CN105001150A - 烷氧基二吡啶叔醇结构的11β-HSD1抑制剂、制备方法及其用途 - Google Patents
烷氧基二吡啶叔醇结构的11β-HSD1抑制剂、制备方法及其用途 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/68—One oxygen atom attached in position 4
Abstract
本发明涉及与2型糖尿病相关的药物领域。具体而言，本发明涉及一类烷氧基二吡啶叔醇结构的11β-HSD1抑制剂、其制备方法以及在制备2型糖尿病药物中的应用。其中，R选自C1-C3的烷基。
Description
技术领域
本发明涉及2型糖尿病治疗的药物领域。具体地讲，本发明涉及对2型糖尿病具有治疗作用的一类含烷氧基二吡啶叔醇结构的11β-HSD1抑制剂、其制备方法，以及在制药上的用途。
背景技术
糖尿病是由多病因引起的疾病过程，影响到全球6％-7％的人口。预计到2025年，患病人数会再增加一倍达到3亿。糖尿病的最重要的临床病理特征是血浆葡萄糖(血糖)浓度增高。血糖浓度增高是导致糖尿病的各种临床症状的主要原因。未控制的高血糖导致诸多糖尿病并发症，包括肾病，神经病，视网膜病，高血压，脑缺血和冠心病等。因此，降低血糖是治疗和预防糖尿病及其并发症的关键。
11-β-羟基类固醇脱氢酶1型(11β-HSD1)是几年来确认的对血糖控制和改善其他糖尿病相关的症状的有效靶点。研究已经确定，糖皮质激素活性不仅通过分泌皮质醇控制而且于组织水平通过活性皮质醇和非活性可的松的细胞内互交控制，这种互交通过经11-β-羟基类固醇脱氢酶，即11β-HSD1(它激活可的松)和11β-HSD-2(它灭活皮质醇)完成(Sandeep TC&Walker BR,Trends Endocrinol&Metab.,2001,12,446-453)。这种机理对于人可能是重要的，最初几于用甘珀酸(一种抑制11β-HSD1和-2的抗渍殇药)治疗，这种治疗导致胰岛素敏感度提高，说明11β-HSD1可通过降低活性糖皮质激素的组织水平有效调控胰岛素作用(WalkerBR et al.J.Clin.Endocrinol.Metab.,1995,80,3155-3159)。
许多具有胰岛素抗性但没有发展为2型糖尿病的患者还有发展称为"综合症X"或"代谢综合症"的症状的风险。综合症X或代谢综合症以胰岛素抗性为特征，并且伴有腹部肥胖、高胰岛素血症、高血压、低的高密度脂蛋白(HDL)和高的极低密度脂蛋白(VLDL)。这些患者，无论是否发展为明显的糖尿病，均有增加的发展上述心血管并发症的风险。11β-HSD1抑制剂除了对2型糖尿病具有治疗作用万，对脂质病症、肥胖症、动脉粥样硬化、阿尔茨海默氏病和相关病症所需的认知增强、高血压、眼内压增加、促进伤口愈合和代谢性综合症等均有一定的治疗和预防作用。
本发明公开了一类含烷氧基二吡啶叔醇结构的11β-HSD1抑制剂，这些化合物可用于制备治疗2型糖尿病及其相关疾病的药物。
发明内容
本发明的一个目的是提供一种具有通式I的良好活性的11β-HSD1抑制剂。
本发明的另一个目的是提供制备具有通式I的化合物的方法。
本发明的再一个目的是提供含有通式I的化合物在治疗2型糖尿病方面的应用。现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物具有下述结构式：
其中，R选自C1-C3的烷基。
更优选通式I的化合物具有以下结构，
本发明所述通式I化合物通过以下路线合成：
化合物II和化合物III在加热的情况下反应生成化合物IV；化合物V用正丁基锂在低温下处理，得到对应的芳基锂VI；化合物IV与两倍当量的化合物VI反应，得到化合物I；R的定义如前所述。
本发明所述通式I化合物具有11β-HSD1抑制作用，可作为有效成分用于制备2型糖尿病治疗药物。本发明所述通式I化合物的活性是通过受体结合试验来验证的。
本发明的通式I化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-700mg/人范围内，分为一次或数次给药。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1化合物I-1的合成
步骤1.化合物IV的合成
化合物II(0.80g,10mmol)和化合物III(0.86g,10mmol)溶于10mL苯中，氮气保护下回流1小时，TLC检查发现反应完成。反应混合物稍冷后在旋转蒸发仪上蒸干，残余物柱层析纯化，得到化合物IV，白色固体，ESI-MS,m/z＝167([M+H]+)。
步骤2.化合物I-1的合成
2-溴吡啶V-1(2.26g,12mmol)溶于20mL干燥的THF中，氮气保护下冷却到-78℃，搅拌下用注射器慢慢滴加7.5mL(12mmol)n-BuLi，滴加完毕后，反应混合物在该温度下继续搅拌1小时，而后再用注射器慢慢滴加化合物IV(0.83g,5mmol)溶于1mL干燥的THF制成的溶液，滴加完毕后，反应混合物在室温下搅拌过夜，TLC显示反应完成。反应混合物倾倒入200mL冰水中，搅拌，用50mL×3CH2Cl2萃取，合并萃取相，用盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂，滤液在旋转蒸发仪上蒸干，残余物使用硅胶柱层析纯化，得到化合物I-1，白色固体，ESI-MS,m/z＝353([M+H]+)。
实施例2-9
参照实施例1的方法，合成了下表所列化合物：
实施例10化合物体外对11β-HSD1的抑制作用
试验化合物的体外酶活性经闪烁亲近测定法(SPA)评价。将优化可的松底物、NADPH辅助因子和结构式(I)的被测定的化合物用11β-HSD1酶在37℃培养使向氢化可的松的转化进行。在培养后，将与抗氢化可的松单克隆抗体预混合的蛋白质A涂覆的SPA珠和非特异性的11β-HSD抑制剂例如18β-甘草次酸的制剂加入每个孔中。混合物在15℃振荡，随后用适合于96孔板的液体闪烁计数器读取。相对于非抑制对照孔计算抑制百分数，得到IC50曲线。具体来讲，向96孔板上指定的孔中加入40μL底物(在50mM HEPES缓冲液中的25nM[3H]-可的松+1.25mM NADPH,pH 7.4)。将化合物以10mM溶解在DMSO中，在DMSO中依次50倍稀释。稀释的物质随后4倍滴定7次。随后一式两份地向底物中分别加入1μL被滴定化合物。为开始反应，在每个孔中以合适的浓度加入10μL由CHO细胞转染物得到的11β-HSD1微粒体以产生约10％的原料转化。为最终计算抑制百分数，向表示最小和最大试验的一系列孔中加入：含有底物而没有化合物或酶(背景)的一组物质，含有底物和酶而没有任何化合物的另一组物质(最大信号)。板在离心机中在低速下简单地离心以汇集反应物，用粘性胶带密封，缓慢混合，在37℃培养2小时。在培养后，在每个孔中加入45μL用抗氢化可的松单克隆抗体预悬浮的SPA珠和式(I)化合物。将板重新密封，在15℃温和振荡1.5小时以上。在板基液体闪烁计数器中收集数据。为控制抗氢化可的松抗体/氢化可的松结合的抑制，将用1.25nM[3H-]氢化可的松作内标的底物加入指定的单一孔中。在每个这样的孔中加入1μL的200μM化合物，同时用10μL缓冲液代替酶。任何计算的抑制归因于化合物对氢化可的松结合于SPA珠上的抗体的干涉。测试结果见下表。
| 化合物 | IC50(nM) |
| 参考化合物R-1 | 18.3 |
| 化合物I-1 | 9.2 |
| 化合物I-2 | 7.7 |
| 化合物I-3 | 12.5 |
| 化合物I-4 | 11.7 |
| 化合物I-5 | 9.8 |
| 化合物I-6 | 13.3 |
| 化合物I-7 | 21.4 |
| 化合物I-8 | 19.6 |
上表结果显示，本发明的化合物对11β-HSD1具有很强的抑制作用，可以作为制备治疗2型糖尿病的的药物。
Claims (4)
1.具有通式I结构的化合物，
其中，R选自C1-C3的烷基。
2.权利要求1所定义的通式I化合物，选自：
3.合成权利要求1-2任一所定义的属于通式I的化合物的方法：
化合物II和化合物III在加热的情况下反应生成化合物IV；化合物V用正丁基锂在低温下处理，得到对应的芳基锂VI；化合物IV与两倍当量的化合物VI反应，得到化合物I；R的定义如权利要求1-2任一所述。
4.权利要求1-3之一所定义的通式I化合物在制备治疗2型糖尿病药物方面的应用。
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