CN101137361A - 具有苯并呋喃并吲哚骨架的钾通道开放剂 - Google Patents
具有苯并呋喃并吲哚骨架的钾通道开放剂 Download PDFInfo
- Publication number
- CN101137361A CN101137361A CNA200680007769XA CN200680007769A CN101137361A CN 101137361 A CN101137361 A CN 101137361A CN A200680007769X A CNA200680007769X A CN A200680007769XA CN 200680007769 A CN200680007769 A CN 200680007769A CN 101137361 A CN101137361 A CN 101137361A
- Authority
- CN
- China
- Prior art keywords
- hydrogen
- chemical compound
- benzofuran
- potassium channel
- cooh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- TYBGSZGTQQIASN-UHFFFAOYSA-N 1h-[1]benzofuro[2,3-g]indole Chemical group C1=CC=C2C3=C(NC=C4)C4=CC=C3OC2=C1 TYBGSZGTQQIASN-UHFFFAOYSA-N 0.000 title abstract 2
- 239000004036 potassium channel stimulating agent Substances 0.000 title abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims description 84
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 51
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47G—HOUSEHOLD OR TABLE EQUIPMENT
- A47G19/00—Table service
- A47G19/22—Drinking vessels or saucers used for table service
- A47G19/2205—Drinking glasses or vessels
- A47G19/2227—Drinking glasses or vessels with means for amusing or giving information to the user
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Abstract
本发明的目的是提供一种具有苯并呋喃并吲哚骨架、式(I)表示的钾通道开放剂，其中R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢或氯，而且R6是氢或氯。
Description
技术领域
本发明涉及一种具有苯并呋喃并吲哚骨架的钾通道开放剂。更具体的说，本发明涉及一种具有可通过取代基取代而制备的苯并呋喃并吲哚骨架的新颖钾通道开放剂及其制备方法。
背景技术
钾通道属于一个广泛存在且异种的蛋白家族，其选择性地允许K+离子跨越细胞膜而迁移。通过维护K+离子的优化调整条件及其对膜电位和膜电阻的多种作用，这些通道在调节细胞兴奋性方面发挥重要的作用。在人体中存在不同种类的K+通道，其被不同的机理激活。考虑到不同因素对不同种类K+通道活性的影响，钙激活的钾通道就是其中之一，它的开放由细胞内钙浓度的提高而决定，并且由跨膜电压和磷酸化状态而调节。
钙激活的钾通道可进一步地分成三种主要类型，其可由它们不同的单通道电导性而在电生理学上辨别开。
BKCa(或Maxi-K)通道具有大的单通道电导性(100～250pS)的特定功能，而其它两种主要类型的钙依赖性钾通道为小电导(92～25pS，SKCa)和中电导型(25～100pS，IKCa)。在这三种通道中，BKCa通道特别地受到关注，理由是大量的K+流出和它们的大单通道电导而导致膜超极化，以及它们在非易兴奋与易兴奋细胞类型(包括神经元和肌肉)范围内的表达。特别是，BKCa通道在形成动作电位以及在神经系统中调节神经元兴奋性和神经-递质释放中起作用。
BKCa通道的治疗潜力在病理状况下更加明显，诸如过量Ca2+进入而引起的潜在神经毒性级联(neurotoxic cascade)，其可由BKCa通道激活剂或开放剂而得到限制或阻断。因此，设计BKCa通道的化学开放剂是用于开发治疗创伤和缺血性事件或神经退化过程而导致的神经元损伤的药物的一种策略。
也可以利用BKCa通道开放剂的舒张血管作用，以开发治疗心血管疾病或高血压、气道平滑肌相关疾病如哮喘和勃起障碍的药物。
BKCa通道是包括两种不同的亚单元：毛孔形成的α亚单元和辅助β亚单元。尽管仅由四个α亚单元形成的通道可以是功能性的，但是β亚单元改变了同型(homomeric)通道的生物物理学和药理学性质，包括Ca2+和电压敏感性以及门控动力学(gating kinetics)。
几种化合物已被开发并报道为BKCa通道开放剂(例如脱氢大豆皂甙-I(dehydrosoyasaponin-I)、maxikdiol、NS-1619、BMS-204352、17-β-雌二醇、溴乙烷他莫昔芬(ethylbromide tamoxifen)、海松酸和环氧二十碳三烯酸)。尽管有些合成的激活剂如NS-1619和BMS-204352作用于α亚单元，但是BKCa通道的其它开放剂包括脱氢大豆皂甙-I和17-β-雌二醇需要β亚单元来起它们的作用。几种衍生自天然产物的激活剂例如脱氢大豆皂甙-I不能透过细胞膜，并且只能对BKCa通道的细胞内侧起作用。
在美国专利号6,288,099中，苯并呋喃并吲哚骨架及其衍生物作为钙通道开放剂已被公开。但是，在这个公开文件中，只是提议了苯并呋喃并吲哚整个骨架及其宽泛的衍生物，而没有指定选择的取代基。
在原型的BKCa通道开放剂1(BMS-204352)、喹诺酮相似物2和取代的苯并呋喃并吲哚相似物3中，据报道，化合物1以剂量依赖的方式选择性地使BKCa通道激活曲线朝着较小的正膜电位的方向移动，而且目前在临床试验中靶向作用于急性缺血性中风。
苯并呋喃并吲哚相似物3被研究作为BKCa通道开放剂，在关于分离大鼠膀胱平滑肌细胞的电压钳试验中，显示膀胱选择性平滑肌松弛作用以及增加向外的电流。但是，没有进一步报道关于被复制BKCa通道中结构活性或生物性质的结果。
发明内容
本发明的目的是提供一种具有苯并呋喃并吲哚骨架、下式(I)所示的钾通道开放剂。
其中，
R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢或氯且R6是氢或氯。
本发明进一步提供了一种化合物，其中包括R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢并且R6是氢；也提供一种化合物，其中包括R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢并且R6是氯；还提供一种化合物，其中包括R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氯并且R6是氢。
本发明进一步提供了一种用于制备具有苯并呋喃并吲哚骨架、下式(I)所示的钾通道开放剂的工艺，其包括以下步骤：
i)通过作为起始原料的式(II)所示的水杨酸衍生物在加入甲醇溶剂的硫酸存在下与溴代乙酸乙酯反应和缩合，随后除去溴化氢，并且用NaOH水溶液除去乙基，
来制备式(III)化合物；
ii)通过在乙酸酐或乙酸钠存在下经回流式(III)化合物的环化反应，制备式(IV)化合物；
iii)根据菲舍尔-吲哚反应(Fisher-indole reaction)，通过在乙醇或p-TsOH溶剂存在下偶合取代的苯肼，制备式(I)化合物。
其中，R1是4-CF3、4-H，R2是1-COOH、1-Cl、3-Cl、4-Cl。
附图说明
图1示例了本发明BKCa通道开放剂的化学结构。
图2示例了本发明苯并呋喃并吲哚化合物与BMS-2043552的层叠结构。
图3说明细胞外应用本发明的苯并呋喃并吲哚相似物后BKCa通道活性的相对增加倍数。柱型图代表各种化合物以20μM细胞外处理而激发BKCa通道电流增加的倍数。
图4说明在各种细胞内的Ca2+浓度下细胞外应用化合物22于rSlo通道的功效。显示了在不同的细胞内Ca2+浓度下代表性的原始踪迹(raw-traces)。细胞内Ca2+浓度自无Ca2+(A)、0.5μM(B)、1μM(C)和2μM(D)而增加。化合物22在细胞外侧的浓度为20μM。
图5说明化合物22对于BKCa通道的浓度依赖性。用Hill方程来拟合数据点。通过最佳拟合而获得化合物22的表观解离常数Kd为4.01±0.75μM，并且n值(Hill系数常数)为1.02±0.07(N＝5，p<0.01)。
图6说明化合物8对于BKCa通道的浓度依赖性活性。图6A说明rSlo通道的浓度依赖性活性。图6B说明与人β1组合的rSlo通道的浓度依赖性活性。图6C说明与大鼠β4亚单元组合的rSlo通道的浓度依赖性活性。
具体实施方式
本发明详细描述如下。
适宜官能团的定位想法得自于如层叠结构(图2)所示的潜在BKCa通道开放剂1(BMS-204352)和苯并呋喃并吲哚骨架的低能量构象异构体与通过应用MOPAC2002方案的半-经验性计算结果的对比。
相应地选择三氟甲基和氯基团分别用于苯并呋喃并吲哚模板7和4位上的取代。还包括具有不同官能团的其它苯并呋喃并吲哚系列的合成，如路线1所概括描述的，以确定构效关系。
路线1
(a)CH3OH，H2SO4，回流，12小时，产率95～98％，
(b)溴代乙酸乙酯，K2CO3，丙酮，回流，24小时，产率70～76％，
(c)在CH3OH中10％NaOH水溶液，25℃，5小时，产率80～87％，
(d)Ac2O，AcOH，CH3COONa，回流，8小时，产率70～75％，
(e)1N-HCl，H2O，CH3OH，回流，7小时，产率55～65％，
(f)取代的苯肼，C2H5OH，H2O，25℃，5小时，产率22～35％，
(g)p-TsOH，C2H5OH，80℃，18小时或微波1～2分钟，产率64～77％。
商业上可获得的、取代的水杨酸进行菲舍尔酯化而得到的水杨酸酯，与溴代乙酸乙酯进行烷基化，随后双支链水解得到5a～e。在乙酸酐、乙酸钠和乙酸存在且回流条件下环化，然后酸化以从烯醇-乙酸酯中间体中除去乙酸酯基团，得到苯并呋喃酮6a～e。苯并呋喃酮与各种取代的苯肼偶连得到相应的腙，所述腙在回流条件下或者在微波反应中，用酸催化剂经过菲舍尔吲哚反应转化成苯并呋喃并吲哚衍生物7-23。表1表示的是根据以上方法得到的各种苯并呋喃并吲哚衍生物。
表1
| 化合物编号 | R1 | R2 | R3 | R4 | R5 | R6 |
| 7891011121314151617181920212223 | BrHHHHHHHHHHHHHHHH | HCF3CF3CF3CF3CF3HCF3CF3OCH3ClCF3CF3CF3CF3CF3CF3 | COOHCOOHHHClCF3COOHOCH3COOCH3COOHCOOHClHHHCOOHCOOH | HHHHHHHHHHHClClHFHH | HHCF3HHHHHHHHHHHHHCl | HHHCF3HHHHHHHHClFHClH |
通过应用被切断的外向外(outside-out)电压钳，记录来自非洲爪蛙卵母细胞表达的克隆α亚单元大鼠BKCa通道rSlo，测定化合物7～23开放BKCa通道和增加BKCa通道电流的生物活性。
本发明的有益效果是提供了一种具有苯并呋喃并吲哚骨架的钾通道开放剂。本发明人报道了从一系列取代的苯并呋喃并吲哚衍生物的合成和有Ca2+独立方式的电生理学性质，用于BKCa通道开放活性的苯并呋喃并吲哚骨架中药效团的优化。
通过下面的实施例更具体地阐明本发明。但是，本发明的保护范围不受下面实施例的限制。
实施例
(制备实施例1)7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物8)
2-羧基甲氧基-4-三氟甲基-苯甲酸(产物5a)：将甲醇(80ml)、浓硫酸(6.7ml)、2-羟基-4-三氟甲基-苯甲酸(31.2g)的搅拌混合物回流加热12小时。冷却至室温后，用碳酸氢钠和乙酸乙酯处理该混合物。应用色谱法(己烷∶EA＝10∶1)纯化来自乙酸乙酯层的2-羟基-4-三氟甲基-苯甲酸甲酯。
将无水碳酸钾(29g)加至搅拌的羟基-4-三氟甲基-苯甲酸甲酯(32.5g)的无水丙酮(100ml)溶液。然后滴加溴代乙酸乙酯(25ml)，并将混合物回流加热(14小时)。冷却至室温后，用水和乙酸乙酯处理该溶液。然后，应用色谱法(己烷∶EA＝15∶1)纯化来自乙酸乙酯层的2-乙氧基羰基甲氧基-4-三氟甲基-苯甲酸甲酯。
将2-乙氧基羰基甲氧基-4-三氟甲基-苯甲酸甲酯(34g)、10％NaOH(132.5g)和甲醇(45ml)混合物在单口圆底烧瓶中混合。得到的混合物室温下混合5小时。用1N HCl酸化至pH2。真空下蒸发。过滤并水洗，得到产物5a。
6-三氟甲基-苯并呋喃-3-酮(产物6a)：将乙酸酐(95ml)、乙酸(14ml)、无水乙酸钠(10.7g)以及5a充分搅拌的混合物回流加热7小时。然后将该混合物冷却至室温，并且用水和乙酸乙酯处理。用乙酸乙酯共蒸剩余的乙酸酐。然后，应用色谱法(己烷∶EA＝10∶1)纯化粗产物，得到乙酸6-三氟甲基-苯并呋喃-3-基酯。
将乙酸6-三氟甲基-苯并呋喃-3-基酯(15g)、甲醇(100ml)、水(53.8ml)和1N HCl(18.8ml)的混合物回流加热6小时。将混合物冷却至室温。真空下蒸发粗产物并且应用色谱法(己烷∶EA＝18∶1)纯化，得到产物6a。
7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物8)：将150mg 6a溶于乙醇(5.2ml)并且将2-肼基苯甲酸溶于水(10.3ml)。将这两种均质混合物混合在一起并室温搅拌4小时。过滤沉淀，先水洗然后乙醇洗。滤液置于真空炉4小时，使其完全蒸发。将2-[N′-(6-三氟甲基-苯并呋喃-3-亚基)-肼基]-苯甲酸(120mg)、p-TsOH(1～2当量)和乙醇(5ml)的混合物回流30小时。冷却至室温并真空下蒸发。用色谱法纯化(CHCl3∶MeOH＝30∶1)所得混合物得到化合物8。
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)11.80(s，1H)，8.29(d，J＝8.4Hz，1H)，8.15(s，1H)，8.11(d，J＝7.5Hz，1H)，7.95(d，J＝7.5Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.30(t，J＝8.4Hz，1H)，MS(ESI)m/z：319.23([M+H]+)
(制备实施例2)
如制备实施例1中所述的同样方式制备下列化合物。得到化合物的化学名、产率、NMR峰数据以及用MS(质谱)测定的分子量描述如下。
8-溴代-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物7)：
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)11.8(s，1H)，8.28(s，1H)，8.09(d，J＝7.8Hz，1H)，7.93(d，J＝7.8Hz，1H)，7.72(d，J＝9Hz，1H)，7.53(d，J＝9Hz，1H)，7.31(t，J＝7.8Hz，1H)，MS(ESI)m/z：330.13([M+H]+)
3，7-双-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物9)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.44(s，1H)，7.97(d，J＝7.8Hz，1H)，7.92(s，1H)，7.84(d，J＝8.1Hz，1H)，7.80(s，1H)，7.63(d，J＝8.1Hz，1H)，7.53(d，J＝7.8Hz，1H)，MS(ESI)m/z：343.22([M+H]+)
4，7-双-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物10)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.47(s，1H)，8.00(s，1H)，7.8(d，J＝8.1Hz，1H)，7.72(d，J＝8.1Hz，1H)，7.64(d，J＝7.5Hz，1H)，7.57(d，J＝7.5Hz，1H)，7.44(t，J＝7.5，1H)，MS(ESI)m/z：343.22([M+H]+)
1-氯代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物11)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.46(s，1H)，7.90(s，1H)，7.81(d，J＝8.1Hz，1H)，7.80(d，J＝8.1Hz，1H)，7.62(d，J＝7.8Hz，1H)，7.35(d，J＝7.8Hz，1H)，7.20(t，J＝7.8Hz，1H)，MS(ESI)m/z：309.67([M+H]+)
1，7-双-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物12)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.63(s，1H)，8.09(d，J＝8.1Hz，1H)，7.93(s，1H)，7.88(d，J＝8.1Hz，1H)，7.66(d，J＝7.5Hz，1H)，7.63(d，J＝7.5Hz，1H)，7.37(t，J＝7.5Hz，1H)，MS(ESI)m/z：343.22([M+H]+)
10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物13)：
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)11.65(s，1H)，8.19(t，J＝4.5Hz，1H)，8.04(d，J＝7.5Hz，1H)，7.9(d，J＝7.5Hz，1H)，7.71(t，J＝4.5Hz，1H)，7.38(d，J＝7.5Hz，1H)，7.36(d，J＝4.5Hz，1H)，7.26(t，J＝7.5Hz，1H)，MS(ESI)m/z：251.24([M+H]+)
1-甲氧基-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物14)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.35(s，1H)，7.87(s，1H)，7.77(d，J＝8.1Hz，1H)，7.58(d，J＝8.1Hz，1H)，7.48(d，J＝7.8Hz，1H)，7.17(t，J＝7.8Hz，1H)，6.8(d，J＝7.8Hz，1H)，4.03(s，3H)，MS(ESI)m/z：305.25([M+H]+)
7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸甲酯(化合物15)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)10.11(s，1H)，8.1(d，J＝7.5Hz，1H)，8.04(d，J＝7.5Hz，1H)，7.90(s，1H)，7.85(d，J＝8.1Hz，1H)，7.62(d，J＝8.1Hz，1H)，7.30(t，J＝8.1Hz，1H)，4.05(s，3H)，MS(ESI)m/z：333.26([M+H]+)
7-甲氧基-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物16)：
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)11.54(s，1H)，7.99(d，J＝8.4Hz，1H)，7.96(d，J＝8.4Hz，1H)，7.83(d，J＝7.5Hz，1H)，7.33(s，1H)，7.22(t，J＝7.5Hz，1H)，7.00(d，J＝7.5Hz，1H)，MS(ESI)m/z：281.26([M+H]+)
7-氯代-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物17)：
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)11.82(s，1H)，8.09(d，J＝7.2Hz，1H)，8.04(d，J＝7.2Hz，1H)，7.91(d，J＝7.8Hz，1H)，7.89(s，1H)，7.44(d，J＝7.8Hz，1H)，7.29(t，J＝7.8Hz，1H)，MS(ESI)m/z：285.68([M+H]+)
1，2-二氯代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物18)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.46(s，1H)，7.89(s，1H)，7.82(d，J＝8.4Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.63(d，J＝8.4Hz，1H)，7.35(d，J＝8.4Hz，1H)，MS(ESI)m/z：344.11([M+H]+)
2，4-二氯代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物19)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.31(s，1H)，7.95(s，1H)，7.79(d，J＝8.1Hz，1H)，7.62(d，J＝8.1Hz，1H)，7.41(s，1H)，7.26(s，1H)，MS(ESI)m/z：344.11([M+H]+)
4-氟代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物20)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.15(s，1H)，7.87(s，1H)，7.79(d，J＝9.00Hz，1H)，7.75(d，J＝8.7Hz，1H)，7.59(d，J＝8.7Hz，1H)，7.21(d，J＝9.00Hz，1H)，7.03(t，J＝9.00Hz，1H)，MS(ESI)m/z：293.22([M+H]+)
2-氟代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚(化合物21)：
产率：64.4％(3.94g).1H NMR(300MHz，CDCl3)δ(ppm)8.25(s，1H)，7.92(s，1H)，7.78(d，J＝8.1Hz，1H)，7.61(d，J＝8.1Hz，1H)，7.30(d，J＝6.6Hz，1H)，7.20(s，1H)，6.95(d，J＝6.6Hz，1H)，MS(ESI)m/z：293.22([M+H]+)
4-氯代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物22)：
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)12.08(s，1H)，8.32(d，J＝8.4Hz，1H)，8.4(s，1H)，7.92(d，J＝8.4Hz，1H)，7.77(d，J＝8.1Hz，1H)，7.37(d，J＝8.1Hz，1H)，MS(ESI)m/z：353.68([M+H]+)
3-氯代-7-三氟甲基-10H-苯并[4，5]呋喃并[3，2-b]吲哚-1-羧酸(化合物23)：
产率：64.4％(3.94g).1H NMR(300MHz，DMSO)δ(ppm)11.97(s，1H)，8.30(d，J＝8.1Hz，1H)，8.23(s，1H)，8.18(s，1H)，7.85(s，1H)，7.76(d，J＝8.1Hz，1H)，MS(ESI)m/z：353.68([M+H]+)
(实施例1)检测本发明化合物的钾通道电流
图3中表示的是合成化合物增加BKCa通道电流的相对倍数。通过比较化合物7、8、13、16和17的通道开放活性，在7或8位上用溴代、三氟甲基或氯代基团的取代显示为通道电流增加3倍以上，而无取代或者供电基团如甲氧基在7位时提供较小得多的功效。
因此，看得出，在苯并呋喃酮一侧上的吸电子取代基对活性是非常重要的。在这些官能团中，三氟甲基，与在图2中所示BMS-204352重叠的官能团，给予最高的开放活性。对于1位上取代基而言，结果是当8与11(氯代)、12(三氟甲基)、14(甲氧基)和15(甲酯)相比较时，羧酸对活性非常重要。
当三氟甲基取代基位于吲哚环一侧的各个位置上的情况下，如9，10和12位，最具活性的位置是4(化合物10)，这表明与图2中BMS-204352重叠的结构可提供线索以改善活性。氯和氟取代基的其它衍生物、18、19、20和21表现的活性接近于基本水平。
化合物22，在1位上有羧酸基团以及与BMS-204352重叠的4位上有氯基团，表现为增加6倍以上的通道开放活性，这会被引起在1位和4位上适宜双取代的协同作用。在3位上带有氯基团的化合物23也显示接近但不优于化合物22的通道开放活性。
考虑到已描述在应用相同化合物浓度(20μM)的类似检验体系中BMS-204352以及化合物2的增加倍数分别为1.5和3.7左右，化合物22和23的效力是显著的。
(实施例2)检测本发明化合物对克隆载体BKCa(rSlo)通道的活性
为了研究在各种细胞内Ca2+浓度下化合物22对rSlo通道的增强作用，在不同浓度的细胞内Ca2+中激活rSlo通道。
通过制备千兆欧姆封接(gigaohm seal)、破膜从卵母细胞取出移液管，得到被切除的外向外膜片构型。池和移液管都含有对称的124mMK+离子。应用电压脉冲激活rSlo通道电流，从-120mV至140mV，每次增加10mV，而且为激活rSlo通道所用细胞内Ca2+浓度在细胞内侧从0(无Ca2+溶液用5mM EGTA螯合)至2μM。
rSlo通道的代表性原始踪迹由膜电压和细胞内Ca2+(图4)激活。记录在加入20μM化合物22前后的rSlo通道电流。在20μm浓度时，化合物22在各种浓度细胞内Ca2+中表现为对rSlo通道电流有显著地重要的作用。
化合物22对rSlo电流的这些增强作用可以通过冲洗而除去。图4表示在实验所有浓度的细胞内Ca2+中，通过细胞外应用化合物22显著地诱导rSlo通道电流，并且在冲洗后恢复。这些结果揭示，细胞内Ca2+浓度不影响化合物22对rSlo通道的增强作用。
从这些结果，我们可设想，神经元BKCa通道可用化合物22激活，甚至在约-60～-80mV静息膜电位、存在低于100nM的无Ca2+临界浓度的情况下。
(实施例3)检测本发明化合物在非洲爪蛙卵母细胞上的活性
我们进行了试验以确定化合物22对在非洲爪蛙卵母细胞中表达的宏观rSlo通道活性的作用与浓度的依赖性。
记录来自加入7种不同浓度化合物22(从0至300μM)前后被切除外向外膜片的电流。rSlo的通道活性在具有2μM细胞内Ca2+的膜片切除后被得出，而且随着化合物22的加入而快速地提高。将膜电位保持在-120mV，并在50ms内步进至50mV。相对电流差值被确定自以2μM细胞内Ca2+和电压50mV激活的对照电流，用对照电流来归一化，并且所获得的数据点较好拟合Hill方程(图5)。
在50nM至300μM的范围内加入的化合物22以浓度依赖的方式增强rSlo电流。归一化的相对电流增加的倍数与Hill方程拟合很好。从最佳拟合获得的化合物22的表观解离常数Kd为4.01±0.75μM，以及n值(Hill系数常数)为1.20±0.07(N＝5，p<0.01)。这些结果表明，化合物22以一比一的比率结合rSlo通道。苯并呋喃并吲哚衍生物对通道的更详细的生物活性和机理将在别处报道。
总之，苯并呋喃并吲哚骨架与已知的BKCa通道开放剂BMS-204352相比，优化了所引入的药效基团。利用在非洲爪蛙卵母细胞中表达的rSlo通道的外向外膜片，对克隆的BKCa通道进行了评价，化合物22被识别为有细胞内钙独立方式的、强效的BKCa通道开放剂。BKCa通道开放剂可进一步地应用于中风、哮喘、高血压、惊厥以及创伤性脑损伤的治疗干预。
(实施例4)检测本发明化合物浓度依赖性通道开放的活性
然后我们还检测了本发明化合物8的浓度依赖性。随着增加化合物8应用于膜片(membrane patched)的细胞外侧的浓度，激活速度以及稳态电流的水平以浓度依赖性方式而增加(图6A)。尽管因化合物8水中溶解度而使我们不能获得高于300μM的化合物8浓度，但是我们注意到化合物8诱导的电流增加在约100μM时达到了坪水平(plateau level)。测定化合物8对rSlo通道的EC50浓度为8.9±1.5μM。我们也检测了化合物8的作用，应用内向外膜片构型确定是否该化合物还从细胞内侧影响通道的活性。将细胞内Ca2+浓度固定于2μM以激活rSlo通道，并且将不同浓度的化合物8加至膜的细胞内侧。尽管细胞内化合物8也增加rSlo电流，具有相似表观亲合力，但是其增加的倍数远小于从细胞外侧所获得的倍数。
BKCa通道的功能性特征可由辅助β亚单元改变，而且某些激活剂和抑制剂的功效极大地受β亚单元的共组装(coassembly)的影响。因此，我们提出问题，化合物8增强作用是否受β亚单元共表达的影响。我们将rSlo与人β1或大鼠β4亚单元一起在非洲爪蛙卵母细胞中表达，并检测在存在不同浓度细胞外化合物8条件下的通道电流。rSlo/人β1(图6B)和rSlo/大鼠β4(图6C)的活性都由该化合物的微摩尔浓度以浓度依赖性方式而增加。但是，这些结果表明，化合物8能够增强没有β亚单元共组装的BKCa通道，并且指出化合物8的受体位点位于BKCa通道的主要亚单元，即Slo蛋白内。
Claims (5)
1.一种具有苯并呋喃并吲哚骨架的钾通道开放剂，如下式(I)所示
其中，
R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢或氯且R6是氢或氯。
2.根据权利要求1所述的具有苯并呋喃并吲哚骨架的钾通道开放剂，其中R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢并且R6是氢。
3.根据权利要求1所述的具有苯并呋喃并吲哚骨架的钾通道开放剂，其中R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氢并且R6是氯。
4.根据权利要求1所述的具有苯并呋喃并吲哚骨架的钾通道开放剂，其中R1是氢，R2是CF3，R3是COOH，R4是氢，R5是氯并且R6是氢。
5.一种用于制备具有苯并呋喃并吲哚骨架、下式(I)所示的钾通道开放剂的工艺，其包括以下步骤：
i)通过作为起始原料的式(II)所示的水杨酸衍生物在加入甲醇溶剂的硫酸存在下与溴代乙酸乙酯反应和缩合，随后除去溴化氢，并且用NaOH水溶液除去乙基，
制备式(III)化合物；
ii)通过在乙酸酐或乙酸钠存在下经回流式(III)化合物的环化反应，
制备式(IV)化合物；
iii)根据菲舍尔-吲哚反应，通过在乙醇或p-TsOH溶剂存在下偶合取代的苯肼，制备式(I)化合物，
其中，
R1是4-CF3、4-H，R2是1-COOH、1-Cl、3-Cl、4-Cl。
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| US9848809B2 (en) | 2011-04-15 | 2017-12-26 | Dexcom, Inc. | Advanced analyte sensor calibration and error detection |
| US20190117131A1 (en) | 2017-10-24 | 2019-04-25 | Dexcom, Inc. | Pre-connected analyte sensors |
| US11331022B2 (en) | 2017-10-24 | 2022-05-17 | Dexcom, Inc. | Pre-connected analyte sensors |
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| US6288099B1 (en) | 1998-12-04 | 2001-09-11 | American Home Products Corporation | Substituted benzofuranoindoles and indenoindoles as novel potassium channel openers |
| US7276603B2 (en) * | 2003-05-02 | 2007-10-02 | Wyeth | Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use |
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|---|---|---|---|---|
| CN106632360A (zh) * | 2016-09-27 | 2017-05-10 | 上海道亦化工科技有限公司 | 基于苯并呋喃并吲哚的化合物及其有机电致发光器件 |
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| KR20050032080A (ko) | 2005-04-06 |
| WO2006096030A1 (en) | 2006-09-14 |
| ATE481098T1 (de) | 2010-10-15 |
| EP1861092A1 (en) | 2007-12-05 |
| JP5053989B2 (ja) | 2012-10-24 |
| DE602006016922D1 (de) | 2010-10-28 |
| KR100659498B1 (ko) | 2006-12-20 |
| EP1861092B1 (en) | 2010-09-15 |
| US20080194837A1 (en) | 2008-08-14 |
| JP2008533001A (ja) | 2008-08-21 |
| US7812177B2 (en) | 2010-10-12 |
| EP1861092A4 (en) | 2009-04-15 |
| CN101137361B (zh) | 2010-11-24 |
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