1-carboxymethyl-3-hydroxy-2-methylpyridin-4-one | 60603-99-8

• 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: 1-carboxymethyl-3-hydroxy-2-methylpyridin-4-one
• 英文别名: 2-(1,4-dihydro-3-hydroxy-2-methyl-4-oxo-1-pyridyl)acetic acid；1-carboxymethyl-3-hydroxy-2-methyl-4(1H)-pyridinone；(3-hydroxy-2-methyl-4-oxopyridin-1-yl)acetic acid；1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone；N-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone；1-carboxymethyl-3-hydroxy-2-methylpyrid-4-one；(3-Hydroxy-2-methyl-4-oxopyridin-1(4h)-yl)acetic acid；2-(3-hydroxy-2-methyl-4-oxopyridin-1-yl)acetic acid
• CAS: 60603-99-8
• 化学式: C₈H₉NO₄
• 分子量: 183.164
• InChiKey: HHEJKMIMUJVQPB-UHFFFAOYSA-N

物化性质

• 熔点：
  260-265 °C (decomp)
• 沸点：
  384.6±42.0 °C(Predicted)
• 密度：
  1.456±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  77.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  甲磺酸去铁敏 、 1-carboxymethyl-3-hydroxy-2-methylpyridin-4-one 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以70%的产率得到DFOB-L1D
  参考文献：
  名称：

  Conjugates of Desferrioxamine B (DFOB) with Derivatives of Adamantane or with Orally Available Chelators as Potential Agents for Treating Iron Overload

  摘要：

  Desferrioxamine B (DFOB) conjugates with adamantane-1-carboxylic acid, 3-hydroxyadamantane-1-carboxylic acid, 3,5-dimethyladamantane-1-carboxylic acid, adamantane-1-acetic acid, 4-methylphenoxyacetic acid, 3-hydroxy-2-methyl-4-oxo-1-pyridineacetic acid (N-acetic acid derivative of deferiprone), or 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol- 1-yl]benzoic acid (deferasirox) were prepared and the integrity of Fe(III) binding of the compounds was established from electrospray ionization mass spectrometry and RP-HPLC measurements. The extent of intracellular Fe-59 mobilized by the DFOB-3,5-dimethyladamantane-1-carboxylic acid adduct was 3-fold greater than DFOB alone, and the IC50 value of this adduct was 6- or 15-fold greater than DFOB in two different cell types. The relationship between logP and Fe-59 mobilization for the DFOB conjugates showed that maximal mobilization of intracellular Fe-59 Occurred at a logP value similar to 2.3. This parameter, rather than the affinity for Fe(III), appears to influence the extent of intracellular Fe-59 mobilization. The low toxicity-high Fe mobilization efficacy of selected adamantane-based DFOB conjugates underscores the potential of these compounds to treat iron overload disease in patients with transfusional-dependent disorders such as beta-thalassemia.

  DOI：

  10.1021/jm9016703
• 作为产物：
  描述：

  3-(苄氧基)-2-甲基-4H-吡喃-4-酮 在 palladium hydroxide - carbon 氢气 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 8.0h， 生成 1-carboxymethyl-3-hydroxy-2-methylpyridin-4-one
  参考文献：
  名称：

  Faerber, M.; Osiander, H.; Severin, T., Journal of Heterocyclic Chemistry, 1994, vol. 31, # 4, p. 947 - 956

  摘要：

  DOI：

文献信息

• In vitro studies of lanthanide complexes for the treatment of osteoporosis
  作者：Yasmin Mawani、Jacqueline F. Cawthray、Stanley Chang、Kristina Sachs-Barrable、David M. Weekes、Kishor M. Wasan、Chris Orvig

  DOI：10.1039/c2dt32373g

  日期：——

  Lanthanide ions, Ln(III), are of interest in the treatment of bone density disorders because they are found to accumulate preferentially in bone (in vivo), have a stimulatory effect on bone formation, and exhibit an inhibitory effect on bone degradation (in vitro), altering the homeostasis of the bone cycle. In an effort to develop an orally active lanthanide drug, a series of 3-hydroxy-4-pyridinone ligands were synthesized and eight of these ligands (H1 = 3-hydroxy-2-methyl-1-(2-hydroxyethyl)-4-pyridinone, H2 = 3-hydroxy-2-methyl-1-(3-hydroxypropyl)-4-pyridinone, H3 = 3-hydroxy-2-methyl-1-(4-hydroxybutyl)-4-pyridinone, H4 = 3-hydroxy-2-methyl-1-(2-hydroxypropyl)-4-pyridinone, H5 = 3-hydroxy-2-methyl-1-(1-hydroxy-3-methylbutan-2-yl)-4-pyridinone, H6 = 3-hydroxy-2-methyl-1-(1-hydroxybutan-2-yl)-4-pyridinone, H7 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H8 = 1-carboxyethyl-3-hydroxy-2-methyl-4-pyridinone) were coordinated to Ln3+ (Ln = La, Eu, Gd, Lu) forming stable tris-ligand complexes (LnL3, L = 1−, 2−, 3−, 4−, 5−, 6−, 7− and 8−). The dissociation (pKan) and metal ligand stability constants (log βn) of the 3-hydroxy-4-pyridinones with La3+ and Gd3+ were determined by potentiometric titrations, which demonstrated that the 3-hydroxy-4-pyridinones form stable tris-ligand complexes with the lanthanide ions. One phosphinate-EDTA derivative (H5XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was also synthesized and coordinated to Ln3+ (Ln = La, Eu, Lu), forming the potassium salt of [Ln(XT)]2−. Cytotoxicity assays were carried out in MG-63 cells; all the ligands and metal complexes tested were observed to be non-toxic to this cell line. Studies to investigate the toxicity, cellular uptake and apparent permeability (Papp) of the lanthanide ions were conducted in Caco-2 cells where it was observed that [La(XT)]2− had the greatest cell uptake. Binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral hydroxyapatite (HAP) are high, as well as moderate to strong for the free ligand with the bone mineral depending on the functional group.

  镧系离子Ln(III)在治疗骨密度紊乱方面具有研究价值，因为它们在体内优先积累于骨组织中，对骨形成有刺激作用，并在体外表现出对骨降解的抑制作用，从而改变骨周期的稳态。为了开发一种口服活性的镧系药物，合成了一系列3-羟基-4-吡啶酮配体，其中的八个配体（H1 = 3-羟基-2-甲基-1-(2-羟基乙基)-4-吡啶酮，H2 = 3-羟基-2-甲基-1-(3-羟基丙基)-4-吡啶酮，H3 = 3-羟基-2-甲基-1-(4-羟基丁基)-4-吡啶酮，H4 = 3-羟基-2-甲基-1-(2-羟基丙基)-4-吡啶酮，H5 = 3-羟基-2-甲基-1-(1-羟基-3-甲基丁烷-2-基)-4-吡啶酮，H6 = 3-羟基-2-甲基-1-(1-羟基丁烷-2-基)-4-吡啶酮，H7 = 1-羧甲基-3-羟基-2-甲基-4-吡啶酮，H8 = 1-羧乙基-3-羟基-2-甲基-4-吡啶酮）与Ln3+（Ln = La, Eu, Gd, Lu）配位，形成了稳定的三配体复合物（LnL3，L = 1−, 2−, 3−, 4−, 5−, 6−, 7− 和 8−）。通过电位滴定法测定了3-羟基-4-吡啶酮与La3+和Gd3+的解离（pKan）和金属配体稳定常数（log βn），结果表明3-羟基-4-吡啶酮与镧系离子形成了稳定的三配体复合物。同时，合成了一种磷酸酯-EDTA衍生物（H5XT = 双[[双(羧甲基)氨基]甲基]磷酸酯），并与Ln3+（Ln = La, Eu, Lu）配位，形成了[Ln(XT)]2−的钾盐。在MG-63细胞中进行了细胞毒性实验，结果显示所有测试的配体和金属复合物对这种细胞系均无毒性。在Caco-2细胞中研究了镧系离子的毒性、细胞摄取和表观渗透性（Papp），观察到[La(XT)]2−具有最大的细胞摄取量。自由镧系离子（Ln = La, Gd 和 Lu）、金属复合物以及自由3-羟基-4-吡啶酮与骨矿物质羟基磷灰石（HAP）的结合亲和力都很高，而自由配体与骨矿物质的结合亲和力则取决于功能团，表现为中等到强。
• Iron-pyridone complexes for anemia
  申请人：National Research Development Corporation

  公开号：US04650793A1

  公开（公告）日：1987-03-17

  Pharmaceutical compositions containing an iron complex of a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or, except in the case of ionizable groups, more than one substituent selected from aliphatic acyl, alkoxy, aliphatic amine, aliphatic amide, carboxy, aliphatic ester, halogen, hydroxy and sulpho groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by aliphatic hydrocarbon groups, are of value for the treatment of iron deficiency anemia.

  含有3-羟基吡啶-2-酮或3-羟基吡啶-4-酮的铁配合物的制药组合物，其中连接到氮原子的氢原子被脂肪酰基、脂肪烃基或被脂肪烃基取代，或者被脂肪烃基取代，该脂肪烃基被选自脂肪酰基、烷氧基、脂肪胺基、脂肪酰胺基、羧基、脂肪酯基、卤素、羟基和磺酸基，并且可选地，其中连接到环碳原子的一个或多个氢原子被上述取代物之一取代，被烷氧基、脂肪酯基、卤素或羟基取代的脂肪烃基取代，但不包括只通过脂肪烃基进行氢原子取代的化合物，对于治疗缺铁性贫血具有价值。
• Pharmaceutical compositions
  申请人：National Research Development Corp.

  公开号：US04585780A1

  公开（公告）日：1986-04-29

  Pharmaceutical compositions containing a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or, except in the case of ionizable groups, more than one substituent selected from aliphatic acyl, alkoxy, aliphatic amine, aliphatic amide, carboxy, aliphatic ester, halogen, hydroxy and sulpho groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, aliphatic ester, halogen or hydroxy group, but excluding compounds in which said replacement of hydrogen atoms in the compound is effected only by aliphatic hydrocarbon groups, or a salt thereof containing a physiologically acceptable ion or ions, are of value for removing toxic amounts of metals, particularly iron, from the body.

  含有3-羟基吡啶-2-酮或3-羟基吡啶-4-酮的药物组合物，其中连接到氮原子的氢原子被脂肪酰基、脂肪烃基或被脂肪烃基取代，并且被脂肪酰基、烷氧基、脂肪胺基、脂肪酰胺基、羧基、脂肪酯基、卤素、羟基和磺酸基中的一个或一个以上的取代基取代，除非是可电离的基团，可选地，其中连接到环碳原子的一个或多个氢原子被上述取代基之一取代，或者被烷氧基、脂肪酯基、卤素或羟基取代的脂肪烃基取代，但不包括化合物，其中所述取代氢原子的取代仅由脂肪烃基完成，或者其盐，含有生理上可接受的离子，对于从体内去除有毒金属，特别是铁，具有价值。
• [EN] DESFERRIOXAMINE CONJUGATES, DERIVATIVES AND ANALOGUES<br/>[FR] CONJUGUÉS DE LA DESFERRIOXAMINE, DÉRIVÉS ET ANALOGUES
  申请人：UNIV SYDNEY

  公开号：WO2009055863A1

  公开（公告）日：2009-05-07

  The present invention relates to desferoxamine conjugates, derivatives and analogues thereof. In particular, the present invention relates to desferoxamine conjugates, analogues and derivatives thereof, and methods for reducing levels of metals, especially iron, in a mammal. Uses of the compounds according to the invention are also provided. Compounds of the present invention may also be used to treat iron dyshomeostasis disorders, cancer, malaria and fungal infections. The compounds of the invention may be formulated into a pharmaceutical composition or packaged into kits.

  本发明涉及去氧胺酸共轭物、衍生物及类似物。具体而言，本发明涉及去氧胺酸共轭物、类似物和衍生物，以及在哺乳动物中降低金属水平，特别是铁的方法。本发明还提供了根据本发明的化合物的用途。本发明的化合物还可用于治疗铁失调疾病、癌症、疟疾和真菌感染。本发明的化合物可制成药物组合物或打包成套装。
• 3-hydroxypyridin-4-one derivatives as pharmaceutical compositions
  申请人：BRITISH TECHNOLOGY GROUP LTD

  公开号：EP0494754A1

  公开（公告）日：1992-07-15

  3-Hydroxypyridin-4-ones of formula (I) in which R₁ is selected from hydrogen, C₁₋₃ aliphatic hydrocarbon groups, 2-hydroxyethyl, C₁₋₄ aliphatic hydrocarbon groups substituted by a single carboxy, sulpho, sulphamoyl or N-methyl or N-ethyl sulphamoyl group, and an ethyl group substituted at the 1-or 2-position by a carboxy, sulpho, sulphamoyl or N-methyl or N-ethyl sulphamoyl group and at the 2-position by a hydroxy group, and R₂, R₃ and R₄ are each separately selected from hydrogen, C₁₋₃ aliphatic hydrocarbon groups, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxymethyl, C₁₋₄ aliphatic hydrocarbon groups substituted by a single carboxy, sulpho, sulphamoyl or N-methyl or N-ethyl sulphamoyl group, and an ethyl group substituted at the 1-or 2-position by a carboxy, sulpho, sulphamoyl or N-methyl or N-ethyl sulphamoyl group and at the 2-position by a hydroxy group, but with the provisos firstly that one of R₁ to R₄ is a C₁₋₄ aliphatic hydrocarbon group substituted by a single carboxy, sulpho, sulphamoyl or N-methyl or N-ethyl sulphamoyl group, or an ethyl group substituted at the 1- or 2-position by a carboxy, sulpho, sulphamoyl or N-methyl or N-ethyl sulphamoyl group and at the 2-position by a hydroxy group, secondly that either R₂ or R₃ is a group other than hydrogen and thirdly that the total number of atoms other than hydrogen present in R₁ to R₄ is no more than eight, the compound optionally being in the form of a physiologically acceptable salt and/or pro-drug thereof, are of value for the treatment of conditions caused by iron dependent parasites, particularly malaria.

  式(I)中，3-羟基吡啶-4-酮，其中R₁选自氢，C₁₋₃脂肪烃基，2-羟乙基，C₁₋₄脂肪烃基，被单个羧基，磺酰基，磺酰胺基或N-甲基或N-乙基磺酰胺基取代，以及在1-或2-位置被羧基，磺酰基，磺酰胺基或N-甲基或N-乙基磺酰胺基取代的乙基基团，在2-位置被羟基取代；R₂，R₃和R₄各自单独选自氢，C₁₋₃脂肪烃基，羟甲基，1-羟基乙基，2-羟基乙基，2-甲氧基甲基，C₁₋₄脂肪烃基，被单个羧基，磺酰基，磺酰胺基或N-甲基或N-乙基磺酰胺基取代，以及在1-或2-位置被羧基，磺酰基，磺酰胺基或N-甲基或N-乙基磺酰胺基取代的乙基基团，在2-位置被羟基取代，但前提是首先R₁至R₄中有一个是被单个羧基，磺酰基，磺酰胺基或N-甲基或N-乙基磺酰胺基取代的C₁₋₄脂肪烃基，或在1-或2-位置被羧基，磺酰基，磺酰胺基或N-甲基或N-乙基磺酰胺基取代的乙基基团，在2-位置被羟基取代；其次，R₂或R₃为除氢之外的基团；第三，除氢之外的原子总数不超过8个。该化合物可选为生理上可接受的盐和/或前药形式，对于治疗由铁依赖性寄生虫引起的疾病特别是疟疾具有价值。