CN1257482A - 喹啉-2-羧酸衍生物及其作为兴奋性氨基酸拮抗剂的用途 - Google Patents
喹啉-2-羧酸衍生物及其作为兴奋性氨基酸拮抗剂的用途 Download PDFInfo
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- CN1257482A CN1257482A CN98805302A CN98805302A CN1257482A CN 1257482 A CN1257482 A CN 1257482A CN 98805302 A CN98805302 A CN 98805302A CN 98805302 A CN98805302 A CN 98805302A CN 1257482 A CN1257482 A CN 1257482A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
E4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉2-羧酸的(+)对映体和其盐,其为兴奋性氨基酸拮抗剂,关于它们的制备方法、含有它们的药用组合物和它们在医疗上的用途。
Description
本发明涉及一个有效的特异性兴奋性氨基酸拮抗剂(±)E 4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉2-羧酸的对映体、制备该物质的方法、含有该物质的药用组合物、其在医疗上的用途。
WO 97/12870特别描述了(±)E 4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸(A)及其盐:
其对定位在N-甲基-D-天门冬氨酸(NMDA)受体复合物上的马钱子碱不敏感甘氨酸结合部位具有拮抗作用。
目前我们已经发现化合物(A)的一个对映体(以后称为(+)对映体)对作为在NMDA受体复合物上的马钱子碱不敏感甘氨酸结合位点的选择性拮抗剂显示了特别有用的活性。
因此本发明提供了基本上不含相应的(-)对映体的E 4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉2-羧酸(下文为化合物(I))的(+)对映体及其盐。
在这里使用的术语基本上不含意指化合物(I)含有低于10%的(-)对映体并且最好低于5%。
在这里使用的术语(+)对映体指的是实施例2、4和5的产物特异性对映体。
为了在医疗中使用,化合物(I)的盐将是生理上可接受的盐。然而其它的盐可用于制备化合物(I)或其生理上可接受的盐。因此除非特别说明,否则所提及的盐包括化合物(I)生理上可接受的盐和非生理上可接受的盐。
本发明化合物适宜的生理上可接受的盐包括碱加成盐。
化合物(I)适宜的生理上可接受的碱加成盐包括碱金属或碱土金属盐例如钠、钾、钙和镁盐以及与氨基酸(例如赖氨酸和精氨酸)和有机碱(例如普鲁卡因、苯基苄胺、乙醇胺、二乙醇胺和N-甲基葡糖胺)形成的铵盐。
化合物(I)的优选盐为钠盐。
本发明化合物和/或其生理上可接受的盐是兴奋性氨基酸拮抗剂。更具体地讲,它们都是与NMDA受体复合物有关的马钱子碱不敏感甘氨酸结合位点的有效拮抗剂。因此它是NMDA受体复合物的有效拮抗剂。因此化合物(I)可用于治疗或预防神经毒性损伤或神经退化性疾病。因而化合物(I)也用于治疗伴有脑中风、血栓栓塞中风、脑溢血中风、脑缺血、脑血管痉挛、低血糖、遗忘症、缺氧、缺氧症、围生期窒息心动停跳的神经毒性损伤。化合物(I)还用于治疗慢性神经退化性疾病如亨廷顿舞蹈病、阿尔滋海默氏老年性痴呆、肌萎缩外侧硬化症、戊二酸血症类型、多梗塞痴呆、癫痫持续状态(statusepilecticus)、挫伤损伤(例如脊髓损伤和头部损伤)、病毒感染诱导的神经退化(例如AIDS、脑病(encephalopaty))、唐氏综合征、癫痫、精神分裂症、抑郁、焦虑、疼痛、神经原性膀胱、刺激性膀胱紊乱、偏头痛、头疼包括急促性(cluster)头疼、紧张性头疼、药物依赖性包括来自酒精、可卡因、阿片制剂、尼古丁、苯并二氮杂的戒除症状以及呕吐。
本发明化合物对于存在于NMDA受体复合物上的马钱子碱不敏感甘氨酸结合位点的有效的选择性作用可使用常规实验步骤进行测定。因此结合于马钱子碱不敏感甘氨酸结合位点的能力使用KishimotoH等在J Neurochem 1981,37 1015-1024中的方法进行测定。化合物(I)对马钱子碱不敏感甘氨酸位点的选择性在其它的已知离子化作用兴奋性氨基酸受体的研究中得到进一步证实。因此发现化合物(I)对于红藻氨酸(kainate)受体、α-氨基-3-羟基-5-甲基-4-异噁唑-proprionic酸(AMPA)受体或在NMDA结合位点上显示很少或不显示亲和性。
使用Chiamulera C等在Psychopharmacology(1990)102,551-552中的方法也已经发现本发明化合物抑制NMDA诱导的小鼠惊厥。
使用Chiamulera C等在European Journal of Pharmacology,216(1992)第335-336页中描述的方法,在由小鼠制备的大脑中动脉阻塞标本中证明本发明化合物的神经保护活性。
因此本发明提供了化合物(I)和/或其生理上可接受的盐在治疗上的用途,尤其是用作拮抗NMDA受体复合物上兴奋性氨基酸作用的药物的用途。
本发明也提供了化合物(I)和/或其生理上可接受的盐的在拮抗NMDA受体复合物上兴奋性氨基酸作用的药物的生产中的用途。
更进一步的方面,本发明也提供了拮抗NMDA受体复合物上兴奋性氨基酸作用的方法,其包括给予需要治疗的患者拮抗量的化合物(I)和/或生理上可接受的盐。
本领域技术人员将意识到这里提及的治疗扩展到预防以及治疗已经确诊的疾病或症状。
更进一步意识到治疗所需的本发明化合物的量将随着所要治疗疾病的性质、给药途径和患者的年龄及状况变化,并将最终在于主治医师的判断。然而一般而言对于成人治疗所使用的剂量一般为每天在2到800mg范围内,这取决于给药途径。
因此对于非肠道给药,每日剂量一般为是在20-800mg范围内,优选每天60-800mg。对于口服给药,每日剂量一般是在200-800mg范围内,例如每天400-600mg。
所需的剂量可便利的以单一剂量提供或在适宜的时间间隔内分开剂量给药,例如每天分成2、3、4或更多个亚剂量。
尽管当用于治疗时,化合物(I)可作为原料化学品给药是可能的,但是最好以药用制剂来提供所述活性成分。
因此本发明进一步提供了药用制剂,其包括化合物(I)或其生理上可接受的盐以及一种或多种药学上可接受的载体,并任选其它治疗的和/或预防成分。从与制剂中其它成分相配伍并对其接受者无害的意义上来讲,所述载体必须是“可接受的”。
本发明组合物包括那些特别是配制以供口服、颊、非肠道、吸入或吹入、植入或直肠给药形式的组合物。优选非肠道给药。
口服给药的片剂和胶囊剂可包含常规赋形剂例如粘合剂像糖浆、阿拉伯胶、明胶、山梨醇、黄蓍胶、淀粉浆或聚乙烯吡咯烷酮;填充剂如乳糖、糖、微晶纤维素、玉米淀粉、磷酸钙或山梨醇;润滑剂如硬脂酸镁、硬脂酸、滑石粉、聚乙二醇或硅石;崩解剂如马铃薯淀粉或淀粉羟乙酸钠,或湿润剂如十二烷基硫酸钠。片剂可根据本领域熟知的方法包衣。口服液体制剂可以例如水性或油性混悬液、溶液、乳剂、糖浆剂或酏剂的形式存在,或者以使用前用水或其它适宜的载体复制的干燥产物存在。这样的液体制剂可含有常规的添加剂如悬浮剂例像山梨醇糖浆、甲基纤维素、葡萄糖/糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪;乳化剂如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶;非水载体(其可包括食用油)例如杏仁油、分馏椰子油、油脂、丙二醇或乙醇;助溶剂例如表面活性剂如聚山梨酸酯或其它试剂如环糊精;和防腐剂例如对-羟基苯甲酸甲酯或丙酯或抗坏血酸。该组合物也可配制为栓剂即含有常规的栓剂基质如椰子油或其它甘油酯。
为了颊给药,该组合物可采用以常规方法配制成片剂或锭剂。
可将本发明组合物配制供经注射或持续输注非肠道给药。注射用制剂可以安瓿中的单位剂型或以加有防腐剂的多剂量容器形式提供。该组合物可采用混悬剂、溶液剂、或以油或水为载体的乳剂的形式,并且可含有配方用试剂例如混悬剂、稳定剂和/或分散剂。或者所述活性成分可以为粉末形式,使用前将其用适当溶媒如无菌、无热原水复制。
吸入给药时,本发明化合物(I)可通过在加压包装中的气溶胶喷雾剂形式便利地传递,使用适合的抛射剂如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适宜的抛射剂,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适宜的气体,或者来自于喷雾器。在为压力气溶胶情况下,剂量单位可通过提供传递计量的阀来确定。
或者,当通过吸入或吹入给药时,本发明的化合物可采用干燥粉组合物的形式,例如该化合物与适合的载体如乳糖或淀粉的粉状混合物。该粉末组合物可以单位剂型提供例如胶囊或明胶的药筒或泡状包装,其中可借助吸入或吹入器给予该粉末。
本发明组合物也可配制成埋植制剂。这样的长效制剂可通过植入(例如皮下或肌肉内植入)或肌内注射给药。因此本发明化合物例如可采用适合的聚合的或疏水性材料(例如在可接受的油中作成乳剂)或离子交换树脂、或者作为略溶性衍生物例如略溶性的盐进行配制。
依据本发明的组合物可含有0.1-99%的所述活性成分,最好片剂和胶囊为30-95%,液体制剂为3-50%。
再一方面,本发明提供了制备化合物1的方法。
因此在第一个方法(在下文为方法A)中,将化合物(1)((+)-E-4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸)可通过用适宜的手性醇酯化化合物A、通过常规方法如层析或结晶来分离生成的非对映的酯,随后水解所需的单一非对映的酯进行制备。
用于方法A的适宜的手性醇包括(+)S-1,2-二氢化茚醇(indanol)、(+)S-扁桃酸甲酯、手性乳酸(C1-4)烷基酯:即(+)R或(-)S乳酸甲酯、(+)R乳酸叔丁酯、(+)R或(-)S乳酸乙酯、(-)S乳酸异丙酯、(-)S乳酸丁酯、(+)R乳酸异丁酯或手性乳酸芳烷基酯(即乳酸苄酯)、(-)S紫苏子醇、(-)(R)-3-羟基-2-甲基丙酸甲酯、(-)(R)-2-丁醇、(-)(S)-2-甲基-1-丁醇。
包括基本上不含其它非对映体的单一非对映酯化合物A的非对映酯为新化合物并代表了本发明的更进一步的方面。
化合物A的非对映酯可通过常规方法制备,例如在非质子传递溶剂如醚像四氢呋喃中,使手性醇与化合物A的活化衍生物反应。使用像那些便利用在肽合成上的制备羧酸基团活化衍生物的常规方法,从化合物A可以制备化合物A的活化衍生物。
制备化合物A的非对映酯的特别便利方法为在手性醇的存在下制备化合物A的活化衍生物。
因此,例如在手性醇存在下,可用Mitsunobu试剂的组合,即偶氮二羧酸二烷基酯如偶氮二羧酸二乙酯同三芳基膦如三苯基膦或三烷基膦(即三丁基膦)处理化合物A。
在适宜的溶剂例如醚(像乙醚或四氢呋喃)、卤代烃(像二氯甲烷)或腈(像乙腈)或它们的混合物存在下,于0-30°的范围,该反应可便利地发生。
通过常规的方法例如通过常规层析法像制备性HPLC的使用或分级结晶,所需的基本上不含其它非对映体的化合物A的单一非对映酯可从其混合物中获得。
通过水解如碱水解,可将化合物(I)从相应的化合物A单一的非对映酯制备。因此例如可在溶剂像醚如四氢呋喃和水中,使用碱金属氢氧化物如氢氧化钠或氢氧化锂进行该水解反应。
化合物(I)可作为游离酸或其盐分离得到。
化合物I也可使用手性HPLC方法从外消旋化合物A获得。
化合物(A)可通过使羧酸(II)的活化衍生物:式中R1是羧酸保护基团并且R3是氢或氮保护基团,与胺(III)反应制备随后如果必要的话,使用WO 97/12870描述的方法和实施例除去羧酸保护基团R1和任何氮保护基团R3。
本发明也提供了化合物(I)制备的另外的方法(在下文为方法B),其包括使羧酸(IV)的活化衍生物与胺(III)反应,式(IV)中R3是氢或氮保护基团,R5是适宜的手性基团:并且使所生成的化合物进行以下反应:
i)如果必要的话,除去氮保护基团R3
ii)分离生成的非对映酯
iii)水解所需的单一非对映酯并作为游离酸或其盐分离该(+)对映体,并且如需要的话,随后将(+)非对映体的游离酸转化为其盐。
用于方法B适宜的手性基团(R5)是那些从手性醇衍化而来的,所述手性醇例如有(+)S-1,2-二氢化茚醇、(+)S-扁桃酸甲酯、手性乳酸(C1-4)烷基酯:即(+)R或(-)S乳酸甲酯、(+)R乳酸叔丁酯、(+)R或(-)S乳酸乙酯、(-)S乳酸异丙酯、(-)S乳酸丁酯、(+)R乳酸异丁酯或手性乳酸芳烷基酯(即乳酸苄酯)、(-)S紫苏子醇、(-)(R)-3-羟基-2-甲基丙酸甲酯、(-)(R)-2-丁醇、(-)(S)-2-甲基-1-丁醇。
R5优选为从手性(C1-4)烷基醇乳酸酯衍化来的基团。更优选地R5为从(+)R叔丁醇乳酸酯(tert-butyl lactate alcohol)衍化来的基团。
羧酸基团适宜的活化衍生物包括相应的酰卤、混合酸酐、活化酯如有硫酯或者由羧酸基团与偶合剂形成的衍生物,所述偶合试剂如在肽化学中使用的像羰基二咪唑或二酰亚胺像二环己基碳二亚胺。
该反应最好在非质子传递溶剂中进行,如烃、卤代烃像二氯甲烷或者醚如四氢呋喃。
当R3是氮保护基团时,适宜基团的实例包括烷氧基羰基如叔丁氧基羰基、芳磺酰基如苯磺酰基或2-三甲基硅烷基乙氧基甲基。
当用作取代基或取代基基团的一部分时,烷基意味着该基团可为直链或者支链。因此C1-4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
羧酸(IV)的活化衍生物可通过常规方法制备。用在这个反应中一个特别适宜的活化衍生物是如从吡啶-2-硫醇衍化而来的硫酯。在适宜的非质子传递溶剂像醚如四氢呋喃、卤代烃如二氯甲烷、酰胺如N,N-二甲基甲酰胺或乙腈中,通过用2,2’-二硫吡啶和三苯基膦处理羧酸(II)可便利地进行制备这些酯。
适宜的非对映衍生物可通过常规方法如层析法或结晶法分离。
在适合的溶剂像醚如四氢呋喃、水或其混合物中,使用碱金属氢氧化物如氢氧化钠或者氢氧化锂或碱性三烷基甲基硅烷酸盐(silanolate)(三甲基硅烷酸盐)可便利地发生水解步骤,随后如果期望或者必要的话,通过加入适宜的酸如盐酸就得到相应的游离羧酸。
式(IV)或式(II)化合物可通过环合式(V)化合物制备其中R2代表溴或碘原子,R3代表氢或氮保护基团,R4代表氢原子或适宜的羧酸保护基团如叔丁基,并且R6代表分别在式(II)或式(IV)中限定的R1或R5,随后使用常规方法除去羧酸保护基团R4。
在该方法的一个实施方案中,使用催化量的钯(O)复合物例如四(三苯膦)钯和适宜的有机碱像三烷基胺如三乙胺或无机碱如碳酸钾可进行该反应。
在温度20至150℃范围内,在非质子传递溶剂中如乙腈或二甲基甲酰胺中,该反应可便利地发生,随后如果必要或者期望的话,除去羧酸保护基团R4和任何保护基团R3。
在该方法的另一个实施方案中,在适宜的有机碱像三烷基胺如三乙胺和三芳基膦如三苯基膦的存在下,使用催化量的钯(II)盐例如乙酸钯可进行该反应。
在加热下,在非质子传递溶剂如乙腈或二甲基甲酰胺中,进行该反应,随后如果必要或者期望的话,除去羧酸保护基团R4和氮保护基团R3。
式(V)化合物可通过使其中R2和R6具有以上限定的含义的式(VI)的亚氨基酯与式(VII)化合物反应制备,式(VII)中R7代表C1-4烷基基团、R4为烃基甲硅烷基像三烷基硅烷基如三甲基硅烷基或者叔丁基二甲基硅烷基或适宜的羧酸保护基团如叔丁基基团,随后如果期望的话,将基团NH转化为氮保护基团NR3。
在路易斯酸如溴化锌和氯化锌存在下,于低温如-78℃,在非质子传递溶剂中像卤代烃如二氯甲烷、氯苯或乙腈中,可进行该反应。
使用引入这样的氮保护基团的常规方法如使其与R3X(其中X是如卤素或甲磺酸酯的离去基团)反应,可以将基团NH转化为氮保护的基团NR3。
当从中间体(VI)和(VII)制备时,使用中间体(V)制备式(II)或(IV)化合物的方法是新颖的,并且形成了本发明的另一个特征。
该制备式(V)化合物的新颖方法的一个特别优选的实施方案是使用了中间体酯(VI),其中R6基团从(+)R叔丁醇乳酸酯衍化而来。这就产生了非对映酯混合物,其中以非对映过量获得所需的非对映酯。
更进一步,使用上面描述的方法条件使如此获得的化合物(V)环合得到所需的化合物(IV),为非对映酯混合物,其中也以非对映过量获得所需的非对映酯。
式(VI)化合物可通过使胺(IX)与式(VIII)化合物反应制备,其中R2、R6具有式(V)化合物限定的含义:
该反应最好在从室温到反应混合物的回流温度范围内、在溶剂如芳香烃(例如苯、甲苯或者二甲苯)中进行。
式(III)、(VII)、(VIII)和(IX)化合物或者是已知的化合物,或者用那些已知的化合物使用的类似方法进行制备。
因此式(VII)化合物可依据在Tetrahedron Letters,第22卷,第29期第2833-2836页,1981年中描述的方法制备。式(VIII)化合物可根据在Helvetica Chimica Acta,1981年第64卷,第2808页中描述的方法制备。
在上面任何反应中,羧酸保护基团可通过除去这样的基团的熟知的常规方法除去。因此对于R1为苄基基团的化合物,可在适宜的溶剂如乙醇或异丙醇、水或其混合物中使用碱金属氢氧化物如氢氧化锂或氢氧化钠水解除去,随后如果期望或者必要的话,加入适宜的酸如盐酸得到相应的游离羧酸。
当R4为叔丁基基团时,可通过使用有机酸例如甲酸水解除去。
在上面任何反应中,所述氮保护基团可通过除去这样基团的熟知的常规方法除去,例如通过酸或碱水解。因此当R3为烷氧基羰基例如叔丁氧基羰基或苯磺酰基时,其可通过在适宜的溶剂如四氢呋喃或烷基醇如异丙醇中,使用例如氢氧化锂碱水解除去。或者,所述烷氧基羰基基团可通过酸水解除去。
化合物I的生理上可接受的盐可通过在适宜的溶剂中采用适宜的碱处理相应的酸制备。例如碱或碱金属盐可从碱和碱金属氢氧化物或者相应的碳酸盐、碳酸氢盐或三烷基硅烷酸盐如三甲基硅烷酸盐进行制备。
或者,碱或碱土盐可通过使用适宜的碱或碱金属氢氧化物直接水解化合物I的羧酸保护衍生物制备得到。
为了使得本发明得到充分理解,通过仅仅例证说明的方式给出下列实施例。
在中间体和实施例中除非另外指出,否则
熔点(m.p.)采用Gallenkamp熔点仪测定且未经校正。所有温度指的是℃。红外光谱在FT-IR仪器上测定。质子共振氢谱(1H-NMR)在400MHz处记录,化学位移用Me4Si作为内标物向低场偏移的ppm记录,并且表示为单峰(s)、双重峰(d)、双双重峰(dd)、三重峰(t)、四重峰(q)或多重峰(m)。柱层析法在硅胶(Merck AG Darmstaadt,德国)上进行。文中所使用的下列缩略语为:EA=乙酸乙酯、CH=环己烷、DCM=二氯甲烷、THF=四氢呋喃、TFA=三氟乙酸、TEA=三乙胺、DMSO=二甲基亚砜、Tlc指的是硅胶板上的薄层层析法。溶液以无水硫酸钠干燥;r.t.(RT)指的是室温。
中间体1
(R)-丙烯酰氧基-2-甲基乙酸-1-叔丁酯
在0℃下,向(R)叔丁醇乳酸酯(4.5g)、三乙胺(9.5ml)和二甲基氨基吡啶(0.73g)的无水二氯甲烷(200ml)溶液中加入丙烯酰氯(5.5ml)的二氯甲烷(100ml)溶液,然后在0℃下将所得到的混合物搅拌1小时,室温下再搅拌1小时。然后加入1M的HCl溶液接着加入乙酸乙酯(600ml)。有机相用水和盐水洗涤。最后以柱层析法(环己烷/乙酸乙酯85/15)纯化,得到为无色油状物的标题化合物(4.6g)。
1H NMR(DMSO)(ppm)6.36(dd,1H),6.22(dd,1H),5.99(dd.1H),4.89(q,1H),1.40(d,3H),1.39(s,9H)
IR(CDCl3)(cm-1)1727
中间体2
(R)-2(氧代乙酰氧基)-2-甲基乙酸-1-叔丁基酯
室温下,使中间体1(4.6g)的THF/H2O(3/1)(28ml)的溶液与四氧化锇(水中4%(重量),5ml)和过碘酸钠(12.3g)反应隔夜。该混合物用乙醚(500ml)处理,分离水相,干燥并浓缩有机相。最后以柱层析法(环己烷/乙酸乙酯60/40)纯化,得到为无色油状物的标题化合物(4.1g)。
1H NMR(DMSO):6.75(d,1H);6.70(d,1H);5.05(t,1H);NMR-4.85m(1H);1.40m(12H).
中间体3
(3,5-二氯-碘苯基亚氨基)乙酸1-(R)-(1-叔丁氧基羰基)乙酯
将中间体2(0.784g)的甲苯(20ml)溶液在迪安-斯达克装置中回流1小时。然后,加入3,5-二氯-2-碘苯胺(0.75g)和MgSO4(5g),并且将该混合物回流1小时。然后冷却混合物,通过硅藻土过滤除去MgSO4,浓缩后得到为淡黄色油状物的标题化合物(1.2g)。
1H NMR(DMSO)(ppm)7.95(s,1H);7.67(d,1H);7.30(d,1H);5.09(q,1H);1.49(d,3H);1.43(s,9H).
IR(薄膜)(cm-1)1743
中间体4
(E)-5-(3,5-二氯-碘苯基亚氨基)己-2-烯二酸6-[1-(R)-(1-叔丁氧基羰基)]-乙酯
向已冷却至-78℃的ZnCl2(0.36g)的无水二氯甲烷(10ml)悬浮液中加入中间体3(1.2g)的无水二氯甲烷(20ml)溶液。然后再加入1,1三甲基甲硅烷氧基1,3丁二烯(1.14g),在-30℃下将所得到的混合物搅拌2小时。然后先后加入饱和的NH4Cl溶液(20ml)和乙酸乙酯(30ml)。有机相用盐水(20ml)洗涤并干燥。以柱层析法(环己烷/乙酸乙酯50/50)纯化,得到为无色油状物的标题化合物(1.13g)(非对映体过量50%)。
1H NMR(DMSO)d(ppm)12.3(bs,1H);7.01(d,1H);6.79(m,1H);6.66(d.1H);5.90(d,1H);5.29(d,1H);4.97(q,1H);4.72(m,1H);2.83(m,2H);1.39(m,12H).
中间体5
(E)-4-羧基亚甲基-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸[1-(R)-(1-叔丁氧基羰基)]乙酯
向中间体4(1.2g)的无水二甲基甲酰胺(10ml)溶液中加入TEA(0.7ml)和Pd(PPh3)4(0.248g)。将该反应混合物加热至100℃ 1小时,然后先后加入乙酸乙酯(20ml)和1M的HCl溶液(10ml)。有机相用盐水(20ml)洗涤,干燥并浓缩。最后以柱层析法(环己烷/乙酸乙酯40/60)纯化,得到为无色油状物的标题化合物(0.5g)(非对映体过量50%)。
1H NMR(DMSO)12.3(s,1H);7.27(bs,1H);6.73(d.1H);6.45(d.1H);6.40(s,1H);4.79(q,1H);4.29(m,1H);3.61(m,1H);3.13(m,1H);1.35(m,10H).
中间体6
(E)-4-[(2-吡啶基)硫羰基亚甲基]-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸[1-(R)-(1-叔丁氧基羰基)]乙酯
向中间体5(0.5g)的无水THF(30ml)溶液中加入PySSPy(0.66g)和PPh3(0.81g)。将该反应混合物室温下搅拌1小时,然后蒸发溶剂并且粗品以柱层析法(环己烷/乙酸乙酯80/20)纯化,得到黄色泡沫状的标题化合物(0.170g)(非对映体过量60%)。
1H NMR(DMSO)p.p.m 8.61(m,1H);7.91(m,1H);7.71(m,1H);7.46(bs,1H);7.45(m,1H);6.88(s,1H);6.78(d,1H);6.76(d,1H);4.81(q,1H);4.36(m,1H);3.73(dd,1H);3.05(m,1H);1.4(m,3H);1.34(s,9H)。
实施例1
(+/-)(E)-4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸(非对映体1a和1b)
在氮气氛中,将偶氮二羧酸二乙酯(0.136ml;)的无水四氢呋喃(10ml)溶液在5分钟内滴加入(±)(E)-4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸(270mg)、三苯基膦(228mg)和(R)-(+)-乳酸叔丁酯(127mg)的无水四氢呋喃(20ml)悬浮液内。
在23℃下将该黄色溶液搅拌30分钟,然后真空浓缩,通过快速层析法纯化,用环己烷/乙酸乙酯4∶6洗脱,得到240mg标题化合物(两个非对映体1a和1b的混合物)。该非对映体通过制备性HPLC(柱:Supelcosil LC-CN;流动相:己烷-四氢呋喃65∶35并且14分钟后60∶40;流速10ml/分钟;λ=260nm)分离,然后进一步在二氧化硅上纯化,用环己烷/乙酸乙酯首先8∶2然后1∶1洗脱,得到为稍带白色固体的非对映体1a:91mg和为黄色固体的非对映体1b:76mg。
实施例1:m.p.175-177℃。IR(液体石蜡):3200(NH),1738(C=O)cm-1。1H-NMR(DMSO):10.09-10.05(2s,1H);9.86-9.84(2s,1H);7.64-7.44(m,4H);7.34-7.19(2d,1H);6.73-6.66(d,2H);6.71-6.64(2s,1H);4.76-4.56(2q,1H);4.39-4.26和3.73(分别为m和dd,2H);3.30-2.68(dd,1H);2.00(s,3H);1.34-1.31(2s,9H);1.29-1.15(2d,3H)。MS:m/z=562[M+H]+
非对映体1a m.p.206-8℃。T.l.c.乙酸乙酯-环己烷7∶3,Rf=047。IR(液体石蜡):3314(NH),1730,1666,1656(C=O)cm-1。1H-NMR(DMSO):10.09(s,1H);9.86(s,1H);7.57(d,2H);7.49(d,2H);7.33(d,1H);6.71(d,2H);6.67(d,1H);6.65(m,1H);4.57(q,1H);4.37(m,1H);4.29(m,1H);2.69(m,1H);2.00(s,3H);1.35(s,9H);1.16(d,3H)。MS:m/z=561[M]+,562[M+H]+。HPLC:保留时间12.56分钟(柱:Supelcosil LC-CN;流动相:己烷-四氢呋喃70∶30;流速0.8ml/分钟;λ=260nm)
非对映体1b:m.p.105-7℃。T.l.c.乙酸乙酯-环己烷7∶3,Rf=040IR(液体石蜡):3310(NH),1738和1659(C=O)cm-1。1H-NMR(DMSO):10.05(s,1H);9.85(s,1H);7.55(d,2H);7.47(d,2H);7.19(d,1H);6.74(d,1H);6.73(d,1H);6.72(s,1H);4.77(q,1H);4.29(m,1H);3.74(dd,1H);3.29(m,1H);2.00(s,3H);1.32(s,9H);1.29(d,3H)。MS:m/z=561[M]+,562[M+H]+。HPLC:保留时间15.60分钟(柱:Supelcosil LC-CN;流动相:己烷-四氢呋喃70∶30;流速0.8ml/分钟;λ=260nm)
实施例2
(+)-E-4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸
将氢氧化锂单水合物(12.84mg)加入到非对映体1a(来自实施例1,86mg)的四氢呋喃(5ml)和水(2.5ml)的溶液中。将该溶液在23℃下搅拌30分钟,然后真空浓缩。残余物用水(10ml)稀释并用乙酸乙酯(2×15ml)提取。水层用5%盐酸酸化至pH=1,再用乙酸乙酯(3×15ml)提取。干燥合并的有机提取物,并真空浓缩,得到为稍带白色固体的标题化合物(56mg)。m.p.224-6°。IR(液体石蜡):3356-3302(NH),3350-2600(OH);1724和1663-1650(C=O)cm-1 。1H-NMR(DMSO):12.71(s,1H);10.10(s,1H);9.87(s,1H);7.56(d,2H);7.50(d,2H);7.10(d,1H);6.70(d,2H);6.68(m,1H);4.11(m,1H);3.87(m,1H);3.08(dd,1H);2.01(s,3H)。
MS:m/z=434[M+H]+.
HPLC:保留时间15.2分钟(柱:cyclobond I 2000 SN;相β-环糊精S萘基乙基氨基甲酸酯,流动相:乙酸铵甲醇缓冲液(pH=3);流速1ml/分钟;λ=260nm)
[α]D=[+16]20。λ=598nm,溶剂:二甲基亚砜
浓度=0.26% w/v
实施例3
(E)-4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸[1-(R)-(1-叔丁氧基羰基)]乙酯
将4-氨基乙酰苯胺(acetanalide)(0.05g)加入到中间体6(0.155g)的无水甲苯(20ml)溶液中。将所生成的混合物在100℃下加热3小时,然后蒸发溶剂,并且粗品用柱层析法纯化(环己烷/乙酸乙酯50∶50)得到为黄色固体的标题化合物(0.05g)。
1H-NMR(DMSO)d 10.05(bs,1H);9.85(bs,1H);7.55(d,2H);7.47(d,2H);7.19(dd,1H);6.74(d,1H);6.73(d,1H);6.72(s,1H);4.77(q,1H);4.29(m,1H);3.74(dd,1H);3.29(m,1H);2.00(s,3H);1.32(s,9H);1.29(d,3H)。
IR(液体石蜡)(cm-1)3310,1738,1659。
实施例4
(+)(E)-4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸
将LiOH(0.005g)加入到实施例3(0.021g)的THF/H2O(3/1)溶液中。15分钟后,蒸发THF并加入水(2ml)。该溶液以乙酸乙酯(2×5ml)洗涤,然后加入1M的HCl溶液,所生成的溶液用乙酸乙酯(2×5ml)提取,并蒸发,得到为淡黄色固体的标题化合物(0.01g)。
1H-NMR(DMSO)d 12.71(s,1H);10.10(s,1H);9.87(s,1H);7.56(d,2H);7.50(d,2H);7.10(d,1H);6.70(d,2H);6.68(m,1H);4.11(m,1H);3.87(m,1H);3.08(dd,1H);2.01(s,3H)。
IR(液体石蜡)(cm-1)3356-3302,1724,1663-1650。
HPLC:保留时间9.7分钟(柱:cyclobond SN;相β-环糊精S萘基氨基甲酸酯,流动相:乙酸铵甲醇缓冲液(pH=5);流速1ml/分钟;λ=260nm)
实施例5
(+)4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸钠盐
在氮气氛中,将三甲基硅烷酸钠(7.74mg)加入到(+)4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉-2-羧酸(30mg)的无水四氢呋喃(3ml)的悬浮液中。将该黄色悬浮液在23℃下搅拌1小时,然后真空浓缩,残余物以乙醚(5ml)研磨。过滤后获得为黄色固体的标题化合物(27mg)。
M.p.202-5℃(分解)。
IR(液体石蜡):3400-3000(NH),1650(C=O)cm-1。1H-NMR(DMSO):11.71(bs,1H);9.26(bs,1H);7.65(d,2H);7.49(d,2H);6.74(d,1H);6.71(bs,1H);6.52(s,1H);6.50(d,1H);3.51(m,1H);3.29(m,1H);2.64(m,1H);2.01(s,3H)。MS:m/z=456[M+H]+,478[M+H]+。HPLC:保留时间14.28分钟。(柱:cyclobond I 2000SN;相b-环糊精氨基S萘基乙基甲酸酯,流动相:甲醇-乙酸铵缓冲液,流速1ml/分钟;λ=260nm)
药剂学实施例
静脉输注剂 % w/v
化合物(I) 0.3-0.5
聚山梨酸酯80 1
三(羟甲基)氨基甲烷 0.54
右旋糖溶液5% w/v 适量至所需体积
将化合物(I)和聚山梨酸酯加入到三(羟甲基)氨基甲烷的适于注射的5%右旋糖水溶液中。该溶液通过无菌的0.2微米除菌滤膜过滤,并且在经过压热处理器灭菌前将其充入容器中。
使用Kishimoto H等在J.Neurochem 1981,37,1015-1024中的方法,测定本发明化合物对于定位在NMDA受体复合物上的马钱子碱不敏感甘氨酸结合位点的亲和力。所获得的pKi值为8.8。
Claims (11)
1.基本上不含(-)对映体的(+)E 4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉2-羧酸及其盐。
2.基本上不含(-)对映体的(+)E 4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉2-羧酸及其生理上可接受的盐。
3.基本上不含(-)对映体的(+)E 4-(4-乙酰氨基-苯基氨基甲酰基亚甲基)-5,7-二氯-1,2,3,4-四氢喹啉2-羧酸的钠盐。
5.如权利要求4的方法,其中所述手性醇为(+)R叔丁醇乳酸酯,或者R5是从(+)R叔丁醇乳酸酯衍化而来的基团。
i)使其中R2代表溴或碘原子、R6是如以上限定的适宜的手性基团R5或如在式(II)中描述的羧酸保护基团R1的式(VI)的亚氨基酯与其中R7代表C1-4烷基基团、并且R4为烃基甲硅烷基团或适宜的羧酸保护基团的式(VII)化合物反应,接着,如果要求的话,将生成的其中R3为氢的式(V)化合物转化为其中R3为氮保护基团的式(V)化合物,
和
7.如权利要求4或5的方法,其中所述中间体(IV)根据权利要求6的方法制备。
8.药用组合物,它包括将权利要求2或权利要求3的化合物与一种或多种生理上可接受的载体或赋形剂混合。
9.如权利要求2或3的化合物在用于拮抗NMDA受体复合物上兴奋性氨基酸作用的药物生产中的用途。
10.如在权利要求2或3中的化合物在治疗中的用途。
11.对于包括人的哺乳动物的疾病的治疗方法,在所述疾病中拮抗NMDA受体复合物上的兴奋性氨基酸的作用具有治疗益处,该方法包括给予有效量的权利要求2或3中的化合物。
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DE10137487A1 (de) | 2001-08-03 | 2003-03-27 | Gruenenthal Gmbh | Substituierte 5,6,6a,11b-Tetrahydro-7-oxa-6-aza- benzo[c]fluoren-6-carbonsäurederivate |
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JP4360891B2 (ja) | 2003-12-09 | 2009-11-11 | アルパイン株式会社 | 放送受信機能を備えた電子装置およびその装置における電子番組ガイドの表示方法 |
RU2451014C2 (ru) * | 2005-07-22 | 2012-05-20 | Мотида Фармасьютикал Ко., Лтд. | Новое производное гетероциклиден ацетамида |
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JP2001518901A (ja) | 2001-10-16 |
NO994679L (no) | 1999-11-24 |
CA2284710A1 (en) | 1998-10-01 |
NO994679D0 (no) | 1999-09-24 |
ID24306A (id) | 2000-07-13 |
IS5186A (is) | 1999-09-17 |
NZ337793A (en) | 2001-02-23 |
GB9706294D0 (en) | 1997-05-14 |
TR199902315T2 (xx) | 2000-05-22 |
BR9808424A (pt) | 2000-05-23 |
PL335865A1 (en) | 2000-05-22 |
IL131919A0 (en) | 2001-03-19 |
YU47699A (sh) | 2001-12-26 |
KR20010005567A (ko) | 2001-01-15 |
HUP0001661A2 (hu) | 2000-09-28 |
AU7209498A (en) | 1998-10-20 |
AU731394B2 (en) | 2001-03-29 |
AP9901659A0 (en) | 1999-09-30 |
EP0971896A1 (en) | 2000-01-19 |
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