TWI391131B - ３－（２，２，２－三甲基肼）丙酸鹽的新用途 - Google Patents
３－（２，２，２－三甲基肼）丙酸鹽的新用途 Download PDFInfo
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- TWI391131B TWI391131B TW097145679A TW97145679A TWI391131B TW I391131 B TWI391131 B TW I391131B TW 097145679 A TW097145679 A TW 097145679A TW 97145679 A TW97145679 A TW 97145679A TW I391131 B TWI391131 B TW I391131B
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- trimethylhydrazinium
- propionate
- myocardial infarction
- meldonium
- medical use
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 title claims description 16
- 208000010125 myocardial infarction Diseases 0.000 claims description 14
- PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 claims description 11
- 235000019260 propionic acid Nutrition 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- -1 propionic acid dihydrogen salt Chemical class 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 claims description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims 1
- JFWLFLLRLZSBRA-UHFFFAOYSA-N 3-[(trimethylazaniumyl)amino]propanoate;dihydrate Chemical compound O.O.C[N+](C)(C)NCCC([O-])=O JFWLFLLRLZSBRA-UHFFFAOYSA-N 0.000 description 12
- 208000019622 heart disease Diseases 0.000 description 8
- 229960002937 meldonium Drugs 0.000 description 6
- 208000031225 myocardial ischemia Diseases 0.000 description 6
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 229960004203 carnitine Drugs 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- JMGQRZWIKKHUNB-UHFFFAOYSA-N (2-carboxyethylamino)-trimethylazanium;dihydrogen phosphate Chemical compound OP(O)([O-])=O.C[N+](C)(C)NCCC(O)=O JMGQRZWIKKHUNB-UHFFFAOYSA-N 0.000 description 2
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 2
- 239000012839 Krebs-Henseleit buffer Substances 0.000 description 2
- 208000021328 arterial occlusion Diseases 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 230000003293 cardioprotective effect Effects 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DSMFFOSDNKPHJP-TYYBGVCCSA-N (e)-but-2-enedioic acid;propanoic acid Chemical compound CCC(O)=O.OC(=O)\C=C\C(O)=O DSMFFOSDNKPHJP-TYYBGVCCSA-N 0.000 description 1
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 1
- JHPNVNIEXXLNTR-UHFFFAOYSA-N 4-(trimethylammonio)butanoate Chemical compound C[N+](C)(C)CCCC([O-])=O JHPNVNIEXXLNTR-UHFFFAOYSA-N 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 229940122224 Gamma butyrobetaine hydroxylase inhibitor Drugs 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229940122439 Hydroxylase inhibitor Drugs 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 241000002163 Mesapamea fractilinea Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000003168 generic drug Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- MCPLVIGCWWTHFH-UHFFFAOYSA-L methyl blue Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[NH+]C=2C=CC(=CC=2)S([O-])(=O)=O)C=2C=CC(NC=3C=CC(=CC=3)S([O-])(=O)=O)=CC=2)C=C1 MCPLVIGCWWTHFH-UHFFFAOYSA-L 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本發明係有關於利用3-(2,2,2-三甲基肼)丙酸延胡索酸氫鹽及3-(2,2,2-三甲基肼)丙酸磷酸二氫鹽治療缺血性心臟病。
心肌梗塞為一種不可逆的心肌壞死，其起因通常為長時間的缺血。
心肌梗塞(心臟病)為一種嚴重的冠狀動脈疾病。心肌梗塞為一種心肌二次缺血所導致的不可逆壞死，由於供給心臟的血液突然減少或停止，因此在醫學上，心臟病或心肌梗塞屬於非常嚴重緊急的疾病，其會導致心肌缺氧而壞死。每年有超過1千1百萬人罹患心臟病(心肌梗塞)，且對許多人而言，心臟病僅為冠狀動脈疾病的第一症狀。心臟病有可能在發生多次後導致死亡，但也可能並無任何徵狀，約每5個人就有一位患者僅有輕微徵狀或完全無徵狀表現，且心臟病通常只能藉由檢查心電圖發現。
心臟病(心肌梗塞)是指因血塊阻塞心臟動脈所引起的疾病。動脈管壁通常會因脂肪堆積而狹窄，而這些堆積的脂肪會被撕扯脫落進而減緩血液流量，並會產生血小板以形成血塊。有些血塊形成於心臟中，並阻塞供給養份的動脈。
3-(2,2,2-三甲基肼)丙酸二水合物已知與心血管疾病有關(此物質即為國際非專利藥品名稱的Meldonium dihydrate)，相關內容可參照美國專利4481218(INST ORGANICHESKOGO SINTEZA)。
目前3-(2,2,2-三甲基肼)丙酸二水合物已被廣泛地用來控制肉鹼及γ-三甲胺基丁酸(γ-butyrobetaine)的濃度比例，並進而控制脂肪酸的β-氧化(DAMBROVAM.,LIEPINSH E.,KALVINSH I. I. Mildronate:cardioprotective action through carnitine-lowing effect. Trends in Cardiovascular Medicine,.2002,vol.12,no.6,p.275-279)。
因此，Meldonium dihydrate已被廣泛地作為抗缺血、壓力保護及心血管藥物，可用來治療心血管疾病及其他組織缺血性疾病(KARPOV R.S.,KOSHELSKAYA O.A.,VRUBLEVSKY A.V.,SOKOLOV A.A.,TEPLYAKOV A.T., SKARDA I.,DZERVE V.,KLINTSARE D.,VITOLS A.,KALNINS U.,KALVINSHI.,MATVEYA L.,URBANE D. Clinical Efficacy and Safety of Mildronate in Patients With Ischemic Heart Disease and Chronic Heart Failure. Kardiologiya. 2000,no.6,p69-74)。3-(2,2,2-三甲基肼)丙酸治療心血管疾病的機制一般認為其可限制肉鹼的生成，並與長鏈脂肪酸的傳送有關(SIMKHOVICH B.Z.,SHUTENKO Z.V.,MEIRENA D.V.,KHAGI K.B.,MEZHAPUKE R.J.,MOLODCHINA T.N.,KALVINS I.J.,LUKEVICS E. 3-(2,2,2,-Trimethylhydrazinium)propionate(THP)-a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties.Biochemical Pharmacology.1988,vol.37,p195-202.,KIRIMOTO T.,ASAKA N.,NAKANO M.,TAJIMA K.,MIYAKE H.,MATSUURA N..)。MET-88為一種γ-丁基甜菜鹼羥化酶抑制劑，其可抑制大鼠的心肌梗塞(European Journal of Pharmacology.2000,vol.395,no.3,p.217-224)。
WO00/003063A(SIGMA TAU IND FARMACEUTI)02.06.2000專利揭示使用L-福馬林肉鹼及其鏈烷酮衍生物所製備之組成物，其可治療器官缺血及大幅降低器官缺血的風險。雖然L-肉鹼與Meldonium dihydrate在結構上非常類似，但Meldonium dihydrate在藥學上會抵消L-肉鹼的功效。因此，此技術領域人士並不會同時合併使用反轉錄酶抑制劑及Meldonium dihydrate。
EP1667960 A(JOINT STOCK COMPAN GRINDEKS)14.06.2006揭示相對於Meldonium dihydrate，延胡索酸氫鹽及磷酸二氫鹽為更穩定的物質。
本發明係提供一種治療缺血性心臟病之組成物，包括一3-(2,2,2-三甲基肼)丙酸鹽，其擇於下列所組成之族群：3-(2,2,2-三甲基肼)丙酸延胡索酸氫鹽及3-(2,2,2-三甲基肼)丙酸磷酸二氫鹽。
為了讓本發明之上述和其他目的、特徵、和優點能更明顯易懂，下文特舉較佳實施例，並配合所附圖示，作詳細說明如下：
Meldonium dihydrate 已知可用來治療缺血性心臟病，然而並沒有任何實驗數據證明Meldonium鹽類可用來治療缺血性心臟病。
令人感到意外，當使用Meldonium延胡索酸氫鹽來治療心肌梗塞及/或局部缺血時，其具有不可預期之功效，且相較於Meldonium dihydrate，其效果更佳。Meldonium的延胡索酸氫鹽及磷酸二氫鹽，因其為Meldonium dihydrate藥學上可接受之鹽類或同功物，理論上應具有相同的藥學活性，然而事實上其功效卻遠大於Meldonium dihydrate。
本發明之實施例使用雄性之成年費城威斯達大鼠，重約300-350g。在實驗過程中，以標準的容器及飼料R70(LABFOR,Lactamin AB,Sweden)進行飼養。動物房的溫度設定於21-23℃，相對濕度為65±10%，日光/黑暗為每12小時循環。
隨機挑選重約300g之大鼠，將大鼠分為4組，每組8隻。第1組餵食食鹽水(對照組)。第2組餵食100mg/kg的Meldonium dihydrate。第3組接受100mg/kg之Meldonium延胡索酸氫鹽，第4組接受100mg/kg之Meldonium磷酸二氫鹽，共14天。
利用巴比妥酸鹽(60mg/kg i.p.)麻醉大鼠，以呼吸器(Rodent Ventilator 7025,Ugo Basile,Itally)進行插管，呼吸器的條件設定為15mL/kg，55breaths/min。將左側胸部第4及第5節胸骨切除，將心蠶打開，以5/0聚丙烯縫線(Surgipro II,Syneture)縫合左側冠狀動脈，並藉由螺紋塑膠管來造成可回復的動脈阻塞。冠狀動脈的血流以超音波流速偵測器(HSE)及PowerLab 8/30系統(ADInstruments)進行偵測。
藉由壓縮螺紋塑膠管造成動脈阻塞，以50mmHg，含氧之Krebs-Henseleit緩衝液(118mmol/L NaCl，2.25mmol/LCaCl2
，1.64mmol/LMgCl2
，24.88mmol/LNaHCO3
，1.18mmol/L KH2
PO4
，10.0mmol/L葡萄醣，0.05mmol/L EDTA(pH7.3-7.5))於37℃重新回復(灌注)120分鐘。將左側冠狀動脈降級，以4mL溶於Krebs-Henseleit緩衝液的0.1%甲基藍溶液注入主動脈根部以界定出危險的區域。將厚約2mm的心臟橫切片置於1%之氯化三苯基四氮唑溶液(pH7.4，37℃)中10分鐘以進行染色，存活的部份呈現紅色，壞死的部份呈現白色。接著，將右心室切除，並以Minolta 7D照像機對左心室切片照像。利用電腦影像平面分析系統及Image-Pro Plus4.5.1軟體分析左心室中缺血區(the area at risk，AR)及壞死區(the area of necrosis，AN)的比例。將所獲得的數據以公式計算缺血區(即梗塞大小)的比例。
以Meldonium dihydrate、Meldonium延胡索酸氫鹽及Meldonium磷酸二氫鹽治療心肌梗塞的結果如表一所示。
雖然本發明已以較佳實施例揭露如上，然其並非用以限定本發明，任何熟習此技藝者，在不脫離本發明之精神和範圍內，當可作些許之更動與潤飾，因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
Claims (3)
- 一種3-(2,2,2-三甲基肼)丙酸鹽用於製備治療心肌梗塞用藥之用途，其擇於下列所組成之族群：磷酸二氫鹽及延胡索酸氫鹽。
- 如申請專利範圍第1所述之3-(2,2,2-三甲基肼)丙酸鹽用於製備治療心肌梗塞用藥之用途，其中該3-(2,2,2-三甲基肼)丙酸鹽為3-(2,2,2-三甲基肼)丙酸延胡索酸氫鹽。
- 如申請專利範圍第1所述之3-(2,2,2-三甲基肼)丙酸鹽用於製備治療心肌梗塞用藥之用途，其中3-(2,2,2-三甲基肼)丙酸鹽為3-(2,2,2-三甲基肼)丙酸磷酸二氫鹽。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07122359 | 2007-12-05 | ||
| EP07122360 | 2007-12-05 |
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| TW200927092A TW200927092A (en) | 2009-07-01 |
| TWI391131B true TWI391131B (zh) | 2013-04-01 |
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|---|---|
| US (1) | US20110028438A1 (zh) |
| EP (1) | EP2222376B1 (zh) |
| JP (1) | JP2011506285A (zh) |
| KR (1) | KR20100084687A (zh) |
| CN (1) | CN101951991A (zh) |
| AR (1) | AR069548A1 (zh) |
| AT (1) | ATE503473T1 (zh) |
| AU (1) | AU2008333263A1 (zh) |
| BR (1) | BRPI0819055A2 (zh) |
| CA (1) | CA2706357C (zh) |
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| DE (1) | DE602008005930D1 (zh) |
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| GE (1) | GEP20125646B (zh) |
| HR (1) | HRP20110468T1 (zh) |
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| MA (1) | MA31992B1 (zh) |
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| MY (1) | MY158799A (zh) |
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| TW (1) | TWI391131B (zh) |
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| WO (1) | WO2009071586A2 (zh) |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140088125A1 (en) * | 2011-04-27 | 2014-03-27 | Jsc Grindeks | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease |
| RU2457198C1 (ru) * | 2011-05-31 | 2012-07-27 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" | Производное 3-(2,2,2-триметилгидразиний)пропионата - глицинат 3-(2,2,2-триметилгидразиний)пропионат калия, обладающее противоишемической активностью |
| RU2467748C1 (ru) * | 2011-08-08 | 2012-11-27 | Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" | Производное 3-(2,2,2-триметилгидразиний)пропионата - глицинат 3-(2,2,2-триметилгидразиний)пропионат калия, обладающее эндотелиопротекторной активностью |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005012233A1 (en) * | 2003-08-04 | 2005-02-10 | 'joint Stock Company Grindeks' | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
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| LV13280B (en) * | 2003-08-04 | 2005-11-20 | Grindeks Publiska As | Sustained release salts of 3-(2,2,2-trimethylhydrazinium)propionate, a method of production and pharmaceutical compositions thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005012233A1 (en) * | 2003-08-04 | 2005-02-10 | 'joint Stock Company Grindeks' | Meldonium salts, method of their preparation and pharmaceutical composition on their basis |
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