WO2013081372A1 - Pharmaceutical composition for preventing or treating hyperlipidemia - Google Patents
Pharmaceutical composition for preventing or treating hyperlipidemia Download PDFInfo
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- WO2013081372A1 WO2013081372A1 PCT/KR2012/010170 KR2012010170W WO2013081372A1 WO 2013081372 A1 WO2013081372 A1 WO 2013081372A1 KR 2012010170 W KR2012010170 W KR 2012010170W WO 2013081372 A1 WO2013081372 A1 WO 2013081372A1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
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- 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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- 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
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- the present invention relates to a pharmaceutical composition for preventing or treating hyperlipidemia. More specifically, the present invention relates to a pharmaceutical composition for preventing or treating hyperlipidemia comprising (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-( ⁇ 2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl ⁇ methyl)-4-methyl-1,3-oxazolidin-2-one or its pharmaceutically acceptable salt; and an angiotensin II receptor blocker as active ingredients.
- Hyperlipidemia involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood. Hyperlipidemias may be classified according to which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Triglycerides are known as one of the independent risk factors of atherosclerosis. Although the relevancy between hypertriglyceridemia and cardiovascular diseases such as atherosclerosis is not still clear, it has been known that hypertriglyceridemia increases the risk of atherosclerosis (Cullen P. Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000; 86:943-9; Le NA, Walter MF.
- the compound of the following formula 1 whose chemical name is (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-( ⁇ 2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl ⁇ methyl)-4-methyl-1,3-oxazolidin-2-one, has a selective cholesterol ester transfer protein (CETP) inhibiting activity.
- CETP cholesterol ester transfer protein
- the compound is being developed as a drug for preventing or treating atherosclerosis (International Patent Publication No. WO 2006/014357).
- the present inventors performed various researches for developing a drug or a drug-combination capable of providing effective therapeutic efficacy against hyperlipidemia. Surprisingly, the present inventors found that co-administration of the compound of Formula 1 and an angiotensin II receptor blocker can remarkably inhibit the concentration of triglycerides in the blood; and increase HDL cholesterols in the blood, in comparison with the administration of the compound of Formula 1 alone.
- compositions for preventing or treating hyperlipidemia comprising the compound of Formula 1 and an angiotensin II receptor blocker as active ingredients.
- a pharmaceutical composition for preventing or treating hyperlipidemia comprising a compound of Formula 1 or its pharmaceutically acceptable salt; and an angiotensin II receptor blocker as active ingredients:
- the angiotensin II receptor blocker may be selected from the group consisting of olmesartan or its salt, olmesartan medoxomil or its salt, telmisartan or its salt, losartan or its salt, and valsartan or its salt.
- the angiotensin II receptor blocker may be olmesartan medoxomil or its salt.
- the hyperlipidemia may be hypertriglyceridemia or hypertriglyceridemia-associated disease.
- the hypertriglyceridemia-associated disease includes atherosclerosis or pancreatitis.
- the hyperlipidemia may be hypercholesterolemia.
- the hyperlipidemia may be combined hyperlipidemia.
- the pharmaceutical composition of the present invention may be formulated into a dosage form for oral administration.
- the dosage form for oral administration may comprise the compound of Formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 10 to 300 mg/day; and/or the angiotensin II receptor blocker in an amount suitable for administering in a dose ranging from 5 to 320 mg/day.
- the pharmaceutical composition of the present invention can be usefully applied for preventing or treating hyperlipidemia, including hypertriglyceridemia (inclusive of hypertriglyceridemia-associated diseases), hypercholesterolemia, and combined hyperlipidemia.
- the present invention provides a pharmaceutical composition for preventing or treating hyperlipidemia comprising a compound of Formula 1 or its pharmaceutically acceptable salt; and an angiotensin II receptor blocker as active ingredients:
- the compound of Formula 1 or its pharmaceutically acceptable salt may be prepared according to the disclosures in the International Publication No. WO 2006/014357.
- the International Publication No. WO 2006/014357 is incorporated into the present specification as a reference.
- the angiotensin II receptor blocker includes olmesartan or its salt, olmesartan medoxomil or its salt, telmisartan or its salt (e.g., sodium salt, etc.), losartan or its salt (e.g., potassium salt, etc.), and valsartan or its salt (e.g., sodium salt, calcium salt, etc.).
- the angiotensin II receptor blocker may be preferably olmesartan medoxomil or its salt.
- the pharmaceutical composition of the present invention may be a pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated disease.
- the hypertriglyceridemia-associated disease refers to a disease originated from abnormally elevated level of the triglycerides in the blood.
- the hypertriglyceridemia-associated disease includes atherosclerosis and pancreatitis, but not limited thereto.
- Preferable example of the hypertriglyceridemia-associated disease includes atherosclerosis.
- the pharmaceutical composition of the present invention may be a pharmaceutical composition for preventing or treating hypercholesterolemia.
- the pharmaceutical composition of the present invention may be a pharmaceutical composition for preventing or treating combined hyperlipidemia.
- the pharmaceutical composition of the present invention may be formulated into oral or parenteral dosage forms, preferably into a dosage form for oral administration. And also, the pharmaceutical composition of the present invention may have a form obtained by formulating the compound of Formula 1 and an angiotensin II receptor blocker into a single unit dosage form. Alternatively, the pharmaceutical composition of the present invention may have a form obtained by formulating the compound of Formula 1 and an angiotensin II receptor blocker into separate dosage forms and then packaging the resulting dosage forms in a single package unit.
- the pharmaceutical composition for oral administration having one or two unit dosage form(s) may include a pharmaceutically acceptable carrier, for example, diluents, disintegrating agents, sweeteners, lubricants, and/or flavoring agents, and can be formulated according to conventional methods into tablets, capsules, powders, granules, suspensions, emulsions, syrups, etc.
- a pharmaceutically acceptable carrier for example, diluents, disintegrating agents, sweeteners, lubricants, and/or flavoring agents
- a pharmaceutically acceptable carrier for example, diluents, disintegrating agents, sweeteners, lubricants, and/or flavoring agents
- a pharmaceutically acceptable carrier for example, diluents, disintegrating agents, sweeteners, lubricants, and/or flavoring agents
- a pharmaceutically acceptable carrier for example, diluents, disintegrating agents, sweeteners, lubricants, and/or flavoring agents
- carriers such as lactose, corn starch
- the active ingredient(s) may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be used.
- emulsifying and/or suspending agents may be used for the pharmaceutical composition for parenteral administration (for example, intramuscular, intraperitoneal, subcutaneous and intravenous administration) having one or two unit dosage form(s).
- sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered with an isotonic agent and/or a buffering agent.
- the compound of Formula 1 or its pharmaceutically acceptable salt contained in the pharmaceutical composition of the present invention may be administered in a therapeutically effective amount ranging from about 10 mg per day to about 300 mg per day to a subject patient.
- the an angiotensin II receptor blocker may be administered in a therapeutically effective amount ranging from about 5 mg per day to about 320 mg per day to a subject patient.
- the dosages may be changed according to the patient's age, weight, susceptibility, symptom, etc.
- the pharmaceutical composition of the present invention may be formulated into a dosage form for oral administration.
- the dosage form for oral administration may comprise the compound of Formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 10 to 300 mg/day; and/or the angiotensin II receptor blocker in an amount suitable for administering in a dose ranging from 5 to 320 mg/day.
- the daily dose of the angiotensin II receptor blocker depends on the kinds thereof.
- the present invention also provides a use of active ingredients comprising the compound of Formula 1 (i.e., (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-( ⁇ 2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl ⁇ methyl)-4-methyl-1,3-oxazolidin-2-one) or its pharmaceutically acceptable salt; and an angiotensin II receptor blocker for the manufacture of a medicament for preventing or treating hyperlipidemia.
- the hyperlipidemia may be hypertriglyceridemia or hypertriglyceridemia-associated disease.
- the hypertriglyceridemia-associated disease includes atherosclerosis and pancreatitis, but not limited thereto.
- Preferable example of the hypertriglyceridemia-associated disease includes atherosclerosis.
- the hyperlipidemia may be hypercholesterolemia or combined hyperlipidemia.
- the present invention comprises, within its scope, a method for treating hyperlipidemia in a patient, which comprises administering a therapeutically effective amount of the compound of Formula 1 (i.e., (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-( ⁇ 2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl ⁇ methyl)-4-methyl-1,3-oxazolidin-2-one) or its pharmaceutically acceptable salt; and a therapeutically effective amount of an angiotensin II receptor blocker to the patient in need thereof.
- a therapeutically effective amount of the compound of Formula 1 i.e., (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-( ⁇ 2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl ⁇ methyl)-4-methyl-1
- the hyperlipidemia may be hypertriglyceridemia or hypertriglyceridemia-associated disease.
- the hypertriglyceridemia-associated disease includes atherosclerosis and pancreatitis, but not limited thereto.
- Preferable example of the hypertriglyceridemia-associated disease includes atherosclerosis.
- the hyperlipidemia may be hypercholesterolemia or combined hyperlipidemia.
- an irradiation-sterilized hypercholesterolemia diet i.e., DYET# 620007 (Purina # 5321 chow with 1% cholesterol, Dyets, Inc., Bethlehem, PA 18017), which was purchased from Central Lab. Animal Inc.
- test materials were dissolved in saline containing 0.5% carboxymethylcellulose sodium and 1% Tween 80 and then administered directly into the stomach using an oral syringe adapted with a latex catheter, once per day for 4 weeks.
- the test groups are as in the following Table 1.
- the blood samples were collected through the jugular vein, from the animals at the day initiating the hypercholesterolemia diet supply (i.e., before feeding), and from the animals (which were fasted for 12 to 16 hours before collecting the blood) at 2 weeks and at 4 weeks after initiating the administration of the test material(s).
- triglyceride concentrations in the hypercholesterolemia-induced animals as in the above are presented in the following Table 2.
- the values in Table 2 represent average triglyceride concentrations (mg/dL) of the respective group.
- the co-administration groups showed remarkably high triglyceride-inhibitory activities, in comparison with the group administered with the compound of Formula 1 alone (G3, 356.7 mg/dL at the 4 weeks after initiating the administration).
- the co-administration group of the compound of Formula 1 and telmisartan showed the most potent triglyceride-inhibitory activity.
- the combination of the compound of Formula 1 and the angiotensin II receptor blocker such as olmesartan, olmesartan medoxomil, telmisartan, losartan, or valsartan can be usefully applied for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated diseases.
- mice Male New Zealand White rabbits were used as a test animal. All animals, except for the G1 group animals (negative control group), were fed with an irradiation-sterilized hypertriglyceridemia and hypercholesterolemia diet, i.e., DYET# 621082 (Purina# 5321 chow with 0.5% cholesterol, 14% coconut oil & 2% Maltose Dextrin, Dyets, Inc., Bethlehem, PA 18017), which was purchased from Saeronbio Inc. In order to induce hypertriglyceridemia and hypercholesterolemia, the animals were supplied with the diet for more than 4 weeks. After collecting the blood samples from the animals, serum biochemical analyses were performed thereon.
- an irradiation-sterilized hypertriglyceridemia and hypercholesterolemia diet i.e., DYET# 621082 (Purina# 5321 chow with 0.5% cholesterol, 14% coconut oil & 2% Maltose Dextrin, Dyet
- mice showing significant changes in total cholesterol levels and triglyceride levels were selected, in comparison with the non-treated control group.
- the selected animals were divided into 4 groups on the basis of the total cholesterol levels and triglyceride levels, thereby all the groups having substantially equal average values in the total cholesterol levels and triglyceride levels.
- the test materials were dissolved in saline containing 0.5% carboxymethylcellulose sodium and 1% Tween 80 and then administered directly into the stomach using an oral syringe adapted with a latex catheter, once per day for 4 weeks.
- the test groups are as in the following Table 3.
- the triglyceride concentrations in the hypertriglyceridemia and hypercholesterolemia-induced animals as in the above are presented in the following Table 4.
- the values in Table 4 represent average triglyceride concentrations (mg/dL) of the respective group.
- the HDL cholesterol concentrations in the blood samples are presented in the following Table 5.
- the values in Table 5 represent average HDL cholesterol concentrations (mg/dL) measured from the blood sample of the respective group.
- the combination of the compound of Formula 1 and the angiotensin II receptor blocker such as olmesartan medoxomil can be usefully applied for preventing or treating hypercholesterolemia and combined hyperlipidemia, as well as hypertriglyceridemia (including hypertriglyceridemia-associated diseases).
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Abstract
Description
Group | Animal(numbers) | Dose volume(mL/kg/day) | Test material | Dose(mg/kg/day) | ||
First material | Second material | First material | Second material | |||
G1 | 4 | 2 | - | - | 0 | 0 |
G2 | 8 | 2 | - | - | 0 | 0 |
G3 | 8 | 2 | Compound of Formula 1 | - | 20 | 0 |
G4 | 8 | 2 | Compound of Formula 1 | Olmesartan medoxomil | 20 | 3 |
G5 | 8 | 2 | Compound of Formula 1 | Telmisartan | 20 | 5 |
G6 | 8 | 2 | Compound of Formula 1 | Losartan | 20 | 10 |
G7 | 8 | 2 | Compound of Formula 1 | Valsartan | 20 | 10 |
Group | 0 week | 2 weeks | 4 weeks |
G1 | 66.3 | 99.5 | 52.5 |
G2 | 192.6 | 315.1 | 544.1 |
G3 | 167.4 | 255.8 | 356.7 |
G4 | 122.0 | 156.6 | 145.6 |
G5 | 188.7 | 123.7 | 111.2 |
G6 | 86.2 | 112.8 | 114.3 |
G7 | 131.4 | 138.4 | 135.0 |
Group | Dose volume (mL/kg/day) | Test material | Dose(mg/kg/day) | ||
First material | Second material | First material | Second material | ||
G1 | 2 | - | - | 0 | 0 |
G2 | 2 | - | - | 0 | 0 |
G3 | 2 | Compound of Formula 1 | - | 20 | 0 |
G4 | 2 | - | Olmesartan medoxomil | 0 | 3 |
G5 | 2 | Compound of Formula 1 | Olmesartan medoxomil | 20 | 3 |
Group | 4 weeks | Percent inhibition of triglyceride in the blood (%) |
G1 | 35.7 | - |
G2 | 326.5 | - |
G3 | 293.1 | 10.2 |
G4 | 217.4 | 33.4 |
G5 | 139.4 | 57.3 |
Group | 4 weeks | Percent increase of HDL cholesterol level (%) |
G1 | 8.1 | - |
G2 | 122.2 | - |
G3 | 168.5 | 37.9 |
G4 | 125.3 | 2.6 |
G5 | 193.9 | 58.7 |
Claims (12)
- The pharmaceutical composition according to claim 1, wherein the angiotensin II receptor blocker is selected from the group consisting of olmesartan or its salt, olmesartan medoxomil or its salt, telmisartan or its salt, losartan or its salt, and valsartan or its salt.
- The pharmaceutical composition according to claim 1, wherein the angiotensin II receptor blocker is olmesartan medoxomil or its salt.
- The pharmaceutical composition according to any one of claims 1 to 3, wherein the hyperlipidemia is hypertriglyceridemia or hypertriglyceridemia-associated disease.
- The pharmaceutical composition according to claim 4, wherein the hypertriglyceridemia-associated disease is atherosclerosis or pancreatitis.
- The pharmaceutical composition according to any one of claims 1 to 3, wherein the hyperlipidemia is hypercholesterolemia.
- The pharmaceutical composition according to any one of claims 1 to 3, wherein the hyperlipidemia is combined hyperlipidemia.
- The pharmaceutical composition according to any one of claims 1 to 3, wherein the composition is formulated into a dosage form for oral administration.
- The pharmaceutical composition according to claim 8, wherein the dosage form for oral administration comprises the compound of Formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 10 to 300 mg/day.
- The pharmaceutical composition according to claim 8, wherein the dosage form for oral administration comprises the angiotensin II receptor blocker in an amount suitable for administering in a dose ranging from 5 to 320 mg/day.
- A method for treating hyperlipidemia in a patient, which comprises administering a therapeutically effective amount of a compound of Formula 1 or its pharmaceutically acceptable salt; and a therapeutically effective amount of an angiotensin II receptor blocker to the patient in need thereof:<Formula 1>
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
UAA201405160A UA114491C2 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
AU2012346754A AU2012346754B2 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
RU2014125702A RU2616522C2 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for hyperlipidemia prevention or treatment |
MX2014006448A MX353660B (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia. |
JP2014544660A JP6108631B2 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
EP12852736.3A EP2785343A4 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
US14/361,371 US9724336B2 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
BR112014012081A BR112014012081A2 (en) | 2011-11-30 | 2012-11-28 | pharmaceutical composition and method for the prevention or treatment of hyperlidemia and use of compound or pharmaceutically acceptable salt thereof and angiotensin receptor blocker ii |
CN201280058939.2A CN104053441B (en) | 2011-11-30 | 2012-11-28 | For preventing or treat the pharmaceutical composition of hyperlipemia |
NZ625006A NZ625006B2 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
CA2857163A CA2857163A1 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
PH12014501088A PH12014501088A1 (en) | 2011-11-30 | 2014-05-14 | Pharmaceutical composition for preventing or treating hyperlipidemia |
Applications Claiming Priority (2)
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KR10-2011-0126431 | 2011-11-30 | ||
KR20110126431 | 2011-11-30 |
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WO2013081372A1 true WO2013081372A1 (en) | 2013-06-06 |
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PCT/KR2012/010170 WO2013081372A1 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hyperlipidemia |
PCT/KR2012/010175 WO2013081373A1 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated diseases |
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PCT/KR2012/010175 WO2013081373A1 (en) | 2011-11-30 | 2012-11-28 | Pharmaceutical composition for preventing or treating hypertriglyceridemia or hypertriglyceridemia-associated diseases |
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US (2) | US9724336B2 (en) |
EP (2) | EP2785342A4 (en) |
JP (2) | JP6030147B2 (en) |
KR (2) | KR101436551B1 (en) |
CN (2) | CN104053440B (en) |
AU (2) | AU2012346754B2 (en) |
BR (2) | BR112014012082A2 (en) |
CA (2) | CA2857164A1 (en) |
MX (2) | MX352611B (en) |
PH (2) | PH12014501087A1 (en) |
RU (2) | RU2604132C2 (en) |
UA (2) | UA114491C2 (en) |
WO (2) | WO2013081372A1 (en) |
Families Citing this family (1)
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CN113121331B (en) * | 2019-12-31 | 2024-01-05 | 华创合成制药股份有限公司 | Phenoxy aromatic acid compounds with cyclopropyl and pharmaceutically acceptable salts thereof, and preparation methods and applications thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080242711A1 (en) * | 2007-03-16 | 2008-10-02 | Concert Pharmceuticals, Inc. | Inhibitors of cholesterol ester transfer protein |
US20090137548A1 (en) * | 2005-12-30 | 2009-05-28 | Amjad Ali | 1,3-Oxazolidin-2-One Derivatives Useful as Cetp Inhibitors |
US20100099716A1 (en) * | 2004-07-02 | 2010-04-22 | Amjad Ali | Cetp inhibitors |
US20110165239A1 (en) * | 2008-09-24 | 2011-07-07 | Laman Alani | Pharmaceutical compositions of atorvastatin |
US20110218177A1 (en) * | 2008-10-01 | 2011-09-08 | Mills Sander G | Prodrugs of oxazolidinone cetp inhibitors |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6004925A (en) * | 1997-09-29 | 1999-12-21 | J. L. Dasseux | Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders |
WO2000038724A1 (en) * | 1998-12-23 | 2000-07-06 | G.D. Searle Llc | Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications |
US7129265B2 (en) * | 1999-04-23 | 2006-10-31 | Mason R Preston | Synergistic effects of amlodipine and atorvastatin metabolite as a basis for combination therapy |
EP1284723A4 (en) | 2000-04-19 | 2004-06-30 | Borody Thomas J | Compositions and therapies for hyperlipidaemia-associated disorders |
US7071210B2 (en) | 2002-07-02 | 2006-07-04 | Pfizer Inc. | CETP inhibitors in combination with antihypertensive agents and uses thereof |
HN2005000340A (en) * | 2004-07-02 | 2009-11-06 | Merck Sharp & Dohme | CETP INHIBITORS |
US7375112B2 (en) * | 2005-01-05 | 2008-05-20 | Medicure International Inc. | Compounds and methods for regulating triglyceride levels |
CN101822836A (en) * | 2010-02-02 | 2010-09-08 | 王丽燕 | Medicine composition containing allisartan isoproxil |
-
2012
- 2012-11-28 US US14/361,371 patent/US9724336B2/en not_active Expired - Fee Related
- 2012-11-28 CA CA2857164A patent/CA2857164A1/en not_active Abandoned
- 2012-11-28 RU RU2014125701/15A patent/RU2604132C2/en not_active IP Right Cessation
- 2012-11-28 MX MX2014006447A patent/MX352611B/en active IP Right Grant
- 2012-11-28 US US14/361,365 patent/US9486443B2/en not_active Expired - Fee Related
- 2012-11-28 JP JP2014544661A patent/JP6030147B2/en not_active Expired - Fee Related
- 2012-11-28 CA CA2857163A patent/CA2857163A1/en not_active Abandoned
- 2012-11-28 AU AU2012346754A patent/AU2012346754B2/en not_active Ceased
- 2012-11-28 AU AU2012346755A patent/AU2012346755B2/en not_active Ceased
- 2012-11-28 RU RU2014125702A patent/RU2616522C2/en not_active IP Right Cessation
- 2012-11-28 WO PCT/KR2012/010170 patent/WO2013081372A1/en active Application Filing
- 2012-11-28 UA UAA201405160A patent/UA114491C2/en unknown
- 2012-11-28 EP EP12852569.8A patent/EP2785342A4/en not_active Withdrawn
- 2012-11-28 BR BR112014012082A patent/BR112014012082A2/en not_active Application Discontinuation
- 2012-11-28 BR BR112014012081A patent/BR112014012081A2/en not_active Application Discontinuation
- 2012-11-28 KR KR1020120136199A patent/KR101436551B1/en not_active IP Right Cessation
- 2012-11-28 MX MX2014006448A patent/MX353660B/en active IP Right Grant
- 2012-11-28 CN CN201280058933.5A patent/CN104053440B/en not_active Expired - Fee Related
- 2012-11-28 CN CN201280058939.2A patent/CN104053441B/en not_active Expired - Fee Related
- 2012-11-28 UA UAA201405161A patent/UA114492C2/en unknown
- 2012-11-28 WO PCT/KR2012/010175 patent/WO2013081373A1/en active Application Filing
- 2012-11-28 EP EP12852736.3A patent/EP2785343A4/en not_active Withdrawn
- 2012-11-28 JP JP2014544660A patent/JP6108631B2/en not_active Expired - Fee Related
- 2012-11-28 KR KR1020120136186A patent/KR101436547B1/en not_active IP Right Cessation
-
2014
- 2014-05-14 PH PH12014501087A patent/PH12014501087A1/en unknown
- 2014-05-14 PH PH12014501088A patent/PH12014501088A1/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100099716A1 (en) * | 2004-07-02 | 2010-04-22 | Amjad Ali | Cetp inhibitors |
US20090137548A1 (en) * | 2005-12-30 | 2009-05-28 | Amjad Ali | 1,3-Oxazolidin-2-One Derivatives Useful as Cetp Inhibitors |
US20080242711A1 (en) * | 2007-03-16 | 2008-10-02 | Concert Pharmceuticals, Inc. | Inhibitors of cholesterol ester transfer protein |
US20110165239A1 (en) * | 2008-09-24 | 2011-07-07 | Laman Alani | Pharmaceutical compositions of atorvastatin |
US20110218177A1 (en) * | 2008-10-01 | 2011-09-08 | Mills Sander G | Prodrugs of oxazolidinone cetp inhibitors |
Non-Patent Citations (1)
Title |
---|
See also references of EP2785343A4 * |
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