CA2895574A1 - Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis - Google Patents
Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis Download PDFInfo
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- CA2895574A1 CA2895574A1 CA2895574A CA2895574A CA2895574A1 CA 2895574 A1 CA2895574 A1 CA 2895574A1 CA 2895574 A CA2895574 A CA 2895574A CA 2895574 A CA2895574 A CA 2895574A CA 2895574 A1 CA2895574 A1 CA 2895574A1
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- aminium
- dimethylpropan
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- atherosclerosis
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- 201000001320 Atherosclerosis Diseases 0.000 title claims abstract description 16
- 150000003839 salts Chemical class 0.000 title claims abstract description 12
- ISMYCKWHOZKHNJ-UHFFFAOYSA-O 3-carboxypropyl-ethyl-dimethylazanium Chemical compound CC[N+](C)(C)CCCC(O)=O ISMYCKWHOZKHNJ-UHFFFAOYSA-O 0.000 title claims abstract description 9
- DQSCWIHGBKJVRY-UHFFFAOYSA-N 3-carboxypropyl-ethyl-dimethylazanium;dihydrogen phosphate Chemical compound OP(O)([O-])=O.CC[N+](C)(C)CCCC(O)=O DQSCWIHGBKJVRY-UHFFFAOYSA-N 0.000 claims abstract description 6
- PPDPFXLNXLDRNM-WLHGVMLRSA-N (e)-but-2-enedioate;3-carboxypropyl-ethyl-dimethylazanium;hydron Chemical compound OC(=O)\C=C\C([O-])=O.CC[N+](C)(C)CCCC(O)=O PPDPFXLNXLDRNM-WLHGVMLRSA-N 0.000 claims abstract description 5
- 230000002265 prevention Effects 0.000 claims abstract description 3
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- 230000003143 atherosclerotic effect Effects 0.000 description 15
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- 230000000879 anti-atherosclerotic effect Effects 0.000 description 4
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 4
- JHPNVNIEXXLNTR-UHFFFAOYSA-O 4-(trimethylammonio)butanoic acid Chemical compound C[N+](C)(C)CCCC(O)=O JHPNVNIEXXLNTR-UHFFFAOYSA-O 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 3
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- JHPNVNIEXXLNTR-UHFFFAOYSA-N 4-(trimethylammonio)butanoate Chemical compound C[N+](C)(C)CCCC([O-])=O JHPNVNIEXXLNTR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical group OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
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- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 2
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 1
- PHIQHXFUZVPYII-LURJTMIESA-O (S)-carnitinium Chemical compound C[N+](C)(C)C[C@@H](O)CC(O)=O PHIQHXFUZVPYII-LURJTMIESA-O 0.000 description 1
- JHLPIJWOGXXOSI-UHFFFAOYSA-N 2-[ethyl(dimethyl)azaniumyl]butanoate Chemical class C(C)[N+](C)(C)C(C(=O)[O-])CC JHLPIJWOGXXOSI-UHFFFAOYSA-N 0.000 description 1
- GELMWIVBBPAMIO-UHFFFAOYSA-N 2-methylbutan-2-amine Chemical compound CCC(C)(C)N GELMWIVBBPAMIO-UHFFFAOYSA-N 0.000 description 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 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102100029470 Apolipoprotein E Human genes 0.000 description 1
- 101710095339 Apolipoprotein E Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 206010054880 Vascular insufficiency Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
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- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 229960004203 carnitine Drugs 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- FIIMLTIASNPROL-UHFFFAOYSA-N dihydrogen phosphate;2-methylbutan-2-ylazanium Chemical compound OP(O)([O-])=O.CCC(C)(C)[NH3+] FIIMLTIASNPROL-UHFFFAOYSA-N 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
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- 208000019622 heart disease Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000004317 lacrimation Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000010344 pupil dilation Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000023577 vascular insufficiency disease Diseases 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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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
- A61K31/19—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
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- Engineering & Computer Science (AREA)
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- 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
Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium and its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate, in the prevention and treatment atherosclerosis.
Description
Use of 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis Technical Field 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. Examples of pharmaceutically acceptable salts of carboxy-N-ethyl-N,N-dimethylpropan-1-aminium are: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate.
1.0 Background Art 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.
Atherosclerotic lesions commonly develop in regions of turbulent blood flow and are found most often in people with elevated cholesterol concentrations. The
1.0 Background Art 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.
Atherosclerotic lesions commonly develop in regions of turbulent blood flow and are found most often in people with elevated cholesterol concentrations. The
2 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).
Sometimes 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), is the most common cause of death, accounting for one-third of all deaths. 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.
Unfortunately, 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.
Sometimes 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), is the most common cause of death, accounting for one-third of all deaths. 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.
Unfortunately, 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.
3 PCT/EP2013/077291 3-Carboxy-N,N,N-trimethylpropan-1-aminium (GBB) is known mostly as a bio-precursor of carnitine, a key molecule in the regulation of myocardial energy metabolism , was primarily characterised as a toxic substance, which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and heart stop in diastole LINNEWEH, W. Gamma- Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Seylers Zeitschrift fur physiologische Chemie. 1929, vol.181 , p.42-53. At the same time, in later papers it has been shown that administration of 3-carboxy-/V/V,N-trimethylpropan-1-aminium does not induce any toxic effects as it is extremely low toxic (LD50 7000 mg/kg, s.c.) 3.0 ROTZSCH, W. lber die Toxizitat des Carnitins und einiger verwandter Stoffe. Acta biol. med. germ. 1959, vol.3, p.28-36.
The combination of 3-carboxy-N,N,N-trimethylpropan-1-aminium with 3-(2,2,2-trimethylhydrazinium)propionate dihydrate in the treatment of atherosclerosis was presented in WO 2010/149654 A (GRINDEKS JSC) 29.10.2010. Nevertheless the effect of 3-carboxy-/V,N,N-trimethylpropan-1-aminium, where it is used alone, for the treatment of atherosclerosis is not reported.
A new derivate of 3-carboxy-N,N,N-trimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium, as a new compound with cardioprotective activity was disclosed in WO 2011/048201 A (GRINDEKS JSC) 28.04.2011.
Apolipoprotein E knockout (ApoE-/-) mice are frequently used experimental model of the atherosclerosis for the assessment of anti-atherosclerotic activity of tested substances.
The combination of 3-carboxy-N,N,N-trimethylpropan-1-aminium with 3-(2,2,2-trimethylhydrazinium)propionate dihydrate in the treatment of atherosclerosis was presented in WO 2010/149654 A (GRINDEKS JSC) 29.10.2010. Nevertheless the effect of 3-carboxy-/V,N,N-trimethylpropan-1-aminium, where it is used alone, for the treatment of atherosclerosis is not reported.
A new derivate of 3-carboxy-N,N,N-trimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium, as a new compound with cardioprotective activity was disclosed in WO 2011/048201 A (GRINDEKS JSC) 28.04.2011.
Apolipoprotein E knockout (ApoE-/-) mice are frequently used experimental model of the atherosclerosis for the assessment of anti-atherosclerotic activity of tested substances.
4 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-N-ethyl-N,N-dimethylpropan-1-aminiumor its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate) or 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate, possibly through alteration of lipid and cholesterol metabolism.
io A therapeutically effective amount of 3-carboxy-N-ethyl-N,N-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.
It was surprisingly and unexpectedy found that 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium and its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumara te and 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate posses pronounced anti-atherosclerotic effect.
The anti-atherosclerotic activity of 3-carboxy-N-ethyl-N,N-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-N-ethyl-/V,N-dimethylpropan-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
The lesion progression inhibition is achieved by treatment with 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminiumor its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate) or 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate, possibly through alteration of lipid and cholesterol metabolism.
io A therapeutically effective amount of 3-carboxy-N-ethyl-N,N-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.
It was surprisingly and unexpectedy found that 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium and its pharmaceutically acceptable salts: 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumara te and 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate posses pronounced anti-atherosclerotic effect.
The anti-atherosclerotic activity of 3-carboxy-N-ethyl-N,N-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-N-ethyl-/V,N-dimethylpropan-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
5 and sterile aqueous or organic solutions. Thus, for oral administration 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. For parenteral administration io 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.
Anti-atherosclerotic activity 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.
Mice were adapted to local conditions for one week before the beginning of the study. At the age of 8 weeks, mice were randomly assigned to five equally sized groups (n = 10). To induce experimental atherosclerosis (atherosclerotic lesions in the aorta), animals of all groups were fed with WESTERN RD (P) diet (Cat 82316)
The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration io 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.
Anti-atherosclerotic activity 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.
Mice were adapted to local conditions for one week before the beginning of the study. At the age of 8 weeks, mice were randomly assigned to five equally sized groups (n = 10). To induce experimental atherosclerosis (atherosclerotic lesions in the aorta), animals of all groups were fed with WESTERN RD (P) diet (Cat 82316)
6 from Special Diets Services (Great Britain) for 4 months. During these 4 months, mice from different experimental groups received following treatment:
1. Control group ¨ drinking water;
2. 3-Carboxy-/VAN-trimethylpropan-1-aminium group ¨ 3-carboxy-/VAN-trimethylpropan-1-aminium 10mg/kg in drinking water;
3. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium group ¨ 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium 10 mg/kg in drinking water;
4. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate group ¨ 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate 17.5 mg/kg in drinking water;
5. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate group ¨ 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate 16.8 mg/kg in drinking water.
The doses of the tested substances were adjusted to be equimolar with 10 mg/kg dose of 3-carboxy-N-ethyl-/V,N-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.
After 4 months, mice were injected intraperitoneally (i.p.) with 1,000 Ul of heparin ip. 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%
1. Control group ¨ drinking water;
2. 3-Carboxy-/VAN-trimethylpropan-1-aminium group ¨ 3-carboxy-/VAN-trimethylpropan-1-aminium 10mg/kg in drinking water;
3. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium group ¨ 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium 10 mg/kg in drinking water;
4. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate group ¨ 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate 17.5 mg/kg in drinking water;
5. 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate group ¨ 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate 16.8 mg/kg in drinking water.
The doses of the tested substances were adjusted to be equimolar with 10 mg/kg dose of 3-carboxy-N-ethyl-/V,N-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.
After 4 months, mice were injected intraperitoneally (i.p.) with 1,000 Ul of heparin ip. 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%
7 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.
All analyses were performed by an observer blinded to the treatment group.
After 4-month exposure to Western RD diet, the apoE-/- mice developed marked atherosclerotic lesions. Analysis of Sudan IV stained aortas showed that area of atherosclerotic lesions in the control group averaged 14-16% of the total aortic surface. Four-month administration of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium at the dose of 10 mg/kg, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate at the dose of 17.5 mg/kg, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate at the dose of 16.8 mg/kg (the latter two equimolar to 10mg/kg of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium) induced a statistically significant reduction in the size of atherosclerotic lesions. 3-Carboxy-/V/V,N-trimethylpropan-1-aminium (10 mg/kg) had no effect on the size of atherosclerotic lesions.
Effects of 4-month treatment with 3-carboxy-/V/V,N-trimethylpropan-1-aminium, carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-
All analyses were performed by an observer blinded to the treatment group.
After 4-month exposure to Western RD diet, the apoE-/- mice developed marked atherosclerotic lesions. Analysis of Sudan IV stained aortas showed that area of atherosclerotic lesions in the control group averaged 14-16% of the total aortic surface. Four-month administration of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium at the dose of 10 mg/kg, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate at the dose of 17.5 mg/kg, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate at the dose of 16.8 mg/kg (the latter two equimolar to 10mg/kg of 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium) induced a statistically significant reduction in the size of atherosclerotic lesions. 3-Carboxy-/V/V,N-trimethylpropan-1-aminium (10 mg/kg) had no effect on the size of atherosclerotic lesions.
Effects of 4-month treatment with 3-carboxy-/V/V,N-trimethylpropan-1-aminium, carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-
8 dimethylpropan-1-aminium dihydrogen phosphate on the area of atherosclerotic lesions in aorta of apoE-/- mice are presented in Table 1.
Table 1 Effects of 3-carboxy-/V/V,N-trimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate on the area of atherosclerotic lesions Treatment group Area of atherosclerotic lesions (%) Control 100.0 10.7 3-Carboxy-NAN-trimethylpropan-1-96.0 10.6 aminium, 10 mg/kg 3-Carboxy-N-ethyl-/V,N-43.6 8.6"
dimethylpropan-1-aminium, 10 mg/kg 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen 47.9 5.7"
fumarate, 17.5 mg/kg 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen 64.4 7.5"
phosphate, 16.8 mg/kg
Table 1 Effects of 3-carboxy-/V/V,N-trimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium, 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen phosphate on the area of atherosclerotic lesions Treatment group Area of atherosclerotic lesions (%) Control 100.0 10.7 3-Carboxy-NAN-trimethylpropan-1-96.0 10.6 aminium, 10 mg/kg 3-Carboxy-N-ethyl-/V,N-43.6 8.6"
dimethylpropan-1-aminium, 10 mg/kg 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium hydrogen 47.9 5.7"
fumarate, 17.5 mg/kg 3-Carboxy-N-ethyl-/V,N-dimethylpropan-1-aminium dihydrogen 64.4 7.5"
phosphate, 16.8 mg/kg
9 Values are given as mean SEM. Statistical analysis was performed by Student's t-test; *p<0.05 versus control group and #p<0.05 versus 3-carboxy-NAN-trimethylpropan-1-aminium group; n=10.
The results are presented as a percentage relative to the control group which was assigned a value of 100%.
Results presented in Table 1 show that 3-carboxy-N-ethyl-NN-dimethylpropan-1-aminium, 3-carboxy-N-ethyl-NN-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-NN-dimethylpropan-1-aminium dihydrogen phosphate had a protective effect on formation of atherosclerotic lesions in aorta of apoE-/-mice.
3-Carboxy-NAN-trimethylpropan-1-aminium, in contrary, was not effective.
The results are presented as a percentage relative to the control group which was assigned a value of 100%.
Results presented in Table 1 show that 3-carboxy-N-ethyl-NN-dimethylpropan-1-aminium, 3-carboxy-N-ethyl-NN-dimethylpropan-1-aminium hydrogen fumarate and 3-carboxy-N-ethyl-NN-dimethylpropan-1-aminium dihydrogen phosphate had a protective effect on formation of atherosclerotic lesions in aorta of apoE-/-mice.
3-Carboxy-NAN-trimethylpropan-1-aminium, in contrary, was not effective.
Claims (3)
1. 3-Carboxy-N-ethyl-N,N-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof for use in the prevention and treatment of atherosclerosis.
2. Use according to claim 1, wherein pharmaceutically acceptable salt is 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium hydrogen fumarate.
3. Use according to claim 1, wherein pharmaceutically acceptable salt is 3-carboxy-N-ethyl-N,N-dimethylpropan-1-aminium dihydrogen phosphate .
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| EP12198627 | 2012-12-20 | ||
| EP12198627.7 | 2012-12-20 | ||
| PCT/EP2013/077291 WO2014096133A1 (en) | 2012-12-20 | 2013-12-19 | Use of 3-carboxy-n-ethyl-n,n-dimethylpropan-1-aminium or a pharmaceutically acceptable salt thereof in the treatment of atherosclerosis |
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| CA2895574C CA2895574C (en) | 2019-11-26 |
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| MX (1) | MX362762B (en) |
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| WO2010149654A1 (en) * | 2009-06-25 | 2010-12-29 | Grindeks, A Joint Stock Company | Pharmaceutical composition of gamma-butyrobetaine or a pharmaceutically acceptable salt and meldonium or a pharmaceutically acceptable salt |
| LV14345B (en) * | 2009-10-22 | 2011-07-20 | Grindeks, A/S | 4-[ethyl(dimethyl)ammonio]butanoate and their use in the treatment of cardiovascular diseases |
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| BR112015014161B1 (en) | 2021-02-17 |
| AR094084A1 (en) | 2015-07-08 |
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| MX2015008138A (en) | 2016-04-25 |
| PE20151587A1 (en) | 2015-12-05 |
| CA2895574C (en) | 2019-11-26 |
| CN104869988B (en) | 2017-07-28 |
| WO2014096133A1 (en) | 2014-06-26 |
| ZA201505093B (en) | 2016-04-28 |
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