quinagolide | 140630-80-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: quinagolide
• 英文别名: (-)-N,N-diethyl-N'-<(3S,4aR,10aR)-1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-propyl-3-benzoquinolinyl>sulfamide；(3a,4aα,10aβ)-(+/-)-N,N-diethyl-N'-(1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-propylbenzo[g]quinolin-3-yl)sulfamide；(3S,4aS,10aR)-3-(diethylsulfamoylamino)-6-hydroxy-1-propyl-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinoline
• CAS: 140630-80-4
• 化学式: C₂₀H₃₃N₃O₃S
• 分子量: 395.566
• InChiKey: GDFGTRDCCWFXTG-ZIFCJYIRSA-N

物化性质

• 沸点：
  539.1±60.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)
• 熔点：
  231-237
• 溶解度：
  Sparingly soluble in water (0.2%)

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  81.3
• 氢给体数：
  2
• 氢受体数：
  6

ADMET

代谢

喹诺前列素经历广泛的首过代谢，其主要循环代谢物是硫酸盐和葡萄糖醛酸苷共轭物。N-脱乙基类似物是一种生物活性代谢物，而硫酸盐或葡萄糖醛酸苷共轭物和N，N-二脱乙基类似物是无活性代谢物。

Quinagolide undergoes extensive first pass metabolism with sulfate and glucuronide conjugates being the major circulating metabolites. N-desethyl analogue is a biologically active metabolite while sulfate or glucuronide conjugates and N,N-didesethyl analogue are inactive metabolites.

来源:DrugBank

代谢

去甲高里得酸是人类已知的代谢物，包括(2S,3S,4S,5R)-6-[[(3S,4aS,10aR)-3-(二乙磺酰氨基)-1-丙基-3,4,4a,5,10,10a-六氢-2H-苯并[g]喹啉-6-基]氧基]-3,4,5-三羟基氧杂环己烷-2-羧酸。

Quinagolide has known human metabolites that include (2S,3S,4S,5R)-6-[[(3S,4aS,10aR)-3-(diethylsulfamoylamino)-1-propyl-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-6-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

毒理性

• 蛋白质结合

血浆蛋白结合被认为是非特异性的，大约有90%的比例。

Plasma protein binding is reported to be non-specific with an approximate ratio of 90%.

来源:DrugBank

吸收、分配和排泄

• 吸收

辛纳戈利德的吸收迅速而广泛，口服摄入后95%的剂量被吸收，但由于系统前代谢，其绝对生物利用度较低（4%）。达到峰值血浆浓度的时间为30-60分钟。在推荐的治疗剂量下，辛纳戈利德在摄入后2小时内开始降低催乳素，在4到6小时内达到最大效果，并能维持至少24小时。

The absorption of quinagolide is rapid and extensive with 95% of the dose absorbed after oral ingestion, however the absolute bioavailability is low (4 %) due to pre-systemic metabolism. The time to reach peak plasma concentration is 30-60 minutes. Prolactin-lowering effect of quinagolide at recommended therapeutic doses occurs within 2 hours after ingestion reaches a maximum within 4 to 6 hours and is maintained for at least 24 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

超过95%的总剂量以代谢物的形式被排出，通过尿液和粪便的排泄大约相等。肾脏消除占总消除的50%，尿液中可以检测到硫酸盐或葡萄糖醛酸苷结合物、N-脱乙基和N,N-二脱乙基类似物。硫酸盐或葡萄糖醛酸苷结合物、N-脱乙基和N,N-二脱乙基类似物的非结合形式被排入粪便中，粪便消除占总药物消除的40%。

More than 95% of total dose is excreted as metabolites and the excretion via urine and feces is approximately equal. Renal elimination accounts for 50% of total elimination, where sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues can be detected in the urine. Unconjugated forms of sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues are excreted into feces, and fecal elimination accounts for 40% of the total elimination of the drug.

来源:DrugBank

吸收、分配和排泄

• 分布容积

单次口服给药后，近似分布容积为100L。母药和代谢物预测将在血管外室广泛分布，主要靶器官为肝脏、肾脏、唾液腺和垂体。

Approximate volume of distribution is 100L following a single oral admininstration. The parent drug and metabolites is predicted to be extensively distributed in the extravascular compartment with primary target organs being the liver, kidneys, salivary glands and pituitary.

来源:DrugBank

反应信息

• 作为产物：
  描述：

  (-)-(3S,4aR,10aR)-1,2,3,4,4a,5,10,10a-octahydro-1,6-dimethoxy-3-(methoxycarbonyl)benzoquinoline 在 盐酸 、 palladium on activated charcoal 、 氢气 、 三溴化硼 、 一水合肼 、 溶剂黄146 、 亚硝酰氯 、 三乙胺 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 丙醇 、 氯仿 、 水 为溶剂， 生成 quinagolide
  参考文献：
  名称：

  Resolution and absolute configuration of the potent dopamine agonist N,N-diethyl-N'-[(3.alpha.,4a.alpha.,10a.beta.)-1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-propyl-3-benzo[g]quinolinyl]sulfamide

  摘要：

  The synthesis and preliminary pharmacological evaluation of the optical antipodes of the title compound (+/-)-1 (CV 205-502) is presented. The dopaminomimetic activity is shown to reside entirely in the (-) enantiomer. Crystallographic analysis has proven that the absolute configuration of the active (-) enantiomer corresponds to that of its ergoline analogue 3 (CQ 32-084) and of apomorphine (5).

  DOI：

  10.1021/jm00148a030

文献信息

• [EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
  申请人：BAYER PHARMA AG

  公开号：WO2016174183A1

  公开（公告）日：2016-11-03

  The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.

  本申请涉及至少两种组分的新型组合，组分A和组分B：·组分A是根据本文所定义的式(I)的IRAK4抑制化合物，或其对映体、对映异构体、代谢物、盐、溶剂合物或其盐的溶剂合物；·组分B是BTK抑制化合物，或其药学上可接受的盐；以及，可选地，·一种或多种组分C，它们是药用产品；其中上述定义的化合物A和B中的一种或两种可选择地存在于用于治疗和/或预防疾病的制剂中，准备用于同时、分开或顺序给药，用于治疗和/或预防疾病，以及用于生产用于治疗和/或预防疾病的药物的用途，特别是用于治疗和/或预防子宫内膜异位症、淋巴瘤、黄斑变性、慢性阻塞性肺病、肿瘤性疾病和牛皮癣。
• [EN] AMIDOIMIDAZOPYRIDAZINES AS MKNK-1 KINASE INHIBITORS<br/>[FR] AMIDOIMIDAZOPYRIDAZINES À TITRE D'INHIBITEURS DE KINASES MKNK-1
  申请人：BAYER PHARMA AG

  公开号：WO2014118135A1

  公开（公告）日：2014-08-07

  The present invention relates to amido-substituted imidazopyridazine compounds of general formula (I) : in which A, R1, R2, R3, R4 and n are as defined in the claims, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及一般式(I)的酰胺取代咪唑吡啶化合物，其中A、R1、R2、R3、R4和n如权利要求中所定义，以及制备所述化合物的方法，用于制备所述化合物的有用中间体化合物，包括所述化合物的药物组合物和组合物，以及利用所述化合物制造用于治疗或预防疾病的药物组合物，特别是用作唯一药剂或与其他活性成分结合。
• [EN] INHIBITORS OF THE WNT SIGNALLING PATHWAYS<br/>[FR] INHIBITEURS DES VOIES DE SIGNALISATION WNT
  申请人：BAYER PHARMA AG

  公开号：WO2015140196A1

  公开（公告）日：2015-09-24

  The present invention relates to inhibitors of the Wnt signalling pathways of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative disorder, as a sole agent or in combination with other active ingredients.

  本发明涉及通式（I）所述和定义的Wnt信号通路抑制剂，涉及制备该类化合物的方法，有用于制备该类化合物的中间化合物，包含该类化合物的药物组合物和组合物，以及利用该类化合物制造用于治疗或预防疾病的药物组合物，特别是用作唯一药剂或与其他活性成分组合使用时，用于治疗或预防过度增殖性疾病。
• [EN] TARGETED RADIOPHARMACEUTICALS FOR THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER<br/>[FR] PRODUITS RADIOPHARMACEUTIQUES CIBLÉS POUR LE DIAGNOSTIC ET LE TRAITEMENT DU CANCER DE LA PROSTATE
  申请人：BAYER AS

  公开号：WO2021013978A1

  公开（公告）日：2021-01-28

  A compound of general formula (I): wherein: n is 1, 2 or 3; R1, R2, R3 and R4, independently represent OH or Q; and 20 Q represents a tissue-targeting moeity selected from the group consisting of or a stereoisomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said 25 compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of soft tissue diseases, as a sole agent or in combination with other active ingredients.

  通用式(I)的化合物：其中：n为1、2或3；R1、R2、R3和R4独立地代表OH或Q；Q代表从群组中选择的组织靶向基团，或其立体异构体、水合物、溶剂合物、盐或其混合物，制备所述化合物的方法，用于制备所述化合物的中间化合物，包含所述化合物的药物组合物和组合物，以及用于制造用于治疗或预防疾病的药物组合物的所述化合物的用途，特别是软组织疾病的治疗或预防，作为唯一药剂或与其他活性成分结合使用。
• [EN] 2-HETEROARYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4-CARBOXAMIDES FOR THE TREATMENT OF CANCER<br/>[FR] 2-HÉTÉROARYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4-CARBOXAMIDES POUR LE TRAITEMENT DU CANCER
  申请人：BAYER AG

  公开号：WO2018146010A1

  公开（公告）日：2018-08-16

  The present invention covers 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I), in which X, R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.

  本发明涵盖了一般式(I)的2-杂环芳基-3-酮基-2,3-二氢吡啶嗪-4-羧酰胺化合物，其中X、R1、R2、R3、R4和R5如本文所定义，制备所述化合物的方法，用于制备所述化合物的有用中间体化合物，包含所述化合物的药物组合物和组合物，以及利用所述化合物制造用于治疗或预防疾病的药物组合物，特别是癌症或与异常AHR信号传导相关的疾病，或与失调免疫反应或其他与异常AHR信号传导相关的疾病，作为单一药剂或与其他活性成分组合使用。