WO2018016795A1 - Orotate of antiviral drug, preparation method therefor, and pharmaceutical composition containing orotate - Google Patents
Orotate of antiviral drug, preparation method therefor, and pharmaceutical composition containing orotate Download PDFInfo
- 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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- WIPO (PCT)
- Prior art keywords
- orotate
- formula
- methyl
- pharmaceutical composition
- ray diffraction
- Prior art date
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- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
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- 239000003443 antiviral agent Substances 0.000 title description 2
- -1 5-phosphanon-1-yl-pivalate orotate Chemical compound 0.000 claims abstract description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
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- 238000004458 analytical method Methods 0.000 claims description 9
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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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Abstract
The present invention relates to: 3-[({1-[(2-amino-9H-furyn-9-yl) methyl] cyclopropyl} oxy) methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-phosphanon-1-yl-pivalate orotate of chemical formula 1; a preparation method therefor; and a pharmaceutical composition containing the orotate.
Description
본 발명은 화학식 1의 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실(besifovir dipivoxil))의 오로트산염, 그의 제조방법 및 상기 염을 포함하는 약제학적 조성물에 관한 것이다. 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-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxil), preparations thereof, and pharmaceutical compositions comprising the salts It is about.
[화학식 1][Formula 1]
상기 화학식 1의 유리 화합물(베시포비르디피복실)은 산이 부가되지 않은 화합물로써 대한민국 등록특허 제0441638호 및 국제공개특허 WO 02/057288호에 개시된 새로운 항바이러스 물질이다. 그러나 이 화합물은 열과 수분에 대해 매우 불안정하여 약제학적 조성물의 원료로 사용되기 어려운 화합물이다.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. However, these compounds are very unstable against heat and moisture and are difficult to use as raw materials for pharmaceutical compositions.
대한민국 등록특허 제0935904호에서는 이와 같은 문제점을 해결하기 위해 약제학적으로 허용되는 여러 종류의 염을 제조하였다. 이 과정에서 일부 염들은 결정성 고체로 얻기가 힘든 것으로 밝혀졌으며, 말레산염, p-톨루엔설폰산염, 메탄설폰산염, 나프탈렌설폰산염 및 에탄설폰산염의 경우에만 결정성 고체로 얻는데 성공하였고, 그 중에서 베시포비르디피복실 말레산 단일염이 그의 유리 화합물이나 기타 염에 비해 열에 대한 안정성이 현저히 우수하다고 기술하고 있다.In Korean Patent No. 0935904, various kinds of pharmaceutically acceptable salts have been prepared to solve such problems. In the process, 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.
그러나 베시포비르디피복실 말레산염은 100 ℃ 이상의 고온에서 매우 불안정하여 6시간 만에 대부분 분해되어 여전히 안정성에서 불충분하며, 접촉할 경우에 발적, 통증, 각막, 진무름까지 동반하는 중증 자극을 일으킬 수 있는 말레산의 특징으로 인하여 제조과정에서 결막염 또는 급성 노출의 경우와 유사한 증상이 생길 수 있어(식품의약품안전평가원 독성정보 자료 참조), 안전에 있어서도 주의를 요한다.However, 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).
본 발명의 일 과제는 독성 등의 문제가 없고, 100℃ 이상의 고온에서 열안정성을 나타내며 제조공정의 안전성, 용해도 및 보관 안정성이 개선된 베시포비르디피복실의 신규염을 제공하고자 한다.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 ℃ or more and improved safety, solubility and storage stability of the manufacturing process.
본 발명의 일 양태는 화학식 1로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트의 오로트산염(이하, 이를 '베시포비르디피복실 오로트산염'이라 한다)에 관한 것이다: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-3λ 5 -phosphanon-1-yl-pivalate (hereinafter referred to as besifovirdiphyxyl orotate) will be:
[화학식 1][Formula 1]
본 발명의 다른 양태는 화학식 2로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실)의 유리 화합물을 화학식 3으로 표시되는 오로트산(orotic acid)과 용매의 존재 하에 혼합하는 것을 포함하는 화학식 1의 베시포비르디피복실 오로트산염의 제조 방법에 관한 것이다: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). Orotic acid represented by the formula (3) as a free compound of, 7-dioxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshpovirdipixyl) And to a process for preparing besypovirdipicolic acid orotate of formula (I) comprising mixing in the presence of a solvent:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 1].[Formula 1].
본 발명의 또 다른 양태는 베시포비르디피복실의 오로트산염 및 약제학적으로 허용되는 부형제를 포함하는 바이러스 감염 치료 혹은 예방용 약제학적 조성물에 관한 것이다.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.
본 발명의 베시포비르디피복실 오로트산염은 빛, 온도 및 습도에 따른 안정성이 우수하며, 특히 기존에 안정하다고 알려진 베시포비르디피복실 말레산염이 분해되는 100℃ 이상의 높은 온도에서도 매우 우수한 열안정성을 나타낸다. 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.
본 발명의 베시포비르디피복실 오로트산염은 매우 우수한 안정성을 나타냄으로써 장기간 보존이 가능하며, 고온다습한 환경에서도 제제연구 및 보관이 용이하다는 장점을 가진다.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.
또한 본 발명의 베시포비르디피복실 오로트산염은 오로트산이 인체에 유해하지 않기 때문에 이의 제조 과정에서 작업자들이 안전하게 베시포비르디피복실 오로트산염을 제조할 수 있다.In addition, since the besipovirdiphyloxyl orotate of the present invention, orthoic acid is not harmful to the human body, workers can safely prepare the Besipovirdipicolic acid orotate.
본 발명에 따른 베시포비르디피복실 오로트산염의 제조 방법에 의해 제조된 베시포비르디피복실 오로트산염은 비교적 간단한 공정으로 매우 높은 순도, 예컨대 99 % 이상, 구체적으로는 99.5 % 이상, 보다 구체적으로는 99.9 % 이상의 순도를 갖는다.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%.
도 1은 본 발명의 베시포비르디피복실 오로트산염과 대조 화합물인 베시포비르디피복실 말레산염의 시간과 온도(100℃)에 따른 중량(%) 변화를 비교한 그래프이다. 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.
도 2는 실시예 1의 베시포비르디피복실 오로트산염의 시차주사열량도(Differential Scanning Calorimeter)를 나타낸 것이다.FIG. 2 shows the differential scanning calorimeter of the Besipovirdiphyxyl orotate of Example 1. FIG.
도 3은 비교예 1의 베시포비르디피복실 말레산염의 시차주사열량도(Differential Scanning Calorimeter)를 나타낸 것이다.FIG. 3 shows a differential scanning calorimeter of Besypovirdipicyl maleate of Comparative Example 1. FIG.
도 4는 실시예 1의 베시포비르디피복실 오로트산염의 분말 X-선 회절 분광도(Powder X-ray Diffraction pattern)를 나타낸 것이다.Figure 4 shows a powder X-ray diffraction pattern (Powder X-ray Diffraction pattern) of the Besipovir difficile orotate of Example 1.
도 5는 실시예 1의 베시포비르디피복실 오로트산염의 적외선 분광(FT-IR)을 나타낸 것이다.Figure 5 shows the infrared spectroscopy (FT-IR) of the Besipovirdiphyxyl orotate of Example 1.
도 6은 실시예 1의 베시포비르디피복실 오로트산염의 1H 핵자기 공명 스펙트럼(NMR)을 나타낸 것이다.FIG. 6 shows the 1 H nuclear magnetic resonance spectrum (NMR) of the besipovirdiphyxyl orotate of Example 1. FIG.
본 발명의 일 양태는 화학식 1로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트의 오로트산염(이하 이를 '베시포비르디피복실 오로트산염'이라 한다)에 관한 것이다: 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-3λ 5 -phosphanon-1-yl-pivalate (hereinafter referred to as besifovirdiphyxyl orotate) :
[화학식 1][Formula 1]
특히 베시포비르디피복실의 오로트산염은 결정성 고체일 수 있으며, 구체적으로 분말 X-선 회절 분석에서 2θ = 2.97°, 8.84°, 10.16°, 15.47° 및 19.94° ± 0.2°의 X선 회절피크를 특징으로 하는 결정형일 수 있다. 보다 구체적으로 분말 X-선 회절 분석에서 2θ = 2.97°, 5.86°, 8.84°, 10.16°, 11.33°, 11.67°, 15.47°, 16.57°, 17.17°, 18.09°, 19.94°, 23.96°, 25.14°, 26.41° 및 27.69° ± 0.2°에서 X선 회절피크를 특징으로 하는 결정형일 수 있다.In particular, the orotates of Besipovirdipisil may be crystalline solids, specifically X-ray diffraction of 2θ = 2.97 °, 8.84 °, 10.16 °, 15.47 ° and 19.94 ° ± 0.2 ° in powder X-ray diffraction analysis It may be a crystalline form characterized by a peak. More specifically, in powder X-ray diffraction analysis, 2θ = 2.97 °, 5.86 °, 8.84 °, 10.16 °, 11.33 °, 11.67 °, 15.47 °, 16.57 °, 17.17 °, 18.09 °, 19.94 °, 23.96 °, 25.14 ° , 26.41 ° and 27.69 ° ± 0.2 ° may be a crystalline form characterized by the X-ray diffraction peaks.
화학식 1로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실)의 오로트산염은 약 1몰 당량의 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트의 양이온 유리 화합물 및 약 1몰 당량의 오로트산 음이온으로 구성될 수 있다. 또한 베시포비르디피복실 오로트산의 융점은 179.0℃ 내지 182℃ 의 범위이다. 3-[({1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo- represented by Formula 1 Orotates of 2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshpovirdiphyxyl) have about 1 molar equivalent of 3-[({1-[(2-amino -9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ 5 -phosphanone-1- It may consist of a cation free compound of mono-pivalate and about 1 molar equivalent of an orotic acid anion. Moreover, melting | fusing point of Besipovirdiphyxyl orotic acid is the range of 179.0 degreeC-182 degreeC.
화학식 1의 베시포비르디피복실 오로트산염은 수분, 광, 고온(예: 100℃ 이상) 등의 가혹 조건에서도 분해되지 않아 안정성이 우수하여 항바이러스용 약제학적 조성물로 사용시 보관 조건에 무관하게 활성 성분이 분해되지 않아 약효를 유지할 수 있는 이점이 있다. 또한 화학식 1의 베시포비르디피복실 오로트산염은 이의 유리 화합물이나 기타 염에 비해 용해도와 안전성이 개선되는 이점이 있다. 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. In addition, 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.
위와 같은 베시포비르디피복실 오로트산염의 개선된 물리 화학적 안정성과 용해도로 인해 바이러스 감염의 예방을 위해 혹은 치료를 위해 유용하게 사용될 수 있다. 특히 베시포비르디피복실 오로트산염의 개선된 물리 화학적 안정성으로 인해, 상기 활성 성분을 포함하는 고체 약제학적 제형에 유리하게 사용될 수 있다.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.
베시포비르디피복실 오로트산염은 고순도, 예컨대 99 % 이상, 구체적으로는 99.5 % 이상, 보다 구체적으로는 99.9 % 이상의 순도, 예컨대 99.91 % 내지 99.98 %의 순도를 가질 수 있다.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%.
본 발명의 다른 양태는 화학식 1의 베시포비르디피복실의 오로트산염의 제조 방법에 관한 것으로, 상기 제조 방법은 베시포비르디피복실의 유리 화합물을 오로트산과 용매의 존재 하에 혼합하는 것을 포함한다. 상세하게는 화학식 2로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실)의 유리 화합물을 화학식 3으로 표시되는 오로트산과 용매의 존재하에 혼합하는 것을 포함하는, 화학식 1의 베시포비르디피복실 오로트산염의 제조 방법이 제공된다: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. . Specifically, 3-[({1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7- represented by Chemical Formula 2 Mixing a free compound of dioxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshfovirdipixyl) in the presence of a solvent and orotic acid represented by the formula (3) Provided is a process for preparing besypovirdipicolic acid orotate of Formula 1, comprising:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 1][Formula 1]
.
.
구체적으로 상기 제조 방법은 베시포비르디피복실의 유리 화합물과 오로트산염을 용매의 존재하에 혼합하고 이를 35℃ 내지 50 ℃의 온도 범위, 구체적으로 40℃ 내지 45℃에서 1분 내지 12시간 동안, 구체적으로는 1분 내지 6시간, 보다 구체적으로는 1분 내지 1시간 가온하고 15℃ 내지 30℃의 범위, 예컨대 20℃ 내지 25℃로 냉각함으로써 제조될 수 있다. 구체예에서 상기 제조 방법은 상기 냉각 후 수득된 고체를 여과하고 용매로 세척한 후 건조하는 단계를 추가로 포함할 수 있다.Specifically, 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 ℃ to 50 ℃, specifically 40 ℃ to 45 ℃ 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. In embodiments, the preparation method may further comprise the step of filtering the solid obtained after the cooling, washing with a solvent and drying.
베시포비르디피복실의 유리 화합물을 용매 1 ml 당 1 mg 내지 700 mg의 비율로 용해시키고, 여기에 오로트산염을 첨가하고 교반하면 베시포비르디피복실의 오로트산염이 생성될 수 있다. 염 생성에 사용될 수 있는 용매로는 예를 들어, 물, 메탄올, 에탄올, 프로판올, 이소프로판올, 사이클로헥산, 노말헥산, 디에틸에테르, 메틸에틸케톤, 테트라하이드로푸란, 아세톤 등을 사용할 수 있다. 첨가되는 오로트산염의 양은 베시포비르디피복실의 유리 화합물 1 당량을 기준으로 0.8 당량 내지 1.2 당량, 구체적으로는 0.9 당량 내지 1.1 당량, 보다 구체적으로는 약 1 당량을 사용할 수 있다. 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. As 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.
상기 방법에 의해 제조된 베시포비르디피복실의 오로트산염은 결정형 고체일 수 있다. 구체적으로 분말 X-선 회절 분석에서 2θ = 2.97°, 8.84°, 10.16°, 15.47° 및 19.94° ± 0.2°의 X선 회절피크를 특징으로 하는 결정형일 수 있다(도 4 참조). 보다 구체적으로, 분말 X-선 회절 분석에서 2θ= 2.97°, 5.86°, 8.84°, 10.16°, 11.33°, 11.67°, 15.47°, 16.57°, 17.17°, 18.09°, 19.94°, 23.96°, 25.14°, 26.41° 및 27.69° ± 0.2°에서 X선 회절피크를 특징으로 하는 결정형일 수 있다(도 4 참조). 시차주사 열량도(10℃/분)에서 상기 결정의 융용점 흡열 피크 시작점은 178.53℃이다(도 5 참조). Orotates of Besipovirdipicil prepared by the method may be crystalline solids. Specifically, in powder X-ray diffraction analysis, it may be a crystalline form characterized by X-ray diffraction peaks of 2θ = 2.97 °, 8.84 °, 10.16 °, 15.47 ° and 19.94 ° ± 0.2 ° (see FIG. 4). More specifically, 2θ = 2.97 °, 5.86 °, 8.84 °, 10.16 °, 11.33 °, 11.67 °, 15.47 °, 16.57 °, 17.17 °, 18.09 °, 19.94 °, 23.96 °, 25.14 in powder X-ray diffraction analysis Crystal form characterized by X-ray diffraction peaks at °, 26.41 ° and 27.69 ° ± 0.2 ° (see FIG. 4). The melting point endothermic peak starting point of the crystal in the differential scanning calorimetry (10 ° C / min) is 178.53 ° C (see Figure 5).
베시포비르디피복실 오로트산염에 의해 예방 또는 치료될 수 있는 질환은 바이러스 감염에 의한 질환이며, 예를 들어 HSV-1(Herpes simplex virus type 1), HSV-2(Herpes simplex virus type 2), 사이토메갈로바이러스, HBV(B형 간염 바이러스) 또는 HIV(인간 면역 결핍 바이러스) 등을 포함하나, 구체적으로는 HBV 또는 HIV 일 수 있다. Diseases that can be prevented or treated by Besifovirdiphyxyl orotate are those caused by viral infections, for example, Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Cytomegalovirus, hepatitis B virus (HBV) or human immunodeficiency virus (HIV), and the like, but may specifically be HBV or HIV.
따라서 본 발명의 또 다른 양태는 베시포비르디피복실의 오로트산염 및 약제학적으로 허용되는 부형제를 포함하는 약제학적 조성물이 제공된다. 상기 약제학적 조성물은 상기 바이러스 질환의 예방 또는 치료, 구체적으로 HBV 또는 HIV 감염의 예방 또는 치료에 특히 유용하다. 베시포비르디피복실의 오로트산염의 총 1일 투여 용량은 1 mg 내지 600 mg, 구체적으로는 1 mg 내지 300 mg, 보다 구체적으로는 100 mg 내지 200 mg의 범위일 수 있으나, 대상체의 체중, 나이, 질환의 중증도, 건강 상태 등에 따라 달라질 수 있다.Accordingly, 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.
베시포비르디피복실의 오로트산염을 포함하는 조성물은 주사용 제제 또는 경구용 제제로 투여될 수 있다.Compositions comprising orthotate of Besipovirdipicil may be administered in injectable or oral formulations.
주사용 제제, 예를 들어, 멸균 주사용 수성 또는 유성 현탁액으로 사용될 수 있으며, 상기 주사용 제제의 용매로는 물, 링거액 또는 등장성 NaCl 용액을 사용할 수 있다. 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.
경구용 제제로는 예를 들면, 정제, 캡슐제, 환제, 산제 등이 있고, 특히 정제 또는 캡슐제일 수 있다. 정제의 형태로 경구 투여하는 경우에 베시포비르디피복실의 오로트산염은 경구용의 비-독성이며 약제학적으로 허용되는 불활성 담체, 예를 들어 락토스, 전분, 수크로스, 글루코스, 메틸 셀룰로스, 마그네슘 스테아레이트, 인산이칼슘, 황산칼슘, 만니톨, 소르비톨 등과 혼합될 수 있으며, 액체 형태로 경구 투여되는 경우에 베시포비르디피복실의 오로트산염은 임의의 경구용이며 비-독성인 약제학적으로 허용되는 불활성 담체, 예를 들어 에탄올, 글리세롤, 물 등과 혼합될 수 있다. 더욱이 경우에 따라 또는 필요에 따라, 적당한 결합제, 윤활제, 붕해제 및 착색제가 혼합물 중에 혼입될 수 있다.Oral formulations include, for example, tablets, capsules, pills, powders, and the like, and in particular, may be tablets or capsules. When administered orally in the form of tablets, 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. Moreover, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can be incorporated into the mixture.
적합한 결합제로는 전분, 젤라틴, 천연 당류, 예컨대 글루코스 또는 베타-락토스, 옥수수 감미제, 천연 및 합성 검, 예컨대 아카시아, 트라가칸트 또는 나트륨 알기네이트, 카복시메틸셀룰로스, 폴리메틸셀룰로스, 폴리에틸렌 글리콜, 왁스 등이 포함된다. 상기 윤활제로는 나트륨 올레에이트, 나트륨 스테아레이트, 마그네슘 스테아레이트, 나트륨 벤조에이트, 나트륨 아세테이트, 염화나트륨 등이 포함된다. 붕해제로는 제한 없이 전분, 메틸 셀룰로스, 아가, 벤토니트, 크산탄 검 등이 포함된다.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.
본 발명의 또 다른 양태는 항바이러스 약물, 구체적으로 항 HBV 약물 또는 항 HIV 약물을 제조하는 데 있어서 베시포비르디피복실의 오로트산염의 용도를 제공한다.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.
본 발명의 또 다른 양태는 예방학적 또는 치료학적 유효량의 베시포비르디피복실의 오로트산염을 바이러스 감염, 구체적으로는 HBV 또는 HIV 감염 치료 또는 예방이 필요한 대상체에게 투여하는 것을 포함하는, 바이러스 질환을 예방 또는 치료하는 방법이 제공된다. 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.
이하 본 발명의 일 구현예를 하기 실시예와 실험예를 통해 보다 상세히 설명한다. 다만 이들 실시예와 실험예는 본 발명의 이해를 돕기 위한 것일 뿐 어떤 의미로든 본 발명의 범위를 제한하려는 의도가 있는 것은 아님을 분명히 밝히고자 한다. Hereinafter, an embodiment of the present invention will be described in more detail with reference to the following examples and experimental examples. However, these Examples and Experimental Examples are intended to make it clear that they are not intended to limit the scope of the present invention in any sense, only to help the understanding of the present invention.
실시예Example
실시예Example
1 : One :
베시포비르디피복실의Besipovir Difficile
오로트산염의Ororate
제조 Produce
2.0 g의 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸] -8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트 (베시포비르디피복실)를 40 mL의 메탄올에 가하여 용해시키고, 이어서 0.62 g의 오로트산과 60 mL의 물을 첨가하였다. 40 ~ 45℃ 에서 30분간 가온 교반한 뒤 상온으로 냉각하여 2시간 동안 교반하였다. 수득한 고체를 여과하여 메탄올과 물로 세척한 후 건조하여 2.21 g의 베시포비르디피복실 오로트산염을 얻었다. (수율: 85.3 %, 순도: 99.96 %) 2.0 g of 3-[({1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo-2, 4,6-Trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshpovirdipicil) was added to 40 mL of methanol to dissolve, followed by addition of 0.62 g of orotic acid and 60 mL of water. . After 30 minutes warm stirring at 40 ~ 45 ℃ cooled to room temperature and stirred for 2 hours. The obtained solid was filtered, washed with methanol and water and dried to 2.21 g of Besifobivir dipsil Orotates were obtained. (Yield 85.3%, Purity: 99.96%)
1H NMR(400MHz, DMSO-d6) : δ 11.32(s, 1H), 10.84(s, 1H), 8.60(s, 1H), 8.13(s, 1H), 6.56(s, 2H), 5.99(d, 1H), 5.55~5.59(d, 4H), 4.25(s, 2H), 4.11~4.13(d, 2H), 1.13(s, 18H), 0.89~0.90(d, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.32 (s, 1H), 10.84 (s, 1H), 8.60 (s, 1H), 8.13 (s, 1H), 6.56 (s, 2H), 5.99 ( d, 1H), 5.55 to 5.59 (d, 4H), 4.25 (s, 2H), 4.11 to 4.13 (d, 2H), 1.13 (s, 18H), 0.89 to 0.90 (d, 4H)
실시예Example
2: 2:
베시포비르디피복실의Besipovir Difficile
오로트산염의Ororate
제조 Produce
2.0 g의 베시포비르디피복실과 0.62 g의 오로트산에 60 mL의 물을 첨가하였다. 40 ~ 45℃에서 4시간 30분간 가온 교반한 뒤 상온으로 냉각하여 1일 교반하였다. 수득한 고체를 여과하여 물로 세척한 후 건조하여 2.42 g의 베시포비르디피복실 오로트산염을 얻었다. (수율: 93.4 %, 순도: 99.92 %)60 mL of water was added to 2.0 g of Besiforivir dipoxyl and 0.62 g of orotic acid. After stirring for 4 hours and 30 minutes at 40 ~ 45 ℃ and cooled to room temperature and stirred for 1 day. The obtained solid was filtered, washed with water and dried to obtain 2.42 g of Besifobivirdioxyl orotate. (Yield 93.4%, Purity: 99.92%)
비교예Comparative example
비교예Comparative example
1: One:
베시포비르디피복실의Besipovir Difficile
말레산염의Maleic
제조 Produce
대한민국 특허 등록 제0935904호의 실시예 3에 기재된 방법에 따라, 1 g의 베시포비르디피복실을 에틸아세테이트 10 ml에 녹인 후 1 당량의 말레산을 첨가하고 한 시간 동안 교반하여 고체를 생성하였다. 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 순도 99.89 %의 베시포비르디피복실 말레산염을 수득하였다. In accordance with the method described in 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%.
비교예Comparative example
2: 2:
베시포비르디피복실의Besipovir Difficile
푸마르산 Fumaric acid
이염의Otitis
제조 Produce
1.0 g의 베시포비르디피복실과 0.46 g의 푸마르산을 10 mL의 메탄올에 가하여 용해시킨 뒤 1시간 동안 상온교반하였다. 반응액을 감압농축한 뒤 에틸아세테이트와 MTBE(Methyl tert-butyl ether, 메틸 터트-부틸 에테르)를 첨가하여 고체를 석출시켰다. 수득한 고체를 여과하여 MTBE로 세척한 후 건조하여 1.16 g의 베시포비르디피복실 푸마르산 이염을 얻었다. (수율: 80.6 %, 순도: 99.84 %)1.0 g of Besipovirdipicil and 0.46 g of fumaric acid were added to 10 mL of methanol to dissolve and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and MTBE (Methyl tert-butyl ether, methyl tert-butyl ether) were added to precipitate a solid. The obtained solid was filtered, washed with MTBE, and dried to obtain 1.16 g of besypovirdipican fumaric acid dichloride. (Yield 80.6%, Purity: 99.84%)
1H NMR(400MHz, DMSO-d6) : δ 8.57(s, 1H), 8.10(s, 1H), 6.63~6.23(d, 4H), 6.46(s, 2H), 5.55~5.58(d, 4H), 4.24(s, 2H), 4.10~4.13(d, 2H), 1.13(s, 18H), 0.89~0.90(d, 4H) 1 H NMR (400MHz, DMSO-d 6 ): δ 8.57 (s, 1H), 8.10 (s, 1H), 6.63 ~ 6.23 (d, 4H), 6.46 (s, 2H), 5.55 ~ 5.58 (d, 4H ), 4.24 (s, 2H), 4.10-4.13 (d, 2H), 1.13 (s, 18H), 0.89-0.90 (d, 4H)
비교예Comparative example
3: 3:
베시포비르디피복실의Besipovir Difficile
피콜린산염의Picolinate
제조 Produce
1.0 g의 베시포비르디피복실과 0.26 g의 피콜리닉산을 10 mL의 메탄올에 가하여 용해시킨 뒤 1시간 동안 상온교반하였다. 반응액을 감압농축한 뒤 에틸아세트산과 헵탄을 첨가하여 고체를 석출시켰다. 수득한 고체를 여과하여 헵탄으로 세척한 후 건조하여 1.04 g의 베시포비르디피복실 피콜린산염을 얻었다. (수율: 83.9 %, 순도: 99.76 %)1.0 g of Besipovirdipicil and 0.26 g of picolinic acid were added and dissolved in 10 mL of methanol, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate and heptane were added to precipitate a solid. The obtained solid was filtered off, washed with heptane and dried to obtain 1.04 g of Besibovirdipicil picolinate. (Yield 83.9%, Purity: 99.76%)
1H NMR(400MHz, DMSO-d6) : δ 8.70~8.71(m, 1H), 8.57(s, 1H), 8.10(s, 1H), 8.03~8.06(m, 1H), 7.96~8.00(m, 1H), 7.61~7.64(m, 1H), 6.46(s, 2H), 5.55~5.59(d, 4H), 4.24(s, 2H), 4.11~4.13(d, 2H), 1.13(s, 18H), 0.89~0.90(d, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.70-8.71 (m, 1H), 8.57 (s, 1H), 8.10 (s, 1H), 8.03-8.06 (m, 1H), 7.96-8.00 (m , 1H), 7.61-7.74 (m, 1H), 6.46 (s, 2H), 5.55-5.59 (d, 4H), 4.24 (s, 2H), 4.11-4.13 (d, 2H), 1.13 (s, 18H ), 0.89-0.90 (d, 4H)
비교예Comparative example
4: 4:
베시포비르디피복실의Besipovir Difficile
N,NN, N
-디메틸글라이신 -Dimethylglycine
이염의Otitis
제조 Produce
1.0 g의 베시포비르디피복실과 0.22 g의 N,N-디메틸글라신을 3 mL의 메탄올에 가하여 용해시킨 뒤 3시간 동안 상온교반하였다. 반응액을 감압농축한 뒤 에틸아세트산과 헵탄을 첨가하여 고체를 석출시켰다. 수득한 고체를 여과하여 헵탄으로 세척한 후 건조하여 0.63 g의 베시포비르디피복실 N,N-디메틸글라이신 이염을 얻었다. (수율: 63.0 %, 순도: 99.76 %)1.0 g of Besipovirdipicil and 0.22 g of N, N -dimethylglycine were added to 3 mL of methanol to dissolve, followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate and heptane were added to precipitate a solid. The obtained solid was filtered, washed with heptane and dried to obtain 0.63 g of Besifobivirdicarboxyl N, N -dimethylglycine dichloride. (Yield 63.0%, Purity: 99.76%)
1H NMR(400MHz, DMSO-d6) : δ 8.56(s, 1H), 8.09(s, 1H), 6.45(s, 2H), 5.54~5.58(d, 4H), 4.24(s, 2H), 4.10~4.12(d, 2H), 3.24(s, 4H), 2.60(s, 12H), 1.12(s, 18H), 0.88~0.89(d, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.56 (s, 1H), 8.09 (s, 1H), 6.45 (s, 2H), 5.54 ~ 5.58 (d, 4H), 4.24 (s, 2H), 4.10 ~ 4.12 (d, 2H), 3.24 (s, 4H), 2.60 (s, 12H), 1.12 (s, 18H), 0.88 ~ 0.89 (d, 4H)
비교예Comparative example
5: 5:
베시포비르디피복실의Besipovir Difficile
인산염의 제조 Preparation of Phosphate
1.0 g의 베시포비르디피복실을 5 mL의 이소프로필알코올에 용해시킨 뒤 0.13 mL의 인산을 천천히 적가하였다. 상온에서 1시간 동안 교반한 뒤, 수득한 고체를 여과하여 이소프로필알코올로 세척한 후 건조하여 1.12 g의 베시포비르디피복실 인산염을 얻었다. (수율: 94.0 %, 순도: 99.83 %)1.0 g of Besipovirdipicil was dissolved in 5 mL of isopropyl alcohol and 0.13 mL of phosphoric acid was slowly added dropwise. After stirring for 1 hour at room temperature, the obtained solid was filtered, washed with isopropyl alcohol, and dried to obtain 1.12 g of Besifobivirdicarboxyl phosphate. (Yield 94.0%, Purity: 99.83%)
1H NMR(400MHz, DMSO-d6) : δ 8.57(s, 1H), 8.10(s, 1H), 6.47(s, 2H), 5.55~5.58(d, 4H), 4.24(s, 2H), 4.10~4.12(d, 2H), 1.12(s, 18H), 0.88~0.90(d, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.57 (s, 1H), 8.10 (s, 1H), 6.47 (s, 2H), 5.55 ~ 5.58 (d, 4H), 4.24 (s, 2H), 4.10 ~ 4.12 (d, 2H), 1.12 (s, 18H), 0.88 ~ 0.90 (d, 4H)
비교예Comparative example
6: 6:
베시포비르디피복실의Besipovir Difficile
브롬산염의 제조 Preparation of Bromate
3.0 g의 베시포비르디피복실을 15 mL의 에틸아세테이트에 용해시킨 뒤 0.65 mg의 브롬화수소를 가하였다. 상온에서 1시간 동안 교반한 뒤, 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 3.39 g의 베시포비르디피복실 브롬산염을 얻었다. (수율: 98.0 %, 순도: 99.83 %)3.0 g of Besipovirdiphyxyl was dissolved in 15 mL of ethyl acetate and 0.65 mg of hydrogen bromide was added. After stirring for 1 hour at room temperature, the obtained solid was filtered, washed with ethyl acetate and dried to obtain 3.39 g of Besypovirdipicil bromate. (Yield 98.0%, Purity: 99.83%)
1H NMR(400MHz, DMSO-d6) : δ 8.96(s, 1H), 8.57(s, 1H), 7.82(br, 2H), 5.54~5.58(d, 4H), 4.31(s, 2H), 4.12~4.15(d, 2H), 1.13(s, 18H), 0.93(s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.96 (s, 1H), 8.57 (s, 1H), 7.82 (br, 2H), 5.54 ~ 5.58 (d, 4H), 4.31 (s, 2H), 4.12-4.15 (d, 2H), 1.13 (s, 18H), 0.93 (s, 4H)
비교예Comparative example
7: 7:
베시포비르디피복실의Besipovir Difficile
황산염의 제조 Preparation of Sulfate
3.0 g의 베시포비르디피복실을 18 mL의 에틸아세테이트에 용해시킨 뒤 0.3 mL의 황산을 적가하였다. 상온에서 2시간 동안 교반한 뒤, 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 3.49 g의 베시포비르디피복실 황산염을 얻었다. (수율: 98.0 %, 순도: 99.83 %)3.0 g of Besipovirdiphyxyl was dissolved in 18 mL of ethyl acetate and 0.3 mL of sulfuric acid was added dropwise. After stirring for 2 hours at room temperature, the obtained solid was filtered, washed with ethyl acetate and dried to obtain 3.49 g of Besypovirdipican sulfate. (Yield 98.0%, Purity: 99.83%)
1H NMR(400MHz, DMSO-d6) : δ 8.96(s, 1H), 8.56(s, 1H), 7.84(br, 2H), 5.55~5.58(d, 4H), 4.31(s, 2H), 4.13~4.15(d, 2H), 1.13(s, 18H), 0.93(s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.96 (s, 1H), 8.56 (s, 1H), 7.84 (br, 2H), 5.55 ~ 5.58 (d, 4H), 4.31 (s, 2H), 4.13-4.15 (d, 2H), 1.13 (s, 18H), 0.93 (s, 4H)
비교예Comparative example
8: 8:
베시포비르디피복실의Besipovir Difficile
염산염 이수화물의 제조 Preparation of Hydrochloride Dihydrate
3.0 g의 베시포비르디피복실을 27 mL의 에틸아세테이트에 용해시킨 뒤 0.48 mL의 염산을 적가하였다. 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 3.03 g의 베시포비르디피복실 염산염 이수화물을 얻었다. (수율: 88.9 %, 순도: 99.93 %)3.0 g of Besipovirdiphyxyl was dissolved in 27 mL of ethyl acetate and 0.48 mL of hydrochloric acid was added dropwise. The obtained solid was filtered, washed with ethyl acetate and dried to obtain 3.03 g of besypovirdipicil hydrochloride dihydrate. (Yield 88.9%, Purity: 99.93%)
1H NMR(400MHz, DMSO-d6) : δ 9.01(s, 1H), 8.58(s, 1H), 8.05(br, 2H), 5.55~5.58(d, 4H), 4.31(s, 2H), 4.13~4.15(d, 2H), 1.12(s, 18H), 0.93(s, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.01 (s, 1H), 8.58 (s, 1H), 8.05 (br, 2H), 5.55 ~ 5.58 (d, 4H), 4.31 (s, 2H), 4.13-4.15 (d, 2H), 1.12 (s, 18H), 0.93 (s, 4H)
상기 실시예 및 비교예 및 하기 실험예에서 화합물의 각 중량은 고성능 액상 크로마토그래피(HPLC)로 측정하였으며, Waters 사의 Alliance 2965 series를 사용하였다. 또한 시차주사열량도(Differential Scanning Calorimeter)의 측정은 TA사의 DSC Q20을 사용하였으며, 분말 X-선 회절 분광 스펙트럼(Powder X-ray Diffraction Spectrum)은 Bruker사의 D8 ADVANCE를 사용하여 측정하였다. 적외선 흡수 스펙트럼(InfraRed Spectrum)은 JASCO사 FT-IR 4100 spectrum을 사용하여 측정하였으며, 1H 핵자기 공명 스펙트럼(NMR)은 Bruker사의 AVANCE II 400(400 MHz)을 사용하여 측정하였다. In the above Examples, Comparative Examples and Experimental Examples, the weight of each compound was measured by high performance liquid chromatography (HPLC), and an Alliance 2965 series from Waters was used. Differential Scanning Calorimeter was measured using DSC Q20 from TA, and Powder X-ray Diffraction Spectrum was measured using Bruker's D8 ADVANCE. InfraRed Spectrum was measured using JASCO's FT-IR 4100 spectrum, and the 1 H nuclear magnetic resonance spectrum (NMR) was measured using Bruker's AVANCE II 400 (400 MHz).
또한 본원에서 분말 X-선 회절 분석 조건은 다음과 같다:In addition, the powder X-ray diffraction analysis conditions herein are as follows:
약 50 mg의 시료를 시료 홀더에 채워 2-50°/2θ의 범위에서 회절 About 50 mg of sample is filled into the sample holder and diffracted in the range of 2-50 ° / 2θ
패턴을 얻었다. 자세한 분석 조건은 아래와 같다:A pattern was obtained. Detailed analysis conditions are as follows:
Time per step : 0.1Time per step: 0.1
Stepsize : 0.02Stepsize: 0.02
Scan Mode : continuous scanScan Mode: continuous scan
Voltage/Current : 40 kV/ 40 mVVoltage / Current: 40 kV / 40 mV
2θ/θ Refection2θ / θ Refection
Cu-target (Ni-filter)Cu-target (Ni-filter)
Source Slit : 1.0 mmSource Slit: 1.0 mm
Detector slits : 8.0 mmDetector slits: 8.0 mm
실험예Experimental Example
실험예 1 : 고체 상태의 가속 안정성 비교 실험 1 Experimental Example 1 Comparative Experiment 1 of Acceleration Stability in Solid State
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1 내지 비교예 8에서 수득한 베시포비르디피복실의 기타염들의 시료를 각각 10 mg ~ 50 mg씩 유리 용기에 넣고 40 ± 2℃, 75 ± 5 % RH의 조건하에서 보관하였다. 1주, 2주 및 4주 후에 시료를 5 mg씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 1에 나타내었다. 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.
| 시험 화합물Test compound | 초기Early |
1주1 |
2주2 |
4주4 Weeks | |
| 실시예 1Example 1 | 오로트산염Orotates | 99.9699.96 | 99.9699.96 | 99.9599.95 | 99.9499.94 |
| 비교예 1Comparative Example 1 | 말레산염Maleate | 99.8999.89 | 99.8999.89 | 99.8999.89 | 99.8999.89 |
| 비교예 2Comparative Example 2 | 푸마르산 이염Fumaric acid dichloride | 99.8499.84 | 99.7699.76 | 99.6999.69 | 99.5499.54 |
| 비교예 3Comparative Example 3 | 피콜린산염Picolinate | 99.7699.76 | 99.6799.67 | 99.3999.39 | 98.4498.44 |
| 비교예 4Comparative Example 4 | N,N-디메틸글라이신 이염 N, N -dimethylglycine dichloride | 99.6799.67 | 99.6799.67 | 99.6499.64 | 99.5899.58 |
| 비교예 5Comparative Example 5 | 인산염phosphate | 99.8399.83 | 99.7399.73 | 99.6399.63 | 99.4499.44 |
| 비교예 6Comparative Example 6 | 브롬산염Bromate | 99.8399.83 | 99.2099.20 | 98.6698.66 | 97.8297.82 |
| 비교예 7Comparative Example 7 | 황산염sulfate | 99.8399.83 | 97.9097.90 | 95.7495.74 | 86.2386.23 |
| 비교예 8Comparative Example 8 | 염산염 이수화물Hydrochloride dihydrate | 99.9399.93 | 99.6999.69 | 99.5899.58 | 99.3399.33 |
상기 표 1의 가속시험(40℃ / 75 % RH, 4주) 결과를 보면, 베시포비르디피복실의 염들 중에서 오로트산염만 중량이 99.9 % 이상으로 거의 유지되는 것을 확인할 수 있다. 즉 베시포비르디피복실 오로트산염이 비교예 1 내지 8에서 수득한 다른 염들에 비해 고온 및 고습 조건에서의 안정성이 보다 높았다. Looking at the results of the accelerated test (40 ℃ / 75% RH, 4 weeks) of Table 1, it can be seen that only the orotates in the salt of Besipovir difficile is almost maintained at 99.9% or more. That is, the Besipobivirdioxyl orotate was more stable at high temperature and high humidity conditions than the other salts obtained in Comparative Examples 1 to 8.
실험예Experimental Example
2: 고체 상태의 가혹 안정성 비교 실험 2 2: Comparative Experimental Stability of Solid State 2
비교예 1에서 수득한 베시포비르디피복실 말레산염과 실시예 1에서 수득한 오로트산염을 약 10 ~ 15 mg씩 여러 개의 유리 용기에 넣고 60℃, 80℃ 및 100 ℃에 각각 보관하였다. 1주, 2주, 4주 및 8주 후 또는 24시간 및 48시간 후에 시료를 5 mg씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 2, 표 3 및 표 4에 나타내었다. 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.
|
시험 화합물 |
60 ℃60 ℃ | ||||
| 초기Early |
1주1 |
2주2 |
4주4 |
8주8 Weeks | |
| 비교예 1(말레산염)Comparative Example 1 (maleate) | 99.8999.89 | 99.8999.89 | 99.8699.86 | 99.8599.85 | 99.8199.81 |
| 실시예 1(오로트산염)Example 1 (Orotate) | 99.9699.96 | 99.9399.93 | 99.9299.92 | 99.9099.90 | 99.8999.89 |
| 시험 화합물Test compound | 초기Early |
80 ℃80 |
|
|
24시간24 |
48시간48 hours | ||
| 비교예 1(말레산염)Comparative Example 1 (maleate) | 99.8999.89 | 99.8899.88 | 99.8399.83 |
| 실시예 1(오로트산염)Example 1 (Orotate) | 99.9699.96 | 99.9399.93 | 99.9099.90 |
| 시험 화합물Test compound | 초기Early |
100 ℃100 |
||||
|
1시간1 |
3시간3 |
6시간6 |
24시간24 |
48시간48 hours | ||
| 비교예 1(말레산염)Comparative Example 1 (maleate) | 99.8999.89 | 98.8898.88 | 83.4083.40 | 1.551.55 | 1.551.55 | 0.530.53 |
| 실시예 1(오로트산염)Example 1 (Orotate) | 99.9699.96 | 99.9699.96 | 99.9299.92 | 99.8999.89 | 99.8599.85 | 99.7599.75 |
상기 표 2와 표 3의 결과를 보면, 60℃와 80℃ 에서는 베시포비르디피복실 오로트산염과 말레산염이 거의 동등한 열안정성을 나타냄을 확인할 수 있다. 하지만 100℃ 이상의 고온(표 4 참조)에서는 6시간 후 말레산염이 대부분 분해되어 거의 남지 않는 것에 비해 오로트산염은 거의 분해되지 않기 때문에 본 발명의 오로트산염이 월등히 우수한 열안정성을 가지고 있음을 확인할 수 있다. 즉 본 발명의 베시포비르디피복실 오로트산염은 밀링 등 가공 또는 기타 가혹한 환경에서도 유연물질의 생성을 최소화할 수 있고, 이로써 다양한 제제 기술을 활용한 약물개발이 가능한 장점을 가진다.Looking at the results of Tables 2 and 3, it can be seen that at 60 ° C and 80 ° C, the Besipobivirdioxyl orotate and maleate show almost equal thermal stability. However, at a high temperature of 100 ° C. or higher (see Table 4), after 6 hours, maleic acid is mostly decomposed and little orolate is hardly decomposed, so the orotate of the present invention has excellent thermal stability. Can be. That is, 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.
실험예Experimental Example
3: 융점 측정 3: melting point measurement
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1의 베시포비르디피복실 말레산염의 융점 측정 및 DSC(시차주사열량계)를 이용한 열분석을 각각 실시하였다.Melting point measurement and the thermal analysis using differential scanning calorimetry (DSC) of the Besipovirdiphyxyl orotate of Example 1 and the Besipovirdiphyxyl maleate of Comparative Example 1 were carried out, respectively.
1) 모세관법 융점 측정1) Capillary Melting Point Measurement
SRS MPA100을 사용하여 각 샘플을 10℃/분의 속도로 가열하면서 융점을 측정하였고, 그 결과를 하기 표 5에 나타내었다.Melting points were measured while heating each sample at a rate of 10 ° C./min using SRS MPA100, and the results are shown in Table 5 below.
| 실시예 1(오로트산염)Example 1 (Orotate) | 비교예 1(말레산염)Comparative Example 1 (maleate) | |
| 1회1 time | 163.4 ℃163.4 ℃ |
125.1 ℃125.1 |
| 2회Episode 2 | 162.3 ℃162.3 ℃ | 124.8 ℃124.8 ℃ |
| 3회3rd time | 162.6 ℃162.6 ℃ | 125.1 ℃125.1 ℃ |
| 평균치Average | 162.8 ℃162.8 ℃ | 125.0 ℃125.0 ℃ |
2) DSC(시차주사열량계)를 이용한 열분석2) Thermal analysis using differential scanning calorimeter
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1의 베시포비르디피복실 말레산염에 대해 TA사의 DSC Q20을 이용하여 각 샘플을 상온에서 200 내지 250℃까지 10℃ /분의 속도로 가열하여 분석하였고, 그 결과를 도 2(실시예 1의 베시포비르디피복실 오로트산염) 및 도 3(비교예 1의 베시포비르디피복실 말레산염)에 각각 나타내었다Each sample was subjected to TAB's DSC Q20 for the Besifovirdiphyxyl Orotate of Example 1 and to the Besifovirdiphyxyl Maleate of Comparative Example 1 at a rate of 10 ° C / min from room temperature to 200 to 250 ° C. The analysis was carried out by heating, and the results are shown in FIGS. 2 (Beshpovirdiphyxyl ororate salt of Example 1) and FIG. 3 (Beshpovirdiphyxyl maleate salt of Comparative Example 1), respectively.
상기의 표 5, 도 2 및 도 3의 결과를 통하여 본 발명의 베시포비르디피복실 오로트산염은 베시포비르디피복실 말레산염보다 융점이 더 높음을 확인할 수 있다.Through the results of Table 5, Figure 2 and Figure 3 it can be confirmed that the besypovirdipicil orotate of the present invention has a higher melting point than the Besifovirdipicil maleate.
실험예Experimental Example
4: 4:
광안정성Light stability
시험 exam
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1의 베시포비르디피복실 말레산염을 각각 100 mg씩 투명한 유리용기에 넣어 광안정성 챔버에서 광원에 노출시킨 채로 3일 동안 보관하였다. 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.
광안정성 측정기는 CARON Photostability Chamber Model 6545을 사용하였으며, 광노출양은 전체 조명(Overall illumination)이 240만 lux-hr/m2, 근자외선(Near UV)가 330 Wㆍhr/m2이다. 광원에 노출시킨 뒤 3일 후, 각각의 시료를 5 mg씩 취하여 HPLC를 이용하여 분석하였고, 그 결과를 하기 표 6에 나타내었다.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.
| 시험 화합물Test compound | 초기Early | 3일 후3 days later |
| 실시예 1(오로트산염)Example 1 (Orotate) | 99.9699.96 | 99.9699.96 |
| 비교예 1(말레산염)Comparative Example 1 (maleate) | 99.8999.89 | 99.8999.89 |
상기의 결과로부터 베시포비르디피복실 오로트산염은 빛에 노출되어도 광분해산물이 전혀 발생하지 않아서 베시포비르디피복실 말레산염과 동등하게 우수한 광안정성을 가지고 있음을 확인할 수 있다.From the above results, it can be seen that the besypovirdiphyxyl ororate does not generate any photodegradation products even when exposed to light, and thus has excellent photostability on par with besypovirdipicyl maleate.
실험예Experimental Example
5: 흡습성 시험 5: hygroscopic test
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1의 베시포비르디피복실 말레산염을 각각 1 g씩 25℃에서 상대습도 60 %와 92 % 챔버에 각각 7일간 보관한 후, 흡습에 의한 중량변화를 관찰하여 표 7에 나타내었다.1 g each of the Besifovirdiphyxyl Orotate of Example 1 and the Besifovirdiphyxyl Maleate of Comparative Example 1 were stored in a 60% and 92% chamber at 25 ° C. for 7 days, and then To observe the change in weight is shown in Table 7.
|
시험 화합물 |
60 % RH60% RH | 92 % RH92% RH |
| 실시예 1(오로트산염)Example 1 (Orotate) | -0.22-0.22 | -0.22-0.22 |
| 비교예 1(말레산염)Comparative Example 1 (maleate) | -0.33-0.33 | +0.06+0.06 |
상기의 결과로부터 오로트산염은 말레산에 비해 흡습성을 더욱 나타내지 않는다는 것을 알 수 있다. 이는 베시포비르디피복실 오로트산염이 공기 중 수분에 노출되더라도 안전하다는 것을 나타낸다. From the above results, it can be seen that ororate does not exhibit more hygroscopicity than maleic acid. This indicates that Besipovirdiphyloxy ororate is safe even when exposed to moisture in the air.
Claims (15)
- 화학식 1로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실)의 오로트산염:3-[({1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo- represented by Formula 1 Orotates of 2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshpovirdiphyxyl):[화학식 1][Formula 1]..
- 제1항에 있어서, 결정성 고체인 것을 특징으로 하는 베시포비르디피복실 오로트산염. The Besipovirdiphyxyl orotate of Claim 1 which is a crystalline solid.
- 제2항에 있어서, 분말 X-선 회절 분석에서 2θ = 2.97°, 8.84°, 10.16°, 15.47° 및 19.94°의 X선 회절피크를 갖는 것을 특징으로 하는 베시포비르디피복실 오로트산염. 3. Bepsifovirdiphyxyl orotate according to claim 2, which has an X-ray diffraction peak of 2θ = 2.97 °, 8.84 °, 10.16 °, 15.47 ° and 19.94 ° in powder X-ray diffraction analysis.
- 제3항에 있어서, 분말 X-선 회절 분석에서 2θ = 2.97°, 5.86°, 8.84°, 10.16°, 11.33°, 11.67°, 15.47°, 16.57°, 17.17°, 18.09°, 19.94°, 23.96°, 25.14°, 26.41° 및 27.69°에서 X선 회절피크를 특징으로 하는 베시포비르디피복실 오로트산염.The method according to claim 3, wherein in the powder X-ray diffraction analysis, 2θ = 2.97 °, 5.86 °, 8.84 °, 10.16 °, 11.33 °, 11.67 °, 15.47 °, 16.57 °, 17.17 °, 18.09 °, 19.94 °, 23.96 ° Besifobivirdioxyl orotate characterized by X-ray diffraction peaks at 25.14 °, 26.41 ° and 27.69 °.
- 제1항 내지 제4항 중 어느 하나의 항에 있어서, 베시포비르디피복실 오로트산염은 99 % 이상의 순도를 갖는 베시포비르디피복실 오로트산염.5. The Bepsifovirdicarboxyl orotate according to claim 1, wherein the Besipovirdipicoryl Orotate has a purity of at least 99%.
- 화학식 2로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실)의 유리 화합물을 화학식 3으로 표시되는 오로트산과 용매 존재하에 혼합하는 것을 포함하는, 화학식 1의 베시포비르디피복실 오로트산염의 제조 방법:3-[({1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo- represented by Formula 2 A chemical formula comprising mixing a free compound of 2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshpovirdipicil) in the presence of a solvent with orotic acid represented by formula (3) 1, Method of Preparation of Besifovirdiphyloxy Orotate:[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 1][Formula 1]..
- 제6항에 있어서, 상기 혼합 후 35℃ 내지 50℃의 온도 범위로 1분 내지 12시간 동안 가온하고 이후 15℃ 내지 30℃의 범위로 냉각하는 것을 추가로 포함하는 제조 방법.The method of claim 6, further comprising warming for 1 minute to 12 hours in the temperature range of 35 ° C. to 50 ° C. after the mixing and then cooling to a range of 15 ° C. to 30 ° C. 8.
- 제6항에 있어서, 상기 용매가 물, 메탄올, 에탄올, 프로판올, 이소프로판올, 사이클로헥산, 노말헥산, 디에틸에테르, 메틸에틸케톤, 테트라하이드로푸란 및 아세톤으로 이루어진 군으로부터 하나 이상 선택된 제조 방법.7. A process according to claim 6 wherein said solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, cyclohexane, normal hexane, diethyl ether, methyl ethyl ketone, tetrahydrofuran and acetone.
- 제6항에 있어서, 상기 제조된 화학식 1의 베시포비르디피복실 오로트산염이 결정성 고체인 제조 방법.7. The process according to claim 6, wherein the prepared Besipovirdipicoryl Orotate of Formula 1 is a crystalline solid.
- 화학식 1로 표시되는 3-[({1-[(2-아미노-9H-퓨린-9-일)메틸]사이클로프로필}옥시)메틸]-8,8-디메틸-3,7-디옥소-2,4,6-트리옥사-3λ5-포스파논-1-일-피발레이트(베시포비르디피복실)의 오로트산염 및 약제학적으로 허용되는 부형제를 포함하는 바이러스 감염 치료 혹은 예방용 약제학적 조성물: 3-[({1-[(2-amino-9 H -purin-9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo- represented by Formula 1 Pharmaceuticals for the treatment or prophylaxis of viral infections comprising orotates of 2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (Beshpovirdiphyxyl) and pharmaceutically acceptable excipients Composition:[화학식 1][Formula 1]..
- 제10항에 있어서, 상기 베시포비르디피복실 오로트산염이 결정성 고체인 약제학적 조성물.The pharmaceutical composition of claim 10, wherein the Besipovirdiphyxyl orotate is a crystalline solid.
- 제10항에 있어서, 상기 바이러스가 HSV-1, HSV-2, 사이토메갈로바이러스, HBV 또는 HIV 인 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 10, wherein the virus is HSV-1, HSV-2, cytomegalovirus, HBV or HIV.
- 제12항에 있어서, 상기 바이러스가 HBV 또는 HIV 인 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 12, wherein the virus is HBV or HIV.
- 제12항에 있어서, 베시포비르디피복실 오로트산염의 총 1일 투여 용량은 1 mg 내지 600 mg인 약제학적 조성물.13. The pharmaceutical composition of claim 12, wherein the total daily dose of bepsifovirdipicol ororate is between 1 mg and 600 mg.
- 제10항 내지 제14항 중 어느 하나의 항에 있어서, 캡슐제 또는 정제의 투여 형태인 약제학적 조성물.The pharmaceutical composition according to any one of claims 10 to 14, which is a dosage form of a capsule or tablet.
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| 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 (en) * | 2007-01-17 | 2010-01-07 | 주식회사 엘지생명과학 | A maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same |
| KR20110095545A (en) * | 2010-02-19 | 2011-08-25 | 주식회사 셀트리온화학연구소 | (s)-rivastigmine orotate and pharmaceutical composition including the same |
| KR101597338B1 (en) * | 2009-09-04 | 2016-02-24 | 탁티칼 떼라페우틱스 인크. | Novel compositions and processes for preparing 5-amino or substituted amino 1,2,3-triazoles and triazole orotate formulations |
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| 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 (en) * | 2007-01-17 | 2010-01-07 | 주식회사 엘지생명과학 | A maleic acid monosalt of antiviral agent and pharmaceutical composition containing the same |
| KR101597338B1 (en) * | 2009-09-04 | 2016-02-24 | 탁티칼 떼라페우틱스 인크. | Novel compositions and processes for preparing 5-amino or substituted amino 1,2,3-triazoles and triazole orotate formulations |
| KR20110095545A (en) * | 2010-02-19 | 2011-08-25 | 주식회사 셀트리온화학연구소 | (s)-rivastigmine orotate and pharmaceutical composition including the same |
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