JP5345065B2 - デプシペプチドおよびその治療的使用 - Google Patents
デプシペプチドおよびその治療的使用 Download PDFInfo
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- JP5345065B2 JP5345065B2 JP2009537705A JP2009537705A JP5345065B2 JP 5345065 B2 JP5345065 B2 JP 5345065B2 JP 2009537705 A JP2009537705 A JP 2009537705A JP 2009537705 A JP2009537705 A JP 2009537705A JP 5345065 B2 JP5345065 B2 JP 5345065B2
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- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229950001139 timonacic Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 206010044325 trachoma Diseases 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 201000007790 vitelliform macular dystrophy Diseases 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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Description
R2およびR4は同一であっても異なっていてもよく、それぞれ−H、−炭素数1〜6のアルキル、−炭素数2〜6のアルケニル、−L−O−C(O)−R’、−L−C(O)−O−R’’、−L−A、−L−NR’’R’’、−L−Het−C(O)−Het−R’’および−L−Het−R’’から選択され、ここでLは炭素数1〜6のアルキレン基であり、Aはフェニルまたは5〜6員環ヘテロアリール基であり、各R’は同一であっても異なっていてもよく、炭素数1〜4のアルキルを表し、各R’’は同一であっても異なっていてもよく、Hまたは炭素数1〜6のアルキルを表し、各−Het−は同一であっても異なっていてもよく、−O−、−N(R’’’)−および−S−から選択されるヘテロ原子スペーサーであり、各R’’’は同一であっても異なっていてもよく、Hまたは炭素数1〜4のアルキルを表し;
各R6は同一であっても異なっていてもよく、水素または炭素数1〜4のアルキルを表し;
そしてPr1およびPr2は同一であっても異なっていてもよく、それぞれ水素または保護基を表す。
(a)チオール基を保護するチオエーテルを形成する保護基であって、例えば炭素数1〜6のアルコキシ(たとえばメトキシ等)、炭素数1〜6のアシルオキシ(たとえばアセトキシ等)、ヒドロキシおよびニトロによって任意に置換されていてもよいベンジル基、ピコリル、ピコリル−N−オキシド、アントリルメチル、ジフェニルメチル、フェニル、t−ブチル、アダマンチル、炭素数1〜6のアシルオキシメチル(例えばピバロイルオキシメチル、第3級ブトキシカルボニルオキシメチル);
(b)チオール基を保護するモノチオ、ジチオまたはアミノチオアセタールを形成する保護基であって、例えば炭素数1〜6のアルコキシメチル(たとえばメトキシメチル、イソブトキシメチル等)、テトラヒドロピラニル、ベンジルチオメチル、フェニルチオメチル、チアゾリジン、アセトアミドメチル、ベンズアミドメチル;
(c)チオール基を保護するチオエステルを形成する保護基であって、例えば第3級ブトキシカルボニル(BOC)、アセチルおよびその誘導体、ベンゾイルおよびその誘導体;または
(d)チオール基を保護するカルバミン酸チオエステルを形成する保護基であって、例えばカルバモイル、フェニルカルバモイル、炭素数1〜6のアルキルカルバモイル(たとえばメチルカルバモイルおよびエチルカルバモイル等);
である。
(a)エーテルを形成してヒドロキシル基を保護する保護基、例えば、炭素数1〜6のアルコキシ(たとえばメトキシ等)、炭素数1〜6のアシルオキシ(たとえばアセトキシ等)、ヒドロキシおよびニトロによって任意に置換されていてもよいベンジル基、ピコリル、ピコリル−N−オキシド、アントリルメチル、ジフェニルメチル、フェニル、t−ブチル、アダマンチル、炭素数1〜6のアシルオキシメチル(たとえばピバロイルオキシメチル、第3級ブトキシカルボニルオキシメチル等);
(b)アセタールまたはアミノアセタールを形成する保護基、例えば炭素数1〜6のアルコキシメチル(たとえばメトキシメチル、イソブトキシメチル等)、テトラヒドロピラニル、アセトアミドメチル、ベンズアミドメチル;
(c)エステルを形成してヒドロキシル基を保護する保護基、例えば第3級ブトキシカルボニル(BOC)、アセチルおよびその誘導体、ベンゾイルおよびその誘導体;または
(d)カルバミン酸エステルを形成してヒドロキシル基を保護する保護基、例えばカルバモイル、フェニルカルバモイル、炭素数1〜6のアルキルカルバモイル(たとえばメチルカルバモイルおよびエチルカルバモイル等);
である。
、エステルもしくはカルバミン酸エステルを形成し、ヒドロキシル基を保護する保護基;を表す。好ましくは、Pr3は水素;または、炭素数1〜6のアルコキシ(たとえばメトキシ等)、炭素数1〜6のアシルオキシ(たとえばアセトキシ等)、ヒドロキシおよびニトロによって任意に置換されていてもよいベンジル基、ピコリル、ピコリル−N−オキシド、アントリルメチル、ジフェニルメチル、フェニル、t−ブチル、アダマンチル、炭素数1〜6のアシルオキシメチル(たとえばピバロイルオキシメチル、第3級ブトキシカルボニルオキシメチル等)、炭素数1〜6のアルコキシメチル(たとえばメトキシメチル、イソブトキシメチル等)、テトラヒドロピラニル、ベンジルチオメチル、フェニルチオメチル、チアゾリジン、アセトアミドメチル、ベンズアミドメチル、第3級ブトキシカルボニル(BOC)、アセチルおよびその誘導体、ベンゾイルおよびその誘導体、カルバモイル、フェニルカルバモイルおよび炭素数1〜6のアルキルカルバモイル(たとえばメチルカルバモイルおよびエチルカルバモイル等)から選択される保護基;を表す。最も好ましくは、Pr3は水素である。
R1が−CH(CH3)2、R2が−H、R3がCH2Ph、R4が水素、およびR6が−Hであるか;
R1が−CH(CH3)2、R2が−H、R3が−CH2−(3−1−t−ブチルオキシカルボニル−インドリル)、R4が水素、およびR6が−Hであるか;
R1が−CH(CH3)2、R2が−H、R3が−CH2CH(CH3)2、R4が水素、およびR6が−Hであるか;
R1がCH2Ph、R2が−H、R3が−CH2C6H5、R4が水素、およびR6が−Hであるか;または
R1がCH2Ph、R2が−H、R3が−CH3、R4が水素、およびR6が−Hであるもの;およびその医薬的に許容される塩である。
R1が−CH(CH3)2、R2が−H、R3がCH2Ph、R4が水素、R6が−H、ならびにPr1およびPr2が水素であるか;
R1が−CH(CH3)2、R2が−H、R3が−CH2−(3−1−t−ブチルオキシカルボニル−インドリル)、R4が水素、R6が−H、ならびにPr1およびPr2が水素であるか;
R1が−CH(CH3)2、R2が−H、R3が−CH2CH(CH3)2、R4が水素、R6が−H、ならびにPr1およびPr2が水素であるか;
R1がCH2Ph、R2が−H、R3が−(CH2)−C6H5、R4が水素、R6が−H、ならびにPr1およびPr2が水素であるか;または
R1がCH2Ph、R2が−H、R3が−CH3、R4が水素、R6が−H、ならびにPr1およびPr2が水素であるもの;およびその医薬的に許容される塩である。
R1は−H、−CH3、−CH(CH3)2、−CH2CH(CH3)2、−CH(CH3)CH2CH3、−(CH2)4NH2、−CH2SH、−CH2CH2SCH3、−CH2OHまたは−CH(OH)CH3であり;
R2は−H、−CH3、−CH(CH3)2、−CH2CH(CH3)2、−CH(CH3)CH2CH3、−(CH2)4NH2、−CH2SH、−CH2CH2SCH3、−CH2OHまたは−CH(OH)CH3であり;
R3は−H、−CH3、−CH(CH3)2、−CH2CH(CH3)2、−CH(CH3)CH2CH3、−(CH2)4NH2、−CH2SH、−CH2CH2SCH3、−CH2OHまたは−CH(OH)CH3であり;そして
R4は−H、−CH3、−CH(CH3)2、−CH2CH(CH3)2、−CH(CH3)CH2CH3、−(CH2)4NH2、−CH2SH、−CH2CH2SCH3、−CH2OHまたは−CH(OH)CH3である。
R1が−H、−CH3、−CH(CH3)2、−CH2CH(CH3)2または−CH(CH3)CH2CH3であり;
R2が−H、−CH3または−CH(CH3)2であり;
R3が−H、−CH3、−CH(CH3)2、−CH2CH(CH3)2または−CH(CH3)CH2CH3であり;そして
R4が水素である;
ものである。
(i) 式(VI)の化合物を式(VII)の化合物と反応させ、
(ii) このようにして得られた中間体を脱保護し、それを式(VIII)の化合物と反応させ、
(iii) このようにして得られた中間体を脱保護し、それを式(IX)の化合物と反応させ、
(iv) このようにして得られた中間体を脱保護し、それを式(X)の化合物と反応させ、
(v) このようにして得られた中間体上のβ−ヒドロキシ基を所望によっては脱保護してR5保護基を除去してそれをHに置換し;
(vi) このようにして得られた中間体を加水分解および環化し;
(vii) このようにして得られた中間体を所望によっては反応させてジスルフィド結合形成を生じさせ、そして、ジスルフィド結合が形成される場合には、このようにして得られた化合物内の該ジスルフィド結合を所望によっては開裂させ、そして、このようにして得られた化合物がチオール基を有する場合には、所望によってはチオール保護基を導入し;そして
(viii) このようにして得られた化合物をスクリーニングしてそのHDAC阻害剤としての活性を測定すること;
によって、式(I)または(I’)の化合物を調製することを含む。
in vitro HDACアッセイを、HDAC蛍光活性アッセイキット(Biomol, UK)を用い、製造者の説明書に従って行った。化合物は分析に先立って還元した;1mMの化合物を、DMSO中の30mM DTTで、一晩、室温で、光から保護し、還元した。次いで、96ウェルプレートでの反応を準備した。各反応用に、10μlの化合物(アッセイバッファー中、5×所要濃度)を、15μlの希釈した(アッセイバッファー中に30倍)Hela核抽出物と混合した。各化合物に対して段階希釈を準備した。Hela抽出物のみおよびアッセイバッファーのみを含んだ反応も準備した。25μlの希釈Fluor de Lys(商標)基質(アッセイバッファー中に100倍)を各反応液に添加し、次いでこれを37℃で1時間インキュベートした。反応を50μlのFluor de Lys(商標)現像剤(アッセイバッファー中に20倍希釈、および100倍希釈のTSA)の添加により停止した。次いで反応液を室温で10分間インキュベートし、蛍光を、CytoFluor II 蛍光マルチウェルプレートリーダーおよびCytoFluor IIソフトウェアを、励起360nM、発光460nMに設定したフィルターとともに用いて測定した。in vitro HDAC活性の阻害を、二重の試料の平均値について、HeLa抽出物のみの反応液に対する百分率として決定した。IC50値をGraphPad Prismソフトウェアを用いて算出した。結果を表2に示す(構造は上記)。
細胞増殖アッセイを、CyQuant(商標)アッセイシステム(Molecular Probes, Inc. USA)を用い、製造者の説明書に従って行った。MCF7乳癌、A2780卵巣癌、PC3およびLNCAP前立腺癌細胞を96ウェルプレート中に、ウェルあたり100μlの細胞培養液中に、MCF7細胞については1000細胞、またはA2780/PC3/LNCAP細胞については5000細胞の密度でプレートした。化合物を、少なくとも5時間経過後に、細胞培養液中に段階希釈で、100μlの容量、2×最終濃度で添加した。細胞培養液を、4日後(A2780、PC3またはLNCAP細胞)または6日後(MCF7細胞)にプレートを吸取紙上に逆さまに置くことで除去し、細胞を穏やかに200μl PBSで一回洗浄した。ただちにプレートを少なくとも1時間−80℃で凍結し、次いで解凍した。色素を添加した200μlの1×CyQuant細胞溶解バッファーを製造者の説明書に従って調製し、ただちに各ウェルに加えて室温で3〜5分間インキュベートした。その後、蛍光を各ウェルについてCytoFluor II 蛍光マルチウェルプレートリーダーおよびCytoFluor IIソフトウェアを、励起480nM、発光極大520nMのフィルターとともに用いて測定した。細胞増殖を、二重の試料の平均値について、非処理細胞試料(=100%)に対する百分率として決定した。IC50値をGraphPad Prismソフトウェアを用いて算出した。その結果を表3に示す(構造は上記)。
TNF−α免疫測定を、Quantikine(登録商標)ヒトTNF−αアッセイキット(R&D systems,Abingdon UK)を用いて、製造者の説明書に従って行った。ヒト全血をFicol paque(商標)Plus(GE Healthcare, Amersham, UK)を用いて分離し、PBMCを24ウェルプレート中に、ウェルあたり500μlの細胞培養液中に2.5×106の密度でプレートした。1時間後に化合物を100μlの容量、6×最終濃度で添加した。5時間後、リポポリサッカライド(LSP,Sigma,Poole,UK)を10μlの容量、60×最終濃度で添加し、プレートを混合して、37℃、5%CO2で一晩放置した。プレートを遠心分離にかけ、細胞上清液を新たなプレートに移した。Quantikine(登録商標)アッセイ試薬および標準を、製造者の説明書に従って調製した。Quantikine(登録商標)アッセイプレートを、各ウェルに50μlのアッセイ希釈剤RD1Fを加えることにより調製した。その後200μlの標準、または100μlのキャリブレーター希釈剤(calibrator diluent)および100μl細胞上清を加え;これを2時間室温(RT)でインキュベートした。プレートを、洗浄バッファーを用いて4回洗浄した。最後の洗浄後、プレートを清浄なペーパータオル上で軽くたたいて全ての残存するバッファーを除いた。200μlのTNF−α複合体を各ウェルに加え、1時間RTでインキュベートした。その後プレートを前述同様に洗浄した。所要の量の基質溶液を、光から保護し、等容積の呈色試薬AおよびBを加えることにより調製した。200μlのこの混合物を各ウェルに加え、20分間RTで、光から保護し、インキュベートした。50μlの停止溶液を、基質溶液と同じ順番(order)で各ウェルに加え、プレートをBiorad 680 96ウェルプレートリーダー(Bio−Rad, Hemel Hempstead, UK)上で、450nmにおいて、570nmにおけるλ補正を用いて読み取った。TNF−α量は、二重の試料の平均値について、nmの吸光度を用いて求め、ゼロ点調整値(calibration zero value)を全ての結果から減算して、アッセイ中のキャリブレーター希釈剤の添加に対する補正を行った。結果を表4に示す。
Claims (33)
- 式(I)または(I’)のスピルコスタチン類似体またはその医薬的に許容される塩であるスピルコスタチン類似体
式中、R2およびR4は同一であっても異なっていてもよく、それぞれ−H、−炭素数1〜6のアルキル、−炭素数2〜6のアルケニル、−L−O−C(O)−R’、−L−C(O)−O−R’’、−L−A、−L−NR’’R’’、−L−Het−C(O)−Het−R’’および−L−Het−R’’から選択され;
R1は−H、−炭素数1〜6のアルキル、−炭素数2〜6のアルケニル、−L−O−C
(O)−R’、−L−C(O)−O−R’’、−L−A、−L−NR’’R’’、−L−Het−C(O)−Het−R’’、−L−Het−R’’および −(炭素数1〜4の
アルキル)−A’から選択され;
R3は−L−O−C(O)−R’、−L−C(O)−O−R’’、−L−A、−L−N
R’’R’’、−L−Het−C(O)−Het−R’’、−L−Het−R’’および−(炭素数1〜4のアルキル)−A’’から選択され;
Lは炭素数1〜6のアルキレン基であり、Aはフェニルまたは5〜6員ヘテロアリール基であり、A’は炭素数6〜10のアリール基または5〜10員ヘテロアリール基であり、A’’は炭素数6〜10のアリール基または5〜10員ヘテロアリール基であり、各R’は同一であっても異なっていてもよく、炭素数1〜4のアルキルを表し、各R’’は同一であっても異なっていてもよく、Hまたは炭素数1〜6のアルキルを表し、各−Het−は同一であっても異なっていてもよく、−O−、−N(R’’’)−および−S−から選択されるヘテロ原子スペーサーであり、各R’’’は同一であっても異なっていてもよく、Hまたは炭素数1〜4のアルキルを表し;
各R6は同一であっても異なっていてもよく、水素または炭素数1〜4のアルキルを表
し;および、
Pr1,Pr2およびPr3は同一であっても異なっていてもよく、それぞれ水素または
保護基を表す。 - 式(I’)の化合物においてR1、R2、R3、R4およびR6全てが同一であるものでは
ない、請求項1記載の類似体。 - 式(I)である、請求項1または2に記載の類似体。
- 請求項1〜3のいずれか1項に記載の類似体であって、R1が−(炭素数1〜4のアル
キル)−A’、またはR3が−(炭素数1〜4のアルキル)−A’’である類似体。 - A’がフェニルであり、かつ、A’’がフェニル、インドリルまたはt−ブトキシカルボニルインドリルである、請求項4記載の類似体。
- Aがフェニルである、請求項1〜5のいずれかに1項に記載の類似体。
- −Het−が−O−または−NR’’’である、請求項1〜6のいずれかに1項に記載の類似体。
- R1が−Hおよび−炭素数1〜6のアルキルより選択される、請求項1〜7のいずれか
1項に記載の類似体。 - R3が−L−C(O)−O−R’’、−L−A、−L−NR’’R’’および−L−N
(R’’’)−C(O)−O−R’’より選択される、請求項1〜8のいずれか1項に記載の類似体。 - R2が−Hおよび−炭素数1〜4のアルキルより選択される、請求項1〜9のいずれか
1項に記載の類似体。 - R4が−Hおよび−炭素数1〜4のアルキルより選択される、上記いずれかの請求項1
〜10のいずれか1項に記載の類似体。 - R6が−Hである、請求項1〜11のいずれか1項に記載の類似体。
- 請求項1〜12のいずれか1項に記載の類似体であって、ここでPr1およびPr2は同一であっても異なっていてもよく、−H;ならびに、炭素数1〜6のアルコキシ、炭素数1〜6のアシルオキシ、ヒドロキシまたはニトロ、ピコリル、ピコリル−N−オキシド、アントリルメチル、ジフェニルメチル、フェニル、t−ブチル、アダマンチル、炭素数1〜6のアシルオキシメチル、炭素数1〜6のアルコキシメチル、テトラヒドロピラニル、ベンジルチオメチル、フェニルチオメチル、チアゾリジン、アセトアミドメチル、ベンズアミドメチル、第3級ブトキシカルボニル(BOC)、アセチルおよびその誘導体、ベンゾイルおよびその誘導体、カルバモイル、フェニルカルバモイルおよび炭素数1〜6のアルキルカルバモイルによって所望によって置換されていてもよいベンジル基より選択される保護基;から選択される類似体。
- Pr1およびPr2がそれぞれ−Hである、請求項13記載の類似体。
- Pr3が−Hである、請求項1〜14のいずれか1項に記載の類似体。
- ヒストン脱アセチル化酵素(HDAC)により媒介される状態の治療または予防に使用される、請求項1〜16のいずれか1項に記載の類似体。
- 前記状態が癌、心肥大、慢性心不全、炎症状態、循環器疾患、異常血色素症、サラセミア、鎌状赤血球病、CNS障害、自己免疫疾患、糖尿病、骨粗しょう症、MDS、良性前立腺肥大、子宮内膜症、口腔白板症、遺伝に関連した代謝障害、感染、Rubens−Taybi、脆弱X症候群、またはα−1アンチトリプシン欠乏症である、請求項17記載の類似体。
- 前記状態が慢性リンパ球性白血病、乳癌、前立腺癌、卵巣癌、中皮腫、T細胞リンパ腫、心肥大、慢性心不全または皮膚炎症状態である、請求項17または請求項18記載の類似体。
- 創傷治癒を促進するため、毛包を保護するため、または免疫抑制剤として使用される、請求項1〜16のいずれかに記載類似体。
- 請求項1〜16のいずれかに記載のスピルコスタチン類似体と、医薬的に許容される担体または希釈剤と、を含む医薬組成物。
- 経口、経腸、非経口、鼻腔内もしくは経皮投与、または吸入もしくは坐剤による投与に適した形態である、請求項21記載の組成物。
- 顆粒剤または錠剤、カプセル剤、トローチ剤、ロゼンジ、水性もしくは油性懸濁剤、または分散可能な粉末剤の形態である、請求項22記載の組成物。
- HDACに媒介される状態の治療または予防用の医薬組成物であって、請求項1〜16のいずれかに記載の類似体の使用を含む医薬組成物。
- 前記状態が請求項17〜19のいずれかに規定されたものである、請求項24記載の組成物。
- (a)請求項1〜16のいずれかに記載のスピルコスタチン類似体と、(b)他のHDAC阻害剤と、を含む、HDACにより媒介される状態の治療または予防において、同時に、別々に、または順次使用される製品。
- (a)請求項1〜16のいずれかに記載のスピルコスタチン類似体と、(b)他の化学療法薬または抗腫瘍薬と、を含む、癌の治療または予防において、同時に、別々に、または順次使用される製品。
- スベロイルアニリドヒドロキサム酸(SAHA)が示すものと少なくとも同等のHDAC阻害活性を有する化合物を選択する方法であって、請求項1〜16のいずれかに規定される式(I)または(I’)の化合物を、
(i) 式(VI)の化合物を式(VII)の化合物と反応させ
式中、R1およびR2は前記式(I)または(I’)の化合物におけるR1およびR2とそれぞれ同じであり、R7は炭素数1〜4のアルキルまたは炭素数2〜4のアルケニルであ
り、Yはアミノ保護基であり;
(ii) このようにして得られた中間体を脱保護し、それを式(VIII)の化合物と反応させ
式中、Y’はアミノ保護基であり、Y’’は水素または保護基であり;
(iii) このようにして得られた中間体を脱保護し、それを式(IX)の化合物と反応させ
式中、R3は前記式(I)または(I’)の化合物におけるR3と同じであり、Y’’’はアミノ保護基であり;
(iv) このようにして得られた中間体を脱保護し、それを式(X)の化合物と反応させ
式中、R4は前記式(I)または(I’)の化合物におけるR4と同じであり、R5は水素またはヒドロキシ保護基であり、LGは脱離基であり、Y’’’’は水素または保護基であり;
(v) このようにして得られた中間体上のβ−ヒドロキシ基を所望によっては脱保護してR5保護基を除去してそれをHに置換し;
(vi) このようにして得られた中間体を加水分解および環化し;
(vii) このようにして得られた中間体を所望によっては反応させてジスルフィド結合形成を生じさせ、および、ジスルフィド結合が形成される場合には、このようにして得られた化合物内のジスルフィド結合を所望によっては開裂させ、および、このようにして得られた化合物がチオール基を有する場合には、所望によってはチオール保護基を導入し;及び、
(viii) このようにして得られた化合物をスクリーニングしてそのHDAC阻害剤としての活性を測定すること;
によって、調製することを含む方法。 - 請求項28記載の方法であって、工程(viii)において前記スクリーニング工程はin vitro HDACアッセイであり、前記アッセイは被験化合物およびSAHAを、各種濃度で、希釈したHela核抽出物と接触させ、Hela核抽出物に対する被験化合物のIC50とSAHAのIC50とを決定することを含む、方法。
- SAHAが示すものと少なくとも同等のヒト癌細胞増殖阻害活性を有する化合物を選択するための方法であって、請求項1〜16のいずれかに規定される式(I)または(I’)の化合物を、
(i) 式(VI)の化合物を式(VII)の化合物と反応させ
式中、R1およびR2は前記式(I)または(I’)の化合物におけるR1およびR2とそれぞれ同じであり、R7は炭素数1〜4のアルキルまたは炭素数2〜4のアルケニルであ
り、Yはアミノ保護基であり;
(ii) このようにして得られた中間体を脱保護し、それを式(VIII)の化合物と反応させ
式中、Y’はアミノ保護基であり、Y’’は水素または保護基であり;
(iii) このようにして得られた中間体を脱保護し、それを式(IX)の化合物と反応させ
式中、R3は前記式(I)または(I’)の化合物におけるR3と同じであり、Y’’’はアミノ保護基であり;
(iv) このようにして得られた中間体を脱保護し、それを式(X)の化合物と反応させ
式中、R4は前記式(I)または(I’)の化合物におけるR4と同じであり、R5は水
素またはヒドロキシ保護基であり、LGは脱離基であり、Y’’’’は水素または保護基であり;
(v) このようにして得られた中間体上のβ−ヒドロキシ基を所望によっては脱保護してR5保護基を除去してそれをHに置換し;
(vi) このようにして得られた中間体を加水分解および環化し;
(vii) このようにして得られた中間体を所望によっては反応させてジスルフィド結合形成を生じさせ、及び、ジスルフィド結合が形成される場合には、このようにして得られた化合物内のジスルフィド結合を所望によっては開裂させ、および、このようにして得られた化合物がチオール基を有する場合には、所望によってはチオール保護基を導入し;および、
(viii) このようにして得られた化合物をスクリーニングしてそのヒト癌細胞増殖阻害剤としての活性を測定すること;
によって、調製することを含む方法。 - 請求項30記載の方法であって、工程(viii)において前記スクリーニング工程はin vitroアッセイであり、前記アッセイは被験化合物およびSAHAを、各種濃度で、MCF7乳癌、HUT78 T細胞白血病、A2780卵巣癌、PC3またはLNCAP前立腺癌細胞株と接触させ、前記細胞株に対する被験化合物のIC50とSAHAのIC50とを測定することを含む、方法。
- SAHAが示すものと少なくとも同等の抗炎症活性を有する化合物を選択するための方法であって、請求項1〜16のいずれかに規定される式(I)または(I’)の化合物を、
(i) 式(VI)の化合物を式(VII)の化合物と反応させ
式中、R1およびR2は前記式(I)または(I’)の化合物におけるR1およびR2とそれぞれ同じであり、R7は炭素数1〜4のアルキルまたは炭素数2〜4のアルケニルであ
り、Yはアミノ保護基であり;
(ii) このようにして得られた中間体を脱保護し、それを式(VIII)の化合物と反応させ
式中、Y’はアミノ保護基であり、Y’’は水素または保護基であり;
(iii) このようにして得られた中間体を脱保護し、それを式(IX)の化合物と反応させ
式中、R3は前記式(I)または(I’)の化合物におけるR3と同じであり、Y’’’はアミノ保護基であり;
(iv) このようにして得られた中間体を脱保護し、それを式(X)の化合物と反応させ
式中、R4は前記式(I)または(I’)の化合物におけるR4と同じであり、R5は水
素またはヒドロキシ保護基であり、LGは脱離基であり、Y’’’’は水素または保護基であり;
(v) このようにして得られた中間体上のβ−ヒドロキシ基を所望によっては脱保護してR5保護基を除去してそれをHに置換し;
(vi) このようにして得られた中間体を加水分解および環化し;
(vii) このようにして得られた中間体を所望によっては反応させてジスルフィド結合形成を達成し、および、ジスルフィド結合が形成される場合には、このようにして得られた化合物内のジスルフィド結合を所望によっては開裂させ、また、このようにして得られた化合物がチオール基を有する場合には、所望によってはチオール保護基を導入し;そして、
(viii) このようにして得られた化合物をスクリーニングしてその抗炎症活性を測定すること;
によって調製することを含む方法。 - 請求項32記載の方法であって、工程(viii)において前記スクリーニング工程はアッセイであり、前記アッセイは、末梢血単核球(PBMC)からのTNFαの産生の阻害における化合物の活性を、SAHAとの比較において測定することを含む、方法。
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GBGB0623388.6A GB0623388D0 (en) | 2006-11-23 | 2006-11-23 | Chemical compounds |
PCT/GB2007/050709 WO2008062232A1 (en) | 2006-11-23 | 2007-11-23 | Depsipeptides and their therapeutic use |
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EP (1) | EP2089416B1 (ja) |
JP (1) | JP5345065B2 (ja) |
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CA (1) | CA2670372A1 (ja) |
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WO (1) | WO2008062232A1 (ja) |
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CA2674309A1 (en) | 2006-12-29 | 2008-07-10 | Gloucester Pharmaceuticals, Inc. | Preparation of romidepsin |
GB0715750D0 (en) * | 2007-08-13 | 2007-09-19 | Karus Therapeutics Ltd | Chemical compounds |
CA2725278A1 (en) * | 2008-05-22 | 2009-11-26 | Karus Therapeutics Limited | Depsipeptides and their therapeutic use |
EP2293845A1 (en) * | 2008-05-22 | 2011-03-16 | Karus Therapeutics Limited | Depsipeptides and their therapeutic use |
GB0905970D0 (en) | 2009-04-06 | 2009-05-20 | Karus Therapeutics Ltd | Depsipeptides and their therapeutic use |
US20110060021A1 (en) * | 2009-08-19 | 2011-03-10 | Yiqiang Cheng | Histone deacetylase inhibitors and uses thereof |
KR20130123301A (ko) | 2010-05-27 | 2013-11-12 | 더 리젠츠 오브 더 유니버시티 오브 콜로라도, 어 바디 코포레이트 | 히스톤 디아세틸라아제의 저해제들로서 유용한 거대고리 화합물들 |
WO2015131355A1 (zh) * | 2014-03-05 | 2015-09-11 | 清安医药科技武汉有限公司 | 天然产物组蛋白去乙酰基酶抑制剂泰兰德普素b的制备 |
CN106317175B (zh) * | 2015-06-23 | 2020-01-31 | 杨思遥 | 组蛋白去乙酰化酶抑制剂及其制备方法和应用 |
JP2019052091A (ja) * | 2016-01-13 | 2019-04-04 | 国立大学法人東北大学 | デプシペプチド類化合物の製造中間体及びその製造方法 |
US11643438B2 (en) | 2018-07-20 | 2023-05-09 | The Board Of Regents Of The University Of Oklahoma | Antimicrobial peptides and methods of use |
JP7359363B2 (ja) * | 2019-03-06 | 2023-10-11 | 敏行 酒井 | 分子標的併用腫瘍治療・予防薬 |
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KR100611265B1 (ko) * | 1999-01-13 | 2006-08-10 | 아스텔라스세이야쿠 가부시키가이샤 | 신규 뎁시펩티드 화합물 |
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JP2010510302A (ja) | 2010-04-02 |
US8247372B2 (en) | 2012-08-21 |
US20100056434A1 (en) | 2010-03-04 |
AU2007323246B2 (en) | 2012-04-19 |
CN101589056A (zh) | 2009-11-25 |
AU2007323246A1 (en) | 2008-05-29 |
EP2089416A1 (en) | 2009-08-19 |
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