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WO2018066947A1 - Composé dérivé d'entécavir lié à un acide gras et son utilisation pharmaceutique - Google Patents

Composé dérivé d'entécavir lié à un acide gras et son utilisation pharmaceutique Download PDF

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Publication number
WO2018066947A1
WO2018066947A1 PCT/KR2017/011022 KR2017011022W WO2018066947A1 WO 2018066947 A1 WO2018066947 A1 WO 2018066947A1 KR 2017011022 W KR2017011022 W KR 2017011022W WO 2018066947 A1 WO2018066947 A1 WO 2018066947A1
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WIPO (PCT)
Prior art keywords
oxo
methylenecyclopentyl
amino
purin
methyl
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PCT/KR2017/011022
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English (en)
Korean (ko)
Inventor
강명주
한영택
이대로
호명진
Original Assignee
단국대학교 천안캠퍼스 산학협력단
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Priority to CN201780012633.6A priority Critical patent/CN108699060A/zh
Priority to BR112018017005-4A priority patent/BR112018017005B1/pt
Publication of WO2018066947A1 publication Critical patent/WO2018066947A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to an enticavir derivative compound to which a fatty acid is bound and its pharmaceutical use. It is to prepare a drug for sustained release parenteral administration by pro-drug entecavir has been used only for conventional oral use.
  • Entecavir ie, compound 2-amino-9-[(1S, 3R, 4S) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentyl] -1H as shown in formula (1) -Purine-6 (9H) -one is an antiviral agent of the nucleoside type.
  • Entercavir is the drug that has the highest anti-HBV activity among commercial anti-HBV (Hepatitis B virus) drugs.
  • the anti-HBV activity of entecavir is known to be 100 and 30 times higher than lamivudine and adefovir difficile, respectively. It also has fewer side effects and therapeutic effects in patients who are resistant to lamivudine. Therefore, entecavir is used as a useful treatment for hepatitis B.
  • prodrugization is a method of improving the undesired drug dynamics that occur during the use of the drug, that is, during the administration, absorption, distribution, excretion, and metabolism of the drug by changing the structure of the drug.
  • prodrugation techniques that covalently bind, ie, acylate, fatty acids can be utilized to design sustained release or sustained release formulations by reducing the water solubility of the drug.
  • the acylated prodrug is administered as an intramuscular or subcutaneous injection, it is present as a solid storage form in vivo and then slowly dissolved and hydrolyzed to break down into active drugs and fatty acids. In most cases, the rate of absorption of the drug is determined by the rate of dissolution of the drug.
  • Acids generated as byproducts through hydrolysis are removed through metabolic processes in vivo, which can cause side effects of inflammation, acute and chronic toxicity.
  • the method of acylating fatty acids such that non-toxic or minimized bio-derived substances are generated as by-products is one of the good methods of prodrug-induced sustained-release drug development and prevention of toxicity by by-products.
  • the present invention provides an enticavir derivative compound, a pharmaceutically acceptable salt thereof or a hydrate thereof covalently bonded to a fatty acid represented by the following formula (2).
  • R 1 is one of C4 to C20 straight or branched alkyl, alkene or alkane.
  • the present invention also provides a pharmaceutical composition for preventing or treating type B infection, which comprises an enticavir derivative compound covalently bonded to a fatty acid represented by Formula 2, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.
  • R 1 is one of C4 to C20 straight or branched alkyl, alkene or alkane.
  • the present invention relates to an enticavir derivative compound having a fatty acid bound thereto and a pharmaceutical use thereof, wherein the entecavir derivative covalently bonded to a fatty acid according to the present invention shows a significantly lower solubility and dissolution rate than entecavir.
  • the fatty acid polymer of entecavir according to the present invention is prepared by parenteral administration preparations such as injections, it can express a sustained effect of several weeks or more after a single administration, and can dramatically improve the patient's compliance with the medication.
  • 1 is a view showing the dissolution test results according to the present invention.
  • the present inventors attempted to reduce the water solubility of entecavir, which has difficulty in formulating sustained release due to high water solubility, and for this purpose, established a method of acylating various fatty acids in entecavir, and thereby synthesized a derivative of entecavir to complete the present invention. Came to.
  • the present invention provides an enticavir derivative compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof in which a fatty acid represented by Formula 2 is covalently bonded.
  • R 1 may be one of C4 to C20 straight or branched alkyl, alkene or alkane.
  • the present invention may include not only enticavir derivative compounds in which the fatty acid of Formula 2 is covalently bonded, but also all possible solvates, hydrates, isomers, and the like, which can be prepared therefrom.
  • an enticavir derivative compound is a covalently bonded fatty acid of formula (2).
  • R 1 may be one of C4 to C20 straight or branched alkyl, alkene or alkane, and R 2 may be hydroxyl, halogen, —OR 3 or —O 2 R 3 .
  • the halogen may be fluorine, chlorine, bromine or iodine.
  • R 3 may be an alkyl group of 1 to 20 carbon atoms.
  • alkyl refers to a straight or branched monovalent hydrocarbon group consisting of carbon atoms and hydrogen atoms.
  • the present invention may be obtained by reacting an enticavir of Formula 1 or a hydrate thereof with a fatty acid of Formula 3 to obtain an entecavir derivative compound of Formula 2.
  • R ⁇ 1> in the said reaction formula means a C4-20 alkyl group.
  • the entecavir derivative compound to which the fatty acid of Formula 2 is bound may be obtained by performing an acylation reaction using a coupling reagent.
  • Coupling reagents mentioned above include dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (N, N'-diisopropylcarbodiimide; DIC), 1-ethyl-3- (3- Reagents of carbodiimide structure, such as dimethylaminopropyl) carbodiimide (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC)).
  • DCC dicyclohexylcarbodiimide
  • N N'-diisopropylcarbodiimide
  • DIC 1-ethyl-3- (3- Reagents of carbodiimide structure, such as dimethylaminopropyl) carbodiimide (1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC)).
  • the coupling reagent is benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yljade Phosphonium structure reagents such as benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP) and the like.
  • the coupling reagent is 2- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethylammonium tetrafluoroborate (2- (1H-benzotriazol-1-yl)- N, N, N'N'-tetramethylammonium tetrafluoroborate (TBTU), 2- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethylammonium hexaflofuophosphate Ammonium structure reagents such as (2- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethylammonium hexafluorophosphate (HATU)).
  • the pharmaceutically acceptable salts are hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, tartarate, maleate, gluconate, succinate, formate, trifluoroacetate, oxalate , Fumarate, methanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, sodium salt, potassium salt, lithium salt, calcium salt and magnesium salt.
  • the present invention also provides a pharmaceutical composition for preventing or treating type B infection, which comprises an enticavir derivative compound covalently bonded to a fatty acid represented by Formula 2, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.
  • R 1 may be one of C4 to C20 straight or branched alkyl, alkene or alkane.
  • the entecavir derivative compound to which the fatty acid represented by Formula 2 is covalently bonded is [(1R, 3S, 5S) -3- (2-amino-6-oxo-1H-purin-9 (6H) -yl) -5-hydride Roxy-2-methylenecyclopentyl] methyl hexanoate, [(1R, 3S, 5S) -3- (2-amino-6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy- 2-methylenecyclopentyl] methyl octanoate, [(1R, 3S, 5S) -3- (2-amino-6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy-2- Methylenecyclopentyl] methyl decanoate, [(1R, 3S, 5S) -3- (2-amino-6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy-2-m
  • the enticavir derivative compounds to which the fatty acid is covalently bonded according to the present invention may be provided in the form of pharmaceutically acceptable salts thereof, and the pharmaceutically acceptable salts thereof include hydrochloride, bromate, sulfate, phosphate, nitrate and citrate.
  • the pharmaceutically acceptable salts thereof include hydrochloride, bromate, sulfate, phosphate, nitrate and citrate.
  • the pharmaceutical composition may further include a suitable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition.
  • Carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
  • compositions according to the invention can be used in the form of injections, granules, tablets, pills, capsules, gels, syrups, suspensions, emulsions or solutions, respectively, according to conventional methods.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed and prepared.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the amount of the compound which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, weight, and disease of the patient, but is 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg once or several times a day. May be administered.
  • the dosage of the compound according to the present invention may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
  • the pharmaceutical composition may be administered to various mammals such as mice, mice, livestock, humans, and the like. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine dural or intracerebroventricular injection.
  • the instrument used to confirm the structure of the product obtained in the present invention is as follows. Nuclear magnetic resonance spectra ( 1 H NMR) were used as JEOL JNM-LA 300, Bruker Analytik ADVANCE digital 500 or ADVANCE digital 600, and the solvent was DMSO-d 6 . Mass spectra were used and expressed in m / z form.
  • TLC Thin layer chromatography
  • silica gel Merk F254 manufactured by Merk
  • silica Merck EM9385, 230-400 mesh
  • Reagents and solvents used in the present invention were purchased from Sigma-aldrich and Tsiyi (TCI) products.
  • TCI Tsiyi
  • the entecavir monohydrate used for the derivative synthesis was purchased from J & H Chem.
  • Example 1-7 was analyzed by HPLC using the following conditions.
  • R ⁇ 1> in the said reaction formula means a C4-20 alkyl group.
  • R ⁇ 1> in the said reaction formula means a C4-20 alkyl group.
  • hexanoic anhydride (0.39 mL, 1.69 mmol) was added to entecavir hydrate (500 mg, 1 equivalent, 1.69 mmol) to obtain the desired [(1R, 3S, 5S). 260 mg (41%) of) -3- (2-amino-6-oxo-1H-purin-9 (6H) -yl) -5-hydroxy-2-methylenecyclopentyl] methyl hexanoate were obtained.
  • Example 1 1 ml of 10 mM phosphate buffered saline and 10 mg of entecavir or fatty acid polymers (Examples 1 to 7) were added to an Eppendorf tube and stirred using a shaking incubator at room temperature for 24 hours. After centrifugation at 13,000 rpm for 10 minutes, the supernatant was taken, diluted with a suitable mobile phase, and analyzed by HPLC.
  • Drug dissolution evaluation was performed using the USP paddle method.
  • the enticavir fatty acid polymers of Examples 6 and 7 corresponding to 40 mg as entecavir and entecavir were added to 900 ml of medium, respectively, and stirred at 50 rpm to evaluate the dissolution rate of the drug.
  • the medium used was 0.001 N hydrochloric acid solution containing 0.5% Polysorbate 20 to secure the sink condition.
  • the temperature of the medium was 37.5 degrees.
  • Entecavir had high water solubility and dissolved more than 80% of the drug at 45 minutes, while Examples 6 and 7 showed low dissolution rates of 13% and 36%, respectively. Such slowly dissolving characteristics can be expected to ensure a sustained release pattern after injection.
  • Example 6 was added to human liver microsomes (0.5 mg / ml) and 0.1 M phosphate buffer (pH 7.4) at a concentration of 1 ⁇ M, pre-incubated at 37 ° C. for 5 minutes, and then NADPH Regeneration system solution was added at 37 ° C. Incubate for 30 minutes. Then, to terminate the reaction by adding an acetonitrile solution containing a chlorpropamide, centrifuged for 5 minutes (14,000 rpm, 4 °C) and the supernatant was injected into the LC-MS / MS system 6 and entercavir were analyzed to evaluate the conversion to the parent drug of Example 6.
  • phosphate buffer pH 7.4
  • Example 6 The amount of entecavir, the parent drug of Example 6 and Example 6 remaining through the reaction, was used using an Agilent 1290 infinity series pump system (Agilent, USA) and Triple Quad 5500 LC-MS / MS system (Applied Biosystems, USA). And analyzed. As a result of the test, it was confirmed that after 6 minutes, Example 6 was converted into entecavir, which is about 76.8% of the parent drug. Through this, it was confirmed that the fatty acid-bound entecavir derivative compound (Example) can be converted into enticavir which is an active substance quickly and completely after administration in the body and exhibit its activity.

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  • Bioinformatics & Cheminformatics (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un composé dérivé d'entécavir lié à un acide gras et une utilisation pharmaceutique de celui-ci. Le dérivé d'entécavir lié de manière covalente à un acide gras selon la présente invention présente une solubilité et un taux de dissolution significativement inférieurs à celui de l'entécavir. Le polymère d'acide gras d'entécavir selon la présente invention peut exercer un effet prolongé pendant plusieurs semaines ou plus après une administration unique lorsqu'une préparation est réalisée pour une administration parentérale telle qu'une injection, et peut considérablement améliorer la conformité de médication du patient.
PCT/KR2017/011022 2016-10-07 2017-09-29 Composé dérivé d'entécavir lié à un acide gras et son utilisation pharmaceutique WO2018066947A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780012633.6A CN108699060A (zh) 2016-10-07 2017-09-29 结合有脂肪酸的恩替卡韦衍生化合物及其药学用途
BR112018017005-4A BR112018017005B1 (pt) 2016-10-07 2017-09-29 Composto derivado de entecavir e composição farmacêutica para prevenir ou tratar hepatite b

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KR1020160129647A KR101996229B1 (ko) 2016-10-07 2016-10-07 지방산이 결합된 엔테카비어 유도체 화합물 및 이의 약학적 용도
KR10-2016-0129647 2016-10-07

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WO2019062924A1 (fr) * 2017-09-29 2019-04-04 广州市恒诺康医药科技有限公司 Promédicament à action prolongée d'entécavir, son procédé de préparation et son application

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WO2022042641A1 (fr) * 2020-08-26 2022-03-03 上海博志研新药物技术有限公司 Sel médicinal d'entécavir, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019062924A1 (fr) * 2017-09-29 2019-04-04 广州市恒诺康医药科技有限公司 Promédicament à action prolongée d'entécavir, son procédé de préparation et son application
US11292811B2 (en) 2017-09-29 2022-04-05 Guangzhou Henovcom Bioscience Co. Ltd Long-acting prodrugs of entecavir, preparing methods and uses thereof

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CN108699060A (zh) 2018-10-23
BR112018017005A2 (pt) 2018-12-26
KR101996229B1 (ko) 2019-07-04
KR20180038697A (ko) 2018-04-17

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