6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester | 186390-66-9

• 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: 6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 6-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]-3,4-dihydro-1H-isoquinoline-2-carboxylate
• CAS: 186390-66-9
• 化学式: C₂₈H₂₇F₃N₂O₃
• 分子量: 496.529
• InChiKey: KTKJCGKOCTXFRX-UHFFFAOYSA-N

物化性质

• 沸点：
  536.0±50.0 °C(Predicted)
• 密度：
  1.266±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide
  参考文献：
  名称：

  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

  摘要：

  组成物包括从胆固醇生物合成抑制剂、胆酸螯合剂、纤维酸、胆固醇吸收抑制剂和烟酸中选择的一种降脂剂，以及用于治疗动脉粥样硬化、肥胖症和相关疾病的微粒体甘油三酯转移蛋白抑制剂。

  公开号：

  EP1181954A3
• 作为产物：
  描述：

  6-氨基-2-N-BOC-1,2,3,4-四氢-异喹啉 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 生成 6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
  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

• [EN] APO B-SECRETION/MTP INHIBITORY AMIDES<br/>[FR] AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
  申请人：PFIZER INC.

  公开号：WO1998023593A1

  公开（公告）日：1998-06-04

  (EN) This invention is directed to compounds of formula (I) or the stereoisomers, pharmaceutically acceptable salts and hydrates thereof. The compounds are Apo B/MTP inhibitors and are useful in the treatment of various disorders and conditions such as atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridemia, hyperlipidemia, and diabetes. The compounds of this invention are also useful in combination with other pharmaceutical agents including cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors; HMG-CoA reductase gene expression inhibitors; CETP inhibitors; bile acid sequestrants; fibrates; cholesterol absorption inhibitors; ACAT inhibitors, squalene synthetase inhibitors, ion-exchange resins, anti-oxidants and niacin. This invention is also directed to intermediates and processes useful in the preparation of compounds of formula (I).(FR) Cette invention se rapporte à des composés représentés par la formule (I) ou aux stéréo-isomères de ces composés, et aux sels et hydrates de ces composés acceptables sur le plan pharmaceutique. Ces composés sont des inhibiteurs d'Apo B et/ou de la protéine MPT et ils sont utiles pour traiter divers troubles et états, tels que l'athérosclérose, la pancréatite, l'obésité, l'hypercholestéremie, l'hypertriglycéridémie, l'hyperlipidémie, et le diabète. Ces composés sont utiles en association avec d'autres agents pharmaceutiques, tels que les inhibiteurs de la biosynthèse du cholestérol et les inhibiteurs de l'absorption du cholestérol, en particulier les inhibiteurs de HMG-CoA réductase et les inhibiteurs des HMG-CoA synthase; des inhibiteurs d'expression des gènes de HMG-CoA réductase; les inhibiteurs de CETP; les chélateurs des acides biliaires; les fibrates; les inhibiteurs de l'absorption du cholestérol; les inhibiteurs d'ACAT, les inhibiteurs de squalène synthétase, les résines d'échange ioniques, les antioxydants et la niacine. Cette invention se rapporte également à des intermédiaires et à des procédés utiles dans la préparation de composés de la formule (I).

  本发明涉及式（I）的化合物或其立体异构体，以及其药学上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病症，如动脉硬化、胰腺炎、肥胖症、高胆固醇血症、高甘油三酯血症、高脂血症和糖尿病等。本发明的化合物还可与其他药物制剂联合使用，包括胆固醇生物合成抑制剂和胆固醇吸收抑制剂，特别是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；胆酸结合树脂；纤维酸；胆固醇吸收抑制剂；ACAT抑制剂、角鲨烷合成酶抑制剂、离子交换树脂、抗氧化剂和烟酸。本发明还涉及制备式（I）化合物的中间体和有用的过程。
• 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.

  化合物的公式(I)，其中X为CH.sub.2，CO，CS或SO.sub.2; Y从以下选取：直接连接，具有最多20个碳原子的脂肪烃基，该基可能被羟基，(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，前提是如果X为CH.sub.2，则Y为直接连接；Z从以下组中选取：(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，硫代苯甲酰基，(C.sub.1-C.sub.10)烷氧羰基，(3) (C.sub.1-C.sub.10)烷氨基，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)多环环烷基，(C.sub.4-C.sub.8)环烯基，(C.sub.7-C.sub.10)多环环烯基，(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) 来自单环基和融合多环基的杂环基，其中所述基团包含从5到14个环原子的总数，其中所述基团包含从氧，氮和硫中独立选择的1到4个环杂原子，其中所述基团的各个环可以独立饱和，部分不饱和或芳香性，前提是如果X为CH.sub.2，则Z为H或从组(4)和(6)中选择的基团，其中，当Z含有一个或多个环时，所述环可以各自独立地承载0到4个取代基，所述取代基独立选择自卤素，羟基，氰基，硝基，氧化物，硫代氧化物，氨基磺酰基，苯基氧基，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)烷氧基(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)烷基和吡咯烷基；以及其药学上可接受的盐。
• 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
• APO B-SECRETION/MTP INHIBITORY AMIDES
  申请人：PFIZER INC.

  公开号：EP0944602A1

  公开（公告）日：1999-09-29
• US5705188A
  申请人：——

  公开号：US5705188A

  公开（公告）日：1998-01-06