CN1411436A - 作为可溶性人cd23形成的抑制剂的异羟肟酸衍生物 - Google Patents
作为可溶性人cd23形成的抑制剂的异羟肟酸衍生物 Download PDFInfo
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- CN1411436A CN1411436A CN00817368A CN00817368A CN1411436A CN 1411436 A CN1411436 A CN 1411436A CN 00817368 A CN00817368 A CN 00817368A CN 00817368 A CN00817368 A CN 00817368A CN 1411436 A CN1411436 A CN 1411436A
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- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
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Abstract
式(I)的化合物可用于治疗s-CD23介导的疾病,其中,R是异丙基;n是0;R1是萘甲基;R2是叔丁基;且R3是甲基。
Description
本发明涉及形成可溶性人CD23的新型抑制剂,以及其在治疗与过量产生可溶性CD-23(s-CD23)有关的疾病如自身免疫疾病、炎症性疾病和变态反应中的应用。CD23(低亲合性IgE受体FceRII,Blast2)是在各种成熟细胞表面上表达的45kDa II型整合蛋白,这些成熟细胞包括B和T淋巴细胞、巨噬细胞、天然杀伤细胞、Langerhans细胞、单核细胞及血小板(Delespesse等,Adv Immunol,49[1991]149-191)。在嗜曙红细胞上有类CD23分子(Grangette等,J Immounol,143[1989]3580-3588)。CD23与免疫应答的调节有关(Delespesse等,Immounol Re,125[1992]77-79)。人CD23存在两种不同调节的同种型,即a和b,其不同之处仅在于细胞内N-末端的氨基酸不同(Yokota等,cell,55[1988]611-618)。在人体中,组成型同种型仅发现于B-淋巴细胞上,而可由IL-4诱导的b型却发现存在于所有能表达CD23的细胞上。
已知完整的细胞结合的CD23(cell bound CD23)(i-CD23)从细胞表面经过裂解,形成大量有明确定义的可溶片段(s-CD23),它们的产生是蛋白水解的复杂序列的结果,对其机理的理解仍然不很清楚(Bourget等,J Biol Chem.,269[1994]6927-6930)。虽然未经证实,但可假定这些蛋白水解产生的大部分可溶片段(Mr37、33、29和25kDa)是通过最初形成37kDa片段而有序出现的,这些中的所有片段都保留着与i-CD23相同的C-末端凝集素区(Letellier等,J Exp Med,
172[1990]693-700)。另一胞内裂解途径导致产生稳定的16kDa片段,它在C-末端区方面不同于i-CD23(Grernier Brosette等,Eur JImmounol,22[1992]1573-1577)。
几种活性已归因于显示在IgE调节中起作用的膜结合的人i-CD23。具体活性包括a)抗原呈递,b)IgE介导的嗜曙红细胞毒性,c)B细胞回至淋巴结和脾的生发中心,及d)IgE合成的下调节(Delespesse等,Adv Immounol,49[1991]149-191)。三种有较高分子量的可溶性CD23片段(Mr37、33和2kDa)具有多功能细胞因子性质,其在IgE形成中可能起主要作用。因此,过量形成的s-CD23则与过量产生IgE(变态反应如外源性哮喘、鼻炎、变应性结膜炎、湿疹、特应性皮炎和过敏症的特点)有关(Sutton和Could,Nature,366[1993]421-428)。其它归因于s-CD23的生物活性包括刺激B细胞生长和诱导介体从单核细胞中释放。从而,已在患有B-慢性淋巴细胞白血病患者的血清中(Sarfati等,Blood,
71[1988]94-98)和在患有类风湿性关节炎患者的滑液中(Chomarat等,Arthritis and Rheumatism,
36[1993]234-242)观察到s-CD23水平的升高。许多资料提到CD23在炎症中起作用。首先,有报道s-CD23结合到细胞外受体上,而该受体在活化时与炎症的细胞介导有关。因此,据报道,s-CD23直接激活单核细胞TNF、IL-1和IL-6的释放(Armant等,180卷,J.Exp.Med.,1005-1011[1994])。据报道,CD23与单核细胞/巨噬细胞上B2-整合蛋白粘附分子CD 11b和CD 11c互相作用(S.Lecoane叔Henchoz等,Immunity,3卷;119-125[1995]),它们引发NO2 -、过氧化氢和细胞因子(IL-1、IL-6和TNF)的释放。最终,IL-4或IFN诱导CD23的表达及其作为s-CD23通过人单核细胞的释放。膜结合CD23受体与IgE/抗-IgE免疫复合物或抗CD23mAb的结合激活了cAMP和IL-6产生及血栓烷B2形成,证明了CD23在炎症中的受体介导作用。
由于CD23的这些不同性质,所以抑制s-CD23形成的化合物应具有双重作用:a)在B细胞表面上通过保持i-CD23的水平来增强IgE合成的负反馈抑制,和b)抑制s-CD23的较高分子量的可溶性片段(Mr37、33和29kDa)的免疫刺激细胞因子的活性。另外,抑制CD23裂解能减缓s-CD23诱导的单核细胞活化和介体形成,因此减少炎症反应。
国际专利申请WO96/02240(Smithkline Beecham plc)公开了抑制基质金属蛋白酶(如胶原酶、溶基质素和明胶酶)作用的化合物是转染入哺乳动物细胞培养系统的人可溶性CD23释放的有效抑制剂。
现已惊奇地发现某些式(I)化合物具有意想不到的好的生物利用度。
因此,本发明提供了上述式(I)的化合物,其中,
n是0;
R是异丙基;
R1是萘甲基;
R2是叔丁基;且
R3是甲基。
本发明另一方面提供了本发明中所述化合物在制备用于治疗或预防与过量产生s-CD23有关的疾病如变态反应、炎症性疾病和自身免疫疾病的药物中的应用。
本发明又一方面提供了治疗或预防与过量产生s-CD23有关的疾病如变态反应、炎症性疾病和自身免疫疾病的方法,该方法包括将该发明中所述化合物给予对此有需要的人或非人哺乳动物。
本发明还提供了一种用于治疗或预防与过量产生s-CD23有关的疾病如变态反应、炎症性疾病和自身免疫疾病这样疾病的药物组合物,其包括本发明中所述化合物及任选的可药用载体。
具体的炎症性疾病包括CNS疾病如阿耳茨海默病、多发性硬化症和多梗死性痴呆,以及炎症性介导的中风和脑损伤后遗症。
应当理解的是,可药用的盐、溶剂化物和本发明中所述化合物的其它可药用衍生物也包括在本发明中。
式(I)化合物的盐包括例如衍生于无机或有机酸的酸加成盐,如盐酸盐、氢溴酸盐、氢碘酸盐、对甲苯磺酸盐、磷酸盐、硫酸盐、乙酸盐、三氟乙酸盐、丙酸盐、柠檬酸盐、马来酸盐、富马酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐。
盐也可与碱形成。这样的盐包括衍生于无机或有机碱的盐,例如碱金属盐如钠或钾盐,有机胺盐如吗啉、哌啶、二甲胺或二乙胺盐。
现已惊奇地发现本发明化合物口服时显示出好的体内吸收的性质,并且是CD23处理中有效的选择性抑制剂。
本发明的化合物可通过应用任何适当的常规方法制备,例如类似于专利申请公开号为WO97/02239(Btitish Biotech Pharmaceuticals Limited)中公开的方法。
因此,本发明的另一方面提供制备如上文所定义的式(I)化合物的方法,该方法包括:
a)将式(II)化合物脱保护:
其中X是保护基如苄基或三甲基甲硅烷基或
b)将式(III)化合物与羟胺或其盐反应:
其中任选地将羟基进行保护。
式(II)和式(III)化合物是新的,它们为本发明的另一个方面。
由式(III)化合物与保护的羟胺反应可制备式(II)化合物。具有一个被保护羟基的式(II)化合物通过水解可转化成相应未保护的式(III)化合物。
异羟肟酸的适合保护基是本领域公知的,包括苄基、三甲基甲硅烷基、叔丁基和叔丁基二甲基硅烷基。
羧酸的适合保护基是本领域公知的,包括叔丁基、苄基和甲基。
通过式(IV)或(IVa)化合物与式(V)化合物反应可以制备式(III)化合物:
其中Y是羧基的保护基,
如果使用式(IVa)化合物,则需要进行羟基的烷基化。
通过保护其中Y是氢的相应化合物可以制得式(IV)化合物,依次按下述反应制备:
其中R1如上述定义,Z是羧基的保护基,和
(b)脱除保护基。
其中Z是氢的式(VI)化合物可由2-羟基琥珀酸的二酯(如二甲酯或二乙酯)与式R1X′化合物在强碱(例如二异丙基酰胺锂)存在的条件下反应(其中R1是萘甲基,X′时离去基团如溴或碘),然后水解所生成的化合物以除去酯基而制备。
本发明化合物的异构体包括立体异构体可以制备为这些异构体的混合物或者单独的异构体。各个单独的异构体可由任何适宜的方法制得,例如通过从手性原料的立体选择化学合成或者用已知方法分离非对映异构体混合物而获得。在优选方面,本发明提供式(IA)化合物:
优选分离的化合物基本为纯品形式。
正如本文所述,抑制形成可溶性人CD23的抑制剂具有有效的医学性质。优选活性化合物以药用组合物的形式给药。
组合物优选适用于口服给药。然而,也可以通过其它方式给药,例如以喷洒剂、气溶胶形式或其它用于吸入剂的常用方法用于治疗呼吸道疾病;或对患心衰的患者经非胃肠道给药。其它可供选择的给药方式包括舌下或经皮给药。
组合物可以是片剂、胶囊、粉剂、颗粒剂、锭剂、栓剂、再溶解型粉剂的形式,或者是液体制剂的形式如口服或灭菌非胃肠道溶液或混悬液的形式。
为了获得给药的一致性,优选本发明的组合物为单位剂量的形式。
用于口服给药的单位剂量的代表形式可以是片剂和胶囊并且可以含有常用的赋形剂如粘合剂,例如糖浆、阿拉伯胶、明胶、山梨醇、黄蓍胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸;制片润滑剂,例如硬脂酸镁;崩解剂,例如淀粉、聚乙烯吡咯烷酮、羟基乙酸淀粉钠或微晶纤维素;或可药用的润湿剂如月桂基硫酸钠。
固体口服组合物可通过混合、填充或压片的常用方法制备。可以使用反复混合操作将活性剂完全分散于含大量填充剂的组合物中。当然这样的操作在本领域是常用的。根据通常的制药学方法可以将片剂包衣,特别是进行肠溶包衣。
口服液体制剂可以是例如乳剂、糖浆剂或酏剂的形式,或以干品形式存在,使用前用水或其它适合载体再溶解。这样的液体制剂可以含有常用的添加剂如混悬剂,例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝胶、氯化可食用脂肪;乳化剂,例如卵磷脂、单油酸脱水山梨醇酯或阿拉伯胶;非水性载体(可以包括食用油),例如杏仁油、精馏椰子油、油性酯如甘油、丙二醇或乙醇的酯;防腐剂,例如对羟基苯甲酸甲酯或丙酯或山梨酸; 如果需要,可以加入常用的矫味剂或着色剂。
对非肠道给药而言,使用化合物和无菌载体制备液体单位剂型。所述液体剂型取决于所使用的浓度,可混悬或溶解在载体中。在制备溶液剂时,将化合物溶解在注射用水中,并在填充到适当的容器或安瓿中之前过滤灭菌,然后密封。有利的是可以将辅剂如局部麻醉剂、防腐剂和缓冲剂溶解在载体中。为增强稳定性,注入至容器后可以冷冻组合物并在真空下除去水份。除了将化合物混悬于载体中而不是溶解于其中外,以基本相同的方法制备非肠道混悬剂,但不能用过滤除菌。化合物可在悬浮于无菌载体中之前暴露于环氧乙烷中而灭菌。有利的是,组合物中包含表面活性剂或湿润剂有助于化合物分散均匀。
也可以将本发明组合物制备成经呼吸道给药的方式,为嗅剂或用于喷雾器的气雾剂或溶液剂,或用于吸入的微细粉剂,其可单独或与惰性载体如乳糖组合。在这样的情况中,活性化合物的颗粒的适宜直径为小于50微米,优选小于10微米,例如为1-50微米,1-10微米或1-5微米。根据需要,也可以包括小量的其它止喘药或支气管扩张药,例如拟交感神经胺类如喘息定、乙基喘息定、舒喘灵、苯福林和麻黄碱;黄嘌呤衍生物如茶碱和氨茶碱和皮质类固醇激素加强的松龙和肾上腺兴奋剂如ACTH。
根据不同给药方法,组合物可以含有0.1%-99%(重量),优选10%-60%(重量)的活性物质。用于吸入给药的优选范围是10%-99%,特别是60-99%,例如90、95或99%。
微细粉末制剂的气雾剂为计量剂量的形式或通过合适的呼吸活化装置而进行适宜地给药。
适合的计量剂量气雾剂制剂包括常用的推进剂,助溶剂如乙醇,表面活性剂如油醇,润滑剂如油醇,干燥剂如硫酸钙和密度调节剂如氯化钠。
用于喷雾剂的适当溶液是等渗的无菌溶液,任选缓冲到例如pH4-7范围内,其中含有多至20mg/ml的化合物,但更常用0.1-10mg/ml的化合物,将其与标准喷雾设备一起使用。
有效剂量将取决于本发明化合物的相对有效性、所治疗疾病的严重程度和患者体重。适合的是,本发明组合物的单位剂型可含有0.1-1000mg的本发明的化合物(0.001-10mg通过吸入),更常用的是1-500mg,例如1-25或5-500mg。这样的组合物可以每日给药1-6次,通常每日2-4次,对于70kg成人而言给药方式要求使得日剂量为1mg-1g,更具体地是5-500mg,即是在约1.4×10-2mg/kg/天-14mg/kg/天的范围,更特别的是在约7×10-2mg/kg/天-7mg/kg/天的范围。
下列实施例用于说明本发明但不以任何方式限制于此。
生物实验方法
步骤1:采用下列步骤研究测试化合物抑制可溶性CD23释放的能力
RPMI8866细胞膜CD23裂解活性试验:
使用水性溶液提取方法,纯化来自RPMI8866细胞的质膜,即表达高水平CD23的人Epstein-Barr病毒转化的B-细胞系(Sarfati等,Immunology,60[1987]539-547)。将细胞重新混悬在均化缓冲液(20mM HEPES,pH7.4,150mM NaCl,1.5mM MgCl2,1mM DTT)中的细胞被帕尔罐中的N2气体击碎,和其它膜混合的质膜部分经10,000Xg离心回收。每1-3g湿细胞使用2ml 0.2M磷酸钾(pH 7.2)重新混悬轻的小团(pellet)并且弃去带核的小团。在每10-15mg膜蛋白总重为16g的0.25M蔗糖中,通过在Dextran 500(6.4%W/W和聚乙二醇(PEG)5000(6.4%W/W)(参考)之间进行分配而对膜进一步分级分离[Morre and Morre,Bio Techniques 7,946-957(1989)]。主要通过1000Xg离心分离各相并收集PEG(上层)相,用20mM磷酸钾缓冲液(pH7.4)稀释3-5倍并在100,000Xg离心以回收所述相中的膜。将小团重新混悬于磷酸盐缓冲的盐水中,由3-4倍富集的质膜以及一些其它细胞膜(如溶酶体,Golgi)组成。将膜等分并在-80℃保存。经6.6%Dextran/PEG分级分离得到富集10倍的质膜。
将所分级分离的膜在37℃下培养4小时以产生CD23片段,这些片段是在用来自P30994的5μM制剂1使试验体系骤冷后,通过0.2微米Durapore滤板(Millipore)过滤而从膜中分离出的。使用The BindingSite(Birmingham,UK)的EIA试剂盒或采用MHM 6抗-CD23mAb[Rowe等,Int.J.Canner,29,373-382(1982)]或另一种抗-CD23mAb作为夹层EIA中捕捉抗体的类似装置测定从膜中释放的s-CD23。通过EIA测得由在总体积为50μl的磷酸盐缓冲的盐水中的0.5μg膜蛋白所制得的可溶性CD23的量,并与在各种浓度的抑制剂存在下所产生的含量作比较。在水溶液或二甲亚砜(DMSO)溶液中制备抑制剂并且最终的DMSO浓度不大于2%。IC50通过相对于s-CD23在无抑制剂培养的对照物之间的差异,抑制50%s-CD23产生的浓度曲线拟合而确定。
结论:N′-[4-(N-羟基氨基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔丁基亮氨酸甲基酰胺在上述试验中给出60nm的IC50。
步骤2:使用下列步骤研究测试化合物抑制胶原酶的能力。
胶原酶抑制试验:
采用Cawston and Barrett Anal.Biochem.99,340-345,1979)(在此引入本发明作参考)的方法测定化合物作为胶原酶抑制剂的效力,其中用胶原和人重组胶原酶(来自从大肠杆菌中)克隆、表达和纯化的滑液纤维原细胞在37℃培养1mM待试抑制剂溶液或其稀释液18小时(用150mM Tris pH7.6缓冲,含有15mM氯化钙,0.05%Brij35,200mM氯化钠和0.02%叠氮化钠)。所述胶原为用Cawston and Murphy方法(Enzymology,
80,711,1981中的方法)制备的乙酰化3H I型牛胶原。样品经离心以沉淀未消化的胶原并移出等份有放射活性的上清液,用闪烁计数器检验其水解。比较在1mM抑制剂或其稀释液存在下的胶原酶活性与无抑制剂的对照物活性,所报告的结果为影响50%胶原酶的浓度(IC50)。
步骤3:使用下列步骤研究测试化合物抑制TNF释放的能力
检验由脂多糖(LPS)内毒素刺激人单核细胞释放TNFα的抑制能力。
将在10%胎牛血清补充的RPMI640培养基中培养的人单核细胞以1000Xg离心5分钟,然后以2×106细胞/毫升的浓度重新混悬在培养基中。每孔1ml,在24孔板中对细胞混悬液进行等分。将待试化合物溶解于无水二甲亚砜(DMSO)中并加入到最终DMSO浓度为0.1%的培养基中。将化合物一式三份加入细胞中。通过加入LPS至最终浓度200ng/ml的细胞中刺激TNFα释放。适当的对照培养物也按一式三份设置。在37℃下、5%二氧化碳中将平板培养18-20小时,然后以1000Xg离心5分钟。使用用于人TNFα(Smithkline Beecham)的特异性ELISA测定没有细胞的培养物上清液中的TNF水平。
结论:
N′-[4-(N-羟按基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔-亮氨酸甲基酰胺在10μM时对TNF释放没有表现出效果。
步骤4:使用下列生物等效性实验研究测试化合物的生物利用度。
该研究用于评价在雄性Sprague Dawley鼠中的静脉内药物动力学参数和口服生物利用度。
该研究采用正交设计,在四个单独的研究日内进行。在研究开始前至少三天,对三只小鼠通过股骨静脉导管外科灌输而注入测试分子,在该研究中所有剂量都是使用结晶试验化合物制备的。
在第一研究日中,对动物(喂食)持续30分钟静脉内注射测试化合物,以4.0μmol/kg(4.0ml/kg)为目标剂量。该剂量溶液在20%Encapsin水溶液(pH=8.0)中制备并含有1%的DMSO。Encapsin(Cerestar USA Inc.,Hammond,IN)是羟丙基-β-环糊精,一种环形低聚糖,用于增加需要使用非水溶剂配制的化合物的溶解度。
在第二研究日中,动物(禁食)通过强制口服,以8μmol/kg(16ml/kg)为目标剂量,以溶液形式接受测试化合物。该剂量溶液在5%琥珀酰化的猪明胶溶液(pH=7.5)中制成并含有1%的DMSO。
血液样品从支端部静脉中收集。将25μL等分的每份血液样品整个加入25μL水中并且在冰上放置约5分钟,以促进完全溶血;在分析之前冷藏样品。测试化合物的血液浓度通过LC/MS/MS(LLQ-10.0ng/mL)来定量。使用WinNonlin在这些数据上进行区划和非区划药物动力学分析(noncompartmental pharmacokinetic analyses)以得到适宜的静脉给药时的药物动力学参数。使用各种区划模型和加权范例;根据标准的模型选则规则(例如:Akaike’s Information Criterion,Schwartz Criterion以及平方余项和),来自中心区域的具有一阶消元的二房室模型和具有1/Y2加权系数的迭代最小二乘加权提供对所观察数据的最佳拟合。药物动力学参数通过最佳拟合区划模型计算得到;所有需要使用AUC值(包括生物利用度)的计算都是使用从非区划分析中得到的AUC而实施的。
该研究用于在评估雄性Beagle狗中的静脉内药物动力学参数和口服生物利用度。
采用正交设计,在两个单独的研究日进行,中间间隔七天。在该研究中用到三只雄性Beagle狗。在每个研究日,在其头部静脉中临时放置导管以提取血样;仅在第一研究日,在隐静脉中临时放置导管以进行静脉输液。
在第一研究日,每只动物通过1-h静脉注射(4.0mL/kg)化合物(2.0μmol/kg目标剂量)。该剂量溶液在20%Encapsin水溶液(pH=8.0)中制成并含有1%的DMSO。Encapsin(Cerestar USA Inc.,Hammonk,IN)是羟丙基-β-环糊精,一种环状低聚糖(7个葡萄糖单元),用于增加需要使用非水溶剂配制的剂量溶液制剂的溶解度。
在第二研究日,每只动物通过强制口服(8.0mL/kg)接受测试化合物(6.0μmol/kg目标剂量)。该剂量溶液在5%琥珀酰化的猪明胶溶液(pH=7.5)中制成并含有1%的DMSO。
测试化合物的血液浓度通过LC//MS/MS(LLQ-10ng/mL)来定量。采用非区划方式来分析血样浓度与时间之间的关系。
该研究用于评估在雄性Cynomolgus猴中的静脉内药物动力学参数和口服生物利用度。
该研究采用正交设计,在两个单独的研究日内进行,中间间隔七天。该研究中用到三只雄性Cynomolgus猴。在两个研究日中,在隐静脉中放置导管以收集血样;在第一研究日,在对侧隐静脉中临时放置导管用于进行静脉输液。
在第一研究日,每只动物(禁食)通过1-h静脉输入(4.0mL/kg)而接受测试化合物(2.0μmol/kg目标剂量)。该剂量溶液在20%Encapsin溶液(pH=8.0)中制成并含有1%的DMSO。Encapsin(Cerestar USA Inc.,Hammond,IN)是羟丙基-β-环糊精,一种环状低聚糖(7个葡萄糖单元),用于增加其它需要使用非水溶剂配制的剂量溶液制剂中的溶解度。
在第二研究日,每只动物(禁食)通过强制口服(8.0mL/kg)而接受测试化合物(6.0μmol/kg目标剂量)。该剂量溶液在5%琥珀酰化的猪明胶溶液(pH=8.0)中制成并含有1%的DMSO。
血样从股骨静脉导管获得;离心分离血浆。测试化合物的血浆浓度通过LC//MS/MS(LLQ-10ng/mL)来定量。非区划方法被用于进行血浆浓度相对于时间数据的药物动力学分析。
结论:
将N′-[4-(N-羟胺基)-3S-丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸甲基酰胺的结果和N′-[4-(N)-羟氨基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸甲氧基酰胺(公开于WO99/67201(SmithKline Beecham))的结果相比较。
Cmax(ng/mL) | 1335±296静脉内剂量=2.0mg/kg | 1414±465静脉内剂量=0.96mg/kg | 1011±175静脉内剂量=0.92mg/kg | 1359±464静脉内剂量=0.99mg/kg |
T1/2(min)(MRT) | 10.8±5.3(α)234±139(β)(128±77) | 252,259,49b(64.4±39.7) | 691,85.1,208b(311,59.5,68.1b) | 5.32±1.14(α)311±106(β)(115±62) |
CL(mL/min/kg) | 26.4±8.5 | 10.6±4.5 | 14.7±3.6 | 10.4±3.7 |
VdSS(L/kg) | 3.25±1.701 | 0.563±0.204 | 4.09,1.11,0.827b | 1.16±0.57 |
口服Fa(%) | 50.6±10.6(3.7mg/kg溶液) | 29.0±3.7口服剂量=2.7mg/kg | 21.1,6.0,22.5b(2.8mg/kg溶液) | 1.4,6.0,1.9b口服剂量=2.8mg/kg |
缩写:
Cmax—静脉内注入后所达到的最大浓度;
T1/2—半衰期;
MRT—测试分子的平均停留时间;
CL—系统血浆清除;
Vdss—分布的稳态体积;
F—百分比生物利用度。
a生物利用度通过用剂量-归一化的AUC0-t(t是口服段具有可观察测试化合物浓度的最后时间点(对于鼠研究而言)或具有在口服或十二指肠股(intraduodenal leg)研究中可测量药物浓度的最后时间点(对于狗和猴研究而言))处于除以静脉内段得到的剂量归一化的AUC0-t并乘以100而得到。
b由于可变性大而列出的单个值;动物通常以相同的顺序列出。
在氩气、-70℃条件下,将在THF(160ml)中的叔丁基-(3R)-羧基-4-(2-萘基)丁酸酯(10g,31.9mmol)进行搅拌,并且滴加双(三甲基甲硅烷基)酰氨基锂(63.7ml在THF中的1M溶液,63.7mmol)。在-60℃至-70℃之间将混合物搅拌1小时,然后冷却到-80℃,并且通过套管加入在THF(20ml)中的N-碘代琥珀酰亚胺(7.17g,31.9mmol)。反应1小时后,将混合物的温度升高至约-30℃,接着用饱和氯化铵溶液使反应终止,加入乙酸乙酯,在室温下快速搅拌两相混合物1.5小时。分离各层,水层用乙酸乙酯(2x)提取,合并后的有机层分别用5%的硫代硫酸钠溶液和盐水洗涤,然后用硫酸钠干燥并蒸发。通过硅胶层析(用10%在己烷中的乙酸乙酯洗脱),用己烷研制所得到产品给出5.70g白色固体(63%)。
MS(AP+ve)M+Na=335
1H NMR(CDCl3):1.31(9H,s),3.29(1H,dd,J=8.5,14.6Hz),3.38(1H,dd,J=6.1,14.6Hz),4.06(1H,m),4.45(1H,d,J=4.4Hz),7.34(1H,dd,J=1.7,8.5Hz),7.48(2H,m),7.68(1H,s),7.82(3H,m)
实施例:
N′-[4-(N-羟胺基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸甲基酰胺
a)N′-[4-(叔丁氧基)-3S-羟基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸苄基酯
将叔亮氨酸苄基酯TFA盐(6.49g)与无水碳酸钾(2.89g)在THF(100ml)中搅拌20分钟。加入HOAT(2.24g)和3S-叔丁氧基端基-2R-(2-萘甲基)丙内酯(4.66g,14.94mmol)后,再搅拌72小时(48小时后补加HOAT(1.02g))。过滤出固体,用THF洗涤。将滤液合并,蒸发得到泡沫状物质,溶解于乙酸乙酯中,依次用0.5M盐酸、饱和碳酸氢钠溶液(2x)、水和盐水进行洗涤;干燥(硫酸镁),蒸发得到胶状物(gum),用己烷/乙醚结晶得到6.35g白色固体产物(80%)。
1H NMR(DMSO-d6):0.88(9H,s),1.40(9H,s),2.88(1H,dd,J=13.5,6Hz),3.00(1H,dd,J=13.5,8.5Hz),3.19(1H,m),3.92(1H,t,J≈6.5Hz),4.18(1H,d,J=8.5Hz),4.77(1H,d,J=12.5Hz),4.84(1H,d,J=12.5Hz),5.53(1H,d,J=7.5Hz),7.24(2H,m),7.30-7.37(4H,m),7.45(2H,m)7.65(1H,s),7.77-7.87(3H,m),8.09(1H,d,J≈9Hz)
向N′-[4-(叔丁氧基)-3S-羟基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸苄基酯(3.0g,5.62mmol)的1,2-二乙氧基乙烷(75ml)中,加入NaH(60%石蜡中悬浊液;0.27g),搅拌2-3分钟后,加入iPrOTf的戊烷溶液(约30%w/w;6mL)。将混合物在室温搅拌25分钟后,再加入NaH(0.054g)和iPrOTf(3mL)。再搅拌20分钟,再加入NaH(0.054g)和iPrOTf(3mL)。搅拌20分钟以后,加入0.5M HCl,将混合物用乙酸乙酯(2X)提取。合并后的提取物依次用饱和碳酸氢钠溶液、水和盐水洗涤;干燥(硫酸镁),蒸发成胶,通过硅胶(己烷/乙醚)层析纯化,得到几乎无色的胶状产物1.33g(41%)。
MS(ES+ve)M+H=576,M+Na=598
1H NMR(CDCl3):0.87(9H,s),1.09(3H,d,J=6.0Hz),1.21(3H,d,J=6.0Hz),1.49(9H,s),2.87-3.00(2H,m),3.10-3.22(1H,m),3.69(1H,7-tet,J=6.0Hz),4.00(1H,d,J=6.5Hz),4.36(1H,d,J=9Hz),4.57(1H,d,表观J=12.5Hz),4.63(1H,d,表观J=12.5Hz)(two halves of Abq),6.50(1H,d,J=9Hz),7.15-7.19(2H,m),7.27-7.40(4H,m,),7.40-7.45(2H,m),7.60(1H,m),7.72-7.80(3H,m)
在常压、钯-硫酸钡(0.67g)催化作用下,将N′-[4-(叔丁氧基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔-亮氨酸苄基酯(1.33g,2.31mmol)在甲醇(38mL)中氢解1小时。滤除催化剂,用甲醇洗涤完全。合并滤液,蒸发,得到泡沫状产物1.09g(97%)。
MS(ES+ve)M+H=486,M+Na=508
1H NMR(DMSO-d6):0.92(9H,s),1.02(3H,d,J=6.0Hz),1.08(3H,d,J=6.0Hz),1.42(9H,s),2.75(1H,dd,J=14.4Hz),3.00(1H,dd,J=14,9.5Hz),3.21(1H,m),3.57(1H,7-tet,J=6.0Hz),3.93(1H,d,J=8.5Hz),4.10(1H,d,J=9Hz),7.29(1H,m),7.44(2H,m),7.62(1H,s),7.74-7.84(3H,m),7.90(1H,d,J≈9Hz),12.35(1H,v.br.)
d)N′-[4-(叔丁氧基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔-亮氨酸甲基酰胺
将N′-[4-(叔丁氧基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔-亮氨酸(1.09g,2.24mmol)溶解于DMF(29mL)中,并用HOAT(0.61g)和DEC(0.86g)处理。室温下搅拌混合物20分钟,接着加入盐酸甲胺(0.61g)和N-甲基吗啉(0.74mL)。将混合物再搅拌2小时,然后真空浓缩。残余物溶解于乙酸乙酯中,依次用0.5M HCl、饱和碳酸氢钠溶液、水和盐水洗涤;用硫酸镁干燥,蒸发至成胶状,通过硅胶(己烷/乙酸乙酯)层析纯化,得到胶状产品0.77g(69%)。
MS(ES+ve)M+H=499,M+Na=521
1H NMR(DMSO-d6):0.84(9H,s),1.02(3H,d,J=6.0Hz),1.09(3H,d,J=6.0Hz),1.45(9H,s),2.16(3H,d,J=4.5Hz),2.74(1H,dd,J=13.5,4.5Hz),2.93(1H,dd,J=13.5,10Hz),3.17(1H,m),3.56(1H,7-tet,J=6Hz),3.94(1H,d,J=8.5Hz),4.06(1H,d,J=9.5Hz),7.25(1H,br.m),7.28(1H,dd,J=8.5,1.5Hz),7.44(2H,m),7.59(1H,m),7.67(1H,d,J=8.5Hz),7.74-7.86(3H,m)
将N′-[4-(叔丁氧基)-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸甲基酰胺(0.77g,1.544mmol)溶解于TFA(11mL)和DCM(22mL)中,并在室温下搅拌2.5小时。真空蒸发溶液,用甲苯再蒸发处理一次。残余物用乙醚/己烷研制,得到白色固体产品0.67g(98%)。
MS(ES+ve)M+H=443,M+Na=465
1H NMR(DMSO-d6):0.85(9H,s),1.02(3H,d,J=6.0Hz),1.09(3H,d,J=6.0Hz),2.16(3H,d,J=4.5Hz),2.78(1H,dd,J=14,5Hz),2.95(1H,dd,J=14,10.5Hz),3.18(1H,m),3.58(1H,7-tet,J=6Hz),4.00(1H,d,J=8.5Hz),4.05(1H,d,J=9.5Hz),7.20(1H,q,J=4.5Hz),7.29(1H,dd,J=8.5,1.5Hz),7.42-7.46(2H,m),7.59(1H,d,J=9Hz),7.60(1H,s),7.74-7.84(3H,m),12.87(1H,br.s)
将N′-[4-羟基-3S-异丙氧基-2R-(2-萘甲基)琥珀酰基]-S-叔亮氨酸甲基酰胺(0.67g,1.514mmol)溶解于DMF(20mL)中,用HOAT(0.41g)和DEC(0.58g)处理。将该溶液在室温下搅拌5分钟,加入盐酸羟胺(0.32g)和N-甲基吗啉(0.5mL)。将混合物在室温下搅拌2小时,接着真空浓缩。残余物在乙酸乙酯之间分配,并用饱和碳酸氢钠水溶液(2X)、水(2X)和盐水洗涤;硫酸镁干燥,蒸发至固体,其用醚研制后得到白色固体产品0.51g(74%)。
MS(ES+ve)M+H=458,M+Na=480
1H NMR(DMSO-d6):0.84(9H,s),1.00(3H,d,J=6.0Hz),1.04(3H,d,J=6.0Hz),2.02(3H,d,J=5Hz),2.65(1H,dd,J=14,4Hz),2.83(1H,dd,J=14,11.5Hz),3.18(1H,m),3.52(1H,7-tet,J=6.0Hz),3.90(1H,d,J=9Hz),4.01(1H,d,J=9Hz),6.93(1H,q,J=5Hz),7.25(1H,dd,J=8.5,1.5Hz),7.44(2H,m),7.53(1H,d,J=9Hz),7.57(1H,s),7.75-7.85(3H,m),9.08(1H,s),10.89(1H,br.s)。
Claims (8)
3.根据权利要求1或2的化合物在制备用于治疗或预防与过量产生s-CD23有关的疾病如变态反应、炎症性疾病和自身免疫疾病的药物中的应用。
4.治疗或预防与过量产生s-CD23有关的疾病如变态反应、炎症性疾病和自身免疫疾病的方法,该方法包括将权利要求1或2所述化合物给予需要进行治疗或预防的人或非人哺乳动物。
5.用于治疗或预防与过量产生s-CD23有关的疾病如变态反应、炎症性疾病和自身免疫疾病的药物组合物,其中包括权利要求1或2所述的化合物和任选的可药用载体。
6.制备权利要求1或2所述化合物的方法,该方法包括:
a)将式(II)化合物脱保护:
其中X是保护基如苄基或三甲基甲硅烷基或
b)将式(III)化合物与羟胺或其盐反应:
其中任选地将羟基进行保护。
7.如权利要求6定义的式(II)化合物。
8.如权利要求6定义的式(III)化合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9925470.8A GB9925470D0 (en) | 1999-10-27 | 1999-10-27 | Novel compounds |
GB9925470.8 | 1999-10-27 |
Publications (2)
Publication Number | Publication Date |
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CN1411436A true CN1411436A (zh) | 2003-04-16 |
CN1182107C CN1182107C (zh) | 2004-12-29 |
Family
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Application Number | Title | Priority Date | Filing Date |
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CNB008173680A Expired - Fee Related CN1182107C (zh) | 1999-10-27 | 2000-10-25 | 作为可溶性人cd23形成的抑制剂的异羟肟酸衍生物 |
Country Status (32)
Country | Link |
---|---|
US (2) | US6673965B1 (zh) |
EP (1) | EP1224164B1 (zh) |
JP (1) | JP3922431B2 (zh) |
KR (1) | KR20020044578A (zh) |
CN (1) | CN1182107C (zh) |
AR (1) | AR026244A1 (zh) |
AT (1) | ATE284382T1 (zh) |
AU (1) | AU766072B2 (zh) |
BR (1) | BR0015082A (zh) |
CA (1) | CA2389319A1 (zh) |
CO (1) | CO5261576A1 (zh) |
CZ (1) | CZ20021424A3 (zh) |
DE (1) | DE60016622T2 (zh) |
DK (1) | DK1224164T3 (zh) |
ES (1) | ES2233474T3 (zh) |
GB (1) | GB9925470D0 (zh) |
GC (1) | GC0000142A (zh) |
HK (1) | HK1049146A1 (zh) |
HU (1) | HUP0203270A3 (zh) |
IL (1) | IL149364A0 (zh) |
MX (1) | MXPA02004228A (zh) |
MY (1) | MY133601A (zh) |
NO (1) | NO20021965L (zh) |
NZ (1) | NZ518566A (zh) |
PE (1) | PE20010898A1 (zh) |
PL (1) | PL356524A1 (zh) |
PT (1) | PT1224164E (zh) |
SI (1) | SI1224164T1 (zh) |
TW (1) | TW561141B (zh) |
UY (1) | UY26416A1 (zh) |
WO (1) | WO2001030747A1 (zh) |
ZA (1) | ZA200203255B (zh) |
Families Citing this family (7)
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CA2735929C (en) * | 2008-09-19 | 2013-12-17 | Pfizer Inc. | Hydroxamic acid derivatives useful as antibacterial agents |
EP2860195A1 (en) | 2009-12-01 | 2015-04-15 | Boston Medical Center Corporation | Treatment of IgE-mediated disease |
CA2782453C (en) | 2009-12-16 | 2015-11-24 | Matthew Frank Brown | N-linked hydroxamic acid derivatives useful as antibacterial agents |
SG192766A1 (en) | 2011-03-07 | 2013-09-30 | Pfizer | Fluoro-pyridinone derivatives useful as antibacterial agents |
EP2694481B1 (en) | 2011-04-08 | 2015-12-30 | Pfizer Inc | Imidazole, pyrazole, and triazole derivatives useful as antibacterial agents |
SG193367A1 (en) | 2011-04-08 | 2013-10-30 | Pfizer | Isoxazole derivatives useful as antibacterial agents |
EP2525213A1 (en) * | 2011-05-16 | 2012-11-21 | Renishaw plc | Spectroscopic apparatus and methods for determining components present in a sample |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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GB9513331D0 (en) * | 1995-06-30 | 1995-09-06 | British Biotech Pharm | Matrix metalloproteinase inhibitors |
GB9813451D0 (en) * | 1998-06-22 | 1998-08-19 | Smithkline Beecham Plc | Novel compounds |
-
1999
- 1999-10-27 GB GBGB9925470.8A patent/GB9925470D0/en not_active Ceased
-
2000
- 2000-10-25 KR KR1020027005340A patent/KR20020044578A/ko not_active Application Discontinuation
- 2000-10-25 CN CNB008173680A patent/CN1182107C/zh not_active Expired - Fee Related
- 2000-10-25 BR BR0015082-7A patent/BR0015082A/pt not_active IP Right Cessation
- 2000-10-25 AU AU13895/01A patent/AU766072B2/en not_active Ceased
- 2000-10-25 DE DE60016622T patent/DE60016622T2/de not_active Expired - Lifetime
- 2000-10-25 MX MXPA02004228A patent/MXPA02004228A/es active IP Right Grant
- 2000-10-25 PL PL00356524A patent/PL356524A1/xx unknown
- 2000-10-25 ES ES00975954T patent/ES2233474T3/es not_active Expired - Lifetime
- 2000-10-25 AR ARP000105622A patent/AR026244A1/es not_active Application Discontinuation
- 2000-10-25 EP EP00975954A patent/EP1224164B1/en not_active Expired - Lifetime
- 2000-10-25 JP JP2001533102A patent/JP3922431B2/ja not_active Expired - Fee Related
- 2000-10-25 CA CA002389319A patent/CA2389319A1/en not_active Abandoned
- 2000-10-25 US US10/111,209 patent/US6673965B1/en not_active Expired - Fee Related
- 2000-10-25 MY MYPI20005012A patent/MY133601A/en unknown
- 2000-10-25 CZ CZ20021424A patent/CZ20021424A3/cs unknown
- 2000-10-25 NZ NZ518566A patent/NZ518566A/en unknown
- 2000-10-25 AT AT00975954T patent/ATE284382T1/de not_active IP Right Cessation
- 2000-10-25 WO PCT/EP2000/010649 patent/WO2001030747A1/en active IP Right Grant
- 2000-10-25 PT PT00975954T patent/PT1224164E/pt unknown
- 2000-10-25 GC GCP2000972 patent/GC0000142A/xx active
- 2000-10-25 SI SI200030603T patent/SI1224164T1/xx unknown
- 2000-10-25 IL IL14936400A patent/IL149364A0/xx unknown
- 2000-10-25 UY UY26416A patent/UY26416A1/es not_active Application Discontinuation
- 2000-10-25 DK DK00975954T patent/DK1224164T3/da active
- 2000-10-25 HU HU0203270A patent/HUP0203270A3/hu unknown
- 2000-10-26 TW TW089122497A patent/TW561141B/zh active
- 2000-10-26 CO CO00081571A patent/CO5261576A1/es not_active Application Discontinuation
- 2000-10-27 PE PE2000001156A patent/PE20010898A1/es not_active Application Discontinuation
-
2002
- 2002-04-24 ZA ZA200203255A patent/ZA200203255B/en unknown
- 2002-04-25 NO NO20021965A patent/NO20021965L/no unknown
- 2002-12-19 HK HK02109235A patent/HK1049146A1/xx not_active IP Right Cessation
-
2003
- 2003-10-03 US US10/678,679 patent/US20040077727A1/en not_active Abandoned
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