CN1265646A - 芳氧基芳基磺酰氨基异羟肟酸衍生物 - Google Patents
芳氧基芳基磺酰氨基异羟肟酸衍生物 Download PDFInfo
- Publication number
- CN1265646A CN1265646A CN98807896A CN98807896A CN1265646A CN 1265646 A CN1265646 A CN 1265646A CN 98807896 A CN98807896 A CN 98807896A CN 98807896 A CN98807896 A CN 98807896A CN 1265646 A CN1265646 A CN 1265646A
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- Prior art keywords
- compound
- amino
- fluorophenoxy
- benzenesulfonyl
- hydrogen
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Abstract
式(Ⅰ)化合物或其药学上可接受的盐,其中R1是(C1－C6)烷基;R2是(C1－C6)烷基;或者R1和R2与它们所连接的碳原子共同构成一个选自(C5－C7)环烷基、4－四氢吡喃基和4－哌啶基的环;R3是氢或(C1－C6)烷基;和Y是苯环上能够提供额外一根键的任意碳原子上的取代基,优选为苯环上的1至2个取代基(更优选为一个取代基,最优选为一个4位取代基),取代基独立地选自氢、氟、氯、三氟甲基、(C1－C6)烷氧基、三氟甲氧基、二氟甲氧基和(C1－C6)烷基。
Description
发明背景
本发明涉及芳氧基芳基磺酰氨基异羟肟酸衍生物。这些化合物是基质金属蛋白酶-13的选择性抑制剂，它们可用于治疗选自下组的疾患：关节炎、癌症、组织溃疡、再狭窄、牙周疾病、大疱性表皮松懈、骨吸收、人造关节植入物松弛、动脉粥样硬化、多发性硬化、眼血管生成(例如黄斑变性)和其他以基质金属蛋白酶活性为特征的疾病。
本发明也涉及在哺乳动物、尤其是人的上述疾病的治疗中使用该化合物的方法，还涉及可用在这里的药物组合物。
有大量的酶可以实现结构蛋白的裂开，它们在结构上是相关的金属蛋白酶。明胶酶、基质溶素和胶原酶等降解基质的金属蛋白酶参与组织基质的降解(例如胶原萎陷)，很多与异常结缔组织和基膜基质代谢有关的病理学状况都涉及到这些酶，例如关节炎(例如骨关节炎和类风湿性关节炎)、组织溃疡(例如角膜、表皮和胃的溃疡)、异常的伤口愈合、牙周疾病、骨疾病(例如佩吉特病和骨质疏松症)、肿瘤转移或侵袭、以及HIV感染(《J.Leuk.Biol.》52(2)：244-248，1992)。
已被确认的是，很多传染性和自体免疫性疾病都涉及肿瘤坏死因子(W.Friers，《欧洲生化学会联合会通讯》(FEBS Letters)1991，285，199)。而且，TNF已显示是脓毒病和脓毒性休克中所见到的炎性反应的主要介质(C.E.Spooner等，《临床免疫学和免疫病理学》(ClinicalImmunology and Immunopathology)1992，62，S11)。
发明概述
本发明涉及下式化合物
或其药学上可接受的盐，其中
R1是(C1-C6)烷基；
R2是(C1-C6)烷基；
或者R1和R2与它们所连接的碳原子共同构成一个选自(C5-C7)环烷基、4-四氢吡喃基和4-哌啶基的环；
R3是氢或(C1-C6)烷基；和
Y是苯环上能够提供额外一根键的任意碳原子上的取代基，优选为苯环上的1至2个取代基(更优选为一个取代基，最优选为一个4位取代基)，取代基独立地选自氢、氟、氯、三氟甲基、(C1-C6)烷氧基、三氟甲氧基、二氟甲氧基和(C1-C6)烷基。
这里所用的术语“烷基”除非另有说明，包括具有直链、支链或环状部分或其组合的饱和一价烃基。
这里所用的术语“烷氧基”包括O-烷基，其中“烷基”定义同上。
本发明也涉及式I化合物的药学上可接受的酸加成盐。用于制备上述本发明碱化合物的药学上可接受的酸加成盐的酸是那些生成无毒酸加成盐的酸，即含有药理学上可接受的阴离子的盐，例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、蔗糖盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即1，1’-亚甲基-双(2-羟基-3-萘甲酸盐))。
本发明也涉及式I的碱加成盐。可用作制备本质上为酸性的式I化合物的药学上可接受的碱盐的试剂的化学碱是那些与该化合物生成无毒碱盐的碱。该无毒的碱盐包括但不限于那些来自药理学上可接受的阳离子如碱金属阳离子(例如钾和钠)和碱土金属阳离子(例如钙和镁)，铵或水溶性胺加成盐如N-甲基葡糖胺(葡甲胺)，以及低级链烷醇铵和其他药学上可接受的有机胺的碱盐。
式I化合物可以具有手性中心，因此存在不同的对映异构形式。本发明涉及式I化合物的所有旋光异构体和立体异构体及其混合物。
本发明也涵盖含有式I化合物的前体药物的药物组合物和治疗或预防方法，该方法包括将式I化合物的前体药物给药。具有游离氨基、酰氨基、羟基或羧基的式I化合物可以转化为前体药物。前体药物包括这样的化合物，其中一个氨基酸残基或两个或多个(例如二、三或四个)氨基酸残基的多肽链通过肽键与式I化合物的游离氨基、羟基或羧基以共价方式结合。氨基酸残基包括通常用三个字母表示的20种天然来源氨基酸，还包括4-羟基脯氨酸、羟基赖氨酸、锁链素(demosine)、异锁链素、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、鸟氨酸和甲硫氨酸砜。前体药物也包括其中碳酸盐、氨基甲酸盐、酰胺和烷基酯通过羰基碳前体药物侧链与上述式I的取代基以共价方式结合的化合物。前体药物也包括这样的式I化合物，其中异羟肟酸和羰基部分共同构成下式基团
其中R1、R2和Y是如式I所定义的，U和V独立地是羰基、亚甲基、SO2或SO3，b是一至三的整数，其中每个亚甲基可选地被羟基取代。
优选的式I化合物包括那些其中Y是氢、氟或氯，优选为4-氟或4-氯的化合物。
其他优选的式I化合物包括那些其中R1和R2与它们所连接的碳原子共同构成环戊基或4-四氢吡喃基的化合物。
其他优选的式I化合物包括那些其中R1和R2都是甲基的化合物。
其他优选的式I化合物包括那些其中R3是氢的化合物。
具体优选的式I化合物包括下列：
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯，
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸，
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸乙酯，和
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸。
其他式I化合物包括下列：
3-[[4-(4-氟苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸，
3-[[4-(4-氟苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸乙酯，
3-[[4-(4-氯苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸，
3-[[4-(4-氯苯氧基)苯磺酰基]-(4-羟基氨基甲酰基四氢吡喃-4-基)氨基]丙酸乙酯，
3-[(4-羟基氨基甲酰基四氢吡喃-4-基)-(4-苯氧基苯磺酰基)氨基]丙酸，
3-[(4-羟基氨基甲酰基四氢吡喃-4-基)-(4-苯氧基苯磺酰基)氨基]丙酸乙酯，
3-[[4-(4-氟苯氧基)苯磺酰基]-(4-羟基氨基甲酰基哌啶-4-基)氨基]丙酸乙酯，
3-[[4-(4-氯苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸，
3-[[4-(4-氯苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸乙酯，
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环己基)氨基]丙酸，
3-[(1-羟基氨基甲酰基环戊基)-(4-苯氧基苯磺酰基)氨基]丙酸，和
3-[[4-(4-氯苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸。
本发明也涉及药物组合物，用于(a)治疗选自下组的疾病：关节炎、癌症、组织溃疡、再狭窄、牙周疾病、大疱性表皮松懈、骨吸收、人造关节植入物松弛、动脉粥样硬化、多发性硬化、眼血管生成(例如黄斑变性)和其他以基质金属蛋白酶活性为特征的疾病，或者(b)选择性抑制哺乳动物、包括人的基质金属蛋白酶-13，该组合物包含治疗有效量的权利要求1的化合物或其药学上可接受的盐，和一种药学上可接受的载体。
本发明也涉及选择性抑制哺乳动物、包括人的基质金属蛋白酶-13的方法，该方法包括将有效量的权利要求1的化合物或其药学上可接受的盐对所述哺乳动物给药。
本发明也涉及在哺乳动物、包括人中治疗选自下组的疾病的方法：关节炎、癌症、组织溃疡、再狭窄、牙周疾病、大疱性表皮松懈、骨吸收、人造关节植入物松弛、动脉粥样硬化、多发性硬化、眼血管生成(例如黄斑变性)和其他以基质金属蛋白酶-13活性为特征的疾病，该方法包括将治疗该疾病有效量的权利要求1的化合物或其药学上可接受的盐对所述哺乳动物给药。
发明详述
下列反应方案阐述了本发明化合物的制备。除非另有说明，反应方案中的Y、R1、R2和R3以及后面的讨论都是定义同上的。
方案1
方案1(续)
方案1指的是从式VII化合物制备式I化合物。参照方案1，其中R16为苄基的式VII氨基酸化合物通过与下式芳基磺酸化合物的反应性官能衍生物反应，
转化为对应的式VI化合物，该反应在一种碱如三乙胺的存在下，在一种极性溶剂如四氢呋喃、1，2-二甲氧基乙烷、二噁烷、水或乙腈，优选1，2-二甲氧基乙烷中进行。反应混合物在室温下搅拌约10分钟至约24小时，优选约60分钟。
其中R16为苄基的式VI芳基磺酰氨基化合物通过与叔丁基-(3-卤丙氧基)二甲基硅烷，优选碘化物衍生物反应，转化为对应的式V化合物，其中R18为3-叔丁基-二甲基硅烷氧基丙基，该反应在一种碱的存在下进行，例如碳酸钾、碳酸铯、六甲基二硅氮化钾或氢化钠，优选六甲基二硅氮化钾。该反应在一种极性溶剂中，例如二甲基甲酰胺或N-甲基吡咯烷-2-酮，在室温下搅拌约2小时至约48小时，优选约18小时。
式V化合物通过与三氟化硼-醚合物配合物反应生成一种醇中间体，然后通过氧化反应和酯化保护作用，转化为式IV的羧酸衍生物。具体来说，与三氟化硼-醚合物配合物的反应是在一种惰性溶剂中，例如二氯甲烷、氯仿，优选二氯甲烷，在室温下进行约15分钟至约4小时，优选约一小时。使用三氧化铬的硫酸水溶液(琼斯试剂)有利于醇的氧化反应，该反应在约0℃下进行约一小时至约6小时，优选约2小时。使用一种烷基化剂如R3-L处理游离酸有利于羧酸的保护作用，其中L是离去基团，例如碘、溴、甲磺酸盐或甲苯磺酸盐，优选碘，该反应在一种碱的存在下，例如碳酸钾或碳酸铯，优选碳酸钾，在一种极性溶剂，例如二甲基甲酰胺、N-甲基吡咯烷-2-酮或四氢呋喃，优选二甲基甲酰胺中，在约室温下进行约1至约24小时，优选16小时。
通过氢解反应除去R16保护基团，将式IV化合物转化为式III化合物，该反应使用钯-碳在一种溶剂如甲醇或乙醇中，在约20℃至约25℃、即室温下进行约30分钟至约48小时，优选16小时。
通过活化式III化合物，然后与苄基羟胺反应，将式III的羧酸化合物转化为式II的异羟肟酸衍生物，其中R16为苄基。在一种碱的存在下，在室温下，在一种极性溶剂中，用(苯并三唑-1-基氧基)三(二甲氨基)六氟磷酸鏻处理，可活化式III化合物。上述反应进行约15分钟至约4小时，优选约1小时。被活化的式III化合物通过与盐酸苄基羟胺反应就地转化为式II化合物。与盐酸苄基羟胺的反应进行约1小时至约5天，优选约16小时，反应温度为约40℃至约80℃，优选约60℃。适用的碱包括N-甲基吗啉或二异丙基乙胺，优选二异丙基乙胺。适用的溶剂包括N，N-二甲基甲酰胺或N-甲基吡咯烷-2-酮，优选N，N-二甲基甲酰胺。
式II化合物通过除去羟基胺保护基团转化为式I化合物。羟基胺保护基团的除去是通过苄基保护基团的氢解反应进行的，该反应使用钯-硫酸钡催化剂，在一种极性溶剂中，在约20℃至约25℃、即室温下进行约1小时至约5小时，优选约3小时。
式VII和VIII化合物是商业上可得到的，或者可以按照本领域普通技术人员所熟知的方法制备。
本发明的酸性化合物的药学上可接受的盐是与碱生成的盐，也就是阳离子盐，例如碱金属和碱土金属盐，例如钠盐、锂盐、钾盐、钙盐、镁盐、以及铵盐，例如铵盐、三甲基铵盐、二乙基铵盐和三(羟甲基)甲基铵盐。
如果一种碱性基团如吡啶基构成结构的一部分，那么类似地也可能是酸加成盐，例如无机酸、有机羧酸和有机磺酸，例如盐酸、甲磺酸、马来酸。
本质上为碱性的式I化合物能够与多种无机酸和有机酸生成多种不同的盐。这些盐在药学上必须是动物给药可接受的，不过在实践中需要最初从反应混合物中分离到式I化合物的药学上不可接受的盐，然后通过一种碱性试剂的简单处理，将该盐转化为游离碱化合物，随后将该游离碱转化为药学上可接受的酸加成盐。本发明碱化合物的酸加成盐易于通过如下方法制备：在一种含水溶剂介质或一种适当的有机溶剂如甲醇或乙醇中，用基本上等量的选定无机酸或有机酸处理碱化合物。小心地蒸发溶剂，得到所需的固体盐。
用于制备本发明碱化合物的药学上可接受的酸加成盐的酸是那些生成无毒酸加成盐的酸，即含有药理学上可接受的阴离子的盐，例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐或硫酸氢盐、磷酸盐或酸式磷酸盐、乙酸盐、乳酸盐、柠檬酸盐或酸式柠檬酸盐、酒石酸盐或酒石酸氢盐、琥珀酸盐、马来酸盐、富马酸盐、葡糖酸盐、蔗糖盐、苯甲酸盐、甲磺酸盐和双羟萘酸盐(即1，1’-亚甲基-双(2-羟基-3-萘甲酸盐))。
本质上也为酸性的式I化合物，例如其中R3是氢的式I化合物，能够与多种药理学上可接受的阳离子生成碱盐。该盐的例子包括碱金属或碱土金属盐，特别是钠盐和钾盐。这些盐均可按常规工艺制备。可用作制备本发明药学上可接受的碱盐的试剂的化学碱是那些与所述式I酸性化合物生成无毒碱盐的碱。这些无毒的碱盐包括那些来源于药理学上可接受的阳离子如钠、钾、钙和镁等的盐。这些盐易于通过用含有所需药理学上可接受的阳离子的水溶液处理对应的酸性化合物，然后蒸发所得溶液至干，优选在减压下蒸发而制备。另一种替代的制备方法也可以是将酸性化合物的低级链烷醇溶液与所需碱金属烷氧化物混合，然后以前述相同方式蒸发所得溶液至干。在两种方法中，为了确保反应完全和产率最高，优选使用化学计算量的试剂。
下列体外试验显示，式I化合物或其药学上可接受的盐(以下也称之为本发明的MMP-13选择性化合物)具有抑制基质金属蛋白酶-13(胶原酶3)的能力，从而证明它们对以基质金属蛋白酶-13为特征的疾病的治疗效果。
生物分析
人胶原酶(MMP-1)的抑制作用
用胰蛋白酶活化人重组胶原酶，二者的比例如下：10mg胰蛋白酶/100mg胶原酶。将胰蛋白酶和胶原酶在室温下温育10分钟，然后加入五倍量(50mg/10mg胰蛋白酶)大豆胰蛋白酶抑制剂。
制备抑制剂的10mM储备溶液，溶剂为二甲基亚砜，然后按照下列程序稀释：
10mM→120μM→12μM→1.2μM→0.12μM
然后向96孔微量滴定板(microfluor plate)的适当孔中加入储备溶液，每种浓度均为二十五微升，一式三份。加入酶和底物后，抑制剂的最终浓度将是1∶4稀释比。在D1-D6孔中设置阳性对照(酶，不含抑制剂)，在D7-D12孔中设置空白(不含酶，不含抑制剂)。
将胶原酶稀释至400ng/ml，然后向微量滴定板的适当孔中加入25ml。分析中胶原酶的最终浓度为100ng/ml。
制备底物(DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)的5mM储备溶液，溶剂为二甲基亚砜，然后在分析缓冲液中稀释至20mM。向微量滴定板的每个小孔中加入50ml底物，使最终浓度为10mM，开始分析。
在时间为0时读取荧光值(360nM激发，460nm发射)，以后每隔20分钟读取。在室温下进行分析，典型的分析时间为3小时。
然后对空白和含有胶原酶的样本标绘荧光-时间曲线(数据为三次测定的平均值)。选择产生良好信号(空白)且位于曲线的直线部分上的时间点(通常在120分钟左右)测定IC50值。零时间作为每种浓度的每种化合物的空白，从120分钟数据中减去这些值。用数据标绘抑制剂浓度-％控制率(抑制剂荧光除以胶原酶荧光×100)曲线。由得到为对照的50％的信号的抑制剂浓度确定IC50。
如果IC50小于0.03mM，那么在0.3mM、0.03mM、0.03mM和0.003mM浓度下分析抑制剂。
MMP-13的抑制作用
在37℃下，用2mM APMA(对氨基苯基乙酸汞(p-aminophenylmercuric acetate))活化人重组MMP-131.5小时，在分析缓冲液(50mMTris，pH 7.5，200mM氯化钠，5mM氯化钙，20mM氯化锌，0.02％brij)中稀释至400mg/ml。向96孔微量滴定板的每个小孔中加入二十五微升稀释的酶。然后加入抑制剂和底物，以1∶4稀释酶，得到最终分析浓度为100mg/ml。
制备抑制剂的10mM储备溶液，溶剂为二甲基亚砜，然后按照上述“人胶原酶(MMP-1)的抑制作用”中的抑制剂稀释程序稀释在分析缓冲液中。每种浓度取二十五微升，加入到微量滴定板中，一式三份。分析中的最终浓度为30mM、3mM、0.3mM和0.03mM。
按照“人胶原酶(MMP-1)的抑制作用”准备底物(Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2)，向每个小孔中加入50ml，得到最终分析浓度为10mM。在时间为0时读取荧光值(360nM激发，450发射)，以后每隔5分钟读取1小时。
阳性对照由酶和底物组成，不含抑制剂，空白仅由底物组成。
按照“人胶原酶(MMP-1)的抑制作用”测定IC50。如果IC50小于0.03mM，那么抑制剂在0.3mM、0.03mM、0.003mM和0.0003mM的最终浓度下进行分析。
与基质金属蛋白酶-1(胶原酶1)相比，本发明化合物对基质金属蛋白酶-13(胶原酶3)具有惊人的选择性活性。具体来说，式I化合物对基质金属蛋白酶-13(胶原酶3)的选择性比基质金属蛋白酶-1(胶原酶1)高100倍，对基质金属蛋白酶-13(胶原酶3)的IC50小于10nM。表1列出几种化合物，证实了本发明化合物的意外选择性。表1
| 实施例 | R1 | R2 | R3 | R | MMP-1IC50(nM) | MMP-13IC50(nM) |
| 1 | 环戊基 | - | 乙基 | 4-氟苯氧基 | 100 | 0.9 |
| 1 | 环戊基 | - | 乙基 | 4-氟苯氧基 | 100 | 0.9 |
| 2 | 环戊基 | - | 氢 | 4-氟苯氧基 | 360 | 1.2 |
| 2 | 环戊基 | - | 氢 | 4-氟苯氧基 | 200 | 0.6 |
| 3 | 甲基 | 甲基 | 乙基 | 4-氟苯氧基 | 1200 | 1.6 |
| 3 | 甲基 | 甲基 | 乙基 | 4-氟苯氧基 | 1800 | 2.3 |
| 4 | 甲基 | 甲基 | 氢 | 4-氟苯氧基 | 3500 | 5.7 |
| 4 | 甲基 | 甲基 | 氢 | 4-氟苯氧基 | 2000 | 2.3 |
| 4 | 甲基 | 甲基 | 氢 | 4-氟苯氧基 | 4800 | 8 |
| 环戊基 | - | 氢 | 甲氧基 | 800 | 21 | |
| 环戊基 | - | 氢 | 甲氧基 | 700 | 25 | |
| 甲基 | 甲基 | 氢 | 甲氧基 | 12000 | 590 | |
| 甲基 | 甲基 | 氢 | 甲氧基 | 12000 | 730 | |
| 环己基 | 氢 | 氢 | 甲氧基 | 18 | 4 | |
| 环己基 | 氢 | 氢 | 甲氧基 | 22 | 2 |
在对人给药用于抑制基质金属蛋白酶-13或产生肿瘤坏死因子(TNF)时，可以使用多种常规途径，包括口服、胃肠外和局部途径。一般来说，活性化合物的口服或胃肠外给药剂量为约0.1至25mg/kg待治疗者体重/天，优选约0.3至5mg/kg。不过，根据待治疗者的身体状况，剂量的某些改变也是必要的。无论怎样，负责给药的人员会为具体受治疗者确定合适的剂量。
本发明化合物能够以多种不同的剂型给药，一般来说，治疗学上有效的本发明化合物存在于该类剂型中的浓度水平范围为约5.0重量％至约70重量％。
对口服给药来说，可以使用片剂，其中含有多种赋形剂，例如微晶纤维素、柠檬酸钠、碳酸钙、磷酸二钙和甘氨酸，还含有多种崩解剂，例如淀粉(优选为玉米、马铃薯或木薯淀粉)、藻酸和某些复合硅酸盐，以及造粒粘合剂，例如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶。另外，润滑剂通常对制片是非常有用的，例如硬脂酸镁、月桂基硫酸钠和滑石。相似类型的固体组合物也可以用作明胶胶囊中的填充剂；在这方面优选的物质也包括乳糖或奶糖以及大分子量的聚乙二醇。当口服给药需要使用水悬液和/或酏剂时，活性成分可以与多种甜味剂或矫味剂、色素或染料混合，必要时还与乳化剂和/或悬浮剂、以及稀释剂如水、乙醇、丙二醇、甘油和多种类似的组合混合。
对胃肠外给药(肌内、腹膜内、皮下和静脉内)来说，通常制备活性成分的无菌注射液。可以使用本发明的治疗化合物在芝麻油或花生油或者在含水丙二醇中的溶液。水溶液应当进行适当的调整和缓冲，优选为pH大于8，必要时液体稀释剂首先被赋予等渗性。这些水溶液适合静脉内注射。油溶液适合关节内、肌内和皮下注射。按照本领域技术人员熟知的标准药学工艺，易于实现所有这些溶液的无菌制备。
下列实施例阐述本发明化合物的制备。熔点是未经校正的。NMR数据以每百万份的份数报告(6)，并以来自样本溶剂(除非另有说明，为氘代二甲基亚砜)的氘锁信号为参照。直接利用商品试剂，无需进一步纯化。THF指的是四氢呋喃。DMF指的是N，N-二甲基甲酰胺。色谱法指的是柱色谱法，使用32-63mm硅胶，在氮压力(快速色谱法)条件下进行。室温或环境温度指的是20至25℃。为了便利和使产率最大，所有非水反应均在氮气氛下进行。在减压下浓缩指使用旋转蒸发器。
实施例1
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯
(A)向1-氨基环戊烷羧酸苄基酯对甲苯磺酸盐(200g，0.51mol)和三乙胺(177ml，1.27mol)的水(1L)与1，2-二甲氧基乙烷(1L)溶液中加入4-(4-氟苯氧基)苯磺酰氯(161g，0.56mol)。混合物在室温下搅拌16小时，然后在真空下蒸发除去大部分溶剂。混合物用乙酸乙酯稀释，连续用稀盐酸溶液、水和盐水洗涤。溶液经硫酸镁干燥，浓缩得到棕色固体。用二乙醚研制，得到1-[4-(4-氟苯氧基)苯磺酰基氨基]环戊烷羧酸苄基酯，为褐色固体，167克(70％)。
(B)在室温下，向1-[4-(4-氟苯氧基)苯磺酰基氨基]环戊烷羧酸苄基酯(199g，0.42mol)的无水N，N-二甲基甲酰胺(2.5L)溶液中加入六甲基二硅氮化钾(100g，0.50mol)，3小时后，加入叔丁基-(3-碘丙氧基)二甲基硅烷(150g，0.50mol)。所得混合物在室温下搅拌16小时。然后再加入叔丁基-(3-碘丙氧基)二甲基硅烷(20g，0.067mol)。继续在室温下搅拌3.5小时。加入饱和氯化铵溶液结束混合物的反应。在真空下蒸发除去N，N-二甲基甲酰胺。将残余物溶于二乙醚，用水和盐水洗涤。经硫酸镁干燥后，蒸发二乙醚，得到粗的1-{[3-(叔丁基二甲基硅烷氧基)丙基]-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯，为琥珀色油(279.6g)。
(C)在室温下，向粗的1-{[3-(叔丁基二甲基硅烷氧基)丙基]-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯(279g)的二氯甲烷(1L)溶液中加入三氟化硼醚合物(103ml，0.84mol)。1小时后，连续加入饱和氯化铵溶液和水以结束反应。分离有机相，用水和盐水洗涤，经硫酸镁干燥。在真空下蒸发溶剂，得到粗的1-[[4-(4-氟苯氧基)苯磺酰基]-(3-羟基丙基)氨基]环戊烷羧酸苄基酯，为琥珀色油(235g)。
(D)将粗的1-[[4-(4-氟苯氧基)苯磺酰基]-(3-羟基丙基)氨基]环戊烷羧酸苄基酯(235g)的丙酮(2L)溶液在冰浴中冷却，用琼斯试剂(约200ml)处理，直至混合物持续为橙色时为止。混合物在0℃至室温下搅拌1小时。用异丙醇(10ml)抵销掉过量的氧化剂后，混合物过滤，滤液在真空下浓缩。将残余物溶于乙酸乙酯，用水和盐水洗涤，经硫酸镁干燥，浓缩得到固体，用二乙醚和己烷的混合物研制，得到1-{(2-羧乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯，为白色固体(147g)。
(E)在室温下，向1-{(2-羧乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯(147g)的N，N-二甲基甲酰胺(3L)溶液中加入碳酸钾(150g，1.08mol)和乙基碘(32.4ml，0.405mol)。混合物在室温下搅拌16小时。过滤后，在真空下除去大部分溶剂。将残余物溶于水，用6N氯化氢水溶液酸化。所得混合物用二乙醚萃取。有机萃取液用水和盐水洗涤，经硫酸镁干燥，浓缩得到1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯，为黄色半固体物(149.1g，96％)。
(F)将1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸苄基酯(74.5g，0.13mol)的乙醇(1.8L)溶液用10％钯-活性炭(7.4g)处理，在3大气压ParrTM震动器中氢化16小时。通过尼龙(孔径0.45μm)过滤除去催化剂后，蒸发溶剂，得到1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸，为白色泡沫。按相等规模重复反应，共得到125.2g所需产物。
(G)向1-{(2-乙氧羰基乙基)-[4-(4-氟苯氧基)苯磺酰基]氨基}环戊烷羧酸(125.2g，0.26mol)的N，N-二甲基甲酰胺(2L)溶液中连续加入二异丙基乙胺(50ml，0.286mol)和(苯并三唑-1-基氧基)三(二甲氨基)六氟磷酸鏻(126.5g，0.286mol)。混合物搅拌1小时。然后再加入二异丙基乙胺(91ml，0.52mol)和盐酸O-苄基羟胺(53.8g，0.338mol)，所得混合物在60℃下搅拌96小时。在真空下浓缩后，将残余物溶于水，用1N氯化氢水溶液酸化。混合物用乙酸乙酯萃取，萃取液连续用水、饱和碳酸氢钠水溶液和盐水洗涤。溶液经硫酸镁干燥，浓缩得到粗的3-{(1-苄氧基氨基甲酰基环戊基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯，为黄色的油(164g)。
(H)将3-{(1-苄氧基氨基甲酰基环戊基)-[4-(4-氟苯氧基)苯磺酰基]氨基}丙酸乙酯(164g)的乙醇(2.4L)溶液用5％钯-硫酸钡(50g)处理，在3大气压ParrTM震动器中氢化3小时。通过尼龙(孔径0.45μm)过滤除去催化剂后，蒸发溶剂，得到油。加入乙酸乙酯和己烷后，过滤收集3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯，为白色晶状固体(73.5g)。滤液浓缩，残余物用硅胶色谱法纯化，用40％乙酸乙酯己烷洗脱，得到更多的所需产物(32.5g)。
Mp：79-83℃.1H NMR(DMSO-d6)：δ10.40(br s，1H)，8.78(br s，1H)，7.80-7.77(m，2H)，7.31-7.03(m，6H).4.02(q，J＝7.3Hz，2H)，349-3.45(m，2H)，2.70-2.67(m，2H)，2.24-2.21(m，2H)，1.86-1.83(m，2H)，1.53-1.50(m，4H)，1.16(t，J＝7.3Hz，3H).MS 493(M-1)。C23H27FN2O7S·H2O的分析计算值：C，53.90；H，5.70；N，5.47；实测值：C，54.52；H，5.63；N，5.27。
实施例2
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸
将3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯(106g，0.214mol)的乙醇(2.5L)溶液用1N氢氧化钠水溶液(856ml，0.856mol)处理，在室温下搅拌2小时。混合物浓缩以除去乙醇，用水稀释，用6N盐酸水溶液酸化，用乙酸乙酯萃取。用水和盐水洗涤后，有机萃取液经硫酸镁干燥，浓缩得到泡沫。从30％乙酸乙酯的己烷溶液中结晶，得到3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸，为白色晶状固体(81.5g，81％)。
Mp：170-172℃.1H NMR(DMSO-d6)：δ12.25(br s，1H)，10.40(br s，1H)，8.74(brs，1H)，7.79-7.77(m，2H)，7.29-7.03(m，6H)，3.45-3.41(m，2H)，2.61-2.57(m，2H)，2.24-2.21(m，2H).1.88-1.82(m，2H)，1.53-1.50(m，4H).MS 465(M-1).C21H23FN2O7S的分析计算值：C，54.07；H，4.97；N，6.00；实测值：C，54.17；H，5.02；N，6.05。
实施例3
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸乙酯
从2-氨基-2-甲基丙酸苄基酯对甲苯磺酸盐开始，按照类似于实施例1所述程序制备标题化合物。
Mp：124.8-125℃.1H NMR(DMSO-d6)δ10.37(s，1H)，8.74(s，1H)，7.86(d，2H，J＝8.9Hz)，7.16-7.30(m，4H)，7.04(d，2H，J＝8.7hz)，3.99(q，2H，J＝7.1Hz)，3.33-3.37(m，2H)，2.62-2.66(m，2H)，1.40(s，6H)，1.13(t，3H，J＝7.1Hz).MS：467(M-1).C21H25FN2O7S的分析计算值：C，53.84；H，5.38；N，5.98；实测值：C，54.00；H，5.12；N，5.87。
实施例4
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸
从3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸乙酯开始，按照类似于实施例2所述程序制备标题化合物。
Mp：162-162.5℃.MS：439(M-1).1H NMR(DMSO-d6)δ12.26(s，1H)10.10.38(s，1H)，8.75(s，1H)，7.86-7.88(m，2H)，7.16-7.7.30(m，4H)，7.03-7.06(m，2H)，3.29-3.35(m，2H)，2.47-2.59(m，2H)，1.40(s，6H).
Claims (15)
1、一种式I化合物
或其药学上可接受的盐，其中
R1是(C1-C6)烷基；
R2是(C1-C6)烷基；
或者R1和R2与它们所连接的碳原子共同构成一个选自(C5-C7)环烷基、4-四氢吡喃基和4-哌啶基的环；
R3是氢或(C1-C6)烷基；和
Y是苯环上能够提供额外一根键的任意碳原子上的取代基，取代基独立地选自氟、氯、三氟甲基、(C1-C6)烷氧基、三氟甲氧基、二氟甲氧基和(C1-C6)烷基。
2、根据权利要求1的化合物，其中Y是氢、氟或氯。
3、根据权利要求1的化合物，其中Y是4-氟或4-氯。
4、根据权利要求1的化合物，其中R1和R2与它们所连接的碳原子共同构成一个环戊基环。
5、根据权利要求3的化合物，其中R1和R2与它们所连接的碳原子共同构成一个环戊基环。
6、根据权利要求1的化合物，其中R1和R2与它们所连接的碳原子共同构成一个4-四氢吡喃基环。
7、根据权利要求1的化合物，其中R1和R2都是甲基。
8、根据权利要求3的化合物，其中R1和R2都是甲基。
9、根据权利要求1的化合物，其中R3是氢。
10、根据权利要求3的化合物，其中R3是氢。
11、根据权利要求4的化合物，其中R3是氢。
12、根据权利要求1的化合物，其中所述化合物选自下组：
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸乙酯，
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基环戊基)氨基]丙酸，
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸乙酯，和
3-[[4-(4-氟苯氧基)苯磺酰基]-(1-羟基氨基甲酰基-1-甲基乙基)氨基]丙酸。
13、一种药物组合物，用于(a)治疗关节炎或癌症和其他以基质金属蛋白酶-13活性为特征的疾病，或者(b)选择性抑制哺乳动物、包括人的基质金属蛋白酶-13，该组合物包含治疗有效量的权利要求1的化合物或其药学上可接受的盐，和一种药学上可接受的载体。
14、一种选择性抑制哺乳动物、包括人的基质金属蛋白酶-13的方法，该方法包括将有效量的权利要求1的化合物或其药学上可接受的盐对所述哺乳动物给药。
15、一种治疗哺乳动物、包括人的关节炎或癌症和其他以基质金属蛋白酶-13活性为特征的疾病的方法，该方法包括将治疗该疾病有效量的权利要求1的化合物或其药学上可接受的盐对所述哺乳动物给药。
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