Hydroxy 2-pipecolate hydroxamide acid derivatives as MMP inhititorsA compound of formula (I) wherein R, R R, R R, R, R, R, R and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, and other diseases characterized by matrix metalloproteinase or mammalian reprolysin activity. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID'S), COX-2 inhibitors and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.The compound of following formula: or its pharmacologically acceptable salt,r wherein 1-r 8be selected from hydroxyl, hydrogen, halogen ,-cn, (c 1-c 6) alkyl, (c 2-c 6) alkenyl, (c 6-c 10) aryl (c 2-c 6) alkenyl, (c 2-c 9) heteroaryl (c 2-c 6) alkenyl, (c 2-c 6) alkynyl group, (c 6-c 10) aryl (c 2-c 6) alkynyl group, (c 2-c 9) heteroaryl (c 2-c 6) alkynyl group, (c 1-c 6) alkylamino, (c 1-c 6) alkylthio, (c 1-c 6) alkoxyl group, perfluor (c 1-c 6) alkyl, (c 6-c 10) aryl, (c 2-c 9) heteroaryl, (c 6-c 10) arylamino, (c 6-c 10) arylthio, (c 6-c 10) aryloxy, (c 2-c 9) heteroaryl amino, (c 2-c 9) heteroarylthio, (c 2-c 9) heteroaryloxy, (c 3-c 6) cycloalkyl, (c 1-c 6) alkyl (hydroxyl methylene radical), piperidyl, (c 1-c 6) alkylpiperidine base, (c 1-c 6) acyl amino, (c 1-c 6) acyl sulfenyl, (c 1-c 6) acyloxy, (c 1-c 6) alkoxyl group-(c=o)-,-co 2h, (c 1-c 6) alkyl-nh-(c=o)-and [(c 1-c 6) alkyl] 2-n-(c=o)-; wherein said (c 1-c 6) alkyl can optionally replace by one or two group, described group is selected from (c 1-c 6) alkylthio, (c 1-c 6) alkoxyl group, trifluoromethyl ,-cn, halogen, (c 6-c 10) aryl, (c 2-c 9) heteroaryl, (c 6-c 10) arylamino, (c 6-c 10) arylthio, (c 6-c 10) aryloxy, (c 2-c 9) heteroaryl amino, (c 2-c 9) heteroarylthio, (c 2-c 9) heteroaryloxy, (c 6-c 10) aryl (c 6-c 10) aryl, (c 3-c 6) cycloalkyl, hydroxyl, piperazinyl, (c 6-c 10) aryl (c 1-c 6) alkoxyl group, (c 2-c 9) heteroaryl (c 1-c 6) alkoxyl group, (c 1-c 6) acyl amino, (c 1-c 6) acyl sulfenyl, (c 1-c 6) acyloxy, (c 1-c 6) alkyl sulphinyl, (c 6-c 10) aryl sulfonyl kia, (c 1-c 6) alkyl sulphonyl, (c 6-c 10) aryl sulfonyl, amino, (c 1-c 6) alkylamino or ((c 1-c 6) alkyl) 2amino; perhaps r 1and r 2, r 3and r 4, or r 5and r 6can lump together the formation carbonyl; perhaps r 1and r 2, r 3and r 4, r 5and r 6, or r 7and r 8can lump together formation (c 3-c 6) group of cycloalkyl, oxa-cyclohexyl, sulfo-cyclohexyl, indanyl or tetralyl or following formula ar is the (c that is optionally replaced by one or more substituting groups 6-c 10) aryl (c 1-c 6) alkoxyl group (c 6-c 10) aryl, (c 6-c 10) aryl (c 1-c 6) alkoxyl group (c 2-c 9) heteroaryl, (c 2-c 9) heteroaryl (c 1-c 6) alkoxyl group (c 6-c 10) aryl, (c 2-c 9) heteroaryl (c 1-c 6) alkoxyl group (c 2-c 9) heteroaryl, wherein, described substituting group be independently from each other halogen ,-the cn, (c that optionally replaced by one or more fluorine atoms 1-c 6) alkyl, hydroxyl, hydroxyl-(c 1-c 6) the alkyl, (c that optionally replaced by one or more fluorine atoms 1-c 6) alkoxyl group, (c 1-c 6) alkoxyl group (c 1-c 6) alkyl, ho-(c=o)-, (c 1-c 6) alkyl-o-(c=o)-, ho-(c=o)-(c 1-c 6) alkyl, (c 1-c 6) alkyl-o-(c=o)-(c 1-c 6) alkyl, (c 1-c 6) alkyl-(c=o)-o-, (c 1-c 6) alkyl-(c=o)-o-(c 1-c 6) alkyl, h (o=c)-, h (o=c)-(c 1-c 6) alkyl, (c 1-c 6) alkyl (o=c)-, (c 1-c 6) alkyl (o=c)-(c 1-c 6) alkyl, no 2, amino, (c 1-c 6) alkylamino, [(c 1-c 6) alkyl] 2amino, amino (c 1-c 6) alkyl, (c 1-c 6) alkylamino (c 1-c 6) alkyl, [(c 1-c 6) alkyl] 2amino (c 1-c 6) alkyl, h 2n-(c=o)-, (c 1-c 6) alkyl-nh-(c=o)-, [(c 1-c 6) alkyl] 2n-(c=o)-, h 2n (c=o)-(c 1-c 6) alkyl, (c 1-c 6) alkyl-hn (c=o)-(c 1-c 6) alkyl, [(c 1-c 6) alkyl] 2n-(c=o)-(c 1-c 6) alkyl, h (o=c)-nh-, (c 1-c 6) alkyl (c=o)-nh-, (c 1-c 6) alkyl (c=o)-[nh] (c 1-c 6) alkyl, (c 1-c 6) alkyl (c=o)-[n (c 1-c 6) alkyl] (c 1-c 6) alkyl, (c 1-c 6) alkyl-s-, (c 1-c 6) alkyl-(s=o)-, (c 1-c 6) alkyl-so 2-, (c 1-c 6) alkyl-so 2-nh-, h 2n-so 2-, h 2n-so 2-(c 1-c 6) alkyl, (c 1-c 6) alkyl hn-so 2-(c 1-c 6) alkyl, [(c 1-c 6) alkyl] 2n-so 2-(c 1-c 6) alkyl, cf 3so 3-, (c 1-c 6) alkyl-so 3-, phenyl, phenyl (c 1-c 6) alkyl, (c 3-c 10) cycloalkyl, (c 2-c 9) heterocyclylalkyl and (c 2-c 9) heteroaryl; condition is r 1-r 8in have at least one to be hydroxyl; further condition be formula i compound can not be (2r, 4s)-1-[4-(4-fluorine benzyloxy) benzenesulfonyl]-4-hydroxy-piperdine-2-formic acid oxyamide; (2r, 3s)-1-[4-(2-chloro-thiazole-5-ylmethoxy) benzenesulfonyl]-3-hydroxy-piperdine-2-formic acid oxyamide; (2r, 3s)-3-hydroxyl-1-[4-(thiazole-5-ylmethoxy) benzenesulfonyl]-piperidines-2-formic acid oxyamide; (2r, 3s)-3-hydroxyl-1-[4-(pyridin-4-yl methoxyl group)-benzenesulfonyl]-piperidines-2-formic acid oxyamide; (2r, 3s)-1-[4-(4-fluorine benzyloxy)-benzenesulfonyl]-3-hydroxy-piperdine-2-formic acid oxyamide; (2r, 3s)-1-{4-[2-(4-fluorophenyl)-oxyethyl group]-benzenesulfonyl }-3-hydroxy-piperdine-2-formic acid oxyamide; (2r, 3s)-3-hydroxyl-1-[4-(2-pyridin-4-yl-oxyethyl group)-benzenesulfonyl]-piperidines-2-formic acid oxyamide; (2r, 3s)-1-[4-(benzothiazole-2-ylmethoxy)-benzenesulfonyl]-3-hydroxy-piperdine-2-formic acid oxyamide; (2r, 3s)-3-hydroxyl-1-[4-(5-trifluoromethyl-benzothiazole-2-ylmethoxy)-benzenesulfonyl]-piperidines-2-formic acid oxyamide; (2r, 3s)-3-hydroxyl-1-[4-(1h-tetrazolium-5-ylmethoxy)-benzenesulfonyl]-piperidines-2-formic acid oxyamide; (2r, 3s)-1-[4-(2-chloro-thiazole-5-ylmethoxy) benzenesulfonyl]-3-hydroxy-3-methyl-piperidines-2-formic ac...
엠엠피 저해제로서의 하이드록시 피페콜레이트하이드록삼산 유도체본 발명은 관절염, 암, 및 매트릭스 메탈로프로티나제 또는 포유류의 레프롤리신 활성에 의해 특징지워 지는 기타 질환으로 이루어진 군으로부터 선택된 증상의 치료에 유용한, R1, R2, R3, R4, R5, R6 , R7, R8, R9 및 Ar이 상기 정의된 바와 같은 화학식 I의 화합물에 관한 것이다. 또한, 본 발명의 화합물은 표준 비스테로이드성 소염제(NSAID), COX-2 저해제 및 진통제와 병용하여 사용하고, 아드리아마이신, 다우노마이신, 시스-백금, 에토포사이드, 탁솔, 탁소테레 및 다른 알칼로이드(예: 빈크리스틴)와 같은 세포 독성제와 함께 사용될 수 있다.하기 화학식 I의 화합물 또는 그의 약학적으로 허용가능한 염: 화학식 I [이미지] 상기 식에서, R1 내지 R8은 하이드록시, 수소, 할로겐, -CN, (C1-C6)알킬, (C2-C6)알케닐, (C6-C10)아릴(C2-C6)알케닐, (C2-C9)헤테로아릴(C2-C6 )알케닐, (C2-C6)알킬닐, (C6-C10)아릴(C2-C6)알키닐, (C2-C9)헤테로아릴(C2-C6)알키닐, (C 1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알콕시, 퍼플루오로(C1-C6)알킬, (C6-C10 )아릴, (C2-C9)헤테로아릴, (C6-C10)아릴아미노, (C6-C10)아릴티오, (C6-C10)아릴옥시, (C2-C 9)헤테로아릴아미노, (C2-C9)헤테로아릴티오, (C2-C9)헤테로아릴옥시, (C3-C6)사이클로알킬, (C1-C6)알킬(하이드록시메틸렌), 피페리딜, (C1-C6)알킬피페리딜, (C1-C6)아실아미노, (C1-C6)아실티오, (C1-C6)아실옥시, (C1-C6)알콕시-(C=O)-, -CO2H, (C1-C 6)알킬-NH-(C=O)- 및 [(C1-C6)알킬]2-N-(C=O)-로 이루어진 군으로부터 선택되어지되; 상기 (C 1-C6)알킬은 (C1-C6)알킬티오, (C1-C6)알콕시, 트리플루오로메틸, 할로, -CN, (C6-C10)아릴, (C2-C9)헤테로아릴, (C6-C10)아릴아미노, (C6-C10)아릴티오, (C6-C10)아릴옥시, (C2-C9)헤테로아릴아미노, (C2-C9)헤테로아릴티오, (C2-C9)헤테로아릴옥시, (C6-C10)아릴(C6-C10)아릴, (C3-C6)사이클로알킬, 하이드록시, 피페라지닐, (C6-C10)아릴(C 1-C6)알콕시, (C2-C9)헤테로아릴(C1-C6)알콕시, (C1-C6)아실아미노, (C1-C6)아실티오, (C1-C6)아실옥시, (C1-C6)알킬설피닐, (C6-C10)아릴설피닐, (C1-C 6)알킬설포닐, (C6-C10)아릴설포닐, 아미노, (C1-C6)알킬아미노 및 ((C1-C6)알킬)2아미노로부터 선택된 하나 또는 2개의 그룹에 의해 선택적으로 치환되거나; R1 및 R2, 또는 R3 및 R4, 또는 R5 및 R6은 함께 카보닐을 형성할 수 있거나; R1 및 R2, 또는 R3 및 R4, 또는 R5 및 R6, 또는 R7 및 R8은 함께 (C3-C6)사이클로알킬, 옥사사이클로헥실, 티오사이클로헥실, 인다닐 또는 테트랄리닐 고리 또는 식 [이미지]그룹을 형성할 수 있고; Ar은, 할로, -CN, 하나 이상의 불소 원자로 선택적으로 치환된 (C1-C6)알킬, 하이드록시, 하이드록시(C1-C6)알킬, 하나 이상의 불소 원자에 의해 선택적으로 치환된 (C1-C6)알콕시, (C1-C6)알콕시(C1-C6)알킬, HO-(C=O)-, (C1-C6)알킬-O-(C=O)-, HO-(C=O)-(C1-C6)알킬, (C1-C6)알킬-O-(C=O)-(C1-C 6)알킬, (C1-C6)알킬-(C=O)-O-, (C1-C6)알킬-(C=O)-O-(C1-C6)알킬, H(O=C)-, H(O=C)-(C1-C6)알킬, (C 1-C6)알킬(O=C)-, (C1-C6)알킬(O=C)-(C1-C6)알킬, NO2, 아미노, (C1-C 6)알킬아미노, [(C1-C6)알킬]2아미노, 아미노(C1-C6)알킬, (C1-C6)알킬아미노(C1-C6 )알킬, [(C1-C6)알킬]2아미노(C1-C6)알킬, H2N-(C=O)-, (C1-C6)알킬-NH-(C=O)-, [(C1-C6)알킬] 2N-(C=O)-, H2N(C=O)-(C1-C6)알킬, (C1-C6)알킬-HN(C=O)-(C1-C6)알킬, [(C1-C6 )알킬]2N-(C=O)-(C1-C6)알킬, H(O=C)-NH-, (C1-C6)알킬(C=O)-NH-, (C1-C6)알킬(C=O)-[NH](C1-C 6)알킬, (C1-C6)알킬(C=O)-[N(C1-C6)알킬](C1-C6)알킬, (C1-C6)알킬-S-, (C1 -C6)알킬-(S=O)-, (C1-C6)알킬-SO2-, (C1-C 6)알킬-SO2-NH-, H2N-SO2-, H2N-SO2-(C1-C 6)알킬, (C1-C6)알킬HN-SO2-(C1-C6)알킬, [(C1-C6)알킬]2N-SO2-(C1-C6)알킬, CF3SO 3-, (C1-C6)알킬-SO3-, 페닐, 페닐(C1-C6)알킬, (C3-C10)사이클로알킬, (C2-C9)헤테로사이클로알킬 및 (C2-C9 )헤테로아릴로부터 독립적으로 선택된 하나 이상의 치환기에 의해 선택적으로 치환된, (C6-C10)아릴(C1-C 6)알콕시(C6-C10)아릴, (C6-C10)아릴(C1-C6)알콕시(C 2-C9)헤테로아릴, (C2-C9)헤테로아릴(C1-C6)알콕시(C6-C10)아릴 또는 (C2-C9)헤테로아릴(C 1-C6)알콕시(C2-C9)헤테로아릴이고; 단, R1 내지 R8중 하나 이상은 하이드록시이고, 화학식 I의 화합물은 하기 화합물은 될 수 없다: (2R,4S)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-(2-클로로-티아졸-5-일메톡시)-벤젠설포닐]-3-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-1-[4-(티아졸-5-일메톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-1-[4-(피리딘-4-일메톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-3-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-[2-(4-플루오로페닐)에톡시]-벤젠설포닐]-3-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-1-[4-(2-피리딘-4-일-에톡시]-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-(벤조티아졸-2-일메톡시]-벤젠설포닐]-3-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-1-[4-(5-트리플루오로메틸-벤조티아졸-2-일메톡시]-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-1-[4-(1H-테트라졸-5-일메톡시]-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-(2-클로로-티아졸-5-일메톡시]-벤젠설포닐]-3-하이드록시-3-메틸-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-3-메틸-1-[4-(티아졸-5-일메톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-3-메틸-1-[4-(피리딘-4-일메톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-3-하이드록시-3-메틸-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-[2-(4-플루오로페닐)-에톡시]-벤젠설포닐]-3-하이드록시-3-메틸-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-3-메틸-1-[4-(2-피리딘-4-일-에톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-[4-(벤조티아졸-2-일메톡시)-벤젠설포닐]-3-하이드록시-3-메틸-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-3-메틸-1-[4-(5-트리플루오로메틸-벤조티아졸-2-일메톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-3-하이드록시-3-메틸-1-[4-(1H-테트라졸-5-일메톡시)-벤젠설포닐]-피페리딘-2-카복실산 하이드록시아미드; (2R,4S)-1-(4-벤질옥시-벤젠설포닐)-4-부틸아미노메틸-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,4S)-4-부틸아미노메틸-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,4R)-1-(4-벤질옥시-벤젠설포닐)-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,4R)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,5S)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-5-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,5S)-1-(4-벤질옥시-벤젠설포닐)-5-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,5R)-1-(4-벤질옥시-벤젠설포닐)-5-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,5R)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-5-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,3S)-1-(4-벤질옥시-벤젠설포닐)-3-하이드록시-피페리딘-2-카복실산 하이드록시아미드; (2R,4S)-1-(4-벤질옥시-벤젠설포닐)-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드; 및 (2R,4S)-1-[4-(4-플루오로벤질옥시)-벤젠설포닐]-4-하이드록시-피페리딘-2-카복실산 하이드록시아미드.