methyl 2,3-dichloro-4-hydroxybenzoate | 219685-78-6

• 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: methyl 2,3-dichloro-4-hydroxybenzoate
• 英文别名: 2,3-dichloro-4-hydroxy-benzoic acid methyl ester；2,3-dichloro-4-hydroxybenzoic acid methyl ester
• CAS: 219685-78-6
• 化学式: C₈H₆Cl₂O₃
• 分子量: 221.04
• InChiKey: JKUMRRWTUNVWJP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 2,3-dichloro-4-hydroxybenzoate 在 肼 作用下， 以 戊醇 为溶剂， 以50%的产率得到2,3-dichloro-4-hydroxybenzoic acid hydrazide
  参考文献：
  名称：

  Optimization of Alkylidene Hydrazide Based Human Glucagon Receptor Antagonists. Discovery of the Highly Potent and Orally Available 3-Cyano-4-hydroxybenzoic Acid [1-(2,3,5,6-Tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide

  摘要：

  Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-eyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylenelhydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, K-B = 760 pM) and of the isolated rat receptor IC50 = 430 pM, K-B = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K-i = 14 nM). This compound was orally available in dogs (F-po = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

  DOI：

  10.1021/jm0208572
• 作为产物：
  描述：

  4-氨基-2-氯苯甲酸 在 N-氯代丁二酰亚胺 、 氯化亚砜 、 硫酸 、 溶剂黄146 、 sodium nitrite 作用下， 反应 40.25h， 生成 methyl 2,3-dichloro-4-hydroxybenzoate
  参考文献：
  名称：

  Optimization of Alkylidene Hydrazide Based Human Glucagon Receptor Antagonists. Discovery of the Highly Potent and Orally Available 3-Cyano-4-hydroxybenzoic Acid [1-(2,3,5,6-Tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide

  摘要：

  Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-eyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure-metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1H-indol-4-ylmethylenelhydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, K-B = 760 pM) and of the isolated rat receptor IC50 = 430 pM, K-B = 380 pM). Glucagon-stimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (K-i = 14 nM). This compound was orally available in dogs (F-po = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.

  DOI：

  10.1021/jm0208572
• 作为试剂：
  描述：

  2-氯-4-羟基苯甲酸甲酯 、 N-氯代丁二酰亚胺 在 水 、 Brine 、 magnesium sulfate 、 methyl 2,3-dichloro-4-hydroxybenzoate 、 乙酸乙酯 作用下， 以 溶剂黄146 为溶剂， 反应 24.0h， 以afforded methyl 2,5-dichloro-4-hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4-hydroxybenzoate isomer (total of 8.4 g, 10%)的产率得到methyl 2,5-dichloro-4-hydroxybenzoate
  参考文献：
  名称：

  Glucagon antagonists/inverse agonists

  摘要：

  本发明揭示了包含中央肼基基团的非肽化合物及其合成方法。这些化合物的作用是拮抗胰高血糖素肽激素的作用。

  公开号：

  US06613942B1

文献信息

• [EN] PYRROLIDINE-2-CARBONITRILE DERIVATIVES AND THEIR USE AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV (DPP-IV)<br/>[FR] DERIVES DE PYRROLIDINE-2-CARBONITRILE ET LEUR UTILISATION COMME INHIBITEURS DE LA DIPEPTIDYLE PEPTIDASE-IV (DPP-IV)
  申请人：ABBOTT LAB

  公开号：WO2005023762A1

  公开（公告）日：2005-03-17

  The present invention relates to compounds of formula (I), (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, b-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.

  本发明涉及式(I)、(I)的化合物，其抑制二肽基肽酶IV（DPP-IV），并且对于预防或治疗糖尿病，特别是II型糖尿病，以及高血糖、X综合征、高胰岛素血症、β细胞功能衰竭、肥胖、饱腹障碍、动脉粥样硬化和各种免疫调节性疾病有用。
• Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
  申请人：Pei Zhonghua

  公开号：US20050131019A1

  公开（公告）日：2005-06-16

  The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, β-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.

  本发明涉及式(I)的化合物，它们抑制二肽基肽酶IV（DPP-IV），并且可用于预防或治疗糖尿病，特别是II型糖尿病，以及高血糖、X综合征、高胰岛素血症、β细胞功能衰竭、肥胖、饱腹障碍、动脉粥样硬化和各种免疫调节性疾病。
• [EN] GLUCAGON ANTAGONISTS/INVERSE AGONISTS<br/>[FR] ANTAGONISTES/AGONISTES INVERSES DU GLUCAGON
  申请人：NOVO NORDISK AS

  公开号：WO1999001423A1

  公开（公告）日：1999-01-14

  Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof. The compounds act to antagonize the action of the glucagon peptide hormone.

  非肽化合物包含一个中心肼基结构，并且其合成方法。这些化合物作用是拮抗胰高血糖素肽激素的作用。
• [EN] INHIBITORS OF alpha 4 MEDIATED CELL ADHESION<br/>[FR] INHIBITEURS DE L'ADHESION CELLULAIRE A MEDIATION PAR alpha 4
  申请人：TANABE SEIYAKU CO., LTD.

  公开号：WO1999036393A1

  公开（公告）日：1999-07-22

  (EN) The present invention relates to a pharmaceutical composition comprising as an active ingredient a compound of formula (I), wherein Ring A is an aromatic or a heterocyclic ring; Q is a bond, carbonyl, lower alkylene, lower alkenylene, -O-(lower alkylene)-, etc.; n is 0, 1 or 2; Z is oxygen or sulfur; W is oxygen, sulfur, -CH=CH-, -NH- or -N=CH-; R1, R2 and R3 are the same or different and are hydrogen, halogen, hydroxyl, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxy group, a substituted or unsubstituted amino group, etc.; R4 is tetrazolyl, carboxyl group, amide or ester; R5 is hydrogen, nitro, amino, hydroxyl, lower alkanoyl, lower alkyl, etc.; R6 is selected from (a) a substituted or unsubstituted phenyl group, (b) a substituted or unsubstituted pyridyl group, (c) a substituted or unsubstituted thienyl group, (d) a substituted or unsubstituted benzofuranyl group, etc.; or a pharmaceutically acceptable salt thereof.(FR) L'invention se rapporte à une composition pharmaceutique comprenant en tant que composant actif le composé correspondant à la formule suivante: (1) dans laquelle Le cycle A est un cycle aromatique ou hétérocyclique; Q est une liaison carbonyle, alkylène inférieur, alcénylène inférieur, -O-(alkylène inférieur)-, etc.; n est 0, 1 ou 2; Z est oxygène ou soufre; W est oxygène, soufre, -CH=CH-, NH- ou -N=CH-; R1, R2 et R3 sont identiques ou différents et sont hydrogène, halogène, hydroxyle, groupe alkyle inférieur substitué ou non substitué, groupe alcoxy inférieur substitué ou non substitué, groupe amino substitué ou non substitué; R4 est tétrazolyle, groupe carboxyle, amide ou ester; R5 est hydrogène, nitro, amino, hydroxyle, alcanoyle inférieur, alkyle inférieur, etc.; R6 est sélectionné entre (a) un groupe phényle substitué ou non substitué, (b) un groupe pyridyle substitué ou non substitué, (c) un groupe thiényle substitué ou non substitué ou (d) un groupe benzofuranyle substitué ou non substitué, etc.; ou à un sel pharmaceutiquement acceptable de ce composé.

  本发明涉及一种药物组合物，其作为活性成分包含式（I）的化合物，其中环A是芳香环或杂环；Q是键，羰基，低碳基，低烯基，-O-（低碳基）-等；n为0，1或2；Z为氧或硫；W为氧，硫，-CH=CH-，-NH-或-N=CH-；R1，R2和R3相同或不同，是氢，卤素，羟基，取代或未取代的低碳基团，取代或未取代的低烷氧基团，取代或未取代的氨基团等；R4为四唑基，羧酸基，酰胺或酯；R5为氢，硝基，氨基，羟基，低烷酰基，低碳基等；R6从（a）取代或未取代的苯基团，（b）取代或未取代的吡啶基团，（c）取代或未取代的噻吩基团，（d）取代或未取代的苯并呋喃基团等中选择；或其药学上可接受的盐。
• GLUCAGON ANTAGONISTS/INVERSE AGONISTS
  申请人：NOVO NORDISK A/S

  公开号：EP0994848A1

  公开（公告）日：2000-04-26