纽甜 | 165450-17-9

• 物质功能分类: 食品添加剂 - 甜味剂
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 纽甜
• 中文别名: 新特姆；N-[N-(3,3-二甲基丁基)-L-Α-天门冬氨酰]-L-苯丙氨酸1-甲酯；N-[N-(3,3-二甲基丁基)-L-ALPHA-天门冬氨酰]-L-苯丙氨酸1-甲酯；N-[N-(3,3-二甲基丁基)-L-alpha-天门冬氨酰]-L-苯丙氨酸1-甲酯；N-[N-(3,3-二甲基丁基)-L-ALPHA-天门冬氨酰]-L-苯丙氨酸 1-甲酯
• 英文名称: neotame
• 英文别名: N-(3,3-dimethylbutyl)-L-α-aspartyl-L-phenylalanine 1-methyl ester；(3S)-3-(3,3-dimethylbutylamino)-4-[[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid；N-[N-(3,3-dimethylbutyl)-l-α-aspartyl]-L-phenylalanine 1-methyl ester；N-(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methyl ester；N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine methyl ester；(3S)-3-(3,3-dimethylbutylazaniumyl)-4-[[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoate
• CAS: 165450-17-9
• 化学式: C₂₀H₃₀N₂O₅
• 分子量: 378.469
• InChiKey: HLIAVLHNDJUHFG-HOTGVXAUSA-N

物化性质

• 熔点：
  83-85°C
• 比旋光度：
  D -54.84° (c = 1 in methanol); D20 -39.8° (c = 0.5 in water)
• 沸点：
  565.3±50.0 °C(Predicted)
• 密度：
  1.133±0.06 g/cm3(Predicted)
• 溶解度：
  氯仿（微溶）、乙醇（微溶）、乙酸乙酯（微溶）、甲醇
• LogP：
  3.834 (est)
• 物理描述：
  white to off-white powder
• 味道：
  Clean sweet taste without bitter, metallic or off flavors
• 蒸汽压力：
  2.71X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：

  The degradation of neotame was assessed at an artificially high concentration of 200 ppm in mock beverages containing phosphate- and citrate-buffered solutions simulating formulations used in commercial cola soft drinks (pH 2.8 and 3.2) lemon-lime soft drink (pH 3.8) and root beer soft drink (pH 4.5), and covered a range of temperatures (5, 20, 30, and 35 °C) and storage for up to 8 weeks. These conditions simulated typical commercial, as well as extreme, storage conditions for beverages, with respect to temperature and time. Dependency on pH, time, and temperature was assessed for all degradation products of neotame. Higher concentrations of neotame were used to allow detection of low concentrations of degradation products. The use of higher concentrations of neotame was justified on the basis of similar kinetic profiles for neotame at 200 ppm and 15 ppm, a concentration relevant to intended use. The principle degradation product of neotame at concentrations of intended use or at the much higher concentrations used in mock beverage formulations was de-esterified neotame. It comprised approximately 7% of the initial amount of neotame after storage for 8 weeks at 20 °C, pH 3.2. Hydrolysis of neotame to de-esterified neotame occurs slowly and is dependent upon pH and temperature. In addition to de-esterified neotame, three minor degradation products were detected, specifically N-(N-(3,3-dimethylbutyl)-L-aspartamidyl)-L-phenylalanine 1-methyl ester formed by cyclization of neotame, N-(N-(3,3-dimethylbutyl)-L-beta-aspartyl)-L-phenylalanine 1-methyl ester formed by beta-rearrangement of neotame, and N-(N-(3,3-dimethylbutyl)-L-aspartamidyl)-L-phenylalanine formed by methyl ester hydrolysis of N-(N-(3,3-dimethylbutyl)-L-aspartamidyl)-L-phenylalanine 1-methyl ester. These minor degradation products represented <1% of the initial concentration of neotame of 200 ppm after 8 weeks of storage at 20 °C. When the initial concentration of neotame was 15 ppm, these products could not be detected.

• 解离常数：
  pKa1 = 4.11; pKa2 = 7.70; pKa3 = 6.45

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  27
• 可旋转键数：
  12
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  6

ADMET

代谢

新甜素（Neotame）在其二甲丁基侧链的1位上标记了碳-14，并在同一侧链的2个末端甲基上标记了碳-13。志愿者在水中共服用了相当于0.25毫克/千克的标记试验物质的单剂量，这相当于将1升饮料加甜所需的新甜素量。新甜素被迅速但不完全吸收，并且被迅速排出。平均来说，给药的放射性物质中有98%在尿液和粪便中被回收，大多数在给药后72小时内。新甜素的平均血浆浓度在0.4小时达到峰值...并且以0.6小时的半衰期下降。新甜素的主要代谢物是通过甲基酯基水解形成的去酯新甜素。这种代谢物的平均血浆浓度在1小时达到峰值...并且比新甜素浓度高出大约2.5倍，以1.5小时的半衰期下降。去酯新甜素平均约占排泄剂量的80%。还有两种其他代谢物在剂量中占1%以上。其中一种，平均约占剂量的4.9%，在粪便中被发现，被鉴定为N-(3,3-二甲基丁基)-L-天冬氨酸。另一种代谢物在尿液中，通过LC/MS/MS、NMR和原始合成被鉴定为3,3-二甲基丁酸 carnitine 酯。所有在剂量中占1%或更多的新甜素代谢物都在安全性研究中使用的物种中被发现，这证实了这些代谢物的安全性。

... Neotame was labelled with Carbon-14 at the 1-position in the dimethylbutyl side chain and with Carbon-13 in the 2 terminal methyl groups of the same side chain. ... Volunteers ingested a single dose of the labelled test substance in water at a level approximately equivalent to 0.25 mg/kg, which corresponds to the amount of neotame needed to sweeten 1 L of beverage. Neotame was rapidly, but incompletely absorbed and rapidly excreted. A mean of 98% of the administered radioactivity was recovered in urine and feces, mostly within 72 hours of dosing. Mean plasma concentrations of neotame peaked at 0.4 hr ... and declined with a half-life of 0.6 hr. The major metabolite of neotame was de-esterified neotame formed by hydrolysis of the methyl ester group. Mean plasma concentrations of this metabolite peaked at 1 hr ... /and/ were approximately 2.5 times higher than neotame concentrations and declined with a half-life of 1.5 hr. De-esterified neotame represented a mean of approximately 80% of the excreted dose. Two other metabolites were detected at greater than 1% of the dose. One, that was a mean of about 4.9% of the dose, was found in the feces and was identified as N-(3, 3 dimethylbutyl)-L aspartic acid. The other metabolite was in urine and was identified by LC/MS/MS, NMR and original synthesis as a carnitine ester of 3, 3-dimethylbutanoic acid. All metabolites of neotame present at 1% or greater of the dose have been shown to occur in the species used in safety studies, confirming the safety of these metabolites.

来源:Hazardous Substances Data Bank (HSDB)

代谢

作为安全性测试的一部分，进行了一项研究，以评估新甜味剂在大鼠和狗体内的吸收、分布、药代动力学、代谢和排泄。为此，新甜味剂在其侧链的1位上用碳-14进行了标记，并以15或120毫克/千克体重的剂量给动物服用。在大鼠和狗中，新甜味剂的口服剂量被迅速但未完全吸收，并迅速排出体外，没有积聚的迹象。在大鼠中，吸收的碳-14主要与胃肠道和代谢及排泄器官（肝脏、肾脏和膀胱）相关。在给大鼠口服给药后，几乎未在（稳定的）血浆或.../排泄物/中检测到新甜味剂。这可能是由于血浆酯酶活性高。新甜味剂的主要代谢物是通过甲基酯基的水解形成的去酯新甜味剂。在大鼠中，这种代谢物的平均血浆浓度在0.5小时达到峰值...并以1小时的半衰期下降。在血浆酯酶活性较低的狗中，口服给药后在血浆中和.../排泄物/中检测到了新甜味剂。新甜味剂的平均血浆浓度在0.5小时达到峰值...并以0.4小时的半衰期下降。去酯新甜味剂在大鼠和狗的排泄口服剂量中平均约占70-80%。检测到的其他代谢物包括N-(3,3-二甲基丁基)-L-天冬氨酸（在大鼠和狗中约占剂量的2%）和3,3-二甲基丁酸的二葡萄糖苷酸共轭物（在大鼠和狗中约占剂量的5%）。此外，3,3-二甲基丁酸 carnitine 酯也出现在雌性大鼠的尿液中。

... As part of the safety testing, studies were conducted to evaluate the absorption, distribution, pharmacokinetics, metabolism and excretion of neotame in laboratory rats and dogs. For this purpose, neotame was labelled with Carbon-14 at the 1-position in the dimethylbutyl side chain and was administered to animals at doses of 15 or 120 mg/kg body weight. In rats and dogs, oral doses of neotame were rapidly, but incompletely absorbed and rapidly excreted with no evidence of potential for accumulation. In rats, absorbed Carbon-14 was mainly associated with the gastrointestinal tract and organs of metabolism and excretion (liver, kidney and bladder). Almost no neotame was detected in (stabilised) plasma or .../excretions/ after oral dosing to rats. This was probably due to high activity of plasma esterases. The major metabolite of neotame was de-esterified neotame formed by hydrolysis of the methyl ester group. In rats, mean plasma concentrations of this metabolite peaked at 0.5 hr ...and declined with a half life of 1 hr. In dogs, which have a lower level of plasma esterase activity, neotame was detected in plasma and ... /excretions/ after oral dosing. Mean plasma concentrations of neotame peaked at 0.5 hr ... and declined with a half-life of 0.4 hr. Deesterified neotame represented a mean of approximately 70-80% of excreted oral doses in both rats and dogs. Other metabolites detected included N-(3, 3 dimethylbutyl)- L aspartic acid (in rats and dogs about 2% of the dose) and a beta-glucuronide conjugate of 3, 3-dimethylbutanoic acid (in rats and dogs about 5% of the dose). In addition the carnitine ester of 3, 3-dimethylbutanoic acid was present in the urine of female rats.

来源:Hazardous Substances Data Bank (HSDB)

代谢

经口服给药后，大约20-30%的给药剂量被吸收，并迅速转化为主要代谢物N-(N-(3,3-二甲基丁基)-L-α-天冬氨酰)-L-苯丙氨酸（去酯化新甜味剂）和若干次要代谢物。新甜味剂及其代谢物迅速通过尿液和粪便排出体外。新甜味剂的主要代谢途径是去酯化成N-[N-(3,3-二甲基丁基)-L-α-天冬氨酰]-L-苯丙氨酸和甲醇。次要代谢物包括N-(3,3-二甲基丁基)-L-天冬氨酸，这是通过新甜味剂的肽或酰胺水解形成的代谢物；3,3-二甲基丁酸，也称为3,3-二甲基丁酸；3,3-二甲基丁酸的肉碱共轭物；以及3,3-二甲基丁酸的葡萄糖醛酸共轭物。

After oral administration, approximately 20-30% of the administered dose is absorbed and rapidly converted to the major metabolite, N-(N-(3,3-dimethylbutyl)-L-alpha-aspartyl)-L-phenylalanine (de-esterified neotame) and a number of minor metabolites. Neotame and its metabolites are rapidly eliminated in the urine and feces. ... The major metabolic pathway is de-esterification of neotame to N-[N-(3,3-dimethylbutyl)-L-alpha-aspartyl]-L-phenylalanine and methanol. Minor metabolites are N-(3,3-dimethylbutyl)-L-aspartic acid, a metabolite formed via peptide or amide hydrolysis of neotame; 3,3-dimethylbutyric acid, also referred to as 3,3-dimethylbutanoic acid; the carnitine conjugate of 3,3-dimethylbutyric acid; and the glucuronide conjugate of 3,3-dimethylbutyric acid.

来源:Hazardous Substances Data Bank (HSDB)

代谢

14(C)-新甜味剂通过灌胃或静脉注射的方式给予六只雄性和六只雌性Sprague-Dawley Crl:CDBR大鼠，单次剂量为15 mg/kg体重。大鼠单独饲养在代谢笼中，给药后72小时内定期收集尿液和粪便。另外三只大鼠接受单次口服剂量120 mg/kg体重。所有大鼠在给药72小时后处死，尸体保留用于分析。所有样本中测量放射性标记，并确定尿液中存在的代谢物。... 48小时后尿液中发现的主要代谢物是去酯新甜味剂，与给药途径或剂量无关。N-(3,3-二甲基丁基)-L-天冬氨酸(NC-00754)在较低浓度下被检测到（约为口服给药后去酯新甜味剂水平的10%）。母体化合物仅在静脉给药后雌性大鼠的尿液中被发现（剂量的3.7%）；其他任何一组大鼠的尿液中均未检测到。尿液中还检测到一种低水平的葡萄糖苷酸代谢物（占给药剂量的0.4-0.5%），与剂量或给药途径无关。还鉴定出两种次要代谢物，每种代谢物占给药剂量的<1.6%。在粪便中，去酯新甜味剂是主要的代谢物（口服给药后约占总剂量的70-80%）。N-(3,3-二甲基丁基)-L-天冬氨酸(NC-00754)的检测水平较低，占给药剂量的0.8-2.5%。还发现了代表给药剂量0.7-1.2%的未知代谢物的低浓度。

14(C)-neotame was administered to groups of six male and six female Sprague-Dawley Crl:CDBR rats by gavage or by intravenous injection as a single dose of 15 mg/kg bw. Rats were individually housed in metabolism cages and urine and feces were collected at intervals for 72 hr after dosing. A additional group of three rats received a single oral dose of 120 mg/kg bw. All rats were killed after 72 hr and the carcasses were retained for analysis. Radiolabel was measured in all samples and the metabolites present in the urine and feces were determined. ... The major metabolite found in urine after 48 hr was de-esterified neotame, independent of the route of administration or the dose. N-(3,3-dimethylbutyl)-L-aspartic acid (NC-00754) was detected at lower concentrations (around 10% of the levels of de-esterified neotame after oral dosing). Parent compound was found only in the urine of female rats after intravenous dosing (3.7% of the dose); none was detected in the urine of any other groups. A glucuronide metabolite was also detected at low levels (0.4-0.5% of the administered dose) in the urine, independent of dose or route of administration. Two minor metabolites, each representing <1.6% of the administered dose, were identified. In the feces, de-esterified neotame was the major metabolite (approximately 70-80% of the dose after oral administration). N(3,3dimethylbutyl)Laspartic acid (NC-00754) was detected at lower levels, 0.8-2.5% of the dose. Low concentrations of an unidentified metabolite were also found, representing 0.7-1.2% of the administered dose.

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和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，按训练操作。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。如果患者呕吐，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：对于无意识、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"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。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……。使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

• 人类毒性摘录

/人体暴露研究/ 在一项为期两周的男性和女性耐受性研究中，新甜素被给予74名健康成人（平均年龄±标准差，32±10岁）。该研究是随机的、双盲的、安慰剂对照的，并使用纳入和排除标准来选择合适的受试者。72名健康男女被随机分为三组，每组24人（12男性和12女性）。两名因与测试文章给药无关的原因被剔除的受试者被同性别的人替代。这些组以0、0.5 mg/kg bw/天或1.5 mg/kg bw/天的剂量服用新甜素胶囊，分为三次等分剂量（分别在07:00、12:00和17:00给予）。男女受试者前往诊所服用每一剂并进食标准化的餐点。第一次早晨的剂量在至少8小时的夜间禁食后进行。在第一次给药前测定体重。在给药日的第1、3、5、7、9、11和14天的早晨剂量前测定坐位血压、体温、脉搏率和呼吸率。在第1、3和7天给药前采集用于临床病理学检查的血液。在第1、2、3、4、7、11和15天采集血液样本以确定新甜素和去酯新甜素的浓度。将血浆分离并冷冻储存以备后续分析。在第1和7天给药前进行尿液药物筛查。在第1和3天给药前进行心电图（ECG）检查，并在第7天进行体检（包括体重测量）。监测男女受试者是否有不良体验或不寻常的症状。治疗结束后进行体检。在最后一份血液样本收集后，测量生命体征和体重，并进行眼科检查、ECG和临床实验室检测。在开始研究的74人（70名白人、1名西班牙裔、1名中东人和2名亚洲人）中，72人成功完成了研究。两名受试者未能完成研究，这与新甜素的给药无关。女性的平均年龄为33岁（范围，20-53岁），男性为31岁（范围，20-53岁）。在整个研究过程中记录了一系列的临床症状。最常见的发现是头痛，即对照组5名男性中有8次头痛，0.5 mg/kg bw/天组7名男性中有16次头痛，1.5 mg/kg bw/天组4名男性中有10次头痛。对照组和0.5 mg/kg bw/天组报告了腹泻，但在1.5 mg/kg bw/天组中未报告。0.5 mg/kg bw/天组1名男性和1.5 mg/kg bw/天组2名男性报告了腹痛。这些临床症

/HUMAN EXPOSURE STUDIES/ In a two-week study of tolerance in men and women, neotame was administered to 74 healthy adults (mean age +/ - SD, 32 +/ - 10 years). The study was randomized, double-blind, and placebo-controlled, and inclusion and exclusion criteria were used to select appropriate subjects. Seventy-two healthy men and women were randomized into three groups of 24 subjects (12 male and 12 female). Two subjects were dropped for reasons unrelated to administration of the test article and were replaced by subjects of the same sex. The groups received neotame at a dose of 0, 0.5 mg/kg bw per day, or 1.5 mg/kg bw per day in capsules, as three divided doses (given at 07:00, 12:00 and 17:00). The men and women attended the clinic to receive each dose and to eat a standardized meal. The first morning dose followed an overnight fast of at least 8 hr. Body weight was determined before the first dose. The sitting blood pressure, temperature, pulse rate and respiratory rate were determined before the morning dose on days 1, 3, 5, 7, 9, 11 and 14. Blood for clinical pathology was taken before dosing on days 1, 3 and 7. Blood samples were taken to determine concentrations of neotame and de-esterified neotame on days 1, 2, 3, 4, 7, 11 and 15. Plasma was separated and stored frozen for later analysis. A screen for drugs in urine was done before dosing on days 1 and 7. An electrocardiogram (ECG) was performed before dosing on days 1 and 3, and a physical examination (including measurement of body weight) was carried out on day 7. Men and women were monitored for adverse experiences or unusual symptoms. A physical examination was done after treatment. Vital signs and body weight were measured, and an ophthalmological examination, ECG and clinical laboratory tests were performed after the last blood sample had been collected. Of the 74 (70 Caucasian, 1 Hispanic, 1 Middle-Eastern and 2 Asian) persons starting the study, 72 successfully completed the study. The failure of two subjects to complete the study was unrelated to administration of neotame. The mean age was 33 (range, 20-53) years for women, and 31 (range, 20-53) years for men. A range of clinical symptoms was documented throughout the study. The most common finding was headache, namely, eight headaches in five men in the control group, 16 headaches in seven men at 0.5 mg/kg bw per day and 10 headaches in four men at 1.5 mg/kg bw per day. Diarrhea was reported in controls and at 0.5 mg/kg bw per day, but was not reported at 1.5 mg/kg bw per day. Abdominal pain was reported in one man at 0.5 mg/kg bw per day and two men at 1.5 mg/kg bw per day. None of these clinical symptoms required medical intervention, and most were considered mild to moderate, although four headaches were documented as severe. These clinical symptoms could not be linked to ingestion of neotame. There were no treatment-related changes in clinical pathology parameters, heart rate, blood pressure, respiratory rate, temperature, body weight or ECG. On analysis of blood samples, concentrations of neotame were below the level of quantification at all time periods. Plasma concentrations of de-esterified neotame were approximately proportional to administered dose. In men and women, plasma concentrations of de-esterified neotame reached steady state after 24 hr and 72 hr, respectively. On the basis of this study, neotame was well tolerated in humans when administered at a dose of up to 1.5 mg/kg bw for a period of 2 weeks.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

人体暴露研究/进行了一项研究，以评估健康男性通过溶液摄入新甜味剂单剂量的耐受性。新甜味剂的安全性是以逐步的方式评估的，从最低剂量开始，然后是中间剂量，最后在高剂量，只有在确认了较低剂量的安全性之后。19名健康男性（平均年龄±SD，28±6岁）分别单次剂量摄入0.10、0.25或0.50 mg/kg bw（每个剂量分别有七人、六人、六人）的新甜味剂溶液。该研究是随机的，单剂量，非双盲的。每位男性在隔夜禁食后只接受一种治疗方案。18名男性完成了研究；由于静脉通路不佳，排除了一名男性。在给药前和给药后大约48小时进行临床评估和实验室检测。在脉搏率或血压方面没有与治疗相关的变化，在血液学、临床化学或尿液分析参数方面也没有变化。两名男性经历了轻微头痛，一名在给药前，一名在每日0.1 mg/kg bw剂量后。在每日0.5 mg/kg bw剂量下，另外两名男性也有轻微头痛，一名在给药前，一名在给药后，还有一名出现下背痛。这些症状在没有进一步治疗的情况下解决，并不认为是新甜味剂给药所致。

/HUMAN EXPOSURE STUDIES/ A study was conducted to evaluate tolerance of a single dose of neotame ingested in solution by healthy men. The safety of neotame was evaluated in a stepwise fashion, starting with the lowest dose, followed by the intermediate dose and then the high dose only after safety at lower doses had been confirmed. Nineteen healthy men (mean age +/ - SD, 28 +/ - 6 years) were given single doses of 0.10, 0.25, or 0.50 mg/kg bw (seven, six, six men per dose, repectively) of neotame in solution. The study was randomized, single dose and not double-blinded. Each man received only one treatment regimen after an overnight fast. Eighteen men completed the study; one man was excluded due to poor venous access. Clinical evaluations and laboratory tests were done immediately before dosing and approximately 48 hr after dosing. There were no treatment-related changes in pulse rate or blood pressure, and no changes in haematology, clinical chemistry or urine analysis parameters. Two men experienced mild headaches, one before dosing and one after a dose of 0.1 mg/kg bw per day. At 0.5 mg/kg bw per day, another two men had mild headaches, one before dosing and one after, and one had lower back pain. These signs resolved without further treatment and were not attributed to dosing with neotame.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

14C-新甜味剂通过灌胃或静脉注射的方式给予六只雄性和六只雌性Sprague-Dawley Crl:CDBR大鼠，单次剂量为15 mg/kg体重。大鼠单独饲养在代谢笼中，给药后72小时内定期收集尿液和粪便。另外三只大鼠接受单次口服剂量120 mg/kg体重。所有大鼠在72小时后处死，尸体保留用于分析。所有样本中测量放射性标记，并确定尿液和粪便中的代谢物。口服给药后，48小时内尿液和粪便中回收的放射性标记物>90%。口服给药14C-新甜味剂15或120 mg/kg体重后72小时内，分别有8.5-10.8%和84.5-87.2%的放射性标记物通过尿液和粪便排出。静脉给药14C-新甜味剂15 mg/kg体重后，大约35%和59%的放射性标记物分别通过尿液和粪便回收。无论是口服还是静脉给药，72小时内尸体中回收的放射性标记物均小于0.3%。未改变的14C-新甜味剂仅在静脉给药后0-6小时内从雌性大鼠尿液中检测到，占给药剂量的3.7%。无论剂量或给药方式如何，任何动物的粪便中均未检测到未改变的14C-新甜味剂。

14(C)-neotame was administered to groups of six male and six female Sprague-Dawley Crl:CDBR rats by gavage or by intravenous injection as a single dose of 15 mg/kg bw. Rats were individually housed in metabolism cages and urine and feces were collected at intervals for 72 hr after dosing. A additional group of three rats received a single oral dose of 120 mg/kg bw. All rats were killed after 72 hr and the carcasses were retained for analysis. Radiolabel was measured in all samples and the metabolites present in the urine and feces were determined. After oral administration, >90% of the radiolabel was recovered in urine and faeces within 48 hr. Within 72 hr after oral administration of (14)C-neotame at a dose of 15 or 120 mg/kg bw, 8.5-10.8% and 84.5-87.2% of the radiolabel was excreted in the urine and feces, respectively. After intravenous administration of (14)C-neotame at dose of 15 mg/kg bw, approximately 35% and 59% of the radiolabel was recovered in urine and feces, respectively. Less than 0.3% of the radiolabel was recovered in the carcasses within 72 hr after either oral or intravenous administration. Unchanged neotame was only detected in urine collected from female rats 0-6 h after intravenous administration and accounted for 3.7% of the administered dose. Unchanged neotame was not detected in the feces of any animal regardless of the dose or route of administration.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

Sprague-Dawley Crl:CDBRVAF Plus大鼠被给予单次口服剂量15 mg/kg bw的(14)C-纽甜，并通过灌胃分成四组。第1组的大鼠（每性别三只），在处理后24小时内间隔取血，分离成细胞和血浆部分，并分析放射性标记。第2组的大鼠（每性别两只）在处理后72小时内被安置在玻璃代谢笼中，收集尿液、粪便和呼出的空气。尸体被溶解以分析保留的放射性标记，尿液和粪便被合并以分析代谢物以及总放射性标记。第3组的大鼠（每性别两只）在给药后0.5小时或2小时被麻醉，并收集血液进行分析。第4组的大鼠（两只雄性）被麻醉，并插管胆管和胃。通过胃管给予放射性标记的纽甜，并在处理后48小时内间隔收集胆汁。收集0-24小时和24-48小时的尿液和粪便，并测量放射性标记。口服(14)C-纽甜后，血浆中放射性标记的浓度在雌性大鼠给药后30分钟达到峰值，在雄性大鼠给药后1小时达到峰值，随后迅速下降。在血浆、尿液、粪便和胆汁中鉴定出的主要代谢物是去酯化的纽甜。(14)C-纽甜的排泄在72小时内进行了检查；8-10%的放射性标记在尿液中回收，90-92%在粪便中，0.01-0.03%在呼出的空气中。72小时后，0.11-0.13%的放射性标记残留在尸体中。在雄性大鼠中，尿液排泄在12小时内几乎完成，而在雌性大鼠中，尿液排泄持续超过24小时。大多数粪便排泄在两性的给药后6小时到24小时之间发生。在第4组的雄性大鼠中，尿液排泄与其他组相似，大约5-9%的给药剂量通过尿液排泄。胆汁排泄约占给药剂量的5.7%，而粪便排泄约占给药剂量的85%。尸体中保留的放射性标记很少。

Sprague-Dawley Crl:CDBRVAF Plus rats were each given a single oral dose of 15 mg/kg bw of (14)C-neotame by gavage and divided among four groups. In rats in group 1 (three rats of each sex), blood was taken at intervals up to 24 hr after treatment, separated into cell and plasma fractions, and analysed for radiolabel. Rats in group 2 (two rats of each sex) were housed in glass metabolism cages for 72 hr after treatment for collection of urine, feces and expired air. Carcasses were solubilized for analysis of retained radiolabel, and urine and feces were pooled for analysis of metabolites as well as total radiolabel. In group 3 (two rats of each sex), rats were anesthetized 0.5 hr or 2 hr after dosing, and blood was collected and analysed. Rats in group 4 (two males) were anesthetized and the bile ducts and stomach cannulated. Radiolabelled neotame was administered via the stomach cannula, and bile was collected at intervals up to 48 hr after treatment. Urine and feces were collected for 0-24 hr and 24-48 hr and radiolabel was measured. Plasma concentrations of radiolabel after oral dosing with (14)C-neotame peaked at 30 min after dosing in females and 1 h after dosing in males, followed by a rapid decline. The major metabolite identified in plasma, urine, feces and bile was de-esterified neotame. The excretion of (14)C-neotame was examined over 72 hr; 8-10% of the radiolabel was recovered in urine, 90-92% in feces, and 0.01-0.03% in expired air. After 72 hr, 0.11-0.13% of the radiolabel remained in the carcass. In males, urinary excretion was virtually complete within 12 hr, while in females, urinary excretion continued over 24 hr. Most fecal excretion occurred between 6 hr and 24 hr after dosing in both sexes. In males in group 4, urinary excretion was similar to that seen in other groups, with around 5-9% of the administered dose being excreted in the urine. Biliary excretion accounted for approximately 5.7% of the administered dose, while fecal excretion accounted for around 85% of the administered dose. Little radiolabel was retained in the carcass.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项旨在通过全身放射性自显影检查源自纽甜的放射活性的分布和消除的研究中，八只怀孕和八只未怀孕的Sprague-Dawley大鼠分别通过灌胃给予单次剂量的14C-纽甜，剂量为15 mg/kg体重。在大鼠给药后不同时间点至24小时处死，并像前一项研究那样处理尸体。放射性同位素在怀孕和未怀孕大鼠体内的分布相似。给药后0.5小时和2小时，胎盘中的放射性同位素浓度较低，类似于在其他外周组织和循环血液中看到的。在任何时间点都没有在胎儿中检测到放射性同位素。放射性同位素最高浓度在给药后不久出现，最初在胃内容物、胃肠 tract、肝脏、肾脏和膀胱中，而身体其他部位的浓度较低。在随后的时间点，可以看到放射性同位素通过排泄器官的传递。没有在组织中看到积累，24小时后浓度非常低。在放射性同位素在组织中分布的时间轮廓方面，怀孕和未怀孕大鼠之间没有显著差异。

In a study designed to examine the distribution and elimination of radioactivity derived from neotame by whole-body autoradiography, eight pregnant and eight non-pregnant Sprague-Dawley rats were each given a single dose of 15 mg/kg bw of (14)C-neotame by gavage. The rats were sacrificed at various times up to 24 hr after dosing and the carcasses treated as in the previous study. The tissue distribution of radiolabel was similar in pregnant and non-pregnant rats. Placental concentrations of radiolabel were low at 0.5 and 2 hr after dosing, similar to those seen in other peripheral tissues and in circulating blood. No radiolabel was detected in the fetus at any time. The highest concentrations of radiolabel were seen shortly after dosing, initially in the stomach contents, gastrointestinal tract, liver, kidneys and bladder, with lower concentrations in the rest of the body. At subsequent time-points, the passage of radiolabel through the excretory organs was seen. No accumulation was seen in tissues, and concentrations were very low after 24 hr. There was no significant difference between pregnant and non-pregnant rats in the time profile with which radiolabel was distributed in the tissues

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项研究中，为了检验新甜味剂在大鼠组织中的分布情况，给21只雄性Lister Hooded大鼠单次口服给予了14C-新甜味剂，剂量为15毫克/千克体重。在给予药物0.5、2、6、12和24小时后，每对大鼠（一雄一雌）被处死，迅速冷冻，并通过六个层面的尸体横断面进行放射自显影检查。对雄性和雌性大鼠中存在的放射性标记进行定性评估表明，在大鼠给药后最早时间点处死的大鼠中含量最高。随着时间的推移，含量迅速下降。在给药后0.5小时和2小时，大部分放射性标记物发现于胃、胃肠道、肝脏、肾脏和膀胱，较小量的放射性标记物分布在整个身体的其他部位。在中枢神经系统中发现了非常小的量，没有观察到与色素性皮肤或眼睛的结合。这些水平与血液循环中的放射性标记物流转一致。在随后时间点（6、12和24小时），可以看到放射性标记物通过排泄器官的排出。在给药后24小时，动物体内只剩下非常小的量，并且没有在任何组织中积聚的证据。

In a ... study to examine the distribution of neotame in rat tissues, 21 male Lister Hooded rats were given (14)C-neotame in a single oral dose of 15 mg/kg bw by gavage. Pairs of rats (one of each sex) were killed after 0.5, 2, 6, 12 and 24 hr, pinned out, frozen rapidly, and sagittal sections taken through the carcass at six levels were examined by autoradiography. Qualitative assessment of radiolabel present in male and female rats indicated that the highest levels were present in rats killed at the earliest time-points after dosing. Levels decreased rapidly with time. At 0.5 hr and 2 hr after dosing, most radiolabel was found in the stomach, the gastrointestinal tract, liver, kidneys and bladder, with smaller amounts being distributed throughout the rest of the body. Very small amounts were found in the central nervous system, and no binding to pigmented skin or the eye was observed. Levels were consistent with the circulation of radiolabel in the bloodstream. At subsequent time-points (6, 12 and 24 hr), the passage of radiolabel through the excretory organs was seen. By 24 hr after dosing, only very small amounts remained in the animal and there was no evidence of accumulation in any tissue.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  S24/25
• WGK Germany：
  3
• 海关编码：
  2924299090
• 危险品运输编号：
  NONH for all modes of transport
• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  室温

SDS

1.1 产品标识符
: Neotame
产品名称
1.2 鉴别的其他方法
N-[N-(3,3-Dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester
1.3 有关的确定了的物质或混合物的用途和建议不适合的用途
仅供科研用途，不作为药物、家庭备用药或其它用途。

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模块 2. 危险性概述
2.1 GHS分类
根据化学品全球统一分类与标签制度(GHS)的规定，不是危险物质或混合物。
2.3 其它危害物 - 无

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模块 3. 成分/组成信息
3.1 物 质
: N-[N-(3,3-Dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester
别名
: C ₂₀ H ₃₀ N ₂ O ₅

制备方法与用途

纽甜是一种人工合成的甜味剂,由美国Kemin公司开发并获得专利。根据您提供的信息,以下是关于纽甜的一些关键点:

1. 特性:

• 非常甜(约2000倍于蔗糖)
• 可用于多种食品和饮料
• 不含卡路里
• 增强某些水果风味

2. 优点:

• 安全无毒,通过正常代谢排出体外
• 对所有人群安全,包括儿童、孕妇等
• 使用灵活,可单独使用或与其他甜味剂混合
• 可用于延长食品保质期

3. 消化与代谢:

• 主要以原形形式经尿液和粪便排出
• 一小部分被氧化生成肉碱酯类物质排出
• 不会积累在体内
• 含量很低时可忽略苯丙氨酸含量问题

4. 安全性:

• 大量研究证明安全无害
• 无致突变、致畸或致癌风险
• 对生殖和目标器官无毒性

5. 应用领域:

• 可用于各种食品饮料
• 在淀粉类食品中可抑制老化
• 在蛋白质食品中可保持良好口感

6. 我国卫生部批准:

• 2003年10月,中国卫生部正式批准纽甜作为甜味剂在各类食品和饮料中使用

总的来说,纽甜是一种安全有效的非营养性甜味剂,具有广阔的应用前景。

反应信息

• 作为反应物：
  描述：

  纽甜 在 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 1.5h， 以79%的产率得到N-(3,3-二甲基丁基)-L-α-门冬氨酰-L-苯丙氨酸
  参考文献：
  名称：

  Crystal structure and physical characterization of N-(3,3-dimethylbutyl)-l-α-aspartyl-l-phenylalanine, the hydrolysis product of neotame

  摘要：

  新甜菊糖的水解产物N-(3,3-二甲基丁基)-L-α-天冬氨酰-L-苯丙氨酸（DMBAP）从水中结晶为无水物，熔点为197℃，并会分解。其晶体结构通过单晶X射线衍射测定。晶体为正交晶系，空间群为P212_121，Z=4，每个不对称单元有一个分子。晶胞常数为a=5.520 (2) Å，$b=10.608$ (5) Å，c= 31.92 (2) Å。将DMBAP的13C固体核磁共振谱与新甜菊糖一水合物和新甜菊糖甲醇溶剂化物的13C核磁共振谱进行了比较。

  DOI：

  10.1007/s10870-005-2962-5
• 作为产物：
  描述：

  L-苯丙氨酸甲酯 在 吡啶 、 四溴化碳 、 palladium on activated carbon 、 氢气 、 sodium cyanoborohydride 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 30.0h， 生成 纽甜
  参考文献：
  名称：

  通过吡啶-CBr4 的新型羧酸光活化模式直接形成酰胺键的高效光介导方案

  摘要：

  提出了利用吡啶-CBr 4的新型光活化模式，由羧酸和胺或氨基酸UVA光介导合成酰胺。DI-HRMS 的机理研究为各种中间体的形成提供了实验证据。展示了在工业上有趣的或生物活性化合物的合成中的应用。

  DOI：

  10.1002/chem.202300556

文献信息

• [EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2017197240A1

  公开（公告）日：2017-11-16

  Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

  本文提供了ASH1L活性的小分子抑制剂，促进ASH1L降解的小分子以及它们的使用方法，用于治疗疾病，包括急性白血病、实体肿瘤和其他依赖于ASH1L活性的疾病。
• [EN] NOVEL COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS
  申请人：UCL BUSINESS LTD

  公开号：WO2019243841A1

  公开（公告）日：2019-12-26

  The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as modulators of alpha 1 antitrypsin and treating diseases associated with alpha antitrypsin, particularly liver diseases.

  本发明涉及含有所述化合物的化合物、组合物、组合物和药物以及其制备方法。该发明还涉及所述化合物、组合物、组合物和药物的用途，例如作为α1抗胰蛋白酶的调节剂和用于治疗与α抗胰蛋白酶相关的疾病，特别是肝脏疾病。
• COMPOUNDS THAT MODULATE INTRACELLULAR CALCIUM
  申请人：Whitten Jeffrey P.

  公开号：US20110263612A1

  公开（公告）日：2011-10-27

  Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.

  本文描述了含有这些化合物的化合物和药物组合物，这些化合物调节储存操作钙（SOC）通道的活性。本文还描述了使用这种SOC通道调节剂的方法，单独或与其他化合物结合，用于治疗需要抑制SOC通道活性的疾病或症状。
• [EN] cGAS ANTAGONIST COMPOUNDS<br/>[FR] COMPOSÉS ANTAGONISTES DU CGAS
  申请人：IMMUNE SENSOR LLC

  公开号：WO2017176812A1

  公开（公告）日：2017-10-12

  Disclosed are novel compounds of Formula (I) that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.

  揭示了一种新型化合物的化学式（I），这些化合物是cGAS拮抗剂，涉及到这些化合物的制备方法、包含这些化合物的药物组合物，以及它们在医学治疗中的应用。
• [EN] COMPOUNDS AND COMPOSITIONS FOR OCULAR DELIVERY<br/>[FR] COMPOSÉS ET COMPOSITIONS POUR ADMINISTRATION OCULAIRE
  申请人：GRAYBUG VISION INC

  公开号：WO2020069353A1

  公开（公告）日：2020-04-02

  The present invention provides new prodrags of Sunitinib, Brinzolamide, and Dorzolamide and compositions to treat medical disorders, for example glaucoma, a disorder or abnormality related to an increase in intraocular pressure (TOP), a disorder requiring neuroprotection, age-related macular degeneration, or diabetic retinopathy.

  本发明提供了新的Sunitinib、Brinzolamide和Dorzolamide的前药，以及用于治疗医学疾病的组合物，例如青光眼、与眼内压增高有关的疾病或异常（TOP）、需要神经保护的疾病、年龄相关性黄斑变性或糖尿病视网膜病变。