CN1512985A - 氨基喹啉和氨基哌啶衍生物和它们的作为腺苷a3配体的应用 - Google Patents
氨基喹啉和氨基哌啶衍生物和它们的作为腺苷a3配体的应用 Download PDFInfo
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- CN1512985A CN1512985A CNA02810840XA CN02810840A CN1512985A CN 1512985 A CN1512985 A CN 1512985A CN A02810840X A CNA02810840X A CN A02810840XA CN 02810840 A CN02810840 A CN 02810840A CN 1512985 A CN1512985 A CN 1512985A
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Abstract
通式(I)的化合物,其中R4,R5代表氢原子或一起形成一个1,3-丁间二烯基,可选择地被一个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;是强效腺苷A3受体配体优选的拮抗剂。
Description
本发明涉及通式(I)的腺苷A3受体配体,在它们之内的优选的拮抗剂和它们的盐,溶剂化物和同分异构体和包含它们的药物组合物,涉及通式(I)的化合物和它们的盐,溶剂化物和同分异构体的应用,涉及通式(I)的化合物和它们的盐,溶剂化物和同分异构体的制备,而且涉及通式(II)(III)和(IV)的新的中间体并涉及它们的制备。
腺苷是若干内源性分子(ATP,NAD+,核酸)中一种众所周知的成分。而且,它在许多生理过程中起很重要的调控作用。腺苷对心脏功能的影响已经在1929年被发现。(Drury和Szentgyrgyi,J Physiol68:213,1929)。由腺苷调控的生理功能的增加的数量的鉴别和新的腺苷受体亚型的发现为具体的配体的治疗应用提供了可能性(Poulse,S.A.和Quinn,R.J.Bioorganic and Chemistry 6:619,1998)。
迄今为止,腺苷受体已经被分为三大类:A1,A2和A3。A1亚型部分地负责通过与GI膜蛋白质耦合来抑制腺苷酸环化酶,部分地影响其它第二信使系统。A2受体亚型能被细分成两种更进一步的亚型-A2a和A2b-,这些受体刺激腺苷酸环化酶活性。腺苷A3受体序列最近已经从大鼠睾丸cDNA库中被鉴别出来。随后,被证实它相应于一种新的,功能性的腺苷受体。A3受体的活化也与若干第二信使系统有关:腺苷酸环化酶的抑制,磷脂酶C和D的刺激。
腺苷受体在若干器官中被发现并且调节它们的功能。A1和A2a受体都在中枢神经系统和心血管系统中起重要的作用。在CNS中,腺苷抑制突触的递质的释放,此作用由A1受体调控。在心脏中,A1受体也调控腺苷的负性变力的,变时的和变传导的作用。腺苷A2a受体相对地以较高的量位于纹状体中,在调控突触的传导中显示与多巴胺受体的功能的相互作用。在内皮的和平滑肌细胞上的A2a腺苷受体负责腺苷诱导的血管舒张。
在mRNA识别的基础上,A2b腺苷受体广泛地分布在不同的组织中。它们几乎在每一种细胞亚型中已经被识别了,但是它的表达在肠和膀胱中是最大的。这一亚型可能也在血管紧张性的调控中有重要的调控功能和在肥大细胞的功能中起作用。
与A1和A2a受体相反,在组织分布被发现在蛋白质水平的地方,A2b和A3受体的存在被发现基于它们的mRNA水平。A3腺苷受体的表达水平与其它亚型相比是相当低并且高物种依赖的。A3腺苷受体基本上在中枢神经系统,睾丸,免疫系统中表达并且好像涉及在速发过敏性反应中从肥大细胞的介质释放的调节。
迄今为止在著作中公布的A3拮抗剂有黄酮类,1,4-二氢吡啶衍生物,三唑喹唑啉,噻唑萘啶和噻唑嘧啶。本发明涉及一种有效的A3拮抗剂的新的类型,它具有氨基喹啉结构。
为了治疗应用,很重要的是确保分子不与或只在非常高的浓度的情况下与腺苷受体的A1和A2a和A2b亚型结合。本发明涉及通式(I)的化合物和它们的盐,溶剂化物和同分异构体,它们对于腺苷受体的A3亚型具有高选择性。
我们的目标是首先制备具有喹啉结构的A3配体,和在它们内的优选的拮抗剂,其具有强效的拮抗效应并且对A3受体显示高选择性,也就是他们以远低于抑制A1,A2a和A2b受体的浓度来抑制A3受体。进一步的目标是有稳定性,生物利用度,治疗指数和毒性数据,它们使得将新的化合物开发成药物物质成为可能并且由于它们的有利的肠内吸收这些化合物能被口服应用。
我们已经发现通式(I)的化合物-其中
R1代表氢原子或一个直链或支链C1-4烷基;
R2代表氢原子或一个直链或支链C1-4烷基;
R3代表氢原子或一个直链或支链C1-4烷基,或一个苯基,噻吩基,或呋喃基,可选择地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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5-或6元芳杂环,可选择地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代表氢原子或一起形成一个1,3-丁间二烯基,可选择地被一个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代表氢原子或一个氰基,氨羰基,C1-4烷氧羰基,或羧基;
R7代表氢原子或一个直链或支链C1-4烷基,或一个苯基,苄基,噻吩基或呋喃基,可选择地被一个亚甲二氧基,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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5或6元芳杂环-可选择地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代表一个CH2-基团,-NH-基团,-NR8基团,或一个硫原子或一个氧原子或一个磺基或一个亚硫酰基-其中R8代表一个直链或支链C1-4烷基或C3-6环烷基-;
n代表0,1或2-和它们的盐,溶剂化物和同分异构体和后者的盐,溶剂化物,满足上述的条件。
上面所列取代基的详细含义如下:
对于一个直链或支链C1-4烷基我们指甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,优选为乙基或甲基。
对于一个直链或支链C1-4烷氧基我们指甲氧基,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,优选为乙氧基或甲氧基。
对于一个C3-6环烷基我们指环丙基,环丁基,环戊基或环己基。
对于1,3-丁间二烯基我们指(-CH=CH-CH=CH-)基,也就是被R4和R5取代基取代的吡啶环指苯基吡啶环或它的俗名为喹啉环。
包含一个或两个或三个氮原子的芳杂环指吡咯,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。此环可选择地被一个C1-4烷基,或烷氧基或被一个卤素原子取代。
包含一个氮原子和一个氧原子或硫原子的芳杂环指噁唑,异噁唑,三唑,异三唑环。此环可选择地被一个C1-4烷基,或烷氧基或被一个卤素原子取代。
通式(I)的化合物的盐指由无机和有机酸与碱形成的盐。优选的盐是那些由药学上可接受的酸形成的盐,例如盐酸,硫酸,乙磺酸,酒石酸,琥珀酸,富马酸,苹果酸,柠檬酸,和碱,例如氢氧化钠,氢氧化钾,乙醇胺。
溶剂化物指由不同的溶剂形成的溶剂化物,例如由水或乙醇。
通式(I)的化合物显示几何学的和光学的同分异构现象,因此本发明也涉及几何异构体的混合物,涉及外消旋的或旋光几何异构体,也涉及它们的盐和溶剂化物。
通式(I)的化合物的有利的基团由通式(IA)的化合物形成,其中
R1代表氢原子或一个直链或支链C1-4烷基;
R2代表氢原子或一个直链或支链C1-4烷基;
R3代表氢原子或一个直链或支链C1-4烷基,或一个苯基,噻吩基,或呋喃基,可选择地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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5-或6元芳杂环-可选择地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;
R9,R10,R11和R12独立地指氢原子或直链或支链C1-4烷基,或直链或支链C1-4烷氧基,或羟基或卤素原子,或
R9和R12代表氢原子和R10和R11一起形成一个亚甲二氧基;
R6代表氢原子或一个氰基,氨羰基,C1-4烷氧羰基,或羧基;
R7代表氢原子或一个直链或支链C1-4烷基,或一个苯基,苄基,噻吩基或呋喃基,可选择地被一个亚甲二氧基,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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5或6元芳杂环-可选择地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代表一个CH2-基团,-NH-基团,-NR8基团,或一个硫原子或一个氧原子或一个磺基或一个亚硫酰基-其中R8代表一个直链或支链C1-4烷基或C3-6环烷基-;
n代表0,1或2-
和它们的盐,溶剂化物,旋光异构体和它的盐,溶剂化物。
通式(IA)的化合物的有利的基团是通过化合物形成的其中
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;
R9,R10,R11和R12独立地指氢原子或直链或支链C1-4烷基,或直链或支链C1-4烷氧基,或羟基或卤素原子,或
R9和R12代表氢原子和R10和R11一起形成一个亚甲二氧基;
R6代表氢原子或氰基;
R7代表4-甲氧基苯基,3-甲基苯基-,3-甲氧基苯基,3-噻吩基,或3-呋喃基,
X代表-NH-基团或氧原子和
n代表1-
和它们的盐,溶剂化物,旋光异构体和它的盐,溶剂化物。
特别有利的是下面依从上述条件的化合物:
3-甲基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺;
4-甲氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺;
3-甲氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺;
3,4-亚甲二氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺;
N-(4-苄氨-3-氰基喹啉-2-基)噻吩-2-甲酰胺;
N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)噻吩-3-甲酰胺;
4-甲氧基-N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)苯甲酰胺;
3,4-亚甲二氧基-N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)苯甲酰胺;
N-(4-[2-呋喃甲基氨]-3-氰基喹啉-2-基)呋喃-2-甲酰胺;
N-(4-[2-呋喃甲基氨]-3-氰基喹啉-2-基)噻吩-3-甲酰胺;
和它们的盐,溶剂化物,旋光异构体和它的盐,溶剂化物。
按照它的另一方面,本发明也涉及包含作为活性要素的通式(I)的化合物或它们的异构体,盐和溶剂化物的药物组合物,其优选是口服组合物,但是吸入的,非肠道的和透皮的制剂也是本发明的主题。上述的药物组合物可以是固体或液体,例如片剂,丸剂,胶囊,贴片,溶液,混悬液或乳剂。固体组合物,首先片剂和胶囊是优选的药物剂型。
上述药物组合物通过应用常规的药用辅料和利用标准的方法来制备。
通式(I)的化合物能被用于治疗在发展中A3受体起作用的病理。
本发明的化合物对A3受体具有选择性能被用作心脏,肾,呼吸系统,中枢神经系统功能紊乱的治疗和/或预防处理。它们抑制在生长的肿瘤细胞中的腺苷的保护效应,预防肥大细胞脱粒,抑制细胞因子产生,降低眼内压,抑制TNFα释放,抑制嗜酸性粒细胞、中性白细胞和其它免疫细胞的迁移,抑制支气管收缩和血浆外渗。
基于这些作用,本发明的腺苷A3受体拮抗剂可以是治疗学上有用的作为抗炎药,平喘药,抗局部缺血药,抗抑郁药,抗心律失常药,肾保护剂,抗肿瘤药,抗帕金森药和认知促进药。它们也可被用作心肌灌注损伤,慢性阻塞性肺病(COPD)和包括慢性支气管炎、肺气肿症或呼吸困难的成人呼吸窘迫综合症(ARDS),过敏反应(例如鼻炎,毒叶藤诱导的反应,风疹,硬皮病,关节炎)其它自身免疫性疾病,炎症性肠病,阿狄森氏病,克罗恩氏病,牛皮癣,风湿病,高血压,神经功能紊乱,青光眼和糖尿病的治疗或预防(K.N.Klotz,Naunyn-Schmiedberg’s Arch.Pharmacol.362:382;P.G.Baraldi es P.A.Borea,TiPS 21:456,2000)。
本发明的化合物可以被优选的用作疾病的治疗,例如哮喘,COPD和ARDS,青光眼,肿瘤,过敏性和炎性疾病,局部缺血,缺氧,心律失常和肾病。
按照它的另一方面,本发明涉及通式(I)的化合物在上述病理的治疗中的应用。建议的日剂量是1-100mg活性成分取决于疾病的性质和严重性和病人的性别,体重等。
本发明的进一步的主题是通式(I)的化合物和通式(II)(III)和(IV)的中间体的制备。
按照本发明被用在制备方法中的通式(II)(III)和(IV)的中间体是新的。通式(II)(III)和(IV)的取代基具有如上所定义的含义。
在按照我们的发明的方法中,通式(II)的双-氨甲酰选择性地被水解并且得到的通式(I)的化合物(如果希望的话)被转化成它的盐,溶剂化物或,从它的盐,溶剂化物中释放出来,并分离成它的几何或光学异构体。
通式(I)的化合物的取代基能通过已知的方法相互转换。
选择性的水解通过利用醇的,优选甲醇的氢氧化碱溶液,优选用氢氧化钾和/或氢氧化钠溶液来进行,但是其它帮助酰胺水解的剂也能被使用。
选择性的水解能在一个宽的温度范围内进行,有利地在20℃-100℃之间。
通式(II)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-能通过许多已知方法获得,在它们当中在流程图1中表示的(图6),通过式(III)化合物的酰化,通过利用在有机化学中已知的酰化方法得到。至于酰化剂优选酰基氯,至于酸结合剂三乙胺和/或嘧啶能被应用,但是其它酸结合剂也能被使用。
通式(III)的化合物-其中R1,R2,R3,R4,R5,R6,R8,X和n的含义如上所定义-可以从式(IV)化合物制备-通过利用本身已知的方法(Nan Zhang,Bioorg.和Med.Chem.Lett.,10,2825,2000)。
通式(IV)的化合物-其中R4,R5和R6的含义如上所定义-可以从式(V)化合物制备,通过本身已知的方法(D.L.Leysen,J.Heterocylic Chem.,24,1611,1987)。
通式(V)的化合物-其中R4,R5和R6的含义如上所定义-可以从式(VI)化合物制备,利用本身已知的方法(Pfizer(Inc)USP4,175,193)。
通式(I),(II),(III)和(IV)的本发明的化合物,它们的制备和生物活性在下面的实施例中说明,而不限制要求保护的范围在实施例范围。
图1是通式(I),图2是通式(IA),图3是通式(II),图4是通式(III)且图5是通式(IV)。图6是流程图1通式(I)化合物的制备的反应路线。
实施例
实施例1
3-甲基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺:
在通式(I)中R1和R2代表氢原子,R3代表苯基,R4和R5一起形成一个1,3-丁间二烯基,R6代表氰基,R7代表3-甲基苯基,X的含义是-NH基,n是1。
a.)
2-氨基-3-氰基-4-氯喹啉:
将10g 2-氨基-3-氰基-4-羟基喹啉和15ml磷酰基氯的混合物在搅拌下在110℃加热。将反应混合物冷却,倒入100ml冰水并用60ml 10%的氢氧化钠溶液中和。将得到的黄色沉淀物过滤,用50ml水洗涤。在干燥后获得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-苄基氨喹啉:
将5g 2-氨基-3-氰基-4-氯喹啉和11ml苄基胺在搅拌下在130℃加热。将反应化合物倒入50ml水中,将得到的沉淀物过滤,用50ml水洗涤。将淡黄色的沉淀物从二甲基甲酰胺中重结晶来获得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,(d,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)
利用2-氨甲基吡啶或3-氨甲基吡啶或4-氨甲基吡啶代替苄基胺,能够得到适当的通式III的化合物。
c.)3-甲基-N-(3-甲基苯酰基)-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺
向在30ml吡啶中的5g 2-氨基-3-氰基-4-苄氨喹啉的溶液中在0℃搅拌下滴加6ml 3-甲基苯酰氯。将反应混合物在80℃搅拌8小时,然后将其倒入150ml冰水中。将沉淀物过滤,用40ml水洗涤两次。将得到的白色晶体物质从200ml乙醇中重结晶来得到9.2g标题化合物,mp.:234℃
通过利用吡啶-3-羰基氯作为酰化剂,能够得到合适的通式II的化合物。
d.)
3-甲基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺
向在80ml乙腈中的5g 3-甲基-N-(3-甲基苯酰基)-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺中加入20ml 1N甲醇氢氧化钾溶液。将反应混合物回流3分钟,然后向其中加入3ml冰醋酸,然后用50ml 1M碳酸氢钠溶液将其中和并将得到的结晶过滤。将白色的结晶物质从130ml乙腈中重结晶得到3.1g通式(I)的标题化合物。Mp.:230℃。
实施例2
4-甲氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是苯基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指4-甲氧基苯基,X指-NH基,n是1。
2-氨基-3-氰基-4-苄氨喹啉(如在实施例1中描述的制备)被4-甲氧基苯甲酰氯转化(与在实施例1中描述的类似)成4-甲氧基-N-(4-甲氧基苯甲酰基)-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺,其在选择性地水解后,通过实施例1中描述的方法,得到通式(I)的标题化合物。标题化合物的熔点:188℃。
标题化合物的钠盐通过下述方法制备:
将4-甲氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺溶解在甲醇中并向其中加入等量的在甲醇中的氢氧化钠。将沉淀的白色晶体物质过滤。Mp.:255℃。
标题化合物的乙磺酸盐通过如下方法制备:
将4-甲氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺溶解在甲醇中并向其中加入等量的乙磺酸。将沉淀的白色晶体物质过滤。Mp.:223℃。
实施例3
3-甲氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是苯基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指3-甲氧基苯基,X指-NH基,n是1。
2-氨基-3-氰基-4-苄氨喹啉(如在实施例1中描述的制备)被3-甲氧基苯甲酰氯转化(与在实施例1中描述的类似)成3-甲氧基-N-(3-甲氧基苯甲酰基)-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺,其在通过在实施例1中描述的方法选择性地水解后,得到通式(I)的标题化合物。标题化合物的熔点:186℃。
实施例4
3,4-亚甲二氧基-N-(4-苄氨-3-氰基喹啉-2-基)苯甲
酰胺
在通式(I)中R1和R2的含义是氢原子,R3是苯基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指3,4-亚甲二氧基苯基,X指-NH基,n是1。
2-氨基-3-氰基-4-苄氨喹啉(如在实施例1中描述的制备)被4-甲氧基苯甲酰氯转化(与在实施例1中描述的类似)成3,4-亚甲二氧基-N-(3,4-亚甲二氧基苯甲酰基)-N-(4-苄氨-3-氰基喹啉-2-基)苯甲酰胺,其在通过在实施例1中描述的方法选择性地水解后,得到通式(I)的标题化合物。标题化合物的熔点:231℃。
实施例5
N-(4-苄氨-3-氰基喹啉-2-基)噻吩-2-甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是苯基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指2-噻吩基,X指-NH基,n是1。
2-氨基-3-氰基-4-苄氨喹啉(如在实施例1中描述的制备),被噻吩-2-羰酰氯转化(与在实施例1中描述的类似)成N-(2-噻吩羰基)-N-(4-苄氨-3-氰基喹啉-2-基)噻吩-2-甲酰胺,其在选择性地水解后(通过在实施例1中描述的方法),得到通式(I)的标题化合物。标题化合物的熔点:197℃。
实施例6
N-(4-[2-噻吩基甲基氨]-3-氰基喹啉-2-基)噻吩-3
-氨甲酰
在通式(I)中R1和R2的含义是氢原子,R3是2-噻吩基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指3-噻吩基,X指-NH基,n是1。
a.)
2-氨基-3-氰基-4-(2-噻吩基甲基氨)喹啉:
将5g 2-氨基-3-氰基-4-氯喹啉(如在实施例1中描述的制备)和11ml 2-噻吩基甲基胺一起在130℃搅拌3小时。将反应混合物倒入50ml水中,将得到的沉淀物过滤,用50ml水洗涤。将淡黄色物质从25ml乙醇中重结晶得到5.2g标题化合物,mp.:208℃。
将如上所述制备的2-氨基-3-氰基-4-(2-噻吩甲基氨)喹啉用噻吩-3-碳酰氯(与在实施例1中描述的类似)转化成N-(3-噻吩羰基)-N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)-噻吩-3-氨甲酰,其在选择性地水解后(通过在实施例1中描述的方法),得到通式(I)的标题化合物。标题化合物的熔点:223℃。
实施例7
4-甲氧基-N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)
苯甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是2-噻吩基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指4-甲氧基苯基,X指-NH基,n是1。
将如在实施例6中描述的制备的2-氨基-3-氰基-4-(2-噻吩甲基氨)喹啉用4-甲氧基苯甲酰氯通过在实施例1中描述的方法转化成4-甲氧基-N-(4-甲氧基苯甲酰基)-N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)苯甲酰胺,其在选择性地水解后得到通式(I)的标题化合物。标题化合物的熔点:173℃。
实施例8
3,4-亚甲二氧基-N-(4-[2-噻吩甲基氨]-3-氰基喹啉
-2-基)-苯甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是2-噻吩基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指3,4-亚甲二氧基苯基,X指-NH基,n是1。
将如在实施例6中描述的制备的2-氨基-3-氰基-4-(2-噻吩甲基氨)喹啉用3,4-亚甲二氧基苯甲酰氯通过在实施例1中描述的方法转化成3,4-亚甲二氧基-N-(3,4-亚甲二氧基苯甲酰基)-N-(4-[2-噻吩甲基氨]-3-氰基喹啉-2-基)苯甲酰胺,其在选择性地水解后得到通式(I)的标题化合物。标题化合物的熔点:241℃。
实施例9
N-(4-[2-呋喃甲基氨]-3-氰基喹啉-2-基)呋喃-2-
甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是2-呋喃基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指2-呋喃基,X指-NH基,n是1。
a.)
2-氨基-3-氰基-4-(2-呋喃甲基氨)喹啉:
将5g 2-氨基-3-氰基-4-氯喹啉(如在实施例1中描述的制备)和1ml 2-呋喃基甲基胺(喃甲基胺)一起在130℃搅拌3小时。将反应混合物倒入50ml水中,将得到的沉淀物过滤,用50ml水洗涤。将淡黄色物质从20ml乙醇中重结晶得到4.8g标题化合物,mp.:208℃。
将如上所述制备的2-氨基-3-氰基-4-(2-呋喃甲基氨)喹啉用呋喃-2-碳酰氯通过在实施例1中描述的方法转化成N-(2-呋喃羰基)-N-(4-[2-呋喃甲基氨]-3-氰基喹啉-2-基)呋喃-2-甲酰胺,其在选择性地水解后得到通式(I)的标题化合物。标题化合物的熔点:196℃。
实施例10
N-(4-[2-呋喃甲基氨]-3-氰基喹啉-2-基)噻吩-3-
甲酰胺
在通式(I)中R1和R2的含义是氢原子,R3是2-呋喃基,R4和R5一起指一个1,3-丁间二烯基,R6指氰基,R7指3-噻吩基,X指-NH基,n是1。
1.
将如在实施例6中描述的相似地制备的2-氨基-3-氰基-4-(2-呋喃甲基氨)喹啉用噻吩-3-碳酰氯通过在实施例1中描述的方法转化成N-(3-噻吩羰基)-N-(4-[2-呋喃甲基氨]-3-氰基喹啉-2-基)噻吩-3-甲酰胺其在选择性地水解后(如在实施例1中描述的进行)得到通式(I)的标题化合物。标题化合物的熔点:118℃。
通过在实施例1中描述的方法制备的通式(I)的进一步的化合物的结构和物理性质显示在表I.和II.中。
表I
表II
通过在实施例1中描述的方法制备的通式(II)的中间体的结构和物理性质显示在表III中。
表III
通过在实施例1中描述的方法制备的通式(III)和(IIIa)的中间体的结构和物理性质显示在表IV中。
表IV
通过在实施例1中描述的方法制备的通式(V)的中间体的结构和物理性质显示在表V中。
表V
实施例172.
下述组合物的片剂通过在制药工业中使用的已知方法制备
活性成分 25mg
乳糖 50mg
微晶纤维素 21mg
交联聚维酮 3mg
硬脂酸镁 1mg
生物学
方法
人类腺苷A3受体结合
制备膜混悬液:收集通过用冰冷PBS洗涤三次的表达hA3受体的CHO细胞,在1000×g离心10分钟,在缓冲液(50mM Tris,10mMMgCl2,1mM EDTA,pH8.0)中匀化15秒,在43.000×g离心10分钟(西格玛3K30),混悬膜制剂在上面提到的缓冲液中,在-80℃储存等分试样。
结合方案:在孵化缓冲液中(50mM Tris,10mM MgCl2,1mMEDTA,3U/mL腺苷脱氨酶,pH8.0)在0.5nM[125I]AB-MECA(p-氨基-苄基-甲基氨甲酰-腺苷)(100.000cpm)和100μM R-PIA(N6-[L-2-苯基异丙基]腺苷)的存在下孵化CHO-hA3膜制剂(2μg蛋白质含量),来在室温下定义总量50μl的非-特异性结合或试验化合物1小时。滤过Whatman GF/B玻璃纤维过滤器(在0.5%聚乙烯亚胺中预先浸泡3小时),在96-孔Brandel Cell Harvester中用1mL冰冷的50mM Tris,10mM MgC12,1mM EDTA(pH8.0)洗涤4x。活性检测:在γ-计数器(1470 Wizard,Wallac)中。抑制[%]=100-((存在的试验化合物的活性-非-特异性活性)/(总活性-非-特异性活性))*100
人类腺苷A1受体结合
制备膜混悬液:收集通过用冰冷PBS洗涤三次的表达hA1受体的CHO细胞,在1000×g离心10分钟,在缓冲液(50mM Tris,pH7.4)中匀化15秒,在43.000×g离心10分钟(西格玛3K30),混悬膜制剂在上面提到的缓冲液中,在-80℃储存等分试样。
结合方案:在孵化缓冲液(50mM Tris,3U/mL腺苷脱氨酶,pH7.4),10nM[3H]CCPA(2-氯-N6-环penthyl-腺苷)(80.000dpm)和10μMR-PIA(N6-[L-2-苯基异丙基]腺苷)中孵化CHO-hA1膜制剂(50μg蛋白质含量),来在室温下定义总量100μl的非-特异性结合或试验化合物3小时。滤过Whatman GF/B玻璃纤维过滤器(在0.5%聚乙烯亚胺中预先浸泡3小时),在96-孔Brandel CellHarvester中用1mL冰冷的50mM Tris,(pH7.4)洗涤4x。活性检测:在96-孔板中在HiSafe-3 coctail的存在下在β-计数器(1450Microbeta,Wallac)中。抑制[%]=100-((存在的试验化合物的活性-非-特异性活性)/(总活性-非-特异性活性))*100
人类腺苷A2a受体结合
结合方案:孵化7μg膜(人类A2a腺苷受体转染入HEK-293细胞,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-[p-(2-羰基乙基)苯基乙基氨]-5′-N-乙基氨甲酰-腺苷)(200.000dpm)和50μm NECA(5′-N-乙基氨甲酰-腺苷)来在室温下定义总量100μl的非-特异性结合或试验化合物90分钟。滤过Whatman GF/B玻璃纤维过滤器(在0.5%聚乙烯亚胺中预先浸泡),在96-孔Brandel Cell Harvester中用1mL冰冷的50mM Tris,10mM MgCl2,1mM EDTA,0.9%NaCl,pH7.4洗涤4x。活性检测:在96-孔板中在HiSafe-3 coctail的存在下在β-计数器(1450Microbeta,Wallac)中。抑制[%]=100-((存在的试验化合物的活性-非-特异性活性)/(总活性-非-特异性活性))*100
人类腺苷A2b受体结合
结合草案:孵化20.8μg膜(人类A2b腺苷受体转染入HEK-293细胞,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penthyl-1,3-二丙基黄嘌呤)(800.000dpm)和100μm NECA(5′-N-乙基氨甲酰-腺苷)来在室温下定义总量100μl的非-特异性结合或试验化合物30分钟。滤过Whatman GF/B玻璃纤维过滤器(在0.5%聚乙烯亚胺中预先浸泡),在96-孔Brandel Cell Harvester中用1mL冰冷的50mM Tris-HCl(pH6.5)洗涤4x。活性检测:在96-孔板中在HiSafe-3 coctail的存在下在β-计数器(1450 Microbeta,Wallac)中。抑制[%]=100-((存在的试验化合物的活性-非-特异性活性)/(总活性-非-特异性活性))*100
结果
我们将化合物认为是生物学上有活性的化合物如果它们在我们的试验条件下在1μM具有高于80%的活性抑制放射性配体在人类腺苷A3受体上的结合。
在CHO-hA3膜制剂上的[125I]AB-MECA的解离常数(Kd)通过在Scatchard分析的帮助下的同位素饱和度研究来决定((G.Scatchard,Ann.N.Y.Acad.Sci.51:660,1949))。IC50通过应用Cheng-Prusoff方程式被转化成一个亲和常数(Ki)(Y.J.Cheng和W.H.Prusoff,Biochem.Pharmacol.22:3099,1973)。
通式(I),(II),(III)和(IV)的一些化合物显示显著的生物活性。通式(IA)的化合物(在权利要求2中定义),作为通式(I)的子群(在权利要求1中定义),发挥最重要的活性。除5化合物之外,他们的Ki值不高于20nM。作为实施例给出的化合物是特别有利的。它们的在人类腺苷A3受体结合研究中的Ki值在0.19和0.69nM之间。最有利的化合物的Ki值在0.14和0.15nM之间。
这些化合物具有适当的生物利用度并且发挥关于人类腺苷A1,A2a和A2b受体亚型至少10,000-倍的选择性。
进一步,它们的静脉内和口服给药的作用的持续时间是足够长的,它们的ED50值低,他们的毒理学的和副作用的情况是有利的。
上面的数据使得通式(I)的化合物能用作治疗应用。
Claims (20)
1.通式(I)的化合物-其中
R1代表氢原子或一个直链或支链C1-4烷基;
R2代表氢原子或一个直链或支链C1-4烷基;
R3代表氢原子或一个直链或支链C1-4烷基,或一个苯基,噻吩基,或呋喃基,可选择地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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5-或6元芳杂环,可选择地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代表氢原子或一起形成一个1,3-丁间二烯基,可选择地被一个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代表氢原子或一个氰基,氨羰基,C1-4烷氧羰基,或羧基;
R7代表氢原子或一个直链或支链C1-4烷基,或一个苯基,苄基,噻吩基或呋喃基,可选择地被一个亚甲二氧基,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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5或6元芳杂环,可选择地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代表一个CH2-基团,-NH-基团,-NR8基团,或一个硫原子或一个氧原子或一个磺基或一个亚硫酰基-其中R8代表一个直链或支链C1-4烷基或C3-6环烷基-;
n代表0,1或2-
和它们的盐和溶剂化物,旋光异构体和它们的盐和溶剂化物。
2.根据权利要求1的通式(IA)的化合物-其中
R1代表氢原子或一个直链或支链C1-4烷基;
R2代表氢原子或一个直链或支链C1-4烷基;
R3代表氢原子或一个直链或支链C1-4烷基,或一个苯基,噻吩基,或呋喃基,可选择地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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5-或6元芳杂环-可选择地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;
R9,R10,R11和R12各自独立地代表氢原子或直链或支链C1-4烷基,或直链或支链C1-4烷氧基,或羟基或卤素原子,或
R9和R12代表氢原子和R10和R11一起形成一个亚甲二氧基;
R6代表氢原子或一个氰基,氨羰基,C1-4烷氧羰基,或羧基;
R7代表氢原子或一个直链或支链C1-4烷基,一个苯基,苄基,噻吩基或呋喃基,可选择地被一个亚甲二氧基,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,或代表包含一个、两个或三个氮原子或一个氮原子和一个氧原子或一个氮原子和一个硫原子的5或6元芳杂环-可选择地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代表一个CH2-基团,-NH-基团,-NR8基团,或一个硫原子或一个氧原子或一个磺基或一个亚硫酰基-其中R8代表一个直链或支链C1-4烷基或C3-6环烷基-;
n代表0,1或2
和它们的盐和溶剂化物,旋光异构体和它们的盐和溶剂化物。
3.根据权利要求2的通式(IA)的化合物-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;
R9,R10,R11和R12各自独立地代表氢原子或直链或支链C1-4烷基,直链或支链C1-4烷氧基,或羟基或卤素原子,或
R9和R12代表氢原子且R10和R11一起形成一个亚甲二氧基;
R6代表氢原子或氰基;
R7代表4-甲氧基苯基,3-甲基苯基-,3-甲氧基苯基,3-噻吩基,或3-呋喃基,
X代表-NH-基团或氧原子和
n代表1-
和它们的盐,溶剂化物和旋光异构体和它们的盐和溶剂化物。
4.根据权利要求1-3的化合物如下:
3-甲基-N-(4-苄氨-3-氰基-喹啉-2-基)苯甲酰胺;
4-甲氧基-N-(4-苄氨-3-氰基-喹啉-2-基)苯甲酰胺;
3-甲氧基-N-(4-苄氨-3-氰基-喹啉-2-基)苯甲酰胺;
3,4-亚甲二氧基-N-(4-苄氨-3-氰基-喹啉-2-基)苯甲酰胺;
N-(4-苄氨-3-氰基-喹啉-2-基)噻吩-3-甲酰胺;
N-(4-[2-噻吩甲基氨]-3-氰基-喹啉-2-基)噻吩-3-甲酰胺;
4-甲氧基-N-(4-[2-噻吩甲基氨]-3-氰基-喹啉-2-基)苯甲酰胺;
3,4-亚甲二氧基-N-(4-[2-噻吩甲基氨]-3-氰基-喹啉-2-基)苯甲酰胺;
N-(4-[2-呋喃甲基氨]-3-氰基-喹啉-2-基)呋喃-2-甲酰胺;
N-(4-[2-呋喃甲基氨]-3-氰基-喹啉-2-基)噻吩-2-甲酰胺;
和它们的盐,溶剂化物,旋光异构体和它们的盐和溶剂化物。
5.制备通式(I)的化合物,它的盐,溶剂化物,旋光异构体和它们的盐和溶剂化物的方法-其中在结构式中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义,其特征在于通过通式(II)的双酸酰胺的选择性的水解-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-并且如果希望的话彼此通过本身已知的方法转化如此获得的通式(I)的化合物的取代基和/或转化如此获得的通式(I)的化合物成它的盐,或溶剂化物,或将它从它的盐或溶剂化物中释放和/或分离它成为它的旋光异构体形式或转化旋光异构体形式成外消旋型。
6.根据权利要求5的方法,其特征在于通过在一种氢氧化碱的存在下在醇介质中进行选择性的水解,优选是氢氧化钾或氢氧化钠。
7.药物组合物包含作为活性成分的一种或多种通式(I)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-或它们的盐、溶剂化物、或旋光异构体和它们的盐、溶剂化物,与一种或多种在制药工业中应用的辅料的混合物。
8.根据权利要求7的药物组合物包含作为活性成分的一种或多种通式(IA)的化合物-其中R1,R2,R3,R6,R7,R8,R9,R10,R11,R12,X和n具有如在权利要求2中定义的相同的含义-或它们的盐,溶剂化物,或旋光异构体和它们的盐,溶剂化物,与一种或多种在制药工业中应用的辅料的混合物。
9.根据权利要求8的药物组合物包含作为活性成分的一种或多种权利要求4的化合物。
10.通式(I)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-在发展中受体A3起作用的疾病的治疗中的应用。
11.通式(I)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-按照权利要求10作为A3配体在心脏病,肾病,呼吸器官疾病和中枢神经系统疾病的情况中,在生长的肿瘤细胞中的腺苷的保护效应的抑制中,在肥大细胞脱粒的预防中,在细胞因子产生的抑制中,在眼内压的降低中,在TNFα释放的抑制中,在嗜酸性粒细胞、中性白细胞和其它免疫细胞的迁移的抑制中,在支气管收缩和血浆外渗的抑制中的应用。
12.通式(I)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-按照权利要求10和11作为A3受体拮抗剂在抗炎,平喘,抗局部缺血,抗抑郁,抗心律失常,肾保护,抗肿瘤,抗帕金森和认知促进药物组合物和在治疗或预防心肌灌注损伤,慢性阻塞性肺病(COPD)和包括慢性支气管炎、肺气肿症或呼吸困难的成人呼吸窘迫综合症(ARDS),过敏反应(例如鼻炎,毒叶藤诱导的反应,风疹,硬皮病,关节炎)其它自身免疫性疾病,炎症性肠病,阿狄森氏病,克罗恩氏病,牛皮癣,风湿病,高血压,神经功能紊乱,青光眼和糖尿病的药物组合物中作为活性成分的应用。
13.通式(I)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-按照权利要求10,11和12作为A3受体拮抗剂在疾病例如哮喘,COPD和ARDS,青光眼,肿瘤,过敏性和炎性疾病,局部缺血,缺氧,心律失常和肾病的治疗中作为活性成分的应用。
14.通式(IA)的化合物-其中R1,R2,R3,R6,R7,R8,R9,R10,R11,R12,X和n具有如在权利要求2中定义的相同的含义-在发展中受体A3起作用的疾病的治疗中的应用。
15.通式(IA)的化合物-其中R1,R2,R3,R6,R7,R8,R9,R10,R11,R12,X和n具有如在权利要求2中定义的相同的含义-按照权利要求13作为A3配体在心脏病,肾病,呼吸器官疾病和中枢神经系统疾病的情况中,在生长的肿瘤细胞中的腺苷的保护效应的抑制中,在肥大细胞脱粒的预防中,在细胞因子产生的抑制中,在眼内压的降低中,在TNFα释放的抑制中,在嗜酸性粒细胞、中性白细胞和其它免疫细胞的迁移的抑制中,在支气管收缩和血浆外渗的抑制中的应用。
16.通式(IA)的化合物-其中R1,R2,R3,R6,R7,R8,R9,R10,R11,R12,X和n具有如在权利要求2中定义的相同的含义-按照权利要求13和14作为A3受体拮抗剂在抗炎,平喘,抗局部缺血,抗抑郁,抗心律失常,肾保护,抗肿瘤,抗帕金森和认知促进药物组合物中和在治疗或预防心肌灌注损伤,慢性阻塞性肺病(COPD)和包括慢性支气管炎,肺气肿症或呼吸困难的成人呼吸窘迫综合症(ARDS),过敏反应(例如鼻炎,毒叶藤诱导的反应,风疹,硬皮病,关节炎)其它自身免疫性疾病,炎症性肠病,阿狄森氏病,克罗恩氏病,牛皮癣,风湿病,高血压,神经功能紊乱,青光眼和糖尿病的药物组合物中作为活性成分的应用。
17.通式(I)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义-按照权利要求14,15和16作为A3受体拮抗剂在疾病例如哮喘,COPD和ARDS,青光眼,肿瘤,过敏性和炎性疾病,局部缺血,缺氧,心律失常和肾病的治疗中作为活性成分的应用。
18.通式(II)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义。
19.通式(III)的化合物-其中R1,R2,R3,R4,R5,R6,R7,R8,X和n具有如在权利要求1中定义的相同的含义,附带条件是R3不能代表苯基,如果R1和R2代表氢原子,n=1,X代表一个-NH-基,R4和R5一起形成一个1,3-丁间二烯基和R6代表一个氰基。
20.通式(IV)的化合物-其中R4,R5和R6具有如在权利要求1中定义的相同的含义。
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HUP0102279 | 2001-05-31 | ||
HU0200774A HUP0200774A2 (hu) | 2002-03-01 | 2002-03-01 | Amino-piridin és amino-kinolin származékok, eljárás előállításukra, ezeket tartalmazó gyógyszerkészítmények és intermedierjeik |
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HUP0203976A3 (en) * | 2002-11-15 | 2004-08-30 | Sanofi Aventis | Adenozine a3 receptors, process for their preparation and pharmaceutical compositions containing them |
US8729107B2 (en) * | 2002-12-06 | 2014-05-20 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US7244748B2 (en) * | 2002-12-06 | 2007-07-17 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
WO2005009969A1 (en) * | 2003-07-31 | 2005-02-03 | Sanofi-Aventis | Aminoquinoline derivatives and their use as adenosine a3 ligands |
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 |
WO2006040645A1 (en) * | 2004-10-11 | 2006-04-20 | Ranbaxy Laboratories Limited | N-(3,5-dichloropyridin-4-yl)-2,4,5-alkoxy and 2,3,4-alkoxy benzamide derivatives as pde-iv (phophodiesterase type-iv) inhibitors for the treatment of inflammatory diseases such as asthma |
KR100788161B1 (ko) * | 2006-01-06 | 2007-12-21 | (주)아모레퍼시픽 | 벤즈이미다졸 아민 유도체 또는 아미노퀴놀린 유도체를 함유하는 피부 미백용 조성물 |
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 |
KR101106050B1 (ko) * | 2009-03-25 | 2012-01-18 | 한국과학기술연구원 | 아미노퀴놀린 화합물, 이의 제조 방법 및 이를 함유하는 의약 조성물 |
US20120053176A1 (en) * | 2010-09-01 | 2012-03-01 | Ambit Biosciences Corp. | Adenosine a3 receptor modulating compounds and methods of use thereof |
CA2754237A1 (en) | 2011-05-27 | 2012-11-27 | The Regents Of The University Of California | Cyanoquinoline compounds having activity in correcting mutant-cftr processing and increasing ion transport and uses thereof |
WO2012166654A1 (en) * | 2011-05-27 | 2012-12-06 | The Regents Of The University Of California | Cyanoquinoline compounds having activity in correcting mutant-cftr processing and increasing ion transport and uses thereof |
ES2578363B1 (es) | 2015-01-22 | 2017-01-31 | Palobiofarma, S.L. | Moduladores de los receptores A3 de adenosina |
KR102697810B1 (ko) * | 2015-08-03 | 2024-08-21 | 브리스톨-마이어스 스큅 컴퍼니 | Tnf 알파의 조정제로서 유용한 헤테로시클릭 화합물 |
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