CN1934069A - 氨基酸衍生物 - Google Patents
氨基酸衍生物 Download PDFInfo
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- CN1934069A CN1934069A CNA2005800095759A CN200580009575A CN1934069A CN 1934069 A CN1934069 A CN 1934069A CN A2005800095759 A CNA2005800095759 A CN A2005800095759A CN 200580009575 A CN200580009575 A CN 200580009575A CN 1934069 A CN1934069 A CN 1934069A
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Abstract
本发明涉及新的氨基酸衍生物、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
本发明涉及氨基酸衍生物、它们的制备方法、它们的用途和包含它们的药物组合物。
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
R1是任选地被OH、C1-2烷氧基或1-6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C1-12烷基,其任选地被以下基团取代:卤素、任选地被取代的环烷基、任选地被取代的苯基、任选地被取代的杂芳基或任选地被取代的杂环基,
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/或杂环基可以被1-5个取代基取代,该取代基选自羟基;卤素;C1-4烷基;被1-5个氟原子取代的C1-4烷基;C1-4烷氧基;被1-5个氟原子取代的C1-4烷氧基;氰基;苯基;和被1-5个选自羟基、卤素、C1-4烷基、被1-5个氟原子取代的C1-4烷基、C1-4烷氧基、被1-5个氟原子取代的C1-4烷氧基和氰基的取代基取代的苯基;
R7是H、任选地被取代的苯基、任选地被取代的杂芳基,其中苯基和/或杂芳基独立地可以被1-5个选自羟基、卤素、C1-4烷基、被1-5个氟原子取代的C1-4烷基、C1-4烷氧基、被1-5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-A-B-COOH,其中A和B各自独立地是键、C=O或CDE,其中D和E各自独立地是H、卤素、C1-3烷基、OH;条件是A和B不均是C=O;和
R4和R5各自独立地是H、任选地被1、2或3个卤素原子取代的C1-4烷基或酰基。
烷基或烷基部分可以是直链或支链,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。炔基可以是例如丙炔-2-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1-4个选自N、O和S的杂原子的5-8元芳环,例如吡啶基、嘧啶基、吡嗪基、呋喃基、唑基、异唑基、噻吩基、噻唑基、异噻唑基、吡咯基、咪唑基或吡唑基。
杂环基是指3-8元、优选5-8元的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以盐形式存在,所述盐形式例如与例如无机酸的加成盐,如盐酸盐、氢溴酸盐或硫酸盐;与有机酸的加成盐,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;羧酸基团也可以以盐形式存在,例如铵盐或与金属如钠、钾、钙、锌或镁的盐,或它们的混合物。水合物或溶剂合物形式的式I化合物和它们的盐也是本发明的一部分。
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。本发明也包括对映体、外消旋物、非对映异构体以及它们的混合物。例如,带有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一般是优选的:
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存在上述不对称碳原子或不饱和键的原料,例如下述的式II、III或IV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CH2-COOH;
3.R4和R5各自是氢;
4.R7是氢、苯基或噻吩基;
5.X是O或键;和
6.如果R2是式a的基团,XR6在-(CH2)2-CR1R3(NR4R5)的对位。
本发明也包括制备式I化合物的方法,该方法包括除去式II化合物中存在的保护基团,
其中R1、R2和R5如上文所定义,R3’是-A-B-COOR8,其中A和B如上文所定义,R8是可水解的或可氢解的基团,并且R4’是氨基保护基团,和,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,例如通过水解进行,例如在酸性介质中、例如用盐酸水解。氨基保护基团的实例有例如在“ProtectiveGroups in Organic 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所公开的那些,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,该方法包括将式III化合物烷基化,
其中R1、R3’、R4’和R5如上文所定义,且R2’是式a’或b’的基团,
以引入所需的残基R6。
式III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Mirsunobu方法(例如,如Hughes,Organic Preparationsand Procedures International 28,127-64,1996或D.L.Hughes,Org.React.42,335,1992中所公开的那样)在溶液中或在固相支持合成物上、例如通过将式III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。
本发明也包括制备式I化合物的方法,该方法包括水解式IV化合物中存在的氰基,
其中R1、R2和R5如上文所定义,R3’是-A-B-CN并且R4’是氨基保护基团,和,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。
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那样进行制备。
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 =二甲基甲酰胺
HPLC =高效液相色谱法
DMSO =二甲亚砜
THF =四氢呋喃
AcOEt =乙酸乙酯
实施例1:(R)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊酸
在微波容器中,将搅拌的[(R)-1-氰甲基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(136mg,0.34mMol)在二烷(2mL)中的溶液用盐酸(37%水溶液,1mL)处理。将混合物加热至160℃达1.3小时。然后,将反应混合物冷却至室温并且在减压下浓缩。用制备型HPLC处理,用5%→95%乙腈的水溶液(+0.1%三氟乙酸)洗脱,得到标题化合物,为无定形白色粉末。
1H-NMR(d6-DMSO):7.95(br s,1H),7.06(d,J=9Hz,2H),6.83(d,J=9Hz,2H),3.89(t,J=7Hz,2H),3.40-3.20(m,2H),2.53-2.45(m,2H),1.86-1.75(m,2H),1.66(q,J=8Hz,2H),1.41-1.20(m,11H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=322.1[M+H]+。
[(R)-1-氰甲基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯的制备
向搅拌的(R)-4-[2-(4-庚氧基-苯基)-乙基]-4-甲基-2,2-二氧代-2λ*6*-[1,2,3]噻唑烷(oxathiazolidine)-3-甲酸叔丁酯(174mg,0.40mMol)在DMF(5mL)中的溶液中加入氰化钠(94mg,1.91mMol)。将混合物在室温下搅拌25小时。加入另外的氰化钠(37mg,0.76mMol)并且将混合物在室温下搅拌18小时。然后,将反应混合物倒在AcOEt与NaHCO3(饱和水溶液)的二相混合物上。水相用AcOEt萃取两次。将合并的有机层干燥(Na2SO4)并在减压下浓缩。用柱色谱法处理,用5%AcOEt的甲苯溶液洗脱,得到标题化合物,为无色油状物。
1H-NMR(CDCl3):7.09-7.04(m,2H),6.83-6.78(m,2H),4.59(br s,1H),3.91(t,J=7Hz,2H),3.08(br d,J=7Hz,1H),2.78(d,J=7Hz,1H),2.59-2.50(m,2H),2.32-2.20(m,1H),1.82-1.70(m,3H),1.48(s,9H),1.48-1.18(m,11H),0.90(t,J=7Hz,3H)。MS(ESI+):m/z=468.3[M+CH3CN+Na]+,827.6[2M+Na]+。
(R)-4-[2-(4-庚氧基-苯基)-乙基]-4-甲基-2,2-二氧代-2λ*6*-[1,2,3]噻唑烷-3-甲酸叔丁酯的制备
向搅拌的(R)-4-[2-(4-庚氧基-苯基)-乙基]-4-甲基-2-氧代-[1,2,3]噻唑烷-3-甲酸叔丁酯(275mg,0.63mMol)在乙腈/水(9/1,10mL)中的溶液中加入高碘酸钠(401mg,1.88mmol)和氯化钌(III)(13mg,0.06mMol)。将混合物在室温下搅拌18小时。加入另外的氯化钌(III)(65mg,0.3mMol)并且将混合物在室温下搅拌65小时。然后,将反应混合物通过硅藻土垫过滤,将滤液倒在AcOEt与Na2S2O3(饱和水溶液)的二相混合物上。水相用AcOEt萃取三次。将合并的有机层干燥(Na2SO4)并在减压下浓缩。用柱色谱法处理,用5%→15%AcOEt的庚烷溶液洗脱,得到标题化合物,为无色油状物。
1H-NMR(CDCl3):7.07(d,J=8Hz,2H),6.81(d,J=8Hz,2H),4.42(d,J=9Hz,1H),4.16(d,J=9Hz,1H),3.92(t,J=6Hz,2H),2.67-2.50(m,2H),2.43-2.32(m,1H),2.09-1.95(m,1H),1.75(qt,J=7Hz,2H),1.62(s,3H),1.53(s,9H),1.50-1.22(m,8H),0.90(t,J=7Hz,3H)。MS(ESI+):m/z=478.2[M+Na]+,933.4[2M+Na]+。
(R)-4-[2-(4-庚氧基-苯基)-乙基]-4-甲基-2-氧代-[1,2,3]噻唑烷-3-甲酸叔丁酯的制备
将搅拌的亚硫酰氯(0.14mL,1.91mMol)在乙腈(10mL)中的溶液冷却至-40℃。在该温度下,依次加入[(R)-3-(4-庚氧基-苯基)-1-羟甲基-1-甲基-丙基]-氨基甲酸叔丁酯(300mg,0.76mMol)在乙腈(5mL)中的溶液和吡啶(0.31mL,3.81mMol)。使混合物历经2.5小时温热至10℃。然后,将反应混合物倒在AcOEt与HCl(水溶液,1M)的二相混合物上。水相用AcOEt萃取两次。将合并的有机层用NaHCO3(饱和水溶液)洗涤、干燥(Na2SO4 )并在减压下浓缩。用柱色谱法处理,用5%→15%AcOEt的庚烷溶液洗脱,得到标题化合物,为无色油状物(2种非对映体,dr=1∶1)。
非对映体1:1H-NMR(CDCl3):7.07(d,J=9Hz,2H),6.81(d,J=9Hz,2H),4.95(br d,J=9Hz,1H),4.28(d,J=9Hz,1H),3.92(t,J=6Hz,2H),2.62(dt,J=5Hz,8Hz,1H),2.50(dt,J=5Hz,8Hz,1H),2.40-2.28(m,1H),2.10-1.99(m,1H),1.76(qt,J=7Hz,2H),1.66-1.23(m,20H),0.90(t,J=7Hz,3H)。MS(ESI+):m/z=462.3[M+Na]+,901.6[2M+Na]+。
非对映体2:1H-NMR(CDCl3):7.04(d,J=8Hz,2H),6.80(d,J=8Hz,2H),4.82(br d,J=9Hz,1H),4.59(d,J=9Hz,1H),3.91(t,J=7Hz,2H),2.59(dt,J=5Hz,8Hz,1H),2.39(dt,J=5Hz,7Hz,1H),2.28-2.16(m,1H),1.93-1.82(m,1H),1.80-1.22(m,22H),0.90(t,J=7Hz,3H)。MS(ESI+):m/z=462.3[M+Na]+,901.6[2M+Na]+。
[(R)-3-(4-庚氧基-苯基)-1-羟甲基-1-甲基-丙基]-氨基甲酸叔丁酯的制备
向搅拌的[(R)-1-羟甲基-3-(4-羟基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(2.06g,6.98mMol)在乙醇(100mL)中的溶液中加入碳酸钾(2.90g,20.8mMol)和甲磺酸庚酯(2.04g,10.5mMol)。将混合物加热至回流温度并在该温度下搅拌6小时。然后,将混合物冷却至室温并在室温下搅拌过夜。然后,将反应混合物倒在AcOEt与HCl(水溶液,1M)的二相混合物上。水相用AcOEt萃取两次。将合并的有机层用NaHCO3(饱和水溶液)洗涤、干燥(Na2SO4)并在减压下浓缩。用柱色谱法处理,用8%AcOEt的甲苯溶液洗脱,得到标题化合物,为无色油状物。
1H-NMR(CDCl3):7.10-7.05(m,2H),6.81-6.76(m,2H),4.60(br s,1H),4.07(br s,1H),3.92(t,J=6Hz,2H),3.70(d,J=12Hz,1H),3.62(d,J=12Hz,1H),2.65-2.43(m,2H),2.07-1.94(m,1H),1.88-1.69(m,1H),1.68-1.60(m,2H),1.45(s,9H),1.50-1.25(m,8H),1.22(s,3H),0.88(t,J=7Hz,3H)。MS(ESI+):m/z=416.1[M+Na]+。
实施例2:(R)-2-氨基-4-(4-庚氧基-苯基)-2-甲基-丁酸
向搅拌的(R)-2-叔丁氧基羰基氨基-4-(4-庚氧基-苯基)-2-甲基-丁酸(43mg,0.11mMol)在CH2Cl2(2mL)中的溶液中加入三氟乙酸(0.1mL)。将混合物在室温下搅拌8小时。然后,将反应混合物在减压下浓缩。用柱色谱法处理,用5%→25%MeOH的CH2Cl2溶液洗脱,得到标题化合物,为无色油状物。
1H-NMR(d6-DMSO):8.32(br s,3H),7.02(d,J=8Hz,2H),6.81(d,J=8Hz,2H),3.88(t,J=7Hz,2H),2.70-2.58(m,1H),2.42-2.31(m,1H),2.04-1.83(m,2H),1.70-1.62(m,2H),1.45(s,3H),1.44-1.21(m,8H),0.72(t,J=7Hz,3H)。MS(ESI-):m/z=306.3[M-H]+。
(R)-2-叔丁氧基羰基氨基-4-(4-庚氧基-苯基)-2-甲基-丁酸的制备
向搅拌的[(R)-1-甲酰基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(103mg,0.26mMol)在叔丁醇(1mL)和10%KH2PO4水溶液(1mL)中的溶液中加入2-甲基-2-丁烯(0.66mL,5.27mMol)和亚氯酸钠(59mg,0.52mMol)。将混合物在室温下搅拌1小时。然后,将反应混合物倒在AcOEt与HCl(水溶液,1M)的二相混合物上。水相用AcOEt萃取两次。将合并的有机层用少量NaHCO3(饱和水溶液)洗涤、干燥(Na2SO4)并在减压下浓缩。用柱色谱法处理,用5%MeOH的CH2Cl2溶液洗脱,得到标题化合物,为无色油状物。
MS(ESI+):m/z=430.2[M+Na]+。
[(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
向搅拌的[(R)-1-羟甲基-3-(4-羟基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(1.98g,5.03mMol)在CH2Cl2(20mL)中的溶液中加入N-吗啉-N-氧化物(884mg,7.54mMol)和过镣酸四正丙基铵(177mg,0.50mMol)。将混合物在室温下搅拌1小时。然后,将混合物通过短SiO2垫过滤并用乙醚洗脱。将滤液在减压下浓缩,得到标题混合物。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]+。
实施例3:(R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己酸
向搅拌的(R)-4-叔丁氧基羰基氨基-6-(4-庚氧基-苯基)-4-甲基-己酸(24mg,0.06mMol)在CH2Cl2(2mL)中的溶液中加入三氟乙酸(0.1mL)。将混合物在室温下搅拌6.5小时。然后,将反应混合物在减压下浓缩,得到标题化合物,为无定形白色粉末。该粗产物足够纯,可不经进一步纯化直接使用。
1H-NMR(d6-DMSO):7.81(br s,3H),7.12-7.07(m,2H),6.85-6.81(m,2H),3.90(t,J=7Hz,2H),2.52-2.29(m,4H),1.88-1.80(m,2H),1.77-1.62(m,4H),1.40-1.21(m,11H),0.85(t,J=7Hz,3H)。MS(ESI+):m/z=336.2[M+H]+。
(R)-4-叔丁氧基羰基氨基-6-(4-庚氧基-苯基)-4-甲基-己酸的制备
向搅拌的(E)-(R)-4-叔丁氧基羰基氨基-6-(4-庚氧基-苯基)-4-甲基己-2-烯酸(53mg,0.12mMol)在AcOEt(10mL)中的溶液中加入披钯碳(10mg,10%)。将反应在H2气氛下于室温下搅拌17小时。将反应混合物通过硅藻土过滤,将滤液在减压下浓缩,得到标题混合物,为无色油状物。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):7.06(d,J=9Hz,2H),6.80(d,J=9Hz,2H),4.42(br s,1H),3.92(t,J=6Hz,2H),2.51(t,J=8Hz,2H),2.38(t,J=8Hz,2H),2.28-2.17(m,1H),2.11-2.00(m,1H),1.97-1.70(m,4H),1.50-1.22(m,20H),0.90(t,J=7Hz,3H)。MS(ESI-):m/z=434.4[M-H]+。
(E)-(R)-4-叔丁氧基羰基氨基-6-(4-庚氧基-苯基)-4-甲基-己-2-烯酸的制备
向搅拌的(E)-(R)-4-叔丁氧基羰基氨基-6-(4-庚氧基-苯基)-4-甲基己-2-烯酸乙酯(56mg,0.12mMol)在甲醇(0.5mL)、THF(0.5mL)和水(0.5mL)中的溶液中加入氢氧化锂(14mg,0.61mMol)。将混合物在室温下搅拌3.5小时。然后,将反应混合物倒在AcOEt与HCl(水溶液,1M)的二相混合物上。水相用AcOEt萃取两次。将合并的有机层用少量NaHCO3(饱和水溶液)洗涤、干燥(Na2SO4)并在减压下浓缩,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(d6-DMSO):12.3(br s,1H),7.08-7.00(m,2H),6.91(br s,1H),6.83(d,J=16Hz,1H),6.79-6.75(m,2H),5.67(d,J=16Hz,1H),3.88(t,J=7Hz,2H),2.50-2.31(m,1H),2.00-1.89(m,1H),1.79-1.60(m,4H),1.40-1.19(m,20H),0.83(t,J=7Hz,3H)。MS(ESI+):m/z=456.3[M+Na]+。
(E)-(R)-4-叔丁氧基羰基氨基-6-(4-庚氧基-苯基)-4-甲基-己-2-烯酸乙酯的制备
在-78℃下,向搅拌的(二乙氧基-磷酰基)-乙酸乙酯(429mg,1.92mMol)在干燥THF(7mL)中的溶液中加入正丁基锂(0.66mL,2.5M的己烷溶液,1.66mMol)。将混合物在-78℃下搅拌1小时。然后,加入[(R)-1-甲酰基-3-(4-庚氧基-苯基)-1-甲基-丙基]-氨基甲酸叔丁酯(500mg,1.28mMol)在THF(4mL)中的溶液并且在-78℃下继续搅拌1.5小时。使混合物温热至室温,然后在室温下搅拌2小时。然后,将反应混合物倒在AcOEt与NaHCO3(饱和水溶液)的二相混合物上,水相用AcOEt萃取两次。将合并的有机层干燥(Na2SO4)并在减压下浓缩。用柱色谱法处理,用4%AcOEt的甲苯溶液洗脱,得到标题化合物,为无色油状物。
1H-NMR(CDCl3):7.10-7.01(m,2H),7.00(d,J=16Hz,1H),6.83-6.78(m,2H),5.86(d,J=16Hz,1H),4.60(br s,1H),4.20(q,J=7Hz,2H),3.92(t,J=7Hz,2H),2.55-2.48(m,2H),2.11-2.01(m,1H),1.99-1.86(m,1H),1.80-1.71(m,2H),1.56(s,3H),1.48-1.22(m,20H),0.89(t,J=7Hz,3H)。
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显示的那样,因此它们适合用于治疗。
A体外
如在以下测定中所测定的那样,式I化合物对于各个人S1P受体具有结合亲和性。
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、10μM GDP、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]。用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受体的结合亲和性<50nM。
实施例 | S1P1EC50[nM] | S1P3EC50[nM] | S1P4EC50[nM] | S1P5EC50[nM] |
1 | 11 Agon | 209 Agon | 117 Agon | 203 Agon |
Agon=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1:3.2mg/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障碍,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障碍、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 ophthalmopathy)、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、免疫学介导的障碍的皮肤表征、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、成人型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、待治疗的特定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令人满意的结果。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;或胃肠外施用,例如以可注射溶液剂或混悬剂的形式胃肠外施用;局部施用,例如以洗剂、凝胶剂、软膏剂或乳膏剂的形式局部施用;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。
式I化合物可以以游离形式或以可药用盐形式、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在需要这类治疗的个体中预防或治疗淋巴细胞介导的障碍或疾病、例如上述那些的方法,该方法包括对所述个体施用有效量的式I化合物或其可药用盐;
1.2在需要这类治疗的个体中预防或治疗急性或慢性移植物排斥反应或T细胞介导的炎性或自身免疫性疾病、例如上述那些的方法,该方法包括对所述个体施用有效量的式I化合物或其可药用盐;
2.用作药物、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,或者与例如作为辅剂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者炎性或自身免疫性障碍的上述药物;或化疗剂,例如抗恶性细胞增殖剂。例如,式I化合物可以与以下物质组合使用:钙调磷酸酶抑制剂,例如环孢菌素A、FK 506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、TAFA-93、biolimus 7或biolimus 9;具有免疫抑制性质的子囊霉素,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-去氧斯潘格宁或其免疫抑制同系物、类似物或衍生物;免疫抑制单克隆抗体,例如白细胞受体例如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,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(例如其是甾类化合物还是钙调磷酸酶抑制剂)、所用的特定药物、待治疗的病症等而变化。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、抗炎或化疗药物,例如上文所述的那些。
6.药物组合,例如套药盒,其包含a)第一种物质,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)至少一种联用物质,例如免疫抑制剂、免疫调节剂、抗炎剂、化疗剂或抗感染剂。该套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化合物与联用物质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化合物与联用物质作为分开的实体被同时、并行或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治疗有效水平的2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)
1.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1-6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C1-12烷基,其任选地被以下基团取代:卤素、任选地被取代的环烷基、任选地被取代的苯基、任选地被取代的杂芳基或任选地被取代的杂环基,
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/或杂环基可以被1-5个取代基取代,该取代基选自羟基;卤素;C1-4烷基;被1-5个氟原子取代的C1-4烷基;C1-4烷氧基;被1-5个氟原子取代的C1-4烷氧基;氰基;苯基;和被1-5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、任选地被取代的苯基、任选地被取代的杂芳基,其中苯基和/或杂芳基独立地可以被1-5个选自羟基、卤素、C1-4烷基、被1-5个氟原子取代的C1-4烷基、C1-4烷氧基、被1-5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O;
R3是-A-B-COOH,其中A和B各自独立地是键、C=O或CDE,其中D和E各自独立地是H、卤素、C1-3烷基、OH;条件是A和B不均是C=O;和
R4和R5各自独立地是H、任选地被1、2或3个卤素原子取代的C1-4烷基或酰基;
条件是:如果R4是H,R5是H,R3是COOH,R2是式a的基团并且R7是H,
i)R1是CH2OH且XR6是未被取代的C1-12烷基,那么XR6不在(CH2)2-CR1R3(NR4R5)的对位;或者
ii)R1是CH3且XR6是未被取代的OC1-12烷基,那么XR6不在(CH2)2-CR1R3(NR4R5)的间位。
2.式II化合物或其盐
其中R1至R3和R5如权利要求1中所定义,并且R4’是保护基团。
3.根据权利要求1或权利要求2所述的化合物,该化合物选自(R)-3-氨基-5-(4-庚氧基-苯基)-3-甲基-戊酸、(R)-4-氨基-6-(4-庚氧基-苯基)-4-甲基-己酸和(R)-2-氨基-4-(4-庚氧基-苯基)-2-甲基-丁酸。
4.药物组合物,其包含权利要求1至3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一种或多种可药用的稀释剂或载体。
5.用作药物的权利要求1至3中任意一项所述的游离形式或可药用盐形式的化合物或权利要求4所述的组合物。
6.权利要求1-3中任意一项所述的游离形式或可药用盐形式的化合物或权利要求4所述的药物组合物在制备药物中的用途,所述药物用于治疗或预防同种异体移植物排斥反应、自身免疫性疾病、移植物抗宿主病、炎性疾病、心肌炎、肝炎、缺血/再灌注损伤、出血性休克、外伤性休克、血管生成、阿尔茨海默病、癌症、感染性疾病或老年性痴呆。
7.药物组合,其包含权利要求1至3中任意一项所述的游离形式或可药用盐形式的化合物和另一种选自免疫抑制剂、免疫调节剂、抗炎剂和化疗剂的物质。
9.治疗或预防同种异体移植物排斥反应、自身免疫性疾病、移植物抗宿主病、炎性疾病、心肌炎、肝炎、缺血/再灌注损伤、出血性休克、外伤性休克、血管生成、阿尔茨海默病、癌症、感染性疾病或老年性痴呆的方法,其包括对所述个体施用治疗有效量的权利要求1至3中任意一项所述的游离形式或可药用盐形式的化合物或权利要求4所述的药物组合物。
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CA2523677A1 (en) * | 2003-04-30 | 2004-11-11 | Novartis Ag | Aminopropanol derivatives as sphingosine-1-phosphate receptor modulators |
PL1772145T3 (pl) * | 2004-07-16 | 2011-08-31 | Kyorin Seiyaku Kk | Sposób skutecznego stosowania leku i sposób dotyczący zapobiegania efektom ubocznym |
WO2006020951A1 (en) | 2004-08-13 | 2006-02-23 | Praecis Pharmaceuticals, Inc. | Methods and compositions for modulating sphingosine-1-phosphate (s1p) receptor activity |
KR101181090B1 (ko) | 2004-10-12 | 2012-09-07 | 교린 세이야꾸 가부시키 가이샤 | 2-아미노-2-[2-[4-(3-벤질옥시페닐티오)-2-클로로페닐]에틸]-1,3-프로판디올 염산염 또는 그 수화물의 제조방법 및 그 제조 중간체 |
MX2007004262A (es) * | 2004-10-12 | 2008-03-04 | Forbes Medi Tech Res Inc | Compuestos y metodos para tratar resistencia a la insulina y cardiomiopatia. |
AP2007004161A0 (en) | 2005-04-28 | 2007-10-31 | Pfizer Ltd | Amino acid derivatives |
PT1932522E (pt) * | 2005-10-07 | 2012-06-26 | Kyorin Seiyaku Kk | Agente terapêutico para doenças do fígado contendo, como princípio activo, um derivado de 2- amino-1,3-propanodiol |
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 |
NZ574011A (en) | 2006-08-08 | 2011-10-28 | Kyorin Seiyaku Kk | Aminophosphoric acid ester derivative and s1p receptor modulator containing the same as active ingredient |
MY146775A (en) | 2006-08-08 | 2012-09-28 | Kyorin Seiyaku Kk | Amino alcohol derivative and immunosuppressive agent having same as an active ingredient |
JP2009269819A (ja) * | 2006-08-25 | 2009-11-19 | Asahi Kasei Pharma Kk | アミン化合物 |
TW200946105A (en) | 2008-02-07 | 2009-11-16 | Kyorin Seiyaku Kk | Therapeutic agent or preventive agent for inflammatory bowel disease containing amino alcohol derivative as active ingredient |
HUE030424T2 (en) | 2008-07-23 | 2017-05-29 | Arena Pharm Inc | Substituted 1,2,3,4-tetrahydrocyclopenta [b] indol-3-ylacetic acid derivatives useful in the treatment of autoimmune and inflammatory disorders |
CN102119140B (zh) * | 2008-08-12 | 2014-09-03 | 阿勒根公司 | 1-磷酸鞘氨醇(s1p)受体拮抗剂及其使用方法 |
SI2342205T1 (sl) | 2008-08-27 | 2016-09-30 | Arena Pharmaceuticals, Inc. | Substituirani triciklični kislinski derivati kot agonisti S1P1 receptorja, uporabni v zdravljenju avtoimunskih in vnetnih obolenj |
ES2937386T3 (es) | 2010-01-27 | 2023-03-28 | Arena Pharm Inc | Procesos para la preparación de ácido (R)-2-(7-(4-ciclopentil-3-(trifluorometil)benciloxi)-1,2,3,4-tetrahidrociclopenta[b]indol-3-il)acético y sales del mismo |
WO2011109471A1 (en) | 2010-03-03 | 2011-09-09 | Arena Pharmaceuticals, Inc. | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
EP3242666A1 (en) | 2015-01-06 | 2017-11-15 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the s1p1 receptor |
JP6838744B2 (ja) | 2015-06-22 | 2021-03-03 | 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 | S1P1レセプター関連障害における使用のための(R)−2−(7−(4−シクロペンチル−3−(トリフルオロメチル)ベンジルオキシ)−1,2,3,4−テトラヒドロシクロペンタ[b]インドール−3−イル)酢酸(化合物1)の結晶性L−アルギニン塩 |
KR20190116416A (ko) | 2017-02-16 | 2019-10-14 | 아레나 파마슈티칼스, 인크. | 원발 담즙성 담관염을 치료하기 위한 화합물 및 방법 |
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