CN103193822A - 氨基丙醇衍生物 - Google Patents
氨基丙醇衍生物 Download PDFInfo
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- CN103193822A CN103193822A CN2013100825423A CN201310082542A CN103193822A CN 103193822 A CN103193822 A CN 103193822A CN 2013100825423 A CN2013100825423 A CN 2013100825423A CN 201310082542 A CN201310082542 A CN 201310082542A CN 103193822 A CN103193822 A CN 103193822A
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- phenyl
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- ester
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- -1 aralkoxy Chemical group 0.000 claims description 27
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Abstract
本发明涉及氨基丙醇衍生物、即式(I)化合物以及它们的生产方法、它们的用途和含有它们的药物组合物,其中R1、R2、n和m如说明书所定义。
Description
本申请是申请日为2004年8月27日、优先权日为2003年8月28日和2003年10月15日的中国专利申请第200480026236.7号和第201110060143.8号的分案申请。
技术领域
本发明涉及有机化合物、它们的生产方法和含有它们的药物组合物。
发明内容
更具体而言,本发明提供了游离形式或盐形式的式I化合物:
其中:
m和n各自独立地是1、2或3;
X是O或直键;
R1是
-其中烷基是直链或支链(C6-20)碳链的苯基烷基;或者
-其中烷基是直链或支链(C1-30)碳链的苯基烷基,其中所述苯基烷基在苯基残基上被如下基团取代:
-任选被卤素取代的直链或支链(C6-20)碳链,
-任选被卤素取代的直链或支链(C6-20)烷氧基链,
-直链或支链(C6-20)链烯氧基,
-苯基烷氧基、卤代苯基烷氧基、苯基烷氧基烷基、苯氧基烷氧基或苯氧基烷基,
-被C6-20烷基取代的环烷基烷基,
-被C6-20烷基取代的杂芳基烷基,
-杂环C6-20烷基,或
-被C2-20烷基取代的杂环烷基,
且其中,烷基部分可以
-在碳链中具有选自双键、叁键、O、S、亚磺酰基、磺酰基或NR5的键或杂原子,其中R5是H、烷基、芳烷基、酰基或烷氧羰基,
-具有作为取代基的烷氧基、链烯氧基、炔氧基、芳烷氧基、酰基、烷基氨基、烷硫基、酰基氨基、烷氧羰基、烷氧羰基氨基、酰氧基、烷基氨甲酰基、硝基、卤素、氨基、羟基或羧基,且
R2是
其中R3和R4各自独立地是H或C1-4烷基,其中烷基任选被1、2或3个卤原子取代。
卤素是F、Cl、Br或I。烷基或烷氧基可以是直链或支链。
环烷基优选是C3-10环烷基,更优选是C3-8环烷基,例如包括环丙基、环丁基、环戊基、环己基或环庚基。
酰基可以是残基Ry-CO-,其中Ry是C1-6烷基、C3-6环烷基、苯基或苯基-C1-4烷基。
当式I化合物中作为R1的碳链被取代时,它优选被卤素、硝基、氨基、羟基或羧基取代。当碳链被任选被取代的亚苯基中断时,该碳链优选是未取代的。当亚苯基部分被取代时,它优选被卤素、硝基、氨基、甲氧基、羟基或羧基取代。
在本发明的化合物中,下列含义单独或在任意亚组合中是优选的:
1.m和n各自是1或2,优选1。
2.X是O。
3.R1是任选被硝基、卤素、氨基、羟基或羧基取代的C13-20烷基,更优选R1是被任选被卤素取代的C6-14烷基链取代的苯基烷基,其中烷基部分是任选被羟基取代的C1-6烷基。更优选R1是苯基-C1-6烷基,例如苯基-C1-6烷基,例如苯基-C2烷基,它在苯基上被直链或支链、优选直链C6-14烷基链取代。C6-14烷基链可以位于邻位、间位或对位,优选对位。
4.R3和R4各自是H。
特别优选的化合物是磷酸单-[2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯。
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、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;当R3或R4是H时,R2还可以以盐形式存在,例如铵盐或金属盐或者它们的混合物,所述金属例如钠、钾、钙、锌或镁。式I化合物及其盐的水合物或溶剂化物形式也是本发明的一部分。
式I化合物在分子中具有一个或一个以上不对称中心,因而可以得到多种旋光异构体。本发明还涵盖对映异构体、外消旋物、非立体异构体和它们的混合物。中心不对称碳原子可以具有R或S构型。而且,当式I化合物包括几何异构体时,本发明涵盖顺式-化合物、反式-化合物和它们的混合物。相似的考虑适用于表现出上述不对称碳原子或不饱和键的原料。
式I化合物可如下制备:使式II化合物:
其中m、n、X、R1和R2如式I中所定义,
与芳族1,2-二甲醛如苯-1,2-二甲醛反应,并回收游离或盐形式的所得式I化合物。
该方法可以按照本领域已知的方法进行,例如实施例所述。
式II化合物(例如其外消旋混合物)可以如WO02/18395或WO02/076995所述得到。
本发明还提供了这样的式I或式II化合物,其中大于70%重量的化合物是S对映异构体形式,或者大于70%重量的化合物是R对映异构体形式,例如大于90%是R或S对映异构体形式。更优选大于95%重量、例如大于99%重量的化合物是R或S对映异构体形式。因而本发明可以涉及式I或式II化合物基本上纯的R或S对映异构体(例如基本上不含R对映异构体的S对映异构体,反之亦然),优选S对映异构体。特别优选的是磷酸单-[2-氨基-2-羟甲基-4-(4-辛基-苯基)-丁基]酯(FTY720-磷酸酯)和磷酸单-[2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯基本上纯的(例如大于99%重量)的R或S对映异构体,尤其是S对映异构体。
具有下述三维构型的化合物通常是优选的:
式I和II化合物的对映异构体不能借助标准方法令人满意地加以分离。按照本发明,利用新的分离技术和合成策略实现了对映异构体的分离。
式I化合物,其中大于70%重量的化合物是R或S对映异构体形式、例如基本上纯的R或S对映异构体,可以这样得到:
a)利用手性固定相色谱法,在式I化合物的外消旋混合物中使S对映异构体与R对映异构体分离;或者
b)使式II化合物,其中大于70%重量的化合物是R或S对映异构体形式、例如式II化合物基本上纯的R或S对映异构体,与芳族1,2-二甲醛如苯-1,2-二甲醛反应。
按照方法a),优选利用手性离子交换相进行色谱法分离,以氨基甲酸奎宁或氨基甲酸奎尼丁作为手性选择剂,例如以商品名ProntoSIL ChiralAX QN-1购得的氨基甲酸奎宁相(8S,9R):
式II化合物,其中大于70%重量的化合物是R或S对映异构体形式,可以通过使式III化合物去保护而得,其中大于70%重量的式III化合物是R或S对映异构体形式,
其中m、n、X、R1和R2如上所定义,且R6是氨基保护基团,
并且酌情将游离形式的所得式II化合物转化为所需的盐形式,或者反之亦然。
适合作为R6的氨基保护基团的实例例如在"Protective Groups inOrganic Synthesis"T.W.Greene,J.Wiley&Sons NY,第2版,第7章,1991和其中的参考文献中有描述,例如酰基,例如叔丁氧羰基、苄氧羰基、9-芴基甲氧羰基、三氟乙酰基、三甲代甲硅烷基乙磺酰基等。
或者和更优选式II化合物,其中大于70%重量的化合物是R或S对映异构体形式,可以通过使式IIIa或IIIb化合物去保护而得,其中大于70%重量的式IIIa或IIIb化合物是R或S对映异构体形式:
其中n、m、X、R1和R2如上所定义,且R6’是OH和氨基两者的保护基团,例如以便R6’与它所连接的O和N原子、不对称碳原子和1至3个其它碳原子一起构成环状残基,例如5-至7-元杂环,例如唑烷-2-酮(IIIa中R6’是-C(O)-)或2-甲基-4,5-二氢-唑(IIIb中R6’是-C(CH3)-)。
式III、IIIa或IIIb化合物中R6或R6’保护基团的除去可以适宜地按照本领域已知的方法进行,例如借助水解,例如在碱性介质中,例如使用氢氧化物如氢氧化钡。还可以借助氢解作用进行,例如在Pearlman’s催化剂的存在下,例如J.Org.Chem.,1998,63,2375-2377所述。
因而在进一步的可选方面,本发明提供了如上所定义的游离或盐形式的式III、IIIa或IIIb化合物。式III、IIIa或IIIb化合物在分子中具有一个或一个以上不对称中心,因而可以得到多种旋光异构体。本发明还涵盖对映异构体、外消旋物、非立体异构体和它们的混合物。
式III、IIIa或IIIb化合物中R6或R6’保护基团的除去可以适宜地按照本领域已知的方法进行,例如借助水解,例如在碱性介质中,例如使用氢氧化物如氢氧化钡。还可以借助氢解作用进行,例如在Pearlman’s催化剂的存在下,例如J.Org.Chem.,1998,63,2375-2377所述。
包含大于70%重量的R或S对映异构体的式III、IIIa或IIIb化合物可如下得到:通过利用基于多糖类的手性固定相的色谱法(MPLC、HPLC、SFC)或者模拟移动床(多层柱)色谱法,使式III、IIIa或IIIb化合物的外消旋混合物中的S对映异构体与R对映异构体分离,所述的固定相优选为直链淀粉型相,例如涂在硅胶基质上的直链淀粉三[(S)-α-甲基苄基氨基甲酸酯],如商品名为CHIRALPAK AS,如下所示,或者在按照WO97/04011和WO97/49733所述方法制备的固定化形式中:
或者,包含大于70%重量的R或S对映异构体的式III、IIIa或IIIb化合物可如下得到:除去存在于包含大于70%重量的R或S对映异构体的式IV、IVa或IVb化合物的R2’中的可水解基团:
其中m、n、X、R1、R6和R6’如上所定义,且R2’是
其中R3’和R4’各自是可水解的基团。
包含大于70%重量的R或S对映异构体的式IV、IVa或IVb化合物可如下得到:使式IV、IVa或IVb化合物的外消旋混合物中的S对映异构体与R对映异构体分离,例如上述式III、IIIa或IIIb化合物的对映异构体的分离中所述。
其中X是O的式IV、IVa或IVb化合物、例如其外消旋混合物可如下得到:使式V、Va或Vb化合物:
其中m、n、R1、R6和R6’如上所定义,
与磷酰化剂反应,例如氯代磷酸酯,例如氯代磷酸二苯基酯或氯代磷酸二苄基酯;磷酸氰乙基酯;氨基磷酸酯,例如N-苯基氨基磷酸酯;3-(二乙氨基)-1,5-二氢-2,4,3-苯并二氧杂磷杂等。反应可以按照本领域已知的方法进行,例如J.Org.Chem.所述,出处同上。在式IIIa化合物中,当R4不是酰基时,氨基优选是被保护的形式,如R4’。
其中X是直键的式IV、IVa或IVb化合物、例如其外消旋混合物可如下得到:使式V’、Va’或Vb’化合物:
其中m、n、R1、R6和R6’如上所定义,且Y是离去基团,例如Br,
在还原条件下、例如在NaH存在下与磷酰化剂、例如亚磷酸二乙酯反应。反应可以按照本领域已知的方法进行。
或者,可以在该方法的早期阶段进行手性分离。因而包含大于70%重量的R或S对映异构体的式IV、IVa或IVb化合物可如下得到:使包含大于70%重量的R或S对映异构体的式V、Va、Vb、V’、Va’或Vb’化合物与磷酰化剂反应。包含大于70%重量的R或S对映异构体的式V、Va、Vb、V’、Va’或Vb’化合物可如下得到:使式V、Va、Vb、V’、Va’或Vb’化合物的外消旋混合物中的S对映异构体与R对映异构体分离,例如通过利用基于多糖类的手性固定相的HPLC或者模拟移动床(多层柱)色谱法来进行,所述固定相如上述式IV、IVa或IVb化合物的对映异构体的分离中所述。
式V或V’化合物可如下制备:使式VI化合物:
其中m、n和R1如上所定义,且R9是OH或离去基团,例如Br,
与氨基保护基团供体化合物反应。式Va、Va’、Vb或Vb’化合物可如下制备:使式VI化合物与OH和氨基保护化合物反应,例如使式VI的游离氨基醇或氨基二醇反应同时进行OH和氨基保护,以得到环状残基,例如5-至7-元杂环,例如唑烷-2-酮或2-甲基-4,5-二氢-唑,例如与Cbo-Cl、Boc-酸酐、原乙酸三乙酯和乙腈反应,或者在碱性条件下与光气反应。
在该方法的任意阶段,任意上式中的R1可以利用已知方法任选转化为替代的R1基团。例如,其中R1是(4-苄氧基-苯基)-乙基的式Vb化合物可以这样转化为其中R1是[4-(6-氟-己氧基)-苯基]-乙基的式Vb化合物:(a)借助氢化作用除去R1中的苄基,留下(4-羟基-苯基)-乙基残基,继之以(b)与1-溴-6-氟己烷反应。替代的式Vb化合物然后可以经历手性分离或者转化为式IVb化合物,如上所述。
用作原料的包含大于70%重量的R或S对映异构体的式III、IIIa、IIIb、IV、IVa和IVb化合物及其盐也是新的,构成本发明的一部分。
在进一步的替代方面,式II化合物,其中大于70%重量的化合物是R或S对映异构体形式,可如下得到:使式VII化合物去保护和水解,其中大于70%重量的化合物是R或S对映异构体形式:
其中m、n、X和R1如上所定义,且R2”是
其中R3’和R4’各自是可水解的基团,例如叔丁基,且R7是氨基保护基团,例如苄氧羰基。
式VII化合物,其中大于70%重量的化合物是R或S对映异构体形式,可如下得到:使式VIII化合物,其中大于70%重量的化合物是R或S对映异构体形式,
与磷酰化剂反应,例如如上所述。
在没有确切描述原料生产的情况下,这些化合物是已知的,或者可以类似于本领域已知方法或下文实施例所述加以制备。
具体实施方式
下列实施例是本发明的说明。
RT=室温
CBO=苄氧羰基
FTY720=2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇
EDTA=乙二胺四乙酸
OPA=邻苯二醛(苯-1,2-二甲醛)
实施例1:磷酸单-[(R/S)-2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯
将氯甲酸苄基酯(0.45ml;3.2mmol)加入FTY720.HCl(1.03g,3mmol)的2N NaOH(20ml)混悬液中。使反应物于室温保持过夜,为了完成反应,加入另外的氯甲酸苄基酯(0.9ml;6.4mmol)。于室温2天后,将反应物用1NHCl酸化,用二氯甲烷萃取,经硅胶柱纯化,使用二氯甲烷/甲醇/乙酸50%(9/1/0.125)作为流动相。[M+H]+:334(ESI-MS)
于0℃向a)的终产物(2.4g;7.2mmol)的二氯甲烷/THF1/1(100ml)溶液中加入四唑(经过重结晶;2.52g;36mmol)和3-(二乙氨基)-1,5-二氢-2,4,3-苯并二氧杂磷杂三苯基-亚磷酸酯(5.17g;21.6mmol)。于室温18小时后,向溶液中加入H2O2(8.2ml[30%水溶液];72mmol)(冷却),于室温另外保持90分钟。用饱和Na2S2O3溶液(100ml)淬灭后,用乙酸乙酯萃取反应物(三次)。将有机层经Na2SO4干燥,化合物经硅胶纯化,使用环己烷/乙酸乙酯1/1作为流动相。
c)磷酸单-{(R/S)-4-[2-(4-辛基-苯基)-乙基]-2-氧代-唑烷-4-基甲基}酯
将步骤b)的终产物(1.03g;2mmol)在常压下氢化(Pd/C10%;50mg)90分钟。过滤后,浓缩反应物,未经进一步纯化用于步骤d)。
d)磷酸单-[(R/S)-2-氨基-2-羟甲基-4-(4-辛基-苯基)-丁基]酯((R/S)-FTY720-磷酸酯)
向步骤c)的终产物的乙醇(20ml)溶液中加入LiOH(20ml;10%水溶液)。回流24小时后,用HCl(1N水溶液)中和反应物,浓缩。将残余物用冰乙酸(5ml)处理,加入水(50ml)后发生终产物的沉淀。过滤后,洗涤(水)并干燥,得到纯的终产物,未经进一步纯化。
e)磷酸单-[(R/S)-2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯(OPA-衍生化)
将步骤d)的终产物((R/S)-FTY720-磷酸酯)(50mg;0.125mmol)悬浮在EDTA溶液(0.5ml;10mM水溶液)和硼酸水溶液(0.5ml;3%水溶液;用KOH10%水溶液调至pH10.5)中。加入OPA(33mg,0.25mmol)后,溶于乙醇(0.5ml),使反应物于室温保持1小时(超声)。然后调节pH至3.5(HCl水溶液;1N),用乙酸乙酯萃取(三次)。将有机层经Na2SO4干燥,化合物经硅胶纯化,使用二氯甲烷/甲醇(95/5→0/100)作为流动相。[M-H]-:502.5(ESI-MS)
实施例2:磷酸单-[(R)-2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯
通过制备规模CHIRALPAK AS柱HPLC(乙醇/正己烷40/60作为流动相),或者通过装有固定化直链淀粉三[(S)-α-甲基苄基氨基甲酸酯]涂覆硅胶的HPLC柱模拟移动床色谱法(正己烷/乙醇/氯仿60/20/20作为流动相,进料浓度1%),分离步骤b]的终产物,再如实施例1所述进行步骤c)、d)和e),得到实施例2化合物。
实施例3:磷酸单-[(S)-2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯
通过制备规模CHIRALPAK AS柱HPLC(乙醇/正己烷40/60作为流动相),或者通过装有固定化直链淀粉三[(S)-α-甲基苄基氨基甲酸酯]涂覆硅胶的HPLC柱模拟移动床色谱法(正己烷/乙醇/氯仿60/20/20作为流动相,进料浓度1%)分离步骤b)最终产物,再如实施例1所述进行步骤c)、d)和e),得到实施例3化合物。
a)向4-(2-羟基-乙基)-苯酚(50g,0.36mol)的乙醇(400ml)溶液中加入碳酸钾(75g,0.54mol,1.5当量)和苄基溴(47.2ml,0.39mol,1.1当量),将反应混合物于室温搅拌过夜。然后将反应混合物通过celite过滤,真空浓缩。用乙醚结晶后,分离出2-(4-苄氧基-苯基)-乙醇。
b)向2-(4-苄氧基-苯基)-乙醇(78.72g,0.34mol)的二氯甲烷(400ml)溶液中加入三乙胺(67.3ml,0.44mol,1.4当量),然后于0℃加入甲磺酰氯(34.8ml,0.44mol,1.3当量)。将反应混合物于0℃搅拌30分钟,升温至RT。将反应混合物用二氯甲烷萃取(2×300ml),合并有机层,然后用盐水洗涤(2×300ml),真空浓缩。
c)向粗产物的乙酸乙酯(600ml)溶液中加入碘化钠(67.2g,0.44mol,1.3当量),将反应混合物回流搅拌6小时。过滤后,将有机层用盐水洗涤(3×400ml),用Na2SO4干燥,过滤,真空浓缩。用乙醚结晶后,分离出1-苄氧基-4-(2-碘-乙基)-苯。
d)在0℃和惰性气氛下,向丙二酸乙酰氨基酯(59.4g,0.27mol,2当量)的无水二甲基甲酰胺(400ml)溶液中加入氢化钠(60%油悬液)(9.94g,0.49mol,1.8当量),将反应混合物于0℃搅拌3小时。然后于0℃缓慢加入1-苄氧基-4-(2-碘-乙基)苯(46.8g,0.13mol,1当量)的无水二甲基甲酰胺(250ml)溶液,将反应混合物于室温搅拌过夜。将反应混合物用几滴甲醇淬灭,真空浓缩近干,然后用乙酸乙酯萃取,随后用1N HCl(2×500ml)、饱和NaHCO3溶液(2×500ml)和盐水(2×500ml)洗涤,用Na2SO4干燥,过滤,真空浓缩。用乙醚多次结晶后,分离出2-乙酰氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙二酸二乙基酯。
e)向2-乙酰氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙二酸二乙基酯(44.1g,0.1mol)的乙醇/水(2/1)(285ml/285ml)溶液中加入CaCl2(28.5g,0.26mol,2.5当量)和逐份的NaBH4(19.4g,0.52mol,5.0当量),将反应混合物于室温搅拌过夜。于0℃,将反应混合物小心地逐滴用甲醇(10ml)淬灭,真空浓缩近干。将粗混合物用乙酸乙酯萃取(4×500ml),随后用1N HCl(2×300ml)、饱和NaHCO3溶液(2×300ml)和盐水(2×300ml)洗涤。合并有机层,然后用Na2SO4干燥,过滤,真空浓缩。N-[3-(4-苄氧基-苯基)-1,1-双-羟甲基-丙基]-乙酰胺未经进一步纯化使用。
f)于室温,向粗的N-[3-(4-苄氧基-苯基)-1,1-双-羟甲基-丙基]-乙酰胺在四氢呋喃/甲醇/水混合物(1/2/2)(450ml/900ml/900ml)中的溶液中加入氢氧化锂(32.7g,1.36mol,8.0当量)。将反应混合物于55℃搅拌5小时,然后用乙酸乙酯(500ml)萃取,用盐水洗涤(2×300ml),合并有机层,然后用Na2SO4干燥,过滤,真空浓缩。用乙酸乙酯结晶后,分离出2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇。
g)向2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇(31.1g,0.10mol)的乙腈(2.38l)溶液中加入原乙酸三乙酯(17.1ml,0.12mol,1.2当量)和乙酸(5.48ml,0.11mol,1.1当量),然后将反应混合物于80℃搅拌5小时。然后真空浓缩反应混合物,用乙酸乙酯结晶后,分离出{4-[2-(4-苄氧基-苯基)-乙基]-2-甲基-4,5-二氢-唑-4-基}-甲醇。
h)向{4-[2-(4-苄氧基-苯基)-乙基]-2-甲基-4,5-二氢-唑-4-基}-甲醇(26.1g,0.08mol)的甲醇(800ml)溶液中加入披钯炭(2.6g,10%wt),将反应混合物在氢气氛和RT下搅拌5小时。然后通过celite过滤反应混合物,真空浓缩。用乙酸乙酯和己烷结晶后,以定量收率分离(R/S)-4-[2-(4-羟甲基-2-甲基-4,5-二氢-唑-4-基)-乙基]-苯酚。
i)在惰性气氛下,向(R/S)-4-[2-(4-羟甲基-2-甲基-4,5-二氢-唑-4-基)-乙基]-苯酚(500mg,2.12mmol)的无水DMF(8ml)溶液中加入Cs2CO3(901mg,2.76mmol,1.3当量)和1-溴-6-氟-己烷(464.1mg,2.55mmol,1.2当量)。将反应混合物在惰性气氛和85℃下搅拌过夜。然后加入饱和NaHCO3溶液(20ml)和乙酸乙酯(40ml)。分离有机层,水相用乙酸乙酯萃取(3×40ml)。合并有机萃取液,用盐水和1M HCl洗涤,经MgSO4干燥,蒸发至干。经快速色谱法纯化(环己烷/乙酸乙酯(9/1)至(1/1)和(0/1)),得到(R/S)-(4-{2-[4-(6-氟-己氧基)-苯基]-乙基}-2-甲基-4,5-二氢-唑-4-基)-甲醇,为无色的油。
借助制备规模CHIRALPAK AD柱HPLC,分离((R/S)-4-{2-[4-(6-氟-己氧基)-苯基]-乙基}-2-甲基-4,5-二氢-唑-4-基)-甲醇的对映异构体(以正己烷/2-丙醇96/6作为流动相)。
实施例5:磷酸单-{(S)-2-氨基-4-[4-(6-氟-己氧基)-苯基]-2-羟甲基-丁基}酯
a)在-25℃下,向手性((S)-4-{2-[4-(6-氟-己氧基)-苯基]-乙基}-2-甲基-4,5-二氢唑-4-基)-甲醇(300mg,0.80mmol)与四唑(337.4mg,4.82mmol,6当量经过甲苯重结晶)的无水THF(6ml)溶液中加入3-二乙氨基-1,5-二氢苯并[e][1,3,2]二氧杂磷杂(433.5μL,1.56mmol,1.95当量)。将反应混合物在氩和-25℃下搅拌3小时,然后恢复至RT。然后于0℃注入H2O2(30%,75μL,4.0mmol,5当量),同时剧烈搅拌。将反应混合物另外搅拌30分钟,继之以加入饱和硫代硫酸钠溶液(1ml)。分离有机层,水相用乙醚萃取(3×20ml)。合并有机萃取液,用盐水洗涤,经MgSO4干燥,蒸发至干。经快速色谱法纯化(乙酸乙酯),得到磷酸二叔丁基酯(S)-4-{2-[4-(6-氟-己氧基)-苯基]-乙基}-2-甲基-4,5-二氢-唑-4-基甲基酯,为无色的油。
b)向磷酸二叔丁基酯(S)-4-{2-[4-(6-氟-己氧基)-苯基]-乙基}-2-甲基-4,5-二氢-唑-4-基甲基酯(33mg,0.050mmol)的乙醇(2ml)溶液中加入浓HCl(2ml)。将反应混合物于85℃搅拌2小时,然后浓缩至干。将残余物重新溶于乙酸乙酯,用己烷沉淀。滤出固体,用无水乙醚洗涤,真空干燥,得到磷酸单-{(S)-2-氨基-4-[4-(6-氟-己氧基)-苯基]-2-羟甲基-丁基}酯,为无色粉末。
实施例6:磷酸单-{(R)-2-氨基-4-[4-(6-氟-己氧基)-苯基]-2-羟甲基-丁基}酯
采用实施例5所述化学进行合成。
实施例7:磷酸单-[(S)-4-[4-(6-氟-己氧基)-苯基]-2-羟甲基-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯
按照实施例1步骤e所给出的工艺进行OPA-衍生化。
实施例8:磷酸单-[(R)-4-[4-(6-氟-己氧基)-苯基]-2-羟甲基-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯
按照实施例1步骤e所给出的工艺进行OPA-衍生化。
实施例9:磷酸单-((R)-2-氨基-4-{4-[2-(3-氟-苯氧基)-乙氧基]-苯基}-2-羟甲基-丁基)酯
向4-(2-羟基-乙基)-苯酚(50g,0.36mol)的乙醇(400ml)溶液中加入碳酸钾(75g,0.54mol,1.5当量)和苄基溴(47.2ml,0.39mol,1.1当量),将反应混合物于室温搅拌过夜。然后通过celite滤出反应混合物,真空浓缩。用乙醚结晶后,分离出2-(4-苄氧基-苯基)-乙醇(82.6g,95%)。
向2-(4-苄氧基-苯基)-乙醇(78.72g,0.34mol)的二氯甲烷(400ml)溶液中加入三乙胺(67.3ml,0.44mol,1.4当量),然后于0℃加入甲磺酰氯(34.8ml,0.44mol,1.3当量)。将反应混合物于0℃搅拌30分钟,升温至室温。将反应混合物用二氯甲烷萃取(2×300ml),合并有机层,然后用盐水洗涤(2×300ml),真空浓缩。向粗产物的乙酸乙酯(600ml)溶液中加入碘化钠(67.2g,0.44mol,1.3当量),将反应混合物回流搅拌6小时。过滤后,将有机层用盐水洗涤(3×400ml),用Na2SO4干燥,过滤,真空浓缩。用乙醚结晶后,分离出1-苄氧基-4-(2-碘-乙基)-苯(116.5g,86%)。
在0℃和惰性气氛下,向丙二酸乙酰氨基酯(59.4g,0.27mol,2当量)的无水二甲基甲酰胺(400ml)溶液中加入氢化钠(60%油悬液)(9.94g,0.49mol,1.8当量),将反应混合物于0℃搅拌3小时。然后于0℃缓慢加入1-苄氧基-4-(2-碘-乙基)-苯(46.8g,0.13mol,1当量)的无水二甲基甲酰胺(250ml)溶液,将反应混合物于室温搅拌过夜。将反应混合物用几滴甲醇淬灭,真空浓缩近干,然后用乙酸乙酯萃取,随后用1N HCl(2×500ml)、饱和NaHCO3溶液(2×500ml)和盐水(2×500ml)洗涤,用Na2SO4干燥,过滤,真空浓缩。用乙醚多次结晶后,分离出2-乙酰氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙二酸二乙基酯(47.3g,80%)。
向2-乙酰氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙二酸二乙基酯(44.1g,0.1mol)的乙醇/水(2/1)(285ml/285ml)溶液中加入CaCl2(28.5g,0.26mol,2.5当量)和逐份的NaBH4(19.4g,0.52mol,5.0当量),将反应混合物于室温搅拌过夜。于0℃将反应混合物小心地逐滴用甲醇(10ml)淬灭,真空浓缩近干。将粗混合物用乙酸乙酯萃取(4×500ml),随后用1N HCl(2×300ml)、饱和NaHCO3溶液(2×300ml)和盐水(2×300ml)洗涤。合并有机层,然后用Na2SO4干燥,过滤,真空浓缩。N-[3-(4-苄氧基-苯基)-1,1-双-羟甲基-丙基]-乙酰胺未经进一步纯化使用。
在室温下,向粗的N-[3-(4-苄氧基-苯基)-1,1-双-羟甲基-丙基]-乙酰胺在四氢呋喃/甲醇/水混合物(1/2/2)(450ml/900ml/900ml)中的溶液中加入氢氧化锂(32.7g,1.36mol,8.0当量)。将反应混合物于55℃搅拌5小时,然后用乙酸乙酯(500ml)萃取,用盐水洗涤(2×300ml),合并有机层,然后用Na2SO4干燥,过滤,真空浓缩。用乙酸乙酯结晶后,分离出2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇(28.8g,97%)。
向2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇(200mg,0.66mmol)的二烷(10ml)溶液中加入1M NaOH溶液(0.73ml,0.73mmol,1.1当量)和Boc酸酐(217mg,0.99mmol,1.5当量)。然后将反应混合物于室温搅拌过夜。用乙酸乙酯(80ml)萃取,用盐水洗涤(2×50ml),合并有机层,然后用Na2SO4干燥,过滤,真空浓缩。经快速色谱法处理(乙酸乙酯/己烷(3/1))和用乙醚结晶后,分离出2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇,为白色固体(204mg,87%)。
在室温下,向2-氨基-2-[2-(4-苄氧基-苯基)-乙基]-丙烷-1,3-二醇(6.31g,0.16mol)的二氯甲烷(120ml)与吡啶(1.26ml,0.16mol)溶液中加入邻-硝基苯甲酰氯(2.27ml.0.017mol)。然后将反应混合物于室温搅拌过夜。用二氯甲烷萃取(300ml),用盐水洗涤(2×200ml),合并有机层,然后用Na2SO4干燥,过滤,真空浓缩。经快速色谱法处理(乙酸乙酯/己烷(1/1))和用乙醚结晶后,分离出2-硝基-苯甲酸4-(4-苄氧基-苯基)-2-叔丁氧羰基氨基-2-羟甲基-丁基酯,为白色固体(6.55mg,76%)。可分离出1.40g原料。
向2-硝基-苯甲酸4-(4-苄氧基-苯基)-2-叔丁氧羰基氨基-2-羟甲基-丁基酯(105mg;0.19mmol)的甲苯(2ml)溶液中加入2,2-二甲氧基丙烷(0.06ml,0.57mmol,3当量)和催化量的对-甲苯磺酸。将反应混合物于95℃搅拌6小时,然后在负压下浓缩至干。经快速色谱法纯化(乙酸乙酯/己烷(1/3))后,分离出4-[2-(4-苄氧基-苯基)-乙基]-2,2-二甲基-4-(2-硝基-苯甲酰氧基-甲基)-唑烷-3-甲酸叔丁酯,为油(88mg,78%)。
向4-[2-(4-苄氧基-苯基)-乙基]-2,2-二甲基-4-(2-硝基-苯甲酰氧基甲基)-唑烷-3-甲酸叔丁酯(80mg,0.13mmol)的甲醇(1ml)与THF(1ml)溶液中加入K2CO3(1.5mg,0.076当量),将反应混合物于室温搅拌过夜。将反应混合物浓缩至干,经快速色谱法处理(乙酸乙酯/己烷(1/4))后,分离出4-[2-(4-苄氧基-苯基)-乙基]-4-羟甲基-2,2-二甲基-唑烷-3-甲酸叔丁酯,为白色固体(51mg,85%)。
向4-[2-(4-苄氧基-苯基)-乙基]-4-羟甲基-2,2-二甲基-唑烷-3-甲酸叔丁酯(25mg,0.05mmol)的甲醇(10ml)溶液中加入催化量的披钯炭(10%wt)。将反应混合物在H2气氛和室温下搅拌2小时。将混悬液通过celite过滤并浓缩至干后,分离出4-羟甲基-4-[2-(4-羟基-苯基)-乙基]-2,2-二甲基-唑烷-3-甲酸叔丁酯,为白色固体。
向(S)-4-羟甲基-4-[2-(4-羟基-苯基)-乙基]-2,2-二甲基-唑烷-3-甲酸叔丁酯(100mg,0.28mmol)的DMF(5ml)溶液中加入Cs2CO3(120.5mg,0.37mmol,1.3当量)和1-(2-溴-乙氧基)-3-氟-苯(80.7mg,0.37mmol,1.3当量)。将反应混合物于85℃搅拌4小时。然后加入乙酸乙酯和水,分离有机层,水相用乙酸乙酯萃取(3×50ml)。合并有机萃取液,用盐水洗涤,经MgSO4干燥,蒸发至干。经快速色谱法纯化(AcOEt/Hx9:1),得到(S)-4-(2-{4-[2-(3-氟-苯氧基)-乙氧基]-苯基}-乙基)-4-羟甲基-2,2-二甲基-唑烷-3-甲酸叔丁酯,为无色的油。
向(S)-4-(2-{4-[2-(3-氟-苯氧基)-乙氧基]-苯基}-乙基)-4-羟甲基-2,2-二甲基-唑烷-3-甲酸叔丁酯(70mg,0.14mmol)与四唑(49mg,0.7mmol,5当量,经过甲苯重结晶)的无水THF(5ml)溶液中加入二-tBu-N,N-二异丙基磷酰胺(155mg,0.56mmol,4当量)。在氩气和RT下搅拌3小时后,于0℃缓慢加入H2O2(30%,10当量),同时剧烈搅拌。将反应混合物另外搅拌30分钟,继之以加入饱和硫代硫酸钠溶液(5ml)。分离有机层,水相用乙醚萃取(3×20ml)。合并有机萃取液,用盐水洗涤,经MgSO4干燥,蒸发至干。经快速色谱法纯化(AcOEt/Hx1:1),得到(R)-4-(二叔丁氧基-磷酰氧基甲基)-4-(2-{4-[2-(3-氟-苯氧基)-乙氧基]-苯基}-乙基)-2,2-二甲基-唑烷-3-甲酸叔丁酯,为无色的油。
实施例10:磷酸单-((S)-2-氨基-4-{4-[2-(3-氟-苯氧基)-乙氧基]-苯基}-2-羟甲基-丁基)酯
实施例11:磷酸单-{(R)-2-氨基-2-羟甲基-4-[4-(2-间-甲苯氧基-乙氧基)-苯基]-丁基}酯
利用与实施例9所述类似的方法制备磷酸单-{(R)-2-氨基-2-羟甲基-4-[4-(2-间-甲苯氧基-乙氧基)-苯基]-丁基}酯。
实施例12:磷酸单-((R)-2-氨基-2-羟甲基-4-{4-[2-(4-甲氧基-苯基)-乙氧基]-苯基}-丁基)酯
利用与实施例9所述类似的方法制备磷酸单-((R)-2-氨基-2-羟甲基-4-{4-[2-(4-甲氧基-苯基)-乙氧基]-苯基}-丁基)酯。
实施例13:磷酸单-{(R)-2-氨基-2-羟甲基-4-[4-(2-对-甲苯基-乙氧基)-苯基]-丁基}酯
利用与实施例9所述类似的方法制备磷酸单-{(R)-2-氨基-2-羟甲基-4-[4-(2-对-甲苯基-乙氧基)-苯基]-丁基}酯。
实施例14:磷酸单-((R)-2-氨基-2-羟甲基-4-{4-[2-(4-三氟甲基-苯基)-乙氧基]-苯基}-丁基)酯
利用与实施例9所述类似的方法制备磷酸单-((R)-2-氨基-2-羟甲基-4-{4-[2-(4-三氟甲基-苯基)-乙氧基]-苯基}-丁基)酯。
向磷酸单-(2-氨基-4-{4-[2-(3-氟-4-甲氧基-苯基)-乙氧基]-苯基}-2-羟甲基-丁基)酯(100mg,0.22mmol)的原乙酸三乙酯(5ml)溶液中加入乙酸(13μL,0.22mmol)。将反应混合物于80℃搅拌2小时,浓缩至干。经快速色谱法纯化(AcOEt/Hx1:4),得到磷酸二乙基酯4-(2-{4-[2-(3-氟-4-甲氧基-苯基)-乙氧基]-苯基}-乙基)-2-甲基-4,5-二氢-唑-4-基甲基酯,为无色的油。
使用磷酸单-(2-氨基-4-{4-[2-(3-氟-4-甲氧基-苯基)-乙氧基]-苯基}-2-羟甲基-丁基)酯,如实施例15所述制备磷酸二乙基酯(S)-2-甲基-4-[2-(4-辛基-苯基)-乙基]-4,5-二氢-唑-4-基甲基酯。
将对映异构体磷酸二乙基酯(S)-2-甲基-4-[2-(4-辛基-苯基)-乙基]-4,5-二氢-唑-4-基甲基酯混合物的10μL0.1%乙醇溶液注射上Chiralpak AD-H柱(0.46×25cm;购自Chiral Technologies)。于室温实现色谱分离,流速1ml/min,使用正己烷/乙醇95/5(体积)混合物作为流动相。在210nm下进行UV检测。对映异构体分别在10.35分钟和12.32分钟洗脱(分离因子α:1.27)。
游离形式或可药用盐形式的包含大于70%R或S对映异构体、尤其是S对映异构体的式II化合物(以下称为本发明的化合物)表现出重要的药理性质,例如淋巴细胞再循环调节性质,例如体外和体内试验所示,因此适用于治疗。
A.体外
如下列测定法所测定的,本发明的化合物对个体人S1P受体具有结合亲和性:
人S1P受体向HEK293细胞的瞬时转染
克隆S1P受体和Gi蛋白,混合等量的S1P受体、Gi-α、Gi-β和Gi-γ的4种cDNA,用于通过磷酸钙沉淀法转染HEK293细胞单层(M.Wigler等人,Cell.1977;11;223和DS.Im等人,Mol.Pharmacol.2000;57;753)。简言之,向HEPES-缓冲的2mM Na2HPO4中加入含有25μg DNA和0.25MCaCl2的DNA混合物。将HEK293细胞亚汇合单层用25mM氯奎毒化,然后向细胞施用DNA沉淀。4小时后,将单层用磷酸盐-缓冲盐水洗涤,重新加入培养基(90%1:1Dulbecco’s改性必需培养基(DMEM):F-12+10%胎牛血清)。加入DNA后48-72小时,于冰上在含有10%蔗糖的HME缓冲液(20mM HEPES,5mM MgCl2,1mM EDTA,pH7.4)中刮取收获细胞,利用Dounce匀化器破坏。在800×g下离心后,将上清液用不含蔗糖的HME稀释,在100,000×g下离心1小时。将所得沉淀重新匀化,在100,000×g下离心第二个1小时。将这种粗的膜沉淀重新悬浮在含蔗糖的HME中,分为等分试样,浸入液氮中骤冷。将膜于70℃贮存。借助Bradford蛋白质测定法分光测定蛋白质浓度。
使用S1P受体/HEK293膜制备物的GTPγS结合测定法
如DS.Im等人,Mol.Pharmacol.2000;57:753所述进行GTPγS结合实验。使用25μg来自瞬时转染的HEK293细胞的膜制备物,在GTP结合缓冲液(50mM HEPES,100mM NaCl,10mM MgCl2,pH7.5)中测量配体-介导的GTPγS与G-蛋白的结合。在10μM GDP和0.1nM[35S]GTPγS(1200Ci/mmol)的存在下向膜中加入配体,于30℃温育30分钟。利用Brandel收获器(盖瑟斯堡,MD)分离已结合与未结合的GTPγS,用液闪计数器计数。
在这些测定法中,本发明的化合物在亚-μM范围内对S1P受体具有结合亲和性。确切而言,下表显示了下列化合物对各S1P受体的EC50值,以nM计:
其中(R)-FTY720-P是(R)-FTY720-磷酸酯,(S)-FTY720-P是(S)-FTY720-磷酸酯。与仅在非常高浓度下显示对S1P受体的激动效应的(R)-FTY720-磷酸酯相反,(S)-FTY720-磷酸酯在低纳摩尔范围内是S1P1与S1P3的全激动剂和S1P4与S1P5的部分激动剂。
B.体内:血液淋巴细胞消减
借助管饲法向大鼠口服给予本发明的化合物或载体。在前1天取尾血供血液学监测,得到个体基线值,在用药后2、6、24、48和72小时取尾血。在这种测定法中,本发明的化合物在0.03至3mg/kg剂量给药时消减外周血液淋巴细胞。
因此,本发明的化合物可用于治疗和/或预防由淋巴细胞相互作用所介导的疾病或紊乱,例如在移植术中,例如细胞、组织或器官同种异体或异种移植物的急性或慢性排斥或者移植物功能延迟、移植物抗宿主疾病;自身免疫性疾病,例如类风湿性关节炎、系统性红斑狼疮、桥本氏甲状腺炎、多发性硬化、重症肌无力、I或II型糖尿病和与之有关的紊乱、脉管炎、恶性贫血、舍格伦综合征、眼色素层炎、牛皮癣、Graves眼病、局限性脱发和其它;变应性疾病,例如过敏性哮喘、特应性皮炎、过敏性鼻炎/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、节段性回肠炎或溃疡性结肠炎;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、刺激性接触性皮炎和进一步的湿疹性皮炎、脂溢性皮炎、免疫介导紊乱的皮肤表现、炎性眼疾病、角膜结膜炎、心肌炎或肝炎;缺血/再灌注损伤,例如心肌梗塞、中风、肠缺血、肾衰竭或出血性休克、创伤性休克等;癌症,例如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(例如超抗原诱发的)、败血症性休克、成人呼吸窘迫综合征或者病毒感染,例如AIDS、病毒性肝炎,或慢性细菌感染。细胞、组织或实体器官移植物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、联合心肺、肾脏、肝脏、肠、胰、气管或食管。
就上述用途而言,所需剂量当然将因给药方式、所治疗的特定病症和所需效果而异。通常而言,以约0.03至2.5mg/kg体重的日剂量全身给药可以获得令人满意的结果。大型哺乳动物、例如人类的指定每日剂量在约0.5mg至约100mg的范围内,方便地以例如一天至多四次的分开剂量或以延迟形式施用。适于口服给药的单元剂型包含约1至50mg活性成分。
本发明的化合物可以借助任意常规途径给药,特别是肠内途径,例如口服,例如以片剂或胶囊形式;胃肠道外途径,例如以可注射溶液或混悬液形式;局部途径,例如以洗剂、凝胶、软膏或霜剂形式,或者鼻用或栓剂形式。包含游离形式或可药用盐形式的本发明的化合物以及至少一种可药用载体或稀释剂的药物组合物可按照常规方式与可药用载体或稀释剂混合来生产。
本发明的化合物可以按游离形式或可药用盐形式给药,例如上文所示。这类盐可以按常规方式制备,表现出与游离化合物相同级别的活性。
按照上述,本发明进一步提供了:
1.1在需要这类治疗的受治疗者中预防或治疗由淋巴细胞介导的紊乱或疾病、例如上文所示那些的方法,该方法包括对所述受治疗者给予有效量的包含大于70%重量的R或S对映异构体的式II化合物或其可药用盐;
1.2在需要这类治疗的受治疗者中预防或治疗急性或慢性移植排斥或者T-细胞介导的炎性或自身免疫性疾病、例如上文所示那些的方法,该方法包括对所述受治疗者给予有效量的包含大于70%重量的R或S对映异构体的式II化合物或其可药用盐;
2.游离形式或可药用盐形式的包含大于70%重量的R或S对映异构体的式II化合物,用作药物,例如在上文1.1或1.2项下所示的任一方法中用作药物;
3.药物组合物,例如用于上文1.1或1.2项下所示的任一方法,该组合物含有游离形式或可药用盐形式的包含大于70%重量的R或S对映异构体的式II化合物以及用于此的可药用稀释剂或载体;
4.包含大于70%重量的R或S对映异构体的式II化合物或其可药用盐,用于制备药物组合物,该组合物用于上文1.1或1.2项下所示的任一方法。
本发明的化合物可以作为唯一活性成分给药或者例如作为辅药与其它药物组合给药,其它药物例如是免疫抑制或免疫调节剂或者其它抗炎剂,例如用于治疗或预防同种异体或异种移植物急性或慢性排斥或者炎性或自身免疫性紊乱,或者化疗剂,例如恶性细胞抗增殖剂。例如,本发明的化合物可以与下列药物组合使用:钙调磷酸酶抑制剂,例如环孢菌素A或FK506;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟乙基)-雷帕霉素、CC1779或ABT578;具有免疫抑制性质的子囊菌素,例如ABT-281、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;麦考酚酸吗乙酯;15-脱氧精胍菌素或其免疫抑制同系物、类似物或衍生物;免疫抑制性单克隆抗体,例如白细胞受体的单克隆抗体,例如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD58、CD80、CD86或它们的配体;其它免疫调节化合物,例如具有CTLA4或其突变体胞外域的至少一部分、例如与非-CTLA4蛋白序列连接的CTLA4或其突变体胞外域的至少一部分、例如CTLA4Ig(例如指定为ATCC68629)或其突变体的重组结合分子,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;或者化疗剂,例如紫杉醇、吉西他滨、顺铂、阿霉素或5-氟尿嘧啶。
若本发明的化合物与其它免疫抑制/免疫调节、抗炎或化疗疗法组合施用,共同施用的免疫抑制、免疫调节、抗炎或化疗化合物的剂量当然将依赖于所采用的辅助药物类型(例如它是类固醇或钙调磷酸酶抑制剂)、所用具体药物、所治疗的病症等而不同。按照上述,本发明在更进一步的方面提供了:
5.如上所定义的方法,该方法包括共同施用、例如同时或依次施用治疗有效无毒量的本发明的化合物和至少一种第二种药物物质,所述第二种药物物质例如是免疫抑制药、免疫调节药、抗炎药或化疗药,例如上文所示;
6.药物组合,例如药盒,包含a)第一种药物,它是如本文所公开的游离形式或可药用盐形式的本发明的化合物,和b)至少一种辅助药物,例如免疫抑制药、免疫调节药、抗炎药或化疗药。药盒可包含其施用指导。
本文所用的术语“共同给药”或“组合给药”等意欲涵盖所选择的治疗剂对个体患者给药,并且意欲包括其中各成分不一定借助相同给药途径或者同时给药的治疗方案。
本文所用的术语“药物组合”表示将一种以上活性成分混合或合并所得的产品,包括活性成分的固定和不固定组合。术语“固定组合”意味着活性成分、例如本发明的化合物和辅助成分以单一实体或剂量形式同时施用于患者。术语“不固定组合”意味着活性成分、例如本发明的化合物和辅助成分作为单独实体同时、并行或没有具体时间限制地依次施用于患者,其中所述施用给患者体内提供了治疗有效水平的两种化合物。后者还应用于鸡尾酒疗法,例如施用3种或3种以上活性成分。
在其它方面,本发明提供了分离式I化合物的R与S对映异构体的方法,该方法包括通过采用手性离子交换相的高效液相色谱法(HPLC)分离对映异构体,例如如上所述基于氨基甲酸奎宁或氨基甲酸奎尼丁。
在其它方面,本发明提供了确定样品中式II化合物的R和/或S异构体含量的方法,该方法包括(a)使样品中的式II化合物与苯-1,2-二甲醛反应,生成式I化合物,通过HPLC分离式I化合物的R与S异构体。优选如上所述进行HPLC,采用手性离子交换相,例如基于氨基甲酸奎宁或氨基甲酸奎尼丁。式I化合物在该方法中可用作中间体。样品可以是例如来自体液的样品,例如血液、血浆、唾液或尿液,可以首先进行一个或一个以上的分离步骤(例如甲醇萃取和/或非手性HPLC),目的是从体液中分离出式II化合物。借助这样的方法,可以测定样品中活性R或S对映异构体的量。因而,该方法可用于例如在对受治疗者给予式II化合物(例如其外消旋混合物)或式II化合物前体(体内生成代谢产物式II化合物)之后,监测受治疗者中式II化合物的活性S对映异构体的血药浓度。
例如,对大鼠口服(7.5mg/kg)或静脉内输注(4mg/kg)给予手性14C-标记的FTY720。手性14C-标记的FTY720-磷酸酯在大鼠体内作为14C-标记的FTY720的代谢产物生成。给药后在不同时间(例如3或72小时)取血样。每份血样用甲醇萃取,借助非手性HPLC分离出[14C]FTY720-磷酸酯。将所分离的[14C]FTY720-磷酸酯用OPA衍生化。衍生物中掺入未标记的OPA-衍生化R-与S-FTY720-磷酸酯作为保留时间标识物(在215nm用UV监测),利用ProntoSIL Chiral AX QN-1柱进行手性HPLC分离。所有血样中的[14C]FTY720-磷酸酯仅仅代表有药理活性的S-对映异构体。无活性的R-对映异构体是不可检测的。
Claims (10)
1.游离形式或盐形式的式I化合物:
其中:
m和n各自独立地是1、2或3;
X是O或直键;
R1是
-其中烷基是直链或支链(C6-20)碳链的苯基烷基;或者
-其中烷基是直链或支链(C1-30)碳链的苯基烷基,其中所述苯基烷基在苯基残基上被如下基团取代:
-任选被卤素取代的直链或支链(C6-20)碳链,
-任选被卤素取代的直链或支链(C6-20)烷氧基链,
-直链或支链(C6-20)链烯氧基,
-苯基烷氧基、卤代苯基烷氧基、苯基烷氧基烷基、苯氧基烷氧基或苯氧基烷基,
-被C6-20烷基取代的环烷基烷基,
-被C6-20烷基取代的杂芳基烷基,
-杂环C6-20烷基,或
-被C2-20烷基取代的杂环烷基,
且其中,烷基部分可以
-在碳链中具有选自双键、叁键、O、S、亚磺酰基、磺酰基或NR5的键或杂原子,其中R5是H、烷基、芳烷基、酰基或烷氧羰基,
-具有作为取代基的烷氧基、链烯氧基、炔氧基、芳烷氧基、酰基、烷基氨基、烷硫基、酰基氨基、烷氧羰基、烷氧羰基氨基、酰氧基、烷基氨甲酰基、硝基、卤素、氨基、羟基或羧基,且
R2是
其中R3和R4各自独立地是H或C1-4烷基,其中烷基任选被1、2或3个卤原子取代。
3.根据权利要求1的式I化合物或根据权利要求2的式II化合物,为基本上纯的对映异构体形式,具有下述三维构型
优选磷酸单-[2-氨基-2-羟甲基-4-(4-辛基-苯基)-丁基]酯和磷酸单-[2-羟甲基-4-(4-辛基-苯基)-2-(1-氧代-1,3-二氢-异吲哚-2-基)-丁基]酯的S对映异构体。
4.生产式I化合物的方法,该方法包括使如权利要求2所定义的式II化合物与芳族1,2-二甲醛反应,并回收游离或盐形式的所得式I化合物。
6.分离式I化合物的R与S对映异构体的方法,该方法包括通过采用基于氨基甲酸奎宁或氨基甲酸奎尼丁的手性离子交换相的高效液相色谱法(HPLC)分离对映异构体。
7.测定样品中式II化合物的R和/或S异构体含量的方法,该方法包括(a)使样品中的式II化合物与芳族1,2-二甲醛反应,生成式I化合物,通过HPLC分离式I化合物的R与S异构体。
8.游离形式或可药用盐形式的如权利要求2所定义的化合物,用作药物。
9.在需要这类治疗的受治疗者中预防或治疗急性或慢性移植排斥或者T-细胞介导的炎性或自身免疫性疾病的方法,该方法包括对所述受治疗者给予有效量的如权利要求2所定义的化合物或其可药用盐。
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CN2004800262367A Expired - Fee Related CN1874996B (zh) | 2003-08-28 | 2004-08-27 | 氨基丙醇衍生物 |
CN2011100601438A Expired - Fee Related CN102175786B (zh) | 2003-08-28 | 2004-08-27 | 氨基丙醇衍生物 |
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CN2004800262367A Expired - Fee Related CN1874996B (zh) | 2003-08-28 | 2004-08-27 | 氨基丙醇衍生物 |
CN2011100601438A Expired - Fee Related CN102175786B (zh) | 2003-08-28 | 2004-08-27 | 氨基丙醇衍生物 |
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US (4) | US7528120B2 (zh) |
EP (1) | EP1660449B1 (zh) |
JP (1) | JP5001653B2 (zh) |
CN (3) | CN103193822A (zh) |
AT (1) | ATE449069T1 (zh) |
AU (1) | AU2004268052B2 (zh) |
BR (1) | BRPI0413151A (zh) |
CA (1) | CA2535704C (zh) |
DE (1) | DE602004024213D1 (zh) |
ES (1) | ES2335410T3 (zh) |
MX (1) | MXPA06002349A (zh) |
PL (1) | PL1660449T3 (zh) |
PT (1) | PT1660449E (zh) |
WO (1) | WO2005021503A1 (zh) |
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WO2006009092A1 (ja) * | 2004-07-16 | 2006-01-26 | Kyorin Pharmaceutical Co., Ltd. | 効果的な医薬の使用法及び副作用発現の防御に関する方法 |
ES2563034T3 (es) | 2004-10-12 | 2016-03-10 | Kyorin Pharmaceutical Co., Ltd. | Procedimiento para producir hidrocloruro de 2-amino-2-[2-[4-(3-benciloxifeniltio)-2-clorofenil]etil]-1,3-propanodiol e hidratos del mismo, e intermedios para la producción de los mismos |
WO2007028821A2 (en) * | 2005-09-09 | 2007-03-15 | Novartis Ag | Treatment of autoimmune diseases |
CN101277687B (zh) * | 2005-10-07 | 2012-07-18 | 杏林制药株式会社 | 以2-氨基-1,3-丙二醇衍生物作为有效成分的肝脏疾病治疗剂及肝脏疾病治疗方法 |
TWI389683B (zh) * | 2006-02-06 | 2013-03-21 | Kyorin Seiyaku Kk | A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient |
MY152176A (en) * | 2006-08-08 | 2014-08-15 | Kyorin Seiyaku Kk | Amino phosphate derivative and s1p receptor modulator having same as an active ingredient |
RU2458044C2 (ru) * | 2006-08-08 | 2012-08-10 | Киорин Фармасьютикал Ко., Лтд. | Производное аминоспирта и иммунодепрессивное средство, содержащее его в качестве активного ингредиента |
KR101710845B1 (ko) | 2007-10-12 | 2017-02-27 | 노파르티스 아게 | 스핑고신 1 포스페이트 (s1p) 수용체 조절제를 포함하는 조성물 |
WO2009099174A1 (ja) | 2008-02-07 | 2009-08-13 | Kyorin Pharmaceutical Co., Ltd. | アミノアルコール誘導体を有効成分とする炎症性腸疾患の治療剤又は予防剤 |
KR20190004843A (ko) | 2008-07-23 | 2019-01-14 | 아레나 파마슈티칼스, 인크. | 자가면역성 및 염증성의 장애의 치료에 유용한 치환된 1,2,3,4-테트라히드로시클로펜타[b]인돌-3-일)아세트산 유도체 |
JP5726737B2 (ja) | 2008-08-27 | 2015-06-03 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 自己免疫障害および免疫性障害の治療において有用なs1p1受容体のアゴニストとしての置換三環式酸誘導体 |
US20120244071A1 (en) * | 2009-12-10 | 2012-09-27 | Novartis Ag | Fty720 halogenated derivatives |
CN103221391B (zh) | 2010-01-27 | 2018-07-06 | 艾尼纳制药公司 | (R)-2-(7-(4-环戊基-3-(三氟甲基)苄基氧基)-1,2,3,4-四氢环戊二烯并[b]吲哚-3-基)乙酸及其盐的制备方法 |
EP2542554B1 (en) | 2010-03-03 | 2015-11-04 | Arena Pharmaceuticals, Inc. | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
AU2011249789B2 (en) | 2010-05-06 | 2015-03-19 | Novartis Ag | Dosage regimen of diaryl sulfide derivatives |
WO2011138393A1 (en) | 2010-05-06 | 2011-11-10 | Novartis Ag | Treatment of autoimmune diseases |
EP2671877A4 (en) * | 2011-01-31 | 2015-07-01 | Univ Nagasaki | PROCESS FOR PRODUCING OPTICALLY ACTIVE COMPOUND OR SALT THEREOF |
NZ734220A (en) | 2015-01-06 | 2022-01-28 | Arena Pharm Inc | Methods of treating conditions related to the s1p1 receptor |
IL285890B (en) | 2015-06-22 | 2022-07-01 | Arena Pharm Inc | Slate-free crystal of the arginine salt of (Ar)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-4,3,2,1-tetrahydro-cyclopent[b]indole-3-yl ) acetic acid |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
KR20190113955A (ko) | 2017-02-16 | 2019-10-08 | 아레나 파마슈티칼스, 인크. | 장-외 증상을 갖는 염증성 장질환의 치료를 위한 화합물 및 방법 |
GB201715786D0 (en) * | 2017-09-29 | 2017-11-15 | Univ College Cardiff Consultants Ltd | Compounds |
CN112955431A (zh) | 2018-09-06 | 2021-06-11 | 艾尼纳制药公司 | 可用于治疗自身免疫性病症和炎性病症的化合物 |
CN111537635B (zh) * | 2020-05-11 | 2021-04-06 | 成都市科隆化学品有限公司 | 精确配制醋酸标准曲线溶液及保护氨基酸醋酸检测方法 |
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US6437165B1 (en) * | 2000-08-31 | 2002-08-20 | Merck & Co., Inc. | Phosphate derivatives as immunoregulatory agents |
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CA2442178A1 (en) * | 2001-03-26 | 2002-10-03 | Novartis Ag | 2-amino-propanol derivatives |
US7612238B2 (en) * | 2002-09-13 | 2009-11-03 | Novartis Ag | Amino-propanol derivatives |
DE60330187D1 (de) * | 2002-12-30 | 2009-12-31 | Celgene Corp | Fluoralkoxy-substituierte 1, 3-dihydro-isoindolyl-verbindungen und ihre pharmazeutischen verwendungen |
US7625950B2 (en) * | 2003-04-30 | 2009-12-01 | Novartis Ag | Amino-propanol derivatives as sphingosine-1-phosphate receptor modulator |
US7129260B2 (en) * | 2003-06-02 | 2006-10-31 | Abbott Laboratories | Isoindolinone kinase inhibitors |
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2004
- 2004-08-27 AT AT04764563T patent/ATE449069T1/de active
- 2004-08-27 CN CN2013100825423A patent/CN103193822A/zh active Pending
- 2004-08-27 US US10/569,696 patent/US7528120B2/en not_active Expired - Fee Related
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- 2004-08-27 PL PL04764563T patent/PL1660449T3/pl unknown
- 2004-08-27 MX MXPA06002349A patent/MXPA06002349A/es active IP Right Grant
- 2004-08-27 PT PT04764563T patent/PT1660449E/pt unknown
- 2004-08-27 CN CN2004800262367A patent/CN1874996B/zh not_active Expired - Fee Related
- 2004-08-27 BR BRPI0413151-7A patent/BRPI0413151A/pt not_active IP Right Cessation
- 2004-08-27 EP EP04764563A patent/EP1660449B1/en not_active Expired - Lifetime
- 2004-08-27 WO PCT/EP2004/009589 patent/WO2005021503A1/en active Application Filing
- 2004-08-27 JP JP2006524339A patent/JP5001653B2/ja not_active Expired - Fee Related
- 2004-08-27 CA CA2535704A patent/CA2535704C/en not_active Expired - Fee Related
- 2004-08-27 CN CN2011100601438A patent/CN102175786B/zh not_active Expired - Fee Related
- 2004-08-27 DE DE602004024213T patent/DE602004024213D1/de not_active Expired - Lifetime
- 2004-08-27 ES ES04764563T patent/ES2335410T3/es not_active Expired - Lifetime
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2009
- 2009-02-24 US US12/391,298 patent/US7902175B2/en not_active Expired - Fee Related
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2011
- 2011-01-28 US US13/015,825 patent/US20110118210A1/en not_active Abandoned
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- 2012-07-11 US US13/546,490 patent/US20120277194A1/en not_active Abandoned
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US6437165B1 (en) * | 2000-08-31 | 2002-08-20 | Merck & Co., Inc. | Phosphate derivatives as immunoregulatory agents |
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MXPA06002349A (es) | 2006-05-22 |
US20090156556A1 (en) | 2009-06-18 |
US7528120B2 (en) | 2009-05-05 |
EP1660449B1 (en) | 2009-11-18 |
DE602004024213D1 (en) | 2009-12-31 |
AU2004268052B2 (en) | 2009-11-19 |
US20110118210A1 (en) | 2011-05-19 |
CA2535704A1 (en) | 2005-03-10 |
CN102175786A (zh) | 2011-09-07 |
ES2335410T8 (es) | 2011-07-01 |
US7902175B2 (en) | 2011-03-08 |
US20120277194A1 (en) | 2012-11-01 |
CN1874996A (zh) | 2006-12-06 |
JP5001653B2 (ja) | 2012-08-15 |
CN102175786B (zh) | 2013-07-17 |
PL1660449T3 (pl) | 2010-05-31 |
WO2005021503A1 (en) | 2005-03-10 |
US20060264403A1 (en) | 2006-11-23 |
BRPI0413151A (pt) | 2006-10-03 |
CN1874996B (zh) | 2011-05-18 |
ES2335410T3 (es) | 2010-03-26 |
AU2004268052A1 (en) | 2005-03-10 |
ATE449069T1 (de) | 2009-12-15 |
JP2007504111A (ja) | 2007-03-01 |
EP1660449A1 (en) | 2006-05-31 |
PT1660449E (pt) | 2010-01-21 |
CA2535704C (en) | 2012-12-11 |
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