2(S)-(2-benzoylphenylamino)-3-(4-hydroxyphenyl)propionic acid | 196814-73-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2(S)-(2-benzoylphenylamino)-3-(4-hydroxyphenyl)propionic acid
• 英文别名: 2(S)-(2-benzoyl-anilino)-3-(4-hydroxyphenyl)-propanoic acid；N-(2-benzoylphenyl)-L-tyrosine；(2S)-2-(2-benzoylanilino)-3-(4-hydroxyphenyl)propanoic acid
• CAS: 196814-73-0
• 化学式: C₂₂H₁₉NO₄
• 分子量: 361.397
• InChiKey: BLWKWOVOFWHFLD-FQEVSTJZSA-N

物化性质

• 沸点：
  654.2±55.0 °C(Predicted)
• 密度：
  1.318±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  86.6
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  氯代(邻氯苯基)二苯基甲烷 、 2,5-二甲基苯甲醇 、 2(S)-(2-benzoylphenylamino)-3-(4-hydroxyphenyl)propionic acid 在 polystyrene resin 、 cesium bicarbonate 、 三苯基膦 、 三氟乙酸 、 偶氮二甲酸二乙酯 作用下， 生成 (S)-2-(2-Benzoyl-phenylamino)-3-[4-(2,5-dimethyl-benzyloxy)-phenyl]-propionic acid
  参考文献：
  名称：

  N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 2. Structure−Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety

  摘要：

  We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic (2) (PPAR gamma pK(i) = 8.94, PPAR gamma, pEC(50) = 9.47) as a potent and selective PPAR gamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPAR gamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (16) (PPAR gamma pK(i) = 8.85, PPAR gamma pEC(50) = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}pheynyl)propionic acid (24) (PPAR gamma pK(i) = 8.6, PPAR gamma pEC(50) = 8.89) provided two potent and selective PPAR gamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPAR gamma ligands (PPAR gamma pK(i)'s 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPAR gamma binding, functional activity, selectivity, and aqueous solubility.

  DOI：

  10.1021/jm980413z
• 作为产物：
  描述：

  甲基N-(2-苯甲酰基苯基)酪氨酸酯 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 3.0h， 以95%的产率得到2(S)-(2-benzoylphenylamino)-3-(4-hydroxyphenyl)propionic acid
  参考文献：
  名称：

  N-(2-Benzoylphenyl)-l-tyrosine PPARγ Agonists. 2. Structure−Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety

  摘要：

  We previously reported the identification of (2S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propanoic (2) (PPAR gamma pK(i) = 8.94, PPAR gamma, pEC(50) = 9.47) as a potent and selective PPAR gamma agonist. We now report the expanded structure-activity relationship around the phenyl alkyl ether moiety by pursuing both a classical medicinal chemistry approach and a solid-phase chemistry approach for analogue synthesis. The solution-phase strategy focused on evaluating the effects of oxazole and phenyl ring replacements of the 2-(5-methyl-2-phenyloxazol-4-yl)ethyl side chain of 2 with several replacements providing potent and selective PPAR gamma agonists with improved aqueous solubility. Specifically, replacement of the phenyl ring of the phenyloxazole moiety with a 4-pyridyl group to give 2(S)-((2-benzoylphenyl)amino)-3-{4-[2-(5-methyl-2-pyridin-4-yloxazol-4-yl)ethoxy]phenyl}propionic acid (16) (PPAR gamma pK(i) = 8.85, PPAR gamma pEC(50) = 8.74) or a 4-methylpiperazine to give 2(S)-((2-benzoylphenyl)amino)-3-(4-{2-[5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl]ethoxy}pheynyl)propionic acid (24) (PPAR gamma pK(i) = 8.6, PPAR gamma pEC(50) = 8.89) provided two potent and selective PPAR gamma agonists with increased solubility in pH 7.4 phosphate buffer and simulated gastric fluid as compared to 2. The second strategy took advantage of the speed and ease of parallel solid-phase analogue synthesis to generate a more diverse set of phenyl alkyl ethers which led to the identification of a number of novel, high-affinity PPAR gamma ligands (PPAR gamma pK(i)'s 6.98-8.03). The combined structure-activity data derived from the two strategies provide valuable insight on the requirements for PPAR gamma binding, functional activity, selectivity, and aqueous solubility.

  DOI：

  10.1021/jm980413z

文献信息

• Combinations comprising dipeptidylpeptidase-iv inhibitor
  申请人：——

  公开号：US20030139434A1

  公开（公告）日：2003-07-24

  The invention relates to a combination which comprises a DPP-IV inhibitor and at least one further antidiabetic compound, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, &agr;-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and &agr; 2 -adrenergic antagonists, for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase-IV (DPP-IV), in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; and the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight.

  该发明涉及一种组合物，包括DPP-IV抑制剂和至少一种其他抗糖尿病化合物，优选选自胰岛素信号通路调节剂组，如蛋白酪氨酸磷酸酶（PTPases）抑制剂，非小分子模拟化合物和谷氨酰基果糖-6-磷酸转移酶（GFAT）抑制剂，影响失调肝葡萄糖产生的化合物，如葡萄糖-6-磷酸酶（G6Pase）抑制剂，果糖-1,6-二磷酸酶（F-1,6-BPase）抑制剂，糖原磷酸化酶（GP）抑制剂，胰高血糖素受体拮抗剂和磷酸烯醇丙酮酸羧化酶（PEPCK）抑制剂，丙酮酸脱氢酶激酶（PDHK）抑制剂，胰岛素敏感性增强剂，胰岛素分泌增强剂，α-葡萄糖苷酶抑制剂，胃排空抑制剂，胰岛素和α2-肾上腺素受体拮抗剂，用于同时、分开或顺序使用以预防、延缓进展或治疗由二肽基肽酶-IV（DPP-IV）介导的疾病的组合物，特别是糖尿病，更特别是2型糖尿病，糖耐量受损（IGT）状况，空腹血浆葡萄糖受损状况，代谢性酸中毒，酮症，关节炎，肥胖和骨质疏松症；以及利用这种组合物进行哺乳动物的化妆治疗，以实现对体重的美容有益减少。
• [EN] TETRAHYDROQUINOLINES AS AGONISTS OF LIVER-RECEPTORS<br/>[FR] TETRAHYDROQUINOLEINES UTILISEES COMME AGONISTES DES RECEPTEURS HEPATIQUES
  申请人：CARE X S A

  公开号：WO2004072041A1

  公开（公告）日：2004-08-26

  The present invention relates to specific compounds and pharmaceutically acceptable salts thereof; methods for synthesizing these compounds; compositions comprising at least one of these compounds or a pharmaceutically acceptable salt thereof; and methods for modulating liver-X receptors (LXRs) activity. The present invention further concerns methods for treating and/or preventing a disease or disorder selected from the group consisting of dyslipidemia, including hyperlipidemia, dyslipoproteinemia, including hyperlipoproteinemia, disorders related to cholesterol or bile acid metabolisms, including hypercholesterolemia, gall stone or gall bladder disorders, cardiovascular disease, including atherosclerotic cardiovascular diseases, coronary artery diseases, peripheral vascular diseases, cerebrovascular diseases, thrombotic disorders, restenosis or septic shock, CNS diseases including those affecting cognitive function or age related disorders such as Alzheimer's disease, Syndrome X, a liver-X receptor-associated disorder, obesity, pancreatitis, hypertension, renal disease, cancer, rheumatoid arthritis, inflammation, skin proliferative disorders, including psoriasis, atopic dermatitis or acne, and sexual impotence, comprising administering a therapeutically effective amount of a composition comprising at least one compound or a pharmaceutically acceptable salt thereof of the invention.

  本发明涉及特定化合物及其药用可接受盐；合成这些化合物的方法；包含至少一种这些化合物或其药用可接受盐的组合物；以及调节肝-X受体（LXRs）活性的方法。本发明还涉及治疗和/或预防以下疾病或疾病选择性群体中的疾病或紊乱的方法，包括脂质代谢异常，包括高脂血症，脂蛋白代谢异常，包括高脂蛋白血症，与胆固醇或胆汁酸代谢有关的紊乱，包括高胆固醇血症，胆结石或胆囊紊乱，心血管疾病，包括动脉粥样硬化心血管疾病，冠状动脉疾病，外周血管疾病，脑血管疾病，血栓性疾病，再狭窄或感染性休克，影响认知功能或与老年疾病如阿尔茨海默病、X综合征、肝-X受体相关疾病、肥胖、胰腺炎、高血压、肾脏疾病、癌症、类风湿性关节炎、炎症、皮肤增生性疾病，包括银屑病、特应性皮炎或痤疮，以及性功能障碍，包括给予本发明至少一种化合物或其药用可接受盐的组合物的治疗有效量。
• [EN] APOPTOSIS SIGNAL-REGULATING KINASE 1 INHIBITORS<br/>[FR] INHIBITEURS DE KINASE 1 DE RÉGULATION DE SIGNAL D'APOPTOSE
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2009123986A1

  公开（公告）日：2009-10-08

  The present invention relates to apoptosis signal-regulating kinase 1 ("ASK1") inhibiting compounds of the formula (I); wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

  本发明涉及具有以下结构的凋亡信号调节激酶1（"ASK1"）抑制化合物（I）；其中变量如本文所定义。该发明还涉及包含这些化合物的药物组合物、试剂盒和制造品；用于制备这些化合物的有用中间体和方法；以及使用这些化合物的方法。
• [EN] INDOLYLMALEIMIDE DERIVATIVES<br/>[FR] DERIVES D'INDOLYLMALEIMIDE
  申请人：NOVARTIS AG

  公开号：WO2005068454A1

  公开（公告）日：2005-07-28

  A compound of formula I wherein R, Re, Rb, Rc, Rd and Re are as defined in the, specification, processes for their production, their uses, in particular in transplantation, and pharmaceutical compositions containing them.

  式I的化合物，其中R、Re、Rb、Rc、Rd和Re如规范中定义的那样，它们的生产方法，它们的用途，特别是在移植中，以及含有它们的药物组合物。
• ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS
  申请人：Christopher J. Ronald

  公开号：US20070060530A1

  公开（公告）日：2007-03-15

  Pharmaceutical compositions comprising 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts thereof are provided as well as kits and articles of manufacture comprising the pharmaceutical compositions as well as methods of using the pharmaceutical compositions.

  提供包含2-[6-(3-氨基哌啶-1-基)-3-甲基-2,4-二氧杂嘧啶-3,4-二氢-2H-嘧啶-1-基甲基]-4-氟苯甲腈及其药用可接受的盐的药物组合物，以及包含该药物组合物的工具箱和制品，以及使用该药物组合物的方法。