N-[(2S)-2-{[L-α-门冬氨酰-N~5~-(二氨基甲亚基)-L-鸟氨酰基-L-缬氨酰]氨基}-2-(4-羟基苯基)乙酰基]-L-异白氨酰-L-组氨酰-L-脯氨酰-N-[(1S,4R)-4-乙酰基-3-氨基-1-(1H-咪唑-5-基甲基)-6-甲基-2-羰基庚基]-L-苯丙氨酸酰胺 | 106898-35-5

• 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: N-[(2S)-2-{[L-α-门冬氨酰-N~5~-(二氨基甲亚基)-L-鸟氨酰基-L-缬氨酰]氨基}-2-(4-羟基苯基)乙酰基]-L-异白氨酰-L-组氨酰-L-脯氨酰-N-[(1S,4R)-4-乙酰基-3-氨基-1-(1H-咪唑-5-基甲基)-6-甲基-2-羰基庚基]-L-苯丙氨酸酰胺
• 英文名称: 3,5-bis(trifluoromethyl)benzylhydrazine
• 英文别名: 3,5-Ditrifluoromethyl-benzyl-hydrazine；[3,5-bis(trifluoromethyl)phenyl]methylhydrazine
• CAS: 106898-35-5
• 化学式: C₉H₈F₆N₂
• mdl: MFCD07786458
• 分子量: 258.166
• InChiKey: SKCQHPUOBZJWOY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  38
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-[(2S)-2-{[L-α-门冬氨酰-N~5~-(二氨基甲亚基)-L-鸟氨酰基-L-缬氨酰]氨基}-2-(4-羟基苯基)乙酰基]-L-异白氨酰-L-组氨酰-L-脯氨酰-N-[(1S,4R)-4-乙酰基-3-氨基-1-(1H-咪唑-5-基甲基)-6-甲基-2-羰基庚基]-L-苯丙氨酸酰胺 在 亚硝酸丁酯 、 sodium ethanolate 作用下， 以 乙醇 为溶剂， 反应 15.0h， 生成 sodium (3,5-bis(trifluoromethyl)phenyl)methanediazoate
  参考文献：
  名称：

  Mechanisms of Benzyl Group Transfer in the Decay of (E)-Arylmethanediazoates and Aryldiazomethanes in Aqueous Solutions

  摘要：

  Rate constants are reported for the buffer-independent decay of ten (E)-arylmethanediazontes in aqueous media at 25 degrees C, ionic strength 1 M (NaClO4), 4% 2-propanol, in the region of pH 4-12. The rate constants are proportional to hydrogen ion concentration at high pH and become pH independent in the low-pH region. Varying concentrations of oxyanion, amine, and hydrazine buffers over the range 0.05-0.2 M increased the pseudo-first-order rate constant for decay of the diazoates by less than 10%. The azide-water selectivities, k(2)/k(5), for partitioning of the benzyl groups in the decay of (E)-(3,5-bis(trifluoromethyl)phenyl)methanediazonate and the (3,5-bis(trifluoromethyl)phenyl)diazomethane are determined to be 0.20 and 0.21 M(-1), respectively, in phosphate buffered water and 0.27 and 0.26 M(-1), respectively, in 20/80 DMSO-water. It is concluded that these two reactants decompose, in these media, via a common free diazonium ion intermediate that is formed in the case of the diazoate upon unassisted N-O bond cleavage of the diazoic acid. A common rate-limiting step is indicated for all the diazoates by the correlation line for the plot of log k(1), the pH independent rate constant, against sigma that has a slope rho = -1.23. Product ratios for trapping of benzyl groups derived from other pairs of arylmethanediazoates and aryldiazomethanes with less electron withdrawing groups are different outside experimental error, indicating the importance of different nitrogen-separated ion pairs in these reactions. The (E)-(p-methoxy)phenyl)methane-(16)-diazoat decomposes in O-16/O-18 water to give alcohol that has an ''excess'' abundance of O-16 compared to solvent, Decomposition of the same compound in 50/50 trifluoroethanol-water with varying concentrations of azide indicates that azide ion appears to trap a limiting amount, similar to 80%, of the p-methoxybenzyl group. Quantitative analysis of the data indicates that 16% of the p-methoxybenzyl cation is trapped by solvent at the nitrogen-separated ion pair stage, in the absence of azide ion, There is a 9-fold enhancement of selectivity for trifluoroethanol at the ion pair stage that is ascribed to a proton switch initiated by the leaving hydroxide ion in the ion pair. The values of k(2)/k(5) similar to 0.2 M(-1) and k(T)/k(H) similar to 0.5-0.6 for the trifluoroethanol-water selectivity and k(ET)/k(T) similar to 1 for the ethanol-trifluoroethanol selectivity are independent of substituent in the decay of arylmethanediazoates (X = H and EWG) in water, water-trifluoroethanol (50/50), and water-trifluoroethanol-ethanol (50/40/10), respectively. It is concluded from this that the product-determining steps do not involve chemical bonding but rather rotational/translational reorientation of the nucleophiles in the first solvation sphere of the carbocation intermediates. It is concluded that the values of k(H)/k(T) = 0.5-0.6 indicate preferential solvation of the cation precursor by trifluoroethanol. It is shown that a preferential interaction for trifluoroethanol of <1 kcal/mol is required to generate the observed selectivities.

  DOI：

  10.1021/ja00120a004
• 作为产物：
  描述：

  3,5-双三氟甲基苄基氯 在 一水合肼 作用下， 以 乙醇 为溶剂， 生成 N-[(2S)-2-{[L-α-门冬氨酰-N~5~-(二氨基甲亚基)-L-鸟氨酰基-L-缬氨酰]氨基}-2-(4-羟基苯基)乙酰基]-L-异白氨酰-L-组氨酰-L-脯氨酰-N-[(1S,4R)-4-乙酰基-3-氨基-1-(1H-咪唑-5-基甲基)-6-甲基-2-羰基庚基]-L-苯丙氨酸酰胺
  参考文献：
  名称：

  某些新型抗增殖吲哚基化学实体的简便合成和分子表征

  摘要：

  癌细胞经常产生耐药性，导致化疗失败。此外，化学疗法因其高毒性而受到阻碍。因此，开发具有改善临床疗效和低毒性的新型化疗药物是当务之急。几种吲哚衍生物表现出独特的抗癌机制，这些机制与各种分子靶标有关。在这项研究中，目标化合物 4a-q 是通过取代的苄基氯与水合肼反应生成苄基肼得到的。随后，使用 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺作为偶联剂，使适当的取代苄基肼与 1H-吲哚-2-羧酸或 5-甲氧基-1H-吲哚-2-羧酸反应. 所有化合物在三种细胞系中均表现出细胞毒性，即 MCF-7、A549 和 HCT。化合物 4e 表现出最高的细胞毒性，平均 IC50 为 2 µM。此外，流式细胞术研究显示 Annexin-V 和 7-AAD 阳性细胞群的流行率显着增加。4a-q 的几种衍生物对测试的细胞系显示出中度至高度的细胞毒性，化合物 4e 具有最高的细胞毒性，表明它可能具有潜在的细胞凋亡诱导能力。

  DOI：

  10.3390/ijms24097862

文献信息

• [EN] NOVEL NEUROKININ 1 RECEPTOR ANTAGONIST COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS ANTAGONISTES DU RÉCEPTEUR DE LA NEUROKININE 1
  申请人：LEO PHARMA AS

  公开号：WO2013124286A1

  公开（公告）日：2013-08-29

  The present invention relates to a compound according to formula (A) wherein n is 1 or 2; R1 and R2 are independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, CD3 or halogen; R3 is hydrogen, C(=O)OR7 or C1-4 alkyl optionally substituted with hydroxy or NR8R9; R4 is hydrogen or oxo; R5 and R6 are independently hydrogen, hydroxy, NR8R9, C( =O)R7, C( =O)OR7, C( =O)NR8R9, C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted with hydroxy, NR8R9 or a 5- or 6-membered heterocyclic ring, wherein said 5- or 6-membered heterocyclic ring is optionally substituted with C1-4 alkyl or C(=O)R7; or R5 and R6, together with the carbon atom to which they are attached, form =CH2 or a 5- or 6-membered heterocycloalkyl, wherein said heterocycloalkyl is optionally substituted with C1-4 alkyl; R7 is hydrogen or C1-4 alkyl; R8 and R9 are independently hydrogen or C1-4 alkyl, or R8 and R9, together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclic ring, or a pharmaceutically acceptable salt or solvate thereof. The invention relates further to intermediates for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating or ameliorating pruritic dermal diseases or conditions with said compounds, and to the use of said compounds in the manufacture of medicaments.

  本发明涉及一种根据公式（A）的化合物，其中n为1或2；R1和R2独立为氢，C1-4烷基，C1-4卤代烷基，C1-4烷氧基，CD3或卤素；R3为氢，C(=O)OR7或C1-4烷基，可选地被羟基或NR8R9取代；R4为氢或氧代；R5和R6独立为氢，羟基，NR8R9，C(=O)R7，C(=O)OR7，C(=O)NR8R9，C1-4烷基，其中所述C1-4烷基可选地被羟基，NR8R9或5-或6-成员的杂环环取代，其中所述5-或6-成员的杂环环可选地被C1-4烷基或C(=O)R7取代；或R5和R6与它们所连接的碳原子一起形成=CH2或5-或6-成员的杂环烷基，其中所述杂环烷基可选地被C1-4烷基取代；R7为氢或C1-4烷基；R8和R9独立为氢或C1-4烷基，或R8和R9与它们所连接的氮原子一起形成一个5-或6-成员的杂环环，或其药用可接受的盐或溶剂化物。本发明进一步涉及用于制备所述化合物的中间体，所述化合物用于治疗，包含所述化合物的药物组合物，使用所述化合物治疗或改善瘙痒性皮肤病或状况的方法，以及所述化合物在药物制造中的用途。
• 3-Arylamino pyridine derivatives
  申请人：Abel Ulricn

  公开号：US20090093462A1

  公开（公告）日：2009-04-09

  The invention provides novel, substituted 3-arylamino pyridine compounds (I) pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R1, R2, R9, R10, R11, R12, R13, R14 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.

  本发明提供了新型的取代的3-芳基氨基吡啶化合物(I)，其药学上可接受的盐、溶剂和前药化合物，其中W、R1、R2、R9、R10、R11、R12、R13、R14如规范中所定义。这些化合物是MEK抑制剂，可用于治疗高增殖性疾病，如癌症、再狭窄和炎症。本发明还揭示了在哺乳动物，特别是人类中治疗高增殖性疾病的这些化合物的用途，以及包含这些化合物的制药组合物。
• 3-Arylamino Pyridine Derivatives
  申请人：Abel Ulrich

  公开号：US20110224192A1

  公开（公告）日：2011-09-15

  The invention provides novel, substituted 3-arylamino pyridine compounds pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R1, R2, R9, R10, R11, R12, R13, R14 are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.

  该发明提供了新型的取代的3-芳基氨基吡啶化合物及其药学上可接受的盐、溶剂化物和前药化合物，其中W、R1、R2、R9、R10、R11、R12、R13、R14在说明书中有定义。这些化合物是MEK抑制剂，可用于治疗过度增殖性疾病，如癌症、再狭窄和炎症。还公开了在哺乳动物，特别是人类中治疗过度增殖性疾病的使用以及含有这些化合物的制药组合物。
• 3-ARYLAMINO PYRIDINE DERIVATIVES
  申请人：Applied Research Systems ARS Holding N.V.

  公开号：EP1802579A1

  公开（公告）日：2007-07-04
• Derivatives of 3-arylaminopyridine
  申请人：Merck Serono SA

  公开号：EP1802579B1

  公开（公告）日：2013-11-20