TW199861B - - Google Patents
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- TW199861B TW199861B TW081101695A TW81101695A TW199861B TW 199861 B TW199861 B TW 199861B TW 081101695 A TW081101695 A TW 081101695A TW 81101695 A TW81101695 A TW 81101695A TW 199861 B TW199861 B TW 199861B
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 9
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- AIDS & HIV (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
經濟部屮央標準乃只工消仰合作社印31 199861 Λ 6 __Β6_ 五、發明説明(1) 本發明是有關核苷衍生物之協同性抗病毒綜合物,含 彼之藥學調和物,及彼於醫學治療特別是治療病毒感染, 尤其是反轉錄病毒感染之用法。 後天免疫缺失症候群(AIDS)是一種免疫抑制或 免疫破壞性疾病,其會個體遭受致命的機會感染。就特性 而言,A IDS與T細胞之逐漸耗盡有關,尤其是攜有 0ΚΤ4表面標誌之輔助一誘導子集。 人類免疫缺失病毒(HIV),已可再生地分離自 A I DS病人或具經常前導A I DS之症狀者。Η I V具 有細胞病變性,且似乎差別地感染及破壞撝有ΟΚΤ4標 誌之Τ細胞。目前已大體地確認,Η IV是A IDS之病 因物。 由於發現Η I V是A I DS之病因物,針對抗一 Η I V化學治療劑已有許多計劃被提出,其係可有效地治 療AIDS患者。因此;如歐洲專利案第〇 382 526掲示抗_H IV之經取代的1,3 —氧硫雜環戊烷 類。美國專利案4724232及歐洲專利案0 196 185,描述一叠氮基一 3’_去氧胸苷(其已准予 命名為叠氤胸苷(zidovudine ),及其於治療A I D S 上之用法。 我們目前發現,1 一 2 — (羥甲基)一 1, 3 —氣硫 雜環戊烷一 5 —基)一 5 —氟胞嘧啶,綜合3 ’一叠氮基 一 3 ’一去氧胸苷可對化合物之抗一 Η I V活性造成令人 驚訝的大的加強作用。使用1 一 2 — (羥甲基)一 1, 3 (請先閲讀背面之注意事項再塡寫本頁) 本紙it尺度边用中SS家標準(CNS)T4規格(210x297公;ίί;) -3 — 199861 Λ 6 Β6 五、發明説明(2) 一氧硫雜環戊烷一5—基)一5—氟胞嘧啶,聯合β氮胸 登(z i dovud i ne ),與個別化合物之抗一 Η I V活性比 較,前者可産生抗一 Η I V活性協同地增加。 依據本發明第一方面,提出(a )式(I ) 1 — 2 — (羥甲基)一1, 3 —氧硫雜環戊烷一 5 —基)一 5 —胞 嘧啶
⑴ 或其生理上具官能性之衍生物,與(b)式(I) 3 叠氮基一 3' —去氧胸M ( zidovudine): (請先閱讀背面之注意事項再塡寫本頁) 經濟部屮央標準乃0工消设合作社卬5i
(II) 或其生理上具官能性之衍生物,之綜合物;綜合物中之( a)及(b)組份一起應用,如此達到協同的抗病毒效應 本紙尺度逍用中國a家標半(CNS)甲4規格(2]0χ297公;11) 一 1 一 Λ 6 Β6 199861 五、發明説明(3) (請先閱讀背面之注意事項再塡寫本頁) 。所諝的ν協同抗病毒效應"在此表示抗病毒作用較綜合 物値別的(a)及(b)組份所預測之純綷加成效應還要 大。 應注意,式(I)化合物含有二個對掌性中心,因此 可呈二對光學異構物型(即對映體)及包括外消旋混合物 之混合物。因此,式(I)化合物可為順式或反式異構物 ,或其混合物。每一順及反式異構物可呈二個對映體之一 ,或其包括外消旋混合物之混合物型。所有此種式(I )異構物及其含外消旋混合物之混合物,及互變異構物型 ,均包括在本發明範圍之内。以式(I)化合物之順式異 構物為較佳。 所謂“生理上具官能性的衍生物"意指式(I)化合 物或其他任何化合物之藥學上可接受之鹽、醯胺、酯或酯 之鹽,其一旦投予至個體後可(直接或間接地)提供該式 (I)化合物或其活性代謝物或殘基。 經濟部屮*榀準乃0工消费合作社卬51 依據本發明較佳的酯類包括羧酸酯,其中酯基羧酸部 份之非羰基基團可選自直或分支的烷基,如正丙基,第三 、丁基、正丁基、烷氧烷基(如甲氧甲基)、芳烷基(如 苄基)、芳氧烷基(如苯氧甲基)及芳基(如苯基);横 酸酯類如烷基一或芳烷基磺酸基(如甲烷磺醯基);胺基 酸酯類(如L 一纈胺醯基或L 一異白胺醯基);二羧酸酯 類(如半琥珀酸酯類);及5’一單、二、或三磷酸酯類 。磷酸酯可進一步酯化,如(1 一 20醇或其反應性衍生 物,或為2,3 —二(Cs-24)醛基甘油。 本紙張尺度通用中8國家標準(CNS)甲4規格(210x297公及) ~ 5 - 199861 Λ 6 Β6 經濟部屮央標準杓Η工消资合作社卬51 五、發明説明(4 ) 存在於此酯類中之烷基部份,可有益地含1至18値 碳原子,特別是1至4値碩原子。存在於此酯類中之任何 芳基部份,可有益地含苯基,視所需地為如:鹵、 院基、C烷氧基或硝基取代。 上述式(I)化合物,藥學上可接受之醯胺,包括其 中胞嘧啶胺基像呈醯胺型式之衍生物,如一NHCOR, 其中R是C2-6烷基或芳基(如苯基,視所需地為鹵、 烷基、Ci-4烷氧基、硝基或羥基取代)。 依據本發明,藥學上可接受之鹽類實例包括鹼鹽,如 衍生自適當的鹼者,如鹸金屬(如鈉)、鹸土金屬(如鎂 )鹽、銨及NX,(其中X是Ci-4烷基)。藥學上可接 受之酸加成鹽包括有機羧酸之鹽類,如醋酸、乳酸、酒石 酸、蘋果酸、二一羥基乙烷磺酸、乳糖酸及琥珀酸;有機 磺酸,如甲烷磺酸、乙烷磺酸、苯磺酸及對位一甲苯磺酸 ,及無機酸如氫氯酸、硫酸、磷酸及磺胺酸。 依據本發明可治療或預防之病毒感染及相闋臨床狀況 實例,包括人類反轉錄病毒感染,如人類免疫缺失病毒( HIV),如HIV — 1或HIV — 2,及人類T細胞親 淋巴病毒(HTLV),如 HTLV—1 或 HTLV—I 感染。本發明的綜合物尤其可用於治療A I D S及相關的 臨床狀況,如A IDS —相關複合症(ARC),漸進的 綜合性淋巴病變(PGL)、AIDS —相關之神經性狀 況,如多發性硬化或下肢輕癱、抗一 Η I V抗體一陽性及 Η IV —陽性狀況、如血小板減少性紫斑。本發明的綜合 (請先閲讀背面之注意事項再填寫本頁) 本紙尺度逍用中Sffi家標準(CNS)T4規格(210x297公扃) -6 — A 6 B6 199861 五、發明説明(5 ) {請先閱讀背面之注意事項再填寫本頁) 物也可用於治療牛皮癖。本發明的綜合物頃發現特別可用 於治療由人類反轉錄病毒或其相關物所引起之無症狀性感 染或疾病。 依據本發明的第二方面,提出如上述之綜合物,以用 於醫學治療,待別是用於治療或預防上述任一種病毒感染 或狀況,尤其是HIV感染,包括AIDS。 本發明進一步包括製備上述綜合物之方法,包括將綜 合物中之(a)及(b)組份結合於藥物中,以提供協同 性抗病毒效應。 本發明再一方面提出本發明綜合物之用法,可製成藥 物以治療上述任一種病毒感染或狀況。 本發明進一步提出於哺乳動物(包括人類)中,治療 或預防病毒感染(尤其是Η I V感染)之方法,此方法包 括對該哺乳動物投予有效劑量之如上述之綜合物。要了解 ,依據本發明,綜合物中之(a)及(b)組份可同時或 依序投予。然而於後一例中,組份之投予需在確定達成協 同性抗病毒效應之夠短間隔時間内投予。 經濟部屮央標準,,T A工消疗合作社印11 本發明也提出於具有病毒感染之哺乳動物(包括人類 )中,加強綜合物(a)及(b)組份抗病毒活性之方法 ,此方法包括對該哺乳動物投予有效協同劑量的(a)組 份,同時,在之前,或在之後加上(b)組份之投予。 本發明綜合物的一個優點是,其在抗病毒組份之一的 特殊劑量下可達到改進的抗病毒效力(與只使用某組份相 比),由此改進組份之治療指數。因此,如,綜合物可用 本紙5良尺度边用中a困家標準(CNS)甲4規格(210x297公犮) -7 - A 6 B6 ^99861 五、發明説明(6 ) (請先閱讀背面之注意事項再填寫本頁) 於治療當其中需相當大劑量抗病毒組份,且此劑量下會發 生毒性問題之例子。綜合物之較小劑量,對受者可提供更 多的便利,且有增加的順服性。 本發明的綜合物,可以合宜方式投予至哺乳動物。如 上文所示,(a)及(b)組份可以同時(如於一個單一 的藥學調和物中),或分別地(如於分別的藥學調和物中 )投藥。一般而言,綜合物可局部、口服、經直腸或腸外 地(如靜脈内、皮下或肌内)投予。要了解,投予路徑可 依如欲治療之狀況嚴重性,及受者本身而定。 要了解,為確使達到最大的加強作用,通常在組份間 有最佳之比率存在,即使極微量的一組份,也足以加強另 一者效應達某程度,且因此任何比率的二加強組份,將仍 具有所需之協同效應。然而,當二組份以待殊比率存在, 通常可觀察到最大的協同性。 經濟部屮央櫺準局员工消赀合作社印製 因此,叠氮胸苷與1一2 — (羥甲基)一 1,3 — 硫氧雜環戊烷一5_基)一 5 -氟胞嘧啶,或其個別的生 理上具官能生衍生物之最佳莫耳濃度比率,依據本發明之 用法為由1 : 1至1 : 600,較好是由1 : 10至1 : 250,且更好是1:25。 下文中,綜合物之組份可稱之為'"活性成份〃。 綜合物之劑量依經處理之狀況及其他臨床因素而定, 如受者之體重及病況,及綜合物組份之投藥路徑。劑量範 圍與組份比率之實例如下: 一般而言,本發明綜合物之適當劑量,依據(a)及 本紙張尺度通用中國國家標準(CNS)干4規格(210X297公足) -8 一 Λ 6 Β6 199861 五、發明説明(7 ) (請先閲讀背面之注意事項再填寫本頁) (b)組份總重量計,在每天每公斤受者體重由3至 120毫克範圍*較好是6 一 9 ◦毫克/公斤/天,且更 好是15_6〇毫克/公斤/天。欲求劑量較好在一天之 適當間隔下以二、三、四、五、六以上之亞劑量呈現。這 些亞劑量可以單位劑型投予,如於每單位劑型中含有1◦ 至1 500毫克,較好是2 ◦- 1〇〇〇毫克,且更好是 50 — 700 毫克。 經濟部屮央標準而只工消费合作社印製 雖然活性成份可單獨投予,但較好呈藥學調合物型式 。本發明的藥學調和物含有依據本發明之綜合物,加上一 種以上之藥學上可接受之載體或賦形劑,及視所需的其他 治療劑。當綜合物之個別組份分別投予,其通常各自呈·藥 學調和物。下文中提及調和物,除非另有所述,僳指含有 綜合物或其組份之調和物。調和物包括適合口服、經直腸 、經#、局部(包括穿皮、經頰及舌下),經陰道或腸外 (包括皮下、肌内、靜脈内及皮内)投藥者。調和物可合 宜地呈單位劑型,且可以藥學技藝中熟知之任一方式製備 。此種方法包括,將活性成份與構成一種以上輔助成份之 載體結合。 大體而言,調和物之製備像將活性成份與液態載體或 細碎的固體載體,或二者均勻且緊密地結合,且若必要時 可再成型。 適合口服的本發明調和物可呈分離的單位,如膠囊劑 、扁囊劑、或錠劑,各自含有預定量之活性成份;可呈散 劑或顆粒劑;呈於水性或非水性液髏中之溶液劑或懸液劑 本紙張尺度边用中S困家標準(CNS)甲4規格(210x297公犮) -9 - Λ 6 Β6 199861 五、發明説明(8 ). ;或呈油水液態乳劑或水油液態乳劑。活性成份也可呈大 丸劑,舐劑或糊劑。 錠劑之製作可採壓製法或模製法,視所需地加上一種 以上的輔助成份。壓製錠之製備傺將呈自由流動型式,如 粉末或顆粒之活性成份於機器中壓縮,梘所需地混合粘合 劑(如普維酮、明膠、羥丙基甲基纖維素)、潤滑劑、惰 性稀釋劑、俦藏劑、崩散劑、(如澱粉羥基乙酸鈉、交聯 的普維酮、交聯的羧甲基纖維素鈉)、界面活性劑或分散 劑。模製錠之製作像將粉末狀化合物以惰性液體稀釋劑潤 濕、再於適當的機器中模製。錠劑可視所需地包衣或刻痕 ,且可調和以提供活性成份緩慢或控制性釋出,其中使用 如:各種比率之羥丙基甲基纖維素,以提供欲求之釋出概 圖。錠劑可視所需地包以腸衣,使其於腸部位釋出而非於 胃中釋出。 適合於口中局部投藥之調和物,包括含錠,傜活性成 份含於芳香的基劑中,通常是蔗糖及阿拉伯膠或西黃耆膠 ;軟錠劑,活性成份於惰性基劑,如明膠及甘油,或蔗糖 及阿拉伯膠;及漱口劑,包括活性成份於適合的液體載體 中。供經直腸投藥之調和物,可呈栓劑傺於適當基劑中, 如可可油脂或水楊酸酯。 局部投藥也可利用穿皮離子電泳裝置。 適合經陰道投藥之調和物,可呈陰道栓劑、棉球、乳 膏、糊劑、泡沫劑或噴霧劑調和物,其中除了活性成份的 、載體係技藝中已知之適用者。 本紙張尺度逍用中國國家標準(CNS)甲4規格(210X297公龙) (請先閱讀背面之注意事項再填寫本頁) 裝- 經濟部中央榣準而只工消费合作社卬製 -10 - 199861 Λ 6 Β 6
經濟部屮央標準局CI:工消t合作社印M 五、發明説明(9 ) 適合腸外投藥之調和物包括水性及非水性等張無_注 射溶液劑,其可含有抗氣化劑、缓衝物質、制菌劑及使調 和物與受者血液呈等張之浴質;及水性及非水性無菌懸液 劑,其可包括助懸劑及稠厚劑;呈脂浴髏或其他微顆粒条 統,其經設計可將化合物送至血中組份或一種以上之器官 。調和物可呈單位劑量或多劑量於熔封容器中,如安瓿及 小瓶,且可於冷凍乾燥條件下貯存,只須於使用前加入無 菌液體載體,如注射用水即可。暫用之注射溶液劑及懸液 劑可製備自無菌的散劑,顆粒劑及上述各種錠劑。 較佳之單位劑量調和物,為含有每天劑量或單位,每 天亞劑量(如上所述)或其適當部份之活性成份者。 應了解,本發明的調和物除了上示之特殊成份之外, 可包括其他技藝中合宜之作用物,依討論中之調和物型式 而定,如適合口服者可進一步包括如甜味劑、稠厚劑及芳 香劑。 本發明之綜合物各化合物,可以合宜的方式製備。叠 氮基胸苷可如美國專利案第4 7 2 4 2 3 2號中所述地製 備,此案已列為本案參考。其也可得自Aldrich Chemical Co" Milwauke WI 53233, USA。 1一2 — (羥甲基)一 1, 3 —氧硫雜環戊烷一 5 — 基)一5—氟胞嘧啶可如下般製備: a)反應經適當保護之5 —氟-胞嘧啶化合物與式(HA )之1, 3—氣硫雜環戊烷 (請先閲讀背面之注意事項再填寫本頁) 丁 本紙張尺度逍用中SB1家標準(CNS)甲4規格(210x297公龙) -11 - I9986i Λ 6 B6 五、發明説明(10) R, 0
V
(ΙΙΙΑ) 其中Ri是强或羥基保護基,且L是離去基園;或 b)反應式(MB)化合物
HN (其中Ri如上文般定義,且R 為胺基保護基)與氟化 劑,以在胞嘧啶環5 —位置上提供氟原子;或 c)反應式(1C)化合物 (請先閲讀背面之注意事項再塡寫本頁) 裝- 線- 經濟部屮央標準而貝工消赀合作社印製 本紙張尺度逍用中囷國家標準(CNS)甲4規格(2U1X297公垃) -12 - 199861 _ — 五、發明說明(1!) Λ 6 Β6 Λ. ην
(IIIC) (請先閱讀背面之注意事項再塡寫本頁) 經濟部屮央標準M工消"合作社卬製 (其中R,如上文般定義)與可將尿嘧啶4 —位置上之酮 基轉化成胺基之作用物反應;任何剩下的保護基可除去、 如利用酸或鹼水解以産生欲求的産物。 關於a )製程,羥基保護基包括保護基,如醯基(如 乙醯)、芳醯基(如苄醯或經取代之苄醯),三苯甲基或 單甲氧基三苯甲基、苄基或經取代之苄基、三烷基矽烷基 、如二甲基一第三,丁基矽烷基)或二苯基甲基矽烷基。 5 — R —胞嘧啶化合物可視所需地以矽烷基保護之。如三 甲基矽烷基。此種基圍可以習知方式移去。離去基團L是 精於核苷化學技藝者典型已知的,如鹵,如氯或溴,烷氧 基如甲氧基或乙氧基,或醛基如乙醯基或苄醛基。 a)製程的反應可於有機溶劑中連成(如1,2 —二 氯乙烷或乙腈),並有路易氏酸之存在,如氯化錯或=甲 基矽烷基三氟磺酸酯。 式(ΒΙΑ)化合物可得自經適當保護的式111 2 一經基 乙醛 裝. *一17- 線- 本紙5fc尺度逍用中as家樣準(CNS)甲4規格(210x297公釐) -13 - Λ 6 Β6 199861 五、發明説明(13 R!OCH2CHO (IV) (請先閲讀背面之注意事項再塡寫本頁) 其中R/如上述般定義,如Can,J. Research,8, pp (1933)及歐洲專利案第Ο 382 526號所述 。式IV化合物與毓基縮醛HSCH2CH (OR) 2反應, 其中R是烷氧基如HSCH2CH (OC2H5) 2, 偽技藝中已知的(Chrn. Ber. 85 : 924 — 932, 1 952),可生成式ΠΑ化合物,其中L是OR (烷氣 基)、如甲氧及乙氧。此外,式ΠΑ化合物,其中L是烷 氧基,可轉化成其中L是鹵或醯基之式IA化合物,利用 碌水化物化學技藝中已知之方法。 式IV化合物可製備自1, 2—鄰亞異丙基甘油,像 引入Ri (如經三取代之矽烷基、苄基或三苯甲基)並以 緩和的酸(如甲酸或醋酸水溶液)移去亞異丙基,或利用 漠化鋅於乙睛、之後以高碘酸鹽水溶液氧化醇基園。 經濟部屮央櫺準乃^:工消奸合作社印51 關於b)製程,5 -氟取代基可以技藝中已知之方法 引入(Μ· J· Robins, et a 1· > in Nucleic Acid Chemistry. Part 2 , L· B. Townsend and R. S. Tipson, editors, J- Wiley and Sons. New York. 895—90 〇 (1 9 7 8)且列為此中參考;R. Duschinsky inNu-leic Acid Chemistry, Part 1 , L. B. Townsend and R. S· Tipson,editors, J . Wiley and Sons , New Yo r-K, 43 — 46 (1 978)且列為此中參考)。氟化劑 可為如三甲基次氟酸鹽/氟三氯甲烷。 一 14 _ 本紙5良尺度逍用中囷届家標準(CNS)甲4規格(210X297公¢) 經濟部中央標準劝U工消疗合作社卬 199861 Λ6 ____B 6 _ 五、發明説明(13 關於製程c),式HC化合物可有益地以1, 2, 4 -三唑處理,有益地加上二氯磷酸4一氯苯基酯,以形成 相當的4一 (1, 2, 4_三唑基)化合物,其再與如甲 醇反應,轉化成欲求之4 一胺基(胞嘧核替)化合物。 式ΠΒ及1C之起始物質,其製備可由適當的(視所 需予以保護)的鹼與式IA化合物,以類似製程a)之方 式反應。5 —氟脲嘧啶與5 —氟胞嘧啶可購自Aldrich Chemical Co·, Milwaukee, WI 53233, USA。 (土)_順式與(土)一反式異構物(如呈經保護型 式)之分離,可利用有機溶劑混合物於矽膠上層析而完成 ,如乙酸乙酯/甲醇、乙酸乙酯/己烷或二氯甲烷/甲醇 。任何保護基可利用針對每種基圍之適當試劑予以再除去 0 式I及式I組份化合物之酯,可以習知方法製備,如 與適當的酯化劑反應,如醯基鹵或酐。式I及1化合物或 其酯可以適當的鹼處理,以轉化成其藥學上可接受之鹽。 組份化合物之酯或鹽可以水解作用轉化成其母化合物。 式(I)化合物藥學上可接受之醯胺,可由如與適當 的醯化劑反應而製備,如醯基鹵或酐,用以醯化5· — 0H及4 — NH2基團。醒基可再自一個或另一値5 _ — 0H及4 _NH2基團上選擇性移去。如,在酸性條件下 (如路易氏酸)處理經二醯化之化合物,如溴化鋅/甲醇 ,可移去4N —醯基,因而生成相當的5· — 0H酯;而 以鹼性條件(如甲氧化鈉)處理經二醯化之化合物,可移 (請先閱讀背面之注意事項再塡寫本頁) 本紙56尺度通用中a a家樣準(哪)甲4規格(210x297公!) -15 - 199861 Λ 6 Β 6 五、發明説明(14 去5 ·— OH醯基, 生成相當的4 一醛胺。醛基也可用 買的酯酶或脂酶辛酵素處理而選擇性地移去,如豬肝酯酶 ,或胰脂酶,或依美國專利案第5 0 7 1 9 8 3中所述— 之方法處理。式(I)化合物可以習知方法轉化成其藥學 上可接受之鹽,如以適當的鹼處理。 以下實例甩以説明,而非以任一方式限制本發明。> 活性成份〃表示組份叠氮胸替(zidovudine )與順式一 1 一 2— (羥甲基)一 1, 3—氧硫雜環戊烷一5—基) 一5—氟胞嘧啶,於1:25莫耳濃度比率之混合物。 啻例1 :綻劑謳和物 以下A、 B及C調和物之製備,像成份與普維酮溶液 行濕粒法,再加硬脂酸鎂及壓錠而成。 A調和物 轰 直 /錠 活性成份 2 5 0 乳糖B . P . 2 1 0 普維酮B . P . 1 5 澱粉羥基乙醇酸鈉 2 0 硬脂酸酶 5 5 0 0 (請先閱讀背面之注意事項再塡寫本頁) 本紙張尺度边用中國S家標準(CNS)甲4規格(210X297公¢) 一 16 — 199861 Λ 6 Β6 經濟部+央標準"M工消赀合作社卬贤 五、發明説明( B調和物 活性成份 臺克/綻 2 5 0 乳糖B . P . 15 0 Av i ce1 pH 101 6 0 普維酮B . P . 15 殿粉羥基乙醇酸鈉 2〇 硬脂酸酶 5 C調和物 活性成份 5 0 0 臺克/錠 2 5 0 乳糖B . P . 2 0 0 澱粉 5 0 普維酮 5 硬脂酸鎭 4 3 5 9 以下D及E調和物,係直接壓製摻合成份而製備。於 E調和物中之乳糖為直接壓製型(Dairy Crest-'' Zepa-rox ) (請先閱讀背面之注意事項再填寫本頁) 裝- -tT. 線- 本紙5k尺度逍用中國声家標準(CNS)甲4規格(210x297公垃) -17 - 199861 Λ 6 Β 6 五、發明説明(16) D調和物 活性成份 預明膠化之澱粉N F 1 5 臺克/錠 2 5 0 15 0 4 0 0 (請先閱讀背面之注意事項再填寫本頁) F:調和物 活性成份 乳糖B . P . Av i ce 1 臺克/綻 2 5 0 15 0 10 0 裝< 線· 5 0 0 經濟部屮央橾準X;A工消赀合作社5-¾ F謳和物(捽制釋出調和物) 調和物之製備是成份與1 酯及壓錠。 活性成份 羥丙基甲基纖維素 (Methoce1 K4M Premium ) 乳糖Β . P . 維酮溶液製粒,再加硬脂酸 臺克/綻 5 0 0 112 5 3 本紙张尺度逍用中國國家標準(CNS)甲4規格(210x297公釐) -18 - 199861 A 6 B6 五、發明説明(17) 普維酮B . P . 2 8 硬脂酸鎂 7 7 0 0 經濟部中央標準U工消"合作社卬51 藥物之釋出歴約6—8小時, 0 且在12小時後可完全 奮例2 :願爨割調和物 A調和物 膠囊調和物之製備偽將實例1 D調和物之成份混合, 再充填至2 Η硬明膠膠囊中。B調和物(下文)以相似方 式製備。 Β調和物 毫克/膠囊劑 活性成份 2 5 0 乳糖B . Ρ . 14 3 澱粉羥基乙醇酸鈉 2 5 硬脂酸鎂 2 4 2 0 (請先閱讀背面之注意事項再填寫本頁) 裝· 訂- 線- 本紙5良尺度逍用中sa家標準(CNS)甲4規格(2】0x297公垃) 一19 - 199861 Λ 6 Β6 五、發明説明( c謳和物 活性成份 Macrogel 4000 B.P. 臺克/瞟蠹割 2 5 0 3 5 0 6 0 0 C調和物之膠囊劑製備俗先熔化Macrogel 4 0 0 0 BP,活性成份分散於熔融物中,再充填至二片硬明膠膠囊 中。 D調和物 活性成份 卵磷脂 花生油 臺克/膠蠹劑 2 5 0 1 0〇 10 0 4 5 0 D調和物之膠囊劑製備,係將活性成份分散於卵磷脂 與花生油中,並將分散相充填至軟,且具彈性之明膠膠囊 中。 E調和物(控制釋出件膠蠹劑) 本紙5fc尺度边用中a a家標準(CNS)甲4規格(210x297公犮) -?0 - (請先閱讀背面之注意事項再填寫本頁) Λ t) 13 6 五、發明説明(1分 以下控制釋出膠囊劑調和物,係由成份a, b及c於 擠壓器中擠壓,之後擠出物成球狀再乾燥。經乾燥之團塊 塗覆以控制釋出膜(d),再充填至二片硬明膠膠囊中。 (a )活性成份 (b )微晶體纖維素 (c )乳糖 B . P . (d )乙基纖維素 臺京/瞟蠹割 2 5 0 12 5 12 5 13 (請先閱讀背面之注意事項再填寫本頁) 5 13 裝- 經濟部+央標準;.;以工消赀合作社卬51 官例3 :可注射謳和物 A謳和物 活性成份 氫氯酸溶液,〇 . 1M或 氫氧化鈉溶液0.1M適量至pH 無菌水適量加至 毫克 2 0 0 4 . 0 — 7 . 0 1 0毫升 活性成份溶於大部份水中(3 5 — 4 0 °C ),p Η再 以氫氯酸或氫氧化鈉依所需調至ΡΗ4. 0及7. 0之間 。以無菌水加至其體積,再濾過無菌徼孔濾膜至無菌的 10毫升褐色玻璃小瓶中(1型),並以無菌封口及外帽 — — 本紙張尺度逍用中圉困家棕準(CNS)甲4規格(210x297公;¢) 21 線. 199861 Λ 6 Β 6 五、發明説明(2d 熔封。 Β讕和物 活性成份 無菌、無熱原、Ρ Η 7磷酸鹽 缓衝溶液,適量加至 窨例4 :肌肉沣射劑 活性成份 苄醇 呋喃糖醇7 5 注射用水適量加至 1 2 5毫克 2 5毫升 2〇0毫克 〇.1〇克 1 . 4 5 克 3毫升 活性成份溶於呋喃糖醇中。再加苄醇並溶解,並加水 至3毫升。之後混合物過濾(經無菌多孔濾膜)並溶於無 菌的3毫升褐色玻璃小瓶中(1型)。 (請先閲讀背面之注意事項再填寫本頁) 裝· 訂- 線. 經 濟 部 屮 央 },ι& 小Κ 準 A ίϊ 工 消 i'i' 社 1:ρ 奮例5 :糖漿劑 活性成份 山梨糖醇溶液 甘油 苄甲酸鈉 梨子香味 純水 2 5 0毫克 1 . 5 0 克 2 . 0 0 克 〇.0 0 5克 0 . 0 1 2 5毫升 5 . 0 0毫升 本紙張尺度边用中國a家榀準(CNS)甲4規格(210x297公犮) -22 - ^99861 Λ 6 136 五、發明説明(21) 活性成份溶於甘油及大部份水之混合液中。再加苄甲 酸鈉水溶液至溶液中,繼而加入山梨糖醇溶液最後是香料 。體積以純水加足,再混合均勻。 啻例6 :栓割 活性成分 硬脂 B. P. (Witepsol Η-15-Dynamit Nobel ) 亳京/矓釁柃割 2 5 0 17 7 0 (請先閱讀背面之注意事項再填寫本頁) 2 0 2 0 經 濟 部 十 央 標 準 i\ 工 消 ί'1· 合 杜 卬 51 1/5的Witepsol Η 15熔於最高45 °C之蒸汽套鍋 中。活性成份經由2 0 0M篩加至熔化之基劑中,攪拌地 ,利用配有Silverson之切頭,直到達到均勻的分散相 為止。混合物保存在451C下,剩下的Witepsol H5加 至懸液中,再攪拌以確使達均勻的混合物。全部懸液通過 250M不綉鋼篩,在繼缠攪拌下,令其冷卻至40^。 達38t:_4〇°C時,2. 02克混合物填至適當的2毫 升塑膠模型上。令栓劑冷卻至室溫。 奮例7 :陰谙栓劑 活性成份 毫克/栓劑 2 5 0 本紙張尺度边用中國困家標準(CNS)甲4規格(210x29'〖公没) -23 - 199861 Λ 6 Β6 五、發明説明(23 無水右旋糖 馬鈐薯澱粉 硬脂酸鎂 3 8 0 3 6 3 7 10 0 0 活性成份直接混合,並將生成的混合物直接壓縮成陰 道栓劑。 3 —氬硫雜瑗戊 (請先閱讀背面之注意事項再填寫本頁) 濟 部 十 央 標 準 入h it 工 消 fi' 合 社 卬 51 音例ft:剪備1一2 — (羥甲基)一 1_ 烷一 PS —某)一 5 —氟胞喃^ A方法:(土)一順式及(土)一反式2 —爷氧甲基一 5 一 (N4—乙醯基一胞嘧啶一 1—基)―1,3 一氧硫雜 環戊烷,如歐洲專利案(EP)〇 3 8 2 526中所 述地製備,且分離成(土)一順式及(土反式異構物 。(土) 一順式異構物在一78Ό下,以次氯酸三氟甲基 酯於氟三氯甲烷(cc$aF)及氯仿中氣化,此依據R-obins,et a 1 · Nucleic Acid Chemistry,Part 2 , 895 — 900,1 978之方法進行。N4 —乙醯基及 2—苄醯基,以二甲胺/乙醇移去,並分離出産物,(± )—順式一 1 一 2 _ (翔甲基)—1,3 —氧硫雜環戊院 一 5 —基)一 5 —氟胞嘧啶。
B 方法:(土)一順式與(土)_反式一 2 —爷醒氧基甲 本紙張尺度逍用中國國家標準(CNS)甲4規格(210X297公!) 裝· .可- -線· Λ 6 136 199861 五、發明説明(23ί (請先閲讀背面之注意事項再填寫本頁) 基一 5- (尿嘧啶一 1 一基)一 1, 3_氧硫雜環戊烷, 如ΕΡ 〇 382 526所述般製備。經以飽和的甲 醇性氨,對2 —羥基去保護後,異構物於矽膠上以E tO Ac/MeOH 為溶離劑(EP 0 3 8 2 5 2 6) 而分離。(土) 一順式異構物與醋酸酐/吡啶在室溫下反 應以生成2 —醋酸鹽。溶劑於<3〇υ2真空下移去。2 一醋酸鹽再溶於,並以碩酸氫鈉水溶液洗滌 。乾燥所分出之有機相,CHC{3再真空下蒸發。(土 )一順式一 2 —乙醯氧基甲基一 5 — (脲嘧啶_1 一基) 一 1, 3 —氧硫雜環戊烷,如上述地氟化(A方法)(像 利用Robins et al之方法)。5 — F-尿嘧啶鹼轉化成 5 — F —胞喃淀驗,偽先依據C· B. Reese,J· Chem. Soc., Perkins I, 1771, 1984 及 W. L. Sung,
Nucleic Acids Res.,9,6 1 39,1 98 1 之方法, 於環境溫度下利用1, 2,4—三唑及2當量的4一氯苯 基二氯磷酸酯/無水吡啶中製備4一 (1, 2, 4—三唑 經濟部十央標準q工消"合作社卬% _1一基)衍生物。此轉化作用後繼以與先前已用氨壓0 °C下飽和之甲醇反應,且2 —醋酸鹽水解生成(±) —順 式一 1一2 — (羥甲基)一1, 3_氧硫雜環戊烷一 5 — 基)一 5 -氟胞嘧啶。 抗病羞活件 依據本發明之綜合物,進行於經Η I V感染之MT4 細胞分析中抗一 Η I V活性之測試,如Averett , D. R., 本紙張尺度边用中國a家標準(CNS)甲4規格(210X297公垃) ~ 25 ~ 199861 Λ 6 Β6 五、發明説明(24) J· Virol. Methods, 23 . 263 - 276 (1989 )所述。細胞曝於Η I V卞1小時,再加抗病毒組份。組 份於連續的2 . 5倍稀釋液中測試。經3 7 °C下培育5天 ,決定細胞數目。估計Η I V誘生之細胞病變效應,以 F I C圖決定協同作用,如Elion. Singer及Hitching ,J. Biol. Chem. 208,477 (1 954)所述。 依據Elion etal (上文)(表1)之方法計算, 叠氮胸苷與順式一 1—2 — (羥甲基)一1, 3 —氧硫雜 環戊烷—5 -基)一5 —氟胞嘧啶之分別抑制劑濃度。 數據可割成圔型,由此決定出順式一 1 一 2 — (羥甲 基)一1, 3 —氧硫雜環戊烷一 5 —基)一 5 —氟胞嘧啶 及疊氮胸Μ為強協同性的。 (請先閱讀背面之注意事項再填寫本頁) 裝. 線· 本紙尺度边用中國囷家標準(CNS)甲4規格(210X^7公及) -26 - 19986i Λ 6 B 6 五、發明説明(25)g_1_分別抑制劑濃度(F I C)之計算 7 ◦ %抑制作用 疊氮胸苷 (u M) 化合物1# (y Μ) FIC 叠氮胸苷 FIC 化合物1 0.004 2.5 0.018 0.48 0.01 2.0 0.045 0.38 0.0256 1.6 0.12 0.31 0.06 1.4 0.27 0.26 0.22 _ 一 5.2 * 化合物1是順式一 1 一 2 — (羥甲基)一 1,3 —氧硫雜環戊烷一 5 —基)一 5 —氟胞嘧啶 (請先閲讀背面之注意事項再塡寫本頁) 裝· 訂' 線 經濟部屮央標準XJn工消疗合作社'-P% 本紙5k尺度边用中國國家標準(CNS)甲4規格(210X25)7公;Ji) -27 -
Claims (1)
19986± Λ7 B7 C7 D7 經濟部中央樣率居貝工消费合作杜印製 六、申請專利範圍 附件1A:第81 101695號專利申請茱 中文申請專利範圍修正本 民國8 1年1 1月修正 1 · 一種用於治療或預防Η I V感染之藥學組合物, 其顯示協同的抗一 Η I V作用,含有以下組份: (a) 順式一 1 一 (2 —(羥甲基)一 1, 3 —氧硫雜環 戊烷一5—基)一5—氟胞嘧啶,或其藥學上可接 受性鹽,及 (b) 3·—叠氮基一 3’去氧胸苷或其藥學上可接受性鹽 Ο 2. 根據申請專利範圍第1項之藥學組合物,其中( a)組份是順式一 1— (2— (羥甲基)_1, 3_氣硫 雜環戊烷一 5 -基)一 5 —氟胞嘧啶,且(b)組份是 3 ·_β氮基一3 ·—去氧胸苷。 3. 根據申請專利範圍第1項之藥學組合物,其中組 份以(a)組份對(b)組份由600 : 1至1 : 1範圍 之莫耳濃度比使用。 4. 根據申請專利範圍第2 項之藥學組合物,其中 組份以(a)組份對(b)組份由600 : 1至1 : 1範 圍之莫耳濃度比使用。 5. 根據申請專利範圍第3項之藥學組合物,其中組 份以(a)組份對(b)組份由250 : 1至10 : 1範 圍之莫耳濃度比使用。 (請先閲讀背面之注意事項再填寫本頁) -丨裝· 訂· f ! 本紙張疋度適用中國國家標準(CNS)甲4规格(2丨〇 X 297公釐) 81.9.10,000 1 A7 199861 c7 _D7_I_ 六、申請專利範圍 6. 根據申請專利範圍第4項之藥學組合物,其中組 份以(a)組份對(b)組份由250 : 1至10 : 1範 圍之莫耳濃度比使用。 7. 根據申請專利範圍第1至6項中任一項之藥學組 合物,其偽用於人類治療。 8. 根據申請專利範圍第7項之藥學組合物,其像用 於治療或預防人類免疫缺失病毒(Η I V)感染。 (請先閲讀背面之注意事項再瑣寫本页) 裝· 訂. 經濟部t央橒準局KS工消费合作杜印M 本紙張义度適用中a BI家捸4*- (CNS)甲4规格(2丨0 X 297公贷) 81.9.10,000 -2 -
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- 1992-03-05 DE DE69230140T patent/DE69230140T2/de not_active Expired - Lifetime
- 1992-03-05 NZ NZ241842A patent/NZ241842A/en not_active IP Right Cessation
- 1992-03-05 AU AU13512/92A patent/AU668860B2/en not_active Expired
-
1993
- 1993-04-27 US US08/054,548 patent/US6107288A/en not_active Expired - Lifetime
-
1998
- 1998-04-22 HK HK98103372A patent/HK1004189A1/xx not_active IP Right Cessation
-
1999
- 1999-12-30 GR GR990403387T patent/GR3032299T3/el unknown
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