西他列汀 | 486460-32-6

• 物质功能分类: 原料药 - 循环系统用药 - 调节血脂药
• 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: 西他列汀
• 中文别名: 西他列汀游离碱；西格列汀；(3R)-3-氨基-1-(3-(三氟甲基)-5,6,7,8-四氢-1,2,4-三唑并(4,3-a)吡嗪-7-基)-4-(2,4,5-三氟苯基)丁-1-酮；(3R)-3-氨基-1-[3-(三氟甲基)-5,6,7,8-四氢-1,2,4-三唑并[4,3-a]吡嗪-7-基]-4-(2,4,5-三氟苯基)丁-1-酮
• 英文名称: sitagliptin
• 英文别名: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine；(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine；(R)-sitagliptin；MK-0431；(R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one；(3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one；(R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine；(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one；sitagliptin phosphate；januvia；(3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one；(3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
• CAS: 486460-32-6
• 化学式: C₁₆H₁₅F₆N₅O
• mdl: MFCD09838015
• 分子量: 407.318
• InChiKey: MFFMDFFZMYYVKS-SECBINFHSA-N

物化性质

• 熔点：
  114.1-115.7 °C
• 沸点：
  529.9±60.0 °C(Predicted)
• 密度：
  1.61±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥ 50 mg/mL（122.76 mM）
• 物理描述：
  Solid
• 颜色/状态：
  Viscous liquid
• 蒸汽压力：
  2.91X10-8 mm Hg at 25 °C (est)
• 稳定性/保质期：

  Stable if stored as directed; avoid strong oxidizing agents. /Sitagliptin phosphate monohydrate/

• 分解：
  Thermal decomposition may produce toxic gases such as carbon monoxide, carbon dioxide, and nitrogen oxides. /Sitagliptin phosphate monohydrate/
• 解离常数：
  pKa = 8.78 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.437
• 拓扑面积：
  77
• 氢给体数：
  1
• 氢受体数：
  10

ADMET

代谢

Sitagliptin大部分未发生代谢，剂量的79%以未改变的母化合物形式从尿液中排出。次要的代谢途径主要由细胞色素p450（CYP）3A4介导，在较小程度上由CYP2C8介导。18小时后，剂量的81%保持未改变，而2%被N-硫酸化成M1代谢物，6%被氧化脱饱和并环化成M2代谢物，不到1%在未知位点发生葡萄糖苷酸化成M3代谢物，不到1%被尿素化和葡萄糖苷酸化成M4代谢物，6%被氧化饱和并环化成M5代谢物，2%在未知位点发生羟基化成M6代谢物。M2代谢物是顺式异构体，而M5代谢物是同一代谢物的反式异构体。

Sitagliptin is mostly not metabolised, with 79% of the dose excreted in the urine as the unchanged parent compound. Minor metabolic pathways are mediated mainly by cytochrome p450(CYP)3A4 and to a lesser extent by CYP2C8. After 18 hours, 81% of the dose has remained unchanged, while 2% has been N-sulfated to the M1 metabolite, 6% has been oxidatively desaturated and cyclized to the M2 metabolite, <1% glucuronidated at an unknown site to the M3 metabolite, <1% has been carbamoylated and glucuronidated to the M4 metabolite, 6% has been oxidatively saturated and cyclized to the M5 metabolite, and 2% has been hydroxylated at an unknown site to the M6 metabolite. The M2 metabolite is the cis isomer while the M5 metabolite is the trans isomer of the same metabolite.

来源:DrugBank

代谢

在单次口服83毫克/193微居里的西格列汀后，研究了人类体内的(14)C西格列汀的代谢和排泄。在长达7天的时间里，定期收集尿液、粪便和血浆。放射性物质的主要排泄途径是通过肾脏，平均有87%的给药剂量在尿液中回收。平均粪便排泄量为给药剂量的13%。原药是血浆、尿液和粪便中的主要放射性成分，只有16%的剂量以代谢物形式排泄（13%在尿液中，3%在粪便中），这表明西格列汀主要通过肾脏排泄。大约74%的血浆总放射性AUC归因于原药。检测到六种微量水平的代谢物，每种代谢物在血浆中的放射性占比小于1%至7%。这些代谢物包括原药的N-硫酸和N-脲基葡萄糖酸苷，羟基衍生物的混合物，一种羟基代谢物的醚葡萄糖苷酸，以及由哌嗪环的氧化脱饱和后环化形成的两种代谢物。这些代谢物也在尿液中以低水平检测到。粪便中的代谢物谱与尿液和血浆中的相似，只是粪便中没有检测到葡萄糖苷酸。CYP3A4是负责西格列汀有限氧化代谢的主要细胞色素P450同种酶，CYP2C8也有少量贡献。

The metabolism and excretion of (14)C sitagliptin ... were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在口服14C标记的西格列汀后，大约16%的放射性以西格列汀代谢物的形式被排泄。检测到六种微量代谢物，预计这些代谢物不会对西格列汀的血浆DPP-4抑制活性产生影响。体外研究表明，负责西格列汀有限代谢的主要酶是CYP3A4，CYP2C8也有所贡献。

Following a (14)C sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

西格列汀是一种粘稠的液体。它是一种二肽基肽酶-4抑制剂，用于改善2型糖尿病患者的血糖控制。人类接触和毒性：西格列汀能改善血糖控制，在2型糖尿病患者中通常耐受性良好。西格列汀的使用与患有预先存在心力衰竭的2型糖尿病患者因心力衰竭相关住院的风险增加有关。最近的一项研究指出，西格列汀可能用于治疗一些外周神经系统的神经退行性疾病。西格列汀似乎没有与其他治疗相关的不良反应，如体重增加和低血糖。动物研究：在大鼠中，当西格列汀的系统暴露量是人类暴露量的58倍时，观察到了肾脏和肝脏毒性。在狗中，当暴露水平大约是临床暴露水平的23倍时，观察到了与治疗相关的暂时性身体征象，其中一些表明神经毒性，如张口呼吸、流涎、白色泡沫状呕吐、共济失调、震颤、活动减少和/或驼背姿势。在小鼠中的致癌性研究没有显示任何器官的肿瘤发生率增加，剂量高达500 mg/kg，但在大鼠中，雄性和雌性在500 mg/kg时肝腺瘤/肝癌的发生率增加，雌性在500 mg/kg时肝细胞癌的发生率增加。在大鼠和兔中，只有在剂量大于250 mg/kg时才观察到生殖效应。在大鼠中西格列汀的暴露水平是临床暴露水平的67倍时，观察到了门齿异常。在西格列汀的ames细菌突变试验、中国仓鼠卵巢(CHO)染色体畸变试验、CHO细胞的体外细胞遗传学试验、体外大鼠肝细胞DNA碱性洗脱试验和体内微核试验中，无论是否经过代谢激活，西格列汀均无致突变或断裂作用。

IDENTIFICATION AND USE: Sitagliptin is a viscous liquid. It is a dipeptidyl peptidase-4 inhibitor and used to improve glycemic control in patients with type 2 diabetes. HUMAN EXPOSURE AND TOXICITY: Sitagliptin improves glycemic control and is generally well-tolerated in patients with type 2 diabetes. Sitagliptin use has been associated with an increased risk of heart failure -related hospitalizations among patients with type 2 diabetes with pre-existing heart failure. More recently a study has pointed to the possible use of sitagliptin in the treatment of some neurodegenerative conditions of the peripheral nervous system. Sitagliptin appears to be free from the adverse effects of weight gain and hypoglycemia that are associated some other treatments. ANIMAL STUDIES: Renal and liver toxicity were observed in rodents at systemic exposure to sitagliptin at values 58 times the human exposure level. Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. Carcinogenicity studies in mice did not show an increased incidence of tumors in any organ up to 500 mg/kg, but in rats there was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. Reproductive effects in rats and rabbits were only seen at doses greater than 250 mg/kg. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO cells, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

西格列汀导致的肝损伤是罕见的。在大规模临床试验中，与西格列汀治疗（0.5%）相比，安慰剂（0.4%）的血清酶升高并不更常见，并且没有报告出现临床明显的肝损伤。自从获得许可以来，已经向FDA和赞助商报告了归因于西格列汀的血清酶升高的情况。已经发表了一例临床明显的肝损伤的个案报告，但该患者同时也有丙型肝炎。血清酶升高的模式是肝细胞型的，血清胆红素峰值达到9.4 mg/dL，停用西格列汀后迅速恢复。免疫过敏特征和自身抗体均未出现。

Liver injury due to sitagliptin is rare. In large clinical trials, serum enzyme elevations were no more common with sitagliptin therapy (0.5%) than with placebo (0.4%), and no instances of clinically apparent liver injury were reported. Since licensure, instances of serum enzyme elevations attributed to sitagliptin have been reported to the FDA and the sponsor. A single case report of clinically apparent liver injury has been published, but in a patient who also had hepatitis C. The pattern of serum enzyme elevations was hepatocellular and peak serum bilirubin was 9.4 mg/dL, with a rapid recovery upon stopping sitagliptin. Immunoallergic features and autoantibodies were absent.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：西格列汀

Compound:sitagliptin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：较少的药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：4

Severity Grade:4

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

西格列汀的口服生物利用度为87%，无论是否与食物同服，都不会影响其药代动力学。西格列汀在2小时内达到最大血浆浓度。

Sitagliptin is 87% orally bioavailable and taking it with or without food does not affect its pharmacokinetics. Sitagliptin reaches maximum plasma concentration in 2 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

大约79%的西格列汀以未改变的母体化合物形式通过尿液排出。剂量的87%通过尿液消除，13%通过粪便消除。

Approximately 79% of sitagliptin is excreted in the urine as the unchanged parent compound. 87% of the dose is eliminated in the urine and 13% in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

198升。

198L.

来源:DrugBank

吸收、分配和排泄

• 清除

350毫升/分钟。

350mL/min.

来源:DrugBank

吸收、分配和排泄

西格列汀在哺乳大鼠的乳汁中以乳汁与血浆比为4:1分泌。目前尚不清楚西格列汀是否会在人类乳汁中排泄。

Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存放在室温、干燥且密封的环境中。

制备方法与用途

西他列汀简介

西他列汀是由美国默克公司研发的一种新型抗Ⅱ型糖尿病药物，是第一个用于治疗Ⅱ型糖尿病的二肽基肽酶-Ⅳ（DPP-Ⅳ）抑制剂类药物。常以磷酸盐形式入药，主要用于预防和治疗2型糖尿病、高血糖、胰岛素抵抗、肥胖和高血压以及某些并发症。磷酸西他列汀于2006年在墨西哥及美国上市，并于2007年获得欧盟批准用于治疗2型糖尿病。目前，磷酸西他列汀片已成为美国口服糖尿病药物的第二大药物。

应用与前景

临床研究表明，西他列汀是一个口服有效、市场前景良好的药物。它单用或与二甲双胍、吡格列酮合用都有显著的降血糖作用，并且服用安全、耐受性好、不良反应少。

作用机制

西他列汀能提高血浆中GLP-1和GIP的活性，轻度增加其含量并减弱GLP-1代谢物的拮抗作用。同时，西他列汀刺激胰岛素分泌具有血糖依赖性，从而大大降低传统口服降糖药低血糖副作用的发生率。

西他列汀通过提高糖尿病患者自身胰岛β细胞产生胰岛素的能力，在血糖升高时增加胰岛素的分泌，从而控制糖尿病患者的血糖水平。其作用机制不同于以往的口服降糖药。

用途

西他列汀（sitagliptin）是FDA批准上市的一种新型抗2型糖尿病药物，是第一个用于治疗2型糖尿病的二肽基肽酶-Ⅳ抑制剂药物。临床研究表明，它单用或与二甲双胍、吡格列酮合用都有显著的降血糖作用，并且服用安全、耐受性好、不良反应少。

生物活性

西他列汀（sitagliptin，MK-0431）是一种具有口服的、高度选择性的DPP-4抑制剂，IC50为18 nM。它被用于治疗2型糖尿病。

Target	Value
DPP-4 (Cell-free)	18 nM

反应信息

• 作为反应物：
  描述：

  西他列汀 在 磷酸 、 水 作用下， 以 异丙醇 为溶剂， 生成 磷酸西他列汀一水合物
  参考文献：
  名称：

  [EN] AMORPHOUS FORM OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
  [FR] FORME AMORPHE D'UN SEL DE L'ACIDE PHOSPHORIQUE D'UN INHIBITEUR DE DIPEPTIDYL PEPTIDASE-IV

  摘要：

  本发明涉及(2R)-4-氧基-4-[3-(三氟甲基)-5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)丁-2-胺的新型非晶态磷酸二氢盐形式，以及其制备方法、含有该新型形式的药物组合物，以及用于治疗糖尿病、肥胖和高血压的新型形式和药物组合物的使用方法。

  公开号：

  WO2006033848A1
• 作为产物：
  描述：

  Boc-(R)-3-氨基-4-(2,4,5-三氟苯基)丁酸 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 水 、 乙酸乙酯 为溶剂， 反应 13.0h， 生成 西他列汀
  参考文献：
  名称：

  西格列汀磷酸一水合物的实用不对称合成。

  摘要：

  光学纯的西他列汀磷酸一水合物是通过手性半缩醛作为主要中间体，从（E）-4-（2,4,5-三氟苯基）but-2-enal和N-boc-保护的羟胺。手性半缩醛片段是由有机催化剂催化的氮杂-迈克尔/半缩醛串联反应构建的，并详细研究了布朗斯台德酸的酸度对氮杂-迈克尔/半缩醛的串联反应的影响。

  DOI：

  10.3390/molecules23061440

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。
• DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US20160221965A1

  公开（公告）日：2016-08-04

  The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

  本申请涉及新颖的2,5-二取代6-(三氟甲基)嘧啶-4(3H)-酮衍生物，其制备方法，其单独或与其他药物联合用于治疗和/或预防疾病，以及用于制备治疗和/或预防疾病的药物，特别是用于治疗和/或预防心血管、肾脏、炎症和纤维化疾病。
• [EN] SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN<br/>[FR] COMPOSÉS DE SULFONYLE QUI INTERAGISSENT AVEC LA PROTÉINE RÉGULATRICE DE LA GLUCOKINASE
  申请人：AMGEN INC

  公开号：WO2013123444A1

  公开（公告）日：2013-08-22

  The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.

  本发明涉及与葡萄糖激酶调节蛋白相互作用的磺酰基化合物。此外，本发明涉及使用这些化合物或其药学上可接受的盐治疗2型糖尿病和其他涉及葡萄糖激酶调节蛋白的疾病和/或症状的方法，以及含有这些化合物或其药学上可接受的盐的药物组合物。
• SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
  申请人：BLUM Andreas

  公开号：US20140135309A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I wherein Ar, R 1 and R 2 are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及公式I的新型磺酰胺取代的喹唑啉衍生物，其中Ar、R1和R2如本文所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。
• [EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2014072244A1

  公开（公告）日：2014-05-15

  This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

  这项发明涉及一种新型的配方(I)的磺酰胺取代喹唑啉衍生物，其中Ar、R1和R2如描述和声明中所定义，并且它们作为MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）激酶抑制剂的用途，含有这些化合物的药物组合物，以及将其用作治疗或改善MNK1（MNK1a或MNK1b）和/或MNK2（MNK2a或MNK2b）介导的疾病的药剂的方法。