CN1433408A - 细胞周期蛋白依赖激酶的氨基噻唑抑制剂 - Google Patents
细胞周期蛋白依赖激酶的氨基噻唑抑制剂 Download PDFInfo
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- CN1433408A CN1433408A CN00818898A CN00818898A CN1433408A CN 1433408 A CN1433408 A CN 1433408A CN 00818898 A CN00818898 A CN 00818898A CN 00818898 A CN00818898 A CN 00818898A CN 1433408 A CN1433408 A CN 1433408A
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- alkyl
- heterocyclylalkyl
- aryl
- heteroaryl
- cycloalkyl
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Classifications
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Landscapes
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Abstract
式(I)化合物和其药学上可接受盐。当在式(I)中使用时,以及在整篇说明书中,所述符号具有以下含义:R1和R2独立为氢、氟或烷基;R3为芳基或杂芳基;R4具有多种含义;R5为氢或烷基;m为一个0到2的整数;而n为一个1到3的整数。式(I)化合物为蛋白激酶抑制剂并用于治疗和预防增生性疾病,例如,癌症、炎症和关节炎。它们也可以用于治疗神经退化性疾病如早老性痴呆、心血管疾病、病毒性疾病和真菌性疾病。
Description
发明简述
本发明涉及下式化合物及其药学上可接受的盐:当在式I中使用时,以及在说明书全文中,符号具有以下含义:
R1和R2独立为氢、氟或烷基;
R3为芳基或杂芳基;
R4为烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NNO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(NH)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢或烷基;
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
m为0到2的整数;和
n为1到3的整数。
式I化合物为蛋白质激酶抑制剂并且用于治疗和预防增生性疾病,例如癌症、炎症和关节炎。它们也可以用于治疗如早老性痴呆的神经退化性疾病、心血管疾病、病毒性疾病和真菌性疾病。
本发明说明书
本发明提供式I化合物、采用此类化合物的药用组合物和使用此类化合物的方法。
用于描述本发明化合物的各种术语的定义列出如下。当在说明书全文中单独或作为一个较大基团的一部分使用这些术语(除非它们在具体事例中另有限定)时,这些定义适用于所述术语。
应该说明,假定任何具有不饱和价的杂原子含有氢原子以便使所述价饱和。
羧酸根阴离子指负电荷基团-COO-。
除非另外说明,术语“烷基”或“alk”指含有1到12个碳原子的单价烷烃(碳氢化合物)衍生的基团。烷基基团任选为取代的直链、支链或环状饱和的烃基。当取代时,在任何可利用的连接点,可以用最多可达四个定义的R取代基团取代烷基基团。当说所述烷基基团被一个烷基基团取代时,可以与“支链烷基基团”互换使用。此类未取代基团的实例包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、异己基、庚基、4,4-二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等。示例性的取代基可包括但不限于一个或多个以下基团:卤代基(如F、Cl、Br、I)、卤代烷基(如CCl3或CF3)、烷氧基、烷硫基、羟基、羧基(-COOH)、烷氧基羰基(-C(O)R)、烷基羰基氧基(-OCOR)、氨基(-NH2)、氨基甲酰基(-NHCOOR或-OCONHR-)、脲(-NHCONHR-)或硫羟基(-SH)。如此定义的烷基基团也可以包括一个或多个碳碳双键或一个或多个碳碳三键。
术语“链烯基”指含有2到12个碳原子并且至少一个碳碳双键的直链、支链或环状的烃基基团。
术语“炔基”指含有2到12个碳原子并且至少一个碳碳三键的直链、支链或环状的烃基基团。
环烷基为含有3到15个碳原子,在碳原子之间没有更迭双键或共振双键的环状烷基。它可以含有1到4个环。此类示例性的未取代基团包括环丙基、环丁基、环戊基、环己基、金刚烷基等。示例性的取代基包括一个或多个以下基团:卤代基、烷基、烷氧基、烷基羟基、氨基、硝基、氰基、硫羟基和/或烷硫基。
当在此使用时,术语“烷氧基”或“烷硫基”表示分别通过氧键(-O-)或硫键(-S-)连接的如上所述的烷基基团。
当在此使用时,术语“烷氧基羰基”表示通过一个羰基基团连接的烷氧基基团。烷氧基羰基基团用式:-C(O)OR表示,其中R基团为直链或支链的C1-6烷基基团。
术语“烷基羰基”指一个通过羰基基团连接的烷基基团。
当在此使用时,术语“烷基羰基氧基”指通过氧键连接的烷基羰基基团。
当在此使用时,术语“芳基烷基”指连接于如上所述的烷基基团的芳香环。
术语“芳基”指单环或双环的芳香环,例如苯基、取代的苯基等,以及稠和的基团如萘基、菲基等。因此一个芳基基团至少含有一个具有至少6个原子的环,最多可存在5个这样的环,其中含有最多可达22个原子,在相邻的碳原子或合适的杂原子之间具有更迭(共振)双键。芳基基团可以任选由一个或多个基团取代,所述基团包括但不限于卤素、烷基、烷氧基、羟基、羧基、氨基甲酰基、烷氧基羰基、硝基、三氟甲基、氨基、环烷基、氰基、烷基S(O)m(m=0,1,2)或硫羟基。
术语“杂芳基”指含有5个或6个环原子的单环芳香烃基团,或指含有8个到10个原子的双环芳香基团,所述基团含有至少一个杂原子,O、S或N,其中一个碳原子或氮原子为连接点,其中一个或两个另外的碳原子任选被选自O或S的杂原子取代,并且其中1到3个另外的碳原子任选被氮杂原子取代,所述杂芳基基团如本文所述被任选取代。示例性的杂芳基基团包括以下基团:噻吩基、呋喃基、吡咯基、吡啶基、咪唑基、吡咯烷基、哌啶基、噻唑基、噁唑基、三唑基、吡唑基、异噁唑基、异噻唑基、吡嗪基、哒嗪基、嘧啶基、三嗪基氮杂基、吲哚基、异吲哚基、喹啉基、异喹啉基、苯并噻唑基、苯并噁唑基、苯并咪唑基、苯并噁二唑基、苯并呋咱基和四氢吡喃基。示例性的取代基包括以下一个或多个基团:卤素、烷基、烷氧基、羟基、羧基、氨基甲酰基、烷氧基羰基、三氟甲基、环烷基、硝基、氰基、氨基、烷基S(O)m(m=0,1,2)或硫羟基。
术语“杂芳基鎓(heteroarylium)”指带有一个季氮原子并且因此带一个阳电荷的杂芳基基团。
术语“杂环烷基”指其中在所述环上的一个碳原子被选自O、S或N的杂原子取代的环烷基基团(非芳香基团),并且其中最多可达三个的另外的碳原子可被所述杂原子取代。
术语“季氮”指四价的正电荷氮原子,例如包括在四烷基铵基团(如四甲基铵、N-甲基吡啶鎓)中带正电荷的氮、在质子化的铵类(如三甲基氢化铵(hydroammonium)、N-氢化吡啶鎓)中带正电荷的氮、在胺N-氧化物(如N-甲基吗啉-N-氧化物、吡啶-N-氧化物)中带正电荷的氮和在N-氨基-铵基团(如N-氨基吡啶鎓)中带正电荷的氮。
术语“杂原子”意指独立选择的O、S或N。
术语“卤素”或“卤代基”指氯、溴、氟或碘。
当称一个官能团为“保护的”,意指该基团为修饰的形式,以便在该保护的位置上预先排除不需要的负反应。考虑本领域技术人员的水平,对于本发明的化合物的适宜保护基团将从本申请中确认,和参阅标准教科书如Greene,T.W.等,在有机合成中的保护基团(ProtectiveGroups in Organic Synthesis),Wiley,N.Y.(1991)。
按照本发明的化合物与无机或有机酸所形成盐的适宜实例为盐酸盐、氢溴酸盐、硫酸盐、磷酸盐。也包括不适宜药物用途但可用于分离或纯化游离的化合物I或它们的药学上可接受的盐的盐。
预期本发明化合物的所有立体异构体为混合物,或纯净的或基本纯净的形式。按照本发明的化合物的定义包含所有可能的立体异构体和它们的混合物。特别是它包括外消旋形式和具有特定活性的分离的光学异构体。通过物理方法拆分该外消旋形式,如分级结晶、非对映衍生物的分离或结晶或通过手性柱层析分离。通过常规的方法如与一种光学活性酸形成盐随后结晶,可以从外消旋体获得单一的光学异构体。
可以理解,式I化合物的溶剂合物(如水合物)也在本发明的范围内。通常溶剂化的方法是本领域所熟知的。因此,本发明化合物可以为游离形式或水合物形式,并且可以通过以下方案的例证性方法获得。方案1
按照方案1所述,在硫氰酸钠或硫氰酸钾的存在下,通过使2-氨基噻唑(II)与溴反应以便获得硫氰酸化的氨基噻唑,具体地说获得5-氰硫基氨基噻唑(III),制备其中X为S的式I化合物。然后在碱如三乙胺的存在下,使化合物III与R4-L反应其中L为一个离去基团如卤素,获得一种5-氰硫基噻唑中间体(IV),其中R4如在本说明书中定义。然后用还原剂如二硫苏糖醇(DTT)、氢硼化钠、锌或其它已知的还原剂将中间体(IV)还原为硫醇(V)。然后在一种碱如碳酸钾的存在下,使化合物(V)与烷基、芳基或杂芳基卤化物如R3(CR1R2)n-L反应,其中L为离去基团如卤素,以获得式I化合物。还原氰硫基噻唑中间体(IV)为硫醇(V)的步骤和还原硫醇(V)提供其中X为S的式I化合物的反应可以继续进行而不需纯化。方案2
在方案2中,结构VI的5-硫代乙酰基-2-乙酰基氨基噻唑与一种醇盐如叔丁醇钾在醇或THF溶剂中的反应,并且产生的硫醇原地与式R3(CR1R2)n-L(其中L为离去基团如卤素)的基团如2-卤基甲基噁唑(VII)反应获得例如式VIII的化合物,其中R1和R2为氢,而R6为乙酰基。可以用几种本领域已知的合成路径制备所述式VII的2-卤代甲基噁唑化合物。Chem.Pharm.Bull.30,1865(1982);Bull.Chem.Soc.Japan 52,3597(1979);JCS Chem.Comm.322(1981);Comprehensive HeterocyclicChemistry,6卷,177,A.Katritzky和C.W.Rees编辑,Pergamon Press(1984)。
在碱如氢氧化钠的存在下,可以水解式VIII化合物(其中R4为乙酰基而X为硫的式I化合物)获得式IX化合物。然后在碱如三乙胺的存在下,使式IX化合物与R4-L(其中L为离去基团如卤素)反应,获得其中X为硫的式I化合物。在所述方法中,可以用试剂如异硫氰酸酯、卤化物、酰基卤、氯代甲酸酯、异氰酸酯或磺酰氯处理式IX化合物(为其中R4为氢的式I化合物),获得硫脲、胺、酰胺、氨基甲酸酯、脲或磺酰胺。在方案2中的方法具体地阐述一个甲基噁唑基团,但是对于式I限定的所有的R3(CR1R2)n-基团该方法是通用的方法。
作为选择,可以通过在二苯甲酰基过氧化物的存在下,用N-溴琥珀酰亚胺卤化2-甲基噁唑制备其中L为溴的式VII化合物。
方案3
方案3阐述了一种制备化合物VII的另一种方法,该化合物为式R3(CR1R2)n-L化合物,其中L为氯而n为整数1。在所述方案中,在碱如三乙胺的存在下,通过式X与式XI化合物的反应获得式XII化合物来制备化合物VII。在一种碱如三乙胺的存在下,可以用氧化剂如乙二酰氯/DMSO氧化化合物XII,获得式XIII化合物,用一种试剂如磷酰氯可以环化式XIII化合物获得其中L为氯的式VII化合物。或者,可以通过对应于X的氨基酮与酰氯如XI反应制备式XIII化合物。
方案4
在方案5中,原料化合物XVI表示一种用于固相合成的树脂结合的苄基醇载体,它可从一种如表示的Merrifield树脂和2-甲氧基-4-羟基苯甲醛,随后用还原剂如NaBH4还原来制备。在步骤1中,用三光气和三苯基膦(PPh3)在二氯甲烷中处理原料化合物XVI得到式XVII的氯苄基树脂。在第二步,在二异丙基乙胺(DIPEA)存在下,用树脂结合的苄基氯(XVII)使氰硫基三氟乙酰胺(XVIII)烷基化,形成一种树脂结合的硫氰酸酯(XIX)。通过采用一种碱如2,6-二甲基吡啶使式III的5-氰硫基氨基噻唑(方案I)与三氟乙酸酐反应制备式XVII的氰硫基三氟乙酰胺。
然后,在第三步用还原试剂如二硫苏糖醇(DTT)在四氢呋喃(THF)和甲醇中将树脂结合的硫氰酸酯(XIX)还原为树脂结合的硫醇(XX)。在80℃、在二甲基甲酰胺(DMF)中、在一种碱如1,8-二氮杂双环[5,4,0]十一碳-7-烯(DBU)的存在下,使所产生的树脂结合的硫醇(XX)与其中L为离去基团的R3(CR1R2)n-L反应,形成式XXI化合物(步骤4)。在步骤5中用氢硼化钠进行XXI化合物的三氟乙酰基基团的去保护获得式XXII化合物。在步骤6中,在碱如二异丙基乙胺的存在下,使该去保护的化合物XXII与其中X为离去基团的R6X反应,获得式XXIII化合物。然后在步骤7中用三氟乙酸(TFA)从该固相树脂上裂解该产物获得其中X为硫的式I化合物。可以通过用一种氧化剂如高碘酸钠、间氯过苯甲酸或过硫酸氢钾制剂氧化,由其中m为0的式I化合物制备其中X为S(O)m而m为1或2的式I化合物。
方案6
方案6说明了从2-溴噻唑XXIV制备式I化合物的方法。在溴化铜的存在下,使式IX化合物与一种重氮化试剂如tBuONO反应获得示例性的式XXIV的2-溴噻唑。然后,加入或不加入一种额外的碱,可使化合物XXIV与式R4NH2化合物反应,获得式I化合物。
方案7
在加入或不加入另外的碱的情况下,也可以通过使2-溴噻唑XXV与式R4NH2化合物反应,得到式XXVI化合物来制备式I化合物。在溴的存在下,式XXVI化合物可以与硫氰化试剂如硫氰酸钠反应获得一种式IV化合物,然后该化合物可以如方案1所述转化为式I化合物。作为选择,可以用溴化剂如溴在乙酸中处理式XXVI化合物产生化合物XXVII。在碱的存在下,式XXVII化合物可以与XXVIII或XXIX(它们本身可以从式VII化合物获得)反应获得式I化合物。
在方案1-7中的原料化合物为商业上获得的或可以通过本领域普通技术人员已知的方法制备。
所有的式I化合物可以通过此中所述的改进方法制备。
式I的优选化合物为那些化合物,其中:
R1和R2独立为氢、氟或烷基;
R3为
其中Y为氧、硫或NR9;
R4为烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NNNO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(H)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢;而
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
R7和R8独立为氢、烷基、环烷基、芳基、烷基环烷基、烷基芳基、杂芳基、烷基杂芳基、杂环烷基、烷基杂环烷基或卤素;
R9为氢或烷基;
m为整数0;和
n为整数1。
式I最优选的化合物为那些化合物,其中:
R1为氢;
R2为氢、氟或烷基;
R3为具有以下结构的取代噁唑:
R4为CO-烷基、CO-烷基-芳基、CO-环烷基、CO-烷基-杂芳基、CO-烷基-杂烷基、CO-烷基-杂环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基;
R5为氢;
R7为氢;
R8为烷基基团,如叔丁基;
m为整数0;和
n为整数1。
按照本发明的化合物具有药理学性质;具体地说,式I化合物为蛋白质激酶如细胞周期蛋白依赖激酶(cdks)如cdc2(cdk1)、cdk2和cdk4的抑制剂。所述新的式I化合物期望用于治疗增生性疾病如癌症、自体免疫性疾病、病毒性疾病、真菌性疾病、神经退化性疾病和心血管疾病。
更具体地说,式I化合物用于治疗各种癌症,包括(但不限于)以下疾病:
-癌症,包括膀胱、乳房、结肠、肾、肝、肺的癌症,包括小细胞肺癌,食道、胆囊、卵巢、胰腺、胃、子宫颈、甲状腺、前列腺的癌症和皮肤癌包括鳞状上皮细胞癌;
-淋巴谱系的血细胞生成肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛样细胞淋巴瘤和Burkett’s淋巴瘤;
-骨髓谱系血细胞生成肿瘤,包括急性和慢性骨髓性白血病、脊髓发育不良综合征和前髓细胞白血病;
-源于间充质的肿瘤,包括纤维肉瘤和横纹肌肉瘤;
-中枢和外围神经系统的肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;和
-其它肿瘤,包括黑素瘤、精原细胞瘤、畸胎样癌、骨肉瘤、xenoderoma色素瘤(pigmentosum)、角化棘皮瘤(Keratoctanthoma)、甲状腺滤泡癌和卡波济氏肉瘤。
由于cdks在调节细胞增生中的关键作用,通常抑制剂可以象可逆的细胞抑制剂一样发挥作用,所述细胞抑制剂可用于治疗以异常的细胞增生为特征的任何疾病过程,如良性前列腺增生、家族性腺上皮增生性息肉病、神经纤维瘤病、动脉粥样硬化、肺纤维化、关节炎、牛皮癣、肾小球性肾炎、血管形成术或血管手术后的再狭窄、肥大性瘢痕形成、肠炎性疾病、移植术排斥反应、内毒素休克和真菌感染。
式I化合物也可以用于治疗早老性痴呆,因为最近的发现提示cdk5与tau蛋白质的磷酸化有关(J.Biochem,117,741-749(1995))。
式I化合物可以诱导或抑制编程性细胞死亡。在人类的各种疾病中所述编程性细胞死亡反应是异常的。式I化合物作为编程性细胞死亡的调节剂可以用于治疗癌症(包括但不限于上述那些类型)、病毒性感染(包括但不限于疱疹病毒、痘病毒、Epstein-Barr病毒、Sindbis病毒和腺病毒)、在HIV感染的个体中预防AIDS的发展、自体免疫性疾病(包括但不限于系统性狼疮、红斑性狼疮、自体免疫介导的肾小球性肾炎、类风湿性关节炎、牛皮癣、肠炎性疾病和自体免疫性糖尿病)、神经退化性疾病(包括但不限于早老性痴呆、与AIDS有关的痴呆、帕金森氏病、肌萎缩性侧索硬化、色素性视网膜炎、脊柱肌肉萎缩和小脑退化)、脊髓发育不良综合征、再生障碍性贫血、与心肌梗塞有关的局部缺血损伤、中风和再灌注损伤、心率失常、动脉粥样硬化、毒素引起的或与酒精有关的肝脏疾病、血液疾病(包括但不限于慢性贫血和再生障碍性贫血)、肌与骨骼系统的退化性疾病(包括但不限于骨质疏松和关节炎)、对阿司匹林过敏的鼻窦炎、胰囊性纤维变性、多发性硬化、肾病和癌症疼痛。
式I化合物作为cdks的抑制剂可以调节细胞RNA和DNA合成的水平。因此,这些药剂可以用于治疗病毒感染(包括但不限于HIV、人乳头瘤病毒、疱疹病毒、痘病毒、Epstein-Barr病毒、Sindbis病毒和腺病毒)。
式I化合物也可以用于癌症的化学预防。化学预防定义为通过阻止引发诱变的事件或通过阻止已经受到损伤的前恶性肿瘤细胞的发展抑制侵入癌症的发展或抑制肿瘤的复发。
式I化合物也可以用于抑制肿瘤的血管生成和肿瘤转移。
式I化合物也可以作为其它蛋白激酶,如蛋白激酶C、her2、raf1、MEK1、MAP激酶、EGF受体、PDGF受体、IGF受体、PI3激酶、Wee1激酶、Src、Ab1的抑制剂发挥作用,因此在治疗与其它蛋白激酶有关的疾病中是有效的。
本发明的化合物也可以与已知的抗癌疗法如放射性治疗或与细胞抑制剂或细胞毒性剂联合用药,例如,所述细胞抑制剂或细胞毒素剂包括但不限于DNA相互作用剂如顺铂或多柔比星;拓扑异构酶II抑制剂如依托泊苷;拓扑异构酶I抑制剂如CPT-11或托泊替堪;微管蛋白相互作用剂如紫杉醇、docetaxel或epothilones;激素药如他莫昔芬;胸苷酸合酶抑制剂如5-氟尿嘧啶;和抗代谢剂如methoxtrexate。式I化合物也可以与p53反式激活作用调节剂联合使用。
如果按照固定的剂量配制,此类组合产品采用在下述剂量范围内的本发明化合物和其它在许可剂量范围内的药学上的活性剂或治疗剂。例如,已经发现在诱使编程性细胞死亡中cdc2抑制剂olomucine与已知的细胞毒性剂协同作用(J。Cell Sci.,108,2897(1995))。当组合配制不适宜时,式I化合物也可以与已知的抗癌剂或细胞毒性剂顺序给药。本发明不限制给药的顺序;式I化合物可以在给予已知的抗癌剂或细胞毒性剂之前或之后给予。例如,细胞周期蛋白依赖性激酶抑制剂flavopiridol的细胞毒性活性受给予抗癌剂的顺序的影响。CancerResearch,57,3375(1997)。
本发明化合物的药理学性质可以通过许多药理学测定法来确定。用本发明的化合物及其盐进行以下示例性的药理学测定。实施例1到14的化合物抑制cdc2/细胞周期蛋白B1激酶的活性具有低于50μM的IC50值。实施例1到14的化合物抑制cdk2/细胞周期蛋白E激酶的活性具有低于50μM的IC50值。实施例1到14的化合物抑制cdk4/细胞周期蛋白D1激酶的活性具有低于50μM的IC50值。
cdc2/细胞周期蛋白B1激酶测定
通过监测结合到组蛋白H1中的32P测定cdc2/细胞周期蛋白B1激酶的活性。该反应物由50ng表达GST-cdc2的杆状病毒、75ng表达GST-细胞周期蛋白B1的杆状病毒、1μg组蛋白HI(BoehringerMannheim)、0.2mCi的32P g-ATP和25mM ATP的激酶缓冲液(50mMTris,pH8.0,10mM MgCl2,1mM EGTA,0.5mM DTT)组成。在30℃孵育该反应物30分钟,然后通过加入使终浓度为15%的冷三氯乙酸(TCA)终止孵育,在冰上孵育20分钟。用一个Packard Filtermate Universal收获器将该反应物收集到GF/C单滤板(unifilter plates)(Packard)上,并在一个Packard Topcount 96孔液体闪烁计数器上对滤物计数(Marshak,D.R.,Vanderberg,M.T.,Bae,Y.S.,Yu,I.J.,J.of Cellular Biochemistry,45,391-400(1991),通过引用合并到本文中)。
cdk2/细胞周期蛋白E激酶测定
通过监测结合到成视网膜细胞瘤蛋白中的32p测定cdk2/细胞周期蛋白E激酶的活性。该反应物由2.5ng表达GST-cdk2/细胞周期蛋白E的杆状病毒、500ng细菌产生的GST-成视网膜细胞瘤蛋白质(aa 776-928)、0.2mCi的32Pg-ATP和25mM ATP的激酶缓冲液(50mM Hepes,pH8.0,10mM MgCl2,5mM EGTA,2mM DTT)组成。在30℃孵育该反应物30分钟,然后通过加入使终浓度为15%的冷三氯乙酸(TCA)终止孵育并在冰上孵育20分钟。用一个Packard Filtermate Universal收获器将该反应物收集到GF/C单滤板(Packard)上,并在一个PackardTopCount 96孔液体闪烁计数器上对滤物计数。
Cdk4/细胞周期蛋白D1激酶活性
通过监测结合到成视网膜细胞瘤蛋白质中的32P测定cdk4/细胞周期蛋白D1激酶的活性。该反应物由165ng表达GST-cdk4的杆状病毒、282ng细菌表达的S-tag细胞周期蛋白D1、500ng细菌产生的GST-成视网膜细胞瘤蛋白(aa 776-928)、0.2uCi的32P r-ATP和25uM ATP的激酶缓冲液(50mM Hepes,pH8.0,10mM MgCl2,5mM EGTA,2mMDTT)组成。在30℃孵育该反应物1小时,然后通过加入使终浓度为15%的冷三氯乙酸(TCA)终止孵育并在冰上孵育20分钟。用一个Packard Filtermate Universal收获器将该反应物收集到GF/C单滤板(Packard)上,并在一个Packard TopCount 96孔液体闪烁计数器上对滤物计数(Coleman,K.G.,Wautlet,B.S.,Morissey,D,Mulheron,J.G.,Sedman,S.,Brinkley,P.,Price,S.,Wedster,K.R.(1997).Identification ofCDK4 Sequences involved in cyclin D,and p16 binding.J.Biol.Chem.272,30:18869-18874,通过引用结合到本文中)。
本发明的另一个主题也包括用于如上所述用途的药物,其用途包括控制癌症、炎症和关节炎,所述制剂含有至少一种如上定义的式I化合物或至少一种其药学上可接受的酸加成盐,以及如上定义的式I化合物在制备一种具有对抗如上所述的增生性疾病,包括对抗癌症、炎症和/或关节炎的活性的药物中的用途。
以下实施例和制备描述了制备和使用本发明的方法和过程,并且它们是示例性的而不是限制。应该理解,在本文所附的权利要求所限定的本发明的实质和范围内可以有其它实施方案。
实施例1N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺A.制备1-苄氧基羰基氨基-2-丁醇
在0℃搅拌1-氨基-2-丁醇(5.5g,61.8mmol)、氯甲酸苄酯(11.5g,67.6mmol)和碳酸钠(7.16g,67.7mmol)在水(50ml)中的混合物3小时。将水(50ml)加入到该反应混合物中并用二氯甲烷(3×20ml)提取该产物。用Na2SO4干燥二氯甲烷提取物并浓缩。使该残余物通过一根短柱(SiO2,己烷∶乙酸乙酯/10∶1;然后乙酸乙酯)获得1-苄氧基羰基氨基-2-丁醇(13.9g,100%),一种液体。1H NMR(CDCl3)δ7.30(m,5H),5.45(s,1H),5.06(s,2H),3.57(s,1H),3.31(m,1H),3.04(m,1H),2.91(m,1H),1.43(m,2H),0.91(t,J=7.6Hz,3H)。B.制备1-苄氧基羰基氨基-2-丁酮
在-78℃、氩气下,向二氯甲烷(60ml)中加入乙二酰氯(2M的二氯甲烷溶液37ml,74mmol),随后加入DMSO(7.8g,100mmol)。在-78℃搅拌该混合物20分钟并向该混合物中加入1-苄氧基羰基氨基-2-丁醇(13.9g,61.8mmol)的二氯甲烷(40ml)溶液。在-78℃搅拌该混合物1小时并将三乙胺(21ml)加入到该混合物中。温热至室温(rt)并连续用1N盐酸和碳酸氢钠溶液洗涤。用MgSO4干燥二氯甲烷溶液并浓缩获得1-苄氧基羰基氨基-2-丁酮(11.2g,82%),为固体,对于下一步反应该固体有足够的纯度。1H NMR(CDCl3)δ7.32(m,5H),5.50(s,1H),5.06(s,2H),4.07(s,2H),2.43(q,J=7.6Hz,2H),1.06(t,J=7.6Hz,3H).C.制备1-氨基-2-丁酮
在室温、氢气氛下,在Pd/C(1.5g,10%)的存在下,搅拌1-苄氧基羰基氨基-2-丁酮(9.30mg,42mmol)的乙醇(50ml)溶液和1N盐酸(46ml)4小时。通过硅藻土滤床过滤该混合物并浓缩该滤液。用乙醚研磨该残余物,得到1-氨基-2-丁酮(5.3g,102%),为一种盐酸盐。1H NMR(CD3OD)δ3.97(s,2H),2.60(q,J=7.6Hz,2H),1.08(t,J=7.6Hz,3H).D.制备2-氨基-5-氰硫基噻唑
将2-氨基噻唑(41g,410mM)和硫氰酸钠(60g,740mM,在130℃,于真空烤箱中干燥过夜)溶解于450ml无水甲醇中并在冷水浴中冷却该溶液。充分搅拌下滴加溴(23ml,445mM)。加入后在室温下搅拌其4小时。向该混合物中加入500ml水,搅拌5分钟,通过硅藻土滤床过滤并用水洗涤滤床。滤液的pH大约为1。在减压下移去大部分甲醇并且在搅拌下缓慢地加入碳酸钠水溶液调节所述溶液的pH到大约7。过滤沉淀的固体并用水洗涤,在干燥后得到37g(57%)深棕色的所需产物,mp140-143℃。1H NMR(CD3OD)δ7.33(s,1H);MS(CI/NH3)m/e 179(M+Na)+,158(M+H)+.E.制备2-乙酰基氨基-5-氰硫基噻唑
在室温下,向2-氨基-5-氰硫基噻唑(15.7g,0.1mol)和吡啶(12g,0.15mol)在二氯甲烷(100ml)的混合物中加入乙酸酐(1.2g,0.12mol)。在室温下搅拌该混合物6小时。将该混合物浓缩至干并加入到剩余的MeOH(50ml)中。收集沉淀并用水洗涤。干燥该固体并从MeOH中重结晶,得到2-乙酰基氨基-5-氰硫基噻唑(15.2g,76%),为一种固体,mp212℃。1H NMR(CD3OD)δ7.79(s,1H),2.23(s,3H).F.[[2-(乙酰基氨基)-5-噻唑基]硫代基]乙酸1,1-二甲基乙酯
在室温、氩气下,向2-乙酰基氨基-5-氰硫基噻唑(5.97g,30mmol)在甲醇(360ml)的混合物中加入二硫苏糖醇(9.26g,60mmol)。在室温下搅拌该混合物2小时并浓缩,得到一种还原的固体产物。将该产物溶解于DMF(30ml)中并向该溶液中加入溴乙酸叔丁酯(5.85g,30mmol)和碳酸钾(5.0g,36mmol)。在室温下搅拌该混合物2小时并将水(200ml)加入到该混合物中。收集该沉淀,用水洗涤并干燥。将所述固体溶解于二氯甲烷(100ml)和MeOH(10ml)中并通过一个硅胶垫过滤。浓缩滤液,得到所需产物(7.5g,87%),为一种固体,mp162-163℃。1H NMR(CDCl3)δ12.2(s,1H),7.48(s,1H),3.37(s,2H),2.32(s,3H),1.45(s,9H);MS m/e 289(M+H)+,287(M-H)-.HPLC(柱:YMC S3 ODS 4.6×150mm;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%MeOH-90%水-0.2% H3PO4;溶剂B:90%MeOH-10%水-0.2% H3PO4;UV:220nm):保留时间6.44分钟。G.制备[[2-(乙酰基氨基)-5-噻唑基]硫代基]乙酸
在室温下搅拌[[2-(乙酰基氨基)-5-噻唑基]硫代基]乙酸1,1-二甲基乙酯(4.32g,15mmol)在二氯甲烷(30ml)和三氟乙酸(20ml)中的溶液过夜并在真空下浓缩。向该残余物中加入乙醚(50ml)。收集沉淀的固体,用乙醚洗涤并干燥,得到所需产物(3.38g,97%),为一种固体,mp210℃。1H NMR(CD3OD)δ7.48(s,1H),3.47(s,2H),2.20(s,3H)ppm;MS m/e231(M-H)-;HPLC(柱:Zorbax Rapid(快速)分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%MeOH-90%水-0.2%H3PO4;溶剂B:90%MeOH-10%水-0.2% H3PO4;UV:254nm):保留时间4.32分钟。H.制备[[2-(乙酰基氨基)-5-噻唑基]硫代基]-N-(2-氧代丁基)乙酰胺
在0℃搅拌[[2-(乙酰基氨基)-5-噻唑基]硫代基]乙酸(9.0g,38.8mmol)、HOBT(5.94g,38.8mmol)和乙基二甲基氨基丙基碳化二亚胺盐酸盐(11.16g,58.2mmol)在DMF(50ml)中的混合物0.5小时。向该混合物中加入1-氨基-2-丁酮盐酸盐(5.27g,42.7mmol),随后加入三乙胺(15ml,107.5mmol)。在0℃搅拌该混合物0.5小时并在室温搅拌1小时。将水(200ml)加入到该混合物中并用含有10%MeOH的二氯甲烷(5×100ml)提取该产物。用Na2SO4干燥二氯甲烷提取液并浓缩。用水研磨该残余物并通过过滤收集沉淀的固体产物。干燥,获得所需产物(10.5g,90%),mp195-196℃。1H NMR(CDCl3)δ7.53(s,1H),4.14(s,2H),3.46(s,2H),2.50(q,J=7.6Hz,2H),2.25(s,3H),1.12(t,J=7.6Hz,3H);MS m/e 302(M+H)+。HPLC(柱:Zorbax快速分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%MeOH-90%水-0.2%H3PO4;溶剂B:90%MeOH-10%水-0.2%H3PO4;UV:254nm):保留时间4.36分钟。I.制备N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺
向[[2-(乙酰基氨基)-5-噻唑基]硫代基]-N-(2-氧代丁基)乙酰胺(10.5g,34.8mmol)的乙酸酐(100ml)溶液中加入浓硫酸(10ml)。在55-60℃搅拌该混合物2小时并且将乙酸钠(15g,0.18mol)加入到该混合物中。在真空下浓缩该混合物。将冷水(100ml)加入到该残余物中。收集沉淀的固体,用水洗涤并干燥。通过快速柱层析(SiO2;二氯甲烷∶MeOH/100:5)纯化,得到N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺(4.2g,43%),为一种固体,mp 147-148℃。1H NMR(CDCl3)δ12.47(s,1H),7.29(s,1H),6.61(s,1H),3.91(s,2H),2.64(q,J=7.6Hz,2H),2.25(s,3H),1.21(t,J=7.6Hz,3H)ppm;MS m/e284(M+H)+。HPLC(柱:Zorbax Rapid(快速)分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%MeOH-90%水-0.2%H3PO4;溶剂B:90%MeOH-10%水-0.2%H3PO4;UV:254nm):保留时间6.50分钟。
实施例2
在80-90℃搅拌N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺(1.3g,4.6mmol)的1N盐酸(15ml)溶液3小时。使其冷却至室温并用碳酸钠调节溶液的pH到7。用二氯甲烷(3×10ml)提取该产物。用Na2SO4干燥合并的提取物并浓缩。用乙醚研磨该残余物并收集沉淀的固体,得到2-氨基-5-[[(5-乙基-2-噁唑基)甲基]硫代基]噻唑(610mg,55%),为一种固体,mp119-120℃。1H NMR(CDCl3)δ6.93(s,1H),6.61(s,1H),5.41(s,2H),3.82(s,3H),2.62(q,J=7.6Hz,2H),1.18(t,J=7.6Hz,3H);MS m/e 242(M+H)+;HPLC(柱:Zorbax快速分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%MeOH-90%水-0.2%H3PO4;溶剂B:90%MeOH-10%水-0.2%H3PO4;UV:254nm):保留时间3.96分钟。B.制备N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]苯甲酰胺
在室温下,搅拌2-氨基-5-[[(5-乙基-2-噁唑基)甲基]硫代基]噻唑(48.2mg,0.2mmol)、苯甲酰氯(24.4mg,0.21mmol)和三乙胺(35mg,0.35mmol)在二氯甲烷(0.5ml)中的混合物10分钟。用水洗涤该有机溶液并浓缩。通过快速柱层析(SiO2:己烷∶乙酸乙酯/2∶1)纯化该残余物,得到N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]苯甲酰胺(41mg,59%),为一种固体,mp122-123℃。1H NMR(CDCl3)δ12.65(s,1H),7.96(m,2H),7.61(m,1H),7.49(m,2H),6.88(s,1H),6.56(s,1H),3.93(s,2H),2.61(q,J=7.6Hz,2H),1.20(t,J=7.6Hz,3H);MS m/e 346(M+H)+;HPLC(柱:Zorbax快速分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%MeOH-90%水-0.2%H3PO4;溶剂B:90%MeOH-10%水-0.2%H3PO4;UV:254nm):保留时间7.94分钟。
实施例3N-[5-[[(4,5-二甲基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺A.制备2-(溴甲基)-4,5-二甲基噁唑
在氮气氛下,于76℃加热2,4,5-三甲基噁唑(0.50ml,4.3mmol)、N-溴丁二酰亚胺(0.77g,4.3mmol)和苯甲酰基过氧化物(0.21g,0.86mmol)在四氯化碳(4ml)中的混合物3小时。在冷却至室温后,通过过滤移去固体。用饱和的NaHCO3水溶液(20ml)洗涤该滤液并浓缩。通过快速柱层析(SiO2:己烷∶乙酸乙酯/4∶1)纯化该残余物,得到2-(溴甲基)-4,5-二甲基噁唑(64mg),为一种黄色的油状物。1H NMR(CDCl3)δ4.4(s,2H),2.25(s,3H),2.05(s,3H)。B.制备N-[5-[[(4,5-二甲基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺
将N-[5-(乙酰基硫代基)-2-噻唑基]乙酰胺(0.050g,0.23mmol)溶解于无水THF(10ml)中并将叔丁醇钾(1.0M的THF溶液,0.25ml,0.25mmol)加入到该混合物中。在室温下搅拌该反应混合物15分钟,并将2-(溴甲基)-4,5-二甲基噁唑(0.064g,0.34mmol)加入到所述混合物中。在室温下搅拌该反应混合物3小时并将饱和的NaHCO3水溶液(20ml)加入到该混合物中。分离有机层并用二氯甲烷(3×20ml)提取水层。浓缩合并的有机层。通过快速柱层析(SiO2:甲醇∶二氯甲烷/1∶20)纯化该残余物,得到N-[5-[[(4,5-二甲基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺(15mg,23%),为一种黄色的固体。1H NMR(CDCl3)δ11.78(s,1H),7.38(s,1H),3.90(s,2H),2.30(s,3H),2.22(s,3H),2.05(s,3H);MS m/e 284(M+H)+;HPLC(柱:Zorbax快速分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%甲醇/90%水/0.2% H3PO4;溶剂B:90%甲醇/10%水/0.2% H3PO4;UV:254nm):保留时间5.87分钟。
实施例4N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺A.制备重氮甲烷
在0℃、搅拌下,向15ml 40%的KOH水溶液和50ml乙醚的混合物中分批加入5g(68mmol)N-甲基-N’-硝基-N-亚硝基胍。在0℃搅拌所产生的混合物0.5小时。将有机相轻轻地倾入一个干燥的烧瓶中并用固体KOH小球干燥,得到50ml重氮甲烷溶液(通过用乙酸滴定测得浓度为0.5M)。B.制备1-重氮基(diazo)-3,3-二甲基-2-丁酮
在0℃、搅拌下,向所述重氮甲烷溶液中滴加1.23ml(1.21g,10mmol,Aldrich)三甲基乙酰氯在1ml乙醚中的溶液。在0℃保持所产生的混合物16小时。用氩气喷射该溶液以便移去过量的重氮甲烷并且在减压下除去乙醚,得到1.33g(10mmol,100%)粗制的1-重氮基-3,3-二甲基-2-丁酮,为一种黄色液体。C.制备2-氯甲基-5-叔丁基噁唑
在0℃向2ml(2.3g,16mmol)三氟化硼合乙醚在20ml氯乙腈中的溶液中滴加1.33g(10mmol)1-重氮基-3,3-二甲基-2-丁酮在5ml氯乙腈中的溶液。在0℃搅拌所产生的溶液0.5小时。将该反应混合物加入到饱和的碳酸氢钠溶液中以便中和酸并用二氯甲烷提取该产物三次。干燥(硫酸钠)合并的提取液,浓缩并通过快速柱层析(Merck硅胶,25×200mm,二氯甲烷)纯化该残余物,得到1.1g 2-(氯甲基)-5-叔丁基噁唑,为一种黄色的液体(6.4mmol,来自于酰氯的全部的64%)。1H NMR(CDCl3)δ1.30(s,9H),4.58(s,2H),6.68(s,1H);MS174(M+H)+;TLC:Rf(硅胶,二氯甲烷)=0.33;HPLC:tR(YMC S-3 ODS 4.6×50mm快速分离;2.5ml/分钟;0-100%B梯度液,8分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2%H3PO4;UV:254nm)=6.5分钟。D.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺
在室温、氩气下,向50mg(0.23mmol,Applied Chemical Laboratory)N-[5-(乙酰基硫代基)-2-噻唑基]乙酰胺在10ml THF中的溶液中加入0.25ml叔丁醇钾溶液(1M溶液,0.25mmol)。在室温下搅拌产生的悬浮液15分钟,然后加入59mg 2-(氯甲基)-5-叔丁基噁唑(0.34mmol)在1mlTHF中的溶液。在室温下搅拌产生的混合物16小时,减压下浓缩并通过快速柱层析(硅胶,25×200mm,1∶1乙酸乙酯/己烷,随后100%乙酸乙酯)纯化,得到44mg(0.14mmol,61%)N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺,为一种白色的固体。1H NMR(CDCl3)δ1.27(s,9H),2.27(s,3H),3.95(s,2H),6.59(s,1H),7.31(s,1H),11.03(宽s,1H);MS 312(M+H)+;TLC:Rf(硅胶,乙酸乙酯)=0.53,UV;HPLC:保留时间(YMC S-3 ODS 4.6×50mm快速分离;2.5ml/分钟;0-100%B梯度液,8分钟。溶剂A:10%MeOH/90%水/0.2%H3PO4;溶剂B:90%MeOH/10%水/0.2%H3PO4;UV:254nm)=6.8分钟。
实施例5
在-78℃、氩气下,向5-氰硫基-2-氨基噻唑(30mmol)和2,6-二甲基吡啶(35mmol)在四氢呋喃(25ml)和二氯甲烷(50ml)的混合物中缓慢地加入三氟乙酸酐(33mmol)。在加入后,让该混合物温热至室温并搅拌过夜。用二氯甲烷(100ml)稀释该混合物,用5%的柠檬酸水溶液、随后用盐水洗涤该有机溶液,用硫酸镁干燥并使其通过一个硅胶垫。浓缩该含有洗脱液的产物,得到5.3g浅棕色固体。1H NMR(CDCl3)δ124(br,1H),7.83(s,1H).B.制备4-羟基甲基-3-甲氧基苯氧基Merrifield树脂(XVI)
在0℃、氩气下,向氢化钠(11.7g,60%的矿物油悬浮液,293mmol)在二甲基甲酰胺(30ml)的悬浮液中缓慢地加入4-羟基-3-甲氧基苯甲醛(44.5g,292.5mmol)在二甲基甲酰胺(100ml)中的溶液。向该产生的混合物中加入Merrifield树脂(1%DVB,来自于Advanced Chemtech,装载量1.24mmol/g,50g,62mmol)和催化量的四正丁基铵idodide,并在65℃加热一天。过滤树脂并用水(2x)、50%二甲基甲酰胺的水溶液(3x)、二甲基甲酰胺(2x)和甲醇(5x)洗涤,并在真空下干燥。用在四氢呋喃(50ml)和乙醇(50ml)中的氢硼化钠(34g,90mmol)处理干燥的树脂(15g)过夜。过滤该树脂,用50%二甲基甲酰胺的水溶液(3x)、二甲基甲酰胺(2x)、甲醇(2x)和二氯甲烷(5x)洗涤,并在真空下干燥。C.制备4-氯甲基-3-甲氧基苯氧基Merrifield树脂(XVII)
在0℃、30分钟内向三苯基膦(17g,65mmol)的二氯甲烷(200ml)溶液中缓慢地分批加入三光气(9.2g,31mmol)。在加入后,在0℃搅拌该反应混合物10分钟。在真空下除去该溶剂并将该残余物溶解于二氯甲烷(200ml)中。将4-羟基甲基-3-甲氧基苯氧基Merrifield树脂(12g)加入到该混合物中。搅动该产生的混合物4小时。用无水二氯甲烷(6x)洗涤该树脂并在真空下干燥。D制备4-[N-[(5-氰硫基)-2-噻唑基三氟乙酰氨基]甲基]-3-甲氧基苯氧基Merrifield树脂(XIX)
搅拌4-氯甲基-3-甲氧基苯氧基Merrifield树脂(15g)、N-[(5-氰硫基)-2-噻唑基]三氟乙酰胺(14g,55.3mmol)和二异丙基乙胺(7.8ml,45mmol)在二甲基甲酰胺(50ml)和二氯甲烷(100ml)中的混合物过夜。用二甲基甲酰胺(2x)、甲醇(2x)和二氯甲烷(4x)洗涤该树脂,并在真空下干燥。E.制备4-[[N-[(5-巯基)-2-噻唑基]三氟乙酰氨基]甲基]-3-甲氧基苯氧基Merrifield树脂(XX)
搅拌4-[N-[(5-氰硫基)-2-噻唑基三氟乙酰氨基]甲基]-3-甲氧基苯氧基Merrifield树脂(XIX,18.5g)和二硫苏糖醇(12g,78mmol)在四氢呋喃(100ml)和甲醇(100ml)中的混合物过夜。用二甲基甲酰胺(2x)、甲醇(2x)、二氯甲烷(4x)洗涤该树脂,在真空下干燥并在-20℃、氩气下贮存。F.制备4-N-[5-[[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]三氟乙酰氨基]甲基-3-甲氧基苯氧基Merrifield树脂(XXI)
使氩气流鼓泡通过4-[[N-[(5-巯基)-2-噻唑基]三氟乙酰氨基]甲基]-3-甲氧基苯氧基Merrifield树脂(XX,500mg)、卤化物(2.0mmol)和1,8-二氮杂双环[5,4,0]十一碳-7-烯(DBU,1.5mmol)在二甲基甲酰胺(3ml)中的混合物5分钟,并在80℃加热该混合物2小时。用二甲基甲酰胺(2x)、甲醇(2x)和二氯甲烷(4x)洗涤该树脂并在真空下干燥。G.制备4-N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]甲基-3-甲氧基苯氧基Merrifield树脂(XXII)
剧烈搅拌4-N-[5-[[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]三氟乙酰氨基]甲基-3-甲氧基苯氧基Merrifield树脂(XXI,500mg)和氢硼化钠(4mmol)在四氢呋喃(2ml)和乙醇(2ml)中的混合物过夜。用50%二甲基甲酰胺水溶液(2x)、二甲基甲酰胺(2x)、甲醇(2x)、二氯甲烷(4x)洗涤该树脂并在真空下干燥。H.制备4-N-[5-[[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]三甲基乙酰氨基]甲基-3-甲氧基苯氧基Merrifield树脂(XXIII)
将在一个装配有聚乙烯玻璃器板(frit)和luer活塞(luer stopcock)的聚丙烯试管中的4-N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]甲基-3-甲氧基苯氧基Merrifield树脂(XXII,100mg)、二异丙基乙胺(1.2mmol)和三甲基乙酰氯(1mmol)在二氯甲烷(2ml)中的混合物搅拌过夜。用二甲基甲酰胺(2x)、甲醇(2x)、二氯甲烷(4x)洗涤该树脂并无须干燥直接用于下一步骤。I.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]三甲基乙酰胺
在一个装配有聚丙烯过滤器板和luer活塞的聚丙烯试管中,用在二氯甲烷(2ml)中的60%三氟乙酸处理4-N-[5-[[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]三甲基乙酰氨基]甲基-3-甲氧基苯氧基Merrifield树脂(XXIII)4小时。将该溶液倾入到一试管中并用二氯甲烷洗涤该树脂。在Speed Vac.中浓缩合并的有机溶液。用制备性HPLC纯化该残余物,得到11.3mg所需要的产物。MS m/e 354(M+H)+。
实施例6
在-70℃下,向2-氨基-1-丁醇(5.0ml,53mmol)和三乙胺(15.0ml,111mmol)在二氯甲烷(20ml)中的混合物中滴加氯乙酰氯(4.6ml,58mmol)。在-70℃搅拌该反应混合物15分钟,然后让其温热至室温。用EtOAc(50ml)稀释并通过加入水(50ml)猝灭该反应。分离该有机层并用EtOAc(3×30ml)提取水层。浓缩合并的有机层,得到2-(2-氯乙酰氨基)-1-丁醇(8.6g,98%),为一种棕色的固体。1H NMR(CDCl3)δ6.75(bs,1H),4.10(s,2H),4.08(dd,1H),3.90(m,1H),3.68(m,2H),2.98(bs,1H),1.60(m,2H),0.97(t,3H).B.制备2-(2-氯乙酰氨基)-1-丁醛
在-78℃、用5分钟时间向乙二酰氯(14.5ml,29.0mmol)的二氯甲烷(30ml)溶液中滴加DMSO(2.75ml,38.8mmol)。在搅拌10分钟后,在-78℃、用15分钟向其中滴加2-(2-氯乙酰氨基)-1-丁醇(4.0g,24mmol)的二氯甲烷(20ml)溶液。在-78℃搅拌该反应混合物40分钟并用5分钟向其中滴加三乙胺(9.4ml,68mmol),让该反应混合物温热至室温并搅拌2小时。通过过滤移去该固体并用EtOAc洗涤。用1N HCl(2×100ml)、饱和的NaHCO3水溶液(1×10ml)洗涤该有机相并浓缩,得到2-(2-氯乙酰氨基)-1-丁醛(3.7g,95%),为棕色的油状物。1H NMR(CDCl3)δ9.60(s,1H),4.52(q,1H),4.12(s,2H),2.05(m,1H),1.80(m,1H),0.97(t,3H).C.制备2-氯甲基-4-乙基噁唑
向2-(2-氯乙酰氨基)-1-丁醛(3.7g,23mmol)的甲苯(10ml)溶液中加入POCl3(6.3ml,68mmol)。在氮气下、在90℃加热该反应混合物1小时。在该反应混合物冷却至室温后,将其倾入冰水(10ml)中并用5NNaOH调节该溶液的pH到7。分离甲苯层并用二氯甲烷(3×20ml)洗涤水层。浓缩合并的有机溶液并蒸馏得到2-氯甲基-4-乙基噁唑(1.1g,31%),为无色的液体。1H NMR(CDCl3)δ7.30(s,1H),4.22(s,2H),2.50(q,2H),1.22(t,3H).D.制备N-[5-[[(4-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺
向2-乙酰氨基-5-噻唑基硫醇(0.010g,0.050mmol)的无水THF(5ml)溶液中加入叔丁醇钾(1.0M的THF溶液,0.060ml,0.060mmol)。在室温下搅拌该反应混合物15分钟并向其中加入2-氯甲基-4-乙基噁唑(0.015g,0.10mmol)。3小时后,将饱和的NaHCO3水溶液(5ml)加入到该混合物中。分离有机层并用二氯甲烷(3×10ml)洗涤水层。浓缩合并的有机层。通过快速色谱法(SiO2,甲醇∶二氯甲烷/1∶20)纯化该残余物,得到N-[5-[[(4-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺(5mg,36%),为白色固体。1H NMR(CDCl3)δ11.25(s,1H),7.34(s,1H),7.31(s,1H),3.95(s,2H),2.50(q,2H),2.27(s,3H),1.19(t,3H);MS m/e 284(M+H)+;HPLC(柱:Zorbax快速分离C-18;流速:2.5ml/分钟;溶剂系统:0-100%B,8分钟。溶剂A:10%甲醇/90%水/0.2% H3PO4;溶剂B:90%甲醇/10%水/0.2% H3PO4;UV:254nm):保留时间6.14分钟。
实施例7制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-N’-氰基-N”-(2,6-二氟苯基)胍
在氩气下、于65℃加热100mg N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-氨基噻唑和68mg 2,6-二氟苯基异硫氰酸酯的溶液16小时。蒸发该溶液至干并通过快速色谱法纯化该残余物,得到91mg中间体硫脲。
向30mg N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-N”-(2,6-二氟苯基)硫脲、52mg乙基-3(3-二甲基氨基)丙基碳化二亚胺盐酸盐和48ul二异丙基乙胺在0.5ml二氯甲烷中的溶液中加入29mg氨基氰在0.1ml四氢呋喃中的溶液。在搅拌1小时后,除去溶剂并用HPLC纯化该粗产物,得到8mg实施例636化合物。MS:(M+H)+449+ 1H NMR(400MHz,CDCl3):d1.27(9H,s),4.19(2H,s),6.69(1H,s),7.03(2H,m),7.35(1H,m),8.74(1H,s)。
实施例8
制备N-[5-[[(5-异丙基-2-噁唑基)氟甲基]硫代基]-2-噻唑基乙酰胺
在氩气下,向乙酸2-乙酰氨基-5-噻唑硫醇酯(141mg)在3ml无水THF中的搅拌混合物中加入1N t-BuOK的THF(0.72ml)溶液。在室温下搅拌该混合物25分钟并加入5-异丙基-(2-(氯氟甲基))噁唑(116mg)的无水THF(2ml)溶液。在60℃搅拌该反应混合物18小时,用150mlEtOAc稀释并用饱和的NH4Cl溶液(2×25ml)、饱和的NaHCO3溶液(1×25ml)和盐水(1×25ml)洗涤。干燥(MgSO4)该有机层,过滤并在真空下浓缩,得到实施例637化合物。MS:(M+H)+316HPLC保留时间3.52分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B梯度液4分钟,溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。
实施例9制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-(2-羟基乙基)磺酰胺A.制备5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-溴噻唑
在0℃向CuBr2(5.14g)的乙腈(100ml)溶液中加入tBuONO(4ml,1.2eq),随后加入5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基胺(5.2g)。在0℃搅拌该混合物一小时,然后在室温下搅拌一小时,加入乙酸乙酯并用盐酸(2×50ml)洗涤该有机混合物,用硫酸镁干燥,通过硅胶垫过滤并在真空下浓缩。在硅胶上层析该残余物,得到所述溴化物,为一种橙色的油状物(3.9g)。MS:(M+H)+334HPLC保留时间4.04分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B的梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。B.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-(2-羟基乙基)磺酰胺
在145℃下,搅拌在二甲基乙酰胺(4ml)中的来自部分A的2-溴噻唑(0.85g)和4-氨基苯基-N-(2-羟基乙基)磺酰胺(2.5g,5eq)的混合物6小时,冷却并加入乙酸乙酯(80ml)。用水(2×20ml)洗涤该反应混合物,用乙酸乙酯提取合并的水溶液并用硫酸钠干燥合并的有机层,在真空下蒸发并在硅胶上层析该残余物,然后通过反相色谱纯化,得到N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-(2-羟基乙基)磺酰胺,为一种黄色固体(0.61g)。MS:(M+H)+469HPLC保留时间3.80分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。
实施例10制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-磺酰胺
在140℃下,搅拌在二甲基乙酰胺(0.5ml)中来自实施例9,部分A的2-溴噻唑(106mg)和4-氨基苯磺酰胺(275mg,5eq)的混合物6小时,冷却并在减压下除去溶剂,得到深红色的油状物,通过制备性反相HPLC(YMC S5 ODS)纯化该油状物,得到N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-磺酰胺(94mg)。MS:(M+H)+425HPLC保留时间3.74分钟。(柱:YMC ODS S05 4.6×50mm柱,0-100%B梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。
向一个50ml单颈烧瓶中加入在无水四氢呋喃(5ml)中的4-氨基嘧啶(142mg)。加入氢化钠分散体(60%,60mg),随后在60℃加热一小时。将该阴离子溶液冷却到室温并加入实施例9,部分A的2-溴噻唑(100mg)。在60℃加热该反应物24小时,冷却至室温,用盐酸猝灭并在水和乙酸乙酯(各25ml)之间分配。用水(2×25ml)、盐水(25ml)洗涤该有机层,用硫酸钠干燥并在真空下浓缩,得到一种固体,用1∶1的乙酸乙酯∶己烷研磨纯化该固体,得到N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-4-氨基嘧啶(42mg)。MS:(M+H)+348HPLC保留时间3.63分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。
在-78℃下,向3-羟基甲基苯胺(2.46g)的无水四氢呋喃(50ml)溶液中加入甲基锂-溴化锂的乙醚溶液(27ml的1.5M溶液)。在-78℃搅拌该反应混合物10分钟,温热到室温10分钟,然后冷却到-78℃并加入2-溴噻唑(1.31g)。在0℃搅拌该反应混合物一小时,然后在室温3小时,加入盐酸(20ml的2N溶液)猝灭,浓缩并用乙酸乙酯提取。用硫酸钠干燥合并的有机提取物,浓缩并在硅胶上层析,得到N-2-[3-(羟基甲基)苯基]氨基噻唑(0.68g)。B.制备N-2-[3-(羟基甲基)苯基]氨基噻唑-5-硫氰酸酯
向冷却(冰-盐浴)的部分A化合物(680mg)和硫氰酸铵(500mg)的甲醇(35m1)溶液中分批加入溴(0.21ml)。在溴的颜色消失后,浓缩该反应物并在乙酸乙酯和水之间分配。用乙酸乙酯提取水层并用硫酸钠干燥合并的有机提取物,浓缩并在硅胶上层析,得到N-2-[3-(羟基甲基)苯基]氨基噻唑-5-硫氰酸酯,为一种黄色的固体(490mg)。C.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-3-(羟基甲基)苯胺
将氢硼化钠(84mg)分批加入到部分B的硫氰酸酯(490mg)的四氢呋喃/乙醇的暗红色溶液中。在气体产生已经停止后,用8分钟将丙酮(0.65ml)加入到搅拌的反应物中,随后加入2-氯甲基-5-叔丁基-噁唑(实施例5,部分C化合物,0.5g)并在室温下搅拌该反应物1小时。浓缩该反应物,用乙酸乙酯提取,用硫酸钠干燥合并的有机提取物并通过硅胶垫过滤,得到所述产物(0.69g).MS:(M+H)+376HPLC保留时间3.84分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。
向氢化钠(60%悬浮液,1.8g)的四氢呋喃(200ml)悬浮液中分批加入2-氨基吡啶(4.23g),并缓慢地将该混合物加热至55℃30分钟。然后将该反应混合物冷却至-10℃并滴加2-溴噻唑(2.46g)的四氢呋喃(2ml)溶液。在55℃搅拌该反应混合物5小时,冷却并用盐酸(2N,20ml)猝灭,浓缩并加入乙酸乙酯。过滤所产生的固体,得到N-2-[吡啶基]氨基噻唑(1.41g)。B.制备N-2-[吡啶基]-5-溴-氨基噻唑
在室温下向部分A化合物(0.88g)的乙酸(15ml)溶液中滴加溴(0.22ml在2ml乙酸中)。在室温下搅拌该反应混合物2小时,在减压下移去溶剂,并用乙醚研磨所产生的固体,得到N-2-[吡啶基]-5-溴-氨基噻唑(1.6g),为一种氢溴酸盐。C.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-氨基吡啶
在室温、氩气下,向N-2-[吡啶基]-5-溴-氨基噻唑(8g)和2-硫代乙酰基-5-叔丁基噁唑(8g)的甲醇(500ml)溶液中加入脱气的氢氧化钠溶液(25ml的3N溶液)。搅拌该反应混合物20分钟并加热到60℃1小时,在真空下浓缩,在水(125ml)和乙酸乙酯(500ml)之间分配并用乙酸乙酯反萃取(2×125ml)水层。用盐水(25ml)洗涤合并的有机层,用硫酸钠干燥,通过硅胶垫过滤并在真空下除去溶剂。从乙酸乙酯中重结晶该固体残余物,得到N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-氨基吡啶(7.5g)。MS:(M+H)+347HPLC保留时间4.01分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2% H3PO4;溶剂B:90%MeOH/10%水/0.2% H3PO4;UV:220nM)。
实施例14制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-[5-[(((3-羟基-2,2-二甲基)丙基)氨基)甲基]]氨基吡啶A.制备N-2-[(5-溴)吡啶基]氨基噻唑
向氢化钠(60%悬浮液,5.2g)的四氢呋喃(150ml)悬浮液中分批加入2-氨基-4-溴吡啶(15g),并在室温下搅拌该混合物15分钟。加入2-溴噻唑(3.8ml)并在室温下搅拌该反应混合物1小时,然后在回流温度加热2.5小时,冷却、用6%柠檬酸猝灭并用乙酸乙酯(2×100ml)提取。浓缩有机层、用硫酸镁干燥并在真空下浓缩滤液,得到一种深棕色的残余物,用乙醚/己烷研磨该残余物,得到N-2-[(5-溴)吡啶基]氨基噻唑,为黄色固体(8.9g).B.制备N-2-[(5-甲醛)吡啶基]氨基噻唑
将部分A化合物(6.4g)在四氢呋喃(300ml)中的悬浮液加热至回流以进行溶解,将该反应混合物冷却至-70℃并用10分钟滴加t-BuMgCl(13ml的2M乙醚溶液)处理。将温度升到-55℃,并滴加t-BuLi(36ml的1.7M己烷溶液),搅拌该反应混合物20分钟。然后冷却该反应混合物到-70℃并加入DMF(8ml),在-50℃搅拌所产生的混合物1小时,然后用1小时将其温热到0℃,用乙酸(8ml)猝灭并在乙酸乙酯和水(各300ml)之间分配。用乙酸乙酯(2×200ml)反萃取水层并用硫酸镁干燥合并的有机层并浓缩,用乙酸乙酯和乙醚洗涤该固体,并干燥得到N-2-[(5-甲醛)吡啶基]氨基噻唑(3.15g)。C.制备N-2-[(5-甲醛)吡啶基]-5-溴-氨基噻唑
用在二氯甲烷(3ml)中的溴(0.12ml)处理N-2-[(5-甲醛)吡啶基]氨基噻唑(0.5g)在乙酸(6ml)和二氯甲烷(20ml)中的溶液。在室温下搅拌该反应混合物30分钟,加入乙醚,并通过过滤收集所产生的沉淀,用乙醚洗涤,得到N-2-[(5-甲醛)吡啶基]-5-溴-氨基噻唑(0.69g)。D.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-氨基吡啶-5-甲醛
在氮气下向部分C化合物(3.8g)和5-叔丁基-2-(S-异硫脲)甲基噁唑(3.06g)的甲醇(300ml)溶液中加入脱气的氢氧化钠(6.4g的50%w/w溶液)。在76℃加热该反应混合物6小时,在真空下除去甲醇,加入水并通过过滤收集该固体,用水和乙酸乙酯洗涤并干燥得到N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-氨基吡啶-5-甲醛(0.53g)。用乙酸乙酯(4×200ml)提取该滤液,用硫酸镁干燥并在真空下浓缩,用乙醚/乙酸乙酯研磨,得到额外的2.02g所需化合物。E.制备N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-[5-[(((3-羟基-2,2-二甲基)丙基)氨基)甲基]]氨基吡啶
向部分D的醛(1.5g)和3-氨基-2,2-二甲基丙醇(2.06g)在四氢呋喃(100ml)中的溶液中加入三乙酸基氢硼化钠(6.0g),随后加入乙酸(5ml)。在室温下搅拌该反应混合物30分钟,在真空下除去溶剂,得到一种黄色的固体,用柱色谱纯化该固体,得到N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-[5-[(((3-羟基-2,2-二甲基)丙基)氨基)甲基]]氨基吡啶(1.08g)。MS:(M+H)+462HPLC保留时间3.22分钟。(柱:YMC ODS S05 4.6×50mm柱,0%-100%B梯度液,4分钟。溶剂A:10%MeOH/90%水/0.2%H3PO4;溶剂B:90%MeOH/10%水/0.2%H3PO4;UV:220nM)。
Claims (46)
R1和R2独立为氢、氟或烷基;
R3为芳基或杂芳基;
R4为烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NNO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NNO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(NH)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢或烷基;
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
m为0到2的整数;和
n为1到3的整数。
2.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为氧、硫或NR9;
R4为烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NNO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NNO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(NH)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢或烷基;
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
R7和R8独立为氢、烷基、取代的烷基、环烷基、芳基、取代的芳基、环烷基烷基、芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;
R9为氢、烷基、环烷基、芳基、烷基环烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
m为一个0到2的整数;和
n为一个1到3的整数。
3.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
其中Y为氧;
R4为烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NNO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NNO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(NH)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢;
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
R7和R8独立为氢、烷基、取代的烷基、环烷基、芳基、取代的芳基、环烷基烷基、芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;
m为一个0到2的整数;和
n为一个1到3的整数。
4.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为硫;
R4为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NNO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NNO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(NH)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢;
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
R7和R8独立为氢、烷基、取代的烷基、环烷基、芳基、取代的芳基、环烷基烷基、芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;
m为一个0到2的整数;和
n为一个1到3的整数。
5.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为NR9;
R4为烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;或
CO-烷基、CO-环烷基、CO-芳基、CO-烷基-环烷基、CO-烷基-芳基、CO-杂芳基、CO-烷基-杂芳基、CO-杂环烷基、CO-烷基-杂环烷基;或
CONH-烷基、CONH-环烷基、CONH-芳基、CONH-烷基-环烷基、CONH-烷基-芳基、CONH-杂芳基、CONH-烷基-杂芳基、CONH-杂环烷基、CONH-烷基-杂环烷基;或
COO-烷基、COO-环烷基、COO-芳基、COO-烷基-环烷基、COO-烷基-芳基、COO-杂芳基、COO-烷基-杂芳基、COO-杂环烷基、COO-烷基-杂环烷基;或
SO2-环烷基、SO2-芳基、SO2-烷基-环烷基、SO2-烷基-芳基、SO2-杂芳基、SO2-烷基-杂芳基、SO2-杂环烷基、SO2-烷基-杂环烷基;或
C(NCN)NH-烷基、C(NCN)NH-环烷基、C(NCN)NH-芳基、C(NCNNH)-烷基-环烷基、C(NCN)NH-烷基-芳基、C(NCN)NH-杂芳基、C(NCN)NH-烷基-杂芳基、C(NCN)NH-杂环烷基、C(NCN)NH-烷基-杂环烷基;或
C(NNO2)NH-烷基、C(NNO2)NH-环烷基、C(NNO2)NH-芳基、C(NNO2)NH-烷基-环烷基、C(NNO2)NH-烷基-芳基、C(NNO2)NH-杂芳基、C(NNO2)NH-烷基-杂芳基、C(NNO2)NH-杂环烷基、C(NNO2)NH-烷基-杂环烷基;或
C(NH)NH-烷基、C(NH)NH-环烷基、C(NH)NH-芳基、C(NH)NH-烷基-环烷基、C(NH)NH-烷基-芳基、C(NH)NH-杂芳基、C(NH)NH-烷基-杂芳基、C(NH)NH-杂环烷基、C(NH)NH-烷基-杂环烷基;或
C(NH)NHCO-烷基、C(NH)NHCO-环烷基、C(NH)NHCO-芳基、C(NH)NHCO-烷基-环烷基、C(NH)NHCO-烷基-芳基、C(NH)NHCO-杂芳基、C(NH)NHCO-烷基-杂芳基、C(NH)NHCO-杂环烷基、C(NH)NHCO-烷基-杂环烷基;或
C(NOR6)NH-烷基、C(NOR6)NH-环烷基、C(NOR6)NH-芳基、C(NOR6)NH-烷基-环烷基、C(NOR6)NH-烷基-芳基、C(NOR6)NH-杂芳基、C(NOR6)NH-烷基-杂芳基、C(NOR6)NH-杂环烷基、C(NOR6)NH-烷基-杂环烷基;
R5为氢;
R6为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
R7和R8独立为氢、烷基、取代的烷基、环烷基、芳基、取代的芳基、环烷基烷基、芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、杂环烷基、杂环烷基烷基;
R9为氢、烷基、环烷基、芳基、环烷基烷基、芳基烷基、杂芳基、杂芳基烷基、杂环烷基或杂环烷基烷基;
m为一个0到2的整数;和
n为一个1到3的整数。
6.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为氧;
R4为CO-烷基、CO-烷基-芳基、CO-环烷基、CO-烷基-杂芳基、CO-烷基-杂烷基、CO-烷基-杂环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、CONH-烷基、CONH-烷基-芳基、CONH-环烷基或CONH-烷基-杂环烷基;
R5为氢;
R7和R8为氢;
m为整数0;和
n为整数1。
10.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为硫;
R4为CO-烷基、CO-烷基-芳基、CO-烷基-杂烷基、CO-环烷基、CO-烷基-杂环烷基、CO-烷基-杂芳基、芳基、芳基烷基、杂芳基、杂芳基烷基、CONH-烷基、CONH-烷基-芳基、CONH-环烷基或CONH-烷基-杂环烷基;
R5为氢;
R7为氢;
R8为烷基;
m为整数0;和
n为整数1。
12.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为NR9;
R4为CO-烷基、CO-烷基-芳基、CO-烷基-杂烷基、CO-环烷基、CO-烷基-杂环烷基、CO-烷基-杂芳基、芳基、芳基烷基、杂芳基、杂芳基烷基、CONH-烷基、CONH-烷基-芳基、CONH-环烷基或CONH-烷基-杂环烷基;
R5为氢;
R7为氢;
R8为烷基;
R9为氢、烷基、环烷基、芳基、烷基-环烷基、烷基-芳基、杂芳基、烷基-杂芳基、杂环烷基或烷基杂环烷基;
m为整数0;和
n为整数1。
13.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中Y为NR9;
R4为CO-烷基、CO-烷基-芳基、CO-烷基-杂烷基、CO-环烷基、CO-烷基-杂环烷基、CO-烷基-杂芳基、芳基、芳基烷基、杂芳基、杂芳基烷基、CONH-烷基、CONH-烷基-芳基、CONH-环烷基或CONH-烷基-杂环烷基;
R5为氢;
R7为烷基;
R8为氢;
R9为烷基;
m为整数0;和
n为整数1。
14.权利要求1所述的化合物,其中
R1和R2独立为氢、氟或烷基;
R3为
其中X为NR9;
R4为CO-烷基、CO-烷基-芳基、CO-环烷基、CO-烷基-杂芳基、CO-烷基-杂烷基、CO-烷基-杂环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、CONH-烷基、CONH-烷基-芳基、CONH-环烷基或CONH-烷基-杂环烷基;
R5为氢;
R7为烷基;
R8为氢;
R9为氢;
m为整数0;
n为整数1。
15.权利要求1所述的化合物,它为以下化合物或其药学上可接受的盐:
N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺;
N-[5-[[(5-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]苯甲酰胺;
N-[5-[[(4,5-二甲基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]三甲基乙酰
胺;
N-[5-[[(4-乙基-2-噁唑基)甲基]硫代基]-2-噻唑基]乙酰胺
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-N’-氰基-
N”-(2,6-二氟苯基)胍;
N-[5-[[(5-异丙基-2-噁唑基)氟甲基]硫代基]-2-噻唑基]乙酰胺;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-
(2-羟基乙基)磺酰胺;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]氨基苯基-4-
磺酰胺;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-4-氨基嘧
啶;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-3-(羟基甲
基)苯胺;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-氨基吡
啶;
N-[5-[[(5-叔丁基-2-噁唑基)甲基]硫代基]-2-噻唑基]-2-[5-[(((3-羟
基-2,2-二甲基)丙基)氨基)甲基]]氨基吡啶。
16.一种药用组合物,该组合物包含权利要求1的化合物和药学上可接受的载体。
17.一种药用组合物,该组合物包含与药学上可接受的载体混合的权利要求1的化合物和按照固定剂量配制的抗癌剂。
18.一种药用组合物,该组合物包含与药学上可接受的载体组合的权利要求1的化合物和按照固定剂量配制的p53反式激活作用调节剂。
19.一种按照权利要求16的药用组合物,该组合物包括与药学上可接受的载体组合的权利要求1的化合物,并按顺序进行一种抗癌疗法或给予抗癌剂。
20.按照权利要求18的药用组合物,其中所述组合包括所述权利要求1的化合物和所述药学上可接受的载体,该组合物可以在进行所述抗癌疗法或给予所述抗癌剂之前给予。
21.按照权利要求18的药用组合物,其中所述组合包括所述权利要求1的化合物和所述药学上可接受的载体,该组合物可以在进行所述抗癌疗法或给予所述抗癌剂之后给予。
22.一种抑制蛋白激酶的方法,该方法包括给予有此需要的哺乳动物类有效的蛋白激酶抑制量的权利要求1的化合物。
23.一种抑制细胞周期蛋白依赖激酶的方法,该方法包括给予有此需要的哺乳动物类有效的细胞周期蛋白依赖激酶抑制量的权利要求1的化合物。
24.一种抑制cdc2(cdk1)的方法,该方法包括给予有此需要的哺乳动物类有效的cdc2抑制量的权利要求1的化合物。
25.一种抑制cdk2的方法,该方法包括给予有此需要的哺乳动物类有效的cdk2抑制量的权利要求1的化合物。
26.一种抑制cdk3的方法,该方法包括给予有此需要的哺乳动物类有效的cdk3抑制量的权利要求1的化合物。
27.一种抑制cdk4的方法,该方法包括给予有此需要的哺乳动物类有效的cdk4抑制量的权利要求1的化合物。
28.一种抑制cdk5的方法,该方法包括给予有此需要的哺乳动物类有效的cdk5抑制量的权利要求1的化合物。
29.一种抑制cdk6的方法,该方法包括给予有此需要的哺乳动物类有效的cdk6抑制量的权利要求1的化合物。
30.一种抑制cdk7的方法,该方法包括给予有此需要的哺乳动物类有效的cdk7抑制量的权利要求1的化合物。
31.一种抑制cdk8的方法,该方法包括给予有此需要的哺乳动物类有效的cdk8抑制量的权利要求1的化合物。
32.一种治疗增生性疾病的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
33.一种治疗癌症的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
34.一种治疗炎症、炎性肠病或移植排斥反应的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
35.一种治疗关节炎的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
36.一种治疗HIV感染的方法或治疗和预防AIDS发展的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
37.一种治疗病毒性感染的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
38.一种治疗真菌感染的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
39.一种预防癌症发展或肿瘤复发的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
40.一种治疗神经退化性疾病的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求16的组合物。
41.一种治疗增生性疾病的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求17的组合物。
42.一种治疗癌症的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求17的组合物。
43.一种预防癌症发展或肿瘤复发的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求17的组合物。
44.一种治疗增生性疾病的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求18的组合物。
45.一种治疗癌症的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求18的组合物。
46.一种预防癌症发展或肿瘤复发的方法,该方法包括给予有此需要的哺乳动物类一种治疗有效量的权利要求18的组合物。
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US09/464,511 US6262096B1 (en) | 1997-11-12 | 1999-12-15 | Aminothiazole inhibitors of cyclin dependent kinases |
US09/464,511 | 1999-12-15 |
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CN (1) | CN1433408A (zh) |
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CA (1) | CA2394538A1 (zh) |
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HK (1) | HK1049662A1 (zh) |
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CN1926121B (zh) * | 2004-01-12 | 2012-06-13 | 默克雪兰诺有限公司 | 噻唑衍生物及其应用 |
CN104177348A (zh) * | 2013-05-21 | 2014-12-03 | 苏州科捷生物医药有限公司 | 抗肿瘤化合物n-(2-(4-氯苯基)-5-恶唑基)-2-(1,3-二氧代-2-异吲哚啉基)乙酰胺的合成方法 |
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US6262096B1 (en) | 1997-11-12 | 2001-07-17 | Bristol-Myers Squibb Company | Aminothiazole inhibitors of cyclin dependent kinases |
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US6392053B2 (en) | 1999-12-15 | 2002-05-21 | Bristol-Myers Squibb Company | Process for preparing arylacetylaminothiazoles |
US6515004B1 (en) | 1999-12-15 | 2003-02-04 | Bristol-Myers Squibb Company | N-[5-[[[5-alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases |
WO2001068592A1 (en) * | 2000-03-13 | 2001-09-20 | Eli Lilly And Company | Sulfonamide derivatives |
SI21099A (sl) * | 2000-07-26 | 2003-06-30 | Bristol-Myers Squibb Company | N-(5-(((5-alkil-2-oksazolil)metil)tio)-2-tiazolil) karboksamidni inhibitorji ciklin odvisnih kinaz |
CA2433018A1 (en) * | 2000-12-21 | 2002-06-27 | Joel C. Barrish | Thiazolyl inhibitors of tec family tyrosine kinases |
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1999
- 1999-12-15 US US09/464,511 patent/US6262096B1/en not_active Expired - Lifetime
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- 2000-12-06 JP JP2001544707A patent/JP2003516981A/ja not_active Withdrawn
- 2000-12-06 EP EP00983935A patent/EP1240153A1/en not_active Withdrawn
- 2000-12-06 IL IL14975700A patent/IL149757A0/xx not_active IP Right Cessation
- 2000-12-06 CN CN00818898A patent/CN1433408A/zh active Pending
- 2000-12-06 PL PL00364890A patent/PL364890A1/xx not_active Application Discontinuation
- 2000-12-06 AU AU20627/01A patent/AU2062701A/en not_active Abandoned
- 2000-12-06 MX MXPA02005879A patent/MXPA02005879A/es active IP Right Grant
- 2000-12-06 CA CA002394538A patent/CA2394538A1/en not_active Abandoned
- 2000-12-06 CZ CZ20022014A patent/CZ20022014A3/cs unknown
- 2000-12-06 BR BR0016420-8A patent/BR0016420A/pt not_active Application Discontinuation
- 2000-12-06 KR KR1020027007614A patent/KR20020062341A/ko not_active Application Discontinuation
- 2000-12-06 WO PCT/US2000/033037 patent/WO2001044217A1/en not_active Application Discontinuation
- 2000-12-06 RU RU2002119015/04A patent/RU2002119015A/ru not_active Application Discontinuation
- 2000-12-06 HU HU0301213A patent/HUP0301213A3/hu unknown
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2001
- 2001-04-20 US US09/839,751 patent/US6521759B2/en not_active Expired - Lifetime
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2002
- 2002-05-30 ZA ZA200204356A patent/ZA200204356B/en unknown
- 2002-05-30 ZA ZA200204349A patent/ZA200204349B/en unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1926121B (zh) * | 2004-01-12 | 2012-06-13 | 默克雪兰诺有限公司 | 噻唑衍生物及其应用 |
CN104177348A (zh) * | 2013-05-21 | 2014-12-03 | 苏州科捷生物医药有限公司 | 抗肿瘤化合物n-(2-(4-氯苯基)-5-恶唑基)-2-(1,3-二氧代-2-异吲哚啉基)乙酰胺的合成方法 |
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KR20020062341A (ko) | 2002-07-25 |
NO20022864L (no) | 2002-08-13 |
AU2062701A (en) | 2001-06-25 |
MXPA02005879A (es) | 2003-01-28 |
HK1049662A1 (zh) | 2003-05-23 |
RU2002119015A (ru) | 2004-02-27 |
BR0016420A (pt) | 2002-08-20 |
ZA200204349B (en) | 2003-09-01 |
ZA200204356B (en) | 2003-10-07 |
IL149757A0 (en) | 2002-12-01 |
HUP0301213A3 (en) | 2009-03-30 |
WO2001044217A1 (en) | 2001-06-21 |
US6262096B1 (en) | 2001-07-17 |
HUP0301213A2 (hu) | 2003-08-28 |
US20020137778A1 (en) | 2002-09-26 |
CZ20022014A3 (cs) | 2003-03-12 |
US6521759B2 (en) | 2003-02-18 |
NO20022864D0 (no) | 2002-06-14 |
JP2003516981A (ja) | 2003-05-20 |
PL364890A1 (en) | 2004-12-27 |
CA2394538A1 (en) | 2001-06-21 |
EP1240153A1 (en) | 2002-09-18 |
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