(1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol | 116666-60-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol
• 英文别名: Ro 40-5966；(1S,2S)-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-napthyl hydroxy hydrochloride；(1S,2S)-2-(2-((3-(1H-benzo[d]imidazol-2-yl)propyl)(methyl)amino)ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol；2-(2-[[3-(benzimidazol-2-yl)propyl]methylamino]ethyl)-6-fluoro-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenol；[1S,2S]-2-[2-[[3-(2-benzimidazolyl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphthalenol；des-methoxyacetyl mibefradil；(1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)-propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol；(1S,2S)-2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-ol
• CAS: 116666-60-5
• 化学式: C₂₆H₃₄FN₃O
• 分子量: 423.574
• InChiKey: XTFWUNVBJAOKDW-UIOOFZCWSA-N

物化性质

• 沸点：
  602.9±55.0 °C(Predicted)
• 密度：
  1.159±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  52.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol 生成 (1S,2S)-2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-ol;oxalic acid
  参考文献：
  名称：

  Preparation of mibefradil via a naphthalenylacetic acid

  摘要：

  一种制备2-\x9b2-{\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯的方法，包括将（6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基）乙酸或（6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基）乙酸的活化衍生物与\x9b3-(1H-苯并咪唑-2-基)丙基!甲基胺接触，形成N-\x9b3-(1H-苯并咪唑-2-基)丙基!-2-(6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)-N-甲基乙酰胺，将其还原为2-\x9b2-{\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇，然后用甲氧基乙酸或甲氧基乙酸的活化衍生物处理2-\x9b2-{\x9b3-(1H-苯并咪唑-2-基)丙基!-甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇。该发明特别适用于制备米贝拉地尔，（1S,2S）-2-\x9b2-{\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯及其二盐酸盐。N-\x9b3-(1H-苯并咪唑-2-基)丙基!-2-(6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)-N-甲基乙酰胺是新的。

  公开号：

  US05811556A1
• 作为产物：
  描述：

  mibefradil dihydrochloride 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以100%的产率得到(1S,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol
  参考文献：
  名称：

  NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-Benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: A New Selective Inhibitor of T-Type Calcium Channels

  摘要：

  米贝地尔是一种 Ca2+ 通道拮抗剂，能抑制 T 型和高压激活的 Ca2+ 通道。我们以前的研究表明，米贝地尔对高电压激活通道的阻断是通过细胞内水解产生活性代谢产物来实现的。在本研究中，我们修改了米贝拉地尔的结构，开发出一种不可水解的类似物，即 (1 S , 2 S )-2-(2-( N -[(3- 苯并咪唑-2-基)丙基]- N -甲基氨基)乙基)-6-氟-1、2,3,4- 四氢-1-异丙基-2-萘基环丙烷羧酸二盐酸盐（NNC 55-0396），它对 T 型通道具有选择性抑制作用。在人胚肾 293 细胞中，NNC 55-0396 阻断重组 α1G T 型通道的急性 IC50 为 7 μM，而在 INS-1 细胞中，100 μM 的 NNC 55-0396 对高电压激活通道没有检测到影响。NNC 55-0396 不影响 T 型 Ca2+ 电流的电压依赖性激活，但改变了稳态失活曲线的斜率。膜超极化可部分缓解对 T 型 Ca2+ 电流的阻滞，并在高刺激频率下增强阻滞。将 NNC 55-0396 从记录室中冲洗出来并不能逆转 T 型 Ca2+ 电流的活性，这表明该化合物溶解在质膜中或通过质膜产生作用；然而，在细胞内灌注该化合物并不能阻断 T 型 Ca2+ 电流，这证明该化合物的作用途径不是细胞质。用 NNC 55-0396 与胰岛素分泌细胞系（INS-1）的细胞培养 20 分钟后，质谱分析仪没有检测到导致 L 型 Ca2+ 通道抑制的米贝拉地尔代谢物。我们的结论是，NNC 55-0396 由于其结构的改变，不会产生导致 L 型 Ca2+ 通道抑制的代谢物，从而使其对 T 型 Ca2+ 通道更具选择性。

  DOI：

  10.1124/jpet.103.060814

文献信息

• Tetrahydronaphthalene derivatives as calcium antagonists
  申请人：Hoffmann-La Roche Inc.

  公开号：US04808605A1

  公开（公告）日：1989-02-28

  Compounds of the formula ##STR1## wherein R is lower-alkyl, R.sup.1 is halogen, R.sup.2 is C.sub.1 -C.sub.12 -alkyl, R.sup.3 is hydroxy, lower-alkoxy, lower-alkyl-carbonyloxy, lower-alkoxy-lower-alkylcarbonoyloxy, lower-alkylaminocarbonyloxy, arylaminocarbonyloxy or aryl-lower alkylaminocarbonyloxy, X is C.sub.1 -C.sub.18 -alkylene which optionally can be interrupted by 1,4-phenylene or interrupted or lengthened by 1,4-cyclohexylene, A is di- or tri-substituted 2-imidazolyl attached via an ethylene group or a substituted or unsubstituted heterocycle selected from the group consisting of benzimidazolyl, benzimidazolonyl, imidazo[4,5-c]pyridinyl, imidazo[4,5-c]pyridinonyl, benzthiazolyl, benzodiazepine-2,5-dion-1-yl and pyrrolo[2,1-c]-[1,4]benzodiazepine-5,11-dion-10-yl and n is the number 0 or 1, in the form of racemates and optical antipodes, as well as N-oxides and pharmaceutically usable acid addition salts thereof. The compounds of formual I have a pronounced calcium-antagonistic and anti-arrhythmic activity and can accordingly be used as medicaments, especially for the control or prevention of angina pectoris, ischaemia, arrhythmias, high blood pressure and cardiac insufficiency.

  式##STR1##中的化合物，其中R是较低烷基，R.sup.1是卤素，R.sup.2是C.sub.1-C.sub.12-烷基，R.sup.3是羟基，较低烷氧基，较低烷基羰氧基，较低烷氧基-较低烷基羰氧基，较低烷基氨基羰氧基，芳基氨基羰氧基或芳基-较低烷基氨基羰氧基，X是C.sub.1-C.sub.18-烷基，可以选择性地被1,4-苯亚甲基所中断，或者被1,4-环己亚甲基中断或延长，A是通过乙烯基连接的二取代或三取代2-咪唑基，或者选择自苯并咪唑基，苯并咪唑酮基，咪唑并[4,5-c]吡啶基，咪唑并[4,5-c]吡啶酮基，苯并噻唑基，苯二氮杂环己烷-2,5-二酮-1-基和吡咯并[2,1-c]-[1,4]苯二氮杂环己烷-5,11-二酮-10-基的取代或未取代杂环，n是数字0或1，以消旋体和光学对映体的形式存在，以及它们的N-氧化物和药用可用的酸盐。式I的化合物具有明显的钙拮抗和抗心律失常活性，因此可以用作药物，特别用于控制或预防心绞痛、缺血、心律失常、高血压和心力衰竭。
• [EN] CALCIUM CHANNEL INHIBITORS<br/>[FR] INHIBITEURS DE CANAUX CALCIQUES
  申请人：CAVION INC

  公开号：WO2018152317A1

  公开（公告）日：2018-08-23

  The present disclosure describes carbamate analogs of mibefradil, as well as their compositions and methods of use. The compounds block the activity of one or more isoforms of voltage-gated calcium channels and are useful in the treatment of diseases including, e.g., cancer.

  本公开描述了米贝非特地的氨甲酸酯类似物，以及它们的组成和使用方法。这些化合物阻断了一个或多个电压门控钙通道的活性，并可用于治疗包括癌症在内的疾病。
• Preparation of mibefradil via an acetamide anion
  申请人：Roche Colorado Corporation

  公开号：US05808088A1

  公开（公告）日：1998-09-15

  A method of preparing 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino)}ethyl!-6-fluoro-1-isopr opyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting 6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with the dianion of N-\x9b3-(1H-benzimidazol-2-yl)propyl!-N-methylacetamide to form N-\x9b3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 ,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (lS,2S)-2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-\x9b3-(1H-Benzimidazol-2-yl)propyl!-N-methylacetamide, and the acetic acid solvate of 2-\x9b2- \x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopropyl-1 ,2,3,4-tetrahydronaphthalen-2-ol dioxalate, are new.

  一种制备2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基)}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯的方法，包括将6-氟-1-异丙基-3,4-二氢-1H-萘-2-酮与N-\x9b3-(1H-苯并咪唑-2-基)丙基!-N-甲基乙酰胺的二阴离子接触以形成N-\x9b3-(1H-苯并咪唑-2-基)丙基!-2-(6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)-N-甲基乙酰胺，将其还原为2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇，然后用甲氧基乙酸或甲氧基乙酸的活化衍生物处理2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇。该发明特别适用于米贝拉地尔，(lS,2S)-2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯及其双盐酸盐的制备。N-\x9b3-(1H-苯并咪唑-2-基)丙基!-N-甲基乙酰胺和2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇草酸二乙酯的乙酸溶剂化物是新的。
• Preparation of mibefradil via a naphthalenylacetic acid
  申请人：Roche Colorado Corporation

  公开号：US05811556A1

  公开（公告）日：1998-09-22

  A method of preparing 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid or an activated derivative of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid with \x9b3-(1H-benzimidazol-2-yl)propyl!methylamine to form N-\x9b3-(1H-benzimidazol-2-yl) propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 ,4-tetrahydronaphthalen-2- yl)-N-methylacetamide, reducing this to 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1, 2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl) propyl!-methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthal en-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}-ethyl!-6-fluoro -1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-\x9b3-(1H-benzimidazol-2yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide is new.

  一种制备2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯的方法，包括将（6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基）乙酸或（6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基）乙酸的活化衍生物与\x9b3-(1H-苯并咪唑-2-基)丙基!甲基胺接触，形成N-\x9b3-(1H-苯并咪唑-2-基)丙基!-2-(6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)-N-甲基乙酰胺，将其还原为2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇，然后用甲氧基乙酸或甲氧基乙酸的活化衍生物处理2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!-甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇。该发明特别适用于制备米贝拉地尔，（1S,2S）-2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯及其二盐酸盐。N-\x9b3-(1H-苯并咪唑-2-基)丙基!-2-(6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)-N-甲基乙酰胺是新的。
• Preparation of mibefradil via an acetonitrile anion
  申请人：Roche Colorado Corporation

  公开号：US05811557A1

  公开（公告）日：1998-09-22

  A method of preparing 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting 6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with the anion of acetonitrile in an aprotic polar solvent; contacting \x9b3-(1H-benzitidazol-2-yl)propyl!methylamine with the thus-formed (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetonit rile in the presence of hydrogen and a hydrogenation catalyst, followed by contacting the thus-formed 2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2-\x9b2-\x9b3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. (6-Fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) acetonitrile is new.

  一种制备2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯的方法包括将6-氟-1-异丙基-3,4-二氢-1H-萘-2-酮与乙腈的阴离子在无水极性溶剂中接触;在氢气和氢化催化剂的存在下将\x9b3-(1H-苯并咪唑-2-基)丙基!甲基胺与由此形成的(6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)乙腈接触，然后将形成的2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-醇与甲氧基乙酸或甲氧基乙酸的活性衍生物接触。该发明特别适用于制备米贝拉地尔，(1S,2S)-2-\x9b2-\x9b3-(1H-苯并咪唑-2-基)丙基!甲基氨基}乙基!-6-氟-1-异丙基-1,2,3,4-四氢萘-2-基甲氧基乙酸酯及其二盐酸盐。 (6-氟-2-羟基-1-异丙基-1,2,3,4-四氢萘-2-基)乙腈是新的。