CN1194643A - 吡咯基四氢喹喔啉二酮、其制备及控制疾病的用途 - Google Patents
吡咯基四氢喹喔啉二酮、其制备及控制疾病的用途 Download PDFInfo
- Publication number
- CN1194643A CN1194643A CN96196618A CN96196618A CN1194643A CN 1194643 A CN1194643 A CN 1194643A CN 96196618 A CN96196618 A CN 96196618A CN 96196618 A CN96196618 A CN 96196618A CN 1194643 A CN1194643 A CN 1194643A
- Authority
- CN
- China
- Prior art keywords
- hydrogen
- pyrryl
- alkyl
- diketone
- tetrahydroquinoxaline
- 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
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
式Ⅰ的吡咯基四氢喹喔啉二酮及其互变异构体和同分异构体、及其生理可接受的盐,其中各符号的意义如下:R1是-氢、环己基,含1至4个碳原子的脂族基团并可带有基团-COOR5,其中R5是氢或C1-C4烷基,优选-(CH2)m-COOR5,其中m=1—4,特别优选-CH2COOH,R2是-COOH,-COO-C1-C4,烷基,-COO-(CH2)m-Ph,-CONR6R7或(a),其中m可以是1至6的整数,R6可以是氢、C1-C4烷基或OH,而R7可以是氢、C1-C4烷基,-(CH2)m-Ph或(b),其中所有的R2中的苯基或吡啶环也可以被不多于三个的如下取代基取代:C1-C4烷基,卤素,-O-C1-C4烷基,-OCF3,NO2,CN,-COOR5或-CONHR5,R3是CF3,NO2,CN,且R4是氢,且R3和R4可以一起是一个稠合的苯环。这些化合物适于用作人药或兽药。
Description
本发明涉及新的吡咯基四氢喹喔啉二酮、其制备方法及其控制疾病的用途。
兴奋性氨基酸,特别是谷氨酸,广泛分布于中枢神经系统。兴奋性氨基酸谷氨酸是受体的递质,这些受体的很多亚型是已知的。例如,一种依据特异激动剂N-甲基-D-天冬氨酸命名的NMDA受体。此NMDA受体上有多个激动剂及拮抗剂结合位点。甘氨酸也结合在NMDA受体上并调节天然激动剂谷氨酸的作用。于是,针对此甘氨酸结合位点的拮抗剂对NMDA受体表现出拮抗作用并能抑制此受体的过度兴奋。
谷氨酸受体的另外两个亚型是AMPA受体和红藻氨酸受体(kainatereceptor),它们是分别根据特异性激动剂2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(AMPA)和红藻氨酸命名的。与已经提及的NMDA受体相似,这些受体的拮抗剂也抑制过度兴奋。
升高的谷氨酸活性发生于一些神经紊乱或生理紊乱中并导致中枢神经系统的过度兴奋或中毒作用。
在若干出版物中,式II的喹喔啉-2,3(1H,4H)-二酮衍生物
已被描述为谷氨酸拮抗剂,如见EP-A374534和EP-A260467。很多已知的衍生物在杂环喹喔啉部分上无取代(II,R1,R2=H)。此外,II中R1不是H的衍生物也是已知的。而EP-A377112和EP-A374534中已要求保护N-羟基喹喔啉(II;R1=OR4)。EP-A315959、EP-A4135871、WO91/13878和WO92/07847描述了R1为烷基的II,而烷基链也可被酸、酯或酰胺取代。在J.R.Epperson等,生物有机和药物化学通讯3(12)(1993),2801-4中也提及了烷酸(=R1)。
带有杂环作为取代基R3的喹喔啉二酮衍生物II也是已知的。EP-A556393描述了咪唑、三唑和吡唑。R3为吡咯基的喹喔啉二酮衍生物在EP-A572852中已被描述为谷氨酸拮抗剂。
本发明的物质适于治疗所有这些疾病,其中预期谷氨酸拮抗剂可起有利作用。
适应症为神经中毒症,特别是中枢神经系统急、慢性氧/(营养素)缺乏状态。即急性缺氧或局部缺血状态,它们可以是脑梗塞、蛛网膜下出血或其它病因的血管痉挛的后遗症,或可发生在心脏/循环系统衰竭,如心动停止、心律失常或循环性虚脱,低血糖后的CNS损伤后;它们也可是产期窒息的后遗症或在颅骨损伤、脊髓损伤、一时性局部缺血发作(TIAs)、延长的可逆性局部缺血神经短缺(PRINDs)和多发性梗塞痴呆及动脉粥样硬化和偏头痛之后发生。
其它可能的适应症为神经变性紊乱,如帕金森病、亨廷顿舞蹈病、阿尔茨海默病、肌萎缩性侧索硬化(ALS)。
此外,谷氨酸拮抗剂可以适用作抗癫痫药、抗焦虑药及抗抑郁药,并可以治疗疼痛,也可治疗精神分裂症、成瘾者的戒断症状,还可在骨骼肌痉挛,如在多发性硬化(MS)时作为肌松药。
本发明的目的是提供式I的新的吡咯基喹喔啉二酮及其互变异构体和同分异构体,及其生理可接受的盐:其中各符号的意义如下:R1是-氢、环己基,-含1至4个碳原子的脂族基团并可带有基团-COOR5,其中R5是氢或C1-C4烷基,优选-(CH2)m-COOR5,其中m=1-4,特别优选-CH2COOH,R2是-COOH,-COO-C1-C4,烷基,-COO-(CH2)m-Ph,-CONR6R7或
,其中m可以是1至6的整数,R6可以是氢、C1-C4烷基或OH而R7可以是氢、C1-C4烷基,-(CH2)m-Ph或
,其中所有在R2中含有的苯基或吡啶环也可以被不多于三个的如下取代基取代:C1-C4烷基,卤素,-O-C1-C4烷基,-OCF3,NO2,CN,-COOR5或-CONHR5,R3是-CF3,NO2,CN,且R4是-氢,且R3和R4-可以一起为一个稠合的苯环。
优选的本发明化合物是下式的喹喔啉二酮衍生物:其中R2是-COOH或-CONHR7,其中R7是氢,-CH2-C6H5,-CH2-Ph-NO2,-(CH2)-CH-C6H5或
R3是-NO2或CF3而R4为氢,或者R3和R4为一个稠合的苯环。
特别优选的化合物为:1-羧甲基-7-(3-羧基-1-吡咯基)-6-硝基喹喔啉-2,3-(1H,4H)-二酮,1-羧甲基-7-(3-羧基-1-吡咯基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮,1-羧甲基-7-(3-羧基-1-吡咯基)-6-苯并[f]喹喔啉-2,3-(1H,4H)-二酮7-(3-苄基氨基甲酰基-1-吡咯基)-1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮,7-(3-苄基氨基甲酰基-1-吡咯基)-1-羧甲基-6-硝基喹喔啉-2,3-(1H,4H)-二酮,1-羧甲基-6-硝基-7-(3-苯基-1-丙基)氨基甲酰基-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮,1-羧甲基-6-硝基-7-(3-(4-吡啶基甲基)氨基甲酰基-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮,7-(3-氨基甲酰基-1-吡咯基)-1-羧甲基-6-硝基喹喔啉-2,3-(1H,4H)-二酮,1-羧甲基-6-硝基-7-(3-(4-硝基苄基)氨基甲酰基-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮。
现已发现,令人惊奇的是,此吡咯基衍生物比EP-A572852提及的化合物更优越。
本发明式I的化合物可以按照下面的反应方案1制备。
醛III的合成在EP-A572852中已描述。这些醛可以通过列出的现有文献的方法被氧化成本发明的酸Ia,例如在R.C.Larock,《综合有机转化》使用,1989,VCH出版,838页以及下列等等。特别要举例的是在溶剂如丙酮中在25-60℃使用高锰酸钾。方案1
如果R1上有酯残基,则接着用酸和碱水解,得到二羧酸Id。此水解优选用在四氢呋喃/水混合物中的氢氧化锂、在室温下进行。
吡咯基羧酸I可以与胺或醇反应转变成衍生物Ib。在此情况下,酸基团COOH以适当的方式活化成COL,其中L是离去基团如叠氮基、咪唑或其它列于R.C.Larock,《综合有机转化》,1989,VCH出版,972页以及下列等等的基团。随后添加反应物HNR6R7或醇得到本发明的产物Ib。如果R1存在酯残基,可以用酸或碱用与上面类似的方法进行水解成羧酸,得到本发明衍生物Ic。
本发明的化合物是兴奋性氨基酸谷氨酸的拮抗剂,特别是NMDA受体、AMPA受体和红藻氨酸受体的甘氨酸结合位点的拮抗剂。
用从鼠大脑分离的膜物质研究化合物I的药学活性。为此目的,用本发明的化合物和结合特异性受体(AMPA、NMDA或红藻氨酸受体)的放射性标记物质3H-2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(3H-AMPA)、[3H]-甘氨酸或[3H]-红藻氨酸处理膜物质。然后用闪烁计数来测量被处理的膜的放射性。由结合的放射性检测结合的3H-AMPA、[3H]-甘氨酸或[3H]-红藻氨酸的量是可能的,或者在每种情况下,测定被置换的这些放射性标记物质的量。
得出的、作为本发明试剂置换作用的度量标准的解离常数KI(I=抑制剂)可以通过迭代非线性回归分析、用IBM计算机中的统计分析系统(SAS)计算。该系统类似于P.J.Munson和D.Rodbard的“配体(Ligand)”程序(分析生物化学.107(1980)220,配体:《确定配体结合体系的通用计算机方法》)。
下面进行了体外研究:
1. 3H-2-氨基-3-羟基-5-甲基-4-异噁唑丙酸(3H-AMPA)的结合
为了制备膜物质,用Ultra-TurraR将新摘除的鼠脑用与15倍体积的缓冲液A均浆化。缓冲液A由30mM三(羟甲基)甲胺盐酸盐(Tris-HCl)和0.5mM乙二胺四乙酸(EDTA)组成,pH7.4。此混悬液以48000g离心20分钟。移出上清液后,将沉积的含蛋白的膜物质悬浮在缓冲液A中洗涤三次并且每次都随后在48000g离心20分钟。然后将膜物质悬浮15倍体积的缓冲液A中并在37℃孵育30分钟。接着通过离心和悬浮将蛋白物质洗涤两次并保存与于-70℃直至使用。在结合实验中,在37℃将蛋白物质解冻并通过在48000g离心(20分钟)洗涤两次,然后在缓冲液B中制成悬浮液。缓冲液B由50mM Tris-HCl、0.1mM硫氰酸钾和2.5mM氯化钙组成,pH7.1。接着,将0.25mg膜物质、0.15μCi3H-AMPA(60Ci/mmol)和化合物I溶解于1ml缓冲液B中并用冰浴孵育60分钟。用CF/B过滤器(Whatman)过滤。过滤器先已用0.5%聚乙烯亚胺水溶液处理至少2小时。接着用5ml冷缓冲液B洗涤膜残余物,以便分离结合和游离的3H-AMPA。用闪烁计数检测膜物质中结合的3H-AMPA的放射活性后,通过位移曲线的回归分析测定KI。
7-(3-羧基-1-吡咯基)-1-(乙氧羰基甲基)-6-硝基喹喔啉-2,3(1H,4H)-二酮(实施例2)的KI<10μM。此物质比EP572852中实施例80的醛,即1-(乙氧羰基甲基)-7-(3-甲酰基-1-吡咯基)-6-硝基喹喔啉-2,3(1H,4H)-二酮明显更有活性。
2.[3H]-甘氨酸的结合
为了制备[3H]-甘氨酸结合实验的膜,将新摘除的鼠海马在10倍体积的制备缓冲液(50mM Tris-HCl,10mM EDTA)中用Potter均浆器均浆化。将均浆以48000g离心20分钟。弃去上清液,通过悬浮和以48000g离心(每次20分钟)两次洗涤小丸状的膜。用液氮冷冻再悬浮的膜并在37℃再解冻。再经洗涤步骤后,在摇动水浴,在37℃孵育膜悬浮液15分钟。再进行4个洗涤步骤(每次以48000g离心20分钟并在制备缓冲液中再悬浮)后,将膜保存于-70℃直至将来使用。
冷冻的膜在37℃解冻并通过以48000g离心20分钟,随后在结合缓冲液(50mM Tris-HCl pH7.4,10mM二氯化镁)中再悬浮洗涤2次。在总量为0.5ml结合缓冲液中,孵育混合物含有0.25mg蛋白(膜)、25nM[3H]-甘氨酸(16Ci/mmol)和被试物质。通过加入1mM甘氨酸,测定非特异性结合。
在4℃孵育60分钟后,用GF/B过滤器过滤并随后用约5ml冰冷的结合缓冲液洗涤,将结合和游离的配体彼此分离。用液体闪烁计数来测定过滤器上保留的放射活性。用迭代非线性回归程序或Cheng和Prusoff方程由位移曲线计算解离常数。
3.[3H]-红藻氨酸的结合
为了制备[3H]-红藻氨酸结合实验的膜,将新摘除的鼠脑在15倍体积的制备缓冲液(30mM Tris-Hcl pH7.4,0.5mM EDTA)中Ultra-TurraxR均浆器均浆化。将均浆以48000g离心20分钟。弃去上清液,通过在制备缓冲液中悬浮和以48000g离心(每次20分钟)3次洗涤小丸状的膜。第三次洗涤后,通过离心和再悬浮,两次洗涤膜并将膜保存于-70℃直至将来使用。
冷冻的膜在37℃解冻并在结合缓冲液(50mM Tris-HCl pH7.4)中悬浮并以48000g离心20分钟。将小丸状的膜再悬浮于结合缓冲液中。在总量为1ml结合缓冲液中,孵育混合物含有0.25mg蛋白(膜)、0.058μCi(58Ci/mmol)[3H]-红藻氨酸和被试物质。通过加入0.1mM谷氨酸测定非特异性结合。在冰浴中孵育60分钟后,用GF/B过滤器过滤并随后用约5ml冰冷的结合缓冲液洗涤,将结合和游离的配体彼此分离。CF/B过滤器先已用0.5%聚乙烯亚胺水溶液处理至少2小时。分析位移曲线,用非线性适用程序按照Cheng和Prusoff方程计算解离常数。
为了显示这些新物质的体内活性,可以使用下面实验结果:
抗惊厥作用
(对鼠进行最大电击)
通过最大电击诱发鼠后腿强直。用被试物质预处理,可以拮抗痉挛的出现。此镇痉作用是可能用作抗癫痫药的证据。
防止由兴奋性氨基酸引起的大脑过度兴奋
(体内NMDA或AMPA拮抗作用,鼠)
脑内注射兴奋性氨基酸(=EAA)引起巨大的过度兴奋,以至于产生了痉挛和短时间内动物死亡。可以通过系统使用(如腹膜内)中枢作用的EAA拮抗剂抑制这些症状。因为中枢神经系统中的EAA受体的过度兴奋在多种神经紊乱的病理中扮演重要角色,可以从检测到的体内EAA拮抗作用断言,此物质可以用来治疗这样的CNS紊乱。它们包括(特别是)病灶性的及普遍性的局部缺血、损伤、癫痫和多种神经变性紊乱如亨廷顿舞蹈病、帕金森病等。
本发明的化合物I适于用作人药及兽药,并可以用来制备治疗中枢神经系统的神经变性紊乱和神经毒性紊乱的药物,还可以制备抗癫痫药、抗焦虑药、抗抑郁药及抗感受伤害药。
本发明的药物制剂含有治疗有效量的化合物I及常规药物辅料。
对于局部外用,如粉状散剂和膏剂,此试剂可以按常规浓度存在。原则地讲,此试剂的含量为0.0001至1%(重量),优选0.001至0.1%(重量)。
对于内用,该制剂可以以单剂量的形式给药。在单剂量中,每公斤体重使用0.1至100mg。依疾病的特性和严重程度,每天可以一次或多次给药使用此制剂。
根据所需的给药形式,除此试剂外,本发明的药物制剂含有常规的赋形剂和稀释剂。局部外用的药物辅料有,例如,乙醇、异丙醇、乙氧基化的蓖麻油、乙氧基化的氢化蓖麻油、聚丙烯酸、聚乙二醇、聚乙二醇硬脂酸酯、乙氧基化脂肪醇、液体石蜡、凡士林和羊毛脂。适于内用的例子为乳糖、丙二醇、乙醇、淀粉、滑石和聚乙烯吡咯烷酮。
此外,还可存在抗氧剂如生育酚、丁基化羟基茴香醚及丁基化羟基甲苯,矫味剂,稳定剂,乳化剂及润滑剂。
根据具体情况,除此试剂外,存在于此制剂中的物质,及用于制备此药物制剂的物质为毒性可接受的、且与此试剂相容的物质。按照常规方法制备此药物制剂,例如通过将此试剂和常规赋形剂及稀释剂混合。
此药物制剂可以通过多种途径给药,如口服、非肠道、皮下、腹膜内及局部给药。于是,可能的形式有片剂、乳剂、输液及注射液、糊剂、膏剂、凝胶剂、霜剂、洗剂、粉状散剂和喷雾剂。
实施例实施例17-(3-羧基-1-吡咯基)-1-(乙氧羰基甲基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮
将5.0g(12.2mmol)l-(乙氧羰基甲基)-7-(3-甲酰基-1-吡咯基)-6-三氟甲基喹喔啉-2,3(1H,4H)-二酮(制备见EP572852,实施例70)和3.2g(12.2mmol)18-冠醚-6在150ml丙酮中回流。然后小批量加入7.7g(48.9mmol)高锰酸钾,并将混合物再加热沸腾30分钟。加入20ml水,然后将此混合物再加热沸腾30分钟。随后,抽滤掉沉淀并用四氢呋喃和甲醇的混合物彻底洗涤。减压浓缩合并的有机相。在碳酸氢钠水溶液和乙酸乙酯之间萃取此残余物。然后用盐酸酸化水相,抽滤出所得的沉淀。得到3.1(60%)产品。熔点:>250℃。
1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),5.0(2H),6.6(1H),
6.9(1H),7.6(1H),7.7(1H),12.1(1H)及12.5(1H)ppm.
本发明的下列实施例按照实施例l的方法,由相应的醛(合成见EP572852)制备。实施例27-(3-羧基-1-吡咯基)-1-(乙氧羰基甲基)-6-硝基喹喔啉-2,3-(1H,4H)-二酮
产率:71%,熔点:>300℃。
1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),5.0(2H),6.6(1H),
7.0(1H),7.6(1H),7.7(1H),7.9(1H),12.2(宽)及12.6
(1H)ppm.实施例39-(3-羧基-1-吡咯基)-1-(乙氧羰基甲基)苯并[f]喹喔啉-2,3-(1H,4H)-二酮
产率:27%,熔点:292-295℃。1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),5.1(2H),6.7(1H),7.1(1H),7.4-7.9(4H),8.8(1H)12.2(1H)及12.5(1H)ppm.实施例47-(3-羧基-1-吡咯基)-1-环己基-6-硝基喹喔啉-2,3-(1H,4H)-二酮
产率:35%,熔点:230℃(分解)。1H-NMR(D6-DMSO):δ=1.2-2.0(8H),2.4(2H),4.5(1H),6.6(1H),7.0(1H),7.6(1H),7.8(1H),7.9(1H),12.2(1H)及12.5(1H)ppm.实施例57-(3-(苄基氨基甲酰基)-1-吡咯基)-1-环己基-6-硝基喹喔啉-2,3-(1H,4H)-二酮,
将1.65g(4.1mmol)实施例4的产物和0.53g(5mmol)苄胺溶解在无水二甲基甲酰胺中。在0℃,滴加1.4g二苯基磷酰叠氮化物的10ml无水二甲基甲酰胺溶液。约15分钟后,滴加0.84g(8.3mmol)三乙胺,混合物在0℃搅拌约5小时。然后将此混合物在室温搅拌16小时。然后减压浓缩此反应混合物。将残余物在乙酸乙酯和碳酸氢钠溶液之间萃取,分离有机相,干燥并减压浓缩。产率:1.3g(64%),熔点:210℃(分解)。1H-NMR(D6-DMSO):δ=1.4-2.0(8H),2.4(2H),4.5(2H),6.7(1H),7.0(1H),7.1-7.4(5H),7.6(1H),7.8(1H),7.9(1H),8.5(1H)及12.2(宽)ppm.
按照实施例5的方法由相应的羧酸(实施例1-4)制备本发明的下列化合物:实施例67-(3-(4-苄基-1-哌嗪基羰基)-1-吡咯基)-1-乙氧羰基甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮,产率:0.6g(90%)1H-NMR(D6-DMSO):δ=1.2(3H),2.4(4H),3.5(2H),3.6(4H),4.2(2H),5.0(2H),6.4(1H),6.9(1H),7.2-7.4(6H),6.6(1H),6.65(1H)及ca.12(宽)ppm.实施例77-(3-苄基氨基甲酰基-1-吡咯基)-1-乙氧羰基甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮,产率:0.7g(70%)1H-NMR(D6-DMSO):δ=1.2(3H),4.1(2H),4.4(2H),5.0(2H),6.7(1H),6.9(1H),7.2-7.4(5H),7.5(1H),7.65(1H),7.7(1H),8.5(1H)及12.5(1H)ppm.实施例87-(3-苄基氨基甲酰基-1-吡咯基)-1-乙氧羰基甲基-6-硝基喹喔啉-2,3-(1H,4H)-二酮,产率:64%,熔点:223℃(分解)。1H-NMR(D6-DMSO):δ=1.2(3H),4.1(2H),4.2(2H),5.1(2H),6.5(1H),6.7(1H),6.9(1H),7.1-7.7(6H),7.8(1H),8.0(1H)及8.5(1H)ppm.实施例91-乙氧羰基甲基-6-硝基-7-(3-(4-(2-苯乙基)-1-哌嗪基羰基)-1-吡咯基)喹喔啉-2,3-(1H,4H)-二酮产率:58%,熔点:>160℃(分解)。1H-NMR(D6-DMSO):δ=1.2(3H),2.6(2H),2.8(2H),3.2-3.6(8H),4.2(2H),5.1(2H),6.4(1H),6.9(1H),7.1-7.4(6H),7.6(1H)及7.9(1H)ppm.实施例101-乙氧羰基甲基-6-硝基-7-(3-(3-苯丙基氨基甲酰基)-1-吡咯基)喹喔啉-2,3-(1H,4H)-二酮产率:69%,熔点:224℃(分解)。1H-NMR(D6-DMSO):δ=1.2(3H),1.8(2H),2.6(2H),3.2(2H),4.1(2H),5.0(2H),6.7(1H),6.9(1H),7.1-7.4(5H),7.5(1H),7.6(1H),7.9(1H),7.95(1H)及11.8(宽)ppm.实施例111-乙氧羰基甲基-6-硝基-7-(3-(4-吡啶甲基氨基甲酰基)-1-吡咯基)喹喔啉-2,3-(1H,4H)-二酮产率:71%,熔点:>300℃。1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),4.4(2H),5.0(2H),6.7(1H),6.9(1H),7.2-7.5(4H),7.6(1H),8.5(2H)及8.6(1H)ppm.实施例121-乙氧羰基甲基-6-硝基-7-(3-(4-硝基苄基氨基甲酰基)-1-吡咯基)喹喔啉-2,3-(1H,4H)-二酮产率:31%,熔点:>300℃。1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),4.6(2H),5.1(2H),6.7(1H),7.0(1H),7.4-7.6(3H),7.7(1H),7.9(1H),8.2(2H),8.7(1H)及12.5(宽)ppm.实施例137-(3-氨基甲酰基-1-吡咯基)-1-乙氧羰基甲基-6-硝基喹喔啉-2,3-(1H,4H)-二酮,产率:80%,熔点:>300℃。1H-NMR(D6-DMSO):δ=1.2(3H),4.2(2H),5.1(2H),6.6(1H),6.9(1H),6.95(1H),7.4(1H),7.5(1H),7.7(1H),7.9(1H)及12.5(1H)ppm.实施例141-羧甲基-7-(3-羧基-1-吡咯基)-6-硝基喹喔啉-2,3-(1H,4H)-二酮
将1.5g(3.8mmol)实施例2的产物溶解于20ml四氢呋喃中,加入0.27g(11.3mmol)氢氧化锂的25ml水溶液。室温将此混合物搅拌1小时。然后减压除去有机溶剂,用盐酸将所得水相微酸化。抽滤出所得沉淀并用少量异丙醇重结晶。产率:0.5g(86%),熔点:>300℃(分解)。1H-NMR(D6-DMSO):δ=5.0(2H),6.6(1H),7.0(1H),7.6(1H),7.7(1H),8.0(1H)及12.5(宽)ppm.
按照实施例14的方法,由适当的羧酸酯制备下列化合物:实施例151-羧甲基-7-(3-羧基-1-吡咯基)-6-苯并[f]喹喔啉-2,3-(1H,4H)-二酮产率:72%,熔点:>300℃。1H-NMR(D6-DMSO):δ=5.1(2H),6.7(1H),7.1(1H),7.3-7.9(5H),8.7(1H)及12.5(宽)ppm.实施例161-羧甲基-7-(3-羧基-1-吡咯基)-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮,产率:36%,熔点:>170℃(分解)。1H-NMR(D6-DMSO):δ=4.9(2H),6.6(1H),6.9(1H),7.5(1H),7.6581H),7.7(1H),ca.12.3(宽)及12.5(1H)ppm.实施例177-(3-(4-苄基-1-哌嗪基羰基)-1-吡咯基)-1-羧甲基-6-硝基-喹喔啉-2,3-(1H,4H)-二酮产率:90%,熔点:>230℃(分解)。1H-NMR(D6-DMSO):δ=2.4(4H),3.4-3.7(6H),4.9(2H),6.4(1H),6.9(1H),7.2(1H),7.2-7.4(5H),7.6(1H),7.65(1H)及12.5(宽)ppm.实施例187-(3-苄基氨基甲酰基-1-吡咯基)-1-羧甲基-6-三氟甲基喹喔啉-2,3-(1H,4H)-二酮产率:70%,熔点:>200℃(分解)。1H-NMR(D6-DMSO):δ=4.6(2H),5.1(2H),6.75(1H),6.9(1H),7.2-7.4(5H),7.5(1H),7.7(1H)及7.8(1H)ppm.实施例197-(3-苄基氨基甲酰基-1-吡咯基)-1-羧甲基-6-硝基喹喔啉-2,3-(1H,4H)-二酮产率:52%,熔点:>200℃(分解)。1H-NMR(D6-DMSO):δ=4.4(2H),5.0(2H),6.7(1H),7.0(1H),7.2-7.4(5H),7.5(1H),7.7(1H),7.9(1H),8.5(1H)及ca.12.5(宽)ppm.实施例201-羧甲基-6-硝基-7-(3-(4-(2-苯乙基)-1-哌嗪基羰基)-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮产率:76%,熔点:>250℃(分解)。1H-NMR(D6-DMSO):δ=2.6(4H),2.7(2H),2.8(2H),3.7(4H),4.9(2H),6.4(1H),6.9(1H),7.1-7.4(6H),7.6(1H),8.0(1H)及12.5(宽)ppm.实施例211-羧甲基-6-硝基-7-(3-(3-苯丙基氨基甲酰基)-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮产率:89%,熔点:224-227℃(分解)。1H-NMR(D6-DMsO):δ=1.8(2H),2.6(2H),3.2(2H),5.0(2H),6.7(1H),6.9(1H),7.1-7.4(5H),7.5(1H),7.7(1H),7.9(1H),8.0(1H)及12.5(宽)ppm.实施例221-羧甲基-6-硝基-7-(3-(4-吡啶甲基氨基甲酰基)-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮产率:64%,熔点:>300℃。1H-NMR(D6-DMSO):δ=4.5(2H),5.0(2H),6.7(1H),7.0(1H),7.4(2H),7.5(1H),7.6(1H),7.9(1H),8.6(2H),8.7(1H)及12.5(宽)ppm.实施例237-(3-氨基甲酰基-1-吡咯基)-1-羧甲基-6-硝基喹喔啉-2,3-(1H,4H)-二酮产率:50%,熔点:>300℃。1H-NMR(D6-DMSO):δ=5.0(2H),6.7(1H),6.9(1),6.95(1H),7.5(1H),7.7(1H),7.9(1H)及12.6(宽)ppm.实施例241-羧甲基-6-硝基-7-(3-(4-硝基苄基氨基甲酰基)-1-吡咯基)-喹喔啉-2,3-(1H,4H)-二酮产率:89%,熔点:>210℃(分解)。1H-NMR(D6-DMSO):δ=3.7 and 3.9(2H),4.7及4.8(2H),7.1(1H),7.5(2H),7.8-8.2(6H)及5.5(1H)ppm.
Claims (6)
1.式I的吡咯基四氢喹喔啉二酮及其互变异构体和同分异构体,及其生理可接受的盐:其中各符号的意义如下:R1是-氢、环己基,-含1至4个碳原子的脂族基团并可带有基团-COOR5,其中R5是氢或C1-C4烷基,优选-(CH2)m-COOR5,其中m=1-4,特别优选-CH2COOH,R2是-COOH,-COO-C1-C4,烷基,-COO-(CH2)m-Ph,-CONR6R7或
,其中m可以是1至6的整数,R6可以是氢、C1-C4烷基或OH而R7可以是氢、C1-C4烷基,-(CH2)m-Ph或
,其中所有在R2中含有的苯基或吡啶环也可以被不多于三个的如下取代基取代:C1-C4烷基,卤素,-O-C1-C4烷基,-OCF3,NO2,CN,-COOR5或-CONHR5,R3是-CF3,NO2,CN,且R4是-氢,且R3和R4-可以一起为一个稠合的苯环。
4.用于治疗疾病的、按权利要求1至3中任一项所述的式I的吡咯基四氢喹喔啉二酮。
5.吡咯基四氢喹喔啉二酮的应用,用于制备治疗表现有中枢神经系统的谷氨酸活性增加的紊乱的药物。
6.权利要求1至3任一项所述的式I的吡咯基四氢喹喔啉二酮的应用,用于制备治疗中枢神经系统的神经变性紊乱、氧和/或营养素缺乏造成的脑神经系统紊乱及制备抗癫痫药、抗焦虑药、抗抑郁药、肌松药和抗伤害感受药物。
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CN (1) | CN1092192C (zh) |
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DE4217952A1 (de) * | 1992-05-30 | 1993-12-02 | Basf Ag | Chinoxalin-2,3(1H,4H)-dione |
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US6407109B1 (en) | 2002-06-18 |
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