CN101903352A - 取代的3-羟基吡啶系化合物及其药物组合物 - Google Patents
取代的3-羟基吡啶系化合物及其药物组合物 Download PDFInfo
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- CN101903352A CN101903352A CN2007801019126A CN200780101912A CN101903352A CN 101903352 A CN101903352 A CN 101903352A CN 2007801019126 A CN2007801019126 A CN 2007801019126A CN 200780101912 A CN200780101912 A CN 200780101912A CN 101903352 A CN101903352 A CN 101903352A
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- hydroxypyridine
- ethyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及式(I)的新颖的治疗化合物或其药学上可接受的盐；含有它们的药物组合物；所述化合物作为治疗药物的应用；以及所述化合物在制备特定的治疗药物中的应用，其中R1选自由C2-8烷基组成的组，R2独立地选自由C1-8烷基组成的组，R3独立地选自由H和C1-8烷基组成的组，R4独立地选自由C1-8烷基组成的组。本发明还涉及包括给药所述化合物的治疗方法。所述的新颖的化合物用于伴随有不正常的胰岛素受体信号传导的年龄相关的障碍的治疗。
Description
技术领域
本发明涉及新颖的治疗化合物或其药学上可接受的盐、含有它们的药物组合物、所述化合物作为治疗药物的应用以及所述化合物在制备特定的治疗药物中的应用。本发明还涉及包括给药所述化合物的治疗方法。所述的新颖的化合物用于伴随有不正常的胰岛素受体信号传导的年龄相关的障碍的治疗。
背景技术
3-羟基吡啶系化合物是一类市场上可以买到的药物。RF专利2168992、2168993、2185826和2190404公开了2-乙基-6-甲基-3-羟基吡啶，其用于治疗关节炎、局部缺血、代谢综合症和动脉粥样硬化。
由于其亲水的性质，2-乙基-6-甲基-3-羟基吡啶具有有限的转运至神经组织和大脑的能力。因而，渴望开发具有增强的亲脂性的新型3-羟基吡啶类化合物。
本发明的目的是提供新颖的被取代的3-羟基吡啶系化合物或其药学上可接受的盐，以及其药物组合物。
发明内容
本发明提供式(I)所示的化合物或其药学上可接受的盐，
式(I)
其中
R1选自由C2-8烷基组成的组，
R2独立地选自由C1-8烷基组成的组，
R3独立地选自由H和C1-8烷基组成的组，
R4独立地选自由C1-8烷基组成的组。
术语“药学上可接受的盐”指无毒的酸加成盐。本发明的药学上可接受的盐是通过将式(I)所示的化合物与药学上可接受的酸由本领域公知的方法进行反应来制备的。这样的盐包括但不限于盐酸盐、氢溴酸盐、琥珀酸盐、富马酸盐、苹果酸盐和乙酸盐。优选地，本发明药学上可接受的盐选自由盐酸盐、琥珀酸盐、富马酸盐、L-苹果酸盐、酮戊二酸盐和柠檬酸盐所组成的组。
本文使用的术语“C2-8烷基”在任何情况下均指具有2-8个碳原子的直链或支链基团，除了对其链的长度进行限定，其包括但不限于乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、正戊基、异戊基、新戊基、己基和辛基，及其简单的脂肪族异构体。
本文使用的术语“C1-8烷基”在任何情况下均指具有1-8个碳原子的直链或支链基团，除了对其链的长度进行限定，其包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、正戊基、异戊基、新戊基、己基和辛基，及其简单的脂肪族异构体。
本发明优选的化合物包括2-乙基-4，6-二甲基-3-羟基吡啶，琥珀酸盐(1∶1)；和2-乙基-4，5，6-三甲基-3-羟基吡啶，琥珀酸盐(1∶1)。
进一步地，本发明提供包含式(I)所示的化合物或其药学上可接受的盐以及药学上可接受的载体的药物组合物，
式(I)
其中，
R1选自由C2-8烷基组成的组，
R2独立地选自由C1-8烷基组成的组，
R3独立地选自由H和C1-8烷基组成的组，
R4独立地选自由C1-8烷基组成的组。
术语“药学上可接受的载体”指一种或多种相容的固体或液体填充剂、稀释剂或封装物质，其适宜于给药至哺乳动物(优选为人)身体的任何部位。
本发明的组合物通过本领域公知的方法按照可接受的制药步骤进行制备，例如按照Remington′s Pharmaceutical Sciences，第17版，Alfonso R.Gennaro，Mack出版公司，Easton，Pa.，第18版(1990)描述的制药步骤。
根据本发明的式(I)所示的化合物或其药学上可接受的盐，其以自由碱或与药学上可接受的酸形成的盐或其溶液的形式，可以制成合适的剂型，例如按照可接受的制药步骤制成经口、经直肠、经皮、非胃肠、经鼻、经肺给药途径的组合物。根据本发明的药物组合物，其包括所述的化合物和相容的药学上可接受的载体材料或稀释剂，这在本技术领域是公知的。所述的载体可以是适于给药的任何无机或有机的惰性材料，例如水、明胶、阿拉伯胶、乳糖、微晶纤维素、淀粉、羟基乙酸淀粉钠、磷酸氢钙、硬脂酸镁、滑石粉、胶体二氧化硅等。所述的组合物还可以包含其他药物活性物质以及常规的添加剂，例如稳定剂、润湿剂、乳化剂、调味剂、缓冲剂、粘合剂、崩解剂、润滑剂、助流剂、防粘剂、抛射剂等。式(I)所示的化合物或其药学上可接受的盐占组合物总重量的含量在0.1～99％的范围内，优选为0.5～10％。
本发明的组合物可以制成多个单元的剂型。这样的剂型包括但不限于注射剂、滴眼液、喷雾剂、凝胶剂、软膏剂、片剂、胶囊剂、缓释剂型和粉末剂。
根据本发明的式(I)所示的化合物或其药学上可接受的盐可以以治疗有效的量通过任何适宜的途径给药。根据本发明的化合物可被制成固体或液体形式，例如片剂、胶囊剂、粉末剂、糖浆剂、酏剂等，气雾剂、无菌溶液剂、混悬剂或乳剂等。
术语“治疗有效的量”指无毒但足以提供所希望的治疗效果的活性物质的剂量。优选地，式(I)所示的化合物的治疗有效剂量为每个本发明组合物的单元剂型1～500mg。更优选为每个单元剂型50～150mg。
本发明的具体化合物的用量将根据其效能、给药方式、患者的年龄和体重以及要治疗的病症的严重程度而发生变化。例如，所述的药物治疗可以是每天口服给药一次或两次，或频度更低地给药，或间歇地给药。
本发明的化合物和组合物可用于治疗年龄相关性疾病，包括代谢性疾病、神经退行性疾病、炎性障碍和中枢神经系统障碍。优选地，本发明的化合物和组合物用于治疗与受损的胰岛素功能相关的疾病、病症、障碍，其包括对需要这样治疗的哺乳动物给药治疗有效量的式(I)所示的化合物或其药学上可接受的盐的步骤；其中，所述的与受损的胰岛素功能相关的疾病(disease)、病症(condition)或障碍(disorder)选自由糖尿病及其并发症、2型糖尿病、胰岛素抵抗、高血糖症、高胰岛素血症、脂肪酸或甘油血水平升高症、高脂血症、肥胖症、高甘油三脂血症、血脂障碍、X综合症、动脉粥样硬化、多囊卵巢综合症、衰老或代谢综合症所组成的组。
本文使用的术语“治疗疾病”指治疗、控制、预防和/或减少需要治疗的哺乳动物的疾病的一种或多种临床症状(即综合症)。
本发明的哺乳动物非专有的示例包括人及其伴侣动物，例如猫和狗。优选地，所述的哺乳动物为人。
进一步地，本发明提供一种制备式(I)所示的化合物的方法，其包括将式(II)的化合物与氨反应的步骤，
式(II)
其中，
R1选自由C2-8烷基组成的组，
R2独立地选自由C1-8烷基组成的组，
R3独立地选自由H和C1-8烷基组成的组，
R4独立地选自由C1-8烷基组成的组。
具有式(II)的起始化合物可以通过本领域公知的方法进行制备。例如式(II)的化合物可以通过本领域公知的反应进行制备：烷基取代的呋喃和羧酸酐在催化剂(优选为磷酸)存在下进行反应。由2-酰基呋喃制备3-羟基吡啶的反应可以由文献获知：P.Bosshard，C.H.Eugser，Adv.Heterocycl.Chem.7，377， 1966.在本发明优选的实施方式中，这个步骤以无水乙醇作为氨气的溶剂进行反应。所述的反应优选在高压釜中在高温下进行，但所述的反应还可能受到不同条件的影响。通过所得到的3-羟基吡啶与酸在无水介质中反应获得最终的药学上可接受的盐。
提供下面的实施例用于阐述本发明。所述的实施例仅是例证性的，不希望以任何方式限制本发明的范围。
实施例1
2-乙基-4，5，6-三甲基-3-羟基吡啶，琥珀酸盐(1∶1)
(1)2-丙酰基-3，4，5-三甲基呋喃
向已加热至40℃的2，3，4-三甲基呋喃(0.3摩尔，CAS登记号[10599-57-2])和丙酸酐(78.1g，0.6摩尔)的混合物中，慢慢加入85％的磷酸(0.05摩尔)。将该反应混合物加热至60℃，反应2小时。温度降至室温，加入120ml水，再搅拌1小时。分离出有机相并用饱和碳酸钠溶液处理，搅拌24小时，以破坏未反应的酸酐和酸。此后，溶液以氯仿(300ml×3)萃取，然后合并有机相，用Na2SO4干燥、蒸去溶剂得到油状的残留物，得到的油状残留物减压蒸馏，回收沸点在86-89℃(0.6mm)的馏分。得到纯的酮(25.1g，49％)
(2)2-乙基-4，5，6-三甲基-3-羟基吡啶
将20℃下制得的氨气饱和的无水乙醇溶液(50ml)加入到高压釜中，然后向其中加入上面制得的酮(0.36摩尔)。在搅拌下将反应混合物加热至170℃，反应15小时。冷却后，减压蒸去乙醇，以得到油状的残留物，其被加入到2N的氢氧化钠溶液(400ml)中。经过搅拌和充分的研磨后，以氯仿(100ml×4)萃取所述的碱溶液以回收未反应的酮。所述的碱液以浓盐酸中和，以分离出2-乙基-4，5，6-三甲基-3-羟基吡啶。液体以氯仿(200ml×8)萃取，有机相水洗、Na2SO4干燥、过滤、蒸去溶剂得到更多的产品。合并两部分固体，重复地以无水乙醚(250ml×6)进行处理，以分离出存在的氯化物。在浓缩过程中，2-乙基-4，5，6-三甲基-3-羟基吡啶逐渐从醚溶液中结晶(27g，61％)；Rf-0.39(乙酸乙酯)。
(3)目标产品
将琥珀酸(0.1摩尔)在无水乙醇中的饱和溶液加入到2-乙基-4，5，6-三甲基-3-羟基吡啶(0.1摩尔)的无水乙醇溶液中。蒸去乙醇，产品从异丙醇-丙酮中重结晶以进行纯化。元素分析为C14H21NO5(283.3)：计算值％C 59.35，H7.47，N 4.94；测定值％C 59.42，H 7.52，N 4.89。核磁共振氢谱分析确证了所希望的结构。
实施例2
2-乙基-4，6-二甲基-3-羟基吡啶，琥珀酸盐(1∶1)
(1)2-丙酰基-3，5-二甲基呋喃
向已加热至40℃的2，4-二甲基呋喃(0.3摩尔，CAS登记号[3710-43-8])和丙酸酐(78.1g，0.6摩尔)的混合物中，慢慢加入85％的磷酸(0.05摩尔)。将该反应混合物加热至60℃，反应2小时。温度降至室温，加入120ml水，再搅拌1小时。分离出有机相并用饱和碳酸钠溶液处理，搅拌24小时，以破坏未反应的酸酐和酸。此后，溶液以氯仿(300ml×3)萃取，然后合并有机相，用Na2SO4干燥、蒸去溶剂得到油状的残留物，得到的油状残留物减压蒸馏，回收沸点在71-75℃(0.6mm)的馏分。得到纯的酮(19.6g，41％)
(2)2-乙基-4，6-二甲基-3-羟基吡啶
将15℃下制得的氨气饱和的无水乙醇溶液(50ml)加入到高压釜中，然后向其中加入上面制得的酮(0.36摩尔)。在搅拌下将该反应混合物加热至170℃，反应15小时。冷却后，减压蒸去乙醇，得到油状的残留物，将该油状的残留物溶解在2N的氢氧化钠溶液(400ml)中。经过搅拌和充分的研磨后，用氯仿(100ml×4)萃取所述的碱溶液以回收未反应的酮。所述的碱液以浓盐酸中和，以分离出2-乙基-4，6-二甲基-3-羟基吡啶。液体用氯仿(200ml×8)萃取，有机相水洗、Na2SO4干燥、过滤、蒸去溶剂得到更多的产品。合并两部分固体，重复地以无水乙醚(250ml×6)进行处理，以分离出存在的氯化物。在浓缩过程中，2-乙基-4，6-二甲基-3-羟基吡啶逐渐从醚溶液中结晶(29g，67％)；Rf-0.37(乙酸乙酯)。
(3)目标产品
将琥珀酸(0.1摩尔)在无水乙醇中的饱和溶液加入到2-乙基-4，6-二甲基-3-羟基吡啶(0.1摩尔)的无水乙醇溶液中。蒸去乙醇，产品从异丙醇-丙酮中重结晶以进行纯化。元素分析为C13H19NO5(269.3)：计算值％C 57.89，H 7.11，N 5.20；测定值％C 57.92，H 7.19，N 5.12。核磁共振氢谱分析确证了所希望的结构。
实施例3
本实施例说明包含式(I)化合物的注射剂。
| 成分 | 含量 |
| 式(I)的化合物磷酸二钠，美国药典/欧洲药典注射用水，美国药典/欧洲药典 | 200mg调节pH至5.5的量调节体积至4.0ml的量 |
式(I)的化合物溶解于注射用水中至希望的体积，加入0.4M磷酸二钠调节pH值至5。这样，制得了式(I)的化合物浓度为5％的溶液。将该溶液通过无菌级的过滤器(0.2μm)过滤，并且装入安瓿瓶中。
实施例4
本实施例说明包含2-乙基-4，6-二甲基-3-羟基吡啶琥珀酸盐(1∶1)的注射剂。
| 成分 | 含量 |
| 2-乙基-4，6-二甲基-3-羟基吡啶，琥珀酸盐(1∶1)磷酸二钠，美国药典/欧洲药典注射用水，美国药典/欧洲药典 | 100mg调节pH至5.5的量调节体积至4.0ml的量 |
2-乙基-4，6-二甲基-3-羟基吡啶琥珀酸盐(1∶1)溶解于注射用水中至希望的体积，加入0.4M磷酸二钠调节pH至5。这样，制得了2-乙基-4，6-二甲基-3-羟基吡啶、琥珀酸盐(1∶1)的浓度为5％的溶液。将该溶液通过无菌级的过滤器(0.2μm)过滤，并且装入安瓿瓶中。
实施例5
本实施例说明包含2-乙基-4，5，6-三甲基-3-羟基吡啶琥珀酸盐(1∶1)的注射剂。
| 成分 | 含量 |
| 2-乙基-4，5，6-三甲基-3-羟基吡啶琥珀酸盐(1∶1)磷酸二钠，美国药典/欧洲药典注射用水，美国药典/欧洲药典 | 100mg调节pH至5.5的量调节体积至4.0ml的量 |
2-乙基-4，5，6-三甲基-3-羟基吡啶、琥珀酸盐(1∶1)溶解于注射用水中至希望的体积，加入0.4M磷酸二钠调节pH值至5。这样，制得了2-乙基-4，5，6-三甲基-3-羟基吡啶、琥珀酸盐(1∶1)浓度为5％的溶液。将该溶液通过无菌级的过滤器(0.2μm)过滤，并且装入安瓿瓶中。
实施例6
本实施例说明本发明的化合物用于增强胰岛素受体活性的效果。
用5nM的胰岛素；50μM的2-乙基-4，5，6-三甲基-3-羟基吡啶琥、珀酸盐(1∶1)；50μM的2-乙基-4，6-二甲基-3-羟基吡啶、琥珀酸盐(1∶1)；或它们的混合物在含有5mM葡萄糖的磷酸盐缓冲盐水中处理人类肝癌HepG2细胞10分钟。采用PhosphoDetectTM胰岛素受体(pTyr1162/1163)ELISA试剂盒(Calbiochem)，通过受体激酶域的区域中酪氨酸残基1162/1163的磷酸化，来评价胰岛素受体的活性。一般认为，相比于未磷酸化，磷酸化使受体活性增加了约200倍。其结果以对于100nM的胰岛素产生响应的百分比来表示，在表1中表示为平均值±SEM(n＝8)。
表1
| 处理 | 胰岛素受体磷酸化，％ |
| 对照(未处理) | 11±3 |
| 胰岛素，5nM | 24±8* |
| 2-乙基-4，6-二甲基-3-羟基吡啶、琥珀酸盐(1∶1)，50μM | 14±4 |
| 2-乙基-4，5，6-三甲基-3-羟基吡啶、琥珀酸盐(1∶1)，50μM | 13±2 |
| 胰岛素，5nM+2-乙基-4，6-二甲基-3-羟基、吡啶琥珀酸盐(1∶1)，50μM | 56±7*# |
| 胰岛素，5nM+2-乙基-4，5，6-三甲基-3-羟基吡啶、琥珀酸盐(1∶1)，50μM | 62±8*# |
*与对照相比有显著差异(P＜0.05)。#与胰岛素5nM相比有显著差异。
表1显示出本发明的化合物能显著增强胰岛素受体的活性。
实施例7
本实施例说明本发明化合物用于治疗胰岛素抵抗、血脂障碍和糖尿病的效果。
将溶于柠檬酸盐缓冲液(0.05M，pH5.5)的链脲菌素(Sigma公司，圣路易斯，密苏里，美国)注射到雄性白化病Wistar大鼠尾部静脉中，剂量为每千克动物体重35mg，以诱导失代偿性的胰岛素抵抗。葡萄糖水平高于14.0mmol/l的大鼠被用于注射链脲菌素一周后的试验。采用葡萄糖氧化酶法测定空腹血糖浓度；采用双抗体放射免疫分析试剂盒测定血浆胰岛素浓度；采用酶催法测定血浆甘油三酯。
链脲菌素诱导的大鼠被分成三个组：对照大鼠(n＝10)和试验大鼠(n＝20)。对照大鼠每天接受腹腔注射盐水，共7天。试验大鼠每天接受腹腔注射2-乙基-4，6-二甲基-3-羟基吡啶、琥珀酸盐(1∶1)或2-乙基-4，5，6-三甲基-3-羟基吡啶、琥珀酸盐(1∶1)，共7天。在治疗一开始和从治疗开始的第14天测定生化参数。
其结果在表2中表示为平均值±SEM(n＝8)
表2
*与对照相比有显著差异(P＜0.05)。
表2说明了本发明的化合物可用于胰岛素抵抗、血脂障碍和糖尿病的治疗。
Claims (7)
1.一种式(I)所示的化合物或其药学上可接受的盐，
其中
R1选自由C2-8烷基组成的组，
R2独立地选自由C1-8烷基组成的组，
R3独立地选自由H和C1-8烷基组成的组，
R4独立地选自由C1-8烷基组成的组。
2.根据权利要求1所述的化合物，其中，所述的药学上可接受的盐选自由盐酸盐、琥珀酸盐、富马酸盐、L-苹果酸盐、酮戊二酸盐和柠檬酸盐所组成的组。
3.2-乙基-4，6-二甲基-3-羟基吡啶，琥珀酸盐(1∶1)；
2-乙基-4，5，6-三甲基-3-羟基吡啶，琥珀酸盐(1∶1)。
4.一种药物组合物，含有式(I)所示的化合物或其药学上可接受的盐以及药学上可接受的载体，
其中
R1选自由C2-8烷基组成的组，
R2独立地选自由C1-8烷基组成的组，
R3独立地选自由H和C1-8烷基组成的组，
R4独立地选自由C1-8烷基组成的组。
5.一种用于制备式(I)所示的化合物的方法，其包括将式(II)所示的化合物与氨反应的步骤，
其中
R1选自由C2-8烷基组成的组，
R2独立地选自由C1-8烷基组成的组，
R3独立地选自由H和C1-8烷基组成的组，
R4独立地选自由C1-8烷基组成的组。
6.根据权利要求5所述的方法，其中，所述的化合物为2-乙基-3，4-二甲基-3-羟基吡啶或2-乙基-3，4，5-三甲基-3-羟基吡啶。
7.一种用于治疗与受损的胰岛素功能相关的疾病、病症或障碍的方法，其包括对需要这样治疗的哺乳动物给药治疗有效量的权利要求1所述的化合物、其药学上可接受的盐的步骤；其中，所述的与受损的胰岛素功能相关的疾病、病症或障碍选自由糖尿病及其并发症、2型糖尿病、胰岛素抵抗、高血糖症、高胰岛素血症、脂肪酸或甘油的血水平升高症、高脂血症、肥胖症、高甘油三脂血症、血脂障碍、X综合症、动脉粥样硬化、多囊卵巢综合症、衰老或代谢综合症。
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| PCT/RU2007/000715 WO2009078746A1 (en) | 2007-12-18 | 2007-12-18 | Substituted 3 -hydroxypyridines and pharmaceutical compositions thereof |
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| RU2605825C1 (ru) * | 2015-12-01 | 2016-12-27 | Виталий Эдуардович Боровиков | Раствор для внутривенного и внутримышечного введения на основе этилметилгидроксипиридина сукцината и способ его получения |
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| EP2231603A1 (en) | 2010-09-29 |
| WO2009078746A1 (en) | 2009-06-25 |
| ES2408172T3 (es) | 2013-06-18 |
| EA201000832A1 (ru) | 2010-12-30 |
| KR101214353B1 (ko) | 2012-12-20 |
| JP5291721B2 (ja) | 2013-09-18 |
| DK2231603T3 (da) | 2013-06-03 |
| KR20100085192A (ko) | 2010-07-28 |
| CN101903352B (zh) | 2013-07-10 |
| EA017927B1 (ru) | 2013-04-30 |
| US20120270908A1 (en) | 2012-10-25 |
| JP2011506597A (ja) | 2011-03-03 |
| US20100261764A1 (en) | 2010-10-14 |
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