TW458981B - Gemcitabine derivatives - Google Patents

Gemcitabine derivatives Download PDF

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TW458981B
TW458981B TW087103708A TW87103708A TW458981B TW 458981 B TW458981 B TW 458981B TW 087103708 A TW087103708 A TW 087103708A TW 87103708 A TW87103708 A TW 87103708A TW 458981 B TW458981 B TW 458981B
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king
special product
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ministry
cns
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Finn Myhren
Bernt Borretzen
Are Dalen
Marit Liland Sandvold
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Norsk Hydro As
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

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Abstract

The invention provides Gemcitabine esters or amides in which the 3'- and/or 5'-OH group and/or the N4-amino group is derivatised with a C18- and/or C20-saturated or mono-unsaturated acyl group, preferably an acyl group selected from oleoyl, elaidoyl, cis-eicosenoyl and trans-eicosenoyl. The Gemcitabine esters and amides are useful as anti-cancer and anti-viral agents.

Description

45 898 1 A7 _ i_07 _ 五、發明說明(/ ) !0. - C 本發明係關於2_,2·-二氟-去氧胞苷(金氏特品( Gemciubine))之特定長鏈的飽和及單不飽和脂肪酸衍生 物,及包含該衍生物之醫藥組成物。金氏特品係具有下式45 898 1 A7 _ i_07 _ 5. Description of the invention (/)! 0.-C The present invention is about the saturation of specific long chains of 2_, 2 · -difluoro-deoxycytidine (Gemciubine) And monounsaturated fatty acid derivatives, and pharmaceutical compositions containing the derivatives. King's special strain has the following formula

OH <請先閱讀背面之注意事項再填寫本頁) 裝·!--r . 經濟部智慧財產局員工消費合作社印製 金氏特品係爲一種核苷類似體,其已經在活體內和活 體外硏究中顯示治療贅生現象(neoplasUc conditions) 的效果° (參見新抗癌劑(New anticancer agents), We1SS等人,癌的化學治療以及生物性反應調節劑第16號 手冊(Cancer Chemotherapy and Biological Response Modifiers Annual 16),編者 Pinedo,Longo 及 Chabner, 1996。Elsevier Science B.V.,腫瘤學討論會補充( Supplement to Seminars in Oncology ) ,Vo 1 . 22, No. 4,Supp丨.11,1995,編者Yarbro等人。金氏特品氫氯化 物(Gemc it abine Hydrochloride):臨床前硏究之狀態( Status of Preclinical Studies))。而在金氏特品臨床 的發展上亦已被觀察到有助益的效果。在這些硏究中,金 3 冢紙張尺度適用中國國家標¥ (CNS)A4規格(2.10 x 297公釐) *ιιιιιιιϊ^ 經濟部智慧財產局員工消費合作社印製 45 8 如 i B7 五、發明說明(α ) 氏特品的臨床和副作用效果都高度地具有計劃依存性° ( 參見腫瘤學討論會(Seminars in Oncology) V〇l. 22,OH < Please read the notes on the back before filling this page) --r. The King ’s special strain printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economics is a nucleoside analogue, which has shown the effect of treating neoplasUc conditions in vivo and in vitro studies ° ( See New anticancer agents, We1SS, et al. Cancer Chemotherapy and Biological Response Modifiers Annual 16 (Editor Pinedo, Longo & Chabner, 1996. Elsevier) Science BV, Supplement to Seminars in Oncology, Vo 1.22, No. 4, Supp 丨. 11, 1995, editor Yarbro et al. Gemc it abine Hydrochloride : Status of Preclinical Studies). In the clinical development of King's specialty products, beneficial effects have also been observed. In these studies, the paper size of the gold 3 mound is applicable to the Chinese national standard ¥ (CNS) A4 specification (2.10 x 297 mm) * ιιιιιιιϊ ^ Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 45 8 Such as i B7 V. Invention Description The clinical and side effects of (α) 's special products are highly plan-dependent ° (see Seminars in Oncology V.l. 22,

No. 4, Suppi. 11, 1995, ρρ 42-46) ΰ 金氏特品在細胞內係藉由去氧胞苷激酶使其活化至'活 化型式,亦即金氏特品三磷酸(dFdCTP)。與此相平行的 是,金氏特品藉由去氧胞苷脫胺酶去活化爲相關的尿喃B定 衍生物(去活化)。 吾人現在已驚訝地發現金氏特品的某種脂肪酸衍生物 具有完全改變之藥物動力學以及組織分布情形。這種情形 特別可以在如RES、肺臟、胰臟、腸部、食道、子宮、卵巢 、黑色瘤及乳房部的惡性疾病的例子中。 本發明之化合物係以下式I表示:No. 4, Suppi. 11, 1995, ρ 42-46) ΰ King's special product is activated intracellularly by deoxycytidine kinase to the 'activated form', which is King's special triphosphate (dFdCTP). In parallel to this, King's special product is deactivated by deoxycytidine deaminase to the related uridine B derivative (deactivation). I have now surprisingly discovered that a certain fatty acid derivative of King's special product has completely changed pharmacokinetics and tissue distribution. This can be particularly the case for malignant diseases such as RES, lungs, pancreas, intestines, esophagus, uterus, ovary, melanoma and breast. The compound of the present invention is represented by the following formula I:

⑴ 其中Ri ’ 1及R3係獨立地選自於氫及Cia-和的飽 和以及單不飽和醯基基團,其條件爲]^,卩2及1不可以全 爲氫。 金氏特品具有三種可衍生性的功能,亦即5,_以及 4 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 x 297公髮) «^1 i 1 n ^^1 . · · ^^1 n n I ^ 0U. · f— n 1 (請先閱讀背面之注意事項再填寫本頁) 45 898 1 A7 B7 五、發明說明(》) 羥基基團和N4-胺基基團。該每一基團可被選擇性地改變成 酯或醯胺衍生物’但是二-加合物(二-脂類或者酯-醯胺類 )以及三-加合物亦可以被改變形成。在二-加合物以及三_ 加合物的例子中,醯基取代基基團並不一定要相同。 目前,本發明之單-醯基衍生物(亦即’ Ri,R2及I中 的兩者爲氫)係爲較佳。具有醯基基團的單取代特別較佳 的是在糖部分的3’-0及5’-0位置,具有5’-0位置取代者 爲最佳。 單不飽和醯基基團的雙鍵位置可能爲順式或反式構型 ,但其治療效果可能會依照其所使用之不同構型而有所不 同。 於單不飽和醯基基團中的雙鍵位置亦可能會影響該活 性。目前,吾人較偏好使用在心9位置爲不飽和之酯類或醯 胺類。在系統之命名中,單不飽和脂肪酸的雙鍵ω位置係 由終端的甲基數起,因此,例如,二十烯酸在 其鏈中具有20個碳原子,而其單一雙鍵則位在鏈終端的甲 基數起第9及10個碳之間。 吾人較偏好者爲fi用由油酸(CwlccT9,順式)、反油 酸,反式)、二十烯酸(Ctlo^,順式)以及( Cwlo'9,反式)所衍生之酯類,酯類-醯胺類以及醯胺類, 而醯胺類及5’-酯類目前則爲本發明最佳之衍生物。 由硬脂酸(Cl8:0)及二十酸(gq:o)所衍生之金氏特 品酯類、酯類-醯胺類以及醯胺類在一些情況下則特別有利 〇 5 (請先閱讀背面之泫意事項再填寫本頁) -I I — t I I 訂 - - -------線 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) d5 898 1 A7 :卜 07 五、發明說明(f ) 根據本發明之金氏特品衍生物,一般而言,其可根據 下列反應式所製備: 驗⑴ where Ri '1 and R3 are independently selected from the group consisting of hydrogen and Cia-saturated and monounsaturated fluorenyl groups, provided that ^, and 卩 2 and 1 may not be all hydrogen. King's special products have three derivable functions, namely 5, _ and 4 paper sizes applicable to China National Standard (CNS) A4 specifications (21〇x 297 issued) «^ 1 i 1 n ^^ 1. · · ^^ 1 nn I ^ 0U. · F— n 1 (Please read the notes on the back before filling out this page) 45 898 1 A7 B7 V. Description of the invention (") Hydroxyl group and N4-amine group. Each of these groups can be selectively changed to an ester or amidine derivative ', but di-adducts (di-lipids or ester-amidamines) and tri-adducts may also be changed to form. In the examples of di-adducts and tri-adducts, the fluorenyl substituent groups need not necessarily be the same. Currently, the mono-fluorenyl derivatives of the present invention (i.e., both of 'Ri, R2 and I are hydrogen) are preferred. Mono-substitutions having a fluorenyl group are particularly preferred at the 3'-0 and 5'-0 positions of the sugar moiety, and those having a 5'-0 position are most preferred. The position of the double bond of the monounsaturated fluorenyl group may be in the cis or trans configuration, but its therapeutic effect may vary depending on the different configurations used. The position of the double bond in the monounsaturated fluorenyl group may also affect the activity. At present, we prefer to use esters or amines which are unsaturated at the 9th position. In the nomenclature of a system, the double bond ω position of a monounsaturated fatty acid starts from the number of methyl groups at the terminal. Therefore, for example, eicosenoic acid has 20 carbon atoms in its chain and its single double bond Between the 9th and 10th carbons from the number of methyl groups at the end of the chain. My preference is fi using esters derived from oleic acid (CwlccT9, cis), transoleic acid, trans), eicosenoic acid (Ctlo ^, cis), and (Cwlo'9, trans) Esters-amidines and amidoamines, and amidines and 5'-esters are currently the best derivatives of the present invention. King's specialty esters, ester-amidamines, and amidines derived from stearic acid (Cl8: 0) and eicosanoic acid (gq: o) are particularly advantageous in some cases. 05 (please first Read the intentions on the back and fill in this page) -II — t II Order------------ Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is printed in accordance with China National Standard (CNS) A4 specifications ( 210 X 297 mm) d5 898 1 A7: Bu 07 V. Description of the invention (f) According to the invention, the Jinshi special product derivative can be generally prepared according to the following reaction formula:

Nu-YH + FaX -> Nu-Y-FaNu-YH + FaX-> Nu-Y-Fa

-HX 經濟部智慧財產局員工消費合作社印製 其中Nu-YH係表示金氏特品,Y爲在糖部分的3’及/或 5’位置的氧,或者在金氏特品的嘧啶部分的4位置的氮, Fa爲一單不飽和h或者C2U脂肪酸的醯基基團,且X爲離 去基,例如,Cl、Br、3-瞳唑烷-2-硫酮( 3-thiazolidine-2-thione)或 OR,,其中 R,爲 Fa、COCIL·、 COEt或者C0CF3。因此,本反應係以核苷的醯化反應來進 行。其中,其係使用脂肪酸、特別是醯基鹵類或酸酐類的 適當反應性衍生物來完成。 一般而言,其需要有質子去除劑的存在,以去除由反 應所釋放之HX酸。因此,可以加入鹼到反應混合物。舉例 來說,當使用醯基鹵例如醯基氯時,三級胺鹼類如三乙基 胺、Ν,Ν-二甲基苯胺、吡啶或者Ν,Ν-二甲基胺基毗啶可被 加入至反應混合物中,以結合到該被釋放之氫鹵酸上。在 其他的例子中,反應中所使用之溶劑可作爲質子去除劑。 正常地,醯化反應之進行可以不需要催化劑。該反應 性的脂肪酸衍生物FaX,在某些例子中,可以藉由偶合劑如 1化-二環己基碳化二亞胺(0〇:)、心乙基州’-(3-二甲基 胺基丙基)碳化二亞胺(EDC)或0- (1H-苯並三唑-1-基) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) {請先閱讀背面之注意事項再填寫本頁) .^1 n It ^TOJa n n n 1 458981 A7-HX Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where Nu-YH represents King's specialty, Y is oxygen at the 3 'and / or 5' position of the sugar portion, or the pyrimidine portion of the King's specialty 4-position nitrogen, Fa is a monounsaturated h or fluorenyl group of a C2U fatty acid, and X is a leaving group, for example, Cl, Br, 3- pupilzolidin-2-thione (3-thiazolidine-2 -thione) or OR, where R is Fa, COCIL ·, COEt or COCF3. Therefore, the present reaction is carried out by a tritiated reaction of nucleosides. Among them, this is accomplished using an appropriate reactive derivative of a fatty acid, particularly a fluorenyl halide or an acid anhydride. Generally, it requires the presence of a proton remover to remove the HX acid released by the reaction. Therefore, a base can be added to the reaction mixture. For example, when using a fluorenyl halide such as fluorenyl chloride, tertiary amine bases such as triethylamine, N, N-dimethylaniline, pyridine, or N, N-dimethylaminopyridine can be Added to the reaction mixture to bind to the released halogen acid. In other examples, the solvent used in the reaction can be used as a proton removing agent. Normally, the tritiation reaction can proceed without a catalyst. The reactive fatty acid derivative FaX may, in some examples, be obtained through a coupling agent such as 1-dicyclohexylcarbodiimide (0: 0), ethyl ethyl '-(3-dimethylamine Propyl) carbodiimide (EDC) or 0- (1H-benzotriazol-1-yl) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) {Please read the back first (Notes on this page, please fill out this page). ^ 1 n It ^ TOJa nnn 1 458981 A7

五、發明說明($ ) L -比1^屮、四甲基脲四氟硼酸鹽(罚罚),而在其原位( i n s i t u)形成。 該反應較佳係於一不反應的溶劑如N,N -二甲基甲醯胺 或鹵化烴如二氯甲烷中進行。若有需要,任何上述的三級 胺鹼類也可以作爲溶劑,此外必須注意的是其係以一適當 的過量存在。在此情況下則不需要一獨立的質子去除劑。 該反應較佳地應保持在5°C和25t之間來進行。在一個! 到60小時的時段之後,該反應將會被徹底地完成。該反應 的過程可以使用薄層色層分析法(TLC)以及適當的溶劑系 統來進行。當該反應在以薄層色層分析法(Τΐχ)決定完成 時,其產物可以有機溶劑萃取,並且以色層分析法及/或由 適當之溶劑系統再結晶來進行純化。因爲在金氏特品中存 在有超過一個羥基基團以及—個胺基基團,所以其亦可產 生醯化化合物的混合物。若有需要,可以藉由例如色層分 析法、結晶法、超臨界萃取法等,來分離出所需要之單獨 的單-及多-醯化衍生物^ 若是需要製備-式I之多醯基化合物,其中&及/或 經濟部智慧財產局員工消費合作杜印製 (請先閱讀背面之注意事項再填寫本頁) L及/或l爲相同之ϋ基基團時,其較佳爲利用上述使用過 量之適當醯基反應劑的方法。 若爲了要製備-式I之多醯基化合物,其中匕及/或 及/或R3爲不同,其較佳係利用上述逐步選擇適當反應劑 的方法。其亦可以藉由選擇適當之保護基團以確保—特定 之反應。這些方法之選擇示於下述流程圖i。這些方法之任 一組合可以被用來製備特定之產物。 ___ 7 本紙張尺度適用令固國家i準(CNS)A4規格(21^^17~ --'V. Description of the invention ($) L-ratio 1 ^ 屮, tetramethylurea tetrafluoroborate (penalty penalty), but formed in its in situ (i n s i t u). This reaction is preferably carried out in an unreacted solvent such as N, N-dimethylformamide or a halogenated hydrocarbon such as dichloromethane. If necessary, any of the above-mentioned tertiary amine bases can also be used as a solvent, and it must be noted that it is present in an appropriate excess. In this case, a separate proton remover is not required. The reaction should preferably be carried out between 5 ° C and 25t. in a! After a period of 60 hours, the reaction will be completely completed. The reaction can be carried out using thin layer chromatography (TLC) and an appropriate solvent system. When the reaction is determined to be complete by TLC, the product can be extracted with an organic solvent and purified by chromatography and / or recrystallization from a suitable solvent system. Because there are more than one hydroxyl group and one amine group in King's special product, it can also produce a mixture of tritiated compounds. If necessary, individual mono- and poly-fluorinated derivatives can be separated by, for example, chromatographic analysis, crystallization, supercritical extraction, etc. ^ If necessary, the polyfluorenyl compound of formula I can be prepared. , Where & and / or the Intellectual Property Bureau of the Ministry of Economic Affairs's employee cooperation cooperation printed (please read the precautions on the back before filling this page) L and / or l are the same fluorenyl group, it is better to use The method described above using an excess of an appropriate amidine-based reactant. In order to prepare a polyfluorenyl compound of formula I, in which dagger and / or and / or R3 are different, it is preferred to use the above-mentioned method of gradually selecting an appropriate reactant. It is also possible to ensure a specific reaction by selecting the appropriate protecting group. The choice of these methods is shown in the flow chart i below. Any combination of these methods can be used to make a specific product. ___ 7 This paper size is applicable to the national standard (CNS) A4 (21 ^^ 17 ~-'

45 898 145 898 1

五、發明說明(6 ) aauuJQ 經濟部智慧財產局員工消費合作社印製 NHCOR·V. Description of the invention (6) aauuJQ Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs NHCOR ·

流程圖1 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用十國圉家標準(CNS)A4規格(210 X 297公釐) 45 898 1 A7 'B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(y) 以下的實施例描述本發明兩種較佳的金氏特品衍生物 之製備。 實施例1 反油酸(5’)-金氏特品酯 將一含有1.6毫莫爾HC1 毫升的DMF,加入 至2’,2’-二氟去氧呋喃核糖基胞嘧啶(金氏特品)(0.42 克,1.6毫莫爾)的30毫升DMF溶液中,然後加入一含有 反油酸氯化物(0.51克,1.7毫莫爾)的3毫升DMF溶液 且該反應混合物在周圍溫度中攪拌12小時。該溶劑在高度 真空下蒸發,而其粗產物則於一矽膠管柱中,以具有15% 甲醇的氯仿溶液作爲洗提系統進行純化。將該不純的流出 物部分進行再純化,得到總共0.25克(30% )之標題化合 物。 ]H NMR(DMS0-d& 300 MHz) 5 :7.5( 1H, d, ArH), 7.45 (2H, br. s, NH2), 6.45(1H, d, -OH), 6.17(1H, t, CH-Γ ), 5.8(1H, d, ArH), 5.35(2H, m, CH=CH), 4.4-4.05(3H, m, CH2-5' and CH-4'), 3.95(1H, m, CH-3'), 2.35(2H, t, CH2-COO), 1.95(4H,m, CH2-CH=), 1.55(29, m, CH2-C-COO), 1.25(20H, m, CHa), 0.85 (3H, t,CH〇。 13C NMR (DMSO-da, 75 MHz) 5 : 172.67(COO), 165.63(04),154.51(C-2), 141.12(C-6),130.08 以及 130.03(C-9, '/c-10'' ), 126.09, 122.67 以及 9 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) tf I i i n n » n - · -_ ϋ (請先閱讀背面之注意事項再填寫本頁) η 〇> 1 \η- 經濟部智慧財產局員工消費合作社印製 Λ B7 修 ΐΕ. 五、發明說明(?) ..h .、 . ...... 119.24(t, C-2/ ), 94.86(C-5), 83.90(C-r ), 77.36(0-4^ ), 70.41, 70.11以及 69.80(t, C-3r), 62.53(C-5, ), 33.24, 31.95, 31.29, 29.00, 28.94, 28.84, 28.72, 28. 50, 28.43, 28. (CH2), 13.94 (CH3). 33, 24.34, 22.1 1 此外,少量的(0.05克)反油酸 由不純流出物部分中被分離出來。 (3’)-金氏特品酯 'H NMR (DMS0-d6, 300 MHz) 5 : 7 .65(1H, d, ArH), 7.40(2H, d, NH2) , 6.25(1H, t, CH- Γ), 5.82(1H, d, ArH), 5.4-5.2(4H, m, OH-5', CH= =CH and CH-3'), 4.15(1H, m, CH-4,) ,3.85-3.55(2H, m, CH2-5'), 2.45(2H, t, CH'2-〇}〇), 1.95(2H, m, CH2-C=), 1.55(2H, m, CH2-C-COO), 1.25(20H, m, CH2), 0.85(3H,t, CHj). nC NMR (DMS0-d6, 75 MHz) δ :171.70 (COO), 165,69 (C-4) , 154.46(C-2), 141.30(C-6), 130.10 以 及 130.03(C-9, ’/C-1011), 125.17 ,121.72 以及 118.27(t, C-2/ ), 94.78(C-5), 83.78(C-T ), 78.41(C-4,), 69.93, 69.60以及 69.30(t, C-3。, 59.15(0-5^ ), 32.95, 31.93, 31.26, 28.98, 28.90, 28.81, 28.69, 28.46, 28.28, 22.09(CH2), 13.95(CH3), 實施例2 反油酸(N4)-金氏特品醯胺 10 28.23, 24.26, ----------- — ----:----訂--------1·ίΑ <請先閱讀背面之注意事項再填寫本頁> 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 898 1 經濟部智慧財產局員Η消費合作社印製 A7 //;- -y-] 々 T37,' 叫 f j 五、發明說明(7 ) ; 將反油酸氯化物(〇·57克,1.9毫莫爾)加入至 2’,2’-二氟-去氧呋喃核糖基胞嘧啶(金氏特品)(0.38克 ,1.3毫莫爾)的5ml吡啶溶液中,然後將反應混合物在周 圍溫度中攪拌2.5小時。該溶劑在高度真空下蒸發,而其 粗產物則於一矽膠管柱中,以具有15%甲醇的氯仿溶液作 爲洗提系統進行純化。含有流出物部分之產物被蒸發,且 將其殘餘物在超音波浴以醚/己烷處理。該結晶物質被乾燥 ,得到0.1克(15% )之標題化合物ϋ Ή NMR (DMS0-d6 300 MHz) δ : 10.95( 1H,s,NHCO), 8.25(1H, d, ArH), 7.25(1H, d, ArH), 6.30(1H, d, -OH), 6.15(1H, t, CH-Γ), 5.35(2H, m, CH 二 CH), 5.30(1H, t, -OH), 4.2(1H, m, CH-4M, 3.9-3.6(3H, m, CH-3, and CH2-51), 2.35(2H, t, CH2-C0N), 1.95(2H, m, CH2-C=), 1.55(2H, in, dC-OX)),1.25 (20H, m,CH2) ,0.85 (3H, t, CH3). I3C NMR (DMSO-ds, 75 MHz) <5 : 174.06 (CONH), 162.89 (C-4), 154.22(02), 144.69(C-6), 130.04(C-9' '/C-10' ' ), 122.94(Jci'= 259Hz, C-2'), 95.9KC-5), 84.11(Jcf= 31Hz, C-V ) , 81.02 (C-Ar ), 68.35(Jcp- 22Hz, C-3'), 58.76(0-5^), 36.38, 31.94, 31.28, 28.99, 28.83, 28.71, 28.56, 28.48, 28.30, 24.34, 22,10 (CH2), 13.94 (CHi). 本發明之較佳的金氏特品衍生物,其在治療惡性疾病 方面,比起金氏特品本身要具有一較高的治療價値。該結 (請先間讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 898 1 Α7 經濟部智慧財產局員工消費合作社印製 Β7 ^ 1|- 五、發明說明(/<0 ':: ·:Ί l-…一..... 1Q ·Flowchart 1 (Please read the notes on the back before filling out this page) This paper size is applicable to the Ten Nations Standard (CNS) A4 (210 X 297 mm) 45 898 1 A7 'B7 Employees ’Consumption of Intellectual Property, Ministry of Economic Affairs Printed by the cooperative V. Description of the invention (y) The following examples describe the preparation of two preferred King's specialty derivatives of the present invention. Example 1 Esterole (5 ')-King's Special Product Ester A DMF containing 1.6 millimolar HC1 ml was added to 2', 2'-difluorodeoxyfuran ribosylcytosine (King's special product) ) (0.42 g, 1.6 mmoles) in 30 ml of DMF, then 3 ml of DMF solution containing transoleate chloride (0.51 g, 1.7 mmoles) was added and the reaction mixture was stirred at ambient temperature for 12 minutes. hour. The solvent was evaporated under high vacuum, and the crude product was purified in a silica gel column using a chloroform solution with 15% methanol as the elution system. This impure effluent portion was repurified to obtain a total of 0.25 g (30%) of the title compound. ] H NMR (DMS0-d & 300 MHz) 5: 7.5 (1H, d, ArH), 7.45 (2H, br. S, NH2), 6.45 (1H, d, -OH), 6.17 (1H, t, CH -Γ), 5.8 (1H, d, ArH), 5.35 (2H, m, CH = CH), 4.4-4.05 (3H, m, CH2-5 'and CH-4'), 3.95 (1H, m, CH -3 '), 2.35 (2H, t, CH2-COO), 1.95 (4H, m, CH2-CH =), 1.55 (29, m, CH2-C-COO), 1.25 (20H, m, CHa), 0.85 (3H, t, CH〇. 13C NMR (DMSO-da, 75 MHz) 5: 172.67 (COO), 165.63 (04), 154.51 (C-2), 141.12 (C-6), 130.08 and 130.03 (C -9, '/ c-10' '), 126.09, 122.67 and 9 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) tf I iinn »n-· -_ ϋ (Please read first Note on the back, please fill in this page again) η 〇 > 1 \ η- Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Λ B7 修 ΐΕ. 5. Description of the invention (?) ..H .. ..... 119.24 (t, C-2 /), 94.86 (C-5), 83.90 (Cr), 77.36 (0-4 ^), 70.41, 70.11 and 69.80 (t, C-3r), 62.53 (C-5, ), 33.24, 31.95, 31.29, 29.00, 28.94, 28.84, 28.72, 28. 50, 28.43, 28. (CH2), 13.94 (CH3). 33, 24.34, 22.1 1 In addition, a small amount of (0.05 g) Esteroleic acid was separated from the impure effluent fraction. (3 ')-Special's NMR (DMS0-d6, 300 MHz) 5: 7.65 (1H, d, ArH) , 7.40 (2H, d, NH2), 6.25 (1H, t, CH- Γ), 5.82 (1H, d, ArH), 5.4-5.2 (4H, m, OH-5 ', CH = = CH and CH- 3 '), 4.15 (1H, m, CH-4,), 3.85-3.55 (2H, m, CH2-5'), 2.45 (2H, t, CH'2-〇} 〇), 1.95 (2H, m , CH2-C =), 1.55 (2H, m, CH2-C-COO), 1.25 (20H, m, CH2), 0.85 (3H, t, CHj). NC NMR (DMS0-d6, 75 MHz) δ: 171.70 (COO), 165,69 (C-4), 154.46 (C-2), 141.30 (C-6), 130.10 and 130.03 (C-9, '/ C-1011), 125.17, 121.72 and 118.27 (t , C-2 /), 94.78 (C-5), 83.78 (CT), 78.41 (C-4,), 69.93, 69.60, and 69.30 (t, C-3. , 59.15 (0-5 ^), 32.95, 31.93, 31.26, 28.98, 28.90, 28.81, 28.69, 28.46, 28.28, 22.09 (CH2), 13.95 (CH3), Example 2 Pinamine 10 28.23, 24.26, ----------------: ---- Order -------- 1 · ίΑ < Please read the precautions on the back first Fill out this page again> This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 45 898 1 Printed by A7, member of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives //;--y-] 々T37, 'Called fj V. Description of the invention (7); Adding oleic acid chloride (0.57 g, 1.9 mmol) to 2', 2'-difluoro-deoxyribofuranosylcytosine (King's special Product) (0.38 g, 1.3 mmol) in 5 ml of pyridine solution, and then the reaction mixture was stirred at ambient temperature for 2.5 hours. The solvent was evaporated under high vacuum, and the crude product was purified in a silica gel column using a chloroform solution with 15% methanol as the elution system. The product containing the effluent fraction was evaporated and its residue was treated with ether / hexane in an ultrasonic bath. The crystalline material was dried to obtain 0.1 g (15%) of the title compound. Ή NMR (DMS0-d6 300 MHz) δ: 10.95 (1H, s, NHCO), 8.25 (1H, d, ArH), 7.25 (1H, d, ArH), 6.30 (1H, d, -OH), 6.15 (1H, t, CH-Γ), 5.35 (2H, m, CH di-CH), 5.30 (1H, t, -OH), 4.2 (1H , m, CH-4M, 3.9-3.6 (3H, m, CH-3, and CH2-51), 2.35 (2H, t, CH2-C0N), 1.95 (2H, m, CH2-C =), 1.55 ( 2H, in, dC-OX)), 1.25 (20H, m, CH2), 0.85 (3H, t, CH3). I3C NMR (DMSO-ds, 75 MHz) < 5: 174.06 (CONH), 162.89 (C -4), 154.22 (02), 144.69 (C-6), 130.04 (C-9 '' / C-10 ''), 122.94 (Jci '= 259Hz, C-2'), 95.9KC-5), 84.11 (Jcf = 31Hz, CV), 81.02 (C-Ar), 68.35 (Jcp- 22Hz, C-3 '), 58.76 (0-5 ^), 36.38, 31.94, 31.28, 28.99, 28.83, 28.71, 28.56, 28.48, 28.30, 24.34, 22,10 (CH2), 13.94 (CHi). The better King's special product derivative of the present invention has a higher treatment of malignant diseases than the King's special product itself. The price of treatment is rampant. The knot (please read the precautions on the back before filling out this page) The paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 45 898 1 Α7 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Β7 ^ 1 |-5. Description of the invention (/ &0; 0 :: ·: Ί l -... 一 ..... 1Q ·

- ~ . J 果已經同時以單一和重複劑量之投與,而表示於兩個不同 的體內模型上。對於單一劑量治療而言,該衍生物之效果 比起金氏特品本身,爲要較佳或者至少可相比擬的。特別 是對於醯胺衍生物’表現其優異之效果只需要金氏特品劑 量的25%。-~. J results have been administered in single and repeated doses simultaneously and are shown on two different in vivo models. For single-dose treatments, the effect of this derivative is better or at least comparable to that of King's special product itself. In particular, the excellent effect of the amidine derivative 'requires only 25% of the amount of King's special product.

有關於重複劑量之投與,金氏特品衍生物與金氏特品 本身相比較時,其效果的差異更爲明顯。此情形同時反映 在增加的存活時間,以及長期的存活者數D 另一個明顯的特徵在於,金氏特品本身不論在高度範 圍或中度範圍的重複劑量上,皆有毒性被觀察到。而雖然 金氏特品本身在無毒低範圍劑量(丨毫克/公斤)上的效果 是很好的’但比起N4-醯胺以及5’-酯衍生物的效果仍嫌遜 色。金氏特品的最佳效果之血漿濃度爲約,但超過 時,就會因爲磷酸化機制的飽和而造成抗癌效果被抑 制的情形。(參見Gandhi,金氏特品中之金氏特品細胞藥 劑學(Cellular Pharmacology of Gemcitabine in Gemciubine):臨床試驗設計與評估之原理(Rationales for Clinical Trial Design and Evaluation) , Mini Symposium, 12.3.96, Vrije Uni vers i tei t Amsterdam) ° 相對的,本發明之較佳的金氏特品衍生物,其最佳的金氏 特品血漿濃度時間被延長,卻不會到達抑制濃度(>35μΜ )。這可能是因爲該衍生物不會磷酸化,以及可能不是一 個該磷酸化機制的抑制劑。 在癌症治療上一個主要的問題就是對於治療的抗性產 本紙張尺度適用中國®家標準(CNS)A4規格(2.10 X 297公釐) ----------- 裝-----r---訂 -------- (請先閱讀背面之注意事項再填寫本頁) 45 898 1 A7 竽B7 經濟部智慧財產局員工消費合作杜印製 五、發明說明(!丨) ' 生。多重藥劑抗性(MDR)是--個造成其原本應爲有效良好 藥劑之主要的失敗原因。吾人已經發現本發明之較佳的衍 生物在某些方面會阻礙MDR-幫浦,因此避開了這個問題產 生。 核苷類以及核苷類似物如金氏特品之細胞性的吸收, 其主要係藉由選擇性的核苷運輸(NT)受器。 該受器的調節/抑制可以被視爲,在臨床狀態中,其對 於藥劑之抗性。該現象在試管中可以經由加入NT抑制劑而 觀察到。吾人已經驚異地發現到這些衍生物,其並不因爲 NT抑制劑的存在而被影響,因爲此較佳之衍生物的細胞穩 定性活性(cytostatic activity)在該抑制劑的存在下會 被保留。 血駿中的金氏特品半生期約爲10分鐘 > 适是因爲其藉 由內生性酵素去氧胞苷脫胺酶,而快速的脫胺成爲相關的 尿嘧啶衍生物。(參見P.G. Johnston等人,癌症化學療 法以及生物性反應的調節劑(Cancer Chromatography and Biological Response Modifiers ) > Annual 16, 1996,Regarding the administration of repeated doses, the difference between King's special product derivatives and King's special product is more obvious when compared. This situation is also reflected in the increased survival time and long-term survivor number D. Another obvious feature is that King's specialty itself has been observed to have toxicity in repeated doses in both high and medium ranges. Although King's special product itself has a good effect in a non-toxic low-range dose (丨 mg / kg) ', it is still inferior to N4-amidamine and 5'-ester derivatives. The optimal plasma concentration of King's special product is about, but when it exceeds, the anti-cancer effect will be suppressed due to the saturation of the phosphorylation mechanism. (See Gandhi, Cellular Pharmacology of Gemcitabine in Gemciubine): Rationales for Clinical Trial Design and Evaluation, Mini Symposium, 12.3.96, Vrije Uni vers i tei t Amsterdam) ° In contrast, the preferred King's special product derivative of the present invention has its plasma concentration time prolonged without reaching the inhibitory concentration (> 35 μΜ) . This may be because the derivative is not phosphorylated and may not be an inhibitor of the phosphorylation mechanism. A major problem in the treatment of cancer is the application of China® Family Standard (CNS) A4 (2.10 X 297 mm) to the paper size of the resistant paper. --r --- Order -------- (Please read the notes on the back before filling out this page) 45 898 1 A7 竽 B7 Consumption Cooperation between Employees and Intellectual Property Bureau of the Ministry of Economy ! 丨) 'Health. Multidrug resistance (MDR) is a major cause of failure that would otherwise be effective and good. We have found that the better derivatives of the present invention hinder MDR-pumps in some ways, and thus avoid this problem. The cellular absorption of nucleosides and nucleoside analogs such as King's special products is mainly through selective nucleoside transport (NT) receptors. The regulation / inhibition of this receptor can be regarded as its resistance to the agent in a clinical state. This phenomenon can be observed in test tubes by adding NT inhibitors. I have surprisingly found that these derivatives are not affected by the presence of NT inhibitors, because the cytostatic activity of this better derivative is retained in the presence of the inhibitor. The half-life of King ’s specialty in Blood Jun is about 10 minutes > It is due to its rapid deamination by the endogenous enzyme deoxycytidine deaminase to become the relevant uracil derivative. (See P.G. Johnston et al. Cancer Chromatography and Biological Response Modifiers) > Annual 16, 1996,

Chap· 1,ed. Pinedo H.M.等人) 相反的,本發明之衍生物則爲此去活化酵素的不良受 質,所以其半生期是增加的。因此,本發明之衍生物比起 金氏特品本身,其在治療系統性或局部性的惡性腫瘤上是 更爲適合的。 本發明之新化合物不只潛在地在治療癌症上有用,其 亦具有如抗病毒劑的活性。 <請先間讀背面之注f項再填寫本頁> 裝 訂---------Θ 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 Β9δ Α7 Β&. _3. 修正 經濟部智慧財產局員工消費合作社印製 五、發明 3兑明(I3* ) ——.....…· 牛物學 實驗 金氏特品反油酸醯胺以及金氏特品-5’-反油酸酯 的細胞毒素活性,其以兩對嚙齒類動物和人類腫瘤細胞株 來進行調查,此二組皆包含一親株以及子株,對於金氏特 品具有抗性或者交互抗性。 該細胞株爲人類卵巢腫瘤細胞株A2780,以及對於金 氏特品具有抗性並具有去氧胞苷激酶缺陷之子株AG6000 ; 和老鼠結腸腫瘤細胞株C26A,以及具有沒有改變的去氧胞 苷激酶、但胸苷激酶I卻減少10倍之子株AG6000。每一化 合物的細胞毒性,都以連續的72小時藥物投與來進行評估 "藉由SRB分析來決定細胞數目,計算每一腫瘤株生長抑 制情形的百分比,以及IC50値、以/xM表示,此爲該化合 物與控制組相比較,其引起50%生長抑制之濃度。 結果 若將金氏特品本身的細胞毒素活性,與金氏特品-N4-反油酸醯胺和金氏特品-5’-反油酸酯的細胞毒素活性相比 較,其以表示之1C50値表示於下表中。金氏特品衍生 物之活性,其比起被測試的細胞株中的金氏特品,細胞毒 素活性要遠遠大的多。 表細胞株 C26-A、C26-G、A2780 以及 AG6000 中, 14 本紙張尺度適用中國國家標準(CNS)A4規格mo X 297公f ) ------ ----- 4^·----r---訂-------ίθ ί請先閱讀背面之注意事項再填寫本頁)Chap. 1, ed. Pinedo H.M. et al.) Conversely, the derivatives of the present invention have a poor substrate for this deactivating enzyme, so their half-life is increased. Therefore, the derivatives of the present invention are more suitable for treating systemic or localized malignant tumors than the King's special product itself. The novel compounds of the present invention are not only potentially useful in the treatment of cancer, they also have activities such as antiviral agents. < Please read note f on the back before filling in this page > Binding --------- Θ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 45 Β9δ Α7 Β &. _3. Revised the printing by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Invented 3 Da Ming (I3 *) ——........... Bovine physiology experiment King's special product oleamide and gold Cytotoxin activity of 5'-transoleate, which was investigated with two pairs of rodent and human tumor cell lines. Both groups contain a parent strain and a daughter strain, which are resistant to King's special product. Or cross-resistance. The cell line is a human ovarian tumor cell line A2780, and a daughter strain AG6000 that is resistant to King's specialty and has deoxycytidine kinase deficiency; and a mouse colon tumor cell line C26A, and has unmodified deoxycytidine kinase , But thymidine kinase I was reduced by a factor of 10 in AG6000. The cytotoxicity of each compound was evaluated by continuous drug administration for 72 hours. "The number of cells was determined by SRB analysis, and the percentage of growth inhibition of each tumor strain was calculated. IC50 値, expressed as / xM, This is the concentration of the compound that caused 50% growth inhibition compared to the control group. Results If the cytotoxic activity of King's special product itself is compared with the cytotoxic activity of King's special product-N4-Erylamide and King's special product 5'-Antioleate, it is expressed as 1C50 値 is shown in the table below. The activity of King's specialty derivatives is much greater than that of King's specialty in the cell line tested. Among the cell lines C26-A, C26-G, A2780 and AG6000, 14 paper sizes are applicable to China National Standard (CNS) A4 specifications mo X 297 male f) ------ ----- 4 ^ ·- --- r --- Order ------- ίθ ί Please read the notes on the back before filling in this page)

45 89R45 89R

其金氏特品本身、金氏特品-N4-反油酸醯胺和金氏特品-5’-反油酸酯的細胞毒素活性 > 該活性係以IC50値(/iM)表 示 C26-A C26-G A2780 AG6000 金氏特品 0.0055 0.0075 0.0005 100 金氏特品-N4 -反油酸醯胺 <0.0001 <0.0001 <0.0001 35 金氏特品-5’-反油酸酯 0.0003 0.0005 <0.0001 100 CEM細胞中,其金氏特品本身和金氏特品-5’-反油酸 酯的細胞穩定性活性,係在有或沒有核苷運輸調節劑(硝 化苄基硫纖維核苷(NBMPR),或者普山定(Persantine) (Pyridamole))的存在下進行測定。 正如可以在下表中見到者,金氏特品之IC50,其比起 金氏特品-5’-反油酸酯之IC50要大過兩倍多。若加入NT 抑制劑時,金氏特品本身之IC50値則會上升10倍之多’ 但與此相對的,金氏特品-5’-反油酸酯的IC50値指略爲受 到影響5的增加)。在「抗性」的狀態中,其較佳 之衍生物比起原始藥劑可達到15〜20倍的效果。 化合物 IC50 値 (/^ Μ) 無抑制劑 _IC50 値(μΜ) NBMPR 100/iM IC50 値(#M) 普山定 4 u g/ml 金丄特品 0. Π ±0.01 1 . 11±0.08 1.26±〇·〇4 _ 金士特品-5s -反汕酸酯 0.047±〇.〇〇6 0.0M±0.〇34 0,065 士 〇.023 15 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注項再填寫本頁) t n .^1--ο*· * n I 1— n n I— 1 經濟部智慧財產局員工消費合作社印製 898 1Cytotoxin activity of King's special product itself, King's special product-N4-Erylamide and King's special product-5'-Eoleate > The activity is expressed as IC50 値 (/ iM) C26 -A C26-G A2780 AG6000 King's special product 0.0055 0.0075 0.0005 100 King's special product -N4 -Phenylamine oleate < 0.0001 < 0.0001 < 0.0001 35 King's special product-5'-transoleate 0.0003 0.0005 < 0.0001 100 In CEM cells, the cell-stabilizing activity of King's own product and King's special-5'- transoleate is based on the presence or absence of a nucleoside transport regulator (nitrogenated benzyl sulfur fiber). The measurement was performed in the presence of a nucleoside (NBMPR) or Persantine (Pyridamole). As can be seen in the table below, the IC50 of King's Specialty is more than twice the IC50 of King's Special-5'- transoleate. If NT inhibitor is added, the IC50 値 of King's special product itself will increase by 10 times'. However, the IC50 値 of King's special product-5'-transoleate will be slightly affected. 5 Increase). In the "resistance" state, its better derivative can achieve 15 to 20 times the effect compared to the original drug. Compound IC50 値 (/ ^ Μ) No inhibitor _IC50 値 (μΜ) NBMPR 100 / iM IC50 値 (#M) Pushanding 4 ug / ml Gold special product 0. Π ± 0.01 1.11 ± 0.08 1.26 ± 〇 · 〇4 _ Kingshi special product-5s-anti-shante acid 0.047 ± 〇.〇〇6 0.0M ± 0.03 0,065 ± 0.023 15 This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the note on the back before filling out this page) tn. ^ 1--ο * · * n I 1— nn I— 1 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 898 1

五、發明說明(/f ) S 金氏特品-N4-反油酸醯胺或金氏特品-5’-反油酸酯, 其抗腫瘤之效果係藉由在老鼠的生體內,調查其兩種不同 之腫瘤型式,以及單獨和重複劑量投與之情形而被決定。 金氏特品-N4-反油酸醯胺或金氏特品-5’-反油酸酯在 以Co-26接種老鼠脾臟之效果 在第0天以惡性直腸腫瘤Co-26,接種至Balb/c雌性 老鼠的脾臟內。在此模型中,腫瘤主要係在肝臟內發育。 在第1天開始進行腹膜腔內之治療。本化合物之單獨劑量 並與金士特品本身之單獨劑量進行比較測試。其中還使用 生理食鹽水作爲控制阻。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 老鼠數Η 物質 劑量 mg/kg 平均存活 時間T/C [% ] 長期之存 活者 (>35d) 中毒死亡 10 生理食鹽水 8 金氏特品-Ν、 反油酸醯胺 25 103.7 5/8 1/8 7 金氏特品-55 _ 反油酸酯 75 128.6 1/7 0/7 7 金氏特品-5 ’ -反油酸酯 100 100.1 4/7 0/7 7 金氏特品 75 132.8 2/7 0/7 7 金氏特品 100 116.2 4/7 0/7 16 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) “ 898 A7Μ ,:. 修 經濟部智慧財產局員工消費合作社印製 五、發明說明(β) 對於被測試之化合物,其死亡動物之平均存活時間均位 於相同範圍之內。金氏特品-Ν4-反油酸醯胺,其比起金氏特 品-5’-反油酸酯以及金氏特品要優異的多,其關於5/8存活 者之需要劑量,只要25mg/kg之劑量,但是金氏特品卻要 100 mg/kg 。 在一個平行實驗中,在第1~11天重複劑量之投與。 老鼠數目 物質 劑量 mg/kg 平均存活 時間T/C {% 1 長期之存 活者 (>46d) 中毒死亡 10 也迎食鹽水 8 金氏特品-N4 ~ 反油酸醯胺 1 155 2/8 0/8 8 金氏特品-N' 反油酸醯胺 4 185.6 1/8 0/8 8 金氏特品-5^ 反油酸酯 1 *—-- 150.6 1/8 0/8 8 金氏特品-5 ’ _ 反油酸酯 4 166.9 3/8 2/8 8 金氏特品 1 170 6 2/8 1/8 8 金氏特品 4 毒性的 0/8 8/8 —^1 在本貫驗中’以金氏特n反細随以及低劑量 金士特品_5,.反油酸酷,比起以低劑量金氏特品本身,其 17 本紙張尺度適用中國國家標準(CNS)A4規格⑵0 X 297公^ (請先閲讀背面之注項再填寫本頁) -lull· — — — 經濟部智慧財產局員工消費合作社印製 45 898 1 门./„ 11 B7 薇 ΪΕ 五、發明說明(u) 年月K u > 1 10. -6 、' 一............................... ....... 所獲得之結果更佳或至少相同。雖然高劑量金氏特品-5’-反油酸酯具有輕微之毒性,但比起高劑量金氏特品本身而 言,則其毒性又輕微了許多。 金氏特品-N4-反油酸醯胺或金氏特品-5’-反油酸酯於老 鼠內以單一劑量或重複劑量腹膜內注射P-388之效果 將老鼠淋巴白血病(murine lymphatic leukaemia) P388細胞植入B6D2F1雌性老鼠腹膜內。在第1天細胞被植 入腹膜內之後開始治療。在單獨劑量治療以及重複劑量治 療之後5天,以及重複劑量治療之後10天,紀錄其平均存 活時間、長期存活者數、以及中毒死亡情形。金氏特品-5’-反油酸酯的單獨劑量投與,比起相同劑量之金士特品, 其具有較延長的存活時間和長期的存活者數。 單獨劑量投與 老鼠數目 物質 劑量 平均存活 長期之存 中毒死亡 mg/kg 時間T/C 活者 [% } (>35d) 9 生理食鹽水 6 金氏特品- 75 186.3 1/6 0/6 5’-反油酸酯 6 金氏特品- 100 138.9 0/6 0/6 5’·反油酸酯 6 金氏特品 75 138.9 0/6 0/7 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1^1 I n H ^1 · H IV ^1 H 訂--------- <請先閱讀背面之注意事項再填寫本頁) 4-5 898 五、發明說明( •w"―' ~ Μ η ίη 。 修正 、c 二·*·υ 重複劑量投與,第1〜4天 老鼠數目 物質 劑量 g/kg 平均存活 時間T/C [% ] 長期之存 活者 (>35d) 中毒死亡 8 生理食鹽水 6 金氏特品-N4-反油酸醯胺 1 178 2/6 0/6 6 金氏特品-N4 · 反油酸醯胺 4 183 1/6 0/6 6 金氏特品 15 58.0 0/6 6/6 在第1〜4天以重複劑量投與之金氏特品-N4-反油酸醯胺 ,不論在1以及4mg/kg投與,皆有長期存活者以及更延長 的平均存活時間,其活性更爲明顯。在控制組中以15mg/kg 金氏特品投與之所有動物均死於中毒。 -----I I---- ---i-il — 訂·----1 — — -.^ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用令國國家標準(CNS)A4規格(210 X 297公釐) 458981 五、發明說明((f) I a7 重複劑量投與,第丄天 老鼠數目 物質 劑量 mg/kg 平均存活 時間T/C 1% ] 長期之存 活者 (>45d) 中毒死C 9 生理食鹽水 6 金氏特品-N4-反油酸醯 胺 1 172.5 1/6 0/6 6 金氏特品. N4-反油酸醯 胺 4 215.7 0/6 0/6 6 金! 特品~ 5’-反油酸酯 1 317.0 0/6 0/6 6 金氏特品-5’-反油酸酯 4 220.6 2/6 0/6 6 金氏特品 1 178.8 0/6 0/6 6 金氏特品 4 71.9 /6 /7 (請先間讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 與短期的治療相比較1 10天期的治療增加了抗腫瘤的 活性。在mg/kg的基礎上金氏特品本身的毒性較強’其4 mg/kg即造成6/6的中毒死亡情形。在以金氏特品-N4-反油 酸醯胺以及金氏特品-5*-反油酸酯來進行重複治療之後’ 發現有長期存活者的存在,同時以金氏特品-N4-反油酸酿 胺以及金氏特品-5’-反油酸酯處理後也實際地增加了平均 20 本紙張尺度適用中國國家標準<CNS)A4規格(210 X 297公釐) 4 B B 9 8 1 ------- 五、發明說明(J) 0的」〇/!_矿 .. ----------------------------------- 存活時間。 本發明之金氏特品酯類或醯胺類可以系統性地投與* 不論是經皮或者非經皮地投與。 對於經皮投與,本發明之活性化合物,其存在之型式 可以爲,例如軟或硬明膠膠囊、錠劑、顆粒、粒狀或粉狀 、糖衣錠、糖漿、懸浮液或溶液。 當非經皮投與時,本發明之金氏特品酯類或醯胺類, 較理想可以爲注射或者輸液型式、懸浮液或乳劑。 該製劑可含有惰性或藥劑動力學上活化的添加劑,以 及熟於此技藝者常用之配方物質。舉例來說,錠劑或顆粒 可以含有一系列的結合劑、塡充劑物質、乳化劑、載劑物 質或者稀釋劑。液體製劑也可以以如經過殺菌的溶液之型 式來存在。 膠囊除了活性成分以外,可以含有一塡充劑物質或者 增稠劑。此外,也可以加入改善風味的添加劑、以及防腐 劑、安定劑、保濕劑、乳化劑、爲改變滲透壓之鹽類、緩 衝液、以及其他添加劑。 本發明製劑劑量所投與的程度,其將根據製劑的使用 型式'以及施用途徑和病患之需要而有所不同。一般而言 ,對於平均成人病患的系統治療上,其每日劑量爲約0.1-150mg/kg體重/日,較佳爲l_4〇mg/kg體重/日。局部投與 ’例如軟膏,則可以含有藥劑配方重量之0.1-10%,特別 是0,5-5%重量。 若有需要,含有金氏特品酯類或醯胺類的醫藥製劑可 本紙張尺度適用十國國家標準(CNS)A4規格(210 X 297公釐) (諝先閱璜背面之庄意事項再填寫本頁) * I I I l· I I I 訂 -------1·^ 經濟部智慧財產局員工消費合作社印製 45 898 1 A7 B7, 五、發明說明( 6 以含有抗氧化劑,例如,生育酚、N-甲基-生育胺、 butylated hydrocyanisole、抗壞血酸或丁基翔甲苯。 組合療法,亦即在投與本發明之金氏特品酯或醯胺的 同時,倂用其他療法,例如外科、輻射療法以及化學療法 等都是可以考慮的。舉例來說,腦瘤的較佳療法似乎就是 組合外科以及本發明之金氏特品酯或醯胺,來進行系統性 或局部性的投與。 I f n m I in Ϊ I 一OJJ n f I (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 2 2 本紙張尺度適用中國國家標準(CNS)A4規格(2】〇χ297公釐)V. Description of the invention (/ f) S King's special product-N4-Phenylamine oleate or King's special product-5'-Eoleate, its antitumor effect is investigated in the living body of mice. Its two different tumor types are determined, as well as in the case of separate and repeated dose administrations. Effect of King's Special-N4-Erylamide or King's Special-5'-Antioleate on Co-26 Vaccination of Mouse Spleen On Day 0, Malignant Rectal Tumor Co-26 was Inoculated to Balb / c Female spleen. In this model, tumors develop primarily in the liver. Intraperitoneal treatment was started on day 1. The individual doses of this compound are tested in comparison with the individual doses of Kingston itself. Among them, physiological saline is used as the control resistance. (Please read the precautions on the back before filling this page) Consumption cooperation by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Du printed mice Number of substances mg / kg Mean survival time T / C [%] Long-term survivors (> 35d) Death from poisoning 10 Physiological saline 8 King's special product-N, glutamine oleate 25 103.7 5/8 1/8 7 King's special product -55 _ transoleate 75 128.6 1/7 0/7 7 King's special product Special product-5 '-transoleate 100 100.1 4/7 0/7 7 King's product 75 132.8 2/7 0/7 7 King's product 100 116.2 4/7 0/7 16 This paper size is applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) "898 A7M,:. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of Invention (β) The average survival of dead animals for the tested compounds The time is in the same range. King's special product -N4-Erylamide is much better than King's special product -5'- transoleate and King's special product, which is about 5 / 8 The required dose for survivors is only 25 mg / kg, but King's special product is 100 mg / kg. In a parallel experiment, the dose was repeated on days 1-11 Number of rats Substance dose mg / kg Mean survival time T / C {% 1 Long-term survivor (> 46d) Poisoned death 10 Also welcomed saline 8 King's special product-N4 ~ Ethanolamine 1 155 2/8 0/8 8 King's special product-N 'phosphonium oleate 4 185.6 1/8 0/8 8 King's special product-5 ^ transoleate 1 * ---- 150.6 1/8 0 / 8 8 King's special product-5 '_ oleate 4 166.9 3/8 2/8 8 King's special product 1 170 6 2/8 1/8 8 King's special product 4 Toxic 0/8 8 / 8 — ^ 1 In this test, 'King's special n anti-following and low-dose King's special product _5, oleic acid is cool, compared with the low-dose King's special product itself, its 17 paper size Applicable to China National Standard (CNS) A4 specification ⑵0 X 297 male ^ (Please read the note on the back before filling this page) -lull · — — — 45 898 1 door printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs. / „ 11 B7 薇 ΪΕ V. Description of the invention (u) Year K u > 1 10. -6 、 '一 ............... ............ The results obtained are better or at least the same. Although the high-dose King's special product-5'-transoleate is slightly toxic, it is much less toxic than the high-dose King's special product itself. King's special product-N4-Erylamide or King's special product-5'-Eoleate in mice in a single dose or repeated doses of intraperitoneal injection of P-388. Murine lymphatic leukaemia ) P388 cells were implanted into the peritoneum of B6D2F1 female mice. Treatment was started after the cells were implanted into the peritoneum on day 1. The average survival time, number of long-term survivors, and poisoning deaths were recorded 5 days after single-dose and repeated-dose treatments, and 10 days after repeated-dose treatments. The single dose administration of King's special product-5'-transoleate has a longer survival time and long-term survivors than King's special product of the same dose. Individual doses administered to mice Number of substance doses Average survival Long-term survival Poisoning death mg / kg Time T / C Living [%] (> 35d) 9 Physiological saline 6 King's special product-75 186.3 1/6 0/6 5'-Antioleate 6 King's Special Product-100 138.9 0/6 0/6 5 '· Antioleate 6 King's Special Product 75 138.9 0/6 0/7 This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297 mm) 1 ^ 1 I n H ^ 1 · H IV ^ 1 H Order --------- < Please read the notes on the back before filling this page) 4- 5 898 5. Description of the invention (• w " ― '~ Μ η ίη. Correction, c Ⅱ ··· υ repeated dose administration, the number of rats on the 1st to 4th days, substance dose g / kg, average survival time T / C [% ] Long-term survivors (> 35d) Poisoning death 8 Physiological saline 6 King's special product-N4-Erylamide 1 178 2/6 0/6 6 King's special product-N4 · Erythramine 4 183 1/6 0/6 6 King's special product 15 58.0 0/6 6/6 King's special product-N4-Erylamide, administered in repeated doses on days 1 to 4, regardless of 4mg / kg administration, both long-term survivors and more The survival time, its activity is more obvious. In the control group, all the animals administered with King's special product died of poisoning. ----- I I ---- --- i-il — order · ---- 1 — —-. ^ (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies the national standard (CNS) A4 specification (210 X 297 mm) 458981 V. Description of the invention ((f) I a7 Repeated dose administration, the number of mice on day 物质 Substance dose mg / kg Mean survival time T / C 1%] Long-term survivor (> 45d) Poisoned to death C 9 Physiological saline 6 King's special product-N4-Erylamide 1 172.5 1/6 0/6 6 King's special product. N4-Erysalamine 4 215.7 0/6 0/6 6 Gold! Special product ~ 5'- transoleate 1 317.0 0/6 0/6 6 King's special product-5'- transoleate 4 220.6 2/6 0/6 6 King's special product 1 178.8 0/6 0 / 6 6 King's special product 4 71.9 / 6/7 (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs compared with short-term treatment 1 10-day treatment increase Anti-tumor activity. On the basis of mg / kg, King's special product itself is more toxic. Its 4 mg / kg caused 6/6 poisoning deaths. After repeated treatments with King's Special-N4-Erylamide and King's Special-5 * -Eoleate ', the presence of long-term survivors was found, while King's Special-N4- After treatment with oleic acid amine and King's special product -5'- transoleate, the average is also increased by an average of 20 paper sizes. Applicable to the Chinese national standard < CNS) A4 size (210 X 297 mm) 4 BB 9 8 1 ------- V. Description of the invention (J) 0 of the "〇 /! _ Ore .. ------------------------ ----------- Survival time. The King's specialty esters or amidines of the present invention can be administered systematically * whether transdermally or non-percutaneously. For transdermal administration, the active compound of the present invention may be present in the form of, for example, soft or hard gelatin capsules, lozenges, granules, granules or powders, dragees, syrups, suspensions or solutions. When administered transdermally, the King's specialty esters or amidines of the present invention may ideally be injectable or infusion types, suspensions or emulsions. The formulation may contain inert or pharmacokinetically activated additives, as well as formulation substances commonly used by those skilled in the art. For example, lozenges or granules may contain a range of binding agents, filler materials, emulsifiers, carrier materials or diluents. Liquid preparations may also be presented in the form of a sterilized solution. In addition to the active ingredients, capsules may contain a filling substance or a thickener. In addition, flavor improving additives, preservatives, stabilizers, humectants, emulsifiers, salts for changing osmotic pressure, buffers, and other additives may be added. The degree to which the dosage of the formulation of the invention is administered will vary depending on the type of formulation used, as well as the route of administration and the needs of the patient. Generally speaking, for the average adult patient's systemic treatment, the daily dose is about 0.1-150 mg / kg body weight / day, preferably 1-4 mg / kg body weight / day. Topical administration, such as ointments, may contain from 0.1 to 10% by weight of the pharmaceutical formulation, especially from 0.5 to 5% by weight. If necessary, pharmaceutical preparations containing King's specialty esters or amidines can be applied to this paper's national standards (CNS) A4 specifications (210 X 297 mm) (please read the solemn matters on the back before reading) (Fill in this page) * III l · Order III ------- 1 · ^ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 45 898 1 A7 B7, V. Description of the invention (6 To contain antioxidants, for example, fertility Phenol, N-methyl-tocopherylamine, butylated hydrocyanisole, ascorbic acid or butyltoluene. Combination therapies, that is, other therapies, such as surgery, radiation therapy, are administered at the same time as the gentamicin or amidine of the present invention. As well as chemotherapy, etc. can be considered. For example, the preferred therapy for brain tumors seems to be a combination of surgery and the gentamicin or amidine of the present invention for systemic or local administration. I fnm I in Ϊ I 一 OJJ nf I (Please read the precautions on the back before filling out this page) Duo printed by the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 2 This paper size applies to China National Standard (CNS) A4 specifications (2). χ297 mm)

Claims (1)

F 898 880059 ABCD it;. 利範圍 種金氏特品(Gemcitabine)衍生物,其具 有下式(IF 898 880059 ABCD it ;. The scope of interest is a kind of Gemcitabine derivative, which has the following formula (I R,0 Λ0, \&gt;ΓR, 0 Λ0, \ &gt; Γ 0、 (I) 其中’ l,1^2及r3係獨立地選自於氫及C18-和c2。-的飽和以 及單不飽和醯基基團,其條件爲h,r2及r3不可以全爲氫 2、 根據申請專利範圍第1項之金氏特品衍生物,其中 比,匕及R3中僅有一個爲醯基基團。 3、 根據申請專利範圍第2項之金氏特品衍生物,其中 該單醯基的取代係位於糖部分的3’-0或5’-◦位置。 — II--I------ 裝 I I I — 丨 I 訂 — — — — — 丨 II -梦 J (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 4、根據申請專利範圍第3項之金氏特品衍生物,其中 該單醯基的取代係位於糖部分的5,-0位置。 5、根據申請專利範圍第1項之金氏特品衍生物,其中 LL及h係選自油醯基、反油醯基 '順-二十烯酸基(cis_ 本紙張尺度適用中國國家標準(CNS)A4規格(2丨0x 297公髮) A5 898 1 經濟部智慧財產局員工消費合作社印製 A8 Π8 C8 D8 六、申請專利範圍 eicosenoyl )及反-二十嫌酸基(trans-eicosenoyl ) ° 6、 一種反油酸(5’)-金氏特品酯。 7、 一種反油酸(N4)-金氏特品醯胺。 8、 一種用於治療癌症之醫藥組成物|其包括根據申請 專利範圍第1項之金氏特品衍生物,以及一藥學上可接受 之載劑或賦形劑。 9、 一種用於治療病毒感染之醫藥組成物,其包括根據 申請專利範圍第1項之金氏特品衍生物,以及一藥學上可 接受之載劑或賦形劑。 10、 根據申請專利範圍第1項之金氏特品衍生物,其 係作爲抗癌劑。 Π、根據申請專利範圍第1項之金氏特品衍生物,其 係作爲抗病毒劑。 12、 根據申請專利範圍第1項之金氏特品衍生物,其 係用於製造一具有抗癌活性之醫藥組成物。 13、 一種製備如申請專利範圍第丨項所定義之金氏特 __ 2 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公t ) ------^-11111, 裝·-------訂----—--I I (靖先閱讀背面之注意事項再填寫本頁) 5 8 9 8 1 A8 B8 C8 D8 申請專利範圍 品衍生物之方法,其特徵在於將金氏特品與下式之化合物 反應: FaX 其中Fa爲一單不飽和(^或C2〇的脂肪酸之醯基基團,且X 爲一離去基。 (請先閱讀背面之注意事項再填寫本頁) 訂----- 線If 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) - 案 號 ί1 /&lt;c) 年 類 別 ML」 月R 七·〜一- 以上各攔由本局填註) 修正 A4 C4 U 458981 裔—專利説明書 經濟部晳^^吒^㈢工^-费合作社印製 發明Λ r 一,新型名稱 中 文 金氏特品衍生物 英 文 GEMCITABINE DERIVATIVES 姓 名 國 籍 1. 菲恩.麥海倫 2. 白恩.波瑞仁 3. 艾瑞.道倫 4. 瑪瑞特.里蘭.聖弗 發明, - '創作 挪威 住、居所 1. 挪威,Ν-3915波爾斯葛蘭,雷爾庫柏7號 2. 挪威,Ν-3940海斯達,葛蘭里爾3號 3. 挪威,Ν-7015佐恩韓,諾達布隆斯維7號 4. 挪威,Ν-3931波爾斯葛蘭,斯奇弗范31號 姓 名 (名稱) 挪斯克海德羅公司 國 籍 挪威 三' 申請人 住、居所 (事務所) 挪威0240奧斯陸,拜道伊街2號 代表人 姓 名 艾林.安得森 1 裝 訂 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐〉 45 898 1 A7 _ i_07 _ 五、發明說明(/ ) !0. - C 本發明係關於2_,2·-二氟-去氧胞苷(金氏特品( Gemciubine))之特定長鏈的飽和及單不飽和脂肪酸衍生 物,及包含該衍生物之醫藥組成物。金氏特品係具有下式0, (I) wherein '1, 1 ^ 2 and r3 are independently selected from hydrogen and C18- and c2. -Saturated and monounsaturated fluorenyl groups, provided that h, r2 and r3 may not be all hydrogen 2. According to the special product of King ’s special product in the scope of the patent application, the ratio of dagger and R3 is only One is a fluorenyl group. 3. The King's special product derivative according to item 2 of the scope of patent application, wherein the substitution of the monofluorenyl group is located at the 3'-0 or 5'-◦ position of the sugar moiety. — II--I ------ Install III — 丨 I Order — — — — — 丨 II-Dream J (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 4. The King's special product derivative according to item 3 of the scope of patent application, wherein the substitution of the monofluorenyl group is located at the 5, -0 position of the sugar moiety. 5. According to the King ’s special product derivative according to item 1 of the scope of the patent application, LL and h are selected from the group consisting of oleyl group and anti-oleyl group cis-icosenoic acid group (cis_ This paper size applies to Chinese national standards ( CNS) A4 specification (2 丨 0x 297) A5 898 1 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 Π8 C8 D8 6. Application scope of patents eicosenoyl and trans-eicosenoyl ° 6. An oleic acid (5 ')-King's special product ester. 7. An oleic acid (N4) -King's specialty pinamide. 8. A medicinal composition for treating cancer | It includes a derivative of King's special product according to the first patent application scope, and a pharmaceutically acceptable carrier or excipient. 9. A pharmaceutical composition for treating a viral infection, comprising a derivative of King's special product according to item 1 of the scope of patent application, and a pharmaceutically acceptable carrier or excipient. 10. The King's special product derivative according to item 1 of the scope of patent application, which is used as an anticancer agent. Π. King's special product derivative according to item 1 of the scope of patent application, which is used as an antiviral agent. 12. The King's special product derivative according to item 1 of the scope of patent application, which is used to manufacture a pharmaceutical composition with anti-cancer activity. 13, a kind of preparation as defined in the scope of the patent application 丨 __ 2 This paper size applies Chinese National Standard (CNS) A4 specifications (21〇X 297 g t) ------ ^-11111, Packing ------- Ordering ------- II (Jing first read the precautions on the back and then fill out this page) 5 8 9 8 1 A8 B8 C8 D8 The method of applying for a patent scope product derivative, which It is characterized by reacting King's special product with a compound of the following formula: FaX, where Fa is a monounsaturated (^ or C20 fatty acid fluorenyl group, and X is a leaving group. (Please read the note on the back first) Please fill in this page again for the order) Order ----- Line If printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm)-Case No. 1 / &lt; c) Year category ML "Month R. 7 ~~ 1-The above blocks are filled by this Office) Amendment A4 C4 U 458981-Patent Specification Clear Ministry of Economics ^^ 吒 ^ ㈢ 工 ^ -Fei Cooperative printed invention Λ r a , New name Chinese King's Special Product Derivatives English GEMCITABINE DERIVATIVES Name Nationality 1. Fein. McHelen 2. Byrne Borrell 3. Erie Doren 4. Mariette Leland Saint-Ferre invented,-'Creating a Norwegian residence and residence 1. Norway, NR-3915 Perth Gram, Rael Cooper 7 No.2, Norway, Ν-3940, Heistar, Gramliel No. 3. 3. Norway, Ν-7015, Zornhan, Noda Bronswei No. 4. Norway, Ν-3931, Bolsglen, Schifferfan No. 31 Name (Name) Norsk Hydero Nationality Norway III 'Applicant's residence, residence (office) Norway 0240 Oslo, No. 2 Baydowy Street Representative name Elin Anderson 1 Binder The paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 45 898 1 A7 _ i_07 _ V. Description of the invention (/)! 0.-C The present invention relates to 2_, 2 · -difluoro-deoxycells Specific long-chain saturated and monounsaturated fatty acid derivatives of glycosides (Gemciubine), and pharmaceutical compositions containing the derivatives. King's special products have the following formula OH &lt;請先閱讀背面之注意事項再填寫本頁) 裝·!--r . 經濟部智慧財產局員工消費合作社印製 金氏特品係爲一種核苷類似體,其已經在活體內和活 體外硏究中顯示治療贅生現象(neoplasUc conditions) 的效果° (參見新抗癌劑(New anticancer agents), We1SS等人,癌的化學治療以及生物性反應調節劑第16號 手冊(Cancer Chemotherapy and Biological Response Modifiers Annual 16),編者 Pinedo,Longo 及 Chabner, 1996。Elsevier Science B.V.,腫瘤學討論會補充( Supplement to Seminars in Oncology ) ,Vo 1 . 22, No. 4,Supp丨.11,1995,編者Yarbro等人。金氏特品氫氯化 物(Gemc it abine Hydrochloride):臨床前硏究之狀態( Status of Preclinical Studies))。而在金氏特品臨床 的發展上亦已被觀察到有助益的效果。在這些硏究中,金 3 冢紙張尺度適用中國國家標¥ (CNS)A4規格(2.10 x 297公釐) *ιιιιιιιϊ^ 經濟部智慧財產局員工消費合作社印製 45 8 如 i B7 五、發明說明(α ) 氏特品的臨床和副作用效果都高度地具有計劃依存性° ( 參見腫瘤學討論會(Seminars in Oncology) V〇l. 22, No. 4, Suppi. 11, 1995, ρρ 42-46) ΰ 金氏特品在細胞內係藉由去氧胞苷激酶使其活化至'活 化型式,亦即金氏特品三磷酸(dFdCTP)。與此相平行的 是,金氏特品藉由去氧胞苷脫胺酶去活化爲相關的尿喃B定 衍生物(去活化)。 吾人現在已驚訝地發現金氏特品的某種脂肪酸衍生物 具有完全改變之藥物動力學以及組織分布情形。這種情形 特別可以在如RES、肺臟、胰臟、腸部、食道、子宮、卵巢 、黑色瘤及乳房部的惡性疾病的例子中。 本發明之化合物係以下式I表示:OH &lt; Please read the notes on the back before filling this page) --r. The King ’s special strain printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economics is a nucleoside analogue, which has shown the effect of treating neoplasUc conditions in vivo and in vitro studies ° ( See New anticancer agents, We1SS, et al. Cancer Chemotherapy and Biological Response Modifiers Annual 16 (Editor Pinedo, Longo & Chabner, 1996. Elsevier) Science BV, Supplement to Seminars in Oncology, Vo 1.22, No. 4, Supp 丨. 11, 1995, editor Yarbro et al. Gemc it abine Hydrochloride : Status of Preclinical Studies). In the clinical development of King's specialty products, beneficial effects have also been observed. In these studies, the paper size of the gold 3 mound is applicable to the Chinese national standard ¥ (CNS) A4 specification (2.10 x 297 mm) * ιιιιιιιϊ ^ Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 45 8 Such as i B7 V. Invention Description The clinical and side effects of (α) 's special products are highly plan-dependent ° (see Seminars in Oncology V.l. 22, No. 4, Suppi. 11, 1995, ρρ 42-46 ) ΰ King's special product is activated intracellularly by deoxycytidine kinase to the 'activated form, which is King's special product triphosphate (dFdCTP). In parallel to this, King's special product is deactivated by deoxycytidine deaminase to the related uridine B derivative (deactivation). I have now surprisingly discovered that a certain fatty acid derivative of King's special product has completely changed pharmacokinetics and tissue distribution. This can be particularly the case for malignant diseases such as RES, lungs, pancreas, intestines, esophagus, uterus, ovary, melanoma and breast. The compound of the present invention is represented by the following formula I: ⑴ 其中Ri ’ 1及R3係獨立地選自於氫及Cia-和的飽 和以及單不飽和醯基基團,其條件爲]^,卩2及1不可以全 爲氫。 金氏特品具有三種可衍生性的功能,亦即5,_以及 4 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 x 297公髮) «^1 i 1 n ^^1 . · · ^^1 n n I ^ 0U. · f— n 1 (請先閱讀背面之注意事項再填寫本頁) 45 898 1 A7 B7 五、發明說明(》) 羥基基團和N4-胺基基團。該每一基團可被選擇性地改變成 酯或醯胺衍生物’但是二-加合物(二-脂類或者酯-醯胺類 )以及三-加合物亦可以被改變形成。在二-加合物以及三_ 加合物的例子中,醯基取代基基團並不一定要相同。 目前,本發明之單-醯基衍生物(亦即’ Ri,R2及I中 的兩者爲氫)係爲較佳。具有醯基基團的單取代特別較佳 的是在糖部分的3’-0及5’-0位置,具有5’-0位置取代者 爲最佳。 單不飽和醯基基團的雙鍵位置可能爲順式或反式構型 ,但其治療效果可能會依照其所使用之不同構型而有所不 同。 於單不飽和醯基基團中的雙鍵位置亦可能會影響該活 性。目前,吾人較偏好使用在心9位置爲不飽和之酯類或醯 胺類。在系統之命名中,單不飽和脂肪酸的雙鍵ω位置係 由終端的甲基數起,因此,例如,二十烯酸在 其鏈中具有20個碳原子,而其單一雙鍵則位在鏈終端的甲 基數起第9及10個碳之間。 吾人較偏好者爲fi用由油酸(CwlccT9,順式)、反油 酸,反式)、二十烯酸(Ctlo^,順式)以及( Cwlo'9,反式)所衍生之酯類,酯類-醯胺類以及醯胺類, 而醯胺類及5’-酯類目前則爲本發明最佳之衍生物。 由硬脂酸(Cl8:0)及二十酸(gq:o)所衍生之金氏特 品酯類、酯類-醯胺類以及醯胺類在一些情況下則特別有利 〇 5 (請先閱讀背面之泫意事項再填寫本頁) -I I — t I I 訂 - - -------線 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) d5 898 1 A7 :卜 07 五、發明說明(f ) 根據本發明之金氏特品衍生物,一般而言,其可根據 下列反應式所製備: 驗 Nu-YH + FaX -&gt; Nu-Y-Fa -HX 經濟部智慧財產局員工消費合作社印製 其中Nu-YH係表示金氏特品,Y爲在糖部分的3’及/或 5’位置的氧,或者在金氏特品的嘧啶部分的4位置的氮, Fa爲一單不飽和h或者C2U脂肪酸的醯基基團,且X爲離 去基,例如,Cl、Br、3-瞳唑烷-2-硫酮( 3-thiazolidine-2-thione)或 OR,,其中 R,爲 Fa、COCIL·、 COEt或者C0CF3。因此,本反應係以核苷的醯化反應來進 行。其中,其係使用脂肪酸、特別是醯基鹵類或酸酐類的 適當反應性衍生物來完成。 一般而言,其需要有質子去除劑的存在,以去除由反 應所釋放之HX酸。因此,可以加入鹼到反應混合物。舉例 來說,當使用醯基鹵例如醯基氯時,三級胺鹼類如三乙基 胺、Ν,Ν-二甲基苯胺、吡啶或者Ν,Ν-二甲基胺基毗啶可被 加入至反應混合物中,以結合到該被釋放之氫鹵酸上。在 其他的例子中,反應中所使用之溶劑可作爲質子去除劑。 正常地,醯化反應之進行可以不需要催化劑。該反應 性的脂肪酸衍生物FaX,在某些例子中,可以藉由偶合劑如 1化-二環己基碳化二亞胺(0〇:)、心乙基州’-(3-二甲基 胺基丙基)碳化二亞胺(EDC)或0- (1H-苯並三唑-1-基) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) {請先閱讀背面之注意事項再填寫本頁) .^1 n It ^TOJa n n n 1 458981 A7 五、發明說明($ ) L -比1^屮、四甲基脲四氟硼酸鹽(罚罚),而在其原位( i n s i t u)形成。 該反應較佳係於一不反應的溶劑如N,N -二甲基甲醯胺 或鹵化烴如二氯甲烷中進行。若有需要,任何上述的三級 胺鹼類也可以作爲溶劑,此外必須注意的是其係以一適當 的過量存在。在此情況下則不需要一獨立的質子去除劑。 該反應較佳地應保持在5°C和25t之間來進行。在一個! 到60小時的時段之後,該反應將會被徹底地完成。該反應 的過程可以使用薄層色層分析法(TLC)以及適當的溶劑系 統來進行。當該反應在以薄層色層分析法(Τΐχ)決定完成 時,其產物可以有機溶劑萃取,並且以色層分析法及/或由 適當之溶劑系統再結晶來進行純化。因爲在金氏特品中存 在有超過一個羥基基團以及—個胺基基團,所以其亦可產 生醯化化合物的混合物。若有需要,可以藉由例如色層分 析法、結晶法、超臨界萃取法等,來分離出所需要之單獨 的單-及多-醯化衍生物^ 若是需要製備-式I之多醯基化合物,其中&amp;及/或 經濟部智慧財產局員工消費合作杜印製 (請先閱讀背面之注意事項再填寫本頁) L及/或l爲相同之ϋ基基團時,其較佳爲利用上述使用過 量之適當醯基反應劑的方法。 若爲了要製備-式I之多醯基化合物,其中匕及/或 及/或R3爲不同,其較佳係利用上述逐步選擇適當反應劑 的方法。其亦可以藉由選擇適當之保護基團以確保—特定 之反應。這些方法之選擇示於下述流程圖i。這些方法之任 一組合可以被用來製備特定之產物。 ___ 7 本紙張尺度適用令固國家i準(CNS)A4規格(21^^17~ --'⑴ where Ri '1 and R3 are independently selected from the group consisting of hydrogen and Cia-saturated and monounsaturated fluorenyl groups, provided that ^, and 卩 2 and 1 may not be all hydrogen. King's special products have three derivable functions, namely 5, _ and 4 paper sizes applicable to China National Standard (CNS) A4 specifications (21〇x 297 issued) «^ 1 i 1 n ^^ 1. · · ^^ 1 nn I ^ 0U. · F— n 1 (Please read the notes on the back before filling out this page) 45 898 1 A7 B7 V. Description of the invention (") Hydroxyl group and N4-amine group. Each of these groups can be selectively changed to an ester or amidine derivative ', but di-adducts (di-lipids or ester-amidamines) and tri-adducts may also be changed to form. In the examples of di-adducts and tri-adducts, the fluorenyl substituent groups need not necessarily be the same. Currently, the mono-fluorenyl derivatives of the present invention (i.e., both of 'Ri, R2 and I are hydrogen) are preferred. Mono-substitutions having a fluorenyl group are particularly preferred at the 3'-0 and 5'-0 positions of the sugar moiety, and those having a 5'-0 position are most preferred. The position of the double bond of the monounsaturated fluorenyl group may be in the cis or trans configuration, but its therapeutic effect may vary depending on the different configurations used. The position of the double bond in the monounsaturated fluorenyl group may also affect the activity. At present, we prefer to use esters or amines which are unsaturated at the 9th position. In the nomenclature of a system, the double bond ω position of a monounsaturated fatty acid starts from the number of methyl groups at the terminal. Therefore, for example, eicosenoic acid has 20 carbon atoms in its chain and its single double bond Between the 9th and 10th carbons from the number of methyl groups at the end of the chain. My preference is fi using esters derived from oleic acid (CwlccT9, cis), transoleic acid, trans), eicosenoic acid (Ctlo ^, cis), and (Cwlo'9, trans) Esters-amidines and amidoamines, and amidines and 5'-esters are currently the best derivatives of the present invention. King's specialty esters, ester-amidamines, and amidines derived from stearic acid (Cl8: 0) and eicosanoic acid (gq: o) are particularly advantageous in some cases. 05 (please first Read the intentions on the back and fill in this page) -II — t II Order------------ Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper is printed in accordance with China National Standard (CNS) A4 specifications ( (210 X 297 mm) d5 898 1 A7: Bu 07 V. Description of the invention (f) According to the special product of King's special product of the present invention, in general, it can be prepared according to the following reaction formula: Nu-YH + FaX -&gt; Nu-Y-Fa -HX Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where Nu-YH represents King ’s special product, Y is oxygen at the 3 'and / or 5' position of the sugar portion, or Nitrogen at the 4-position of the pyrimidine part of King ’s special product, Fa is a fluorenyl group of a monounsaturated h or C2U fatty acid, and X is a leaving group, for example, Cl, Br, 3- pupilzolidine-2- 3-thiazolidine-2-thione or OR, wherein R is Fa, COCIL ·, COEt or COCF3. Therefore, the present reaction is carried out by a tritiated reaction of nucleosides. Among them, this is accomplished using an appropriate reactive derivative of a fatty acid, particularly a fluorenyl halide or an acid anhydride. Generally, it requires the presence of a proton remover to remove the HX acid released by the reaction. Therefore, a base can be added to the reaction mixture. For example, when using a fluorenyl halide such as fluorenyl chloride, tertiary amine bases such as triethylamine, N, N-dimethylaniline, pyridine, or N, N-dimethylaminopyridine can be Added to the reaction mixture to bind to the released halogen acid. In other examples, the solvent used in the reaction can be used as a proton removing agent. Normally, the tritiation reaction can proceed without a catalyst. The reactive fatty acid derivative FaX may, in some examples, be obtained through a coupling agent such as 1-dicyclohexylcarbodiimide (0: 0), ethyl ethyl '-(3-dimethylamine Propyl) carbodiimide (EDC) or 0- (1H-benzotriazol-1-yl) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) {Please read the back first Please note this page before filling in this page). ^ 1 n It ^ TOJa nnn 1 458981 A7 V. Description of the invention ($) L-ratio 1 ^ 屮, tetramethylurea tetrafluoroborate (penalty penalty), and in its original Insitu formation. This reaction is preferably carried out in an unreacted solvent such as N, N-dimethylformamide or a halogenated hydrocarbon such as dichloromethane. If necessary, any of the above-mentioned tertiary amine bases can also be used as a solvent, and it must be noted that it is present in an appropriate excess. In this case, a separate proton remover is not required. The reaction should preferably be carried out between 5 ° C and 25t. in a! After a period of 60 hours, the reaction will be completely completed. The reaction can be carried out using thin layer chromatography (TLC) and an appropriate solvent system. When the reaction is determined to be complete by TLC, the product can be extracted with an organic solvent and purified by chromatography and / or recrystallization from a suitable solvent system. Because there are more than one hydroxyl group and one amine group in King's special product, it can also produce a mixture of tritiated compounds. If necessary, individual mono- and poly-fluorinated derivatives can be separated by, for example, chromatographic analysis, crystallization, supercritical extraction, etc. ^ If necessary, the polyfluorenyl compound of formula I can be prepared. , Where &amp; and / or the Intellectual Property Bureau of the Ministry of Economic Affairs's employee cooperation cooperation printed (please read the precautions on the back before filling this page) L and / or l are the same fluorenyl group, it is better to use The method described above using an excess of an appropriate amidine-based reactant. In order to prepare a polyfluorenyl compound of formula I, in which dagger and / or and / or R3 are different, it is preferred to use the above-mentioned method of gradually selecting an appropriate reactant. It is also possible to ensure a specific reaction by selecting the appropriate protecting group. The choice of these methods is shown in the flow chart i below. Any combination of these methods can be used to make a specific product. ___ 7 This paper size is applicable to the national standard (CNS) A4 (21 ^^ 17 ~-' 45 898 1 五、發明說明(6 ) aauuJQ 經濟部智慧財產局員工消費合作社印製 NHCOR·45 898 1 V. Description of Invention (6) aauuJQ Printed by Consumer Consumption Cooperative of Intellectual Property Bureau, Ministry of Economic Affairs NHCOR · 流程圖1 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用十國圉家標準(CNS)A4規格(210 X 297公釐) 45 898 1 A7 'B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(y) 以下的實施例描述本發明兩種較佳的金氏特品衍生物 之製備。 實施例1 反油酸(5’)-金氏特品酯 將一含有1.6毫莫爾HC1 毫升的DMF,加入 至2’,2’-二氟去氧呋喃核糖基胞嘧啶(金氏特品)(0.42 克,1.6毫莫爾)的30毫升DMF溶液中,然後加入一含有 反油酸氯化物(0.51克,1.7毫莫爾)的3毫升DMF溶液 且該反應混合物在周圍溫度中攪拌12小時。該溶劑在高度 真空下蒸發,而其粗產物則於一矽膠管柱中,以具有15% 甲醇的氯仿溶液作爲洗提系統進行純化。將該不純的流出 物部分進行再純化,得到總共0.25克(30% )之標題化合 物。 ]H NMR(DMS0-d&amp; 300 MHz) 5 :7.5( 1H, d, ArH), 7.45 (2H, br. s, NH2), 6.45(1H, d, -OH), 6.17(1H, t, CH-Γ ), 5.8(1H, d, ArH), 5.35(2H, m, CH=CH), 4.4-4.05(3H, m, CH2-5' and CH-4'), 3.95(1H, m, CH-3'), 2.35(2H, t, CH2-COO), 1.95(4H,m, CH2-CH=), 1.55(29, m, CH2-C-COO), 1.25(20H, m, CHa), 0.85 (3H, t,CH〇。 13C NMR (DMSO-da, 75 MHz) 5 : 172.67(COO), 165.63(04),154.51(C-2), 141.12(C-6),130.08 以及 130.03(C-9, '/c-10'' ), 126.09, 122.67 以及 9 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) tf I i i n n » n - · -_ ϋ (請先閱讀背面之注意事項再填寫本頁) η 〇&gt; 1 \η- 經濟部智慧財產局員工消費合作社印製 Λ B7 修 ΐΕ. 五、發明說明(?) ..h .、 . ...... 119.24(t, C-2/ ), 94.86(C-5), 83.90(C-r ), 77.36(0-4^ ), 70.41, 70.11以及 69.80(t, C-3r), 62.53(C-5, ), 33.24, 31.95, 31.29, 29.00, 28.94, 28.84, 28.72, 28. 50, 28.43, 28. (CH2), 13.94 (CH3). 33, 24.34, 22.1 1 此外,少量的(0.05克)反油酸 由不純流出物部分中被分離出來。 (3’)-金氏特品酯 'H NMR (DMS0-d6, 300 MHz) 5 : 7 .65(1H, d, ArH), 7.40(2H, d, NH2) , 6.25(1H, t, CH- Γ), 5.82(1H, d, ArH), 5.4-5.2(4H, m, OH-5', CH= =CH and CH-3'), 4.15(1H, m, CH-4,) ,3.85-3.55(2H, m, CH2-5'), 2.45(2H, t, CH'2-〇}〇), 1.95(2H, m, CH2-C=), 1.55(2H, m, CH2-C-COO), 1.25(20H, m, CH2), 0.85(3H,t, CHj). nC NMR (DMS0-d6, 75 MHz) δ :171.70 (COO), 165,69 (C-4) , 154.46(C-2), 141.30(C-6), 130.10 以 及 130.03(C-9, ’/C-1011), 125.17 ,121.72 以及 118.27(t, C-2/ ), 94.78(C-5), 83.78(C-T ), 78.41(C-4,), 69.93, 69.60以及 69.30(t, C-3。, 59.15(0-5^ ), 32.95, 31.93, 31.26, 28.98, 28.90, 28.81, 28.69, 28.46, 28.28, 22.09(CH2), 13.95(CH3), 實施例2 反油酸(N4)-金氏特品醯胺 10 28.23, 24.26, ----------- — ----:----訂--------1·ίΑ &lt;請先閱讀背面之注意事項再填寫本頁&gt; 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 898 1 經濟部智慧財產局員Η消費合作社印製 A7 //;- -y-] 々 T37,' 叫 f j 五、發明說明(7 ) ; 將反油酸氯化物(〇·57克,1.9毫莫爾)加入至 2’,2’-二氟-去氧呋喃核糖基胞嘧啶(金氏特品)(0.38克 ,1.3毫莫爾)的5ml吡啶溶液中,然後將反應混合物在周 圍溫度中攪拌2.5小時。該溶劑在高度真空下蒸發,而其 粗產物則於一矽膠管柱中,以具有15%甲醇的氯仿溶液作 爲洗提系統進行純化。含有流出物部分之產物被蒸發,且 將其殘餘物在超音波浴以醚/己烷處理。該結晶物質被乾燥 ,得到0.1克(15% )之標題化合物ϋ Ή NMR (DMS0-d6 300 MHz) δ : 10.95( 1H,s,NHCO), 8.25(1H, d, ArH), 7.25(1H, d, ArH), 6.30(1H, d, -OH), 6.15(1H, t, CH-Γ), 5.35(2H, m, CH 二 CH), 5.30(1H, t, -OH), 4.2(1H, m, CH-4M, 3.9-3.6(3H, m, CH-3, and CH2-51), 2.35(2H, t, CH2-C0N), 1.95(2H, m, CH2-C=), 1.55(2H, in, dC-OX)),1.25 (20H, m,CH2) ,0.85 (3H, t, CH3). I3C NMR (DMSO-ds, 75 MHz) &lt;5 : 174.06 (CONH), 162.89 (C-4), 154.22(02), 144.69(C-6), 130.04(C-9' '/C-10' ' ), 122.94(Jci'= 259Hz, C-2'), 95.9KC-5), 84.11(Jcf= 31Hz, C-V ) , 81.02 (C-Ar ), 68.35(Jcp- 22Hz, C-3'), 58.76(0-5^), 36.38, 31.94, 31.28, 28.99, 28.83, 28.71, 28.56, 28.48, 28.30, 24.34, 22,10 (CH2), 13.94 (CHi). 本發明之較佳的金氏特品衍生物,其在治療惡性疾病 方面,比起金氏特品本身要具有一較高的治療價値。該結 (請先間讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 898 1 Α7 經濟部智慧財產局員工消費合作社印製 Β7 ^ 1|- 五、發明說明(/&lt;0 ':: ·:Ί l-…一..... 1Q · - ~ . J 果已經同時以單一和重複劑量之投與,而表示於兩個不同 的體內模型上。對於單一劑量治療而言,該衍生物之效果 比起金氏特品本身,爲要較佳或者至少可相比擬的。特別 是對於醯胺衍生物’表現其優異之效果只需要金氏特品劑 量的25%。 有關於重複劑量之投與,金氏特品衍生物與金氏特品 本身相比較時,其效果的差異更爲明顯。此情形同時反映 在增加的存活時間,以及長期的存活者數D 另一個明顯的特徵在於,金氏特品本身不論在高度範 圍或中度範圍的重複劑量上,皆有毒性被觀察到。而雖然 金氏特品本身在無毒低範圍劑量(丨毫克/公斤)上的效果 是很好的’但比起N4-醯胺以及5’-酯衍生物的效果仍嫌遜 色。金氏特品的最佳效果之血漿濃度爲約,但超過 時,就會因爲磷酸化機制的飽和而造成抗癌效果被抑 制的情形。(參見Gandhi,金氏特品中之金氏特品細胞藥 劑學(Cellular Pharmacology of Gemcitabine in Gemciubine):臨床試驗設計與評估之原理(Rationales for Clinical Trial Design and Evaluation) , Mini Symposium, 12.3.96, Vrije Uni vers i tei t Amsterdam) ° 相對的,本發明之較佳的金氏特品衍生物,其最佳的金氏 特品血漿濃度時間被延長,卻不會到達抑制濃度(&gt;35μΜ )。這可能是因爲該衍生物不會磷酸化,以及可能不是一 個該磷酸化機制的抑制劑。 在癌症治療上一個主要的問題就是對於治療的抗性產 本紙張尺度適用中國®家標準(CNS)A4規格(2.10 X 297公釐) ----------- 裝-----r---訂 -------- (請先閱讀背面之注意事項再填寫本頁) 45 898 1 A7 竽B7 經濟部智慧財產局員工消費合作杜印製 五、發明說明(!丨) ' 生。多重藥劑抗性(MDR)是--個造成其原本應爲有效良好 藥劑之主要的失敗原因。吾人已經發現本發明之較佳的衍 生物在某些方面會阻礙MDR-幫浦,因此避開了這個問題產 生。 核苷類以及核苷類似物如金氏特品之細胞性的吸收, 其主要係藉由選擇性的核苷運輸(NT)受器。 該受器的調節/抑制可以被視爲,在臨床狀態中,其對 於藥劑之抗性。該現象在試管中可以經由加入NT抑制劑而 觀察到。吾人已經驚異地發現到這些衍生物,其並不因爲 NT抑制劑的存在而被影響,因爲此較佳之衍生物的細胞穩 定性活性(cytostatic activity)在該抑制劑的存在下會 被保留。 血駿中的金氏特品半生期約爲10分鐘 &gt; 适是因爲其藉 由內生性酵素去氧胞苷脫胺酶,而快速的脫胺成爲相關的 尿嘧啶衍生物。(參見P.G. Johnston等人,癌症化學療 法以及生物性反應的調節劑(Cancer Chromatography and Biological Response Modifiers ) &gt; Annual 16, 1996, Chap· 1,ed. Pinedo H.M.等人) 相反的,本發明之衍生物則爲此去活化酵素的不良受 質,所以其半生期是增加的。因此,本發明之衍生物比起 金氏特品本身,其在治療系統性或局部性的惡性腫瘤上是 更爲適合的。 本發明之新化合物不只潛在地在治療癌症上有用,其 亦具有如抗病毒劑的活性。 &lt;請先間讀背面之注f項再填寫本頁&gt; 裝 訂---------Θ 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 Β9δ Α7 Β&amp;. _3. 修正 經濟部智慧財產局員工消費合作社印製 五、發明 3兑明(I3* ) ——.....…· 牛物學 實驗 金氏特品反油酸醯胺以及金氏特品-5’-反油酸酯 的細胞毒素活性,其以兩對嚙齒類動物和人類腫瘤細胞株 來進行調查,此二組皆包含一親株以及子株,對於金氏特 品具有抗性或者交互抗性。 該細胞株爲人類卵巢腫瘤細胞株A2780,以及對於金 氏特品具有抗性並具有去氧胞苷激酶缺陷之子株AG6000 ; 和老鼠結腸腫瘤細胞株C26A,以及具有沒有改變的去氧胞 苷激酶、但胸苷激酶I卻減少10倍之子株AG6000。每一化 合物的細胞毒性,都以連續的72小時藥物投與來進行評估 &quot;藉由SRB分析來決定細胞數目,計算每一腫瘤株生長抑 制情形的百分比,以及IC50値、以/xM表示,此爲該化合 物與控制組相比較,其引起50%生長抑制之濃度。 結果 若將金氏特品本身的細胞毒素活性,與金氏特品-N4-反油酸醯胺和金氏特品-5’-反油酸酯的細胞毒素活性相比 較,其以表示之1C50値表示於下表中。金氏特品衍生 物之活性,其比起被測試的細胞株中的金氏特品,細胞毒 素活性要遠遠大的多。 表細胞株 C26-A、C26-G、A2780 以及 AG6000 中, 14 本紙張尺度適用中國國家標準(CNS)A4規格mo X 297公f ) ------ ----- 4^·----r---訂-------ίθ ί請先閱讀背面之注意事項再填寫本頁) 45 89RFlowchart 1 (Please read the notes on the back before filling out this page) This paper size is applicable to the Ten Nations Standard (CNS) A4 (210 X 297 mm) 45 898 1 A7 'B7 Employees ’Consumption of Intellectual Property, Ministry of Economic Affairs Printed by the cooperative V. Description of the invention (y) The following examples describe the preparation of two preferred King's specialty derivatives of the present invention. Example 1 Esterole (5 ')-King's Special Product Ester A DMF containing 1.6 millimolar HC1 ml was added to 2', 2'-difluorodeoxyfuran ribosylcytosine (King's special product) ) (0.42 g, 1.6 mmoles) in 30 ml of DMF, then 3 ml of DMF solution containing transoleate chloride (0.51 g, 1.7 mmoles) was added and the reaction mixture was stirred at ambient temperature for 12 minutes. hour. The solvent was evaporated under high vacuum, and the crude product was purified in a silica gel column using a chloroform solution with 15% methanol as the elution system. This impure effluent portion was repurified to obtain a total of 0.25 g (30%) of the title compound. ] H NMR (DMS0-d &amp; 300 MHz) 5: 7.5 (1H, d, ArH), 7.45 (2H, br. S, NH2), 6.45 (1H, d, -OH), 6.17 (1H, t, CH -Γ), 5.8 (1H, d, ArH), 5.35 (2H, m, CH = CH), 4.4-4.05 (3H, m, CH2-5 'and CH-4'), 3.95 (1H, m, CH -3 '), 2.35 (2H, t, CH2-COO), 1.95 (4H, m, CH2-CH =), 1.55 (29, m, CH2-C-COO), 1.25 (20H, m, CHa), 0.85 (3H, t, CH〇. 13C NMR (DMSO-da, 75 MHz) 5: 172.67 (COO), 165.63 (04), 154.51 (C-2), 141.12 (C-6), 130.08 and 130.03 (C -9, '/ c-10' '), 126.09, 122.67 and 9 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) tf I iinn »n-· -_ ϋ (Please read first Note on the back, please fill in this page again) η 〇 &gt; 1 \ η- Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Λ B7 修 ΐΕ. 5. Description of the invention (?) ..H .. ..... 119.24 (t, C-2 /), 94.86 (C-5), 83.90 (Cr), 77.36 (0-4 ^), 70.41, 70.11 and 69.80 (t, C-3r), 62.53 (C-5, ), 33.24, 31.95, 31.29, 29.00, 28.94, 28.84, 28.72, 28. 50, 28.43, 28. (CH2), 13.94 (CH3). 33, 24.34, 22.1 1 In addition A small amount (0.05 g) of oleic acid was separated from the impure effluent fraction. (3 ')-Special Ester'H NMR (DMS0-d6, 300 MHz) 5: 7.65 (1H, d, ArH), 7.40 (2H, d, NH2), 6.25 (1H, t, CH- Γ), 5.82 (1H, d, ArH), 5.4-5.2 (4H, m, OH-5 ', CH = = CH and CH-3 '), 4.15 (1H, m, CH-4,), 3.85-3.55 (2H, m, CH2-5'), 2.45 (2H, t, CH'2-〇} 〇), 1.95 (2H , m, CH2-C =), 1.55 (2H, m, CH2-C-COO), 1.25 (20H, m, CH2), 0.85 (3H, t, CHj). nC NMR (DMS0-d6, 75 MHz) δ: 171.70 (COO), 165,69 (C-4), 154.46 (C-2), 141.30 (C-6), 130.10 and 130.03 (C-9, '/ C-1011), 125.17, 121.72, and 118.27 (t, C-2 /), 94.78 (C-5), 83.78 (CT), 78.41 (C-4,), 69.93, 69.60, and 69.30 (t, C-3. , 59.15 (0-5 ^), 32.95, 31.93, 31.26, 28.98, 28.90, 28.81, 28.69, 28.46, 28.28, 22.09 (CH2), 13.95 (CH3), Example 2 Pinamine 10 28.23, 24.26, ----------------: ---- Order -------- 1 · ίΑ &lt; Please read the precautions on the back first Fill out this page again> This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 45 898 1 Printed by A7, member of the Intellectual Property Bureau of the Ministry of Economic Affairs, Consumer Cooperatives //;--y-] 々T37, 'Called fj V. Description of the invention (7); Adding oleic acid chloride (0.57 g, 1.9 mmol) to 2', 2'-difluoro-deoxyribofuranosylcytosine (King's special Product) (0.38 g, 1.3 mmol) in 5 ml of pyridine solution, and then the reaction mixture was stirred at ambient temperature for 2.5 hours. The solvent was evaporated under high vacuum, and the crude product was purified in a silica gel column using a chloroform solution with 15% methanol as the elution system. The product containing the effluent fraction was evaporated and its residue was treated with ether / hexane in an ultrasonic bath. The crystalline material was dried to obtain 0.1 g (15%) of the title compound. Ή NMR (DMS0-d6 300 MHz) δ: 10.95 (1H, s, NHCO), 8.25 (1H, d, ArH), 7.25 (1H, d, ArH), 6.30 (1H, d, -OH), 6.15 (1H, t, CH-Γ), 5.35 (2H, m, CH di-CH), 5.30 (1H, t, -OH), 4.2 (1H , m, CH-4M, 3.9-3.6 (3H, m, CH-3, and CH2-51), 2.35 (2H, t, CH2-C0N), 1.95 (2H, m, CH2-C =), 1.55 ( 2H, in, dC-OX)), 1.25 (20H, m, CH2), 0.85 (3H, t, CH3). I3C NMR (DMSO-ds, 75 MHz) &lt; 5: 174.06 (CONH), 162.89 (C -4), 154.22 (02), 144.69 (C-6), 130.04 (C-9 '' / C-10 ''), 122.94 (Jci '= 259Hz, C-2'), 95.9KC-5), 84.11 (Jcf = 31Hz, CV), 81.02 (C-Ar), 68.35 (Jcp- 22Hz, C-3 '), 58.76 (0-5 ^), 36.38, 31.94, 31.28, 28.99, 28.83, 28.71, 28.56, 28.48, 28.30, 24.34, 22,10 (CH2), 13.94 (CHi). The better King's special product derivative of the present invention has a higher treatment of malignant diseases than the King's special product itself. The price of treatment is rampant. The knot (please read the precautions on the back before filling out this page) The paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 45 898 1 Α7 Printed by the Consumers ’Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Β7 ^ 1 |-V. Description of the invention (/ <0 ':: ·: Ί l-… 一 ..... 1Q ·-~. J The results have been given in single and repeated doses at the same time, and shown in two On different in vivo models. For a single-dose treatment, the effect of this derivative is better or at least comparable to that of King's special product itself. Especially for the amidine derivative, it has excellent performance. The effect requires only 25% of the dose of King's special product. Regarding the administration of repeated doses, the difference between the effects of King's special product and King's special product is more obvious. This situation is also reflected in the increase Survival time, and long-term survivor number D Another significant feature is that King's special product itself has been observed to be toxic regardless of its high or medium range of repeated doses. Although King's special product itself In non-toxic low range agents (丨 mg / kg) The effect is very good, but it is still inferior to the effect of N4-amidine and 5'-ester derivatives. The plasma concentration of the best effect of King's special product is about, but exceeds At times, the anti-cancer effect is inhibited due to the saturation of the phosphorylation mechanism. (See Gandhi, Cellular Pharmacology of Gemcitabine in Gemciubine: Clinical trial design and Principles of Evaluation (Rationales for Clinical Trial Design and Evaluation), Mini Symposium, 12.3.96, Vrije Uni vers i tei t Amsterdam) ° Relatively, the better King's special product derivative of the present invention, its best gold The plasma concentration time of Pruritus is prolonged, but it does not reach the inhibitory concentration (&gt; 35 μM). This may be because the derivative does not phosphorylate and may not be an inhibitor of the phosphorylation mechanism. The main problem is that the Chinese paper standard (CNS) A4 (2.10 X 297 mm) is applied to the paper size of the resistant paper. -Order -------- (Please read first Note on the back, please fill out this page again) 45 898 1 A7 竽 B7 Consumer Cooperation of Intellectual Property Bureau of the Ministry of Economic Affairs Du printed 5. Invention Description (! 丨) 'Health. Multiple drug resistance (MDR) It should have been the main cause of failure for effective good medicines. We have found that the better derivatives of the present invention hinder MDR-pumps in some ways, and thus avoid this problem. The cellular absorption of nucleosides and nucleoside analogs such as King's special products is mainly through selective nucleoside transport (NT) receptors. The regulation / inhibition of this receptor can be regarded as its resistance to the agent in a clinical state. This phenomenon can be observed in test tubes by adding NT inhibitors. I have surprisingly found that these derivatives are not affected by the presence of NT inhibitors, because the cytostatic activity of this better derivative is retained in the presence of the inhibitor. The half-life of King ’s specialty in Blood Jun is about 10 minutes &gt; It is due to its rapid deamination by the endogenous enzyme deoxycytidine deaminase to become the relevant uracil derivative. (See PG Johnston et al. Cancer Chromatography and Biological Response Modifiers &gt; Annual 16, 1996, Chap. 1, ed. Pinedo HM et al.) In contrast, derivatives of the present invention For this reason, the detoxification of enzymes is bad, so its half-life is increased. Therefore, the derivatives of the present invention are more suitable for treating systemic or localized malignant tumors than the King's special product itself. The novel compounds of the present invention are not only potentially useful in the treatment of cancer, they also have activities such as antiviral agents. &lt; Please read note f on the back before filling in this page &gt; Binding --------- Θ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 45 Β9δ Α7 Β &amp;. _3. Revised the printing by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Invented 3 Da Ming (I3 *) ——........... Bovine physiology experiment King's special product oleamide and gold Cytotoxin activity of 5'-transoleate, which was investigated with two pairs of rodent and human tumor cell lines. Both groups contain a parent strain and a daughter strain, which are resistant to King's special product. Or cross-resistance. The cell line is a human ovarian tumor cell line A2780, and a daughter strain AG6000 that is resistant to King's specialty and has deoxycytidine kinase deficiency; and a mouse colon tumor cell line C26A, and has unmodified deoxycytidine kinase , But thymidine kinase I was reduced by a factor of 10 in AG6000. The cytotoxicity of each compound was evaluated by continuous drug administration for 72 hours. "The number of cells was determined by SRB analysis, and the percentage of growth inhibition of each tumor strain was calculated. IC50 値, expressed as / xM, This is the concentration of the compound that caused 50% growth inhibition compared to the control group. Results If the cytotoxic activity of King's special product itself is compared with the cytotoxic activity of King's special product-N4-Erylamide and King's special product 5'-Antioleate, it is expressed as 1C50 値 is shown in the table below. The activity of King's specialty derivatives is much greater than that of King's specialty in the cell line tested. Among the cell lines C26-A, C26-G, A2780 and AG6000, 14 paper sizes are applicable to China National Standard (CNS) A4 specifications mo X 297 male f) ------ ----- 4 ^ ·- --- r --- Order ------- ίθ ί Please read the notes on the back before filling in this page) 45 89R 其金氏特品本身、金氏特品-N4-反油酸醯胺和金氏特品-5’-反油酸酯的細胞毒素活性 &gt; 該活性係以IC50値(/iM)表 示 C26-A C26-G A2780 AG6000 金氏特品 0.0055 0.0075 0.0005 100 金氏特品-N4 -反油酸醯胺 &lt;0.0001 &lt;0.0001 &lt;0.0001 35 金氏特品-5’-反油酸酯 0.0003 0.0005 &lt;0.0001 100 CEM細胞中,其金氏特品本身和金氏特品-5’-反油酸 酯的細胞穩定性活性,係在有或沒有核苷運輸調節劑(硝 化苄基硫纖維核苷(NBMPR),或者普山定(Persantine) (Pyridamole))的存在下進行測定。 正如可以在下表中見到者,金氏特品之IC50,其比起 金氏特品-5’-反油酸酯之IC50要大過兩倍多。若加入NT 抑制劑時,金氏特品本身之IC50値則會上升10倍之多’ 但與此相對的,金氏特品-5’-反油酸酯的IC50値指略爲受 到影響5的增加)。在「抗性」的狀態中,其較佳 之衍生物比起原始藥劑可達到15〜20倍的效果。 化合物 IC50 値 (/^ Μ) 無抑制劑 _IC50 値(μΜ) NBMPR 100/iM IC50 値(#M) 普山定 4 u g/ml 金丄特品 0. Π ±0.01 1 . 11±0.08 1.26±〇·〇4 _ 金士特品-5s -反汕酸酯 0.047±〇.〇〇6 0.0M±0.〇34 0,065 士 〇.023 15 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) (請先閱讀背面之注項再填寫本頁) t n .^1--ο*· * n I 1— n n I— 1 經濟部智慧財產局員工消費合作社印製 898 1Cytotoxin activity of King's special product itself, King's special product-N4-Erylamide and King's special product-5'-Eoleate &gt; The activity is expressed as IC50 値 (/ iM) C26 -A C26-G A2780 AG6000 King's special product 0.0055 0.0075 0.0005 100 King's special product -N4 -Phenylamine oleate &lt; 0.0001 &lt; 0.0001 &lt; 0.0001 35 King's special product-5'-transoleate 0.0003 0.0005 &lt; 0.0001 100 In CEM cells, the cell-stabilizing activity of King's own product and King's special-5'- transoleate is based on the presence or absence of a nucleoside transport regulator (nitrogenated benzyl sulfur fiber). The measurement was performed in the presence of a nucleoside (NBMPR) or Persantine (Pyridamole). As can be seen in the table below, the IC50 of King's Specialty is more than twice the IC50 of King's Special-5'- transoleate. If NT inhibitor is added, the IC50 値 of King's special product itself will increase by 10 times'. However, the IC50 値 of King's special product-5'-transoleate will be slightly affected. 5 Increase). In the "resistance" state, its better derivative can achieve 15 to 20 times the effect compared to the original drug. Compound IC50 値 (/ ^ Μ) No inhibitor _IC50 値 (μΜ) NBMPR 100 / iM IC50 値 (#M) Pushanding 4 ug / ml Gold special product 0. Π ± 0.01 1.11 ± 0.08 1.26 ± 〇 · 〇4 _ Kingshi special product-5s-anti-shante acid 0.047 ± 〇.〇〇6 0.0M ± 0.03 0,065 ± 0.023 15 This paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the note on the back before filling out this page) tn. ^ 1--ο * · * n I 1— nn I— 1 Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 898 1 五、發明說明(/f ) S 金氏特品-N4-反油酸醯胺或金氏特品-5’-反油酸酯, 其抗腫瘤之效果係藉由在老鼠的生體內,調查其兩種不同 之腫瘤型式,以及單獨和重複劑量投與之情形而被決定。 金氏特品-N4-反油酸醯胺或金氏特品-5’-反油酸酯在 以Co-26接種老鼠脾臟之效果 在第0天以惡性直腸腫瘤Co-26,接種至Balb/c雌性 老鼠的脾臟內。在此模型中,腫瘤主要係在肝臟內發育。 在第1天開始進行腹膜腔內之治療。本化合物之單獨劑量 並與金士特品本身之單獨劑量進行比較測試。其中還使用 生理食鹽水作爲控制阻。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 老鼠數Η 物質 劑量 mg/kg 平均存活 時間T/C [% ] 長期之存 活者 (&gt;35d) 中毒死亡 10 生理食鹽水 8 金氏特品-Ν、 反油酸醯胺 25 103.7 5/8 1/8 7 金氏特品-55 _ 反油酸酯 75 128.6 1/7 0/7 7 金氏特品-5 ’ -反油酸酯 100 100.1 4/7 0/7 7 金氏特品 75 132.8 2/7 0/7 7 金氏特品 100 116.2 4/7 0/7 16 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) “ 898 A7Μ ,:. 修 經濟部智慧財產局員工消費合作社印製 五、發明說明(β) 對於被測試之化合物,其死亡動物之平均存活時間均位 於相同範圍之內。金氏特品-Ν4-反油酸醯胺,其比起金氏特 品-5’-反油酸酯以及金氏特品要優異的多,其關於5/8存活 者之需要劑量,只要25mg/kg之劑量,但是金氏特品卻要 100 mg/kg 。 在一個平行實驗中,在第1~11天重複劑量之投與。 老鼠數目 物質 劑量 mg/kg 平均存活 時間T/C {% 1 長期之存 活者 (&gt;46d) 中毒死亡 10 也迎食鹽水 8 金氏特品-N4 ~ 反油酸醯胺 1 155 2/8 0/8 8 金氏特品-N' 反油酸醯胺 4 185.6 1/8 0/8 8 金氏特品-5^ 反油酸酯 1 *—-- 150.6 1/8 0/8 8 金氏特品-5 ’ _ 反油酸酯 4 166.9 3/8 2/8 8 金氏特品 1 170 6 2/8 1/8 8 金氏特品 4 毒性的 0/8 8/8 —^1 在本貫驗中’以金氏特n反細随以及低劑量 金士特品_5,.反油酸酷,比起以低劑量金氏特品本身,其 17 本紙張尺度適用中國國家標準(CNS)A4規格⑵0 X 297公^ (請先閲讀背面之注項再填寫本頁) -lull· — — — 經濟部智慧財產局員工消費合作社印製 45 898 1 门./„ 11 B7 薇 ΪΕ 五、發明說明(u) 年月K u &gt; 1 10. -6 、' 一............................... ....... 所獲得之結果更佳或至少相同。雖然高劑量金氏特品-5’-反油酸酯具有輕微之毒性,但比起高劑量金氏特品本身而 言,則其毒性又輕微了許多。 金氏特品-N4-反油酸醯胺或金氏特品-5’-反油酸酯於老 鼠內以單一劑量或重複劑量腹膜內注射P-388之效果 將老鼠淋巴白血病(murine lymphatic leukaemia) P388細胞植入B6D2F1雌性老鼠腹膜內。在第1天細胞被植 入腹膜內之後開始治療。在單獨劑量治療以及重複劑量治 療之後5天,以及重複劑量治療之後10天,紀錄其平均存 活時間、長期存活者數、以及中毒死亡情形。金氏特品-5’-反油酸酯的單獨劑量投與,比起相同劑量之金士特品, 其具有較延長的存活時間和長期的存活者數。 單獨劑量投與 老鼠數目 物質 劑量 平均存活 長期之存 中毒死亡 mg/kg 時間T/C 活者 [% } (&gt;35d) 9 生理食鹽水 6 金氏特品- 75 186.3 1/6 0/6 5’-反油酸酯 6 金氏特品- 100 138.9 0/6 0/6 5’·反油酸酯 6 金氏特品 75 138.9 0/6 0/7 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1^1 I n H ^1 · H IV ^1 H 訂--------- &lt;請先閱讀背面之注意事項再填寫本頁) 4-5 898 五、發明說明( •w&quot;―' ~ Μ η ίη 。 修正 、c 二·*·υ 重複劑量投與,第1〜4天 老鼠數目 物質 劑量 g/kg 平均存活 時間T/C [% ] 長期之存 活者 (&gt;35d) 中毒死亡 8 生理食鹽水 6 金氏特品-N4-反油酸醯胺 1 178 2/6 0/6 6 金氏特品-N4 · 反油酸醯胺 4 183 1/6 0/6 6 金氏特品 15 58.0 0/6 6/6 在第1〜4天以重複劑量投與之金氏特品-N4-反油酸醯胺 ,不論在1以及4mg/kg投與,皆有長期存活者以及更延長 的平均存活時間,其活性更爲明顯。在控制組中以15mg/kg 金氏特品投與之所有動物均死於中毒。 -----I I---- ---i-il — 訂·----1 — — -.^ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用令國國家標準(CNS)A4規格(210 X 297公釐) 458981 五、發明說明((f) I a7 重複劑量投與,第丄天 老鼠數目 物質 劑量 mg/kg 平均存活 時間T/C 1% ] 長期之存 活者 (&gt;45d) 中毒死C 9 生理食鹽水 6 金氏特品-N4-反油酸醯 胺 1 172.5 1/6 0/6 6 金氏特品. N4-反油酸醯 胺 4 215.7 0/6 0/6 6 金! 特品~ 5’-反油酸酯 1 317.0 0/6 0/6 6 金氏特品-5’-反油酸酯 4 220.6 2/6 0/6 6 金氏特品 1 178.8 0/6 0/6 6 金氏特品 4 71.9 /6 /7 (請先間讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 與短期的治療相比較1 10天期的治療增加了抗腫瘤的 活性。在mg/kg的基礎上金氏特品本身的毒性較強’其4 mg/kg即造成6/6的中毒死亡情形。在以金氏特品-N4-反油 酸醯胺以及金氏特品-5*-反油酸酯來進行重複治療之後’ 發現有長期存活者的存在,同時以金氏特品-N4-反油酸酿 胺以及金氏特品-5’-反油酸酯處理後也實際地增加了平均 20 本紙張尺度適用中國國家標準&lt;CNS)A4規格(210 X 297公釐) 4 B B 9 8 1 ------- 五、發明說明(J) 0的」〇/!_矿 .. ----------------------------------- 存活時間。 本發明之金氏特品酯類或醯胺類可以系統性地投與* 不論是經皮或者非經皮地投與。 對於經皮投與,本發明之活性化合物,其存在之型式 可以爲,例如軟或硬明膠膠囊、錠劑、顆粒、粒狀或粉狀 、糖衣錠、糖漿、懸浮液或溶液。 當非經皮投與時,本發明之金氏特品酯類或醯胺類, 較理想可以爲注射或者輸液型式、懸浮液或乳劑。 該製劑可含有惰性或藥劑動力學上活化的添加劑,以 及熟於此技藝者常用之配方物質。舉例來說,錠劑或顆粒 可以含有一系列的結合劑、塡充劑物質、乳化劑、載劑物 質或者稀釋劑。液體製劑也可以以如經過殺菌的溶液之型 式來存在。 膠囊除了活性成分以外,可以含有一塡充劑物質或者 增稠劑。此外,也可以加入改善風味的添加劑、以及防腐 劑、安定劑、保濕劑、乳化劑、爲改變滲透壓之鹽類、緩 衝液、以及其他添加劑。 本發明製劑劑量所投與的程度,其將根據製劑的使用 型式'以及施用途徑和病患之需要而有所不同。一般而言 ,對於平均成人病患的系統治療上,其每日劑量爲約0.1-150mg/kg體重/日,較佳爲l_4〇mg/kg體重/日。局部投與 ’例如軟膏,則可以含有藥劑配方重量之0.1-10%,特別 是0,5-5%重量。 若有需要,含有金氏特品酯類或醯胺類的醫藥製劑可 本紙張尺度適用十國國家標準(CNS)A4規格(210 X 297公釐) (諝先閱璜背面之庄意事項再填寫本頁) * I I I l· I I I 訂 -------1·^ 經濟部智慧財產局員工消費合作社印製 45 898 1 A7 B7, 五、發明說明( 6 以含有抗氧化劑,例如,生育酚、N-甲基-生育胺、 butylated hydrocyanisole、抗壞血酸或丁基翔甲苯。 組合療法,亦即在投與本發明之金氏特品酯或醯胺的 同時,倂用其他療法,例如外科、輻射療法以及化學療法 等都是可以考慮的。舉例來說,腦瘤的較佳療法似乎就是 組合外科以及本發明之金氏特品酯或醯胺,來進行系統性 或局部性的投與。 I f n m I in Ϊ I 一OJJ n f I (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 2 2 本紙張尺度適用中國國家標準(CNS)A4規格(2】〇χ297公釐) a b 898 1 ----- ------------·*ί A5 --—___________\_I_B5_________ 四、中丈發明摘要(發明以稱:I U B9.10--6 · '-j 一............——--------- 金氏特品衍牛物 本發明提供金氏特品(Gemcitabine)酯類或醯胺類, 其中3,-及/或5,-OH基團及/或N4-胺基基團係衍生自C『及 /或C2〇-的飽和或單不飽和醯基基團,較佳地爲選自油醯基 、反油醯基、順-二十烯酸基(cis-eicosenoyl)及反-二十烯 酸基(tmnS-eicosen〇yl)之醯基基團。該金氏特品酯類或醯 胺類係可作爲抗癌劑及抗病毒劑。 ^— (請先間讀背面之注意事項再填寫本瓦各搁) 英文發明摘要(發明μ稱:GEMCITABINE DERIVATIVES The invention provides Gemcitabine esters or amides in which the 3'- and/or 51 - OH group and/or the N4-amino group is derivatised. with a Cia- and/or C20- saturated or mono-unsaturated acyl group, preferably an acyl group selected from oleoyl, elaidoyl, cis-eicosenoyl and trans-eicosenoyl. The Gemcitabine esters and amides are useful as anti-cancer and anti-viral agents. 訂 線 經濟部智慧財產局員工消費合作社印挺 本紙張尺度通用中國國家標準(CNS ) A4規格(210X297公釐)V. Description of the invention (/ f) S King's special product-N4-Phenylamine oleate or King's special product-5'-Eoleate, its antitumor effect is investigated in the living body of mice. Its two different tumor types are determined, as well as in the case of separate and repeated dose administrations. Effect of King's Special-N4-Erylamide or King's Special-5'-Antioleate on Co-26 Vaccination of Mouse Spleen On Day 0, Malignant Rectal Tumor Co-26 was Inoculated to Balb / c Female spleen. In this model, tumors develop primarily in the liver. Intraperitoneal treatment was started on day 1. The individual doses of this compound are tested in comparison with the individual doses of Kingston itself. Among them, physiological saline is used as the control resistance. (Please read the precautions on the back before filling this page) Consumption cooperation by employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Du printed mice Number of substances mg / kg Mean survival time T / C [%] Long-term survivors (&gt; 35d) Death from poisoning 10 Physiological saline 8 King's special product-N, glutamine oleate 25 103.7 5/8 1/8 7 King's special product -55 _ transoleate 75 128.6 1/7 0/7 7 King's special product Special product-5 '-transoleate 100 100.1 4/7 0/7 7 King's product 75 132.8 2/7 0/7 7 King's product 100 116.2 4/7 0/7 16 This paper size is applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) "898 A7M,:. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of Invention (β) The average survival of dead animals for the tested compounds The time is in the same range. King's special product -N4-Erylamide is much better than King's special product -5'- transoleate and King's special product, which is about 5 / 8 The required dose for survivors is only 25 mg / kg, but the King's special product is 100 mg / kg. In a parallel experiment, the weight of Administration of multiple doses Number of rats Substance dose mg / kg Mean survival time T / C {% 1 Long-term survivor (&gt; 46d) Poisoned death 10 Also welcomed saline 8 King's special product-N4 ~ linoleic acid Amine 1 155 2/8 0/8 8 King's specialty-N 'oleyl amine 4 185.6 1/8 0/8 8 King's specialty-5 ^ oleate 1 * --- 150.6 1 / 8 0/8 8 King's Special Product-5 '_ Antioleate 4 166.9 3/8 2/8 8 King's Special Product 1 170 6 2/8 1/8 8 King's Special Product 4 Toxic 0/8 8/8 — ^ 1 In this test, 'King's special n anti-following and low-dose King's special product _5 ,. oleic acid is cool, compared with the low-dose King's special product itself, its 17 books The paper size applies the Chinese National Standard (CNS) A4 specification ⑵0 X 297 male ^ (Please read the note on the back before filling this page) -lull · — — — 45,898 1 door printed by the Employees ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. / „11 B7 薇 ΪΕ 5. Description of the invention (u) Year K u &gt; 1 10. -6 、 'a ............. ............. The results obtained are better or at least the same. Although the high-dose King's special product-5'-transoleate is slightly toxic, it is much less toxic than the high-dose King's special product itself. King's special product-N4-Erylamide or King's special product-5'-Eoleate in mice in a single dose or repeated doses of intraperitoneal injection of P-388. Murine lymphatic leukaemia ) P388 cells were implanted into the peritoneum of B6D2F1 female mice. Treatment was started after the cells were implanted into the peritoneum on day 1. The average survival time, number of long-term survivors, and poisoning deaths were recorded 5 days after single-dose and repeated-dose treatments, and 10 days after repeated-dose treatments. The single dose administration of King's special product-5'-transoleate has a longer survival time and long-term survivors than King's special product of the same dose. Individual doses administered to mice Number of substance doses Average survival Long-term survival Poisoning death mg / kg Time T / C Living [%] (&gt; 35d) 9 Physiological saline 6 King's special product-75 186.3 1/6 0/6 5'-Antioleate 6 King's Special Product-100 138.9 0/6 0/6 5 '· Antioleate 6 King's Special Product 75 138.9 0/6 0/7 This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297 mm) 1 ^ 1 I n H ^ 1 · H IV ^ 1 H Order --------- &lt; Please read the notes on the back before filling this page) 4- 5 898 5. Description of the invention (• w &quot; ― '~ Μ η ίη. Correction, c Ⅱ ··· υ repeated dose administration, the number of rats on the 1st to 4th days, substance dose g / kg, average survival time T / C [% ] Long-term survivors (&gt; 35d) Poisoning death 8 Physiological saline 6 King's special product-N4-Erylamide 1 178 2/6 0/6 6 King's special product-N4 · Erythramine 4 183 1/6 0/6 6 King's special product 15 58.0 0/6 6/6 King's special product-N4-Erylamide, administered in repeated doses on days 1 to 4, regardless of 4mg / kg administration, both long-term survivors and more The average survival time, its activity is more obvious. In the control group, all animals administered with King's special product died of poisoning. ----- I I ---- --- i-il — Order · ---- 1 — —-. ^ (Please read the notes on the back before filling out this page) Printed on the paper by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, this paper applies the national standard (CNS) A4 specification ( 210 X 297 mm) 458981 V. Description of the invention ((f) I a7 Repeated dose administration, the number of rats on the following day The substance dose mg / kg Mean survival time T / C 1%] Long-term survivors (&gt; 45d) Poisoned to death C 9 Physiological saline 6 King's special product-N4-Erylamide 1 172.5 1/6 0/6 6 King's special product. N4-Erysalamine 4 215.7 0/6 0/6 6 Gold! Specialty ~ 5'- transoleate 1 317.0 0/6 0/6 6 King's specialty-5'- transoleate 4 220.6 2/6 0/6 6 King's specialty 1 178.8 0 / 6 0/6 6 King's special product 4 71.9 / 6/7 (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs compared with short-term treatment 1 10-day period Treatment increases anti-tumor active. On the basis of mg / kg, King's special product itself is more toxic. Its 4 mg / kg caused 6/6 poisoning deaths. After repeated treatments with King's Special-N4-Erylamide and King's Special-5 * -Eoleate ', the presence of long-term survivors was found, while King's Special-N4- After treatment with oleic acid amine and King's special product -5'- transoleate, the average is also increased by an average of 20 paper sizes. Applicable to the Chinese national standard &lt; CNS) A4 size (210 X 297 mm) 4 BB 9 8 1 ------- V. Description of the invention (J) 0 of the "〇 /! _ Ore .. ------------------------ ----------- Survival time. The King's specialty esters or amidines of the present invention can be administered systematically * whether transdermally or non-percutaneously. For transdermal administration, the active compound of the present invention may be present in the form of, for example, soft or hard gelatin capsules, lozenges, granules, granules or powders, dragees, syrups, suspensions or solutions. When administered transdermally, the King's specialty esters or amidines of the present invention may ideally be injectable or infusion types, suspensions or emulsions. The formulation may contain inert or pharmacokinetically activated additives, as well as formulation substances commonly used by those skilled in the art. For example, lozenges or granules may contain a range of binding agents, filler materials, emulsifiers, carrier materials or diluents. Liquid preparations may also be presented in the form of a sterilized solution. In addition to the active ingredients, capsules may contain a filling substance or a thickener. In addition, flavor improving additives, preservatives, stabilizers, humectants, emulsifiers, salts for changing osmotic pressure, buffers, and other additives may be added. The degree to which the dosage of the formulation of the invention is administered will vary depending on the type of formulation used, as well as the route of administration and the needs of the patient. Generally speaking, for the average adult patient's systemic treatment, the daily dose is about 0.1-150 mg / kg body weight / day, preferably 1-4 mg / kg body weight / day. Topical administration, such as ointments, may contain from 0.1 to 10% by weight of the pharmaceutical formulation, especially from 0.5 to 5% by weight. If necessary, pharmaceutical preparations containing King's specialty esters or amidines can be applied to this paper's national standards (CNS) A4 specifications (210 X 297 mm) (please read the solemn matters on the back before reading) (Fill in this page) * III l · Order III ------- 1 · ^ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 45 898 1 A7 B7, V. Description of the invention (6 To contain antioxidants, for example, fertility Phenol, N-methyl-tocopherylamine, butylated hydrocyanisole, ascorbic acid or butyltoluene. Combination therapies, that is, other therapies, such as surgery, radiation therapy, are administered at the same time as the gentamicin or amidine of the present invention. As well as chemotherapy, etc. can be considered. For example, the preferred therapy for brain tumors seems to be a combination of surgery and the gentamicin or amidine of the present invention for systemic or local administration. I fnm I in Ϊ I 一 OJJ nf I (Please read the precautions on the back before filling out this page) Duo printed by the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs 2 2 This paper size applies to China National Standard (CNS) A4 specifications (2). χ297 mm ) Ab 898 1 ----- ------------ · * ί A5 ---___________ \ _ I_B5_________ 4. Abstract of Zhongzhang Invention (Invention is called: IU B9.10--6 · '-j ............------------ King's Special Product Derivatives The present invention provides Gemcitabine esters or amidines. Where 3,-and / or 5, -OH groups and / or N4-amino groups are derived from C 'and / or C20- saturated or monounsaturated fluorenyl groups, and are preferably selected The fluorenyl group from oleyl, transoleyl, cis-eicosenoyl and tmnS-eicosenyl. The gold special esters Or amines can be used as anticancer agents and antiviral agents. ^ — (Please read the precautions on the back before filling in this article) English Abstract of Invention (Invention μ: GEMCITABINE DERIVATIVES The invention provides Gemcitabine esters or amides in which the 3'- and / or 51-OH group and / or the N4-amino group is derivatised. with a Cia- and / or C20- saturated or mono-unsaturated acyl group, preferably an acyl group selected from oleoyl, elaidoyl , cis-eicosenoyl and tr ans-eicosenoyl. The Gemcitabine esters and amides are useful as anti-cancer and anti-viral agents. Ordering Printed by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs This paper standard is in accordance with Chinese National Standard (CNS) A4 (210X297 mm)
TW087103708A 1997-01-24 1998-03-13 Gemcitabine derivatives TW458981B (en)

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WO2009128805A1 (en) * 2008-04-17 2009-10-22 The Johns Hopkins University On01910. na enhances chemotherapeutic agent activity in drug-resistant tumors
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