Octreotide | 83150-76-9

• 物质功能分类: 原料药 - 激素及调节内分泌功能类药 - 其它
• 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
• 英文名称: Octreotide
• 英文别名: Octreotida [Spanish]；(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-[[(2R)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-N-[(2R,3R)-1,3-dihydroxybutan-2-yl]-7-(1-hydroxyethyl)-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide
• CAS: 83150-76-9；79517-01-4
• 化学式: C₄₉H₆₆N₁₀O₁₀S₂
• 分子量: 1019.26
• InChiKey: DEQANNDTNATYII-RRCPSWKPSA-N

物化性质

• 熔点：
  153-156°C
• 比旋光度：
  D20 -42° (c = 0.5 in 95% acetic acid)
• 溶解度：
  可溶于水中
• 物理描述：
  Liquid

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  71
• 可旋转键数：
  17
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  383
• 氢给体数：
  13
• 氢受体数：
  14

ADMET

毒理性

• 肝毒性

轻微的、短暂的、无症状的血清转氨酶水平升高发生在接受奥曲肽治疗的小部分患者中，有些人转氨酶水平升高持续存在，并随着时间的推移而恶化，可能需要停药。此外，已经描述了几例归因于奥曲肽的急性、临床上明显的肝损伤。发病通常在开始治疗后的1到6个月内，并且随着剂量增加，损伤可能更频繁。与奥曲肽治疗相关的肝损伤大多数是无症状和非黄疸的，以血清ALT和AST显著升高为特征，血清碱性磷酸酶、GGT和胆红素正常或接近正常。然而，在某些情况下，尤其是在重新挑战时，会出现黄疸。尚无急性肝衰竭或消失性胆管综合征与奥曲肽相关的实例，并且损伤的特征之一是停止注射或输注后迅速改善。在连续输注高剂量奥曲肽治疗的新生儿和婴儿中，已经报告了几例转氨酶显著升高并在停止治疗后迅速改善的情况。 奥曲肽会导致胆囊收缩力抑制和胆汁分泌减少，长期治疗与胆结石形成的高发生率相关。在前瞻性研究中，接受维持性奥曲肽治疗的肢端肥大症患者中，有25%至65%的患者通过超声检查发现胆结石，其中一部分患者发展为有症状的胆石症，需要住院和胆囊切除术。即使在胆囊切除术后，胆总管和肝内胆管也可能形成胆固醇结石，导致症状、败血症发作和需要部分肝切除术。尽管熊去氧胆酸治疗可能有所帮助，但它似乎并不能预防奥曲肽治疗期间的胆结石形成。奥曲肽还与急性胰腺炎有关，这可能是由于它对胃肠道激素释放的抑制作用，尽管其他病例可能是由于胆结石通过和胰腺导管阻塞。 可能性评分：C（可能是临床上明显肝损伤的原因）。

Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in a small proportion of patients receiving octreotide, and in some individuals the elevations are persistent and worsen over time and may require drug discontinuation. In addition, several instances of acute, clinically apparent liver injury attributable to octreotide have been described. The onset is generally within 1 to 6 months of starting therapy and injury may be more frequent with higher doses. Most cases of liver injury associated with octreotide therapy have been asymptomatic and anicteric, and marked by prominent elevations in serum ALT and AST with normal or near normal serum alkaline phosphatase, GGT and bilirubin. In some instances, however, jaundice has arisen, particularly with rechallenge. There have been no instances of acute liver failure or vanishing bile duct syndrome associated with octreotide, and a characteristic feature of the injury is the rapidity of improvement upon stopping the injections or infusions. Several instances of marked aminotransferase elevations with rapid improvements on stopping have been reported in newborns and infants with congenital hyperinsulinemia who were treated with continuous infusions of high doses of octreotide. Octreotide causes inhibition of gall bladder contractility and decrease in bile secretion, and long term therapy is associated with a high rate of cholesterol gallstone formation. In prospective studies, between 25% and 65% of patients with acromegaly treated with maintenance octreotide developed gallstones detected by ultrasonography and a proportion developed symptomatic cholelithiasis requiring hospitalization and cholecystectomy. Even after cholecystectomy, cholesterol stones may form in the common bile duct and intrahepatic ducts causing symptoms, episodes of sepsis and need for partial hepatic resection. Therapy with ursodiol does not appear to prevent gallstone formation during octreotide therapy, although it may help. Octreotide has also been associated with acute pancreatitis, which may be due to its inhibitory effect on gastrointestinal hormone release, although other cases may be secondary to passage of gall bladder stones and pancreatic duct obstruction. Likelihood score: C (probable cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：奥曲肽进入母乳的情况尚未进行研究。然而，由于其分子量高达1019道尔顿，它很可能不易被排入母乳中。它口服吸收不良，已经通过注射直接安全地给予婴儿，因此不太可能对哺乳婴儿产生不利影响。至少有3名婴儿成功母乳喂养，没有报告不良反应。在获得更多数据之前，应谨慎在哺乳母亲中使用奥曲肽，并密切监测婴儿，特别是如果婴儿年龄在2个月以下。 ◉ 对哺乳婴儿的影响：一名孕妇在怀孕期间和产后使用奥曲肽治疗肢端肥大症（剂量未说明）。她母乳喂养了4个月的婴儿，婴儿未发现明显问题。 一名患有肢端肥大症的女性在产后每6周注射一次长效奥曲肽（善龙；剂量未说明）的同时进行母乳喂养。产后6个月，注射频率增加到每4周一次。她母乳喂养了12个月的婴儿（喂养程度未说明）。在孩子5岁时，发育正常。 ◉ 对泌乳和母乳的影响：一名患有肢端肥大症的孕妇在怀孕12周开始每月使用长效奥曲肽10毫克。分娩后，她一直母乳喂养到产后6周，当时她需要将奥曲肽LAR增加到每月20毫克。她继续成功地使用奥曲肽进行母乳喂养。

◉ Summary of Use during Lactation:The excretion of octreotide into breastmilk has not been studied. However, because it has a high molecular weight of 1019 daltons it is likely to be poorly excreted into breastmilk. It is poorly absorbed orally and has been safely administered directly to infants by injection, so it is unlikely to adversely affect the breastfed infant. At least 3 infants have been successfully breastfed with no adverse effects reported. Until more data are available, octreotide should be used in nursing mothers with careful infant monitoring, especially if the infant is under 2 months of age. ◉ Effects in Breastfed Infants:One mother was treated for acromegaly during pregnancy and postpartum with octreotide (dose not stated). She breastfed (extent not stated) her infant for 4 months with no apparent problems noted in the infant. A woman with acromegaly took long-acting octreotide (Sandostatin LAR; dose not stated) every 6 weeks postpartum while breastfeeding. At 6 months postpartum, the frequency of the injections was increased to every 4 weeks. She breastfed her infant (extent not stated) for 12 months. At age 5 years the child had developed normally. ◉ Effects on Lactation and Breastmilk:A pregnant woman with acromegaly started long-acting octreotide 10 mg monthly at 12 weeks gestation. After delivery, she breastfed her until 6 weeks postpartum when she required an increase in octreotide LAR to 20 mg monthly. She continued to breastfeed successfully on octreotide.

来源:Drugs and Lactation Database (LactMed)

安全信息

• WGK Germany：
  3
• 危险品运输编号：
  NONH for all modes of transport
• 海关编码：
  3004909090

制备方法与用途

消化系统用药

奥曲肽属于消化系统用药，是一种人工合成的八肽环状化合物，为天然生长抑素的同系物。它具有天然生长抑素（Somatostatin）的药理活性，并且作用更持久，其半衰期约为1.5小时，而天然生长抑素仅为2～3分钟。奥曲肽对生长激素、胰高血糖素和胰岛素的分泌有选择性抑制作用，效果比天然生长抑素更强。动物实验表明，静注本品15分钟后，对生长激素的抑制作用是天然生长抑素的70倍，对胰岛素的抑制作用则是其3倍。此外，奥曲肽还能抑制促甲状腺素、促肾上腺皮质激素、胃泌素、胆囊收缩素以及肠血管活性多肽的分泌，从而减慢胃肠道通过时间，促进水和电解质吸收，并具有收缩内脏血管的作用，有助于降低门脉压及血流量。

奥曲肽的化学结构中第1、4、8个氨基酸为非天然氨基酸，使其不易被酶破坏，半衰期更长。皮下注射后，其吸收迅速而完全，血药浓度在0.5小时内达到峰值，分布容积为0.27L/kg，半衰期为1.5小时，代谢清除率为每分钟160ml。静注时呈双相消除，α相和β相的半衰期分别为10分钟和90分钟，血浆蛋白结合率约为65%。

临床应用方面，奥曲肽主要用于治疗门脉高压引起的食管静脉曲张出血、肢端巨大症、消化道出血（如肝硬化、食管静脉曲张出血、消化性溃疡出血和应激性溃疡出血）、胰腺疾病（如重型急性胰腺炎、胰损伤或手术后胰瘘），以及预防胰腺术后并发症。此外，它还用于胃肠道瘘管、消化系内分泌肿瘤（如肠血管活性肽瘤、胃泌素瘤、胰高血糖素瘤、异位ACTH综合征、类癌综合征）、肢端肥大症、突眼性甲亢症、全结肠切除后出现的持续性顽固腹泻和艾滋病相关性腹泻。鞘内注射可用于治疗癌性疼痛。

用法用量

1. 预防胰腺手术后并发症：术前1小时皮下注射0.1mg奥曲肽；术后每8小时1次，每次0.1mg，连续7天。
2. 门脉高压引起的食管静脉曲张出血：初始剂量为0.1mg静脉注射，随后每2小时静滴0.5mg。
3. 应激性溃疡及消化道出血：每日三次，每次皮下注射0.1mg。
4. 重型胰腺炎：每日三次，每次0.1mg，持续7天；之后改为肌内注射5mg每周四次。
5. 其他应用：如胃肠道瘘管、内分泌肿瘤等。

性质 毒性

奥曲肽属于有毒物质，分类为高毒。静脉给药大鼠和小鼠的半数致死量分别为18.1毫克/公斤和72.3毫克/公斤。

火灾危险特性

该药物可燃，在火场分解产生有毒氮氧化物、硫氧化物烟雾。

储运及灭火方法

应低温储存于通风干燥处，避免与食品原料混存。使用水、二氧化碳、干粉或砂土进行灭火。

文献信息

• [EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
  申请人：GILEAD APOLLO LLC

  公开号：WO2017075056A1

  公开（公告）日：2017-05-04

  The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.

  本发明提供了化合物I和II，这些化合物可用作乙酰辅酶A羧化酶（ACC）的抑制剂，以及它们的组合物和使用方法。
• [EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
  申请人：UNIV GEORGIA STATE RES FOUND

  公开号：WO2010129858A1

  公开（公告）日：2010-11-11

  Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.

  本文披露了适用作抗肿瘤药剂的化合物，用于治疗癌症的方法，其中所披露的化合物用于制备治疗癌症的药物，治疗肿瘤的方法包括向受试者施用包含一种或多种所披露的细胞毒性药剂的组合物，以及制备所披露的抗肿瘤药剂的方法。
• [EN] INHIBITORS OF BRUTON'S TYROSINE KINASE<br/>[FR] INHIBITEURS DE TYROSINE KINASE DE BRUTON
  申请人：BIOCAD JOINT STOCK CO

  公开号：WO2018092047A1

  公开（公告）日：2018-05-24

  The present invention relates to a new compound of formula I: or pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: V1 is C or N, V2 is C(R2) or N, whereby if V1 is C then V2 is N, if V1 is C then V2 is C(R2), or if V1 is N then V2 is C(R2); each n, k is independently 0, 1; each R2, R11 is independently H, D, Hal, CN, NR'R", C(O)NR'R", C1-C6 alkoxy; R3 is H, D, hydroxy, C(O)C1-C6 alkyl, C(O)C2-C6 alkenyl, C(O)C2-C6 alkynyl, C1-C6 alkyl; R4 is H, Hal, CN, CONR'R", hydroxy, C1-C6 alkyl, C1-C6 alkoxy; L is CH2, NH, O or chemical bond; R1 is selected from the group of the fragments, comprising: Fragment 1, Fragment 2, Fragment 3 each A1, A2, A3, A4 is independently CH, N, CHal; each A5, A6, A7, A8, A9 is independently C, CH or N; R5 is H, CN, Hal, CONR'R", C1-C6 alkyl, non-substituted or substituted by one or more halogens; each R' and R" is independently selected from the group, comprising H, C1-C6 alkyl, C1-C6 cycloalkyl, aryl; R6 is selected from the group: [formula II] each R7, R8, R9, R10 is independently vinyl, methylacetylenyl; Hal is CI, Br, I, F, which have properties of inhibitor of Bruton's tyrosine kinase (Btk), to pharmaceutical compositions containing such compounds, and their use as pharmaceuticals for treatment of diseases and disorder.

  本发明涉及一种新的化合物，其化学式为I：或其药学上可接受的盐、溶剂化合物或立体异构体，其中：V1为C或N，V2为C(R2)或N，如果V1为C，则V2为N，如果V1为C，则V2为C(R2)，或者如果V1为N，则V2为C(R2)；每个n，k独立地为0或1；每个R2，R11独立地为H，D，Hal，CN，NR'R"，C(O)NR'R"，C1-C6烷氧基；R3为H，D，羟基，C(O)C1-C6烷基，C(O)C2-C6烯基，C(O)C2-C6炔基，C1-C6烷基；R4为H，Hal，CN，CONR'R"，羟基，C1-C6烷基，C1-C6烷氧基；L为CH2，NH，O或化学键；R1从包括的片段组中选择：片段1，片段2，片段3，每个A1，A2，A3，A4独立地为CH，N，CHal；每个A5，A6，A7，A8，A9独立地为C，CH或N；R5为H，CN，Hal，CONR'R"，C1-C6烷基，未取代或被一个或多个卤素取代；每个R'和R"独立地从包括H，C1-C6烷基，C1-C6环烷基，芳基的组中选择；R6从组中选择：[化学式II]每个R7，R8，R9，R10独立地为乙烯基，甲基乙炔基；Hal为CI，Br，I，F，具有布鲁顿酪氨酸激酶（Btk）抑制剂的性质，以及含有这种化合物的药物组合物，以及它们作为治疗疾病和紊乱的药物的用途。
• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• [EN] COMPOUNDS AND METHODS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LE TRAITEMENT DE MALADIES NEURODÉGÉNÉRATIVES
  申请人：TAVARES FRANCIS XAVIER

  公开号：WO2016168118A1

  公开（公告）日：2016-10-20

  Novel compounds of formula (II) are disclosed. Compounds of formula (II) comprise ornithine derivatives or compounds that may metabolize to ornithine. Also disclosed are methods for the treatment of neurodegenerative diseases such as Alzheimer's Disease using compounds of formula (II).

  公开了化学式（II）的新化合物。化学式（II）的化合物包括鸟氨酸衍生物或可能代谢成鸟氨酸的化合物。还公开了使用化学式（II）的化合物治疗神经退行性疾病，如阿尔茨海默病的方法。