TWI593700B - 一種替諾福韋前藥及其在醫藥上的應用 - Google Patents
一種替諾福韋前藥及其在醫藥上的應用 Download PDFInfo
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- TWI593700B TWI593700B TW102126234A TW102126234A TWI593700B TW I593700 B TWI593700 B TW I593700B TW 102126234 A TW102126234 A TW 102126234A TW 102126234 A TW102126234 A TW 102126234A TW I593700 B TWI593700 B TW I593700B
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- Prior art keywords
- compound
- tenofovir
- pharmaceutically acceptable
- isomer
- group
- Prior art date
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- 229910052760 oxygen Inorganic materials 0.000 description 1
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- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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- 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
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- 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
- A61P31/20—Antivirals for DNA viruses
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Description
本發明涉及一種替諾福韋前藥或其異構體、可藥用鹽、水合物或溶劑化物,及其在醫藥上的應用。
乙型肝炎病毒(hepatitis B virus)是指引起人類急性肝炎和慢性肝炎的DNA病毒,簡稱HBV。由於HBV感染直接導致人類嚴重的肝臟疾病,包括肝硬化和肝細胞癌,因此,乙型肝炎是人類健康的一大威脅。乙型肝炎病毒DNA(去氧核糖核酸),是乙肝病毒的核心物質和病毒複製的基礎,核苷類化合物可藉由直接競爭性地與天然去氧核糖基質相結合而抑制病毒聚合酶,及藉由插入DNA中終止DNA鏈,因此核苷類化合物是治療乙型肝炎的主要藥物,其中包括,西多福韋、阿德福韋、拉米夫定以及替諾福韋(tenofovir)等。替諾福韋是一種新型核苷酸類逆轉錄酶抑制劑,可有效對抗多種病毒,用於治療病毒感染性疾病。由於替諾福韋在生理pH條件下為雙負離子的膦酸基團,故替諾福韋不易透過細胞膜吸收,生物利用度很低,並且還存在劑量依賴性腎毒性,限制了其治療作用,因此必須藉由酯化、成鹽等手段製成膦酸酯前藥才能用於臨床。例如,富馬酸替諾福韋酯(Tenofovir disoproxil fumarate)是吉裏德科學公司(Gilead Science)研發的第一
代口服有效的替諾福韋前藥,用於治療愛滋病感染和乙型肝炎。
由於富馬酸替諾福韋酯對由血清酶介導的水解反應高度敏感,不能有效增加作用部位藥物濃度,同時在代謝過程釋放兩當量的具有潛在毒性的甲醛,在臨床治療過程中發現乳酸性酸中毒,嚴重的肝腫大,以及脂肪代謝障礙等副作用。為了提高替諾福韋前藥在血漿中的穩定性,降低其代謝產物-替諾福韋在血漿中的濃度從而降低藥物毒性,許多製藥公司正在進行研究和開發新一代替諾福韋前藥,並已取得了一些成果,有的新型前藥已處在I/II臨床研究階段,例如,WO0208241披露了一類用天然胺基酸(單取代)合成的替諾福韋磷醯胺酯前藥(例如,GS-7340),WO2009105513公開了一類新型替諾福韋磷酸雙醯胺前藥,與替諾福韋磷酸雙酯相比,此類新型前藥增加了血漿中的穩定性,從而增加了外周血單核細胞(PBMCs)中活性代謝物替諾福韋的累積濃度,提高了治療效果,例如,GS-7340與替諾福韋酯和替諾福韋相比,GS-7340在PBMCs中產生的活性成分替諾福韋總濃度為替諾福韋酯和替諾福韋的10倍和30倍。然而,GS-7340在血漿中還有一定程度的降解,在血漿中可檢測到1-2%的代謝產物-替諾福韋,從而不可避免地存在像替諾福韋酯所產生的毒副作用,導致
藥物使用的安全性存在問題。因此,進一步研究開發具有高療效低毒性的替諾福韋前藥具有重要意義。本發明從進一步提高替諾福韋前藥在血漿中的穩定性設計理念出發,利用雙取代胺基酸合成了一系列替諾福韋磷醯胺酯前藥,該類前藥一方面在血漿中非常穩定,在血漿中完全沒有檢測到代謝產物-替諾福韋,另一方面,與GS-7340相比,外周血單核細胞(PBMCs)中活性代謝物替諾福韋的濃度顯著增加,從而有可能提供一類提高療效減低毒副作用的新型替諾福韋前藥。
發明人意外地發現了一些與現有技術相比藥效更高而副作用大幅降低的化合物,與GS-7340相比,本發明化合物在血漿中足夠穩定,其代謝產物-替諾福韋在血漿中完全檢測不到,而其在PBMCs中的濃度反而大大提高了,這樣的結果完全出乎本領域技術人員預料之外。
本發明涉及一種如通式(I)所示的化合物或其異構體、可藥用鹽、水合物或溶劑化物,
其中:R1,R2分別為C1-6烷基,或者R1、R2與所連的碳原子形成C3-7環烷基;
R3是氫或C1-6烷基、取代或非取代的C6-10芳基或6至10員雜芳基;Ar為取代或非取代的C6-10芳基或6至10員雜芳基。
本發明所述通式(I)所示的化合物可作為替諾福韋的前藥,該類前藥在血漿中穩定,而且在外周血單核細胞(PBMCs)中的活性代謝物替諾福韋的濃度與GS-7340相比顯著提高。
所述的如通式(I)所示的化合物中磷原子具有手性,其構型是S-或R-構型,或者是S-構型和R-構型的混合物。
在本發明的具體實施方案中,如通式(I)所示的化合物或其異構體、可藥用鹽、水合物或溶劑化物中,該異構體包括互變異構體、順反異構體、構象異構體、內消旋化合物和具有對映或非對映關係的光學異構體。
在本發明的較佳的具體實施方案中公開了具有如下的結構的化合物,但本發明的如通式(I)所示的化合物不僅限於以下結構:
在本發明的較佳的具體實施方案中進一步公開了具有如下的結構的手性化合物,但本發明的如通式(I)所示的化合物不僅限於以下結構:
本發明的如通式(I)所示的化合物可經如下方法製備得到:
其中,如通式(II)所示的化合物可藉由中國專利ZL01813161.1中提供的方法製備,也可藉由本領域的其他常規方法使用替諾福韋製備得到。
手性異構體(I1)可以藉由對異構體混合物(I’)的逆
相管柱分離或手性管柱分離得到。
本發明還提供了一種醫藥組成物,其含有如通式(I)所示的化合物或其異構體、可藥用鹽、水合物或溶劑化物與藥學上可接受載體,其中藥學上可接受載體可以選自注射用水、凍乾粉劑輔料或口服製劑輔料。
本發明另一方面還涉及如通式(I)所示的化合物或其異構體、可藥用鹽、水合物或溶劑化物或前述的醫藥組成物在製備治療病毒感染性疾病的藥物中的用途,較佳在製備治療乙型肝炎或乙肝病毒引起的疾病的藥物中的用途。
除非有相反陳述,本發明中的術語具有下列的含義:“烷基”指飽和的脂族烴基團,包括1至6個碳原子的直鏈和支鏈基團。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上被取代,較佳為一個或多個以下基團,獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷
基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基。
“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基,其包括3至7個碳原子。單環環烷基的非限制性實例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基等。多環環烷基包括螺環、稠環和橋環的環烷基。環烷基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個以下基團,獨立地選自烷基、烷氧基、鹵素、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基。
“芳基”指6至10員全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團,具有共軛的π電子體系的多環(即其帶有相鄰對碳原子的環)基團,例如苯基和萘基。芳基可以是取代的或未取代的,當被取代時,取代基較佳為一個或多個以下基團,獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。
“雜芳基”是指包含1、2、3或4個雜原子,6至10個環原子的雜芳族體系,較佳為5至6個環原子,其中雜原子包括氧、硫和氮;例如吡啶基、嘧啶基等。“雜芳基”可以是任選取代的或未取代的,當被取代時,取代基較佳為一個或多個以下基團,獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、硫醇、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。
以下將結合具體實施例詳細地解釋本發明,使得本領域技術人員更全面地理解本專利,具體實施例僅用於說明本發明的技術方案,並不以任何方式限定本發明。
在0℃下,向苯酚(5g)和三乙胺(10.1mL)的二氯甲烷(150mL)溶液中,滴加三甲基氯矽烷(6.0g),滴加結束後,升溫至20℃,攪拌反應18小時。濾去白色固體,用二氯甲烷洗滌固體。合併濾液,蒸除溶劑後,得到無色油狀苯氧基三甲基矽烷4.2g。
在70℃下,向替諾福韋(1g,從蘇州漢德森醫藥科技有限公司購買)的環丁碸(2.5mL)混濁液中,滴加和DMF(0.1mL)和二氯亞碸(0.73g),升溫至100℃,混合物在100℃下繼續反應1.5小時至混合物全部澄清,快速加入苯氧基三甲基矽烷(0.70g),混合物在100℃下反應1.5小時後,減壓蒸除溶劑,得到黏稠狀黃色油狀液體,甲醇溶解後,用45%的氫氧化鉀水溶液調節pH至3,
過濾,乾燥得到白色粉末狀固體IIa 0.7g。MS(m/z)363.96(MH+).
在60℃下,向化合物IIa(600mg)的環丁碸(1mL)混合物中加入DMF(0.1mL)和二氯亞碸(343mg),混合物在60℃下攪拌反應30分鐘至溶解澄清。在0℃下將上述溶液加到胺基酸酯IIIa(750mg,從上海達瑞精細化學品有限公司購買)和二異丙胺(452mg)的二氯甲烷(7mL)溶液中。升溫至20℃反應2小時,依次用5%磷酸二氫鈉水溶液,飽和食鹽水洗滌後,無水硫酸鈉乾燥。蒸除溶劑得黃色油狀粗產物,經管柱層析純化後,得到油狀液體產物Ia 150mg。
1H-NMR(400MHz,CDCl3)δ 8.34(m,1H),8.05(m,1H),7.36~6.95(m,5H),6.49(b,2H),6.22~5.84(m,1H),5.01(m,1H),4.42(m,1H),4.40~3.60(m,3H),1.52~1.18(m,15H).MS(m/z)491.13(MH+).
粗產物Ia(150mg)經HPLC製備分離(製備管柱:Waters Symmetry C18,流動相:A:0.02%磷酸水溶液;B:甲醇)後得到50mg化合物Ia1(保留時間:50.65min):MS(m/z)491.17(MH+)和61mg化合物Ia2(保留時間:47.57min):MS(m/z)491.10(MH+).
粗產物Ia(150mg)經HPLC製備分離(製備管柱:Chiralpak AS-H,流動相:A:正己烷;B:乙醇)後得到62mg化合物Ia1(保留時間:6.53min)和78mg化合物Ia2(保留時間:6.11min)。
在60℃下,向IIa(600mg)的環丁碸(1mL)混合物中加入DMF(0.1mL)和二氯亞碸(343mg),混合物在60℃下攪拌反應30分鐘至溶解澄清。在0℃下,將上述溶液加到胺基酸酯IIIb(760mg,從上海達瑞精細化學品有限公司購買)和二異丙胺(452mg)的二氯甲烷(7mL)溶液中。升溫至20℃反應2小時,依次用5%磷酸二氫鈉水溶液,飽和食鹽水洗滌後,無水硫酸鈉乾燥。蒸除溶劑,得黃色油狀粗產物,經管柱層析純化後,得到油狀液體產物Ib 221mg。
1H-NMR(400MHz,CDCl3)δ 8.38(m,1H),8.01(m,1H),7.34~6.95(m,5H),6.48~6.18(m,1H),5.84(b,2H),5.01~4.82(m,1H),4.42(m,1H),4.20~3.60(m,5H),2.68(m,1H),1.41~1.10(m,12H).
粗產物Ib(100mg)經HPLC製備分離(製備管柱:
Chiralpak AS-H,流動相:A:正己烷;B:乙醇)後得到35mg化合物Ib1。MS(m/z)489.26(MH+).
在0℃下,向對氯苯酚(5g)和三乙胺(10.8mL)的二氯甲烷(150mL)溶液中,滴加三甲基氯矽烷(6.3g),滴加結束後,升溫至20℃,攪拌反應18小時。蒸除溶劑後,得到無色油狀對氯苯氧基三甲基矽烷5.1g。
在70℃下,向替諾福韋(1g)的環丁碸(2.5mL)混濁液中,滴加DMF(0.1mL)和二氯亞碸(0.73g),升溫至100℃,混合物在100℃下繼續反應1.5小時至混合物全部澄清,加入對氯苯氧基三甲基矽烷(0.77g),混合物在100℃下反應1.5小時後,減壓蒸除溶劑,得到黏稠狀黃色油狀液體,加甲醇溶解(2mL)後,於0℃用45%的氫氧化鉀水溶液調節pH至3,過濾,乾燥得到白色粉末狀固體IIc 800mg。MS(m/z)398.05(MH+).
在60℃下,向IIc(600mg)的環丁碸(1mL)混合物中加入DMF(0.1mL)和二氯亞碸(343mg),混合物在60℃下攪拌反應30分鐘至溶解澄清。在0℃下,將上述溶液加到胺基酸酯IIIa(731mg)和二異丙胺(452mg)的二氯甲烷(7mL)溶液中。升溫至20℃反應2小時,依次用5%磷酸二氫鈉水溶液,飽和食鹽水洗滌後,無水硫酸鈉乾燥。蒸除溶劑,得一黃色油狀粗產物,經管柱層析純化後得到油狀液體產物Ic 121mg。
1H-NMR(400MHz,CDCl3)δ 8.35(m,1H),8.01(m,1H),7.28(m,1H),7.22(m,1H),7.15~7.13(m,1H),6.94(m,1H),5.88(b,2H),5.07(m,2H),4.42(m,1H),4.21(m,1H),3.90~3.81(m,2H),3.71~3.54(m,1H),1.56~1.24(m,15H).
粗產物Ic(70mg)經HPLC製備分離(製備管柱:Chiralpak AS-H,流動相:A:正己烷;B:乙醇)後得到21mg化合物Ic1。MS(m/z)525.26(MH+).
在0℃下,向對甲氧基苯酚(5g)和三乙胺(10.8mL)的二氯甲烷(150mL)溶液中,滴加三甲基氯矽烷(6.3g),升溫至20℃攪拌反應18小時。蒸除溶劑後,得到無色油狀對甲氧苯氧基三甲基矽烷4.7g。
在70℃下,向替諾福韋(1g)的環丁碸(2.5mL)混濁液中,滴加和DMF(0.1mL)和二氯亞碸(0.73g),升溫至100℃,混合物在100℃下繼續反應1.5小時至混合物全部澄清,加對甲氧苯氧基三甲基矽烷(0.75g),混合物在100℃下反應1.5小時後,減壓蒸除溶劑,得到黏稠狀黃色油狀液體,加甲醇溶解(2mL)後,於0℃用45%的氫氧化鉀水溶液調節pH至3,過濾,乾燥得到白色粉末狀固體IId 600mg。MS(m/z)394.11(MH+).
在60℃下,向IId(300mg)的環丁碸(1mL)混合物中加
DMF(0.1mL)和二氯亞碸(181mg,1.52mmol),混合物在60℃下攪拌反應30分鐘至溶解澄清。在0℃下將上述溶液加到胺基酸酯IIIa(386mg)和二異丙胺(343mg)的二氯甲烷(5mL)溶液中。升溫至20℃,反應2小時,依次用5%磷酸二氫鈉水溶液,飽和食鹽水洗滌後,無水硫酸鈉乾燥。蒸除溶劑,得黃色油狀粗產物,經管柱層析純化後得到油狀液體產物Id 40mg。
1H-NMR(400MHz,CDCl3)δ 8.35(m,1H),8.04(m,1H),7.12~6.85(m,4H),5.86(b,2H),5.06(m,1H),4.42(m,1H),4.18(m,1H),4.08~3.94(m,3H),3.82(m,3H),3.77~3.61(m,1H),1.55~1.17(m,15H).
粗產物Id(30mg)經HPLC製備分離(製備管柱:Chiralpak AS-H,流動相:A:正己烷;B:乙醇)後得到12mg化合物Id1。MS(m/z)521.23(MH+).
按合成化合物Ic和Ic1類似的方法,合成了化合物Ie和Ie1。
Ie:1H-NMR(400MHz,CDCl3)δ 8.27(m,1H),8.04(s,1H),7.96
(m,1H),7.84(m,1H),7.62(m,1H),7.52~7.33(m,4H),5.78(b,2H),5.04~4.98(m,1H),4.38~3.71(m,6H),1.57~1.06(m,15H).
Ie1:MS(m/z)541.11.
按合成化合物Ic和Ic1類似的方法,合成了化合物If和If1。
If:1H-NMR(400MHz,CDCl3)δ 8.33(m,1H),8.02(s,1H),7.81~7.66(m,4H),7.49~7.41(m,2H),7.31~7.06(m,1H),5.72(b,2H),5.06~4.99(m,1H),4.43~4.35(m,1H),4.19~3.91(m,4H),3.74~3.65(m,1H),1.57~1.20(m,15H).
If1:MS(m/z)541.10.
按合成化合物Ic和Ic1類似的方法,合成了化合物Ih和Ih1。
Ih:1H-NMR(400MHz,CDCl3)δ 8.33(m,1H),7.95(m,1H),7.00~6.95(m,3H),5.83(b,2H),5.05~4.99(m,2H),4.35~4.31(m,1H),
4.23~4.17(m,1H),4.01~3.83(m,3H),3.80~3.77(m,1H),2.35(s,3H),2.31(s,3H),1.33~1.19(m,15H).
Ih1:MS(m/z)519.15.
按合成化合物Ic和Ic1類似的方法,合成了化合物Ii和Ii1。
Ii:1H-NMR(400MHz,CDCl3)δ 8.36(m,1H),8.00(m,1H),7.17(m,1H),7.02(m,1H),6.97(m,2H),5.71(b,2H),5.06(m,1H),4.43(m,1H),4.20(m,1H),4.06~3.84(m,3H),3.72~3.61(m,1H),1.56~1.22(m,15H).
Ii1:MS(m/z)509.25.
按合成化合物Ic和Ic1類似的方法,合成了化合物Ij和Ij1。
Ij:1H-NMR(400MHz,CDCl3)δ 8.32(m,1H),8.06(s,1H),7.58(m,2H),7.52(m,2H),5.89(b,2H),5.02~4.96(m,1H),4.43~4.36(m,2H),
4.04~3.91(m,4H),1.58~1.23(m,15H).
IJ1:MS(m/z)559.08.
在20℃下,向一個單口燒瓶中依次加入化合物Ia1(480mg),富馬酸(120mg)和乙腈,升溫到60℃並在此溫度下攪拌直至固體全部溶解,繼續攪拌5分鐘,冷卻至20℃,過濾,得白色顆粒狀固體Ia1富馬酸鹽490mg。
1H NMR(400MHz,D2O):δ 7.21(m,2H),7.11(m,1H),6.67(m,2H),6.57(s,2H),4.77(m,1H),4.29(m,1H),4.17(m,1H),4.06(m,1H),3.93(m,1H),1.07(m,6H),1.21(m,9H).
以HepG 2.2.15細胞為乙型肝炎病毒載體,測定化合物抑制乙型肝炎病毒進行DNA複製的能力。
測試方法:HepG 2.2.15細胞接種96孔培養板,24小時後按不同稀釋度分別加入樣品及陽性對照藥,同時設細胞對照孔,加藥72小時後分別更換含不同稀釋濃度樣品的培養液,於加藥後第6天分別收集細胞上清及2.2.15細胞,採用點雜交的方法檢測細胞中HBV DNA複製程度,計算IC50(結果見表1)。
測試方法:HepG 2.2.15細胞接種96孔培養板,按不同稀釋度分別加入樣品及陽性對照藥,於加藥後第6天加CellTiter-Blue(Promega,Catalog #G8081),使用Flexstation 3儀測得螢光讀數,計算CC50(結果見表1)。
陽性對照藥使用的是中國授權專利ZL01813161.1的實施例2和實施例3中公開的化合物GS-7171和GS-7340,其中GS-7171可拆分成兩個非對映異構體GS-7340和GS-7339,GS7340藥效更佳。
實驗結果顯示化合物Ia1、Ib1、Ic1、Id1、Ie1、If1、Ih1、Ii1和Ij1對乙型肝炎病毒DNA複製具有強烈的抑制作用,但沒有細胞毒性,其中化合物Ia1、Ic1、Id1、Ie1、If1、Ih1、Ii1和Ij1對乙型肝炎病毒DNA複製的抑制作用優於陽性化合物
GS7340。
精密量取4.5mL 36%鹽酸到1L容量瓶中,加水至刻度,搖勻備用,標示為儲備液。再精密量取10mL上述溶液至50mL的容量瓶中,加水至刻度,搖勻,測量pH為2.0,標示為鹽酸溶液。
精密量取儲備液10mL至50mL容量瓶中,再精確稱取500.0mg的胃蛋白酶至50mL容量瓶中,加水至刻度,超音溶解(此時溶液不澄清),過濾既得澄清溶液。標示為模擬胃液。
精密稱取5.0mg GS-7340到5mL容量瓶中,先加2.5mL異丙醇至容量瓶中,振搖溶解,然後加鹽酸溶液(pH 2.0)至刻度。振盪搖勻,過濾備用。
精密稱取5.0mg GS-7340到5mL容量瓶中,先加2.5mL異丙醇至容量瓶中,振搖溶解,然後加模擬胃液至刻度。振盪搖勻,過濾備用。
精密稱取5.0mg Ia1到5mL容量瓶中,先加2.5mL異丙醇至容量瓶中,振搖溶解,然後加鹽酸溶液(pH 2.0)至刻度。振盪搖勻,過濾備用。
精密稱取5.0mg Ia1到5mL量瓶中,先加2.5mL異丙醇至容量瓶中,振搖溶解,然後加模擬胃液至刻度。振盪搖勻,過濾備用。
把配製好的樣品裝入進樣小瓶後馬上進樣,作為初始樣品。與此同時把剩餘的樣品馬上放入已達到和處於穩定37度的恆溫箱裏,6.0小時後取樣進高效液相。
化合物Ia1和GS-7340在酸介質和模擬胃液中的穩定性結果見表2。
實驗結果表明,與用單取代胺基酸製得的替諾福韋磷醯胺酯前藥(GS-7340)相比,用雙取代胺基酸製得的替諾福韋磷醯胺酯前藥(Ia1)在酸介質和模擬胃液中的穩定性顯著提高。
化合物:化合物Ia1和GS-7340
在37℃條件下,將不同替諾福韋前藥和新鮮人全血共同孵育,分別在孵育1小時、2小時後分離血漿和PBMC細胞(Ficoll密度梯度離心法),測定血漿和PBMCs細胞中藥物原形及代謝物替諾福韋的濃度,細胞計數儀計算PBMCs細胞,並以每個PBMC細胞為200fL計算細胞內藥物濃度。
向100μL血漿樣品或PBMC樣品中分別加入20μL內標溶液(400ng/mL SN-38溶液),5.0μL甲醇-水(50:50,v/v)和200μL乙腈,渦流混勻1min,離心5min(14000rpm)。取20μL上清液和180μl流動相混勻,渦流1min,取10μL進行LC/MS/MS分析。
替諾福韋前藥在新鮮人全血中的代謝穩定性和在PBMCs細胞中的分佈結果見表3。
從表3可以看出,陽性對照物GS-7340在與新鮮人全血共同孵育後,在血漿中檢測到一定量的活性代謝產物-替諾福韋,並且隨著孵育時間的延長,在血漿中所釋放的活性代謝產物-替諾福韋成倍增長,而本發明的化合物Ia1在與新鮮人全血共同孵育後,完全沒有檢測到活性代謝產物-替諾福韋,並且即使隨著孵育時間的延長,在血漿中始終也未檢測到活性代謝產物-替諾福韋,說明化合物Ia1在血漿中的穩定性顯著優於陽性對照物GS-7340,因此,與陽性對照物GS-7340相比,本發明的化合物Ia1在降低因血漿中代謝生產替諾福韋所產生的毒副作用方面具有顯著的優越性。
從表3還可以看出,隨著孵育時間的延長,本發明化合物Ia1在外周血單核細胞(PBMCs)中的活性代謝產物-替諾福韋的濃度顯著增大,而GS-7340在外周血單核細胞(PBMCs)中的活性代謝產物-替諾福韋的濃度基本上不隨孵育時間的延長而增
加。本發明化合物Ia1經2小時孵育後在外周血單核細胞(PBMCs)中的活性代謝產物-替諾福韋的濃度大約是陽性對照物GS-7340的三倍。因此,與陽性對照物GS-7340相比,本發明的化合物Ia1在療效方面也具有顯著的優越性。
化合物:化合物Ia1、GS-7340和替諾福韋酯
RPMI 培養基(Invitrogen 21969-035)
DMEM 培養基(Invitrogen 21969-035)
谷胺酸 200mM(Invitrogen 25030)
胎牛血清((Invitrogen 16000-044)
盤尼西林/鏈黴素((Invitrogen 15140-122)
DPBS 緩衝液(Invitrogen 14190-094)
胰蛋白酶-EDTA(Invitrogen 25200)
台盼藍 Sigma T8154
DMSO Sigma D2650
MUG Biochemika 69590
1)MT-2細胞感染HIV-1(Ⅲb)形成感染複數(MOI)0.01TCID50每細胞
2)將病毒和細胞混合物在384孔板中孵育3天
3)用於細胞毒性檢測的細胞在384孔板中孵育3天
4)將上清轉移到新孔板中然後加入報告細胞(Hela)共同孵育24h
5)檢測beta-GAL活性評價藥物抗HIV活性
6)未加入病毒的細胞孵育三天后檢測冷光信號評價細胞毒性
7)按以下方程計算抗病毒活性和細胞毒性
抗病毒活性(%)=100-(檢測值-最高值)/(最低值-最高值)*100
細胞毒性(%)=100-(檢測值-最高值)/(最低值-最高值)*100
8)使用Graphpad Prism 5擬合曲線,計算EC50、CC50值(結果見表4)。
實驗結果顯示化合物Ia1對HIV病毒具有強烈的抑制作用,但沒有細胞毒性。
由於已根據其特殊的實施方案描述了本發明,某些修飾和等價變化對於精通本領域的技術人員是顯而易見的且包括在本發明的範圍內。
Claims (10)
- 一種如通式(I)所示的化合物或其異構體或可藥用鹽,
- 如申請專利範圍第1項所述的如通式(I)所示的化合物或其異構體或可藥用鹽,其選自:
- 如申請專利範圍第1項所述的如通式(I)所示的化合物或其異構體或可藥用鹽,其選自:
- 一種如式(Ia1)所示的化合物或其異構體或可藥用鹽,
- 一種醫藥組成物,其含有申請專利範圍第1至4項中任一項所述的化合物或其異構體或可藥用鹽與藥學上可接受的載體。
- 如申請專利範圍第5項所述的醫藥組成物,其中該藥學上可接受載體選自注射用水、凍乾粉劑輔料或口服製劑輔料。
- 一種申請專利範圍第1至4項中任一項所述的化合物或其異構體或可藥用鹽的用途,其係用在製備治療病毒感染性疾病的藥 物。
- 如申請專利範圍第7項所述的用途,其係用在製備治療愛滋病感染、乙型肝炎或乙肝病毒引起的疾病的藥物。
- 一種申請專利範圍第5或6項所述的醫藥組成物的用途,其係用在製備治療病毒感染性疾病的藥物。
- 如申請專利範圍第9項所述的用途,其係用在製備治療愛滋病感染、乙型肝炎或乙肝病毒引起的疾病的藥物。
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CN107312039A (zh) | 2017-11-03 |
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BR112015003778B1 (pt) | 2021-11-16 |
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CN103665043A (zh) | 2014-03-26 |
RU2664534C9 (ru) | 2018-09-28 |
BR112015003778A2 (pt) | 2017-07-04 |
US9908908B2 (en) | 2018-03-06 |
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