Ranitidine | 82530-72-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: Ranitidine
• 英文别名: Zantac；(E)-1-N'-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine
• CAS: 82530-72-1
• 化学式: C₁₃H₂₂N₄O₃S
• 分子量: 314.409
• InChiKey: VMXUWOKSQNHOCA-UKTHLTGXSA-N

物化性质

• 沸点：
  437.1±45.0 °C(Predicted)
• 密度：
  1.184±0.06 g/cm3(Predicted)
• 物理描述：
  Solid
• 颜色/状态：
  SOLID
• 气味：
  Characteristic
• 味道：
  Bitter taste
• 熔点：
  69.5 °C
• 溶解度：
  Water soluble
• 稳定性/保质期：
  Ranitidine hydrochloride injection is stable for up to 48 hr @ room temp when added to or diluted with most IV soln. ... The commercially available IV infusion soln of the drug in 0.45% sodium chloride is stable through the expiration date noted on the container when stored as recommended. When the pharmacy bulk package is used, infusion soln of ranitidine hydrochloride should be prepared within 24 hr after the vial is first entered; any drug remaining in the bulk package after this period should be discarded. /Ranitidine hydrochloride/
• 碰撞截面：
  167 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
• 保留指数：
  2087;2093.9

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  21
• 可旋转键数：
  9
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

雷尼替丁在口服给药后经历显著的首过代谢。它在肝脏中被代谢为药理学上不活跃的去甲基雷尼替丁、雷尼替丁-N-氧化物和雷尼替丁-S-氧化物。

Ranitidine undergoes significant first-pass metabolism after oral admin. It is metabolized in the liver to the pharmacologically inactive desmethylranitidine, ranitidine-N-oxide, and ranitidine-S-oxide.

来源:Hazardous Substances Data Bank (HSDB)

代谢

静脉注射剂量中的10%以下以代谢物的形式排出；静脉注射剂量的68%至79%和口服剂量的30%以未改变的药物形式出现在尿液中。

Less than 10% of an iv or oral dose is excreted as metabolites; 68% to 79% of an iv dose and 30% of an oral dose appear in the urine as unchanged drug.

来源:Hazardous Substances Data Bank (HSDB)

代谢

疑似N-氧化物代谢物相对于母体氨基酸化合物的色谱行为，旨在预测N-氧化物的保留数据。模型化合物通过反相高效液相色谱和标准薄层色谱系统进行评估，并生成数据以预测根据母体化合物预测雷尼替丁N-氧化物和三苯氧胺N-氧化物的保留值。实际值和预测值之间的偏差大于预期。

The chromatographic behavior of putative N-oxide metabolites relative to the parent amino compounds with the aim of predicting retention data for N-oxides is described. Model compounds were evaluated by reversed phase HPLC and standard TLC systems and the data generated to predict retention values for ranitidine N-oxide and tamoxifen N-oxide based upon those of the parent compounds. The deviation between actual and predicted values was larger than expected.

来源:Hazardous Substances Data Bank (HSDB)

代谢

雷尼替丁已知的人类代谢物包括去甲基雷尼替丁。

Ranitidine has known human metabolites that include Desmethylranitidine.

来源:NORMAN Suspect List Exchange

毒理性

• 肝毒性

慢性使用雷尼替丁治疗与1%至4%的患者血清转氨酶水平小幅升高有关，但安慰剂接受者中也有类似的报告率。ALT（丙氨酸氨基转移酶）升高通常是无症状和短暂的，可能会在剂量不变的情况下解决。在接受雷尼替丁治疗的患者中已有临床明显的肝损伤的报告，但发病时间和损伤模式有很大差异（案例1-3）。发病时间可能短至几天，长达几个月，但通常在6周内。血清酶升高的模式从肝细胞到胆汁淤积不等，大多数病例为“混合”肝细胞-胆汁淤积。损伤很少严重，通常在停药后迅速解决，通常在4到12周内。肝活检组织学常显示中央小叶坏死。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）可能出现（案例2），但并不常见，自身抗体的形成也不常见。

Chronic therapy with ranitidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. Rare instances of clinically apparent liver injury have been reported in patients receiving ranitidine, but the time to onset and pattern of injury has varied greatly (Cases 1-3). Onset can be as short as a few days to as long as several months, but is usually within 6 weeks. The pattern of serum enzyme elevation varies from hepatocellular to cholestatic, most cases being “mixed” hepatocellular-cholestatic. The injury is rarely severe and usually resolves rapidly upon stopping, generally within 4 to 12 weeks. Liver biopsy histology often shows prominent centrolobular necrosis. Immunoallergic features (rash, fever, eosinophilia) can occur (Case 2) but are uncommon, as is autoantibody formation.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：雷尼替丁

Compound:ranitidine

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：较少关注药物性肝损伤

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：5

Severity Grade:5

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

十二名正常男性受试者在开始连续输注pentagastrin（胃泌素），2微克/千克/小时之前90分钟口服了20、40或80毫克的雷尼替丁。雷尼替丁使氢离子输出量分别减少了29%，50%和70%，分泌体积分别减少了21%，37%和47%。相同剂量的雷尼替丁使胃蛋白酶活性分别降低了8%，50%和49%。血清峰浓度与氢离子输出量（r=0.81，P小于0.001）和体积（r=0.71，P小于0.01）的百分比减少在2小时内呈正相关。氢离子输出量减少50%与165微克/升的雷尼替丁血清峰浓度相关，受试者在口服给药后60至120分钟达到血清峰浓度。

Twelve normal male subjects received 20, 40, or 80 mg of ranitidine orally 90 min before starting a 3-hr continuous infusion of pentagastrin, 2 ug/kg/hr. Ranitidine reduced hydrogen ion output by 29%, 50% and 70% & secretion volume by 21%, 37%, and 47%. Pepsin activity was reduced by 8%, 50% & 49% by the same doses. Peak serum concn was correlated positively with percent reduction in hydrogen ion output (r= 0.81, P= less than 0.001) & volume (r= 0.71, P less than 0.01) over a 2-hr period. A 50% inhibition of hydrogen ion output was associated with a peak ranitidine serum concn of 165 ug/l and subjects reached peak serum concn 60 to 120 min after oral dosing.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

雷尼替丁口服给药后从胃肠道迅速吸收，肌肉注射后从注射部位迅速吸收；然而，口服给药后，药物会经历广泛的首过代谢。口服给药的雷尼替丁的绝对生物利用度据报道约为50%；在3.5至16岁的儿童中，药物的类似口服生物利用度已有报道。口服给药后，与较年轻的成年人相比，老年个体的血浆浓度-时间曲线下面积可能会显著增加。肌肉注射后，雷尼替丁的绝对生物利用度为90-100%。

Ranitidine is rapidly absorbed from the GI tract following oral admin and from parenteral sites following IM injection; however, following oral admin, the drug undergoes extensive first-pass metabolism. ... The absolute bioavailability of orally admin ranitidine has been reported to be about 50%; similar oral bioavailability of the drug has been reported in children 3.5-16 yr of age. Following oral admin, area under the plasma conc-time curve may be substantially increased in geriatric individuals compared with younger adults. Following IM admin, the absolute bioavailability of ranitidine is 90-100%.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在口服150毫克剂量后，成人的平均血清雷尼替丁浓度在2-3小时内达到372-545纳克/毫升，并且可能与年龄正相关。在一项研究中，单次口服给药后，某些个体的血清药物浓度出现双峰现象，初始峰出现在给药后0.5-1.5小时，第二个峰大约在给药后3小时出现。在单次肌内注射50毫克药物后，平均血清雷尼替丁浓度在15分钟内达到576纳克/毫升。

Following oral admin of 150 mg doses, mean peak serum ranitidine conc of 372-545 ng/ml occur within 2-3 hr and may be positively correlated with age in adults. Following oral admin of single doses of the drug in one study, peak serum conc were biphasic in some individuals with an initial peak occurring @ 0.5-1.5 hr after admin and a second peak occurring about 3 hr after admin. Following IM admin of a single 50-mg dose of the drug, mean peak serum ranitidine conc of 576 ng/ml occur within 15 min.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

雷尼替丁在体内广泛分布，并且有10-19%与蛋白结合。雷尼替丁的表观分布容积据报道为1.2-1.9升/千克。3.5-16岁儿童中的表观分布容积据报道为2.3-2.5升/千克（范围：1.1-3.7升/千克）。

Ranitidine is widely distributed throughout the body and is 10-19% protein bound. The apparent volume of distribution of ranitidine is reported to be 1.2-1.9 l/kg. The apparent volume of distribution in children 3.5-16 yr of age is reported to be 2.3-2.5 l/kg (range: 1.1-3.7 l/kg).

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  Ranitidine 在 盐酸 作用下， 反应 2.03h， 生成 ranitidine hydrochloride
  参考文献：
  名称：

  Preparation of acid addition salts of amine bases by solid phase-gas phase reactions

  摘要：

  将有机碱以固体形式暴露于气态酸中，制备有机碱的酸加盐的方法，但须排除齐拉西酮、其酸加盐和中间体。

  公开号：

  US20060205944A1
• 作为产物：
  描述：

  N-[2-[[5-(1,3-dioxolan-2-yl)-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine 在 盐酸 、 sodium borohydrid 、 氨 、 溶剂黄146 、 二甲胺 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 Ranitidine
  参考文献：
  名称：

  Process for the preparation of a furan derivative

  摘要：

  雷尼替丁是通过将化学式（II）的醛与二甲胺和一种还原剂反应制备而成，该还原剂能够进行还原烷基化反应以引入Me.sub.2 NCH.sub.2基团，但不会还原硝基乙烯基团。反应在适当的溶剂中进行，最好在酸的存在下进行或在处理后进行酸处理。适当的还原剂包括二硼烷、铝氢化物和碱金属或碱土金属硼氢化物。醛（II）可以从化学式（III）的缩醛中原位生成，其中R.sub.1和R.sub.2都是烷基或R.sub.1 OCHOR.sub.2形成环状缩醛。

  公开号：

  US04399294A1
• 作为试剂：
  描述：

  2-(((5-二甲基氨基)甲基)-2-呋喃基)甲基)硫代乙胺 、 N-甲基-1-甲硫基-2-硝基乙烯胺 、 盐酸 在 氯仿 、 水 、 resultant solution 、 正己烷 、 Ranitidine 作用下， 以 水 为溶剂， 反应 4.0h， 以to give the crude product (66.2 g), m.p. 68°-70° C.的产率得到Ranitidine
  参考文献：
  名称：

  Process for the manufacture of pharmaceutical grade ranitidine base

  摘要：

  一种制造药用级雷尼替丁（N-\x9b2-\x9b\x9b\x9b5-(二甲氨基)甲基!-2-呋喃基!甲基!硫醇!乙基-N'-甲基-2-硝基-1,1-乙烯二胺）的工艺被描述。体外和体内药理学研究以及急性毒性研究表明，它与2型雷尼替丁盐酸盐一样活性和安全。

  公开号：

  US05696275A1

文献信息

• [EN] CATHEPSIN CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE PROTÉASES À CYSTÉINE DE TYPE CATHEPSINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2015054038A1

  公开（公告）日：2015-04-16

  This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

  这项发明涉及一类新型化合物，它们是半胱氨酸蛋白酶抑制剂，包括但不限于对卡特普辛K、L、S和B的抑制剂。这些化合物可用于治疗需要抑制骨吸收的疾病，如骨质疏松症。
• [EN] CATHEPSIN INHIBITORS<br/>[FR] INHIBITEURS DE LA CATHEPSINE
  申请人：ACADEMISCH ZIEKENHUIS LEIDEN

  公开号：WO2019112426A1

  公开（公告）日：2019-06-13

  This invention relates to compounds that are useful as inhibitors, in particular as inhibitors of Cathepsin K (CatK), and to a method of inhibiting cathepsin activity, comprising administering a compound or formulation comprising a compound according to the invention.

  这项发明涉及一种作为抑制剂有用的化合物，特别是作为Cathepsin K（CatK）的抑制剂，并涉及一种抑制蛋白酶活性的方法，包括给予根据该发明的化合物或配方的化合物。
• [EN] COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH<br/>[FR] COMPOSÉS MODULANT L'ACTIVITÉ DES RÉCEPTEURS EGFR ET MÉTHODES POUR TRAITER OU PRÉVENIR DES TROUBLES À L'AIDE DE CEUX-CI
  申请人：GATEKEEPER PHARMACEUTICALS INC

  公开号：WO2011140338A1

  公开（公告）日：2011-11-10

  Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.

  提供了用于治疗或预防激酶介导的疾病的化合物和方法。
• [EN] KINASE INHIBITORS FOR THE TREATMENT OF DISEASE<br/>[FR] INHIBITEURS DE KINASE POUR LE TRAITEMENT D'UNE MALADIE
  申请人：DANA FARBER CANCER INST INC

  公开号：WO2015006492A1

  公开（公告）日：2015-01-15

  The invention relates to compounds and their use in the treatment of disease. Novel irreversible inhibitors of wild-type and mutant forms of EGFR, FGFR, ALK, ROS, JAK, BTK, BLK, ITK, TEC, and/or TXK and their use for the treatment of cell proliferation disorders are described.

  这项发明涉及化合物及其在治疗疾病中的应用。描述了用于治疗细胞增殖紊乱的新型EGFR、FGFR、ALK、ROS、JAK、BTK、BLK、ITK、TEC和/或TXK的野生型和突变型不可逆抑制剂及其应用。
• Substituted 1,3-thiazole compounds, their production and use
  申请人：——

  公开号：US20040053973A1

  公开（公告）日：2004-03-18

  (1) A 1,3-thiazole compound of which the 5-position is substituted with a 4-pyridyl group having a substituent including no aromatic group or (2) a 1,3-thiazole compound of which the 5-position is substituted with a pyridyl group having at the position adjacent to a nitrogen atom of the pyridyl group a substituent including no aromatic group has an excellent p38 MAP kinase inhibitory activity.

  (1) 一种1,3-噻唑化合物，其5位被取代为含有一个取代基的4-吡啶基团，该取代基不包括芳香基，或者(2) 一种1,3-噻唑化合物，其5位被取代为一个吡啶基团，该吡啶基团的氮原子邻近位置有一个取代基，该取代基不包括芳香基，具有出色的p38 MAP激酶抑制活性。

表征谱图