CN1620461A - 2-氨基-丙醇衍生物 - Google Patents
2-氨基-丙醇衍生物 Download PDFInfo
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- CN1620461A CN1620461A CNA028068378A CN02806837A CN1620461A CN 1620461 A CN1620461 A CN 1620461A CN A028068378 A CNA028068378 A CN A028068378A CN 02806837 A CN02806837 A CN 02806837A CN 1620461 A CN1620461 A CN 1620461A
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- Prior art keywords
- phenyl
- alkyl
- amino
- compound
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Abstract
式I化合物及其相应的非磷酸化化合物具有多种有益作用,例如免疫抑制作用,在式I中,m、R、R1和R3-R6定义见说明书,m为1、2或3,X为O或直接为键。
Description
本发明涉及2-氨基-丙醇衍生物、其制备方法以及包含所述化合物的药用组合物。
更具体地讲,本发明涉及游离形式或盐形式的式I化合物:
其中
m为1、2或3;
X为O或直接为键;
R1为H;任选被OH、酰基、卤素、环烷基、苯基或羟基-亚苯基取代的C1-6烷基;C2-6链烯基;C2-6炔基;或任选被OH取代的苯基;
R2为
其中R5为H或任选被1、2或3个卤原子取代的C1-4烷基,R6为H或任选被卤素取代的C1-4烷基;
R3和R4各自独立为H、任选被卤素取代的C1-4烷基或为酰基;
R为C13-20烷基,它可以在链中任选包含氧原子并且任选被硝基、卤素、氨基、羟基或羧基取代;或为式(a)残基
其中R7为H、C1-4烷基或C1-4烷氧基;
R8为取代的C1-20链烷酰基;苯基C1-14烷基,其中C1-14烷基任选被卤素或OH取代;环烷基C1-14烷氧基或苯基C1-14烷氧基,其中环烷基环或苯环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;苯基C1-14烷氧基C1-14烷基;苯氧基C1-14烷氧基或苯氧基C1-14烷基,
当R1为C1-4烷基、C2-6链烯基或C2-6炔基时,R也可以为其中R8为C1-14烷氧基的式(a)残基。
卤素为F、Cl、Br或I。烷基或烷氧基可以为直链或支链。
环烷基优选为C3-10环烷基,更优选C3-8环烷基,包括例如环丙基、环丁基、环戊基、环己基或环庚基。
酰基为任选取代的链烷酰基或芳酰基,其中链烷酰基为1-20个碳原子的直链或支链链烷酰基,例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基或己酰基。芳酰基的实例包括例如苯甲酰基。C1-20链烷酰基优选为C2-14链烷酰基并且可任选被例如苯基或环烷基(例如环己基)取代,并优选在末端位置被取代。取代的链烷酰基的实例包括例如苯甲酰基、苯基乙酰基、苯基丙酰基、苯基丁酰基、环己基乙酰基、环己基丙酰基或环己基丁酰基。
在苯基C1-14烷基或苯基C1-14烷氧基中,C1-14烷基或C1-14烷氧基部分优选包含1-10碳原子。
当R1为取代的C1-6烷基时,它可以为被OH取代的C1-6烷基并优选在末端位置取代,或者为被1、2或3个选自酰基、卤素、环烷基、苯基和羟基-亚苯基的取代基取代的C1-6烷基。
在本发明化合物中,无论是单独使用还是以任何方式组合使用时,本文中所用的符号都优选具有以下含义:
1.m为1或2,优选为1。
2.X为O。
3.R1为任选被OH取代的C1-6烷基;C2-6链烯基或C2-6炔基。
4.R3和R4各自独立为H。
5.R5和R6各自独立为H。
6.R为式(a)残基。
7.R7为H。
8.R7为C1-4烷氧基,例如甲氧基。
9.R8为取代的C1-20链烷酰基;苯基C1-14烷基,其中C1-14烷基被卤素或OH取代;环烷基C1-14烷氧基;或苯基C1-14烷氧基,其中苯环任选被卤素、C1-4烷基和/或C1-4烷氧基取代。
10.R1为C2-6链烯基或C2-6炔基,R为式(a)残基,其中R8为C1-14烷氧基。
11.R为式(a)残基,其中R8为C4-8烷氧基。
12.式(a)残基中,-(CH2)2-4-为-CH2-CH2-。
13.R8在-(CH2)2-4-的间位或对位,优选对位。
14.R7在R8的邻位。
式I化合物可以以游离形式或盐形式存在,例如与无机酸的加成盐,例如盐酸盐、氢溴酸盐或硫酸盐;与有机酸的盐,例如乙酸盐、延胡索酸盐、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;当R5或R6为H时,R2也可以为盐形式,例如铵盐或金属(例如钠、钾、钙、锌或镁)盐,或者它们的混合物。式I化合物及其盐的水合物或溶剂化物也是本发明的一部分。
当式I化合物的分子中含有一个或多个不对称中心时,可获得各种旋光异构体。本发明还包括对映异构体、外消旋体、非对映异构体以及它们的混合物。举例来说,连接R和R1的中心碳原子可具有R构型或S构型。此外,当式I化合物包括几何异构体时,则本发明包括顺式化合物、反式化合物以及它们的混合物。类似原则也适用于具有上述不对称碳原子或不饱和键的原料。
优选的式I化合物为例如2-氨基-2-十四烷基-1,3-丙二醇的一磷酸酯、磷酸单-{2-氨基-2-羟基甲基-4-[4-(5-苯基-戊酰基)-苯基]-丁基}酯和磷酸单-{2-氨基-2-羟基甲基-4-[4-(7-苯基-庚酰基)-苯基]-丁基}酯。
本发明还包括制备式I化合物的方法,该方法包括脱除下式II化合物中R’2中的可水解基团以及氨基的保护基团R’4,
其中m、X、R1和R3的定义同上,
R’2为
R’5和R’6各自独立为可水解基团,
R’4为氨基的保护基团,
并且如果需要,可将所得的游离形式的式I化合物转化为所需的盐形式,反之亦然。
优选R’5和R’6相同并具有以下含义:例如苯基、苄基或者一起构成环状体系例如1,5-二氢-2,4,3-苯并二氧杂磷庚环(benzodioxaphosphepin)。合适的氨基保护基团R’4的实例参见例如“Protective Groups in OrganicSynthesis”T.W.Greene,J.Wiley & Sons NY,第2版,第7章,1991及其参考文献,例如像叔丁氧基-羰基、苄氧基羰基、9-芴基甲氧基羰基、三氟乙酰基、三甲硅烷基乙磺酰基等酰基。
在X为O的化合物中,脱除氨基保护基团和/或R’5或R’6基团可以根据本领域已知方法方便地完成,例如在碱性介质(例如使用氢氧化物如氢氧化钡)中进行水解反应。也可以在例如Pearlman氏催化剂存在下通过氢解完成,参见例如J.Org.Chem.,1998,63,2375-2377中所述的方法。在X直接为键的化合物中,脱除氨基保护基团和/或R’5或R’6基团可以根据本领域已知方法方便地完成,例如在酸性介质中进行水解反应,或通过氢解反应或参见例如G.sapay等Tetrahedron 43(13),2977-2983中公开的方法。
用作原料的式II化合物及其盐也是新化合物并且构成本发明的一部分。
其中X为O的式II化合物可以如下制备:使式IIIa化合物:
其中m、R、R1、R3和R4的定义同上,
与磷酰化剂反应,例如氯代磷酸酯(例如二苯基氯代磷酸酯或二苄基氯代磷酸酯)、氰基乙基磷酸酯、氨基磷酸酯(例如N-苯基氨基磷酸酯)、3-(二乙基氨基)-1,5-二氢-2,4,3-苯并二氧杂磷庚环等。上述反应可以按照本领域已知方法进行,参见例如J.Org.Chem.,同上。当R4不是酰基时,式IIIa化合物中的氨基优选为R’4保护形式。
X直接为键的式II化合物可以如下制备:使式IIIb化合物:
其中R1、,R3、R’4和m的定义同上,且
Y为离去基团,例如Br,
与例如亚磷酸二乙酯在还原条件下(例如在NaH存在下)反应。此反应可以按照本领域已知方法完成,例如参见G.sapay等,同上。
在上述反应中,OH和氨基的保护可以同时如下进行:为了获得由氨基和醇基构成的环状残基(例如噁唑烷-2-酮),使式IIIa或IIIb游离氨基醇或氨基二醇与Cbo-Cl、Boc-酸酐或碳酰氯在碱性条件下反应。
原料的制备没有具体介绍,但是所述化合物为已知化合物或者可以按照类似于本领域的已知方法制备或者参照下文的实施例制备。例如,保护或未保护形式的式IIIa或IIIb化合物,例如其中R4具有R’4的含义,可以参照例如EP-A1-0 627 406、WO 96/06068或EP-A1-1 002 792中所述的方法制备,其内容通过引用结合到本文中。
在式IIIa化合物中,游离形式或盐形式的式X化合物为新化合物并且为本发明的一部分:
其中
n为2、3或4;
R1x为H;任选被OH、酰基、卤素、环烷基、苯基或羟基-亚苯基取代的C1-6烷基;C2-6链烯基;C2-6炔基;或任选被OH取代的苯基;
R2x为H、C1-4烷基或酰基;
R3x和R4x各自独立为H、任选被卤素取代的C1-4烷基或酰基;
R5x为H、C1-4烷基或C1-4烷氧基;且
R6x为被环烷基取代的C1-20链烷酰基;环烷基C1-14烷氧基,其中环烷基环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;苯基C1-14烷氧基,其中苯环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;
R6x还可以在R1x为被OH取代的C3-4烷基时为C4-14烷氧基,或者在R1x为C1-4烷基时为戊氧基或己氧基;
前提是当R5x为H或R1x为甲基时,R6x不为苯基-丁烯氧基。
R6x为C4-14烷氧基时,优选为C5-10烷氧基。
式X化合物可以游离形式或盐形式存在,例如与无机酸的加成盐,例如盐酸盐、氢溴酸盐或硫酸盐;与有机酸的盐,例如乙酸盐、延胡索酸盐、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。式X化合物及其盐的水合物或溶剂化物和形式也是本发明的一部分。
当式X化合物的分子中含有一个或多个不对称中心时,可获得各种旋光异构体。本发明还包括对映异构体、外消旋体、非对映异构体以及它们的混合物。举例来说,式X的中心碳原子可具有R或S构型。当式X化合物包括几何异构体时,则本发明包括顺式化合物、反式化合物以及它们的混合物。类似原则也适用于具有不对称碳原子的原料。
式X化合物可以按照本领域已知的方法制备,例如参照EP-A1-0 778263或EP-A1-0 627 406中的方法,例如式X化合物中R1x或R2x包含羟基保护基团时,脱除R1x或R2x的羟基-保护基团,或者式X化合物中R4x或R3x包含氨基保护基团时,脱除R4x或R3x的氨基保护基团,例如参照实施例17-27中的方法。如果R3x和R4x之一为氨基保护基团,则另一基团优选为H。其中R1x和R2x各自包含末端羟基的式X化合物,还可以通过噁唑烷-2-酮环或按照EP-A1-0 778,263中介绍的更高级同系物中间步骤制备。如果需要,所得的式X化合物游离形式可以转化为所需的盐形式,反之亦然。式X化合物可以按照例如以下流程制备:
其中R’6x为C4-14烷基、环烷基C1-14烷基或苯基C1-14烷基,其中环烷基环或苯环如同R6x的定义任选被取代。R6x为C1-20链烷酰基的式X化合物可以用醛作原料参照EP-A1-1 002 792进行制备,接着进行Grignard反应引入所需的R6x基团。
原料的制备没有具体介绍,但是所述化合物为已知的或者可以按照类似于本领域的已知方法制备或者参照下文的实施例制备,例如实施例6。
以下实施例示例性地说明本发明。
RT =室温
DMF =二甲基甲酰胺
Fmoc =9-芴基甲氧基羰基
Boc =叔丁氧基羰基
Cbo =羧基苯甲酸基
TEA =三乙胺
HOSu =羟基丁二酰亚胺
FTY720 =2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇
实施例1:磷酸单-{2-氨基-2-羟基甲基-4-[4-(5-苯基-戊酰基)-苯基]-丁基}酯
a){1,1-双-羟基甲基-3-[4-(5-苯基-戊酰基)-苯基]-丙基}-氨基甲酸9H-
芴-9-基甲基酯
将1-[4-(3-氨基-4-羟基-3-羟基甲基-丁基)-苯基]-5-苯基-戊-1-酮(1.07g,3mmol)溶于DMF/水(100ml,8/2)中。加入NaHCO3(1g)和FmocHOSu(1.21g,3.6mmol)后,使反应在RT下进行24小时。然后将反应物倾入碳酸氢钠水溶液(6%,500ml)中,滤出形成的沉淀,干燥。用环己烷/乙酸乙酯(1/1)作为流动相在硅胶上提纯所得Fmoc保护的化合物。
[M+H]+:558(ESI-MS)
b){1-(二苯氧基-磷酰氧基甲基)-1-羟基甲基-3-[4-(5-苯基-戊酰基)-苯基]-丙基}-氨基甲酸9H-芴-9-基甲基酯
将步骤a)的化合物(1.1g,2mmol)溶于二氯甲烷(100ml)中,然后用TEA(0.42ml;3mmol)和二苯基磷酰氯(0.45ml,2.2mmol)处理。在室温下16小时后,反应介质用0.5N HCl萃取,分离出有机相,干燥后浓缩。用环己烷/乙酸乙酯(3/1)作为流动相在硅胶上提纯粗制化合物。
[M+H]+:809(ESI-MS)
c)磷酸单-[2-氨基-2-羟基甲基-4-(4-辛基-苯基)-丁基]酯
将步骤b)的化合物(0.32g,0.4mmol)溶于乙醇/水(10ml,3/2),加入后氢氧化钡-八水合物(0,56mg,1.8mmol)在75℃保持14h。冷却至室温后,浆状物用固体二氧化碳中和后过滤。将残余物溶于乙酸(95%;5ml),然后用水稀释至50ml。滤出形成的沉淀,用P4O10干燥。
NMR,CD3OD+0.1N DCl,δ(ppm):1.70(m,4H,ArCH2CH2CH2CH2),2.02(q,2H,CH2CH2C),2.65(t,2H,CH2Ph),2.78(m,2H,CH2CO),3.01(t,2H,COArCH2),3.73(s,2H,CH2OH)4.16(2H,CH2OP),7.10-7.25(m,5H,芳族CH),7.38(d,2H,芳族CH),7.91(d,2H,芳族CH)。MS:(ES-):434.3(M-H)-
实施例2:磷酸单-{2-氨基-4-[4-(5-环己基-戊酰基)-苯基]-2-羟基甲基-丁基}酯
按照实施例1中介绍的方法,采用适当的原料制备获得以下化合物:
NMR,CD3OD+0.1N DCl,δ(ppm):).85-1.80(m,15H,脂族H),2.02(m,2H,CH2CH2C),2.80(m,2H,CH2Ph),3.34(t,2H,CH2CO),3.74(s,2H,CH2OH)4.02(t,2H,CH2OP),7.43(d,2H,芳族CH),7.95(d,2H,芳族CH),
MS:(ES-):440.3(M-H)-;MS:(ES+):442.3(MH+)
实施例3:磷酸单-{2-氨基-2-羟基甲基-4-[4-(1-羟基-5-苯基-戊基)-苯基]-丁基}酯
该化合物通过还原保护形式的实施例2化合物获得。
MS(ES)438.2[M+H]+
实施例4:磷酸单-{2-氨基-2-羟基甲基-4-[4-(7-苯基-庚酰基)-苯基]-丁基}酯
按照实施例1中介绍的方法,采用适当的原料制备获得以下化合物:
MS(ES)463.2[M+H]+
实施例5:磷酸单-{2-氨基-2-羟基甲基-4-[4-(7-苯基-庚酰基)-苯基]-丁基}酯
该化合物通过还原保护形式的实施例4化合物获得。
MS(ES)464.2[M+H]+
实施例6:磷酸单-{(R)-2-氨基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-2-甲基-丁基}酯
在室温下,将步骤i)终产物(60mg;0.11mmol)用冰醋酸(1ml)和浓HCl(0.1ml)处理30min。用水(10ml)稀释后,冷冻干燥反应混合物。获得无需再提纯的纯标题化合物。
MS(ES)438.2[M+H]+
a)2-[3-甲氧基-4-(4-苯基-丁氧基)-苯基}-乙醇
向高香草醇(10g,59.3mmol)的无水甲醇(140ml)溶液中加入12ml1N NaOCH3的甲醇溶液。加入1-溴-4-苯基丁烷(12.6g,59.3mmol)的THF(10ml)溶液后,将反应混合物保持回流3h。冷却后,反应混合物用饱和NaHCO3水溶液猝灭,用乙酸乙酯萃取(2次,每次500ml)。有机层用硫酸镁干燥,蒸发除去溶剂。然后用乙酸乙酯/正己烷(1/1)作为流动相在硅胶上提纯粗制残余物。
b)4-(2-碘-乙基)-2-甲氧基-1-(4-苯基-丁氧基)-苯
将三乙胺(5.3ml)加入步骤a)终产物(8.1g;27mmol)的无水二氯甲烷(150ml)溶液中。冷却反应混合物至0℃,加入甲磺酰氯(2.5ml;32.4mmol)后,反应物保持在0℃ 30min。用水猝灭后,有机层用硫酸镁干燥,蒸发至获得无色油状物。将残余物溶于无水丙酮(200ml),加入NaI(5.3g;35.1mmol),反应混合物在室温下保持14h,然后回流4h。过滤并蒸发后,将残余物溶于乙酸乙酯,用水萃取(2次)。有机相用硫酸镁干燥,减压除去溶剂。用乙醚/己烷重结晶获得纯结晶终产物。
c)(2R,5S)-3,6-二乙氧基-2-异丙基-5-{2-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-乙基}-2,5-二氢-吡嗪
在-78℃,向(R)-3,6-二乙氧基-2-异丙基-2,5-二氢-吡嗪(2.2g;10.4mmol;Lohr,Birgit等,Synlett,1999,7,1139-1141)的无水THF(30ml)溶液中加入正丁基锂(6.5ml;10.4mmol;1.6M的正己烷溶液)。在-78℃保持30分钟后,在10分钟内滴加溶于无水THF(15ml)的步骤b)终产物(4.3g;10.4mmol)。反应混合物升至室温,在室温保持20h。用饱和氯化铵水溶液猝灭并用乙酸乙酯萃取(2次)后,有机相用硫酸镁干燥,减压浓缩。用乙醚/正己烷(1/9)作为流动相在硅胶上提纯粗制产物。
d)(2R,5R)-3,6-二乙氧基-2-乙基-5-异丙基-2-{2-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-乙基}-2,5-二氢-吡嗪
在-78℃下,向步骤c)终产物(2.5g;5.0mmol)的无水THF(10ml)溶液中加入正丁基锂(3.4ml;5.5mmol;1.6M的正己烷溶液)。在-78℃保持30min后,在10分钟内滴加溶于无水THF(15ml)的甲基碘(0.37ml;6mmol)。反应混合物升至室温,在室温保持3h。用饱和氯化铵水溶液猝灭并用乙酸乙酯萃取(2次)后,有机相用硫代硫酸钠溶液萃取,随后用硫酸镁干燥,减压浓缩。用乙醚/正己烷(5/95)作为流动相在硅胶上提纯粗制产物。
e)(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁酸乙酯
将TFA(60ml;1M的水溶液)的水溶液加入步骤d)终产物(1.3g;3.0mmol)的乙腈(90ml)溶液中。在室温下6天后,将澄清溶液调节至pH8(饱和NaHCO3溶液),用乙酸乙酯萃取(2次)。有机层用硫酸镁干燥,蒸发,用乙酸乙酯作流动相在硅胶上提纯残余物。
f)(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇
将LiAlH4(1.13ml;1.13mmol;1M的THF溶液)加入步骤e)终产物(0.31g;0.75mmol)的无水THF(91ml)溶液中。回流30分钟后,冷却至室温,用0.4ml饱和Na2SO4水溶液小心地猝灭反应混合物。过滤后减压蒸发溶液,用乙酸乙酯/甲醇(9/1)作为流动相在硅胶上提纯残余物。MS(ES+):358.3[MH+]
g)N-Boc-(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇
向(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇(2.4g;6.5mmol)的二氯甲烷溶液中加入三乙胺(1.08ml;7.8mmol)和二碳酸二叔丁酯(1.56g;7.15mmol)。进一步加入二氯甲烷(10ml)和THF(5ml)后,反应混合物在室温下保持14h。减压蒸去溶剂,用乙酸乙酯/正己烷重结晶获得纯标题化合物。MS(ES)458.3[M+H]+
h)[(R)-3-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-1-甲基-1-(3-氧代-1,5-二氢-3λ*5*-苯并[e][1,3,2]二氧杂磷庚环-3-基氧基甲基)-丙基]-氨基甲酸叔丁基酯
向N-Boc-(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇(0.23g;0.5mmol)的THF溶液(5ml)溶液中加入N,N-二乙基-1,5-二氢-2,4,3-苯并二氧杂磷庚环-3-胺(0.24g;1mmol)和四唑(0.11g;1.5mmol)。在室温下2h后加入H2O2(30%的水溶液;0.58ml),混合物在室温再保持2h。反应混合物用Na2S2O3猝灭,用乙酸乙酯萃取,然后用柠檬酸水溶液和饱和NaHCO3水溶液洗涤。将有机层干燥、浓缩,然后用二氯甲烷/乙醇(95/5)作为流动相在硅胶上提纯。
i){(R)-3-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-1-甲基-1-膦酰氧基甲基-丙基}-氨基甲酸叔丁基酯
将步骤h)终产物(82mg;0.13mmol)溶于乙醇/乙酸乙酯(30ml 2/1),用催化剂Pd/C10%在常压下氢化2h。过滤并蒸发后,分离出无色油状标题化合物。
MS(ES)538,3[M+H]+
实施例7:磷酸单-{(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁基}酯
用乙基碘替代实施例6步骤d)中的甲基碘。MS(ES)452.2[M+H]+
实施例8:磷酸单-{(R)-2-氨基-2-甲基-4-[4-(3-苯基-丙氧基)-苯基]-丁基}酯
以下步骤f)终产物用冰醋酸(1ml)和浓HCl(0.1ml)在室温下处理30min。用水(10ml)稀释后冷冻干燥反应混合物。获得无需再提纯的纯标题化合物。
NMR,DMSO,δ(ppm):1.29(s,3H,CCH3),1.82(m,2H,CCH2),2.02(五重峰,2H,CH2CH2CH2),2.58(m,2H,CH2PhO),2.77(t,2H,PhCH2),3.80-3.98(4H,CH2O),6.88(d,2H,芳族CH),7.12(d,2H,芳族CH),7.18-7.35(m,5H,芳族CH)。
MS(ES-):785.3(2M-H),392.3(M-H)。
a)(R)-2-氨基-4-(4-苄氧基-苯基)-2-甲基-丁-1-醇
用2-[4-(苄氧基)苯基]乙基溴替代实施例6步骤c)的4-(2-碘-乙基)-2-甲氧基-1-(4-苯基-丁氧基)-苯。MS(ES)286.2[M+H]+
b)N-Boc-(R)-2-氨基-4-(4-苄氧基-苯基)-2-甲基-丁-1-醇
向(R)-2-氨基-4-(4-苄氧基-苯基)-2-甲基-丁-1-醇(1.85g;6.5mmol)的二氯甲烷溶液中加入三乙胺(1.08ml;7.8mmol)和二碳酸二叔丁酯(1.56g;7.15mmol)。进一步加入二氯甲烷(10ml)和THF(5ml)后,反应混合物在室温下保持14h。减压蒸去溶剂,用乙酸乙酯/正己烷重结晶获得纯标题化合物。MS(ES)386.2[M+H]+
c)N-Boc-(R)-2-氨基-4-(4-羟基-苯基)-2-甲基-丁-1-醇
将步骤i)终产物(2.4g;6.2mmol)的乙醇(240ml)溶液用Pd/C10%(300mg)在常压下氢化。3小时后滤出催化剂,减压浓缩滤液。用乙醇/乙醚/正己烷重结晶纯化。MS(ES)296.2[M+H]+
d)N-Boc-(R)-2-氨基-2-甲基-4-[4-(3-苯基-丙氧基)-苯基]-丁-1-醇
将K2CO3(233mg;1.7mmol)和(3-溴-丙基)-苯(0.16g;0.82mmol)加入步骤b)终产物(200mg;0.68mmol)的乙醇(4ml)溶液。在50℃ 6h后,再次加入(3-溴-丙基)-苯(0.1g g;0.82mmol),反应混合物在50℃再保持14h。冷却后,反应混合物用乙酸乙酯稀释,用水萃取(2次)。有机相用硫酸镁干燥,浓缩,用乙醚/正己烷作为流动相在硅胶上提纯粗制产物。MS(ES)413.3[M+H]+
e) & f){(R)-1-甲基-3-[4-(3-苯基-丙氧基)-苯基]-1-膦酰氧基甲基-丙基}-氨基甲酸叔丁基酯
根据实施例6步骤h) & i)介绍的方法合成制得。MS(ES)494.2[M+H]+
实施例9:磷酸单-{(R)-2-氨基-4-[4-(4-乙基-苄氧基)-苯基]-2-甲基-丁基}酯
按照实施例8的方法,在步骤d)用(4-乙基-苯基)-甲醇的甲磺酸酯替代(3-溴-丙基)-苯合成制得。MS(ES)394.2[M+H]+
实施例10:磷酸单-((R)-2-氨基-4-{4-[3-(4-甲氧基-苯基)-丙氧基]-苯基}-2-甲基-丁基)酯
按照实施例8的方法,在步骤d)用3-(4-甲氧基-苯基)-丙-1-醇的甲磺酸酯替代(3-溴-丙基)-苯合成制得。MS(ES)324.2[M+H]+
实施例11:磷酸单-{(R)-2-氨基-4-[4-(3-环己基-丙氧基)-苯基]-2-甲基-丁基}酯
按照实施例8的方法,在步骤d)用3-环己基-丙-1-醇的甲磺酸酯替代(3-溴-丙基)-苯合成制得。
MS(ES)400.2[M+H]+
实施例12:磷酸单-{(R)-2-氨基-2-甲基-4-[4-(5-苯基-戊氧基)-苯基]-丁基}酯
按照实施例8的方法,在步骤d)用1-溴-5-苯基戊烷替代(3-溴-丙基)-苯合成制得。
MS(ES)422.2[M+H]+
实施例13:磷酸单-{(R)-2-氨基-2-甲基-4-[4-(4-苯基-丁氧基)-苯基]-丁基}酯
按照实施例8的方法,在步骤d)用1-溴-4-苯基丁烷替代(3-溴-丙基)-苯合成制得。MS(ES)408.2[M+H]+
实施例14:磷酸单-{(S)-2-氨基-2-[2-(4-庚氧基-苯基)-乙基]-戊-4-炔基}酯
按照实施例6的方法,在步骤c)用1-庚氧基-4-(2-碘-乙基)-苯替代4-(2-碘-乙基)-2-甲氧基-1-(4-苯基-丁氧基)-苯并且在步骤d)用3-溴-1-丙炔替代甲基碘合成制得。
NMR,DMSO,δ(ppm):0.90(t,3H,CH2CH3),1.22-1.45(br,8H,(CH2)4),1.70(五重峰,2H,CH2CH2O),1.90(m,2H,CCH2),2.59(m,2H,CH2Ph),2.67(d,2H,HCCCH2),3.18(CCH),3.93(m,4H,CH2O),6.87(d,2H,芳族CH),7.12(d,2H,芳族CH)。
MS(ES-):793.3(2M-H),396(M-H);MS(ES+):795.3(2M+H),398.3(MH)。
实施例15:磷酸单-[(R)-2-氨基-2-甲基-4-(4-戊氧基-苯基)-丁基]酯)
NMR,DMSO,δ(ppm):0.92(t,3H,CH2CH3),1.29(s,3H,CCH3),1.30-1.50和1.65-1.95(br,8H,CH2CH2CH2,CCH2),2.55(m,2H,CH2Ph),3.80-3.98(4H,CH2O),6.87(d,2H,芳族CH),7.12(d,2H,芳族CH)。
MS(ES-):689.3(2M-H),380(M+Cl),344(M-H)。
实施例16a:磷酸单-[(R)-2-氨基-4-(4-己氧基-苯基)-2-甲基-丁基]酯
MS(ES)360.4[M+H]+
实施例16b:磷酸单-[(R)-2-氨基-2-乙基-4-(4-庚氧基-苯基)-丁基]酯
NMR,DMSO,δ(ppm):0.91(2x t,6H,CCH3,CH2CH3),1.23-1.48和1.64-1.83(br,14H,CH2CH3,CCH2,(CH2)5),2.55(m,2H,CH2Ph),3.93(m,4H,CH2O),6.87(d,2H,芳族CH),7.12(d,2H,芳族CH)。
MS(ES-):773.4(2M-H),386.3(M-H)。
实施例17:(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇
除了在步骤d)用乙基碘(0.48ml;6mmol)替代甲基碘外,标题化合物按照实施例6步骤a)至f)的方法制备。MS(ES+):372.3[MH+]
实施例18:(R)-2-乙基-4-(4-庚基氧基-苯基)-2-甲基氨基-丁-1-醇
在实施例步骤6c)中用1-庚氧基-4-(2-碘-乙基)-苯(参照WO 9408943A1)替代4-(2-碘-乙基)-2-甲氧基-1-(4-苯基-丁氧基)-苯。MS(ES+):322.3[MH+]
(R)-2-氨基-2-乙基-4-(4-庚氧基-苯基)-丁酸乙酯的N-甲基化反应如下进行:
将(R)-2-氨基-2-乙基-4-(4-庚氧基-苯基)-丁酸乙酯(175mg;0.5mmol)溶于二氯甲烷(2l)和甲酸(100μl),加入p-甲醛(100μl;30%的水溶液)和NaBH3CN。在室温下1h后,反应混合物用饱和NaHCO3水溶液萃取,有机层用硫酸镁干燥,用正己烷/乙酸乙酯(1/1--->1/9)作为流动相在硅胶上提纯。
实施例19:(S)-2-氨基-2-(2-苄氧基-乙基)-4-(4-庚氧基-苯基)-丁-1-醇
在实施例6)步骤c)用1-庚氧基-4-(2-碘-乙基)-苯替代4-(2-碘-乙基)-2-甲氧基-1-(4-苯基-丁氧基)-苯并且在实施例6)步骤d)用苄基(3-溴-丙氧基甲基)-苯替代乙基碘。
MS(ES+):428.3[MH+]
实施例20:(S)-2-氨基-2-[2-(4-庚氧基-苯基)-乙基]-丁烷-1,4-二醇
将实施例19终产物(43mg;0.1mmol)的乙醇(2.5ml)溶液在常压下用Pd(OH)2(120mg,分3次加入)氢化。三天后滤除催化剂,减压浓缩溶液。用硅胶提纯(叔丁基甲基醚/甲醇/NH4OH25%(90/10/1-->75/25/1))获得纯终产物。MS(ES+):338.3[MH+]
实施例21:(R)-2-氨基-2-甲基-4-(4-戊氧基-苯基)-丁-1-醇
在室温下将步骤iii)终产物(50mg;0.14mmol)用冰醋酸(0.5ml)和浓HCl(0.05ml)处理20min。反应混合物用乙酸乙酯(2ml)稀释,然后用乙醚(20ml)处理获得白色沉淀。将沉淀滤出,用乙醚洗涤2次,干燥。
MS(ES+):266.2[MH+]
i)N-Boc-(R)-2-氨基-4-(4-苄氧基-苯基)-2-甲基-丁-1-醇按照实施例8b)的方法制备。
ii)N-Boc-(R)-2-氨基-4-(4-羟基-苯基)-2-甲基-丁-1-醇按照实施例8c)的方法制备。
iii)N-Boc-(R)-2-氨基-4-(4-戊氧基-苯基)-2-甲基-丁-1-醇
向步骤ii)终产物(200mg;0.68mmol)的乙醇(4ml)溶液中加入K2CO3(233mg;1.7mmol)和1-碘代戊烷(0.11ml;0.82mmol)。在50℃ 6h后,再次加入1-碘代戊烷(0.11ml;0.82mmol),反应混合物在50℃再保持14h。冷却后,反应混合物用乙酸乙酯稀释,用水萃取(2次)。有机相用硫酸镁干燥,浓缩,用乙醚/正己烷作为流动相在硅胶上提纯粗制产物。
实施例22:(R)-2-氨基-2-甲基-4-[4-(5-苯基-戊氧基)-苯基]-丁-1-醇
在实施例21步骤iii)中用1-溴-5-苯基-正戊烷替代1-碘代戊烷。
MS(ES+):342.3[MH+]
实施例23:(R)-2-氨基-2-甲基-4-[4-(3-苯基-丙氧基)-苯基]-丁-1-醇
在实施例21步骤iii)中用1-溴-3-苯基-丙烷替代1-碘代戊烷。
MS(ES+):314.2[MH+]
实施例24:(R)-2-氨基-4-[4-(4-乙基-苄氧基)-苯基]-2-甲基-丁-1-醇
在实施例21步骤iii)中用(4-乙基-苯基)-甲醇的甲磺酸酯[根据实施例6步骤b)合成]替代1-碘代戊烷。
MS(ES+):314.2[MH+]
实施例25:(R)-2-氨基-4-[4-(4-乙基-苄氧基)-苯基]-2-甲基-丁-1-醇
在实施例21步骤iii)中用3-(4-甲氧基-苯基)-丙-1-醇的甲磺酸酯[根据实施例6步骤b)合成]替代1-碘代戊烷。
MS(ES+):344.2[MH+]
实施例26:(R)-2-氨基-4-[4-(3-环己基-丙氧基)-苯基]-2-甲基-丁-1-醇
在实施例21步骤iii)中用3-环己基-丙-1-醇的甲磺酸酯[根据实施例6步骤b)合成]替代1-碘代戊烷。MS(ES+):320.3[MH+]
实施例27:1-[4-(3-氨基-4-羟基-3-羟基甲基-丁基)-苯基]-5-环己基-戊-1-酮
根据US 6,214,873 B1(col.20)使用(4-溴-丁基)-环己烷替代(4-溴-丁基)-苯进行Grignard反应合成此化合物。
MS(ES+):362.3[MH+]
游离形式或其药学上可接受的盐形式的式I化合物和式X化合物(下文统称为“本发明化合物”)具有多种有意义的药理作用,例如调节淋巴细胞再循环作用,例如体外和体内测试显示的作用,因此表明本发明化合物可以用于治疗。
A.体外测试
本发明化合物对个别人S1P受体具有结合亲合力,见以下检测测定结果。
瞬时转染人S1P受体到HEK293细胞
克隆EDG受体和Gi蛋白质,混合等量的4种EDG受体、Gi-α、Gi-β和Gi-γ的cDNAs,采用磷酸钙沉淀法转染单层HEK293细胞(M.Wigler等,Cell.1977,;11;223和DS.Im等,Mol.Pharmacol.2000;57;753)。简单地讲,将包含25μgDNA和0.25M CaCl2的DNA混合物加入HEPES-缓冲的2mM Na2HPO4中。用25mM氯喹使接近汇合的单层HEK293细胞中毒,然后将DNA沉淀加入细胞中。4h后,用磷酸缓冲盐水洗涤单层细胞,然后再加入培养基(90% 1∶1 Dulbecco氏改良基本培养液(DMEM):F-12+10%胎牛血清)。加入DNA后48-72h,在冰上于包含10%蔗糖的HME缓冲液(20mM HEPES,5mM MgCl2,1mM EDTA,pH7.4)中刮擦收获细胞,之后用Dounce匀浆器破碎细胞。800×g离心后,上清液用不含蔗糖的HME稀释,以100,000×g离心1h。将所得沉淀再次均浆后再以100,000×g离心1h。将粗制膜沉淀重新悬浮于含蔗糖的HME,等分试样,然后浸入液氮中快速冷冻。70℃贮存膜。蛋白质浓度按照Bradford蛋白质检测法用光谱检测。
用S1P受体/HEK293膜制剂检测GTPγ
S结合
GTPγS结合试验按照DS.Im等,Mol.Pharmacol.2000;57:753介绍方法进行。在GTP结合缓冲液(50mM HEPES、100mM NaCl、10mM MgCl2,pH7.5)中用25μg瞬间转染的HEK293细胞膜制剂检测配体-介导的GTPγS与G-蛋白的结合。在10μM GDP和0.1nM[35S]GTPγS(1200Ci/mmol)存在下,将配体加入膜制剂中,在30℃温育30min。用Brandel收集器(Gaithersburg,MD)将结合的GTPγS与未结合的GTPγS分开,用液体闪烁计数器计数。
在上述检测中,本发明化合物对S1P受体在亚μM浓度范围具有结合亲合力。
B.体内测试:减少血液淋巴细胞作用
管饲法口服给予大鼠本发明化合物或溶媒。采集尾部血液用于血液学监测,给药前一天采血检测获得个体基础值,并在给药后2、6、24、48和72h采血。在本检测中,当给予0.03-3mg/kg的剂量时,本发明化合物减少外周血液淋巴细胞。例如,分别以0.4、0.6、0.5、0.1、0.05、0.2和0.3mg/kg的剂量给予实施例1、2、6f、20、22、23、26化合物24小时后,可减少外周血液淋巴细胞50%以上。
因此,本发明化合物可用于治疗和/或预防以下疾病或病症:例如移植时淋巴细胞相互作用介导性疾病或病症,例如细胞、组织或器官的同种移植或异种移植的急性或慢性排斥反应、移植物功能恢复延迟、移植物抗宿主疾病;自身免疫疾病,例如类风湿关节炎、系统性红斑狼疮、桥本氏甲状腺炎、多发性硬化、重症肌无力、I型或II型糖尿病及其并发病症、结节性脉管炎、恶性贫血、Sjoegren综合症、眼色素层炎、牛皮癣、Grave氏眼病、斑形脱发等;过敏性疾病,例如变应性气喘、特应性皮炎、变应性鼻炎/结膜炎、过敏性接触性皮炎;任选伴有异常反应的炎性疾病,例如炎性肠病、克罗恩氏病或溃疡性结肠炎、内因性哮喘、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湿疹性皮炎、脂溢性皮炎、免疫性疾病的皮肤表现、炎性眼病、角膜结膜炎、心肌炎或肝炎;局部缺血/再灌注损伤,例如心肌梗塞、中风、肠局部缺血、肾衰竭或出血性休克、外伤性休克等;癌症,例如T细胞淋巴瘤或T细胞白血病;传染性疾病,例如中毒性休克(例如超敏抗原诱导性)、脓毒性休克、成人呼吸窘迫综合征;病毒感染,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实例包括例如胰岛、干细胞、骨髓、角膜组织、神经组织、心脏、肺、心肺、肾、肝、肠、胰腺、气管或食管移植。本发明化合物没有鞘氨醇-1磷酸具有的负面变时作用。
当然对于上述用途,所需剂量会因为给药方式、需要治疗的具体疾病以及所需的效果不同而不同。一般来说,获得系统性满意结果的日剂量约为0.03-2.5mg/kg体重。较大哺乳动物例如人的建议日剂量范围约为0.5mg至约100mg,以适当方式用药,例如最多以每日4次分剂量用药或使用延迟剂型。合适的口服单位剂型包含约1-50mg活性成分。
本发明化合物可以通过任何常规途径给药,尤其是肠道给药(例如口服片剂或胶囊剂),或者胃肠外给药(例如注射溶液剂或混悬剂)、局部用药(例如洗剂、凝胶剂、软膏或乳膏)或者鼻内给药或以栓剂形式给药。包含本发明化合物游离形式或其药学上可接受的盐形式和至少一种药学上可接受载体或稀释剂的药用组合物可以按照常规方法用本发明化合物与药学上可接受的载体或稀释剂混合制备。
本发明化合物的使用形式可以为例如如上所述的游离形式或其药学上可接受的盐形式。所述盐可以按照常规方法制备并且具有与游离化合物相同的活性。
根据前述内容,本发明进一步提供:
1.1一种预防或治疗需要这种治疗的患者淋巴细胞介导性病症或疾病(例如上述病症或疾病)的方法,该方法包括给予所述患者有效量的本发明化合物或其药学上可接受的盐;
1.2一种预防或治疗需要这种治疗的患者慢性或急性移植排斥或T细胞介导的炎症或自身免疫性疾病(例如上述疾病)的方法,该方法包括给予所述患者有效量的本发明化合物或其药学上可接受的盐;
2.作为药物的游离形式或其药学上可接受的盐形式的本发明化合物,例如在以上1.1或1.2任一所述方法中作为药物。
3.一种药用组合物,例如用于以上1.1或1.2中的任何方法,该组合物包含游离形式或其药学上可接受的盐形式的本发明化合物和药学上可接受的稀释剂或载体。
4.用于制备在以上1.1或1.2的任一方法中使用的药用组合物的本发明化合物或其药学上可接受的盐。
本发明化合物可以为唯一活性成分用药或与(例如作为辅助剂)其它药物联合用药,例如用于治疗或预防同种移植或异种移植的急性或慢性排斥反应、炎性病症或自身免疫性病症的免疫抑制剂、免疫调节剂或其它抗炎药物,或者与化疗药物(例如抗恶性细胞增殖药)联合用药。举例来讲,本发明化合物可与以下药物联合应用:钙调磷酸酶抑制剂,例如环孢菌素A或FK 506;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟基乙基)-雷帕霉素、CCI779或ABT578;具有免疫抑制作用的子囊霉素,例如ABT-281、ASM981等;皮质类固醇类;环磷酰胺;硫唑嘌呤(azathioprene);甲氨蝶呤;来氟米特;咪唑立宾;霉酚酸;麦考酚酸吗乙酯;15-脱氧精胍菌素或它们的免疫抑制的同系物、类似物或衍生物;免疫抑制单克隆抗体,例如白血细胞受体(例如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD58、CD80、CD86或它们的配体)的单克隆抗体;其它免疫调节化合物,例如至少具有CTLA4或其突变体的胞外域部分的重组结合分子,例如至少具有结合非CTLA4蛋白序列的CTLA4或其突变体的细胞外部分(例如CTLA4Ig(例如ATCC 68629)或其突变体,例如LEA29Y);粘连分子抑制剂,例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂;或者化疗药物,例如紫杉醇、吉西他滨、顺铂、阿霉素或5-氟尿嘧啶。
当本发明化合物结合其它免疫抑制/免疫调节、抗炎或化疗治疗用药时,联合给予的免疫抑制、免疫调节、抗炎或化疗的化合物的剂量必将根据使用的联合药物的类型(例如无论是类固醇还是钙调磷酸酶抑制剂)、使用的具体药物、所治疗的疾病等变化。根据前述内容,本发明还提供:
5.一种以上定义的方法,包括联合给予(例如同时或序贯)治疗有效、无毒量的本发明化合物和至少一种另外的药物,例如上述的免疫抑制剂、免疫调节剂、抗炎或化疗药物。
6.一种药用组合品,例如药盒,包括a)第一种药物,为游离形式或其药学上可接受的盐形式的本发明公开的化合物;b)至少一种联合药物,例如免疫抑制剂、免疫调节剂、抗炎或化疗药物。所述药盒包含其使用说明。
本文使用的术语“联合给药”等是指包括给予一个患者选定的多种治疗药物并且包括其中各药物不一定以相同给药途径或相同时间给药的治疗方案。
本文使用的术语“药用组合”是指混合或组合一种以上活性成分获得的产品并且该产品既包括各活性成分固定组合的产品也包括各活性成分非固定组合的产品。术语“固定组合”是指各种活性成分例如本发明化合物和一种联合药物二者以一种药物实体或剂型同时给予患者。术语“非固定组合”是指各种活性成分例如本发明化合物和一种联合药物二者以独立的两种实体同时、并行或序贯(没有特殊的给药时间限制)给予患者,其中这种给药方法使两种化合物在患者体内都达到治疗有效水平。后者还适用于混合疗法,例如给予3种或3种以上的活性成分。
本发明的优选化合物为实施例1的化合物。
Claims (10)
1.游离形式或盐形式的式I化合物:
其中:
m为1、2或3;
X为O或直接为键;
R1为H;任选被OH、酰基、卤素、环烷基、苯基或羟基-亚苯基取代的C1-6烷基;C2-6链烯基;C2-6炔基;或任选被OH取代的苯基;
R2为
其中R5为H或任选被1、2或3个卤原子取代的C1-4烷基,R6为H或任选被卤素取代的C1-4烷基;
R3和R4各自独立为H、任选被卤素取代的C1-4烷基或酰基;
R为C13-20烷基,它可以在链中任选包含氧原子并且任选被硝基、卤素、氨基、羟基或羧基取代;或者为式(a)残基:
其中R7为H、C1-4烷基或C1-4烷氧基;
R8为取代的C1-20链烷酰基;苯基C1-14烷基,其中C1-14烷基任选被卤素或OH取代;环烷基C1-14烷氧基或苯基C1-14烷氧基,其中环烷基环或苯环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;苯基C1-14烷氧基C1-14烷基;苯氧基C1-14烷氧基或苯氧基C1-14烷基;
当R1为C1-4烷基、C2-6链烯基或C2-6炔基时,R也可以为其中R8为C1-14烷氧基的式(a)残基。
2.权利要求1的化合物,其中R为式(a)残基。
3.游离形式或盐形式的式X化合物:
其中:
n为2、3或4;
R1x为H;任选被OH、酰基、卤素、环烷基、苯基或羟基-亚苯基取代的C1-6烷基;C2-6链烯基;C2-6链炔基;或任选被OH取代的苯基;
R2x为H、C1-4烷基或酰基;
R3x和R4x各自独立为H、任选被卤素取代的C1-4烷基或为酰基;
R5x为H、C1-4烷基或C1-4烷氧基;且
R6x为环烷基取代的C1-20链烷酰基;环烷基C1-14烷氧基,其中环烷基环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;苯基C1-14烷氧基,其中苯环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;
R6x也可以在R1x为OH取代的C3-4烷基时为C4-14烷氧基,或者在R1x为C1-4烷基时为戊氧基或己氧基;
前提是当R5x为H或R1x为甲基时,R6x不为苯基-丁烯氧基。
4.权利要求3的化合物,其中n为2。
5.权利要求3的化合物,其中R6x为环烷基取代的链烷酰基;环烷基C1-14烷氧基,其中环烷基环任选被卤素、C1-4烷基和/或C1-4烷氧基取代;苯基C1-14烷氧基,其中苯环任选被卤素、C1-4烷基和/或C1-4烷氧基取代。
6.权利要求1的化合物,所述化合物选自磷酸单-{2-氨基-2-羟基甲基-4-[4-(5-苯基-戊酰基)-苯基]-丁基}酯、磷酸单-{2-氨基-4-[4-(5-环己基-戊酰基)-苯基]-2-羟基甲基-丁基}酯、磷酸单-{2-氨基-2-羟基甲基-4-[4-(7-苯基-庚酰基)-苯基]-丁基}酯、磷酸单-{(R)-2-氨基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-2-甲基-丁基}酯、磷酸单-{(R)-2-氨基-2-甲基-4-[4-(5-苯基-戊氧基)-苯基]-丁基}酯和磷酸单-[(R)-2-氨基-4-(4-己氧基-苯基)-2-甲基-丁基]酯,或者它们的盐。
7.权利要求3的化合物,所述化合物选自(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇、(R)-2-氨基-2-乙基-4-[3-甲氧基-4-(4-苯基-丁氧基)-苯基]-丁-1-醇、(R)-2-氨基-2-甲基-4-[4-(5-苯基-戊氧基)-苯基]-丁-1-醇、(R)-2-氨基-2-甲基-4-[4-(3-苯基-丙氧基)-苯基]-丁-1-醇、(R)-2-氨基-4-[4-(3-环己基-丙氧基)-苯基]-2-甲基-丁-1-醇和1-[4-(3-氨基-4-羟基-3-羟基甲基-丁基)-苯基]-5-环己基-戊-1-酮,或者它们的盐。
8.用作药物的游离形式或其药学上可接受的盐形式的权利要求1或3的化合物。
9.一种药用组合物,该组合物包含游离形式或其药学上可接受的盐形式的权利要求1或3的化合物和药学上可接受的稀释剂或载体。
10.一种预防或治疗需要这种治疗的患者T淋巴细胞性病症或疾病的方法,该方法包括给予所述患者有效量权利要求1或3的化合物或其药学上可接受的盐。
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ES2254675T3 (es) | 2006-06-16 |
NO20034291L (no) | 2003-11-24 |
EP1377593A2 (en) | 2004-01-07 |
CA2442178A1 (en) | 2002-10-03 |
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BR0208365A (pt) | 2004-03-09 |
PL367348A1 (en) | 2005-02-21 |
US20040147490A1 (en) | 2004-07-29 |
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US7326801B2 (en) | 2008-02-05 |
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SK11942003A3 (sk) | 2004-03-02 |
CZ20032560A3 (cs) | 2003-12-17 |
DK1377593T3 (da) | 2006-04-10 |
KR20030093279A (ko) | 2003-12-06 |
MXPA03008755A (es) | 2004-02-18 |
NO20034291D0 (no) | 2003-09-25 |
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