4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide

• 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: 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide
• 英文别名: N-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-2-[4-(trifluoromethyl)phenyl]benzamide
• 化学式: C₂₃H₂₀F₃NO₃
• 分子量: 415.412
• InChiKey: GYPJVCGKIBMXFE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4'-trifluoromethyl-biphenyl-2-carboxylic acid-[3-(2-hydroxy-ethyl)-4-hydroxymethyl-phenyl]-amide 、 甲基磺酰氯 在 盐酸 、 ammonium hydroxide 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 以20%的产率得到4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide
  参考文献：
  名称：

  Apo B-secretion/MTP inhibitory amides

  摘要：

  本发明涉及式(I)的化合物或其立体异构体、药用可接受的盐和水合物。这些化合物是Apo B/MTP抑制剂，可用于治疗各种疾病和状况，如动脉硬化、胰腺炎、肥胖、高胆固醇血症、高甘油三酯血症、高脂血症和糖尿病。本发明的化合物还与其他药物联合使用，包括胆固醇生物合成抑制剂和胆固醇吸收抑制剂，尤其是HMG-CoA还原酶抑制剂和HMG-CoA合酶抑制剂；HMG-CoA还原酶基因表达抑制剂；CETP抑制剂；胆酸螯合剂；纤维酸；胆固醇吸收抑制剂；ACAT抑制剂、角鲨烯合酶抑制剂、离子交换树脂、抗氧化剂和烟酸。本发明还涉及用于制备式(I)化合物的前体和工艺。

  公开号：

  US06121283A1

文献信息

• Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide
  申请人：Pfizer INc.

  公开号：US05919795A1

  公开（公告）日：1999-07-06

  Compounds of formula (I), ##STR1## wherin X is CH.sub.2, CO, CS or SO.sub.2 ; Y is selected from: a direct link, aliphatic hydrocarbylene radicals having up to 20 carbon atoms, which radical may be mono-substituted by hydroxy, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)acyloxy, or (C.sub.6 -C.sub.10)aryl, NH, and O, provided that if X is CH.sub.2,Y is a direct link; Z is selected from the following groups: (1) H, halo, cyano, (2) hydroxy, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)a1kylthio, (C.sub.1 -C.sub.10)acyl, thiophenylcaronyl (C.sub.1 -C.sub.10)alkoxycarbonyl, (3) (C.sub.1 -C.sub.10)aklkyammo, di(C.sub.1 -C.sub.10)alylamino, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.10)alkylamino, provided that Y is not O or NH, (4) unsubstituted vinyl, (C.sub.6 -C.sub.10)aryl, (C.sub.3 -C.sub.8)cycloalkyl and fused benz derivatives thereof, (C.sub.7 -C.sub.10)polycycloalkyl, (C.sub.4 -C.sub.8)cycloalkenyl, (C.sub.7 -C.sub.10)polycycloalkenyl, (5) (C.sub.6 -C.sub.10)aryloxy, (C.sub.6 -C.sub.10)aryltio, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.10)alkoxy, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.10)alkylthio, (C.sub.3 -C.sub.8)cycloalkyloxy, (C.sub.4 -C.sub.8)cycloalkenyloxy, (6) heterocyclyl sclected from the group consisting of monocyclic radicals and fused polycycuic radicals, wherein said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selocted from oxygen, nitrogen, and sulfur, and wherein the individual rings of said radicals may be independendy satated, partally unsaturated, or aromatic, provided that if X is CH.sub.2, Z is H or is selected from groups (4) and (6), wherein, when Z contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.10)alkoxycarbonyl, (C.sub.1 -C.sub.10)althyltio, (C.sub.1 -C.sub.10)altylamino, (C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkylamino, di(C.sub.1 -C.sub.10)alkylaminocarbonyl, di(C.sub.1 -C.sub.10)alkyo(C.sub.1 -C.sub.10)alkoxy, (C.sub.1 -C.sub.3)perfluoroalkyl, (C.sub.1 -C.sub.3)perfluoroalkoxy, (C.sub.1 -C.sub.10)acyl, (C.sub.1 -C.sub.10)acyloxy, (C.sub.1 -C.sub.10)acyloxy(C.sub.1 -C.sub.10)alkyl, and pyrrolidinyl; and pharmaceutically acceptable salts thereof.

  化合物的化学式（I），其中X为CH.sub.2，CO，CS或SO.sub.2；Y从以下选项中选择：直接连接，具有多达20个碳原子的脂肪烃基，该基团可以被羟基，（C.sub.1-C.sub.10）烷氧基，（C.sub.1-C.sub.10）酰基，（C.sub.1-C.sub.10）酰氧基或（C.sub.6-C.sub.10）芳基单取代，NH和O取代，前提是如果X为CH.sub.2，则Y为直接连接；Z从以下组中选择：（1）H，卤素，氰基，（2）羟基，（C.sub.1-C.sub.10）烷氧基，（C.sub.1-C.sub.10）烷基硫基，（C.sub.1-C.sub.10）酰基，硫代苯甲酰（C.sub.1-C.sub.10）烷氧羰基，（3）（C.sub.1-C.sub.10）烷基氨基，二（C.sub.1-C.sub.10）烷基氨基，（C.sub.6-C.sub.10）芳基（C.sub.1-C.sub.10）烷基氨基，前提是Y不是O或NH，（4）未取代的乙烯基，（C.sub.6-C.sub.10）芳基，（C.sub.3-C.sub.8）环烷基及其融合苯衍生物，（C.sub.7-C.sub.10）多环烷基，（C.sub.4-C.sub.8）环烯基，（C.sub.7-C.sub.10）多环烯基，（5）（C.sub.6-C.sub.10）芳氧基，（C.sub.6-C.sub.10）芳硫基，（C.sub.6-C.sub.10）芳基（C.sub.1-C.sub.10）烷氧基，（C.sub.6-C.sub.10）芳基（C.sub.1-C.sub.10）烷基硫基，（C.sub.3-C.sub.8）环烷氧基，（C.sub.4-C.sub.8）环烯氧基，（6）从单环基团和融合多环基团中选择的杂环基，其中所述基团包含总共5至14个环原子，其中所述基团包含总共1至4个环杂原子，独立选择自氧，氮和硫，并且所述基团的各个环可以独立饱和，部分不饱和或芳香，前提是如果X为CH.sub.2，则Z为H或从组（4）和（6）中选择，其中，当Z含有一个或多个环时，所述环可以各自独立地携带0至4个取代基，独立选择自卤素，羟基，氰基，硝基，氧代硫代，氨基磺酰基，苯基苯氧基，苯基硫基，卤苯基硫基，苄基，苄氧基，（C.sub.1-C.sub.10）烷基，（C.sub.1-C.sub.10）烷氧基，（C.sub.1-C.sub.10）烷氧羰基，（C.sub.1-C.sub.10）烷硫基，（C.sub.1-C.sub.10）烷基氨基，（C.sub.1-C.sub.10）烷基氨基羰基，二（C.sub.1-C.sub.10）烷基氨基，二（C.sub.1-C.sub.10）烷基氨基羰基，二（C.sub.1-C.sub.10）烷氧（C.sub.1-C.sub.10）烷氧基，（C.sub.1-C.sub.3）全氟烷基，（C.sub.1-C.sub.3）全氟烷氧基，（C.sub.1-C.sub.10）酰基，（C.sub.1-C.sub.10）酰氧基，（C.sub.1-C.sub.10）酰氧（C.sub.1-C.sub.10）烷基和吡咯啉基；及其药学上可接受的盐。
• Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivatives, their preparation and use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (ApoB) secretion
  申请人：PFIZER INC.

  公开号：EP1181954A2

  公开（公告）日：2002-02-27

  Compositions comprising a lipid lowering agent selected from cholesterol biosynthesis inhibitors, bile acid sequestrants, fibrates, cholesterol absorption inhibitors, and niacin; and an inhibitor of microsomal triglyceride transfer protein for treating atherosclerosis, obesity and related diseases.

  包含一种降脂药的组合物，该降脂药选自胆固醇生物合成抑制剂、胆汁酸螯合剂、纤维酸盐、胆固醇吸收抑制剂和烟酸；以及一种微粒体甘油三酯转移蛋白抑制剂，用于治疗动脉粥样硬化、肥胖症和相关疾病。
• BIPHENYL-2-CARBOXYLIC ACID-TETRAHYDRO-ISOQUINOLIN-6-YL AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND/OR APOLIPOPROTEIN B (Apo B) SECRETION
  申请人：PFIZER INC.

  公开号：EP0832069B1

  公开（公告）日：2003-03-05
• US6121283A
  申请人：——

  公开号：US6121283A

  公开（公告）日：2000-09-19
• [EN] BIPHENYL-2-CARBOXYLIC ACID-TETRAHYDRO-ISOQUINOLIN-6-YL AMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND/OR APOLIPOPROTEIN B (Apo B) SECRETION<br/>[FR] DERIVES DE BIPHENYL-2-ACIDE CARBOXYLIQUE-TETRAHYDRO-ISOQUINOLEINE-6-YL AMIDES, PREPARATION DE CES AMIDES ET UTILISATION EN TANT QU'INHIBITEURS DE LA PROTEINE DE TRANSFERT DE TRIGLYCERIDE MICROSOMAL ET/OU DE LA SECRETION D'APOLIPOPROTEINES B (Apo B)
  申请人：PFIZER INC.

  公开号：WO1996040640A1

  公开（公告）日：1996-12-19

  (EN) Compounds of formula (I), wherein X is CH2, CO, CS or SO2; Y is selected from: a direct link, aliphatic hydrocarbylene radicals having up to 20 carbon atoms, which radical may be mono-substituted by hydroxy, (C1-C10)alkoxy, (C1-C10)acyl, (C1-C10)acyloxy, or (C6-C10)aryl, NH, and O, provided that if X is CH2, Y is a direct link; Z is selected from the following groups: (1) H, halo, cyano, (2) hydroxy, (C1-C10)alkoxy, (C1-C10)alkylthio, (C1-C10)acyl, thiophenylcarbonyl, (C1-C10)alkoxycarbonyl, (3) (C1-C10)alkylamino, di(C1-C10)alkylamino, (C6-C10)aryl(C1-C10)alkylamino, provided that Y is not O or NH, (4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8)cycloalkyl and fused benz derivatives thereof, (C7-C10)polycycloalkyl, (C4-C8)cycloalkenyl, (C7-C10)polycycloalkenyl, (5) (C6-C10)aryloxy, (C6-C10)arylthio, (C6-C10)aryl(C1-C10)alkoxy, (C6-C10)aryl(C1-C10)alkylthio, (C3-C8)cycloalkyloxy, (C4-C8)cycloalkenyloxy, (6) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur, and wherein the individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, provided that if X is CH2, Z is H or is selected from groups (4) and (6), wherein, when Z contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino, di(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino(C1-C10)alkoxy, (C1-C3)perfluoroalkyl, (C1-C3)perfluoroalkoxy, (C1-C10)acyl, (C1-C10)acyloxy, (C1-C10)acyloxy(C1-C10)alkyl, and pyrrolidinyl; and pharmaceutically acceptable salts thereof. This invention relates to compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion, and which are accordingly useful for the prevention and treatment of atherosclerosis and its clinical sequelae, for lowering serum lipids, and related diseases. The invention further relates to compositions comprising the compounds and to methods of treating atherosclerosis, obesity, and related diseases and/or conditions with the compounds.(FR) Cette invention concerne des composés représentés par la formule (I) ainsi que des sels pharmaceutiquement acceptables de ces composés. Dans la formule (I), X est CH2, CO, CS ou SO2, Y est sélectionné dans le groupe constitué par (a) une liaison directe, (b) des radicaux aliphatiques d'hydrocarbylène ayant jusqu'à 20 atome de carbone, ces radicaux pouvant être mono-substitués par hydroxy, (C1-C10)alkoxy, (C1-C10)acyle, (C1-C10)acyloxy ou (C6-C10)aryle, (c) NH, et O, à condition que lorsque X est CH2, Y soit une liaison directe; Z est sélectionné dans l'ensemble des groupes suivants: (1) H, halo, cyano, (2) hydroxy, (C1-C10)alkoxy, (C1-C10)alkylthio, (C1-C10)acyle, thiophénylcarbonyle, (C1-C10)alkoxycarbonyle, (3) (C1-C10)alkylamino, di(C1-C10)alkylamino, (C6-C10)aryle(C1-C10)alkylamino, à condition que Y ne soit ni O ni NH, (4) vinyle non substitué, (C6-C10)aryle, (C3-C8)cycloalkyle et ses dérivés benzo condensés, (C7-C10)polycycloalkyle, (C4-C8)cycloalkényle, (C7-C10)polycycloalkényle, (5) (C6-C10) aryloxy, (C6-C10)arylthio, (C6-C10)aryle(C1-C10)alkoxy, (C6-C10)aryle(C1-C10)alkylthio, (C3-C8)cycloalkyloxy, (C4-C8)cycloalkényloxy, (6) hétérocyclyle sélectionné dans le groupe constitué de radicaux monocycliques et de radicaux polycycliques condensés, lesdits radicaux contenant un total de 5 à 14 atomes cycliques, lesdits radicaux contenant un total de 1 à 4 hétéroatomes cycliques sélectionnés indépendamment parmi l'oxygène, l'azote et le soufre, et les noyaux individuels desdits radicaux pouvant être indépendamment saturés, partiellement insaturés ou aromatiques, à condition que si X est CH2, alors Z soit H ou soit choisi parmi les groupes (4) et (6), où, lorsque Z contient un ou plusieurs noyaux, lesdits noyaux peuvent porter chacun indépendamment de 0 à 4 substituants sélectionnés indépendamment parmi halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyle, phényle, phénoxy, phénylthio, halophénylthio, benzyle, benzyloxy, (C1-C10)alkyle, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyle, (C1-C10)alkylthio, (C1-C10)alkylamino, (C1-C10)alkylaminocarbonyle, di(C1-C10)alkylamino, di(C1-C10)alkylaminocarbonyle, di(C1-C10)alkylamino(C1-C10)alkoxy, (C1-C3)perfluoroalkyle, (C1-C3)perfluoroalkoxy, (C1-C10)acyle, (C1-C10)acyloxy, (C1-C10)acyloxy(C1-C10)alkyle et pyrrolidinyle. Cette invention se rapporte à des composés qui sont des inhibiteurs de la protéine de transfert de triglycéride microsomal et/ou de la sécrétion d'apolipoprotéines B (Apo B), et qui de ce fait s'avèrent utiles s'agissant de la prévention et du traitement de l'athérosclérose et de ses séquelles cliniques, de la réduction des lipides sériques et du traitement des maladies associées. Cette invention se rapporte en outre à des compositions contenant lesdits composés ainsi qu'à des procédés de traitement, avec ces composés, de l'athérosclérose, de l'obésité, et de maladies et/ou de troubles associés.