WO2009071586A2 - 3-(2,2,2-trimethylhydrazinium) propionate salts for treating ischemic heart disease - Google Patents

3-(2,2,2-trimethylhydrazinium) propionate salts for treating ischemic heart disease Download PDF

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Publication number
WO2009071586A2
WO2009071586A2 PCT/EP2008/066712 EP2008066712W WO2009071586A2 WO 2009071586 A2 WO2009071586 A2 WO 2009071586A2 EP 2008066712 W EP2008066712 W EP 2008066712W WO 2009071586 A2 WO2009071586 A2 WO 2009071586A2
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Prior art keywords
trimethylhydrazinium
propionate
heart disease
ischemic heart
meldonium
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PCT/EP2008/066712
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French (fr)
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WO2009071586A3 (en
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Ivars Kalvins
Ilmars Stonans
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CHEMCO VENTURES (CYPRUS) Ltd
Grindeks JSC
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CHEMCO VENTURES (CYPRUS) Ltd
Grindeks JSC
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Priority to MX2010006257A priority Critical patent/MX2010006257A/en
Priority to JP2010536439A priority patent/JP2011506285A/en
Priority to US12/734,785 priority patent/US20110028438A1/en
Priority to PL08857821T priority patent/PL2222376T3/en
Priority to CN200880119405XA priority patent/CN101951991A/en
Priority to EA201000739A priority patent/EA016971B1/en
Priority to AU2008333263A priority patent/AU2008333263A1/en
Priority to EP08857821A priority patent/EP2222376B1/en
Priority to AT08857821T priority patent/ATE503473T1/en
Priority to HR20110468T priority patent/HRP20110468T1/en
Priority to UAA201006836A priority patent/UA100249C2/en
Application filed by CHEMCO VENTURES (CYPRUS) Ltd, Grindeks JSC filed Critical CHEMCO VENTURES (CYPRUS) Ltd
Priority to SI200830294T priority patent/SI2222376T1/en
Priority to DE602008005930T priority patent/DE602008005930D1/en
Priority to BRPI0819055 priority patent/BRPI0819055A2/en
Priority to NZ586518A priority patent/NZ586518A/en
Priority to DK08857821.6T priority patent/DK2222376T3/en
Priority to CA2706357A priority patent/CA2706357C/en
Publication of WO2009071586A2 publication Critical patent/WO2009071586A2/en
Publication of WO2009071586A3 publication Critical patent/WO2009071586A3/en
Priority to ZA2010/03640A priority patent/ZA201003640B/en
Priority to IL205962A priority patent/IL205962A0/en
Priority to TN2010000249A priority patent/TN2010000249A1/en
Anticipated expiration legal-status Critical
Priority to MA32977A priority patent/MA31992B1/en
Ceased legal-status Critical Current

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    • 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

Definitions

  • the present invention relates to use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate, and 3-(2,2,2-trimethylhydrazinium) propionate dihydrogen phosphate in the treatment of ischemic heart disease.
  • Myocardiac infarction is a condition of irreversible necrosis of heart muscle that results from prolonged ischemia.
  • Myocardial infarction (heart attack) is a serious result of coronary artery disease.
  • Myocardial infarction (Ml) is the irreversible necrosis of heart muscle secondary to prolonged ischemia.
  • a heart attack or myocardial infarction is a medical emergency in which the supply of blood to the heart is suddenly and severely reduced or cut off, causing the muscle to die from lack of oxygen. More than 1.1 million people experience a heart attack (myocardial infarction) each year, and for many of them, the heart attack is their first symptom of coronary artery disease. A heart attack may be severe enough to cause death or it may be silent.
  • a heart attack (myocardial infarction) is usually caused by a blood clot that blocks an artery of the heart.
  • the artery has often already been narrowed by fatty deposits on its walls. These deposits can tear or break open, reducing the flow of blood and releasing substances that make the platelets of the blood sticky and more likely to form clots.
  • 3- (2,2,2-Thmethylhydrazinium) propionate dihydrate is known as compound with cardioprotective properties (this substance being known under its International Nonproprietary Name of Meldonium dihydrate).
  • 3- (2,2,2-Thmethylhydrazinium) propionate is disclosed in US 4481218 (INST ORGANICHESKOGO SINTEZA) 06.11.1984 It is well known that 3- (2, 2,2-trimethylhydrazinium) propionate as dihydrate is widely used for controlling carnitine and gamma-butyrobetaine concentration ratio and consequently the speed of fatty acid beta-oxidation in the body DAMBROVA M., LIEPINSH E., KALVINSH I. I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends in Cardiovascular Medicine,. 2002, vol.12, no.6, p.275-279.
  • WO 00/003063 A SIGMA TAU IND FARMACEUTI 02.06.2000 patent disclosed use of L-carnitine acid fumarate and its alkanoyl derivatives to prepare a composition suitable for reducing, in a broad range of users and/or patients, the risk of onset of organ ischemia, and for preventing and/or therapeutically treating it, particularly as affecting the cardiocirculatory apparatus.
  • L-carnitine and Meldonium dihydrate are structurally very similar. However, the pharmacolgical effect of Meldonium dihydrate has been regarded as counteracting the effect of L- carnitine. Consequently, it is not considered obvious to the man skilled in the art to combine a reverse transcriptase inhibitor with Meldonium dihydrate. Hydrogen fumarate and dihydrogen phosphate salts of Meldonium are disclosed in EP 1667960 A (JOINT STOCK COMPANY GRINDEKS) 14.06.2006 as more stable substance comparatively with Meldonium dihydrate. Disclosure of Invention
  • Rats weighing approximately 300 g were randomly divided into 4 groups of 8 animals each.
  • the first group received saline by mouth (control group)
  • the second received 100 mg/kg Meldonium dihydrate by mouth
  • the third 100mg/kg Meldonium hydrogen fumarate
  • the fourth 100mg/kg Meldonium dihydrogen phosphate received for 14 days.
  • Rats were anesthetized with sodium pentobarbital (60 mg/kg i.p.). They were intubated and artificially respirated with rodent respirator (Rodent Ventilator 7025, Ugo Basile, Itally) with 15 mL/kg room air at a respiration rate of 55 breaths/min.
  • rodent respirator Rodent Ventilator 7025, Ugo Basile, Itally
  • Thoracic was open on the left side of breastbone by cutting fourth and fifths, if necessary, ribs.
  • the pericard was open and 5/0 polypropylene suture (Surgipro II, Syneture) was passed under the left anterior descending coronary artery and threaded through a small plastic tube to permit reversible occlusion of the coronart artery.
  • Coronary flow was measured using an ultrasound flow detector (HSE) and PowerLab 8/30 system from ADInstruments. Occlusion was performed by constricting threads through a plastic tube.
  • Hearts were sectioned transversely from the apex to the base of 2 mm thickness and incubated in 1 % triphenyl-tetrazolium chloride in phosphate buffer (pH 7.4, 37°C) for 10 minutes to stain viable tissue red and necrotic tissue white. Afterward, the right ventricle was cut off and photos of the left-ventricle slices were made with a Minolta 7D photo camera. Computerized planemetric analysis of photographs was performed using Image-Pro Plus 4.5.1 software to determine the area at risk (AR) and area of necrosis (AN) expressed as percentage of the left ventricle (LV). Obtained values were then used to calculate the infarct size (IS) as percentage of risk area according to formula:

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The present invention relates to highly effective treatment of ischemic heart disease with 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate, and 3-(2,2,2-trimethylhydrazinium) propionate dihydrogen phosphate.

Description

New medical use of 3-(2,2,2-trimethylhydraziniunn) propionate salts
Technical Field
The present invention relates to use of 3-(2,2,2-trimethylhydrazinium) propionate hydrogen fumarate, and 3-(2,2,2-trimethylhydrazinium) propionate dihydrogen phosphate in the treatment of ischemic heart disease. Background Art
Myocardiac infarction is a condition of irreversible necrosis of heart muscle that results from prolonged ischemia. Myocardial infarction (heart attack) is a serious result of coronary artery disease. Myocardial infarction (Ml) is the irreversible necrosis of heart muscle secondary to prolonged ischemia. A heart attack or myocardial infarction is a medical emergency in which the supply of blood to the heart is suddenly and severely reduced or cut off, causing the muscle to die from lack of oxygen. More than 1.1 million people experience a heart attack (myocardial infarction) each year, and for many of them, the heart attack is their first symptom of coronary artery disease. A heart attack may be severe enough to cause death or it may be silent. As many as one out of every five people have only mild symptoms or none at all, and the heart attack may only be discovered by routine electrocardiography done some time later. A heart attack (myocardial infarction) is usually caused by a blood clot that blocks an artery of the heart. The artery has often already been narrowed by fatty deposits on its walls. These deposits can tear or break open, reducing the flow of blood and releasing substances that make the platelets of the blood sticky and more likely to form clots. Sometimes a clot forms inside the heart itself, then breaks away and gets stuck in an artery that feeds the heart. A spasm in one of these arteries causes the blood flow to stop.
3- (2,2,2-Thmethylhydrazinium) propionate dihydrate is known as compound with cardioprotective properties (this substance being known under its International Nonproprietary Name of Meldonium dihydrate). 3- (2,2,2-Thmethylhydrazinium) propionate is disclosed in US 4481218 (INST ORGANICHESKOGO SINTEZA) 06.11.1984 It is well known that 3- (2, 2,2-trimethylhydrazinium) propionate as dihydrate is widely used for controlling carnitine and gamma-butyrobetaine concentration ratio and consequently the speed of fatty acid beta-oxidation in the body DAMBROVA M., LIEPINSH E., KALVINSH I. I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends in Cardiovascular Medicine,. 2002, vol.12, no.6, p.275-279.
Due to these properties, Meldonium dihydrate is extensively applied in medicine as an anti-ischemic, stress-protective and cardioprotective drug in treating various cardio- vascular diseases and other pathologies involving tissue ischemia KARPOV R.S., KOSHELSKAYA O.A., VRUBLEVSKY A.V., SOKOLOV A.A., TEPLYAKOV AT., SKARDA I., DZERVE V., KLINTSARE D., VITOLS A., KALNINS U., KALVINSH I., MATVEYA L., URBANE D.. Clinical Efficacy and Safety of Mildronate in Patients With Ischemic Heart Disease and Chronic Heart Failure. Kardiologiya. 2000, no.6, p.69-74. . In the treatment of cardiovascular diseases the mechanism of action of 3-(2,2,2-trimethylhydrazinium)propionate based on limitation of carnitine biosynthesis rate and related long-chain fatty acid transport limitation through mitochondria membranes 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,-Thmethylhydrazinium) propionate (THP) - a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochemical Pharmacology. 1988, vol.37, p.195-202., KIRIMOTO T., ASAKA N., NAKANO M., TAJIMA K., MIYAKE H., MATSUURA N.. Beneficial effects of MET-88, a γ-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. European Journal of Pharmacology. 2000, vol.395, no.3, p.217-224.
WO 00/003063 A (SIGMA TAU IND FARMACEUTI) 02.06.2000 patent disclosed use of L-carnitine acid fumarate and its alkanoyl derivatives to prepare a composition suitable for reducing, in a broad range of users and/or patients, the risk of onset of organ ischemia, and for preventing and/or therapeutically treating it, particularly as affecting the cardiocirculatory apparatus. L-carnitine and Meldonium dihydrate are structurally very similar. However, the pharmacolgical effect of Meldonium dihydrate has been regarded as counteracting the effect of L- carnitine. Consequently, it is not considered obvious to the man skilled in the art to combine a reverse transcriptase inhibitor with Meldonium dihydrate. Hydrogen fumarate and dihydrogen phosphate salts of Meldonium are disclosed in EP 1667960 A (JOINT STOCK COMPANY GRINDEKS) 14.06.2006 as more stable substance comparatively with Meldonium dihydrate. Disclosure of Invention
As it was known what Meldonium dihydrate is used for treatment of Ischemic Heart Disease; however there are no data what Meldonium salts is used for treatment of Ischemic Heart Disease.
To our surprise, by using Meldonium hydrogen fumarate in myocardial infarction and/or ischemja treatment it shows unexpected effect, and was more effective as Meldonium dihydrate in vivo myocardial infarction model. The hydrogen fumarate and dihydrogen phosphate salts of Meldonium, what is pharmaceutical acceptable salt, bioequivalent wit Meldonium dihydrate and should show the same medical effect like a Meldonium dihydrate, unexpectedly showed statistically better therapeutically effect than Meldonium dihydrate. Best Mode for Carrying Out the Invention The following examples further illustrate the invention. Anti- ischemic activity
Experiments were conducted on adult male Wistar rats with initial weight of 300- 35Og. During the experiment, the animals were kept in Standard crates in groups of 8. The feed was a standardized diet R70 (LABFOR, Lactamin AB, Sweden). The room temperature was kept at 21-23°C, relative humidity at 65±10%, 12 hour light/darkness cycle.
The experimental procedures were carried out in accordance with the guidelines of the European Community and local laws and policies and were approved by Latvian Animal Protection Ethical Committee, the Food and Veterinary Service. Experiment 1 Myocardial infarction in vivo
Rats weighing approximately 300 g were randomly divided into 4 groups of 8 animals each. The first group received saline by mouth (control group), the second received 100 mg/kg Meldonium dihydrate by mouth, the third 100mg/kg Meldonium hydrogen fumarate and the fourth 100mg/kg Meldonium dihydrogen phosphate received for 14 days. Rats were anesthetized with sodium pentobarbital (60 mg/kg i.p.). They were intubated and artificially respirated with rodent respirator (Rodent Ventilator 7025, Ugo Basile, Itally) with 15 mL/kg room air at a respiration rate of 55 breaths/min. Thoracic was open on the left side of breastbone by cutting fourth and fifths, if necessary, ribs. The pericard was open and 5/0 polypropylene suture (Surgipro II, Syneture) was passed under the left anterior descending coronary artery and threaded through a small plastic tube to permit reversible occlusion of the coronart artery. Coronary flow was measured using an ultrasound flow detector (HSE) and PowerLab 8/30 system from ADInstruments. Occlusion was performed by constricting threads through a plastic tube. At the end of the 120 minute reperfusion, After reperfusion hearts were excised and retrogradely perfused via aorta at a constant pressure of 50 mm Hg, with oxygenated Krebs-Henseleit buffer ( content in mmol/L: NaCI 118, Ca CI2 2.52, MgCI2 1.64, NaHCO3 24.88, KH2PO4 1.18, glucose 10.0, EDTA 0.05) pH 7.3-7.5 at 37°C. Then after 10 min the left anterior descending coronary artery was relegated and the risk zone was delineated with 4 ml_ of 0.1 % methylene blue solution in Krebs-Henseleit buffer infused via the aorta root. Hearts were sectioned transversely from the apex to the base of 2 mm thickness and incubated in 1 % triphenyl-tetrazolium chloride in phosphate buffer (pH 7.4, 37°C) for 10 minutes to stain viable tissue red and necrotic tissue white. Afterward, the right ventricle was cut off and photos of the left-ventricle slices were made with a Minolta 7D photo camera. Computerized planemetric analysis of photographs was performed using Image-Pro Plus 4.5.1 software to determine the area at risk (AR) and area of necrosis (AN) expressed as percentage of the left ventricle (LV). Obtained values were then used to calculate the infarct size (IS) as percentage of risk area according to formula:
IS(%) = — x 100 AR Results of myocardial infarction in vivo by administration with Meldonium dihydrate, Meldonium hydrogen fumarate and Meldonium dihydrogen phosphate for 14 days are summarize in Table 1.
Table 1
Results of myocardial infarction in vivo
Figure imgf000006_0001
kp<0.01 relative to the control group; #p<0.01 to Meldonium dihydrate group.

Claims

Claims
1. Use of 3-(2,2,2-trimethylhydrazinium)propionate salt selected from the group consisting of dihydrogen phosphate and hydrogen fumarate for the manufacture of a medicament for the treatment of ischemic heart disease. 2. 3-(2,2,
2-Trimethylhydrazinium)propionate salt for the treatment of ischemic heart disease.
3. Use of according to claim 1 or claim 2 where ischemic heart disease is myocardial infarction.
4. 3-(2,2,2-Trimethylhydrazinium)propionate salt according to claim 1-3 where it is 3-(2,2,2-trimethylhydrazinium)propionate hydrogen fumarate.
5. 3-(2,2,2-Trimethylhydrazinium)propionate salt according to claim 1-3 where it is 3-(2,2,2-trimethylhydrazinium)propionate dihydrogen phosphate.
PCT/EP2008/066712 2007-12-05 2008-12-03 3-(2,2,2-trimethylhydrazinium) propionate salts for treating ischemic heart disease Ceased WO2009071586A2 (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
BRPI0819055 BRPI0819055A2 (en) 2007-12-05 2008-12-03 "USE OF 3- (2,2,2-TRIMETHYLHYDRAZINE) PROPIONATE AND ITS SALTS"
SI200830294T SI2222376T1 (en) 2007-12-05 2008-12-03 3-(2,2,2-trimethylhydrazinium) propionate salts for treating myocardial infarction
US12/734,785 US20110028438A1 (en) 2007-12-05 2008-12-03 Medical use of 3-2,2,2-trimethylhydrazinium propionate salts.
PL08857821T PL2222376T3 (en) 2007-12-05 2008-12-03 3-(2,2,2-trimethylhydrazinium) propionate salts for treating myocardial infarction
CN200880119405XA CN101951991A (en) 2007-12-05 2008-12-03 New medical use of 3-(2,2,2-trimethylhydrazinium) propionate salts
EA201000739A EA016971B1 (en) 2007-12-05 2008-12-03 New medical use of 3-(2,2,2-trimethylhydrazinium)propionate salts
AU2008333263A AU2008333263A1 (en) 2007-12-05 2008-12-03 New medical use of 3-(2,2,2-trimethylhydrazinium) propionate salts
EP08857821A EP2222376B1 (en) 2007-12-05 2008-12-03 3-(2,2,2-trimethylhydrazinium) propionate salts for treating myocardial infarction
AT08857821T ATE503473T1 (en) 2007-12-05 2008-12-03 3-(2,2,2-TRIMETHYLHYDRAZINIUM) PROPIONATE SALTS FOR THE TREATMENT OF MYOCARDIAL INFARCTION
JP2010536439A JP2011506285A (en) 2007-12-05 2008-12-03 3- (2,2,2-trimethylhydrazinium) propionate salt for new use in medicine
UAA201006836A UA100249C2 (en) 2007-12-05 2008-12-03 Novel medical use of 3-(2,2,2-trimethylhydrazinium) propionate salts
MX2010006257A MX2010006257A (en) 2007-12-05 2008-12-03 New medical use of 3-(2,2,2-trimethylhydrazinium) propionate salts.
DE602008005930T DE602008005930D1 (en) 2007-12-05 2008-12-03 3- (2,2,2-TRIMETHYLHYDRAZINIUM) PROPIONATE SALTS FOR THE TREATMENT OF THE MYOKARDIN FARCT
CA2706357A CA2706357C (en) 2007-12-05 2008-12-03 3-(2,2,2-trimethylhydrazinium) propionate salts for treating ischemic heart disease
HR20110468T HRP20110468T1 (en) 2007-12-05 2008-12-03 3-(2,2,2-trimethylhydrazinium) propionate salts for treating myocardial infarction
NZ586518A NZ586518A (en) 2007-12-05 2008-12-03 Use of meldonium salts to treat myocardial infarction
DK08857821.6T DK2222376T3 (en) 2007-12-05 2008-12-03 3- (2,2,2-trimethylhydrazinium) propionate salts for the treatment of myocardial infarction
ZA2010/03640A ZA201003640B (en) 2007-12-05 2010-05-21 3-(2,2,2-trimethylhhydrazinuim) propionate salts for treating ischemic heart disease treating
IL205962A IL205962A0 (en) 2007-12-05 2010-05-25 3-(2,2,2-trimethlhydrazinium)propionate salts for treating ischemic heart disease
TN2010000249A TN2010000249A1 (en) 2007-12-05 2010-06-01 New medical use of 3-(2,2,2-trimethylhydrazinium ) propionate salts
MA32977A MA31992B1 (en) 2007-12-05 2010-07-01 New medical use of 3-salts (2,2,2-trimetylhydrazinium) propionate

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP07122360.6 2007-12-05
EP07122359.8 2007-12-05
EP07122359 2007-12-05
EP07122360 2007-12-05

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WO2009071586A3 WO2009071586A3 (en) 2009-09-24

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US (1) US20110028438A1 (en)
EP (1) EP2222376B1 (en)
JP (1) JP2011506285A (en)
KR (1) KR20100084687A (en)
CN (1) CN101951991A (en)
AR (1) AR069548A1 (en)
AT (1) ATE503473T1 (en)
AU (1) AU2008333263A1 (en)
BR (1) BRPI0819055A2 (en)
CA (1) CA2706357C (en)
CL (1) CL2008003552A1 (en)
CO (1) CO6280507A2 (en)
DE (1) DE602008005930D1 (en)
DK (1) DK2222376T3 (en)
DO (1) DOP2010000162A (en)
EA (1) EA016971B1 (en)
GE (1) GEP20125646B (en)
HR (1) HRP20110468T1 (en)
IL (1) IL205962A0 (en)
MA (1) MA31992B1 (en)
MX (1) MX2010006257A (en)
MY (1) MY158799A (en)
NZ (1) NZ586518A (en)
PA (1) PA8806001A1 (en)
PE (1) PE20091209A1 (en)
PL (1) PL2222376T3 (en)
PT (1) PT2222376E (en)
RS (1) RS51785B (en)
SI (1) SI2222376T1 (en)
SV (1) SV2010003585A (en)
TN (1) TN2010000249A1 (en)
TW (1) TWI391131B (en)
UA (1) UA100249C2 (en)
UY (1) UY31499A1 (en)
WO (1) WO2009071586A2 (en)
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RU2457198C1 (en) * 2011-05-31 2012-07-27 Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" 3-(2,2,2-trimethylhydrazinium) propionate derivative - potassium glycinate 3-(2,2,2-trimethylhydrazinium) propionate
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

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2467748C1 (en) * 2011-08-08 2012-11-27 Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" 3-(2,2,2-trimethylhydrazinium) propionate derivative - 3-(2,2,2-trimethylhydrazinium) potassium propionate glycinate exhibiting endothelioprotective activity

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MXPA06000955A (en) * 2003-08-04 2006-03-30 Grindeks Jsc Meldonium salts, method of their preparation and pharmaceutical composition on their basis.
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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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
AU2012247467B2 (en) * 2011-04-27 2016-07-28 Grindeks, A Joint Stock Company Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease
US10351534B2 (en) 2011-04-27 2019-07-16 Jsc Grindeks Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium salts in the treatment of cardiovascular disease
RU2457198C1 (en) * 2011-05-31 2012-07-27 Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет" 3-(2,2,2-trimethylhydrazinium) propionate derivative - potassium glycinate 3-(2,2,2-trimethylhydrazinium) propionate

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