CN1122601A - [1,2,4]三唑并[4,3-a]喹喔啉衍生物,其制备及用途 - Google Patents
[1,2,4]三唑并[4,3-a]喹喔啉衍生物,其制备及用途 Download PDFInfo
- Publication number
- CN1122601A CN1122601A CN94191979A CN94191979A CN1122601A CN 1122601 A CN1122601 A CN 1122601A CN 94191979 A CN94191979 A CN 94191979A CN 94191979 A CN94191979 A CN 94191979A CN 1122601 A CN1122601 A CN 1122601A
- Authority
- CN
- China
- Prior art keywords
- compound
- ketone
- triazolo
- quinoxalines
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- QNSRYVDGWDXBHV-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]quinoxaline Chemical class C1=CC=C2N3C=NN=C3C=NC2=C1 QNSRYVDGWDXBHV-UHFFFAOYSA-N 0.000 title description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 8
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000001425 triazolyl group Chemical group 0.000 claims abstract description 4
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 claims abstract 3
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- -1 Hydrogen Chemical class 0.000 claims description 53
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- 238000000034 method Methods 0.000 claims description 18
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- CLAKAYYJMKYMRC-UHFFFAOYSA-N 2-diethoxyphosphorylacetyl chloride Chemical compound CCOP(=O)(CC(Cl)=O)OCC CLAKAYYJMKYMRC-UHFFFAOYSA-N 0.000 description 5
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- 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 System
- C07F9/02—Phosphorus compounds
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Abstract
通式(I)的喹喔啉化合物,其中R1为COX′,POX′X″或被COX′或POX′X″取代的烷基,而X′和X″各自为羟基或烷氧基,以及R6、R7,R8和R9各自为氢、烷基、卤素、NH2,NO2,CN,CF3,其中Z′为NY′Y″或烷基而Y′和Y″各自为氢或烷基,三唑基,咪唑基,被苯基或烷基取代的咪唑基,或者R6和R7,或R8和R9,一起形成进一步稠合的环,用于治疗由兴奋性神经介质活动过强引起的疾病。
Description
本发明涉及具有治疗活性的杂环化合物,制备该化合物的方法,含该化合物的药物组合物,以及用它来治疗疾病的方法。
L-谷氨酸、L-天冬氨酸以及某些密切相关的其他氨基酸通常具有活化中枢神经系统(CNS)神经元的能力。对此已进行生物化学,电生理学和药理学研究并证明酸性氨基酸为哺乳动物CNS中大多数兴奋性神经元的介质。
对以谷氨酸为介质的神经传递作用被认为有助于神经病和精神病的治疗。例如,已知的兴奋性氨基酸拮抗剂已显示出抗焦虑(Stephens等,Psychopharmacology 90,143-147,1985)。抗惊厥活性(Croucher等,Science 216,899-901,1982)和肌肉松弛活性(Turski等,Neurosci.Lett.53,321-326,1985)。
有人提出细胞外兴奋性氨基酸的累积,接着过度刺激神经元,可解释神经疾病如肌萎缩性侧索硬化,帕金森氏综合症,阿尔茨海默氏病,亨廷顿氏病、癫痫,和脑局部缺血后出现的智能运动机能缺陷,缺氧及低血糖或头及脊髓创伤中出现的神经元变性(McGeer等,Nature 263,517-519,1976;Simon等,Science 226,850-852,1984;Wieloch,Science 230,681-683,1985:Faden等,Science244,798-800,1989;Turski等,Nature 349,414-418,1991)。其他可能的适应症为精神病,肌强直,呕吐和痛觉缺失。
兴奋性氨基酸通过突触后或突触前的特殊受体而作用。目前,这些受体按电生理学和神经化学方便地分为三组:1.NMDA(N-甲基-D-天冬氨酸)受体,2.AMPA受体,和3.红藻氨酸受体。L-谷氨酸和L-天冬氨酸能活化所有上述类型的兴奋性氨基酸受体,并可能活化其他类型的兴奋性氨基酸受体。
将兴奋性氨基酸受体分成NMDA、AMPA,和红藻氨酸受体的上述分类主要基于下列电生理学和神经化学的发现。
1)N-甲基-D-天冬氨酸(NMDA)受体对兴奋性NMDA具有高度的选择性。鹅膏蕈氨酸,L-高磺基丙氨酸高半胱氨酸、D-谷氨酸和反式-2,3-哌啶-二甲酸(反式-2,3-PDA)对这些受体具有强到中等程度的拮抗活性。效力最高,选择性最强的拮抗剂为D-构型的2-氨基-5-膦酰基羧酸,例如2-氨基-5-膦酰基戊酸(D-APV)和3-[(±)-2-羧基哌嗪-4-基]-丙基-1-膦酸(CPP),而中等强度的拮抗剂为长链2-氨基二羧酸(例如D-2-氨基己二酸)和长链二氨基二羧酸(例如二氨基庚二酸)。哺乳动物CNS,特别是脊髓中NMDA诱导的突触反应已被广泛地研究(J.Dauies等,J.Physiol.297,621-635,1979)该反应被Mg2+强烈地抑制。
2)AMPA受体选择性地被AMPA(2-氨基-3-羟基-5-甲基-4-异噁唑丙酸)活化,其他有效拮抗剂为使君子酸(quisqualicacid)和L-谷氨酸。谷氨酸二乙酯(GDEE)对受体为选择性的但是很弱的拮抗剂。相对地,AMPA受体对Mg2+不敏感。
长期已来,谷氨酸的释放被认为在由大脑局部缺血导致的神经元坏死中起着重要作用(Benueniste,H.等,J.Neurochem.43,1369-1374,1984)。已知使Ca2+流入的NMDA受体为局部缺血性神经元细胞损伤中的重要机制。与离子载体结合的非NMDA受体不能渗透钙。但是CA1区Scaffer侧突的兴奋通过非NMDA受体产生,这对局部缺血后期的过程很重要。最新研究显示甚至在再灌注后几小时里选择性AMPA拮抗剂对沙土鼠小球小体局部缺血都具有神经元保护作用(Sheardown等,Science 247,571-574,1990)。
因此AMPA拮抗剂可用于治疗脑局部缺血。
3)红藻氨酸受体。相对地,红藻氨酸的兴奋性响应对NMDA-拮抗剂和GDEE的拮抗作用不敏感,现已认为红藻氨酸活化酸性氨基酸受体的第三亚类。某些红藻氨酸内酯化衍生物为选择性的拮抗剂(O.Goldberg等,Neurosci.Lett.23,187-191,1981),二肽3-谷氨酰-甘氨酸也对红藻氨酸受体显示出某种程度的选择性。Ca2+而不是Mg2+为红藻氨酸结合的强抑制剂。
一种物质对一种或更多不同类型的兴奋性氨基酸受体的亲合力可在简单的结合实验中研究。实质上,该方法包括将特殊选择的放射性标记的配位体和被研究的特定物质用含该受体的脑浆培养。通过测定与脑浆结合的放射性并减去非特定结合来测量受体占有率。
可通过使用3H-AMPA作为放射性配位体来研究AMPA受体的结合。
可通过体外应用鸡视网膜中的伸展凹陷来研究谷氨酸类似物对谷氨酸受体相互作用的副作用的影响。这样的实验将提供试验物质功效(激动/拮抗)的信息。这和结合研究成为对照,即这仅能提供化合物对受体亲合力的信息。
现已发现本发明化合物对AMPA受体具有亲合性,为与该类受体有关的拮抗剂,这使其可用于治疗由兴奋性氨基酸活动过强引起的神经系统适应症。
本发明化合物或其药学上可接受的盐由通式I表示(I)其中R1为COX′,POX′X″或由COX′或POX′X″取代的直链或支链C1-6-烷基,而X′和X″各自为羟基或C1-6-烷氧基,以及氢、C1-6-烷基,卤素,NH2,NO2、CN,CF,SO2 NY′Y″或COZ′其中Z′为NY′Y″或C1-6-烷基,而Y′和Y″各自为氢或C1-6-烷基,三唑基,咪唑基,由苯基或C1-6-烷基取代的咪唑基,或R6和R7,或R8和R9,一起形成进一步稠合的环。
当R6和R7,或R8和R9,一起形成进一步稠合的环时,该稠环优选苯并环,四氢苯并环,吡啶并环,嘧啶并环或吡喃并环。
本发明也涉及上述化合物的制备方法。式I化合物用下列方法制备:a)用苄基卤将式II化合物(II)其中R6,R7,R8和R9定义如上,烷基化形成式III化合物(III)其中R6,R7,R8和R9定义如上,并将其卤化形成式IV化合物(IV)其中R6,R7,R8和R9定义如上而Q为Br,Cl或I;再将该化合物与肼反应形成式V化合物(V)其中R8,R7,R8和R9定义如上,用通式(VI)的酰卤
R1-COCl (VI)其中R1定义如上述通式I化合物其中X′和X″为C1-6-烷氧基将该化合物酰化形成式VII化合物(VII)其中R6,R7,R8和R9定义如上,并将该化合物氢解形成式VIII化合物(VIII)其中R6,R7,R8和R9定义如上,接着热环化并同时去氧形成式I化合物,其中X′和X″为C1-6烷氧基,或b)将式IX化合物(IX)其中R6,R7,R8和R9定义如上,而Q为Br,Cl或I;与通式VI化合物
R1-COCl (VI)其中R1定义如上述通式I化合物中所限其中X′和X″为C1-6-烷氧基反应形成式XI化合物(XI)其中R6,R7,R8和R9定义如上,而Q为Br,Cl或I;然后环化再水解或同时环化和水解形成式I化合物,其中X′和X″为C1-6-烷氧基,或c)用单—,双—,或三甲氧基取代的苄胺取代式XII化合物(XII)其中R6,R7,R8和R9定义如上而Z为卤素或C1-6-烷氧基;形成式XIII化合物(XIII)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,并将该化合物与乙基草酰氯反应形成式XIV化合物(XIV)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,然后氢化形成环化的N-羟基化合物中间体接着脱氢或者氢化环化形成式XV化合物(XV)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,卤化式XV化合物,将所得化合物与肼反应,接着用定义如上的通式VI酰卤酰化,然后环化形成式XVI化合物(XVI)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,并水解形成式I化合物,其中X′和X″为C1-6-烷氧基,或者d)用碱水溶液水解其X′和X″为C1-6-烷氧基的式I化合物形成其中X′为羟基而X″为C1-6烷氧基的式I化合物,或者e)将其中X′为羟基或C1-6-烷氧基而X″为C1-6-烷氧基的式I化合物与卤代三甲基甲硅烷反应形成其中X′和X″为羟基的式I化合物。
本发明化合物的药理性质可通过测定其从AMPA型受体取代放射性标记的2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)的能力来说明。化合物的拮抗性质由其拮抗使君子氨酸刺激的鸡视网膜伸展凹陷的能力来证明。
可通过测定导致50%的3H-AMPA的特定结合的取代的浓度(μM),即IC50值来显示化合物的取代活性。
通过测定对使君子氨酸刺激的鸡视网膜申展凹陷产生50%最大抑制的浓度,即IC50值来测量拮抗活性。3H-AMPA结合(试验1)
将500μl融化的于pH7.1的Tris-HCl(30mM),CaCl2(2.5mM)和KSCN(100mM)中的鼠大脑皮层粘膜匀浆与25μl 3H-AMPA(最终浓度为5nM)和受试化合物和缓冲液在0℃培养30分钟。通过用L-谷氨酸(最终浓度为600μM)培养来测定非特定结合。通过加入5ml冰冷却的缓冲液接着通过Whatman GF/C玻璃纤维过滤器过滤并用2×5ml冰冷却的缓冲液洗涤来测定结合反应。通过闪烁计数测量结合的放射性。IC50通过试验化合物的至少四种浓度的Hill分析来测定。伸展(试验2)
将小鸡(3-10天龄处死,将眼剜出并沿中纬线平面切断。除去前室和玻璃体后,将每只眼的后室放入装有含下列组分(mM)NaCl(100),KCl(6.0),CaCl2(1.0),MgSO4(1.0),NaHCO3(30),NaH2PO4(1.0),葡萄糖(20)的生理盐水溶液(P.S.S.)的陪替氏培养皿中。
将溶液用100%O2饱和并使温度保持在26℃。
将眼最初在常规P.S.S.中培养15-30分钟,然后移入含使君子氨酸(1μg/ml)的P.S.S.中。在此“刺激性溶液”中。S.D.s通常自发地从视网膜的边缘开始,并可容易地用肉眼观察。测量每只眼S.D.开始的时间。
在常规P.S.S.中再培养15分钟后,将试验眼球移入含试验化合物的常规P.S.S.中并培养15分钟。然后将眼球移入含相同浓度的试验化合物的“刺激性溶液”中。再测量每只眼S.D.开始的时间。随后将眼球放回常规P.S.S.中,15分钟后再则量S.D.开始的时间,以便评价从药物作用中恢复的程度。
S.D.开始此对照时间增加30秒钟被认为是S.D.的100%抑制。因此按所给剂量得到的最大响应百分率表示药效。因此可按产生50%最大抑制的试验化合物的浓度(μM)(IC50)来表示试验值。
某些本发明化合物的试验结果如下列表1所示
表1
试验1 | 试验2 | |
化合物实施例 | IC50μM | IC50μM |
20 | 0.26 | 0.4 |
30 | 0.48 | 1.4 |
可通过口服,直肠或非肠道途径对人或动物给药含本发明化合物的组合物的药剂。
该活性化合物或其药学上可接受的盐的有效量可由通常的因素,如疾病的性质和严重程度以及需要治疗的动物的体重来决定。
常规的赋形剂是与活性化合物无有害反应的,适于非肠道或肠道内给药的药学上可接受的有机或无机载体物质。
载体的实例有水、盐溶液、醇、聚乙二醇、多羟基乙氧基化蓖麻油、明胶、乳糖、直链淀粉、硬脂酸镁、滑石、硅酸、脂肪酸单酸甘油酯和甘油二酯、季戊四醇脂肪酸酯、羟甲基纤维素和聚乙烯吡咯烷酮。
该药物制剂可被灭菌,如果需要,可与辅助试剂,如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、调节渗透压的盐、缓冲剂和/或色素等混合,只要其与活性化合物无有害反应。
注射液或悬浮液,优选将含有活性化合物的水溶液溶于多羟基化的蓖麻油的水溶液,特别适用于非肠道给药。
安瓿剂为方便的单剂量形式。
含滑石和/或载体或粘合剂等的片剂,糖锭剂,或胶囊特别适于口服给药。载体优选乳糖和/或玉米淀粉和/或土豆淀粉。
当可使用或需要甜味剂时,可使用糖浆,酏剂,等。
一般地,本发明化合物被分散在单剂量形式中,每个单剂量由10-200mg活性成分组成或与药学上可接受的载体一起组成。
当作为药时,用于患者如人,本发明化合物的剂量为1-500mg/天,例如,每剂量为大约100mg。
可通过常规制片制术制备的典型的片剂含:
片芯:
活性化合物(游离化合物或其盐) 100mg
胶体二氧化硅(Aerosi) 1.5mg
微晶纤维素(Avicel) 70mg
改性纤维素胶(Ac-Di-Sol) 7.5mg
硬脂酸镁 1mg
包衣:
HPMC 大约9mg
*Mywacett9-40T 大约0.9mg
*酰化单甘油酯用作包衣增塑剂
在盐的形式中,可使用本发明游离化合物的碱金属或碱土金属盐。这样的碱金属或碱土金属盐通常通过该化合物与等量或过量的选定的碱金属或碱土金属氢氧化物,经常地或适当地在盐可从其中沉淀或以其他常规方式,例如蒸发,回收及在中性溶剂的存在下,反应而生成。本发明化合物常优选地以其药学上可接受的水溶性碱金属或碱土金属盐的形式,并以其中含有药学上可接受的液体或固体载体或稀释剂的药物组合物的形式口服、直肠或非肠道给药。
本发明化合物可与常规辅剂、载体或稀释剂一起置于药物组合物及其单剂量形式中,对于口服用药,该形式可为固体,如片剂或填充胶囊,或液体,如溶液、悬浮液、乳剂、酏剂、或由它们填充的胶囊;对于直肠用药,该形式为栓剂;对于非肠道(包括皮下)给药,该形式为无菌注射溶液。这样的药物组合物和其单剂量形式可以常规比例包括常规组分,包括或不包括另外的活性化合物或成分,这样的单剂量形式可含有相当于欲使用的日剂量范围的适于有效拮抗AMPA的任何量的活性组分。相应地,每片含10mg到200mg,优选50mg活性组分的片剂为典型的单剂量形式。
由于它们的高度AMPA拮抗活性和它们的低毒性,一起提供了非常令人满意的治疗指数,本发明化合物,常优选其碱金属或碱土金属盐,同时,或者与药学上可接受的载体或稀释剂一起,特别地并优选地以其药物组合物形式,不论经口服,直肠,或非肠道(包括皮下)途径,以有效量,可被用于需要治疗,消除,减轻,改善对AMPA受体状况变化敏感的适应症,例如硬化,帕金森氏综合症,阿尔茨海默氏病,亨廷顿氏病、癫痫,啮局部缺血后出现的机能缺陷,缺氧,低血糖,头和脊髓创伤,精神病,肌肉强直,呕吐和痛觉缺失的患者,例如,动物活体。
优选的剂量范围为每日10-200毫克,优选每日50-100毫克,特别优选每日70-100毫克,这通常取决于具体给药方式,剂型,所治疗的疾病,受治疗者的种类及患者的体重,以及主治医师和兽医的爱好和经验。
治疗涉及兴奋性神经介质特别与AMPA受体活动过强或者由其导致的疾病的方法包括对受治疗者使用神经学有效量的拮抗AMPA的本发明化合物或其药学上可接受的盐。
进一步,本发明涉及本发明化合物在制备治疗涉及兴奋性神经介质,特别与AMPA受体活动过强,或由其导致的疾病的药物中的用途。
这里将根据下列实施例更详细地说明本发明。
实施例1
A. 3-氯-2-(2-乙草酰肼基)-6-硝基喹喔啉
在搅拌着的2.1g(~8.8mmol)3-氯-2-肼基-6-硝基喹喔啉于125ml无水四氢呋喃中的悬浮液中加入1.35ml(~9.8mmol)无水三乙胺,然后逐渐地加入1.1ml(~9.9mmol)乙草酰氯。在25℃继续搅拌90分钟。将蒸发过的反应混合物与水搅拌,得到2.9g(~96%)标题化合物。1H-NMR(DMSO-d6):δ11.4(1H,s),10.4(1H,br.s),8.7(1H,d,J=3.5Hz),8.4(1H,dd,J=3.5Hz and 9.2Hz),7.8(1H,d,J=9.2Hz).B. 4-氯-1-乙氧羰基-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉
将2.0g(~5.9ml)3-氯-2-(2-乙草酰基肼基)-6-硝基喹喔啉和20ml磷酰氯的混合物回流90分钟。冷却至50℃后,将反应混合物倒入冰水中,得到1.7g(~90%)标题化合物沉淀。C. 1-乙氧羰基-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4-(5H)-酮
将1.5g(~4.7mmol)4-氯-1-乙氧羰基-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉与25ml冰醋酸的混合物回流60分钟。冷却到25℃后,滤出沉淀,得到1.5g粗产品。通过柱层析(硅胶;洗脱剂:乙酸乙酯)纯化,得到1.2g(~90%)标题化合物。1H-NMR(DMSO-d6):δ8.5(1H,d,J=9.2Hz),8.08(1H,d,J=3.5Hz),7.8(1H,dd,J=3.5Hz and 9.2Hz),4.55(2H,q),1.4(3H,t).
以相似方法,由3-氯-2-肼基-6-硝基喹喔啉和乙基琥珀酰氯制备下列实施例化合物。
实施例2
1-(2-乙氧羰基乙基)-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4-(5H)-酮M.p.220℃分解1H-NMR(DMSO-d6):δ12.4(1H,s),8.27(1H,d,J=9.2Hz),8.2(1H,d,J=3.5Hz),8.1(1H,dd,J=3.5Hz和9.2Hz),4.1(2H,q),3.6(2H,t),3.05(2H,t),1.2(3H,t).
实施例3
1-(2-羧乙基)-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4-(5H)-酮
将0.5g(~1.5mmol)1-(2-乙氧羧基乙基)-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4-(5H)-酮加50ml水与1.5ml2N氢氧化钠的混合物中。25℃下继续搅拌24小时。加入4N盐酸使pH=2-3,得到标题化合物(0.42g;92%)沉淀。M.p.>300℃分解1H-NMR(DMSO-d6):δ12.4(1H,s),12.35(1H,s),8.25(1H,d,J=9.2Hz),8.2(1H,d,J=3.5Hz),8.12(1H,dd,J=3.5Hz and 9.2Hz),3.6(2H,t),3.0(2H,t).
实施例4
A. 1-苄氧基-7-氰基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮
将14g(~81mmol)苄基溴加入10.0g(~36.9mmol)7-氰基-1-羟基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮在700ml乙醇与175ml 1M磷酸二氢钾pH7.4缓冲溶液的混合物中的溶液中。25℃下继续搅拌2小时。将沉淀滤出并用冰冷却的乙醇洗涤,得到标题化合物(9.9g;75%)。1H-NMR(DMSO-d6):δ7.75(1H,s),7.65(2H,m),7.5(1H,s),7.4(3H,m),5.2(2H,s).B. 1-苄氧基-3-氯-7-氰基-6-三氟甲基喹喔啉-2(1H)-酮
0℃下将在甲苯(~74.3mmol)中的38.5ml 1.93M碳酰氯加到7.0g(~19.4mmol)1-苄氧基-7-氰基-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮在250ml无水N,N-二甲基甲酰胺中的溶液中。将蒸发过的反应混合物与水搅拌,得到标题化合物(6.6g;89%)。1H-NMR(DMSO-d6):δ8.45(1H,s),8.3(1H,s),7.7(2H,m),7.45(3H,m),5.3(2H,s)。C. 1-苄氧基-7-氰基-3-肼基-6-三氟甲基喹喔啉-2(1H)-酮
0℃下将2.7ml肼的单水合物(~55.7mmol)加入5.2g(13.7mmol)1-苄氧基-3-氯-7-氰基-6-三氟甲基喹喔啉-2(1H)-酮在150ml二氯甲烷中的溶液中。在0℃下继续搅拌1小时。将蒸发过的反应混合物与水搅拌,得到标题化合物(5.0g;97%)。1H-NMR(DMSO-d6):δ7.8(1H,s),7.7(1H,s),7.6(2H,m),7.4(3H,m),5.25(2H,s)。D. 1-苄氧基-7-氰基-3-(2-乙氧基琥珀酰肼基)-6-三氟甲基喹喔啉-2(1H)-酮
在2.1g(~5.6mmol)1-苄氧基-7-氰基-3-肼基-6-三氟甲基喹喔啉-2(1H)-酮于100ml无水四氢呋喃中的悬浮液中加入0.85ml(~6.18mmol)无水三乙胺,然后加入0.88ml(~6.18mmol)乙基琥珀酰氯。24℃下继续搅拌90分钟。将蒸发后的反应混合物与水搅拌,得到标题化合物(2.8g,98%)。1H-NMR(DMSO-d6):δ10.4(1H,br.s),10.2(1H,s),8.05(1H,8),7.8(1H,s),7.75(2H,m),7.45(3H,m),5.35(2H,s),4.1(2H,q),2.6(2H,s),1.2(3H,t).E. 7-氰基-3-(2-乙氧基琥珀酰肼基)-1-羟基-6-三氟甲基喹喔啉-2(1H)-酮
大气压下使用5% Pd-C(0.2g)作为催化剂,将2.7g(~5.4mmol)1-苄氧基-7-氰基-3-(2-乙氧基琥珀酰肼基)-6-三氟甲基喹喔啉-2(1H)-酮在150ml乙酸乙酯与150ml乙醇的混合物中的溶液氢化。过滤反应混合物,真空蒸发滤液,得到标题化合物(2.2g;92%)。1H-NMR(DMSO-d6):δ12.5(1H,br.s),10.3(1H,br.s),10.2(1H,s),8.15(1H,s),7.8(1H,s),4.05(2H,q),2.5(2H,s),1.15(3H,t).F. 7-氨基甲酰基-1-(2-羧乙基)-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将0.18g(~0.69mmol)三苯瞵加入0.2g(~0.48mmol)7-氰基-3-(2-乙氧基琥珀酰肼基)-1-羟基-6-三氟甲基喹喔啉-2(1H)-酮在8ml无水N,N-二甲基甲酰胺中的溶液中。120℃下继续搅拌48小时。将蒸发过的反应混合物与10ml 2N氢氧化钠搅拌72小时。在过滤的反应混合物中加入4N盐酸使pH=2。滤出沉淀,得到70mg(~40%)标题化合物。1H-NMR(DMSO-d6):δ12.5(2H,br.s),8.2(2H,s),7.8(1H,s),7.5(1H,s).
实施例5
A. 5-苄氧基-7-氰基-1-(2-乙氧羰基乙基)-8-三氟甲基-[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
70℃下将5.3g(~10.5mmol)1-苄氧基-7-氰基-3-(2-乙氧基琥珀酰肼基)-6-三氟甲基喹喔啉-2(1H)-酮和50ml磷酰氯的混合物搅拌90分钟。将混合物倒入300ml冰水中,得到粗产物沉淀。经柱层折(硅胶;洗脱剂=乙酸乙酯)得到标题化合物(1.06g;~21%)。1H-NMR(DMSO-d6):δ8.40(1H),s),8.28(1H,s),7.7(2H,m),7.95(3H,m),5.33(2H,s),4.13(2H,q),3.75(2H,t),3.05(2H,t),1.2(3H,t).MS(m/e):485(M+,10%).B. 7-氰基-1-(2-乙氧羰基乙基)-8-三氟甲基-[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
大气压下,使用5%Pd-C(0.2g)作为催化剂将1.0g(~2.1mmol)5-苄氧基-7-氰基-1-(2-乙氧羰基乙基)-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮在50ml乙醇和50ml乙酸乙酯的混合物中的溶液氢化。过滤后真空蒸发,得到N-羟基衍生物的黄色结晶。
将此粗中间体溶于30ml无水N,N-二甲基甲酰胺并加入1.5g(5.8mmol)三苯膦。将反应混合物在120℃搅拌20小时。真空蒸发后经闪式层析(硅胶;洗脱剂:二氯甲烷)得到标题化合物(0.5g;64%)。C. 1-(2-羧乙基)-7-氰基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
25℃下将0.5g(~1.3mmol)7-氰基-1-(2-乙氧羰基乙基)-8-三氟甲基-[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮和25ml 1N氢氧化钠的混合物搅拌2小时。将该溶液在冰浴中冷却并用4N盐酸酸化至pH=2。滤出沉淀得到0.29g(~63%)标题化合物。1H-NMR(DMSO-d6):δ12.6(1H,s).12.3(1H,s),8.35(1H,s),7.95(1H,s),3.65(2H,t),2.95(2H,t).
实施例6
A. 3-氯-2-(2-乙氧基琥珀酰肼基)-6-三氟甲基喹喔啉
将乙基琥珀酰氯(0.60ml,4.21mmol)滴入搅拌的3-氯-2-肼基-6-三氟甲基喹喔啉(1.1g,4.17mmol)和无水三乙胺(0.60ml,4.30mmol)在5ml无水四氢呋喃中的溶液中。将此混合物在室温下搅拌2小时,并过滤。蒸发滤液至干,残留物用水研制,得到1.60g(98%)粗标题化合物。B. 1-(2-乙氧羰基乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将粗品3-氯-2-(2-乙氧基琥珀酰肼基)-6-三氟甲基喹喔啉(1.41g,3.6mmo1)在7ml磷酰氯中的溶液在120℃回流1小时,冷却,倒入150ml冰/水中。将此混合物在0℃搅拌3小时,然后过滤得到0.94g(70%)4-氯三唑并喹喔啉中间体。然后将其在10ml冰醋酸中回流2小时,蒸发至干并用水研制残留物。用乙醇重结晶,得到240mg(19%)标题化合物。M.p.262℃(DSC)。1H-NMR(DMSO-d6):δ1.21(t,3H),3.05(t,2H),3.61(t,2H),4.11(q,2H),7.62-7.71(m,2H),8.24(d,1H),12.26(br.s,1H);MS(m/e):354(M+,8%).
实施例7
1-(2-羧乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
室温下将1-(2-乙氧羰基乙基)-7-三氰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(177mg,0.5mmol)在6ml1N氢氧化钠中的悬浮液搅拌150分钟。将该溶液在冰浴中冷却并用4M盐酸酸化至pH1。将沉淀滤出,用水、乙醇和乙醚洗涤,得到131mg(80%)标题化合物。M.p.333℃(DSC)。1H-NMR(DMSO-d6):δ2.99(t,2H),3.58(t,2H),7.61-7.72(m,2H),8.25(d,1H),12.3(br.s,2H):MS(m/e):326(M+,14%).
实施例8
A. 1-苄氧基-7-三氟甲基喹喔啉-2,3(1H,4H)-二酮
将苄基溴(72mg,0.60mol)加入1-羟基-7-三氟甲基喹喔啉-2,3(1H,4H)-二酮(49.2g,0.20mol)在2.5l乙醇和800ml1M磷酸二氢钾缓冲液(pH7.4)中的悬浮液中。混合物在室温下搅拌过夜,过滤。将沉淀用水洗涤并干燥,得到59.5g(89%)标题化合物。M.p.>220℃分解。1H-NMR(DMSO-d6):δ5.23(s,2H),7.29-7.61(m,8H),12.4(br.s,1H).B. 1-苄氧基-3-氯-7-三氟甲基喹喔啉-2(1H)-酮
0℃搅拌下将20%碳酰氯的甲苯溶液(120ml,0.23mol)加入1-苄基-7-三氟甲基喹喔啉-2,3(1H,4H)-二酮(27g,80mmol)在300ml无水N,N-二甲基甲酰胺中的溶液中。将混合物在室温下搅拌过夜并蒸发至干。残留物用冰/水研制,过滤并用五氧化二磷真空干燥,得到27.4g(96%)标题化合物。M.p.148-150℃。1H-NMR(DMSO-d6):δ5.33(s,2H),7.38-7.44(m,3H),7.56-7.62(m,3H),7.72(dd,1H),8.02(d,1H).C. 1-苄氧基-3-肼基-7-三氟甲基喹喔啉-2(1H)-酮
将1-苄氧基-3-氯-7-三氟甲基喹喔啉-2(1H)-酮(27g,76mmol)和肼的水合物(14.7ml,0.30mol)在250ml二氯甲烷中的混合物在0℃搅拌2小时。滤出沉淀,用二氯甲烷和水洗涤并干燥,得到22.8g(76%)的标题化合物。M.p.174-176℃。1H-NMR(DMSO-d6):δ5.29(s,2H),7.35-7.61(m,8H).D. 1-苄氧基-3-[2-[(二乙氧磷酰基)乙酰基]肼基]-7-三氟甲基喹喔啉-2(1H)-酮
将(二乙氧磷酰基)乙酰氯(5.8g,27mmol)在40ml无水四氢呋喃中的溶液加入1-苄氧基-3-肼基-7-三氟甲基喹喔啉-2(1H)-酮(8.75g,25mmol)和无水三乙胺(3.6ml,27mmol)在200ml无水四氢呋喃中的溶液中。将此混合物在室温下搅拌3小时并过滤。滤液蒸发至干,通过用水(200ml)研制而使残留物结晶,得到12.85g(97%)标题化合物。M.p.163-166℃。1H-NMR(DMSO-d6):δ1.27(t,6H),3.07(d,2H),4.10(五重峰4H),5.35(s,2H),7.36-7.61(m,8H),10.10 and 10.27(br.s,2H).E. 3-[2-[(二乙氧磷酰基)乙酰基]肼基]-1-羟基-7-三氟甲基喹喔啉-2(1H)-酮
在大气压,室温,250mg 5%钯炭存在下,将1-苄氧基-3-[2-[(二乙氧磷酰基)乙酰基]肼基]-1-羟基-7-三氟甲基喹喔啉-2(1H)-酮(5.28g,10mmol)在500ml乙醇中的溶液氢化1小时。滤除催化剂,蒸干滤液,用乙醚和石油醚研制残留物,得到4.0g(91%)标题化合物。M.p.193-196℃。1H-NMR(DMSO-d6):δ1.26(t,6H),3.05(d,2H),4.08(五重峰4H),7.54(s,2H),7.78(s,1H),9.96(br.s,1H),10.26(br.s,1H),ca.12.35(br.s,1H).F. 1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将3-[2-[(二乙氧磷酰基)乙酰基]肼基]-1-羟基-7-三氟甲基喹喔啉-2(1H)-酮(438mg,1mmol)和三苯膦(525mg,2mmol)在25ml冰醋酸中的溶液加热回流过夜(约15h)。蒸干混合物,并将残留物经闪式层析(SiO2),用二氯甲烷除去过量三苯膦,然后用乙酸乙酯除去氧化三苯瞵,最后用5%乙酸的乙酸乙酯溶液,得到161mg(40%)标题化合物。M.p.224-226℃,分解(乙醇)。1H-NMR(DMSO-d6):δ1.17(t,6H),4.05(quint,4H),4.27(d,2H),7.54(dd,1H),7.65(d,1H),8.33(d,1H);MS(m/e):404(M+,13%).(C15H16F3N4O4P0.25H2O)计算值 C 44.07 H 4.07 N 13.71实测值:C 44.05 H 4.11 N 13.69
按相似的方法从由常规方法制备的适当的1-羟基喹喔啉-2,3(1H,4H)-二酮和(二乙氧磷酰基)酰氯制备下列实施倒的化合物。
实施例9
1-[2-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.242-248℃分解1H-NMR(DMSO-d6):δ1.27(t,6H),2.34-2.54(m,2H),3.48-3.65(m,2H),4.07(quint,4H),7.61-7.72(m,2H),8.10(d,1H).
实施例10
7-氰基-1-[(二乙氧磷酰基)甲基]-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.200-203℃1H-NMR(DMSO-d6):δ1.19(t,6H),4.07(quint,4H),4.41(d,2H),7.91(s,1H),8.63(s,1H);1R(KBr):2238,1714cm-1。
实施例11
1-[1-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.238-241℃;1H-NMR(DMSO-d6):δ1.08(t,3H),1.14(t,3H),1.75(dd,3H),3.95(五重峰2H),4.04(五重峰2H),4.60(dq,1H),7.60(dd,1H),7.69(dd,1H),8.40(dd,1H).
实施例12
1-[1-(二乙氧磷酰基)丙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>130℃分解;1H-NMR(DMSO-d6):δ0.97(t,3H),1.06(t,3H),1.13(t,3H),2.12-2.56(m,2H),3.92(五重峰2H),4.03(五重峰2H),4.34-4.54(m,1H),7.66(dd,1H),7.71(d,1H),8.49(d,1H),12.3(br s,1H).
实施例13
A. 3-氯-6-氰基-2-[2-[(二乙氧磷酰基)乙酰基]肼基]喹喔啉
将(二乙氧磷酰基)乙酰氯(2.15g,10mmol)在20ml无水四氢呋喃中的溶液加入3-氯-6-氰基-2-肼基喹喔啉(2.0g,9mmol)和无水三乙胺(1.4ml,10mmol)在100ml和无水四氢呋喃中的溶液中。混合物在室温下搅拌过夜,并过滤。蒸发滤液,分离出的标题化合物为半固体状残留物,它无需进一步纯化即可用于下步反应。1H-NMR(DMSO-d6):δ1.26(t,6H),3.09(d,2H),4.10(五重峰,4H),7.71(d,1H),7.97(dd,1H),8.39(d,1H)。B. 7-氰基-1-[(二乙氧磷酰基)甲基][1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
氮气下将粗品3-氯-6-氰基-2-[2-[(二乙氧磷酰基)乙酰基]肼基]喹喔啉在100ml冰醋酸中的溶液加热回流1小时。蒸发该混合物,并将残留物用水研制,用乙腈重结晶,得到1.87g(57%总收率)标题化合物。m.p.223-225℃;1H-NMR(DMSO-d6):δ1.17(t,6H),4.07(五重峰,4H),4.29(d,2H),7.72(d,1H),7.80(dd,1H),8.37((d,1H),12.32(s,1H)。
实施例14
8-氯-1-[(二乙氧磷酰基)甲基][1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
按实施例13所述的方法,由2,6-二氯-3-肼基喹喔啉(830mg,3.62mmol)和(二乙氧磷酰基)乙酰氯(800mg,3.72mmol)制备标题化合物(619mg;44%)。M.p.223-227℃(乙醇):1H-NMR(DMSO-d6):δ1.19(t,6H),4.07(五重峰,4H),4.32(d,2H),7.39(d,1H),7.56(dd,1H),8.19(d,1H),12.2(s,1H)。
实施例15
1-[(二乙氧磷酰基)甲基]-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
按实施例13所述的方法,由3-氯-2-肼基-6-硝基喹喔啉和(二乙氧磷酰基)乙酰氯制备标题化合物。粗产品无需进一步纯化便可被水解(实施例28)。
实施例16
1-[(二乙氧磷酰基)甲基]-8-硝基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
0℃下将硝酸钾(1.82g,18mmol)粉末加入搅拌的1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(3.7g,9.15mmol)在50ml浓硫酸的溶液中。将此混合物在室温下搅拌过夜,并在冰/水(300g)中急剧冷却。用乙酸乙酯(5×100ml)萃取水相,并将合并的有机萃取液用无水硫酸钠干燥,蒸发。用乙醚研制残留物,得到3.25g(79%)标题化合物。m.p.222-228℃;1H-NMR(DMSO-d6):δ1.20(t,6H),4.10(五重峰,4H),4.39(d,2H),7.88(s,1H),8.96(s,1H),12.67(br s,1H)。
实施例17
8-氨基-1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
在兰尼镍(Raney-Ni)存在下,在40psi压力及室温下,将1-[(二乙氧磷酰基)甲基]-8-硝基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(3.25g,7.2mmol)在500ml乙醇中的溶液氢化6小时。将催化剂和固体沉淀过滤分离并用乙醇洗涤。倒出含乙醇的滤液,并用N,N-二甲基甲酰胺洗涤滤饼。蒸发滤液,并用水研制残留物,得到淡黄色固体状标题化合物(2.4g,80%)。m.p.260-263℃;1H-NMR(DMSO-d6):δ1.18(t,6H),4.07(五重峰,4H),4.13(d,2H),5.74(br s,2H),7.42(s,1H),7.69(s,1H),11.8(s,1H)。
实施例18
A. 4-溴-1-(2,4-二甲氧基苄氨基)-2-硝基萘
将无水四氢呋喃(15ml)中的2,4-二甲氧基苄胺(8.5g,41.6mmol)滴入4-溴-1-甲氧基-2-硝基萘(3.5g,12.5mmol)在无水四氢呋喃(l5ml)中的溶液中。将此混合物在室温下搅拌过夜并蒸发至干。残留物经闪式层析(SiO2),用甲苯/乙酸乙酯(1∶1)洗脱。产物溶入乙酸乙酯并用石油醚使其沉淀,得到4.1g(78%)标题化合物。M.p104-105℃。1H-NMR(CDCl3):δ3.72(s,3H),3.80(s,3H),4.70(d,2H),6.40(m,2H),7.08(d,1H),7.58(m,1H),7.75(m,1H),8.20(d,1H),8.38(m,2H),8.75(m,1H).B. 4-溴-2-硝基-1-(N-(2,4-二甲氧基苄基)乙草酰氨基萘
将四氢呋喃(15ml)中的乙草酰氯(2.2ml,19.5mmol)滴入4-溴-1-(2,4-二甲氧基苄氨基)-2-硝基萘(4.1g,9.7mmol)和三乙胺(2.7ml,19.5mmol)在四氢呋喃(70ml)中的溶液中。将此混合物在室温下搅拌过夜,并过滤。蒸干滤液,残留物经闪式层析(SiO2),用甲苯到甲苯乙酸乙酯(1∶1)梯度洗脱,得到3.97g(79%)标题化合物。M.p.108-109℃;1H-NMR(CDCl3):δ1.02(t,3H),3.02(s,3H),3.75(s,3H),3.98(q,2H),4.85(d,1H),5.20(d,1H),6.05(d,1H),6.38(m,1H),7.22(m,1H),7.65(m,1H),7.78(m,1H),7.95(m,1H),8.20(s,1H),8.30(m,1H).C. 1-(2,4-二甲氧基苄基)苯并[f]喹喔啉-2,3(1H,4H)-二酮
在兰尼镍(Raney-Ni)(1g)的存在下,在大气压及室温下,将4-溴-2-硝基-1-[N-(2,4-二甲氧基苄基)]乙草酰氨基萘(3.97g,7.7mmol)在N,N-二甲基甲酰胺(350ml)和乙醇(450ml)中的溶液氢化。滤除催化剂并将滤液蒸干。将残留物溶入乙醇(200ml),加入冰醋酸(10ml)并将混合物在80℃搅拌10小时。将该混合物真空浓缩到30ml,使其沉淀。得到1.2克(43%)的标题化合物。
M.p.223℃。1H-HNMR(DMSO-d6):δ3.75(s,3H),3.80(s,3H),5.22(bs,2H),6.45(m,1H),6.65(m,1H),7.30(m,4H),7.75(d,1H),7.90(m,2H)。D. 3-氯-1-(2,4-二甲氧苄基)苯并[f]喹喔啉-2(1H)-酮
0℃搅拌下将20%碳酰氯的甲苯(10ml,19mmol)溶液加入1-(2,4-二甲氧基苄基)苯并[f]喹喔啉-2,3(1H,4H)-二酮(950mg:2.6mmol)在无水N,N-二甲基甲酰胺(100ml)中的溶液中。将此混合物在室温下搅拌过夜,并蒸干。将残留物用冰/水研制,过滤并真空干燥,得到900mg(90%)标题化合物。M.p.186℃。1H-NMR(DMSO-d6):δ3.80(s,3H),3.82(s,3H),5.65(s,2H),6.45(dd,1H),6.55(d,1H),7.00(d,1H),7.35(m,1H),7.55(m,1H),7.75(m,2H),7.90(m,1H),8.22(d,1H)。E. 1-(2,4-二甲氧基苄基)-3-肼基苯并[f]喹喔啉-2(1H)-酮
将3-氯-1-(2,4-二甲氧基苄基)苯并[f]喹喔啉-2(1H)-酮(900mg,2.4mmol)和肼水合物(250μl,5.1mmol)在二氯甲烷(70ml)中的混合物在室温下搅拌,48小时后,将混合物蒸干。将残留物用冰/水研制,过滤并真空干燥,得到800mg(85%)标题化合物。M.p.182-183℃,1H-NMR(CDCl3):δ3.80(s,3H),3.85(s,3H),4.15(br.s,2H),5.58(s,2H),6.45(dd,1H),6.58(d,1H),7.05(d,1H),7.40(m,3H),7.70(s,2H),7.85(dd,1H),8.10(d,1H).F. 3-(2-(二乙氧磷酰乙酰基)肼基)-1-(2,4-二甲氧基苄基)-苯并[f]喹喔啉-2(1H)-酮
将(二乙氧磷酰基)乙酰氯(480mg,2.2mmol)在无水四氢呋喃(10ml)中的溶液加入1-(2,4-二甲氧基苄基)-3-肼基苯并[f]喹喔啉-2(1H)-酮(750mg,2mmol)和无水三乙胺(220mg,2.2mmol)在无水四氢呋喃(40ml)中的混合物中。将此混合物在室温下搅拌1.5小时并过滤。蒸发滤液,得到1.1g标题化合物粗产品。G. 3-[(二乙氧磷酰基)甲基]苯并[f]-1,2,4-三唑并[4,3-a]喹喔啉-12(11H)-酮
将3-(2-二乙氧磷酰乙酰基)肼基-1-(2,4-二甲氧基苄基)苯并[f]喹喔啉-2(1H)-酮(1.1g粗产品)和冰醋酸(40ml)的溶液加热回流12小时。蒸干该混合物。将残留物用异丙醇重结晶,得到400mg标题化合物。m.p.195-197℃。1H-NMR(DMSO-d6):δ1.18(t,6H),4.08(五重峰,4H),4.35(d,2H),7.68(m,2H),7.90(d,1H),8.08(m,1H)8.35(d,1H),8.82(m,1H),12.25(s,1H)。
实施例19
1-[(二乙氧磷酰基)甲基]-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
除中间体1-[(二乙氧磷酰基)甲基]-5-(2,4-二甲氧基苄基)-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮在室温下用三氟乙酸处理过夜而去保护外,该化合物可按实施例18所述的方法,由4-氟-3-硝基三氟甲苯和2,4-二甲氧基苄胺开始制备。蒸干混合物,用乙醇将残留物重结晶,得到纯的标题化合物。m.p.204-208℃。1H-NMR(DMSO-d6):δ1.17(t,6H),4.06(五重峰,4H),4.34(d,2H),7.57(d,1H),7.86(d,1H),8.44(s,1H),12.42(s,1H)。
实施例20
1-膦酰甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
在氨气中,在火焰干燥的烧瓶中,将溴代三甲基硅烷(0.75ml,5.8mmol)加入1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(315mg,0.78mmol)在15ml无水乙腈中的悬浮液中.并将所得溶液在40℃下搅拌过夜。蒸发至干后,将残留物与25ml水搅拌1小时。然后,通过与1-丙醇共沸蒸溜减压除去水,并通过用乙醚和乙醇的混合物,接着用石油醚研制,使残留物结晶。将所得固体用水重结晶,真空干燥得到189mg(70%)标题化合物。m.p.>290℃分解(DSC);1H-NMR(DMSO-d6):δ3.96(d,2H),7.64(d,1H),7.69(s,1H),8.47(d,1H),12.28(s,1H),IR(KBr):1712cm-1;MS(FAB):m/e 349(MH+)。(C11H8N4F3O4P.H2O)计算值:C 36.08,H 2.75,N 15.30实测值:C 35.97,H 2.77,N 15.22
按相似的方法由适当的二乙基膦酸酯制备下列实施例的化合物。
实施例21
1-(2-膦酰乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>300℃;1H-NMR(DMSO-d6):δ2.08-2.35(m,2H),3.42-3.64(m,2H),7.68(d,1H),7.72(s,1H),8.14(d,1H),12.26(br s,1H);MS(FAB):m/e 363(MH+).(C12H10N4F3O4P)计算值:C 39.78,H 2.76,N 15.47实测值:C 39.68,H 2.73,N 15.34
实施例22
7-氰基-1-膦酰甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>255℃分解;1H-NMR(DMSO-d6):δ4.01(d,2H),7.91(s,1H),8.77(s,1H),12.66(s,1H);IR(KBr):2246,1719cm-1;MS(FAB):m/e 374(MH+).(C12H7N5F3O4P·H2O)计算值:C 36.84,H 2.32,N 17.90实测值:C 36.56,H 2.39,N 17.70
实施例23
7-氰基-1-膦酰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>275℃分解;1H-NMR(DMSO-d6):δ3.94(d,2H),7.70(s,1H),7.75(d,1H),8.40(d,1H),12.32(br s,1H);1R(KBr):2242,1720 cm-1;MS(FAB):m/e 306(MH+).
(C11H8N5O4P·2.25H2O)计算值:C 38.22,H 3.64,N 20.26实测值:C 38.23,H 3.57,N 20.12
实施例24
1-(1-膦酰乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>300℃分解;1H-NMR(DMSO-d6):δ1.75(dd,3H),4.27(dq,1H),7.61(d,1H),7.69(s,1H),8.47(d,1H),12.28(s,1H);MS(FAB):m/e 363(MH+).(C12H10N4F3O4P·0.25H2O)计算值:C 39.30,H 2.89,N 15.28实测值:C 39.33,H 2.84,N 14.91
实施例25
8-氯-1-膦酰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>250分解;1H-NMR(DMSO-d6):δ3.93(d,2H),7.39(d,1H),7.55(dd,1H),8.31(d,1H),12.19(s,1H);MS(FAB):m/e 315(MH+).(C10H8N4ClO4P·0.5H2O)计算值:C 37.11,H 2.80,N 17.31实测值:C 36.84,H 2.97,N 17.15
实施例26
8-硝基-1-膦酰甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.245-248℃.1H-NMR(DMSO-d6):δ4.00(d,2H)17.89(s,1H),9.04(s,1H),12.65(br s,1H);MS(FAB):m/e 394(MH+).(C11H7N5F3O6P·0.5H2O)计算值 C 32.85,H 2.01,N 17.41实测值:C 32.94,H 2.01,N 17.11
实施例27
1-膦酰甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.282-284℃.1H-NMR(DMSO-d6):δ3.95(d,2H),7.57(d,1H),7.85(d,1H),8.59(s,1H),12.39(s,1H).(C11H8N4F3O4P·1H2O)计算值:C 36.08,H 2.75,N 15.30实测值:C 36.32,H 2.68,N 15.03
实施例28
7-硝基-1-膦酰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>265℃分解;1H-NMR(DMSO-d6):δ3.98(d,2H),8.08(dd,1H),8.22(d,1H),8.49(d,1H),12.40(s,1H);MS(FAB):m/e 326(MH+).
实施例29
1-(1-膦酰丙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮M.p.>240℃分解(从乙醚/乙醇中制得):1H-NMR(DMSO-d6):δ0.95(t,3H),2.08-2.61(m,2H),3.95-4.15(m,1H),7.62(d,1H),7.69(s,1H),8.50(d,1H),12.28(s,1H)。
(C13H12N4P3O4P·0.5H2O·0.25C2H5OH)计算值:C 40.87,H 3.68,N 14.12实测值:C 40.81,H 3.80,N 13.95
实施例30
3-膦酰甲基苯并[f]-1,2,4-三唑并[4,3-a]喹喔啉-12(11H)-酮M.p.>270℃;1H-NMR(DMSO-d6):δ4.02(d,2H),7.65(m,2H),7.85(m,1H),8.05(m,1H),8.40(m,1H),8.80(m,1H),12.15(s,1H).
实施例31
1-[(乙氧基羟基磷酰基)甲基]-7-三氯甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(750mg,1.85mmol)在20ml乙醇和20ml 10%氢氧化钠中的溶液在室温下搅拌1小时。减压除去溶剂,将残留物溶于水并置于先用4M盐酸后用去离子水预洗过的离子交换柱(Amberlite IR-120,H+-form)上。用去离子水洗脱,得到酸性洗脱液,真空浓缩,得到448mg(65%)标题化合物。m.p.276-280℃(从水中制得):1H-NMR(DMSO-d6):δ1.16(t,3H),3.98(五重峰,2H),4.08(d,2H),7.64(d,1H),7.68(s,1H),8.42(d,1H),12.28(s,1H),MS:m/e 377(MH+)。
实施例32
8-溴-1-[1-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
将1-[1-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮(811mg,1.94mmol),硫酸银(605mg,1.94mmol)和溴(100μl,1.94mmol)在5ml浓硫酸中的混合物在室温下搅拌过夜。将该混合物过滤,将滤液滴加到100ml冰/水中。将所得沉淀过滤分离,用水洗涤并干燥,得到514mg(53%)标题化合物。m.p.>200℃,分解。1H-NMR(DMSO-d6):δ1.12(t,3H),1.18(t,3H),1.74(dd,3H),3.95(五重峰,2H),4.07(五重峰,2H),4.78(dq,1H),7.81(s,1H),8.59(s,1H),12.35(s,1H)。
实施例33
8-溴-1-(1-膦酰乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮
按实施例20所述的方法,由8-溴-1-[1-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮制备标题化合物。M.p.>300℃;1H-NMR(DMSO-d6):δ1.66(畸变dd,3H),3.87(畸变dq,1H),17.76(s,1H),8.80(s,1H),12.3(br.s,1H);MS(FAB):m/e 441,443(MH+)。
(C13H9N5F3O4P·1.5H2O)计算值:C 30.79 H 2.58 N 11.97实测值:C 30.42 H 2.30 N 11.90
Claims (11)
2.根据权利要求1的喹喔啉化合物,其中稠合环是苯环。
3.根据权利要求1或2的化合物,1-乙氧羰基-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(2-乙氧羰基乙基)-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(2-羧乙基)-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;7-氨基甲酰基-1-(2-羧乙基)-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(2-羧乙基)-7-氰基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(2-乙氧羰基乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(2-羧乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-[2-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;7-氰基-1-[(二乙氧磷酰基)甲基]-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-[1-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-[1-(二乙氧磷酰基)丙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;7-氰基-1-[(二乙氧磷酰基)甲基][1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;8-氯-1-[(二乙氧磷酰基)甲基][1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-[(二乙氧磷酰基)甲基]-7-硝基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-[(二乙氧磷酰基)甲基]-8-硝基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;8-氨基-1-[(二乙氧磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;3-[(二乙氧磷酰基)甲基]苯并[f]-1,2,4-三唑并[4,3-a]喹喔啉-12(11H)-酮;1-[(二乙氧磷酰基)甲基]-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-膦酰甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(2-膦酰甲基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;7-氰基-1-膦酰甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;7-氰基-1-膦酰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(1-膦酰乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;8-氯-1-膦酰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;8-硝基-1-膦酰甲基-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-膦酰甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;7-硝基-1-膦酰甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;1-(1-膦酰丙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;3-膦酰甲基苯并[f]-1,2,4-三唑并[4,3-a]喹喔啉-12(11H)-酮;1-[(乙氧基羟基磷酰基)甲基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;8-溴-1-[1-(二乙氧磷酰基)乙基]-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮;8-溴-1-(1-磷酰乙基)-7-三氟甲基[1,2,4]三唑并[4,3-a]喹喔啉-4(5H)-酮。
4.一种药物组合物,其中包括作为活性组分的根据权利要求1、2或3的化合物或其药学上可接受的盐和药学可接受的载体或稀释剂。
5.根据权利要求4的药物组合物,该药物组合物为含10-200mg活性化合物的单剂量形式。
6.适用于治疗涉及兴奋性神经介质活动过强的疾病的药物组合物,其中包括作为活性组分的根据权利要求1、2或3的化合物或其药学上可接受的盐和药学上可接受的载体或稀释剂。
7.根据权利要求1、2或3的化合物用于制备治疗涉及兴奋性神经介质活动过强的疾病的药物的用途。
9.根据权利要求8的方法,其中疾病为大脑局部缺血。
10.根据权利要求8的方法,其中疾病为帕金森氏综合症。
11.制备根据权利要求1的化合物的方法,其中包括:a)用苄基卤将式II化合物:(II)其中R6,R7,R8和R9定义如上,烷基化形成式III化合物(III)其中R6,R7,R8和R9定义如上.并将其卤化形成式IV化合物(IV)其中R6,R7,R8和R9定义如上,而Q为Br,Cl,或I;再将该化合物与肼反应形成式V化合物(V)其中R6,R7,R8和R9定义如上,用通式VI的酰氯
R1-COCl (VI)其中R1定义如上述对其中X′和X″为C1-6-烷氧基的通式I化合物的定义。将该化合物酰化形成式VII化合物(VII)其中R6,R7,R8和R9定义如上,并将化合物氢解形成式VIII化合物(VIII)其中R6,R7,R9和R9定义如上,接着热环化并同时去氧形成式I化合物,其中X′和X″为C1-6-烷氧基,或b)将式IX化合物(IX)其中R6,R7,R8和R9定义如上,而Q为Br,Cl,或I;与通式VI化合物
R1-COCl (VI)其中R1定义如上述通式I化合物中所限,其中X′和X″为C1-6-烷氧基反应形成式XI化合物(XI)其中R6,R7,R8和R9定义如上,而Q为Br,Cl,或I;然后环化再水解或同时环化和水解形成式I化合物,其中X′和X″为C1-6-烷氧基,或c)用单-、双-,或三甲氧基取代的苄胺取代式XII化合物(XII)其中R6,R7,R8和R9定义如上,而Z为卤素,或C1-6-烷氧基,形成式XIII化合物(XIII)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,并将该化合物与乙基草酰氨反应形成式XIV化合物(XIV)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,然后氢化形成环化的N-羟基化合物中间体,接着脱氧或者氢化环化形成式XV化合物(XV)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,卤化式XV化合物,将所得化合物与肼反应,接着用定义如上的通式VI的酰氯酰化,然后环化形成式XVI化合物(XVI)其中R6,R7,R8和R9定义如上,而V′和V″各自为氢或甲氧基,并水解形成式I化合物,其中X′和X″为C1-6-烷氧基,或者d)用碱水溶液水解其X′和X″为C1-6-烷氧基的式I化合物形成其中X′为羟基而X″为C1-6-烷氧基的式I化合物,或者e)将其中X′为羟基或C1-6-烷氧基而X″为C1-6-烷氧基的式I化合物与三甲基卤硅烷反应形成其中X′和X″为羟基的式I化合物。
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US (1) | US5559106A (zh) |
EP (1) | EP0691969A1 (zh) |
JP (1) | JPH08507536A (zh) |
KR (1) | KR100313051B1 (zh) |
CN (1) | CN1041930C (zh) |
AU (1) | AU685783B2 (zh) |
CA (1) | CA2158545A1 (zh) |
DK (1) | DK31093D0 (zh) |
FI (1) | FI954386A (zh) |
HU (1) | HUT73419A (zh) |
IL (1) | IL108800A (zh) |
NO (1) | NO305286B1 (zh) |
NZ (1) | NZ262365A (zh) |
TW (1) | TW304195B (zh) |
WO (1) | WO1994021639A1 (zh) |
ZA (1) | ZA941926B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102341399A (zh) * | 2009-03-05 | 2012-02-01 | 安斯泰来制药株式会社 | 喹喔啉化合物 |
CN103619846A (zh) * | 2011-06-27 | 2014-03-05 | 詹森药业有限公司 | 1-芳基-4-甲基-[1,2,4]三唑[4,3-a]喹喔啉衍生物 |
US9669035B2 (en) | 2012-06-26 | 2017-06-06 | Janssen Pharmaceutica Nv | Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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DE4314592A1 (de) * | 1993-04-28 | 1994-11-03 | Schering Ag | Benzo(f)chinoxalindionderivate, deren Herstellung und Verwendung in Arzneimitteln |
ATE190616T1 (de) * | 1994-09-16 | 2000-04-15 | Novo Nordisk As | (1,2,4)triazolo(4,3-a)chinoxylinonderivate, ihre darstellung und verwendung als antagonisten von ampa-rezeptoren |
CA2200056A1 (en) * | 1994-09-16 | 1996-03-21 | Novo Nordisk A/S | [1,2,4]triazolo[4,3-a]quinoxalinone derivatives, their preparation and use |
US5679680A (en) * | 1995-02-16 | 1997-10-21 | Warner-Lambert Company | α-substituted hydrazides having calpain inhibitory activity |
FR2743363A1 (fr) * | 1996-01-10 | 1997-07-11 | Rhone Poulenc Rorer Sa | 5h,10h-imidazo(1,2-a)indeno(1,2-e)pyrazine-a-ones substituees en position 2, leur preparation et les medicaments les contenant |
IL125950A0 (en) * | 1997-09-05 | 1999-04-11 | Pfizer Prod Inc | Methods of administering ampa receptor antagonists to treat dyskinesias associated with dopamine agonist therapy |
AU9651198A (en) | 1997-11-11 | 1999-05-31 | Ono Pharmaceutical Co. Ltd. | Fused pyrazine compounds |
AU2298399A (en) * | 1998-02-06 | 1999-08-23 | Yoshitomi Pharmaceutical Industries, Ltd. | Novel azapeptide type hydroxamic acid derivatives |
US20040152694A1 (en) * | 2003-02-04 | 2004-08-05 | Istvan Kurucz | Methods and compositions for treating inflammatory disorders of the airways |
ES2536906T3 (es) * | 2006-12-13 | 2015-05-29 | Aska Pharmaceutical Co., Ltd. | Derivado de quinoxalina |
EP2338492A1 (en) | 2009-12-24 | 2011-06-29 | Universidad del Pais Vasco | Methods and compositions for the treatment of alzheimer |
AU2011299936A1 (en) | 2010-09-07 | 2013-03-28 | Astellas Pharma Inc. | Quinoxaline compound |
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US4354027A (en) * | 1980-05-19 | 1982-10-12 | Usv Pharmaceutical Corporation | Triazoloquinoxalin-4-ones |
US4547501A (en) * | 1983-09-02 | 1985-10-15 | Pfizer Inc. | Method of using [1,2,4]triazolo[4,3-a]quinoxaline-4-amine derivatives as antidepressant and antifatigue agents |
US5153196A (en) * | 1991-06-05 | 1992-10-06 | Eli Lilly And Company | Excitatory amino acid receptor antagonists and methods for the use thereof |
AU3767793A (en) * | 1992-04-03 | 1993-11-08 | Yamanouchi Pharmaceutical Co., Ltd. | Fused quinoxalinone derivative and pharmaceutical composition containing the same |
-
1993
- 1993-03-19 DK DK93310A patent/DK31093D0/da not_active Application Discontinuation
-
1994
- 1994-02-25 AU AU62018/94A patent/AU685783B2/en not_active Ceased
- 1994-02-25 CN CN94191979A patent/CN1041930C/zh not_active Expired - Fee Related
- 1994-02-25 CA CA002158545A patent/CA2158545A1/en not_active Abandoned
- 1994-02-25 NZ NZ262365A patent/NZ262365A/en unknown
- 1994-02-25 JP JP6520538A patent/JPH08507536A/ja active Pending
- 1994-02-25 WO PCT/DK1994/000077 patent/WO1994021639A1/en not_active Application Discontinuation
- 1994-02-25 EP EP94908979A patent/EP0691969A1/en not_active Withdrawn
- 1994-02-25 KR KR1019950703970A patent/KR100313051B1/ko not_active IP Right Cessation
- 1994-02-25 HU HU9502726A patent/HUT73419A/hu unknown
- 1994-02-28 TW TW083101703A patent/TW304195B/zh active
- 1994-03-01 IL IL108800A patent/IL108800A/en active IP Right Grant
- 1994-03-18 ZA ZA941926A patent/ZA941926B/xx unknown
- 1994-12-07 US US08/350,744 patent/US5559106A/en not_active Expired - Fee Related
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1995
- 1995-09-18 NO NO953673A patent/NO305286B1/no not_active IP Right Cessation
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102341399A (zh) * | 2009-03-05 | 2012-02-01 | 安斯泰来制药株式会社 | 喹喔啉化合物 |
CN103619846A (zh) * | 2011-06-27 | 2014-03-05 | 詹森药业有限公司 | 1-芳基-4-甲基-[1,2,4]三唑[4,3-a]喹喔啉衍生物 |
CN103619846B (zh) * | 2011-06-27 | 2016-08-17 | 詹森药业有限公司 | 1-芳基-4-甲基-[1,2,4]三唑[4,3-a]喹喔啉衍生物 |
US10604523B2 (en) | 2011-06-27 | 2020-03-31 | Janssen Pharmaceutica Nv | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives |
US9669035B2 (en) | 2012-06-26 | 2017-06-06 | Janssen Pharmaceutica Nv | Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders |
Also Published As
Publication number | Publication date |
---|---|
CN1041930C (zh) | 1999-02-03 |
AU685783B2 (en) | 1998-01-29 |
IL108800A (en) | 1998-02-22 |
NO305286B1 (no) | 1999-05-03 |
HUT73419A (en) | 1996-07-29 |
FI954386A0 (fi) | 1995-09-18 |
JPH08507536A (ja) | 1996-08-13 |
KR960701057A (ko) | 1996-02-24 |
EP0691969A1 (en) | 1996-01-17 |
KR100313051B1 (ko) | 2002-02-28 |
TW304195B (zh) | 1997-05-01 |
NO953673L (no) | 1995-11-17 |
IL108800A0 (en) | 1994-06-24 |
NO953673D0 (no) | 1995-09-18 |
ZA941926B (en) | 1995-09-18 |
DK31093D0 (zh) | 1993-03-19 |
HU9502726D0 (en) | 1995-11-28 |
US5559106A (en) | 1996-09-24 |
CA2158545A1 (en) | 1994-09-29 |
FI954386A (fi) | 1995-09-18 |
AU6201894A (en) | 1994-10-11 |
NZ262365A (en) | 1997-05-26 |
WO1994021639A1 (en) | 1994-09-29 |
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