CN1726213A - 作为腺苷a3受体配体的咪唑并喹啉衍生物 - Google Patents
作为腺苷a3受体配体的咪唑并喹啉衍生物 Download PDFInfo
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- CN1726213A CN1726213A CNA2003801062293A CN200380106229A CN1726213A CN 1726213 A CN1726213 A CN 1726213A CN A2003801062293 A CNA2003801062293 A CN A2003801062293A CN 200380106229 A CN200380106229 A CN 200380106229A CN 1726213 A CN1726213 A CN 1726213A
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了通式(I)的化合物,其中X、Z、R1-R10、m、n、o、p、r如说明书中所述,其为强力的腺苷A3受体配体、优选为拮抗剂。
Description
本发明涉及通式(I)的腺苷A3受体配体,
其中优选拮抗剂,还涉及它们的盐、溶剂合物和异构体、含有它们的药物组合物、通式(I)化合物及其盐、溶剂合物和异构体的用途以及通式(I)化合物及其盐、溶剂合物和异构体的制备。
腺苷是几种内源分子(ATP、NAD+、核苷酸)的熟知成分。此外,它在许多生理过程中均起着重要的调节作用。在1929年就已经发现腺苷对心脏功能的作用(Drury和Szentgyorgyi,J Physiol 68:213,1929)。越来越多由腺苷介导的生理功能的确定和新腺苷受体亚型的发现使得特异性配体的治疗应用成为可能(Poulse,S.A.和Quinn,R.J.Bioorganic and MedicinalChemistry 6:619,1998)。
迄今为止,腺苷受体主要分为三种类型:A1、A2和A3。A1亚型通过与Gi膜蛋白偶联而部分担负抑制腺苷酸环化酶的作用,并影响其它第二信使系统。A2受体亚型可刺激腺苷酸环化酶活性,可进一步再分为2种亚型A2a和A2b。最近已从大鼠睾丸cDNA文库中鉴定了腺苷A3受体序列。随后证明该序列与一个新的功能性腺苷受体相对应。A3受体的活化还与几种第二信使系统相关联:即抑制腺苷酸环化酶和激活磷酸酯酶C和D。
腺苷受体存在于几种器官中并调节其功能。A1和A2a受体均在中枢神经系统和心血管系统中起重要作用。在CNS中,腺苷可抑制突触递质的释放,该作用由A1受体介导。在心脏中也是由A1受体介导腺苷的负性肌力作用、变时作用和变传导作用。腺苷A2a受体以较高量存在于纹状体中,它在调节突触传递作用中显示出与多巴胺受体的功能性相互作用。内皮细胞和平滑肌细胞上的腺苷A2a受体担负腺苷诱导的血管舒张作用。
基于mRNA鉴定,A2b腺苷受体广泛分布于不同组织中。其已被鉴定存在于几乎每种细胞类型中,但其在肠和膀胱中的表达最高。这种亚型可能在血管紧张度调节中也具有重要的调节功能并且在肥大细胞功能中发挥一定的作用。
与在蛋白质水平检测A1和A2a受体的组织分布正好相反,A2b和A3受体的存在基于它们的mRNA水平进行检测。与其他亚型相比,腺苷A3受体的表达水平相当低并且具有高度物种依赖性。腺苷A3受体主要表达于中枢神经系统、睾丸和免疫系统中,它似乎与速发型超敏反应中调节肥大细胞释放介质有关。
目前文献中公开的A3拮抗剂属于黄酮类化合物、1,4-二氢吡啶衍生物、三唑并喹唑啉类、噻唑并萘啶类和噻唑并嘧啶类化合物。本发明涉及一种有效的具有氨基喹啉结构的新型A3拮抗剂。
为用于治疗,有必要确保该分子不与腺苷受体的A1、A2a和A2b亚型结合或者仅在很高浓度的情况下才与之结合。我们目前的发明涉及通式(I)化合物及其盐、溶剂合物和异构体,它们对A3亚型腺苷受体具有很高的选择性。
我们的目的是制备A3配体、其中优选拮抗剂,首先它们具有喹啉结构,对A3受体产生强拮抗作用和高选择性,即它们以其抑制A1、A2a和A2b受体时低得多的浓度抑制A3受体。进一步的目的是获得稳定性、生物利用度、治疗指数和毒性数据,以使这些新化合物能够研发成为药品,同时使这些新化合物具有良好的肠道吸收性质以口服应用。
我们已发现:通式(I)化合物及其盐、溶剂合物和异构体及其盐和溶剂合物满足以上标准,
其中:
R1代表氢原子或直链或支链C1-4烷基;
R2代表氢原子或直链或支链C1-4烷基;
R3代表氢原子,或直链或支链C1-4烷基、C3-6环烷基、苯基、噻吩基或呋喃基,可选被一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基或卤素原子取代;含有一个、二个或三个氮原子的六或五元杂芳环,或者含有一个氮原子和一个氧原子或一个氮原子和一个硫原子的五元杂芳环,可选被一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基或卤素原子取代;
R4、R5、R6和R7独立地代表氢原子、直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子,或者R4和R7代表氢原子并且R5和R6一同形成亚甲二氧基;
R8代表氢原子或氰基、氨羰基、C1-4烷氧羰基或羧基;
R9和R10独立地代表氢原子、直链或支链C1-4烷基、C3-6环烷基;
X代表-CH2-基、-NH-基、-NR11-基或硫原子、氧原子、磺基或亚硫酰基,其中R11代表直链或支链C1-4烷基或C3-6环烷基;
Z指氧原子、硫原子、-NH-基或-NR12-基,其中R12代表直链或支链C1-4烷基或C3-6环烷基;
m代表0、1、2或3;
n代表0、1或2;
0代表0、1、2或3;
p代表0或1;
r代表0或1,条件是至少m和o之一不为0。
以上列出取代基的详细意义如下::
直链或支链C1-4烷基指甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,优选乙基或甲基。
直链或支链C1-4烷氧基指甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基,优选乙氧基和甲氧基。
C3-6环烷基指环丙基、环丁基、环戊基或环己基。
含有一个或二个或三个氮原子的杂芳环指吡咯、咪唑、吡唑、1,2,3-三唑、1,2,4-三唑、吡啶、嘧啶、哒嗪、吡嗪和1,3,4-三嗪环。该环可选被C1-4烷基或烷氧基或卤素原子取代。
含有一个氮原子和一个氧原子或硫原子的杂芳环指噁唑、异噁唑、噻唑、异噻唑环。该环可选被C1-4烷基或烷氧基或卤素原子取代。
-(CH2)m-Z-(CH2)o-基与氮原子一同形成氧杂氮杂环丙烷子基(oxaziridino-)、二氮杂环丙烷子基(diaziridino-)、1,2-二氮杂环丁烷基、1,3-二氮杂环丁烷基、异噁唑烷基、噁唑烷基、咪唑烷基、吡唑烷基、噻唑烷基、吗啉代、哌嗪子基或4-甲基-哌嗪子基,可选被C1-4烷基或C3-6环烷基取代。
通式(I)化合物的盐指与无机酸和有机酸和碱形成的盐。优选的盐是那些与可药用酸例如盐酸、硫酸、乙烷磺酸、酒石酸、琥珀酸、苹果酸、柠檬酸,以及与可药用碱例如氢氧化钠、氢氧化钾、乙醇胺形成的盐。
溶剂合物指与各种溶剂例如与水或乙醇形成的溶剂合物。
通式(I)化合物显示几何和光学异构现象,因此本发明也涉及几何异构体的混合物、外消旋体或光学活性的几何异构体、以及它们的盐和溶剂合物。
优选的一组化合物是那些通式(I)化合物及其盐、溶剂合物,以及光学活性异构体及其盐和溶剂合物,
其中:
R1代表氢原子或直链或支链C1-4烷基;
R2代表氢原子或直链或支链C1-4烷基;
R3代表氢原子,或直链或支链C1-4烷基、C3-6环烷基、苯基、噻吩基或呋喃基,可选被一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基或卤素原子取代;
R4、R5、R6和R7独立地代表氢原子、直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子,或者R4和R7代表氢原子并且R5和R6一同形成亚甲二氧基;
R8 代表氢原子或氰基、氨羰基、C1-4烷氧羰基或羧基;
R9和R10独立地代表氢原子、直链或支链C1-4烷基或C3-6环烷基;
X代表-CH2-基、-NH-基、-NR11-基或硫原子、氧原子、磺基或亚硫酰基,其中R11代表直链或支链C1-4烷基或C3-6环烷基;
Z代表氧原子、硫原子、-NH-基或-NR12-基,其中R12代表直链或支链G1-4烷基或C3-6环烷基;
m代表0、1、2或3;
n代表0、1或2;
o代表0、1、2或3;
p代表0或1;
r代表0或1,条件是至少m和o之一不为0。
更优选的一组化合物是那些通式(I)化合物及其盐、溶剂合物和异构体及其盐和溶剂合物,
其中:
R1代表氢原子或甲基;
R2代表氢原子或甲基;
R3代表苯基、噻吩基或呋喃基;
R4、R5、R6和R7独立地代表氢原子、直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子,或者
R4和R7代表氢原子并且R5和R6一同形成亚甲二氧基;
R8代表氢原子或氰基;
R9和R10代表氢原子、甲基、乙基或环丙基;
X代表-NH-基或氧原子;
Z指氧原子、硫原子、-NH-基或-NR12-基,其中R12代表直链或支链C1-4烷基或C3-6环烷基;
m代表2;
n代表1;
o代表2;
p代表0;
r代表0。
特别优选的是满足以上标准的下列化合物及其盐、溶剂合物和异构体及其盐和溶剂合物:
1-(9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪,
1-(9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉,
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪,
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-哌嗪,
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉,
1-(9-噻吩甲基-氨基-10-氰基-咪唑并11,2-a]喹啉-2-羰基)-吗啉,
1-(9-噻吩甲基-氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-哌嗪,
本发明还涉及含有通式(I)化合物或其异构体、盐和溶剂合物作为活性成分的药物组合物,其优选为口服组合物,但吸入、胃肠外和经皮施用制剂也是本发明的主题。上述药物组合物可以是固体或液体例如片剂、丸剂、胶囊剂、贴剂、溶液剂、混悬剂或乳剂。优选固体组合物、首先优选片剂和胶囊剂。
上述药物组合物通过使用常规药物辅料和标准方法制备。
通式(I)化合物可用于治疗A3受体在疾病的发展过程中起一定作用的病变。
对A3受体具有选择性活性的化合物可用于治疗性和/或预防性治疗心脏、肾脏、呼吸系统、中枢神经系统的功能障碍。它们可阻断腺苷对生长期肿瘤细胞的保护作用、防止肥大细胞脱粒、阻碍细胞因子的形成、降低眼内压、防止TNFα释放、阻碍嗜酸性粒细胞和嗜中性粒细胞和其他炎症细胞的迁移、防止气管收缩并防止血浆透过血管壁。
基于上述效应,腺苷A3受体拮抗剂在治疗上可以用作抗炎、止喘、抗局部缺血、抗抑郁、抗心律失常、肾功能保护、肿瘤预防、抗帕金森和认知功能激发药物。它们还可用于治疗或预防以下疾病:再灌注过程中的心肌损伤、慢性阻塞性肺病(COPD)、成人呼吸功能不全(ARDS)-包括慢性支气管炎、肺气肿或呼吸困难-、过敏反应(例如鼻炎、毒葛诱导反应、荨麻疹、硬皮病、关节炎)、其他自身免疫性疾病、炎性肠疾病、艾迪生病、局限性回肠炎、银屑病、关节病、张力过强、神经系统功能异常、青光眼和糖尿病(K.N.Klotz,Naunyn-Schmiedberg′s Arch.Pharmacol.362:382,2000;P.G.Baraldi es P.A.Borea,TiPS 21:456,2000)。
本发明的化合物可以有利地用于治疗功能障碍如哮喘、COPD和ARDS、青光眼、肿瘤、过敏性和炎性疾病、局部缺血、缺氧、心律不齐和肾脏疾病。
此外,本发明还涉及通式(I)化合物在治疗上述疾病中的用途。取决于疾病的性质和严重程度和患者性别、体重等,建议日剂量为0.1-1000mg活性成分。
本发明的另一个主题涉及通式(I)化合物的制备。
通式(II)、(III)、(IV)、(V)、(VI)、(VII)和(VIII)的中间产物的化学式中的取代基具有以上所定义的含义。
在根据本发明的方法中,通过应用有机化学中已知的酰化方法将通式(VIII)化合物
用通式(II)的酸或其活性衍生物酰化,
关于酰化剂,优选酰卤或混合酸酐。如需要,可将所得通式(I)化合物
转化为它的一种盐或溶剂合物,或者由其盐或溶剂合物中释放出来并且分离为其几何或光学异构体。
通式(I)化合物的取代基可通过已知方法互相转化。
用于酰化反应的混合酸酐可使用新戊酰氯制备,优选通过使用溶于氯仿的有机碱、优选使用三乙胺制备,但也可应用有机化学中已知的其他方法。酰化反应可在宽泛的温度范围内进行、优选0℃和100℃之间。
通式(II)的中间体
其中R1、R2、R3、R4、R5、R6、R7、R8、X和n的含义如以上所定义,可通过几种已知方法、例如方案1中所示的方法
从通式(III)的化合物开始、
应用有机化学中已知的水解方法获得。关于水解试剂可用碱金属氢氧化物,但也可应用其他促进酯类水解的化合物。
通式(III)的化合物
其中R1、R2、R3、R4、R5、R6、R7、R8、X和n的含义如上所定义,R13指C1-4烷基,
可由式(IV)化合物
通过本身已知的方法制备(I.R.Ager和R.Westwood,J.Med.Chem.31,1098,1988)。
通式(IV)的化合物
其中R1、R2、R3、R4、R5、R6、R7、R8、X和n的含义如上所定义,可由式(V)的化合物
通过本身已知的方法制备(Nan Zhang,Bioorg.and Med.Chem.Lett.,10,2825,2000)。
通式(V)的化合物
其中R4、R5、R6、R7和R8的含义如上所定义,可由式(VI)的化合物
通过本身已知的方法制备(D.L.Leysen,J.Heterocyclic Chem.,24,1611,1987)。
通式(VI)化合物
其中R4、R5、R6、R7和R8的含义如上所定义,可通过使用本身已知的方法制备(Pfizer(Inc)USP 4,175,193)。
通式(1)、(II)、(III)、(IV)和(V)的本发明化合物、它们的制备方法和生物活性通过下列实施例说明,但权利要求并不局限于这些实例。
实施例1
1-(9-苄基氨基-10-氰基-咪唑并[1,2-al喹啉-2-羰基)-4-甲基哌嗪:
通式(1)中,R1和R2代表氢原子、R3代表苯基、R4、R5、R6和R7代表氢原子、R8代表氰基、R12代表甲基、X指-NH-基、Z指氮原子、n值为1、m和o值为2、r和p值为0。
a.)2-氨基-3-氰基-4-氯喹啉:
在110℃、搅拌下加热1.0g 2-氨基-3-氰基-4-羟基喹啉和15ml磷酰氯的混合物。将反应混合物冷却,倾入100ml冰水中并用60ml 10%氢氧化钠溶液中和。将所得黄色沉淀滤出,用50ml水洗涤。干燥后得到7.5g标题化合物。mp:210℃。NMR,δH(400MHz,DMSO-d6):7.21ppm,(s,2H,NH2),7.35-7.40ppm,(dd,1H,6-H),7.53-7.57ppm,(d,1H,5-H),7.70-7.75ppm,(dd,1H,7-H),7.93-7.98ppm,(d,1H,8-H)。
b.)2-氨基-3-氰基-4-苄基氨基喹啉:
将5g 2-氨基-3-氰基-4-氯喹林和11ml苄基胺在130℃下搅拌。将反应混合物倾入50ml水中,将所得沉淀滤出、用50ml水洗涤。浅黄色沉淀自25ml二甲基甲酰胺中重结晶,获得5.2g标题化合物。Mp:206℃。NMR,δH(400MHz,DMSO-d6):5.02-5.03ppm,(d,2H,N-CH2),6.22ppm,(s,2H,NH2),7.14-7.16ppm,(dd,1H,6-H),7.24-7.26ppm,(dd,1H,5-H),7.30ppm,(s,5H,Ph),7.50-7.52ppm,(dd,1H,7-H),8.16-8.19ppm,(d,1H,8-H),8.30-8.33ppm,(t,1H,NH)。
使用2-氨基甲基吡啶或3-氨基甲基吡啶或4-氨基甲基吡啶代替苄基胺,可获得适当的通式(IV)的化合物。
c.)9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸乙酯一水合物:
在70℃、搅拌下,向2.74g 2-氨基-3-氰基-4-苄基氨基喹啉在100ml无水乙醇中的溶液中加入2.14g溴丙酮酸乙酯。将反应混合物回流加热2小时、滤出所得沉淀。将这些白色晶体自120ml乙腈中重结晶,获得1.1g标题化合物。mp:112-114℃。NMR,δH(400MHz,DMSO-d6):1.32ppm(t,3H,COOCH2CH3),4.30ppm(q,2H,COOCH2CH3),5.09ppm(d,2H,PhCH2),7.25-7.38ppm(m,5H),7.64-7.67ppm(m,1H),7.85-7.88ppm(m,1H),8.43-8.53ppm(m,3H),9.04ppm(s,1H,3-H)。
d.)9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸:
将2.71g 9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸乙酯一水合物、42ml乙醇和40ml 10%氢氧化钠的混合物在25℃下搅拌6小时。向该浓悬液中加入100ml水并用96%乙酸将混合物pH调至3。将浅黄色晶体滤出、用25ml水洗涤三次,干燥,获得2.3g标题化合物。mp:178-182℃。NMR,δH(200MHz,DMSO-d6):5.09ppm(d,2H,PhCH2),7.22-7.40ppm(m,5H),7.59-7.67ppm(m,1H),7.81-7.89ppm(m,1H),8.37-8.54ppm(m,3H),8.90ppm(s,1H,3-H).
e.)1-(9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪:
在5℃、搅拌下,于15分钟内向1.71g 9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和0.8ml三乙胺在15ml氯仿中的溶液中滴加0.6g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后向其中加入0.5g N-甲基哌嗪、10ml氯仿和0.8ml三乙胺的混合物。将混合物在25℃下搅拌7小时、用100ml氯仿稀释,连续用50ml水、50ml 5%的碳酸氢钠溶液和50ml水萃取,经硫酸钠干燥并真空浓缩。将浅黄色晶体物质自6mlN,N-二甲基甲酰胺中重结晶,获得0.6g标题化合物。mp:217℃。NMR,δH(400MHz,DMSO-d6):2.17ppm(s,3H),2.24ppm(m,4H),3.57ppm(m,2H),4.11ppm(m,2H),5.08ppm(d,2H,PhCH2),7.23-7.38ppm(m,5H),7.62-7.65ppm(m,1H),7.83-7.87ppm(m,1H),8.36-8.42ppm(m,2H),8.50-8.52ppm(m,1H),8.80ppm(s,1H,3-H)。
实施例2
1-(9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉:
在通式(1)中,R1和R2代表氢原子、R3代表苯基、R4、R5、R6和R7代表氢原子、R8代表氰基、X指-NH-基、Z指氧原子、n值为1、m和o值为2且r和p值为0。
在5℃、搅拌下,于15分钟内向1.71g 9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和0.8ml三乙胺在15ml氯仿中的混合物中加入0.6g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后加入0.45g吗啉、10ml氯仿和1.6ml三乙胺的混合物。将混合物在25℃下搅拌3小时,然后按照前一实施例中所述进行处理。将所得浅黄色晶体自10ml N,N-二甲基甲酰胺中重结晶,获得0.55g化合物。mp:279℃。NMR,δH(400MHz,DMSO-d6):3.6ppm(m,6H),4.2ppm(m,2H),5.08ppm(d,2H,PhCH2),7.23-7.38ppm(m,5H),7.62-7.65ppm(m,1H),7.84-7.87ppm(m,1H),8.37-8.39ppm(m,2H),8.50-8.53ppm(m,1H),8.75ppm(s,1H,3H)。
实施例3
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪:
在通式(1)中,R2和R2代表氢原子、R3代表2-呋喃基、R4、R5、R6和R7代表氢原子、R8代表氰基、R12代表甲基、X指-NH-基、Z指氮原子、n值为1、m和0值为2且r和p值为0。
a.)2-氨基-3-氰基-4-糠基氨基喹啉:
将10g 2-氨基-3-氰基-4-氯喹啉与19g糠基氨基在120℃下加热3小时。将反应混合物冷却至25℃并与50ml水混合6次。滤出晶体并干燥。所得产物自60ml N,N-二甲基甲酰胺中重结晶,获得5.8g标题化合物。mp:206℃。NMR,δH(200MHz,DMSO-d6):4.98ppm(d,2H,呋喃基-CH2),6.29ppm(s,2H),6.35-6.42ppm(m,2H),7.10-7.18ppm(m,1H),7.31-7.35ppm(m,1H),7.47-7.60ppm(m,2H),8.13-8.20ppm(m,2H)。
b.)9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸乙酯一水合物:
在70℃、搅拌下,向2.64g 2-氨基-3-氰基-4-糠基氨基喹啉在100ml无水乙醇中的溶液中加入2.14g溴丙酮酸乙酯。将反应混合物回流加热2小时,滤出沉淀的晶体,获得1.15g标题化合物。mp:242-245℃。NMR,δH(200MHz,DMSO-d6):1.33ppm(t,3H,COOCH2CH3),4.31ppm(q,2H,COOCH2CH3),5.05ppm(d,2H,呋喃基-CH2),6.40-6.43ppm(m,2H),7.58-7.66ppm(m,2H),7.80-7.88ppm(m,1H),8.31ppm(t,1H),8.41-8.45ppm(m,2H),9.04ppm(s,1H,3-H)。
c.)9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸:
将2.52g 9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸乙酯一水合物、40ml乙醇和33ml 10%氢氧化钠的混合物在25℃下搅拌3小时。向该浓悬液中加入80ml水,并用96%乙酸将混合物酸化至pH=3。滤出浅黄色晶体,用25ml水洗涤三次,干燥,获得2.32g标题化合物。mp:180-185℃。NMR,δH(200MHz,DMSO-d6):5.05ppm(d,2H,呋喃基-CH2),6.39-6.42ppm(m,2H),7.56-7.64ppm(m,2H),7.79-7.87ppm(m,1H),8.27ppm(t,1H),8.36-8.46ppm(m,2H),8.93ppm(s,1H,3-H)。
d.)1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪:
在5℃、搅拌下,于15分钟内向1.79g 9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和0.8ml三乙胺在15ml氯仿中的混合物中滴加0.6g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后向其中加入0.46g N-甲基哌嗪、10ml氯仿和0.8ml三乙胺的混合物。将混合物在25℃下搅拌3小时、用100ml氯仿稀释,连续用50ml水、50ml 5%碳酸氢钠溶液和50ml水萃取,经硫酸钠干燥,真空浓缩。将浅黄色晶体物质自50ml乙醇中重结晶,获得0.18g标题化合物。mp:237℃。NMR,δH(200MHz,DMSO-d6):2.17ppm(s,3H),2.24ppm(m,4H),3.57ppm(m,2H),4.11ppm(m,2H),5.05ppm(d,2H,呋喃基-CH2),6.40-6.44ppm(m,2H),7.57-7.65ppm(m,2H),7.80-7.88ppm(m,1H),8.23ppm(t,1H),8.39-8.46ppm(m,2H),8.81ppm(s,1H,3-H)。
实施例4
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-哌嗪:
在通式(1)中,R1和R2代表氢原子、R3代表2-呋喃基、R4、R5、R6和R7代表氢原子、R8代表氰基、X指-NH-基、Z指-NH-基、n值为1、m和o值为2且r和p值为0。
在5℃、搅拌下,于15分钟内向1.79g如实施例3中所述获得的9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和0.8ml三乙胺在15ml氯仿中的混合物中滴入0.6g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后向其中加入0.46g哌嗪、10ml氯仿和0.8ml三乙胺的混合物。将混合物在25℃下搅拌3小时、用100ml氯仿稀释,连续用50ml水、50ml 5%碳酸氢钠溶液和50ml水萃取,经硫酸钠干燥并真空浓缩。将浅黄色晶体物质自50ml乙醇中重结晶,获得0.14g标题化合物。mp:239℃。NMR,δH(200MHz,DMSO-d6):2.7ppm(m,4H),3.5ppm(m,2H),4.05ppm(m,2H),5.05ppm(d,2H,呋喃基-CH2),6.40-6.44ppm(m,2H),7.57-7.65ppm(m,2H),7.80-7.88ppm(m,1H),8.23ppm(t,1H),8.39-8.46ppm(m,2H),8.81ppm(s,1H,3-H)。
实施例5
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉:
在通式(1)中,R1和R2代表氢原子、R3代表2-呋喃基、R4、R5、R6和R7代表氢原子、R8代表氰基、X指-NH-基、Z指氧原子、n值为1、m和o值为2且r和p值为0。
在5℃、搅拌下,于15分钟内向1.79g如实施例3中所述获得的9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和0.8ml三乙胺在15ml氯仿中的混合物中滴加0.6g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后向其中加入0.66g吗啉、10ml氯仿和0.8ml三乙胺的混合物。将混合物在25℃下搅拌3小时、用100ml氯仿稀释,连续用50ml水、50ml5%碳酸氢钠溶液和50ml水萃取,经硫酸钠干燥并真空浓缩。将浅黄色晶体物质在50ml乙醇中重结晶,获得0.18g标题化合物。mp:267℃。NMR,δH(200MHz,DMSO-d6):3.6ppm(m,6H),4.2ppm(m,2H),5.05ppm(d,2H,呋喃基-CH2),6.40-6.44ppm(m,2H),7.57-7.65ppm(m,2H),7.80-7.88ppm(m,1H),8.23ppm(t,1H),8.39-8.46ppm(m,2H),8.81ppm(s,1H,3-H)。
实施例6
1-(9-噻吩甲基-氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉:
在通式(1)中,R1和R2代表氢原子、R3代表2-噻吩基、R4、R5、R6和R7代表氢原子、R8代表氰基、X指-NH-基、Z指氧原子、n值为1、m和o值为2且r和p值为0。
a.)2-氧基-3-氰基-4-噻吩甲基氨基喹啉:
将10g 2-氨基-3-氰基-4-氯喹啉与19g噻吩甲基胺在115℃下加热4小时。将反应混合物冷却至25℃并与50ml水混合6次。滤出晶体并用50ml水洗涤2次后干燥。所得产物自60ml N,N-二甲基甲酰胺中重结晶,获得6.8g浅黄色标题化合物。mp:208-209℃。NMR,δH(200MHz,DMSO-d6):5.18ppm(d,2H,噻吩基-CH2),6.28ppm(s,2H),6.96-7.00ppm(m,1H),7.07-7.19ppm(m,2H),7.31-7.42ppm(m,2H),7.48-7.56ppm(m,1H),8.09-8.13ppm(m,1H),8.30ppm(t,1H)。
b.)9-噻吩甲基-氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸乙酯:
在70℃、搅拌下,向5.61g 2-氨基-3-氰基-4-噻吩甲基氨基喹啉在200ml无水乙醇中的溶液中加入4.29g溴丙酮酸乙酯。将反应混合物回流加热2小时,滤出沉淀的晶体,获得2.54g标题化合物。mp:255-256℃。NMR,δH(200MHz,DMSO-d6):1.33ppm(t,3H,COOCH2CH3),4.31ppm(q,2H,COOCH2CH3),5.24ppm(d,2H,噻吩基-CH2),6.96-7.00ppm(m,1H),7.14ppm(m,1H),7.40-7.43ppm(m,1H),7.61-7.68ppm(m,1H),7.82-7.90ppm(m,1H),8.42-8.46ppm(m,3H),9.05ppm(s,1H,3-H)。
c.)9-噻吩甲基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸:
将2.54g 9-噻吩甲基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸乙酯、40ml乙醇和33ml 10%氢氧化钠的混合物在25℃下搅拌6小时。向该浓悬液中加入80ml水并用96%乙酸将混合物酸化至pH=3。滤出浅黄色晶体,用10ml水洗涤5次并干燥,获得2.18g标题化合物。mp:209-217℃分解。NMR,δH(400MHz,DMSO-d6):5.24ppm(d,2H,噻吩基-CH2),8,88ppm(s,1H,3-H)。
d.)1-(9-噻吩甲基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉:
在5℃、搅拌下,于15分钟内向1.80g 9-噻吩甲基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和1.1ml三乙胺在10ml氯仿中的混合物中滴加0.87g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后向其中加入0.61g吗啉、10ml氯仿和1.1ml三乙胺的混合物。将混合物在25℃下搅拌3小时、用100ml氯仿稀释,连续用50ml水、50ml 5%的碳酸氢钠溶液和50ml水萃取,经硫酸钠干燥并真空浓缩。将黄色晶体物质自200ml乙醇中重结晶,获得0.19g标题化合物。mp:315℃。NMR,δH(400MHz,DMSO-d6):3.6ppm(m,6H),4.2ppm(m,2H),5.24ppm(d,2H,噻吩基-CH2),6.97-7.00ppm(m,1H),7.14ppm(m,1H),7.41ppm(m,1H),7.61-7.65ppm(m,1H),7.83-7.87ppm(m,1H),8.37-8.45ppm(m,3H),8.82ppm(s,1H,3-H)。
实施例7
1-(9-噻吩甲基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-哌嗪:
在通式(1)中,R1和R2代表氢原子、R3代表2-噻吩基、R4、R5、R6和R7代表氢原子、R8代表氰基、X指-NH-基、Z指-NH-基、n值为1、m和0值为2且r和p值为0。
在5℃、搅拌下,于15分钟内向1.80g如实施例6中所述获得的9-噻吩甲基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-甲酸和1.1ml三乙胺在10ml氯仿中的混合物中滴加0.87g新戊酰氯在10ml氯仿中的溶液。将反应混合物在5℃下搅拌1小时,然后向其中加入0.61g哌嗪、10ml氯仿和1.1ml三乙胺的混合物。将混合物在25℃下搅拌3小时、用100ml氯仿稀释,连续用50ml水、50ml 5%碳酸氢钠溶液和50ml水萃取,经硫酸钠干燥并真空浓缩。将浅黄色晶体物质自50ml乙醇中重结晶,获得0.19g标题化合物。mp:269℃。NMR,δH(400MHz,DMSO-d6):2.7ppm(m,4H),3.5ppm(m,2H),4.05ppm(m,2H),5.24ppm(d,2H,噻吩基-CH2),6.97-7.00ppm(m,1H),7.14ppm(m,1H),7.41ppm(m,1H),7.61-7.65ppm(m,1H),7.83-7.87ppm(m,1H),8.37-8.45ppm(m,3H),8.82ppm(s,1H,3-H)。
根据实施例1制备的式(III)化合物的结构和物理参数如表1所示。
表1
根据实施例1制备的式(IV)化合物的结构和物理参数如表II所示。
表2
根据实施例1制备的式(V)化合物的结构和物理参数如表3所示。
表3
No: | R4 | R5 | R6 | R7 | Mp[℃] |
42. | H | OH | H | H | 360 |
43. | H | Cl | H | H | 250 |
44. | H | H | Cl | H | 278 |
45. | H | Me | H | H | 283 |
46. | H | OMe | H | H | 360 |
47. | H | H | H | OMe | 234 |
48. | Me | H | H | H | 246 |
49. | H | H | H | Me | 267 |
50. | H | I | H | H | 293 |
实施例51
由已知方法制备具有下列组成的片剂:
活性成分 25mg
乳糖 50mg
微晶纤维素(Avicel) 21mg
交联聚维 3mg
硬脂酸镁 1mg
生物学
方法
人腺苷A3受体结合
制备膜悬液:将表达人A3受体的克隆金仓鼠卵巢细胞(以下称为CHO-hA3)适当地培养和传代。获得铺满的细胞层后,通过用37℃PBS洗涤细胞将培养液除去,然后将细胞混悬于冰冷的PBS中、离心(1000xg 10perc)(Sigma 3K30)并使用Teflon匀化器(B.Braun Potter S)以1500/分钟旋转速度在下列缓冲液中均化15秒:50mM Tris、10mM MgCl2、1mM EDTApH 8.0。将匀浆离心(43,000g,10分钟)。将沉淀悬浮于上述缓冲液中,使蛋白质浓度为0.1mg/ml(Bradford法)。膜制备物的等分试样储存于-80℃。
结合实验方案:为定义供试化合物的非特异性结合,在0.5nM[125I]AB-MECA(对-氨基-3-碘-苄基-5′-N-甲基甲酰氨基-腺苷)(100,000cpm)和100μM R-PIA(N6-[L-2-苯基异丙基]-腺苷)存在下,将CHO-hA3膜制备物(蛋白质含量2μg)在室温下于培养缓冲液(50mM Tris、10mM MgCl2、1mM EDTA、3U/mL腺苷脱氨酶(pH 8.0)中培养1小时,总体积为50μL。用Whatman GF/B玻璃纤维滤纸(在0.5%聚乙烯亚胺中预浸渍3小时)过滤,在96孔Brandel细胞收集器中用1mL冰冷的50mMTris、10mM MgCl2、1mM EDTA(pH 8.0)洗涤4次。
活性检测:在γ计数器(1470 Wizard,Wallac)中进行。抑制[%]=100-((供试化合物存在下的活性-非特异活性)/(总活性-非特异活性))×100。
人腺苷A1受体结合实验
制备膜悬液:将表达人A1受体的克隆金仓鼠卵巢细胞(以下称为CHO-hA1)适当地培养和传代。获得连生细胞层后,通过用37℃PBS洗涤细胞将培养液移去、然后将细胞混悬于冰冷的PBS中、离心(1000xg 10perc)(Sigma 3K30)并使用Teflon匀化器(B.Braun Potter S)以1500/分钟旋转速度在下列缓冲液中均化15秒:50mM Tris、10mM HCl pH 7.4。将匀浆离心(43,000g,10分钟)。将沉淀悬浮于上述缓冲液中,使蛋白质浓度为5mg/ml(Bradford法)。将膜制备物的等分试样储存于-80℃。
结合实验方案:为定义供试化合物的非特异性结合,将CHO-hA1膜制备物(蛋白质含量50μg)在室温下于培养缓冲液(50mM Tris、3U/mL腺苷脱氨酶pH 7.4)、10nM[3H]CCPA(2-氯-N6-环戊基-腺苷)(80,000dpm)和100μM R-PIA(N6-[L-2-苯基异丙基]-腺苷)中培养3小时,总体积为100μL。用Whatman GF/B玻璃纤维滤纸(在0.5%聚乙烯亚胺中预浸渍3小时)过滤,在96孔Brandel细胞收集器中用1mL冰冷的50mM Tris(pH 7.4)洗涤4次。
活性检测:在200μL HiSafe-3合剂存在下于γ计数器(1450 Microbeta,Wallac)中进行。抑制[%]=100-((供试化合物存在下的活性-非特异活性)/(总活性-非特异活性))×100。
人腺苷A2a受体结合
结合实验方案:为定义供试化合物的非特异性结合,将7μg膜(转染入HEK-293细胞的人A2a腺苷受体,来源:Receptor Biology,Inc.)、缓冲液(50mM Tris-HCl、10mM MgCl2、1mM EDTA、2U/mL腺苷脱氨酶pH7.4)、20nM[3H]CGS-21680(2-[对-(2-羰基乙基)-苯基乙基氨基]-5′-N-乙基甲酰氨基-腺苷)(200.000dpm)和50μM NECA(5′-N-乙基甲酰氨基-腺苷)在室温下培养90分钟,总体积为100μL。用Whatman GF/B玻璃纤维滤纸(在0.5%聚乙烯亚胺中预浸渍3小时)过滤,在96孔Brandel细胞收集器中用1mL冰冷的50mM Tris、10mM MgCl2、1mM EDTA、0.9%NaCl(pH 7.4)洗涤4次。
活性检测:在200μL HiSafe-3合剂存在下于β计数器(1450 Microbeta,Wallac)中进行。抑制[%]=100-((供试化合物存在下的活性-非特异活性)/(总活性-非特异活性))×100。
人腺苷A2b受体结合
结合实验方案:为定义供试化合物的非特异性结合,将20.8μg膜(转染入HEK-293细胞的人A2b腺苷受体,来源:Receptor Biology,Inc.)、缓冲液(50mM Tris-HCl、10mM MgCl2、1mM EDTA、0.1mM苯甲脒、2U/mL腺苷脱氨酶pH6.5)、32.4nM[3H]DPCPX(8-环戊基-1,3-二丙基黄嘌呤)(800,000dpm)和100μM NECA(5′-N-乙基甲酰氨基-腺苷)在室温下培养30分钟,总体积为100μL。在25Hgmm真空下用Whatman GF/B玻璃纤维滤纸(在0.5%聚乙烯亚胺中预浸渍3小时)过滤,在96孔Brandel细胞收集器中用1mL冰冷的50mM Tris-HCl(pH 6.5)洗涤4次。
活性检测:在200μL HiSafe-3合剂存在下于β计数器(1450Microbeta,Wallac)中进行。抑制[%]=100-((供试化合物存在下的活性-非特异活性)/(总活性-非特异活性))×100。
结果
如果在我们的实验条件下,浓度为1μM时对放射性配体与人腺苷A3受体结合的抑制活性高于80%,则认为该化合物具有生物活性。
CHO-hA3膜制备物上[125I]AB-MECA的解离常数(Kd)通过同位素饱和实验、借助Scatchard分析法(G.Scatchard,Ann.N.Y.Acad.Sci.51:660,1949)确定。应用Cheng-Prusoff方程将IC50转换为亲合常数(Ki)(Y.J.Cheng和W.H.Prusoff,Biochem.Pharmacol.22:3099,1973)。
通式(I)、(II)、(III)、(IV)和(V)的几种化合物显示出显著的生物效应。权利要求1-3中所定义的通式(I)化合物显示出最重要的活性。特别具有优势的是实施例中给出的化合物,它们的Ki值的范围在0.8nM和700nM之间。最具优势化合物的Ki值为0.8和15nM。
这些化合物具有适当的生物利用度,选择性为至少3个数量级(相对于人腺苷A1、A2a和A2b受体亚型)。
此外,它们在静脉注射和口服施用时的作用持续时间长、ED50值低、毒性和副作用特点具有优势。
上述这些数据支持通式(I)化合物的治疗应用。
Claims (15)
1.通式(I)的化合物及其盐、溶剂合物和异构体及其盐和溶剂合物,
其中:
R1代表氢原子或直链或支链C1-4烷基;
R2代表氢原子或直链或支链C1-4烷基;
R3代表氢原子,或直链或支链C1-4烷基、C3-6环烷基、苯基、噻吩基或呋喃基,可选被一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基或卤素原子取代;含有一个、二个或三个氮原子的六或五元杂芳环,或者含有一个氮原子和一个氧原子或一个氮原子和一个硫原子的五元杂芳环,可选被一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基或卤素原子取代;
R4、R5、R6和R7独立地代表氢原子、直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子,或者R4和R7代表氢原子并且R5和R6一同形成亚甲二氧基;
R8代表氢原子或氰基、氨羰基、C1-4烷氧羰基、羧基;
R9和R10独立地代表氢原子、直链或支链C1-4烷基、C3-6环烷基;
X代表-CH2-基、-NH-基、-NR11-基或硫原子、氧原子、磺基或亚硫酰基,其中R11代表直链或支链C1-4烷基或C3-6环烷基;
Z指氧原子、硫原子、-NH-基或-NR12-基,其中R12代表直链或支链C1-4烷基或C3-6环烷基;
n的值为0、1或2;
m的值为0、1、2或3;
o的值为0、1、2或3;
p的值为0或1;
r的值为0或1,条件是至少m和o之一不为0。
2.权利要求1所定义的通式(I)化合物及其盐、溶剂合物和异构体及其盐和溶剂合物,
其中:
R1代表氢原子或直链或支链C1-4烷基;
R2代表氢原子或直链或支链C1-4烷基;
R3代表氢原子,或直链或支链C1-4烷基、C3-6环烷基、苯基、噻吩基或呋喃基,可选被一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基或卤素原子取代;
R4、R5、R6和R7独立地代表氢原子、直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子,或者R4和R7代表氢原子并且R5和R6一同形成亚甲二氧基;
R8代表氢原子或氰基、氨羰基、C1-4烷氧羰基、羧基;
R9和R10独立地代表氢原子、直链或支链C1-4烷基、C3-6环烷基;
X代表-CH2-基、-NH-基、-NR11-基或硫原子、氧原子、磺基或亚硫酰基,其中R11代表直链或支链C1-4烷基或C3-6环烷基;
Z代表氧原子、硫原子、-NH-基或-NR12-基,其中R12代表直链或支链C1-4烷基或C3-6环烷基;
n的值为0、1或2;
m的值为0、1、2或3;
o的值为0、1、2或3;
p的值为0或1;
r的值为0或1,条件是至少m和o之一不为0。
3.权利要求1-2所定义的通式(I)化合物及其盐、溶剂合物和异构体及其盐和溶剂合物,
其中:
R1代表氢原子或甲基;
R2代表氢原子或甲基;
R3代表苯基、噻吩基或呋喃基;
R4、R5、R6和R7独立地代表氢原子、直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子,或者
R4和R7代表氢原子并且R5和R6一同形成亚甲二氧基;
R8代表氢原子或氰基;
R9和R10代表氢原子、甲基、乙基或环丙基;
X代表-NH-基或氧原子;
Z指氧原子、硫原子、-NH-基或-NR12-基,其中R12代表直链或支链C1-4烷基或C3-6环烷基;且
n的值为1;
m的值为2;
o的值为2;
p的值为0;
r的值为0。
4.根据权利要求1-3的下列化合物及其盐、溶剂合物和异构体及其盐和溶剂合物:
1-(9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪,
1-(9-苄基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉,
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-4-甲基哌嗪,
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-哌嗪,
1-(9-糠基氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉,
1-(9-噻吩甲基-氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-吗啉,
1-(9-噻吩甲基-氨基-10-氰基-咪唑并[1,2-a]喹啉-2-羰基)-哌嗪。
5.通式(I)化合物及其盐、溶剂合物和异构体的制备方法,
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、Z、n、m、o、p和r具有权利要求1所定义的含义,该方法的特征为
将通式(VIII)的化合物,
其中R9、R10、Z、n、m、o、p和r具有权利要求1所定义的含义,
用通式(II)的酸或活性酸衍生物酰化,
其中R1、R2、R3、R4、R5、R6、R7、R8、X和n具有权利要求1所定义的含义,
并且如需要,将所得通式(I)化合物的取代基通过已知方法互相转化,和/或将通式(I)化合物转化为其盐或溶剂合物,或从其盐或溶剂合物释放出来,和/或将其拆分为其光学活性异构体,或将光学活性异构体转化为外消旋化合物。
6.权利要求5所定义的方法,其特征在于酰化在碱存在下、在有机溶剂中进行。
7.权利要求5-6所定义的方法,其特征在于通式(I)的酸的活性衍生物是适当的酰卤或混合酸酐。
8.权利要求5-7所定义的方法,其特征在于有机溶剂为卤代烃、优选氯仿。
9.权利要求5-8所定义的方法,其特征在于碱为有机碱、优选三乙胺。
11.权利要求10所定义的药物组合物,其特征为含有一种或多种权利要求3所定义的化合物作为活性物质。
13.通式(I)化合物作为A3受体配体在心脏、肾脏、呼吸系统和中枢神经系统的功能异常中的用途,用于抑制腺苷对生长期肿瘤细胞的保护作用、防止肥大细胞脱粒、抑制细胞因子的形成、降低眼内压、抑制TNFα释放、阻碍嗜酸性粒细胞和嗜中性粒细胞和其他炎症细胞的迁移、抑制气管收缩并阻碍血浆渗透通过血管壁,
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、Z、n、m、o、p和r具有权利要求1所定义的含义。
14.通式(I)化合物作为A3受体拮抗剂的用途,作为抗炎、止喘、抗局部缺血、抗抑郁、抗心律失常、肾功能保护、肿瘤预防、抗帕金森和认知功能激发药物组合物的活性成分,以及作为可用于治疗或预防下列疾病的组合物的活性成分:再灌注过程中的心肌损伤、慢性阻塞性肺病(COPD)、成人呼吸功能不全(ARDS)-包括慢性支气管炎、肺气肿或呼吸困难-、过敏反应(例如鼻炎、毒葛诱导反应、荨麻疹、硬皮病、关节炎)、其他自身免疫性疾病、炎性肠疾病、艾迪生病、局限性回肠炎、银屑病、关节病、张力过强、神经系统功能异常、青光眼和糖尿病,
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、Z、n、m、o、p和r具有权利要求1所定义的含义。
15.通式(I)化合物作为活性成分用于治疗病变如哮喘、COPD和ARDS、青光眼、肿瘤、过敏性和炎性疾病、局部缺血、缺氧、心律失常和肾脏疾病的用途,
其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、X、Z、n、m、o、p和r具有权利要求1所定义的含义。
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HU0203976A HUP0203976A3 (en) | 2002-11-15 | 2002-11-15 | Adenozine a3 receptors, process for their preparation and pharmaceutical compositions containing them |
HUP0203976 | 2002-11-15 |
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EP (1) | EP1560828B9 (zh) |
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CN (1) | CN1332960C (zh) |
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CA (1) | CA2505910C (zh) |
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DE (1) | DE60305058T2 (zh) |
DK (1) | DK1560828T3 (zh) |
EA (1) | EA007595B1 (zh) |
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HUP0105406A3 (en) * | 2001-12-21 | 2003-12-29 | Sanofi Aventis | Imidazo[1,2-a]quinolin derivatives, process for their preparation, pharmaceutical compositions thereof and intermediates |
HUP0203976A3 (en) * | 2002-11-15 | 2004-08-30 | Sanofi Aventis | Adenozine a3 receptors, process for their preparation and pharmaceutical compositions containing them |
HUP0400812A2 (en) * | 2004-04-19 | 2006-02-28 | Sanofi Aventis | Crystalline forms of 2-amino-3-cyano-quinoline derivatives, process for their preparation and pharmaceutical compositions containing them |
GT200600381A (es) | 2005-08-25 | 2007-03-28 | Compuestos organicos | |
US20090088403A1 (en) * | 2007-05-07 | 2009-04-02 | Randy Blakely | A3 adenosine receptors as targets for the modulation of central serotonergic signaling |
HUP0700395A2 (en) * | 2007-06-07 | 2009-03-02 | Sanofi Aventis | Substituted [1,2,4] triazolo [1,5-a] quinolines, process for their preparation, pharmaceutical compositions thereof, and intermediates |
US9199102B2 (en) | 2009-07-21 | 2015-12-01 | Oradin Pharmaceutical Ltd. | A3 adenosine receptor ligands for modulation of pigmentation |
DK2950649T3 (da) | 2013-02-01 | 2020-05-04 | Wellstat Therapeutics Corp | Aminforbindelser med antiinflammations-, antisvampe-, antiparasit- og anticanceraktivitet |
KR101820909B1 (ko) * | 2017-07-07 | 2018-01-23 | 퓨쳐메디신 주식회사 | 아데노신 유도체를 포함하는 만성신장질환 예방 및 치료용 약학적 조성물 |
WO2019055877A1 (en) | 2017-09-15 | 2019-03-21 | Forma Therapeutics, Inc. | TETRAHYDROIMIDAZO QUINOLINE COMPOSITIONS AS INHIBITORS OF CBP / P300 |
SG11202012767UA (en) | 2018-06-29 | 2021-01-28 | Forma Therapeutics Inc | Inhibiting creb binding protein (cbp) |
CA3132628A1 (en) * | 2019-03-15 | 2020-09-24 | Forma Therapeutics, Inc. | Inhibiting cyclic amp-responsive element-binding protein (creb) |
US11801243B2 (en) | 2020-09-23 | 2023-10-31 | Forma Therapeutics, Inc. | Bromodomain inhibitors for androgen receptor-driven cancers |
US11795168B2 (en) | 2020-09-23 | 2023-10-24 | Forma Therapeutics, Inc. | Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP) |
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US4075343A (en) * | 1976-09-13 | 1978-02-21 | Pfizer Inc. | Anti-allergenic 5-alkoxyimidazo[1,2-A]quinoline-2-carboxylic acids and derivatives thereof |
GB1596652A (en) * | 1977-01-20 | 1981-08-26 | Roussel Lab Ltd | Imidazo (1,2-a) quinoline-2-carboxylic acid and derivatives |
FR2448541A1 (fr) | 1979-02-09 | 1980-09-05 | Roussel Uclaf | Nouveaux derives de l'oxoimidazoquinoxaline et leurs sels, leur procede de preparation, leur application comme medicaments et les compositions pharmaceutiques les renfermant |
IL59104A (en) * | 1979-02-09 | 1984-02-29 | Roussel Uclaf | Heterotricyclic derivatives,process for their preparation and pharmaceutical compositions incorporating them |
US4644002A (en) | 1979-02-09 | 1987-02-17 | Roussel Uclaf | Imidazo[2,1-C]quinolines, useful as antiallergic agents |
US6376521B1 (en) | 1998-07-10 | 2002-04-23 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | A3 adenosine receptor antagonists |
US6448253B1 (en) * | 1998-09-16 | 2002-09-10 | King Pharmaceuticals Research And Development, Inc. | Adenosine A3 receptor modulators |
ATE265459T1 (de) | 1999-09-28 | 2004-05-15 | Otsuka Pharma Co Ltd | Triazolpurin-derivate, medikamentzusammensetzungen, die diese enthalten und mittel, die affinität zum adenosin a3 rezeptor zeigen |
US7160890B2 (en) * | 1999-12-02 | 2007-01-09 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
JP4579497B2 (ja) * | 2000-12-01 | 2010-11-10 | オーエスアイ・ファーマスーティカルズ・インコーポレーテッド | アデノシンa1、a2a、およびa3受容体に特異的な化合物、ならびにそれらの使用 |
CZ20033510A3 (cs) | 2001-05-31 | 2005-01-12 | Sanofi-Aventis | Aminochinolinové a aminopyridinové deriváty a jejich použití jako adenosinových A3 ligandů |
HUP0105407A3 (en) * | 2001-12-21 | 2004-04-28 | Sanofi Aventis | Triazolo[1,5-a]quinolin derivatives, process for their preparation, pharmaceutical compositions thereof and intermediates |
HUP0105406A3 (en) | 2001-12-21 | 2003-12-29 | Sanofi Aventis | Imidazo[1,2-a]quinolin derivatives, process for their preparation, pharmaceutical compositions thereof and intermediates |
HUP0203976A3 (en) * | 2002-11-15 | 2004-08-30 | Sanofi Aventis | Adenozine a3 receptors, process for their preparation and pharmaceutical compositions containing them |
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