WO2017091041A1 - Novel salt of fimasartan - Google Patents

Novel salt of fimasartan Download PDF

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Publication number
WO2017091041A1
WO2017091041A1 PCT/KR2016/013727 KR2016013727W WO2017091041A1 WO 2017091041 A1 WO2017091041 A1 WO 2017091041A1 KR 2016013727 W KR2016013727 W KR 2016013727W WO 2017091041 A1 WO2017091041 A1 WO 2017091041A1
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WO
WIPO (PCT)
Prior art keywords
salt
fimasartan
organic acid
hydrate
solvate
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Application number
PCT/KR2016/013727
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French (fr)
Korean (ko)
Inventor
김지한
김창모
Original Assignee
보령제약 주식회사
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Priority claimed from KR1020150166616A external-priority patent/KR20170061493A/en
Application filed by 보령제약 주식회사 filed Critical 보령제약 주식회사
Publication of WO2017091041A1 publication Critical patent/WO2017091041A1/en

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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
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to novel salts of fimasartan. More specifically, the present invention relates to a novel salt of fimasartan having excellent physicochemical properties such as stability, hygroscopicity, flowability, and anti-adhesion, as well as excellent solubility and bioavailability.
  • the physicochemical properties of the drug also have an important effect on the drug's effect.
  • the drug must meet physicochemical criteria such as good stability, non-hygroscopicity and processability into the formulation, as well as excellent solubility and bioavailability, and research on new salts of pimasartan that can satisfy these properties is ongoing. have.
  • Fimasartan is a hypertensive drug that is an angiotensin II receptor antagonist.
  • Canabra is marketed in three doses of 30, 60, and 120 mg under the trade name, and the main component is fimasartan potassium salt.
  • the fimasartan exhibits excellent pharmacological activity but has low solubility and has been used in the form of fimasartan potassium salt for its improvement.
  • It is an object of the present invention to provide a pharmaceutical composition comprising a novel salt of fimasartan.
  • the present invention provides a novel salt of fimasartan, a method for preparing the same, and a pharmaceutical composition comprising the same.
  • the present invention provides novel salts of fimasartan.
  • the pimasartan novel salt of the present invention may be an organic salt of fimasartan or an amine salt of fimasartan.
  • the present invention provides a hydrate or solvate of the fimasartan organic acid salt or fimasartan amine salt.
  • Fimasartan organic acid salts or fimasartan amine salts, or hydrates or solvates thereof according to the present invention exhibit excellent solubility and bioavailability, have excellent stability and non-hygroscopicity, and have excellent processability and good drug efficacy as formulations.
  • the present invention provides organic salts of fimasaltan or hydrates or solvates thereof.
  • the organic acid salt of fimasartan is methanesulfonate of fimasartan, benzenesulfonate of fimasartan, camphorsulfonate of fimasartan, toluenesulfonate of fimasartan, ethanedisulfonate of fimasartan, and fimasaltan It may be naphthalenedi sulfonate of, preferably may be campa sulfonate or benzene sulfonate of fimasaltan.
  • the fimasaltan organic acid salt may be a compound represented by the following Chemical Formula 1.
  • HX may be methanesulfonic acid, benzenesulfonic acid, campasulfonic acid, toluenesulfonic acid, and preferably may be campasulfonic acid or benzenesulfonic acid.
  • the fimasaltan organic acid salt may be a compound represented by the following Chemical Formula 2.
  • H 2 X may be ethane disulfonic acid or naphthalenedisulfonic acid.
  • the fimasartan organic acid salt may be a crystal. In the present invention, the fimasartan organic acid salt may be anhydrous crystals.
  • the organic acid salt of fimasartan refers to both fimasartan organic acid salts, geometric isomers thereof, optical isomers and racemates.
  • the camphorsulfonate of pimisaltan refers to both the geometric isomers, optical isomers, and racemates together with campasulfonate of pimasaltan.
  • Fimasaltan organic acid salt, or a hydrate or solvate thereof which is a novel salt of fimasartan according to the present invention, has high solubility, excellent oral absorption rate, and can exhibit excellent therapeutic effect even at a small dose, thereby significantly improving the convenience of patient medication. It can be improved.
  • it is suitable for the preparation of pharmaceutical formulations due to its excellent pharmaceutical physical properties such as stability, non-hygroscopicity and processability as a formulation.
  • the present invention provides fimasartan amine salts or hydrates or solvates thereof.
  • the amine salt of fimasartan may be choline salt, meglumine salt, ammonium salt or arginine salt of fimasartan.
  • Fimasaltan choline salt according to the present invention may be a compound represented by the following formula (3).
  • the meglumine salt of fimasaltan according to the present invention may be a compound represented by the following formula (4).
  • R 1 and R 2 may be H, R 3 is CH 3 and R 4 may be CH 2 (CHOH) 4 CH 2 OH.
  • Ammonium salt of fimasaltan according to the present invention may be a compound represented by Formula 4, and in Formula 4 R 1, R 2 , R 3 and R 4 is H.
  • Arginine salt of fimasaltan according to the present invention may be a compound represented by the following formula (5).
  • Fimasartan choline salts, meglumine salts, fimasartan ammonium salts, fimasartan arginine salts or hydrates or solvates thereof are non-hygroscopic and exhibit good stability in the solid state so that the formulation can maintain a uniform content for a long time.
  • the fimasartan amine salt preferably fimasartan choline salt, meglumine salt, ammonium salt or arginine salt may be a crystal.
  • the fimasartan choline salt, meglumine salt, ammonium salt or arginine salt may be anhydrous crystals or a hydrate, for example, a dihydrate of fimasartan meglumine salt.
  • the choline salt, meglumine salt, ammonium salt or arginine salt of fimasartan includes all of the geometric isomers, optical isomers, and racemates of choline salt, meglumine salt, ammonium salt or arginine salt of fimasartan.
  • Fimasaltan amine salt, or a hydrate or solvate thereof, which is a novel salt of fimasartan according to the present invention shows high bioavailability upon oral administration, and thus can show an excellent therapeutic effect even when a small amount is used. It can be remarkably improved. In addition, it has excellent pharmaceutical physicochemical properties such as stability, non-hygroscopicity and processability as a formulation, making it suitable for the preparation of pharmaceutical formulations compared to fimasartan potassium salt.
  • fimasartan In the case of fimasartan, poor solubility as a poorly soluble drug was not easy to formulate and the bioavailability was not high enough. Therefore, in order to exhibit a sufficient therapeutic effect through oral administration, fimasartan should be included in the formulation in a high content, and as a result, there was a problem in that the patient's convenience of medication was lowered. Has been.
  • the fimasartan organic acid salt and the fimasartan amine salt of the present invention are excellent in physicochemical and pharmacological properties required for drugs such as solubility and bioavailability, and thus are easier to formulate than conventional fimasartan potassium salts, and the convenience of patient medication Can be improved.
  • the fimasartan organic acid salt and the amine salt are non-hygroscopic and exhibit excellent stability in the solid state, so that the formulation can maintain a uniform content for a long time, and the physicochemical properties required for the pharmaceutical are excellent.
  • the excellent physical and chemical properties it is possible to mass-produce the formulation, which is economical, and can produce the fimasartan salt in high yield.
  • the present invention provides a method for preparing the organic acid salt of fimasartan or a hydrate or solvate thereof.
  • the method is a
  • It provides a method for preparing an organic acid salt of fimasartan comprising the step of adding an organic acid to the reactant.
  • the preparing of the reactant may include adding the fimasaltan or a salt thereof to a solvent.
  • the organic acid may be a known acid, for example, the organic acid may be a sulfonic acid, preferably benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, ethanedisulfonic acid or naphthalenedi Sulfonic acid.
  • the organic acid may be a sulfonic acid, preferably benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, ethanedisulfonic acid or naphthalenedi Sulfonic acid.
  • the acid may be determined according to the kind of fimasaltan organic acid salt to be prepared.
  • the acid when preparing campasulfonic acid salt of fimasaltan, the acid may be campasulfonic acid.
  • the camphorsulfonic acid may be a racemate or a stereoisomer thereof, and may be (S)-(-)-campasulfonic acid, (R)-(-)-campasulfonic acid or racemates thereof, For example, (S)-(-)-campasulfonic acid.
  • the solvent may include an organic solvent.
  • the organic solvent may be ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate or mixtures thereof,
  • it may be ethyl acetate, ethanol, isopropanol, acetonitrile, tetrahydrofuran, or a mixture thereof, more preferably ethanol.
  • the solvent when the organic solvent is a solvent miscible with water, the solvent may further include water in addition to the organic solvent.
  • the starting material in the preparation of the fimasartan organic acid salt, is fimasartan or a fimasartan salt, and preferably may be pimasartan.
  • the starting material is a salt of fimasartan, it may be a fimasartan potassium salt.
  • the method may further include heating after adding an acid.
  • the heating may be performed at 20 ° C to 80 ° C, preferably at 25 ° C to 65 ° C.
  • the method may further include adding an organic solvent after performing the heating step.
  • the type of the organic solvent is as described above.
  • the organic solvent added to the reactant may be the same or different from the previous organic solvent.
  • the present invention provides a process for preparing the amine salt of fimasartan or a hydrate or solvate thereof.
  • the method is a
  • It provides a method for preparing the amine salt of fimasaltan comprising the step of adding an amine to the reactant.
  • the preparing of the reactant may include mixing the fimasaltan or a salt thereof with the solvent.
  • the amine added to the reactant may be choline, choline salt, meglumine, ammonia or arginine.
  • the choline salt may be choline hydroxide (choline hydroxide).
  • a solution containing choline hydroxide may be added to the reactant, and preferably, the solution including choline hydroxide may be a methanol solution including choline hydroxide.
  • the ammonia may be preferably an ammonia solution, and specifically, may be added in a solution state in which ammonia gas is dissolved in methanol.
  • the solvent may include an organic solvent.
  • the organic solvent may be ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate, or mixtures thereof ,
  • the solvent when the organic solvent is a solvent miscible with water, the solvent may further include water in addition to the organic solvent.
  • the solvent may be a mixture of acetonitrile and water, in which case the volume ratio of acetonitrile and water may be about 30 to 10: 1.
  • the starting material in the preparation of the fimasartan amine salt is the fimasartan or the fimasartan salt.
  • the starting material is a salt of fimasartan, it may be a fimasartan potassium salt, preferably fimasartan is used.
  • the method may further include heating after adding the amine.
  • the heating may be performed at 20 ° C to 80 ° C, preferably at 25 ° C to 65 ° C.
  • the method may further include adding an organic solvent after performing the heating step.
  • the type of the organic solvent is as described above.
  • the organic solvent added to the reactant may be the same or different from the previous organic solvent.
  • the present invention provides compositions comprising fimasartan organic acid salts, hydrates or solvates thereof.
  • the present invention relates to methanesulfonate of fimasartan, benzenesulfonate of fimasartan, campasulfonate of fimasartan, toluenesulfonate of fimasartan, ethanedisulfonate of fimasartan or naphthalenedi of fimasartan.
  • compositions comprising sulfonates, hydrates or solvates thereof.
  • the present invention provides compositions comprising fimasartan amine salts, hydrates or solvates thereof.
  • the fimasartan amine salt may be fimasartan choline salt, meglumine salt, ammonium salt or arginine salt.
  • the composition is a pharmaceutical composition as stroke, stroke, cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation Or a pharmaceutical composition for treating or preventing renal failure.
  • the pharmaceutical composition may further include a pharmaceutically acceptable additive.
  • the pharmaceutically acceptable is a physiologically acceptable and when administered to a human, usually in the manufacture of self-pharmaceutical compositions having ordinary knowledge in the art without causing gastrointestinal disorders, allergic reactions such as dizziness or the like.
  • the additives may be carriers, excipients, extenders, antioxidants, buffers, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, suspending agents, surfactants and preservatives.
  • the additive may include lactose, dextrose, calcium silicate, corn starch, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid, magnesium stearate, calcium stearate, gelatin, mineral oil, saline solution, aqueous glucose solution, pseudosugar solution, alcohol , Glycols, ethers (eg polyethylene glycol 400), oils, fatty acids
  • compositions of the present invention may be formulated according to conventional methods, may be prepared as oral dosage forms or parenteral dosage forms, and may preferably be oral dosage forms.
  • the preparation for oral administration may be a solid preparation such as tablets, pills, powders, granules, capsules, or liquid preparations such as suspensions, solvents, emulsions, and syrups, and preferably solid preparations. Most preferably, more preferably a tablet.
  • the fimasartan organic acid salt or amine salt according to the present invention has excellent stability, excellent solubility in various solvents, and non-hygroscopicity, and thus has excellent physicochemical properties such as processability as a formulation. Therefore, when formulated in the form of tablets or capsules, it is possible to produce a tablet or capsule with excellent dispersibility and uniform pharmacological effect, and does not cause a problem that the pharmacological effect is lowered during the formulation process. Therefore, it is possible to economically produce a formulation having excellent pharmacological effects and having a uniform pharmacological effect.
  • the pharmaceutical composition of the present invention is formulated as an oral solid preparation
  • examples of the additives used are cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , Gelatin, talc and the like.
  • the pharmaceutical composition When the pharmaceutical composition is formulated as a liquid preparation for oral administration, the pharmaceutical composition may be formulated by adding various additives such as water, simple diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, preservatives, colorants, and the like. have.
  • additives such as water, simple diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, preservatives, colorants, and the like. have.
  • the additives include water, saline solution, aqueous glucose solution, pseudo-aqueous solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerol Ride etc. are mentioned.
  • the content of the additive included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the content range used in conventional formulation.
  • the pharmaceutical composition may include fimasartan organic acid salt or fimasartan amine salt so that the content of fimasartan is about 1 mg to 240 mg, preferably about 5 to 180 mg. More preferably 10 to 120 mg.
  • the pharmaceutical composition may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically), and the dosage may be weight, age, sex, health of the patient.
  • the range may vary depending on the condition, diet, administration time, administration method, administration period or interval, excretion rate, constitution specificity, nature of the preparation, severity of disease, and the like.
  • the dose of fimasartan may be orally administered so that the dose of fimasartan is about 1 to 240 mg, preferably 5 to 180 mg, more preferably 10 to 120 mg per day, based on a normal adult weighing about 60 kg. It may be applied once or several times.
  • the pharmaceutical composition may further include other pharmacologically active substances in addition to fimasartan organic acid salt or amine salt, hydrate or solvate thereof.
  • the pharmacologically active substance may have the same pharmacological activity as the fimasartan organic acid salt or the amine salt, or may have other pharmacological activity.
  • pharmacologically active substances included in the pharmaceutical composition include anti-hyperlipidemic agents such as amlodipine, lercardidipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, metformin, hydrochlorothiazide, cytagliptin, and billaggle Liptin, linagliptin, saxagliptin, tenelligliptin, anagliptin, melogliptin, dutogliptin, gemigliptin, and the like for diabetes treatment, pharmaceutically acceptable salts or mixtures thereof And more preferably amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, citagliptin, bilagliptin, linagliptin and pharmaceutically acceptable salts thereof or mixtures thereof.
  • anti-hyperlipidemic agents such as amlodipine, lercardidipine, ni
  • compositions of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers to ameliorate, alleviate, treat or prevent disease.
  • novel fimasartan organic acid salts and amine salts according to the present invention have excellent solubility and bioavailability, and thus have excellent therapeutic effects, and are excellent in properties such as stability, adhesiveness, flowability, and non-hygroscopicity, so that they are easy to formulate and the patient's convenience of medication is remarkable. It can be improved.
  • Fimasartan choline salt prepared in Example 7 according to the method described in the Korean Pharmacopoeia, fimasartan meglumine salt prepared in Example 8 and fimasartan arginine salt and fimasaltan potassium salt prepared in Example 10 Solubility for) was measured.
  • the fimasartan novel salts and fimasartan potassium salts prepared in Examples 8, 9 and 11 were added until supersaturated, respectively, and then 25 ° C ⁇ 3 ° C. Stir for 24 h at and stabilize for 1 h. Thereafter, the solution was analyzed by liquid chromatography (HPLC) to determine the amount of dissolution based on fimasartan base (free base), and the results are shown in Table 1 below.
  • the fimasartan novel salts of the present invention are 10 to 100 times at all pHs as compared to conventional fimasartan potassium salts.
  • the fimasartan meglumine salt of Example 8 exhibited about 3 to 50 times higher solubility at all pHs, and the fimasartan arginine salt of Example 10 had a potassium salt at pH 1.2. Similar solubility was shown, and the solubility was about 10 and 50 times higher at pH 4.0 and 6.8, respectively.
  • Ten beagle dogs were divided into five groups of groups 1 to 6 and fasted for one day.
  • the capsule 5 filled in and the capsule 6 filled with gelatin capsules 30 mg of pimasartan potassium salt were prepared.
  • the first group includes a capsule 1 containing 30 mg of pimasartan camphorsulfonic acid salt
  • the second group includes a capsule 2 containing 30 mg of fimasartan benzenesulfonate salt
  • the third group includes a capsule 3 containing 30 mg of pimasartan choline salt
  • the fourth group includes Oral capsule 4 containing 30 mg of fimasartan meglumine salt
  • capsule 5 containing 30 mg of fimasartan arginine salt in group 5
  • capsule 6 containing 30 mg of fimasartan potassium salt in group 6 orally And immediately taken in a negative 30 mL / 1 dose.
  • fimasartan novel salts in particular fimasartan campasulfonate, benzenesulfonate, choline salt, meglumine salt or arginine salt, according to the present invention are higher in blood compared to fimasaltal potassium salt. Concentration. In particular, even when administered in the same content it can be seen that more than three times the Cmax and 1.5 times more than AUC.
  • the novel fimasartan organic acid salt or amine salt according to the present invention is significantly superior in bioavailability as compared to the conventional fimasartan potassium salt, and as a result, can exhibit a significantly high therapeutic effect.

Abstract

The present invention provides: a novel salt of Fimasartan having excellent solubility, bioavailability, and physicochemical properties; a method for preparing the same; and a pharmaceutical composition containing the same.

Description

피마살탄의 신규 염New Salts of Fimasaltan
본 발명은 피마살탄의 신규 염에 관한 것이다. 보다 구체적으로 우수한 용해도 및 생체 이용률뿐만 아니라 안정성, 흡습성, 흐름성 및 부착방지성 등 우수한 물리화학적 성질을 가지는 피마살탄의 신규 염에 관한 것이다. The present invention relates to novel salts of fimasartan. More specifically, the present invention relates to a novel salt of fimasartan having excellent physicochemical properties such as stability, hygroscopicity, flowability, and anti-adhesion, as well as excellent solubility and bioavailability.
의약품 분야에서 약물의 약리학적 활성에 더하여 약물의 물리화학적 물성 역시 약물의 효력 발휘에 중요한 영향을 미친다. In addition to the pharmacological activity of the drug in the pharmaceutical field, the physicochemical properties of the drug also have an important effect on the drug's effect.
예를 들면, 약리학적 활성이 아무리 우수하더라도 약물이 난용성이면 경구 섭취 시 약물이 잘 용해되지 않아 약물이 효과를 발휘하기 어렵다. 이것은 약물의 용해가 어려워 제제화가 용이하지 않으며 제제화를 하더라도 낮은 용해도로 인해 제제들 사이의 약물 용출율의 편차가 클 수 있고 또한 용출율이 낮은 문제가 발생할 수 있기 때문이다. For example, no matter how excellent the pharmacological activity, if the drug is poorly soluble, the drug is difficult to dissolve when orally ingested, so the drug is difficult to exert an effect. This is because the dissolution of the drug is difficult to formulate, and even if formulated, the low solubility may cause a large variation in the drug dissolution rate between the agents and a problem of low dissolution rate may occur.
또한, 약리학적 활성이 아무리 우수하여도 약물의 생체 이용률이 낮으면 경구 투여 시 혈중에서 약물의 농도가 낮아 충분한 치료 효과를 수득할 수 없으며, 충분한 치료 효과를 수득하기 위해서는 경구 투여되는 약물의 양이 증가되어 복약 편의성이 저하되거나 부작용이 수반되는 문제점이 발생할 수 있다. In addition, no matter how excellent the pharmacological activity, the low bioavailability of the drug can not obtain a sufficient therapeutic effect due to the low concentration of the drug in the blood during oral administration, the amount of drug orally administered to obtain a sufficient therapeutic effect There may be a problem that the increased convenience or lower the medication convenience, accompanied by side effects.
따라서 우수한 약리 활성을 가지는 약물이라 하더라도 충분한 효과를 발휘하기 위해서는 약물의 용해도와 경구 투여에 따른 생체 이용률을 향상시킬 수 있는 많은 방법이 시도되고 있다. Therefore, even in the case of drugs having excellent pharmacological activity, many methods have been attempted to improve the solubility of drugs and the bioavailability according to oral administration.
또한 약물은 우수한 용해도 및 생체 이용률과 더불어 우수한 안정성, 비흡습성 및 제형으로의 가공성과 같은 물리화학적 기준을 충족해야 하며, 상기와 같은 성질을 만족시킬 수 있는 피마살탄 신규 염에 대한 연구가 꾸준히 진행되고 있다.In addition, the drug must meet physicochemical criteria such as good stability, non-hygroscopicity and processability into the formulation, as well as excellent solubility and bioavailability, and research on new salts of pimasartan that can satisfy these properties is ongoing. have.
피마살탄은 안지오텐신 II 수용체 길항제인 고혈압 약물로 카나브라는 상품명 하에 30, 60, 120mg의 세 가지 용량으로 시판되고 있으며, 주성분은 피마살탄 포타슘염이다. Fimasartan is a hypertensive drug that is an angiotensin II receptor antagonist. Canabra is marketed in three doses of 30, 60, and 120 mg under the trade name, and the main component is fimasartan potassium salt.
상기 피마살탄은 우수한 약리학적 활성을 나타내지만 용해도가 낮기 때문에 이의 개선을 위해 피마살탄 포타슘염의 형태로 사용되어왔다. The fimasartan exhibits excellent pharmacological activity but has low solubility and has been used in the form of fimasartan potassium salt for its improvement.
그러나 앞서 살핀 바와 같이, 용해도와 같은 물리화학적 성질이 우수하면 생체 이용률의 상승 등 이점이 있으며, 안정성, 비흡습성 및 제형으로서의 가공성과 같은 물리화학적 성질이 우수하면 대량생산이 용이하여 경제성 등 여러 가지 이점이 있다. However, as described above, if the physical and chemical properties such as solubility is excellent, there are advantages such as an increase in bioavailability, and if the physical and chemical properties, such as stability, non-hygroscopicity and processability as a formulation, are excellent, mass production is easy and economic benefits There is this.
따라서 피마살탄 포타슘염보다 용해도 및 생체 이용률에서 우수하며, 약물의 안정성, 비흡습성 및 제형으로서의 가공성에서 우수한 특성을 나타낼 수 있는 새로운 염의 개발을 위해 많은 노력이 행해지고 있다.Therefore, much effort is being made to develop new salts which are superior in solubility and bioavailability than fimasartan potassium salts and can exhibit excellent properties in drug stability, non-hygroscopicity and processability as formulation.
[선행기술문헌][Preceding technical literature]
대한민국 특허등록번호 제100354654호Republic of Korea Patent Registration No. 100354654
대한민국 특허등록번호 제100617953호Republic of Korea Patent Registration No. 100617953
본 발명의 목적은 피마살탄의 신규 염을 제공하는 것이다. It is an object of the present invention to provide novel salts of fimasartan.
본 발명의 목적은 또한, 용해도, 생체 이용률, 안정성 및 비흡습성이 우수한 피마살탄의 신규 염을 제공하는 것이다.It is also an object of the present invention to provide novel salts of fimasartan which are excellent in solubility, bioavailability, stability and nonhygroscopicity.
본 발명의 목적은 피마살탄의 신규 염의 제조방법을 제공하는 것이다.It is an object of the present invention to provide a process for the preparation of novel salts of fimasartan.
본 발명의 목적은 피마살탄의 신규 염을 포함하는 약제학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a pharmaceutical composition comprising a novel salt of fimasartan.
본 발명은 피마살탄의 신규 염, 이의 제조방법 및 이를 포함하는 약제학적 조성물을 제공한다.The present invention provides a novel salt of fimasartan, a method for preparing the same, and a pharmaceutical composition comprising the same.
신규 염New salt
본 발명은 피마살탄의 신규 염을 제공한다. The present invention provides novel salts of fimasartan.
본 발명의 상기 피마살탄 신규 염은 피마살탄의 유기산염 또는 피마살탄의 아민염일 수 있다.The pimasartan novel salt of the present invention may be an organic salt of fimasartan or an amine salt of fimasartan.
본 발명은 상기 피마살탄 유기산염 또는 피마살탄 아민염의 수화물 또는 용매화물을 제공한다.The present invention provides a hydrate or solvate of the fimasartan organic acid salt or fimasartan amine salt.
본 발명에 따른 피마살탄 유기산염 또는 피마살탄 아민염, 또는 이들의 수화물 또는 용매화물은 우수한 용해도 및 생체 이용률을 나타내며, 안정성 및 비흡습성이 우수하여 제형으로서의 가공성이 뛰어나고 약효가 우수하다.Fimasartan organic acid salts or fimasartan amine salts, or hydrates or solvates thereof according to the present invention exhibit excellent solubility and bioavailability, have excellent stability and non-hygroscopicity, and have excellent processability and good drug efficacy as formulations.
본 발명은 피마살탄의 유기산염 또는 이의 수화물 또는 용매화물을 제공한다. The present invention provides organic salts of fimasaltan or hydrates or solvates thereof.
본 발명에 있어서, 상기 피마살탄의 유기산염은 피마살탄의 메탄술폰산염, 피마살탄의 벤젠술폰산염, 피마살탄의 캄파술폰산염, 피마살탄의 톨루엔술폰산염, 피마살탄의 에탄디술폰산염, 피마살탄의 나프탈렌디술폰산염일 수 있으며, 바람직하게는 피마살탄의 캄파술폰산염 또는 벤젠술폰산염일 수 있다. In the present invention, the organic acid salt of fimasartan is methanesulfonate of fimasartan, benzenesulfonate of fimasartan, camphorsulfonate of fimasartan, toluenesulfonate of fimasartan, ethanedisulfonate of fimasartan, and fimasaltan It may be naphthalenedi sulfonate of, preferably may be campa sulfonate or benzene sulfonate of fimasaltan.
본 발명에 있어서, 상기 피마살탄 유기산염은 하기 화학식 1로 표시되는 화합물일 수 있다. In the present invention, the fimasaltan organic acid salt may be a compound represented by the following Chemical Formula 1.
[화학식 1][Formula 1]
Figure PCTKR2016013727-appb-I000001
Figure PCTKR2016013727-appb-I000001
상기 화학식 1에서 HX는 메탄술폰산, 벤젠술폰산, 캄파술폰산, 톨루엔술폰산일 수 있으며, 바람직하게는 캄파술폰산 또는 벤젠술폰산일 수 있다. In Formula 1, HX may be methanesulfonic acid, benzenesulfonic acid, campasulfonic acid, toluenesulfonic acid, and preferably may be campasulfonic acid or benzenesulfonic acid.
본 발명에 있어서, 상기 피마살탄 유기산염은 하기 화학식 2로 표시되는 화합물일 수 있다.In the present invention, the fimasaltan organic acid salt may be a compound represented by the following Chemical Formula 2.
[화학식 2][Formula 2]
Figure PCTKR2016013727-appb-I000002
Figure PCTKR2016013727-appb-I000002
상기 화학식 2에서 H2X는 에탄디술폰산 또는 나프탈렌디술폰산일 수 있다. 상기 에탄디술폰산 또는 나프탈렌디술폰산은 피마살탄과 1: 2의 몰비(산:피마살탄 = 1: 2)로 결합하여 염을 형성할 수 있다.In Formula 2, H 2 X may be ethane disulfonic acid or naphthalenedisulfonic acid. The ethane disulfonic acid or naphthalenedisulfonic acid may be combined with pimasaltan in a molar ratio of 1: 2 (acid: pimasaltan = 1: 2) to form a salt.
본 발명에 있어, 상기 피마살탄 유기산염은 결정일 수 있다. 본 발명에 있어, 상기 피마살탄 유기산염은 무수 결정일 수 있다. In the present invention, the fimasartan organic acid salt may be a crystal. In the present invention, the fimasartan organic acid salt may be anhydrous crystals.
본 발명에 있어, 피마살탄의 유기산염은 피마살탄 유기산염, 이의 기하 이성질체, 광학이성질체 및 라세미체를 모두 지칭한다. 예를 들면, 피미살탄의 캄파술폰산염은 피마살탄의 캄파술폰산염과 함께 이의 기하이성질체, 광학이성질체 및 라세미체를 모두 지칭한다.In the present invention, the organic acid salt of fimasartan refers to both fimasartan organic acid salts, geometric isomers thereof, optical isomers and racemates. For example, the camphorsulfonate of pimisaltan refers to both the geometric isomers, optical isomers, and racemates together with campasulfonate of pimasaltan.
본 발명에 따른 피마살탄의 신규염인 피마살탄 유기산염, 또는 이의 수화물 또는 용매화물은 용해도가 높고, 경구흡수율도 우수하여 적은 양을 복용하여도 우수한 치료 효과를 나타낼 수 있어 환자의 복약 편의성을 현저히 개선할 수 있다. 또한, 안정성, 비흡습성 및 제형으로서의 가공성 등 제제학적 물리학적 성질이 우수하여 약제학적 제형의 제조에 적합하다. Fimasaltan organic acid salt, or a hydrate or solvate thereof, which is a novel salt of fimasartan according to the present invention, has high solubility, excellent oral absorption rate, and can exhibit excellent therapeutic effect even at a small dose, thereby significantly improving the convenience of patient medication. It can be improved. In addition, it is suitable for the preparation of pharmaceutical formulations due to its excellent pharmaceutical physical properties such as stability, non-hygroscopicity and processability as a formulation.
본 발명은 피마살탄 아민염 또는 이의 수화물 또는 용매화물을 제공한다. The present invention provides fimasartan amine salts or hydrates or solvates thereof.
본 발명에 있어서, 상기 피마살탄의 아민 염은 피마살탄의 콜린염, 메글루민염, 암모늄염 또는 아르기닌염일 수 있다. In the present invention, the amine salt of fimasartan may be choline salt, meglumine salt, ammonium salt or arginine salt of fimasartan.
본 발명에 따른 피마살탄 콜린염은 하기 화학식 3으로 표시되는 화합물일 수 있다.Fimasaltan choline salt according to the present invention may be a compound represented by the following formula (3).
[화학식 3][Formula 3]
Figure PCTKR2016013727-appb-I000003
Figure PCTKR2016013727-appb-I000003
본 발명에 따른 피마살탄의 메글루민 염은 하기 화학식 4로 표시되는 화합물일 수 있다.The meglumine salt of fimasaltan according to the present invention may be a compound represented by the following formula (4).
[화학식 4][Formula 4]
Figure PCTKR2016013727-appb-I000004
Figure PCTKR2016013727-appb-I000004
상기 화학식 4에서 R1 및 R2는 H, R3는 CH3이고 R4는 CH2(CHOH)4CH2OH일 수 있다.In Formula 4, R 1 and R 2 may be H, R 3 is CH 3 and R 4 may be CH 2 (CHOH) 4 CH 2 OH.
본 발명에 따른 피마살탄의 암모늄염은 상기 화학식 4로 표시되는 화합물일 수 있으며, 상기 화학식 4에서 R1, R2, R3 및 R4는 H이다. Ammonium salt of fimasaltan according to the present invention may be a compound represented by Formula 4, and in Formula 4 R 1, R 2 , R 3 and R 4 is H.
본 발명에 따른 피마살탄의 아르기닌염은 하기 화학식 5로 표시되는 화합물일 수 있다.Arginine salt of fimasaltan according to the present invention may be a compound represented by the following formula (5).
[화학식 5][Formula 5]
Figure PCTKR2016013727-appb-I000005
Figure PCTKR2016013727-appb-I000005
피마살탄 콜린염, 메글루민염, 피마살탄 암모늄염, 피마살탄 아르기닌염 또는 이들의 수화물 또는 용매화물은 비흡습성이며, 고체 상태에서 우수한 안정성을 나타내어 제제가 장기간 동안 균일한 함량을 유지할 수 있다. Fimasartan choline salts, meglumine salts, fimasartan ammonium salts, fimasartan arginine salts or hydrates or solvates thereof are non-hygroscopic and exhibit good stability in the solid state so that the formulation can maintain a uniform content for a long time.
본 발명에 있어, 상기 피마살탄 아민염, 바람직하게는 피마살탄 콜린염, 메글루민염, 암모늄염 또는 아르기닌염은 결정일 수 있다. In the present invention, the fimasartan amine salt, preferably fimasartan choline salt, meglumine salt, ammonium salt or arginine salt may be a crystal.
본 발명에 있어, 상기 피마살탄 콜린염, 메글루민염, 암모늄염 또는 아르기닌염은 무수 결정이거나 또는 수화물일 수 있으며, 예를 들면 피마살탄 메글루민염의 이수화물일 수 있다. In the present invention, the fimasartan choline salt, meglumine salt, ammonium salt or arginine salt may be anhydrous crystals or a hydrate, for example, a dihydrate of fimasartan meglumine salt.
본 발명에 있어서, 상기 피마살탄의 콜린염, 메글루민염, 암모늄염 또는 아르기닌염은 피마살탄의 콜린염, 메글루민염, 암모늄염 또는 아르기닌염의 기하 이성질체, 광학이성질체 및 라세미체를 모두 포함한다. In the present invention, the choline salt, meglumine salt, ammonium salt or arginine salt of fimasartan includes all of the geometric isomers, optical isomers, and racemates of choline salt, meglumine salt, ammonium salt or arginine salt of fimasartan.
본 발명에 따른 피마살탄의 신규염인 피마살탄 아민염, 또는 이들의 수화물 또는 용매화물은 경구 투여 시 높은 생체 이용률을 나타내는바 적은 양을 복용하여도 우수한 치료 효과를 나타낼 수 있어 환자의 복약 편의성을 현저하게 개선할 수 있다. 또한, 안정성, 비흡습성 및 제형으로서의 가공성 등 제제학적 물리학적 성질이 우수하여, 피마살탄 포타슘염에 비해 약제학적 제형의 제조에 적합하다. Fimasaltan amine salt, or a hydrate or solvate thereof, which is a novel salt of fimasartan according to the present invention shows high bioavailability upon oral administration, and thus can show an excellent therapeutic effect even when a small amount is used. It can be remarkably improved. In addition, it has excellent pharmaceutical physicochemical properties such as stability, non-hygroscopicity and processability as a formulation, making it suitable for the preparation of pharmaceutical formulations compared to fimasartan potassium salt.
피마살탄의 경우, 난용성 약물로서 용해도가 낮아 제제화가 용이하지 않고 생체 이용률이 충분히 높지 못하였다. 따라서, 경구 투여를 통해 충분한 치료 효과를 나타내기 위해서는 피마살탄이 제제에 높은 함량으로 포함되어야 하며, 그 결과, 환자의 복약 편의성이 저하되는 문제점이 있었고 이와 같은 점을 고려하여 피마살탄 포타슘염이 사용되어 왔다.In the case of fimasartan, poor solubility as a poorly soluble drug was not easy to formulate and the bioavailability was not high enough. Therefore, in order to exhibit a sufficient therapeutic effect through oral administration, fimasartan should be included in the formulation in a high content, and as a result, there was a problem in that the patient's convenience of medication was lowered. Has been.
본 발명의 상기 피마살탄 유기산염 및 피마살탄 아민염은 용해도와 생체 이용률 등 약물에 요구되는 물리화학적 및 약리학적 특성이 우수한 바, 종래의 피마살탄 포타슘염 보다 제제화가 보다 용이하고, 환자의 복약 편의성을 개선할 수 있다.The fimasartan organic acid salt and the fimasartan amine salt of the present invention are excellent in physicochemical and pharmacological properties required for drugs such as solubility and bioavailability, and thus are easier to formulate than conventional fimasartan potassium salts, and the convenience of patient medication Can be improved.
본 발명에 있어서, 상기 피마살탄 유기산염 및 아민염은 비흡습성이고, 고체 상태에서 우수한 안정성을 나타내어 제제가 장기간 동안 균일한 함량을 유지할 수 있으며, 제제학적으로 요구되는 물리화학적 성질이 우수하다. 또한, 우수한 물리화학적 특성에 따라, 제제의 대량생산이 가능하여 경제적이며, 높은 수율로 피마살탄 염을 제조할 수 있다.In the present invention, the fimasartan organic acid salt and the amine salt are non-hygroscopic and exhibit excellent stability in the solid state, so that the formulation can maintain a uniform content for a long time, and the physicochemical properties required for the pharmaceutical are excellent. In addition, according to the excellent physical and chemical properties, it is possible to mass-produce the formulation, which is economical, and can produce the fimasartan salt in high yield.
제조방법Manufacturing method
본 발명은 상기 피마살탄의 유기산염 또는 이의 수화물 또는 용매화물을 제조하는 방법을 제공한다. The present invention provides a method for preparing the organic acid salt of fimasartan or a hydrate or solvate thereof.
상기 방법은 The method is
용매와 피마살탄 또는 이의 염을 포함하는 반응물을 제조하는 단계; 및Preparing a reactant comprising a solvent and fimasartan or a salt thereof; And
상기 반응물에 유기산을 첨가하는 단계를 포함하는 피마살탄의 유기산염을 제조하는 방법을 제공한다. It provides a method for preparing an organic acid salt of fimasartan comprising the step of adding an organic acid to the reactant.
본 발명에 있어 상기 반응물을 제조하는 단계는 용매에 상기 피마살탄 또는 이의 염을 첨가하는 것일 수 있다. In the present invention, the preparing of the reactant may include adding the fimasaltan or a salt thereof to a solvent.
본 발명에 있어서, 상기 유기산은 공지된 산을 사용할 수 있으며, 예를 들면, 상기 유기산은 술폰산을 사용할 수 있고, 바람직하게는 벤젠술폰산, 톨루엔술폰산, 메탄술폰산, 캄파술폰산, 에탄디술폰산 또는 나프탈렌디술폰산일 수 있다. In the present invention, the organic acid may be a known acid, for example, the organic acid may be a sulfonic acid, preferably benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, ethanedisulfonic acid or naphthalenedi Sulfonic acid.
본 발명에 있어서, 상기 산은 제조하고자 하는 피마살탄 유기산염의 종류에 따라 결정될 수 있다. 예를 들면, 피마살탄의 캄파술폰산염을 제조하는 경우, 상기 산은 캄파술폰산일 수 있다. In the present invention, the acid may be determined according to the kind of fimasaltan organic acid salt to be prepared. For example, when preparing campasulfonic acid salt of fimasaltan, the acid may be campasulfonic acid.
본 발명에 있어, 상기 캄파술폰산은 라세미체 또는 이의 입체이성질체일 수 있으며, (S)-(-)-캄파술폰산, (R)-(-)-캄파술폰산 또는 이들의 라세미체일 수 있으며, 예를 들면 (S)-(-)-캄파술폰산일 수 있다.In the present invention, the camphorsulfonic acid may be a racemate or a stereoisomer thereof, and may be (S)-(-)-campasulfonic acid, (R)-(-)-campasulfonic acid or racemates thereof, For example, (S)-(-)-campasulfonic acid.
본 발명에 있어서, 상기 용매는 유기 용매를 포함할 수 있다. 상기 유기 용매는 에틸 아세테이트, 에탄올, 아세토니트릴, 메탄올, 이소프로판올, 아세톤, 메틸 에틸 케톤, 메틸 이소부틸 케톤, 부탄올, 테트라히드로푸란, 1,4-디옥산, 메틸 아세테이트 또는 이들의 혼합물일 수 있으며, 바람직하게는 에틸 아세테이트, 에탄올, 이소프로판올, 아세토니트릴, 테트라히드로푸란, 또는 이들의 혼합물일 수 있으며, 보다 바람직하게는 에탄올일 수 있다. In the present invention, the solvent may include an organic solvent. The organic solvent may be ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate or mixtures thereof, Preferably it may be ethyl acetate, ethanol, isopropanol, acetonitrile, tetrahydrofuran, or a mixture thereof, more preferably ethanol.
본 발명에 있어서, 상기 유기 용매가 물과 혼화성이 있는 용매인 경우, 상기 용매는 유기 용매 외에 물을 더 포함할 수 있다. In the present invention, when the organic solvent is a solvent miscible with water, the solvent may further include water in addition to the organic solvent.
본 발명에 있어서, 상기 피마살탄 유기산염의 제조에 있어 출발물질은 피마살탄 또는 피마살탄 염이며, 바람직하게는 피마살탄일 수 있다. 상기 출발물질이 피마살탄의 염인 경우, 피마살탄 포타슘염일 수 있다. In the present invention, in the preparation of the fimasartan organic acid salt, the starting material is fimasartan or a fimasartan salt, and preferably may be pimasartan. When the starting material is a salt of fimasartan, it may be a fimasartan potassium salt.
본 발명에 있어서, 상기 방법은 산을 첨가한 후, 가열하는 단계를 더 포함할 수 있다. 예를 들면, 상기 가열은 20℃ 내지 80℃로 수행될 수 있으며, 바람직하게는 25℃ 내지 65℃에서 수행될 수 있다. In the present invention, the method may further include heating after adding an acid. For example, the heating may be performed at 20 ° C to 80 ° C, preferably at 25 ° C to 65 ° C.
본 발명에 있어서, 상기 방법은 가열하는 단계를 수행한 후, 유기 용매를 첨가하는 단계를 더 포함할 수 있다. 상기 유기 용매의 종류는 앞서 설명한 바와 같다. 상기 반응물에 추가되는 유기 용매는 앞서의 유기 용매와 동일하거나 또는 상이할 수 있다. In the present invention, the method may further include adding an organic solvent after performing the heating step. The type of the organic solvent is as described above. The organic solvent added to the reactant may be the same or different from the previous organic solvent.
본 발명은 피마살탄의 아민염 또는 이의 수화물 또는 용매화물을 제조하는 방법을 제공한다. The present invention provides a process for preparing the amine salt of fimasartan or a hydrate or solvate thereof.
상기 방법은 The method is
용매와 피마살탄 또는 이의 염을 포함하는 반응물을 제조하는 단계; 및Preparing a reactant comprising a solvent and fimasartan or a salt thereof; And
상기 반응물에 아민을 첨가하는 단계를 포함하는 피마살탄의 아민염을 제조하는 방법을 제공한다. It provides a method for preparing the amine salt of fimasaltan comprising the step of adding an amine to the reactant.
본 발명에 있어서, 상기 반응물을 제조하는 단계는, 상기 피마살탄 또는 이의 염과 상기 용매를 혼합하는 것일 수 있다. In the present invention, the preparing of the reactant may include mixing the fimasaltan or a salt thereof with the solvent.
본 발명에 있어서, 반응물에 첨가되는 아민은 콜린, 콜린염, 메글루민, 암모니아 또는 아르기닌일 수 있다.In the present invention, the amine added to the reactant may be choline, choline salt, meglumine, ammonia or arginine.
상기 콜린염은 콜린하이드록사이드 (수산화콜린)일 수 있다. 예를 들어, 상기 반응물에 콜린하이드록사이드를 포함하는 용액을 첨가할 수 있으며, 바람직하게는 상기 콜린하이드록사이드를 포함하는 용액은 콜린하이드록사이드를 포함하는 메탄올 용액일 수 있다. The choline salt may be choline hydroxide (choline hydroxide). For example, a solution containing choline hydroxide may be added to the reactant, and preferably, the solution including choline hydroxide may be a methanol solution including choline hydroxide.
상기 암모니아는 바람직하게는 암모니아 용액일 수 있으며, 구체적으로 암모니아 가스를 메탄올에 용해시킨 용액 상태로 첨가될 수 있다.The ammonia may be preferably an ammonia solution, and specifically, may be added in a solution state in which ammonia gas is dissolved in methanol.
본 발명에 있어서, 상기 용매는 유기 용매를 포함할 수 있다. 상기 유기 용매는 에틸 아세테이트, 에탄올, 아세토니트릴, 메탄올, 이소프로판올, 아세톤, 메틸 에틸 케톤, 메틸 이소부틸 케톤, 부탄올, 테트라히드로푸란, 1,4-디옥산, 메틸 아세테이트, 또는 이들의 혼합물일 수 있으며, 바람직하게는 에틸 아세테이트, 에탄올, 이소프로판올, 아세토니트릴, 테트라히드로푸란, 또는 이들의 혼합물일 수 있으며, 보다 바람직하게는 에틸아세테이트일 수 있다. In the present invention, the solvent may include an organic solvent. The organic solvent may be ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate, or mixtures thereof , Preferably ethyl acetate, ethanol, isopropanol, acetonitrile, tetrahydrofuran, or mixtures thereof, and more preferably ethyl acetate.
본 발명에 있어서, 상기 유기 용매가 물과 혼화성이 있는 용매인 경우, 상기 용매는 유기 용매 외에 물을 더 포함할 수 있다. 예를 들면, 상기 용매는 아세토니트릴과 물의 혼합물일 수 있으며, 이 경우 상기 아세토니트릴과 물의 부피비는 약 30~10:1일 수 있다. In the present invention, when the organic solvent is a solvent miscible with water, the solvent may further include water in addition to the organic solvent. For example, the solvent may be a mixture of acetonitrile and water, in which case the volume ratio of acetonitrile and water may be about 30 to 10: 1.
본 발명에 있어서, 상기 피마살탄 아민염의 제조에 있어 출발물질은 피마살탄 또는 피마살탄 염이다. 상기 출발물질이 피마살탄의 염인 경우, 피마살탄 포타슘염일 수 있으며, 바람직하게는 피마살탄을 사용한다.In the present invention, the starting material in the preparation of the fimasartan amine salt is the fimasartan or the fimasartan salt. When the starting material is a salt of fimasartan, it may be a fimasartan potassium salt, preferably fimasartan is used.
본 발명에 있어서, 상기 방법은 아민을 첨가한 후, 가열하는 단계를 더 포함할 수 있다. 예를 들면, 상기 가열은 20℃ 내지 80℃로 수행될 수 있으며, 바람직하게는 25℃ 내지 65℃에서 수행될 수 있다. In the present invention, the method may further include heating after adding the amine. For example, the heating may be performed at 20 ° C to 80 ° C, preferably at 25 ° C to 65 ° C.
본 발명에 있어서, 상기 방법은 가열하는 단계를 수행한 후, 유기 용매를 더 첨가하는 단계를 더 포함할 수 있다. 상기 유기 용매의 종류는 앞서 설명한 바와 같다. 상기 반응물에 추가되는 유기 용매는 앞서의 유기 용매와 동일하거나 또는 상이할 수 있다. In the present invention, the method may further include adding an organic solvent after performing the heating step. The type of the organic solvent is as described above. The organic solvent added to the reactant may be the same or different from the previous organic solvent.
약제학적 조성물Pharmaceutical composition
본 발명은 피마살탄 유기산염, 이들의 수화물 또는 용매화물을 포함하는 조성물을 제공한다. The present invention provides compositions comprising fimasartan organic acid salts, hydrates or solvates thereof.
본 발명은 상기 피마살탄 유기산염인 피마살탄의 메탄술폰산염, 피마살탄의 벤젠술폰산염, 피마살탄의 캄파술폰산염, 피마살탄의 톨루엔술폰산염, 피마살탄의 에탄디술폰산염 또는 피마살탄의 나프탈렌디술폰산염, 이들의 수화물 또는 용매화물을 포함하는 조성물을 제공한다.The present invention relates to methanesulfonate of fimasartan, benzenesulfonate of fimasartan, campasulfonate of fimasartan, toluenesulfonate of fimasartan, ethanedisulfonate of fimasartan or naphthalenedi of fimasartan. Provided are compositions comprising sulfonates, hydrates or solvates thereof.
본 발명은 피마살탄 아민염, 이들의 수화물 또는 용매화물을 포함하는 조성물을 제공한다. The present invention provides compositions comprising fimasartan amine salts, hydrates or solvates thereof.
본 발명에 있어서, 상기 피마살탄 아민염은 피마살탄 콜린염, 메글루민염, 암모늄염 또는 아르기닌염일 수 있다.In the present invention, the fimasartan amine salt may be fimasartan choline salt, meglumine salt, ammonium salt or arginine salt.
본 발명에 있어서, 상기 조성물은 약제학적 조성물로 중풍, 뇌졸중, 뇌일혈, 뇌경색, 알츠하이머, 혈관성 치매, 크로이츠펠트-야콥병, 당뇨병, 비만증, 고지혈증, 관상 동맥 질환, 협심증, 심근경색, 고혈압, 심부전, 염증 또는 신부전을 치료 또는 예방하는 약제학적 조성물일 수 있다. In the present invention, the composition is a pharmaceutical composition as stroke, stroke, cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, heart failure, inflammation Or a pharmaceutical composition for treating or preventing renal failure.
본 발명에 있어서, 상기 약제학적 조성물은 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있다. In the present invention, the pharmaceutical composition may further include a pharmaceutically acceptable additive.
상기 약제학적으로 허용 가능한이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않고 이 분야의 통상의 지식을 가진 자가 의약 조성물 제조 시 통상적으로 사용하는 것으로, Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA의 문헌을 참조할 수 있다. The pharmaceutically acceptable is a physiologically acceptable and when administered to a human, usually in the manufacture of self-pharmaceutical compositions having ordinary knowledge in the art without causing gastrointestinal disorders, allergic reactions such as dizziness or the like. In use, reference may be made to Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.
상기 첨가제는 담체, 부형제, 증량제, 항산화제, 완충액, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 현탁제, 계면활성제 및 방부제 등일 수 있다. 예를 들면, 상기 첨가제는 락토즈, 덱스트로즈, 규산칼슘, 옥수수전분, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 광물유, 식염수, 포도당 수용액, 유사 당수용액, 알콜, 글리콜, 에테르(예: 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세라이드 또는 이들의 혼합물일 수 있다. 그러나 본 발명에 따른 조성물에 포함될 수 있는 첨가제는 상기 열거된 물질들로 한정되는 것은 아니며, 이들은 단지 예시에 불과하다. The additives may be carriers, excipients, extenders, antioxidants, buffers, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, suspending agents, surfactants and preservatives. For example, the additive may include lactose, dextrose, calcium silicate, corn starch, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, stearic acid, magnesium stearate, calcium stearate, gelatin, mineral oil, saline solution, aqueous glucose solution, pseudosugar solution, alcohol , Glycols, ethers (eg polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides or mixtures thereof. However, the additives which may be included in the composition according to the present invention are not limited to the above-listed materials, which are merely exemplary.
본 발명의 약제학적 조성물은 통상적인 방법에 따라 제제화될 수 있으며, 경구 투여 제제 또는 비경구 투여 제제로 제조될 수 있고, 바람직하게는 경구 투여 제제일 수 있다. The pharmaceutical compositions of the present invention may be formulated according to conventional methods, may be prepared as oral dosage forms or parenteral dosage forms, and may preferably be oral dosage forms.
본 발명에 있어서, 상기 경구 투여를 위한 제제는 정제, 환제, 산제, 과립제, 캡슐제 등의 고형 제제이거나 또는 현탁제, 내용액제, 유제, 시럽제 등의 액상 제제일 수 있으며, 바람직하게는 고형 제제일 수 있으며, 보다 바람직하게는 정제일 수 있다. In the present invention, the preparation for oral administration may be a solid preparation such as tablets, pills, powders, granules, capsules, or liquid preparations such as suspensions, solvents, emulsions, and syrups, and preferably solid preparations. Most preferably, more preferably a tablet.
본 발명에 따른 피마살탄 유기산염 또는 아민염은 안정성이 우수하고, 다양한 용매에 대한 용해도가 뛰어나며, 비흡습성이어서, 제형으로서의 가공성 등 제제학적으로 요구되는 물리화학적 성질이 우수하다. 따라서, 정제 또는 캡슐과 같은 형태로 제형화 시, 분산성이 우수하여 약리 효과가 균일한 정제 또는 캡슐을 생산할 수 있으며, 제형화 공정 동안 약리 효과가 저하되는 문제가 발생하지 않는다. 따라서, 약효가 우수하면서 균일한 약리 효과를 가지는 제제를 경제적으로 생산할 수 있다.The fimasartan organic acid salt or amine salt according to the present invention has excellent stability, excellent solubility in various solvents, and non-hygroscopicity, and thus has excellent physicochemical properties such as processability as a formulation. Therefore, when formulated in the form of tablets or capsules, it is possible to produce a tablet or capsule with excellent dispersibility and uniform pharmacological effect, and does not cause a problem that the pharmacological effect is lowered during the formulation process. Therefore, it is possible to economically produce a formulation having excellent pharmacological effects and having a uniform pharmacological effect.
본 발명의 약제학적 조성물이 경구 고형 제제로 제제화되는 경우, 사용되는 첨가제의 예로는 셀룰로오스, 규산칼슘, 옥수수전분, 락토오스, 수크로스, 덱스트로스, 칼슘 포스페이트, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크 등을 들 수 있다.When the pharmaceutical composition of the present invention is formulated as an oral solid preparation, examples of the additives used are cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , Gelatin, talc and the like.
상기 약제학적 조성물을 경구투여용 액상 제제로 제제화하는 경우, 상기 약학 조성물에 물, 리퀴드 파라핀과 같은 단순희석제, 습윤제, 감미제, 방향제, 보존제, 방부제, 착색제 등과 같은 여러 가지 첨가제를 첨가하여 제제화 할 수 있다. When the pharmaceutical composition is formulated as a liquid preparation for oral administration, the pharmaceutical composition may be formulated by adding various additives such as water, simple diluents such as liquid paraffin, wetting agents, sweeteners, fragrances, preservatives, preservatives, colorants, and the like. have.
본 발명의 약제학적 조성물이 주사제의 형태로 제조되는 경우 상기 첨가제로는 물, 식염수, 포도당 수용액, 유사 당수용액, 알콜, 글리콜, 에테르(예: 폴리에틸렌글리콜 400), 오일, 지방산, 지방산에스테르, 글리세라이드 등을 들 수 있다.When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additives include water, saline solution, aqueous glucose solution, pseudo-aqueous solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester, glycerol Ride etc. are mentioned.
본 발명에 있어서, 상기 약제학적 조성물에 포함되는 첨가제의 함량은 특별히 한정되는 것은 아니며 통상의 제제화에 사용되는 함량 범위 내에서 적절하게 조절될 수 있다. In the present invention, the content of the additive included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the content range used in conventional formulation.
본 발명에 있어서, 상기 약제학적 조성물은 피마살탄 유기산염 또는 피마살탄 아민염을 피마살탄의 함량이 약 1mg 내지 240mg이 되도록 포함할 수 있으며, 바람직하게는 약 5 내지 180 mg이 되도록 포함할 수 있으며, 보다 바람직하게는 10 내지 120 mg이 되도록 포함할 수 있다. In the present invention, the pharmaceutical composition may include fimasartan organic acid salt or fimasartan amine salt so that the content of fimasartan is about 1 mg to 240 mg, preferably about 5 to 180 mg. More preferably 10 to 120 mg.
본 발명에 있어서, 상기 약제학적 조성물은 경구 투여되거나 비경구 투여(예를 들면, 정맥 내, 피하 내, 복강 내 또는 국소에 적용)될 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 투여기간 또는 간격, 배설율, 체질 특이성, 제제의 성질, 질환의 중증 등에 따라 그 범위가 다양할 수 있다. 예를 들면, 60kg 정도의 일반 성인을 기준으로 피마살탄의 투여량이 1일 약 1 내지 240mg, 바람직하게는 5 내지 180mg, 보다 바람직하게는 10 내지 120mg이 되도록 경구 투여할 수 있으며, 상기 적용은 하루에 한번 또는 수회 나누어 적용할 수도 있다.In the present invention, the pharmaceutical composition may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically), and the dosage may be weight, age, sex, health of the patient. The range may vary depending on the condition, diet, administration time, administration method, administration period or interval, excretion rate, constitution specificity, nature of the preparation, severity of disease, and the like. For example, the dose of fimasartan may be orally administered so that the dose of fimasartan is about 1 to 240 mg, preferably 5 to 180 mg, more preferably 10 to 120 mg per day, based on a normal adult weighing about 60 kg. It may be applied once or several times.
본 발명에 있어서, 상기 약제학적 조성물은 피마살탄 유기산염 또는 아민염, 이들의 수화물 또는 용매화물 외에 다른 약리학적 활성물질을 더 포함할 수 있다. 상기 약리학적 활성물질은 상기 피마살탄 유기산염 또는 아민염과 동일한 약리활성을 가질 수도 있으며, 또는 다른 약리활성을 가질 수도 있다. 상기 약제학적 조성물에 포함되는 다른 약리학적 활성물질은 암로디핀, 레르카르디핀, 니카르디핀, 심바스타틴, 아토르바스타틴, 프라바스타틴, 로수바스타틴등의 고지혈증 치료제, 메트포르민, 하이드로클로로티아지드, 시타글립틴, 빌다글립틴, 리나글립틴, 삭사글립틴, 테넬리글립틴, 아나글립틴, 멜로글립틴, 두토글립틴, 제미글립틴등의 당뇨병 치료제, 이들의 약제학적으로 허용 가능한 염 또는 이들의 혼합물일 수 있으며, 보다 바람직하게는 암로디핀, 로수바스타틴, 아토바스타틴, 하이드로클로로티아지드, 시타글립틴, 빌다글립틴, 리나글립틴이고 이들의 약제학적으로 허용 가능한 염 또는 이들의 혼합물일 수 있다. In the present invention, the pharmaceutical composition may further include other pharmacologically active substances in addition to fimasartan organic acid salt or amine salt, hydrate or solvate thereof. The pharmacologically active substance may have the same pharmacological activity as the fimasartan organic acid salt or the amine salt, or may have other pharmacological activity. Other pharmacologically active substances included in the pharmaceutical composition include anti-hyperlipidemic agents such as amlodipine, lercardidipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, metformin, hydrochlorothiazide, cytagliptin, and billaggle Liptin, linagliptin, saxagliptin, tenelligliptin, anagliptin, melogliptin, dutogliptin, gemigliptin, and the like for diabetes treatment, pharmaceutically acceptable salts or mixtures thereof And more preferably amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, citagliptin, bilagliptin, linagliptin and pharmaceutically acceptable salts thereof or mixtures thereof.
본 발명의 약제학적 조성물은 질병을 개선, 완화, 치료 또는 예방을 위하여 단독으로, 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.The pharmaceutical compositions of the present invention may be used alone or in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers to ameliorate, alleviate, treat or prevent disease.
본 발명에 따른 신규한 피마살탄 유기산염 및 아민염은 용해도와 생체 이용률이 우수하여 치료 효과가 뛰어나며, 안정성, 점착성, 흐름성 및 비흡습성 같은 성질이 우수하여 제제화가 용이하고 환자의 복약 편의성을 현저히 개선할 수 있다.The novel fimasartan organic acid salts and amine salts according to the present invention have excellent solubility and bioavailability, and thus have excellent therapeutic effects, and are excellent in properties such as stability, adhesiveness, flowability, and non-hygroscopicity, so that they are easy to formulate and the patient's convenience of medication is remarkable. It can be improved.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다. Hereinafter, examples will be described in detail to help understand the present invention. However, the following examples are merely to illustrate the content of the present invention is not limited to the scope of the present invention. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
<실시예 1> 피마살탄 캄파술폰산염의 제조Example 1 Preparation of Fimasaltan Campasulfonate
25 ml 플라스크에 2.60 g의 피마살탄과 6.3 ml의 에탄올을 넣고 교반하면서 1.25 g의 (S)-(-)-캄파술폰산을 가하였다. 가열하여 용해시킨 후, 25 ml의 에틸 아세테이트를 첨가하고 침전을 생성시켰다. 실온에서 3시간 교반 후 여과하여 고체상태의 생성물을 수득하고 2 ml 에틸아세테이트로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 3.56 g의 피마살탄 캄파술폰산염을 수득하였다. 2.25 g of fimasartan and 6.3 ml of ethanol were added to a 25 ml flask, and 1.25 g of (S)-(-)-campasulfonic acid was added while stirring. After dissolving by heating, 25 ml of ethyl acetate were added and a precipitate formed. After stirring for 3 hours at room temperature, the product was filtered and washed with 2 ml of ethyl acetate. The solid obtained was dried at 43 ° C. for 1 day to afford 3.56 g of fimasartan camphorsulfonate.
수율: 96.9%, Yield: 96.9%,
1H NMR (400MHz, DMSO-d6):δ 7.67(m,2H), 7.58(m,2H), 7.13(m,2H), 7.06(d,2H), 5.34(s,2H),3.83(s,3H), 3.44(d,6H), 3.38(m,3H), 2.90(d,1H), 2.70(m,2h), 2.40(d,1H), 2.23(s,3H), 1.90(m,2H), 1.48(m,2H), 1.28(m,4H), 1.05(s,3H), 0.80(t,3H), 0.75(s,3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.67 (m, 2H), 7.58 (m, 2H), 7.13 (m, 2H), 7.06 (d, 2H), 5.34 (s, 2H), 3.83 ( s, 3H), 3.44 (d, 6H), 3.38 (m, 3H), 2.90 (d, 1H), 2.70 (m, 2h), 2.40 (d, 1H), 2.23 (s, 3H), 1.90 (m , 2H), 1.48 (m, 2H), 1.28 (m, 4H), 1.05 (s, 3H), 0.80 (t, 3H), 0.75 (s, 3H).
<실시예 2> 피마살탄 메탄술폰산염의 제조Example 2 Preparation of Fimasaltan Methanesulfonate
25 ml 플라스크에 0.52 g의 피마살탄과 2.5 ml의 에탄올을 넣고 교반하면서 0.10 g의 메탄술폰산을 가하였다. 가열하여 용해시킨 후, 5 ml의 에틸아세테이트를 첨가하고 침전을 생성시켰다. 실온에서 3시간 교반 후 여과하여 고체상태의 생성물을 수득하고 1 ml 에틸아세테이트로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 0.56 g의 피마살탄 메탄술폰산염을 수득하였다. 0.52 g of fimasartan and 2.5 ml of ethanol were added to a 25 ml flask, and 0.10 g of methanesulfonic acid was added while stirring. After dissolving by heating, 5 ml of ethyl acetate was added to form a precipitate. After stirring for 3 hours at room temperature, the product was filtered and washed with 1 ml ethyl acetate. The solid obtained was dried at 43 ° C. for 1 day to afford 0.56 g of fimasartan methanesulfonate.
수율: 93.3%, Yield: 93.3%,
1H NMR (400MHz, DMSO-d6):δ 7.68-7.64(m, 2H), 7.59-7.51(m, 2H), 7.13(d, J=8.4Hz, 2H), 7.05(d, J=8.4Hz, 2H), 5.33(s, 2H), 3.83(s, 2H), 3.46(s, 3H), 3.41(s, 3H), 2.76(br, 2H), 2.36(s, 3H), 2.23(s, 3H), 1.47-1.45(m, 2H), 1.31-1.27(m, 2H), 0.80(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.68-7.64 (m, 2H), 7.59-7.51 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 5.33 (s, 2H), 3.83 (s, 2H), 3.46 (s, 3H), 3.41 (s, 3H), 2.76 (br, 2H), 2.36 (s, 3H), 2.23 (s , 3H), 1.47-1.45 (m, 2H), 1.31-1.27 (m, 2H), 0.80 (t, J = 7.2 Hz, 3H).
<실시예 3> 피마살탄 벤젠술폰산염의 제조Example 3 Preparation of Fimasaltan Benzenesulfonate
25 ml 플라스크에 2.60 g의 피마살탄과 11 ml의 에탄올을 넣고 교반하면서 0.90 g의 벤젠술폰산을 가하였다. 가열하여 용해시킨 후, 25 ml의 에틸아세테이트를 첨가하고 침전을 생성시켰다. 실온에서 3시간 교반 후 여과하여 고체상태의 생성물을 수득하고 2 ml 에틸아세테이트로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 3.02 g의 피마살탄 벤젠술폰산염을 수득하였다. 2.60 g fimasartan and 11 ml ethanol were added to a 25 ml flask, and 0.90 g of benzenesulfonic acid was added while stirring. After dissolving by heating, 25 ml of ethyl acetate were added to form a precipitate. After stirring for 3 hours at room temperature, the product was filtered and washed with 2 ml of ethyl acetate. The solid obtained was dried at 43 ° C. for 1 day to yield 3.02 g of fimasaltan benzenesulfonate.
수율: 91.4%, Yield: 91.4%,
1H NMR (400MHz, DMSO-d6):δ 7.68-7.51(m, 6H), 7.32-7.31(m, 3H), 7.14(d, J=8.4Hz, 2H), 7.06(d, J=8.4Hz, 2H), 5.34(s, 2H), 3.83(s, 2H), 3.46(s, 3H), 3.41(s, 3H), 2.78(br, 2H), 2.24(s, 3H), 1.48-1.42(m, 2H), 1.29-1.24(m, 2H), 0.79(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.68-7.51 (m, 6H), 7.32-7.31 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.34 (s, 2H), 3.83 (s, 2H), 3.46 (s, 3H), 3.41 (s, 3H), 2.78 (br, 2H), 2.24 (s, 3H), 1.48-1.42 (m, 2H), 1.29-1.24 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H).
<실시예 4> 피마살탄 p-톨루엔술폰산염의 제조Example 4 Preparation of Fimasaltan p-Toluenesulfonate
25 ml 플라스크에 1.05 g의 피마살탄과 5 ml의 에탄올을 넣고 교반하면서 0.40 g의 p-톨루엔술폰산을 가하였다. 가열하여 용해시킨 후, 10 ml의 에틸아세테이트를 첨가하고 침전을 생성시켰다. 실온에서 3시간 교반 후 여과하여 고체상태의 생성물을 수득하고 1 ml 에틸아세테이트로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 1.1 g의 피마살탄 톨루엔술폰산염을 수득하였다. 1.05 g fimasartan and 5 ml ethanol were added to a 25 ml flask, and 0.40 g of p-toluenesulfonic acid was added while stirring. After dissolving by heating, 10 ml of ethyl acetate was added to form a precipitate. After stirring for 3 hours at room temperature, the product was filtered and washed with 1 ml ethyl acetate. The solid obtained was dried at 43 ° C. for 1 day to afford 1.1 g of fimasartan toluenesulfonate.
수율: 98.9%, Yield: 98.9%,
1H NMR (400MHz, DMSO-d6):δ 7.68-7.47(m, 6H), 7.16-7.05(m, 6H), 5.35(s, 2H), 3.84(s, 2H), 3.45(s, 3H), 3.41(s, 3H), 2.81(br, 2H), 2.28(s, 3H), 2.25(s, 3H), 1.46-1.41(m, 2H), 1.28-1.25(m, 2H), 0.78(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.68-7.47 (m, 6H), 7.16-7.05 (m, 6H), 5.35 (s, 2H), 3.84 (s, 2H), 3.45 (s, 3H ), 3.41 (s, 3H), 2.81 (br, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 1.46-1.41 (m, 2H), 1.28-1.25 (m, 2H), 0.78 ( t, J = 7.2 Hz, 3H).
<실시예 5> 피마살탄 1/2 에탄디술폰산염의 제조Example 5 Preparation of Fimasaltan 1/2 Ethane Disulfonate
25 ml 플라스크에 0.52 g의 피마살탄과 7.5 ml의 에틸아세테이트를 넣고 교반하면서 0.21 g의 1,2-에탄디술폰산을을 가하였다. 가열하여 용해시킨 후, 실온으로 냉각하여 침전을 생성시켰다. 실온에서 3시간 교반 후 여과하여 고체상태의 생성물을 수득하고 1 ml 에틸아세테이트로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 0.59 g의 피마살탄 에탄디술폰산염을 수득하였다. Into a 25 ml flask, 0.52 g of fimasartan and 7.5 ml of ethyl acetate were added and 0.21 g of 1,2-ethanedisulfonic acid was added while stirring. After dissolving by heating, cooling to room temperature gave a precipitate. After stirring for 3 hours at room temperature, the product was filtered and washed with 1 ml ethyl acetate. The solid obtained was dried at 43 ° C. for 1 day to afford 0.59 g of fimasaltan ethanedisulfonate.
수율: 98.9%, Yield: 98.9%,
1H NMR (400MHz, DMSO-d6):δ 7.70-7.51(m, 4H), 7.15-7.05(m, 4H), 5.34(s, 2H), 3.83(s, 2H), 3.46(s, 3H), 3.42(s, 3H), 2.77(br, 2H), 2.69(s, 2H), 2.24(s, 3H), 1.47-1.42(m, 2H), 1.31-1.23(m, 2H), 0.79(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.70-7.51 (m, 4H), 7.15-7.05 (m, 4H), 5.34 (s, 2H), 3.83 (s, 2H), 3.46 (s, 3H ), 3.42 (s, 3H), 2.77 (br, 2H), 2.69 (s, 2H), 2.24 (s, 3H), 1.47-1.42 (m, 2H), 1.31-1.23 (m, 2H), 0.79 ( t, J = 7.2 Hz, 3H).
<실시예 6> 피마살탄 1/2 나프탈렌디술폰산염의 제조Example 6 Preparation of Fimasaltan 1/2 Naphthalenedisulfonate
25 ml 플라스크에 1.05 g의 피마살탄과 5 ml의 에탄올을 넣고 교반하면서 0.40 g의 나프탈렌디술폰산을을 가하였다. 가열하여 용해시킨 후, 10ml의 에틸아세테이트를 첨가하고 침전을 생성시켰다. 실온에서 3시간 교반 후 여과하여 고체상태의 생성물을 수득하고 1 ml 에틸아세테이트로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 1.03 g의 피마살탄 나프탈렌디술폰산염을 수득하였다. 1.05 g fimasartan and 5 ml ethanol were added to a 25 ml flask, and 0.40 g of naphthalenedisulfonic acid was added thereto while stirring. After dissolving by heating, 10 ml of ethyl acetate was added to form a precipitate. After stirring for 3 hours at room temperature, the product was filtered and washed with 1 ml ethyl acetate. The solid obtained was dried at 43 ° C. for 1 day to afford 1.03 g of fimasartan naphthalenedisulfonate.
수율: 99.8%, Yield: 99.8%,
1H NMR (400MHz, DMSO-d6):δ 8.86(dd, J1=8.0Hz, J2=0.8Hz, 1H), 7.93(dd, J1=7.2Hz, J2=1.6Hz, 1H), 7.68-7.64(m, 2H), 7.57-7.50(m, 2H), 7.41(dd, J1=8.4Hz, J2=7.2Hz, 1H), 7.15(d, J=8.4Hz, 2H), 7.06(d, J=8.4Hz, 2H), 5.35(s, 2H), 3.82(s, 2H), 3.45(S, 3H), 3.41(s, 3H), 2.81(br, 2H), 2.23(s, 3H), 1.48-1.39(m, 2H), 1.30-1.22(m, 2H), 0.78(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.86 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 7.93 (dd, J1 = 7.2 Hz, J2 = 1.6 Hz, 1H), 7.68-7.64 (m, 2H), 7.57-7.50 (m, 2H), 7.41 (dd, J1 = 8.4 Hz, J2 = 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.35 (s, 2H), 3.82 (s, 2H), 3.45 (S, 3H), 3.41 (s, 3H), 2.81 (br, 2H), 2.23 (s, 3H), 1.48- 1.39 (m, 2H), 1.30-1.22 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).
<실시예 7> 피마살탄 콜린염의 제조Example 7 Preparation of Fimasartan Choline Salt
500ml 플라스크에 20.8g의 피마살탄과 100ml의 에틸아세테이트를 넣고 11.85g의 콜린하이드록사이드 용액(45% 메탄올 용액)을 가한다. 50℃로 가열 교반하면서 280ml의 에틸아세테이트를 첨가하였다. 이 온도에서 침전이 생성되면 실온에서 2시간 더 교반하고 여과하여 고체상태의 생성물을 수득하고 5ml 에틸아세테이트로 2회 세척하였다. 상기 수득된 고체를 43℃에서 16시간 건조하여 23.01g의 피마살탄 콜린염을 수득하였다. Into a 500 ml flask, 20.8 g of fimasartan and 100 ml of ethyl acetate are added, and 11.85 g of choline hydroxide solution (45% methanol solution) is added. 280 ml of ethyl acetate was added to the mixture while heating and stirring to 50 ° C. When precipitation formed at this temperature, the mixture was stirred for 2 hours at room temperature and filtered to give a solid product, which was washed twice with 5 ml of ethyl acetate. The obtained solid was dried at 43 ° C. for 16 hours to obtain 23.01 g of fimasartan choline salt.
수율: 92.4% Yield: 92.4%
1H NMR (400MHz, DMSO-d6):δ 7.48(m,1H), 7.38(m,2H), 7.29(m,1H), 7.02(d,2H), 6.94(d,2H), 5.60(s,1H), 5.21(s,2H), 3.51(m,3H), 3.37(d,6H), 3.06(s,1H), 2.59(m,2H), 2.13(s,3H), 2.07(s,1H), 1.51(m,2H), 0.78(t,3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.48 (m, 1H), 7.38 (m, 2H), 7.29 (m, 1H), 7.02 (d, 2H), 6.94 (d, 2H), 5.60 ( s, 1H), 5.21 (s, 2H), 3.51 (m, 3H), 3.37 (d, 6H), 3.06 (s, 1H), 2.59 (m, 2H), 2.13 (s, 3H), 2.07 (s , 1H), 1.51 (m, 2H), 0.78 (t, 3H).
<실시예 8> 피마살탄 메글루민염의 제조Example 8 Preparation of Fimasaltan Meglumine Salt
25 ml 플라스크에 2.60 g의 피마살탄과 15 ml의 아세토니트릴과 0.7 ml의 정제수를 넣고 50℃로 가열 교반하면서 0.98 g의 메글루민을 가하였다. 이 온도에서 침전이 생성되면 10 ml의 아세토니트릴을 첨가한다. 실온에서 1시간 교반 후 여과하여 고체상태의 생성물을 수득하고 2 ml 아세토니트릴로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 3.52 g의 피마살탄 메글루민염의 이수화물을 수득하였다. 2.60 g of fimasartan, 15 ml of acetonitrile and 0.7 ml of purified water were added to a 25 ml flask, and 0.98 g of meglumine was added thereto while heating and stirring to 50 ° C. If precipitation occurs at this temperature, 10 ml of acetonitrile are added. After stirring for 1 hour at room temperature, the product was filtered and washed with 2 ml acetonitrile. The solid obtained was dried at 43 ° C. for 1 day to yield 3.52 g of dimasate of fimasartan meglumine salt.
수율: 98.5% Yield: 98.5%
1H NMR (400MHz, DMSO-d6): δ 7.49(m,1H), 7.38(m,2H), 7.29(m,1H), 7.06(d,2H), 6.94(d,2H), 4.00(d,6H), 2.95(m,2H), 2.59(m,2H), 2.10(s,3H), 2.13(s,3H), 1.51(m,2H), 1.24(m,2H), 0.78(t,3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.49 (m, 1H), 7.38 (m, 2H), 7.29 (m, 1H), 7.06 (d, 2H), 6.94 (d, 2H), 4.00 ( d, 6H), 2.95 (m, 2H), 2.59 (m, 2H), 2.10 (s, 3H), 2.13 (s, 3H), 1.51 (m, 2H), 1.24 (m, 2H), 0.78 (t , 3H).
<실시예 9> 피마살탄 암모늄염의 제조Example 9 Preparation of Fimasaltan Ammonium Salt
250 ml 플라스크에 20.8 g의 피마살탄과 80 ml의 아세토니트릴을 넣고 7.60 g의 암모니아 용액(10.9wt%, 암모니아 가스를 메탄올에 포집하여 제조)을 가한다. 50℃로 가열 교반하면서 침전이 생성되면 실온에서 2.5시간 더 교반하고 여과하여 고체상태의 생성물을 수득하고 4 ml 아세토니트릴로 2회 세척하였다. 상기 수득된 고체를 43℃에서 16시간 건조하여 19.53 g의 피마살탄 암모늄염을 수득하였다. 20.8 g of fimasartan and 80 ml of acetonitrile were added to a 250 ml flask, and 7.60 g of ammonia solution (10.9 wt%, prepared by collecting ammonia gas into methanol) was added thereto. After precipitation with heating and stirring at 50 ° C., the mixture was stirred for 2.5 hours at room temperature and filtered to give a solid product, which was washed twice with 4 ml acetonitrile. The solid obtained was dried at 43 ° C. for 16 hours to afford 19.53 g of fimasartan ammonium salt.
수율: 94.3% Yield: 94.3%
1H NMR (400MHz, DMSO-d6): δ 7.66(m,2H), 7.56(m,2H), 7.06(m,4H), 5.27(s,2H), 3.78(s,2H), 3.60(d,6H), 2.58(m,2H), 2.15(s,3H), 1.54(m,2H), 1.26(m,2H), 0.81(t,3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.66 (m, 2H), 7.56 (m, 2H), 7.06 (m, 4H), 5.27 (s, 2H), 3.78 (s, 2H), 3.60 ( d, 6H), 2.58 (m, 2H), 2.15 (s, 3H), 1.54 (m, 2H), 1.26 (m, 2H), 0.81 (t, 3H).
<실시예 10> 피마살탄 L-아르기닌염의 제조Example 10 Preparation of Fimasaltan L-Arginine Salt
25 ml 플라스크에 0.52 g의 피마살탄과 2.5 ml의 에탄올 및 0.25 ml의 물을 넣고 교반하면서 0.17 g의 L-아르기닌을 가하였다. 상온에서 10 ml의 아세토니트릴을 첨가하여 침전을 생성시켰다. 실온에서 추가로 1시간 교반 후 여과하여 고체상태의 생성물을 수득하고 2 ml 아세토니트릴/이소프로필에테르(5:5) 혼합용매로 세척하였다. 상기 수득된 고체를 43℃에서 1일간 건조하여 0.49 g의 피마살탄 L-아르기닌염을 수득하였다.0.52 g of fimasartan, 2.5 ml of ethanol and 0.25 ml of water were added to a 25 ml flask, and 0.17 g of L-arginine was added while stirring. At room temperature, 10 ml of acetonitrile were added to produce a precipitate. After further stirring at room temperature for 1 hour, the mixture was filtered to obtain a solid product, which was washed with 2 ml of acetonitrile / isopropyl ether (5: 5) mixed solvent. The solid obtained was dried at 43 ° C. for 1 day to afford 0.49 g of fimasartan L-arginine salt.
수율: 72.8%Yield: 72.8%
1H NMR (400MHz, DMSO-d6): δ 9.02(br, 1H), 7.85-7.52(m, 6H), 7.39-7.29(m, 4H), 7.05(d, J=8.0Hz, 2H), 6.96(d, J=8.0Hz, 2H), 5.24(s, 2H), 3.78(s, 2H), 3.45(s, 3H), 3.41(s, 3H), 3.32(t, J=5.6Hz, 1H), 3.13-3.06(m, 2H), 2.64-2.62(m, 2H), 2.16(s, 3H), 1.76-1.54(m, 6H), 1.31-1.25(m, 2H), 0.82(t, J=7.2Hz, 3H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.02 (br, 1H), 7.85-7.52 (m, 6H), 7.39-7.29 (m, 4H), 7.05 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0Hz, 2H), 5.24 (s, 2H), 3.78 (s, 2H), 3.45 (s, 3H), 3.41 (s, 3H), 3.32 (t, J = 5.6Hz, 1H ), 3.13-3.06 (m, 2H), 2.64-2.62 (m, 2H), 2.16 (s, 3H), 1.76-1.54 (m, 6H), 1.31-1.25 (m, 2H), 0.82 (t, J) = 7.2 Hz, 3H).
<실험예 1> 용해도의 측정Experimental Example 1 Measurement of Solubility
대한약전에 기재된 방법에 따라 실시예 7에서 제조된 피마살탄 콜린염, 실시예 8에서 제조된 피마살탄 메글루민염 및 실시예 10에서 제조된 피마살탄 아르기닌염과 피마살탄 포타슘염(보령제약(주))에 대한 용해도를 측정하였다.  Fimasartan choline salt prepared in Example 7 according to the method described in the Korean Pharmacopoeia, fimasartan meglumine salt prepared in Example 8 and fimasartan arginine salt and fimasaltan potassium salt prepared in Example 10 Solubility for)) was measured.
pH 1.2의 인산 수용액, pH 4.0 인산 수용액 및 pH 6.8 인산 수용액에 상기 실시예 8, 9 및 11에서 제조된 피마살탄 신규 염 및 피마살탄 포타슘염을 과포화될때까지 각각 첨가한 후, 25℃±3℃에서 24시간 동안 교반하고 1시간 동안 정치시켜 안정화하였다. 이 후 용액을 액체 크로마토그래피(HPLC)로 분석하여 피마살탄 염기(free base)를 기준으로 용해된 양을 측정하였으며, 그 결과는 하기 표 1에 나타내었다. To the aqueous phosphoric acid solution of pH 1.2, the aqueous solution of pH 4.0 and the aqueous solution of pH 6.8 phosphoric acid, the fimasartan novel salts and fimasartan potassium salts prepared in Examples 8, 9 and 11 were added until supersaturated, respectively, and then 25 ° C ± 3 ° C. Stir for 24 h at and stabilize for 1 h. Thereafter, the solution was analyzed by liquid chromatography (HPLC) to determine the amount of dissolution based on fimasartan base (free base), and the results are shown in Table 1 below.
표 1(단위: mg/mL)Table 1 (unit: mg / mL)
Figure PCTKR2016013727-appb-I000006
Figure PCTKR2016013727-appb-I000006
위 표 1에서 확인할 수 있위 표 1에서 확인할 수 있는 바와 같이, 본원발명에 따른 피마살탄 신규염, 특히 실시예 7의 피마살탄 콜린염은 종래의 피마살탄 포타슘염에 비하여 모든 pH에서 10배 내지 100배 정도의 높은 용해도를 나타내었고, 실시예 8의 피마살탄 메글루민염은 모든 pH에서 3배 내지 50배 정도의 높은 용해도를 나타내었으며, 실시예 10의 피마살탄 아르기닌염은 pH 1.2에서 포타슘염과 유사한 용해도를 나타내었고, pH 4.0 및 6.8에서 각각 10배 및 50배 정도의 높은 용해도를 나타내었다. As can be seen in Table 1 above, as shown in Table 1, the fimasartan novel salts of the present invention, in particular the fimasartan choline salt of Example 7, are 10 to 100 times at all pHs as compared to conventional fimasartan potassium salts. The fimasartan meglumine salt of Example 8 exhibited about 3 to 50 times higher solubility at all pHs, and the fimasartan arginine salt of Example 10 had a potassium salt at pH 1.2. Similar solubility was shown, and the solubility was about 10 and 50 times higher at pH 4.0 and 6.8, respectively.
<실험예 2> 생체이용률 측정Experimental Example 2 Bioavailability Measurement
비글견을 사용하여 실시예 1, 3, 7, 8 및 10의 피마살탄 신규 염과 피마살탄 포타슘염(보령제약(주))의 생체 이용률을 측정하였다. Beagle dogs were used to measure the bioavailability of the fimasartan novel salts and fimasartan potassium salts of Boryeong Pharmaceutical Co., Ltd.
10마리의 비글견을 5마리씩 제1군 내지 제6군으로 나누고 하루 동안 절식시켰다.Ten beagle dogs were divided into five groups of groups 1 to 6 and fasted for one day.
한편, 실시예 1에서 수득한 피마살탄 캄파술폰산 염 30mg을 젤라틴 캡슐에 충진한 캡슐 1, 실시예 3에서 수득한 피마살탄 벤젠술폰산 염 30mg을 젤라틴 캡슐에 충진한 캡슐 2, 실시예 7에서 수득한 피마살탄 콜린염 30mg을 젤라틴 캡슐에 충진한 캡슐 3, 실시예 8에서 수득한 피마살탄 메글루민 염 30mg을 젤라틴 캡슐에 충진한 캡슐 4, 실시예 10에서 수득한 피마살탄 아르기닌 염 30mg을 젤라틴 캡슐에 충진한 캡슐 5 및 피마살탄 포타슘염 30mg을 젤라틴 캡슐에 충진한 캡슐 6을 준비하였다. On the other hand, the capsule 1 filled with 30 mg of fimasartan camphorsulfonic acid salt obtained in Example 1 in a gelatin capsule, the capsule 2 filled with 30 mg of fimasaltan benzenesulfonic acid salt obtained in Example 3 in a gelatin capsule, obtained in Example 7 Capsule 3 filled with gelatin capsules 30 mg of pimasartan choline salt, capsule 4 filled with gelatin capsules 30 mg of fimasartan meglumine salt obtained in Example 8 gelatin capsules obtained with 30 mg fimasartan arginine salt obtained in example 10 The capsule 5 filled in and the capsule 6 filled with gelatin capsules 30 mg of pimasartan potassium salt were prepared.
제1군에는 피마살탄 캄파술폰산 염 30mg 포함하는 캡슐 1을, 제2군에는 피마살탄 벤젠술폰산 염 30mg 포함하는 캡슐 2를, 제3군에는 피마살탄 콜린염 30mg 포함하는 캡슐 3을, 제4군에는 피마살탄 메글루민염 30mg 포함하는 캡슐 4를, 제5군에는 피마살탄 아르기닌염 30mg 포함하는 캡슐 5를, 제6군에는 피마살탄 포타슘염 30mg을 포함하는 캡슐 6을 1캡슐/1마리 경구 복용시키고 즉시 음수 30mL/1마리의 용량으로 섭취시켰다. 이 후, 약물과 음수 복용 즉시, 10분, 1시간, 2시간, 3시간, 4시간, 6시간, 8시간, 12시간 및 24시간 후 비글견의 슬와 정맥으로부터 채혈하여 혈액 중 피마살탄의 농도를 측정하였으며, 이로부터 약동학적 파라미터를 구하였다. The first group includes a capsule 1 containing 30 mg of pimasartan camphorsulfonic acid salt, the second group includes a capsule 2 containing 30 mg of fimasartan benzenesulfonate salt, and the third group includes a capsule 3 containing 30 mg of pimasartan choline salt, and the fourth group. Oral capsule 4 containing 30 mg of fimasartan meglumine salt, capsule 5 containing 30 mg of fimasartan arginine salt in group 5, capsule 6 containing 30 mg of fimasartan potassium salt in group 6 orally And immediately taken in a negative 30 mL / 1 dose. Immediately thereafter, after 10 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours, the blood and blood concentrations of fimasartan were collected from the beagle dog veins. Was measured, and the pharmacokinetic parameters were obtained from this.
그 결과는 하기 표 2에 나타내었다. The results are shown in Table 2 below.
표 2TABLE 2
Figure PCTKR2016013727-appb-I000007
Figure PCTKR2016013727-appb-I000007
위 표 2에서 확인할 수 있는 바와 같이, 본원발명에 따른 피마살탄 신규염, 특히 피마살탄 캄파술폰산염, 벤젠술폰산염, 콜린염, 메글루민염 또는 아르기닌염은 피마살탈 포타슘염과 비교하여 더 높은 혈중 농도를 나타내었다. 특히 동일한 함량으로 투여하여도 3배 이상의 Cmax와 1.5배 이상의 AUC를 나타냄을 알 수 있었다. As can be seen in Table 2 above, fimasartan novel salts, in particular fimasartan campasulfonate, benzenesulfonate, choline salt, meglumine salt or arginine salt, according to the present invention are higher in blood compared to fimasaltal potassium salt. Concentration. In particular, even when administered in the same content it can be seen that more than three times the Cmax and 1.5 times more than AUC.
따라서 본원발명에 따른 신규의 피마살탄 유기산염 또는 아민염은 종래의 피마살탄 포타슘염과 비교하여 생체 이용률이 현저히 우수하며, 그 결과 현저히 높은 치료 효과를 나타낼 수 있음을 알 수 있다.Therefore, it can be seen that the novel fimasartan organic acid salt or amine salt according to the present invention is significantly superior in bioavailability as compared to the conventional fimasartan potassium salt, and as a result, can exhibit a significantly high therapeutic effect.

Claims (23)

  1. 피마살탄 유기산염 또는 이의 수화물 또는 용매화물. Fimasartan organic acid salt or a hydrate or solvate thereof.
  2. 제1항에 있어서, 상기 유기산염은 메탄술폰산염, 벤젠술폰산염, 캄파술폰산염, 톨루엔술폰산염, 에탄디술폰산염 또는 나프탈렌디술폰산염인 피마살탄 유기산염 또는 이의 수화물 또는 용매화물.The fimasaltan organic acid salt or hydrate or solvate thereof according to claim 1, wherein the organic acid salt is methane sulfonate, benzene sulfonate, camphor sulfonate, toluene sulfonate, ethanedisulfonate or naphthalenedisulfonate.
  3. 제2항에 있어서, 상기 유기산염은 캄파술폰산염 또는 벤젠술폰산염인 피마살탄 유기산염 또는 이의 수화물 또는 용매화물.The fimasaltan organic acid salt or a hydrate or solvate thereof according to claim 2, wherein the organic acid salt is camphor sulfonate or benzene sulfonate.
  4. 제1항에 있어서, 상기 피마살탄 유기산염은 무수물인 피마살탄 유기산염 또는 이의 수화물 또는 용매화물.The fimasartan organic acid salt of claim 1 or a hydrate or solvate thereof according to claim 1, wherein the fimasartan organic acid salt is an anhydride.
  5. 제4항에 있어서, 상기 피마살탄 염은 무수 결정형인 피마살탄 유기산염 또는 이의 수화물 또는 용매화물.The fimasartan organic acid salt or a hydrate or solvate thereof according to claim 4, wherein the fimasartan salt is anhydrous crystalline form.
  6. 피마살탄 아민염 또는 이의 수화물 또는 용매화물.Fimasaltan amine salt or a hydrate or solvate thereof.
  7. 제6항에 있어서, 상기 아민염은 콜린염, 메글루민염, 암모늄염 또는 아르기닌염인 피마살탄 아민염 또는 이의 수화물 또는 용매화물.The fimasartan amine salt or a hydrate or solvate thereof according to claim 6, wherein the amine salt is choline salt, meglumine salt, ammonium salt or arginine salt.
  8. 제7항에 있어서, 상기 피마살탄 메글루민 염은 피마살탄 메글루민 염의 이수화물인 피마살탄 아민염 또는 이의 수화물 또는 용매화물.8. The fimasartan amine salt or hydrate or solvate thereof of claim 7, wherein the fimasartan meglumine salt is a dihydrate of the fimasartan meglumine salt.
  9. 용매와 피마살탄 또는 이의 염을 포함하는 반응물을 제조하는 단계; 및Preparing a reactant comprising a solvent and fimasartan or a salt thereof; And
    상기 반응물에 유기산을 첨가하는 단계를 포함하는 피마살탄 유기산염 또는 이의 수화물 또는 용매화물을 제조하는 방법.A method for preparing fimasaltan organic acid salt or a hydrate or solvate thereof comprising the step of adding an organic acid to the reactant.
  10. 제9항에 있어서, 상기 첨가되는 유기산은 벤젠술폰산, 톨루엔술폰산, 메탄술폰산, 캄파술폰산, 에탄디술폰산 또는 나프탈렌디술폰산인 방법.10. The method of claim 9, wherein the added organic acid is benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, campasulfonic acid, ethanedisulfonic acid or naphthalenedisulfonic acid.
  11. 제9항에 있어서, 상기 산을 첨가한 후 가열하는 단계를 더 포함하는 것인 방법.10. The method of claim 9, further comprising heating after adding the acid.
  12. 용매와 피마살탄 또는 이의 염을 포함하는 반응물을 제조하는 단계; 및Preparing a reactant comprising a solvent and fimasartan or a salt thereof; And
    상기 반응물에 아민을 첨가하는 단계를 포함하는 것인 피마살탄 아민염 또는 이의 수화물 또는 용매화물을 제조하는 방법.Adding a amine to the reactant, the method for preparing fimasartan amine salt or a hydrate or solvate thereof.
  13. 제12항에 있어서, 상기 아민은 콜린, 메글루민, 암모니아 또는 아르기닌인 것인 피마살탄 아민 염 또는 이의 수화물 또는 용매화물을 제조하는 방법.13. The method of claim 12, wherein the amine is choline, meglumine, ammonia or arginine.
  14. 제9항 또는 제12항에 있어서, 상기 유기 용매는 에틸 아세테이트, 에탄올, 아세토니트릴, 메탄올, 이소프로판올, 아세톤, 메틸 에틸 케톤, 메틸 이소부틸 케톤, 부탄올, 테트라히드로푸란, 1,4-디옥산 및 메틸 아세테이트로 이루어진 그룹으로부터 선택된 적어도 하나인 것인 방법.The method of claim 9 or 12, wherein the organic solvent is ethyl acetate, ethanol, acetonitrile, methanol, isopropanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanol, tetrahydrofuran, 1,4-dioxane and At least one selected from the group consisting of methyl acetate.
  15. 제14항에 있어서, 상기 용매는 물을 더 포함하는 것인 방법. The method of claim 14, wherein the solvent further comprises water.
  16. 제12항에 있어서, 상기 아민을 첨가한 후 가열하는 단계를 더 포함하는 것인 방법.13. The method of claim 12, further comprising heating after adding the amine.
  17. 피마살탄 유기산염 또는 이의 수화물 또는 용매화물을 포함하는 약제학적 조성물.A pharmaceutical composition comprising fimasartan organic acid salt or a hydrate or solvate thereof.
  18. 제17항에 있어서, 상기 유기산염은 메탄술폰산염, 벤젠술폰산염, 캄파술폰산염, 톨루엔술폰산염, 에탄디술폰산염 또는 나프탈렌디술폰산염인 약제학적 조성물.The pharmaceutical composition of claim 17, wherein the organic acid salt is methanesulfonate, benzenesulfonate, camppasulfonate, toluenesulfonate, ethanedisulfonate or naphthalenedisulfonate.
  19. 피마살탄 아민 염 또는 이의 수화물 또는 용매화물을 포함하는 약제학적 조성물.A pharmaceutical composition comprising fimasartan amine salt or a hydrate or solvate thereof.
  20. 제19항에 있어서, 상기 피마살탄 아민 염은 피마살탄 콜린염, 메글루민 염, 암모늄염 또는 아르기닌염인 약제학적 조성물.The pharmaceutical composition of claim 19, wherein the fimasartan amine salt is fimasartan choline salt, meglumine salt, ammonium salt or arginine salt.
  21. 제17항 또는 제19항에 있어서, 상기 약제학적 조성물은 중풍, 뇌졸중, 뇌일혈, 뇌경색, 알츠하이머, 혈관성 치매, 크로이츠펠트-야콥병, 당뇨병, 비만증, 고지혈증, 관상 동맥 질환, 협심증, 심근경색, 고혈압, 심부전, 염증 및 신부전으로 이루어지는 그룹으로부터 선택된 적어도 하나의 질환을 예방 또는 치료하기 위한 약제학적 조성물.20. The method of claim 17 or 19, wherein the pharmaceutical composition is stroke, stroke, cerebral hemorrhage, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, hypertension, A pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of heart failure, inflammation and renal failure.
  22. 제17항 또는 제19항에 있어서, 상기 약제학적 조성물은 피마살탄 염과 상이한 약리학적 활성물질을 더 포함하는 약제학적 조성물.The pharmaceutical composition of claim 17 or 19, wherein the pharmaceutical composition further comprises a pharmacologically active substance different from the fimasartan salt.
  23. 제22항에 있어서, 상기 약리학적 활성물질은 암로디핀, 레르카르디핀, 니카르디핀, 심바스타틴, 아토르바스타틴, 프라바스타틴, 로수바스타틴, 메트포르민, 하이드로클로로티아지드, 시타글립틴, 빌다글립틴 및 리나글립틴으로 이루어지는 그룹으로부터 선택된 적어도 하나인 약제학적 조성물. The method according to claim 22, wherein the pharmacologically active substance is amlodipine, lercardidipine, nicardipine, simvastatin, atorvastatin, pravastatin, rosuvastatin, metformin, hydrochlorothiazide, citagliptin, bilagliptin and linagliptin At least one pharmaceutical composition selected from the group consisting of.
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