TWI262080B - Process for reacting alkaloids and use of the reaction products - Google Patents
Process for reacting alkaloids and use of the reaction products Download PDFInfo
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- TWI262080B TWI262080B TW091125317A TW91125317A TWI262080B TW I262080 B TWI262080 B TW I262080B TW 091125317 A TW091125317 A TW 091125317A TW 91125317 A TW91125317 A TW 91125317A TW I262080 B TWI262080 B TW I262080B
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- reaction product
- alkaloid
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- producing
- reaction
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- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
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Description
1262080 九、發明說明: 【發明所屬之技術領域】 本發明係有關於一種利用生物鹼與填衍生物進行反應 新方法以及所得的反應產物之應用。 【先前技術】 按,眾所皆知的,生物鹼可於外在的有機體中具有生 物活性’如白屈菜(CTze/zWom’ww way·似Z·)之乳汁可作為 治療夜的通用藥物’白展茱(Chelidonium majus L.)中含有超 過30種的生物驗,其中白屈菜驗(cheiid〇nine )佔組成物 的量80%以上。 若將細胞抑制劑與/或致癌的磷衍生物加入生物鹼 中’合成的產物較起始物質毒性低,但對於某些癌細胞株 具有細胞毒性。 DE 2028330 與 US 3865830 揭露由白屈菜(CTze/zWow/wm Ζ·)中選擇的生物鹼及三(1-氮丙啶)膦硫化物 (tris(l_aziridmyl)phosphine sulphide)於有機溶劑中反應而 製備三胺硫磷-異奎寧的加成物。 AT 3M644與AT 377988揭露可藉由與致癌的磷化合 物反應以製備生物鹼的磷衍生物,並利用轉換成鹽的方 式,提供水溶性的型式。此步驟之缺陷為轉換反應產物成 水/谷性鹽類不完全且反應產物的主要成分保持在不溶於水 的狀態。 US 598751 揭露了 在 AT 377988 與 AT 354644 揭露之物 貝可於輕射損傷治療中使用。 1262080 上述之專利所揭露的化合物具有不同的細胞抑制與致 癌('生。生物驗的此合物’尤其是在白屈菜 mq/似Ζ·)中總生物鹼中,於療效上證實為有效的,且在一 些研究中證明其對癌細胞治療具有藥學活性,此外,亦發 現所製備的化合物在臨床功效上十分重要。根據植物化學 因子與植物療法,可假設除了個別的成份外,其反應生物 鹼之總混合物亦具有藥學活性。 於反應之後,需將未反應試劑的殘留物由合成混合物 中移除,然而,由於三(1-氮丙咬)膦硫化物 (tris(l-aziridinyl)phosphine sulphide)溶於有機溶劑中,如 苯、_或氯仿’因此根據習用技術所揭露的製造步驟中, 利用St沖洗反應產物以由合成混合物中移除未反應的三 (1-氮丙唆)膦硫化物(tris(l-aziridinyl)phosphine sulphide)。 由是,本發明之主要的目的,即在提供一種以礙衍生 物製備生物驗的反應產物之新製程,此製造方法可將生物 驗轉換成水溶性狀態,連所選擇的生物驗及白屈菜 L·)的總生物驗也可轉換,且可得到具有 寬闊的作用光譜之低毒性藥物製劑。 為達上述目的,本發明之製備方法,將包含生物驗或 生物鹼的混合物與磷衍生物於有機溶劑中反應,隨彳灸以 沖洗反應產物,其中填衍生物以至少需包含一氮丙σ定基者 較佳。此水洗之反應產物可於隨後轉換成水溶性狀態,尤 其是若具有毒性,磷衍生物為水溶性狀態較佳。 反應產物以水沖洗’可實際上簡化製備方法,不再需 6 1262080 要因為醚爆炸的危險而設置的複雜安全性預防措施,因 此,此製造方法可於工業規模下進行無任何問題。此外, 决定藥學活性的反應產物的組成物,會於沖洗步驟中改 夂,因以液恶-液態分配使水溶性成份會溶解而從反應產物 中離開且移除。令人意外地發現,水同時於反應產物中具 有催化的效果,且以此方式影響結構及由合成所得之產物 、、、成另 了轉換成水溶性狀態之反應產物的量,於水中 沖洗為用有機溶劑沖洗的產物之1〇至15倍。 利用水冲洗轉換反應產物至一個便利隨後轉換成水溶 f生狀L之升y悲,此方式適用於白屈菜z ) 之生物驗與其餘來源產生之生物驗。本製造方法可適用於 如於AT 377988之Claim 1所提及之生物鹼的與致癌的磷化 合物反應,而第3圖中所示之磷衍生物,特別以含有氮丙 ϋ疋基的構衍生物較適用。 適用的有機溶劑為欲反應之生物鹼可溶之任何溶劑, 舉例說明之,如生物鹼可溶之二氯甲烷或氣仿。 生物鹼的反應可於升高的溫度下進行,此溫度以溶劑 的沸點較佳。 反應產物於以水沖洗後,轉換成水溶性狀態較佳,可 根據AT 377988與ΑΤ 354644描述之步驟進行,可轉換成 水溶性鹽類,尤其是鹽酸鹽型式。例如,利用通過鹽酸氣 體或加入鹽酸溶液於水洗後反應產物的有機溶液中,隨後 鹽酸鹽沉澱,所得之反應產物水溶性鹽可用於注射溶液中 使用。 7 1262080 本發明之實施例,與三(1-氮丙啶)膦硫化物 (tris(l-aziridinyl)phosphine sulphide) ( CAS No· 52-24-4)進 行反應,三(1-氮丙 σ定)膦硫化物(tris(l_aziridinyl)phosphine sulphide)於藥典中解釋如同嗟替派(thiotepa,一種腫瘤抑 制劑),而同義字為 ledertepa、Onco thiotepa、TESPA、 tespamin、thiophosphamide、thio- ΤΕΡΑ、硫代三乙烯石粦 醯胺 (thiotriethylenephosphoroamide) 、 tifosyl 、 triaziridinylphosphine sulphide 、 N,N’,N"-tri_ 1,2-ethanediylphosphorothioine triamide 、 N,N’,Nff_tri-1,2-ethanediylthiophosphoramide 、 tri-(ethyleneimino) thio-phosphoramide 、 N,Nf,N"-triethylenethiophosphoramide 、 triethylenethiophosphortriamide 、 m-triethylenethiophosphoramide 、 m-tris(aziridin-1 -yl)phosphine sulphide 、 triethylenethiophosphoramide 、tris(l-aziridinyl)phosphine sulphor、tris(ethylene-imino)thiophosphate、TSPA、WR 45312 。 於本發明之進一步的實施例中,由白屈菜(CTze//办 )中之生物驗的萃取物、自由選擇的總生物驗於有 機溶劑中與三(1-氮丙啶)膦硫化物 (tris(l-aziridinyl)phosphine sulphide)反應,所得之反應產物 可隨意存在如一複合物,隨後以水沖洗至少一次。而且三 (1-氮丙咬)膦硫化物(tris(l-aziridinyl)phosphine sulphide) 8 1262080 可於水中分解,反應後未轉換的三(1-氮丙啶)膦硫化物 (tris(l_aziridinyl)phosphine sulphide)過剩的殘留物可利用 此方式由有機相中移除。較好的方式是將包含反應產物之 有機溶劑水洗數次,且每一次皆須浸透水,重複沖洗至過 量之高毒性三(1-氮丙啶)膦硫化物 (tris( 1 -aziridinyl)phosphine sulphide)完全的由反應產物中 移除。 此外,利用水相由合成混合物中移除會造成藥學應用 上不良反應或肝硬化的毒性生物鹼或降低其濃度。然而, 以致突變測試法(Ames test,安氏試驗)測試,結果顯示根 據本發明所製造具體實施例之反應產物不具致突變性。 此反應產物為生物驗、三(1-說丙σ定)麟硫化物 (tris(l -aziridnyl)phosphine sulphide)與生物驗之高分子量反 應產物及二(1-氮丙σ定)麟硫化物(tris(l-aziridnyl)phosphine sulphide)分解物之複合物的混合物。 合成步驟的結果,會使得生物驗的溶解性改變,四級 生物驗的濃度會減少,三級生物驗的濃度會增加。反應產 物包含一複合物,此複合物為60%至70%之白屈菜生物鹼 及 30 至 40 % 的三(1-氮丙啶)膦硫化物 (tris(l-aziridnyl)phosphine sulphide)反應產物。 三級白屈菜生物驗相當於成分的主要部分,如下列的 三級生物鹼可以被包含於合成的混合物中:白屈菜鹼 (chelidonine)、protopin、stylopin、allocryptopin、α -高白 屈菜驗(a -homochelidonine)、白屈菜定驗(chelamidine)、 9 1262080 白屈菜明驗(chelamine)、L-司巴丁(L-sparteine)、二聚體白 屈菜默驗(chelidimerine)、 二氫血根驗 (dihydrosanguinarine)、氧化血根鹼(oxysanguarine)、氧化白 屈菜鹼(oxychelidonine)、 曱氧基白屈菜鹼 (methoxychelidonine)。 大部分的四級白屈菜驗(如小檗驗)可藉由水以液態_ 液態分配的方式由合成混合物中移除,在所敘述的反應條 件下,小檗鹼與三(1-氮丙唆)膦硫化物(tris (丨-犯别㈣) phosphine sulphide)不會形成化合物。 本實施例之反應產物較以醚沖洗的反應產物具有較佳 之藥物的作用範圍,可利用編程性細胞死亡毀壞癌細胞_與 已知的細胞生長抑制劑相對比_不會攻擊到健康的細胞。這 種製劑於治療上具有良好的耐受性,並且可適用於預防治 療上,操作簡單且於治療用量上並沒有明顯的不良反應。 其藥物效用疋由於合成混合物中物質的相互作用的結果。 白屈菜(C/ze/zWom·細廳y⑽z.)的總生物鹼之反應產物 於代謝的調控上具有生物活性且適合用於新陳代謝症的防 ^與治療,如骨質疏鬆、而且還可用於風濕病、過敏、病 毒感染、癲癇症、多發性硬化症、瘢痕、皮膚癌與手術後 傷口。 白屈菜(C7ze/zW〇m•贿2)的乾燥根中萃取物用作 合成反應的起始物質是較佳,白屈菜(C/zAW⑽以所历办似上) 的根較葉及莖中具有較高的生物鹼含量。 習慣上的藥物賦形劑,尤其是用溶液,如注射液或輸 10 1262080 注液,或用軟膏、敷布絲一帶的主藥,都適用於包含 本發明之反應產物的藥。 以下為本發明實施例的描述: 實施例1 (A )生物鹼的萃取 a· 25克的生物鹼鹽混合物懸浮於水中且轉移到分 液漏斗内,在加入1〇〇1111的二氯甲烷之後,搖晃 分液漏斗,可分開有機相且過濾至玻璃瓶中。 b · iN的NaQH (PH8_9)加人液相直到產生混濁。 在加入100ml的二氣甲烷之後,搖晃混合物,隨 後有機相會分開且與步驟a之二氣甲烷相化合在 一起,重複此步驟,如重複3次。有機相皆過濾 與化合。 c ·利用加入NaOH將液相調整至pH1〇,在加入二氯 曱烷之後,搖晃混合物,隨後有機相分開、過濾 與會與其他的有機相混合。將液相利用加入 NaOH將液相調整至pHl3,並利用二氣曱烷重複 萃取。 d ·化合的有機相蒸發至一油質的、棕色物質。 (B)與三(1_氮丙啶)膦硫化物(tris phosphine sulphide)反應 生物鹼殘留物溶解於二氯曱烷中,加入三(1-氮丙啶) 膦硫化物(tris ( 1-aziridnyl) phosphine sulphide),此混合物 回流加熱於8 0 °C 2小時,在冷卻至室溫以後,澄清反應 1262080 混合物。隨後進行過濾且濾出物以250ml的水於分液漏斗_ 沖洗數次,如3次或是更多。 (C )與HC1反應 水洗的溶液轉換至玻璃燒杯中,充滿HC1氣體且授掉, 鹽酸鹽複合物開始沉澱,沉澱產物過濾且以二乙_沖洗, 乾燥隨後並溶解在水中。 在大鼠(rat)中,實施例1之反應產物之LDw (半數致 死量測試)為485mg/kg。於小鼠(mice )與大鼠(rat)中 的研究顯示,本發明之產物調節胸腺贺爾蒙調控且在移& 胸腺的動物中誘導具有似胸腺素活性的物質合成,此效果 與劑量有直接關係。此製劑於動物實驗中,可增加周圍血 液中的T淋巴細胞的數量直到處理前的50% (處理前4.〇4± 0.43\109/1,處理後6.24±0.73\109/1)、調節體液性免疫反 應至滲透抗原與脾臟細胞的自然殺傷性細胞活性(198.2〇 ±17.69%與控制組71.50±9.1〇%相比)且增強干擾素釋出潛 在的白血球,因此,於癌症病人中可發現免疫指數改善。 於預防治療及免疫的應用上,體重每70kg攝取實施例1 之製劑5mg劑量,若是於癌症的處理上,體重每2〇竑攝取 5mg劑量較佳。 實施例2 :高效率液相層析儀(HPLC)指紋圖譜 以離子對反向層析儀於漸變模式進行測定,且利用 DAD檢測器以285nm作為光譜測量,相同時間下,利用參 考生物鹼製作色層分析譜,此外,也進行HPLC-MSD分析, 12 1262080 結果顯示沒有高峰(peak)由這些生物鹼中分開。第1圖與 第2圖之HPLC圖譜基於下述的實驗資料中獲得。 層析儀參數: 管柱:LiChrospher 60 RP select B填料,5 // m,125 mmx4mm 沖提液:(A ) 200ml (乙腈)+800 ml (水)+1.5g (hexanesulphonic acid) + 0.3ml ( 85% 的石粦酸)(B ) 900ml (乙腈)+100 ml (水)+1.5g ( hexanesulphonic acid) +0·3ηι1 (85%的磷酸) 梯度:5分鐘等度100% A ; 直到40% B於24分鐘; 直到100% B於1分鐘; 5分鐘100% B; 5分鐘利用100% A平衡 檢測:285nm的UV光 沖提速度:lml/min,於35分鐘後停止 注入體積:10# 1 樣品製備: 在反應之前萃取(第1圖):以超音波方式將25克的生 物鹼溶解在40ml的甲醇,製成50ml且以膜過濾器過濾。 反應產物(第2圖):反應產物轉換至鹽酸鹽,#lmg/ml 的濃度溶解於水中,並將pH調整至2.5至6.5。 下述之實施例顯示由實施例1之步驟製造之化合物(於 下述稱之為UkrainR)的各種應用。 實施例3 : I及Π型骨質疏鬆 13 1262080 3〇個1及Π型骨質疏鬆的病人接受UkrainR治療,以 ¥的濃度5叫的劑量通過靜脈提供,每個星期—次超 過1〇的星期。利用檢測血液及生化的參數及測量血清中^足 素,、促黃體生成激侧 素(prolactm)以監控正在造 測量賴。在治療三個月後,;有病人::床青中 改善,且生理上增加时’轉時沒树現任;^良反應有 實施例4 :成骨形成不全症 14歲的女ϋ病人#斷為壞的成骨形成不全症。L射線 圖顯示發生瀰漫骨f疏鬆、鞏膜有明顯的藍眼珠(blue =lera)、乳齒(齒質形成不全)、圓錐形的胸腔、脊 。病人通過靜脈以每星期—次提供μ :g、: 以三個月做三個治療循環,循環間有間 歇、療、、、σ果於肌肉功能重大的改善;且鞏膜及牙齒變白, =改善會椎侧t H療的物理運動程度顯著 的何重能力。病人的身體變好且均衡,體重與體型大小對 2齡雙正常。x_射線圖指出修復骨結構;且x-射線圖不 再有任何可發覺的骨質疏鬆徵狀。 實施例5 :脊椎關節炎 -位7i歲的女性病人抱怨於腰背部的嚴重疼痛,於^ 至L3部分’且移動性受到限制。病人透過靜脈以每星期一 次5mg的劑量提供瓜—治療,且利用敷布敷於表面超過 14 1262080 4個星期。病人的情況獲得改善且移動性完全恢復。 實施例6 :皮膚病灶潰瘍形成 一位7歲的男孩於肩胛骨左部手術後的皮膚病灶有大 的潰瘍形成,由於瘢痕太大以致於需要整形手術,病人以 包含UkrainR的敷布敷於表面超過12個星期,瘢痕獲得明顯 的感善,潰瘍減低且無任何發炎產生。 實施例7 :氣喘過敏症 一位12歲的男病人患有嚴重的過敏、咳嗷及氣喘發 作,每日以UkrainR5mg的劑量治療超過3個星期,情況有明 顯的改善,且如今病人認為已治癒。 實施例8 :牛乳過敏症 一位12歲的男病人患有嚴重的牛乳過敏症,過敏發生 的原因是因為包含有牛乳的食品,如巧克力。病人透過肌 肉以每兩天5mg劑量的UkrainR提供治療2個星期。情況有 明顯的改善,且如今病人認為已治癒。 實施例9 :對貓過敏症 一位9歲的女性病人對於貓過敏,會造成氣喘發作。此 病人每個星期兩次以UkrainR5mg的劑量治療,其情況具有 明顯的改善且如今病人認為已治癒。 15 1262080 實施例ίο ·•帶狀庖疹 一位64歲的女性病人診斷受到帶狀庖疹感染復發,傳 統的巵疹撕裂Th3-Th4部分且形成潰瘍。病人透過靜脈以每 生期兩夂5mg的劑量之UkrainR治療超過8星期,四年沒有再 復發的情形。 實施例11 : C型肝炎 一位患有慢性的C型肝炎的42歲男性病人,其 HCV-RNA ( C型肝炎病毒核糖核酸)結果呈陽性,且11(:¥ genotype (病毒基因型)為比,病人會抱怨疲倦、且伴隨 著疼痛與虛弱的體力。病人通過靜脈以每星期兩次5mg的 劑量之UkrainR治療超過5星期,治療的絲,病人感覺不 再疼痛’且整體情況獲得改善,體力增進,病人如今之 HCV-RNA結果呈陰性。 ’ 實施例12 ·•過敏 ’伴隨咳嗽並包 在4星期治療之 病人Α·Ν·,12歲,患有嚴重的過敏發作 含氣喘。病人每曰口服UkrainR5mg劑量, 後’病人具有顯著的改善且未曾發作。 貫施例U ·子術後的傷口(皮膚病灶潰瘍) 病人S.D.,7歲,在手術後於左肩部位有大的皮 由於此皮膚潰瘍太大以致需要整形重建,病人、$ ’貝蕩’
UkrainR的敷布治療3個月,皮膚潰瘍大大的減少=局部的 〃、大小, 16 1262080 並且沒有潰瘍,也沒有發炎。 實施例14 :骨質疏鬆 病人H.J.,68歲,行走困難、疲勞,在透過臨床與實驗 室的研究,診斷為I型骨質疏鬆,病人透過靜脈以每星期5 m g 的劑量之UkrainR治療,10星期治療後,病人主觀上認為有 改善,且實驗結果證實骨密度、鈣及荷爾蒙的程度都有明 顯的改變。 實施例15 :帶狀庖疹 病人K.R.,37歲,7歲時患有水痘,如今顯示沿著肋骨有 典型的皮膚疼痛發療-帶狀庖療(Herpes zoster),病人在4 星期中每星期兩次透過靜脈以UkrainR5mg的劑量治療,6 年内沒有再復發。 實施例16 : B型肝炎 病人G.H.,48歲,顯得虛弱、疲勞、減少活力,在透過 臨床的與實驗室的研究,診斷為慢性B型肝炎,其HBS-Ag (表面抗原)為陽性反應,增加血液中的酵素程度。病人 通過靜脈以每星期一次UkrainR5mg劑量治療,主觀上認為 改善且活力增加,實驗室實驗結果顯示病毒負荷量(viral load)明顯的減少,且酵素程度恢復正常化。 實施例17 :風濕病,化骨性關節炎 17 1262080
病人I.N.,71歲,患有嚴重背痛於L1-L3部位,配合移動 性限制,在透過臨床的與實驗室的研究,診斷為化骨性關 節炎(關節退化)。病人通過靜脈每星期兩次以UkrainR5mg 的劑量治療6星期,疼痛明顯的減低,病人與參考範圍相比 移動範圍增加Q 實施例18 :癲癇症 病人IXR.,46歲,患有複雜性局部癲癇發作,且症狀有 惡化的傾向。然而高劑量的雙苯内醯脲會伴隨有腺病的副 作用。病人通過靜脈每星期兩次以UkrainRIOmg劑量治療6 星期,可注意到症狀減低相當的多,發作稀少且診斷有減 少。減少使用高劑量抗癲癇藥。 實施例19 :多發硬化症 病人M.G.,36歲,腿部感覺無法解釋的虛弱並且隨後會 有頭昏的情況,發病的間隔變短,研究後診斷為多發硬化 症,使用物理治療不成功。病人通過靜脈每星期兩次以 UkrainR劑量5mg治療4個月後,可注意到發作的間隔變長, 病人感覺腿更有力且不會頭昏。 實施例2 0 :瘋痕 病人I.N.,在腹部手術後於腹部上具有大的硬瘢痕,在 病人通過靜脈每星期兩次以UkrainR劑量5mg治療4星期並 配合局部的敷布,注意到有明顯的實際修飾效果。 18 !262〇8〇 貫施例21 ·•流行性感冒 病人Β·Ν·,24歲,受到周年的流 案例中還會伴隨肺炎,UkminR用你 α目傳木,於一些 ^ UkramR用作預防處理·· 5mm 脈每星期兩次,在流行 a §通過靜 丁病毛生期之珂總劑量為5〇m 人如今四年沒有患過疾病。 g 此病 實施例22 : II型糖尿病 病人B丄·,62歲,患有_糖尿病(非 尿病),每日使用1〇m劑量 、賴型糖 … 里的ghPizule (包含石黃醯尿 的抗糖尿病藥物)治療,、忘人顧-A人r I基 徵病人顯不鬲血壓、不論如何飲食 ,制都超重、不耐煩、容易疲勞且活力低。以透過靜脈每 星期兩次以UkrainR劑量5mg治療2個月後,整體的情況獲得 改善,活力增加,體重減少。Glipizide逐漸地中斷且病人 感覺良好。 實施例23 :復健 病人0丄”74歲,左髖關節骨折,在大手術持續數小時 伴隨植入關節,病人限制在床上,以通過靜脈每星期兩次 以UkrainR劑量5mg治療6個星期後,整體的情況獲得改善, 復健時間明顯的縮短。 實施例24 :巧克力過敏症 病人Υ·Ρ·,8歲,對巧克力過敏,在每昱期3次口服 19 1262080
UkrainR劑量5mg治療4星期,沒有進一步的過敏發生。 實施例25 :復健 病人J.R·,78歲,接受膽石及膽囊炎(膽囊切除)外科 手術,在手術後,口服UkrainR 5mg每個星期3次治療2個星 期。注意到快速且少痛苦的復原,並且無任何的併發症。 病人較預期更快速離開醫院。 實施例26 :痔瘡 病人J.N.,64歲,患有外部疼痛的痒瘡於典型的位置3及 7點鐘方向,且糞便中帶血。坐藥(置於肛門内或陰道内在 體溫情況下可溶藥)中含有0.5%UkrainR以每日一次整夜治 療的方式持續兩個星期。痒瘡縮小且病人兩年内沒有更多 的疼痛。 實施例27 :痤瘡 病人R.G.,14歲,患有孩童型痤瘡/青春痘(Acne Juvenilis)以阻礙療程治療超過4個月,以包含0.1% UkrainR 的藥貧每日兩次治療10天後,痤瘡永久的移除。 實施例28 :扁桃腺炎 病人H.D·, 1〇歲,患有扁桃腺炎、咽喉部分疼痛、吞嚥 困難且發燒至38.2。扁桃體上包覆有白色薄層,病人每曰 給予兩次口服UkrainR溶液5πύ,在治療5天後,病人完全的 20 1262080 康復。 所有的應用於實施例3至25成功的執行-於一些案例中 功效較小-配合AT 377988描述的化合物。 雖本發明以一較佳實施例揭露如上,但並非用以限定 本發明實施之範圍,任何熟習此項技藝者,在不脫離本發 明之精神與範圍内,當可做些許的更動與潤飾,及凡依本 發明所做的均等變化與修飾,應以本發明之申請專利範圍 所涵蓋,其界定應已申請專利範圍為準。 【圖式簡單說明】 第1圖係為白屈菜(CTze/zWom’ww Z·)根中特有之總生 物鹼組成物之HPLC圖譜。 第2圖係為根據實施例1製備之HPLC圖譜。 第3圖係為US 5981512可選擇作為試劑之磷衍生物。 21
Claims (1)
- Τ〇/:〇 Α^Α Λ-- 4 i „, 丄厶 υζ^<ρ% 口叫 「 ^ !*«、,-一一—.丰〜〜.4一」 ! ^j f' 、·'‘ 》J ί— i 十、申請專利範一-- 」 1、 一種反應生物鹼的製作方法,包括以下步驟: (a) 至少一種生物鹼與至少包含一氮丙啶基的麟衍生 物於有機溶劑及升高的溫度中反應,此溫度以溶 劑的沸點較佳,且 (b) 沖洗由步驟(a)所得之反應產物,其特徵為反應產 物以水沖洗。 2、 如申凊專利範圍第1項所述之反應生物驗的製作方 法’其中磷衍生物為三(1_氮丙啶)膦硫化物 (tris(l-aziridinyl)ph〇Sphine sulphide)。 3、 如申請專利範圍第1項所述之反應生物鹼的製作方 法其中生物鹼由白屈菜(Chelidonium majus L·)的生 物驗中選擇。 4、 如申請專利範圍第丨項所述之反應生物鹼的製作方 法’其中反應使用生物鹼混合物。 5、 如申請專利範圍第4項所述之反應生物鹼的製作方 法其中反應使用白屈菜(Chelidonium majus L·)所有 的生物鹼混合物。 6、 如申請專利範圍第1項所述之反應生物鹼的製作方 法,其中溶劑為二氯甲烷。 7、 如申請專利範圍第丨項所述之反應生物鹼的製作方 法,其中反應產物在沖洗步驟之後轉換成鹽類。 8、 如申凊專利範圍第7項所述之反應生物鹼的製作方 法,其中鹽類為水溶性鹽類。 22 1262080 9、 10 如申請專利範圍第7項所述之反應生物驗的製作方 法,其中鹽類為氣化物。 種反應產物,係由至少_種包含於白㈣㈣&物 鹼包3於白屈米中的生物驗及與至少包含一氮丙咬 基的鱗衍生物的反應物,以及包含至少—減丙咬基 的填衍生物的分解物,該反應產物由下财法製造得 到: ⑷至少在-種包含於白屈菜中的生物驗與至少包含 -氮丙縣_衍生物於有機溶液及升 南的溫度 中反應,此溫度以溶劑的沸點較佳, (b)隨後以水沖洗上述⑷所得之反應產物,此反應產物 為混合物包含生物鹼、生物鹼及磷衍生物反應產物 與磷衍生物的分解物。 11、 如申請專利範圍第10項所述之反應產物,其中此反應 產物為混合物包含生物鹼、生物鹼及三(1β氮丙啶)膦 硫化物(tris( 1 _aziridinyl)phosphine sulphide)反應產物 與三(1 -氮丙唆)膦硫化物(tris (1 -aziridinyl)phosphine sulphide)的分解物。 12、 如申請專利範圍第10項所述之反應產物,其中至少包 含一種生物驗,係選自白屈菜驗(chelidonine )、 protopin、stylopin、allocryptopin、高白屈菜驗 (homochelidonine )、血根驗(sanguinarine)、 chelamidine、chelamine、L-司巴丁( L-sparteine )、 氧化白屈菜驗(oxychelidonine)所組成之群組。 23 1262080 13、 一種作為藥劑之反應產物,係由至少一種生物鹼與至 少包含一氮丙啶基的磷衍生物於有機溶液及升高的溫 度中反應,此溫度以溶劑的沸點較佳,隨後以水沖洗 上述所得之反應產物,此反應產物為混合物包含生物 驗、生物驗及填衍生物反應產物與礙衍生物的分解物。 14、 如申請專利範圍第13項所述之作為藥劑之反應產物, 其中藥劑可用於疾病的預防及治療或有機障礙由癌 症、免疫的疾病與新陳代謝的疾病中選擇。 15、 如申請專利範圍第13項所述之作為藥劑之反應產物, 其中疾病包含過敏、骨質疏鬆、皮膚癌、病毒感染、 風濕病、瘢痕、手術後傷口、癲癇與多發性硬化症。 24
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Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1459753A1 (en) | 2003-03-18 | 2004-09-22 | Nowicky, Wassyl, Dipl.-Ing. DDr. | Quaternary chelidonine and alkaloid derivatives, process for their preparation and their use in the manufacture of medicaments |
WO2006053680A1 (en) * | 2004-11-19 | 2006-05-26 | Nowicky Wassili | Ex vivo cancer diagnostic method |
WO2006053649A1 (en) * | 2004-11-19 | 2006-05-26 | Nowicky Wassili | Method for the detection of cancer |
WO2007073919A2 (en) | 2005-12-28 | 2007-07-05 | Nowicky Wassili | Method and kit for the detection of cancer |
ITMI20080284A1 (it) * | 2008-02-22 | 2009-08-23 | Indena Spa | Agenti antitumorali a struttura benzofenantridinica e formulazioni che li contengono |
CA2941315C (en) * | 2016-08-12 | 2018-03-06 | Api Labs Inc. | High thebaine poppy and methods of producing the same |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
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SU368254A1 (ru) | 1969-06-16 | 1973-01-26 | А. И. Потопальский , В. М. Новицкий Львовский государственный медицинский институт | Способ получения соединений тиофосфамида с алкалоидами чистотела большого |
US3865830A (en) * | 1969-06-16 | 1975-02-11 | Nikolai Mikhailovich Turkevich | Thiophosphamide derivatives of isoquinoline alkaloids, method of producing and application thereof |
AT354644B (de) * | 1975-12-19 | 1980-01-25 | Nowicky Wassili | Verfahren zur herstellung von neuen salzen von alkaloidderivaten von thiophosphorsaeure |
AT377988B (de) * | 1976-06-28 | 1985-05-28 | Nowicky Wassili | Verfahren zur herstellung von neuen phosphorderivaten von alkaloiden |
DE3128018A1 (de) * | 1981-07-13 | 1983-04-07 | Wassyl 1060 Wien Nowicky | "verfahren zum diagnostizieren und fuer die therapeutische behandlung von tumoren und/oder infektioesen krankheiten verschiedenster art unter praeparativem einsatz von alkaloid-verbindungen bzw. deren salze" |
US4970212A (en) * | 1982-05-18 | 1990-11-13 | Nowicky Wassili | Method of treating human illnesses which compromise the ability to mount an effective immunological response |
AT407608B (de) * | 1994-03-18 | 2001-05-25 | Nowicky Wassili | Mittel zur behandlung von osteoporose |
AT407833B (de) * | 1995-06-01 | 2001-06-25 | Nowicky Wassyl Dr | Mittel zur behandlung von strahlenschäden |
AT408719B (de) * | 2000-03-22 | 2002-02-25 | Nowicky Wassili | Mittel zur behandlung von hepatitis c |
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