KR910004789B1 - 2-피롤리돈 유도체 - Google Patents
2-피롤리돈 유도체 Download PDFInfo
- Publication number
- KR910004789B1 KR910004789B1 KR1019860003628A KR860003628A KR910004789B1 KR 910004789 B1 KR910004789 B1 KR 910004789B1 KR 1019860003628 A KR1019860003628 A KR 1019860003628A KR 860003628 A KR860003628 A KR 860003628A KR 910004789 B1 KR910004789 B1 KR 910004789B1
- Authority
- KR
- South Korea
- Prior art keywords
- pyrrolidone
- group
- butyl
- compound
- hydroxybenzylidene
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 150000003953 γ-lactams Chemical class 0.000 claims abstract description 13
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 48
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- 238000000034 method Methods 0.000 claims description 11
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- 238000002360 preparation method Methods 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
내용 없음.
Description
본 발명은 3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈 및 N-치환 유도체를 포함하는 신규한 2-피롤리돈 유도체에 관한 것이다.
치환체는 알킬, 알콕시, 알케닐, 페닐-알킬렌, 히드록시-알킬렌 및 아미노-알킬렌을 포함한다.
그것은 고도의 안전성을 가진 소염제(anti-inflammatory agent), 진통제 및 해열제로서 특히 효과적이다.
본 발명은 또한 상기 유도체의 제법 및 상기 유도체와 제약상 허용되는 담체로 이루어지는 의약조성물에 관한 것이다. 2-피롤리돈 유도체는 탁월한 의약효과를 미친다.
조성물에 있어서, 본 발명 화합물은 치료학적 유효량으로 사용된다. 발명화합물은 일반식(Ⅰ)
과, 제약상 허용되는 그의 염, 그의 제법 그리고 그것을 유효성분으로하여 이루어지는 약제로 정의된다.
상기식에서, R은 수소원자, 저급 알킬, 저급 알콕시 또는 저급 알키닐기 또는 일반식
-(CH2)n-X
(여기서 R1과 R2는 동일 또는 서로 상이하며 각각 수소원자 또는 저급 알킬기를 나타낸다)의 기를 나타내며, n은 1 또는 2의 정수를 나타낸다].
R, R1및 R2를 정의하는데 위에서 사용한바 "저급 알킬기"라는 말은 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 1-메틸프로필, t-부틸, n-펜틸, 1-에틸프로필, 이소아밀 및 n-헥실기와 같은 1 내지 6탄소원자를 갖는 직쇄 또는 분기쇄 알킬기를 포함한다.
상기한바 저급 알콕시 및 저급 알키닐기는 상기한 저급 알킬기로부터 유도된 것들을 포함한다.
본 발명 화합물(Ⅰ)은 필요하다면 해당 나트륨 또는 칼륨염으로 전환될 수 있다.
R이 일반식의 기일 때, 염산, 브롬화수소산 또는 요오드화수소산과 같은 무기산 또는 말레산, 푸마르산, 숙신산, 말론산, 아세트산, 시트르산 또는 메탄술폰산과 같은 유기산으로 제약상 허용되는 그의 염으로 더 전환시킬 수 있다.
본 발명 화합물(Ⅰ)은 여러 가지 방법으로 제조될 수 있다. 몇가지 전형적인 실시예는 다음과 같다.
[제조방법 1]
(여기서 R은 상기한 바와 같다).
즉, 3, 5-디-t-부틸-4-히드록시벤즈알데히드(Ⅱ)는 종래의 방법으로 위티그시약(Ⅲ)과 반응하여 목적 화합물(Ⅰ)을 제공한다. 반응에 참가하지 않는 어떠한 용매든 사용할 수 있다. 바람직한 용매의 예들은 디메틸포름아미드(DMF), 디메틸술폭시드(DMSO), 에탄올, 에틸아세테이트 및 벤젠이다. 반응은 대략 0 내지 150℃, 바람직하게는 30 내지 100℃에서 수행될 수 있다.
[제조방법 2]
(여기서 R은 상기한 바이고 Hal은 할로겐원자를 나타낸다).
즉, 3, 5-디-t-부틸-4-히드록시벤즈알데히드(Ⅲ)는 염기의 존재하에 위티그염(Ⅳ)과 반응시켜 이로써 위티그 반응을 수행하여 목적화합물(Ⅰ)을 얻는다. 염기의 예들은 크리에틸아민 및 피리딘과 같은 유기염기와 탄산나트륨 및 탄산칼륨과 같은 무기염기들이다. 반응에 참가하지 않는 어떠한 용매도 사용할 수 있다. 바람직한 용매의 예들은 디메틸포름아미드(DMF), 디메틸술폭시드(DMSO), 에탄올, 에틸아세테이트 및 벤젠이다. 반응은 대략 0 내지 150℃, 바람직하게는 30 내지 100℃에서 수행될 수 있다.
위에 나타낸 화합물(Ⅳ)은 일반식(Ⅶ)
을 갖는 신규한 중간체 화합물로부터 유도된다. 상기식에서 R은 상기한 바이고 X는 할로겐이다. R이 메톡시이고 X가 브롬인 것이 바람직하다.
중간체 화합물(Ⅶ)의 제법을 아래에 예시한다.
Y는 할로겐 또는 유기술포닐옥시기이고, X는 할로겐이며, R은 저급 알콕시기이다.
상기한 과정에서, 화합물(Ⅶ)은 -50 내지 +100℃의 온도에서 에탄올 및 벤젠과 같은 용매중에서 NaH, K2CO3및 알콕시화나트륨과 같은 염기와 고리형성 반응시킴으로써 얻어진다. 화합물(Ⅳ)은 트리페닐포스핀과의 반응에 의해 얻어진다. 이 단계에서, 위티그시약을 얻기 위해 아인산트리에틸을 교대로 사용할 수 있다.
R이 메톡시이고 X 및 Y가 각각 브롬인 구체예를 아래에 나타낸다.
[제조방법 3]
R이 저급 알킬 또는 저급 알키닐기이거나 또는 일반식 -(CH2)n-X의 기(X는 상기한 바이다)인 목적화합물(Ⅰ)은 다음의 방법으로 제조될 수 있다.
(여기서 R은 상기한 바이고 Y는 할로겐원자 또는 메실옥시 또는 토실옥시기와 같은 유기술포닐옥시기를 나타낸다.)
즉, 화합물(Ⅴ)은 알킬화제로서 기여하는데, 수소화나트륨, 소디움아미드 또는 t-부톡시화칼륨과 같은 염기의 존재하에 본 발명 화합물(Ⅵ)과 반응하여 목적화합물(Ⅰ)을 제공한다.
반응에 참가하지 않는 어떠한 용매도 사용될 수 있다. 바람직한 용매의 예들은 디메틸포름아미드(DMF), 디메틸술폭시드(DMSO), 벤젠, 테트라히드로푸란(THF) 및 t-부탄올이다. 반응은 대략 -20 내지 100℃ 바람직하게는 0 내지 30℃에서 수행될 수 있다.
본 발명을 더 예시하기 위하여, 제한하려는 의도는 아니나 발명화합물의 전형적인 예들을 제공하기로 한다.
N-메틸-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-에틸-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-메톡시-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-(2-디메틸아미노에틸)-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-벤질-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-프로파르길-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-(2-히드록시에틸)-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-n-부틸-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-(2-디에틸아미노에틸-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-에톡시-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈,N-헥실-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈 및N-n-부톡시-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈.
본 발명에 희해 제공된 2-피롤리돈 유도체 각각은 어떠한 문헌에도 결코 보고된 적이 없는 신규한 화합물이며 저특성 및 현저한 소염효과를 나타낸다.
소염제는 다음의 네 그룹, 즉 스테로이드 호르몬, 비스테로이드제, 소염(antiphlogistic)효소 및 면역억제제(immunosuppressive agent)로 크게 분류될 수 있다. 이들 네 그룹중, 비스테로이드제가 가장 중요한데, 이것은 최근에 전 세계에 걸쳐 비스테로이드 소염제를 개발하려는 활발한 시도를 일으키고 있다.
현재 빈번히 사용되고 있는 비스테로이드제는 인도메타신과 같은 인돌아세트산 유도체 ; 이 뷰페낙(ibufenac) 및 이뷰프로펜(ibuprofen)과 같은 페닐아세트산 유도체 ; 아스피린, 살리실산 및 살시실로살리실산과 같은 살시실산 유도체 ; 메페나믹산(mefenamic acid) 및 플루페나믹산(flufenamic acid)과 같은 안트라닐산 유도체 ; 페닐부타존, 옥시페닐부타존 및 케토페닐부타존과 같은 피라졸리딘디온 유도체 ; 그리고 벤지드아민(benzydamine), 메피리졸(mepirizol) 및 티노리딘(tinoridine)과 같은 염기성 약품을 포함한다.
그러나 이들 비스테로이드제는 임상적 관점에서 볼 때 심각한 불리점을 갖는다. 즉, 그들은 위장 및 신장 장해를 유발하는 부작용을 나타낸다. 따라서 전 세계에 걸쳐 여전히 더 좋은 비스테로이드 소염제를 개발하려는 시도가 있어 왔다.
이들 상황하에서, 본 발명자는 장기간동안 신규한 소염제를 개발하려는 연구를 하였고 그 결과 일반식(Ⅰ)의 2-피롤리돈 유도체가 종래의 비스테로이드 소염제와는 다른 화학구조를 갖는데, 탁월한 소염효과를 미친다는 것을 발견하였다.
따라서 본 발명 화합물은 일반식(Ⅰ)
의 2-피롤리돈 유도체 및 제약상 허용되는 그의 염이다.
상기식에서 R은 수소원자, 저급 알킬, 저급 알콕시 또는 저급 알키닐기 또는 일반식
-(CH2)n-X
의 기를 나타낸다[여기서 X는 페닐기 또는 일반식
(여기서 R1과 R2는 동일 또는 서로 상이하며 각각 수소원자 또는 저급 알킬기를 나타낸다)의 기를 타나내며, n은 1 또는 2의 정수를 나타낸다].
본 발명의 각 화합물은 높은 안전성의 소염제, 진통제 및 해열제로서의 가치가 있다.
또한 제약상 다음 사실들로 특징지어진다.
1. 인도메타신, 이뷰프로페론 및 피록시캄과 같은 종래의 소염제보다 더 넓은 안전범위를 갖는다.
2. 종래의 비스테로이드 소염제에서 결코 관찰되지 않는 지방산 산화효소억제 및 항산화제 효과를 미친다.
본 발명 화합물은 종래의 소염제가 적용되는 증상들에 적용될 수 있다. 이들 증상의 예들은 관절염, 류마티즘, 신경염, 관절통, 신경통, 감기증후군, 급성 및 만성 기관지염, 외상성 및 수술후염증, 열병 및 치통과 두통을 포함하는 통증이다.
본 발명 화합물의 유용성을 상세히 예시하기 위해, 다음의 약리학적 실시예를 제공하기로 한다.
[약리학 실시예 1]
염증의 국소표면온도의 하강효과
(1) 실험방법
액체 파라핀중의 우락균(butter bacillus) 현탁액(10mg/ml) 0.05ml를 6주생 피셔(Fisher) 숫쥐의 뒷발바닥에 주사하여 이로써 보조약 염증을 유발시킨다. 3 내지 5일 후, 염증생긴 발의 표면온도는 정상 발의 온도보다 8 내지 10℃ 더 높게 지속되었다.
이하에 기술하는바 시험화합물과 대조표준화합물(즉 인도메타신 및 피록시캄)을 아라비아고무 5% 수용액에 부유시키고 5ml/kg 체중의 투여량으로 쥐에 경구투여하였다. 염증부위의 국소표면온도를 시로타(H. Shirota et al., J. Pharmacol. Methods, 12, 35-43(1984))의 방법에 따라 2,4 및 6시간 후 구하였다. 투여이전의 온도보다 표면온도를 적어도 2℃ 아래로 낮추는데 요구된 투여량을 두동물의 데이터를 평균함으로써 계산하여, 이와 같이 각 시험화합물의 항염증타이터를 구하였다.
(2) 시험화합물
화합물 A : N-메틸-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈, 화합물 B : N-메톡시-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈 및 화합물 C : 3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈.
(3) 결과
표 1은 결과를 나타낸다.
[표 1]
[약리학 실시예 2]
발바닥에서 카라기난수종 억제효과
(1) 실험방법
5주생 피셔 숫쥐를 각각 5마리를 갖는 군으로 분류하였다. 각 시험화합물을 아라비아고무 5% 수용액에 부유시키고 0.5mg/100g 체중의 투여량으로 각 쥐에 투여하였다. 한시간 후, 1% 카라기난 용액을 동물의 오른쪽 뒷발바닥에 주사하여 이로써 염증을 유발시켰다. 카라기난주사 3시간 후, 동물의 각 뒷발바닥의 부피를 측정하여 카라기난을 주사한 발바닥의 부피증가를 계산하였다. 얻은 데이터를 대조표준군의 데이터와 비교하여, 이와 같이 시험화합물의 억제비율을 구하였다. 약리학 실시예 1에서 사용한 바와 같은 시험화합물을 사용하였다.
(2) 결과
표 2는 결과를 나타낸다.
[표 2]
[약리학 실시예 3]
위궤양 유발효과
(1) 실험방법
7주생 피셔 숫쥐를 24시간동안 단식시켜 둔 다음 아라비아고무 5% 수용액에 부유시킨 각 시험화합물을 거기에 경구투여하였다. 6시간 후, 시험화합물 50% 궤양 투여량을 위점막에서 관찰된 출혈반점으로부터 구하였다.
(2) 결과
표 3은 결과를 나타내는데, 여기서 각 UD50은 50% 궤양유발 투여량(mg/kg)을 나타낸다.
[표 3]
이들 약리학 실시예의 결과는 본 발명의 각 화합물이 종래의 소염제의 경우에 빈번히 관찰되는 위장해를 유발하는 부작용이 거의 등반되지 않는 강한 소염효과를 나타냄을 명백히 가리키고 있다. 그러므로 본 발명 화합물은 장기간동안 연속적으로 복용되어야 하는 소염제로서 대단히 탁월하다.
[급성독성시험]
본 발명 범위내에 드는 화합물 B의 LD50을 쥐와 생쥐를 사용하여 급성독성에 관하여 조사하였다. 결과를 표 4에 나타낸다.
[표 4]
LD50과 신뢰범위
이와 같이 본 발명은 크게 가치가 있다.
소염약품으로서 본 발명 화합물을 사용하는데 있어서, 경구적으로 또는 비경구적으로(즉 근육내, 피하 또는 정맥내 투여 또는 좌약에 의해)투여된다. 투여량은 환자의 증상, 연령 및 개인차에 의존하여 다양하며 일반적으로 성인에 대하여 약 1-500mg/일, 바람직하게는 5-300mg/일, 더 바람직하게는 10-100mg/일이다.
발명화합물은 종래기술에 따라 정제, 과립, 분말, 캡슐, 주사액, 좌약, 연고와 같은 외용의 제약상 조제의 형태로 사용될 수 있다.
경구용 고형생성물의 제조에 있어서, 부형제와, 필요하다면, 결합제, 붕해제, 윤활제, 착색제 및 교정제(향미제)를 유효성분에 가하고 다음에 혼합물을 정제, 피복정제, 과립, 분말 또는 캡슐로 형성시킨다.
부형제로서, 예를들면, 락토오스, 콘스타아치, 백설탕, 글루코오스, 소르비톨 결정성셀룰로오스 및 이산화규소를 사용할 수 있다. 결합제로서, 예를들면, 폴리비닐알코올, 폴리비닐에테르, 에틸셀룰로오스, 메틸셀룰로오스, 아카시아, 트라가칸스(tragacanth), 젤라틴, 셀락, 히드록시프로필셀룰로오스, 히드록시메틸 프로필셀룰로오스, 히드록시프로필스타아치, 폴리비닐피롤리돈, 백설탕 및 소르비톨을 사용할 수 있다. 붕해제로서, 예를들면, 스타아치, 한천, 젤라틴분말, 결정성셀룰로오스, 탄산칼슘 탄산수소나트륨, 시트르산칼슘, 덱스트린 및 펙틴을 사용할 수 있다. 윤활제로서, 예를들면 스테아린산마그네슘, 활석, 폴리에틸렌글리콜, 실리카 및 경화식물유를 사용할 수 있다. 착색제로서, 의약용 첨가제로서 허용된 것들을 사용할 수 있다. 교정제로서, 코코아분말, 맨틀, 방향성분말, 페파민트유, 보르네올 및 신나몬분말을 사용할 수 있다. 이들 정제 및 과립은 설탕, 젤라틴으로 알맞게 피복될 수 있다.
경구투여를 위한 액상의약의 제조에 있어서, 필요하다면 교정제, 완충액, 안정제 등을 유효성분에 가하며, 혼합물을 처리하여 예로써 시럽을 형성시킨다.
주사용액의 제조에서는 필요하다면, pH 조절제, 완충액, 현탁제, 용해제, 안정제, 등장제(isotonizer) 및 방부제를 유효성분에 가하고 혼합물을 처리하여 피하, 근육내 또는 정맥내 주사용액을 형성시킨다.
현탁제로서, 예를들면, 메틸셀룰로오스, 폴리소르베이트 80, 히드록시에틸셀룰로오스, 아카시아, 트라가칸스분말, 소디움카르복시메틸셀룰로오스 및 폴리옥시에틸렌소르비탄 모노라우레테이트를 사용할 수 있다. 용해제로서, 폴리옥시에틸렌-경화 아주까리유, 폴리소르베이트 80, 니코틴산아미드, 폴리옥시소르비탄 모노라우레이트, 마크로골(Macrogol) 아주까리유 및 지방산 에틸에스테르를 사용할 수 있다. 안정제로서, 예를들면, 아황산나트륨, 메타아황산나트륨 및 에테르를 사용할 수 있다. 방부제로서, 메틸 p-히드록시벤조에이트, 에틸 p-히드록시벤조에이트, 소르빈산, 페놀, 크레졸 및 클로로크레졸을 사용할 수 있다.
본 발명을 더 예시하기 위해 제한하려는 의도는 아니나, 다음의 실시예들을 제공한다.
[실시예 1]
N-메틸-3-(3,5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
3, 5-디-t-부틸-4-히드록시벤즈알데히드 1.2g, (N-메틸-2-피롤리돈-3-일)트리페닐포스포늄브로마이드 2.5g 및 트리에틸아민 1.0ml를 에탄올중에서 환류하에 2시간동안 가열하였다. 에탄올을 증발시켜버린 후, 잔사를 클로로포름에 용해시키고, 물로 세척하고 이어서 포화식염수용액으로 세척하고 무수황산마그네슘상에서 건조시켰다. 클로로포름을 증발시킨 후, 잔사를 실리카겔과 벤젠/아세톤을 사용하여 칼럼 크로마토그라피를 시키고 에틸아세테이트와 헥산의 혼합물로부터 재결정시켜 표제화합물 1.0g을 얻었다.
융점 : 185℃
NMR(δ, CDCl3) : 1.47(18H, s), 3.50(2H, t, J=6Hz), 3.01(3H, s), 5.43(1H, s), 7.30(1H, t, J=3Hz) 및 7.36(2H, s).
[실시예 2 내지 4]
다음 화합물을 실시예 1의 방법에 따라 제조하였다.
[실시예 2]
N-에틸-3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피릴리돈
융점 : 186.5℃
NMR(δ, CDCl3) : 1.45(18H, s), 2.9-3.1(2H, m), 3.3-3.6(4H, m), 5.40(1H, s), 7.26(1H, t, J=3Hz) 및 7.32(2H, s).
[실시예 3]
N-메톡시-3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
3, 5-디-t-부틸-4-히드록시벤즈알데히드 2.76g, (N-메톡시-2-피롤리돈-3-일)트리페닐포스포늄 브로마이드 54.0g 및 트리에틸아민 33.0ml를 에탄올중에서, 50℃에서 4시간동안 가열하였다. 에탄올을 증발시킨 후, 잔사를 클로로포름에 용해시키고 물로 세척한 다음 포화식염수용액으로 세척하고 무수황산마그네슘상에서 건조시켰다. 클로로포름을 증발시킨 후, 실리카겔 그리고 벤젠과 아세톤의 담체액을 사용하여 칼럼 크로마토그라피로 처리하고 에틸아세테이트와 헥산의 혼합물로 재결정시켜 표제화합물 26.5g을 얻었다.
융점 : 169℃
NMR(δ, CDCl3) : 1.46(18H, s), 3.05(2H, dt, J=3Hz, 7Hz), 3.66(2H, t, J=7Hz), 3.88(3H, s), 5.44(1H, s), 7.30(2H, s), 및 7.35(1H, t, J=3Hz).
[실시예 4]
3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
융점 : 210℃(분해)
NMR(δ, CDCl3) : 1.46(18H, s), 3.13(2H, 브로오드, dt, J=3Hz, 6Hz), 3.52(2H, t, J=6Hz), 5.45(1H, s), 6.98(1H, 브로오드), 7.32(1H, t, J=2Hz) 및 7.37(2H, s).
[실시예 5]
N-(2-디메틸아미노에틸)-3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈 500mg을 디메틸포름아미드 5ml에 용해시키고 수소화나트륨 0.2g과 염화 2-디메틸아미노에틸 0.2g을 빙냉하에 계속해서 거기에 가하였다. 다음에, 얻은 혼합물을 실온에서 1시간동안 반응하도록 두었다. 반응혼합물을 에틸아세테이트로 추출하고 물로 세척하고 이어서 포화식염수용액으로 세척하고 무수황산마그네슘상에서 건조시켰다. 에틸아세테이트를 증발시킨후, 잔유물을 실리카겔 및 벤젠/아세톤을 사용하여 컬럼 크로마토그라피에 의해 정제하고 에틸아세테이트/헥산으로부터 재결정하여 표제화합물 300mg을 얻었다.
융점 : 150℃
NMR(δ, CDCl3) : 1.46(18H, s), 2.26(6H, s), 2.50(2H, t, J=7Hz), 2.9-3.1(2H, m), 3.54(4H, t, J=7Hz), 5.37(1H, s), 7.26(1H, t, J=3Hz) 및 7.31(2H, s).
[실시예 6 내지 8]
다음 화합물을 실시예 5의 방법에 따라 제조하였다.
[실시예 6]
N-벤질-3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
융점 : 166℃
NMR(δ, CDCl3) : 1.45(18H, s), 2.9-3.1(2H, m), 3.38(2H, t, J=6Hz), 4.62(2H, s), 5.41(1H, s) 및 7.3 - 7.5 (8H, 7.31, 7.36).
[실시예 7]
N-프로파르길-3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
융점 : 212℃
NMR(δ, CDCl3) : 1.46(18H, s), 2.23(1H, t, J=3Hz), 2.9-3.2(2H, m), 3.59(2H, t, J=7Hz), 4.26(2H, d, J=3Hz), 5.41(1H, s) 및 7.2-7.4(3H, m).
[실시예 8]
N-(2-히드록시에틸)-3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
N-2-(2-테트라히드로피라닐옥시)에틸-3-(3.5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈
300mg을 실시예 5의 방법에 따라 메탄올중의 염산으로 가수분해시켜 표제화합물 150mg을 얻었다.
융점 : 191℃
NMR(δ, CDCl3) : 1.45(18H, s), 2.9-3.2(2H, m), 3.38(1H, t), 3.5-3.7(4H, m), 3.84(2H, q, J=6Hz), 5.41(1H, s) 및 7.2-7.4(3H, m).
[실시예 9]
신규한 중간체 화합물, N-메톡시-3-브로모-2-피롤리돈의 한 구체예를 아래에 예시한 방법에 의해 얻은 다음 마지막 생성물을 위해 사용하였다.
염화 2, 4-디브로모부타노일(2)
γ-부티로락톤 500g과 PBr310ml의 혼합액을 100℃까지 가열하였다. 다음에, 반응혼합물을 교반하며 110 내지 115℃로 유지시키면서, 대기에 노출되지 않게하여 6시간의 기간에 걸쳐 브롬수 Br2250ml를 혼합물에 서서히 적가하였다. 첨가 후, 반응혼합물을 같은 온도에서 1시간동안 더 교반하였다. 그 다음 90℃로 냉각시켰다. 90℃로 유지시킨 오일욕에서 2시간에 걸쳐 디메틸포름아미드 0.5ml를 거기에 적가하였다. 혼합물을 같은 온도에서 3시간동안 더 교반하였다. 생성액을 1mmHg에서 60 내지 65℃에서 중발시켜 표제화합물(2) 1.0kg을 얻었다.
N-메톡시-2, 4-디브로모부탄아미드(3)
아세토아미드 520g, 물 1리터 및 클로로포름 5리터를 빙염욕으로 -5℃로 냉각시켰다. 염화 2,4-디브로모부타노일 1450g과 클로로포름 1리터의 혼합물을 거기에 가하였다. 다음에 물 1리터중의 수산화나트륨 500g 용액을 거기에 적가하여 반응온도를 10℃ 보다 높지않은 온도로 유지시켰다. 첨가완결 후, 반응혼합물을 같은온도에서 1시간동안 더 교반시켰다. 클로로포름층을 반응혼합물로부터 분리시키고 먼저 0.5N 수성염산, 두번째로 포화중탄산나트륨수용액, 그리고 세번째로 포화염수용액으로 세척하였다. 다음에 황산마그네슘으로 건조시키고, 클로로포름을 증발시켜 잔유물로서 오일 1400g을 얻었다. 그것을 그대로 후속 과정에 사용하였다.
N-메톡시-3-브로모-2-피롤리돈(4)
미정제 N-메톡시-2, 4-디브로모부탄아미드 1400g을 벤젠 1리터에 용해시켰다. 다음에 반응혼합물을 빙수욕으로 냉각시키면서 15 내지 20℃에서 NaH 125g을 용액에 조금씩 가하였다. 반응 후, 잔유 NaH를 얼음으로 분해시키고 생성물 혼합물을 포화염수용액으로 세척하였다. 그것을 황산마그네슘으로 건조시켰다. 그 다음 벤젠을 증발시켰다. 생성물을 실리카겔 그리고 아세톤과 벤젠의 혼합물을 사용하여 표제화합물(4) 500g을 얻었다.
NMR(δ, CDCl3) : 3-CH 4.38(1H, dd, J=3.6Hz, 7.2Hz), 4-CH22,2-2,9(2H, m), 5-CH23, 4-3, 9(2H, m), 1-CH3O 3,82(3H, s).
(N-메톡시-2-피롤리돈-3-일)트리페닐포스포늄브로마이드(5)
N-메톡시-3-브로모-2-피롤리돈 75g, 트리페닐포스핀 105g 및 테트라히드로푸란 700ml의 혼합물을 가열하고 24시간동안 환류시켰다. 냉각시킨 후, 결과된 침전을 여과하여 취하고 테트라히드로푸란으로 세척하였다. 건조시켜, 표제화합물(5) 54g을 얻었다.
화합물(5)을 실시예 3에 나타낸 바와 같은 방법으로 반응시켜 본 발명의 2-피롤리돈 유도체를 얻었다.
Claims (3)
- 3,5-디-t-부틸-4-히드록시벤즈알데히드를 용매중에서 0-150℃ 온도하에서, 다음 일반식의 화합물과 위티그 반응시켜 목적하는 2-피롤리돈 유도체를 얻는데, 그 다음 필요하다면 이것을 염으로 전환시키는 것을 특징으로 하는 일반식.
- 3, 5-디-t-부틸-4-히드록시벤즈알데히드를 염기존재하에 용매중에서 0-150℃ 온도하에서 일반식,의 화합물과 위티그 반응시켜 목적하는 2-피롤리돈 유도체를 얻는데 그 다음 이것을 필요하다면 염으로 전환시키는 것을 특징으로 하는 일반식
- 일반식 R-Y[여기서 R은 저급 알킬 또는 저급 알키닐기 도는 일반식 -(CH2)n-X의 기[여기서 X는 페닐 또는 히드록실기 또는 일반식의 기(여기서 R1과 R2는 동일 또는 서로 상이하며 각각 수소원자 또는 저급 알킬기를 나타낸다)를 나타내며, n은 1 또는 2의 정수를 나타낸다]. Y는 할로겐원자를 나타내거나 메실옥시 또는 토실옥시기와 같은 유기술포닐옥시기를 나타낸다]의 화합물을 염기존재하에 용매중에서 -20-100℃ 온도하에서 3-(3, 5-디-t-부틸-4-히드록시벤질리덴)-2-피롤리돈과 반응시켜 목적하는 2-피롤리돈 유도체를 얻는데, 그 다음 이것을 필요하다면 염으로 전환시키는 것을 특징으로 하는 일반식(여기서 R은 위에 정의한 대로이다)의 2-피롤리돈 유도체 및 제약상 허용되는 그의 염의 제조방법.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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JP60-96799 | 1985-05-09 | ||
JP96799 | 1985-05-09 | ||
JP60096799A JPH066571B2 (ja) | 1985-05-09 | 1985-05-09 | 2−ピロリドン誘導体 |
Publications (2)
Publication Number | Publication Date |
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KR860008973A KR860008973A (ko) | 1986-12-19 |
KR910004789B1 true KR910004789B1 (ko) | 1991-07-13 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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KR1019860003628A KR910004789B1 (ko) | 1985-05-09 | 1986-05-09 | 2-피롤리돈 유도체 |
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Country | Link |
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US (1) | US4833160A (ko) |
EP (1) | EP0204964B1 (ko) |
JP (1) | JPH066571B2 (ko) |
KR (1) | KR910004789B1 (ko) |
CN (1) | CN1014058B (ko) |
AT (1) | ATE66673T1 (ko) |
AU (1) | AU581078B2 (ko) |
CA (1) | CA1264762A (ko) |
DE (1) | DE3681076D1 (ko) |
DK (1) | DK213286A (ko) |
ES (1) | ES8800148A1 (ko) |
FI (1) | FI84172C (ko) |
HU (2) | HU199117B (ko) |
MX (1) | MX162717A (ko) |
NO (1) | NO861820L (ko) |
NZ (1) | NZ216092A (ko) |
PH (2) | PH23189A (ko) |
PT (1) | PT82540B (ko) |
ZA (1) | ZA863352B (ko) |
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US5691367A (en) * | 1985-08-09 | 1997-11-25 | Eli Lilly And Company | Aryl-substituted rhodanine derivatives |
US5356917A (en) * | 1985-08-09 | 1994-10-18 | Eli Lilly And Company | Aryl-substituted rhodanine derivatives |
US5202341A (en) * | 1987-03-11 | 1993-04-13 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Hydroxystyrene compounds having tyrosine kinase inhibiting activity |
WO1988007035A1 (en) * | 1987-03-11 | 1988-09-22 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Hydroxystyrene derivatives |
US5089516A (en) * | 1987-03-11 | 1992-02-18 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | 1-phenyl-3,5-pyrazolidinedione hydroxystyrene compounds which have tyrosine kinase inhibiting activity |
US5216002A (en) * | 1989-12-21 | 1993-06-01 | Eli Lilly And Company | Method of treating inflammatory bowel disease |
US5143928A (en) * | 1990-03-27 | 1992-09-01 | Warner-Lambert Company | 3,5-di-tertiarybutyl-4-hydroxyphenylmethylene derivatives of 2-substituted thiazolidinones, oxazolidinones, and imidazolidinones as antiinflammatory agents |
HU214333B (hu) * | 1991-01-21 | 1998-03-02 | Shionogi Seiyaku Kabushiki Kaisha | Eljárás benzilidén-karbamoil-2-pirrolidon, -4-tiazolidinon, -4-oxazolidinon, -3-izotiazolidinon- és -3-izoxazolidinon-analógok és az ezeket tartalmazó gyógyszerkészítmények előállítására |
US5270339A (en) * | 1991-04-05 | 1993-12-14 | Kanagafuchi Kagaku Kogyo Kabushiki Kaisha | Phenoxybenzene derivative |
ES2089736T3 (es) * | 1992-10-28 | 1996-10-01 | Shionogi & Co | Derivados de bencilideno. |
US5358964A (en) * | 1993-07-26 | 1994-10-25 | Warner-Lambert Company | Benzylidene-lactone and their thiocarbonyl analogs as inhibitors of proteoglycan degradation |
GB9704499D0 (en) | 1997-03-05 | 1997-04-23 | Glaxo Wellcome Spa | Method of manufacture |
CN103342672B (zh) * | 2013-07-02 | 2015-12-23 | 扬州大学 | 取代吡咯烷-2-酮的新合成方法 |
Family Cites Families (13)
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US3714153A (en) * | 1970-06-22 | 1973-01-30 | Roussel Uclaf | Novel cyclopropanecarboxylic acids |
DE2329308A1 (de) * | 1972-03-03 | 1975-01-02 | Gruenenthal Chemie | Neue lactame |
AU518986B2 (en) * | 1977-10-11 | 1981-10-29 | Takeda Chemical Industries Ltd. | Lactams |
US4138495A (en) * | 1978-05-19 | 1979-02-06 | Stauffer Chemical Company | N-Substituted pyrrolidones and their use as miticides |
JPS5879944A (ja) * | 1981-11-09 | 1983-05-13 | Kanegafuchi Chem Ind Co Ltd | 3,5−ジ・タ−シヤリ−・ブチルスチレン誘導体及び抗炎症、鎮痛、解熱剤並びに血小板凝集阻害剤 |
US4431656A (en) * | 1981-02-05 | 1984-02-14 | Kanegafuchi Chemical Industry Company Limited | 3,5-di-Tert-butylstyrene derivatives, salts thereof, and pharmaceutical compositions containing the same as an active ingredient |
JPS57130950A (en) * | 1981-02-05 | 1982-08-13 | Kanegafuchi Chem Ind Co Ltd | 3,5-di-tert-butyl-4-hydroxystyrene derivative and anti- inflammatory, analgesic, antipyretic agent and inhibitor for blood platelet aggregation |
US4440784A (en) * | 1981-02-05 | 1984-04-03 | Kanegafuchi Chemical Industry Company, Ltd. | Anti-inflammatory, analgesic, and antipyretic pharmaceutical composition |
DE3326724A1 (de) * | 1983-07-25 | 1985-02-07 | Boehringer Ingelheim KG, 6507 Ingelheim | In 1-stellung substituierte 4-hydroxymethyl-pyrrolidinone, verfahren zu ihrer herstellung, pharmazeutische zusammensetzungen und zwischenprodukte |
JPS6112660A (ja) * | 1984-06-27 | 1986-01-21 | Kanegafuchi Chem Ind Co Ltd | 新規2−ピロリドン誘導体及び抗炎症剤 |
JPH0623194B2 (ja) * | 1985-03-23 | 1994-03-30 | 鐘淵化学工業株式会社 | 新規ラクタム誘導体及び抗炎症剤 |
JPS6412660A (en) * | 1987-07-07 | 1989-01-17 | Canon Kk | Original reader |
JP3611676B2 (ja) * | 1996-06-24 | 2005-01-19 | アサマ化成株式会社 | パン生地の改良剤およびパンの製造方法 |
-
1985
- 1985-05-09 JP JP60096799A patent/JPH066571B2/ja not_active Expired - Lifetime
-
1986
- 1986-04-22 FI FI861698A patent/FI84172C/fi not_active IP Right Cessation
- 1986-04-23 US US06/856,068 patent/US4833160A/en not_active Expired - Fee Related
- 1986-04-28 AU AU56766/86A patent/AU581078B2/en not_active Ceased
- 1986-04-30 PH PH33721A patent/PH23189A/en unknown
- 1986-05-05 ZA ZA863352A patent/ZA863352B/xx unknown
- 1986-05-07 HU HU872041D patent/HU199117B/hu not_active IP Right Cessation
- 1986-05-07 EP EP86106249A patent/EP0204964B1/en not_active Expired - Lifetime
- 1986-05-07 DE DE8686106249T patent/DE3681076D1/de not_active Expired - Fee Related
- 1986-05-07 NO NO861820A patent/NO861820L/no unknown
- 1986-05-07 AT AT86106249T patent/ATE66673T1/de active
- 1986-05-07 DK DK213286A patent/DK213286A/da not_active Application Discontinuation
- 1986-05-08 CA CA000508748A patent/CA1264762A/en not_active Expired - Fee Related
- 1986-05-08 HU HU861911A patent/HU196749B/hu not_active IP Right Cessation
- 1986-05-08 ES ES554775A patent/ES8800148A1/es not_active Expired
- 1986-05-08 NZ NZ216092A patent/NZ216092A/xx unknown
- 1986-05-08 MX MX2417A patent/MX162717A/es unknown
- 1986-05-08 PT PT82540A patent/PT82540B/pt not_active IP Right Cessation
- 1986-05-09 CN CN86103227A patent/CN1014058B/zh not_active Expired
- 1986-05-09 KR KR1019860003628A patent/KR910004789B1/ko not_active IP Right Cessation
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1987
- 1987-05-27 PH PH35306A patent/PH23225A/en unknown
Also Published As
Publication number | Publication date |
---|---|
DE3681076D1 (de) | 1991-10-02 |
AU5676686A (en) | 1986-11-13 |
EP0204964A1 (en) | 1986-12-17 |
HUT43040A (en) | 1987-09-28 |
ATE66673T1 (de) | 1991-09-15 |
NZ216092A (en) | 1988-08-30 |
FI861698A0 (fi) | 1986-04-22 |
FI84172C (fi) | 1991-10-25 |
US4833160A (en) | 1989-05-23 |
HU196749B (en) | 1989-01-30 |
ES8800148A1 (es) | 1987-11-01 |
PT82540B (pt) | 1988-08-17 |
AU581078B2 (en) | 1989-02-09 |
CA1264762A (en) | 1990-01-23 |
FI861698A (fi) | 1986-11-10 |
HUT45493A (en) | 1988-07-28 |
EP0204964B1 (en) | 1991-08-28 |
NO861820L (no) | 1986-11-10 |
CN1014058B (zh) | 1991-09-25 |
JPS61257967A (ja) | 1986-11-15 |
PH23225A (en) | 1989-06-06 |
HU199117B (en) | 1990-01-29 |
FI84172B (fi) | 1991-07-15 |
DK213286D0 (da) | 1986-05-07 |
ZA863352B (en) | 1986-12-30 |
ES554775A0 (es) | 1987-11-01 |
JPH066571B2 (ja) | 1994-01-26 |
CN86103227A (zh) | 1987-01-21 |
PH23189A (en) | 1989-05-29 |
DK213286A (da) | 1986-11-10 |
MX162717A (es) | 1991-02-18 |
KR860008973A (ko) | 1986-12-19 |
PT82540A (en) | 1986-06-01 |
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