CN1307175C - 用作腺苷受体配体的三唑并喹啉衍生物 - Google Patents
用作腺苷受体配体的三唑并喹啉衍生物 Download PDFInfo
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- CN1307175C CN1307175C CNB028256468A CN02825646A CN1307175C CN 1307175 C CN1307175 C CN 1307175C CN B028256468 A CNB028256468 A CN B028256468A CN 02825646 A CN02825646 A CN 02825646A CN 1307175 C CN1307175 C CN 1307175C
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Abstract
本发明涉及通式(I)的腺苷A3受体的配体,那些之中优选拮抗剂,以及它们的盐、溶剂化物和异构体,含有它们的药物组合物,通式(I)化合物以及它们的盐、溶剂化物和异构体的用途,通式(I)化合物以及它们的盐、溶剂化物和异构体的制备,还涉及新的通式(II)的中间体及其制备。
Description
本发明涉及通式(I)的腺苷A3受体的配体,那些之中优选拮抗剂,以及它们的盐、溶剂化物和异构体,含有它们的药物组合物,通式(I)化合物以及它们的盐、溶剂化物和异构体的用途,通式(I)化合物以及它们的盐、溶剂化物和异构体的制备,还涉及新的通式(II)的中间体及其制备。
腺苷是众所周知的一些内源性分子(ATP、NAD+、核酸)的成分。此外,它还在很多生理过程中起重要的调节作用。腺苷对心脏功能的作用早已于1929年发现。(Drury和Szentgy_rgyi,J Physiol 68:213,1929)。对腺苷介导的生理功能数增加的证实和新的腺苷受体亚型的发现为特定配体的治疗性应用提供了可能性(Poulse,S.A.和Quinn,R.J.Bioorganic and Medicinal Chemistry 6:619,1998)。
迄今为止,腺苷受体分为3个主要的种类:A1、A2和A3。A1亚型通过与Gi膜蛋白偶联部分负责抑制腺苷酸环化酶,部分影响其它第二信使系统。A2受体亚型可再分为两个亚型-A2a和A2b-,该受体可刺激腺苷酸环化酶的活性。近来,已经从大鼠睾丸cDNA库中鉴定了腺苷A3受体的序列。随后,证实了它与新的、功能性腺苷受体相对应。A3受体的激活还与若干第二信使系统有关:例如抑制腺苷酸环化酶,并刺激磷脂酶C和D。
腺苷受体可在很多器官中找到,并调节它们的功能。A1和A2a受体在中枢神经系统和心血管系统中起着重要的作用。在CNS中,腺苷可抑制突触递质的释放,其作用是由A1受体介导的。在心脏中,A1受体还可介导腺苷的减弱肌收缩力效应、变时效应和变传导效应。腺苷A2a受体以相对较高的含量位于纹状体中,在调节突触传导方面,显示与多巴胺受体的功能性相互作用。内皮和平滑肌细胞上的A2a腺苷受体负责腺苷诱导的血管舒张。
以mRNA鉴定为基础,A2b腺苷受体广泛分布于不同的组织中。它们几乎已经在所有细胞类型中被鉴定,但它在肠和膀胱中的表达水平最高。这种亚型还很可能在血管紧张的调节方面具有重要的调节功能,并在肥大细胞的功能方面起作用。
与在蛋白水平检测组织分布的A1和A2a受体相反,A2b和A3受体存在的检测是以它们的mRNA水平为基础的。与其它亚型相比,A3腺苷受体的表达水平较低,而且是高度物种依赖性的。A3腺苷受体主要在中枢神经系统、睾丸、免疫系统中表达,而且似乎涉及从肥大细胞释放的介质在即发型超敏反应中的调节。
迄今为止在文献中公开的A3拮抗剂为类黄酮、1,4-二氢吡啶衍生物、三唑并喹唑啉、噻唑并萘啶和噻唑并嘧啶。本发明涉及一种新的有效的A3拮抗剂类型,它具有三唑并喹啉结构。
就治疗用途而言,它基本确保该分子不结合,或仅仅在非常高的浓度下结合腺苷受体的A1、A2a和A2b亚型。我们的发明涉及通式(I)的化合物和它们的盐、溶剂化物和异构体,它对腺苷受体的A3亚型具有较高选择性。
我们的目的首先是制备具有三唑并喹啉结构的A3配体,且那些之内优选拮抗剂,它具有较强的拮抗作用,并对A3受体显示较高的选择性,即它们以明显低于抑制A1、A2a和A2b受体的浓度抑制A3受体。另一目的是了解稳定性、生物可利用率、治疗指数和毒性数据,从而将所述新化合物开发成药物,且由于它们良好的肠吸收,该化合物可用于口服。
我们已经发现了通式(I)的化合物和它们的盐、溶剂化物、及其旋光异构体和盐、溶剂化物满足上述标准-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,或苯基、噻吩基、或呋喃基,任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,或代表含有1个、2个或3个氮原子的5-或6-元杂芳环、或含有1个氮原子和1个氧原子或1个氮原子和1个硫原子的5元杂芳环,任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和R5共同形成1,3-丁二烯基,任选用亚甲二氧基或一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子取代;
R6代表氢原子或氰基,氨羰基、C1-4烷氧羰基、或羧基;
R7代表氢原子或直链或支链C1-4烷基,或C1-4亚烷基,任选被苯基取代,或代表苯基、苄基、噻吩基或呋喃基,任选被亚甲二氧基、或一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基、三氟甲基、氰基或卤素原子取代,氨基,一或二烷氨基,或代表含有1个、2个或3个氮原子的5或6元杂芳环,或含有1个氮原子和1个氧原子或1个氮原子和1个硫原子的5元杂芳环,任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;
X代表-CH2-、-NH-、-NR12-、或硫原子或氧原子或磺基或亚硫酰基-其中R12代表直链或支链C1-4烷基或C3-6环烷基;
n代表0、1或2。
上面所列取代基的详细含义如下:
直链或支链C1-4烷基是指甲基-、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烷氧基是指甲氧基-、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-或甲氧基。
含有1个或2个或3个氮原子的杂芳环是指吡咯、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。该环可任选被C1-4烷基取代。
含有1个氮原子和1个氧原子或硫原子的杂芳环是指_唑、异_唑、噻唑、异噻唑环。该环可任选被C1-4烷基取代。
通式(I)化合物的盐是指用无机和有机酸和碱得到的盐。优选的盐是用药学上可接受的酸,如盐酸、硫酸、乙磺酸、酒石酸、琥珀酸、富马酸、苹果酸、柠檬酸得到的那些。
溶剂化物是指用各种溶剂,如用水或乙醇得到的溶剂化物。
通式(I)的化合物表现出立体异构和旋光异构现象,因此本发明还涉及立体异构体的混合物、涉及外消旋或旋光立体异构体,并涉及它们的盐和溶剂化物。
通式(I)化合物的优选组是由通式(Ia)的化合物和它们的盐、溶剂化物、及其旋光异构体和盐、溶剂化物形成的,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;
R8、R9、R10和R11彼此独立地代表氢原子、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
R8和R11代表氢原子且R9和R10共同形成亚甲二氧基;
R6代表氢原子、或氰基;
R7代表4-甲氧苯基、3-甲基苯基、3-甲氧苯基、3-噻吩基、3-吡啶基、3-羟苯基或3-呋喃基;
X代表-NH-或氧原子;且
n代表1。
特别优选的是符合上述条件的下列化合物和它们的盐、溶剂化物、及其旋光异构体和盐、溶剂化物:
2-(4-甲氧苯基)-9-苄氨基-10-氰基-s-三唑并[1,5-a]喹啉,
2-(2-呋喃基)-9-(2-呋喃基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉,
2-(3,4-亚甲二氧基苯基)-9-(2-呋喃基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉,
2-(3-吡啶基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉,
2-(3-羟苯基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉。
另一方面,本发明还涉及含有作为活性成分的通式(I)化合物或它们的异构体、盐和溶剂化物的药物组合物,优选口服的组合物,但可吸入的、肠胃外及透皮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,如片剂、颗粒剂、胶囊剂、贴剂、溶液、混悬液或乳状液。固体组合物,片剂和胶囊剂是首先优选的药物形式。
上述药物组合物是利用标准方法通过使用常规的药物赋形剂制备的。
通式(I)的化合物可用于治疗A3受体在其发展中起作用的病变。
本发明的化合物对A3受体具有选择活性,可用于治疗和/或预防性治疗心脏、肾、呼吸系统、中枢神经系统的官能障碍。它们可抑制腺苷对生长癌细胞的保护作用、防止肥大细胞脱粒、抑制细胞因子产生、降低眼内压、抑制TNFα释放、抑制嗜酸细胞、中性白细胞和其它免疫细胞迁移、抑制支气管收缩和血浆外渗。
以这些作用为基础,本发明的腺苷A3受体拮抗剂可治疗性用作抗炎、止喘、抗局部缺血、抗抑郁、抗心律失常、肾脏保护、抗肿瘤、抗帕金森氏病和提高认知的药物。它们还可用于治疗或预防心肌再灌注损伤、慢性梗阻性肺病(COPD)和成人呼吸窘迫综合征(ARDS)包括慢性支气管炎、肺气肿或呼吸困难、变态反应(例如,鼻炎、毒叶藤诱导的反应、荨麻疹、硬皮病、关节炎)、其它自身免疫疾病、炎性肠疾病、阿狄森氏病、克罗恩氏病、牛皮癣、风湿病、高血压、神经官能症、青光眼和糖尿病(K.N.Klotz,Naunyn-Schmiedberg′s Arch.Pharmacol.362:382,2000;P.G.Baraldi és P.A.Borea,TiPS 21:456,2000)。
本发明的化合物优选用于治疗疾病,如哮喘、COPD和ARDS、青光眼、肿瘤、变应性和炎性疾病、局部缺血、低氧症、心律失常和肾病。
另一方面,本发明涉及通式(I)的化合物在治疗上述病变中的用途。根据疾病的性质和严重程度以及患者的性别、体重等,建议每日剂量为0.1-1000mg活性成分。
本发明的其它主题是通式(I)的化合物和通式(II)、(III)和(IV)的中间体的制备。
本发明制备过程中所用的通式(II)的中间体是新的。通式(II)、(III)和(IV)的取代基具有上面所限定的含义。
在本发明的方法中,使通式(II)的1,2-二氨基-azinium盐与通式(VII)的化合物反应,其中R7如上面所定义,且Y代表氢原子、卤素原子或C1-4烷氧基,优选与适宜的酰基卤或酯反应(D.W.Robertson,J.Med.Chem.,28,717,(1985)),因此获得通式(I)的化合物,如果需要,还可转化成它的盐、溶剂化物,或从其盐、溶剂化物中释放出来,并分离成它的立体异构或旋光异构体。
闭环可在二甲基甲酰胺中,在有三乙胺或作为相似类型闭环催化剂已知的其它化合物存在的条件下进行。
闭环可在较宽的温度范围,优选20℃-150℃间进行。
利用已知方法可将通式(I)化合物的取代基相互转换。
通式(II)的化合物-其中R1、R2、R3、R4、R5、R6、X和n的含义是如上面所定义的-可通过若干已知方法获得,这些方法的其中1个在流程1中表示,即利用有机化学已知的N-胺化方法对通式(III)的化合物进行N-胺化(E.E.Glover,R.T.Rowbotton,J.Chem.Soc.Perkin.TransI.,376(1976),G.Timári,Gy.Hajós,S.Bátori és A.Messmer,Chem.Ber.,125,929(1992))。就N-胺化剂而言,优选使用0-甲苯磺酰基-羟基胺,但也可使用已知进行N-胺化的其它试剂。
通式(III)的化合物-其中R1、R2、R3、R4、R5、R6、X和n的含义是如上面所定义的-可通过本来已知的方法从通式(IV)的化合物制备(Nan Zhang,Bioorg.和Med.Chem.Lett.,10,2825(2000))。
通式(IV)的化合物-其中R4、R5、R6如上面所定义的-可通过本来已知的方法从通式(V)的化合物制备(D.L.Leysen,J.HeterocyclicChem.,24,1611,(1987))。
通式(V)的化合物-其中R4、R5、R6如上面所定义的-可通过本来已知的方法制备(Pfizer(Inc)USP 4,175,193)。
本发明通式(I)、(II)、(III)和(IV)的化合物,它们的制备和生物活性在下列实施例中给出,这些实施例不是对要求保护范围的限制。
图1表示式(I)的化合物,
图2表示式(Ia)的化合物,
图3表示式(II)的化合物,
图4表示式(III)的化合物,
图5表示式(IV)的化合物,
图6表示式(V)的化合物,
图7表示式(VI)的化合物,
图8表示式(VII)的化合物,
图9表示反应流程1。
实施例
实施例1
2-(4-甲氧苯基)-9-苄氨基-10-氰基-s-三唑并[1,5-a]喹啉
在通式(I)中,R1和R2代表氢原子,R3代表苯基,R4和R5共同形成1,3-丁二烯基,R6代表氰基,R7代表4-甲氧苯基,X的含义是-NH,n是1。
a.)
2-氨基-3-氰基-4-氯喹啉
搅拌下,110℃加热10g 2-氯基-3-氰基-4-羟喹啉和15ml磷酰氯的混合物。将反应混合物冷却,倾注在100ml冰水上,并用60ml 10%氢氧化钠溶液中和。滤出所得黄色沉淀物,用50ml水洗涤。干燥后,获得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-苄氨基喹啉
搅拌下,130℃加热5g 2-氨基-3-氰基-4-氯喹啉和11ml苄胺的混合物。将反应混合物倾注在50ml水上,滤出所得沉淀物,用50ml水洗涤。将浅黄色沉淀物自二甲基甲酰胺中重结晶出来,获得5.2g的标题化合物。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)
c.)
1,2-二氨基-3-氰基-4-苄氨基-喹啉鎓-甲苯磺酸盐
20℃下,在15分钟内,向2.0g 2-氨基-3-氰基-4-苄氨基喹啉溶于30ml二甲基甲酰胺的溶液滴加1.78g 0-甲苯磺酰基-羟胺溶于20ml二氯甲烷的溶液。搅拌反应混合物5小时,然后滤出沉淀物。将所得白色晶体物质自乙腈中重结晶出来,得到3.1g标题化合物,mp.:207℃。
d.)
2-(4-甲氧苯基)-9-苄氨基-10-氰基-s-三唑并[1,5-a]喹啉
向2.0g 1,2-二氨基-3-氰基-4-苄氨基-喹啉_-甲苯磺酸盐和15ml吡啶的混合物中加入2g aniseacid-氯化物。100℃下搅拌反应混合物8小时。将混合物倾注在50ml水上,滤出沉淀的晶体,并自乙腈重结晶,得到1.1g标题化合物,Mp.:237℃。
NMR,δH(400MHz,DMSO-d6):8.78ppm(t,1H),8.58(d,1H),8.38(d,1H),8.10(d,2H),7.98(t,1H),7.39(m,5H),7.07(d,2H),5.14(d,2H),3.82(s,3H)
实施例2
2-(2-呋喃基)-9-(2-呋喃基甲氨基)-10-氰基-s-三唑并[1,5-a] 喹啉
在通式(I)中,R1和R2是氢原子,R3是2-呋喃基,R4和R5共同形成1,3-丁二烯基,R6代表氰基,R7代表2-呋喃基,X是-NH-,n是1。
a.)2-氨基-3-氰基-4-(2-呋喃基甲氨基)-喹啉
130℃搅拌下,加热5g 2-氨基-3-氰基-4-氯喹啉和1ml呋喃基甲胺(糠胺)。将反应混合物倾注在50ml水上,滤出所得沉淀物,用50m水洗涤。将浅黄色沉淀物自20ml乙醇中重结晶出来,获得4.8g标题化合物,Mp.:208℃。
b.)1,2-二氨基-3-氰基-4-(2-呋喃基甲氨基)-喹啉鎓-甲苯磺酸 盐
20℃下,在15分钟内,向2.0g 2-氨基-3-氰基-4-(2-呋喃基甲氨基)-喹啉溶于30ml二甲基甲酰胺的溶液中滴加1.78g 0-甲苯磺酰基-羟胺溶于20ml二氯甲烷的溶液。搅拌反应混合物5小时,滤出沉淀的白色晶体物质,并自乙腈重结晶,得到2.1g标题化合物,mp.:211℃。
c.)2-(2-呋喃基)-9-(2-呋喃基甲氨基)-10-氰基-s-三唑并[1,5-a] 喹啉
向2.0g 1,2-二氨基-3-氰基-4-(2-呋喃基甲氨基)-喹啉鎓-甲苯磺酸盐和15ml吡啶的混合物中加入2g呋喃-2-羧酸氯化物。100℃下搅拌反应混合物8小时。将混合物倾注在50ml水上,滤出沉淀的晶体,并自乙腈重结晶,得到1.1g标题化合物,Mp.:203℃。
NMR,δH(400MHz,DMSO-d6):8.74ppm(t,1H),8.52(d,1H),8.32(d,1H),7.90(m,3H),7.63(m,2H),7.14(m,1H),6.68(m,1H),6.44(m,2H),5.11(d,2H)
实施例3
2-(3,4-亚甲二氧基苯基)-9-(2-呋喃基甲氨基)-10-氰基-s- 三唑并[1,5-a]喹啉
在通式(I)中,R1和R2是氢原子,R3是呋喃基,R4和R5共同形成1,3-丁二烯基,R6代表氰基,R7代表3,4-亚甲二氧基苯基,X是-NH-,n是1。
a.)2-(3,4-亚甲二氧基苯基)-9-(2-呋喃基甲氨基)-10-氰基-s- 三唑并[1,5-a]喹啉
向2.0g 1,2-二氨基-3-氰基-4-(2-呋喃基甲氨基)-喹啉鎓-甲苯磺酸盐和15ml吡啶的混合物中加入2g 3,4-亚甲二氧基-苯甲酸氯化物。100℃下搅拌反应混合物8小时。将混合物倾注在50ml水上,滤出沉淀的晶体,并自乙腈重结晶,获得1.4g标题化合物,Mp.:185℃。
NMR,δH(400MHz,DMSO-d6):8.55ppm(m,1H),8.51(d,1H),8.31(d,1H),7.93(t,1H),7.57-7.70(m,3H),7.05(d,1H),6.44(m,2H),6.11(s,2H),5.08(d,2H)
实施例4
2-(3-吡啶基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a] 喹啉
在通式(I)中,R1和R2是氢原子,R3是2-噻吩基,R4和R5共同形成1,3-丁二烯基,R6代表氰基,R7代表3-吡啶基,X是-NH-,n是1。
a)
2-氨基-3-氰基-4-(2-噻吩基甲氨基)喹啉
130℃搅拌下,加热5g 2-氨基-3-氰基-4-氯喹啉和11ml噻吩基甲胺。将反应混合物倾注在50ml水上,滤出所得沉淀物,用50ml水洗涤。将浅黄色沉淀物自25ml乙醇中重结晶出来,获得5.2g标题化合物,Mp.:208℃。
b.)1,2-二氨基-3-氰基-4-(2-噻吩基甲氨基)-喹啉鎓-甲苯磺酸 盐
20℃下,在15分钟内,向2.0g 2-氨基-3-氰基-4-(2-噻吩基甲氨基)-喹啉溶于30ml二甲基甲酰胺的溶液中滴加1.78g 0-甲苯磺酰基-羟胺溶于20ml二氯甲烷的溶液。搅拌反应混合物5小时,滤出沉淀的白色晶体物质,并自乙腈重结晶,得到2.1g标题化合物,mp.:198℃。
c.)2-(3-吡啶基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并 [1,5-a]喹啉
向2.0g 1,2-二氨基-3-氰基-4-(2-噻吩基甲氨基)-喹啉鎓-甲苯磺酸盐和20ml二甲基甲酰胺的混合物中加入4ml三乙胺和4g吡啶-3-carboxaldehyde。100℃下搅拌反应混合物8小时。将混合物倾注在50ml水上,滤出沉淀的晶体,并自乙腈重结晶,获得0.8g标题化合物,Mp.:249℃。
NMR,δH(400MHz,DMSO-d6):9.25ppm(s,1H),8.71(m,2H),8.35(m,3H),7.86(m,1H),7.51(m,3H),7.17(m,1H),6.98(m,1H),5.25(d,2H)
实施例5
2-(3-羟苯基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a] 喹啉
在通式(I)中,R1和R2是氢原子,R3是2-噻吩基,R4和R5共同形成1,3-丁二烯基,R6代表氰基,R7代`表3-羟苯基,X是-NH-,n是1。
a.)
2-(3-羟苯基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a] 喹啉
向2.0g 1,2-二氨基-3-氰基-4-(2-噻吩基甲氨基)-喹啉鎓-甲苯磺酸盐和20ml二甲基甲酰胺的混合物中加入4ml三乙胺和4g 3-羟基-苯甲醛。100℃下搅拌反应混合物8小时。将混合物倾注在50ml水上,滤出沉淀的晶体,并自乙腈重结晶,获得0.9g标题化合物,Mp.:248℃。
NMR,δH(400MHz,DMSO-d6):9.66ppm(s,1H),8.81(m,1H),8.52(m,1H),8.35(m,1H),7.96(m,1H),7.62(m,3H),7.44(m,1H),7.32(m,1H),7.18(m,1H),7.01(m,1H),6.88(m,1H),5.29(d,2H)
利用实施例1中描述的方法制备的通式(I)其它化合物的结构和物理性质在表I中给出。
表I.
利用实施例1中描述的方法制备的通式(III)中间体的结构和物理性质在表(II)中给出。
表II
利用实施例1中描述的方法制备的通式(IV)中间体的结构和物理性质在表(III)中给出。
表III
实施例74
下列组成的片剂是通过制药工业所用的已知方法制备的。
活性成分 25mg
乳糖 50mg
微晶纤维素 21mg
聚乙烯吡咯烷酮 3mg
硬脂酸镁 1mg
生物学
方法
人腺苷A3受体的结合
制备膜混悬液:通过用冰冷的PBS洗涤3次而收集表达hA3受体的CHO细胞,1000xg离心10分钟,在缓冲液(50mM Tris、10mM MgCl2、1mM EDTA,pH8.0)中匀化15秒,43,000xg离心10分钟(Sigma 3K30),将膜制品悬浮于上述缓冲液中,-80℃贮存等分试样。
结合方案:在有0.5nM[125I]AB-MECA(对-氨基-苯甲基-甲基酰氨基-腺苷)(100.000cpm)和100μM R-PIA(N6-[L-2-苯基异丙基]腺苷)存在的条件下,室温下在培养缓冲液(50mM Tris、10mM MgCl2、1mM EDTA、3U/mL腺苷脱氨酶,pH8.0)中培养CHO-hA3膜制品(2μg蛋白内容物)1小时,从而测定非-特异性结合或供试化合物,总体积50μL。在WhatmanGF/B玻璃纤维滤膜(在0.5%聚氮丙啶中预浸泡3小时)上过滤,在96-孔Brandel细胞收集器上用1mL冰冷的50mM Tris、10mM MgCl2、1mMEDTA(pH8.0)洗涤4次。活性检测:在γ-计数器中(1470 Wizard,Wallac)。抑制[%]=100-((有供试化合物存在下的活性-非特异性活性)/(总活性-非特异性活性))*100
人腺苷A1受体的结合
制备膜混悬液:通过用冰冷的PBS洗涤3次而收集表达hA1受体的CHO细胞,1000xg离心10分钟,在缓冲液(50mM Tris,pH7.4)中匀化15秒,43,000xg离心10分钟(Sigma 3K30),将膜制品悬浮于上述缓冲液中,-80℃贮存等分试样。
结合方案:室温下,在培养缓冲液(50mM Tris、3U/mL腺苷脱氨酶,pH7.4)、10nM[3H]CCPA(2-氯-N6-环戊基-腺苷)(80.000dpm)和10μMR-PIA(N6-[L-2-苯基异丙基]腺苷)中,培养CHO-hA1膜制品(50μg蛋白内容物)3小时,从而测定非-特异性结合或供试化合物,总体积100μL。在Whatman GF/B玻璃纤维滤膜(在0.5%聚氮丙啶中预浸泡3小时)上过滤,在96-孔Brandel细胞收集器上用1mL冰冷的50mM Tris(pH7.4)洗涤4次。活性检测:在β-计数器(1450 Microbeta,Wallac)中、有HiSafe-3 coctail存在的条件下、在96孔平板中。抑制[%]=100-((有供试化合物存在下的活性-非特异性活性)/(总活性-非特异性活性))*100
人腺苷A2a受体的结合
结合方案:室温下,培养7μg膜(转染到HEK-293细胞中的人A2a腺苷受体,来源:Receptor Biology,Inc.)、缓冲液(50mM Tris-HCl,10mMMgCl2,1mM EDTA,2U/mL腺苷脱氨酶,pH7.4)、20nM[3H]CGS-21680(2-[对(2-羰乙基)苯基乙氨基]-5’-N-乙酰氨基-腺苷)(200.000dpm)和50μM NECA(5’-N-乙酰氨基-腺苷)中90分钟,从而测定非-特异性结合或供试化合物,总体积100μl。在Whatman GF/B玻璃纤维滤膜(在0.5%聚氮丙啶中预浸泡)上过滤,在96-孔Brandel细胞收集器上用1mL冰冷的50mM Tris、10mM MgCl2、1mM EDTA、0.9%NaCl,pH7.4)洗涤4次。活性检测:在β-计数器(1450 Microbeta,Wallac)中、有HiSafe-3coctail存在的条件下、在96孔平板中。抑制[%]=100-((有供试化合物存在下的活性-非特异性活性)/(总活性-非特异性活性))*100
人腺苷A2b受体的结合
结合方案:室温下,培养20.8μg膜(转染到HEK-293细胞中的人A2b腺苷受体,来源:Receptor Biology,Inc.)、缓冲液(50mM Tris-HCl、10mM MgCl2、1mM EDTA、0.1mM苄脒、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-乙酰氨基-腺苷)中30分钟,从而测定非-特异性结合或供试化合物,总体积100μl。在Whatman GF/C玻璃纤维滤膜(在0.5%聚氮丙啶中预浸泡)上过滤,在96-孔Brandel细胞收集器上用1mL冰冷的50mM Tris-HCl(pH6.5)洗涤4次。活性检测:在β-计数器(1450Microbeta,Wallac)中、有HiSafe-3 coctail存在的条件下、在96孔平板中。抑制[%]=100-((有供试化合物存在下的活性-非特异性活性)/(总活性-非特异性活性))*100
结果
在我们的实验条件和1μM浓度下,如果化合物能够以高于80%的活性抑制放射性配体在人腺苷A3受体上的结合,则我们认为该化合物是生物活性的化合物。
CHO-hA3膜制品上[125I]AB-MECA的解离常数(Kd)是在Scatchard分析的帮助下,利用同位素饱和研究测定的(G.Scatchard,Ann.N.Y.Acad.Sci.51:660,1949)。通过使用Cheng-Prusoff方程可将IC50值转化成亲和性常数(Ki)(Y.J.Cheng和W.H.Prusoff,Biochem.Pharmacol.22:3099,1973)。
通式(I)、(II)、(III)和(IV)的若干化合物显示出显著的生物作用。权利要求2中限定的通式(IA)化合物作为权利要求1中限定的通式(I)副组,发挥了最重要的活性。除9种化合物外,它们的Ki值均不高于20nM。实施例给出的化合物是特别优选的。它们在人腺苷A3受体结合研究中的Ki值为3.5-0.78nM。最优选化合物的K1值为0.82和0.78nM。
这些化合物具有适当的生物活力,并对人腺苷A1、A2a和A2b受体亚型具有至少1,000倍的选择性。
此外,在静脉内和口服给药时,它们作用的持续时间足够长,它们的ED50值较低,它们的毒理学和副作用分布十分有利。
上述数据说明通式(I)的化合物可用于治疗用途。
Claims (17)
1.通式(I)的化合物或它们的盐
—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,或苯基、噻吩基、或呋喃基,任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和R5共同形成1,3-丁二烯基,任选用亚甲二氧基或一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基或卤素原子取代;
R6代表氢原子或氰基,氨羰基、C1-4烷氧羰基、或羧基;
R7代表苯基、苄基、噻吩基或呋喃基,任选被亚甲二氧基、或一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基、三氟甲基、氰基或卤素原子取代,氨基,或代表含有1个氮原子的5或6元杂芳环;
X代表-CH2-、-NH-、-NR12-、或硫原子或氧原子或磺基或亚硫酰基-其中R12代表直链或支链C1-4烷基或C3-6环烷基;
n代表0、1或2。
2.根据权利要求1所述的通式(Ia)化合物或它们的盐
—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,或苯基、噻吩基、或呋喃基,任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;
R8、R9、R10和R11彼此独立地代表氢原子、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
R8和R11代表氢原子且R9和R10共同形成亚甲二氧基;
R6代表氢原子或氰基、氨羰基、C1-4烷氧羰基、或羧基;
R7代表苯基、苄基、噻吩基或呋喃基,任选被亚甲二氧基、或一个或多个直链或支链C1-4烷基、直链或支链C1-4烷氧基、羟基、三氟甲基、氰基或卤素原子取代,氨基,或代表含有1个氮原子的5或6元杂芳环;
X代表-CH2-、-NH-、-NR12-、或硫原子或氧原子或磺基或亚硫酰基—其中R12代表直链或支链C1-4烷基或C3-6环烷基;
n代表0、1或2。
3.根据权利要求2所述的通式(Ia)化合物或它们的盐
—其中
R1代表氢原子、或甲基;
R2代表氢原子、或甲基;
R3代表苯基或噻吩基或呋喃基;
R8、R9、R10和R11彼此独立地代表氢原子、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
R8和R11代表氢原子且R9和R10共同形成亚甲二氧基;
R6代表氢原子、或氰基;
R7代表4-甲氧苯基、3-甲基苯基、3-甲氧苯基、2-噻吩基、3-吡啶基、3-羟苯基或2-呋喃基;
X代表-NH-或氧原子;且
n代表1。
4.根据权利要求3所述的如下化合物或它们的盐:
2-(4-甲氧苯基)-9-苄氨基-10-氰基-s-三唑并[1,5-a]喹啉,
2-(2-呋喃基)-9-(2-呋喃基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉,
2-(3,4-亚甲二氧基苯基)-9-(2-呋喃基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉,
2-(3-吡啶基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉或
2-(3-羟苯基)-9-(2-噻吩基甲氨基)-10-氰基-s-三唑并[1,5-a]喹啉。
7.根据权利要求5所述的方法,其特征在于在吡啶中进行通式(VII)化合物的闭环,
其中Y代表卤素原子。
10.根据权利要求9所述的药物组合物,它含有作为活性成分的一种或多种权利要求4的化合物。
12.根据权利要求11所述的通式(I)化合物
—其中R1、R2、R3、R4、R5、R6、R7、X和n具有与权利要求1相同的含义—作为A3配体在心脏、肾、呼吸器官和中枢神经系统疾病的情况下,用于制备抑制腺苷对生长肿瘤细胞的保护,防止肥大细胞脱粒,抑制细胞因子产生,降低眼内压,抑制TNFα释放,抑制嗜酸性细胞、中性白细胞和其它免疫细胞迁移,抑制支气管收缩和血浆外渗的药物中的用途。
13.根据权利要求12所述、作为活性成分的通式(I)化合物
—其中R1、R2、R3、R4、R5、R6、R7、X和n具有与权利要求1相同的含义—作为A3受体拮抗剂,在制备抗炎、止喘、抗局部缺血、抗抑郁、抗心律失常、肾脏保护、抗肿瘤、抗帕金森氏病和提高认知的药物组合物和用于制备治疗或预防心肌再灌注损伤、慢性梗阻性肺病和成人呼吸窘迫综合征、变态反应,自身免疫疾病、炎性肠疾病、阿狄森氏病、克罗恩氏病、牛皮癣、风湿病、高血压、神经官能症、青光眼和糖尿病的组合物中的用途。
14.根据权利要求13的用途,其中所述成人呼吸窘迫综合征为慢性支气管炎、肺气肿或呼吸困难。
15.根据权利要求13的用途,其中所述变态反应为鼻炎、毒叶藤诱导的反应、荨麻疹、硬皮病或关节炎。
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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 |
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 |
CA2570319A1 (en) * | 2004-06-25 | 2006-01-12 | Amgen Inc. | Condensed triazoles and indazoles useful in treating citokines mediated diseases and other diseases |
CN102702312A (zh) * | 2006-11-30 | 2012-10-03 | 首都医科大学 | 具有靶向抗血栓活性的rgdvyigsk、制备和应用 |
CN102702313A (zh) * | 2006-11-30 | 2012-10-03 | 首都医科大学 | 具有靶向抗血栓活性的rgdvyigsr、制备和应用 |
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CN102702314A (zh) * | 2006-11-30 | 2012-10-03 | 首都医科大学 | 具有靶向抗血栓活性的rgdfyigsr、制备和应用 |
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 |
DE102007061763A1 (de) * | 2007-12-20 | 2009-06-25 | Bayer Healthcare Ag | Substituierte azabicyclische Verbindungen und ihre Verwendung |
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