KR20020003559A - INHIBITORS OF LFA-1 BINDING TO ICAMs AND USES THEREOF - Google Patents

INHIBITORS OF LFA-1 BINDING TO ICAMs AND USES THEREOF Download PDF

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KR20020003559A
KR20020003559A KR1020017012479A KR20017012479A KR20020003559A KR 20020003559 A KR20020003559 A KR 20020003559A KR 1020017012479 A KR1020017012479 A KR 1020017012479A KR 20017012479 A KR20017012479 A KR 20017012479A KR 20020003559 A KR20020003559 A KR 20020003559A
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sulfide
chlorophenyl
amino
chloro
dichlorophenyl
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포울러캐리
오르메마아크
스턴튼도날드이
아돌프슨자넷
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게리 엘. 윌콕스
이코스 코포레이션
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Abstract

LFA-1가 천연 리간드 결합 파트너에 결합하는 것을 저해하는 신규의 화합물이 개시되어 있다. 이 화합물의 용도도 제공되어 있다.Novel compounds are disclosed that inhibit LFA-1 from binding to natural ligand binding partners. Uses of this compound are also provided.

Description

ＬＦＡ-1의 ＩＣＡＭ에 대한 결합 저해제 및 그 용도{INHIBITORS OF LFA-1 BINDING TO ICAMs AND USES THEREOF}Binding inhibitor of LFA-1 to ICAM and its use {INHIBITORS OF LFA-1 BINDING TO ICAMs AND USES THEREOF}

백혈구 기능-관련 항원(LFA-1, CD11a/CD18)은 세포/세포 접착에 참여하는 백혈구-특이 β2인테그린이다. LFA-1의 결합 활성은 염증 반응에서 순환으로부터 상처 부위로의 백혈구 혈관외유출에 중요하다. 3개의 주요 리간드, ICAM-1, ICAM-2 및 ICAM-3가 LFA-1에 결합한다고 알려져 있으며, 이들은 상처부위의 내피세포에 백혈구 접착을 국한시키는데 중요한 역할을 하는 세포내 접착 분자이다. 또한, ICAM-4 및 ICAM-5도 LFA-1에 결합한다고 알려졌다. 대부분의 백혈구는 구성적으로 LFA-1을 발현하나, 리간드 결합에는 입체구조 변화를 유도할 것으로 여겨지고 리간드 결합력을 증가시키는 활성화가 필요하다. 예를들면, ICAM-1은 통상 내피세포층 상에서 낮은 수준으로 발현되나 상처-유도성 염증 매개인자는 상처 부위의 세포에서 강화된 표면 발현을 증진시키고, 차례로, 활성화된 LFA-1과의 결합을 통해 국한되어진 백혈구 접착을 증진시킨다.Leukocyte function-related antigens (LFA-1, CD11a / CD18) are leukocyte-specific β 2 integrins that participate in cell / cell adhesion. The binding activity of LFA-1 is important for leukocyte extravasation from the circulation to the wound site in the inflammatory response. Three major ligands, ICAM-1, ICAM-2 and ICAM-3, are known to bind to LFA-1, and are intracellular adhesion molecules that play an important role in confining leukocyte adhesion to endothelial cells at the wound site. In addition, ICAM-4 and ICAM-5 are also known to bind to LFA-1. Most leukocytes express LFA-1 constitutively, but ligand binding is believed to induce conformational changes and requires activation to increase ligand binding capacity. For example, ICAM-1 is usually expressed at low levels on the endothelial layer, but wound-induced inflammatory mediators promote enhanced surface expression in cells at the wound site, which in turn, through binding to activated LFA-1 Promotes localized leukocyte adhesion.

LFA-1의 구조는 ICAM 결합에 참여하고/하거나 ICAM 결합을 조절하는 것으로생각되는 별개의 세포내 및 세포외 도메인을 포함한다. 특히 관심이 있는 것은 I 도메인으로 지칭되는 αL내에 있는 대략 200개 아미노산 영역으로, 모든 β2인테그린 뿐만아니라 기타 다수의 단백질에서 발견된다. 증거에 의하면 I 도메인은 ICAM-1 및 3에 LFA-1이 결합하는데 중요하다는 것을 제시한다. 예를들면, 항-LFA-1 차단 단클론성 항체들이 I 도메인 내의 에피토프로 지도화되었다. 게다가, 재조합 I 도메인 폴리펩티드 단편은 인테그린-매개성 접착을 저해하고 ICAM-1에 결합하는 것으로 나타났다. LFA-1(및 기타 단백질)의 I 도메인 안에는 망간 또는 마그네슘 이온에 선호적으로 결합하는 단일의 금속 이온 의존성 접착 부위(MIDAS)가 있다. 이중 어느 한 양이온의 결합은 리간드 상호작용에 필요하며, 결합에 필요한 LFA-1의 입체구조 변화를 야기한다고 여겨진다. 따라서, 양이온 결합은 세포외 백혈구 환경의 변화에 반응하는 조절성 작용기작일 수 있다. 이러한 가설은 칼슘 이온 결합이 실질적으로 ICAM-1과 LFA-1의 상호작용을 저해한다는 관찰결과에 의해 지지된다. 게다가, 불활성 LFA-1 입체구조는 칼슘 결합의 결과이며 칼슘이온이 망간 또는 마그네슘 이온으로 치환되는 것이 LFA-1 활성화에 필요한 단계라는 것이 제시되어왔다[Griggs,et al., J.Biol.Chem. 273:22113-22119(1998)]. 또한 다른 인자들이 T세포 수용체 관여, 사이토킨 자극 및 시험관내 PMA 자극을 포함한 LFA-1 활성화를 유도하는 것으로 나타났다.The structure of LFA-1 includes distinct intracellular and extracellular domains that are thought to participate in and / or regulate ICAM binding. Of particular interest is the approximately 200 amino acid region within α L , referred to as the I domain, found in all β 2 integrins as well as many other proteins. Evidence suggests that the I domain is important for binding LFA-1 to ICAM-1 and 3. For example, anti-LFA-1 blocking monoclonal antibodies have been mapped to epitopes in the I domain. In addition, recombinant I domain polypeptide fragments have been shown to inhibit integrin-mediated adhesion and bind ICAM-1. Within the I domain of LFA-1 (and other proteins) is a single metal ion dependent adhesion site (MIDAS) that preferentially binds manganese or magnesium ions. The binding of either cation is necessary for ligand interaction and is believed to cause the conformational change of LFA-1 required for binding. Thus, cationic binding may be a regulatory mechanism that responds to changes in the extracellular leukocyte environment. This hypothesis is supported by the observation that calcium ion binding substantially inhibits the interaction of ICAM-1 with LFA-1. In addition, the inactive LFA-1 conformation is the result of calcium binding and it has been suggested that the substitution of calcium ions with manganese or magnesium ions is a necessary step for LFA-1 activation [Griggs, et al., J. Biol. Chem. 273 : 22113-22119 (1998). Other factors have also been shown to induce LFA-1 activation including T cell receptor involvement, cytokine stimulation and in vitro PMA stimulation.

실질적인 의미에서, LFA-1/ICAM 결합 부위의 규명은 백혈구 염증 반응을 조절하는 표적을 제공한다. LFA-1 활성화를 유도할 수 있는 다수의 항체들[예를들면, Landis,et al., J.Cell Biol. 120:1519-1527(1993) 참조] 또는 ICAM-1 상호작용을방해할 수 있는 다수의 항체들[예를들면, Randi and Hogg, J.Biol.Chem. 269:12395-12398(1994)]이 분리되었다. 항-LFA-1 활성화 항체가 다수의 그리고 구별되는 세포외 에피토프를 인식한다는 이전의 규명은 세포 신호전달과 무관한 것으로 여겨지는 하나이상의 조절성 영역이 존재한다는 것을 제시한다. ICAM-1과 결합하는 LFA-1 부위의 국부화는 사람 및 쥐 성분들을 포함하는 키메라 LFA-1 α서브유닛 단백질을 사용함으로써 조사되었다[Huang and Springer,J.Biol.Chem. 270:19008-19016(1995)]. 연구에 의하면, 양이온 결합을 조정하는 잔기 및 상기 부위에 인접한 잔기는 비교적 편평한 접촉면에서의 ICAM-1 결합에 중요하다고 한다. 세포외 조절성 영역(들) 및 ICAM-1 결합의 접촉점에 대한 더욱 정확한 설명에 의해 효과적인 모듈레이터를 고안할 수 있을 것이다.In a practical sense, the identification of the LFA-1 / ICAM binding site provides a target for regulating the leukocyte inflammatory response. Many antibodies capable of inducing LFA-1 activation (eg, Landis, et al., J. Cell Biol. 120 : 1519-1527 (1993)] or a number of antibodies that may interfere with ICAM-1 interactions (eg, Randi and Hogg, J. Biol. Chem. 269: 12395-12398 (1994). Previous identification that anti-LFA-1 activating antibodies recognize multiple and distinct extracellular epitopes suggests that there is more than one regulatory region that is believed to be independent of cellular signaling. Localization of LFA-1 sites that bind ICAM-1 was investigated by using chimeric LFA-1 α subunit proteins including human and murine components [Huang and Springer, J. Biol. Chem. 270 : 19008-19016 (1995). Studies have shown that residues that modulate cation binding and residues adjacent to these sites are important for ICAM-1 binding at relatively flat contact surfaces. More accurate descriptions of the extracellular regulatory region (s) and the point of contact of ICAM-1 binding may devise effective modulators.

따라서, 당업계에서는 염증 반응에 참여하는 단백질과, 특히 LFA-1 및 LFA-1에 결합하는 ICAM에 대한 조절성 영역을 정확하게 규명할 필요가 있다. 단백질의 삼차(또는 사차) 구조를 확인하면, 염증성 장애에 대한 치료적 및 예방적 조정을 하기 위한 생물학적으로 적합성있는 소분자를 논리적으로 고안하도록 하는 가능성있는 조절성 영역을 규명할 수 있다. 나아가, 당업계에서는 염증성 장애 치료에 사용될 수 있는, ICAM에 결합하는 LFA-1를 저해할 수 있는 화합물을 규명할 필요가 있다.Thus, there is a need in the art to accurately identify regulatory regions for proteins that participate in the inflammatory response and, in particular, ICAMs that bind LFA-1 and LFA-1. Identifying the tertiary (or quaternary) structure of a protein can identify potential regulatory regions that allow for the logical design of biologically compatible small molecules for therapeutic and prophylactic adjustments to inflammatory disorders. Furthermore, there is a need in the art to identify compounds that can inhibit LFA-1 binding to ICAM, which can be used to treat inflammatory disorders.

본 발명은 LFA-1가 천연 리간드 결합 파트너에 결합하는 것을 저해하는 신규의 화합물에 관한 것이다.The present invention relates to novel compounds that inhibit the binding of LFA-1 to natural ligand binding partners.

발명의 요약Summary of the Invention

본 발명은 LFA-1의 I 도메인에 있는 신규의 조절성 부위에 결합하여 LFA-1과결합하는 ICAM들에 LFA-1이 결합하는 것을 저해하는 화합물에 관한 것이다. 따라서, 본 발명은 내피세포로의 백혈구 접착을 조절하는 방법도 제공한다. 본 발명의 화합물은 염증성 질환, 자가면역 질환, 종양 전이, 동종이식 거부반응 및 리퍼퓨젼(reperfusion) 외상과 관련된 것 같은 병변을 치료하는데 유용하다. 특히, 본 발명은 일반 구조 화학식 1의 디아릴 설파이드, 이의 약학적 허용염, 또는 이의 프로드럭에 관한 것이며, LFA-1과 결합하는 ICAM에 LFA-1이 결합하는 것을 저해하는데 있어서 디아릴 설파이드와, 특히 화학식 1의 화합물의 용도에 관한 것이다.The present invention relates to a compound that binds to a novel regulatory site in the I domain of LFA-1 and inhibits the binding of LFA-1 to ICAMs that bind to LFA-1. Accordingly, the present invention also provides a method for regulating leukocyte adhesion to endothelial cells. The compounds of the present invention are useful for treating lesions such as those associated with inflammatory diseases, autoimmune diseases, tumor metastasis, allograft rejection and reperfusion trauma. In particular, the present invention relates to a diaryl sulfide of the general formula (1), a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the present invention relates to diaryl sulfide in inhibiting the binding of LFA-1 to ICAM that binds to LFA-1. And, in particular, to the use of the compound of formula (1).

여기서, A 및 B는 독립적이며, 비제한적으로 페닐, 티에닐, 푸릴, 피리미디닐, 이미다졸릴, 피라졸릴, 피리딜, 피라지닐, 피롤릴 및 피리다지닐을 포함하는 5원 방향족환 및 6원 방향족환으로 구성된 군에서 선택된 아릴기이고;Wherein A and B are independent and include, but are not limited to, five-membered aromatic rings including phenyl, thienyl, furyl, pyrimidinyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrrolyl and pyridazinyl; and An aryl group selected from the group consisting of six-membered aromatic rings;

R1, R2및 R3은 독립적이며 수소, -Ra(이때, Ra는 수소 또는, 포화된 직쇄 또는 분지쇄의 1 내지 6개 탄소 원자를 함유하는 알킬기(C1-6알킬)임), -O-Ra, 할로(이때, 할로는 Cl, F, Br 또는 I임), -NRbRc(이때, Rb및 Rc은 독립적이며, H, C1-6알킬, 또는 -CH2-아릴 임), -NO2, -C(=O)Ra, -CN, 퍼플루오로 Ra(예, 트리플루오로메틸), -N-C(=O)Ra, -(CH2)n-NRbRc(이때 n은 1 내지 6의 정수), 모르폴리노와 같이 선택적으로 치환되고 하나이상의 O, N 또는 S를 함유하는 5원 또는 6원 헤테로시클릭 고리(지방족 또는 방향족) 및 -S-아릴(이때, 아릴은 5원 또는 6원 방향족환이며 선택적으로 치환됨)로 구성된 군에서 선택되고;R 1 , R 2 and R 3 are independent and hydrogen, —R a , wherein R a is hydrogen or an alkyl group containing 1 to 6 carbon atoms in saturated straight or branched chain (C 1-6 alkyl) ), -OR a , halo (where halo is Cl, F, Br or I), -NR b R c (where R b and R c are independent and H, C 1-6 alkyl, or -CH 2 -aryl), -NO 2 , -C (= 0) R a , -CN, perfluoro R a (e.g. trifluoromethyl), -NC (= 0) R a ,-(CH 2 ) n- NR b R c where n is an integer from 1 to 6, a 5- or 6-membered heterocyclic ring (aliphatic or aromatic) optionally substituted with morpholino and containing one or more O, N or S and -S-aryl, wherein aryl is a 5- or 6-membered aromatic ring and is optionally substituted;

R4, R5및 R6은 독립적이며 수소, -Ra, -O-Ra, 할로, -NRbRc, -NO2, -C(=O)Ra, -CN, 퍼플루오로 Ra, -N-C(=O)Ra, -(CH2)n-NRbRc, 및 선택적으로 치환되고 하나이상의 O, N 또는 S를 함유하는 5원 또는 6원 헤테로시클릭 고리(지방족 또는 방향족) 및 -S-아릴로 구성된 군에서 선택되거나, 여기서 R4및 R5는 함께 5원 또는 6원 방향족 환을 형성하고 선택적으로 고리 내에 하나이상의 O, N 또는 S를 포함하고 선택적으로 치환됨.R 4 , R 5 and R 6 are independent and are hydrogen, -R a , -OR a , halo, -NR b R c , -NO 2 , -C (= O) R a , -CN, perfluoro R a , —NC (═O) R a , — (CH 2 ) n —NR b R c , and a 5- or 6-membered heterocyclic ring optionally substituted and containing one or more O, N or S (aliphatic or aromatic ) And -S-aryl, wherein R 4 and R 5 together form a 5- or 6-membered aromatic ring and optionally comprise one or more O, N or S in the ring and optionally substituted.

ICAM으로의 LFA-1 결합에 대한 신규의 음성 조절인자의 예는 비제한적으로 표 1에 나타난 화합물을 포함한다.Examples of novel negative regulators of LFA-1 binding to ICAM include, but are not limited to, the compounds shown in Table 1.

[표 1]TABLE 1

전형적인 음성 조절인자Typical voice modulator

3-클로로-4-(2-클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-chlorophenylsulfanyl) -phenylamine hydrochloride

4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide

3-클로로-4-(2-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-naphthylsulfanyl) -phenylamine hydrochloride

3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride

3-클로로-4-(2,4,5-트리클로로페닐설파닐)-페닐아민 히드로클로라이드3-chloro-4- (2,4,5-trichlorophenylsulfanyl) -phenylamine hydrochloride

3-클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine

3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine

3-메톡시-4-(2,3-디클로로페닐설파닐)-페닐아민3-methoxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine

5-아미노-2-(2,3-디클로로페닐설파닐)-아세토페논 히드로클로라이드5-amino-2- (2,3-dichlorophenylsulfanyl) -acetophenone hydrochloride

4-(2,3-디클로로페닐설파닐)-페닐아민4- (2,3-dichlorophenylsulfanyl) -phenylamine

3-클로로-4-(1-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (1-naphthylsulfanyl) -phenylamine hydrochloride

3-메틸-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-methyl-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene

4-메틸아미노-2,2',4'-트리클로로디페닐설파이드4-methylamino-2,2 ', 4'-trichlorodiphenylsulfide

3-브로모-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Bromo-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride

6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole

4-아미노-2-클로로페닐-(2' 4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 '4'-dimethylphenyl) -sulfide hydrochloride

2,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드2,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 히드로클로라이드4-amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride

4-아미노-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(3',4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide

비스-(4,4'-디아미노-2,2'-디클로로페닐)-설파이드Bis- (4,4'-diamino-2,2'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-(4'-아세트아미도-2'클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'chlorophenyl) -sulfide

4-아미노-2-클로로페닐-6-(5-니트로퀴놀리노)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinolino) -sulfide

4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide

2-클로로-4-아미노-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-아미노-5-N-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-N-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘 설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine sulfide

4-아미노메틸-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4,5-디클로로-2-(2,4-디클로로페닐설파닐)-페닐아민4,5-dichloro-2- (2,4-dichlorophenylsulfanyl) -phenylamine

3,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민3,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine

2,3-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민2,3-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine

4-아미노-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

5-아미노-3-클로로페닐-(2',4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine

1-(3-니트로-4-페닐설파닐-페닐)-에타논1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone

1-(3-니트로-4-페닐설파닐-페닐)-에타논 옥심1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone oxime

5-트리플루오로메틸-2-페닐설파닐-벤조니트릴5-trifluoromethyl-2-phenylsulfanyl-benzonitrile

1-(3,5-디클로로페닐)-3-페닐설파닐-피롤리딘-2,5-디온1- (3,5-Dichlorophenyl) -3-phenylsulfanyl-pyrrolidine-2,5-dione

비스-2,4,6-트리니트로페닐-설파이드Bis-2,4,6-trinitrophenyl-sulfide

2-메틸-1-(2-o-톨릴설파닐-페닐)-1H-피롤2-methyl-1- (2- o -tolylsulfanyl-phenyl) -1H-pyrrole

3-[2-(4-클로로-2-니트로-페닐설파닐)-페닐아미노-3H-이소벤조푸란-1-온3- [2- (4-Chloro-2-nitro-phenylsulfanyl) -phenylamino- 3H -isobenzofuran-1-one

4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine

2-니트로-4-클로로페닐-(2' 아미노페닐)-설파이드2-nitro-4-chlorophenyl- (2 'aminophenyl) -sulfide

6-아미노-2-클로로페닐-(4'-메틸페닐)-설파이드6-Amino-2-chlorophenyl- (4'-methylphenyl) -sulfide

4-니트로페닐-(2'-클로로페닐)-설파이드4-nitrophenyl- (2'-chlorophenyl) -sulfide

2,4-디니트로페닐-(4'-클로로페닐)-설파이드2,4-dinitrophenyl- (4'-chlorophenyl) -sulfide

4-아미노페닐-(2'-클로로페닐)-설파이드4-Aminophenyl- (2'-chlorophenyl) -sulfide

2,4-디아미노페닐-(4'-이소프로필페닐)-설파이드2,4-diaminophenyl- (4'-isopropylphenyl) -sulfide

4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘-설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine-sulfide

구조 화학식 1에 의해 표시되는 화합물은 합성 방법 또는 대사과정에 의해 제조될 수 있다. 대사과정에 의한 화합물의 제조는 생체내 및 시험관내 과정을 포함한다. 또한, 본 발명의 화합물을 포함하는 약학적 조성물도 포함된다.The compound represented by Structural Formula 1 may be prepared by synthetic methods or metabolic processes. Preparation of compounds by metabolic processes includes in vivo and in vitro procedures. Also included are pharmaceutical compositions comprising a compound of the present invention.

또한, 본 발명은 디아릴 설파이드, 특히 구조 화학식 1의 화합물과 LFA-1를 접촉시키는 단계를 포함하여 LFA-1과 결합하는 ICAM으로의 LFA-1 결합을 저해하는 방법을 제공한다. 마찬가지로, 본 발명은 디아릴 설파이드, 특히 구조 화학식 1의화합물과 LFA-1를 발현하는 백혈구를 접촉시키는 단계를 포함하여 내피세포에 백혈구 접착을 저해하는 방법을 제공한다. 또한, 본 발명은 LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드에 LFA-1의 결합을 저해하기에 충분한 함유량으로 본 발명의 약학적 조성물을 포유류에게 투여하는 단계를 포함하여 염증성 장애를 치료하는 방법을 포함한다. 또한, 본 발명은 LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드에 LFA-1이 결합함으로써 야기되는 염증성 장애를 치료하는 방법으로서, LFA-1에 천연 리간드의 결합을 저해하기에 충분한 함유량으로 LFA-1과의 결합에 대해 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민과 경쟁하는 화합물을 필요한 포유류에 투여하는 단계를 포함하는 방법을 포함한다. 게다가, 본 발명은 ICAM으로의 LFA-1 결합을 저해하는 디아릴 설파이드, 특히 구조 화학식 1의 화합물을 유효량으로 필요한 개체에 투여하는 단계를 포함하여 LFA-1에 결합하는 ICAM으로의 LFA-1 결합과 관련있는 병리학적 상태를 개선시키는 방법을 제공한다.The present invention also provides a method of inhibiting LFA-1 binding to an ICAM that binds to LFA-1, including contacting a diaryl sulfide, in particular LFA-1 with a compound of formula (1). Likewise, the present invention provides a method of inhibiting leukocyte adhesion to endothelial cells, including contacting a diaryl sulfide, in particular a compound of formula 1, with leukocytes expressing LFA-1. In addition, the present invention provides mammalian pharmaceutical compositions of the invention in an amount sufficient to inhibit the binding of LFA-1 to a natural ligand of LFA-1 that competes with ICAM-1 or ICAM-3 for binding to LFA-1. It comprises a method for treating an inflammatory disorder, including administering to. In addition, the present invention provides a method for treating an inflammatory disorder caused by LFA-1 binding to a natural ligand of LFA-1 that competes with ICAM-1 or ICAM-3 for binding to LFA-1. To a mammal in need of a compound that competes with 3-chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine for binding to LFA-1 in an amount sufficient to inhibit binding of the natural ligand. It includes a method comprising the step of. In addition, the present invention comprises the administration of aryl sulfides that inhibit LFA-1 binding to ICAM, particularly LFA-1 binding to LFA-1 binding to IFA, comprising administering to a subject in need thereof an effective amount of a compound of formula It provides a method for improving pathological conditions associated with the disease.

본 발명의 저해제의 예는 비제한적으로 표 1에 나열한 화합물을 포함한다.Examples of inhibitors of the invention include, but are not limited to, the compounds listed in Table 1.

또한, 본 발명은 ICAM-1으로의 LFA-1 결합과 관련된 병변을 치료하는 의약을 생산하는데 있어서 본 발명의 화합물의 용도를 제공한다.The present invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a lesion associated with LFA-1 binding to ICAM-1.

또한, 본 발명은 LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드와의 LFA-1의 결합에 대한 음성 조절인자를 규명하는 방법으로서, a) LFA-1 결합의 활성인자와 LFA-1를 접촉시키는 단계; b) 시험 화합물의 존재 및 부재 하에 천연 리간드와의 LFA-1 결합을 측정하는 단계; 및 c) 시험 화합물의존재하에 리간드와 LFA-1 결합이 감소된 것이 검출될 때 저해제로서 시험 화합물을 확인하는 단계를 포함하는 방법을 제공한다. 일면에서 활성인자는 크리스탈 바이올렛이다.In addition, the present invention is a method for identifying a negative regulator of the binding of LFA-1 to the natural ligand of LFA-1 competing with ICAM-1 or ICAM-3 for binding to LFA-1, a) LFA Contacting LFA-1 with an activator of -1 binding; b) measuring LFA-1 binding with natural ligands in the presence and absence of the test compound; And c) identifying the test compound as an inhibitor when a decrease in ligand and LFA-1 binding in the presence of the test compound is detected. In one embodiment, the activator is crystal violet.

본 발명의 상세한 설명Detailed description of the invention

화합물에 대한 IC50값은 관심있는 생물학적 활성을 50% 저해하는데 필요한 화합물의 농도로서 정의된다. 본 명세서에서 음성 조절인자는 LFA-1과 천연 리간드의 결합을 저해하는 IC50로 특징지워진 화합물로서 정의된다. LFA-1 결합의 음성 조절인자는 IC50이 약 200μM 이하, 약 100 μM 이하, 약 50 μM이하, 그리고 바람직하게는 0.05 μM 내지 40 μM인 것으로 정의된다.The IC 50 value for a compound is defined as the concentration of compound required to 50% inhibit the biological activity of interest. Negative regulators are defined herein as compounds characterized by an IC 50 that inhibits the binding of LFA-1 to a natural ligand. The negative regulator of LFA-1 binding is defined as an IC 50 of about 200 μM or less, about 100 μM or less, about 50 μM or less, and preferably 0.05 μM to 40 μM.

본 명세서에서 "약학적으로 허용가능한 캐리어"는 수용체 동물과 접촉하는 경우 사용하기에 적절하며, 적절한 잇점/위험의 비율에 상응하는 부적절한 독성, 과민상태, 알러지 반응을 갖으며, 목적하는 용도에 효과적인 본 발명의 화합물의 프로드럭을 지칭한다.As used herein, a "pharmaceutically acceptable carrier" is suitable for use in contact with a recipient animal, has inadequate toxicity, irritability, allergic reactions corresponding to the appropriate benefit / risk ratio, and is effective for the intended use. Refers to a prodrug of a compound of the invention.

본 명세서에서 "프로드럭"은 예를들면 가수분해에 의해 상기 화학식의 모(母)화합물로 신속하게 생체내 변형되는 화합물을 지칭한다. 문헌[Higuchi,et al, Prodrugs as Novel Delivery Systems, vol. 14 of the A.C.S.D Symposium Series, 본 명세서에 인용됨] 및 문헌[Roche(ed),Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press, 1987, 본 명세서에 인용됨]에 면밀히 검토되어 있다. 프로드럭 고안은 문헌[Hardma,et al.,(Eds),Goodman & Gilman's The Pharmacological Basis of Therapeutics,Ninth Edition, New York, New York(1996), pp11-16]에 일반적으로 검토되어 있다. 간단히 말하자면, 약물이 투여되면 신체로부터 제거되거나 약물의 생물학적 활성이 감소 또는 제거되는 생물학적 변형이 일어난다. 대신, 생물학적 변형 과정은 처음 투여된 약물과 비교할 때 더 활성적이거나 동등한 활성을 갖는 대사 부산물을 생성시킬 수도 있다. 이러한 생물학적 변형 과정을 더 잘 이해할수록, 생물학적 변형 이후 변형된 상태에서 더욱 생리학적으로 활성이 되는 소위 "프로드럭"을 고안할 수 있다. 따라서, 프로드럭은 생물학적으로 활성인 대사물로 전환되는 생리학적으로 불활성인 화합물이다. 몇몇 형태의 경우, 프로드럭은 예를들면 에스테르 또는 아미드 결합의 가수분해를 통해 생리학적으로 활성이 되며, 가수분해는 종종 프로드럭 상에 작용기를 도입 또는 노출시킨다. 따라서, 수정된 약물도 내인성 화합물과 반응하여, 예를들어 순환 반감기가 증가된 결과 화합물의 약리학적 특성을 더 증가시키는 수용성 접합체를 형성할 수 있다.As used herein, “prodrug” refers to a compound that is rapidly transformed in vivo into the parent compound of the formula, for example by hydrolysis. See Higuchi, et al, Prodrugs as Novel Delivery Systems , vol. 14 of the ACSD Symposium Series, incorporated herein by reference and Roche (ed), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, cited herein. Prodrug design is described by Hardma, et al. (Eds), Goodman &Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, New York, New York (1996), pp 11-16. In short, administration of a drug results in a biological modification that is removed from the body or that reduces or eliminates the biological activity of the drug. Instead, biological modification processes may produce metabolite byproducts that are more active or have equivalent activity when compared to the drug initially administered. The better we understand this biological modification process, the more so-called "prodrugs" can be devised which become more physiologically active in the modified state after biological modification. Thus, prodrugs are physiologically inactive compounds that are converted into biologically active metabolites. In some forms, prodrugs are physiologically active, for example, through hydrolysis of ester or amide bonds, which often introduce or expose functional groups on the prodrug. Thus, the modified drug may also react with the endogenous compound to form a water soluble conjugate that further increases the pharmacological properties of the compound, for example as a result of increased circulating half-life.

또다른 대안으로, 프로드럭을 고안하여 예를들어 글루쿠론산, 황산, 글루타티온, 아미노산 또는 아세테이트로 작용기를 공유결합으로 수정하도록 할 수 있다. 결과로 생긴 접합체는 불활성화되며 뇨로 분비되거나 모 화합물보다 더욱 강력하게 된다. 또한, 고분자량의 접합체는 담즙으로 분비되어 효소에 의해 절단되고 순환으로 다시 방출되어 원래 투여된 화합물의 생물학적 반감기가 효과적으로 증가될 수 있다.Alternatively, prodrugs can be designed to covalently modify functional groups, for example with glucuronic acid, sulfuric acid, glutathione, amino acids or acetate. The resulting conjugate is inactivated and secreted into urine or more potent than the parent compound. In addition, high molecular weight conjugates can be secreted into bile, cleaved by enzymes, and released back into the circulation, effectively increasing the biological half-life of the originally administered compound.

본 발명의 화합물은 비대칭 또는 키랄성 중심이 존재하는 입체이성질체로서존재할 수 있다. 입체이성질체는 키랄성 탄소 원자 주위의 치환기의 배치에 따라 "S" 또는 "R"에 의해 명명된다. 입체이성질체의 혼합물은 본 발명에 포함된다. 입체이성질체는 거울상이성질체, 부분입체이성질체 및 이들 둘의 혼합물을 포함한다. 본 발명의 화합물의 개별적인 입체이성질체는 비대칭 또는 키랄성 중심을 함유하는 상업적으로 구입가능한 출발물질로부터 합성할 수 있거나 라세미 혼합물을 준비한 후 당업계에 잘 알려진 분리 또는 분해 기법에 의해 준비될 수 있다. 분해 방법은 (1) 키랄성 보조물로의 거울상이성질체 혼합물 부착, 재결정 또는 크로마토그래피에 의한 생성된 혼합물의 분리, 및 보조물로부터 광학적으로 순수한 생성물의 방출; (2) 광학적으로 활성인 분해 반응제(resolving agent)를 사용한 염 형성, 및 (3) 키랄성 크로마토그래피 컬럼 상에서의 광학적 거울상이성질체 혼합물의 직접적인 분리를 포함한다.The compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. Stereoisomers are named by "S" or "R" depending on the placement of substituents around the chiral carbon atom. Mixtures of stereoisomers are included in the present invention. Stereoisomers include enantiomers, diastereomers and mixtures of both. Individual stereoisomers of the compounds of the present invention can be synthesized from commercially available starting materials containing asymmetric or chiral centers or prepared by separation or degradation techniques well known in the art after preparing racemic mixtures. Degradation methods include (1) attachment of enantiomeric mixtures to chiral auxiliaries, separation of the resulting mixture by recrystallization or chromatography, and release of optically pure product from the auxiliaries; (2) salt formation using an optically active resolving agent, and (3) direct separation of the optical enantiomeric mixture on a chiral chromatography column.

본 발명의 화합물은 비제한적으로 상기 일반 구조 화학식 1에 의해 포함되는 것 및 표 1에 나열된 화합물을 포함한다.Compounds of the present invention include, but are not limited to, those encompassed by General Structural Formula 1 and the compounds listed in Table 1.

또한, 본 발명은 하나이상의 본 발명의 화합물을 포함하는 약학적 조성물을 제공하며, 약학적으로 허용가능한 캐리어 또는 희석제를 더 포함하는 것이 바람직하다.In addition, the present invention provides a pharmaceutical composition comprising one or more compounds of the present invention, preferably further comprising a pharmaceutically acceptable carrier or diluent.

나아가, 본 발명은 LFA-1 또는 이의 ICAM-결합 단편을 음성 조절인자 화합물과 접촉시키는 단계를 포함하여, LFA-1과 결합하는 ICAM에 LFA-1이 결합하는 것을 저해하는 방법을 제공한다. 여기서 상기 음성 조절인자는, 디아릴 설파이드에 결합하는 입체구조 또는 사람 LFA-1 αL폴리펩티드의 Ile259, Leu298, Ile235, Val157, Leu161및 Ile306에 의해 정의된 결합 부위로 구성된 군에서 선택된 부위에서 그리고 상술한 구조를 갖는 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민에 결합하는 LFA-1 도메인에서 LFA-1 αL폴리펩티드, 또는 이의 단편과 결합한다. 대안으로, LFA-1 상의 음성 조절인자 결합 부위는 아미노산 잔기 Ile259, Leu298, Ile235, Val157, Leu161, Ile306, Leu302, Tyr257, Leu132, Val233, Val130및 Tyr166에 의해 정의된다. 또다른 대안으로, LFA-1 상의 음성 조절인자 결합 부위는 아미노산 잔기 Lys287, Leu298, Ile259, Leu302, Ile235, Val157, Tyr257, Lys305, Leu161, Leu132, Val233, Ile255, Val130, Tyr166, Ile306, Phe134, Phe168, Phe153, Tyr307, Val308, Ile309, Thr231, Glu284, Phe285, Glu301, Met154, Ile237, Ile150, 및 Leu295에 의해 정의된다. LFA-1 조절성 결합 부위는 함께 출원중인 미국 특허 출원[제목 "LFA-1 조절성 결합 부위 및 이의 용도, 1999. 4. 2. 출원, 대리인 명부 번호 27866/35375, 일련번호 09/285,477, 본 명세서에 그 전체가 인용됨]에 기재되어 있다. 일 구체예에서, 본 발명의 방법은 LFA-1 또는 ICAM을 발현하는 세포의 사용을 포함한다. 결합 파트너 중 하나가 세포에서 발현되는 방법에서, 또다른 결합 파트너는 개체로부터 취출한 액상 시료(정제되거나 부분적으로 정제되거나 정제되지 않은 것임)에서 또는 세포 용해물에서 정제 및 분리된다. 또한, 본 발명은 LFA-1 및 ICAM가 모두 세포에서 발현되는 방법을 포함한다. LFA-1 및 ICAM 결합 파트너는 동일한 세포 유형 또는 상이한 세포 유형에서 발현될 수 있다. 바람직하게는 LFA-1 폴리펩티드는 백혈구 즉, 림프구, 단핵구 또는 과립구에서 발현되고 ICAM 폴리펩티드는 내피세포에서 발현된다.Furthermore, the present invention provides a method of inhibiting LFA-1 binding to ICAM that binds LFA-1, including contacting LFA-1 or an ICAM-binding fragment thereof with a negative regulator compound. Wherein said negative regulator is a group consisting of binding sites defined by Ile 259 , Leu 298 , Ile 235 , Val 157 , Leu 161 and Ile 306 of a conformational or human LFA-1 α L polypeptide that binds to a diaryl sulfide LFA-1 α L polypeptide, or fragment thereof, at a site selected from and in an LFA-1 domain that binds 3-chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine having the structure described above Combine with Alternatively, the negative regulator binding sites on LFA-1 may comprise amino acid residues Ile 259 , Leu 298 , Ile 235 , Val 157 , Leu 161 , Ile 306 , Leu 302 , Tyr 257 , Leu 132 , Val 233 , Val 130 and Tyr 166 Is defined by In another alternative, the negative regulator binding site on LFA-1 may comprise amino acid residues Lys 287 , Leu 298 , Ile 259 , Leu 302 , Ile 235 , Val 157 , Tyr 257 , Lys 305 , Leu 161 , Leu 132 , Val 233 , Ile 255 , Val 130 , Tyr 166 , Ile 306 , Phe 134 , Phe 168 , Phe 153 , Tyr 307 , Val 308 , Ile 309 , Thr 231 , Glu 284 , Phe 285 , Glu 301 , Met 154 , Ile 237 , Ile 150 , And Leu 295 . LFA-1 regulatory binding sites are described together in the US patent application [Title “LFA-1 regulatory binding sites and uses thereof, April 2, 1999, Representative Directory No. 27866/35375, Serial No. 09 / 285,477, present Which is hereby incorporated by reference in its entirety. In one embodiment, the methods of the present invention comprise the use of cells expressing LFA-1 or ICAM In a method wherein one of the binding partners is expressed in a cell, Another binding partner is purified and isolated from a liquid sample (purified, partially purified or unpurified) taken from an individual, or from cell lysates, furthermore, the present invention provides that both LFA-1 and ICAM are expressed in cells. Methods may be expressed in the same cell type or in different cell types, preferably the LFA-1 polypeptide is expressed in leukocytes, ie lymphocytes, monocytes or granulocytes; ICAM polypeptide is expressed in endothelial cells.

또한 본 발명은 내피세포로의 백혈구 접착을 저해하는 방법으로서, LFA-1에 결합하는 ICAM와의 LFA-1 결합의 음성 조절인자와 상기 백혈구를 접촉시키는 단계를 포함하며, 상기 음성 조절인자가 디아릴 설파이드에 결합하는 입체구조 또는 사람 LFA-1 αL폴리펩티드의 Ile259, Leu298, Ile235, Val157, Leu161및 Ile306에 의해 정의된 결합 부위로 구성된 군에서 선택된 LFA-1 조절성 부위 또는 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민에 결합하는 LFA-1 도메인에서 결합하는 것을 특징으로 하는 방법을 제공한다. 대안으로, 디아릴 설파이드 결합 입체구조는 상술한 바와 같은 아미노산 잔기에 의해 정의된다. 생체내 및 시험관내 방법이 포함된다.The present invention also provides a method for inhibiting leukocyte adhesion to endothelial cells, the method comprising contacting the leukocytes with a negative regulator of LFA-1 binding to an ICAM that binds to LFA-1, wherein the negative regulator is diaryl. LFA-1 regulatory sites selected from the group consisting of binding sites defined by Ile 259 , Leu 298 , Ile 235 , Val 157 , Leu 161 and Ile 306 of a conformational or human LFA-1 α L polypeptide that binds to sulfides, or Provided is a method characterized by binding in an LFA-1 domain that binds 3-chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine. Alternatively, the diaryl sulfide bond conformation is defined by amino acid residues as described above. In vivo and in vitro methods are included.

또한, 본 발명은 ICAM와의 LFA-1의 결합에 의해 발생하는 병변을 개선하는 방법으로서, ICAM에 결합하는 LFA-1의 음성 조절인자를 ICAM와의 LFA-1 결합을 저해하기에 유효한 함유량으로 필요한 개체에 투여하는 단계를 포함하며, 상기 음성 조절인자는 디아릴 설파이드에 결합하는 입체구조 또는 사람 LFA-1의 Ile259, Leu298, Ile235, Val157, Leu161및 Ile306에 의해 정의된 결합 부위로 구성된 군에서 선택된 LFA-1 조절성 부위 또는 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민에 결합하는 LFA-1 도메인에 결합하는 것을 특징으로 하는 방법을 제공한다.In addition, the present invention provides a method for improving lesions caused by the binding of LFA-1 to ICAM, wherein the negative regulator of LFA-1 that binds to ICAM is required in an amount effective to inhibit LFA-1 binding to ICAM. Wherein the negative regulator is a conformational structure that binds to diaryl sulfide or a binding site defined by Ile 259 , Leu 298 , Ile 235 , Val 157 , Leu 161 and Ile 306 of human LFA-1. To a LFA-1 regulatory site selected from the group consisting of or to LFA-1 domain which binds to 3-chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine to provide.

바람직한 구체예에서, 본 발명의 방법은 ICAM와의 LFA-1 결합을 저해하는 디아릴 설파이드 화합물의 사용을 포함한다. 바람직한 방법은 상기 언급한 바와 같이 일반 구조 화학식 1의 화합물, 이의 약학적 허용염 또는 프로드럭의 사용을 포함한다.In a preferred embodiment, the methods of the present invention comprise the use of diaryl sulfide compounds that inhibit LFA-1 binding with ICAM. Preferred methods include the use of compounds of general structural formula (1), their pharmaceutically acceptable salts or prodrugs as mentioned above.

치료 방법How to treat

내피세포와의 백혈구 접착이 병리학적 장애를 일으키는 정도만큼, 본 발명은 LFA-1에 결합하는 ICAM와의 LFA-1 결합의 결과인 백혈구 축적과 관련있는 병변을 개선하는 방법으로서, ICAM와의 LFA-1 결합의 저해제를 ICAM와의 LFA-1 결합을 저해하기에 유효한 함유량으로 필요한 개체에 투여하는 단계를 포함하며, 상기 저해제는 아미노산 잔기 Ile259, Leu298, Ile235, Val157, Leu161및 Ile306에 의해 나타나는 부위에서 LFA-1과 결합하는 것을 특징으로 하는 방법을 제공한다. 전형적인 의학 상태는 비제한적으로, 염증성 질환, 자가면역 질환, 리퍼퓨젼 외상, 심근 경색증, 졸증, 출혈성 쇼크, 기관 이식 등을 포함한다. 본 발명의 방법은 예컨대, 성인 호흡 장애 증후군, 폐혈증에 부수적인 다발성 기관 상해 증후군, 외상에 부수적인 다발성 기관 상해; 조직의 리퍼퓨젼 상해, 급성 사구체신염, 반응성 관절염, 급성 염증 성분을 갖는 피부병, 졸증, 화상, 크론병(Crohn's disease); 괴사성 소장결장염, 과립구 수혈 관련 증후군, 및 사이토킨 유도성 독성 및 T세포 매개성 질환을 비롯한 다양한 병변을 개선하기 위해 제공된다.To the extent that leukocyte adhesion with endothelial cells causes pathological disorders, the present invention provides a method for ameliorating lesions associated with leukocyte accumulation resulting from LFA-1 binding to ICAM that binds LFA-1. Administering an inhibitor of binding to a subject in need thereof in an amount effective to inhibit LFA-1 binding to ICAM, wherein the inhibitor is administered to amino acid residues Ile 259 , Leu 298 , Ile 235 , Val 157 , Leu 161 and Ile 306 . It provides a method characterized by binding to LFA-1 at the site indicated by. Typical medical conditions include, but are not limited to, inflammatory diseases, autoimmune diseases, reperfusion trauma, myocardial infarction, sleepiness, hemorrhagic shock, organ transplantation, and the like. The methods of the invention include, for example, adult respiratory disorder syndrome, multiple organ injury syndrome concomitant with pulmonary disease, multiple organ injury concomitant with trauma; Reperfusion injury of tissues, acute glomerulonephritis, reactive arthritis, skin diseases with acute inflammatory components, drowsiness, burns, Crohn's disease; It is provided to ameliorate various lesions, including necrotic colitis, granulocyte transfusion related syndromes, and cytokine-induced toxicity and T cell mediated diseases.

염증성 세포 활성화 및 과도하거나 조절되지 않은 사이토킨(예, TNFα 및 IL-1β)생산은, 류마티스성 관절염, 고관절염, 통풍성 관절염, 척추염, 갑상선 관련 안과장애(ophthalmopathy), 베세트(Behcet)병, 패혈증, 패혈성 쇼크, 내독성 쇼크, 그램 음성 패혈증, 그램 양성 페혈증, 독성 쇼크 증후군, 천식, 만성 기관지염, 알러지성 호흡 장애 증후군, 만성 폐 염증성 질환(예, 만성 저해 폐 질환, 규폐증, 폐 사르코이드증, 심근, 뇌 및 사지의 리퍼퓨전 상해, 섬유증, 낭포성 섬유증, 켈로이드 형성, 상처 형성, 아테롬성 동맥경화증, 이식 거부 장애(예, 이식대숙주 반응 동종이식 거부반응), 만성 사구체신염, 낭창, 염증성 장 질환(예, 궤양성 대장염), 증식성 림프구 질환(예, 백혈병) 및 염증성 피부병(예, 아토피 피부병, 건선, 두드러기, 포도막염)과 같은 장애와도 연루되어 있다.Inflammatory cell activation and excessive or unregulated cytokine (eg, TNFα and IL-1β) production include rheumatoid arthritis, hip joints, gouty arthritis, spondylitis, thyroid-related ophthalmopathy, Behcet's disease, sepsis, Septic shock, toxic shock, gram-negative sepsis, gram-positive sepsis, toxic shock syndrome, asthma, chronic bronchitis, allergic respiratory disorder syndrome, chronic pulmonary inflammatory disease (e.g. chronic inhibited lung disease, silicosis, pulmonary sarcoidosis) , Myocardial, brain and limb reperfusion injury, fibrosis, cystic fibrosis, keloid formation, wound formation, atherosclerosis, graft rejection disorders (e.g. graft versus host allograft rejection), chronic glomerulonephritis, lupus, inflammatory Involved with disorders such as intestinal disease (eg ulcerative colitis), proliferative lymphocyte disease (eg leukemia) and inflammatory skin disease (eg atopic dermatitis, psoriasis, urticaria, uveitis) It can control.

사이토킨이 상승된 것이 특징인 기타 상태는 온화한 외상에 의한 뇌 상해(J.Neurotrauma, 12, pp.1033-1043(1995) 참조), 심근증(예, 울혈성 심장 장애(Circulation, 97,pp.1340-1341(1998)) 참조), 악액질, 감염 또는 악성 종양에 부수적인 악액질, 후천성 면역결핍증후군(AIDS)에 부수적인 악액질, ARC(AIDS 관련 증후군), 감염에 의한 근통열, 뇌성 말라리아, 골다공증 및 골흡수질환, 켈로이드 형성, 반흔 조직 형성 및 발열을 포함한다.Other conditions characterized by elevated cytokines include brain injury due to mild trauma (see J. Neurotrauma , 12, pp. 1033-1043 (1995)), cardiomyopathy (e.g., congestive heart disorder ( Circulation , 97, pp. 1340)). -1341 (1998))), cachexia concomitant to cachexia, infection or malignancy, cachexia concomitant with acquired immunodeficiency syndrome (AIDS), ARC (AIDS-related syndrome), muscle pain due to infection, cerebral malaria, osteoporosis and Bone resorption disease, keloid formation, scar tissue formation and fever.

본 발명의 음성 조절인자가 관절염을 치료하는 능력은 쥐 콜라겐-유도성 관절염 모델[Kakimoto,et al., Immunol. 142:326-337(1992)], 래트 콜라겐-유도성 관절염 모델[Knoerzer,et al., Toxical Pathol. 25:13-19(1997)], 래트 아쥬반트 관절염 모델[Halloran,et al., Arthritis Rheum 39:810-819(1996)], 래트 연쇄상구균성 세포벽-유도성 관절염 모델[Schimmer,et al., J.Immunol. 160:1466-1477(1998)] 또는 SCID-마우스 사람 류마티스성 관절염 모델[Oppenheimer-Marks,et al., J. Clin Invest 101:1261-1272(1998)]에서 확인될 수 있다.The ability of the negative modulators of the present invention to treat arthritis is demonstrated in the rat collagen-induced arthritis model [Kakimoto, et al., Immunol. 142 : 326-337 (1992), rat collagen-induced arthritis model [Knoerzer, et al., Toxical Pathol. 25 : 13-19 (1997)], rat adjuvant arthritis model [Halloran, et al., Arthritis Rheum 39 : 810-819 (1996)], rat streptococcal cell wall-induced arthritis model [Schimmer, et al. , J. Immunol. 160 : 1466-1477 (1998) or the SCID-mouse human rheumatoid arthritis model [Oppenheimer-Marks, et al., J. Clin Invest 101 : 1261-1272 (1998)].

음성 조절인자가 라임(Lyme) 관절염을 치료하는 능력은 문헌[Gross,et al., Science, 218:703-706(1998)]의 방법에 따라 확인될 수 있다.The ability of negative regulators to treat Lyme arthritis can be identified according to the method of Gross, et al., Science, 218 : 703-706 (1998).

음성 조절인자가 천식을 치료하는 능력은 문헌[Wegner,et al., Science, 247:456-459,(1990)]의 방법에 따른 쥐 알러지성 천식 모델, 또는 문헌[Bloemen,et al., Am.J.Respir.Crit.Care Med. 153:521-529(1996)]의 방법에 따른 쥐 비알러지성 천식 모델에서 확인될 수 있다.The ability of negative regulators to treat asthma is described in the mouse allergic asthma model according to the method of Wegner, et al., Science, 247 : 456-459, (1990), or Bloemen, et al., Am. .J.Respir.Crit.Care Med. 153 : 521-529 (1996)] can be found in the rat non-allergic asthma model.

음성 조절인자가 염증성 폐 상해를 치료하는 능력은 문헌[Wegner,et al., Lung, 170:267-279(1992)]의 방법에 따른 쥐 산소-유도성 폐 상해 모델, 문헌[Mulligan,et al., J.Immunol., 154:1350-1363(1995)]의 방법에 따른 쥐 면역 복합체-유도성 폐 상해 모델, 또는 문헌[Nagase,et al.,Am.J.Respir.Crit.Care Ned., 154:504-510(1996)]의 방법에 따른 쥐 산-유도성 폐 상해 모델에서 확인될 수 있다.The ability of negative regulators to treat inflammatory lung injuries is described in the mouse oxygen-induced lung injury model according to the method of Wegner, et al., Lung, 170 : 267-279 (1992), Mulgan, et al. , J. Immunol., 154 : 1350-1363 (1995)], a model of rat immune complex-induced lung injury, or Nagase, et al., Am. J. Respir. Crit. Care Ned. , 154 : 504-510 (1996)] can be identified in a rat acid-induced lung injury model.

음성 조절인자가 염증성 장 질환을 치료하는 능력은 문헌[Bennett,et al.,J.Pharmacol.Exp.Ther., 280:988-1000(1997)]의 방법에 따른 쥐 화학물질-유도성 대장염 모델에서 확인될 수 있다.The ability of negative regulators to treat inflammatory bowel disease is modeled in rat chemical-induced colitis according to the method of Bennett, et al., J. Pharmacol. Exp . Ther ., 280 : 988-1000 (1997) . Can be identified at

음성 조절인자가 자가면역 당뇨병을 치료하는 능력은 문헌[Hasagawa,et al., Int. Immunol. 6:831-838(1994)]의 방법에 따른 NOD 마우스 모델 또는문헌[Herrold,et al., Cell Immunol. 157:489-500(1994)]의 방법에 따른 쥐 스트렙토조토신-유도성 당뇨병에서 확인될 수 있다.The ability of negative regulators to treat autoimmune diabetes is described by Hasagagawa, et al., Int. Immunol. 6 : 831-838 (1994)] or a NOD mouse model or Herrold, et al., Cell Immunol. 157 : 489-500 (1994)] can be found in rat streptozotocin-induced diabetes.

음성 조절인자가 염증성 간 상해를 치료하는 능력은 문헌[Tanaka, et al., J.Immunol., 151:5088-5095(1993)]의 방법에 따른 쥐 간 상해 모델에서 확인될 수 있다.The ability of negative regulators to treat inflammatory liver injury can be identified in a rat liver injury model according to the method of Tanak a, et al., J. Immunol., 151 : 5088-5095 (1993).

음성 조절인자가 염증성 사구체 상해를 치료하는 능력은 문헌[Kawasaki,et al., J.Immunol., 151:1074-1083(1993)]의 방법에 따른 래트 신독성 혈청 신염 모델에서 확인될 수 있다.The ability of negative regulators to treat inflammatory glomerular injury can be identified in a rat nephrogenic serum nephritis model according to the method of Kawasaki, et al., J. Immunol., 151 : 1074-1083 (1993).

음성 조절인자가 방사선-유도성 장염을 치료하는 능력은 문헌[Panes,et al., Gastroenterology, 108:1761-1769(1995)]의 방법에 따른 래트 복부 과민상태 모델에서 확인될 수 있다.The ability of negative regulators to treat radiation-induced enteritis can be identified in a rat abdominal hypersensitivity model according to the method of Panes, et al., Gastroenterology, 108 : 1761-1769 (1995).

음성 조절인자가 방사선 폐렴을 치료하는 능력은 문헌[Hallahan,et al., Proc. Natl. Acad. Sci(USA), 94:6432-6437(1997)]의 방법에 따른 쥐 폐 과민상태 모델에서 확인될 수 있다.The ability of negative regulators to treat radiation pneumonia is described by Hallahan, et al., Proc. Natl. Acad. Sci (USA), 94 : 6432-6437 (1997)] can be identified in the rat lung hypersensitivity model.

음성 조절인자가 리퍼퓨젼 상해를 치료하는 능력은 문헌[Tamiya,et al., Immunopharmacology, 29:53-63(1995)]의 방법에 따른 분리된 심장 또는 문헌[Hartman,et al, Cardiovasc. Res. 30:47-54(1995)]의 모델에 따른 마취된 개에서 확인될 수 있다.The ability of negative regulators to treat reperfusion injuries can be found in isolated hearts according to the method of Tamiya, et al., Immunopharmacology, 29 : 53-63 (1995) or in Hartman, et al, Cardiovasc. Res. 30 : 47-54 (1995)].

음성 조절인자가 폐 리퍼퓨젼 상해를 치료하는 능력은 문헌[DeMeester,et al., Transplantation, 62:1477-1485(1996)]의 방법에 따른 래트 폐 동종이식 리퍼퓨젼 상해 모델 또는 문헌[Horgan,et al., Am.J.Physiol. 261:H1578-H1584(1991)]의 모델에 따른 토끼 폐 부종 모델에서 확인될 수 있다.The ability of negative regulators to treat pulmonary reperfusion injury is described in Rat lung allograft reperfusion injury model according to the method of DeMeester, et al., Transplantation, 62 : 1477-1485 (1996) or by Horgan, et. al., Am. J. Physiol. 261 : H1578-H1584 (1991)] can be identified in the rabbit lung edema model.

음성 조절인자가 졸증을 치료하는 능력은 문헌[Bowes,et al., Exp. Neurol., 119:215-219(1993)]의 방법에 따른 토끼 뇌 색전증 졸증 모델 또는 문헌[Chopp,et al., Stroke, 25:869-875(1994)]의 방법에 따른 래트 중뇌 동맥 허혈-리퍼퓨젼 모델, 또는 문헌[Clarket al., Neurosurg., 75:623-627(1991)]의 방법에 따른 토끼 가역 척수 허혈 모델에서 확인될 수 있다. 음성 조절인자가 뇌 혈관경련을 치료하는 능력은 문헌[Oshiro,et al., Stroke, 28:2031-2038(1997)]의 방법에 따른 쥐 실험용 혈관경련 모델에서 확인될 수 있다.The ability of negative regulators to treat sleepiness is described by Bowes, et al., Exp. Neurol., 119 : 215-219 (1993)] rat cerebral embolism ataxia model or rat middle cerebral artery ischemia according to the method of Chopp, et al., Stroke, 25 : 869-875 (1994). Reperfusion model, or rabbit reversible spinal cord ischemia model according to the method of Clark et al., Neurosurg., 75 : 623-627 (1991). The ability of negative regulators to treat cerebral vasospasm can be identified in a rat experimental vasospasm model according to the method of Oshiro, et al., Stroke, 28 : 2031-2038 (1997).

음성 조절인자가 말초 동맥 폐색을 치료하는 능력은 문헌[Gute,et al., Mol. Cell Biochem., 179:169-187(1998)]의 방법에 따른 래트 골격근 허혈/리퍼퓨젼 모델에서 확인될 수 있다.The ability of negative regulators to treat peripheral arterial occlusion is described by Gute, et al., Mol. Cell Biochem., 179 : 169-187 (1998)] can be identified in the rat skeletal muscle ischemia / lipperfusion model.

음성 조절인자가 이식 거부반응을 치료하는 능력은 문헌[Isobe,et al., Science, 255:1125-1127(1992)]의 방법에 따른 쥐 심장 동종이식 거부반응 모델 또는 문헌[Talento,et al., Transplanation, 55:418-422(1993)]의 방법에 따른 쥐 갑상선 신장 피막 모델, 문헌[Cosimi,et al., J.Immunol., 144:4604-4612(1990)]의 방법에 따른 사이노몰거스(cynomolgus) 원숭이 신장 동종이식 모델, 문헌[Nakao,et al., Muscle Nerve, 18:93-102(1995)]의 방법에 따른 래트 신경 동종이식 모델, 문헌[Gorczynski and Wojcik,J.Immunol. 152:2011-2019(1994)]의 방법에 따른 쥐 피부 동종이식 모델, 문헌[He,et al., Opthalmol. Vis. Sci.,35:3218-3225(1994)]의 방법에 따른 쥐 각막 동종이식 모델, 또는 문헌[Zeng,et al., Transplantation, 58:681-689(1994)]의 방법에 따른 이종발생 췌장도 세포 이식 모델에서 확인될 수 있다.The ability of negative regulators to treat graft rejection is described in the rat cardiac allograft rejection model according to the method of Isobe, et al., Science, 255 : 1125-1127 (1992) or by Talento, et al. , Transplanation, 55 : 418-422 (1993)], cynomol according to the method of rat thyroid kidney membrane model, Cosimi, et al., J. Immunol., 144 : 4604-4612 (1990) Rat neuro allograft model according to the method of cynomolgus monkey kidney allograft model, Nakao, et al., Muscle Nerve, 18 : 93-102 (1995), Gorczynski and Wojcik, J. Immunol. 152 : 2011-2019 (1994)], mouse skin allograft model, He, et al., Opthalmol. Vis. Sci., 35 : 3218-3225 (1994)], a mouse corneal allograft model, or xenogeneous pancreas according to the method of Zeng, et al., Transplantation, 58 : 681-689 (1994). It can be identified in a cell transplant model.

음성 조절인자가 이식 대 숙주 질환(GVHD)을 치료하는 능력은 문헌[Harning,et al., Transplantation, 52:842-845(1991)]의 방법에 따른 쥐 치사 GVHD 모델에서 확인될 수 있다.The ability of negative regulators to treat graft-versus-host disease (GVHD) can be identified in a rat lethal GVHD model according to the method of Harning, et al., Transplantation, 52 : 842-845 (1991).

음성 조절인자가 암을 치료하는 능력은 문헌[Aoudjit,et al., J.Immunol., 161:2333-2338(1998)]의 방법에 따른 사람 림프종 전이 모델(마우스)에서 확인될 수 있다.The ability of negative regulators to treat cancer can be identified in the human lymphoma metastasis model (mouse) according to the method of Aoudjit, et al., J. Immunol., 161 : 2333-2338 (1998).

약학적 조성물Pharmaceutical composition

또한, 본 발명은 하나이상의 약학적 허용 캐리어와 함께 제제화된 디아릴 설파이드를 포함하는 약학적 조성물을 제공한다.The present invention also provides pharmaceutical compositions comprising diaryl sulfides formulated with one or more pharmaceutically acceptable carriers.

본 발명의 약학적 조성물은 사람 및 기타 동물에게 임의의 적절한 경로로 투여할 수 있다. 예컨대, 조성물은 경구적으로, 직장으로, 비경구적으로, 조내로(intracisternally), 질내로, 복막내로, 국부적으로(분말, 연고, 점적제에 의해), 구강으로, 코로 투여될 수 있다. 본 명세서에서 "비경구적" 투여는 정맥내, 동맥내, 근육내, 복막내, 흉골내, 포막내, 피하 및 관절내 주사/주입을 포함하는 투여 형식을 지칭한다.The pharmaceutical composition of the present invention can be administered to humans and other animals by any suitable route. For example, the composition can be administered orally, rectally, parenterally, intracranially, intravaginally, intraperitoneally, topically (by powder, ointment, drops), orally, nasal. "Parenteral" administration herein refers to a dosage form that includes intravenous, intraarterial, intramuscular, intraperitoneal, intrasternal, intravesicular, subcutaneous and intraarticular injection / injection.

비경구적으로 주사하기 위한 본 발명의 약학적 조성물은 약학적으로 허용가능한 멸균 수용액 또는 비수용액, 분산액, 서스펜젼 또는 에멀젼 뿐만아니라, 사용직전에 멸균 주사 용액 또는 분산액으로 재구성하기 위한 멸균 분말을 포함한다. 적절한 수성 및 비수성 캐리어, 희석제, 용매 또는 부형제의 예는 물, 에탄올, 폴리올(예, 글리세롤, 프로필렌, 글리콜, 폴리에틸렌 글리콜 등), 이들의 적절한 혼합물, 식물유(예, 올리브유) 및 주사가능한 유기 에스테르(예, 에틸 올레이트)를 포함한다. 레시틴 같은 피복 물질의 사용, 분산의 경우 필요한 입자 크기의 유지 및 계면활성제의 사용에 의해 적당한 유동성을 유지시킬 수 있다.Pharmaceutical compositions of the present invention for parenteral injection include pharmaceutically acceptable sterile aqueous solutions or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution with sterile injectable solutions or dispersions immediately prior to use. do. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (e.g. glycerol, propylene, glycols, polyethylene glycols, etc.), suitable mixtures thereof, vegetable oils (e.g. olive oil) and injectable organic esters. (Eg ethyl oleate). Proper fluidity can be maintained by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

또한, 본 발명의 조성물은 보존제, 습윤제, 에멀젼화제 및 분산제와 같은 보강제를 함유할 수 있다. 각종 항균제 및 항진균제(예, 파라벤, 클로로부탄올, 페놀 소르브산 등)를 함유시킴으로써 미생물의 활동을 예방할 수 있다. 또한, 등장제(예, 설탕, 염화나트륨 등)를 포함하는 것이 바람직할 수 있다. 알루미늄 모노스테아레이트 및 젤라틴 같이 흡수를 지연시키는 제제를 함유시킴으로써 주사가능한 약학적 형태의 흡수를 연장시킬 수 있다.In addition, the compositions of the present invention may contain reinforcing agents such as preservatives, wetting agents, emulsifiers and dispersants. By containing various antibacterial and antifungal agents (eg, parabens, chlorobutanol, phenol sorbic acid, etc.), the activity of microorganisms can be prevented. It may also be desirable to include isotonic agents (eg, sugars, sodium chloride, and the like). By incorporating agents that delay absorption, such as aluminum monostearate and gelatin, the absorption of injectable pharmaceutical forms can be extended.

몇몇 경우, 약물의 효과를 연장시키기 위해, 피하주사 또는 근육내주사로부터 약물의 흡수를 느리게 하는 것이 바람직할 수 있다. 이는 낮은 수용성을 갖는 결정질 또는 무정형 물질의 액상 서스펜젼을 사용함으로써 달성될 수 있다. 이어서, 약물의 흡수 속도는 차례로 결정 크기 및 결정질 형태에 좌우될 수 있는 분해 속도에 달려있다. 대안으로, 오일 부형제 내에 약물을 용해 또는 현탁시킴으로써 비경구적으로 투여된 약물 흡수를 지연시킬 수 있다.In some cases, to prolong the effect of the drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with low water solubility. The rate of absorption of the drug then depends on its rate of degradation, which in turn may depend on crystal size and crystalline form. Alternatively, parenteral administration of drug absorption can be delayed by dissolving or suspending the drug in an oil excipient.

생체분해가능한 폴리머(예, 폴리액티드-폴리콜리드) 내에 약물의 미세캡슐화 매트릭스를 형성시킴으로써, 주사가능한 저류물 형태를 제조한다. 약물 대 폴리머의 비율 및 사용되는 특정 폴리머의 특성에 따라, 약물 방출 속도를 제어할 수 있다. 기타 생체분해가능한 폴리머의 예에는 폴리(오르토에스테르) 및 폴리(안히드리드)를 포함한다. 저류물 주사 제제는 신체 조직과 상용성 있는 리포좀 또는 마이크로에멀젼 내에 약물을 포획함으로써 제조된다.Injectable retention forms are prepared by forming microencapsulated matrices of the drug in biodegradable polymers (eg, polyacted-polycolide). Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Retention injection preparations are prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

주사 제제는 세균 또는 바이러스 보유 필터를 통해 여과시키거나 사용직전에 멸균수 또는 기타 멸균 주사 매질 내 용해 또는 분산시킬 수 있는 멸균 고형 조성물의 형태로 멸균제를 혼입시킴으로써 멸균될 수 있다.Injectable formulations can be sterilized by filtration through a bacterial or viral retention filter or by incorporation of the sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection media immediately before use.

경구 투여의 고형 복용 형식은 캡슐, 정제, 알약, 분말 및 과립을 포함한다. 이러한 고형 복용 형식에서, 활성 화합물은 하나이상의 불활성 약학적 허용 부형제 또는 캐리어(나트륨 시트레이트 또는 인산이칼슘 및/또는 (a) 충전재 또는 증량제(예, 전분, 락토즈, 수크로즈, 글루코즈, 만니톨 및 실릭산, (b) 결합제(예, 카르복시메틸셀룰로즈, 검(예, 알지네이트, 아카시아) 젤라틴, 폴리비닐피롤리돈 및 수크로즈), (c) 습윤제(humectant, 예, 글리세롤), (d) 붕해제(예, 아가-아가, 탄산칼슘, 감자 또는 타피오카 전분, 알긴산, 몇몇 실리케이트 및 탄산나트륨, (e) 용액 지연제(예, 파라핀), (f) 흡수가속제(예, 4차 암모늄 화합물), (g) 습윤제(wetting agent, 예, 세틸 알콜 및 글리세롤 모노스테아레이트), (h) 흡수제(예, 카올린 및 벤토나이트 점토) 및 (i) 윤활제(예, 탈크, 칼슘 스테아레이트, 마그네슘 스테아레이트, 고체 폴리에틸렌 글리콜, 나트륨 라우릴 설페이트 및 이들의 혼합물)와 함께 혼합된다. 캡슐, 정제 및 알약에서, 복용형식은 또한 완충제를 함유할 수 있다.Solid dosage forms of oral administration include capsules, tablets, pills, powders, and granules. In this solid dosage form, the active compound is selected from one or more inert pharmaceutically acceptable excipients or carriers (sodium citrate or dicalcium phosphate and / or (a) fillers or extenders (e.g. starch, lactose, sucrose, glucose, mannitol and Silicic acid, (b) binder (e.g. carboxymethylcellulose, gum (e.g. alginate, acacia) gelatin, polyvinylpyrrolidone and sucrose), (c) humectant (e.g. glycerol), (d) boron Release (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, (e) solution retardants (e.g. paraffin), (f) absorption accelerators (e.g. quaternary ammonium compounds), (g) wetting agents (e.g. cetyl alcohol and glycerol monostearate), (h) absorbents (e.g. kaolin and bentonite clay) and (i) lubricants (e.g. talc, calcium stearate, magnesium stearate, solids) Polyethylene glycol, sodium Us, it is mixed with a sulfate, and mixtures thereof). In capsules, tablets and pills, dose form may also contain buffering agents.

또한, 유사한 유형의 고형 조성물은 락토즈 또는 우유당과 같은 부형제뿐만아니라 고분자량 폴레에틸렌 글리콜 등을 사용함으로써 연질 및 경질-충전된 젤라틴 캡슐 내 충전재로 사용될 수 있다.Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules by using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

정제, 드라제, 캡슐, 알약 및 과립의 고형 복용 형식은 약학 제제 업계에 잘 알려진 장 피막 및 기타 피막과 같은 피막 및 쉘로 제조될 수 있다. 이들은 선택적으로 불투명제를 함유할 수 있으며, 또한 장관의 일부에서, 선택적으로 서방형으로, 오직 활성 성분만을 또는 활성 성분을 우선적으로 방출하는 조성물일 수 있다. 전형적인 물질은 pH 민감성 용해성을 갖는 폴리머 물질(예, Eudragit 상표명으로 구입가능한 물질)을 포함한다. 사용될 수 있는 충전 조성물의 예는 폴리머 물질 및 왁스를 포함한다.Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric and other coatings well known in the pharmaceutical formulation art. They may optionally contain an opaque agent and may also be in some parts of the intestine, optionally in a sustained release, composition which releases only the active ingredient or preferentially releases the active ingredient. Typical materials include polymeric materials having pH sensitive solubility (eg, materials available under the Eudragit trade name). Examples of fill compositions that can be used include polymeric substances and waxes.

또한, 활성 화합물은, 적절한 경우 하나 이상의 상기 부형제를 갖는 마이크로캡슐화 형식일 수 있다.The active compound may also be in microencapsulated form with one or more such excipients as appropriate.

경구 투여용 액상 복용 형식은 약학적 허용 에멀젼, 용액, 서스펜젼, 시럽 및 엘릭서를 포함한다. 활성 화합물에 부가하여, 액상 복용 형식은 당업계에 통상 사용되는 불활성 희석제(예, 물, 기타 용매), 용매화제 및 에멀젼화제(예, 에틸 알콜, 이소프로필 알콜, 에틸 카보네이트, 에틸 아세테이트, 벤질 알콜, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸렌 글리콜, 디메틸 포름아미드, 오일(특히, 면실, 그라운넛(groundnut), 옥수수, 씨, 올리브, 캐스토르 및 참깨유), 글리세롤, 테트라히드로퍼푸릴 알콜, 폴리에틸렌 글리콜 및 소르비탄의 지방산 에스테르, 및 이들의 혼합물)을 함유할 수 있다.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms are inert diluents (e.g. water, other solvents), solvating and emulsifying agents (e.g. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol) commonly used in the art. , Benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (especially cottonseed, groundnut, corn, seed, olive, castor and sesame oil), glycerol, tetrahydrofur Fatty acid esters of furyl alcohol, polyethylene glycol and sorbitan, and mixtures thereof).

불활성 희석제 외에, 경구 조성물은 또한 습윤제, 에멀젼화제 및 서스펜젼화제, 감미료, 향신료 및 향료제와 같은 보강제를 포함할 수 있다.In addition to inert diluents, oral compositions may also include adjuvant such as wetting agents, emulsifying and suspending agents, sweeteners, spices and flavoring agents.

활성 성분 외에 서스펜젼은 에톡실화된 이소스테아릴 알콜, 폴리옥시에틸렌 소르비톨 및 소르비탄 에스테르, 미세결정질 셀룰로오즈, 알루미늄 메타히드록사이드, 벤토나이트, 아가-아가 및 트래거캔스, 및 이들의 혼합물 같은 현탁제를 함유할 수 있다.In addition to the active ingredient, the suspension may be suspended such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof It may contain an agent.

직장 또는 질 투여용 조성물은 본 발명의 화합물을 적당한 비자극성 부형제 또는 캐리어(예, 코코아 버터, 폴리에틸렌 글리콜 또는 또는 좌약 왁스)와 혼합함으로써 준비될 수 있는 좌약이 바람직하며, 상기 부형제 또는 캐리어는 실온에서 고형이나 신체온도에서 액상인 것으로 직장 또는 질 공동에서 용해되어 활성 성분을 방출한다.Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol or suppository wax), wherein the excipient or carrier is at room temperature Liquid at solid or body temperature, dissolved in the rectum or vaginal cavity to release the active ingredient.

또한, 본 발명의 화합물은 리포좀의 형식으로 투여될 수 있다. 당업계에 알려진 바와 같이, 리포좀은 통상 인지질 또는 기타 지질 물질로부터 유도된다. 수성 매질에 분산되어 있는 단일- 또는 다중-라멜라 수화된 액상 결정에 의해 형성된다. 임의의 비독성, 생리학적으로 허용가능하고 대사가능한 지질로서 리포좀을 형성할 수 있는 것을 사용할 수 있다. 리포좀 형식의 본 발명의 조성물은, 본 발명의 화합물 외에, 안정화제, 보존제, 부형제 등을 함유할 수 있다. 바람직한 지질은 인지질 및 포스파티딜 콜린(레시틴)이며, 천연 지질 또는 합성 지질일 수 있다. 리포좀을 형성시키는 방법은 당업계에 잘 알려져 있다. 문헌[Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p33 et seq]을 참조하라.In addition, the compounds of the present invention may be administered in the form of liposomes. As known in the art, liposomes are usually derived from phospholipids or other lipid substances. It is formed by single- or multi-lamellae hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid can be used that can form liposomes. The composition of the present invention in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are phospholipids and phosphatidyl choline (lecithin) and can be natural or synthetic lipids. Methods of forming liposomes are well known in the art. See Prescott, Ed., Methods in Cell Biology , Volume XIV, Academic Press, New York, NY (1976), p33 et seq.

본 발명의 화합물은 무기산 또는 유기산 유래의 약학적 허용염의 형식으로 사용될 수 있다. "약학적 허용염"은 의약적 판단의 범위 내에서 사람의 조직 및 하등 동물과 접촉시 과도한 독성, 과민상태, 알러지성 반응 등 없이 사용하기에 적절하고 적절한 잇점/위험 비율로 균형잡힌 염을 의미한다. 약학적 허용염은 당업계에 잘 알려져 있다. 예컨대, 문헌[S.M.Berge,et al., J. Pharmaceutical Science, 66:1(1977)]에는 약학적 허용염이 자세히 설명되어 있다. 염은 본 발명의 화합물을 최종 분리 및 정제하는 동안 바로 그자리에서 제조될 수 있거나, 적절한 산과 유리 염기 작용을 반응시킴으로써 별개로 제조될 수 있다. 대표적인 산 부가 염은 비제한적으로 아세테이트, 아디페이트, 알지네이트, 시트레이트, 아스파르테이트, 벤조에이트, 벤젠설포네이트, 비설페이트, 부티레이트, 캠포레이트, 캠포로설포네이트, 디글루코네이트, 글리세로포스페이트, 헤미설페이트, 헵타노에이트, 헥사노에이트, 푸마레이트 히드로클로라이드, 히드로브로마이드, 히드로아이오다이드, 2-히드록시에탄설포네이트(이소티오네이트), 락테이트, 말리에이트, 메탄설포네이트, 니코티네이트, 2-나프탈렌설포네이트, 옥살레이트, 파모에이트, 펙티네이트, 퍼설페이트, 3-페닐프로피오네이트, 피크레이트, 피발레이트, 프로피오네이트, 숙시네이트, 타르트레이트, 티오시아네이트, 포스페이트, 글루타메이트, 비카르보네이트, p-톨로엔설포네이트 및 운데카노에이트를 포함한다. 약학적 허용 산 부가 염을 형성하는데 사용될 수 있는 산의 예에는 염산, 브롬화수소산, 황산 및 인산과 같은 무기산 및 옥살산, 말레산, 숙신산 및 시트르산과 같은 유기산을 포함한다.The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. "Pharmaceutically acceptable salts" means salts that are balanced at an appropriate and appropriate benefit / risk ratio for use without undue toxicity, hypersensitivity, allergic reactions, etc., in contact with human tissues and lower animals within the scope of medicinal judgments. do. Pharmaceutically acceptable salts are well known in the art. For example, SMBerge, et al., J. Pharmaceutical Science, 66 : 1 (1977) describe pharmaceutically acceptable salts in detail. Salts may be prepared in situ during the final separation and purification of the compounds of the present invention or may be prepared separately by reacting the free acid with the appropriate acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camporosulfonate, digluconate, glycerophosphate, Hemisulfate, heptanoate, hexanoate, fumarate hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate , 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, Bicarbonate, p-toloenesulfonate and undecanoate. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid.

염기성 질소-함유 기는 메틸, 에틸, 프로필 및 부틸 클로라이드, 브로마이드, 및 요오다이드와 같은 저급 알킬 할로겐화물; 디메틸, 디에틸, 디부틸 및 디아밀 설페이트와 같은 디알킬 설페이트; 데실, 라우릴, 미리스틸 및 스테아릴 클로라이드, 브로마이드 및 아이오다이드 같은 장쇄 할로겐화물; 벤질 및 페네틸 브로마니드와 같은 아릴알킬 할로겐화물 등과 같은 화학제로 사차화(quaternized)된다. 이로인해 물 또는 오일-가용성 또는 분산성 생성물이 수득된다.Basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide, and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; Quaternized with chemical agents such as arylalkyl halides such as benzyl and phenethyl bromanide. This gives water or oil-soluble or dispersible products.

염기성 부가 염은 약학적 허용 금속 양이온의 수산화물, 탄산염 또는 중탄산염 같은 적절한 염기와, 또는 암모니아 또는 유기 제1차, 제2차 또는 제3차 아민과 카르복실산 함유 부분을 반응시킴으로써 본 발명의 화합물을 최종 분리 및 정제하는 동안 바로 그 자리에서 제조할 수 있다. 약학적 허용 염기 부가 염은 비제한적으로 알칼리 금속 또는 알칼리 토금속(예, 리듐, 나트륨, 칼륨, 칼슘, 마그네슘 및 알루미늄 염 등)계 양이온, 비독성 제3차 암모니아 및 아민 양이온(예, 암모늄, 테트라메틸암모늄, 테트라에틸암모늄, 메틸아민, 디메틸아민, 트리메틸아민, 트리에틸아민, 디에틸아민, 에틸아민 등)을 포함한다. 염기 부가 염을 형성하는데 유용한 기타 대표적인 유기 아민은 에틸렌디아민, 에탄올아민, 디에탄올아민, 피페리딘, 피페라진 등을 포함한다.The basic addition salts react the compounds of the present invention by reacting a suitable base such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine and a carboxylic acid containing moiety. It can be prepared in situ during final separation and purification. Pharmaceutically acceptable base addition salts include, but are not limited to, alkali metal or alkaline earth metal (eg, lithium, sodium, potassium, calcium, magnesium, and aluminum salts) cations, non-toxic tertiary ammonia and amine cations (eg ammonium, tetra Methylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like). Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

본 발명의 화합물의 국부적 투여용 복용 형식은 분말, 스프레이, 연고, 흡입제를 포함한다. 활성 화합물은 멸균 조건하에 약학적 허용 캐리어 및 임의의 필요한 보존제, 완충제, 또는 필요할 수 있는 분사제와 혼합된다. 안과용 제제, 눈 연고, 분말 및 용액도 본 발명의 범위에 포함된다.Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments, inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants that may be necessary. Ophthalmic formulations, eye ointments, powders and solutions are also included within the scope of the present invention.

본 발명의 약학적 조성물 내에서 활성 성분의 실질적인 용량 수준은 특정 환자의 바람직한 치료적 반응을 얻는데 유효한 활성 성분의 함유량, 조성 및 투여 방식을 얻기 위해 다양할 수 있다. 선택된 용량 수준은 특정 화합물의 활성, 투여 경로, 치료하고자 하는 상태의 심각성 및 치료대상의 환자의 상태 및 이전 병력에 좌우될 것이다. 그러나, 당업자는 원하는 치료 효과를 얻기 위해 필요한 것보다 더 낮은 수준으로 화합물 복용을 시작하여 원하는 효과가 달성될 때까지 점차적으로 증가시킬 수 있다.Substantial dosage levels of the active ingredient in the pharmaceutical compositions of the present invention may vary to obtain the content, composition and mode of administration of the active ingredient effective to achieve the desired therapeutic response of a particular patient. The dose level chosen will depend on the activity of the particular compound, the route of administration, the severity of the condition to be treated and the condition and previous history of the patient to be treated. However, one skilled in the art can start taking the compound at a lower level than necessary to achieve the desired therapeutic effect and gradually increase until the desired effect is achieved.

일반적으로, 하루에 체중 1kg 당 활성 화합물을 약 0.1 내지 약 1000mg, 약 0.5 내지 약 500mg, 약 1 내지 약 250mg, 약 1.5 내지 약 100mg, 바람직하게는 약 5 내지 약 20mg의 복용 수준으로 포유류 환자에게 경구적으로 또는 정맥주사로 투여한다. 원하는 경우, 유효한 일일 용량은 투여 목적으로 다수의 용량(예, 일일 2 내지 4개로 분리된 용량)으로 분배될 수 있다.In general, a mammalian patient is administered at a dosage level of about 0.1 to about 1000 mg, about 0.5 to about 500 mg, about 1 to about 250 mg, about 1.5 to about 100 mg, preferably about 5 to about 20 mg of active compound per kg of body weight per day. It is administered orally or intravenously. If desired, the effective daily dose may be divided into multiple doses (eg, divided into two to four daily doses) for administration purposes.

하기 실시예에 의해 본 발명을 설명한다. 실시예 1은 LFA-1에 결합하는 ICAM와의 LFA-1 결합의 음성 조절인자를 스크린하는 고효율 분석법을 설명하였다. 실시예 2는 ICAM와의 LFA-1 결합을 저해하는 각종 화합물의 능력을 평가하는 결합 분석법에 관한 것이다. 실시예 3은 음성 조절인자의 합성법을 기재하고 있다. 실시예 4는 음성 조절인자를 사용하여 세포를 기초로 한 분석법으로부터 나온 결과를 제공한다.The invention is illustrated by the following examples. Example 1 described a high efficiency assay for screening negative regulators of LFA-1 binding with ICAMs that bind to LFA-1. Example 2 relates to binding assays that assess the ability of various compounds to inhibit LFA-1 binding with ICAM. Example 3 describes the synthesis of negative regulators. Example 4 provides results from cell based assays using negative regulators.

실시예 1: LFA-1/ICAM 결합 저해제를 찾기 위한 고효율 스크리닝Example 1 High Efficiency Screening to Find LFA-1 / ICAM Binding Inhibitors

LFA-1/ICAM-1 결합의 제해제를 동정하고자, 고효율 스크리닝(HTS) 분석법을고안하여 하기와 같이 독점적인 라이브러리에서 다수의 화학 화합물을 효율적으로 스크린하였다.To identify inhibitors of LFA-1 / ICAM-1 binding, high efficiency screening (HTS) assays were devised to efficiently screen multiple chemical compounds in proprietary libraries as follows.

LFA-1/ICAM-1 상호작용의 직선적인 범위를 정의하기 위해 초기 실험을 수행하였다. 미국특허 제5,770,686호, 제5,837,478호 및 5,869,262호(이들 각각은 본 명세서에 인용됨)에 기재된 바와 같이, 재조합 ICAM-1/IgG1 융합 단백질(전장 ICAM-1을 포함)을 제조하였다. 피어스 케미칼(Rockford, IL)에서 구입한 키트를 사용하여 융합 단백질을 비오틴화하였다. 280nm의 흡광도를 측정함으로써 비오틴화된 단백질(BioIgICAM-1) 농도를 결정하고, 순차적인 희석액을 제조하여 최종 농도 범위가 50㎍/ml 내지 0.008㎍/ml가 되도록 하였다. 분석 플레이트 상의 웰 안으로 최초로 분취된 단백질로 BioIgICAM-1을 적정하였다.재조합 LFA-1를 각 웰에 동일 농도로 첨가하고, 실험(하기 기술됨)을 완성하였다. 결합량을 각 웰에 대하여 측정하고, 이어서 결과들을 그래프화한 것으로부터 단일 농도의 BioIgICAM-1을 차후 실험을 위해 선택하였다. 유사한 방법으로, 상기와 같이 선택된 BioIgICAM-1 농도를 사용하여 LFA-1을 적정하였다.Initial experiments were conducted to define a linear range of LFA-1 / ICAM-1 interactions. Recombinant ICAM-1 / IgG1 fusion proteins (including full length ICAM-1) were prepared as described in US Pat. Nos. 5,770,686, 5,837,478 and 5,869,262, each of which is incorporated herein. The fusion protein was biotinylated using a kit purchased from Pierce Chemical (Rockford, IL). By measuring the absorbance at 280 nm, the biotinylated protein (BioIgICAM-1) concentration was determined and sequential dilutions were prepared to give a final concentration range of 50 μg / ml to 0.008 μg / ml. BioIgICAM-1 was titrated with the protein first aliquoted into the wells on the assay plate. Recombinant LFA-1 was added to each well at the same concentration and the experiment (described below) was completed. The amount of binding was measured for each well, and then a single concentration of BioIgICAM-1 was selected for subsequent experiments from graphing the results. In a similar manner, LFA-1 was titrated using the BioIgICAM-1 concentration selected as above.

HTS 절차 1일째, 포획 항체, 즉 비차단 항-LFA-1 단클론성 항체(TS2/4.1;ATCC #HB244)를 플레이트 피복 완충액(50mM 탄산나트륨/중탄산염, 0.05% ProClinR300, pH 9.6)에서 희석하여 최종농도가 2㎍/ml이 되게 하였다. ImmulonR4(Dynex Technologies, Chantilly, VA) 플레이트 웰을 각 웰당 100㎕ 희석 항체 용액으로 피복하고, 4℃에서 밤새도록 항온처리하였다. 2일째, 플레이트를 실온으로 가온하고 세척 완충액(0.05% Tween-20R을 함유하며 칼슘 및 마그네슘이 없는 인산 완충 식염수)로 2번 세척하였다. 각 웰에 200㎕의 차단 용액(0.05% ProClinR300를 함유하는 CMF-PBS 중 5% 어류 외피 젤라틴)을 첨가하고, 차단 항온처리를 실온에서 30분간 수행하였다. 차단 용액을 흡입에 의해 제거하고, 플레이트는 세척하지 않았다. LFA-1를 희석하여 분석 완충액(CMF-PBS 중 1% 어류 외피 젤라틴 및 2mM MgCl2) 내 최종 농도를 1㎍/㎖로 만들었으며, 100㎕를 각 웰에 첨가하였다. 1시간 동안 항온처리하였으며 플레이트를 세척 완충액으로 2번 세척하였다.On day 1 of the HTS procedure, the capture antibody, ie, the non-blocking anti-LFA-1 monoclonal antibody (TS2 / 4.1; ATCC # HB244), was diluted in plate coating buffer (50 mM sodium carbonate / bicarbonate, 0.05% ProClin R 300, pH 9.6) The final concentration was 2 μg / ml. Immulon R 4 (Dynex Technologies, Chantilly, VA) plate wells were coated with 100 μl diluted antibody solution per well and incubated overnight at 4 ° C. On day 2, the plates were warmed to room temperature and washed twice with wash buffer (phosphate buffered saline containing 0.05% Tween-20 R and free of calcium and magnesium). 200 μl of blocking solution (5% fish shell gelatin in CMF-PBS containing 0.05% ProClin R 300) was added to each well, and blocking incubation was performed for 30 minutes at room temperature. The blocking solution was removed by suction and the plates were not washed. LFA-1 was diluted to make a final concentration of 1 μg / ml in assay buffer (1% fish envelope gelatin and 2 mM MgCl 2 in CMF-PBS) and 100 μl was added to each well. Incubated for 1 hour and plates were washed twice with wash buffer.

분석 완충액 내(EG&G Wallac, Gaithersburg, MD) 0.1㎍/㎖의 BioIgICAM-1과 4μM 크리스탈 바이올렛(LFA-1/ICAM-1 결합의 활성화제로 밝혀짐)을 함유한 BioIgICAM-1의 2X 공급 용액을 제조하였다. 화학물질 라이브러리로부터 수집한 화학물질(22개의 화합물/100% DMSO 중 풀)의 분취액(50㎕)을 웰에 첨가하고, BioIgICAM-1의 2X 공급 용액을 첨가하여, 최종 분석 부피를 100㎕(2% DMSO 함유)로 제공하였다. 플레이트를 1시간동안 실온에서 항온처리하고, 세척 완충액으로 한번 세척하였다. Europium-표지된 스트렙타비딘(Eu-SA; #1244-360, EG&G Wallac)을 분석 완충액에서 1:500로 희석하고, 희석된 Eu-SA 100㎕을 각 웰에 첨가하고 플레이트를 실온에서 1시간 동안 항온처리하였다.Prepare a 2X feed solution of BioIgICAM-1 containing 0.1 μg / ml BioIgICAM-1 and 4 μM crystal violet (found as activator of LFA-1 / ICAM-1 binding) in assay buffer (EG & G Wallac, Gaithersburg, MD) It was. An aliquot (50 μl) of the chemical (pool in 22 compounds / 100% DMSO) collected from the chemical library was added to the wells and a 2 × feed solution of BioIgICAM-1 was added to give a final assay volume of 100 μl ( 2% DMSO). Plates were incubated for 1 hour at room temperature and washed once with wash buffer. Dilute Europium-labeled streptavidin (Eu-SA; # 1244-360, EG & G Wallac) 1: 500 in assay buffer, add 100 μl of diluted Eu-SA to each well and plate for 1 hour at room temperature Incubated for 2 hours.

플레이트를 세척 완충액으로 8번 세척하고, 1:2로 희석한 DELFIAR강화 용액(EG&G Wallac) 100㎕을 각 웰에 첨가하고, 고속으로 Wallac 진탕기를 사용하여5분간 진탕하였다. Wallac DELFIAR형광 판독기(형광계측기)를 사용하여 플레이트를 판독하였다. 대조군은 양성 웰 및 음성 웰 모두, 차단 항체, 즉 항-LFA-1 단클론성 항체(TS1/22.1, ATCC#HB202) 또는 항-ICAM-1 단클론성 항체를 사용하여 확립된 50% 결합 웰을 포함한다. ICAM-1과의 LFA-1 결합을 50% 이상 저해하는 웰 내 화합물질 풀을 동정하였으며 이 풀로부터 개별적인 화학물질을 사용하여 실험을 반복하였다. LFA-1/ICAM-1 결합의 저해제를 동정하고 더 스크린하여 저해 활성의 용량 의존도를 측정하였다. 선별된 화합물에 대해 생화학적 분석 기법 및 세포 분석 기법을 사용하여 더 연구하였다.Plates were washed eight times with wash buffer, 100 μl of DELFIA R enriched solution (EG & G Wallac) diluted 1: 2 was added to each well and shaken for 5 minutes using a Wallac shaker at high speed. Plates were read using a Wallac DELFIA R fluorescence reader (fluorometer). Controls include 50% binding wells established with both positive and negative wells, blocking antibodies, ie anti-LFA-1 monoclonal antibody (TS1 / 22.1, ATCC # HB202) or anti-ICAM-1 monoclonal antibody do. Compound pools in wells that inhibited at least 50% LFA-1 binding to ICAM-1 were identified and the experiment repeated using individual chemicals from this pool. Inhibitors of LFA-1 / ICAM-1 binding were identified and further screened to determine dose dependence of inhibitory activity. Selected compounds were further studied using biochemical and cellular assay techniques.

공통된 구조 특성에 따라 화합물을 그룹으로 나누었으며, (하기 나열된) 화합물의 서브세트가 특징적인 디아릴 설파이드 구조를 포함하는 것으로 나타났다.Compounds were grouped according to common structural properties, and subsets of compounds (listed below) were found to contain characteristic diaryl sulfide structures.

3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine

1-(3-니트로-4-페닐설파닐-페닐)-에타논1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone

1-(3-니트로-4-페닐설파닐-페닐)-에타논 옥심1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone oxime

5-트리플루오로메틸-2-페닐설파닐-벤조니트릴5-trifluoromethyl-2-phenylsulfanyl-benzonitrile

1-(3,5-디클로로페닐)-3-페닐설파닐-피롤리딘-2,5-디온1- (3,5-Dichlorophenyl) -3-phenylsulfanyl-pyrrolidine-2,5-dione

비스-2,4,6-트리니트로페닐-설파이드Bis-2,4,6-trinitrophenyl-sulfide

2-메틸-1-(2-o-토일설파닐-페닐)-1H-피롤2-methyl-1- (2-o-toylsulfanyl-phenyl) -1H-pyrrole

3-[2-(4-클로로-2-니트로-페닐설파닐)-페닐아미노-3H-이소벤조푸란-1-온3- [2- (4-chloro-2-nitro-phenylsulfanyl) -phenylamino-3H-isobenzofuran-1-one

4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine

2-니트로-4-클로로페닐-(2'아미노페닐)-설파이드2-nitro-4-chlorophenyl- (2'aminophenyl) -sulfide

6-아미노-2-클로로페닐-(4'-메틸페닐)-설파이드6-Amino-2-chlorophenyl- (4'-methylphenyl) -sulfide

4-니트로페닐-(2'-클로로페닐)-설파이드4-nitrophenyl- (2'-chlorophenyl) -sulfide

2,4-디니트로페닐-(4'-클로로페닐)-설파이드2,4-dinitrophenyl- (4'-chlorophenyl) -sulfide

4-아미노페닐-(2'-클로로페닐)-설파이드4-Aminophenyl- (2'-chlorophenyl) -sulfide

2,4-디아미노페닐-(4'-이소프로필페닐)-설파이드2,4-diaminophenyl- (4'-isopropylphenyl) -sulfide

확인된 화합물의 음성 조절 능력을 적정화하고자, 각종 디아릴 설파이드 유도체를 하기 실시예 3에 기재한 바와 같이 처리하였다. 부가적인 디아릴 설파이드 유도체는 함께 계류 중이며 1999. 4. 2. 출원된 부분 특허 출원 "Cell Adhesion-Inhibiting Antiinflammatory and Immune Suppressive Compounds"(대리인 명부 번호 6446.US.Z3, 일련번호 09/286,645, 본 명세서에 인용되어 있음)에 기재되어 있다.In order to optimize the negative control ability of the identified compounds, various diaryl sulfide derivatives were treated as described in Example 3 below. Additional diaryl sulfide derivatives are pending together with the partial patent application filed on April 2, 1999 "Cell Adhesion-Inhibiting Antiinflammatory and Immune Suppressive Compounds" (Agent No. 6446.US.Z3, Serial No. 09 / 286,645, herein Cited therein).

실시예 2Example 2

결합 분석Binding analysis

A. ICAM-1/LFA-1 생화학적 상호작용 분석A. ICAM-1 / LFA-1 Biochemical Interaction Analysis

생화학적 분석 및 세포에 기초한 분석 모두를 사용하여 ICAM-1과 LFA-1 간의 상호작용에 대해 길항작용을 하는 화합물들을 동정할 수 있으며 이들의 활성을 정량화할 수 있다. 일차 생화학적 분석은 당해 화합물이 하기 기술된 바와 같이 LFA-1과 그의 접착 파트너인 ICAM-1 사이의 상호작용을 차단하는 능력을 측정한다.Both biochemical and cell-based assays can be used to identify compounds that antagonize the interaction between ICAM-1 and LFA-1 and to quantify their activity. Primary biochemical assays measure the ability of a compound to block the interaction between LFA-1 and its adhesion partner ICAM-1 as described below.

이러한 생화학적 분석에서, 둘베코 인산 완충 식염수(D-PBS) 중 5㎍/㎖와 결합한 항-LFA-1 항체 100㎕을 사용하여 96-웰 미세역가 플레이트의 웰들을 밤새도록4℃에서 피복하였다. 웰들을 세척 완충액(CMF-PBS, 0.05% TweenR20)으로 2번 세척하고, 5% 어류 외피 젤라틴을 함유한 D-PBS 200㎕를 첨가하여 차단시켰다. D-PBS 중 재조합 LFA-1(0.7㎍/㎖, 100㎕)을 각 웰에 첨가하였다. 실온에서 1시간동안 항온처리를 계속하고 웰을 세척 완충액으로 2번 세척하였다. DMSO 중 10mM 공급 용액으로 제조된 LFA-1/ICAM-1 음성 조절인자로서 분석할 화합물의 순차적인 희석액을 D-PBS에서 희석하고, 2mM MgCl2, 1% 어류 외피 젤라틴 및 각 희석액 500㎕을 각 웰에 첨가한 후, 0.8㎍/㎖ BioIgICAM-1 50㎕을 웰에 첨가하고, 플레이트를 상온에서 1시간 동안 항온처리하였다. 이어서, 웰을 세척 완충액으로 2번 세척하고 DelfiaR분석 완충액(EG&G Wallac)에서 1:100로 희석한 Eu-SA(EG&G Wallac) 100㎕을 웰에 첨가하였다. 실온에서 1시간동안 항온처리하였다. 웰을 세척 완충액으로 8번 세척하고, 강화 용액(EG&G Wallac) 100㎕을 각 웰에 첨가하였다. 지속적으로 혼합하면서 항온처리를 5분동안 계속하였다. Victor 1420 Multilabel Counter(EG&G Wallac)를 사용하여 시간-소산된 형광측정(time-resolved fluorimetry)을 하였고, 각 후보 화합물의 퍼센트 저해를 하기 식을 이용하여 계산하였다.In this biochemical assay, wells of 96-well microtiter plates were coated overnight at 4 ° C. using 100 μl of anti-LFA-1 antibody bound to 5 μg / ml in Dulbecco's Phosphate Buffered Saline (D-PBS). . Wells were washed twice with wash buffer (CMF-PBS, 0.05% Tween R 20) and blocked by adding 200 μl of D-PBS containing 5% fish shell gelatin. Recombinant LFA-1 (0.7 μg / ml, 100 μl) in D-PBS was added to each well. Incubation was continued for 1 hour at room temperature and the wells were washed twice with wash buffer. As a LFA-1 / ICAM-1 negative regulator prepared as a 10 mM feed solution in DMSO, sequential dilutions of the compounds to be analyzed were diluted in D-PBS, 2 mM MgCl 2 , 1% fish shell gelatin and 500 μl of each dilution After addition to the wells, 50 μl of 0.8 μg / ml BioIgICAM-1 was added to the wells and the plates were incubated for 1 hour at room temperature. The wells were then washed twice with wash buffer and 100 μl of Eu-SA (EG & G Wallac) diluted 1: 100 in Delfia R assay buffer (EG & G Wallac) was added to the wells. Incubated at room temperature for 1 hour. Wells were washed eight times with wash buffer and 100 μl of enrichment solution (EG & G Wallac) was added to each well. Incubation was continued for 5 minutes with continuous mixing. Time-resolved fluorimetry was performed using Victor 1420 Multilabel Counter (EG & G Wallac), and the percent inhibition of each candidate compound was calculated using the following equation.

[식 1][Equation 1]

% 저해=100×{1-평균 OD w/화합물 마이너스 백그라운드/평균 OD w/o 화합물 마이너스 백그라운드} % Inhibition = 100 × { 1 - Mean OD w / compound negative background / Mean OD w / o compound minus background }

여기서 "백그라운드"는 항-LFA-1 항체로 피복되지 않은 웰을 지칭한다.“Background” herein refers to wells that are not coated with an anti-LFA-1 antibody.

B.B. ICAM-1/JY-8 세포 접착 분석ICAM-1 / JY-8 Cell Adhesion Assay

본 발명에서 화합물의 생물학적으로 관련있는 활성은, 화합물이 하기와 같이 고정화된 ICAM-1과의 JY-8세포(표면 상에서 LFA-1를 발현하는 사람 EBV-형질전환 B 세포주)의 점착을 차단하는 능력을 측정하는 세포-기초한 접착 분석을 사용하여 확인하였다. 이 분석은 첨가된 IL-8 존재 또는 부재하에 수행되었다. 표준 JY-8 세포를 IL-8 자극하기 위해, IL-8 30ng/㎖을 첨가하면서 세포와 30분동안 37℃에서 항온처리하였다.The biologically relevant activity of the compounds in the present invention is that the compounds block adhesion of JY-8 cells (human EBV-transformed B cell lines expressing LFA-1 on the surface) with immobilized ICAM-1 as follows: Confirmation was made using a cell-based adhesion assay to measure the ability. This assay was performed with or without added IL-8. To stimulate IL-8 of standard JY-8 cells, the cells were incubated at 37 ° C. for 30 minutes with addition of 30ng / ml IL-8.

세포-기초한 접착 분석에서 저해 활성을 측정하기 위해, 96-웰 미량 역가 플레이트를 4℃ 밤새도록 CMF-PBS 중 5㎍/㎖의 농도의 재조합 ICAM-1/Ig 70㎕로 피복하였다. D-PBS로 웰을 2번 세척하고, 실온에서 1시간동안 항온처리함으로써 D-PBS 200㎕, 5% 어류 외피 젤라틴을 첨가하여 차단하였다. 형광-태그 JY-8 세포(2×106세포 / RPMI-1640 중 ㎖ / 1% 태아 소 혈청(FBS) 50㎕)를 웰에 첨가하였다. JY-8 세포를 형광으로 표지하기 위해, RPMI 1640으로 한번 세척한 5×106세포를, 2μM Calcein AM(분자 프로브, OR)을 함유하는 RPMI-1640 1㎖로 재현탁시키고, 37℃에서 30분 동안 항온처리하고, RPMI-1640/ 1% FBS로 한번 세척하였다. LFA-1/ICAM-1 길항제 활성을 분석하고자 하는 화합물의 희석액을 DMSO 중 10mM 공급 용액으로부터 RPMI-1640/1% FBS에서 준비하고, 50㎕ 분취액을 2개로 만든 웰에 첨가하였다. 미량역가 플레이트를 45분 동안 실온에서 항온처리하고, RPMI-1640/1% FBS로 한번 온화하게 웰을 세척하였다. 형광 강도는 495 nm의 여기 파장 및 530 nm의 방사 파장으로 형광 플레이트 판독기에서 측정하였다. 주어진 농도에서 후보 화합물의 퍼센트 저해는 하기 식을 사용하여 계산하였다.To measure the inhibitory activity in cell-based adhesion assays, 96-well microtiter plates were coated with 70 μl of recombinant ICAM-1 / Ig at a concentration of 5 μg / ml in CMF-PBS overnight at 4 ° C. The wells were washed twice with D-PBS and incubated at room temperature for 1 hour to block by adding 200 μl of D-PBS, 5% fish shell gelatin. Fluorescence-tagged JY-8 cells (2 × 10 6 cells / 50 μL in RPMI-1640 / 1 μL fetal bovine serum (FBS)) were added to the wells. To fluoresce JY-8 cells, 5 × 10 6 cells washed once with RPMI 1640 were resuspended with 1 mL of RPMI-1640 containing 2 μM Calcein AM (Molecular Probe, OR) and 30 at 37 ° C. Incubate for minutes and wash once with RPMI-1640 / 1% FBS. Dilutions of the compounds to be analyzed for LFA-1 / ICAM-1 antagonist activity were prepared in RPMI-1640 / 1% FBS from a 10 mM feed solution in DMSO and 50 μl aliquots were added to two wells. Microtiter plates were incubated for 45 minutes at room temperature and the wells washed once gently with RPMI-1640 / 1% FBS. Fluorescence intensity was measured in a fluorescent plate reader with an excitation wavelength of 495 nm and an emission wavelength of 530 nm. Percent inhibition of candidate compounds at a given concentration was calculated using the following formula.

[식 2][Equation 2]

% 저해=100×{1-평균 OD w/화합물/평균 OD w/o 화합물} % Inhibition = 100 × { 1 - mean OD w / compound / mean OD w / o compound }

C.C. ICAM-3/JY-8 세포 접착 분석ICAM-3 / JY-8 Cell Adhesion Assay

본 발명의 화합물은 인테그린 LFA-1과의 상호작용을 통해 작용한다는 것을 밝혔으며, 특히 이러한 상호작용은 다양한 세포 접착 분자로의 LFA-1의 접착에 중요한 것으로 알려진 αLI 도메인과의 결합에 의한 것이다. 그것에 의해, 이들 화합물이 기타 CAM들과의 LFA-1의 상호작용을 차단한다고 예상되며, 이러한 저해는 ICAM-3와의 LFA-1 결합에 대해 확인되었다. 본 발명의 화합물은 하기와 같이 고정화된 ICAM-3에 JY-8 세포가 접착하는 것을 차단하는 능력으로 평가되었다.The compounds of the present invention have been shown to function through interactions with integrin LFA-1, in particular by interaction with α L I domains known to be important for the adhesion of LFA-1 to various cellular adhesion molecules. will be. Thereby, it is expected that these compounds block the interaction of LFA-1 with other CAMs, and this inhibition was confirmed for LFA-1 binding with ICAM-3. Compounds of the invention were evaluated for their ability to block the adhesion of JY-8 cells to immobilized ICAM-3 as follows.

세포-기초한 접착 분석에서 저해 활성을 측정하기 위해, 96-웰 미량역가 플레이트를 4℃ 밤새도록 CMF-PBS 중 10㎍/㎖ 농도의 재조합 ICAM-3/Ig 50㎕로 피복하였다. D-PBS로 웰을 2번 세척하고, 실온에서 1시간동안 항온처리함으로써 D-PBS 100㎕, 1% 소 혈청 알부민(BSA)을 첨가하여 차단하고, RPMI 1640/5% 열-불활성화된 FBS(접착 완충액)으로 한번 세척하였다. LFA-1/ICAM-3 길항제 활성을 분석하고자 하는 화합물의 희석액을 DMSO 중 10mM 공급 용액으로부터 접착 완충액에서 준비하고, 100㎕ 분취액을 2개로 만든 웰에 첨가하였다. 이어서, JY-8 세포 (0.75×106세포/접착 완충액 중 ㎖, 100㎕)를 웰에 (30ng/ml IL-8 존재 또는 부재하에) 첨가하였다. 미량역가 플레이트를 30분 동안 실온에서 항온처리하고, 부착해 있는 세포를14% 글루타르알데히드/D-PBS 50㎕로 고정시키고, 추가 90분동안 항온처리하였다. dH2O로 온화하게 웰을 세척하고, dH2O 50㎕를 첨가한 후 1% 크리스탈 바이올렛 50㎕를 첨가하였다. 5분 후, 플레이트를 dH2O로 2번 세척하고 에탄올 (EtOH) 225㎕를 각 웰에 첨가하여, 각 세포로부터 크리스탈 바이올렛을 추출하였다. 흡광도는 ELISA 플레이트 판독기로 570 nm에서 측정하였다. 후보 화합물의 퍼센트 저해는 하기 식을 사용하여 계산하였다.To measure the inhibitory activity in cell-based adhesion assays, 96-well microtiter plates were coated with 50 μl of recombinant ICAM-3 / Ig at a concentration of 10 μg / ml in CMF-PBS overnight at 4 ° C. Wash wells twice with D-PBS and incubate for 1 hour at room temperature by blocking addition of 100 μl D-PBS, 1% bovine serum albumin (BSA), RPMI 1640/5% heat-inactivated FBS Wash once with (adhesive buffer). Dilutions of the compounds to be analyzed for LFA-1 / ICAM-3 antagonist activity were prepared in adhesion buffer from a 10 mM feed solution in DMSO and 100 μl aliquots were added to two wells. JY-8 cells (ml in 0.75 × 10 6 cells / adhesion buffer, 100 μl) were then added to the wells (with or without 30ng / ml IL-8). Microtiter plates were incubated for 30 minutes at room temperature and adhered cells were fixed with 50 μl of 14% glutaraldehyde / D-PBS and incubated for an additional 90 minutes. gently washed well with dH 2 O, followed by addition of 1% crystal violet 50㎕ After addition of dH 2 O 50㎕. After 5 minutes, the plates were washed twice with dH 2 O and 225 μl of ethanol (EtOH) was added to each well to extract crystal violet from each cell. Absorbance was measured at 570 nm with an ELISA plate reader. Percent inhibition of the candidate compound was calculated using the following formula.

[식 3][Equation 3]

% 저해=100×{1-평균 OD w/화합물/평균 OD w/o 화합물} % Inhibition = 100 × { 1 - mean OD w / compound / mean OD w / o compound }

실시예 3Example 3

음성 조절인자의 합성Synthesis of Negative Regulators

본 발명에 따른 다양한 디아릴 설파이드 화합물의 합성이 하기에 기재되어 있다.The synthesis of various diaryl sulfide compounds according to the invention is described below.

일반 공정 및 출발 물질General process and starting materials

통상, 용매는 무수물로 구입하고, 더이상 건조 또는 정제하지 않았으며, 출발물질은 상업적으로 구입가능한 최상의 것이었다. E.Merck, 실리카겔 60F254, 0.25mm, 유리 또는 알루미늄 피복된 플레이트, 또는 Analtech 실리카겔 유니플레이트(250 마이크론의 실리카)를 사용하여 박층 크로마토그래피(TLC)를 수행하였다. UV로 가시화하였다. 기록된 Rf는 검출된 단일 점을 가리킨다. E.Merck 실리카겔 60, 230-400 메쉬 상에서 플래쉬 크로마토그래피를 수행하였다. 핵 자기 공명법(NMR)스펙트럼을 Bruker DPX 300 또는 Varian 300 Gemini 2000 스펙트로미터 상에서 기록하였다. 화학적 이동(shift)이 테트라메틸실란(TMS)으로부터 ppm 다운필드로 기록된다. 커플링 상수는 Hz에 있다. 기타 경우, NMR 스펙트럼은 Unity XL-200 스펙트로미터를 사용하여 기록하였다. 질량 스펙트럼은 VG 70 SEG 기구[the University of Washington, Department of Medicinal Chemistry, Mass Spectrometry Facility](고 분해능) 또는 Finnigan Mat TSQ 70 스펙트로미터(저 분해능) 상에서 기록하였다. 오직 분자내 이온만이 기록된다. Quantitative Technologies, Inc.에 의해 성분 분석을 수행하였다.Typically, the solvent was purchased as anhydride and no longer dried or purified and the starting material was the best commercially available. Thin layer chromatography (TLC) was performed using E. Merck, silica gel 60F254, 0.25 mm, glass or aluminum coated plates, or Analtech silica gel uniplate (250 microns of silica). Visualized by UV. The recorded R f points to the single point detected. Flash chromatography was performed on E.Merck silica gel 60, 230-400 mesh. Nuclear magnetic resonance (NMR) spectra were recorded on Bruker DPX 300 or Varian 300 Gemini 2000 spectrometers. Chemical shifts are reported in ppm downfield from tetramethylsilane (TMS). Coupling constants are in Hz. In other cases, NMR spectra were recorded using the Unity XL-200 spectrometer. Mass spectra were recorded on the VG 70 SEG instrument (the University of Washington, Department of Medicinal Chemistry, Mass Spectrometry Facility) (high resolution) or Finnigan Mat TSQ 70 spectrometer (low resolution). Only intramolecular ions are recorded. Component analysis was performed by Quantitative Technologies, Inc.

A.A. 일반 합성 방법 A: 아미노디아릴설파이드General Synthesis Method A: AminoDiarylsulfide

1.합성 방법 A의 일반적인 설명 1. General description of synthesis method A

원하는 디오페놀 1 몰당량(eq)과 각 니트로 아릴 화합물의 1 몰당량을 질소 하 건조 플라스크내에 정치하고, 무수 아세톤에 용해시켰다. 1.5 몰당량의 무수 탄산염칼륨(K2CO3)을 첨가하고, 혼합물을 밤새도록 격렬하게 교반하였다. 이어서, 에테르로 반응물을 희석하고, 포화 NaHCO3, 3% NaHSO4및 포화 NaCl로 세척하였다. 유기물을 Na2SO4상에서 건조하고 여과하였다. 이어서, 헵탄을 첨가하고, 대부분의 에테르가 제거될 때까지 끓여서 용액을 농축시켰다. 냉각하면서, 니트로디아릴 설파이드를 결정화시켰다. 생성물을 여과로 수집하고, 펜탄으로 세척하고, 진공에서 건조시켰다.One molar equivalent (eq) of desired diophenol and one molar equivalent of each nitro aryl compound were left in a dry flask under nitrogen and dissolved in anhydrous acetone. 1.5 molar equivalents of anhydrous potassium carbonate (K 2 CO 3 ) were added and the mixture was stirred vigorously overnight. The reaction was then diluted with ether and washed with saturated NaHCO 3 , 3% NaHSO 4 and saturated NaCl. The organics were dried over Na 2 SO 4 and filtered. Heptane was then added and the solution concentrated by boiling until most of the ether was removed. While cooling, nitrodiaryl sulfide was crystallized. The product was collected by filtration, washed with pentane and dried in vacuo.

디아릴 설파이드 1 몰당량과 주석 클로라이드 이수화물 5 몰당량을에탄올(10 내지 30 부피)에 용해시켰다. 혼합물을 유조에서 60℃로 가열하고, 포화 HCl을 첨가하였다(10 내지 30 부피). 3시간 후 반응물을 냉각시키고, 20 내지 60 부피의 얼음을 첨가하였다. 5N NaOH를 첨가하여 혼합물을 pH 10-12로 중화시켰다. 에테르로 2번 혼합물을 추출하고 배합한 에테르 추출물을 포화 NaHCO3및 포화 NaCl로 세척하였다. 유기 층을 Na2SO4상에서 건조하고, 여과하고, 회전식 증발에 의해 용매를 제거하였다. 형성된 고형물 또는 오일은 에테르 내에 취하고, 에테르 중 1N HCl 약 5 몰당량을 적가하였다. 형성된 고형물을 여과로 수집하고, 에테르로 세척하고, 진공에서 건조하였다.One molar equivalent of diaryl sulfide and 5 molar equivalents of tin chloride dihydrate were dissolved in ethanol (10-30 vol). The mixture was heated to 60 ° C. in an oil bath and saturated HCl was added (10-30 vol). After 3 hours the reaction was cooled and 20 to 60 volumes of ice was added. The mixture was neutralized to pH 10-12 by addition of 5N NaOH. The mixture was extracted twice with ether and the combined ether extracts were washed with saturated NaHCO 3 and saturated NaCl. The organic layer was dried over Na 2 S0 4 , filtered and the solvent removed by rotary evaporation. The solid or oil formed was taken up in ether and about 5 molar equivalents of 1N HCl in ether was added dropwise. The solid formed was collected by filtration, washed with ether and dried in vacuo.

일반 합성 방법 A는 하기와 같이 도식화되어 있다.General synthesis method A is plotted as follows.

여기서 X는 할로겐, 예컨대, 염소이다.Where X is halogen such as chlorine.

2.일반 합성 방법 A의 특정 예 2. Specific Examples of General Synthesis Method A

상기 반응식에 나타낸 바람직한 주석 클로라이드 이수화물 대신에 주석 과립을 사용하는 것을 제외하고 하기 구체적으로 기술한 바와 같이 일반적인 합성 방법 A를 사용하였다.General Synthesis Method A was used as described in detail below except that tin granules were used in place of the preferred tin chloride dihydrate shown in the above scheme.

2,4-디클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드2,4-dichlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide

1.54g(8.60mmol)의 2,4-디클로로티오페놀 및 1.65g(1 eq, 8.60mmol)의 3,4-디클로로니트로벤젠을 질소대기하 건조 플라스크내에 정치하고, 20ml 무수 아세톤에 용해하였다. 1.78g(1.5eq, 12.9mmol) 무수 탄산칼륨(K2CO3)을 첨가하고, 혼합물을 20시간동안 자석으로 교반하였다. 이어서, 반응물을 150ml 에테르로 희석하고 나서, 포화 NaHCO3(2×75ml), 3% NaHSO4(2×75ml) 및 포화 NaCl(2×75ml)로 세척하였다. 이어서, 유기상을 무수 Na2SO4상에서 건조하고 여과하였다. 이어서, 50ml 헵탄을 첨가하고, 용액을 증기조 상에서 끓여 약 50ml로 농축시켰다. 냉각하여 고품질의 결정을 형성시켰다. 여과로 결정을 수집하고, 3개 분배량의 펜탄으로 세정하고, 진공(70℃, 0.05mm Hg, 2시간) 하에 건조시켰다. 1.43g(50% 수율)의 황색 결정을 수득하였다. mp 145-146℃, Rf0.37(에틸 아세테이트[EtAc]/헵탄, 1:20).1H NMR(CDCl3) 6.71(d, J=8.9, 1H), 7.38(d of d, J1=2.2, J2=8.2, 1H), 7.59(d, J=8.2, 1H), 7.63(d, J=2.2, 1H), 7.94(d of d, J1=2.2, J2=8.9, 1H), 8.26(d, J=2.5, 1H). MS(EI)m/z 333(M+, 98). Anal. Calcd for C12H6Cl3NO2S: C, 43.08;H, 1.81;N, 4.19. Found: C, 43.06; H, 1.77; N, 4.02.1.54 g (8.60 mmol) of 2,4-dichlorothiophenol and 1.65 g (1 eq, 8.60 mmol) of 3,4-dichloronitrobenzene were placed in a dry flask under nitrogen atmosphere and dissolved in 20 ml anhydrous acetone. 1.78 g (1.5 eq, 12.9 mmol) anhydrous potassium carbonate (K 2 CO 3 ) was added and the mixture was magnetically stirred for 20 hours. The reaction was then diluted with 150 ml ether and washed with saturated NaHCO 3 (2 × 75 ml), 3% NaHSO 4 (2 × 75 ml) and saturated NaCl (2 × 75 ml). The organic phase was then dried over anhydrous Na 2 SO 4 and filtered. Then 50 ml heptane was added and the solution was boiled in a steam bath and concentrated to about 50 ml. Cool to form high quality crystals. The crystals were collected by filtration, washed with three portions of pentane and dried under vacuum (70 ° C., 0.05 mm Hg, 2 hours). 1.43 g (50% yield) of yellow crystals were obtained. mp 145-146 ° C., R f 0.37 (ethyl acetate [EtAc] / heptane, 1:20). 1 H NMR (CDCl 3 ) 6.71 (d, J = 8.9, 1H), 7.38 (d of d, J 1 = 2.2, J 2 = 8.2, 1H), 7.59 (d, J = 8.2, 1H), 7.63 ( d, J = 2.2, 1H), 7.94 (d of d, J 1 = 2.2, J 2 = 8.9, 1H), 8.26 (d, J = 2.5, 1H). MS (EI) m / z 333 (M < + >, 98). Anal. Calcd for C 12 H 6 Cl 3 NO 2 S: C, 43.08; H, 1.81; N, 4.19. Found: C, 43.06; H, 1.77; N, 4.02.

3-클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

0.680g(2.03mmol)의 2,4-디클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드 및 0.844g(3.5 eq, 7.11mmol)의 주석 과립을 20ml의 진한 HCl 내에서 교반하였다. 격렬하게 교반하면서 2일 동안 환류로 가열하였다. 혼합물을 실온으로 냉각한 후, 50ml 얼음으로 희석하였다. 교반하면서, 대략 80ml 5N NaOH를 첨가하여 이 혼합물을 pH 10으로 중화하였다. 이어서, 생성물을 에테르(2×100ml)로 추출하였다. 배합 유기물을 100ml의 진한 NaHCO3및 2×100ml의 진한 NaCl로 세척하였다. 생성물을 Na2SO4상에서 건조하고 여과하였다. 생성물을 회전증기(rotavapor) 상에서 농축하여 갈색 오일을 얻었다. 오일을 50ml 에테르에 넣고 나서, 에테르 중 4ml의 1N HCl을 적가하여 백색 고형물을 생산하였다. 생성물을 여과로 수집하고, 수개 분배량의 펜탄으로 세정하고, 건조시켰다(90℃, 0.05mm Hg, 3시간). 0.548g(79% 수율)의 백색 고형물을 수득하였다. mp 183-185℃(dec), Rf0.33(EtAc/헵탄 1:2 w/1% TEA).1H NMR(DMSO-d6) 6.55(d, J=8.6, 1H), 6.66(d of d, J1=2.5, J2=8.6, 1H), 6.89(br s, 3H), 6.89(d, J=2.5, 1H), 7.29(d, J=2.2, 1H), 7.32(d, J=2.2, 1H), 7.62(d, J=2.2, 1H). MS(EI)m/z 303 M+[100]. Anal. Calcd for C12H8Cl3NS·HCl: C, 42.26;H, 2.66;N, 4.11. Found: C, 42.39; H, 2.57; N, 4.14.0.680 g (2.03 mmol) of 2,4-dichlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide and 0.844 g (3.5 eq, 7.11 mmol) of tin granules were stirred in 20 ml of concentrated HCl. . Heated to reflux for 2 days with vigorous stirring. The mixture was cooled to room temperature and then diluted with 50 ml ice. While stirring, approximately 80 ml 5N NaOH was added to neutralize the mixture to pH 10. The product was then extracted with ether (2 x 100 ml). The combined organics were washed with 100 ml of concentrated NaHCO 3 and 2 × 100 ml of concentrated NaCl. The product was dried over Na 2 S0 4 and filtered. The product was concentrated on rotavapor to give a brown oil. The oil was added to 50 ml ether and then 4 ml of 1N HCl in ether was added dropwise to produce a white solid. The product was collected by filtration, washed with several portions of pentane and dried (90 ° C., 0.05 mm Hg, 3 hours). 0.548 g (79% yield) of a white solid was obtained. mp 183-185 ° C. (dec), R f 0.33 (EtAc / heptane 1: 2 w / 1% TEA). 1 H NMR (DMSO-d6) 6.55 (d, J = 8.6, 1H), 6.66 (d of d, J 1 = 2.5, J 2 = 8.6, 1H), 6.89 (br s, 3H), 6.89 (d, J = 2.5, 1H), 7.29 (d, J = 2.2, 1H), 7.32 (d, J = 2.2, 1H), 7.62 (d, J = 2.2, 1H). MS (EI) m / z 303 M + [100]. Anal. Calcd for C 12 H 8 Cl 3 NS.HCl: C, 42.26; H, 2.66; N, 4.11. Found: C, 42.39; H, 2.57; N, 4.14.

3.일반 합성 방법 A에 의해 제조된 화합물의 추가 예. 3. Further Examples of Compounds Prepared by General Synthesis Method A.

하기 화합물은 일반 합성 방법 A를 사용하여 상업적으로 구입가능한 반응제들로부터 제조하였다. 중간물질(티올+니트로아릴→중간물질)과 함께 출발물질 티올및 니트로아릴 화합물을 제공한다.The following compounds were prepared from commercially available reactants using General Synthetic Method A. A starting material thiol and nitroaryl compound are provided together with the intermediate (thiol + nitroaryl → intermediate).

3-클로로-4-(2-클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-chlorophenylsulfanyl) -phenylamine hydrochloride

2-클로로티오페놀 + 3,4-디클로로니트로벤젠 →4-니트로-2-클로로페닐-(2'-클로로페닐)-설파이드2-Chlorothiophenol + 3,4-dichloronitrobenzene → 4-nitro-2-chlorophenyl- (2'-chlorophenyl) -sulfide

회색 고형물, mp 197-198℃(dec), Rf0.16(EtAc/헵탄 1:4 w/1% TEA).1H NMR(DMSO-d6) 6.61(d of d, J1=1.9, J2=7.3, 1H), 6.70(d fo d, J1=2.4, J2=8.4, 1H), 6.94(d, J=2.5, 1H), 7.18(m, 2H), 7.28(d, J=8.9, 1H), 7.45(d of d, J1=1.6, J2=7.6, 1H), 7.78(br s, 3H). MS(EI)m/z 269 M+[100]. Anal. Calcd for C12H10Cl3NS·HCl: C, 47.22;H, 3.30;N, 4.59. Found: C, 47.34; H, 3.15; N, 4.45.Gray solid, mp 197-198 ° C. (dec), R f 0.16 (EtAc / heptane 1: 4 w / 1% TEA). 1 H NMR (DMSO-d6) 6.61 (d of d, J 1 = 1.9, J 2 = 7.3, 1H), 6.70 (d fo d, J 1 = 2.4, J 2 = 8.4, 1H), 6.94 (d, J = 2.5, 1H), 7.18 (m, 2H), 7.28 (d, J = 8.9, 1H), 7.45 (d of d, J 1 = 1.6, J 2 = 7.6, 1H), 7.78 (br s, 3H ). MS (EI) m / z 269 M + [100]. Anal. Calcd for C 12 H 10 Cl 3 NS.HCl: C, 47.22; H, 3.30; N, 4.59. Found: C, 47.34; H, 3. 15; N, 4.45.

3-클로로-4-(2-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-naphthylsulfanyl) -phenylamine hydrochloride

2-나프탈렌티올 + 3,4-디클로로니트로벤젠 →4-니트로-2-클로로페닐-2-나프틸설파이드2-naphthalenethiol + 3,4-dichloronitrobenzene → 4-nitro-2-chlorophenyl-2-naphthylsulfide

회색 고형물, mp 188℃(dec), Rf0.16(EtAc/헵탄 1:4 w/1% TEA).1H NMR(DMSO-d6) 6.08(br s, 3H), 6.60(d of d, J1=2.4, J2=8.4, 1H), 6.90(d, J=2.5, 1H), 7.20(d of d, J1=1.9, J2=8.6, 1H), 7.30(d, J=8.6, 1H), 7.45(m, 2H), 7.53(s, 1H), 7.76(m, 1H), 7.83(m, 2H). MS(EI)m/z 285 M+[100]. Anal. Calcd for C16H12ClNS·HCl: C, 59.64;H, 4.07;N, 4.35. Found: C, 59.59; H, 4.07; N, 4.09.Gray solid, mp 188 ° C. (dec), R f 0.16 (EtAc / heptane 1: 4 w / 1% TEA). 1 H NMR (DMSO-d6) 6.08 (br s, 3H), 6.60 (d of d, J 1 = 2.4, J 2 = 8.4, 1H), 6.90 (d, J = 2.5, 1H), 7.20 (d of d, J 1 = 1.9, J 2 = 8.6, 1H), 7.30 (d, J = 8.6, 1H), 7.45 (m, 2H), 7.53 (s, 1H), 7.76 (m, 1H), 7.83 (m , 2H). MS (EI) m / z 285 M + [100]. Anal. Calcd for C 16 H 12 ClNS-HCl: C, 59.64; H, 4.07; N, 4.35. Found: C, 59.59; H, 4.07; N, 4.09.

3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride

2,3-디클로로티오페놀 + 3,4-디클로로니트로벤젠 →4-니트로-클로로페닐-(2',3'-디클로로페닐)-설파이드2,3-dichlorothiophenol + 3,4-dichloronitrobenzene → 4-nitro-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide

회색 고형물, mp 207-209℃(dec), Rf0.33(EtAc/헵탄 1:2 w/1% TEA).1H NMR(DMSO-d6) 6.45(d of d, J1=1.4, J2=8.1, 1H), 6.62(d of d, J1=2.2, J2=8.6, 1H), 6.79(br s, 3H), 6.86(d, J=2.5, 1H), 7.21(t, J=7.9, 1H), 7.33(d, J=8.2, 1H), 7.38(d, of d, J1=1.4, J2=8.1, 1H). MS(EI)m/z 303 (M+, 93). Anal. Calcd for C12H8Cl3NS·HCl: C, 42.26;H, 2.66;N, 4.11. Found: C, 42.49; H, 2.56; N, 4.10.Gray solid, mp 207-209 ° C. (dec), R f 0.33 (EtAc / heptane 1: 2 w / 1% TEA). 1 H NMR (DMSO-d6) 6.45 (d of d, J 1 = 1.4, J 2 = 8.1, 1H), 6.62 (d of d, J 1 = 2.2, J 2 = 8.6, 1H), 6.79 (br s , 3H), 6.86 (d, J = 2.5, 1H), 7.21 (t, J = 7.9, 1H), 7.33 (d, J = 8.2, 1H), 7.38 (d, of d, J 1 = 1.4, J 2 = 8.1, 1H). MS (EI) m / z 303 (M < + >, 93). Anal. Calcd for C 12 H 8 Cl 3 NS.HCl: C, 42.26; H, 2.66; N, 4.11. Found: C, 42.49; H, 2.56; N, 4.10.

3-클로로-4-(2,4,5-트리클로로페닐설파닐)-페닐아민 히드로클로라이드3-chloro-4- (2,4,5-trichlorophenylsulfanyl) -phenylamine hydrochloride

2,3,4-트리클로로티오페놀 + 3,4-디클로로니트로벤젠 →4-니트로-2-클로로페닐-(2',4',5'-트리클로로페닐)-설파이드2,3,4-trichlorothiophenol + 3,4-dichloronitrobenzene → 4-nitro-2-chlorophenyl- (2 ', 4', 5'-trichlorophenyl) -sulfide

회색 고형물, mp 192-194℃(dec), Rf0.33(EtAc/헵탄 1:2 w/1% TEA).1H NMR(DMSO-d6) 6.46(br s, 3H), 6.53(s, 1H), 6.65(d of d, J1=2.3, J2=8.4, 1H), 6.89(d, J=2.2, 1H), 7.35(d, J=8.6, 1H), 7.88(s, 1H). MS(EI)m/z 337 (M+, 73). Anal. Calcd for C12H7Cl4NS·HCl: C, 38.38;H, 2.15;N, 3.73. Found: C, 38.73; H, 2.07; N, 3.60.Gray solid, mp 192-194 ° C. (dec), R f 0.33 (EtAc / heptane 1: 2 w / 1% TEA). 1 H NMR (DMSO-d6) 6.46 (br s, 3H), 6.53 (s, 1H), 6.65 (d of d, J 1 = 2.3, J 2 = 8.4, 1H), 6.89 (d, J = 2.2, 1H), 7.35 (d, J = 8.6, 1H), 7.88 (s, 1H). MS (EI) m / z 337 (M < + >, 73). Anal. Calcd for C 12 H 7 Cl 4 NS.HCl: C, 38.38; H, 2.15; N, 3.73. Found: C, 38.73; H, 2.07; N, 3.60.

3-메톡시-4-(2,3-디클로로페닐설파닐)-페닐아민3-methoxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine

2,3-디클로로티오페놀 + 2-브로모-5-니트로아니솔 →4-니트로-2-메톡시페닐-(2',3'-디클로로페닐)-설파이드2,3-dichlorothiophenol + 2-bromo-5-nitroanisole → 4-nitro-2-methoxyphenyl- (2 ', 3'-dichlorophenyl) -sulfide

이 화합물은 HCl 염의 형성 보다는 에테르로부터 결정화함으로써 분리하였다. 회색 결정이 수득되었다. mp 166-167℃, Rf0.17(EtAc/헵탄 1:2 w/1% TEA).1H NMR(DMSO-d6) 3.67(s, 3H), 5.75(br s, 2H), 6.26(d of d, J1=1.9, J2=8.3, 1H), 6.37(d, J=1.9, 1H), 6.46(d, J=7.9, 1H), 7.13(d, J=8.2, 1H), 7.16(t, J=8.1, 1H), 7.31(d, J=7.9, 1H). MS(EI)m/z 299 M+[100]. Anal. Calcd for C13H11Cl2NOS: C, 52.01;H, 3.69;N, 4.67. Found: C, 51.97; H, 3.59; N, 4.67.This compound was isolated by crystallization from ether rather than formation of HCl salt. Gray crystals were obtained. mp 166-167 ° C., R f 0.17 (EtAc / heptane 1: 2 w / 1% TEA). 1 H NMR (DMSO-d6) 3.67 (s, 3H), 5.75 (br s, 2H), 6.26 (d of d, J 1 = 1.9, J 2 = 8.3, 1H), 6.37 (d, J = 1.9, 1H), 6.46 (d, J = 7.9, 1H), 7.13 (d, J = 8.2, 1H), 7.16 (t, J = 8.1, 1H), 7.31 (d, J = 7.9, 1H). MS (EI) m / z 299 M + [100]. Anal. Calcd for C 13 H 11 Cl 2 NOS: C, 52.01; H, 3.69; N, 4.67. Found: C, 51.97; H, 3.59; N, 4.67.

5-아미노-2-(2,3-디클로로페닐설파닐)-아세토페논 히드로클로라이드5-amino-2- (2,3-dichlorophenylsulfanyl) -acetophenone hydrochloride

2,3-디클로로티오페놀 + 2-클로로니트로아세토페논→4-니트로-2-에세틸페닐-(2',3'-디클로로페닐)-설파이드2,3-dichlorothiophenol + 2-chloronitroacetophenone-> 4-nitro-2-acetylphenyl- (2 ', 3'- dichlorophenyl) -sulfide

황색 고형물, mp 151-153℃(dec), Rf0.35(EtAc/헵탄 1:1 w/ 1% TEA).1H NMR(DMSO-d6) 2.51(s, 3H), 7.00-7.09(m, 3H), 7.34(t, J=7.9, 1H), 7.41(br s, 1H), 7.44(br s, 3H), 7.58(d, J=7.9, 1H). MS(EI)m/z 311 M+[100]. Anal. Calcd for C13H11Cl3NOS·HCl: C, 48.23;H, 3.47;N, 4.02. Found: C, 47.78; H, 3.43; N, 3.79.Yellow solid, mp 151-153 ° C. (dec), R f 0.35 (EtAc / heptane 1: 1 w / 1% TEA). 1 H NMR (DMSO-d6) 2.51 (s, 3H), 7.00-7.09 (m, 3H), 7.34 (t, J = 7.9, 1H), 7.41 (br s, 1H), 7.44 (br s, 3H) , 7.58 (d, J = 7.9, 1 H). MS (EI) m / z 311 M + [100]. Anal. Calcd for C 13 H 11 Cl 3 NOS.HCl: C, 48.23; H, 3.47; N, 4.02. Found: C, 47.78; H, 3. 43; N, 3.79.

4-(2,3-디클로로페닐설파닐)-페닐아민4- (2,3-dichlorophenylsulfanyl) -phenylamine

2,3-디클로로티오페놀 + 4-브로모니트로페놀 →4-니트로페닐-(2',3'-디클로로페닐-설파이드2,3-dichlorothiophenol + 4-bromonitrophenol → 4-nitrophenyl- (2 ', 3'-dichlorophenyl-sulfide

회색 고형물, mp 175℃(dec), Rf0.31(EtAc/헵탄 1:2 w/ 1% TEA).1H NMR(DMSO-d6) 7.13(d, J=8.2, 2H), 7.26(t, J=7.8, 1H), 7.42(d, J=8.6, 2H), 7.47(d of d, J1=1.9, J2=7.8, 1H), 7.76(d of d, J1=1.3, J2=7.9, 1H), 8.04(br s, 3H). MS(EI)m/z 269 M+[100]. Anal. Calcd for C12H9Cl2NS·HCl: C, 47.00;H, 3.29;N, 4.57. Found: C, 46.92; H, 3.36; N, 4.27.Gray solid, mp 175 ° C. (dec), R f 0.31 (EtAc / heptane 1: 2 w / 1% TEA). 1 H NMR (DMSO-d6) 7.13 (d, J = 8.2, 2H), 7.26 (t, J = 7.8, 1H), 7.42 (d, J = 8.6, 2H), 7.47 (d of d, J 1 =) 1.9, J 2 = 7.8, 1H), 7.76 (d of d, J 1 = 1.3, J 2 = 7.9, 1H), 8.04 (br s, 3H). MS (EI) m / z 269 M + [100]. Anal. Calcd for C 12 H 9 Cl 2 NS.HCl: C, 47.00; H, 3.29; N, 4.57. Found: C, 46.92; H, 3. 36; N, 4.27.

3-클로로-4-(1-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (1-naphthylsulfanyl) -phenylamine hydrochloride

1-나프탈렌티올 + 3,4-디클로로니트로벤젠 →4-니트로-2-클로로페닐-(1-나프틸)-설파이드1-naphthalenethiol + 3,4-dichloronitrobenzene → 4-nitro-2-chlorophenyl- (1-naphthyl) -sulfide

회색 고형물, mp 192-194℃, Rf0.37(EtAc/헵탄 1:2 w/ 1% TEA).1H NMR(DMSO-d6) 6.84(m, 2H), 7.20(d, J=1.9, 1H), 7.40(d, J=7.0, 1H), 7.50(t, J=7.8, 1H), 7.56-7.61(m, 2H), 7.94(d, J=8.2, 1H), 7.99(m, 1H), 8.12-8.15(m, 5H). MS(EI)m/z 285 M+[100]. Anal. Calcd for C16H12ClNS·HCl: C, 59.64;H, 4.07;N, 4.35. Found: C, 59.59; H, 4.19; N, 4.11.Gray solid, mp 192-194 ° C., R f 0.37 (EtAc / heptane 1: 2 w / 1% TEA). 1 H NMR (DMSO-d6) 6.84 (m, 2H), 7.20 (d, J = 1.9, 1H), 7.40 (d, J = 7.0, 1H), 7.50 (t, J = 7.8, 1H), 7.56- 7.61 (m, 2H), 7.94 (d, J = 8.2, 1H), 7.99 (m, 1H), 8.12-8.15 (m, 5H). MS (EI) m / z 285 M + [100]. Anal. Calcd for C 16 H 12 ClNS-HCl: C, 59.64; H, 4.07; N, 4.35. Found: C, 59.59; H, 4. 19; N, 4.11.

3-메틸-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-methyl-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

2,4-디클로로티오페놀 + 2-브로모-5-니트로톨루엔 →4-니트로-2-메틸페닐-(2',4'-디클로로페닐)-설파이드2,4-dichlorothiophenol + 2-bromo-5-nitrotoluene → 4-nitro-2-methylphenyl- (2 ', 4'-dichlorophenyl) -sulfide

회색 고형물 mp 195-197℃, Rf0.41(EtAc/헵탄 1:2 w/ 1% TEA).1HMR(DMSO-d6) 2.22(s, 3H), 6.62(d, J=8.6, 1H), 6.94(d, J=8.2, 1H), 7.04(br s, 1H), 7.29(s, 1H), 7.32(s, 1H), 7.66(d, J=2.2, 1H), 7.89(br s, 3H). MS(EI)m/z 283 M+[100]. Anal. Calcd for C13H11Cl2NS·HCl: C, 48.69;H, 3.77;N, 4.37. Found: C, 48.87; H, 3.73; N, 4.34.Gray solid mp 195-197 ° C., R f 0.41 (EtAc / heptane 1: 2 w / 1% TEA). 1 HMR (DMSO-d6) 2.22 (s, 3H), 6.62 (d, J = 8.6, 1H), 6.94 (d, J = 8.2, 1H), 7.04 (br s, 1H), 7.29 (s, 1H) , 7.32 (s, 1 H), 7.66 (d, J = 2.2, 1 H), 7.89 (br s, 3 H). MS (EI) m / z 283 M + [100]. Anal. Calcd for C 13 H 11 Cl 2 NS.HCl: C, 48.69; H, 3.77; N, 4.37. Found: C, 48.87; H, 3.73; N, 4.34.

3-브로모-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Bromo-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

2,4-디클로로티오페놀 + 3-브로모-4-클로로니트로벤젠 →4-니트로-2-브로모페닐-(2',4'-디클로로페닐)-설파이드2,4-dichlorothiophenol + 3-bromo-4-chloronitrobenzene → 4-nitro-2-bromophenyl- (2 ', 4'-dichlorophenyl) -sulfide

회색 고형물, mp 171-173℃(dec), Rf0.69(EtAc/헵탄 1:1 w/ 1% TEA).1H NMR(DMSO-d6) 6.66(d, J=8.6, 1H), 6.81(d of d, J1=2.2, J2=8.4, 1H), 7.19(d, J=2.2, 1H), 7.29(d, J=8.2, 1H), 7.32(d of d, J1=2.2, J2=8.6, 1H), 7.64(d, J=2.2, 1H), 7.92(br s, 3H). MS(EI)m/z 347 (M+, 60). Anal. Calcd for C12H8BrCl2NS·HCl: C, 37.39;H, 2.35;N, 3.63. Found: C, 37.78; H, 2.28; N, 3.61.Gray solid, mp 171-173 ° C. (dec), R f 0.69 (EtAc / heptane 1: 1 w / 1% TEA). 1 H NMR (DMSO-d6) 6.66 (d, J = 8.6, 1H), 6.81 (d of d, J 1 = 2.2, J 2 = 8.4, 1H), 7.19 (d, J = 2.2, 1H), 7.29 (d, J = 8.2, 1H), 7.32 (d of d, J 1 = 2.2, J 2 = 8.6, 1H), 7.64 (d, J = 2.2, 1H), 7.92 (br s, 3H). MS (EI) m / z 347 (M < + >, 60). Anal. Calcd for C 12 H 8 BrCl 2 NSHCl: C, 37.39; H, 2.35; N, 3.63. Found: C, 37.78; H, 2. 28; N, 3.61.

2,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드2,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride

2,4-디클로로티오페놀 + 2,4,5-트리클로로니트로페놀 →4-니트로-2,5-디클로로페닐-(2',4'-디클로로페닐)-설파이드2,4-dichlorothiophenol + 2,4,5-trichloronitrophenol → 4-nitro-2,5-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

회색 고형물, mp 168-176℃, Rf0.39(EtAc/헵탄 1:2 w/ 1% TEA).1HNMR(DMSO-d6) 6.57(d, J=8.6, 1H), 6.83(br s, 3H), 7.06(s, 1H), 7.30(d of d, J1=2.2, J2=8.6, 1H), 7.55(s, 1H), 7.63(d, J=2.2, 1H). MS(EI)m/z 347 (M+, 60). Anal. Calcd for C12H7Cl4NS·0.75HCl: C, 39.34;H, 2.13;N, 3.82. Found: C, 39.34; H, 2.11; N, 3.71.Gray solid, mp 168-176 ° C., R f 0.39 (EtAc / heptane 1: 2 w / 1% TEA). 1 HNMR (DMSO-d6) 6.57 (d, J = 8.6, 1H), 6.83 (br s, 3H), 7.06 (s, 1H), 7.30 (d of d, J 1 = 2.2, J 2 = 8.6, 1H ), 7.55 (s, 1 H), 7.63 (d, J = 2.2, 1 H). MS (EI) m / z 347 (M < + >, 60). Anal. Calcd for C 12 H 7 Cl 4 NS.0.75 HCl: C, 39.34; H, 2.13; N, 3.82. Found: C, 39.34; H, 2.11; N, 3.71.

4,5-디클로로-2-(2,4-디클로로페닐설파닐)-페닐아민4,5-dichloro-2- (2,4-dichlorophenylsulfanyl) -phenylamine

2,4-디클로로티오페놀 + 3,4-디클로로-2-플루오로니트로벤젠 →4-니트로-2-클로로-5-플루오로페닐-(2',4'-디클로로페닐)-설파이드2,4-dichlorothiophenol + 3,4-dichloro-2-fluoronitrobenzene → 4-nitro-2-chloro-5-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

3,4-디클로로-2-플루오로니트로벤젠으로 시작하여, 플루오르화물을 치환하여 2-설파닐 화합물을 얻었다. 이 화합물을 플래쉬 크로마토그래피에 의해 유리 아민으로 정제하였다. 회색 고형물, mp 119-122℃, Rf0.20(EtAc/헵탄 1:20).1H NMR(DMSO-d6) 5.93(s, 2H), 6.61(d, J=8.6, 1H), 7.08(s, 1H), 7.31(d of d, J1=2.1, J2=8.5, 1H), 7.55(s, 1H), 7.65(d, J=1.9, 1H). MS(EI)m/z 337 (M+, 75). Anal. Calcd for C12H7Cl4NS: C, 42.51;H, 2.08;N, 4.13. Found: C, 42.94; H, 1.97; N, 4.08.Starting with 3,4-dichloro-2-fluoronitrobenzene, the fluoride was substituted to give a 2-sulfanyl compound. This compound was purified by flash chromatography to free amines. Gray solid, mp 119-122 ° C., R f 0.20 (EtAc / heptane 1:20). 1 H NMR (DMSO-d6) 5.93 (s, 2H), 6.61 (d, J = 8.6, 1H), 7.08 (s, 1H), 7.31 (d of d, J 1 = 2.1, J 2 = 8.5, 1H ), 7.55 (s, 1 H), 7.65 (d, J = 1.9, 1 H). MS (EI) m / z 337 (M < + >, 75). Anal. Calcd for C 12 H 7 Cl 4 NS: C, 42.51; H, 2.08; N, 4.13. Found: C, 42.94; H, 1.97; N, 4.08.

3,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민3,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine

2,4-디클로로티오페놀 + 3,4,5-트리클로로니트로벤젠 →4-니트로-2,6-디클로로페닐-(2',4'-디클로로페닐)-설파이드2,4-dichlorothiophenol + 3,4,5-trichloronitrobenzene → 4-nitro-2,6-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

이 화합물을 유리 아민으로 재결정하여 백색 고형물을 얻었다. mp 128-131℃, Rf0.36(EtAc/헵탄 1:2).1H NMR(DMSO-d6) 6.33(br s, 2H), 6.46(d, J=8.5, 1H), 6.83(s, 2H), 7.32(d of d, J1=2.1, J2=8.5, 1H), 7.65(d, J=2.2, 1H). MS(EI)m/z 337 (M+, 77). Anal. Calcd for C12H7Cl4NS: C, 42.51;H, 2.08;N, 4.13. Found: C, 42.15; H, 2.10; N, 4.01.This compound was recrystallized from free amine to give a white solid. mp 128-131 ° C., R f 0.36 (EtAc / heptane 1: 2). 1 H NMR (DMSO-d6) 6.33 (br s, 2H), 6.46 (d, J = 8.5, 1H), 6.83 (s, 2H), 7.32 (d of d, J 1 = 2.1, J 2 = 8.5, 1H), 7.65 (d, J = 2.2, 1H). MS (EI) m / z 337 (M < + >, 77). Anal. Calcd for C 12 H 7 Cl 4 NS: C, 42.51; H, 2.08; N, 4.13. Found: C, 42.15; H, 2.10; N, 4.01.

2,3-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민2,3-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine

2,4-디클로로티오페놀 + 2,3,4-트리니트로벤젠 →2,3-디클로로-4-(2,4-디클로로페닐티오)-니트로벤젠2,4-dichlorothiophenol + 2,3,4-trinitrobenzene → 2,3-dichloro-4- (2,4-dichlorophenylthio) -nitrobenzene

이 화합물을 플래쉬 크로마토그래피에 의해 유리 아민으로 정제하여 백색 고형물을 얻었다. mp 116-119℃, Rf0.33(EtAc/헵탄 1:4 w/ 1% TEA).1H NMR(DMSO-d6) 6.09(s, 2H), 6.47(d, J=8.7, 1H), 6.86(d, J=8.7, 1H), 7.32(d of d, J1=2.3, J2=8.7, 1H), 7.46(d, J=8.7, 1H), 7.69(d, J=2.2, 1H). MS(EI)m/z 337 (M+, 71). Anal. Calcd for C12H7Cl4NS: C, 42.51;H, 2.08;N, 4.13. Found: C, 42.83; H, 2.02; N, 4.06.This compound was purified by flash chromatography with free amine to give a white solid. mp 116-119 ° C., R f 0.33 (EtAc / heptane 1: 4 w / 1% TEA). 1 H NMR (DMSO-d6) 6.09 (s, 2H), 6.47 (d, J = 8.7, 1H), 6.86 (d, J = 8.7, 1H), 7.32 (d of d, J 1 = 2.3, J 2 = 8.7, 1H), 7.46 (d, J = 8.7, 1H), 7.69 (d, J = 2.2, 1H). MS (EI) m / z 337 (M < + >, 71). Anal. Calcd for C 12 H 7 Cl 4 NS: C, 42.51; H, 2.08; N, 4.13. Found: C, 42.83; H, 2.02; N, 4.06.

B.B. 일반 합성 방법 BGeneral Synthesis Method B

일반 합성 방법 V는 하기에 도식화하였다.General Synthesis Method V is plotted below.

여기서 X는 할로겐, 바람직하게는 염소이다.Wherein X is halogen, preferably chlorine.

하기 화합물은 일반 합성 방법 B를 사용하여 제조하였다.The following compounds were prepared using General Synthesis Method B.

4-니트로-2-클로로페닐-(2', 4'-디메틸페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide

4-아미노-2-클로로페닐-(2', 4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide hydrochloride

4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2', 4'-디플루오로페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride

4-아미노-2-클로로페닐-(2', 4', 6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(3', 4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide

비스-(4, 4'-디아미노-2, 2'-디클로로페닐)-설파이드Bis- (4, 4'-diamino-2, 2'-dichlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2', 4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-아미노-5-메틸아미노페닐-(2', 4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-아미노-5-모르폴리노페닐-(2', 4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-트리플루오로메틸페닐-(2', 4'-디클로로페닐)-설파이드4-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-아미노-2-플루오로페닐-(2', 4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

5-아미노-3-클로로페닐-(2', 4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

일반 합성 방법 B에서 초기 단계는 바로 하기에서 기술한 중간 화합물의 제조에 의해 예시된다.The initial step in general synthesis method B is illustrated by the preparation of the intermediate compounds described immediately below.

4-니트로-2-클로로페놀-(2',4'-디메틸페닐)-설파이드4-nitro-2-chlorophenol- (2 ', 4'-dimethylphenyl) -sulfide

2,4-디메틸티오페놀(1.0g) 및 3,4-디클로로니트로벤젠(1eq)를 100ml의 아세톤 함유 K2CO3(5g)에 첨가하였다. 혼합물을 24시간동안 환류시켰다. 실온으로 냉각한 후, 혼합물을 여과하고, 회전식 진공을 사용하여 아세톤을 제거하였다. 결과 잔류물을 소부피의 CH2Cl2에 용해시키고 여과하였다. 이어서, CH2Cl2를 회전식 진공을 사용하여 제거하였다. 결과 잔류물을 메탄올(MeOH)로 처리하여 생성물을 침전시켰다. 이어서, 황색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 40℃ 진공 오븐에서 건조시켰다. 생성물 수율은 66%이고, 융점은 128-130℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.2,4-dimethylthiophenol (1.0 g) and 3,4-dichloronitrobenzene (1 eq) were added to 100 ml of acetone containing K 2 CO 3 (5 g). The mixture was refluxed for 24 hours. After cooling to room temperature, the mixture was filtered and acetone was removed using a rotary vacuum. The resulting residue was dissolved in small volume of CH 2 Cl 2 and filtered. CH 2 Cl 2 was then removed using a rotary vacuum. The resulting residue was treated with methanol (MeOH) to precipitate the product. The yellow solid product was then collected by filtration and dried in a 40 ° C. vacuum oven for 24 hours. The product yield was 66% and the melting point was 128-130 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

일반적으로 하기 화합물은 상기 예시한 중간물질과 일치하여 초기 단계를 사용하여 제조하였다.In general, the following compounds were prepared using initial steps in accordance with the intermediates exemplified above.

4-아미노-2-클로로페닐-(2',4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide hydrochloride

2-클로로-4니트로페닐-(2',4'-디메틸페닐)-설파이드(0.85g) 및 MeOH(300ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:4)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 회색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 50℃ 진공 오븐에서 건조시켰다. 생성물 수율은 57%이고, 융점은 180-185℃이었다(분해). 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 2-chloro-4nitrophenyl- (2 ', 4'-dimethylphenyl) -sulfide (0.85 g) and MeOH (300 ml) was added to a 20 ml aqueous NH 4 Cl solution in a substrate: iron powder: NH 4 Cl = 1. It was added in a molar ratio of 3: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 4) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The gray solid product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. Product yield was 57% and melting point was 180-185 ° C. (decomposition). The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide

2-니트로-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드(1.0g) 및 MeOH(300ml) 중 철 분말을 5ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름:헥산(1:4)에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:1)의 용매 시스템을 사용하여 용출시킴으로써, 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 백색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 60℃ 진공 오븐에서 건조시켰다. 생성물 수율은 71%이고, 융점은 91-93℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 2-nitro-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide (1.0 g) and MeOH (300 ml) in 5 ml of aqueous NH 4 Cl solution: substrate: iron powder: NH 4 It was added in a molar ratio of Cl = 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform: hexanes (1: 4) and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 1) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The white solid product was collected by filtration and dried in a 60 ° C. vacuum oven for 24 hours. Product yield 71% and melting point 91-93 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 히드로클로라이드4-amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride

4-니트로-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 및 MeOH(300ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:5)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 무색의 고형 생성물을 여과에 의해 수집하고, 24시간 동안 50℃ 진공 오븐에서 건조시켰다. 생성물 수율은 88%이고, 융점은 187-190℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide and MeOH (300 ml) in 20 ml aqueous NH 4 Cl solution substrate: iron powder: NH 4 Cl = 1: It was added in a molar ratio of 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 5) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The colorless solid product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. Product yield was 88% and melting point was 187-190 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드(0.6g) 및 MeOH(250ml) 중 철 분말을 32ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:3)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 백색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 40℃ 진공 오븐에서 건조시켰다. 생성물 수율은 72%이고, 융점은 109-111℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide (0.6 g) and MeOH (250 ml) was dissolved in 32 ml aqueous NH 4 Cl solution. NH 4 Cl = 1: 3: 5 added in a molar ratio. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 3) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The white solid product was collected by filtration and dried in a 40 ° C. vacuum oven for 24 hours. Product yield was 72% and melting point was 109-111 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드(1.02g) 및 MeOH (300ml) 중 철 분말을 60ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:7)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 회색 고형 생성물을 여과에 의해 수집하고,24시간 동안 50℃ 진공 오븐에서 건조시켰다. 생성물 수율은 59%이고, 융점은 86-88℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide (1.02 g) and MeOH (300 ml) in 60 ml of aqueous NH 4 Cl solution: substrate: iron powder: NH 4 It was added in a molar ratio of Cl = 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 7) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The gray solid product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. The product yield was 59% and the melting point was 86-88 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(3',4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(3',4'-디클로로페닐)-설파이드(1.0g) 및 MeOH (250ml) 중 철 분말을 40ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:7)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 무색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 70℃ 진공 오븐에서 건조시켰다. 생성물 융점은 103-105℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide (1.0 g) and MeOH (250 ml) was added to 40 ml of aqueous NH 4 Cl solution in a substrate: iron powder: NH 4 Cl = It was added in a molar ratio of 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 7) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The colorless solid product was collected by filtration and dried in a 70 ° C. vacuum oven for 24 hours. The product melting point was 103-105 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide

4-니트로-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드(1.5g) 및 MeOH(250ml) 중 철 분말을 80ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:7)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고, 회전식 진공을 사용하여 용매를 제거하였다. 무색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 60℃ 진공 오븐에서 건조시켰다. 생성물 수율은 97%이고, 융점은 96-98℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide (1.5 g) and MeOH (250 ml) in 80 ml aqueous NH 4 Cl solution: Mal: NH 4 Cl = 1: 3: 5 at molar ratio. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 7) to give the product using preparative chromatography. Fractions containing product were combined and the solvent removed using a rotary vacuum. The colorless solid product was collected by filtration and dried in a 60 ° C. vacuum oven for 24 hours. The product yield was 97% and the melting point was 96-98 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

비스-(4,4'-디아미노-2,2'-디클로로페닐-설파이드Bis- (4,4'-diamino-2,2'-dichlorophenyl-sulfide

4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드 및 MeOH(125ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:7)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 회색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 60℃ 진공 오븐에서 건조시켰다. 생성물 수율은 66%이고, 융점은 113-115℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide and MeOH (125 ml) in 20 ml aqueous NH 4 Cl solution substrate: iron powder: NH 4 Cl = 1: It was added in a molar ratio of 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 7) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The gray solid product was collected by filtration and dried in a 60 ° C. vacuum oven for 24 hours. Product yield 66% and melting point 113-115 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-니트로페닐-(2',4'-디클로로페닐)-설파이드 및 MeOH(50ml) 중 철 분말을 50ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과한 후, 회전식 증발기를 사용하여 여과액으로부터 용매를 제거하였다. 잔류물을 75ml의 증류수(dH2O)와 함께 교반함으로써 생성물을 수득하였다. 무색 고형 생성물을 여과에 의해 수집하였다. 생성물 수율은 83%이고, 융점은 105-107℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 2-chloro-4-nitrophenyl- (2 ', 4'-dichlorophenyl) -sulfide and MeOH (50 ml) was added to 50 ml of aqueous NH 4 Cl solution in a substrate: iron powder: NH 4 Cl = 1: 3: It was added at a molar ratio of five. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered, then the solvent was removed from the filtrate using a rotary evaporator. The residue was stirred with 75 ml of distilled water (dH 2 O) to give the product. Colorless solid product was collected by filtration. Product yield was 83% and melting point was 105-107 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드 및 MeOH (250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:4)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 회색 고형 생성물을 여과에 의해 수집하고,24시간 동안 60℃ 진공 오븐에서 건조시켰다. 생성물 수율은 76%이고, 융점은 170-175℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide and MeOH (250 ml) was added to a 20 ml aqueous NH 4 Cl solution in a substrate: iron powder: NH 4 Cl = It was added in a molar ratio of 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 4) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The gray solid product was collected by filtration and dried in a 60 ° C. vacuum oven for 24 hours. The product yield was 76% and the melting point was 170-175 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드(0.2g) 및 MeOH(250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(2:3)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 담황색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 60℃ 진공 오븐에서 건조시켰다. 생성물 수율은 58%이고, 융점은 133-135℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide (0.2 g) and MeOH (250 ml) was added to a 20 ml aqueous NH 4 Cl solution: substrate: iron powder: NH 4 Cl = 1: 3: 5 at a molar ratio. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (2: 3) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The pale yellow solid product was collected by filtration and dried in a 60 ° C. vacuum oven for 24 hours. The product yield was 58% and the melting point was 133-135 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

2-클로로-4-아미노-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-니트로-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드(0.2g) 및 MeOH(250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:4)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 갈색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 50℃ 진공 오븐에서 건조시켰다. 생성물 수율은 16%이고, 융점은 65-70℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 2-chloro-4-nitro-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide (0.2 g) and MeOH (250 ml) was added to a 20 ml aqueous NH 4 Cl solution. It was added in a molar ratio of: NH 4 Cl = 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 4) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The brown solid product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. Product yield was 16% and melting point was 65-70 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

2-클로로-4-아미노-5-N-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-N-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-니트로-5-N-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드(0.9g) 및 MeOH(250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 혼합물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:2)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 회색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 50℃ 진공 오븐에서 건조시켰다. 생성물 융점은 153-155℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Substitute iron powder in 2-chloro-4-nitro-5-N-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide (0.9 g) and MeOH (250 ml) in 20 ml aqueous NH 4 Cl solution. : Iron powder: NH 4 Cl = 1: 3: 5 in a molar ratio. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved mixture was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 2) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The gray solid product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. The product melting point was 153-155 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드(0.6g) 및 MeOH(250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 기질:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:1)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 생성물을 여과에 의해 수집하고, 24시간 동안 50℃ 진공 오븐에서 건조시켰다. 생성물이 무색 오일이기때문에 융점이 측정되지 않았다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide (0.6 g) and MeOH (250 ml) was added to a 20 ml aqueous NH 4 Cl solution in a substrate: iron powder: NH 4 It was added in a molar ratio of Cl = 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 1) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. No melting point was determined because the product was a colorless oil. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드 및 MeOH(250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 재료:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(1:1)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 담황색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 30℃ 진공 오븐에서 건조시켰다. 생성물 수율은 55%이고, 융점은 101-102℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 4-nitro-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide and MeOH (250 ml) was added to 20 ml of aqueous NH 4 Cl solution: iron powder: NH 4 Cl = 1: 3 It was added in the molar ratio of 5: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (1: 1) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The pale yellow solid product was collected by filtration and dried in a 30 ° C. vacuum oven for 24 hours. The product yield was 55% and the melting point was 101-102 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

5-아미노-3-클로로페닐-(2',4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

3-클로로-5-니트로페닐-(2',4'-디클로로페닐)-설파이드(1.0g) 및 MeOH (250ml) 중 철 분말을 20ml의 NH4Cl 수용액에 재료:철분말:NH4Cl=1:3:5의 몰비로 첨가하였다. 혼합물을 환류 조건하에 밤새 자석으로 교반하였다. 회전식 진공을 사용하여 용매를 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:2)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 생성물을 여과에 의해 수집하고, 24시간 동안 25℃ 진공 오븐에서 건조시켰다. 생성물 수율은 16%이고, 생성물이 갈색 오일이기 때문에 융점이 측정되지 않았다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.Iron powder in 3-chloro-5-nitrophenyl- (2 ', 4'-dichlorophenyl) -sulfide (1.0 g) and MeOH (250 ml) was added to a 20 ml aqueous NH 4 Cl solution: iron powder: NH 4 Cl = It was added in a molar ratio of 1: 3: 5. The mixture was stirred with magnet overnight under reflux conditions. Solvent was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 2) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The product was collected by filtration and dried in a 25 ° C. vacuum oven for 24 hours. The product yield was 16% and no melting point was determined because the product is a brown oil. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

C. 일반 합성 방법 CC. General Synthetic Methods C

일반 합성 방법 C를 하기에 도식화하였다:General Synthesis Method C is plotted below:

하기 화합물은 일반 합성 방법 C에 의해 제조되었다:The following compounds were prepared by General Synthesis Method C:

4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-6-(5-니트로퀴놀리노)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinolino) -sulfide

4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide

2-클로로-4-아미노티오페놀(2.0g) 및 3,4-디클로로니트로벤젠(1 eq.)를 300ml의 아세톤 함유 K2CO3(20g)에 첨가하였다. 혼합물을 24시간동안 60℃에서 환류시켰다. 실온으로 냉각시킨 후, 혼합물을 여과하고, 회전식 진공을 사용하여 아세톤을 제거하였다. 생성된 잔류물을 소부피의 클로로포름에 용해시키고 여과시켰다. 이어서, 회전식 진공을 사용하여 클로로포름을 제거하였다. 형성된 잔류물은 MeOH와 함께 분쇄하여 생성물을 침전시키도록 하였다. 침전물을 여과에 의해 수집하고, 황색 고형 생성물을 24시간 동안 80℃ 진공 오븐에서 건조시켰다. 생성물 수율은 59%이고, 융점은 135-136℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.2-chloro-4-aminothiophenol (2.0 g) and 3,4-dichloronitrobenzene (1 eq.) Were added to 300 ml of acetone containing K 2 CO 3 (20 g). The mixture was refluxed at 60 ° C. for 24 h. After cooling to room temperature, the mixture was filtered and acetone was removed using a rotary vacuum. The resulting residue was dissolved in small volume of chloroform and filtered. Subsequently, chloroform was removed using a rotary vacuum. The residue formed was triturated with MeOH to precipitate the product. The precipitate was collected by filtration and the yellow solid product was dried in an 80 ° C. vacuum oven for 24 hours. The product yield was 59% and the melting point was 135-136 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide

2-클로로-4-아미노티오페놀(2.0g) 및 2,5-디클로로니트로벤젠(1 eq.)를300ml의 아세톤 함유 K2CO3(20g)에 첨가하였다. 혼합물을 24시간동안 60℃에서 환류시켰다. 실온으로 냉각시킨 후, 혼합물을 여과하고, 회전식 진공을 사용하여 아세톤을 제거하였다. 생성된 잔류물을 소부피의 CH2Cl2에 용해시키고 여과하였다. 이어서, 회전식 진공을 사용하여 CH2Cl2를 제거하였다. 형성된 잔류물은 MeOH와 함께 분쇄하여 생성물을 침전시키도록 하였다. 침전물을 여과에 의해 수집하고 황색 고형 생성물을 24시간 동안 60℃ 진공 오븐에서 건조시켰다. 생성물 수율은 57%이고, 융점은 191-193℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.2-chloro-4-aminothiophenol (2.0 g) and 2,5-dichloronitrobenzene (1 eq.) Were added to 300 ml of acetone containing K 2 CO 3 (20 g). The mixture was refluxed at 60 ° C. for 24 h. After cooling to room temperature, the mixture was filtered and acetone was removed using a rotary vacuum. The resulting residue was dissolved in small volume of CH 2 Cl 2 and filtered. Subsequently, CH 2 Cl 2 was removed using a rotary vacuum. The residue formed was triturated with MeOH to precipitate the product. The precipitate was collected by filtration and the yellow solid product was dried in a 60 ° C. vacuum oven for 24 hours. The product yield was 57% and the melting point was 191-193 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노-2-클로로페닐-6-(5-니트로퀴놀린)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinoline) -sulfide

2-클로로-4-아미노티오페놀(0.474g) 및 6-클로로-5-니트로퀴놀린(1eq)을 250ml의 아세톤 함유 K2CO3(20g)에 첨가하였다. 혼합물을 24시간동안 60℃에서 환류시켰다. 실온으로 냉각시킨 후, 혼합물을 여과하고, 회전식 진공을 사용하여 아세톤을 제거하였다. 결과 잔류물을 소부피의 클로로포름에 용해시키고 여과하였다. 이어서, 회전식 진공을 사용하여 클로로포름을 제거하였다. 형성된 잔류물을 MeOH와 함께 분쇄하여, 생성물을 침전시키도록 하였다. 용해된 잔류물을 실리카겔(70-230 메쉬)로 충전된 소규모 컬럼에 적용하고 클로로포름:헥산(3:2)의 용매 시스템을 사용하여 용출시킴으로써 예비 크로마토그래피를 사용하여 생성물을 수득하였다. 생성물을 함유하는 분획을 배합하고 회전식 진공을 사용하여 용매를 제거하였다. 황색 고형 생성물을 여과에 의해 수집하고, 24시간 동안 50℃ 진공 오븐에서건조시켰다. 생성물 수율은 62%이고, 융점은 129-131℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.2-chloro-4-aminothiophenol (0.474 g) and 6-chloro-5-nitroquinoline (1 eq) were added to 250 ml of acetone containing K 2 CO 3 (20 g). The mixture was refluxed at 60 ° C. for 24 h. After cooling to room temperature, the mixture was filtered and acetone was removed using a rotary vacuum. The resulting residue was dissolved in a small volume of chloroform and filtered. Subsequently, chloroform was removed using a rotary vacuum. The residue formed was triturated with MeOH to precipitate the product. The dissolved residue was applied to a small column packed with silica gel (70-230 mesh) and eluted using a solvent system of chloroform: hexane (3: 2) to give the product using preparative chromatography. Fractions containing product were combined and solvent removed using rotary vacuum. The yellow solid product was collected by filtration and dried in a 50 ° C. vacuum oven for 24 hours. Product yield 62% and melting point 129-131 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

D. 특이적인 합성 절차D. Specific Synthetic Procedures

하기 화합물의 경우 전체 제조 방법을 제공한다:For the following compounds the whole process of preparation is provided:

1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene

3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride

6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole

1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene

0.165g(2.1 eq, 1.35mmol)의 4-디메틸아미노피리딘(4-DMAP)을 질소대기하 건조 플라스크내에 정치하고 5ml의 무수 테트라히드로푸란(THF)에 용해시켰다. 2ml의 아세트 무수화물을 첨가하고 0.220g(1 eq, 0.643mmol) 의 3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드를 첨가하였다. 혼합물을 18시간동안 교반하였다. 이어서, 혼합물을 75ml 에테르로 희석하고, 포화 NaHCO3(3×50ml), 0.3N HCl(3×30ml) 및 포화 NaCl(2×30ml)로 세척하였다. 이어서, Na2SO4상에서 건조하고 여과한 후, 용매를 회전증기 상에서 제거하였다. 플래쉬 크로마토그래피 (1.9×27cm, EtAc/헵탄(1:1))로 0.135g(61% 수율)의 백색 고형물을 얻었다. mp 167-169℃, Rf0.25(EtAc/헵탄 1:1).1H NMR(DMSO-d6) 2.07(s, 3H), 6.59(d of d,J1=1.3, J2=7.9, 1H), 7.24(t, J=8.1, 1H), 7.46(d of d, J1=1.4, J2=8.1, 1H), 7.55(m, 2H), 8.04(d, J=1.9, 1H), 10.35(s, 1H). MS(EI)m/z 345 (M+, 82). Anal. Calcd for C14H10Cl3NOS: C, 48.51;H, 2.91;N, 4.04. Found: C, 48.29; H, 2.88; N, 3.92.0.165 g (2.1 eq, 1.35 mmol) of 4-dimethylaminopyridine (4-DMAP) was placed in a dry flask under nitrogen atmosphere and dissolved in 5 ml of anhydrous tetrahydrofuran (THF). 2 ml of acet anhydride were added and 0.220 g (1 eq, 0.643 mmol) of 3-chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride was added. The mixture was stirred for 18 hours. The mixture was then diluted with 75 ml ether and washed with saturated NaHCO 3 (3 × 50 ml), 0.3N HCl (3 × 30 ml) and saturated NaCl (2 × 30 ml). Then, dried over Na 2 SO 4 and filtered, the solvent was removed on rotary steam. Flash chromatography (1.9 × 27 cm, EtAc / heptane (1: 1)) gave 0.135 g (61% yield) of white solid. mp 167-169 ° C., R f 0.25 (EtAc / heptane 1: 1). 1 H NMR (DMSO-d6) 2.07 (s, 3H), 6.59 (d of d, J 1 = 1.3, J 2 = 7.9, 1H), 7.24 (t, J = 8.1, 1H), 7.46 (d of d , J 1 = 1.4, J 2 = 8.1, 1H), 7.55 (m, 2H), 8.04 (d, J = 1.9, 1H), 10.35 (s, 1H). MS (EI) m / z 345 (M < + >, 82). Anal. Calcd for C 14 H 10 Cl 3 NOS: C, 48.51; H, 2.91; N, 4.04. Found: C, 48.29; H, 2.88; N, 3.92.

3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride

0.19g(0.67mmol)의 3-메톡시-4-(2,3-디클로로페닐설파닐)페닐아민을 질소대기하 건조 플라스크내에 정치하고 10ml의 무수 CH2Cl2에 용해시키고, -78℃로 냉각하였다. 0.32ml(5eq., 3.3mmol)의 붕소 트리브로마이드를 교반하면서 적가하였다. 냉(冷)조를 제거한 후 20시간동안 반응하도록 두었다. 다시 용액을 -78℃로 냉각시키고 나서, 10ml의 MeOH를 적가하였다. 생성물을 실온으로 가온하고 1시간동안 교반하였다. 용매를 회전증기 상에서 제거하고, 생성된 오일을 2번 10ml MeOH에 취하고 다시 제거하였다. 물질을 다시 10ml MeOH에 취하고 나서 100ml EtAc로 희석하였다. 형성된 백색 침전물을 여과로 제거하고 나서, 여과액을 포화 NaCl(3×50ml)로 세척하고 Na2SO4상에서 건조하고, 여과하고, 용매를 회전식 증발에 의해 제거하였다. 형성된 오일을 플래쉬 크로마토그래피(2.9×28cm, EtAc/헵탄(1:3))에 의해 정제한 후, 25ml의 에테르에 용해시키고 에테르 중 5ml의 1N HCl를 첨가함으로써 HCl 염으로서 침전시켰다. 이것을 여과에 의해 수집하고, 에테르로 세척하고, 건조시켜(90℃ ,3시간, 0.3mmHG), 0.17g(80% 수율)의 회색 고형물을 얻었다. mp 222℃(dec), Rf0.49(EtAc/헵탄 1:1).1H NMR(DMSO-d6) 6.56-6.61(m, 2H), 6.79(d, J=1.9, 1H), 6.90(br hump), 7.19(t, J=8.1, 1H), 7.27(d, J=8.2, 1H), 7.38(d of d, J1=1.4, J2=8.1, 1H), 10.37(br s, 1H). MS(EI)m/z 285 M+[100]. Anal. Calcd for C12H9Cl2NOS·HCl: C, 44.67;H, 3.12;N, 4.34. Found: C, 44.53; H, 2.91; N, 4.17.0.19 g (0.67 mmol) of 3-methoxy-4- (2,3-dichlorophenylsulfanyl) phenylamine was placed in a dry flask under nitrogen atmosphere and dissolved in 10 ml of anhydrous CH 2 Cl 2 , and brought to -78 ° C. Cooled. 0.32 ml (5eq., 3.3 mmol) of boron tribromide was added dropwise with stirring. After removing the cold bath, it was allowed to react for 20 hours. The solution was again cooled to −78 ° C. and then 10 ml of MeOH was added dropwise. The product was allowed to warm to rt and stirred for 1 h. The solvent was removed on rotary steam and the resulting oil was taken up twice in 10 ml MeOH and removed again. The material was again taken up in 10 ml MeOH and diluted with 100 ml EtAc. The white precipitate formed was removed by filtration, then the filtrate was washed with saturated NaCl (3 x 50 ml), dried over Na 2 S0 4 , filtered and the solvent removed by rotary evaporation. The oil formed was purified by flash chromatography (2.9 × 28 cm, EtAc / heptane (1: 3)), then dissolved in 25 ml of ether and precipitated as an HCl salt by adding 5 ml of 1N HCl in ether. It was collected by filtration, washed with ether and dried (90 ° C., 3 h, 0.3 mm HG) to yield 0.17 g (80% yield) of a gray solid. mp 222 ° C. (dec), R f 0.49 (EtAc / heptane 1: 1). 1 H NMR (DMSO-d6) 6.56-6.61 (m, 2H), 6.79 (d, J = 1.9, 1H), 6.90 (br hump), 7.19 (t, J = 8.1, 1H), 7.27 (d, J = 8.2, 1H), 7.38 (d of d, J 1 = 1.4, J 2 = 8.1, 1H), 10.37 (br s, 1H). MS (EI) m / z 285 M + [100]. Anal. Calcd for C 12 H 9 Cl 2 NOS.HCl: C, 44.67; H, 3.12; N, 4.34. Found: C, 44.53; H, 2.91; N, 4.17.

6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole

플래쉬 크로마토그래피에 의해 유리 아민으로서 정제하는 것을 제외하고는 일반 공정에 의해 4-클로로-2-니트로-5-(2,4-디클로로페닐설파닐)-페닐아민을 제조하였다. 1.37g(3.93mmol)의 유리 아민을 10ml의 DMF 및 10ml의 EtOH에 첨가하였다. 4.43g(5 eq, 19.7mmol) 의 주석 클로라이드 이수화물을 첨가한 후 10ml의 진한 HCl을 첨가하였다. 이것을 20시간동안 60℃로 가열하였다. 반응물을 실온으로 냉각시키고 난 후, 30ml의 물로 희석하고, 30ml의 5N NaOH를 첨가하여 pH 12를 만들었다. 이 혼합물을 2회 150ml 에테르로 추출하였다. 배합된 유기물을 100ml의 포화 NaHCO3및 2×100ml의 포화 NaCl로 세척하고 Na2SO4상에서 건조하고 여과시켰다. 이어서, 40ml의 헵탄을 첨가하고, 이것을 회전증기 상에서 농축시키고 진공으로 건조시켜(100℃, 2시간, 0.3mmHg), 분석상 순수한 백색 고형물 10.6g(82% 수율)을 얻었다. mp 206-208℃, Rf0.51(CH2Cl2/MeOH(9:1) w/ 1% TEA).1H NMR(DMSO-d6) 6.63(d, J=8.6, 1H), 7.28(d of d, J1=2.2, J2=8.7, 1H), 7.69(d, J=2.2, 1H),7.86(br s, 1H), 7.93(s, 1H), 8.38(s, 1H), 12.80(s, 1H). MS(EI)m/z 328 (M+, 97). Anal. Calcd for C13H7Cl3N2S: C, 47.37;H, 2.14;N, 8.50. Found: C, 47.40; H, 2.04; N, 8.32.4-Chloro-2-nitro-5- (2,4-dichlorophenylsulfanyl) -phenylamine was prepared by the general procedure except purification as free amine by flash chromatography. 1.37 g (3.93 mmol) of free amine was added to 10 ml of DMF and 10 ml of EtOH. 4.43 g (5 eq, 19.7 mmol) of tin chloride dihydrate were added followed by 10 ml of concentrated HCl. It was heated to 60 ° C. for 20 hours. After the reaction was cooled to room temperature, it was diluted with 30 ml of water and pH 12 was made by adding 30 ml of 5N NaOH. This mixture was extracted twice with 150 ml ether. The combined organics were washed with 100 ml of saturated NaHCO 3 and 2 × 100 ml of saturated NaCl, dried over Na 2 SO 4 and filtered. 40 ml of heptane were then added, which was concentrated on rotary steam and dried in vacuo (100 ° C., 2 h, 0.3 mm Hg) to give 10.6 g (82% yield) of analytical pure white solid. mp 206-208 ° C., R f 0.51 (CH 2 Cl 2 / MeOH (9: 1) w / 1% TEA). 1 H NMR (DMSO-d6) 6.63 (d, J = 8.6, 1H), 7.28 (d of d, J 1 = 2.2, J 2 = 8.7, 1H), 7.69 (d, J = 2.2, 1H), 7.86 (br s, 1 H), 7.93 (s, 1 H), 8.38 (s, 1 H), 12.80 (s, 1 H). MS (EI) m / z 328 (M < + >, 97). Anal. Calcd for C 13 H 7 Cl 3 N 2 S: C, 47.37; H, 2.14; N, 8.50. Found: C, 47.40; H, 2.04; N, 8.32.

E. 특정 합성 프로토콜E. Specific Synthesis Protocols

다음 화합물은 하기 기재된 방법으로 제조하였다.The following compounds were prepared by the method described below.

4-메틸아미노-2, 2', 4'-트리클로로디페닐설파이드4-methylamino-2, 2 ', 4'-trichlorodiphenylsulfide

4-아미노-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide

4-아미노메틸-2-클로로페닐-(2', 4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-메틸아미노-2,2',4'-트리클로로디페닐설파이드4-methylamino-2,2 ', 4'-trichlorodiphenylsulfide

4-아미노-2,2',4'-트리클로로디페닐-설파이드(0.305g, 1.0mmol)를 15ml의 포름산에 첨가하였다. 혼합물을 8시간 교반한 후 0.23ml의 37% 포름알데히드를 첨가하고 혼합물을 8시간동안 환류시켰다. 이어서, 회전식 증발을 사용하여 용매를 제거하였다. 이어서, 형성된 잔류물을 실리카겔(70-230메쉬)을 함유한 소규모 컬럼에 적용시켰다. 이어서, 클로로포름을 사용하여 컬럼으로부터 생성물을 용출시켰다. 회전식 증발을 사용하여 용출물로부터 용매를 제거하고 담황색 고형 생성물을 수집하였다. 생성물의 수율은 44%이고 융점은 211℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.4-amino-2,2 ', 4'-trichlorodiphenyl-sulfide (0.305 g, 1.0 mmol) was added to 15 ml of formic acid. After stirring the mixture for 8 hours, 0.23 ml of 37% formaldehyde was added and the mixture was refluxed for 8 hours. The solvent was then removed using rotary evaporation. The residue formed was then applied to a small column containing silica gel (70-230 mesh). The product was then eluted from the column using chloroform. Rotary evaporation was used to remove solvent from the eluate and collect the pale yellow solid product. The yield of product was 44% and the melting point was 211 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-니트로-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide

4-아미노-2,2'-디클로로-4'-니트로디페닐설파이드(1.0g, 3.17mmol)를 미량의p-톨루엔설폰산을 함유한 15ml의 아세트 무수화물에서 가온하였다. 혼합물을 1시간동안 정치한 후, 회전식 증발을 사용하여 용매를 제거하였다. 잔류물을 EtAc에 용해하고 실리카겔(70-230메쉬)의 소규모 컬럼 상에 따랐다. 여과물을 수집하고, 증발하여 건조하고, 아세토니트릴로부터 재결정화하여 황색 고형 생성물을 얻었다. 생성물 수율은 97%이고 융점은 163-165℃이었다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.4-amino-2,2'-dichloro-4'-nitrodiphenylsulfide (1.0 g, 3.17 mmol) was warmed in 15 ml of acet anhydride containing traces of p -toluenesulfonic acid. After the mixture was left for 1 hour, the solvent was removed using rotary evaporation. The residue was dissolved in EtAc and poured onto a small column of silica gel (70-230 mesh). The filtrate was collected, evaporated to dryness and recrystallized from acetonitrile to give a yellow solid product. Product yield was 97% and melting point was 163-165 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-니트로-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide

4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드(1.0g, 3.17mmol)를 0℃에서 250ml의 THF 중 60% 나트륨 수소화물(1.43g)의 현탁액에 첨가하였다. 이어서, 요오드메탄(0.2ml, 20ml의 THF 중)을 첨가하고, 실온에서 48시간동안 혼합물을 교반하였다. 이어서, 혼합물을 아날테크(Analthech) 실리카겔 플레이트에 적용시켰다. 각 플레이트는 실리카의 두께가 1000미크론이었다. 2개의 반응 생성물, 즉 4-니트로-2-클로로페닐-(4'-메틸아미노-2'-클로로페닐)-설파이드 및 4-니트로-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드를 CHCl3: 헥산 = 1:1의 혼합물을 사용하여 용출시켰다. 저속의 용출 밴드는 전자 생성물에 해당하고, 고속의 용출 밴드는 후자 생성물에 해당하였다. 밴드를 수집한 후, 화합물을 CHCl3에 용해시켰다. 용매를 회전식 증발에 의해 제거하여 황색 고형 생성물을 제공하였다. 원하는 생성물의 수율은 36%이고 융점은 138-139℃이었다. 양성자 NMR분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.4-amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide (1.0 g, 3.17 mmol) was added to a suspension of 60% sodium hydride (1.43 g) in 250 ml of THF at 0 ° C. Added. Iodine methane (0.2 ml, 20 ml of THF) was then added and the mixture was stirred at rt for 48 h. The mixture was then applied to Analthech silica gel plates. Each plate had a thickness of 1000 microns of silica. Two reaction products, namely 4-nitro-2-chlorophenyl- (4'-methylamino-2'-chlorophenyl) -sulfide and 4-nitro-2-chlorophenyl- (4'-dimethylamino-2'- Chlorophenyl) -sulfide was eluted using a mixture of CHCl 3 : hexane = 1: 1. The slow eluting bands corresponded to the former product and the high speed eluting bands corresponded to the latter product. After collecting the bands, the compounds were dissolved in CHCl 3. The solvent was removed by rotary evaporation to give a yellow solid product. The yield of the desired product was 36% and the melting point was 138-139 ° C. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

4-아미노메틸-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-시아노페닐-(2',4'-디클로로페닐)-설파이드(1.0g, 3.18mmol)를 0℃에서 질소 하 200ml의 THF에 첨가하였다. 이어서, 리튬 알루미늄 수소화물(0.24g)을 분배하여 용액에 첨가하였다. 이어서, 혼합물을 0℃에서 2시간동안 정치시킨 후, 1ml의 20% NaOH를 혼합물에 첨가하고, 1ml의 dH2O를 첨가혔다. 이어서, 용액을 여과하고, 회전식 증발을 사용하여 용매를 제거하였다. 이어서, 형성된 잔류물을 실리카겔(70-230 메쉬)를 함유한 소규모 컬럼에 적용시켰다. 컬럼을 클로로포름:헥산 = 1:1의 혼합물로 세척한 후 회전식 증발을 사용하여 생성물을 용출시키고 무색의 오일로서 생성물을 얻었다. 생성물 수율은 40%이고, 융점은 측정되지 않았다. 양성자 NMR 분광법, 성분 분석법 및 박층 크로마토그래피를 포함한 표준 분석 기법을 사용하여 생성물의 특성을 규명하였다.2-Chloro-4-cyanophenyl- (2 ', 4'-dichlorophenyl) -sulfide (1.0 g, 3.18 mmol) was added to 200 ml THF under nitrogen at 0 ° C. Then, lithium aluminum hydride (0.24 g) was distributed and added to the solution. The mixture was then left at 0 ° C. for 2 hours, then 1 ml of 20% NaOH was added to the mixture and 1 ml of dH 2 O was added. The solution was then filtered and the solvent removed using rotary evaporation. The formed residue was then applied to a small column containing silica gel (70-230 mesh). The column was washed with a mixture of chloroform: hexane = 1: 1 and then rotary evaporation was used to elute the product to give the product as a colorless oil. Product yield was 40% and no melting point was measured. The product was characterized using standard analytical techniques including proton NMR spectroscopy, component analysis and thin layer chromatography.

F. 기타 화합물F. Other Compounds

일반 합성 방법에 따라 합성되는 기타 화합물은 하기와 같다.Other compounds synthesized according to the general synthetic method are as follows.

[표 2]TABLE 2

4-니트로-2-클로로페닐-(2', 4'-디메틸페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide

4-니트로-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide

4-니트로-2-클로로페닐-(2', 4'-디플루오로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide

4-니트로-2-클로로페닐-(2', 4', 6'-트리클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(3', 4'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-nitro-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide

2-클로로-4-니트로페닐-(2', 4'-디클로로페닐)-설파이드2-Chloro-4-nitrophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide

2-클로로-4-니트로-5-메틸아미노페닐-(2', 4'-디클로로페닐)-설파이드2-Chloro-4-nitro-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide

2-클로로-4-니트로-5-모르폴리노페닐-(2', 4'-디클로로페닐)-설파이드2-Chloro-4-nitro-5-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-트리플루오로메틸페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-플루오로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

3-클로로-5-니트로페닐-(2',4'-디클로로페닐)-설파이드3-chloro-5-nitrophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(1-나프틸)-설파이드4-nitro-2-chlorophenyl- (1-naphthyl) -sulfide

4-니트로-2-메틸페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2-methylphenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-브로모페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2-bromophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2, 5-디클로로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2, 5-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2, 6-디클로로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2, 6-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로-5-플루오로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2-chloro-5-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2, 3-디클로로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-2, 3-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-클로로-2'-아미노페닐)-설파이드4-nitro-2-chlorophenyl- (4'-chloro-2'-aminophenyl) -sulfide

4-니트로-5-아세트아미도-2-클로로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-5-acetamido-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-메틸아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-methylamino-2'-chlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-벤질아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-benzylamino-2'-chlorophenyl) -sulfide

4-니트로-2-클로로페닐-(4'-디벤질아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-dibenzylamino-2'-chlorophenyl) -sulfide

4-니트로-5-페닐설포-2-클로로페닐-(2', 4'-디클로로페닐)-설파이드4-nitro-5-phenylsulfo-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

3-니트로-5-클로로페닐-(2', 4'-디클로로페닐)-설파이드3-nitro-5-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide

실시예 4Example 4

세포를 기초로 한 분석 결과Cell-based assay

본 발명의 화합물은 전술한 세포를 기초로 한 분석 상 활성을 하기 표 3에 나열한 바와 같이 나타내었으며, 시험된 ICAM-1 및 ICAM-3와의 LFA-1결합의 저해에 대한 μM IC50값을 제공한다. 쌍으로 나타낸 값(X/Y)은 IL-8의 부재 및 존재하 저해를 의미한다. 다중 쌍으로 나타난 값(W/X; Y/Z)은 반복된 실험을 의미한다. 대쉬(--/X)는 실험이 수행되지 않은 것을 의미한다. "NT"는 화합물이 특정 분석에서 시험되지 않은 것을 의미한다.The compounds of the present invention are shown as listed in Table 3 below for assays based on the cells described above and provide μM IC 50 values for inhibition of LFA-1 binding with ICAM-1 and ICAM-3 tested. do. Paired values (X / Y) mean inhibition in the absence and presence of IL-8. Values represented by multiple pairs (W / X; Y / Z) refer to repeated experiments. The dash (-/ X) means that the experiment was not performed. "NT" means that the compound was not tested in a particular assay.

본 발명은 특정 구체예로서 기술되지만 당업자는 변형 및 수정 할 수 있다고 이해된다. 따라서, 본 발명은 하기 청구범위에서만 제한되어야 한다.While the present invention has been described in particular embodiments, it is understood that one of ordinary skill in the art can make modifications and variations. Accordingly, the invention should be limited only in the following claims.

[표 3-1]Table 3-1

화합물compound LFAl/ICAM-1IC50 -/+ IL-8 LFAl / ICAM-1 IC50-/ + IL-8 LFA-1/ICAM-3IC50 -/+ IL-8 LFA-1 / ICAM-3 IC50-/ + IL-8 3-클로로-4-(2-클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-chlorophenylsulfanyl) -phenylamine hydrochloride 7.6/4.7; 17.7/16.37.6 / 4.7; 17.7 / 16.3 NTNT 3-클로로-4-(2-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-naphthylsulfanyl) -phenylamine hydrochloride 7.8/7.2; 10.0/9.37.8 / 7.2; 10.0 / 9.3 NTNT 3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 1.1/0.7; 3.4/3.91.1 / 0.7; 3.4 / 3.9 1.8/1.01.8 / 1.0 3-클로로-4-(2,4,5-트리클로로페닐설파닐)-페닐아민 히드로클로라이드3-chloro-4- (2,4,5-trichlorophenylsulfanyl) -phenylamine hydrochloride 7.5/12.5; 18.9/22.67.5 / 12.5; 18.9 / 22.6 NTNT 3-클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 1.6/1.9;3.0/4.1;5.0/6.01.6 / 1.9; 3.0 / 4.1; 5.0 / 6.0 1.2/1.41.2 / 1.4 3-메톡시-4-(2,3-디클로로페닐설파닐)-페닐아민3-methoxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine --/7.5; 8.7/7.0-/ 7.5; 8.7 / 7.0 NTNT 5-아미노-2-(2,3-디클로로페닐설파닐)-아세토페논 히드로클로라이드5-amino-2- (2,3-dichlorophenylsulfanyl) -acetophenone hydrochloride --/20-/ 20 NTNT 4-(2,3-디클로로페닐설파닐)-페닐아민4- (2,3-dichlorophenylsulfanyl) -phenylamine --/8.0; 8.5/7.6-/ 8.0; 8.5 / 7.6 NTNT 3-클로로-4-(1-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (1-naphthylsulfanyl) -phenylamine hydrochloride --/31-/ 31 NTNT 3-메틸-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-methyl-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 7.9/8.2; 7.0/6.57.9 / 8.2; 7.0 / 6.5 NTNT 1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene --/29.5-/ 29.5 NTNT 4-메틸아미노-2,2',4'-트리클로로디페닐설파이드4-methylamino-2,2 ', 4'-trichlorodiphenylsulfide 34.0/>4034.0 /> 40 NTNT 3-브로모-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Bromo-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 4.0/7.5; 2.6/3.14.0 / 7.5; 2.6 / 3.1 NTNT 3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 14.2/14.214.2 / 14.2 NTNT 6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole 27.8/>4127.8 /> 41 NTNT 4-아미노-2-클로로페닐-(2',4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide hydrochloride 12.6/23.012.6 / 23.0 NTNT 2,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드2,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 3.3/3.9;3.6/3.1;2.2/4.03.3 / 3.9; 3.6 / 3.1; 2.2 / 4.0 1.1/1.11.1 / 1.1 4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide 13.4/22.613.4 / 22.6 NTNT 4-아미노-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 히드로클로라이드4-amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride 16.5/17.816.5 / 17.8 NTNT 4-아미노-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide 8.7/12.48.7 / 12.4 NTNT 4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide 29.0/36.029.0 / 36.0 NTNT 4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide 10.0/12.010.0 / 12.0 NTNT

[표 3-2]Table 3-2

화합물compound LFAl/ICAM-1IC50 -/+ IL-8 LFAl / ICAM-1 IC50-/ + IL-8 LFA-1/ICAM-3IC50 -/+ IL-8 LFA-1 / ICAM-3 IC50-/ + IL-8 4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide 6.7/7.8; 6.0/5.66.7 / 7.8; 6.0 / 5.6 2.5/2.3;1.1/3.02.5 / 2.3; 1.1 / 3.0 4-아미노-2-클로로페닐-(3',4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide 17.4/14.517.4 / 14.5 NTNT 4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide 9.3/13.5; 7.6/7.39.3 / 13.5; 7.6 / 7.3 NTNT 비스-(4,4'-디아미노-2,2'-디클로로페닐)-설파이드Bis- (4,4'-diamino-2,2'-dichlorophenyl) -sulfide 35.5/30.535.5 / 30.5 NTNT 4-아미노-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 6.0/6/7; 5.9/4.26.0 / 6/7; 5.9 / 4.2 2.1/2.02.1 / 2.0 4-아미노-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide 17.0/29.017.0 / 29.0 NTNT 4-아미노-2-클로로페닐-6-(5-니트로퀴놀리노)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinolino) -sulfide 6.0/7.3; 3.8/76.0 / 7.3; 3.8 / 7 2.5/3.82.5 / 3.8 4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide 9.7/9.29.7 / 9.2 NTNT 2-클로로-4-아미노-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide 17.7/31.617.7 / 31.6 NTNT 2-클로로-4-아미노-5-N-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-N-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide 35.7/24.335.7 / 24.3 NTNT 4-아미노-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide 7.5/6.67.5 / 6.6 NTNT 4-아미노메틸-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide >40/18.7> 40 / 18.7 NTNT 4,5-디클로로-2-(2,4-디클로로페닐설파닐)-페닐아민4,5-dichloro-2- (2,4-dichlorophenylsulfanyl) -phenylamine 31.5/35.0; 33.7/3631.5 / 35.0; 33.7 / 36 NTNT 3,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민3,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 3.9/5.03.9 / 5.0 NTNT 2,3-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민2,3-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 27.5/27.527.5 / 27.5 NTNT 4-아미노-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4.8/5.94.8 / 5.9 NTNT 5-아미노-3-클로로페닐-(2',4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 31.8/32.931.8 / 32.9 NTNT 4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine 10.0/8.3; 7.8/810.0 / 8.3; 7.8 / 8 3.0/3.53.0 / 3.5 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine 1.0/1.51.0 / 1.5 0.5/0.30.5 / 0.3 4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide 29.0/40.029.0 / 40.0 NTNT 4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘-설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine-sulfide >40/31.0> 40 / 31.0 NTNT

Claims (17)

3-클로로-4-(2-클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-chlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-naphthylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,4,5-트리클로로페닐설파닐)-페닐아민 히드로클로라이드3-chloro-4- (2,4,5-trichlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-메톡시-4-(2,3-디클로로페닐설파닐)-페닐아민3-methoxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine 5-아미노-2-(2,3-디클로로페닐설파닐)-아세토페논 히드로클로라이드5-amino-2- (2,3-dichlorophenylsulfanyl) -acetophenone hydrochloride 4-(2,3-디클로로페닐설파닐)-페닐아민4- (2,3-dichlorophenylsulfanyl) -phenylamine 3-클로로-4-(1-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (1-naphthylsulfanyl) -phenylamine hydrochloride 3-메틸-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-methyl-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene 4-메틸아미노-2,2',4'-트리클로로디페닐설파이드4-methylamino-2,2 ', 4'-trichlorodiphenylsulfide 3-브로모-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Bromo-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole 4-아미노-2-클로로페닐-(2' 4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 '4'-dimethylphenyl) -sulfide hydrochloride 2,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드2,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 히드로클로라이드4-amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride 4-아미노-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(3',4-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (3 ', 4-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide 비스-(4,4'-디아미노-2,2'-디클로로페닐)-설파이드Bis- (4,4'-diamino-2,2'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-6-(5-니트로퀴놀리노)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinolino) -sulfide 4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide 2-클로로-4-아미노-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide 2-클로로-4-아미노-5-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노메틸-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4,5-디클로로-2-(2,4-디클로로페닐설파닐)-페닐아민4,5-dichloro-2- (2,4-dichlorophenylsulfanyl) -phenylamine 3,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민3,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 2,3-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민2,3-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 4-아미노-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 5-아미노-3-클로로페닐-(2',4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로페닐-(2',4'-디메틸페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide 4-니트로-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide 4-니트로-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide 4-니트로-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide 4-니트로-2-클로로페닐-(3',4'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-nitro-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide 2-클로로-4-니트로페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-nitrophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide 4-니트로-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide 2-클로로-4-니트로-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-nitro-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide 2-클로로-4-니트로-5-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-nitro-5-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 3-클로로-5-니트로페닐-(2',4'-디클로로페닐)-설파이드3-chloro-5-nitrophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로페닐-(1-나프틸)-설파이드4-nitro-2-chlorophenyl- (1-naphthyl) -sulfide 4-니트로-2-메틸페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2-methylphenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-브로모페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2-bromophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2,5-디클로로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2,5-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2,6-디클로로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2,6-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로-5-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2-chloro-5-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2,3-디클로로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-2,3-dichlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로페닐-(4'-클로로-2'-아미노페닐)-설파이드4-nitro-2-chlorophenyl- (4'-chloro-2'-aminophenyl) -sulfide 4-니트로-5-아세트아미도-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-5-acetamido-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-니트로-2-클로로페닐-(4'-메틸아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-methylamino-2'-chlorophenyl) -sulfide 4-니트로-2-클로로페닐-(4'-벤질아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-benzylamino-2'-chlorophenyl) -sulfide 4-니트로-2-클로로페닐-(4'-디벤질아미노-2'-클로로페닐)-설파이드4-nitro-2-chlorophenyl- (4'-dibenzylamino-2'-chlorophenyl) -sulfide 4-니트로-5-페닐설포-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-nitro-5-phenylsulfo-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 3-니트로-5-클로로페닐-(2',4'-디클로로페닐)-설파이드3-nitro-5-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 로 구성된 군에서 선택된 화합물.Compound selected from the group consisting of. 제1항의 화합물 및 약학적 허용가능한 캐리어를 함유하는 약학적 조성물.A pharmaceutical composition containing the compound of claim 1 and a pharmaceutically acceptable carrier. 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine 1-(3-니트로-4-페닐설파닐-페닐)-에타논1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone 1-(3-니트로-4-페닐설파닐-페닐)-에타논 옥심1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone oxime 5-트리플루오로메틸-2-페닐설파닐-벤조니트릴5-trifluoromethyl-2-phenylsulfanyl-benzonitrile 1-(3,5-디클로로페닐)-3-페닐설파닐-피롤리딘-2,5-디온1- (3,5-Dichlorophenyl) -3-phenylsulfanyl-pyrrolidine-2,5-dione 비스-2,4,6-트리니트로페닐-설파이드Bis-2,4,6-trinitrophenyl-sulfide 2-메틸-1-(2-o-톨릴설파닐-페닐)-1H-피롤2-methyl-1- (2- o -tolylsulfanyl-phenyl) -1 H -pyrrole 3-[2-(4-클로로-2-니트로-페닐설파닐)-페닐아미노-3H-이소벤조푸란-1-온3- [2- (4-Chloro-2-nitro-phenylsulfanyl) -phenylamino-3 H -isobenzofuran-1-one 4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine 2-니트로-4-클로로페닐-(2' 아미노페닐)-설파이드2-nitro-4-chlorophenyl- (2 'aminophenyl) -sulfide 6-아미노-2-클로로페닐-(4'-메틸페닐)-설파이드6-Amino-2-chlorophenyl- (4'-methylphenyl) -sulfide 4-니트로페닐-(2'-클로로페닐)-설파이드4-nitrophenyl- (2'-chlorophenyl) -sulfide 2,4-디니트로페닐-(4'-클로로페닐)-설파이드2,4-dinitrophenyl- (4'-chlorophenyl) -sulfide 4-아미노페닐-(2'-클로로페닐)-설파이드4-Aminophenyl- (2'-chlorophenyl) -sulfide 2,4-디아미노페닐-(4'-이소프로필페닐)-설파이드2,4-diaminophenyl- (4'-isopropylphenyl) -sulfide 4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘 설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine sulfide 4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide 로 구성된 군에서 선택된 화합물을 함유하는 약학적 조성물.A pharmaceutical composition containing a compound selected from the group consisting of. LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드에 LFA-1의 결합을 저해하기에 충분한 함유량으로 제2항 또는 제3항의 약학적 조성물을 포유류에 투여하는 단계를 포함하여 염증성 장애를 치료하는 방법.The pharmaceutical composition of claim 2 or 3 in a mammal sufficient to inhibit the binding of LFA-1 to the natural ligand of LFA-1 which competes with ICAM-1 or ICAM-3 for binding to LFA-1. A method of treating an inflammatory disorder comprising administering. 디아릴 설파이드와 LFA-1을 접촉시키는 단계를 포함하여 LFA-1에 결합하는 ICAM과의 LFA-1 결합을 저해하는 방법.A method of inhibiting LFA-1 binding to ICAM binding to LFA-1, comprising contacting diaryl sulfide with LFA-1. 제5항에 있어서, 디아릴 설파이드는 치환된 것이 특징인 방법.The method of claim 5, wherein the diaryl sulfide is substituted. 제5항에 있어서, 디아릴 설파이드는 일반 구조 화학식 1로 표시되는 화합물인 것이 특징인 방법.The method according to claim 5, wherein the diaryl sulfide is a compound represented by the general structural formula (I). [화학식 1][Formula 1] 여기서, A 및 B는 독립적이며, 비제한적으로 페닐, 티에닐, 푸릴, 피리미디닐, 이미다졸릴, 피라졸릴, 피리딜, 피라지닐, 피롤릴 및 피리다지닐을 포함하는 5원 방향족환 및 6원 방향족환으로 구성된 군에서 선택된 아릴기이고;Wherein A and B are independent and include, but are not limited to, five-membered aromatic rings including phenyl, thienyl, furyl, pyrimidinyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrrolyl and pyridazinyl; and An aryl group selected from the group consisting of six-membered aromatic rings; R1, R2및 R3은 독립적이며 수소, -Ra(이때, Ra는 수소 또는, 포화된 직쇄 또는 분지쇄의 1 내지 6개 탄소 원자를 함유하는 알킬기(C1-6알킬)임), -O-Ra, 할로(이때, 할로는 Cl, F, Br 또는 I임), -NRbRc(이때, Rb및 Rc은 독립적이며, H, C1-6알킬, 또는 -CH2-아릴 임), -NO2, -C(=O)Ra, -CN, 퍼플루오로 Ra(예, 트리플루오로메틸), -N-C(=O)Ra, -(CH2)n-NRbRc(이때, n은 1 내지 6의 정수), 모르폴리노와 같이 O, N 또는 S 중 하나이상을 함유하고 선택적으로 치환된 5원 또는 6원 헤테로시클릭 고리(지방족 또는 방향족) 및 -S-아릴(이때, 아릴은 5원 또는 6원 방향족환이며 선택적으로 치환됨)로 구성된 군에서 선택되고;R 1 , R 2 and R 3 are independent and hydrogen, —R a , wherein R a is hydrogen or an alkyl group containing 1 to 6 carbon atoms in saturated straight or branched chain (C 1-6 alkyl) ), -OR a , halo (where halo is Cl, F, Br or I), -NR b R c (where R b and R c are independent and H, C 1-6 alkyl, or -CH 2 -aryl), -NO 2 , -C (= 0) R a , -CN, perfluoro R a (e.g. trifluoromethyl), -NC (= 0) R a ,-(CH 2 ) n- NR b R c wherein n is an integer from 1 to 6, a 5- or 6-membered heterocyclic ring optionally substituted with one or more of O, N or S, such as morpholino (aliphatic or aromatic ) And -S-aryl, wherein aryl is a 5- or 6-membered aromatic ring and is optionally substituted; R4, R5및 R6은 독립적이며 수소, -Ra, -O-Ra, 할로, -NRbRc, -NO2, -C(=O)Ra, -CN, 퍼플루오로 Ra, -N-C(=O)Ra, -(CH2)n-NRbRc, 선택적으로 치환되고 O, N 또는 S 중 하나이상을 함유한 5원 또는 6원 헤테로시클릭 고리(지방족 또는 방향족) 및 -S-아릴로 구성된 군에서 선택되거나 여기서 R4및 R5는 함께 5원 또는 6원 방향족 환을 형성하고 선택적으로 고리 내에 O, N 또는 S 중 하나이상을 포함하고 선택적으로 치환됨.R 4 , R 5 and R 6 are independent and are hydrogen, -R a , -OR a , halo, -NR b R c , -NO 2 , -C (= O) R a , -CN, perfluoro R a , -NC (= 0) R a ,-(CH 2 ) n -NR b R c , a 5- or 6-membered heterocyclic ring optionally substituted with one or more of O, N or S (aliphatic or aromatic ) And -S-aryl or wherein R 4 and R 5 together form a 5- or 6-membered aromatic ring and optionally comprise one or more of O, N or S in the ring and optionally substituted. 제7항에 있어서, 디아릴 설파이드는The method of claim 7, wherein the diaryl sulfide is 3-클로로-4-(2-클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-chlorophenylsulfanyl) -phenylamine hydrochloride 4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide 3-클로로-4-(2-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-naphthylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,4,5-트리클로로페닐설파닐)-페닐아민 히드로클로라이드3-chloro-4- (2,4,5-trichlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine 3-메톡시-4-(2,3-디클로로페닐설파닐)-페닐아민3-methoxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine 5-아미노-2-(2,3-디클로로페닐설파닐)-아세토페논 히드로클로라이드5-amino-2- (2,3-dichlorophenylsulfanyl) -acetophenone hydrochloride 4-(2,3-디클로로페닐설파닐)-페닐아민4- (2,3-dichlorophenylsulfanyl) -phenylamine 3-클로로-4-(1-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (1-naphthylsulfanyl) -phenylamine hydrochloride 3-메틸-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-methyl-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene 4-메틸아미노-2,2',4'-트리클로로디페닐설파이드4-methylamino-2,2 ', 4'-trichlorodiphenylsulfide 3-브로모-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Bromo-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole 4-아미노-2-클로로페닐-(2',4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide hydrochloride 2,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드2,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 히드로클로라이드4-amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride 4-아미노-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(3',4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide 비스-(4,4'-디아미노-2,2'-디클로로페닐)-설파이드Bis- (4,4'-diamino-2,2'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-6-(5-니트로퀴놀리노)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinolino) -sulfide 4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide 2-클로로-4-아미노-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide 2-클로로-4-아미노-5-N-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-N-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘 설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine sulfide 4-아미노메틸-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4,5-디클로로-2-(2,4-디클로로페닐설파닐)-페닐아민4,5-dichloro-2- (2,4-dichlorophenylsulfanyl) -phenylamine 3,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민3,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 2,3-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민2,3-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 4-아미노-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 5-아미노-3-클로로페닐-(2',4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine 1-(3-니트로-4-페닐설파닐-페닐)-에타논1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone 1-(3-니트로-4-페닐설파닐-페닐)-에타논 옥심1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone oxime 5-트리플루오로메틸-2-페닐설파닐-벤조니트릴5-trifluoromethyl-2-phenylsulfanyl-benzonitrile 1-(3,5-디클로로페닐)-3-페닐설파닐-피롤리딘-2,5-디온1- (3,5-Dichlorophenyl) -3-phenylsulfanyl-pyrrolidine-2,5-dione 비스-2,4,6-트리니트로페닐-설파이드Bis-2,4,6-trinitrophenyl-sulfide 2-메틸-1-(2-o-톨릴설파닐-페닐)-1H-피롤2-methyl-1- (2- o -tolylsulfanyl-phenyl) -1 H -pyrrole 3-[2-(4-클로로-2-니트로-페닐설파닐)-페닐아미노-3H-이소벤조푸란-1-온3- [2- (4-chloro-2-nitro-phenylsulfanyl) -phenylamino-3H-isobenzofuran-1-one 4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine 2-니트로-4-클로로페닐-(2' -아미노페닐)-설파이드2-nitro-4-chlorophenyl- (2'-aminophenyl) -sulfide 6-아미노-2-클로로페닐-(4'-메틸페닐)-설파이드6-Amino-2-chlorophenyl- (4'-methylphenyl) -sulfide 4-니트로페닐-(2'-클로로페닐)-설파이드4-nitrophenyl- (2'-chlorophenyl) -sulfide 2,4-디니트로페닐-(4'-클로로페닐)-설파이드2,4-dinitrophenyl- (4'-chlorophenyl) -sulfide 4-아미노페닐-(2'-클로로페닐)-설파이드4-Aminophenyl- (2'-chlorophenyl) -sulfide 2,4-디아미노페닐-(4'-이소프로필페닐)-설파이드2,4-diaminophenyl- (4'-isopropylphenyl) -sulfide 4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘-설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine-sulfide 로 구성된 군에서 선택된 것이 특징인 방법.Characterized in that selected from the group consisting of. LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드에 LFA-1이 결합함으로써 야기되는 염증성 장애를 치료하는 방법으로서, LFA-1에 천연 리간드의 결합을 저해하기에 충분한 함유량으로 LFA-1과의 결합에 대해 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민과 경쟁하는 화합물을 필요한 포유류에 투여하는 단계를 포함하는 것이 특징인 방법.A method for treating an inflammatory disorder caused by the binding of LFA-1 to a natural ligand of LFA-1 that competes with ICAM-1 or ICAM-3 for binding to LFA-1, wherein Administering to a mammal in need thereof a compound that competes with 3-chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine for binding to LFA-1 in a sufficient amount to inhibit; How is it characterized. 제9항에 있어서, 화합물은 디아릴 설파이드인 것이 특징인 방법.The method of claim 9, wherein the compound is diaryl sulfide. 제10항에 있어서, 디아릴 설파이드는 치환된 것이 특징인 방법.The method of claim 10, wherein the diaryl sulfide is substituted. 제10항에 있어서, 디아릴 설파이드는 일반 구조 화학식 1로 표시되는 화합물인 것이 특징인 방법.The method of claim 10, wherein the diaryl sulfide is a compound represented by the general structural formula (I). [화학식 1][Formula 1] 여기서, A 및 B는 독립적이며, 비제한적으로 페닐, 티에닐, 푸릴, 피리미디닐, 이미다졸릴, 피라졸릴, 피리딜, 피라지닐, 피롤릴 및 피리다지닐을 포함하는 5원 방향족환 및 6원 방향족환으로 구성된 군에서 선택된 아릴기이고;Wherein A and B are independent and include, but are not limited to, five-membered aromatic rings including phenyl, thienyl, furyl, pyrimidinyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrrolyl and pyridazinyl; and An aryl group selected from the group consisting of six-membered aromatic rings; R1, R2및 R3은 독립적이며 수소, -Ra(이때, Ra는 수소 또는, 포화된 직쇄 또는 분지쇄의 1 내지 6개 탄소 원자를 함유하는 알킬기(C1-6알킬)임), -O-Ra, 할로(이때, 할로는 Cl, F, Br 또는 I임), -NRbRc(이때, Rb및 Rc은 독립적이며, H, C1-6알킬, 또는 -CH2-아릴 임), -NO2, -C(=O)Ra, -CN, 퍼플루오로 Ra(예, 트리플루오로메틸), -N-C(=O)Ra, -(CH2)n-NRbRc(이때 n은 1 내지 6의 정수), 모르폴리노와 같이 O, N 또는 S 중 하나이상을 함유하고 선택적으로 치환된 5원 또는 6원 헤테로시클릭 고리(지방족 또는 방향족) 및 -S-아릴(이때, 아릴은 5원 또는 6원 방향족환이며 선택적으로 치환됨)로 구성된 군에서 선택되고;R 1 , R 2 and R 3 are independent and hydrogen, —R a , wherein R a is hydrogen or an alkyl group containing 1 to 6 carbon atoms in saturated straight or branched chain (C 1-6 alkyl) ), -OR a , halo (where halo is Cl, F, Br or I), -NR b R c (where R b and R c are independent and H, C 1-6 alkyl, or -CH 2 -aryl), -NO 2 , -C (= 0) R a , -CN, perfluoro R a (e.g. trifluoromethyl), -NC (= 0) R a ,-(CH 2 ) n- NR b R c where n is an integer from 1 to 6, a 5- or 6-membered heterocyclic ring optionally substituted with one or more of O, N or S, such as morpholino (aliphatic or aromatic) And -S-aryl, wherein aryl is a 5- or 6-membered aromatic ring and is optionally substituted; R4, R5및 R6은 독립적이며 수소, -Ra, -O-Ra, 할로, -NRbRc, -NO2, -C(=O)Ra,-CN, 퍼플루오로 Ra, -N-C(=O)Ra, -(CH2)n-NRbRc, 선택적으로 치환되고 O, N 또는 S 중 하나이상을 함유하는 5원 또는 6원 헤테로시클릭 고리(지방족 또는 방향족) 및 -S-아릴로 구성된 군에서 선택되거나 여기서 R4및 R5는 함께 5원 또는 6원 방향족 환을 형성하고 선택적으로 고리 내에 하나이상의 O, N 또는 S를 포함하고 선택적으로 치환됨.R 4 , R 5 and R 6 are independent and are hydrogen, -R a , -OR a , halo, -NR b R c , -NO 2 , -C (= 0) R a , -CN, perfluoro R a , -NC (= 0) R a ,-(CH 2 ) n -NR b R c , a 5- or 6-membered heterocyclic ring optionally substituted with one or more of O, N or S (aliphatic or aromatic ) And -S-aryl or wherein R 4 and R 5 together form a 5- or 6-membered aromatic ring and optionally comprise one or more O, N or S in the ring and optionally substituted. 제12항에 있어서, 디아릴 설파이드는The method of claim 12, wherein the diaryl sulfide is 3-클로로-4-(2-클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-chlorophenylsulfanyl) -phenylamine hydrochloride 4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide 3-클로로-4-(2-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2-naphthylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,4,5-트리클로로페닐설파닐)-페닐아민 히드로클로라이드3-chloro-4- (2,4,5-trichlorophenylsulfanyl) -phenylamine hydrochloride 3-클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine 3-메톡시-4-(2,3-디클로로페닐설파닐)-페닐아민3-methoxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine 5-아미노-2-(2,3-디클로로페닐설파닐)-아세토페논 히드로클로라이드5-amino-2- (2,3-dichlorophenylsulfanyl) -acetophenone hydrochloride 4-(2,3-디클로로페닐설파닐)-페닐아민4- (2,3-dichlorophenylsulfanyl) -phenylamine 3-클로로-4-(1-나프틸설파닐)-페닐아민 히드로클로라이드3-Chloro-4- (1-naphthylsulfanyl) -phenylamine hydrochloride 3-메틸-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-methyl-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 1-아세트아미도-3-클로로-4-(2,3-디클로로페닐설파닐)-벤젠1-acetamido-3-chloro-4- (2,3-dichlorophenylsulfanyl) -benzene 4-메틸아미노-2,2',4'-트리클로로디페닐설파이드4-methylamino-2,2 ', 4'-trichlorodiphenylsulfide 3-브로모-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-Bromo-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 3-히드록시-4-(2,3-디클로로페닐설파닐)-페닐아민 히드로클로라이드3-hydroxy-4- (2,3-dichlorophenylsulfanyl) -phenylamine hydrochloride 6-클로로-5-(2,4-디클로로페닐설파닐)-1H-벤즈이미다졸6-chloro-5- (2,4-dichlorophenylsulfanyl) -1H-benzimidazole 4-아미노-2-클로로페닐-(2',4'-디메틸페닐)-설파이드 히드로클로라이드4-Amino-2-chlorophenyl- (2 ', 4'-dimethylphenyl) -sulfide hydrochloride 2,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민 히드로클로라이드2,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine hydrochloride 4-아미노-2-클로로페닐-(2'-메틸-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-methyl-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2',4'-디플루오로페닐)-설파이드 히드로클로라이드4-amino-2-chlorophenyl- (2 ', 4'-difluorophenyl) -sulfide hydrochloride 4-아미노-2-클로로페닐-(2',4',6'-트리클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2 ', 4', 6'-trichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-아미노-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-amino-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-클로로-4'-니트로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-chloro-4'-nitrophenyl) -sulfide 4-아미노-2-클로로페닐-(2'-니트로-4'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (2'-nitro-4'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-(3',4'-디클로로페닐)-설파이드4-Amino-2-chlorophenyl- (3 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(3-클로로-5-트리플루오로메틸피리딜)-설파이드4-Amino-2-chlorophenyl-2- (3-chloro-5-trifluoromethylpyridyl) -sulfide 비스-(4,4'-디아미노-2,2'-디클로로페닐)-설파이드Bis- (4,4'-diamino-2,2'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-amino-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-(4'-아세트아미도-2'-클로로페닐)-설파이드4-Amino-2-chlorophenyl- (4'-acetamido-2'-chlorophenyl) -sulfide 4-아미노-2-클로로페닐-6-(5-니트로퀴놀리노)-설파이드4-amino-2-chlorophenyl-6- (5-nitroquinolino) -sulfide 4-아미노-2-클로로페닐-(4'-디메틸아미노-2'-클로로페닐)-설파이드4-amino-2-chlorophenyl- (4'-dimethylamino-2'-chlorophenyl) -sulfide 2-클로로-4-아미노-5-메틸아미노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-methylaminophenyl- (2 ', 4'-dichlorophenyl) -sulfide 2-클로로-4-아미노-5-N-모르폴리노페닐-(2',4'-디클로로페닐)-설파이드2-Chloro-4-amino-5-N-morpholinophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4-아미노-2-트리플루오로메틸페닐-(2',4'-디클로로페닐)-설파이드IC864054-Amino-2-trifluoromethylphenyl- (2 ', 4'-dichlorophenyl) -sulfideIC86405 4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘 설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine sulfide 4-아미노메틸-2-클로로페닐-(2',4'-디클로로페닐)-설파이드4-Aminomethyl-2-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 4,5-디클로로-2-(2,4-디클로로페닐설파닐)-페닐아민4,5-dichloro-2- (2,4-dichlorophenylsulfanyl) -phenylamine 3,5-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민3,5-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 2,3-디클로로-4-(2,4-디클로로페닐설파닐)-페닐아민2,3-dichloro-4- (2,4-dichlorophenylsulfanyl) -phenylamine 4-아미노-2-플루오로페닐-(2',4'-디클로로페닐)-설파이드4-Amino-2-fluorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 5-아미노-3-클로로페닐-(2',4'-디클로로페닐)-설파이드5-Amino-3-chlorophenyl- (2 ', 4'-dichlorophenyl) -sulfide 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민3-Chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine 1-(3-니트로-4-페닐설파닐-페닐)-에타논1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone 1-(3-니트로-4-페닐설파닐-페닐)-에타논 옥심1- (3-Nitro-4-phenylsulfanyl-phenyl) -ethanone oxime 5-트리플루오로메틸-2-페닐설파닐-벤조니트릴5-trifluoromethyl-2-phenylsulfanyl-benzonitrile 1-(3,5-디클로로페닐)-3-페닐설파닐-피롤리딘-2,5-디온1- (3,5-Dichlorophenyl) -3-phenylsulfanyl-pyrrolidine-2,5-dione 비스-2,4,6-트리니트로페닐-설파이드Bis-2,4,6-trinitrophenyl-sulfide 2-메틸-1-(2-o-톨릴설파닐-페닐)-1H-피롤2-methyl-1- (2- o -tolylsulfanyl-phenyl) -1 H -pyrrole 3-[2-(4-클로로-2-니트로-페닐설파닐)-페닐아미노-3H-이소벤조푸란-1-온3- [2- (4-Chloro-2-nitro-phenylsulfanyl) -phenylamino-3 H -isobenzofuran-1-one 4-(벤조티아졸-2-일설파닐)-3-클로로-페닐아민4- (benzothiazol-2-ylsulfanyl) -3-chloro-phenylamine 2-니트로-4-클로로페닐-(2' -아미노페닐)-설파이드2-nitro-4-chlorophenyl- (2'-aminophenyl) -sulfide 6-아미노-2-클로로페닐-(4'-메틸페닐)-설파이드6-Amino-2-chlorophenyl- (4'-methylphenyl) -sulfide 4-니트로페닐-(2'-클로로페닐)-설파이드4-nitrophenyl- (2'-chlorophenyl) -sulfide 2,4-디니트로페닐-(4'-클로로페닐)-설파이드2,4-dinitrophenyl- (4'-chlorophenyl) -sulfide 4-아미노페닐-(2'-클로로페닐)-설파이드4-Aminophenyl- (2'-chlorophenyl) -sulfide 2,4-디아미노페닐-(4'-이소프로필페닐)-설파이드2,4-diaminophenyl- (4'-isopropylphenyl) -sulfide 4-니트로-2-클로로페닐-(2',3'-디클로로페닐)-설파이드4-nitro-2-chlorophenyl- (2 ', 3'-dichlorophenyl) -sulfide 4-아미노-2-클로로페닐-2-(5-니트로-3-브로모)-피리딘-설파이드4-Amino-2-chlorophenyl-2- (5-nitro-3-bromo) -pyridine-sulfide 로 구성된 군에서 선택된 것이 특징인 방법.Characterized in that selected from the group consisting of. LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드와의 LFA-1의 결합을 저해하는 방법으로서, 천연 리간드에 LFA-1의 결합을 저해하기에 충분한 함유량으로 LFA-1과의 결합에 대해 3-클로로-4-(1-클로로-나프탈렌-2-일설파닐)-페닐아민과 경쟁하는 화합물을, LFA-1을 표면상에 발현하는 세포와 접촉시키는 단계를 포함하는 방법.A method of inhibiting the binding of LFA-1 to the natural ligand of LFA-1 that competes with ICAM-1 or ICAM-3 for binding to LFA-1, which is sufficient to inhibit the binding of LFA-1 to the natural ligand. Contacting a compound that competes with 3-chloro-4- (1-chloro-naphthalen-2-ylsulfanyl) -phenylamine for binding to LFA-1 by content, with cells expressing LFA-1 on the surface Making a step; 제9항 또는 제14항에 있어서, 리간드는 ICAM-1 또는 ICAM-3인 것이 특징인 방법.The method of claim 9 or 14, wherein the ligand is ICAM-1 or ICAM-3. LFA-1과의 결합에 대해 ICAM-1 또는 ICAM-3과 경쟁하는 LFA-1의 천연 리간드와의 LFA-1의 결합에 대한 음성 조절인자를 확인하는 방법으로서, a) LFA-1 결합의 활성인자와 LFA-1을 접촉시키는 단계; b) 시험 화합물의 존재 및 부재 하에 천연 리간드와의 LFA-1 결합을 측정하는 단계; 및 c) 시험 화합물의 존재하에 리간드와 LFA-1의 결합이 감소된 것이 검출될 때 음성 조절인자로서 시험 화합물을 확인하는 단계를 포함하는 방법.A method for identifying negative regulators of the binding of LFA-1 to natural ligands of LFA-1 that compete with ICAM-1 or ICAM-3 for binding to LFA-1, comprising: a) activity of LFA-1 binding Contacting the factor with LFA-1; b) measuring LFA-1 binding with natural ligands in the presence and absence of the test compound; And c) identifying the test compound as a negative regulator when it is detected that the binding of the ligand to LFA-1 in the presence of the test compound is reduced. 제16항에 있어서, 활성인자는 크리스탈 바이올렛인 것이 특징인 방법.The method of claim 16, wherein the activator is crystal violet.
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WO2000059878A3 (en) 2001-08-09
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CN1721401A (en) 2006-01-18
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HUP0201904A3 (en) 2003-04-28
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