TW202140041A - Fosalvudine and fozivudintidoxil for use in the treatment of the disease covid-19 and the use of their of structurally simplified derivatives thereof - Google Patents
Fosalvudine and fozivudintidoxil for use in the treatment of the disease covid-19 and the use of their of structurally simplified derivatives thereof Download PDFInfo
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- TW202140041A TW202140041A TW110102544A TW110102544A TW202140041A TW 202140041 A TW202140041 A TW 202140041A TW 110102544 A TW110102544 A TW 110102544A TW 110102544 A TW110102544 A TW 110102544A TW 202140041 A TW202140041 A TW 202140041A
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- Prior art keywords
- methyl
- decyloxy
- propyl
- pyrimidin
- dioxo
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 5
- 201000010099 disease Diseases 0.000 title claims description 3
- 208000025721 COVID-19 Diseases 0.000 title abstract description 7
- JHXLLEDIXXOJQD-WELGVCPWSA-N (2-decoxy-3-dodecylsulfanylpropyl) [(2r,3s,5r)-3-fluoro-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl hydrogen phosphate Chemical compound C1[C@H](F)[C@@H](COP(O)(=O)OCC(CSCCCCCCCCCCCC)OCCCCCCCCCC)O[C@H]1N1C(=O)NC(=O)C(C)=C1 JHXLLEDIXXOJQD-WELGVCPWSA-N 0.000 title abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 10
- -1 nucleoside phospholipid Chemical class 0.000 claims description 30
- 241000711573 Coronaviridae Species 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
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- 159000000007 calcium salts Chemical class 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 206010035664 Pneumonia Diseases 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 8
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
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- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- GRJCIXKOALIDNC-UHFFFAOYSA-N (2-decoxy-3-dodecylsulfanylpropyl) dihydrogen phosphate Chemical compound CCCCCCCCCCCCSCC(COP(O)(O)=O)OCCCCCCCCCC GRJCIXKOALIDNC-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Description
本發明涉及用於治療新冠病毒肺炎疾病(covid-19 disease)之氟沙定替酯和福齊夫定替酯，以及其結構簡化之衍生物用於製備抗新冠病毒肺炎之藥物之用途。 The present invention relates to the use of floxadine and fozivudine for the treatment of covid-19 disease, as well as derivatives with simplified structures for the preparation of anti-covid-19 drugs.
氟沙定替酯[(2S,3S,5R)-3-氟基-5-(5-甲基-2,4-二側氧基-嘧啶-1-基)四氫呋喃-2-基]甲基[(2RS)-癸氧基-3-十二烷基氫硫基-丙基]磷酸氫鹽)(Fosalviudine[(2S,3S,5R)-3-fluoro-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2RS)-decoxy-3-dodecylsulfanyl-propyl]hydrogen phosphate)，根據取代(substitution)亦是福齊夫定替酯，[(2S,3S,5R)-3-疊氮基-5-(5-甲基-2,4-二側氧基-嘧啶-1-基)四氫呋喃-2-基]甲基[(2RS)-癸氧基-3-十二烷基氫硫基-丙基]磷酸氫鹽(fozivudintidoxil,[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2RS)-decoxy-3-dodecylsulfanyl-propyl]hydrogen phosphate)，其結構如下： Fluxatin ester [(2S,3S,5R)-3-fluoro-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl [(2RS)-Decyloxy-3-dodecyl hydrogensulfanyl-propyl] hydrogen phosphate)(Fosalviudine[(2S,3S,5R)-3-fluoro-5-(5-methyl-2, 4-dioxo-pyrimidin-1-yl)tetrahydrofuran-2-yl]methyl[(2RS)-decoxy-3-dodecylsulfanyl-propyl]hydrogen phosphate), according to the substitution (substitution) is also fozifudine ester, [( 2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxy-pyrimidin-1-yl)tetrahydrofuran-2-yl)methyl[(2RS)-decyl Oxy-3-dodecyl hydrogensulfanyl-propyl) hydrogen phosphate (fozivudintidoxil,[(2S,3S,5R)-3-azido-5-(5-methyl-2,4-dioxo-pyrimidin- 1-yl)tetrahydrofuran-2-yl]methyl[(2RS)-decoxy-3-dodecylsulfanyl-propyl]hydrogen phosphate), its structure is as follows:
一項活體內(in vivo)研究顯示，在獼猴(macaques)體內和體外之抗病毒活性。獼猴對7mg/kg(相當於人類之150mg)之給藥四週之耐受性良好，其中極小之血液學異常(minimal hematologic abnormality)，並且亦沒有觀察到肝毒性(liver toxicity)。該化合物在第一階段(phase I)研究中，單次給藥量為5mg至40mg。(卡恩P等人，國際後天免疫不全症候群研討會2006年，摘要編號ThPE0025(Cahn P et al,Int Conf AIDS.2006,Abstract No.ThPE0025))。氟沙定替酯耐受性良好(well tolerated)，顯示出對血藥面積(AUC)和對血峰濃度(Cmax)之線性劑量關係，其中觀察到之半衰期為4至7小時，允許每日給藥，不會累積重複之劑量。 An in vivo study showed antiviral activity in macaques in vivo and in vitro. Rhesus monkeys had a good tolerance to 7 mg/kg (equivalent to 150 mg of humans) administration for four weeks, with minimal hematologic abnormality, and no liver toxicity was observed. The compound in the first phase (phase I) study, a single dose of 5mg to 40mg. (Kahn P et al, International Acquired Immunity Syndrome Symposium 2006, Abstract No. ThPE0025 (Cahn P et al, Int Conf AIDS. 2006, Abstract No. ThPE0025)). Fluxatin axetil is well tolerated, showing a linear dose relationship between blood area (AUC) and blood peak concentration (Cmax). The observed half-life is 4 to 7 hours, allowing daily administration The medicine does not accumulate repeated doses.
根據觀察到之體內分佈情況，以及由於對骨髓和肝臟細胞之毒性而得出之劑量，停止了對福齊夫定替酯之開發(A.C.範霍夫，D.勒布雷希特，F.U.羅伊斯，B.赫克．奧斯特雷，R.韋爾，U.A.沃克，N.溫 霍夫：福齊夫定替酯誘導之大鼠肝臟線粒體DNA減少，一種新型核苷反轉錄酶抑制劑前驅藥。於：抗微生物試劑和化學療法。第53卷，第7號，2009年7月，第2748-2751頁；A.C.Venhoff,D.Lebrecht,F.U.Reuss,B.Heckl-Ostreicher,R.Wehr,U.A.Walker,N.Venhoff：Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil,a novel nucleoside reverse transcriptase inhibitor prodrug.In：Antimicrobial agents and chemotherapy.Volume 53,Number 7,July 2009,pp.2748-2751)。不可接受之毒性主要是由於對HIV需要非常高之劑量來為體內所有組織類型提供足夠濃度之活性物質。 Based on the observed distribution in the body and the dose due to the toxicity to bone marrow and liver cells, the development of fozivudine ester was stopped (AC Van Hoff, D. Lebrecht, FU Roy S, B. Heck Osterley, R. Weir, UA Walker, N. Wen Hoff: Fozifudine ester-induced reduction of rat liver mitochondrial DNA, a new type of prodrug of nucleoside reverse transcriptase inhibitor. Yu: Antimicrobial agents and chemotherapy. Volume 53, No. 7, July 2009, pages 2748-2751; ACVenhoff, D. Lebrecht, FU Reuss, B. Heckl-Ostreicher, R. Wehr, UA Walker, N. Venhoff: Mitochondrial DNA depletion in rat liver induced by fosalvudine tidoxil, a novel nucleoside reverse transcriptase inhibitor prodrug. In: Antimicrobial agents and chemotherapy. Volume 53, Number 7, July 2009, pp. 2748-2751). The unacceptable toxicity is mainly due to the very high dose required for HIV to provide sufficient concentrations of active substances for all tissue types in the body.
福齊夫定替酯與瑞德西韋(remdesivir)在藥理活性部位上有結構上之相似性。瑞德西韋，其結構式如下。 Fozifudinate and remdesivir (remdesivir) have structural similarities in pharmacologically active sites. Remdesivir, its structural formula is as follows.
氟沙定替酯和福齊夫定替酯(fozivudine tidoxil)之原理相似 之作用機制，使得人們期望所展示之抗病毒特性也將對新冠病毒肺炎起作用。 The principles of floxadine and fozivudine tidoxil are similar The mechanism of action makes people expect that the displayed antiviral properties will also work against new coronavirus pneumonia.
補充之一個特性是，從較早之對HIV之療效研究中觀察到之事實為，當對小鼠(mice)給予15mg/kg體重之放射性同位素標記之物質時，在所研究之小鼠之器官中所檢測到之活性成分，其濃度如下： A supplementary feature is the fact that it is observed from earlier studies on the efficacy of HIV that when mice are given 15 mg/kg body weight of radioisotope-labeled substances, the organs of the mice under study The concentrations of the active ingredients detected in, are as follows:
由此可見，該物質對肺組織具有很強之親和力。正好這種 在愛滋病毒(HIV)研究中被認為是相當次要且亦是不利之對肺部之親和力，有助於確保此種抗病毒藥物能夠成功地用於治療新冠病毒肺炎。 It can be seen that the substance has a strong affinity for lung tissue. Just this In the study of HIV (HIV), the affinity to the lungs, which is considered to be quite minor and unfavorable, helps to ensure that this antiviral drug can be successfully used in the treatment of new coronavirus pneumonia.
在國際專利申請案WO 1992/003462 A1中，首次教示了核苷(nucleosides)之新磷脂衍生物(phospholipid derivatives)、其製備和作為抗病毒藥物之用途。其中所教示之該等物質之特徵為，於分子結構中之磷脂部分之該等烷基殘基(alkyl residues)經由硫原子進行偶合(coupling)。 In the international patent application WO 1992/003462 A1, new phospholipid derivatives of nucleosides, their preparation and use as antiviral drugs were taught for the first time. The characteristic of the substances taught therein is that the alkyl residues of the phospholipid moiety in the molecular structure are coupled via sulfur atoms.
國際專利申請案WO 95/20596公開一種不對稱磷酸二酯之製備方法。其中所教示之該等物質之特徵為，於分子結構中磷脂部分之該等烷基(alkyl radicals)經由亞甲基基團(methylene group)與碳之鍵聯(linkage)進行偶合，亞甲基基團(methylene group)與碳之鍵聯經由烷氧基(alkoxy radicals)、烷硫基(alkylthio radicals)、烷基亞磺醯基(alkylsulfinyl radicals)或烷基磺醯基(alkylsulfonyl radicals)。 International patent application WO 95/20596 discloses a method for preparing asymmetric phosphodiester. The characteristic of the substances taught is that the alkyl radicals of the phospholipid moiety in the molecular structure are coupled via the linkage between the methylene group and the carbon, and the methylene group The bond between the methylene group and the carbon is via alkoxy radicals, alkylthio radicals, alkylsulfinyl radicals, or alkylsulfonyl radicals.
本發明之目的係提供本身已知之物質，氟沙定替酯和福齊夫定替酯之第二醫學適應症(second medical indication)，用於治療新冠病毒肺炎疾病之用途，以及使用其結構簡化之衍生物製備抗新冠病毒肺炎之藥物。 The purpose of the present invention is to provide a second medical indication (second medical indication) of the substances known per se, floxadinate and fozivudinate, for the treatment of new coronavirus pneumonia diseases, and to simplify the use of their structure Derivatives of the preparation of anti-coronavirus pneumonia drugs.
氟沙定替酯和福齊夫定替酯之特徵是一齊多夫定(zidovudine)(亦稱疊氮胸苷(azidothymidine)，或簡稱AZT)之化合物，即核苷胸苷(nucleoside thymidine)與磷脂之化學衍生物。因此，氟沙定替酯和福齊夫定替酯具有三個不同之區域(domain)： The characteristics of floxadine axetil and fozivudine axetil are a compound of zidovudine (also known as azidothymidine, or AZT), namely nucleoside thymidine and Chemical derivatives of phospholipids. Therefore, floxadinate and fozifudinate have three different domains:
該結構圖顯示經氟取代之氟沙定替酯(fluorine-substituted fosalvudine)。其左邊部分是脂質殘基，中間是作為連接體(linker)之磷酸基團，以及右邊是經氟取代之齊多夫定(zidovudine)殘基。 The structure diagram shows fluorine-substituted fosalvudine (fluorine-substituted fosalvudine). The left part is a lipid residue, the middle is a phosphate group as a linker, and the right is a fluorine-substituted zidovudine residue.
在藥理上，齊多夫定屬於核苷反轉錄酶抑制劑(NRTI)，是一類抗反轉錄病毒物質(antiretroviral substances)。作為聯合抗反轉錄病毒療法(combination antiretroviral therapy)之一部分，齊多夫定被用於治療HIV-1感染病患。 Pharmacologically, zidovudine belongs to nucleoside reverse transcriptase inhibitors (NRTI), a class of antiretroviral substances. As part of combination antiretroviral therapy (combination antiretroviral therapy), zidovudine is used to treat patients with HIV-1 infection.
氟沙定替酯和福齊夫定替酯經由磷脂基團增強齊多夫定部分(zidovudine moiety)之作用。一般之概念為磷脂會累積在活細胞之表面。因此，磷脂殘基之性質決定了對某些細胞類型之親和力。曾經觀察到之對肺組織之親和力，使得此種物質成為新冠病毒肺炎治療之候選者。累積在細胞之表面，該磷脂殘基藉由使齊多夫定在病毒附著於細胞表面之部位與病毒在空間上接近，而將齊多夫定送到目標病毒處。 Fozivudine axetil and fozivudine axetil enhance the effect of zidovudine moiety through the phospholipid group. The general concept is that phospholipids will accumulate on the surface of living cells. Therefore, the nature of phospholipid residues determines the affinity for certain cell types. The once observed affinity for lung tissue makes this substance a candidate for the treatment of new coronavirus pneumonia. Accumulate on the surface of the cell, the phospholipid residues are brought to the target virus by bringing zidovudine close to the virus at the site where the virus attaches to the cell surface.
該物質作為藥物在人體中之使用量為介於50mg和800mg 之間，每天1至2個劑量(doses)。在大流行病中，需要特別大量之活性成分，以向患病人群提供足夠之活性成分。在氟沙定替酯和福齊夫定替酯之多步驟合成期間，在含硫之脂質殘基(sulfur-containing lipid residue)之處出現了不小之問題，因為氫硫基硫(sulfanyl sulfur)具有很強之氧化傾向，並且在此過程中會形成亞碸(sulfoxides)。合成之氟沙定替酯之純化是可能的，但使合成複雜化，需要花費不小之時間。由於在合成過程中，必須從藥學活性物質中定量地去除亞碸之殘留物(residues of the sulfoxides)，因為推測其作為雜質具有很強之毒性。 The amount of the substance used as a medicine in the human body is between 50mg and 800mg In between, 1 to 2 doses per day. In a pandemic, a particularly large amount of active ingredients is required to provide sufficient active ingredients to the affected population. During the multi-step synthesis of floxadine and fozivudine, a lot of problems appeared in the sulfur-containing lipid residues, because sulfur-containing sulfur (sulfanyl sulfur) ) Has a strong tendency to oxidize, and sulfoxides are formed in the process. It is possible to purify the synthetic floxadipate, but it takes a lot of time to complicate the synthesis. In the synthesis process, the residues of the sulfoxides must be quantitatively removed from the pharmacologically active substances, because it is speculated that they are very toxic as impurities.
在已知之氟沙定替酯和福齊夫定替酯之結構中，在磷脂中也有一個掌性碳原子(chiral carbon atom)。在已經進行之第二階段(phase II)研究中，尚未進一步研究關於此碳原子之鏡像異構(enatiomeric)之這兩種型式之效果之差異。 In the known structures of floxadine and fozivudine, there is also a chiral carbon atom in the phospholipid. In the second phase (phase II) research that has been carried out, the difference between the effects of the two forms of enatiomeric of this carbon atom has not been further studied.
氟沙定替酯和福齊夫定替酯之合成是經由大量之化學中間物進行的。有些中間物對氧化非常敏感。 The synthesis of floxadinate and fozifudinate is carried out through a large number of chemical intermediates. Some intermediates are very sensitive to oxidation.
因此，提議對已知之氟沙定替酯和福齊夫定替酯之結構進行修飾(modify)，以及使其成為可獲得之用於治療新冠病毒肺炎之用途之衍生藥物。 Therefore, it is proposed to modify the structure of the known floxadinate and fozifudinate, and make them available as derivative drugs for the treatment of new coronavirus pneumonia.
在磷脂殘基之區域中提出了一種結構上之變化，其中癸氧基基團(decoxy group)和十二烷基氫硫基團(dodecylsulfanyl group)被酯基團(ester group)取代，其中酯可以是基於線性烷酸(alkanoic acid)，即己酸(caproic acid)(正己酸；n-hexanoic acid)、庚酸(enanthic acid)(正庚酸；n-heptanoic acid)、辛酸(caprylic acid)(正辛酸；n-octanoic acid)、壬酸(pelargonic acid)(正 壬酸；n-nonanoic acid)、癸酸(capric acid)(正癸酸；n-decanoic acid)、十一酸(undecanoic acid)、月桂酸(lauric acid)(正十二酸；n-dodeacnic acid)、十三酸(tridecanoic acid)、肉豆蔻酸(myristic acid)(正十四酸；n-tetradecanoic acid)、十五酸(pentadecanoic acid)、棕櫚酸(palmitic acid)(正十六酸；n-hexadecanoic acid)、十七酸(heptadecanoic acid)、硬脂酸(stearic acid)(正十八酸；n-octadecanoic acid) A structural change is proposed in the region of phospholipid residues, where the decoxy group and the dodecylsulfanyl group are replaced by an ester group, where the ester It can be based on alkanoic acid, namely caproic acid (n-hexanoic acid), enanthic acid (n-heptanoic acid), caprylic acid (N-octanoic acid; n-octanoic acid), pelargonic acid (positive Nonanoic acid; n-nonanoic acid), capric acid (n-decanoic acid), undecanoic acid, lauric acid (n-dodeacnic acid) ), tridecanoic acid, myristic acid (n-tetradecanoic acid), pentadecanoic acid, palmitic acid (n-hexadecanoic acid) -hexadecanoic acid), heptadecanoic acid, stearic acid (n-octadecanoic acid)
代替齊多夫定殘基中之氟取代，亦可以用疊氮化物(azide)、溴或用氯取代。脂質鏈(lipid chains)上之碳殘基可以從C6H13、己基，遍及C7H15(庚基)、C8H17(辛基)、C9H19(壬基)、C10H21(癸基)，C11H23(十一烷基)、C12H25(十二烷基)、C13H27(十三烷基)、C14H29(十四烷基)、C15H31(十五烷基)、C16H33(十六烷基)、C17H35(十七烷基)至C18H35(十八烷基)之範圍。 Instead of fluorine substitution in zidovudine residues, azide, bromine or chlorine substitution can also be used. The carbon residues on the lipid chains can range from C6H13, hexyl, C7H15 (heptyl), C8H17 (octyl), C9H19 (nonyl), C10H21 (decyl), C11H23 (undecyl), C12H25 (dodecyl), C13H27 (tridecyl), C14H29 (tetradecyl), C15H31 (pentadecyl), C16H33 (hexadecyl), C17H35 (heptadecyl) to C18H35 ( Octadecyl) range.
圖1顯示與用福齊夫定替酯(Fozivudine)處理之樣品相比，病毒負荷量(viral load)為1/ml之對照樣品。非洲綠猴腎細胞(Vero cells)以30μM濃度之Fozivudin進行預培養(pre-incubated)。比較顯示，Fozivudin對新型冠狀病毒(SARS-CoV-2)之複製具有一適度(moderate)但顯著之影響。 Figure 1 shows a control sample with a viral load of 1/ml compared to a sample treated with Fozivudine. African green monkey kidney cells (Vero cells) were pre-incubated with Fozivudin at a concentration of 30 μM. The comparison shows that Fozivudin has a moderate but significant effect on the replication of the new coronavirus (SARS-CoV-2).
製備福齊夫定替酯(fozivudintidoxil)Preparation of fozivudintidoxil (fozivudintidoxil)
1.5-癸氧基-2-苯基-1,3-二 
將19.1kg苯甲醛(benzaldehyde)、16.6kg甘油(glycerol)和534克甲磺酸(methanesulfonic acid)在60升(l)甲苯(toluene)中之溶液，在回流(reflux)下加熱約4小時，直到能分離出3.2升水。 A solution of 19.1 kg benzaldehyde, 16.6 kg glycerol and 534 g methanesulfonic acid in 60 liters (l) toluene (toluene) was heated under reflux for about 4 hours, Until 3.2 liters of water can be separated.
將該溶液冷卻至0至5℃，並在30至45分鐘之一段時間上加入180升異己烷(lsohexane)。將懸浮液(suspension)在0°至5℃攪拌3小時(h)，使之結晶。 The solution was cooled to 0 to 5°C and 180 liters of lsohexane were added over a period of 30 to 45 minutes. The suspension was stirred at 0° to 5°C for 3 hours (h) to allow it to crystallize.
加入60升之50%氫氧化鈉(NaOH)溶液和120升之甲苯後，在減壓下蒸餾掉(distilled off)異己烷-甲苯-水混合物(isohexane-toluene-water mixture)，直到蒸汽溫度達到80℃。如此就得到了200公升之蒸餾液(distillate)。這樣就產生了200公升之蒸餾液。 After adding 60 liters of 50% sodium hydroxide (NaOH) solution and 120 liters of toluene, distilled off the isohexane-toluene-water mixture under reduced pressure until the steam temperature reached 80°C. In this way, 200 liters of distillate is obtained. This produced 200 liters of distillate.
加入60公升之1-溴癸烷(1-bromodecane)和2.1kg之Aliquat 336(斯塔克之催化劑(Starks' catalyst)，一種四級銨鹽(quaternary ammonium salt))，並將混合物加熱到85°至90℃持續3小時。然後將混合物重新加熱。 Add 60 liters of 1-bromodecane and 2.1 kg of Aliquat 336 (Starks' catalyst, a quaternary ammonium salt), and heat the mixture to 85° To 90°C for 3 hours. Then the mixture is reheated.
冷卻至室溫後，並用220公升去礦質水(demineralized water)稀釋，有機相被分離，以及用180公升去礦質水萃取3次。甲苯相(toluene phase)在真空中蒸發，並且殘留物(residue)在薄膜蒸發器(thin film evaporator)中以1毫巴(mbar)和150℃之操作溫度處理，以移除癸醇(decanol)和溴癸烷(bromodecane)。 After cooling to room temperature, it was diluted with 220 liters of demineralized water, the organic phase was separated, and extracted 3 times with 180 liters of demineralized water. The toluene phase is evaporated in vacuum, and the residue is treated in a thin film evaporator at 1 mbar and an operating temperature of 150°C to remove decanol And bromodecane.
將58kg之粗製品(crude product)溶於370公升之異己烷中，以及用2kg之活性炭(activated carbon)純化。過濾後，將溶液冷卻至-20℃過夜。 58kg of crude product was dissolved in 370 liters of isohexane and purified with 2kg of activated carbon. After filtration, the solution was cooled to -20°C overnight.
分離出之晶體(crystals)用5公升之冷的異己烷洗滌，並且在15°至20℃下乾燥。 The separated crystals were washed with 5 liters of cold isohexane and dried at 15° to 20°C.
產量：44kg(76%，根據使用之苯甲醛) Output: 44kg (76%, according to the benzaldehyde used)
純度(GC)：98% Purity (GC): 98%
2.3-溴-2-癸氧基-1-丙基)苯甲酸酯(3-bromo-2-decyloxy-1-propyl)benzoate)之製備。2. Preparation of 3-bromo-2-decyloxy-1-propyl benzoate (3-bromo-2-decyloxy-1-propyl)benzoate.
將7kg 5-癸氧基-2-苯基-1,3-二
得到之原油(crude oil)被用於下一階段，並在0°至5℃下儲存。儲存不應超過2天。 The crude oil obtained is used in the next stage and stored at 0° to 5°C. Storage should not exceed 2 days.
產量：8.9kg Output: 8.9kg
純度(GC)：約90% Purity (GC): about 90%
3.3-十二烷基硫基-2-癸氧基-1-丙醇(3-dodecylthio-2-deyloxy-1-propanol)之製備3.3 Preparation of 3-dodecylthio-2-deyloxy-1-propanol (3-dodecylthio-2-deyloxy-1-propanol)
將在6.3公升之甲醇(methanol)中之5.4公升之1-十二烷基 硫醇(1-dodecyl mercaptan)，用在32公升甲醇中之4.19公升之甲醇鈉溶液(sodium methylate solution；30%)處理，保持溫度低於30℃。然後，在室溫下將(3-溴-2-癸氧基-1-丙基)苯甲酸酯(3-bromo-2-decyloxy-1-propyl)benzoate)之原油(8.7kg，90%純度)加入15公升之甲醇中，並將溶液攪拌15小時。 Will be 5.4 liters of 1-dodecyl in 6.3 liters of methanol Mercaptan (1-dodecyl mercaptan), treated with 4.19 liters of sodium methylate solution (30%) in 32 liters of methanol, keeping the temperature below 30°C. Then, the crude oil (8.7kg, 90% of 3-bromo-2-decyloxy-1-propyl)benzoate (3-bromo-2-decyloxy-1-propyl)benzoate at room temperature Purity) was added to 15 liters of methanol, and the solution was stirred for 15 hours.
然後加入3.4公升NaOH溶液(50%)，保持溫度低於45℃。然後將該溶液加熱到40°至45℃，持續兩小時。 Then add 3.4 liters of NaOH solution (50%) and keep the temperature below 45°C. The solution was then heated to 40° to 45°C for two hours.
在真空中抽出50公升甲醇/水，並加入60公升去礦質水。再次蒸餾掉30公升之甲醇/水。殘留物用47公升之甲基三級丁基醚(methyl tert-butyl ether)攪拌30分鐘。有機相被分離，以及用14公升之飽和氯化鈉溶液(sodium chloride solution)洗滌一次，並在真空中濃縮。 Pump out 50 liters of methanol/water in a vacuum and add 60 liters of demineralized water. Distill off 30 liters of methanol/water again. The residue was stirred with 47 liters of methyl tert-butyl ether for 30 minutes. The organic phase was separated and washed once with 14 liters of saturated sodium chloride solution and concentrated in vacuo.
殘留物在小於1毫巴(mbar)壓力和200℃下進行薄膜蒸發器蒸餾。非揮發性之油不經進一步純化(purification)而用於下一步。 The residue was subjected to thin-film evaporator distillation at a pressure of less than 1 mbar (mbar) and 200°C. The non-volatile oil is used in the next step without further purification.
產量：8.8kg Output: 8.8kg
純度(GC)：>85 Purity (GC): >85
二十二烷基二硫化物(Didodecyl disulfide)：1.5-2% Didodecyl disulfide: 1.5-2%
4.(3-十二烷基硫基-2-癸氧基-1-丙基)磷酸二氫鹽((3-dodecylthio-2-decyloxy-1-propyl)dihydrogen phosphate)之製備4. Preparation of (3-dodecylthio-2-decyloxy-1-propyl)dihydrogen phosphate ((3-dodecylthio-2-decyloxy-1-propyl)dihydrogen phosphate)
將18.8kg之3-十二烷基硫酮-2-癸氧基-1-丙醇(3-dodecylthione-2-decyloxy-1-propanol)和6.9kg之2,6-二甲吡啶(2,6-lutidine)在92公升甲苯中之溶液，在0°至3℃下2小時之期間中，加到在92公升甲苯中之10公斤之氧氯化磷(phophoroxychloride)。將反應混合物在0°至3℃下再攪拌3小時，使反應進行反應(react out)。沉澱之氫氯化物(hydrochloride)藉由過濾被移除，用96公升之甲苯洗滌，並在冷卻下將濾液(filtrate)緩慢加入109公升之去礦質水中，同時將溫度保持在25°至30℃之間。在室溫下攪拌約6小時後，該乳化液(emulsion)用12公升之甲基三級丁基醚處理，並加熱至50°至60°。有機相被分離，並在真空中移除溶劑。將剩餘之油溶解在450公升之乙基甲基酮(ethyl methyl ketone)中。對劇烈攪拌之溶液，在1.5小時之期間中加入在33公升去礦質水中之5.4kg之醋酸鈣(calcium acetate)。將懸浮液攪拌至少8小時，並且然後過濾。所得之鈣鹽(calcium salt)用50公升之乙基甲基酮和100公升之去礦質水洗滌。 Combine 18.8kg of 3-dodecylthione-2-decyloxy-1-propanol (3-dodecylthione-2-decyloxy-1-propanol) and 6.9kg of 2,6-lutidine (2, A solution of 6-lutidine in 92 liters of toluene was added to 10 kg of phophoroxychloride in 92 liters of toluene over a period of 2 hours at 0° to 3°C. The reaction mixture was stirred at 0° to 3°C for another 3 hours to allow the reaction to react (react out). The precipitated hydrochloride was removed by filtration, washed with 96 liters of toluene, and slowly added the filtrate to 109 liters of demineralized water under cooling while maintaining the temperature at 25° to 30°C between. After stirring at room temperature for about 6 hours, the emulsion was treated with 12 liters of methyl tertiary butyl ether and heated to 50° to 60°. The organic phase is separated and the solvent is removed in vacuum. Dissolve the remaining oil in 450 liters of ethyl methyl ketone. For the vigorously stirred solution, add 5.4 kg of calcium acetate in 33 liters of demineralized water over a period of 1.5 hours. The suspension was stirred for at least 8 hours, and then filtered. The obtained calcium salt is washed with 50 liters of ethyl methyl ketone and 100 liters of demineralized water.
濕潤之鈣鹽在不乾燥之情況下被用於下一步驟。 The moist calcium salt is used in the next step without drying.
產量：22.5kg鈣鹽(基於乾物質) Output: 22.5kg calcium salt (based on dry matter)
5.3'-疊氮基-3'-去氧-5'-胸腺核苷酸，單(3-十二烷基硫基-2癸氧基丙基)酯鈉鹽(3'-azido-3'-deoxy-5'-thymidylic acid,mono(3-dodecylthio-2decyloxypropyl)ester sodium salt)之製備。5.3'-azido-3'-deoxy-5'-thymonucleotide, mono(3-dodecylthio-2 decyloxypropyl) ester sodium salt (3'-azido-3' -Preparation of deoxy-5'-thymidylic acid, mono(3-dodecylthio-2decyloxypropyl)ester sodium salt).
將8.3kg之前步驟4之濕的(3-十二烷基硫基-2-癸氧基-1-丙基)磷酸二氫鹽作為鈣鹽(基於乾物質)溶解在30公升之甲基三級丁基醚和6公升之6M鹽酸(hydrochloric acid)中，並攪拌。然後有機相被分離，在真空中濃縮，並以10公升乾吡啶(pyridine)共蒸發(co-evaporated)，以移除水份(traces of water)。將殘餘物溶解在42公升之乾吡啶中，並加入6.92kg之2,4,6-三異丁基苯磺醯基氯(2,4,6-triisobutylbenolsulfonyl chloride)和4.06kg之3'-疊氮胸苷(3'-azidothymidine)(齊多夫定(zidovudine)，亦稱疊氮胸苷(azidothymidine)，或AZT)。該混合物在氮氣氣氛下於20°至25℃攪拌4小時。在最高溫度為60℃(真空<5毫巴(mbar)持續一小時)之情況下，在真空中移 除吡啶。 Dissolve 8.3 kg of the wet (3-dodecylthio-2-decyloxy-1-propyl) dihydrogen phosphate from step 4 as the calcium salt (based on dry matter) in 30 liters of methyl three Butyl ether and 6 liters of 6M hydrochloric acid (hydrochloric acid), and stir. The organic phase was then separated, concentrated in vacuo, and co-evaporated with 10 liters of dry pyridine to remove traces of water. Dissolve the residue in 42 liters of dry pyridine, and add 6.92kg of 2,4,6-triisobutylbenolsulfonyl chloride and 4.06kg of 3'-stack 3'-azidothymidine (zidovudine, also known as azidothymidine, or AZT). The mixture was stirred at 20° to 25°C for 4 hours under a nitrogen atmosphere. When the maximum temperature is 60°C (vacuum<5 mbar for one hour), move in vacuum In addition to pyridine.
將殘餘物在50°至55℃下懸浮(suspend)在33公升之甲基三級丁基醚中，並冷卻至20°至25℃。過濾掉沉澱之鹽，並用20公升之甲基三級丁基醚洗滌。(10kg三異丁基苯磺醯基吡啶鹽(triisobutylbenzenesulfonyl-pyridine salt))。 The residue was suspended in 33 liters of methyl tertiary butyl ether at 50° to 55°C and cooled to 20° to 25°C. The precipitated salt was filtered off, and washed with 20 liters of methyl tertiary butyl ether. (10kg triisobutylbenzenesulfonyl-pyridine salt).
濾液在真空中蒸發。將剩餘之黏稠油(viscous oil)溶解在75公升丙酮中，並且在劇烈攪拌之情況下加入到在15公升去礦質水中之2kg醋酸鈣水合物(calcium acetate hydrate)之溶液中。再繼續攪拌一小時，以及過濾掉鹽，並用20公升之丙酮和100公升之去礦質水洗滌。粗鈣鹽(crude calcium salt)未經事先乾燥而被儲存。 The filtrate was evaporated in vacuum. Dissolve the remaining viscous oil in 75 liters of acetone and add with vigorous stirring to a solution of 2 kg of calcium acetate hydrate in 15 liters of demineralized water. Continue stirring for another hour, filter out the salt, and wash with 20 liters of acetone and 100 liters of demineralized water. Crude calcium salt is stored without prior drying.
產量：9.5kg粗鈣鹽，基於乾物質。 Yield: 9.5 kg of crude calcium salt, based on dry matter.
6.高效能液相層析(HPLC)溶液之製備6. Preparation of high performance liquid chromatography (HPLC) solution
將粗鈣鹽溶解在30公升之甲基三級丁基醚和3.5公升之6M鹽酸中，並攪拌。然後有機相被分離，在真空中濃縮，並再次溶解在136公升之甲醇中。加入12公升之水和40g醋酸鈉(sodium acetate)。藉由加入濃NaOH溶液將pH值調節到5.0至5.5。將該混合物過濾以移除任何剩餘之渾濁物(turbidity)，並儲存起來供進一步之HPLC純化。 Dissolve the crude calcium salt in 30 liters of methyl tertiary butyl ether and 3.5 liters of 6M hydrochloric acid, and stir. The organic phase was then separated, concentrated in vacuo, and re-dissolved in 136 liters of methanol. Add 12 liters of water and 40 g of sodium acetate. Adjust the pH to 5.0 to 5.5 by adding concentrated NaOH solution. The mixture was filtered to remove any remaining turbidity and stored for further HPLC purification.
7.高效能液相層析(HPLC chromatography)7. HPLC chromatography
將先前製備之溶液以4公升之數份裝入高效能液相層析管柱(HPLC column)(200-350mm，默克(Merck)，LiChroprep RP 18，15-25μm)，並用約50公升之甲醇/0.02M醋酸鈉溶液(Na acetate solution)87.5/12.5洗提(elute)作為流動相。在兩次操作(runs)之間，用20公升之甲醇沖洗(rinse) 管柱。 Load the previously prepared solution in 4 liters into a high performance liquid chromatography column (200-350mm, Merck, LiChroprep RP 18, 15-25μm), and use about 50 liters Methanol/0.02M Na acetate solution 87.5/12.5 elute was used as the mobile phase. Between two runs, rinse with 20 liters of methanol Pipe string.
從約40次操作(700至800公升)中收集析出液(eluate)，用130公升之去礦質水稀釋，並用在22公升水中之1.15kg之醋酸鈣(calcium acetate)溶液處理。得到之懸浮液在環境溫度下攪拌5小時，以及鈣鹽被過濾，並用50公升之去礦質水洗滌。純淨之鈣鹽被用於下一步驟，而不進一步乾燥。 The eluate was collected from about 40 operations (700 to 800 liters), diluted with 130 liters of demineralized water, and treated with 1.15 kg of calcium acetate solution in 22 liters of water. The resulting suspension was stirred at ambient temperature for 5 hours, and the calcium salt was filtered and washed with 50 liters of demineralized water. The pure calcium salt is used in the next step without further drying.
產量：6.0至7.0kg鈣鹽，基於乾物質。 Yield: 6.0 to 7.0 kg calcium salt, based on dry matter.
8.3'-疊氮基-3'-去氧-5'-胸腺核苷酸，單(3-十二烷基硫基-2癸氧基丙基)酯鈉鹽(3'-azido-3'-deoxy-5'-thymidylic acid,mono(3-dodecylthio-2-decyloxypropyl)ester sodium salt)之製備。8.3'-azido-3'-deoxy-5'-thymonucleotide, mono(3-dodecylthio-2 decyloxypropyl) ester sodium salt (3'-azido-3' -Preparation of deoxy-5'-thymidylic acid, mono(3-dodecylthio-2-decyloxypropyl)ester sodium salt).
將10.0kg純化之鈣鹽懸浮在65公升之甲基三級丁基醚中，並在室溫下攪拌1小時。加入14.4公升之2M鹽酸，並且繼續攪拌至所有沉澱物被溶解。 Suspend 10.0 kg of purified calcium salt in 65 liters of methyl tertiary butyl ether and stir at room temperature for 1 hour. Add 14.4 liters of 2M hydrochloric acid and continue stirring until all the precipitate is dissolved.
攪拌器停止，有機相被分離，並用20公升之去礦質水萃取。將有機相過濾，並在真空中移除溶劑。將殘餘物溶解於60公升甲苯中，以及蒸餾掉30公升甲苯以移除水份(traces of water)。剩餘之溶液在20°至25℃下用甲醇鈉溶液(sodium methylate solution)攪拌調節至pH值為6.9至7.1。 The agitator was stopped, the organic phase was separated and extracted with 20 liters of demineralized water. The organic phase was filtered and the solvent was removed in vacuum. The residue was dissolved in 60 liters of toluene, and 30 liters of toluene were distilled off to remove traces of water. The remaining solution was stirred with sodium methylate solution at 20° to 25°C to adjust the pH to 6.9 to 7.1.
在攪拌下對甲苯溶液緩慢加入240公升之沸騰之丙酮。回流(reflux)維持15分鐘。然後在3小時內將懸浮液冷卻至0°至5℃，並在此溫度下額外攪拌2小時。將鈉鹽過濾掉，用40公升丙酮洗滌，乾燥，研磨(ground)，並再次乾燥。 Slowly add 240 liters of boiling acetone to the toluene solution while stirring. Reflux is maintained for 15 minutes. The suspension was then cooled to 0° to 5°C within 3 hours and stirred at this temperature for an additional 2 hours. The sodium salt was filtered off, washed with 40 liters of acetone, dried, ground, and dried again.
產量：9.5kg Output: 9.5kg
9.福齊夫定替酯(Fozivudin)對新型冠狀病毒(SARV-CoV-2)複製之影響之分析。9. Analysis of the effect of Fozivudin on the replication of the new coronavirus (SARV-CoV-2).
非洲綠猴腎細胞(Vero cells)以30μM濃度之Fozivudin進行預培養(pre-incubated)。用取自病患之SARS-2冠狀病毒(COVID19)感染細胞。感染3天後，收集細胞上清液(cellular supernatants)，並在2000rpm離心5分鐘，以移除分離之細胞(detached cells)。使用MagNA Pure 24系統(德國羅氏；Roche)萃取病毒RNAs。新型冠狀病毒RNA基因組用TIB MOLBIOL LightMix Assay SARS-CoV-2 RdRP RTqPCR檢測試劑組與RNA處理控制PCR試劑組(RNA Process Control PCR Kit(羅氏；Roche))進行定量。PCR反 應設置係使用BRAND LHS實驗室機器人(BRAND LHS laboratory robot)進行，以確保品質。擴增(amplification)係使用LightCycler 480 II(羅氏)(圖1)來進行。Fozivudin對新型冠狀病毒(SARS-CoV-2)之複製具有一適度(moderate)之影響。 African green monkey kidney cells (Vero cells) were pre-incubated with Fozivudin at a concentration of 30 μM. Infect the cells with the SARS-2 coronavirus (COVID19) taken from the patient. After 3 days of infection, cellular supernatants were collected and centrifuged at 2000 rpm for 5 minutes to remove detached cells. Viral RNAs were extracted using MagNA Pure 24 system (Roche, Germany; Roche). The novel coronavirus RNA genome was quantified with TIB MOLBIOL LightMix Assay SARS-CoV-2 RdRP RTqPCR detection reagent set and RNA processing control PCR reagent set (RNA Process Control PCR Kit (Roche)). PCR reverse The BRAND LHS laboratory robot should be set up to ensure quality. Amplification was performed using LightCycler 480 II (Roche) (Figure 1). Fozivudin has a moderate effect on the replication of the new coronavirus (SARS-CoV-2).
圖1顯示與用福齊夫定替酯(Fozivudine)處理之樣品相比，病毒負荷量(viral load)為1/ml之對照樣品。非洲綠猴腎細胞(Vero cells)以30μM濃度之Fozivudin進行預培養(pre-incubated)。比較顯示，Fozivudin對新型冠狀病毒(SARS-CoV-2)之複製具有一適度(moderate)但顯著之影響。 Figure 1 shows a control sample with a viral load of 1/ml compared to a sample treated with Fozivudine. African green monkey kidney cells (Vero cells) were pre-incubated with Fozivudin at a concentration of 30 μM. The comparison shows that Fozivudin has a moderate but significant effect on the replication of the new coronavirus (SARS-CoV-2).
Claims (10)
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| PCT/IB2020/052996 WO2021198725A1 (en) | 2020-03-30 | 2020-03-30 | Fosalvudine and fozivudine tidoxil for use in the treatment of covid-19, and use of the structurally simplified derivatives thereof |
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