2-(3,5-dichloropyridin-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone | 208043-53-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(3,5-dichloropyridin-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone
• 英文别名: [2-(3,5-Dichloro-pyridin-4-yl)-1-oxoethyl]-2,3-dihydroxy-4-methoxybenzene；2-(3,5-dichloro-4-pyridyl)-1-(2,3-dihydroxy-4-methylphenyl)ethanone；[2-(3,5-Dichloro-4-pyridyl)-1-oxoethyl]-2,3-dihydroxy-4-methoxybenzene；2-(3,5-Dichloro-pyridin-4-yl)-1-(2,3-dihydroxy-4-methoxy-phenyl)-ethanone
• CAS: 208043-53-2
• 化学式: C₁₄H₁₁Cl₂NO₄
• 分子量: 328.152
• InChiKey: AKCQHFGKRPCYBM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  79.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(3,5-dichloropyridin-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone 在 potassium carbonate 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 、 3-戊酮 为溶剂， 反应 42.0h， 生成 1-(3-cyclopentoxy-2,4-dimethoxyphenyl)-2-(3,5-dichloropyridin-4-yl)ethanone
  参考文献：
  名称：

  Discovery and Early Clinical Development of 2-{6-[2-(3,5-Dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a Soft-Drug Inhibitor of Phosphodiesterase 4 for Topical Treatment of Atopic Dermatitis

  摘要：

  Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the dinic for PDE4 inhibitors, primarily due to PDE4 mediated side effects. Here we describe our approach to circumvent this issue by applying a soft-drug concept in the design of a topically acting PDE4 inhibitor for treatment of dermatological diseases. We used a fast follower approach, starting from piclamilast. In particular, simultaneous introduction of 2'-alkoxy substituents and changing an amide to a keto linker proved to be beneficial when designing potential soft-drug candidates. This effort culminated in identification of LEO 29102 (20), a potent, selective, and soft-drug PDE4 inhibitor with properties suitable for patient-friendly formulations giving efficient drug delivery to the skin. Compound 20 has reached phase 2 and demonstrated clinically relevant efficacy in the treatment of atopic dermatitis.

  DOI：

  10.1021/jm500378a
• 作为产物：
  描述：

  2,3,4-三甲氧基苯甲酰氯 在 甲醇 、 三氯化硼 、 三乙胺 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 27.5h， 生成 2-(3,5-dichloropyridin-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone
  参考文献：
  名称：

  PDE4抑制剂K-34的工艺开发

  摘要：

  开发了一种简短实用的PDE4抑制剂K-34（1）合成方法。该合成分四个步骤完成，总收率达58％。利用邻近的羧酸助剂，以极高的收率创造出独特的螺缩醛。该合成还具有使用4-吡啶基甲基阴离子9和酯18进行高效酮构建的特点，其中应通过快速就地形成烯醇化物来防止过度反应。整个合成在温和的条件下进行，并使用适合大规模生产的简单程序。

  DOI：

  10.1021/op100291g

文献信息

• DERIVATIVES OF BENZOFURAN OR BENZODIOXOLE
  申请人：——

  公开号：US20020128290A1

  公开（公告）日：2002-09-12

  An oxygen-containing heterocyclic compound represented by following Formula (I): 1 wherein R 1 and R 2 independently represent hydrogen, lower alkyl, cyano, —(CH 2 ) n —E 1 —CO—G 1 (wherein E 1 represents a bond, O, or NH; and G 1 represents hydrogen, substituted or unsubstituted lower alkyl, OR 6 , or NR 7 R 8 ; and n represents an integer of 0 to 4), or the like; R 1 and R 2 are combined to represent a saturated carbon ring together with a carbon atom adjacent thereto; or R 2 , and R 11 or R 13 described below are combined to form a single bond; R 3 represents hydrogen, phenyl, or halogen; R 4 represents hydroxy, lower alkoxy, or the like; A represents —C(R 9 )(R 10 )— or O; B represents O, NR 11 , —C(R 12 )(R 13 )—, or —C(R 14 )(R 15 )—C(R 16 )(R 17 )—; D represents (i) —C(R 18 )(R 19 )—X— (wherein X represents —C(R 21 )(R 22 )—, S, or NR 23 ), (ii) —C(R 19a )═Y— [Y represents —C(R 24 )—Z— (wherein Z represents CONH, CONHCH 2 , or a bond), or N], or (iii) a bond; and R 5 represents aryl, an aromatic heterocyclic group, cycloalkyl, pyridine-N-oxide, cyano, or lower alkoxycarbonyl; or pharmaceutically acceptable salts thereof.

  以下是由下式（I）表示的含氧杂环化合物： 其中R1和R2独立地表示氢、较低的烷基、氰基、—（CH2）n—E1—CO—G1（其中E1表示键、O或NH；G1表示氢、取代或未取代的较低烷基、OR6或NR7R8；n表示0到4的整数），或类似物；R1和R2结合表示与相邻碳原子一起形成饱和碳环；或R2，以及下文描述的R11或R13结合形成单键；R3表示氢、苯基或卤素；R4表示羟基、较低的烷氧基或类似物；A表示—C（R9）（R10）—或O；B表示O、NR11、—C（R12）（R13）—或—C（R14）（R15）—C（R16）（R17）—；D表示（i）—C（R18）（R19）—X—（其中X表示—C（R21）（R22）—、S或NR23）、（ii）—C（R19a）═Y—［Y表示—C（R24）—Z—（其中Z表示CONH、CONHCH2或键），或N］，或（iii）键；R5表示芳基、芳香杂环基、环烷基、吡啶-N-氧化物、氰基或较低烷氧羰基；或其药学上可接受的盐。
• SUBSTITUTED ACETOPHENONES USEFUL AS PDE4 INHIBITORS
  申请人：Felding Jakob

  公开号：US20100035908A1

  公开（公告）日：2010-02-11

  The present invention relates to a compound according to formula: (I); wherein X 1 , X 2 , X 3 , X 4 and X 5 independently of each other represent —CH— or N; or X 3 , X 4 and X 5 independently of each other represent —CH— or N, and Xi and X 2 independently of each other represent C and form part of an additional 6-membered aromatic ring; R 1 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or alkylcarbonyl, all of which are optionally substituted; R 2 and R 3 independently represent hydrogen, —CH 2 —C(O)NR—R′, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, alkylalkoxycarbonyl, alkylcarbonyloxy, or alkoxyalkyl, all of which are optionally substituted; R 11 represents hydrogen, halogen, cyano, amino, alkoxy or alkylamino, X 1 -X 5 represent —CH— or N, including N-oxides, enantiomers and diastereomers; and pharmaceutically acceptable salts, hydrates, or solvates thereof. The invention relates further to processes for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases, e.g. dermal diseases, with said compounds, and to the use of said compounds in the manufacture of medicaments.

  本发明涉及一种化合物，其化学式为（I）; 其中X1，X2，X3，X4和X5相互独立地表示—CH—或N; 或者X3，X4和X5相互独立地表示—CH—或N，Xi和X2相互独立地表示C，并形成额外的6元芳香环的一部分; R1表示氢，烷基，烯基，炔基，卤代烷基，羟基烷基或烷基羰基，所有这些都可以被取代; R2和R3相互独立地表示氢，—CH2—C（O）NR—R′，烷基，环烷基，烯基，环烯基，炔基，卤代烷基，羟基烷基，杂环烯基，烷基芳基，烷基烷氧羰基，烷基羰氧基或烷氧基烷基，所有这些都可以被取代; R11表示氢，卤素，氰基，氨基，烷氧基或烷基氨基，X1-X5表示—CH—或N，包括N-氧化物，对映体和非对映体;以及其药学上可接受的盐，水合物或溶剂化物。本发明还涉及制备该化合物的方法，使用该化合物进行治疗的方法，包括该化合物的制药组合物，治疗疾病的方法，例如皮肤疾病，并且涉及使用该化合物制造药物的用途。
• Substituted acetophenones useful as PDE4 inhibitors
  申请人：Leo Pharma A/S

  公开号：US08148537B2

  公开（公告）日：2012-04-03

  The present invention relates to a compound according to formula: (I); wherein X1, X2, X3, X4 and X5 independently of each other represent —CH— or N; or X3, X4 and X5 independently of each other represent —CH— or N, and Xi and X2 independently of each other represent C and form part of an additional 6-membered aromatic ring; R1 represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or alkylcarbonyl, all of which are optionally substituted; R2 and R3 independently represent hydrogen, —CH2—C(O)NR—R′, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, alkylalkoxycarbonyl, alkylcarbonyloxy, or alkoxyalkyl, all of which are optionally substituted; R11 represents hydrogen, halogen, cyano, amino, alkoxy or alkylamino, X1-X5 represent —CH— or N, including N-oxides, enantiomers and diastereomers; and pharmaceutically acceptable salts, hydrates, or solvates thereof. The invention relates further to processes for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases, e.g. dermal diseases, with said compounds, and to the use of said compounds in the manufacture of medicaments.

  本发明涉及一种化合物，其化学式为：（I）；其中X1、X2、X3、X4和X5分别独立地表示—CH—或N；或X3、X4和X5分别独立地表示—CH—或N，而Xi和X2分别独立地表示C并构成一个额外的6元芳香环；R1表示氢、烷基、烯基、炔基、卤代烷基、羟基烷基或烷基羰基，所有这些均可选择性地被取代；R2和R3独立地表示氢、—CH2—C（O）NR—R′、烷基、环烷基、烯基、环烯基、炔基、卤代烷基、羟基烷基、杂环烯基、烷基芳基、烷基烷氧羰基、烷基羰氧基或烷氧基烷基，所有这些均可选择性地被取代；R11表示氢、卤素、氰基、氨基、烷氧基或烷基氨基，X1-X5表示—CH—或N，包括N-氧化物、对映体和非对映异构体；以及其药学上可接受的盐、水合物或溶剂化物。本发明还涉及制备这些化合物的方法，以及将这些化合物用于治疗、包括皮肤疾病等疾病的药物组成物，以及将这些化合物用于制造药物的用途。
• OXYGENIC HETEROCYCLIC COMPOUNDS
  申请人：KYOWA HAKKO KOGYO KABUSHIKI KAISHA

  公开号：EP0943613A1

  公开（公告）日：1999-09-22

  Oxygen-containing heterocyclic compounds represented by following Formula (I): wherein n represents an integer of 1 to 4; R1, R2, R3 and R4 are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, or the like; R5 represents hydrogen or halogen; R6 represents hydroxy or substituted or unsubstituted lower alkoxy; D represents (1) -C(R8)(R9)-X- or (2) a bond; R7 represents (1) substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted heterocyclic group, or pyridine-N-oxide, (2) -Y-ZR14, (3) -Y-Z-(CH2)m-N(R16a)R16b, or (4) -Y-CON(R17a)R17b, or pharmaceutically acceptable salts thereof.

  下式(I)所代表的含氧杂环化合物： 其中 n 代表 1 至 4 的整数；R1、R2、R3 和 R4 相同或不同，代表氢、取代或未取代的低级烷基或类似物； R5 代表氢或卤素；R6 代表羟基或取代或未取代的低级烷氧基；D 代表 (1) -C(R8)(R9)-X- 或 (2) 键；R7 代表 (1) 取代或未取代的低级烷基、取代或未取代的环烷基、多环烷基、取代或 未取代的芳基、取代或未取代的芳烷基、(2) -Y-ZR14, (3) -Y-Z-(CH2)m-N(R16a)R16b, 或 (4) -Y-CON(R17a)R17b, 或其药学上可接受的盐。
• WO2008/77404
  申请人：——

  公开号：——

  公开（公告）日：——