CN100575335C - 氨基-丙醇衍生物 - Google Patents
氨基-丙醇衍生物 Download PDFInfo
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- CN100575335C CN100575335C CN200580012823A CN200580012823A CN100575335C CN 100575335 C CN100575335 C CN 100575335C CN 200580012823 A CN200580012823 A CN 200580012823A CN 200580012823 A CN200580012823 A CN 200580012823A CN 100575335 C CN100575335 C CN 100575335C
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
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Abstract
本发明涉及式(I)化合物,在式(I)中,R1、R2、R3、Ra和R5如说明书中所定义,本发明还涉及它们的制备方法、它们的用途(特别是在移植中的用途)以及包含它们的药物组合物。
Description
本发明涉及氨基-丙醇衍生物、它们的制备方法、它们的用途以及包含它们的药物组合物。
更特别地,本发明提供了游离形式或盐形式的式I化合物
其中
R1是任选地被OH、C1-2烷氧基或1至6个氟原子取代的C1-6烷基;C2-6链烯基;或C2-6炔基;
R2是式(a)、(b)或(c)的基团
其中
R6是任选地被环烷基、苯基、杂芳基或杂环残基取代的C1-12烷基,
其中C1-12烷基任选地被一个或多个O或C=O间断;并且
其中苯基、杂芳基、环烷基和/或杂环残基可以被1至5个取代基取代,该取代基选自羟基,卤素,C1-4烷基,C1-4烷氧基,氰基,苯基和被1至5个选自羟基、卤素、C1-4烷基、C1-4烷氧基和氰基的取代基取代的苯基;
R7是H、苯基或杂芳基,其中苯基和/或杂芳基独立地可以被1至5个选自羟基、卤素、C1-4烷基、被1至5个氟原子取代的C1-4烷基、C1-4烷氧基、被1至5个氟原子取代的C1-4烷氧基和氰基的取代基取代;
X是O、C=O、S或键;
Z是N或CH;
R3是式(d)或(e)的基团
其中Y是CH或CF,R8是C1-6烷基、C2-6链烯基、C2-6炔基、苯基,Z1是直接的键、CH2、CHF、CF2或O,并且R9和R10各自独立地是H或任选地被1、2或3个卤原子取代的C1-4烷基;
并且
R4和R5各自独立地是H、任选地被1、2或3个卤原子取代的C1-4烷基或酰基。
烷基或烷基部分可以是直链或支链的,例如甲基、乙基、丙基、异丙基或丁基。链烯基可以是例如乙烯基。环烷基可以是例如C3-6环烷基。
酰基可以是残基W-CO,其中W是C1-6烷基、C3-6环烷基、苯基或苯基C1-4烷基。
卤素可以是F、Cl或Br,优选为F或Cl。
杂芳基可以是包含1至4个选自N、O和S的杂原子的5至8元芳环,例如吡啶基、嘧啶基、吡嗪基、呋喃基、噁唑基、异噁唑基、噻吩基、噻唑基、噻吩基(thiophenyl)、异噻唑基、吡咯基、咪唑基或吡唑基。
杂环残基指的是3至8元、优选为5至8元饱和或不饱和的杂环,包括例如四氢呋喃基、四氢吡喃基、吖丙啶基、哌啶基、吡咯烷基、哌嗪基。
式I化合物可以以游离形式或盐形式存在,例如与如无机酸的加成盐,例如盐酸盐、氢溴酸盐或硫酸盐,与有机酸的盐,例如乙酸盐、富马酸盐、马来酸盐、苯甲酸盐、柠檬酸盐、苹果酸盐、甲磺酸盐或苯磺酸盐。水合物或溶剂化物形式的式I化合物和其盐也是本发明的部分。
当式I化合物在分子中具有不对称中心时,可以获得多种旋光异构体。本发明也包含对映异构体、外消旋体、非对映异构体以及它们的混合物。例如,连有R1、R3和NR4R5的中心碳原子可以具有R或S构型。具有以下三维构型的化合物是通常优选的:
另外,当式I化合物包括几何异构体时,本发明包括顺式化合物、反式化合物以及它们的混合物。类似的考虑也适用于以上提及的存在不对称碳原子或不饱和键的原料,例如,以下说明的式II或式III化合物。
在式I化合物中,单独地或以任何亚组合优选以下含义:
1.R1是CH3或CH2-OH;
2.R3是式-CH(R8)(OH)或式-CH(R8)(OPO(OR9)(OR10))残基;
3.R4和R5各自是氢;
4.X是O或键;
5.式(a)的XR6是在对位与式I连接的;
6.在式(b)的萘基中,XR6是在5位;
7.R7是氢、苯基或噻吩基;并且
8.R8是甲基、乙基、乙炔基或苯基;
9.R9是H;
10.R10是H。
本发明也包括制备式I化合物的方法,该方法包括:
a)除去式II化合物中存在的保护基团
其中R1、R2和R5如上文所定义,R’3是-Y(R8)(OH),其中Y和R8如上文所定义,并且R’4是氨基保护基团,
b)除去式III化合物中存在的保护基团
其中R1、R2、R’4和R5如上文所定义,R”3是式(e’)残基
其中Y、Z1和R8如上文所定义,并且R’9和R’10各自是可水解的或可氢解的基团或R’9和R’10共同形成二价桥连残基,该残基任选地与环(例如苯环)稠合,
并且,如果需要,将获得的游离形式的式I化合物转化为所需的盐形式,反之亦然。
保护基团的除去可以根据本领域中公知的方法进行。氨基保护基团的除去可以方便地根据本领域中公知的方法进行,例如,在酸性介质中如应用盐酸通过水解进行。氨基保护基团的实例是例如在“Protective Groups inOrganic Synthesis”T.W.Greene,J.Wiley & Sons NY,第二版.,第七章,1991以及其中的参考文献中公开的,例如苄基、对甲氧基苄基、甲氧基甲基、四氢吡喃基、三烷基硅烷基、酰基、叔丁氧基羰基、苄氧基羰基、9-芴基甲氧基羰基、三氟乙酰基等。
本发明也包括制备式II化合物的方法,其中X是O或S,该方法包括将式IV化合物烷基化
其中R1、R’3、R’4、R5如上文所定义,并且
R’2是式(a’)或(b’)或(c’)或(d’)的基团
其中R7如上文所定义
以引入所需的残基R6。
式IV化合物的烷基化可以根据本领域中公知的方法进行,例如通过亲核取代进行,例如通过与烷基化试剂R6-X3反应,其中X3是甲磺酸根、甲苯磺酸根、三氟甲磺酸根、硝基苯磺酸根(nosylate)或卤素如氯、溴或碘。烷基化也可以按照Mitsunobu方法(例如在Hughes,Organic Preparationsand Procedures International 28,127-64,1996或D.L.Hughes,Org.React.42,335,1992中公开的)在溶液中或在固相支持合成物上,例如通过将式IV化合物连接到树脂上进行。或者,可以使用三苯膦或例如与树脂例如聚苯乙烯键合的偶氮二甲酸二乙酯。
在没有具体描述原料的制备的情况下,这些化合物是已知的或者可以根据与本领域中公知的方法相类似的方法或如下文实施例中所公开的方法制备。用下面的实施例来对本发明进行说明。熔点是未经校正的。
RT =室温
DMF =N,N-二甲基甲酰胺
AcOEt =乙酸乙酯
THF =四氢呋喃
RP-HPLC =反相高效液相色谱
TFA =三氟乙酸
流程图1:合成概述
方法A、B、G和H是本领域公知的,并且可以按照K.Hinterding等人,Synthesis 2003,1667中公开的方法进行。
M可以是本领域公知的应用于醛加成反应的任何金属或金属盐,例如MgCl、MgBr、MgI、Li、Zn、Cu。
PG指保护基团。
[(R)-1-甲酰基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯的制备(方法D):
向搅拌的含[(R)-1-羟甲基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(1.98g,5.03mmol)的CH2Cl2(20mL)溶液中加入N-吗啉-N-氧化物(884mg,7.54mmol)和四-正丙基过镣酸铵(177mg,0.50mmol)。混合物在室温下搅拌1小时。然后将混合物通过SiO2短柱过滤,用乙醚洗脱。滤液在减压下浓缩得到标题化合物。该粗产物足够纯,可不经进一步纯化直接用于下一步骤。
1H-NMR(CDCl3):9.33(s,1H),7.06-7.01(m,2H),6.82-6.76(m,2H),5.18(br s,1H),3.92(t,2H),2.60-2.49(m,1H),2.44-2.19(m,2H),2.01-1.93(m,1H),1.80-1.71(m,2H),1.55(s,3H),1.48-1.25(m,17H),0.89(t,J=7Hz,3H)。MS(ESI+):m/z=414.2[M+Na]+。
{(R)-3-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-1-甲酰基-1-甲基-丙基}-氨基甲酸叔丁酯的制备
标题化合物按照以上描述的方法制备(方法D)。
MS(ESI+):m/z=430.2[M+Na]+,837.5[2M+Na]+
{(R)-3-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-1-羟甲基-1-甲基-丙基}-氨基甲酸叔丁酯的制备(方法C):
向搅拌的含[(R)-1-羟甲基-3-(4-羟基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(1.0g,3.39mmol)的DMF(2mL)溶液中加入咪唑(1.15g,16.9mmol)和叔丁基二甲基硅烷氯(1.28g,8.49mmol)。反应物在室温下搅拌6小时。然后将反应混合物倾倒至AcOEt和NaHCO3(饱和水溶液)的二相混合物中。水相用AcOEt萃取两次。将合并的有机层干燥(Na2SO4)并且在减压下浓缩。柱色谱用含3%AcOEt的庚烷洗脱得到{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-3-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-1-甲基-丙基}-氨基甲酸叔丁酯,为无色油状物。
MS(ESI+):m/z=546.3[M+Na]+,1069.5[2M+Na]+。
向搅拌的含{(R)-1-(叔丁基-二甲基-硅烷氧基甲基)-3-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-1-甲基-丙基}-氨基甲酸叔丁酯(8.84g,16.8mmol)的乙腈(150mL)溶液中加入H2O(1.52mL,84.3mmol)和Sc(OTf)3(83mg,0.2mmol)。反应物在室温下搅拌3小时。然后将反应混合物倾倒至AcOEt和NaHCO3(饱和水溶液)的二相混合物中。水相用AcOEt萃取(3次)。将合并的有机层干燥(Na2SO4)并且在减压下浓缩。柱色谱用含0%→40%AcOEt的庚烷洗脱得到{(R)-3-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-1-羟甲基-1-甲基-丙基}-氨基甲酸叔丁酯,为无色油状物。
MS(ESI+):m/z=473.2[M+Na+CH3CN]+,841.3[2M+Na]+。
{(1R,2R)-1-[2-(4-庚氧基-苯基)-乙基]-2-羟基-1-甲基-丙基}-氨基甲酸叔丁酯和{(1R,2S)-1-[2-(4-庚氧基-苯基)-乙基]-2-羟基-1-甲基-丙基}-氨基甲酸叔丁酯的制备(方法E):
将搅拌的含[(R)-1-甲酰基-3-(4-庚氧基-苯基)-1-甲基-丙基]+氨基甲酸叔丁酯(380mg,0.97mmol)的乙醚(3mL)溶液冷却至0℃。加入MeMgBr(1.62mL,3.0M的Et2O,4.9mmol)并且反应物在0℃下搅拌1.25小时。然后将反应混合物倾倒至AcOEt和NH4Cl(饱和水溶液)的二相混合物中。水相用AcOEt萃取(3次)。将合并的有机层干燥(Na2SO4)并且在减压下浓缩。柱色谱用含20%AcOEt的庚烷洗脱得到标题化合物的混合物(d.r.=3∶1)。非对映异构体通过RP-HPLC在ZORBAX Extend C-18柱上分离,用5%→95%CH3CN的水溶液(+0.1%TFA)洗脱。
(1R,2R):1H-NMR(CDCl3):7.10-7.02(m,2H),6.82-6.77(m,2H),458(br s,1H),3.92(t,2H),3.86(d,J=7Hz,1H),3.83(d,J=7Hz,1H),2.60-2.48(m,2H),2.10-2.00(m,1H),1.79-1.71(m,2H),1.70-1.61(m,1H),1.48-1.25(m,20H),1.25(d,J=6Hz,3H),0.89(t,J=7Hz,3H)。 (c=0.65,CHCl3)。
(1R,2S):1H-NMR(CDCl3):7.11-7.06(m,2H),6.83-6.78(m,2H),4.56(br s,1H),3.92(t,2H),3.82(d,J=7Hz,1H),3.78(d,J=7Hz,1H),2.63(dt,J=5Hz,12Hz,1H),2.48(dt,J=5Hz,12Hz,1H),2.15(dt,J=5Hz,12Hz,1H),1.95(dt,J=5Hz,12Hz,1H),1.78-1.70(m,2H),1.70-1.25(m,17H),1.19(d,J=7Hz,3H),1.15(s,3H),0.89(t,J=7Hz,3H)。 (c=1.0,CHCl3)。
{(1S,2S)-1-[2-(4-庚氧基-苯基)-乙基]-2-羟基-1-甲基-丙基}-氨基甲酸叔丁酯和{(1S,2R)-1-[2-(4-庚氧基-苯基)-乙基]-2-羟基-1-甲基-丙基}-氨基甲酸叔丁酯的制备
标题化合物按照以上描述的方法制备(方法E)。
(1S,2S):1H-NMR(CDCl3):7.10-7.02(m,2H),6.82-6.77(m,2H),4.58(br s,1H),3.92(t,2H),3.86(d,J=7Hz,1H),3.83(d,J=7Hz,1H),2.60-2.48(m,2H),2.10-2.00(m,1H),1.79-1.71(m,2H),1.70-1.61(m,1H),1.48-1.25(m,20H),1.25(d,J=6Hz,3H),0.89(t,J=7Hz,3H)。 (c=0.65,CHCl3)。
(1S,2R):1H-NMR(CDCl3):7.11-7.06(m,2H),6.83-6.78(m,2H),4.56(br s,1H),3.92(t,2H),3.82(d,J=7Hz,1H),3.78(d,J=7Hz,1H),2.63(dt,J=5Hz,12Hz,1H),2.48(dt,J=5Hz,12Hz,1H),2.15(dt,J=5Hz,12Hz,1H),1.95(dt,J=5Hz,12Hz,1H),1.78-1.70(m,2H),1.70-1.25(m,17H),1.19(d,J=7Hz,3H),1.15(s,3H),0.89(t,J=7Hz,3H)。 (c=1.2,CHCl3)。
((1R,2R)-1-{2-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-乙基}-2-羟基-1-甲基-丙基)-氨基甲酸叔丁酯和((1S,2R)-1-{2-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-乙基}-2-羟基-1-甲基-丙基)-氨基甲酸叔丁酯的制备
标题化合物按照以上描述的方法制备(方法E)。
MS(ESI+):m/z=869.4[2M+Na]+。
{(1R,2R)-2-羟基-1-[2-(4-羟基-苯基)-乙基]-1-甲基-丙基}-氨基甲酸叔丁酯的制备(方法F):
向搅拌的含((1R,2R)-1-{2-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-乙基}-2-羟基-1-甲基-丙基)-氨基甲酸叔丁酯(19mg,0.045mmol)的乙腈(2mL)溶液中加入HF(0.2mL,40%溶液),并且反应物在室温下搅拌3.5小时。然后将反应混合物倾倒至AcOEt和NaHCO3(饱和水溶液)的二相混合物中。水相用AcOEt萃取(3次)。将合并的有机层干燥(Na2SO4)并且在减压下浓缩。柱色谱用含30%AcOEt的庚烷洗脱得到标题化合物。
1H-NMR(CDCl3):7.03(d,J=9Hz,2H),6.72(d,J=9Hz,2H),4.58(br s,1H),3.80(q,J=6Hz,1H),2.62(dt,J=5Hz,13Hz,1H),2.46(dt,J=5Hz,13Hz,1H),2.19(dt,J=5Hz,13Hz,1H),1.95(dt,J=5Hz,13Hz,1H),1.45(s,9H),1.20(d,J=7Hz,3H),1.15(s,3H)。
实施例1:(2R,3R)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇
将{(1R,2R)-1-[2-(4-庚氧基-苯基)-乙基]-2-羟基-1-甲基-丙基}-氨基甲酸叔丁酯(30mg,0.074mmol)溶解于饱和的含HCl的甲醇溶液中。溶液在室温下搅拌2小时。在减压下去除溶剂后,化合物通过与Et2O研磨而纯化并且获得其盐酸盐。
1H-NMR(CDCl3):8.12(br s,3H),7.09(d,J=9Hz,2H),6.72(d,J=9Hz,2H),4.60(br s,1H),4.07-4.00(m,1H),3.85(t,J=7Hz,2H),2.79-2.70(m,2H),1.97-1.88(m,2H),1.77-1.61(m,2H),1.47-1.23(m,11H),1.20(d,J=6Hz,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=308.2[M+H]+。
实施例2:(2S,3R)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(d6-DMSO):7.79(br s,3H),7.09(d,J=9Hz,2H),6.82(d,J=9Hz,2H),5.39(d,J=5Hz,1H),3.90(t,J=7Hz,2H),3.72-3.63(m,1H),2.65-2.45(m,2H),1.81(dt,J=4Hz,13Hz,1H),1.70-1.58(m,3H),1.42-1.22(m,8H),1.20(s,3H),1.11(d,J=7Hz,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=308.2[M+H]+。
实施例3:(2S,3S)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物通过用Et2O处理而纯化并且获得其盐酸盐。
1H-NMR(CDCl3):8.12(br s,3H),7.09(d,J=9Hz,2H),6.72(d,J=9Hz,2H),4.60(br s,1H),4.07-4.00(m,1H),3.85(t,J=7Hz,2H),2.79-2.70(m,2H),1.97-1.88(m,2H),1.77-1.61(m,2H),1.47-1.23(m,11H),1.20(d,J=6Hz,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=308.2[M+H]+。
实施例4:(2R,3S)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(d6-DMSO):7.79(br s,3H),7.09(d,J=9Hz,2H),6.82(d,J=9Hz,2H),5.39(d,J=5Hz,1H),3.90(t,J=7Hz,2H),3.72-3.63(m,1H),2.65-2.45(m,2H),1.81(dt,J=4Hz,13Hz,1H),1.70-1.58(m,3H),1.42-1.22(m,8H),1.20(s,3H),1.11(d,J=7Hz,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=308.2[M+H]+。
实施例5:(3R,4R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-3-醇
向搅拌的含{(1R,2R)-1-[2-(4-庚氧基-苯基)-乙基]-2-羟基-1-甲基-丁基}-氨基甲酸叔丁酯(25mg,0.06mmol)的CH2Cl2(3mL)溶液中加入TFA(0.3mL)。溶液在室温下搅拌2小时。在减压下去除溶剂后,残留物从二噁烷中冻干得到标题化合物,为其三氟乙酸盐,白色、无定形粉末。
1H-NMR(d6-DMSO):7.69(br s,3H),7.08(d,J=9Hz,2H),6.83(d,J=9Hz,2H),5.41(d,J=6Hz,1H),3.90(t,J=7Hz,2H),3.35-3.22(m,1H),2.60-2.45(m,2H),1.81(dt,J=4Hz,13Hz,1H),1.70-1.44(m,5H),1.40-1.25(m,11H),0.92(t,J=7Hz,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=322.2[M+H]+。
实施例6:(3S,4R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-3-醇
标题化合物应用适当的原料按照实施例5中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(d6-DMSO):7.66(br s,3H),7.10-7.04(m,2H),6.85-6.80(m,2H),5.45(br s,1H),3.89(t,J=7Hz,2H),3.40-3.25(m,1H),2.60-2.40(m,2H),1.80(dt,J=4Hz,13Hz,1H),1.70-1.61(m,4H),1.52-1.42(m,1H),1.40-1.19(m,8H),1.12(s,3H),0.92(t,J=7Hz,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=322.2[M+H]+。
实施例7:(1R,2R)-2-氨基-4-(4-庚氧基-苯基)-2-甲基-1-苯基-丁-1-醇
标题化合物应用适当的原料按照类似实施例1中描述的方法制备。产物通过RP-HPLC(ZORBAX Extend C-18)纯化,用5%→95%CH3CN的水溶液(+0.1%TFA)洗脱。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(d6-DMSO):7.70(br s,3H),7.41-7.30(m,5H),7.05-6.99(m,2H),6.82-6.78(m,2H),6.40(br s,1H),4.66(s,1H),3.88(t,J=7Hz,2H),2.67-2.41(m,2H),1.70-1.59(m,4H),1.40-1.20(m,8H),1.11(s,3H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=370.2[M+H]+。
实施例8:(1S,2R)-2-氨基-4-(4-庚氧基-苯基)-2-甲基-1-苯基-丁-1-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(d6-DMSO):7.90(br s,3H),7.40-7.28(m,5H),7.00(d,J=9Hz,2H),6.79(d,J=9Hz,2H),6.40-6.36(m,1H),4.70-4.65(m,1H),3.88(t,J=7Hz,2H),3.33-3.28(m,1H),2.60-2.40(m,2H),1.89-1.78(m,1H),1.69-1.61(m,2H),1.45-1.20(m,11H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=370.2[M+H]+。
实施例9:(R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-1-炔-3-醇
在-78℃下,向搅拌的含三甲基甲硅烷基乙炔(0.18mL,1.27mmol)的THF(18mL)溶液中加入正丁基锂(0.49mL,2.5M的环己烷溶液)。5分钟后,加入含[(R)-1-甲酰基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(200mg,0.51mmol)的THF(2mL)溶液并且反应物在-78℃搅拌5小时。之后,去除冷却并且反应物在室温下搅拌16小时。然后将反应混合物倾倒至AcOEt和NaHCO3(饱和水溶液)的二相混合物中。水相用AcOEt萃取(3次)。将合并的有机层干燥(Na2SO4)并且在减压下浓缩。柱色谱用含8%→45%AcOEt的庚烷洗脱得到(R)-5-乙炔基-4-[2-(4-庚氧基-苯基)-乙基]-4-甲基-噁唑烷-2-酮以及其C5差向异构体。
向搅拌的含(R)-5-乙炔基-4-[2-(4-庚氧基-苯基)-乙基]-4-甲基-噁唑烷-2-酮的乙醇(1mL)溶液中加入NaOH(1mL,1M水溶液)。混合物在回流温度下加热20小时。然后将反应混合物倾倒至AcOEt和NaHCO3(饱和水溶液)的二相混合物中。水相用AcOEt萃取(3次)。将合并的有机层干燥(Na2SO4)并且在减压下浓缩。产物通过RP-HPLC(ZORBAX Extend C-18)纯化,用5%→95%CH3CN的水溶液(+0.1%TFA)洗脱得到标题化合物。
1H-NMR(d6-DMSO):7.70(br s,3H),7.03(d,J=9Hz,2H),6.78(d,J=9Hz,2H),4.53(br s,1H),3.89(t,J=7Hz,2H),2.70-2.57(m,2H),2.53(s,1H),2.11-1.92(m,2H),1.73(qt,J=7Hz,2H),1.50-1.21(m,11H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=318.2[M+H]+。
实施例10:(R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-1-炔-3-醇(实施例9的C3差向异构体)
标题化合物应用适当的原料按照实施例9中描述的方法制备。产物通过RP-HPLC(ZORBAX Extend C-18)纯化,用5%→95%CH3CN的水溶液(+0.1%TFA)洗脱得到标题化合物。
1H-NMR(d6-DMSO):7.85(br s,3H),7.09(d,J=9Hz,2H),6.79(d,J=9Hz,2H),4.52(br s,1H),3.90(t,J=7Hz,2H),2.75-2.50(m,3H),2.23-2.12(m,1H),2.10-2.00(m,1H),1.75(qt,J=7Hz,2H),1.50-1.23(m,11H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=318.2[M+H]+。
实施例11:(2S,3R)-3-氨基-5-(6-戊氧基-萘-2-基)-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.82(t,J=8Hz,2H),7.72(s,1H),7.45(dd,J=1Hz,8Hz,1H),7.32(d,J=2Hz,1H),7.22(dd,J=2Hz,8Hz,1H),4.69(s,3H),4.20(t,J=7Hz,2H),3.95(q,J=7Hz,1H),2.95(t,J=9Hz,2H),2.25-2.13(m,1H),2.07-1.91(m,3H),1.68-1.50(m,7H),1.38(d,J=8Hz,3H),1.10(t,J=7Hz,3H)。MS(ESI+):m/z=330.2[M+H]+。
实施例12:(2R,3R)-3-氨基-5-(6-戊氧基-萘-2-基)-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.68(t,J=8Hz,2H),7.58(s,1H),7.30(dd,J=1Hz,8Hz,1H),7.16(d,J=2Hz,1H),7.08(dd,J=2Hz,8Hz,1H),4.55(s,3H),4.08(t,J=7Hz,2H),3.88(q,J=7Hz,1H),2.90-2.71(m,2H),2.09-1.99(m,1H),1.92-1.78(m,3H),1.55-1.39(m,4H),1.32(s,3H),1.25(d,J=8Hz,3H),0.95(t,J=7Hz,3H)。MS(ESI+):m/z=330.2[M+H]+。
实施例13:(2S,3R)-3-氨基-3-甲基-5-[4-(5-苯基-戊氧基)-苯基]-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.28-7.10(m,7H),6.88-6.80(m,2H),4.60(br s,3H),3.95(t,J=7Hz,2H),3.70(q,J=7Hz,1H),2.70-2.59(m,4H),2.04-1.92(m,1H),1.85-1.66(m,5H),1.55-1.45(m,2H),1.38(s,3H),1.25(d,J=7Hz,3H)。MS(ESI+):m/z=356.2[M+H]+。
实施例14:(2R,3R)-3-氨基-3-甲基-5-[4-(4-苯基-丁氧基)-苯基]-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.28-7.08(m,7H),6.86-6.80(m,2H),4.57(br s,3H),3.98-3.92(m,2H),3.82(q,J=7Hz,1H),2.70-2.53(m,4H),1.94-1.86(m,1H),1.82-1.71(m,5H),1.26(s,3H),1.21(d,J=7Hz,3H)。MS(ESI+):m/z=342.3[M+H]+。
实施例15:(2S,3R)-3-氨基-3-甲基-5-[4-(4-苯基-丁氧基)-苯基]-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.27-7.08(m,7H),6.84-6.80(m,2H),4.58(br s,3H),3.97-3.92(m,2H),3.72(q,J=7Hz,1H),2.70-2.54(m,4H),1.91-1.84(m,1H),1.80-1.75(m,4H),1.74-1.67(m,1H),1.28(s,3H),1.20(d,J=7Hz,3H)。MS(ESI+):m/z=342.2[M+H]+。
实施例16:(2S,3R)-3-氨基-5-[4-(2-联苯-4-基-乙氧基)-苯基]-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.64-7.55(m,4H),7.47-7.38(m,4H),7.36-7.30(m,1H),7.17-7.12(m,2H),6.90-6.85(m,2H),4.60(br s,3H),4.22(t,J=7Hz,2H),3.73(q,J=7Hz,1H),3.11(t,J=7Hz,2H),2.68-2.58(m,2H),1.93-1.83(m,1H),1.78-1.67(m,1H),1.28(s,3H),1.22(d,J=7Hz,3H)。MS(ESI+):m/z=390.2[M+H]+。
实施例17:(2R,3R)-3-氨基-5-[4-(2-联苯-4-基-乙氧基)-苯基]-3-甲基-戊-2-醇
标题化合物应用适当的原料按照实施例1中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.67-7.58(m,4H),7.50-7.40(m,4H),7.39-7.33(m,1H),7.17(d,J=9Hz,2H),6.90(d,J=9Hz,2H),4.60(br s,3H),4.23(t,J=7Hz,2H),3.82(q,J=7Hz,1H),3.16(t,J=7Hz,2H),2.72-2.56(m,2H),1.93(dt,J=5Hz,14Hz,1H),1.77(dt,J=5Hz,14Hz,1H),1.28(s,3H),1.26(d,J=7Hz,3H)。MS(ESI+):m/z=390.3[M+H]+。
实施例18:磷酸单-[(1R,2R)-2-氨基-4-(4-庚氧基-苯基)-1,2-二甲基-丁基]酯
将{(1R,2R)-2-(二叔丁氧基-磷酰基氧基)-1-[2-(4-庚氧基-苯基)-乙基]-1-甲基-丙基}-氨基甲酸叔丁酯(40mg,0.067mmol)溶解于饱和的含HCl的甲醇(5mL)溶液中并且在室温下搅拌24小时。溶剂在减压下蒸发。从二噁烷/H2O(3∶1)中冻干得到标题化合物,为白色、无定形粉末。
1H-NMR(MeOD):7.14(d,J=8Hz,2H),6.82(d,J=8Hz,2H),4.46-4.40(m,1H),3.92(t,J=7Hz,2H),2.73(dt,J=5Hz,14Hz,1H),2.57(dt,J=5Hz,14Hz,1H),2.00(dt,J=4Hz,14Hz,1H),1.82(dt,J=4Hz,14Hz,1H),1.76-1.69(m,2H),1.50-1.27(m,14H),0.90(t,J=7Hz,3H)。MS(ESI+):m/z=388.2[M+H]+,776.4[2M+H]+。
实施例19:磷酸单-[(1S,2R)-2-氨基-4-(4-庚氧基-苯基)-1,2-二甲基-丁基]酯
标题化合物应用适当的原料按照实施例18中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(MeOD):7.13(d,J=8Hz,2H),6.83(d,J=8Hz,2H),4.38-4.31(m,1H),3.93(t,J=7Hz,2H),2.70-2.58(m,2H),2.02-1.94(m,1H),1.88-1.79(m,1H),1.78-1.70(m,2H),1.48-1.27(m,14H),0.90(t,J=7Hz,3H)。MS(ESI+):m/z=388.2[M+H]+,776.4[2M+H]+。
实施例20:磷酸单-[(1R,2R)-2-氨基-1,2-二甲基-4-(6-戊氧基-萘-2-基)-丁基]酯
标题化合物应用适当的原料按照实施例18中描述的方法制备。化合物从二噁烷中冻干得到白色、无定形粉末。
1H-NMR(d6-DMSO):7.71-7.63(m,2H),7.60(s,1H),7.33(d,J=9Hz,1H),7.22(s,1H),7.10-7.04(m,1H),4.33-4.21(m,1H),4.03(t,J=7Hz,2H),2.88-2.60(m,2H),1.84-1.67(m,4H),1.47-1.30(m,4H),1.22(s,3H),1.18(d,J=7Hz,3H),0.88(t,J=7Hz,3H)。MS(ESI+):m/z=432.1[M+Na]+。
游离形式或可药用盐形式的式I化合物表现出有价值的药理学性质,例如淋巴细胞再循环调节性质,例如如在体外和体内试验中所说明的,因此它们适合用于治疗。
A.体外
如在以下测定中所测定的,式I化合物对于各个人S1P受体具有结合亲合性。
1-磷酸鞘氨醇(S1P)受体的情况
用人S1P受体EDG-1(S1P1)、EDG-3(S1P3)、EDG-5(S1P2)、EDG-6(S1P4)和EDG-8(S1P5)试验了化合物的激动剂活性。通过对化合物诱导的GTP[γ-35S]与膜蛋白的结合进行定量来评价功能受体活化,所述的膜蛋白是由稳定表达适当的人S1P受体的转染的CHO或RH7777细胞制备的。所用的测定技术是SPA(闪烁亲近测定法)。简言之,将DMSO溶解的化合物连续稀释并在50mM Hepes、100mM NaCl、10mM MgCl2、10μMGDP、0.1%无脂肪BSA和0.2nM GTP[γ-35S](1200Ci/mmol)存在下加入到SPA-珠(Amersham-Pharmacia)固定的表达S1P受体的膜蛋白(10-20μg/孔)中。在96孔微量滴定板中于室温下孵育120分钟后,通过离心步骤分离未结合的GTP[γ-35S]。由TOPcount读板仪(Packard)定量由膜结合的GTP[γ-35S]引发的SPA珠的发光。用标准曲线拟合软件计算EC50。在该测定中,式I化合物对S1P1受体的结合亲合性<50nM。
实施例 | S1P<sub>1</sub>EC<sub>50</sub>[nM] | S1P<sub>3</sub>EC<sub>50</sub>[nM] | S1P<sub>4</sub>EC<sub>50</sub>[nM] | S1P<sub>5</sub>EC<sub>50</sub>[nM] |
18 | 0.51激动剂 | 4.6激动剂 | 0.70激动剂 | 0.74激动剂 |
19 | 0.07激动剂 | 1.4激动剂 | 0.40激动剂 | 0.15激动剂 |
20 | 0.13激动剂 | 8.5激动剂 | 0.67激动剂 | 0.29激动剂 |
B.体内:血淋巴细胞消减
将式I化合物或媒介物通过管饲法口服施用于大鼠。在第1天尾部采血以进行血液监测,得到各个基线值,并且在施用后2、6、24、48和72小时尾部采血以进行血液监测。在该测定中,当以0.03-3mg/kg的剂量施用时,式I化合物消减外周血淋巴细胞。例如,获得以下结果:外周血淋巴细胞消减大于50%。
实施例1:0.07mg/kg,口服,6小时后
实施例12:0.4mg/kg,口服,6小时后
实施例13:0.5mg/kg,口服,6小时后
实施例14:0.1mg/kg,口服,6小时后
实施例15:0.6mg/kg,口服,6小时后
实施例17:0.2mg/kg,口服,6小时后
因此,式I化合物可用于治疗和/或预防淋巴细胞相互作用介导的疾病或病症,例如在移植中,如细胞、组织或器官的同种异体移植物或异种移植物的急性或慢性排斥反应或移植物功能延迟恢复(delayed graftfunction)、移植物抗宿主病、自身免疫性疾病例如类风湿性关节炎、系统性红斑狼疮、桥本甲状腺炎、多发性硬化、重症肌无力、I型或II型糖尿病和与其相关的病症、脉管炎、恶性贫血、舍格伦综合征、眼色素层炎、银屑病、格雷夫斯眼病(Graves opthalmopathy)、斑秃等、变应性疾病例如变应性哮喘、特应性皮炎、变应性鼻炎/结膜炎、变应性接触性皮炎、任选地伴有潜在异常反应的炎性疾病例如炎性肠病、克隆病或溃疡性结肠炎、内源性哮喘、炎性肺损伤、炎性肝损伤、炎性肾小球损伤、动脉粥样硬化、骨关节炎、刺激性接触性皮炎以及另外的湿疹性皮炎、脂溢性皮炎、免疫学介导的病症的皮肤表征、炎性眼病、角膜结膜炎、心肌炎或肝炎、缺血/再灌注损伤例如心肌梗死、中风、肠局部缺血、肾衰竭或出血性休克、外伤性休克、血管生成、阿尔茨海默病、癌症例如乳腺癌、T细胞淋巴瘤或T细胞白血病、感染性疾病例如中毒性休克(例如超抗原诱导的)、败血症性休克、成人呼吸窘迫综合征或病毒性感染例如AIDS、病毒性肝炎、慢性细菌性感染或老年性痴呆。细胞、组织或实体器官移植的实例包括例如胰岛、干细胞、骨髓、角膜组织、神经元组织、心、肺、心肺联合、肾、肝、肠、胰腺、气管或食管。对于以上用途,所需剂量当然将根据施用方式、待治疗的具体疾病和所需的效果而变化。
一般而言,表明以约0.03-2.5mg/kg体重的日剂量全身性施用时可获得满意的结果。在较大的哺乳动物例如人中,适用的日剂量在约0.5mg至约100mg范围内,该日剂量可以方便地例如以每天不超过4次的分剂量施用或以缓释形式施用。对于口服施用而言,适合的单位剂量形式包含约0.1-50mg活性成分。
式I化合物可以通过任何常规途径施用,特别是肠道施用,例如口服施用,例如以片剂或胶囊剂的形式肠道施用;或非肠道施用,例如以可注射溶液剂或混悬剂的形式非肠道施用;局部施用,例如以洗剂、凝胶剂、软膏剂或乳剂的形式局部施用;或以鼻用形式或栓剂形式施用。包含游离形式或可药用盐形式的式I化合物以及至少一种可药用的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的载体或稀释剂混合来制备。
优选地,其中R3是式(d)基团的式I化合物,即式1.1化合物,口服施用,并且优选地具有R,R构型(如图1所示)。优选地,其中R3是式(e)基团的式I化合物,即式1.2化合物,非肠道施用,并且优选地具有S,R构型(如图1所示)。
图1.式1.1和1.2化合物优选的构型
式I化合物可以以游离形式或可药用盐形式,例如上述的可药用盐形式施用。该类盐可以用常规方法制备并且具有与游离化合物相同级别的活性。
根据前述内容,本发明还提供了:
1.1在需要这类治疗的受试者中预防或治疗如上所述的淋巴细胞介导的病症或疾病的方法,该方法包括对所述的受试者施用有效量的式I化合物或其可药用盐;
1.2在需要这类治疗的受试者中预防或治疗如上所述的急性或慢性移植排斥反应或T-淋巴细胞介导的炎性或自身免疫性疾病的方法,该方法包括对所述的受试者施用有效量的式I化合物或其可药用盐;
2.例如在以上1.1或1.2项下所述的任意一种方法中用作药物的游离形式或可药用盐形式的式I化合物。
3.药物组合物,例如在以上1.1或1.2项下所述的任意一种方法中使用的药物组合物,其包含游离形式或可药用盐形式的式I化合物以及可药用的稀释剂或载体。
4.用于制备在以上1.1或1.2项下所述的任意一种方法中使用的药物组合物的式I化合物或其可药用盐。
式I化合物可以作为唯一的活性成分被施用,或者与例如作为辅药的其它药物联合施用,所述的其它药物例如免疫抑制或免疫调节剂或其它抗炎剂,例如用于治疗或预防同种异体移植物或异种移植物的急性或慢性排斥反应或炎性或自身免疫性病症的上述药物;或化疗剂,例如抗恶性细胞增殖剂。例如,式I化合物可以与以下药物组合使用:钙调磷酸酶抑制剂,例如环孢菌素A、FK506或ISATX247;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟乙基)-雷帕霉素、CCI779、ABT578、AP23573、AP23464、AP23675、AP23841、TAFA93、biolimus 7或biolimus 9;具有免疫抑制性质的子囊菌素,如ABT281、ASM981等;皮质类固醇;环磷酰胺;硫唑嘌呤;甲氨蝶呤;来氟米特;咪唑立宾;麦考酚酸或其盐,例如钠盐;麦考酚酸吗乙酯;15-去氧斯潘格宁或免疫抑制同系物、类似物或其衍生物;免疫抑制单克隆抗体,如白细胞受体例如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD58、CD80、CD86或其配体的单克隆抗体;其它免疫调节化合物,例如具有至少一部分CTLA4或其突变体的胞外结构域,例如至少与非CTLA4蛋白序列结合的CTLA4或其突变体,例如CTLA4Ig(例如称为ATCC 68629)或其突变体的胞外部分的重组结合分子,例如LEA29Y;粘附分子抑制剂,如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂;或化疗剂,例如紫杉醇、吉西他滨、顺铂、阿霉素或5-氟尿嘧啶;或抗感染剂。
当式I化合物与其它免疫抑制/免疫调节、抗炎、化疗或抗感染治疗联合施用时,共同施用的免疫抑制、免疫调节、抗炎、化疗或抗感染化合物的剂量当然将根据所用的共同施用药物的类型(例如它是甾类化合物还是钙调磷酸酶抑制剂)、所用的具体药物、待治疗的症状等而变化。根据上述内容,本发明在另一方面还提供了:
5.如上所定义的方法,其包括共同施用,例如以并行或相继方式共同施用治疗有效的无毒量的式I化合物和至少一种第二种药物,例如免疫抑制、免疫调节、抗炎、化疗或抗感染药物,例如上文所述的那些。
6.药物组合,如药盒,其包含a)第一种药物,其是本文所公开的游离形式或可药用盐形式的式I化合物,和b)至少一种联用药物,例如免疫抑制、免疫调节、抗炎、化疗或抗感染剂。该药盒可以包含关于其施用的说明书。
本文所用的术语“共同施用”或“组合施用”等意指包括将所选择的治疗剂施用于单个患者,并且旨在包括其中各物质不一定通过相同的施用途径或在相同时间进行施用的治疗方案。
本文所用的术语“药物组合”意指通过将一种以上的活性成分相混合或组合而得到的产品,它包括活性成分的固定组合和非固定组合。术语“固定组合”意指活性成分,例如式I化合物与联用药物以单一实体或剂量的形式被同时施用于患者。术语“非固定组合”意指活性成分,例如式I化合物与联用药物作为分开的实体被同时、并行或者无特定时间限制地相继施用于患者,其中所述施用在患者体内提供了治疗有效水平的两种化合物。后者也适用于鸡尾酒疗法(cocktail therapy),例如施用3种或更多种活性成分。
Claims (9)
2.根据权利要求1中所述的化合物,其中R8是甲基、乙基、乙炔基或苯基;其他基团与权利要求1中定义相同。
3.根据权利要求1中所述的化合物,其中该化合物选自(2S,3S)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇;(2R,3S)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇;(3R,4R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-3-醇;(3S,4R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-3-醇;(1R,2R)-2-氨基-4-(4-庚氧基-苯基)-2-甲基-1-苯基-丁-1-醇;(1S,2R)-2-氨基-4-(4-庚氧基-苯基)-2-甲基-1-苯基-丁-1-醇;(R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己-1-炔-3-醇;(2S,3R)-3-氨基-5-(6-戊氧基-萘-2-基)-3-甲基-戊-2-醇;(2R,3R)-3-氨基-5-(6-戊氧基-萘-2-基)-3-甲基-戊-2-醇;(2S,3R)-3-氨基-3-甲基-5-[4-(5-苯基-戊氧基)-苯基]-戊-2-醇;(2R,3R)-3-氨基-3-甲基-5-[4-(4-苯基-丁氧基)-苯基]-戊-2-醇;(2S,3R)-3-氨基-3-甲基-5-[4-(4-苯基-丁氧基)-苯基]-戊-2-醇;(2S,3R)-3-氨基-5-[4-(2-联苯-4-基-乙氧基)-苯基]-3-甲基-戊-2-醇;(2R,3R)-3-氨基-5-[4-(2-联苯-4-基-乙氧基)-苯基]-3-甲基-戊-2-醇;和磷酸单-[(1R,2R)-2-氨基-1,2-二甲基-4-(6-戊氧基-萘-2-基)-丁基]酯。
4.根据权利要求1的化合物,所述化合物为(2S,3R)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊-2-醇或其盐。
5.根据权利要求1的化合物,所述化合物为磷酸单-[(1S,2R)-2-氨基-4-(4-庚氧基-苯基)-1,2-二甲基-丁基]酯或其盐。
6.药物组合物,该药物组合物包括根据权利要求1至5中任意一项所述的游离形式或可药用盐形式的化合物以及可药用的稀释剂或载体。
7.根据权利要求1至5中任意一项所述的游离形式或可药用盐形式的化合物或根据权利要求6中所述的药物组合物在制备用于治疗或预防淋巴细胞介导的疾病或病症的药物中的用途。
8.根据权利要求1至5中任意一项所述的游离形式或可药用盐形式的化合物或根据权利要求6中所述的药物组合物在制备用于治疗和/或预防T-淋巴细胞介导的急性或慢性炎性疾病或病症、自身免疫性疾病、急性或慢性移植物排斥反应、癌症或感染性疾病的药物中的用途。
9.药物组合物,该药物组合物包括根据权利要求1至5中任意一项所述的游离形式或可药用盐形式的化合物,以及另一种选自免疫抑制、免疫调节、抗炎、化疗、抗增殖和抗感染剂的药物。
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KR100837897B1 (ko) | 2008-06-13 |
WO2005118523A1 (en) | 2005-12-15 |
KR20070015439A (ko) | 2007-02-02 |
PT1753712E (pt) | 2009-08-06 |
CA2562332A1 (en) | 2005-12-15 |
JP2008500302A (ja) | 2008-01-10 |
AU2005250112A1 (en) | 2005-12-15 |
PL1753712T3 (pl) | 2009-10-30 |
DE602005014473D1 (en) | 2009-06-25 |
ES2327250T3 (es) | 2009-10-27 |
ATE431333T1 (de) | 2009-05-15 |
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