calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-(C-oxido-N-phenylcarbonimidoyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate;(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-(C-oxido-N-phenylcarbonimidoyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate;(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
• 化学式: C66H68CaF2N4O10
• 分子量: 1155.3
• InChiKey: FQCKMBLVYCEXJB-MNSAWQCASA-L

计算性质

• 辛醇/水分配系数(LogP)：
  9.58
• 重原子数：
  83
• 可旋转键数：
  22
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  229
• 氢给体数：
  6
• 氢受体数：
  12

ADMET

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：共识意见是，由于担心干扰婴儿脂质代谢，服用他汀类药物的妇女不应哺乳。然而，也有人认为，对于家族性高胆固醇血症的纯合子儿童，从1岁开始就使用他汀类药物，他汀类药物的口服生物利用度低，对哺乳婴儿的风险很低，尤其是使用罗苏伐他汀和普伐他汀。一些证据表明，阿托伐他汀可以由哺乳母亲服用，他们的婴儿没有明显的发展问题。在更多数据出现之前，可能会优先选择另一种药物，特别是在哺乳新生儿或早产儿时。 ◉ 对哺乳婴儿的影响：在一项纯合子家族性高胆固醇血症患者的病例系列中，6名患者在产后重新开始服用他汀类药物后，哺乳了11名婴儿。这些妇女使用的特定他汀类药物没有报告，大多数服用他汀类药物的妇女使用的是阿托伐他汀，每日40或80毫克。所有后代的正常早期儿童发展得到了报告。孩子们在适当的年龄开始上学，没有报告学习困难。 ◉ 对泌乳和母乳的影响：在接受阿托伐他汀治疗的男性中报告了男性乳房发育症。在一个测量了血清催乳素的案例中，催乳素水平正常。在另一个案例中，可能的罗苏伐他汀诱导的男性乳房发育症在患者药物改为阿托伐他汀后得到了解决。

◉ Summary of Use during Lactation:The consensus opinion is that women taking a statin should not breastfeed because of a concern with disruption of infant lipid metabolism. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with rosuvastatin and pravastatin. Some evidence indicates that atorvastatin can be taken by nursing mothers with no obvious developmental problems in their infants. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants:In a case series of patients with homozygous familial hypercholesterolemia, 6 patients breastfed 11 infants after restarting statin therapy postpartum. The specific statin used by these women was not reported, most of the women on statin therapy were using atorvastatin, either 40 or 80 mg, daily. Normal early child development was reported for all offspring. Children started school at the appropriate age and no learning difficulties were reported. ◉ Effects on Lactation and Breastmilk:Gynecomastia has been reported in men taking atorvastatin. Serum prolactin was normal in one case where it was measured. In another case, possible rosuvastatin-induced gynecomastia resolved after the patient’s medication was changed to atorvastatin.

来源:Drugs and Lactation Database (LactMed)

反应信息

• 作为反应物：
  描述：

  calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-(C-oxido-N-phenylcarbonimidoyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate;(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid 在 sodium hydrogen sulfate 、 magnesium sulfate 作用下， 以 乙酸乙酯 为溶剂， 以to afford 2.85 g (5.11 mmole) of atorvastatin acid的产率得到Atorvastatin acid
  参考文献：
  名称：

  Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase

  摘要：

  本发明提供物质组成、套件及其使用方法，用于治疗与MAP激酶相关的疾病和/或HMG-CoA还原酶相关疾病。具体而言，本发明提供用于通过抑制p38α MAP激酶和/或HMG-CoA还原酶来治疗动物主体的炎症和/或心血管疾病的组成物，以及提供这些组成物的配方和给药方式。本发明进一步提供用于有理设计MAP激酶、HMG-CoA还原酶或二者的抑制剂的方法，以在本发明的实践中使用。

  公开号：

  US20050261354A1
• 作为产物：
  描述：

  阿伐他汀钠 生成 calcium;(3R,5R)-7-[2-(4-fluorophenyl)-4-(C-oxido-N-phenylcarbonimidoyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate;(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
  参考文献：
  名称：

  (R-(R*R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl-3-phenyl-4((phenylamino)-carbonyl)-1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof

  摘要：

  [R-(R*,R*)]-2-(4-氟苯基)-β,δ-双羟基-5-((1-甲基乙基)-3-苯基-4-[(苯氨酰)基]-1H-吡咯-1-庚酸或(2R-trans)-5-(4-氟苯基)-2-(1-甲基乙基-N,4-二苯基-1-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-羧酰胺；以及其制备方法和药学上可接受的盐。

  公开号：

  EP1061073A1

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。
• [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。
• Small molecules for treatment of hypercholesterolemia and related diseases
  申请人：Sircar C. Jagadish

  公开号：US20050277690A1

  公开（公告）日：2005-12-15

  The present invention provides compositions adapted to enhance reverse cholesterol transport in mammals. The compositions are suitable for oral delivery and useful in the treatment and/or prevention of hypercholesterolemia, atherosclerosis and associated cardiovascular diseases.

  本发明提供了适用于增强哺乳动物体内逆向胆固醇转运的组合物。这些组合物适合口服给药，并可用于治疗和/或预防高胆固醇血症、动脉粥样硬化及相关心血管疾病。
• [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。
• 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。