氟胞嘧啶 | 2022-85-7

• 物质功能分类: 原料药 - 人工合成抗感染类药 - 抗真菌类药
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 氟胞嘧啶
• 中文别名: 4-氨基-5-氟-2(1H)-嘧啶酮氟胞嘧啶安拉喷5-氟氧胺嘧啶5-氟胞嗪4-氨基-5-氟嘧啶酮-2(1H)；5-氟胞嗪；4-氨基-5-氟-2(1H)-嘧啶酮；5-氟胞嘧啶；4-氨基-5-氟嘧啶酮-2(1H)；5-氟氧胺嘧啶；安拉喷；5-氟-4-氨基-2(1H)-嘧啶酮
• 英文名称: Flucytosine
• 英文别名: 5-fluorocytosine；5-flucytosine；fluorocytosine；5-fluorocytosin；4-amino-5-fluoropyrimidin-2-ol
• CAS: 2022-85-7
• 化学式: C₄H₄FN₃O
• mdl: MFCD00006035
• 分子量: 129.094
• InChiKey: XRECTZIEBJDKEO-UHFFFAOYSA-N

物化性质

• 熔点：
  298-300 °C (dec.) (lit.)
• 密度：
  1.3990 (estimate)
• 溶解度：
  微溶于水，微溶于乙醇（96%）
• LogP：
  -1.36 at 22.1℃ and pH6.4-6.9
• 解离常数：
  2.74-10.71 at 21.4℃
• 物理描述：
  Solid
• 颜色/状态：
  White crystalline solid
• 气味：
  Odorless
• 蒸汽压力：
  4.5X10-6 mm Hg at 25 °C (est)
• 稳定性/保质期：
  如果按照规定使用和储存，则不会分解，没有已知的危险反应。请避免与氧化物接触。
• 分解：
  When heated to decomposition it emits very toxic fumes of /floride ions and nitrogen oxides/.
• 碰撞截面：
  118.4 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  9
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  67.5
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

氟胞嘧啶可能通过肠道细菌或真菌靶标去氨化，转化为5-氟尿嘧啶，即活性代谢物。

Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite.

来源:DrugBank

代谢

氟胞嘧啶的作用可能是抑菌或杀菌，这取决于药物的浓度。已经确定了氟胞嘧啶的两种可能作用机制。氟胞嘧啶似乎是通过真菌特异性胞嘧啶渗透酶的作用进入真菌细胞。在细胞内，氟胞嘧啶通过胞嘧啶脱氨酶转化为氟尿嘧啶（5-FU），然后经过几个中间步骤转化为5-氟尿嘧啶三磷酸（FUTP）。FUTP被并入真菌RNA中，干扰蛋白质合成。氟胞嘧啶还似乎转化为5-氟脱氧尿嘧啶一磷酸，它非竞争性地抑制胸苷酸合成酶并干扰DNA合成。氟胞嘧啶似乎没有抗肿瘤活性。

Flucytosine may be fungistatic or fungicidal in action depending on the concentration of the drug. Two possible mechanisms of action have been identified for flucytosine. Flucytosine appears to enter fungal cells via the action of fungal-specific cytosine permease. Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then after several intermediate steps is converted into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA and interferes with protein synthesis. Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis. Flucytosine does not appear to have antineoplastic activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究旨在调查氟尿嘧啶（5-FU）是否是导致接受氟胞嘧啶（5-FC）治疗的病人出现骨髓抑制的原因。这个初步研究包括了6名接受5-FC治疗的病人。通过血小板和白细胞的计数来监测毒性。使用高效液相色谱（HPLC）法同时测定5-FC和5-FU的血清水平。在34份可用的血清样本中，5-FU的量始终低于定量限（< 0.05 mg/L），而所有样本中都可以检测到5-FC的水平。然而，在几个调查的血清样本中检测到了5-FU代谢物α-氟-β-丙氨酸（FBAL）的较低水平。在3名患者中，血小板计数在5-FC治疗期间保持在正常范围内，而一名患者在治疗期间发展为血小板减少症（50 x 10(9) 血小板/L）。此外，一名患者在5-FC治疗期间发展为白细胞减少症（2.6 x 10(9) 白细胞/L），而其余五名患者在5-FC治疗前已经患有白细胞增多症。总之，在接受静脉注射5-FC的重症监护患者中，我们发现5-FU的血清浓度不可检测（< 0.05 mg/L），这使得5-FC相关毒性不太可能是由患者接受静脉注射5-FC治疗时的5-FU暴露引起的。这些发现可能是因为我们的患者接受的是静脉注射5-FC而不是口服，因此不允许人类肠道微生物群将5-FC活性转化为5-FU。

The aim of this study is to investigate whether fluorouracil (5-FU) could be responsible for bone-marrow depression occurring in fluorocytosine (5-FC) treated patients. Six 5-FC treated patients were included in this pilot study. Toxicity was monitored by means of thrombocyte and leucocyte counts. 5-FC and 5-FU serum levels were measured using a high-performance liquid chromatography (HPLC) assay that allows simultaneous determination of both compounds. The amounts of 5-FU in the 34 available serum samples remained below the limit of quantitation (< 0.05 mg/L), whereas 5-FC levels could be detected in all samples. Instead, low levels of the 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) were detected in several of the investigated serum samples. In case of three patients thrombocyte counts remained within the normal range during 5-FC treatment, whereas one patient developed thrombocytopenia (50 x 10(9) thrombocytes/L) during therapy. Furthermore, one patient developed leucocytopenia (2.6 x 10(9) leucocytes/L) during 5-FC therapy, whereas the remaining five patients were suffering from leucocytosis prior to 5-FC therapy. In conclusion, we found nondetectable 5-FU serum concentrations (< 0.05 mg/L) in ICU patients treated with intravenous 5-FC, making it unlikely that 5-FC-associated toxicity results from 5-FU exposure in patients receiving intravenous 5-FC therapy. These findings may be explained by the fact that our patients received 5-FC intravenously instead of orally, therefore not allowing active conversion of 5-FC to 5-FU by the human intestinal microflora. /5-Fluorouracil/

来源:Hazardous Substances Data Bank (HSDB)

代谢

一种用于检测血清中5-氟尿嘧啶（5-FU）的方法，浓度低至10 ng/mL，被用来确定接受口服5-氟胞嘧啶（5-FC）治疗的患者的血清中5-FU的存在程度。在两名患者和两名健康志愿者中进行的初步研究显示，在服用5-FC药物后的5小时内，血清中5-FU水平持续升高（>100 ng/mL）。这些研究中使用的5-FC药物制剂与5-FU的污染可以忽略不计（<0.03%），这表明5-FC转化为5-FU是在体内发生的。对接受两性霉素B和5-FC治疗的七名隐球菌性脑膜炎患者的血清样本进行了5-FU检测。在这七名患者中，有五名在治疗过程中某个时间点经历了归因于5-FC的血液学或其他毒性。在41份血清样本中，有20份观察到5-FU水平超过1,000 ng/mL，这一水平与已知与血液学毒性相关的癌症化疗剂量5-FU的范围相符。因此，可以得出结论，5-FC转化为5-FU在人类中发生，而且5-FU可能是观察到的5-FC毒性的部分原因。

A gas chromatographic-mass spectrometric method for detecting 5-fluorouracil (5-FU) in serum at concentrations as low as 10 ng/mL was used to determine to what extent 5-FU was present in the serum of patients taking oral 5-fluorocytosine (5-FC). Preliminary studies in two patients and two healthy volunteers given an initial 2-g oral dose of 5-FC demonstrated sustained serum 5-FU levels (>100 ng/mL) during the 5 hr after ingestion of drug. Pharmaceutical preparations of 5-FC used in these studies were shown to be insignificantly contaminated with 5-FU (<0.03%), suggesting in vivo conversion of 5-FC to 5-FU had occurred. Serum samples from seven patients with cryptococcal meningitis treated with amphotericin B and 5-FC were examined for 5-FU. Five of these patients had experienced hematological or other toxicity attributed to 5-FC at some time during the course of therapy. Of 41 serum samples, 20 were observed to have 5-FU levels greater than 1,000 ng/mL in the range observed with cancer chemotherapeutic doses of 5-FU known to be associated with hematological toxicity. It is concluded that conversion of 5-FC to 5-FU occurs in humans and furthermore that 5-FU may account for some of the toxicity observed with 5-FC. /5-Fluorouracil/

来源:Hazardous Substances Data Bank (HSDB)

代谢

5-氟胞嘧啶-6-14C（5-FC）在口服和皮下、单次和重复给药后在小鼠、大鼠、兔和狗体内的代谢进行了研究。在所有种类的尿液中，完整的5-FC在任何治疗时间点都占总放射活性的90%以上。狗的平均尿代谢物比例约为5%，兔为3%，大鼠为2.5%，小鼠为2%。在重复剂量下，小鼠的代谢物增加，但皮下给药的大鼠的代谢物减少。兔（口服给药）和狗的代谢物既没有增加也没有减少。确定了两种代谢物，α-氟-β-脲基丙酸（FUPA）和α-氟-β-丙氨酸，后者主要在口服治疗后出现。这些化合物可能代表5-FC被脱氨成5-氟尿嘧啶（5-FU）或直接成5-氟二氢尿嘧啶的那部分。FUPA是5名志愿者中有4名在单次口服给药3.5克放射性标记药物后的前12小时内收集的尿液中发现的唯一代谢物。其最大比例为总放射活性的1.1%。第5名志愿者和3名念珠菌病患者（在至少2周的未标记5-FC[150 mg/kg/天]常规化疗后给予放射性剂量）的尿液中没有检测到代谢物。该方法的灵敏度阈值为总放射活性的0.1-0.4%。其中一名患者出现了可能由5-FC化疗引起的血小板减少症。大多数受检物种对5-FC不耐受的症状与5-FU观察到的症状相似[9]。然而，除了人类是代谢和毒性都最低的物种外，代谢物比例与5-FC毒性之间没有明显的定量相关性。尚未证明接受5-FC化疗的一小部分患者（主要是白细胞减少症、血小板减少症）出现的不耐受实际上是由于转化为5-FU。

Metabolism of 5-fluorocytosine-6-14C (5-FC) was studied in mice, rats, rabbits and dogs after oral and subcutaneous, single and repeated administration. In the urines of all species, intact 5-FC accounted for more than 90% of the total radioactivity at any time of the various treatment schedules. The average proportion of the urinary metabolites was around 5% in dogs, 3% in rabbits, 2.5% in rats, and 2% in mice of the total radioactivity. At repeated dosage, there was an increase of metabolites in mice but a decrease in rats treated subcutaneously. Neither increase nor decrease was observed in rabbits (treated orally) and dogs. Two metabolites were identified, alpha-fluoro-beta-ureido-propionic acid (FUPA) and alpha-fluoro-beta-alanine, the latter occurring mainly after oral treatment. These compounds represent probably that part of 5-FC which was deaminated to 5-fluorouracil (5-FU) or directly to 5-fluorodihydrouracil. FUPA was the only metabolite found in the urines collected from 4 out of 5 human volunteers during the first 12 h after single oral administration of 3.5 g of the radiolabelled drug. Its maximum proportion was 1.1% of the total radioactivity. No metabolites were detected in the urine neither of the 5th volunteer nor in those of 3 mycosis patients who were given the radioactive dose after they had received regular chemotherapy with unlabelled 5-FC (150 mg/kg/day) for at least 2 weeks. The sensitivity threshold of the method was 0.1-0.4% of the total radioactivity. One of the patients had developed thrombocytopenia which was probably due to 5-FC chemotherapy. The symptoms of 5-FC intolerance were in most of the examined species similar to those observed with 5-FU [9]. However, no quantitative correlation between proportion of metabolites and 5-FC toxicity is apparent except that man is the species in which both metabolism and toxicity are the lowest. It has not been proved yet that 5-FC intolerance occurring in a small percentage of patients receiving 5-FC chemotherapy (mainly leukopenia, thrombocytopenia) results in fact from conversion to 5-FU.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：氟胞嘧啶是一种固体。它被用作抗真菌剂和抗代谢物。氟胞嘧啶胶囊仅用于治疗由易感念珠菌和/或隐球菌引起的严重感染。人体研究：可以合理预期，过量使用可能会导致已知的临床不良反应显著表现。血清浓度长时间超过100微克/毫升可能会增加毒性事件的发生率，特别是胃肠道（腹泻、恶心、呕吐）、血液学（白细胞减少、血小板减少）和肝脏（肝炎）。在一例使用氟胞嘧啶治疗的患者中报告了尿结晶尿症。在接受该药物的患者中，约有6%-10%描述了与氟胞嘧啶相关的腹泻。有报告称，4名患者出现了可能致命的溃疡性肠炎。动物研究：在小鼠中，孕期第7天至第13天给予400毫克/千克/天的氟胞嘧啶与低发生率的腭裂有关，但无统计学意义。在兔中，孕期第6天至第18天给予最高100毫克/千克/天的氟胞嘧啶并未表现出致畸性。在大鼠中，孕期第7天至第13天给予40毫克/千克/天的氟胞嘧啶显示出致畸性（脊椎融合）。在更高剂量（700毫克/千克/天）下，在孕期第9天至第12天给药，报告了唇裂和腭裂以及小颌。子宫内治疗对小鼠后代的生育能力或生殖性能没有不利影响。在五种不同突变体的鼠伤寒沙门氏菌的Ames型研究中评估了氟胞嘧啶的致突变潜力，无论在激活酶的存在与否下，均未检测到致突变性。在三种不同的修复评估系统中，氟胞嘧啶均未表现出致突变性。

IDENTIFICATION AND USE: Flucytosine is a solid. It is used as antifungal agent and antimetabolite. Flucytosine Capsules are indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. HUMAN STUDIES: It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 ug/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis). A case of urinary crystalluria was reported in a patient during treatment with flucytosine. Flucytosine-associated diarrhea has been described in 6%-10% of patients receiving the drug. A potentially fatal ulcerating enterocolitis has been reported in 4 patients. ANIMAL STUDIES: In mice, 400 mg/kg/day of flucytosine administered on days 7 to 13 of gestation was associated with a low incidence of cleft palate that was not statistically significant. Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day administered on days 6 to 18 of gestation. Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day) administered on days 9 to 12 of gestation), cleft lip and palate and micrognathia were reported. The in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring in mice. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of Salmonella typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes. Flucytosine was nonmutagenic in three different repair assay systems.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

尽管确切的的作用机制尚不清楚，但据推测，氟胞嘧啶通过竞争性抑制嘌呤和嘧啶的摄取以及通过细胞内代谢为5-氟尿嘧啶间接作用于真菌。氟胞嘧啶通过胞嘧啶透酶进入真菌细胞；因此，氟胞嘧啶在真菌生物体内被代谢为5-氟尿嘧啶。5-氟尿嘧啶广泛地并入真菌RNA中，并抑制DNA和RNA的合成。其结果是真菌生物体生长失衡和死亡。它还似乎是一种真菌胸苷酸合成酶的抑制剂。

Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

在使用氟胞嘧啶治疗的患者中，多达41%的患者会出现轻至中度的血清转氨酶或碱性磷酸酶水平短暂升高。这些酶异常通常无症状，并在停用氟胞嘧啶后消失，有时甚至在继续使用氟胞嘧啶的情况下也会消失。临床上明显的肝毒性非常罕见。在氟胞嘧啶治疗的临床试验中提到了急性肝损伤和肝衰竭的实例，但提供的细节很少，且没有发表过令人信服的黄疸急性肝损伤的病例报告。

Transient mild-to-moderate elevations in serum aminotransferase or alkaline phosphatase levels occur in up to 41% of patients treated with flucytosine. The enzyme abnormalities are usually asymptomatic and resolve with stopping flucytosine, and sometimes even with its continuation. Clinically apparent hepatotoxicity is very rare. Instances of acute liver injury and hepatic failure have been mentioned in clinical trials of flucytosine therapy, but few details were provided and no convincing case reports of acute hepatic injury with jaundice have been published.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：氟胞嘧啶

Compound:flucytosine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

口服给药后迅速且几乎完全吸收。生物利用度为78%至89%。

Rapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%.

来源:DrugBank

吸收、分配和排泄

• 消除途径

氟胞嘧啶通过肾小球滤过从肾脏排出，没有明显的肾小管重吸收。小部分剂量通过粪便排出。

Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. A small portion of the dose is excreted in the feces.

来源:DrugBank

吸收、分配和排泄

氟胞嘧啶从胃肠道快速且良好地吸收，连续给药几天后的动物在1-2小时内血浆浓度达到峰值。药物在体内广泛分布，分布容积接近总体水含量。氟胞嘧啶与血浆蛋白的结合很少。它能够极好地渗透到体液中去，如脑脊液、滑液和房水。

Flucytosine is rapidly and well absorbed from the GI tract, with plasma levels peaking in 1-2 hr in animals that have received the drug for several days. The drug is widely distributed in the body, with a volume of distribution approximating the total body water. Flucytosine is minimally bound to plasma proteins. There is excellent penetration into body fluids such as the CSF, synovial fluids, and aqueous humor.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

氟胞嘧啶从胃肠道快速且几乎完全吸收。口服给药后的生物利用度为78-89%。食物降低了吸收速率，但并不影响吸收程度。

Flucytosine is rapidly and almost completed absorbed from the GI tract. Bioavailability is 78-89% following oral administration. Food decreases the rate, but not the extent, of absorption.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在有限数量的新生儿中，接受口服氟胞嘧啶治疗系统性念珠菌病，剂量为每天25、50或100毫克/千克，治疗5天后，中位峰值血清浓度分别为19.6、27.7和83.9微克/毫升，平均达到峰值浓度的时间为2.5小时。血清浓度在个体间有较大差异，且与胎龄无关，一些新生儿的血清氟胞嘧啶浓度超过100微克/毫升。

In a limited number of neonates receiving oral flucytosine in a dosage of 25, 50, or 100 mg/kg daily for the treatment of systemic candidiasis, median peak serum concentrations after 5 days of treatment were 19.6, 27.7, and 83.9 ug/mL, respectively, and the mean time to peak concentrations was 2.5 hours. There was considerable interindividual variation in serum concentrations, which did not correlate with gestational age, and some neonates had serum flucytosine concentrations greater than 100 ug/mL.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险等级：
  IRRITANT, LIGHT SENSITIVE
• 危险品标志：
  Xn
• 安全说明：
  S22,S24/25,S36/37,S45
• 危险类别码：
  R40
• WGK Germany：
  2
• 海关编码：
  2933599090
• 危险品运输编号：
  NONH for all modes of transport
• RTECS号：
  HA6040000
• 危险标志：
  GHS08
• 危险性描述：
  H361
• 危险性防范说明：
  P281
• 储存条件：
  请将贮藏器密封，并存放在阴凉、干燥处。同时，确保工作环境有良好的通风或排气设施。

SDS

Name:	5-Fluorocytosine 98% Material Safety Data Sheet
Synonym:
CAS:	2022-85-7

Section 1 - Chemical Product MSDS Name:5-Fluorocytosine 98% Material Safety Data Sheet
Synonym:

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Section 2 - COMPOSITION, INFORMATION ON INGREDIENTS

CAS#	Chemical Name	content	EINECS#
2022-85-7	5-Fluorocytosine		217-968-7

Hazard Symbols: XN
Risk Phrases: 40

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Section 3 - HAZARDS IDENTIFICATION
EMERGENCY OVERVIEW
Limited evidence of a carcinogenic effect.Light sensitive.
Potential Health Effects
Eye:
May cause eye irritation.
Skin:
May cause skin irritation.
Ingestion:
No hazard expected in normal industrial use.
Inhalation:
May cause respiratory tract irritation. The toxicological properties of this substance have not been fully investigated.
Chronic:
Prolonged or repeated exposure may cause adverse reproductive effects.

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Section 4 - FIRST AID MEASURES
Eyes: Flush eyes with plenty of water for at least 15 minutes, occasionally lifting the upper and lower eyelids. Get medical aid.
Skin:
Get medical aid. Flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes.
Ingestion:
Get medical aid. Wash mouth out with water.
Inhalation:
Remove from exposure and move to fresh air immediately. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical aid.
Notes to Physician:

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Section 5 - FIRE FIGHTING MEASURES
General Information:
As in any fire, wear a self-contained breathing apparatus in pressure-demand, MSHA/NIOSH (approved or equivalent), and full protective gear.
Extinguishing Media:
Use water spray, dry chemical, carbon dioxide, or chemical foam.

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Section 6 - ACCIDENTAL RELEASE MEASURES
General Information: Use proper personal protective equipment as indicated in Section 8.
Spills/Leaks:
Vacuum or sweep up material and place into a suitable disposal container.

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Section 7 - HANDLING and STORAGE
Handling:
Avoid breathing dust, vapor, mist, or gas. Avoid contact with skin and eyes. Store protected from light.
Storage:
Store in a cool, dry place. Store in a tightly closed container.
Keep refrigerated. (Store below 4C/39F.)

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Section 8 - EXPOSURE CONTROLS, PERSONAL PROTECTION
Engineering Controls:
Use adequate ventilation to keep airborne concentrations low.
Exposure Limits CAS# 2022-85-7: Personal Protective Equipment Eyes: Not available.
Skin:
Wear appropriate protective gloves to prevent skin exposure.
Clothing:
Wear appropriate protective clothing to prevent skin exposure.
Respirators:
Follow the OSHA respirator regulations found in 29 CFR 1910.134 or European Standard EN 149. Use a NIOSH/MSHA or European Standard EN 149 approved respirator if exposure limits are exceeded or if irritation or other symptoms are experienced.

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Section 9 - PHYSICAL AND CHEMICAL PROPERTIES

Physical State: Solid
Color: white
Odor: odorless
pH: Not available.
Vapor Pressure: Not available.
Viscosity: Not available.
Boiling Point: Not available.
Freezing/Melting Point: 296 deg C dec
Autoignition Temperature: Not available.
Flash Point: 296 deg C ( 564.80 deg F)
Explosion Limits, lower: Not available.
Explosion Limits, upper: Not available.
Decomposition Temperature: 296 deg C
Solubility in water: IN WATER: 1.5 G/100 ML (25C)
Specific Gravity/Density:
Molecular Formula:
Molecular Weight: 129.09

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Section 10 - STABILITY AND REACTIVITY
Chemical Stability:
Not available.
Conditions to Avoid:
Incompatible materials, light, excess heat, exposure to flame.
Incompatibilities with Other Materials:
Oxidizing agents.
Hazardous Decomposition Products:
Hydrogen cyanide, carbon monoxide, oxides of nitrogen, carbon dioxide, hydrogen fluoride gas.
Hazardous Polymerization: Has not been reported

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Section 11 - TOXICOLOGICAL INFORMATION
RTECS#:
CAS# 2022-85-7: HA6040000 LD50/LC50:
CAS# 2022-85-7: Oral, rat: LD50 = >15 gm/kg.
Carcinogenicity:
5-Fluorocytosine - Not listed by ACGIH, IARC, or NTP.
Other:
See actual entry in RTECS for complete information.

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Section 12 - ECOLOGICAL INFORMATION

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Section 13 - DISPOSAL CONSIDERATIONS
Dispose of in a manner consistent with federal, state, and local regulations.

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Section 14 - TRANSPORT INFORMATION

IATA
No information available.
IMO
No information available.
RID/ADR
No information available.

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Section 15 - REGULATORY INFORMATION

European/International Regulations
European Labeling in Accordance with EC Directives
Hazard Symbols: XN
Risk Phrases:
R 40 Limited evidence of a carcinogenic effect.
Safety Phrases:
S 36/37 Wear suitable protective clothing and
gloves.
S 45 In case of accident or if you feel unwell, seek
medical advice immediately (show the label where
possible).
WGK (Water Danger/Protection)
CAS# 2022-85-7: No information available.
Canada
None of the chemicals in this product are listed on the DSL/NDSL list.
CAS# 2022-85-7 is not listed on Canada's Ingredient Disclosure List.
US FEDERAL
TSCA
CAS# 2022-85-7 is not listed on the TSCA inventory.
It is for research and development use only.

---

SECTION 16 - ADDITIONAL INFORMATION
N/A

制备方法与用途

简介

5-氟胞嘧啶（5-FC）又称氟胞嘧啶、5-氟胞苷、安确治或安拉喷，是一种白色或类白色的结晶性粉末。它对真菌的抑制作用是通过进入敏感真菌细胞后，在胞核嘧啶脱氨酶的作用下脱去氨基形成抗代谢物——5-氟尿嘧啶（5-FU）。后者进一步转化为5-氟尿嘧啶脱氧核苷，从而抑制胸腺嘧啶核苷合成酶，阻止尿嘧啶脱氧核苷转变为胸腺嘧啶核苷，影响DNA的合成。它对念珠菌、隐球菌和地丝菌有良好的抑制作用，并且对部分曲菌以及引起皮肤真菌病的分支孢子菌、瓶真菌等也有一定的疗效。

应用

除了作为抗菌药外，5-氟胞嘧啶还是制备卡培西他滨的主要中间体。卡培西他滨能够抑制细胞分裂和干扰RNA及蛋白质合成，是一种可以在体内转化为5-FU的抗代谢氟嘧啶脱氧核苷氨基甲酸酯类药物。主要应用于治疗大肠肿瘤、结肠肿瘤、胰腺肿瘤以及转移性乳腺癌等。

不良反应

使用5-氟胞嘧啶可能出现恶心呕吐、厌食、腹泻、皮疹、发热、贫血、转氨酶升高及血细胞和血小板减少等症状。有时还会出现肝坏死、全血细胞减少、骨髓抑制或再生障碍性贫血等严重不良反应。

化学性质

5-氟胞嘧啶为白色或类白色的结晶粉末，具有微弱的气味。在水中溶解度约为1.2%（20℃），在乙醇中微溶；几乎不溶于氯仿和乙醚，在稀盐酸或稀氢氧化钠溶液中易溶。室温下稳定，遇冷析出结晶，加热部分会转变为5-氟尿嘧啶。

用途

作为一种抗真菌药，主要用于治疗皮肤黏膜念珠菌病、念珠菌性心内膜炎、念珠菌关节炎、隐球菌脑膜炎和着色真菌病等。在用药期间需要定期检查血象。肝肾功能不全、血液病患者以及孕妇需谨慎使用；严重肾功能不全的患者禁用。

5-氟胞嘧啶在国外被广泛用于治疗全身性白色念珠菌及隐球菌感染，可用于真菌性髓膜炎、真菌性呼吸道感染及黑色真菌症等疾病的治疗。

生产方法

1. 氯化：以抗癌药氟尿嘧啶为起始原料，在甲苯中加入二甲基苯胺并加热至50-60℃，滴加三氯氧磷，于105-110℃反应3小时后冷却至室温。

2. 水解：将上述产物与盐酸在100-105℃条件下反应3小时，减压浓缩后用水溶解，加入氨水调pH值至7-8，放置过夜。过滤、洗涤结晶经精制即得氟胞嘧啶成品。

另一种方法是使用2-甲氧基-4-羟基-5-氟嘧啶为原料，经氯化、氨化及水解反应得到产品，总收率为70%。该工艺路线更为高效。

反应信息

• 作为反应物：
  描述：

  氟胞嘧啶 在 cytosine deaminase 作用下， 生成 5-氟脲嘧啶
  参考文献：
  名称：

  Click Nucleic Acid Mediated Loading of Prodrug Activating Enzymes in PEG–PLGA Nanoparticles for Combination Chemotherapy

  摘要：

  同时向单一部位递送多种疗法已显示出癌症靶向和治疗的前景。然而，由于药物和生物分子之间电荷和大小的固有差异，需要新的方法来将不同成分共定位在一种运载工具中。在这项工作中，我们证明含有点击核酸（CNA）的三嵌段共聚物可用于在单个聚合物纳米颗粒中同时负载前药酶（胞嘧啶脱氨酶，CodA）和化疗药物（阿霉素，DOX）。 CNA 是 DNA 的合成类似物，由硫醇骨架和可与 DNA 互补链杂交的核苷酸碱基组成。在这项研究中，CodA 附加了互补的 DNA 序列和荧光染料，以使其封装在 PEG-CNA-PLGA 纳米颗粒中。使用改良的荧光测定法发现，DNA 修饰的 CodA 保留了将前药 5-氟胞嘧啶 (5-FC) 转化为活性 5-氟尿嘧啶 (5-FU) 的酶活性。然后将 DNA 缀合的 CodA 加载到 PEG-CNA-PLGA 纳米颗粒中，并在 5-FC 前药存在的情况下测试细胞毒性。为了研究在单个纳米颗粒内共同负载 DOX 和 CodA 的效果，进行了细胞毒性测定，以比较双重负载的纳米颗粒与仅负载 DOX 或 CodA 的纳米颗粒。我们发现，当 DOX 和 CodA 在 5-FC 存在的情况下同时被捕获并递送至细胞时，细胞死亡水平最高。

  DOI：

  10.1021/acs.biomac.9b00040
• 作为产物：
  描述：

  胞嘧啶 在 fluorine 、 1-丙基-3-甲基咪唑双（三氟甲烷磺酰）亚胺 作用下， 以97.1 %的产率得到氟胞嘧啶
  参考文献：
  名称：

  一种5-氟胞嘧啶制备的方法

  摘要：

  本发明涉及一种5‑氟胞嘧啶的制备方法，所述制备方法包括：原料胞嘧啶和氟气在催化剂的作用下，发生氟化反应获得5‑氟胞嘧啶，所述催化剂为离子液体，选自咪唑类离子液体、吡啶类离子液体、吡咯烷类离子液体或哌啶类离子液体中的至少一种。本发明具有产物选择性高、反应效率高、适于工业化生产等优点。

  公开号：

  CN117050023A
• 作为试剂：
  描述：

  (1R,2S,5R)-2-异丙基-5-甲基环己基 (2R,5R)-5-乙酰氧基-1,3-恶噻戊环-2-羧酸酯 、 氟胞嘧啶 在 氟胞嘧啶 作用下， 以91的产率得到(5S)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate
  参考文献：
  名称：

  [EN] PROCESS AND INTERMEDIATES FOR PREPARING EMTRICITABINE
  [FR] PROCEDE ET INTERMEDIAIRES POUR PREPARER DE L'EMTRICITABINE

  摘要：

  本发明涉及一种制备恩曲他滨的新工艺，更具体地说，涉及一种制备恩曲他滨的工艺，其特征在于以盐化形式形成和分离中间化合物。

  公开号：

  WO2004085432A1

文献信息

• [EN] NOVEL MODULATORS OF CELL CYCLE CHECKPOINTS AND THEIR USE IN COMBINATION WITH CHECKPOINT KINASE INHIBITORS<br/>[FR] NOUVEAUX MODULATEURS DE POINTS DE CONTRÔLE DU CYCLE CELLULAIRE ET LEUR UTILISATION EN COMBINAISON AVEC DES INHIBITEURS DE KINASE DE POINT DE CONTRÔLE
  申请人：SCHERING CORP

  公开号：WO2009061781A1

  公开（公告）日：2009-05-14

  In its many embodiments, the present invention provides a novel class of pyrimidine analogs of formula (V) as targeted mechanism-based modulators of cell cycle checkpoints. Cancers and/or malignancies can be treated by administration of a cell cycle checkpoint modulator of the invention. Also discussed are suitable combinations of the cell cycle checkpoint modulator with a checkpoint kinase inhibitor to produce synergistic apoptosis in cancer cells. The invention includes methods of treating cancers by administering the combination of the cell cycle checkpoint modulator and the checkpoint kinase inhibitor, pharmaceutical compositions comprising the activator as well as the combination and pharmaceutical kits.

  在其多种实施方式中，本发明提供了一类新型的嘧啶类似物，其化学式为（V），作为细胞周期检查点的靶向机制调节剂。可以通过给予本发明的细胞周期检查点调节剂来治疗癌症和/或恶性肿瘤。还讨论了适当的细胞周期检查点调节剂与检查点激酶抑制剂的组合，以在癌细胞中产生协同凋亡。该发明包括通过给予细胞周期检查点调节剂和检查点激酶抑制剂的组合来治疗癌症的方法，以及包含激活剂以及该组合的药物组合和药物配套工具。
• [EN] TARGETED THERAPEUTICS<br/>[FR] THÉRAPEUTIQUE CIBLÉE
  申请人：SYNTA PHARMACEUTICALS CORP

  公开号：WO2015038649A1

  公开（公告）日：2015-03-19

  The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.

  本发明提供了包括与将效应子导向至感兴趣的生物靶点的结合基团共轭的药理化合物。同样，本发明提供了包括这些化合物的组合物、试剂盒和方法（例如治疗、诊断和成像）。这些化合物可以被描述为蛋白质相互作用结合基团-药物共轭（SDC-TRAP）化合物，其中包括蛋白质相互作用结合基团和效应子。例如，在针对治疗癌症的某些实施方式中，SDC-TRAP可以包括Hsp90抑制剂共轭到细胞毒性药剂作为效应子。
• [EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF FUNGAL INFECTIONS<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE TRAITEMENT D'INFECTIONS FONGIQUES
  申请人：CELLIX BIO PRIVATE LTD

  公开号：WO2018096497A1

  公开（公告）日：2018-05-31

  The invention relates to the compounds or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or Formula X and, the methods for the treatment of fungal infections may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fungal infections.

  该发明涉及化合物或其药用可接受的多型体、溶剂合物、对映体、立体异构体及其水合物。包括有效量的I式、II式、III式、IV式、V式、VI式、VII式、VIII式、IX式或X式化合物的药物组合物，以及用于治疗真菌感染的方法可以制备为口服、颊部、直肠、局部、经皮、经粘膜、含片、喷雾、静脉注射、口服溶液、颊粘膜层片剂、肠外给药、糖浆或注射剂。这些组合物可用于治疗真菌感染。
• Synthesis, structure and rearrangement of iodinated imidazo[1,2- c ]pyrimidine-5(6 H )-ones derived from cytosine
  作者：Josef Jansa、Antonín Lyčka、Aleš Růžička、Martin Grepl、Jan Vaněček

  DOI：10.1016/j.tet.2014.11.049

  日期：2015.1

  8-substituted imidazo[1,2-c]pyrimidine-5(6H)-ones (ethenocytosines). Starting ethenocytosines were obtained by cyclization of 5-halogenocytosines with chloroacetaldehyde or by subsequent Suzuki–Miyaura cross-coupling between 8-iodoimidazo[1,2-c]pyrimidine-5(6H)-one 1d and corresponding arylboronic acids. When imidazo[1,2-c]pyrimidine-5(6H)-one or 8-iodoimidazo[1,2-c]pyrimidine-5(6H)-one 1d was iodinated

  我们描述了各种8-取代的咪唑并[1,2 - c ]嘧啶-5（6 H）-ones（ethenocytosines）的温和和选择性碘化。通过将5-卤代胞嘧啶与氯乙醛环化或随后的Suzuki-Miyaura交叉偶联在8-碘咪唑并[1,2 - c ]嘧啶-5（6 H）-1d和相应的芳基硼酸中获得起始的胞嘧啶。当咪唑并[1,2 Ç ]嘧啶5（6 ħ） -酮或8碘咪唑并[1,2- c ^ ]嘧啶5（6 ħ） -酮1D通过碘化Ñ在DMF碘代丁二酰亚胺（NIS） ，纯3,8-二碘代衍生物2d获得了。在碱性或酸性条件下，该分子会重排为2,8-二十二烷基衍生物3d，随后可将其碘代为2,3,8-三十二烷基衍生物4d。由于仅通过NMR光谱不能令人信服地确定碘原子在咪唑环上的位置，因此对2d进行X射线分析以毫无疑问地确认其结构。将相同的反应顺序应用于另外八个乙炔胞嘧啶，可提供出色的区域选择性，易重排和高产率的碘化产物。通过1
• N1-acyl-5-fluoropyrimidinone derivatives
  申请人：Boebel Timothy A.

  公开号：US20110034490A1

  公开（公告）日：2011-02-10

  This present disclosure is related to the field of N1-acyl-5-fluoropyrimidinones and their derivatives and to the use of these compounds as fungicides.

  本公开涉及N1-酰基-5-氟嘧啶酮及其衍生物领域，以及将这些化合物用作杀真菌剂的用途。

表征谱图