methyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate | 1054314-92-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: methyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate
• 英文别名: Methyl 7-methoxy-3-phenylmethoxynaphthalene-2-carboxylate
• CAS: 1054314-92-9
• 化学式: C₂₀H₁₈O₄
• 分子量: 322.361
• InChiKey: QQKVSNRBEHDJQW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  44.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate 在 锂硼氢 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 以96%的产率得到(3-benzyloxy-7-methoxynaphthalen-2-yl)methanol
  参考文献：
  名称：

  Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach

  摘要：

  Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.

  DOI：

  10.1021/jm800683c
• 作为产物：
  描述：

  Methyl 7-methoxy-3-hydroxy-2-naphthoate 、 溴甲苯 在 18-冠醚-6 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 以79%的产率得到methyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate
  参考文献：
  名称：

  Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach

  摘要：

  Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.

  DOI：

  10.1021/jm800683c

文献信息

• AZEPANES AND THEIR RING HOMOLOGUES FOR THERAPY AND PROPHYLAXIS OF PROTEIN KINASE MEDIATED DISEASES
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0836592A1

  公开（公告）日：1998-04-22
• US5907038A
  申请人：——

  公开号：US5907038A

  公开（公告）日：1999-05-25
• US6136969A
  申请人：——

  公开号：US6136969A

  公开（公告）日：2000-10-24
• [EN] NOVEL AZEPANES AND THEIR RING HOMOLOGUES FOR THERAPY AND PROPHYLAXIS OF PROTEIN KINASE MEDIATED DISEASES<br/>[FR] AZEPANES NOUVEAUX ET LEURS HOMOLOGUES CYCLIQUES POUR LE TRAITEMENT ET LA PROPHYLAXIE DES MALADIES A MEDIATION PAR LA PROTEINE-KINASE
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：WO1997002249A1

  公开（公告）日：1997-01-23

  (EN) Compounds of general formula (I), wherein R1 is phenyl or alpha- or beta- naphthyl, which groups can be substituted by hydroxy, lower-alkyl, lower-alkoxy, lower alkoxy-carbonyl, phenoxy, acyloxy, hydroxyphenoxy-sulfonyl, halogen, nitro, amino, acylamino or N-lower-alkyl-acylamino; R2 is phenyl or phenyl substituted by hydroxy or acyloxy; Y is a carbon-carbon bond or is vinylene; and n is 1, 2 or 3; and pharmaceutically acceptable acid addition salts thereof are protein kinase inhibitors and can be used for the treatment of disorders mediates by such enzymes, e.g., inflammatory diseases.(FR) Les composés de formule générale (I) dans laquelle R1 est phényle ou alpha- ou bêta-naphtyle, ces groupes pouvant être substitués par hydroxy, alkyle inférieur, alcoxy inférieur, alcoxy-carbonyl de faible PM, phénoxy, acyloxy, hydroxyphénoxy-sulfonyle, halogène, nitro, amino, acylamino ou N-alkylacylamino inférieur; R2 est phényle ou phényle substitué par hydroxy ou acyloxy; Y est une liaison carbone-carbone ou est vinylène; et n vaut 1, 2 ou 3; ainsi que leurs sels d'addition acide pharmaceutiquement acceptables, sont des inhibiteurs de la protéine kinase et peuvent être utilisés pour le traitement des troubles dont celle-ci est le médiateur, tels que les maladies inflammatoires.
• Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach
  作者：Simon Lucas、Ralf Heim、Matthias Negri、Iris Antes、Christina Ries、Katarzyna E. Schewe、Alessandra Bisi、Silvia Gobbi、Rolf W. Hartmann

  DOI：10.1021/jm800683c

  日期：2008.10.9

  Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position. These additional aromatic moieties have been hypothesized to fit into the newly identified hydrophobic pharmacophore feature HY3. Subsequent docking studies in our refined CYP11B2 protein model have been performed prior to synthesis to estimate the inhibitory properties of the proposed molecules. While phenyl-substituted compound 11 (IC50 > 500 nM) did not dock under the given pharmacophore constraint (i.e., the Fe(heme)-N(ligand) interaction), benzyl-substituted compound 12 (IC50 = 154 nM) was found to exploit a previously unexplored subpocket of the inhibitor binding site. By structural optimization based on the pharmacophore hypothesis, 25 novel compounds were synthesized, among them highly potent CYP11B2 inhibitors (e.g., 17, IC50 = 2.7 nM) with pronounced selectivity toward the most important steroidogenic and hepatic CYP enzymes.