N-methyl-N'-(5-hydroxy-3-carboxyphenyl)thiourea | 717138-32-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-methyl-N'-(5-hydroxy-3-carboxyphenyl)thiourea
• 英文别名: 3-hydroxy-5-[[(methylamino)thioxomethyl]amino]benzoic acid；3-hydroxy-5-(methylcarbamothioylamino)benzoic acid
• CAS: 717138-32-4
• 化学式: C₉H₁₀N₂O₃S
• 分子量: 226.256
• InChiKey: ZMZDKHCLDXKEGB-UHFFFAOYSA-N

物化性质

• 沸点：
  436.7±55.0 °C(Predicted)
• 密度：
  1.506±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  114
• 氢给体数：
  4
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-methyl-N'-(5-hydroxy-3-carboxyphenyl)thiourea 在 N-甲基吗啉 、 sodium hydroxide 、 氯甲酸异丁酯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.25h， 生成 (3R)-3-(5-bromo-3-chloro-2-hydroxyphenyl)-3-(2-(3-hydroxy-5-(5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-ylamino)benzamido)acetamido)propanoic acid
  参考文献：
  名称：

  R-Isomers of Arg-Gly-Asp (RGD) mimics as potent αvβ3 inhibitors

  摘要：

  The integrin alpha(v)beta(3), vitronectin receptor, is expressed in a number of cell types and has been shown to mediate adhesion of osteoclasts to bone matrix, vascular smooth muscle cell migration, and angiogenesis. We recently disclosed the discovery of a tripeptide Arg-Gly-Asp (RGD) mimic, which has been shown to be a potent inhibitor of the integrin alpha(v)beta(3) and has excellent anti-angiogenic properties including its suppression of tumor growth in animal models. In other investigations involving RGD mimics, only compounds containing the S-isomers of the beta-amino acids have been shown to be potent. We were surprised to find the potencies of analogs containing enantiomerically pure S-isomers of beta-amino acids which were only marginally better than the corresponding racemic mixtures. We therefore synthesized RGD mimics containing R-isomers of beta-amino acids and found them to be relatively potent inhibitors of alpha(v)beta(3). One of the compounds was examined in tumor models in mice and has been shown to significantly reduce the rate of growth and the size of tumors. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.03.034
• 作为产物：
  描述：

  3,5-二羟基苯甲酸 在 ammonium hydroxide 、 氯化铵 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 25.0~190.0 ℃ 、3.07 MPa 条件下， 反应 12.0h， 生成 N-methyl-N'-(5-hydroxy-3-carboxyphenyl)thiourea
  参考文献：
  名称：

  Pilot-Plant Preparation of an α_vβ₃ Integrin Antagonist. Part 2. Synthesis of N-[2-(5-Hydroxy-4,6-tetrahydropyrimidine)]-3-amino-5-hydroxybenzoic Acid

  摘要：

  Studies directed toward the process research and development of a scalable method for preparing tetrahydropyrimidine 2, a key intermediate to the (alpha(v)beta(3) integrin antagonist 1, are described. A linear approach employing 3-amino-5-hydroxybenzoic acid, methyl isothiocyanate, and 1,3-diaminopropan-2-ol as key reagents is detailed. The results of process development research, a successful pilot run, and a production campaign are explained.

  DOI：

  10.1021/op049968w

文献信息

• 3,5 Phenyl-Substituted Beta Amino Acid Derivatives as Integrin Antagonists
  申请人：Saint Louis University

  公开号：US20140051715A1

  公开（公告）日：2014-02-20

  Disclosed herein are novel pharmaceutical agents which are useful as integrin receptor antagonists that mediate the pathologic processes of angiogenesis and fibrosis and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by these integrins by inhibiting or antagonizing these integrins. The novel pharmaceutical agents include those of the formula: wherein X is bromo or iodo, or pharmaceutically acceptable salts thereof. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such pharmaceutical agents. Methods and intermediates useful for making the pharmaceutical agents and methods of using the pharmaceutical agents are also provided.

  披露的是新颖的药物制剂，这些药物制剂作为整合素受体的拮抗剂是有用的，它们介导了血管生成和纤维化的病理过程，因此可用于药物组合物中，以及在通过抑制或拮抗这些整合素来治疗由这些整合素介导的条件的方法中。这些新颖的药物制剂包括以下公式的那些：其中X是溴或碘，或其药物可接受的盐。还提供了包含这样的药物制剂的药物组合物、试剂盒和制造物。还提供了用于制造药物制剂的方法和中间体，以及使用药物制剂的方法。
• [EN] THE R-ISOMER OF BETA AMINO ACID COMPOUNDS AS INTEGRIN RECEPTOR ANTAGONISTS DERIVATIVES<br/>[FR] ISOMERE R DE COMPOSES D'ACIDES AMINES BETA EN TANT QUE DERIVES ANTAGONISTES DU RECEPTEUR DES INTEGRINES
  申请人：PHARMACIA CORPRATION

  公开号：WO2004060376A1

  公开（公告）日：2004-07-22

  The present invention relates to a class of compounds represented by the Formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula (I), and methods of selectively inhibiting or antagonizing the αVβ3 and/or the αV β5 integrin without significantly inhibiting the αV β6 integrin

  本发明涉及一类由公式(I)表示的化合物或其药用可接受的盐，包含公式(I)化合物的药物组合物，以及在不显著抑制αVβ6整合素的情况下选择性抑制或拮抗αVβ3和/或αVβ5整合素的方法。
• [EN] META-AZACYCLIC AMINO BENZOIC ACID DERIVATIVES AS PAN INTEGRIN ANTAGONISTS<br/>[FR] DÉRIVÉS D'ACIDE AMINOBENZOÏQUE MÉTA-AZACYCLIQUE À TITRE D'ANTAGONISTES DE PAN-INTÉGRINE
  申请人：UNIV SAINT LOUIS

  公开号：WO2017117538A1

  公开（公告）日：2017-07-06

  The present disclosure provides pharmaceutical agents of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such pharmaceutical agents. Methods of using the pharmaceutical agents for the treatment of a variety of diseases and disorders are also provided.

  本公开提供了以下公式的药物代理：其中变量在此处定义。还提供了包含这种药物代理的药物组合物、工具包和制造品。还提供了使用这种药物代理治疗各种疾病和疾病的方法。
• [EN] INTEGRIN TARGETING LIGANDS AND USES THEREOF<br/>[FR] LIGANDS CIBLANT UNE INTÉGRINE ET LEURS UTILISATIONS
  申请人：ARROWHEAD PHARMACEUTICALS INC

  公开号：WO2022056286A1

  公开（公告）日：2022-03-17

  Synthetic ανβ6 integrin ligands of Formula (I) having serum stability and affinity for integrin ανβ6, which is a receptor expressed in a variety of cell types, are described. The described ligands are usful for delivering cargo molecules, such as RNAi agents or other oligonucleotide-based compounds, to cells that express integrin ανβ6, and thereby facilitating the uptake of the cargo molecules into these cells. Compositions that include ανβ6 integrin ligands and methods of use are also described Formula (I).

  本文描述了具有血清稳定性和与细胞表达的受体ανβ6亲和力的合成ανβ6整合素配体的公式（I）。所述配体可用于向表达ανβ6整合素的细胞输送载荷分子，例如RNAi剂或其他基于寡核苷酸的化合物，从而促进这些细胞对载荷分子的摄取。本文还描述了包括ανβ6整合素配体的组合物和使用方法。
• [EN] SKELETAL MUSCLE DELIVERY PLATFORMS AND METHODS OF USE<br/>[FR] PLATEFORMES D'ADMINISTRATION À DES MUSCLES SQUELETTIQUES ET MÉTHODES D'UTILISATION
  申请人：ARROWHEAD PHARMACEUTICALS INC

  公开号：WO2022056269A1

  公开（公告）日：2022-03-17

  The present disclosure relates to delivery platforms that specifically and efficiently direct payloads to skeletal muscle cells in a subject, in vivo. The delivery platforms diclosed herein include targeting ligands (such as compounds that have affinity for integrins, including alpha- v-beta-6) and pharmacokinetic/pharmacodynamic (PK/PD) modulators, to facilitate the delivery of payloads to cells, including to skeletal muscle cells. Suitable payloads for use in the delivery platforms disclosed herein include RNAi agents, which can be linked or conjugated to the delivery platofrms, and when delivered in vivo, provide for the inhibition of gene expression in skeletal muscle cells. Pharmaceutical compositions that include the skeletal muscle cell delivery platform are also described, as well as methods of use for the treatment of various diseases and disorders where delivery of a therapeutic payload to a skeletal muscle cell is desirable.

  本公开涉及将有效载荷有针对性地且高效地引导至体内骨骼肌细胞的传递平台。所述传递平台包括靶向配体（例如具有亲和力的化合物，包括α-v-β-6整合素）和药代动力学/药效学（PK/PD）调节剂，以促进有效载荷传递到细胞，包括骨骼肌细胞。适用于本公开的传递平台的有效载荷包括RNAi剂，可以链接或结合到传递平台上，在体内传递时，可以抑制骨骼肌细胞的基因表达。还描述了包括骨骼肌细胞传递平台的药物组合物，以及用于治疗各种疾病和疾病的方法，其中传递治疗有效载荷至骨骼肌细胞是可取的。