(+/-)-4-chloro-6-phenylpyrrolo<2,1-d><1,5>benzothiazepin-7(6H)-one | 155908-94-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• 英文名称: (+/-)-4-chloro-6-phenylpyrrolo<2,1-d><1,5>benzothiazepin-7(6H)-one
• 英文别名: 4-chloro-6-phenylpyrrolo<2,1-d><1,5>benzothiazepin-7(6H)-one；4-Chloro-6-phenylpyrrolo[2,1-d][1,5]benzothiazepin-7-one
• CAS: 155908-94-4
• 化学式: C₁₈H₁₂ClNOS
• 分子量: 325.818
• InChiKey: NMZYZIUWYURCDQ-UHFFFAOYSA-N

物化性质

• 沸点：
  502.7±50.0 °C(predicted)
• 密度：
  1.35±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  47.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (+/-)-4-chloro-6-phenylpyrrolo<2,1-d><1,5>benzothiazepin-7(6H)-one 在 sodium tetrahydroborate 、 三乙胺 作用下， 以 四氢呋喃 、 异丙醇 为溶剂， 反应 3.0h， 生成 Acetic acid (4R,5R)-7-chloro-5-phenyl-4,5-dihydro-6-thia-10b-aza-benzo[e]azulen-4-yl ester
  参考文献：
  名称：

  吡咯并[2,1-d] [1,5]苯并硫氮杂derivatives衍生物选择性结合至外周型苯并二氮杂receptor受体（PBR）的心血管特征：从双重PBR亲和力和钙拮抗剂活性到新型和选择性的钙进入阻滞剂。

  摘要：

  描述了一系列新型吡咯并[2,1-d] [1,5]-苯并硫氮杂derivatives衍生物（54-68）的合成和心血管表征。最近发现选择性外围型苯并二氮杂receptor受体（PBR）配体（例如PK 11195和Ro 5-4864）具有低但显着的L型钙通道抑制活性，并且该特性与通过观察到的心血管作用有关。这些化合物。在功能研究中，PK 11195（1-（2-氯苯基）-N-甲基-N-（1-甲基丙基）-3-异喹啉羧甲）和Ro 5-4864（4'-氯二氮杂）均未显示对心脏和心脏的选择性。血管组织。因此，我们最近开发出了几种7-（酰氧基）-6-芳基吡咯并[2,1-d] [1,5]苯并噻氮平，有效的和选择性的外围型苯并二氮杂receptor受体配体（3，7-20），进行钙通道受体结合测定。这些化合物中的某些显示出从L型钙通道置换[3H]硝苯地平的结合作用的出乎意料的效力，远高于PK 11195和Ro

  DOI：

  10.1021/jm960162z
• 作为产物：
  描述：

  bis(6-chloro-2-N-pyrrolylphenyl)disulfide 在 sodium tetrahydroborate 、 五氯化磷 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 生成 (+/-)-4-chloro-6-phenylpyrrolo<2,1-d><1,5>benzothiazepin-7(6H)-one
  参考文献：
  名称：

  线粒体苯并二氮杂receptor受体特异的新型配体：6-芳基吡咯并[2,1-d] [1,5]苯并噻氮pine衍生物。合成，构效关系和分子模型研究。

  摘要：

  已鉴定出一类新的对MBR受体具有特异性的配体：6-芳基吡咯并[2,1-d] [1,5]苯并硫氮杂derivatives衍生物。大多数新合成的酯37-64以及一些中间酮对[3H] PK 11195的结合抑制表现出微摩尔或纳摩尔的亲和力。一项对42种化合物的SAR研究和分子建模方法得出了初步的结构选择性特征：6,7-双键，7位的氨基甲酰氧基，alcanoyloxy和甲磺酰氧基侧链以及4位的预期氯取代位置似乎是提高亲和力的最重要的结构特征。因此，合成了7-[（（二甲基氨基甲酰基）氧基]-和7-乙酰氧基-4-氯-6-苯基吡咯并[2，1-d] [1，5]苯并硫氮杂（（43和57）。与7-[（二甲基氨基甲酰基）氧基] -6-（对甲氧基苯基）吡咯并[2,1- d] [1,5]苯并噻氮平（65），

  DOI：

  10.1021/jm00036a007

文献信息

• A Comparative Molecular Field Analysis Model for 6-Arylpyrrolo[2,1-d][1,5]benzothiazepines Binding Selectively to the Mitochondrial Benzodiazepine Receptor
  作者：Giovanni Greco、Ettore Novellino、Isabella Fiorini、Vito Nacci、Giuseppe Campiani、Silvia M. Ciani、Antonio Garofalo、Paola Bernasconi、Tiziana Mennini

  DOI：10.1021/jm00050a007

  日期：1994.11

  A series of 42 6-arylpyrrolo[2,1-d][1,5]benzothiazepines which we have recently described as selective ligands of the mitochondrial benzodiazepine receptor (MBR) (Fiorini I.; et al. J. Med. Chem. 1994, 37, 1427-1438), have been investigated using the comparative molecular field analysis (CoMFA) approach. The resulting 3D-QSAR model rationalizes the steric and electronic factors which modulate affinity to the MBR with a cross-validation standard error of 0.648 pIC(50) unit. A set of seven novel pyrrolobenzothiazepine congeners has successively been synthesized and tested. The CoMFA model forecasts the binding affinity values of these new compounds with a prediction standard error of 0.536.
• New pyrrolobenzothiazepine derivatives as molecular probes of the ‘peripheral-type’ benzodiazepine receptor (PBR) binding site
  作者：G Campiani、V Nacci、I Fiorini、MP De Filippis、A Garofalo、SM Ciani、G Greco、E Novellino、C Manzoni、T Mennini

  DOI：10.1016/s0223-5234(97)83975-x

  日期：1997.1

  A number of new pyrrolobenzothiazepine derivatives and a pyrrolobenzothiazocine derivative have been synthesized and evaluated for their affinity towards the 'peripheral-type' benzodiazepine receptor (PER). The new compounds were tested in rat cortex, a tissue expressing a high density of mitochondrial PER. Some of the pyrrolobenzothiazepines exhibited IC50 values in the low nanomolar range as measured by the displacement of [H-3]PK 11195 binding. Compound 4i was found to be the most potent ligand for this receptor in the pyrrolobenzothiazepine subgroup with an IC50 practically identical to that determined for PK 11195. Structure-affinity relationships (SARs) have been developed to elucidate the topology of the PER binding site.
• Pyrrolobenzothiazepinones and Pyrrolobenzoxazepinones:  Novel and Specific Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors with Antiviral Activity
  作者：Giuseppe Campiani、Vito Nacci、Isabella Fiorini、Maria P. De Filippis、Antonio Garofalo、Giovanni Greco、Ettore Novellino、Sergio Altamura、Laura Di Renzo

  DOI：10.1021/jm950702c

  日期：1996.1.1

  Two novel classes of pyrrolobenzothiazepinones and pyrrolobenzoxazepinones were investigated as potential anti-AIDS drugs. These compounds were found to inhibit HIV-1 reverse transcriptase (RT) enzyme in vitro and to prevent HIV-1 cytopathogenicity in T4 lymphocytes, without appreciable activity on HIV-2 cytopathic effects, and against HBV as well as calf-thymus DNA alpha-polymerase. Their potency is influenced by substituents at position 6 and on the fused aromatic ring. Specifically, small lipophilic substituents at C-6 were preferred, whereas substitutions on the benzo-fused ring were found to be detrimental to activity, with respect to the unsubstituted compounds. Modification of the pi-system at C-6 is well tolerated, although the replacement of the benzo-fused with a [2,3]naphtho-fused ring leads to a less active compound. Maximum potency and specificity is achieved with a phenyl and an ethyl group at position 6 of the pyrrolobenzoxazepinone system. In the enzymatic assay the oxazepinone derivative (+/-)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5] 16e (IC50 = 0.25 mu M) was found to be more potent than nevirapine (IC50 = 0.5 mu M), tested in the same experimental conditions using rC . dG as a template-primer. In cell culture assay benzoxazepine 16e was active against HIV-1, both wild type and AZT-sensitive, and HIV-1 (IIIB) strains, but not against HIV-2. In enzyme assay although 16e inhibited HIV-1 RT, it was inactive against the nevirapine-resistant recombinant RT Y181C at 50 mu M. Molecular modeling studies suggest that these derivatives present a 3D pharmacophoric arrangement similar to that of other nonnucleoside inhibitors such as nevirapine.
• Cardiovascular Characterization of Pyrrolo[2,1-<i>d</i>][1,5]benzothiazepine Derivatives Binding Selectively to the Peripheral-Type Benzodiazepine Receptor (PBR):  From Dual PBR Affinity and Calcium Antagonist Activity to Novel and Selective Calcium Entry Blockers
  作者：Giuseppe Campiani、Isabella Fiorini、Maria P. De Filippis、Silvia M. Ciani、Antonio Garofalo、Vito Nacci、Gianluca Giorgi、Alessandro Sega、Maurizio Botta、Alberto Chiarini、Roberta Budriesi、Giancarlo Bruni、Maria R. Romeo、Cristina Manzoni、Tiziana Mennini

  DOI：10.1021/jm960162z

  日期：1996.1.1

  with these compounds. In functional studies both PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide) and Ro 5-4864 (4'-chlorodiazepam) did not display selectivity between cardiac and vascular tissue. Therefore, several 7-(acyloxy)-6-arylpyrrolo[2,1-d][1,5]benzothiazepines, potent and selective peripheral-type benzodiazepine receptor ligands recently developed by us (3

  描述了一系列新型吡咯并[2,1-d] [1,5]-苯并硫氮杂derivatives衍生物（54-68）的合成和心血管表征。最近发现选择性外围型苯并二氮杂receptor受体（PBR）配体（例如PK 11195和Ro 5-4864）具有低但显着的L型钙通道抑制活性，并且该特性与通过观察到的心血管作用有关。这些化合物。在功能研究中，PK 11195（1-（2-氯苯基）-N-甲基-N-（1-甲基丙基）-3-异喹啉羧甲）和Ro 5-4864（4'-氯二氮杂）均未显示对心脏和心脏的选择性。血管组织。因此，我们最近开发出了几种7-（酰氧基）-6-芳基吡咯并[2,1-d] [1,5]苯并噻氮平，有效的和选择性的外围型苯并二氮杂receptor受体配体（3，7-20），进行钙通道受体结合测定。这些化合物中的某些显示出从L型钙通道置换[3H]硝苯地平的结合作用的出乎意料的效力，远高于PK 11195和Ro
• Novel Ligands Specific for Mitochondrial Benzodiazepine Receptors: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine Derivatives. Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies
  作者：Isabella Fiorini、Vito Nacci、Silvia Maria Ciani、Antonio Garofalo、Giuseppe Campiani、Luisa Savini、Ettore Novellino、Gianni Greco、Paola Bernasconi、Tiziana Mennini

  DOI：10.1021/jm00036a007

  日期：1994.5

  important structural features improving affinity. Therefore, 7-[(dimethylcarbamoyl)oxy]- and 7-acetoxy-4-chloro-6-phenylpyrrolo[2,1-d][1,5]benzothiazepine (43 and 57) were synthesized. With 7-[(dimethylcarbamoyl)oxy]-6-(p-methoxyphenyl)pyrrolo[2,1- d][1,5]benzothiazepine (65), these were the most promising compounds with IC50s of respectively 9, 8, and 9 nM, under conditions where PK 11195 had an IC50

  已鉴定出一类新的对MBR受体具有特异性的配体：6-芳基吡咯并[2,1-d] [1,5]苯并硫氮杂derivatives衍生物。大多数新合成的酯37-64以及一些中间酮对[3H] PK 11195的结合抑制表现出微摩尔或纳摩尔的亲和力。一项对42种化合物的SAR研究和分子建模方法得出了初步的结构选择性特征：6,7-双键，7位的氨基甲酰氧基，alcanoyloxy和甲磺酰氧基侧链以及4位的预期氯取代位置似乎是提高亲和力的最重要的结构特征。因此，合成了7-[（（二甲基氨基甲酰基）氧基]-和7-乙酰氧基-4-氯-6-苯基吡咯并[2，1-d] [1，5]苯并硫氮杂（（43和57）。与7-[（二甲基氨基甲酰基）氧基] -6-（对甲氧基苯基）吡咯并[2,1- d] [1,5]苯并噻氮平（65），