螺内酯 | 52-01-7

• 物质功能分类: 原料药 - 泌尿系统用药 - 利尿药
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 螺内酯
• 中文别名: (7α,17α)-7-(乙酰巯基)-17-羟基-3-氧代孕甾-4-烯-21-羧酸γ-内酯；17beta-羟基-3-氧-7alpha-(乙酰硫基)-17alpha-孕甾-4-烯-21-羧酸-gamma-内酯；安体舒通；螺瑞酮
• 英文名称: SPIRONOLACTONE
• 英文别名: S-[(7R,8R,9S,10R,13S,14S,17R)-10,13-dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-yl] ethanethioate
• CAS: 52-01-7
• 化学式: C₂₄H₃₂O₄S
• mdl: MFCD00071615
• 分子量: 416.582
• InChiKey: LXMSZDCAJNLERA-ZHYRCANASA-N

物化性质

• 熔点：
  207-208 °C (lit.)
• 比旋光度：
  -37 º (c=1, CHCl3)
• 沸点：
  504.87°C (rough estimate)
• 密度：
  1.1061 (rough estimate)
• 溶解度：
  几乎不溶于水，溶于乙醇 (96%)。
• LogP：
  2.780
• 物理描述：
  Solid
• 颜色/状态：
  Crystals from methanol
• 气味：
  Mild mercaptan-like odor
• 蒸汽压力：
  3.24X10-11 mm Hg at 25 °C (est)
• 稳定性/保质期：
  STABLE IN AIR
• 旋光度：
  Specific optical rotation = -33.5 deg (chloroform)
• 分解：
  When heated to decomposition it emits toxic fumes of sulfoxides.

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  29
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.791
• 拓扑面积：
  85.7
• 氢给体数：
  0
• 氢受体数：
  5

ADMET

代谢

螺内酯脱乙酰化成为7α-硫螺内酯。7α-硫螺内酯通过S-甲基化转变为7α-硫甲基螺内酯，或者发生消除反应生成坎利酮。7α-硫甲基螺内酯还原为3α-羟基硫甲基螺内酯或3β-羟基硫甲基螺内酯。最初认为坎利酮是主要的循环代谢物，但近年来的研究表明，主要的代谢物实际上是7α-硫甲基螺内酯。

Spironolactone is deacetylated to 7α-thiospironolactone. 7α-thiospironolactone is S-methylated to 7α-thiomethylspironolactone or undergoes an elimination reaction to canrenone. 7α-thiomethylspironolactone is reduced to 3α-hydroxythiomethylspironolactone or 3β-hydroxythiomethylspironolactone. Canrenone was originally thought to be the primary circulating metabolite, however more recent studies have demonstrated that the primary metabolite is actually 7α-thiomethylspironolactone.

来源:DrugBank

代谢

螺内酯在体内被迅速且广泛地代谢成在尿液和粪便中排出的化合物。它经历肠肝循环，但未改变的药物不会出现在尿液或粪便中。螺内酯的代谢物可以分为两大类：一类是保留了硫原子的，另一类是通过脱硫乙酰化去除硫原子的。多年来，人们一直认为脱硫乙酰化代谢物，即坎利酮，是主要的代谢物；然而，随着更具体分析方法的采用，如高效液相色谱（HPLC），7α-硫甲基螺内酯被认为是螺内酯的主要代谢物。这种代谢物是通过水解硫乙酰基团形成7α-硫螺内酯（作为中间体），随后通过S-甲基化形成7α-硫甲基螺内酯。然后，这可以通过羟基化形成6β-羟基-7α-硫甲基螺内酯，并通过氧化形成7α-甲基亚磺酰基-和7α-甲基磺酰基螺内酯，或者通过亚磺酰化形成6α-羟基-7α-甲基亚磺酰基-和6β-羟基-7α-甲基磺酰基螺内酯。对于形成去除硫原子的代谢物组，7α-硫甲基螺内酯也会通过脱硫乙酰化形成坎利酮，坎利酮进一步通过三条途径代谢：水解γ-内酯环形成坎利酸，坎利酸以葡萄糖苷酸酯的形式在尿液中排出，接下来，羟基化形成15α-羟基-坎利酮或还原产生几种二、四和六氢衍生物。坎利酮和坎利酸彼此处于平衡状态。不仅螺内酯，而且它的几种代谢物都具有生物活性；按照效力递减的顺序，这些是7α-硫螺内酯、7α-硫甲基螺内酯和坎利酮。

Spironolactone is rapidly and extensively metabolized to compounds that are excreted in the urine and faeces. It undergoes enterohepatic recirculation, but no unchanged drug appears in urine or feces. The metabolites of spironolactone can be divided into two main groups: those in which the sulfur moiety is retained and those in which the sulfur is removed by dethioacetylation. For many years, it was thought that the dethioacetylated metabolite, canrenone, was the major metabolite; however, with more specific analytical methods such as HPLC, 7alpha-thiomethylspirolactone was recognized as the major metabolite of spironolactone. This metabolite is formed by hydrolysis of the thioacetate group to form 7alpha-thiospirolactone (as an intermediate), followed by S-methylation to 7alpha-thiomethylspirolactone. This can then be hydroxylated to form 6â-hydroxy-7alpha-thiomethylspirolactone and oxidized to form 7alpha-methylsulfinyl- and 7alpha-methylsulfonylspirolactone or via sulfoxidation to form 6alpha-hydroxy-7alpha-methylsulfinyl- and 6beta-hydroxy-7alpha-methylsulfonylspirolactone. For formation of the group of metabolites in which sulfur is removed, 7alpha-thiomethylspirolactone is also dethioacetylated to canrenone, which is further metabolized by three pathways: hydrolysis of the gamma-lactone ring to form canrenoate, which is excreted in the urine as a glucuronic ester, and, next, hydroxylation to form 15alpha-hydroxy-canrenone or reduction to produce several di-, tetra- and hexa-hydro derivatives. Canrenone and canrenoate are in equilibrium with one another. Not only spironolactone but several of its metabolites have biological activity; in decreasing order of potency, these are 7alpha-thiospirolactone, 7alpha-thiomethylspirolactone and canrenone.

来源:Hazardous Substances Data Bank (HSDB)

代谢

旋酮类药物的生物转化在物种间存在差异。在大鼠和狗的血浆中，坎仑酮是主要的可提取代谢物，而在猴子和人类中，坎仑酮和一个非常极性的、未识别的代谢物是主要的成分。在所有四种物种的尿液中，坎仑酮是一个主要成分。在旋酮类药物的粪便代谢物中发现了显著的物种差异，狗粪便中的代谢物模式与大鼠、猴子或人类的显著不同。总体而言，得出结论，猴子中的旋酮类药物的处置和代谢，而不是大鼠或狗的，更接近于人类的。

Species differences were ... noted in the biotransformation of spironolactone. Canrenone was a principal extractable metabolite in rat and dog plasma, whereas in monkeys and humans, both canrenone and a very polar, unidentified metabolite were the major constituents. In the urine of all four species, canrenone was a principal constituent. Notable species differences in the metabolites of spironolactone in the feces were found, the pattern of metabolites in dog feces being markedly different from that in rats, monkeys or humans. Overall, it was concluded that the disposition and metabolism of spironolactone in monkeys, rather than that in rats or dogs, is closest to that in humans.

来源:Hazardous Substances Data Bank (HSDB)

代谢

六种螺内酯代谢物已在接受治疗的受试者尿液中检测到。其中一种是去硫乙酰化物，即3-(3-氧代-17β-羟基-4,6-雄甾二烯-17α-基)丙酸γ-内酯的坎利酮。

SIX METABOLITES OF SPIRONOLACTONE ... /HAVE/ BEEN DETECTED IN URINE OF TREATED SUBJECTS. ... /ONE IS/ DETHIOACETYLATED COMPD CANRENONE, 3-(3-OXO-17BETA-HYDROXY-4,6-ANDRO-STADIEN-17ALPHA-YL)PROPIONIC ACID GAMMA-LACTONE...

来源:Hazardous Substances Data Bank (HSDB)

代谢

使用荧光法测定服用螺内酯（安体舒通）25毫克每日两次后，28岁女性牛奶中坎利酮的浓度。

A FLUOROMETRIC METHOD WAS USED TO DETERMINE CONCN OF CANRENONE IN MILK FOLLOWING INGESTION OF SPIRONOLACTONE (ALDACTONE) 25 MG TWICE DAILY IN 28-YR-OLD FEMALE.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

螺内酯是醛固酮的特定药理拮抗剂，主要通过在远曲肾小管的醛固酮依赖性钠-钾交换位点上与受体的竞争性结合发挥作用。螺内酯导致钠和水的排泄量增加，同时保留钾。螺内酯通过这种机制既作为利尿剂又作为抗高血压药物发挥作用。它可以单独使用，也可以与其他在肾小管中更近端发挥作用的利尿剂一起使用。醛固酮与细胞质中的盐皮质激素受体相互作用，增强在远曲小管中参与钠、钾运输的Na+, K+-ATP酶和Na+通道的表达。螺内酯与这种矿物质皮质激素受体结合，阻止醛固酮对基因表达的作用。醛固酮是一种激素；其主要功能是在肾脏中保留钠和排泄钾。

Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule. Aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in a Na+ K+ transport in the distal tubule . Spironolactone bind to this mineralcorticoid receptor, blocking the actions of aldosterone on gene expression. Aldosterone is a hormone; its primary function is to retain sodium and excrete potassium in the kidneys.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

螺内酯引起的临床明显肝损伤是罕见的，仅有少数个案报告。肝损伤通常在治疗4到8周后出现，血清酶升高的模式通常是肝细胞型或混合型。免疫过敏特征（皮疹、发热、嗜酸性粒细胞增多）是罕见的，自身抗体形成也很少见。停药后1到3个月内恢复，所有病例在病程中都是轻微和自限性的（案例1）。

Clinically apparent liver injury from spironolactone is rare and only a few instances have been reported as isolated case reports. The liver injury typically arises after 4 to 8 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular or mixed. Immunoallergic features (rash, fever, eosinophilia) are rare as is autoantibody formation. Recovery has occurred within 1 to 3 months of stopping and all cases have been mild and self-limited in course (Case 1).

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：螺内酯

Compound:spironolactone

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：2

Severity Grade:2

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

螺内酯在2.6小时内达到最高浓度，其活性代谢物（坎利酮）在4.3小时内达到最高浓度。与食物同服时，螺内酯的生物利用度增加到95.4%。与食物同服螺内酯可将最高浓度从209ng/mL增加到301ng/mL。达到最高浓度的时间也从2.28小时增加到3.05小时。曲线下的面积从2103ng/mL*小时变化到4544ng/mL*小时。

Spironolactone reaches a maximum concentration in 2.6 hours and an active metabolite (canrenone) reaches a maximum concentration in 4.3 hours. When taken with food, the bioavailability of spironolactone increases to 95.4%. Giving spironolactone with food increases the maximum concentration from 209ng/mL to 301ng/mL. The time to maximum concentration also increases from 2.28 hours to 3.05 hours. The area under the curve varies from 2103ng/mL\*hr to 4544ng/mL*hr.

来源:DrugBank

吸收、分配和排泄

• 消除途径

螺内酯的代谢产物在尿液中排出42-56%，在大便中排出14.2-14.6%。尿液中没有未代谢的螺内酯。

Metabolites of spironolactone are excreted 42-56% in urine, and 14.2-14.6% in the feces. No unmetabolized spironolactone is present in the urine.

来源:DrugBank

吸收、分配和排泄

• 分布容积

分布容积数据不易获得。

Volume of distribution data is not readily available.

来源:DrugBank

吸收、分配和排泄

• 清除

清除数据并不容易获得。

Clearance data is not readily available.

来源:DrugBank

吸收、分配和排泄

当螺内酯被引入临床使用时，它的生物利用度不足，通过将药物制备成细粉或微粉形式，这一点得到了改善。螺内酯的绝对生物利用度间接估计约为73%，在食物存在的情况下会增强。几乎所有的吸收螺内酯（> 90%）都与血浆蛋白结合，在重复给药后，8天内达到稳态。口服100毫克剂量后，螺内酯的血浆半衰期为1-2小时，达到最大血浆浓度的时间为2-3.2小时，最大血浓度为92-148纳克/毫升，浓度-时间（0-24小时）曲线下的面积为1430-1541纳克/毫升每小时，消除半衰期为18-20小时。

At the time spironolactone was introduced for clinical use, its bioavailability was inadequate, and this was improved by preparing the drug in finely powdered or micronized form. The absolute bioavailability was indirectly estimated at approximately 73%, which was enhanced in the presence of food. Nearly all absorbed spironolactone (> 90 %) is bound to plasma proteins and, with repeated dosing, a steady state is achieved within 8 days. After oral intake of a 100-mg dose, the plasma half-time of spironolactone was 1-2 h, the time to maximum plasma concentration was 2-3.2 hr, the maximum blood concentration was 92-148 ng/mL, the area under the concentration--time (0-24 hr) curve was 1430-1541 ng/mL per hr and the elimination half-time was 18-20 hr.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• TSCA：
  Yes
• 危险品标志：
  T
• 安全说明：
  S22,S26,S36,S36/37/39,S45,S53
• 危险类别码：
  R60,R40
• WGK Germany：
  3
• 海关编码：
  2937290090
• RTECS号：
  TU4725000

制备方法与用途

螺内酯 理化性质

螺内酯为白色或类白色的细微结晶性粉末，微有苦味，无臭或带有轻微硫醇臭。它在氯仿中极易溶解，不溶于水但易溶于乙醇，且能溶于苯或醋酸乙酯。

简介

螺内酯是一种弱的保钾利尿药，又名安体舒通、螺旋内酯，其化学结构与醛固酮相似。它通过竞争性地阻断远曲小管及集合管细胞浆内的醛固酮受体，从而影响醛固酮和受体的结合，抑制K+-Na+交换，减少钾的排出，起到保钾利尿的作用。

螺内酯在市场上有螺内酯片与安体舒通乳两种形式。虽然它们成分相似，但药物形态不同。这种药物自发明以来已有40多年的历史，主要配合其他药物用于治疗原发性高血压和水肿性疾病。由于它能减少体内雄性激素的分泌，在医学上也用于治疗雄性脱发。尽管螺内酯的抗雄激素作用较弱，但它仍然可能影响激素水平，导致乳房触痛等问题。

制备 方法一

17-酮基甾环与乙炔通过加成反应生成乙炔基醇，随后进行羧化和氢化还原炔键的反应。这一系列步骤后得到五元螺环，即最终产物螺内酯。

方法二

使用Corey环氧化试剂氧化甾环的17-酮基环，然后加入丙二酸酯，形成五元螺环。通过雄烯二酮和原甲酸三乙酯反应生成3-乙氧基雄甾-3,5-二烯，经过碘化、格式反应、还原等步骤合成螺内酯。

用途

螺内酯作为一种合成的17-内酯类固醇，属于肾竞争性醛固酮拮抗剂。它主要用于治疗肝病、低肾素高血压和低钾血症。其活性代谢物即安体舒通具有抑制醛固酮生物合成的效果，并且可以阻断哇巴因效应。

生产方法

螺内酯可由乙炔雄二醇通过格式反应、羧化、成盐、氢化、内酯化、氧化、消除等步骤合成。

类别与毒性

螺内酯属于有毒物品，其毒性分级为高毒。急性毒性腹腔给药大鼠的半数致死量（LD50）为277毫克/公斤，口腹腔小鼠的LD50为260毫克/公斤。储存时需注意库房通风、低温干燥，并与食品原料分开存放。

灭火剂

使用干粉、泡沫、砂土或二氧化碳扑灭火灾。雾状水也可用于灭火。

请注意，以上信息仅供参考，在实际应用中请遵循专业指导和安全规范。

反应信息

• 作为反应物：
  描述：

  螺内酯 在 sodium hypochlorite 、 octabromotetrakis(2,6-dichlorophenyl)porphyrin Fe(III)Cl 作用下， 以 水 、 乙腈 为溶剂， 反应 0.5h， 生成 (7R,8R,9S,10R,13S,14S,17R)-3-hydroxy-10,13-dimethyl-7-methylsulfanylspiro[1,2,3,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-17,5'-oxolane]-2'-one
  参考文献：
  名称：

  [EN] EX VIVO METHODS FOR PREDICTING AND CONFIRMING IN VIVO METABOLISM OF PHARMACEUTICALLY ACTIVE COMPOUNDS
  [FR] MÉTHODES EX VIVO PERMETTANT DE PRÉDIRE ET DE CONFIRMER LE MÉTABOLISME IN VIVO DE COMPOSÉS PHARMACEUTIQUEMENT ACTIFS

  摘要：

  用于催化氧化药用活性化合物的方法和组合物，更具体地用于预测药用活性化合物体外代谢的方法，包括预测两种或更多药用活性化合物之间的体内相互作用。

  公开号：

  WO2015089089A1
• 作为产物：
  描述：

  3-乙氧基-雄甾-3,5-二烯-17-酮 在 三氟甲磺酸酐 、 C₃₀H₃₁Cl₃N₃⁽¹⁺⁾*BF₄^(1-) 、 四氯苯醌 、 三乙胺 、 lithium bromide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 1,2-二氯乙烷 为溶剂， 反应 7.0h， 生成 螺内酯
  参考文献：
  名称：

  一种制备螺内酯的方法

  摘要：

  本发明公开了一种制备螺内酯的方法，包括下列步骤：步骤1，将式(II)化合物与丙烯醛在催化剂、碱及路易斯酸作用下反应，得到式(III)化合物；步骤2，将式(III)化合物与氯醌反应，制得(IV)化合物；步骤3，将式(IV)化合物与硫代乙酸发生加成即制得螺内酯。本发明提供的螺内酯的制备方法具有合成路线短，所用的试剂价廉、易得，操作简单，总收率高，适于工业化生产的优点；为制备螺内酯提供了一条新的途径。

  公开号：

  CN107312060B
• 作为试剂：
  描述：

  methyl (2S)-2-(butoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate 在 盐酸 、 氨 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 螺内酯 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 (S)-2-Butoxycarbonylamino-3-{[2-(4-carbamimidoyl-phenyl)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid methyl ester
  参考文献：
  名称：

  Design, synthesis and in vitro activities of a series of benzimidazole/benzoxazole glycoprotein IIb/IIIa inhibitors

  摘要：

  A potent centrally constrained series of benzimidazole and benzoxazole glycoprotein IIb/IIIa inhibitors has been discovered based on the solution conformation of a cyclic RGD-containing peptide, DMP 728. The high potency of this series of compounds in the inhibition of platelet aggregation requires a benzamidine as the basic moiety and an alpha-carbamate or sulfonamide substituted beta-alanine as the acidic moiety.

  DOI：

  10.1016/0960-894x(95)00590-p

文献信息

• 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。
• NOVEL GLUCOKINASE ACTIVATORS AND METHODS OF USING SAME
  申请人：Ryono Denis E.

  公开号：US20080009465A1

  公开（公告）日：2008-01-10

  Compounds are provided which are phosphonate and phosphinate activators and thus are useful in treating diabetes and related diseases and have the structure wherein is a heteroaryl ring; R 4 is —(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 ), —(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g , —(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g , —(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10 ), or —(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10 ); R 5 and R 6 are independently selected from H, alkyl and halogen; Y is R 7 (CH 2 ) s or is absent; and X, n, Z, m, R 4 , R 5 , R 6 , R 7 , and s are as defined herein; or a pharmaceutically acceptable salt thereof. A method for treating diabetes and related diseases employing the above compounds is also provided.

  提供了磷酸酯和磷酸酯激活剂，因此在治疗糖尿病和相关疾病方面非常有用，并具有以下结构： 其中 是杂环芳基环； R 4 为—(CH 2 ) n -Z-(CH 2 ) m —PO(OR 7 )(OR 8 )、—(CH 2 ) n Z-(CH 2 ) m —PO(OR 7 )R g 、—(CH 2 ) n -Z-(CH 2 ) m —OPO(OR 7 )R g 、—(CH 2 ) n Z—(CH 2 ) m —OPO(R 9 )(R 10) 或—(CH 2 ) n Z—(CH 2 ) m —PO(R 9 )(R 10) ； R 5 和R 6 分别选择自H、烷基和卤素； Y为R 7 (CH 2 ) s 或不存在；以及 X、n、Z、m、R 4 、R 5 、R 6 、R 7 和s如本文所定义；或其药用盐。 还提供了一种利用上述化合物治疗糖尿病和相关疾病的方法。
• [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。
• PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
  申请人：Rewcastle Gordon William

  公开号：US20110009405A1

  公开（公告）日：2011-01-13

  Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.

  本文提供了式I的嘧啶基和1,3,5-三嗪基苯并咪唑化合物，以及它们的药物组合物、制备方法，以及作为抗癌治疗药物或药剂的用途，可以单独使用，也可以与放疗和/或其他抗癌药物联合使用。
• BRM TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
  申请人：Arvinas Operations, Inc.

  公开号：US20190300521A1

  公开（公告）日：2019-10-03

  The present disclosure relates to bifunctional compounds, which find utility as modulators of SMARCA2 or BRM (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand that binds to the Von Hippel-Lindau E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为SMARCA2或BRM（靶蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合Von Hippel-Lindau E3泛素连接酶的配体，另一端结合靶蛋白的双功能化合物，使得靶蛋白与泛素连接酶靠近以实现靶蛋白的降解（和抑制）。本公开展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由靶蛋白聚集或积累导致的疾病或紊乱。

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