2-(3-Cyano-phenoxy)-nicotinic acid | 83164-83-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(3-Cyano-phenoxy)-nicotinic acid
• 英文别名: 2-(3-cyanophenoxy)pyridine-3-carboxylic acid
• CAS: 83164-83-4
• 化学式: C₁₃H₈N₂O₃
• mdl: MFCD09806586
• 分子量: 240.218
• InChiKey: GFDPNUPEIBITSU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  83.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(3-Cyano-phenoxy)-nicotinic acid 以 氯化亚砜 为溶剂， 生成 2-(3-Cyano-phenoxy)-N-(5-methyl-pyrazin-2-ylmethyl)-nicotinamide
  参考文献：
  名称：

  Nicotinamide derivatives

  摘要：

  一种具有式（I）的化合物，其中m、n、o、p、q、r、A、B、D、E、R1、R2、R3、R4、R5、R6、R7和R8如描述中所定义，在治疗呼吸系统、过敏、类风湿、体重调节、炎症和中枢神经系统疾病方面有用，如哮喘、慢性阻塞性肺疾病、成人呼吸系统疾病综合征、休克、纤维化、肺部过敏、过敏性鼻炎、特应性皮炎、牛皮癣、体重控制、类风湿性关节炎、虚弱、克罗恩病、溃疡性结肠炎、关节炎症状和其他炎症性疾病、抑郁症、多发性梗塞性痴呆和艾滋病的治疗。

  公开号：

  US06380218B1
• 作为产物：
  描述：

  2-氯烟酸 以30%的产率得到
  参考文献：
  名称：

  SACCOMANO, NICHOLAS A.;VINICK, FREDERIC J.

  摘要：

  DOI：

文献信息

• Design, Synthesis, and Herbicidal Activity of Novel Diphenyl Ether Derivatives Containing Fast Degrading Tetrahydrophthalimide
  作者：Li-Xia Zhao、Mao-Jun Jiang、Jia-Jun Hu、Yue-Li Zou、Yuan Cheng、Tao Ren、Shuang Gao、Ying Fu、Fei Ye

  DOI：10.1021/acs.jafc.0c00947

  日期：2020.3.25

  against maize PPO and similar herbicidal activities to Oxyfluorfen in weeding experiments in greenhouses and field weeding experiments. In view of the inspected bioactivities, the structure-activity relationship (SAR) of this series of compounds was also discussed. Crop selection experiments demonstrates that compound 6c is safe for soybeans, maize, rice, peanuts and cotton at a dose of 300 g ai/ha. Accumulation

  为了寻找具有更好生物活性的新型原卟啉原氧化酶（PPO）抑制剂，基于亚结构剪接和生物异构化的原理，设计了一系列新型的含有四氢邻苯二甲酰亚胺的二苯醚衍生物。PPO抑制实验显示6c是最有潜力的化合物，其半数最大抑制浓度（IC50）值为0.00667 mg / L，显示出比抗氧氟芬（IC50 = 0.0426 mg / L）高7倍的抗玉米PPO活性和类似的除草活性在温室除草实验和田间除草实验中使用Oxyfluorfen。鉴于所检查的生物活性，还讨论了该系列化合物的结构-活性关系（SAR）。作物选择实验表明，化合物6c对于大豆，玉米，大米，花生和棉花的剂量为300 g ai / ha。积累分析实验表明，某些作物（大豆，花生和棉花）中6c的积累显着低于Oxyfluorfen。当前的工作表明化合物6c可以作为田间除草剂的新候选物开发。
• 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、—NO2、—(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、—NO2、—C(═O)NR16R17、—OC(═O)NR16R17、—NR22aC(═O)NR16R17、—NR22aC(═NR12)NR6R17—NR22aC(═NCN)NR16R17、—NR22aC(═N—NO2)NR16R17、—C(═NR22a)NR16R17、—CH2C(═NR22a)NR16R17、—OC(═NR22a)NR16R17、—OC(═N—NO2)NR16R17、—NR16R17、—CH2NR16R17、—NR22aC(═O)R″、—NR22aC(═O)OR16、═NOR16、—NR22aS(═O)pR17、—S(═O)pNR16R17；或—CH2C(═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）—(CH2)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、—CF3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，-NO2，-(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。
• Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes
  申请人：Pfizer Inc.

  公开号：US20020193612A1

  公开（公告）日：2002-12-19

  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 where j is 0 or 1 provided that when j is 0, n must be 2; k is 0 or 1; m is 0, 1, or 2; n is 1 or 2; W 1 is —O—; or —S(═O) t —, where t is 0, 1, or 2; or —N(R 3 )—; W 2 is —O—CR A R B — or is absent; Y is ═C(R 1 a )— or —[N (O) k ]— where k is 0 or 1; R A and R B are —H; —F; —CF 3 ; —(C 1 -C 4 ) alkyl; —(C 3 -C 7 ) cycloalkyl; phenyl; or benzyl substituted with 0 to 3 substituents R 10 ; or R A and R B are taken together, but only in the case where m is 1, to form a spiro moiety; R C and R D have the same meaning 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 ; and —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 in addition to other meanings may be taken together to form, e.g., 2 Q 1 is a saturated or unsaturated carbon ring system that is a 3- to 7-membered monocyclic, or that is a 7- to 12-membered, fused polycyclic; provided that Q 1 is not a discontinuous or restricted biaryl moiety as defined under Q 2 ; where optionally one carbon atom may be replaced by a heteroatom selected from N, O, and S; where optionally a second carbon atom thereof, and further optionally a third carbon atom thereof may be replaced by N; Q 2 is a discontinuous or restricted biaryl moiety consisting of a saturated or unsaturated carbon ring system that is a 3- to 7-membered monocyclic, or that is a 7- to 12-membered, fused polycyclic; where optionally one carbon atom may be replaced by a heteroatom selected from N, O, and S; where optionally a second carbon atom thereof, and further optionally a third carbon atom thereof may be replaced by N; Z is selected from: 3

  这是一段关于治疗哮喘、慢性支气管炎和慢性阻塞性肺疾病等疾病中，通过抑制PDE4来调节嗜酸性粒细胞的激活和脱颗粒的化合物的公式描述。其中j为0或1，当j为0时，n必须为2；k为0或1；m为0、1或2；n为1或2；W1为—O—或—S(═O)t—，其中t为0、1或2；或—N(R3)—；W2为—O—CRARB—或不存在；Y为═C(R1a)—或—[N(O)k]—，其中k为0或1；RA和RB为—H；—F；—CF3；—(C1-C4)烷基；—(C3-C7)环烷基；苯基；或取代有0-3个取代基R10的苄基；或在m为1的情况下RA和RB共同形成螺环基；RC和RD与RA和RB的含义相同，但其中一个必须为—H；R1和R2为—H；—F；—Cl；—CN；—NO2；—(C1-C4)烷基；—(C2-C4)炔基；氟代的—(C1-C3)烷基；—OR16；和—C(═O)NR22aR22b；R3为—H；—(C1-C3)烷基；苯基；苄基；或—OR16；除了其他含义外，R4、R5和R6还可以共同形成，例如2；Q1为饱和或不饱和的碳环系统，是一个3-7个成员的单环，或是7-12个成员的融合多环；前提是Q1不是不连续或受限的双芳基基团，如Q2所定义；其中可选地，一个碳原子可以被N、O和S中选择的杂原子所替换；其中可选地，第二个碳原子，进一步可选地，第三个碳原子可以被N所替换；Q2为不连续或受限的双芳基基团，由饱和或不饱和的碳环系统组成，是一个3-7个成员的单环，或是7-12个成员的融合多环；其中可选地，一个碳原子可以被N、O和S中选择的杂原子所替换；其中可选地，第二个碳原子，进一步可选地，第三个碳原子可以被N所替换；Z可选择为：3。
• Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes
  申请人：Pfizer Inc.

  公开号：US20020111495A1

  公开（公告）日：2002-08-15

  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, k is 0 or 1, m is 0, 1, or 2; n is 1 or 2; A is selected from the partial Formulas: 2 where q is 1, 2, or 3, W 3 is —O—; —N(R 9 )—; or —OC(═O)—; R 7 is selected from —H; —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, or —(C 2 -C 6 ) alkynyl substituted by 0 to 3 substituents R 10 ; —(CH 2 ) u —(C 3 -C 7 ) cycloalkyl where u is 0, 1 or 2, substituted by 0 to 3 R 10 ; and phenyl or benzyl substituted by 0 to 3 R 14 ; R 8 is 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; 1,3,4-oxadiazolyl; 1,3,4-oxadiazol-2-on-5-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; 1,2,5-thiadiazolyl; 1,3,4-thiadiazolyl; morpholinyl; parathiazinyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl; pyrrolyl; pyrazolyl; succinimidyl; glutarimidyl; pyrrolidonyl; 2-piperidonyl; 2-pyridonyl; 4-pyridonyl; pyridazin-3-onyl; pyridyl; pyrimidinyl; pyrazinyl; pyridazinyl; indolyl; indolinyl; isoindolinyl; benzo[b]furanyl; 2,3-dihydrobenzofuranyl; 1,3-dihydroisobenzofuranyl; 2H-1-benzopyranyl; 2-H-chromenyl; chromanyl; benzothienyl; 1H-indazolyl; benzimidazolyl; benzoxazolyl; benzisoxazolyl; benzothiazolyl; benzotriazolyl; benzotriazinyl; phthalazinyl; 1,8-naphthyridinyl; quinolinyl; isoquinolinyl; quinazolinyl; quinoxalinyl; pyrazolo[3,4-d]pyrimidinyl; pyrimido[4,5-d]pyrimidinyl; imidazo[1,2-a]pyridinyl; pyridopyridinyl; pteridinyl; or 1H-purinyl; or A is selected from phosphorous and sulfur acid groups; W is —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 4 , R 5 and R 6 are (1) —H; provided that R 5 and R 6 are not both —H at the same time, —F; —Cl; —(C 2 -C 4 ) alkynyl; —R 16 ; —OR 16 ; —S(═O) p R 16 ; —C(═O)R 16 , —C(═O)OR 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 12 a C(═O)NR 16 R 17 ; —NR 12 a C(═NR 12 )NR 16 R 17 ; —NR 12 a C(═NCN)NR 16 R 16 ; —NR 12 a C(═N—NO 2 )NR 15 R 16 ; —C(═NR 12 a )NR 15 R 16 ; —CH 2 C(═NR 12 a )NR 16 R 17 ; —OC(═NR 12 a )NR 16 R 17 ; —OC(═N—NO 2 )NR 16 R 17 ; —NR 16 R 17 ; —CH 2 NR 16 R 17 ; —NR 12 a C(═O)R 16 ; —NR 12 a C(═O)OR 16 ; ═NOR 16 ; —NR 12 a S(═O) p R 17 —S(═O) p NR 16 R 17 ; and —CH 2 C(═NR 12 a )NR 16 R 17 ; (2) —(C 1 -C 4 ) alkyl including dimethyl and —(C 1 -C 4 ) alkoxy substituted with 0 to 3 substituents —F or —Cl; or 0 or 1 substituent (C 1 -C 2 ) alkoxycarbonyl-, (C 1 -C 2 ) alkylcarbonyl-, or (C 1 -C 2 ) alkylcarbonyloxy-; or (3) an aryl or heterocyclic moiety; or (4) R 5 and R 6 are taken together to form a moiety of partial Formulas (1.3.1) through (1.3.15): 3 or a pharmaceutically acceptable salt thereof.

  本发明涉及一种化合物，其在治疗由嗜酸性粒细胞活化和脱颗粒调节的疾病中，特别是哮喘、慢性支气管炎和慢性阻塞性肺疾病中作为PDE4抑制剂有用，其化学式为：其中j为0或1，k为0或1，m为0、1或2；n为1或2；A从部分式中选取：其中q为1、2或3，W3为—O—；—N(R9)—；或—OC(═O)—；R7选自—H；—(C1-C6)烷基、—(C2-C6)烯基或—(C2-C6)炔基，其上可有0至3个取代基R10；—(CH2)u—(C3-C7)环烷基，其中u为0、1或2，其上可有0至3个取代基R10；以及苯基或苄基，其上可有0至3个取代基R14；R8为四唑-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；咪唑啉-2-酮-4-基；1,3,4-噁二唑基；1,3,4-噁二唑-2-酮-5-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；1,2,5-噻二唑基；1,3,4-噻二唑基；吗啉基；对噻嗪基；噁唑基；异噁唑基；噻唑基；异噻唑基；吡咯基；吡唑基；琥珀酰亚胺基；戊二酰亚胺基；吡咯烷基；2-哌啶酮基；2-吡啶酮基；4-吡啶酮基；吡啶嗪-3-酮基；吡啶基；嘧啶基；吡嗪基；吡啶嗪基；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；1,3-二氢异苯并呋喃基；2H-1-苯并吡喃基；2-H-香豆素基；香豆素基；苯并噻吩基；1H-吲唑基；苯并咪唑基；苯并噁唑基；苯并异噁唑基；苯并噻唑基；苯并三唑基；苯并三唑啉基；邻苯二酚基；1,8-萘啶基；喹啉基；异喹啉基；喹唑啉基；喹啉酮基；吡唑并[3,4-d]嘧啶基；嘧啶并[4,5-d]嘧啶基；咪唑并[1,2-a]吡啶基；吡啶吡啶基；噻吩基；或1H-嘌呤基；或A选自磷和硫酸基；W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；R4、R5和R6为(1) —H；但是当R5和R6同时不为—H时，可以为—F；—Cl；—(C2-C4)炔基；—R16；—OR16；—S(═O)pR16；—C(═O)R16、—C(═O)OR16、—C(═O)OR16；—OC(═O)R16；—CN；—NO2；—C(═O)NR16R17；—OC(═O)NR16R17；—NR12aC(═O)NR16R17；—NR12aC(═NR12)NR16R17；—NR12aC(═NCN)NR16R16；—NR12aC(═N—NO2)NR15R16；—C(═NR12a)NR15R16；—CH2C(═NR12a)NR16R17；—OC(═NR12a)NR16R17；—OC(═N—NO2)NR16R17；—NR16R17；—CH2NR16R17；—NR12aC(═O)R16；—NR12aC(═O)OR16；═NOR16；—NR12aS(═O)pR17—S(═O)pNR16R17；和—CH2C(═NR12a)NR16R17；(2) —(C1-C4)烷基，包括二甲基和—(C1-C4)烷氧基，其上可有0至3个取代基—F或—Cl；或者0或1个取代基(C1-C2)烷氧羰基、(C1-C2)烷基羰基或(C1-C2)烷基羰氧基；或者(3) 芳基或杂环基；或者(4) R5和R6聚合形成部分式(1.3.1)到(1.3.15)中的一个基团；或其药学上可接受的盐。