CN1893934B - 1-磷酸-鞘氨醇(s1p)受体激动剂用于制备治疗脑变性性疾病的药物的应用 - Google Patents
1-磷酸-鞘氨醇(s1p)受体激动剂用于制备治疗脑变性性疾病的药物的应用 Download PDFInfo
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- CN1893934B CN1893934B CN2004800378611A CN200480037861A CN1893934B CN 1893934 B CN1893934 B CN 1893934B CN 2004800378611 A CN2004800378611 A CN 2004800378611A CN 200480037861 A CN200480037861 A CN 200480037861A CN 1893934 B CN1893934 B CN 1893934B
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Abstract
公开了1-磷酸-鞘氨醇(S1P)受体激动剂,优选2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇在治疗进行性痴呆或脑变性性疾病中的新应用。
Description
本发明涉及1-磷酸-鞘氨醇(S1P)受体激动剂的新应用,特别是在治疗进行性痴呆或脑变性性疾病中的应用。
S1P受体激动剂是作为激动剂向一种或多种1-磷酸-鞘氨醇受体例如S1P1至S1P8发信号的化合物。激动剂与S1P受体结合可使得例如细胞内的异源三聚体G-蛋白离解成Gα-GTP和Gβγ-GTP和/或增加激动剂占据的受体的磷酸化作用和下游信号途径/激酶的活化,或由于超激动作用而导致受体的内在化/脱敏并由此通过天然配体S1P而产生受体信号的拮抗作用。
可以用下面的试验来测定S1P受体激动剂对人类个体S1P受体的结合亲合力:
用人S1P受体S1P1、S1P3、S1P2、S1P4和S1P5对化合物的S1P受体激动剂活性进行试验。通过对化合物诱导的与由稳定表达适宜人S1P受体的转染CHO或RH7777细胞制得的膜蛋白结合的GTP[γ-35S]进行定量来对功能受体活化进行评估。所用的分析技术是SPA(闪烁亲近测定法)。简单地说,将用DMSO溶解的化合物连续稀释并在存在50mM Hepes、100mM NaCl、10mM MgCl2、10μM GDP、0.1%无脂肪的BSA和0.2nM GTP[γ-35S](1200Ci/mmol)的情况下将其加入到SPA-小珠(Amersham-Pharmacia)固定的表达S1P受体的膜蛋白(10-20μg/孔)中。在将其在96孔微量滴定板中在室温下培养120分钟后,通过离心将未结合的GTP[γ-35S]分离出来。用TOPcount板式读数器(Packard)对通过膜结合的GTP[γ-35S]触发的SPA小珠的发光进行定量。用标准曲线拟合软件计算EC50。在这种试验中,S1P受体激动剂对S1P受体的结合亲合力优选地<50nM。
用例如用myc-标记的人S1P受体转染的中国仓鼠卵巢(CHO)细胞来测定S1P受体的内在化和脱敏。通过使用荧光标记的抗-myc抗体的FACS分析来测定由于激动剂的刺激所产生的受体内在化。
优选的S1P受体激动剂是那些例如除其S1P结合性外还具有加速淋巴细胞复位特性的化合物,例如可引起由于淋巴细胞从循环系统向次级淋巴组织的再分布(优选可逆性再分布)而导致的淋巴细胞减少并同时不会引起全面免疫抑制的化合物。分离细胞;来自血液的CD4和CD8T-细胞以及B-细胞被刺激迁移到淋巴结(LN)和派伊尔氏淋巴集结(PP)中。
在下面的血液淋巴细胞消耗试验中对淋巴细胞复位特性进行测量:
通过管饲法将S1P受体激动剂或载体口服给药于大鼠。在第-1天获取用于进行血液学监测的尾部血以获得个体的基准值,并且在应用后第2、6、24、48和72小时取尾部血来进行血液学监测。在该试验中,S1P受体激动剂消耗了外周血的淋巴细胞,例如当以<20mg/kg的剂量被给药时消耗了50%。优选的S1P受体激动剂还包括除其S1P结合性外还可内在化/脱敏S1P受体,从而拮抗血管细胞例如内皮细胞上的溶血磷脂(包括例如1-磷酸-鞘氨醇(S1P)、鞘磷酸胆碱(SPC)、溶血磷脂酸(LPA)等等)驱动的炎性过程的化合物。使用用人myc-标记的S1P受体转染的CHO细胞来测定化合物的内在化/脱敏容量。
适宜的S1P受体激动剂的实例有例如:
-EP627406A1中所公开的化合物,例如式I的化合物
其中R1是直链-或支链(C12-22)碳链
-其可在所说的链中具有选自双键、三键、O、S、NR6和羰基的键或杂原子,其中R6是H、烷基、芳烷基、酰基或烷氧基羰基,和/或
-其可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、烷氧基羰基、烷氧基羰基氨基、酰氧基、烷基氨基甲酰基、硝基、卤素、氨基、羟基亚氨基、羟基或羧基;或者R1是
-其中的烷基是直链-或支链(C6-20)碳链的苯基烷基;或者
-其中的烷基是直链-或支链(C1-30)碳链的苯基烷基,其中所说的苯基烷基被下列基团所取代:
-任选地被卤素所取代的直链-或支链(C6-20)碳链,
-任选地被卤素所取代的直链-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,
并且其中
所说的烷基部分可
-在碳链中具有选自双键、三键、O、S、亚磺酰基、磺酰基或NR6的键或杂原子,其中R6具有上述定义,和
-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、烷氧基羰基、烷氧基羰基氨基、酰氧基、烷基氨基甲酰基、硝基、卤素、氨基、羟基或羧基,和
R2、R3、R4和R5各自独立地是H、C1-4烷基或酰基
或其可药用的盐;
-EP 1002792A1中所公开的化合物,例如式II的化合物
其中m为1至9并且R’2、R’3、R’4和R’5各自独立地是H、烷基或酰基,
或其可药用的盐;
-EP0778263 A1中所公开的化合物,例如式III的化合物
其中W是H;C1-6烷基、C2-6链烯基或C2-6炔基;未被取代的或被OH取代的苯基;R”4O(CH2)n;或者被1至3个选自卤素、C3-8环烷基、苯基和被OH取代的苯基的取代基取代的C1-6烷基;
X是H或未被取代或被取代的具有p个碳原子的直链烷基或者未被取代或被取代的具有(p-1)个碳原子的直链烷氧基,例如其被1至3个选自C1-6烷基、OH、C1-6烷氧基、酰氧基、氨基、C1-6烷基氨基、酰基氨基、氧代、卤代C1-6烷基、卤素、未被取代的苯基和被1至3个选自C1-6烷基、OH、C1-6烷氧基、酰基、酰氧基、氨基、C1-6烷基氨基、酰基氨基、卤代C1-6烷基和卤素的取代基取代的苯基的基团所取代;Y是H、C1-6烷基、OH、C1-6烷氧基、酰基、酰氧基、氨基、C1-6烷基氨基、酰基氨基、卤代C1-6烷基或卤素,Z2是单键或具有q个碳原子的直链亚烷基,
p和q各自独立地是1至20的整数,条件是6≤p+q≤23,m’是1、2或3,
n是2或3,
R”1、R”2、R”3和R”4各自独立地是H、C1-4烷基或酰基,
或其可药用的盐,
-WO02/18395中所公开的化合物,例如式IVa或IVb的化合物
其中Xa是O、S、NR1s或基团-(CH2)na-,该基团未被取代或者被1至4个卤素所取代;na是1或2,R1s是H或(C1-4)烷基,所说的烷基未被取代或者被卤素所取代;R1a是H、OH、(C1-4)烷基或O(C1-4)烷基,其中所说的烷基未被取代或者被1至3个卤素所取代;R1b是H、OH或(C1-4)烷基,其中所说的烷基未被取代或者被卤素所取代;各R2a独立地选自H或(C1-4)烷基,所说的烷基未被取代或者被卤素所取代;R3a是H、OH、卤素或O(C1-4)烷基,其中所说的烷基未被取代或者被卤素所取代;R3b是H、OH、卤素、(C1-4)烷基(其中所说的烷基未被取代或者被羟基所取代)或O(C1-4)烷基(其中所说的烷基未被取代或者被卤素所取代);Ya是-CH2-、-C(O)-、-CH(OH)-、-C(=NOH)-、O或S,且R4a是(C4-14)烷基或(C4-14)链烯基;或其可药用的盐或水合物;
-WO 02/076995中所公开的化合物,例如式V的化合物
其中
mc是1、2或3;
Xc是O或直连键;
R1c是H;任选地被OH、酰基、卤素、C3-10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;或者任选地被OH取代的苯基;
R2c是
其中R5c是H或任选地被1、2或3个卤素原子取代的C1-4烷基,R6c是H或任选地被卤素取代的C1-4烷基;
R3c和R4c各自独立地是H、任选地被卤素取代的C1-4烷基或酰基,和
Rc是在链中可任选地具有氧原子并且可任选地被硝基、卤素、氨基、羟基或羧基取代的C13-20烷基;或者是式(a)的残基
其中R7c是H、C1-4烷基或C1-4烷氧基,R8c是被取代的C1-20烷酰基、苯基C1-14烷基(其中所说的C1-14烷基任选地被卤素或OH所取代)、环烷基C1-14烷氧基或苯基C1-14烷氧基(其中所说的环烷基或苯基环任选地被卤素、C1-4烷基和/或C1-4烷氧基所取代)、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,
Rc还可以是式(a)的残基,其中R8c是C1-14烷氧基,其中R1c是C1-4烷基、C2-6链烯基或C2-6炔基,
或式VI的化合物
其中
nx是2、3或4
R1x是H;任选地被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;或者任选地被OH取代的苯基;
R2x是H、C1-4烷基或酰基
R3x和R4x各自独立地是H、任选地被卤素或酰基取代的C1-4烷基,
R5x是H、C1-4烷基或C1-4烷氧基,和
R6x是被环烷基取代的C1-20烷酰基;环烷基C1-14烷氧基,其中所说的环烷基环任选地被卤素、C1-4烷基和/或C1-4烷氧基所取代;苯基C1-14烷氧基,其中所说的苯基环任选地被卤素、C1-4烷基和/或C1-4烷氧基所取代,或者
当R1x是被OH取代的C2-4烷基时R6x还是C4-14烷氧基,或者当R1x是C1-4烷基时R6x还是戊氧基或己氧基,
条件是当R5x是H或者R1x是甲基时R6x不是苯基-亚丁氧基,或其可药用的盐;
-WO02/06268AI中所公开的化合物,例如式VII的化合物
其中R1d和R2d各自独立地是H或氨基-保护基团;
R3d是氢、羟基-保护基团或下式的残基
R4d是低级烷基;
nd是1至6的整数;
Xd是亚乙基、亚乙烯基、亚乙炔基、式-D-CH2-的基团(其中D是羰基、-CH(OH)-、O、S或N)、芳基或被最多三个选自下文所定义的a组的取代基所取代的芳基;
Yd是单键、C1-10亚烷基、被最多三个选自a和b组的取代基取代的C1-10亚烷基、在碳链的中间或末端具有O或S的C1-10亚烷基、或者被最多三个选自a和b组的取代基取代的在碳链的中间或末端具有O或S的C1-10亚烷基;
R5d是氢、环烷基、芳基、杂环、被最多三个选自a和b组的取代基取代的环烷基、被最多三个选自a和b组的取代基取代的芳基、或被最多三个选自a和b组的取代基取代的杂环;
R6d和R7d各自独立地是H或者选自a组的取代基;
R8d和R9d各自独立地是H或者任选地被卤素取代的C1-4烷基;
<a组>是卤素、低级烷基、卤代低级烷基、低级烷氧基、低级烷硫基、羧基、低级烷氧基羰基、羟基、低级脂族酰基、氨基、单-低级烷基氨基、二-低级烷基氨基、低级脂族酰基氨基、氰基或硝基;和
<b组>是环烷基、芳基、杂环,其各自任选地被最多三个选自a组的取代基所取代;
条件是当R5d是氢时,Yd是单键或直链C1-10亚烷基,
或其可药用的盐或酯;
-JP-14316985(JP2002316985)中所公开的化合物,例如式VIII的化合物:
其中R1e、R2e、R3e、R4e、R5e、R6e、R7e、ne、Xe和Ye如JP-14316985中所公开的那样;
或其可药用的盐或酯;
-WO 03/29184和WO 03/29205中所公开的化合物,例如式IX的化合物
其中Xf是O或S,R1f、R2f、R3f和nf如WO 03/29184和WO 03/29205中所公开的那样,R4f和5f各自独立地是H或下式的残基
其中R8f和R9f各自独立地是H或任选地被卤素取代的C1-4烷基;例如2-氨基-2-[4-(3-苄氧基苯氧基)-2-氯苯基]丙基-1,3-丙烷-二醇或2-氨基-2-[4-(苄氧基苯硫基)-2-氯苯基]丙基-1,3-丙烷-二醇,或其可药用盐;
-WO03/062252A1中所公开的化合物,例如式X的化合物
其中
Ar是苯基或萘基;mg和ng各自独立地是0或1;A选自COOH、PO3H2、PO2H、SO3H、PO(C1-3烷基)OH和1H-四唑-5-基;R1g和R2g各自独立地是H、卤素、OH、COOH或任选地被卤素取代的C1-4烷基;R3g是H或任选地被卤素或OH取代的C1-4烷基;各R4g独立地是卤素或任选地被卤素取代的C1-4烷基或C1-3烷氧基;并且Rg和M各自具有WO03/062252A1中关于B和C所示含义中的一种;
-WO 03/062248A2中所公开的化合物,例如式XI的化合物
其中Ar是苯基或萘基;n是2、3或4;A是COOH、1H-四唑-5-基、PO3H2、PO2H2、-SO3H或PO(R5h)OH(其中R5h选自C1-4烷基、羟基C1-4烷基、苯基、-CO-C1-3烷氧基和-CH(OH)-苯基,其中所说的苯基或苯基部分任选地被取代);R1h和R2h各自独立地是H、卤素、OH、COOH或任选地被卤代的C1-6烷基或苯基;R3h是H或任选地被卤素和/OH取代的C1-4烷基;各R4h独立地是卤素、OH、COOH、C1-4烷基、S(O)0,1或2C1-3烷基、C1-3烷氧基、C3-6环烷氧基、芳基或芳烷氧基,其中所说的烷基部分任选地被1-3个卤素所取代;并且Rg和M各自具有WO03/062248A2中关于B和C所示含义中的一种;
-WO 04/026817中所公开的化合物,例如式XII的化合物
其中R1j是卤素、三卤代甲基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、芳烷基或任选地被取代的苯氧基或芳烷氧基,R2j是H、卤素、三卤代甲基、C1-4烷基、C1-4烷氧基、芳烷基或芳烷氧基,R3j是H、卤素、三氟甲基、C1-4烷基、C1-4烷氧基、C1-4烷硫基或苄氧基,R4j是H、C1-4烷基、苯基、任选地被取代的苄基、具有1至5个C的低级脂族酰基或任选地被取代的苯甲酰基,R5j是H、单卤代甲基、C1-4烷基、C1-4烷氧基、C1-4烷硫基、羟基乙基、羟基丙基、苯基、芳烷基、C2-4链烯基或C2-4炔基,R6j和R7j各自独立地是H或C1-4烷基,Xj是O、S、SO或SO2,nj是1、2、3或4,或其可药用的盐。
根据本发明的另一个实施方案,用于本发明的组合的S1P受体激动剂还可以是选择性S1P1受体激动剂,例如在用对S1P1受体的EC50与对S1P3受体的EC50的比例进行测量时,对S1P1受体的选择性比对S1P3受体的选择性高至少20倍,例如,高100、500、1000或2000倍的化合物,其中所说的EC50是在35S-GTPγS结合试验中进行评估的,在用35S-GTPγS结合试验进行评估时,所说化合物与S1P1受体结合的EC50为100nM或更低。典型的S1P1受体激动剂有例如在WO 03/061567(其内容在这里被引入作为参考)中所列举的化合物,例如式的化合物。
当式I至XIV的化合物在分子中具有一个或多个不对称中心时,应当清楚的是本发明包括其各种光学异构体以及外消旋体、非对映异构体以及其混合物。当带有氨基的碳原子是不对称的碳原子时,式III或IVb的化合物优选地在该碳原子上具有R-构型。
式I至XIV的化合物可以以游离形式或者盐形式存在。式I至XIII化合物的可药用盐的实例包括与无机酸形成的盐,如盐酸盐、氢溴酸盐和硫酸盐,与有机酸形成的盐,如醋酸盐、富马酸盐、马来酸盐、苯甲酸盐、枸橼酸盐、苹果酸盐、甲磺酸盐和苯磺酸盐等等,或者当适宜时,可以是与金属如钠、钾、钙和铝形成的盐、与胺,如三乙胺形成的盐、与二价氨基酸,如赖氨酸形成的盐。本发明的组合的化合物以及盐包括水合物和溶剂化物形式。
在给出专利申请的引证的各种情况中,涉及所说化合物的主题被引入到本申请中作为参考。
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。除非特别说明,否则烷基、烷氧基、链烯基或炔基可以是直链或支链的。
当式I化合物中的R1的碳链被取代时,其优选地被卤素、硝基、氨基、羟基或羧基所取代。当该碳链被任选地被取代的亚苯基中断时,该碳链优选地是未被取代的。当该亚苯基部分被取代时,其优选地被卤素、硝基、氨基、甲氧基、羟基或羧基所取代。
优选的式I的化合物是其中R1是C13-20烷基(任选地被硝基、卤素、氨基、羟基或羧基取代)的化合物,并且更优选地是其中R1是被C6-14-烷基链(其任选地被卤素所取代并且其烷基部分是任选地被羟基取代的C1-6烷基)取代的苯基烷基的化合物。更优选地,R1是在苯基上被直链或支链,优选直链C6-14烷基链取代的苯基-C1-6烷基。该C6-14烷基链可以位于邻、间或对位上,优选地位于对位上。
R2至R5各自优选地是H。
一种优选的式I的化合物是2-氨基-2-十四烷基-1,3-丙二醇。一种特别优选的式I的S1P受体激动剂是游离或可药用盐形式的FTY720,即2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇(在下文被称为化合物A),例如如下所示的盐酸盐:
一种优选的式II的化合物是一种其中R’2至R’5各自是H且m是4的游离或可药用盐形式的化合物,即2-氨基-2-{2-[4-(1-氧代-5-苯基戊基)苯基]乙基}丙烷-1,3-二醇(在下文被称为化合物B),例如盐酸盐。
一种优选的式III的化合物是一种其中W是CH3,R”1至R”3各自是H,Z2是乙烯基,X是庚氧基并且Y是H的游离或可药用盐形式的化合物,即2-氨基-4-(4-庚氧基苯基)-2-甲基-丁醇(在下文被称为化合物C),例如盐酸盐。特别优选其R-对映异构体。
一种优选的式IVa的化合物是FTY720-磷酸盐(R2a是H,R3a是OH,Xa是O,R1a和R1b是OH)。一种优选的式IVb的化合物是化合物C-磷酸盐(R2a是H,R3b是OH,Xa是O,R1a和R1b是OH,Ya是O且R4a是庚基)。一种优选的式V的化合物是化合物B-磷酸盐。
一种优选的式V的化合物是磷酸单-[(R)-2-氨基-2-甲基-4-(4-戊氧基-苯基)-丁基]酯。
一种优选的式VIII的化合物是(2R)-2-氨基-4-[3-(4-环己氧基丁基)-苯并[b]噻吩-6-基]-2-甲基丁-1-醇。
优选的式XII的化合物是其中R1j是CF3或苄氧基且R6j是H的化合物。
根据所观察到的活性,例如如EP-A1-627,406中所述的活性,已经发现式I至XIV的化合物可用作例如免疫抑制剂,例如可用于治疗急性同种异体移植物排斥或自身免疫性病症。
因为老年群体的人口越来越多,所以脑变性性疾病在发达国家越来越常见。还不清楚这种疾病的病因。也不清楚为什么一些人在30或40岁就开始患上痴呆,而另一些人直至七八十岁也不会出现痴呆。阿耳茨海默氏病是一种脑的进行性变性疾病,其特征为痴呆的起病隐袭。记忆、判断、精神集中时间、问题解决技巧受损,然后全面丧失认识能力。仍然需要可有效治疗该类疾病和病症的药物,例如需要用于降低或预防疾病进程和/或缓解其症状和/或改善生活质量的物质。已经发现S1P受体激动剂具有令人感兴趣的性质,该性质使其可用于治疗进行性痴呆和脑变性。
根据本发明的特定发现,本发明提供了:
1.1一种在需要治疗的个体中治疗进行性痴呆或脑变性的方法,其包括给所说的个体施用治疗有效量的1-磷酸-鞘氨醇(S1P)受体激动剂,例如式I的化合物或其可药用的盐。
1.2一种在需要治疗的个体中治疗与β-淀粉样蛋白有关的炎性疾病或病症的方法,其包括给所说的个体施用治疗有效量的1-磷酸-鞘氨醇(S1P)受体激动剂,例如式I的化合物或其可药用的盐。
该类疾病和病症的实例有例如阿耳茨海默氏病、淀粉样变性病、路易体病、多发性梗死性痴呆、皮克氏病或脑动脉粥样硬化。
1.3一种减轻或抑制有此需要的个体的认识能力降低的方法,其包括给所说的个体施用治疗有效量的1-磷酸-鞘氨醇(S1P)受体激动剂,例如式I的化合物或其可药用的盐。
2.用于制备用于上面1.1至1.3下任意一项所定义的方法的药物组合物的1-磷酸-鞘氨醇(S1P)受体激动剂,例如式I的化合物或其可药用的盐。
3.一种用于上面1.1至1.3下任意一项所述方法的药物组合物,其包含1-磷酸-鞘氨醇(S1P)受体激动剂,例如式I的化合物或其可药用的盐以及一种或多种可药用的稀释剂或载体。
所说的进行性痴呆或脑变性优选地不是老年痴呆。
可以用动物试验方法以及在临床中,例如用下文所述的方法证明所说的1-磷酸-鞘氨醇(S1P)受体激动剂,例如式I的化合物在治疗上文所指定的疾病中的实用性。
A.1外周血单核细胞是由健康志愿者的外周静脉血(用EDTA抗凝)制得的。在LymphoprepR密度梯度离心后,收集外周血单核细胞并用生理盐水将其洗涤三次。根据制造商的指导,通过向位于MACS缓冲液(含有5mM EDTA和0.5%牛血清白蛋白的PBS)中的新制备的冷却外周血单核细胞制剂中加入与单克隆抗人CD14抗体轭合的MACS胶体超顺磁(superparamagnetic)微珠来进行单核细胞的正向选择。将细胞和微珠在4-6℃下培养15分钟。期间,将分离柱安置在MACS磁场中并用MACS缓冲液在室温下对其进行洗涤。将这些细胞用MACS缓冲液洗涤,再混悬,并将其负载到分离柱的顶端上。除去包含CD14细胞的洗脱液并在从磁体上取下所说的柱后,用六倍数量的冷MACS缓冲液对所捕获的单核细胞(CD14+)进行洗脱,离心,将其重新混悬于包含0.5%BSA的培养基中。通过免疫细胞化学检测,这些制备物的纯度约为98%。
趋化性试验
白细胞迁移是用用于单核细胞趋化性的配有5μm孔径硝酸纤维素滤器的改性的48-盲孔(blindwell)微型趋化室(microchemotaxis chamber)来进行测量的。在一些实验中,将细胞用GFX[500nM]、星形孢菌素[10ng/mL]、tyrphostin-23[10ng/mL]、渥曼青霉素[10nM]、霍乱毒素[1nM]、DMS[20pg/mL至20μg/mL]或百日咳毒素[1nM]一起培养20分钟。为了测定Aβ影响单核细胞对fMLP的趋化性的效力,将这些细胞与Aβ[1aM至1μM]一起培养20分钟。在洗涤两次后,将50μl细胞混悬液[1x106个细胞/mL]放到趋化室的上层分隔室中并使细胞向fMLP迁移90分钟。在该迁移期后,将滤器脱水,固定并用苏木精-曙红染色。用显微镜检查对迁移深度进行定量,所说的深度为从滤器表面到所测量三个细胞前沿的距离。将数据表示为“趋化性指数”,其是定向迁移和不定向迁移距离之间的比例。
半定量RT-PCR
通过苯酚-氯仿-异戊醇萃取(RNACleanTM;Hybaid-AGS,Ulm,德国)从8x106个细胞中分离出全部RNA。在1μg RNA上用无规六聚物逆转录酶(Gibco BRL,Life Technologies,Vienna,奥地利)进行逆转录酶反应。然后,将10μL的该逆转录酶反应混合物在50μL包含1pmol有义和反义引物对的反应混合物中在Perkin-Elmer热循环器中进行35个PCR循环:95℃-30秒(变性),53℃-60秒(退火),72℃-30秒(延伸)。Hot Start Taq聚合酶得自Qiagen Inc.(Valencia,CA,USA)。引物(MWG Biotech,Ebersdorf,德国)被设计为将受体的编码序列放大约400bp。引物的设计如下:1-磷酸-鞘氨醇受体(S1PR)1,有义:CTG TGA ACA ATG CAC TGG,反义:CCT ACG TAC TCA ACA TAG CC。S1PR 3,有义:ATC TGCAGC TTC ATC GTC,反义:AGA TTG AGG CAG TTC。S1PR 2,有义:ACC ACG CAC AGC ACA TAA TG,反义:AAA CAG CAA GTT CCACTC GG。S1PR 4,有义:TGA ACA TCA CGC TGA GTG,反义:ATCATC AGC ACC GTC TTC。S1PR 5,有义:GAA ATG CAG CCA AAGGTG,反义:TT ATC ACC CAC AAG GTC CTT C。对该PCR产物进行琼脂糖凝胶分析。
结果
Aβ-和Aβ前体蛋白-诱导的趋化性.
为了证实Aβ可诱导单核细胞趋化性以及为了研究Aβ前体蛋白(Aβ-PP)是否能起同等作用,使单核细胞向不同浓度的Aβ[10nmol/L至1μmol/L]或Aβ-PP[10nmol/L至1μmol/L]迁移90分钟。用用于单核细胞趋化性的配有5μm孔径硝酸纤维素滤器的改性的48-盲孔微型趋化室来测量单核细胞的定向迁移。用显微镜检查对迁移深度进行定量,所说的深度为从滤器表面到所测量三个细胞前沿的距离。将数据表示为“趋化性指数”,其是定向迁移和不定向迁移距离之间的比例。不定向迁移的平均距离为57±4.5μm。这些结果证实了Aβ诱导了人单核细胞的趋化性,其在1pmol/L下具有最大响应。Aβ-PP以浓度依赖性方式诱导了趋化性,也是在1pM下具有最大响应。
神经肽对Aβ和Aβ-前体蛋白-诱导的单核细胞迁移的抑制作用.
为了描述吸引神经肽的单核细胞能否影响Aβ-和Aβ-PP-诱导的单核细胞运动,使细胞与神经肽,例如铃蟾肽、CGRP、SP、SN或VIP接触,并如上所述的那样对细胞对Aβ和Aβ-PP的趋化性进行试验。所有的神经肽都浓度依赖性地抑制了趋化性。
发信号的酶抑制剂对Aβ-诱导的迁移的影响
用一些酶阻滞剂对单核细胞进行培养。首先用蛋白激酶C抑制剂GFX、酪氨酸激酶抑制剂tyrphostin-23和磷脂酶-3抑制剂WTN阻断发信号的酶;然后,用已知可诱导Gi蛋白的PTX和可诱导Gs蛋白的CTX对涉及的G蛋白进行检测。在洗涤后,进行对Aβ(1pmol/l)和Aβ-PP(1pmol/l)的趋化性实验。将数据表示为趋化性指数,其是定向迁移和随机迁移距离之间的比例。随机迁移的平均距离为54±3.2μm。
表1
N,N-二甲基鞘氨醇对Aβ-和Aβ-PP-诱导的单核细胞迁移的抑制
将人单核细胞用不同浓度的(例如100fmol/l至100nmol/l)选择性鞘氨醇激酶抑制剂DMS预处理。用fMLP作为对照吸引剂。用DMS进行处理抑制了Aβ-和Aβ-PP-诱导的趋化性,而fMLP-诱导的趋化性不受影响。
S1P受体激动剂消除了人单核细胞向Aβ和趋化因子的迁移
将单核细胞用DMS、化合物A或培养基培养20分钟。在洗涤后,进行向Aβ[1pmol/L]的趋化性实验。将数据表示为趋化性指数,其是定向迁移和随机迁移距离之间的比例。随机迁移的平均距离为56±5.6μm。DMS和S1P受体激动剂单独处理时抑制了细胞的迁移,而用两种物质一起进行处理恢复了Aβ和Aβ-PP的趋化性作用。化合物A的结果如下:
表2
趋化性 | |
处理 | 均值(+/-SEM) |
中值 | 1.825(0.14) |
DMS(2ng/ml) | 1.423(0.18) |
化合物A(2ng/ml) | 1.077(0.18) |
Aβ对S1P受体mRNA表达的调节
在用各种浓度[20pg/mL至20μg/mL]的化合物A预处理20分钟后,对细胞进行洗涤并如上所述的那样对其对Aβ和Aβ-PP[1pM]的趋化性进行试验。将数据表示为“趋化性指数”,其是细胞定向迁移和不定向迁移之间的比例。在培养期后,进行RT-PCR并用等量cDNA进行琼脂糖凝胶电泳。在Aβ-处理的细胞中观察到诱导了S1PR 2和S1PR 5mRNA。
B.临床试验
该试验是用包含6至10名个体的组进行的,根据DSM-III所定义的参数(Diagnostic and Statistical Manual of Mental Disorders,第3版),所说的个体被确定为表现出轻度至中度的阿耳茨海默氏痴呆并排除表现出严重心血管疾病、低血压、严重的内分泌障碍性疾病、严重的肝病、肾机能不全的个体。在0时,用EEG和智力测验开始该试验。然后,如下所述那样给这些个体施用安慰剂或试验药物,并且在给药后60、120和180分钟重复进行EEG和智力测验。所用的智力测验包括:
(i)选择性提醒试验(The Selective Reminding Test)/Buschke:“用于记忆和学习分析的选择性提醒(Selective Reminding for Analysis of Memoryand Learning)”,J.Verbal Learning and Verbal Behaviour 12,543-550(1973);
(ii)建造能力测量(Muratomo等人:“Physiostigmin对阿耳茨海默氏病中建造和记忆任务的影响(Effect of Physiostigmin on Constructional andMemory Tasks in Alzheimer′s disease)”,Arch.Neurol.36,501-503(1973);和
(iii)几何图形的记忆力(Benton修正的视觉保留试验)。
在试验期间,个体以约0.25至约10mg/口服给药的剂量接受安慰剂或者S1P受体激动剂,例如化合物A,该剂量被一次给药或者以2或3个分割剂量形式被给药。
还对下面的附加参数进行监测:
血液学:R.B.C.,HB,HCT,W.B.C,分类计数,沉积速率,血糖。
尿:白蛋白,葡萄糖。
血清:碱性磷酸酶,ALT,AST,S-GT,S-胆红素,S-T4,S-T3,S-TSH,肌酸酐。
正如EEG结果和智力测验的结果所证明的那样,与接受安慰剂的个体相比,以上面所示的剂量接受S1P受体激动剂,例如化合物A的个体的情况得到了改善。
当使用S1P受体激动剂时,在实施本发明的方法时所需的日剂量将根据例如所用的化合物、主体、给药方式和被治疗情况的严重程度来进行变化。优选的日剂量为约0.1至100mg,为单剂量或分割剂量形式。对于患者而言,适宜的口服日剂量为例如0.1至50mg。所说的S1P受体激动剂可以用任何常规途径进行给药,特别是可以被肠道给药,例如口服给药,例如以片剂、胶囊、饮用溶液的形式被口服给药,可以通过鼻、肺(通过吸入)给药或被胃肠外给药,例如以可注射的溶液或混悬液的形式被胃肠外给药。用于口服给药的适宜单位剂型包含约0.1至30mg,通常0.25至30mg S1P受体激动剂,例如化合物A和一种或多种可药用的稀释剂或载体。
所说的S1P受体激动剂可以通过任何常规途径被给药,特别是可以被肠道给药,例如被口服给药,例如以用于饮用的溶液、片剂或胶囊的形式被口服给药或者被胃肠外给药,例如以可注射溶液或混悬液的形式被胃肠外给药,或者可以被局部给药。可以用常规方式,例如如EP-A1-627,406或EP-A1-1,002,792中所述的方式来制备包含S1P受体激动剂,例如式I化合物的药物组合物。
所说的S1P受体激动剂可以以单一成分的形式被给药或者可以与用于缓解或治疗脑变性性疾病或进行性痴呆的其它药物,例如AMPA受体激动剂、益智药、止痛药或抗炎药一起给药。
这里所用的术语“AMPA受体拮抗剂”非限制性地包括喹喔啉-二酮氨基烷基膦酸酯,例如WO 98/17672中所公开的化合物,或者另外的化合物如EGIS 8332(7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂-8-腈)、GYKI 47261 4-(7-氯-2-甲基-4H-3,10,10a-三氮杂-苯并[f]薁-9-基)-苯基胺)、伊仑帕奈(BIIR 561;N,N-二甲基-2-[2-(3-苯基-1,2,4-噁二唑-5-基)苯氧基]乙胺)、KRP 199(7-[4-[[[[(4-羧基苯基)-氨基]羰基]氧基]甲基]-1H-咪唑-1-基]-3,4-二氢-3-氧代-6-(三氟甲基)-2-喹喔啉甲酸)、NS 1209(2-[[[5-[4-[(二甲基氨基)-磺酰基]苯基]-1,2,6,7,8,9-六氢-8-甲基-2-氧代-3H-吡咯并[3,2-h]异喹啉-3-亚基]氨基]氧基]-4-羟基丁酸单钠盐,例如如WO 98/14447中所述那样制得的)、托吡酯(TOPAMAX,2,3:4,5-二-O-(1-甲基亚乙基)-β-D-吡喃果糖氨基磺酸酯,其制备例如如US 535475中所述)和他仑帕奈(LY-300164,(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-二氧杂环戊烯并[4,5-h][2,3]苯并二氮杂,其制备例如如EP 492485中所述)、YM90K(6-咪唑-1-基-7-硝基-1,4-二氢-喹喔啉-2,3-二酮)、S-34730(7-氯-6-氨磺酰基-2-(1H)-喹啉酮-3-膦酸)、Zonampanel(YM-872;(7-咪唑-1-基-6-硝基-2,3-二氧代-3,4-二氢-2H-喹喔啉-1-基)-乙酸)、GYKI-52466(4-(8-甲基-9H-1,3-二氧杂-6,7-二氮杂-环庚三烯并[f]茚-5-基)-苯基胺)、ZK-200775(MPQX,(7-吗啉-4-基-2,3-二氧代-6-三氟甲基-3,4-二氢-2H-喹喔啉-1-基甲基)-膦酸)、CP-465022(3-(2-氯-苯基)-2-[2-(6-二乙基氨基甲基-吡啶-2-基)-乙烯基]-6-氟-3H-喹唑啉-4-酮)、SYM-2189(4-(4-氨基-苯基)-6-甲氧基-1-甲基-1H-酞嗪-2-甲酸丙基酰胺)、SYM-2206(8-(4-氨基-苯基)-5-甲基-5H-[1,3]间二氧杂环戊烯并[4,5-g]酞嗪-6-甲酸丙酰胺)、RPR-117824((4-氧代-2-膦酰基-5,10-二氢-4H-咪唑并[1,2-a]茚并[1,2-e]吡嗪-9-基)-乙酸)、LY-293558(6-[2-(1H-四唑-5-基)-乙基]-十氢-异喹啉-3-甲酸)。
这里所用的术语“益智药”非限制性地包括益智的(nootropical)植物提取物、钙拮抗剂、胆碱酯酶抑制剂、二氢麦角碱、尼麦角林、吡拉西坦(piracetame)、嘌呤衍生物、吡硫醇、长春蔓胺和长春乙酯。这里所用的术语“益智的植物提取物”非限制性地包括得自银杏叶的提取物。这里所用的术语“钙拮抗剂”非限制性地包括桂利嗪和尼莫地平。这里所用的术语“胆碱酯酶抑制剂”非限制性地包括盐酸多奈哌齐、立伐斯的明和氢溴酸加兰他敏。这里所用的术语“嘌呤衍生物”非限制性地包括喷替茶碱(pentifyllin)。这里所用的止痛药非限制性地包括布洛芬。适宜的抗炎剂有例如NSAID,例如萘普生。
得自银杏叶的提取物可以以例如市售的形式,例如以GinkodilatTM的商标市售的形式根据包装说明书上所提供的信息进行给药。桂利嗪可以以例如市售的形式,例如以Cinnarizin forte-ratiopharmTM的商标市售的形式被给药。尼莫地平可以以例如市售的形式,例如以NimotopTM的商标市售的形式被给药。盐酸多奈哌齐可以以例如市售的形式,例如以AriceptTM的商标市售的形式被给药。立伐斯的明可以如US 5,602,176中所公开的那样来进行制备。其可以以例如市售的形式,例如以ExelonTM的商标市售的形式被给药。氢溴酸加兰他敏可以以例如市售的形式,例如以ReminylTM的商标市售的形式被给药。二氢麦角碱可以以例如市售的形式,例如以HyderginTM的商标市售的形式被给药。尼麦角林可以以例如市售的形式,例如以SermionTM的商标市售的形式被给药。吡拉西坦可以以例如市售的形式,例如以CerebroforteTM的商标市售的形式被给药。喷替茶碱可以以例如市售的形式,例如以CosaldonTM的商标市售的形式被给药。吡硫醇可以以例如市售的形式,例如以EncephabolTM的商标市售的形式被给药。长春乙酯可以以例如市售的形式,例如以CavintonTM的商标市售的形式被给药。
用这里所述的代号、类名或商标名确定的活性成分的结构可以得自标准纲要“默克索引(The Merck Index)”的现行版本或数据库,例如PatentsInternational(例如IMS World Publications)。其相应内容在这里被引入作为参考。本领域技术人员完全能根据这些参考资料确定所说的活性成分并且同样能制造这些活性成分。
在所说的S1P受体激动剂与其它药物联合给药的情况中,共同给药的化合物的剂量当然将根据所用的共同给药药物的类型、所用的具体药物、被治疗的情况等等来进行变化。术语“共同给药”或“联合给药”或这里所用的其它类似术语指的是包括给单个患者施用所选择的治疗剂,并且还包括其中所说的物质不一定用相同的给药途径给药或者不一定被同时给药的治疗方案。
根据前面所述的,本发明另一方面还提供了:
5.一种药物组合产品,其包含a)是S1P受体激动剂的第一种物质,例如式I的化合物,例如化合物A或其可药用的盐,和b)共同治疗剂,例如上面所定义的第二种药物。
6.上面所定义的方法,其包括共同给予,例如同时或相继给予治疗有效量的S1P受体激动剂,例如式I的化合物,例如化合物A或其可药用的盐和第二种药物,例如上面所示的药物。
S1P受体激动剂在根据本发明应用的所需剂量下可以被良好耐受。例如,在口服给药时,化合物A对大鼠和猴的急性LD50>10mg/kg。
Claims (2)
1.游离形式或可药用盐形式的2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇在制备用于治疗皮克氏病或脑动脉粥样硬化的药物中的应用。
2.权利要求1所述的应用,其中所用的是2-氨基-2-[2-(4-辛基苯基)乙基]丙烷-1,3-二醇的盐酸盐。
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