CN113234060B - 一种稠杂环吡啶巯乙酸类衍生物及其制备方法与应用 - Google Patents
一种稠杂环吡啶巯乙酸类衍生物及其制备方法与应用 Download PDFInfo
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- CN113234060B CN113234060B CN202110482124.8A CN202110482124A CN113234060B CN 113234060 B CN113234060 B CN 113234060B CN 202110482124 A CN202110482124 A CN 202110482124A CN 113234060 B CN113234060 B CN 113234060B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及一种稠杂环吡啶巯乙酸类衍生物及其制备方法和应用。所述化合物具有通式I或II所示的结构。本发明还涉及含有通式I或II结构化合物的制备方法以及药物组合物。本发明还提供上述化合物在制备抗痛风的药物中的应用。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域，具体涉及一种稠杂环吡啶巯乙酸类衍生物及其制备方法及应用。
背景技术
痛风是一种由嘌呤代谢紊乱造成的尿酸生成增多或排泄减少，从而导致单钠尿酸盐晶体沉积于关节组织中所引起的代谢性疾病，其临床主要表现为高尿酸血症。近年来，随着人们生活水平和饮食结构的改善，痛风和高尿酸血症患者人数不断增多且呈年轻化趋势，给患者和社会带来沉重负担。而在我国，痛风的发病率为1.1％，高尿酸血症发病率为13.3％，痛风成为仅次于糖尿病的第二大代谢类疾病，而高尿酸血症也成为继高血压、高血脂、高血糖之后的“第四高”。目前，临床上用于治疗痛风和高尿酸血症的药物主要包含非甾体抗炎药、抑制尿酸生成药及促尿酸排泄药，尿酸盐转运蛋白1(URAT1)是在人体肾近曲小管上皮细胞顶膜表达的负责尿酸重吸收的转运蛋白，是目前促进尿酸排泄药物的一个新型热门靶标，抑制URAT1，可有效减少尿酸的重吸收，增加尿酸的代谢。该类抑制剂的上市药物有丙磺舒(Probenecid)、磺吡酮(Sulfinpyrazone)、苯溴马隆(Benzbromarone)和雷西纳德(Lesinurad)等，但这些药物都存在愈后效果差或严重的毒副作用，极大地限制了临床使用。因此发现高效、低毒且具有自主知识产权的新型抗痛风URAT1抑制剂具有重要的应用价值。
发明内容
针对现有技术的不足，本发明提供了一种稠杂环吡啶巯乙酸类衍生物及其制备方法，本发明还提供了上述化合物作为抗痛风药物的活性筛选结果及其制药应用。
本发明的技术方案如下：
一、稠杂环吡啶巯乙酸类衍生物
本发明的一种稠杂环吡啶巯乙酸衍生物，具有如下通式I或II所示的结构：
其中，
R1为被0、1或2个R取代的C1～C5烷基；R为C1～C5的烷基或C3～C6的环烷基；
R2为-H、C1～C5的烷基、氨基或药学上可以接受的阳离子。
根据本发明优选的，R1为
R2为-H或-CH3或-CH2CH3。
根据本发明进一步优选的，稠杂环吡啶巯乙酸类衍生物是下列之一：
表1.化合物结构式
二、稠杂环吡啶巯乙酸类衍生物的制备方法
本发明稠杂环吡啶巯乙酸类衍生物的制备方法为如下之一：
(1)四氢异喹啉吡啶巯乙酸类目标化合物(I)的制备方法
以4-氯烟酸为起始原料，在2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和N,N-二异丙基乙胺(DIEA)的催化下与1,2,3,4-四氢异喹啉缩合反应生成中间体I-1，I-1再与九水合硫化钠微波反应生成中间体(3,4-二氢异喹啉-2(1H)-基)(4-巯基吡啶-3-基)甲酮(I-2)，接着I-2与各种酯发生亲核取代反应得到具备通式I结构的目标化合物，部分酯类目标化合物在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到羧酸类目标化合物；
合成路线一如下：
反应试剂和条件：(i)1,2,3,4-四氢异喹啉，HATU，DIEA，DCM，0℃～RT，5h；(ii)Na2S·9H2O，DMF，微波反应，130℃，30min；(iii)K2CO3，DMF，45℃，6h；(iv)一水合氢氧化锂，THF，MeOH，室温，6h。
其中，R1、R2同上述通式I所示。
(2)苯并吗啉吡啶巯乙酸类目标化合物(II)的制备方法
以4-氯烟酸为起始原料，在HATU和DIEA的催化下与苯并吗啉缩合反应生成中间体II-1，再以DMF为溶剂与九水合硫化钠微波反应生成中间体(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(4-巯基吡啶-3-基)甲酮(II-2)，接着II-2与各种酯发生亲核取代反应得到具备通式II结构的目标化合物，部分酯类目标化合物在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到羧酸类目标化合物。
合成路线二如下：
反应试剂和条件：(i)苯并吗啉，HATU，DIEA，DCM，0℃～RT，5h；(ii)Na2S·9H2O，DMF，微波反应，130℃，30min；(iii)K2CO3，DMF，45℃，6h；(iv)一水合氢氧化锂，THF，MeOH，室温，6h。
其中，R1、R2同上述通式II所示。
本发明所述的室温是指20-30℃。
三、稠杂环吡啶巯乙酸类衍生物的应用
本发明公开了稠杂环吡啶巯乙酸类衍生物降血尿酸活性筛选结果及其作为抗痛风药物的首次应用。通过实验证明本发明稠杂环吡啶巯乙酸类衍生物可作为降血尿酸药物应用。具体地说，作为降血尿酸化合物用于制备抗痛风药物。本发明还提供上述化合物在制备抗痛风的药物中的应用。
目标化合物的抗痛风活性
对按照上述方法合成的24个化合物(化合物的结构式见表1)，并对其进行了体外靶标抑制活性筛选，它们的靶标抑制活性数据列于表2中，以Lesinurad为阳性对照。由表2可以看出目标化合物均呈现出较好的URAT1抑制活性。
因此，本发明的稠杂环吡啶巯乙酸类衍生物是一系列结构新颖的URAT1抑制剂，可作为抗痛风的先导化合物加以利用。
本发明的稠杂环吡啶巯乙酸类衍生物可作为URAT1抑制剂应用。具体地说，作为尿酸盐转运蛋白1(URAT1)抑制剂用于制备抗痛风药物。
一种抗痛风药物组合物，包括本发明的稠杂环吡啶巯乙酸类衍生物和一种或多种药学上可接受载体或赋形剂。
具体实施方式
通过下述实例有助于理解本发明，但是不能限制本发明的内容，在下列实例中，所有目标化合物的编号与表1相同。
合成路线：
实施例1.中间体(3,4-二氢异喹啉-2(1H)-基)(4-巯基吡啶-3-基)甲酮(I-2)的制备中间体(4-氯吡啶-3-基)(3,4-二氢异喹啉-2(1H)-基)甲酮(I-1)的制备：
冰浴条件下，将4-氯烟酸(1.0g，6.37mmol)，HATU(3.63g，9.5mmol)溶于20mL二氯甲烷中，将DIEA(1.65g，12.74mmol，2.11mL)缓慢滴加到上述溶液中，继续冰浴搅拌活化，1h后，缓慢滴加1,2,3,4-四氢异喹啉(1.02g，7.64mmol，0.96mL)，撤去冰浴，室温搅拌反应5h；TLC监测反应完全后，减压蒸除溶剂，残余物加入30mL乙酸乙酯，先后用饱和NaHCO3、1mol/L稀盐酸、饱和NaCl溶液水洗(20mL×2次)，合并有机相，无水硫酸钠干燥，过滤。减压浓缩后产物经快速柱层析(乙酸乙酯：石油醚＝1:1)得到中间体I-1，为淡黄色固体，收率49.71％，熔点:108～109℃。1H NMR(400MHz,DMSO-d6)δ8.68–8.56(m,2H),7.69(dd,J＝8.9,5.5Hz,1H),7.26(dd,J＝16.5,7.1Hz,1H),7.22–7.16(m,2H),7.09(dd,J＝42.1,8.7Hz,1H),4.84(d,J＝30.9Hz,1H),4.39(d,J＝8.9Hz,1H),3.90(d,J＝57.7Hz,1H),3.43(t,J＝5.9Hz,1H),2.94–2.78(m,2H).ESI-MS:m/z 273.3[M+H]+,C15H13ClN2O[272.07].
中间体(3,4-二氢异喹啉-2(1H)-基)(4-巯基吡啶-3-基)甲酮(I-2)的制备
将中间体I-1(1g，3.68mmol)和九水合硫化钠(1.76g，7.35mmol)溶解在约5mL DMF中，在微波反应仪中130℃条件下反应30min；待反应结束后，将反应体系冷却至室温，加入30mL清水，用乙酸乙酯(20mL×3次)萃取，取水相，然后用1mol/L稀盐酸调节pH至4～5，出现沉淀，搅拌15min后，过滤，滤饼用清水洗涤，干燥，得中间体I-2，为橙色固体，收率35.26％，熔点:102～103℃。1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),7.79(d,J＝16.3Hz,1H),7.60(d,J＝6.8Hz,1H),7.30–7.24(m,1H),7.24–7.14(m,3H),7.14–7.00(m,1H),4.83–4.34(m,2H),3.77(ddt,J＝90.7,12.7,5.9Hz,1H),3.51–3.38(m,1H),2.99–2.71(m,2H).ESI-MS:m/z 269.3[M-H]-,C15H14N2OS[270.08].
实施例2.化合物I-z1的制备
将中间体I-2(0.5g，1.85mmol)与K2CO3(0.51g，3.7mmol)混合于50mL圆底烧瓶中，用约15mL DMF溶解，室温搅拌15min后，逐滴加入溴乙酸甲酯(0.425g，2.78mmol)，45℃回流反应6h；TLC监测，待反应完全后，冷却至室温，加入乙酸乙酯20mL，用饱和NaCl溶液洗涤(30mL×3次)，合并有机相，无水硫酸钠干燥，过滤，取滤液，减压蒸去溶剂。减压浓缩后产物经快速柱层析(乙酸乙酯：石油醚＝1:1)得到目标产物I-z1，油状物，收率72.67％。
化合物I-z1波谱数据：1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝5.5Hz,1H),8.36(d,J＝18.5Hz,1H),7.41(d,J＝5.3Hz,1H),7.32–7.12(m,4H),4.82(s,1H),4.41(s,1H),4.12(d,J＝24.5Hz,2H),3.65(d,J＝18.7Hz,3H),3.44(t,J＝5.9Hz,2H),2.92–2.82(m,2H).13CNMR(100MHz,DMSO-d6)δ169.44,165.95,150.04,146.51,145.18,134.54,133.07,131.00,129.05,127.08,126.97,126.79,120.49,53.03,44.60,44.09,32.59,29.36.ESI-MS:m/z343.3[M+H]+,C18H18N2O3S[342.10].
实施例3.化合物I-z2的制备
操作同实施例2，所不同的是，使用的酯为3-溴丙酸甲酯，油状物，收率63.6％。
化合物I-z2波谱数据：1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝5.4Hz,1H),8.33(d,J＝19.9Hz,1H),7.49(d,J＝5.3Hz,1H),7.30–7.10(m,4H),4.80(s,1H),4.37(s,1H),3.57(d,J＝23.2Hz,3H),3.40(t,J＝5.9Hz,2H),3.32–3.20(m,2H),2.85(dt,J＝33.2,6.0Hz,2H),2.66(dt,J＝46.5,7.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ171.83,166.05,150.13,146.62,145.41,134.53,133.07,131.40,129.01,127.07,126.94,126.78,120.28,52.07,44.49,44.07,33.29,29.42,25.73.ESI-MS:m/z 357.2[M+H]+,C19H20N2O3S[356.12].
实施例4.化合物I-z3的制备
操作同实施例2，所不同的是，使用的酯为4-溴丁酸甲酯，油状物，收率58.98％。
化合物I-z3波谱数据：1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝5.5Hz,1H),8.33(d,J＝20.0Hz,1H),7.49(d,J＝5.8Hz,1H),7.32–7.09(m,4H),4.81(s,1H),4.37(s,1H),3.59(d,J＝5.9Hz,3H),3.41(t,J＝5.9Hz,2H),3.07(dt,J＝28.8,7.5Hz,2H),2.86(dt,J＝32.4,6.0Hz,2H),2.34(t,J＝7.2Hz,2H),1.80(dt,J＝46.1,7.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.17,166.10,149.99,146.57,145.79,134.51,133.10,131.40,129.02,127.06,126.94,126.79,120.16,51.85,44.47,44.04,32.49,29.37,28.24,24.08.ESI-MS:m/z 371.4[M+H]+,C20H22N2O3S[370.14].
实施例5.化合物I-z4的制备
操作同实施例2，所不同的是，使用的酯为2-溴丙酸甲酯，油状物，收率51.5％。
化合物I-z4波谱数据：1H NMR(400MHz,DMSO-d6)δ8.53(d,J＝5.4Hz,1H),8.39(d,J＝20.8Hz,1H),7.58–7.51(m,1H),7.32–7.11(m,4H),4.81(s,1H),4.58–4.43(m,1H),4.40(d,J＝18.7Hz,1H),3.63(d,J＝20.4Hz,3H),3.41(t,J＝5.8Hz,2H),2.87(dt,J＝34.8,6.0Hz,2H),1.42(dd,J＝44.6,5.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.24,165.87,150.09,146.87,144.03,134.51,133.04,131.78,129.05,127.09,126.96,126.80,122.01,53.07,44.56,44.11,41.87,29.37,17.56.ESI-MS:m/z 357.3[M+H]+,C19H20N2O3S[356.12].
实施例6.化合物I-z5的制备
操作同实施例2，所不同的是，使用的酯为2-溴代异丁酸甲酯，油状物，收率59.1％。
化合物I-z5波谱数据：1H NMR(400MHz,DMSO-d6)δ8.60(dd,J＝26.6,5.5Hz,1H),8.51–8.43(m,1H),7.76(dd,J＝17.7,5.4Hz,1H),7.32–7.10(m,4H),4.83(d,J＝14.4Hz,1H),4.41(d,J＝56.5Hz,1H),3.69(d,J＝10.6Hz,1H),3.51(t,J＝5.9Hz,1H),3.37(s,3H),2.90(dd,J＝13.0,6.3Hz,2H),1.52(d,J＝14.1Hz,3H),1.33(d,J＝9.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ174.00,165.78,150.12,147.39,141.65,134.89,134.51,133.02,129.05,127.08,126.80,126.53,125.41,53.38,51.28,44.52,44.08,29.34,28.17,26.55.ESI-MS:m/z 371.4[M+H]+,C20H22N2O3S[370.14].
实施例7.化合物I-z6的制备
操作同实施例2，所不同的是，使用的酯为1-溴环丁羧酸乙酯，油状物，收率47.7％。
化合物I-z6波谱数据：1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝5.5Hz,1H),8.39(d,J＝16.2Hz,1H),7.31–7.14(m,4H),7.06(d,J＝5.5Hz,1H),4.83(s,1H),4.39(s,1H),4.13(dd,J＝13.7,6.9Hz,2H),3.43(d,J＝6.1Hz,1H),2.93(s,1H),2.88–2.82(m,2H),2.39–2.22(m,2H),2.14(d,J＝32.3Hz,2H),2.03–1.83(m,2H),1.16–1.07(m,3H).13C NMR(100MHz,DMSO-d6)δ172.77,165.75,149.97,146.96,144.51,134.49,133.05,131.11,129.05,127.09,126.81,126.61,120.85,62.06,51.27,44.55,44.11,32.24,29.39,28.20,16.77,14.29.ESI-MS:m/z 397.3[M+H]+,C22H24N2O3S[396.15].
实施例8.化合物I-s1的制备
将化合物I-z1(0.2g)溶于5mL甲醇和2.5mL四氢呋喃的混合溶液中，搅拌溶解，将一水合氢氧化锂溶于少量水中，慢慢滴加到上述溶液中，常温下搅拌反应12h；TLC监测，待反应完全后，加入5mL水，减压旋蒸除去体系中的甲醇和四氢呋喃，滴加1mol/L稀盐酸将溶液pH调至5～6，析出固体，过滤，清水洗涤，干燥，得目标化合物I-s1。淡紫色固体，收率55.21％，熔点:194～196℃。
化合物I-s1波谱数据：1H NMR(400MHz,DMSO-d6)δ13.02(s,1H),8.48(d,J＝3.7Hz,1H),8.33(d,J＝21.0Hz,1H),7.40(d,J＝5.4Hz,1H),7.29–6.99(m,4H),4.81(s,1H),4.41(s,1H),3.99(d,J＝17.5Hz,2H),3.87(d,J＝6.4Hz,1H),3.43(t,J＝5.8Hz,1H),2.87(dt,J＝27.6,6.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.22,166.01,149.98,146.46,145.63,134.56,133.09,130.96,129.05,127.08,126.96,126.78,120.45,44.57,44.09,33.21,29.40.ESI-MS:m/z326.94[M-H]-,C17H16N2O3S[328.09].
实施例9.化合物I-s2的制备
操作同实施例8，所不同的是，被水解的化合物为I-z2，淡黄色固体，收率88.54％，熔点:104～110℃。
化合物I-s2波谱数据：1H NMR(400MHz,DMSO-d6)δ12.80(s,1H),7.80(dd,J＝16.3,4.7Hz,1H),7.61(t,J＝5.8Hz,1H),7.27–7.24(m,1H),7.24–6.99(m,4H),4.83–4.33(m,2H),3.78(ddt,J＝91.2,12.6,5.9Hz,1H),3.54–3.38(m,2H),3.37(s,1H),3.00–2.71(m,2H),2.57–2.50(m,2H).13C NMR(100MHz,DMSO-d6)δ187.03,166.73,138.24,135.04,134.00,133.46,132.71,132.43,131.50,128.85,127.01,126.78,126.58,47.05,43.95,43.81,29.84,28.53.ESI-MS:m/z 341.02[M-H]-,C18H18N2O3S[342.10].
实施例10.化合物I-s3的制备
操作同实施例8，所不同的是，被水解的化合物为I-z3，白色固体，收率83.3％，熔点:145～150℃。
化合物I-s3波谱数据：1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.48(d,J＝5.4Hz,1H),8.32(d,J＝21.8Hz,1H),7.50(d,J＝5.7Hz,1H),7.29–7.00(m,4H),4.81(s,1H),4.37(s,1H),3.87(s,1H),3.42(t,J＝6.0Hz,1H),3.07(dt,J＝28.4,7.5Hz,2H),2.86(dt,J＝33.0,6.0Hz,2H),2.33(dt,J＝42.0,7.3Hz,2H),1.78(dt,J＝42.2,7.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ174.00,165.55,150.40,146.88,145.97,134.50,132.94,130.57,129.06,127.08,126.83,126.61,120.33,53.44,44.83,44.27,29.40,28.23,24.92.ESI-MS:m/z 355.00[M-H]-,C19H20N2O3S[356.12].
实施例11.化合物I-s4的制备
操作同实施例8，所不同的是，被水解的化合物为I-z4，白色固体，收率83.3％，熔点:122～126℃。
化合物I-s4波谱数据：1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.51(d,J＝5.5Hz,1H),8.36(d,J＝24.2Hz,1H),7.55(t,J＝6.5Hz,1H),7.28–6.99(m,4H),4.81(s,1H),4.34(dd,J＝30.0,7.5Hz,2H),4.02–3.69(m,1H),3.41(t,J＝6.1Hz,1H),2.86(d,J＝35.7Hz,2H),1.40(dd,J＝44.9,7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.26,165.93,150.00,146.75,144.67,134.53,133.04,131.53,129.05,127.09,126.95,126.80,121.67,44.52,44.09,42.19,29.39,17.70.ESI-MS:m/z 341.08[M-H]-,C18H18N2O3S[342.10].
实施例12.化合物I-s5的制备
操作同实施例8，所不同的是，被水解的化合物为I-z5，白色固体，收率81.25％，熔点:167～171℃。
化合物I-s5波谱数据：1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),8.60(d,J＝5.4Hz,1H),8.45(d,J＝17.4Hz,1H),7.87(dd,J＝15.7,5.5Hz,1H),7.33–6.98(m,4H),4.84(s,1H),4.47(s,1H),3.90(s,1H),3.50(s,1H),2.90(d,J＝28.6Hz,2H),1.47(s,3H),1.30(s,3H).13C NMR(100MHz,DMSO-d6)δ174.02,165.54,150.41,146.87,145.98,134.50,132.93,130.55,129.06,127.09,126.83,126.62,120.31,53.42,44.82,44.27,29.39,28.23,24.90.ESI-MS:m/z355.10[M-H]-,C19H20N2O3S[356.12].
实施例13.化合物I-s6的制备
操作同实施例8，所不同的是，被水解的化合物为I-z6。白色固体，收率75.27％，熔点:118～121℃。
化合物I-s6波谱数据：1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.48(d,J＝5.5Hz,1H),8.37(d,J＝19.6Hz,1H),7.31–7.10(m,5H),4.82(s,1H),4.40(s,1H),3.89(s,1H),3.43(t,J＝5.6Hz,1H),2.87–2.81(m,2H),2.29–2.16(m,2H),2.13–1.96(m,2H),1.95–1.73(m,2H).13C NMR(100MHz,DMSO-d6)δ174.47,165.81,149.85,146.84,145.05,134.52,133.06,131.05,129.06,127.08,126.96,126.80,120.88,55.30,51.37,44.55,44.11,32.08,29.39,16.71,15.37.ESI-MS:m/z 367.06[M-H]-,C20H20N2O3S[368.12].
实施例14.中间体(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(4-巯基吡啶-3-基)甲酮(II-2)的制备中间体(4-氯吡啶-3-基)(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)甲酮(II-1)的制备
冰浴条件下，将4-氯烟酸(1.0g，6.37mmol)、HATU(3.63g，9.5mmol)溶于20mL二氯甲烷中，将DIEA(1.65g，12.74mmol，2.11mL)缓慢滴加到上述溶液中，继续冰浴搅拌活化1h，缓慢滴加苯并吗啉(1.00g，7.64mmol，0.94mL)撤去冰浴，室温搅拌反应5h；TLC监测反应完全后，减压蒸除溶剂，残余物加入20mL乙酸乙酯，先后用饱和NaHCO3、1mol/L稀盐酸、饱和NaCl溶液水洗(20mL×2次)，合并有机相，无水硫酸钠干燥，过滤。减压浓缩后产物经快速柱层析(乙酸乙酯：石油醚＝1:1)得到中间体II-1，为白色固体，收率39.0％，熔点:122～124℃。1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.62(d,J＝23.1Hz,1H),7.63(d,J＝70.6Hz,1H),7.03(d,J＝65.4Hz,3H),6.43(d,J＝74.6Hz,1H),4.32(s,2H),3.73(d,J＝82.2Hz,2H).ESI-MS:m/z 275.2[M+H]+,C14H11ClN2O2[274.05]
中间体(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(4-巯基吡啶-3-基)甲酮(II-2)的制备
将中间体II-1(1g，3.65mmol)和九水合硫化钠(1.75g，7.3mmol)溶解在约5mL DMF中，在微波反应仪中130℃条件下反应30min；待反应结束后，将反应体系冷却至室温，加入30mL清水，用乙酸乙酯(20mL×3次)萃取，取水相，然后用1mol/L稀盐酸调节pH至4～5，出现沉淀，搅拌15min后，过滤，滤饼用清水洗涤，干燥，得中间体II-2，为橙色固体，收率39.3％，熔点:102～103℃。1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.32(d,J＝8.2Hz,1H),7.97(s,1H),7.65(s,1H),7.28(d,J＝6.6Hz,1H),6.99(d,J＝54.6Hz,3H),4.34(s,2H),3.59(d,J＝24.3Hz,2H).ESI-MS:m/z 271.3[M-H]-,C14H12N2O2S[272.06].
实施例15.化合物II-z1的制备
将中间体II-2(0.5g，1.84mmol)与K2CO3(0.51g，3.7mmol)混合于50mL圆底烧瓶中，用约15mL DMF溶解，室温搅拌15min后，再逐滴加入溴乙酸甲酯(0.42g，2.76mmol)，45℃回流反应6h；TLC监测，待反应完全后，冷却至室温，加入乙酸乙酯20mL，用饱和NaCl溶液水洗(30mL×3次)，合并有机相，无水硫酸钠干燥，过滤，取滤液，减压蒸去溶剂。减压浓缩后产物经快速柱层析(乙酸乙酯：石油醚＝1:1)得到目标化合物II-z1。油状物，收率57.0％。
化合物II-z1波谱数据：1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝5.5Hz,1H),8.43(s,1H),7.44(d,J＝5.5Hz,1H),7.19–6.59(m,4H),4.39(s,2H),4.17(s,2H),3.82(s,2H),3.66(s,3H).13C NMR(100MHz,DMSO-d6)δ169.43,165.26,150.34,147.64,146.74,145.87,130.77,126.44,125.48,123.94,120.81,120.21,117.48,66.32,53.06,32.84.ESI-MS:m/z345.3[M+H]+,C17H16N2O4S[344.08].
实施例16.化合物II-z2的制备
操作同实施例15，所不同的是，使用的酯为3-溴丙酸甲酯。油状物，收率55.1％。
化合物II-z2波谱数据：1H NMR(400MHz,DMSO-d6)δ8.49(d,J＝5.5Hz,1H),8.44(s,1H),7.48(d,J＝5.6Hz,1H),7.19–6.48(m,4H),4.36(s,2H),3.80(s,2H),3.61(s,3H),3.29(t,J＝7.0Hz,2H),2.65(d,J＝7.1Hz,2H).13C NMR(100MHz,DMSO-d6)δ171.81,165.41,150.42,147.80,146.80,145.82,131.04,126.41,125.49,123.80,120.49,120.12,117.43,66.21,52.09,33.23,25.85,19.12.ESI-MS:m/z 359.3[M+H]+,C18H18N2O4S[358.10].
实施例17.化合物II-z3的制备
操作同实施例15，所不同的是，使用的酯为4-溴丁酸甲酯，油状物，收率55.5％。
化合物II-z3波谱数据：1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝4.9Hz,1H),8.44(s,1H),7.45(d,J＝5.5Hz,1H),7.12–6.51(m,4H),4.37(s,2H),3.82(s,2H),3.59(s,3H),3.08(d,J＝7.5Hz,2H),2.41(t,J＝7.2Hz,2H),1.77(t,J＝7.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ173.15,165.48,150.29,147.84,146.85,146.09,131.07,129.14,126.40,125.51,123.75,120.29,117.42,66.23,65.50,51.86,32.44,29.50,24.00.ESI-MS:m/z 373.1[M+H]+,C19H20N2O4S[372.11].
实施例18.化合物II-z4的制备
操作同实施例15，所不同的是，使用的酯为2-溴丙酸甲酯，白色固体，收率53.2％，熔点:115～117℃。
化合物II-z4波谱数据：1H NMR(400MHz,DMSO-d6)δ8.52(d,J＝5.5Hz,1H),8.47(s,1H),7.55(d,J＝5.5Hz,1H),7.15–6.56(m,4H),4.56–4.49(m,1H),4.39(s,2H),3.79(d,J＝33.2Hz,2H),3.65(s,3H),1.45(d,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.25,165.16,150.41,147.99,146.81,144.41,131.45,126.48,125.45,123.95,122.22,120.15,117.50,66.23,53.13,42.02,17.48.ESI-MS:m/z 359.2[M+H]+,C18H18N2O4S[358.10].
实施例19.化合物II-z5的制备
操作同实施例15，所不同的是，使用的酯为2-溴代异丁酸甲酯，油状物，收率51.17％。
化合物II-z5波谱数据：1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.57(d,J＝5.4Hz,1H),7.26(s,1H),7.15–6.14(m,4H),4.42(s,2H),3.68(s,5H),1.56–1.35(m,6H).13C NMR(100MHz,DMSO-d6)δ173.80,165.28,150.51,141.16,134.41,126.52,126.03,125.50,124.23,119.99,117.42,66.07,53.35,51.41,30.48,26.36,14.55.ESI-MS:m/z 373.2[M+H]+,C19H20N2O4S[372.11].
实施例20.化合物II-z6的制备
操作同实施例15，所不同的是，使用的酯为1-溴环丁羧酸乙酯，油状物，收率58.74％。
化合物II-z6波谱数据：1H NMR(400MHz,DMSO-d6)δ8.47(d,J＝9.3Hz,2H),7.20–6.55(m,5H),4.41(s,2H),4.13(q,J＝7.1Hz,2H),3.85(s,2H),2.82(q,J＝10.3,8.2Hz,2H),2.14(d,J＝24.4Hz,2H),2.08–1.84(m,2H),1.12(t,J＝6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.82,165.06,150.36,148.30,146.92,144.70,130.87,126.52,125.50,123.86,121.09,120.02,117.49,66.24,62.12,51.34,32.19,16.64,14.29.ESI-MS:m/z399.3[M+H]+,C21H22N2O4S[398.13].
实施例21.化合物II-s1的制备
将化合物II-z1(0.2g)溶于5mL甲醇和2.5mL四氢呋喃的混合溶液中，搅拌溶解，将一水合氢氧化锂溶于少量水后，缓慢滴加到上述溶液中，常温下搅拌反应12h；TLC监测，待反应完全后，加入5mL清水，减压旋蒸除去体系中的甲醇和四氢呋喃，滴加1mol/L稀盐酸将溶液pH调至5～6，析出固体，过滤，清水洗涤，干燥，得目标化合物II-s1。黄色固体，收率83.3％，熔点:120～121℃。
化合物II-s1波谱数据：1H NMR(400MHz,DMSO-d6)δ10.48(s,1H),9.17(d,J＝1.0Hz,1H),8.97(s,1H),8.57(d,J＝5.7Hz,1H),8.40(d,J＝5.5Hz,1H),8.01(dd,J＝5.6,1.1Hz,1H),7.93–7.91(m,1H),6.56(s,1H),3.87(s,2H),3.51–3.36(m,4H).ESI-MS:m/z328.94[M-H]-,C16H14N2O4S[330.07].
实施例22.化合物II-s2的制备
操作同实施例21，所不同的是，被水解的化合物为II-z2，淡黄色固体，收率79.17％，熔点:240～242℃。
化合物II-s2波谱数据：1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.31(d,J＝8.2Hz,1H),7.97(s,1H),7.61(d,J＝42.3Hz,1H),7.28(d,J＝6.6Hz,1H),7.13–6.99(m,1H),6.92(s,2H),4.27(d,J＝52.9Hz,2H),3.59(d,J＝22.4Hz,2H),3.36(s,2H),2.52(d,J＝2.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ186.48,166.44,146.43,138.03,133.11,131.63,126.17,125.51,123.60,120.25,117.22,66.36,44.52.ESI-MS:m/z 342.96[M-H]-,C17H16N2O4S[344.08].
实施例23.化合物II-s3的制备
操作同实施例21，所不同的是，被水解的化合物为II-s3，白色固体，收率88.54％，熔点:180～182℃。
化合物II-s3波谱数据：1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.47(d,J＝5.6Hz,1H),8.44(s,1H),7.47(d,J＝5.5Hz,1H),6.97(dd,J＝41.8,8.0Hz,4H),4.38(s,2H),3.82(s,2H),3.08(t,J＝7.3Hz,2H),2.34(t,J＝7.2Hz,2H),1.76(t,J＝7.5Hz,2H).13CNMR(100MHz,DMSO-d6)δ174.23,165.49,150.27,147.77,146.83,146.26,131.04,126.40,125.52,123.76,120.30,120.10,117.43,66.24,32.77,29.65,24.06.ESI-MS:m/z 356.91[M-H]-,C18H18N2O4S[358.10].
实施例24.化合物II-s4的制备
操作同实施例21，所不同的是，被水解的化合物为II-s4，白色固体，收率88.5％，熔点:226～229℃。
化合物II-s4波谱数据：1H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.49(d,J＝5.6Hz,1H),8.44(s,1H),7.55(d,J＝5.6Hz,1H),7.17–6.57(m,4H),4.40(d,J＝7.1Hz,1H),4.37(d,J＝6.6Hz,2H),3.81(d,J＝87.9Hz,2H),1.43(d,J＝7.1Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.22,165.27,150.29,147.80,146.78,145.28,131.34,126.43,125.50,124.00,122.00,120.19,117.45,66.27,42.48,17.62.ESI-MS:m/z 343.2[M-H]-,C17H16N2O4S[344.08].
实施例25.化合物II-s5的制备
操作同实施例21，所不同的是，被水解的化合物为II-s5，白色固体，收率83.33％，熔点:140～141℃。
化合物II-s5波谱数据：1H NMR(400MHz,DMSO-d6)δ13.19(s,1H),8.57(s,1H),8.54(d,J＝5.4Hz,1H),7.35(s,1H),7.07–6.42(m,4H),4.40(s,2H),3.74(s,2H),1.45(s,6H).13C NMR(100MHz,DMSO-d6)δ175.05,164.90,149.25,147.02,144.41,133.46,126.57,125.44,124.53,124.14,120.09,117.44,66.11,60.23,51.56,21.23,14.56.ESI-MS:m/z357.15[M-H]-,C18H18N2O4S[358.10].
实施例26.化合物II-s6的制备
操作同实施例21，所不同的是，被水解的化合物为II-s6，白色固体，收率86.02％，熔点:177～179℃。
化合物II-s6波谱数据：1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),8.47(d,J＝5.1Hz,2H),7.09(d,J＝5.5Hz,1H),7.07–6.54(m,4H),4.41(s,2H),3.85(s,2H),2.87–2.77(m,2H),2.06(dd,J＝74.6,9.2Hz,4H).13C NMR(100MHz,DMSO-d6)δ174.47,165.18,150.26,148.10,146.88,145.35,130.84,126.49,125.54,123.95,121.02,120.12,117.43,66.28,51.54,32.28,16.64.ESI-MS:m/z 369.41[M-H]-,C19H18N2O4S[370.10].
实施例27.目标化合物的体外靶点抑制活性测试(分两个批次)
测试原理
在稳定表达hURAT1蛋白的HEK293T细胞中，利用14C标记的底物尿酸，检测在不同浓度下的化合物以及阳性对照药物雷西纳德对于hURAT1所介导的底物尿酸的摄入影响，再通过测定细胞摄取的尿酸的放射性强度，来计算各化合物对于该蛋白的抑制作用(IC50)。
实验材料
pcDNA3.1(+)-hURAT1-T2A-eGFP质粒(深圳前海东泽生物科技有限公司)；质粒提取试剂盒(OMEGA生物技术公司)；脂粉Agar(美国OXOID公司)；酵母提取物Yeast Extract(美国OXOID公司)；蛋白胨Tryptone(美国OXOID公司)；氨苄青霉素(美国Sigma公司)；纯化水；甘油(碧云天生物技术有限公司)；胎牛血清(美国Corning公司)；DMEM培养基(美国Corning公司)；DMSO(美国Sigma公司)；96孔微孔板(美国Corning公司)；PBS(美国Corning公司)；HEPES(美国Sigma公司)；14C-Uric acid(美国American Radiolabeled Chemicals公司)。
测试方法
将96孔板与聚-D-赖氨酸溶液(0.1mg/mL)预孵育12小时，以获得更好的细胞粘附性。然后将细胞接种到平板中，当细胞达到90％融合时，将opti和lip 3000分别以5μL/孔和0.15μL/孔相混匀，静置5min；同时将opti、P3000和质粒DNA分别以5μL/孔和0.2μL/孔和500ng/孔相混匀，静置5min；上两步混匀的液体相混匀，室温静置15min；加入到更换了完全培养基的96孔板中。置于37℃，含5％CO2培养箱中培养16-20h，用荧光倒置显微镜观察绿色荧光蛋白EGFP的表达验证转染是否成功，成功后除去培养基，并用PBS洗涤细胞两次。为了评价药物对URAT1的抑制效果，我们以雷西纳德为阳性药，对药物进行了初筛(20uM)，吸收率＝(加药组CPM-空白组CPM)/(模型组CPM-空白组CPM)。并进行了IC50的测定。吸收实验前，吸弃孔内液体，向每孔加入50μl含各种特定浓度化合物(20μM、10μM、5μM、2.5μM、1.25μM)，模型组与空白组不加药物。孵育15分钟后吸弃，后加入含50μM 14C-尿酸的尿酸吸收缓冲液以开始尿酸吸收，置于37℃孵育15min。吸弃孔内液体同时加入100μL冰冷的DPBS洗三次，向每孔加入40μL 0.1M NaOH以裂解细胞。室温裂解30分钟后，向每孔加入0.2mL闪烁液，将板放置于震板机上以260rpm/min震摇15分钟。使用液体闪烁计数仪测定14C-尿酸的放射值(CPM)，重复测定三次，取平均值。
表2.系列I化合物体外靶点抑制活性
表3.系列II化合物体外靶点抑制活性
注：*为第一批次测试结果，其余为第二批次测试结果
结论：结果显示，系列I、II化合物都具有URAT1抑制活性，且多数与雷西纳德相当。当刚性骨架是四氢异喹啉(系列I)时，侧链羧酸邻位为单甲基取代(I-s4)和环丁基取代(I-s6)时活性最佳；当刚性骨架是苯并吗啉(系列II)时，反而是侧链羧酸邻位没有取代基(II-s1、II-s2)时活性最佳。可作为全新结构的药物先导物进一步开发。
实施例28.目标化合物的体内抗痛风活性试验
测试材料和方法
(1)实验动物：雄性昆明小鼠，由山东大学实验动物中心提供。
(2)样品处理：选出靶点抑制活性较好的待测化合物及其相应的酯，临用前用CMC-Na配成适当的浓度。
(3)造模药物：黄嘌呤、氧嗪酸钾。
(4)阳性对照药：Lesinurad
(5)测试方法：将20g左右的雄性昆明小鼠适应性喂养1周，随机分为空白组和模型组，空白组给予灌胃5％CMC-Na溶液0.2mL，模型组灌胃600mg/Kg次黄嘌呤混悬液0.2mL并皮下注射400mg/kg氧嗪酸钾混悬液0.2mL，4小时后进行摘眼球取血，分离上清，进行血尿酸浓度检测。
表4.动物体内活性结果
结论：由表4可以看出所测化合物均具有不同程度降低血尿酸的能力。当侧链是单甲基取代时，两类化合物的酸和酯的形式均活性较好(I-z4：49.00％、I-s4：52.90％、II-z4：39.54％、II-s4：40.93％，Lesinuard：28.80％)，值得进一步的研究。
Claims (7)
1.一种稠杂环吡啶巯乙酸衍生物，具有如下通式I或II所示的结构：
其中，
R1为C1～C5的烷基；R2为-H、C1～C5的烷基。
2.如权利要求1所述的稠杂环吡啶巯乙酸衍生物，其特征在于当R1为
时，R2为-H或-CH3；当R1为
时，R2为-H或-CH2CH3。
3.如权利要求2所述的稠杂环吡啶巯乙酸衍生物，其特征在于是下述结构的化合物之一：
4.如权利要求1所述的稠杂环吡啶巯乙酸衍生物的制备方法，其特征在于通式I的制备方法如下：
以4-氯烟酸为起始原料，在2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)和N,N-二异丙基乙胺(DIEA)的催化下与1,2,3,4-四氢异喹啉缩合反应生成中间体I-1，I-1再与九水合硫化钠微波反应生成中间体(3,4-二氢异喹啉-2(1H)-基)(4-巯基吡啶-3-基)甲酮I-2，接着I-2发生亲核取代反应，得到具备通式I结构且R2为C1～C5烷基的目标化合物，随后在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到具备通式I结构且R2为H的目标化合物；
合成路线一如下：
反应试剂和条件：(i)1,2,3,4-四氢异喹啉，HATU，DIEA，DCM，0℃～RT，5h；(ii)Na2S.9H2O，DMF，微波反应，130℃，30min；(iii)K2CO3，DMF，45℃，6h；(iv)一水合氢氧化锂，THF，MeOH，室温，6h；
其中，R1、R2同权利要求1中通式I所示。
5.如权利要求1所述的稠杂环吡啶巯乙酸衍生物的制备方法，其特征在于通式II的制备方法如下：
以4-氯烟酸为起始原料，在HATU和DIEA的催化下与苯并吗啉缩合反应生成中间体II-1，再以DMF为溶剂与九水合硫化钠微波反应生成中间体(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-基)(4-巯基吡啶-3-基)甲酮II-2，接着Ⅱ-2发生亲核取代反应，得到具备通式Ⅱ结构且R2为C1～C5烷基的目标化合物，随后在四氢呋喃和甲醇的混合溶液中用氢氧化锂水解得到具备通式Ⅱ结构且R2为H的目标化合物；
合成路线二如下：
反应试剂和条件：(i)苯并吗啉，HATU，DIEA，DCM，0℃～RT，5h；(ii)Na2S.9H2O，DMF，微波反应，130℃，30min；(iii)K2CO3，DMF，45℃，6h；(iv)一水合氢氧化锂，THF，MeOH，室温，6h；
其中，R1、R2同权利要求1中通式II所示。
6.权利要求1-3任一所述的稠杂环吡啶巯乙酸衍生物在制备抗痛风的药物中的应用。
7.一种抗痛风药物组合物，包含权利要求1-3任一所述的稠杂环吡啶巯乙酸衍生物和一种或多种药学上可接受载体或赋形剂。
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