KR102623581B1 - Orotic acid salt of antiviral agent, a method for preparing the salt and pharmaceutical composition comprising the salt - Google Patents
Orotic acid salt of antiviral agent, a method for preparing the salt and pharmaceutical composition comprising the salt Download PDFInfo
- Publication number
- KR102623581B1 KR102623581B1 KR1020160090800A KR20160090800A KR102623581B1 KR 102623581 B1 KR102623581 B1 KR 102623581B1 KR 1020160090800 A KR1020160090800 A KR 1020160090800A KR 20160090800 A KR20160090800 A KR 20160090800A KR 102623581 B1 KR102623581 B1 KR 102623581B1
- Authority
- KR
- South Korea
- Prior art keywords
- besifovir
- dipivoxil
- orotate
- formula
- methyl
- Prior art date
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- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical class OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims description 16
- 150000003839 salts Chemical class 0.000 title abstract description 15
- 239000003443 antiviral agent Substances 0.000 title description 3
- JLKJXDOWBVVABZ-UHFFFAOYSA-N [[1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethyl-(2,2-dimethylpropanoyloxymethoxy)phosphoryl]oxymethyl 2,2-dimethylpropanoate Chemical compound C1=NC2=CN=C(N)N=C2N1CC1(OCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)CC1 JLKJXDOWBVVABZ-UHFFFAOYSA-N 0.000 claims abstract description 83
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 12
- -1 1 , 4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate Chemical compound 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229960005010 orotic acid Drugs 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- SHGVMNPGAPQLTG-UHFFFAOYSA-N 7-butylphosphanyl-2,2-dimethylheptanoic acid Chemical compound CCCCPCCCCCC(C)(C)C(O)=O SHGVMNPGAPQLTG-UHFFFAOYSA-N 0.000 claims description 7
- 238000002441 X-ray diffraction Methods 0.000 claims description 7
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- KDNSSKPZBDNJDF-UHFFFAOYSA-N [1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethylphosphonic acid Chemical compound C12=NC(N)=NC=C2N=CN1CC1(OCP(O)(O)=O)CC1 KDNSSKPZBDNJDF-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
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(이하 '베시포비르디피복실')의 오로트산염, 그의 제조방법 및 상기 염을 포함하는 약제학적 조성물에 관한 것이다:
[화학식 1]
[Formula 1]
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 relates to 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2 of Formula 1 , 4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate ('besifovir dipivoxil) orotate salt, its preparation method, and pharmaceutical composition containing the salt. It's about.
[화학식 1][Formula 1]
상기 화학식 1의 유리 화합물(베시포비르디피복실)은 산이 부가되지 않은 화합물로써 대한민국 등록특허 제 0441638호 및 국제공개특허 WO 02/057288 호에 개시된 새로운 항바이러스 물질이다. 그러나, 이 화합물은 열과 수분에 대해 매우 불안정하여 약제학적 조성물의 원료로 사용되기 어려운 화합물이다.The free compound of Formula 1 (besifovir dipivoxil) is a compound without added acid and is a new antiviral substance disclosed in Korean Patent No. 0441638 and International Publication Patent No. WO 02/057288. However, this compound is very unstable to heat and moisture, making it difficult to use as a raw material for pharmaceutical compositions.
대한민국 등록특허 제 0935904호에서는 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 Republic of Korea Patent No. 0935904, various types of pharmaceutically acceptable salts were prepared to solve this problem. In this process, some salts were found to be difficult to obtain as crystalline solids, and only maleate, p-toluenesulfonate, methanesulfonate, naphthalenesulfonate, and ethanesulfonate were successfully obtained as crystalline solids. Among them, it is described that besifovir dipivoxil maleic acid single salt has significantly better heat stability than its free compound 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, besifovir dipivoxil maleate is very unstable at high temperatures above 100℃ and is mostly decomposed in 6 hours, so its stability is still insufficient, and when it comes into contact, it can cause severe irritation accompanied by redness, pain, cornea, and even swelling. Due to the characteristics of maleic acid, symptoms similar to conjunctivitis or acute exposure may occur during the manufacturing process (refer to the Korea Food and Drug Safety Evaluation Institute's toxicity information data), so caution is required for safety.
본 발명은 독성 등의 문제가 없고, 100℃ 이상의 고온에서 열안정성을 나타내며 제조공정의 안전성, 용해도 및 보관 안정성이 개선된 베시포비어의 신규염을 제공하고자 한다.The present invention seeks to provide a new salt of besifovir that has no problems such as toxicity, shows thermal stability at high temperatures of 100°C or higher, and has improved manufacturing process safety, solubility, and storage stability.
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 aspect of the present invention is 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7 represented by Formula 1 -Dioxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate orotate (hereinafter referred to as 'besifovir dipivoxyl orotate'):
[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 오로트산과 유기 용매의 존재하에 혼합하는 것을 포함하는, 화학식 1의 베시포비르디피복실 오로트산염의 제조 방법에 관한 것이다:Another aspect of the present invention is 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3, The free compound of 7-dioxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxyl) is prepared in the presence of orotic acid represented by Formula 3 and an organic solvent. It relates to a process for preparing besifovir dipivoxil orotate of formula 1, comprising mixing:
[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 present invention relates to a pharmaceutical composition for treating or preventing viral infections, comprising orotate salt of besifovir dipivoxil 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. Besifovir dipivoxil orotate of the present invention has excellent stability according to light, temperature, and humidity, and in particular, has excellent heat resistance even at temperatures above 100°C, where besifovir dipivoxil maleate, which is known to be stable, decomposes. It indicates stability.
본 발명의 베시포비르디피복실 오로트산염은 매우 우수한 안정성을 나타냄으로써 장기간 보존이 가능하며, 고온다습한 환경에서도 제제연구 및 보관이 용이하다는 장점을 가진다.Besifovir dipivoxil orotate of the present invention has the advantage of being able to be stored for a long period of time by exhibiting very excellent stability and being easy to prepare and store even in a high temperature and 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 orotic acid is not harmful to the human body, workers can safely produce besifovir dipivoxil orotate salt during the production process.
본 발명에 따른 베시포비르디피복실 오로트산염의 제조 방법에 의해 제조된 베시포비르디피복실 오로트산염은 비교적 간단한 공정으로 매우 높은 순도, 예컨데, 99% 이상, 구체적으로는 99.5% 이상, 보다 구체적으로는 99.9% 이상의 순도를 갖는다.Besifovir dipivoxil orotate prepared by the method for producing besifovir dipivoxil orotate according to the present invention has a very high purity, for example, 99% or more, specifically 99.5% or more, by a relatively simple process. Specifically, it has a purity of 99.9% or more.
도 1은 본 발명의 베시포비르디피복실 오로트산염과 대조 화합물인 베시포비르디피복실 말레산염의 시간과 온도(100℃)에 따른 함량(%) 변화를 비교한 그래프이다.
도 2는 실시예 1의 베시포비르디피복실 오로트산염의 시차주사열량도(Differential Scanning Calorimeter)를 나타낸 것이다.
도 3은 비교예 1의 베시포비르디피복실 말레산염의 시차주사열량도(Differential Scanning Calorimeter)를 나타낸 것이다.
도 4는 실시예 1의 베시포비르디피복실 오로트산염의 분말 X-선 회절 분광도(Powder X-ray Diffraction pattern)를 나타낸 것이다.
도 5는 실시예 1의 베시포비르디피복실 오로트산염의 적외선 분광(FT-IR)을 나타낸 것이다.
도 6은 실시예 1의 베시포비르디피복실 오로트산염의 1H 핵자기 공명 스펙트럼(NMR)을 나타낸 것이다.Figure 1 is a graph comparing the change in content (%) of besifovir dipivoxil orotate of the present invention and besifovir dipivoxil maleate, a control compound, with time and temperature (100°C).
Figure 2 shows the Differential Scanning Calorimeter of besifovir dipivoxil orotate of Example 1.
Figure 3 shows the Differential Scanning Calorimeter of besifovir dipivoxil maleate of Comparative Example 1.
Figure 4 shows the powder X-ray diffraction pattern of besifovir dipivoxil orotate of Example 1.
Figure 5 shows infrared spectroscopy (FT-IR) of besifovir dipivoxil orotate of Example 1.
Figure 6 shows the 1 H nuclear magnetic resonance spectrum (NMR) of besifovir dipivoxil orotate of Example 1.
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 aspect of the present invention is 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3, represented by Formula 1, It relates to the orotate salt of 7-dioxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (hereinafter referred to as 'besifovir dipivoxyl orotate') :
[화학식 1][Formula 1]
특히, 베시포비르디피복실의 오로트산염의 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, it may be a crystalline solid of the orotate salt of besifovir dipivoxil, specifically the It may be a crystalline form characterized by diffraction peaks. More specifically, from powder It may be a crystalline form characterized by X-ray diffraction peaks at °, 26.41° and 27.69° ± 0.2°.
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 오로트산은 융점이 179.0~182℃의 범위이다. 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2, represented by Formula 1, The orotate salt of 4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxil) contains about 1 molar equivalent of 3-[({1-[2-amino-9H -purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pival of the cationic free compound and about 1 molar equivalent of the orotic anion. Additionally, besifovir dipivoxil orotic acid has a melting point in the range of 179.0 to 182°C.
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. Besifovir dipivoxil orotate of Formula 1 does not decompose even under harsh conditions such as moisture, light, and high temperature (e.g., over 100°C) and has excellent stability, so it is active regardless of storage conditions when used as an antiviral pharmaceutical composition. It has the advantage of maintaining medicinal efficacy because the ingredients do not decompose. In addition, besifovir dipivoxil orotate of Formula 1 has the advantage of improved solubility and safety compared to its free compound or other salts.
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.Due to the improved physical and chemical stability and solubility of besifovir dipivoxil orotate as described above, it can be usefully used for the prevention or treatment of viral infections. In particular, due to the improved physicochemical stability of besifovir dipivoxil orotate, it can be advantageously used in solid pharmaceutical formulations containing the above active ingredients.
베시포비르디피복실 오로트산염은 고순도, 예컨데, 99% 이상, 구체적으로는 99.5% 이상, 보다 구체적으로는 99.9% 이상의 순도, 예컨데 99.91% 내지 99.98%의 순도를 갖는다.Besifovir dipivoxil orotate has a high purity, such as 99% or higher, specifically 99.5% or higher, more specifically 99.9% or higher, 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 유기 용매의 존재하에 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 유기 용매의 존재하에 혼합하는 것을 포함하는, 화학식 1의 베시포비르디피복실 오로트산염의 제조 방법이 제공된다:Another aspect of the present invention relates to a method for producing orotic acid salt of besifovir dipivoxil of Formula 1, which method comprises mixing the free compound of besifovir dipivoxil with orotic acid in the presence of an organic solvent. Includes. Specifically, 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-di represented by Formula 2 Mixing the free compound of oxo-2,4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxyl) with orotic acid represented by Formula 3 in the presence of an organic solvent. A process for preparing besifovir dipivoxil orotate of Formula 1 is provided, comprising:
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 1][Formula 1]
구체적으로, 상기 제조 방법은, 베시포비르디피복실의 유리 화합물과 오로트산염을 유기 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, 예컨데, 20℃ 내지 25℃로 냉각함으로써 제조될 수 있다. 구체예에서, 상기 제조 방법은 상기 냉각 후 수득된 고체를 여과하고 유기 용매로 세척한 후 건조하는 단계를 추가로 포함할 수 있다.Specifically, the production method involves mixing the free compound of besifovir dipivoxil and orotate in the presence of an organic solvent and mixing them at a temperature range of 35°C to 50°C, specifically 40°C to 45°C for 1 minute to 12 minutes. It can be prepared by heating for a period of time, specifically 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 an embodiment, the production method may further include filtering the solid obtained after cooling, washing with an organic solvent, and then drying.
베시포비르디피복실의 유리 화합물을 유기 용매 ml 당 1mg 내지 700mg의 비율로 용해시키고, 여기에 오로트산염을 첨가하고 교반하면 베시포비르디피복실의 오로트산염이 생성될 수 있다. 유기 용매는 염 생성에 사용될 수 있는 유기용매로, 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 1 당량을 사용할 수 있다. When the free compound of besifovir dipivoxil is dissolved at a rate of 1 mg to 700 mg per ml of organic solvent, orotate is added thereto and stirred, orotate salt of besifovir dipivoxil can be produced. Organic solvents are organic solvents that can be used to produce salts, for example, water, methanol, ethanol, propanol, isopropanol, cyclohexane, n-hexane, diethyl ether, methyl ethyl ketone, tetrahydrofuran, acetone, etc. there is. The amount of orotate added can be 0.8 to 1.2 equivalents, specifically 0.9 to 1.1 equivalents, more specifically 1 equivalent, based on 1 equivalent of the free compound of besifovir dipivoxil.
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). The orotate salt of besifovir dipivoxil prepared by the above method may be a crystalline solid. Specifically, 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° in powder More specifically, from powder °, 26.41° and 27.69° ± 0.2°. It may be a crystalline form characterized by X-ray diffraction peaks (see Figure 4). In the differential scanning calorimetry (10°C/min), the starting point of the melting point endothermic peak of the crystal is 178.53°C (see Figure 5).
베시포비르디피복실 오로트산염에 의해 예방 또는 치료될 수 있는 질환은 바이러스 감염에 의한 질환이며, 예를 들어, HSV-1, HSV-2, 사이토메갈로바이러스, HBV(B형 간염 바이러스) 또는 HIV(인간 면역 결핍 바이러스) 등을 포함하나, 구체적으로는, HBV 또는 HIV일 수 있다. Diseases that can be prevented or treated with besifovir dipivoxil orotate are diseases caused by viral infections, such as HSV-1, HSV-2, cytomegalovirus, HBV (hepatitis B virus), or HIV. (human immunodeficiency virus), etc., but specifically, it may 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 1mg 내지 600mg, 구체적으로는 1mg 내지 300mg, 보다 구체적으로는 100mg 내지 200mg의 범위일 수 있으나, 대상체의 체중, 나이, 질환의 중증도, 건강 상태 등에 따라 달라질 수 있다.Accordingly, in another aspect of the present invention, a pharmaceutical composition is provided comprising the orotate salt of besifovir dipivoxil, and a pharmaceutically acceptable excipient. The pharmaceutical composition is particularly useful for the prevention or treatment of the viral disease, specifically the prevention or treatment of HBV or HIV infection. The total daily dose of besifovir dipivoxil orotate may range from 1 mg to 600 mg, specifically 1 mg to 300 mg, and more specifically 100 mg to 200 mg, but may vary depending on the subject's weight, age, severity of disease, It may vary depending on health status, etc.
베시포비르디피복실의 오로트산염을 포함하는 조성물은 주사용 제제 또는 경구용 제제로 투여될 수 있다.The composition containing the orotate salt of besifovir dipivoxil may be administered as an injectable formulation or an oral formulation.
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. It can be used as an injectable preparation, for example, a sterile injectable aqueous or oily suspension, and the solvent for the injectable preparation 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 preparations include, for example, tablets, capsules, pills, powders, etc., and may especially be tablets or capsules. For oral administration in the form of tablets, the orotate salt of besifovir dipivoxil may be administered in an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, Can be mixed with magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc., and when administered orally in liquid form, besifovir dipivoxil orotate is an optional oral and non-toxic pharmaceutical agent. It can be mixed with an acceptable inert carrier, such as ethanol, glycerol, water, etc. Moreover, as the case may be or as required, suitable binders, lubricants, disintegrants and colorants may 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 glycol, waxes, etc. This is included. The lubricant includes sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
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 invention provides the use of besifovir dipivoxil orotate in the preparation of an antiviral drug, specifically 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 present invention is a viral disease comprising administering a prophylactically or therapeutically effective amount of besifovir dipivoxil orotate to a subject in need of treatment or prevention of a viral infection, specifically HBV or HIV infection. A method for preventing or treating is 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 through the following examples and experimental examples. However, it should be clearly stated that these examples and experimental examples are only intended to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way.
실시예Example
실시예Example 1 : One : 베시포비르디피복실의vesipovirdiclothyl 오로트산염의of orotate 제조 manufacturing
2.0g의 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 40mL의 MeOH에 가하여 용해시키고, 이어서 0.62g의 오로트산과 60mL의 물을 첨가하였다. 40℃~45℃에서 30분간 가온 교반한 뒤 상온으로 냉각하여 2시간 동안 교반하였다. 수득한 고체를 여과하여 메탄올과 물로 세척한 후 건조하여 2.21g 의 베시포비르디피복실 오로트산염을 얻었다. 2.0 g of 3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4, 6-Trioxa-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxil) was dissolved in 40 mL of MeOH, followed by the addition of 0.62 g of orotic acid and 60 mL of water. The mixture was heated and stirred at 40°C to 45°C for 30 minutes, then cooled to room temperature and stirred for 2 hours. The obtained solid was filtered, washed with methanol and water, and dried to obtain 2.21 g of besifovir dipivoxil. Orotate was obtained.
(수율 85.3%, 순도 99.96%) (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), 5.55~5.59(d, 4H), 4.25(s, 2H), 4.11~4.13(d, 2H), 1.13(s, 18H), 0.89~0.90(d, 4H)
실시예Example 2: 2: 베시포비르디피복실의vesipovirdiclothyl 오로트산염의of orotate 제조 manufacturing
2.0g의 베시포비르디피복실과 0.62g의 오로트산에 60mL의 물을 첨가하였다. 40℃~45℃에서 4시간 30분간 가온 교반한 뒤 상온으로 냉각하여 1일 교반하였다. 수득한 고체를 여과하여 물로 세척한 후 건조하여 2.42g의 베시포비르디피복실 오로트산염을 얻었다. (수율 93.4%, 순도: 99.92%)60 mL of water was added to 2.0 g of besifovir dipivoxil and 0.62 g of orotic acid. The mixture was heated and stirred at 40°C to 45°C for 4 hours and 30 minutes, then 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 besifovir dipivoxil orotate. (Yield 93.4%, Purity: 99.92%)
비교예Comparative example
비교예Comparative example 1: One: 베시포비르디피복실의vesipovirdiclothyl 말레산염의maleic 제조 manufacturing
대한민국 특허 등록 제0935904호의 실시예 3에 기재된 방법에 따라, 1 g의 베시포비르디피복실을 에틸아세테이트 10ml에 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. According to the method described in Example 3 of Korean Patent Registration No. 0935904, 1 g of besifovir dipivoxil was dissolved in 10 ml of ethyl acetate, then 1 equivalent of maleic acid was added and stirred for one hour to produce a solid. The obtained solid was filtered, washed with ethyl acetate, and dried to obtain besifovir dipivoxil maleate with a purity of 99.89%.
비교예Comparative example 2: 2: 베시포비르디피복실의vesipovirdiclothyl 푸마르산 fumaric acid 이염의otitis media 제조 manufacturing
1.0g의 베시포비르디피복실과 0.46g의 푸마르산을 10mL의 MeOH에 가하여 용해시킨 뒤 1시간 동안 상온교반하였다. 반응액을 감압농축한 뒤 에틸아세테이트와 MTBE(Methyl tert-butyl ether)를 첨가하여 고체를 석출시켰다. 수득한 고체를 여과하여 MTBE로 세척한 후 건조하여 1.16g의 베시포비르디피복실 푸마르산 이염을 얻었다. (수율 80.6%, 순도 99.84%)1.0 g of besifovir dipivoxil and 0.46 g of fumaric acid were dissolved in 10 mL of MeOH 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) were added to precipitate a solid. The obtained solid was filtered, washed with MTBE, and dried to obtain 1.16 g of besifovir dipivoxil fumaric acid disalt. (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) 1H 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: 베시포비르디피복실의vesipovirdiclothyl 피콜린산염의of picolinate 제조 manufacturing
1.0g의 베시포비르디피복실과 0.26g의 피콜리닉산을 10mL의 MeOH에 가하여 용해시킨 뒤 1시간 동안 상온교반하였다. 반응액을 감압농축한 뒤 에틸아세트와 헵탄을 첨가하여 고체를 석출시켰다. 수득한 고체를 여과하여 헵탄으로 세척한 후 건조하여 1.04g의 베시포비르디피복실 피콜린산염을 얻었다. (수율 83.9%, 순도 99.76%)1.0 g of besifovir dipivoxil and 0.26 g of picolinic acid were dissolved in 10 mL of MeOH and stirred 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, washed with heptane, and dried to obtain 1.04 g of besifovir dipivoxil 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 (400MHz, 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), 7.61~7.64(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)
비교예Comparative example 4: 4: 베시포비르디피복실의vesipovirdiclothyl N,NN,N -디메틸글라이신 -Dimethylglycine 이염의otitis media 제조 manufacturing
1.0g의 베시포비르디피복실과 0.22g의 N,N-디메틸글라신을 3mL의 MeOH에 가하여 용해시킨 뒤 3시간 동안 상온교반하였다. 반응액을 감압농축한 뒤 에틸아세트와 헵탄을 첨가하여 고체를 석출시켰다. 수득한 고체를 여과하여 헵탄으로 세척한 후 건조하여 0.63g의 베시포비르디피복실 N,N-디메틸글라이신 이염을 얻었다. (수율 63.0%, 순도 99.76%)1.0 g of besifovir dipivoxil and 0.22 g of N, N-dimethylglycine were dissolved in 3 mL of MeOH and stirred 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 besifovir dipivoxil 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) 1H NMR (400MHz, 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: 베시포비르디피복실의vesipovirdiclothyl 인산염의 제조 Manufacture of Phosphate
1.0g의 베시포비르디피복실을 5mL의 이소프로필알코올에 용해시킨 뒤 0.13mL의 인산을 천천히 적가하였다. 상온에서 1시간 동안 교반한 뒤, 수득한 고체를 여과하여 이소프로필알코올로 세척한 후 건조하여 1.12g의 베시포비르디피복실 인산염을 얻었다. (수율 94.0%, 순도 99.83%)1.0 g of besifovir dipivoxil was dissolved in 5 mL of isopropyl alcohol, and then 0.13 mL of phosphoric acid was slowly added dropwise. After stirring at room temperature for 1 hour, the obtained solid was filtered, washed with isopropyl alcohol, and dried to obtain 1.12 g of besifovir dipivoxil 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) 1H NMR (400MHz, 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: 베시포비르디피복실의vesipovirdiclothyl 브롬산염의 제조 Preparation of Bromate
3.0g의 베시포비르디피복실을 15mL의 에틸아세테이트에 용해시킨 뒤 0.65mg의 브롬화수소를 가하였다. 상온에서 1시간 동안 교반한 뒤, 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 3.39g의 베시포비르디피복실 브롬산염을 얻었다. (수율: 98.0%, 순도 99.83%)3.0 g of besifovir dipivoxil was dissolved in 15 mL of ethyl acetate, and then 0.65 mg of hydrogen bromide was added. After stirring at room temperature for 1 hour, the obtained solid was filtered, washed with ethyl acetate, and dried to obtain 3.39 g of besifovir dipivoxil 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) 1H NMR (400MHz, 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: 베시포비르디피복실의vesipovirdiclothyl 황산염의 제조 Preparation of Sulphate
3.0g의 베시포비르디피복실을 18mL의 에틸아세테이트에 용해시킨 뒤 0.3mL의 황산을 적가하였다. 상온에서 2시간 동안 교반한 뒤, 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 3.49g의 베시포비르디피복실 황산염을 얻었다.3.0 g of besifovir dipivoxil was dissolved in 18 mL of ethyl acetate, and then 0.3 mL of sulfuric acid was added dropwise. After stirring at room temperature for 2 hours, the obtained solid was filtered, washed with ethyl acetate, and dried to obtain 3.49 g of besifovir dipivoxil sulfate.
(수율 98.0%, 순도 99.83%)(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) 1H NMR (400MHz, 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: 베시포비르디피복실의vesipovirdiclothyl 염산염 이수화물의 제조 Preparation of hydrochloride dihydrate
3.0g의 베시포비르디피복실을 27mL의 에틸아세테이트에 용해시킨 뒤 0.48mL의 염산을 적가하였다. 수득한 고체를 여과하여 에틸아세테이트로 세척한 후 건조하여 3.03g의 베시포비르디피복실 염산염 이수화물을 얻었다. (수율 88.9%, 순도 99.93%)3.0 g of besifovir dipivoxil was dissolved in 27 mL of ethyl acetate, and then 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 besifovir dipivoxil 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 (400MHz, 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 함량은 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(400MHz)을 사용하여 측정하였다. In the above Examples, Comparative Examples, and the following Experimental Examples, the content of each compound was measured by high-performance liquid chromatography (HPLC) using Waters' Alliance 2965 series. In addition, the differential scanning calorimeter was measured using TA's DSC Q20, and the powder X-ray diffraction spectrum was measured using Bruker's D8 ADVANCE. The infrared absorption spectrum (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 (400MHz).
또한, 본원에서 분말 X-선 회절 분석 조건은 다음과 같다:Additionally, the powder X-ray diffraction analysis conditions herein are as follows:
약 50mg의 시료를 시료 홀더에 채워 2∼50°/2θ의 범위에서 회절 패턴을 얻었다. 자세한 분석 조건은 아래와 같다:Approximately 50 mg of sample was filled into the sample holder, and a diffraction pattern was obtained in the range of 2 to 50°/2θ. 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/θRefection
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
실험예Experiment example
실험예 1 : 고체 상태의 가속 안정성 비교 실험 1 Experimental Example 1 : Solid State Accelerated Stability Comparison Experiment 1
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1 내지 비교예 8에서 수득한 베시포비르디피복실의 기타염들의 시료를 각각 10mg~50mg씩 유리 용기에 넣고 40±2℃, 75±5% RH에서 보관하였다. 1주, 2주 및 4주 후에 시료를 5mg씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 1에 나타내었다. Besifovirdipivoxil of Example 1 Orotate and besifovir dipivoxil obtained in Comparative Examples 1 to 8 Samples of other salts, 10 mg to 50 mg each, were placed in glass containers and stored at 40 ± 2°C and 75 ± 5% RH. After 1, 2, and 4 weeks, 5 mg of each sample was taken and analyzed using HPLC. The results are shown in Table 1 below.
상기 표 1의 가속시험(40℃/75% RH, 4주) 결과를 보면, 베시포비르디피복실의 염들 중에서 오로트산염만 함량이 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°C/75% RH, 4 weeks) in Table 1 above, it can be seen that among the salts of besifovir dipivoxil, only the orotate content is maintained at more than 99.9%. That is, besifovir dipivoxil orotate had higher stability under high temperature and high humidity conditions than the other salts obtained in Comparative Examples 1 to 8.
실험예Experiment example 2: 고체 상태의 가혹 안정성 비교 실험 2 2: Experiment 2 for comparing the harsh stability of solid state
비교예 1에서 수득한 베시포비르디피복실 말레산염과 실시예 1에서 수득한 오로트산염을 약 10~15mg씩 여러 개의 유리 용기에 넣고 60℃, 80℃ 및 100℃에 각각 보관하였다. 1주, 2주, 4주 및 8주 후 또는 24시간 및 48시간 후에 시료를 5mg씩 취하여 HPLC를 이용하여 분석하였다. 그 결과를 하기 표 2, 표 3 및 표 4에 나타내었다. Approximately 10 to 15 mg of besifovir dipivoxil maleate obtained in Comparative Example 1 and orotate obtained in Example 1 were placed in several glass containers and stored at 60°C, 80°C, and 100°C, respectively. After 1, 2, 4, and 8 weeks, or 24 and 48 hours, 5 mg of sample was taken and analyzed using HPLC. The results are shown in Tables 2, 3, and 4 below.
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 in Tables 2 and 3 above, it can be seen that besifovir dipivoxil orotate and maleate show almost equal thermal stability at 60°C and 80°C. However, at high temperatures of 100°C or higher (see Table 4), most of the maleate is decomposed after 6 hours, leaving almost nothing remaining, while orotate is hardly decomposed, confirming that the orotate of the present invention has significantly superior thermal stability. You can. In other words, besifovir dipivoxil orotate of the present invention can minimize the production of related substances even in processing such as milling or in other harsh environments, and thus has the advantage of enabling drug development using various formulation technologies.
실험예Experiment 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 thermal analysis using DSC (differential scanning calorimetry) were performed on besifovir dipivoxil orotate of Example 1 and besifovir dipivoxil maleate of Comparative Example 1, respectively.
1) 모세관법 융점 측정1) Capillary method melting point measurement
SRS MPA100을 사용하여 각 샘플을 10℃/분의 속도로 가열하면서 융점을 측정하였고, 그 결과를 하기 표 5에 나타내었다.The melting point was measured while heating each sample at a rate of 10°C/min using SRS MPA100, and the results are shown in Table 5 below.
2) DSC(시차주사열량계)를 이용한 열분석2) Thermal analysis using DSC (differential scanning calorimetry)
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 나타내었다For besifovir dipivoxil orotate of Example 1 and besifovir dipivoxil maleate of Comparative Example 1, each sample was measured from room temperature to 200°C to 250°C at a rate of 10°C/min using DSC Q20 from TA. It was heated and analyzed, and the results are shown in Figure 2 (Besifovir dipivoxil orotate of Example 1) and Figure 3 (Besifovir dipivoxil maleate 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, Figures 2 and 3 above, it can be confirmed that the melting point of besifovir dipivoxil orotate of the present invention is higher than that of besifovir dipivoxil maleate.
실험예Experiment example 4: 4: 광안정성photostability 시험 test
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1의 베시포비르디피복실 말레산염을 각각 100mg씩 투명한 유리용기에 넣어 광안정성 챔버에서 광원에 노출시킨 채로 3일 동안 보관하였다. 100 mg each of besifovir dipivoxil orotate of Example 1 and besifovir dipivoxil maleate of Comparative Example 1 were placed in transparent glass containers and stored in a light stability chamber for 3 days while exposed to a light source.
광안정성 측정기는 CARON Photostability Chamber Model 6545을 사용하였으며, 광노출양은 전체 조명(Overall illumination)이 240만 lux-hr/m2, 근자외선(Near UV)가 330 W·hr/m2이다. 광원에 노출시킨 뒤 3일 후, 각각의 시료를 5mg씩 취하여 HPLC를 이용하여 분석하였고, 그 결과를 하기 표 6에 나타내었다.The CARON Photostability Chamber Model 6545 was used as a light stability meter, and the light exposure amount was 2.4 million lux-hr/m 2 for overall illumination and 330 W·hr/m 2 for near UV. Three days after exposure to the light source, 5 mg of each sample was taken and analyzed using HPLC, and the results are shown in Table 6 below.
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 confirmed that besipovir dipivoxil orotate does not generate any photodecomposition products even when exposed to light, and thus has excellent photostability equivalent to that of besipovir dipivoxil maleate.
실험예Experiment example 5: 흡습성 시험 5: Hygroscopicity test
실시예 1의 베시포비르디피복실 오로트산염과 비교예 1의 베시포비르디피복실 말레산염을 각각 1g씩 25℃에서 상대습도 60%와 92% 챔버에 각각 7일간 보관한 후, 흡습에 의한 중량변화를 관찰하여 표 7에 나타내었다.1 g each of besifovir dipivoxil orotate of Example 1 and besifovir dipivoxil maleate of Comparative Example 1 were stored in chambers of 60% and 92% relative humidity at 25°C for 7 days, respectively, and then dried by moisture absorption. Weight changes were observed and shown in Table 7.
상기의 결과로부터 오로트산염은 말레산에 비해 흡습성을 더욱 나타내지 않는다는 것을 알 수 있다. 이는 베시포비르디피복실 오로트산염이 공기 중 수분에 원료가 노출되더라도 안전하다는 것을 나타낸다. From the above results, it can be seen that orotate is no more hygroscopic than maleic acid. This indicates that besifovir dipivoxil orotate is safe even if the raw material is exposed to moisture in the air.
Claims (15)
[화학식 1]
[Formula 1]
[화학식 2]
[화학식 3]
[화학식 1]
.3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2, represented by Formula 2, Formula, comprising mixing the free compound of 4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxil) with orotic acid represented by Formula 3 in the presence of an organic solvent. Method for preparing besifovir dipivoxil orotate of 1:
[Formula 2]
[Formula 3]
[Formula 1]
.
[화학식 1]
.3-[({1-[2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2, represented by Formula 1, Pharmaceutical composition for treating or preventing viral infection comprising orotate salt of 4,6-trioxa-3λ 5 -phosphanon-1-yl-pivalate (besifovir dipivoxil) and pharmaceutically acceptable excipients :
[Formula 1]
.
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