CN1494425B - 用作治疗剂的羧酰胺衍生物 - Google Patents
用作治疗剂的羧酰胺衍生物 Download PDFInfo
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- CN1494425B CN1494425B CN028059948A CN02805994A CN1494425B CN 1494425 B CN1494425 B CN 1494425B CN 028059948 A CN028059948 A CN 028059948A CN 02805994 A CN02805994 A CN 02805994A CN 1494425 B CN1494425 B CN 1494425B
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- compound
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- diethylaminopropoxy
- rage
- alkyl
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Abstract
本发明提供特定的化合物、其制备方法、含有该化合物的药物组合物、以及其在治疗人类和动物疾病中的应用。本发明的化合物可用作高级糖基化终产物受体(RAGE)与其配体如高级糖基化终产物(AGEs)、S100/calgranulin/EN-RAGE、β-淀粉样蛋白和两性素的相互作用的调制剂,用于处理、治疗、控制由RAGE引起的人类疾病或作为其辅助治疗。这样的疾病或疾病状态包括急性和慢性炎症,糖尿病晚期并发症发作如血管通透性增加、肾病、动脉硬化症、和视网膜病,阿尔茨海默氏病的发展、勃起功能障碍、和肿瘤侵袭和/或肿瘤转移。
Description
相关申请声明
本申请根据35USC119要求以下美国临时申请的优先权:序列号60/273,454,2001年3月5日提交,题为“用作治疗剂的α-氨基酸的α-取代的酰胺衍生物”;序列号60/273,445,2001年3月5日提交,题为“用作治疗剂的取代的杂环基羧酰胺衍生物”;序列号60/273,429,2001年3月5日提交,题为“用作治疗剂的氨基链烷酰胺”;序列号60/273,455,2001年3月5日提交,题为“用作治疗剂的取代的氮杂环烷基羧酰胺衍生物”;序列号60/273,446,2001年3月5日提交,题为“用作治疗剂的稠合芳基杂环基羧酰胺”;序列号60/273,404,2001年3月5日提交,题为“用作治疗剂的芳基链烷酸衍生物”;和序列号60/273,403,2001年3月5日提交,题为“用作治疗剂的烷基咪唑羧酰胺衍生物”,这些文献在此引入本文。
发明领域
本发明涉及作为高级糖基化终产物受体(RAGE)的调制剂,及该受体与其配体如高级糖基化终产物(AGEs)、S100/钙粒蛋白/EN-RAGE、β-淀粉状蛋白和两性素(amphoterin)的相互作用的调制剂,用以处理、治疗、控制由RAGE引起的疾病或作为该疾病的辅助治疗的化合物。
发明背景
用醛糖培育蛋白质或类脂导致蛋白质氨基的非酶促糖基化和氧化,形成Amadori加合物。随时间推移,该加合物发生另外的重排、脱水和与其它蛋白质交联,形成称为高级糖基化终产物(AGEs)的复合物。促进AGEs形成的因素包括蛋白质转换延迟(例如,淀粉样变性中那样),赖氨酸含量高的大分子的累积,以及高血糖值(例如,糖 尿病中那样)(Hori等,J.Biol.Chem.270:25752-761,(1995))。AGEs牵涉到多种病症,包括与糖尿病和自然老化关联的并发症。
AGEs与微脉管系统的内皮细胞、单核细胞和巨噬细胞、平滑肌细胞、膜细胞(mesengial cell)、和神经元的细胞表面受体具有特异和可饱和的结合。高级糖基化终产物受体(RAGE)是细胞表面分子的免疫球蛋白总科的一个成员。RAGE的细胞外(N-末端)区包括三个免疫球蛋白型区域,一个V(可变)型区,后面是两个C型(恒定)区(Neeper等,J.Biol.Chem.267:14998-15004(1992))。跟随细胞外区的是一个单一的跨膜的跨越区(spanning domain),和一个短的强电荷细胞溶质尾巴。N-末端、细胞外区可以通过RAGE的蛋白质水解生成由V和C区构成的可溶RAGE(sRAGE)来加以分离。
RAGE在大多数组织中表达,特别是在胚胎形成时的皮层神经元中发现(Hori等,J.Biol.Chem.270:25752-761(1995))。在老化的组织(Schleicher等,J.Clin.Invest.99(3):457-468(1997))、糖尿病患者的视网膜、脉管系统和肾(Schmidt等,Nature Med.1:1002-1004(1995))中还发现了增长量的RAGE。活化不同的组织和器官中的RAGE会导致大量病理生理结果。RAGE牵涉到多种病症,包括:急性和慢性炎症(Hofmann等,Cell97:889-901(1999))、糖尿病晚期并发症如血管通透性增加的发作(Wautier等,J.Clin.Invest.97:238-243(1995))、肾病(Teillet等,J.Am.Soc.Nephrol.11:1488-1497(2000))、动脉硬化症(Vlassara等,The Finnish Medical Society DUODECIM,Ann.Med.28:419-426(1996))、和视网膜病(Hammes等,Diabetologia42:603-607(1999))。RAGE还牵涉到阿尔茨海默氏病(Yan等,Nature382:685-691,(1996))、勃起功能障碍、和肿瘤侵袭和肿瘤转移(Taguchi等,Nature405:354-357,(2000))。
除AGEs外,其它化合物也可以与RAGE结合并对其进行调节。在正常发展中,RAGE与两性素相互作用,这是一种介导培养的胚胎 神经元中长出神经突的多肽(Hori等,1995)。RAGE还发现与EN-RAGE相互作用,这是一种与钙粒蛋白基本类似的蛋白质(Hofmann等,Cell97:889-901(1999))。RAGE还发现与β-淀粉状蛋白相互作用(Yan等,Nature389:589-595,(1997);Yan等,Nature382:685-691(1996);Yan等,Proc.Natl.Acad.Sci.,94:5296-5301(1997))。
象AGEs、S100/钙粒蛋白/EN-RAGE、β-淀粉状蛋白、CML(Nε-羧甲基赖氨酸)和两性素这样的配体与RAGE结合已证明会改变多种基因的表达。例如,在多种细胞类型中,RAGE与其配体的相互作用产生氧化应力,从而导致自由基敏感的转录因子NF-κB的活化,以及NF-κB调节的基因如细胞因子IL-1β、TNF-α等的活化。此外,若干其它的调节路径,如涉及p21ras、MAP激酶、ERK1和ERK2的那些业已证明通过AGEs和其它配体与RAGE的结合活化。事实上,RAGE自身的转录至少部分由NF-κB调节。因此,通过由配体结合引发的正反馈回路为上升的且经常是有害的螺旋提供了能源。因此,拮抗生理配体与RAGE的结合是我们的下调病理生理变化的目标,这些病理生理变化由对RAGE来说过多的AGEs和其它配体浓度引起。
因此,需要开发能够拮抗生理配体与RAGE受体结合的化合物。
发明概述
本发明提供特定的取代的羧酰胺化合物,其中酰胺部分由至少一个亲油基构成。本发明的实施方案提供下述的式(I)的化合物;其制备方法;含有该化合物的药物组合物;以及其在治疗人类或动物疾病中的使用方法。本发明的化合物可用作高级糖基化终产物受体(RAGE)与其配体如高级糖基化终产物(AGEs)、S100/钙粒蛋白/EN-RAGE、β-淀粉状蛋白和两性素的相互作用的调制剂。该化合物可用于多种应用,包括处理、治疗、控制和/或作为由RAGE引起的人类疾病的辅药。这样的疾病或疾病状态包括急性和慢性炎症,糖尿病晚期并发症如血管通透性增加的发展、肾病、动脉硬化症、和视网膜病,阿尔茨海默 氏病的发展、勃起功能障碍、和肿瘤侵袭和肿瘤转移。
本发明的详细描述
本发明的第一方面提供特定的取代的羧酰胺衍生物。这样的化合物可用于调制,优选抑制RAGE与其生理配体的相互作用,这将在下面详细描述。
本发明的第二方面提供式(I)的化合物:
其中
G1包括C1-C6亚烷基或(CH2)k,其中k为0-3;
G2包括a)氢
b)-C1-6烷基;
c)-芳基;
d)-C1-6烷基芳基;
e)
其中R5和R6独立地包括
i)-H;
ii)-C1-6烷基;
iii)-芳基;
iv)-C1-6烷基芳基;
v)-C(O)-O-C1-6烷基;
vi)-C(O)-O-C1-6烷基芳基;
vii)-C(O)-O-C1-6烷基环烷基芳基;
viii)-C(O)-NH-C1-6烷基;
ix)-C(O)-NH-C1-6烷基芳基;
x)-SO2-C1-6烷基;
xi)-SO2-C1-6烷基芳基;
xii)-SO2-芳基;
xiii)-SO2-NH-C1-6烷基;
xiv)-SO2-NH-C1-6烷基芳基;
xv)
xvi)-C(O)-C1-6烷基;或
xvii)-C(O)-C1-6烷基芳基;或
f)下列式表示的基团:
或
其中
R9、R10、R11可以包括氢;或
R9、R10和R11独立地包括
i)-C1-6烷基;
ii)-芳基;
iii)-C1-6烷基芳基;
iv)-C(O)-O-C1-6烷基;
v)-C(O)-O-C1-6烷基芳基;
vi)-C(O)-NH-C1-6烷基;
vii)-C(O)-NH-C1-6烷基芳基;
viii)-SO2-C1-6烷基;
ix)-SO2-C1-6烷基芳基;
x)-SO2-芳基;
xi)-SO2-NH-C1-6烷基;
xii)-SO2-NH-C1-6烷基芳基;
xiii)-C(O)-C1-6烷基;或
xiv)-C(O)-C1-6烷基芳基;
或R10和R11可以一起构成含有与R10和R11键合的原子的稠合环烷基、稠合杂环基或稠合芳环;
R1包括
a)氢;
b)-C1-6烷基;
c)-芳基;或
d)-C1-6烷基芳基;
R2包括
a)-C1-6烷基;
b)-芳基;
c)-C1-6烷基芳基;或
d)下式表示的基团:
其中m和n独立地选自1、2、3或4;X包括直接键、CH2-、-O-、 -S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-C(O)-、-NHSO2NH-、
-Q1-包括C1-6亚烷基、C2-6亚烯基或C2-6亚炔基;
R3包括
a)氢;
b)-C1-6烷基;
c)-C1-6烷基芳基;或
d)-C1-6烷氧基芳基;
R4包括
a)-C1-6烷基芳基;
b)-C1-6烷氧基芳基;或
c)-芳基;
R7、R8、R12和R13独立地包括氢、C1-C6烷基、C1-C6烷基芳基、或芳基;
以及其中
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12和R13中的芳基和/或烷基可以选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R16、R17和R18包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;以及
R14和R15独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;以及其中
R14和R15可以一起形成具有与连接了R14和R15的氮原子键合的式-(CH2)o-Z-(CH2)p-的环,和/或R7和R8可以独立地一起形成具有与连接了R7和R8的原子键合的式-(CH2)o-Z-(CH2)p-的环,其中o和p独立地为1、2、3或4;Z包括直接键、-CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-CO-、-NHSO2NH-、
R19和R20独立地包括氢、芳基、C1-C6烷基或C1-C6烷基芳基。
根据本发明的第三方面,本发明提供式(Ia)的化合物、或其可药用盐、溶剂化物或前药:
其中,
x和w独立地等于0、1或2;条件是x和w不同时为0;其中值0、1和2包括直接键、-CH2-、和-CH2-CH2-,可以选择性被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R16、R17和R18包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;
G1包括直接键;
G2包括
R1包括H;
R3包括
b)氢;
c)-C1-6烷基;
d)-C1-6烷基芳基;或
e)-C1-6烷氧基芳基;
R4包括
a)-C1-6烷基芳基;
b)-C1-6烷氧基芳基;或
c)-芳基;
R5和R2一起形成下面结构的环:
R6包括
a)-H;
b)-C1-6烷基;
c)-芳基;
d)-C1-6烷基芳基;或
e)基团,选自-C(O)R25、-C(O)OR25、-C(O)NR26R25、-S(O)2R25、和-S(O)2NR26R25;其中R25和R26独立地包括-C1-6烷基、芳基或-C1-6烷 基芳基;
其中R21、R22、R23和R24独立地包括
i)-H;
ii)-C1-6烷基;
iii)-芳基;
iv)-C1-6烷基芳基;或
v)式-U-R27的基团,其中U选自-C(O)、-C(O)O-、-O-、-S-、-S(O)-、-S(O)2-、-NR28-,
其中R27和R28独立地包括-H、-芳基、-C1-6烷基或-C1-6烷基芳基;
R3、R4和R6中的芳基和/或烷基可以选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R16、R17和R18独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;以及
R14和R15独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;以及其中
R14和R15可以一起形成具有与连接了R14和R15的氮原子键合的式-(CH2)o-Z-(CH2)p-的环,其中o和p独立地为1、2、3或4;Z包括直接键、-CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-CO-、-NHSO2NH-、
R19和R20独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基。
根据本发明的第四方面,本发明提供式(Ib)的化合物、或其可药用盐、溶剂化物或前药:
其中,
y和z独立地为0-3的整数;其中值0、1和2分别包括直接键、-CH2-、-CH2-CH2-和-CH2-CH2-CH2-,可以选择性被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R16、R17和R18包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;
G1包括直接键;
G2包括
R3包括
a)氢;
b)-C1-6烷基;
c)-C1-6烷基芳基;或
d)-C1-6烷氧基芳基;
R4包括
a)-C1-6烷基芳基;
b)-C1-6烷氧基芳基;或
c)-芳基;
R6包括
a)-H;
b)-C1-6烷基;
c)-芳基;
d)-C1-6烷基芳基;或
e)基团,选自-C(O)R25、-C(O)OR25、-C(O)NR26R25、-S(O)2R25、和-S(O)2NR26R25;其中R25和R26独立地包括-C1-6烷基、芳基或-C1-6烷基芳基;
R3、R4和R6中的芳基和/或烷基可以选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R16、R17和R18独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;以及
R14和R15独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;以及其中
R14和R15可以一起形成具有与连接了R14和R15的氮原子键合的 式-(CH2)o-Z-(CH2)p-的环,其中o和p独立地为1、2、3或4;Z包括直接键、-CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-C(O)-、-NHSO2NH-、
R19和R20独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;
R5和R2一起形成下面结构的环:
其中R29和R30独立地包括
a)-H;
b)-C1-6烷基;
c)-芳基;
d)-C1-6烷基芳基;
e)-C(O)-O-C1-6烷基;
f)-C(O)-O-C1-6烷基芳基;
g)-C(O)-NH-C1-6烷基;
h)-C(O)-NH-C1-6烷基芳基;
i)-SO2-C1-6烷基;
j)-SO2-C1-6烷基芳基;
k)-SO2-芳基;
l)-SO2-NH-C1-6烷基;
m)-SO2-NH-C1-6烷基芳基;
n)-C(O)-C1-6烷基;
o)-C(O)-C1-6烷基芳基;或
p)式-V-R31的基团,
其中V包括式-C(O)、-OC(O)-、-O-、-S-、-S(O)-、-S(O2)-、-NH-和-N(R32)-;
其中R31和R32独立地包括
a)-H;
b)-C1-6烷基;
c)-芳基;
d)-C1-6烷基芳基;
e)-C(O)-O-C1-6烷基;
f)-C(O)-O-C1-6烷基芳基;
g)-C(O)-NH-C1-6烷基;-C(O)-NH-C1-6烷基芳基;
h)-SO2-C1-6烷基;
i)-SO2-C1-6烷基芳基;
j)-SO2-芳基;
k)-SO2-NH-C1-6烷基;
l)-SO2-NH-C1-6烷基芳基;
m)-C(O)-C1-6烷基;或
n)-C(O)-C1-6烷基芳基;
其中R29、R30、R31和R32可以选择性被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
b)-H;
c)-L-C1-6烷基;
-L-芳基;
-L-C1-6烷基芳基;
-L-C1-6烷基-NR33R34;
-L-C1-6烷基-Q2-R35;
其中L和Q2独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、 -NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R35、R36和R37独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;和
d)卤素、羟基、氰基、氨基甲酰基、或羧基;以及
R33和R34独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;以及其中
R33和R34可以一起形成具有与连接了R33和R34的氮原子键合的式-(CH2)e-J-(CH2)k-的环,其中e和k独立地为1、2、3或4;J包括直接键、-CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-CO-、-NHSO2NH-、
R38和R39独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基。
根据本发明的第五方面,本发明提供式(Ic)的化合物:
其中,
R1包括氢或C1-3烷基芳基,其中芳基被-Y-C1-6烷基芳基取代;
R2包括C1-3烷基芳基,其中芳基被-Y-C1-6烷基芳基取代;
其中Y包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R17和R18独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;
R3的定义同式(I);
R4的定义同式(I);
G1的定义同式(I);以及
G2的定义同式(I)。
根据本发明的第六方面,本发明提供式(Id)的化合物:
其中,
R1包括氢或C1-3烷基芳基,其中芳基被-Y-C1-6烷基芳基取代;
R2包括C1-3烷基芳基,其中芳基被-Y-C1-6烷基芳基取代;
其中Y包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R17和R18独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;以及
R3包括氢或-L-C1-6烷基-N(烷基)2;
R4包括-L-C1-6烷基-N(烷基)2;
其中L包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R35、R36和R37独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;以及
G1的定义同式(I);以及
G2的定义同式(I)。
根据本发明的第七方面,本发明提供式(Ie)的化合物:
其中,
G1包括直接键;
G2包括下面式的基团:
其中R9、R10和R11可以为氢;或
R9、R10和R11独立地包括
i)-C1-6烷基;
ii)-芳基;
iii)-C1-6烷基芳基;
iv)-C(O)-O-C1-6烷基;
v)-C(O)-O-C1-6烷基芳基;
vi)-C(O)-NH-C1-6烷基;
vii)-C(O)-NH-C1-6烷基芳基;
viii)-SO2-C1-6烷基;
ix)-SO2-C1-6烷基芳基;
x)-SO2-芳基;
xi)-SO2-NH-C1-6烷基;
xii)-SO2-NH-C1-6烷基芳基;
xiii)-C(O)-C1-6烷基;或
xiv)-C(O)-C1-6烷基芳基;或
R10和R11可以一起形成含有与R10和R11键合的原子的稠合环烷基、稠合杂环基、或稠合芳环;
R1包括H;
R2包括
a)-C1-6烷基;
b)-芳基;或
c)-C1-6烷基芳基;
R3包括
a)氢;
b)-C1-6烷基;
c)-C1-6烷基芳基;或
d)-C1-6烷氧基芳基;
R4包括
a)-C1-6烷基芳基;
b)-C1-6烷氧基芳基;或
c)-芳基;
R2、R3、R4、R9、R10和R11中的芳基和/或烷基可以选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
或
R16、R17和R18独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;以及
R14和R15独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;以及其中
R14和R15可以一起形成具有与连接了R14和R15的氮原子键合的式-(CH2)o-Z-(CH2)p-的环,其中o和p独立地为1、2、3或4;Z包括直接键、-CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-CO-、-NHSO2NH-、
R19和R20独立地包括氢、芳基、C1-C6烷基或C1-C6烷基芳基;
根据本发明的第八方面,本发明提供式(If)的化合物:
其中,
G1包括直接键;
G2包括
R1包括H;
R2包括下式的基团:
其中m和n独立地选自1、2、3或4;X包括直接键CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-C(O)-、-NHSO2NH-、
-Q1-包括C1-6亚烷基、C2-6亚烯基或C2-6亚炔基;R12和R13独立地包括氢、C1-C6烷基、C1-C6烷基芳基、或芳基;
R3包括
a)氢;
b)-C1-6烷基;
c)-C1-6烷基芳基;或
d)-C1-6烷氧基芳基;
R4包括
a)-C1-6烷基芳基;
b)-C1-6烷氧基芳基;或
c)-芳基;
R5和R6独立地包括
a)-H;
b)-C1-6烷基;
c)-芳基;
d)-C1-6烷基芳基;或
e)基团,选自-C(O)R25、-C(O)OR25、-C(O)NR26R25、-S(O)2R25、和-S(O)2NR26R25;其中R25和R26独立地包括-C1-6烷基、芳基或-C1-6烷基芳基;
R3、R4、R5、R6、R12和R13中的芳基和/或烷基可以选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团包括:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
-Y-C1-6烷基-W-R16;
其中Y和W独立地包括-CH2-、-O-、-N(H)-、-S-、-SO2-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-NHSO2NH-、-O-CO-、
R16、R17和R18独立地包括氢、芳基、C1-C6烷基、C1-C6烷基芳基、C1-C6烷氧基、或C1-C6烷氧基芳基;或
c)卤素、羟基、氰基、氨基甲酰基、或羧基;以及
R14和R15独立地包括氢、芳基、C1-C6烷基、或C1-C6烷基芳基;以及其中
R14和R15可以一起形成具有与连接了R14和R15的氮原子键合的式-(CH2)o-Z-(CH2)p-的环,其中o和p独立地为1、2、3或4;Z包括直接键、-CH2-、-O-、-S-、-S(O2)-、-C(O)-、-CON(H)-、-NHC(O)-、-NHCON(H)-、-NHSO2-、-SO2N(H)-、-C(O)-O-、-O-CO-、-NHSO2NH-、
R19和R20独立地包括氢、芳基、C1-C6烷基或C1-C6烷基芳基。
在上述的化合物中,表示的各种官能团应理解为在有连字号的官能团上具有连接点。换句话说,对于-C1-6烷基芳基,应理解该连接点为烷基;其一例为苄基。对于象-C(O)-NH-C1-6烷基芳基这样的基团,连接点为羰基碳。
在上式的化合物中,带有下标m、n、w、x、y、z的基团“()”表示最多达2或3个亚甲基键的存在;换句话说,如果m为3,表示-CH2CH2CH2-键。如果m为0,表示任何一侧的基团之间为直接键,即通过共价键连接。
上式(I)表示的化合物的各单独对映异构体及其任何全部或部分外消旋化合物也包括在本发明的范围内。本发明也包括由上式表示的化 合物的各单独对映异构体与它的其中一个或多个立构中心反向的非对映异构体的混合物。
因高生物活性而优选的本发明的化合物按名称列在下表1中。
表1
在另一方面,本发明包括含有本发明的化合物以及一种或多种可药用载体、赋形剂或稀释剂的药物组合物。
在一个实施方案中,该药物组合物是以口服剂量或肠胃外剂量单位的形式。优选以每天约0.01-500mg/kg体重的剂量给用本发明的化合物。更优选以每天约0.1-200mg/kg体重的剂量给用该化合物。甚至更优选以每天约0.1-100mg/kg体重的剂量给用该化合物。
在一个实施方案中,该药物组合物进一步含有一种或多种治疗剂,所述治疗剂选自烷基化剂、抗代谢物、植物碱、抗生素、激素、生物应答调节剂、止痛剂、NSAIDs、DMARDs、糖皮质激素、磺酰脲类、双胍类、胰岛素、胆碱酯酶抑制剂、抗精神病药、抗抑郁药、和抗惊厥药。
根据另一方面,本发明包括抑制RAGE与其生理配体的相互作用的方法,该方法包括对需要的患者给用至少一种本发明的化合物。
在一个实施方案中,配体选自高级糖基化终产物(AGEs)、S100/钙粒蛋白/EN-RAGE、β-淀粉状蛋白、和两性素。
根据再一方面,本发明包括治疗疾病状态的方法,所述的疾病状态选自急性和慢性炎症,糖尿病症状、血管通透性、肾病、动脉硬化症、视网膜病,阿尔茨海默氏病、勃起功能障碍、和肿瘤侵袭和/或肿瘤转移,所述的方法包括对需要的患者给用治疗有效量的至少一种本发明的化合物。
根据再一个方面,本发明包括预防和/或治疗RAGE介导的人类疾病的方法,所述的方法包括对需要的人给用治疗有效量的权利要求1所述的式(I)的化合物,其中治疗有效量包括足够用来至少部分抑制配体与RAGE受体结合的化合物。
在一个实施方案中,该方法包括对需要的患者给用至少一种辅药和/或另外的治疗剂。优选治疗剂选自烷基化剂、抗代谢物、植物碱、抗生素、激素、生物应答调节剂、止痛剂、NSAIDs、DMARDs、糖皮质激素、磺酰脲类、双胍类、胰岛素、胆碱酯酶抑制剂、抗精神病药、抗抑郁药、和抗惊厥药。
也优选RAGE介导的人类疾病包括急性和慢性炎症,血管通透性异常、肾病、动脉硬化症、视网膜病、阿尔茨海默氏病、勃起功能障碍、肿瘤侵袭和/或肿瘤转移。
在本发明的化合物中,表示的各种官能团应理解为在有连字号的官能团上具有连接点。换句话说,对于-C1-6烷基芳基,应理解该连接点为烷基;其一例为苄基。对于象-C(O)-NH-C1-6烷基芳基这样的基团,连接点为羰基碳。
本文使用的术语“烷基”指含有指定数目的碳原子的直链或支链烃基。本文使用的“烷基”的例子包括但不限于甲基、正丁基、正戊基、异丁基、和异丙基等。
本文使用的术语“亚烷基”指含有指定数目的碳原子的直链或支链二价烃基。本文使用的“烷基”的例子包括但不限于亚甲基、亚乙基等。
本文使用的术语“亚烯基”指含有指定数目的碳原子和一个或多个碳碳双键的直链或支链二价烃基。本文使用的“亚烯基”的例子包括但不限于乙烯-1,2-二基、丙烯-1,3-二基、亚甲基-1,1-二基等。
本文使用的术语“亚炔基”指具有指定数目的碳原子和一个或多个碳碳叁键的直链或支链二价烃基。本文使用的“亚炔基”的例子包 括但不限于乙炔-1,2-二基、丙炔-1,3-二基等。
本文使用的术语“芳基”指选择性地含有一个或多个氮、氧或硫杂原子的5-7员芳环,或选择性取代的苯环体系,其中N-氧化物和一氧化硫和二氧化硫是允许的取代基。这样的环可以稠合成一个或多个选择性地含有一个或多个氮、氧或硫杂原子的5-7员芳香环。优选的芳基包括苯基、联苯基、2-萘基、1-萘基、菲基、1-蒽基、吡啶基、呋喃基、呋喃基、噻吩基、吲哚基、异噻唑基、咪唑基、苯并咪唑基、四唑基、吡嗪基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并吲哚基、吡唑基、异吲哚基、嘌呤基、咔唑基、异噁唑基、噻唑基、噁唑基、苯并噻唑基、苯并噁唑基等。在这点上,特别优选的芳基包括选择性地被叔丁氧基、苄氧基、正丁氧基、异丙氧基和苯氧基取代的苯基、2-萘基、1-萘基、联苯基等环体系。
本文使用的术语“选择性地”指随后描述的事件可以发生或不发生,并且包括发生的事件和不发生的事件。
本文使用的术语“取代的”指用指定的取代基进行的取代,如果没有特别指明,多程度的取代也允许。
本文使用的化学结构术语“含有(contain)”或“含有(containg)”指在沿在O、S、SO、SO2、N或N-烷基的一个或多个上的上述定义的取代基的任何位置的在线取代,包括例如,-CH2-O-CH2-、-CH2-SO2-CH2-、-CH2-NH-CH3等。
本文使用的术语“溶剂化物”是由溶质(本发明中,为式(I)的化合物)与溶剂形成的化学计量可变的复合物。满足本发明该目的溶剂可以不影响溶质的生物活性。举例来说,溶剂可以是水、乙醇、或乙酸。
本文使用的术语“可生物水解的酯”是药物物质(在本发明中,是上述的化合物)的酯,其a)不影响母体物质的生物活性,但在体内赋予该物质有利性质,如作用持续时间、作用的开始等,或b)为生物学惰性,但可以由患者容易地在体内转变成生物学有效成分。利点有例如,可生物水解的酯口服从肠管吸收,并在血浆中转变为(I)。这样的许多例子在本领域是已知的,例如包括低级烷基酯(例如,C1-C4)、低级酰氧基烷基酯、低级烷氧基酰氧基烷基酯、烷氧基酰氧基酯、烷基酰胺基烷基酯、和胆碱酯。
本文使用的术语“可生物水解的酰胺”是药物物质(在本发明中,是式(I)的化合物)的酰胺,其a)不影响母体物质的生物活性,但在体内赋予该物质有利性质,如作用持续时间、作用的开始等,或b)为生物学惰性,但可以由患者容易地在体内转变成生物学有效成分。利点有例如,可生物水解的酰胺口服从肠管吸收,并在血浆中转变为(I)。这样的许多例子在本领域是已知的,例如包括低级烷基酰胺、α-氨基酸酰胺、烷氧基酰基酰胺、和烷基氨基烷基羰基酰胺。
本文使用的术语“前药”包括可生物水解的酰胺和可生物水解的酯,也包括a)化合物,其中这样的前药中的可生物水解的官能团包括在式(I)的化合物中:例如,由R2中的羧基和R4中的胺形成的内酰胺,和b)化合物,可在指定的官能团上被生物氧化或还原,产生式(I)的前药物质。这些官能团的例子包括但不限于1,4-二氢吡啶、N-烷基羰基-1,4-二氢吡啶、1,4-环己二烯、叔丁基等。
术语“药理有效量”应指研究者或临床医生所探寻的将引起组织、动物或人类的生物或医学应答的药物或药剂的量。该量可以是治疗有效量。
无论何时术语“烷基”或“芳基”或它们的任何前缀词根(prefix roots)出现在取代基(例如,芳基烷氧基芳氧基)的名称中,它们应解释为包括上述对于“烷基”和“芳基”的那些限定。应该承认烷基取代基与具有一个或多个不饱和度的那些在官能上等价。指定数目的碳原子(例如C1-6)应独立地指烷基部分的碳原子数目或指更大取代基(其中术语“烷基”以其前缀根出现)的烷基部分。同样地,术语“C2-C8亚烯基”和“C2-C8亚炔基”指具有2-8个碳原子以及分别具有至少一个碳碳双键或碳碳叁键的基团。
本文使用的术语“氧代”应指取代基=O。
本文使用的术语“卤素(halogen)”或“卤素(halo)”应包括碘、溴、氯和氟。
本文使用的术语“巯基”应指取代基-SH。
本文使用的术语“羧基”应指取代基-COOH。
本文使用的术语“氰基”应指取代基-CN。
本文使用的术语“氨基磺酰基”应指取代基-SO2NH2。
本文使用的术语“氨基甲酰基”应指取代基-C(O)NH2。
本发明还提供可用作制备式(I)化合物的中间体的化合物的合成方法,以及制备式(I)化合物的方法。
适当保护的α-氨基酸(1)(其中PG为胺保护基,如叔丁氧羰基)在偶联剂例如但不限于二异丙基碳二亚胺(DIC)的存在下用胺处理,形成酰胺(2)。
然后,使用强酸,例如在PG为叔丁氧羰基时使用盐酸,对(2)中的α-氨基脱保护,得到游离碱或盐形式的自由NH化合物(3)(路线1)。没有氨基保护基时,酸(4)的处理得到酰胺(5)。
路线1
为进一步衍生化合物(6)的氨基,可以在还原剂如氰基硼氢化钠或三乙酰氧基硼氢化钠的存在下,用醛或酮R40C(O)R41处理游离氨基化合物或其适当的盐,得到化合物(7),其中R40和R41的定义是使(7)中的R5与式(I)的规定相符。或者,可以用叔胺碱如DIEA和一摩尔当量(或稍过量)的一般结构为R5-Q3(其中,Q3为离核基团,如溴)的烷基化剂处理胺化合物(6),形成仲胺化合物(7)(路线2)。可以用叔胺碱如三乙胺和2摩尔当量(或稍过量)的一般结构为R5-Q3(其中,Q3为离核基团,如溴)的烷基化剂处理胺化合物(6),形成仲胺化合物(8)。
路线2
为进一步衍生化合物(3)的氨基,可以用磺酰氨如苯磺酰氯处理游离氨基化合物或其适当盐,形成磺酰胺(10)(路线3),其中R43为C1-6烷基、C1-6烷基芳基、或芳基。或者,可以用硫酰氯处理胺R44-NH2,然后用(3)处理中间体,得到磺酰脲(8),其中R45为-NH-C1-6烷基或-NH-C1-6烷基芳基。
路线3
为进一步衍生化合物(3)的氨基,可以在叔胺碱如TEA或不存在叔胺碱的条件下,用异氰酸酯R46NCO处理游离氨基化合物或其适当盐,形成脲(11)(路线4),其中R46为-C1-6烷基或-C1-6烷基芳基,A为NH。或者,可以用R46O-C(O)Cl和叔胺碱如TEA处理化合物(3), 得到脲(11),其中R46为-C1-6烷基或-C1-6烷基芳基,A为O。
路线4
在除去保护基PG后,可以用三苯膦、偶氮二甲酸二异丙酯(DIAD)和偶氮二甲酸二乙酸(DEAD)的任一种、和醇R47-OH处理化合物(12),形成化合物(13)(路线5)。R47为-C1-6烷基、-C1-6烷基芳基、-C1-6烷基-OSi(C1-6烷基)3、-C1-6烷基-OSi(C1-6烷基芳基)3、或-C1-6烷基-NR14R15(条件是R14和R15均不为氢)。PG可以是例如叔丁氧羰基、苄氧羰基等。
路线5
可以在存在或不存在吡啶或DMAP的条件下,用酸酐(R48-CO)2O和碱如TEA处理化合物(3)或其适当的盐,得到化合物(14)(路线6)。取代基R48可以这样选择:基团R48-CO-按式(I)的R6限定。或者,可以在存在或不存在吡啶或DMAP的条件下,用酰氯R48-COCl和叔胺碱如TEA处理化合物(3),得到化合物(14)。或者,可以在存在或不存在HOBt的条件下,用羧酸R48-CO2H和碳二亚胺试剂如EDC、DIC或DCC处理化合物(3),得到化合物(14)。
路线6
可以在叔胺碱如TEA的存在下,用活性脒试剂如N,N’-二-BOC-1-脒基吡唑或3,5-二甲基吡唑-1-甲脒(carboxamidine)硝酸盐处理化合物(3)或其适当的盐,得到胍化合物(15)(路线7)。胍取代基保护基可以除去。例如,当使用N,N’-二-BOC-1-脒基吡唑时,加合物的BOC基团可以用强酸如盐酸除去,得到游离胍化合物(15),其中R7和R8的定义如式(I)中的定义。
路线7
在上面的路线中,“PG”是指氨基保护基。本文使用的术语“氨基保护基”是指通常在化合物上的其它官能团发生反应时,用于阻断或保护氨基官能团的氨基取代基。这样的氨基保护基的例子包括甲酰基、三苯甲基、邻苯二甲酰亚氨基、三氯乙酰基、氯乙酰基、溴乙酰基和碘乙酰基、尿烷型保护基(本文使用的PG)如苄氧羰基、4-苯基苄氧羰基、2-甲基苄氧羰基、4-甲氧基苄氧羰基、4-氟苄氧羰基、4-氯苄氧羰基、3-氯苄氧羰基、2-氯苄氧羰基、2,4-二氯苄氧羰基、4-溴苄氧羰基、3-溴苄氧羰基、4-硝基苄氧羰基、4-氰基苄氧羰基、2-(4-联苯基)异丙氧羰基、1,1-二苯基乙烷-1-基氧羰基、1,1-二苯基丙烷-1-基 氧羰基、2-苯基丙烷-2-基氧羰基、2-(对甲苯甲酰基)丙烷-2-基氧羰基、环戊烷基氧羰基、1-甲基环戊烷基氧羰基、环己烷基氧羰基、1-甲基环己烷基氧羰基、2-甲基环己烷基氧羰基、2-(4-甲苯甲酰基磺酰基)乙氧羰基、2-(甲磺酰基)乙氧羰基、2-(三苯膦基)乙氧羰基、9-芴基甲氧羰基(“FMOC”)、叔丁氧羰基(“BOC”)、2-(三甲基甲硅烷基)乙氧羰基、烯丙氧羰基、1-(三甲基甲硅烷基甲基)丙烯-1-基氧羰基、5-苯并异噁唑基(benzisoxalyl)甲氧羰基、4-乙酰氧基苄氧羰基、2,2,2-三氯乙氧羰基、2-乙炔基-2-丙氧羰基、环丙基甲氧羰基、4-(癸氧基)苄氧羰基、异冰片基氧羰基、1-哌啶基氧羰基等;苯甲酰甲磺酰基、2-(硝基)苯亚磺酰基、二苯基氧化膦基团等氨基保护基。只要衍生化的氨基在随后对于式(I)化合物的其它位置上的反应条件下是稳定的并且可以在希望的点上除去,同时不使分子的剩余部分断裂,则使用的氨基保护基的种类不重要。优选的氨基保护基为烯丙氧羰基、叔丁氧羰基、9-芴基甲氧羰基、和三苯甲基。用于头孢菌素、青霉素和肽领域的类似的氨基保护基也包括在上述术语中。由上述术语所指的其它基团的例子见J.W.Barton,“有机化学中的保护基”(“Protective Groups InOrganic Chemistry”),J.G.W.McOmie,著,Plenum Press,New York,N.Y.,1973,第二章;和T.W.Greene,“有机合成中的保护基”(“Protective Groups In Organic Synthesis”),John Wiley and Sons,New York,N.Y.,1981,第7章的描述。相关的术语“保护的氨基”定义一个氨基,它由上述的氨基保护基所取代。
一般实验
LC-MS数据是在装备有2487双波长检测器和Leap TechnologiesHTS PAL自动取样器的Waters600上,采用YMC Combiscreen ODS-A50×4.6mm柱,使用梯度洗脱得到的。三分钟梯度是从25%B(97.5%乙腈,2.5%水,0.05%TFA)和75%A(97.5%水,2.5%乙腈,0.05%TFA)到100%B进行的。MS为Micromass ZMD设备。如果没有特别说明,所有数据均是以正模式(positive mode)得到的。1H NMR数据是在Varian300MHz光谱仪上得到的。
实施例中使用的缩写如下所述:
APCI = 大气压化学电离
BOC = 叔丁氧羰基
BOP = 六氟磷酸(1-苯并三唑基氧基)三(二甲胺基)鏻
d = 天
DIAD = 偶氮二甲酸二异丙酯
DCC = 二环己基碳二亚胺
DCM = 二氯甲烷
DIEA = 二异丙基乙胺
DMF = N,N-二甲基甲酰胺
DMPU = 1,3-二甲基亚丙基脲
DMSO = 二甲亚砜
EDC = 1-乙基-3-(3-二甲胺基丙基)-碳二亚胺盐酸盐
EDTA = 乙二胺四乙酸
ELISA = 酶联免疫吸附分析
ESI = 电喷雾电离
ether = 乙醚
EtOAc = 乙酸乙酯
FBS = 胎牛血清
g = 克
h = 小时
HBTU = O-苯并三唑-1-基-N,N,N’,N’-四甲基脲六氟磷酸盐
HMPA = 六甲基磷酰三胺
HOBt = 1-羟基苯并三唑
Hz = 赫兹
i.v. = 静脉内的
kD = 千道尔顿
L = 升
LAH = 氢化铝锂
LDA = 二异丙基氨化锂
LPS = 脂多糖
M = 摩尔的
m/z = 质荷比
mbar = 毫巴
MeOH = 甲醇
mg = 毫克
min = 分钟
mL = 毫升
mM = 毫摩尔的
mmol = 毫摩尔
mol = 摩尔
mp = 熔点
MS = 质谱
N = 正常
NMM = N-甲基吗啉,4-甲基吗啉
NMR = 核磁共振光谱法
p.o. = 口服
PBS = 磷酸盐缓冲的盐水溶液
PMA = 乙酸肉豆蔻佛波醇
ppm = 百万分率
psi = 磅每平方英寸
Rf = 相对TLC迁移率
rt = 室温
s.c. = 皮下的
SPA = 闪烁亲近测定法
TEA = 三乙胺
TFA = 三氟乙酸
THF = 四氢呋喃
THP = 四氢吡喃基
TLC = 薄层色谱法
Tf = 保留时间
根据路线图合成下列化合物。
通用过程A:合成2,4-二烷氧基苯胺
步骤1:在2,4-二氟硝基芳香族化合物(1当量)的THF溶液(0.1-0.5M)中,加入醇(2.2当量),并将反应混合物冷却到0℃。0℃下分批加入碱(NaH,叔丁醇钾)(>2.2当量)。加热反应混合物并使其回流24小时。然后将反应混合物冷却到室温,用固体氯化铵处理,并搅拌10分钟。过滤溶液,真空浓缩并通过硅胶柱色谱法纯化,得到2,4-二烷氧基硝基芳香族化合物。或者,可以将反应混合物冷却到室温,用冷水骤冷,并用EtOAc萃取。干燥、浓缩,得到粗硝基芳香族化合物,它可以不经进一步纯化或使用硅胶柱色谱法纯化后用于下一步骤。
步骤2:将2,4-二烷氧基硝基芳香族化合物溶于乙醇中(0.05-0.5M),并用4M HCl/二氧六环(1-1.5当量)处理,然后用SnCl2·2H2O(5-10当量)处理,然后在氮气氛下使所得的反应混合物回流过夜。反应结束后,加入固体碳酸氢钠,直到反应混合物的pH呈碱性。过滤混合物,真空浓缩、干燥,得到2,4-二烷氧基苯胺。
通用过程B:合成2,4-二烷氧基苯胺
步骤1:在室温下搅拌3-氟-4-硝基苯酚(1当量,4mmol)的DMF(60.1-0.5Mml)溶液,并加入固体K2CO3(2当量,8mmol)。在反应混合物中加入卤代烷或甲磺酸酯(从相应的醇和甲磺酰氯制备)(1.1当量,4.4mmol),并加热到80℃,直到由TLC或HPLC表明反应结束。冷却到室温后,将反应混合物倒入乙酸乙酯(40ml)中,并用水(2×20ml)和盐水(30ml)洗涤。用硫酸镁干燥有机层,并除去干燥剂,然后真空除去溶剂,得到希望的产物。该粗产物可以不经进一 步纯化或使用硅胶柱色谱法纯化后用于进一步转化。
步骤2:搅拌上面得到的2-氟-4-烷氧基硝基苯(1当量,2mmol)的溶液,并加入醇(1.2当量),然后将反应混合物冷却到0℃。在0℃下分批加入碱(NaH,叔丁醇钾)。加热反应混合物,并使其回流过夜或直到由TLC或HPLC判定反应结束。然后将反应混合物冷却到室温,用固体氯化铵处理,并搅拌10分钟。过滤溶液,真空浓缩,并通过硅胶柱色谱法纯化,得到2,4-二烷氧基硝基芳香族化合物。或者,可以将反应混合物冷却到室温,用冷水骤冷,并用EtOAc萃取。干燥、浓缩,得到粗硝基芳香族化合物,它可以不经进一步纯化或通过硅胶柱色谱法纯化后用于下一步骤。
步骤3:将2,4-二烷氧基硝基化合物溶于乙醇中(0.05-0.5M),并用4M HCl/二氧六环(1-1.5当量)处理,然后用SnCl2·2H2O(5-10当量)处理,然后在氮气氛下使所得的反应混合物回流过夜。反应结束后,加入固体碳酸氢钠,直到反应混合物的pH呈碱性。过滤混合物,真空浓缩、干燥,得到2,4-二烷氧基苯胺。
通用过程C:胺或苯胺的还原性胺化
将胺和醛或酮(1.5当量)在15ml1,2-二氯乙烷(胺中0.2-0.5M)混合,并用三乙酰氧基硼氢化钠(1.5当量)处理。将混合物在氮气氛下搅拌过夜。用饱和碳酸氢钠淬灭反应混合物,并用乙醚或EtOAc萃取。用硫酸钠干燥有机萃取液,并真空浓缩,得到粗产物,如果需要,通过快速色谱法,用EtOAc/己烷洗脱,对该产物进行纯化,得到产物。
通用过程D:羧酸与胺的偶联
在羧酸(1.25当量)的二氯乙烷溶液(0.1-0.5M)中加入DCC(1.25当量),然后加入适当保护的苯胺(1当量)。然后将反应混合物在室温下搅拌过夜。过滤反应混合物,用DCM稀释滤液,并用饱和Na2CO3 和盐水洗涤。然后用Na2SO4干燥有机相,过滤,浓缩滤液,并通过硅胶柱色谱法纯化,得到酰胺衍生物。
通用过程E:甲硅烷基保护
将醇或酚溶于DMF中(0.1-0.5M),并加入咪唑(1.3当量),然后加入TBDMS-Cl(1.3当量)。将反应物搅拌过夜,用水稀释,并用EtOAc萃取。将有机层合并,并用盐水洗涤,用无水硫酸钠干燥,并真空除去溶剂,得到甲硅烷基醚。
通用过程F:甲硅烷基脱保护
将甲硅烷基醚在THF中(0.05-0.5M)搅拌,并在溶液中加入1N四丁基氟化铵的THF(3当量)溶液。将混合物搅拌过夜并真空除去溶剂,得到粗产物。或者,可以用水处理粗产物并用EtOAc萃取。干燥有机相并真空浓缩,得到游离醇或酚。
通用过程G:三苯膦/偶氮二甲酸酯偶联
将底物酚或羧酸溶于THF中(0.05-0.5M),并冷却到0℃。依次加入三苯膦(1-4当量)、醇(1-4当量)和偶氮二甲酸二异丙酯(DIAD)或偶氮二甲酸二乙酯(DEAD)(1-4当量)。缓慢升到室温的同时搅拌反应物过夜。用EtOAc/水稀释反应混合物,分层。进一步用EtOAc萃取水层。将有机层合并,并用水和盐水洗涤,用Na2SO4干燥。真空浓缩混合物,得到粗产物,可以通过硅胶快速色谱法将其纯化,得到偶联产物。
通用过程H:除去氨基甲酸芴甲酯基团
将保护的化合物在二乙胺在DCM中的20%溶液中搅拌。搅拌反应液5小时,除去溶剂,并几次用己烷将产物弄碎,得到希望的产物。通用过程I:除去氨基甲酸叔丁酯基团
将保护的化合物在4NHCl/二氧六环中搅拌1小时。除去溶剂, 并几次用乙醚将产物弄碎,得到希望的产物。
实施例1
根据下面的过程制备3-(4-苄氧基苯基)丙酸2,4-二(3-二乙胺基-1-丙氧基)苯胺酰胺
将4-羟基苯基丙酸(1.66g)溶于DMF(10mL)中。在反应混合物中加入溴化苄(3.76g),并冷却到0℃。0℃下分批加入固体NaH(油中的60%分散液;1g)。将反应混合物缓慢加热到60℃,并在该温度下搅拌过夜。然后将反应混合物冷却到室温,并加入1N HCl直到反应混合物的pH呈中性。然后用乙酸乙酯(2×50mL)萃取反应混合物,并将萃取液合并,然后用水(50mL)和盐水(50mL)洗涤。用Na2SO4干燥有机萃取液,过滤并浓缩,得到产物醚中间体1a,白色固体(2.6g)。
将1g上面得到的产物中间体溶于1∶1的甲醇/水(10mL)中,并加入固体NaOH(200mg),室温下搅拌过夜。然后用10%HCl酸化反应混合物,将pH变为2-3。然后用乙酸乙酯(2×50mL)萃取反应混合物,并将萃取液合并,然后用水(50mL)和盐水(50mL)洗涤。用Na2SO4干燥有机萃取液,过滤并浓缩,得到4-苄氧基苯基丙酸中间体1b,白色固体(350mg)。
将300mg上面得到的羧酸中间体1b溶于CH2Cl2(5mL)中,并加入亚硫酰氯(250μL)。然后使所得的混合物回流1小时,并冷却到室温。真空除去溶剂,静置,得到浅褐色固体中间体1c(290mg)。
在2,4-二氟硝基苯(800mg)的THF(20mL)溶液中,加入N,N-二乙基丙醇(2.2mL),并将反应混合物冷却到0℃。0℃下分批加入固体NaH(油中的60%分散液;用己烷洗过;600mg)。缓慢加热反应混合物,使其回流24小时。然后将反应混合物冷却到室温,加入固体氯化铵并搅拌10分钟。过滤溶液,真空浓缩并通过硅胶柱色谱法使用2∶10∶90的三乙胺/甲醇/氯仿为洗脱剂纯化,得到1.4g硝基产物中间体1d。
将上面得到的硝基产物中间体溶于乙醇中(0.05-0.5M),并用4MHCl/二氧六环(1-1.5当量)处理,然后用SnCl2·2H2O(5g)处理。然后在氮气氛下使所得的反应混合物回流过夜。反应结束后,加入固体碳酸氢钠,直到反应混合物的pH呈碱性。过滤溶液,真空浓缩、干燥,得到2,4-(N,N-二乙基氨基)丙基苯胺中间体1e,褐色树脂状物(950mg)。
在如上在CH2Cl2(5mL)中制备的中间体1c酰氯(70mg)的冷却(0℃)溶液中,加入中间体1e2,4-(N,N-二乙基氨基)丙基苯胺(80mg)。然后将反应混合物缓慢加热到室温,并搅拌1小时。在反应混合物中加入甲醇(0.5mL),以淬灭过量的酰氯。用CH2Cl2(10mL)稀释所得的溶液,加入饱和碳酸氢钠(5mL)并搅拌5分钟。将反应混合物放入分液漏斗中,分层。用水(10mL)和盐水(10mL)洗涤有机层。用Na2SO4干燥有机萃取液,过滤、浓缩,并通过硅胶柱色谱法使用5%甲醇/氯仿进行纯化,得到3-(4-苄氧基苯基)丙酸2,4-二(3-二乙胺基-1-丙氧基)苯胺酰胺,浅黄色固体(120mg)。MS:m/z590.4(M+H)
实施例2
根据下面的过程制备3-(3-叔丁氧基苯基)-3-(9-芴基甲氧羰基氨基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺
在3-(3-叔丁氧基苯基)-3-(9-芴基甲氧羰基氨基)丙酸(192mg)的乙腈(5mL)溶液中,室温下加入HBTU(200mg)和DIEA(106mg),然后加入2,4-二(3-二乙胺基丙氧基)苯胺(137mg)。然后在室温下将反应混合物搅拌过夜。浓缩滤液并在硅胶柱上纯上,得到210mg3-(3-叔丁氧基苯基)-3-(9-芴基甲氧羰基氨基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。LC:Tr2.17min;MS:m/z793(M+H)+。
实施例3
根据下面的过程制备3-(3-叔丁氧基苯基)-3-氨基丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺
如通用过程H所述处理实施例2的化合物(20mg)。收集固体产物并真空干燥,得到实施例3的胺,浅褐色固体(10.5mg)。
实施例4
根据下面的过程制备3-(4-四氢吡喃基)-2-氨基丙酸4-二乙胺基乙氧羰基-2-丁氧基苯胺酰胺二盐酸盐
室温下,在BOC-(4-四氢吡喃基)丙氨酸(97mg)和4-二乙胺基乙氧羰基-2-丁氧基苯胺盐酸盐(120mg)的乙腈(2mL)溶液中依次加入HBTU(160mg)和DIEA(175μL)。将反应混合物搅拌过夜。用EtOAc/水(5mL/3mL)稀释深红色反应混合物,分层。另外用EtOAc(5mL)萃取水层。合并有机层,并用水和盐水洗涤,用Na2SO4干燥。过滤溶液并真空除去溶剂。通过硅胶柱色谱法,使用甲醇/CHCl3/己烷(1∶20∶20)作为洗脱剂,纯化所得的粗产物,得到55mg酰胺产物中间体4A。LC:Tr1.90min;MS:m/z564(M+H)+。
如通用过程I所述处理酰胺中间体4A。收集固体产物并干燥,得到实施例4的胺盐,浅黄色固体(30mg)。
实施例5
根据下面的过程制备(2S,4R)-4-叔丁氧基吡咯烷-2-羧酸2,4-二(3-二乙胺基-1-丙氧基)苯胺酰胺
室温下用HBTU(116mg,0.30mmol)和DIEA(0.10mL,0.6mmol) 处理(2S,4R)-4-叔丁氧基-1-(9-芴基甲氧羰基)吡咯烷-2-羧酸(111mg,0.27mmol)的乙腈(5mL)溶液。5分钟后,加入2,4-二(3-二乙胺基-1-丙氧基)苯胺(90mg,0.26mmol),并搅拌所得的溶液过夜。用10mL盐水稀释反应混合物并用乙酸乙酯萃取(3×10mL)。用水(2×10mL)、饱和Na2CO3(1×10mL)、盐水(1×10mL)洗涤有机层。用Na2SO4干燥有机层,并真空除去溶剂。用己烷弄碎油状残余物,并在硅胶柱上纯化,得到118mg酰胺中间体5a,为固体。Tr1.88min;m/z743(M+H)+。
如通用过程H所述处理20mg中间体5a,得到9mg实施例5的胺,为固体。
实施例6
根据下面的过程制备(3S)-1,2,3,4-四氢异喹啉-3-羧酸4-二乙胺基乙氧羰基-2-丁氧基苯胺酰胺二盐酸盐
室温下用DCC(412mg)处理BOC-L-四氢异喹啉-3-羧酸(1.1g)的DMF溶液,并搅拌1小时。然后过滤反应混合物,并用2-丁氧基-4-二乙胺基乙氧羰基苯胺盐酸盐(345mg)和三乙胺(139μL)处理滤液。在室温下搅拌所得的溶液过夜。然后用乙酸乙酯和5%碳酸钠溶液稀释反应混合物。将内容物在分液漏斗中振摇,分层。用水和盐水洗涤有机层。然后用MgSO4干燥萃取液,过滤并真空除去溶剂。通过硅胶柱色谱法纯化得到的残余物,得到希望的产物中间体6a。LC: Tr4.72min;MS:m/z568.6(M+H)。
如通用过程I所述处理上面得到的产物。然后收集固体产物并真空干燥,得到实施例6的产物,为浅黄色固体(30mg)。LC:Tr3.83min;MS:m/z468.6(M+H)。
实施例7
根据下面的过程制备(R)-3-(4-苄氧基苯基)-2-(1-咪唑基)丙酸4-二乙胺基乙氧羰基-2-丁氧基苯胺酰胺
在BOC-D-Tyr(Bzl)-OH(1.11g)的CH2Cl2(15mL)溶液中,室温下在氮气氛下加入HOBT(406mg)和DCC(681mg)。2小时后,加入三乙胺(840μL)和4-二乙胺基乙氧羰基-2-丁氧基苯胺盐酸盐(1.04g),然后加入DMAP(36mg)。然后在室温下将反应混合物搅拌3天并过滤除去二环己基脲。浓缩滤液并通过硅胶柱色谱法纯化,得到1.2g产物酰胺中间体7a。LC:Tr2.18min;MS:m/z662(M+H)。
如通用过程I所述处理165mg中间体7a。然后真空干燥产物,得到浅黄色固体中间体7b。(105mg)。LC:Tr1.75min;MS:m/z562(M+H)。
用100μL含水乙二醛、100μL含水甲醛和38mg乙酸铵处理上面得到的32mg盐酸盐中间体7b,并将反应混合物加热到100℃过夜。然后使反应混合物冷却到室温,并加入饱和碳酸氢钠溶液,直到反应混合物的pH为7-8。然后用乙酸乙酯萃取(2×5mL)反应混合物,合并萃取液并用水(5mL)和盐水(5mL)洗涤。用Na2SO4干燥有机 萃取液,过滤、浓缩并通过硅胶快速色谱法,用5%甲醇/氯仿洗脱予以纯化,得到15mg希望的实施例7产物,为黄色固体。LC:Tr1.80min;MS:m/z613(M+H)。
实施例8
根据下面的过程制备3-(4-叔丁氧基苯基)-3-(9-芴基甲氧羰基氨基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺
在3-(9-芴基甲氧羰基氨基)-3-(4-叔丁氧基)苯基丙酸(384mg)的乙腈(10mL)溶液中,室温下加入HBTU(400mg)和DIEA(212mg),然后加入2,4-二(3-二乙胺基丙氧基)苯胺(274mg)。然后在室温下搅拌反应混合物过夜。浓缩滤液并在硅胶柱上纯化,得到325mg实施例8的产物酰胺。LC:Tr2.19min;MS:m/z793(M+H)+。
实施例9
根据下面的过程制备3-氨基-3-(4-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺
如通用过程H所述处理实施例8的化合物(200mg)。收集固体产物并真空干燥,得到实施例9的胺,为浅褐色固体(105mg)。MS:m/z571(M+H)+。
实施例10
根据下面的过程制备3-(9-芴基甲氧羰基氨基)-3-(2-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺
在3-(9-芴基甲氧羰基氨基)-3-(2-叔丁氧基)苯基丙酸(370mg)的乙腈(10mL)溶液中,室温下加入HBTU(390mg)和DIEA(212mg),然后加入2,4-二(3-二乙胺基丙氧基)苯胺(265mg)。然后在室温下将反应混合物搅拌过夜。浓缩滤液,并在硅胶柱上纯化,得到305mg实施例8的产物酰胺。LC:Tr2.23min;MS:m/z793(M+H)+。
实施例11
根据下面的过程制备3-氨基-3-(2-叔丁氧基苯基)丙酸2,4-二(3-二 乙胺基丙氧基)苯胺酰胺
如通用过程H所述处理实施例10的化合物(75mg)。收集固体产物并真空干燥,得到实施例11的胺,为褐色固体(30mg)。MS:m/z571(M+H)+。
实施例12
根据下面的过程制备3-异丙基氨基-3-(3-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺
在实施例3的化合物(650mg)的甲醇(5mL)溶液中,加入丙酮(0.06mL)。40分钟后,加入1.2mL氰基硼氢化钠的1M THF溶液。搅拌反应混合物过夜,真空除去溶剂,并通过硅胶快速色谱法(4:1己烷:EtOAc,10%TEA)纯化粗产物,得到637mg实施例12的化合物。
LC:Tr1.84min;MS:m/z613(M+H)+。
实施例13
根据下面的过程制备(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-苄基苯胺酰胺
根据通用过程C用苯甲醛将对氨基苯酚还原性胺化。根据通用过程E用叔丁基二甲基甲硅烷基保护酚。产物4-O-叔丁基二甲基甲硅烷基-N-苄基苯胺(274mg)用于根据通用过程D与N-Boc-O-苄基酪氨酸偶联。根据通用过程F将产物脱甲硅烷基,得到109mg实施例13的化合物。LC:Tr2.32min;MS:m/z667(M+H)+。
实施例14
根据下面的过程制备(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-环戊基甲基苯胺酰胺
根据通用过程C用环戊醛(cyclopentylcarboxaldehyde)将对氨基苯酚还原性胺化。根据通用过程E用叔丁基二甲基甲硅烷基保护酚。产物4-O-叔丁基二甲基甲硅烷基-N-苄基苯胺(274mg)用于根据通用过程D与N-Boc-O-苄基酪氨酸偶联。根据通用过程F将产物脱甲硅烷基,得到96mg实施例14的化合物。LC:Tr2.21min;MS:m/z659(M+H)+。
实施例15
根据下面的过程制备(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-异丙基苯胺酰胺
根据通用过程C用异丁醛将对氨基苯酚还原性胺化。根据通用过程E用叔丁基二甲基甲硅烷基保护酚。产物4-O-叔丁基二甲基甲硅烷基-N-苄基苯胺(274mg)用于根据通用过程D与N-Boc-O-苄基-D-酪氨酸偶联。根据通用过程F将产物脱甲硅烷基,得到114mg实施例15的化合物。LC:Tr2.19min;MS:m/z619(M+H)+。
实施例16
根据下面的过程制备(2R)-2-氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-环己基甲基苯胺酰胺
根据通用过程C用环己醛(cyclohexanecarboxaldehyde)将对氨基苯酚还原性胺化。根据通用过程E用叔丁基二甲基甲硅烷基保护酚。产物4-O-叔丁基二甲基甲硅烷基-N-苄基苯胺(274mg)用于根据通用 过程D与N-Boc-O-苄基-D-酪氨酸偶联。根据通用过程F将产物脱甲硅烷基,得到78mg实施例16的化合物。LC:Tr2.02min;MS:m/z573(M+H)+。
实施例17
根据下面的过程制备(2R)-2-氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-环戊基甲基苯胺酰胺
根据通用过程C用环戊醛(cyclopentanecarboxaldehyde)将对氨基苯酚还原性胺化。根据通用过程E用叔丁基二甲基甲硅烷基保护酚。产物4-O-叔丁基二甲基甲硅烷基-N-苄基苯胺(274mg)用于根据通用过程D与N-Boc-O-苄基-D-酪氨酸偶联。根据通用过程F将产物脱甲硅烷基,得到56mg实施例16的化合物。LC:Tr2.26min;MS:m/z559(M+H)+。
实施例18
根据下面的过程制备(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺
室温下在丁酸(1.4mL;15mmol)的DCM(20mL)溶液中加入 4-氨基苯酚(550mg;5mmol)并剧烈搅拌。在该溶液中加入DCC(2.48g;12mmol),然后加入DMAP(24mg),并在室温下将内容物搅拌过夜。然后过滤反应混合物并用DCM洗涤。浓缩滤液并再溶于甲醇中,加入10%碳酸氢钠水溶液并剧烈搅拌直到二酰化的副产物消失(通过LC-MS检测),产生4-丁酰胺基苯酚作为唯一的产物。该产物不纯化直接用于进一步转化。
搅拌N,N-二乙基氨基丙醇(6.0mmol)、TEA(6.0mmol)的无水DCM(6mL)溶液,并且在0℃下,在其中滴加入甲磺酰氯(6.0mmol),在相同温度下搅拌混合物10分钟,并在室温搅拌1小时。真空除去溶剂后,将固体残余物与无水DMF(10mL)中的4-丁酰胺基苯酚(5.0mmol)、和K2CO3(10mmol)混合,按照通用过程B。使用硅胶柱色谱法,以5%MeOH/DCM作为洗脱剂纯化粗产物,得到4-(N,N-二乙基氨基丙氧基)丁酰苯胺(1.4g)。
将上面得到的酰基苯胺(2.5mmol)溶于THF(5mL)并冷却到0℃。在反应混合物中加入LAH的THF溶液(1M;4mL),并加热到室温。使内容物回流6小时,冷却到室温,并加入甲醇直到氢的逸出停止。然后浓缩反应混合物,用CHCl3萃取,用10%NH4OH洗涤,然后用水、再用盐水洗涤,用Na2SO4干燥。除去干燥剂后,将粗产物4-(3-二乙胺基丙氧基)苯胺(400mg)不纯化直接用于进一步转化。
在上面得到的苯胺(0.65mmol)的乙腈(2mL)溶液中加入Boc-Tyr(Bzl)-OH(0.65mmol)和HBTU(0.72mmol)。然后在室温下搅拌反应混合物过夜。浓缩滤液,并在硅胶柱上纯化,得到100mg希望的产物。LC:Tr2.21min;MS m/z632.8(M+H)+。
实施例19
根据下面的过程制备(2R)-2-氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺
如通用过程I所述处理实施例18的化合物(100mg),产生60mg终产物。LC:Tr1.90min;MS m/z532.7(M+H)+。
实施例20
根据下面的过程制备(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸3-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺
室温下在丁酸(1.4mL;15mmol)的DCM(20mL)溶液中加入3-氨基苯酚(550mg;5mmol)并剧烈搅拌。在该溶液中加入DCC(2.48g;12mmol),然后加入DMAP(24mg),并在室温下将内容物搅拌过夜。然后过滤反应混合物并用DCM洗涤。浓缩滤液并再溶于甲醇中,加入10%碳酸氢钠水溶液并剧烈搅拌直到二酰化的副产物消失(通过LC-MS检测),产生3-丁酰胺基苯酚作为唯一的产物。该产物不纯化直接用于进一步转化。
将如实施例18所述制备的N,N-二乙基氨基丙醇(6mmol)的甲磺酸酯与无水DMF(10mL)中的3-丁酰胺基苯酚(5.0mmol)、和K2CO3(10mmol)混合,按照通用过程B进行反应。使用硅胶柱色谱法,以5%MeOH/DCM作为洗脱剂纯化粗产物,得到3-(N,N-二乙基氨基丙氧基)丁酰苯胺(1.3g)。
将上面得到的酰基苯胺(2.5mmol)溶于THF(5mL)并冷却到0℃。在反应混合物中加入LAH的THF溶液(1M;4mL),并加热到室温。使内容物回流6小时,冷却到室温,并加入甲醇直到氢的逸出停止。然后浓缩反应混合物,用CHCl3萃取,用10%NH4OH洗涤,然后用水、再用盐水洗涤,用Na2SO4干燥。除去干燥剂后,将粗产物3-(3-二乙胺基丙氧基)苯胺(500mg)不纯化直接用于进一步转化。
在上面得到的苯胺(0.65mmol)的乙腈(2mL)溶液中加入Boc-Tyr(Bzl)-OH(0.65mmol)和HBTU(0.72mmol)。然后在室温下搅拌反应混合物过夜。浓缩滤液,并在硅胶柱上纯化,得到100mg希望的产物。LC:Tr2.14min;MS m/z632.7(M+H)+。
实施例21
根据下面的过程制备(2R)-2-氨基-3-[4-(苄氧基)苯基]丙酸3-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺
如通用过程I所述处理实施例20的化合物(100mg),产生60mg终产物。LC:Tr1.78min;MS m/z532.7(M+H)+。
实施例22
根据下面的过程制备3-(1-叔丁氧羰基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
搅拌3-氟-4-硝基苯酚(5mmol)的DMF溶液,并在其中加入N,N-二乙基氨基丙醇的甲磺酸酯(6mmol)和K2CO3(10mmol),并根据下面的酚烷基化过程进行反应。粗产物2-氟-4-(N,N-二乙基氨基丙氧基)硝基苯不纯化直接用于进一步转化。
在0℃下将上面的产物溶于干THF(10mL)中,并加入正丁醇(6mmol)和KOtBu(5.5mmol),根据通用过程。粗产物2-丁氧基-4-(N,N-二乙基氨基丙氧基)硝基苯不纯化直接用于进一步转化。
根据上面的通用过程B的步骤3所述将上面的硝基产物(5mmol)氢化。这样得到的产物2-丁氧基-4-(N,N-二乙基氨基丙氧基)苯胺不纯化直接用于进一步转化。
在上面得到的苯胺(0.5mmol)的DCM(2mL)溶液中加入Fmoc-Ala(4-N-Boc-哌啶基)-OH(0.65mmol)和HBTU(0.72mmol)。然后将反应混合物在室温下搅拌过夜。浓缩滤液,并在硅胶柱上纯化,得到300mg希望的产物。LC:Tr2.45min;MS m/z772.0(M+H)+。
实施例23
根据下面的过程制备3-(哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
根据通用过程I所述处理实施例22的化合物(100mg),产生52mg终产物。LC:Tr2.02min;MS m/z672.0(M+H)+。
实施例24
根据下面的过程制备3-(1-苄基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
根据通用过程C用苯甲醛处理实施例23的化合物(100mg),产生110mg终产物。LC:Tr2.20min;MS m/z762.0(M+H)+。
实施例25
根据下面的过程制备3-(1-苄基哌啶-4-基)-2-氨基丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
根据通用过程H所述处理实施例24的化合物(75mg),产生48mg终产物。LC:Tr2.20min;MS m/z762.0(M+H)+。
实施例26
根据下面的过程制备3-(1-苄氧羰基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
用二氧六环(1.5mL)和1M碳酸氢钠水溶液(0.5mL)的混合溶液中的N-(苄氧羰基氧基)丁二酰亚胺(60mg)处理实施例23的化合物(60mg)。将反应混合物搅拌4小时,用EtOAc萃取,并用Na2SO4干燥有机层。除去溶剂并通过柱色谱法纯化产物。产生55mg终产物。LC:Tr2.60min;MS m/z806.0(M+H)+。
实施例27
根据下面的过程制备3-(1-苯甲酰基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
在0℃下用DCM(1mL)中的苄基氯(55mg)处理实施例23的化合物(45mg)。将反应混合物加热到室温,并将其搅拌2小时。用DCM稀释反应混合物,用饱和碳酸氢钠洗涤,并用Na2SO4干燥有机层。除去溶剂并通过柱色谱法纯化产物。产生27mg终产物。LC:Tr 2.34min;MS m/z776.0(M+H)+。
实施例28
根据下面的过程制备3-(1-苯甲酰基哌啶-4-基)-2-苯甲酰基氨基丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
根据通用过程H将实施例27的化合物(45mg)脱保护。然后在0℃下用DCM(1mL)中的苄基氯(55mg)处理产物。将反应混合物加热到室温,并将其搅拌2小时。用DCM稀释反应混合物,用饱和碳酸氢钠洗涤,并用Na2SO4干燥有机层。除去溶剂并通过柱色谱法纯化产物。产生27mg终产物。LC:Tr2.34min;MS m/z776.0(M+H)+。
实施例29
根据下面的过程制备3-(叔丁氧羰基哌啶-3-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
搅拌3-氟-4-硝基苯酚(5mmol)的DMF溶液,并在其中加入N,N-二乙基氨基丙醇的甲磺酸酯(6mmol)和K2CO3(10mmol),并根据下面的酚烷基化过程进行反应。粗产物2-氟-4-(N,N-二乙基氨基丙氧基)硝基苯不纯化直接用于进一步转化。
在0℃下将上面的产物溶于干THF(10mL)中,并加入正丁醇(6mmol)和KOtBu(5.5mmol),根据通用过程A。粗产物2-丁氧基-4-(N,N-二乙基氨基丙氧基)硝基苯不纯化直接用于进一步转化。
根据上面的通用过程B的步骤3所述将上面的硝基产物(5mmol)氢化。这样得到的产物2-丁氧基-4-(N,N-二乙基氨基丙氧基)苯胺不纯化直接用于进一步转化。
在上面得到的苯胺(0.5mmol)的DCM(2mL)溶液中加入Fmoc-Ala(3-N-Boc-哌啶基)-OH(0.65mmol)和HBTU(0.72mmol)。然后将反应混合物在室温下搅拌过夜。浓缩滤液,并在硅胶柱上纯化,得到300mg希望的产物。LC:Tr2.56min;MS m/z772.0(M+H)+。
实施例30
根据下面的过程制备3-(哌啶-3-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺
根据通用过程I所述处理实施例29的化合物(100mg),产生52mg终产物。LC:Tr1.96min;MS m/z672.0(M+H)+。
生物测定
使用以下的测定法,鉴定式(I)中有效与RAGE结合,并因此可用作RAGE的调制剂,优选拮抗剂的化合物。该方法也在该日提交的共同待审美国专利申请09/799,152(Attorney Docket TTP2000-02)中描述和要求保护。
通用测定过程
将100mM碳酸氢钠/碳酸钠缓冲液(pH9.8)中的S100b、β-淀粉状蛋白和CML(500ng/100μL/孔)加载到NUNC Maxisorp平底96孔微滴定板的孔中。将板在4℃保温过夜。从孔中抽气并用含有1%牛血清白蛋白(BSA)的50mM咪唑缓冲盐水(pH7.2)(含有1mMCaCl2/MgCl2)(300μL/孔)在37℃处理2小时。从孔中抽气并用155mMNaClpH7.2缓冲盐水洗涤三次(400μL/孔),并在各次洗涤之间浸泡10秒。
将试验化合物溶于纳米纯(nanopure)水中(浓度:10-100μM)。可以使用DMSO作为助溶剂。在各孔中加入试验化合物在2%DMSO中的溶液25μL,以及75μL sRAGE(4.0×10-4mg/mL FAC),并在37℃温育试样1小时。用155mM NaCl pH7.2缓冲盐水将孔洗涤三次,并在各次洗涤之间浸泡10秒。
非放射性结合通过在含有0.2%牛血清白蛋白和1mM CaCl2的50mM咪唑缓冲盐水(pH7.2)5mL中加入:
10μL生物素化山羊F(ab’)2抗小鼠IgG.(8.0×10-4mg/mL,FAC)
10μL碱性磷酸酯酶Sterptavidin(3×10-3mg/mL FAC)
10μL抗sRAGE的多克隆抗体(FAC6.0×10-3mg/mL)
来进行。将混合物在37℃温育30分钟。在各孔中加入100μL复合物并在室温下进行温育1小时。用洗涤缓冲液将孔洗涤3次,并在各次洗涤之间浸泡10秒。加入1M二乙醇胺中的1mg/mL(pNPP)(pH用HCl调至9.8)100μL。室温下在黑暗中显色1-2小时。用10μL终止液(50%乙醇中0.5N NaOH)结束反应,并使用微板读数器,用分光光度法测定了405nm的吸光率。
ELISA测定的IC50(μM)表示50%信号被抑制时的化合物浓度。
NA=ELISA测定数据不能提供
解释
+++++ | <0.5μM |
++++ | 0.5μM与1μM之间 |
+++ | 1μM与5μM之间 |
++ | 5μM与10μM之间 |
+ | 10μM与20μM之间 |
[0696] 本发明进一步提供含有本发明的RAGE调节化合物的药物组合物。本文使用的术语“药物组合物”指一种组合物,它以含有常规无毒载体、稀释剂、助剂、载体等的单位剂量制剂形式,例如口服、局部、肠胃外、通过吸入喷雾或经直肠等方式给用到哺乳动物个体体内。本文使用的术语“肠胃外”包括皮下注射、静脉内、肌肉内、脑池内注射、或通过注入技术。
含有本发明的化合物的药物组合物可以以适合口服的形式,例如,以片剂、锭剂(troches)、糖锭(lozenges)、水性或油性悬浮液、可分散粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂的形式。打算口服使用的组合物可以通过任何公知的方法调制,并且这样的组合物可以含有选自甜味剂、调味剂、着色剂、和防腐剂的一种或多种药剂,以提供制药上雅致和美味的制剂。片剂可以含有与适合片剂制造的无毒可药用赋形剂混合的有效成分。这些赋形剂可以是,例如,惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;成粒和崩解剂如玉米淀粉或藻酸;粘合剂如淀粉、明胶或阿拉伯树胶;和润滑剂如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的或它们也可以通过公知的技术包衣以延迟在胃肠道中的崩解和吸收,从而提供长期的持续作用。例如,可以使用延时物质如甘油单硬脂酸酯或甘油二硬脂酸酯。它们也可以通过美国专利4,356,108、4,166,452和4,265,874中描述的技术进行包衣,以形成控释渗透性治疗片剂,这些专利文献在此并入本文作参考。
口服使用的制剂也可以是以硬明胶胶囊的形式,其中有效成分与惰性固体稀释剂如碳酸钙、磷酸钙或高岭土混合,或者是以软明胶胶囊的形式,其中有效成分与水或油介质如花生油、液体石蜡或橄榄油混合。
水性悬浮液可以含有与适合制造水性悬浮液的赋形剂混合的有效 化合物。这样的赋形剂为悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯基吡咯烷酮、黄蓍胶和阿拉伯树胶;分散或湿润剂可以是天然存在的磷脂如卵磷脂、或环氧烷与脂肪酸的缩合产物如聚氧乙烯硬脂酸酯、或环氧乙烷与长链脂肪醇的缩合产物如十七环氧乙烷鲸蜡醇(heptadecaethyl-eneoxycetanol)、或环氧乙烷与由脂肪酸和己糖醇衍生的偏酯的缩合产物如聚氧乙烯山梨醇单油酸酯、或环氧乙烷与由脂肪酸与己糖醇脱水物衍生的偏酯的缩合产物如聚氧乙烯失水山梨醇单油酸酯。水性悬浮液可以含有一种或多种着色剂、一种或多种调味剂、以及一种或多种甜味剂如蔗糖或糖精。
油性悬浮液可以通过将有效成分悬浮在植物油如花生油、橄榄油、芝麻油或椰子油中,或者悬浮在矿物油如液体石蜡中进行配制。油性悬浮液可以含有增稠剂如蜂蜡、硬石蜡或鲸蜡醇。可以加入甜味剂如上述的那些以及调味剂,以提供美味的口服制剂。这些组合物可以通过加入抗氧剂如抗坏血酸来保存。
适于通过加水调制水性悬浮液的可分散粉末和颗粒提供与分散剂或湿润剂、悬浮剂和一种或多种防腐剂混合的有效成分。合适的分散剂或湿润剂和悬浮剂为上述已经列举的那些。也可以存在另外的赋形剂,例如甜味剂、调味剂和着色剂。
本发明的药物组合物也可以是以水包油乳剂的形式。油相可以是植物油如橄榄油或花生油,或者矿物油如液体石蜡,或者它们的混合物。合适的乳化剂可以是天然存在的树胶如阿拉伯树胶或黄蓍胶,天然存在的磷脂类如大豆、卵磷脂,衍生自脂肪酸和己醇糖脱水物的酯或偏酯如失水山梨糖醇单油酸酯,以及所述的偏酯与环氧乙烷的缩合产物如聚氧乙烯失水山梨糖醇单油酸酯。乳剂也可以含有甜味剂和调味剂。
糖浆和酏剂可以用甜味剂如甘油、丙二醇、山梨醇或蔗糖进行配 制。这样的制剂也可以含有缓和剂、防腐剂和调味及着色剂。药物组合物可以是无菌可注射水性或油性悬浮液的形式。该悬浮液可以根据公知的方法,使用上述的合适的分散或湿润剂和悬浮剂进行配制。无菌可注射制剂也可以是在无毒肠胃外用容许的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如1,3-丁二醇溶液。在容许的可使用的载体和溶剂中,有水、林格液、和等渗氯化钠溶液。另外,无菌非挥发油通常用作溶剂或悬浮介质。为此,可使用任何品牌的非挥发油,使用合成甘油单酯和甘油二酯。此外,脂肪酸如油酸可以用于可注射液的调制。
该组合物也可以是以本发明的化合物的用于直肠给药的栓剂形式。这些组合物可以通过将药物与合适的常温为固体但在直肠温度下为液体的并且将在直肠中融化而释放药物的无刺激赋形剂混合进行调制。这样的物质例如包括可可脂和聚乙二醇。
对于局部应用,期待有含有本发明化合物的霜剂、油膏、冻胶、溶液或悬浮液等。为此应用目的,局部应用应包括洗口药和含漱剂。本发明的化合物也可以以脂质体输送体系的形式给用,如小的单层囊泡或大的单层囊泡以及多层囊泡。脂质体可以由多种磷脂如胆固醇、十八烷胺或磷脂酰胆碱制成。
本发明也提供本发明的前药。
本发明的化合物的可药用盐(结构中存在碱性或酸性基团)也包括在本发明的范围内。术语“可药用盐”指本发明化合物的无毒盐,一般可以通过将游离碱与合适的有机或无机酸反应或将酸与合适的有机或无机碱反应来制备。有代表性的盐包括下列盐:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、乙二胺四乙酸钙(Calcium Edetate)、樟脑磺酸盐(Camsylate)、碳酸盐、氯化物、克拉维酸盐(Clavulanate)、柠檬酸盐、二盐酸化物、乙二胺 四乙酸盐、乙二磺酸盐(Edisylate)、丙酸酯十二烷基硫酸盐(Estolate)、乙磺酸盐(Esylate)、富马酸盐、葡萄庚糖酸盐(Gluceptate)、葡萄糖酸盐、谷氨酸盐、乙醇酰基对氨苯砷酸盐(Glycollylarsanilate)、己基间苯二酚盐、哈胺(Hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐(Hydroxynaphthoate)、碘化物、羟乙磺酸盐(isethionate)、乳酸盐、乳糖酸盐(Lactobionate)、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、马来酸一钾、粘液酸盐(Mucate)、萘磺酸盐、硝酸盐、N-甲基葡糖胺盐、草酸盐、双羟萘酸盐(embonate)、棕榈酸盐、泛酸盐、磷酸盐/磷酸氢盐、多聚半乳糖醛酸盐、钾盐、水杨酸盐、钠盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、丹宁酸盐、酒石酸盐、8-氯茶碱盐(Teoclate)、甲苯磺酸盐、三乙碘化物(Triethiodide)、三甲基铵盐和戊酸盐、当存在酸性取代基时,如-COOH,可以形成铵盐、吗啉鎓盐、钠盐、钾盐、钡盐、钙盐等用作剂型。当存在碱性基团时,如氨基或碱性杂芳基如吡啶基,可以形成酸盐如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、三氟乙酸盐、三氯乙酸盐、乙酸盐、草酸盐、马来酸盐、丙酮酸盐、丙二酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、富马酸盐、扁桃酸盐、苯甲酸盐、肉桂酸盐、甲磺酸盐、乙磺酸盐、苦味酸盐等,并且包括Journal of PharmaceuticalScience,66,2(1977)1-19页所列的与可药用盐相关的酸。
其它非药用盐可以用于制备本发明的化合物,这构成本发明的进一步的一方面。
另外,本发明的某些化合物可以与水或常用的有机溶剂形成溶剂化物。这样的溶剂化物也包括在本发明的范围内。
因此,在一个进一步的实施方案中,提供含有本发明的化合物、或其可药用盐、溶剂化物或前药,以及一种或多种可药用载体、赋形剂或稀释剂的药物组合物。
本发明的化合物选择性地充当RAGE与单一内源配体结合的调制剂,即β-淀粉状蛋白-RAGE相互作用的选择性调制剂,因此在治疗阿尔茨海默氏病和相关的痴呆方面特别有利。
另外,本发明的化合物充当RAGE与两种或多种内源配体而先于其它配体相互作用的调制剂。这样的化合物在治疗由RAGE介导的相关或不相关病状,即阿尔茨海默氏病和癌症方面是有利的。
另外,本发明的化合物充当RAGE相互及与其各配体结合的调制剂,因此防止了氧化应力的产生以及NF-κB调节的基因如细胞因子IL-l和TNF-α的活化。因此,对于生理配体与RAGE结合的拮抗防止了目标病理生理结果,并可用于处理或治疗疾病,即导致糖尿病并发症的AGE-RAGE相互作用、导致炎症的S100/EN-RAGE/钙粒蛋白-RAGE相互作用、导致阿尔茨海默氏病的β-淀粉状蛋白-RAGE相互作用、以及导致癌症的两性素-RAGE相互作用。
I.RAGE与糖尿病并发症
如上所述,本发明的化合物可用于治疗糖尿病的并发症。已经证明最终导致高级糖基化终产物(AGEs)形成的大分子的非酶促糖基化在发炎部位、肾衰竭、存在高血糖症时以及与全身或局部氧化应力有关的其它病状时被增强(Dyer,D.,等,J.Clin.Invest.,91:2463-2469(1993);Reddy,S.,等,Biochem.,34:10872-10878(1995);Dyer,D.,等,J.Biol.Chem.,266:11654-11660(1991);Degenhardt,T.,等,Cell Mol.Biol.,44:1139-1145(1998))。正如在患有与透析有关的淀粉样变性的病人中发现的由AGE-β2-小球蛋白构成的关节淀粉状蛋白中那样(Miyata,T.,等,J.Clin.Invest.,92:1243-1252(1993);Miyata,T.,等,J.Clin.Invest.,98:1088-1094(1996)),或一般如糖尿病患者的脉管系统和组织所说明的(Schmidt,A-M.,等,Nature Med.,1:1002-1004(1995)),AGEs在脉管系统中的积累可能集中发生。AGEs随时间推移在糖尿病患者体内的逐渐积累暗示内源清除机理在AGE沉积部位不能有效起 作用。这样的积累的AGEs能够通过许多机理改变细胞性质。尽管RAGE在正常组织和脉管系统中表面为低水平,但在受体的配体积累的环境中,已经证明RAGE变为向上调节(Li.,J.,等,J.Biol.Chem.,272:16498-16506(1997);Li.,J.,等,J.Biol.Chem.,273:30870-30878(1998);Tanaka,N.,等,J.Biol.Chem.,275:25781-25790(2000))。RAGE的表达在糖尿病患者的脉管系统中的内皮细胞、平滑肌细胞和刺激性单核巨噬细胞中增加。另外,细胞培养研究证明AGE-RAGE相互作用引起在脉管动态平衡中起重要作用的细胞性质的变化。
II.RAGE和淀粉样变性病中的细胞机能障碍
也如前所述,本发明的化合物可用于治疗淀粉样变性病和阿尔茨海默氏病。RAGE看来是一种与β-片纤维状材料结合的细胞表面受体,与亚基(淀粉状蛋白-β肽、Aβ、糊精、血清淀粉样蛋白A、朊病毒由来的肽)的组成无关(Yan,S.-D.,等,Nature,382:685-691(1996);Yan,S-D.,等,Nat.Med.,6:643-651(2000))。淀粉样蛋白的沉积已证明导致RAGE的表达增强。例如,在阿尔茨海默氏病(AD)患者的脑中,RAGE的表达在神经元和神经胶质中增加(Yan,S.-D.,等,Nature,382:685-691(1996))。Aβ与RAGE的相互作用的结果看起来在对于神经元和小神经胶质极为不同。尽管小神经胶质由于Aβ-RAGE相互作用被活化,这由细胞因子的游动性和表达的增强反映出来,但早期RAGE介导的神经元活化在随后的时间里被细胞毒性代替。另外关于RAGE在Aβ的细胞相互作用中的角色的证据涉及到当受体被阻碍时,Aβ-诱导的大脑血管收缩的抑制及肽传递通过血脑屏障到达脑实质(Kumar,S.,等,Neurosci.Program,141-#275.19(2000))。RAGE-淀粉样蛋白相互作用的抑制被证明减少细胞RAGE的表达和细胞应力标志(以及NF-κB活化),并且减少淀粉样蛋白沉积(Yan,S-D,等,Nat.Med.,6:643-651(2000)),这暗示着RAGE-淀粉样蛋白相互作用在淀粉样蛋白富集的环境(即使在初期阶段)中以及在淀粉样蛋白积累时的细胞性质的混乱中的作用。
III.RAGE与免疫/炎症反应的传播
如上所述,本发明的化合物可用于治疗炎症。例如,S100/钙粒蛋白已证明包括一系列密切相关的钙结合多肽,特征是由一个连接肽连接的两个EF手区域(Schafer,B.,等,TIBS,21:134-140(1996);Zimmer,D.,等,Brain Res.Bull.,37:417-429(1995);Rammes,A.,等,J.Biol.Chem.,272:9496-9502(1997);Lugering,N.,等,Eur.J.Clin.Invest.,25:659-664(1995))。尽管S100/钙粒蛋白缺少信号肽,但人们长期以来知道它们可以使用细胞外空间,特别是在慢性免疫/炎症反应的部位,与在囊性纤维化和风湿性关节炎中一样。RAGE是S100/钙粒蛋白家族的多个成员的受体,介导它们对细胞如淋巴细胞和单核巨噬细胞的促炎效果。另外,对于延迟型超敏感反应、IL-10裸小鼠的结肠炎、胶原蛋白诱导的关节炎、以及实验自动免疫脑炎模型的研究暗示RAGE-配体相互作用(假定与S100/钙粒蛋白)在炎症级联中具有近源作用。
IV.RAGE与两性素
如上所述,本发明的化合物可用于治疗肿瘤和肿瘤转移。例如,两性素是高活动性群I非组蛋白染色体DNA结合蛋白(Rauvala,H.,等,J.Biol.Chem.,262:16625-16635(1987);Parkikinen,J.,等,J.Biol.Chem.,268:19726-19738(1993)),已证明可与RAGE相互作用。已证明两性素促进神经突长出,以及用作蛋白酶复合物在纤维蛋白溶解系统中组装的表面(也已知是对细胞运动性有贡献)。另外,阻碍RAGE产生的局部肿瘤生长抑制效果已经在原发性肿瘤模型(C6神经胶质瘤)、路易斯肺瘤转移模型(Taguchi,A.,等,Nature405:354-360(2000))、以及在表达v-Ha-ras转基因的小鼠中的自发出现的刺瘤(Leder,A.,等,Proc.Natl.Acad.Sci.,87:9178-9182(1990))中观察到。
两性素是高活动性群I非组蛋白染色体DNA结合蛋白(Rauvala,H.和R.Pihlaskari.1987.Isolation and some characteristics of an adhesivefactor of brain that enhances neurite outgrowth in central neurons.J.Biol. Chem.262:16625-16635;Parkikinen,J.,E.Raulo,J.Merenmies,R.Nolo,E.Kajander,M.Baumann和H.Rauvala.1993.两性素,the 30 kDaprotein in a family of HIMG1-type polypeptides.J.Biol.Chem.268:19726-19738)。
V.RAGE与勃起功能障碍
海绵体小动脉和窦中的平滑肌细胞的松弛导致进入阴茎的血流增加,使海绵体的压力在阴茎勃起时升高到顶点。氧化氮被认为是海绵体平滑肌松弛的主要刺激物(参见Wingard CJ,Clinton W,Branam H,Stopper VS,Lewis RW,Mills TM,Chitaley K.Antagonism of Rho-kinasestimulates rat penile erection via a nitric oxide-independent pathway.Nature Medicine 2001 Jan;7(1):119-122)。RAGE活化通过NADH氧化酶类酶产生氧化物(参见,Yan,S-D.,Schmidt A-M.,Anderson,G.,Zhang,J.,Brett,J.,Zou,Y-S.,Pinsky,D.,和Stern,D.Enhanced cellularoxidant stress by the interaction of advanced glycation endproducts withtheir receptors/binding proteins.J.Biol.Chem.269:9889-9887,1994),从而抑制氧化氮的循环。可能通过由减少细胞内产生AGEs来抑制RAGE信号途径的活化,氧化物的产生将削弱。RAGE阻碍物通过阻碍配体与RAGE的接触,可以促进和助长阴茎勃起。
钙敏化的ρ-激酶路径可能在海绵体的血管收缩中起协同作用,以维持阴茎软弱。ρ-激酶的拮抗导致海绵体压力增加,引起不依赖氧化氮的勃起反应(Wingard等)。由RAGE活化的一种信号机理涉及ρ-激酶家族如cdc42和rac(参见Huttunen HJ,Fages C,Rauvala H.Receptorfor advanced glycation end products(RAGE)-mediated neurite outgrowthand activation of NF-kappaB require the cytoplasmic domain of thereceptor but different downstream signaling pathways.J Biol Chem1999Jul9:274(28):19919-24)。因此,通过抑制RAGE信号途径抑制ρ-激酶的活化将增强并刺激不依赖氧化氮的阴茎勃起。
因此,根据另一个方面,本发明提供抑制RAGE与生理配体相互作用的方法。在该方面的一个优选实施方案中,本发明提供治疗选自下列的疾病状态的方法:急性和慢性炎症、血管通透性、肾病、动脉硬化症、视网膜病、阿尔茨海默氏病、勃起功能障碍和肿瘤侵袭和/或转移,该方法包括向需要的患者给用本发明的化合物,用量优选为药理有效量,更优选治疗有效量。在优选的实施方案中,使用了至少一种式(I)的化合物,或者单独使用或者与一种或多种已知的治疗剂结合使用。在另一个优选实施方案中,本发明提供预防和/或治疗RAGE介导的人类疾病的方法,治疗包括将一种或多种由该疾病引起的症状缓解到完全治愈该特殊疾病或预防该疾病的发作,该方法包括向需要的人给用治疗有效量的本发明的化合物,优选式(I)的化合物。
在该方法中,影响多少量构成有效量的因素取决于患者的身材和体重、治疗剂的生物降解性、治疗剂的活性、以及其生物利用度。本文使用的表述“需要的患者”包括患有一种或多种上述的疾病或疾病状态或有患病风险的哺乳动物患者,优选人。因此,在本发明的治疗方法的范围中,该方法也由预防性地治疗哺乳动物患者或在开始诊断这样的疾病或疾病状态之前治疗哺乳动物患者的方法构成。
根据本发明的另一方面,本发明的RAGE调制剂用于辅助治疗或与其它已知的治疗剂组合治疗处置。
本文使用的术语“治疗”是指对患者所患特定疾病的宽范围治疗,包括将大多数由该疾病引起的症状的一种缓解到完全治愈该特定疾病或预防该疾病的发作。
下面列出的是辅药和额外的治疗剂的非完全名单,它们可以与本发明的RAGE调制剂结合使用:
抗癌剂的药理分类:
1.烷基化剂:环磷酰胺、亚硝基脲、卡铂(carboplatin)、顺铂、甲基苄肼
2.抗生素:博来霉素、柔毛霉素、阿霉素
3.抗代谢物:甲氨蝶呤、阿糖胞苷、氟尿嘧啶
4.植物碱:长春碱、长春新碱、依托泊苷(Etoposide)、紫杉醇
5.激素:它莫西芬、乙酸奥曲肽(Octreotide acetate)、非那雄胺(Finasteride)、氟他胺(Flutamide)
6.生物应答调节剂:干扰素、白介素,
治疗风湿性关节炎(炎症)的药理分类:
1.止痛剂:阿斯匹林
2.NSAIDs(非甾族抗炎症药):布洛芬、萘普生、环氟拉嗪
3.DMARDs(病情缓解抗风湿药):甲氮喋呤、金制剂、羟基氯喹、柳氮磺胺吡啶
4.生物应答调节剂,DMARDs:依那西普(Etanercept)、因福利美(Infliximab)、糖皮质激素
治疗糖尿病的药理分类:
1.磺酰脲类:甲苯磺丁脲、甲磺吖庚脲、优降糖、格列甲嗪
2.双胍类:二甲双胍
3.杂项口服剂:阿卡波糖(Acarbose)、曲格列酮(Troglitazone)
4.胰岛素
治疗阿尔茨海默氏病的药理分类:
1.胆碱酯酶:四氢氨基吖啶、多奈哌齐(Donepezil)
2.抗精神病药:氟哌啶醇、硫醚嗪
3.抗抑郁药:去郁敏、氟西汀(Fluoxetine)、曲唑酮(Trazodone)、帕罗西汀(Paroxetine)
4.抗惊厥药:卡巴咪嗪、丙戊酸
在另一个优选的实施方案中,本发明提供治疗RAGE介导的疾病的方法,该方法包括向需要的患者给用治疗有效量的式(I)化合物,并与选自下列的治疗剂结合使用:烷基化剂、抗代谢物、植物碱、抗生素、激素、生物应答调节剂、止痛剂、NSAIDs、DMARDs、糖皮质激素、磺酰脲类、双胍类、胰岛素、胆碱酯酶抑制剂、抗精神病药、抗抑郁药和抗惊厥药。在另一个优选的实施方案中,本发明提供如上所述的本发明的药物组合物,进一步含有选自下列的一种或多种治疗剂:烷基化剂、抗代谢物、植物碱、抗生素、激素、生物应答调节剂、止痛剂、NSAIDs、DMARDs、糖皮质激素、磺酰脲、双胍类、胰岛素、胆碱酯酶抑制剂、抗精神病药、抗抑郁药和抗惊厥药。
一般来说,本发明的化合物,优选式(I)的化合物,是以约0.01-500mg/kg被治疗患者的体重的日剂量来给用的,优选的日剂量范围是0.01-200mg/kg,最优选0.1-100mg/kg体重。可以与载体物质结合来制备单一剂量的有效成分的量随被治疗患者和具体的给药方式而变化。例如,用于人口服的制剂可以含有1mg-2g式(I)的化合物,并含有合适且方便量的载体物质,其量可以在占组合物总量的约5-95%的范围内变化。剂量单位形式一般含有约5mg至约500mg有效成分。该剂量必须由临床医生根据被治疗患者的特定临床条件分别决定。因此,将理解任何具体病人的特定剂量水平将取决于多种因素,包括使用的特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给用途径、排泄速度、药物组合及进行治疗的具体疾病的严重程度。
尽管参照特定的优选实施方案描述、说明了本发明,但本领域的技术人员将理解在不偏离本发明的精神和范围的情况下可以进行多种变化、改进和替代。例如,由于在患有RAGE介导的疾病的哺乳动物的响应性的变化,上述优选剂量以外的有效剂量可能是合适的。同样地,观察到的特定的药理反应可以根据并取决于选择的特定有效化合物或是否存在药用载体、以及剂量和采用的给用方式来变化,并且结果的这样的预期变化或差别也符合本发明的目的和实践。
Claims (43)
1.式(I)的化合物:
其中
G1为C1-C6亚烷基或直接键;
G2为
其中R5和R6独立地选自由
i)-H;
ii)-C1-6烷基;
iii)-C(O)-O-C1-6烷基;和
iv)-C(O)-O-C1-6烷基芳基;
组成的组;
R1为
a)氢;
b)-C1-6烷基;或
c)-芳基;
R2为
a)-C1-6烷基;
b)-芳基;
c)-C1-6烷基芳基;或
d)下式表示的基团:
其中m和n独立地选自1、2、3或4;
X为直接键、CH2-、-O-、
其中-Q1-为C1-6亚烷基;
R3为
a)氢;
b)-C1-6烷基;或
c)-C1-6烷基芳基;
R4为
-芳基,其为选择性取代的苯环体系;
R12选自由氢、C1-C6烷基、C1-C6烷基芳基和芳基组成的组;
以及其中
R1、R2、R3、R4、R5、R6和R12中的芳基和/或烷基选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团为:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
其中Y选自由-CH2-、-O-、-N(H)-和-C(O)-O-组成的组,
R14和R15独立地选自由C1-C6烷基组成的组。
2.权利要求1的化合物,由式(Ic)表示:
其中,
R1为氢;
R2为C1-3烷基芳基,其中芳基被-Y-C1-6烷基芳基取代;
其中Y选自由-CH2-、-O-、-N(H)-和-C(O)-O-组成的组。
3.权利要求1的化合物,由式(If)表示:
其中,
G2为
R1为H;
R2为下式的基团:
其中m和n独立地选自1、2、3或4;
-Q1-为C1-6亚烷基;
R12选自由氢、C1-C6烷基、C1-C6烷基芳基和芳基组成的组;
R3为
a)氢;
b)-C1-6烷基;或
c)-C1-6烷基芳基;
R4为
a)-芳基,其为选择性取代的苯环体系;
R5和R6独立地选自:
a)-H;和
b)-C1-6烷基;
R3、R4、R5、R6和R12中的芳基和/或烷基选择性地被取代基取代1-4次,其中所述的取代基或取代的术语所指的基团为:
a)-H;
b)-Y-C1-6烷基;
-Y-芳基;
-Y-C1-6烷基芳基;
-Y-C1-6烷基-NR14R15;
其中Y选自由-CH2-、-O-、-N(H)-和-C(O)-O-组成的组;以及
R14和R15独立地选自由C1-C6烷基组成的组。
4.权利要求1的化合物,其中该化合物为3-(3-叔丁氧基苯基)-3-(9-芴基甲氧羰基氨基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
5.权利要求1的化合物,其中该化合物为3-(3-叔丁氧基苯基)-3- 氨基丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
6.权利要求1的化合物,其中该化合物为3-(4-四氢吡喃基)-2-氨基丙酸4-二乙胺基乙氧羰基-2-丁氧基苯胺酰胺二盐酸盐。
7.权利要求1的化合物,其中该化合物为(2S,4R)-4-叔丁氧基吡咯烷-2-羧酸2,4-二(3-二乙胺基-1-丙氧基)苯胺酰胺。
8.权利要求2的化合物,其中该化合物为(3S)-1,2,3,4-四氢异喹啉-3-羧酸4-二乙胺基乙氧羰基-2-丁氧基苯胺酰胺二盐酸盐。
9.权利要求1的化合物,其中该化合物为3-(4-叔丁氧基苯基)-3-(9-芴基甲氧羰基氨基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
10.权利要求1的化合物,其中该化合物为3-氨基-3-(4-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
11.权利要求1的化合物,其中该化合物为3-(9-芴基甲氧羰基氨基)-3-(2-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
12.权利要求1的化合物,其中该化合物为3-氨基-3-(2-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
13.权利要求1的化合物,其中该化合物为3-异丙基氨基-3-(3-叔丁氧基苯基)丙酸2,4-二(3-二乙胺基丙氧基)苯胺酰胺。
14.权利要求1的化合物,其中该化合物为(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-苄基苯胺酰胺。
15.权利要求1的化合物,其中该化合物为(2R)-2-叔丁氧羰基氨 基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-异丙基苯胺酰胺。
16.权利要求1的化合物,其中该化合物为(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺。
17.权利要求1的化合物,其中该化合物为(2R)-2-氨基-3-[4-(苄氧基)苯基]丙酸4-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺。
18.权利要求1的化合物,其中该化合物为(2R)-2-叔丁氧羰基氨基-3-[4-(苄氧基)苯基]丙酸3-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺。
19.权利要求1的化合物,其中该化合物为(2R)-2-氨基-3-[4-(苄氧基)苯基]丙酸3-(3-二乙胺基丙氧基)-N-丁基苯胺酰胺。
20.权利要求1的化合物,其中该化合物为3-(1-叔丁氧羰基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺。
21.权利要求1的化合物,其中该化合物为3-(哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺。
22.权利要求1的化合物,其中该化合物为3-(1-苄基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺。
23.权利要求1的化合物,其中该化合物为3-(1-苄基哌啶-4-基)-2-氨基丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺。
24.权利要求1的化合物,其中该化合物为3-(1-苄氧羰基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰 胺。
25.权利要求1的化合物,其中该化合物为3-(1-苯甲酰基哌啶-4-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺。
26.权利要求1的化合物,其中该化合物为3-(哌啶-3-基)-2-(9-芴基甲氧羰基氨基)丙酸4-二乙胺基丙氧基-2-丁氧基苯胺酰胺。
27.药物组合物,含有如权利要求1、2和3中任一项所述的化合物,以及一种或多种可药用赋形剂。
28.权利要求27的药物组合物,其是以口服剂量或肠胃外剂量单位的形式。
29.权利要求27的药物组合物,其进一步含有一种或多种治疗剂,所述的治疗剂选自:烷基化剂、抗代谢物、植物碱、抗生素、激素、生物应答调节剂、止痛剂、NSAIDs、DMARDs、磺酰脲类、双胍类、胰岛素、胆碱酯酶抑制剂、抗精神病药、抗抑郁药、和抗惊厥药。
30.如权利要求1、2和3中任一项所述的化合物在制备用于抑制RAGE与其生理配体相互作用的药物中的应用。
31.权利要求30的应用,其中的配体选自高级糖基化终产物、S100/钙粒蛋白/EN-RAGE、β-淀粉状蛋白和两性素。
32.如权利要求1、2和3中任一项所述的化合物在制备用于治疗疾病状态的药物中的应用,所述的疾病状态选自急性和慢性炎症,糖尿病症状,血管通透性、肾病、动脉硬化症、视网膜病,阿尔茨海默氏病、勃起功能障碍、和肿瘤侵袭和肿瘤转移。
33.治疗有效量的如权利要求1、2和3中任一项所述的化合物在制备用于预防和/或治疗RAGE介导的人类疾病的药物中的应用,其中治疗有效量包括足够用来至少部分抑制配体与RAGE受体结合的化合物。
34.权利要求33的应用,其中药物进一步包括至少一种辅药和/或另外的治疗剂。
35.权利要求34的应用,其中治疗剂选自烷基化剂、抗代谢物、植物碱、抗生素、激素、生物应答调节剂、止痛剂、NSAIDs、DMARDs、磺酰脲类、双胍类、胰岛素、胆碱酯酶抑制剂、抗精神病药、抗抑郁药、和抗惊厥药。
36.权利要求33的应用,其中RAGE介导的人类疾病包括急性和/或慢性炎症。
37.权利要求33的应用,其中RAGE介导的人类疾病包括血管通透性。
38.权利要求33的应用,其中RAGE介导的人类疾病包括肾病。
39.权利要求33的应用,其中RAGE介导的人类疾病包括动脉硬化症。
40.权利要求33的应用,其中RAGE介导的人类疾病包括视网膜病。
41.权利要求33的应用,其中RAGE介导的人类疾病包括阿尔茨海默氏病。
42.权利要求33的应用,其中RAGE介导的人类疾病包括勃起功能障碍。
43.权利要求33的应用,其中RAGE介导的人类疾病包括肿瘤侵袭和/或肿瘤转移。
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EP1377295A4 (en) | 2007-05-09 |
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CA2440042A1 (en) | 2002-09-12 |
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US7776919B2 (en) | 2010-08-17 |
CA2440042C (en) | 2011-09-27 |
US20100286197A1 (en) | 2010-11-11 |
JP2005500254A (ja) | 2005-01-06 |
AU2002245591B2 (en) | 2007-05-17 |
WO2002070473A2 (en) | 2002-09-12 |
JP2010065043A (ja) | 2010-03-25 |
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