TW211572B - - Google Patents
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- TW211572B TW211572B TW080105996A TW80105996A TW211572B TW 211572 B TW211572 B TW 211572B TW 080105996 A TW080105996 A TW 080105996A TW 80105996 A TW80105996 A TW 80105996A TW 211572 B TW211572 B TW 211572B
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- 239000003814 drug Substances 0.000 claims abstract description 20
- 229940079593 drug Drugs 0.000 claims abstract description 19
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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Description
A6 ___B6 五、發明说明(1 ) 本發明偽有關具有治療價值之葸環素與載劑例如多株及 單株抗體或天然或合成來源之蛋白質或肽所生成之共铌接 合物;其製法,含有此等共軛接合物之藥物組成物,及其 用於治療某些晡乳動物腫瘤之用法。本發明也關於新穎 葸環素衍生物及其製備。 近年來曽經合成多種具有高度細胞毒性之Μ環素。舉例 言之,攜帶喁啉環或取代嗎啉環連結於糖部分之C-3’位置 者,對實驗性鼠腫瘤顯示可能具有抗腫瘤活性[參見:生 物活性分子,55-101 , v〇l. 6,J ' Wi 11 iam Lown编輯, E 1 ve i ser 1988]。 本發明像、有關從生物活性劑中釋放出治療有效藥物之新 穎連結劑俾改善藥物之治療功效及當投予人體時減少其毒 性作用者。恃定言之,生物活性劑包括帶有游離一級或二 级羥基之藥物且屬於治療類別,例如抗生素,抗腫瘤或抗 病毒化合物,與載劑例如與特選的細胞族群具有反鼴性的 抗體接合,或與受器組織具有反應性之天然或合成來源之 蛋白質肽或聚合物接合。 經濟部中央搮準局印裝 {請先閱讀背面之注意事頊再填"本頁) 至少含一一级或二級羥基之各種藥物與載劑經由連結.臂 共價接合;且經由於其一级或二级羥基位置的酸敏感性縮 醛鍵與該連結臂結合。本發明之生物活性劑之酸敏感性縮 醛鍵,允許於標的組織的外在或内在酸性環境中,釋放出 活性藥物。 如此,本發明提供通式1之共铌接合物: [A-0-W-Z]a-T 1 甲 4(210X 297公沒) 4 A6 B6 五、發明說明(2 式中A-Ο-部分為式Α-0-Η藥物之殘基,其中-0-H為一級或 二级羥基;a為1至30之整數;W為通式2之基:
〇-(CHa)te-c(0) {請先閱讀背面之注意事項再填寫本頁) λ 式中b為1至4之整數,Β代表q -C3次烷基而1^及R2各自獨 立代表氫,鹵基,烷基,苯基或取代苯基;Z為間隔基及T 為載劑部分。 較好a為1至5。B適合代表-(Cr2)2-。1^及1?2之定義中, 鹵基典型地為氨,溴或碘而烷基可為q-c4者如甲基或乙 基。取代苯基可為鹵基-或烷基-取代之苯基,而該情況下 鹵基及烷基可如前述。較佳Z基為: (i ) -NH-; (i〖)-NH-(CH2)e-S-S式中C為1至4之整數; (iii) -NH-[C]d-M=CH-式中: a ) d 為 0 , “(3為1而[(:]代表-關-(:0((:112)6-0-((^2、-,式中 e為2至4之整數, c)d為 1 至 4之整數而[C]代表-(CH2)f -0- (CH2 )f -, 式中f為1或2 ,或 (1)(1為2至6之整數而[(:]為(^2; 烴濟部中央搮準局印裝 (iv) -NH-[C]d_NH-C0-式中[C]及 d 定義如上; (v) -[D]-NH-,式中[D]代表-NH-[CH2]g-C0-,其中g為 2 至6之整數; 甲 4 (210X297 公沒) 5 ·'< ,ί· 2
A B 五、發明説明(3) (vi) -[E]-CO-,其中[E]代表-NH-(CH2)g-NH-,其中 g 為 2至6之整數;或 CHa-CH2 (vii) 如下式之_肼羰基部分:^N-CO- ch2-ch2 如上式i中,藥物A-0-H較好代表屬於葸環素類別之抗腫 瘤劑,例如刀削茹必辛(doxorubicin),其3’-去胺基-3’-嗎啉基衍生物,其中嗎啉環於位置2"任意取代以烷氧基如 (^-(:4烷氣基;嘧啶類似物例如 氟去氣尿核苷或阿拉伯 糖呋喃糖基胞嘧啶(cytarabine),長春花生物鹼衍生物例 如4-去乙醛基乙烯基blast ine ;或其他抗腫瘤劑例如 podophyllotoxin或 illudines。另外,藥物- Α- 0- Η可為抗 病毒劑,例如:Γ-叠氮-3’-去氣胸腺核苷(AZT),溴乙烯基 去氧尿核苷(BVDU) , 9-[(2-羥乙氧基)甲基]鳥糞嘌昤 (acyclovir),或9-[ (1,3-二羥-2-丙氣基)甲基]鳥糞嘌昤 (gancyclovir);或抗生素,如thienamycin或吾等新穎之 配念(penen)衍生物,例如(5R, 6S)-2-胺甲酵氧甲基-6-[ (1R)-羥乙基]-2-配念-3-羧酸,及乙酷氣甲基(5R, 6S) - 2 -胺甲醛氣甲基-6-[(lR)-羥乙基]-2-配念-3-羧酸酯。 當A-Ο-部分衍生自葸環素Α-0-Η時,典型地A-Ο部分代表 {請先聞讀背面之注意事項再填寫本頁) •装· 經 濟 部 中 央 標 準 局 印 甲 4 (210X297 公发) 6 2ilbV2 A6 B6 五、發明説明(4 )
0.
式中R1()為氫原子或羥基或甲氧塞,
及R 中之一者為 11 一!2 氫原子而另一者為羥基;或為氫原子或碘原子而Ri2為 氫原子,及r13為胺基或代表含括於嗎琳環内之—氮原子 。嗎琳環例如為嗎琳(M0),· 3-氣基-4-嗎琳(CM)或2 -甲氣 基-4-噶啉(MM)環,其中氮原子連結於Cy者如下: ό
(CM)
0U 一請先Μ讀背面之注意事項#Λ寫本11) • ΜΑ (MM) (Μ0) 載劑部分T典型地選自多株抗髏或其H斷,其中包括一 抗原結合址而可與腫瘤相關抗原結合者;單株抗體或其Η 斷,其中包括一抗原結合址而可與偏好或選擇性地表現於 腫瘤細胞族群上之抗原結合者;偏好或選擇性地與腫瘤細 胞結合之肽或蛋白質;及聚合物載劑。 m劑部坌較好為衍生自下述物質之載劑部分,該物質可 甲 4 (210X297 公沒) 7 五、發明说明(5 ) Α6 Β6 經 濟 部 中 央 揉 準 局 印 製 表示為τ-[νη2]χ,式中X代表可供縮合用之胺基數目,載 劑部分可選自對鼷瘤相關抗原提引出之多株抗體;或選自 可與偏好或選擇性地於腫瘤細胞族群上表現的抗原結合之 單株抗體;或選自镐好或選擇性地與腫瘤細胞結合之天然 或重組肽或蛋白質或生長因子;或選自天然或合成聚合物 載劑例如聚離胺酸。載劑部分也可衍生自前述載劑之一部 分,例如抗體之Fab或p(ab*)2&,或衍生自經由重組DNA 技術所得的前述肽或蛋白質之一部分。 前述抗體及各別可能之治療用途之代表例有: -抗-T-細胞抗體,例如抗體TIOURoyston, I. et a丨,J. Immunol . .1980, 125, 725] -抗-CD5 抗體,如抗體 0KTl(0rtho)ATCC CRL8000 (慢性淋 巴細胞白血病) -抗轉移素(trasferrin )受器抗體,例如抗體0 K T9 ( 0 r t h 〇 ) ATCC CRL 8021(卵巢及其他腫瘤) -抗黑素瘤抗體,如抗體MAb 9.2.27(Bu«ol, T.P.立t立1., Proc. Natl. Acad. Sci. USA 1982,11, 1245)(黑素瘤) -抗癌瘤標記標體,如: -抗-CEA 1116 NS-3d ATCC CRL 8019 -抗α-胎蛋白〇M 3-1.1 ATCC HB134(亦名肝腫瘤) -791T/36 [Erab 1 eton , M.J. e_t_ 旦1.,Br . J . Cancer 1981 , _43., 5 82](亦名骨原性肉瘤) -B 72.3[US-A-4, 522, 918(1. 985)](結腸直腸癌及其他 腫瘤) (請先閏讀背面之注意事項再填寫本頁) _裝· •訂· •線· 甲 4(210X297公沒) 8 2ίΙ〇1^ Α6 Β6 五、發明説明(6 ) 經 濟 中 央 揉 準 局 印 裝 -抗卵巢癌抗體,如抗體OVB 3 ATCC ΗΒ9147 _抗乳癌抗體,如抗體(HMGP抗原)[Aboud-Pirak, E. e t a 1. . Cancer Res, 1988, 48, 3188] -抗膀胱癌抗髏,如抗體1G3. 10[Yu, D.S. Eur. J. Urol. 1987 , U_t 198] 〇 前述天然或重組來源之生長因子及蛋白質之代表例有 PGF, EGP, PDGF, TGF-ct, a-MS,介白素(interleukines ),干擾素,TNF,促黑色素檄素(MSH)等。 衍生自一種均質之載劑部分可以T-[SH]xl代表之,式中 Η代表可供縮合用之氫硫基數目,此載劑部分較好衍生自 使用下列各者所得之氫硫基化多株或單株抗體:例如H-丁 二醯亞胺基-S-乙醸基硫代乙酸酯(SATA), N-丁二醛亞胺 基-3-(2-吡啶硫基)丙酸酯(5卩〇{>),0几-高半胱胺酸硫代 内酯,H-乙酵基-D,L-高半胱胺酸硫代内_或2-亞胺硫代 内酯。 衍生自T-[CH0]x2代表之物質之載劑部分(式中x2代表可 供縮合用之甲醸基總數)較好衍生自具有硝水化合物部分 之多株或單株抗體,此碩水化合物部分較好位在Pc區,藉 化學或晦催方法被選擇性氧化成醛基,如USA-4,671,958 所述。載劑T-[CHO]x2也可衍生自甲醒基化反應或衍生自 適當聚合物載劑之氧化反應,或衍生自適當糖蛋白之磺水 化合物殘基氣化成醛基。 衍生自由T- [C00H]x3代表之物質之載劑部分(式中χ3代 表可供縮合之羧基總數)較好衍生自聚天冬酸或聚麩胺酸 {請先閱讀背面之注意事項再填蔣本页) .装. •訂· .線. 甲 4(210X297 公发) 9 211^^ A6 B6 五、發明説明(7 ) ,或衍生自可溶性及生物可降解性合成共聚物,例如衍生 自具有如下結構式之N-(2-羥丙基)甲代丙烯醍胺(HMPA)
(請先聞頊背面之注意事項再填寫本頁) 經濟部中央揉準局印製 [X] : -Gly-Phe-Leu-Gly; -HN-(CHa)„-c〇-; η 爲 1 至 5· [P] : CH, 0-CeH4pN02 x/y (90/10 95/5 mol/mol %); MW 10000-40000, 較好12000-20000 [參見:J. Kopecek,"生物醫學用之聚 合物之生物降解”於IUPAC巨分子H. Benoit & P.Renpp, Ed. :505-520(1982)Pergamon Press.牛津,英國] 或衍生自聚(胺基酸)共聚物,例如聚(GluNa, Ala, Tyr) 或Mw 25000-50000道爾頓,其可用作肺組織之標的藥物載 劑(參見下文)[R* 〇unca n等人,參見生物活性及相容性 聚合物期刊,第4期,1刪年7月];或衍生自天然存在於 單株或多株抗體上之羧基,或經由使用雙官能酐(例如馬 來酐)處理抗髏而藉化學方式引進的羧基。 聚(GluNa,Ala, Ty「)共聚物之結構式 .¾. _線· 中 4(210X297 公沒) 1〇 211^^ A6 B6 五、發明說明(g)
NIH THai 1 ^^—^1 Η Η
CH
··丨C丨CH-^^^-0H (請先M讀背面之注意事項再填寫本頁) 本發明又提供一種製備式1共軛接合物之方法,該方法 包括:令式3衍生物
A-0-W-0H (式中A-Ο-及W定義如上)與為或可提供所述式1共轭接合物 中之所述間隔基Z及載劑部分T者之物質縮合,藉此生成式 1接合物。縮合反應可經由活化衍生物進行,例如式&衍生 物之混合酐,昼氮化物或活化酯;或經由於縮合劑如二環 己基甲二醻亞胺共存之下直接反應。一種適當方法包括將 式3衍生物轉成式4活化衍生物 土
0 - W - L 經 中 央 揉 準 局 印 裝 式中A-Ο-及W定義如上及L代表可産生酵胺鍵聯之活化基如 N-氧丁二醸亞胺基,其水溶性衍生物氧硫基丁二酵亞胺 基或2,4 -二硝基苯氧基,2,3,4,5,6 -五氟苯氧基或三级丁 氧羰氧基;及 (i ’)將所得式立化合物與式T- [HH2]X物質(定義如前)縮 11 甲 4(210X297 公沒) 211 A6 B6 五、發明説明(9 ) 合而得具有醒胺鍵聯之式1生物活性劑;或 (ί i ’)令式1化合物與式HH2 - (CH2)e -SH硫醇衍生物(如其 中C = 2之2-胺基乙烷硫醇)縮合,及將所得式5化合物: A-0-W-NH-(CH2)c-SH 立 (式中A-Ο-, W及C定義如上)與如前所定義之式T-[SH]xl物 質縮合而得具有雙硫鍵聯之式1共軛接合物;或 — . (i i i *)令式1化合物與肼,丁二酸或己二酸二醯肼衍生 物或二胺化合物反應,及令所得式&化合物: A-0-W-HH- [C] d -NH2 6 ^ (式中A-Ο-, W, [C]及d定義如上),與如前所定義之式T-[CH0]x2物質縮合而得具有肟鍵聯之式1生物活性劑。 一種有用方法(iv)包括令如上所定義之通式兰化合物與 式了物質縮合: T-[CO-L']y 7 (其偽衍生自涉及如前所定義之式T-[C00H]x3載劑之反應 ,及其中Y為1至30之整數且代表活化羧基總數,T為所生 成之式1共軛接合物中之載劑部分,及1^代表可産生醯胺 鍵聯之羥基或活化基),非必要地於縮合劑共存之下縮合 而得式J_共軛接合物,其中未反應的非必要存在的活化羧 基,可使用藥物可接受性胺如1-胺-2-丙醇淬熄。 其他有用的方法包括(v ’)令式生化合物與式H2N-[CH2 ]g 經 濟 -C00H胺基衍生物(式中g定義如上)縮合,藉此生成式8衍 部 — t 生物 採 準 A-0-W-[D]-0H 8 局 一 印 裂 甲 4(210X 297公沒) 12 (請先閲讀背面之注意事項再填寫本頁) •襄· •打· .線· 經濟部中央揉準局印¾‘ A6 B6 五、發明説明(10) (式中A-0-,W及[D]定義如上)非必要地將式!化合物轉成 式&活化衍生物: A-0-W- [D]-L 2 (式中A-0-, W, [D]及L定義如上),及令所生成之式$化合 物或式&化合物於縮合劑共存之下,與如前所定義之式T-[HH2]X物質縮合而得式1生物活性劑。 其他方法包括(vi 1令式4化合物與式H2N - (CH2 )g-HH2衍 生物(式中g定義如上)反應,藉此生成式U衍生物 A-0-W- [E]-H 10 ' (式中[E]定義如上)或 (vl i ')令式4化合物與_肼反而生成式11衍生物 — — A - 0 - W - [ _ W ] - Η 11 及令式1 或式化合物(如前述)與如前述之式叉物質縮合 而得式i共軛接合物。 舉例言之,將式2或§_化合物轉成衍生物i或色之活化方法 包括令式立或立化合物與N-羥丁二醭亞胺或其水溶性3-取代 磺酸銷鹽,於N,Ν’-二環己基甲二醯亞胺共存之下,於溶 劑如乙酸乙酯或Ν,Ν-二甲基甲醯胺内反應。此種情況下式 i及立中L代表殘基:
式中R a代表氫原子或硫酸納基 甲4(210X 297公沒) 13 (請先閲讀背面之注意事項再填寫本頁)
經濟部中央橾準局印裝 A6 B6 五、發明説明(iJj 將T-[COOH]以型載劑轉成通式7化合物之活化方法包括 ,令此種載劑與對-硝基酚於N , N 二環己基甲二醛亞胺共 存之下,於溶劑如二甲基甲酷胺内反應,該種情況下L*代 表pN02 C6H5-0-;或與N-乙氧羧基-2-乙氧基-1,2-二氫輥 (EEDQ )[參見:B. Bel leau y , JACS, Μ 1651 (1968) ]於溶劑例如四氫呋喃或二甲基甲醛胺内反應,該種情況 下式J中之L,代表殘基:
另一程序包括令載劑Τ- [cooh]x3之鹼鹽如納鹽與院基-鹵基-磺酸酯如((:厂^)烷基-齒基-磺酸酯,較好乙基氣磺 酸酯(c2h5o-coc見)於溶劑如水或二甲基甲醒胺内反應。 該種情況下,式2中之殘基L ·代表-C00C2 H5。 製備式1共轭接合物之縮合反應,始於式互或兰衍生物及 式Τ-[ΗΗ2]χ載劑,偽於可産生醯胺型共價鍵聯且可與載劑 之結構式相容的條件下進行。依據載劑於含水或有機溶劑 内之化學安定性而定,可採用不同程序進行與通式m 及11中間物之偶合反應。又於對有機溶劑敏感之載劑 ,較佳條件包括使用於PH7-9.5之緩衝水溶液,溫度4-37 υ經歷數小時至數日。 經由令衍生物5與式-T- [SH] xl載劑縮合而製備式上共鈪 接合物之方法,倍(於下述條件下進行:包括使用 甲 4(210X297公发) 14 {請先聞讀背面之注意事項再填寫本百) .¾. -線· 211〇^ A6 B6 經濟部中央揉準局印裂 五、發明説明(12) 緩衝水溶液,溫度4它經歴數小時至數日。 經由令衍生物6與式T-[CH0]x2載劑縮合而製備式j_共軛 接合物之方法傜於下述條件下進行:該條件可産生肟類或 腙類共價鍵聯且可與載劑之結構式相容。較佳條件包括使 用PH4-7.5之缓衝水溶液,溫度4-371:經歴數小時至數日。 經由令衍生物6, 10或11與式T-[C〇-Li]y載劑编合而製 備式丄共軛接合物之方法偽於可産生醛胺類型共價鍵聯且 可與載劑結構式相容的條件下進行。較佳條件包括使用pH 7-9.5之緩衝水溶液,溫度4-37ΤΓ經歴數小時至數日。 其他條件包括使用乾二甲亞璀或二甲基甲醗胺於室溫經 歴1至3小時。 本文中,期間”數小時至數日”可由4小時至5日。 舉例言之,式i及立化合物與抗體T-[NH2]X進行縮合反應 之適當條件有:含lmg/mil單株抗體於PH8之0.1M磷酸納水 液及0.1M氛化納水液,使用30倍莫耳過量之10% w/q或i 於N , N -二甲基甲_胺之溶液於20 t:處理24小時。共铌接合 産物藉凝膠過濾於西法第斯G-25柱(Pharmacia Fine Cheai cal,紐澤西州,匹Η卡威市)純化,以PBS (磷酸鹽缓 衝鹽水)溶離。 式i化合物與撝帶氫硫基之官能化抗體間之偶合反應之 適當條件為:含lmg/nJl單株抗體於pH6之0.1M乙酸銷水液 及0.1 Μ氨化鈉水液,使用30倍莫耳過量之5% 於相同 缓衝液之溶液,於4Ό處理24小時。共軛接合物如前述藉 凝膠過濾純化。 {請先閱讀背面之注意事項再填寫本頁) .¾. •訂· •綠· 甲 4(21〇X 297W沒) 15 A6 B6 五、發明説明(13) 式6化合物與型T- [CHO] ^載劑間之偶合反應用之適當條 件為:含1»8/|«見單株抗體之於PH6-7之0.1M乙酸納水液 及0.1M氯化納水液,使用30倍莫耳過量之5« w/v之6於相 同缓衝液之溶液,於20Ϊ:處理24小時。共軛接合物俗如前 述葙凝膠過濾純化。 式iϋ及II之化合物與式活化載劑間之縮合反應之適 當條件為:含5至5〇Bg/B儿化合物上,12或ϋ之無水極性溶 劑如二甲基甲醯胺,使用等當量化合物2於20t:處理1至24 小時。 ^ 通式2化合物及式A, U及U之活化化合物為 新穎,因此屬於本發明之範圍。 化合物立,上,U及皆為有用中間物及/或治療活性 劑。特別,通式2之中間物可用作如前述之通式Α-0-Η化合 物之原體。式1化合物可藉圖1所例示說明之方法製備。此 法包括令式Α-0-Η藥物與攜帶有經遮蔽的羧基之適當稀醇 醚衍生物,如式ϋ者縮合: (請先閱讀背面之注意事項再填寫本頁)
(式中B, b, 義如前,及R3代表保護基,如甲基 或乙基);及由所生成之化合物中去除保護基。 反應圖1 16 甲 4 (210X297 公沒) ,ii〇l
A6 B6
-> A-O^C^O-(CH2)bCOOH «XrR* 12 2 並非限制本發明之範圍,抗匯瘤的M環素代表可供製造通 式丄生物活性衍生物之適當羥基化藥物(A-OH )。於葸環素 類別中,以通式(13)之3’-去胺基-3·-嗎啉基衍生物如3*_ 去胺基-3’-(4-嗎啉基)刀削茹必辛(13a)或3’-去胺基-3 (2-甲氣-4-噍啉基)刀削茹必辛(13b)為上選化合物[黎見 :E.M. Acton等人;嗎淋基替環素,見於生物活性分子, Vol 6. Edt. by J.W. Lown, Elsevier, 1988] 一請先M讀卄面之注意事項再填寫本页) .装·
«4
.線. A-OH = 13a; R‘=〇H, R/H A-OH = 13b: R,〇H, R,^0^3 A-0- = 13a’ ; R-.=〇-/ R»=H — A-0- = 13b* : R*=〇-» R»=〇CH3 部 央 橾 準 局 印 裂 式13a, b恵環素轉成如前所定義之通式之新穎酸敏感 性衍生物,可經由以式化合物(如前示例說明其中“為 甲 4(210X 297公沒) 17 ^1x0 i A6 B6 五、發明説明(15) 例如乙基之殘基)處理而進行,式21化合物偽如J. A · Landgrebe等人於 J. Org. Chem ,1244(1975)所述, 經由令攜帶酮基之適當化合物與重氮乙酸乙酯反應而製備 。進行Μ環素及其他具有一级及二级羥基之北合物與化合 物12之反應之較佳條件包括使用磺酸觸媒如對-甲苯磺酸 或樟腦磺酸,於極性溶劑如二甲基甲酵胺内,於室溫經歷 數小時至1日。於式3化合物中,與慈環素連結的酸感敏部 分之,經遮蔽的羧基被轉成通式±化合物之活化羰基,由 此式立化合物經由與適當載劑偶合而製備新穎生物活性劑 。非必要地,通式1之葸璟素衍‘物可被轉成通式互,色,8 ,!,U及11之衍生物且舆適當載劑反應而製成通式1新穎 生物活性劑。治療有效藥物例如前述者,也可與通式12化 合物以對葸環素所述之相同方式反應,及轉成可供治療某 些哺乳動物疾病用之生物活性劑。 本發明之式1生物活性劑為有用治療劑,歸因於其含有 縮醛鍵,此鍵當進行氫陽離子晦催水解或”活體試驗"晦催 裂解時,可放出親代藥物Α-ΟΗ。舉例言之,眾所周知,惡 性腫瘤之糖分解速率比正常組織更高。如此使得乳酸鹽産 量增加,因而使得腫瘤之pH下降[參見H.M. Rauen et al., Z. Naturforsch, Teil B, 23 (1968) 1461 ]〇 經濟部中央標準局印裝 (請先閱讀背面之注意事項再填寫本頁) 依所述方法生成的共轭接合物可遵照不同的化學物理方 法予以特徵化。舉例言之,藉層析凝膠過濾程序(Yu . D . S. et al . , J. Urol . 1_40 , 4 1 5,1988)評估原始分子量 之保有及不會生成聚集體,同時且獨立於不同波長檢測Μ 環素及抗體,以及藉凝_電泳法評估。所得化合物之總電 荷分佈偽藉凝膠離子交換法評估。Μ環素濃度偽經由分光 甲 4(210X297 公沒) 18 經濟部中央標準局印裴 “, A6 _______ B6 五、發明說明(16) 光度滴定法,相對於得自親代Μ環素之標準校準曲線進行 評估。蛋白質濃度僳藉比色法 ,如 bicinconic acid檢定 法(Sdth, P.K· et al .,Anal . Biochem, 150, 76, 1985)或 Bradford染料法(Bradford, M.M.,Anal.
Biochee. 72^, 248, 1976)評估。共轭接合程序之後,抗 體之抗原結合活性的保有情形愾藉EL IS A方法(Yu. D.S, et a 1 . , J . Urol. 140, 41 5,1983 )及細胞氟計量法 (Qallego, J. et al., Int. J. Cancer, 33, 737, ! 1984)進行評估。共軛接合物之涵胞毒性之保有情形與親 代藥物進行比較評估,像利用培育一段時間足夠獲得最大 細胞毒性功效之後,對3 H-胸腺核苷被標的細胞攝取之抑 制作用進行試驗(Dill ma.nn·,R.O. et al.,Cancer Res, 丑,6097, 1988)。 共軛接合物對抗原陽性細胞条比起對抗原陰性細胞条之 選擇性細胞毒性之評估方法,偽經簡短時間培育後,利用 抗原陽性細胞条相對於抗原陰性細胞条對3 H-胸腺核苷攝 取之抑制作用進行試驗(Dillmann,R.O. et al.,
Cancer Res. 48,6096,1988)。 共轭接合物之酸敏感度像經由化合物於適當缓衝液内培 育後,藉前述層析方法評估。 另外,共軛接合物於抗體部分(125 I)及/或於葸環素部 分(U C)進行放射性標幟及HPLC分析法,可用於評估血漿 安定性。 生物活性 甲 4(210X 297公沒) 19 (請先閱讀背面之注意事項再填寫本頁) •装. •線· A6 B6 經濟部中央揉準局印装 五、發明説明(JJ) 化合物立•(於實施例1製備)於試管試驗中對LoVo (人結腸 腺癌)及LoVo-Doxo抗性(LoVo/DX)細胞進行試驗;及與刀 削茹必辛及3’-去胺基-3’-[2-(S)_甲氧-4-嗎啉基]刀削茹 必辛(11^)經4小時處理後,使用單一細胞塗布技術(菌落 檢定法)進行比較。從濃度-反鼴曲線算出50X抑制濃度 uc5())。表1之資料顯示化合物立’對敏感性及抗性細胞条 比較刀削茹必辛更具細胞毒性,但比親代化合物13b之細 胞毒性低15-2P倍。 化合物3’於活體試驗用於帶有ί>388-刀削茹必辛-抗性白 血病(P388/DX Johnson)之CDP-1小鼠進行試驗,且與刀削 茹必辛及化合物比較。表2報告資料顯示匯瘤接種後第 1日,以0.22mg/kg腹腔投予化合物:Γ,極為具有活性(TC% 184)。 式丄,,i_”,_LV,J_vi及丄vii之共辆接合物(分別於實施 例5, 6,9, 11及12中製備),其中細胞毒性藥物3’·去胺基 -3 ’ [2 (S)-甲氧-4-嗎啉基]刀削節必辛之殘基經由酸敏感 性連結劑連結者,僳於活體試驗中對P388/DX Johnson白 血球進行試驗,且與刀削茹必辛及游離藥物11^比較。表3 報告資料顯示於腫瘤接種後第1日,靜脈投予所有新穎化 合物,皆能維持等於游離藥物0之活性。以LD 50_100與最 適劑量之比表示的治療指數,於有所共轭接合物皆比游離 藥物1 3 b更高。 表4報告於37 於pH3 (乙酵鹽缓衝液)由共铌接合物中釋 放出3匕去胺-3 · [2(S)-甲氧-4-嗎啉基]刀削茹必辛(13b)。 {請先聞讀背面之注意事項再填寫本頁) .¾.. •訂. •線· 审4(210乂 297公角) 20 11〇7 <· A6 B6 五、發明説明(18) 表1 :處理4小時後之細胞毒性 IC5〇 = ng/ajld) 化合物 Lo Vo LoVo/DX R. I.(2) ID 5〇 (n g / n 見) ID5〇 (ng/mA.) 刀削茹必辛 60 2 1 8 0 36.3 13b 16 33 2 3, 240 745 3 IC5〇 = R . I.= =可抑制50%菌落生長之濃度 =抗性指數=(IC5〇 L〇V〇/DXH(IC50 LoVo) (請先聞讀背面之注意事項再填寫本页) 表2:對P388/DX Johnson白血病之抗腫瘤活性,於第1日 經腹腔注射處理 化合物 劑量 、τ/c⑶ 毒性 (mg /kg ) % 死亡 刀_ M必辛 10 100 0/10 15 100 0/10 22 100 10/10 13b 0.1 136 0/10 0.125 155 1/10 3 , 0.22 184 0/10 (3)中間存活時間 ;相對於未處理對照之% (4)基於死亡小鼠進行屍體解剖的發現進行評估 經濟部中央橾準局印裝 甲 4(210X297 公发) 21 經濟部中央標準局印裂
2i.iiVV J A6 B6 五、發明說明(19) 表3 :對P388/DX Johnson白血病之抗腫瘤活性,於第1曰 經靜脈注射處理 化合物 劑量⑸ τ/c (3) 毒性( (ng /kg ) % 死亡 刀削茹必辛 16.9 105 0/10 22 100 3/10 13b 0.076 177 0/28 0.091 192 0/39 1, 0.16 1414 0/10 0.25ΐ 175 0/20 0.5 167 0/10 1,, 0.16 、 156 0/10 0.25 含 200 0/10 0.5 133 0/10 lv 0.25 111 0/10 0.5 144 0/10 1 1 20 5 0/20 1.25 200 0/10 lvi 0.66 172 0/10 1 1 194 0/10 1 vii 0.661 233 0/10 1 177 0/10 (請先閱讀背面之注意事項再填寫本頁) •装· •訂· •線. 甲 4(210X 297公沒) 22 1 最適劑量 (5)劑量(ng/kg):以共軛接合物中之13b含量表示 11^' A6 B6 五、發明説明(20) 表4:於PH5及溫度37它於乙酸鹽缓衝液1 2中從共軛接合 物中釋放出Ilk 化合物 t (6) 50% (hours) Γ 24 lvi 22 1 vii 20 jviii 3 (請先閱讀计面之注意事項再填寫本頁) •装. •線. 經 濟 央 揉 準 局 印 甲 4(210X297公沒) 23 1 釋放出50%游離藥物m所需時間。使用化合物13b之校 準曲線,藉HPLC測定。 2
離子強度0.05M 化合物之治療功效,及其治療功效之改良與親代進行比 較,傺於人移植腫瘤之動物模式中進行評估。帶有人腫瘤 之異體移植片的裸鼠使用適當劑量之共轭接合物,游離藥 物、抗體、及藥物與抗體之物理混合物,以相當劑量進行 處理;且記錄腫瘤生長,及與不同處理組間進行比較。 共軛接合物與藥物可接受性載劑或稀釋劑調配出藥物組 成物。可使用任一種適當之載劑或稀釋劑。適當載劑及稀 釋劑含生理鹽溶液及林格氏葡萄糖溶液。 下列各實施例例示說明本發明而絶非限制其範圍。 實施例1 A6 B6 五、發明説明(21) 14-0-(1-羧甲氣-環己基)-3’-去胺_3'-[2(S)-甲氣-4- (請先閱讀背面之注意事項再瑱寫本頁) 嗎啉基]刀削茹必辛之製備[2’ ; A-0- = 13b',b = 1 , B = -(CH2)2-» Ri=R2=H]
如英國申請案第8928654.6號所述製備之3'-去胺-3’-[2 (S)-甲氧-4-嗎啉基]刀削茹必辛(11^) ( 〇.68g, lmrnole )溶 解於無水二甲基甲酵胺(20mJl )内,且使用2-(環己烯-1-基)氣基乙酸乙酯[y;b=l, R3=C2H5, B=-(CH2)2-, R 1:= r2=: H] (6g , 32 mm〇ie)於熔融對-甲苯磺酸(50呢)共存 之下進行處理。温合物於室溫攪拌2小時,隨後倒入硝酸 氫納水液内且以亞甲基氣抽取。有機相以水洗滌,以無水 硫酸銷乾燥及過濾。減壓去除溶劑及殘渣於閃蒸矽酸柱上 層析,使用亞甲基氣/甲醇之混合物(98/2體積比)作溶離 条統而得標題化合物立’之酯衍生物(R3 = C2H5) 此衍生物於0¾藉攪拌,且於氮共存之下,使用〇.IN氫 甲 4(210X297公沒) 24 Α6 Β6 五、發明説明(22) 氧化銷水液(200iail )處理1小時。随後以乙酸將混合物調 整為PH8.2及以正-丁醇抽取。有機相以水洗,減歷濃縮成 小體積及於矽酸柱上層析,使用亞甲基氣/甲醇之混合物 (80/20體積比)作溶離条統而得標題化合物(0.35g,産 率43%)呈游離酸衍生物,此衍生物以相當量之鹽酸水液處 理及凍晶乾燥。 於基索膠板(Merck) P 254進行TLC,溶離条統亞甲基氣/ 甲醇(95/5 體積比),R2=0.13 MS-FD: n/e 783 (M+)。 ^NMR (200 MHz, DMSO d.) &: 1.12 (d, J=6.4Hz, 3H, £Η,-5'); 1.3-1.9 (», 12H, , CTa-2*) 2.0-2.7 (m, 7H, CHa-8, 0-CHaCH2-N, 0-CH-CHa-N, H-3'); 2.94 (S, 2H, CH2-l〇); 3.24 (s, 3H, CH-0CH3) ; 3.40, 3.73 (two m, 2H, NCH2CHaO); 3.57 (m, 1H, H-4'); 3.91 (s, 2H, 〇ai2COOH); 3.97 (s, 3H, OCH3-4); 4.04 (dq, J=6.4, 1.0Hz, 1H, H-5'); 4.35 (dd; J=2.2, 5.2Hz, 1H, OCH-OCH,); 4.61 (s, 2H, CH2-14); 4.92 (m, 1H, H-7); 5.24 (m,' 1H, H-l'); 7.6-7.9 (m, 3H, H-l, H-2, H-3); 13.20 (bs, 1H, OH-H); 14.02 [s, 1H, OH-6). {請先聞讀背面之注意事項再填寫本页) 經 濟 部 中 央 揉 準 局 印 裂 實施例2 14-0-(1-羧甲氣-環己基)-3’-去胺-3’[2(5)-甲氣-4-嗎啉 基]刀削Μ必辛之N -氧基丁二醯亞胺基衍生物之製備[4 ’ ;—ΓΓη. A-0-= 13b b 1, B = - (CH2 ) 2 R, .線· 肀 4(210X297公发) 25 fj Α6 Β6 五、發明説明(公3)
(請先閱讀背面之注意事項再填寫本頁) -裝· 如例1所述製備之化合物3’(0.2g,0.25 mmole )溶解於無 水二甲基甲醯胺(810見)内,於冷卻及以N-羥丁二酷亞 胺(0.2g)及二環己基甲二醯亞胺(〇*4g)處理。混合物於〇 Ό維持2小時,然後於室溫放置隔夜。隨後,混合物經搣 壓濃縮成小體積及於閃蒸矽酸柱上層析,以亞甲基氣,甲 醇(97/3體積比)混合物作溶離条統。含標題化合物之溶離 分經減壓濃縮至乾,然後殘渣攝取於乙酸乙酯内,過據及 減壓濃縮成小體積。最後加入乙醚及於燒結玻璃漏斗上收案 標題化合物4’(0.130ε:),以乙醚洗滌及儲存於氮下。 經 濟 部 中 央 準 局 印 裝 於基索膠板(Merck) Ρ254進行TLC ,溶離条統亞甲基氛/ 甲醇(95/5 體積 l;b)Rf=〇.37 MS-FD: ai/e 864(Μ+)。 實施例3 14-0-(1-阱羰基甲氣-環己基)_3·-去胺[2 (S)-甲氧-4-^ 甲 4(210X297 公沒) 26 211^'^ A6 --- 五、發明説明(24) 啉基]刀削茹必辛之製備[6*,A-0-= ^ _(CH2)2_» 紀]_ =尺2=忖,C=〇]
(請先聞請背面之注意事項再瑱珥本頁) .¾. .打· 如實施例2所製備之化合物土 *(2〇»g)溶解於四氫肤喃 (5nJl )内及添加肼水合物於異丙醇之1M溶液。混合物於 Οΐ!維持70分鐘。隨後加入亞甲基氯及混合物以冷水洗3次 。分離有機層以無水硫酸納乾燥,過濾及真空去除溶劑。 殘渣於矽酸柱上層析,使用亞甲基氮/甲醇之混合物(99/1 體積比)作溶離条統。以乙醚沈澱化合物且J,20职。 於基索膠板(Merck) F 254上進行TLC,溶離条統亞甲基氛/ 甲醇(95/5 體積比)Rf=0.25 MS-FD: m/e 797(M + )。 aNKR (200 MHz, DMSO d.) 6: 1.36 (d, J=6.6Hz, 3H, CH3-5'); 1.4-1.7 (m, l〇H, ); 1.76 (m, 2H, CHa-2'); 2.30 (m, 2H, Oi2-8); 2.50 (in, lH, H-3'); 經 濟 部 t 央 抹 準 局 印 裝 甲 4(210X297公发) 27 A6 B6 五、發明説明(25) 2.55 (m, 4H, N-CH2-CH(0CH3), N-CHa-CH2-0); 2.98 (df J=18.8Hz, 1H, H-lOax); 3.22 (dd, J=1.0, 18.8Hz, 1H, H-lOe); 3.39 (s, 3H, CH(〇gj3)); 3.55, 3.95 (two m, 2H, NCHa^aO); 3.70 (m, iH, H-4'); 3.95 (m, 1H, H-5*); 4.09 (ε, 3H, ^3-0-4); 4.10 (m,2H, 0-CH2C0NH); 4.50 (in, 1H# NCH2-CH(OCH3)) ; 4.67 (sf 2H, CH2-14); 5.28 (m, 1H, H-7); 5.54 (m, 1H, H-1M; 7.64 (bs, 1H, C〇if^NH2); 7.78 (t, J=7.9Hz, 1H, H·2); 8.04 (d, J=7.9Hz, 1H, H-l); 13.32 (s, 1H, OH-11); 13.98 (s, 1H, OH-6). 實施例4 14-0-[l- (4-羧-1-正-丁基)胺甲醯基甲氧-I—環己基)]一3 ’ -去胺-3 ’-[2 (S)-甲氧-4-嗎啉基]刀削茹必辛之製備U ·, A-〇- = 13b’,b=l,B=-(CH2)2-,8=4] ^co-nh^c^-cooh 經濟部中央標準局印裝
8· v -胺丁酸(15wg * 0*15 mmole )溶解於0.05M隣酸鹽缓衝被 f>H7.6 (2 > 5m JI )内及添加如例2製備之化合物4 ’(30mg , 28 {請先閱讀背面之注意事項再填寫本頁) 甲 4(210X 297公沒)
A6 B6 五、發明説明(2β) (請先«I讀背面之注意事項再填寫本頁) 0.033 mmole)溶解於乙睛(3π«儿)。混合物於室溫維持隔夜, 然後於乙酸調整至ΡΗ6,及以正-丁酵抽取。分離有機層及 真空蒸發。殘渣於矽酸柱上層析,使用亞甲基氣/甲醇混 合物(95/5體積比)作溶離系統而得20»g標題化合物。 於基索膠板(Merck) F 254進行TLC,溶離条統亞甲基氨/甲 醇(95/1 體積比)Rf=0.55 MS-PD: */e 884(M + )。 實施例5 式1’之聚麩胺酸-共軛接合物之製備[1’: A-0-=13b’, — — b=l, B=-(CH2)2-, Ι^ = Ι?2=Η: Z=-NH-NH-C0_, a=2 ,T=聚-L-麩胺酸] .線. 聚-L-麩胺酸,分子量2000-15000 (Sigma) (85mg )及如例 3製備之化合物立’(20«g )溶解於二甲基甲醒胺(2m儿)及攢 拌3小時。隨後加入N-乙氧羰基-2-乙氧-1,2-二氫輥(25ng )。混合物經攪拌隔夜,然後倒入乙醚及石油醚之混合物 内。於燒結玻璃過濾器上收集沈澱,以乙醚洗滌及以2.5% 碳酸氫納水溶液(8«见)溶解。溶液通過反相柱1^-8,40-63w n(Me「ck)(3〇x 1.3cn),及以水及乙睛之混合物由0至 20¾乙腈溶離。含共軛接合物之溶離分經凍晶乾燥,然後 收集於燒結玻璃過濾器上,以甲醇及乙醚洗滌而得標題化 合物l’(45mg)。藉光譜評估得知共軛接合物含有13%式13b 之甲氧螞啉基。 經濟部中央橾準局印裂 實施例6 式1”之聚(GluHa,Ala, Tyr)-共铌接合物之製備: A-0-= 13b' , b = 1, B= - (CH2) 2-,R工=R2= Η,Z = 甲 4(210X297 公沒) 29 A6 _B6__ 五、發明説明(2了) -NH-NH-CO-, a=2, T=聚(GluNa, Ala, Tyr)] 遵照例5所述之相同程序,聚(GluHa, Ala, Tyr)(l: 1 :1), Mv25000-50000 (SigBa)(60ng)及如例 3 所述製備之 化合物旦’(20呢)溶解於二甲基甲酵胺(2m儿)内,攪拌3小 時及以N-乙氧羰基-2-乙氣-1,2-二氫喹啉(25»g )處理,及 反相柱純化後獲得35呢標題化合物。 實施例7 式1_’ "之抗黑素瘤共痴接合物之製備 [j_,”: A-0-= 13b,,b=l, B=r-(CH2)2-, R1=R2=H, Z= -NH-, T= Epl ] 10_2M之例2所述化合物4 ’於N,H-二甲基甲醯胺(37.5acl) — 經濟部中央橾準局印裝 {請先聞請卄面之注意事項再填寫本頁) 之溶液,於室溫藉攪拌缓慢'加入lmJl 2«g /bJI純小鼠單株 抗-人黑素瘤抗體 E p 1 [G ί acorn i n i , Ρ. et al., Int. J. Cancer·义 729(1978)]於0.1M NaH2P〇4, 0.1M NaCA , pH8之溶液内。反慝混合物於室溫暗處攪拌隔夜及離心。 於西法雷斯-G25柱(PD-10, Pharmacia)上藉凝膠過濾層析 分離共軛接合物,以PBSUibco, 10X, Gat. H. 042-04200M)pH7.3溶離。收集排它峰及於480nm藉分 光光度分析法檢定Μ環素含量。蛋白質含量偽使用比色化 學分析(BCA, Pierce)檢定。共軛接合物含有1.27wg/B.(l 抗體,而Μ環素/蛋白質比為11.4/1.0。産物之化學物理 /¾ 像藉HPLC-凝膠過濾分析(BioSil SEC-250柱,0.1M NaH2P04, 0.1M NaCJl, pH7.0)使用雙重波長檢定法(280 及480nm)及藉SDS-PAGE測定。藉HPLC測得50%蛋白質聚集 甲 4(210X 297 公沒) 30 經濟部中央標準局印製 A6 B6 五、發明説明(28) 體生成,以柱空隙體積溶離。 藉SDS-PAGE得知Μ環素吸收反應及庫馬西染料蛋白質反 慝位在160KD分子量,證實生成共價鍵且指示由於非共價 交互作用生成聚集體。 實施例8 式iiV之抗-結腸癌共軛接合物之製備 [j_iv : A - 0 - = 13b ' , b= 1 , B= - (CH2)2-, R! = R2 = Η , Z= -NH-NH- , T= B72.3] B72.3抗體(US-A- 4,522,918)以 2./nil 於 0.1 M MaH2P04, pH6缓衝液(lB.d)之溶液,於於暗處使用0.1 bJI 0.1M NaI04於水之溶液處理。1小時後,産物藉凝嘐 過濾層析純化,此層析偽於西法雷斯G25柱(PD-10 Pharnacia)上進行,使用0.1M NaH2P04缓衝液,pH6溶離。 含蛋白質之溶離分(1.7ng,2mJl )以30莫耳當量之10% w/v如例3所述之化合物於相同缓衝液之溶液處理。於37 它於暗處經24小時後,反應混合物如例7所述純化。 共拥接合物含有〇.48»g/mJl抗髏而Μ環素/蛋白質之比、 為2.4/1且為85¾:單體形式。 實施例9 3-甲代丙烯酵基胺基-2-羥丙烷與14-0-{1-[4-(h-甲代丙 烯醒基甘胺醇基苯丙胺醯基白胺醯基甘胺酵基)肋:基]-欺 基甲氣-環己基}-3^ -去胺-3’[2(S) -甲氧-4 -嗎淋基]刀削 茹必辛(j_v )之共聚物之製備 (請先閱讀背面之注意事項再填寫本页) •裝· 甲 4(210X297 公发) 31 五、發明説明(29; [lv: A-Q-=13b,· b=l, B=-(CHa) T=HPMA X=Gly-Phe-Leu-Gly].
CHa—C 一 I CO NH I caos ca.-<
rr S*fu co NH •CB(au) A6 B6
Rx=Ra==H f Z= CH#»C —f° •CO~ t
Im *h I *r f r r
CBOUr CBca» cof- f8*r r CB,I caca cb, C.B. ca(ca,
Jt (請先閱讀背面之注意事項再填寫本頁) 故· •訂· •綠· 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)甲4規格(210x297公釐)32 A6 B6 五、發明説3月(3〇) 0.58g共聚物 HPMA【X=Gly-Phe-I*ue-GlY, 4.2%(.B〇l/molX)之 P=0C6H4pN0 2含量](如《J.Kopeceketal.,MakroBol, Chen. 177 , 2833-2848 (1976)所述,經由3-甲代丙烯酵胺 基-2-羥丙烷及N-甲代丙烯醛基甘胺醸基苯丙胺醒基白胺 酵基甘胺酸之4-硝苯酯進行基團聚合反應而製備)與如例3 所述製備之衍生物l(〇.lg)共同溶解於乾二甲亞 内。於室溫經2日後加入卜胺-2-丙醇(0.4»見)及反應混合 物,倒入l/l(v/v)丙酮及乙K混合物(300bJI )内。收集沈 澱及再度溶解於95X乙醇(10m见)内,由此自丙酮(80·見) 中沉澱出標題化合物lv ,經收集及以醚洗滌。 産率:0.51g Μ環素含量U/wS:),偽以3.’-去胺-3’-[2 (S卜甲氣-4-嗎啉 基]刀削茹必辛鹽酸計算:3.3% 呈式 lv 之% 莫耳比(r: s: t) = (95.7: 0.79: 3.52)。 實施例1 〇 14-0-(1-_肼羰基甲氧-環己基)-3’-去胺-[2(S)_甲氧-4-嗎啉基]刀削茹必辛之製備 [11', A-0-= 13b'. b=lf B»-(CHa)a-» Rx^Ra^H] / t請先閲讀背面之注意事項再瑱寫本頁) .装· •線· 經濟部中央橾準局印裝
,N、0
K 甲 4(210X 297公沒) 33 A6 ___B6 五、發明説明(31) 如例2所述製備化合物£(1〇〇呢)溶解於無水四氧呋喃 (2〇Bil )内,於0它冷卻及添加睬肼(50呢)於無水四氫呋喃 (2a見)之溶液。反蘸混合物於Ot:攪拌15分鐘,然後以亞 甲基氯(100·Α)稀釋,以水(3x50nJl)洗滌。分離有機相 ,於無水硫酸銷上乾燥及減壓去除溶劑。粗産物於矽酸柱 上層析,使用亞甲基氯/甲醇之混合物(80/20體積比 >作溶 離系統。使用乙醚沈澱出化合物JJJ , 80«g。 於基索膠板(MerclOF^進行TLC,溶離系統亞甲基氡/甲 酵(70/30體積比)Rf= 0.60。 FD-MS: m/z 868 (100, [M+H]*) ^HNMR (200 MHz, CDC13) 6:
I. 35 (d, J=6.6Hzf 3H, 5'-CH3); 1.3-1.9 (m, 12H, 2'-CH ' —, cyclohexane); 2.11 (dd, J=4.2, 14.6Hz, 1H, 8ax-g); 2.3-2.5 (m, 5H, 8eq-Hf 3'-H. 3"ax-Hr 2.60 (dd# J=3.9 II. 2Hz, 1H, 3"eq-H); 2.86 (in, 4H, CH2-NH-g|2); 3.00 J=18.9Hz, 1H, lOax-H); 3.23 (dd, J=1.2, 18.9Hz, 1H, 10eq-H); 3.37 (s, 3H, 2"-0〇13); 3.4-3.6 (m, 5H, CON(CHa)2, 6"ax-H); 3.90 (m, 1H, 6"eq-H); 3.98 (q, J=6.6Hz, lHf 5'-H); 4.07 (s# 3H, 4-0CH3); 4.18 (s, 2H, 〇gi2CON); 4.48 (dd, J=2.5, 3·9h2 1H, 2"eq-H); 4.79 (m, 2H, 14-CHa); 5.24 (m, 1H, 7-H) ; 5.53 (m, 1H, l'-H); 7.37 (d, J=7.7H2, 1H, 3-H); 7.76 (dd, J=7.7 6.8Hz, 1H, 2-H); 8.02 (d, J=6.8Hz, 1H, 1-H); 13.30 (bs, iH 11-OH); 13.98 (s, 1H, 6-OH). {請先閱讀背面之注意事項再填寫本頁) •裝· .線· 經濟部中央搮準局印裝 甲 4(210X 297公沒) 34 A6 B6 S1.UV2 五、發明説明(32) 實施11 3-甲代丙烯酵基胺基-2-羥-丙烷與14-0-{1-[4-Ν-甲代丙 铺醛基甘胺酵)_肼-1-基]羰基甲氧-環己基}-3,-去胺-3 -U(S)-甲氧,4-嗎啉基]刀削茹必辛)Uvi )之共聚物之製 備 [1V;L: A-0-=13b«, b=l, B=-(CHa)a-, R!=Ra=H, Z=[1,4-峨’〇乎基】-C0-, T=HPMA 及 X=HN-CH2-CO-] 請先W讀背面之注意事項再瑱寫本頁)
^a> -ch,-c-- f° r WH {h· cacm ch, -装. 經濟部中央搮準局印裝 0.428共聚物1^“(^=關-(^2-(:0-,7.6;«(11«〇1/||»〇1;1〇之 P=〇C6H4P〇2含量](如 J.Kopecek et al., Makromol. Chen. 177, 2833-2848(1976)所述,經由3-甲代丙烯酵胺 甲 4(210X 297公发) 35
五 '發明説明(33) 基-2-羥-丙烷及N-甲代丙烯酵基甘胺酸之4-硝苯酯進行基 團聚合反而製備)溶解於乾二甲亞《(2.2η見)内且與如 例10所述製備之衍生物UJ (0.07g)反應。於室溫經2小時 後加入卜胺-2-丙醇(0.05m見)及反窿混合物倒入丙酮及乙 醚之l/l(v/v)混合物(200mA )内。收集沈澱物及溶解於95 5;乙醇(l〇m見)内,由此自丙酮UOnil )中沈殺出標題化合 物j_vi,收集及以醚洗滌。 産率:0.39g。 葸環素含量U/w%),偽以3 去胺-3 ·_[2($)-甲氣-4-嗎啉 基]刀削茹必辛鹽酸(13a)計算:9.74% 呈式 ivi 之 %莫耳比(r : s : t) = (92.4 : 2.15 : 5.45) 實施例12 3-甲代丙烯醸基胺基-2-羥-丙烷與14-0-U-[4-(6-甲代丙 烯酷基胺己二醯基)_阱基]羰基甲氧-環己基)-3’-去胺-3 ’ [2 (S)-甲氣-4-嗎_基]刀削茹必辛(lvii )之共聚物之製 備 [lv±i-: A-0-=13b·, b=l, B=-(CHa)a-, Z=[l,4-^ Q淨基]-CO-, T=HPMA 及 X=HN-(CH2}s-CO-】· (請先W讀背面之注意事項再填寫本頁) 經濟部中央橾準局印裝 iUUlOX 297公角) 36 Α6 Β6 五、發明説明(34)
(請先聞讀卄面之注意事項再填寫本頁) *装· 0.6g 共聚物 HPMA[X=HN-(CH2)5-C0-,5.3Χ(β〇1/β〇1Χ) 之 P=0C6H4PN02 含量](如 J· Kopecek et al,, Makronol. Cheffl. 177 , 2833-2848 (1976)所述,經由3-甲代丙烯酵胺 -2-羥-丙烷及N-甲代丙烯酵胺基己酸4-硝苯酯進行基團聚 合反應而製備)溶解於乾二甲亞璀(3mJl )内且與如例10所 述製備如例10衍生物U’(〇.lg)反應。 於室溫經2小時後,加入1-胺-2-丙醇(0·1·Α),及反應 混合物倒入丙酮及乙醚1/1(ν/ν)之混合物(200mJl)内。 遵照例11所述之相同程序回收0.58g標題化合物J_vii。 葸環素含量(w/w%),以3’-去胺-3’[2(S)-甲氣-4-嗎啉 •訂· -線. 經濟部中央捃準局印仗 甲 4(210X 297公沒) 37 Α6 Β6 2U… 五、發明説明(3δ) 基]刀削茹必辛鹽酸(ϋ£)計算:9.2%。 呈式]_vii 之 %莫耳比(r : s : t) = (94.7 : 2.05 : 3.31) 實施例13 聚(Glu-Na,Ala , Tyr) (1 : 1 : 1)與 14-0-(1-_ 肼羰基甲烷-環己基)~~3’ -去胺-[2(S)_甲氧-4-嗎淋基]刀削$5必辛之共 軛接合物之製備qviii) (請先閲讀背面之注意事項再填寫本頁) .汊·
央 揉 準 局 印 裝
訂. •線· «*»· / ο λ*1?/、、 38 μ A6 B6 五、發明說明(3δ) 聚(Glu-Ha,Ala,Tyr)(l: 1: l)Mw25000-40000 (SUma) t請先閱讀背面之注意事項再滇寫本頁) ,(〇.2g)於攢拌下於室溫溶解於水(5nJl)内。於PH3使用 0.1N HCJI酸化,從水溶液中沈澱出對慝的游離酸。回收 及經臭空乾燥之聚(Glu-OH, Ala, Tyr)(0.17g)溶解於乾 二甲基甲酵胺(1〇»見)内,及加入如實施例10所述而製備 之14-0-U-晡肼羰基甲氧-環己基)-3’-去胺-[2(S)-甲氧-4-皭啉基]刀削茹必辛(ϋ')(0*035δ),及H-乙氧羰基- 2-乙氧-1,2-二氫蝰啉(EEDQ)(0.08g)。3小時後又加入另一 整分之EEDQ(〇.〇8g)。反應混合g於室溫攪拌隔夜,然後 倒入乙醚(300βΑ)内。沈澱物懸浮於水(lOmJl)内且以 0.1H HaOHp4»Jl)處理;溶液以0.1H HCA調整至ρΗ8·5及 通過西法雷斯G1 〇柱。水溶液經凍晶乾燥而得0 . 16 g標題化 合物iviii 。 *打· 慈環素含量(w/wX),像以3’-去胺-3’[2(S) -甲氧-4-嗎淋 基]刀削茹必辛鹽酸(1-3a)計算:10¾。 呈式玉viii化合物之%莫耳比(r : s : t : u) = (31 . 33 : 2.01 :33.33 : 33.33)〇 甲 4(210X297 公发) 39
Claims (1)
- A7 B7 C7 Π7 R9 i 正名1 . 一種如通式1之共軛接合物 ! A - 0 - W - Z ] a - T 丄 % 六、申請專利範圍 式中Α-ϋ-部分代表0·xt中R1()為氫原子或羥基或甲氣基,及R12中 > 一者為 氫原T而另-者為羥基,或Ru為氫原子或碘原子而R 12完 氣原?,及r 13為胺基或代表含括於嗎唞環内之一 m原子 a為丨至30之整數; W為通式2之基: 0-(CHa)to-C(0) 2 式中b為1至4之整數,B代表Q - C3次烷基而Ri及R 2各向 獨、X代表氫,鹵原f或苯基; Z 代表間隔基,選自 Ν Η N N C Ο , Ν Η , Ν Η N H , N H ( C Η 2 ) 4 C ϋ 岐 丨1 , 4 - _唞基丨0 ; Τ代表載劑部份,選D多株抗體或其Η 斷,其中包活一抗原結合址而可與腫瘤相關抗原結合者; 單株抗體或其Η斷,其中包括一抗原結合址而可與偏好或 選擇性地表現於腫瘤細胞族群上之抗原結合#;偏好或選 本紙張尺度適用中國國家標準(CNS)甲4規格(210 X 297公釐)I -------i------------(------裝------訂 (請先閱讀背而之注意事項再塡寫本頁)經濟部中夬標準局员工消费合作社印製 21谈 A7 B7 C7 D7 六、申請專利範園 擇性地與陳瘤細胞結合之肽或蛋白質;及聚合物載劑 2 .如申請專利範圍第]項之共軛接合物,其中a為1至5之 替數/ 3 .如申請專利範圍第1項之共軛接合物,其中B代表-i C Η 2) 2、 4 .如申請專利範圍第〗項所述之共軛接合物,其中之載 劑部份Τ偽選:杭-Τ -細胞抗體,抗-C ϋ 5抗體,杭轉移素 受器抗體,抗-黑素瘤杭體,抗-癌瘤標記抗體,抗-卵m 癌杭體,抗乳癌抗體及抗膀胱癌抗體,, 5 .如申請專利範圍第4項之共鈪接合物,其中之載劑部 份T為一種生長因子。 6 . —種製備如申請專利範圍第1項所定義之式1共軛接合 物之方法,該方法包括令式3衍生物·· I (請先閲請背面之注意事項再填寫本頁) 經浙部屮央標準局員工消费合作社印製 (式中A - Ο -及W定義如申請專利範圍第1項)與為或可提供申 專利範_第!項定義之間隔基z及載_部分T之物質縮合 ,藉此生成所述共鈪接合物 7 .如申譆專利範圍第6項之方法 由式!衍生物之活化衍生物而進行 直接反應而進行,-, 8 .如申請專利範圍第6項之方法 成式4活化衍生物: 其中之縮合反應傜經 或於縮合劑共存之下 包括將式3衍生物轉變 A - 0 - W - L 4 式中A-Ο -及W定義如申請專利範圍第6項,及L代表可生成 本纸張尺度適用中國國家搮準(CNS)甲4規格(210x297公釐)2 AT B7六、申汸4利苑園 1 醛胺鍵聯之活化基,及 經濟部屮央櫺準局貝工消费合作社印製 (i ’)令所得式i化合物與式T - [N H 2 ]x物質(式中T為載劑 部分而X代表可供縮合之胺基數目)進行縮合反應或 (ί ί ')今式立化合物與肼反應;及令所得式^_化合物: A-0-W-NH-NH2 δ t式中A - Ο -及W定義如申請專利範圍第1項)與式τ - [ C Η Ο ] χ2 物質(式中τ為載劑部分,及χ2代.表可供縮合之甲醛基數目 )進行縮合反應。 9 .如申請專利範圍第6項之方法,S活 Π丨厂)今通式i化合物(按申^專利範圍第3項所述製備) 與式2物質: T - [ C 0 - L · ] χ 7 · 丨(式中了 -為載劑部分,y為1至3 0之整數且代表載劑部分上 之羧酸總數,及L’代表羥基或可生成醯胺鍵聯之活化基) 縮合.該縮合反應視需要可於縮合劑共存之下進行。 1 9 .如申請專利範圍第S項所述之方法,包括 · Πν’)令式!化合物與式H2N-[CH 2]>-(:ΟΟΗ胺基衍生物縮 合,藉此生成式互之衍生物: A - 0 - W - ( C Η 2 ) ^ - Ο Η 3 (式中A - Ο -及W定義如申請專利範圍第1項);視需要可將式 !化合物轉變成式9活化衍生物: A - 0 - W - ( C Η 山-L 9 (式中A - ϋ - Si»r定義如前,及L為生成趦胺鍵聯之活化基 及令所得式i化合物或式3化合物於縮合劑共存之下與式T- (熗先閱請背面之注意事碛再唭寫本頁) 本纸張尺度適用t S a家樣準(CNS) T4規格(210x297公釐) 3 經濟部屮央標準局員工消费合作社印製 C7 _D7_ 六'申請專利範圍 [Ν Η 2 l,x物質(定義如申請專利範圍第8項丨進行縮合反應。 1 1 .如申Μ專利範圍第6項之方法,包括 (ν ’)令申請專利範圍第8項定義之式1化合物與蛾唞反應 而生成式11化合物 A - Γ) - W -丨 nil 哄基 1 - Η 11 (式中A - Π吱W定義如申請專利範圃第丨項);及令如前述之 式 1丄化合物與如申請專利範圍第9項所述之式2物質縮合 1 2 · —種用於治療哺乳動物腫瘤之醫藥組成物,其中包 括一種醫藥可接受性載劑或稀釋劑,以及作為活性成分之 如申謓專利範圍第〗,2 , 3 , 4或5項之共軛接合物或經由 如申請專利範圍第6 , 7, 8 , 9 . 1 β或1 1項之方法所製備之 共鈪接合物. 1 3 . —種如式立之衍生物: A - 0 - W - Η 3. (式中A - 0及W定義如申請專利範圍第1項),-, ]4 .如申謓專利範圍第〗3項之衍屯物,其為H 0 -(卜羧 甲氣-環己基)-3 ’ -去胺基-3 ’ -「2 ( S » -甲氧-4 -嗎唞基1刀削 ίίι必〒:、 1 5 .-種製備如申請專利範圍第1 3項之式!衍生物之方法 ,該方法包括令式A - ϋ - H藥物(式中A - 0 -定義如申謓專利範 _第1項)與式g化合物縮合: 0-(CH 入 COOR, 8 1 12 (請先間讀背面之注意事項再填寫本頁) 本纸張尺度適用中B國家標準(CNS)甲4規格(210x297公釐) 4 A7 B7 C7 D7 六、申請專利範® (式中B , b , R 1及R 2定義如申請專利範圍第1項,及R 3代表 保護基);及由所生成之化合物中去除保護基,, 0 -榑如式4之衍生物 4_ (式中A - ϋ , W及L定義如申請專利範圍第8項)。 1 7 .如申請專利範圍第1 6項之衍生物,其為Ν -氣丁二醯 亞胺i m ( 1 -羧甲氣--環己基)-3 ’ -上胺基-3 ; 2 ( S卜甲 氧-4 -螞唞基:刀削必辛,., 】8 .-種製備如申請專利範圍第〗6項之式£衍生物之方法 ,該方法包括將申請專利範圍第1 3項之式2衍生物轉變成 該式i衍生物。 1 9 .-種如式6之衍生物: A - 0 - W - N Η - N Η 1 (請先閲讀背面之注意事項再填寫本頁) 經濟部屮央標準局員工消费合作社印製 (式中A - U及W定義如申請專利範圍第]項)。 2 0 .如申請專利範圍第1 9項之衍生物,其為1 4 - 0 - ( 1 -肼 羰基甲氣-環d基)-3 ’ -去胺-3 ’丨2 ( S )-甲氣- 嗎唞基1刀 削砧必辛, 2 1 . —種製備如申請專利範圍第1 9項之式豆衍生物之方法 ,該方法包括按照申請專利範圍第8項所述之方法,從式2 衍生物製備該式立衍生物。 2 2 · —種如式旦之衍生物: 9. 式中A-Ο, W及L定義如申請專利範圍第10項)。 2 3 . —種製備如申請專利範圍第2 2項之式9衍生物之方法 本纸張尺度適用中ΒΒ家楳準(CNS)甲4規格(210x297公嫠)5 C- 六、申請專利範園 請 照 按 括式 包該 法備 方 製 該物 , 生 .Q 式 法 衍 41 生 AT Β7 C7 D7 31 式 從 法 方 之 述 所 項 0 第 圍 範 利 項 1— 第 圍 11I 範 : 利 物 專 ,生SI 物;ff.H 申 生之;-如 衍U基義 式唞定 如Ri彳 •I 福 - 9- 第 圍 範 利i物 專卩生 請If衍 Ji'1 * {女1 D ί 弋 $ gil 備;;¾ 製 ί 備 種f製 一 ί物 方 之 物 生 衍 11I 式 之 項 第 圍 範 -3¾ πν 禾 專 式 從 法 方 之 述 所 (請先閲讀背面之注竞事項再填寫本頁 經濟部屮央標平局員工消费合作社印製 本纸張尺度適用中國困家標準(CNS)甲4規格(210x297公釐)6
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Families Citing this family (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5439936A (en) * | 1989-10-03 | 1995-08-08 | The Regents Of The University Of California | Method of treating certain tumors using illudin analogs |
GB9017024D0 (en) * | 1990-08-03 | 1990-09-19 | Erba Carlo Spa | New linker for bioactive agents |
DE4236237A1 (de) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
GB9309663D0 (en) * | 1993-05-11 | 1993-06-23 | Erba Carlo Spa | Biologically active compounds |
GB9416007D0 (en) * | 1994-08-08 | 1994-09-28 | Erba Carlo Spa | Anthracyclinone derivatives |
US5783178A (en) * | 1994-11-18 | 1998-07-21 | Supratek Pharma. Inc. | Polymer linked biological agents |
CA2252706A1 (en) * | 1996-05-01 | 1997-11-06 | Antivirals Inc. | Polypeptide conjugates for transporting substances across cell membranes |
US6030941A (en) * | 1996-05-01 | 2000-02-29 | Avi Biopharma, Inc. | Polymer composition for delivering substances in living organisms |
US5932553A (en) | 1996-07-18 | 1999-08-03 | The Regents Of The University Of California | Illudin analogs useful as antitumor agents |
US5723632A (en) * | 1996-08-08 | 1998-03-03 | Mgi Pharma, Inc. | Total synthesis of antitumor acylfulvenes |
DE19636889A1 (de) | 1996-09-11 | 1998-03-12 | Felix Dr Kratz | Antineoplastisch wirkende Transferrin- und Albuminkonjugate zytostatischer Verbindungen aus der Gruppe der Anthrazykline, Alkylantien, Antimetabolite und Cisplatin-Analoga und diese enthaltende Arzneimittel |
AU7124598A (en) * | 1997-04-18 | 1998-11-13 | Access Pharmaceuticals, Inc. | Polymer-platinum compounds |
US5965118A (en) * | 1997-04-18 | 1999-10-12 | Access Pharmaceuticals, Inc. | Polymer-platinum compounds |
GB2341390B (en) * | 1997-05-21 | 2000-11-08 | Univ Leland Stanford Junior | Composition and method for enhancing transport across biological membranes |
US6531230B1 (en) * | 1998-01-13 | 2003-03-11 | 3M Innovative Properties Company | Color shifting film |
US7141603B2 (en) * | 1999-02-19 | 2006-11-28 | The Regents Of The University California | Antitumor agents |
US6025328A (en) | 1998-02-20 | 2000-02-15 | The Regents Of The University Of California | Antitumor agents |
ES2222719T3 (es) * | 1998-07-30 | 2005-02-01 | Oakville Trading Hong Kong Limited | Procedimiento para preparar conjugados reticulados solubles en agua. |
US6706892B1 (en) * | 1999-09-07 | 2004-03-16 | Conjuchem, Inc. | Pulmonary delivery for bioconjugation |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
WO2002032400A1 (en) * | 2000-10-16 | 2002-04-25 | Neopharm, Inc. | Liposomal formulation of mitoxantrone |
CA2441484A1 (en) * | 2001-03-23 | 2002-10-03 | Napro Biotherapeutics, Inc. | Molecular conjugates for use in treatment of cancer |
WO2002090390A1 (en) * | 2001-05-04 | 2002-11-14 | University Of Utah Research Foundation | Hyaluronic acid containing bioconjugates : targeted delivery of anti-cancer drugs to cancer cells |
US7087600B2 (en) | 2001-05-31 | 2006-08-08 | Medarex, Inc. | Peptidyl prodrugs and linkers and stabilizers useful therefor |
CA2483696A1 (en) * | 2002-05-06 | 2003-11-20 | University Of Utah Research Foundation | Preblocking with non-ha gags increases effectiveness of ha conjugated anticancer agents |
US7691962B2 (en) * | 2004-05-19 | 2010-04-06 | Medarex, Inc. | Chemical linkers and conjugates thereof |
NZ550934A (en) * | 2004-05-19 | 2010-05-28 | Medarex Inc | Chemical linkers and conjugates thereof |
US20060105941A1 (en) * | 2004-11-12 | 2006-05-18 | Allergan, Inc. | Mixed antibiotic codrugs |
US7714016B2 (en) * | 2005-04-08 | 2010-05-11 | Medarex, Inc. | Cytotoxic compounds and conjugates with cleavable substrates |
WO2007019308A2 (en) * | 2005-08-03 | 2007-02-15 | The Regents Of The University Of California | Illudin analogs useful as anticancer agents |
CA2623652C (en) * | 2005-09-26 | 2013-11-26 | Medarex, Inc. | Antibody-drug conjugates and methods of use |
EP1940789B1 (en) | 2005-10-26 | 2011-11-23 | Medarex, Inc. | Methods and compounds for preparing cc-1065 analogs |
WO2007059404A2 (en) | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
TWI412367B (zh) | 2006-12-28 | 2013-10-21 | Medarex Llc | 化學鏈接劑與可裂解基質以及其之綴合物 |
KR20090122439A (ko) * | 2007-02-21 | 2009-11-30 | 메다렉스, 인코포레이티드 | 단일 아미노산을 갖는 화학적 링커 및 이의 접합체 |
US8742076B2 (en) * | 2008-02-01 | 2014-06-03 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
AU2009270988A1 (en) * | 2008-07-15 | 2010-01-21 | Genentech, Inc. | Anthracycline derivative conjugates, process for their preparation and their use as antitumor compounds |
CA2818713C (en) | 2010-12-02 | 2019-03-26 | Nerviano Medical Sciences S.R.L. | Process for the preparation of morpholinyl anthracycline derivatives |
CN104755482B (zh) | 2012-10-30 | 2017-04-26 | 内尔维阿诺医学科学有限公司 | 官能化的9‑溴‑喜树碱衍生物 |
US10131682B2 (en) | 2012-11-24 | 2018-11-20 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules |
CN105358174B (zh) | 2013-03-15 | 2019-03-15 | 酵活有限公司 | 具细胞毒性和抗有丝分裂的化合物以及其使用方法 |
PL3086815T3 (pl) | 2013-12-27 | 2022-06-13 | Zymeworks Inc. | Układy łącznikowe dla koniugatów leków zawierające ugrupowanie sulfonamidowe |
CN114262344A (zh) | 2014-02-28 | 2022-04-01 | 杭州多禧生物科技有限公司 | 带电荷链接体及其在共轭反应上的应用 |
WO2016041082A1 (en) | 2014-09-17 | 2016-03-24 | CDRD Ventures, Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
CA2991973C (en) | 2015-07-12 | 2021-12-07 | Suzhou M-Conj Biotech Co., Ltd. | Bridge linkers for conjugation of a cell-binding molecule |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
EP3442574A4 (en) | 2016-04-15 | 2019-12-11 | MacroGenics, Inc. | NOVEL B7-H3 BINDING MOLECULES, THEIR ANTIBODY-MEDICINAL CONJUGATES AND METHODS OF USE |
KR20220150408A (ko) | 2016-11-14 | 2022-11-10 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
US10386338B2 (en) | 2017-10-30 | 2019-08-20 | Cynthia Rena Wright | DNA/RNA PEMS microcantilever probe for detection of viral infection and detection of genetic variants |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2098219A (en) * | 1981-05-08 | 1982-11-17 | Erba Farmitalia | Daunorubicin-protein conjugates |
JPS63241541A (ja) * | 1987-03-30 | 1988-10-06 | Konica Corp | 感光性組成物および感光性平版印刷版 |
IL106992A (en) * | 1988-02-11 | 1994-06-24 | Bristol Myers Squibb Co | Noble hydrazonic history of anthracycline and methods for their preparation |
US5066490A (en) * | 1988-06-01 | 1991-11-19 | The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services | Protein crosslinking reagents cleavable within acidified intracellular vesicles |
GB9017024D0 (en) * | 1990-08-03 | 1990-09-19 | Erba Carlo Spa | New linker for bioactive agents |
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1990
- 1990-08-03 GB GB909017024A patent/GB9017024D0/en active Pending
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1991
- 1991-07-29 NZ NZ239165A patent/NZ239165A/xx unknown
- 1991-07-29 IL IL9898691A patent/IL98986A/en active IP Right Grant
- 1991-07-30 MY MYPI91001364A patent/MY106526A/en unknown
- 1991-07-30 PH PH42855A patent/PH31048A/en unknown
- 1991-07-31 ZA ZA916025A patent/ZA916025B/xx unknown
- 1991-07-31 TW TW080105996A patent/TW211572B/zh active
- 1991-08-01 DE DE69118350T patent/DE69118350T2/de not_active Expired - Fee Related
- 1991-08-01 AT AT91914151T patent/ATE135919T1/de not_active IP Right Cessation
- 1991-08-01 EP EP91914151A patent/EP0495053B1/en not_active Expired - Lifetime
- 1991-08-01 WO PCT/EP1991/001449 patent/WO1992002255A1/en active IP Right Grant
- 1991-08-01 HU HU9201146A patent/HUT61898A/hu unknown
- 1991-08-01 KR KR1019920700754A patent/KR920702234A/ko not_active Application Discontinuation
- 1991-08-01 CA CA002067184A patent/CA2067184C/en not_active Expired - Fee Related
- 1991-08-01 RU SU5011981A patent/RU2116087C1/ru active
- 1991-08-01 ES ES91914151T patent/ES2088013T3/es not_active Expired - Lifetime
- 1991-08-01 US US07/842,171 patent/US5387578A/en not_active Expired - Fee Related
- 1991-08-01 JP JP51314491A patent/JP3169222B2/ja not_active Expired - Fee Related
- 1991-08-01 AU AU83113/91A patent/AU650900B2/en not_active Ceased
- 1991-08-01 PT PT98545A patent/PT98545B/pt not_active IP Right Cessation
- 1991-08-01 DK DK91914151.5T patent/DK0495053T3/da active
- 1991-08-02 CS CS912414A patent/CS241491A3/cs unknown
- 1991-08-02 IE IE275791A patent/IE76467B1/en not_active IP Right Cessation
- 1991-08-02 YU YU134691A patent/YU48441B/sh unknown
- 1991-08-02 CN CN91105270A patent/CN1058598A/zh active Pending
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1992
- 1992-04-02 FI FI921451A patent/FI100697B/fi active
- 1992-04-02 NO NO92921287A patent/NO921287L/no unknown
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1994
- 1994-10-25 US US08/328,697 patent/US5547667A/en not_active Expired - Fee Related
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1995
- 1995-03-23 IL IL11310195A patent/IL113101A0/xx not_active IP Right Cessation
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1996
- 1996-03-28 GR GR960400748T patent/GR3019449T3/el unknown
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