CN1329024C - 新型铬(Ⅲ)－α氨基酸络合物 - Google Patents
新型铬(Ⅲ)－α氨基酸络合物 Download PDFInfo
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- CN1329024C CN1329024C CNB038018446A CN03801844A CN1329024C CN 1329024 C CN1329024 C CN 1329024C CN B038018446 A CNB038018446 A CN B038018446A CN 03801844 A CN03801844 A CN 03801844A CN 1329024 C CN1329024 C CN 1329024C
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- complex
- chromium
- ion
- alpha amino
- amino acid
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Abstract
本发明涉及1∶3铬(Ⅲ)-α氨基酸络合物及其作为动物营养补充品的应用。
Description
技术领域
本发明涉及1∶3铬(III)-α氨基酸络合物及其作为动物营养补充品的应用。
发明背景
Schwarz和Mertz在1959年(Schwarz，K.和Mertz，W.，Chromium(III)andthe glucose tolerance factor，
Archs Biochem.Biophys.85：292(1959))第一次确认了营养品中铬的基本作用。这些研究人员发现，喂饲了产朊假丝酵母的大鼠发展为葡萄糖耐受不良。然而，喂饲了啤酒酵母的大鼠不会发展此病况。葡萄糖耐受因子(GTF)是存在于啤酒酵母中但不存在于产朊假丝酵母的一种物质。后来证实了GTF的活性成分是铬(III)。根据这些早期研究结果，人们开始进行许多研究途径以更好地理解铬的营养作用。虽然现在关于人和动物中铬的作用已知之甚多，但仍有许多方面尚未弄清楚，并且铬在人疾病中的许多作用还存在争议，也未被很好地记载。最近发表了几篇综述，总结了现时关于营养品中铬的作用的认识(Henry C.Lukaski，Chromium as aSupplement，
Ann Rev Nutr.19：279(1999)；Richard A.Anderson，Chromium，Glucose Intolerance and Diabetes，
Journal of the American College of Nutrition，17，548(1998)；John B.Vincent，The Biochemistry of Chromium，
J.Nutr.130：715(2000)；John B.Vincent，Quest for the Molecular Mechanism of ChromiumAction and its Relationship to Diabetes，
Nutrition Reviews，58：67(2000))。
最初于1959年提出的葡萄糖耐受因子的确切性质到现在仍然不清楚。从酸水解啤酒酵母和猪肾中部分纯化了能增强葡萄糖代谢的含铬物质。该酵母提取的物质受到普遍重视，通称为酵母GTF。据报，酵母GTF中的铬比源自无机物的铬更易被吸收。此外，有人提出，酵母GTF由铬(III)离子、烟酸、甘氨酸、谷氨酸和半胱氨酸组成(W.Mertz，M.M.Polansky等，Preparation ofchromium-containing material of glucose tolerance factor activity from Brewer’syeast extracts and by synthesis，E.W Toepfer，
J Agric Food Chem，25：162(1977))。该酵母GTF组合物一直存在争议，而且其他实验室不能重现它的分离。另外，还有人提出，分离的酵母GTF可能是特殊铬结合蛋白酸水解而产生的一种产物(K.H.Sumrall和J.B.Vincent，Is glucose tolerance factor anartifact produced by acid hydrolysis of low-molecular weight，chromium bindingsubstance？
Polyhedron，16：4171(1997))。
最近，关于铬在调节碳水化合物和脂质代谢的作用基础取得了一些进展。已经分离出一种称为低分子量铬结合物质(LMWCr)的肽，并且认为它在调节胰岛素对其受体的作用起关键作用。这种肽似乎广泛分布于哺乳动物组织，已经从许多来源中分离出来。LMWCr由甘氨酸、半胱氨酸、谷氨酸和天冬氨酸组成。谷氨酸和天冬氨酸占氨基酸残基一半以上。这种肽的分子量为1500道尔顿，结合四种铬离子。它在组织中主要以无金属形式存在。这种蛋白的氨基酸序列以及其铬络合物的晶体结构尚未知道(J.B.Vincent，TheBiochemistry of Chromium，
J.Nutr.130：715(2000))。 LMWCr结合铬似乎主要以阴离子桥连多核羧酸铬组合形式存在(Truitt Ellis等，Synthetic Models forLow Molecular Weight Chromium-Binding Substance：Synthesis andcharacterization of Oxo-Bridged Tetranuclear Chromium(III) Assemblies，
Inorg. Chem.，33：5522(1994))。已经发现，合成的多核铬组合与LMWCr相似，能激活胰岛素受体活性(C.M.Davis等，Synthetic Multinuclear ChromiumAssembly Activates Insulin Receptor Kinase Activity：Functional Model forLow-Molecular-Weight Chromium-Binding Substance，
Inorg.Chem.，36：5316(1997))。
认识一种未知的铬(III)和有机配体络合物负责调节碳水化合物和脂质代谢对开发在人和动物营养品中的使用新含铬化合物产生了重大意义。有很多授权专利描述了结合各种配体的含铬化合物。1975年授予本申请其中一名发明人的专利公开了1∶1和1∶2铬-α氨基酸络合物盐(US 3,925,433)。这些络合物盐以离子对存在，其中阳离子由铬(III)离子与一或两个α氨基酸分子的络合物组成。阳离子带1+或2+，取决于形成络合物的氨基酸分子数。相反离子(阴离子)可以是氯离子、硫酸根离子或酸性硫酸根离子。美国专利US5,278,329公开了L-甲硫氨酸的主要金属络合物，包括1∶1 L-甲硫氨酸铬络合物。而美国专利US 5,698,724描述了通过蛋白水解获得的氨基酸金属络合物，包括铬-氨基酸络合物。
1982年授权的美国专利US 4,343,905描述了一种从啤酒酵母制备浓缩葡萄糖耐受因子的方法。有些授权专利叙述了具有调节碳水化合物或脂质代谢生物活性的酵母或酵母衍生物的生产方法，例如美国专利US 4,348,483；6,140,107；6,159,466和6,248,323。
美国专利US 4,571,391描述了前述已知化合物乙酰丙酮酸铬作为食物补充品和药剂的应用。这种水不溶性化合物具有热稳定性，并且在酸和弱碱性溶液中很稳定。据报，口服乙酰丙酮酸铬后在胃肠道内被快速吸收，有效增强胰岛素对葡萄糖代谢的作用。
美国专利US 4,315,927第一次公开了用基本金属吡啶甲酸盐包括吡啶甲酸铬作为食物补充，1992年7月7日再颁布为Re33,988。美国专利US 4,315,927描述了吡啶甲酸铬的制备(实施例4)。Re33,988的具体权利要求书包括了铬、钴、铜和锰以及美国专利US 4,315,927所述的锌和铁的吡啶甲酸盐络合物。美国专利US 5,677,461描述了一种生产吡啶甲酸铬络合物的方法。很多专利也公开了吡啶甲酸铬在治疗和预防各种疾病中的应用，包括5,087,623；5,087624；5,175,156和6,329,361 B1。美国专利5,614,553；5,929,066；6,093,711；6,136,317；6,143,301；6,251,888 B1和6,251,889 B1叙述了含有吡啶甲酸铬的组合物及这些组合物的应用。
美国专利US 4,923,855和5,194,615描述了称作“GTF铬材料”的烟酸铬及其制备方法。烟酸铬降低血脂水平的应用可参见美国专利US 4,954,492。有多项专利包括US 5,905,075；5,948,772；5,980,905；6,100,250；6,100,251和6,323,192叙述了含有烟酸铬的组合物及其应用。
美国专利5,266,560公开了具有GTF样活性且在药学上能促进胰岛素活性的铬(III)络合物。这些络合物由铬(III)、烟酸或它的其中一种衍生物以及谷胱甘肽(含有L-谷氨酸、L-半胱氨酸和甘氨酸的肽)组成。这些络合物在体外对分离的脂肪细胞中葡萄糖运送具有促胰岛素活性已见报导，并且与以前文献中所报导的类似络合物作了比较。
美国专利5,707,679和6,303,158 B1描述了包括丙酸铬在内的金属丙酸盐的应用。含有短链脂肪酸铬盐的组合物及其在动物营养中的应用可参见美国专利5,846,581。生产用作动物食物补充品的金属羧酸盐的方法在美国专利5,591,878和5,795,615中有所描述。
肌氨酸和基本金属(包括铬在内)的有生物利用性的螯合物在美国专利US6,114,379中有所描述。该专利要求保护肌氨酸-铬络合物，所述络合物的每个铬离子含有1-3当量的配体。
美国专利6,149,948和6,197,816 B1叙述了已公知的三核铬(III)络合物作为营养补充品或在治疗医学病况中的应用。该络合物的分子式是[Cr3O(O2CCH2CH3)6(H2O)3]+。这些专利描述了该络合物对参与碳水化合物和脂质代谢中的许多酶的生物作用。美国专利US 5,872,102描述了分离牛低分子量铬结合物质的方法及其应用。这种物质增强了大鼠脂肪细胞中胰岛素激活的葡萄糖摄取，并激活了大鼠脂肪细胞膜酪氨酸激酶和磷酸酪氨磷酸酶的活性。
业已发现，一些缺点限制文献中所述各种铬络合物的有效性。通过商业途径获得的铬络合物中最常见的是吡啶甲酸铬。然而，这种化合物的水溶性较低，有些最新研究还质疑它的安全性。虽然已经证实了氯化铬和吡啶甲酸铬在大鼠体内无毒性(Anderson等，Lack of Toxicity of Chromium Chloride and ChromiumPicolinate in Rats，
J.Amer.Coll.Nutr.16：273(1997))，但最新研究报导吡啶甲酸铬切割DNA，对中国仓鼠卵巢细胞的染色体造成破坏(J.K.Speetjens等，TheNutritional Supplement Chromium(III)Tris(picolinate)Cleaves DNA，
Chem.Res. Toxicol.12：483(1999)以及D.M.Steams，Chromium(III)picolinate produceschromosome damage in Chinese hamster ovary cells，
FASEB J.，9：1643(1995))。一项关于吡啶甲酸铬(III)在大鼠体内分布的研究得出结论：该化合物在体内停留时间短会减弱该食物补充品潜在的有毒作用(D.D.D.Hepburn和J.B.Vincent，InVivo Distribiution of Chromium from Chromium Picolinate in Rates and Impliationsfor the Safety of the Ditary Supplement，
Chem.Res.Toxicol.，15：93(2002))。因此，需要具有可溶性、生物利用性、有效性和安全性的食用铬的替代来源是显然的。
本发明的主要目的是满足上述需要。
本发明的另一个目的是提供新的1∶3铬(III)和α氨基酸络合物，用作人和家畜动物的营养补充品。
本发明的另一个目的是提供这些新络合物的制备方法，例如，一种形成可溶于极性溶剂的本发明铬-α氨基酸1∶3络合物的方法。
本发明的再一个目的是提供并描述这些络合物对动物生产性能的理想作用。例如，所述动物为猪，剂量最高是300ppm铬；或者，所述动物是牛，剂量是0.03毫克/千克体重至0.06毫克/千克体重。
本发明又一个目的是证明这些新络合物在实验动物中无毒性。
本发明还提供一种增强家畜生物利用性的营养组合物，所述组合物包括本发明的铬络合物和动物营养载体。所述载体可选自由天然盐、磨碎玉米棒子、玉米粉和羽毛粉的惰性动物营养载体。所述载体可以是液态载体，例如溶剂，所述溶剂选白水、乙醇、糖浆或其混合物。
本发明的结构是1∶3铬(III)和α氨基酸络合物。有人早已研究了大部分现有营养相关的铬络合物的结构和性质。例如，已经合成了吡啶甲酸铬(III)单核和双核络合物，而且它们的结构也已通过X射线结晶学测定。氯化铬(III)与吡啶甲酸在水(pH＜4.0)中反应，生成单核络合物，其中金属与氨基酸之比为1∶3(三吡啶甲酸铬)。但如果溶液的pH值＞4.0，就会形成双核络合物。双核络合物中铬与氨基酸之比是1∶2(D.M.Stearns和W.H.Armstrong，Mononuclear and BinuclearChromium(III)Picolinate Complexes，
Inorg.Chem.，31：51(1992))。
还研究了吡啶甲酸和烟酸的铬络合物的组合物与生物活性。用这些吡啶羧酸形成的铬络合物是不同的，这是因为两种化合物的结构不同。烟酸不是α氨基酸，因此起单齿状配体的作用。它通过羧酸根阴离子与铬结合，形成双核和三核络合物。两种络合物(1∶1和1∶2)都是在铬和烟酸之间形成。在本研究所用的测试组中没有一种络合物有生物活性，除了二烟酸铬在大鼠分离脂肪组织中促进了胰岛素活性。另一方面，吡啶甲酸是一种α氨基酸，起双齿状配体的作用。它通过吡啶上的氮原子和羧基上的氧原子与铬离子结合，形成稳定的五元环。当氯化铬溶液用吡啶甲酸处理时，根据反应混合物中吡啶甲酸与铬之比形成了三种不同络合物。在氯化铬溶液中加入1或2摩尔当量吡啶甲酸，改变了溶液的颜色。用氢氧化钠调溶液至pH 7.4，产生络合物沉淀。经高效液相层析法(HPLC)发现这些络合物是均匀的。当使用1摩尔当量吡啶甲酸时，产物的结构是CrPic(H2O)2(OH)2。当使用2摩尔当量吡啶甲酸时，沉淀物的结构是Cr(Pic)2(H2O)(OH).(H2O)。因为这些络合物都是在pH＞4的条件下形成，所以它们最有可能是双核络合物。这两种络合物中没有一种有生物活性。在氯化铬水溶液中加入3摩尔当量吡啶甲酸，形成一种在溶液中沉淀的红色固体。用HPLC发现该沉淀物是均匀的。对该沉淀物的分析表明，它是三吡啶甲酸铬一水合物(Cr(Pic)3(H2O))。这种物质最可能是单核络合物。该络合物增进了体外大鼠骨胳肌培养液对葡萄糖的摄取。在大鼠饮食中加入该络合物，显着降低了血糖，并防止了血红蛋白的糖化。人食用补充了三吡啶甲酸铬的食物之后，男性和女性的瘦体重都有明显上升(G W Evans和D JPouchnick，Composition and Biological Activity of Chromium-PyridineCarboxylate complexes，
J.Inorg.Biochem.，49：177(1993))。
由此可见，现有的全部结构均与本发明的铬化合物不同，本发明的铬化合物有不同的经验式和不同的空间化学。
发明内容
本发明涉及新的1∶3铬(III)络合物的制备。这些络合物含有氧化态铬和3个氨基酸。络合物中的铬与三个α氨基酸分子结合。与在极性溶剂中实际不溶的已知中性铬络合物不同，本专利申请所述的新络合物极易溶于极性溶剂中，如水和甲醇。这些络合物在酸和碱性溶液中是稳定的。该水溶性络合物当加在食物中时，是容易获得具有生物利用性的铬的有用来源。这些络合物用作动物营养品的饲料添加剂提高了动物的生产性能。这些络合物以高剂量喂饲实验室大鼠时不会引起中毒。
具体实施方式
铬以几种氧化态存在，但最稳定和重要的形态是铬(III)。在此最稳定形态中，三价铬的配位数是6。有6个配位数的三价铬与多种配体形成八面体络合物。这些络合物的特点在于其在水溶液中的相对分子运动惰性。这些络合物中有许多的配体置换反应的半衰期是数小时。由于有这种分子运动惰性，所以很多络合物以固体被分离出来，甚至在热力学不稳定时也能在水溶液中稳定存在相当长的时间。
本发明涉及新的安全有效铬-氨基酸络合物的设计、合成和评估。赋予金属-氨基酸络合物生物活性的特征包括溶解度、络合物在肠胃内pH值时的稳定性、络合物的吸收率和络合物参与生化反应的能力。使用天然氨基酸以及提高其生物利用性以减少为满足动物营养需要而向饲养添加的金属用量，都可以增加金属-氨基酸络合物的安全性。
美国专利US 3,925,433描述了1∶1和1∶2铬-α氨基酸络合物盐。虽然这些络合物与铬无机源相比营养有重要的提高，但它们也存在一些不足。氯化铬溶液与1、2或3摩尔当量α氨基酸混合，形成澄清绿色溶液。这些溶液的pH值分别是0.932、1.324和1.627。小心加入氢氧化钠或碳酸钠溶液调这些溶液至pH 7，使铬化合物沉淀，这表明这些化合物在胃肠道pH值范围内可能非常不稳定的。当铬-α氨基酸络合物(1∶3)以3当量氢氧化钠处理时，形成紫色沉淀物。该沉淀物实际上不溶于水、稀释酸和碱、甲醇、乙醇、异丙醇和乙酸乙酯。元素分析和它的傅立叶红外光谱(FTIR)检查显示，它是铬-氨基酸络合物(1∶3)与一些多核铬-氨基酸络合物的混合物。该络合物的不溶性及其不确定组成使我们可以假定，它不可能具有营养价值。
结构1
本发明所述的新络合物以结构式1表示，是1∶3铬-氨基酸络合物盐。这些络合物以离子对存在，其中一价阳离子由三价铬与三个α氨基酸分子复合组成。其中一个氨基酸分子保留了它的两性离子特征，使络合物带净正电荷。该氨基酸的羧基与铬(III)离子形成两个键，从而形成一个满足铬6个配位中的2个配位的应变四元环。其余两个α氨基酸分子通过α氨基和羧基结合铬，形成五元环。这将使铬(III)的全部6个配位饱和。本文把离子对中的阴离子称为“X”，它可以是水溶性阴离子，例如水溶性一价阴离子或二价阴离子，如氯离子、溴离子、碘离子、磷酸根离子、乙酸根离子和丙酸根离子或硫酸根离子。“R”是α氨基酸的有机基团。它可由精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯基丙氨酸、苏氨酸、色氨酸、缬氨酸、甘氨酸等衍生而来。虽然甘氨酸不是基本氨基酸，但它也是优选的α氨基酸，因为它容易获得，并能轻易合成本发明的络合物盐。最优选的两种天然α氨基酸是甘氨酸和甲硫氨酸。对于甘氨酸，R表示氢原子，对于甲硫氨酸，R表示基团CH3-SC-H2-CH2-。
这些络合物可用简单实用方法制成。把氯化铬水溶液加热至90-95℃。溶液的颜色通常呈深绿色。小心加入氨基酸(3摩尔当量)，继续加热。溶液的颜色慢慢变成深蓝绿色。再将溶液冷却至约40℃，缓慢小心地加入氢氧化钠溶液调溶液至pH 3.9-4.0。调节pH值需要2摩尔当量氢氧化钠。溶液的颜色转为深紫色。蒸发液体得到固体，该固体由所希望的产物和氯化钠组成。用甲醇或乙醇萃取，可从氯化钠中分离出产物。另外，也可通过合适的尺寸排斥树脂层析法从氯化钠中分离出产物。
用上述方法得到的产物有一些独特性质。它是一种稳定固体。它的颜色呈深紫色。该产物易溶于水和甲醇中，溶于乙醇中，微溶于异丙醇中，不溶于乙酸乙酯。0.1M该产物水溶液的pH值为4.078。该溶液的紫外/可见光光谱的最大吸收峰在400nm(摩尔吸光度，44.08)和541nm(摩尔吸光度，50.60)处。与之不同的是，氯化铬的紫外/可见光光谱的最大吸收峰在429nm(摩尔吸光度，18.10)和608nm(摩尔吸光度，14.43)处。加入20摩尔当量的0.1M碳酸氢钠溶液将溶液的pH值调至8.097，但无形成沉淀。在一实施例中，加入80摩尔当量的0.1M碳酸氢钠溶液。混合物的pH值是8.354，但无形成铬化合物沉淀。与之相反，在0.1M氯化铬溶液中加入稍高于2当量的0.1M碳酸氢钠溶液，形成大量沉淀物，但混合物的pH值只有4.356。加入20摩尔当量盐酸调0.1M络合物溶液至约pH1.0，溶液的紫外/可见光光谱无改变，这表明络合物不会分解。
用HPLC测定，用上述方法得到的固体络合物是均匀的。用尺寸排斥柱分析甲醇溶液，显示存在单个组分。检测两种不同波长的峰(一种波长检测铬，另一种波长检测氨基酸)表明，两种波长都洗脱出单峰。对氯化铬甲醇溶液分析表明，它洗脱出多峰，没有一个峰与络合物的峰相似。而且，氯化铬的主峰停留时间比络合物短，表示络合物的分子量较大。
用不同α氨基酸得到具有相似物化性质的络合物。这些络合物的元素分析得出的结果与所提出的结构一致。络合物的FTIR光谱与用来形成络合物的氨基酸不同，而与其它金属氨基酸络合物相类似。
测试了由铬(III)和L-甲硫氨酸形成的络合物作为乳牛铬营养源，结果发现乳牛的生产性能有所改善。饮食中补充三L-甲硫氨酸铬盐酸盐不会影响乳牛摄取干物质，但增加了牛奶产量。检查该络合物在大鼠中的毒性，发现所用剂量不会引起中毒。
实施例1 三L-甲硫氨酸铬(III)盐酸盐的制备
把水(550毫升)倒入2000毫升烧杯中。加入氯化铬六水合物(79.959克，0.3摩尔)。混合物搅拌加热至沸腾。加入L-甲硫氨酸(134.306克，0.9摩尔)。混合物搅拌加热直至固体完全溶解。持续搅拌加热多30分钟。溶液由深绿色转为深蓝绿色。将溶液冷却至30℃。氢氧化钠(23.317克，0.5829摩尔)溶于100毫升水中，将溶液冷却至30℃。边搅拌边向甲硫氨酸铬溶液逐滴加入氢氧化钠溶液。溶液由深蓝绿色转为紫色。减压蒸干溶液。残留物用甲醇萃取，得到白色结晶固体。蒸干甲醇萃取液，得到深紫色结晶固体(161.352克，得率为100.91％)。
将产物置于溴化钾片上进行FTIR，吸光结果为3421.5(s)、2916.2(s)、1635.5(s)、1508.2(m)、1438.8(m)、1338.8(m)、1338.5(s)、1272.9(w)、1242.1(w)和1145.6(m)cm-1。(s表示强、m表示中等，w表示弱)
0.01M水溶液的可见光光谱有两个最大吸收峰：400nm(摩尔吸光度，44.08)和541nm(摩尔吸光度，50.60)。
0.1M水溶液的pH值是4.078。取10毫升该溶液用200毫升0.1M碳酸氢钠溶液稀释。无形成沉淀。溶液的pH值是8.097。加入另外600毫升0.1M碳酸氢钠溶液。无形成沉淀，溶液的pH值是8.354。
对络合物在甲醇中的溶液(含有0.9555毫克/毫升铬)用HPLC和紫外/可见光检测仪进行分析，HPLC层析柱为60A Macrosphere GPC柱(AlltechAssociates，Inc.)，流动相为甲醇，流速0.5毫升/分钟。获得一个单峰，停留时间为6.48分钟。当在相同条件下对含有0.4666毫克/毫升铬的氯化铬六水合物溶液进行分析时，洗脱出一个峰，停留时间为6.67分钟。停留时间延长表明铬络合物的分子量比氯化铬大。
除了把检测仪设在210nm外，重复一次HPLC分析以检测氨基酸。检测灵敏度比405nm高100倍，因而需要将样品稀释至含有0.009555毫克/毫升铬。407nm时该稀释样品出现单峰，停留时间为6.19分钟。210nm时有多个次峰与一个主峰，而主峰的停留时间为6.19分钟。在相同条件下把检测仪设在210nm，分析L-甲硫氨酸盐酸盐样品，结果显示有多个次峰与一个主峰，而主峰的停留时间为7.6分钟。这些结果表明，络合物完全转移到柱上，它的分子量比氯化铬和L-甲硫氨酸盐酸盐大。
实施例2 三亮氨酸铬(III)盐酸盐的制备
把水(150毫升)倒入600毫升烧杯中。加入氯化铬六水合物(13.325克，0.05摩尔)。混合物搅拌加热至沸腾。加入L-亮氨酸(19.685克，0.15摩尔)。混合物搅拌加热直至固体完全溶解。持续搅拌加热多30分钟。溶液由深绿色转为深蓝绿色。将溶液冷却至30℃。氢氧化钠(4.014克，0.10摩尔)溶于20毫升水中，将溶液冷却至30℃。边搅拌边向亮氨酸铬溶液逐滴加入氢氧化钠溶液。溶液由深蓝绿色转为深紫色。减压蒸干溶液。残留物用甲醇萃取，得到白色结晶固体。蒸干甲醇萃取液，得到深紫色结晶固体(28.363克，理论值是23.948克，得率118.44％，这表示产物含有残余的氯化钠)。
将产物置于溴化钾片上进行FTIR，吸光结果为3425.3(m)、2916.2(s)、1635.5(s)、1508.2(m)、1438.8(m)、1384.8(m)、1338.5(s)、1272.9(w)、1242.1(w)和和1141.8(m)cm-1。(s表示强、m表示中等，w表示弱)
0.01M水溶液的可见光光谱有两个最大吸收峰：406nm(摩尔吸光度，38.79)和545nm(摩尔吸光度，42.81)。
0.1M水溶液的pH值是3.996。取10毫升该溶液用200毫升0.1M碳酸氢钠溶液稀释。无形成沉淀。溶液的pH值是7.987。溶液的可见光光谱有两个最大吸收峰：409nm(摩尔吸光度，47.46)和558nm(摩尔吸光度，47.67)。
实施例3 三甲硫氨酸铬(III)盐酸盐预混合物(0.1％铬)的制备
量取100毫升蒸馏水，倒入400毫升烧杯中。加入氯化铬六水合物(6.672克，0.0251摩尔)，混合物搅拌加热直至固体完全溶解。加入L-甲硫氨酸(11.201克，0.0751摩尔)，所得的混合物搅拌加热。溶液的颜色由深绿色转为蓝绿色。再在90-95℃加热多60分钟。将溶液冷却至30℃。边搅拌边逐滴加入氢氧化钠(1.967克，0.0492摩尔)在50毫升水中的冷却溶液。溶液的颜色转为深紫色。减压蒸发溶液。残留物溶于100毫升甲醇中，把该溶液加在1000克载体中。将混合物放入60℃烘箱内24小时。如实施例1所述用紫外/可见光检测仪、比色法和HPLC分析干燥的预混合物样品。该预混合物用于猪的喂饲试验。
实施例4 三甲硫氨酸铬(III)(1.75％铬)的制备
量取1500毫升水，倒入4升烧杯中。加入氯化铬六水合物(390.993克，1.4675摩尔)，混合物搅拌加热直至固体完全溶解。连续搅拌加热多1小时，直至铬盐完全形成水合物。加入L-甲硫氨酸(1094.845克，7.338摩尔)，所得的混合物搅拌加热直至全部固体溶解。连续搅拌加热1小时。溶液的颜色转为深紫色。用蒸馏水把溶液配至4升。
溶液的pH值是2.336。它含有25.61％甲硫氨酸和1.86％铬。
0.01M水溶液的可见光光谱有两个最大吸收峰：416nm(摩尔吸光度，102.5)和579.5nm(摩尔吸光度，101.9)。
0.1M水溶液的pH值是2.285。取10毫升该溶液用200毫升0.1M碳酸氢钠溶液稀释。无形成沉淀。溶液的pH值是7.546。溶液的可见光谱有两个最大峰：409.5nm(摩尔吸光度，43.89)和558nm(摩尔吸光度，46.83)。
实施例5 三L-甲硫氨酸铬盐酸盐对乳牛生产性能的影响
研究了以三L-甲硫氨酸铬盐酸盐形式存在的铬补充品对临近分娩的乳牛的生产性能的影响。用了72只乳牛来确定临近分娩期在食物中加入三L-甲硫氨酸铬盐酸盐是否会影响牛奶产量和干物质的摄取。从预产期前21天直至分娩的期间给乳牛喂饲高非草料纤维食物或高非纤维碳水化合物食物，然后再喂饲一般哺乳食物。每日以胶囊锭(gelcap)形式补充1次三L-甲硫氨酸铬盐酸盐，剂量为0、0.03或0.06毫克/千克代谢体重。铬的补充在预产期前第21天开始，持续至产后第28天。按照确立的程序在乳牛产下小牛后挤奶。在整个实验期间记下每只乳牛每日的食物摄取量。每周抽取食物样品，测定干物质含量。在实验的泌乳期记录每次挤奶时各乳牛的牛奶重量。每周都在一个24小时的时段内，从全部挤出的牛奶采牛奶样品，根据每次的奶量把这些样品混合，分析其脂肪、蛋白质、乳糖和总固体。
食物中补充了三L-甲硫氨酸铬盐酸盐不会影响乳牛的干物质摄取。然而，补充了铬有增加牛奶产率的趋势(p＜0.13，表1)。
表1
| 三L-甲硫氨酸铬盐酸盐毫克/千克体重75 | |||
| 0.00 | 0.03 | 0.06 | |
| 产前干物质的摄取千克/天 | 13.6 | 13.9 | 13.7 |
| 产后干物质的摄取千克/天 | 17.9 | 18.9 | 19.4 |
| 牛奶产量千克/天 | 40.4 | 40.6 | 42.8 |
| 牛奶脂肪千克/天 | 1.73 | 1.76 | 1.81 |
| 牛奶脂肪百分比 | 4.43 | 4.41 | 4.33 |
| 牛奶蛋白质千克/天 | 1.28 | 1.33 | 1.31 |
| 牛奶蛋白质百分比 | 3.32 | 3.37 | 3.15 |
| 牛奶乳糖千克/天 | 1.86 | 1.91 | 1.98 |
| 牛奶乳糖百分比 | 4.63 | 4.69 | 4.61 |
| 牛奶固体千克/天 | 5.27 | 5.37 | 5.51 |
| 牛奶固体百分比 | 13.38 | 13.39 | 13.03 |
本实施例和本发明的铬(III)络合物可与常用惰性营养载体，例如蒸馏发酵溶质、饲料谷物、家禽和鱼双产物、饲料粉、乳清、天然盐、磨碎玉米棒子、羽毛粉等一起使用。
实施例6 三L-甲硫氨酸铬盐酸盐在大鼠中的毒性
在大鼠单剂量口服三L-甲硫氨酸铬盐酸盐之后，研究它在大鼠中的毒性。研究用了50只6周龄的大鼠(25只雄性和25只雌性)。雄性大鼠重130克至220克，雌性大鼠重120克至190克。这些动物关在聚碳酸酯笼内，笼内以无尘木屑为垫料，每组5只。将笼置于温度22℃和相对湿度55％的空调室内。给大鼠随意喂饲丸状完全食物。在给药前使动物禁食一晚，给药后3-4小时再进食。动物随意饮水。随机指派动物接受5种处理之一。两组动物(每组5只)、一组雄性动物、一组雌性动物分别接受一种处理。这些处理就是对照处理、给予250毫克/千克、500毫克/千克、1000毫克/千克、和2000毫克/千克化合物。化合物的水溶液经胃灌流以单剂量口服给予。动物接受给药后观察14天。在第14天处死存活动物。就在处理前、研究期间每周2次以及死亡时记录动物的重量。
研究期间无动物死亡，给予任何剂量水平化合物的动物也没有发现有与处理相关的临床症状。此外，口服剂量后第14天对动物进行尸检，肉眼观察也没有发觉有任何异常。但给予2000毫克/千克剂量的雄性大鼠增体下降5％。此剂量是猪推荐剂量的4000倍。另外还发现，给予1000和2000毫克/千克剂量的两组动物与对照组动物相比，食物摄取量下降与剂量有关。
这些结果表明，在实验条件下，以猪推荐剂量的1000倍水平给大鼠单剂量口服三L-甲硫氨酸铬盐酸盐不会引起中毒。给予猪推荐剂量的2000倍会导致食物摄取量下降，但与体重增加的减少无关。2000毫克/千克剂量是猪推荐剂量的4000倍，食物摄取量减少与增重轻微下降有关。
Claims (12)
1.一种铬-α氨基酸1∶3络合物，其特征在于：所述络合物以下式表示：
式中，“R”是天然α氨基酸正常所带的有机基团，“X”是水溶性阴离子。
2.如权利要求1所述的络合物，其特征在于：所述“X”是水溶性一价阴离子。
3.如权利要求1所述的络合物，其特征在于：所述“X”选自氯离子、溴离子、碘离子、硫酸根离子、磷酸根离子、乙酸根离子和丙酸根离子。
4.如权利要求1所述的络合物，其特征在于：选取“R”以致α氨基酸为一种选自精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯基丙氨酸、苏氨酸、色氨酸、缬氨酸和甘氨酸的氨基酸。
5.一种增强家畜生物利用性的营养组合物，其特征在于：所述组合物包括权利要求1所述的络合物和动物营养载体。
6.如权利要求5所述的组合物，其特征在于：所述络合物中的“X”选自氯离子、溴离子、碘离子、硫酸根离子、磷酸根离子、乙酸根离子和丙酸根离子。
7.如权利要求5所述的组合物，其特征在于：选取络合物中的“R”以致α氨基酸为一种选自精氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、甲硫氨酸、苯基丙氨酸、苏氨酸、色氨酸、缬氨酸和甘氨酸的氨基酸。
8.如权利要求5所述的组合物，其特征在于：所述载体是选自天然盐、磨碎玉米棒子、玉米粉和羽毛粉的惰性动物营养载体。
9.一种改善动物生产性能的方法，包括给予动物权利要求1所述的络合物。
10.如权利要求9所述的方法，其特征在于：所述动物是猪，剂量最高是300ppm铬。
11.如权利要求9所述的方法，其特征在于：所述动物是牛，剂量是0.03毫克/千克体重至0.06毫克/千克体重。
12.一种形成可溶于极性溶剂的铬-α氨基酸1∶3络合物的方法，所述络合物以下式表示：
式中，“R”是天然α氨基酸正常所带的有机基团，“X”是水溶性阴离子；
所述方法包括：将三价铬盐水溶液加热至90至95℃；在加热混合物中加入3当量的天然α氨基酸；继续加热直至颜色由深绿色转为深蓝绿色；以及冷却并调pH值至3.9至4.0之间，溶液转为深紫色，由此使络合物稳定。
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- 2003-04-29 CA CA002467805A patent/CA2467805C/en not_active Expired - Lifetime
- 2003-04-29 DE DE60314137T patent/DE60314137T2/de not_active Expired - Lifetime
- 2003-04-29 CN CNB038018446A patent/CN1329024C/zh not_active Expired - Lifetime
- 2003-04-29 MX MXPA04011793A patent/MXPA04011793A/es active IP Right Grant
- 2003-04-29 AT AT03719972T patent/ATE363272T1/de active
- 2003-04-29 DK DK03719972T patent/DK1509212T3/da active
- 2003-04-29 PT PT03719972T patent/PT1509212E/pt unknown
- 2003-04-29 NZ NZ531747A patent/NZ531747A/en not_active IP Right Cessation
- 2003-04-29 KR KR1020047005138A patent/KR100613037B1/ko active IP Right Grant
- 2003-04-29 BR BRPI0306160A patent/BRPI0306160B1/pt unknown
- 2003-04-29 ES ES03719972T patent/ES2286425T3/es not_active Expired - Lifetime
- 2003-04-29 WO PCT/US2003/013233 patent/WO2003101436A1/en active IP Right Grant
- 2003-04-29 EP EP03719972A patent/EP1509212B1/en not_active Expired - Lifetime
- 2003-04-29 AU AU2003223768A patent/AU2003223768B2/en not_active Expired
- 2003-04-29 BR BR0306160-4A patent/BR0306160A/pt active IP Right Grant
- 2003-04-29 JP JP2004508794A patent/JP4148366B2/ja not_active Expired - Lifetime
- 2003-05-20 TW TW092113546A patent/TWI258371B/zh not_active IP Right Cessation
- 2003-05-28 AR ARP030101871A patent/AR039865A1/es active IP Right Grant
-
2004
- 2004-03-03 ZA ZA2004/01741A patent/ZA200401741B/en unknown
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2005
- 2005-04-20 HK HK05103370A patent/HK1070584A1/xx not_active IP Right Cessation
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2007
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- 2007-07-26 CY CY20071100999T patent/CY1108027T1/el unknown
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103030584A (zh) * | 2012-12-04 | 2013-04-10 | 山东省化工研究院 | 饲料添加剂色氨酸铬络合物的制备方法 |
| CN104569238A (zh) * | 2013-10-21 | 2015-04-29 | 中国科学院过程工程研究所 | 一种氨基酸铬螯合物中氨基酸含量的测定方法 |
Also Published As
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|---|---|
| HK1070584A1 (en) | 2005-06-24 |
| TWI258371B (en) | 2006-07-21 |
| AU2003223768A1 (en) | 2003-12-19 |
| ZA200401741B (en) | 2005-01-26 |
| NZ531747A (en) | 2006-02-24 |
| US7445803B2 (en) | 2008-11-04 |
| US20070134300A1 (en) | 2007-06-14 |
| US7247328B2 (en) | 2007-07-24 |
| CY1108027T1 (el) | 2013-09-04 |
| DE60314137D1 (de) | 2007-07-12 |
| DE60314137T2 (de) | 2008-01-24 |
| KR20040045498A (ko) | 2004-06-01 |
| ES2286425T3 (es) | 2007-12-01 |
| AU2003223768B2 (en) | 2005-04-14 |
| DK1509212T3 (da) | 2007-09-03 |
| BRPI0306160B1 (pt) | 2018-11-21 |
| KR100613037B1 (ko) | 2006-08-16 |
| MXPA04011793A (es) | 2005-03-31 |
| EP1509212A1 (en) | 2005-03-02 |
| WO2003101436A1 (en) | 2003-12-11 |
| PT1509212E (pt) | 2007-08-08 |
| JP2005519993A (ja) | 2005-07-07 |
| TW200306845A (en) | 2003-12-01 |
| CA2467805C (en) | 2009-09-15 |
| US20030228394A1 (en) | 2003-12-11 |
| JP4148366B2 (ja) | 2008-09-10 |
| CA2467805A1 (en) | 2003-12-11 |
| AR039865A1 (es) | 2005-03-02 |
| CN1610541A (zh) | 2005-04-27 |
| BR0306160A (pt) | 2004-10-19 |
| ATE363272T1 (de) | 2007-06-15 |
| EP1509212B1 (en) | 2007-05-30 |
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