TWI500618B - 包含新茅屋黴素衍生物之細胞毒性劑及該等衍生物之治療用途 - Google Patents
包含新茅屋黴素衍生物之細胞毒性劑及該等衍生物之治療用途 Download PDFInfo
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- TWI500618B TWI500618B TW097127553A TW97127553A TWI500618B TW I500618 B TWI500618 B TW I500618B TW 097127553 A TW097127553 A TW 097127553A TW 97127553 A TW97127553 A TW 97127553A TW I500618 B TWI500618 B TW I500618B
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- 125000002636 imidazolinyl group Chemical group 0.000 description 1
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- 239000002596 immunotoxin Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
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- 239000002502 liposome Substances 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 238000011363 radioimmunotherapy Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
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- 229910052711 selenium Inorganic materials 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
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- VUFNRPJNRFOTGK-UHFFFAOYSA-M sodium;1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 VUFNRPJNRFOTGK-UHFFFAOYSA-M 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- QUAVPFUWJQJVBL-UHFFFAOYSA-N tert-butyl 4-[2,6-bis(hydroxymethyl)pyridin-4-yl]oxybutanoate Chemical compound CC(C)(C)OC(=O)CCCOC1=CC(CO)=NC(CO)=C1 QUAVPFUWJQJVBL-UHFFFAOYSA-N 0.000 description 1
- HJEZRYIJNHAIGY-UHFFFAOYSA-N tert-butyl 4-bromobutanoate Chemical compound CC(C)(C)OC(=O)CCCBr HJEZRYIJNHAIGY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- XDLNRRRJZOJTRW-UHFFFAOYSA-N thiohypochlorous acid Chemical compound ClS XDLNRRRJZOJTRW-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- REJLGAUYTKNVJM-SGXCCWNXSA-N tomatine Chemical class O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H]1[C@@H](CO)O[C@H]([C@@H]([C@H]1O)O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4C[C@H]5[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@@H]([C@@]1(NC[C@@H](C)CC1)O5)C)[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O REJLGAUYTKNVJM-SGXCCWNXSA-N 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Description
本發明係關於新穎茅屋黴素衍生物及該等衍生物作為細胞毒性劑之治療用途。該治療用途係藉由使茅屋黴素衍生物與細胞結合劑化學鍵聯而將茅屋黴素衍生物以靶向方式傳遞至特定細胞群體的結果。本發明亦係關於包含一或多個與視情況經修飾之細胞結合劑化學鍵聯之該等茅屋黴素衍生物的結合物分子。
已出現許多關於嘗試以單株抗體-藥物結合物特異性靶向腫瘤細胞的報導(Sela等人,Immuno-conjugates
中,189-216(C. Vogel編輯,1987);Ghose等人,Targeted Drugs
中,1-22(E. Goldberg編輯,1983);Diener等人,Antibody mediated delivery systems
中,1-23(J. Rodwell編輯,1988);Pietersz等人,Antibody mediated delivery systems
中,25-53(J. Rodwell編輯,1988);Bumol等人,Antibody mediated delivery systems
中,55-79(J. Rodwell編輯,1988);G.A. Pietersz及K. Krauer,2,J. Drug Targeting
,183-215(1994);R.V.J. Chari,31Adv. Drug Delivery Revs.
,89-104(1998);W.A. Blattler及R.V.J.Chari,Anticancer Agents,Frontiers in Cancer Chemotherapy
中,317-338,ACS Symposium Series 796;Ojima等人編輯,American Chemical Society
2001;J.M.Lambert,5Current Opinion in Pharmacology
,543-549(2005);P.R. Hamann,15Expert Opinion on Therapeutics Patents
,1087-1103(2005))。本文中所引用之所有參考文獻及專利均以引用的方式併入。
已將諸如甲胺喋呤(methotrexate)、道諾黴素(daunorubicin)、阿黴素(doxorubicin)、長春新鹼(Vincristine)、長春鹼(Vinblastine)、美法侖(melphalan)、絲裂黴素C(mitomycin C)及苯丁酸氮芥(chlorambucil)之細胞毒性藥物與多種鼠科單株抗體結合。在一些情況下,藥物分子與抗體分子經由中間載體分子(諸如血清白蛋白)鍵聯(Garnett等人,46,Cancer Res.
2407-2412(1986);Ohkawa等人,23,Cancer Immunol. Immunother.
81-86(1986);Endo等人,47Cancer Res.
1076-1080(1980))、葡聚糖(Hurwitz等人,2Appl. Biochem.
25-35(1980);Manabi等人,34Biochem. Pharmacol.
289-291(1985);Dillman等人,46Cancer Res.
,4886-4891(1986);Shoval等人,85,Proc. Nat1. Acad. Sci.
,8276-8280(1988))或聚麩胺酸(Tsukada等人,73,J. Natl. Canc. Inst.
,721-729(1984);Kato等人,27J. Med. Chem.
,1602-1607(1984);Tsukada等人,52,Br. J. Cancer
,111-116(1985))。
已採用多種連接子技術來製備該等免疫結合物,且已研究出可裂解及不可裂解之連接子。然而,在大多數情況下,藥物之高細胞毒性潛能僅可在若藥物分子在靶向位點處可使用可裂解連接子以未經修飾之形式自結合物釋放的情況下觀察到。
然而,活體外細胞毒性測試揭示抗體-藥物結合物不僅可殺死抗原-陽性細胞,且可殺死附近之其他細胞,而與細胞表面上之抗原表現無關。該現象稱為旁觀者效應。該效應在抗CanAg抗體,huC242,與美登素(maytansinoid)及與CC1065類似物之結合物中觀察到(Erickson等人,66Cancer Res.
,4426-4433(2006);Kovtun等人,66Cancer Res.
,3214-3221(2006))。迄今為止,僅經由可裂解鍵(諸如可還原之雙硫鍵)鍵聯之結合物展示旁觀者細胞毒性,而經由不可還原之硫醚鍵所鍵聯之結合物不展示旁觀者效應。
與諸如抗體之靶向劑鍵聯之高效細胞毒性效應分子可在結合物之細胞內加工之後產生有效之藥物衍生物。此在所產生之細胞代謝物展示不當或不易控制之副作用的情況下可能出現問題。為控制抗體-藥物結合物之毒性,使用不可裂解之連接子可能極為有利。
大多數抗體-藥物結合物之另一主要缺點為由於抗癌藥物(如甲胺喋呤、道諾菌素及長春新鹼)之有限數目的靶向抗原及相對中等之細胞毒性而使其不能將足夠濃度之藥物傳遞至靶向位點。為達成顯著細胞毒性,需要使大量藥物分子直接或經由聚合載體分子與抗體鍵聯。然而,該等經大量修飾之抗體通常展示與靶向抗原削弱之結合及自血流經活體內快速清除。因此,替代性方法為使用更為有效之藥物分子,諸如下文中所揭示者。
不可裂解連接子亦已用於結合中。其尤其對於放射性免疫療法應用而言有利。其亦已用於將毒素連接至單株抗體,如對於綠膿桿菌外毒素(Pseudomonas
exotoxin)與MAb 9.2.27而言,使用雜雙官能基4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸順丁烯二醯亞胺丁二醯亞胺酯(SMCC)(EP 306943
)。與相應雙硫鍵結合物相比,MAb毒素結合物對於陽性細胞株具有更大活體外特異性,且因此在小鼠模型中具有較小毒性。當使用不可裂解連接子時,非特異性毒性顯著減少。該不可裂解連接子已用於靶向HER2(ErbB)之曲妥珠單抗(trastuzumab,赫賽汀(Herceptin))的情況。HERR2為關鍵標靶且正在研究使用MAb使得抑制該受體之效應最大化的方法。一種方法旨在藉由使曲妥珠單抗(赫賽汀)與化療劑偶合來加強其功效,由此使得可在細胞水平上傳遞細胞毒性療法(Ranson及Sliwkowski,63(增刊1)Oncology
,17-24(2002))。
存在其他形式之SMCC試劑,例如水溶性4-(N-順丁烯二醯亞胺基甲基)環己烷-1-甲酸磺基丁二醯亞胺酯(磺基-SMCC),其亦已用於結合反應中。其他不可裂解之連接子尤其包括N-丁二醯亞胺基-S-乙醯基硫乙酸酯(SATA)、SATA-SMCC、2-亞胺基噻唑(2IT)及2IT-SMCC(Foulon等人,10,Bioconjugate Chem.
,867-876(1999))。亦已使用包含基於鹵基乙醯基之部分的交聯劑且包括N
-丁二醯亞胺基-4-(碘乙醯基)-胺基苯甲酸酯(SIAB)、碘乙酸N
-丁二醯亞胺酯(SIA)、溴乙酸N
-丁二醯亞胺酯(SBA)及3-(溴-乙醯胺基)丙酸N
-丁二醯亞胺酯(SBAP)。該等交聯試劑形成衍生自基於鹵基乙醯基部分之不可裂解連接子。
儘管由於藥物分子而存在以上所報導之困難,但已報導適用之包含細胞結合部分及稱為美登素之細胞毒性藥物群的細胞毒性劑(USP 5,208,020、USP 5,416,064
及R. V. J. Chari,31Advanced Drug Delivery Reviews
89-104(1998))。類似地,亦已報導適用之包含細胞結合部分及類似物以及有效抗腫瘤抗生素CC-1065之衍生物的細胞毒性劑(USP 5,475,092、USP 5,585,499及USP 6,756,397
)。
茅屋黴素衍生物為吡咯幷[1,4]苯并二氮呯(PBD),其係一種已知類別之藉由與DNA小溝中鳥嘌呤之N2共價結合而發揮其生物學特性的化合物。PBD包括大量小溝結合劑,諸如安麯黴素(anthramycin)、新麯黴素(neothramycin)及DC-81。然而,茅屋黴素抗腫瘤活性因其對正常細胞之非特異性毒性而有限。因此需要增加茅屋黴素化合物之治療活性,且減少其非特異性毒性效應。本發明之發明者已展示此需要可藉由使茅屋黴素化合物與細胞結合劑鍵聯來靶向傳遞該等茅屋黴素化合物而得以滿足。此外,需要開發在水溶液中可溶解且穩定之茅屋黴素衍生物。此外,茅屋黴素不足以有效地用於細胞結合劑之結合物中。
新近已揭示少數新的PBD衍生物及其在臨床前模型中之抗腫瘤活性(WO 00/12508
及WO 2005/085260
)。然而,基於可向人類投與之極低劑量,人類中之初期臨床試驗表明此類化合物具有嚴重毒性(I. Puzanov,Proc. AACR-NCI-EORTC International Conference,Philadelphia,USA 2005,摘要#B117)。因此,需要提供展示較少副作用而不損害細胞毒性活性的替代性衍生物。
國際申請案WO 2007/085930
及WO 2008/010101描述可經由連接子與細胞結合劑鍵聯之茅屋黴素衍生物,但該連接子並非關於本發明化合物所定義之連接子。
文章"Tetrahedron Letters,第29卷,第40期,第5105-5108頁"描述不具有任何連接子之茅屋黴素衍生物(參考(13)-(15))。
國際申請案WO 2005/085250
描述以下通式之PBD二聚體:PBD-A-Y-X-(Het)na
-L-(Het)nb
-L-(Het)nc
-T-(Het')nd
-L-(Het')ne
-L-(Het')nf
-X'-Y'-A'-PBD',其中Het及Het'為式-J-G-J'或J'-G-J-之胺基-伸雜芳基-基團,其中G為視情況經取代之伸雜芳基,na
-nf
為0與5之間的整數,L可為β-丙胺酸、甘胺酸、4-胺基丁酸或單鍵。X及X'均為-NH-或-C(=O)-,且Y及Y'為二價基團以使得HY為烷基、雜環基或芳基或單鍵。A及A'係選自O、S、NH或單鍵。T為具有-NH-Q-NH-或-C(=O)-Q-C(=O)-形式之二價連接子,其中Q為二價基團以使得QH為烷基、雜環基或芳基(視情況經取代)。根據該通式之化合物均包含-NH-或-C(=O)-作為X及X',及-NH-Q-NH-或-C(=O)-Q-C(=O)-,而本發明之化合物並非該情況。
國際申請案WO 2005/023814
描述氮原子N10上由R10
-COO-保護之PBD二聚體,其包含橋鍵-X-R"-X-,其中R"為視情況經一或多個雜原子NH、O或S中斷之伸烷基及/或芳族環,且X為O、S或NH。未提及橋鍵-X-R"-X-上之連接子。此外,本發明之化合物在N10上未經保護。
文章"European Journal of Medicinal Chemistry,第40卷,第7期,第641-654頁"描述不包含如關於本發明化合物之任何連接子的PBD二聚體(參考(38)-(40))。
文章"Expert opinion;Monoclonal antibody-drug conjugates",Ashley Publications,第15卷,第9期,2005,第1087-1103頁,ISSN:1354-3774未描述本發明之化合物且文章"Cancer Res. 2006,66(8),第4426-4433頁"描述與細胞結合劑鍵聯之美登素。
本發明係關於如請求項1至30之包含連接子的新茅屋黴素衍生物。本發明亦係關於包含一或多個與細胞結合劑經由茅屋黴素衍生物之連接子上所存在之鍵聯基團共價鍵聯之該等茅屋黴素衍生物的結合物分子。本發明亦係關於茅屋黴素衍生物及結合物分子之製備。
‧Alk表示烷基、烯烴或炔烴;
‧"烷基"意謂可為鏈中具有1至20個碳原子之直鏈或支鏈脂族烴基或具有3至10個碳原子之環狀脂族烴基。較佳烷基之鏈中具有1至12個碳原子。"支鏈"意謂一或多個低碳烷基(諸如甲基、乙基或丙基)與直鏈烷基鏈連接。例示性烷基包括甲基、乙基、正丙基、異丙基、正丁基、第三丁基、正戊基、3-戊基、辛基、壬基、癸基、環戊基及環己基;
‧"烯烴"意謂含有碳碳雙鍵且可為鏈中具有2至15個碳原子之直鏈或支鏈的脂族烴基。較佳烯基之鏈中具有2至12個碳原子;且更佳地,鏈中具有約2至4個碳原子。例示性烯基包括乙烯基、丙烯基、正丁烯基、異丁烯基、3-甲基丁-2-烯基、正戊烯基、庚烯基、辛烯基、壬烯基、癸烯基;
‧"炔烴"意謂含有碳碳參鍵且可為鏈中具有2至15個碳原子之直鏈或支鏈的脂族烴基。較佳炔基之鏈中具有2至12個碳原子;且更佳地,鏈中具有2至4個碳原子。例示性炔基包括乙炔基、丙炔基、正丁炔基、2-丁炔基、3-甲基丁炔基、正戊炔基、庚炔基、辛炔基及癸炔基;
‧"鹵素原子"係指氟、氯、溴或碘原子;較佳為氟及氯原子;
‧"芳基"意謂具有6至14個碳原子,較佳具有6至10個碳原子之芳族單環或多環烴環系統。例示性芳基包括苯基或萘基;
‧"Het"意謂雜環或雜芳基;
‧術語"雜環"係指飽和、部分不飽和或不飽和,非芳族穩定之3至14員、較佳5至10員單環、雙環或多環環,其中環之至少一個成員為雜原子。一般而言,雜原子包括(但不限於)氧、氮、硫、硒及磷原子。較佳雜原子為氧、氮及硫。合適雜環亦揭示於The Handbook of Chemistry and Physics
,第76版,CRC Press, Inc.,1995-1996,第2-25至2-26頁中,其揭示內容係以引用的方式併入本文中。
較佳非芳族雜環包括(但不限於)吡咯啶基、吡唑啶基、咪唑啶基、氧基、四氫呋喃基、二氧戊環基、四氫哌喃基、二噁烷基、二氧戊環基、哌啶基、哌嗪基、嗎啉基、哌喃基、咪唑啉基、吡咯啉基、吡唑啉基、噻唑啶基、四氫噻喃基、二噻烷基、硫代嗎啉基、二氫哌喃基、四氫哌喃基、二氫哌喃基、四氫吡啶基、二氫吡啶基/四氫嘧啶基、二氫噻喃基、氮雑環庚烷基以及由與苯基縮合而產生之稠合系統;
‧術語"雜芳基"或芳族雜環係指5至14員,較佳5至10員芳族雜環、單環、雙環或多環環。實例包括吡咯基、吡啶基、吡唑基、噻吩基、嘧啶基、吡嗪基、四唑基、吲哚基、喹啉基、嘌呤基、咪唑基、噻吩基、噻唑基、苯并噻唑基、呋喃基、苯并呋喃基、1,2,4-噻二唑基、異噻唑基、三唑基、四唑基、異喹啉基、苯并噻吩基、異苯并呋喃基、吡唑基、咔唑基、苯并咪唑基、異噁唑基、吡啶基-N-氧化物以及由與苯基縮合而產生之稠合系統;
‧"烷基"、"環烷基"、"烯基"、"炔基"、"芳基"、"雜芳基"、"雜環"及其類似基團亦係指藉由移除兩個氫原子而形成之相應"伸烷基"、"伸環烷基"、"伸烯基"、"伸炔基"、"伸芳基"、"伸雜芳基"、"伸雜環基"及其類似基團;
‧"不可裂解連接子"意謂適合於使該茅屋黴素衍生物與細胞結合劑共價鍵聯之任何基團,其中該基團不含雙硫基、酸不穩定基團、光不穩定基團、肽酶不穩定基團及酯酶不穩定基團。較佳地,該"不可裂解連接子"包含末端羧基或醯胺基或其前驅體。該連接子在結合物分子於細胞內內化及細胞結合劑之潛在蛋白水解之後的細胞內加工期間不裂解;
‧表述"可與細胞結合劑鍵聯"係指包含至少一個連接子之茅屋黴素衍生物,該連接子又包含適合於將該等衍生物鍵結至細胞結合劑之鍵聯基團或其前驅體;較佳鍵聯基團為羧基、醯胺鍵或其前驅體;
‧表述"與細胞結合劑鍵聯"係指包含至少一種與細胞結合劑經由合適鍵聯基團或其前驅體結合之茅屋黴素衍生物的結合物分子;較佳鍵聯基團為不可裂解鍵或其前驅體;
‧給定基團之"前驅體"係指可藉由任何去保護、化學修飾或偶合反應產生彼基團之任何基團;
‧"患者"係指動物,諸如有價值之用於繁殖、同伴或保護目的之動物,或較佳為人類或人類兒童,其受本文所述之一或多種疾病及病狀折磨或具有受本文所述之一或多種疾病及病狀折磨之可能性。
‧"治療有效量"係指本發明之化合物有效預防、減少、消除、治療或控制本文所述疾病及病狀之症狀的量。術語"控制"意欲係指可能存在本文所述疾病及病狀之進程減緩、中斷、停滯或停止的所有方法,但不必指示所有疾病及病狀症狀完全消除,且意欲包括預防性治療;
‧"醫藥學上可接受"係指在合理醫學判斷範疇內適合於與人類及動物組織接觸而無過度毒性、刺激、過敏性反應或其他問題併發症,相應具有合理之益處/風險比率的彼等化合物、材料、賦形劑、組合物或劑型。
‧"醫藥學上可接受之鹽"係指所揭示化合物之衍生物,其中母體化合物係藉由製備其酸式或鹼式鹽而改質。醫藥學上可接受之鹽包括(例如)由無毒性無機或有機酸形成之母體化合物之習知無毒性鹽或四級銨鹽。舉例而言,該等習知無毒性鹽包括衍生自無機酸之鹽,該等無機酸諸如鹽酸、氫溴酸、硫酸、胺磺酸、磷酸、硝酸及其類似物;及由有機酸製備之鹽,該等有機酸諸如乙酸、丙酸、丁二酸、酒石酸、檸檬酸、甲烷磺酸、苯磺酸、葡糖醛酸、麩胺酸、苯甲酸、水楊酸、甲苯磺酸、草酸、反丁烯二酸、順丁烯二酸、乳酸及其類似物。其他加成鹽包括銨鹽,諸如緩血酸胺、葡甲胺、依泊胺(epolamine)等;金屬鹽,諸如鈉、鉀、鈣、鋅或鎂。本發明之醫藥學上可接受之鹽可藉由習知化學方法由含有鹼性或酸性部分之母體化合物來合成。一般而言,該等鹽可藉由使該等化合物之游離酸或鹼形式與化學計量之量的適當鹼或酸在水中或在有機溶劑中或在兩者之混合物中反應來製備。一般而言,如乙醚、乙酸乙酯、乙醇、異丙醇或乙腈之非水性介質為較佳的。合適鹽之列表見於Remington
之Pharmaceutical Sciences
,第17版,Mack Publishing Company,Easton,PA,1985,第1418頁,該參考文獻之揭示內容係以引用的方式併入本文中。
‧"治療"意謂逆轉、減輕、抑制該術語所應用之病症或病狀或該病症或病狀之一或多種症狀的進程,或預防該病症或病狀或該病症或病狀之一或多種症狀。
‧"治療有效量"意謂本發明之化合物/藥劑有效預防或治療本文所提及之病理學病狀之量;
‧"醫藥學"或"醫藥學上可接受"係指視需要當向動物、人類投與時不產生不利、過敏性或其他不良反應之分子實體及組合物;
‧"醫藥學上可接受之賦形劑"包括任何載劑、稀釋劑、佐劑或媒劑,諸如防腐劑或抗氧化劑、填充劑、崩解劑、濕潤劑、乳化劑、懸浮劑、溶劑、分散介質、塗料、抗菌劑及抗真菌劑、等張劑及吸收延遲劑及其類似物。該等介質及藥劑用於醫藥活性物質之用途在此項技術中係熟知的。除非任何習知介質或藥劑與活性成份均不相容,否則涵蓋其在治療組合物中之用途。補充活性成份亦可作為合適治療組合併入該等組合物中。
本發明係基於保持高細胞毒性且可與細胞結合劑以不可裂解連接子有效鍵聯之新穎茅屋黴素衍生物的合成,該等結合物展示殺死腫瘤細胞之高效能。先前已展示使用可裂解連接子(諸如雙硫鍵)使高細胞毒性藥物與抗體鍵聯確保在細胞內釋放全活性藥物,且該等結合物以抗原特異性方式具有細胞毒性(US 6,340,701;US 6,372,738;US 6,436,931
)。然而,此項技術揭示極難修飾現有藥物而不減少其細胞毒性潛能。所揭示之本發明藉由以化學部分修飾所揭示之茅屋黴素衍生物來克服此問題。因此,所揭示之新穎茅屋黴素衍生物保持,且在一些情況下甚至可增強茅屋黴素衍生物之細胞毒性效能。細胞結合劑-茅屋黴素衍生物複合物使得欲經施加之茅屋黴素衍生物可以靶向方式僅針對不當細胞完全發揮其細胞毒性作用,因此避免由於損傷非靶向健康細胞所致之副作用。因此,本發明提供適用於消除欲經殺死或溶解之病態或異常細胞(諸如腫瘤細胞,尤其實體腫瘤細胞)的藥劑。
本發明之細胞毒性劑包含一或多個視情況經由非可裂解鍵聯基團可與細胞結合劑鍵聯或與細胞結合劑鍵聯之茅屋黴素衍生物。鍵聯基團為與茅屋黴素衍生物經由習知方法共價結合之化學部分的部分。
根據一態樣,本發明係關於式(I)之茅屋黴素衍生物:
其中:----表示可選單鍵;表示單鍵或雙鍵;其限制條件為,當表示單鍵時,相同或不同之U及U'獨立地表示H,且相同或不同之W及W'係獨立地選自由以下各基組成之群:OH;醚,諸如-OR;酯(例如乙酸酯),諸如-OCOR或-COOR;碳酸酯,諸如-OCOOR;胺基甲酸酯,諸如-OCONRR';環狀胺基甲酸酯,使得N10及C11為環之一部分;脲,諸如-NRCONRR';硫代胺基甲酸酯,諸如-OCSNHR;環狀硫代胺基甲酸酯,使N10及C11為環之一部分;-SH;硫化物,諸如-SR;亞碸,諸如-SOR;碸,諸如-SOOR;磺酸根,諸如-SO3 -
;磺醯胺,諸如-NRSOOR';胺,諸如-NRR',視情況之環胺,使得N10及C11為環之一部分;羥基胺衍生物,諸如-NROR';醯胺,諸如-NRCOR';疊氮基,諸如-N3
;氰基,-CN;鹵化物(Hal);三烷基或三芳基鏻;較佳地,W及W'係相同或不同且為-OH、-OMe、-OEt、-NHCONH2
、-SMe;且當表示雙鍵時,U及U'不存在且W及W'表示H。
■R1、R2、R1'、R2'為相同或不同的且獨立地選自H;鹵化物或經一或多個以下基團取代之烷基:Hal、CN、NRR'、CF3
、OR、芳基、Het、S(O)q
R,或R1與R2及R1'與R2'一起形成各自含有基團=B及=B'之雙鍵。
較佳地,R1與R2及R1'與R2'一起形成各自含有基團=B及=B'之雙鍵。
■B及B'為相同或不同的且獨立地選自視情況經一或多個以下基團取代之烯基:Hal、CN、NRR'、CF3
、OR、SR、SOR、SO2
R、芳基、Het,或B及B'表示氧原子。
較佳地,B=B'。
更佳地,B=B'==CH2
或=CH-CH3
。
■X、X'為相同或不同的且獨立地選自一或多個以下基團:-O-、-S-、-NR-、-(C=O)-、-SO-、-SO2
-;較佳地,X=X'。
更佳地,X=X'=O。
■A、A'為相同或不同的且獨立地選自各自視情況經一或多個以下基團取代之烷基或烯基:Hal、CN、NRR'、CF3
、OR、SR、SOR、SO2
R、芳基、Het、烷基、烯基。
較佳地,A=A'。
更佳地,A=A'=直鏈未經取代之烷基。
■Y、Y'為相同或不同的且獨立地選自H、OR;較佳地,Y=Y'。
更佳地,Y=Y'=O烷基,更佳為O甲基。
■T為-NR-或各自經一或多個不可裂解連接子取代且視情況經一或多個Hal、CN、NRR'、CF3
、R、OR、SOR或SO2
R取代之4至10員芳基、環烷基、雜環、雜芳基或直鏈或支鏈烷基。
■n、n'相等或不同,為0或1;
■q為0、1或2;根據一變化態樣,茅屋黴素衍生物具有式(I'):
其中R1、R1'、R2、R2'、W、W'、U、U'、Y、Y'、X、X'、A、A'、n、n'係如上所述,且T為-NR-或各自經一或多個式-G-D-(Z)p
-C(=O)-Z'R"之連接子取代且視情況經一或多個Hal、CN、NRR'、CF3
、R、OR、SOR、SO2
R取代之4至10員芳基、環烷基、雜環、雜芳基或直鏈或支鏈烷基。
橋基-X-An-T-A'n'
-X-不含有任何-NH-C(=O)-鍵聯。
連接子具有下式:
-G-D-(Z)p
-C(=O)-Z'R",
其中:
■G為單鍵、雙鍵或參鍵、-O-、-S-或-NR-;
■D為單鍵或-E-、-E-NR-、-E-NR-F-、-E-O-、-E-O-F-、-E-NR-CO-、-E-CO-NR-、-E-NR-CO-F-、-E-CO-NR-F-、-E-CO-、-CO-E-、-E-CO-F、-E-S-、-E-S-F-、-E-NR-CS-、-E-CS-NR-、-E-NR-CS-F-、-E-CS-NR-F-;
■E及F為相同或不同的且獨立地選自直鏈或支鏈-(OCH2
CH2
)i
烷基(OCH2
CH2
)j
-、-烷基(OCH2
CH2
)i
-烷基-、-(OCH2
CH2
)j
-、-(OCH2
CH2
)i
環烷基(OCH2
CH2
)j
-、-(OCH2
CH2
)i
雜環(OCH2
CH2
)j
-、-(OCH2
CH2
)i
芳基(OCH2
CH2
)j
-、-(OCH2
CH2
)i
雜芳基(OCH2
CH2
)j
-、-烷基-(OCH2
CH2
)i
烷基(OCH2
CH2
)j
-、-烷基-(OCH2
CH2
)i
-、-烷基-(OCH2
CH2
)i
環烷基(OCH2
CH2
)j
-、-烷基(OCH2
CH2
)i
雜環(OCH2
CH2
)j
-、-烷基-(OCH2
CH2
)i
芳基(OCH2
CH2
)j
-、-烷基(OCH2
CH2
)i
雜芳基(OCH2
CH2
)j
-、-環烷基-烷基-、-烷基-環烷基-、-雜環-烷基-、-烷基-雜環-、-烷基-芳基-、-芳基-烷基-、-烷基-雜芳基-、-雜芳基-烷基-;
■相同或不同之i及j為整數且獨立地選自0、1至2000;
■Z為視情況經溶解性官能基(諸如胺基、醚、磺酸基及羧基)取代之直鏈或支鏈烷基、環烷基、芳基、雜芳基、雜環基、芳烷基、環烷基、雜芳烷基或雜環基烷基;
■P為0或1;
■-C(=O)-Z'R"為含羧基官能基,其中:
-Z'表示單鍵或-O-、-S-、-NR-,且
-R"表示H;各自視情況經一或多個Hal、CN、NRR'、CF3
、R、OR、SOR、SO2
R、芳基、Het取代之烷基、環烷基、芳基、雜芳基或雜環;R、R'為相同或不同的且獨立地選自H;各自視情況經Hal、CN、COOH、COOR、CONHR、CONRR'、NRR'、CF3
、R、OR、SOR、SO2
R、芳基、Het取代之烷基、芳基。
連接子包含由不含任何可裂解基團(諸如雙硫基、酸不穩定基團、光不穩定基團、肽酶不穩定基團及酯酶不穩定基團)之鍵聯基團封端之鏈。末端鍵聯基團不含-S-V基團,其中V為H、硫醇保護基(諸如COR)、R20
或SR20
,R20
為H、甲基、烷基、視情況經取代之環烷基、芳基、雜芳基或雜環基。連接子不為WO 2007/085930
或WO 2008/010101
中所揭示之任一者。本發明之茅屋黴素衍生物之末端鍵聯基團較佳為位於側鏈末端之羧基或醯胺基。側鏈可為直鏈或支鏈,芳族或雜環。一般熟習此項技術者可易於確定合適側鏈。較佳連接子包含含有溶解性官能基(諸如胺基、羥基、醚、磺酸基及羧基)之直鏈。
T較佳為經一或多個該(等)連接子取代且視情況經一或多個Hal、CN、NRR'、CF3
、R、OR、SOR或SO2
R取代之4至10員芳基或雜芳基,更佳為苯基或吡啶基。與苯基相比,吡啶基提供茅屋黴素衍生物於水溶液中之較高溶解度。較高溶解度可有助於製備以疏水性抗體製備結合物分子,因為較高溶解度傾向於存在較少聚集體,其可有助於增加結合物分子之產率。
該等化合物之醫藥學上可接受之鹽、水合物或水合鹽或多晶型結晶結構以及光學異構體、外消旋體、非對映異構體或對映異構體亦形成本發明之部分。當化合物呈離子形式(例如磺酸根)時,可能存在平衡離子(例如Na+
或K+
)。
本發明係指以下較佳實施例或其中任一者之任何組合:
■G為單鍵或-O-;
■D為單鍵或-E-或-E-O-;
■D為-E-;
■E為直鏈或支鏈-烷基-或-烷基(OCH2
CH2
)i
-;
■Z為直鏈或支鏈-烷基-;
■p為0;
■Z'為單鍵或O;
■Z'為O;
■R"為H或直鏈或支鏈-烷基-或取代之雜環;
■R"為H或烷基或丁二醯亞胺基()。
連接子之特定實例包括以下各者:-(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-(CR13
R14
)t
(OCH2
CH2
)y
O(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-(CR13
R14
)t
(NR19
CO)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-(CR13
R14
)t
(OCO)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-(CR13
R14
)t
(CO)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-(CR13
R14
)t
(CONR19
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-(CR13
R14
)t
-苯基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-呋喃基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-噁唑基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-噻唑基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-噻吩基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-咪唑基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-哌嗪基-CO(CR15
R16
)u
COZ'R"、-(CR13
R14
)t
-苯基-QCOZ'R"、-(CR13
R14
)t
-呋喃基-QCOZ'R"、-(CR13
R14
)t
-噁唑基-QCOZ'R"、-(CR13
R14
)t
-噻唑基-QCOZ'R"、-(CR13
R14
)t
-噻吩基-QCOZ'R"、-(CR13
R14
)t
-咪唑基-QCOZ'R"、-(CR13
R14
)t
-哌嗪基-QCOZ'R"、-(C≡C)-(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-O(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-O(CR13
R14
)t
(NR19
CO)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-O(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-O-苯基-QCOZ'R"、-O-呋喃基-QCOZ'R"、-O-噁唑基-QCOZ'R"、-O-噻唑基-QCOZ'R"、-O-噻吩基-QCOZ'R"、-O-咪唑基-QSCOZ'R"、-O-嗎啉基-QCOZ'R"、-O-哌嗪基-QCOZ'R"、-OCO(CR13
R14
)t
(NR19
CO)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-OCO-(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"-OCONR12
(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-OCO-苯基-QCOZ'R"、-OCO-呋喃基-QCOZ'R"、-OCO-噁唑基-QCOZ'R"、-OCO-噻唑基-QCOZ'R"、-OCO-噻吩基-QCOZ'R"、-OCO-咪唑基-QCOZ'R"、-OCO-哌嗪基-QCOZ'R"或-CO(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-CO-(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-CONR12
(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-CO-苯基-QCOZ'R"、-CO-呋喃基-QCOZ'R"、-CO-噁唑基-QCOZ'R"、-CO-噻唑基-QCOZ'R"、-CO-噻吩基-QCOZ'R"、-CO-咪唑基-QCOZ'R"、-CO-哌嗪基-QCOZ'R"、-CO-哌啶基-QCOZ'R"、-NR19
(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-NR19
CO(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-NR19
(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-NR19
CO(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-NR19
CONR12
(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-NR19
CONR12
(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-NR19
CO-苯基-QCOZ'R"、-NR19
CO-呋喃基-QCOZ'R"、-NR19
CO-噁唑基-QCOZ'R"、-NR19
CO-噻唑基-QCOZ'R"、-NR19
CO-噻吩基-QCOZ'R"、-NR19
CO-咪唑基-QCOZ'R"、-NR19
CO-嗎琳基-QCOZ'R"、-NR19
CO-呱瑧基-QCOZ'R"、-NR19
CO-呱咬基-QCOZ'R"、-NR19
-苯基-QCOZ'R"、-NR19
-呋喃基-QCOZ'R"、-NR19
-噁唑基-QCOZ'R"、-NR19
-噻唑基-QCOZ'R"、-NR19
-噻吩基-QCOZ'R"、-NR19
-咪唑基-QCOZ'R"、-NR19
-哌嗪基-QCOZ'R"、-NR19
-哌啶基-QCOZ'R"、-NR19
CO-NR12
-苯基-QCOZ'R"、-NR19
CO-NR12
-噁唑基-QCOZ'R"、-NR19
CO-NR12
-噻唑基-QCOZ'R"、-NR19
CO-NR12
-噻吩基-QCOZ'R"、-NR19
CO-NR12
-哌啶基-QCOZ'R"、-S(O)q
(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-S(O)q
(CR13
R14
)t
(CR17
=CR18
)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-SCONR12
(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"、-SCO-哌嗪基-QCOZ'R"及-SCO-哌啶基-QCOZ'R",其中:
‧Q為直接鍵,或具有1-10個碳原子之直鏈烷基或支鏈烷基,或具有2至20個重複伸乙基氧基單元之聚乙二醇間隔基;
‧R19
及R12
為相同或不同的且為具有1至10個碳原子之直鏈烷基、支鏈烷基或環烷基,或簡單或經取代之芳基或雜環,且R12
可另外為H;
‧R13
、R14
、R15
及R16
為相同或不同的且為H或具有1至4個碳原子之直鏈或支鏈烷基;
‧R17
及R18
為H或烷基;
‧u為1至10之整數且亦可為0;
‧t為1至10之整數且亦可為0;
‧y為1至20之整數且亦可為0。
連接子更特定言之可為:
‧-(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R";
‧-(CR13
R14
)t
(OCH2
CH2
)y
O(CR15
R16
)u
COZ'R";
‧-O(CR13
Rl4
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R";
‧-O(CR13
R14
)t
(NR19
CO)(CR15
R16
)u
(OCH2
CH2
)y
COZ'R";
‧-(C≡C)-(CR13
R14
)t
(CR15
R16
)u
(OCH2
CH2
)y
COZ'R"。
或以下各者中之一者:
‧-O(CR13
R14
)t
COZ'R";
‧-(OCH2
CH2
)y
COZ'R";
‧-(C≡C)-(CR13
R14
)t
COZ'R";
‧-O(CR13
R14
)t
(NR19
CO)(CR15
R1
6)u
COZ'R";
‧-(CR13
R14
)t
(OCH2
CH2
)y
COZ'R"。
-Z'R"更特定言之為-OH、-O烷基或。合適連接子及-Z'R"可見於本文所包括之實例中。特定基團傾向於增加酯官能基之反應性。
化合物之子群包含以下化合物:
或
其中X、X'、A、A'、Y、Y'、T、n、n'係如上所定義。
另一子群包含以下化合物:
或
其中Y、Y'、G、D、Z、p、Z'及R"係如上所定義且M表示CH或N。如上所述,當M為N時,茅屋黴素衍生物於水溶液中之溶解度得以改良。
根據另一較佳態樣,本發明之化合物係選自由以下各物組成之群:
‧4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸;
‧4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸;
‧3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;
‧6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸;
‧3-(2-{2-[2-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡比咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;
‧4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸;
‧N-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙基]-N-甲基-丁二醯胺酸;
‧4-(3,5-雙-[(S)-2-次甲基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-丙酸;
‧(2-{2-[2-(2-{3-[3,5-雙-(7-甲氧基-2-亞甲基-5-側氧基-2,3,5,11a-四氫-1H-苯并[e]吡咯幷[1,2-a][1,4]二氮呯-8-基氧基甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-乙酸;
‧(3-{2-[2-(2-{3-[3,5-雙-(7-甲氧基-2-亞甲基-5-側氧基-2,3,5,11a-四氫-1H-苯并[e]吡咯幷[1,2-a][1,4]二氮呯-8-基氧基甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-丙酸;
以及相應酯或N-羥基丁二醯亞胺酯,或其醫藥學上可接受之鹽、水合物或水合鹽,或該等化合物之多晶型結晶結構或其光學異構體、外消旋體、非對映異構體或對映異構體。
通式(I)或(I')之化合物的幾何異構體及立體異構體亦為本發明之部分。
已知茅屋黴素衍生物之N10、C11雙鍵可易於在水、乙醇、硫醇、一級或二級胺、尿素及其他親核試劑存在下以可逆方式轉化為相應亞胺加合物。該過程係可逆的且可易於在真空或高溫下在脫水劑存在下於非質子有機溶劑中再生成相應茅屋黴素衍生物(Z. Tozuka,36,J. Antibiotics,276(1983))。因此,本發明亦提供通式(II)之茅屋黴素衍生物的可逆衍生物:
其中A、X、Y、n、T、A'、X'、Y'、n'、R1、R2、R1'、R2'係如式(I)或式(I')中所定義,且W、W'為相同或不同的且係選自由以下各基組成之群:OH;醚,諸如-OR;酯(例如乙酸酯),諸如-OCOR或-COOR;碳酸酯,諸如-OCOOR;胺基甲酸酯,諸如-OCONRR';環狀胺基甲酸酯,使得N10及C11為環之一部分;脲,諸如-NRCONRR';硫代胺基甲酸酯,諸如-OCSNHR;環狀硫代胺基甲酸酯,使得N10及C11為環之一部分;-SH;硫化物,諸如-SR;亞碸,諸如-SOR;碸,諸如-SOOR;磺酸根,諸如-SO3 -
;磺醯胺,諸如-NRSOOR';胺,諸如-NRR',視情況之環胺,使得N10及C11為環之一部分;羥基胺衍生物,諸如-NROR';醯胺,諸如-NRCOR'、-NRCONRR';疊氮基,諸如-N3
;氰基;鹵基;三烷基或三芳基鏻;胺基酸衍生基團。較佳地,W及W'為相同或不同的且為OH、OMe、OEt、NHCONH2
、SMe。因此可認為式(II)化合物為溶劑合物,當溶劑為水時包括水;該等溶劑合物可能尤其適用。
如熟習此項技術者所瞭解,該等化合物可藉由應用或改進下述方法或其變化來合成。適當修改及替換對於熟習此項技術者而言將顯而易見且熟知或可易於由科學文獻而獲得。詳言之,該等方法可見於R.C. Larock,Comprehensive Organic Transformations
,Wiley-VCH Publishers,1999。
應瞭解,本發明之化合物可含有一或多個經不對稱取代之碳原子且可分離為光學活性或外消旋形式。因此,除非特別指示特定立體化學或異構體形式,否則意指結構之所有對掌性、非對映異構、外消旋形式及所有幾何異構體形式。此項技術中熟知如何製備及分離該等光學活性形式。舉例而言,立體異構體之混合物可藉由標準技術(包括(但不限於)外消旋形式之拆分,正相、逆相及對掌性層析,優先鹽形成,再結晶及其類似方法)或藉由自對掌性起始物質對掌性合成或藉由標靶對掌性中心之計劃性合成來分離。
在下文所述之反應中,可能需要保護反應性官能基以避免其不必要地參與反應,該等反應性官能基例如為羥基、胺基、亞胺基、硫基或羧基,其中該等基團為最終產物中所需。習知保護基可根據標準操作規程使用,例如參見T.W. Greene及P. G. M. Wuts,於Protective Groups in Organic Chemistry
,第三版,John Wiley及Sons,1999中;J. F. W. McOmie,於Protective Groups in Organic Synthesis
,Plenum Press,1973中。
一些反應可在鹼存在下進行。對欲用於該反應中之鹼的性質無特定限制,且習知用於此類反應之任何鹼可同樣用於此處,其限制條件為其對於分子之其他部分無副作用。合適鹼之實例包括:氫氧化鈉、碳酸鉀、三乙基胺、鹼金屬氫化物(諸如氫化鈉及氫化鉀)、烷基鋰化合物(諸如甲基鋰及丁基鋰)及鹼金屬烷醇鹽(諸如甲醇鈉及乙醇鈉)。
反應通常在合適溶劑中進行。可使用各種溶劑,其限制條件為其對於反應或所涉及之試劑無副作用。合適溶劑之實例包括:烴,其可為芳族、脂族或環脂族烴,諸如己烷、環己烷、苯、甲苯及二甲苯;醯胺,諸如二甲基甲醯胺;醇,諸如乙醇及甲醇;及醚,諸如乙醚及四氫呋喃。
反應可在較寬溫度範圍內進行。一般而言,反應可在-20℃至150℃(更佳約室溫至100℃)之溫度下進行。視多種因素而定,尤其視反應溫度及試劑之性質而定,反應所需之時間亦可廣泛變化。然而,若反應在上述較佳條件下實施,則3小時至20小時之時段通常係足夠的。
由此製備之化合物可藉由習知方式自反應混合物中回收。舉例而言,化合物可藉由自反應混合物蒸餾出溶劑來回收,或若必要,則在自反應混合物蒸餾出溶劑之後將殘餘物傾入水中,繼而以水不混溶性有機溶劑萃取且自萃取物中蒸餾出溶劑。此外,若需要,則產物可藉由各種熟知技術進一步純化,該等技術諸如再結晶、再沈澱或各種層析技術,尤其為管柱層析或製備型薄層層析。
根據第一途徑,其中T包含末端羧基之化合物的製備方法包含使下式化合物去保護之步驟:
其中Y、Y'、X、A、A'、X'、n、n'、W、W'、U、U'、----、R1、R2、R1'、R2'、係如上所定義,且T'對應於其中末端羧基由N-丁二醯亞胺基保護或經酯化之T。
去保護之代表性反應為式(I)化合物之水解,其中T'對應於其中末端羧基呈酯形式之T。該水解反應通常在鹼性條件中,在有機或無機鹼(諸如LiOH)存在下,繼而添加有機或無機酸(諸如鹽酸)來進行。
該等化合物可藉由使相應式(IV)、(IV')及(V)之化合物偶合而獲得:
其中Lg為離去基,諸如鹵素、-OMs(甲磺酸酯基)、-OTs(甲苯磺酸酯基)或-OPPh3 +
(三信反應(Mitsunobu reaction)中所形成之中間物)。
式(IV)及(IV')化合物通常為已知的,如(例如)WO 00/12508
、WO 00/12507
、WO 2005/040170
、WO 2005/085260
中所揭示,或可市售,且/或可藉由全合成而獲得(M.Mori等人,42 Tetrahedron
,3793-3806,1986)或由鏈黴菌(Streptomyces
)種產生,詳言之根據法國專利FR 1,516,743
程序,或可藉由應用或改進實例中所給之說明性程序來製備。
式(V)化合物可自式HO-An-T'-A'n'-OH(VI)之相應化合物而獲得。反應通常在PPh3
及CHal4
存在下進行,或藉由在鹼(諸如三乙基胺或氫氧化鉀,較佳三乙基胺)存在下與磺醯氯(甲烷磺醯氯或甲磺醯氯)反應來進行。
式(VI)化合物可自式HO-An-T"-A'n'-OH(VII)之相應化合物而獲得,其中T"為T之前驅體基團。T之前驅體基團係指可藉由任何去保護、化學修飾或偶合產生T之任何基團。較佳地,T係藉由將T'與互補部分偶合而獲得,其中T'及互補部分包含彼此具有反應性之官能基,例如,T'包含羥基官能基且互補部分包含溴官能基。該反應之代表性實例如下所述:
一般而言,該反應係在碳酸鉀存在下進行。
式(VII)化合物可市售或藉由改進或應用已知方法或根據實例而製成。
該途徑之例示性非限制性流程如下給出:
根據第二途徑,化合物可自式(III)之相應化合物獲得:
其中Y、Y'、X、A、A'、X'、n、n'、W、W'、U、U'、----、、R1、R2、R1'、R2'係如上所定義,且T"為T之視情況經保護之前驅體基團。T之前驅體基團係指可藉由化學修飾或偶合產生T之任何基團。較佳地,T係藉由將T'與相應互補部分偶合而獲得,其中T'及互補部分包含彼此具有反應性之官能基,例如,T'包含胺官能基且互補部分包含酸官能基。一般而言,該反應係在N-羥基丁二醯亞胺及HOBT(N-羥基苯并三唑)存在下進行。
式(III)化合物可由使式(IV)、(IV')及(V')之相應化合物偶合而獲得:
其中Lg為離去基,諸如鹵素或-OMs、-OTs或-OPPh3 +
(三信反應中所形成之中間物)。
式(V')化合物可自式HO-An-T"-A'n'-OH(VII)之相應化合物獲得,其中T"為T'之視情況經保護之前驅體基團。該反應通常係在PPh3
及CHal4
存在下進行或藉由羥基官能基之甲磺醯基化反應而進行。式(VII)化合物可市售或藉由改進或應用已知方法或根據實例而製成。
根據第三途徑,具有對稱結構(R1=R1',R2=R'2且Y=
Y')之化合物可藉由使式(VIII)之相應化合物環化來製備:
其中Y、X、X'、A、A'、n、n'、R1、R2、T係如上所定義。一般而言,該反應係在諸如亞硫酸氫鈉(Na2
S2
O4
)之試劑存在下,於適當溶劑(諸如混合物THF/水)中繼而添加MeOH及AcCl來進行。
式(VIII)化合物可自式(IX)之相應化合物獲得:
該反應在諸如氫化二異丁基鋁(DIBAL-H)之試劑存在下,於適當溶劑(諸如甲苯)中進行。式(IX)化合物可由使式(X)及(XI)之相應化合物偶合而獲得:
一般而言,該反應係藉由向(X)中添加諸如於適當溶劑(諸如DMF)中之乙二醯氯之試劑,繼而添加於適當溶劑(諸如THF)中之(XI)來進行。
該途徑之例示性非限制性流程如下給出:
上述反應可由熟習此項技術者藉由應用或改進下文實例中所說明之方法來進行。此外,本文所述之方法可包含分離任何最終或中間產物之其他步驟。此可由熟習此項技術者藉由已知習知方式(諸如上述回收方法)中之任一者來進行。起始產物可市售或可藉由應用或改進任何已知方法或實例中所述之彼等方法來獲得。合成亦可在一罐中以多組份反應之形式進行。
本發明亦係關於一種結合物分子,其包含至少一個與細胞結合劑經由連接子之鍵聯基團化學鍵聯之茅屋黴素衍生物。化學鍵較佳為共價鍵。該結合物包含一或多個本發明之與細胞結合劑經由茅屋黴素衍生物之連接子的鍵聯基團共價鍵聯之茅屋黴素衍生物。作為代表性實例,該結合物包含本發明之與細胞結合劑經由連接子之末端-CO-Z'R"基團共價鍵聯之茅屋黴素衍生物。該鍵聯基團使細胞結合劑與茅屋黴素衍生物之連接子共價鍵聯。
較佳地,連接子係經由對(例如)細胞結合劑之分別來自經還原雙硫鍵及離胺酸殘基之硫醇及胺基官能基具有反應性之官能基與細胞結合劑鍵聯。更特定言之,該衍生物係經由-CO-基團與該細胞結合劑之離胺酸殘基的胺基官能基鍵聯以形成醯胺鍵。
細胞結合劑可為任何種類且包括肽及非肽。一般而言,其可為抗體(尤其單株抗體)或含有至少一個結合位點之抗體片段、淋巴激素、激素、生長因子、營養輸送分子(諸如轉鐵蛋白)或任何其他細胞結合分子或物質。可使用之細胞結合劑的更特定實例包括單株抗體;嵌合抗體;人源化抗體;全人類抗體;單鏈抗體;抗體片段,諸如Fab、Fab'、F(ab')2
及Fv
{Parham,131 J. Immunol. 2895-2902(1983);SPring等人,113 J. Im munol. 470-478(1974);Nisonoff等人,89 Arch. Biochem. Biophys. 230-244(1960)};干擾素;肽;淋巴激素,諸如IL-2、IL-3、IL-4、IL-6;激素,諸如胰島素、TRH(促甲狀腺素釋放激素)、MSH(促黑素細胞激素)、類固醇激素(諸如雄激素及雌激素);生長因子及集落刺激因子,諸如EGF,TGFα,胰島素樣生長因子(IGF-I、IGF-II)G-CSF、M-CSF及GM-CSF{Burgess,5 Immunology Today 155-158(1984)};維生素,諸如葉酸及轉鐵蛋白{O'Keefe等人,260 J. Biol. Chem. 932-937(1985)}。表述"細胞結合劑"亦包括經修飾之細胞結合劑,其中該細胞結合劑藉由修飾劑修飾以提高該細胞結合劑對茅屋黴素衍生物之連接子之鍵聯基團的反應性。
單株抗體技術使得可以特異性單株抗體之形式產生極具選擇性之細胞結合劑。此項技術中特別熟知者為使用所關注之抗原(諸如完整標靶細胞、自標靶細胞分離之抗原、全病毒、減毒全病毒及病毒蛋白(諸如病毒鞘蛋白))製造由免疫小鼠、大鼠、倉鼠或任何其他哺乳動物產生之單株抗體的技術。
選擇適當細胞結合劑為關鍵問題,其取決於欲靶向之特定細胞群體,但一般而言若可獲得適當細胞結合劑,則單株抗體為較佳的。舉例而言,單株抗體MY9為與CD33抗原特異性結合之鼠科IgG1
抗體{J.D. Griffin等人,8Leukemia Res.,521(1984)}且若標靶細胞表現CD33(如在急性骨髓性白血病(AML)中)則可使用。類似地,單株抗體抗B4為與B細胞上之CD19抗原結合之鼠科IgG1
{Nadler等人,131 J. Immunol.244-250(1983)}且若標靶細胞為表現該抗原之B細胞或病態細胞(諸如在非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)或慢性淋巴母細胞白血病中)則可使用。如上所述,MY9及抗B4抗體可為鼠科、嵌合、人源化或全人類抗體。
此外,與骨髓細胞結合之GM-CSF可用作來自急性骨髓性白血病之病態細胞的細胞結合劑。與活化T-細胞結合之IL-2可用於預防經移植移植物排斥反應,用於治療及預防移植物抗宿主疾病,且用於治療急性T-細胞白血病。與黑素細胞結合之MSH可用於治療黑素瘤。
可用於製備結合物分子之合適單株抗體的實例可為hu2H11(由ATCC以PTA-7662註冊)、描述於WO 2004/043344中之huMy9-6之一者、描述於WO 2005/009369中之huDS6或描述於WO 2008/047242、WO 2005/061541或WO 02/16101中之一者。
茅屋黴素衍生物可與抗體或其他細胞結合劑經由醯胺型官能基鍵聯。較佳地,該等衍生物經合成為含有羧基官能基,且隨後一或多個含羧酸衍生物各自與細胞結合劑經由醯胺鍵共價鍵聯。
本發明之代表性結合物為抗體-茅屋黴素衍生物、抗體片段-茅屋黴素衍生物、表皮生長因子(EGF)-茅屋黴素衍生物、促黑素細胞激素(MSH)-茅屋黴素衍生物、促甲狀腺激素(TSH)-茅屋黴素衍生物、雌激素-茅屋黴素衍生物、雌激素類似物-茅屋黴素衍生物、雄激素-茅屋黴素衍生物、雄激素類似物-茅屋黴素衍生物及葉酸-茅屋黴素衍生物。該等結合物可藉由HPLC或藉由凝膠過濾來純化。
較佳地,單株抗體-茅屋黴素衍生物結合物或細胞結合劑-茅屋黴素衍生物結合物為如上所述經由醯胺鍵接合、能夠傳遞茅屋黴素衍生物之彼等結合物。結合物可使用茅屋黴素二聚體連接子末端之羧基官能基的N-羥基丁二醯亞胺衍生物來製備。含有1至10個經由醯胺鍵鍵聯之茅屋黴素衍生物藥物的結合物易於藉由該方法來製備。
更特定言之,將8mg/ml濃度之抗體於含有0.05M磷酸鉀、0.05M氯化鈉及2mM乙二胺四乙酸(EDTA)之緩衝劑水溶液(PH 8)中之溶液以5倍莫耳過量之茅屋黴素二聚體之N-羥基丁二醯亞胺衍生物於二甲基乙醯胺(DMA)中之溶液處理,以使得DMA於緩衝液中之最終濃度為20%。將反應混合物在室溫(rt)下攪拌70min。將抗體-茅屋黴素衍生物結合物藉由經Sephadex G-25或Sephacryl S300或Superdex 200管柱凝膠過濾而純化且除去未反應之藥物及其他低分子量物質。亦可將樣品於PH 6.5之緩衝液中透析隔夜以進一步純化產物。每個抗體分子所結合之茅屋黴素衍生物部分的數目可藉由量測320nm及280nm下之吸光率來測定。藉由該方法可經由醯胺鍵來鍵聯每個抗體分子平均1-10個茅屋黴素衍生物分子。
結合物對抗原表現細胞之結合親和力的效應可使用先前由Liu等人,93 Proc. Natl. Acad. Sci 8618-8623(1996)所述之方法來測定。茅屋黴素衍生物及其抗體結合物對細胞株之細胞毒性可藉由如Goldmacher等人,135 J. Immunol. 3648-3651(1985)中所述之細胞增殖曲線的反向外推法來量測。該等化合物對黏附細胞株之細胞毒性可藉由如Goldmacher等人,102 J. Cell Biol. 1312-1319(1986)中所述之細胞菌落檢定來測定。
本發明之代表性結合物為茅屋黴素衍生物與抗體、抗體片段、表皮生長因子(EGF)、促黑素細胞激素(MSH)、促甲狀腺激素(TSH)、雌激素、雌激素類似物、雄激素及雄激素類似物之結合物。
製備衍生物與細胞結合劑之各種結合物的代表性實例係如下描述。
醯胺連接子:舉例而言,單株抗體MY9為與CD33抗原特異性結合之鼠科IgG1
抗體{J.D. Griffin等人,8 Leukemia Res.,521(1984)}且若標靶細胞表現CD33(如在急性骨髓性白血病(AML)之疾病中)則可使用。類似地,單株抗體抗B4為與B細胞上之CD19抗原結合之鼠科IgG1
{Nadler等人,131 J. Immunol. 244-250(1983)}且若標靶細胞為表現該抗原之B細胞或病態細胞(諸如在非霍奇金氏淋巴瘤或慢性淋巴母細胞白血病中)則可使用。
此外,與骨髓細胞結合之GM-CSF可用作來自急性骨髓性白血病之病態細胞的細胞結合劑。與活化T-細胞結合之IL-2可用於預防經移植移植物排斥反應,用於治療及預防移植物抗宿主疾病,且用於治療急性T-細胞白血病。與黑素細胞結合之MSH可用於治療黑素瘤。
使抗體或其他細胞結合劑與N-羥基-丁二醯亞胺酸衍生物反應以產生醯胺鍵聯之結合物。
藉由上述方法製得之結合物可藉由以下方法來純化:標準層析技術,諸如尺寸排阻法,吸附層析法,包括(但不限於)離子交換法,疏水性相互作用層析法,親和層析法,陶瓷羥基磷灰石或PorpPak層析法,或藉由HPLC來純化。亦可使用藉由透析或透濾之純化。
較佳地,單株抗體或細胞結合劑與本發明之衍生物之間的結合物為如上所述經由醯胺鍵接合之彼等結合物。該等細胞結合結合物係藉由已知方法來製備,諸如修飾具有羧基官能基之可鍵聯藥物分子以獲得N-羥基-丁二醯亞胺酸衍生物。所得活化羧基隨後醯化抗體之含離胺酸殘基以產生醯胺鍵聯結合物。含有1至10個經由醯胺橋鍵鍵聯之衍生物的結合物易於藉由該方法來製備。
根據較佳態樣,細胞結合劑為抗體,尤其為單株抗體。根據另一較佳態樣,細胞結合劑為抗原特異性抗體片段,諸如sFV、Fab、Fab'或F(ab')2
。
本發明亦係關於包含本發明之結合物分子或如上所定義之茅屋黴素衍生物以及醫藥學上可接受之載劑的醫藥組合物。
本發明亦係關於一種以有效量之醫藥組合物殺死或抑制細胞生長,較佳包含接觸標靶細胞或含有標靶細胞之組織的所選細胞群體生長之方法。所選細胞群體為彼等癌細胞及/或增殖細胞。本發明亦係關於一種治療,較佳選擇性治療癌症之方法,其包含向有需要之患者投與有效量之醫藥組合物。"選擇性治療癌症"係指殺死癌細胞及/或增殖細胞而大體上不殺死正常細胞及/或非增殖細胞。
本發明亦係關於如上所定義之結合物分子或茅屋黴素衍生物用於製備用以治療癌症之藥劑的用途。
抑制所選細胞群體生長之方法可以活體外、活體內或離體方式實踐。活體外用途之實例包括治療細胞培養物以殺死除不表現標靶抗原之所需變體以外的所有細胞,或殺死表現不當抗原之變體。非臨床活體外使用之條件易於由熟習此項技術者來確定。離體用途之實例包括在將自體骨髓移植至同一患者之前處理自體骨髓以殺死病態或惡性細胞;在移植骨髓之前處理骨髓以殺死感受態T細胞且預防移植物抗宿主疾病(GVHD)。臨床離體處理以在癌症治療或治療自體免疫疾病中在自體移植之前自骨髓移除腫瘤細胞或淋巴樣細胞,或在移植之前自同種異體骨髓或組織移除T細胞及其他淋巴樣細胞以預防GVHD可如下進行。自患者或其他個體獲取骨髓,且隨後將其在約37℃下在含有血清、添加有本發明之濃度介於約10μM至1PM之細胞毒性劑的培養基中培育約30分鐘至約48小時。濃度及培育時間(=劑量)之確切條件易於由熟習此項技術者來確定。培育之後,將骨髓細胞以含有血清之培養基洗滌且根據已知方法藉由靜脈內輸注返回至患者體內。在患者在獲取骨髓與再輸注經處理細胞之時之間接受其他治療(諸如清除性化療或全身輻射之過程)的情況下,使用標準醫療設備將經處理之骨髓細胞冷凍儲存於液氮中。對於臨床活體內用途而言,本發明之細胞毒性劑將以經無菌及內毒素含量測試之溶液形式提供,或以可再溶解於無菌注射水中之凍乾固體形式提供。結合物投與之合適方案的實例如下。將結合物每週以靜脈內團注之形式給予歷時6週。將團注劑量在50至400ml標準生理食鹽水中給予,可向生理食鹽水中添加人類血清白蛋白(例如0.5至1mL人類血清白蛋白之100mg/mL濃溶液)。劑量將為每週每公斤體重靜脈內約50μg至10mg(每次注射介於每公斤10μg至100mg之範圍)。治療六週後,患者可接受第二治療過程。當臨床情況批准時,關於投藥途徑、賦形劑、稀釋劑、劑量、時間等之特定臨床方案可由熟習此項技術者來確定。
可根據殺死所選細胞群體之活體內或離體方法來治療之醫學病狀的實例包括任何類型之惡性病症,包括(例如)肺癌、乳癌、結腸癌、前列腺癌、腎癌、胰腺癌、卵巢癌及淋巴器官癌;黑素瘤;自體免疫疾病,諸如全身性狼瘡、類風濕性關節炎及多發性硬化症;移植排斥反應,諸如腎移植排斥反應、肝臟移植排斥反應、肺移植排斥反應、心臟移植排斥反應及骨髓移植排斥反應;移植物抗宿主疾病;病毒感染,諸如CMV感染、HIV感染、AIDS等;細菌感染;及寄生蟲感染,諸如梨形鞭毛蟲病(giardiasis)、阿米巴病(amoebiasis)、血吸蟲病(schistosomiasis),及其他由熟習此項技術者確定之病狀。
治療有效量可易於由作為熟習此項技術者之主治診斷醫師藉由使用習知技術及藉由觀察類似情況下所獲得之結果來確定。在確定治療有效量時,主治診斷醫師考慮大量因素,包括(但不限於):受檢者物種;其大小、年齡及一般健康狀況;所涉及之特定疾病;涉及之程度或疾病之嚴重程度;個別受檢者之反應;所投與之特定化合物;投藥模式;所投與製劑之生物可用性特徵;所選劑量方案;伴隨藥物之使用;及其他相關情況。
達成所需生物效應所需之量將視大量因素而變化,該等因素包括所用化合物之化學特徵(例如疏水性)、化合物之效能、疾病之類型、患者所屬之物種、患者之疾病狀況、投藥途徑、化合物由所選途徑之生物可用性、指示欲投與之所需劑量、傳遞及方案的所有因素。
一般而言,本發明之化合物可在含有0.1至10% w/v化合物之生理學緩衝劑水溶液中提供以用於非經腸投藥。典型劑量範圍為每日每公斤體重1μg至0.1g;較佳劑量範圍為每日每公斤體重0.01mg至10mg或於人類兒童中之等效劑量。欲投與之較佳藥物劑量可能視以下變數而定:諸如疾病或病症之類型及進程程度、特定患者之總體健康狀況、所選化合物之相對生物學功效、化合物之調配物、投藥途徑(靜脈內、肌肉內、腹膜內、皮下或其他)、化合物由所選傳遞途徑之藥物代謝動力學特性及投藥速度(團注或連續輸注)及時程(在給定時期內之重複次數)。
組合物可以單位劑型便利地投與,且可藉由醫藥技術中熟知方法中之任一者來製備,該等方法例如Remington:The Science and Practice of Pharmacy,第20版;Gennaro,A. R.編輯;Lippincott Williams & Wilkins:Philadelphia,PA,2000中所述。
非經腸投藥之液體製劑包括無菌水溶液或非水溶液、懸浮液及乳液。液體組合物亦可包括結合劑、緩衝液、防腐劑、螯合劑、甜味劑、調味劑及著色劑及其類似物。非水性溶劑包括酒精、丙二醇、聚乙二醇、諸如橄欖油之植物油,及諸如油酸乙酯之有機酯。水性載劑包括酒精與水之混合物、經緩衝介質及生理食鹽水。詳言之,生物相容、生物可降解之丙交酯聚合物,丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可為控制活性化合物釋放之適用賦形劑。靜脈內媒劑可包括流體及營養補充劑、電解質補充劑(諸如基於林格氏右旋糖(Ringer's dextrose)之彼等補充劑)及其類似物。其他可能適用於該等活性化合物之非經腸傳遞系統包括乙烯-乙酸乙烯酯共聚物粒子、滲透泵、可植入式輸注系統及脂質體。
方法A1:高壓液相層析-質譜(LCMS)
使用Micromass MassLynx軟體且在以下各物上執行分析:具有WATERS XBridge C18
3.5μm管柱(100×3mm,使用(A)甲醇與(B)水/0.1%甲酸之混合物梯度溶離(梯度:5%A:95% B經10min升至95% A:5% B,95% A:5% B經1min降至5% A:95% B,5% A:95% B歷時2min)且流動速率為1.1mL/min)之Waters Alliance HPLC;具有電噴霧(正電離及負電離)之Waters-Micromass Platform II光譜儀;直插式二極體陣列(190-500nm);輔助偵測器Sedere(France)型SEDEX 85蒸發光散射(ELS)偵測器。
方法A2:高壓液相層析-質譜(LCMS)
使用Micromass MassLynx軟體且在以下各物上執行分析:具有XBridge C18
2.5μm管柱(50×3mm,使用(A)乙腈與(B)水/0.1%甲酸之混合物梯度溶離(梯度:5% A:95% B經5分鐘升至100% A,100% A歷時0.5min,100% A經1min降至5% A:95% B,5% A:95% B歷時0.5min)且流動速率為1.1mL/min)之Agilent 1100系列HPLC;具有電噴霧(正電離及負電離)之Waters-Micromass ZQ光譜儀;直插式二極體陣列(210-254nm)。
方法A3:高壓液相層析-質譜(LCMS)
在以下各物上執行分析:具有ACQUITY BEH C18
1.7μm-2.1×50mm管柱(在50℃下使用(A)H2
O/0.1%甲酸與(B)CH3
CN/0.1%甲酸之混合物梯度溶離(梯度:95% A:5% B經0.8min降至50% A:50% B,50% A:50% B經1.2min降至100% B,100% B歷時1.85min,100% B經1.95min升至95% A:5% B)且流動速率為1mL/min)之Waters UPLC-SQD;電噴霧(正電離及/或負電離)。
方法A4:高壓液相層析-質譜(LCMS)
在以下各物上執行分析:具有XBridge C18
2.5μm管柱(50×3mm,在70℃下使用(A)乙腈與(B)水/0.1%甲酸之混合物梯度溶離(梯度:5% A:95%B經5.3min升至100% A,100% A歷時5.5min,5% A:95% B歷時6.3min)且流動速率為0.9mL/min)之Waters ZQ光譜儀;電噴霧(正電離及/或負電離)。
方法B:1
H核磁共振(NMR)光譜
1
H NMR光譜係記錄於BRUKER AVANCE DRX-500、BRUKER AVANCE DRX-400光譜儀或BRUKER AVANCE DRX-300光譜儀上。所報導之13
C NMR光譜係記錄於BRUKER AVANCE DRX-300光譜儀上。
方法C:化學電離(CI)質譜
CI質譜係使用WATERS GCT質譜儀(氨)記錄。
方法D:化學電離(CI)質譜
CI質譜係使用FINNIGAN SSQ 7000質譜儀(氨)記錄。
實例1:4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯可如下製備:
向4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸(11.3mg)於四氫呋喃(0.4mL)中之懸浮液中添加碳酸N,N'-二丁二醯亞胺酯(7.7mg)及N,N-二異丙基乙基胺(15.8μL)。在室溫下2.5h之後,將乙酸乙酯(6mL)添加至反應混合物中,且將有機溶液以水(4mL)洗滌兩次,隨後以飽和氯化鈉水溶液(5mL)洗滌,經硫酸鎂乾燥且在真空中濃縮成殘餘物。將殘餘物藉由使用MeOH(甲醇)(A)/DCM(二氯甲烷)(B)之混合物梯度溶離(梯度:2%A:98% B升至4% A:96% B)之矽膠層析法(Merck MiniVarioFlash 2.5g管柱,Si60 15-40μm)純化以產生4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯(17.6mg):LC/MS(方法A4):ES:m/z846(M+H)+
;滯留時間(RT)=3.89min;1H NMR(400MHz,CDCl3
-d1,δppm):δ=1.75(d,J=6.8Hz,6H);2.23(m,2H);2.73-2.87(m,6H);2.97(m,4H);3.84-3.95(m,2H);3.97(s,6H);4.06(m,2H);4.26(m,4H);5.14(d,J=12.4Hz,2H);5.21(d,J=12.4Hz,2H);5.62(m,2H);6.84(s,2H);6.96(s,2H);7.09(s,1H);7.53(s,2H);7.63(m,2H)。
4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸可如下製備:
向4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯(60mg)於四氫呋喃(0.9mL)中之溶液中添加MeOH(0.3mL)、水(0.3mL)及氫氧化鋰水溶液(1M,87μL)。3小時之後,將反應混合物以水(10mL)稀釋,且藉由添加1N鹽酸水溶液將PH值調整至2。將水相以DCM(10mL)萃取三次,且將經合併之有機溶液經硫酸鈉乾燥,且在真空中濃縮成殘餘物。將殘餘物藉由以DCM/MeOH/乙酸(100:4:0.5)混合物溶離之矽膠層析法(Merck SuperVarioFlash 10g管柱,SiOH 15-40μm)純化以產生4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸:LC/MS(方法A2):ES:m/z=749MH+
;m/z=375(M+2H)2+
/2;RT=3.7min;l
H N.M.R.(400MHz,DMSO-d6,δ,以PPm計):δ=1.69(d,J=6.5Hz,6H);1.95(m,2H);2.39(t,J=6.5Hz,2H);2.91(m,2H);3.05(m,2H);3.83(s,6H);3.98(m,2H);4.01(t,J=6.5Hz,2H);4.10(m,4H);5.11(d,J=12.5Hz,2H);5.20(d,J=12.5Hz,2H);5.55(m,2H);6.90至7.15(m,5H);7.34(s,2H);7.77(m,2H);12.1(多寬峰,1H)。
4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯可如下製備:
向4-(3,5-雙-羥基甲基-苯氧基)-丁酸甲酯(50mg)及三乙基胺(110μL)於THF(四氫呋喃)(1.4mL)中之冷卻(0℃)溶液中添加甲烷磺醯氯(46μL)。1h之後,將反應混合物以DCM(10mL)稀釋且以水(5mL)洗滌兩次。將有機溶液經硫酸鈉乾燥且在真空中濃縮成殘餘物。將殘餘物藉由使用MeOH(A)/DCM(B)之混合物梯度溶離(梯度:100% B降至5% A:95% B)之矽膠層析法(Merck SuperVarioFlash 10g管柱,SiOH 15-40μm)純化以產生71.8mg二甲磺酸酯化合物。向茅屋黴素(80mg)、碘化鉀(49mg)、碳酸鉀(122mg)於DMF(二甲基甲醯胺)(1mL)中之混合物中添加二甲磺酸酯化合物(71.8mg)於DMF(1.6mL)中之溶液。將反應混合物在30℃下攪拌16h。添加水(12mL)且將所得固體過濾,以水洗滌且在真空中乾燥以產生殘餘物。將殘餘物藉由使用MeOH(A/DCM(B)之混合物梯度溶離(梯度:100% B降至5% A:95% B)之矽膠層析法(Merck SuperVarioFlash 30g管柱,SiOH 15-40μm)純化以產生4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]-苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯(65.4mg):LC/MS(方法A2):ES:m/z=763MH+
;m/z=382(M+2H)2+
/2;RT=4.0min;l
H N.M.R.(500MHz,CDCl3
-dl,δ,以PPm計):1.75(d,J=6.5Hz,6H);2.11(m,2H);2.53(t,J=6.5Hz,2H);2.98(m,4H);3.69(s,3H);3.89(m,2H);3.97(S,6H);4.00(t,J=6.5Hz,2H);4.28(單寬峰,4H);5.12(d,J=12.5Hz,2H);5.19(d,J=12.5Hz,2H);5.61(m,2H);6.82(s,2H);6.92(s,2H);7.06(s,1H);7.52(s,2H);7.64(d,J=4,5Hz,2H)。
4-(3,5-雙-羥基甲基-苯氧基)-丁酸甲酯可如下製備:
向3,5-雙-羥基甲基苯酚(Felder,D.;Gutirrez Nava,M.;del Pilar Carreon,M.;Eckert,J.F.;Luccisano,M.;Schall,C.;Masson,P.;Gallani,J.L.;Heinrich,B.;Guillon,D.;Nierengarten,J.F. Helv. Chimica Acta 2002,85,288)(200mg)、碘化鉀(50mg)及碳酸鉀(540mg)於THF(2.5mL)中之溶液中添加4-溴-丁酸甲酯(400μL)。將反應混合物在室溫下攪拌20h,隨後將不溶解部分濾出。將濾液在真空中濃縮且將殘餘物藉由使用MeOH(A)/DMC(B)之混合物梯度溶離(梯度:100% B降至5% A:95% B)之矽膠層析法(Merck Super VarioFlash 30g管柱,Si60 15-40μm)純化以產生4-(3,5-雙-羥基甲基-苯氧基)-丁酸甲酯(53.5mg):LC/MS(方法A2):ES:m/z=255MH+
;m/z=237(M+H-H2
O)+
;RT=2.5min;1
H N.M.R.(400MHz,DMSO-d6,δ,以ppm計):δ=1.96(m,2H);2,47(t,J=6.5Hz,2H);3.61(s,3H);3.96(t,J=6.5Hz,2H);4.43(d,J=6.0Hz,4H);5.11(t,J=6.0Hz,2H);6.71(s,2H);6.82(s,1H)。
實例2:4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸之程序,以4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸甲酯開始來製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸:LC/MS(方法A2):ES:m/z=721MH+
;m/z=361(M+2H)2+
/2;RT=3.5min。
4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸甲酯
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之程序,以4-(3,5-雙-羥基甲基-苯氧基)-乙酸甲酯開始來製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸甲酯:LC/MS(方法A2):ES:m/z=735MH+
;m/z=368(M+2H)2+
/2;RT=3.8min;l
H N.M.R.(500MHz,CDCl3
-d1,δ,以PPm計):δ=1.76(d,J=6.5Hz,6H);2.96(m,4H);3.78(s,3H);3.88(m,2H);3.97(s,6H);4.27(單寬峰,4H);4.64(s,2H);5.13(d,J=12.5Hz,2H);5.19(d,J=12.5Hz,2H);5.60(m,2H);6.80(s,2H);6.96(s,2H);7.11(s,1H);7.53(s,2H);7.63(d,J=4.5Hz,2H)。
4-(3,5-雙-羥基甲基-苯氧基)-乙酸甲酯:
可根據製備4-(3,5-雙-羥基甲基-苯氧基)-丁酸甲酯之程序,以4-溴-乙酸甲酯開始來製備4-(3,5-雙-羥基甲基-苯氧基)-乙酸甲酯:LC/MS(方法A2):ES:m/z=227MH+
;m/z=209(M+H-H2
O)+
;RT=1.9min;1
H N.M.R.(400MHz,DMSO-d6,δ,以PPm計):δ=3.70(s,3H);4.43(d,J=6.0Hz,4H);4.74(s,2H);5.14(t,J=6.0Hz,2H);6.72(s,2H);6.88(s,1H)。
實例3:3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羥基丁二醯亞胺酯:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯之程序,以3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸開始來製備3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羥基丁二醯亞胺酯:LC/MS(方法A3):ES:m/z 964(M+H)+
;RT=0.90min;1
H NMR(500MHz,CDCl3
-d1,δPPm):δ=1.75(dd,J=6.7Hz,6H);2.82(m,4H);2.89(t,J=6.6Hz,2H);2.97(m,4H);3.57-4.23(m,16H);3.97(s,6H);4.27(m,4H);5.13(d,J=12.7Hz,2H);5.20(d,J=12.2Hz,2H);5.61(m,2H);6.82(s,2H);6.96(s,2H);7.07(s,1H);7.53(s,2H);7.64(d,J=4.4Hz,2H)。
3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸之程序,以3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯開始來製備3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸:LC/MS(方法A3):ES:m/z 867(M+H)+
;m/z 434(M+2H)2+
/2;RT=0.84min;1
H NMR(400MHz,CDCl3
-dl,δPPm):δ=1.76(dd,J=8.6,1.5Hz,6H);2.61(t,2H);2.94-3.00(m,4H);3.63-3.75(m,8H);3.80(t,J=6.5Hz,2H);3.85-3.95(m,4H);3.98(s,6H);4.17(t,J=4.9Hz,2H);4.27(br.s.,4H);5.14-5.21(m,2H);5.18(d,J=12.7Hz,2H);5.23(d,2H);5.23(d,J=12.7Hz,2H)5.62(td,J=4.5,2.2Hz,2H);6.88(d,J=0.5Hz,2H);6.97-7.02(m,2H);7.09(s,1H);7.54(S,2H);7.68(d,J=4.9Hz,2H)。
3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之程序,以3-(2-{2-F2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯開始來製備3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:LC/MS(方法A3):ES:m/z 881(M+H)+
;m/z 441(M+2H)2+
/2;RT=0.91min;1
H NMR(400MHz,CDCl3
-d1,δPPm):δ=1.75(雙寬峰,J=6.7Hz,6H);2.60(t,J=6.7Hz,2H);2.97(m,4H);3.54-4.21(m,16H);3.68(s,3H);3.97(s,6H);4.27(m,4H);5.13(d,J=12.2Hz,2H);5.21(d,J=12.2Hz,2H);5.61(m,2H);6.83(s,2H);6.96(s,2H);7.08(s,1H);7.53(s,2H);7.64(d,J=4.2Hz,2H)。
3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯可如下製備:
向3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯(607mg)於DCM(8.7mL)中之溶液中添加三氟乙酸(2.2mL)。將反應混合物在室溫下攪拌3日,隨後在真空中濃縮且將所獲得之殘餘物溶解於甲醇(5mL)中。向冷卻(0℃)之甲醇溶液中添加2M於己烷(3.6mL)中之(三甲基矽烷基)重氮甲烷直至持續為黃色。隨後添加乙酸(10μL),且將所得溶液在真空中濃縮成殘餘物。將殘餘物藉由使用DCM(A)與MeOH(B)之混合物梯度溶離(梯度:99% A:1% B降至90% A:10% B)之矽膠層析法(Analogix Super Flash SiO2
SF25-40g)純化以產生3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯(232mg)。LC/MS(方法A3):ES:m/z 373 (M+H)+
;m/z 395(M+Na)+
;RT=0.50min。
3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯:
可根據製備4-(3,5-雙-羥基甲基-苯氧基)-丁酸甲酯之程序,以3-{2-[2-(2-溴-乙氧基)-乙氧基]-乙氧基}-丙酸第三丁酯開始(WO 2004/091542)來製備3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯:
LC/MS(方法A3):ES:m/z 415(M+H)+
;m/z 432(M+NH4
)+
;RT=0.75min。
實例4:6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸N-羥基丁二醯亞胺酯
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯之程序,以6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸開始來製備6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸N-羥基丁二醯亞胺酯:LC/MS(方法A3):ES:m/z 854(M+H)+
;RT=1.25min。
6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸之程序,以6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸甲酯開始來製備6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸:LC/MS(方法A3):ES:m/z 757(M+H)+
;RT=0.89min;1
H NMR(400MHz,CDCl3
-d1,δPPm):δ=1.76(d,J=6.8Hz,6H);1.98(m,2H);2.55(m,4H);2.97(m,4H);3.91(m,2H);3.97(s,6H);4.27(m,4H);5.15(d,J=12.8Hz,2H);5.21(d,J=12.8Hz,2H);5.61(m,2H);6.88(s,2H);7.48(s,3H);7.53(s,2H);7.67(m,2H)。
6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸甲酯
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之程序,以6-(3,5-雙-羥基甲基-苯基)-己-5-炔酸甲酯開始來製備6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸甲酯:LC/MS(方法A3):ES:m/z 771(M+H)+
;RT=1.00min;1
H NMR(500MHz,CDCl3
-d1,δ ppm):δ=1.75(d,J=6.6Hz,6H);1.93(m,2H);2.50(m,4H);2.96(m,4H);3.69(s,3H);3.90(m,2H);3.97(s,6H);4.27(m,4H);5.12(d,J=12.3Hz,2H);5.19(d,J=12.3Hz,2H);5.61(m,2H);6.81(s,2H);7.43(s,3H);7.54(s,2H);7.64(d,J=4.4Hz,2H)。
6-(3,5-雙-羥基甲基-苯基)-己-5-炔酸甲酯係如下製備:
向6-[3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯基]-己-5-炔酸甲酯(140mg)於無水四氫呋喃(0.3mL)中之冷卻(0℃)溶液中少量添加氟化四丁基銨於THF(716μL)中之1M溶液。在室溫下75min之後,添加乙酸乙酯(20mL),且將有機相以水(5mL)洗滌三次且以飽和氯化鈉水溶液(5mL)洗滌一次,經硫酸鈉乾燥且在真空中濃縮成殘餘物。將殘餘物藉由使用庚烷(A)/乙酸乙酯(B)之混合物梯度溶離(梯度:50% A:50% B降至10% A:90% B)之矽膠層析法(Merck SuperVarioFlash 15g管柱,Si60 15-40μm)純化以產生呈淺黃色油狀物之6-(3,5-雙-羥基甲基-苯基)-己-5-炔酸甲酯(64.3mg)。LC/MS(方法A3):ES:m/z 263(M+H)+
;RT=0.62min。
6-[3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯基]-己-5-炔酸甲酯可如下製備:
向1,3-雙-羥基甲基-5-碘-苯(Zeng,F.;Zimmerman,S.C.J. Am. Chem. Soc. 1996,118(22),5326-5327)(1.7g)於二氯甲烷(10mL)中之溶液中添加三乙基胺(3.59mL)、第三丁基二甲基矽烷基氯(2.91g)及DMF(2mL)。1小時之後,添加乙酸乙酯(200mL),且將有機相以水(50mL)洗滌三次且以飽和氯化鈉水溶液(50mL)洗滌一次,經硫酸鎂乾燥且在真空中濃縮成殘餘物(3.65g)。向先前之殘餘物(200mg)於DMF(0.90mL)中之溶液中添加碘化銅(I)(7.7mg)、二氯雙(三苯基膦)鈀(II)(28.5mg)、5-己炔酸甲酯(102.4mg)及三乙基胺(113μL)。45min之後,添加乙酸乙酯(40mL),且將有機相以水(10mL)洗滌三次且以飽和氯化鈉水溶液(10mL)洗滌一次,經硫酸鎂乾燥且在真空中濃縮成殘餘物。將殘餘物藉由使用庚烷(A)/乙酸乙酯(B)之混合物梯度溶離(梯度:100% A降至90% A:10% B)之矽膠層析法(Merck SuPerVarioFlash30g管柱,Si60 15-40μm)純化以產生呈黃色油狀物之6-[3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯基]-己-5-炔酸甲酯(145.3mg)。MS(方法C):CI:m/z494(M+NH4
)+
;1
HN.M.R.(400MHz,DMSO-d6,δ,以PPm計):δ=0.07(s,12H);0.89(s,18H);2.55-2.69(m,2H);3.63(s,3H);4.67(s,4H);7.15(單大峰,2H);7.28(單寬峰,1H)。
實例5:3-(2-{2-[2-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之程序,以3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯開始來製備3-(2-{2-[2-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:LC/MS(方法A3):ES:m/z 882(M+H)+
;m/z 441.5(M+2H)2+
/2;RT=0.82min;l
H NMR(400MHz,CDCl3
-d1,δppm):δ=1.76(d,J=6.8Hz,6H);2.59(t,J=6.5Hz,2H);2.97(m,4H);3.58-3.72(m,9H);3.75(t,J=6.5Hz,2H);3.80-3.97(m,4H);4.00(s,6H);4.20(多寬峰,2H);4.27(m,4H);5.31-5.42(m,4H);5.61(多寬峰,2H);6.87(s,2H);7.02-7.15(多寬峰,2H);7.56(s,2H);7.65(d,J=4.4Hz,2H)。
3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:
可根據製備3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯之程序,以3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯開始來製備3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯:LC/MS(方法A3):ES:m/z 374(M+H)+
;m/z 418(M+HCO2
H-H)-
;RT=0.31min。
3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯:
向4-(2-{2-[2-(2-第三丁氧基羧基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二甲酸二乙酯(1.36g)於無水乙醇(72mL)中之溶液中添加硼氫化鈉(309mg)及氯化鈣(921mg)。攪拌30min之後,氫氣釋放停止,且將反應以水中止。在減壓下濃縮之後,添加氯化銨且將水相以乙酸乙酯萃取三次。將經合併之有機溶液經硫酸鎂乾燥,且在真空中濃縮成殘餘物。將殘餘物藉由使用DCM(A)與MeOH(B)之混合物梯度溶離(梯度:100%A降至90%A:10%B)之矽膠層析法(Analogix Super Flash SiO2
SF25-80g)純化以產生3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯(720mg):LC/MS(方法A3):ES:m/z 416(M+H)+
;RT=0.52min。
4-(2-{2-[2-(2-第三丁氧基羧基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二甲酸二乙酯:
向12-羥基-4,7,10-三氧雜癸酸第三丁酯(1.91mL)於DCM(12.9mL)中之冷卻(0℃)溶液中添加三乙基胺(1.13mL),添加甲烷磺醯氯(622μL)。3小時之後,將反應混合物在真空中濃縮成殘餘物,隨後溶解於乙酸乙酯(13mL)中。將不溶解部分濾出,以乙酸乙酯(7mL)洗滌兩次,且將經合併之有機溶液在真空中濃縮成殘餘物(2.77g)。向1.64g殘餘物於無水乙腈(10mL)中之溶液中添加白屈胺酸之二乙酯(Scrimin,P.;Tecilla,P.;Tonellato,U.;Vendrame,T. J. Org. Chem. 1989,54,5988)(1g)及碳酸鉀(2.88g)。回流24h之後,將不溶解部分濾出且以乙酸乙酯洗滌。隨後將有機相在真空中濃縮成殘餘物。將殘餘物藉由使用DCM(A)與MeOH(B)之混合物梯度溶離(梯度:100% A降至97% A:3% B)之矽膠層析法(Merck Super VarioPrep 200g管柱,Si60 15-40μm)純化以產生4-(2-{2-[2-(2-第三丁氧基羧基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二甲酸二乙酯(1.36g):LC/MS(方法A4):ES:m/z 500 (M+H)+
;m/z 522 (M+Na)+
;m/z444(M-C4
H8
+H)+
;RT=4.32min。
實例6:4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸N-羥基丁二醯亞胺酯:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯之程序,以4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸開始來製備4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸N-羥基丁二醯亞胺酯:LC/MS(方法A3):ES:m/z 847 (M+H)+
;m/z 424(M+2H)2+
/2;RT=0.80min;1
H NMR(400MHz,CDCl3
-dl,δPPm):1.75(雙寬峰,J=6.6Hz,6H);2.23(多寬峰,2H);2.76-2.89(多寬峰,6H);2.97(多寬峰,4H);3.91(多寬峰,2H);4.00(單寬峰,6H);4.14(多寬峰,2H);4.27(多寬峰,4H);5.28(多寬峰,4H);5.61(多寬峰,2H);6.87(單寬峰,2H);7.03(單寬峰,2H);7.56(單寬峰,2H);7.65(多寬峰,2H)。
4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸氫氯化物:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸之程序,以4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸甲酯開始來製備4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸氫氯化物:LC/MS(方法A3):ES:m/z 750(M+H)+
;m/z 375,5(M+2H)2
+/2 m/z 332,5(M-C4
H6
O2
+2H)2+
/2;RT=0.73min;1
H NMR(400MHz,CDCl3
-d1,δPPm):δ=1.75(d,J=6.6Hz,6H);2.02(m,2H);2.42(m,2H);2.97(m,4H);3.83-4.14(m,4H);4.00(s,6H);4.27(m,4H);5.20-5.42(m,4H);5.61(m,2H);6.85(s,2H);6.94(s,2H);7.56(s,2H);7.63(m,2H)。
4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸甲酯:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之程序,以4-(2,6-雙-羥基甲基-吡啶-4-基氧基)-丁酸甲酯開始來製備4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸甲酯:LC/MS(方法A4):ES:m/z 764(M+H)+
m/z 664(M-C5
H8
O2
+H)+
m/z 762(M-H)-
RT=3.64min;1H NMR(500MHz,CDCl3
-dl,δ ppm):δ=1.76(d,J=6.8Hz,6H);2.12(m,2H);2.50(t,J=7.3Hz,2H);2.97(m,4H);3.68(s,3H);3.90(m,2H);4.00(s,6H);4.07(多寬峰,2H);4.27(m,4H);5.29(多寬峰,4H);5.61(m,2H);6.86(s,2H);6.99(單寬峰,2H);7.56(s,2H);7.65(d,J=4.4Hz,2H)。
4-(2,6-雙-羥基甲基-吡啶-4-基氧基)-丁酸甲酯:
可根據製備3-(2-{2-[2-(3,5-雙-羥基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯之程序,以4-(2,6-雙-羥基甲基-吡啶-4-基氧基)-丁酸第三丁酯開始來製備4-(2,6-雙-羥基甲基-吡啶-4-基氧基)-丁酸甲酯:LC/MS(方法A3):ES:m/z 256(M+H)+
RT=0.25min。
4-(2,6-雙-羥基甲基-吡啶-4-基氧基)-丁酸第三丁酯:
可根據製備3-(2-{2-[2-(2,6-雙-羥基甲基-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸第三丁酯之程序,以4-(3-第三丁氧基羧基-丙氧基)-吡啶-2,6-二甲酸二乙酯開始來製備4-(2,6-雙-羥基甲基-吡啶-4-基氧基)-丁酸第三丁酯:LC/MS(方法A4):ES:m/z 298(M+H)+
;m/z 156(M-C8
H14
O2
+H)+
RT=2.45min。
4-(3-第三丁氧基羧基-丙氧基)-吡啶-2,6-二甲酸二乙酯:
可根據製備4-(2-{2-[2-(2-第三丁氧基羧基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-吡啶-2,6-二甲酸二乙酯之程序,以4-溴-丁酸第三丁酯開始來製備4-(3-第三丁氧基羧基-丙氧基)-吡啶-2,6-二甲酸二乙酯:LC/MS(方法A4):ES:m/z 382(M+H)+
m/z 404(M+Na)+
m/z 785(2M+Na)+
m/z 240(M-C8
H14
O2
+H)+
RT=4.65min。
實例7:N-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯:
可根據製備4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之程序,以N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯開始來製備N-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯:LC/MS(方法A3):ES:m/z 834(M+H)+
RT=0.87min;1
H NMR(400MHz,CDCl3
-d1,δ PPm):a=1.75(d,J=6.6 Hz,6H);2.54-3.21(m,11H);3.61-4.17(m,6H);3.69(s,3H);3.97(s,6H);4.27(m,4H);5.10-5.21(m,4H);5.61(m,2H);6.82(s,2H);6.91-6.95(m,2H);7.06-7.12(m,1H);7.53(s,2H);7.63(d,J=4.4Hz,2H)。
N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯可如下製備:
向N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-N-甲基-丁二醯胺酸(225mg)於甲醇(1mL)中之冷卻(0℃)溶液中添加2M於己烷(840μL)中之(三甲基矽烷基)重氮甲烷直至持續為黃色。40min之後,添加乙酸乙酯(5mL)及乙酸(50μL),隨後,一分鐘之後添加碳酸氫鈉飽和水溶液直至PH=7。將水相以乙酸乙酯萃取。將經合併之有機層以氯化鈉飽和水溶液洗滌,經硫酸鎂乾燥且在真空中濃縮成殘餘物。將殘餘物藉由使用DCM(A)/MeOH(B)之混合物梯度溶離(梯度:98% A:2% B降至90% A:10% B)之矽膠層析法(Merck SuperVarioFlash 25g管柱,Si60 15-40μm)純化以產生N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯(103mg)。LC/MS(方法A3):ES:m/z 348(M+Na)+
;m/z 326(M+H)+
;m/z 308(M-H2
O+H)+
;RT=0.43min。
N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-N-甲基-丁二醯胺酸可如下製備:
可根據製備N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-丁二醯胺酸之程序,以3,5-雙-羥基甲基-(2-甲基胺基-乙氧基)-苯開始來製備N-[2-(3,5-雙-羥基甲基-苯氧基)-乙基]-N-甲基-丁二醯胺酸:LC/MS(方法A3):ES:m/z 312(M+H)+
;m/z 294(M-H2
O+H)+
;m/z 310(M-H)-
;RT=0.35min。
3,5-雙-羥基甲基-(2-甲基胺基-乙氧基)-苯氫氯化物
向1-(2-(第三丁氧基羧基)-甲基胺基-乙氧基)-3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯(590mg)於二噁烷(4mL)中之溶液中添加4N鹽酸於二噁烷(3.3mL)中之溶液。在室溫下15h之後,將所得固體過濾,以二噁烷洗滌且在真空中乾燥以產生呈白色粉末狀之3,5-雙-羥基甲基-(2-甲基胺基-乙氧基)-苯氫氯化物(240mg)。LC/MS(方法A2):ES:m/z 212(M+H)+
;RT=0.14min。
1-(2-(第三丁氧基羧基)-甲基胺基-乙氧基)-3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯可如下製備:
向1-(2-第三丁氧基羧基胺基-乙氧基)-3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯(270mg)於四氫呋喃(5mL)中之溶液中添加碘甲烷(70μL),且使反應混合物冷卻(0℃)。向該冷卻溶液中添加氫化鈉(68mg)。1小時之後,使溫度溫至室溫。
16小時之後,少量添加THF與水之1:1混合物(2mL),隨後添加檸檬酸直至PH=2。將水相以乙酸乙酯萃取三次。將經合併之有機層以飽和氯化鈉水溶液洗滌,經硫酸鎂乾燥且在真空中濃縮成殘餘物。將殘餘物藉由使用庚烷(A)/乙酸乙酯(B)之混合物梯度溶離(梯度:100%A降至85%A:15% B)之矽膠層析法(Merck SuperVarioFlash 25 g管柱,Si60 15-40μm)純化以產生1-(2-(第三丁氧基羧基)-甲基胺基-乙氧基)-3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯(220mg):LC/MS(方法A2):ES:m/z 562(M+Na)+
;m/z 308(M+H-C5
H8
O2
-OSiC6
H16
)+
;RT=1.50 min。
1-(2-第三丁氧基羧基胺基-乙氧基)-3,5-雙-(第三丁基-二甲基矽烷氧基甲基)-苯可如下製備:
向1-(2-第三丁氧基羧基胺基-乙氧基)-3,5-雙-(羥基甲基)-苯(600mg)於DMF(8mL)中之冷卻(0℃)溶液中添加第三丁基二甲基氯矽烷(913mg)及三乙基胺(936μL)。18小時之後,添加水且將水相以乙酸乙酯萃取兩次。將經合併之有機層以飽和氯化鈉水溶液洗滌,經硫酸鎂乾燥且在真空中濃縮以產生1-(2-第三丁氧基羧基胺基-乙氧基)-3,5-雙-(第三丁基-二甲基-矽烷氧基甲基)-苯(1g):LC/MS(方法A2):ES:m/z 548(M+Na)+;m/z 294(M+H-C5
H8
O2
-OSiC6
H16
)+
;RT=1,45min。
實例8:4-(3,5-雙-[(S)-2-次甲基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-丙酸N-羥基丁二醯亞胺酯,化合物10
化合物2:在0℃下在1h期間向氫化鋰鋁(2.19g,54.8mmol)於無水THF(50mL)中之懸浮液中添加5-溴間苯二甲酸二甲酯(9.98g,36.5mmol)於THF(100mL)中之溶液。完成添加之後,將混合物在室溫下攪拌2h。此時添加150mL THF。使混合物再冷卻至0℃且以飽和NaCl水溶液中止。將白色沈澱物濾出,且將固體進一步以額外THF(100mL)洗滌。將經合併之THF溶液以Na2
SO4
乾燥,過濾且濃縮。以矽膠急驟層析法(95:5CH2
Cl2
/CH3
OH)進一步純化提供呈白色固體狀之2(7.42g,95%)。
化合物3:將化合物2(3.36g,15.5mmol)懸浮於無水CH2
Cl2
(31mL)中。添加TBSC1(5.14g,34.1mmol),繼而添加咪唑(3.16g,46.5mmol)。將混合物在室溫下攪拌1h。將白色沈澱物濾出且將濾液以旋轉蒸發儀濃縮。將所得殘餘物藉由急驟層析法(矽膠,97:3己烷/EtOAc)純化以產生呈無色油狀物之3(6.15g,89%):1
H NMR(400MHz,CDCl3
)δ=0.081(s,12H),0.92(s,18H),4.67(s,4H),7.18(s,1H),7.31(s,2H)。
化合物4:將含有於19mL CH3
CN中之化合物3(4.16g,9.36mmol)、丙烯酸甲酯(1.3mL,14.0mmol)、Pd(OAc)2
(105mg,0.47mmol)、P(鄰甲苯基)3
(285mg,0.94mmol)及Et3
N(9mL)的燒瓶在氬氣氛下加熱至回流歷時16h。冷卻至室溫之後,添加冰水(20mL)。將混合物以EtOAc(3×40mL)萃取。將經合併之有機層以1N HCl、鹽水洗滌,經Na2
SO4
乾燥,且濃縮。將殘餘物以急驟層析法(矽膠,97:3己烷/EtOAc)進一步純化以產生呈無色油狀物之4(3.91g,93%):1
HNMR(400MHz,CDCl3
)δ0.089(s,12H),0.93(s,18H),3.79(s,3H),4.72(s,4H),6.41(d,J=16Hz,1H),7.29(s,1H),7.34(s,2H),7.68(d,J=16Hz,1H)。EIMS m/z 473([M]+
+Na)。
化合物5:將4(2.54g,5.63mmol)與Pd/C(563mg)於55mL EtOAc中之混合物在大氣壓力下經30min氫化。隨後使該溶液通過矽藻土,將固體以額外EtOAc(25mL)洗滌。將經合併之EtOAc溶液濃縮以提供呈無色油狀物之5(2.55g,99+%),其對於下一步驟而言足夠純。1
HNMR(400MHz,CDCl3
)δ=0.067(s,12H),0.91(s,18H),2.60(t,J=8.0Hz,2H),2.92(t,J=8.0Hz,2H),3.65(s,3H),4.68(s,4H),7.00(s,2H),7.12(S,1H).EIMS m/z 475([M]+
+Na)。
化合物6:在0℃下向5(1.48g,3.28mmol)於無水THF(33mL)中之溶液中添加8.2mL TBAF於THF中之1M溶液。在該溫度下攪拌1h之後,將飽和NH4
Cl水溶液(30mL)添加至該混合物中。將混合物以EtOAc(3×40mL)萃取。將經合併之有機層以鹽水洗滌,經Na2
SO4
乾燥,且濃縮。將殘餘物以急驟層析法(矽膠,95:5DCM/CH3
OH)進一步純化產生呈無色油狀物之6(625mg,85%),其在冷凍中靜置之後固化。1
HNMR(400MHz,CDCl3
)δ=2.59(t,J=8.0Hz,2H),2.91(t,J=8.0Hz,2H),3.63(s,3H),4.61(s,4H),7.08(s,2H),7.16(s,1H)。
化合物7:將二醇6(59mg,0.26mmol)溶解於DCM(2.6mL)中。將溶液冷卻至0℃,且以Et3
N(82μL,0.58mmol)及MsCl(46μL,0.58mmol)處理。將混合物在0℃下攪拌30min,且以冰水(2mL)中止。使各層分離且將水層進一步以DCM(3×2mL)萃取。將經合併之DCM層以鹽水洗滌,經Na2
SO4
乾燥,且濃縮。在高真空泵下進一步乾燥提供呈淺黃色油狀物之7,其不經進一步純化即立即用於下一步驟。
化合物8:向PBD單體(165mg,0.64mmol)與7(假定為0.26mmol)於DMF(2.7mL)中之混合物中依次添加K2
CO3
(147mg,1.06mmol)、KI(22mg,0.13mmol)及Bu4
NI(49mg,0.13mmol)。將混合物在氬氣下在室溫下攪拌7h。隨後以高真空將DMF移除。使殘餘物在DCM與水之間分溶,且使各層分離。將水層進一步以DCM(3×3mL)萃取。將經合併之DCM層以鹽水洗滌,乾燥(Na2
SO4
)且濃縮。以矽膠層析法(25:1,CH2
Cl2
/CH3
OH)純化殘餘物提供呈淺黃色玻璃樣固體狀之8(101mg,54%)。EIMS m/z 763([M]+
+Na+2H2
O),745([M]+
+Na+H2
O),727([M]+
+Na)。
化合物9:在室溫下向甲酯8(16mg,0.023mmol)於THF-MeOH-H2
O(3:1:1,0.45mL)中之攪拌溶液中添加1M LiOH水溶液(0.025mL,1.1當量),且藉由TLC監控反應。3.5小時之後,將混合物以H2
O(5mL)稀釋,且以1N HCl將PH值調整至2。隨後將混合物以DCM(3×5mL)萃取。將經合併之DCM層以鹽水洗滌,經Na2
SO4
乾燥且濃縮。藉由矽膠急驟層析法(DCM:MeOH:AcOH=100:4:0.5)進一步純化提供所需酸9(8.2mg,60%brsm),EIMS m/z 749([M]+
+Na+2H2
O),731([M]+
+Na+H2
O),713([M]+
+Na);加上少量(約2mg)甲酯8。
化合物10:向酸9(8.2mg,0.011mmol)於CH2
C12
(1mL)中之溶液中添加聚DCC(38mg,0.059mmol)及N-羥基丁二醯亞胺(NHS)(2.7mg,0.024mmol)。將混合物在室溫下攪拌2h,隨後經由小型矽藻土床過濾,以DCM洗滌,濃縮。將所得殘餘物藉由急驟層析法(DCM:MeOH/100:3)純化以提供所需產物10(7mg,81%)。EIMS m/z 874([M]+
+Na+2MeOH),842([M]+
+Na+MeOH),810([M]+
+Na)。
實例9:(2-{2-[2-(2-{3-[3,5-雙-(7-甲氧基-2-亞甲基-5-側氧基-2,3,5,11a-四氫-1H-苯并[e]吡咯幷[1,2-a][1,4]二氮呯-8-基氧基甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-乙酸N-羥基丁二醯亞胺酯,化合物20
化合物12:將NaOH水溶液(50%,6.9 mL)添加至四乙二醇(68.08g,350 mmol)中。將混合物在室溫下攪拌2小時,繼而添加烯丙基碘(8 mL,87.6 mmol)。再攪拌24h之後,使混合物在H2
O與EtOAc(50/50 mL)之間分溶。將水層進一步以EtOAc(5×30 mL)萃取。將經合併之EtOAc
層經Na2SO4乾燥且濃縮。將殘餘物急驟層析(矽膠,己烷:EtOAc 4:6至0:1)提供呈無色油狀物之12:1
H NMR(400 MHz,CDC13)δ=2.44(brs,1H),3.63-3.71(m,16H),3.99-4.01(m,2H),5.13-5.17(m,1H),5.22-5.27(m,1H),5.84-5.92(m,1H);13
CNMR δ61.8,69.4,70.4,70.59,70.61,70.63,72.2,72.5,117.0,134.8。EIMS m/z 257([M]+
+Na)。
化合物13:在0℃、氬氣下向NaH(89 mg,2.2 mmol)於無水THF(2.5 mL)中之懸浮液中添加12(370 mg,1.58 mmol)於THF(5 mL)中之溶液。將混合物在該溫度下攪拌30 min,隨後在室溫下再攪拌30 min。使混合物再冷卻至0℃,且逐滴添加溴乙酸甲酯(0.29 mL,3.16 mmol)。在0℃下攪拌1h之後,移除冰浴,且繼續在室溫下再攪拌24h。使反應經由矽藻土過濾且將濾液濃縮。將殘餘物以急驟層析法(矽膠,1:1己烷/EtOAc)進一步純化產生呈淡黃色油狀物之13(220 mg):1
H NMR(400 MHz,CDC13
)δ=3.57-3.74(m,19H),3.98-4.0(m,2H),4.26(s,2H),5.15(d,J=10.4Hz,1H),5.24(dd,J=16,1.6Hz,1H),5.84-5.93(m,1H);13
C NMRδ=51.7,68.6,69.4,70.56,70.60,70.62,70.9,72.2,117.0,134.8,170.9。EIMS m/z 329([M]+
+Na)。
化合物14:將含有於30mL CH3
CN中之化合物3(1.30g,2.92mmol)、13(0.986g,3.220mmol)、Pd(OAc)2
(33mg,0.15mmol)、P(鄰甲苯基)3
(89mg,0.29mmol)及Et3
N(2mL)的燒瓶在氬氣氛下加熱至回流歷時12h。冷卻至室溫之後,藉由蒸發移除乙腈,且添加乙酸乙酯(40ml),且使混合物通過矽藻土,以乙酸乙酯沖洗且濃縮。將殘餘物以急驟層析法(矽膠,6:4己烷/EtOAc)進一步純化以產生呈無色油狀物之14(1.02g):1
H NMR(400MHz,CDCl3
)δ=0.076(s,12H),0.92(s,18H),3.61-3.72(m,19H),4.14(s,2H),4.15-4.17(m,2H),4.69(s,4H),6.23-6.28(m,1H),6.57(d,J=16.0Hz,1H),7.16(s,1H),7.19(s,2H);13
C NMRδ=-5.2,14.2,18.4,26.0,51.7,64.9,68.6,69.4,70.57,70.61,70.64,70.7,70.9,71.9,122.8,123.2,125.9,132.8,136.5,141.7,170.9。EIMS m/z 693([M]+
+Na)。
化合物15:將14(0.062g,0.092mmol)與Pd/C(9mg)於2.5mL EtOAc中之混合物在大氣壓力下氫化30min。隨後使該溶液通過矽藻土,將固體以額外EtOAc(10mL)洗滌。將經合併之EtOAc溶液濃縮以提供呈無色油狀物之15,其不經進一步純化即使用。1
H NMR(400 MHz,CDCl3
)δ=0.072(s,12H),0.92(s,18H),1.87-1.89(m,2H),2.64(t,J=8.0Hz,2H),3.43-3.70(m,21H),4.14(s,2H),4.68(s,4H),6.98(s,2H),7.10(s,1H)。EIMS m/z 695([M]+
+Na)。
化合物16:在0℃下向先前步驟之15於無水THF(1.8mL)中之溶液中添加0.23mL TBAF於THF中之1M溶液。在該溫度下攪拌1h之後,將飽和NH4
Cl水溶液(2mL)添加至該混合物中。將混合物以EtOAc(3×5mL)萃取。將經合併之有機層以鹽水洗滌,經Na2
SO4
乾燥,且濃縮。將殘餘物以急驟層析法(矽膠,95:5CH2
Cl2
1CH3
OH)進一步純化產生呈無色油狀物之16(27mg,85%):1
H NMR(400MHz,CDCl3
)δ=1.86-1.89(m,2H),2.66(t,J=8.0Hz,2H),3.40(t,J=6.4Hz,2H),3.50-3.70(m,19H),4.10(s,2H),4.61(s,4H),7.09(s,2H),7.13(s,1H)。EIMS m/z 467([M]+
+Na)。
化合物17:將二醇16(26.8mg,0.06mmol)溶解於DCM(1.2mL)中。將溶液冷卻至0℃,且以Et3
N(18.5μL,0.13mmol)及MsCl(10.3μL,0.13mmol)處理。將混合物在0℃下攪拌30min,且以冰水(2mL)中止。使各層分離且將水層進一步以DCM(3×2mL)萃取。將經合併之DCM層以鹽水洗滌,經Na2
SO4
乾燥,且濃縮。在高真空泵下進一步乾燥提供呈淺黃色油狀物之17,其不經進一步純化即立即用於下一步驟。EIMS m/z 623.1([M]+
+Na)。
化合物18:向PBD單體(40mg,0.15mmol)與先前步驟之17於DMF(1.57mL)中之混合物中依次添加K2
CO3
(25mg,0.18mmol)及KI(10mg,0.06mmol)。將混合物在氬氣下在室溫下攪拌20h。隨後以高真空將DMF移除。使殘餘物在DCM與水之間分溶,且使各層分離。將水層進一步以DCM(3×3mL)萃取。將經合併之DCM層以鹽水洗滌,乾燥(Na2
SO4
)且濃縮。將殘餘物以矽膠層析法(25:1,DCM/CH3
OH)純化提供呈淺黃色玻璃樣固體狀之18。EIMSm/z 1011.5([M]+
+Na+2CH3
OH),979.5([M]+
+Na+CH3
OH),947.5([M]+
+Na)。
化合物19:在室溫下向甲酯18(16mg,0.017mmol)於THF-MeOH-H2
O(3:1:1,0.7mL)中之攪拌溶液中添加1M LiOH水溶液(0.019mL,1.1當量),且藉由TLC(薄層層析)監控反應。5小時之後,將混合物以H2
O(5mL)稀釋,且以1N HCl將PH值調整至2。隨後將混合物以DCM(3×5mL)萃取。將經合併之DCM層以鹽水洗滌,經Na2
SO4
乾燥且濃縮。藉由矽膠急驟層析法(DCM:MeOH:AcOH=100:4:0.5)進一步純化提供所需酸19。EIMS m/z 933.4([M]+
+Na)。
化合物20:向酸19(5.9mg,0.006mmol)於CH2
Cl2
(1.0mL)中之溶液中添加EDC(2mg,0.0097mmol)及NHS(1.0mg,0.0084mmol)。將混合物在室溫下攪拌3h,隨後經由小型矽藻土床過濾,以DCM洗滌且濃縮以提供所需產物10,其不經進一步純化即使用,因為發現該物質在二氧化矽純化之後分解。EIMS m/z 1030.4([M]+
+Na)。
實例10:(3-{2-[2-(2-{3-[3,5-雙-(7-甲氧基-2-亞甲基-5-側氧基-2,3,5,11a-四氫-1H-苯并[e]吡咯幷[1,2-a][1,4]二氮呯-8-基氧基甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-丙酸N-羥基丁二醯亞胺酯,化合物31
化合物21:向四乙二醇(162mL,940mmol)於無水THF(500mL)中之溶液中添加鈉(215mg,9.4mmol)。當鈉溶解時,添加丙烯酸第三丁酯(45mL,310mmol)。將混合物在室溫下攪拌20h且以8mL 1N HCl中和。移除溶劑之後,使殘餘物在鹽水與EtOAc之間分溶。將水層進一步以EtOAc萃取。將經合併之有機層以鹽水洗滌,經Na2
SO4
乾燥,且濃縮。將所得殘餘物藉由矽膠急驟層析法(己烷:乙酸乙酯=4:6)純化,提供所需酯21。1
H NMR(400MHz,CDCl3
)δ=1.41(s,9H),2.34(br. S,1H),2.47(t,J=6.4Hz,2H),3.56-3.71(m,18H)。EIMS m/z 345([M]+
+Na)。
化合物22:將硫酸氫四丁基銨(1.27g,3.75mmol)及NaOH(225mg,5.63mmol)於H2
O(7mL)中之溶液添加至21(1.20g,3.75mmol)與烯丙基溴(0.48mL,5.63mmol)於DCM(14mL)中之混合物中。將兩相系統劇烈攪拌45min。使水層分離且以DCM萃取三次。將經合併之DCM層濃縮。添加Et2
O(15mL)導致溴化四丁基銨沈澱,將其藉由過濾而分離。將濾液以鹽水洗滌,經由Na2
SO4
乾燥,且濃縮。將殘餘物以急驟層析法(矽膠,1:1己烷/EtOAc)進一步純化產生呈無色油狀物之22。1
H NMR(400MHz,CDCl3
)δ=1.42(s,9H),2.47(t,J=6.4Hz,2H),3.56-3.70(m,18H),4.00(m,2H),5.15(dq,J=6.0,1.2Hz,1H),5.25(dq,J=16,1.6Hz,1H),5.84-5.94(m,1H)。EIMS m/z 385.2([M]+
+Na)。
化合物23:將化合物22(478mg,1.32mmol)於三氟乙酸(9mL)中之溶液在室溫下攪拌1.5h,此時所有起始物質均耗盡。在真空下移除TFA且將殘餘物藉助於甲苯進一步乾燥。將粗產物直接用於下一步驟中。1
H NMR(400MHz,CDCl3
)δ=2.60(t,J=6.0Hz,2H),3.56-3.70(m,18H),4.01(d,J=5.6Hz,2H),5.16(dd,J=6.4,1.2Hz,1H),5.25(dd,J=16,1.6Hz,1H),5.84-5.94(m,1H)。EIMS m/z 329.2([M]+
+Na)。
化合物24:將酸23於DMF(6.6mL)中之溶液以Cs2
CO3
(451mg,1.38mmol)及MeI(90μL,1.45mmol)處理。將混合物在室溫下攪拌2h。隨後在高真空下蒸發DMF。將殘餘物懸浮於EtOAc中且濾出固體。濃縮濾液。將殘餘物以急驟層析法(矽膠,97:3己烷/EtOAc)進一步純化產生呈無色油狀物之24。1
H NMR(400MHz,CDCl3
)δ=2.58(t,J=6.4Hz,2H),3.56-3.70(m,18H),4.00(d,J=5.6Hz,2H),5.14(dd,J=6.4,1.2Hz,1H),5.24(dd,J=16,1.6Hz,1H),5.84-5.94(m,1H)。EIMS m/z 343.2([M]+
+Na)。
化合物25:將含有於3mL CH3
CN中之化合物3(0.066g,0.15mmol)、24(0.05g,0.16mmol)、Pd(OAc)2
(1.7mg,0.0074mmol)、P(鄰甲苯基)3
(4.5mg,0.015mmol)及Et3
N(0.1mL)的燒瓶在氬氣氛下加熱至回流歷時8h。冷卻至室溫之後,藉由蒸發移除乙腈,且添加乙酸乙酯(40ml),且使混合物通過矽藻土,以乙酸乙酯沖洗。將經合併之有機層以鹽水洗滌,經硫酸鈉乾燥,且濃縮。將殘餘物以急驟層析法(矽膠,6:4己烷/EtOAc)進一步純化以產生呈無色油狀物之25:1
H NMR(400MHz,CDCl3
)δ=0.076(s,12H),0.92(s,18H),2.57(t,J=6.4Hz,2H),3.57-3.68(m,20H),3.73(t,J=6.4Hz,2H),4.14(d,J=6.0Hz,2H),4.69(s,4H),6.23-6.29(m,1H),6.56(d,J=16.0Hz,1H),7.16(s,2H),7.19(s,1H)。EIMS m/z 707.4([M]+
+Na)。
化合物26:將25(0.216g,0.31mmol)與Pd/C(32mg)於6.3mL EtOAc中之混合物在大氣壓力下氫化30min。隨後使該溶液通過矽藻土,將固體以額外EtOAc(10mL)洗滌。將經合併之EtOAc溶液濃縮以提供呈無色油狀物之26,其不經進一步純化即使用。1
H NMR(400MHz,CDCl3
)δ=0.071(s,12H),0.91(s,18H),1.87(m,2H),2.58(t,J=6.4Hz,2H),2.64(t,2H),3.44(t,J=6.4Hz,2H),3.54-3.67(m,20H),3.72(t,J=6.4Hz,2H),4.68(s,4H),6.98(s,2H),7.10(s,1H)。EIMS m/z 709.4([M]+
+Na)。
化合物27:在0℃下向先前步驟之26於無水THF(3mL)中之溶液中添加0.38mL TBAF於THF中之1M溶液。在該溫度下攪拌1h之後,將飽和NH4
Cl水溶液(2mL)添加至該混合物中。將混合物以EtOAc(3×5mL)萃取。將經合併之有機層以鹽水洗滌,經Na2
SO4
乾燥,且濃縮。將殘餘物以急驟層析法(矽膠,95:5 CH2
Cl2
/CH3
OH)進一步純化產生呈無色油狀物之27。1
H NMR(400MHz,CDCl3
)δ=1.87(m,2H),2.56(t,J=6.4Hz,2H),2.69(t,J=7.2Hz,2H),3.42(t,J=6.4Hz,2H),3.54-3.67(m,20H),3.70(t,J=6.4Hz,2H),4.64(S,4H),7.12(s,2H),7.16(s,1H)。EIMS m/z 481.3([M]+
+Na)。
化合物28:將二醇27(54mg,0.126mmol)溶解於DCM(2.4mL)中。將溶液冷卻至0℃,且以Et3
N(41μL,0.29mmol)及MsCl(23μL,0.29mmol)處理。將混合物在0℃下攪拌30min,且以冰水(2mL)中止。使各層分離且以CH2
Cl2
(3×2mL)進一步萃取水層。將經合併之DCM層以鹽水洗滌,以Na2
SO4
乾燥,且濃縮。在高真空泵下進一步乾燥提供呈淺黃色油狀物之28,其不經進一步純化即立即用於下一步驟。EIMSm/z637.2([M]+
+Na)。
化合物29:向PBD單體(76mg,0.29mmol)與先前步驟之28於DMF(2.9mL)中之混合物中依次添加K2
CO3
(49mg,0.35mmol)及KI(20mg,0.12mmol)。將混合物在氬氣下在室溫下攪拌20h。隨後以高真空將DMF移除。使殘餘物在DCM與水之間分溶,且使各層分離。將水層進一步以DCM(3×3mL)萃取。將經合併之DCM層以鹽水洗滌,乾燥(Na2
SO4
)且濃縮。將殘餘物以矽膠層析法(100:3,DCM/CH3
OH)純化提供呈淺黃色玻璃樣固體狀之29。EIMSm/z 1025.6([M]+
+Na+2CH3
OH),993.5([M]+
+Na+CH3
OH),961.5([M]+
+Na)。
化合物30:在室溫下向甲酯29(11.8mg,0.012mmol)於THF-MeOH-H2
O(3:1:1,0.5mL)中之攪拌溶液中添加1MLiOH水溶液(0.014mL,1.1當量),且藉由TLC監控反應。5h之後,將混合物以AcOH(0.014mmo1)中止且蒸發揮發物。藉由矽膠急驟層析法(DCM:MeOH=95:5)進一步純化提供所需酸30。EIMSm/z947.5([M]+
+Na)。
化合物31:向酸30(4.6mg,0.005mmol)於DCM(1.0mL)中之溶液中添加作為偶合劑之EDC(1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺)(1.4mg,0.0075mmol)及NHS(0.74mg,0.0065mmol)。將混合物在室溫下攪拌隔夜,隨後經由小型矽藻土床過濾,以DCM洗滌且濃縮以提供所需產物31。藉由矽膠急驟層析法(DCM:MeOH=100:3)進一步純化提供所需NHS酯31。EIMS m/z 1022.5([M]+
+Na)。
實例11:huMy9-6-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物
將1.45mL、6.4mg/mL濃度之huMy9-6抗體於含有0.05M磷酸鉀及0.05M氯化鈉之緩衝劑水溶液(pH 8)中之溶液以7.5倍莫耳過量之實例1之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯於二甲基乙醯胺(DMA)中之9.5mM溶液處理,以使得huMY9-6之最終濃度為5mg/mL且DMA於緩衝液中之濃度為20%。將反應混合物在室溫下攪拌195min,經MillexR
-HV 0.45μM(PVDF Durapore Millipore #SLHV013SL)過濾,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(pH 6.5)中平衡之SuperdexTM
200製備級凝膠過濾管柱(HiloadTM
16/60管柱GE# 17-1069-01)上。將含結合抗體之溶離份收集、彙集且經Vivaspin 2(10000 MWCO HY Sartorius #VS02H02)濃縮以產生產物(1.8mL)。使用對於4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯(ε319nm
=9087M-1
cm-1
且ε280nm
=12166M-1
cm-1
)及huMy9-6抗體(ε280nm
=206,539M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子(1.6mg/mL)鍵聯平均2.1個4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基部分。圖4展示實例11之去糖基化huMy9-6-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物(由UV確定具有2.1個藥物/Ab)之MS(質譜)分析。
實例12:huB4-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物
將3.4mL、8mg/mL濃度之huB4抗體於含有0.05M磷酸鉀及0.05M氯化鈉之緩衝劑水溶液(PH8)中之溶液以8倍莫耳過量之實例1之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯於DMA中之11.5mM溶液處理,以使得huB4之最終濃度為5.6mg/mL且DMA於緩衝液中之濃度為20%。將反應混合物在室溫下攪拌3h,經MillexR
-HV 0.45μM(PVDF Durapore Millipore#SLHV013SL)過濾,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(PH6.5)中平衡之SuperdexTM
200製備級凝膠過濾管柱(HiloadTM
16/60管柱GE#17-1069-01)上。將含結合抗體之溶離份收集、彙集且經Vivaspin 15R(10000 MWCO HY Sartorius #VS02H02)濃縮以產生產物(5mL)。使用對於4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯(ε319nm
=9087M-1
cm-1
且ε280nm
=12166M-1
cm-1
)及huB4抗體(ε280nm
=222,960M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子(1.49mg/mL)鍵聯平均4.48個4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基部分。圖5展示實例12之去糖基化huB4-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物(由UV確定具有4.48個D/A)之MS分析。
實例13:hu2H11-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物
將3.45mL、5.1mg/mL濃度之hu2H11(參見WO 2008/010101;由ATCC以登錄號PTA-7662註冊)抗體於含有0.05M磷酸鉀及0.05M氯化鈉之緩衝劑水溶液(PH8)中之溶液以8倍莫耳過量之實例1之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸N-羥基丁二醯亞胺酯於DMA中之10.5mM溶液處理,以使得hu2H11之最終濃度為4.3mg/mL且DMA於緩衝液中之濃度為20%。將反應混合物在室溫下攪拌3h,經MillexR
-HV 0.45μM(PVDFDurapore Millipore #SLHV013SL)過濾,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(pH 6.5)中平衡之SuperdexTM
200製備級凝膠過濾管柱(HiloadTM
16/60管柱GE# 17-1069-01)上。將含結合抗體之溶離份收集、彙集且經Vivaspin 15R(10000 MWCO HY Sartorius #VS02H02)濃縮以產生產物(2.2mL)。使用對於4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯(ε319nm
=9087M-1
cm-1
且ε280nm
=12166M-1
cm-1
)及hu2H11抗體(ε280nm
=208,380M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子(1.55mg/mL)鍵聯平均3.74個4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基部分。圖6展示實例13之去糖基化hu2H11-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物(由UV確定具有3.74個D/A)之MS分析。
實例14:huMy9-6-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物
將8.2mL、7.2mg/mL濃度之huMy9-6抗體於含有0.05M N-(2-羥基乙基)-哌嗪-N'-2-乙烷磺酸(HEPES)、0.05M氯化鈉及2mM乙二胺四乙酸(EDTA)之緩衝劑水溶液(PH8)中之溶液以10倍莫耳過量之實例3之3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羥基丁二醯亞胺酯於DMA中之10.4mM溶液處理,以使得huMY9-6之最終濃度為3mg/mL且DMA於緩衝液中之濃度為20%。將反應混合物在室溫下攪拌3h,經MillexR
-SV 5μM(PVDF Durapore Millipore#SLSV025SL)過濾,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(PH 6.5)中平衡之SuperdexTM
200製備級凝膠過濾管柱(HiloadTM
26/60管柱GE#17-1071-01)上。將含結合抗體之溶離份收集、彙集且經Amicon Ultra-15(Ultracel 10k MilliPore#UFC901024)濃縮以產生產物(7mL)。使用對於3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯(ε319nm
=7566M-1
cm-1
且ε280nm
=7078M-1
cm-1
)及huMY9-6抗體(ε280nm
=206,539M-1
cm-l
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子(3.44mg/mL)鍵聯平均4.80個3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基部分。圖7展示實例14之去糖基化huMy9-6-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物(由UV確定具有4.8個D/A)之MS分析。
實例15:hu2H11-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物
將13.2mL、4.7mg/mL濃度之hu2H11抗體於含有0.05MN-(2-羥基乙基)-哌嗪-N'-2-乙烷磺酸(HEPES)、0.05M氯化鈉及2mM乙二胺四乙酸(EDTA)之緩衝劑水溶液(PH 8)中之溶液以聚乙二醇四氫呋喃甲基醚及10倍莫耳過量之實例3之3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸N-羥基丁二醯亞胺酯於DMA中之10.6mM溶液處理,以使得hu2H11之最終濃度為3mg/mL,聚乙二醇四氫呋喃甲基醚於緩衝液中之濃度為10%且DMA於緩衝液中之濃度為20%。將反應混合物在室溫下攪拌3h,經-SV 5μm(PVDF Durapore MilliPore #SLSV025SL)過濾,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(PH 6.5)中平衡之SuperdexTM
200製備級凝膠過濾管柱(HiloadTM
26/60管柱GE# 17-1071-01)上。將含結合抗體之溶離份收集、彙集且經Amicon Ultra-15(Ultracel 10k Millipore #UFC901024)濃縮以產生產物(3.6mL)。使用對於3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯(ε319nm
=7566M-1
cm-1
且ε280nm
=7078M-1
cm-1
)及hu2H11抗體(ε280nm
=208,380M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子(1.33mg/mL)鍵聯平均4.08個3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基部分。圖8展示實例15之去糖基化hu2H11-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物(由UV確定具有4.08個D/A)之MS分析。
實例16:hu2H11-6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-醯基結合物
將0.95mL、3.2mg/mL濃度之hu2H11抗體於含有0.05M磷酸鉀及0.05M氯化鈉之緩衝劑水溶液(PH8)中之溶液以8倍莫耳過量之實例4之6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸N-羥基丁二醯亞胺酯於DMA中之10.5mM溶液處理,以使得hu2H11之最終濃度為2.5mg/mL且DMA於緩衝液中之濃度為20%。將反應混合物在室溫下攪拌4h,經MillexR
-HV0.45μM(PVDF Durapore Millipore #SLHV013SL)過濾,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(PH6.5)中平衡之SuperdexTM
200製備級凝膠過濾管柱(HiloadTM
16/60管柱GE# 17-1069-01)上。將含結合抗體之溶離份收集、彙集且經Amicon Ultra-4(Ultracel 10k MilliPore #UFC801096)濃縮以產生產物(275μL)。使用對於6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸甲酯(ε319
=13594M-1
cm-1
且ε280
=19416M-1
cm-1
)及hu2H11抗體(ε280nm
=208,380M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子(0.48mg/mL)鍵聯平均1.75個6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-醯基部分。
實例17:IGP-08-NHS儲備溶液製備
將IGP-08-NHS(實例8之化合物10)之溶液新鮮製備成基於787.81之分子量的於DMA中之0.005M儲備液。使用在320nm
下測定之參考消光係數(ε320
=9137 M-1
cm-1
)對該儲備溶液進行分光光度檢定。
實例18:huMy9-6-IGP-08
選擇與CD33抗原結合之huMy9-6抗體用於結合PBD衍生物。將5mg/mL濃度之huMy9-6抗體於含有0.05M N-(2-羥基乙基)-哌嗪-N'-2-乙烷磺酸(HEPES)及2mM乙二胺四乙酸(EDTA)之緩衝劑水溶液(PH8)中之溶液以6倍莫耳過量之IGP-08-NHS(實例8之化合物10)於DMA中之溶液處理,以使得DMA於緩衝液中之最終濃度為20%。將反應混合物在室溫下攪拌120min,且隨後裝載於先前已於含有0.01M檸檬酸鈉、0.135M氯化鈉之緩衝劑水溶液(PH5.5)中平衡之Sephadex G25凝膠過濾管柱(HiPrepTM
26/10脫鹽管柱GE#17-5087-01)上。將含結合抗體之溶離份收集且彙集以產生產物。將所彙集之樣品針對相同溶離緩衝液(0.01M檸檬酸鈉、0.135M氯化鈉,PH5.5)透析隔夜以進一步純化該產物。使用對於實例8之化合物8(ε320
=9137 M-1
cm-1
且ε280
=7743 M-1
cm-1
)及huMy9-6抗體(ε280nm
=206,460 M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子鍵聯平均4.5個PBD分子(實例8之化合物9)。圖9展示實例18之去糖基化huMy9-6-IGP08(藥物/抗體=4.2)之質譜分析。
實例19:huB4-IGP-08
選擇與優先在人類淋巴瘤細胞表面上表現之CD19抗原結合之Hu-抗-B4抗體用於結合PBD衍生物。將8mg/mL濃度之huB4抗體於含有0.05M磷酸鉀、0.05M氯化鈉及2mM乙二胺四乙酸(EDTA)之緩衝劑水溶液(PH7.1)中之溶液以5倍莫耳過量之IGP-08-NHS(實例8之化合物10)於二甲基乙醯胺(DMA)中之溶液處理,以使得DMA於緩衝液中之最終濃度為20%。將反應混合物在室溫下攪拌70min,且隨後裝載於先前已於含有0.010M磷酸鹽、0.140M氯化鈉之緩衝劑水溶液(pH 6.5)中平衡之Sephadex G25凝膠過濾管柱(NAPTM
管柱,GE#17-0852-02)上。將含結合抗體之溶離份收集且彙集以產生產物。將所彙集之樣品針對相同溶離緩衝液(0.010M磷酸鹽、0.140M氯化鈉,pH 6.5)透析隔夜以進一步純化該產物。使用對於實例8之化合物8(ε320
=9137M-1
cm-1
且ε28
0=7743M-1
cm-1
)及huB4抗體(ε280nm
=222,960M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子鍵聯平均3.1個PBD分子(實例8之化合物9)。圖12展示實例19之去糖基化huB4-IGP08之MS分析。
實例20:IGP-13-NHS儲備溶液製備
將IGP-13-NHS(實例10之化合物31)之溶液新鮮製備成基於1022.1之分子量的於DMA中之0.0062M儲備液。使用在320nm下測定之參考消光係數(ε320
=9137M-1
cm-1
)對儲備溶液進行分光光度檢定。
實例21:hu2H11-IGP-13
選擇與EPCAM抗原結合之Hu2H11抗體用於結合PBD衍生物。將5mg/mL濃度之hu2H11抗體於含有0.05MN-(2-羥基乙基)-哌嗪-N'-2-乙烷磺酸(HEPES)及2mM乙二胺四乙酸(EDTA)之緩衝劑水溶液(pH 8)中之溶液以8倍莫耳過量之IGP-13-NHS(實例10之化合物31)於DMA中之溶液處理,以使得DMA於緩衝液中之最終濃度為15%。將反應混合物在室溫下攪拌120min,且隨後裝載於先前已於含有0.01M檸檬酸鈉、0.135M氯化鈉之緩衝劑水溶液(pH 5.5)中平衡之Sephadex G25凝膠過濾管柱(HiPrepTM
26/10脫鹽管柱GE#17-5087-01)上。將含結合抗體之溶離份收集且彙集以產生產物。將所彙集之樣品針對相同溶離緩衝液(0.01M檸檬酸鈉、0.135M氯化鈉,PH 5.5)透析隔夜以進一步純化該產物。使用對於實例10之化合物29(ε320
=9137M-1
cm-1
且ε280
=7743M-1
cm-1
)及hu2H11抗體(ε280nm
=215,525M-1
cm-1
)所確定之消光係數對最終結合物進行分光光度檢定。每個抗體分子鍵聯平均4.7個PBD分子(實例10之化合物31)。圖15展示實例21之去糖基化hu2H11-IGP-13(由UV確定具有4.7個D/A)之MS分析。
實例22:結合檢定
使用基於螢光之檢定測定抗B4抗體及其茅屋黴素結合物對抗原表現Ramos細胞之相對結合親和力。將起始濃度為1×10-7
M之抗體-茅屋黴素結合物及裸抗體添加至96孔圓底培養板中且使用3倍連續稀釋液滴定以使得每一濃度存在雙份。將Ramos細胞以每孔50,000個細胞添加至含有各種濃度抗體或結合物之各孔以及對照孔中。將培養板在冰上培育3小時。培育期之後,洗滌培養板中之細胞,且添加與人源化IgG(如抗B4)結合之螢光標記二級抗體,且將培養板在冰上培育1小時。培育期之後再次洗滌該等培養板,且將細胞以1%甲醛/PBS溶液固定。使用BectonDickinson FACSCalibur螢光分析器讀取培養板各孔中之螢光值。將資料作為在抗體或結合物之最高濃度下所獲得之最大螢光值的百分率來繪圖。圖10展示實例18之huMY9-6抗體及huMY9-6-IGP08結合物與CD33抗原之結合。圖14展示實例19之hu-B4抗體及huB4-IGP08結合物之結合。
實例23:茅屋黴素衍生物或茅屋黴素衍生物結合物之活體外效能及特異性(生存力檢定)
欲使用之一般方案
將無茅屋黴素衍生物或茅屋黴素衍生物結合物之樣品添加至96孔平底組織培養板中,且使用介於1×10-12
M至3×10-7
M範圍內之連續稀釋液滴定。將抗原陽性腫瘤細胞或抗原陰性腫瘤細胞以一定方式添加至各孔中以使每一細胞株之每一藥物濃度存在三份重複樣品。將該等培養板在37℃下在5% CO2
氣氛中培育4日。
在培育期結束時,將20μl四唑鎓試劑WST-8(2-(2-甲氧基-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺基苯基)-2-四唑鎓,單鈉鹽)添加至各孔中,且將培養板放回恆溫箱歷時2小時。隨後使用Molecular Devices板讀取器在450nm下量測該等培養板各孔中之吸光度。繪製茅屋黴素衍生物或結合物之每一濃度下的細胞存活分率。
測試化合物之細胞毒性及其相對於本發明之結合物針對MOLT-4、BJAB、HL60/QC、HL60/ATCC及Ramos細胞株之特異性。結果如圖1、2、3、11、13、19、20、21及23中所說明。圖1展示實例1之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之活體外效能測定曲線。圖2展示實例2之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸甲酯之活體外效能測定曲線。圖3展示實例8之化合物8(IGP08)及9(IGP08-OMe)之活體外效能測定曲線,其展示酯IGP08-OMe與酸IGP08相比具有較高效能。圖11展示My9-6-IGP08對HL60/QC(Ag+)及Ramos(Ag-)細胞之細胞毒性資料。圖13展示huB4-IGP08(3.1個D/A)相對於BJAB(Ag+)、RamoS(Ag+)及MOLT-4(Ag-)細胞之細胞毒性資料。圖19展示實例7之N-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯之活體外細胞毒性資料。圖20展示實例11之huMy9-6-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物對HL60/ATCC(Ag+)及Ramos(Ag-)細胞之活體外細胞毒性資料。圖21展示實例12之huB4-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物對Ramos(Ag+)及MOLT-4(Ag-)細胞之活體外細胞毒性資料。圖23展示實例14之huMy9-6-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物對HL60/ATCC(Ag+)及Ramos(Ag-)細胞之活體外細胞毒性資料。
實例24:細胞菌落檢定
欲使用之一般程序
將MDA-MB-231細胞以每孔3000個細胞塗敷於兩個獨立6孔培養板中;將PC-3及SK-MEL-28以每孔2000個細胞塗敷於2個獨立培養板中。添加測試物以使各培養板產生每孔0、5×10-13
、5×10-12
、5×10-11
、5×10-10
及5×10-9
M之最終濃度(或類似劑量範圍)。舉例而言,當塗敷1ml細胞時,則將1ml 2倍濃度之測試化合物或結合物添加至適當孔中以產生於2m1中之最終所需濃度。在與細胞株相同之培養基中製備測試物之最終溶液;因此對於每種不同細胞株而言必須製備不同之結合物稀釋液。將該等培養板置於37℃下5%CO2
中之恆溫箱中。監控細胞生長,且當"0"(對照)孔中之細胞形成菌落但未長滿(對於該等細胞株而言通常為7日)時,將上清液藉由吸出而移除。將細胞以PBS(磷酸鹽緩衝液)洗滌一次且將上清液吸出。向各孔中每孔添加0.5ml 0.1%結晶紫/10%福馬林(formalin)/PBS。使該等培養板在室溫下培育10-15分鐘。將上清液吸出且將該等孔以蒸餾水洗滌3次且隨後風乾。對各孔中之菌落進行計數,且各加料孔中之菌落數目除以"0"孔中之菌落數目以得到存活分率。隨後由該等資料計算IC50
值。
實例中所揭示之化合物及結合物分子展示<1PM與10000PM之間的IC50
值(各細胞株之特定值參見所包括之圖及表I)。圖16展示具有增加藥物負載之hu2H11-IGP13對PC-3(Ag+)、MDA-MB-231(Ag+)及SK-MEL-28(Ag-)細胞株之活體外細胞毒性資料。圖17展示實例5之3-(2-{2-[2-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯之活體外細胞毒性資料。圖18展示實例6之4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸甲酯之活體外細胞毒性資料。圖22展示實例13之hu2H11-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物對MDA-MB-231(Ag+)、PC-3(Ag+)及SK-MEL-28(Ag-)細胞之活體外細胞毒性資料。圖24展示實例15之hu2H11-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物對MDA-MB-231(Ag+)、PC-3(Ag+)及SK-MEL-28(Ag-)細胞之活體外細胞毒性資料。
圖1:實例1之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸甲酯之活體外細胞毒性;
圖2:實例2之4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸甲酯之活體外細胞毒性;
圖3:實例8之化合物8(IGP08)及9(IGP08-OMe)之活體外細胞毒性效能;
圖4表示實例11之去糖基化huMy9-6-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物(由UV確定具有2.1個藥物/Ab,亦即如由UV所確定每1個抗體具有2.1個茅屋黴素衍生物)之質譜分析;
圖5:實例12之去糖基化huB4-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物(由UV確定具有4.48個藥物/Ab)之質譜分析;
圖6:實例13之去糖基化hu2H11-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物(由UV確定具有3,74個藥物/Ab)之MS分析;
圖7:實例14之huMy9-6-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物(由UV確定具有4.8個藥物/Ab)之MS分析;
圖8:實例15之hu2H11-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物(由UV確定具有4.08個藥物/Ab)之MS分析;
圖9:去糖基化huB4-IGP08(實例18之化合物)之MS分析;
圖10:裸huMy9-6及huMy9-6-IGP08(實例18之化合物)與抗原CD33之比較結合特性;
圖11:huB4-IGP08(實例18之化合物)抗Ramos(Ag-)及HL60/QC(Ag+)細胞之活體外細胞毒性效能;
圖12:實例19之去糖基化huB4-IGP08(由UV確定3.1個藥物/Ab)之MS分析;
圖13:huB4-IGP08(實例19之化合物)抗BJAB(Ag+)、RamoS(Ag+)及MOLT-4(Ag-)細胞之細胞毒性特性;
圖14:裸huB4及huB4-IGP08(實例19之化合物)之比較結合特性;
圖15:實例21之去糖基化hu2H11-IGP13(由UV確定具有4.7個藥物/Ab)之MS分析;
圖16:hu2H11-IGP13(實例21之化合物)針對PC3(Ag+)、MDA-MB-231(Ag+)及SK-MEL-28(Ag-)細胞之細胞毒性特性;
圖17:實例5之3-(2-{2-[2-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸甲酯之細胞毒性特性;
圖18:實例6之4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸甲酯之細胞毒性特性;
圖19:實例7之N-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙基]-N-甲基-丁二醯胺酸甲酯之細胞毒性特性;
圖20:實例11之huMy9-6-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物之活體外細胞毒性資料;
圖21:實例12之huB4-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物之活體外細胞毒性資料;
圖22:實例13之hu2H11-4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁醯基結合物之活體外細胞毒性資料;
圖23:實例14之huMy9-6-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物之活體外細胞毒性資料;
圖24:實例15之hu2H11-3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙醯基結合物之活體外細胞毒性資料。
(無元件符號說明)
Claims (31)
- 一種式(I)化合物,
- 如請求項1之化合物,其中W及W'為相同或不同的且為-OH、-OMe、-OEt、-NHCONH2 、-SMe。
- 如請求項1或2之化合物,其具有下式(II):
- 如請求項1之化合物,其為下式:
- 2及4中任一項之化合物,其中A=A'。
- 2及4中任一項之化合物,其中A=A'=直鏈未經取代之烷基。
- 2及4中任一項之化合物,其中Y=Y'。
- 2及4中任一項之化合物,其中Y=Y'=O烷基。
- 2及4中任一項之化合物,其中Y=Y'=OMe。
- 2及4中任一項之化合物,其中n=n'=1。
- 2及4中任一項之化合物,其中B=B'==CH2 或=CH-CH3 。
- 如請求項1之化合物,其中T為苯基或吡啶基。
- 2及4中任一項之化合物,其中Z'為單鍵或O。
- 2及4中任一項之化合物,其中Z'為O。
- 2及4中任一項之化合物,其中R"為H或直鏈或支鏈-烷基-或經取代或未經取代之雜環。
- 2及4中任一項之化合物,其中R"為H或烷基 或丁二醯亞胺基團。
- 2及4中任一項之化合物,其中-Z'R"為 -OH、-O烷基或。
- 2及4中任一項之化合物,其中該連接子係選自:‧-(CR13 R14 )t (CR15 R16 )u (OCH2 CH2 )y COZ'R";‧-(CR13 R14 )t (OCH2 CH2 )y O(CR15 R16 )u COZ'R";‧-O(CR13 R14 )t (CR15 R16 )u (OCH2 CH2 )y COZ'R";‧-O(CR13 R14 )t (NR19 CO)(CR15 R16 )u (OCH2 CH2 )y COZ'R";‧-(C≡C)-(CR13 R14 )t (CR15 R16 )u (OCH2 CH2 )y COZ'R";‧-O(CR13 R14 )t COZ'R";‧-(OCH2 CH2 )y COZ'R";‧-(C≡C)-(CR13 R14 )t COZ'R";‧-O(CR13 R14 )t (NR19 CO)(CR15 R16 )u COZ'R";‧-(CR13 R14 )t (OCH2 CH2 )y COZ'R"。
- 一種化合物,其係選自由以下各物組成之群:‧4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-丁酸;‧4-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙酸;‧3-(2-{2-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基 氧基甲基]-苯氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;‧6-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-己-5-炔酸;‧3-(2-{2-[2-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-乙氧基]-乙氧基}-乙氧基)-丙酸;‧4-(2,6-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-吡啶-4-基氧基)-丁酸;‧N-[2-(3,5-雙-[(S)-2-(E)-亞乙基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯氧基)-乙基]-N-甲基-丁二醯胺酸;‧4-(3,5-雙-[(S)-2-次甲基-7-甲氧基-1,2,3,11a-四氫-吡咯幷[2,1c][1,4]苯并二氮呯-5-酮-8-基氧基甲基]-苯基)-丙酸;‧(2-{2-[2-(2-{3-[3,5-雙-(7-甲氧基-2-亞甲基-5-側氧基-2,3,5,11a-四氫-1H-苯并[e]吡咯幷[1,2-a][1,4]二氮呯-8-基氧基甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-乙酸;‧(3-{2-[2-(2-{3-[3,5-雙-(7-甲氧基-2-亞甲基-5-側氧基-2,3,5,11a-四氫-1H-苯并[e]吡咯幷[1,2-a][1,4]二氮呯-8-基氧基甲基)-苯基]-丙氧基}-乙氧基)乙氧基]-乙氧基}-乙氧基)-丙酸; 以及相應N-羥基丁二醯亞胺酯,或其醫藥學上可接受之鹽,或其外消旋體。
- 一種化合物,其選自下列之群:
- 一種結合物分子,其包含一或多個如請求項1至20中任一項之化合物,其與未經修飾或經修飾之細胞結合劑經由該連接子化學鍵聯。
- 一種結合物分子,其包含一或多個如請求項1至20中任一項之與細胞結合劑共價鍵聯之化合物,其中該共價鍵聯係經由該化合物之連接子的鍵聯基團而達成。
- 如請求項21或22之結合物分子,其中該細胞結合劑係選自抗體或含有至少一個結合位點之抗體片段、淋巴激素、激素、生長因子、營養輸送分子或任何其他細胞結合分子或物質。
- 如請求項21或22之結合物分子,其中該細胞結合劑係選自單株抗體;嵌合抗體;人源化抗體;全人類抗體;單鏈抗體;抗體片段;干擾素;肽;淋巴激素;激素、TRH(促甲狀腺素釋放激素)、MSH(促黑素細胞激素)、類固醇激素;生長因子及集落刺激因子;維生素。
- 如請求項21或22之結合物分子,其中細胞結合劑與該(等)化合物係經由醯胺基鍵聯。
- 一種製備結合物分子之方法,其包含以下步驟:其中使如請求項1至20中任一項之化合物(其中該連接子包含末端羧基,該羧基係視情況經活化為醯胺基或其前驅體)與細胞結合劑反應以使得該化合物與該細胞結合劑經由醯胺鍵鍵聯在一起。
- 如請求項26之方法,其中該細胞結合劑係抗體或單株抗體。
- 如請求項27之方法,其中該結合物係藉由尺寸排阻法、吸附層析法、離子交換法、疏水性相互作用層析法、親和層析法、HPLC、羥基磷灰石層析法、透析或透濾法純化。
- 一種醫藥組合物,其包含如請求項21至25中任一項之結合物分子或如請求項1至20中任一項之化合物以及醫藥學上可接受之載劑。
- 2、4、19及20中任一項之化合物,其係用於治療癌症之方法中。
- 如請求項21或22之結合物分子,其係用於治療癌症之方法中。
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