NR5、N=R5、NR5R5’、NO2、SOR5R5’、SO2R5、SO3R5、OSO3R5、PR5R5’、POR5R5’、PO2R5R5’、OPO(OR5)(OR5’)、又はOCH2PO(OR5)(OR5’)であり、式中、R5及びR5’はそれぞれ独立して、H、C1-C8アルキル;C2-C8アルケニル、アルキニル、ヘテロアルキル、又はアミノ酸;C3-C8のアリール、複素環、炭素環、シクロアルキル、ヘテロシクロアルキル、ヘテロアラルキル、アルキルカルボニル、又はグリコシド;又は薬用陽イオン塩から選択される;
(B)次の構造のいずれかを含む非自壊性連結体成分;
式中、(*)で標識された原子は、追加スペーサー若しくは放出可能連結体単位、細胞毒性剤、及び/又は結合分子との結合点である;X1、Y1、U1、R5、R5’は、上記で定義されたとおりである;rは0~100である;m及びnは独立して0~20である;
(C)生理的条件で崩壊することができる少なくとも1つの結合;pH不安定性、酸不安定性、塩基不安定性、酸化不安定性、代謝不安定性、生物化学的不安定性、又は酵素不安定性の結合を含み、以下の構造のうちの1つを有する放出可能成分:
-(CR15R16)m(Aa)r(CR17R18)n(OCH2CH2)t-、-(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t-、-(Aa)r-(CR15R16)m(CR17R18)n(OCH2CH2)t-、-(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t-、-(CR15R16)m(CR17=CR18)(CR19R20)n(Aa)t(OCH2CH2)r-、-(CR15R16)m(NR11CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(CO)(Aa)t-(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(OCO)(Aa)t(CR19R20)n-(OCH2CH2)r-、-(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-(CR15R16)m-フェニル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-フリル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-オキサゾリル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-チアゾリル-(CO)(Aa)t(CR17R18)n-、-(CR15R16)t-チエニル-(CO)(CR17R18)n-、-(CR15R16)t-イミダゾリル-(CO)(CR17R18)n-、-(CR15R16)t-モルホリノ-(CO)(Aa)t(CR17R18)n-、-(CR15R16)t-ピペラジノ-(CO)(Aa)t(CR17R18)n-、-(CR15R16)t-N-メチルピペラジン-(CO)(Aa)t(CR17R18)n-、-(CR15R16)m-(Aa)tフェニル-、-(CR15R16)m-(Aa)tフリル-、-(CR15R16)m-オキサゾリル(Aa)t-、-(CR15R16)m-チアゾリル(Aa)t-、-(CR15R16)m-チエニル(Aa)t-、-(CR15R16)m-イミダゾリル(Aa)t-、-(CR15R16)m-モルホリノ-(Aa)t-、-(CR15R16)m-ピペラジノ-(Aa)t-、-(CR15R16)m-N-メチルピペラジノ-(Aa)t-、-K(CR15R16)m(Aa)r(CR17R18)n(OCH2CH2)t-、-K(CR15R16)m(CR17R18)n(Aa)r(OCH2CH2)t-、-K(Aa)r(CR15R16)m(CR17R18)n(OCH2CH2)t-、-K(CR15R16)m(CR17R18)n(OCH2CH2)r(Aa)t-、-K(CR15R16)m(CR17=R18)(CR19R20)n(Aa)t(OCH2CH2)r-、-K(CR15R16)m(NR11CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(Aa)t(NR21CO)(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(NR21CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(OCNR17)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m(CO)(Aa)t(CR19R20)n(OCH2CH2)r-、-K(CR15R16)m-フェニル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-フリル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-オキサゾリル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-チアゾリル-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)t-チエニル-(CO)(CR17R18)n-、-K(CR15R16)t-イミダゾリル-(CO)(CR17R18)n-、-K(CR15R16)t-モルホリノ-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)t-ピペラジノ-(CO)(Aa)t(CR17R8)n-、-K(CR15R16)t-N-メチルピペラジン-(CO)(Aa)t(CR17R18)n-、-K(CR15R16)m-(Aa)tフェニル-、-K(CR15R16)m-(Aa)tフリル-、-K(CR15R16)m-オキサゾリル(Aa)t-、-K(CR15R16)m-チアゾリル(Aa)t-、-K(CR15R16)m-チエニル(Aa)t-、-K(CR15R16)m-イミダゾリル(Aa)t-、-K(CR15R16)m-モルホリノ-(Aa)t-、-K(CR15R16)m-ピペラジノ-(Aa)tG-、-K(CR15R16)m-N-メチルピペラジノ-(Aa)t;式中、m、Aa、m、n、R13、R14、及びR15の定義は上記の通りである;t及びrは独立して0~100であ
る;R16、R17、R18、R19、及びR20は独立して、H;ハロゲン化物;C1~C8アルキル若しくはヘテロアルキル;C2~C8アリール、アルケニル、アルキニル、エーテル、エステル、アミン、若しくはアミド;又は1以上のハロゲン化物、CN、NR12R12’、CF3、OR12、アリール、複素環、S(O)R12、SO2R12、-CO2H、-SO3H、-OR12、-CO2R12、-CONR12、-PO2R12R13、-PO3H、又はP(O)R12R12’R13’で任意に置換されていてもよいC3~C8アリールから選択される;KはNR12、-SS-、-C(=O)-、-C(=O)NH-、-C(=O)O-、-C=NH-O-、-C=N-NH-、-C(=O)NH-NH-、O、S、Se、B、Het(C3~C12の複素環又は複素芳香環)、又は同一の若しくは異なる1~20個のアミノ酸を含むペプチドである。 - 以下に示すa001~a198、49(C-30)、50(C-40)、51(C-48)、78、125、14、149、163、171、174(C-173)、179、187、C-238、C-247、C-255、C-271、C-279、C-312、C-313、132(C-131)、135(C-134)、C-321、及びC-322の構造を有する、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマーである請求項1及び2に記載の共役体化合物:
式中、R1、R2、R3、R4、R5、R4、R5、R7、R8、R9、R10、X1、X2、X3、X4、X5、X6、Y1、Y2、Y3、Y5、R12、R12’、R13、R13’、R25、R25’、p1、p2、q1、q2、m、m1、n、及びmAbは、請求項1、2、3、及び6の記載と同じである;Aaは天然又は非天然のアミノ酸である;rは0~12である;(Aa)rは、r>2の場合、同一の又は異なるアミノ酸配列を含むペプチドであり、r=0の場合、(Aa)rが不存在であることを意味する。 - 以下に示すb001~b197、30、40、48、77、124、140、148、162、170、173、178、186、202、238、247、255、271、279、312、313、131、134、321、及び322の構造を有する、又はそれらの薬学的に許容される塩、水和物、若しくは水和塩;又はこれらの化合物の多形結晶構造;又はそれらの同位体、光学異性体、ラセミ体、ジアステレオマー、若しくはそれらのエナンチオマーである、請求項3及び4に記載の化合物:
式中、R1、R2、R3、R4、R5、R4、R5、R7、R8、R9、R10、X1、X2、X3、X4、X5、X6、X8、Y1、Y2、Y3、Y5、R12、R12’、R13、R13’、R25、R25’、Z2、Z3、p、p1、p2、p3、q1、q2、Lv1、Lv2、Lv3、Lv3’、m、m1、n、及びmAbは、請求項3及び6の記載と同じである;Aaは天然又は非天然のアミノ酸である;rは0~12である;(Aa)rは、天然又は非天然アミノ酸を含むペプチドであり、r>2である;r=0は、(Aa)rが不存在であることを意味する。 - 細胞結合剤/分子(T又はmAb)が以下から選択される、請求項1、2、又は9に記載の化合物:
(A)抗体、タンパク質、プロボディ、ナノボディ、ビタミン(葉酸を含む)、ペプチド、高分子ミセル、リポソーム、リポタンパク質ベースの薬物担体、ナノ粒子薬物担体、デンドリマー、及び細胞結合リガンドと結合若しくは細胞結合リガンドによりコーティングされた上記の分子若しくは粒子、又はこれらの組み合わせからなる群;
(B)抗体様タンパク質、全長抗体(ポリクローナル抗体、モノクローナル抗体、二量体、多量体)、若しくは多重特異性抗体(二重特異性抗体、三重特異性抗体、若しくは四重特異性抗体から選択される);単鎖抗体、標的細胞と結合する抗体断片、モノクローナル抗体、単鎖モノクローナル抗体、標的細胞と結合するモノクローナル抗体断片、キメラ抗体、標的細胞と結合するキメラ抗体断片、ドメイン抗体、標的細胞と結合するドメイン抗体断片、表面再構成型抗体、単鎖表面再構成型抗体、標的細胞と結合する表面再構成型抗体断片、ヒト化抗体若しくは表面再構成型ヒト化抗体、単鎖ヒト化抗体若しくは標的細胞と結合するヒト化抗体断片、抗イディオタイプ(抗Id)抗体、CDR、二量体、三量体、四量体、ミニ抗体、プロボディ(probody)、プロボディ断片、小分子免疫タンパク質(SIP)、リンホカイン、ホルモン、ビタミン、成長因子、コロニー刺激因子、栄養輸送分子、大分子量タンパク質、融合タンパク質、キナーゼ阻害剤、遺伝子標的薬、及び抗体又は大分子量タンパク質で改変されたナノ粒子又はポリマー;
(C)以下から選択される細胞結合リガンド又は受容体アゴニスト:葉酸誘導体;グルタミン酸尿素誘導体;ソマトスタチン及びその類縁体(オクトレオチド(サンドスタチン)及びランレオチド(ソマトリン)からなる群から選択される);芳香族スルホンアミド;下垂体アデニル酸シクラーゼ活性化ペプチド(PACAP)(PAC1);血管作動性腸管ペプチド(VIP/PACAP)(VPAC1、VPAC2);メラニン細胞刺激ホルモン(α-MSH);コレシストキニン(CCK)/ガストリン受容体アゴニスト;ボンベシン(Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2からなる群から選択される)/ガストリン放出ペプチド(GRP);ニューロテンシン受容体リガンド(NTR1、NTR2、NTR3);サブスタンスP(NK1受容体)リガンド;ニューロペプチドY(Y1-Y6);RGD(Arg-Gly-Asp)、NGR(Asn-Gly-Arg)、二量体及び多量体環状RGDペプチド(cRGDfVcから選択される)、TAASGVRSMH及びLTLRWVGLMS(コンドロイチン硫酸プロテオグリカンNG2受容体リガンド)及びF3ペプチドを含むホーミングペプチド;細胞透過性ペプチド(CPPs);テストステロン産生と同様に、卵胞刺激ホルモン(FSH)及び黄体形成ホルモン(LH)を標的とすることによって作用する、黄体形成ホルモン放出ホルモン(LHRH)アゴニスト及びアンタゴニスト、並びに性腺刺激ホルモン放出ホルモン(GnRH)アゴニストからなる群から選択され、ブセレリン(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt)、ゴナドレリン(Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2)、ゴセレリン(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2)、ヒストレリン(Pyr-His-Trp-Ser-Tyr-D-His(N-ベンジル)-Leu-Arg-Pro-NHEt)、ロイプロリド(Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt)、ナファレリン(Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2)、トリプトレリン(Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2)、ナファレリン、デスロレリン、アバレリックス(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-イソプロピル-Pro-DAla-NH2)、セトロレリックス (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2)、デガレリックス (Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-4-amioPhe(L-ヒドロオロチル)-D-4-amioPhe(カルバモイル)-Leu-イソプロピルLys-Pro-D-Ala-NH2)、及びガニレリックス(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-ピリジル)Ala-Ser-Tyr-D-(N9, N10-ジエチル)-ホモArg-Leu-(N9, N10-ジエチル)-ホモArg-Pro-D-Ala-NH2)からなる群から選択されるペプチドホルモン;Toll様受容体(TLR)リガンド、C型レクチン、及びNod様受容体(NLRs)リガンドからなる群から選択されるパターン認識受容体(PRRs);カルシトニン受容体アゴニスト;インテグリン受容体及びそれらの受容体サブタイプ(αVβ1、αVβ3、αVβ5、αVβ6、α6β4、α7β1、αLβ2、αIIbβ3からなる群から選択される。)アゴニスト(GRGDSPK、シクロ(RGDfV)(L1)及びその誘導体[シクロ(-N(Me)R-GDfV)、シクロ(R-Sar-DfV), シクロ(RG-N(Me)D-fV)、シクロ(RGD-N(Me)f-V)、シクロ(RGDf-N(Me)V-)(シレンジタイド)];ナノボディ(VHH(ラクダIg)の誘導体);ドメイン抗体(dAb、VH又はVLドメインの誘導体)、二重特異的T細胞誘導(Bite、二重特異性抗体);二重親和性リターゲティング(DART、二重特異性抗体);四価のタンデム抗体(TandAb、二量化二重特異性抗体);アンチカリン(リポカリリンの誘導体);アドネクチン類(10番目のFN3(フィブロネクチン));設計されたアンキリン反復タンパク質(DARPins);アビマー(avimer);EGF受容体及びVEGF受容体アゴニスト;
(D)以下から選択される細胞結合分子/リガンドの小分子又は細胞受容体アゴニスト:以下に示す構造のLB01(葉酸共役体)、LB02(PMSAリガンド)、LB03(PMSAリガンド)、LB04(PMSAリガンド)、LB05(ソマトスタチン)、LB06(ソマトスタチン)、LB07(オクトレオチド、ソマトスタチン類縁体)、LB08(ラマレオチド、ソマトスタチン類縁体)、LB09(バプレオチド(サンバー)、ソマトスタチン類縁体)、LB10(CAIXリガンド)、LB11(CAIXリガンド)、LB12(ガストリン放出ペプチド受容体(GRPr)、MBA)、LB13(黄体形成ホルモン放出ホルモン(LH-RH)リガンド及びGnRH)、LB14(黄体形成ホルモン放出ホルモン(LH-RH)及びGnRHリガンド)、LB15(GnRHアンタゴニスト、アバレリックス)、LB16(コバラミン、ビタミンB12類縁体)、LB17(コバラミン、ビタミンB12類縁体)、LB18(αvβ3インテグリン受容体のための、環状RGDペンタペプチド)、LB19(VEGF受容体のためのヘテロ二価ペプチドリガンド)、LB20(ニューロメジンB)、LB21(Gタンパク質共役受容体のためのボンベシン)、LB22(トール様受容体のためのTLR2)、LB23(アンドロゲン受容体のための)、LB24(αvインテグリン受容体のためのシレンギチド(Cilengitide)/シクロ(-RGDfV-))、LB23(フルドロコルチゾン)、LB25(リファブチン類縁体)、LB26(リファブチン類縁体)、LB27(リファブチン類縁体)、LB28(フルドロコルチゾン)、LB29(デキサメタゾン)、LB30(プロピオン酸フルチカゾン)、LB31(ジプロピオン酸ベクロメタゾン)、LB32(トリアムシノロンアセトニド)、LB33(プレドニゾン)、LB34(プレドニゾロン)、LB35(メチルプレドニゾロン)、LB36(ベタメタゾン)、LB37(イリノテカン類縁体)、LB38(クリゾチニブ類縁体)、LB39(ボルテゾミブ類縁体)、LB40(カーフィルゾミブ類縁体)、LB41(カーフィルゾミブ類縁体)、LB42(リュープロリド類縁体)、LB43(トリプトレリン類縁体)、LB44(クリンダマイシン)、LB45(リラグルチド類縁体)、LB46(セマグルチド類縁体)、LB47(レタパムリン類縁体)、LB48(インジブリン類縁体)、LB49(ビンブラスチン類縁体)、LB50(リキシセナチド類縁体)、LB51(オシメルチニブ類縁体)、LB52(ヌクレオシド類縁体)、LB53(エルロチニブ類縁体)、又はLB54(ラパチニブ類縁体);
(E):1以上のDNA、RNA、mRNA、低分子干渉RNA(siRNA)、マイクロRNA(miRNA)、及びPIWI相互作用RNA(piRNA):
(F):免疫毒素:ジフテリア毒素(DT)、コレラ毒素(CT)、トリコサンチン(TCS)、ダイアンチン、シュードモナス外毒素A(ETA’)、発赤毒素、ジフテリア毒素、AB毒素、III型外毒素;
式中、
は、本特許の側鎖連結体との連結部位である;
は、一本鎖または二本鎖のDNA、RNA、mRNA、siRNA、miRNA、又はpiRNAである;X4及びY1は独立して、O、NH、NHNH、NR1、S、C(O)O、C(O)NH、OC(O)NH、OC(O)O、NHC(O)NH、NHC(O)S、OC(O)N(R1)、N(R1)C(O)N(R1)、CH2、C(O)NHNHC(O)、及びC(O)NR1である;X1は、H、CH2、OH、O、C(O)、C(O)NH、C(O)N(R1)、R1、NHR1、NR1、C(O)R1、又はC(O)Oである;X5は、H、CH3、F、又はClである;M1及びM2は独立して、H、Na、K、Ca、Mg、NH4、N(R12R12’R13R13’)である;R12、R12’、R13、及びR13’は、請求項1で定義されている。 - 細胞結合分子T又はmAbが、式(I)、(II)、又は(III)のV1及び/又はV2に結合する場合、あるいはV1及び/又はV2が不存在であり、細胞結合分子Tが、式(I)、(II)、又は(III)のL1及び/又はL2に直接結合する場合、前記共役体化合物は、以下の結合構造の1以上を有する、請求項1、2、又は11に記載の化合物:
式中、R20及びR21は独立して、C1~C8アルキル;C2~C8ヘテロアルキル、又は複素環;C3~C8アリール、Ar-アルキル、シクロアルキル、アルキルシクロアルキル、ヘテロシクロアルキル、ヘテロアルキルシクロアルキル、炭素環、又はアルキルカルボニル;又は(CH2CH2O)pの式を有するC2~C100ポリエチレングリコールである。 - 前記細胞結合剤が、腫瘍細胞、ウイルス感染細胞、微生物感染細胞、寄生虫感染細胞、自己免疫疾患細胞、活性化腫瘍細胞、骨髄細胞、活性化T細胞、影響されているB細胞、若しくはメラニン細胞、又は以下の抗原若しくは受容体のうちの1以上を発現する細胞を標的とすることができる、請求項1、2、9、又は11のいずれか1項に記載の化合物:CD1、CD1a、CD1b、CD1c、CD1d、CD1e、CD2、CD3、CD3d、CD3e、CD3g、CD4、CD5、CD6、CD7、CD8、CD8a、CD8b、CD9、CD10、CD11a、CD11b、CD11c、CD12w、CD14、CD15、CD16、CD16a、CD16b、CDw17、CD18、CD19、CD20、CD21、CD22、CD23、CD24、CD25、CD26、CD27、CD28、CD29、CD30、CD31、CD32、CD32a、CD32b、CD33、CD34、CD35、CD36、CD37、CD38、CD39、CD40、CD41、CD42、CD42a、CD42b、CD42c、CD42d、CD43、CD44、CD45、CD46、CD47、CD48、CD49b、CD49c、CD49c、CD49d、CD49f、CD50、CD51、CD52、CD53、CD54、CD55、CD56、CD57、CD58、CD59、CD60、CD60a、CD60b、CD60c、CD61、CD62E、CD62L、CD62P、CD63、CD64、CD65、CD65s、CD66、CD66a、CD66b、CD66c、CD66d、CD66e、CD66f、CD67、CD68、CD69、CD70、CD71、CD72、CD73、CD74、CD74、CD75、CD75s、CD76、CD77、CD78、CD79、CD79a、CD79b、CD80、CD81、CD82、CD83、CD84、CD85、CD85a、CD85b、CD85c、CD85d、CD85e、CD85f、CD85g、CD85g、CD85i、CD85j、CD85k、CD85m、CD86、CD87、CD88、CD89、CD90、CD91、CD92、CD93、CD94、CD95、CD96、CD97、CD98、CD99、CD100、CD101、CD102、CD103、CD104、CD105、CD106、CD107、CD107a、CD107b、CD108、CD109、CD110、CD111、CD112、CD113、CD114、CD115、CD116、CD117、CD118、CD119、CD120a、CD120b、CD121、CD121a、CD121b、CD122、CD123、CD123a、CD124、CD125、CD126、CD127、CD128、CD129、CD130、CD131、CD132、CD133、CD134、CD135、CD136、CD137、CD138、CD139、CD140、CD140a、CD140b、CD141、CD142、CD143、CD144、CD145、CDw145、CD146、CD147、CD148、CD149、CD150、CD151、CD152、CD153、CD154、CD155、CD156a、CD156b、CD156c、CD156d、CD157、CD158、CD158a、CD158b1、CD158b2、CD158c、CD158d、CD158e1、CD158e2、CD158f2、CD158g、CD158h、CD158i、CD158j、CD158k、CD159、CD159a、CD159b、CD159c、CD160、CD161、CD162、CD163、CD164、CD165、CD166、CD167、CD167a、CD167b、CD168、CD169、CD170、CD171、CD172、CD172a、CD172b、CD172g、CD173、CD174、CD175、CD175s、CD176、CD177、CD178、CD179、CD179a、CD179b、CD180、CD181、CD182、CD183、CD184、CD185、CD186、CDw186、CD187、CD188、CD189、CD190、CD191、CD192、CD193、CD194、CD195、CD196、CD197、CD198、CDw198、CDw199、CD200、CD201、CD202(a,b)、CD203、CD203c、CD204、CD205、CD206、CD207、CD208、CD209、CD210、CDw210a、CDw210b、CD211、CD212、CD213、CD213a1、CD213a2、CD214、CD215、CD216、CD217、CD218、CDw218a、CD218、CD21b9、CD220、CD221、CD222、CD223、CD224、CD225、CD226、CD227、CD228、CD229、CD230、CD231、CD232、CD233、CD234、CD235a、CD235b、CD236、CD236R、CD238、CD239、CD240、CD240ce、CD240d、CD241、CD242、CD243、CD244、CD245、CD246、CD247、CD248、CD249、CD250、CD251、CD252、CD253、CD254、CD255、CD256、CD257、CD258、CD259、CD260、CD261、CD262、CD263、CD264、CD265、CD266、CD267、CD268、CD269、CD270、CD271、CD272、CD273、CD274、CD275、CD276、CD277、CD278、CD279、CD281、CD282、CD283、CD284、CD285、CD286、CD287、CD288、CD289、CD290、CD291、CD292、CD293、CD294、CD295、CD296、CD297、CD298、CD299、CD300、CD300a、CD300b、CD300c、CD301、CD302、CD303、CD304、CD305、CD306、CD307、CD307a、CD307b、CD307c、CD307d、CD307e、CD307f、CD308、CD309、CD310、CD311、CD312、CD313、CD314、CD315、CD316、CD317、CD318、CD319、CD320、CD321、CD322、CD323、CD324、CD325、CD326、CD327、CD328、CD329、CD330、CD331、CD332、CD333、CD334、CD335、CD336、CD337、CD338、CD339、CD340、CD341、CD342、CD343、CD344、CD345、CD346、CD347、CD348、CD349、CD350、CD351、CD352、CD353、CD354、CD355、CD356、CD357、CD358、CD359、CD360、CD361、CD362、CD363、CD364、CD365、CD366、CD367、CD368、CD369、CD370、CD371、CD372、CD373、CD374、CD375、CD376、CD377、CD378、CD379、CD381、CD382、CD383、CD384、CD385、CD386、CD387、CD388、CD389、CRIPTO、CRIPTO、CR、CR1、CRGF、CRIPTO、CXCR5、LY64、TDGF1、4-1BB、APO2、ASLG659、BMPR1B、4-1BB、5AC、5T4(栄養芽細胞糖タンパク質、TPBG、5T4、Wnt活性化阻害因子1又はWAIF1)、腺癌抗原、AGS-5、AGS-22M6、アクチビン受容体様キナーゼ1、AFP、AKAP-4、ALK、αインテグリン、αvβ6、アミノペプチダーゼN、アミロイドβ、アンドロゲン受容体、アンジオポイエチン2、アンジオポイエチン3、アネキシンA1、炭疽菌トキシン防御抗原、抗トランスフェリン受容体、AOC3(VAP-1)、B7-H3、炭疽菌、BAFF(B-細胞活性化因子)、BCMA、B-リンパ腫細胞、bcr-abl、ボンベシン、BORIS、C5、C242抗原、CA125(炭水化物抗原125、MUC16)、CA-IX(又はCAIX、炭酸脱水酵素9)、CALLA、CanAg、イヌIL31、炭酸脱水酵素IX、心筋ミオシン、CCL11(C-Cモチーフケモカイン11)、CCR4(CCケモカイン受容体4型、CD194)、CCR5、CD3E(イプシロン)、CEA(癌胎児性抗原)、CEACAM3、CEACAM5(癌胎児性抗原)、CFD(因子D)、Ch4D5、コレシストキニン2(CCK2R)、CLDN18(クラウディン-18)、CLDN18.1(クラウディン-18.1)、CLDN18.2(クラウディン-18.2)、クランピング因子A、cMet、CRIPTO、FCSF1R(コロニー刺激因子1受容体、CD115)、CSF2(コロニー刺激因子2、顆粒球マクロファージコロニー刺激因子(GM-CSF))、CSP4、CTLA4(細胞傷害性Tリンパ球関連タンパク質4)、CTAA16.88腫瘍抗原、CXCR4、CXCケモカイン受容体4型、cADPリボースヒドロラーゼ、Cyclin B1、CYP1B1、サイトメガロウイルス、サイトメガロウイルス糖タンパク質B、ダビガトラン、DLL3(デルタ様リガンド3)、DLL4(デルタ様リガンド4)、DPP4(ジペプチジルペプチダーゼ4)、DR5(デスレセプター5)、大腸菌志賀毒素1型、大腸菌志賀毒素2型、ED-B、EGFL7(タンパク質7含有EGF様ドメイン)、EGFR、EGFRII、EGFRvIII、エンドグリン、エンドセリンB受容体、エンドトキシン、EpCAM(上皮細胞接着分子)、EphA2、エピシアリン、ERBB2(上皮成長因子受容体2)、ERBB3、ERG(TMPRSS2ETS融合遺伝子)、大腸菌、ETV6-AML、FAP(線維芽細胞活性化タンパク質α)、線維芽細胞表面抗原、FCGR1、α-フェトプロテイン、フィブリンII、β鎖、フィブロネクチン外部ドメインB、FOLR(葉酸受容体)、葉酸受容体α、葉酸ヒドロラーゼ、RSウイルスのFos関連抗原1Fタンパク質、Frizzled受容体、フコシルGM1、GD2ガングリオシド、G-28(細胞表面糖脂質抗原)、GD3イディオタイプ、GloboH、グリピカン3、N-グリコリルノイラミン酸、GM3、GMCSF受容体α鎖、成長分化因子、GP100、GPNMB(膜貫通タンパク質NMB)、GUCY2C(グアニル酸シクラーゼ2C、グアニル酸シクラーゼC(GC-C)、腸グアニル酸シクラーゼ、グアニル酸シクラーゼ-C受容体、熱安定性エンテロトキシン受容体(hSTAR))、熱ショックタンパク質、血球凝集素、B型肝炎表面抗原、B型肝炎ウイルス、HER1(ヒト上皮成長因子受容体1)、HER2、HER2/neu、HER3(ERBB-3)、IgG4、HGF/SF(幹細胞増殖因子/細胞分散因子)、HHGFR、HIV-1、ヒストン複合体、HLA-DR(ヒト白血球抗原)、HLA-DR10、HLA-DRB、HMWMAA、ヒト絨毛性ゴナドトロピン、HNGF、ヒト細胞散乱因子受容体キナーゼ、HPV E6/E7、Hsp90、hTERT、ICAM-1(細胞間接着分子1)、イディオタイプ、IGF1R(IGF-1、インスリン様増殖因子1受容体)、IGHE、IFN-γ、インフルエンザ赤血球凝集素、IgE、IgE Fc領域、IGHE、インターロイキン類(IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-6R、IL-7、IL-8、IL-9、IL-10、IL-11、L-12、IL-13、IL-15、IL-17、IL-17A、IL-18、IL-19、IL-20、IL-21、IL-22、IL-23、IL-27、又はIL-28を含む。)、IL-31RA、ILGF2(インスリン様増殖因子2)、インテグリン(α4、αIIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、α
IIβ3、α5β5、αvβ5)、インターフェロンγ誘導タンパク質、ITAGA2、ITGB2、KIR2D、Kappa Ig、LCK、Le、レグマイン、ルイス-Y抗原、LFA-1(リンパ球機能関連抗原1、CD11a)、LHRH、LINGO-1、リポタイコ酸、LIV1A、LMP2、LTA、MAD-CT-1、MAD-CT-2、MAGE-1、MAGE-2、MAGE-3、MAGEA1、MAGEA3、MAGE4、MART1、MCP-1、MIF(マクロファージ遊走阻止因子又はグリコシル化阻害因子(GIF))、MS4A1(膜貫通4ドメインサブファミリーAメンバー1)、MSLN(メソテリン)、MUC1(ムチン1、細胞表面関連(MUC1)又はPolymorphic epithelial mucin(PEM))、MUC1-KLH、MUC16(CA125)、MCP1(単球走化性タンパク質1)、MelanA/MART1、ML-IAP、MPG、MS4A1(膜貫通型4ドメインサブファミリーA)、MYCN、ミエリン関連糖タンパク質、ミオスタチン、NA17、NARP-1、NCA-90(顆粒球抗原)、Nectin-4(ASG-22ME)、NGF、神経アポトーシス制御プロテイナーゼ1、NOGO-A、Notch受容体、ヌクレオリン、Neu癌遺伝子産物、NY-BR-1、NY-ESO-1、OX-40、OxLDL(酸化低密度リポタンパク質)、OY-TES1、P21、p53非変異体、P97、Page4、PAP、抗(N-グリコリルノイラミン酸)のパラトープ、PAX3、PAX5、PCSK9、PDCD1(PD-1、プログラムされた細胞死タンパク質1)、PDGF-Rα、(血小板由来成長因子受容体α)、PDGFR-β、PDL-1、PLAC1、PLAP様精巣アルカリホスファターゼ、血小板由来成長因子受容体β、リン酸ナトリウム共輸送体、PMEL17、ポリシアル酸、プロテイナーゼ3(PR1)、前立腺癌、PS(ホスファチジルセリン)、前立腺癌細胞、緑膿菌、PSMA、PSA、PSCA、狂犬病ウイルス糖タンパク質、RHD(Rhポリペプチド1(RhPI))、アカゲザル因子(Rhesus factor)、RANKL、PhoC,Ras変異体、RGS5、ROBO4、RSウイルス、RON、ROR1、肉腫転移ブレイクポイント、SART3、スクレロスチン、SLAMF7(SLAMファミリーメンバー7)、セレクチンP、SDC1(シンデカン1)、sLe(a)、ソマトメジンC、SIP(スフィンゴシン-1-ホスフェート)、ソマトスタチン、精子タンパク質17、SSX2、STEAP1(前立腺1の6回膜貫通上皮抗原)、STEAP2、STn、TAG-72(腫瘍関連糖タンパク質72)、サバイビン、T細胞受容体、T細胞膜貫通タンパク質、TEM1(腫瘍上皮マーカー1)、TENB2、テナスシンC(TN-C)、TGF-α、TGF-β(トランスフォーミング増殖因子β)、TGF-β1、TGF-β2(トランスフォーミング増殖因子β2)、Tie(CD202b)、Tie2、TIM-1(CDX-014)、TN、TNF、TNF-α、TNFRSF8、TNFRSF10B(腫瘍壊死因子受容体スーパーファミリーメンバー10B)、TNFRSF13B(腫瘍壊死因子受容体スーパーファミリーメンバー13B)、TPBG(栄養膜糖タンパク質)、TRAIL-R1(腫瘍壊死アポトーシス誘導リガンド受容体1)、TRAILR2(細胞死受容体5(DR5))、腫瘍関連カルシウムシグナルトランスデューサー2、MUC1の腫瘍特異的グリコシル化、TWEAK受容体、TYRP1(糖タンパク質75)、TRP-1(Trop1)、TRP-2(Trop2)、チロシナーゼ、VCAM-1、VEGF、VEGF-A、VEGF-2、VEGFR-1、VEGFR2、又はビメンチン、WT1、XAGE1、又は任意のインスリン成長因子受容体を発現する細胞、又は任意の上皮増殖因子受容体。 - 請求項13に記載の腫瘍細胞は、リンパ腫細胞、骨髄腫細胞、腎細胞、乳癌細胞、前立腺癌細胞、卵巣癌細胞、結腸大腸癌細胞、胃癌細胞、扁平上皮癌細胞、小細胞肺癌細胞、非小細胞肺癌細胞、精巣癌細胞、悪性細胞、又は無秩序に成長及び分裂し、癌を引き起こすペースを促進する任意の細胞から選択される。
- 治療有効量の請求項1、2、又は9のいずれか1項に記載の共役体化合物と、薬学的に許容される塩、担体、希釈剤、又は賦形剤と、を含む医薬組成物、又は感染症の治療若しくは予防のための共役体の組み合わせ。
- 以下を含み、液体処方物又は凍結乾燥固体/粉末製剤である、請求項15に記載の医薬組成物:
請求項1、2、又は9のいずれかに記載の1以上の共役体を、重量基準で0.01%~99%;
ポリオールを0.0%~20.0%;
1以上の界面活性剤を0.0%~2.0%;
1以上の保存剤を0.0%~5.0%;
1以上のアミノ酸を0.0%~30%;
1以上の抗酸化剤を0.0%~5.0%;
1以上の金属キレート剤を0.0%~0.3%;
製剤のpHを4.5~7.5に調整するための1以上の緩衝塩を0.0%~30.0%;
患者への投与のために再構成された後、浸透圧を約250から350mOsmの間で調整するための1以上の等張化剤を0.0%~30.0%;
前記ポリオールは、フルクトース、マンノース、マルトース、ラクトース、アラビノース、キシロース、リボース、ラムノース、ガラクトース、グルコース、スクロース、トレハロース、ソルボース、メレジトース、ラフィノース、マンニトール、キシリトール、エリスリトール、マルチトール、ラクチトール、エリスリトール、ソルビトールから選択される。グリセロール、又はL-グルコン酸塩とその金属塩から選択される;
前記界面活性剤は、ポリソルベート20、ポリソルベート40、ポリソルベート65、ポリソルベート80、ポリソルベート81、又はポリソルベート85、ポロキサマー、ポリ(エチレンオキシド)-ポリ(プロピレンオキシド)、ポリエチレン-ポリプロピレン、トリトン;ドデシル硫酸ナトリウム(SDS)、ラウリル硫酸ナトリウム;オクチルグリコシドナトリウム;ラウリル-、ミリスチル-、リノレル-、又はステアリル-スルホベタイン;ラウリル-、ミリスチル-、リノレル-、又はステアリル-サルコシン;リノレイル-、ミリスチル-、又はセチル-ベタイン;ラウロアミドプロピル-、コカミドプロピル-、リノレアミドプロピル-、ミリスタミドプロピル-、パルミドプロピル-、又はイソステアミドプロピル-ベタイン(ラウロアミドプロピル);ミリスタミドプロピル-、パルミドプロピル-、又はイソステアラミドプロピル-ジメチルアミン;ナトリウムメチルココイル-、又は二ナトリウムメチルオレイル-タウレート;ドデシルベタイン、ドデシルジメチルアミンオキシド、コカミドプロピルベタイン、及びココアンフォグリシネート;又はイソステアリルエチルイミドニウムエトサルフェート;ポリエチルグリコール、ポリプロピルグリコール、及びエチレンとプロピレングリコールの共重合体から選択される;
前記保存剤は、ベンジルアルコール、オクタデシルジメチルベンジル塩化アンモニウム、塩化ヘキサトニウム、塩化ベンザルコニウム、塩化ベンゼトニウム、フェノール、ブチルアルコール、メチル又はプロピルパラベン等のアルキルパラベン、カテコール、レソルシノール、シクロヘキサノール、3-ペンタノール、又はm-クレゾールから選択される;
前記抗酸化剤は、アスコルビン酸、グルタチオン、シスチン、又はメチオニンから選択される;
前記キレート剤は、EDTA又はEGTAから選択される;
前記アミノ酸は、アルギニン、シスチン、グリシン、リジン、ヒスチジン、オルニチン、イソロイシン、ロイシン、アラニン、グリシン、グルタミン酸、又はアスパラギン酸から選択される;
前記緩衝塩は、クエン酸、アスコルビン酸、グルコン酸、炭酸、酒石酸、コハク酸、酢酸、又はフタル酸のナトリウム、カリウム、アンモニウム、又はトリヒドロキシエチルアミノ塩;トリス又は塩酸トロメタミン、リン酸塩又は硫酸塩;アルギニン、グリシン、グリシルグリシン、又はヒスチジンの陰イオン性の酢酸塩、塩化物、リン酸塩、硫酸塩、又はコハク酸塩から選択される;
前記等張化剤は、マンニトール、ソルビトール、酢酸ナトリウム、塩化カリウム、リン酸ナトリウム、リン酸カリウム、クエン酸三ナトリウム、又は塩化ナトリウムから選択される。 - バイアル、ボトル、プレフィルドシリンジ、又はプレフィルド自動注入器シリンジに、液体又は凍結乾燥固体の形態で充填される、請求項15又は16に記載の医薬組成物。
- インビトロ(in vitro)、インビボ(in vivo)、又はエクスビボ(ex vivo)で細胞殺傷活性を有する、請求項1、2若しくは9に記載の共役体、又は15若しくは16に記載の医薬組成物の形態中の共役体。
- 化学療法薬、放射性療法、免疫治療薬、自己免疫性疾患薬、抗感染症薬、又は相乗的にがん、自己免疫性疾患、若しくは感染疾患を治療若しくは予防するための他の共役体と同時に投与される、請求項15又は16に記載の医薬組成物。
- 請求項19に記載の化学療法剤は、以下の薬剤のうちの1以上から選択される:
(1)a)以下からなる群から選択されるアルキル化剤:ナイトロジェンマスタード:クロラムブシル、クロルナファジン、シクロホスファミド、ダカルバジン、エストラムスチン、イホスファミド、メクロレタミン、塩酸メクロレタミンオキサイド、マンノムスチン、ミトブロニトール、メルファラン、ミトラクトール、ピポブロマン、ノベンビチン、フェネステリン、プレドニムスチン、チオテパ、トロホスファミド、ウラシルマスタード;CC-1065並びにアドゼレシン、カルゼレシン及びビゼレシンの合成類似体;デュオカルマイシン並びにその合成類似体、KW-2189、CBI-TMI、又はCBI二量体;ベンゾジアゼピン二量体又はピロロベンゾジアゼピン(PBD)二量体、トマイマイシン二量体、インドリノベンゾジアゼピン二量体、イミダゾベンゾチアヂアゼピン二量体、又はオキサゾリジノベンゾジアゼピン二量体;カルムスチン、ロムスチン、クロロゾトシン、フォテムスチン、ニムスチン、ラニムスチンを含むニトロソ尿素化合物;ブスルファン、トレオスルファン、イムプロスルファン、及びピポスルファンを含むアルキルスルホネート;トリアゼン又はダカルバジン;カルボプラチン、シスプラチン、及びオキサリプラチンを含む白金含有化合物;アジリジン類、ベンゾドパ、カルボクオン、メツレドパ、及びウレドパ;エチレンイミン類、並びにアルトレタミン、トリエチレンメラミン、トリエチレンホスホルアミド、トリエチレンチオホスホルアミン、トリメチロロメラミン(trimethylolomelamine)を含むメチラメラミン類;
b)以下からなる群から選択される植物アルカロイド:ビンクリスチン、ビンブラスチン、ビンデシン、ビノレルビン、ナベルビンを含むビンカアルカロイド類;パクリタキセル及びドセタキセルを含むタキソイド類並びにこれらの類似体;DM1、DM2、DM3、DM4、DM5、DM6、DM7、メイタンシン、アンサマイトシンを含むメイタンシノイド類並びにこれらの類似体;クリプトフィシン1及びクリプトフィシン8の群を含むクリプトフィシン類;エポチロン類、エリュテロビン、ディスコデルモライド、ブリオスタチン類、ドロスタチン類、オーリスタチン類、チューブリシン類、セファロスタチン類;パンクラチスタチン;サルコジクチイン;スポンジスタチン;
c)以下から選択されるDNAトポイソメラーゼ阻害剤:9-アミノカンプトテシン、カンプトテシン、クリスナトール、ダウノマイシン、エトポシド、リン酸エトポシド、イリノテカン、ミトキサントロン、ノバントロン、レチノイン酸(レチノール類)、テニポシド、トポテカン、9-ニトロカンプトテシン又はRFS 2000を含むエピポドフィリン類;及びマイトマイシン類、並びにそれらの類縁体;
d)代謝拮抗剤:{[抗葉酸:(DHFR阻害剤:メトトレキサート、トリメトレキサート、デノプテリン、プテロプテリン、アミノプテリン(4-アミノプテロイン酸)、又はその他の葉酸類縁体を含む。);IMPデヒドロゲナーゼ阻害剤(ミコフェノール酸、チアゾフリン、リバビリン、EICARを含む。);リボヌクレオチド還元酵素阻害薬(ヒドロキシウレア、デフェロキサミンを含む。)];[ピリミジン類縁体:ウラシル類縁体(アンシタビン、アザシチジン、6-アザウリジン、カペシタビン、カルモフール、シタラビン、ジデオキシウリジン、ドキシフルリジン、エノシタビン、5-フルオロウラシル、フロクスウリジン、ラルチトレキセドを含む。);シトシン類似体:(シタラビン、シトシンアラビノシド、フルダラビンを含む。);プリン類縁体:(アザチオプリン、フルダラビン、メルカプトプリン、チアミプリン、チオグアニン)を含む。];フォリン酸等の葉酸補充剤}からなる群から選択される;
e)ホルモン療法剤:受容体拮抗薬:[抗エストロゲン:(メゲストロール、ラロキシフェン、タモキシフェンを含む);LHRHアゴニスト:(ゴセレリン、酢酸リュープロリドを含む);抗アンドロゲン:(ビカルタミド、フルタミド、カルステロン、プロピオン酸ドロモスタノロン、エピチオスタノール、ゴセレリン、リュープロリド、メピチオスタン、ニルタミド、テストラクトン、トリロスタン、及び他の類似のアンドロゲン阻害剤を含む。)];レチノイド類/三角筋:[ビタミンD3類縁体:(CB1093、EB1089、KH1060、コレカルシフェロール、エルゴカルシフェロールを含む);光線力学的療法剤:(ベルテポルフィン、フタロシアニン、光増感剤Pc4、デメトキシヒポクレリンAを含む);サイトカイン類:(インターフェロンα、インターフェロンγ、腫瘍壊死因子(TNF)、TNFドメイン含有ヒトタンパク質を含む)]}から選択される;
f)キナーゼ阻害剤:BIBW2992(抗EGFR/Erb2)、イマチニブ、ゲフィチニブ、ペガプタニブ、ソラフェニブ、ダサチニブ、スニチニブ、エルロチニブ、ニロチニブ、ラパチニブ、アキシチニブ、パゾパニブ、バンデタニブ、E7080(抗VEGFR2)、ムブリチニブ、ポナチニブ、バフェチニブ、ボスチニブ、カボザンチニブ、ビスモデギブ、イニパリブ、ルキソリチニブ、CYT387、アキシチニブ、チボザニブ、ソラフェニブ、ベバシズマブ、セツキシマブ、トラスツズマブ、ラニビズマブ、パニツムマブ、イスピネシブからなる群から選択される;
g)オラパリブ、ニラパリブ、イニパリブ、タラゾパリブ、ベリパリブ、CEP9722(セファロン)、E7016(エーザイ)、BGB-290(ベイジーン)、又は3-アミノベンズアミドからなる群から選択されるポリ(ADP-リボース)ポリメラーゼ(PARP)阻害剤;
h)エンジイン系抗生物質(カリケアマイシン類、カリケアマイシンγ1、δ1、α1、又はβ1;ダイネミシンA及びデオキシダイネミシンを含むダイネミシン;エスペラミシン、ケダルシジン、C-1027、マズロペプチン、又はネオカルジノスタチンクロモフォア及び関連する色素タンパク質エンジイン抗生物質クロモフォアから選択される。)、アクラシノマイシン類、アクチノマイシン、アンスラマイシン(authramycin)、アザセリン、ブレオマイシン類、カクチノマイシン(cactinomycin)、カラビシン(carabicin)、カルミノマイシン、カルジノフィリン;クロモマイシン類、ダクチノマイシン、ダウノルビシン、デトルビシン、6-ジアゾ-5-オキソ-L-ノルロイシン、ドキソルビシン、モルホリノ-ドキソルビシン、シアノモルホリノ-ドキソルビシン、2-ピロリノ-ドキソルビシン及びデオキシドキソルビシン、エピルビシン、エリブリン、エソルビシン、イダルビシン、マルセロマイシン、マイトマイシン類(nitomycins)、ミコフェノール酸、ノガラマイシン、オリボマイシン類、ペプロマイシン、ポトフィロマイシン、ピューロマイシン、クエラマイシン、ロドルビシン、ストレプトニグリン(streptonigrin)、ストレプトゾシン、ツベルシジン、ウベニメクス、ジノスタチン、ゾルビシンから選択される抗生物質;
i)ポリケチド(アセトゲニン類)、ブラタシン及びブラタシノン;ゲムシタビン、エポキソミシン類及びカルフィルゾミブ、ボルテゾミブ、サリドマイド、レナリドミド、ポマリドマイド、トセドスタット、ザイブレスタット、PLX4032、STA-9090、スチムバックス(Stimuvax)、アロベクチン-7、ザイゲバ、プロベンジ、エルボイ、イソプレニル化阻害剤及びロバスタチン、ドーパミン作動性神経毒及び1-メチル-4-フェニルピリジンイオン、細胞周期阻害剤(スタウロスポリンを含む。)、アクチノマイシン類(アクチノマイシンD、ダクチノマイシンを含む。)、アマニチン類、ブレオマイシン類(ブレオマイシンA2、ブレオマイシンB2、ペプロマイシンを含む。)、アントラサイクリン類(ダウノルビシン、ドキソルビシン(アドリアマイシン)、イダルビシン、エピルビシン、ピラルビシン、ゾルビシンを含む。)、ミトキサントロン、MDR阻害剤又はベラパミル、Ca2+ATP阻害剤又はタプシガルギン、ヒストン脱アセチル化酵素阻害剤(ボリノスタット、ロミデプシン、パノビノスタット、バルプロ酸、モセチノスタット(MGCD0103)、ベリノスタット、PCI-24781、エンチノスタット、SB939、レスミノスタット、ギビノスタット、AR-42、CUDC-101、スルフォラファン、トリコスタチンAを含む。);タプシガルギン、セレコキシブ、グリタゾン類、エピガロカテキンガレート、ジスルフィラム、サリノスポラミドA、抗副腎薬(アミノグルテチミド、ミトタン、トリロスタンカからなる群から選択される);アセグラトン;アルドホスファミドクリコシド;アミノレブリン酸;アムサクリン(amsacrine);アラビノシド、ベストラブシル;ビサントレン;エダトレキサート;デフォファミン;デメコルシン;ジアジコン;エルフォルニチン(DFMO)、エルフォミチン;酢酸エリプチニウム;エトクルシド、硝酸ガリウム、ガシトシン、ヒドロキシ尿素;イバンドロネート、レンチナン;ロニダミン;ミトグアゾン;モピダモール;ニトラクリン;ペントスタチン;フェナメット;ピラルビシン;ポドフィリン酸;2-エチルヒドラジド;プロカルバジン;PSK(登録商標);ラゾキサン;リゾキシン;シゾフィラン;スピロゲルマニウム;テニュアゾン酸;トリアジコン;2,2’,2’’-トリクロロトリエチルアミン;トリコテセン類(T2トキシン、ベルカリンA、ロリジンA、及びアングイジンを含む。);ウレタン、siRNA、アンチセンス医薬;
2)抗自己免疫疾患薬:シクロスポリン、シクロスポリンA、アミノカプロン酸、アザチオプリン、ブロモクリプチン、クロラムブシル、クロロキン、シクロホスファミド、コルチコイド類(アムシノニド、ベタメタゾン、ブデソニド、ヒドロコルチゾン、フルニソリド、フルチカゾンプロピオン酸エステル、フルオコートロンダナゾール(fluocortolone danazol)、デキサメタゾン、トリアムシノロンアセトニド、ジプロピオン酸ベクロメタゾンを含む。)、DHEA、エタネルセプト、ヒドロキシクロロキン、インフリキシマブ、メロキシカム、メトトレキサート、モフェチル、ミコフェノール酸、プレドニゾン、シロリムス、タクロリムス;
3)以下を含む抗感染症薬:
a)アミノグリコシド類:アミカシン、アストロマイシン、ゲンタマイシン(ネチルマイシン、シソマイシン、イセパマイシン)、ハイグロマイシンB、カナマイシン(アミカシン、アルベカシン、ベカナマイシン、ジベカシン、トブラマイシン)、ネオマイシン(フラマイシン、パロモマイシン、リボスタマイシン)、ネチルマイシン, スペクチノマイシン、ストレプトマイシン、トブラマイシン、ベルダミシン;
b)アンフェニコール類:アジダムフェニコール、クロラムフェニコール、フロルフェニコール、チアンフェニコール;
c)アンサマイシン類:ゲルダナマイシン、ハービマイシン;
d)カルバペネム類:ビアペネム、ドリペネム、エルタペネム、イミペネム、シラスタチン、メロペネム、パニペネム;
e)セフェム類:カルバセフェム(ロラカルベフ)、セファセトリル、セファクロル、セフラジン、セファドロキシル、セファロニウム、セファロリジン、セファロチン又はセファロチン、セファレキシン、セファログリシン、セファマンドール、セファピリン、セファトリジン、セファザフル、セファゼドン、セファゾリン、セフブペラゾン、セフカペン、セフダロキシム、セフェピム、セフミノックス、セフォキシチン、セフプロジル、セフロキサジン、セフテゾル、セフロキシム、セフィキシム、セフジニル、セフジトレン、セフェピム、セフェタメト、セフメノキシム、セフォジジム、セフォニシド、セフォペラゾン、セフォラニド、セフォタキシム、セフォチアム、セフォゾプラン、セファレキシン、セフピミゾール、セフピラミド、セフピロム、セフポドキシム、セフプロジル、セフキノム、セフスロジン、セフタジジム、セフテラム、セフチブテン、セフチオレン、セフチゾキシム、セフトビプロル、セフトリアキソン、セフロキシム、セフゾナム、セファマイシン(セフォキシチン、セフォテタン、セフメタゾールを含む。)、オキサセフェム(フロモキセフ、ラタモキセフ);
f)糖ペプチド類:ブレオマイシン、バンコマイシン(オリタバンシン、テラバンシンを含む。)、テイコプラニン(ダルババンシン)、ラモプラニン;
g)グリシルサイクリン類:チゲサイクリン;
h)β-ラクタマーゼ阻害剤:ペナム(スルバクタム、タゾバクタム)、クラバム(クラブラン酸);
i)リンコサミド類:クリンダマイシン、リンコマイシン;
j)リポペプチド類:ダプトマイシン、A54145、カルシウム依存性抗生物質(CDA);
k)マクロライド類:アジスロマイシン、セスロマイシン、クラリスロマイシン、ジリスロマイシン、エリスロマイシン、フルリスロマイシン、ジョサマイシン、ケトライド(テリスロマイシン、セスロマイシン)、ミデカマイシン、ミオカマイシン、オレアンドマイシン、リファマイシン(リファンピシンン、リファンピン、リファブチン、リファペンチン)、ロキタマイシン、ロキシスロマイシン、スペクチノマイシン、スピラマイシン、タクロリムス(FK506)、トロレアンドマイシン、テリスロマイシンン;
l)モノバクタム類:アズトレオナム、チゲモナム;
m)オキサゾリジノン類:リネゾリド;
n)ペニシリン類:アモキシシリン、アンピシリン、ピバンピシリン、ヘタシリン、バカンピシリン、メタンピシリン、タランピシリン、アジドシリン、アズロシリン、ベンジルペニシリン、ベンザチンベンジルペニシリン、ベンザチンフェノキシメチルペニシリン、クロメトシリン、プロカインベンジルペニシリン、カルベニシリン(カリンダシリン)、クロキサシリン、ジクロキサシリン、エピシリン、フルクロキサシリン、メシリナム(ピブメシリナム)、メズロシリン、メチシリン、ナフシリン、オキサシリン、ペナメシリン、ペニシリン、フェネチシリン、フェノキシメチルペニシリン、ピペラシリン、プロピシリン、スルベニシリン、テモシリン、チカルシリン;
o)ポリペプチド類:バシトラシン、コリスチン、ポリミキシンB;
p)キノロン類:アラトロフロキサシン、バロフロキサシン、シプロフロキサシン、クリナフロキサシン、ダノフロキサシン、ジフロキサシン、エノキサシン、エンロフロキサシン、フロキシン、ガレノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、カノトロバフロキサシン、レボフロキサシン、ロメフロキサシン、マルボフロキサシン、モキシフロキサシン、ナジフロキサシン、ノルフロキサシン、オルビフロキサシン、オフロキサシン、ペフロキサシン、トロバフロキサシン、グレパフロキサシン、シタフロキサシン、スパルフロキサシン、テマフロキサシン、トスフロキサシン、トロバフロキサシン;
q)ストレプトグラミン類:プリスチナマイシン、キヌプリスチン/ダルフォプリスチン;
r)スルホンアミド類:マフェニド、プロントジル、スルファセタミド、スルファメチゾール、スルファニルアミド、スルファサラジン、スルフィソキサゾール、トリメトプリム、トリメトプリム-スルファメトキサゾール(コ-トリモキサゾール);
s)ステロイド系抗菌薬:フシジン酸から選択される;
t)テトラサイクリン類:ドキシサイクリン、クロルテトラサイクリン、クロモサイクリン、デメクロサイクリン、リメサイクリン、メクロサイクリン、メタサイクリン、ミノサイクリン、オキシテトラサイクリン、ペニメピサイクリン、ロリテトラサイクリン、テトラサイクリン、グリシルサイクリン(チゲサイクリンを含む。);
u)その他の抗生物質:アンノナシン、アルスフェナミン、バクトプレノール阻害剤(バシトラシン)、DADAL/AR阻害剤(サイクロセリン)、ジクチオスタチン、ディスコデルモライド、エレウテロビン、エポチロン、エタンブトール、エトポシド、ファロペネム、フシジン酸、フラゾリドン、イソニアジド、ラウリマリド、メトロニダゾール、ムピロシン、マイコラクトン、NAM合成阻害剤(ホスホマイシン)、ニトロフラントイン、パクリタキセル、プラテンシマイシン、ピラジナミド、キヌプリスチン/ダルホプリスチン、リファンピシン(リファンピン)、タゾバクタムチニダゾール、ウバリシン;
(4)以下を含む抗ウイルス薬:
a)侵入/融合阻害剤:アプラビロック、マラビロク、ビクリビロック、gp41(エンフビルチド)、PRO140、CD4(イバリズマブ);
b)インテグラーゼ阻害剤:ラルテグラビル、エルビテグラビル、グロボイドナンA;
c)成熟阻害剤:ベビリマット、ヴィヴェコン;
d)ノイラミニダーゼ阻害剤:オセルタミビル、ザナミビル、ペラミビル;
e)ヌクレオシド及びヌクレオチド:アバカビル、アシクロビル、アデフォビル、アムドキソビル、アプリシタビン、ブリブジン、シドフォビル、クレブジン、デキセルブシタビン、ジダノシン(DDI)、エルブシタビン、エムトリシタビン(FTC)、エンテカビル、ファムシクロビル、フルオロウラシル(5-FU)、3’-フルオロ置換2’,3’-デオキシヌクレオシド類似体(3’-フルオロ-2’,3’-ジデオキシチミジン(FLT)及び3’-フルオロ-2’,3’-ジデオキシグアノシン(FLG)からなる群を含む)、ホミビルセン、ガンシクロビル、イドクスウリジン、ラミブジン(3TC)、L-ヌクレオシド(β-L-チミジン及びβ-L-2’-デオキシシチジンからなる群を含む)、ペンシクロビル、ラシビル、リバビリン、スタンピジン、スタブジンセット(d4T)、タリバビリン(ビラミジン)、テルビブジン、テノホビル、トリフルリジン、バラシクロビル、バルガンシクロビル、ザルシタビン(ddC)、ジドブジン(AZT);
f)非ヌクレオシド:アマンタジン、アテビリジン、カプラビリン、ジアリルピリミジン(エトラビリン、リルピビリン)、デラビルジン、ドコサノール、エミビリン、エファビレンツ、ホスカルネット(ホスホリルギ酸)、イミキモド、インターフェロンα、ロビリド、ロデノシン、メチサゾン、ネビラピン、NOV-205、ペグインターフェロンα、ポドフィロトキシン、リファンピシン、リマンタジン、レシキモド(R-848)、トロマンタジン;
g)プロテアーゼ阻害剤:アンプレナビル、アタザナビル、ボセプレビル、ダルナビル、ホスアンプレナビル、インジナビル、ロピナビル、ネルフィナビル、プレコナリル、リトナビル、サキナビル、テラプレビル(VX-950)、チプラナビル;
h)その他の抗ウイルス薬:アブザイム、アルビドール、カラノリドA、セラゲニン、シアノビリン-N、ジアリルピリミジン、没食子酸エピガロカテキン(EGCG)、ホスカルネット、グリフィスシン、タリバビリン(ビラミジン)、ヒドロキシウレア、KP-1461、ミルテフォシン、プレコナリル、ポートマントー阻害剤、リバビリン、セリシクリブ;
(5)上記の任意の薬物の、薬学的に許容される塩、酸、誘導体、水和物若しくは水和塩;又は結晶構造;又は光学異性体、ラセミ体、ジアステレオマー若しくはエナンチオマー。 - 請求項20に記載の相乗剤は、以下の薬剤の1種又は数種から選択される:アバタセプト、酢酸アビラテロン、アブラキサン、アセトアミノフェン/ヒドロコドン、アカラブルチニブ、アデュカヌマブ、アダリムマブ、ADXS31-142、ADXS-HER2、アファチニブジマレート、アルデスロイキン、アレクチニブ、アレムツズマブ、アリトレチノイン、アルペリシブ、アド-トラスツズマブエムタンシン、アンフェタミン/デキストロアンフェタミン、アナロチニブ、アナストロゾール、アパルタミド、アリピプラゾール、アントラサイクリン、アリピプラゾール、アタザナビル、アテゾリズマブ、アトルバスタチン、アヴェルマブ、アキシカブタゲン シロロイセル、アキシチニブ、ベリノスタット、生BCG、ベバシズマブ、ベキサロテン、ブリナツモマブ、ボルテゾミブ、ボスチニブ、ブレンツキマブ ベドチン、ブリガチニブ、ブデソニド、ブデソニド/ホルモテロール、ブプレノルフィン、カバジタキセル、カボザチニブ、カムレリズマブ、カンマチニブ、カペシタビン、カルフィルゾミブ、キメラ抗原受容体改変T(CAR-T)細胞、セレコキシブ、セリチニブ、セツキシマブ、チダミド、シクロスポリン、シナカルセット、クリゾチニブ、コビメチニブ、コセンティクス、クリゾチニブ、CTL019、ダビガトラン、ダブラフェニブ、ダカルバジン、ダクリズマブ、ダコミチニブ、ダコモチニブ、ダプトマイシン、ダラツムマブ、ダルベポエチンアルファ、ダロルタミド、ダルナビル、ダサチニブ、デニロイキンジフチトックス、デノスマブ、デパコテ、デキスランソプラゾール、デクスメチルフェニデート、デキサメタゾン、ディグニキャップクーリングシステム、ジヌツキシマブ、ドキシサイクリン、デュロキセチン、デュベリシブ、ダルマブマブ、エロツズマブ、エムトリシビン/リルピビリン/テノフォビル、フマル酸ジソプロキシル、エムトリシビン/テノフォビル/エファビレンツ、エンフォルツマブ ベドチン-ejfv、エノキサパリン、エンサルチニブ、エントレクチニブ、エンザルタミド、エポエチンアルファ、エルロチニブ、エルダフィチニブ、エソメプラゾール、エスゾピクロン、エタネルセプト、エベロリムス、エキセメスタン、エベロリムス、エクセナチドER、エゼチミブ、エゼチミブ/シンバスタチン、fam-トラスツズマブ デュラクステカン、フェノフィブラート、フィルグラスチム、フィンゴリモド(fingolimod)、プロピオン酸フルチカゾン、フルチカゾン/サルメテロール、フルベストラント、ガジバ、ゲフィチニブ、グラチラマー、酢酸ゴセレリン、イコチニブ、イマチニブ、イブリツモマブチウセタン、イブルチニブ、イデラリシブ、イホスファミド、インフリキシマブ、イミキモド、イミュCyst、イムノBCG、イニパリブ、インスリンアスパルト、インスリンデテミル、インスリングラルギン、インスリンリスプロ、インターフェロンアルファ、インターフェロンアルファ-1b、インターフェロンアルファ-2a、インターフェロンアルファ-2b、インターフェロンベータ、インターフェロンベータ1a、インターフェロンベータ1b、インターフェロンガンマ-1a、ラパチニブ、イピリムマブ、臭化イプラトロピウム/サルブタモール、イキサゾミブ、カヌマ、酢酸ランレオチド、レナリドミド、レナリオミド、メシル酸レンバチニブ、レトロゾール、レボチロキシン、レボチロキシン、リドカイン、リネゾリド、リラグルチド、リスデキサンフェタミン、LN-144、ロラチニブ、メマンチン、メチルフェニデート、メトプロロール、メキニスト、メリシタビン/リルピビリン/テノフォビル、モダフィニル、モメタゾン、マイシダック-C(Mycidac-C)、ネシツムマブ、ネラチニブ、ニロチニブ、ニラパリブ、ニボルマブ、オファツムマブ、オビヌツズマブ、オラパリブ、オルメサルタン、オルメサルタン/ヒドロクロロチアジド、オマリズマブ、オメガ3脂肪酸エチルエステル、オンコリン、オセルタミビル、オシメルチニブ、オキシコドン、パルボシクリブ、パリビズマブ、パニツムマブ、パノビノスタット、パゾパニブ、ペンブロリズマブ、塩酸ペキシダルチニブ、PD-1抗体、PD-L1抗体、ペメトレキセド、ペルツズマブ、肺炎球菌共役ワクチン、ポラツズマブ ベドチン、ポマリドミド、プレガバリン、プロスカバックス(ProscaVax)、プロプラノロール、クエチアピン、ラベプラゾール、ラジウム223塩化物、ラロキシフェン、ラルテグラビル、ラムシルマブ、ラニビズマブ、レルゴリクス、レゴラフェニブ、リツキシマブ、リバロキサバン、ロミデプシン、ロスバスタチン、ルキソリチニブリン酸塩、サルブタモール、サボリチニブ、セマグルチド、セリネキサー、セベラマー、シルデナフィル、シルツキシマブ、シプロイセル-T(Sipuleusel-T)、シタグリプチン、シタグリプチン/メトホルミン、ソリフェナシン、ソラネズマブ、ソニデギブ、ソラフェニブ、スニチニブ、タクロリムス、タクリムス、タダラフィル、タモキシフェン、タフィンラー、タリモジネラヘルパレプベク(Talimogenelaherparepvec)、タラゾパリブ、テラプレビル、タラゾパリブ、テモゾロミド、テンシロリムス、テノフォビル/エムトリシタビン、テノフォビルジソプロキシルフマル酸塩、テストステロンゲル、タリドミド、TICE BCG、臭化チオトロピウム、チサゲンレクロイセル(Tisagenlecleucel)、トレミフェン、トラメチニブ、トラスツズマブ、トラスツズマブ/ヒアルロニダーゼ-oysk、トラベクチン(エクテナサイジン743)、トラメチニブ、トレメリムマブ、トリフルリジン/チピラシル、トレチノイン、チスレリズマブ、ウロ-BCG、ウステキヌマブ、バルサルタン、ベリパリブ、バンデタニブ、ベムラフェニブ、ベネトクラックス、ボリノスタット、ザヌブルチニブ、ジブ-アフリベルセプト、及びゾスタバックス、並びにこれらの類縁体、誘導体、薬学的に許容される塩、担体、希釈剤若しくは賦形剤、又はこれらの組み合わせ。
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US11873281B2 (en) | 2012-07-12 | 2024-01-16 | Hangzhou Dac Biotech Co., Ltd. | Conjugates of cell binding molecules with cytotoxic agents |
WO2018156180A1 (en) | 2017-02-24 | 2018-08-30 | Kindred Biosciences, Inc. | Anti-il31 antibodies for veterinary use |
EP3927729A4 (en) | 2019-02-18 | 2023-10-11 | Eli Lilly and Company | THERAPEUTIC ANTIBODY FORMULATION |
CA3138197A1 (en) | 2019-05-14 | 2020-11-19 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
EP4058464A1 (en) | 2019-11-13 | 2022-09-21 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
CA3108168A1 (en) * | 2020-02-05 | 2021-08-05 | Yue Zhang | Conjugates of cell-binding molecules with cytotoxic agents |
US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
WO2023004349A1 (en) * | 2021-07-20 | 2023-01-26 | Ohio State Innovation Foundation | 7-ethyl-10-hydroxy-camptothecin (sn-38) albumin conjugates for treatment of cancers |
CN113845563B (zh) * | 2021-09-28 | 2024-02-20 | 遵义医药高等专科学校 | 一种FAPα酶激活式鬼臼毒素衍生物及其制备方法与应用 |
CN114209652B (zh) * | 2021-12-29 | 2022-08-09 | 中山大学附属第一医院 | 一种微环境nk细胞免疫调控递送系统及其制备方法和应用 |
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