他索沙坦 | 145733-36-4

• 物质功能分类: 生物 - 细胞培养 - 添加剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 他索沙坦
• 中文别名: 他沙索坦；2,4-二甲基-8-[[4-[2-(2H-四唑-5-基)苯基]苯基]甲基]-5,6-二氢吡啶并[6,5-D]嘧啶-7-酮；2,4-二甲基-8-[[4-[2-(2H-四唑-5-基)苯基]苯基]甲基]-5,6-二氢吡啶并[6,5-d]嘧啶-7-酮
• 英文名称: tasosartan
• 英文别名: 2,4-dimethyl-8-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one；2,4-dimethyl-5,6,8-trihydro-8-[[2'-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-7H-pyrido[2,3-d]pyrimidin-7-one；8-[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl-methyl]-2,4-dimethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one；2,4-dimethyl-8-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]-5,6-dihydropyrido[2,3-d]pyrimidin-7-one
• CAS: 145733-36-4
• 化学式: C₂₃H₂₁N₇O
• 分子量: 411.466
• InChiKey: ADXGNEYLLLSOAR-UHFFFAOYSA-N

物化性质

• 熔点：
  197-199°
• 沸点：
  759.4±70.0 °C(Predicted)
• 密度：
  1.328±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO（微溶）、甲醇（微溶、超声处理）
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  6

ADMET

代谢

已知Tasosartan在人体内的代谢物包括enoltasosartan。

Tasosartan has known human metabolites that include enoltasosartan.

来源:NORMAN Suspect List Exchange

毒理性

• 药物性肝损伤

化合物：tasosartan

Compound:tasosartan

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：最令人关注的药物性肝损伤

DILI Annotation:Most-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：8

Severity Grade:8

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：已停产

Label Section:Discontinued

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

安全信息

• 包装等级：
  II
• 危险类别：
  4.1
• 危险性防范说明：
  P240,P210,P241,P264,P280,P302+P352,P370+P378,P337+P313,P305+P351+P338,P362+P364,P332+P313
• 危险品运输编号：
  1325
• 危险性描述：
  H228,H315,H319
• 储存条件：
  2-8℃

制备方法与用途

生物活性

Tasosartan 是一种长效的血管紧张素 II (AngII) 受体拮抗剂。

靶点

• 血管紧张素 II (AngII) 受体

体外研究

• Tasosartan 是一种口服活性非肽类 AngII 抗体，表现出对 AT1 受体的特异性和选择性拮抗作用。在体外实验中，其抑制特定结合放射性标记血管紧张素-II (¹²⁵I-AngII) 到大鼠肾上腺膜的能力为 1.2±0.6 nM。

体内研究

• 给予剂量分别为 1.0 mg/kg 和 3.0 mg/kg 的 Tasosartan (iv)，显著（p<0.05）减弱了大鼠对血管紧张素 II 的升压反应。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ——	5,8-dihydro-2,4-dimethyl-8-<(2'-(2-tert-butyl-2H-tetrazol-5-yl)<1,1'-biphenyl>-4-yl)methyl>pyrido<2,3-d>pyrimidin-7(6H)-one	153042-17-2	C27H29N7O	467.574
  ——	2,4-dimethyl-5,6,8-trihydro-8-[[2'-(1-tert-butyl-1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-7H-pyrido[2,3-d]pyrimidin-7-one	149049-80-9	C27H29N7O	467.574
  8-[(4-溴苯基)甲基]-5,8-二氢-2,4-二甲基吡啶并[2,3-D]嘧啶-7(6H)-酮	2,4-dimethyl-5,6,8-trihydro-8-[(4-bromophenyl)methyl]-7H-pyrido[2,3-d]pyrimidin-7-one	145733-62-6	C16H16BrN3O	346.227

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	2-methyl-7-oxo-8-<(2'-(1H-tetrazol-5-yl)<1,1'-biphenyl>-4-yl)methyl>-5,6,7,8-tetrahydropyrido<2,3-d>pyrimidine-4-carbaldehyde	153042-14-9	C23H19N7O2	425.45
  ——	2,4-dimethyl-5-hydroxy-8-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one	——	C23H21N7O2	427.465
  ——	2,4-dimethyl-8-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one	——	C42H35N7O	653.786
  ——	methyl (2S,3S,4S,5R,6R)-6-[5-[2-[4-[(2,4-dimethyl-7-oxo-5,6-dihydropyrido[2,3-d]pyrimidin-8-yl)methyl]phenyl]phenyl]tetrazol-2-yl]-3,4,5-trihydroxyoxane-2-carboxylate	215437-29-9	C30H31N7O7	601.619

反应信息

• 作为反应物：
  描述：

  他索沙坦 在 甲醇 、 potassium cyanide 、 氢氧化钾 、 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 26.0h， 生成 sodium;(2S,3S,4S,5R,6R)-6-[5-[2-[4-[(2,4-dimethyl-7-oxo-5,6-dihydropyrido[2,3-d]pyrimidin-8-yl)methyl]phenyl]phenyl]tetrazol-2-yl]-3,4,5-trihydroxyoxane-2-carboxylate
  参考文献：
  名称：

  Metabolites of the Angiotensin II Antagonist Tasosartan:  The Importance of a Second Acidic Group

  摘要：

  Described in this paper is the synthesis and pharmacological activity of five metabolites of the angiotensin II antagonist tasosartan (1). Of particular interest is the effect of the additional acidic group of the enol metabolite (8) on activity. As suggested by the structural-activity relationship of other angiotensin II antagonist series, a second acidic group can improve receptor binding activity but decrease in vivo activity after oral dosing. The metabolic introduction of a second acidic group in tasosartan bypasses this problem and contributes to the excellent profile of the compound. A molecular modeling study provides a rationale for the role of the enol group of 8 in AT(1) receptor binding.

  DOI：

  10.1021/jm970690q
• 作为产物：
  描述：

  5,8-dihydro-2,4-dimethyl-8-<(2'-(2-tert-butyl-2H-tetrazol-5-yl)<1,1'-biphenyl>-4-yl)methyl>pyrido<2,3-d>pyrimidin-7(6H)-one 以73的产率得到他索沙坦
  参考文献：
  名称：

  Substituted pyrrolopyrimidines, azepinopyrimidines and pyridopyrimidines

  摘要：

  本发明涉及一般式I的吡咯烷，吡啶，氮杂环庚烷和氮杂环吡咯嘧啶，其中R.sup.1，R.sup.2，R.sup.3和R.sup.4分别是H，含有1至6个碳原子的低碳基或含有1至6个碳原子的全氟碳基；R.sup.5是H或当n为1时，R.sup.5与R.sup.3一起构成双键；n为0至1；p为0至2；m为0至3；Ar.sup.1为##STR2##其中W为H，含有1至6个碳原子的低碳基，卤素，羟基或含有1至6个碳原子的低烷氧基；Ar.sup.2为##STR3##其中X为##STR4##其中R.sup.6为H，叔丁基，三正丁基锡或三苯甲基；以及其药学上可接受的盐，由于其拮抗血管紧张素II的能力，可用于治疗高血压，充血性心力衰竭和再狭窄。这些化合物也可用于降低血浆中的脂质水平，因此可用于治疗高脂血症和高胆固醇血症。还公开了生产该化合物的过程和含有该化合物的制药组合物。

  公开号：

  US05256654A1

文献信息

• [EN] HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES POUR LE TRAITEMENT D'ÉTATS LIÉS AU STRESS
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2010137738A1

  公开（公告）日：2010-12-02

  The present invention provides a novel heterocyclic compound. A heterocyclic compound represented by general formula (1) wherein, R1 and R2, each independently represent hydrogen; a phenyl lower alkyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and the like on a benzene ring and/or a lower alkyl group; or a cyclo C3-C8 alkyl lower alkyl group; or the like; R3 represents a lower alkynyl group or the like; R4 represents a phenyl group that may have a substituent(s) selected from the group consisting of a 1,3,4-oxadiazolyl group that may have e.g., halogen or a heterocyclic group selected from pyridyl group and the like; the heterocyclic group may have at least one substituent(s) selected from a lower alkoxy group and the like or a salt thereof.

  本发明提供了一种新颖的杂环化合物。一种由通式（1）表示的杂环化合物，其中，R1和R2分别独立表示氢；苯基较低烷基基团，可能在苯环和/或较低烷基基团上具有从较低烷基基团等组成的取代基；或环C3-C8烷基较低烷基基团；或类似物；R3表示较低炔基基团或类似物；R4表示可能具有从1,3,4-噁二唑基团（例如，卤素）或从吡啶基团等组成的取代基的苯基团；所述杂环基可能具有至少一个从较低烷氧基等选择的取代基或其盐。
• [EN] FUSED RING COMPOUNDS AND USE THEREOF<br/>[FR] COMPOSÉS CYCLIQUES CONDENSÉS ET UTILISATION DE CEUX-CI
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2009125873A1

  公开（公告）日：2009-10-15

  The present invention aims to provide a glucokinase activator useful as a pharmaceutical agent such as an agent for the prophylaxis or treatment of diabetes, obesity and the like. The present invention provides a glucokinase activator containing a compound represented by the formula (I): wherein each symbol is defined in the specification, or a salt thereof or a prodrug thereof.

  本发明旨在提供一种葡萄糖激酶激活剂，可用作药用剂，如用于预防或治疗糖尿病、肥胖等疾病的药剂。本发明提供一种包含由式(I)表示的化合物的葡萄糖激酶激活剂：其中每个符号在规范中有定义，或其盐或前药。
• [EN] AGENT FOR PREVENTING OR TREATING NEUROPATHY<br/>[FR] AGENT POUR LA PRÉVENTION OU LE TRAITEMENT DE NEUROPATHIE
  申请人：TAKEDA CHEMICAL INDUSTRIES LTD

  公开号：WO2004039365A1

  公开（公告）日：2004-05-13

  The present invention provides an agent for preventing or treating neuropathy having superior action and low toxicity. This agent comprises a compound represented by the formula:wherein ring A is a 5-membered aromatic heterocycle containing 2 or more nitrogen atoms, which may further have substituent(s);B is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;X is a divalent acyclic hydrocarbon group;Z is -O-, -S-, -NR2-, -CONR2- or -NR2CO- (R2 is a hydrogen atom or an optionally substituted alkyl group);Y is a bond or a divalent acyclic hydrocarbon group;R1 is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group, provided that when the 5-membered aromatic heterocycle represented by ring A is imidazole, then Z should not be -O-, or a salt thereof.

  本发明提供了一种具有优越作用和低毒性的预防或治疗神经病的药剂。该药剂包括一个由以下式表示的化合物：其中环A是含有2个或更多氮原子的5元芳香杂环，可能进一步具有取代基；B是一个可选择取代的碳氢基团或可选择取代的杂环基团；X是二价的无环碳氢基团；Z是-O-，-S-，-NR2-，-CONR2-或-NR2CO-（R2是氢原子或可选择取代的烷基基团）；Y是键或二价的无环碳氢基团；R1是可选择取代的环基团，可选择取代的氨基团或可选择取代的酰基团，但当环A表示的5元芳香杂环是咪唑时，Z不应为-O-，或其盐。
• [EN] 4-PHENOXY-NICOTINAMIDE OR 4-PHENOXY-PYRIMIDINE-5-CARBOXAMIDE COMPOUNDS<br/>[FR] COMPOSÉS DE 4-PHÉNOXYNICOTINAMIDE OU DE 4-PHÉNOXY-PYRIMIDINE-5-CARBOXAMIDE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2011089099A1

  公开（公告）日：2011-07-28

  This invention relates to novel phenyl amide or pyridyl amide derivatives of the formula (I), wherein A1, A2, B1, B2 and R1 to R11 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are GPBAR1 agonists and can be used as medicaments for the treatment of diseases such as type II diabetes.

  这项发明涉及公式（I）中的新型苯基酰胺或吡啶基酰胺衍生物，其中A1、A2、B1、B2和R1至R11如描述和索赔中所定义，并且其药学上可接受的盐。这些化合物是GPBAR1激动剂，可用作治疗疾病如2型糖尿病的药物。
• [EN] NOVEL CYCLIC BENZIMIDAZOLE DERIVATIVES USEFUL ANTI-DIABETIC AGENTS<br/>[FR] NOUVEAUX AGENTS ANTIDIABÉTIQUES UTILES AVEC DES DÉRIVÉS DE BENZIMIDAZOLE CYCLIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010051176A1

  公开（公告）日：2010-05-06

  Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

  结构式（I）的新化合物是AMP-蛋白激酶的激活剂，可用于治疗、预防和抑制由AMPK激活的蛋白激酶介导的疾病。本发明的化合物对于治疗2型糖尿病、高血糖、代谢综合征、肥胖、高胆固醇血症和高血压是有用的。