KR20010001219A - Novel Acetaminophen Derivatives and their Preparation - Google Patents

Novel Acetaminophen Derivatives and their Preparation Download PDF

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KR20010001219A
KR20010001219A KR1019990020289A KR19990020289A KR20010001219A KR 20010001219 A KR20010001219 A KR 20010001219A KR 1019990020289 A KR1019990020289 A KR 1019990020289A KR 19990020289 A KR19990020289 A KR 19990020289A KR 20010001219 A KR20010001219 A KR 20010001219A
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acetaminophen
acid addition
pyruvate
group
addition salt
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KR1019990020289A
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Korean (ko)
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박상철
강흔수
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박상철
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    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K31/00—Actuating devices; Operating means; Releasing devices
    • F16K31/02—Actuating devices; Operating means; Releasing devices electric; magnetic
    • F16K31/06—Actuating devices; Operating means; Releasing devices electric; magnetic using a magnet, e.g. diaphragm valves, cutting off by means of a liquid
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
    • F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
    • F16K27/00—Construction of housing; Use of materials therefor
    • F16K27/02—Construction of housing; Use of materials therefor of lift valves
    • F16K27/029—Electromagnetically actuated valves

Abstract

PURPOSE: A novel acetaminophen derivatives is provided, which shows good stability, and shows similar analgesic and antipyretic effect compared with existing acetaminophen preparations but gives less liver-toxicity, so can be used as analgesics and antipyretics. CONSTITUTION: A process for the preparation of acetaminophen-O-L-aspartate or acetaminophen-O-pyruvate(a kind of novel acetaminophen derivatives) comprises: dissolving acetaminophen, Boc-amino-L-aspartic acid or pyruvic acid, and DMAP(Dimethyl 4-amino pyridine) in organic solvent, desirably anhydrous ethylacetate; adding a mixed solution of DCC(Dicyclohexylcarbodiimide) in anhydrous ethylacetate, and reacting at room temperature for 2hrs; filtering and removing produced crystal, and removing solvent under decompression; separating with silica gel column chromatography; dissolving the product in tetrahydropurane, adding ether chlorite, and reacting at -20°C for 2hrs; filtering produced solid under decompression, and re-crystallizing to get the objective substances.

Description

신규 아세트아미노펜 유도체 및 제조방법{Novel Acetaminophen Derivatives and their Preparation}Novel Acetaminophen Derivatives and their Preparation

본 발명은 신규 아세트아미노펜 유도체 및 그 제조방법과 이를 유효성분으로 하는 진통제 및 해열제에 관한 것이다.The present invention relates to a novel acetaminophen derivative, a method for producing the same, and an analgesic and antipyretic agent using the same as an active ingredient.

아세트아미노펜은 공지된 진통제 및 해열제로서 전세계적으로 통상적인 액제, 좌약제, 캡슐및 정제등의 투여형태로 비처방전으로 판매되고 있다.Acetaminophen is a known analgesic and antipyretic agent and is sold over the world in over-the-counter dosage forms in conventional liquids, suppositories, capsules and tablets.

이러한 대표적인 퀴논성 약물인 아세트아미노펜은 그 자체로는 독성이 없으나 일단 인체내 흡수되면 주로 간에서 대사되며 극심한 간세포독성을 유발한다. 아세트아미노펜은 흡수된 후 간에서 환원적으로 대사되는데 아미노펜의 환원경로로는 1전자 환원경로와 2전자 환원경로가 있다. 2전자환원은 간세포질에 함유된 퀴논리덕타제에 의하여 NADH로 부터 2개의 전자를 받아 무독성 히드로퀴논인 아세트아미노펜으로 전환되어 곧 UDPGA(uridine diphosphate-glucuronsyl transferase)나 설페이트조효소와 포합되어 답즙이나 소변을 통해 체외로 배설된다. 한편 단일 전자 환원은 간세포 소포체에 분포된 P-450 리덕타제에 의하여 NADPH로부터 전자 하나를 받아 N-아세틸이미도퀴논이라는 맹독성 대사산물을 생성하여 일단은 간세포내의 글루타티온을 고갈시킨후 간세포대사를 유발한다. 이와 같은 N-아세틸이미도퀴논이라는 맹독성 대사산물이 야기하는 문제점을 해결하기 위해 독성이 적은 새로운 아세트아미노펜 유도체 약물(미국특허 제 4,520,134 )을 개발하거나 항산화제 또는 라디칼제거 효소들의 병용요법이 제안되고 있지만 사용에 많은 제한을 받고 있다. 최근 항산화제인 베타-카로틴(미국특허 제 5,670,549)과 디알릴설퍼화합물(미국특허 제 5,474,757)혹은 공지의 글루타티온이나 N-아세틸시스틴을 병용하는 방법이 보고 되고 있으나 맹독성 대사물질인 세미-퀴논을 제거하는 적절한 조건이 확립되어 있지 않고, 각종 항산화제들은 그들 자체가 높은 반응성을 가지고 있기 때문에 문제가 있다.Acetaminophen, a typical quinone drug, is not toxic in itself, but once absorbed into the body, it is metabolized mainly by the liver and causes severe hepatotoxicity. Acetaminophen is metabolized reductively in the liver after being absorbed. The reduction pathways of aminophene include one-electron reduction pathway and two-electron reduction pathway. The two-electron reduction receives two electrons from NADH by the quinone reductase in the hepatocellular cytoplasm and is converted into acetaminophen, a non-toxic hydroquinone, which is then combined with UDPGA (uridine diphosphate-glucuronsyl transferase) or sulfate coenzyme to produce bile or urine. Excreted through the body. On the other hand, single electron reduction generates an toxic metabolite called N-acetylimidoquinone by receiving one electron from NADPH by P-450 reductase distributed in hepatocyte endoplasmic reticulum, and depletes glutathione in hepatocytes and causes hepatocellular metabolism. In order to solve the problems caused by such a toxic metabolite, N-acetylimidoquinone, a new low-toxic acetaminophen derivative drug (US Pat. No. 4,520,134) has been developed or a combination therapy of antioxidants or radical scavenging enzymes has been proposed. Are under many restrictions. Recently, a method of using beta-carotene (US Pat. No. 5,670,549) and diallylsulfur compound (US Pat. No. 5,474,757) or known glutathione or N-acetylcystine in combination with antioxidants has been reported. Proper conditions are not established and various antioxidants are problematic because they themselves have high reactivity.

따라서 종래 기술의 상기와 같은 문제점으로 인하여 약물의 부작용을 감소시키는 효율적인 항산화제의 역활을 수행하면서도 안전성이 높으며 또한 약의 효능을 유지할 수 있는 새로운 차원의 신규 아세트아미노펜 유도체의 개발이 절실하게 요구되고 있는 실정이다.Therefore, there is an urgent need for the development of novel acetaminophen derivatives of a new level that can maintain the efficacy of the drug while maintaining the safety of the drug while performing the role of an effective antioxidant that reduces side effects of drugs due to the above problems of the prior art. It is true.

아세트아미노펜이 체내 흡수되면 간세포내에서는 1전자환원 독성세포괴사경로와 2전자 환원 무독성 배설경로가 경쟁적으로 작동하여 아세트아미노펜을 대사시킨다. 독성화 1전자환원 경로는 주로 NADPH/NADP 조효소의 비에 의하고, 무독성화 2전자환원 경로는 주로 NADH/NAD 의 비에 의해 조절이 가능하다. 따라서 본 발명자는 간세포 독성의 요인이 되는 대사산물인 세미-퀴논생성은 NAD/NADH 비의 보정을 통하여 조절할 수 있음에 착안하여 아세트아미노펜의 간장독성을 경감시키기 위한 방안을 연구하던 중, 아스파르트산 및 그 염과 피루베이트산 및 그염이 생체내 NADH/NAD 비율을 조절함으로써 독소루비신과 같은 퀴논화합물에 의한 심독성을 경감시킬 수 있다는 선행 발명특허(한국특허출원번호 94-012769, 98-016349)에 근거하여 신규 아세트아미노펜-아스파르테이트와 아세트아미노펜-피루베이트 유도체의 발명을 완성하였다.When acetaminophen is absorbed into the body, one-electron-reducing toxic cell necrosis pathway and two-electron reducing non-toxic excretory pathway operate competitively in hepatocytes to metabolize acetaminophen. Toxic one-electron reduction pathway is mainly controlled by the ratio of NADPH / NADP coenzyme, and the non-toxicized two-electron reduction pathway is mainly controlled by the ratio of NADH / NAD. Therefore, the present inventors focused on the fact that semi-quinone production, a metabolite that is a factor of hepatotoxicity, can be regulated through the correction of NAD / NADH ratio, and while studying a method for reducing hepatotoxicity of acetaminophen, aspartic acid and Based on the prior invention patent (Korean Patent Application No. 94-012769, 98-016349) that the salt and pyruvate and its salt can alleviate cardiotoxicity by quinone compounds such as doxorubicin by controlling the in vivo NADH / NAD ratio. The invention of novel acetaminophen-aspartate and acetaminophen-pyruvate derivatives has been completed.

따라서, 본 발명의 목적은 상기 구조식의 공지의 아세트아미노펜보다 간독성이 훨씬 경감된 신규 저간독성 진통 및 해열제인 아세트아미노펜 유도체 및 그 제조방법을 제공하는데 있다.Accordingly, it is an object of the present invention to provide a novel low hepatotoxic analgesic and antipyretic acetaminophen derivative and a method for producing the same, which have much reduced hepatotoxicity than the known acetaminophen of the above structural formula.

본 발명의 신규 아세트아미노펜 유도체는 기존의 아세트아미노펜과 L-아스파르테이트산 및 피루베이트산을 반응시켜 아세트아미노펜의 히드록시기 위치에 에스테르결합을 이룬 하기 구조식으로 표시된다.The novel acetaminophen derivative of the present invention is represented by the following structural formula which reacts existing acetaminophen with L-aspartate acid and pyruvate to form an ester bond at the hydroxyl group position of acetaminophen.

상기식에서 R은 L-아스파르테이트기 혹은 피루베이트기를 나타낸다.In the formula, R represents an L-aspartate group or pyruvate group.

또한 본 발명의 아세트아미노펜 유도체의 산 부가염의 가능한 형태로는 염화수소, 브롬화수소, 인산염 또는 황산염과 같은 무기산으로 부터 유도된 염 또는 수산염, 유산염, 석신산염, 주석산염, 초산염, 살리실산염, 구연산염, 안식향산염 또는 아디페이트 같은 유기산으로 부터 유도된 염 등이 있다.Also possible forms of acid addition salts of the acetaminophen derivatives of the present invention include salts derived from inorganic acids such as hydrogen chloride, hydrogen bromide, phosphates or sulfates or oxalates, lactates, succinates, tartarates, acetates, salicylates, citrates, benzoic acids. Salts or salts derived from organic acids such as adipates.

본 발명인 아세트아미노펜으로 부터 아세트아미노펜O-L-아스파르테이트 혹은 아세트아미노펜-O-피루베이트의 제조방법은 다음과 같다.The method for preparing acetaminophen O-L-aspartate or acetaminophen-O-pyruvate from acetaminophen of the present invention is as follows.

(ⅰ). 유기용매, 바람직하기로는 무수 에틸아세테이트에 아세트아미노펜, Boc-아미노-L-아스파르트산 또는 피루베이트산 및 DMAP(Dimethyl 4-amino pyridine)를 적량 첨가하고, 여기에 무수에틸아세테이트에 DCC(Dicyclohexylhexylcarbodiimide)를 적량 첨가한 용액을 가하여 상온에서 반응시키는 과정; 및(Iii). An appropriate amount of acetaminophen, Boc-amino-L-aspartic acid or pyruvate and DMAP (Dimethyl 4-amino pyridine) is added to an organic solvent, preferably ethyl acetate, and dicyclohexylhexylcarbodiimide (DCC) is added thereto to anhydrous ethyl acetate. Adding an appropriate amount of the solution and reacting at room temperature; And

(ⅱ). (ⅰ)에 의하여 생성된 결정은 여과하여 제거하고 용매는 감압제거하여 얻어진 생성물을 컬럼크로마토 그라피로 분리하여 신규 아세트아미노펜 유도체를 얻는다.(Ii). The crystal produced by (iii) is filtered off and the solvent is removed under reduced pressure to separate the product obtained by column chromatography to obtain a novel acetaminophen derivative.

이하 본 발명에 의한 신규 아세트아미노펜 유도체의 제조과정을 실시예에 의하여 구체적으로 설명하고자 하나 본 발명의 권리범위가 이들 실시예에 의하여 한정되어지지는 아니한다.Hereinafter, a process for preparing a novel acetaminophen derivative according to the present invention will be described in detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

〈 실시예 1 〉 아세트아미노펜-O-L-아스파르테이트의 제조<Example 1> Preparation of acetaminophen-O-L-aspartate

무수 에틸아세테이트 250 미리리터에 아세트아미노펜 2.6 그람, Boc-아미노-L-아스파르트산 3.0 그람과 DMAP(Dimethyl 4-amino pyridine) 1.5그람을 녹인 용액에 무수 에틸아세테이트 250미리리터에 DCC(Dicyclohexylhexylcarbodiimide) 12.6 그람을 녹인 용액을 가한후 2시간 동안 상온에서 반응시켰다. 생성된 결정은 여과하여 제거하였고 용매는 감압 제거하여 얻어진 생성물을 컬럼크로마토그래피(실리카겔; 용출제 에틸아세테이트/헥산 3:1)로 분리하여 아세트아미노펜-O-Boc-아미노-L-아스파르테이트를 얻었다. 여기서 얻어진 생성물을 다시 테트라히드로푸란 200 미리리터에 녹여 에테르염산염을 가하여 - 20 ℃에서 2시간 반응시킨 후 생성된 고체를 감압 여과하여 에틸아세테이트-헥산 재결정하여 아세트아미노펜-O-L-아스파르테이트 1.7 그람(수율 35 %)를 얻었다.A solution of 2.6 grams of acetaminophen, 250 grams of Boc-amino-L-aspartic acid and 1.5 grams of DMAP (dimethyl 4-amino pyridine) in 250 ml of anhydrous ethyl acetate was dissolved in 12.6 grams of DCC (Dicyclohexylhexylcarbodiimide) in 250 milliliters of anhydrous ethyl acetate. The solution was added and reacted at room temperature for 2 hours. The resulting crystals were removed by filtration and the solvent was removed under reduced pressure. The product obtained was separated by column chromatography (silica gel; eluent ethyl acetate / hexane 3: 1) to obtain acetaminophen-O-Boc-amino-L-aspartate. Got it. The obtained product was dissolved in 200 ml of tetrahydrofuran again, ether hydrochloride was added, and the resultant was reacted at -20 ° C for 2 hours. The resulting solid was filtered under reduced pressure, and ethyl acetate / hexane was recrystallized to obtain 1.7 grams of acetaminophen-OL-aspartate. 35%).

녹는점: 135-137 CMelting Point: 135-137 C

IR스펙트럼(cm-1)IR spectrum (cm -1 )

3100-3000(페닐), 1750-1740(에스테르) 1715-1650(아미드)3100-3000 (phenyl), 1750-1740 (ester) 1715-1650 (amide)

1H-NMR스펙트럼(CH3OD, ppm) 1 H-NMR spectrum (CH 3 OD, ppm)

2.12( s, 3H, CH3), 3.80(d, 2H, CH2), 4.60(t, 1H, CH), 7.01-7.61(m, 4H, Ph)2.12 (s, 3H, CH 3 ), 3.80 (d, 2H, CH 2 ), 4.60 (t, 1H, CH), 7.01-7.61 (m, 4H, Ph)

〈 실시예 2 〉 아세트아미노펜-O-피루베이트의 제조<Example 2> Preparation of acetaminophen-O-pyruvate

무수 에틸아세테이트 250 미리리터에 아세트아미노펜 2.6 그람, 피루베이트 3.0 그람과 DMAP(Dimethyl 4-amino pyridine) 1.5그람을 녹인 용액에 무수 에틸아세테이트 250미리리터에 DCC(Dicyclohexylhexylcarbodiimide) 12.5 그람을 녹인 용액을 가한후 2시간 동안 상온에서 반응시켰다. 생성된 결정은 여과하여 제거하고 용매는 감압 제거하여 얻어진 생성물을 컬럼크로마토그래피(실리카겔; 용출제 에틸아세테이트/헥산 3:1)로 분리하여 아세트아미노펜-O-피루베이트 1.2 그람(수율 30 %)를 얻었다.A solution of 2.6 grams of acetaminophen, 250 grams of pyruvate and 1.5 grams of DMAP (dimethyl 4-amino pyridine) in 250 ml of anhydrous ethyl acetate was added to a solution of 12.5 grams of dicyclohexylhexylcarbodiimide (DCC) in 250 milliliters of anhydrous ethyl acetate. The reaction was carried out at room temperature. The resulting crystals were removed by filtration and the solvent was removed under reduced pressure. The product obtained was separated by column chromatography (silica gel; eluent ethyl acetate / hexane 3: 1) to obtain 1.2 grams of acetaminophen-O-pyruvate (30% yield). Got it.

녹는점: 124-126 CMelting Point: 124-126 C

IR스펙트럼(cm-1)IR spectrum (cm -1 )

3100-3000(페닐), 1740-1720(에스테르) 1710-1650(아미드)3100-3000 (phenyl), 1740-1720 (ester) 1710-1650 (amide)

1H-NMR스펙트럼(CH3OD, ppm) 1 H-NMR spectrum (CH 3 OD, ppm)

2.17( s, 3H, CH3), 2.29( s, 3H, CH3), 7.02-7.50(m, 4H, Ph)2.17 (s, 3H, CH 3 ), 2.29 (s, 3H, CH 3 ), 7.02-7.50 (m, 4H, Ph)

본 발명에 의한 신규 아세트아미노펜 유도체는 저간독성을 가지면서 우수한 해열 및 진통작용을 나타내어 진통 및 해열제로 사용할 수 있다. 따라서 약품으로 사용 가능한 희석제나 매체로 구성되는 약품조성의 형태로 인간을 포함한 동물에 투여될 수 있으며, 이러한 약품 조성물은 생리적으로 허용 가능한 부형제, 결합제, 방부제, 안정제, 향미제 또는 다른 화합물 성분을 포함할 수 있다. 또한, 상기 약품 조성물은 약품으로 사용하기 위해 통상적인 단위 복용량의 형태로 제조되어 질 수도 있다.The novel acetaminophen derivative according to the present invention can be used as an analgesic and antipyretic agent with low hepatotoxicity and showing excellent antipyretic and analgesic action. Thus, it can be administered to animals, including humans, in the form of a pharmaceutical composition consisting of diluents or media that can be used as drugs, and such pharmaceutical compositions include physiologically acceptable excipients, binders, preservatives, stabilizers, flavoring agents or other compound components. can do. In addition, the pharmaceutical composition may be prepared in a conventional unit dosage form for use as a medicine.

약품 조성물은 부드러운 젤라틴 캡슐, 두 조각으로 된 경질의 젤라틴 캡슐, 정제, 엘틱시트, 유탁액 중에 함유되거나 주사용액 또는 현탁액이나 오일현탁액 또는 용액 내에 함유될 수 있으며, 함유된 활성물질의 양은 각각의 단위 복용량, 바람직하게는 활성 성분을 약 250-1000mg 제공하도록 선택되어진다. 또한, 다른 치료요법에서 유용한 물질을 첨가하여 사용할 수도 있다.The pharmaceutical composition may be contained in a soft gelatin capsule, a two-piece hard gelatine capsule, a tablet, an eltic sheet, an emulsion, or in an injectable solution or suspension or an oil suspension or solution, the amount of active substance contained in each unit. The dosage is preferably selected to provide about 250-1000 mg of the active ingredient. It is also possible to add and use substances useful in other therapies.

본 발명의 화합물을 실제로 투여하는 경우에는 일반적으로 의약제제 분야에서 사용가능한 통상의 담체와 혼합하여 정제 또는 제제형의 형태의 것을 경구적으로 투여할 수 있다.In the case of actually administering a compound of the present invention, it may be administered orally in the form of a tablet or a formulation, generally in combination with a conventional carrier usable in the pharmaceutical field.

또한 비경구적인 투여 방법으로는 동물의 경우, 복강내 주사, 피하주사, 정맥 또는 동맥의 혈관내 주사 및 국소 투여등의 주사제로서, 사람의 경우는 정맥 또는 동맥의 혈관내 주사 또는 국소 투여등의 주사제로서 투여되고, 이러한 투여량은 투여방법, 환자 또는 피처리 동물의 상황, 예를 들면, 연령, 체중, 성별, 감수성, 식이, 투여시간, 병용하는 약제, 환자 또는 그 병의 정도에 따라서 적당하게 변화시켜 투여할 수 있다.In addition, the parenteral administration method is an injection such as intraperitoneal injection, subcutaneous injection, intravenous injection of a vein or artery and local administration in animals, and intravenous injection or local administration of veins or arteries in humans. It is administered as an injection, and the dosage is appropriate depending on the method of administration, the situation of the patient or treated animal, for example, age, weight, sex, sensitivity, diet, time of administration, medication used, patient or degree of the disease. Can be administered.

본 발명의 화합물을 진통 및 해열제로서 사용하는 경우에, 종래의 아세트아미노펜의 것보다 투여량을 넓게 할 수 있으나 통상 1일 500-5000mg의 범위내에서 사용하는 것이 바람직하다.In the case of using the compound of the present invention as an analgesic and antipyretic agent, the dosage can be wider than that of conventional acetaminophen, but it is generally preferred to use within the range of 500-5000 mg per day.

이들 신규 아세트아미노펜 유도체들에 의한 해열 및 진통 작용시험예는 공지의 방법에 따라 다음과 같이 실시하였다.The antipyretic and analgesic action test examples of these novel acetaminophen derivatives were carried out as follows according to a known method.

〈 시험예 1 〉 해열작용시험〈Test Example 1〉 Antipyretic Test

1) 시험 방법 및 체온 측정 : 리포폴리사카라이드(Lipopolysaccharide, LPS)를 피하주사하여 유발된 체온 상승에 대한 시료의 해열작용시험을 다음과 같이 실시하였다. 시험 전에 체온이 거의 유사한 체중 20∼25g의 ICR 계 마우스를 암, 수 각각 4마리씩 시험군별로 8마리로 하여, 16시간 절식시킨 후 LPS를 피하투여하였다. 투여 1시간 후 시료약물을 복강투여하여 대조군과 시험군을 디지탈 체온측정 장치 (Karl Kolb 사)로 마우스의 직장온도를 측정하였다. 대조군(LPS, 0.1mg/kg/10ml), 시험군(아세트아미노펜-아스파르테이트, 111mg/kg/10ml) 아세트아미노펜-피루베이트, 151mg/kg/10ml) 및 대조약물군(아세트아미노펜 75mg/kg/10ml)으로 나누어 해당 시료를 복강투여한 다음, 1, 2, 4, 5, 6, 8 시간대의 체온을 측정하여 체온의 변화를 관찰하였다.1) Test method and body temperature measurement: The antipyretic effect test of the sample for body temperature increase induced by subcutaneous injection of lipopolysaccharide (LiPS) was performed as follows. Before the test, ICR-based mice with body weights of approximately 20-25 g having almost similar body temperature were used for each of the four groups of four males and four males, and fasted for 16 hours, and then subcutaneously administered LPS. After 1 hour of administration, the sample drug was intraperitoneally administered, and the control and test groups were measured for rectal temperature of the mice with a digital thermometer (Karl Kolb). Control group (LPS, 0.1 mg / kg / 10 ml), test group (acetaminophen-aspartate, 111 mg / kg / 10 ml) acetaminophen-pyruvate, 151 mg / kg / 10 ml) and control drug group (acetaminophen 75 mg / kg / 10ml), and the sample was intraperitoneally administered, and then the body temperature was measured at 1, 2, 4, 5, 6, and 8 time periods to observe changes in body temperature.

2) 실험결과 : 대조군의 체온은 5시간까지 계속 상승하는 것을 볼 수 있었으나, 본 발명의 시료는 공히 아세트아미노펜과 같이 투여 후에 모두 현저한 해열 효과를 나타냄을 알수 있었다.2) Experimental results: Although the body temperature of the control group was continuously increased up to 5 hours, it was found that the samples of the present invention showed a significant antipyretic effect after administration together with acetaminophen.

(표 1) LPS 체온 유발 마우스에 있어서의 아세트아미노펜 유도체의 해열효과Table 1 Antipyretic effect of acetaminophen derivatives in LPS body temperature-inducing mice

실험군Experimental group 투여량(mg/kg,복강투여)Dose (mg / kg, intraperitoneal administration) 동물수The number of animals 체온±S.EBody temperature ± S.E 0hr0hr 1hr1hr 2hr2hr 4hr4hr 5hr5hr 6hr6hr 8hr8hr 대조군Control -- 88 37.5±0.3737.5 ± 0.37 37.8±0.4337.8 ± 0.43 37.7±0.3737.7 ± 0.37 38.2±0.33a 38.2 ± 0.33 a 38.4±0.24a 38.4 ± 0.24 a 37.9±0.3537.9 ± 0.35 37.6±0.3137.6 ± 0.31 AP-aspAP-asp 111111 88 37.5±0.3537.5 ± 0.35 37.8±0.3537.8 ± 0.35 37.4±0.4637.4 ± 0.46 37.7±0.44b 37.7 ± 0.44 b 37.9±0.36b 37.9 ± 0.36 b 37.6±0.3637.6 ± 0.36 37.4±0.4437.4 ± 0.44 AP-pyrAP-pyr 151151 88 37.4±0.3537.4 ± 0.35 37.6±0.4037.6 ± 0.40 37.3±0.4137.3 ± 0.41 37.6±0.37b 37.6 ± 0.37 b 37.8±0.25b 37.8 ± 0.25 b 37.7±0.3937.7 ± 0.39 37.5±0.3337.5 ± 0.33 아세트아미노펜Acetaminophen 7575 88 37.2±0.3737.2 ± 0.37 37.5±0.3237.5 ± 0.32 37.3±0.2037.3 ± 0.20 37.5±0.36b 37.5 ± 0.36 b 37.7±0.21b 37.7 ± 0.21 b 37.6±0.3837.6 ± 0.38 37.4±0.3837.4 ± 0.38

AP-asp: 아세트아미노펜-아스파르테이트군, AP-pyr: 아세트아미노펜-피루베이트군AP-asp: acetaminophen-aspartate group, AP-pyr: acetaminophen-pyruvate group

〈 시험예 2 〉 진통작용시험<Test Example 2> Analgesic test

1) 진통작용 측정: 16시간 절식시킨 체중 20∼25g의 마우스를 암, 수 각각 4마리씩 시험군별로 8마리로 하여 공지의 초산 리팅법(Writhing method)에 따라 대조군(생리식염수 10ml/kg), 시험군(아세트아미노펜-아스파르테이트, 111mg/kg/10ml과 아세트아미노펜-피루베이트(151㎎/㎏/10ml) 및 대조약물군(아세트아미노펜 75mg/kg)으로 나누어 해당 시료를 복강투여한 다음, 1시간후에 0.6% 초산 생리식염수액 10ml을 복강내에 주사하였다. 투여 10분 후부터 10분간 발현되는 리팅(Writhing)횟수를 측정하였다.1) Measurement of analgesic activity: 20 to 25 g of the body weight fasted for 16 hours, 4 rats and 4 males, 8 rats per test group, according to the known acetate method (physiological saline 10ml / kg), Intraperitoneally administer the sample by dividing it into the test group (acetaminophen-aspartate, 111mg / kg / 10ml and acetaminophen-pyruvate (151mg / kg / 10ml) and the control drug group (acetaminophen 75mg / kg), and then 1 10 hours after injection, 10 ml of 0.6% physiological saline solution was injected intraperitoneally.

2) 실험결과 : 초산으로 유발한 리팅 증후군(writhing symptom)의 평균회수와 억제율은 표 2에 나타내었다. 대조군의 평균회수 12.4회에 비해 시료을 투여한 군에서는 4.1회로 유의성 있는 결과를 얻었다.2) Experimental Results: The average recovery and inhibition rate of acetic acid-induced writhing symptom is shown in Table 2. Compared with the average number of times of the control group, 12.4 times, the sample group received 4.1 results.

(표 2) 초산 유발 마우스에 있어서의 리팅 증후군에 대한 아세트아미노펜 유도체의 효과Table 2 Effect of Acetaminophen Derivatives on Litting Syndrome in Acetic Acid-Induced Mice

실험군Experimental group 투여량(mg/kg,복강투여)Dose (mg / kg, intraperitoneal administration) 동물수The number of animals 리팅증후군의 평균수±S.E/10분Mean number of lifting syndrome ± S.E / 10 min 대조군Control -- 88 12.4±3.9a 12.4 ± 3.9 a AP-AspAP-Asp 111111 88 5.9±2.4b 5.9 ± 2.4 b AP-PyrAP-Pyr 151151 88 5.5±1.9b 5.5 ± 1.9 b 대조약물군(아세토아미노펜)Control drug group (acetoaminophen) 7575 88 4.1±1.8b 4.1 ± 1.8 b

AP-asp: 아세트아미노펜-아스파르테이트군, AP-pyr: 아세트아미노펜-피루베이트군AP-asp: acetaminophen-aspartate group, AP-pyr: acetaminophen-pyruvate group

본 발명의 신규 아세트아미노펜 유도체가 상기와 같은 약리효과를 보이는 것은 생체내에서 세포내의 에스테르 분해효소에 의해 신규화합물의 에스테르결합이 분해되어 기존의 아세트아미노펜으로 존재하는 것이 가능하므로 기존의 아세트아미노펜과 유사한 약리활성을 나타내는 것으로 보여진다.The novel acetaminophen derivative of the present invention exhibits the above pharmacological effect, which is similar to conventional acetaminophen since it is possible to exist as an existing acetaminophen by breaking down the ester bond of the new compound by intracellular esterase. It is shown to exhibit pharmacological activity.

상기 시험예의 결과에서 볼 수 있듯이, 본 발명의 신규 아세트아미노펜 유도체는 진통해열활성이 임상에서 실용화할 수 있는 진통제 및 해열제로서 극히 유용할 것으로 기대된다.As can be seen from the test results, the novel acetaminophen derivative of the present invention is expected to be extremely useful as an analgesic and antipyretic agent whose analgesic antipyretic activity can be put to practical use in clinical practice.

한편 신규 항암약물들에 대한 간독성시험은 다음과 같이 실시하였다.Meanwhile, hepatotoxicity tests on new anticancer drugs were conducted as follows.

〈시험예 3〉 기존 아세트아미노펜 대비 신규 아세트아미노펜유도체의 간독성 평가Test Example 3 Hepatotoxicity Evaluation of New Acetaminophen Derivatives Compared to Existing Acetaminophen

간독성시험Hepatotoxicity Test

1) 시험 방법 및 간손상 정도 관찰 : 16시간 절식시킨 체중 20∼25g의 마우스를 암, 수 4마리씩 각 시험군별로 8마리로 하여 공지의 방법에 따라 대조군(생리식염수 10ml/kg), 시험군(아세트아미노펜-아스파르테이트 1106mg/kg/10ml, 아세트아미노펜-피루베이트, 1513mg/kg/10ml) 및 대조약물군(아세트아미노펜 750mg/kg/10ml)으로 나누어 해당 시료를 경구투여한 다음, 24시간 후에 쥐를 희생 시킨 즉시 간 소엽을 2mm 두께로 절제하여 10% 포르말린에 고정시킨 후 파라핀 왁스로 포매하였다. 포매된 조직은 microtome으로 6um 두께로 자른후 슬라이드에 부착하여 헤마토실린-에오신(Hematoxylin-Eosin)으로 염색을 하여 광학현미경으로 간조직의 손상정도를 관찰하였다. 간기능 지표인 GPT(glutamate-pyruvate transaminase)와 LDH (lactate dehydrogenase)에 대한 혈액검사는 혈액자동분석기(Technicon autoanalyzer)로 분석하였다.1) Observation of the test method and the degree of liver damage: 20 to 25 g of the body weight fasted for 16 hours, 8 rats and 4 males each for each test group. (Acetaminophen-aspartate 1106mg / kg / 10ml, Acetaminophen-pyruvate, 1513mg / kg / 10ml) and the control drug group (acetaminophen-750mg / kg / 10ml) were administered orally to the sample, and after 24 hours Immediately after sacrifice, the liver lobules were excised to 2 mm thickness, fixed in 10% formalin, and embedded in paraffin wax. Embedded tissues were cut to 6um thickness with a microtome and attached to slides and stained with Hematoxylin-Eosin. Blood tests for glutamate-pyruvate transaminase (GPT) and lactate dehydrogenase (LDH), which are indicators of liver function, were analyzed with a technicon autoanalyzer.

2) 실험결과 : 본 발명의 시료는 공히 아세트아미노펜에 비해 현저한 저간독성 효과를 나타냈다.2) Experimental results: The sample of the present invention showed a significant low hepatotoxic effect compared to acetaminophen.

(표 3) 아세트아미노펜 대비 신규 아세트아미노펜유도체의 간독성 효과Table 3 Hepatotoxic Effects of New Acetaminophen Derivatives Compared to Acetaminophen

시험군Test group 생존수Survival GPT U/LGPT U / L LDH U/LLDH U / L 대조군Control 8/88/8 45±1745 ± 17 540±115a 540 ± 115 a 아세토아미노펜군Acetoaminophene group 5/85/8 203±15203 ± 15 12274±6926c 12274 ± 6926 c AP-AspAP-Asp 8/88/8 89±1489 ± 14 3945±272b 3945 ± 272 b AP-PyrAP-Pyr 8/88/8 84±2784 ± 27 3719±245b 3719 ± 245 b

AP-asp: 아세트아미노펜-아스파르테이트군 AP-pyr: 아세트아미노펜-피루베이트군AP-asp: acetaminophen-aspartate group AP-pyr: acetaminophen-pyruvate group

본 발명의 신규 아세트아미노펜유도체는 진통 및 해열 활성이 공지의 아세트아미노펜 약물과 유사하면서도 공지의 아세트아미노펜 약물보다 간독성이 매우 경감된 우수한 약물로써 평가되어지고, 임상에서 실용화할 수 있는 진통 및 해열제로서 공지의 아세트아미노펜 약물과 같이 각종치료에 있어 매우 유용하다. 또한 본 발명의 아세트아미노펜 유도체는 물에 대한 용해도가 매우 좋고 안정성도 높기 때문에 화학적으로 취급이 용이한 장점이 있다.The novel acetaminophen derivatives of the present invention are evaluated as superior drugs having analgesic and antipyretic activity similar to known acetaminophen drugs but with much less hepatotoxicity than known acetaminophen drugs, and are known as analgesic and antipyretic agents that can be put to practical use in clinical practice. It is very useful for various treatments such as acetaminophen drug. In addition, the acetaminophen derivative of the present invention has an advantage in that it is easy to handle chemically because of its high solubility in water and high stability.

Claims (6)

일반식 (Ⅰ) 으로 표시되는 아세트아미노펜 유도체 및 약학적으로 허용되는 산부가염.Acetaminophen derivatives represented by general formula (I) and pharmaceutically acceptable acid addition salts. 상기식에서 R는 L-아스파르테이트기 또는 피루베이트기를 나타낸다.In the formula, R represents an L-aspartate group or pyruvate group. 제 1항에 있어서, 산부가염은 염화수소, 브롬화수소, 인산염 또는 황산염과 같은 무기산으로 부터 유도된 염 또는 수산염, 유산염, 석신산염, 주석산염, 초산염, 살리실산염, 구연산염, 안식향산염 또는 아디페이트 같은 유기산으로 부터 유도된 염에서 선택된 1종인 것을 특징으로 하는 아세트아미노펜 유도체 및 약학적으로 허용되는 산부가염.The acid addition salt according to claim 1, wherein the acid addition salt is a salt derived from an inorganic acid such as hydrogen chloride, hydrogen bromide, phosphate or sulfate, or an organic acid such as oxalate, succinate, tartarate, acetate, salicylate, citrate, benzoate or adipate. Acetaminophen derivatives and pharmaceutically acceptable acid addition salts, characterized in that one species selected from salts derived from. 아세트아미노펜을 L-아스파르테이트 또는 피루베이트와 에스테르결합시키는 것을 특징으로 하는 일반식(Ⅰ)의 신규 아세트아미노펜 유도체 또는 약학적으로 허용되는 산부가염의 제조방법.A method for producing a novel acetaminophen derivative of formula (I) or a pharmaceutically acceptable acid addition salt, characterized in that the acetaminophen is esterified with L-aspartate or pyruvate. 상기식에서 R는 L-아스파르테이트기 또는 피루베이트기를 나타낸다Wherein R represents an L-aspartate group or a pyruvate group 제 3항에 있어서, 산부가염은 염화수소, 브롬화수소, 인산염 또는 황산염과 같은 무기산으로 부터 유도된 염 또는 수산염, 유산염, 석신산염, 주석산염, 초산염, 살리실산염, 구연산염, 안식향산염 또는 아디페이트 같은 유기산으로 부터 유도된 염에서 선택된 하나임을 특징으로 하는 아세트아미노펜 유도체의 제조방법.4. The acid addition salt according to claim 3, wherein the acid addition salt is a salt derived from an inorganic acid such as hydrogen chloride, hydrogen bromide, phosphate or sulfate, or an organic acid such as oxalate, succinate, tartarate, acetate, salicylate, citrate, benzoate or adipate. Method for producing an acetaminophen derivative, characterized in that one selected from salts derived from. 일반식(Ⅰ)으로 표시되는 아세트아미노펜 유도체 또는 약학적으로 허용되는 산부가염을 유효성분으로 하는 해열 진통제.An antipyretic analgesic agent comprising as an active ingredient an acetaminophen derivative represented by the general formula (I) or a pharmaceutically acceptable acid addition salt. 제 5항에 있어서, 분말의 중량을 기준으로 아세트아미노펜 63 ∼77중량%, 에틸 셀룰로즈 15∼30중량 % 및 가소제 2∼7중량 %를 필수 성분으로 포함하며, 용해되거나 현탁된 가소제가 함유되어 있는 물 중의 아세트아미노펜 및 에틸 셀룰로즈의 분산액으로부터 분무 건조된 것을 특징으로 하는 아세트아미노펜 유도체 또는 약학적으로 허용되는 산부가염을 유효성분으로 하는 해열 진통제.The composition according to claim 5, comprising 63 to 77% by weight of acetaminophen, 15 to 30% by weight of ethyl cellulose and 2 to 7% by weight of plasticizer as essential components, and containing dissolved or suspended plasticizer. An antipyretic analgesic agent comprising as an active ingredient an acetaminophen derivative or a pharmaceutically acceptable acid addition salt which is spray dried from a dispersion of acetaminophen and ethyl cellulose in water.
KR1019990020289A 1999-06-02 1999-06-02 Novel Acetaminophen Derivatives and their Preparation KR20010001219A (en)

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