CN1113862C - 芳基磺酰氨基异羟肟酸衍生物 - Google Patents
芳基磺酰氨基异羟肟酸衍生物 Download PDFInfo
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Abstract
具式(I)的化合物(其中R1,R2和Q的定义同上)对于下列疾病状态的治疗是有用的,其包括关节炎,癌症,组织溃疡形成,斑退化,(心瓣膜)再狭窄,牙周疾病,表皮松懈bullosa,巩膜炎,以及其他以基质金属蛋白酶活性为特征的疾病,AIDS,脓毒病,脓毒性休克以及其它涉及TNF生成的疾病。另外本发明化合物可与其它标准的非甾体抗炎药物(NSAID’S)以及止痛药合用进行治疗,在癌症的治疗中,其可与细胞毒药物(例如阿霉素,柔红霉素,顺铂,鬼臼乙叉甙,紫杉酚,紫杉烷衍生物以及生物碱,长春新碱)合用。
Description
本发明涉及芳基磺酰氨基异羟肟酸衍生物,其为基质金属蛋白酶或肿瘤坏死因子(TNF)产生的抑制剂,可以用来治疗下列疾病:关节炎,癌症,组织溃疡,斑退化,(心瓣膜)再狭窄,牙周疾病,大疱性表皮松懈,巩膜炎,以及其他以基质金属蛋白酶活性为特征的疾病,AIDS,脓毒症,脓毒性休克以及其它涉及TNF生成的疾病。另外本发明化合物可与其它标准的非甾体抗炎药物(NSAID’S)以及止痛药合用进行关节炎的治疗,还可与细胞毒药物(例如阿霉素,柔红霉素,顺铂,鬼臼乙叉甙,紫杉酚,紫杉烷衍生物(taxotere)以及生物碱,长春新碱)合用进行癌症的治疗。
本发明还涉及使用这类化合物来治疗哺乳动物(尤其是人类)体内的上述疾病的方法,本发明还涉及可用于上述方法中的药物组合物。
有许多酶可以破坏蛋白质的结构,它们在结构上与金属蛋白酶有关。基质降解金属蛋白酶(例如明胶酶,溶基质素和胶原酶)与组织基质降解有关(例如胶原萎陷),并且与许多涉及异常连接组织和底膜基质代谢的病原状况有关,例如关节炎(如骨关节炎和风湿性关节炎),组织溃疡形成,(如角膜、表皮和胃溃疡形成),异常创伤愈合,牙周疾病,骨病(如Paget’s疾病和骨质疏松),肿瘤转移或侵入,以及HIV-感染(
J.Leuk.Biol.,
52(2):244-248,1992)。
人们已认识到,肿瘤坏死因子(TNF)与许多感染和自身免疫疾病有关(W.Fiers,
FEBS Letters,1991,
285,199)。进一步地,已有显示,在脓毒病和脓毒性休克的炎症反应中,TNF是主要的递质(C.E.Spooner et al.,
Clinical Immunology and Immunopathology,1992,
62 S11)。
本发明涉及下式化合物或其药用盐,其中R1和R2各自独立为(C1-C6)烷基,三氟甲基,三氟甲基(C1-C6)烷基,(C1-C6)烷基(二氟亚甲基),(C1-C3)烷基(二氟亚甲基(C1-C3)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,或R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环或下式基团其中的n和m各自独立为1或2且X为CF2,S,O或NR3,其中R3为氢,(C1-C6)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基或酰基;并且
Q为(C1-C6)烷基,(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基,(C6-C10)芳基(C2-C9)杂芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基,(C1-C6)烷基(C6-C10)芳基,(C1-C6)烷氧基(C6-C10)芳基,(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基,(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基,(C2-C9)杂芳氧基(C6-C10)芳基,(C1-C6)烷基(C2-C9)杂芳基,(C1-C6)烷氧基(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基,(C2-C9)杂芳氧基(C2-C9)杂芳基,(C6-C10)芳氧基(C1-C6)烷基,(C2-C9)杂芳氧基(C1-C6)烷基,(C1-C6)烷基(C6-C10)芳氧基(C6-C10)芳基,(C1-C6)烷基(C2-C9)杂芳氧基(C6-C10)芳基,(C1-C6)烷基(C6-C10)芳氧基(C2-C9)杂芳基,(C1-C6)烷氧基(C6-C10)芳氧基(C6-C10)芳基,(C1-C6)烷氧基(C2-C9)杂芳氧基(C6-C10)芳基或(C1-C6)烷氧基(C6-C10)芳氧基(C2-C9)杂芳基,其中的每一个芳基基团可以任意地被1-3个下面基团取代,氟,氯,溴,(C1-C6)烷基,(C1-C6)烷氧基或全氟(C1-C3)烷基(C6-C10)芳氧基,三氟甲氧基或二氟甲氧基取代。
除非另有说明,这里的术语“烷基”是指具有直链、支链或环状基团或其混合物的饱和单键烃类基团。
这里的术语“烷氧基”包括O-烷基基团,其中“烷基”的定义同上。
除非另有说明,这里的术语“芳基”包括衍生自移去一个氢原子后的芳烃有机基团,例如苯基或萘基,它们可以任意地被1-3个下列基团取代:氟,氯,溴,全氟(C1-C3)烷基,三氟甲基,(C1-C6)烷氧基,(C6-C10)芳氧基,三氟甲氧基,二氟甲氧基以及(C1-C6)烷基。
除非另有说明,这里的术语“杂环芳基”包括衍生自移去一个氢原子后的芳烃杂环化合物的有机基团,例如吡啶基,呋喃基,吡咯基,噻吩基,异噻唑基,咪唑基,苯并咪唑基,四唑基,吡嗪基,嘧啶基,喹啉基,异喹啉基,苯并呋喃基,异苯并呋喃基,苯并噻吩基,吡唑基,吲哚基,异吲哚基,嘌呤基,咔唑基,异噁唑基,噻唑基,噁唑基,苯并噻唑基或苯并噁唑基,它们可以任意地被1-2个下列基团取代:氟,氯,三氟甲基,(C1-C6)烷氧基,(C6-C10)芳氧基,三氟甲氧基,二氟甲氧基以及(C1-C6)烷基。
除非另有说明,这里的术语“酰基”包括具有通式RCO的基团,其中的R为烷基,烷氧基,芳基,芳烷基或芳烷氧基,并且术语“烷基”和“芳基”的定义同上。
这里的术语“酰氧基”包括O-酰基基团,其中“酰基”的定义同上。
式I的化合物可以具有手性中心,因此可以不同的的对映体形式存在。本发明涉及式I化合物所有的光学异构体和立体异构体以及它们的混合物。
优选的式I的化合物包括这些化合物,其中R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环或下式基团其中的n和m各自独立为1或2且X为CF2,S,O或NR3,其中R3为氢,(C1-C6)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基或酰基。
其它优选的式I化合物包括那些化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环。
其它优选的式I化合物包括那些化合物,其中Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
其它优选的式I的化合物包括那些化合物,其中Q为(C6-C10)芳氧基(C6-C10)芳基。
其它优选的式I化合物包括那些化合物,其中的R1和R2各自独立为(C1-C6)烷基。
更优选的式I的化合物包括那些化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环或下式基团其中的n和m各自独立为1或2且X为CF2,S,O或NR3,其中R3为氢,(C1-C6)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基或酰基;且Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
更优选的式I的化合物包括那些化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环;并且Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
更优选的式I的化合物包括那些化合物,其中的R1和R2各自独立为(C1-C6)烷基,且Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
更优选的式I的化合物包括那些化合物,其中的R1和R2各自独立为(C1-C6)烷基;并且Q为(C6-C10)芳氧基(C6-C10)芳基。
具体的优选化合物包括下列化合物:
3-[4-(4-氟苯氧基)苯磺酰氨基]氮杂环丁烷-3-甲酸羟基酰胺;
4-[4-(4-氟苯氧基)苯磺酰氨基]哌啶-4-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺;
1-[4-(4-氯苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环丁烷-1-甲酸羟基酰胺;
1-[4-(4-氯苯氧基)苯磺酰氨基]环丁烷-1-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环戊烷-1-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环己烷-1-甲酸羟基酰胺;
2-[4-(4-氟苯氧基)苯磺酰氨基]-N-羟基-2-甲基丙酰胺;
2-[4-(4-氯苯氧基)苯磺酰氨基]-N-羟基-2-甲基丙酰胺;
N-羟基-2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)丙酰胺;
1-(5-吡啶-2-基-噻吩-2-磺酰氨基)环戊烷-1-甲酸羟基酰胺;
1-(4’-氟代联苯基-4-磺酰氨基)环丙烷-1-甲酸羟基酰胺;
1-(4’-氟代联苯基-4-磺酰氨基)环丁烷-1-甲酸羟基酰胺;
1-(4’-氟代联苯基-4-磺酰氨基)环戊烷-1-甲酸羟基酰胺;
2-(4-甲氧基苯磺酰氨基)1,2-二氢化茚-2-羧酸羟基酰胺;以及
2-[4-(4-氟苯氧基)苯磺酰氨基]1,2-二氢化茚-2-甲酸羟基酰胺。
本发明还涉及用于下列目的的药物组合物(a)与细胞毒抗肿瘤剂协同作用治疗下列疾病:关节炎,癌症,组织溃疡形成,斑退化,(心瓣膜)再狭窄,牙周疾病,大疱性表皮松懈,巩膜炎,与其它标准的NSAID’S和止痛药合用以及其它以基质金属蛋白酶活性为特征的疾病,AIDS,脓毒病,脓毒性休克以及其它涉及肿瘤坏死因子(TNF)生成的疾病,或(b)抑制哺乳动物(包括人类)体内基质金属蛋白酶或肿瘤坏死因子(TNF)的生成,其包括在这类治疗中,给予有效剂量的式I的化合物或其药用盐以及药用载体。
本发明涉及下述抑制方法抑制哺乳动物(包括人类)体内(a)基质金属蛋白酶或(b)肿瘤坏死因子(TNF)的生成,其包括给予所述哺乳动物有效剂量的式I化合物或其药用盐。
本发明还涉及治疗下列疾病的方法:关节炎,癌症,组织溃疡形成,斑退化,(心瓣膜)再狭窄,牙周疾病,大疱性表皮松懈,巩膜炎,与NSAID’S和止痛药合用,并且可与细胞毒抗肿瘤剂合用以及其它以基质金属蛋白酶活性为特征的疾病,AIDS,脓毒病,脓毒性休克以及其它涉及哺乳动物(包括人类)体内肿瘤坏死因子(TNF)生成的疾病,该方法包括,在这类治疗中给予所述哺乳动物有效剂量的式I的化合物或其药用盐。
下列路线将说明本发明化合物的制备。除非另有说明,反应路线和随后讨论中的R1,R2和Q的定义同上。
路线1
在制备A反应1中,于惰性溶剂中(例如苯或甲苯,甲苯为优选),用苄醇和具式HX的酸(其中X优选为4-甲苯磺酸盐)处理式III氨基酸,得到相应的式V苄酯酸盐。正常情况下,反应在所用溶剂的回流温度下进行1-24小时。此反应过程中形成的水用Dean-Strar捕获器进行收集。
在制备A反应2中,使V与磺酸(QSO2OH)的反应活性功能衍生物(如磺酰氯(QSO2Cl))在碱(如氢氧化钠或三乙胺)和溶剂(如二氯甲烷,四氢呋喃,二噁烷,水或乙腈,优选的是二噁烷和水的混合物)的存在下进行反应,使式V化合物转化为相应的式VI化合物。反应混合物在约0-50℃(最好是室温下)下搅拌10分钟-2天,优选的是约60分钟。
在制备A反应3中,将式VI中间体化合物氢解,得到中间体式II。反应于氢气下(优选的是3个大气压),在溶剂中(例如乙醇)使用10%Pd/C催化剂进行。室温下搅拌反应混合物约30分钟-24小时,优选的是1.5小时。
在路线1反应1中,使III与具式QSO2OH的磺酸的反应活性功能衍生物(其中Q的定义同上)(如磺酰氯(QSO2Cl))在碱(如氢氧化钠或三乙胺)和极性溶剂(如四氢呋喃,二噁烷,水或乙腈,优选的是二噁烷和水的混合物)的存在下进行反应,将式III化合物转化为相应的式II化合物。反应混合物在约0-50℃(最好是室温下)下搅拌10分钟-2天,优选的是约60分钟。
在路线1反应2中,使II与1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺和1-羟基苯并三唑在极性溶剂(如N,N-二甲基甲酰胺)进行反应,约15分钟-1小时后(优选的是约30分钟),向反应混合物中加入羟胺,使式II化合物转化为式I异羟肟酸化合物。优选地,在碱存在下(如三乙胺),羟胺从其盐的形式就地生成,例如从羟胺盐酸盐。另外,也可以用羟胺的保护衍生物或其盐的形式(其中的羟基被叔丁基、苄基,烯丙基或2-三乙基甲硅烷基乙基醚保护)代替羟胺或羟胺盐酸盐。羟基保护基团的去除采用与苄基保护基团氢解一样的条件进行(优选的是以5%Pd/硫酸钡作催化剂),或采用叔丁基保护基去除的方法,即用强酸(如三氟乙酸)进行处理。在催化的双(三苯基膦)氯化钯(II)的存在下,用三丁基锡氢化物和乙酸进行处理,可以去除烯丙基保护基。使2-三甲基甲硅烷基乙基醚与强酸(如三氟乙酸)或与氟供给体(如三氟化硼醚化物)进行反应,可以去除2-三甲基甲硅烷基乙基醚。式II与羟胺,羟胺盐,羟胺保护衍生物或羟胺保护衍生物盐的反应可在(苯并三唑-1-基氧)三(二甲基氨基)-磷鎓六氟化磷酸盐(酯)和碱(如三乙胺)的存在下,于惰性溶剂(如二氯甲烷)中进行。反应混合物在0-50℃下(优选的是室温下)搅拌1小时-3天,优选的是1天。优选地,转化化合物II至化合物I的过程是使II与O-苄基羟胺盐酸盐在(苯并三唑-1-基氧)三(二甲基氨基)-磷鎓六氟磷酸盐(酯)和三乙胺存在下,于二氯甲烷中进行反应。室温3大气压氢气下,用5%Pd/硫酸钡作催化剂,进行氢解,去除O-苄基保护基团,得到式I化合物。优选的溶剂是甲醇。反应时间约为1-5小时(优选的是3.5小时)。
在某些情况下,优选的是使羟胺,羟胺盐,羟胺保护衍生物或羟胺保护衍生物盐与式IV活性酯进行反应,得到式I化合物,如路线1反应3所示。反应在惰性溶剂(如N,N-二甲基甲酰胺)中进行,反应温度约为室温至80℃,优选的是约50℃,反应时间约为1小时-2天。如果采用羟胺保护衍生物或羟胺保护衍生物的盐,则按上述方法去除保护基团。在惰性溶剂(例如二氯甲烷)中,用(苯并三唑-1-基氧)三(二甲基氨基)-磷鎓六氟磷酸(酯)和碱(如三乙胺)处理式II化合物可以得到式IV活性酯衍生物(见路线1反应4)。反应混合物在约0-50℃(优选的是室温)下搅拌约1小时-3天,优选的是1天。
本发明酸性化合物的药用盐是与碱形成的盐类,称为阳离子盐类,如碱和碱土金属盐,比如钠,锂,钾,钙,镁以及铵盐,如铵,三甲基铵,二乙基铵以及三(羟基甲基)-甲基铵盐。
相似地,酸加成盐(例如无机酸,有机羧酸和有机磺酸,如盐酸,甲磺酸,马来酸)也可以与碱性基团(如吡啶基)构成结构的一部分。
式I化合物或它们药用盐(下文中也称为本发明化合物)抑制基质金属蛋白酶或肿瘤坏死因子(TNF)生成的能力,以及它们治疗以基质金属蛋白酶或肿瘤坏死因子生成为特征的疾病的有效性的证明,可以参见下面的体外分析结果。
生物试验
人类胶原酶的抑制(MMP-1)
采用下列比例,使用胰蛋白酶可以活化人类重组胶原酶:每100μg胶原酶10μg胰蛋白酶。将胰蛋白酶和胶原蛋白在室温下培养10分钟。然后加入5倍过量的(50μg/10μg胰蛋白酶)大豆胰蛋白酶抑制剂。
在二甲亚砜中制备10mM的抑制剂贮备液,然后按下面稀释。
10mM→120μM→12μM→1.2μM→0.12μM
取每个浓度25mL溶液加到96孔显微平皿的合适孔内,每个样品制备三份。加入酶和底物后抑制剂的最终浓度按1∶4稀释。在D1-D6孔中建立阳性对照(有酶,无抑制剂),在D7-D12孔中建立空白对照(无酶,无抑制剂)。
将胶原酶稀释至400ng/mL,向上述显微平皿的合适孔内加入25μL该溶液。试验中胶原酶的最终浓度为100ng/mL。
制备5mM底物(DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)的二甲亚砜贮备溶液,然后用分析缓冲液稀释至20μM。在显微平皿的每个孔中加入50μL底物,得到的最终浓度为10μM,开始进行分析。
在0分钟以及每20分钟为一间隔时进行荧光读数(360nM激发,460nM发射)。分析在室温下进行,典型的分析时间为3小时。
然后就空白及含有样品的胶原酶的荧光相对于时间的结果绘图(取三个样品的平均数)。选择提供较好信号的时间点(空白)以及曲线上的直线部分时间点(通常在120分钟左右)来确定IC50值。零时刻被作为每个化合物在每个浓度下的空白,并且,这些值须从120分钟得到的数据中扣除。就抑制浓度相对于%对照样品的数据进行绘图(抑制剂荧光值除去单独胶源酶的荧光值×100)。给出相当于对照样品50%信号值时对应的抑制剂浓度被确定为IC50值。
如果报告的IC50值<0.03μM,则在0.3μM,0.03μM,0.03μM以及0.003μM浓度下分析抑制剂。
明胶酶抑制(MMP-2)
在与人类胶原酶抑制(MMP-1)相同的条件下,采用DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2底物(10μM)分析明胶酶的活性。
在4℃下,用1mMAPMA(对氨基苯基乙酸汞)使72KD的明胶酶活化,并将其稀释至最终浓度为100mg/mL。将用于抑制人类胶原酶(MMP-1)的抑制剂进行稀释,得到最终浓度为30μM,3μM,0.3μM和0.03μM,每个浓度制备3份。
在0分钟以及每20分钟为一间隔时进行荧光读数(360nM激发,460nM发射),共持续4小时。
测定每一个人类胶原酶(MMP-1)的抑制。如果报告的IC50值<0.03μM,则在0.3μM,0.03μM,0.003μM以及0.003μM的最终浓度下检测抑制剂。
溶基质素活性的抑制(MMP-3)
溶基质素活性抑制是基于Weingarten和Feder(Weingarten,H.和Feder,J.,Spectrophotometric Assay for VertebrateCollagenase,Anal.Biochem.
147,437-440(1985))所描述的改进的分光光度分析法进行的。硫代肽酯(peptolide)底物[Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5]的水解产生了硫醇片断,在Ellman’s试剂的存在下,可对其进行监测。
用胰蛋白酶活化人类重组前溶基质素,使用比例为每26μg溶基质素1μL的10mg/mL胰蛋白酶贮备液。胰蛋白酶和溶基质素在37℃下培养15分钟,接着与10μL 10mg/mL大豆胰蛋白酶抑制剂于37℃下培养10分钟以终止胰蛋白酶活性。
用96孔显微平皿并在总体积为250μL的分析缓冲液(200mM氯化钠,50mM MES以及10mM氯化钙,pH6.0)中进行分析。用分析缓冲液将活化的溶基质素稀释至25μg/mL。在二甲基甲酰胺中制备1M的Ellman’s试剂(3-羧基-4-硝基苯基二硫化物)储备溶液,并用缓冲液稀释至浓度为5mM,以使在每孔50μL加量下可以产生1mM的最终浓度。
在二甲基亚砜中制备10mM抑制剂贮备溶液,并用缓冲液进行系列稀释,以便将50μL该溶液加到合适的孔中时,可以产生的最终浓度为3μM,0.3μM,0.003μM以及0.0003μM。所有的条件制备3份样品。
用分析缓冲液将300mM肽底物的二甲基亚砜贮备溶液稀释到15mM,向每孔中加入50μL该溶液后得到最终浓度为3mM的底物,开始进行分析。背景含有肽底物和Ellman’s试剂,但没有酶。用Molecular Devices Uvmax平皿读数器在405nm处监测产品的形成。
用与同胶原酶相同的方法测定IC50值。
MMP-13的抑制
37℃下,用2mM APMA(对氨基苯基乙酸汞)使人类重组MMP-13活化1.5小时,并用分析缓冲液(50mM Tris,pH7.5,200mM氯化钠,50mM氯化钙,20μM氯化锌以及0.02% brij)将其稀释至400mg/ml。96孔显微平皿的每一个孔中加25μl稀释液。在分析缓冲液中以1∶4的比例加入抑制剂和底物对酶进行稀释,使其在分析缓冲液中的最终浓度为100mg/ml。
在二甲基亚砜中制备10mM抑制剂贮备溶液,并按照用于抑制人类胶原酶(MMP-1)的抑制剂稀释路线用缓冲液对其进行稀释,向显微平皿中加入25μl各个浓度的溶液,每个样品制备3份。分析缓冲液中的最终浓度为30μM,3μM,0.3μM和0.03μM。
制备用于抑制人类胶原酶(MMP-1)的底物(Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NNA)-NH2],并向每孔中加入50μL该溶液,使最终的分析浓度为10μM。在0时刻以及每5分钟时进行荧光读数(360nM激发,450nM发射),持续1小时。
阳性对照含有酶和底物,但不含抑制剂,空白仅含有底物。
用与同人类胶原酶(MMP-1)相同的方法测定IC50值。如果报告的IC50值<0.03μM,则在0.3μM,0.03μM,0.003μM以及0.0003μM的最终浓度下进-步分析抑制剂。
TNF生成的抑制
下列体外分析显示了化合物或其药用盐抑制TNF生成的能力并随之证明了它们在治疗与TNF生成有关疾病方面的效力:
采用一步Ficoll-hypaque(3,5-二乙酰胺基-2,4,6-三碘苯甲酸钠)分离技术,从人抗凝血中将人类单核细胞分离出来。(2)在Hanks平衡盐溶液(HBSS)中,用二价阳离子溶液将单核细胞洗涤三次,并将其再悬浮于含有1%BSA、密度为2×106/ml的HBSS中。用Abbott Cell Dyn 3500分析仪测定得到的分化计数表明:在这些制备物中,单细胞占细胞总数的17-24%。
将180μL细胞悬浮物等分到96孔平皿的平整底部(Costar)。加入化合物和LPS(最终浓度为100ng/ml),最终体积达到200μL。所有条件制备3份。在一个加湿二氧化碳培养器中培养4小时后,移去平皿,离心(大约250×g,10分钟),除去上清液,用R&D ELISAKit分析TNFa。
就哺乳动物(包括人类)的给药来说,为了抑制基质金属蛋白酶或肿瘤坏死因子(TNF)的生成,可以采用各种常规的给药途径,包括口服、非肠道以及局部给药。通常活性成分以口服或非肠道途径给药,剂量在约0.1至25mg/Kg接受者体重/每天,优选的是0.3至5mg/Kg。然而,根据接受治疗对象的情况,剂量可进行必要的变化。在任何情况下,负责给药的人将根据给药对象的情况来决定合适的给药剂量。
本发明化合物可以很多不同的剂型给药,一般来说,上述剂型的治疗有效剂量的本发明化合物的浓度水平在约5.0%至70%(重量比)。
对于口服给药而言,可以采用含有各种赋形剂(例如微晶纤维素,柠檬酸钠,碳酸钙,磷酸二钙以及甘油)的片剂,其可带有各种崩解剂,例如淀粉(优选的是玉米、土豆或木著淀粉),藻酸以及某些复合硅酸盐,还可以含有粒化粘合剂,如聚乙烯吡咯烷酮,蔗糖,明胶以及金合欢素。另外,片剂中还常使用润滑剂,例如硬脂酸镁,月桂基硫酸钠以及滑石。相似类型的固体组合物也被用作明胶胶囊中的填充剂;在这种情况中,优选的材料包括乳糖或牛奶糖以及高分子量的聚乙二醇。当需要水合悬浮液和/或酏剂进行口服给药时,可将活性成分与各种增甜剂或增味剂,增色物质以及染料合用,并且如有所需,还可与乳化剂及悬浮剂合用,同时其还可以含有稀释剂,如水,乙醇,丙二醇,甘油以及各种它们的组合物质。在进行动物给药时,较好的是将这些物质含于动物饲料或饮用水中,浓度为5-5000ppm,优选的是25-500ppm。
对于非肠道给药(肌内,腹膜内,皮下以及静脉内)来说,通常是制备活性成分的无菌注射溶液。可以应用本发明治疗化合物的芝麻油或花生油溶液,或者是丙二醇的水溶液。水溶液应适当调节和缓冲,优选的是pH大于8,如有所需,须首先使液体稀释剂等渗。这些水溶液适合于静脉给药。油性溶液适合于关节内,肌内和皮下注射给药。采用本领域内专家们熟知的方法,可以方便地在无菌条件下完成所有这些溶液的制备。在进行动物给药时,可以采用肌内和皮下注射给药,剂量水平在约0.1-50mg/Kg/天,优选的是0.2-10mg/Kg/天,可以采取单一剂量或多至3个分开剂量进行给药。
下列实施例将说明本发明,但并不限制本发明的详细内容。
制备A
4-(4-氟苯氧基)苯磺酰基氯化物
在机械搅拌下,将氯代磺酸(26ml,0.392mole)滴加到冰冷的4-氟代苯氧基苯(36.9g,0.196mole)。加入完毕,混合物于室温下搅拌4小时。将其倾入冰水中。滤集产品4-(4-氟苯氧基)苯磺酰基氯化物(18.6g,33%),并在空气中干燥。
制备B
4-(3-甲基丁氧基)苯磺酸钠
使4-羟基苯磺酸(10.0g,43.1mmole)以及氢氧化钠(3.3g,83mole)的水溶液(40mL)与1-碘-3-甲基丁烷(11.3mL,86.4mmole)的异丙醇溶液(60mL)进行混合,生成的混合物加热回流2天。减压蒸除异丙醇。过滤并用异丙醇洗涤,得到10.0g(87%)标题化合物。
制备C
4-(3-甲基丁氧基)苯磺酰氯
使4-(3-甲基丁氧基)苯磺酸钠(2.5g,9.4mmole),亚硫酰氯(10mL)以及5滴N,N-二甲基甲酰胺的混合物一起回流5小时。冷却后,蒸除多余的亚硫酰氯,残渣溶于乙酸乙酯中。溶液在冰浴上冷却,加水。分出有机相,用水和盐水洗涤。硫酸钠干燥后,蒸除溶剂,得到2.4g(95%)标题化合物,其为油状物。
制备D
4-(2-环戊基乙氧基)苯磺酸钠
将4-羟基苯磺酸(65g,282mmole)以及氢氧化钠(2.2g,55mole)的水溶液(15mL)与2-(溴乙基)环戊烷(15.0g,84.7mmole)的异丙醇溶液(40mL)进行混合,生成的混合物加热回流2天。减压蒸除异丙醇。过滤并用异丙醇洗涤,得到4.7g(57%)标题化合物。
制备E
4-(3-甲基丁氧基)苯磺酰氯
使4-(2-环戊基乙氧基)苯磺酸钠(2.5g,8.6mmole),亚硫酰氯(15mL)以及几滴N,N-二甲基甲酰胺的混合物一起回流5小时。冷却后,蒸除多余的亚硫酰氯,残渣溶于乙酸乙酯中。溶液在冰浴上冷却,加水。分出有机相,用水和盐水洗涤。硫酸钠干燥后,蒸除溶剂,得到2.24g(90%)标题化合物,其为油状物。
制备F
4’-氟代联苯基磺酰基氯化物
在冰浴搅拌下,将氯代磺酸(8.7mL,0.13mole)滴加到4-氟代联苯(10.2g,59mole)中。冰浴下继续搅拌0.5小时,然后将混合物倾入冰中。滤集生成的白色沉淀并将其溶于氯仿中。用水和盐水洗涤氯仿溶液,硫酸镁干燥,浓缩,得到一白色固体。通过用乙酸乙酯对其进行重结晶,将所需产品4’-氟代联苯基磺酰基氯化物(4.3g,27%)从4’-氟代联苯基磺酸(不想要的副产物)中分离出来,剩余的物质用己烷进行重结晶。
制备G
4-(4-氟代苄氧基)苯磺酸钠
向4-羟基苯磺酸(513g,221mmole)的1N氢氧化钠水溶液(23mL)中加入4-氟代溴苄(33mL,265mmole)的乙醇溶液(20mL)。生成的混合物加热回流2天。冷却并放置后,出现白色沉淀。滤集沉淀,并用乙酸乙酯和乙醚进行洗涤,得到4.95g(74%)4-(4-氟代苄氧基)苯磺酸钠。
制备H
4-(4-氟代苄氧基)苯磺酰氯
向4-(4-氟代苄氧基)苯磺酸钠(0.5g,1.64mmole)的二氯甲烷(5mL)浆状物中加入五氯化磷(275mg,1.31mmole)。生成的混合物一起回流7小时。冰浴冷却后用水(15mL)终止反应,用乙酸乙酯提取。有机相用盐水洗涤。硫酸钠干燥后,蒸除溶剂,得到4-(4-氟代苄氧基)苯磺酰氯(130mg,26%),其为白色固体。
制备I
4-(4-氯代苄氧基)苯磺酰氯
室温搅拌下,将氯代苯磺酸(9.7mL,0.147mole)滴加到4-氯代苯氧基苯(12.6mL,73.4mmole)中。加入完毕,生成的混合物于室温下搅拌1小时,然后将其倾入冰水中。滤集固体,空气中干燥,用石油迷和乙酸乙酯重结晶,得到4-(4-氯代苄氧基)苯磺酰氯(7.43g,33%)
实施例1 1-(4-甲氧基苯磺酰基氨基)环戊烷-1-甲酸羟基酰胺
(A)向1-氨基环戊烷-1-甲酸(6.0g,46.5mmole)和三乙胺(14mL,100mmole)的二噁烷(90mL)和水(90mL)溶液中加入4-甲氧基苯磺酰氯(10.6g,51.3mmole)。混合物于室温下搅拌4小时,用1N盐酸溶液酸化,乙酸乙酯提取两次。合并的乙酸乙酯提取液用盐水洗涤,硫酸镁干燥,浓缩,得到一个褐色固体,用氯仿研制,5.42g(39%)得到1-(4-甲氧基苯磺酰基氨基)环戊烷-1-甲酸,其为白色固体。
(B)向1-(4-甲氧基苯磺酰基氨基)环戊烷-1-甲酸(4.65g,15.2mmole)和三乙胺(2.5mL,17.9mmole)的二氯甲烷(120mL)溶液中加入(苯并三唑-1-基氧)三(二甲基氨基)-磷鎓六氟磷酸盐(酯)(7.4g,16.3mmole)。混合物于室温下搅拌2.5天。蒸除溶剂,残渣用乙酸乙酯提取。溶液依次用0.5N盐酸溶液,水和盐水洗涤。硫酸镁干燥后浓缩溶剂,得到1-(4-甲氧基苯磺酰基氨基)环戊烷-甲酸苯并三唑-1-基酯,其为黄色固体。将其溶于N,N-二甲基甲酰胺(120mL)中,向生成的溶液中加入二异丙基乙基胺(5.3mL,30mmole)和O-苄基羟胺盐酸盐(3.2g,20mmole)。混合物在50℃的油浴上加热20小时。蒸除溶剂,加入乙酸乙酯。过滤混合物,收集白色固体。滤液依次用0.5N盐酸溶液,饱和碳酸氢钠水溶液和盐水洗涤。蒸除溶剂,得到的固体与前述过滤得到的固体合并,用乙酸乙酯研制,得到2.92g(47%)1-(4-甲氧基苯磺酰基氨基)环戊烷-1-甲酸苄氧基酰胺,其为白色固体。
(C)用5%Pd/硫酸钡(0.75g)处理1-(4-甲氧基苯磺酰基氨基)环戊烷-1-甲酸苄氧基酰胺(1.50mL,3.71mmole)的甲醇溶液(200mL),并在3个大气压下,于Parr shaker中进行氢化3.5小时。使混合物通过0.45μm的尼龙过滤器,滤液浓缩,得到1.13g(97%)1-(4-甲氧基苯磺酰基氨基)环戊烷-1-甲酸羟基酰胺,其为白色固体。MS:313(M-1)。
采用与实施例1中相似的方法,使用下列试剂,可以制备实施例2-8中的标题化合物。
实施例2 1-(4-甲氧基苯磺酰基氨基)环己烷-1-甲酸羟基酰胺
1-氨基环己烷-1-甲酸;4-甲氧基苯磺酰氯。MS:327(M-1)。
实施例31-[4-(4-氟苯氧基)苯磺酰氨基]环戊烷-1-甲酸羟基酰胺
1-氨基环戊烷-1-甲酸;4-(4-氟苯氧基)苯磺酰氯。MS:393(M-1)。元素分析(C18H19FN2O5S.0.25H2O)理论值:C 54.19,H4.93,N 7.02。实测值:C 54.20,H 5.13,N 7.08
实施例4 1-[4-(4-氟苯氧基)苯磺酰氨基]环己烷-1-甲酸羟基酰胺
1-氨基环己烷-1-甲酸;4-(4-氟苯氧基)苯磺酰氯。氯仿重结晶。MP:174℃;MS:393(M-1)。
实施例5 1-[4-(4-氟苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺
1-氨基环丙烷-1-甲酸;4-(4-氟苯氧基)苯磺酰氯。MP:184℃;MS:365(M-1);元素分析(C16H15FN2O5S)理论值:C 52.45,H4.13,N 7.65。实测值:C 52.20,H 4.34,N 7.44。
实施例6 1-(4’-氟代联苯基-4-磺酰氨基)环戊烷-1-甲酸羟基酰胺
1-氨基环戊烷-1-甲酸;4’-氟代联苯基磺酰氯。氯仿重结晶。MP:159℃;MS:377(M-1)。
实施例7 1-[4-(4-氟苯氧基)苯磺酰氨基]环丁烷-1-甲酸羟基酰胺
1-氨基环丁烷-1-甲酸;4-(氟苯氧基)苯磺酰氯。MS:379(M-1)。
实施例8 1-[4-(4-氟苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺
1-氨基环丙烷-1-甲酸;4-(4-氟苯氧基)苯磺酰氯。MS:379(M-1)。
实施例9 N-羟基-2-(4-甲氧基苯磺酰氨基)-2-甲基丙酰胺
(A)在冰浴上,将2-氨基-2-甲基丙酸苄酯盐酸盐(12.0g,52.2mmole)和4-甲氧基苯磺酰(11.9g,57.6mmole)的二噁烷溶液(100mL)以及水(100mL)进行冷却。加入三乙胺(18.2mL,0.13mole)。移去冰浴,混合物于室温下搅拌2天。减压蒸除溶剂,残余物溶于乙酸乙酯和水,分出水层,用乙酸乙酯提取两次,合并的有机层依次用饱和碳酸氢钠水溶液、1N盐酸以及盐水洗涤。硫酸钠干燥后,蒸发溶剂,得到黄色油状物(19.3g),其中的一部分(10g)用硅胶层析纯化,以3∶7的乙酸乙酯/己烷进行洗脱,乙酸乙酯/己烷重结晶后,得到6.59g(67%)2-(4-甲氧基苯磺酰氨基)-2-甲基丙酸苄酯,其为白色固体。
(B)在Parr振荡器中,用10%Pd/C(0.17g)和3大气压的氢气对2-(4-甲氧基苯磺酰氨基)-2-甲基丙酸苄酯(1.5g,4.13mmole)的乙醇溶液(80mL)处理1.5小时。使混合物通过0.45μm的尼龙过滤器除去催化剂,浓缩滤液,得到1.09g(96%)2-(4-甲氧基苯磺酰氨基)-2-甲基丙酸,其为白色固体。
(C)将2-(4-甲氧基苯磺酰氨基)-2-甲基丙酸(1.08g,3.95mmole)的二氯甲烷(120mL)溶液在冰浴上进行冷却。依次加入三乙胺(2.2mL,15.8mmole),(苯并三唑-1-基氧)三(二甲基氨基)-磷鎓六氟磷酸(酯)盐(2.6g,5.88mmole)以及O-苄基羟胺盐酸盐(0.95g,5.95mmole)。生成的混合物于室温下搅拌16小时。蒸除溶剂,残余物溶于用乙酸乙酯和水,溶液依次用1N盐酸,饱和碳酸氢钠水溶液,水及盐水洗涤。硫酸钠干燥后,蒸发溶剂,得到油状物。对其进行硅胶层析纯化,以1∶2的乙酸乙酯/己烷进行洗脱,得到1.41g(95%)所需的N-苄氧基-2-(4-甲氧基苯磺酰氨基)-2-甲基丙酰胺,其为白色固体。
(D)在Parr振荡器中,用5%Pd/硫酸钡(0.75g)和3大气压的氢气对N-苄氧基-2-(4-甲氧基苯磺酰氨基)-2-甲基丙酰胺,(1.40g,3.70mmole)的甲醇溶液(80mL)处理1.5小时。使混合物通过0.45μm尼龙过滤器,除去催化剂,浓缩滤液,得到1.06g(100%)N-羟基-2-(4-甲氧基苯磺酰氨基)-2-甲基丙酰胺,其为白色固体。MP:122-125℃,MS:289(M+1):元素分析(C11H16N2O5S)理论值:C 45.82,H 5.59,N 9.72;实测值:C 45.88,H 5.60,N 9.69。
采用与实施例9中相似的方法,使用下列试剂,可以制备实施例10-12中的标题化合物。
实施例10 2-[4-(4-氟苯氧基)苯磺酰氨基]-N-羟基-2-甲基丙酰胺
2-氨基-2-甲基丙酸苄酯盐酸盐;4-(4-氟苯氧基)苯磺酰氯。MP:133-134℃,MS:369(M+1):元素分析(C16H17FN2O5S)理论值:C 52.17,H 4.65,N 7.60;实测值:C 52.21,H 4.83,N 7.80。
实施例11 N-羟基-2-甲基-2-[4-(3-甲基丁氧基)苯磺酰氨基]-丙酰胺
2-氨基-2-甲基丙酸苄酯盐酸盐;4-(3-甲基丁氧基)苯磺酰氯。乙酸乙酯/己烷重结晶。MP:126.5-128℃,MS:343(M-1):元素分析(C15H24N2O5S)理论值:C 52.31,H 7.02,N 8.13;实测值:C 52.30,H 7.07,N 8.16。
实施例12 2-[4-(2-环戊基乙氧基)苯磺酰氨基]-N-羟基-2-甲基-丙酰胺
2-氨基-2-甲基丙酸苄酯盐酸盐;4-(2-环戊基乙氧基)苯磺酰氯。乙酸乙酯/己烷重结晶。MP:126-127℃,MS:369(M-1):元素分析(C17H26N2O5S)理论值:C 55.12,H 7.07,N 7.56;实测值:C 55.46,H 7.09,N 7.38。
实施例13 N-羟基-2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)-丙酰胺
(A)向2-氨基-2-甲基丙酸(2.0g,19.4mmole)的1N氢氧化钠溶液(45mL)中加入5-吡啶-2-基噻吩-2-磺酰氯(8.41g,32.4mmole)。生成的混合物于室温下搅拌16小时。再向其中加入1N氢氧化钠溶液(45mL),用乙醚提取。弃去有机层,水层用1N盐酸溶液酸化,乙酸乙酯提取。乙酸乙酯部分用盐水洗涤。硫酸钠干燥后,浓缩,得到2.18g(34%)2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)丙酸,其为白色固体。
(B)向2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)丙酸(1.60g,4.91mmole)的二氯甲烷(160ml)溶液中加入三乙胺(2.3mL,16.5mmole),(苯并三唑-1-基氧)三(二甲基氨基)-磷鎓六氟磷酸盐(酯)(2.4g,5.41mmole)以及O-(2-三甲基甲硅烷基乙基)羟胺盐酸盐(0.92g,5.41mmole)。生成的混合物于室温下搅拌16小时。蒸除溶剂,残渣用乙酸乙酯和水提取。溶液依次用水,1N盐酸,饱和碳酸氢钠水溶液及盐水洗涤。硫酸钠干燥后,蒸发溶剂,得到白色泡沫状物。对其进行硅胶层析纯化,以3∶2的乙酸乙酯/己烷进行洗脱,得到220mg(10%)所需的2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)-N-2-(三甲基硅烷基乙氧基)丙酰胺,其为白色固体。
(C)将2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)-N-2-(三甲基硅烷基乙氧基)丙酰胺(80mg,0.18mmole)溶于三氟乙酸中,生成的混合物于室温下搅拌16小时。减压蒸除三氟乙酸,用甲醇使之溶解,得到N-羟基-2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)-丙酰胺(60mg,97%),其为黄色油状物,再用乙醇重结晶。MP:165-166℃。MS:342(M+1)。
采用与实施例13中相似的方法,使用下列试剂,可以制备实施例14-15中的标题化合物。
实施例14 1-(5-吡啶-2-基-噻吩-2-磺酰氨基)环戊烷-1-甲酸羟基酰胺
1-氨基环戊烷-1-甲酸;5-吡啶-2-基噻吩-2-磺酰氯。MS:368(M+1)。
实施例15 1-[4-(4-氯苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺
1-氨基环丙烷-1-甲酸;4-(4-氯苯氧基)苯磺酰氯。MS:381(M-1)。
Claims (14)
1、具下式的化合物或其药用盐,
其中R1和R2各自独立为(C1-C6)烷基,三氟甲基,三氟甲基(C1-C6)烷基,(C1-C6)烷基(二氟亚甲基),(C1-C3)烷基(二氟亚甲基(C1-C3)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,或R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环或下式基团其中的n和m各自独立为1或2且X为CF2,S,O或NR3,其中R3为氢,(C1-C6)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基或酰基;并且
Q为(C1-C6)烷基,(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基(C1-C6)烷基,(C6-C10)芳基(C2-C9)杂芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基,(C1-C6)烷基(C6-C10)芳基,(C1-C6)烷氧基(C6-C10)芳基,(C6-C10)芳基(C1-C6)烷氧基(C6-C10)芳基,(C6-C10)芳基(C1-C6)烷氧基(C1-C6)烷基,(C2-C9)杂芳氧基(C6-C10)芳基,(C1-C6)烷基(C2-C9)杂芳基,(C1-C6)烷氧基(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷氧基(C2-C9)杂芳基,(C2-C9)杂芳氧基(C2-C9)杂芳基,(C6-C10)芳氧基(C1-C6)烷基,(C2-C9)杂芳氧基(C1-C6)烷基,(C1-C6)烷基(C6-C10)芳氧基(C6-C10)芳基,(C1-C6)烷基(C2-C9)杂芳氧基(C6-C10)芳基,(C1-C6)烷基(C6-C10)芳氧基(C2-C9)杂芳基,(C1-C6)烷氧基(C6-C10)芳氧基(C6-C10)芳基,(C1-C6)烷氧基(C2-C9)杂芳氧基(C6-C10)芳基或(C1-C6)烷氧基(C6-C10)芳氧基(C2-C9)杂芳基,其中的每一个芳基基团可以任意地被氟,氯,溴,(C1-C6)烷基,(C1-C6)烷氧基或全氟(C1-C3)烷基取代。
2、权利要求1中的化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环或下式基团其中的n和m各自独立为1或2且X为CF2,S,O或NR3,其中R3为氢,(C1-C6)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基或酰基。
3、权利要求2中的化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环。
4、权利要求1中的化合物,其中的Q为(C1-C6)烷基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
5、权利要求4中的化合物,其中的Q为(C6-C10)芳氧基(C6-C10)芳基。
6、权利要求1中的化合物,其中的R1和R2各自独立地为(C1-C6)烷基。
7、权利要求1中的化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环或下式基团其中的n和m各自独立为1或2且X为CF2,S,O或NR3,其中R3为氢,(C1-C6)烷基,(C6-C10)芳基,(C2-C9)杂芳基,(C6-C10)芳基(C1-C6)烷基,(C2-C9)杂芳基(C1-C6)烷基,(C1-C6)烷基磺酰基,(C6-C10)芳基磺酰基或酰基;且Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
8、权利要求1中的化合物,其中的R1和R2一起构成(C3-C6)环烷基或苯并稠合(C3-C6)环烷基环;并且Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
9、权利要求1中的化合物,其中的R1和R2各自独立为(C1-C6)烷基,且Q为(C6-C10)芳基,(C6-C10)芳基(C6-C10)芳基,(C6-C10)芳氧基(C6-C10)芳基,(C6-C10)芳氧基(C2-C9)杂芳基,(C2-C9)杂芳基,(C2-C9)杂芳基(C2-C9)杂芳基,(C6-C10)芳基(C2-C9)杂芳基,(C2-C9)杂芳基(C6-C10)芳基或(C2-C9)杂芳氧基(C6-C10)芳基。
10、权利要求1中的化合物,其中的R1和R2各自独立为(C1-C6)烷基;并且Q为(C6-C10)芳氧基(C6-C10)芳基。
11、权利要求1中的化合物,其中所述的化合物选自下列化合物:
1-[4-(4-氟苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺;
1-[4-(4-氯苯氧基)苯磺酰氨基]环丙烷-1-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环丁烷-1-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环戊烷-1-甲酸羟基酰胺;
1-[4-(4-氟苯氧基)苯磺酰氨基]环己烷-1-甲酸羟基酰胺;
2-[4-(4-苯氧基)苯磺酰氨基)-N-羟基-2-甲基丙酰胺;
2-[4-(4-氟苯氧基)苯磺酰氨基]-N-羟基-2-甲基丙酰胺;
N-羟基-2-甲基-2-(5-吡啶-2-基噻吩-2-磺酰氨基)丙酰胺;
1-(5-吡啶-2-基-噻吩-2-磺酰氨基)环戊烷-1-甲酸羟基酰胺;
N-羟基-2-甲基-2-[4-(3-甲基丁氧基)苯磺酰氨基]-丙酰胺;
1-(4’-氟代联苯基-4-磺酰氨基)环戊烷-1-甲酸羟基酰胺;
2-[4-(2-环戊基乙氧基)苯磺酰氨基]-N-羟基-2-甲基-丙酰胺。
12、用于(a)与NASID和止痛药联用或与细胞毒抗癌药联用治疗关节炎,癌症,组织溃疡形成,斑退化,心瓣膜再狭窄,牙周疾病,大疱性表皮松懈,巩膜炎,AIDS,脓毒病,脓毒性休克或(b)抑制包括人类哺乳动物体内基质金属蛋白酶或肿瘤坏死因子的生成的药物组合物,其包括治疗有效剂量的权利要求1化合物和药用载体。
13、式I化合物在制备用于抑制(a)包括人类哺乳动物体内基质金属蛋白酶或(b)肿瘤坏死因子生成的药物中用途。
14、权利要求1化合物与NSAID和止痛药联用及与细胞毒抗肿瘤剂联用在制备用于治疗下列疾病的药物中用途:关节炎,癌症,组织溃疡形成,斑退化,心瓣膜再狭窄,牙周疾病,大疱性表皮松懈,巩膜炎,AIDS,脓毒病,脓毒性休克。
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