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WO2020101450A1 - Composés dérivés d'azilsartan, leurs intermédiaires, leur procédé de préparation et composition pharmaceutique les comprenant - Google Patents

Composés dérivés d'azilsartan, leurs intermédiaires, leur procédé de préparation et composition pharmaceutique les comprenant Download PDF

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WO2020101450A1
WO2020101450A1 PCT/KR2019/015706 KR2019015706W WO2020101450A1 WO 2020101450 A1 WO2020101450 A1 WO 2020101450A1 KR 2019015706 W KR2019015706 W KR 2019015706W WO 2020101450 A1 WO2020101450 A1 WO 2020101450A1
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group
formula
pharmaceutically acceptable
compound
azilsartan
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PCT/KR2019/015706
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English (en)
Korean (ko)
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황성관
이홍우
박장하
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엠에프씨 주식회사
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    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel azartartan derivative compound or a pharmaceutically acceptable salt thereof, an intermediate thereof, a method for preparing the same, and a composition comprising the same as an angiotensin II antagonist useful in the treatment of hypertensive disease.
  • Hypertension refers to a chronic disease in which blood pressure is higher than the normal range. Hypertension causes the heart to do more to circulate blood through the blood vessels. Blood pressure is summarized by two measurements of the systolic highest blood pressure and diastolic lowest blood pressure at the pulse, normal blood pressure at rest is 100-140 mmHg at contraction, 60-90 mmHg at relaxation, and blood pressure is continuously above 140/90 mmHg. Say you have high blood pressure.
  • Hypertension is divided into essential hypertension and secondary hypertension. About 90 to 95% are classified as 'essential hypertension' with no clear underlying medical cause, and the remaining 5 to 10% (secondary hypertension) are associated with other health conditions affecting the kidneys, arteries, heart or endocrine system. Is caused.
  • Hypertension is a major risk factor for stroke, myocardial infarction (heart attack), heart failure, vascular aneurysms (eg aortic aneurysms), lower extremity aneurysms, and may also cause chronic renal failure. Even moderately high arterial blood pressure can be associated with shortened life expectancy, and diet and lifestyle changes can improve blood pressure control to reduce risk, and in those cases where this is not effective or insufficient, medication is often need.
  • Azilsartan is an angiotensin II receptor antagonist, which blocks the vasoconstriction activity of angiotensin II by selectively blocking the binding of angiotensin II and vascular smooth muscle AT1 receptor.
  • Potassium nitrite medoxomil is a pro-drug that hydrolyzes upon absorption, is a selective AT1 sub-type angiotensin II receptor antagonist, and the Azilsartan medoxomil potassium is Takeda His angiotensin II receptor antagonist activity is disclosed in Japanese Patent Application 2004-048928 and Korean Patent Application 10-2006-7016710 by Takanobu Kuroita (Japan). It is a commercially available therapeutic agent for hypertension in humans. It is commercially available under the trade name Lee Dal-bi as a film coated tablet of 20mg, 40mg, and 80mg.
  • compositions must be effective, safe and stable.
  • the effectiveness, safety and stability of the pharmaceutical product are not only closely related to the effectiveness and stability of the active ingredient itself, but also the properties of the pharmaceutical preparation, such as the stability of the active ingredient in the pharmaceutical preparation, and the active ingredient from the pharmaceutical preparation, etc. It is affected by the dissolution properties, and these are extremely important. Even if the pharmaceutical preparation is effective and safe immediately after preparation, when the active ingredient is easily decomposed or denatured over time, the pharmaceutical preparation has problems in effectiveness and stability.
  • the dissolution characteristics of the active ingredient from the pharmaceutical preparation if the dissolution of the active ingredient from the pharmaceutical preparation is too slow, the blood concentration of the active ingredient cannot reach an effective level and cannot sufficiently exhibit the expected effect. . On the other hand, if the dissolution of the active ingredient from the pharmaceutical preparation is too fast, the blood concentration of the active ingredient may increase rapidly in vivo and the risk of side effects may increase.
  • Another object of the present invention is to provide a novel method for preparing azartartan derivative compounds, optical isomers and pharmaceutically acceptable salts thereof.
  • Another object of the present invention is to provide a method for preparing an intermediate for preparing a novel nitrite derivative compound, an optical isomer and a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a composition effective for the prevention and treatment of hypertension, which includes a novel nitrite derivative compound, an optical isomer and a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a novel nitrite derivative compound and a method for producing the same.
  • the present invention provides an intermediate production method for preparing the novel azilsartan derivative compound of the present invention.
  • the present invention provides a method for preparing a pharmaceutically acceptable salt using the novel azilsartan derivative compound of the present invention.
  • alkyl when used alone or in combination with “heteroalkyl” refers to a straight, branched or cyclic hydrocarbon radical, respectively, each carbon atom having one or more cyano, hydroxy, alkoxy, oxo, Halogen, carbonyl, sulfonyl, cyanyl, and the like.
  • alkoxy refers to -O-alkyl, where alkyl is as defined above.
  • heteroalkyl means an alkyl containing one or more hetero atoms selected from N, O, S.
  • aryl means an aromatic group including phenyl, naphthyl, and the like, and may be optionally substituted with one or more alkyl, alkoxy, halogen, hydroxy, carbonyl, sulfonyl, cyanyl, and the like.
  • heteroaryl includes one or more, such as 1 to 4, or, in some embodiments, 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbons from 5 to 7 -Aromatic aromatic, monocyclic ring;
  • the other ring atom is carbon and at least one ring is aromatic and at least one is selected from N, O, and S, including one or more, for example 1 to 4, or in some embodiments 1 to 3 heteroatoms Heteroatoms are 8- to 12-membered bicyclic rings present in aromatic rings;
  • one or more, for example 1 to 4, or in some embodiments 1 to 3 heteroatoms selected from N, O, and S the remaining ring atoms are carbon and at least one ring is aromatic and at least one Heteroatoms refer to 11- to 14-membered tricyclic rings present in aromatic rings.
  • heteroaryl group examples include pyridyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, Tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolyl, indolyl, indolinyl, pyrrolyl, thiophenyl, pyridinyl, triazolyl, quinolinyl, pyrazolyl, pyrrolopyridinyl , Pyrazolopyridinyl, benzooxazolyl, benzothiazolyl, indazolyl and 5,6,7,8-tetrahydroisoquinoline.
  • m of R 2 means the number of substituents that can be substituted, that is, it means the number of R 2 , and when m is 0, it means that all hydrogen atoms are substituted, and when R 2 is 2 or more, each other It can be the same or different.
  • R 3 may be the same or different from each other, and when R 3 are all hydrogen atoms, it means that -NH 2 is substituted.
  • n means the number of alkylene (-CH 2- ), and when n is 0, it means that the atom is bonded.
  • the present invention provides a novel azilsartan derivative compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • A is H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, N (R 3 ) 2 , , or ego,
  • R 3 is H or a C 1-6 alkyl group
  • R a to R c are each independently an aryl group or a heteroaryl group
  • R d to R f and R g are each independently a C 1-6 alkyl group or a C 1-6 alkoxy group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • novel azilsartan derivative compound according to the formula (I) of the present invention, its optical isomer or its pharmaceutically acceptable salt can be obtained with high purity, its hygroscopicity is remarkably low, its heat stability is excellent, and its electrostatic property is low. It has excellent physical and chemical properties such as low cost. Therefore, the novel azilsartan derivative compound according to the formula (I) of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof is easy to formulate, has excellent stability, and is pre-arranged during the storage / distribution period after preparation with the preparation process or preparation with the preparation It does not require strict storage conditions, so mass production is easy and economical. In addition, the novel azilsartan derivative compound according to the formula (I) of the present invention, its optical isomer or its pharmaceutically acceptable salt has excellent plasma stability, and exhibits excellent bioavailability when taken orally, thereby exhibiting excellent therapeutic effect. .
  • the novel nitrousartan derivative may be a novel ester compound of nitrousartan.
  • R 1 is a C 1-6 alkyl group
  • R 2 is a C 1-6 alkoxy group
  • A is hydrogen
  • m is 1
  • n can be 0, more preferably R 1 may be a t-butyl group, and R 2 may be a methoxy group.
  • R 1 is a C 1-6 alkyl group
  • R 2 is a C 1-6 alkoxy group
  • A is a C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 Hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, N (R 3 ) 2 , , or
  • R a to R c are each independently an aryl group
  • R d to R f are each independently C 1-6 alkyl
  • R g is a C 1-6 alkoxy group
  • m is 1, n is 0
  • R a to R c may each independently be an aryl group. More preferably, it may be any one selected from trityl, t-butyl dimethylsilyl (TBDMS) and t-butyl dicarbonyl (BOC), and is limited to this. It is not.
  • the structure of the most preferred compound of formula 1 of the present invention according to the above may be a compound represented by the following formula 1-1 or formula 1-2.
  • novel nitrite derivative compounds according to [Chemical Formula 1-1] and [Chemical Formula 1-2] of the present invention, optical isomers thereof, or pharmaceutically acceptable salts thereof can be obtained with high purity, and the hygroscopicity is remarkably low. It has excellent thermal stability, low electrostaticity and low cost, and has excellent physical and chemical properties. Therefore, the novel nitrite derivative compounds according to [Chemical Formula 1-1] and [Chemical Formula 1-2] of the present invention, their optical isomers or their pharmaceutically acceptable salts are easy to formulate, have excellent stability, and prepare the formulation. It is easy and economical for mass production because it does not require separate strict storage conditions during the storage / distribution period after manufacture as a process or preparation.
  • novel nitrite derivative compounds according to [Chemical Formula 1-1] and [Chemical Formula 1-2] of the present invention have excellent plasma stability, and are excellent when taken orally. It can show excellent bioavailability and show excellent therapeutic effect.
  • the acceptable salt of the present invention may be a sodium salt represented by the following formula 1A or a potassium salt represented by the following formula 1B.
  • R 1 and R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • the compound according to [Chemical Formula 1A] or [Chemical Formula 1B] of the present invention can be obtained with high purity, and has excellent physicochemical properties such as remarkably low hygroscopicity, excellent heat stability, low static electricity and low cost. . Therefore, the compound according to [Chemical Formula 1A] or [Chemical Formula 1B] of the present invention is easy to formulate, has excellent stability, and does not require a separate strict storage condition during the storage / distribution period after preparation as a formulation manufacturing process or as a formulation. It is easy to produce and economical. In addition, the compounds according to [Chemical Formula 1A] or [Chemical Formula 1B] of the present invention have excellent plasma stability, and exhibit excellent bioavailability when taken orally, thereby exhibiting excellent therapeutic effects.
  • R 1 is a C 1-6 alkyl group
  • R 2 is a C 1-6 alkoxy group
  • R 1 is tert butyl
  • R2 is methoxy
  • X is -OH, Cl, Br or I
  • W is H or -Ph 3
  • A is H or -Ph 3
  • n may be 0 and m may be 1.
  • acceptable salts include alkali salts, alkaline earth metal salts, and zinc (Zn). It can be strontium (Sr), basic amino acid salt (lysine, arginine, histidine), preferably sodium (Na), potassium (K), lithium (Li), calcium (Ca), magnesium (Mg), zinc (Zn) ), And more preferably sodium and potassium.
  • the structure of the most preferred compound of Formula 1A of the present invention may be a compound represented by Formula 1A1 below, and the most preferred structure of Formula 1B may be a compound represented by Formula 1B1 below.
  • the compound according to [Chemical Formula 1A1] or [Chemical Formula 1B1] of the present invention can be obtained with high purity, has excellent low hygroscopicity, excellent heat stability, low physical static electricity, low cost, and excellent physical and chemical properties. . Therefore, the compounds according to [Chemical Formula 1A1] or [Chemical Formula 1B1] of the present invention are easy to formulate, have excellent stability, and do not require separate stringent storage conditions during preparation / preparation during preparation / preparation of the preparation process or mass production. This is easy and economical. In addition to this, the compounds according to the compounds according to [Chemical Formula 1A1] or [Chemical Formula 1B1] of the present invention have excellent plasma stability, and exhibit excellent bioavailability when taken orally, thereby exhibiting excellent therapeutic effects.
  • the present invention provides a method for preparing a compound represented by Chemical Formula 1, which will be described in detail below.
  • the present invention provides a method for preparing a compound represented by Formula 1 by reacting a compound represented by Formula 6 and a compound represented by Formula 7 below.
  • R 1 to R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • X is any of -OH, F, Cl, Br and I,
  • n is any integer from 0 to 4,
  • n is any one of 0 to 6
  • W is H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, N (R 3 ) 2 , , or ego,
  • R 3 is H or a C 1-6 alkyl group
  • M is H, C 1-6 alkyl, Na or K
  • R a to R c are each independently an aryl group or a heteroaryl group
  • R d to R f and R g are each independently a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R 1 and R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • A is H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, N (R 3 ) 2 , , or ego,
  • R 3 is H or a C 1-6 alkyl group
  • R a to R c are each independently an aryl group or a heteroaryl group
  • R d to R f and R g are each independently a C 1-6 alkyl group or a C 1-6 alkoxy group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • a covalent bond may be formed with O (oxygen atom), and when M is Na or K, an ion bond with O (oxygen atom), that is, , -O - type anions and cations represented by Na + or K + can form ionic bonds.
  • M of Formula 7 may be preferably H, C 1-6 alkyl or Na, and is a compound represented by Compound 1-1 by condensation reaction with 4- (bromomethyl) -2-methoxyphenyl pivalate. Can be produced.
  • the reaction may include a coupling reaction performed in the presence of a base, and the base is potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, diisopropylamine, triethylamine, diethylamine, etc. Can be used, and the type of base is not limited thereto.
  • the formula 7 used in the method for preparing the compound of formula 1 of the present invention can be directly prepared according to methods known in the art, and in the method for preparing the compound of formula 1 of the present invention, the coupling reaction is It can be made by a method known in the art (US Patent No. 5,616,599, Korean Patent Publication No. 2007-0020411).
  • a polar solvent such as dimethylformamide (DMF), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), etc.
  • the temperature of the reaction is 20 to 110 ° C, preferably It can be carried out at 50 ⁇ 70 °C.
  • the step of deprotecting the functional group W in Formula 7 may be further included. That is, when W is substituted with a functional group other than a hydrogen atom, in order to prepare a compound in which A in Formula 1 is a hydrogen atom, a reaction in which a substituent is removed in the presence of a base or an acid may be further performed.
  • W is a trityl group, a t-butyl dimethylsilyl group (TBDMS) and a t-butyl dicarbonate group (tert-butyl dicarbonyl, BOC).
  • the deprotection reaction can be carried out under acidic conditions, wherein the acid is preferably acetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, etc., and more preferably hydrochloric acid.
  • the reaction solvent organic solvents such as methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, and isopropyl ether and purified water can be used, and the reaction temperature is 0 ° C to 110 ° C. , Preferably 15 °C ⁇ 30 °C, most preferably can be carried out in the range of 20 °C ⁇ 25 °C.
  • the deprotection reaction may be performed under basic conditions, wherein the base may include an inorganic base consisting of NaHCO 3 , Na 2 CO 3 , Mg (OH) 2 , Cs 2 CO 3 , and Zn (OH) 2 It is possible, and the type of inorganic base is not limited thereto.
  • the present invention provides a method for preparing a pharmaceutically acceptable salt of a compound represented by Formula 1 by reacting the compound represented by Formula 1 with at least one selected from Na + or K +. Specifically, the compound represented by the formula (1) is reacted with potassium 2-ethyl hexanoate or sodium 2-ethyl hexanoate (Sodium 2-ethyl hexanoate) and represented by the formula (1) Potassium or sodium salts of the compounds can be prepared.
  • K + may be used in the form of potassium 2-ethyl hexanoate, and Na + is sodium 2-ethyl hexanoate.
  • the step of forming the salt may be performed under at least one solvent selected from the group consisting of acetone, ethyl acetate, isopropyl ether, or mixtures thereof.
  • the present invention comprises the steps of preparing a compound represented by the following formula [1-1] by reacting the compound represented by the following formula [6-1] with a compound represented by the following formula [7-1]
  • a method for preparing an azilsartan derivative compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is provided.
  • the method may further include the step of purifying the compound represented by Formula 1-1.
  • the solvent used in the purification step may be ethanol, acetone, acetonitrile, water, or a mixture thereof, specifically, a mixture of acetonitrile and water.
  • the sodium salt or potassium salt of the compound represented by Chemical Formula [1-1] may be prepared by reacting the compound represented by Chemical Formula 1-1 with Na + or K +. Specifically, the compound represented by Chemical Formula 1-1 is reacted with Potassium 2-ethyl hexanoate or Sodium 2-ethyl hexanoate to form [1]. The sodium salt or potassium salt of the compound represented by -1] can be prepared.
  • the step of forming the salt may be performed under at least one solvent selected from the group consisting of acetone, ethyl acetate, isopropyl ether, or mixtures thereof.
  • a compound represented by Formula 6 may be prepared from a compound represented by Formula 5 below.
  • R 1 to R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • R 1 to R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • X is any of -OH, F, Cl, Br and I,
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • the step of preparing a compound represented by Formula 6 from the compound represented by Formula 5 may be performed by halogenating a substitution reaction of the compound represented by Formula 5.
  • the halogenation substitution reaction may be performed by a method known in the art, and a halogenation substitution reaction may be performed using a halogenating agent such as phosphorus tribromide (PBr 3 ) or thionyl chloride (SOCl 2 ), and more Phosphorous tribromide can be used as a preferred halogenating agent.
  • the reaction solvent may be an organic halogen solvent such as dichloromethane or chloroform, and the type of the reaction solvent is not limited thereto.
  • the compound represented by Formula 5 may be prepared by reducing the compound represented by Formula 4 below.
  • R 1 to R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • the reducing agent used in the reduction may be lithium borohydride (LiBH 4 ), potassium borohydride (KBH 4 ), sodium borohydride (LiBH 4 ), lithium aluminum hydride (LiAlH 4 ), and the like.
  • lithium borohydride (LiBH 4 ) and sodium borohydride (NaBH 4 ) are useful, and more preferably sodium borohydride (NaBH 4 ) can be used.
  • Sodium borohydride has the advantages of low commercial cost, easy post-treatment, and eco-friendliness.
  • reaction solvent a solvent such as tetrahydrofuran, dioxane, methanol, ethanol, or isopropanol may be used, and preferably tetrahydrofuran may be used.
  • a compound represented by Chemical Formula 4 may be prepared by ester-reacting a compound represented by Chemical Formula 2 and a compound represented by Chemical Formula 3 in the presence of a base.
  • R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N (R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • R 1 is H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N (R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • X is any one selected from the group consisting of F, Cl, Br and I.
  • the esterification reaction can be carried out according to methods known in the art.
  • pyridine, diisopropylethylamine, triethylamine, pyrrolidine, calcium carbonate, sodium carbonate, and caustic soda can be used as the base used in the presence of a base, preferably pyridine, di Isopropylamine, triethylamine, piperidine can be used and more preferably pyridine can be used.
  • the reaction solvent may be an organic halogenated solvent such as dichloromethane, chloroform, and the like, but is not limited thereto.
  • R1 in [Formula 1], [Formula 2], [Formula 3], [Formula 4], [Formula 5] [Formula 6] or [Formula 7] is tert butyl; R2 is methoxy; X is -OH, Cl, Br or I; W is H or -Ph 3 ; M is methyl or H; A is H or -Ph 3 , n may be 0 and m may be 1.
  • composition comprising a novel azilsartan derivative compound of Formula 1, use thereof
  • the present invention provides a pharmaceutical compound composition for the treatment or prevention of hypertension, and the use thereof, using the nitrite derivative compound represented by Formula 1 of the present invention and a pharmaceutically acceptable salt thereof as an active ingredient.
  • the composition may include at least one selected from the sodium salt represented by the formula (1A) and the potassium salt represented by the formula (1B), and may preferably include the salts represented by the following compounds (1A and 1B).
  • one or more active ingredients having the same or similar function as the present invention may be included.
  • R 1 and R 2 are each independently H, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 hydroxyalkyl group, C 1-6 cyanoalkyl group, C 1-6 haloalkyl group, or N ( R 3 ) 2 ,
  • R 3 is H or a C 1-6 alkyl group
  • n is any integer from 0 to 4,
  • n is an integer of 0-6.
  • the composition may include a compound represented by the following Chemical Formula 1-1 or a pharmaceutically acceptable salt thereof, and specifically, from the group consisting of a compound represented by the following Chemical Formula 1-1, a sodium salt thereof and a potassium salt thereof It may include one or more selected.
  • the present invention provides a pharmaceutical composition comprising an nitrite derivative compound represented by Formula 1 of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is a pharmaceutical composition for the prevention or treatment of hypertension, comprising the azilsartan derivative compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, the treatment of the disease
  • the azilsartan derivative compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of the azilsartan derivative compound represented by Formula 1 above, an optical isomer thereof or a pharmaceutical thereof It provides a method for treating the disease, comprising administering to the subject an acceptable salt.
  • the present invention provides a use of the nitrite derivative compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of hypertension, and the prevention or treatment of hypertension It provides an azilsartan derivative compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the nitrite derivative compound may be a compound represented by Formula 1-1 or a pharmaceutically acceptable salt thereof, specifically, a compound represented by Formula 1-1, It may be one or more selected from the group consisting of sodium salts and potassium salts thereof.
  • prophylaxis refers to all actions that suppress hypertension or delay the onset of disease by administration of the pharmaceutical composition according to the present invention.
  • treatment means any action in which symptoms of hypertension are improved or beneficially altered by administration of a pharmaceutical composition according to the present invention.
  • composition of the present invention may be prepared by including at least one pharmaceutically acceptable carrier in addition to the above components for administration.
  • Pharmaceutically acceptable carriers can be used by mixing one or more of these components: saline, sterile water, Ringer's solution buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and, if necessary, antioxidants, buffers Other conventional additives, such as, bacteriostatic agents, may be added.
  • diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate into injectable formulations such as aqueous solution suspensions, emulsions, pills, capsules, granules, or tablets.
  • injectable formulations such as aqueous solution suspensions, emulsions, pills, capsules, granules, or tablets.
  • it can be preferably formulated according to each disease or ingredient by using methods appropriate in the art or using methods described in Remington's Pharmaceutical
  • composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is the patient's weight, sex, age, health status, diet ,
  • the administration time, administration method, excretion rate, and the extent of the disease vary in scope.
  • the daily dosage of the novel azilsartan ester derivative compound of Formula 1 or 2A, 2B of the present invention is about 1 mg to 100 mg, preferably 10 mg to 80 mg, more preferably 20 mg to 80 mg, divided once or several times a day It is more preferable to administer.
  • composition of the present invention alone or hormone therapy, treatment of other hypertensive drug preparations, diabetes (e.g. DPP-IV, SGLT2, etc., drug-A Glyflozines) and hyperlipidemia treatment (e.g. atorvastatin, Statins such as rochevastatin, phytavastatin) and biological response modifiers.
  • diabetes e.g. DPP-IV, SGLT2, etc., drug-A Glyflozines
  • hyperlipidemia treatment e.g. atorvastatin, Statins such as rochevastatin, phytavastatin
  • biological response modifiers e.g. atorvastatin, Statins such as rochevastatin, phytavastatin
  • composition of the present invention alone or hormone therapy, treatment of other hypertensive drug preparations, diabetes (e.g., DPP-IV, SGLT2, etc.
  • Drug-A Glyflozines e.g. atorvastatin Statins such as Rochevastatin and Pitavastatin
  • a drug using a biological response modifier and a combination of 2 or 3 agents may be used.
  • nitrite sartan derivatives of the present invention optical isomers thereof or pharmaceutically acceptable salts thereof also apply to the pharmaceutical compositions as long as there is no contradiction.
  • novel azilsartan derivative compound represented by Formula 1 of the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof has excellent pharmaceutical properties such as solubility, stability, non-absorption, and the treatment or prevention of hypertension. It has the effect of showing excellent efficacy. Therefore, there is an effect that can be usefully used as an active ingredient of a pharmaceutical composition for protecting the heart and blood vessels by being formulated with a pharmaceutically acceptable carrier or a drug for treating hypertension.
  • Example 1 is a result of the stability analysis in the plasma over time of the nitrite salt compound (AZM) of the nitrite salt of the nitrite compound or a salt thereof and Comparative Example 2 according to the present invention.
  • ZAM nitrite salt compound
  • AUC 3 is a result of the maximum concentration in plasma and area under the curve (AUC) according to oral intake of a suspension of an nitrite derivative compound or a salt thereof according to the present invention.
  • FIG. 5 shows the maximum concentration in plasma and area under the curve (AUC) according to oral intake of a solution of an azilsartan derivative compound or a salt thereof according to the present invention.
  • reaction order can be appropriately changed. That is, any reaction step may be performed first or any substituent change may be inserted, and if necessary, any reagent other than the illustrated reagents may be used.
  • the obtained reaction solution was separated into layers using 800 mL of water and 800 mL of ethyl acetate, and the water layer was extracted three times (500 mLx3 times) with 500 mL of ethyl acetate.
  • the obtained ethyl acetate organic layer was collected, extracted with 250 mL of 1N hydrochloric acid solution, adjusted to pH 10 by adding 1N NaOH solution to the obtained aqueous layer, and extracted twice with 500 mL of ethyl acetate (500 mLx2 times).
  • the organic layer was washed with water and brine, and then dried using magnesium sulfate (MgSO 4 ). Thereafter, the solvent was concentrated under reduced pressure to obtain a crude compound, and ethyl acetate-methanol-hexane solvent was added to obtain 38.1 g (85%) of a compound as a solid label.
  • DMSO dimethylsulfoxide
  • CDI 1,1'-carbonyldiimidazole
  • the labeling compound was recrystallized from ethyl acetate-isopropyl ether (1: 3) to obtain 62.7 g (88%) of the compound as a solid label.
  • Example 1 3-methoxy-4- (pivaloyloxy) benzyl 2-ethoxy-1-((2 '-(5-oxo-4-trityl-4,5-dihydro-1,2 , 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (3-methoxy-4- ( pivaloyloxy) benzyl 2-ethoxy-1-((2 '-(5-oxo-4-trityl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] Preparation of -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate)
  • Example 2 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxa Diazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (3-methoxy-4- (pivaloyloxy) benzyl 2 -ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl)- Synthesis of 1H-benzo [d] imidazole-7-carboxylate)
  • Example 3-1 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))
  • the obtained solid compound was dissolved in 18 mL of ethanol under reflux, 0.1 g of activated carbon was added to the solution, and the mixture was refluxed and stirred for 30 minutes. The insoluble material was removed by filtration, and the filtrate was cooled at room temperature. After 12 hours, the precipitated sieve was collected by filtration, and the solid was washed with ice-cold ethanol, and dried under reduced pressure at room temperature to obtain 3.0 g (50%) of the title compound.
  • Example 3-2 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))
  • Example 3-3 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))
  • Example 3-4 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))
  • Example 3-5 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4 -Oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy ) benzyl 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) Synthesis of methyl) -1H-benzo [d] imidazole-7-carboxylate))
  • the organic layer was washed with 400 ml of 20% brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated under reduced pressure. 200 ml of ethyl acetate was added to the residue, followed by heating to dissolve, followed by stirring under ice-cooling for 2 hours, and then filtering the solid. The filtered solid was dried under reduced pressure at 35 ° C. to give 47.94 g (65%) of the title compound.
  • Example 4 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxa Diazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate ((3-methoxy-4- (pivaloyloxy) benzyl) 2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) Synthesis of -1H-benzo [d] imidazole-7-carboxylate))
  • Example 5-1 Sodium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (a sodium nitrite pivalate sodium salt) Produce
  • Example 5-2 Sodium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (a sodium nitrite pivalate sodium salt) Synthesis of
  • Example 6-1 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Produce
  • Example 6-2 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, Preparation of 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (potassium nitrite pivalate)
  • Example 6-3 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of
  • Example 6-4 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of
  • Example 6-5 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of
  • Example 6-6 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of
  • Example 6-7 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of
  • Example 6-8 Potassium 3-methoxy-4- (pivaloyloxy) benzyl-2-ethoxy-1-((2 '-(5-oxo-4,5-dihydro-1,2, 4-oxadiazol-3-yl)-[1,1'-biphenyl] -4-yl) methyl) -1H-benzo [d] imidazole-7-carboxylate (azitartan pivalate potassium salt) Synthesis of
  • Activated carbon (1.7 g) was added to the solution, stirred at reflux for 30 minutes, and then the insoluble material was removed by filtration. The filtered filtrate was cooled to room temperature for 12 hours to obtain precipitated crystals through filtration, washed with ice-cold ethanol, and dried at room temperature under reduced pressure to obtain the title compound (50.0 g, 50%).
  • Purity of sodium nitrate salt, potassium nitrite of nitrite prepared according to Example 6-3, Example 6-4 and Example 6-6 was measured using HPLC, and the results are shown in Table 1 below. .
  • Example 3-1 Example 3-2
  • Example 3-4 Example 3-5 water 99.78% 99.82% 99.87% 99.80% salt
  • Example 6-2 Example 6-4
  • Example 6-6 Example 5-2 water 99.92% 99.87% 99.85% 99.79%
  • Example 3-1, Example 3-2, Example 3-4 and Example 3-2, Example 5-2, and the nitrite free radical prepared by the preparation method of Example 3-5 It was confirmed that the purity of the nitrite salt of the nitrite salt prepared in Example 6-3, Example 6-4, and Example 6-5 was 99.5% or more. It is very difficult to introduce a separate purification process due to its poorly soluble nature, and the nitrite free radical of the present invention and the free nitrite salt of the nitrite can be secured with high purity, which is very suitable for pharmaceutical use, only by manufacturing. Yes, it was confirmed.
  • Example 6-3 an azilsartan pivalate free base prepared in Examples 3-2, 3-4 and 3-5 was prepared and Example 6-3, carried out After vacuum drying (P 2 O 5 , 1 day or more) of the nitrite potassium salt of nitrite prepared in Example 6-4 and Example 6-6 and Comparative Example 2, the initial moisture value was measured by the Karl Fischer method.
  • Moisture measurement device (model name: Hydrosorb 1000, manufacturer: Quantachrome Instruments) using a 25 °C and relative humidity 15, 35, 55, 75, 95% of the moisture was automatically measured moisture, the results are shown in Table 2 below It was described. However, the initial moisture value was set to be a moisture value in a state that is continuously dried and no longer reduced.
  • nitrite pyrvalate free base prepared according to Example 3-2, Example 3-4 and Example 3-5 and Example 6-3, Example 6-4 and Example 6 The nitrite potassium pivalate potassium salt prepared according to -6 showed a very low hygroscopicity of about 0.2% at the relative humidity of the entire range where the experiment was conducted, and it was found that it can be stably stored even when the raw material is exposed to moisture in the air.
  • the nitrite-sartan pivalate free base of the present invention and the potassium nitrite-pithalate potassium salt have excellent non-hygroscopic (non-hygroscopic) properties that are not humidified even when exposed to air at normal relative humidity.
  • Comparative Example 2 has a very poor property as a raw material for pharmaceutical use by drawing moisture in the air exponentially as the relative humidity increases, and Comparative Example 2 is too large for formulation. It is expected that it is difficult to formulate or require separate strict conditions for formulation.
  • the azilsartan pivalate free base and potassium salt of the present invention have excellent non-humidity characteristics, and are excellent in formulating as a raw material for formulation. It can be seen that formulation is easy and economical.
  • Example 3-1 99.78% 99.69%
  • Example 3-2 99.82% 99.77%
  • Example 3-4 99.87% 99.85%
  • Example 3-5 99.80% 99.76%
  • Example 6-3 99.92% 99.89%
  • Example 6-4 99.87% 99.86%
  • Example 6-6 99.85% 99.83%
  • nitrite pyrvalate free base prepared according to Example 3-2, Example 3-4 and Example 3-5 and Example 5-2, Example 6-3, Example 6
  • the compounds prepared in -4 and Examples 6-6 showed excellent stability to heat, and Comparative Example 2 was found to have relatively poor stability to heat.
  • the nitrite sarvalidate free base, sodium salt, and potassium salt prepared according to the present invention have significantly better stability than conventional nitrite medoxomil potassium salts.
  • Example 3-1, Example 3-2, Example 3-4, Example 3-5, and Example Example Example 5-2, Example 6-2, Example 6-3, Example 6-4 and the Faraday cage device for measuring the static electricity by shielding the external static electric field of the sample of Comparative Example 2 (model name: 325 Faraday Cage with SmartStirTM, manufacturer: AMETEK PAR) was tested for the electrostatic properties of each compound and the results are shown in Table 4.
  • Example 3-1 15 nc / g Example 3-2 8 nc / g Example 3-4 6 nc / g Example 3-5 10 nc / g Example 6-2 7 nc / g Example 6-3 10 nc / g Example 6-4 11 nc / g Example 5-2 14 nc / g Comparative Example 2 25 nc / g
  • Example 3-1, Example 3-2, Example 3-4 and Example 3-2 and Example 5-2 of the nitrite free base prepared by the preparation method of Example 3-5 Example It was confirmed that the samples prepared in Example 6-3, Example 6-4 and Example 6-6 had lower electrostatic properties than the samples of Comparative Example 2.
  • the nitrite free radicals, sodium nitrite pivalate sodium salt and potassium salt prepared according to the present invention have low static electricity compared to the comparative example 2, which is a conventional nitrite medoxomil potassium salt. It can be seen that the workability is remarkably low.
  • the cost of the solid may affect process convenience and the size of the formulation, and when the cost is large, the processability is very poor. As it can, cost effectiveness is an important factor in formulation.
  • Example 3-1, Example 3-2, Example 3-4, Example 3-5, Example 5 to confirm the cost of the samples of Example 6-4, Example 6-6 and Comparative Example 2 -2, Example 6-3, Example 6-4, Example 6-6, and the samples prepared in Comparative Example 2 were placed in a measuring cylinder and repeated 20 times or more at a height of 10 cm vertically to compress sufficiently. To drop naturally. The cost was measured before and after tapping, and the results are shown in Table 5.
  • Example 3-1 3.88mL / g 2.65 mL / g
  • Example 3-2 3.76 mL / g 2.71 mL / g
  • Example 3-4 3.62 mL / g 2.65 mL / g
  • Example 3-5 3.79mL / g 2.70 mL / g
  • Example 6-3 3.22mL / g 2.31mL / g
  • Example 6-4 3.86 mL / g 2.77 mL / g
  • Example 6-6 3.73 mL / g 2.67 mL / g
  • Example 5-2 3.89mL / g 2.68 mL / g
  • Example 5-2 the compounds of Example 5-2, Example 6-3, Example 6-4, and Example 6-6 had a cost reduction effect.
  • the pharmaceutical raw material in powder form has a high cost, it is designed as a formulation (tablet or capsule) that can be administered to the human body after compression molding at all times, so if the cost is large, the processability of the formulation is very poor.
  • the nitrite satan pivalate or the salt thereof of the present invention has excellent physicochemical properties of pharmaceutical processability.
  • the nitrite derivative compound prepared according to Example 6-3 has an IC50 value of 2.9 nM, which is a measure of inhibition of AT 1 activity, and exhibits efficacy similar to that of Azilsartan (IC50 2.6 nM). see.
  • the nitrite derivative compound prepared according to Example 6-3 of the present invention can exhibit excellent pharmacological effects.
  • Bioequivalence was assessed through pharmacokinetic testing of the nitrite potassium salt of the present invention.
  • the concentration of the potassium salt of the nitrite derivative compound of the present invention in the plasma of the rat separated from the blood of the rat collected for each time was measured, and the result is FIG. 1. Same as
  • CMC carboxymethylcellulose
  • MFCk potassium nitrite
  • FIGS. 2 and 3 are when a suspension containing azilsartan pivalate free base (MFC) and azilsartan pivalate potassium salt (MFCk) is administered
  • FIGS. 4 and 5 are azilsartan pivalate free bases (MFC) shows the results of blood concentrations of nitrite of nitrite when administered with a solution containing potassium nitrite salt (MFCk).
  • the nitrite pivalate free base (MFC) and the nitrite pivalate potassium salt (MFCk) according to the present invention exhibit a sufficient effect in the blood even when taken orally. It can be seen that it has an excellent therapeutic effect.

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Abstract

La présente invention concerne un nouveau composé dérivé d'azilsartan, un isomère optique de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci. Le nouveau composé dérivé d'azilsartan selon la présente invention, un isomère optique, ou un sel pharmaceutiquement acceptable de celui-ci présente un excellent effet médicinal dans le traitement ou la prévention de l'hypertension, ainsi que d'excellentes propriétés pharmacologiques telles que la solubilité, la stabilité, l'absorptivité spécifique, etc. Le nouveau composé dérivé d'azilsartan, un isomère optique ou un sel pharmaceutiquement acceptable de celui-ci peut être formulé avec un véhicule pharmaceutiquement acceptable ou un agent thérapeutique pour l'hypertension etc., peut être utilisé de manière avantageuse en tant que principe actif d'une composition pharmaceutique pour la protection du cœur et des vaisseaux.
PCT/KR2019/015706 2018-11-16 2019-11-15 Composés dérivés d'azilsartan, leurs intermédiaires, leur procédé de préparation et composition pharmaceutique les comprenant WO2020101450A1 (fr)

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KR20100110438A (ko) * 2009-04-03 2010-10-13 주식회사종근당 올메살탄의 신규한 에스테르 화합물, 이의 중간체, 이의 제조방법 및 이를 포함하는 조성물
WO2012139536A1 (fr) * 2011-04-11 2012-10-18 Zentiva, K.S. Procédé de préparation de 2-éthoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphényl- 4-yl)méthyl)-1h-benzo[d]imidazole-7-carboxylates et leur conversion en azilsartan
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WO2012139536A1 (fr) * 2011-04-11 2012-10-18 Zentiva, K.S. Procédé de préparation de 2-éthoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphényl- 4-yl)méthyl)-1h-benzo[d]imidazole-7-carboxylates et leur conversion en azilsartan
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