1-[4-Hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione | 7057-42-3

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: 1-[4-Hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-(trifluoromethyl)pyrimidine-2,4-dione
• CAS: 7057-42-3
• 化学式: C₁₀H₁₁F₃N₂O₅
• 分子量: 296.2
• InChiKey: VSQQQLOSPVPRAZ-UHFFFAOYSA-N

物化性质

• 密度：
  1.646±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  99.1
• 氢给体数：
  3
• 氢受体数：
  8

ADMET

代谢

三氟尿嘧啶的主要代谢物（5-羧基-2'-脱氧尿嘧啶）似乎具有一些抗病毒活性，但远低于母药。

The major metabolite of trifluridine (5-carboxy-2'-deoxyuridine appears) to have some antiviral activity but substantially less than that of the parent drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

19F NMR光谱已被用于进一步研究5-三氟甲基-2'-脱氧尿嘧啶（三氟尿嘧啶；F3TdR）的代谢。现在报告了alpha-三氟甲基-beta-丙氨酸甘氨酸（F3MBAG），F3TdR的一种假定新代谢物的合成和表征。本研究描述了使用19F NMR光谱在携带EMT-6肿瘤的雄性BALB/C小鼠中体外和体内检测F3MBAG和其他先前报道的三氟尿嘧啶代谢物。另一项使用F3TdR处理的大鼠进行的平行19F NMR光谱研究也进行了，以观察另一种物种中F3TdR代谢的定性模式。出乎意料的是，5-三氟甲基-5,6-二羟基尿嘧啶（DOHF3T）、alpha-三氟甲基-beta-脲丙酸（F3MUPA）和氟化物，这些是F3TdR代谢降解的产物，在小鼠给药的各个生物样本中可以检测到，但在大鼠尿液中或匀浆组织提取物中无法鉴定。由于在这些样本的19F NMR光谱中总是显示出一个广泛的共振“隆起”，涵盖这些代谢物的化学位移范围，因此这些代谢物在完整组织中的存在是不确定的。还没有合理解释这种光谱分辨率损失的原因。合成了N-羧基-alpha-三氟甲基-beta-丙氨酸（F3MBA-CO2）、alpha-三氟甲基-beta-丙氨酰丙氨酸（F3MBAA）和N-乙酰基-alpha-三氟甲基-beta-丙氨酸（Ac-F3MBA），并对其进行了表征，但在检查的任何生物标本中都没有检测到它们作为代谢物。

19F NMR spectroscopy has been used to study further the metabolism of 5-trifluoromethyl-2'-deoxyuridine (trifluridine; F3TdR). The synthesis and characterization of alpha-trifluoromethyl-beta-alanyl glycine (F3MBAG), a putative new metabolite of F3TdR, are now reported. This study describes ex vivo and in vivo detection of F3MBAG and other previously reported metabolites of trifluridine, using 19F NMR spectroscopy, in male BALB/C mice bearing EMT-6 tumors. A parallel 19F NMR spectroscopic study was also performed on rats dosed with F3TdR, to observe the qualitative pattern of F3TdR metabolism in another species. Unexpectedly, 5-trifluoromethyl-5,6-dihydroxyuracil (DOHF3T), alpha-trifluoromethyl-beta-ureidopropionic acid (F3MUPA) and fluoride, which result from the metabolic degradation of F3TdR and which were detected in various biological samples from mice dosed with F3TdR, could not be identified in rat urine or in homogenized tissue extracts. The presence of these metabolites in intact tissues is uncertain since in this study 19F NMR spectroscopy of these samples always displayed a broad resonance "hump" across the range of chemical shifts that would encompass these metabolites. No clear explanation for the loss of spectroscopic resolution in this region has been rationalized. N-Carboxy-alpha-trifluoromethyl-beta-alanine (F3MBA-CO2), alpha-trifluoromethyl-beta-alanyl alanine (F3MBAA) and N-acetyl-alpha-trifluoromethyl-beta-alanine (Ac-F3MBA) were synthesized and characterized, but were not detected as metabolites in any of the biological specimens examined.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练进行操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者向前倾或将其置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，协助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预期癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能够吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒药A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于失去意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流速/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸钠林格液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

紧急和支持性措施：保持呼吸道通畅，必要时协助通气。如果出现昏迷、癫痫、低血压或过敏性反应，则进行治疗。通过静脉注射晶体液补充由胃肠炎引起的液体损失。通过静脉输液维持稳定的尿流，以缓解结晶尿并逆转肾功能不全。用适量的碳酸氢钠治疗乳酸酸中毒，并停用引起问题的药物。/抗病毒和抗逆转录病毒药物/

Emergency and supportive measures: Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. /Antiviral and antiretroviral agents/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

人类暴露研究/已经回顾了文献，以了解局部抗病毒药物引起的接触性皮炎。已经确定了15种药物，包括阿昔洛韦、咪喹莫德、足叶草毒素、足叶草素、西多福韦、喷昔洛韦、维达拉宾、碘苷、三氟尿嘧啶、曲安奈德、拉米夫定、干扰素皮内注射和眼药水、福米韦生和福斯科内特玻璃体内注射以及更昔洛韦眼内植入物。在某些个体中已经记录了斑贴测试，并且观察到交叉敏感化显著导致某些过敏反应。

/HUMAN EXPOSURE STUDIES/ The literature has been reviewed for contact dermatitis from topical antiviral drugs. 15 agents have been identified including acyclovir, imiquimod, podophyllin, podofilox, cidofovir, penciclovir, vidarabine, idoxuridine, trifluridine, tromantadine, lamivudine, interferon intralesional injections and ophthalmic solution, fomivirsen and foscarnet intravitreal injections and ganciclovir intraocular implants. Patch testing has been documented in certain individuals and cross-sensitization has been observed to contribute significantly to some allergic reactions.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

滴入眼内后，三氟尿嘧啶能够渗透角膜，并在房水中被检测到。

Following topical application of trifluridine to the eye, the drug penetrates the cornea and can be detected in the aqueous humor.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在健康个体中进行的一项研究中，将1%三氟尿嘧啶眼药水每天7次连续14天应用于眼部，并未导致检测到三氟尿嘧啶或5-羧基-2'-脱氧尿嘧啶的血清浓度。

Systemic absorption following ocular application of trifluridine appears to be negligible. In one study in healthy individuals, topical application of trifluridine 1% ophthalmic solution to the eyes 7 times daily for 14 consecutive days did not result in detectable serum concentrations of trifluridine or 5-carboxy-2'-deoxyuridine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在体外研究中，使用切取的兔角膜，发现三氟尿嘧啶的主要代谢物5-羧基-2'-脱氧尿嘧啶除了母化合物外，还位于角膜的内皮侧；然而，在人类房水中并未发现可检测水平的该代谢物。

During in vitro studies using excised rabbit corneas, the major metabolite of trifluridine, 5-carboxy-2'-deoxyuridine, was found on the endothelial side of the cornea in addition to the parent compound; however, detectable levels of the metabolite have not been found in the aqueous humor in humans.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

不太可能在局部滴眼使用三氟尿嘧啶后，三氟尿嘧啶会排入人乳中，因为剂量相对较小（<= 5毫克/天），在体液中稀释，并且其半衰期极短（大约12分钟）。

It is unlikely that trifluridine is excreted in human milk after ophthalmic instillation of trifluridine because of the relatively small dosage (</= 5mg/day), its dilution in body fluids and its extremely short half-life (approximately 12 minutes).

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为产物：
  描述：

  5-trifluoromethyl-2′-deoxyuridine-3′,5′-diacetate 、 氨 以82%的产率得到
  参考文献：
  名称：

  TANABE, YOO;MATSUO, NORITADA;OHNO, NOBUO, J. ORG. CHEM., 53,(1988) N 19, C. 4582-4585

  摘要：

  DOI：

文献信息

• Macroheterocyclic nucleoside derivatives and their analogues, production and use thereof
  申请人：Ivachtchenko Alexandre Vasilievich

  公开号：US20180099989A1

  公开（公告）日：2018-04-12

  Nucleosides and nucleotides (nucleos(t)ides) have been in clinical use for almost 50 years and have become cornerstones of treatment for patients with viral infections or cancer. The approval of several additional drugs over the past decade demonstrates that this family still possesses strong potential. Therefore nucleos(t)ide are of great interest as promising chemotherapeutic agents, including: 2′-deoxy-L-uridine (CAS No 31501-19-6), 2′-deoxy-D-uridine (CAS No 951-78-0), telbivudine (CAS No 3424-98-4), zidovudine (AZT, CAS No 30516-87-1), trifluridine (CAS No 70-00-8), clevudine (CAS No 163252-36-6), PSI-6206 (CAS No 863329-66-2), 2′-(5)-2′-chloro-2′-deoxy-2′-fluorouridine (CAS No 1673560-41-2), ND06954 (CAS No 114248-23-6), stavudine (CAS No 3056-17-5), 5-ethynyltavudine (Festinavir, CAS No 634907-30-5), torcitabine (CAS No 40093-94-5), (−)-beta-D-(2R,4R)-dioxolane-thymine (DOT, 1-((2R,4R)-2-(hydroxymethyl)-1,3-dioxolan-4-yl)-5-methyl-2,4 (1H,3H)-pyrimidinedione, CAS No. 127658-07-5), 2-(6-amino-purin-9-yl)-ethanol (CAS No 707-99-3), 2′-C-methylcytidine (CAS No 20724-73-6), PSI-6130 (CAS No 817204-33-4), gemcitabine (CAS No 95058-81-4), 2′-chloro-2′-deoxy-2′-fluorocytidine (CAS No 1786426-19-4), 2′,2′-dichloro-2′-deoxycytidine (CAS No 1703785-65-2), 2′-C-methylcytidine (CAS No 20724-73-6), PSI-6130 (CAS No 817204-33-4), lamivudine (3TC, CAS No 134678-17-4), emtricitabine (CAS No 143491-57-0), 2′-deoxyadenosine (CAS No 958-09-8), 2′-deoxy-β-L-adenosine (CAS No 14365-45-8), 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine (CAS No 865363-93-5), didanosine (CAS No 69655-05-6), entecavir (CAS No 209216-23-9), FMCA (CAS No 1307273-70-6), dioxolane-G (DOG, CAS No 145514-01-8), β-D-2′-deoxy-2′-(R)-fluoro-2′-β-C-methylguanosine (CAS No 817204-45-8), abacavir (ABC, CAS No 136470-78-5), dioxolane-A (DOA, CAS #145514-02-9), [(2R,4R)-4-(6-cyclopropylamino-purin-9-yl)-[1,3]dioxolan-2-yl]-methanol (CAS No 1446751-04-7), amdoxovir (AMDX, CAS No 145514-04-1), (R)-1-(6-amino-purin-9-yl)-propan-2-ol (CAS No 14047-28-0), and [(2S,5R)-5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yl]-methanol. Macroheterocyclic nucleoside derivative and its analogue of the general formula 1 or general formula 2, a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, wherein: Ar is aryl or hetaryl; R 1 and R 2 are not necessarily the same substituents selected from H, F, Cl, CH 3 , OH; R 3 is H or CH 3 ; X is oxygen or ethanediyl-1,1 (C═CH 2 ); Y is CH(R 4 )(CH 2 ) k , CH(R 4 )(CH 2 ) m C(O)O(CH 2 ) n ; R 4 is H or CH 3 ; k has a value from zero to six; m has a value from zero to two; n has a value of one to four; Q is a radical selected from Q1-Q4; wherein: R 5 is the substituent selected from H, F, Cl, CH 3 , OH; the arrow (→) indicates the location, joined by Q1-Q4.

  核苷和核苷酸（核苷（t）酸）已经在临床上使用了近50年，已成为治疗病毒感染或癌症患者的治疗基石。过去十年批准了几种额外的药物，表明这个家族仍然具有强大的潜力。因此，核苷（t）酸作为有前途的化疗药物具有很大的吸引力，包括：2'-脱氧-L-尿苷（CAS号31501-19-6）、2'-脱氧-D-尿苷（CAS号951-78-0）、替比夫定（CAS号3424-98-4）、阿司匹林（AZT，CAS号30516-87-1）、三氟胸苷（CAS号70-00-8）、克雷胸苷（CAS号163252-36-6）、PSI-6206（CAS号863329-66-2）、2'-(5)-2'-氯-2'-脱氧-2'-氟尿苷（CAS号1673560-41-2）、ND06954（CAS号114248-23-6）、司他夫定（CAS号3056-17-5）、5-乙炔基司他夫定（费司那韦，CAS号634907-30-5）、托西他滨（CAS号40093-94-5）、（-）-β-D-(2R,4R)-二氧杂环己嘧啶（DOT，1-((2R,4R)-2-(羟甲基)-1,3-二氧杂环己-4-基)-5-甲基-2,4(1H,3H)-嘧啶二酮，CAS号127658-07-5）、2-(6-氨基嘌呤-9-基)-乙醇（CAS号707-99-3）、2'-C-甲基胞苷（CAS号20724-73-6）、PSI-6130（CAS号817204-33-4）、吉西他滨（CAS号95058-81-4）、2'-氯-2'-脱氧-2'-氟胞苷（CAS号1786426-19-4）、2',2'-二氯-2'-脱氧胞苷（CAS号1703785-65-2）、2'-C-甲基胞苷（CAS号 ）、PSI-6130（CAS号 ）、拉米夫定（3TC，CAS号134678-17-4）、恩替卡韦（CAS号143491-57-0）、2'-脱氧腺苷（CAS号958-09-8）、2'-脱氧-β-L-腺苷（CAS号14365-45-8）、2'-脱氧-4'-C-乙炔基-2-氟腺苷（CAS号865363-93-5）、地达诺辛（CAS号69655-05-6）、恩替卡韦（CAS号209216-23-9）、FMCA（CAS号1307273-70-6）、二氧杂环己胞苷（DOG，CAS号145514-01-8）、β-D-2'-脱氧-2'-(R)-氟-2'-β-C-甲基鸟苷（CAS号817204-45-8）、阿巴卡韦（ABC，CAS号136470-78-5）、二氧杂环己-A（DOA，CAS号145514-02-9）、[(2R,4R)-4-(6-环丙基氨基嘌呤-9-基)-[1,3]二氧杂环己-2-基]-甲醇（CAS号1446751-04-7）、阿姆多氧韦（AMDX，CAS号145514-04-1）、(R)-1-(6-氨基嘌呤-9-基)-丙醇（CAS号14047-28-0）、和[(2S,5R)-5-(6-氨基嘌呤-9-基)-4-氟-2,5-二氢呋喃-2-基]-甲醇。 宏环核苷衍生物及其一般式1或一般式2的类似物，立体异构体，同位素富集类似物，药学上可接受的盐，水合物，溶剂合物，或其结晶或多形式， 其中： Ar是芳基或杂芳基； R 1 和R 2 不一定相同，选自H，F，Cl，CH 3 ，OH的取代基； R 3 是H或CH 3 ； X是氧或乙烯二基-1,1（C═CH 2 ）； Y是CH(R 4 )(CH 2 ) k ，CH(R 4 )(CH 2 ) m C(O)O(CH 2 ) n ； R 4 是H或CH 3 ； k的值从零到六； m的值从零到二； n的值从一到四； Q是从Q1-Q4中选择的基团； 其中：R 5 是选自H，F，Cl，CH 3 ，OH的取代基； 箭头（→）表示位置，由Q1-Q4连接。
• 2,4-Pyrimidinediamine Compounds and Their Uses
  申请人：Singh Rajinder

  公开号：US20150266828A1

  公开（公告）日：2015-09-24

  The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

  本发明提供了抑制IgE和/或IgG受体信号级联反应的2,4-嘧啶二胺化合物，该级联反应导致化学介质的释放，以及合成这些化合物的中介体和方法，以及在多种情况下使用这些化合物的方法，包括在治疗和预防由脱粒和其他由IgE和/或IgG受体信号级联反应激活引起的化学介质释放所表征、引起或相关的疾病。
• [EN] CATALYST-FREE AND REDOX-NEUTRAL INNATE TRIFLUOROMETHYLATION AND ALKYLATION OF (HETERO)AROMATICS ENABLED BY LIGHT<br/>[FR] TRIFLUOROMÉTHYLATION INNÉE EXEMPTE DE CATALYSEUR ET NEUTRE À L'OXYDORÉDUCTION, ET ALKYLATION DE COMPOSÉS (HÉTÉRO)AROMATIQUES ACTIVÉS PAR LA LUMIÈRE
  申请人：THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING/MCGILL UNIV

  公开号：WO2019060998A1

  公开（公告）日：2019-04-04

  The present disclosure relates to reagents and method for performing trifluoromethylation, difluoromethylation or alkylation of aromatic or heteroaromatic rings in a redox-neutral manner without any catalyst which are enabled by light. In addition, there are methods for synthesizing the starting reagents used in the trifluoromethylation, difluoromethylation or alkylation reactions.

  本公开涉及一种在无需任何催化剂的情况下通过光启动对芳香或杂环芳香环进行三氟甲基化、二氟甲基化或烷基化的试剂和方法。此外，还有用于合成进行三氟甲基化、二氟甲基化或烷基化反应中所使用的起始试剂的方法。
• [EN] PHOSPHORAMIDATE NUCLEOSIDE PRODRUG FOR TREATING VIRAL DISEASES AND CANCER, PROCESSES FOR THEIR PREPARATION AND THEIR USE<br/>[FR] PROMÉDICAMENT NUCLÉOSIDE PHOSPHORAMIDATE DESTINÉ AU TRAITEMENT DES MALADIES VIRALES ET DU CANCER, LEURS PROCÉDÉS DE PRÉPARATION ET LEUR UTILISATION
  申请人：IVACHTCHENKO ALEXANDRE VASILIEVICH

  公开号：WO2018022221A1

  公开（公告）日：2018-02-01

  The present invention pertains to chemotherapeutic agents and their use for treating viral and cancerous diseases. These compounds are inhibitors of HCV NS5B polymerase, HBV DNA polymerase and, HIV-1 reverse transcriptase (RT) inhibitor, and for treatment of hepatitis B and C infection in mammals. These compounds are also of interest for the treatment of cancer. The phosphoramidate nucleoside prodrug of the general formula (1), a stereoisomer, isotope-enriched analogue, pharmaceutically acceptable salt, hydrate, solvate, or crystalline or polymorphic form thereof, formula (1) wherein: Ar is aryl or hetaryl; R1 is H or CH3, R2 is the substituent selected from OCH2CH=CH2, OCH2CH≡CH, OCH2CH2CH2OCH3, formula (2), formula (3) or formula (4), R3 is H or CH3; R4 is OH, OR5, NR6R7; R5 is C1-C4-alkyl; R6 and R7 are not necessarily the same substituents selected from H or CH3, Z = O, or NH; an arrow (→) indicates the place of substituent connection; Nuc is formula (5) or (6); R8 and R9 are not necessarily the same substituents selected from H, F, Cl, CH3 or OH provided when continuous line and its accompanying dotted line ( ) together are the single carbon-carbon (C-C) bond or R8 and R9 are hydrogen provided when continuous line and its accompanying dotted line ( ) together are the double carbon-carbon bond (C=C); R10 is the substituent selected from R10.1- R10.5; R10.1 R10.2 R10.4 R10.5 ; R11 is the substituent selected from H, F, CI, CH3, or CF3; R12 is hydrogen, C1-C4-alkyl or C3-C6-cycloalkyl; X is oxygen or ethanediyl-1,1 (C=CH2); Y is O, S, CH2, or HO-CH group provided when continuous line and its accompanying dotted line (formula 7) together are the single carbon-carbon (C-C) bond or Y is CH group provided when continuous line and its accompanying dotted line (formula 7) together are the double carbon-carbon bond (C=C), and compound of the general formula (1), stereoisomers, isotope-enriched analogues, pharmaceutically acceptable salts, hydrates, solvates, or crystalline or polymorphic forms thereof, wherein: Ar is aryl or hetaryl; R1 is H or CH3; R2 is isopropyl; Nuc is formula (8), (9) or (10).

  本发明涉及化疗药物及其用于治疗病毒性和癌症疾病的用途。这些化合物是HCV NS5B聚合酶、HBV DNA聚合酶和HIV-1逆转录酶（RT）抑制剂，用于治疗哺乳动物中的乙型和丙型肝炎感染。这些化合物也对癌症治疗具有兴趣。通用式（1）的磷酰胺核苷前药的立体异构体、同位素富集类似物、药学上可接受的盐、水合物、溶剂合物或晶体或多形式，式（1）其中：Ar为芳基或杂芳基；R1为H或CH3，R2为从O CH=CH2、O CH≡CH、O O 、式（2）、式（3）或式（4）中选择的取代基，R3为H或 ；R4为OH、OR5、NR6R7；R5为C1-C4-烷基；R6和R7不一定相同，选择自H或 的取代基，Z=O或NH；箭头（→）表示取代基连接的位置；Nuc为式（5）或（6）；R8和R9不一定相同，选择自H、F、Cl、 或OH，提供当连续线及其相应的虚线（）一起为单碳-碳（C-C）键时，或R8和R9为氢，提供当连续线及其相应的虚线（）一起为双碳-碳键（C=C）时；R10为从R10.1-R10.5中选择的取代基；R10.1 R10.2 R10.4 R10.5；R11为从H、F、Cl、 或CF3中选择的取代基；R12为氢、C1-C4-烷基或C3-C6-环烷基；X为氧或乙烯二基-1,1（C= ）；Y为O、S、 或HO-CH基，提供当连续线及其相应的虚线（式7）一起为单碳-碳（C-C）键时，或Y为CH基，提供当连续线及其相应的虚线（式7）一起为双碳-碳键（C=C）时，以及通用式（1）的化合物、立体异构体、同位素富集类似物、药学上可接受的盐、水合物、溶剂合物或晶体或多形式，其中：Ar为芳基或杂芳基；R1为H或 ；R2为异丙基；Nuc为式（8）、（9）或（10）。
• BIOCATALYTIC PRODUCTION OF NUCLEOSIDE ANALOGUES AS ACTIVE PHARMACEUTICAL INGREDIENTS
  申请人：PLASMIA BIOTECH, S.L.

  公开号：US20160076070A1

  公开（公告）日：2016-03-17

  A biocatalytic process for producing active pharmaceutical ingredients (APIs) or intermediates thereof, wherein those APIs or their intermediates are nucleoside analogues (NAs) of formula I and wherein said NAs are active as pharmaceutically relevant antivirals and anticancer medicaments, intermediates or prodrugs thereof.

  一种生物催化过程，用于生产活性药用成分（API）或其中间体，其中这些API或其中间体是式I的核苷类似物（NAs），并且所述的NAs作为药用抗病毒和抗癌药物具有活性，以及其中间体或前药。