替来他明 | 14176-49-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 中文名称: 替来他明
• 中文别名: 替莱他明,乙胺噻吩环己酮；乙胺噻吩环己酮；替莱他明
• 英文名称: Tiletamine
• 英文别名: 2-(ethylamino)-2-(2-thienyl)cyclohexanone；2-ethylamino-2-(2-thienyl)-cyclohexanone；2-(ethylamino)-2-thiophen-2-ylcyclohexan-1-one
• CAS: 14176-49-9
• 化学式: C₁₂H₁₇NOS
• 分子量: 223.339
• InChiKey: QAXBVGVYDCAVLV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  57.3
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

毒理性

• 相互作用

北极熊（Ursus maritimus）三种药物组合的心肺效应进行了研究。1995年，五只成年北极熊接受肌肉注射，分别注射了8.2 ± 1.3 mg/kg的泰拉唑（Telazol）或159 ± 34 μg/kg的美托咪定（medetomidine）与4 ± 0.8 mg/kg的氯胺酮（ketamine）的组合，采用交叉设计。使用美托咪定-氯胺酮组合时，平均动脉压显著更高，心率更低，动脉血氧分压（Pao2）更低。1996年，六只成年北极熊接受肌肉注射，分别注射了8.2 ± 2 mg/kg的佐拉唑仑-替来他明（zolazepam-tiletamine）或74.8 ± 11.8 μg/kg的美托咪定加上2.2 ± 0.3 mg/kg的佐拉唑仑-替来他明组合，采用交叉设计。与单独使用佐拉唑仑-替来他明相比，美托咪定-佐拉唑仑-替来他明组合导致了显著更高的平均动脉压和更低的心率、碱剩余和PaO2。高血压、心动过缓和PaO2降低在使用美托咪定-氯胺酮和美托咪定-佐拉唑仑-替来他明组合时都被观察到。这两种组合对健康的熊应该是可以很好耐受的，但两者都有可能在心肺疾病的动物中产生不良反应。佐拉唑仑-替来他明产生了最小的心肺不良反应，这与这种组合在熊身上的宽安全边际一致。根据对有害刺激后心率和平均动脉压显著增加的情况来看，佐拉唑仑-替来他明的镇痛效果显然较差。

The cardiopulmonary effects of three drug combinations in polar bears (Ursus maritimus) were studied. In 1995, five adult polar bears received im injections of either 8.2 +/- 1.3 mg/kg of Telazol or a combination of 159 +/- 34 ug/kg of medetomidine with 4 +/- 0.8 mg/kg of ketamine in a crossover design. Significantly higher mean arterial pressure, lower heart rate, and lower partial pressure of arterial oxygen (Pao2) occurred with medetomidine-ketamine. In 1996, six adult polar bears were immobilized with im injections of either 8.2 +/- 2 mg/kg of zolazepam-tiletamine or a combination of 74.8 +/- 11.8 ug/kg of medetomidine plus 2.2 +/- 0.3 mg/kg of zolazepam-tiletamine in a crossover design. Significantly higher mean arterial pressure and lower heart rate, base excess, and PaO2 occurred with medetomidine-zolazepam-tiletamine compared with zolazepam-tiletamine alone. Hypertension, bradycardia, and decreased PaO2 were observed with both medetomidine-ketamine and medetomidine-zolazepam-tiletamine. Both combinations should be well tolerated by healthy bears, but both have the potential to produce adverse effects in animals with cardiopulmonary disease. Zolazepam-tiletamine produced minimal adverse cardiopulmonary effects, consistent with the wide margin of safety of this combination in bears. The analgesic effect of zolazepam-tiletamine was apparently poor on the basis of the marked increases in pulse rate and mean arterial pressure after noxious stimuli.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

被训练来区分苯环利定和生理盐水的老鼠被用来测试各种药物模仿或阻断苯环利定信号的能力。发现氯胺酮、得克萨斯罗尔、替来他明和苯环利定类似物能够模仿苯环利定的行为效应。使用腺苷受体激动剂N6-环己基腺苷和L-苯异丙基腺苷的治疗阻断了苯环利定的鉴别特性...

Rats trained to discriminate between phencyclidine and saline vehicle were used to test various agents for their ability to mimic or block the phencyclidine cue. Ketamine, dexoxadrol, tiletamine, and phencyclidine analogs were found to mimic phencyclidine's behavioral effects. Treatment with the adenosine receptor agonists N6-cyclohexyladenosine and L-phenylisopropyladenosine blocked the discriminative properties of phencyclidine...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

研究了tiletamine/zolazepam、propofol以及tiletamine/zolazepam加propofol对五只杂种狗的心血管和肺功能的影响。通过插入升主动脉的导管连续测量平均动脉压（MAP）和心率，并收集动脉血以确定pH、PO2、PCO2、碳酸氢盐和碱平衡。同时记录呼吸频率和直肠温度。在两个propofol组中，预给药对拔除气管导管的时间和对胸部恢复仰卧位的时间没有显著影响。单独使用tiletamine/zolazepam和tiletamine/zolazepam加propofol后，MAP和心率升高，而单独使用propofol则降低了MAP并短暂增加了心率。在两个propofol组中，呼吸频率短暂下降，伴随着PaCO2的显著升高和PaO2的降低。最显著的变化是在tiletamine/zolazepam加propofol组中出现的低氧血症，其中PaO2降低。所有单独给予tiletamine/zolazepam的狗都出现了不良副作用，这些副作用也发生在给予tiletamine/zolazepam加propofol的狗恢复期间。

The cardiovascular and pulmonary effects of tiletamine/zolazepam, propofol and tiletamine/zolazepam plus propofol were studied in five mongrel dogs. A cannula inserted into a raised carotid artery was used to measure mean arterial pressure (MAP) and heart rate continuously and to collect arterial blood for the determination of pH, PO2, PCO2, bicarbonate and base balance. Respiratory frequency and rectal temperature were also recorded. In the two propofol groups premedication had no significant effect on the time to rejection of an endotracheal tube and the return to sternal recumbency. The MAP and heart rate increased after tiletamine/zolazepam alone and after tiletamine/zolazepam plus propofol, although propofol alone reduced MAP and transiently increased heart rate. Respiratory frequency decreased transiently in both propofol groups in association with a significant increase in PaCO2 and decrease in PaO2. The most notable change was the hypoxemia in the tiletamine/zolazepam plus propofol group in which the PaO2 was reduced. In all the dogs given tiletamine/zolazepam alone undesirable side effects were observed, effects which also occurred during the recovery of the dogs given tiletamine/zolazepam plus propofol.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

研究了单独使用替来他明-唑拉西泮或与赛拉嗪或布托啡诺联合使用时，在成年雄性大鼠中的抗痛觉性质，使用尾部 flick 测试。在大鼠腹腔注射无菌水、戊巴比妥钠、吗啡、替来他明-唑拉西泮、赛拉嗪、布托啡诺以及替来他明-唑拉西泮加赛拉嗪或布托啡诺后15、45和75分钟，测定尾部 flick 潜伏期的变化。吗啡处理的大鼠在注射后15-75分钟，尾部 flick 潜伏期接近100%的最大可能效应（MPE）。单独使用替来他明-唑拉西泮、赛拉嗪和布托啡诺，在任何使用的剂量下，产生的MPE均小于50%。然而，替来他明-唑拉西泮与布托啡诺或赛拉嗪联合使用时，尾部 flick 潜伏期的增加大约是单独使用替来他明-唑拉西泮的三倍。这些结果表明：a) 与早期发现一致，镇痛和麻醉是独立的状态；b) 替来他明-唑拉西泮不是一种有效的镇痛组合；但c) 与适当的药物联合使用时，它可以展现出强大的抗痛觉性质。

The antinociceptive properties of tiletamine-zolazepam alone or combined with xylazine or butorphanol were determined in the adult male rat using the tail-flick test. Changes in tail-flick latency were determined at 15, 45, and 75 min after IP drug administration of sterile water, sodium pentobarbital, morphine, tiletamine-zolazepam, xylazine, butorphanol, and tiletamine-zolazepam plus xylazine or butorphanol. Tail-flick latency approximated 100% maximum possible effect (MPE) at 15-75 min postinjection in morphine-treated rats. Tiletamine-zolazepam, xylazine, and butorphanol alone, at any dose utilized, produced less than 50% MPE. However, the combination of tiletamine-zolazepam with butorphanol or xylazine increased tail-flick latency approximately three times greater than tiletamine-zolazepam alone. These results demonstrate that: a) consonant with earlier findings, analgesia and anesthesia are independent states; b) tiletamine-zolazepam is not an effective combination with respect to analgesia; but c) in concert with appropriate drugs, it can exhibit potent antinociceptive properties.

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，让患者身体前倾或将其置于左侧（如果可能，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。寻求医疗救助。 /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)

吸收、分配和排泄

为了评估加拿大北极地区因摄入了镇定剂泰拉唑（由盐酸替来他明和盐酸佐拉唑仑混合而成）的北极熊对人类食用所构成的风险，进行了一项药物动力学和组织残留研究。二十二头北极熊被远程注射了大约10毫克/公斤的泰拉唑。在北极熊被麻醉后，定期在常规时间间隔内连续收集血清样本，直到北极熊醒来。其中十六头北极熊在用药后0.5至11天内的不同时间被当地猎人根据许可重新定位并杀死。北极熊死亡后立即收集血清、肾脏、肌肉和脂肪组织样本。...此外，收集的血清和组织样本在死亡时被分析，以检测原药、替来他明的一个代谢物（CI-398）以及佐拉唑仑的三个代谢物（代谢物1、2和4）。一室模型，包括一级吸收和消除，最能拟合麻醉期间血清中药物的时间序列数据。该模型给出的替来他明和佐拉唑仑的半衰期（平均值±标准误）分别为1.8±0.2小时和1.2±0.08小时，清除率分别为2.1±0.3升×小时^-1×公斤^-1和1.1±0.1升×小时^-1×公斤^-1，分布体积分别为5.2±0.6升/公斤和1.8±0.2升/公斤。两种药物及其代谢物的浓度在用药后24小时内迅速下降到微量水平，尽管在整个采样期间偶尔会遇到某些代谢物的极低浓度。特别是，佐拉唑仑代谢物2在研究结束时，即用药后11天，在脂肪和肌肉组织中仍然可以被检测到。研究结论是，在麻醉期间，替来他明和佐拉唑仑的水平迅速以单指数方式下降，北极熊的药物动力学参数与在其他物种中观察到的相似。药物及其代谢物在组织中的水平下降得足够快，以至于食用受暴露北极熊肉的人不太可能经历药物的药理作用。尽管如此，在用药后的一段时间内，仍可能轻微接触到药物及其代谢物。

A pharmacokinetic and tissue residue study was conducted to assess the risks associated with human consumption of polar bears in arctic Canada that have been exposed to the immobilizing drug Telazol, a mixture of tiletamine hydrochloride and zolazepam hydrochloride. Twenty-two bears were remotely injected with about 10 mg/kg of Telazol. Following immobilization, serum samples were collected serially at regular intervals until the bears awakened. Sixteen of the bears were relocated and killed under permit by local hunters at various times from 0.5 to 11 days after dosing. Serum, kidney, muscle and adipose tissue samples were collected immediately after death. ... In addition, the serum and tissue samples collected at the time of death were analyzed for both parent drugs, for one metabolite of tiletamine (CI-398), and for three metabolites of zolazepam (metabolites 1, 2 and 4). A one-compartment model with first-order absorption and elimination best fit the time-series data for the drugs in serum during the immobilization period. This model gave half-lives (mean +/- SE) for tiletamine and zolazepam of 1.8+/-0.2 hr and 1.2+/-0.08 hr, respectively, clearance values of 2.1+/-0.3 l x hr(-1) x kg(-1) and 1.1+/-0.1 l x hr(-1) x kg(-1), and volumes of distribution of 5.2+/-0.6 L/kg and 1.8+/-0.2 L/kg. The concentrations of both drugs and their metabolites declined rapidly to trace levels by 24 hr post-dosing, although extremely low concentrations of some metabolites were encountered sporadically over the entire sampling period. In particular, zolazepam metabolite 2, remained detectable in fat and muscle tissue at the end of the study, 11 days after dosing. It was concluded that during immobilization, both tiletamine and zolazepam levels decline rapidly in a monoexponential fashion, and their pharmacokinetic parameters in polar bears are similar to those observed in other species. Tissue levels of the drugs and their metabolites declined sufficiently rapidly that individuals eating meat from exposed bears would be unlikely to experience pharmacological effects from the drugs. Nevertheless, slight exposure to the drugs and/or their metabolites might be possible for an indeterminate time after dosing.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  替来他明 在 盐酸 作用下， 以 乙醚 、 水 为溶剂， 反应 2.0h， 以100%的产率得到盐酸替来他明
  参考文献：
  名称：

  N-（苯甲酰氧基）烯酰胺的顺序[3,3]-正向重排/亲核酰化反应制备环状β-芳基-β-氨基醇

  摘要：

  摘要 已开发出一种新方法，可通过N-（苯甲酰氧基）烯酰胺的[3,3]-σ重排，然后与α-苯甲酸进行亲核芳基化反应，高效合成带有四取代碳中心的环状β-芳基-β-氨基醇衍生物。三芳基铝试剂的范围。将所得产物转化为相应的空间拥挤的环状β-氨基醇以及解离麻醉剂Tiltamine。 已开发出一种新方法，可通过N-（苯甲酰氧基）烯酰胺的[3,3]-σ重排，然后与α-苯甲酸进行亲核芳基化反应，高效合成带有四取代碳中心的环状β-芳基-β-氨基醇衍生物。三芳基铝试剂的范围。将所得产物转化为相应的空间拥挤的环状β-氨基醇以及解离麻醉剂Tiltamine。

  DOI：

  10.1055/s-0035-1561294
• 作为产物：
  描述：

  2-硝基环己酮 在 sodium cyanoborohydride 、 potassium carbonate 、 溶剂黄146 、 锌 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 2.17h， 生成 替来他明
  参考文献：
  名称：

  硝基酮与二芳基碘鎓盐的无过渡金属α-芳基化反应，用于合成叔α-芳基，α-硝基酮†

  摘要：

  首次实现了带有二芳基碘鎓盐的无过渡金属的α-硝基酮的α-芳基化。作为该方法的一种应用，还可以通过三步操作从2-硝基环己酮中合成三丁胺，从而实现临床药物tiletamine的简明合成，而无需分离中间体。

  DOI：

  10.1039/c8cc08920e

文献信息

• [EN] IMIDAZOTHIADIAZOLE AND IMIDAZOPYRAZINE DERIVATIVES AS PROTEASE ACTIVATED RECEPTOR 4 (PAR4) INHIBITORS FOR TREATING PLATELET AGGREGATION<br/>[FR] DÉRIVÉS D'IMIDAZOTHIADIAZOLE ET D'IMIDAZOPYRAZINE UTILISÉS COMME INHIBITEURS DU RÉCEPTEUR 4 ACTIVÉ PAR UNE PROTÉASE (PAR4) POUR LE TRAITEMENT DE L'AGRÉGATION PLAQUETTAIRE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2013163279A1

  公开（公告）日：2013-10-31

  The present invention provides thiazole compounds of Formula I wherein W, Y, R0, R2, R4, R5, R6, R7, X1, X2, X3 and X4 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are inhibitors of platelet aggregation and thus can be used as medicaments for treating or preventing thromboembolic disorders.

  本发明提供了式I的噻唑化合物，其中W、Y、R0、R2、R4、R5、R6、R7、X1、X2、X3和X4如本文所定义，或其立体异构体、互变异构体、药学上可接受的盐、前药酯或溶剂化合物形式，其中所有变量均如本文所定义。这些化合物是血小板聚集抑制剂，因此可用作治疗或预防血栓栓塞性疾病的药物。
• ANTHELMINTIC COMPOUNDS AND COMPOSITIONS AND METHOD OF USING THEREOF
  申请人：Meng Charles Q.

  公开号：US20140142114A1

  公开（公告）日：2014-05-22

  The present invention relates to novel anthelmintic compounds of formula (I) below: wherein Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.

  本发明涉及以下式（I）的新型驱虫化合物： 其中 Y和Z分别是双环碳环或双环杂环基团，或者Y或Z中的一个是双环碳环或双环杂环基团，另一个是烷基，烯基，炔基，环烷基，苯基，杂环基或杂芳基，以及变量X 1 ，X 2 ，X 3 ，X 4 ，X 5 ，X 6 ，X 7 和X 8 如本文所定义。本发明还提供了包含本发明的驱虫化合物的兽药组合物，以及它们用于治疗和预防动物寄生虫感染的用途。
• Novel Bicyclic Pyridinones
  申请人：Pettersson Martin Youngjin

  公开号：US20120252758A1

  公开（公告）日：2012-10-04

  Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I as defined herein. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

  所述化合物及其药用可接受的盐被披露，其中所述化合物具有如本文所定义的Formula I的结构。相应的药物组合物、治疗方法、合成方法和中间体也被披露。
• [EN] ANTHELMINTIC DEPSIPEPTIDE COMPOUNDS<br/>[FR] COMPOSÉS DEPSIPEPTIDIQUES ANTHELMINTHIQUES
  申请人：MERIAL INC

  公开号：WO2018093920A1

  公开（公告）日：2018-05-24

  The present invention provides cyclic depsipeptide compounds of formula (I) wherein the stereochemical configuration of at least one carbon atom bearing the groups Cy1, Cy2, R1, R2, R3, R4, Ra and Rb is inverted compared with the naturally occurring cyclic depsipeptide PF1022A. The invention also provides compositions comprising the compounds that are effective against parasites that harm animals. The compounds and compositions may be used for combating parasites in or on mammals and birds. The invention also provides for an improved method for eradicating, controlling and preventing parasite infestation in birds and mammals.

  本发明提供了公式（I）的环状脱氨肽化合物，其中至少一个碳原子的立体化学构型与自然存在的环状脱氨肽PF1022A的基团Cy1、Cy2、R1、R2、R3、R4、Ra和Rb相比发生了倒置。该发明还提供了包含这些化合物的组合物，对危害动物的寄生虫具有有效性。这些化合物和组合物可用于对抗哺乳动物和鸟类体内或体表的寄生虫。该发明还提供了一种改进的方法，用于根除、控制和预防鸟类和哺乳动物的寄生虫感染。
• [EN] A NEW CLASS OF MU-OPIOID RECEPTOR AGONISTS<br/>[FR] NOUVELLE CLASSE D'AGONISTES DU RÉCEPTEUR MU-OPIOÏDE
  申请人：UNIV COLUMBIA

  公开号：WO2015138791A1

  公开（公告）日：2015-09-17

  The present invention provides a compound having the structure (I) or a pharmaceutically acceptable salt or ester thereof.

  本发明提供了一种具有结构（I）的化合物或其药用可接受的盐或酯。

表征谱图