WO2019011176A1 - 一种2-三氟甲基苯磺酰胺类衍生物的医药用途 - Google Patents

一种2-三氟甲基苯磺酰胺类衍生物的医药用途 Download PDF

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WO2019011176A1
WO2019011176A1 PCT/CN2018/094615 CN2018094615W WO2019011176A1 WO 2019011176 A1 WO2019011176 A1 WO 2019011176A1 CN 2018094615 W CN2018094615 W CN 2018094615W WO 2019011176 A1 WO2019011176 A1 WO 2019011176A1
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compound
pharmaceutically acceptable
etoac
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mmol
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王亚平
郑国君
刘礼飞
周结波
丁芳
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浙江海正药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • the present invention relates to the field of medicaments for the treatment of hyperuricemia and gout. Specifically, it relates to a pharmaceutical use of a 2-trifluoromethylbenzenesulfonamide derivative.
  • Gout is a chronic metabolic disease characterized by pain caused by hyperuricemia and uric acid monosodium salt (MSU) deposited on joints and other parts.
  • MSU uric acid monosodium salt
  • the main cause is sputum metabolism disorder and/or uric acid excretion disorder. It is estimated that there are more than 20 million gout patients worldwide.
  • the drugs currently used to treat gout are very limited: 1) emergency drugs: colchicine tablets, non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids for pain relief; 2) inhibition of uric acid production: allopurinol, side effects Large; febuxostat, some patients are ineffective; 3) promote uric acid excretion drugs: benzbromarone, etc., easy to cause liver damage, not suitable for patients with renal insufficiency; at the same time, these types of drugs have different degrees of toxic side effects.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • glucocorticoids for pain relief
  • inhibition of uric acid production allopurinol, side effects Large
  • febuxostat some patients are ineffective
  • the URAT1 target inhibitor reduces the reabsorption of uric acid in the kidneys and acts as a stimulating effect, thereby reducing uric acid content.
  • a number of compounds for the treatment of hyperuricemia and gout have been in clinical trials and market stages. Among them, AstraZeneca's lesinurad has been successfully listed as a URAT1 inhibitor, and the company's new-generation URAT1 inhibitor RDEA-3170 has also entered the second phase of clinical practice.
  • the currently disclosed URAT1 inhibitor patents include WO2011046800, WO2011159839, WO2014183555A1, etc., but there are not many that actually enter the clinic. In order to achieve better therapeutic results and better meet market demand, we hope to develop a new generation of highly effective and low-toxic inhibitors against the URAT1 target.
  • JP02001483A discloses a series of 2-trifluoromethylbenzenesulfonamide derivatives for use in agricultural fungicides, but in the preparation of a medicament for inhibiting URAT1, or in the preparation of treatment and/or prevention of abnormal uric acid levels.
  • the use of drugs for characterized disorders has not been reported.
  • the present invention provides a 2-trifluoromethylbenzenesulfonamide derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in the preparation of a medicament for inhibiting URAT1, or for preparing a therapeutic and/or prophylactic uric acid level
  • a drug having an abnormally characterized condition the 2-trifluoromethylbenzenesulfonamide derivative having a structure as shown in formula (I):
  • R 1 is selected from the group consisting of H, F, Cl, Br, CN, nitro, CH 2 F, CHF 2 , CF 3 , NH 2 , OH, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 Alkoxy;
  • X is S or O.
  • R 1 is selected from H, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy; preferably, R 1 is selected from H, Cl, Br, methyl or isobutoxy.
  • the compound of formula (I) may preferably be the following compound:
  • condition characterized by abnormal uric acid level is selected from the group consisting of gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, and Le-naphthalene Syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine - guanine Phosphoribosyltransferase deficiency or the like, preferably gout or hyperuricemia.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the formula (I) of the present invention, and a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, Diluent or excipient.
  • the 2-trifluoromethylbenzenesulfonamide derivative provided by the invention exhibits excellent serum uric acid concentration, has a very good effect on treating hyperuricemia and gout, and can be used for preparing hyperuricemia and gout. medicine.
  • An alkyl group a saturated hydrocarbon group is a hydrocarbon group in which one hydrogen atom is removed from an alkane molecule.
  • Alkoxy group a group in which the corresponding alcohol has one hydrogen atom removed.
  • a cycloalkyl group is a hydrocarbon group in which a hydrogen atom is missing from a cycloalkane molecule.
  • URAT1 Urate Transporter1, uric acid transporter 1.
  • LDA lithium diisopropylamide.
  • a pharmaceutically acceptable salt means a salt which is prepared to be harmless or non-invasive to the human body in order to increase the solubility of the drug or to enhance the stability of the drug.
  • the column chromatography used was a silica gel column, 200 to 300 mesh.
  • the compounds of the present invention can be synthesized using the methods described below and known synthetic methods in the field of synthetic organic chemistry, or variations known to those skilled in the art.
  • Preferred methods include, but are not limited to, the methods described below; the reaction is carried out in a solvent compatible with the reagents and materials employed, as well as the effective conversion; those skilled in the art of organic synthesis can understand the functionality exhibited on the molecule. It should be consistent with the planned transformation; in order to obtain the desired compounds of the invention, a judgement is sometimes required to change the order of the synthetic steps or to select a particular process scheme.
  • the present invention contemplates screening assays for compounds that affect uric acid uptake at the human urate transporter 1 (hURAT1) target.
  • HEK-293T cells stably transfected with human URAT1 (ordered from ATCC) were added to polylysine-coated 96-well plates at 6 ⁇ 10 4 cells/well at 37 ° C, 5% CO 2 , 100% relative humidity Culture in the incubator; pre-warmed HBSS buffer (8g/L NaCl, 0.4g/L KCl, 1g/glucose, 60mg/L KH 2 PO 4 , 47.5mg/L Na 2 ) will be placed in the 96-well plate after at least 12h.
  • IC 50 the half maximal inhibitory concentration
  • the experimental measure is the ability of the compound to inhibit the absorption of uric acid in HEK-293T cells transfected with hURAT1. The lower the IC 50 value.
  • the 2-trifluoromethylbenzenesulfonamide derivatives of the present invention have a significant inhibitory effect on human urate transporter 1 (hURAT1) and can be used for the treatment of disorders associated with abnormal uric acid levels such as hyperuricemia and gout. .

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  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

一种如式(I)所示的2-三氟甲基苯磺酰胺类衍生物作为URAT1抑制剂，特别是作为与尿酸水平异常相关的病症的治疗剂的用途。

Description

一种2-三氟甲基苯磺酰胺类衍生物的医药用途 技术领域
本发明涉及治疗高尿酸血症和痛风相关的药物领域。具体而言，涉及一种2-三氟甲基苯磺酰胺类衍生物的医药用途。
背景技术
痛风是一种慢性代谢性疾病，以高尿酸血症和尿酸单钠盐(MSU)沉积在关节等部位而引起的痛疼为主要特征，主要原因为嘌呤代谢紊乱和/或尿酸排泄障碍。据估计，目前全球痛风患者有2000多万。目前用于治疗痛风的药物非常有限：1)应急药：秋水仙碱片，非甾类抗炎药(NSAIDs)和糖皮质激素，用于缓解疼痛；2)抑制尿酸产生：别嘌呤醇，副作用大；非布索坦，部分患者无效；3)促进尿酸排泄药物：苯溴马隆等，易致肝损伤，不适合肾功能不全患者；同时这几类药物都存在不同程度的毒副作用。
另一方面，随着国民生活水平的提高、寿命的延长、饮食结构的改变(富含核蛋白的食物增多)、肥胖者的增加，以及对本病的重视程度加强等，痛风已不再是国人的罕见病，其患病率较15年前增长约15～30倍。因此，市场目前急需新的治疗痛风药物的出现。
URAT1靶点抑制剂，即尿酸转运酶抑制剂，减少尿酸在肾脏重吸收，起到促排作用，从而降低尿酸含量。目前已有多个治疗高尿酸血症和痛风的化合物处于临床试验和上市阶段。其中阿斯利康公司的lesinurad作为URAT1抑制剂已顺利上市，而该公司新一代URAT1抑制剂RDEA-3170也进入了临床二期。目前公开的URAT1抑制剂专利包括WO2011046800、WO2011159839、WO2014183555A1等，但是真正进入临床的并不多。为了达到更好的治疗效果的目的，更好的满足市场需求，我们希望能开发出新一代的高效低毒的针对URAT1靶点的抑制剂。
目前JP02001483A公开了一系列的2-三氟甲基苯磺酰胺类衍生物，用于农用杀菌剂，但在制备抑制URAT1的药物中的用途，或者在制备治疗和/或预防以尿酸水平异常为特征的病症的药物中的用途尚未见报道。
发明内容
本发明提供了2-三氟甲基苯磺酰胺类衍生物或其药学上可接受的盐、或者药物组合物在制备抑制URAT1的药物中的用途，或者在制备治疗和/或预防以尿酸水平异常为特征的病症的药物中的用途，该2-三氟甲基苯磺酰胺类衍生物具有如式(I)所示的结构:
Figure PCTCN2018094615-appb-000001
其中，R 1选自H、F、Cl、Br、CN、硝基、CH 2F、CHF 2、CF 3、NH 2、OH、C1-C6烷基、C3-C6环烷基或C1-C6烷氧基；X为S或O。
在本发明的进一步优选的实施方案中，其中，R 1选自H、Cl、Br、C1-C6烷基、C3-C6环烷基或C1-C6烷氧基；优选地，R 1选自H、Cl、Br、甲基或异丁氧基。
在本发明的进一步优选的实施方案中，其中，式(I)化合物可以优选为以下化合物：
Figure PCTCN2018094615-appb-000002
Figure PCTCN2018094615-appb-000003
本发明的优选方案，其中所述以尿酸水平异常为特征的病症选自痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症等，优选痛风或高尿酸血症。
本发明的优选方案，其中所述药物组合物含有治疗有效量的本发明通式(I) 所示的化合物及其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明提供的2-三氟甲基苯磺酰胺类衍生物表现出了优异的降血清尿酸浓度，对治疗高尿酸血症和痛风有非常良好的效果，可用于制备治疗高尿酸血症和痛风的药物。
本申请中基团的定义如下：
烷基：即饱和烃基，是烷烃分子中少掉一个氢原子而成的烃基。
烷氧基：即相应的醇少掉一个氢原子而成的基团。
环烷基：是环烷烃分子中少掉一个氢原子而成的烃基。
DMAP：4-二甲氨基吡啶。
URAT1：即Urate Transporter1，尿酸转运子1。
LDA：二异丙基胺锂。
THF：四氢呋喃。
药学上可接受的盐：是指为了增加药物溶解性或为了增强药物的稳定性而将药物制备成对人体无害或无影响的盐。
采用的柱层析为硅胶柱，200～300目。
具体实施方式
以下举例说明，应当说明本发明并不仅仅只限于下述实施例。
本发明的化合物可以使用以下描述的方法和合成有机化学领域的已知合成方法，或者本领域技术人员所知道的变化的方法进行合成。优选的方法包括，但不限于以下所描述的方法；反应在与所应用的试剂和材料以及有效的转化相匹配的溶剂中进行；有机合成领域的技术人员能够理解在分子上表现出的功能性应当与所计划的转化一致；为了得到本发明的所需化合物，有时需要一种判断以改变合成步骤的顺序或者选择一种特定的工艺方案。
实施例中化合物2-氨基-6-氰基苯并噻唑1-A及类似物参考文献Journal of Chemical Research,2006,(12),769-770制备。
实施例中化合物2-氨基-6-氰基苯并噁唑2-A及类似物参考文献Journal of Enzyme Inhibition and Medicinal Chemistry,(2011),26(6),813-818制备。
实施例1
Figure PCTCN2018094615-appb-000004
将化合物2-氨基-6-氰基苯并噻唑1-A(700mg，4mmol)溶于7ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:3，得到化合物1(1.2g，产率82％)。
MS m/z(ESI):384[M+1]； 1HNMR(400MHz,d-DMSO)13.9(s,br,1H),8.27-8.35(m,2H),7.83-7.97(m,4H),7.43(d,J＝7.2Hz,1H).
实施例2
Figure PCTCN2018094615-appb-000005
将化合物2-氨基-6-氰基苯并噁唑2-A(636mg，4mmol)溶于7ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:3，得到化合物2(1.15g，产率78％)。
MS m/z(ESI):368[M+1]； 1HNMR(400MHz,d-DMSO)8.34(d,J＝8.0Hz,1H),8.10(s,1H),7.96(d,J＝8.0Hz,1H),7.82-7.91(m,2H),7.74(d,J＝8.0Hz,1H),7.43(d,J＝8.0Hz,1H).
实施例3
Figure PCTCN2018094615-appb-000006
将化合物2-氨基-4-甲基-6-氰基苯并噻唑3-A(756mg，4mmol)溶于8ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:2，得到化合物3(1.25g，产率79％)。
MS m/z(ESI):398[M+1]； 1HNMR(400MHz,d-DMSO)13.76(s,br,1H),8.28(d,J＝8.0Hz,1H),8.20(s,1H),7.99(d,J＝8.0Hz,1H),7.86-7.91(m,2H),7.70(s,1H),2.43(s,3H).
实施例4
Figure PCTCN2018094615-appb-000007
将化合物2-氨基-5-氰基苯并噁唑4-A(636mg，4mmol)溶于7ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:3，得到化合物4(1.07g，产率73％)。
MS m/z(ESI):368[M+1]； 1HNMR(400MHz,d-DMSO)8.28(d,J＝7.6Hz,1H),7.79(d,J＝7.6Hz,1H),7.74(t,J＝7.6Hz,1H),7.64((t,J＝7.6Hz,1H),7.48(s,1H),7.31-7.37(m,2H).
实施例5
Figure PCTCN2018094615-appb-000008
将化合物2-氨基-6-溴-4-氰基苯并噻唑5-A(1.02g，4mmol)溶于10ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)， 加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:2，得到化合物5(1.16g，产率63％)。
MS m/z(ESI):462[M+1]；1HNMR(400MHz,d-MeOH)8.27(d,J＝7.2Hz,1H),7.96(J＝2.0Hz,1H),7.78(d,J＝7.2Hz,1H),7.67(d,J＝2.0Hz,1H),7.60-7.66(m,2H).
实施例6
Figure PCTCN2018094615-appb-000009
将化合物2-氨基-6-异丁氧基-7-氰基苯并噻唑6-A(988mg，4mmol)溶于10ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:3，得到化合物6(1.38g，产率76％)。
MS m/z(ESI):456[M+1]； 1HNMR(400MHz,CDCl3)8.49(d,J＝8.4Hz,1H),8.14(J＝9.2Hz,1H),7.84(d,J＝7.6Hz,1H),7.78-7.81(m,1H),7.70-7.74(m,1H),7.01(d,J＝9.2Hz,1H),3.86(d,J＝6.4Hz,2H),2.13-2.20(m,1H),1.06(d,J＝6.8Hz,6H).
实施例7
Figure PCTCN2018094615-appb-000010
将化合物2-氨基-7-溴-5-氰基苯并噁唑7-A(952mg，4mmol)溶于10ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)， 加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:2，得到化合物7(1.09g，产率61％)。
MS m/z(ESI):446[M+1]； 1HNMR(400MHz,d-DMSO)8.37(d,J＝7.6Hz,1H),7.98(s,1H),7.95(d,J＝7.6Hz,1H),7.85-7.92(m,1H),7.81-7.83(m,1H),7.70(s,1H).
实施例8
Figure PCTCN2018094615-appb-000011
将化合物2-氨基-4-溴-6-氰基苯并噁唑8-A(952mg，4mmol)溶于10ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:2，得到化合物8(1.14g，产率64％)。
MS m/z(ESI):446[M+1]； 1HNMR(400MHz,d-DMSO)8.38(d,J＝8.0Hz,1H),7.79(d,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H),7.65-7.69(m,3H).
实施例9
Figure PCTCN2018094615-appb-000012
将化合物2-氨基-4-甲基-6-氰基苯并噁唑9-A(692mg，4mmol)溶于7ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g， 4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:2，得到化合物9(1.28g，产率84％)。
MS m/z(ESI):382[M+1]； 1HNMR(400MHz,d-DMSO)8.38(d,J＝8.0Hz,1H),7.75-7.82(m,2H),7.65-7.68(m,1H),7.56(s,1H),7.31(s,1H),2.25(s,3H).
实施例10
Figure PCTCN2018094615-appb-000013
将化合物2-氨基-4-氰基-6-异丁氧基苯并噻唑10-A(988mg，4mmol)溶于10ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:3，得到化合物10(1.42g，产率78％)
MS m/z(ESI):456[M+1]； 1HNMR(400MHz,d-DMSO)8.24(d,J＝7.6Hz,1H),7.92(d,J＝7.6Hz,1H),7.73-7.85(m,2H),7.72(s,1H),7.35(s,1H),3.77(d,J＝6.4Hz,2H),1.96-2.03(m,1H),0.97(s,3H),0.95(s,3H).
实施例11
Figure PCTCN2018094615-appb-000014
将化合物2-氨基-6-氰基-5-异丁氧基苯并噁唑11-A(924mg，4mmol)溶于10ml无水THF，冷却至-20℃左右，缓慢滴加LDA/THF溶液(4.8mL,1mmol/ml，1.2eq)，加完后在该温度下继续搅拌0.5h，加入2-三氟甲基苯-1磺酰氯(1.17g，4.8mmol,1.2eq)，加完后在0℃下继续搅拌2小时。乙酸乙酯萃取，粗品经硅胶柱层析分离纯化，洗脱液为石油醚:乙酸乙酯(V/V)＝1:2，得到 化合物11(1.39g，产率79％)
MS m/z(ESI):440[M+1]； 1HNMR(400MHz,CDCl3)8.22(d,J＝7.6Hz,1H),8.07(d,J＝7.6Hz,1H),7.95(t,J＝7.6Hz,1H),7.84(t,J＝7.6Hz,1H),7.31(s,br,1H),7.08(s,1H),6.81(s,1H),3.84(d,J＝6.0Hz,2H),2.14-2.21(m,1H),1.08(s,3H),1.06(s,3H).
活性评价
为了了解本发明化合物的降尿酸活性，本发明设计了人尿酸盐转运子1(hURAT1)靶点上影响尿酸吸收的化合物筛选试验。
人尿酸盐转运子1(hURAT1)靶点上影响尿酸吸收的化合物筛选试验
试验步骤：
hURAT1转染细胞中 14C标记的尿酸吸收：
稳定转染人URAT1的HEK-293T细胞(从ATCC订购)，以6×10 4细胞/孔加入多聚赖氨酸包被的96孔板，于37℃、5％CO 2、100％相对湿度培养箱中培养；至少12h以后将铺好的96孔板用预热的HBSS缓冲液(8g/L NaCl，0.4g/LKCl，1g/葡萄糖，60mg/LKH 2PO 4，47.5mg/L Na 2HPO 4，pH＝7.2)200μl/孔洗三遍，最后一次去掉板内所有的缓冲液；每孔加入50μL的无Cl离子HBSS缓冲液，其中含尿酸(0.1μCi/孔)以及不同浓度的待测化合物，37℃孵育5min；5min后，弃孵育溶液并加入100μl预冷的无Cl离子HBSS缓冲液停止尿酸吸收；再用这种缓冲液洗三遍，最后一次去掉板内所有的缓冲液，加入50μL/孔lysis缓冲液(购自美国abcam公司)，震荡10min，600rpm；震荡后取45μL上清液于另一96孔板，于每孔加入150μL/孔Ultima Gold TM XR scintillation cocktail(闪烁液，购自PERKIN ELMER)震荡10min，600rpm；于液体闪烁/发光计数仪(MicroBeta2，购自PERKIN ELMER)上读取数值，分析数据。
试验结果：
IC 50，即half maximal inhibitory concentration，半最大抑制浓度，它是用来衡量药物诱导凋亡的能力，实验衡量的是化合物抑制转染hURAT1的HEK-293T细胞尿酸吸收的能力，抑制能力越强，IC 50值越低。本筛选中，它是根据样品(对照品苯溴马隆(购自阿拉丁，纯度大于99％)及本发明化合物 1-11)在10种不同浓度(即20μM、5μM、1.25μM、0.3125μM、0.07831μM、0.01953μM、0.00488μM、0.00122μM、0.00031μM、0.00008μM)条件下基于上文试验测试对受体的抑制情况计算出来的。
各化合物IC 50值如下表所示：
化合物 IC 50(nM)
苯溴马隆 407
1 4
2 1
3 9
4 110
5 119
7 54
8 21
9 18
10 347
11 341
结论：本发明2-三氟甲基苯磺酰胺类衍生物对人尿酸盐转运子1(hURAT1)具有明显的抑制作用，可用于治疗高尿酸血症和痛风等与尿酸水平异常相关的病症。
Figure PCTCN2018094615-appb-000015

Claims (7)

  1. Figure PCTCN2018094615-appb-100001
  2. 如权利要求1-3任一项所述的用途，其特征在于，所述的药物组合物含有治疗有效量的通式(I)所示的化合物及其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  3. 一种抑制URAT1，或者治疗和/或预防以尿酸水平异常为特征的病症的方法，包括施用式(I)所示的化合物或其药学上可接受的盐、或者含有式(I)所示的化合物或其药学上可接受的盐的药物组合物：
    Figure PCTCN2018094615-appb-100002
    其中，R 1选自H、F、Cl、Br、CN、硝基、CH 2F、CHF 2、CF 3、NH 2、OH、C1-C6烷基、C3-C6环烷基或C1-C6烷氧基；X为S或O。
  4. 如权利要求6所述的方法，其特征在于，所述以尿酸水平异常为特征的病症选自痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症，优选痛风或高尿酸血症。
  5. 如权利要求6所述的方法，其特征在于，R 1选自H、Cl、Br、C1-C6烷基、C3-C6环烷基或C1-C6烷氧基；优选地，R 1选自H、Cl、Br、甲基或异丁氧基。
  6. 如权利要求6-8任一项的方法，其特征在于，式(I)所示的化合物选自：
    Figure PCTCN2018094615-appb-100003
    Figure PCTCN2018094615-appb-100004
  7. 如权利要求6-8任一项所述的方法，其特征在于，所述的药物组合物含有治疗有效量的通式(I)所示的化合物及其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
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