Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • 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
  • A61K31/4245—Oxadiazoles
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
  • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
  • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton

Definitions

• the present invention relates to azilsartan organic amine salt and a process for the preparation thereof, and to a pharmaceutical composition comprising a therapeutically effective amount of the compound, and its use for the preparation of an antihypertensive drug. Background technique
• Azilsartan is a selective angiotensin II type 1 receptor (ATI) antagonist that blocks the contractile vasoconstriction of angiotensin- ⁇ by selectively blocking the binding of angiotensin II to vascular smooth muscle ATI receptors. Thereby lowering blood pressure.
• ATI angiotensin II type 1 receptor
• Azilsartan has a carboxyl group in its molecular structure, which is poorly absorbed in the body and is not suitable for preparation into a pharmaceutical dosage form. In order to improve its bioavailability, it can be made into an active ester by chemical modification, ie, azisartan, but its bioavailability is not ideal. In addition, the modification makes the molecular structure of the drug complicated and increases the difficulty of synthesis. . Summary of the invention
• the present invention has found that the salt formation of azilsartan and organic amine can improve its pharmacokinetic characteristics, improve its bioavailability, and is more suitable for conventional preparation processes.
• B is an organic amine selected from the group consisting of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, amino Butanetriol, tetramethyl Quaternary ammonium or choline; preferably ethanolamine
• Another object of the present invention is to provide a process for the preparation of the above compound which comprises separately adding azilsartan acid and an organic amine B to an alcoholic organic solvent, and forming a salt at room temperature or under heating.
• the alcohol solvent described therein is selected from the group consisting of methanol, ethanol, propanol or isopropanol.
• Another object of the present invention is to provide a pharmaceutical composition for treating hypertension comprising a therapeutically effective amount of azilsartan organic amine salt as an active ingredient and a pharmaceutically acceptable carrier.
• the present invention provides the use of azilsartan organic amine salt and a pharmaceutical composition containing the same for the preparation of an antihypertensive drug.
• the drug substance is in a form that is convenient to handle and handle. This is important not only from the viewpoint of obtaining a commercially viable preparation method, but also from the viewpoint of subsequently preparing a pharmaceutical preparation containing the active compound.
• the chemical stability, solid state stability and "shelf life" of the active ingredients are also very important factors.
• the drug substance and the composition comprising the same should preferably be capable of being effectively stored for a considerable period of time, while the physicochemical properties of the active ingredient (e.g., its chemical composition, density, hygroscopicity, and solubility) do not exhibit significant changes.
• the effective amount of the active ingredient means an effective non-toxic dose, preferably in the range of 0.001 to 100 mg/kg of total body weight, more preferably 0.001 to 50 mg/kg.
• oral or parenteral administration is preferred, including topical, rectal, transdermal, injection or continuous infusion.
• the human oral administration dose preferably comprises from 0.05 to 3500 mg of the active ingredient, most preferably from 0.5 to 1000 mg of the active ingredient. It is preferred to use a lower dose oral administration form. Of course, high dose parenteral administration can also be administered when it is safe and convenient for the patient.
• the above dosages relate to the preferred amount of active ingredient expressed as the free acid.
• the optimal dose and interval of the individual dose of the active ingredient depends on the nature and extent of the treatment of the disease, the dosage form, the route and the site, the specific patient to be treated, and the best solution can be commonly used. Technical determination. It will also be apparent to those skilled in the art that the optimal course of treatment, i.e., the number of doses of the active ingredient administered per day for a given period of time, can be determined by those skilled in the art using commonly used procedures for determining the course of treatment.
• the compounds of the present invention can be administered orally or parenterally, and can be formulated into tablets, pills, powders, and granules for various routes of administration.
• the active ingredient is mixed with at least one inert diluent.
• Oral formulations may also include, in addition to inert diluents, such as lubricants, glidants, and antioxidants, as is conventional practice. If capsules, tablets, and pills are prepared, a buffer is included in the formulation. Tablets and pills can also be formulated as sustained release formulations.
• the parenteral administration preparation of the present invention includes a sterile aqueous solution, although a nonaqueous solution of the emulsion can also be used.
• These dosage forms may also include adjuvants such as preservatives, wetting agents, penetrants, buffers, emulsifiers and dispersing agents.
• the sterilization may be carried out by filtration using a bacteria retaining filter, adding a sterilizing agent to the composition, and sterilizing by irradiating the composition or heating the composition.
• the salt of the present invention has a markedly increased solubility in a conventional solvent such as water, methanol and 0.1% hydrochloric acid, and is suitable for use in a conventional preparation.
• the salt of the present invention has an improved stability property.
• the salt of the present invention has a better bioavailability.
• the salt of the present invention is prepared in high yield, high purity, fast, convenient and low cost, wherein the ethanolamine salt and the choline salt are advantageous in the process route.
• Test Example 1 Inhibition of angiotensin II-induced pressor response by a compound of the present invention in rats
• test compound After establishing an angiotensin II (All, 100 ng/kg, i.v.) induced pressor response, equimolar doses of test compound were administered. After 24 hours, sputum was administered, and the increase in blood pressure was measured based on the calculation of the inhibition rate with respect to the blood pressure value before administration. All compounds were suspended in 0.5% methylcellulose and orally administered in a volume of 2 mL/kg. The test results are expressed as mean SEM (Table 1).
• Test Example 2 Inhibition of angiotensin II-induced pressor response by a compound of the present invention in dogs
• male beagle dogs (weight 12.0-14.7 kg, KITAYAMA LABES, CO., LTD.) were used. They were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and inserted into the tracheal tube to control the airway. Shave the femoral region and the posterior neck and sterilize (polypyrrolidone iodine solution, MEIJI SEIKA KAISHA, LTD to fix the dog in the dorsal position, cut the right femoral region. Insert the catheter (5F, MILLER INDUSTRIES) and place Place the polyurethane tube in the femoral artery and in the femoral vein.
• Penicillin G potassium (MEIJI SEIKA KAISHA, LTD., 40000 units) was administered once a day for 3 days from the next day. After 3 days of recovery, the dog was used for the test.
• the dog was placed in a small metabolic cage.
• the catheter tube inserted into the femoral artery was connected to a conduction unit (MILLER INDUSTRIES), passed through a DC amplifier (N4777, NEC San-ei Instruments) and a blood pressure monitoring amplifier (N4441, NEC San-ei Instruments) in the recorder (RECTI-HORIZ) Systemic blood pressure (mean blood pressure:) was recorded on 8K, NEC San-ei Instruments.
• the polyurethane tube inserted into the femoral vein was fixed outside the cage and used to give All (PEPTIDE INSTITUTE, INC.).
• test results are expressed as mean SEM (Table 2).
• the compounds of the invention have significant long-lasting and potent pharmacological effects.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 2010
  • 2010-11-29 CN CN2010800449716A patent/CN102548988B/zh not_active Expired - Fee Related
  • 2010-11-29 CA CA2782224A patent/CA2782224A1/en not_active Abandoned
  • 2010-11-29 RU RU2012124332/04A patent/RU2554947C2/ru active
  • 2010-11-29 EP EP10832671.1A patent/EP2508522A4/en not_active Withdrawn
  • 2010-11-29 BR BR112012012484A patent/BR112012012484A2/pt not_active IP Right Cessation
  • 2010-11-29 MX MX2012005776A patent/MX2012005776A/es not_active Application Discontinuation
  • 2010-11-29 AU AU2010324249A patent/AU2010324249B2/en not_active Ceased
  • 2010-11-29 JP JP2012540278A patent/JP2013512199A/ja active Pending
  • 2010-11-29 WO PCT/CN2010/079222 patent/WO2011063764A1/zh not_active Ceased
  • 2010-11-29 US US13/512,652 patent/US20120238606A1/en not_active Abandoned
• 2012
  • 2012-04-13 ZA ZA2012/02683A patent/ZA201202683B/en unknown

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