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WO2018016795A1 - Orotate de médicament antiviral, son procédé de préparation et composition pharmaceutique contenant de l'orotate - Google Patents

Orotate de médicament antiviral, son procédé de préparation et composition pharmaceutique contenant de l'orotate Download PDF

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Publication number
WO2018016795A1
WO2018016795A1 PCT/KR2017/007460 KR2017007460W WO2018016795A1 WO 2018016795 A1 WO2018016795 A1 WO 2018016795A1 KR 2017007460 W KR2017007460 W KR 2017007460W WO 2018016795 A1 WO2018016795 A1 WO 2018016795A1
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Prior art keywords
orotate
formula
methyl
pharmaceutical composition
ray diffraction
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Ceased
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PCT/KR2017/007460
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English (en)
Korean (ko)
Inventor
서명원
권재욱
윤진영
이미영
이건희
강재훈
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Ildong Pharmaceutical Co Ltd
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Ildong Pharmaceutical Co Ltd
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention provides 3-[( ⁇ 1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl ⁇ oxy) methyl] -8,8-dimethyl-3,7-dioxo of Formula 1 Orotates of -2,4,6-trioxa-3 ⁇ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxil), preparations thereof, and pharmaceutical compositions comprising the salts It is about.
  • the free compound of formula (1) is a novel antiviral material disclosed in the Republic of Korea Patent No. 0441638 and WO 02/057288 as a compound to which no acid is added.
  • these compounds are very unstable against heat and moisture and are difficult to use as raw materials for pharmaceutical compositions.
  • Korean Patent No. 0935904 various kinds of pharmaceutically acceptable salts have been prepared to solve such problems.
  • some salts were found to be difficult to obtain as crystalline solids, and only maleic acid, p-toluenesulfonate, methanesulfonate, naphthalenesulfonate and ethanesulfonate were successfully obtained as crystalline solids.
  • Besipovirdipicyl maleic acid single salt is described as having significantly better heat stability than its free compounds or other salts.
  • Besifobivirdi maleic acid is very unstable at high temperatures above 100 ° C and is mostly decomposed in 6 hours and still insufficient in stability, and on contact may cause severe irritation with redness, pain, cornea and erosion. Due to the characteristics of maleic acid, similar symptoms may occur in the manufacturing process as in case of conjunctivitis or acute exposure (see toxicological information sheet of the Korea Food and Drug Administration).
  • An object of the present invention is to provide a novel salt of Besipovir difficile without problems such as toxicity, heat stability at a high temperature of 100 °C or more and improved safety, solubility and storage stability of the manufacturing process.
  • One embodiment of the present invention is 3-[( ⁇ 1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl ⁇ oxy) methyl] -8,8-dimethyl-3 represented by Formula 1 Of orotates of, 7-dioxo-2,4,6-trioxa-3 ⁇ 5 -phosphanon-1-yl-pivalate (hereinafter referred to as besifovirdiphyxyl orotate) will be:
  • Another embodiment of the present invention is 3-[( ⁇ 1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl ⁇ oxy) methyl] -8,8-dimethyl-3 represented by the formula (2).
  • Beshpovirdipixyl And to a process for preparing besypovirdipicolic acid orotate of formula (I) comprising mixing in the presence of a solvent:
  • Another aspect of the invention relates to a pharmaceutical composition for treating or preventing a viral infection comprising orthotate of besipovirdipicil and a pharmaceutically acceptable excipient.
  • Besipovirdiphyloxyl orotate of the present invention has excellent stability according to light, temperature and humidity, and particularly excellent thermal stability even at a high temperature of 100 ° C. or higher at which Bezofovirdiphyxyl maleate known to be stable is decomposed. Indicates.
  • Besipovirdiphyloxyl orotate of the present invention exhibits very excellent stability and can be stored for a long time, and has the advantage of easy formulation research and storage even in a high temperature and high humidity environment.
  • Besipovirdiphyxyl orotate prepared by the process for producing besypovirdiphyxyl orotate according to the present invention is a relatively simple process with a very high purity, such as 99% or more, specifically 99.5% or more, more specifically It has a purity of at least 99.9%.
  • 1 is a graph comparing the change in weight (%) with time and temperature (100 ° C.) of the besipovirdiphyxyl orotate of the present invention and the control compound besipovirdiphyxyl maleate.
  • FIG. 2 shows the differential scanning calorimeter of the Besipovirdiphyxyl orotate of Example 1.
  • FIG. 3 shows a differential scanning calorimeter of Besypovirdipicyl maleate of Comparative Example 1.
  • Figure 4 shows a powder X-ray diffraction pattern (Powder X-ray Diffraction pattern) of the Besipovir difficile orotate of Example 1.
  • Figure 5 shows the infrared spectroscopy (FT-IR) of the Besipovirdiphyxyl orotate of Example 1.
  • FIG. 6 shows the 1 H nuclear magnetic resonance spectrum (NMR) of the besipovirdiphyxyl orotate of Example 1.
  • One embodiment of the present invention is 3-[( ⁇ 1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl ⁇ oxy) methyl] -8,8-dimethyl-3 represented by Formula 1 Orotates of, 7-dioxo-2,4,6-trioxa-3 ⁇ 5 -phosphanon-1-yl-pivalate (hereinafter referred to as besifovirdiphyxyl orotate) :
  • Besipovirdiphyxyl orotate of formula (1) does not decompose under harsh conditions such as moisture, light, high temperature (eg 100 ° C. or more), and thus has excellent stability and is active regardless of storage conditions when used as an antiviral pharmaceutical composition. Ingredients do not decompose, there is an advantage that can maintain the efficacy.
  • besypovirdipicolic acid orotate of formula (1) has the advantage that the solubility and safety is improved compared to the free compound or other salts thereof.
  • Besipovirdiphyxyl ororate Because of the improved physicochemical stability and solubility of the above-mentioned Besipovirdiphyxyl ororate, it may be useful for the prevention or treatment of viral infections. In particular, due to the improved physicochemical stability of besypovirdicarboxyl ororate, it may be advantageously used in solid pharmaceutical formulations comprising the active ingredient.
  • Besipovirdiphyxyl ororate may have high purity, such as at least 99%, specifically at least 99.5%, more specifically at least 99.9%, such as 99.91% to 99.98%.
  • Another aspect of the present invention relates to a process for preparing orthotate of besypovirdipicil of formula (1), which comprises mixing the free compound of besipovirdipicil in the presence of orotic acid and a solvent. .
  • Beshfovirdipixyl a free compound of dioxo-2,4,6-trioxa-3 ⁇ 5 -phosphanon-1-yl-pivalate (Beshfovirdipixyl) in the presence of a solvent and orotic acid represented by the formula (3)
  • a process for preparing besypovirdipicolic acid orotate of Formula 1 comprising:
  • the preparation method is mixed with the free compound of the Besipovirdipicil in the presence of a solvent in the presence of a solvent and in the temperature range of 35 °C to 50 °C, specifically 40 °C to 45 °C for 1 minute to 12 hours, Specifically, it may be produced by heating to 1 minute to 6 hours, more specifically 1 minute to 1 hour, and cooling to a range of 15 ° C to 30 ° C, such as 20 ° C to 25 ° C.
  • the preparation method may further comprise the step of filtering the solid obtained after the cooling, washing with a solvent and drying.
  • Dissolving the free compound of Besipovirdiboxil at a rate of 1 mg to 700 mg per ml of solvent, adding orotate to it and stirring can produce the orotate of Besipovirdiboxil.
  • a solvent which can be used for salt formation water, methanol, ethanol, propanol, isopropanol, cyclohexane, normal hexane, diethyl ether, methyl ethyl ketone, tetrahydrofuran, acetone, etc. can be used, for example.
  • the amount of ororate added may be used in the amount of 0.8 to 1.2 equivalents, specifically 0.9 to 1.1 equivalents, and more specifically about 1 equivalent, based on 1 equivalent of free compound of Besipovirdipicil.
  • HBV-1 Herpes simplex virus type 1
  • HSV-2 Herpes simplex virus type 2
  • HBV hepatitis B virus
  • HV human immunodeficiency virus
  • another aspect of the present invention provides a pharmaceutical composition comprising orthotate of besipovirdipicil and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is particularly useful for the prevention or treatment of the viral disease, in particular for the prevention or treatment of HBV or HIV infection.
  • the total daily dose of orthotate of besipovirdipicil may range from 1 mg to 600 mg, specifically 1 mg to 300 mg, more specifically 100 mg to 200 mg, but the subject's body weight, It may vary depending on your age, the severity of the disease, and your health.
  • compositions comprising orthotate of Besipovirdipicil may be administered in injectable or oral formulations.
  • Injectable preparations for example, can be used as sterile injectable aqueous or oily suspensions, and as solvents of the injectable preparations can be water, Ringer's solution or isotonic NaCl solution.
  • Oral formulations include, for example, tablets, capsules, pills, powders, and the like, and in particular, may be tablets or capsules.
  • the beotfovirdipicil orotate is an oral non-toxic and pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium It can be mixed with stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like, and when administered orally in liquid form, orthotates of besifovirdipixyl are any oral and non-toxic pharmaceutically acceptable.
  • Inert carriers such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polymethylcellulose, polyethylene glycols, waxes and the like. This includes.
  • Such lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrants include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Another aspect of the present invention provides the use of orthotate of besipovirdipicil in the manufacture of an antiviral drug, in particular an anti-HBV drug or an anti-HIV drug.
  • Another aspect of the invention provides a method for treating a viral disease comprising administering a prophylactic or therapeutically effective amount of orthotate of besypovirdipicil to a subject in need of treatment or prevention of a viral infection, specifically HBV or HIV infection. Methods of preventing or treating are provided.
  • Example 3 of Korean Patent Registration No. 0935904 1 g of Besifobivirdiphyxyl was dissolved in 10 ml of ethyl acetate, and then 1 equivalent of maleic acid was added and stirred for an hour to produce a solid. The obtained solid was filtered, washed with ethyl acetate and dried to obtain besypovirdimaleic maleate having a purity of 99.89%.
  • Source Slit 1.0 mm
  • Besipovir difficile chamber of Example 1 Of orthotate and the besipovirdiphyxyl obtained in Comparative Examples 1 to 8 Samples of other salts were placed in glass containers of 10 mg to 50 mg each and stored under conditions of 40 ⁇ 2 ° C. and 75 ⁇ 5% RH. After 1, 2 and 4 weeks, 5 mg of the sample was taken and analyzed using HPLC. The results are shown in Table 1 below.
  • Besipovirdipicil maleate obtained in Comparative Example 1 and the orotate obtained in Example 1 were placed in several glass containers, each about 10 to 15 mg, and stored at 60 ° C, 80 ° C, and 100 ° C, respectively. Samples were taken at 5 mg after 1, 2, 4 and 8 weeks or 24 and 48 hours and analyzed using HPLC. The results are shown in Tables 2, 3, and 4 below.
  • the Besipobivirdioxyl orotate and maleate show almost equal thermal stability.
  • the orotate of the present invention has excellent thermal stability.
  • the Besipovirdiphyloxyl orotate of the present invention can minimize the generation of the flexible material even in the processing or other harsh environments, such as milling, thereby having the advantage of drug development using a variety of formulation technology.
  • Example 1 (Orotate) Comparative Example 1 (maleate) 1 time 163.4 °C 125.1 °C Episode 2 162.3 °C 124.8 °C 3rd time 162.6 °C 125.1 °C Average 162.8 °C 125.0 °C
  • the Besipovirdiphyxyl Orotate of Example 1 and the Besipovirdiphyxyl Maleate of Comparative Example 1 were each placed in 100 mg of transparent glass containers and stored for 3 days while being exposed to a light source in a light stable chamber.
  • the light stability meter used CARON Photostability Chamber Model 6545, and the total exposure was 2.4 million lux-hr / m 2 and near UV of 330 W ⁇ hr / m 2 . After 3 days of exposure to the light source, each sample was taken by 5 mg and analyzed using HPLC, the results are shown in Table 6 below.
  • the besypovirdiphyxyl ororate does not generate any photodegradation products even when exposed to light, and thus has excellent photostability on par with besypovirdipicyl maleate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Molecular Biology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'orotate : 3- [( {1- [(2-amino- 9H -furyn-9-yl) méthyl] cyclopropyl} oxy) méthyl] -8,8-diméthyl -3,7-dioxo -2,4,6-trioxa -3 lambda 5 -phosphanon-1-yl-pivalate de formule chimique 1; un procédé de préparation associé; et une composition pharmaceutique contenant l'orotate.
PCT/KR2017/007460 2016-07-18 2017-07-12 Orotate de médicament antiviral, son procédé de préparation et composition pharmaceutique contenant de l'orotate Ceased WO2018016795A1 (fr)

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Application Number Priority Date Filing Date Title
KR10-2016-0090800 2016-07-18
KR1020160090800A KR102623581B1 (ko) 2016-07-18 2016-07-18 항바이러스성 약물의 오로트산염, 이의 제조 방법 및 상기 염을 포함하는 약제학적 조성물

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102208009B1 (ko) * 2018-04-26 2021-01-28 주식회사 경보제약 신규한 리나글립틴 염 화합물, 이의 제조 방법 및 신규한 리나글립틴 염 화합물로부터 제조된 리나글립틴

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040063668A1 (en) * 2001-01-19 2004-04-01 Jong-Ryoo Choi Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US20060052346A1 (en) * 2004-02-17 2006-03-09 Averett Devron R Nucleoside phosphonate derivatives useful in the treatment of HIV infections
KR100935904B1 (ko) * 2007-01-17 2010-01-07 주식회사 엘지생명과학 항바이러스성 약물의 말레산 단일염 및 이를 함유하는약제학적 조성물
KR20110095545A (ko) * 2010-02-19 2011-08-25 주식회사 셀트리온화학연구소 (ｓ)-리바스티그민 오로트산염 및 이를 포함하는 약제학적 조성물
KR101597338B1 (ko) * 2009-09-04 2016-02-24 탁티칼 떼라페우틱스 인크. 5-아미노 또는 치환된 아미노 1,2,3-트리아졸 화합물 및 이의 오로트산염 제형들의 신규한 조성물들 및 이의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040063668A1 (en) * 2001-01-19 2004-04-01 Jong-Ryoo Choi Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same
US20060052346A1 (en) * 2004-02-17 2006-03-09 Averett Devron R Nucleoside phosphonate derivatives useful in the treatment of HIV infections
KR100935904B1 (ko) * 2007-01-17 2010-01-07 주식회사 엘지생명과학 항바이러스성 약물의 말레산 단일염 및 이를 함유하는약제학적 조성물
KR101597338B1 (ko) * 2009-09-04 2016-02-24 탁티칼 떼라페우틱스 인크. 5-아미노 또는 치환된 아미노 1,2,3-트리아졸 화합물 및 이의 오로트산염 제형들의 신규한 조성물들 및 이의 제조방법
KR20110095545A (ko) * 2010-02-19 2011-08-25 주식회사 셀트리온화학연구소 (ｓ)-리바스티그민 오로트산염 및 이를 포함하는 약제학적 조성물

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KR20180009195A (ko) 2018-01-26

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