KR20210105238A - Co-crystal compound of 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile and L-malic acid, and manufacturing method thereof - Google Patents
Co-crystal compound of 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile and L-malic acid, and manufacturing method thereof Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
본 발명은 신규의 결정형 고체 화합물인 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 말레이트, 이 화합물의 제조방법, 그리고 이 화합물을 활성성분으로 포함하는 약학 조성물에 관한 것이다.The present invention relates to a novel crystalline solid compound, 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile maleate, a method for preparing the compound, and using the compound as an active ingredient It relates to a pharmaceutical composition comprising
하기 화학식 1로 표시되는 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 수화물은 Perampanel(제품명 Fycompa)이라는 물질명을 가지며, Eisai 사에서 개발한 의약품이다. 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile hydrate represented by the following formula (1) has a substance name of Perampanel (product name Fycompa), and is a drug developed by Eisai am.
Perampanel은 뇌전증 환자의 부분발작(partial-onset seizures) 및 전신성 강직성 발작(primary generalized tonic-clonic seizures)에 처방되는 약물이다. 이러한 Perampanel은 AMPA(alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid) 수용체의 선택적 비경쟁성 길항제(selective non-competitive antagonist)로서 AMPA 수용체의 길항작용을 통해 신경세포사멸을 막고, 발작의 발생 및 확산을 저해하는 기전을 갖는다. Perampanel is prescribed for partial-onset seizures and primary generalized tonic-clonic seizures in patients with epilepsy. Perampanel is a selective non-competitive antagonist of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, and prevents neuronal cell death through antagonism of AMPA receptors, and prevents seizures. It has a mechanism to inhibit the occurrence and spread of
미국등록특허 제6949571호에는 AMPA 수용체 조절작용을 갖는 물질군으로서 Perampanel을 포함한 피리디논 화합물들이 개시되어 있다. US Patent No. 6949571 discloses pyridinone compounds including Perampanel as a group of substances having an AMPA receptor modulating action.
또, 미국등록특허 제8772497호에는 상기 화학식 1의 결정성 Perampanel 수화물과 그의 제조방법이 개시되어 있다. In addition, US Patent No. 8772497 discloses a crystalline Perampanel hydrate of Formula 1 and a method for preparing the same.
본 발명자들은 상기 화학식 1의 결정성 Perampanel 수화물을 가속조건 하에서 보관 시 하기 화학식 2의 구조를 갖는 N-Oxide 불순물이 쉽게 발생하는 것을 확인하였다.The present inventors confirmed that the N-Oxide impurity having the structure of the following Chemical Formula 2 is easily generated when the crystalline Perampanel hydrate of Chemical Formula 1 is stored under accelerated conditions.
상기 화학식 2의 N-Oxide 화합물은 Aromatic N-oxide 군에 속하는 물질인데, 이러한 물질은 잠재적인 유전독성 유연물질(genotoxic impurity)로 관리가 되는 물질이며, 적은 양이라 할지라도 인체에 장기간 노출 시에 발암성, 유전독성, 생식독성 등의 발현가능성이 높은 것으로 알려져 있다 (Plo
따라서 본 발명이 해결하고자 하는 과제는 안정성 및 안전성이 높고, 의약 원료로 사용되기에 우수한 물성을 가지는 perampanel 화합물을 제공하는 것이다. Therefore, the problem to be solved by the present invention is to provide a perampanel compound having high stability and safety and excellent physical properties for use as a pharmaceutical raw material.
또, 본 발명이 해결하고자 하는 다른 과제는 상기와 같은 우수성을 가지는 perampanel 화합물의 제조방법을 제공하는데 있다.In addition, another problem to be solved by the present invention is to provide a method for producing a perampanel compound having the above-mentioned superiority.
또한, 본 발명이 해결하고자 하는 또 다른 과제는 상기와 같은 우수성을 가지는 perampanel 화합물을 활성성분으로 포함하는 약학 조성물을 제공하는데 있다. In addition, another problem to be solved by the present invention is to provide a pharmaceutical composition comprising a perampanel compound having the above-described superiority as an active ingredient.
상기 과제를 해결하기 위하여, 본 발명의 일 양태는 하기 화학식 3으로 표시되는 Perampanel malate 화합물, 특히 특정 결정성을 가지는 Perampanel malate 화합물을 제공한다. In order to solve the above problems, one aspect of the present invention provides a Perampanel malate compound represented by the following Chemical Formula 3, in particular, a Perampanel malate compound having specific crystallinity.
본 발명자들은 의약 원료로 사용되어 우수한 물성과 안정성을 가지고 있고, 그리고 보관 조건 하에서 경시변화에 의해 상기 화학식 2의 잠재적 유전독성 유연물질을 생성시키지 않으며, 결정전이가 발생하지 않으며 열역학적으로 안정한 하기 화학식 3으로 표시되는 Perampanel malate, 특히 이의 새로운 결정성 화합물을 제조함으로써 본 발명을 완성하게 되었다.The present inventors have used as a pharmaceutical raw material, have excellent physical properties and stability, do not generate the potentially genotoxic related substance of Formula 2 by aging under storage conditions, do not undergo crystal transition, and are thermodynamically stable. The present invention was completed by preparing a new crystalline compound of Perampanel malate represented by
본 발명자들은 Perampanel의 결정성 고체화합물이 경시변화 등에 의해 유전독성 유연물질이 발생하지 않도록 하기 위해 많은 연구를 거듭하였고, 특이하게도 다양한 물질들 중 l-말릭산과의 특정한 결정성 공결정(crystalline co-crystal)에서 화학식 2의 유연물질이 전혀 발생하지 않음을 확인할 수 있었다. The present inventors have repeated many studies to prevent the generation of genotoxic related substances due to changes in the crystalline solid compound of Perampanel over time, and specifically, a specific crystalline co-crystal with l-malic acid among various substances. crystal), it was confirmed that the related substance of Chemical Formula 2 did not occur at all.
본 발명은 시차주사 열량계 (DSC)로 측정한 흡열온도가 156.70±3 ℃과 224.86±3 ℃로서 두 개의 흡열피크를 갖는, 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물을 제공한다.The present invention provides a crystalline perampanel malate compound represented by Formula 3, having two endothermic peaks as endothermic temperatures measured by differential scanning calorimetry (DSC) of 156.70±3 ℃ and 224.86±3 ℃.
본 발명의 바람직한 구현예에 따르면, 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물은 X-선 분말 회절 분석하여 상대강도가 20% 초과인 2θ 회절각 (2θ±0.2°)이 5.39±0.2, 10.69±0.2, 13.35±0.2, 16.59±0.2, 18.18±0.2, 22.41±0.2, 23.27±0.2 및 26.82±0.2°일 수 있다.According to a preferred embodiment of the present invention, the crystalline perampanel malate compound represented by Formula 3 has a 2θ diffraction angle (2θ±0.2°) of 5.39±0.2, 10.69 with a relative intensity greater than 20% by X-ray powder diffraction analysis. ±0.2, 13.35±0.2, 16.59±0.2, 18.18±0.2, 22.41±0.2, 23.27±0.2 and 26.82±0.2°.
본 발명의 다른 바람직한 구현예에 따르면, 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물은 X-선 분말 회절 분석하여 상대강도가 10% 초과인 2θ 회절각 (2θ±0.2°)이 5.39±0.2, 10.69±0.2, 11.91±0.2, 12.27±0.2, 13.35±0.2, 14.57±0.2, 16.59±0.2, 17.59±0.2, 18.18±0.2, 18.65±0.2, 19.24±0.2, 19.60±0.2, 20.26±0.2, 21.39±0.2, 21.76±0.2, 22.41±0.2, 22.71±0.2, 23.27±0.2, 23.89±0.2, 24.72±0.2, 및 26.82±0.2°일 수 있다.According to another preferred embodiment of the present invention, the crystalline Perampanel malate compound represented by Formula 3 has a 2θ diffraction angle (2θ±0.2°) of 5.39±0.2 with a relative intensity of more than 10% by X-ray powder diffraction analysis, 10.69±0.2, 11.91±0.2, 12.27±0.2, 13.35±0.2, 14.57±0.2, 16.59±0.2, 17.59±0.2, 18.18±0.2, 18.65±0.2, 19.24±0.2, 19.60±0.2, 20.26±0.2, 21.39± 0.2, 21.76±0.2, 22.41±0.2, 22.71±0.2, 23.27±0.2, 23.89±0.2, 24.72±0.2, and 26.82±0.2°.
본 발명은 다른 하나의 양태로서, 하기의 제조단계를 포함하는 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물의 제조방법을 제공한다:As another aspect, the present invention provides a method for preparing a crystalline Perampanel malate compound represented by Formula 3, comprising the following preparation steps:
a) Perampanel과 L-Malic acid를 N-methyl-2-pyrrolidone과 Ethanol의 혼합 용매(바람직하게는, N-methyl-2-pyrrolidone : Ethanol = 1 : 3-9 비율, 더욱 바람직하게는, N-methyl-2-pyrrolidone : Ethanol = 1 : 6 비율의 혼합용매)에 용해시키는 단계;a) Perampanel and L-Malic acid in a mixed solvent of N-methyl-2-pyrrolidone and Ethanol (preferably, N-methyl-2-pyrrolidone : Ethanol = 1: 3-9 ratio, more preferably, N- methyl-2-pyrrolidone : Ethanol = 1 : dissolving in a mixed solvent in a ratio of 6);
b) 상기 a)의 반응액을 가온 상태(바람직하게는, 50~60 ℃에서) 1시간 교반 후 서서히 냉각하여(바람직하게는, 0 ~ -5 ℃까지 냉각하여) 고체를 석출하는 단계; 및 b) precipitating a solid by slowly cooling the reaction solution of a) after stirring for 1 hour in a warm state (preferably at 50 to 60 ℃) (preferably by cooling to 0 to -5 ℃); and
c) 생성된 고체를 여과한 후 세척(바람직하게는, Ethanol과 n-Heptane의 혼합용매, 더욱 바람직하게는 Ethanol : n-Heptane = 1 : 3-5 비율의 혼합용매로 세척) 및 건조하여 하기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물을 얻는 단계. c) After filtering the resulting solid, washing (preferably, a mixed solvent of Ethanol and n-Heptane, more preferably, Ethanol: n-Heptane = 1:3-5 ratio is washed with a mixed solvent) and dried to the following Obtaining a crystalline Perampanel malate compound represented by the formula (3).
본 발명은 다른 하나의 양태로서, 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물이 활성성분으로 포함되어 있는, 뇌전증 환자의 부분발작(partial-onset seizures) 및/또는 전신성 강직성 발작(primary generalized tonic-clonic seizures)의 치료용 약학 조성물을 제공한다.In another embodiment, the present invention provides partial-onset seizures and/or primary generalized tonic seizures in patients with epilepsy, wherein the crystalline Perampanel malate compound represented by Formula 3 is included as an active ingredient. A pharmaceutical composition for the treatment of -clonic seizures is provided.
본 발명의 바람직한 구현예에 따르면, 상기 약학 조성물은 산제, 과립제, 정제, 캅셀제, 현탁액, 에멀젼, 및 시럽으로 이루어진 군에서 선택된 제형 형태로 제제화될 수 있다.According to a preferred embodiment of the present invention, the pharmaceutical composition may be formulated in a dosage form selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, and syrups.
본 발명이 제공하는 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물은 Perampanel 수화물에 대비하여 열과 수분에 대한 안정성이 현저하게 우수하다. The crystalline perampanel malate compound represented by Formula 3 provided by the present invention has remarkably superior stability to heat and moisture compared to perampanel hydrate.
또한, 본 발명이 제공하는 결정성 Perampanel malate 화합물은 유동성, 압축성 등 약물 제조에 유리한 물성을 가지고 있을 뿐만 아니라, 열과 수분에 대한 안정성이 우수하여 제조된 약물은 유통기간을 초과하여 장기간 보관되어서도 활성성분이 분해되지 않거나 결정형이 전이되지 않고 안정하게 보존된다. In addition, the crystalline perampanel malate compound provided by the present invention not only has advantageous properties for drug manufacture, such as fluidity and compressibility, but also has excellent stability to heat and moisture, so that the manufactured drug can be stored for a long period of time beyond the shelf life as an active ingredient It is not degraded or the crystal form is not transferred and is stably preserved.
따라서 본 발명이 제공하는 결정성 Perampanel malate 화합물은 뇌전증 환자의 부분발작(partial-onset seizures) 및/또는 전신성 강직성 발작(primary generalized tonic-clonic seizures) 치료를 목적하는 약제 제조 시에 활성성분으로 유용하다. 구체적으로, 결정성 Perampanel malate 화합물은 경구용 제제로 제형화되는 약물의 의약원료로서 용이하게 사용될 수 있다. Therefore, the crystalline Perampanel malate compound provided by the present invention is useful as an active ingredient in the preparation of a medicament for the treatment of partial-onset seizures and/or primary generalized tonic-clonic seizures in epilepsy patients. do. Specifically, the crystalline Perampanel malate compound can be easily used as a pharmaceutical raw material of a drug formulated for oral administration.
도 1은 결정성 Perampanel malate 화합물의 X-선 분말 회절 패턴이다.
도 2는 결정성 Perampanel malate 화합물과 Perampanel과 malate의 혼합물, Parampanel의 DSC 열분석도를 비교한 것이다. 도 2에서 
도 3은 결정성 Perampanel malate 화합물의 1H NMR 스펙트럼이다.1 is an X-ray powder diffraction pattern of a crystalline Perampanel malate compound.
2 is a comparison of the DSC thermal analysis diagram of a crystalline Perampanel malate compound, a mixture of Perampanel and malate, and Parampanel. in Figure 2
3 is a 1 H NMR spectrum of a crystalline Perampanel malate compound.
본 발명은 Perampanel malate 화합물, 특히 바람직하게는 특정 결정성의 perampanel malate 화합물, 이러한 화합물의 제조방법, 및 이 화합물이 활성성분으로 포함된 약학 조성물을 제공한다. The present invention provides a perampanel malate compound, particularly preferably a specific crystalline perampanel malate compound, a method for preparing such a compound, and a pharmaceutical composition comprising the compound as an active ingredient.
본 발명에 따른 특정 결정성 Perampanel malate 화합물은 유동성, 압축성, 흡습성 등 약물 제조에 유리한 물성을 가지고 있고, 열과 수분에 대하여 안정하고, 유동 보관 중에 활성성분이 분해되거나 결정형 전이가 발생하지 않는 되는 안정성이 충분히 확보된 화합물이다.The specific crystalline Perampanel malate compound according to the present invention has properties advantageous for drug manufacture, such as fluidity, compressibility, and hygroscopicity, is stable against heat and moisture, and has stability that the active ingredient does not decompose or crystalline transition does not occur during fluid storage. It is a sufficiently secured compound.
본 발명이 제공하는 결정성 Perampanel malate 화합물은 하기 화학식 3으로 표시되 바와 같이 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 모핵에 L-말릭산이 부가된 공결정성 화합물이다. The crystalline Perampanel malate compound provided by the present invention is 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile L-malic in the parent nucleus as represented by the following formula (3) It is a co-crystalline compound to which an acid has been added.
[화학식 3][Formula 3]
2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴의 pKa는 3.24임이 보고되고 있으며, L-말릭산의 pKa는 3.40임이 보고되고 있다(J Bioequiv Availab Volume 9(5): 501-508 (2017), Advances in Applied Microbiology, Volume 9, Wayne W. Umbreit, Academic Press, P264 (2014)). It has been reported that the pKa of 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile is 3.24, and that the pKa of L-malic acid is 3.40 (J Bioequiv). Availab Volume 9(5): 501-508 (2017), Advances in Applied Microbiology, Volume 9, Wayne W. Umbreit, Academic Press, P264 (2014)).
산부가염이 형성되기 위해서는 최소한 pKa의 차이가 1 이상이 되어야 하며, 이온결합력을 위해 바람직하게는 3 이상이 되는 것이 바람직하다. 상기 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴과 L-말릭산의 pKa의 차이는 0.16에 불과하며, FDA에서는 API와 coformer간의 ΔpKa (pKa (base) - pKa (acid))가 1 이하인 경우 두 물질로 이뤄진 신규한 결정성 고체를 공결정(co-crystal)로 분류하고 있다(Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Pharmaceutical Quality/CMC, August 2016). In order to form an acid addition salt, at least the difference in pKa should be 1 or more, and preferably 3 or more for ionic bonding strength. The difference between the pKa of 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile and L-malic acid is only 0.16, and in the FDA, ΔpKa ( When pKa (base) - pKa (acid)) is 1 or less, a novel crystalline solid composed of two substances is classified as a co-crystal (Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Pharmaceutical Quality/CMC, August 2016).
따라서, 본 발명에 의한 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴과 L-말릭산의 경우에 있어서도 두 물질의 정량적인 비율 1 : 1 몰비로 구성된 신규한 결정성 고체는 공결정으로 분류할 수 있다. Therefore, in the case of 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile and L-malic acid according to the present invention, the quantitative ratio of the two substances is 1:1. A novel crystalline solid composed of a molar ratio can be classified as a co-crystal.
본 발명자들은 종래의 Perampanel 3/4 수화물이 가속조건하에서 분해산물로서 하기 화학식 2로 표시되는 화합물이 생성되는 것을 확인할 수 있었다. The present inventors were able to confirm that the conventional Perampanel 3/4 hydrate was produced as a decomposition product under accelerated conditions, as a compound represented by the following formula (2).
[화학식 2][Formula 2]
상기 화학식 2의 N-Oxide 화합물은 잠재적인 유전독성 유연물질(genotoxic impurity)로 관리가 되는 Aromatic N-oxide군에 속하는 물질이며, 이러한 물질은 적은 양이라 할지라도 인체에 장기간 노출 시에 발암성, 유전독성, 생식독성 등의 발현가능성이 높은 것으로 알려져 있다. The N-Oxide compound of
Perampanel의 신규 공결정 화합물이 의약으로 적용되기 위한 요건으로는, 첫째, 제제화하는 과정에서 물리화학적으로 안정해야 하고, 둘째, 보관 유통 중에 경시변화에 의해 다른 결정 형태로 쉽게 전이되지 않아야 하고, 셋째, 보관 유통 중에 화학식 2로 표시되는 피리딘의 N-O- 화합물은 생성되지 않아야 하며, 기타 유연물질의 생성을 최소화할 수 있어야 한다.The requirements for the novel co-crystal compound of Perampanel to be applied as a drug are: first, it must be physicochemically stable during the formulation process; second, it must not be easily transferred to other crystalline forms due to changes over time during storage and distribution; and third, During storage and distribution, the NO - compound of pyridine represented by
이에, 본 발명자들은 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 유리염기를 열역학적으로 안정화시킬 수 있는 다양한 시도를 하였으며, 여러 시도들 중에서 말릭산과의 공결정(Cocrystal), 특히 특정 결정형을 가진 공결정이 통상적인 보관 조건하에서 활성성분이 분해되지 않고 안정되게 보존되는 동시에 화학식 2로 표시되는 피리딘의 N-O- 화합물이 생성되지 않음을 확인하였다. Accordingly, the present inventors have made various attempts to thermodynamically stabilize the 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile free base, and among several attempts, malic It was confirmed that co-crystals with acids, particularly co-crystals having a specific crystalline form, were stably preserved without decomposition of the active ingredient under normal storage conditions, and the NO - compound of pyridine represented by Formula 2 was not generated.
또한, 본 발명은 결정성 Perampanel malate 화합물의 제조방법을 제공한다. 본 발명에 따른 결정성 Perampanel malate 화합물의 제조방법은 구체적으로, a) Perampanel과 L-Malic acid를 N-methyl-2-pyrrolidone과 Ethanol의 혼합 용매(바람직하게는, N-methyl-2-pyrrolidone : Ethanol = 1 : 3-9 비율, 더욱 바람직하게는, N-methyl-2-pyrrolidone : Ethanol = 1 : 6 비율의 혼합용매)에 용해시키는 단계; b) 상기 a)의 반응액을 가온 상태(바람직하게는, 50~60 ℃에서) 교반 후 (바람직하게는, 약 1시간) 서서히 냉각하여(바람직하게는, 0~-5 ℃까지 냉각하여) 고체를 석출하는 단계; 및 c) 생성된 고체를 여과한 후 세척(바람직하게는, Ethanol과 n-Heptane의 혼합용매, 더욱 바람직하게는 Ethanol : n-Heptane = 1 : 3-5 비율의 혼합용매로 세척) 및 건조하여 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물을 얻는 단계를 포함한다.In addition, the present invention provides a method for preparing a crystalline Perampanel malate compound. The method for preparing the crystalline Perampanel malate compound according to the present invention is specifically, a) Perampanel and L-Malic acid in a mixed solvent of N-methyl-2-pyrrolidone and Ethanol (preferably, N-methyl-2-pyrrolidone: Ethanol = 1 : 3-9 ratio, more preferably, N-methyl-2-pyrrolidone : Ethanol = 1 : dissolving in a mixed solvent of 6 ratio); b) After stirring the reaction solution of a) in a warm state (preferably at 50 to 60 ° C.) (preferably, for about 1 hour), cool slowly (preferably by cooling to 0 to -5 ° C.) precipitating a solid; and c) washing (preferably, a mixed solvent of Ethanol and n-Heptane, more preferably Ethanol: n-Heptane = 1:3-5 ratio) and drying after filtering the resulting solid. and obtaining a crystalline Perampanel malate compound represented by Formula 3 above.
본 발명에 따른 결정성 Perampanel malate 화합물의 제조방법을 각 단계별로 보다 구체적으로 설명하면 하기와 같다.The method for preparing the crystalline perampanel malate compound according to the present invention will be described in more detail for each step as follows.
상기 a)단계는 Perampanel 대비 1~1.1 몰비를 갖는 L-말릭산을 사용한다. 바람직하게는 L-말릭산을 1.05 몰비 사용할 수 있다. L-말릭산이 1몰보다 적을 경우 공결정이 제대로 형성되지 않을 우려가 있고, 1.1몰보다 많을 경우 여분의 L-말릭산이 제거되지 않고 공결정에 남아 있을 우려가 있다. In step a), L-malic acid having a molar ratio of 1 to 1.1 compared to Perampanel is used. Preferably, L-malic acid may be used in a molar ratio of 1.05. When the amount of L-malic acid is less than 1 mol, there is a risk that the co-crystal may not be properly formed, and when it is more than 1.1 mol, there is a risk that the excess L-malic acid is not removed and remains in the co-crystal.
상기 b)단계는 Perampanel과 L-말릭산을 반응시킨 후에 고체화하는 과정으로서, 완전한 용해와 반응을 위해 가열하는 것이 바람직하며, 더욱 바람직하게는 대략 50 ~ 60 ℃ 온도 범위에서 적절히 수행할 수 있다. 상기 냉각은 0 ~ -5 ℃ 범위가 적당하며, 냉각온도가 너무 높으면 고체의 생성속도가 느리고 수율이 적을 수 있고, 냉각온도가 너무 낮으면 여분의 L-말릭산이 잔류할 수 있다. Step b) is a process of solidifying after reacting Perampanel with L-malic acid. It is preferable to heat for complete dissolution and reaction, and more preferably, it can be appropriately carried out in a temperature range of about 50 to 60 ℃. The cooling is suitable in the range of 0 to -5 ° C. If the cooling temperature is too high, the solid formation rate may be slow and the yield may be low, and if the cooling temperature is too low, excess L-malic acid may remain.
상기 c)단계는 생성된 결정을 여과, 세척 및 건조하여 결정성 Perampanel malate 화합물을 얻는 과정이다. 상기 세척용매는 Ethanol과 n-Heptane의 혼합용매, 더욱 바람직하게는 Ethanol : n-Heptane = 1 : 3-5 중량비로 포함된 혼합용매를 사용한다. 세척 시 상기 용매는 0 ~ 10 ℃로 냉각하여 사용하는 것이 좋다. 상기 건조는 통상의 건조방법, 예를 들어 동결건조, 회전증발건조, 분무건조, 진공건조 또는 유동층 건조에 의해 수행될 수 있으며, 구체적으로 진공건조에 의해 수행될 수 있다. 좋기로는 40~50 ℃에서 진공 건조할 수 있다.Step c) is a process of obtaining a crystalline Perampanel malate compound by filtering, washing and drying the resulting crystals. As the washing solvent, a mixed solvent of Ethanol and n-Heptane, more preferably Ethanol: n-Heptane = 1:3-5 by weight, is used. When washing, the solvent is preferably cooled to 0 ~ 10 ℃ before use. The drying may be performed by a conventional drying method, for example, freeze drying, rotary evaporation drying, spray drying, vacuum drying or fluidized bed drying, and specifically, vacuum drying. Preferably, vacuum drying may be performed at 40 to 50°C.
또한, 본 발명은 결정성 Perampanel malate 화합물이 활성성분으로 포함된 약학 조성물을 제공한다. 본 발명이 제공하는 결정성 Perampanel malate 화합물은 뇌전증 환자의 부분발작(partial-onset seizures) 및/또는 전신성 강직성 발작(primary generalized tonic-clonic seizures) 치료를 목적하는 약제 제조 시에 활성성분으로 유용하다. 본 발명의 상기 치료는 예방적 목적의 치료 또한 포함하는 개념이다. In addition, the present invention provides a pharmaceutical composition comprising a crystalline Perampanel malate compound as an active ingredient. The crystalline Perampanel malate compound provided by the present invention is useful as an active ingredient in the manufacture of a medicament for the treatment of partial-onset seizures and/or primary generalized tonic-clonic seizures in patients with epilepsy. . The treatment of the present invention is a concept that also includes treatment for prophylactic purposes.
본 발명의 약학 조성물은 활성성분으로서 결정성 Perampanel malate 화합물을 포함한다. 상기 활성성분의 함량은 환자의 나이, 몸무게 등을 고려하여 산정될 수 있는데, 일반적으로 약학 조성물 총 충량을 기준으로 0.01 내지 10 중량% 범위로 함유될 수 있다. The pharmaceutical composition of the present invention contains a crystalline Perampanel malate compound as an active ingredient. The content of the active ingredient may be calculated in consideration of the patient's age, weight, etc., and may generally be contained in the range of 0.01 to 10% by weight based on the total amount of the pharmaceutical composition.
또한, 본 발명의 약학 조성물은 유효성분의 효과를 헤치지 않는 범위 내에서 담체, 희석제, 결합제, 붕해제, 윤활제, pH 조절제, 산화방지제, 용해보조제 등의 약학적으로 허용 가능한 첨가제를 포함할 수 있다. 본 발명의 약학 조성물을 제형화하는데 사용될 수 있는 약학적으로 허용 가능한 첨가제의 예로는 미정질 셀룰로즈, 자일리톨, 에리스리톨, 메틸 셀룰오스, 폴리비닐피롤리돈, 전분, 아카시아, 알지네이트, 젤라틴, 락토즈, 덱스트로오스, 수크오스, 프로필히드록시벤, 조에이트, 셀룰로오스, 물, 메틸히드록시벤조에이트, 마그네슘 스테아레이트 탈크, 솔비톨, 만니톨, 말티톨, 칼슘 포스페이트, 칼슘 실리케이트, 또는 광물유 등이 사용될 수 있다. In addition, the pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives such as carriers, diluents, binders, disintegrants, lubricants, pH adjusters, antioxidants, and solubilizing agents within the range that does not impair the effect of the active ingredient. have. Examples of pharmaceutically acceptable additives that can be used in formulating the pharmaceutical composition of the present invention include microcrystalline cellulose, xylitol, erythritol, methyl cellulose, polyvinylpyrrolidone, starch, acacia, alginate, gelatin, lactose, Dextrose, sucrose, propylhydroxybene, zoate, cellulose, water, methylhydroxybenzoate, magnesium stearate talc, sorbitol, mannitol, maltitol, calcium phosphate, calcium silicate, or mineral oil may be used.
또한, 본 발명의 약학 조성물은 통상의 제제화 방법에 따라 산제, 과립제, 정제, 캅셀제, 현탁액, 에멀젼, 시럽으로 이루어진 군에서 선택된 제형 형태로 제형화될 수 있다. 본 발명은 상기 제형 형태에 특별한 제한을 두지 않는다.In addition, the pharmaceutical composition of the present invention may be formulated in a dosage form selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, and syrups according to a conventional formulation method. The present invention is not particularly limited in the form of the formulation.
이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명의 내용이 하기 실시예에 의해 제한되는 것은 아니다.Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.
[실시예][Example]
실시예 1. 결정성 Perampanel malate 공결정(co-crystal) 화합물의 제조Example 1. Preparation of crystalline Perampanel malate co-crystal compound
둥근 플라스크에 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 유리염기와 L-말릭산을 1 : 1.05 몰비로 가하고 N-methyl-2-pyrrolidone: Ethanol = 1 : 6을 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 기준 10% w/v 용액이 되도록 가하였다. 질소 대기 하에서 1시간 동안 60 ℃에서 교반하였다. 반응액을 0 ℃로 냉각시킨 후에 생성된 고체를 감압 여과한 후 10 ℃도 미리 냉각시킨 Ethanol : n-Heptane = 1 : 4 혼합용매로 세척하였다. 생성된 결정을 50 ℃에서 24시간 진공 건조하여 결정성 Perampanel malate 공결정(co-crystal) 화합물을 얻었다. (수율 94.5%)In a round flask, 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile free base and L-malic acid were added in a molar ratio of 1:1.05 and N-methyl-2-pyrrolidone : Ethanol = 1 : 6 was added to obtain a 10% w/v solution based on 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile. The mixture was stirred at 60° C. for 1 hour under a nitrogen atmosphere. After the reaction solution was cooled to 0 °C, the resulting solid was filtered under reduced pressure, and then washed with an Ethanol: n-Heptane = 1:4 mixed solvent previously cooled to 10 °C. The resulting crystals were vacuum dried at 50° C. for 24 hours to obtain a crystalline Perampanel malate co-crystal compound. (yield 94.5%)
상기 실시예 1에서 제조된 화합물에 대한 X-선 분말 회절 (PXRD) 분석도, DSC 열분석도 및 1H NMR 스펙트럼 측정 결과는 각각 도 1 내지 3에 첨부하였다.X-ray powder diffraction (PXRD) analysis diagram, DSC thermal analysis diagram, and 1 H NMR spectrum measurement results for the compound prepared in Example 1 are attached to FIGS. 1 to 3, respectively.
실시예 2. Perampanel과 L-Malic acid의 1 : 1 혼합물 제조Example 2. Preparation of 1:1 mixture of Perampanel and L-Malic acid
막자사발에 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 유리염기와 L-말릭산을 1 : 1 몰비로 가하고 10분간 분쇄하였다. 분쇄한 고체혼합물을 Agitator에 옮겨 담고 실온에서 6시간 동안 격렬하게 교반하여 균질한 혼합물을 제조하였다.In a mortar, 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile free base and L-malic acid were added in a 1:1 molar ratio, and the mixture was pulverized for 10 minutes. The pulverized solid mixture was transferred to an agitator and stirred vigorously at room temperature for 6 hours to prepare a homogeneous mixture.
상기 실시예 2에서 제조된 Perampanel과 L-Malic acid의 1 : 1 혼합물에 대한 DSC 열분석도 결과를 도 2에 비교예로서 첨부하였다.The results of the DSC thermal analysis of the 1:1 mixture of Perampanel and L-Malic acid prepared in Example 2 are attached to FIG. 2 as a comparative example.
[실험예][Experimental example]
실험예 1. 안정성 비교 시험Experimental Example 1. Stability comparison test
결정성 Perampanel malate 화합물 (실시예 1), Perampanel과 L-Malic acid의 1 : 1 혼합물 (실시예 2) 및 Perampanel 3/4 수화물 각각에 대하여 안정성 비교실험을 실시하였다.Stability comparison experiments were performed on crystalline Perampanel malate compound (Example 1), a 1:1 mixture of Perampanel and L-Malic acid (Example 2), and Perampanel 3/4 hydrate, respectively.
시험화합물은 온도 40 ℃ 및 상대습도 75%의 가속 보존조건 하에서 안정성 챔버에 넣고 6개월 동안 보관하였다. 보관은 각 시험화합물을 이중 폴리에틸렌 백 (bag)에 넣어 두었고, 상기 폴리에틸렌 백의 사이에 실리카 젤 파우치를 충진한 후, 소형 종이상자 (Fiber drum)에 넣었다.The test compound was placed in a stability chamber under accelerated storage conditions of a temperature of 40 °C and a relative humidity of 75% and stored for 6 months. For storage, each test compound was placed in a double polyethylene bag, and a silica gel pouch was filled between the polyethylene bags, and then placed in a small paper box (Fiber drum).
6개월 동안 가속 보존조건으로 보관한 후에 측정한 상기 화학식 2의 분해산물의 농도와 전체 유연물질의 농도를 HPLC 분석을 통해 측정한 결과를 하기 표 1에는 정리하여 나타내었다.Table 1 below summarizes the results of the concentration of the decomposition product of
[액체크로마토그래피 (HPLC)의 분석 조건][Analysis conditions for liquid chromatography (HPLC)]
컬럼: 4.6mm X 250mm, 5um, 100Å pore sizeColumn: 4.6mm X 250mm, 5um, 100Å pore size
컬럼온도: 35℃Column temperature: 35℃
검출기: UV Detector (227 nm)Detector: UV Detector (227 nm)
유속: 1.5 mL/minFlow rate: 1.5 mL/min
시간: 10 분Time: 10 minutes
이동상의 조건 : ACN:Buffer (0.5 ml Triethylamine in 500 ml water adjust pH 2.5 with OPA) (60:40v/v)Conditions of mobile phase: ACN:Buffer (0.5 ml Triethylamine in 500 ml water adjust pH 2.5 with OPA) (60:40v/v)
분해산물 농도 (%)
Decomposition product concentration (%)
Perampanel 3/4 수화물comparative example
Perampanel 3/4 Carb
상기 표 1의 결과에 의하면, 결정성 Perampanel malate 화합물 (실시예 1)은 화학식 2로 표시되는 분해산물이 전혀 생성되지 않았음에 비해 Perampanel과 L-Malic acid의 1 : 1 혼합물 (실시예 2) 및 Perampanel 3/4 수화물은 화학식 2로 표시되는 분해산물의 농도가 현저하게 높다는 것을 확인할 수 있다. 화학식 2의 화합물은 잠재적인 유전독성물질인데, 이러한 유연물질이 보관조건 하에서 생성 및 검출될 경우 해당 원료물질은 의약의 원료로 사용이 제한된다. 따라서, 상기 안정성 결과에서 실시예 1의 공결정을 제외하곤 의약원료로 적합하다고 볼 수 없다.According to the results of Table 1, the crystalline Perampanel malate compound (Example 1) was a 1:1 mixture of Perampanel and L-Malic acid (Example 2), while no degradation product represented by
또한, 초기 대비하여 6개월 후에 측정된 전체 유연물질의 농도의 경우, 결정성 Perampanel malate 화합물 (실시예 1)에 대비하여 Perampanel과 L-Malic acid의 1 : 1 혼합물 (실시예 2) 및 Perampanel 3/4 수화물은 확연하게 증가함을 확인할 수 있다. In addition, in the case of the total concentration of related substances measured 6 months after the initial preparation, a 1:1 mixture of Perampanel and L-Malic acid (Example 2) and Perampanel 3 in comparison to the crystalline Perampanel malate compound (Example 1) It can be seen that the /4 hydrate is significantly increased.
실험예 2. 결정전이 (Polymorphic transition) 여부 평가Experimental Example 2. Evaluation of polymorphic transition
결정성 Perampanel malate 화합물 (실시예 1)에 대하여 보관조건에서 결정전이 현상이 발생하는지를 확인하기 위하여, 초기 상태의 PXRD 분석 결과와 경시 변화에 따른 결정전이 가능성을 알아보았다.For the crystalline Perampanel malate compound (Example 1), in order to confirm whether crystal transition occurs under storage conditions, the PXRD analysis result of the initial state and the possibility of crystal transition according to the change over time were investigated.
상기 실험예 1의 가속조건하에서 6개월 보관한 시료에 대해 초기 상태와 6개월 후에 각각 측정한 PXRD 및 DSC 분석 결과를 비교하였다. 그 결과는 하기 표 2에 정리하여 나타내었다.The PXRD and DSC analysis results measured in the initial state and after 6 months for the samples stored for 6 months under the accelerated conditions of Experimental Example 1 were compared. The results are summarized in Table 2 below.
결정성 Perampanel malate 화합물 (실시예 1)은 보관 후 6개월이 지난 시점에 PXRD와 DSC를 확인해 본 결과, 경시 변화에 따른 결정전이가 발생되지 않았음을 알 수 있다. 따라서 결정성 Perampanel malate 화합물(실시예 1)은 열역학적으로 매우 안정한 것임을 알 수 있다.As a result of checking the PXRD and DSC of the crystalline Perampanel malate compound (Example 1) after 6 months of storage, it can be seen that crystal transition did not occur due to change over time. Therefore, it can be seen that the crystalline Perampanel malate compound (Example 1) is thermodynamically very stable.
실험예 3. 물성 분석 Experimental Example 3. Analysis of physical properties
(1) 분말 X-선 회절 (PXRD) 분석 (1) Powder X-ray diffraction (PXRD) analysis
상기 실시예 1에서 제조된 결정성 Perampanel malate 화합물에 대한 X-선 분말 회절 분석은 브루커 (Bruker)사의 D8 Advance X-선 분말 회절계 상에서 Cu Kα선을 사용하였다. 전류량은 45 kV 및 40 mA로 설정하였다. 발산 및 산란 슬릿은 1°로 설정하였고, 수광 슬릿은 0.2 mm 로 설정하였다. 2θ는 5 에서 35°까지 6°/minute로 측정하였다. PXRD 분석결과는 도 1에 나타내었다. For the X-ray powder diffraction analysis of the crystalline Perampanel malate compound prepared in Example 1, Cu Kα was used on a D8 Advance X-ray powder diffractometer manufactured by Bruker. The amperage was set at 45 kV and 40 mA. The divergence and scattering slits were set at 1°, and the light receiving slits were set at 0.2 mm. 2θ was measured from 5 to 35° at 6°/minute. The PXRD analysis results are shown in FIG. 1 .
(2) 온도 시차주사 열량법 (DSC) 분석(2) Temperature differential scanning calorimetry (DSC) analysis
상기 실시예 1서 제조된 결정성 Perampanel malate 화합물의 녹는점은 온도 시차주사 열량법 (DSC) 분석을 통해 측정하였다.The melting point of the crystalline Perampanel malate compound prepared in Example 1 was measured through temperature differential scanning calorimetry (DSC) analysis.
SCINCO사로부터 입수한 DSC N-650을 사용하였으며, 질소기류 하에 20℃에서 300 ℃까지 10 ℃/min의 스캔속도로, 밀폐 팬에서 DSC 측정을 수행하였다. 그 결과는 도 2에 나타내었다.DSC N-650 obtained from SCINCO was used, and DSC measurement was performed in a closed pan at a scan rate of 10 °C/min from 20 °C to 300 °C under a nitrogen stream. The results are shown in FIG. 2 .
또한, 실시예 2에서 제조된 Perampanel과 L-Malic acid의 1 : 1 혼합물 및 Perampanel 3/4 수화물에 대해서도 상기의 동일 조건으로 DSC 측정을 수행하였다. 그 결과를 도 2에 모두 나타내어 그 차이를 비교할 수 있도록 하였다. 본원발명이 제공하는 결정성 Perampanel malate 화합물은 Perampanel과 L-Malic acid의 1 : 1 혼합물(실시예 2) 및 Perampanel 3/4 수화물과 대비하여 물리화학적 특성이 전혀 다른 별개 화합물임을 DSC 측정결과 비교를 통해 알 수 있다.In addition, DSC measurement was performed on the 1:1 mixture of Perampanel and L-Malic acid and Perampanel 3/4 hydrate prepared in Example 2 under the same conditions as described above. The results are all shown in FIG. 2 so that the differences can be compared. The crystalline Perampanel malate compound provided by the present invention is a separate compound with completely different physicochemical properties compared to a 1:1 mixture of Perampanel and L-Malic acid (Example 2) and Perampanel 3/4 hydrate. can be known through
이상의 실험결과에 의하면, 상기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물은 안정성이 우수하며, 경시 변화에 따른 결정전이 가능성이 없으며, 특히 잠재적 유전독성 물질로 분류되는 화학식 2의 유연물질이 생성되지 않는 신규한 공결정으로서 종래의 수화물 대비 의약원료로서 최적화된 것임을 확인할 수 있었다. According to the above experimental results, the crystalline perampanel malate compound represented by Chemical Formula 3 has excellent stability, there is no possibility of crystal transition with time change, and in particular, the related substance of
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto.
따라서 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (5)
[화학식 3]
[Formula 3]
상기 공결정은 X-선 분말 회절 분석하여 상대강도가 20% 초과인 2θ 회절각 (2θ±0.2°)이 5.39±0.2, 10.69±0.2, 13.35±0.2, 16.59±0.2, 18.18±0.2, 22.41±0.2, 23.27±0.2 및 26.82±0.2°인 것을 특징으로 하는 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 말레이트 공결정. The method of claim 1,
The co-crystals were X-ray powder diffraction analysis, and the 2θ diffraction angles (2θ±0.2°) having a relative intensity greater than 20% were 5.39±0.2, 10.69±0.2, 13.35±0.2, 16.59±0.2, 18.18±0.2, 22.41± 2-(2-oxo-1-phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile maleate co-crystal, characterized in that 0.2, 23.27±0.2 and 26.82±0.2°.
b) 상기 a)의 반응액을 가온 교반 후 냉각하여 고체를 석출하는 단계; 및
c) 생성된 고체를 여과한 후 Ethanol과 n-Heptane의 혼합용매로 세척하고, 건조하여 하기 화학식 3으로 표시되는 결정성 Perampanel malate 화합물을 얻는 단계를 포함하는, 2-(2-옥소-1-페닐-5-피리딘-2-일피리딘-3-일)벤조니트릴 말레이트 공결정의 제조방법.
[화학식 3]
b) precipitating a solid by heating and stirring the reaction solution of a) and cooling; and
c) filtering the resulting solid, washing with a mixed solvent of ethanol and n-Heptane, and drying to obtain a crystalline Perampanel malate compound represented by the following Chemical Formula 3, 2-(2-oxo-1- A method for preparing a phenyl-5-pyridin-2-ylpyridin-3-yl)benzonitrile maleate co-crystal.
[Formula 3]
상기 약학 조성물은 산제, 과립제, 정제, 캅셀제, 현탁액, 에멀젼, 및 시럽으로 이루어진 군에서 선택된 제형 형태로 제제화된 것을 특징으로 하는 약학 조성물.5. The method of claim 4,
The pharmaceutical composition is a pharmaceutical composition, characterized in that it is formulated in a dosage form selected from the group consisting of powders, granules, tablets, capsules, suspensions, emulsions, and syrups.
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| US6949571B2 (en) | 2000-06-12 | 2005-09-27 | Eisai Co., Ltd. | 1,2-dihydropyridine compounds, process for preparation of the same and use thereof |
| US8772497B2 (en) | 2004-07-06 | 2014-07-08 | Eisai R&D Management Co., Ltd. | Method for producing 1, 2-dihydropyridine-2-one compound |
| WO2016172333A1 (en) * | 2015-04-21 | 2016-10-27 | Teva Pharmaceuticals International Gmbh | A solid state form of perampanel |
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| US6949571B2 (en) | 2000-06-12 | 2005-09-27 | Eisai Co., Ltd. | 1,2-dihydropyridine compounds, process for preparation of the same and use thereof |
| US8772497B2 (en) | 2004-07-06 | 2014-07-08 | Eisai R&D Management Co., Ltd. | Method for producing 1, 2-dihydropyridine-2-one compound |
| WO2016172333A1 (en) * | 2015-04-21 | 2016-10-27 | Teva Pharmaceuticals International Gmbh | A solid state form of perampanel |
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