WO2014096133A1 - Utilisation du 3-carboxy-n-éthyl-n,n-diméthylpropan-1-aminium ou d'un sel pharmaceutiquement acceptable pour le traitement de l'athérosclérose - Google Patents

Utilisation du 3-carboxy-n-éthyl-n,n-diméthylpropan-1-aminium ou d'un sel pharmaceutiquement acceptable pour le traitement de l'athérosclérose Download PDF

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Publication number
WO2014096133A1
WO2014096133A1 PCT/EP2013/077291 EP2013077291W WO2014096133A1 WO 2014096133 A1 WO2014096133 A1 WO 2014096133A1 EP 2013077291 W EP2013077291 W EP 2013077291W WO 2014096133 A1 WO2014096133 A1 WO 2014096133A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxy
aminium
dimethylpropan
ethyl
atherosclerosis
Prior art date
Application number
PCT/EP2013/077291
Other languages
English (en)
Inventor
Ivars Kalvins
Reinis Vilskersts
Osvalds Pugovics
Maija Dambrova
Ilmars Stonans
Janis Kuka
Edgars Liepins
Einars Loza
Viktors ANDRIANOVS
Solveiga Grinberga
Daina Gustina
Daina LOLA
Marina Makrecka
Original Assignee
Grindeks, A Joint Stock Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grindeks, A Joint Stock Company filed Critical Grindeks, A Joint Stock Company
Priority to CN201380066810.0A priority Critical patent/CN104869988B/zh
Priority to CA2895574A priority patent/CA2895574C/fr
Priority to BR112015014161-7A priority patent/BR112015014161B1/pt
Priority to MX2015008138A priority patent/MX362762B/es
Publication of WO2014096133A1 publication Critical patent/WO2014096133A1/fr
Priority to TNP2015000236A priority patent/TN2015000236A1/fr
Priority to CUP2015000067A priority patent/CU20150067A7/es
Priority to ZA2015/05093A priority patent/ZA201505093B/en

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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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • 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 3-carboxy-N-ethyl-N,N-dimethylpropan-1 -aminium or a pharmaceutically acceptable salt thereof for use in the prevention and treatment of atherosclerosis.
  • pharmaceutically acceptable salts of 3- carboxy-N-ethyl-N,N-dimethylpropan-1 -aminium are: 3-carboxy-A-ethyl-/V,AA dimethylpropan-1 -aminium hydrogen fumarate and 3-carboxy-A-ethyl-/V,A- dimethylpropan-1 -aminium dihydrogen phosphate.
  • Atherosclerosis is a complex chronic inflammatory process of the vascular wall that progresses over decades. It is characterized by the accumulation of oxidized low-density lipoproteins (LDL), increased cell death and hypertrophic degeneration of the arterial wall, causing narrowing of the inner diameter of the vessel and, thus, impairing blood flow. It can occur in any area of the body, but is most important when it develops in the blood vessels of the heart or brain. The narrowing is due to the formation of plaques (raised patches) in the inner lining of the arteries. These plaques consist of oxidized LDL, decaying muscle cells, fibrous tissue, clumps of blood platelets, cholesterol, macrophages, T-lymphocytes and sometimes calcium.
  • LDL low-density lipoproteins
  • Atherosclerotic lesions commonly develop in regions of turbulent blood flow and are found most often in people with elevated cholesterol concentrations.
  • the number and thickness of plaques increases with age, causing loss of the smooth lining of the blood vessels and encouraging the formation of thrombi (blood clots).
  • thrombi blood clots
  • fragments of thrombi break off and form emboli, which travel through the bloodstream and block smaller vessels, thus, causing ischemic damage of the tissues.
  • Atherosclerosis and its clinical manifestations are a major cause of morbidity and mortality in the modern society.
  • Atherosclerotic heart disease involving the coronary arteries (coronary heart disease)
  • Atherosclerotic interference with blood supply to the brain (stroke) is the third most common cause of death after cancer.
  • Vascular insufficiency is another clinical manifestation of atherosclerosis which causes a great deal of serious illness by reducing the flow of blood in other major arteries, such as to the kidneys, legs, and intestines.
  • Atherosclerosis produces no symptoms until the damage to the arteries is severe enough to restrict blood flow. Restriction of blood flow to the heart muscle due to atherosclerosis can cause angina pectoris or a myocardial infarction (a heart attack). Restriction of blood flow to the muscles of the legs induces intermittent claudication (pain in the legs that occurs during exercise and is relieved by rest). Narrowing of the arteries supplying blood to the brain may cause transient ischemic attacks (symptoms and signs of a stroke lasting less than 24 hours) and episodes of dizziness, or ultimately, to a stroke itself.
  • GEB 3-Carboxy-N,N,N-trimethylpropan-1 -aminium
  • Apolipoprotein E knockout mice are frequently used experimental model of the atherosclerosis for the assessment of anti-atherosclerotic activity of tested substances. Disclosure of the invention
  • This invention is directed to treating atherosclerosis by decreasing the total area and volume of atherosclerotic lesions.
  • the lesion progression inhibition is achieved by treatment with 3-carboxy-/V-ethyl- N,N-dimethylpropan-1 -aminiumor its pharmaceutically acceptable salts: 3-carboxy- N-ethyl-N,N-dimethylpropan-1 -aminium hydrogen fumarate) or 3-carboxy-/V-ethyl- A/,/V-dimethylpropan-1 -aminium dihydrogen phosphate, possibly through alteration of lipid and cholesterol metabolism.
  • a therapeutically effective amount of 3-carboxy- N-ethyl-A,/V-dimethylpropan-1 - aminium or its pharmaceutically acceptable salt is about 0.01 to 500 mg/kg/day, preferably 0.1 to 100 mg/kg/day.
  • the anti-atherosclerotic activity of 3-carboxy- AAethyl-N,A/-dimethylpropan-1 - aminium, 3-carboxy- N-ethyl-N,N-dimethylpropan-1 -aminium-hydrogen fumarate or 3-carboxy-N-ethyl-N,N-dimethylpropan-1 -aminium dihydrogen phosphate can be determined by assessing the effect of these compounds on the portion of the aortic surface covered by atherosclerotic lesions.
  • 3-Carboxy-AAethyl-/V,AAdimethylpropan-1 -aminium can be used in pharmaceutical preparations containing the compound, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent.
  • Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • parenteral administration the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. The injectable solutions can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly.
  • mice Female ApoE-'- mice weighing 18 - 20 g were maintained on a 12 h dark/12 h light cycle in air-conditioned rooms (22.5 ⁇ 0.5°C, 50 ⁇ 5% humidity) with unlimited access to food and water.
  • the doses of the tested substances were adjusted to be equimolar with 10 mg/kg dose of 3-carboxy-/V-ethyl-/V,/V-dimethylpropan-1 -aminium.
  • the dosing of the test compounds was confirmed by measuring the consumption of drinking water every 2 days and adjusting the concentration of supplemented substances.
  • mice were injected intraperitoneally (i.p.) with 1 ,000 Ul of heparin i.p. and sacrificed under anesthesia (sodium pentobarbital, 50 mg/kg i.p.).
  • the size of atherosclerotic lesions was determined in whole aorta.
  • the aortas from arch to bifurcation were cleaned from surrounding tissues, cut out and fixed in 4% formaldehyde. Afterwards whole aorta was longitudinally opened, pinned onto silicone plates and stained for lipids with Sudan IV. Images of the aorta were captured using a digital camera and the total area of the lesion was calculated using Image-Pro Plus 6.3 software.
  • the extent of atherosclerosis was expressed as the percentage of the aortic surface covered by lesions compared to the total aortic surface.

Landscapes

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

Abstract

L'invention concerne l'utilisation du 3-carboxy-N-éthyl-N,N-diméthylpropan-1-aminium et de ses sels pharmaceutiquement acceptables : le fumarate hydrogéné du 3-carboxy-N-éthyl-N,N-diméthylpropan-1-aminium et le phosphate hydrogéné du 3-carboxy-N-éthyl-N,N-diméthylpropan-1-aminium, pour la prévention et le traitement de l'athérosclérose.
PCT/EP2013/077291 2012-12-20 2013-12-19 Utilisation du 3-carboxy-n-éthyl-n,n-diméthylpropan-1-aminium ou d'un sel pharmaceutiquement acceptable pour le traitement de l'athérosclérose WO2014096133A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN201380066810.0A CN104869988B (zh) 2012-12-20 2013-12-19 3‑羧基‑n‑乙基‑n,n‑二甲基丙‑1‑铵或其药学上可接受的盐在治疗动脉粥样硬化中的用途
CA2895574A CA2895574C (fr) 2012-12-20 2013-12-19 Utilisation du 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium ou d'un sel pharmaceutiquement acceptable pour le traitement de l'atherosclerose
BR112015014161-7A BR112015014161B1 (pt) 2012-12-20 2013-12-19 uso de 3-carbóxi-n-etil-n,n-dimetilpropan-1-amínio ou seu sal farmaceuticamente aceitável no tratamento da aterosclerose
MX2015008138A MX362762B (es) 2012-12-20 2013-12-19 Uso de 3-carboxi-n-etil-n,n-dimetilpropan-1-aminio o una sal del mismo farmaceuticamente aceptable en el tratamiento de la aterosclerosis.
TNP2015000236A TN2015000236A1 (en) 2012-12-20 2015-06-01 Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis
CUP2015000067A CU20150067A7 (es) 2012-12-20 2015-06-19 3-carboxi-n-etil-n,n-dimetilpropan-1-aminio y sales farmacéuticamente aceptables para tratar la ateroclerosis
ZA2015/05093A ZA201505093B (en) 2012-12-20 2015-07-15 Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP12198627 2012-12-20
EP12198627.7 2012-12-20

Publications (1)

Publication Number Publication Date
WO2014096133A1 true WO2014096133A1 (fr) 2014-06-26

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ID=47458734

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/077291 WO2014096133A1 (fr) 2012-12-20 2013-12-19 Utilisation du 3-carboxy-n-éthyl-n,n-diméthylpropan-1-aminium ou d'un sel pharmaceutiquement acceptable pour le traitement de l'athérosclérose

Country Status (11)

Country Link
CN (1) CN104869988B (fr)
AR (1) AR094084A1 (fr)
BR (1) BR112015014161B1 (fr)
CA (1) CA2895574C (fr)
CU (1) CU20150067A7 (fr)
JO (1) JO3117B1 (fr)
MX (1) MX362762B (fr)
PE (1) PE20151587A1 (fr)
TN (1) TN2015000236A1 (fr)
WO (1) WO2014096133A1 (fr)
ZA (1) ZA201505093B (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010151095A1 (fr) * 2009-06-25 2010-12-29 Tetra, Sia Nouveaux sels de l'acide acétylsalicylique
WO2010149654A1 (fr) * 2009-06-25 2010-12-29 Grindeks, A Joint Stock Company Composition pharmaceutique de gamma-butyrobétaïne ou sel pharmaceutiquement acceptable et de meldonium ou sel pharmaceutiquement acceptable
WO2011048201A1 (fr) * 2009-10-22 2011-04-28 Grindeks, A Joint Stock Company Utilisation de 4[éthyl(diméthyl)ammonio]butanoate dans le traitement d'une maladie cardiovasculaire
WO2012146736A1 (fr) * 2011-04-27 2012-11-01 Grindeks, A Joint Stock Company Utilisation de sels de 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium pour traiter une maladie cardiovasculaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010151095A1 (fr) * 2009-06-25 2010-12-29 Tetra, Sia Nouveaux sels de l'acide acétylsalicylique
WO2010149654A1 (fr) * 2009-06-25 2010-12-29 Grindeks, A Joint Stock Company Composition pharmaceutique de gamma-butyrobétaïne ou sel pharmaceutiquement acceptable et de meldonium ou sel pharmaceutiquement acceptable
WO2011048201A1 (fr) * 2009-10-22 2011-04-28 Grindeks, A Joint Stock Company Utilisation de 4[éthyl(diméthyl)ammonio]butanoate dans le traitement d'une maladie cardiovasculaire
WO2012146736A1 (fr) * 2011-04-27 2012-11-01 Grindeks, A Joint Stock Company Utilisation de sels de 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium pour traiter une maladie cardiovasculaire

Also Published As

Publication number Publication date
TN2015000236A1 (en) 2016-10-03
CN104869988B (zh) 2017-07-28
CA2895574C (fr) 2019-11-26
MX362762B (es) 2019-02-06
JO3117B1 (ar) 2017-09-20
CU20150067A7 (es) 2016-01-29
MX2015008138A (es) 2016-04-25
AR094084A1 (es) 2015-07-08
BR112015014161B1 (pt) 2021-02-17
CN104869988A (zh) 2015-08-26
ZA201505093B (en) 2016-04-28
PE20151587A1 (es) 2015-12-05
BR112015014161A2 (pt) 2017-07-11
CA2895574A1 (fr) 2014-06-26

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