KR930003488B1 - Hypoglycemic hydantion derivatives - Google Patents
Hypoglycemic hydantion derivatives Download PDFInfo
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- KR930003488B1 KR930003488B1 KR1019930001016A KR930001016A KR930003488B1 KR 930003488 B1 KR930003488 B1 KR 930003488B1 KR 1019930001016 A KR1019930001016 A KR 1019930001016A KR 930001016 A KR930001016 A KR 930001016A KR 930003488 B1 KR930003488 B1 KR 930003488B1
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
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Description
본 발명은 신규 히단토인(Hydantoin)유도체 및 그 약학적으로 허용할 수 있는 염과, 그 화합물을 유효성분으로서 함유하는 의약조성물에 관한 것이다.The present invention relates to a novel hydantoin derivative, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient.
현재, 경구(經口)혈당 저하제로서는 술포닐우레아계(系) 및 비구아나이드계의 약제가 일반적으로 사용되고 있다. 그러나, 이들의 약제는 자주 투여할 때에 있어서 과도의 저혈당이나 유산(乳酸)아시도오시스등의 증상을 초래하여 그 부작용이 문제로 되어 있었다.At present, as an oral blood glucose lowering agent, sulfonylurea-based and biguanide-based drugs are generally used. However, these drugs often cause symptoms such as excessive hypoglycemia or lactic acidosis, and their side effects have been problematic.
한편, 당뇨병 치료약으로서 저명한 인슐린제제는 그 성질상 정맥용 주사제로서만 사용가능한 것이므로, 그 적용할 때의 있어서의 번잡성, 불편한 점은 환자로서는 큰 부담으로 되어 있었다.On the other hand, the insulin preparation, which is remarkable as a diabetes treatment drug, can only be used as an intravenous injection because of its nature, and thus the troublesome and uncomfortable use of the application has been a burden on the patient.
본 발명자등은 유효하며 보다 안전하고, 또한 경구투여가 가능한 혈당저하 작용을 보유하는 화합물을 탐구하던 중, 본 발명 히단토인 유도체 및 그 약학적으로 허용할 수 있는 염이 우수한 혈당저하작용과 함께 이뇨(利尿)작용을 보유하며, 또한 저독성으로서 극히 안전성이 높은 것임을 발견하여서 본 발명을 완성하였다.The inventors of the present invention, while exploring a compound that has a hypoglycemic action that is effective, safer, and orally administrable, have a diuresis with excellent hypoglycemic action of the hydantoin derivative and its pharmaceutically acceptable salts. The present invention was completed by finding that it possesses a (利尿) action and is extremely low in toxicity and extremely safe.
본 발명의 목적은 부작용이 적고 또한 저독성으로서, 극히 안정한 경구 혈당저하작용 및 이뇨작용을 보유하는 신규 히단토인 유도체 및 그 약학적으로 허용할 수 있는 염과, 그 화합물을 유효성분으로서 함유하는 의약 조성물을 제공함에 있다.An object of the present invention is a novel hydantoin derivative having a very stable oral hypoglycemic action and diuretic effect with low side effects and low toxicity, and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound as an active ingredient. In providing.
본 발명화합물은 하기한 일반식(Ⅰ)로서 표시되는 신규 히단토인 유도체이다.The compound of the present invention is a novel hydantoin derivative represented by the following general formula (I).
(식중, X는 수소 또는 OR4를 표시하며, R1,R2,R3,R4는 각각 동일 혹은 다른 수소, 알킬기 또는 시클로알킬기를 표시한다.)(Wherein X represents hydrogen or OR 4 , and R 1 , R 2 , R 3 , and R 4 each represent the same or different hydrogen, alkyl group or cycloalkyl group).
상기한 일반식(Ⅰ)에 있어서 X는 수소 또는 OR4이며, R4는 수소, 알킬기, 바람직하게는 메틸, 에틸, 프로필, i-프로필, 부틸, i-부틸, sec-부틸, t-부틸, 펜틸, i-펜틸, neo-펜틸, t-펜틸 헥실, i-헥실, 디메틸부틸, 헵틸, 옥틸, 노닐, 데실, 스테아릴 등의 직쇄 또는 분지상의 탄소수 1 내지 20의 알킬기 또는 시클로알킬기, 바람직하게는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵헤틸, 시클로옥틸 등의 탄소수 3 내지 8의 시클로알킬기를 표시한다.In the general formula (I), X is hydrogen or OR 4 , and R 4 is hydrogen, an alkyl group, preferably methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl Linear or branched C1-C20 alkyl or cycloalkyl groups such as pentyl, i-pentyl, neo-pentyl, t-pentyl hexyl, i-hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl, stearyl, Preferably, a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohephetyl, and cyclooctyl is represented.
R1,R2및 R3는 각각 동일 혹은 다른 수소, 알킬기, 바람직하게는 메틸, 에틸, 프로필, i-프로필, 부틸, i-부틸, sec-부틸, t-부틸, 펜틸, i-펜틸, neo-펜틸, t-펜틸, 헥실, i-헥실, 디메틸부틸, 헵틸, 옥틸, 노닐, 데실, 스테아릴 등의 직쇄 또는 분지상 탄소수 1 내지 20의 알킬기 또는 시클로알킬기, 바람직하게는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸, 시클로옥틸 등의 탄소수 3 내지 8의 시클로알킬기를 표시한다.R 1 , R 2 and R 3 are the same or different hydrogen, alkyl groups, preferably methyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl, pentyl, i-pentyl, linear or branched C1-C20 alkyl or cycloalkyl groups such as neo-pentyl, t-pentyl, hexyl, i-hexyl, dimethylbutyl, heptyl, octyl, nonyl, decyl and stearyl, preferably cyclopropyl, cyclo And a cycloalkyl group having 3 to 8 carbon atoms such as butyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
본 발명 화합물 중 특히, 바람직한 화합물은 이하와 같다. 5-히드록시-1-메틸히단토인 5-히드록시-3-메틸히단토인, 5-히드록시-1-에틸히단토인, 5-히드록시-1-부틸히단토인, 5-히드록시-1-t-부틸히단토인, 5-히드록시-1-헥실히단토인, 5-히드록시-1-데실히단토인, 5-히드록시-1-스테아릴히단토인, 5-히드록시-1-시클로펜틸히단토인, 5-히드록시-1-시클로헥실히단토인, 5-히드록시-1,3-디메틸히단토인, 5-히드록시-1,5-디메틸히단토인, 5-히드록시-3,5-디메틸히단토인, 5-히드록시-1-(1,3-디메틸부틸)히단토인, 5-히드록시-1-시클로헥실-3-메틸히단토인, 5-히드록시-1,3-디시클로헥실히단토인, 5-메톡시-1-메틸히단토인, 5-메톡시-3-메틸히단토인, 5-에톡시-1-메틸히단토인, 5-부톡시-3-메틸히단토인, 5-메톡시-1-시클로헥실히단토인, 5-메톡시-3-시클로헥실히단토인, 1-메틸히단토인.Among the compounds of the present invention, preferred compounds are as follows. 5-hydroxy-1-methylhydantoin 5-hydroxy-3-methylhydantoin, 5-hydroxy-1-ethylhydantoin, 5-hydroxy-1-butylhydantoin, 5-hydroxy-1- t-butylhydantoin, 5-hydroxy-1-hexylhydantoin, 5-hydroxy-1-decylhydantoin, 5-hydroxy-1-stearylhydantoin, 5-hydroxy-1-cyclo Pentylhydantoin, 5-hydroxy-1-cyclohexylhydantoin, 5-hydroxy-1,3-dimethylhydantoin, 5-hydroxy-1,5-dimethylhydantoin, 5-hydroxy-3, 5-dimethylhydantoin, 5-hydroxy-1- (1,3-dimethylbutyl) hydantoin, 5-hydroxy-1-cyclohexyl-3-methylhydantoin, 5-hydroxy-1,3-dish Clohexylhydantoin, 5-methoxy-1-methylhydantoin, 5-methoxy-3-methylhydantoin, 5-ethoxy-1-methylhydantoin, 5-butoxy-3-methylhydantoin, 5-methoxy-1-cyclohexylhydantoin, 5-methoxy-3-cyclohexylhydantoin, 1-methylhydantoin.
본 발명 히단토인유도체는 상기한 일반식(Ⅰ)로서 표시되는 화합물의 약학적으로 허용할 수 있는 염을 포함하며, 예컨대, 리튬, 나트륨, 칼륨 등의 알칼리금속, 칼슘, 마그네슘 등의 알카리토류금속, 기타 알루미늄, 은 등과의 금속염, 암모니아, 유기아민 등과의 염을 들 수가 있다.Hydantoin derivative of the present invention contains a pharmaceutically acceptable salt of the compound represented by the general formula (I) described above, for example, alkali metals such as lithium, sodium, potassium, alkali earth metals such as calcium, magnesium And metal salts with other aluminum and silver, salts with ammonia, organic amines and the like.
이들의 염은 공지의 방법에 의하여 유리된 본 발명 히단토인 유도체로서 제조할 수 있으며, 혹은 상호 변환이 가능하다.These salts can be prepared as the present invention's hydantoin derivatives liberated by known methods, or can be mutually converted.
본 발명 화합물에 있어서 광학이성체가 존재하는 경우에는, 본 발명은 그 d1-체(體), d-체 및 1-체의 어느것이나 포함한다.When an optical isomer exists in the compound of this invention, this invention includes all the d1-form, d-form, and 1-form.
다음에 본 발명 화합물의 제조방법의 1예를 설명한다.Next, an example of the method for producing the compound of the present invention will be described.
(1) 일반식(Ⅱ)(1) General formula (II)
또는 일반식(Ⅲ)으로 표시되는 화합물과,Or the compound represented by general formula (III),
(식중, R5,R6,R7은 각각 동일 혹은 다른 수소, 알킬기 또는 아랄킬기를 표시한다.)(Wherein R 5 , R 6 and R 7 each represent the same or different hydrogen, alkyl or aralkyl groups)
일반식(Ⅳ)로서 표시되는 화합물을Compound represented by general formula (IV)
(식중, R1,R2는 각각 동일 혹은 다른 수소, 알킬기 또는 시클로알킬기를 표시한다.)(Wherein R 1 and R 2 each represent the same or different hydrogen, alkyl group or cycloalkyl group)
적당한 용매중, 예컨대 물, 초산, 부탄올 등의 알코올 혹은 이들의 혼합용매중, 실온 내지 환류하에서 1시간 내지 수(數)시간 반응시켜서 일반식(Ⅰ)로 표시되는 본 발명 화합물을 얻을 수 있다.In a suitable solvent, for example, alcohol, such as water, acetic acid, butanol, or a mixed solvent thereof, the compound of the present invention represented by the general formula (I) can be obtained by reacting for 1 hour to several hours at room temperature to reflux.
(식중, X는 수소 또는 OR4를 표시하며, R1,R1,R,R 각각 동일 혹은 다른 수소, 알킬기 또는 시클로알킬기를 표시한다.)(Wherein X represents hydrogen or OR 4 and represents the same or different hydrogen, alkyl or cycloalkyl group, respectively, R 1 , R 1 , R, R.)
일반식(Ⅱ) 또는 (Ⅲ)의 R6이 수소인 화합물은 알코올류 혹은 2-메톡시에탄올 등과, 벤젠, 톨루엔, 크실렌, 4염화탄소 등의 아프로틱 용매중, p-톨루엔술폰산, 캄파술폰산 등의 유기산 촉매하에서 생성되는 물을 제거하면서 수시간 내지 1일간 실온 내지 가열하거나 혹은 환류하여 반응을 행하고 생성물을 단리(單離)하지않고 혹은 정제한 후 일반식(Ⅳ)와 상기한 반응을 행한다.Compounds in which R 6 in formula (II) or (III) is hydrogen include p-toluenesulfonic acid and camphorsulfonic acid in alcohols or 2-methoxyethanol and the like and in aprotic solvents such as benzene, toluene, xylene and carbon tetrachloride. The reaction is carried out by heating to reflux for several hours to one day while removing the water generated under an organic acid catalyst such as, or refluxing the product, without isolating or purifying the product, and then reacting with the general formula (IV). .
(2) 본 발명 화합물 중 R4가 알킬기 또는 시클로알킬기인 것에 대해서는, 이하와 같이 통상의 0-알킬화반응으로서 합성할 수도 있다.(2) About R <4> which is an alkyl group or a cycloalkyl group in the compound of this invention, it can also synthesize | combine as normal 0-alkylation reaction as follows.
즉 반응을, 저해하지 않는 적당한 용매중, 예컨대 저급 알킬아민, 알카리금속 알콕시드 등의 유기염기의 존재하에서, 예컨대 p-톨루엔 술포닐클로라이드, 메실클로라이드 등과 반응시켜서 5위(位)수산기에 탈리기(脫離基)를 도입하고, 동시에, 혹은 그후에 소망하는 R4기에 대응하는 알코올류와 반응시켜서 본 발명화합물을 얻을 수가 있다. 상기한 반응은 실온 또는 적당하게 가열하거나 혹은 환류하에서 수시간 내지 수일간 반응시키므로서 실시할 수 있다.That is, in a suitable solvent which does not inhibit the reaction, for example, in the presence of organic base such as lower alkylamine, alkali metal alkoxide and the like, for example, p-toluene sulfonyl chloride, mesyl chloride and the like The compound of the present invention can be obtained by introducing a base material and reacting with alcohols corresponding to a desired R 4 group at the same time or thereafter. The above reaction can be carried out by reacting for several hours to several days at room temperature or heating appropriately or under reflux.
(3) 또 본 발명 화합물은 이하와 같은 통상의 N-알킬화반응에 의해서도 합성할 수 있다.(3) The compound of the present invention can also be synthesized by the following general N-alkylation reaction.
즉, 반응을 저해하지 않는 적당한 용매중, 예컨대 무수알코올, 디메틸 술폭시드중, 예컨대 저급알킬아민, 알카리금속 알콕시드 등의 유기염기 혹은 수산화 알킬금속 등의 염기존재하에서, 예컨대 할로겐화알킬, 할로겐화시클로알킬, 디메틸황산 등의 디알킬황산, p-톨루엔술폰산 알킬에스테르, p-톨루엔술폰산시클로알킬에스테르 등을 반응시켜서 N-알킬화 혹은 N-시클로알킬화를 행할 수가 있다.That is, in a suitable solvent that does not inhibit the reaction, such as anhydrous alcohol, dimethyl sulfoxide, for example, in the presence of an organic base such as lower alkylamine, alkali metal alkoxide or base such as alkyl metal hydroxide, for example, halogenated alkyl, halogenated cycloalkyl , N-alkylation or N-cycloalkylation can be carried out by reacting dialkyl sulfuric acid such as dimethyl sulfuric acid, p-toluenesulfonic acid alkyl ester, p-toluenesulfonic acid cycloalkyl ester and the like.
상기한 반응은 실온 내지 적당하게 가열하여서 수시간내지 수일간 반응시키므로서 실시할 수 있다.The above reaction can be carried out by reacting for several hours to several days by heating to room temperature to moderately.
얻어진 본 발명 화합물은 증류, 크로마토그라피, 재결정 등의 통상의 방법으로 정제하고, 원소분석, 융점, IR, NMR, UV, 매스스펙트럼 등으로 동일함을 확인하였다.The obtained compound of the present invention was purified by conventional methods such as distillation, chromatography, recrystallization, and the like was confirmed by elemental analysis, melting point, IR, NMR, UV, mass spectrum, and the like.
이하에, 실시예에 의하여 본 발명 화합물의 제조예를 표시한다.Below, the manufacture example of a compound of this invention is shown by an Example.
[실시예 1]Example 1
글리옥실산, n-부틸에스테르, 1수화물 15.0g 및 N-메틸요소 7.4g을 80% 초산수용액중에서 1시간 환류 하였다.Glyoxylic acid, n-butyl ester, 15.0 g of monohydrate and 7.4 g of N-methyl urea were refluxed in an aqueous 80% acetic acid solution for 1 hour.
반응후 용매를 증발시키고 소량의 메탄올을 가하여 난용물을 여과 선별하였다.After the reaction, the solvent was evaporated and a small amount of methanol was added, and the solubles were filtered out.
여과액을 감압하여 건조고화하면 잔유물이 결정화하지만, 초산 에틸에서 재결정하여 5-히드록시-1-메틸히단토인(화합물 1)의 백색결정 10.4g을 얻었다.The filtrate was dried under reduced pressure and the residue was crystallized. However, the residue was recrystallized from ethyl acetate to obtain 10.4 g of white crystals of 5-hydroxy-1-methylhydantoin (Compound 1).
융점 : 135.0-136.0℃Melting Point: 135.0-136.0 ℃
IR(KBr) : 3180,1750,1715,1446,1115,750cm-1 IR (KBr): 3180,1750,1715,1446,1115,750cm -1
NMR(DMSO-d6)δ=2.72(s,3H), 4.98(d,1H,J=8Hz), 6.88(D,1H,J=8Hz), 10.74(br.s,1H)NMR (DMSO-d 6 ) δ = 2.72 (s, 3H), 4.98 (d, 1H, J = 8Hz), 6.88 (D, 1H, J = 8Hz), 10.74 (br.s, 1H)
[실시예 2]Example 2
글리옥실산을 출발원료로하여, 전기한 실시예 1과 동일하게 하여서 5-히드록시-3-메틸히단토인(화합물 2)을 얻었다.5-hydroxy-3-methylhydantoin (Compound 2) was obtained in the same manner as in Example 1 described above using glyoxylic acid as a starting material.
융점 : 115.5-116.5℃Melting Point: 115.5-116.5 ℃
IR(KBr) : 3350,1765,1700,1465,1068,823cm-1 IR (KBr): 3350,1765,1700,1465,1068,823cm -1
NMR(DMSO-d6)δ=2.80(s,3H), 5.16(d,1H,J=8Hz), 6.72(d,1H,J=8Hz), 8.61(s,1H)NMR (DMSO-d 6 ) δ = 2.80 (s, 3H), 5.16 (d, 1H, J = 8Hz), 6.72 (d, 1H, J = 8Hz), 8.61 (s, 1H)
[실시예 3]Example 3
글리옥실산·1수화물 19.0g을 디인스타아크의 장치를 부착한 500ml의 가지형 플라스크에 넣고 80ml의 메틸셀로솔브와 150ml의 톨루엔의 혼합용매에 용해하며, 촉매량인 p-톨루엔술폰산을 가하여 하룻밤 환류하였다.19.0 g of glyoxylic acid monohydrate was added to a 500 ml eggplant flask equipped with a Diinstaak apparatus, dissolved in a mixed solvent of 80 ml of methyl cellosolve and 150 ml of toluene, and then added with a catalytic amount of p-toluenesulfonic acid overnight. It was refluxed.
반응용액을 감압하에서 농축하여 건조고화한 후 정제하지 않고 N-에틸요소 18.8g을 가하며, 초산 160ml, 물 40ml을 가하여 용해하고 유욕중(油浴中)에서 2시간 환류하였다. 반응 종료후 반응용액을 농축하고 건조 고화하여 톨루엔과 함께 비등으로서 초산을 제거하였다. 실리카겔컬럼 크로마토그라피(초산에틸)로서 정제후, 초산에틸에서 재결정하여 5-히드록시-1-에틸히단토인(화합물 3)의 백색 결정 23g을 얻었다.The reaction solution was concentrated under reduced pressure, dried to solidify, 18.8 g of N-ethyl urea was added without purification, and 160 ml of acetic acid and 40 ml of water were added thereto, and the mixture was refluxed in an oil bath for 2 hours. After completion of the reaction, the reaction solution was concentrated and dried to remove acetic acid as boiling with toluene. Purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethyl acetate to give 23g of white crystals of 5-hydroxy-1-ethylhydantoin (Compound 3).
융점 : 119.0-120.0℃Melting Point: 119.0-120.0 ℃
IR(KBr) : 3340,1778,1702,1470,1102cm-1 IR (KBr): 3340,1778,1702,1470,1102cm -1
NMR(DMSO-d6)δ=1.10(t,3H,J=7Hz), 3.14(dq,1H,J1=14Hz,J2=7Hz), 3.34(Dq,1H,J1=14Hz,J2=7Hz), 5.09(d,1H,J=9Hz), 6.88(d,1H,J=9Hz), 10.74(br.s,1H)NMR (DMSO-d 6 ) δ = 1.10 (t, 3H, J = 7Hz), 3.14 (dq, 1H, J 1 = 14Hz, J 2 = 7Hz), 3.34 (Dq, 1H, J 1 = 14Hz, J 2 = 7 Hz), 5.09 (d, 1H, J = 9 Hz), 6.88 (d, 1H, J = 9 Hz), 10.74 (br.s, 1H)
동일하게 하여서 이하의 화합물을 얻었다.In the same manner, the following compounds were obtained.
5-히드록시-1-부틸히단토인(화합물 4)5-hydroxy-1-butylhydantoin (Compound 4)
융점 : 94.0-95.0℃Melting Point: 94.0-95.0 ℃
IR(KBr) : 3330.1778,1704,1463,1080,750cm-1 IR (KBr): 3330.1778,1704,1463,1080,750cm -1
NMR(DMSO-d6)δ=0.89(t,3H,J=7Hz), 1.2-1.4(m,2H), 1.4-1.6(m,2H), 3.0-3.4(m,2H), 5.06(d,1H,J=8Hz), 6.88(d,1H,J=8Hz), 10.71(br.s,1H)NMR (DMSO-d 6 ) δ = 0.89 (t, 3H, J = 7Hz), 1.2-1.4 (m, 2H), 1.4-1.6 (m, 2H), 3.0-3.4 (m, 2H), 5.06 (d , 1H, J = 8Hz, 6.88 (d, 1H, J = 8Hz), 10.71 (br.s, 1H)
5-메톡시-1-메틸히단토인(화합물 5)5-methoxy-1-methylhydantoin (Compound 5)
융점 : 95.0-96.0℃Melting Point: 95.0-96.0 ℃
IR(KBr) : 3160,1764,1718,1442,1080cm-1 IR (KBr): 3160,1764,1718,1442,1080cm -1
NMR(DMSO-d6)δ=2.79(s,3H), 3.21(s,3H), 5.09(s,1H), 11.05(br.s,1H)NMR (DMSO-d 6 ) δ = 2.79 (s, 3H), 3.21 (s, 3H), 5.09 (s, 1H), 11.05 (br.s, 1H)
5-부톡시-3-메틸히단토인(화합물 6)5-butoxy-3-methylhydantoin (Compound 6)
융점 : 37.0-39.0℃Melting Point: 37.0-39.0 ℃
IR(KBr) : 3300,2950,1780,1720,1462,1075cm-1 IR (KBr): 3300,2950,1780,1720,1462,1075cm -1
NMR(DMSO-d6)δ=0.88(t,3H,J=7Hz), 1.2-1.5(m,2H), 1.4-1.6(m,2H), 2.83(s,3H), 3.4-3.6(m,2H), 5.21(d,1H,J=2Hz), 8.84(br.s,1H)NMR (DMSO-d 6 ) δ = 0.88 (t, 3H, J = 7Hz), 1.2-1.5 (m, 2H), 1.4-1.6 (m, 2H), 2.83 (s, 3H), 3.4-3.6 (m , 2H), 5.21 (d, 1H, J = 2 Hz), 8.84 (br.s, 1H)
[실시예 4]Example 4
5.0g의 5-히드록시-1-메틸히단토인(화합물 1)을 200ml의 무수메탄올에 용해하고 6.7g의 트리에틸아민을 첨가한 후, 10.9g(1.5당량)의 p-톨루엔 술폰산염화물을 가하여 실온하에서 3일간 교반하였다. 반응후 반응용액을 농축하여 건조고화하고, 소량이 물을 가하고 초산에틸로서 추출하였다. 유기층을 황산나트륨으로서 건조시킨 후 농축하여 건조고화하고, 또다시 실리카겔크로마토그래피(초산에틸)로서 정제하였다.Dissolve 5.0 g of 5-hydroxy-1-methylhydantoin (Compound 1) in 200 ml of anhydrous methanol, add 6.7 g of triethylamine, and then add 10.9 g (1.5 equivalents) of p-toluene sulfonate. Stir at room temperature for 3 days. After the reaction, the reaction solution was concentrated to dryness, and a small amount of water was added and extracted as ethyl acetate. The organic layer was dried over sodium sulfate, concentrated to dryness, and further purified by silica gel chromatography (ethyl acetate).
얻어진 조결정(粗結晶)을 초산에틸-헥산의 혼합용매에서 재결정하여 5-메톡시-1-메틸히단토인(화합물 5)의 백색결정 3.8g을 얻었다. 동일하게 하여서 이하의 화합물을 얻었다.The obtained crude crystal was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 3.8 g of white crystals of 5-methoxy-1-methylhydantoin (Compound 5). In the same manner, the following compounds were obtained.
5-에톡시-1-메틸히단토인(화합물 7)5-ethoxy-1-methylhydantoin (Compound 7)
융점 : 96.0-97.0℃Melting Point: 96.0-97.0 ℃
IR(KBr) : 3160,1765,1720,1443,1115cm-1 IR (KBr): 3160,1765,1720,1443,1115cm -1
NMR(DMSO-d6)δ=1.15(t,3H,J=7Hz), 2.79(s,3H), 3.43(DQ,1H,J1=2Hz,J2=7Hz), 3.56(Dq,1H,J1=2Hz,J2=7Hz), 5.08(s,1H), 11.00(br.s,1H)NMR (DMSO-d 6 ) δ = 1.15 (t, 3H, J = 7Hz), 2.79 (s, 3H), 3.43 (DQ, 1H, J 1 = 2Hz, J 2 = 7Hz), 3.56 (Dq, 1H, J 1 = 2 Hz, J 2 = 7 Hz), 5.08 (s, 1H), 11.00 (br.s, 1H)
5-메톡시-3-메틸히단토인(화합물 8)5-methoxy-3-methylhydantoin (Compound 8)
융점 : 57.0-58.0℃Melting Point: 57.0-58.0 ℃
IR(KBr) : 3300,1760,1715,1468,1082cm-1 IR (KBr): 3300,1760,1715,1468,1082cm -1
NMR(DMSO-d6)δ=2.83(s,3H), 3.26(s,3H), 5.12(d,1H,J=2Hz), 8.85(br.s,1H)NMR (DMSO-d 6 ) δ = 2.83 (s, 3H), 3.26 (s, 3H), 5.12 (d, 1H, J = 2Hz), 8.85 (br.s, 1H)
MS : M+: 144m/z : 116,114,86,74,59MS: M + : 144m / z: 116,114,86,74,59
5-메톡시-1-시클로헥실히단토인(화합물 9)5-methoxy-1-cyclohexylhydantoin (Compound 9)
융점 : 121.0-122.0℃Melting Point: 121.0-122.0 ℃
IR(KBr) : 3175,3050,2940,2852,1780,1700,1430,1103,768cm-1 IR (KBr): 3175,3050,2940,2852,1780,1700,1430,1103,768cm -1
NMR(DMSO-d6)δ=0.9-1.35(m,3H), 1.35-1.7(m,3H), 1.7-1.9(m,4H), 3.18(s,3H), 3.56(tt,1H,J1=3.6Hz,J2=12.0Hz), 5.25(s,1H), 11.0(br.s,1H)NMR (DMSO-d 6 ) δ = 0.9-1.35 (m, 3H), 1.35-1.7 (m, 3H), 1.7-1.9 (m, 4H), 3.18 (s, 3H), 3.56 (tt, 1H, J 1 = 3.6 Hz, J 2 = 12.0 Hz), 5.25 (s, 1H), 11.0 (br.s, 1H)
MS : M+: 212m/z : 197,182,169,131,103,98,82,67,60,55,41MS: M + : 212m / z: 197,182,169,131,103,98,82,67,60,55,41
[실시예 5]Example 5
214g의 피루브산메틸을 3ℓ의 가지형플라스크에 넣고 155g의 N메틸요소를 가하였다. 초산 800ml, 물 200ml를 첨가하여 용해시키고 2시간 30분간 환류하였다. 반응후 반응용액을 농축하여 건조고화하고, 톨루엔을 첨가하여 초산과 함께 비등시켜서 제거하였다. 얻어진 조(租)생성물을 실리카겔크로마토그라피(초산에틸 및 5% 메탄올/클로로포름)로서 정제하여 5-히드록시-1,5-디메틸히단토인(화합물 10)을 95g 얻었다.214 g of methyl pyruvate was placed in a 3 L eggplant flask and 155 g of N methyl urea was added thereto. 800 ml of acetic acid and 200 ml of water were added to dissolve and refluxed for 2 hours 30 minutes. After the reaction, the reaction solution was concentrated to dryness, and then added toluene and boiled and removed with acetic acid. The obtained crude product was purified by silica gel chromatography (ethyl acetate and 5% methanol / chloroform) to obtain 95 g of 5-hydroxy-1,5-dimethylhydantoin (Compound 10).
융점 : 122.0-123.0℃Melting Point: 122.0-123.0 ℃
IR(KBr) : 3340,3200,1780,1765,1720,1440cm-1 IR (KBr): 3340,3200,1780,1765,1720,1440cm -1
NMR(DMSO-d6)δ=1.34(s,3H), 2.70(s,3H), 6.59(s,1H), 10.78(s,1H)NMR (DMSO-d 6 ) δ = 1.34 (s, 3H), 2.70 (s, 3H), 6.59 (s, 1H), 10.78 (s, 1H)
MS : M+: 144m/z : 129,116,73,58,43MS: M + : 144m / z: 129,116,73,58,43
동일하게 하여서 5-히드록시-3,5-디메틸히단토인(화합물 11)을 얻었다.In the same manner, 5-hydroxy-3,5-dimethylhydantoin (Compound 11) was obtained.
융점 : (유상물)Melting Point: (Oil)
NMR(DMSO-d6)δ=1.37(s,3H), 2.81(s,3H), 6.50(s,1H), 8.63(s,1H)NMR (DMSO-d 6 ) δ = 1.37 (s, 3H), 2.81 (s, 3H), 6.50 (s, 1H), 8.63 (s, 1H)
[실시예 6]Example 6
글리옥실산벤질에스테르·벤질알콕시드 21.0g 및 N-헥실요소 10.0g을 80% 초산 수용액중에서 1시간 30분간 환류하였다. 반응후 냉각하고, 반응용액을 감압하에서 농축하여 건조고화하였다. 얻어진 조생성물을 실리카겔칼럼크로마토그라피(초산에틸 : 헥산=1 : 1)로서 정제한 후, 벤젠에서 재결정하여 5-히드록시-1-헥실 히단토인(화합물 12)의 무색침상결정 7.4g을 얻었다.21.0 g of glyoxylic acid benzyl ester and benzyl alkoxide and 10.0 g of N-hexyl urea were refluxed for 1 hour and 30 minutes in an aqueous 80% acetic acid solution. After the reaction was cooled, the reaction solution was concentrated under reduced pressure and dried to solidify. The crude product thus obtained was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and then recrystallized from benzene to give 7.4 g of colorless acicular crystal of 5-hydroxy-1-hexyl hydantoin (Compound 12).
융점 : 96.0-97.0℃Melting Point: 96.0-97.0 ℃
IR(KBr) : 3360,3140,2950,1780,1760,1710,1475,1097,755cm-1 IR (KBr): 3360,3140,2950,1780,1760,1710,1475,1097,755cm -1
NMR(DMSO-d6)δ=0.85(t,3H,J=6.6Hz), 1.24(s,6H), 1.3-1.6(m,2H), 3.09(ddd,1H,J1=5.9Hz,J2=8.2Hz,J3=14.0Hz), 3.25(ddd,1H,J1=7.3Hz,J2=8.2Hz,J3=14.0Hz), 5.04(d,1H,J=8.8Hz), 6.84(d,1H,J=8.8Hz), 10.7(br.s,1H)NMR (DMSO-d 6 ) δ = 0.85 (t, 3H, J = 6.6Hz), 1.24 (s, 6H), 1.3-1.6 (m, 2H), 3.09 (ddd, 1H, J 1 = 5.9Hz, J 2 = 8.2 Hz, J 3 = 14.0 Hz, 3.25 (ddd, 1H, J 1 = 7.3 Hz, J 2 = 8.2 Hz, J 3 == 14.0 Hz), 5.04 (d, 1H, J = 8.8 Hz), 6.84 (d, 1H, J = 8.8Hz), 10.7 (br.s, 1H)
MS : M+: 200m/z : 129,116,89,85,58,41,30MS: M + : 200m / z: 129,116,89,85,58,41,30
동일하게 하여서 이하의 화합물을 얻었다.In the same manner, the following compounds were obtained.
5-히드록시-1-데실히단토인(화합물 13)5-hydroxy-1-decylhydantoin (Compound 13)
융점 : 100.0-101.0℃Melting Point: 100.0-101.0 ℃
IR(KBr) : 3350,2920,2855,1780,1760,1710,1470,1100,755cm-1 IR (KBr): 3350,2920,2855,1780,1760,1710,1470,1100,755cm -1
NMR(DMSO-d6)δ=0.85(t,3H,J=6.6Hz), 1.23(s,14H), 1.3-1.6(m,2H), 3.08(ddd,1H,J1=5.9Hz,J2=8.1Hz,J3=13.9Hz), 3.24(dt,1H,J1=7.7Hz,J2=13.9Hz), 5.03(d,1H,J=8.8Hz), 6.84(d,1H,J=8.8Hz), 10.7(br.s,1H)NMR (DMSO-d 6 ) δ = 0.85 (t, 3H, J = 6.6Hz), 1.23 (s, 14H), 1.3-1.6 (m, 2H), 3.08 (ddd, 1H, J 1 = 5.9Hz, J 2 = 8.1 Hz, J 3 = 13.9 Hz), 3.24 (dt, 1H, J 1 = 7.7 Hz, J 2 = 13.9 Hz), 5.03 (d, 1H, J = 8.8 Hz), 6.84 (d, 1H, J = 8.8 Hz), 10.7 (br.s, 1H)
MS : M+: 256m/z : 129,116,99,85,69,58,41,30MS: M + : 256 m / z: 129,116,99,85,69,58,41,30
5-히드록시-1-스테아릴히단토인(화합물 14)5-hydroxy-1-stearylhydantoin (Compound 14)
융점 : 112.0-114.0℃Melting Point: 112.0-114.0 ℃
IR(KBr) : 3320,2910,2850,1780,1760,1710,1480,1095,750cm-1 IR (KBr): 3320,2910,2850,1780,1760,1710,1480,1095,750cm -1
NMR(DMSO-d6)δ=0.84(t,3H,J=6.6Hz), 1.23(s,30H), 1.4-1.6(m,2H), 3.08(ddd,1H,J1=6.1Hz,J2=7.9Hz,J3=14.0Hz), 3.24(dd,1H,J1=6.4Hz,J2=14.0Hz), 5.03(d,1H,J=8.8Hz), 6.82(d,1H,J=8.8Hz), 10.68(br.sM1H)NMR (DMSO-d 6 ) δ = 0.84 (t, 3H, J = 6.6Hz), 1.23 (s, 30H), 1.4-1.6 (m, 2H), 3.08 (ddd, 1H, J 1 = 6.1Hz, J 2 = 7.9Hz, J 3 = 14.0Hz ), 3.24 (dd, 1H, J 1 = 6.4Hz, J 2 = 14.0Hz), 5.03 (d, 1H, J = 8.8Hz), 6.82 (d, 1H, J = 8.8 Hz), 10.68 (br.sM1H)
MS : M+: 368m/z : 352,296,129,113,101,69,57,43,30MS: M + : 368m / z: 352,296,129,113,101,69,57,43,30
5-히드록시-1-시클로펜틸히단토인(화합물 15)5-hydroxy-1-cyclopentylhydantoin (Compound 15)
융점 : 139.0-141.0℃Melting Point: 139.0-141.0 ℃
IR(KBr) : 3320,2950,2870,1778,1715,1470,1078,763cm-1 IR (KBr): 3320,2950,2870,1778,1715,1470,1078,763cm -1
NMR(DMSO-d6)δ=1.3-1.9(m,8H), 4.00(tt,1H,J1=8.1Hz,J2=8.1Hz), 5.11(d,1H,J=8.8Hz), 6.79(d,1H,J=8.8Hz), 10.70(br.s,1H)NMR (DMSO-d 6 ) δ = 1.3-1.9 (m, 8H), 4.00 (tt, 1H, J 1 = 8.1Hz, J 2 = 8.1Hz), 5.11 (d, 1H, J = 8.8Hz), 6.79 (d, 1H, J = 8.8Hz), 10.70 (br.s, 1H)
MS : M+: 184m/z : 155,117,99,89,84,67,56,41,27MS: M + : 184m / z: 155,117,99,89,84,67,56,41,27
5-히드록시-1-시클로헥실히단토인(화합물 16)5-hydroxy-1-cyclohexylhydantoin (Compound 16)
융점 : 176.0-178.0℃Melting Point: 176.0-178.0 ℃
IR(KBr) : 3310,2920,2850,1770,1700,1450,1115,753cm-1 IR (KBr): 3310,2920,2850,1770,1700,1450,1115,753cm -1
NMR(DMSO-d6)δ=0.9-1.4(m,3H), 1.4-1.9(m,7H), 3.51(tt,1H,J1=4.0Hz,J2=11.8Hz), 5.10(d,1H,J=8.8Hz), 6.76(d,1H,J=8.8Hz), 10.7(br.s,1H)NMR (DMSO-d 6 ) δ = 0.9-1.4 (m, 3H), 1.4-1.9 (m, 7H), 3.51 (tt, 1H, J 1 = 4.0 Hz, J 2 = 11.8 Hz), 5.10 (d, 1H, J = 8.8 Hz, 6.76 (d, 1H, J = 8.8 Hz), 10.7 (br.s, 1H)
MS : M+: 198m/z : 155,117,82,67,56,41,27MS: M + : 198m / z: 155,117,82,67,56,41,27
5-히드록시-1-(1,3-디메틸부틸)히단토인(화합물 17)5-hydroxy-1- (1,3-dimethylbutyl) hydantoin (Compound 17)
융점 : 148.0-149.0℃Melting Point: 148.0-149.0 ℃
IR(KBr) : 3250,2950,1762,1700,1445,1100cm-1 IR (KBr): 3250,2950,1762,1700,1445,1100cm -1
NMR(DMSO-d6)δ=0.7-1.0(m,6H), 1.1-1.2(m,3H), 1.2-1.7(m,3H), 3.8-4.0(m,1H), [5.06(d,J=8.8Hz), 5.10(d,J=8.8Hz); total1H], [6.78(d,J=8.8Hz), 6.80(d,J=8.8Hz); total1H], 10.72(br.s,1H)NMR (DMSO-d 6 ) δ = 0.7-1.0 (m, 6H), 1.1-1.2 (m, 3H), 1.2-1.7 (m, 3H), 3.8-4.0 (m, 1H), [5.06 (d, J = 8.8 Hz), 5.10 (d, J = 8.8 Hz); total 1 H], [6.78 (d, J = 8.8 Hz), 6.80 (d, J = 8.8 Hz); total 1H], 10.72 (br.s, 1H)
MS : M+: 200m/z : 143,100,72,44,43,41MS: M + : 200m / z: 143,100,72,44,43,41
5-히드록시-1-t-부틸히단토인(화합물 18)5-hydroxy-1-t-butylhydantoin (Compound 18)
융점 : 189.0-190.5℃Melting Point: 189.0-190.5 ℃
IR(KBr) : 3230,2965,1760,1710,1436,1230,1080cm-1 IR (KBr): 3230,2965,1760,1710,1436,1230,1080cm -1
NMR(DMSO-d6)δ=1.37(s,9H), 5.14(s,1H), 6.78(br.s,1H), 10.47(br.s,1H)NMR (DMSO-d 6 ) δ = 1.37 (s, 9H), 5.14 (s, 1H), 6.78 (br.s, 1H), 10.47 (br.s, 1H)
MS : M+: 172m/z : 157,84,58,41MS: M + : 172m / z: 157,84,58,41
5-히드록시-1,3-디시클로헥실히단토인(화합물 19)5-hydroxy-1,3-dicyclohexylhydantoin (Compound 19)
융점 : 148.0-149.0℃Melting Point: 148.0-149.0 ℃
IR(KBr) : 3275,2930,2850,1766,1700,1678,1450,1112,760cm-1 IR (KBr): 3275,2930,2850,1766,1700,1678,1450,1112,760cm -1
NMR(DMSO-d6)δ=0.9-1.4(m,6H), 1.4-1.8(m,12H), 1.8-2.0(m,2H), 3.54(tt,1H,J1=4.0Hz,J2=11.0Hz), 3.69(tt,1H,J1=3.8Hz,J2=12.0Hz), 5.09(s,1H), 6.82(br.s,1H)NMR (DMSO-d 6 ) δ = 0.9-1.4 (m, 6H), 1.4-1.8 (m, 12H), 1.8-2.0 (m, 2H), 3.54 (tt, 1H, J 1 = 4.0Hz, J 2 = 11.0 Hz), 3.69 (tt, 1H, J 1 = 3.8 Hz, J 2 = 12.0 Hz), 5.09 (s, 1H), 6.82 (br.s, 1H)
MS : M+: 280m/z : 237,199,181,155,117,99,83,67,55,41MS: M + : 280m / z: 237,199,181,155,117,99,83,67,55,41
[실시예 7]Example 7
글리옥실산 메틸에스테르·메틸알콕시드 750mg 및 N-시클로헥실요소 920mg을 50ml의 초산 : 메틸알코올(4 : 1)의 혼합용액중에서 1시간 환류하였다. 냉각후, 용매를 증발시키고 실리카겔칼럼으로서 정제하였다. 얻어진 조결정을 벤젠에서 재결정하여 5-메톡시-3-시클로헥실히단토인(화합물 20)의 무색침상결정 420mg을 얻었다.750 mg of glyoxylic acid methyl ester and methyl alkoxide and 920 mg of N-cyclohexyl urea were refluxed in 50 ml of a mixed solution of acetic acid: methyl alcohol (4: 1) for 1 hour. After cooling, the solvent was evaporated and purified as silica gel column. The resultant crude crystal was recrystallized from benzene to give 420 mg of colorless needles of 5-methoxy-3-cyclohexylhydantoin (Compound 20).
융점 : 135.0-137.0℃Melting Point: 135.0-137.0 ℃
IR(KBr) : 3320,2915,2850,1768,1710,1422,1105cm-1 IR (KBr): 3320,2915,2850,1768,1710,1422,1105cm -1
NMR(DMSO-d6)δ=0.9-1.4(m,3H), 1.4-1.8(m,4H), 1.8-2.1(m,3H), 3.22(s,3H), 3.70(tt,1H,J1=4.0Hz,J2=14.0Hz), 5.09(s,1H), 8.80(br.s,1H)NMR (DMSO-d 6 ) δ = 0.9-1.4 (m, 3H), 1.4-1.8 (m, 4H), 1.8-2.1 (m, 3H), 3.22 (s, 3H), 3.70 (tt, 1H, J 1 = 4.0 Hz, J 2 = 14.0 Hz), 5.09 (s, 1H), 8.80 (br.s, 1H)
MS : M+: 182m/z : 131,99,60,55,41MS: M + : 182m / z: 131,99,60,55,41
[실시예 8]Example 8
2.0g의 5-히드록시-1-시클로헥실히단토인을 600mg 나트륨 메톡시드를 함유하는 메탄올 300ml에 용해하였다. 20분 후 0.7ml 요오드화메틸을 적하하여서 가하고, 반응온도 50℃로서 1시간 반응을 계속하였다. 용매를 증발시키고 잔유물을 실리카겔박층크로마토그라피(초산에틸 : 헥산=1 : 1)로서 정제하였다. 얻어진 조결정을 벤젠에서 재결정하여 5-히드록시-1-시클로헥실-3-메틸히단토인(화합물 21)의 무색침상결정 500mg을 얻었다.2.0 g of 5-hydroxy-1-cyclohexylhydantoin was dissolved in 300 ml of methanol containing 600 mg sodium methoxide. After 20 minutes, 0.7 ml of methyl iodide was added dropwise, and the reaction was continued for 1 hour at a reaction temperature of 50 deg. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 1). The obtained crude crystal was recrystallized from benzene to obtain 500 mg of colorless acicular crystals of 5-hydroxy-1-cyclohexyl-3-methylhydantoin (Compound 21).
융점 : 140.0-141.0℃Melting Point: 140.0-141.0 ℃
IR(KBr) : 3360,2940,2802,1770,1700,1445,1070,762cm-1 IR (KBr): 3360,2940,2802,1770,1700,1445,1070,762cm -1
NMR(DMSO-d6)δ=0.9-1.4(m,3H), 1.4-1.9(m,7H), 2.81(s,3H), 3.55(tt,1H,J1=4.0Hz,J2=11.8Hz), 5.16(d,1H,J=8.8Hz), 6.82(d,1H,J=8.8Hz)NMR (DMSO-d 6 ) δ = 0.9-1.4 (m, 3H), 1.4-1.9 (m, 7H), 2.81 (s, 3H), 3.55 (tt, 1H, J 1 = 4.0Hz, J 2 = 11.8 Hz), 5.16 (d, 1H, J = 8.8 Hz), 6.82 (d, 1H, J = 8.8 Hz)
MS : M+: 212m/z : 169,131,82,67,56,41,27MS: M + : 212m / z: 169,131,82,67,56,41,27
동일하게 하여서 이하의 화합물을 얻었다.In the same manner, the following compounds were obtained.
5-히드록시-1,3-디메틸히단토인(화합물 22)5-hydroxy-1,3-dimethylhydantoin (Compound 22)
융점 : (무색유상물)Melting Point: (Colorless Oil)
IR(KBr) : 3300,3000,1776,1715,1195,703cm-1 IR (KBr): 3300,3000,1776,1715,1195,703cm -1
NMR(DMSO-d6)δ=3.02(s,6H), 5.14(s,1H), 5.25(br.s,1H)NMR (DMSO-d 6 ) δ = 3.02 (s, 6H), 5.14 (s, 1H), 5.25 (br.s, 1H)
MS : M+: 144m/z : 127,116,88,59,42MS: M + : 144m / z: 127,116,88,59,42
본 발명 화합물은 앞에서 설명한 각각의 제조방법으로서 제조되는 것이며, 전기한 실시예에 의하여 그 제법이 한정되는 것은 아니다.The compounds of the present invention are prepared as the respective production methods described above, and the production method is not limited by the above-described examples.
다음에, 본 발명 화합물의 약리작용에 대해서 설명한다.Next, the pharmacological action of the compound of the present invention will be described.
(1) 급성독성(1) Acute Toxicity
1군(群) 10마리의 ddy계 웅성 마우스를 사용하여 피검약투여후 7일간의 사망률에서 릿치피일드-윌코기손법을 사용하여 LD50을 산출하였다.Group 1 (群) using ddy male mice of the system 10 after the test drug administration blood Ile glitches in the mortality for 7 days were calculated the LD 50 using the Wilco group sonbeop.
그 결과, 전기한 실시예에 표시한 본 발명 화합물을 경구, 정맥내, 복강내, 피하투여하였을 때, 어느 경우에도 5,000mg/kg 이상의 투여에 있어서도 사망에는 전혀 볼수 없었고, 투여직후의 일과적인 증상도 관찰되지 않았다.As a result, when oral, intravenous, intraperitoneal, or subcutaneous administration of the compound of the present invention shown in the above-described examples, death was not seen at all even at 5,000 mg / kg or more. Was not observed.
따라서 본 발명 화합물의 LD50값은 5,000mg/kg 이상이다. 또한 실험종료후의 부검에 있어서도 내장 각기관에 하등의 변화도 관찰되지 않았다.Therefore the LD 50 value of the compound of the present invention is at least 5,000 mg / kg. In addition, no change was observed in the internal organs at the autopsy after the end of the experiment.
(2) 혈당저하작용(2) hypoglycemic action
체중 250g 전후의 스프라규-다울레이(Sprague-Dawley)계 웅성 랫트를 1군 10마리로 하여서 사용하였다. 랙트는 18시간 절식(絶食)후 피검약의 혈당저하작용을 두우린등의 방법[(Dulin, W.L.etal., Proc.Soc.Expl.Med., 107 245(1961)]을 변경하여서 측정하였다.Sprague-Dawley male rats with a body weight of about 250 g were used as one group of 10 rats. The rats were measured by changing the method for reducing blood glucose of the test drug after 18 hours of fasting (Dulin, W. L. et al., Proc. Soc. Expl. Med., 107 245 (1961)).
즉 랫트의 절식에 의한 혈당값의 저하를 방지하기 위하여 랫트 등부분피부에 20% 포도당 수용액 0.5ml/100g을 피하투여하고, 그 직후에 피검약을 경구투여하였다. 22시간후 팬토바르비탈 마취하에서 개복(開腹)하여 하행대정맥에서 체혈하였다. 얻어진 혈액을 30분간 방치하여 완전히 응고시킨 후 원심분리하여 혈청을 채취하였다. 얻어진 혈청을 사용하여 무타로타아제 GOD법으로서 혈당값을 측정하였다. 결과의 일예를 표1에 표시한다.That is, in order to prevent a drop in blood glucose values due to fasting of rats, 0.5 ml / 100 g of a 20% glucose aqueous solution was subcutaneously administered to the rat dorsal skin, and immediately after that, the test drug was orally administered. After 22 hours, laparotomy was performed under pantobarbital anesthesia, and blood was collected from the descending venous vein. The obtained blood was left for 30 minutes to completely coagulate and centrifuged to collect serum. The blood serum value was measured by the mutarotase GOD method using the obtained serum. An example of the results is shown in Table 1.
[표 1]TABLE 1
(화합물 23 : 1-메틸히단토인)(Compound 23: 1-methylhydantoin)
(3) 이뇨작용(3) diuretic effect
랫트에 본 발명 화합물 1을 20mg/kg 경구투여하고, 이후 1일의 나트륨 배설량을 리프싯쓰의 방법[JPFT, 79,97(1943)]으로서 측정하였다.Rats were dosed orally with 20 mg / kg of Compound 1 of the present invention, and then the amount of sodium excretion on the day was measured by the method of Liftitz (JPFT, 79,97 (1943)).
그 결과, 화합물 1을 투여한 군에서는 대조군에 비해서 1.8배의 나트륨배설량의 증가가 관찰되었다.As a result, an increase in sodium excretion of 1.8-fold was observed in the group administered with Compound 1 compared to the control group.
또 본 발명 화합물 1을 마우스에 100mg/kg 피하 투여하였을 경우, 2시간후까지 대조군에 비해서 50.5%의 소변량의 증가가 관찰되었다. 또한, 글루코오스 부하한 랫트에 본 발명화합물 1을 200mg/kg 경구투여 하였을 때의 뇨(尿) 혈당값은 대조군에 비해서 변동은 없었다.In addition, when 100 mg / kg of the compound 1 of the present invention was administered to the mouse subcutaneously, an increase in urine volume of 50.5% was observed until 2 hours later compared to the control group. In addition, the urine blood glucose value when oral administration of the compound 1 of the present invention 200 mg / kg in glucose-loaded rats did not change compared to the control group.
상기한 약리시험의 결과에 명백한 바와같이, 본 발명 화합물은 우수한 혈당저하 작용을 나타낸다.As evident from the results of the above pharmacological test, the compound of the present invention exhibits an excellent hypoglycemic action.
즉, 대량으로 투여하였을 경우에 있어서도 과도하게 혈당값을 저하시키지 않고 항상 정상값에 가까운 상태로 피검사자를 유지하는 우수한 특징을 보유하며, 정상과 다른 고혈당상태를 개선하는 약제로서 극히 유용성이 높은 것이다.In other words, even when administered in large quantities, it has an excellent characteristic of maintaining the subject in a state always close to the normal value without excessively lowering the blood sugar value, and is extremely useful as a drug for improving normal and other hyperglycemic states.
또 본 발명 화합물은 앞에서 설명한 바와같이 저독성으로서 극히 안정성이 높기 때문에 장기 연속투여가 가능하고, 또한 경구제로서 투여가능하므로 당뇨병의 치료는 물론이며, 그것에 따라서 야기되는 각종 질환, 예컨대 당뇨병성 동백경화증, 당뇨병성 망막증, 당뇨병성 신증, 당뇨병성 신경증, 당뇨병성 세소혈관증 등의 혈관장해 등의 치료에 극히 유용한 약제이다. 또한, 본 발명 화합물은 이뇨작용도 아울러 보유하고 있어서 전기한 질환의 치료상 유용한 약제이다.In addition, since the compound of the present invention has low toxicity and extremely high stability as described above, long-term continuous administration is possible, and also can be administered as an oral agent, so as well as the treatment of diabetes, various diseases caused by it, such as diabetic camellia, It is an extremely useful drug for the treatment of vascular disorders such as diabetic retinopathy, diabetic nephropathy, diabetic neurosis, and diabetic microangiopathy. In addition, the compound of the present invention also possesses a diuretic effect, and thus is a useful drug for treating the aforementioned diseases.
본 발명 화합물은 적당한 의약용 담체 혹은 희석제와 결합시켜서 의약으로 사용가능하며, 통상의 어떠한 방법에 의해서도 제제화 할 수 있고, 경구 또는 비경구 투여하기 위한 고체, 반고체, 액체 또는 기체의 제형(劑型), 예컨대 정제, 캡슐제, 산제(散劑), 과립제, 분말, 연고, 액제, 좌제, 주사제, 흡입제, 에어졸재, 퍼프제 등의 제형으로 처방할 수가 있다. 처방에 있어서, 본 발명 화합물은 그 약제적으로 허용가능한 염의 형태로서 사용해도 좋고, 본 발명 화합물을 단독으로 혹은 적당하게 결합하여 사용할 수 있으며, 또 다른 의약 활성성분과의 배합제로서도 좋다. 경구투여제제에는, 그대로 혹은 적당한 첨가제, 예컨대 유당, 만닛트, 옥수수전분, 마령서전분 등의 관용의 부형제와 함께 결정셀룰로오스, 셀룰로오스유도체, 아라비아고무, 옥수수전분, 젤라틴 등의 결합제, 옥수수전분, 마령서전분, 카르복시메틸셀룰로오스나트륨 등의 붕괴제, 탈크, 스테아린마그네슘 등의 활택제, 기타의 증량제, 습윤화제, 완충제, 보존제, 향료 등을 적당하게 결합시켜서, 정제, 산제, 과립제 혹은 캡슐제로하거나 또는 연고기제(基劑), 예컨대 와세린, 파라핀, 프라스티베이스, 단연고, 단연(單鉛)연고, 친수연고, 친수와세린, 친수플라스티베이스 등과 결합시켜서 연고로 할 수 있다.The compound of the present invention can be used as a medicine in combination with a suitable medical carrier or diluent, can be formulated by any conventional method, and is a solid, semisolid, liquid or gaseous formulation for oral or parenteral administration, For example, it may be prescribed in the form of tablets, capsules, powders, granules, powders, ointments, solutions, suppositories, injections, inhalants, aerosols, puffs and the like. In the formulation, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt thereof, the compound of the present invention may be used alone or in combination as appropriate, or as a compounding agent with another pharmaceutically active ingredient. Oral administration agents, as it is or with suitable additives such as lactose, mannite, corn starch, horseshoe starch, and other conventional excipients, such as crystalline cellulose, cellulose derivatives, gum arabic, corn starch, gelatin, corn starch, horseshoe starch Disintegrating agents such as sodium carboxymethylcellulose, lubricants such as talc, stearin magnesium, other extenders, wetting agents, buffers, preservatives, fragrances, etc., as tablets, powders, granules or capsules, or ointments. For example, it can be combined with waserine, paraffin, plasticibase, sweetened ointment, sweetened ointment, hydrophilic ointment, hydrophilic washerin, hydrophilic plastibase and the like to form an ointment.
또한 본 발명 화합물을 각종기제, 예컨대 유제성 기제 또는 수용성기제와 혼화하여 좌제를 제조할 수 있다. 주사제로서는, 수성용제 또는 비수성용제, 예컨대 식물유, 합성지방산글리세리드, 고급지방산에스테르, 프로필렌글리콜 등의 용액, 현탄액 혹은 유화액을 사용할 수 있으며, 이 경우 필요에 따라서 용해 보조제, 등장(等張)화제, 현탁화제, 유화제, 안정제, 보존제 등의 통상 사용되는 첨가제를 첨가해도 좋다. 흡입제, 에어졸제로서의 사용에는 본발명 화합물을 액체 또는 미소분체의 형태로서, 기체 또는 액체분사제와 함께 또한 소망에 따라서 습윤제 또는 분산제와 같은 통상의 보조제와 함께 에어졸 용기내에 충전한다. 본 발명 화합물은 내브라이서 또는 아토마이서와 같은 비가압형(非加壓型)의 제형도 좋다. 퍼프제로서는, 박하유(油), 진한글리세린, 카오린 등과 혼합하여 제조할 수 있다.In addition, suppositories can be prepared by mixing the compounds of the present invention with various bases such as emulsion bases or water-soluble bases. As the injection, an aqueous or non-aqueous solvent such as vegetable oil, synthetic fatty acid glycerides, higher fatty acid esters, propylene glycol, solutions, suspensions or emulsions can be used. In this case, dissolution aids, isotonic agents, You may add the additive normally used, such as a suspending agent, an emulsifier, a stabilizer, and a preservative. Use as inhalants, aerosols is filled into aerosol containers with the present invention in the form of liquids or micropowders, together with gases or liquid sprays, and with conventional auxiliaries such as wetting or dispersing agents as desired. The compound of the present invention may be a non-pressurized formulation such as Nabraser or Atomizer. As a puff agent, it can manufacture by mixing with mint oil, concentrated glycerin, kaolin, etc.
본 발명 화합물의 바람직한 투여량은 투여대상, 제형, 투여방법, 투여기간 등에 따라서 변하지만, 소망하는 효과를 얻기 위해서, 일반적으로 성인에 대해서 1일에 본 발명 화합물을 1 내지 1000mg/kg, 바람직하게는 5 내지 600mg/kg을 경구투여할 수 있으며, 또 본 발명 화합물을 적당량 함유하는 단위제제를 1일 1 내지 수단위 투여할 수 있다. 비경구투여(예컨대 주사제)의 경우, 1일 투여량은 전기한 투여량의 3 내지 10분의 1의 용량 정도가 바람직하다.The preferred dosage of the compound of the present invention varies depending on the administration target, the dosage form, the administration method, the administration period, and the like, but in order to obtain a desired effect, generally 1 to 1000 mg / kg of the compound of the present invention per adult, preferably Can be administered orally from 5 to 600mg / kg, and may be administered 1 to several units per day of a unit preparation containing an appropriate amount of the compound of the present invention. In the case of parenteral administration (such as injection), the daily dosage is preferably about 3 to 1/10 of the aforementioned dosage.
이하에 본 발명 화합물을 유효성분으로 함유하는 의약조성물의 처방예를 표시한다.The prescription example of the pharmaceutical composition containing the compound of this invention as an active ingredient is shown below.
[처방예 1 (정제)][Prescription 1 (tablet)]
성 분 1정당(mg)Per tablet (mg)
본 발명 화합물 100Inventive Compound 100
유 당 130Lactose 130
옥수수 전분 40Corn Starch 40
스테아린산마그네슘 10Magnesium Stearate 10
합계 280mg280 mg
[처방제 2 (캡슐제)][Prescription 2 (capsules)]
성 분 1캡슐당(mg)Per capsule (mg)
본 발명 화합물 50Inventive Compound 50
유 당 250Lactose 250
합계 300mg300 mg in total
[처방예 3 (주사제)][Prescription 3 (injective)]
성 분 1앰플당(mg)Per Ampoule (mg)
본 발명 화합물 10Inventive Compound 10
염화나트륨 적당량Sodium Chloride
주사용 증류수 적당량Appropriate amount of distilled water for injection
전체량 1mlTotal amount 1ml
[처방예 4 (연고제)][Prescription 4 (Ointment)]
성 분 중량(g)Component weight (g)
본 발명 화합물 1Inventive Compound 1
유화왁스 30Emulsified Wax 30
백색와세린 50White Waserine 50
유동파라핀 20Liquid Paraffin 20
합계 101g101 g in total
[처방예 5 (좌제)][Prescription Example 5 (Suppository)]
성 분 1단위당(mg)Per unit of ingredient (mg)
본 발명 화합물 20Inventive Compound 20
카카오지방 1980Cacao Region 1980
합계 2000mgTotal 2000 mg
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019930001016A KR930003488B1 (en) | 1984-03-08 | 1993-01-27 | Hypoglycemic hydantion derivatives |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59045278A JPH062748B2 (en) | 1984-03-08 | 1984-03-08 | Novel hydantoin derivative and pharmaceutical composition containing the compound as an active ingredient |
| JP59241439A JPH0686436B2 (en) | 1984-11-15 | 1984-11-15 | Novel hydantoin derivative and pharmaceutical composition containing the compound |
| KR1019850001348A KR930001835B1 (en) | 1984-03-08 | 1985-03-04 | Hypoglycemic hydantion derivatives |
| KR1019930001016A KR930003488B1 (en) | 1984-03-08 | 1993-01-27 | Hypoglycemic hydantion derivatives |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019850001348A Division KR930001835B1 (en) | 1984-03-08 | 1985-03-04 | Hypoglycemic hydantion derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR930003488B1 true KR930003488B1 (en) | 1993-05-01 |
Family
ID=27292173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019930001016A KR930003488B1 (en) | 1984-03-08 | 1993-01-27 | Hypoglycemic hydantion derivatives |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR930003488B1 (en) |
-
1993
- 1993-01-27 KR KR1019930001016A patent/KR930003488B1/en not_active IP Right Cessation
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