CN1413108A - 治疗炎症的6-甲氧基-2-萘乙酸前药组合物 - Google Patents
治疗炎症的6-甲氧基-2-萘乙酸前药组合物 Download PDFInfo
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Abstract
本发明提供用于治疗人体炎症的组合物,并涉及其治疗方法。在一实施方案中,所述组合物为式(A)。在另一实施方案中,所述组合物为式(B)。在又一实施方案中,所述组合物为式(C)。另外的可选择实施方案为疗效基团的R和R″。
Description
相关申请
本申请要求1999年10月27日提交的美国临时申请60/161,864的优先权,其公开的全文通过引用结合到本文中。
本发明的领域和背景
本发明涉及用于人体炎症的治疗的药用组合物,所述药用组合物使用为6-甲氧基-2-萘乙酸(下文中称作“6MNA”)的前药的化合物。
已知各种萘衍生物对治疗炎症和各种类风湿病及关节炎疾病是有用的,例如,Fried等在美国专利4,009,197号中所述的具有下式(I)的萘普生:然而,当用量仅略大于过量的治疗剂量时,化合物(I)可引起胃肠道的严重刺激作用。
另一萘衍生物为如Lake等在美国专利4,061,779和4,420,639号中所述的具有式(II)的萘丁美酮:萘丁美酮通过抑制环加氧酶(一种负责生成为炎症介质的前列腺素的酶)来起作用。萘丁美酮是一种经肝的生物转化成活性成分6-甲氧基-2-萘乙酸(式(III))的前药(参见Haddock,R.E.等的“Metabolism of Nabumetone(BRL 14777 byvarious species including man”Xenobiotica;14(4):327-337(1984))。可市售获得的萘丁美酮为Smithkline Beecham,Inc的Relafen。但是,仅约35%的口服给予的萘丁美酮在体内被转化为6MNA。
所以,本发明的目的之一是提供比萘丁美酮更易于转化成6MNA的6MNA前药。相信人体水解和溶解所述前药的能力的改善可有益于这种转化。因此,另一目的是提高所述前药的水解和溶解性以更好地转化成6MNA。
对6MNA及其相关前药的另一关注点为羧酸部分的存在会产生胃刺激和/或溃疡。因此,本发明的另一目的是提供具有减少引起胃刺激的倾向的6MNA前药。
本发明概述
本发明提供用于治疗人体炎症的组合物及其相关的治疗炎症方法。在一个实施方案中,所述组合物为其中R选自(CH2)mO(CH2)n;(CH2)m(OC2H4)pO(CH2)n;(CH2)m(CHOH)r(CHOH)s及其(R)和(S)对映体及其混合物;和CHCOR′;其中m为2-4的整数,n和p为1-4的整数而r和s为1-2的整数,R′选自C1-C6烷基、(CH2)mO(CH2)n、CH2(OC2H4)pO(CH2)n和CH2(OC2H4)p。
在另一实施方案中,所述组合物为其中R″选自C1-C6烷基、CH2(OC2H4)nO(CH2)n、CH2(OC2H4)pOCH3、(OC2H4)nONO2、(OC2H4)nO(CH2)n、(CH2)n(OC2H4)mONO2、(OC2H4)nO(CH2)mOH、NH(CH2)m(OC2H4)n、NH(CH2)m(OC2H4)mONO2、NHO(CH2)nCH3、NH(CH2)m(OC2H4)pOCH3和NH(OC2H4)pOCH3,其中m为2-4的整数,而n和p为1-4的整数。
在又一个实施方案中,所述组合物为其中的R选自氢、O(CH2)nCH3、C1-C6烷基、(CH2)m(OC2H4)pO(CH2)n、(CH2)m(OC2H4)p、(CH2)m(OC2H4)nONO2、(CH2)m(OC2H4)pO(CH2)mOH和(CH2)mNHO(CH2)nCH3,其中m为2-4的整数,而n和p为1-4的整数。
另外的可选择的实施方案是R或R″为疗效基团。这类组合物可用于治疗炎症的方法中。
图的简要说明
图1和图2为本发明的6MNA前药的合成途径的示意图。
本发明的详细说明
以下参照附图将更充分地描述本发明,其中显示了本发明的优选实施方案。然而,本发明可具体表现为不同的形式,但不应视为是对本文所提出的实施方案的限制。更确切地说,提供这些实施方案是为了本公开更加充分和完整,并向本领域的技术人员充分地传达本发明的范围。
本文中用来说明本发明的术语只是为了描述具体的实施方案的目的,而不是要限制本发明。如本发明的说明书及所附权利要求书中所用的,单数形式“一种”和“该”也打算包括复数形式,除非文中另外明确表示。
除非另行定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同意义。本文中所提及的所有出版物、专利申请、专利及其它参考文献全文通过引用结合到本文中。
“治疗有效量”指预防、延缓或减轻炎症的严重性的必需量,也包括增强正常生理功能的必需量。
如本文所用的,根据本发明的制剂的“药学上可接受的”成分(如盐、载体、赋形剂或稀释剂)是这样一种成分,所述成分(1)是与所述制剂的其它成分相适配的,以便它可与本发明的6MNA前药相结合而不消除6MNA前药的生物活性;和(2)适用于动物(如人体)而无过度有害的副作用,如毒性、刺激和过敏反应的成分。当副作用的风险高于由所述药用组合物所带来的益处时,副作用为“过度的”。
如上所述,本发明提供治疗有效量的6MNA前药。相信各种6MNA衍生物具有比现有组合物更好的性质。例如,相信下述基团具有改进的水解性(因而有更高的产率),和其中的R、R″和R基团有助于改善溶解性和提高抗溃疡作用。
特别地,在一个实施方案中,所述药用组合物为其中R选自(CH2)mO(CH2)n;(CH2)m(OC2H4)pO(CH2)n;(CH2)m(CHOH)r(CHOH)s及其(R)和(S)对映体及其混合物;和CHCOR′;其中m为2-4的整数,n和p为1-4的整数而r和s为1-2的整数,R′选自C1-C6烷基、(CH2)mO(CH2)n、CH2(OC2H4)pO(CH2)n和CH2(OC2H4)p。特别优选的实施方案是R为CH2CH2OCH3、CH2CH2OCH2CH2OCH3、CHCOCH2COCH3、CHCOCH2COCH3(OC2H4)OCH3和CHCOCH2COCH2OCH3时。
在另一实施方案中,所述药用组合物为其中R″选自C1-C6烷基、CH2(OC2H4)nO(CH2)n、CH2(OC2H4)pOCH3、(OC2H4)nONO2、(OC2H4)nO(CH2)n、(CH2)n(OC2H4)mONO2、(OC2H4)nO(CH2)mOH、NH(CH2)m(OC2H4)n、NH(CH2)m(OC2H4)mONO2、NHO(CH2)nCH3、NH(CH2)m(OC2H4)pOCH3和NH(OC2H4)pOCH3,其中m为2-4的整数,而n和p为1-4的整数。
在又一个实施方案中,所述药用组合物为其中的R选自氢、O(CH2)nCH3、C1-C6烷基、(CH2)m(OC2H4)pO(CH2)n、(CH2)m(OC2H4)p、(CH2)m(OC2H4)nONO2、(CH2)m(0C2H4)pO(CH2)mOH和(CH2)mNHO(CH2)nCH3。其中m为2-4的整数,而n和p为1-4的整数。
本发明的6MNA前药可任选与用于治疗炎症或用于治疗其它与炎症相关的适应症如疼痛的其它化合物联合用药。其它化合物可任选同时(concurrently)给药。此处所用的“同时”意指对产生联合效果而言在时间上足够接近(即,同时可以是一起(simultaneously)发生,或者可以是两个或多个事件在短时间内相互先后发生)。
如本文所用的,两或多种化合物“联合”给药意指两种化合物的给药时间足够接近,以至于一种化合物的存在改变了另一种化合物的生物作用。所述两种化合物可一起(即同时)或相继给药。可通过给药前将化合物混合,或在同一时间点上但在不同解剖学部位给予化合物,或采用不同的给药途径来实施一起给药。
本文可交换使用的术语“同时给药”、“联合用药”、“共同给药”或“一起给药”,意指在同一时间点上或彼此紧随的顺序给予所述化合物。在后一种情况下,两种化合物在足够接近的时间内给予,以使至于所观察的结果与在同一时间点上给予这些化合物所达到的结果没有区别。
本发明主要涉及病人的治疗,但出于兽医和药物筛选及药物开发的考虑,也可对患病的动物,尤其是患病的哺乳动物如小鼠、大鼠、狗、猫、家畜和马实施本发明。
如上所述,本文公开的6MNA前药可被制成其药学上可接受的盐的形式。药学上可接受的盐指维持母体化合物所需的生物活性且不产生不希望的毒理作用的盐。这类盐的实例有,(a)与无机酸如盐酸、氢溴酸、硫酸、磷酸、硝酸等形成的酸加成盐;及与有机酸如乙酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、甲磺酸、对甲苯磺酸、萘二磺酸、聚半乳糖醛酸等形成的盐;(b)由元素阴离子如氯、溴和碘形成的盐,和(c)衍生自碱的盐如铵盐、碱金属盐如钠盐和钾盐、碱土金属盐如钙盐和镁盐及与有机碱如二环己胺和N-甲基-D-葡糖胺形成的盐。
上述6MNA前药可根据已知的技术用药用载体进行配制以便给予。参见如,Remington的The Science And Practice of Pharmacy(第9版,1995)。在根据本发明的药物制剂的制备中,前药(包括其生理上可接受的盐)通常与特别是可接受的载体混和。当然,所述载体在与制剂中的任何其它成分相适配的意义上而言,必须是可接受的且对患者无害。所述载体可以是固体或液体或两者皆是,并优选与所述化合物一起配制为单位-剂量制剂(如,可含0.01或0.5%-95%或99%重量的6MNA前药的片剂)的所述化合物一起配制。一种或多种6MNA前药可加入本发明的制剂中,这些制剂可通过任何熟知的制药技术主要包括将各成分混合,任选地包括一种或多种助剂)制备。
本发明的制剂包括那些适于经口服、直肠、局部、颊(如,舌下)、阴道、不经肠(如,皮下、肌内、真皮内或静脉内)、局部(即皮肤和粘膜表面,包括气管表面)和经皮给药的制剂,尽管在任何给定的情况下,最适合的途径将取决于待治疗的疾病的性质和严重性及采用的具体6MNA前药的性质。
适用于口服给予的制剂可以为分开的单位,如,各含预定量的6MNA前药的胶囊、扁囊剂、锭剂或片剂;为粉剂或颗粒剂;为含水或不含水液体的溶液或悬液;或为水包油或油包水的乳剂。这类制剂可通过任何合适的制药方法制备,该方法包括将6MNA前药与合适的载体(所述载体包含一种或多种上述助剂)相混合的步骤的制药方法制备。一般说来,通过将6MNA前药与液体或细分散的固体载体或两者均匀和紧密地混合,然后,如需要,将生成的混合物成形来制备本发明的制剂。例如,通过压制或模压含6MNA前药、任选含一种或多种助剂的粉末或颗粒可制备片剂。通过用合适的机器压制呈自由流动形式的化合物,如任选与粘合剂、润滑剂、惰性稀释剂和/或表面活性剂/分散剂混和的粉末或颗粒的所述化合物可以制备压制片剂。通过在合适的机器中模压用惰性液体粘合剂湿润过的粉末状化合物可以制备模压片剂。
适用于口腔(舌下)给药的制剂包括含有在调味基质,通常为蔗糖和阿拉伯胶或黄蓍胶中的6MNA前药的锭剂;和含有在惰性基质如明胶和甘油或蔗糖和阿拉伯胶中的所述化合物的软锭剂。
适用于不经肠给药的本发明制剂包括无菌的、含水或不含水的6MNA前药的注射液,优选所述制剂与计划的接受者的血液等渗。这些制剂可以含有抗氧化剂、缓冲剂、制菌剂和溶质,所述溶质可以使该制剂与计划的接受者的血液等渗。含水和不含水的无菌悬液可包括悬浮剂和增稠剂。所述制剂可以以单位剂量或多剂量容器,如密封的安瓿和小瓶的形式存在,并且可以在冷冻干燥(冻干)的条件下贮存,临用前只需加入无菌液体载体,如盐水或注射用水即可。可以由前述各种无菌粉剂、颗粒剂和片剂制备临时配制的注射溶液和悬液。例如,在本发明的一个方面,提供一种以单位剂量形式置于密封容器中的含式(I)化合物或其盐的可注射的、稳定的、无菌组合物。该化合物或盐以冻干的形式提供,这种形式能够用合适的药学上可接受的载体重新配制,以形成适用于注射入患者的液体组合物。所述单位剂量形式一般包括约10mg-10g所述化合物或盐。当所述化合物或盐基本上不溶解于水时,可足量使用生理上可接受的足量乳化剂乳化在含水载体中的该化合物或盐。一种这样的有用的乳化剂为卵磷脂。
适用于直肠给药的制剂优选为单位剂量的栓剂。通过将6MNA前药与一种或多种常规固体载体如可可油混合,再使生成的混合物成形可制备栓剂。
适用于对皮肤局部用药的制剂优选采用软膏、霜剂、洗剂、糊剂、凝胶剂、喷雾剂、气溶胶或油的形式。可用的载体包括凡士林、羊毛脂、聚乙二醇、醇、透皮促进剂及其两种或多种载体的组合。
适用于经皮给药的制剂可以为适于与接受者的表皮保持长时间的紧密接触的分开的贴剂。适用于经皮给药的制剂也可经离子电渗疗法传递(参见,如Pharmaceutical Research 3(6):318(1986)),并通常采用6MNA前药的任选缓冲水溶液的形式。适用的制剂包括柠檬酸或二/三羟甲基氨基甲烷缓冲液(pH6)或乙醇/水并含有0.1-0.2M活性成分。
任何6MNA前药的治疗有效剂量(其应用属于本发明的范围)会随化合物的不同、患者的不同而有所变化,并且将取决于诸如患者的年龄和疾病以及给药途径等因素。可根据本领域的技术人员所知道的常规药理学方法确定其剂量。
任何具体化合物的治疗有效剂量(其应用属于本发明的范围)会因化合物的不同、患者的不同而有所变化,并将取决于患者的疾病和给药途径。作为一般的建议,约0.1-50mg/kg的剂量会有疗效,该剂量是基于6MNA前药的重量计算出的全部重量,包括使用盐的情况。与较高水平有关的毒性可限制静脉内剂量在较低的水平,例如最高不超过约10mg/kg,这是基于活性基质的重量计算出的全部重量,包括使用盐的情况。约10-50mg/kg的剂量可用于口服给药。一般来说,约0.5-5mg/kg的剂量可用于肌内注射。每天一次时,疗程通常持续两至三周或直到病情基本得到控制。较少次数地给予低剂量可以预防性地阻止或减少感染复发的发生率。
合成本发明化合物的总的路线表示于图1和2中;具体合成描述于非限制性实施例中。
实施例
实施例1(6-甲氧基-萘-2-基)-乙酸2-氧代-丙酯的合成
在100ml圆底烧杯中,将6MNA(1.00g,4.65mmol)溶于无水DMF(50ml)中,搅拌下加入Na2CO3(1.08g,10.2mmol)。室温下,将氯丙酮(0.407ml,5.12mmol)逐滴加入反应混合物中并继续搅拌过夜。减压除去DMF,再将CH2Cl2(75ml)加入到剩下的残余物中。用水(3×100ml)和盐水(3×100ml)洗涤所生成的溶液。用MgSO4干燥有机层,过滤,减压除去溶剂得到灰白的固体。从乙酸乙酯中重结晶以57.6%的产率得到灰白色固体结晶的所需产物(0.729g):熔点122-124℃;IR(KBr)2939,1761,1731,1642,1607,1513,1490,1418,1395,1348,1283,1236,1200,1159,1053,1029,917,864,811cm-1;1HNMR(CDCl3)2.11(s,3H),3.88(s,2H),3.91(s,3H),4.66(s,2H),7.12(s,1H),7.15(d,J=2.7Hz,1H),7.40(dd,J=1.8,8.4Hz,1H),7.68(s,1H),7.72(d,J=3.9Hz,2H);FABMS(NBA)m/z 272(M)+。
实施例2(6-甲氧基-萘-2-基)-乙酸2-(2-硝基氧基-乙氧基)-乙酯的合成
在反应烧杯(1号)中:在氮气下,将NaH(60%在油中的悬浮液,0.43g,0.011mol)悬浮于无水DMF中,再逐滴加入溶于无水DMF(60ml)中的6MNA(2g,0.00926mol)。搅拌反应混合物1小时,再倒入装有溶于30ml DMF的2-溴代醚(11.07g,0.027mol)的另一反应烧杯(2号)中。充氮条件下,室温下搅拌反应混合物过夜(约17小时),然后于40-50℃下搅拌1小时。然后加入去离子水,用二氯甲烷萃取产物几次,再用硫酸钠干燥,过滤,经旋转蒸发器浓缩。用乙酸乙酯/己烷溶剂混合物洗脱,粗品物质经硅胶柱层析处理,然后层析,用乙醚/己烷溶剂系统作为展开剂。收集含所述产物的部分,浓缩,重结晶,用IR、NMR分析2.52g的所述化合物(产率74%)。
实施例3(6-甲氧基-萘-2-基)-乙酸羧基甲酯的合成
将溴代乙酰溴(0.432ml,4.95mmol)溶于无水CH2Cl2(10ml)中,再于冰浴中冷却到0℃。向该溶液中加入三乙胺(0.829ml,5.94mmol),立即形成沉淀。0℃下,边搅拌边向反应溶液中逐滴加入2-三甲基甲硅烷基乙醇(0.710ml,4.95mmol)。完成加入后,将反应物加热到室温并再搅拌20分钟。将反应混合物置于分液漏斗中,用1MHCl(1×50ml)、饱和NaHCO3(1×50ml)和盐水(2×50ml)洗涤。用MgSO4干燥有机层,过滤,降压除去溶剂,得到棕色油状的所需酯(0.736g,62.2%)。IR显示完全转化为所述酯;IR(NaCl):2952,2899,1739,1627,1421,1407,1360,1249,1169,1112,1043,983,944,844cm-1;1HNMR(CDCl3)σ0.017(d,J=6.9Hz,9H),0.97(m,2H),3.71(t,J=8.1Hz,2H),4.24(t,J=8.1Hz,2H)。
在50ml圆底烧杯中,将6MNA(0.602g,2.80mmol)溶于无水DMF(25ml)中,搅拌下加入Na2CO3(0.297g,2.80mmol)。室温下,将上面制备的溴代乙酸2-三甲基硅烷基乙酯(0.736ml,3.08mmol)逐滴加入反应混合物,并继续搅拌过夜。减压除去DMF,再将CH2Cl2(60ml)加入剩下的残余物中。用水(3×60ml)和盐水(3×60ml)洗涤所生成的溶液。用MgSO4干燥有机层,过滤,减压除去溶剂得到深褐色油状的所需产物(0.630g,60.3%产率)。IR表明完全转化成酯,IR(NaCl):2951,2892,1755,1672,1637,1607,1507,1490,1466,1413,1389,1301,1218,1159,1065,1042,936,894,847cm-1。
在50ml圆底烧瓶中,在氮气下,将上面制备的6MNA酯(0.630g,2.93mmol)溶于无水DMF(20ml)中并搅拌。再用2分钟向反应混合物中逐滴加入氟化四丁铵(1.0M在THF中,1.70ml,5.86mmol)。在惰性气体下继续搅拌反应混合物另外2小时,将二氯甲烷(15ml)和水(10ml)加入反应混合物中,用水(3×60ml)、盐水(3×60ml)洗涤有机层,再用硫酸镁干燥,过滤并蒸发。用柱层析(SiO2∶乙酸乙酯/己烷1∶2,再用甲醇)提纯生成的深色油,以25.0%的产率得到褐色固体状的所需产物(0.117g):熔点190-192℃(分解);IR(KBr)3310(br),2951,1725,1602,1507,1495,1431,1324,1277,1224,1142,1030,965,900,853,818cm-1;FABMS(NBA)m/z 274(M)+。
实施例4(6-甲氧基-萘-2-基)-乙酸乙氧基羰基甲酯的合成
在250ml圆底烧杯中,将6MNA(3.00g,14.0mmol)溶解于无水DMF(100ml)中,搅拌下加入Na2CO3(1.62g,15.3mmol)。向反应混合物中逐滴加入溴乙酸乙酯(1.70ml,15.3mmol)并于室温下继续搅拌过夜。减压除去DMF,向剩下的残余物中加入CH2Cl2(100ml)。用水(3×150ml)和盐水(3×150ml)洗涤形成的溶液,再用硫酸镁干燥有机层,过滤,减压除去溶剂得到灰白色的固体。用柱层析提纯(SiO2:乙酸乙酯/己烷1∶2),以78.9%的产率得到灰白色固体的所需产物(3.32g):熔点38-40℃;IR(KBr)2956,1749,1637,1607,1500,1484,1378,1266,1236,1159,1059,1024,953,912,853,811cm-1;1H NMR(CDCl3)σ1.23(t,J=7.2Hz,3H),3.87(s,2H),3.91(s,3H),4.19(m,2H),4.63(s,2H),7.11(s,1H),7.15(d,J=2.7Hz,1H),7.40(dd,J=1.8,8.4Hz,1H),7.68(s,1H),7.71(d,J=4.5Hz,2H);FABMS(NBA)m/z 302(M)+。
大鼠爪水肿和水解数据提供于表1-3中。
表1
大鼠爪水肿结果
化合物 | 剂量(mg/kg) | 抑制率% | ED50(mg/kg) |
萘丁美酮 | 79.0 | 60 | 35.9 |
6-MNA | 75.0 | 45 | |
吲哚美辛 | 10.0 | 51 | |
实施例1 | 94.3 | 65 | 33.9 |
实施例2 | 121.0 | 57 | |
实施例3 | 94.9 | 58 | |
实施例4 | 121.0 | 38 |
表2
化学水解
PH3 | PH7.4 | PH8 | |
实施例1 | >25h | 22h | 7h |
实施例2 | >300h | ~280h | ~280h |
实施例4 | 稳定达3小时 |
表3
在大鼠血浆中的水解
PH3 | |
实施例1 | 在约2小时,21%转化为6-MNA |
实施例2 | T1/2>5分钟 |
实施例5(6-甲氧基-萘-2-基)-乙酸3-硝基氧基-2-氧代-丙酯的合成
在反应烧杯(1号)中:在氮气下,将NaH(于油中的60%的悬浮液,0.43g,0.011mol)悬浮于无水DMF中,再逐滴加入6MNA(2g,0.00926mol)。搅拌反应混合物2小时,再倒入装有溶于DMF中的二溴丙酮(7.9g,0.0379mol)的溶液的另一反应烧杯(2号)中。室温下将反应混合物搅拌过夜(约17小时)并检测TLC。然后加入去离子水,用二氯甲烷萃取产物几次,再用硫酸钠干燥,过滤并浓缩。粗品物质经硅胶柱层析,用乙酸乙酯/己烷溶剂混合物洗脱,然后层析用乙醚/己烷溶剂系统作为展开剂。收集含所述产物的部分,浓缩,重结晶,用MS分析化合物。所述化合物含一个溴原子;这是它有与分子离子(因为存在含81Br同位素的分子离子)质谱法,350.8和352,8几乎相同强度的一个M+2峰的原因。
将1.71mg,0.203mmol的这种化合物溶解于乙腈(15ml)中,再加入溶于2ml乙腈中的79.5mg,0.468mmol硝酸银溶液。于暗处80℃下搅拌该反应混合物再过滤。减压将溶剂从所生成的溶液中蒸发掉,并向所得残余物中加入二氯甲烷。再过滤出沉淀,并浓缩二氯甲烷相,通过硅胶柱,采用乙醚/己烷洗脱,然后重结晶,用己烷洗涤,真空干燥,得到最终产物。用元素分析法、IR、MS、NMR分析最终产物。
实施例6(6-甲氧基-萘-2-基)-乙酸2-(2-甲氧基-乙氧基)-乙酯的合成
在10ml圆底烧杯中,将6MNA(1.00g,4.63mmol)悬浮于草酰氯(7ml)中,室温下搅拌该反应混合物1小时,其间6MNA溶解。真空蒸馏除去草酰氯得到红色固体状6MNA酰基氯(2.18g,100%产率)。IR表明完全转化为酰基氯;IR(KBr):3061,3020,2949,2901,2831,1800,1605,1493,1393,1275,1234,1128,1028,951,869cm-1;熔点80-82℃。
0℃下,将二甘醇一甲醚(1.22g,10.2mmol)溶于无水CH2Cl2(20ml)中,并逐滴加入悬浮于无水CH2Cl2(10ml)中的NaH(60%在矿物油中,0.407g,10.2mmol)悬液中。将该反应混合物加热到室温并搅拌2小时,其间加入溶于无水CH2Cl2(50ml)中的6MNA酰基氯(1.08g,4.63mmol)。室温下将所形成的反应混合物搅拌过夜。将该反应混合物移入分液漏斗中,并用水(2×100ml)和盐水(2×100ml)洗涤。用MgSO4干燥有机层,过滤,减压除去溶剂得到橙色油。用柱层析提纯(SiO2:乙酸乙酯/己烷2∶1)得到产率为69.3%的油状的所需产物(1.11g):IR(NaCl)2939,2892,1737,1636,1607,1483,1454,1389,1224,1035,858cm-1;FABMS(NBA)m/z 318(M+H)+。
实施例7(6-甲氧基-萘-2-基)-乙酸2-甲氧基-苯酯的合成
在10ml圆底烧杯中,将6MNA(1.50g,6.94mmol)悬浮于草酰氯(7ml)中,室温下搅拌该反应混合物3小时,其间6MNA溶解。真空蒸馏除去草酰氯得到红色固体状6MNA酰基氯(1.63g,100%产率)。IR表明完全转化为酰基氯;IR(KBr):3061,3020,2949,2901,2831,1800,1605,1493,1393,1275,1234,1128,1028,951,869cm-1;熔点80-82℃。
将愈创木酚(0.840ml,7.64mmol)溶于无水DMF(30ml)中,并逐滴加入悬浮于无水DMF(10ml)中的NaH(60%在矿物油中,0.304g,7.64mmol)悬液中。将该反应混合物于室温下搅拌1.5小时,其间加入溶于无水DMF(10ml)中的6MNA酰基氯(1.63g,7.64mmol)。室温下将所形成的反应混合物搅拌过夜。减压除去DMF,将CH2Cl2(50ml)加入该残余物中。用水(2×50ml)和盐水(2×50ml)洗涤所生成的溶液。用MgSO4干燥有机层,过滤,减压除去溶剂得到深色油。用柱层析提纯(SiO2∶乙酸乙酯/己烷1∶2)得到加入乙醚会生成沉淀的油状所需产物(0.800g,35.8%产率)。熔点90.5-92.5℃;IR(KBr)3060,2966,2936,2836,1757,1609,1506,1463,1392,1311,1267,1224,1115,1028,952,854cm-1;FABMS(NBA)m/z 322(M+H)+。
实施例8N-(2-甲氧基-乙基)-2-(6-甲氧基-萘-2-基)-乙酰胺的合成
将6MNA酰基氯(1.50g,6.8mmol)和2-甲氧基乙胺溶解于无水THF(10ml)中。再加入三乙胺,随即生成沉淀。于室温下将该反应混合物搅拌过夜。将粗反应混合物溶于CH2Cl2(50ml)中,用H2O(50ml)、饱和NaHCO3(2×40ml)和H2O(50ml)洗涤,用MgSO4干燥,并蒸发至干。然后将粗产物从CH2Cl2/己烷中重结晶得到褐色晶体(0.853g,产率48%);熔点129℃;IR(NaCl)3237(br),3065,2886,1633,1613,1575,1493,1460,1394,1275,1229,1129,857,811cm-1。1H NMR(CDCl3)σ3.26(s,3H),3.97(m,4H),3.70(s,2H),3.93(s,3H),7.14(m,2H),7.18(d,J=2.4Hz,1H),7.34(dd,J=1.5,8.7Hz,1H),7.69(m,3H);FABMS(NBA)m/z 274(m+H)+。
实施例9[2-(6-甲氧基-萘-2-基)-乙酰氨基]-乙酸甲酯的合成
在10ml圆底烧杯中,将6MNA(1.08g,5.02mmol)悬浮于亚硫酰氯(7ml)中,室温下搅拌该反应混合物1小时,其间6MNA溶解。真空蒸馏除去亚硫酰氯得到红色固体状6MNA酰基氯(1.18g,100%产率)。IR表明完全转化为酰基氯;IR(KBr):3061,3020,2949,2901,2831,1800,1605,1493,1393,1275,1234,1128,1028,951,869cm-1;熔点80-82℃。
将6MNA酰基氯(1.18g,5.02mmol)溶于无水DMF(20ml)中,逐滴加入溶于无水DMF(10ml)中的甘氨酸甲酯盐酸盐(0.633g,5.04mmol)和三乙胺(1.55ml,11.1mmol)的搅拌溶液中。在氮气氛及室温下将该反应混合物搅拌过夜。减压除去DMF,向剩下的残余物中加入CH2Cl2(40ml)。用水(3×60ml)和盐水(3×60ml)洗涤所生成的溶液。用MgSO4干燥有机层,过滤,减压除去溶剂得到棕色固体。用柱层析提纯(SiO2∶乙酸乙酯)得到产率为30.6%的灰白色固体的所需产物(0.441g)。熔点118-120℃;IR(KBr)3222,3062,2951,1739,1640,1573,1441,1381,1266,1215,1171,1043,997,894,853cm-1。FABMS(NBA)m/z 288(M)+。
实施例102-(6-甲氧基-萘-2-基)-乙酰胺的合成
在10ml圆底烧杯中,将6MNA(1.84g,8.56mmol)悬浮于草酰氯(7ml)中,室温下搅拌该反应混合物3小时,其间6MNA溶解。真空蒸馏除去草酰氯,得到红色固体状6MNA酰基氯(2.00g,100%产率)。IR表明完全转化为酰基氯;IR(KBr):3061,3020,2949,2901,2831,1800,1605,1493,1393,1275,1234,1128,1028,951,869cm-1;熔点80-82℃。
将6MNA酰基氯(2.00g,8.56mmol)溶于无水DMF(20ml)中,并在冰浴中冷却至0℃。边搅拌边将氨(在0.5M二噁烷中,34.2ml,17.1mmol)逐滴加入酰基氯溶液中。注意将反应湿度保持在0℃。加入一结束,就将反应混合物加热至室温并继续搅拌过夜。生成沉淀后,加入水(20ml)和乙酸乙酯(20ml)。通过吸滤作用收集该固体,并从乙醇中重结晶,以产率65.4%得到褐色固体状的所需产物(1.20g):熔点234-236℃;IR(KBr)3364,3171,1640,1490,1414,1235,1162,1030,857cm-1;FABMS(NBA)m/z 216(M+H)+。
以上为对本发明的说明,而不应视为是对其的限制。本发明通过下列权利要求,包括在本文中的权利要求的等价物来限定。
Claims (24)
2.权利要求1的药用组合物,其中R选自CH2CH2OCH3、CH2CH2OCH2CH2OCH3和CH2CHOHCH2OH。
3.权利要求1的药用组合物,其中R′选自CH2COCH3、CH2COCH2(OC2H4)OCH3和CH2COCH2OCH3。
4.一种用于治疗人体炎症的药用组合物,它包含治疗有效量的下式化合物:其中R″选自C1-C6烷基、CH2(OC2H4)nO(CH2)n、CH2(OC2H4)pOCH3、(OC2H4)nONO2、(OC2H4)nO(CH2)n、(CH2)n(OC2H4)mONO2、(OC2H4)nO(CH2)mOH、NH(CH2)m(OC2H4)n、NH(CH2)m(OC2H4)mONO2、NHO(CH2)nCH3、NH(CH2)m(OC2H4)pOCH3和NH(OC2H4)pOCH3,其中m为2-4的整数,而n和p为1-4的整数。
5.权利要求4的药用组合物,其中R″选自CH2COCH3、CH2COCH2(OC2H4)2OCH3和CH2COCH2OCH3。
7.权利要求6的药用组合物,其中R为氢或甲基。
10.一种用于治疗人体炎症的药用组合物,它包含治疗有效量的下式化合物:其中R″为疗效基团。
13.权利要求12的方法,其中R选自CH2CH2OCH3、CH2CH2OCH2CH2OCH3和CH2CHOHCH2OH。
14.权利要求12的方法,其中R′选自CH2COCH3、CH2COCH2(OC2H4)OCH3和CH2COCH2OCH3。
15.一种治疗炎症的方法,该方法包括向有需要的患者给予治疗有效量的下式化合物:其中R″选自C1-C6烷基、CH2(OC2H4)nO(CH2)n、CH2(OC2H4)pOCH3、(OC2H4)nONO2、(OC2H4)nO(CH2)n、(CH2)n(OC2H4)mONO2、(OC2H4)nO(CH2)mOH、NH(CH2)m(OC2H4)n、NH(CH2)m(OC2H4)mONO2、NHO(CH2)nCH3、NH(CH2)m(OC2H4)pOCH3和NH(OC2H4)pOCH3,其中m为2-4的整数,而n和p为1-4的整数。
16.权利要求15的方法,其中R″选自CH2COCH3、CH2COCH2(OC2H4)2OCH3和CH2COCH2OCH3。
17.一种治疗炎症的方法,该方法包括向有需要的患者给予治疗有效量的下式化合物:其中R选自氢、O(CH2)nCH3、C1-C6烷基、(CH2)m(OC2H4)pO(CH2)n、(CH2)m(OC2H4)p、(CH2)m(OC2H4)nONO2、(CH2)m(OC2H4)pO(CH2)mOH和(CH2)mNHO(CH2)nCH3,其中m为2-4的整数,而n和p为1-4的整数
18.权利要求17的方法,其中R为氢或甲基。
19.一种治疗炎症的方法,该方法包括向有需要的患者给予治疗有效量的下式化合物:其中R为疗效基团。
21.一种治疗炎症的方法,该方法包括向有需要的患者给予治疗有效量的下式化合物:其中R″为疗效基团。
23.治疗炎症的所述方法,该方法包括向有需要的患者给予治疗有效量的下式化合物:其中R选自氢、O(CH2)nCH3、C1-C6烷基、(CH2)m(OC2H4)pO(CH2)n、(CH2)m(OC2H4)p、(CH2)m(OC2H4)nONO2、(CH2)m(OC2H4)pO(CH2)mOH和(CH2)mNHO(CH2)nCH3,其中m为2-4的整数,而n和p为1-4的整数
24.权利要求23的方法,其中R为氢或甲基。
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- 2000-10-27 EP EP00992732A patent/EP1223922A2/en not_active Withdrawn
- 2000-10-27 CN CN00817762A patent/CN1413108A/zh active Pending
- 2000-10-27 AU AU15761/01A patent/AU1576101A/en not_active Abandoned
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2002
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2003
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2004
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