CN1377642A - 用于制备治疗或预防非胰岛素依赖型糖尿病或肥胖的药物之化合物的用途 - Google Patents
用于制备治疗或预防非胰岛素依赖型糖尿病或肥胖的药物之化合物的用途 Download PDFInfo
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- CN1377642A CN1377642A CN02106295A CN02106295A CN1377642A CN 1377642 A CN1377642 A CN 1377642A CN 02106295 A CN02106295 A CN 02106295A CN 02106295 A CN02106295 A CN 02106295A CN 1377642 A CN1377642 A CN 1377642A
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- diazanyl
- milliliters
- methyl
- diabetes
- glycine
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
- C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
一种化合物在制备用于治疗或预防非胰岛素依赖型糖尿病或肥胖的药物中的用途,其中该化合物具有结构式III,式中R3为H,甲基,乙基,苄基或正己基。
Description
相关申请
本申请是1995年11月13日递交的中国专利申请95196384.8的分案申请。
本发明提供了一种化合物在制备用于治疗或预防非胰岛素依赖型糖尿病或肥胖的药物中的用途,其中该化合物具有结构式III:
HN=C(NH2)-HN-N=CR3-COOH式中R3为H,甲基,乙基,苄基或正己基。
发明背景
非胰岛素依赖型糖尿病,或NIDDM,和II型糖尿病是同义词。NIDDM病人在禁食时具有异常高的血糖浓度,而在进餐或诊断性试验(例如葡萄糖耐量试验)后,细胞对葡萄糖的摄取延迟。NIDDM的诊断基于公认的标准〔美国糖尿病协会,胰岛素依赖型(I型)糖尿病的医生指南,1988;美国糖尿病协会,非胰岛素依赖型(II型)糖尿病的医生指南,1988〕。
胰岛素依赖型糖尿病,IDDM,和I型糖尿病是同义词。IDDM病人在禁食时具有异常高的血糖浓度,而在进餐或诊断性试验(例如葡萄糖耐量试验)后,细胞对葡萄糖的摄取延迟。IDDM的诊断基于公认的标准〔美国糖尿病协会,胰岛素依赖型(I型)糖尿病的医生指南,1988〕。
当经口服或胃肠外给予标准剂量的萄萄糖后,血液中的葡萄糖代谢清除率低于普通人群的一般水平时,出现受损的葡萄糖耐量〔美国糖尿病协会,非胰岛素依赖型(II型)糖尿病的医生指南,1988〕。受损的葡萄糖耐量可发生于NIDDM、IDDM、妊娠糖尿病和肥胖。受损的萄萄糖耐量还可发生于不满足这些疾病的诊断标准的个体。在非糖尿病个体中,受损的葡萄糖耐量是NIDDM发展的促成因素。
肥胖是一种因体内脂肪含量增加而导致体重超出关于年龄、性别、身高和体格的公认标准的情况〔Bray,肥胖,内分泌展望,2303页,多激素***和疾病(1989)〕。公认的标准由人寿保险死亡率的经验和与身体组成有关的疾病发生率决定。发生于肥胖个体的高死亡率是由于该情况引起的疾病所造成。所述疾病包括癌症、心血管疾病、消化疾病、呼吸疾病和糖尿病。
在患有慢性高血糖(例如非胰岛素依赖型糖尿病和胰岛素依赖型糖尿病)的患者中,葡萄糖依赖型蛋白质交联的速率高于标准值(Bunn,美国医学期刊(American Journal of Medicine),Vol.70,325页,1981),导致蛋白质三级结构的改变(Brownlee,第18章,糖尿病,279页,1990)。蛋白质的过度非酶催糖基化可导致糖尿病并发症和没有糖尿病的人的老年并发症,例如神经病、肾病、视网膜病、高血压和动脉粥样硬化(Brownlee,1990,同上)。
高血糖的定义是血糖浓度超过普通人群的公认标准〔美国糖尿病协会,非胰岛素依赖型(II型)糖尿病的医生指南,1988〕。
理解了这些情况之间的关系后,将有利于开发出一种治疗或预防所有这些情况的药物。
***息
在JP 54128523(CA 92:75899h)中报道了可用作杀真菌剂和杀虫剂的3-(1-(氨甲基)肼基))丙酸。在Gante,化学研究期刊(J.Chem.Ber.)1968,101,1195中报道了N-(肼基亚氨基甲基)-甘氨酸的合成。在发明名称为“用2-亚烷基氨基:胍衍生物抑制机体蛋白质的过度糖基化,用于治疗糖尿病的并发症或尤其预防牙齿染色”的美国专利5272165中记载了一些烷基化的氨基胍衍生物。在DE 4244539-A1和WO 9104-023-A中公开了精氨酸的氨基胍类似物。美国专利5132453公开了N6-(肼基:亚氨基:甲基)-赖氨酸可以用作氧化氮形成的抑制剂并可用于治疗高血压。EP-230-037-A公开了一些具有抗局部缺血和心脏保护活性的新的2-取代-胍衍生物。美国专利3412105公开了用作MAO抑制剂和长效降压药的β-芳基-N-胍基-(β-丙氨酸或α-羧基-β-丙氨酸)。
发明概述
本发明特别提供:(1)结构式I或II的化合物:AG-(CH2)n-CO2R1
a)N-氨基胍,
b)N,N′-二氨基胍,或
c)N,N′,N″-三氨胍;其中n是从1-5的整数;其中R1是
a)氢,
b)苯基,
c)C1-5烷基,或
d)C1-3烷基-苯基;并且其中R2是
a)氢,
b)苯基,
c)C1-10烷基,或
d)C1-5烷基-苯基;条件是:
a)在结构式I中,当n是2时,R1不为氢;
b)在结构式I中,当n是1时,R1不为甲基;
c)在结构式II中,当R2是乙基时,R1不为氢;
d)在结构式II中,当R2是苯基时,R1不为氢;和
e)在结构式I中,当n是3时,R1不为氢。(2)对易患或患有非胰岛素依赖型糖尿病的患者治疗或预防所述NIDDM的方法,包括全身给予治疗或预防NIDDM有效量的结构式III的化合物其中R3是氢、甲基、乙基、CH2苯基或正己基。
对于通式I和II,AG片段的连接是不确定的,即,与邻近碳原子的结合可以发生在AG片段的任何一个氮上。AG片段上剩余的氮为未取代的。
含碳基团的碳原子含量用前缀“Ci-Cj”表示,其中i是最低碳原子数而j是最高碳原子数。
含有1至10个碳原子的烷基的例子包括,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、正庚基、正辛基、正壬基、正癸基,以及它们的其它异构体形式。
可药用的酸加成盐的例子包括,乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、亚硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一烷酸盐。
结构式I-III的化合物的使用剂量在0.1和100mg/kg体重/天之间。优选的剂量为1-50mg/kg/天。可以通过口服、胃肠外、鼻内、颊、舌下、直肠内或经皮的途径给药。优选口服途径。
本发明的新化合物由通式I和II给出。要求保护治疗NIDDM用途的已知化合物由结构式III表示。
由通式I和II所表示的本发明的化合物中,列于表1的化合物是特别优选的,它们的优选用途是治疗NIDDM及其并发症。
表2列出了一组没有被要求保护的相关化合物。列出它们是为了证明要求保护的化合物的出人意料的效果,这些化合物与要求保护的化合物非常相近,但在试验的最高剂量下仍无活性。
表3列出了一组在通式I和II范围内的化合物,这些化合物在试验的最高剂量下仍无活性,从而构成了例外,如权利要求1的条件所示。
表4列出了一组具体要求保护的本发明范围内的新化合物。它们的制备方法由第4节给出。
表5列出了一组要求保护治疗NIDDM用途的已知化合物。
因此,本发明提供了具有意外抗糖尿病特性的新的以及已知化合物。
以约100-500mg/kg/天的剂量将本发明化合物给予KKAy小鼠,导致非胰岛素依赖型糖尿病啮齿动物模型中高血糖的部分或完全消除(特定化合物列于表4和表5中;参见Chang,Wyse,Copeland,Peterson,和Ledbetter,糖尿病(Diabetes)1985,第466页,1986)。KKAy小鼠对胰岛素是耐受的(Chang等,同上),这些动物中非空腹血糖水平降低表明在用要求保护的化合物处理后胰岛素的耐受性最可能降低。KKAy小鼠与正常异系交配小鼠相比肥大(Chang等,同上)并给予本发明化合物后可使体重减轻。
对患糖尿病的KKAy小鼠给予此系列优选的化合物-N-(二肼基亚甲基)-甘氨酸4天后可降低动物非空腹血糖水平(见表6)。60mg/kg/天的剂量可降低35%的血糖水平,与对照相比有统计学显著差异。更高的剂量使血糖浓度降低更多。给予500mg/kg/天的3-胍基丙酸可产生与60mg/kg/天N-(二肼基亚甲基)-甘氨酸类似的血糖浓度降低。
给予患糖尿病的KKAy小鼠N-(二肼基亚甲基)-甘氨酸4天可减轻动物体重(见表6)。100mg/kg/天的剂量可减轻4%的体重,与对照相比有统计学显著差异。更高的剂量对超体重的KKAy小鼠体重减轻更多。给予500mg/kg/天的3-胍基丙酸可产生与100mg/kg/天N-(二肼基亚甲基)-甘氨酸类似的体重减轻。
给予正常C57BL小鼠100mg/kg N-(二肼基亚甲基)-甘氨酸可降低这些动物空腹血糖浓度(表7)。
给予患糖尿病的KKAy小鼠或正常C57BL小鼠100mg/kg N-(二肼基亚甲基)-甘氨酸可改善葡萄糖耐受性,如注射标准试验剂量葡萄糖后较低的血糖水平所示(表7)。
蛋白质的非酶催糖基化是蛋白质的葡萄糖依赖***联的初始步骤(Brownlee,同上)。体外人血清白蛋白的非酶催糖基化可通过N-(二肼基亚甲基)-甘氨酸、N-(肼基亚氨基甲基)-甘氨酸和[2-(氨基亚氨基甲基)肼基]-乙酸一盐酸盐降低(表8)。氨基胍(已表明可体外(Khatami,Suldan,David,Li和Rockey,生命科学(Life Sciences),第43卷,1725-1731页,1988)和体内(Brownlee,同上)抑制蛋白质非酶催糖基化)在该试验中也是有效的(表8)。3-胍基丙酸在该试验中对白蛋白非酶催糖基化没有作用。
在糖尿病患者中,需要治疗一些代谢疾病:饭后及空腹状态时异常升高的血糖水平,葡萄糖从血流中的延迟清除(美国糖尿病协会,胰岛素依赖型(I型)糖尿病的医生指南,1988;美国糖尿病协会,非胰岛素依赖型(II型)糖尿病的医生指南,1988)以及促使糖尿病并发症发展的蛋白质的过度糖基化(Brownlee,同上)。另外,肥胖越来越与非胰岛素依赖型糖尿病相关并可加重这些患者中已紊乱的葡萄糖代谢(Horton和Jeanrenaud,Chapter 27,肥胖和糖尿病(Obesity and DiabetesMellitus),1990)。对非胰岛素依赖型糖尿病的最佳治疗可纠正所有这些紊乱。蛋白质的过度糖基化(例如发生在非胰岛素依赖型糖尿病和胰岛素依赖型糖尿病患者中)可通过阻断葡萄糖和蛋白质分子的化学反应(Brownlee,同上)及降低糖尿病状态中异常血糖浓度的升高(Holman和Turner,糖尿病药物(Diabetic Medicine),5:582-588,1988;Benjamin和Sacks,临床化学(Clin Chem.),4015:683-687,1994)而防止。最需要的治疗是发挥这两种方法以更彻底地降低非酶催蛋白质糖基化的速率。
本发明化合物可正向影响多种代谢缺陷(包括糖尿病)并可通过不止一种机制防止代谢缺陷,这使它们的药理作用明显不同于先前所述的其它治疗糖尿病的胍化合物。本发明化合物在治疗NIDDM方面意外地比氨基胍、二氨基胍、3-胍基丙酸和甲福明优越,因为它们提供更为完全的所需活性谱且在低剂量下有效。
本发明化合物在治疗糖尿病方面与二氨基胍和氨基胍相比意外地优越,因为本发明化合物可代谢作用降低过量的血糖浓度并直接阻断蛋白质非酶催糖基化。本发明化合物在治疗受损的葡萄糖耐量或肥胖方面与二氨基胍和氨基胍相比意外地优越,因为氨基胍和二氨基胍在此方面无效。氨基胍和二氨基胍可抑制体外蛋白质非酶催糖基化并且可抑制体内高级糖基化终产物的形成(Kumari,Umar,Bansal,和Sahib,糖尿病(Diabetes),40:1079-1084,1991)。基于其对非酶催蛋白质糖基化的抑制,已建议用氨基胍治疗糖尿病(Brownlee,同上)。氨基胍对正常啮齿动物或通过注射四氧嘧啶或链脲霉素而得糖尿病的大鼠的血糖水平没有作用(Kumari,Umar,Bansal,Sahib,同上;Yagihashi,Kamijo,Baba,Yagihashi和Nagai,糖尿病,41:47-52,1992;Edelstein和Brownlee,Diabetologia,35:96-97,1992;Oxlund和Andreassen,Diabeterologia,35:19-25,1992)。二氨基胍对正常或四氧嘧啶致糖尿病大鼠的血糖水平没有作用(Kumari,Umar,Bansal,Sahib,同上)。氨基胍对正常或糖尿病大鼠的体重没有影响(Kumari,Umar,Bansal,Sahib,同上;Yagihashi,Kamijo,Baba,Yagihashi和Nagai,同上;Oxlund和Andreassen,Diabetologia,35:19-25,1992)或者导致人及大鼠体重的增加(Baylin,Horakova,和Beaven,Experientia,31:562,1975)。二氨基胍对正常或四氧嘧啶致糖尿病大鼠的体重没有作用(Kumari,Umar,Bansal,Sahib,同上)。氨基胍或二氨基胍对葡萄糖耐量的作用尚未阐明。
本发明化合物在治疗糖尿病方面比3-胍基丙酸意外优越,因为后者不能有效控制高血糖并缺乏抑制蛋白质非酶催糖基化的能力。本发明化合物在治疗受损的葡萄糖耐量或肥胖方面比3-胍基丙酸意外优越,因为这些化合物更有效。已表明3-胍基丙酸可降低高血糖和额外体重并可改善糖尿病啮齿动物的葡萄糖耐量(Meglasson,Wilson,Yu,Robinson,Wyse,和deSouza,药理和试验治疗学期刊(J.Pharm.And Exp.Therapeutics),266:1454-1462,1993)。本发明优选的化合物-N-(二肼基亚甲基)-甘氨酸在降低KKAy小鼠异常升高的血糖水平和体重方面比3-胍基丙酸更有效。降低KKAy小鼠20%血糖水平需要130mg/kg/天的后一化合物。达到类似的血糖水平降低需要30mg/kg/天的N-(二肼基亚甲基)-甘氨酸。给予KKAy小鼠60mg/kg/天的N-(二肼基亚甲基)-甘氨酸的效果与500mg/kg/天的3-胍基丙酸类似。当在饲料中以1%混合物给予3-胍基丙酸(约以1000mg/kg/天的剂量释放)可改善患糖尿病KKAy小鼠葡萄糖耐量(美国专利5132324)。比较而言,当给予正常C57BL和患糖尿病KKAy小鼠100mg/kg/天的N-(二肼基亚甲基)-甘氨酸时即可改善葡萄糖耐量。对体重减轻而言,100mg/kg/天的N-(二肼基亚甲基)-甘氨酸的效果与500mg/kg/天的3-胍基丙酸类似。与本发明化合物相比,3-胍基丙酸不能抑制体外白蛋白非酶催糖基化。
本发明化合物在治疗糖尿病、葡萄糖不耐性和肥胖方面比甲福明意外优越,因为后者在相同动物模型中检测时不如本发明化合物有效。此外,在其减轻体重及防止非酶催蛋白质糖基化方面的有效性而言,所公开的甲福明的数据是矛盾的,不能揭示一致的结果。先前已表明,以1000-3000mg/kg/天给予甲福明可降低非胰岛素依赖型糖尿病患者的高血糖并且当以1500-2500mg/kg/天给予时可增加这些患者中葡萄糖清除率(Bailey,糖尿病护理(Diabetes Care),15:755-772,1992)。啮齿动物对甲福明不如人敏感,因此需要较高剂量(以体重为基础)才能达到降低血糖的效果(Bailey,Flatt,Wilcock,和Day,糖尿病研究的新领域(Frontiersin Diabetes Research),pp.277-282,1990;Penicaud,Hitier,Ferre,和Girard,生物化学期刊(Biochem.J.)262:881-885,1989)。当使新生的链脲霉素致糖尿病大鼠以100mg/kg/天(Rossetti,DeFronzo,Gherzi,Stein等,代谢(Metabolism),39:425-435,1990)、使DBM小鼠以400mg/kg/天(Bailey,Flatt,Wilcock,和Day,同上)、使Zuckerfa/fa小鼠以350mg/kg/天(Penicaud,Hitier,Ferre,和Girard,同上)以及使KKAy小鼠以300mg/kg/天或更多(Meglasson,Wilson,Yu,Robinson,de Souza,同上)长期口服甲福明时可降低高血糖。正常鼠以250mg/kg/天的剂量、链脲霉素致糖尿病大鼠以250mg/kg/天剂量(Bailey,Flatt,Wilcock,和Day,同上)或者患糖尿病的ob/ob小鼠以250mg/kg/天剂量(Bailey,Flatt,和Ewan,国际药代学期刊(Arch.Int.Pharmacodyn.),282:233-239,1986)长期口服甲福明对血糖浓度没有影响。短期给予264mg/kg甲福明或其类似物132mg/kg丁福明对大鼠血糖水平没有影响(Tutwiler和Bridi,糖尿病,27:868-876,1978)。当在KKAy小鼠中检测本发明优选的化合物-N-(二肼基亚甲基)-甘氨酸时,其在降低该模型异常升高的血糖水平方面比甲福明更有效。降低KKAy小鼠25%血糖水平需要300mg/kg/天的甲福明(Meglasson,Wilson,Yu,Robinson,Wyse,和de Souza,同上)。用30-60mg/kg/天剂量的N-(二肼基亚甲基)-甘氨酸可获得类似降低的血糖浓度。至于增加葡萄糖耐量,已报道当使正常大鼠以750mg/kg的剂量(Tutwiler和Bridi,同上)或者使正常小鼠以50mg/kg的剂量(Bailey,Flatt,Wilcock和Day,同上)给予甲福明时不影响葡萄糖耐量。当以250mg/kg的剂量给予正常小鼠或链脲霉素致糖尿病大鼠时,口服葡萄糖耐量增加(Bailey,Flatt,Wilcock和Day,同上)。比较而言,当以低剂量(100mg/kg)给予正常C57BL或患糖尿病KKAy小鼠时,N-(二肼基亚甲基)-甘氨酸可增加葡萄糖耐量。至于减轻体重,已报道用甲福明治疗1年时可减轻非胰岛素依赖型糖尿病患者的体重(Bailey,同上),或者在治疗类似长的时间中对肥胖的非胰岛素依赖型糖尿病患者的体重没有明显影响(多中心研究(Multi-centre Study),Diabetologia,24:404-411,1983)。当以240mg/kg/天的剂量给予患糖尿病的ob/ob小鼠或者以60mg/kg/天的剂量给予链脲霉素致糖尿病小鼠时甲福明不能减轻体重(Lord,Atkins,和Bailey,Diabetologia25:108-113,1983)。当用1700mg/kg/天的甲福明治疗KKAy小鼠时会引起统计学显著的体重减轻,但是较低剂量时没有(Meglasson,Wilson,Yu,Robinson,Wyse,和de Souza,同上)。比较而言,当以100mg/kg的剂量给予KKAy小鼠时,N-(二肼基亚甲基)-甘氨酸对肥胖小鼠体重的减轻与1700mg/kg/天的甲福明效果类似(Meglasson,Wilson,Yu,Robinson,Wyse,和de Souza,同上)。已报道甲福明在0.5和5微摩尔/升的浓度可抑制红细胞浆膜的非酶催糖基化,这基于其防止体外与葡萄糖培养的浆膜的电子顺磁共振光谱序参数降低的能力(Freisleben,Ruckert,Wiernsperger,和Zimmer,生化药理学(Biochemical Pharmacology),43:1185-1194,1992)。在较高的浓度,如50和100微摩尔/升甲福明具有不良作用并可导致极低的序参数。因此,甲福明是否可用来降低或加重糖尿病患者中蛋白质非酶催糖基化取决于甲福明在受治疗患者血清中的浓度。在口服1克甲福明的糖尿病患者中,平均Cmax血浆浓度为3.24微克/毫升(或25微摩尔/升)(Tucker,Casey,Phillips,Connor等,英国临床药理学期刊(Br.J.Clin.Pharmacol.),2:235-246,1981),因此,其处于可降低红细胞非酶催糖基化的最高浓度和促进此过程的最低浓度之间。基于公开的糖尿病患者中甲福明的血浆浓度,得不到当作为治疗剂给予患者时甲福明是否可抑制蛋白质非酶催糖基化或者以某种方式加重此过程的结论。
制备本发明化合物的一般方法列于方案1-4中。这些技术的特殊实施例可以在“优选实施方案的说明”中所给的实验方法中找到。使用其它起始物和反应物可制备不同的本发明化合物。以下参考文献讨论了本发明化合物的一般合成方法。
方案1:Gante,化学研究期刊(J.Chem.Ber.)1968,101,1195。Armarego,W.L.F.;Kobayashi T.化学会志(C)1971,238。Evans,D.A.;Britton,T.C.;Dorow,R.L.;Dellaria,J.F. 美国化学会志1986,108,6395。Evans,D.A.;Britton,T.C.;Dorow,R.L.;Dellaria,J.F.四面体1988,44,5525。
方案3:Gut,J.;Hesoun,D.;Novacek,A.捷克化学公报(Coll.Czech.Chem.Comm.)1966,31,2014。Miura,K.;Ikeda,M.;Kondo,T.;Setogawa,K.C.A.1962,56:4767b。Pankaskie,M.;Abdel-Monem,M.M.药物科学期刊(J.Pharm Sci.)1980,69,1000。
方案4:Lee,K.;Kim,S.;Um,H.;Park,H.;合成1989,638。Reddy,T.I.;Bhawal,B.M.;Rajappa,S.四面体1993,49,2101。体内和体外筛选方法。
优选实施方案的说明
以下实验方法是说明本发明的大量化合物的制备的具体例子:实施例1:[2-(氨基亚氨基甲基)肼基]-乙酸
将肼基乙酸乙酯盐酸盐(7.73g,50mmol)在100mL 1N NaOH中回流2小时进行皂化。然后向该热溶液中加入2-甲基-2-硫代异脲硫酸盐(6.95g,50mmol)并将溶液继续回流2小时。将该混合物浓缩至约1/2体积,此时析出白色固体沉淀。将溶液冷却并过滤得到3.34g白色固体。用水重结晶得到2.41g(36%)白色固体结晶状[2-(氨基亚氨基甲基)肼基基]-乙酸。MP:247-248℃(分解);1H NMR:(D2O)δ3.40(s,2H)。实施例2:[2-(氨基亚氨基甲基)肼基]-乙酸一盐酸盐
向搅拌下的[(氨基亚氨基甲基)亚肼基]-乙酸一盐酸盐一水合物(10g,60mmol)的甲醇(300mL)溶液中加入10%Pd-C(0.25g)并将混合物在30psi下氢化过夜。将混合物过滤并将溶剂蒸发至干。残余物用EtOH重结晶得到4.2g(42%)白色固体状标题化合物(m.p.163-165℃)。1H NMR:(D2O)δ3.68(s,2H)。实施例3:[2-(氨基亚氨基甲基)肼基]乙酸苯甲酯一盐酸盐
向[2-(氨基亚氨基甲基)肼基]乙酸(2.00g,15.2mmol)的苄醇(30mL)悬浮液中通入HCl(g)气泡。将反应液搅拌约一小时至所有物质均溶解。加入Et2O使产物粗品沉淀。将该物质用MeOH/EtOAc重结晶得到白色结晶固体状[2-(氨基亚氨基甲基)肼基]乙酸苯甲酯一盐酸盐(3.20g,82%)。MP:162-164℃1H NMR(CD3OD):δ3.69(s,2H),5.24(s,2H),7.34-7.42(m,5H)。实施例4:α-肼基苯丙酸
将LDA(50mL 1.5M的THF溶液)在250mL干燥THF中的溶液冷却至-78℃。向其中滴加氢化肉桂酸乙酯(12.0mL,68.2mmol)在250mL干燥THF中的溶液。将该溶液在-78℃搅拌30分钟。然后滴加偶氮二甲酸二叔丁酯(18.84g,81.8mmol)在100mL干燥THF中的溶液。10分钟后,加入14mL HOAc终止反应并将温度升至室温。将混合物在Et2O和水之间进行分配。水层用Et2O(3×100mL)萃取。将合并的有机层用饱和NaHCO3水溶液(2×100mL)和盐水(1×100mL)洗涤,硫酸钠干燥并浓缩。产物粗品用硅胶进行色谱分离(90/10己烷/EtOAc)得到15.33g(55%)二-BOC保护的肼基酯。
将该酯溶于200mL CH2Cl2。向其中加入120mL三氟乙酸。将混合物在室温下搅拌2小时。蒸除溶剂后,将产物粗品溶于75mL 1N NaOH并回流2小时。将溶液冷却,用Et2O萃取、中和、浓缩至体积的一半、冷却并过滤。得到的棕色固体在沸腾的i-PrOH中搅拌5分钟以除去有色杂质。过滤并干燥得到3.35g(27%)白色固体状α-肼基苯丙酸。MP:198-201℃(分解)。1H NMR(D2O):δ7.41-7.29(m,5H),3.89(dd J=7 6Hz1H),3.23-3.08(m,2H)。实施例5:α-[2-(氨基亚氨基甲基)肼基]苯丙酸一水合物
将α-肼基苯丙酸(3.00g,16.7mmol)和2-甲基-2-硫代异脲硫酸盐(2.55g,18.3mmol)在17mL 1N NaOH中的溶液加热回流2小时。将该混合物用3N HCl中和并浓缩至有沉淀生成(约1/2体积)。滤出产物粗品并用水重结晶得到1.81g(41%)α-[2-(氨基亚氨基甲基)肼基]苯丙酸一水合物。MP:127-130℃(分解)。1H NMR(D2O):δ7.40-7.27(m,5H),3.60(dd,J=8,6Hz,1H),3.04(dd,J=14,6Hz,1H),2.86(dd,J=14,8Hz,1H)。2-[2-(氨基亚氨基甲基)肼基]丙酸
将10.0g(55.4mmol)2-[(氨基亚氨基甲基)亚肼基]丙酸盐酸盐(药物科学期刊(J.Pharmaceut.Sci.)1980,69,1000-1004)、1.5g 10%碳载钯和300mL蒸馏水的混合物在50psi氢气压力下于25℃振摇16小时。将混合物过滤。向滤液中加入75g Dowex IR118H氢型强酸性阳离子交换树脂。将混合物搅拌1小时,然后将混合物过滤。树脂用3份150mL的蒸馏水洗涤。弃除合并的滤液和洗涤液并将树脂用5份200mL 20%(v/v)的吡啶蒸馏水溶液洗涤。合并洗涤液并减压(25℃,1torr)蒸除溶剂。将得到的白色粉末溶于30mL回流的蒸馏水中并将得到的溶液用90mL热的无水乙醇稀释。将混合物冷却至25℃,24小时后过滤收集形成的沉淀。将固体干燥(20torr/50℃/24小时)后得到3.8g白色固体状标题化合物,mp239-241℃。实施例6:[1-(氨基亚氨基甲基)肼基]乙酸一氢溴酸盐
向搅拌下的氨基胍碳酸氢盐(100g,734mmol)的水(200mL)悬浮液中加入溴代乙酸(100g,720mmol)。开始起泡后将该均相溶液回流过夜,冷却至室温,蒸除溶剂至干。将残余物悬浮于EtOH(200mL)中并声处理。滤出固体得到13.6g(9%)白色固体状标题化合物(mp163-165℃)。1H NMR(D2O):δ4.25(s,2H)。实施例7:3-[[亚氨基[(1-甲基亚乙基)肼基]甲基]氨基]丙酸
将β-丙氨酸(6.00g,67.5mmol)溶于67.5mL 1N NaOH中。向其中加入N-氨基-S-甲基异硫脲氢碘酸盐(15.69g,67.5mmol)。将该混合物加热回流1.5小时。蒸除溶剂。将产物粗品溶于大约50mL水中,加入50mL丙酮。蒸除溶剂得到橙色固体,将其用硅胶进行色谱分离(80/20 CHCl3/MeOH,然后是60/40 CHCl3/MeOH)得到5.88g(47%)浅橙色固体状3-[[亚氨基[(1-甲基亚乙基)肼基]甲基]氨基]丙酸。MP:~125℃(分解)。1H NMR(D2O):δ3.36(t,J=6Hz,2H),2.35(t,J=6Hz,2H),1.87(s,3H),1.80(s,3H)。实施例8:N-(肼基亚氨基甲基)-β-丙氨酸
将3-[[亚氨基[(1-甲基亚乙基)肼基]甲基]氨基]丙酸(5.88g,31.61mmol)溶于125mL水并加热至60℃保持72小时。蒸除溶剂并将产物在4∶1的EtOH和MeOH混合物中搅拌。将得到的浅橙色沉淀过滤,用乙醇洗涤并干燥,得3.16g(68%)浅橙色固体状N-(肼基亚氨基甲基)-β-丙氨酸。MP:177-179℃。1H NMR(D2O):δ3.39(t,J=6Hz,2H),2.42(t,J=6Hz,2H)。实施例9:N-(二肼基亚甲基)-1-丙氨酸
在L-丙氨酸(10.0克,0.11摩尔)和三乙胺(33.5毫升,0.24摩尔)的乙醇(90毫升)和水(6毫升)悬浮液中加入二硫化碳(7.2毫升,0.12摩尔)。搅拌过夜后,将甲基碘(7.5毫升,0.12摩尔)加到黄色溶液中。搅拌混合物1小时并浓缩成浆液。将残余物溶于水(25毫升),加入浓盐酸成酸性。用***(3×100毫升)萃取混合物,干燥(硫酸镁)有机相并浓缩而得18.4克(93%)纯净淡黄色固体状的相应二硫代氨基甲酸酯。从***/己烷中重结晶而得分析纯样品:熔点90-92;1H NMR(D2O)δ4.89(q,J=7Hz,1H), 2.59(s,3H),1.52(d,J=7Hz,3H)。
在二硫代氨基甲酸酯(5.0克,28毫摩尔)的二氯甲烷(50毫升)溶液中于0℃加入三氟甲磺酸甲酯(3.5毫升,31毫摩尔)。将混合物升温至室温并搅拌20小时。减压浓缩混合物而得无色油。将所得油溶于水(5毫升),加入1.0M氢氧化钠(28毫摩尔)。用乙酸乙酯萃取(3×100毫升)混合物,干燥(硫酸镁)有机相。过滤后,真空除去溶剂而得粘稠油。将此油溶于无水乙醇(25毫升),加入无水肼(4.4毫升,0.14摩尔)。搅拌混合物1.5小时,过滤收集所形成的固体(2.5克)。将白色粉末从水/IPA中结晶而进一步纯化得2.2克(49%)的白色粉末状二氨基胍:熔点174-176(分解);1H NMR(D2O)δ3.69(q,J=7Hz,1H),1.20(d,J=7Hz,3H)。实施例10:N-(二肼基亚甲基)-β-丙氨酸
按照类似N-(二肼基亚甲基)-1-丙氨酸所使用的方法,将β-丙氨酸转化为N-(二肼基亚甲基)-β-丙氨酸(熔点192℃,分解)。1H NMR(D2O)δ3.40(t,2H,J=7Hz),2.48(t,2H,J=7Hz)。实施例11:N-(二肼基亚甲基)-甘氨酸
将甲基化硫代对称二氨基脲(25.0克,101毫摩尔)和甘氨酸(6.314克,83.98毫摩尔)的水(50毫升)溶液及12.5N NaOH(8.89毫升,111毫摩尔)溶液于75-80℃氮气下搅拌3小时。将该溶液于冰上冷却,在逐步加入无水乙醇(550毫升,每次50毫升)前一直在氮气下,每次加入之间都要搅拌直至加完。过滤前于0℃将混合物搅拌15分钟。收集的固体用无水乙醇彻底洗涤。干燥而得淡粉色粉末(8.04克)。将粗品固体溶于水(30毫升),过滤除去一些细不溶物,然后用无水乙醇稀释至250毫升。几乎立即出现沉淀,通过声处理数秒加速。室温放置10分钟后,过滤混合物而得淡玫瑰色粉末(5.25克,42%,熔点200℃,分解)。1H NMR(D2O)3.78(s)。实施例12:[2-(肼基亚氨基甲基)肼基]乙酸
将肼基乙酸乙酯盐酸盐(9.28克,60毫摩尔)在120毫升1N氢氧化钠中回流2小时而皂化。在热溶液中加入N-氨基-S-甲基异硫脲氢碘酸盐(13.98克,60毫摩尔),然后再回流溶液2小时。除去溶剂。粗产物溶于甲醇,过滤除去氯化钠。浓缩滤液,通过高真空干燥。然后将残余物与150毫升甲醇搅拌过夜。过滤所得白色固体。然后将该固体在100毫升甲醇中回流2小时以除去任何不纯物。然后冷却混合物并过滤。真空干燥所得固体而得2.14克(24%)[2-(肼基亚氨基甲基)肼基]乙酸的灰白色固体。熔点:201-203℃(分解)。1H NMR(D2O)δ3.78(s,2H)。实施例13:N-(二肼基亚甲基)-d-丙氨酸
在D-丙氨酸(1.8克,20毫摩尔)和三乙胺(6.1毫升,44毫摩尔)的乙醇(15毫升)和水(1毫升)悬浮液中加入二硫化碳(1.3毫升,22毫摩尔)。搅拌过夜后,将甲基碘(1.4毫升,22毫摩尔)加到黄色溶液中。搅拌混合物1小时并浓缩成浆液。将残余物溶于水并加入浓盐酸成酸性。用甲基叔丁醚(3×50毫升)萃取混合物,干燥(硫酸镁)有机相并浓缩得黄色油,声处理并加入少量己烷而固化。进一步干燥得2.9克黄色固体。然后通过重结晶(***/己烷)进一步纯化而得1.67克(47%)表9化合物A的膏状固体:熔点89-91℃;1H NMR(D2O)δ4.67(m,1H),2.39(s,3H),1.32(d,J=7Hz,3H)。
在表9化合物A的二硫代氨基甲酸酯(15.1克,84.3毫摩尔)的二氯甲烷(170毫升)溶液中于0℃加入三氟甲磺酸甲酯(10.5毫升,92.7毫摩尔)。将混合物升温至室温并搅拌20小时。减压浓缩混合物而得无色油。将所得油溶于水(40毫升),加入1.0M氢氧化钠(84.3毫摩尔)。用乙酸乙酯萃取(3×200毫升)混合物,干燥(硫酸镁)有机相。过滤后,真空除去溶剂而得粘稠油。将此油溶于无水乙醇(85毫升),加入无水肼(13.2毫升,0.42摩尔)。搅拌混合物1.5小时,过滤收集所形成的固体(7.5克)。将白色粉末从水/IPA中结晶而进一步纯化得6.48克(48%)的白色粉末状标题化合物:熔点175-177℃(分解);1H NMR(D2O)δ3.69(q,J=7Hz,1H),1.20(d,J=7Hz,3H)。实施例14:N-(二肼基亚甲基)-缬氨酸
在L-缬氨酸(5.0克,42.7毫摩尔)和三乙胺(13.1毫升,93.9毫摩尔)的乙醇(30毫升)和水(2毫升)悬浮液中加入二硫化碳(2.8毫升,47.0毫摩尔)。搅拌过夜后,将甲基碘(2.9毫升,47.0毫摩尔)加到黄色溶液中。搅拌混合物2小时并浓缩成浆液。将残余物溶于水(10毫升)并加入浓盐酸成酸性。用***(3×100毫升)萃取混合物,干燥(硫酸镁)有机相并浓缩得黄色油,引晶后得黄色固体。将该固体悬浮于己烷中并过滤而得7.7克灰白色表9化合物B固体。冷却滤液至0℃而得第二批0.27克表9化合物B的白色固体(总共7.97克,90%):熔点76-78℃;1H NMR(CDCl3)δ5.30(m,1H),2.40(m,1H),1.08(d,J=7Hz,3H),1.04(d,J=7Hz,3H)。
在表9化合物B(8.0克,38.6毫摩尔)的二氯甲烷(60毫升)溶液中于0℃加入三氟甲磺酸甲酯(4.8毫升,42.5毫摩尔)。将混合物升温至室温并搅拌20小时。减压浓缩混合物而得无色油。将所得油溶于水(10毫升),加入1.0M氢氧化钠(38.6毫升)。用乙酸乙酯萃取(3×100毫升)混合物,干燥(硫酸镁)有机相。过滤后,真空除去溶剂而得粘稠油。将此油溶于异丙醇(150毫升),加入一水合肼(9.4毫升,0.19摩尔)。搅拌混合物2小时,加入THF得到更易过滤的固体。过滤而得2.4克(33%)微吸湿的白色固体状标题化合物:熔点112-116℃;1H NMR(D2O)δ3.70(d,J=5.0Hz,1H),2.20(m,1H),0.97(d,J=7.0Hz,3H),0.94(d,J=7.0Hz,3H)。实施例15:[1-(氨基亚肼基甲基)肼基]乙酸(参考方案5)9的制备
在搅拌下的肼基乙酸乙酯盐酸盐(5.0克,32.34毫摩尔)和N-甲基吗啉(3.26克,32.34毫摩尔)悬浮液中于0℃加入固体N-(苄氧羰基氧基)琥珀酰亚胺(8.06克,32.34毫摩尔)。使混合物升温至室温过夜,真空除去溶剂。将残余物悬浮在乙酸乙酯/水中,振摇各层,分离有机层并用硫酸钠干燥。除去溶剂,将残余物在SiO2闪式色谱上进行色谱分离(洗脱液4∶1己烷/乙酸乙酯)而得5.7克(70%)白色固体状标题化合物。熔点95-97℃。将随后反应中的残余物从乙酸乙酯/己烷中重结晶纯化而得略低产率的标题化合物。1H NMR(CDCl3)δ1.27(t,J=7Hz,3H),3.66(s,2H),4.19(q,J=7Hz,2H),5.13(s,2H),6.77(br s,1H),7.33(m,5H)。10的制备
在搅拌下的9(3.0克,11.89毫摩尔)的乙醇(30毫升)悬浮液中于室温加入NaOH水溶液(1N,11.89毫升)。在此混合物中再加入水(10毫升),搅拌1小时(混合物成均匀溶液,然后沉淀出固体)。然后加入盐酸水溶液(1N,11.89毫升),真空除去乙醇,用乙酸乙酯(2×100毫升)萃取水层。合并有机层,用硫酸钠干燥,除去溶剂而得2.31克(87%)白色固体状标题化合物,熔点131-133℃。1H NMR(CD3OD)δ3.59(s,2H),5.15(s,2H),7.37(m,5H)。11的制备
在搅拌下的10(25.44克,112.7毫摩尔)的乙酸乙酯(500毫升)悬浮液中加入异硫代氰酸三甲基甲硅烷基酯(14.79克,112.7毫摩尔),加热混合物至温和回流(80℃)过夜。将所得溶液冷却至室温,用水(2×100毫升)洗涤。分离有机层,用硫酸钠干燥,蒸发溶剂至干。将油状残余物溶于二氯甲烷,室温放置3分钟而形成固体。过滤固体,用二氯甲烷(100毫升)洗涤,真空干燥。将固体在热乙酸乙酯(300毫升)中浆化以溶解任何含硫副产物并用己烷(200毫升)研制而得17.1克标题化合物(53%)的白色固体。熔点148-149℃。1H NMR(CD3OD)δ5.20(s,2H),7.30(m,5H),未观察到剩余的CH2。12的制备
室温下,向搅拌下的11(5.0g,17.64mmol)的EtOH(150ml)溶液中加入碘甲烷(2.73g,19.41mmol)并将得到的溶液搅拌过夜。真空蒸除溶剂得到7.50g(定量)黄色泡沫状标题化合物。1H NMR(CD3OD):δ2.69(brs,0.6H),2.84(brs,0.4H),4.40-4.70(m,2H),5.31(brs,2H),7.46(m,5H)。13的制备
室温下,向剧烈搅拌下的12(25.5g,60mmol)的H2O(150ml)溶液中缓慢加入水合肼(6.06g,120mmol)直至已加入1/2的量。向形成的固体团中加入H2O(10ml)并用钢铲将固体机械捣碎。加入剩余的肼并将溶液剧烈搅拌1小时。将该非均相混合物声处理并持续搅拌直至形成粘稠的团。加入EtOH(50ml),滤出固体,用EtOH洗涤并真空干燥,得9.24g(55%)白色固体状标题化合物。m.p.168-170℃。1H NMR(D2O):δ3.86(brs,1H),4.21(brs,1H),5.17(s,2H),7.39(s,5H)。[1-(肼基亚氨基甲基)肼基]乙酸
向13(9.20g,32.71mmol)的MeOH/H2O(400ml,~2∶1 v/v)溶液中加入10%Pd-C(1.0g)并将该混合物在30psi氢化4小时。用硅藻土滤除催化剂并再次加入10%Pd-C(1.0g)。将该混合物在30psi氢化2.5小时并通过TLC(洗脱剂85∶14∶1 CH2Cl2/MeOH/HCO2H)确定反应完全。将混合物用硅藻土过滤并蒸除溶剂至约50ml,此时有固体沉淀析出。滤出固体,用极少量的H2O洗涤并真空干燥,得到3.60g(75%)米色固体状标题化合物。m.p.196-198℃。将滤液浓缩至有固体产生,得第二批产品。过滤得到0.9g(19%,总产率:94%)熔点完全相同的物质。1H NMR(D2O):δ4.06(s,2H)。
生物学试验
按照如下方法测定本发明的化合物降低血糖及体重的能力:
KKAy小鼠是NIDDM和肥胖的啮齿类动物模型(Chang,Wyse,Copeland,Peterson和Ledbetter,1986)。治疗前的血液样品从眶后窦获得,并将小鼠分成6组以使所有组的平均治疗前血糖水平的均值相同。将试验化合物以0.5%的浓度掺入食物中并让小鼠随意食用。对照小鼠接受未添加药物的食物。在第0天,将小鼠称重并喂以对照食物或添加有试验化合物的食物。食用对照食物或添加有试验化合物的食物3天后,抽取血样以测定葡萄糖浓度并将动物称重以测定重量损失。通过称重试验开始时提供的食物重量和试验结束时残余的食物重量来确定食用的食物量。从提供的食物重量中减去残余的食物重量计算出食用的食物量。将食用的食物量乘以0.5%计算出药物摄取量。用该方法计算出药物的摄取量大约为500mg/kg/天。血糖数据用试验组的平均血糖浓度除以对照组的平均血糖浓度(治疗/对照或T/C)来表达。引起T/C值等于或低于0.9的化合物被认为是有活性的抗高血糖药物。体重损失数据用体重改变的百分数来表示。与对照相比,在三天内引起体重减少1%或更多的化合物被认为是有活性的治疗肥胖的药物。
表1
本发明的优选化合物 [2-(氨基亚氨基甲基)-肼基]-乙酸 [2-(氨基亚氨基甲基)-肼基]-乙酸一盐酸盐 N-(肼基亚氨基甲基)-甘氨酸N-(肼基亚氨基甲基)-甘氨酸盐酸盐(2∶1) N-(二肼基亚甲基)-甘氨酸 [2-(肼基亚氨基甲基)-肼基]-乙酸 [1-(肼基亚氨基甲基)-肼基]-乙酸
表4具体要求保护的本发明化合物[2-(氨基亚氨基甲基)-肼基]-乙酸[2-(氨基亚氨基甲基)-肼基]-乙酸,一盐酸盐[2-(氨基亚氨基甲基)-肼基]-乙酸苯甲酯,一盐酸盐α-[2-(氨基亚氨基甲基)-肼基]-苯丙酸,一水合物外消旋体[1-(氨基亚氨基甲基)-肼基]-乙酸,一氢溴酸盐N-(肼基亚氨基甲基)-β-丙氨酸N-(二肼基亚甲基)-甘氨酸[2-(肼基亚氨基甲基)-肼基]-乙酸N-(二肼基亚甲基)-β-丙氨酸N-(二肼基亚甲基)-L-丙氨酸N-(二肼基亚甲基)-d-丙氨酸N-(二肼基亚甲基)-缬氨酸[1-(氨基亚肼基甲基)-肼基]-乙酸
表5要求保护治疗NIDDM用途的已知化合物[(氨基亚氨基甲基)亚肼基]-乙酸,一盐酸盐,一水合物2-[(氨基亚氨基甲基)亚肼基]-丙酸,一盐酸盐2-[(氨基亚氨基甲基)亚肼基]-丁酸,一盐酸盐N-(肼基亚氨基甲基)-甘氨酸N-(肼基亚氨基甲基)-甘氨酸,盐酸盐(2∶1)α-[(氨基亚氨基甲基)亚肼基]-苯丙酸2-[(氨基亚氨基甲基)亚肼基]-辛酸,一盐酸盐
表6口服给予KKAy小鼠N-(二肼基亚甲基)-甘氨酸对降低高血糖和肥胖的剂量-响应
将KKAy小鼠用N-(二肼基亚甲基)-甘氨酸进行上述治疗,不同之处在于将化合物以0.03、0.06、0.10、0.20、0.30和0.40%掺入食物中,以便给予大约30、60、100、200、300和400mg/kg的每日剂量。对照小鼠接受未添加药物的食物。为了与N-(二肼基亚甲基)-甘氨酸进行比较,以0.5%含量的食物混合物给予3-胍基丙酸(3-GPA)(大约剂量,500mg/kg/天)。数据以与试验第1天相比,第3天的血糖浓度和体重改变的百分数来表示。平均值±S.E.M.,N=6只小鼠/组。用JMP3.0.2软件(SAS研究所)进行方差分析以确定统计学显著性。*,P<0.05 vs Nil;
,明显低于3-GPA(P<0.05)。添加剂 血糖改变% 体重改变%Nil -5.8±7.1 -0.71±0.65N-(二肼基亚甲基)-甘氨酸 -13.5±10.5 -0.92±0.350.03%N-(二肼基亚甲募)-甘氨酸 -34.9±17.1* -1.51±2.110.06%N-(二肼基亚甲基)-甘氨酸 -45.2±6.4* -4.04±0.76*0.10%N-(二肼基亚甲基)-甘氨酸 -69.9±3.2*,
-8.22±1.05*0.2%N-(二肼基亚甲基)-甘氨酸 -70.4+1.5*,
-9.94+1.62*,
0.3%N-(二肼基亚甲基)-甘氨酸 -70.3±3.9*,
-10.3±0.97*,
0.4%0.5%3-GPA -38.4+4.4* -5.4±0.81**,P<0.05 vs.Nil,明显低于3-GPA(P<0.05)
表7
腹膜内葡萄糖耐量的提高
葡萄糖耐量在无糖尿病的C57BL小鼠和患糖尿病的KKAy小鼠中测定。通过管饲法经口向动物给予蒸馏水(对照)或100mg/kg的N-(二肼基亚甲基)-甘氨酸,然后禁食16-17小时。从眶后窦抽取用于葡萄糖测定的血样。血样在即将对腹膜内给予2g/kg葡萄糖之前(时间=0)以及注射后的30、60和90分钟抽取。血糖用葡萄糖自动分析仪测定。数据用平均值±S.E.M.表示,每组5-6只小鼠。用JMP3.0.2软件(SAS研究所)进行方差分析以确定统计学显著性。*,P<0.05vs.对照。
小鼠 组 时间(分钟) 血糖(mg/dl)
C57BL 对照 0 143±8
30 233±14
60 240±8
90 226±9
N-(二肼基亚甲
基)-甘氨酸 0 114±9*
30 174±17*
60 153±7*
90 161±19*
KKAy 对照 0 188±43
30 487±10
60 469±20
90 486±26
N-(二肼基亚甲 115±16(P=0.12vs.对
基)-甘氨酸 0 照)
30 383±38*
60 396±63
90 392±67
表8
对蛋白质非酶催糖基化的抑制
对蛋白质非酶催糖基化的测定用公认的方法进行(Dolhofer和Wieland,1979;Khatami,Suldan,DAvis,Li和Rickey,1988)。将人血清白蛋白(Sigma化学公司)、[14C]-葡萄糖、和葡萄糖溶于生理盐水溶液并在37℃孵育8天,以测定100mM[14C]-D-葡萄糖在人血清白蛋白中的掺入量。将试验化合物以19.1mM加入溶液中。为了测定白蛋白的糖基化,加入1体积12%的三氯乙酸使蛋白质沉淀,离心,将沉积的小团用6%的三氯乙酸洗涤两次,并且每次洗涤后均进行离心。将洗涤过的小团溶解、加入闪烁体并通过液体闪烁计数测定放射性标记的葡萄糖的掺入量。数据用掺入到白蛋白中的[14C]-葡萄糖的百分数表示(两次测量的平均值)。用JMP3.0.2软件(SAS研究所)进行方差分析以确定统计学显著性。添加的物质 掺入的[14C]-葡萄糖%对照(Nil) 1.50氨基胍 0.96(P<0.05vs.对照)3-胍基丙酸 1.52N-(二肼基亚甲基)-甘氨酸 0.81(P<0.05vs.对照)N-(肼基亚氨基甲基)-甘氨酸 1.21(P<0.05vs.对照)乙酸一盐酸盐 1.29(P<0.05vs.对照)
表9
Claims (2)
1.一种化合物在制备用于治疗或预防非胰岛素依赖型糖尿病或肥胖的药物中的用途,其中该化合物具有结构式III:
HN=C(NH2)-HN-N=CR3-COOH式中R3为H,甲基,乙基,苄基或正己基。
2.权利要求1的用途,其中的化合物选自:
[(氨基亚氨基甲基)亚肼基]-乙酸,一盐酸盐,
2-[(氨基亚氨基甲基)亚肼基]-丙酸,一盐酸盐,
2-[(氨基亚氨基甲基)亚肼基]-丁酸,一盐酸盐,
N-(肼基亚氨基甲基)-甘氨酸及其盐酸盐(2∶1),
α-[(氨基亚氨基甲基)亚肼基]-苯丙酸,和
2-[(氨基亚氨基甲基)亚肼基]-辛酸。
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AU3117497A (en) | 1996-05-21 | 1997-12-09 | Pharmacia & Upjohn Company | Aminoguanidine carboxylate lactams for the treatment of non-insulin-dependent diabetes mellitus |
EP0957909A1 (en) * | 1997-02-13 | 1999-11-24 | Smithkline Beecham Plc | Use of nitric oxid synthase inhibitors for the treatment of diabetes |
SE9702457D0 (sv) * | 1997-06-26 | 1997-06-26 | Pharmacia & Upjohn Ab | Screening |
US6001578A (en) * | 1997-06-26 | 1999-12-14 | Pharmacia & Upjohn Ab | Methods of screening for modulators of uncoupling protein-2 (UCP-2) as potential treatments for obesity |
US6288124B1 (en) | 1998-05-22 | 2001-09-11 | Rima Kaddurah-Daouk | Methods of inhibiting undesirable cell growth using an aminoguanidine compound |
US6169115B1 (en) | 1998-05-22 | 2001-01-02 | Rima Kaddurah-Daouk | Use of aminoguanidine analogs for the treatment of diseases of the nervous system |
US6815421B1 (en) * | 2001-03-22 | 2004-11-09 | Osteopharm Inc. | Polypeptides for use in ameliorating effects of aging in mammals |
WO2009133152A1 (en) * | 2008-04-29 | 2009-11-05 | Becton, Dickinson And Company | Method and system for measuring a sample to determine the presence of and optionally treat a pathologic condition |
BRPI0822909B8 (pt) * | 2008-06-26 | 2021-05-25 | Laboratorios Silanes S A De C V | sal de glicinato de metformina para o controle da glicose sanguínea |
GB201300435D0 (en) * | 2013-01-10 | 2013-02-27 | Medical Res Council | Benzylideneguanidine Derivatives and Therapeutic Use for the Treatment of Protein Misfolding Diseases |
WO2016171038A1 (ja) * | 2015-04-23 | 2016-10-27 | 三菱瓦斯化学株式会社 | ガス発生剤、及びそれを用いた発泡体の製造方法 |
US20170056352A1 (en) * | 2015-08-25 | 2017-03-02 | Rgenix, Inc. | PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF |
WO2018160178A1 (en) | 2017-03-01 | 2018-09-07 | Rgenix, Inc. | Pharmaceutically acceptable salts of b-guanidinopropionic acid with improved properties and uses thereof |
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US3412105A (en) | 1966-01-05 | 1968-11-19 | American Home Prod | beta-aryl-n-guanidino-beta-alanines |
US3943253A (en) * | 1974-06-27 | 1976-03-09 | Barer Sol J | Guanido acids as fungicides |
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US5130324A (en) * | 1984-03-19 | 1992-07-14 | The Rockefeller University | 2-alkylidene-aminoguanidines and methods of use therefor |
US5272165A (en) * | 1984-03-19 | 1993-12-21 | The Rockefeller University | 2-alkylidene-aminoguanidines and methods of use therefor |
US4758583A (en) * | 1984-03-19 | 1988-07-19 | The Rockefeller University | Method and agents for inhibiting protein aging |
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US5059712A (en) | 1989-09-13 | 1991-10-22 | Cornell Research Foundation, Inc. | Isolating aminoarginine and use to block nitric oxide formation in body |
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