CN101830889A - 嘧啶衍生物 - Google Patents
嘧啶衍生物 Download PDFInfo
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- CN101830889A CN101830889A CN201010197457A CN201010197457A CN101830889A CN 101830889 A CN101830889 A CN 101830889A CN 201010197457 A CN201010197457 A CN 201010197457A CN 201010197457 A CN201010197457 A CN 201010197457A CN 101830889 A CN101830889 A CN 101830889A
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Abstract
Description
本申请是中国专利申请03806101.5的分案申请,原申请的申请日是2003年3月14日,发明名称是“嘧啶衍生物”。
本发明涉及嘧啶衍生物,涉及它们的生产方法、它们用作药物的用途,以及涉及包含它们的药物组合物。
更具体地,本发明在第一方面提供了游离形式或盐形式的式I化合物,
其中,X为=CR0-或=N-;
R0,R1,R2,R3和R4中的每一个独立地是氢;羟基;C1-C8烷基;C2-C8链烯基;C3-C8烷基;C3-C8环烷基-C1-C8烷基;羟基C1-C8烷基;C1-C8烷氧基C1-C8烷基;羟基C1-C8烷氧基C1-C8烷基;任选地在环上可以被羟基、C1-C8烷氧基、羧基或C1-C8烷氧基羰基取代的芳基C1-C8烷基;
或R3和R4及与它们连接的氮和碳原子一起形成5到10元杂环,并额外地包含1、2或3个选自N、O和S的杂原子;
或R1、R2和R3中的每一个独立地是卤素、卤代-C1-C8烷基;C1-C8烷氧基、卤代-C1-C8烷氧基、羟基C1-C8烷氧基;C1-C8烷氧基C1-C8烷氧基;芳基;芳基C1-C8烷氧基;杂芳基;杂芳基-C1-C4烷基;5到10元杂环;硝基;羧基;C2-C8烷氧基羰基;C2-C8烷基羰基;-N(C1-C8烷基)C(O)C1-C8烷基;-N(R10)R11;-CON(R10)R11;-SO2N(R10)R11;或-C1-C4-亚烷基-SO2N(R10)R11;其中R10和R11中的每一个独立地是氢;羟基;C1-C8烷基;C2-C8链烯基;C3-C8环烷基;C3-C8环烷基-C1-C8烷基;C1-C8烷氧基C1-C8烷基;羟基C1-C8烷氧基C1-C8烷基;羟基C1-C8烷基;(C1-C8烷基)-羰基;任选地可以在环上被羟基、C1-C8烷氧基、羧基或C2-C8烷氧基羰基取代的芳基C1-C8烷基;或5到10元杂环;
或R1和R2和与它们连接的C-原子一起形成芳基或包含一个或两个选自N、O和S的杂原子的5到10元杂芳基;或
R5和R6中的每一个独立地是氢;卤素;氰基;C1-C8烷基;卤代-C1-C8烷基;C2-C8链烯基;C2-C8炔基;C3-C8环烷基;C3-C8环烷基C1-C8烷基;C5-C10芳基C1-C8烷基;
R7、R8和R9中的每一个独立地是氢;羟基;C1-C8烷基;C2-C8链烯基;卤代-C1-C8烷基;C1-C8烷氧基;C3-C8环烷基;C3-C8环烷基C1-C8烷基;芳基C1-C8烷基;
-Y-R12,其中Y是一直接键或O,且R12是一个取代的或未取代的包含1、2或3个选自N、O和S的杂原子的5、6或7元杂环;羧基、(C1-C8烷氧基)-羰基;-N(C1-8烷基)-CO-NR10R11;-CONR10R11;-N(R10)(R11);-SO2N(R10)R11;R7和R8或R8和R9,分别和与它们连接的碳原子一起形成包含选自N、O和S的1、2或3个杂原子的5或6元杂芳基;或5或6元碳环。
任何芳基可以是苯基、萘基或1,2,3,4-四氢化萘基,优选苯基。杂芳基是芳香族杂环,如5或6元芳香杂环,其任选地缩合到1或2个苯环和/或别的杂环上。
任何杂环可以是饱和的或不饱和的,并任选地缩合到1或2个苯环和/或别的杂环上。
杂环或杂芳基的实例包括例如吗啉基、哌嗪基、哌啶基、吡咯烷基、吡啶基、嘌呤基、嘧啶基、N-甲基-氮杂-环庚烷-4-基、吲哚基、喹啉基、异喹啉基、1,2,3,4-四氢喹啉基、苯并噻唑基、噻唑基、咪唑基、苯并咪唑基、苯并噁二唑基、苯并***基、2,3-二氢化茚基、噁二唑基、吡唑基、***基和四唑基。优选的杂环或杂芳基是吗啉基、哌嗪基、哌啶基、吡咯烷基、吡啶基、N-甲基-氮杂-环庚烷-4-基、噻唑基、咪唑基和四唑基。
当R7和R8或R8和R9和与其连接的碳原子一起形成5或6元碳环时,此环可优选地为环戊基或环己基。
卤代-烷基是其中一个或多个H被卤素取代的烷基(如CF3)。
任何烷基或烷基部分可以是直链或支链。C1-8烷基优选地是C1-4烷基。C1-8烷氧基优选地是C1-4烷氧基。任何烷基、烷氧基、链烯基、环烷基、杂环、芳基或杂芳基可以(除非另作说明)未被取代或被一个或多个选自卤素;OH;C1-C8烷基;C1-C8烷氧基;硝基;氰基;COOH;氨基甲酰基;C(NH2)=NOH;-N(R10)R11;C3-C6环烷基;3到7元杂环;苯基;苯基-C1-4烷基;5或6元杂芳基的取代基取代。当烷基、烷氧基或链烯基被取代时,其取代基优选地位于末端C原子上。当杂环或杂芳香环被取代(如上面公开的),取代可以在一个或多个环碳原子和/或环氮原子(如果存在)上。环氮原子上的取代基的实例是,例如C1-8烷基、氨基甲酰基、-C(NH2)=NOH、-NR10R11、C3-6环烷基或苯基-C1-4烷基,优选地是C1-8烷基、C3-6环烷基或苯基-C1-4烷基。
优选地取代的烷基或烷氧基(如R7)是其末端C原子被OH、C1-4烷氧基或杂环取代的烷基或烷氧基。当R10或R11是5到10元杂环时,它可以是例如噻唑基。
卤素可以是F、Cl、Br或I。
优选地,至多R1、R2或R3其中之一是CONR10R11或SO2NR10R11,更优选地为SO2NR10R11。
本发明化合物可以以游离形式或盐的形式存在,例如与如有机或无机酸(例如三氟乙酸或氢氯酸)形成的加成盐,或当它们包含羧基基团时,例如通过和碱(例如碱金属的盐,如钠、钾或取代的或非取代的铵盐)反应而可获得的盐。
在式I中,独立地、共同地或以任何组合或亚组合方式优选地具有下列意义:
(a)X是=CR0;
(b)R0是氢;卤素(如Cl);C1-C4烷基(如甲基或乙基);C1-4烷基(如甲氧基);优选氢;
(c)R1是氢、卤素(如Cl或F);OH;C1-C8烷基(如甲基或乙基);取代的C1-8烷基(如末端OH取代的C1-8烷基);-SO2N(R10)R11;-N(C1-4烷基)C(O)C1-4烷基;环上N原子任选地被取代(当可能时)的5或6元杂环;C1-C8烷氧基(如甲氧基);芳基(如苯基);或和R2及与R1和R2连接的C-原子一起形成5到10元芳基或杂芳基,后者包含1或2个氮原子;
(d)R2是氢;羟基、C1-C8烷基(如甲基或乙基);取代的C1-8烷基(如末端OH-或C1-4-烷氧基取代的C1-8烷基);C1-8烷氧基;C1-C4烷氧基C1-C8烷氧基;-CON(R10)R11;-SO2N(R10)R11;或和R1及R1和R2连接的C-原子一起形成5到10元芳基或杂芳基,后者包含1或2个氮原子;
(e)R3是氢;卤素(如Cl、Br);羟基;C1-C8烷基(如甲基或乙基);取代的C1-C8烷基(如末端OH取代的C1-8烷基);羧基;CONR10R11;-SO2N(R10)R11;环氮原子(当可能时)任选地被取代的5或6元杂环;或和R4及与R3和R4连接的N和C原子一起形成6元杂环。
(f)R4是氢;或和R3及与R3和R4连接的N和C原子一起形成6元杂环;优选氢;
(g)R5是氢;卤素;C1-4烷基;或CF3;
(h)R6是氢
(i)R7是氢;羟基;C1-4烷基;取代的C1-4烷基(如末端OH取代的C1-4烷基);C1-8烷氧基;取代的C1-8烷氧基(如末端被OH、C1-4烷氧基或杂环取代);NR10R11;-SO2N(R10)R11;-Y-R12;CF3;或R7和R8及与R7和R8相连的C-原子一起形成5元杂环(如通过-NH-CH=CH-、-CH=CH-NH-、-NH-N=CH-、-CH=N-NH-、-NH-N=N-或-N=N-NH-桥接);
(k)R8是氢;羟基;C1-4烷氧基;羧基;环C或N原子被任选地取代的5或6元杂环;N(C1-4烷基)-CO-NR10R11;或和R7或R9及与R7和R8或R8和R9分别相连的C-原子一起形成5元杂芳基(如通过-NH-CH=CH-、-CH=CH-NH-、-NH-N=CH-、-CH=N-NH-、-NH-N=N-或-N=N-NH-桥接);
(1)R9是氢;C1-4烷氧基;NR10R11;或和R8及与R8和R9相连的C原子一起形成5元杂芳基(如通过-NH-CH=CH-,-CH=CH-NH-,-NH-N=CH-,-CH=N-NH-,-NH-N=N-或-N=N-NH-桥接);
(m)R10和R11其中之一独立地是氢或C1-4烷基,另外一个是氢;OH;C1-8烷基、取代的C1-8烷基(如末端被OH、C3-6环烷基或杂环取代);C2-8链烯基;C3-8环烷基;羟基C1-8烷氧基C1-8烷基;或5元杂环。
R3优选地是SO2NR10R11。
本发明也提供用于产生式I化合物的方法,此方法包括将式II化合物
其中R1、R2、R3、R4、R5、R6和X是如上面定义的,Y是离去基团,优选卤素,例如
溴、碘,或特别是氯
和式III化合物反应
其中R7、R8和R9是如上面定义,
然后回收得到的游离形式或盐形式的式I化合物,并且根据需要,将以游离形式获得的式I化合物转化为想要的盐形式,反之亦然。
此方法可以根据本领域已知方法实施,例如实施例1到4中描述的。
用作起始物质的式II化合物可以通过将式IV化合物
与式V化合物反应得到:
其中R1、R2、R3、R4、R5、R6、Y和X是如上面定义的。
式IV和V化合物为已知或可根据已知方法生产。
下列实施例阐明本发明而不构成对本发明的任何限制。
下列缩写被采用:APC=别藻蓝蛋白,BINAP=2,2’-双(二苯基膦基)-1,1’-联萘基,cDNA=互补DNA,DCM=二氯甲烷,DIAD=偶氮二羧酸二异丙酯,DMAP=4-二甲氨基吡啶,DMF=二甲基甲酰胺,DMSO=二甲亚砜,DMF=二甲基甲酰胺;Pmc=2,2,5,7,8-五甲基苯并二氢吡喃;tBu=叔丁基;DIPCDI=N,N′-二异丙基碳二亚胺;DTT=1,4-二硫-D,L-苏糖醇;DNA=脱氧核糖核酸,EDTA=乙二胺四乙酸,Lck=淋巴样T-细胞蛋白酪氨酸激酶,LAT-11=用于T细胞活化的转接蛋白,RT=室温;RT-PCR=反转录聚合酶链反应,MS=电喷雾质谱测定的分子离子(如M+H1+),Eu=铕;ZAP-70=ζ链相关70kD蛋白;Syk=p72syk蛋白酪氨酸激酶;SA=链亲和素。
实施例1:2-[2-(1H-吲唑-6-基氨基)-嘧啶-4-基氨基]-苯磺酰胺
(a)2-(2-氯-嘧啶-4-基氨基)-苯磺酰胺:将22.1g(148.42mmol,3当量)2,4-二氯嘧啶和200ml10M盐酸(200mmol,4当量)加至8.52g(49.47mmol)2-氨基苯磺酰胺在200ml异丙醇的悬液中。悬液于60℃搅拌2小时15分钟。用2升乙酸乙酯稀释反应混合物,加入500ml水。通过加入碳酸氢钠将pH调整到8-9。分层,随后用500ml乙酸乙酯再萃取水层。用硫酸钠干燥有机层,过滤,然后蒸发至300ml体积。晶体沉淀形成并通过过滤去除(副产物)。将滤液蒸发至100ml,由此产物结晶产生2-(2-氯-嘧啶-4-基氨基)-苯磺酰胺(通过HPLC达到97%纯度)。通过柱层析法进一步纯化此结晶的母液,结晶产生更多2-(2-氯-嘧啶-4-基氨基)-苯磺酰胺。
(b)2-[2-(1H-吲唑-6基氨基)-嘧啶-4-基氨基]-苯磺酰胺:将13ml浓HCl*(130mmol,5当量)加至7.25g(25.46mmol)2-(2-氯-嘧啶-4-基氨基)-苯磺酰胺和4.07g(30.55mmol,1.2当量)6-氨基吲唑在400ml异丙醇中的悬液。回流悬液4小时30分钟。用1.5升乙酸乙酯稀释反应混合物,加入1升水。通过加入碳酸氢钠将pH调整到8-9。分层,用500ml乙酸乙酯再萃取水层。用硫酸钠干燥有机层,过滤,然后蒸发至300ml体积。晶体沉淀(1.01g)形成并通过过滤去除(副产物)。在200g硅胶上用乙酸乙酯/甲醇95/5v/v洗脱的色谱法纯化滤液。蒸发后形成结晶并过滤产生标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.42(s,1H),8.34(d,1h),8.28(d,1H),8.27(s,1H),7.93(s,1H,7.88(d,1H),7.62(m,2H),7.32(d,1H),7.24(t,1H),6.40(d,1H)。
MSm/z(%):382(M+H,100);
实施例2:2-[2-(3,4,5-三甲氧基-苯基氨基)-嘧啶-4-基氨基]-苯磺酰胺
除了在步骤(b)用3,4,5-三甲氧基-苯基胺代替6-氨基吲唑外,按实施例1所描述从2-(2-氯-嘧啶-4-基氨基)-苯磺酰胺制备标题化合物。
1H NMR(400MHz,DMSO-d6):δ9.18(s,1H),8.22(d,1H),8.17(d,1H),7.89(d,1H),7.55(t,1H),7.25(t,1H),7.14(s,2H),6.40(d,1H),3.69(s,6H),3.62(s,3H).MSm/z(%):432(M+H,100);
实施例3:2-甲基-6-[2-(3,4,5-三甲氧基-苯基氨基)-嘧啶-4-基氨基]-苯磺酰胺
除了在步骤(a)中使用2-氨基-6-甲基-苯磺酰胺代替2-氨基苯磺酰胺外,按实施例1所描述制备标题化合物。
按照Girard,Y等人;J.J.Chem.Soc.Perkin Trans.I 1979,4,1043-10472描述可以制备2-氨基-6-甲基-苯磺酰胺:氮环境下-55-49℃时,将间甲苯胺(32.1g,32.5ml,0.30mmol)滴加入氯磺酰异氰酸酯(51.3ml,83.6g,0.59mmol)的硝基乙烷(400ml)溶液中。移去冷浴,将混合物升温至-8℃随后加入氯化铝(51g,0.38mmol)。加热混合物至100℃20分钟,形成澄清褐色溶液,将其冷却至室温然后倾倒于冰上。过滤、用冰水和二***洗涤后,收集沉淀,将其溶解于二氧杂环己烷(300ml)。加入水(1000ml)和浓HCl(1500ml)形成悬液,将其加热至120℃18小时。冷却至RT后用二***/己烷(1400ml,1/1v/v)洗涤此澄清褐色溶液,通过加入碳酸钠调整使pH=8。用乙酸乙酯(2x1000ml)萃取、用水(500ml)和盐水(500ml)洗涤有机相、干燥(用硫酸镁),然后浓缩产生褐色固体,在二氧化硅上用二氯甲烷/乙醇(100/1v/v)洗脱的色谱法纯化此褐色固体产生白色固体的目标产物。
熔点:72-75℃(异丙醇);
1H NMR(400MHz,DMSO-d6):δ2.64(s,3H,Me),3.63(s,3H,OMe),3.68(s,6H,OMe),6.31(d,J=5Hz,1H,嘧啶CH),7.07(d,J=8Hz,1H,芳族CH),7.15(s,2H,芳族CH),7.40(t,J=8Hz,1H,芳族CH),7.65(s,2H,SO2NH2),8.04(d,J=8Hz,1H,芳族CH),8.12(d,J=5Hz,1H,嘧啶CH),9.14(s,1H,NH),9.40(s,1H,NH).
MS(ES+)m/z:446(MH+),468(MNa+)
MS(ES-):444(M-H)-
实施例4:2-甲氧基-6-[2-(3,4,5-三甲氧基-苯基氨基)-嘧啶-4-基氨基]-苯磺酰胺
除了在步骤(a)中使用2-氨基-6-甲氧基-苯磺酰胺代替2-氨基-6-甲基-苯磺酰胺外,按照实施例1描述可以制备标题化合物。
按照与实施例1a描述的类似方法可以从12.3g间-甲氧基苯胺制备2-氨基-6-甲氧基-苯磺酰胺。
NMR(400MHz,DMSO-d6):δ3.62(s,3H,OMe),3.69(s,6H,OMe),3.91(s,3H,OMe),6.31(d,J=5Hz,1H,嘧啶CH),6.86(d,J=8Hz,1H,芳族CH),7.12(s,2H,芳族CH),7.43(t,J=8Hz,1H,芳族CH),8.01(d,J=8Hz,1H,芳族CH),8.11(d,J=5Hz,1H,嘧啶CH),9.18(s,1H,NH),9.79(br,1H,NH).
MS(ES+):462.2(MH+),484.2(MNa+)
MS(ES-):460.3(M-H)-
式X1化合物,
其中R3、R7和R8如表1定义,可以通过用合适的起始物按照实施例1的方法制备。
表1
式X2化合物,
其中R3和R8如表2定义,可以通过用合适的起始物按照实施例1的方法制备。
表2
式X3化合物,
其中R1,R7,R8和R9如表3定义,可以通过用合适的起始物按照实施例1的方法制备。
表3
实施 | R1 | R7 | R8 | R9 | MS数据 |
例 | *ES+ | *ES- | ||||
61 | -SO2NH-CH2CH2-O-CH2CH2-OH | -H | -N(CH3)-C(O)CH3 | -H | ||
62 | -SO2NH2 | -OCH3 | -OCH3 | -OCH3 | ||
63 | -SO2NH2 | -O-CH2CH2-1-咪唑基 | -OCH3 | -H | ||
64 | -SO2NH-CH2CH2-O-CH2CH2-OH | -OCH3 | -OCH3 | -OCH3 | 520 | 518 |
65 | -N(CH3)C(O)CH3 | -OCH3 | -OCH3 | -OCH3 | 424 | 422 |
66 | -CH2CH2-OH | -SO2NH-CH2CH2CH2CH3 | -H | -H | ||
67 | -SO2NH2 | -OCH3 | -H | -OCH3 | ||
68 | -SO2NH2 | -O-CH2CH2-1-咪唑基 | -H | -H | ||
69 | -CH2CH2-OH | -O-CH2CH2-1-咪唑基 | -H | -H | ||
70 | -CH2CH2-OH | -OCH3 | -H | -OCH3 | ||
71 | -SO2NH2 | -OH | -H | -H | ||
72 | -O-CH2CH2-OH | -O-CH2CH2-1-咪唑基 | -H | -H | ||
73 | -SO2NH-2-噻唑基 | -OCH3 | -OCH3 | -OCH3 | 515 | 513 |
式X4化合物,
其中R2,R5,R7,R8和R9如表4定义,可以通过用合适的起始物按照实施例1的方法制备。
表4
式X5化合物,
其中R0,R1,R2,R3和R4如表5定义,可以通过用合适的起始物按照实施例1的方法制备。
表5
式X6化合物,
其中R5,R7,R8和R9如表6定义,可以通过用合适的起始物按照实施例1的方法制备。
表6
式X7化合物,
其中R1,R2,R3,R7和R8如表7定义,可以通过用合适的起始物按照实施例1的方法制备。
表7
式X8化合物,
其中R1,R2,R3和R8如表8定义,可以通过用合适的起始物按照实施例1的方法制备。
表8
式X9化合物,
其中R7,R8和R9如表9定义,可以通过用合适的起始物按照实施例1的方法制备。
表9
实施例 | R7 | R8 | R9 | *ES+ | *ES- |
173 | -O-CH2CH2-1-哌啶基 | -OCH3 | -H | 470.3 | 468.3 |
174 | -O-(1-甲基-氮杂环庚-4-基) | -H | -H | 440 | |
175 | -O-(1-甲基-氮杂环戊-2-基) | -H | -H | 440 | 438 |
176 | -O-CH2CH2-CH2-1-咪唑基 | -OCH3 | -H | 467 | 465 |
177 | -OCH3 | -OCH3 | -OCH3 | ||
178 | -O-CH2CH2-1-(1,2,4-***基) | -H | -H | 424 | 422 |
179 | -O-CH2CH2-1-哌啶基 | -H | -H | ||
180 | -O-CH2CH2-OH | -OCH3 | -H | ||
181 | -O-CH2CH2-4-吗啉代 | -H | -H | 442 | 440 |
182 | -O-CH2CH2CH2-1-咪唑基 | -H | -H |
式X10化合物,
其中R1,R7和R9如表10定义,可以通过用合适的起始物按照实施例1的方法制备。
表10
实施例 | R1 | R7 | R9 | *ES+ | *ES- |
183 | -CH2CH2-OH | -OCH3 | -OCH3 | 411 | 409 |
184 | -SO2NH2 | -O-CH2CH2-1-咪唑基 | -H | 496.3 | 494.3 |
式X11化合物,
其中R8是-OCH3(实施例185)或-OH(实施例186),可以通过用合适的起始物按照实施例1的方法制备。
式X12化合物,
其中R0,R1,R7,R8和R9如表12定义,可以通过用合适的起始物按照实施例1的方法制备。
表12
式X13化合物,
其中R1,R2,R3和R5如表13定义,可以通过用合适的起始物按照实施例1的方法制备。
表13
实施例 | R1 | R2 | R3 | R5 | *ES+ | *ES- |
208 | -H | -H | -SO2NHCH3 | -CF3 | 514.0 | |
209 | -H | -H | -SO2NHC3H7 | -Br | ||
210 | -H | -H | -SO2NH-CH2CH-环丙基 | -Br | ||
211 | -H | -H | -SO2NHCH3 | -CH3 | ||
212 | -H | -H | -SO2N(CH3)2 | -Br | ||
213 | -H | -H | -SO2NHCH3 | -Cl | ||
214 | -H | -H | -SO2NHCH3 | -I | ||
215 | -H | -H | -SO2NHCH3 | -Br | ||
216 | -CH3 | -OCH3 | -SO2NH2 | -H | 476 | 474 |
217 | -H | 哌啶子基 | -SO2NH2 | -H | 515.5 | 513.4 |
218 | -H | 吗啉代 | -SO2NH2 | -H | 517.4 | 515.4 |
219 | -H | -C2H5 | -SO2NH2 | -H | ||
220 | -H | -CH3 | -SO2NH2 | -Cl | ||
221 | -H | -CH3 | -SO2NHCH3 | -H | 460.4 | |
222 | -H | 苯基 | -SO2NH2 | -H | 508.2 | 506.3 |
式X14化合物,
其中R2,R3,R5,R7,R8和R9如表14定义,可以通过用合适的起始物按照实施例1的方法制备。
表14
ES+指电雾化MS正离子模式;ES-指电雾化MS负离子模式;且EL指电子碰撞MS
式I化合物和它们的可药用盐在体外测定中显示出有价值的药学性质,因此可用作药物。
特别地本发明化合物显示ZAP-70(70KD的ζ链-相关蛋白)、粘着斑激酶(FAK)和/或Syk蛋白酪氨酸激酶抑制活性。更特别地,本发明的化合物对人ZAP-70、FAK和/或Syk蛋白酪氨酸激酶有活性。本发明化合物与ZAP-70、FAK和/或Syk蛋白酪氨酸激酶间的相互作用可以通过它们阻止人ZAP-70蛋白酪氨酸激酶磷酸化例如LAT-11(SEQ ID NO:1)、阻止人FAK蛋白酪氨酸激酶磷酸化例如Biot-Y397(SEQ ID NO:2),和/或阻止在例如水溶液中人Syk蛋白酪氨酸激酶磷酸化例如多聚谷氨酸-酪氨酸(Glu,Tyr)的能力显示,这一点例如按照下面的实验方法显示。
1.无细胞激酶测定法:ZAP-70和Syk激酶测定法
ZAP-70,Lck和Syk在Upstate Biotechnology,Lake Placid,NY有市售。
LAT-11(SEQ ID NO:1)的制备:在ZAP-70激酶测定法中用作底物的肽LAT-11,可如WO 02/12275的实施例1A中所公开的那样制备,其内容特别是关于实施例1A此处引用作为参考。
ZAP-70激酶测定法:本发明试剂的活性在基于时间分辨荧光共振能量转移的均相ZAP-70激酶测定法中测定。简而言之,80nM ZAP-70与80nM Lck和4μM ATP在ZAP-70激酶缓冲液(20mM Tris,pH 7.5,10μMNa3VO4,1mM DTT,1 mM MnCl2,0.01%牛血清白蛋白,0.05%Tween20)在硅化聚丙烯试管中室温下孵育1小时。然后,加入选择性LCK抑制剂PP2(4-氨基-5-(4-氯-苯基)-7-(叔丁基)吡唑[3,4-d]嘧啶;AlexisBiochemicals)(终浓度为1.2μM)再孵育10分钟。10μl该溶液与10μl作为底物的生物素化肽LAT-11(1μM)和20μl系列稀释的抑制剂混合,室温下孵育4小时。激酶反应用10μl 10mMEDTA溶液在检测缓冲液(20mM Tris,pH 7.5,0.01%牛血清白蛋白,0.05%Tween 20)中终止。检测阶段通过在检测缓冲液中加入50μl铕(Eu)标记的抗磷酸酪氨酸抗体(例如Eu-PT66;终浓度0.125nM;Advant/Wallac)和50μl链亲和素-别藻蓝蛋白(SA-APC;终浓度40nM)进行。室温孵育1小时后如在Victor2多标记计数器上(Wallac)于665nm处检测荧光。背景值(低对照)在无实验样品和ATP情况下获得并从全部值中减去。在没有试验样品条件下获得的信号作为100%(高对照)。将在有试验化合物时获得的抑制作用计算为高对照的百分抑制率。导致50%抑制作用(IC50)的试验化合物浓度由剂量-反应曲线确定。在此测定法中,本发明化合物IC50值的范围从10nM到2μM,优选地从10nM到100nM。实施例4的化合物显示IC50值12nM。
Syk激酶测定法:本发明试剂的活性在基于解离-增强的镧系荧光免疫分析(DELFIA)技术的非均相Syk激酶测定法中测定。这个方法使用铕螯合标记的抗磷酸酪氨酸抗体来检测通过Syk进行的将磷酸转移至包被于微量滴定板上的多聚谷氨酸-酪氨酸(Glu,Tyr)底物,如(Braunwalder AF,Yarwood DR,Sills MA,Lipson KE,使用铕螯合剂的时间分辨荧光法测定C-Src的蛋白酪氨酸激酶活性,Anal.Biochem.1996;238(2):159-64)所描述。然后用时间分辨的解离-增强荧光定量磷酸化的量。简而言之,将100μl的多聚(Glu,Tyr)(4:1;2μg/ml在磷酸盐缓冲液PBS中包被到ELISA板上,室温过夜。去除多聚(Glu,Tyr)溶液,加入250μl含1%牛血清白蛋白的PBS,室温下放置1小时。然后用350μl洗涤缓冲液(25mM Tris-HCl,pH 7.4,含0.03%Tween-20)洗板三次。通过将30μl抑制剂的系列稀释液与30μl Syk激酶(20g/ml)和ATP(1μM)在激酶缓冲液(20mM Tris,pH 7.5,10μMNa3VO4,1mM DTT,10mM MnCl2,2mM MgCl2,0.01%牛血清白蛋白,0.05%Tween 20)中混合,激酶反应在室温下进行1小时。如上所述洗板四次后,加入60μl DELFIA铕N1-标记的抗-磷酸酪氨酸抗体PY20(Advant/Wallac)(在50mM Tris-HCl中100ng/ml,pH7.4,150mMNaCl,20μM Titriplex V,0.2%牛血清白蛋白,0.05%Tween-20)并在室温下孵育1小时。洗板八次后,加入60μl增强溶液(Wallac)。在615nm处测定荧光(Victor2;Wallac)。高对照值(100%信号)在没有试验样本条件下获得,而低对照值(背景)在没有试验样本及ATP条件下得到。从全部值中减去低对照值。在存在试验化合物时获得的抑制作用计算为对高对照的百分抑制率。导致50%抑制作用的试验化合物浓度(IC50)从剂量-反应曲线确定。在此测定法中,本发明化合物具有从100nM到10μM,优选地从100nM到1μM的IC50值范围。实施例128的化合物有IC50值具为150nM。
2.同种异型混合淋巴细胞反应(MLR)
本发明化合物显示出T细胞抑制活性。更特别地,本发明化合物阻止T细胞在例如水溶液中的活化和/或增殖,例如如依照以下实验方法所示。根据标准方法(J.Immunol.Methods,1973,2,279和Meo T.等人,Immunological Methods,New York,Academic Press,1979,227-39)进行双向MLR。简而言之,来自CBA和BALB/c小鼠的脾细胞(每种小鼠1.6x 105个细胞置于平底组织培养微量滴定板的每个孔中,共计3.2x 105)在含有10%FCS,100U/ml青霉素、100μg/ml链霉素(Gibco BRL,Basel,Switzerland)、50μM 2-巯基乙醇(Fluka,Buchs,Switzerland)、系列稀释化合物的RPMI培养基中孵育。每个试验化合物进行7个3倍稀释步骤,每一稀释进行2次。孵育4天后,加入1μCi3H-胸腺嘧啶。另外5小时培养期后收集细胞,根据标准方法测定掺入的3H-胸腺嘧啶。MLR的背景值(低对照)是单独BALB/c细胞增殖。从所有值中减去低对照。无任何样品的高对照作为100%增殖。计算样品引起的抑制百分率,并测定50%抑制作用(IC50值)所需的浓度。在本测定法中,本发明化合物具有从10nM到10μM IC50值范围,优选地从10nM到100nM。实施例120的化合物显示IC50值为13nM。
3.FAK测定法
所有步骤都在96-孔黑微量滴定板上进行。纯化的重组6-组氨酸标记的人FAK激酶结构域用稀释缓冲液(50mM HEPES,pH 7.5,0.01%BSA,0.05%Tween-20在水中)稀释至94ng/mL(2.5nM)的浓度。通过将10μL5x激酶缓冲液(250mM HEPES、pH7.5,50μM Na3VO4、5mM DTT、10mM MgCl2、50mM MnCl2、0.05%BSA、0.25%Tween-20的水溶液)、20μL水、5μL 4μM生物素化肽底物(Biot-Y397)的水溶液、在DMSO中的5μL试验化合物与5μL重组酶溶液混合,并在室温孵育30分钟来制备反应混合物。通过加入5μL 5μM ATP水溶液开始酶反应,混合物在37℃孵育3小时。加入200μL检测混合物(在稀释缓冲液中1nM Eu-PT66,2.5μg/mL SA-(SL)APC,6.25mM EDTA)终止反应,室温下孵育30分钟后,从铕到别藻蓝蛋白的FRET信号通过ARVOsx+L(Perkin Elmer)测定。665nm与615nm的荧光强度之比用作用于数据分析的FRET信号以消除试验化合物引起的颜色淬灭作用。结果以酶活性的抑制百分率测定。DMSO和0.5M EDTA分别作为0%和100%抑制对照。IC50值使用OriginPro6.1程序(OriginLab)的非线性曲线拟合分析确定。在本测定法中,式I的化合物抑制FAK活性的IC50<1μM。实施例188,208和213分别显示IC50值为15nM、1nM和7nM。
Biot-Y397肽(Biotin-SETDDYAEIID铵盐,SEQ ID NO:2)设计为与人GeneBank登录号L13616从S392到D402区域具有相同氨基酸序列并用标准方法制备。
纯化的重组6-组氨酸标记的人FAK激酶结构域由如下方法获得:通过使用5,PCR引物(ATGGCAGCTGCTTACCTTGAC,SEQ ID NO:3)和3’PCR引物(TCAGTGTGGTCTCGTCTGCCC,SEQ ID NO:4)从人胎盘Marathon-ReadyTM cDNA(Clontech,No.7411-1)进行PCR扩增,分离全长的人FAK cDNA,并亚克隆入pGEM-T载体(Promega,No.A3600)。用AccIII消化后,纯化的DNA片段用Klenow片段处理。cDNA片段用BamHI消化并克隆到预先用BamHI和Stu I切割的pFastBacHTb质粒(Invitrogen Japan K.K.,Tokyo)。对得到的质粒hFAKKD(M384-G706)/pFastBacHTb进行测序以确认其结构。得到的DNA编码一个364个氨基酸的蛋白质,此蛋白含有6-组氨酸标记,一段间隔区和一个在N-端的rTEV蛋白酶切割位点以及从29到351位的FAK激酶结构域(Met384-Gly706)。
使用MaxEfficacy DH10Bac大肠杆菌(E.coli)细胞,将供体质粒转座进杆状病毒基因组。通过在Bac-to-杆状病毒表达***(Invitrogen)中描述的简单碱裂解法制备Bacmid DNA。基于供货商(Invitrogen)提供的方法,转染Sf9昆虫细胞。每一裂解物中FAK的表达通过SDS-PAGE和用抗-人FAK单克隆抗体(克隆#77,来自TransductionLaboratories)进行Western印迹分析。
显示最高表达的病毒克隆通过转染到Sf9细胞进一步扩增。在ExpresSFcells(Protein Sciences Corp.,Meriden,Connecticut,USA)中的表达提供了高水平的几乎无降解的蛋白质。细胞裂解物上样到填充硫酸镍并用50mM HEPES pH 7.5,0.5M氯化钠和10mM咪唑平衡的柱子HiTrapTM Chelating Sepharose HP(Amersham Biosciences)。捕获的蛋白质用不断增加咪唑量的HEPES缓冲液/氯化钠洗脱,并通过在50mMHEPES pH 7.5,10%甘油和1mM DTT中透析进一步纯化。
4.FAK的磷酸化水平
通过夹心ELISA定量FAK在Tyr397处磷酸化水平。小鼠乳腺癌4T1细胞(1x105)加入96-孔培养板的孔中并与存在或不存在不同浓度的式I化合物在含10%FBS的Dulbecco’s改良的eagle培养基中孵育1小时。移去培养基并将细胞在含有1%NP-40、0.25%脱氧胆酸钠、150mM NaCl、1mM EDTA、1mM PMSF、1mM Na3VO4、1mM NaF、1μg/mL抑酶肽、1μg/mL亮抑蛋白酶肽和1μg/mL抑胃酶肽的200μL 50mMTris-HCl,pH 7.4中裂解。离心后,上清液用夹心ELISA来定量磷酸化FAK和总FAK。细胞裂解液置于96-孔平底ELISA板4℃下18小时,此板事先用100μL/孔的4μg/mL小鼠单克隆抗-FAK抗体(克隆77,BectonDickinson Transduction Laboratories)的50mM Tris-HCl,pH 9.5,150mM氯化钠的溶液包被,并用水1∶4稀释的300μL BlockAce(DainipponPharmaceuticals Co.)室温下封闭2小时。用TBSN(20mM Tris-HCl,pH8.3,含300mM NaCl,0.1%SDS和0.05%NP-40)洗涤后,用100μL 1μg/ml的抗-FAK多克隆抗体(#65-6140,Upstate Biology Inc.)检测总FAK,而磷酸化FAK用100μL 0.25μg/μL抗-磷酸化FAK(Y397)抗体(Affinity BioReagents,#OPA1-03071)的BlockAce溶液(用水1∶10稀释)检测。室温下孵育1小时,平板用TBSN洗涤后,加入100μL用下述BlockAce 1∶2000稀释的生物素化抗-兔IgG(#65-6140,Zymed LaboratoliesInc.),室温孵育1小时,其中所述BlockAce用水1∶10稀释。用TBSN洗涤后,用ABTS溶液底物试剂盒(#00-2011,Zymed Lobolatories Inc.)显色。室温下孵育20分钟后测量405nm处的吸收度。测定引起FAK磷酸化水平下降50%(IC50)的化合物浓度。在本测定法中,式I化合物降低磷酸化的IC50<1μM。实施例190、198和210显示IC50值分别为0.44μM,0.043μM和0.01μM。
5.非贴壁依赖性肿瘤细胞生长测定法
将小鼠乳腺癌4T1细胞(5x103)置于96-孔Ultra low Attachment板(#3474,Corning Inc.)中的100μL含10%FBS的Dulbecco改良的eagle培养基。细胞培养2小时,加入DMSO终浓度为0.1%的不同浓度抑制。48小时后,细胞生长用细胞计数试剂盒-8(Wako Pure Chemical)测定,该试剂盒使用水溶性四唑鎓盐WST8。每孔加入20μL试剂并继续培养细胞2小时。在450nm测量光密度。引起50%生长抑制的化合物浓度可以由此测定。实施例204,213和206显示IC50值分别为0.4μM、0.016μM和0.09μM。
因此本发明的化合物可用于预防或治疗通过ZAP-70抑制和/或Syk抑制发生作用的紊乱或疾病,例如T淋巴细胞、B淋巴细胞、肥大细胞和/或嗜酸性粒细胞介导的疾病或紊乱,例如急性或慢性器官或组织同种异体移植或异种移植排斥,动脉粥样硬化,由于血管损伤如血管形成术、血管再狭窄、高血压、心力衰竭、慢性肺梗阻疾病造成的血管阻塞,CNS疾病如阿尔茨海默病或肌萎缩侧索硬化,癌症,感染性疾病如AIDS,脓毒性休克或成人呼吸困难综合症,局部缺血/再灌注损伤例如心肌梗塞、中风、肠局部缺血、肾衰竭或出血性休克、或外伤性休克。本发明试剂也可用于治疗和/或预防急性或慢性炎症或紊乱或自身免疫疾病例如类风湿性关节炎、骨关节炎、***性红斑狼疮、桥本氏甲状腺炎(Hashimoto’s thyroidis)、多发性硬化症、重症肌无力、糖尿病(I型和II型)以及与之相关的紊乱、呼吸性疾病例如哮喘或炎性肝损伤、炎性肾小球损伤、免疫介导的紊乱或疾病的皮肤表症、炎性和过度增生性皮肤病(如牛皮癣、异位性皮炎、过敏性接触皮炎、刺激性接触皮炎以及湿疹皮炎、脂溢性皮炎)、炎性眼病如斯耶格伦综合征、角膜结膜炎或葡萄膜炎、炎性肠疾病、节段性回肠炎或溃疡性结肠炎。
本发明的化合物也可用于预防或治疗与FAK相关的信号级联功能障碍导致的疾病,例如肿瘤,例如脑和其它中枢神经***肿瘤(如脑膜、脑、脊索、颅侧神经肿瘤和其它部分中枢神经***肿癌例如成胶质细胞瘤或骨髓胚细胞瘤);头和/或颈部癌症;胸部肿瘤;循环***肿瘤(例如心脏、纵膈和胸膜以及其它胸廓内器官、血管肿瘤和肿瘤相关的血管组织);******肿瘤(如肾、肾盂、输尿管、膀胱等及非特异泌尿器官);胃肠道肿瘤(例如食道、胃、小肠、结肠、结肠直肠、乙状直肠连接部、直肠、***和***道),累及肝和肝内胆管、胆囊、等及非特异胆道部分、胰等及消化器官的肿瘤);头和颈;口腔(唇、舌、齿龈、口底、腭和口其它部分、腮腺、和唾液腺其它部分、扁桃体、口咽、鼻咽、梨状窦、喉咽和唇、口腔和咽的其它部位);生殖***肿瘤(例如外阴、***、子宫颈、子宫体、子宫、卵巢、和其它雌性生殖器官相关部位、胎盘、***、***、睾丸、和其它雄性生殖器官相关部位的肿瘤);呼吸道肿瘤(例如鼻腔和中耳、附属窦、喉、气管、支气管和肺,例如小细胞肺癌或非-小细胞肺癌);骨骼***肿瘤(例如骨和四肢官阶软骨、骨关节软骨和其它部位);皮肤肿瘤(例如皮肤恶性黑色素瘤、皮肤非黑色素瘤、皮肤基底细胞癌、皮肤鳞状细胞癌、间皮瘤、卡波济肉瘤);以及包括其它组织肿瘤,包括周围神经和自主神经***、***和软组织、腹膜后腔和腹膜、眼和附属器、甲状腺、肾上腺、和其它内分泌腺和相关结构、二级和非特异性恶性***赘瘤、呼吸和消化***的二级恶性赘生物和其它部位的二级恶性赘瘤、血液和淋巴***肿瘤(例如:何杰金病、非何杰金淋巴瘤、Burkitt’s淋巴瘤、AIDS-相关淋巴瘤、恶性免疫增生性疾病、多发性骨髓瘤和恶性浆细胞赘瘤、淋巴细胞白血病、急慢性骨髓白血病、急慢性淋巴细胞白血病、单核细胞白血病、其它非特异细胞型白血病、非特异型细胞白血病、其它和非特异恶性***、造血和相关组织赘瘤,例如弥漫大细胞淋巴瘤、T细胞淋巴瘤或表皮T细胞淋巴瘤)有作用。骨髓癌包括急、慢性骨髓性白血病。
在上文和后文中,提到肿瘤、肿瘤疾病、癌症或癌时,备选地或另外也指在原始器官或组织和/或任何其它位置中的癌转移,不管肿瘤和/或癌转移的位置是什么。
用任何常规途径可施用本发明组合物,特别是肠胃外地(例如以可注射溶液或悬液的形式),肠内地(例如口服地,例如以片剂或胶囊形式),局部施用,例如以洗液、凝胶剂、软膏或霜的形式,或以滴鼻剂或栓剂的形式。包括本发明试剂和至少一种可药用载体或稀释剂的药物组合物可以用常规方法,通过与可药用载体或稀释剂混合而生产。口服施用的单位剂型包括例如从大约0.1mg到约500mg活性物质。局部施用指例如施用至皮肤。局部施用的另一种形式是用于眼。
式I化合物可以以游离的形式或可药用盐的形式,例如如上所述施用。
这类盐可以用常规方法制备并显示出与游离化合物同量级的活性。
与前面一致,本发明还提供:
(1)式I化合物或其可药用盐,用作药物;
(2)式I化合物或其可药用盐,用作ZAP-70、FAK和/或Syk酪氨酸激酶抑制剂,例如用于此前所述的任一特定适应症;
(3)包含式I化合物或其可药用盐,并包含一种或多种可药用稀释剂或载体的药物组合物,例如用于此前所述的任一适应症;
(4)在需要它的受试者中治疗任何如此前所述特定适应症的方法,包括施用有效量的式I化合物或其可药用盐;
(5)式I化合物或其可药用盐的用途,用于制备治疗或预防ZAP-70、FAK和/或Syk酪氨酸激酶活化在其中起作用或相关的疾病的药物;例如如上所讨论。
本发明的化合物可以作为单独的活性成分或与其它对抗肿瘤疾病、炎性紊乱的药物一同施用或在免疫调节疗法中施用。例如,本发明的化合物可以与对上述各类疾病有效的活性剂联合使用,所述活性剂例如环孢菌素、雷帕霉素或子囊霉素,或它们的免疫抑制类似物或衍生物如环孢菌素A、环孢菌素G,Isa tx247、FK-506、西罗莫司或everolimus;CCI-779、ABT578、AP23573、皮质类激素,例如强的松、环磷酰胺、硫唑嘌呤、甲氨蝶呤、金制剂、柳氮磺吡啶、抗疟药、来氟洛米、咪唑立宾、霉酚酸、霉酚酸酯、15-脱氧斯潘格宁、具有促进淋巴细胞归巢活性的EDG受体激动剂(例如FTY720或其类似物)、免疫抑制性单克隆抗体,例如白细胞受体例如MHC、CD2、CD3、CD4、CD7、CD25、CD28、CD40、CD45、CD58、CD80、CD86、CD152、CD137、CD154、ICOS、LFA-1、VLA-4或它们配体的单克隆抗体;或其它免疫调节性化合物,例如CTLA4Ig。
式I化合物也可以有利地与其它抗增生剂联合使用。这类抗增生剂包括但不限于芳香酶抑制剂、抗***药物、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、微管活性剂、烷基化试剂、组蛋白脱乙酰基酶抑制剂、法呢基转移酶抑制剂、COX-2抑制剂、MMP抑制剂、mTOR抑制剂、抗肿瘤的抗代谢剂、铂化合物、降低蛋白激酶活性的化合物以及抗血管发生的化合物、促性腺释放因子激动剂、抗雄激素药、bengamides、双磷酸盐类(bisphosphonates)、抗增生抗体和泰莫佐罗
此处所用的术语“芳香酶抑制剂”涉及抑制***产生即将底物雄烯二酮和睾酮分别转化为雌酮和***的化合物。该术语包括但不限于类固醇,尤其是依西美坦和福美司坦,特别地是非类固醇,尤其是氨鲁半特、伏罗唑、法曲唑、阿那曲唑以及非常特别地是来曲唑(letrozole)。包含抗肿瘤剂(其为芳香酶抑制剂)的本发明组合物可以特别用于治疗激素受体阳性的***肿瘤。
此处所用的术语“抗***药”涉及在***受体水平对抗***作用的化合物。该术语包括但不限于他莫昔芬、fulvestrant、雷洛昔芬和盐酸雷洛昔芬。
此处所用的术语“拓扑异构酶I抑制剂”包括但不限于拓扑替康、伊立替康、9-硝基喜树碱和大分子的喜树碱共轭物PNU-166148(在WO99/17804中的化合物A1)。
此处所用的术语“拓扑异构酶II制剂”包括但不限于antracyclines、阿霉素(包括脂质体制剂,例如AELYXTM)、表阿霉素、去甲柔毛霉素和nemorubicin、蒽醌类的半托蒽醌和洛索蒽醌、以及表鬼臼毒素吡喃葡糖苷和替尼泊苷(teniposide)。
此处所用的术语“微管活性剂”涉及微管稳定与微管去稳定剂,包括但并不限于紫杉烷类的紫杉醇和多西紫杉,长春花属生物碱,例如长春花碱,特别是长春花碱硫酸盐,长春新碱,特别是长春新碱硫酸盐,和长春烯碱、discodermolide和埃坡霉素如埃坡霉素B和D。
此处所用的术语“烷基化试剂”包括但不限于环磷酰胺、异环磷酰胺和苯丙氨酸氮芥。
此处所用的术语“组蛋白脱乙酰基酶抑制剂”涉及抑制组蛋白脱乙酰基酶并具有抗增生活性的化合物。
此处所用的术语“法呢基移酶抑制剂”涉及抑制法尼基转移酶并具有抗增生活性的化合物。
此处所用的术语“MMP抑制剂”涉及抑制基质金属蛋白酶(MMP)和具有抗增生活性的化合物。
此处所用的术语“抗肿瘤的抗代谢剂”包括但不限于5-氟尿嘧啶、喃氟啶、卡培他滨、克拉利平、阿糖胞苷、氟达拉滨磷酸盐、氟尿嘧啶、吉西他滨、6-巯基嘌呤、羟基脲、氨甲蝶呤、依达曲沙和这类化合物的盐类,以及ZD 1694(RALTITREXEDTM)、LY231514(ALIMTATM)、LY264618(LOMOTREXOLTM)和OGT719。
此处所用的术语“铂化合物”包括但不限于碳铂、顺铂和草酸铂。
此处所用的术语“降低蛋白激酶活性的化合物和其它抗血管发生化合物”包括但不限于降低例如血管内皮生长因子(VEGF)、表皮生长因子(EGF)、c-Src、蛋白激酶C、血小板源性生长因子(PDGF)、Bcr-Abl酪氨酸激酶、c-kit、Flt-3和***I受体(IGF-IR)和细胞周期蛋白依赖性激酶(CDKs)活性的化合物和具有降低蛋白激酶活性以外的其它作用机制的抗血管发生化合物。
降低VEGF活性的化合物特别是抑制VEGF受体,尤其是VEGF受体的酪氨酸激酶活性的化合物,以及结合VEGF的化合物,特别是那些分类并具体地公开在WO 98/35958(描述式I化合物)、WO 00/09495、WO00/27820、WO 00/59509、WO 98/11223、WO 00/27819、WO 01/55114、WO 01/58899和EP 0 769 947中的化合物、蛋白质和单克隆抗体;那些被M.Prewett等人在Cancer Research 59(1999)5209-5218,被F.Yuan等人在Proc.Natl.Acad.Sci.USA,vol.93,pp.14765-14770,December 1996,被Z.Zhu等人在Cancer Res.58,1998,3209-3214,和被J.Mordenti等人在Toxicologic Pathology,vol.27,no.1,pp 14-21,1999中所描述;在WO 00/37502和WO 94/10202;AngiostatinTM,被M.S.O’Reilly等人,Cell 79,1994,315-328所描述;和EndostatinTM,被M.S.O’Reilly等人,Cell 88,1997,277-285所描述的化合物;
降低EGF活性的化合物尤其是抑制EGF受体,尤其是EGF受体酪氨酸激酶活性的化合物,以及结合EGF的化合物,以及特别是那些分类并具体地公开在WO 97/02266(描述式IV化合物)、EP 0 564 409、WO99/03854、EP 0520722、EP 0566 226、EP 0787 722、EP 0837 063、WO98/10767、WO 97/30034、WO 97/49688、WO 97/38983和尤其是在WO 96/33980的化合物;
降低c-Src活性的化合物包括但不限于如下定义的抑制c-Src蛋白酪氨酸激酶活性的化合物和SH2相互作用抑制剂,如那些在WO97/07131and WO97/08193中所公开的;
抑制c-Src蛋白酪氨酸激酶活性的化合物包括但不限于属于吡咯并嘧啶,尤其是吡咯并[2,3-d]嘧啶、嘌呤、吡唑并嘧啶、尤其是吡唑并[3,4-d]嘧啶、吡唑并嘧啶,尤其是吡唑并[3,4-d]嘧啶和吡啶并嘧啶,尤其是吡啶并[2,3-d]嘧啶结构类的化合物。优选地,本术语涉及那些在WO 96/10028、WO 97/28161、WO97/32879和WO97/49706中公开的化合物;
降低蛋白激酶C活性的化合物尤其是那些公开在EP 0 296 110(在WO 00/48571描述药物制备)中的为蛋白激酶C抑制剂的星形孢菌素衍生物;
降低蛋白激酶活性并可能与本发明组合使用的其它特定化合物是ImatinibPKC412、IressaTM(ZD1839)、PKI166、PTK787、ZD6474、GW2016、CHIR-200131、CEP-7055/CEP-5214、CP-547632和KRN-633;
具有降低蛋白激酶活性以外的其它作用机制的抗血管发生化合物包括但不限于,例如沙立度胺(THALOMID)、塞来昔布(Celebrex)、SU5416和ZD6126。
此处所用的术语“***释放因子激动剂”包括但不限于abarelix、性瑞林和醋酸性瑞林。性瑞林公开在US 4,100,274中。
此处所用的术语“抗雄激素药”包括但不限于可如US 4,636,505中所公开的那样制剂的比卡鲁胺(CASODEXTM)。
术语“bengamides”涉及bengamides及其具有抗增生性质的衍生物。
此处所用的术语“双磷酸盐类”包括但不限于etridonic acid、氯屈磷酸(clodronic acid)、替鲁磷酸(tiludronic acid)、帕米磷酸(pamidronicacid)、阿仑磷酸(alendronic acid)、伊巴磷酸(ibandronic acid)、利塞磷酸(risedronic acid)和唑来磷酸(zoledronic acid)。
此处所用的术语“抗增生抗体”包括但不限于司徒曼布(HerceptinTM)、司徒曼步-DM1、erlotinib(TarcevaTM)、bevacizu mab(AvastinTM)、利妥希玛PRO64553(抗-CD40)和2C4抗体。
通过代号、属名或商品名确定的活性剂的结构可从标准纲要“TheMerck Index”的现行版本或从例如Patents International数据库(如IMSWorld Publications)获得。
与前述一致,本发明还进一步提供了以下方面:
(6)如上定义的方法,包括例如同时或依次联合施用治疗有效量的a)式I化合物或其可药用盐和b)第二种药物,所述第二种药物例如用于此前所述的任一特定适应症。
(7)包含ZAP-70、FAK和/或Syk酪氨酸激酶抑制剂例如式I化合物或其可药用盐和第二种药物的治疗有效量的组合物,其中所述第二种药物例如如上所公开。
如果ZAP-70、FAK和/或Syk酪氨酸激酶抑制剂,例如式I化合物与其它例如如上所公开的免疫抑制性/免疫调节性、抗炎或抗肿瘤剂联合施用时,被共施用的药物或试剂的剂量当然要根据所共用药物或试剂的类型,或所用特定药物或试剂,或受治疗的疾病等改变。
代表性的FAK抑制剂是实施例187-203和209-212的化合物。
序列表
<110>诺瓦提斯公司
<120>嘧啶衍生物
<130>4-32366A
<150>GB 0206215.6
<151>2002-03-15
<160>4
<170>PatentIn版本3.1
<210>1
<211>15
<212>PRT
<213>人工序列
<220>
<223>LAT-11为用于ZAP-70激酶测定法中的人工序列
<220>
<221>MISC_FEATURE
<222>(1)..(1)
<223>X=L(+)-生物素化的氨基己酰基
<400>1
Xaa Glu Glu Gly Ala Pro Asp Tyr Glu Asn Leu Gln Gln Leu Asn
1 5 10 15
<210>2
<211>12
<212>PRT
<213>人工序列
<220>
<223>Biot-Y397为用于FAK测定法中的序列
<220>
<221>MISC_FEATURE
<222>(1)..(1)
<223>生物素
<400>2
Xaa Ser Glu Thr Asp Asp Tyr Ala Glu Ile Ile Asp
1 5 10
<210>3
<211>21
<212>DNA
<213>人工序列
<220>
<223>用于制备人FAK cDNA的PCR引物
<400>3
atggcagctg cttaccttga c 21
<210>4
<211>21
<212>DNA
<213>人工序列
<220>
<223>用于制备人FAK cDNA的PCR引物
<400>4
tcagtgtggt ctcgtctgcc c 21
Claims (8)
1.游离形式或盐形式的式I化合物,
其中
X是=CR0-;
R0是氢;
R2是-SO2N(R10)R11;
R1和R3中的每一个独立地是氢;羟基;C1-C8烷基;C2-C8链烯基;C3-C8环烷基;C3-C8环烷基-C1-C8烷基;羟基C1-C8烷基;C1-C8烷氧基C1-C8烷基;羟基C1-C8烷氧基C1-C8烷基;任选地在环上可以被羟基、C1-C8烷氧基、羧基或C1-C8烷氧基羰基取代的芳基C1-C8烷基;
或者R1和R3中的每一个独立地是卤素、卤代-C1-C8烷基;C1-C8烷氧基、卤代-C1-C8烷氧基、羟基C1-C8烷氧基;C1-C8烷氧基C1-C8烷氧基;芳基;芳基C1-C8烷氧基;杂芳基;杂芳基-C1-C4烷基;5到10元杂环;硝基;羧基;C2-C8烷氧基羰基;C2-C8烷基羰基;-N(C1-C8烷基)C(O)C1-C8烷基;-N(R10)R11;-CON(R10)R11;或-C1-C4-亚烷基-SO2N(R10)R11;其中R10和R11中的每一个独立地是氢;羟基;C1-C8烷基;C2-C8链烯基;C3-C8环烷基;C3-C8环烷基-C1-C8烷基;C1-C8烷氧基C1-C8烷基;羟基C1-C8烷氧基C1-C8烷基;羟基C1-C8烷基;(C1-C8烷基)-羰基;任选地可以在环上被羟基、C1-C8烷氧基、羧基或C2-C8烷氧基羰基取代的芳基C1-C8烷基;或5到10元杂环;
R4是氢;
R5是氢;卤素;C1-4烷基;或CF3;
R6是氢;
R7、R8和R9中的每一个独立地是氢;羟基;C1-C8烷基;C2-C8链烯基;卤代-C1-C8烷基;C1-C8烷氧基;C3-C8环烷基;C3-C8环烷基C1-C8烷基;芳基C1-C8烷基;-Y-R12,其中Y是一直接键或O,且R12是一个取代的或未取代的包含1、2或3个选自N、O和S的杂原子的5、6或7元杂环;羧基、(C1-C8烷氧基)-羰基;-N(C1-8烷基)-CO-NR10R11;-CONR10R11;-N(R10)(R11);-SO2N(R10)R11;R7和R8或R8和R9,分别和与它们连接的碳原子一起形成包含选自N、O和S的1、2或3个杂原子的5或6元杂芳基;或5或6元碳环;
其中任何烷基、烷氧基、链烯基、环烷基、杂环、芳基或杂芳基可以未被取代或被一个或多个选自卤素;OH;C1-C8烷基;C1-C8烷氧基;硝基;氰基;COOH;氨基甲酰基;C(NH2)=NOH;-N(R10)R11;C3-C6环烷基;3到7元杂环;苯基;苯基-C1-4烷基;5或6元杂芳基的取代基取代。
2.根据权利要求1所述的化合物,其中至多R1或R3之一是-CON(R10)R11。
5.游离形式或可药用盐形式的根据权利要求1至3任一项的化合物,其用作药物。
6.药物组合物,其包含根据权利要求1至3任一项的式I化合物或其可药用盐,并还包含一种或多种可药用载体或稀释剂。
7.游离形式或可药用盐形式的根据权利要求1至3任一项的式I化合物,作为药物用于治疗或预防其中ZAP-70、FAK和/或Syk酪氨酸激酶活性发挥作用的或相关的疾病或病症。
8.一种组合物,其包含(a)治疗有效量的作为ZAP-70、FAK和/或Syk抑制剂的根据权利要求1至3任一项的式I化合物和(b)第二种药物。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112390760A (zh) * | 2020-10-15 | 2021-02-23 | 北京师范大学 | 靶向fak的化合物及其制备方法和应用 |
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