CN1043576C - 吡啶并[1,2,3-de]对二氮萘衍生物,其制备方法及其药物上的应用 - Google Patents
吡啶并[1,2,3-de]对二氮萘衍生物,其制备方法及其药物上的应用 Download PDFInfo
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- CN1043576C CN1043576C CN94191912A CN94191912A CN1043576C CN 1043576 C CN1043576 C CN 1043576C CN 94191912 A CN94191912 A CN 94191912A CN 94191912 A CN94191912 A CN 94191912A CN 1043576 C CN1043576 C CN 1043576C
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- Prior art keywords
- hydrogen
- pyrido
- trifluoromethyl
- phenopiazine
- dioxo
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明介绍了式Ⅰ的吡啶并[1，2，3，-de]对二氮萘衍生物及其制备和在药物上的应用
其中R1，R2和R3各是氢、-POXY，卤素或-COR，R4是氢或OH
R5，R6和R7相同或不同并且是氢，卤素、硝基、NR12R13，氰基，CF3、C1-6-烷基或C1-4烷氧基或R5和R6或R6和R7代表一种稠合苯环，并且代表单键或双键。
Description
本发明涉及吡啶并〔1,2,3-de〕对二氮萘衍生物，其制备及在药物上的应用。
已知对二氮萘衍生物对使君子氨酸(Quisqualat)受体有亲合性使并且由于这种亲合性它适合作为药物治疗中枢神经系统的疾病。在WO30115058中描述了类似的取代的对二氮萘衍生物。
已发现本发明的化合物适合于对抗兴奋性氨基酸的超活性。
本发明的化合物具有式Ⅰ
其中R1,R2和R3各是氢、-POXY，卤素或-COR,R4是氢或OH，R5,R6和R7相同或不同并且是氢，卤素、硝基、NR12R13，氰基，CF3,C1-6烷基或C1-4烷氧基或R5和R6或R6和R7代表一种稠合苯环，并且
代表单键或双键，其中X和Y相同或不同并且是羟基，C1-6烷氧基，-O-(CH2)n-O-,C1-4烷基或NR9R10且n=1,2或3，R代表羟基，C1-6烷氧基或NR9R10并且R9和R10,R12和R13相同或不同并且是氢，-CO-C1-6-烷基，苯基或C1-6-烷基，其可任选地用C1-4-烷氧基或一个可能用C1-4-烷基单取代或双取代的氨基所取代，或共同和N原子形成一个饱和5-7元杂环，该杂环还含有其它的氧原子，硫原子或氮原子并可能被取代或形成一个不饱和的5元杂环，该杂环含有1-3个N原子并且可被取代，以及其异构体或盐。
通式1的化合物还包含可能的互变异构形式和包括所有可能的异构体，以及若存在手性中心则还有(外)消旋体和对映体。
烷基总理解为直链或支链烷基如甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，戊基，异戊基，己基。
卤素理解为氟，氯，溴和碘。
若R9,R10和/或R12,R13与N原子共同形成一个饱和杂环，则认为是哌啶，吡咯烷、吗啉，硫代吗啉、六氢化氮杂或哌嗪。杂环可用C1-4-烷基或芳基如苯基进行1-3元取代。例如提到的N-甲基哌嗪，N-苯基哌嗪，2,6-二甲基-吗啉。
若R9,R10和R12,R13与N原子共同形成一个不饱和杂环，则认为是咪唑，吡唑，吡咯和三唑，其可用氰基，C1-4-烷基、苯基或CO2C1-6-烷基进行一元和二元取代。
有机和无机碱的生理相容盐适合作为盐，例如易溶碱金属盐和碱土金属盐以及N-甲基葡糖胺，二甲基葡糖胺，乙基葡糖胺，糊氨酸，1,6-己二胺，乙醇胺，葡糖胺，肌氨酸，丝氨酸，三-羟基甲基氨基甲烷，氨丙二醇，Sovak碱，1-氨基-2,3,4-丁三醇和有机和无机酸的生理相容盐如HCl,HBr,H2SO4,磷酸，柠檬酸、酒石酸、磺酸等。
式1化合物及其生理相容盐由于其对AMPA-受体的亲合性可用作药物。由于这种作用特征本发明的化合物适合治疗由于兴奋性氨基酸如谷氨酸或天冬氨酸的超活性而引起的疾病。因为通过它竞争性排斥AMPA受体的放射性标记的特殊增效药(Agonisten)(RS)-a-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)，这种新型化合物有作为兴奋性氨基酸的拮抗药的效果和对AMPA受体显示高的特殊亲合性。这种化合物特别适合治疗由于兴奋性氨基酸的受体特别是AMPA受体引起的这一类疾病。
按照本发明这种化合物用来治疗AMPA受体过激引起的神经疾病和精神病。属于能被官能地和预防地治疗的神经病为神经变性疾病如帕金森氏病，阿耳茨海默氏病，享廷顿氏舞蹈病，肌萎缩性侧索硬化和橄榄脑桥小脑变性。本发明的这种化合物能被用来预防在中风，组织缺氧、缺氧(Anoxie)和低血糖时的细胞死亡，Postischamisch细胞死亡、脑外伤后的细胞死亡和治疗老年性痴呆，多梗塞(Multiinfarkt)痴呆以及癫痫和肌痉挛(Muskelspastik)。属于精神病的是恐惧症，精神分裂症，偏头痛，疼痛症和睡眠障碍以及滥用药物后去除症状特征的治疗和预防以及用于戒酒，戒可卡因，戒苯杂二氮或戒鸦片制剂。
为了把本发明的化合物用作药物将它制成制药制剂，这种制剂除有效成份外还含有适宜于肠道或非肠道给药的制药用的、有机或无机惰性载体材料，如水，明胶，阿拉伯树胶，乳糖，淀粉，硬脂酸镁，滑石粉，植物油，聚亚烷基二醇等。该制药制剂可制作成固体形式，如片剂，糖衣药丸、栓剂，胶囊或制作成液体形式，如溶液，悬浮液或乳液。此外它必要时含有辅助材料如保藏剂，稳定剂，湿润剂，或乳化剂，改变渗透压的盐或缓冲剂。
特别适合于非肠道给药的是注射液或悬浮液，特别是活性化合物在聚羟基乙氧化的蓖麻油中的水溶液。
界面活化的辅助材料如胆酸的盐或动物磷脂或植物的磷脂、还有由此得到的混合物以及脂质体或其组成部分也可用作载体体系。
特别适合于口服应用的是带有滑石粉和/或烃载体或烃粘结材料如乳糖、玉米淀粉或马铃薯淀粉的片剂，糖衣药丸或栓剂。也可做成液体形式进行应用如做成汁液，必要时添加增甜剂。
有效物质的剂量可根据给药方式，病人的年纪和体重、所治疗疾病的种类和严重性以及类似因素加以改变。日剂量总计为0.5-1000mg，优选50-200mg，其中这一剂量可作为一次性给药剂量或分作两次或多次日剂量给药。
制备本发明的化合物按照已知方法进行。例如通过下列步骤得到式1化合物，把
a)式Ⅱ化合物
其中R11是H,NO2或-NH-R4及R1-R7含义如上，和草酸或活性的草酸衍生物进行反应且必要时在引入和还原NO2基团后进行环化并且，若R1,R2和/或R3都是卤素，必要时和XYP-O-C1-4烷基进行反应或羰基化或
b)式Ⅲ化合物
〔其中R1-R4含义如上及R5-,R6-或R7-是氢或一个吸电子基团)进行卤化或硝化，并且必要时紧接着把酯基皂化或把酸基酯化，或酰胺化或把硝基还原成氨基，或把氨基烷基化或酰基化，或把氨基换成卤素或氰基，或引入硝基或卤素或进行亲核取代，或分离异构体或形成盐。
式Ⅱ化合物与草酸或-活性的草酸衍生物的环化可以一步或也可两步进行。优选两步方法，其中二胺和一个草酸衍生物如乙二酸单酯酰氯或活性的乙二酸咪唑烷衍生物在极性溶剂如环醚或非环醚或卤代烃如四氢呋喃、二乙基醚或二氯甲烷中，在碱如有机胺诸如三乙胺、吡啶、Hünig碱或二乙基氨基吡啶的存在下进行反应。随后的环化可碱性或酸性，但优选在酸环境里进行，这时可添加溶剂醇。
适用于两步法的碱也可是碱金属氢化物如NaH，将其加入到惰性溶剂如烃或醚中。
若式Ⅱ化合物中的R11代表氢，则用活性草酸衍生物酰基化后用通常方式进行硝化。以已知的硝化方法用硝酸钠在三氟醋酸或用四氟硼酸硝鎓在氯代烃中进行反应是特别适合的。硝基R11的还原以通常方式催化地或通过在较高温度下在醋酸中用铁粉还原或用硫酸钠和氢氧化铵在乙醇中进行。
取代基-POXY和-COR的引入是按照常用方法，例如在碱如有机胺和过渡金属催化剂如四重-(三苯膦)-钯(O)存在下在较高温度下在极性溶剂如二甲基甲酰胺或在环醚或非环醚或卤代烃中进行。
通过在直到反应混合物沸点温度的高温下在酸如高浓度的含水盐酸存在下在溶剂如三氟醋酸或醇中进行水解，必要时接着的酯基皂化可碱性地或优选酸性地进行。膦酸酯优选通过在高浓度的含水的酸例如浓盐酸中加热或通过用卤化三甲基硅烷处理和随后用水处理进行水解。
羧酸或膦酸的酯化是用已知的方式用相应的醇在酸中或在活性酸衍生物中进行。考虑例如酰氯，酸咪唑烷(Sauerimidazolid)或酸酐作为活性的酸衍生物。在膦酸的酯化时通过与原酸酯必要时加入催化剂如对甲苯磺酸的反应达到酯化。
酰胺化是游离酸或其活性衍生物如酰氯，混保酸酐，咪唑烷或叠氮化合物通过在室温下与相应胺的反应进行。
许多已知的卤代方法例如亲电芳族取代适合于引入卤素基团。碘化是用碘/碘酸在冰醋中按照Wirth et al.〔Liebigs Ann.Chem.634,84(1960)〕的方法或用N-碘琥珀酰亚胺进行。
NO2基团的引入是通过一系列已知的硝化方法进行。例如用四氟硼酸硝在惰性溶剂如卤代烃或在环丁砜或冰醋中进行硝化或通过硝化酸在0℃-30℃温度下在作为溶剂的浓硫酸中的进行。
把硝基还原成氨基是在极性溶剂中室温或更高温度下在氢压下(Wasserstoffdruck)催化地进行。金属如阮内镍或贵重金属催化剂如必要时有硫酸钡存在或在载体上的钯或铂适合于用作催化剂。也可用已知的方式使用甲酸铵代替氢。如必要时存在重金属盐条件下的络合氢化物一样，还原剂如二氯化锡或三氯化钛同样能被使用。在还原前引入酯基会更好。硝基也能选择地以通常方式用Na2S或连二亚硫酸钠还原。
若希望对氨基进行烷基化，则按通常的方法用卤代烷或按照Mitsonubo改良法(Variante)在三苯膦和偶氮二甲酸酯的存在下通过与醇的反应进行烷基化或用醛或酮必要时先后用两个不同的羧基化合物对胺进行还原性胺化用作，这时得到混合的衍生物(文献如Verardo et al Synthesis 1993,121；Synlhesis 1991,447；Kawaguchi,Synthesis 1985,701；Micovic et al.Synthesis 1991,1043)。
用通常方式进行氨基的酰化，例如用酰氯或酸酐必要时在碱如二甲基氨基吡啶存在下在溶剂如二氯甲烷四氢呋喃或吡啶中或按照Scotten Baumann反应进行。
引入氰基可借助Sandmeyer反应进行，例如把由氨基化合物与亚硝酸盐中间形成的重氮盐与碱金属氰化物在氰化亚铜的存在下进行反应。
经过氨基引入卤素氯、溴或碘也可以按照Sandmeyer进行即通过把与亚硝酸盐中间形成的重氮盐与氯化亚铜或溴化亚铜在相应酸(盐酸或氢溴酸)存在下或与碘化钾进行反应。如果使用有机亚硝酸酯代替亚硝酸盐，则能通过添加二碘甲烷或四溴甲烷引入卤素。
氟的引入是通过四氟硼酸重氮盐的Balz Schiemann反应进行的。
亲核取代按照文献已知的方法在碱存在下进行并且通过活化的吸电子基团如硝基，氰基，三氟甲基优选在邻位上促进取代。适合于作为亲核试剂的是伯胺和仲胺，含氮的饱合与不饱含杂环、氰化物，醇化物等等。此反应可在极性溶剂如醇，卤代烃，二甲基亚砜，二甲基乙酰胺，乙腈或水中或没有溶剂时进行。适合用作碱的是无机碱如碱金属或碱土金属氢氧化物或碱金属或碱土金属的碳酸盐或有机碱如环状的、脂环的和芳族的胺，如DBU、Hiinig碱、吡啶或二甲基氨基吡啶。
在用胺的情况下亲核试剂在过量时本身用作碱，这时必要时不需要其它的溶剂或在加压下进行处理。
异构体混合物能按通常方法如结晶，色谱法或盐析分离成对映体即E/Z-异构体。
盐的制备是用通常方式进行，即通过把式1化合物的溶液和等量或过量的必要时在溶液中的碱金属或碱土金属化合物进行混合并分离沉淀物或用通常方式处理溶剂。
到目前为止，起始化合物的制备未有描述，该已知或类似已知的化合物例如按WO93/08173或此处描述的方法制备。
下列实施例应该说明了本发明的方法。实施例1：a)1-(2,2,2,-三氯乙氧基羰基)-6-三氟甲基-1,2-二氢喹啉-2-膦酸二乙酯
41.4g6-三氟甲基喹啉在0℃时加入250ml乙腈中，连续滴入29ml氯甲酸-2,2,2-三氯乙酯和搅拌混合物30分钟。滴入36.4ml亚磷酸三乙酯和一份份地加入49.8g碘化钠。加热10分钟至50℃，浓缩溶液，与400ml水混合并且各用400ml醋酸乙酯萃取四次。粗产品通过柱色谱分离法纯化且从异丙醚中进行重结晶。
熔点：71℃
b)1-(2,2,2-三氯乙氧基羰基)-6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯
71.6gl-(2,2,2-三氯乙氧基羰基)-6-三氟甲基-1,2-二氢喹啉-2-磷酸二乙酯溶解于800ml乙醇中，与3.6g四氧化铂混合和在常压下氢化。过滤、浓缩和从异丙醚中进行重结晶。
熔点：84℃
c)6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯
15.4g 1-(2,2,2-三氯乙氧基羰基)-6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯溶于400ml甲醇中，与7.2g锌粉混合和在氮气下于90℃搅拌1.5小时。用硅藻土过滤和浓缩滤液。粗产品通过柱色谱纯化和从异丙醚中进行重结晶
熔点：129℃。
d)1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯
5.39g 6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯溶于100ml四氢呋喃中。在充氮气和用冰冷却下加入0.56g氢化钠。在5℃温度保持30分钟后滴入2ml乙二酸单乙酯酰氯和在室温下把混合物搅拌过夜。用硅藻土进行过滤并浓缩滤液。粗产物通过柱色谱法纯化并从异丙酯中进行重结晶。
熔点：115℃。
e)1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯
5.25g 1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯溶于100ml二氯甲烷。与4.78g四氟硼酸硝混合。室温下搅拌23小时。溶液各用40ml 5％的碳酸氢钠溶液洗涤两次并浓缩。
f)9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
6.27g 1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-2-膦酸二乙酯溶于100ml冰醋酸中并与13g铁粉混合。在90℃时搅拌混合物1小时。冷却到室温后进行吸滤，把残余物加入到400ml醋酸乙酯中并且重新吸滤悬浮液。滤液用50ml5％的碳酸氢钠溶液洗涤，用硫酸镁干燥并浓缩。粗产物通过柱色谱法纯化并从醋酸乙酯中进行重结晶，得到2.31g 9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯，熔点161℃。
用类似的方法制备：
9-氯-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸二乙酯，熔点173℃。
用基本类似的方法制备：
9-硝基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡并啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
9-氰基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯实施例2：
9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸1.63g 9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯室温时在氮气下加入到40ml乙腈中。连续地滴入3.63ml溴化三甲基硅烷。溶液在室温下搅拌20小时并浓缩。残余物悬浮在50ml的水中，吸滤并用水洗涤。残余物在105℃和0.7托下干燥。得到1.12g 9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸，熔点：262℃。
用类似的方法制备：
9-氯-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸，熔点：305℃
9-硝基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
9-氰基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-6-膦酸
熔点：294-295℃
9-氰基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-7-羧酸
9-氯-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-7-膦酸
9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-7-膦酸
熔点：从235℃开始分解
8-硝基-9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
熔点：318℃(分解)
9-氯-8-硝基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
9-三氟甲基-8-哌啶子基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
8-氨基-9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
8-氟-9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
8-吗啉代-9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
2,3,-二氧代-1,2,3,5,6,7-六氢-苯并〔h〕吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
5,6-二氧代-1,2,3,5,6,7-六氢-苯并〔g〕吡啶并〔1,2,3-de〕对二氮萘-3-膦酸
9-氯-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-羧酸
8-〔1-(1,2,4-三唑基)〕9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
8-(1-吡咯基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
熔点＞300℃(分解温度)实施例3：
a)3-溴-6-三氟甲基-喹啉
19.7g 6-三氟甲基-喹啉加入200ml四氯甲烷中。滴入5.2ml溴和在回流下加热溶液1小时。20分钟内把8ml四氯甲烷中的7.9g吡啶滴加到沸腾的溶液中。1小时后进行冷却，从沉淀下来的盐中倾析并浓缩溶液。柱色谱法分离后得到14.6g 3-溴-6-三氟甲基-喹啉，熔点79℃。
b)6-三氟甲基-喹啉-3-膦酸二乙酯
1.44g四重-(三苯膦)-钯(O)室温时在氮气下加入到16ml甲苯、3.8ml三乙胺和3.6ml亚磷酸二乙酯中并与6.90g 3-溴-6-三氟甲基-喹啉混合。在90℃的浴温下搅拌2小时。混合物用醚稀释，吸滤并浓缩滤液。柱色谱分离后得到8.3g 6-三氟甲基喹啉-3-膦酸二乙酯，熔点：69℃。
c)6-三氟甲基1,2,3,4-四氢喹啉-3-膦酸二乙酯
6.66g 6-三氟甲基-喹啉-3-膦酸二乙酯溶入70ml冰醋酸中并于室温在常压下经二氧化铂进行氢化。柱色谱分离后得到3.52g 6-三氟甲基-1,2,3,4-四氢喹啉-3-膦酸二乙酯，熔点：112℃。
d)1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-3-膦酸二乙基酯
4.04g 6-三氟甲基-1,2,3.4-四氢喹啉-3-膦酸二乙酯在氮气和冰冷下加入80ml四氢呋喃中。搅拌下加入0.43g 80％的氢化钠。30分钟后滴加1.6ml乙二酸单乙酯酰氯。室温下搅拌2小时，用硅藻土过滤并浓缩。柱色谱分离后得到4.87g 1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-3-膦酸二乙酯，为无色的油。
e)1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-3-膦酸二乙酯
4.37g 1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-3-膦酸二乙酯加入100ml二氯甲烷中并与3.98g四氟硼酸硝混合。室温下搅拌24小时，各用30ml5％的碳酸氢钠溶液洗涤两次并浓缩。柱色谱分离后得到4.25g 1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-3-膦酸二乙酯，熔点：70-72℃。
f)9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-6-膦酸二乙酯
4.25g 1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4,-四氢喹啉-3-膦酸二乙酯溶于75ml冰醋酸中并与8.5g铁粉混合。在90℃浴温下搅拌1小时，吸滤并浓缩滤液，柱色谱分离和从醋酸乙酯中重结晶后得到1.45g9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-6-膦酸二乙酯，熔点：253℃。
用基本类似的方法制备：
9-氯-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-6-羧酸乙酯。实施例4：
a)4-羟基-6-三氟甲基-喹啉
这种化合物用在Am.Chem.Soc.68,2685-2688(1946)中描述的类似方法由4-三氟甲基胺制备。
b)4-溴-6-三氟甲基-喹啉
25.8g磷酰溴(Phosphoroxybromid)放置在室温并在缓慢加热下-份份地与6.39g 4-羟基-6-三氟甲基-喹啉混合。在90℃搅拌1小时，用120ml冰水进行分解并用50ml32％的苛性钠溶液调至碱性。1小时后吸滤沉淀产品，用水洗涤并干燥，晶体溶在热己烷中，过滤掉不溶成分并浓缩滤液。得到7.34g 4-溴-6-三氟甲基-喹啉，熔点56℃。
c)6-三氟甲基-喹啉-4-膦酸二乙酯
在20ml甲苯中的1.73g四重-(三苯膦)钯(0)与4.6ml三乙胺、4.3ml亚磷酸二乙酯和8.28g 4-溴-6-三氟甲基-喹啉混合并在90℃搅拌3小时，再添加0.17g四重-(三苯膦)钯(0)和各0.4ml三乙胺和亚磷酸二乙酸并在90℃时搅拌1小时。冷却后用醚稀释，吸滤，用醚洗涤并浓缩滤液。产物用柱色谱分离法纯化。得到8.33g6-三氟甲基-喹啉-4-膦酸二乙酯，为无色油。
d)6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯
8.32g 6-三氟甲基-喹啉-4-膦酸二乙酯溶于100ml冰醋酸中，与1.0g二氧化铂混合并在室温下氢化。柱色谱分离后得5.44g 6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯，熔点94℃。
e)1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯
5.05g 6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯在氮气下加入100ml四氢呋喃中并与0.54g 80％的氢化钠混合。30分钟后在室温下滴入1.9ml乙二酸单乙酯酰氯。室温下搅拌15小时，用硅藻上过滤并浓缩。柱色谱分离后得到5.99g 1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯，为无色油。
f)1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯
5.68g 1-乙氧基乙二酰-6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯溶于100ml二氯甲烷中并与5.18g四氟硼酸硝混合。溶液在室温下搅拌20小时，用5％的碳酸氢钠溶液洗涤并浓缩，柱色谱分离后得到5.34g 1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯，为无色油。
g)9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-7-膦酸二乙酯
5.30g 1-乙氧基乙二酰-8-硝基-6-三氟甲基-1,2,3,4-四氢喹啉-4-膦酸二乙酯加入到90ml冰醋酸中，与10.6g铁粉混合并在90℃下搅拌1小时。悬浮液进行热吸滤，用醋酸乙酯洗涤并浓缩滤液。产物用柱色谱分离法提纯并从醋酸乙酯中重结晶。得到2.47g 9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-7-膦酸二乙酯，熔点：250℃。实施例5：
8-硝基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
812mg 9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯溶于15ml二氯甲烷中并在室温下531mg四氟硼酸硝鎓混合。搅拌15小时并浓缩。残余物收入到醋酸乙酯中并用5％的碳酸氢钠溶液洗涤。柱色谱分离后得到470mg 8-硝基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯，熔点：254℃。实施例6：
8-氨基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
226mg 8-硝基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯溶于20ml乙醇中，与在活性碳上的50mg 10％的钯混合并在室温和常压下氢化。吸滤催化剂后浓缩并从乙醇中重结晶。得到146mg 8-氨基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯，熔点：242℃(分解)。实施例7：
8-(1-吡略基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
211mg 8-氨基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯和66mg2,5-二甲氧基四氢呋喃在140℃浴温下反应1小时。从乙醇中重结晶后得到123mg 8-(1-吡咯基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯，熔点：268℃。实施例8：
8-碘-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯。
406mg 9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯在2ml冰醋酸中与0.05ml水、0.025ml浓硫酸、178mg碘和70mg碘酸混合并在80℃浴温下搅拌15小时。浓缩后与水混合并吸滤产物。得到60mg 8-碘-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸，熔点307℃(分解)。实施例9：
8-碘-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
100mg 8-氨基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯加入到8ml乙醇的盐酸液中并浓缩和把氯化氢收入到6ml二甲基甲酰胺和3ml二碘甲烷中并在80℃浴温下和0.08ml亚硝酸异戊酯混合。在此温度下搅拌3小时后真空下浓缩沉积物。得到95mg 8-碘-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯。
用基本类似的方法经重氮化在水介质中制备：
8-氟-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
9-氰基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸甲酯。实施例10：
8-(哌啶-1-基)-9-氰基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯
在0℃时把由0.15ml 25％的戊二醛的水溶液和0.45ml3M硫酸在3ml四氢呋喃：甲醇=2∶3中形成的溶液滴加到110mg 8-氨基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯和30mg氢硼化钠药片在3ml四氢呋喃的悬浮液中。反应消失后再次补入30mg氢硼化钠药片并随后在室温搅拌1小时。然后用苛性钠溶液调至中性并用醋酸乙酯振荡卒取。干燥醋酸乙酯相,过滤并浓缩。经硅胶用甲苯∶冰醋酸∶水=10∶10∶1色谱分离后得到50mg 8-(哌啶-1-基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并[1,2,3-de〕对二氮萘-5-膦酸二乙酯。
用基本类似的方法制备：
8-吗啉代-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酯实施例11：
8-(1-咪唑基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸
150mg 8-氟-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸二乙酸与600mg咪唑一起在160℃浴温下搅拌2小时。然后把反应混合物在10ml浓盐酸中回流沸煮1.5小时，浓缩并收入到5ml水中并吸滤。得到100mg 8-(1-咪唑基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3-de〕对二氮萘-5-膦酸。
Claims (4)
1．式Ⅰ的化合物
其中R1,R2和R3各是氢、-POXY，卤素，且R1、R2、R3不同时为氢
R4是氢，
R5,R6和R7相同或不同并且是氢，卤素、硝基、NR12R13，氰基，CF3，或R5和R6或R6和R7代表一种稠合苯环，并且代表单键或双键，
其中X和Y相同或不同并且是羟基，C1-6-烷氧基，-O-(CH2)n-O-,C1-4-烷基或NR9R10且n=1,2，或3
且R9和R10,R12和R13相同或不同并且是氢，-CO-C1-6烷基，苯基或C1-6烷基，其可任选地用C1-4烷氧基或一个可能用C1-4烷基单取代或双取代的氨基所取代，或共同和N原子形成一个饱和5-7元杂环，该杂环还可含有其它的氧原子，硫原子或氮原子并能被取代，或形成一个不饱和的5元杂环，这种杂环可含有1-3个N原子并且可被取代，以及其异构体或盐。
2．如权利要求1的式Ⅰ化合物，其中该式Ⅰ化合物为
8-(1-咪唑基)-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
8-碘-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
8-(1-吡咯基)-9-三氟甲基-2,3,-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
8-吗啉代-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
8-氨基-9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-6-膦酸
9-氯-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸
9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-7-膦酸
9-三氟甲基-2,3-二氧代-1,2,3,5,6,7-六氢-吡啶并〔1,2,3,-de〕对二氮萘-5-膦酸二乙酯
3．-种药物组合物，它含有如权利要求1或2的化合物作为活性成分。
4．制备根据权利要求1的式Ⅰ化合物的方法，其特征是：a)式Ⅱ化合物
(其中R11是H,NO2或-NH-R4和R1-R7含义如上)和草酸或活性草酸衍生物进行反应和必要时在引入和还原NO2基后进行环化并且，若R1,R2和/或R3都是卤素，需要时和XYP-O-C1-4-烷基进行反应或羰基化或
b)式Ⅲ化合物
(其中R1-R4含义如上和R5-,R6-或R7-是氢或一个吸电子基团)进行卤化或硝化并且必要时紧接着把酯基皂化，或把酸基酯化或酰胺化，或把硝基还原成氨基，或把氨基烷基化或酰基化或把氨基换成卤素或氰基，或引入硝基或卤素，或进行亲核取代，或分离异构体或形成盐。
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| DE4314593A DE4314593A1 (de) | 1993-04-28 | 1993-04-28 | Pyrido(1,2,3-de)chinoxalinderivate, Verfahren zu deren Herstellung und ihre Verwendung von Arzneimitteln |
| DEP4314593.0 | 1993-04-28 |
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| CN1043576C true CN1043576C (zh) | 1999-06-09 |
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| US (1) | US5750526A (zh) |
| EP (1) | EP0696291B1 (zh) |
| JP (1) | JPH09500359A (zh) |
| KR (1) | KR960701885A (zh) |
| CN (1) | CN1043576C (zh) |
| AT (1) | ATE169925T1 (zh) |
| AU (1) | AU686160B2 (zh) |
| CA (1) | CA2161427A1 (zh) |
| CZ (1) | CZ277795A3 (zh) |
| DE (2) | DE4314593A1 (zh) |
| DK (1) | DK0696291T3 (zh) |
| ES (1) | ES2122274T3 (zh) |
| FI (1) | FI955141A0 (zh) |
| HU (1) | HUT74173A (zh) |
| IL (1) | IL109396A (zh) |
| NO (1) | NO305439B1 (zh) |
| NZ (1) | NZ265600A (zh) |
| PL (1) | PL174418B1 (zh) |
| RU (1) | RU2140924C1 (zh) |
| SK (1) | SK131995A3 (zh) |
| WO (1) | WO1994025472A1 (zh) |
| ZA (1) | ZA942970B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0903144A4 (en) * | 1996-04-17 | 2001-10-31 | Sumitomo Pharma | MEDICINE FOR RETINAL NEUROPATHY |
| ZA9711274B (en) * | 1996-12-16 | 1998-06-23 | Warner Lambert Co | Tricyclic quinoxaline derivatives as neuroprotective agents. |
| CN113620890A (zh) * | 2020-05-07 | 2021-11-09 | 普济生物科技（台州）有限公司 | 苯并喹喔啉酮化合物及其合成方法和用途 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993008188A1 (en) * | 1991-10-23 | 1993-04-29 | Sumitomo Pharmaceuticals Company, Limited | Tricyclic quinoxalinediones as glutamate receptor antagonists |
| US5273975A (en) * | 1989-06-09 | 1993-12-28 | The Upjohn Company | Heterocyclic amines having central nervous system activity |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0480939T3 (da) * | 1989-06-09 | 1995-07-10 | Upjohn Co | Heterocycliske aminer med virkning på centralnervesystemet |
-
1993
- 1993-04-28 DE DE4314593A patent/DE4314593A1/de not_active Withdrawn
-
1994
- 1994-04-22 IL IL109396A patent/IL109396A/xx not_active IP Right Cessation
- 1994-04-28 NZ NZ265600A patent/NZ265600A/en unknown
- 1994-04-28 AU AU66756/94A patent/AU686160B2/en not_active Ceased
- 1994-04-28 SK SK1319-95A patent/SK131995A3/sk unknown
- 1994-04-28 EP EP94914314A patent/EP0696291B1/de not_active Expired - Lifetime
- 1994-04-28 DK DK94914314T patent/DK0696291T3/da active
- 1994-04-28 HU HU9502810A patent/HUT74173A/hu unknown
- 1994-04-28 ES ES94914314T patent/ES2122274T3/es not_active Expired - Lifetime
- 1994-04-28 WO PCT/DE1994/000494 patent/WO1994025472A1/de not_active Application Discontinuation
- 1994-04-28 DE DE59406739T patent/DE59406739D1/de not_active Expired - Lifetime
- 1994-04-28 JP JP6523752A patent/JPH09500359A/ja active Pending
- 1994-04-28 RU RU95119828A patent/RU2140924C1/ru active
- 1994-04-28 CZ CZ952777A patent/CZ277795A3/cs unknown
- 1994-04-28 US US08/535,250 patent/US5750526A/en not_active Expired - Fee Related
- 1994-04-28 ZA ZA942970A patent/ZA942970B/xx unknown
- 1994-04-28 CA CA002161427A patent/CA2161427A1/en not_active Abandoned
- 1994-04-28 AT AT94914314T patent/ATE169925T1/de not_active IP Right Cessation
- 1994-04-28 CN CN94191912A patent/CN1043576C/zh not_active Expired - Fee Related
- 1994-04-28 KR KR1019950704707A patent/KR960701885A/ko not_active Application Discontinuation
- 1994-04-28 PL PL94311295A patent/PL174418B1/pl unknown
-
1995
- 1995-10-27 NO NO954317A patent/NO305439B1/no unknown
- 1995-10-27 FI FI955141A patent/FI955141A0/fi unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5273975A (en) * | 1989-06-09 | 1993-12-28 | The Upjohn Company | Heterocyclic amines having central nervous system activity |
| WO1993008188A1 (en) * | 1991-10-23 | 1993-04-29 | Sumitomo Pharmaceuticals Company, Limited | Tricyclic quinoxalinediones as glutamate receptor antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| PL174418B1 (pl) | 1998-07-31 |
| DE4314593A1 (de) | 1994-11-03 |
| PL311295A1 (en) | 1996-02-05 |
| FI955141A (fi) | 1995-10-27 |
| JPH09500359A (ja) | 1997-01-14 |
| FI955141A0 (fi) | 1995-10-27 |
| DE59406739D1 (de) | 1998-09-24 |
| US5750526A (en) | 1998-05-12 |
| ATE169925T1 (de) | 1998-09-15 |
| AU686160B2 (en) | 1998-02-05 |
| EP0696291B1 (de) | 1998-08-19 |
| AU6675694A (en) | 1994-11-21 |
| NZ265600A (en) | 1996-09-25 |
| NO954317L (no) | 1995-12-28 |
| HU9502810D0 (en) | 1995-11-28 |
| CN1121720A (zh) | 1996-05-01 |
| DK0696291T3 (da) | 1999-05-25 |
| HUT74173A (en) | 1996-11-28 |
| ES2122274T3 (es) | 1998-12-16 |
| EP0696291A1 (de) | 1996-02-14 |
| KR960701885A (ko) | 1996-03-28 |
| WO1994025472A1 (de) | 1994-11-10 |
| IL109396A (en) | 1997-11-20 |
| NO305439B1 (no) | 1999-05-31 |
| CZ277795A3 (en) | 1996-02-14 |
| IL109396A0 (en) | 1994-07-31 |
| CA2161427A1 (en) | 1994-11-10 |
| NO954317D0 (no) | 1995-10-27 |
| RU2140924C1 (ru) | 1999-11-10 |
| ZA942970B (en) | 1995-01-19 |
| SK131995A3 (en) | 1996-07-03 |
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