KR100903549B1 - Complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt, preparation method thereof and pharmaceutical composition comprising the same - Google Patents
Complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt, preparation method thereof and pharmaceutical composition comprising the same Download PDFInfo
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Abstract
본 발명은 약학적으로 이용이 용이한 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다. 본 발명에 따른 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 유용한 생리활성물질인 아세틸-L-카르니틴과 티옥트산을 균질하게 혼합하여 제제화하는데 어려웠던 문제점을 해결하고, 물에 대한 용해도를 증가시켜 생체이용률을 증가시킬 수 있다. The present invention relates to a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt, a preparation method thereof, and a pharmaceutical composition comprising the same. The complex salt of the homogeneous crystalline acetyl-L-carnitine and potassium titanate salt according to the present invention solves the problem of difficulty in formulating a homogeneous mixture of useful physiologically active acetyl-L-carnitine and thioctic acid, and for water Increasing solubility can increase bioavailability.
Description
본 발명은 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다. 보다 구체적으로, 본 발명은 유용한 생리활성물질인 아세틸-L-카르니틴과 티옥트산을 균질하게 제제화하는데 용이한 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt, a preparation method thereof, and a pharmaceutical composition comprising the same. More specifically, the present invention provides a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thioctal salt, which is easy to homogeneously prepare acetyl-L-carnitine and thioctic acid, which are useful bioactive substances, and a preparation method thereof. It relates to a pharmaceutical composition.
아세틸-L-카르니틴은 L-카르니틴의 하이드록시기에 아세틸기가 도입된 화합물로 L-카르니틴보다 생체이용률이 우수한 것으로 알려져 있다. 이러한 아세틸-L-카르니틴은 1차적 퇴행성 질환 또는 뇌혈관 질환에 대한 2차적 퇴행성 질환의 치료제로 사용되고 있으며 하기 화학식 (II)로 표시된다.Acetyl-L-carnitine is a compound in which an acetyl group is introduced into the hydroxy group of L-carnitine and is known to have better bioavailability than L-carnitine. Such acetyl-L-carnitine is used as a therapeutic agent for secondary degenerative diseases for primary degenerative diseases or cerebrovascular diseases and is represented by the following general formula (II).
티옥트산(또는 알파 리포산)은 피루베이트 데하이드로게나제 복합제, 알파-케토글루타레이트 데하이드로게나제 복합제 및 아미노산 하이드로게나제 복합제에서 조효소로 작용하는 생리활성물질로 당뇨병성 다발성 신경염의 완화를 위한 치료제로 사용되고 있으며 하기 화학식 (III)으로 표시된다. 티옥트산은 자유라디칼 포획작용과 지질과산화 억제작용을 통해 산화성 스트레스를 감소시키고, 고혈당에 의한 단백당화를 감소시키며, 포도당 이용률 개선을 통해 신경세포의 ATP 에너지 생성을 정상화하고, 신경의 전기전도도를 개선하는 약리작용를 가지고 있다. Tioctic acid (or alpha lipoic acid) is a bioactive agent that acts as a coenzyme in pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, and amino acid hydrogenase complex, to alleviate diabetic polyneuritis It is used as a therapeutic agent and is represented by the following general formula (III). Tioctic acid reduces oxidative stress through free radical capture and lipid peroxidation, decreases glycosylation due to hyperglycemia, normalizes ATP energy production of neurons through improved glucose utilization, and improves nerve electrical conductivity. Has a pharmacological action.
이러한 아세틸-L-카르니틴과 티옥트산을 함께 사용하면 자유라디칼에 의해 유발된 병리학적 상태를 예방하거나 치료하기 위하여 이용될 수 있다는 것이 미국특허등록 제6,365,622호에 기재되어 있으며, 노화에 따른 미토콘드리아의 손상을 회복시킬 수 있다는 것이 선행논문[Ann N Y Acad Sci 1033 (1): 10816]에 보고되어 있다. 또한 아세틸-L-카르니틴과 티옥트산, 또는 이들 혼합물과 또 다른 물질들이 함께 사용되어 뇌의 기능을 향상시키거나 피부질환을 치료하거나 항산화작용을 하는 예들이 국제특허공개 제07/145993호, 미국특허공개 제2007/0212431호, 미국특허공개 제2005/0186196호, 미국특허공개 제2004/0265345호, 국제특허공개 제 02/009652호, 미국특허등록 제6,365,622호, 국제특허공개 제98/057627호 등에 기재되어 있다. 특히 아세틸-L-카르니틴과 티옥트산을 이용한 동물실험에서 생체의 노화를 억제하고 회복시킬 수 있다는 것이 확인되었으며, 이는 선행논문[PNAS 99 (4): 1870~1875]에 보고되고 있다. It is described in US Patent No. 6,365,622 that the use of such acetyl-L-carnitine and thioctic acid together to prevent or treat pathological conditions caused by free radicals, damage to mitochondria due to aging It is reported in the preceding paper [Ann NY Acad Sci 1033 (1): 10816]. In addition, examples of acetyl-L-carnitine and thioctic acid, or mixtures thereof and other substances used together to improve brain function, treat skin diseases, or have antioxidant activity are disclosed in WO 07/145993, US Patent. Publication No. 2007/0212431, US Patent Publication No. 2005/0186196, US Patent Publication No. 2004/0265345, International Patent Publication No. 02/009652, US Patent Registration No. 6,365,622, International Patent Publication No. 98/057627, and the like. It is described. In particular, animal experiments using acetyl-L-carnitine and thioctic acid have been shown to be able to inhibit and restore the aging of the living body, which is reported in the preceding paper [PNAS 99 (4): 1870 ~ 1875].
따라서 아세틸-L-카르니틴과 티옥트산을 간편하고 용이하게 병행 투여하기 위하여 동일 투약 단위에 포함시킬 필요성이 큼에도 불구하고, 수용성인 아세틸-L-카르니틴과 지용성인 티옥트산을 완전히 균일하게 혼합하기 어렵다는 문제점이 있다. 아울러 아세틸-L-카르니틴의 강한 흡습성도 제제화 과정에서 두 물질을 균질하게 혼합하는데 어려움을 주는 요인이 되고 있다. 실제로 이들 두 물질을 고체상으로 혼합하였을 때 동일 뱃치의 제제 단위에서도 활성 성분의 중량비가 동일하지 않아 역가에 변동이 생기는 문제점이 발생하게 된다. Therefore, despite the high necessity to include acetyl-L-carnitine and thioctic acid in the same dosage unit for simple and easy parallel administration, it is difficult to completely and uniformly mix water-soluble acetyl-L-carnitine and fat-soluble thioctic acid. There is a problem. In addition, the strong hygroscopicity of acetyl-L-carnitine is also a factor that makes it difficult to homogeneously mix the two materials in the formulation process. In fact, when these two substances are mixed in the solid phase, the weight ratio of the active ingredient is not the same even in the formulation unit of the same batch, there is a problem that the fluctuation occurs in the titer.
한편, 대한민국특허등록 제0034827호에는 아세틸-L-카르니틴과 아스파르트산, 시트르산, 인산, 푸마르산, 락트산, 말레산, 옥살산, 황산 또는 오로트산의 염이 개시되어 있다. 이 특허에서는 아세틸-L-카르니틴 분자내 염을 앞서 기재한 산들 중에서 선택한 하나의 산과 함께 물 또는 알코올에 녹이고 농축한 후 선택적으로 결정화하여 얻었다. 또한 미국특허공개 제2003/0119904호에서는 아세틸-L-카르니틴과 푸마르산의 염 및 이의 제조방법에 대해 기재하고 있다. 이 특허에서는 아세틸-L-카르니틴과 푸마르산을 에탄올에 녹인 후 5℃에서 결정화하여 얻었다. Meanwhile, Korean Patent Registration No. 0034827 discloses a salt of acetyl-L-carnitine and aspartic acid, citric acid, phosphoric acid, fumaric acid, lactic acid, maleic acid, oxalic acid, sulfuric acid, or orotic acid. In this patent, an acetyl-L-carnitine intramolecular salt is obtained by dissolving and concentrating in water or alcohol with one acid selected from the above-described acids and then selectively crystallizing. US Patent Publication No. 2003/0119904 also describes salts of acetyl-L-carnitine and fumaric acid and methods for their preparation. In this patent, acetyl-L-carnitine and fumaric acid were dissolved in ethanol and crystallized at 5 ° C.
그러나 아세틸-L-카르니틴과 지용성인 티옥트산의 염을 제조하는 방법은 전혀 알려져 있지 않을 뿐만 아니라, 상기한 선행문헌에 기재된 방법으로는 목적하는 아세틸-L-카르니틴과 티옥트산의 염을 제조할 수 없다. 아세틸-L-카르니틴과 티옥트산은 물리적 성질의 현격한 차이로 인해 균질 혼합물로 제조하는 것이 불가능할 뿐만 아니라, 유기용매나 수용액을 이용한 균질 용액으로의 제조도 거의 불가능하다. However, a method for preparing a salt of acetyl-L-carnitine and a fat-soluble thioctic acid is not known at all, and the salts of the desired acetyl-L-carnitine and thioctic acid can be prepared by the above described method. none. Acetyl-L-carnitine and thioctic acid are not only possible to prepare a homogeneous mixture due to the marked difference in physical properties, but also almost impossible to prepare into a homogeneous solution using an organic solvent or an aqueous solution.
한편, 대한민국특허공개 제2006-0011936호에는 L-카르니틴과 티옥트산의 염기성염 및 그의 제조방법이 개시되어 있다. 이 특허에서는 티옥트산을 2-부탄온에 용해시킨 후 메탄올에 녹인 알칼리금속성 염기와 L-카르니틴을 적가하고, 용매를 감압하에서 제거한 후 2-부탄온으로 고체화하면 티옥트산과 L-카르니틴의 염기성 염을 얻을 수 있는 것으로 보고되어 있다. 그러나 아세틸-L-카르니틴은 염기성 조건에서 아세틸기가 쉽게 이탈되기 때문에, 이러한 방법에 의할 경우 목적하는 아세틸-L-카르니틴과 티옥트산의 칼륨염이 생성되지 않고 L-카르니틴과 티옥트산의 칼륨염만이 생성된다. On the other hand, Korean Patent Laid-Open No. 2006-0011936 discloses a basic salt of L-carnitine and thioctic acid and a preparation method thereof. In this patent, the basic salt of thioctic acid and L-carnitine is dissolved by dissolving thioctic acid in 2-butanone and then dropping an alkali metal base and L-carnitine dissolved in methanol dropwise, removing the solvent under reduced pressure, and solidifying to 2-butanone. It is reported that can be obtained. However, since acetyl-L-carnitine is easily released from the acetyl group under basic conditions, this method does not produce the desired potassium salt of acetyl-L-carnitine and thioctic acid, but only the potassium salt of L-carnitine and thioctic acid. Is generated.
본 발명자들은 상기한 문제점들을 해결하고자 예의 연구 검토한 결과, 본 발명에 따른 방법을 통해 아세틸-L-카르니틴과 티옥트산이 균질하게 포함되어 있는 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염을 제조할 수 있음을 발견하고 본 발명을 완성하게 되었다. The present inventors have studied diligently to solve the above problems, and as a result, a complex salt of crystalline acetyl-L-carnitine and potassium titanate salt containing acetyl-L-carnitine and thioctic acid homogeneously through the method according to the present invention. It was found that can be prepared to complete the present invention.
따라서 본 발명의 목적은 유용한 생리활성물질인 아세틸-L-카르니틴과 티옥트산을 균질하게 제제화하는데 용이한 균질한 결정성의 아세틸-L-카르니틴과 티옥 트산 칼륨염의 복합염을 제공하는 것이다. It is therefore an object of the present invention to provide a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thioctate salt which is easy to homogeneously formulate useful physiologically active acetyl-L-carnitine and thioctic acid.
본 발명의 다른 목적은 상기 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염을 고수율 및 고순도로 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing a complex salt of the homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt in high yield and high purity.
본 발명의 또 다른 목적은 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염을 포함하는 약학적 조성물을 제공하는 것이다. It is another object of the present invention to provide a pharmaceutical composition comprising a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thioctate salt.
본 발명은 균질한 결정성의 하기 화학식 (I)로 표시되는 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염에 관한 것이다.The present invention relates to a complex salt of acetyl-L-carnitine and potassium thiocate salt represented by the following general formula (I) of homogeneous crystallinity.
상기 복합염은 상기 화학식 (I)에 나타낸 바와 같이 아세틸-L-카르니틴과 티옥트산 칼륨염을 1:1의 몰 비로 포함한다. The complex salt includes acetyl-L-carnitine and potassium thioctate salt in a molar ratio of 1: 1, as shown in formula (I).
본 발명에서 사용하는 티옥트산은 라세미형의 티옥트산 뿐만 아니라 R(+)-티옥트산과 S(-)-티옥트산과 같은 광학 활성을 갖는 티옥트산을 포함한다. The thioctic acid to be used in the present invention includes not only racemic type thioctic acid but also thioctic acid having optical activity such as R (+)-thioctic acid and S (-)-thioctic acid.
티옥트산이 라세미형인 경우, 본 발명에 따른 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 X-선 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 10% 이상인 회절각(2θ)의 값이 7.9±0.2, 12.0±0.2, 13.5±0.2, 14.0±0.2, 15.0±0.2, 15.6±0.2, 17.4±0.2, 18.6±0.2, 18.9±0.2, 19.9±0.2, 21.0±0.2, 21.4±0.2, 23.4±0.2, 24.2±0.2, 25.5±0.2, 27.6±0.2, 28.4±0.2, 29.4±0.2, 31.0±0.2, 31.9±0.2, 35.7±0.2 인 것을 특징으로 한다.When the thioctic acid is racemic, the complex salt of the acetyl-L-carnitine and potassium titanate salt according to the present invention is characterized by I / I 0 (I: intensity of peak at each diffraction angle, I 0 : The diffraction angle (2θ) with the intensity of the largest peak) of 10% or more is 7.9 ± 0.2, 12.0 ± 0.2, 13.5 ± 0.2, 14.0 ± 0.2, 15.0 ± 0.2, 15.6 ± 0.2, 17.4 ± 0.2, 18.6 ± 0.2, 18.9 ± 0.2, 19.9 ± 0.2, 21.0 ± 0.2, 21.4 ± 0.2, 23.4 ± 0.2, 24.2 ± 0.2, 25.5 ± 0.2, 27.6 ± 0.2, 28.4 ± 0.2, 29.4 ± 0.2, 31.0 ± 0.2, 31.9 ± 0.2, 35.7 ± It is characterized in that 0.2.
한편 티옥트산이 R(+)-티옥트산인 경우, 본 발명에 따른 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 X-선 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 10% 이상인 회절각(2θ)의 값이 7.8±0.2, 12.0±0.2, 13.4±0.2, 13.9±0.2, 15.0±0.2, 15.5±0.2, 16.0±0.2, 17.4±0.2, 18.6±0.2, 19.6±0.2, 21.0±0.2, 21.3±0.2, 23.3±0.2, 24.1±0.2, 25.4±0.2, 27.5±0.2, 28.3±0.2, 29.4±0.2, 30.9±0.2, 31.6±0.2, 35.7±0.2 인 것을 특징으로 한다. On the other hand, when the thioctic acid is R (+)-thioctic acid, the complex salt of the acetyl-L-carnitine and the potassium titanate potassium salt according to the present invention has a peak at I / I 0 (I: peak at each diffraction angle in X-ray diffraction analysis. Intensity, I 0 : the intensity of the largest peak), the value of the diffraction angle (2θ) of 10% or more is 7.8 ± 0.2, 12.0 ± 0.2, 13.4 ± 0.2, 13.9 ± 0.2, 15.0 ± 0.2, 15.5 ± 0.2, 16.0 ± 0.2, 17.4 ± 0.2, 18.6 ± 0.2, 19.6 ± 0.2, 21.0 ± 0.2, 21.3 ± 0.2, 23.3 ± 0.2, 24.1 ± 0.2, 25.4 ± 0.2, 27.5 ± 0.2, 28.3 ± 0.2, 29.4 ± 0.2, 30.9 ± 0.2, It is characterized in that 31.6 ± 0.2, 35.7 ± 0.2.
다른 한편으로, 본 발명은 균질한 결정성의 상기 화학식 (I)로 표시되는 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조방법에 관한 것으로, 본 발명의 제조방법은 On the other hand, the present invention relates to a process for the preparation of a complex salt of acetyl-L-carnitine and potassium titanate salt represented by the above general formula (I) of homogeneous crystallinity.
(i) 하기 화학식 (III)으로 표시되는 티옥트산을 메탄올에 녹인 후 메탄올에 용해된 수산화칼륨 용액을 적가하여 티옥트산 칼륨염의 메탄올 용액을 수득하는 단계; (i) dissolving the thioctic acid represented by the following formula (III) in methanol and then dropwise adding a potassium hydroxide solution dissolved in methanol to obtain a methanol solution of potassium thiocate salt;
(ii) 하기 화학식 (II)로 표시되는 아세틸-L-카르니틴을 메탄올에 녹이고, 상기 단계 (i)에서 수득한 티옥트산 칼륨염의 메탄올 용액을 적가한 후, 감압하에서 농축하는 단계; 및(ii) dissolving the acetyl-L-carnitine represented by the following formula (II) in methanol, and dropwise adding a methanol solution of the potassium titanate salt obtained in step (i), and then concentrating under reduced pressure; And
(iii) 상기 단계 (ii)에서 수득한 농축 잔사에 테트라하이드로퓨란, 아세톤 및 2-부탄온으로 구성된 군으로부터 선택된 하나 이상의 유기용매를 가하여 결정화하고, 생성된 결정성 고체를 여과하는 단계를 포함한다. (iii) crystallizing by adding one or more organic solvents selected from the group consisting of tetrahydrofuran, acetone and 2-butanone to the concentrated residue obtained in step (ii), and filtering the resulting crystalline solid. .
이하, 본 발명에 따른 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조방법을 단계별로 더욱 상세히 설명한다. Hereinafter, a method for preparing a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt according to the present invention will be described in more detail step by step.
제1단계: 티옥트산 칼륨염의 메탄올 용액의 제조Step 1: Preparation of Methanol Solution of Potassium Thiocate Salt
티옥트산 칼륨염의 메탄올 용액은 화학식 (III)으로 표시되는 티옥트산을 메탄올에 녹인 후 메탄올에 용해된 수산화칼륨을 적가하여 제조한다. 수산화칼륨은 화학식 (III)으로 표시되는 티옥트산에 대해 약 0.9 내지 1당량비로 사용하는 것이 바람직하다. 반응온도는 20 내지 40℃가 바람직하며, 반응시간은 10분 내지 1시간이 바람직하다. 수득한 티옥트산 칼륨염의 메탄올 용액은 별도의 처리과정 없이 다음 단계에서 바로(in situ) 사용될 수 있다. A methanol solution of potassium thiocate salt is prepared by dissolving thioctic acid represented by the formula (III) in methanol and dropwise adding potassium hydroxide dissolved in methanol. Potassium hydroxide is preferably used in a ratio of about 0.9 to 1 equivalents to the thioctic acid represented by the formula (III). The reaction temperature is preferably 20 to 40 ° C, and the reaction time is preferably 10 minutes to 1 hour. The methanol solution of the potassium titanate salt obtained can be used in situ without further treatment.
제2단계: 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 농축 잔사의 제조Second Step: Preparation of Complex Salt Concentrated Residues of Acetyl-L-Carnitine and Potassium Thiocate
아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 농축 잔사는 화학식 (II)로 표시되는 아세틸-L-카르니틴을 메탄올에 녹이고, 제1단계에서 수득한 티옥트산 칼륨염의 메탄올 용액을 적가한 후, 감압하에서 농축하여 제조한다. 티옥트산 칼륨염은 화학식 (II)로 표시되는 아세틸-L-카르니틴에 대해 1당량비로 사용하는 것이 바람직하다. 정확히 1당량비가 아닌 경우에는 고체상의 생성물이 얻어지지 않거나 비균질 생성물이 얻어진다. 반응온도는 0 내지 30℃가 바람직하며, 반응시간은 10분 내지 30분이 바람직하다. 감압하에서 용매를 농축할 때는 반응용액의 온도를 25℃ 이하로 유지하는 것이 바람직하다. The combined salt concentration residue of acetyl-L-carnitine and potassium thiocate salt was dissolved in acetyl-L-carnitine represented by the formula (II) in methanol, and the reaction solution was added dropwise with methanol solution of potassium thiocate salt obtained in the first step. Concentrated under It is preferable to use potassium thioctate salt in 1 equivalent ratio with respect to acetyl-L-carnitine represented by General formula (II). If it is not exactly 1 equivalent ratio, a solid product is not obtained or a heterogeneous product is obtained. The reaction temperature is preferably 0 to 30 ° C, and the reaction time is preferably 10 minutes to 30 minutes. When concentrating a solvent under reduced pressure, it is preferable to keep the temperature of a reaction solution at 25 degrees C or less.
제3단계: 결정화된 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Step 3: Preparation of a Complex Salt of Crystallized Acetyl-L-Carnitine and Potassium Tioctate Salt
결정화된 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 제2단계에서 수득한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 농축 잔사에 테트라하이드로퓨란, 아세톤 및 2-부탄온으로 구성된 군으로부터 선택된 유기용매를 가하여 결정화하고, 생성된 결정성 고체를 여과하여 제조한다. 바람직하게는 잔사에 유기용매를 가하고 실온에서 30분 내지 2시간 동안 교반한 후에 온도를 0℃로 낮추고 30분 내지 2시간 동안 유지하여 결정화한다. 그런 다음, 생성된 결정성 고체를 여과하고, 결정화에 사용한 유기용매로 세척한 후 진공하에 30 내지 50℃에서 6 내지 24시간 동안 건조하는 것이 바람직하다. The complex salt of the crystallized acetyl-L-carnitine and potassium titanate potassium salt was obtained from the group consisting of tetrahydrofuran, acetone and 2-butanone in the complex salt concentrated residue of acetyl-L-carnitine and potassium titanate salt obtained in the second step. The selected organic solvent is added to crystallize, and the resulting crystalline solid is produced by filtration. Preferably, the organic solvent is added to the residue and stirred at room temperature for 30 minutes to 2 hours, and then the temperature is lowered to 0 ° C. and maintained for 30 minutes to 2 hours to crystallize. The resulting crystalline solid is then filtered, washed with the organic solvent used for crystallization and then dried under vacuum at 30-50 ° C. for 6-24 hours.
또 다른 한편으로, 본 발명은 균질한 결정성의 상기 화학식 (I)로 표시되는 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염을 약학적으로 허용되는 담체와 함 께 포함하는 약학적 조성물, 구체적으로는 노화를 억제하거나, 뇌기능을 향상시키거나, 피부질환, 간질환, 허혈성 심질환, 고지혈증, 당뇨, 비만 등을 치료하거나 예방하기 위한 약학적 조성물에 관한 것이다. On the other hand, the present invention relates to a pharmaceutical composition comprising a complex salt of acetyl-L-carnitine and potassium thioctal acid salt represented by the above formula (I) together with a pharmaceutically acceptable carrier, specifically The present invention relates to a pharmaceutical composition for inhibiting aging, improving brain function, or treating or preventing skin disease, liver disease, ischemic heart disease, hyperlipidemia, diabetes, obesity, and the like.
본 발명의 약학적 조성물은 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염을 단독으로 또는 다른 생리활성물질과 함께 포함할 수 있으며, 필요에 따라 아세틸-L-카르니틴이나 L-카르니틴을 함께 포함할 수도 있다. The pharmaceutical composition of the present invention may include a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt alone or in combination with other physiologically active substances, and if necessary, acetyl-L-carnitine or L-carnitine. It may also include together.
본 발명에 따른 약학적 조성물은 경구적으로 (예를 들면, 복용 또는 흡입) 또는 비경구적으로 (예를 들면, 주사, 경피흡수, 이식, 직장투여 등) 투여될 수 있으며, 주사는 예를 들면, 정맥주사, 피내주사, 피하주사, 근육내 주사 또는 복강내 주사일 수 있다. 본 발명의 약학적 조성물은 투여 경로에 따라 정제, 캡슐제, 과립제, 파인 서브틸래 (fine subtilae), 산제, 설하 정제, 좌약, 연고, 주사제, 유탁액제, 현탁액제, 시럽제, 분무제 등 여러 형태로 제형화될 수 있다. 상기 여러 형태의 약학적 조성물은 부형제, 충진제, 증량제, 결합제, 붕해제 (disintegrator), 윤활제, 방부제, 항산화제, 등장제 (isotonic agent), 완충제, 피막제, 감미제, 용해제, 기제 (base), 분산제, 습윤제, 현탁제, 안정제, 착색제, 방향제 등 각 제형에 통상적으로 사용되는 약학적으로 허용되는 담체 (carrier)를 사용하여 공지 기술에 의해 제조될 수 있다.The pharmaceutical compositions according to the invention may be administered orally (eg, by taking or inhaling) or parenterally (eg, by injection, transdermal absorption, transplantation, rectal administration, etc.) and the injection may for example , Intravenous injection, intradermal injection, subcutaneous injection, intramuscular injection or intraperitoneal injection. The pharmaceutical compositions of the present invention may be in various forms such as tablets, capsules, granules, fine subtilae, powders, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, syrups, sprays, etc., depending on the route of administration. Can be formulated. The various types of pharmaceutical compositions include excipients, fillers, extenders, binders, disintegrators, lubricants, preservatives, antioxidants, isotonic agents, buffers, coatings, sweeteners, solubilizers, bases, dispersants It can be prepared by known techniques using pharmaceutically acceptable carriers commonly used in each formulation, such as wetting agents, suspending agents, stabilizers, colorants, fragrances.
상기 약제의 제조에 있어서 본 발명의 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 함량은 약제의 형태에 따라 다르지만, 바람직하게는 0.01 내지 100 중량%의 농도이다. The content of the complex salt of the homogeneous crystalline acetyl-L-carnitine and potassium thioctal acid salt of the present invention in the preparation of the medicament depends on the form of the medicament, but is preferably in a concentration of 0.01 to 100% by weight.
본 발명의 약학적 조성물의 투여량은 치료되는 사람을 포함한 포유동물의 종류, 투여경로, 체중, 성별, 나이, 질환의 정도, 의사의 판단 등에 따라 넓은 범위에서 다양하게 변화된다. 일반적으로 경구투여의 경우에는 체중 1kg당 하루에 활성성분 0.01 내지 50 mg이 투여될 수 있고, 비경구투여의 경우에는 체중 1kg당 하루에 활성성분 0.01 내지 10 mg이 투여될 수 있다. 상술한 일일 투여량은 질환의 정도, 의사의 판단 등에 따라 한번에 또는 나누어서 사용될 수 있다.The dosage of the pharmaceutical composition of the present invention varies in a wide range depending on the type of mammal including the person to be treated, the route of administration, the weight, sex, age, the extent of the disease, the judgment of the doctor and the like. In general, in the case of oral administration, 0.01 to 50 mg of the active ingredient may be administered per day per 1 kg of body weight, and in the case of parenteral administration, 0.01 to 10 mg of the active ingredient may be administered per day of 1 kg of body weight. The above-described daily dose may be used at one time or dividedly depending on the extent of the disease, the judgment of the doctor, and the like.
본 발명에 따른 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 아세틸-L-카르니틴과 티옥트산이 물과 유기용매에 대한 용해도가 현저히 상이하여 균질하게 혼합하여 제제화하는데 어려웠던 문제점을 해결하고, 물에 대한 용해도를 증가시켜 생체이용률을 증가시킬 수 있는 장점을 갖는다. 본 발명에 따른 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 아세틸-L-카르니틴과 티옥트산이 균질하게 혼합되어 있어, 제제 단위에 따른 역가의 변동 없이 아세틸-L-카르니틴과 티옥트산을 간편하고 용이하게 병행 투여할 수 있는 약학적 조성물을 제조하는데 광범위하게 사용될 수 있다. The complex salt of the homogeneous crystalline acetyl-L-carnitine and potassium titanate salt according to the present invention has a problem that acetyl-L-carnitine and thioctic acid have a very different solubility in water and an organic solvent, making it difficult to formulate a homogeneous mixture. And it has the advantage that can increase the bioavailability by increasing the solubility in water. In the complex salt of the homogeneous crystalline acetyl-L-carnitine and potassium titanate salt according to the present invention, acetyl-L-carnitine and thioctic acid are mixed homogeneously, and thus acetyl-L-carnitine and acetyl-L-carnitine do not change. It can be widely used to prepare pharmaceutical compositions which can be administered simply and easily in parallel with thioctic acid.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다. Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1: 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Example 1 Preparation of a Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 아세톤 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 결정성 고체를 여과하여 아세톤 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 5.16g을 얻었다. 얻어진 수율은 92%였다. 수득된 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 X-선 회절분석 및 시차주사열량분석을 수행하여 그 결과를 각각 도 1 및 도 2에 나타내었다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of acetone was added to the obtained residue, followed by stirring at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained crystalline solid was filtered, washed with 20 ml of acetone, and dried in vacuo at 50 ° C. for 24 hours to obtain 5.16 g of a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium titanate salt. The yield obtained was 92%. X-ray diffraction analysis and differential scanning calorimetry of the obtained complex crystal of homogeneous crystalline acetyl-L-carnitine and potassium titanate salt were performed and the results are shown in FIGS. 1 and 2, respectively.
융점 : 140~144℃Melting Point: 140 ~ 144 ℃
[α]D : -12.0 (H2O: c 1.0)[α] D : -12.0 (H 2 O: c 1.0)
1H NMR (400 MHz, CDCl3) δ 5.48 (m, 1H), 3.73 (dd, 1H), 3.60 (m, 1H), 3.49 (d, 1H), 3.13 (m, 2H), 3.09 (s, 9H), 2.52 (dd, 1H), 2.39 (m, 2H), 2.10 (t, 2H), 2.02 (s, 3H), 1.89 (m, 1H), 1.26-1.69 (m, 6H) 1 H NMR (400 MHz, CDCl 3 ) δ 5.48 (m, 1H), 3.73 (dd, 1H), 3.60 (m, 1H), 3.49 (d, 1H), 3.13 (m, 2H), 3.09 (s, 9H), 2.52 (dd, 1H), 2.39 (m, 2H), 2.10 (t, 2H), 2.02 (s, 3H), 1.89 (m, 1H), 1.26-1.69 (m, 6H)
실시예 2: 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Example 2: Preparation of a Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 결정성 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 5.34g을 얻었다. 얻어진 수율은 95.3%였다. 수득된 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 융점, [α]D, 1H NMR, X-선 회절분석 및 시차주사열량분석 결과는 상기 실시예 1과 동일하였다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained crystalline solid was filtered, washed with 20 ml of 2-butanone, and dried in vacuo at 50 ° C for 24 hours to obtain 5.34 g of a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium titanate salt. The yield obtained was 95.3%. The melting point, [α] D , 1 H NMR, X-ray diffraction analysis and differential scanning calorimetry of the resultant complex crystal of homogeneous crystalline acetyl-L-carnitine and potassium titanate salt were the same as in Example 1.
실시예 3: 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Example 3: Preparation of a Complex Salt of Acetyl-L-Carnitine and Potassium Tioctate Salt
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 테트라하이드로퓨란 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1 시간 동안 유지하였다. 얻어진 결정성 고체를 여과하여 테트라하이드로퓨란 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 5.23g을 얻었다. 얻어진 수율은 93%였다. 수득된 균질한 결정성의 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 융점, [α]D, 1H NMR, X-선 회절분석 및 시차주사열량분석 결과는 상기 실시예 1과 동일하였다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. After adding 60 ml of tetrahydrofuran to the obtained residue and stirring at room temperature for 1 hour, the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained crystalline solid was filtered, washed with 20 ml of tetrahydrofuran, and dried under vacuum at 50 ° C. for 24 hours to obtain 5.23 g of a complex salt of homogeneous crystalline acetyl-L-carnitine and potassium titanate salt. The yield obtained was 93%. The melting point, [α] D , 1 H NMR, X-ray diffraction analysis and differential scanning calorimetry of the resultant complex crystal of homogeneous crystalline acetyl-L-carnitine and potassium titanate salt were the same as in Example 1.
실시예 4: 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염의 제조Example 4: Preparation of a Complex Salt of Acetyl-L-Carnitine and R (+)-Thiocyanate Potassium Salt
R(+)-티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 결정성 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 균질한 결정성의 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염 5.16g을 얻었다. 얻어진 수율은 92%였다. 수득된 균질한 결정성의 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염의 X-선 회절분석 및 시차주사열량분석을 수행하여 그 결과를 각각 도 3 및 도 4에 나타내었다. 2.84 g (13.77 mmol) of R (+)-thioctic acid was dissolved in 30 ml of methanol, followed by dropwise addition of 0.83 g (12.52 mmol) of potassium hydroxide in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained crystalline solid was filtered, washed with 20 ml of 2-butanone, and dried under vacuum at 50 ° C. for 24 hours to obtain 5.16 g of a complex salt of homogeneous crystalline acetyl-L-carnitine and R (+)-thiocate potassium salt. Got it. The yield obtained was 92%. X-ray diffraction analysis and differential scanning calorimetry of the resultant complex salts of the homogeneous crystalline acetyl-L-carnitine and R (+)-thiocyanate potassium salt were carried out and the results are shown in FIGS. 3 and 4, respectively.
융점 : 140~144℃Melting Point: 140 ~ 144 ℃
[α]D : +28.0 (H2O: c 1.0)[a] D : +28.0 (H 2 O: c 1.0)
1H NMR (400 MHz, CDCl3) δ 5.48 (m, 1H), 3.73 (dd, 1H), 3.60 (m, 1H), 3.49 (d, 1H), 3.13 (m, 2H), 3.09 (s, 9H), 2.52 (dd, 1H), 2.39 (m, 2H), 2.10 (t, 2H), 2.02 (s, 3H), 1.89 (m, 1H), 1.26-1.69 (m, 6H) 1 H NMR (400 MHz, CDCl 3 ) δ 5.48 (m, 1H), 3.73 (dd, 1H), 3.60 (m, 1H), 3.49 (d, 1H), 3.13 (m, 2H), 3.09 (s, 9H), 2.52 (dd, 1H), 2.39 (m, 2H), 2.10 (t, 2H), 2.02 (s, 3H), 1.89 (m, 1H), 1.26-1.69 (m, 6H)
실시예 5: 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 결정성 구조 확인Example 5: Determination of the Crystal Structure of a Complex Salt of Acetyl-L-Carnitine and Potassium Tioctate Salt
도 1 및 도 3으로부터, 상기 실시예 1에서 제조된 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염 및 상기 실시예 4에서 제조된 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염은 분말 X-선 회절분석에서 각각 특징적인 결정형태를 갖는 것을 확인할 수 있었다. 도 1 및 도 3의 분말 X-선 회절분석도에 나타난 특징적인 피크(peak)를 각각 하기 표 1과 2에 나타내었으며, 여기서 ‘2θ’는 회절각을, ‘d’는 결정면간의 거리를, ‘I/I0'는 피크(peak)의 상대강도를 의미한다. 1 and 3, a complex salt of acetyl-L-carnitine and potassium thiocate salt prepared in Example 1, and a complex of acetyl-L-carnitine and R (+)-thioctate salt prepared in Example 4 It was found that the salts each had characteristic crystal forms in powder X-ray diffraction analysis. Characteristic peaks shown in the powder X-ray diffractograms of FIGS. 1 and 3 are shown in Tables 1 and 2, respectively, where '2θ' is a diffraction angle and 'd' is a distance between crystal planes, 'I / I 0 ' means the relative intensity of the peak.
[표 1] 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 분말 X-선 회절분석TABLE 1 Powder X-ray diffraction analysis of complex salt of acetyl-L-carnitine and potassium thiocate salt
[표 2] 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염의 분말 X-선 회절분석TABLE 2 Powder X-ray Diffraction Analysis of a Complex Salt of Acetyl-L-Carnitine and R (+)-Thiocyanate Potassium Salt
실시예 6: 생체내 pH범위에서의 용해도 시험Example 6: Solubility Test in pH Range In Vivo
활성성분의 체내이용률 및 조성물의 용출속도에 큰 영향을 미치는 용해도 시험을 증류수와 생체흡수에 요구되는 생체내 pH 범위, 즉 장에서의 pH(5.2), 위에서의 pH(1.2), 혈액의 pH(7.4)에 근접하는 pH 범위에서 행하였다. Solubility tests, which have a significant effect on the availability of the active ingredient and the dissolution rate of the composition, are performed in vivo pH ranges required for distilled water and bioabsorption, namely pH in the intestines (5.2), stomach pH (1.2), blood pH ( 7.4) in the pH range approaching.
상기 실시예 1에서 제조된 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 용해도를 상업적으로 시판되는 아세틸-L-카르니틴 염산염과 티옥트산의 단순 혼합물 및 티옥트산의 용해도와 비교하여 표 2에 나타내었다. 각각의 pH 조건에서 각각의 물질을 포화상태에 도달하도록 용해시킨 후, 상기 용액을 고성능액체크로마토그래피(HPLC)로 분석하여 티옥트산을 기준으로 용해된 양을 측정하였다. The solubility of the complex salt of acetyl-L-carnitine and potassium titanate salt prepared in Example 1 is shown in Table 2 in comparison with the solubility of commercially available simple mixtures of acetyl-L-carnitine hydrochloride and thioctic acid and thioctic acid. . After dissolving each material to reach saturation at each pH condition, the solution was analyzed by high performance liquid chromatography (HPLC) to determine the amount dissolved based on thioctic acid.
[표 3] 용해도 시험TABLE 3 Solubility Test
상기 표 3에서 보는 바와 같이, 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 모든 pH 범위에서 티옥트산에 비하여 용해도가 크게 향상된 것으로 나타났다. 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 티옥트산과는 달리 아세틸-L-카르니틴이 함께 용해되어야 하는 불리한 점이 있음에도 불구하고 크게 향상된 용해도를 보여주었다. 이러한 결과로부터 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염이 생체이용률에 있어 티옥트산 보다 우수할 것으로 예측된다. As shown in Table 3, the complex salt of acetyl-L-carnitine and potassium thiocate salt was found to have greatly improved solubility compared to thioctic acid in all pH range. The complex salts of acetyl-L-carnitine and potassium thiocate salts showed greatly improved solubility, despite the disadvantage that acetyl-L-carnitine had to dissolve together, unlike thioctic acid. From these results, it is predicted that the combined salt of acetyl-L-carnitine and potassium titanate salt is superior to thioctic acid in bioavailability.
참고예 1: 선행문헌(대한민국특허공개 제2006-0011936호)의 방법을 이용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 1 Preparation of a Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate Salt Using the Method of Prior Art (Korean Patent Publication No. 2006-0011936)
티옥트산 2.84g(13.77mmol)을 2-부탄온 30㎖에 녹인 후, 아세틸-L-카르니틴 2.54g(12.52mmol)과 수산화칼륨 0.83g(12.52mmol)을 메탄올 50㎖에 녹여 적가하였 다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 4.55g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염은 전혀 얻어지지 않고 L-카르니틴과 티옥트산 칼륨염의 복합염만이 얻어졌다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of 2-butanone, 2.54 g (12.52 mmol) of acetyl-L-carnitine and 0.83 g (12.52 mmol) of potassium hydroxide were added dropwise in 50 ml of methanol. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The solid obtained was filtered, washed with 20 mL of 2-butanone and dried for 24 hours at 50 ° C. in vacuo to give 4.55 g of a solid product. As a result of NMR analysis, no complex salt of acetyl-L-carnitine and potassium titanate salt was obtained, but only a complex salt of L-carnitine and potassium titanate salt.
참고예 2: 유기용매로 2-프로판올을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 2: Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate Salt Using 2-Propanol as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-프로판올 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-프로판올 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 1.97g을 얻었다. NMR분석 결과 티옥트산 칼륨염만이 얻어졌다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-propanol was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The solid obtained was filtered, washed with 20 mL of 2-propanol and dried under vacuum at 50 ° C. for 24 hours to give 1.97 g of a solid product. NMR analysis showed only potassium thioctate salt.
참고예 3: 유기용매로 다이클로로메탄을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 3 Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate with Dichloromethane as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 다이클로로메탄 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 다이클로로메탄 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 1.31g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:3.9로 얻어졌다.After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of dichloromethane was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The solid obtained was filtered, washed with 20 mL of dichloromethane and dried at 50 ° C. for 24 hours under vacuum to obtain 1.31 g of a solid product. NMR analysis showed that the content ratio of acetyl-L-carnitine and potassium thiocate salt was 1: 3.9.
참고예 4: 유기용매로 아세토나이트릴을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 4: Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Tiotate Salt Using Acetonitrile as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 아세토나이트릴 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 아세토나이트릴 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 3.52g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:3.8로 얻어졌다.After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of acetonitrile were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The solid obtained was filtered, washed with 20 ml of acetonitrile and dried at 50 ° C. for 24 hours under vacuum to obtain 3.52 g of a solid product. NMR analysis showed that the content ratio of acetyl-L-carnitine and potassium titanate salt was 1: 3.8.
참고예 5: 유기용매로 1,2-다이클로로에탄을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 5 Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Tiotate Salt Using 1,2-Dichloroethane as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 1,2-다이클로로에탄 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 1,2-다이클로로에탄 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 1.1g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:4.7로 얻어졌다.After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 1,2-dichloroethane was added to the obtained residue, followed by stirring at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained solid was filtered, washed with 20 ml of 1,2-dichloroethane and dried at 50 ° C. for 24 hours under vacuum to obtain 1.1 g of a solid product. NMR analysis showed that the content ratio of acetyl-L-carnitine and potassium thiocate salt was 1: 4.7.
참고예 6: 유기용매로 에틸아세테이트를 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 6 Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Tiotate Salt Using Ethyl Acetate as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 에틸아세테이트 60㎖를 가하여 실온에서 1시간 동안 교반하였다. 혼합물을 0℃로 냉각시키고 1시간 동안 유지하여도 고체는 생성되지 않고 점성 또는 오일상의 물질이 생성되었다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of ethyl acetate was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Cooling the mixture to 0 ° C. and holding for 1 hour produced no solids but a viscous or oily material.
참고예 7: 유기용매로 에테르를 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 7 Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Tioctate Salt Using Ether as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 에테르 60㎖를 가하여 실온에서 1시간 동안 교반하였다. 혼합물을 0℃로 냉각시키고 1시간 동안 유지하여도 고체는 생성되지 않고 점성 또는 오일상의 물질이 생성되었다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of ether was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Cooling the mixture to 0 ° C. and holding for 1 hour produced no solids but a viscous or oily material.
참고예 8: 유기용매로 클로로포름을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 8: Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate with Chloroform as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 클로로포름 60㎖를 가하여 실온에서 1시간 동안 교반하였다. 혼합물을 0℃로 냉각시키고 1시간 동안 유지하여도 고체는 생성되지 않고 점성 또는 오일상의 물질이 생성되었다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of chloroform was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Cooling the mixture to 0 ° C. and holding for 1 hour produced no solids but a viscous or oily material.
참고예 9: 유기용매로 헥산을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 9 Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate Salt Using Hexane as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 헥산 60㎖를 가하여 실온에서 1시간 동안 교반하였다. 혼합물을 0℃로 냉각시키고 1시간 동안 유지하여도 고체는 생성되지 않고 점성 또는 오일상의 물질이 생성되었다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 mL of hexane was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Cooling the mixture to 0 ° C. and holding for 1 hour produced no solids but a viscous or oily material.
참고예 10: 유기용매로 톨루엔을 사용한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 제조Reference Example 10 Preparation of Complex Salt of Acetyl-L-Carnitine and Potassium Thiocate Salt Using Toluene as Organic Solvent
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 톨루엔 60㎖를 가하여 실온에서 1시간 동안 교반하였다. 혼합물을 0℃로 냉각시키고 1시간 동안 유지하여도 고체는 생성되지 않고 점성 또는 오일상의 물질이 생성되었다. After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of toluene was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. Cooling the mixture to 0 ° C. and holding for 1 hour produced no solids but a viscous or oily material.
참고예 11: 아세틸-L-카르니틴과 티옥트산 나트륨염의 복합염의 제조Reference Example 11 Preparation of Complex Salt of Acetyl-L-Carnitine and Sodium Thiocate Salt
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화나트륨 0.51g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 나트륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 2.66g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 나트륨염의 함량비가 1:4.9로 얻어졌다. 2.84 g (13.77 mmol) of thioctic acid was dissolved in 30 ml of methanol, and 0.51 g (12.52 mmol) of sodium hydroxide was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained sodium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained solid was filtered, washed with 20 ml of 2-butanone and dried at 50 ° C. for 24 hours under vacuum to obtain 2.66 g of a solid product. NMR analysis showed that the content ratio of acetyl-L-carnitine and sodium thioctate was 1: 4.9.
참고예 12: 아세틸-L-카르니틴과 티옥트산 나트륨염의 복합염의 제조Reference Example 12 Preparation of Complex Salt of Acetyl-L-Carnitine and Sodium Thiocate Salt
나트륨 0.29g(12.52mmol)을 메탄올 10㎖에 넣고 교반하여 녹인 후, 티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 나트륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 2.45g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 나트륨염의 함량비가 1:4.4로 얻어졌다.0.29 g (12.52 mmol) of sodium was added to 10 ml of methanol, stirred, and dissolved. Then, 2.84 g (13.77 mmol) of thioctic acid was added dropwise to 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained sodium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained solid was filtered, washed with 20 ml of 2-butanone and dried for 24 hours at 50 ° C. under vacuum to obtain 2.45 g of a solid product. NMR analysis showed that the content ratio of acetyl-L-carnitine and sodium thiocate was 1: 4.4.
참고예 13: 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 1.5:1인 복합염의 제조Reference Example 13 Preparation of a Compound Salt in which the Ratio of Acetyl-L-Carnitine and Potassium Thiocate Salt is 1.5: 1
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 3.82g(18.78mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 6.3g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:0.7인 비균질 혼합물로 확인되었다. 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 1.5:1인 복합염은 제조할 수 없었다.After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 3.82 g (18.78 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and then the methanol solution of the potassium titanate salt thus obtained was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The solid obtained was filtered, washed with 20 mL of 2-butanone and dried at 50 ° C. for 24 hours in vacuo to give 6.3 g of a solid product. NMR analysis showed an inhomogeneous mixture in which the content ratio of acetyl-L-carnitine and potassium titanate salt was 1: 0.7. Compound salts having a ratio of acetyl-L-carnitine and potassium thiocate salt of 1.5: 1 could not be prepared.
참고예 14: 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 1.2:1인 복합염의 제조Reference Example 14 Preparation of a Composite Salt wherein the Ratio of Acetyl-L-Carnitine and Potassium Thiocate Salt is 1.2: 1
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 3.05g(15.02mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 5.72g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:0.72인 비균질 혼합물로 확인되었다. 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 1.2:1인 복합염은 제조할 수 없었다.After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. After dissolving 3.05 g (15.02 mmol) of acetyl-L-carnitine in 20 ml of methanol, the methanol solution of the potassium titanate salt thus obtained was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained solid was filtered, washed with 20 ml of 2-butanone and dried at 50 ° C. for 24 hours in vacuo to give 5.72 g of a solid product. NMR analysis showed an inhomogeneous mixture in which the content ratio of acetyl-L-carnitine and potassium titanate salt was 1: 0.72. Compound salts having a ratio of acetyl-L-carnitine and potassium thioctic acid salt of 1.2: 1 could not be prepared.
참고예 15: 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 2:1인 복합염의 제조Reference Example 15 Preparation of a Composite Salt with a Ratio 2: 1 of Acetyl-L-Carnitine and Potassium Tioctate Salt
티옥트산 2.84g(13.77mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 0.83g(12.52mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 5.09g(25.04mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도 를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 8.34g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:0.26인 비균질 혼합물로 확인되었다. 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 2:1인 복합염은 제조할 수 없었다.After dissolving 2.84 g (13.77 mmol) of thioctic acid in 30 ml of methanol, 0.83 g of potassium hydroxide (12.52 mmol) was added dropwise in 30 ml of methanol. 5.09 g (25.04 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature below 25 ° C. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The solid obtained was filtered, washed with 20 mL of 2-butanone and dried at 50 ° C. for 24 hours in vacuo to give 8.34 g of solid product. NMR analysis showed an inhomogeneous mixture in which the content ratio of acetyl-L-carnitine and potassium titanate salt was 1: 0.26. Compound salts with a 2: 1 ratio of acetyl-L-carnitine and potassium thiocate salt could not be prepared.
참고예 16: 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 1:2인 복합염의 제조Reference Example 16 Preparation of a Composite Salt in which the Ratio of Acetyl-L-Carnitine and Potassium Thiocate Salt is 1: 2
티옥트산 5.69g(27.59mmol)을 메탄올 30㎖에 녹인 후, 수산화칼륨 1.65g(25.04mmol)을 메탄올 30㎖에 녹여 적가하였다. 아세틸-L-카르니틴 2.54g(12.52mmol)을 메탄올 20㎖에 녹인 후, 수득한 티옥트산 칼륨염의 메탄올 용액을 15 내지 20분간 적가하였다. 실온에서 10분 동안 교반한 후 반응용액의 온도를 25℃ 이하로 유지하면서 감압하에서 농축하였다. 얻어진 잔사에 2-부탄온 60㎖를 가하여 실온에서 1시간 동안 교반한 후, 혼합물을 0℃로 냉각시키고 1시간 동안 유지하였다. 얻어진 고체를 여과하여 2-부탄온 20㎖로 세척하고 진공하에 50℃에서 24시간 동안 건조하여 고체상의 생성물 7.89g을 얻었다. NMR분석 결과 아세틸-L-카르니틴과 티옥트산 칼륨염의 함량비가 1:2.6인 비균질 혼합물로 확인되었다. 아세틸-L-카르니틴과 티옥트산 칼륨염의 비가 1:2인 복합염은 제조할 수 없었다. 5.69 g (27.59 mmol) of thioctic acid was dissolved in 30 ml of methanol, and 1.65 g (25.04 mmol) of potassium hydroxide was added dropwise in 30 ml of methanol. 2.54 g (12.52 mmol) of acetyl-L-carnitine was dissolved in 20 ml of methanol, and the methanol solution of the obtained potassium thiocate salt was added dropwise for 15 to 20 minutes. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure while maintaining the temperature of 25 ° C or lower. 60 ml of 2-butanone was added to the obtained residue, which was stirred at room temperature for 1 hour, and then the mixture was cooled to 0 ° C. and maintained for 1 hour. The obtained solid was filtered, washed with 20 mL of 2-butanone and dried at 50 ° C. for 24 hours under vacuum to obtain 7.89 g of a solid product. NMR analysis showed an inhomogeneous mixture in which the content ratio of acetyl-L-carnitine and potassium titanate salt was 1: 2.6. Compound salts in which the ratio of acetyl-L-carnitine and potassium thioctate salt were 1: 2 could not be prepared.
도 1은 실시예 1에서 수득한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 X선 회절분석도이다. 1 is an X-ray diffraction diagram of a complex salt of acetyl-L-carnitine and potassium thiocate salt obtained in Example 1. FIG.
도 2는 실시예 1에서 수득한 아세틸-L-카르니틴과 티옥트산 칼륨염의 복합염의 시차주사열량 기록도(Differential Scanning Calorimeter Thermogram)이다.FIG. 2 is a differential scanning calorimeter thermogram of a complex salt of acetyl-L-carnitine and potassium titanate salt obtained in Example 1. FIG.
도 3은 실시예 4에서 수득한 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염의 X선 회절분석도이다. FIG. 3 is an X-ray diffraction diagram of a composite salt of acetyl-L-carnitine and R (+)-thiocyanate salt obtained in Example 4. FIG.
도 4는 실시예 4에서 수득한 아세틸-L-카르니틴과 R(+)-티옥트산 칼륨염의 복합염의 시차주사열량 기록도(Differential Scanning Calorimeter Thermogram)이다.FIG. 4 is a differential scanning calorimeter thermogram of a complex salt of acetyl-L-carnitine and R (+)-thioctate potassium salt obtained in Example 4. FIG.
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| KR1020090007250A Expired - Fee Related KR100903549B1 (en) | 2008-07-29 | 2009-01-30 | Complex salt of homogeneous crystalline acetyl-L-carnitine and potassium thiocate salt, preparation method thereof and pharmaceutical composition comprising the same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010151008A3 (en) * | 2009-06-24 | 2011-05-19 | Celltrion Chemical Research Institute | Piperazine dithioctate and pharmaceutical composition comprising the same |
| KR101858452B1 (en) | 2016-08-30 | 2018-05-23 | 엔자이텍 주식회사 | Solid form Acetyl-L-Carnitine and Method of Preparing Thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR900003020B1 (en) * | 1983-12-28 | 1990-05-04 | 씨그마-라우 인더스트리에 파마쎄리게 류미떼 에스. 피. 에이. | Method for preparing L-carnitine and alkanoyl L-carnitine salts |
| US6365622B1 (en) * | 1998-09-01 | 2002-04-02 | Sigma-Tau Healthscience S.P.A. | Antioxidant composition comprising acetyl L-carnitine and α-lipoic acid |
| WO2002096218A2 (en) | 2001-05-28 | 2002-12-05 | Basf Aktiengesellschaft | Combination of lipoic acids, carnitines, and creatines in food and pharmaceuticals |
| KR20060011936A (en) * | 2003-04-22 | 2006-02-06 | 라보라토리오 치미코 인터나지오날레 에스.피.에이. | Basic salts of thioctic acid with L-carnitine |
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2009
- 2009-01-30 KR KR1020090007250A patent/KR100903549B1/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR900003020B1 (en) * | 1983-12-28 | 1990-05-04 | 씨그마-라우 인더스트리에 파마쎄리게 류미떼 에스. 피. 에이. | Method for preparing L-carnitine and alkanoyl L-carnitine salts |
| US6365622B1 (en) * | 1998-09-01 | 2002-04-02 | Sigma-Tau Healthscience S.P.A. | Antioxidant composition comprising acetyl L-carnitine and α-lipoic acid |
| WO2002096218A2 (en) | 2001-05-28 | 2002-12-05 | Basf Aktiengesellschaft | Combination of lipoic acids, carnitines, and creatines in food and pharmaceuticals |
| KR20060011936A (en) * | 2003-04-22 | 2006-02-06 | 라보라토리오 치미코 인터나지오날레 에스.피.에이. | Basic salts of thioctic acid with L-carnitine |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010151008A3 (en) * | 2009-06-24 | 2011-05-19 | Celltrion Chemical Research Institute | Piperazine dithioctate and pharmaceutical composition comprising the same |
| CN102803243A (en) * | 2009-06-24 | 2012-11-28 | 株式会社瑟成恩化学研究所 | Piperazine Dithioctate And Pharmaceutical Composition Comprising The Same |
| US8541601B2 (en) | 2009-06-24 | 2013-09-24 | Celltrion Chemical Research Institute | Piperazine dithioctate and pharmaceutical composition comprising the same |
| KR101858452B1 (en) | 2016-08-30 | 2018-05-23 | 엔자이텍 주식회사 | Solid form Acetyl-L-Carnitine and Method of Preparing Thereof |
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