1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as ahr activatorsThe present invention relates to compounds which are 1, 2-dihydro-4- hydroxy-2-oxo-quinoline-3-carboxanilides, their thieno-pyridone analogs, and prodrugs thereof. This invention specifically relates to such derivatives containing an N-hydrogen in the carboxanilide moiety and which exhibit modulating activity towards the aromatic hydrocarbon receptor (AhR), and, specifically, also to prodrugs thereof. The present invention also relates to use of said compounds as a medicament, and for the treatment of cancer, autoimmune disorders and other disorders with an immunological component, and a pharmaceutical composition comprising one or more of said compounds and a method of treatment.The compound of a general formula iwhereina, b and c are independently selected from the group that is comprised of the following: h, me, et, iso-pr, tert-bu, ome, oet, o-iso-pr, sme, s (o) me, s (o) 2me, cf 3, ocf 3, f, cl, br, i and cn, perhaps a and b represent och 2o and c are h; the group that rn selects free the following to form: h, c (o) h, c (o) me, c (o) et, c (o) pr, c (o) ch (me) 2, c (o) c (me) 3, c (o) ph, c (o) ch 2ph, co 2h, co 2me, co 2et, co 2ch 2ph, c (o) nhme, c (o) nme 2, c (o) nhet, c (o) net 2, c (o) nhph, c (o) nhch 2ph, the acyl residue of c5-c20 carboxylic acid that randomly contains 1-3 multiple bond and the acyl residue of amino acid glycine, l-ala, α-amino-isovaleric acid, leucine, isoleucine, serine, threonine, halfcystine, methionine(met), proline(pro), l-asparagine, glutamine, aspartic acid, l-glutamic acid, methionin, arginine, histidine, phenylalanine, tyrosine and tryptophane, and randomly the substituting group of the group that forms of selected free the following replaces 1-3 time: me, et, ome, oet, sme, s (o) me, s (o) 2me, s (o) 2nme 2, cf 3, ocf 3, f, cl, oh, co 2h, co 2me, co 2et, c (o) nh 2, c (o) nme 2, nh 2, nh 3+, nme 2, nme 3+, nhc (o) me, nc (=nh) nh 2, os (o) 2oh, s (o) 2oh, op (o) are (oh) 2and p (o) (oh) 2r4 is rn, and perhaps when rn was h, r4 selects the group that free the following forms: h, p (o) were (oh) 2, p (o) (ome) 2, p (o) (oet) 2, p (o) (oph) 2, p (o) (och 2ph) 2, s (o) 2oh, s (o) 2nh 2, s (o) 2nme 2, c (o) h, c (o) me, c (o) et, c (o) pr, c (o) ch (me) 2, c (o) c (me) 3, c (o) ph, c (o) ch 2ph, co 2h, co 2me, co 2et, co 2ch 2ph, c (o) nhme, c (o) nme 2, c (o) nhet, c (o) net 2, c (o) nhph, c (o) nhch 2ph, the acyl residue of c5-c20 carboxylic acid that randomly contains 1-3 multiple bond and the acyl residue of amino acid glycine, l-ala, α-amino-isovaleric acid, leucine, isoleucine, serine, threonine, halfcystine, methionine(met), proline(pro), l-asparagine, glutamine, aspartic acid, l-glutamic acid, methionin, arginine, histidine, phenylalanine, tyrosine and tryptophane, and randomly the substituting group of the group that forms of selected free the following replaces 1-3 time: me, et, ome, oet, sme, s (o) me, s (o) 2me, s (o) 2nme 2, cf 3, ocf 3, f, cl, oh, co 2h, co 2me, co 2et, c (o) nh 2, c (o) nme 2, nh 2, nh 3+, nme 2, nme 3+, nhc (o) me, nc (=nh) nh 2, os (o) 2oh, s (o) 2oh, op (o) are (oh) 2and p (o) (oh) 2r5 and r6 are independently selected from the group that is comprised of the following: h, me, et, iso-pr, tert-bu, ome, oet, o-iso-pr, sme, s (o) me, s (o) 2me, cf 3, ocf 3, f, cl, br, i and cn, or r5 and r6 represent och 2o； and x is-ch=ch-or s,or the pharmaceutical salts of compound of formula i,condition is the group that compound i does not select free the following to form:n-phenyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(4-aminomethyl phenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(4-p-methoxy-phenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(4-ethoxyl phenenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(4-trifluoromethoxyphen-l)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(4-chloro-phenyl-)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(4-bromophenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3,4-dichlorophenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-3-quinoline-3-methane amide,n-(3,5-3,5-dimethylphenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3-aminomethyl phenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3-chloro-phenyl-)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3-p-methoxy-phenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3-methylthio group phenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3-trifluoromethyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3-bromophenyl)-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-(3,4-(methylenedioxy))-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-phenyl-5-chloro-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-phenyl-5-fluoro-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide,n-phenyl-1,2-dihydro-4-hydroxyl-1,6-dimethyl-2-oxo-quinoline-3-methane amide,n-phenyl-1,2-dihydro-4-hydroxyl-6-methoxyl group-1-methyl-2-oxo-quinoline-3-methane amide,n-phenyl-1,2-dihydro-4-hydroxyl-1-methyl-6-methylthio group-2-oxo-quinoline-3-methane amide, andn-phenyl-6-chloro-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3-methane amide.
AHR 활성화제로서의 1,2-디히드로-4-히드록시-2-옥소-퀴놀린-3-카르복사닐리드본 발명은 1,2-디히드로-4-히드록시-2-옥소-퀴놀린-3-카르복사닐리드, 이들의 티에노-피리돈 유사체, 및 그의 전구약물에 관한 것이다. 본 발명은 특히 카르복사닐리드 모이어티에 N-수소를 함유하고, 방향족 탄화수소 수용체 (AhR)에 대한 조절 활성을 나타내는 그러한 유도체, 특히 그의 전구약물에 관한 것이다. 본 발명은 또한 의약으로서의 상기 화합물의 용도, 암, 자가면역질환 및 자가면역 성분과 관련한 기타 질환의 치료를 위한 상기 화합물, 및 상기 화합물 1종 이상을 포함하는 의약 조성물 및 치료방법에 관한 것이기도 하다.다음 일반식 I의 화합물 또는 일반식 I의 화합물의 약학적으로 허용가능한 염:[이미지]식 중,A, B 및 C는 독립적으로 H, Me, Et, 이소-Pr, 3차-Bu, OMe, OEt, O-이소-Pr, SMe, S(O)Me, S(O)2Me, CF3, OCF3, F, Cl, Br, I, 및 CN으로부터 선택되거나, 또는 A 및 B는 OCH2O를 나타내고 C는 H이며;RN은 H, C(O)H, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2H, CO2Me, CO2Et, CO2CH2Ph, C(O)NHMe, C(O)NMe2, C(O)NHEt, C(O)NEt2, C(O)NHPh, C(O)NHCH2Ph, 다중결합을 1-3개 가질 수 있는 C5-C20 카르복실산의 아실 잔기, 아미노산인 글리신, 알라닌, 발린, 류신, 이소류신, 세린, 쓰레오닌, 시스테인, 메티오닌, 프롤린, 아스파라긴, 글루타민, 아스파르트산, 글루탐산, 라이신, 아르기닌, 히스티딘, 페닐알라닌, 티로신 및 트립토판의 아실 잔기를 포함하는 군으로부터 선택되고, Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, Cl, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2, NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O)(OH)2, 및 P(O)(OH)2를 포함하는 군으로부터 선택된 치환기에 의해 1-3회 치환되어도 좋은 것이고;R4는 RN이거나, 또는 RN이 H이면, R4는 H, P(O)(OH)2, P(O)(OMe)2, P(O)(OEt)2, P(O)(OPh)2, P(O)(OCH2Ph)2, S(O)2OH, S(O)2NH2, S(O)2NMe2, C(O)H, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2H, CO2Me, CO2Et, CO2CH2Ph, C(O)NHMe, C(O)NMe2, C(O)NHEt, C(O)NEt2, C(O)NHPh, C(O)NHCH2Ph, 다중결합을 1-3개 가질 수 있는 C5-C20 카르복실산의 아실 잔기 및 아미노산인 글리신, 알라닌, 발린, 류신, 이소류신, 세린, 쓰레오닌, 시스테인, 메티오닌, 프롤린, 아스파라긴, 글루타민, 아스파르트산, 글루탐산, 라이신, 아르기닌, 히스티딘, 페닐알라닌, 티로신 및 트립토판의 아실 잔기를 포함하는 군으로부터 선택되고, Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, Cl, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2, NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O)(OH)2 및 P(O)(OH)2;를 포함하는 군으로부터 선택된 치환기에 의해 1-3회 치환되어도 좋은 것이며;R5 및 R6는 H, Me, Et, 이소-Pr, 3차-Bu, OMe, OEt, O-이소-Pr, SMe, S(O)Me, S(O)2Me, CF3, OCF3, F, Cl, Br, I, 및 CN을 포함하는 군으로부터 독립적으로 선택되거나, 또는 R5 및 R6는 OCH2O를 나타내고, X는 -CH=CH-, 또는 S를 나타내며, 단, 화합물 I은N-페닐-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드, N-(4-메틸페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드, N-(4-메톡시페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(4-에톡시페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(4-트리플루오로메톡시페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(4-클로로페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(4-브로모페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3,4-디클로로페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-3-퀴놀린-3-카르복사미드,N-(3,5-디메틸페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3-메틸페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3-클로로페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3-메톡시페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3-메틸티오페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드, N-(3-트리플루오로메틸페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3-브로모페닐)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-(3,4-메틸렌디옥소)-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-페닐-5-클로로-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-페닐-5-플루오로-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-페닐-1,2-디히드로-4-히드록시-1,6-디메틸-2-옥소-퀴놀린-3-카르복사미드,N-페닐-1,2-디히드로-4-히드록시-6-메톡시-1-메틸-2-옥소-퀴놀린-3-카르복사미드,N-페닐-1,2-디히드로-4-히드록시-1-메틸-6-메틸티오-2-옥소-퀴놀린-3-카르복사미드, 및N-페닐-6-클로로-1,2-디히드로-4-히드록시-1-메틸-2-옥소-퀴놀린-3-카르복사미드로부터 선택되지 않는다.