(+/-)-2-[3-Fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid | 445295-01-2

• 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: (+/-)-2-[3-Fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid
• 英文别名: 2-[4-[[[2-(3-cyanophenoxy)pyridine-3-carbonyl]amino]methyl]-3-fluorophenoxy]propanoic acid
• CAS: 445295-01-2
• 化学式: C₂₃H₁₈FN₃O₅
• 分子量: 435.411
• InChiKey: OEULFPLADPUDRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  122
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (+)-2-[3-Fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid tert-butyl ester 、 (+/-)-2-[4-({[2-(benzo[2,1,3]oxadiazol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid tert-butyl ester 生成 (+/-)-2-[3-Fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid
  参考文献：
  名称：

  ETHER DERIVATIVES USEFUL AS INHIBITORS OF PDE4 ISOZYMES

  摘要：

  以下化合物可用作PDE4的抑制剂，用于治疗由嗜酸性粒细胞的活化和脱颗粒调控的疾病，特别是哮喘、慢性支气管炎和慢性阻塞性肺疾病，其化学式如下：其中取代基如规范中所定义。

  公开号：

  US20070161681A1

文献信息

• Ether derivatives useful as inhibitors of PDE4 isozymes
  申请人：Pfizer Inc.

  公开号：US20030027845A1

  公开（公告）日：2003-02-06

  Compounds useful as inhibitors of PDE4 in the treatment of diseases regulated by the activation and degranulation of eosinophils, especially asthma, chronic bronchitis, and chronic obstructuive pulmonary disease, of the formula: 1 wherein j is 0 or 1, provided that when j is 0, n must be 2; k is 0 or 1; m is 1, 2, or 3; n is 1 or 2; W 1 and W 2 are —O—; —S(═O) t —, where t is 0, 1, or 2, or —N(R 3 )—; Y is ═C(R 1 a )—, or —[N (O) k ]— where k is 0 or 1; R 1 a is —H, —F, —Cl, —CN, —NO 2 , —(C 1 -C 4 )alkyl, —(C 2 -C 4 ) alkynyl, fluorinated-(C 1 -C 3 ) alkyl, fluorinated-(C 1 -C 3 ) alkoxy, —OR 16 , or —C(═O)NR 22 a R 22 b ; R A and R B are —H, —F, —CF 3 , —(C 1 -C 4 ) alkyl, —(C 3 -C 7 ) cycloalkyl, phenyl, or benzyl substituted by 0-3 R 10 ; or R A and R B are taken together to form a spiro moiety 2 where r and s are 0-4 provided r+s is ≧1 but not >5; and X A is —CH 2 —, —CHF, —CF 2 , —NR 15 —, —O—, or —S(═O) t —, where t is 0, 1; R C and R D are the same as R A and R B except that one of them must be —H; R 1 and R 2 are —H, —F, —Cl, —CN, —NO 2 , —(C 1 -C 4 ) alkyl, —(C 2 -C 4 ) alkynyl, fluorinated-(C 1 -C 3 ) alkyl, —OR 16 ), or —C(═O)NR 22 a R 22 b ; R 3 is —H, —(C 1 -C 3 ) alkyl, phenyl, benzyl, or —OR 16 ; R 4 , R 5 and R 6 are (a) —H, —F, —Cl, —(C 2 -C 4 ) alkynyl, —R 16 ,—OR 16 , —S(═O) p R 16 , —C(═O)R 16 , —C(═O)OR 16 , —OC(═O)R 16 , —CN, —NO 2 , —C(═O)NR 16 R 17 , —OC(═O)NR 16 R 17 , —NR 22 a C(═O)NR 16 R 17 , —NR 22 a C(═NR 12 )NR 6 R 17 —NR 22 a C(═NCN)NR 16 R 17 , —NR 22 a C(═N—NO 2 )NR 16 R 17 , —C(═NR 22 a )NR 16 R 17 , —CH 2 C(═NR 22 a )NR 16 R 17 , —OC(═NR 22 a )NR 16 R 17 , —OC(═N—NO 2 )NR 16 R 17 , —NR 16 R 17 , —CH 2 NR 16 R 17 , —NR 22 a C(═O)R″, —NR 22 a C(═O)OR 16 , ═NOR 16 , —NR 22 a S(═O) p R 17 , —S(═O) p NR 16 R 17 ; or —CH 2 C(═NR 22 a )NR 16 R 17 ; where p is 0, 1, or 2; (b) —(C 1 -C 4 ) alkyl or —(C 1 -C 4 ) alkoxy substituted by 0-3 of —F or —Cl; or 0 or 1 of (C 1 -C 2 ) alkoxycarbonyl-, (C 1 -C 2 )alkylcarbonyl-, or (C 1 -C 2 ) alkylcarbonyloxy-; or (c) phenyl, benzyl, furanyl, tetrahydrofuranyl, oxetanyl, thienyl, tetrahydrothienyl, pyrrolyl, pyrrolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, pyrazolyl, pyrazolidinyl, oxadiazolyl, thiadiazolyl, imidazolyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, triazolyl, triazinyl, tetrazolyl, pyranyl, azetidinyl, morpholinyl, parathiazinyl, indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, 2-H-chromenyl, chromanyl, benzothienyl, 1-H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, or purinyl, all substituted by 0-2 of R 14 , or (d) R 5 and R 6 are taken together to form a moiety of partial Formulas (1.3.1) through (1.3.15); D is a group of partial Formulas (1.1.1) through (1.1.9): 3 where q is 1-3, provided where q is 2 or 3, R 9 is —H; v is 0-1; W 3 is —O—, —N(R 9 )—, or —OC(═O)═; R 7 is (a) —H; (b) —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, or —(C 2 -C 6 ) alkynyl, all substituted by 0-3 of R 10 ; (c) —(CH 2 ) u —(C 3 -C 7 ) cycloalkyl where u is 0-2, substituted by 0-3 of R 10 ; or (d) phenyl or benzyl substituted by 0-3 of R 10 ; R 8 is (a) tetrazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-3-on-5-yl, 1,2,3-triazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazolidin-2-on-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-on-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-oxadiazol-3-on-5-yl, 1,3,4-oxadiazolyl, 1,3,4-oxadiazol-2-on-5-yl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, succinimidyl, glutarimidyl, pyrrolidonyl, 2-piperidonyl, 2-pyridonyl, 4-pyridonyl, pyridazin-3-onyl, thiadiazolyl, parathiazinyl; (b) indolyl, indolinyl, isoindolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, 2-H-chromenyl, chromanyl, benzothienyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzotriazolyl, benzotriazinyl, quinazolinyl, quinoxalinyl, pyrazolo[3,4-d]pyrimidinyl, pyrimido[4,5-d]pyrimidinyl, imidazo[1,2-a]pyridinyl, pyridopyridinyl, pteridinyl, or purinyl, all optionally substituted on a carbon atom by R 14 , on a nitrogen atom by R 15 and all tautomer forms thereof, or on a sulfur atom by 0-2 oxygen atoms; R 9 is —H, —(C 1 -C 4 ) alkyl, —(C 3 -C 7 ) cycloalkyl, phenyl, benzyl, —C(═O)OR 16 , —C(═O)R 16 , —OR 16 , —(C 1 -C 2 ) alkyl-OR 16 , or —(C 1 -C 2 ) alkyl-C(═O)OR 16 ; or (c) —O—P(═O)(OH) 2 (phosphoric), —PH(═O)OH (phosphinic), —P(═O)(OH) 2 (phosphonic), —[P(═O)(OH)—O(C 1 -C 4 ) alkyl](alkylphosphono), —P(═O)(OH)—O(C 1 -C 4 ) alkyl) (alkylphosphinyl), —P(═O)(OH)NH 2 (phosphoramido), —P(═O)(OH)NH(C 1 -C 4 ) alkyl and —P(═O)(OH)NHR 25 , (substituted phosphoramido), —O—S(═O) 2 OH (sulfuric), —S(═O) 2 OH (sulfonic), —S(═O) 2 NHR 26 or —NHS(═O) 2 R 26 (sulfonamido) where R 26 is —CH 3 , —CF 3 , or o-toluyl, and acylsulfonamido selected from the group consisting of —C(═O)NHS(═O) 2 R 25 , —C(═O)NHS(═O) 2 NH 2 , —C(═O)NHS(═O) 2 (C 1 -C 4 ) alkyl, —C(═O)NHS(═O) 2 NH(C 1 -C 4 ) alkyl, —C(═O)NHS(═O) 2 N[(C 1 -C 4 ) alkyl] 2 , —S(═O) 2 NHC(═O)(C 1 -C 4 ) alkyl, —S(═O) 2 NHC(═O)NH 2 , —S(═O) 2 NHC(═O)NH(C 1 -C 4 ) alkyl, —S(═O) 2 NHC(═O)N[(C 1 -C 4 ) alkyl] 2 , —S(═O) 2 NHC(═O)R 25 , —S(═O) 2 NHCN, —S(═O) 2 NHC(═S)NH 2 , —S(═O) 2 NHC(═S)NH(C 1 -C 4 ) alkyl, —S(═O) 2 NHC(═S)N[(C 1 -C 4 ) alkyl] 2 , or —S(═O) 2 NHS(═O) 2 R 25 , where R 25 is —H, —(C 1 -C 4 ) alkyl, phenyl, or —OR 16 ; 1 and 2 are a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic; wherein optionally one carbon atom of said carbon ring system may be replaced by a heteroatom selected from N, O, and S; and where N is selected, optionally a second carbon atom thereof may be replaced by a heteroatom selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

  该化合物的公式为：1，其中j为0或1，但当j为0时，n必须为2；k为0或1；m为1、2或3；n为1或2；W1和W2为—O—、—S(═O)t—，其中t为0、1或2，或—N(R3)—；Y为═C(R1a)—或—[N(O)k]—，其中k为0或1；R1a为—H、—F、—Cl、—CN、—NO2、—(C1-C4)烷基、—(C2-C4)炔基、氟代-(C1-C3)烷基、氟代-(C1-C3)烷氧基、—OR16或—C(═O)NR22aR22b；RA和RB为—H、—F、—CF3、—(C1-C4)烷基、—(C3-C7)环烷基、苯基或苄基，其中0-3个位置可被R10取代；或RA和RB结合形成一个螺环基团；其中r和s为0-4，但r+s≥1且r+s≤5；XA为—CH2—、—CHF、—CF2、—NR15—、—O—或—S(═O)t—，其中t为0或1；RC和RD与RA和RB相同，但其中一个必须为—H；R1和R2为—H、—F、—Cl、—CN、— 、—(C1-C4)烷基、—(C2-C4)炔基、氟代-(C1-C3)烷基、—OR16或—C(═O)NR22aR22b；R3为—H、—(C1-C3)烷基、苯基、苄基或—OR16；R4、R5和R6为：（a）—H、—F、—Cl、—(C2-C4)炔基、—R16、—OR16、—S(═O)pR16、—C(═O)R16、—C(═O)OR16、—OC(═O)R16、—CN、— 、—C(═O)NR16R17、—OC(═O)NR16R17、—NR22aC(═O)NR16R17、—NR22aC(═NR12)NR6R17—NR22aC(═NCN)NR16R17、—NR22aC(═N— )NR16R17、—C(═NR22a)NR16R17、— C(═NR22a)NR16R17、—OC(═NR22a)NR16R17、—OC(═N— )NR16R17、—NR16R17、— NR16R17、—NR22aC(═O)R″、—NR22aC(═O)OR16、═NOR16、—NR22aS(═O)pR17、—S(═O)pNR16R17；或— C(═NR22a)NR16R17，其中p为0、1或2；（b）0-3个位置被—F或—Cl取代的（C1-C4）烷基或（C1-C4）烷氧基；或0或1个位置被（C1-C2）烷氧羰基-、（C1-C2）烷基羰基-或（C1-C2）烷基羰氧基-取代的（C1-C4）烷基或（C1-C4）烷氧基；或（c）苯基、苄基、呋喃基、四氢呋喃基、氧杂环戊烷基、噻吩基、四氢噻吩基、吡咯基、吡咯烷基、噁唑基、噁唑烷基、异噁唑基、异噁唑烷基、噻唑基、噻唑烷基、异噻唑基、异噻唑烷基、吡唑基、吡唑烷基、吡嗪基、吡啶基、嘧啶基、吡咯啉基、哌啶基、三唑基、三嗪基、四唑基、吡喃基、氮杂环己烷基、吩咯噻嗪基、吲哚基、吲哚啉基、苯并[b]呋喃基、2,3-二氢苯并呋喃基、2-H-香豆素基、香豆素基、苯并噻吩基、1H-吲哚基、苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并三嗪基、吡唑吡啶基、吡啶吡啶基、嘧啶吡啶基、嘧啶吡嗪基、吡嗪吡啶基、吡啶并吡嗪基、嘧啶基、氨基甲酸酯基、吡咯烷酰基、戊二酰亚胺基、戊二酰胺基、吡咯烷酮基、2-哌啶酮基、2-吡啶酮基、4-吡啶酮基、吡嗪嗪基、硫代噻唑基、对苯硫代噻唑基；（d）R5和R6结合形成部分式（1.3.1）至（1.3.15）的基团；D为部分式（1.1.1）至（1.1.9）的基团：3，其中q为1-3，但当q为2或3时，R9为—H；v为0-1；W3为—O—、—N(R9)—或—OC(═O)═；R7为：（a）—H；（b）—(C1-C6)烷基、—(C2-C6)烯基或—(C2-C6)炔基，其中0-3个位置可被R10取代；（c）—( )u—(C3-C7)环烷基，其中u为0-2，0-3个位置可被R10取代；或（d）苯基或苄基，其中0-3个位置可被R10取代；R8为：（a）四唑-5-基、1,2,4-三唑-3-基、1,2,4-三唑-3-酮-5-基、1,2,3-三唑-5-基、咪唑-2-基、咪唑-4-基、咪唑烷-2-酮-4-基、1,2,4-噁二唑-3-基、1,2,4-噁二唑-5-酮-3-基、1,2,4-噁二唑-5-基、1,2,4-噁二唑-3-酮-5-基、1,3,4-噁二唑基、1,3,4-噁二唑-2-酮-5-基、噁唑基、异噁唑基、吡咯基、吡唑基、琥珀酰亚胺基、戊二酰亚胺基、吡咯烷酰胺基、2-哌啶酮基、2-吡啶酮基、4-吡啶酮基、吡嗪嗪-3-酮基、硫代噻唑基、对硫代噻唑基；（b）吲哚基、吲哚啉基、异吲哚啉基、苯并[b]呋喃基、2,3-二氢苯并呋喃基、2-H-香豆素基、香豆素基、苯并噻吩基、苯并吲哚基、苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并吡啶基、嘧啶基、吡咯啉基、苯并[b]噻吩基、1H-吲哚基、苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并三嗪基、吡唑吡啶基、吡啶并吡嗪基、嘧啶吡啶基、嘧啶吡嗪基、吡嗪吡啶基、吡咯烷酰基、噻唑基、对苯二甲酰亚胺基、对苯二甲酰胺基、吡咯烷酮基、2-哌啶酮基、2-吡啶酮基、4-吡啶酮基、吡嗪嗪-3-酮基、硫代噻唑基；或在一个碳原子上由R14取代，在一个氮原子上由R15取代，或在一个硫原子上由0-2个氧原子取代；R9为—H、—(C1-C4)烷基、—(C3-C7)环烷基、苯基、苄基、—C(═O)OR16、—C(═O)R16、—OR16、—(C1-C2)烷基-OR16或—(C1-C2)烷基-C(═O)OR16；或为—O—P(═O)(OH)2（磷酸）、—PH(═O)OH（亚磷酸）、—P(═O)(OH)2（膦酸）、—[P(═O)(OH)—O(C1-C4)烷基]（烷基膦酸酯）、—P(═O)(OH)—O(C1-C4)烷基）（烷基膦酸酰基）、—P(═O)(OH)NH2（磷酰胺基）、—P(═O)(OH)NH(C1-C4)烷基和—P(═O)(OH)NHR25（取代磷酰胺基）、—O—S(═O)2OH（硫酸）、—S(═O)2OH（磺酸）、—S(═O)2NHR26或—NHS(═O)2R26（磺酰胺基），其中R26为—CH3、— 或邻甲苯基，以及从羰基磺酰胺基中选择的基团，所述基团选自：—C(═O)NHS(═O)2R25、—C(═O)NHS(═O)2NH2、—C(═O)NHS(═O)2（C1-C4）烷基、—C(═O)NHS(═O)2NH（C1-C4）烷基、—C(═O)NHS(═O)2N[（C1-C4）烷基]2、—S(═O)2NHC(═O)（C1-C4）烷基、—S(═O)2NHC(═O)NH2、—S(═O)2NHC(═O)NH（C1-C4）烷基、—S(═O)2NHC(═O)N[（C1-C4）烷基]2、—S(═O)2NHC(═O)R25、—S(═O)2NHCN、—S(═O)2NHC(═S)NH2、—S(═O)2NHC(═S)NH（C1-C4）烷基、—S(═O)2NHC(═S)N[（C1-C4）烷基]2或—S(═O)2NHS(═O)2R25，其中R25为—H、—(C1-C4)烷基、苯基或—OR16；1和2为一个饱和或不饱和的碳环系统，其为3-至7-成员单环或7-至12-成员融合或不连续的多环，其中可选地，该碳环系统的一个碳原子可被N、O和S中的一个杂原子取代，且当N被选中时，可选地，该碳环系统的第二个碳原子可被N、O和S中的一个杂原子取代；或其药学上可接受的盐。
• [EN] ETHER DERIVATIVES USEFUL AS INHIBITORS OF PDE4 ISOZYMES<br/>[FR] ETHER DERIVATIVES USEFUL AS INHIBITORS OF PDE4 ISOZYMES
  申请人：PFIZER PROD INC

  公开号：WO2002060896A1

  公开（公告）日：2002-08-08

  Compounds useful as inhibitors of PDE4 in the treatment of diseases regulated by the activation and degranulation of eosinophils, especially asthma, chronic bronchitis, and chronic obstructive pulmonary disease, of the formula (I) wherein j is 0 or 1, provided that when j is 0, n must be 2; k is 0 or 1; m is 1, 2, or 3; n is 1 or 2; W?1 and W2¿ are -O-; -S(=O)¿t?-, where t is 0, 1, or 2, or -N(R?3¿)-; Y is =C(R1a)-, or -[N∊(O)k]- where k is 0 or 1; R1a is -H, -F, -Cl, -CN, -NO2, -(C1-C4) alkyl, -(C2-C4) alkynyl, fluorinated-(C1-C3) alkyl, fluorinated-(C1-C3) alkoxy, -OR16, or -C(=O)NR22aR22b; R?A and RB¿ are -H, -F, -CF¿3?, -(C1-C4) alkyl, -(C3-C7) cycloalkyl, phenyl, or benzyl substituted by 0-3 R?10; or RA and RB¿ are taken together to form a spiro moiety of the formula (Ia) where r and s are 0-4 provided r + s is ≥1 but not > 5; and XA is -CH¿2?-, -CHF, -CF2, -NR?15¿-, -O-, or -S(=O)¿t?-, where t is 0, 1; R?C and RD¿ are the same as R?A and RB¿ except that one of them must be -H; R?1 and R2¿ are -H, -F, -Cl, -CN, -NO¿2?, -(C1-C4) alkyl, -(C2-C4) alkynyl, fluorinated-(C1-C3) alkyl, -OR?16¿, or -C(=O)NR22aR22b; R3 is -H, -(C¿1?-C3) alkyl, phenyl, benzyl, or -OR?16; R4, R5 and R6¿, D, J¿1? and J2 are defined in the application.

  化合物（I）的公式，用于治疗由嗜酸性粒细胞的激活和脱颗粒调节的疾病，特别是哮喘，慢性支气管炎和慢性阻塞性肺疾病的PDE4抑制剂，其中j为0或1，但当j为0时，n必须为2；k为0或1；m为1、2或3；n为1或2；W1和W2为-O-；-S（=O）t-，其中t为0、1或2，或-N（R3）-；Y为=C（R1a）-，或-[N∊（O）k]-，其中k为0或1；R1a为-H，-F，-Cl，-CN，-NO2，-(C1-C4)烷基，-(C2-C4)炔基，氟代-(C1-C3)烷基，氟代-(C1-C3)烷氧基，-OR16或-C（=O）NR22aR22b；R?A和RB为-H，-F，-CF3，-(C1-C4)烷基，-(C3-C7)环烷基，苯基或苄基，可以由0-3个R10取代；或RA和RB一起形成公式（Ia）的螺环部分，其中r和s为0-4，但r+s≥1但不大于5；XA为-CH2-，-CHF，-CF2，-NR15-，-O-或-S（=O）t-，其中t为0或1；R?C和RD与R?A和RB相同，但其中一个必须为-H；R1和R2为-H，-F，-Cl，-CN，- ，-(C1-C4)烷基，-(C2-C4)炔基，氟代-(C1-C3)烷基，-OR16或-C（=O）NR22aR22b；R3为-H，-(C1-C3)烷基，苯基，苄基或-OR16；R4，R5和R6，D，J1和J2在申请中有定义。
• US6828333B2
  申请人：——

  公开号：US6828333B2

  公开（公告）日：2004-12-07
• US7183293B2
  申请人：——

  公开号：US7183293B2

  公开（公告）日：2007-02-27