KR20020030009A - 신규 티오우레아 화합물 및 이를 함유하는 약제학적 조성물 - Google Patents

신규 티오우레아 화합물 및 이를 함유하는 약제학적 조성물 Download PDF

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KR20020030009A
KR20020030009A KR1020010050093A KR20010050093A KR20020030009A KR 20020030009 A KR20020030009 A KR 20020030009A KR 1020010050093 A KR1020010050093 A KR 1020010050093A KR 20010050093 A KR20010050093 A KR 20010050093A KR 20020030009 A KR20020030009 A KR 20020030009A
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KR100453078B1 (ko
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서영거
오우택
김희두
이지우
박형근
박영호
이정범
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서경배
주식회사 태평양
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Abstract

본 발명은 티오우레아 화합물 및 이를 함유하는 약제학적 조성물에 관한 것으로서, 특히 바닐로이드 수용체(Vanilloid Receptor; VR)에 대한 길항제로서 신규한 티오우레아 화합물 및 이를 함유하는 약제학적 조성물에 관한 것이다.
바닐로이드 수용체의 활성과 연관된 질환에는 통증, 급성 통증, 만성 통증, 신경병적 통증, 수술후 통증, 편두통, 관절통, 신경병증, 신경손상, 당뇨병성 신경병, 신경변성 질환, 신경성 피부질환, 뇌졸중, 방광과민증, 과민성 장증후군, 천식과 만성폐색성 폐질환등 호흡기 이상, 피부, 눈, 점막의 자극, 발열, 위-십이지장궤양, 염증성 장 질환 및 염증성 질환 등이 포함될 수 있다. 본 발명은 이들 질환의 예방, 치료를 위한 약제학적 조성물을 제공한다.

Description

신규 티오우레아 화합물 및 이를 함유하는 약제학적 조성물{Novel thiourea compounds and the pharmaceutical compositions containing the same}
본 발명은 티오우레아 화합물 및 이를 함유하는 약제학적 조성물에 관한 것으로서, 특히 바닐로이드 수용체(Vanilloid Receptor; VR)에 대한 길항제로서의 효능이 우수한 티오우레아 화합물 및 이를 함유하는 약제학적 조성물에 관한 것이다.
바닐로이드 수용체의 활성과 연관된 질환에는 통증, 급성 통증, 만성 통증, 신경병적 통증, 수술후 통증, 편두통, 관절통, 신경병증, 신경손상, 당뇨병성 신경병, 신경변성 질환, 신경성 피부질환, 뇌졸중, 방광과민증, 과민성 장증후군, 천식과 만성폐색성 폐질환등 호흡기 이상, 피부, 눈, 점막의 자극, 발열, 위-십이지장궤양, 염증성 장 질환 및 염증성 질환 등이 포함될 수 있다. 본 발명은 이들 질환의 예방, 치료를 위한 약제학적 조성물을 제공한다.
단, 상기 기술된 질환은 예시를 위한 것일 뿐 위의 예로 바닐로이드 수용체 길항제의 임상적용 범위를 한정하는 것은 아니다.
캡사이신 (capsaicin; 8-methyl-N-vanillyl-6-nonenamide)은 고추의 주된 신미성분이다. 고추는 향신료로서뿐만 아니라 전통의약으로서 위장질환뿐 아니라 특히 국소적용으로서 통증, 염증의 치료제로 오랫동안 사용되어 왔다 (Szallasi and Blumberg, 1999, Pharm. Rev. 51, pp159-211). 캡사이신은 아주 다양한 생리활성을 나타내는데, 심혈관계, 호흡계에 강력한 자극성을 나타낼 뿐만 아니라 국소적용시 통증과 자극성을 유발한다. 하지만 캡사이신은 이러한 통증유발 후에 탈감작(desensitization)을 유도해 캡사이신 자체 뿐만 아니라 다른 유해자극에 대해서도 통증을 느끼지 못하게 하는데, 이러한 특성을 활용하여 캡사이신, 올바닐(olvanil), 누바닐(nuvanil), DA-5018, SDZ-249482, 레시니페라톡신(resiniferatoxin) 등의 유사체가 진통제, 요실금 치료제 또는 피부질환 치료제로 사용되고 있거나 개발 중에 있다(Wriggleworth and Walpole, 1998, Drugs of the Future 23, pp531-538).
기계적, 열적, 화학적 유해자극에 대한 전도는 주로 가는 무수신경(C-섬유)과 얇은 유수신경(A -섬유)의 일차 구심성 신경섬유가 담당하는데 캡사이신과 바닐로이드(vanilloid)로 통칭되는 그 유사체의 주된 작용점도 바로 이들 유해감각을 전달하는 신경섬유에 존재한다. 캡사이신은 이들 신경에 존재하는 수용체에 작용해 칼슘, 나트륨등 이가, 일가 양이온을 강력하게 유입시킴으로서 초기에 강력한 자극을 일으킨 다음 신경기능을 차단함으로서 강력한 진통효과를 발휘한다(Wood et al., 1988, J. Neurosci. 8, pp3208-3220). 바닐로이드 수용체는(VR-1) 최근에야 클로닝되어 그 존재가 확실해졌는데(Caterina et al., 1997, Nature 389, pp816-824) 이 수용체는 캡사이신류(바닐로이드) 뿐만 아니라 프로톤, 열자극 등 다양한 유해자극도 전도함이 밝혀졌다(Tominaga et al., 1998, Neuron 21, pp531-543). 이로부터 바닐로이드 수용체는 다양한 유해자극에 대한 통합적 조절자로서의 역할을 가져 통증 및 유해자극 전달에 핵심적인 기능을 수행할 것으로 판단되고 있다. 최근에는 바닐로이드 수용체의 유전자가 제거된 녹아웃 마우스가 제조되었는데(Caterina et al., 2000, Science 288, pp306-313; Davis et al., 2000, Nature 405, pp183-187), 일반행동에 있어서는 정상 마우스와 차이가 없고 열자극, 열성 통각과민에 대해선 그 반응이 현저히 감약된 것으로 나타나 유해감각 전달에서의 이 수용체의 중요성을 재확인시켜 주었다. 그런데 캡사이신과 같은 외인성 리간드가 아닌 실제 바닐로이드 수용체에서 유해자극 전달에 관여하는 내인성 리간드로는 프로톤 외에는 잘 알려지지 않았는데, 12-하이드로퍼옥시아이코사테트라노익산(12-HPETE)으로 대표되는 류코트라이엔류 대사체와(Hwang et al., 2000, PNAS 11, pp6155-6160) 아난다마이드 (anandamide) 등의 아라키돈산 유도체가(Zygmunt et al., 2000, Trends Pharmacol. Sci. 21, pp43-44) 이 수용체에 대한 유력한 내인성 리간드로서 작용하고 프로톤은 직접적인 리간드라기보다는 수용체활성 항진작용을 지닌 보조인자로 판단된다.
이와 같이 캡사이신 반응성 감각신경세포 및 그 세포에 존재하는 바닐로이드 수용체는 전신에 분포해 통증과 유해자극을 전달하는 기본적인 기능을 수행할 뿐만 아니라, 신경성 염증의 발현에도 역시 중요인자로 작용하여 신경병증, 신경손상, 뇌졸중, 천식, 만성 폐색성 폐질환, 방광 과민증, 과민성 장증후군, 염증성 장 질환, 발열, 피부질환 및 염증성 질환의 병인과 밀접한 관련성을 지니며, 최근에는 신경변성 질환과의 상관성도 제시되고 있다 (WO 99/00125). 최근에는 위장관 손상에서 캡사이신에 반응성을 나타내는 구심성 감각신경의 역할이 특히 주목받고 있는데, 구심성 신경은 CGRP(calcitonin gene-related peptide)등의 말초 신경펩티드를 유리해 위장 미세혈류를 개선하고 위 손상에 대한 방어작용을 나타낼뿐만 아니라 교감신경계를 자극해 위장손상을 유발하는 이중적 성격을 발휘할 가능성도 제시되었다 (Ren et al., 2000, Dig. Dis. Sci. 45, pp830-836). 바닐로이드 수용체 길항제는 이와 같이 다양한 기능을 수행하는 바닐로이드 수용체를 차단함으로서 상기의 다양한 질환군에 대해 예방 또는 치료 목적으로 사용될 수 있는 가능성이 매우 높다고 판단된다.
이론상 이 수용체에 대한 길항제는 통증 및 신경성 염증에 대해 상당한 억제능을 발휘할 것으로 예상할 수 있으나, 지금까지 거의 유일하게 알려진 이 수용체에 대한 경쟁적 길항제인 캡사제핀(capsazepine)의 경우 별다른 진통, 소염효과를 발휘하지 못한다고 알려졌기 때문에(Perkins and Campbell, 1992, Br. J. Pharmacol. 107, pp329-333) 이에 대한 연구는 답보상태에 있었다. 그러나 최근 캡사제핀의 진통작용에 대한 동물실험결과에서 유효한 결과가 보고된 바 있고 (Kwak et al., 1998, Neurosci. 86, pp619-626; Santos and calixto, 1997, Neurosci. Lett. 235, pp73-76), 특히 본 발명자들은 실험실에서의 실험을 통해 밝혀진 바닐로이드 수용체의 강력 길항제에 대한 동물실험을 통해 그 진통 및 소염작용을 명확히 밝혀냈으며, 이에 따라 바닐로이드 수용체 길항제의 진통, 소염제로서의 개발가능성을 유력하게 제시하였다. 단, 본 연구에서 도출된 바닐로이드 수용체의 길항제는 주로 그 자체의 길항 활성을 통해 작용할 것이나, 체내 흐수된 후 대사과정을거쳐 효능제로 변환되어 그 약리작용을 나타낼 가능성도 배제하지는 않는다.
상술한 문제점을 해결하기 위하여, 본 발명에서는 바닐로이드 수용체에 대하여 선택적으로 길항할 수 있으며, 자극성을 전혀 보이지 않으면서 진통, 소염 효과를 나타내는 신규 화합물 및 이를 함유하는 조성물을 제공하고자 하는 것이다.
상기 목적을 달성하기 위하여, 본 발명에서는 다음 화학식 (I)의 신규 화합물을 제공한다.
X는 황 또는 산소원자이며;
R1은 할로겐으로 치환 또는 비치환된 탄소수 탄소수 1내지 5의 저급알킬설폰, 아릴설폰 또는 탄소수 1내지 5의 저급알킬카보닐기이며;
R2는 수소원자, 메톡시기 또는 할로겐기이며;
A가 -NHCH2- 인 경우, B는(식중 n 은 0 또는 1)이고,
또는
A가 -CH2- 인 경우, B는 4-t-부틸벤질, 3,4-디메틸페닐에틸,또는 올레일기이며;
Y는 -CH2- 또는 -CH2CH2- 이며;
R3는 수소원자, 탄소수 1 내지 5의 저급알킬기이며;
R4는 탄소수 1 내지 5의 저급알킬기 또는 페닐기임.
본 발명은 또한, 상기 화학식(I)의 화합물 또는 약제학적으로 허용가능한 그의 염을 유효성분으로 포함하는 약제학적 조성물을 제공한다.
본 발명의 화합물들은 하기의 반응식들에 도시된 방법에 의해 화학적으로 합성될 수 있다. 그러나, 이는 단지 예시를 들기 위한 것으로서, 본 발명이 이에 한정되는 것은 아니다.
상기 반응식 1에서와 같이, 4-아미노벤질아민을 선택적으로 Boc(t-butoxycarbonyl)기로 보호한 화합물1-1을 합성하였다. 화합물1-1의 아민을 여러 종류의 설포닐클로라이드(sulfonylchloride) 또는 아실클로라이드(acyl chloride) 시약과 반응시켜 화합물1-2를 합성하고, 화합물1-2로부터 Boc기를 산성조건 하에 제거한 후, 여러 종류의 이소티오시아네이트(isothiocyanate)계 화합물과 반응하여 화합물1-4a~1-4h를 제조하였다.
상기 반응식 2에서와 같이, 3-메톡시-4-니트로벤질클로라이드에 아지드를 도입한 다음, 아지드기를 환원시킨 후, Boc기로 보호하여 화합물2-3을 합성하였다. 화합물2-3의 니트로기를 환원하여 아민2-4를 만든 후, 메탄설포닐아미노기(메실기)를 도입하여 화합물2-5를 합성하였고 Boc기를 제거하여 아민2-7을 합성하였다. 아민화합물2-7을 1,1-티오-1H-2-카르보닐-디-2-피리돈 (1,1-thio-1H-carbonyl-di-2-pyridone)으로 처리하여 주요중간체인 이소티오시아네이트 화합물2-9을 합성하였고, 화합물2-9과 이미 제조된 아지드화합물들을 반응시켜, 화합물2-13 ~ 2-16을 제조하였다. 상기식에서 RB=H인 경우, 출발물질을 4-니트로벤질클로라이드를 사용하여 상기와 같은 공정을 거쳐서 합성된 화합물2-8을 아지드 화합물과 반응시켜 화합물2-10 ~ 2-12, 2-17, 2-18을 제조하였다.
상기 반응식 3에서와 같이, 화합물3-1을 출발물질로 하여 일반적 방법에 의해 아민염3-6을 합성하고, 이어서 이소티오시아네이트2-8을 반응시켜 화합물3-7, 3-8을 제조하였다.
4-메탄설포닐아미노페닐아세트산의 펜타플루오르페닐 에스테르와 알려진 아민류와 축합하여, 화합물4-1 ~ 4-4를 제조하였다.
본 발명의 화학식(I)의 화합물들은 약제학적으로 허용가능한 담체, 보조제또는 희석액과 함께 약제학적으로 조성물을 제공할 수 있다. 예를 들면, 본 발명의 화합물은 주사용액의 제조에 통상적으로 사용되는 오일, 프로필렌글리콜 또는 다른 용매에 용해시킬 수 있다. 적당한 담체로는 특별히 한정되지는 않지만, 예를들면, 생리식염수, 폴리에틸렌글리콜, 에탄올, 식물성오일 및 이소프로필미리스테이트 등이 있다. 국소적용을 위해서는 본 발명의 화합물을 연고나 크림으로 제형화할 수 있다.
본 발명의 화합물을 활성성분으로 하는 약제학적 조성물은 급성,만성,염증성,신경병적 통증의 치료, 방광과민증 및 과민성 대장증후군의 치료, 천식의 치료, 신경퇴화적 질환의 예방 및 치료 또는 신경병성 피부질환, 피부, 눈, 점막의 자극에 대한 예방 및 치료를 위해 사용될 수 있다.
이하, 제형방법 및 부형제를 설명하지만, 이들 예로만 한정되는 것은 아니다.
본 발명의 화합물의 약제학적 투여형태는 이들의 약제학적 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 다른 약제학적 활성화합물과 결합 뿐만 아니라 적당한 집합으로 사용될 수 있다.
본 발명의 화합물은 일반적인 식염수, 5%덱스트로스와 같은 수용성 용매, 또는 식물성오일, 합성지방산 글리세라이드, 고급 지방산 에스테르 또는 프로필렌글리콜과 같은 비수용성 용매에 화합물을 용해시키거나, 현탁시키거나 또는 유화시켜 주사제로 제형화 될 수 있다. 본 발명의 제형은 용해제, 등장화제(isotonic agents), 현탁화제, 유화제, 안정화제 및 방부제와 같은 종래의 첨가제를 포함할수 있다.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당 업자에 의해 적절하게 선택 될 수 있다. 바람직하게는 본 발명의 화합물을 1일 0.001 ~ 100mg/체중 kg으로, 보다 바람직하게는 0.01 ~ 30mg/체중kg으로 투여한다. 투여는 하루에 한번 할수 있고, 여러 번으로 나누어서도 가능하다. 조성물에서 본 발명의 화합물은 전체 조성물 총 중량에 대하여 0.0001 ~ 10중량%, 바람직하게는 0.001 ~ 1중량%의 양으로 존재하여야 한다.
본 발명의 약제학적 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여 될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구,직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관(intracerbroventricular)주사에 의해 투여될 수 있다.
이하, 실시예를 통하여 본 발명을 구체적으로 설명하되, 본 발명이 실시예에 한정되는 것이 아니다.
실시예 1 ~ 실시예 8
실시예 1 내지 실시예 8은 제1, 2, 3단계로 나타내었고 각 화합물의 일반적인 합성법을 아래에 나타내었다.
제 1 단계: 화합물1-2의 일반적 합성방법
화합물1-1(5.3 mmol)를 피리딘 (10 mL)에 녹인후 0oC 로 냉각하고, 여기에아실 클로라이드(6.34 mmol)를 서서히 가해주었다. 반응혼합물을 상온에서 24시간동안 교반하였다. 반응 혼합물을 1몰의 염산용액으로 중화한 후 물로 희석하고 디클로로메탄으로 수회 추출하였다. 추출한 유기층을 모아 물과 포화염화나트륨수용액으로 세척후에 황산마그네슘으로 건조하고 감압농축하여 얻은 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=1:1)로 정제하여 화합물1-2를 얻었다.
실시예-단계 화합물 번호 R1 스펙트럼 데이타
1-1 1-2a SO2CH3 1H NMR(300MHz, CDCl3) : δ 7.1-7.3 (m, 4H), 6.77 (s, 1H), 4.88 (bs, 1H), 4.28 (d, 2H), 2.99 (s, 3H), 1.46 (s, 9H)
2-1 1-2b SO2Et 1H NMR(300MHz, CDCl3) : δ 7.1-7.3 (m, 4H), 6.80 (s, 1H), 4.88 (bs, 1H), 4.25 (d, 2H),3.07 (q, 3H), 1.46 (s, 9H), 1.36 (t, 3H)
3-1 1-2c SO2Pr 1H NMR(300MHz, CDCl3) : δ 7.23 (dd, 4H), 6.85 (s, 1H), 4.89 (bs, 1H), 4.28 (d, 2H), 3.05 (m, 2H), 1.67 (m, 2H), 1.46 (s, 9H), 1.01 (t, 3H)
4-1 1-2d SO2iPr 1H NMR(300MHz, CDCl3) : δ 7.17-7.31 (m, 4H), 6.98 (s, 1H), 4.87 (bs, 1H), 4.28 (d, 2H), 3.28 (m, 1H), 1.3-1.5 (m, 15H)
5-1 1-2e SO2Ph 1H NMR(300MHz, CDCl3) : δ 7.75 (d, 2H), 7.54 (m, 3H), 7.15 (d, 2H), 7.02 (d, 2H), 6.68 (s, 1H), 4.80 (t, 1H), 4.23 (d, 2H), 1.44 (s, 9H)
6-1 1-2f SO2CF3 1H NMR(300MHz, CDCl3) : δ 7.2-7.4 (m, 4H), 6.68 (s, 1H), 4.21 (d, 2H), 1.37 (s, 9H)
7-1 1-2g COCH3 1H NMR(300MHz, CDCl3) : δ 7.46 (d, 2H), 7.24 (d, 2H), 4.80 (bs, 1H), 4.27 (d, 2H), 2.17 (s, 3H), 1.45 (s, 9H)
8-1 1-2h COiPr 1H NMR(300MHz, CDCl3) : δ 7.50 (d, 2H), 7.24 (d, 2H), 7.11 (bs, 1H), 4.78 (bs, 1H), 4.25 (d, 2H), 2.50 (m, 1H), 1.45 (s, 9H), 1.24 (d, 6H)
제 2 단계: 화합물1-3의 일반적인 합성법
화합물1-2(4.8 mmol)을 디클로로메탄(20mL)에 녹인후 0oC로 냉각하고, 여기에 트리플루오로아세트산 (5mL)을 서서히 가해주었다. 0oC에서 1시간 30분 동안 교반후에 용매를 감압농축하여 주황색잔사물을 얻었다. 잔사물을 에틸에테르로 세척하고 여과하여 화합물1-3을 얻었다.
실시예-단계 화합물번호 R1 스펙트럼 데이타
1-2 1-3a SO2CH3 1H NMR(300MHz, DMSO) : δ 8.14 (bs, 3H), 7.39 (d, 2H), 7.22 (d, 2H), 3.97 (s, 2H), 2.99 (s, 3H)
2-2 1-3b SO2Et 1H NMR(300MHz, DMSO) : δ 8.09 (bs, 3H), 7.51 (d, 2H), 7.33 (d, 2H), 4.01 (s, 2H), 2.79 (q, 2H), 1.46 (t, 3H)
3-2 1-3c SO2Pr 1H NMR(300MHz, DMSO) : δ 7.69 (d, 2H), 7.35 (d, 2H), 4.03 (s, 2H) 2.76 (t, 2H), 1.92 (m, 2H), 1.05 (t, 3H)
4-2 1-3d SO2iPr 1H NMR(300MHz, DMSO) : δ 7.82 (d, 2H), 7.37 (d, 2H), 3.99 (s, 2H) 3.53 (m, 1H), 1.53 (d, 6H)
5-2 1-3e SO2Ph 1H NMR(300MHz, DMSO) : δ 8.17 (d, 2H), 7.89 (d, 2H), 7.4-7.6 (m, 3H), 4.03 (s, 2H)
6-2 1-3f SO2CF3 1H NMR(300MHz, DMSO) : δ 7.9 (bs, 3H), 7.1-7.3 (m, 4H), 4.00 (bs, 2H)
7-2 1-3g COCH3 1H NMR(300MHz, CDCl3) : δ 7.49 (m, 4H), 4.17 (s, 2H), 2.18 (s, 3H)
8-2 1-3h COiPr 1H NMR(300MHz, CDCl3) : δ 7.50 (m, 4H), 4.17 (s, 2H), 2.70 (m, 1H), 1.22 (d, 6H)
제 3 단계: 화합물1-4의 일반적인 합성법
화합물1-3(0.38 mmol)을 DMF (1 mL) 에 녹인후 트리에틸아민 (0.38 mmol)을 가하고 상온에서 질소 치환하에 1시간동안 교반하였다. 여기에 2,2-디메틸-프로피온산 3-(3,4-디메틸페닐)-2-이소티오시아네이토메틸프로필에스테르 (0.38 mmol) 을 가해준 후 24시간동안 교반하였다. 반응혼합물을 물로 희석하고 에틸아세테이트로 수회 추출하여 얻은 유기층을 물과 포화염화나트륨수용액으로 세척한 후 황산마그네슘으로 건조하여 감압농축하였다. 얻은 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=3:2) 로 정제하여 화합물1-4을 얻었다.
실시예-단계 화합물번호 R1 스펙트럼 데이타
1-3 1-4a SO2CH3 1H NMR(300MHz, CDCl3) : δ 7.28 (d, 2H), 7.17 (d, 2H), 6.8-7.1 (m, 3H), 6.68 (s, 1H), 6.34 (m, 1H), 6.09 (brs, 1H), 4.51 (bs, 2H), 4.17 (m, 1H), 3.79 (m, 2H), 3.22 (m, 1H), 2.99 (s, 3H), 2.5-2.7 (m, 2H), 2.2-2.3 (m, 7H), 1.23 (s, 9H) ; mp=60℃
2-3 1-4b SO2Et 1H NMR(300MHz, CDCl3) : δ 7.25 (d, 2H), 7.16 (d, 2H), 6.8-7.1 (m, 3H), 6.40 (m, 1H), 6.21 (bs, 1H), 4.50 (brs, 2H), 4.15 (m, 1H), 3.78 (m, 2H), 3.24 (m, 1H), 3.08 (q, 3H), 2.5-2.7 (m, 2H), 2.2-2.3 (m, 7H), 1.24 (s, 9H); mp=48℃
3-3 1-4c SO2Pr 1H NMR(300MHz, CDCl3) : δ 7.25 (d, 2H), 7.14 (d, 2H), 6.8-7.1 (m, 3H), 6.45 (bs, 1H), 6.30 (brs, 1H), 4.51 (brs, 2H), 4.15 (m, 1H), 3.81 (m, 2H), 3.24 (m, 1H), 3.03 (t, 2H), 2.5-2.7 (m, 2H), 2.23 (m, 7H), 1.83 (q, 2H), 1.24 (s, 9H), 1.00 (t, 3H); mp=54℃
4-3 1-4d SO2iPr 1H NMR(300MHz, CDCl3) : δ 7.1-7.3 (m, 4H), 6.8-7.0 (m, 3H), 6.48 (m, 2H), 4.50 (brs, 2H), 4.13 (m, 1H), 3.80 (m, 2H), 3.25 (m, 2H), 2.5-2.7 (m, 2H), 2.25 (m, 7H), 1.34 (d, 6H), 1.23 (s, 9H); mp=48℃
5-3 1-4e SO2Ph 1H NMR(300MHz, CDCl3) : δ 7.76 (d, 2H), 7.52 (m, 2H), 6.8-7.1 (m, 3H), 6.41 (bs, 2H), 6.19 (brs, 2H), 4.43 (brs, 2H), 4.12 (m, 1H), 3.78 (m, 2H), 3.21 (m, 1H), 2.5-2.7 (m, 2H), 2.23 (m, 7H), 1.23 (s, 9H);mp=66℃
6-3 1-4f SO2CF3 1H NMR(300MHz, CDCl3) : δ 7.28 (d, 2H), 7.17 (d, 2H), 6.8-7.1 (m, 3H), 6.48 (brs, 1H), 6.36 (brs, 1H), 4.50 (brs, 2H), 4.15 (m, 1H), 3.75 (m, 2H), 3.28 (m, 1H), 2.58 (m, 2H), 2.11-2.24 (m, 7H), 1.23 (s, 9H); mp=44℃
7-3 1-4g COCH3 1H NMR(300MHz, CDCl3) : δ7.46 (d, 2H), 7.24 (d, 2H), 6.9 (m, 3H), 6.28 (brs, 1H), 6.07 (brs, 1H), 4.43 (bs, 2H), 4.13 (m, 1H), 3.75 (m, 2H), 3.27 (m, 1H), 2.54 (m, 2H), 2.21 (m, 10H), 1.22 (s, 9H)
8-3 1-4h COiPr 1H NMR(300MHz, CDCl3) : δ 7.51 (d, 2H), 7.22 (m, 2H), 6.93 (m, 3H), 6.28 (brs, 1H), 6.07 (brs, 1H), 4.41 (brs, 2H), 4.13 (m, 1H), 3.74 (m, 2H), 3.27 (m, 1H), 2.52 (m, 3H), 2.21 (m, 7H), 1.24 (m, 15H)
실시예 9 ~ 실시예 17
제 1 단계: 4-클로로메틸-2-메톡시-1-니트로벤젠(2-1)의 합성
(3-메톡시-4-니트로페닐)메탄올 (4.43 mmol)을 디클로로메탄(10mL)에 녹인후 트리에틸아민(13.3mmol)을 가해주었다. 반응혼합물을 0℃로 냉각한 후 메탄술포닐클로라이드(6.64 mmol)를 서서히 가해준 후, 질소 치환하에 혼합물을 24시간동안 상온에서 교반하였다. 암모늄클로라이드용액을 가하여 반응을 종결시키고 물로 희석후에 디클로로메탄으로 수회 추출하였다. 추출한 유기층을 물과 브라인으로 세척후에 황산마그네슘으로 건조하고 감압농축하였다. 얻어진 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=4:1)로 정제하여 노란고체화합물2-1(93 %)를 얻었다.
1H NMR (CDCl3) δ 7.86 (d, 1H), 7.05 (s, 1H), 6.98 (d, 1H), 4.56 (s, 2H), 3.99 (s, 3H)
제 2 단계: 4-아지도메틸-2-메톡시-1-니트로-벤젠(2-2)의 합성
화합물2-1(4.12mmol)과 소듐아지드 (16.5 mmol)를 디메틸포름아미드 (3 mL) 에 녹인후 반응혼합물을 상온에서 질소 치환하에 한시간동안 교반하였다. 반응혼합물을 물로 희석후에 에틸아세테이트로 수회 추출한 다음, 유기층을 모아 물과 포화염화나트륨수용액으로 세척하고 황산마그네슘으로 건조한 후, 감압농축하였다. 얻어진 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=3:1)로 정제하여 노란색고액체화합물2-2(95 %)을 얻었다.
1H NMR (CDCl3) δ 7.87 (d, 1H), 7.05 (s, 1H), 6.99 (d, 1H), 4.45 (s, 2H), 3.99 (s, 3H)
제 3 단계: (3-메톡시-4-니트로-벤질)-카르밤산 t-부틸에스테르(2-3)의 합성
화합물2-2(3.91 mmol)과 트리페닐포스핀 (7.83 mmol), 물(7.83 mmol)을 THF (30mL)에 녹인후 상온에서 24시간동안 교반하였다. 반응혼합물을 감압농축하여 얻은 잔사물을 에탄올 (20mL)에 녹인후, Boc2O (1.71g)를 가하고 상온에서 2시간동안 교반하였다. 반응혼합물을 감압농축한 후, 얻어진 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=2:1)로 정제하여 노란색액체 화합물2-3(86%)을 얻었다.
1H NMR (CDCl3)) δ 7.83 (d, 1H), 7.02 (s, 1H), 6.93 (d, 1H), 5.01 (brs, 1H), 4.35 (d, 2H), 3.95 (s, 3H), 1.47 (s, 9H)
제 4 단계: (4-아미노-3-메톡시벤질)카르밤산 t-부틸 에스테르(2-4)의 합성
화합물2-3(3.13mmol)을 메탄올(20 mL)에 녹인 후 10% 팔라듐/탄소촉매(85mg)을 가하고 수소풍선 치환하에 상온에서 1시간동안 교반하였다. 반응혼합물을 여과, 감압농축하여 갈색액체화합물2-4(90%)을 얻었다.
1H NMR (CDCl3) δ 6.6-6.7 (m, 3H), 4.19 (d, 2H), 3.88 (s, 3H), 1.46 (s, 9H)
제 5 단계: (4-메탄설포닐아미노-3-메톡시벤질)카르밤산 t-부틸 에스테르(2-5)의 합성
화합물2-4(3.13 mmol)을 출발물질로 하여, 화합물1-2a의 합성방법과 동일한 방법으로 합성, 정제하여 분홍색 고체 화합물2-5(67%)을 얻었다.
1H NMR (CDCl3) δ 7.47 (d, 1H), 6.86 (m, 2H), 6.74 (s, 1H), 4.88 (bs, 1H), 3.88 (s, 3H), 2.94 (s, 3H), 1.47 (s, 9H)
제 6 단계: 4-메탄설포닐아미노-3-메톡시벤질암모늄트리플루오로아세테이트 (2-7)
화합물2-5(2.1mmol)을 출발물질로 하여, 화합물1-3a과 동일한 방법으로 합성, 정제하여 녹색고체화합물2-7(87%)을 얻었다.
1H NMR (DMSO) δ 8.16 (bs, 3H), 7.29 (d, 1H), 7.20 (s, 1H), 6.99 (d, 1H), 4.00 (s, 2H), 3.82 (s, 3H), 2.95 (s, 3H)
제 7 단계: 화합물2-8, 2-9의 일반적인 합성법
화합물2-6또는2-7(12 mmol)을 DMF(1mL)에 녹인후 트리에틸아민 (12 mmol) 을 가하고 상온에서 질소 치환하에 1시간동안 교반하였다. 여기에 1,1-티오-1H-2-카보닐-디-2-피리돈 (12 mmol)을 가해준 후 24시간동안 교반하였다. 반응혼합물을 물로 희석하고 에틸아세테이트로 수회추출하여 얻은 유기층을 물과 포화염화나트륨수용액으로 세척한 후, 황산마그네슘로 건조하고 감압농축하였다. 이렇게 얻은 잔사물을 컬럼크로마토그래피(헥산:에틸아세테이트=3:2)로 정제하여2-8과2-9을 얻었다.
화합물번호 RB 스펙트럼 데이타
2-8 H 1H NMR(300MHz, CDCl3) : δ 7.32 (d, 2H) 7.25 (d, 2H), 6.62 (s, 1H), 4.70 (s, 2H) 3.04 (s, 3H)
2-9 OCH3 1H NMR(300MHz, CDCl3) : δ 7.29 (s, 1H) 6.96 (m, 2H), 5.09 (s, 2H), 3.82 (s, 3H), 3.04 (s, 3H)
제 8 단계: 화합물2-10 ~ 2-18의 일반적인 합성법
이미 그 합성법이 알려져 있는 아지드화합물 (0.5 mmol), 린들러촉매(Lindlers catalyst, 50 mmol) 및 화합물2-8를 에탄올 (5 mL) 에 녹인후, 수소풍선 장치하에 2시간동안 수소반응시켰다. 반응혼합물을 여과하여 여액을 감압농축하고 컬럼크로마토그래피 (에틸아세테이트:헥산 =1:1)로 정제하여 화합물2-10 ~ 2-18을 얻었다.
실시예 화합물번호 R 스펙트럼 데이타
9 2-10 RB= HR3=3,4-di-MeR4= Phn=1 1H NMR(300MHz, CDCl3) : δ 8.01 (m, 2H), 7.4-7.6 (m, 3H), 7.1-7.3 (m, 4H), 6.9-7.0 (m, 3H), 6.53 (m, 1H), 6.40 (brs, 1H), 4.52 (brs, 2H), 4.35 (m, 1H), 4.17 (m, 1H), 3.82 (m, 1H), 3.41 (m, 1H), 2.93 (s, 3H), 2.5-2.7 (m, 2H), 2.1-2.3 (m, 7H); mp=46℃
10 2-11 RB= HR3= 4-t-BuR4= t-Bun=1 1H NMR(300MHz, CDCl3) : δ 7.31 (d, 4H), 7.18 (d, 2H), 7.10 (d, 2H), 6.51 (s, 1H), 6.33 (t, 1H), 6.03 (brs, 1H), 4.53 (brs, 2H), 4.15 (m, 1H), 3.82 (m, 2H), 3.23 (m, 1H), 2.99 (s, 3H), 2.60 (t, 2H), 2.32 (m, 1H), 1.25 (d, 18H);mp=61℃
11 2-12 RB= HR3= 4-t-BuR4= Phn=1 1H NMR(300MHz, CDCl3) : δ 8.01 (d, 2H), 7.4-7.6 (m, 3H), 7.1-7.3 (m, 4H), 6.54 (s, 1H), 6.39 (t, 1H), 6.10 (brs, 1H), 4.53 (brs, 2H), 4.39 (m, 1H), 4.07 (m, 1H), 3.82 (m, 1H), 3.38 (m, 1H), 2.97 (s, 3H), 2.68 (t, 2H), 2.48 (m, 1H, CH), 1.29 (s, 9H);mp=68℃
12 2-13 RB= OMeR3=3,4-di-MeR4= t-Bun=1 1H NMR(300MHz, CDCl3) : δ 7.48 (d, 2H), 6.9-7.1 (m, 5H), 6.77 (s, 1H), 6.31 (m, 1H), 5.99 (brs, 1H), 4.49 (bs, 2H), 4.20 (m, 1H), 3.88 (s, 3H), 3.85 (m, 2H), 3.22 (m, 1H), 2.93 (s, 3H), 2.56 (m, 2H), 2.2-2.3 (m, 7H), 1.23 (s, 9H) ;mp=49℃
13 2-14 RB= OMeR3=3,4-di-MeR4= Phn=1 1H NMR(300MHz, CDCl3) : δ 8.02 (t, 2H), 7.4-7.6 (m, 3H), 6.9-7.1 (m, 3H), 6.77 (s, 1H), 6.38 (m, 1H), 6.09 (bs, 1H), 4.45 (m, 3H), 4.05 (m, 1H) 3.85 (s, 3H), 3.37 (m, 1H), 2.92 (s, 3H), 2.67 (m, 2H), 2.43 (m, 1H), 2.25 (m, 6H); mp=62℃
14 2-15 RB= OMeR3= 4-t-BuR4= t-Bun=1 1H NMR(300MHz, CDCl3) : δ 7.45 (d, 2H), 7.30 (d, 2H), 7.08 (d, 2H), 6.8-7.0 (m, 3H), 6.39 (t, 1H), 6.24 (bs, 1H), 4.52 (bs, 2H), 4.15 (m, 1H), 3.82 (m, 5H), 3.25 (m, 1H2.93 (s, 3H), 2.60 (m, 2H), 2.31 (m, 1H), 1.25 (d, 18H );mp=62℃
15 2-16 RB= OMeR3= 4-t-BuR4= Phn=1 1H NMR(300MHz, CDCl3) : δ 8.03 (d, 2H), 7.4-7.6 (m, 3H), 7.1-7.3 (m, 4H), 6.77 (s, 1H), 6.38 (t, 1H), 6.10 (bs, 1H), 4.51 (bs, 2H), 4.43 (m, 1H), 4.08 (m, 1H), 3.82 (m, 4H), 3.38 (m, 1H), 2.92 (s, 3H), 2.69 (t, 2H), 2.36 (m, 1H), 1.29 (s, 9H); mp=57℃
16 2-17 RB= HR3=3,4-di-MeR4= t-Bun=2 1H NMR(300MHz, CDCl3) : δ 7.1-7.3 (m, 7H), 6.39 (t, 1H), 6.06 (bs, 1H), 4.59 (d, 2H), 4.16 (m, 1H), 3.97 (m, 1H) 3.77 (m, 2H), 3.22 (m, 1H), 2.99 (s, 3H), 2.68 (t, 2H), 2.05 (m, 1H), 1.58 (m, 2H), 1.25 (d, 9H)
17 2-18 RB= HR3= 4-t-BuR4= t-Bun=2 1H NMR(300MHz, CDCl3) : δ 7.33 (d, 2H), 7.17 (d, 2H), 6.9-7.1 (m, 3H), 6.42 (s, 1H), 6.36 (t, 1H), 6.06 (bs, 1H), 4.59 (d, 2H), 4.21 (m, 1H), 3.97 (m, 1H) 3.72 (m, 1H), 3.22 (m, 2H), 2.99 (s, 3H), 2.65 (t, 2H), 2.23 (m, 7H), 1.60 (m, 2H), 1.23 (s, 9H)
실시예 18- 실시예 19
제 1 단계: 화합물3-1의 일반적인 합성법
N-(디페닐메틸렌글리신)에틸 에스테르(1.83 mmol)을 디클로로메탄(5mL)에 녹인후, 50% 수산화나트륨 용액(3.66 mmol), 테트라부틸암모늄브로마이드(1.83 mmol)및 알킬할라이드(2.50 mmol)을 가해주었다. 반응혼합물을 상온에서 24시간동안 교반후에 6N 염산용액으로 중화하고 물로 희석한 다음, 디클로로메탄으로 수회 추출하였다. 유기층을 황산마그네슘로 건조, 여과후에 여액을 감압농축하고 컬럼크로마토그래피 ( 헥산:에틸아세테이트= 10:1)로 분리 정제하여3-1를 얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-1 3-1a 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 7.59 (t, 2H), 7.2-7.4 (m, 10H), 6.95 (m, 1H), 4.16-4.28 (m, 3H), 3.35 (dd, 1H), 3.17 (m, 1H), 2.12 (m, 6H), 1.23 (q, 3H)
19-1 3-1b 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.59 (d, 2H), 7.2-7.4 (m, 10H), 6.95 (d, 2H), 4.11-4.24 (m, 3H), 3.1-3.3 (m, 2H), 1.25 (m, 12H)
제 2 단계: 화합물3-2의 일반적인 합성법
화합물3-1(1.18 mmol)을 THF(10mL)에 녹인후 1N염산용액으로 pH 4를 유지하도록 조절하여 상온에서 30분간 교반하였다. 여기에 에틸아세테이트 (10 mL)와 물 (10mL)을 가해준 후, 수층을 1N 수산화나트륨 용액으로 pH 9가 되도록 중화하고 에틸아세테이트로 수회 추출하였다. 유기층을 무수황산마그네슘로 건조, 여과후에 여액을 감압농축하고 컬럼크로마토그래피(헥산:에틸아세테이트=2:1)로 분리 정제하여화합물3-2을 얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-2 3-2a 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 6.9-7.1 (m, 3H), 4.19 (q, 2H), 3.73 (m, 1H), 3.55 (dd, 1H), 3.17 (dd, 1H), 2.22 (m, 6H), 1.24 (m, 3H)
19-2 3-2b 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.33 (d, 2H), 7.24 (d, 2H), 4.18 (q, 2H), 3.70 (m, 1H), 3.05 (dd, 1H), 2.83 (dd, 1H), 1.25 (m, 12H)
제 3 단계: 화합물3-3의 일반적인 합성법
화합물3-2(0.68 mmoL)을 디클로로메탄(3 mL)에 녹인후, 0℃로 냉각하고 (Boc)2O(0.75 mmol)을 가해주었다. 반응혼합물을 상온에서 24시간동안 교반후에 감압농축하여 얻은 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=4:1)로 분리 정제하여 화합물3-3을 얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-3 3-3a 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 6.9-7.2 (m, 3H), 4.97 (m, 1H), 4.50 (m, 1H), 4.15 (q, 2H), 3.05 (m, 2H), 2.22 (m, 6H), 1.42 (s, 9H), 1.20 (t, 3H)
19-3 3-3b 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.31 (d, 2H), 7.06 (d, 2H), 4.56 (m, 1H), 4.18 (q, 2H), 3.05 (d, 2H), 1.41 (s, 9H), 1.29 (s, 9H), 1.19 (t, 3H)
제 4 단계: 화합물3-4의 일반적인 합성법
리튬알루미늄하이드라이드 (1.79 mmol)를 디에틸에테르(5 mL)에 현탁시켜 0oC로 냉각하고, 여기에 화합물3-3(0.48 mmol)을 디에틸에테르 (diethyl ether, 5 mL)에 녹인 용액을 적가하였다. 상온에서 5시간동안 교반 후에 반응혼합물을 0oC 로 냉각하고, 물(700㎕), NaOH(1.4 mL), 물(2.1mL)을 차례로 가하여 교반하였다. 이 혼합물을 에틸아세테이트로 세척, 여과하고 여액을 감압 농축하였다. 잔사물을 컬럼크로마토그래피 (에틸아세테이트:헥산=4:1)로 정제하여 화합물3-4을 얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-4 3-4a 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 6.9-7.2 (m, 3H), 4.71 (bs, 1H), 3.83 (m, 1H), 3.5-3.7 (m, 2H), 2.85 (dd, 2H), 2.24 (m, 6H), 1.41 (s, 9H)
19-4 3-4b 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.32 (d, 2H), 7.13 (d, 2H), 4.71 (bs, 1H), 3.87 (m, 1H), 3.5-3.7 (m, 2H), 2.79 (d, 2H), 1.41 (s, 9H), 1.30 (s, 9H)
제 5 단계: 화합물3-5의 일반적인 합성법
화합물3-4(0.71 mmol), 트리에틸아민 (2.8 mmol) 및 촉매량의 4-디메틸아미노피리딘(DMAP)을 디클로로메탄(7mL)에 녹이고, 0oC로 냉각한 후 트리메틸아세틸클로라이드(2.8mmol)를 가해주었다. 1시간동안 상온에서 교반한 후에, 반응 혼합물을 디클로로메탄으로 희석하고 1N HCl, 물, 포화염화나트륨수용액으로 각각 1회씩 세척 후에 무수황산마그네슘으로 건조하였다. 감압농축하여 얻은 잔사물을 컬럼크로마토그래피(에틸아세테이트:헥산=1:4)로 정제하여 화합물3-5을 얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-5 3-5a 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 6.9-7.2 (m, 3H), 4.61 (bs, 1H), 4.01 (m, 3H), 2.86 (m, 2H), 2.24 (m, 6H), 1.41 (m, 9H), 1.23 (m, 9H)
19-5 3-5b 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.30 (d, 2H), 7.10 (d, 2H), 4.57 (bs, 1H), 4.13 (m, 3H), 2.78 (m, 2H), 1.41 (m, 9H), 1.2-1.3 (m, 18H)
제 6 단계: 화합물3-6의 일반적인 합성법
화합물3-5(0.71 mmol)을 디클로로메탄(6mL)에 녹인 후, 0℃로 냉각하고 트리플루오르아세트산(1.5mL)을 서서히 가해주었다. 반응혼합물을 상온에서 3시간동안 교반후에 감압 농축하여 정제되지 않은 아민염3-6을 얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-6 3-6a 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 7.37 (d, 1H), 7.13 (m, 2H), 4.1-4.3 (m, 2H), 3.71 (m, 1H), 3.04 (m, 2H), 2.22 (m, 6H), 1.22 (m, 9H)
19-6 3-6b 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.35 (m, 2H), 7.13 (m, 2H), 4.1-4.2 (m, 3H), 2.80 (d, 2H), 1.30 (s, 9H), 1.09 (s, 9H)
제 7 단계: 화합물3-7, 3-8의 합성법
화합물3-6(0.46 mmol)을 디메틸포름아마이드(1mL)에 녹인후, 트리에틸아민 (0.46 mmol)을 가하고 상온에서 질소치환하에 30분동안 교반하였다. 여기에 화합물2-8(0.46 mmol)를 가해준 후 상온에서 24시간동안 교반하였다. 반응혼합물을 물로 희석한 후에 에틸아세테이트로 수회 추출하고, 얻어진 유기층을 물과 브라인으로 세척후에 황산마그네슘으로 건조한 다음, 감압농축하였다. 이렇게 얻은 잔사물을 컬럼크로마토그래피(헥산:에틸아세테이트=1:1)로 정제하여 화합물3-7또는3-8을얻었다.
실시예-단계 화합물번호 R3 스펙트럼 데이타
18-7 3-7 3,4-di-Me 1H NMR(300MHz, CDCl3) : δ 7.19 (m, 4H), 7.04 (m, 3H), 6.28 (brs, 1H), 6.07 (brs, 1H), 4.56 (m, 2H), 4.17 (m, 1H), 3.99 (m, 1H), 3.01 (m, 5H), 2.76 (m, 1H), 2.26 (m, 6H), 1.19 (s, 9H)
19-7 3-8 4-t-Bu 1H NMR(300MHz, CDCl3) : δ 7.27 (m, 8H), 6.68 (brs, 1H)6.51 (brs, 1H), 6.11 (m, 1H), 4.58 (m, 2H), 4.20 (m, 1H), 3.99 (m, 1H), 3.12 (m, 5H), 2.76 (m, 1H), 1.30 (m, 18H)
실시예 20 ~ 실시예 23
화합물4-1 ~ 4-4의 일반적인 합성법
아민화합물(0.5 mmol)과 (4-메탄술포닐아미노페닐)아세트산 펜타플루오로페닐에스테르(0.5 mmol)를 디클로로메탄에 녹여 상온에서 24시간동안 교반하였다. 반응혼합물을 감압 농축하여 얻은 잔사물을 컬럼크로마토그래피 (헥산:에틸아세테이트=1:2)로 분리, 정제하여 화합물4-1 ~ 4-4를 얻었다.
이하에서, 본 발영의 화합물들이 바닐로이드 수용체의 길항제임을 칼슘도입(Calcium influx)검색으로 확인하고, 또한 이들이 진통효과 검색에 있어서도 효능제에서 나타나는 자극성을 전혀 보이지 않으면서 강한 진통효과가 있음을 확인하기로 한다.
실험예. 생물학적 효능 검색
(1)45Ca 도입실험
1) 신생쥐의 척수후근신경절 분리 및 일차배양
생후 2일 이내의 SD 신생쥐를 5분 동안 얼음 속에 두어 저온마취 후 70% 에탄올로 소독하고 해부경하에서 척수 전부위에서 DRG를 분리해내어 (Wood et al., 1988, J. Neurosci. 8, pp3208-3220), 1.2 g/l 중탄산나트륨, 50 mg/l 젠타마이신이 첨가된 DME/F12 배지중에 모았다. 200 U/ml 콜라게네아제, 2.5 mg/mL 트립신을 37℃에서 각 30분씩 DRG에 처리하였다. 10% 말혈청을 함유한 DME/F12 배지로 신경절을 두번 세척하고 열처리한 파스테르 피펫에 여러번 통과시킨 후 니텍스 40 멤브레인(Nitex 40 membrane)으로 여과해 단일세포 현탁액을 얻었다. 이를 원심분리후 세포배양용 배지에 세포농도가 일정수준이 되도록 조절해 재현탁시켰다. 세포배양용 배지로는, 말 혈청이 10% 함유된 DME/F12 배지와 C6-글리오마(C6-glioma)를 이 배지하에서 이틀동안 키운 배지 (C6-glioma-conditioned medium for 2 days on a confluent monolayer)를 1:1로 섞어 사용하였는데, NGF는 최종농도가 200 ng/ml가 되도록 첨가했다. 분열가능한 비신경세포를 죽이기 위해 사이토신 아라비노사이드(cytosine arabinoside) (Ara-C, 100 M)가 포함된 배지에서 이틀간 키운 후 Ara-C가 없는 배지로 교환하였다. 재현탁한 세포는 폴리-D-오르니틴(poly-D-ornithine)을 10 g/ml 농도로 코팅한 테라사키 플레이트(Terasaki plate)에 1500-1700 neurons/well의 밀도가 되게 깔았다.
2)45Ca 도입 실험
2 내지 3일간 일차배양한 DRG 신경세포를 HEPES (10 mM, pH 7.4)-buffered Ca2+, Mg2+-free HBSS (H-HBSS)로 4회 세척해 평형이 이뤄지도록 하였다. 각 웰의 액을 제거하고, H-HBSS를 용매로 하여 시험물질과 캡사이신(최종농도 0.5 μM),45Ca (최종농도 10 Ci/ml)를 섞어 조제한 시액을 가하고 실온에 10분간 두었다. 테라사키 플레이트를 H-HBSS로 6회 세척 후 오븐에서 건조시켰다. 각 웰에 10 ㎕의 0.3%SDS를 가해45Ca을 용출시키고 2 ml의 신틸레이션 칵테일(scintillation cocktail)을 가해 방사능을 측정함으로써 각 웰의 신경세포에 도입된45Ca을 정량하였다. 시험물질의 바닐로이드 수용체에 대한 길항효능은 0.5 μM의 캡사이신의 효능을 최대 반응으로 해서 이를 저해하는 시험물질의 효력을 백분율로 계산하였고 결과는 IC50로 표시하였다 (표 1).
(2) 채널 활성 검색
바닐로이드 수용체와 연결된 양이온 채널의 전기적 변화를 통한 시험 화합물의 길항제로서의 활성을 검색하였으며 실험방법은 문헌에 보고된 방법에 의하여(Oh et al., 1996, J. Neuroscience 16, pp1659-1667) 수행하였다 (표 1).
칼슘도입 및 패치클램프 실험 결과
실시예 칼슘도입실험(IC50) 패치클램프법(길항활성효력)
1 0.45 ++
2 2.5
3 4.3
4 32
5 >50
6 11
7 NR
8 NR
9 13
10 2.5
11 >50
12 0.68
13 38
14 2.8
15 >50
16 1.1
17 1.8
NR: no response(무 응답)
+: 캡사제핀 수준의 길항효력
++: 캡사제핀 10배 수준의 길항효력
(3) 진통실험: 페닐피퀴논 유도성 마우스 라이딩(writhing) 테스트
평균 체중 25 g의 웅성 ICR 생쥐를 12 시간 명암 주기로 조절된 환경에서 사육해 실험에 이용하였다. 화학적 자극제인 페닐피퀴논(phenyl-p-quinone, 4.5 mg/kg의 투여용량이 되게 5% 에탄올을 함유하는 생리식염수에 조제) 0.3 mL을 복강 주사로 투여하고 6분 후부터 6분간 복부 수축의 횟수를 측정하였다. 한 군에 10마리의 동물을 사용했으며, 약물은 에탄올/Tween-80/생리식염수(10/10/80)의 용매에 녹여 페닐피퀴논 투여 30분 전 0.2 mL 용량으로 복강 투여하였다. 생리식염수만 투여한 대조군에서의 동물의 뒤틀림 반응과 비교해 약물 투여군에서의 뒤틀림 횟수의 감소를 진통 효과의 지표로 활용했다. 진통효력은 % 저해도 식(% 저해도 = (C - T)/C × 100)을 활용해 계산했는데 C와 T는 각각 대조군과 약물처리군에서의 뒤틀림 횟수를 나타낸다 (표 2).
실험결과에 따르면 본 실험에 사용한 화합물의 진통활성이 강력함을 알 수 있는데, 특히 바닐로이드 수용체 길항제가 이와 같이 강력한 진통효력을 나타낼 수 있다는 것을 밝힌 것은 큰 의의가 있고, 바닐로이드 길항제의 진통제로서의 개발 가능성을 제시해주는 실험결과로 볼 수 있다.
페닐피퀴논 라이딩(writhing) 진통실험 결과
실시예 용량(mg/kg) 진통효력(% 저해도)
1 1 50
12 1 65
(4) 소염실험: 티피에이(TPA) 유도 마우스 귀 부종 테스트
실험군당 10 마리의 웅성 ICR 생쥐의(체중 25∼30 g) 오른쪽 귀에 아세톤에 녹인 2.5 ㎍의 TPA 30 ㎕를 처리하고 15분후 아세톤 자체 또는 아세톤에 녹인 약물을 30 ㎕ 국소 적용하였다. 6시간후 동일한 방법과 용량의 약물을 처리하고 TPA 처리후 24시간째에 동물을 희생시키고 6 mm 직경의 펀치를 이용해 귀 조직을 잘라내었다. 0.1 mg 단위까지 측정 가능한 전자 저울로 귀 조직의 무게를 측정해 음성 대조군과 비교한 중량의 증가를 염증의 지표로 보았다. % 저해도 식(% 저해도 = (C - T)/C × 100)을 활용해 계산했는데 C와 T는 각각 TPA 처리군, TPA + 약물 처리군에서의 귀 무게의 증가를 나타낸다 (표 3).
본 실험에 의하면 바닐로이드 수용체 길항제는 유의한 소염효력을 발휘함을 알 수 있다. 이는 바닐로이드 수용체의 신경성 염증에서의 작용과 관련해 이해될 수 있는데, 각종 염증성 질환 특히 신경성 염증질환에 대한 바닐로이드 수용체 길항제의 응용 가능성을 제시해준다고 볼 수 있다.
티피에이(TPA) 유도 마우스 귀 부종실험결과
실시예 용량(mg/ear) 소염효력(% 저해도)
1 1 34
12 1 41
본 발명의 화합물은 통증, 급성 통증, 만성 통증, 신경병적 통증, 수술후 통증, 편두통, 관절통, 신경병증, 신경손상, 당뇨병성 신경병, 신경변성 질환, 신경성 피부질환, 뇌졸중, 방광과민증, 과민성 장증후군, 천식과 만성폐색성 폐질환등 호흡기 이상, 피부, 눈, 점막의 자극, 위-십이지장 궤양, 염증성 장 질환 및 염증성 질환 등의 예방, 치료에 유용하다.

Claims (3)

  1. 다음 화학식(I)로 표시되는 화합물 또는 이의 약제학적으로 허용가능한 염.
    X는 황 또는 산소원자이며;
    R1은 할로겐으로 치환 또는 비치환된 탄소수 1 내지 5의 저급알킬설폰, 아릴설폰 또는 탄소수 1내지 5의 저급알킬카보닐기이며;
    R2는 수소원자, 메톡시기 또는 할로겐기이며;
    A가 -NHCH2- 인 경우, B는(식중 n 은 0 또는 1)이고,
    또는
    A가 -CH2- 인 경우, B는 4-t-부틸벤질, 3,4-디메틸페닐에틸,또는 올레일기이며;
    Y는 -CH2- 또는 -CH2CH2- 이며;
    R3는 수소원자, 탄소수 1 내지 5의 저급알킬기이며;
    R4는 탄소수 1 내지 5의 저급알킬기 또는 페닐기임.
  2. 약제학적으로 허용가능한 담체와 함께 활성 성분으로서 상기 청구항 1항 기재의 화합물(I) 또는 그의 약제학적으로 허용가능한 염을 함유함을 특징으로 하는 약제학적 조성물.
  3. 제2항에 있어서, 약제학적으로 허용가능한 담체와 함께 활성 성분으로서 제 1항의 화합물 또는 그의 약제학적으로 허용가능한 염을 통증, 급성 통증, 만성 통증, 신경병적 통증, 수술후 통증, 편두통, 관절통, 신경병증, 신경손상, 당뇨병성 신경병, 신경변성 질환, 신경성 피부질환, 뇌졸중, 방광과민증, 과민성 장증후군, 천식과 만성폐색성 폐질환등 호흡기 이상, 피부, 눈, 점막의 자극, 발열, 위-십이지장궤양, 염증성 장 질환 및 염증성 질환의 예방, 치료에 유효한 양으로 함유함을 특징으로 하는 약제학적 조성물.
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KR100468520B1 (ko) 2005-01-28
US7067553B2 (en) 2006-06-27
AU2001280230A1 (en) 2002-03-04
US20030212140A1 (en) 2003-11-13
DE60120421T2 (de) 2006-12-28
ATE328868T1 (de) 2006-06-15
EP1311478B1 (en) 2006-06-07
JP2004506714A (ja) 2004-03-04
KR20040048393A (ko) 2004-06-09
WO2002016319A1 (en) 2002-02-28
DE60120421D1 (de) 2006-07-20
EP1311478A4 (en) 2004-08-04
ES2266227T3 (es) 2007-03-01
US20030153596A1 (en) 2003-08-14
KR100453078B1 (ko) 2004-10-15

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