CN1224416A - 肌酸丙酮酸盐及其生产方法 - Google Patents
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Abstract
公开了通式(Ⅰ)的肌酸丙酮酸盐(肌酸)x(丙酮酸)y(H2O)n(Ⅰ)其中x=1—100y=1—10n=0—10。这些肌酸丙酮酸盐通过相对简单的肌酸和丙酮酸的反应制得,可用于在运动领域中增强耐力和力量,在健康领域中减轻体重和身体脂肪,用于治疗缺氧情况(局部缺血)、肥胖和体重过重,用作食品添加物和自由基清除剂。
Description
本发明涉及肌酸丙酮酸盐及其生产方法，所述肌酸丙酮酸盐为丙酮酸和肌酸的无水或水合形式的盐以及这些盐与肌酸或丙酮酸的混合物。
众所周知，丙酮酸的盐、即丙酮酸盐对于治疗多种疾病例如肥胖和体重过重具有非常有价值的生理学和治疗特性，并可用于预防自由基形成和增强耐力(参见US5508308、US5480909、US5472980、US5395822、US5312985、US5283260、US5256697、US4548937和US4351835)。
碱金属和碱土金属丙酮酸盐是本领域已知的，但是，丙酮酸的钠盐和钾盐分别由于其所含的钠离子和钾离子而不适于治疗应用或作为食品添加物。丙酮酸的镁盐和钙盐虽然从生理学的角度来看是安全的，但其明显的缺点是保存期不够长，因为镁和钙离子强烈加速丙酮酸和丙酮酸根离子分解形成二聚体、聚合物、环状化合物等。
因此，本发明的目的是开发在生理学上安全并且同时保存期足够长的丙酮酸产品。
具体地讲，本发明的目的是提供式(Ⅰ)的肌酸丙酮酸盐
(肌酸)x(丙酮酸)y(H2O)n (Ⅰ)其中x=1-100
y=1-10
n=0-10。
根据化学计量的需要，在式(Ⅰ)化合物中，肌酸以不带电荷的形式或阳离子的形式存在，丙酮酸以丙酮酸或阴离子形式存在。
令人惊奇的是，尽管丙酮酸是一种非常不稳定的2-氧代羧酸并且已知的肌酸盐很容易分解形成肌酸酐，但本发明的肌酸丙酮酸盐的保存期却很长。由于肌酸以内盐的形式存在并且是弱碱，因此难以预见可以从一元羧酸制得稳定的肌酸盐。根据现有技术的记载，迄今为止只有强的二元和多元羧酸的肌酸盐是已知的(参见WO96/04240)。
本发明的肌酸丙酮酸盐具有通式(Ⅰ)的结构，含有生理学安全的式(Ⅱ)的肌酸阳离子。
肌酸不仅是一种内源性物质和有价值的食品添加物，而且还具有有价值的治疗特性。100多年以前就已经知道肌酸是一种肌肉内的物质并且是肌肉能量的来源。一系列科学研究证实，摄入肌酸可以导致肌肉组织的增加和肌肉性能的改善。科学研究还表明，在肌酸的影响下，胰腺会释放出更多的胰岛素。胰岛素可促进肌肉细胞对葡萄糖和氨基酸的摄取并刺激蛋白质合成。胰岛素还可降低蛋白质分解代谢速率。
本发明肌酸丙酮酸盐中的丙酮酸根阴离子通常呈现式(Ⅲ)的结构。
在含有结晶水的肌酸丙酮酸盐中，丙酮酸根阴离子还可以是式(Ⅳ)的2,2-二羟基的形式：
本发明的肌酸丙酮酸盐包括肌酸阳离子和丙酮酸根阴离子或2,2-二羟基丙酸根阴离子的摩尔比优选为1∶1或摩尔比接近1∶1的盐。本发明的化合物还可以是这些盐与肌酸或丙酮酸的混合物。
本发明的肌酸丙酮酸盐可以通过相对简单的肌酸和丙酮酸的反应进行生产，反应在-10至90℃的温度下进行，优选10至30℃。将肌酸和丙酮酸以100∶1至1∶10的摩尔比反应，优选5∶1至1∶2。该反应中使用的肌酸可以是无水形式、一水合物形式或是湿的产品。所用的丙酮酸可以是无水的酸或水溶液的形式。
反应在含或不含溶剂或稀释剂的条件下进行。很多种极性溶剂均适于作为溶剂或稀释剂。其中，优选醇(例如甲醇、乙醇、异丙醇或环己醇)、醚(例如***、四氢呋喃、1,4-二氧六环或乙二醇二甲醚)、酮(例如丙酮、甲乙酮或环己酮)、酯(例如乙酸甲酯、乙酸乙酯或甲酸乙酯)或它们的混合物。
反应可以用常规的装置如混合器、叶片干燥器和搅拌容器进行。
含有结晶水的肌酸丙酮酸盐可以通过在丙酮酸和肌酸的反应过程中或反应后加入水和/或用含水的肌酸和/或含水的丙酮酸进行反应而制得。本发明还包括在肌酸丙酮酸盐的生产过程中或生产后添加其它物质，例如药物配制添加剂、维生素、矿物质、微量元素、碳水化合物如葡萄糖、右旋糖或麦芽糖以及氨基酸如L-肉碱或其它食品添加物。
因此，本发明的目的还包括含有肌酸丙酮酸盐以及至少一种其它的生理相容性物质的生理相容性组合物，所述生理相容性物质选自药物辅剂或载体、维生素、矿物质、碳水化合物、氨基酸或其它食品添加物。
由于其极佳的特性，例如在生理学上是安全的，保存期长、在水中的溶解度大并且生物利用度高，本发明的肌酸丙酮酸盐特别适于药物治疗应用或作为食品添加物，可以同时表现出丙酮酸盐和肌酸的有价值的生物学和药物特性。
令人惊奇的是，当用于药物以及作为食品添加物时，本发明的肌酸丙酮酸盐表现出显著的协同效果。它们特别适用于治疗缺氧的情况(局部缺血)、体重过重和肥胖，因为在治疗过程中减少了肌肉物质的分解代谢；肌酸丙酮酸盐的肌肉增强效果在饮食疗法中是特别重要的。这些肌酸丙酮酸盐还可防止自由基的形成，可以作为自由基和氧的氧化性物种的清除剂。当将肌酸丙酮酸盐用于增强耐力时，协同效果也特别明显。
以下实施例用来更详细地说明本发明。实施例实施例1
室温下，将26.4g(0.3mol)丙酮酸溶于100ml乙酸乙酯。向该溶液中加入26.2g(0.2mol)肌酸并将该混合物搅拌4小时。然后过滤分离白色的细结晶状产物并用25ml乙酸乙酯洗涤2次。将其在真空干燥室内于50℃干燥4小时。收率95.0％。该肌酸丙酮酸盐(1∶1)于106-110℃熔化并分解(毛细管)。元素分析C7H13N3O5：计算值：C38.36％,H5.94％,N19.18％；实测值：C38.23％,H6.06％,N19.28％；IB(KBr)]1/cm]:620,829,880,976,1049,1110,1177,1209,1269,1354,1404,1605,1663,1697,1734,1763,2518,2593,3147,3397；1H-NMR(D2O,300MHz):δ=2.34(s,3H,MeCO),3.08(s,3H,Me-N),4.06(s,2H,CH2)；HPLC含量：肌酸59.8％,丙酮酸40.2％。实施例2
将26.2g(0.2mol)肌酸与17.6g(0.2mol)丙酮酸在研钵内混合。该混合物粘度逐渐增加并最终固化成白色的细结晶状产物。收率为定量的(＞99％)。该肌酸丙酮酸盐(1∶1)于109-114℃熔化并分解(毛细管)。实施例3
将29.8g(0.2mol)肌酸一水合物与35.2g(0.4mol)丙酮酸在玻璃烧杯内紧密混合。将该混合物放置，最终固化成白色的细结晶状产物。将其在研钵研磨并在真空干燥室内于50℃干燥4小时。收率为定量的(＞99％)。由此得到的肌酸丙酮酸盐(1∶2)于90-95℃熔化并分解(毛细管)。实施例4
将29.8g(0.2mol)肌酸一水合物与8.8g(0.1mol)丙酮酸在研钵内混合并加入20ml四氢呋喃。该混合物粘度逐渐增加并最终固化成白色的细结晶状产物，将其在真空干燥室内于50℃干燥4小时。收率为定量的(＞99％)。该肌酸丙酮酸盐(2∶1)于118-120℃熔化并分解(毛细管)。
Claims (10)
1．通式(Ⅰ)的肌酸丙酮酸盐
(肌酸)x(丙酮酸)y(H2O)n (Ⅰ)其中 x=1-100
y=1-10
n=0-10。
2．权利要求1的肌酸丙酮酸盐，其中x=1-5,y=1-2,n=0-2。
3．权利要求1和2中任意一项的肌酸丙酮酸盐，其中丙酮酸根阴离子以2,2-二羟基丙酸根阴离子形式存在。
4．权利要求1-3中任意一项所述肌酸丙酮酸盐的生产方法，其中将丙酮酸和肌酸以摩尔比为100∶1至1∶10肌酸∶丙酮酸于-10至90℃的温度下反应。
5．权利要求4的方法，其中肌酸与丙酮酸的摩尔比为5∶1至1∶2。
6．权利要求4和5中任意一项的方法，其中反应在10至30℃的温度下进行。
7．权利要求4-6中任意一项的方法，其中反应在极性溶剂的存在下进行。
8．权利要求7的方法，其中使用醇、醚、酮、酯或它们的混合物作为溶剂。
9．生理相容性组合物，该组合物含有权利要求1-3中任意一项所述的肌酸丙酮酸盐和至少一种其它的生理相容性物质，所述生理相容性物质选自药物辅剂或载体、维生素、矿物质、碳水化合物、氨基酸或其它食品添加物。
10．权利要求1-3中任意一项所述的肌酸丙酮酸盐用于在运动领域中增强耐力和力量，在健康领域中减轻体重和身体脂肪，用于治疗缺氧情况(局部缺血)、肥胖和体重过重，以及作为食品添加物和自由基清除剂的用途。
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| DE19653225A DE19653225A1 (de) | 1996-12-20 | 1996-12-20 | Kreatin-pyruvate und Verfahren zu deren Herstellung |
| DE19653225.6 | 1996-12-20 | ||
| US08/893,423 | 1997-07-11 | ||
| US08/893,423 US6166249A (en) | 1996-12-20 | 1997-07-11 | Creatine pyruvates |
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| CN1076343C CN1076343C (zh) | 2001-12-19 |
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| CN102740706A (zh) * | 2009-12-29 | 2012-10-17 | 希尔氏宠物营养品公司 | 用于伴侣动物的包含丙酮酸盐的组合物及其使用方法 |
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| EP1051914A1 (de) * | 1999-05-08 | 2000-11-15 | DSM Fine Chemicals Austria GmbH | Verwendung von Kreatin als Futterzusatz |
| US6242491B1 (en) * | 1999-06-25 | 2001-06-05 | Rima Kaddurah-Daouk | Use of creatine or creatine compounds for skin preservation |
| DE19929995B4 (de) | 1999-06-30 | 2004-06-03 | Skw Trostberg Ag | Verwendung von Kreatin und/oder Kreatin-Derivaten zur Behandlung von Befindlichkeitsstörungen bei Frauen |
| WO2001003325A2 (de) * | 1999-06-30 | 2001-01-11 | Skw Trostberg Aktiengesellschaft | Verwendung von kreatin und/oder kreatin-derivaten zur behandlung von befindlichkeitsstörungen bei frauen |
| DE10003835A1 (de) * | 2000-01-28 | 2001-08-16 | Sueddeutsche Kalkstickstoff | Formulierungen bei Dehydratationszuständen |
| US20030212136A1 (en) | 2001-09-14 | 2003-11-13 | Vennerstrom Jonathan L. | Creatine ester pronutrient compounds and formulations |
| EP1688139A1 (en) * | 2000-09-14 | 2006-08-09 | Board of Regents of the University of Nebraska | Creatine ester pronutrient compounds and formulations |
| DE10064312C2 (de) * | 2000-12-22 | 2003-05-22 | Degussa | Cholinpyruvat-Hydrat, Verfahren zu dessen Herstellung, Cholinpyruvat-Hydrat enthaltende Formulierung sowie deren Verwendung |
| US6838562B2 (en) * | 2003-04-01 | 2005-01-04 | Sal Abraham | Process for preparing a creatine heterocyclic acid salt and method of use |
| DE10355716A1 (de) * | 2003-11-26 | 2005-06-23 | Beiersdorf Ag | Kosmetische Zubereitungen mit einem Gehalt Kreatin und/oder Kreatinderivaten und/oder Kreatinin und/oderKreatininderivaten und organischen Verdickern |
| PT1758463E (pt) | 2004-06-09 | 2008-04-03 | Alzchem Trostberg Gmbh | Ácido guanidinoacético como aditivo para rações para animais |
| DE102006031441B4 (de) * | 2006-07-05 | 2011-12-29 | Hans Matt | Orales Creatin-Supplement, sowie Verfahren zur Herstellung desselben |
| DE102007004781A1 (de) | 2007-01-31 | 2008-08-07 | Alzchem Trostberg Gmbh | Verwendung von Guanidinoessigsäure(-Salzen) zur Herstellung eines gesundheitsfördernden Mittels |
| DE102007030495A1 (de) | 2007-06-30 | 2009-01-15 | Alzchem Trostberg Gmbh | Verwendung einer eine Kreatin-Komponente enthaltende Zusammensetzung zur Verbesserung der Gedächtnisleistung, der Merkfähigkeit, des Langzeitgedächtnisses und zur Vorbeugung geistiger Ermüdungszustände |
| DE102007053369A1 (de) | 2007-11-09 | 2009-07-02 | Alzchem Trostberg Gmbh | Verwendung einer eine Kreatin-Komponente enthaltende Zusammensetzung zur Verbesserung der männlichen Fruchtbarkeit |
| DE102007062288A1 (de) | 2007-12-21 | 2009-06-25 | Alzchem Trostberg Gmbh | Kreatin-Zubereitung und Verfahren zu deren Herstellung |
| US20110123654A1 (en) * | 2008-06-06 | 2011-05-26 | Ralf Jaeger | Synergistic enhancement of cellular ergogenic nutrient uptake, like creatine or carnitine, with tarragon |
| US8466198B2 (en) * | 2008-09-02 | 2013-06-18 | Bruce Kneller | Compositions comprising creatine salts and methods of use thereof |
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| WO2019185408A1 (en) | 2018-03-27 | 2019-10-03 | Evonik Degussa Gmbh | Use of guanidinoacetic acid and/or creatine in aquaculture |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102740706A (zh) * | 2009-12-29 | 2012-10-17 | 希尔氏宠物营养品公司 | 用于伴侣动物的包含丙酮酸盐的组合物及其使用方法 |
| US8999375B2 (en) | 2009-12-29 | 2015-04-07 | Hill's Pet Nutrition, Inc. | Compositions including pyruvate for companion animals and methods of use thereof |
| US9011900B2 (en) | 2009-12-29 | 2015-04-21 | Hill's Pet Nutrition, Inc. | Compositions including pyruvate for companion animals and methods of use thereof |
| US9173422B2 (en) | 2009-12-29 | 2015-11-03 | Hill's Pet Nutrition, Inc. | Compositions including pyruvate for companion animals and methods of use thereof |
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| CA2255665C (en) | 2002-05-14 |
| ATE186295T1 (de) | 1999-11-15 |
| RU2179970C2 (ru) | 2002-02-27 |
| CN1076343C (zh) | 2001-12-19 |
| SK155698A3 (en) | 1999-05-07 |
| NO992603D0 (no) | 1999-05-31 |
| JP3090960B2 (ja) | 2000-09-25 |
| US6172111B1 (en) | 2001-01-09 |
| IL127148A0 (en) | 1999-09-22 |
| EP0894083A1 (de) | 1999-02-03 |
| CA2255665A1 (en) | 1998-07-02 |
| NO992603L (no) | 1999-05-31 |
| PL330279A1 (en) | 1999-05-10 |
| DK0894083T3 (da) | 2000-04-03 |
| BR9711954A (pt) | 1999-08-24 |
| SK283195B6 (sk) | 2003-03-04 |
| AU5857698A (en) | 1998-07-17 |
| BG102932A (en) | 1999-09-30 |
| NO311354B1 (no) | 2001-11-19 |
| WO1998028263A1 (de) | 1998-07-02 |
| AU727524B2 (en) | 2000-12-14 |
| JPH11509560A (ja) | 1999-08-24 |
| CZ293282B6 (cs) | 2004-03-17 |
| TR199900470T2 (xx) | 1999-06-21 |
| HK1020718A1 (en) | 2000-05-19 |
| BG63537B1 (bg) | 2002-04-30 |
| DE59700666D1 (de) | 1999-12-09 |
| CZ362698A3 (cs) | 1999-03-17 |
| ES2139465T3 (es) | 2000-02-01 |
| GR3031754T3 (en) | 2000-02-29 |
| NZ332830A (en) | 2000-04-28 |
| EP0894083B1 (de) | 1999-11-03 |
| IL127148A (en) | 2002-11-10 |
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