CN1354659A - 新的二苯乙烯化合物 - Google Patents
新的二苯乙烯化合物 Download PDFInfo
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- CN1354659A CN1354659A CN99816644A CN99816644A CN1354659A CN 1354659 A CN1354659 A CN 1354659A CN 99816644 A CN99816644 A CN 99816644A CN 99816644 A CN99816644 A CN 99816644A CN 1354659 A CN1354659 A CN 1354659A
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Abstract
提供口服给药以降低大鼠血糖水平的新的二苯乙烯和苯乙烯类化合物。采用胰岛素抗性大鼠进行了葡萄糖耐量试验,并采用胰岛素抗性、高胰岛素血和高甘油三酯血大鼠进行了降低血清甘油三酯水平试验。这些化合物是口服给药有效的抗糖尿病药,具有降低糖尿病的异常葡萄糖和脂代谢的潜在能力。
Description
发明领域
本发明涉及新的二苯乙烯化合物及其治疗糖尿病的用途。
发明背景
囊状紫檀树(Pterocarpus marsupium Roxb.)(豆科)，也称为印度奇诺树，其叶、花和树胶的提取物一直被传统地用于治疗腹泻、牙痛、发热和泌尿道与皮肤感染。树皮的提取物一直被认为对于治疗糖尿病非常有用。Manickam等在J.Nat.Prod.，1997，60：609-610中报道了由紫檀的心材中分离的天然存在的紫檀芪，即反式-1-(3，5-二甲氧苯基)-2-(4-羟苯基)-乙烯的降血糖活性。然而，此紫檀芪是水不溶性的，并且在治疗糖尿病方面未显示出有效，尤其是在胰岛素存在但不具有活性的情况下。尽管与遗传和环境因素均相关，但是引起糖尿病的原因尚不明确。糖尿病的类型有胰岛素依赖型(I型)和非-胰岛素依赖型(II型)。I型糖尿病是自身免疫性疾病，其致病的自身抗原尚属未知。I型患者需要静脉注射胰岛素来维持生命。II型糖尿病，此为更常见的糖尿病类型，则是由于机体不能制造足够量的胰岛素或者不能恰当利用机体内已产生的胰岛素而导致的代谢障碍。胰岛素分泌和胰岛素抗性被认为是主要缺陷，但是，仍不知道发病机制中所涉及的确切遗传因素。
糖尿病患者通常具有下述一种或多种缺陷：胰腺产生胰岛素量较少；肝脏过度分泌葡萄糖；骨骼肌摄取葡萄糖减少；葡萄糖转运蛋白缺陷；胰岛素受体不敏感；和多糖分解代谢缺陷。除了静脉应用胰岛素外，还有四类口服使用的降糖药：
| 种类 | 批准的药物 | 作用机制 | 缺点 |
| 硫脲类 | 4(第一代)和2(第二代) | 作用于胰腺以释放更多的胰岛素 | 产生胰岛素抗性 |
| 双胍类 | 二甲双胍 | 降低肝脏葡萄糖分泌；增进胰岛素敏感性 | 肝损害，乳酸酸中毒 |
| α-葡糖苷酶抑制剂 | 阿卡糖 | 干预消化过程；减少葡萄糖吸收 | 仅在饭后(post-pradiandio)水平有用 |
| 噻唑烷-二酮 | Troglipzone | 降低胰岛素抗性 | 胰岛素“加量(add-on)”；不能用于心脏病和肝病患者 |
由上表可以看出，目前可利用的治疗糖尿病的每一种药物均有一定的缺点。因而，鉴定和开发治疗糖尿病的新的药物，尤其是可以口服给药的水溶性药物，一直是热点问题。
除了前面讨论的紫檀芪外，Sheehan等从紫檀中分离出了(-)-表儿茶素，并报道其具有降血糖作用，J.Nat.Prod.，1983，46：232。也参见Chakravarthy等，Life Sciences，1981，29：2043-2047。还从紫檀中分离出来其它酚类化合物，Maurya等，J.Nat.Prod.1984，47：179-181；Jahromi等，J.Nat.Prod.，1993，56：989-994；和Maurya等，Heterocycles，1982，19：2103-2107。
发明概述
提供具有下式I的新一类二苯乙烯化合物，
其中R是氢或-CO2Z，Z是氢或阳离子；
和R1、R2和R3各自独立地为H、-OH或-OR4，其中R4是具有1-12个碳原子的直链或支链烷基；前提是当R是氢和R2＝R3＝-OMe时，R1不是-OH。
还提供具有下式II的新一类苯乙烯化合物，
其中R5是氢或甲基；R6和R7独立地为氢或OMe；R8是氢或羟基。
提供用于治疗糖尿病的式I或式II化合物的药物组合物，所述组合物包括在生理可接受载体中的治疗有效量的化合物。
也提供治疗糖尿病的方法，包括对患糖尿病的病人经口给予治疗有效量的式I或式II化合物的步骤。
附图简述
图1显示给予实施例1的化合物对STZ诱导的糖尿病大鼠血糖的影响。
图2显示实施例1的化合物对血胰岛素过多和胰岛素抗性Zucker大鼠葡萄糖耐量的影响。
图3显示实施例1化合物对Zucker大鼠血浆甘油三酯水平的影响。
图4显示实施例1化合物对Zucker大鼠葡萄糖耐量的影响。
图5A、5B和5C分别显示在第0天对Swiss Webster小鼠施用剂量为16.7、167和333mg/kg/体重进行的致死作用研究结果。
优选实施方案描述
通过采用本领域一般公知的合成方法提供式I的二苯乙烯和式II的苯乙烯。具体地，优选其中R2和R3是甲氧基的式I化合物。尤其优选的一类化合物是其中R2和R3是甲氧基、R是CO2Z及R1是OH的化合物。Z代表的阳离子通常是钠、锂、钾或任何其它可经口给予病人的生理适用的阳离子。
特别优选的式II的苯乙稀是那些R6和R7是甲氧基、R8是氢的化合物。式II的另一类优选化合物包括R6和R7是氢、R8是羟基的化合物。
使用本领域已知的方法制备式I和式II化合物。通常，对于式I化合物而言，使适宜的苯甲醛和苯乙酸起始物料缩合，如果需要，然后脱去羧基。
方案I
式II化合物一般由苯甲醛起始物料和(1，1-)亚烷基三苯基正膦通过Wittig反应制备。
方案II
示例性的式I和式II化合物如下：
在药物组合物中，本发明化合物可以与生理可接受的载体结合。特别优选的组合物剂型是：口服给药的胶囊或化合物以水、生理盐水、磷酸盐缓冲液为载体给药的溶液，或者片剂或胶囊形式的冻干粉末，其中还可含有各种填料和粘合剂。组合物中化合物的有效剂量将由本领域普通技术人员加以选择并且根据经验来确定。
本发明化合物非常适用于治疗诸如以存在高水平血糖为特征的糖尿病等疾病，也就是，高血糖性病症如糖尿病，既包括I型也包括II型糖尿病，还包括其它与高血糖有关的病症如肥胖、胆固醇升高、肾有关的病症等。
“治疗”，是指给予化合物后至少降低患有高血糖性病症的患者的血糖水平。给予足够量的化合物，将血糖水平降低至可接受范围，所述可接受范围是指病人正常平均血糖水平的±10％，通常为±8％，和通常为±5％。化合物可用于治疗各种病人，如牲畜、珍稀动物、宠物以及人类，以降低血糖水平。可以使用方便的给药技术将化合物给予患有高血糖病症的病人，所述技术包括静脉内、皮内、肌内、皮下、口服等。然而，特别优选口服给药途径。递送给宿主的剂量有必要取决于化合物递送的途径，但是，一般的剂量范围是5～500mg/70kg人体重，或者代表性地是50～200mg/70kg人体重。
特别关注的是治疗人高血糖病症如糖尿病(包括I型和II型糖尿病)的方法，该方法是将化合物给予患有高血糖病症的人以使病人的血糖水平至少降至人大致正常的血糖范围。
下面的实施例是以举例说明的方式给出的，而不是旨在以任何方式限定本发明。
实施例1
制备2-(4-羟苯基)-3-(3，5-二甲氧苯基)-丙烯酸钠
向3，5-二甲氧苯甲醛(30mM)和对羟苯乙酸(30mM)混合物中加入5mL乙酸酐和2.5mL三乙胺(TEA)。130-140℃搅拌24小时后，冷却混合物至室温，并用25mL浓盐酸终止反应，用CH2Cl2萃取。有机萃取物进一步用1N的NaOH萃取，然后用水洗涤NaOH萃取物，用浓HCl酸化含水层，并用水洗涤得到粗品。粗品用乙醇/水重结晶得到酸I。
为了得到1g脱羧的I，在氮气下，搅拌回流3g铜粉和30mL喹啉4小时。过滤反应混合物，用水稀释并用CH2Cl2萃取。干燥并浓缩有机层，用快速色谱纯化脱羧产物。
为了使酸I转化为标题化合物，室温下向1gI中加入NaOH溶液。摇荡混合物，冷冻干燥得到标题产品的酸式盐，1。
实施例2
制备苯乙烯衍生物的一般步骤
一般步骤：向在-78℃无水THF中的搅拌的Wittig盐溶液(1mM)中加入(双三甲基甲硅烷基)氨基钾(1mM)。N2气下，于-78℃搅拌2小时后，加入HMPA(2mM)和THF中的醛(1mM)，并于室温下搅拌16小时。用水终止反应，用二乙醚提取。用快速色谱纯化产品。
实施例3
参见图1，通过静脉注射链脲霉素(STZ)(40mg/kg/体重)得到STZ-诱导的糖尿病大鼠。注射STZ后72小时测定血糖水平。表现出空腹血糖水平大于200mg/dl的大鼠用于实验。将实施例1的化合物按照20mg/kg/体重的剂量给试验大鼠口服。同时，给予对照组载体PBS(磷酸盐缓冲盐水)。给药后不久即进行葡萄糖耐量试验：给予葡萄糖(2g/kg/体重)，在不同时间点监测血糖水平。结果示于图1。给药后30和60分钟期间，给予试验化合物的大鼠的血糖水平开始下降。
实施例4
参见图2，在Zucker(fa/fa)大鼠中进行葡萄糖耐量试验。将血胰岛素过多和胰岛素抗性Zucker大鼠随机分为两组，其一为测试组，另一为对照组，以检测实施例1的化合物对葡萄糖耐量和胰岛素水平的影响。对6只测试组的大鼠给予实施例1的化合物(20mg/kg/体重/口服)，每日一次，为期三天。对照组饲以等体积的PBS。试验第三天，在给予测试物质后不久，即对前一夜未进食的大鼠进行口服葡萄糖(2g/kg/体重)耐量试验。参见图2，表明实施例1的化合物改善了胰岛素抗性肥胖Zucker大鼠的葡萄糖耐量。
实施例5
参见图3，将12只胰岛素抗性血胰岛素过多的肥胖Zucker(fa/fa)大鼠随机分成测试组和对照组。测试组的6只大鼠在零点接受实施例1的化合物(20mg/kg/体重)。对照组接受等体积PBS。在进食状态监测24小时期间的血浆甘油三酯水平。结果示于图3。实施例1的化合物降低胰岛素抗性血胰岛素过多的和血甘油三酯过多的肥胖Zucker大鼠的血浆甘油三酯水平。
实施例6
参见图4，将12只肥胖的血胰岛素过多和胰岛素抗性Zucker(fa/fa)大鼠随机分成测试组和对照组。给测试组的6只大鼠灌以实施例1的化合物(20mg/kg/体重/口服)，每日一次，为期13天。给对照组灌以等体积PBS。在进行研究的13天期间，每3天或4天间歇监测基础血浆胰岛素水平。结果示于图4，表明在这种动物模型中该化合物对于降低的血浆胰岛素水平有效。
实施例7
将9只健康雄性Swiss Webster小鼠分成3个实验组，每组3只。在实验第0天，第一实验组(图5A)接受剂量为16.7mg/kg/体重，第二实验组(图5B)接受剂量为167mg/kg/体重，第三实验组(图5C)接受剂量为333mg/kg/体重的实施例1的化合物。在整个实验期间，小鼠保持正常进食和饮水。实验中，小鼠处于严密观察之下，监测其行为、肉眼可见的生理机能和死亡/存活状况。图5A、5B和5C显示：在实验期间的整个过程中，这些小鼠的存活率为100％。
Claims (30)
1.式I化合物，
其中，R是氢；和
R1、R2、R3各自独立地为H、-OH、-OR4，其中R4是1-12个碳原子的直链或支链烷基；
前提条件是：当R是H和R2＝R3＝-OMe时，R1不是-OH。
2.权利要求1所述化合物，其中R2和R3是-OMe。
3.权利要求2所述化合物，其中R1是-OMe。
4.权利要求2所述化合物，其中R1是H。
5.权利要求1所述化合物，其中R2和R3是氢，R1是OH。
6.权利要求1所述化合物，其中R2是-OMe，R3是氢，R1是OH。
7.权利要求1所述化合物，其中R2和R3是OH，R1是-OMe。
8.式II化合物，
其中，R5是氢或甲基；R6和R7各自独立地为氢或-OMe，R8为H或OH。
9.权利要求8所述化合物，其中R5和R8是氢，R6和R7为OMe。
10.权利要求8所述化合物，其中R5是甲基，R6和R7为OMe，R8是氢。
11.权利要求8所述化合物，其中R5是甲基，R6和R7为氢，R8是OH。
12.权利要求19-30任一项所述组合物，其适于口服给药。
13.治疗糖尿病的方法，包括将在生理可接受载体中的治疗量的权利要求
19-30任一项所述组合物或其混合物给予患有糖尿病病症的病人的步骤。
14.权利要求13所述方法，其中所述组合物口服给予所述病人。
15.治疗糖尿病的药物组合物，包括在生理可接受载体中治疗有效量的下式化合物
16.权利要求15所述组合物，其中所述组合物适于口服给药。
17.治疗糖尿病的方法，包括将在生理可接受载体中治疗有效量的下式化合物给予患有糖尿病病症的病人的步骤。
18.权利要求17所述方法，其中所述化合物口服给予所述病人。
19.治疗糖尿病的药物组合物，包括治疗有效量的下式化合物或其混合物和生理可接受载体：
其中R是氢或-CO2Z，Z是H或者阳离子；和
R1、R2、R3各自独立地为H、-OH、-OR4，其中R4是1-12个碳原子的直链或支链烷基；
前提条件是：当R是H和R2＝R3＝-OMe时，R1不是-OH。
20.权利要求19所述组合物，其中R2和R3是OMe。
21.权利要求20所述组合物，其中R是-CO2Z，R1是OH。
22.权利要求20所述组合物，其中R是H，R1是OMe。
23.权利要求20所述组合物，其中R是H，R1是H。
24.权利要求19所述组合物，其中R2和R3是H，R1是OH。
25.权利要求19所述组合物，其中R2是OMe，R3和R是H，R1是OH。
26.权利要求19所述组合物，其中R2和R3是OH，R是H，R1是OMe。
27.治疗糖尿病的药物组合物，包括治疗有效量的下式化合物或其混合物和生理可接受载体：
其中，R5是氢或甲基；R6和R7各自独立地为氢或-OMe，R8为H或OH。
28.权利要求27所述组合物，其中R5和R8是氢，R6和R7为OMe。
29.权利要求27所述组合物，其中R5是甲基，R6和R7为OMe，R8是氢。
30.权利要求27所述组合物，其中R5是甲基，R6和R7为氢，R8是OH。
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| EP (1) | EP1178788A4 (zh) |
| JP (1) | JP2002544227A (zh) |
| KR (1) | KR100598638B1 (zh) |
| CN (1) | CN1194674C (zh) |
| AU (1) | AU778767C (zh) |
| CA (1) | CA2373603A1 (zh) |
| HK (1) | HK1046642B (zh) |
| MX (1) | MXPA01011760A (zh) |
| WO (1) | WO2000069430A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100384801C (zh) * | 2006-06-23 | 2008-04-30 | 中国科学院广州化学研究所 | (e)-3,5-二甲氧基-4＇-羟基二苯乙烯的合成方法 |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7323496B2 (en) | 1999-11-08 | 2008-01-29 | Theracos, Inc. | Compounds for treatment of inflammation, diabetes and related disorders |
| MXPA02007514A (es) * | 2000-02-04 | 2004-02-26 | Calyx Therapeutics Inc | Compuestos novedosos de difeniletileno. |
| US6410596B1 (en) * | 2000-08-16 | 2002-06-25 | Insmed Incorporated | Compositions containing hypoglycemically active stillbenoids |
| US6552085B2 (en) | 2000-08-16 | 2003-04-22 | Insmed Incorporated | Compositions containing hypoglycemically active stilbenoids |
| CN1398838A (zh) | 2001-07-26 | 2003-02-26 | 中国人民解放军军事医学科学院放射医学研究所 | 二苯乙烯类化合物制备以及它们在治疗和预防糖尿病中的应用 |
| JP4781580B2 (ja) * | 2001-09-26 | 2011-09-28 | 日本メナード化粧品株式会社 | コラゲナーゼ阻害剤 |
| AU2004312072B2 (en) | 2003-12-29 | 2011-06-23 | President And Fellows Of Harvard College | Compositions for treating or preventing obesity and insulin resistance disorders |
| US8017634B2 (en) | 2003-12-29 | 2011-09-13 | President And Fellows Of Harvard College | Compositions for treating obesity and insulin resistance disorders |
| CN1723884A (zh) * | 2004-07-21 | 2006-01-25 | 中国人民解放军军事医学科学院放射医学研究所 | 顺式－1，2－取代的二苯乙烯衍生物用于制备治疗或预防糖尿病的药物的用途 |
| WO2006138418A2 (en) | 2005-06-14 | 2006-12-28 | President And Fellows Of Harvard College | Improvement of cognitive performance with sirtuin activators |
| FR2904311B1 (fr) | 2006-07-28 | 2013-01-11 | Clariant Specialty Fine Chem F | Nouveau procede de synthese de derives (e) stilbeniques perm permettant d'obtenir le resveratrol et le piceatannol |
| FR2921921B1 (fr) | 2007-10-03 | 2011-08-19 | Clariant Specialty Fine Chem F | Procede de synthese de composes polyhydroxystilbeniques. |
| CN107324976B (zh) * | 2017-07-28 | 2020-06-16 | 安徽理工大学 | 一种制备(E)-β-烷基苯乙烯类化合物的方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5314693A (en) * | 1992-02-07 | 1994-05-24 | Kioritz Corporation | Pest control chemicals against pine wood nematodes |
| US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
| US5770620A (en) * | 1995-06-19 | 1998-06-23 | Ontogen Corporation | Aryl acrylic acid derivatives useful as protein tyrosine phosphatase inhibitors |
| US5827898A (en) * | 1996-10-07 | 1998-10-27 | Shaman Pharmaceuticals, Inc. | Use of bisphenolic compounds to treat type II diabetes |
| FR2778337B1 (fr) * | 1998-05-05 | 2001-08-31 | Inst Nat Sante Rech Med | Antagonistes des ligands du recepteur des arylhydrocarbures |
-
1999
- 1999-05-18 EP EP99924332A patent/EP1178788A4/en not_active Withdrawn
- 1999-05-18 JP JP2000617889A patent/JP2002544227A/ja active Pending
- 1999-05-18 AU AU40857/99A patent/AU778767C/en not_active Ceased
- 1999-05-18 KR KR1020017014590A patent/KR100598638B1/ko not_active IP Right Cessation
- 1999-05-18 WO PCT/US1999/011001 patent/WO2000069430A1/en active IP Right Grant
- 1999-05-18 CN CNB998166448A patent/CN1194674C/zh not_active Expired - Fee Related
- 1999-05-18 CA CA002373603A patent/CA2373603A1/en not_active Abandoned
- 1999-05-18 MX MXPA01011760A patent/MXPA01011760A/es not_active IP Right Cessation
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2002
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100384801C (zh) * | 2006-06-23 | 2008-04-30 | 中国科学院广州化学研究所 | (e)-3,5-二甲氧基-4＇-羟基二苯乙烯的合成方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100598638B1 (ko) | 2006-07-07 |
| JP2002544227A (ja) | 2002-12-24 |
| HK1046642B (zh) | 2005-11-25 |
| EP1178788A4 (en) | 2005-08-10 |
| HK1046642A1 (en) | 2003-01-24 |
| CA2373603A1 (en) | 2000-11-23 |
| CN1194674C (zh) | 2005-03-30 |
| AU778767B2 (en) | 2004-12-23 |
| EP1178788A1 (en) | 2002-02-13 |
| KR20020012220A (ko) | 2002-02-15 |
| AU4085799A (en) | 2000-12-05 |
| AU778767C (en) | 2006-09-07 |
| WO2000069430A1 (en) | 2000-11-23 |
| MXPA01011760A (es) | 2003-09-04 |
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