CN1723884A - 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 - Google Patents
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 Download PDFInfo
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Abstract
本发明涉及顺式1,2-取代的二苯乙烯衍生物或其药学上可接受的盐、其糖苷或溶剂化物用于制备治疗或预防糖尿病或改善其并发症的药物的用途。
Description
技术领域:
本发明涉及顺式-1,2-取代的二苯乙烯衍生物或其药学上可接受的盐、其糖苷或溶剂化物用于制备治疗或预防糖尿病及改善其并发症的药物的用途。
背景技术
糖尿病是一种全球性的临床常见的代谢性慢性疾病。近年来,随着经济的发展和人们饮食结构的改变,糖尿病的患病率正在世界范围内迅速升高。据统计,全球患者总数可达一亿两千多万,我国估计约有三千多万,多数为非胰岛素依赖型即II型糖尿病。可见糖尿病已成为继心血管、肿瘤之后的又一严重危害人们健康的严重疾病。
糖尿病的病程长,调治失当常有并发症发生,如慢性血管性并发症(包括脑血管障碍、缺血性心脏病)、糖尿病性肾病等。糖尿病并发症所致的死亡率也正在逐年增加。因此,对糖尿病及其并发症的防治成为全球医药工作者的重点研究课题。
目前临床应用的口服降血糖药物主要以西药为主。按其化学结构可分为:磺酰脲类、双胍类、苯丙氨酸类、噻唑烷二酮类、糖酯类。此外,还有正在研究开发中的1,2-二苯乙烯类化合物。据US6,410,596和CN1398838A报道,1,2-二苯乙烯类化合物存在于许多植物中,目前发现至少在21个科31个属的几十种植物中都存在此类化合物,同时还发现它们具有广泛的生理作用,如抗氧化作用、抗肿瘤作用、抗瘀血综合症作用、降血糖作用等。但是,具有上述这些作用的1,2-二苯乙烯类化合物的结构均为反式1,2-二苯乙烯的衍生物。关于顺式1,2-取代的二苯乙烯衍生物的生物活性,只有美国专利5,525,632中报道了风车子新碱(combrotastatin)及其衍生物具有抗肿瘤活性。
发明内容
本发明人经研究发现,顺式1,2-取代的二苯乙烯类化合物、其药学上可接受的盐、其糖苷或溶剂化物具有良好的降血糖等作用,因而可用于糖尿病及其并发症的治疗和预防。
因此,本发明涉及式I顺式1,2-取代的二苯乙烯化合物、其药学上可接受的盐、其糖苷或溶剂化物用于制备治疗或预防糖尿病或改善其并发症的药物的用途,
其中,
R1-R12可以相同或不相同,各自独立地为氢、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酯基、氨基、C1-C6烷氨基、C1-C6烷基磺酰基、磺酰氨基、磺酰脲基、胍基、羧基、C1-C6酰基、硝基、氰基、卤素、OM1、M2或SO2OM3基团,其中M1、M2、M3可以相同或不同,各自独立地代表氢或选自碱金属或碱土金属的阳离子或NH4 +,或为含糖的苷。
本发明的另一个方面涉及药物组合物,其中含有作为活性成分的式I顺式1,2-取代的二苯乙烯化合物、其药学上可接受的盐、其糖苷或溶剂化物以及一或多种药学上可接受的载体。
本发明的再一个方面涉及治疗或预防糖尿病及改善其并发症的方法,包括给予糖尿病患者治疗有效量的上述式I化合物。
在本发明的一个优选实施方案中,所述的式I化合物具有以下式II,式III和式IV结构:
在本发明的另一个优选实施方案中,所述的糖苷为葡萄糖苷或甘露糖苷,或者,所述的溶剂化物为水合物。
本发明式I化合物可参考文献(Tetrahedron 2003,59,3315-3321)描述的方法制得。
根据本发明,顺式1,2-取代的二苯乙烯衍生物可按本领域常规的方法制成肠道或非肠道给药的制剂,如片剂、胶囊剂、颗粒剂、注射剂、栓剂、滴剂或贴剂等。
具体实施方式
下面实施例是对本发明的进一步详细说明但不意味着对本发明的任何限制。
实施例1
顺式-1-苯基-2-(3-甲氧基-4-羟基苯基)乙烯(式II化合物)的制备:
称取1.5克α-3-甲氧基-4-羟基苯基肉桂酸,置于100毫升配备有回流管的三口瓶中,在磁力搅拌下,加入7毫升喹啉和0.25克铜粉,电热功当量煲加热至210℃,并搅拌1小时,反应过程中有二氧化碳气体放出,发出轻微的***声。反应完毕后稍微冷却,加入20毫升乙酸乙酯,过滤后,用2N的盐酸洗涤反应液,水洗涤,无水MgSO4干燥,得到黄色固体。TCL(氯仿∶甲醇:9.5∶0.5)显示原料α-3-甲氧基-4-羟基苯基肉桂酸没有荧光,而脱羧后生成的产物二苯乙烯具有很强的荧光。
MS(FAB)m/z:M+ 226.0;
1H-NMR(DMSO)δ9.16(s 1H-OH),3.84(s 3H-OCH3),7.54(d 2H2,6-H),6.78(d 1H 2-H),7.37(t 2H α,β-H),7.35,7.26,7.09(arom5H)。
实施例2
顺式-2-苯基-3-(3-羟基-4-甲氧基苯基)丙烯酸(式III化合物)的制备:
在250毫升的三口瓶中加入13.6克(0.1摩尔)苯乙酸,15.2克(0.1摩尔)异兰香素,12毫升(0.07摩尔)三乙胺,18毫升(0.18摩尔)乙酸酐,磁力搅拌,110℃油浴回流12小时,反应完毕后,冷却到室温,加入200毫升乙酸乙酯,用水洗涤到中性,无水硫酸钠干燥过夜,除去干燥剂,减压除去溶剂,加入无水***,析出白色固体7.55克,产率27.9%,熔点180-190℃。
MS(FAB)m/z M+270.0;
1H-NMR(DMSO)δ8.81(s 1H,-OH),12.60(s 3H,-OCH3),7.40,7.39,7.18.6.95(2-H),6.72(s 1H,β-H),3.72(s 3H,-OCH3),7.40,7.39,7.18,6.95(arom 7H)。
实施例3
顺式2-苯基-3-(3-甲氧基-4-羟基苯基)丙烯酸(式IV化合物)的制备:
在250毫升的三口瓶中加入13.6克(0.1摩尔)苯乙酸,15.2克(0.1摩尔)香草醛,12毫升(0.07摩尔)三乙胺,18毫升(0.18摩尔)乙酸酐,磁力搅拌,110℃油浴回流12小时,反应完毕后,冷却到室温,加入200毫升乙酸乙酯,用水洗至中性,无水硫酸钠干燥过夜,除去干燥剂,减压除去溶剂,加入无水***,析出白色固体11.1克,产率40%,熔点200-210℃。
MS(FAB)m/z M+270.0;
1H-NMR(DMSO)δ8.92(s 1H,-OH),12.73(s 1H,-COOH),7.76(s 1H,2-H),6.67(s 1H,β-H),3.35(s,3H,OCH3),(s 1H,β-H),7.43,7.22,7.21,6.95(arom 7H).
实施例4本发明化合物的降糖活性
以反式1,2-二苯乙烯衍生物E2,即3,3’,5-三羟基-4’-甲氧基芪-3-O-β-D-葡糖苷(rhaponticin,参见CN 01120597.0)作为阳性对照药,对本发明化合物的降糖效果进行了初步评价。
实验选用雄性昆明小鼠(合格证:医动字D01-3023),体重21-33克,禁食并自由摄取16小时后给药。对照药物或受试药物分别以二甲亚砜为溶剂按400mg或800mg/2.5ml/Kg配制灌胃,15分钟后口服葡萄糖2g/10ml/Kg。在1小时时断尾采血1滴,用美国强生集团理康公司稳捷基础型血糖监测仪,葡萄糖氧化酶法试纸测试血糖水平。对照组给予二甲亚砜2.5ml/Kg及葡萄糖2g/10ml/Kg灌胃。结果如表1所示:
表1.本发明化合物对高糖小鼠的降糖作用
代号 | 剂量(mg/Kg) | 动物数 | 给药后1小时血糖M±SD(mmol/L) |
DMSOE2式II化合物式III化合物式IV化合物 | 400800400400400 | 555555 | 9.50±1.069.14±1.907.02±1.01**7.62±1.59*7.30±0.68*8.20±0.99 |
*P<0.05,**P<0.01,与对照组比较,给予本发明化合物的给药组血糖下降。
由表中数据可见,本发明化合物能有效降低高血糖小鼠的血糖,说明其可用于治疗或预防糖尿病及改善其并发症。
Claims (5)
3.权利要求1或2的用途,其中的糖苷为葡萄糖苷或甘露糖苷。
4.权利要求1或2的用途,其中的溶剂化物为水合物。
5.权利要求1或2的用途,其中的药物以片剂、胶囊、颗粒剂、贴剂、栓剂、滴剂或注射剂的形式存在。
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Application Number | Priority Date | Filing Date | Title |
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CNA2004100693745A CN1723884A (zh) | 2004-07-21 | 2004-07-21 | 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 |
PCT/CN2005/001086 WO2006007794A1 (fr) | 2004-07-21 | 2005-07-20 | Derives de stilbene cis-1,2-substitues et utilisation de ceux-ci pour la preparation de medicaments servant au traitement ou a la prevention du diabete |
EP05766919A EP1801087B1 (en) | 2004-07-21 | 2005-07-20 | Cis-1,2-substituted stilbene derivatives for treating and/or preventing diabetes |
CN200580024419XA CN1989090B (zh) | 2004-07-21 | 2005-07-20 | 顺式-1,2-取代的二苯乙烯衍生物及其用于制备治疗和/或预防糖尿病的药物的用途 |
US11/658,239 US8039513B2 (en) | 2004-07-21 | 2005-07-20 | Cis-1,2-substituted stilbene derivatives and their use in preparation of drugs for treatment and/or prevention of diabetes |
JP2007521774A JP4991537B2 (ja) | 2004-07-21 | 2005-07-20 | シス−1,2−置換スチルベン誘導体、および糖尿病の治療および/または予防のための薬剤の製造におけるそれらの使用 |
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CN200580024419XA Expired - Fee Related CN1989090B (zh) | 2004-07-21 | 2005-07-20 | 顺式-1,2-取代的二苯乙烯衍生物及其用于制备治疗和/或预防糖尿病的药物的用途 |
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US (1) | US8039513B2 (zh) |
EP (1) | EP1801087B1 (zh) |
JP (1) | JP4991537B2 (zh) |
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US7939703B2 (en) | 2007-12-03 | 2011-05-10 | Technical Institute of Physics and Chemistry of Chinese Academy of Science | Method for photocatalytic isomerization of 1,2-diphenylethylene analogues |
CN105362282A (zh) * | 2015-07-23 | 2016-03-02 | 黄冈师范学院 | 一种治疗糖尿病的活性物质及其制备方法和药物 |
Families Citing this family (4)
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WO2005069998A2 (en) * | 2004-01-20 | 2005-08-04 | Brigham Young University Technology Transfer Office | Novel sirtuin activating compounds and methods for making the same |
AU2010337825A1 (en) | 2009-12-29 | 2012-07-05 | Mapi Pharma Limited | Intermediate compounds and processes for the preparation of tapentadol and related compounds |
CN102584805B (zh) * | 2011-12-07 | 2015-04-01 | 浙江农林大学 | 天然植物中一个活性成分的制备方法 |
CN117736099A (zh) * | 2022-09-22 | 2024-03-22 | 中国科学院上海药物研究所 | 用于防治血管扩张性疾病的化合物及其制法和用途 |
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US4996237A (en) * | 1987-01-06 | 1991-02-26 | Arizona Board Of Regents | Combretastatin A-4 |
TW325458B (en) * | 1993-09-08 | 1998-01-21 | Ajinomoto Kk | Stilbene derivatives and pharmaceutical compositions comprising the same for anti-cancer |
US5731353A (en) * | 1993-09-08 | 1998-03-24 | Ajinomoto Co., Inc. | Stilbene derivatives and pharmaceutical compositions containing them |
JPH0959245A (ja) | 1995-08-25 | 1997-03-04 | Yamanouchi Pharmaceut Co Ltd | N−(2−プロペノイル)グアニジン誘導体 |
FR2778337B1 (fr) | 1998-05-05 | 2001-08-31 | Inst Nat Sante Rech Med | Antagonistes des ligands du recepteur des arylhydrocarbures |
US6245814B1 (en) * | 1998-05-08 | 2001-06-12 | Calyx Therapeutics, Inc. | Diphenylethylene compounds |
GB9903403D0 (en) * | 1999-02-16 | 1999-04-07 | Angiogene Pharm Ltd | Substituted stilbene compounds with vascular damaging activity |
JP2000256259A (ja) * | 1999-03-11 | 2000-09-19 | Nippon Zoki Pharmaceut Co Ltd | メイラード反応阻害剤 |
AU778767C (en) * | 1999-05-18 | 2006-09-07 | Theracos, Inc. | Novel diphenylethylene compounds |
GB9918912D0 (en) | 1999-08-12 | 1999-10-13 | Angiogene Pharm Ltd | New stilbenes with vascular damaging activity |
CN1224383C (zh) | 1999-11-05 | 2005-10-26 | 中国人民解放军军事医学科学院放射医学研究所 | 一类新型降低血糖化合物 |
NZ520829A (en) | 2000-02-04 | 2004-12-24 | Calyx Therapeutics Inc | Diphenylethylene compounds for treating diabetes and related conditions |
GB0031263D0 (en) | 2000-12-21 | 2001-01-31 | Paterson Inst For Cancer Res | Materials and methods for synthesizing stilbenes |
WO2002050007A2 (en) | 2000-12-21 | 2002-06-27 | Cancer Research Technology Limited | Substituted stilbenes, their reactions and anticancer activity |
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 |
WO2003035008A2 (en) | 2001-10-26 | 2003-05-01 | Oxigene, Inc. | Functionalized stilbene derivatives as improved vascular targeting agents |
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2004
- 2004-07-21 CN CNA2004100693745A patent/CN1723884A/zh active Pending
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- 2005-07-20 WO PCT/CN2005/001086 patent/WO2006007794A1/zh active Application Filing
- 2005-07-20 JP JP2007521774A patent/JP4991537B2/ja not_active Expired - Fee Related
- 2005-07-20 US US11/658,239 patent/US8039513B2/en not_active Expired - Fee Related
- 2005-07-20 CN CN200580024419XA patent/CN1989090B/zh not_active Expired - Fee Related
- 2005-07-20 EP EP05766919A patent/EP1801087B1/en not_active Not-in-force
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7939703B2 (en) | 2007-12-03 | 2011-05-10 | Technical Institute of Physics and Chemistry of Chinese Academy of Science | Method for photocatalytic isomerization of 1,2-diphenylethylene analogues |
CN105362282A (zh) * | 2015-07-23 | 2016-03-02 | 黄冈师范学院 | 一种治疗糖尿病的活性物质及其制备方法和药物 |
Also Published As
Publication number | Publication date |
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US20090076114A1 (en) | 2009-03-19 |
WO2006007794A1 (fr) | 2006-01-26 |
JP2008506722A (ja) | 2008-03-06 |
EP1801087B1 (en) | 2012-08-29 |
EP1801087A4 (en) | 2009-09-16 |
US8039513B2 (en) | 2011-10-18 |
CN1989090B (zh) | 2011-06-01 |
CN1989090A (zh) | 2007-06-27 |
EP1801087A1 (en) | 2007-06-27 |
JP4991537B2 (ja) | 2012-08-01 |
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