CN100465186C - 抑制血小板聚集的组合物和方法 - Google Patents
抑制血小板聚集的组合物和方法 Download PDFInfo
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- CN100465186C CN100465186C CNB018166679A CN01816667A CN100465186C CN 100465186 C CN100465186 C CN 100465186C CN B018166679 A CNB018166679 A CN B018166679A CN 01816667 A CN01816667 A CN 01816667A CN 100465186 C CN100465186 C CN 100465186C
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Abstract
本发明针对一种预防或治疗与血小板聚集相关的疾病或病况的方法。该方法还针对一种治疗血栓形成的方法。该方法包括对个体施用一种药物组合物,该药物组合物含有治疗有效量的P2Y12受体拮抗剂化合物,其中所述量有效结合血小板上的P2Y12受体,并抑制ADP-诱导的血小板聚集。本发明有用的P2Y12受体拮抗剂化合物包括通式(I)的单核苷多磷酸和二核苷多磷酸或其盐。本发明还提供了新颖组合物,包括式(Ia)和(Ib)的单核苷多磷酸和二核苷多磷酸。
Description
技术领域
本发明涉及单和二核苷多磷酸的组合物和使用这些化合物预防或治疗与血小板聚集有关的疾病或病况,包括人和其它哺乳动物的血栓生成的方法。
发明背景
止血是受损血管停止出血的自发过程。当切开时前毛细血管立即收缩;在几秒钟内,凝血细胞或血小板通过称为血小板粘附的过程向受损血管暴露的基质集中。在称为血小板聚集的现象中,血小板还彼此粘合形成血小板栓,以迅速停止出血。
血管内血栓导致止血的病理性紊乱。血小板粘附和聚集是血管内血栓形成的关键事件。在患病血管中的湍流血流条件下,或由于其它循环细胞和血管中排列的受损内皮细胞释放介导物,血小板在血管损伤位点聚集,并引来更多血小板开始形成血栓。血栓可长到足够大,以封闭动脉血管。血栓还可以在静脉内的静止区域或缓慢血流中形成。静脉血栓可以容易的部分分离,称为栓塞,它通过循环系统运动,可导致其它血管,例如肺动脉堵塞。因此,动脉血栓通过局部堵塞可引起严重的疾病,而静脉血栓主要是通过远端堵塞,或形成栓塞起作用。这些病况包括静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状和大脑动脉血栓生成、不稳定型心绞痛、心肌梗塞、中风、脑栓塞、肾栓塞和肺栓塞。
许多聚集途径导致血小板聚集。不论最初的刺激是什么,最终的共同事件是通过纤维蛋白原与膜结合位点,糖蛋白IIb/IIa(GPIIb/IIa)交联血小板。作为GPIIb/IIa受体拮抗剂的化合物已显示抑制血小板聚集(美国专利号6,037,343和6,040,317)。针对GPIIb/IIa的抗体也显示具有高抗血小板效力(EPIC调查员,NewEng.J.Med.(1994)330:956-961)。然而,该类抗血小板剂有时导致出血问题。
凝血酶可几乎不依赖于其它途径,产生血小板聚集,但在其它机制首先活化血小板前,不太可能存在足够数量的凝血酶。凝血酶抑制剂,例如水蛭素是非常有效的抗血栓药。然而,由于作为抗血小板和抗凝血药物的功能,凝血酶抑制剂也会产生过量出血。(TIMI 9a调查员,GUSTO Iia调查员,Circulation,90:1624-1630(1994);Circulation,90:1631-1637(1994);Neuhaus K.L.等,Circulation,90:1638-1642(1994))。
研究了各种抗血小板药物多年,作为抑制血栓形成的可能目标。一些药物,例如阿司匹林和双嘧达莫已被用作预防性抗血栓药,其它也是临床研究的目标。迄今,显示强有效的药物,例如解离素和噻喃吡啶噻氯匹定和氯吡格雷已显示出很强的副作用,而阿司匹林等药物是有用的但是效力有限(Hass等,N.Eng.J.Med.,321:501-507(1989);Weber等,Am.J.Cardiol.66:1461-1468(1990);Lekstrom和Bell,Medicine 70:161-177(1991))。特别是,噻喃匹定在抗血小板治疗中的使用已显示提高了可能的有生命危险的血栓性血小板减少性紫癜的发病率(Benett,C.L.等,N.Eng.J.Med(2000)342:1771-1777)。阿司匹林对血小板聚集有有益效果(Br.Med.J.(1994)308:81-106;159-168)是通过诱导前列腺素合成的阻碍起作用的。阿司匹林对于ADP-诱导的血小板聚集没有作用,因此对血小板聚集作用有限。另外,在文献中充分记载了它对于肠胃副作用的高发生率,限制了其在很多病人中的使用。一些较新的药物,例如ReoPro(73)的临床效力是令人印象深刻的,但是近来的实验发现这些方法与大出血风险增加有联系,有时需要输血(New.Engl.J.Med.(1994)330:956-961)。因此似乎理想的“益处/风险”比还未达到。
近来的研究提示,5’-二磷酸腺苷(ADP),一种常规激动剂,在刺激和进行动脉血栓形成中起到了关键作用(Bernad等,Thromb.Haemostas(1993)70:812-826;Maffrand等,Thromb.Haemostas.(1988)59:225-230;Herbert等,Arterioscl.Thromb.(1993)13:1171-1179)。ADP诱导血小板聚集,形状改变,分泌,Ca2+的注入和胞内运动,以及腺苷酸环化酶的抑制。ADP与血小板受体的结合是引起ADP-诱导的血小板应答所必需的。在人血小板中至少表达三种P2受体:阳离子通道受体P2X1,一种G蛋白偶联受体P2Y1,和一种G蛋白偶联受体P2Y12(也称为P2Yac和P2T)。P2X1受体负责迅速钙流入,由ATP和ADP激活。然而,它在血小板聚集中的直接作用还不清楚。P2Y1受体负责钙迁移,形状改变和聚集的引发。P2Y12受体负责腺苷酸环化酶的抑制,是完全聚集所必需的(Hourani等,The PlateletADP Receptors Meeting,La Thuile,Italy March 29-31,2000)。
Ingall等(J.Med.Chem.42:213-220(1999))描述了三磷酸腺苷(ATP)的类似物对ADP-诱导的血小板聚集的剂量相关抑制,该类似物是一种弱的非选择性但是竞争性的P2Y12受体拮抗剂。Zamencnik(USPN5,049,550)公开了一种抑制哺乳动物中血小板聚集的方法,通过对所述哺乳动物施用App(CH2)ppA或其类似物的四磷酸二腺苷化合物。Kim等(USPN 5,681,823)公开了P1,P4-二硫代-P2,P3-一氯亚甲基5’,5”’二腺苷P1,P4四磷酸作为抗血栓生成药物。噻喃匹定噻氯匹定和氯吡格雷被代谢为血小板P2Y12受体的拮抗剂,显示了在体内抑制血小板的功能(Quinn和Fitzgerald,Circulation 100:1667-1672(1999);Geiger等,Arterioscler.Thromb.Vasc.Biol.19:2007-2011(1999))。
在心血管和脑血管治疗领域中,需要一种药物,可用于预防和治疗血栓,副作用例如不良延长出血小,同时预防或治疗靶标血栓。
发明简述
本发明针对一种治疗或预防与血小板聚集有关的疾病或病况的方法。该方法还针对一种治疗血栓形成的方法。该方法包括对个体施用一种药物组合物,该药物组合物含有治疗有效量的P2Y12受体拮抗剂化合物,其中所述量有效结合血小板上的P2Y12受体,并抑制ADP-诱导的血小板聚集。
本发明有用的P2Y12受体拮抗剂化合物包括通式(I)的化合物或其盐:
其中:
X1、X2和X3分别是氧、亚甲基、一氯亚甲基、二氯亚甲基、一氟亚甲基、二氟亚甲基或亚酰氨基;
T1、T2、W和V分别是氧或硫:
m=0,1或2;
n=0或1;
p=0,1,或2;
其中m+n+p之和是1-5;
M=H或药物学上可接受的无机或有机抗衡离子;
D1=O或CH2;
B'是式IV和V的嘌呤或嘧啶残基,它分别通过碱基的9-或1-位与呋喃糖或碳环的1'位连接;
Y'=H、OH或OR1;
Z'=H、OH或OR2;
条件是当A=M时,Y'和Z'都不是H,都不是OH,当A=M时,存在至少一个残基R1和R2;
A=M或
A是核苷残基,定义为:
其通过呋喃糖或碳环的5'位与磷酸链连接,
其中D2=O或CH2;
Z=H、OH或OR3;
Y'=H、OH或OR4;
条件是当Y'和Z'是H或OH,存在至少一个残基R3或R4时,Z和Y都不是H;
B是通式IV和V的嘧啶残基,它分别通过碱基的9-或1-位与呋喃糖或碳环的1'位连接;
R1、R2、R3和/或R4是通过通式II的碳原子直接与呋喃糖或碳环的2'和/或3'羟基连接的残基,或通过式III所述的同一碳原子与呋喃糖或碳环的2'和3'羟基中的两个直接连接的残基,即存在符合式II定义的R1、R2、R3和R4的一个至四个独立残基,或存在由R1+R2和/或R3+R4构成的1-2个独立残基。
本发明还提供了新颖药物组合物,包括式Ia和Ib的化合物,它是对血小板上P2Y12受体高度选择性的拮抗剂。本发明还提供了一种与血小板聚集有关的疾病或病况的预防和治疗方法;这些疾病包括:静脉血栓形成、血栓性静脉炎、动脉栓塞、冠状和大脑动脉血栓生成、不稳定型心绞痛、心肌梗塞、中风、脑栓塞、肾栓塞和肺栓塞。
附图简述
图1显示了通过不同化合物抑制ADP诱导的聚集作用。
发明详述
本发明提供了一种抑制或预防与血小板聚集有关的疾病或病况的方法。该方法还针对一种治疗血栓形成的方法。该方法包括对个体施用一种药物组合物,该药物组合物含有治疗有效量的P2Y12受体拮抗剂化合物,其中所述量有效结合血小板上的P2Y12受体,并抑制ADP-诱导的血小板聚集。本发明有用的P2Y12受体拮抗剂化合物包括通式(I)的化合物或其盐:
其中:
X1、X2和X3分别是氧、亚甲基、一氯亚甲基、二氯亚甲基、一氟亚甲基、二氟亚甲基或亚酰氨基;
T1、T2、W和V分别是氧或硫:
m=0,1或2;
n=0或1;
p=0,1,或2;
其中m+n+p之和是1-5;
M=H或药物学上可接受的无机或有机抗衡离子;
D1=O或CH2;
B'是式IV和V的嘌呤或嘧啶残基,它分别通过碱基的9-或1-位与呋喃糖或碳环的1'位连接;
Y'=H、OH或OR1;
Z'=H、OH或OR2;条件是Y'和Z'至少一个是OR1或OR2;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2'和/或3'羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2'和3'羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的对应的2'和/或3'氧;
C是碳原子;
R5、R6和R7是H、烷基、环烷基、芳烷基、芳基、取代的芳烷基或取代的芳基,这样式II定义的基团是醚;或
R5和R6是H、烷基、环烷基、芳烷基、芳基、取代的芳烷基或取代的芳基,R7是烷氧基、环烷氧基、芳烷氧基、芳氧基、取代的芳烷氧基或取代的芳氧基,这样式II定义的基团是非环状缩醛或缩酮;或
R5和R6合起来作为与C双键键合的氧或硫,R7是烷基、环烷基、芳烷基、芳基、取代的芳烷基或取代的芳基,这样式II定义的基团是酯或硫代酯;或
R5和R6合起来作为与C双键键合的氧或硫,R7是氨基或一或二取代的氨基,其中取代基是烷基、环烷基、芳烷基、芳基、取代的芳烷基或取代的芳基,这样式II的基团是氨基甲酸酯或硫代氨基甲酸酯;或
R5和R6合起来作为与C双键键合的氧或硫,R7是烷氧基、环烷基、芳烷氧基、芳氧基、取代的芳烷氧基或取代的芳氧基,这样式II的基团是碳酸酯或硫代碳酸酯;或
R7不存在,R5和R6合起来作为与C双键键合的氧或硫,呋喃糖的2'和3'氧直接与C键合,形成环状碳酸酯或硫代碳酸酯;
式III
其中:
O是呋喃糖或碳环的2'和3'氧,呋喃糖或碳环的2'和3'氧与同一碳原子(C)连接,形成环状缩醛、环状缩酮或环状原酸酯;
对于环缩醛和环缩酮,R8和R9分别是氢、烷基、环烷基、芳烷基、芳基、取代的芳烷基、取代的芳基,或可以合起来形成由3-8个原子,优选3-6个原子组成的同环或杂环;对于环状原酸酯,R8是氢、烷基、环烷基、芳烷基、芳基、取代的芳烷基、或取代的芳基,R9是烷氧基、环烷氧基、芳烷氧基、芳氧基、取代的芳烷氧基、或取代的芳氧基。
当存在时,R5-R9的烷基、环烷基、芳烷基、芳基、取代的芳烷基和取代的芳基组分可一般定义为,但不限于下列:
1-12个碳,更优选2-8个碳,最优选2-6个碳,直链或支链,饱和或不饱和,具有杂原子或不具有杂原子的烷基;
3-12个碳,更优选3-10个碳,最优选3-8个碳,饱和或不饱和,具有或不具有杂原子的环烷基;
烷基部分1-8个碳原子,更优选1-6个碳,最优选1-4个碳的芳烷基,在芳基部分是每个环具有4-8个碳,更优选4-7个碳,最优选5-6个碳,具有或不具有杂原子的单环或多环基团;
芳基,单环或多环,每个环4-8个碳,优选4-7个碳,最优选5-6个碳,具有或不具有杂原子;这些基团可以或可以不带有取代基。
上述基团上的优选取代基可以是,但不限于羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、取代的氨基、三氟甲基、苯基、环丙基、环戊基和环己基;优选的杂原子是氧、氮和硫。
本发明的一个实施例是A=M,其中M=H或药物学上可接受的无机或有机抗衡离子。在这些实施例中,化合物是二磷酸核苷、三磷酸核苷、四磷酸核苷、五磷酸核苷和六磷酸核苷,其呋喃糖或碳环的2'-和/或3'位被修饰。最优选的是二磷酸核苷、三磷酸核苷和四磷酸核苷。当T2、W、V或T1是硫时,该原子的优选取代位是在多磷酸链的末端磷上(即从核苷残基开始离得最远的磷)。
本发明的另一个实施例是A是核苷残基,定义如下:
并通过呋喃糖或碳环的5'位与磷酸链连接(多磷酸二核苷,呋喃糖或碳环的2,3,2'和3'位至少之一被修饰);
其中:
D2=O或CH2;
B是式IV和V的嘌呤或嘧啶残基,它分别通过碱基的9-或1-位与呋喃糖或碳环的1'位连接;
Z=H,OH或OR3;
Y=H,OH或OR4;
根据式II,R3和/或R4是通过通式II所定义的碳原子直接与呋喃糖或碳环的2'和/或3'羟基连接的残基,或直接与呋喃糖或碳环的二个2'和3'羟基通过式III的同一碳原子连接。
当T2、W、V和/或T1是硫时,该原子的优选位置是T1和T2。
其它条件是当D1和D2是氧时,呋喃糖优选是β-构型;呋喃糖最优选是β-D-构型。
通式I的优选化合物是其结构符合式Ia和式Ib定义的分子:
式Ia
其中D1=O或CH2;
D2=O或CH2;
B和B'分别是通式IV或V的嘌呤或嘧啶残基;
m和p=0,1或2;n=0或1;这样m+n+p的和是1-5,优选1-4,最优选1-3;
X1、X2和X3=分别是O、NH、CH2、CHF、CHCl、CF2、CCl2;
T1、T2、V和W分别是O或S;
M=H+、NH4 +、Na+或其它药物学上可接受的无机或有机抗衡离子;
Y'=H、OH或OR1;
Z'=OH或OR2;
Z=OH或OR3;
Y=H、OH或OR4,其中R1、R2、R3和R4符合通式II或III的定义,条件是Y'、Z'、Z和Y中至少一个是OR1、OR2、OR3或OR4。
式Ia的优选化合物包括:
D1=O或CH2;
D2=O或CH2;
X1、X2和X3=O;
T1、T2、V和W=O;或
D1=O或CH2;
D2=O或CH2;
X1和X3=O;
X2=亚甲基、一氯亚甲基、二氯亚甲基、一氟亚甲基、二氟亚甲基或亚酰氨基;
T、T1、T2、V和W=O;或
D1=O或CH2;
D2=O或CH2;
m、n和p=1;或
X1和X3=O;
X2=亚甲基、一氯亚甲基、二氯亚甲基、一氟亚甲基、二氟亚甲基或亚酰氨基;
T1和T2=S;
V和W=O。
式Ib
D1=O或CH2;
n和p=0,1,或2,这样n+p之和是0-3;
A=M;其中M=H+、NH4 +、Na+或其它药物学上可接受的无机或有机抗衡离子;
B是通式IV和V的嘌呤或嘧啶残基;
X1和X2分别是O、NH、CH2、CHF、CHCl、CF2、CCl2;
T1、V和W分别是O或S;
Y'=H、OH或OR1,
Z'=H、OH或OR2,其中R1和R2符合通式II或III的定义;条件是Y'和Z'的至少一个分别是OR1或OR2。
式Ib的优选化合物包括:
D1=O或CH2;
n和p=0,1,或2,这样n+p之和是0-3,优选1-2;
X1和X2=O;
T1、V和W=O;或
D1=O或CH2;
X1和X2=O;
T1和V=O;
W=S;或
D1=O或CH2;
p=0,1或2,这样n+p之和是1-3;n=1;
X1=O;
X2=亚甲基、一氯亚甲基、二氯亚甲基、一氟亚甲基、二氟亚甲基或亚酰氨基;
T1、V和W=O;
Y'=H、OH或OR1;
Z'=H、OH或OR2,其中R1和R2符合通式II或III的定义;条件是Y'和Z'中至少一个分别是OR1或OR2。
B和B'分别是式IV中的嘌呤残基,通过9-位连接,或式V的嘧啶残基,通过1-位连接。核糖基部分是D-构型如所示,但可以是L-或D-和L-。D-构型优选的。
式IV
式V
其中:
R10和R14是羟基、氧代、氨基、巯基、烷硫基、烷氧基、芳氧基、烷基氨基、环烷基氨基、芳烷基氨基、芳基氨基、二芳烷基氨基、二芳基氨基或二烷基氨基,其中烷基可任选的连接,形成杂环;或
R10和R14是酰基氨基,条件是它们掺入嘌呤C-6位或嘧啶C-4位的氨基残基;或
当嘌呤中的R10,或嘧啶中的R14的第一个原子是氮时R10和R11或R14和R15合起来形成5-元稠合咪唑环(亚乙烯基化合物),在亚乙烯基环上可任选的被如上R5-R9所述的烷基、环烷基,芳烷基或芳基基团取代;
J是碳或氮,条件是当是氮,R12不存在;
R11是氢、O(1-氧化腺嘌衍生物)或不存在(腺嘌呤衍生物);
R15是氢或酰基(例如取代或未取代的乙酰基、苯甲酰基、苯基酰基);
R12是氢、烷基、溴、叠氮基、烷基氨基、芳基氨基或芳烷基氨基、烷氧基、芳氧基或芳烷氧基、烷硫基、芳硫基或芳烷硫基、或ω-A(C1-6烷基)B-,其中A和B分别是氨基、巯基、羟基或羧基;
R13是氢、氯、氨基、一取代氨基、二取代氨基、烷硫基、芳硫基或芳烷硫基,其中硫上的取代基含有最多达20个饱和或不饱和的碳原子;
R16是氢、甲基、烷基、卤素、烷基、链烯基、取代的链烯基炔基或取代的炔基。
式IV和V的化合物(其中R10或R14大部分是酰基氨基)符合式VI的范围:
式VI
其中:
NH是嘌呤的C-6位的氨基残基或嘧啶C-4位的氨基残基;
C是碳原子;
W是氧或硫;
R17是氨基或一或二取代的氨基,这样式VI的基团是脲或硫脲;或R17是烷氧基、芳烷氧基、芳氧基、取代的芳烷氧基或取代的芳氧基,这样式VI的基团是氨基甲酸酯或硫代氨基甲酸酯;或
R17是具有或不具有取代基或杂原子的烷基、环烷基、芳烷基或芳基,这样式VI的基团是酰胺;烷基、环烷基、芳烷基或芳基的定义如先前在R5-R9的可比较基团中定义的。
本领域技术人员可方便的用熟知化学方法合成本发明的化合物。可从商品来源获得一、二和三磷酸单核苷,或用化学文献中找到的各种磷酸化反应方法从核苷合成。可通过用偶联剂,例如但不限于二环己基碳二亚胺或1,1'-羰基二咪唑活化一、二或三磷酸核苷,然后与另一一、二或三磷酸核苷(可以与活化的分子相同或不同)缩合,制备对称或非对称的多磷酸二核苷。用二环己基碳二亚胺活化三磷酸核苷得到作为活化物质的环状三偏磷酸酯,它可以有利的与各种亲核试剂反应,将特定取代基加到三磷酸酯的末端磷酸酯上。
可通过在核苷水平衍生或取代,然后如前所述磷酸化或缩合制备本发明的化合物,或反应可以直接在预先形成的单或二核苷酸上进行。在通式Ia和Ib中,Y'、Z'、Y和Z的取代基可以是酯、氨基甲酸酯或碳酸酯,如式II一般描述的。酯可以方便的通过使核苷或核苷酸中呋喃糖的羟基与合适的有机酸的活化形式,例如酸酰卤或酸酐在有机或无机碱的存在下反应制备。另外,可用合适的偶联试剂,例如二环己基碳二亚胺、1,1'-羰基二咪唑等活化有机酸,达到相同的结果。
通过在惰性溶剂中,使核苷或核苷酸中呋喃糖上的羟基与许多市售异氰酸酯或异硫氰酸酯之一反应,可最方便地制备氨基甲酸酯或硫代氨基甲酸酯。另外,当不能从商品来源获得所需异氰酸酯或异硫氰酸酯时,可从相应的胺,分别使用光气或硫光气或其化学等价物制备。可通过在有机或无机碱的存在下,使核苷或核苷酸中的呋喃糖的羟基与合适的卤代甲酸酯反应,合成碳酸酯或硫代碳酸酯。
在通式Ia和Ib中,Y'和Z、Y和Z上的取代基可合起来意味着缩醛基、缩酮基或原酸酯,如通式III所示。可通过在酸性催化剂的存在下,使合适的核苷或核苷酸中呋喃糖的邻近2'和3'羟基分别与醛或酮或其等价物反应,容易制备缩醛和缩酮。特别有利的是使用有机酸,它可以实现转化而不影响分子其余部分的完整性。另外,可以催化量使用强酸,例如三氯乙酸、对甲苯磺酸、甲磺酸等和惰性溶剂。最优选的是甲酸,它理想的适合作为这些反应的溶剂和催化剂。将甲酸利用于该目的发现是本发明的一个特别方面。
环状原酸酯可以通过在酸存在下使呋喃糖的邻位2'和3'羟基与非环状原酸酯反应而制备。当要衍生的核苷或核苷酸是含有6-氨基官能团的嘌呤或含有4-氨基官能团的嘧啶时,它可以通过分别用异氰酸酯或异硫氰酸酯处理而化为各自的脲或硫脲,如先前对于呋喃糖2'或3'羟基的氨基甲酸酯或硫代氨基甲酸酯所述。发现氨基与异氰酸酯或异硫氰酸酯的反应可通过合适操纵反应的化学计量在呋喃糖的羟基存在下进行。
所述的所有衍生化反应可在预先形成的多磷酸二核苷酸上进行,根据反应的化学计量和是否存在多重反应性基团得到多种产物。当获得多重产物时,这些可以通过使用制备性反相高效液相层析(HPLC)方便的分离。特别有利的是使用C18或苯基反相柱并结合和梯度,从乙酸铵缓冲液开始,以甲醇结束。缓冲液的使用提供了核苷酸稳定性,改善了洗脱产物的峰形状,使用甲醇能够有效地使这些亲脂化合物从柱上解吸。特别有利的是使用乙酸铵缓冲溶液联合甲醇,因为这些溶剂可以任何比例混合,并不难从层析产物通过蒸发,然后冻干除去。
虽然可用HPLC进行多重产物的分离,另一种策略是使用含有仅一个反应官能团的核苷或核苷酸,不论是仅存在一个基团,或使用保护性基团封闭分子内其它位置的副反应。这可以在预先形成的多磷酸二核苷酸水平进行,或者可以在一、二或三磷酸核苷进行,生成它们自身的新产物,或可以与其它一、二或三磷酸核苷通过先前所述的方法偶联。
本发明的发明人还发现了作为ADP对其血小板膜受体P2Y12受体的作用的拮抗剂的化合物。该化合物通过其封闭ADP,阻止其作用于其血小板受体位点,从而防止血小板聚集提供作为抗血栓药物的效力。因此,这些化合物可以比阿司匹林提供更有效的抗血栓作用,但对于出血的影响比纤维蛋白受体的拮抗剂较小。由于ADP-诱导的血小板聚集是通过同时活化P2Y12和P2Y1受体介导的,本文所述的化合物与血小板P2Y1受体拮抗剂的联合给药在各拮抗剂的浓度低于在其它系统中封闭各受体亚型的有效浓度下,应可以提供更有效的抗血栓效果,导致副作用的可能发生下降。另外,这些化合物可与较低剂量的通过不同机制抑制血小板聚集的其它试剂联合使用,来减少这些药物的毒性。最后,如果本发明的化合物具有足够的结合亲和力,并携带荧光基团,可以用作P2Y12受体的生物化学探针。
通式I的化合物可用于治疗,特别是用于预防血小板聚集。本发明的化合物因此用作抗血栓药物,因此用于治疗或预防不稳定型心绞痛、冠状动脉血管成形术(PTCA)和心肌梗塞。
本发明的化合物还用于治疗或预防动脉粥样硬化的原发性动脉血栓并发症,例如血栓性中风,周围血管疾病,心肌梗塞而不溶栓。
还可使用本发明化合物的适应症是治疗或预防由于动脉粥样硬化疾病的干预,例如血管成形术、动脉内膜切除术、支架放置、冠状和其它血管移植手术引起的动脉血栓并发症。
还可使用本发明化合物的其它适应症是治疗或预防手术或机械损伤,例如手术或偶然创伤后的组织补救,重建性手术包括皮瓣,和“还原性”手术例如乳房减小的血栓并发症。
本发明的化合物还用于预防体内机械诱导的血小板活化,例如心肺分流术(预防微血栓栓塞),预防体外机械诱导的血小板活化,例如使用血液产品,例如血小板浓缩物的防腐化合物,预防阻塞分流,例如肾透析和血浆置换、由于血管损伤/炎症,例如血管炎、动脉炎、肾小球肾炎和器官移植排斥。
本发明化合物有用的其它适应症是具有弥散性血栓/血小板消耗成分的适应症,例如播散性血管内凝结、血栓性血小板减少性紫癜、溶血性尿毒症综合征、肝素诱导的血小板减少症和先兆子痫/子痫。
本发明化合物可用的其它适应症是治疗或预防静脉血栓,例如深静脉血栓、静脉栓塞疾病、血液学病况,例如血小板增多症和红细胞增多症,以及偏头痛。
在本发明的特别优选例中,化合物用于治疗不稳定性心绞痛、冠状动脉血管成形术和心肌梗塞。
在本发明的另一个特别优选例中,化合物在治疗不稳定性心绞痛、冠状动脉血管成形术和急性心肌梗塞中用作附属治疗,即周围血栓溶解。可使用在血栓疾病的治疗中常用作辅助治疗的药物,例如肝素和/或阿司匹林,仅提出一些。
治疗哺乳动物,减轻动脉粥样硬化和动脉硬化、急性MI、慢性稳定性心绞痛、不稳定性心绞痛、短暂性局部缺血发作和中风、周围血管疾病、动脉血栓形成、先兆子痫、栓塞、血管成形术、颈动脉内膜切除术和血管移植吻合术后的再狭窄或突然闭合。
本发明的化合物可在体外用于抑制血液和血液产品中的血小板聚集,例如用于储藏或体外操作,例如诊断或研究用途。本发明还提供了一种抑制哺乳动物,尤其是人的血小板聚集和凝块形成的方法,它包括内服式(I)的化合物和药物学上可接受的载体。
过聚集性的慢性或急性状态,例如弥散性血管内凝血(DIC)、败血症、手术或感染性休克、手术后和产后创伤、心肺分流术、不兼容输血、胎盘早期脱离、血栓性血小板减少性紫癜(TTP)、蛇毒和免疫疾病也可能对这些治疗有反应。
本发明还提供了一种在纤维蛋白溶解治疗后抑制动脉或静脉重新阻塞的方法,它包括体内施用式(I)的化合物和纤维蛋白溶解剂。当在本发明中使用时,术语纤维蛋白溶解剂是指任何化合物,不论天然或合成产物,直接或间接导致纤维蛋白凝块的溶解。纤溶酶原活化剂是一类熟知的纤维蛋白溶解剂。有用的纤溶酶原活化剂包括例如复合纤溶酶链激酶、尿激酶(UK)、前尿激酶(pUK)、链激酶(SK)、组织纤溶酶原活化剂(tPA)和突变剂,或其变体,它维持纤溶酶原活化剂活性,例如化学修饰过,或其中加入、缺失或取代一个或多个氨基酸,或其中通过联合一种纤溶酶原活化剂的活性位点或另一种纤溶酶原活化剂或纤溶酶结合分子的纤溶酶结合域,加入、缺失或改变一个或多个功能域的变体。
在心血管手术中常规使用体外循环,以对血液充氧。血小板粘附在体外回路表面。从人工表面释放的血小板显示受损的止血功能。本发明的化合物可用于防止粘附。
这些化合物的其它应用包括预防血栓治疗中和后的血小板血栓形成、栓塞和重新阻塞,和预防冠状和其它动脉的血管成形术后和冠状动脉分流术后的血小板血栓形成、栓塞和重新阻塞。
本发明的化合物还包括其无毒的药物学上可接受的盐,例如而不限于碱金属盐,例如钠或钾盐;碱土金属盐,例如锰盐、镁盐或钙盐;或铵或四烷基铵盐,即NX4 +(其中X是C1-4)。药物学上可接受的盐是维持母化合物所需生物活性,而不带来不良毒物学作用的盐。
本领域技术人员将认识到可使用许多合成方法来制备无毒的药物学上可接受的盐,和化合物的酰化前药。
本发明活性化合物可全身施给需要治疗的个体的目标位点,例如提高P2Y12激动剂的胞外浓度,以封闭ADP与P2Y12受体的结合,从而抑制血小板聚集。本文所用的术语“全身性”包括皮下注射、静脉内、肌肉内、胸骨内注射、玻璃体内注射、输液、吸入、透皮给药、口腔给药、直肠给药和手术内滴注。还包括泵导管系统和连续或选择性释放装置的装置将所述化合物输注给目标血小板。
对于全身性给药,例如注射和输液,药物制剂可制备在无菌介质中。根据所用的载体和浓度,活性成分可以悬浮或溶解在载体内。佐剂,例如局部麻醉剂、防腐剂和缓冲剂也可溶于载体。无菌可检控制剂可以是无毒可接受的去污剂或溶剂中的无菌可检控溶液或悬液。在使用的可接受的载体和溶剂中有无菌水、盐水溶液或Ringer氏溶液。
全身施用活性化合物的另一种方法涉及口腔给药,其中含有活性化合物的药物组合物的形式是片剂、锭剂、水相或油相悬液、粘性凝胶、口香糖、可分散粉末或颗粒、乳液、硬或软胶囊或糖浆或酏剂。
对于口腔使用,在可分散粉末和颗粒中加入水和分散或湿润剂、悬浮剂、一种或多种防腐剂和其它赋形剂,制备水相悬液。悬浮剂包括例如羧甲基纤维素钠、甲基纤维素和海藻酸钠。分散剂或湿润剂包括天然存在的磷脂,环氧丙烯与脂肪酸的缩合产物、环氧乙烷与脂肪酸和己糖醇的部分酯的缩合产物,和环氧乙烷与衍生自脂肪酸和己糖醇酐的部分酯的缩合产物。防腐剂包括例如对羟基苯甲酸乙酯和正丙酯。其它赋形剂包括甜味剂(例如蔗糖、糖精)、调味剂和着色剂。本领域技术人员应认识到上面的一般描述包括许多具体的赋形剂和湿润剂。
对于口腔给药,通过将活性化合物与适用于制造片剂的无毒的药物学上可接受的赋形剂混合来制备片剂。这些赋形剂可以是例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;粒化剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是不上糖衣或可以通过已知技术上糖衣,以延迟在胃肠道内崩解和吸收的时间,从而在更长的时间内提供缓释作用。例如,可使用一种时间延迟材料,例如甘油单硬脂酸酯或甘油二硬脂酸酯。还可存在口腔使用的制剂,例如硬明胶胶囊,其中活性成分与惰性固相稀释剂,例如碳酸钙、磷酸钙或高岭土混合,或作为软明胶胶囊,其中活性成分与水或油基质,例如花生油、液态石蜡或橄榄油混合。口腔使用的制剂还可以作为口香糖存在,通过将活性成分包埋在胶中,从而活性成分可以随着咀嚼缓慢释放。
对个体目标血小板全身性施用活性化合物的另一种方法涉及活性化合物的栓剂形式,这样化合物的治疗有效量可通过全身性吸收和循环到达目标位点。
对于直肠给药,可以通过将活性成分与合适的无刺激性赋形剂(在常温是固体但在直肠温度下是液体,从而能够在直肠中融化,以释放化合物)混合,制备栓剂形式的组合物。这些赋形剂包括可可脂和聚乙二醇。
还可用透皮贴片或垫通过皮肤吸收,对血小板聚集位点全身性施用活性化合物。活性化合物可通过皮肤吸收到血流中。可用含有不同浓度活性化合物的贴片控制活性化合物的血浆浓度。
一种全身性方法涉及含有活性化合物的可呼吸颗粒的气溶胶悬液,它被个体吸入。活性化合物可以通过肺被吸收入血流,然后以药物有效量接触目标血小板。可呼吸颗粒可以是液体或固体,颗粒尺寸足够小,在吸入后能通过口腔和喉咙;一般约1-10微米,但更优选是1-5微米大小的颗粒被认为是合适的。
另一种对个体的血小板聚集位点全身性施用活性化合物的方法涉及施用滴眼液或洗眼液的液体/悬液,或液体形式的滴鼻液,或让个体吸入的可呼吸颗粒的鼻部喷雾。可通过将活性化合物与合适的载体,例如无菌无热原水或无菌盐水,通过本领域技术人员已知的技术混合,来制备用于制备鼻部喷雾或鼻或眼药水的活性化合物的液体药物组合物。
玻璃体内传递可包括一次或多次玻璃体内注射,或通过以缓释形式释放P2Y12拮抗剂的可植入玻璃体内装置。玻璃体内传递还可包括在手术过程中作为眼内冲洗溶液的附加成分传递,或直接在手术过程中对玻璃体施用。
对于全身性给药,传递的活性化合物的血浆浓度可根据化合物改变,但通常是1×10-10-1×10-5摩尔/升,优选1×10-8-1×10-6摩尔/升。
本发明的P2Y12拮抗剂化合物的药物利用性是由其对ADP-诱导的血小板聚集的抑制表示的。该广泛使用的试验,如S.M.O.Hourani等,Br.J.Pharmacol.105,453-457(1992)所述,依赖于在添加聚集剂,例如ADP后血小板悬液的聚集的测定。
本发明还提供了主题的新颖组合物。组合物是药物学上可接受的制剂,含有高纯度的式I的化合物和/或药物学上可接受的载体。可由本领域技术人员使用常规条件选择药物学上可接受的载体。药物学上可接受的载体包括但不限于盐水和电解质水溶液,水聚醚例如聚乙二醇,聚乙烯基例如聚乙烯醇和聚乙烯吡咯酮,纤维素衍生物,例如甲基纤维素和羟丙基甲基纤维素,石油醚衍生物例如矿物油和白矿脂,动物脂肪例如羊毛脂,丙烯酸的聚合物例如羧基聚甲烯凝胶,植物脂肪例如花生油,和多糖例如葡聚糖,和葡糖胺聚糖,例如透明质酸钠,和盐例如氯化钠和氯化钾。
本发明的优选组合物包括式Ib化合物(单核苷酸),条件是当n=1时,X1和X2都不是O,当n=0,X1不是O;和条件是当Y'=H时,X2分别是O、CH2、CHF、CHCl、CF2、CCl2;和条件是当R10=NH2或O,当R5和R6合起来作为与C双键键合的O,则R7不等于邻甲基氨基苯基;另外的条件是当n=p=1,X2=CH2,B'=腺嘌呤,则R1和R2不等于亚萘基甲基、亚萘基亚甲基或苯基亚甲基。
本发明的优选组合物还包括式Ia的化合物,其中B和B'分别是嘧啶(嘧啶/嘧啶二核苷酸),条件是当m+n+p=1时,R16=CH3,R5和R6合起来作为与C双键键合的氧,则R7不等于CH3(Z'不等于乙酸酯);和条件是当m+n+p=3,B和B'是尿苷,R5和R6合起来作为与C双键键合的氧,则R7不等于苯基。因为Y'=OR1和/或Y=OR4(Y和Y'不等于苯甲酰基);还有条件是当m+n+p=1,则R8和R9不是CH3(Z'和Y'合起来不等于异亚丙基(isopropylidine))。
本发明的优选组合物还含有式Ia的化合物,其中B是嘌呤或通式IV的残基,B'是通式V的嘧啶残基(嘌呤/嘧啶二核苷酸);条件是当Z'、Y或Y'=H或OH时,Y'不等于OCH3;还有条件是当R9=H时,R8不等于OCH2CH3(Z'和Y'或Z和Y合起来不等于原酸乙酯)。
本发明的优选化合物还含有式Ia的化合物,其中B和B'分别是通式IV的嘌呤残基(嘌呤/嘌呤二核苷酸);条件是(a)当R10=NH2或O时,Y或Y'不等于OCH3;(b)当R9=H时,R8不等于OCH3或OCH2CH3;(c)R8和R9不等于CH3;(d)当m+n+p=1时,R8和R9不等于OCH2CH3;(e)当R10=NH2时,和当R5和R6合起来作为与C双键键合的氧时,R7不等于邻甲基氨基苯基;(f)当m+n+p=1和当R5和R6合起来作为与C双键键合的氧时,则R7不等于CH(CH2CH2SCH3)NH3(o-NO2-Ph)或CH(CH2Ph)NHS(o-NO2-Ph)。
本发明的更优选组合物包括下列化合物:2'或3'苯基氨基甲酸酯UTP、2',3'二苯基氨基甲酸酯UTP、2',3'苯基乙醛缩醛ADP、二[3'(苯基氨基甲酸酯)dUp2dU]、2'3'苯基乙醛缩醛Up3U、二2'3'苯基乙醛缩醛Up3U、2'3'苯基乙醛缩醛Up4A、2'3'苯基乙醛缩醛AP4U、二2'3'苯基乙醛缩醛AP4U、2'3'苯基乙醛缩醛Ip4U、2'3'苯基乙醛缩醛Up4U、2'3'苯基乙醛缩醛Ip4U、2'3'苯基乙醛缩醛Up4dC、四苯基氨基甲酸酯Up4U、二2'3'苯甲醛缩醛Ip4U、二2',3'苯甲醛缩醛Up4U、2',3'苯甲醛缩醛Up4U、二2',3'苯基乙醛缩醛Cp4U、2',3'苯基乙醛缩醛Cp4U、2',3'苯基乙醛缩醛Up4C、2',3'苯基乙醛缩醛Up4T、二2',3'苯甲醛缩醛Cp4U、2',3'苯甲醛缩醛Ip4U、2',3'苯甲醛缩醛Up4U、2',3'苯甲醛缩醛Up4dC、2'3'苯甲醛缩醛Cp4U、2'3'苯甲醛缩醛Up4C、2',3'苯基丙醛缩醛Up4U、二2',3'苯基丙醛缩醛Up4U、2',3'苯甲醛缩醛Cp4C、二MANT Up4U、Mant Up4U、二2'/3'苄基缩醛Up4U、单2'/3'苄基缩醛Up4U、三苯基氨基甲酸酯Up4U、2'3'苯基氨基甲酸酯Up4U和一苯基氨基甲酸酯Up4U。
优选组合物还包含下列化合物1-21。在下列结构中理解存在的氢为了简化被省略了。
化合物1
化合物2
化合物3
2-(3-三氟甲基丙基)硫代-6-(2-甲硫基)乙基氨基-2',3'-(苄基)亚甲基二氧嘌吟核糖核苷5'-α,β-二氟亚甲基二磷酸酯
化合物4
化合物5
化合物6
化合物7
化合物8
化合物9
化合物10
化合物11
化合物12
化合物13
化合物14
P1-[2-(3-三氟甲基丙基)硫代-6-(2-甲硫基)乙基氨基2',3'-(苄基)亚甲基二氧嘌呤核糖核苷]-P4-(2',3'-(苄基)亚甲基二氧尿苷)四磷酸酯
化合物15
化合物16
化合物17
化合物18
化合物20
化合物21
用下列实施例进一步说明了本发明。这些实施例不是为了将本发明限于说明书所描述的方法范围内。
实施例
实施例1
2'(3')-O-((苯基氨基羰基)-尿苷5'-)三磷酸
在无水DMF(1ml)中溶解5'-三磷酸尿苷、二三丁基铵盐(100mg,0.176mmol;从三钠盐通过用dowex 50Wx4H+在水中处理,然后将质子化的物质与过量三丁胺反应,反萃取并冻干),加入异氰酸苯酯(19微升,0.176mmol)。反应混合物在45℃加热15分钟,该点再加入一份异氰酸苯酯(19微升,0.176mmol)。溶液在45℃加热过夜,在旋转蒸发器上除去DMF。剩余的油在水(2mL)和乙酸乙酯(2ml)之间分配,并分层。用乙酸乙酯(各2ml)再萃取水层2次,在旋转蒸发器上除去水。剩余物溶于水(1.5ml),重复将产物注射入制备级HPLC柱(AlltechNucleotide/Nucleoside C18,7微米,10×250mm,梯度为0.1M乙酸铵-甲醇,经过30分钟,5ml/min,在260nm监测)分离产物。氨基甲酸酯的产率是26mg(22%,对于季铵盐计算)。1H NMR显示产物是2'和3'氨基甲酸酯的混合物。如此获得的产物本身可用于本发明,或可用适合的偶联剂(例如碳二亚胺)活化,并与各种核苷酸反应,以产生新颖的多磷酸二核苷。
1H NMR(D2O,300MHz):δ 4.10-4.47(m,4H),5.17(m,1H),5.83(dd,1H),5.96(m,1H),7.04(t,1H),7.25(m,4H),7.79(m,1H).31P NMR(D2O,121.47MHz):δ-9.54(m,1P),-10.20(m,1P),-21.87(m,1P)。
实施例2
2'(3')-O-(苯基氨基羰基)-P1,P4-二(尿苷5'-)四磷酸酯[“一苯基氨基甲酸酯Up4U”],二-2'(3')-O-(苯基氨基羰基)-P1,P4-二(尿苷5'-)四磷酸酯[“二苯基氨基甲酸酯Up4U”]和三-2'(3')-O-(苯基氨基羰基)-P1,P4-二(尿苷5'-)四磷酸酯[“三苯基氨基甲酸酯Up4U”]
在无水DMF(2ml)中溶解P1,P4-二(尿苷5')'-四磷酸酯、二三丁基铵盐(211mg,0.182mmol;从四钠盐通过用Dowex 50Wx4H+的水溶液处理,然后将质子化物质与过量三丁胺反应,反萃取并冻干),加入一份异氰酸苯酯(40微升,3.64mmol)。均匀反应混合物在45℃加热过夜,此时TLC(硅胶,50%异丙醇/50%氢氧化铵)表明基本转化成两种产物。在旋转蒸发器上除去溶剂,剩余物在水(7mL)和乙酸乙酯(10ml)之间分配。分离层,用乙酸乙酯(各10ml)再萃取水层2次。从水提取物中除去水,剩余的油冻干过夜。获得的固体在水(3ml)中重建,重复将产物注射入半制备级HPLC柱(Alltech Nucleotide/Nucleoside C18,7微米,10×250mm,梯度为0.1M乙酸铵-甲醇,经过30分钟,5ml/min,在260nm监测)分离两种产物。反萃取和冻干得到一苯基氨基甲酸酯(48mg,产率27%)、二苯基氨基甲酸酯(16mg,产率8%)和痕量的三苯基氨基甲酸酯,作为季铵盐。所有三种产物是相应的2'/3'区域异构体的混合物。
一苯基氨基甲酸酯:1H NMR(D2O,300MHz):δ 4.08-4.65(m,9H),5.14(d,1H),5.75-5.94(m,4H),7.01(t,1H),7.22(m,4H),7.76(m,2H).31P NMR(D2O,121.47MHz):δ-10.17(m,2P),-21.81(m,2P)。
二苯基氨基甲酸酯:1H NMR(D2O,300MHz):δ 4.13-4.43(m,8H),5.12(m,2H),5.84(m,4H),7.01(m,2H),7.21(m,8H),7.75(dd,2H).31P NMR(D2O,121.47MHz):δ-10.19(m,2P),-21.65(m,2P)。
三苯基氨基甲酸酯:1H NMR(D2O,300MHz):δ 4.29(m,7H),4.5.10(m,1H),5.27(m,2H),5.87(m,4H),7.09(m,15H),7.76(d,2H).31P NMR(D2O,121.47MHz):δ-10.30(m,2P),-21.73(m,2P)。
实施例3
P1,P4-四(2'(3')-O-(苯基氨基羰基)-二(尿苷5'-)四磷酸酯[四苯基氨基甲酸酯Up4U”]
根据实施例2的方法制备了该衍生物。用16当量异氰酸苯酯(300微升,2.76mmol)的DMF溶液处理P1,P4-二(尿苷5'-)四磷酸酯、二三丁基铵盐(200mg,0.172mmo),35℃搅拌过夜。蒸发溶剂,用乙酸乙酯萃取产物水溶液除去过量试剂。如前所述制备级HPLC后,获得93mg(30%产率)的四苯基氨基甲酸酯。
四苯基氨基甲酸酯:1H NMR(D2O,300MHz):δ 7.75(d,2H),7.11(m,16H),6.94(m,4H),5.95(d,2H),5.80(d,2H),5.32(m,2H),5.23(m,2H),4.42(m,2H),4.25(m,2H),4.16(m,2H).31P NMR(D2O,121.47MHz):):δ-10.30(m,2P),-22.32(m,2P)。
实施例4
2',3'-(苄基)亚甲基二氧基-P1,P4-二(尿苷5'-)四磷酸酯[“一2'/3'苄基缩醛Up4U”]和P1,P4-二-(2',3'-((苄基)亚甲基二氧基)二(尿苷5'-)四磷酸酯[“二2'/3'苄基缩醛Up4U”]
在98%甲酸中溶解P1,P4-二(尿苷5')'-四磷酸四钠盐(290mg,0.332mmol),加入苯基乙醛二甲基缩醛(110微升,0.662mmol)。在环境温度下搅拌反应物3天,此时TLC(硅胶,50%异丙醇/50%氢氧化铵)和HPLC(C18)表明良好转化成两种极性较小的产物。在旋转蒸发器上除去甲酸,剩余物在0.7M碳酸氢钠(15mL)和乙酸丁酯(15ml)之间分配。分离层,用另一份乙酸丁酯(10ml)洗涤水层。反萃取水层,剩余物冻干过夜。将粗产物溶于水(5ml),通过制备级HPLC柱(Waters NovapakC18,6微米,25×100mm,梯度为0.1M乙酸铵-甲醇,经过30分钟,30ml/min,在260nm监测)分离组分。单缩醛的产率是88mg(28%),二缩醛是60mg(17%)都是季铵盐。
单缩醛:1H NMR(D2O,300MHz):δ 2.99(d,2H),4.01-4.32(m,8H),4.77(m,2H),5.33(m,2H),5.74(d,1H),5.81(m,2H),7.21(m,5H),7.64(d,1H),7.79(d,1H).31P NMR(D2O,121.47MHz):δ-10.18(m,1P),-10.78(m,1P),-22.00(m,2P)。
二缩醛:1H NMR(D2O,300MHz):δ 2.98(d,4H),3.99(m,4H),4.27(m,2H),5.27(m,2H),5.36(m,2H),5.73(d,J=8.1Hz,2H),7.21(m,10H),7.61(d,J=8.1Hz,2H).31P NMR(D2O,121.47MHz):δ-10.57(m,2P),-21.81(m,2P)。
实施例5
2',3'-((苄基)亚甲基二氧基)P1,P3尿苷5'-)三磷酸酯[“2'3'苯基乙醛缩醛Up3U”]和P1,P3-二-(2',3'-((苄基)亚甲基二氧基)尿苷5'-)三磷酸酯[“二2'3'苯基乙醛缩醛Up3U”]
在98%甲酸中溶解P1,P3-二(尿苷5')'-三磷酸三钠盐(100mg,0.129mmol),加入苯基乙醛二甲基缩醛(64微升,0.386mmol)。在室温下搅拌过夜后,除去甲酸,剩余物在1M碳酸氢钠和乙酸乙酯之间分配。除去有机层,用制备级HPLC柱如前所述纯化产物。冻干后,获得40mg(36%)单缩醛和24mg(19%)二缩醛。
单缩醛:1H NMR(D2O,300MHz):δ 7.7s(d,2H),7.54(d,2H),7.16(s,5H),5.70(m,3H),5.31(s,1H),5.23(s,1H),4.66(m,2H),4.10(m,8H),2.93(d,2H).31PNMR(D2O,121.47MHz):δ-10.30(m,1P),10.81(m,1P),-21.99(m,1P)。
二缩醛:1H NMR(D2O,300MHz):δ 7.51(d,2H),7.15(m,10H),5.65(d,2H),5.31(d,2H),5.20(t,2H),4.63(m,2H),4.13(m,2H),3.88(m,4H),2.90(d,4H).31PNMR(D2O,121.47MHz):δ-10.75(m,2P),-21.97(m,1P)。
实施例6
P1-2',3'-((苄基)亚甲基二氧)(尿苷5'-)P4-(脱氧胸苷5'-)四磷酸[“2'3'苯基乙醛缩醛Up4dC”]
在98%甲酸(1ml)中溶解P1-(尿苷5'-)P4-(脱氧胸苷5'-)四磷酸四钠盐(100mg,0.16mmol),加入苯基乙醛二甲基缩醛(57微升,0.384mmol)。搅拌过夜后,除去甲酸,剩余物在1M碳酸氢钠和乙酸乙酯之间分配。分离层后,用制备级HPLC柱如前所述纯化产物。产率40mg(36%)。该产品易于用实施例9-13所述的方法随后修饰脱氧胸苷碱基,产生在本发明范围内的亲脂性双功能分子。
一乙缩醛:1H NMR(D2O,300MHz):δ 7.98(d,1H),7.62(d,1H),7.21(m,5H),6.11(m,2H),5.74(d,1H),5.39(d,1H),5.31(t,1H),4.77(m,2H),4.45(m,1H),4.32(m,1H),4.03(m,5H),2.99(d,2H),2.29和2.21(M,2H).31P NMR(D2O,121.47MHz):δ-10.15(m,1P),-10.68(m,1P),-21.98(m,2P)。
实施例7
3'-O-(苯基氨基羰基)-2'-脱氧(尿苷5'-)-一磷酸
将脱氧尿苷5'-一磷酸四丁基铵盐(135mg,0.274mmol;用Dowex 50Wx4H+处理,然后搅拌得到的中性物质和过量三丁胺,反萃取和冻干)溶于无水DMF(1ml)。加入异氰酸苯酯(60微升,0.547mmol),并45℃加热过夜,此时TLC(硅胶,50%异丙醇/50%氢氧化铵)和HPLC(C18)表明基本转化成极性较小的产物。在旋转蒸发器上反萃取DMF,油状残余物在水(10ml)和乙酸乙酯(10ml)之间分配。分离层,重新用乙酸乙酯(2×10ml)洗涤水层。除去水并将剩余物溶于水(2ml)。通过重复注射入半制备级HPLC(Alltech Nucleotide/Nucleoside C18,7微米,10×250mm,0.1M乙酸铵到甲醇梯度,经30分钟,5ml/分钟,260nm监测)分离产物。产量为67mg二铵盐(53%)。
1H NMR(D2O,300MHz):δ 2.21(m,2H),3.84(s,2H),4.13(s,1H),5.08(d,1H),5.63(d,1H),6.06(t,1H),6.89(br.t,1H),7.10(m,4H),7.72(d,1H)。
31P NMR(D2O,121.47MHz):δ-2.31(s)。
P1-(3'-O-(苯基氨基羰基)-2'-脱氧尿苷5'-)P4-(尿苷5'-)四磷酸
在室温下用1.5当量二环己基碳二亚胺的DMF溶液处理尿苷5'-三磷酸二三丁基铵盐(从三钠盐通过用Dowex 50Wx4H+处理,然后将得到的中性物质与过量三丁胺一起搅拌,反萃取并冻干制备)。滤去二环己基脲,用'-O-(苯基氨基羰基)-2'-脱氧(尿苷5')一磷酸(单三丁基铵盐形式)处理得到的尿苷5'-环三磷酸。45℃搅拌反应混合物数日,除去溶剂。如上所述用制备级HPLC分离产物。
实施例8
2'(3')-(2-甲基氨基)苯甲酰基-P1,P4-二(尿苷5'-)四磷酸(“MANT Up4U”)和P1,P4-二-(2'(3')-(2-甲基氨基)苯甲酰基尿苷5'-)四磷酸(“二MANT Up4U”)
将P1,P4-二(尿苷5'-)四磷酸四钠盐(800mg,0.93mmol)溶于水(5ml),通过加入固态碳酸氢钠将pH调节到7.6。加入N,N-二甲基甲酰胺(DMF,5ml),然后加入N-甲基靛红酸酐(231mg,1.3mmol),50℃加热悬液2.5小时。TLC(硅胶,50%异丙醇,50%氢氧化铵)表明此时不进行反应,因此加入另一份N-甲基靛红酸酐(100mg,0.56mmol),反应物再加热一小时。在旋转蒸发器上除去DMF,并将残基溶于少量水,加到DEAE Sephadex A-25柱(3×60cm)上。用水到1M碳酸氢铵的分布梯度洗脱柱,用定为254nm的UV检测仪监测洗脱。洗脱出的两种产物分别收集,并从各自除去溶剂,剩余物冻干过夜。1H NMR表明洗脱的第一种产物是单酰化化合物,而后者是二酰化衍生物,而且它们都是在2'或3'羟基酰化的混合物,但在同一糖上没有两个氨基甲酸酯。一氨基苯甲酰化产物的产率是150mg(16%);二氨基苯甲酰化化合物的产量是91mg(8.7%)。
一氨基苯甲酰化衍生物:1H NMR(D2O,300MHz):δ 2.70(s,3H),4.09-4.55(m,9H),5.34(m,1H),5.71(m,2H),5.83(dd,1H),6.01(m,1H),6.57(m,1H),6.65(m,1H),7.25(t,1H),7.72(d,2H),7.81(m,2H).31P NMR(D2O,121.47MHz):δ-10.20(m,2P),-21.83(m,2P)。
二氨基苯甲酰化衍生物:1H NMR(D2O,300MHz):δ 2.69(s,6H),4.15-4.51(m,8H),5.27(m,2H),5.86(m,4H),6.60(m,4H),7.30(m,2H),7.79(m,4H).31PNMR(D2O,121.47MHz):δ-10.16(m,2P),-21.76(m,2P)。
实施例9
P1-(4-N-(4-甲氧基苯基)氨基羰基胞苷-5'-)-P4-(尿苷5'-)四磷酸
将P1-(胸苷5'-)-P4-(尿苷5'-)四磷酸二三丁基铵盐(50mg,0.043mmol;用Dowex50Wx4H+的水溶液处理四铵盐,然后混合质子化物质和过量三丁胺的甲醇溶液,反萃取和冻干制备)溶于无水DMF(1ml),一步加入三丁胺(10微升,0.43mmol)和异氰酸对甲氧基苯酯(8.4微升,0.648mmol)。均匀反应混合物在35℃加热过夜,此时TLC(硅胶,50%异丙醇/50%氢氧化铵)和HPLC(C18)表明基本转化成单一产物。在旋转蒸发器上除去溶剂,剩余物溶于水(1ml)。通过重复注射入半制备级HPLC(Alltech Nucleotide/Nucleoside C18,7微米,10×250mm,0.1M乙酸铵到甲醇梯度,经30分钟,5ml/分钟,260nm监测)分离产物。反萃取和冻干得到作为季铵盐的对甲氧基苯基脲(24mg,55%产率)。
获得的产物可在2'和/或3'羟基上根据上述方法(例如实施例2-6)衍生化。
1H NMR(D2O,300MHz):δ 3.59(s,3H),4.01-4.20(m,10H),5.68(m,3H),6.19(d,1H),6.71(d,2H),7.18(d,2H),7.67(d,1H),8.06(d,1H).31P NMR(D2O,121.47MHz):δ-10.13(m,2P),-21.76(m,2P)。
实施例10
P1-((4-溴苯基)亚乙烯基胞苷5'-)-P4-(尿苷5'-)四磷酸
将P1-(胞苷5'-)-P4-(尿苷5'-)四磷酸四钠盐(500mg,0.57mmol溶于水(5ml),加入2,4'-二溴苯乙酮(792mg,2.85mmol)的DMF(15ml)溶液。40℃加热混合物过夜,加入另一份二溴酮(400mg,1.44mmol)的DMF(5ml)溶液。再加热反应物5小时,蒸发除去溶剂。剩余物在水(20ml)和乙酸乙酯(25ml)之间分配并分离层。再用乙酸乙酯(2×15ml)洗涤水层,蒸发水层至干。剩余物溶于水(5ml),通过重复注射入半制备级HPLC(条件见实施例6)分离产物。纯亚乙烯化合物的产量为80mg(13.5%)。
1H NMR(D2O,300MHz):δ 4.06(m,8H),4.36(m,2H),5.64(dd,2H),6.07(d,1H),6.74(d,1H),7.45(d,2H),7.54(d,2H),7.59(d,1H),7.63(d,1H),7.93(s,1H).31P NMR(D2O,121.47MHz):δ-10.09(m,2P),-21.59(m,2P)。
实施例11
P1-((4-溴苯基)亚乙烯基-2′-脱氧胞苷5'-)-P4-(尿苷5'-)四磷酸
根据实施例7的通用方法,用100mg P1-(2'-脱氧胞苷5'-)-P4-(尿苷5'-)四磷酸四钠盐和2,4'-二溴苯乙酮制备实施例8产物。产率=35mg(30%)。
1H NMR(D2O,300MHz):δ 2.31(m,2H),4.03(m,8H),5.60(dd,2H),6.41(t,1H),6.73(d,1H),7.53(m,5H),7.65(d,1H),7.93(s,1H).31P NMR(D2O,121.47MHz):δ-10.11(m,2P),-21.58(m,2P)。
实施例12
P1,P4-二((4-溴苯基)亚乙烯基胞苷5'-)-四磷酸
根据实施例7的通用方法,用50mgP1,P4-二(胞苷5'-)四磷酸四钠盐和2,4'-二溴苯乙酮制备实施例9的产物。产率=20mg(29%)。
1H NMR(D2O,300MHz):δ 4.24(m,10H),5.98(d,2H),6.39(d,2H),7.14(m,8H),7.45(m,4H).).31P NMR(D2O,121.47MHz):δ-10.13(m,2P),-21.68(m,2P)。
实施例13
P1-((4-苯基苯基)亚乙烯基胞苷5'-)-P4-(胞苷5'-)四磷酸
根据实施例7的通用方法,用50mg P1,P4-二(胞苷5'-)四磷酸四钠盐和2-溴-4'-苯基苯乙酮制备实施例10的产物。产率=15mg(13%)。
1H NMR(D2O,300MHz):δ 4.10(m,10H),5.48(d,1H),5.87(m,2H),6.68(d,1H),7.20(m,3H),7.36(m,6H),7.68(m,3H).31P NMR(D2O,121.47MHz):δ-10.08(m,2P),-21.78(m,2P)。
可根据实施例2-6的方法进一步衍生化实施例7-10的产物,得到在本发明范围内的双功能分子。
实施例14
ADP-诱导的血小板聚集的抑制
血小板分离:从接到通知的健康志愿者获得人血。在1/6体积的ACD中收集血液(2.5g柠檬酸钠,1.5g柠檬酸和2.5g葡萄糖的100ml dH2O)。室温下800xg离心血液15分钟,去除富含血小板的血浆,在1mM乙酰水杨酸存在下37℃保温60分钟,并在室温下1000xg离心10分钟。将血小板沉淀以2×108细胞/毫升的密度用HEPES-缓冲的Tyrodes溶液(137mM NaCl,2.7mM KCl,1mM MgCl2,3mMNaH2PO4,5mM葡萄糖,10mMHEPES pH7.4,0.2%牛血清清蛋白和0.05U/ml三磷酸腺苷双磷酸酶)重悬浮。
聚集研究:通过测量37℃下光集合度计中0.5ml搅拌的(900rpm)阿司匹林处理的洗涤血小板(Chrono-Log Corp.Havertown,PA),测定ADP-诱导的血小板聚集。用0.5ml Hepes缓冲的Tyrode缓冲液设定仪器基线。在聚集测定前,用2mM CaCl2和1mg/ml纤维蛋白原补充血小板悬液。加入指定浓度的ADP或其它激动剂,引发血小板聚集,连续记录至少8分钟的光透射。当测试血小板聚集的抑制剂时,在指定浓度的抑制剂中保温血小板3-6分钟,然后加入ADP或其它激动剂,连续记录至少8分钟的反应。用Graphpad软件包(GraphPad Corp.San Diego,CA)将数据拟合到四参数对数等式,从两种聚集速率和各测定的最大聚集程度计算血小板聚集的激动剂和抑制剂的能力。
本申请中描述了P2Y12拮抗剂抑制血小板聚集的能力,作为ADP最大有效浓度诱导的聚集的抑制百分数。当测试广泛浓度范围的P2Y12拮抗剂时(通常为1nM-100μM),还可获得IC50值。IC50值代表抑制给定浓度的ADP引起的聚集的50%所需的拮抗剂浓度。
实施例15
对体内血小板聚集的效果
为了评估这些化合物在体内抑制血小板聚集的作用,进行了与R.G.Humphries等(Br.J.Pharmacol.115:1110-1116,1995)的方法相似的实验方案。
手术准备和仪器:麻醉雄性Sprague-Dawley大鼠。用加热灯将体温维持在37℃±5℃。动物自主呼吸,并进行气管切开以确保开放气道。将含有肝素化的盐水的套管插入左侧股动脉,并与传感器连接,以记录血压和心跳速率。将含有非肝素化盐水的套管插入左总颈动脉和左颈静脉,分别用于抽取动脉血样并静脉施用化合物。
实验方案:各化合物或载体通过输液施给各动物。在第一次输液前,每次输液结束时和最后一次输液停止后20分钟立即抽取血样,以测定体外血小板聚集。采样结束后,立即以一式两份在0.5ml用盐水1:1稀释的血样中测定ADP-诱导的血小板聚集,并在37℃保温4分钟。对于该阶段的最后一分钟,将比色杯转移到光聚集度计中,900rpm搅拌样品。以20微升体积加入ADP(3μM),记录聚集反应。
实施例16
麻醉的大鼠中血栓形成的抑制
为了评估这些化合物对于体内血栓形成的作用,进行了下列实验方案:
用戊巴比妥钠(70mg/kg腹膜内)麻醉大鼠(CD-1;雄性;约350g;Charles River,Raleigh,NC)。腹部剃毛,在侧尾静脉中插入22口径静脉内导管。进行中线切割,将小肠包扎在浸渍盐水的纱布中,放置成可接触腹主动脉。小心分离下腔静脉和腹主动脉,解剖一段(约1cm)腹主动脉(远离肾动脉,靠近分叉)。将该段主动脉中的所有分枝用4-0丝缝合线连接。在动脉上安装与Transonic流量表连接的2.5mm直径流量探头,记录基线(狭窄前)流量。用两个夹子夹住动脉,将血管直径减少约80%。记录第二基线流量(狭窄后),测试充血反应。然后用化合物或盐水通过尾静脉导管静脉内处理动物。用止血钳重复外部压缩血管后5分钟引起血栓。受伤2分钟后,重复压缩血管,开始10分钟的流量监测期。连续监测动物最少受伤后的最初10分钟。20分钟(受伤后)后,重复流量测定,使动物安乐死。收集包括受伤区段的动脉区段,并置于10%福尔马林中用于可能的组织学评估。
实施例17
在麻醉的犬中对血栓形成的抑制
为了评估这些化合物对于体内动态血栓形成的作用,进行了与J.L.Romson等(Thromb.Res.17:841-853,1980)的方法相似的下列实验方案。
手术准备和仪器:简单说,麻醉为特定目的而饲养的犬,插管并通室内空气。在第15根肋骨空间左侧切开胸廓,暴露心脏,并用心脏吊架悬挂。通过钝头分离分离左冠状动脉回旋支(LCCA)的2-3cm区段。动脉装有从近端到远端的流量探头、刺激电极和Goldblatt夹。流量探头监测平均和阶段LCCA血流速度。刺激电极和它在LCCA中的位置和诱导阻塞性冠状动脉血栓的方法如先前所述(J.K.Mickelson等,Circulation 81:617-627,1990;R.J.Shebuski等,Circulation 82:169-177,1990;J.F.Tschopp等,Coron.Artery Dis.4:809-817,1993)。
实验方案:随即对狗进行4种处理方案之一(每处理组n=6),其中对照组静脉内接受盐水,三个药物处理组静脉内施用化合物。在手术干预稳定化后,犬接受盐水或化合物。记录在形成阻塞性血栓前循环流动变化的数量和频率。这些循环现象是由于血小板聚集在狭窄的管腔中形成的血小板血栓导致的(J.D.Folts等,Circulation 54:365-370,1976;Bush等,Circulation 69:1161-1170,1984)。LCCA中的0流动最少30分钟表明缺乏抗血栓形成效力(L.G.Frederick等,Circulation 93:129-134,1996)。
实施例18
不同化合物对ADP-诱导的聚集
测试了不同化合物对ADP-诱导的聚集的抑制,其根据实施例14的方案的IC50;结果如图1所示。图中的柱状图说明100μM浓度的化合物对ADP-诱导的血小板聚集的作用,数据表示成ADP-反应的抑制百分数。
图1显示了各化合物的结构和缩写名称,以及其活性。理解其中氢的存在,它们是由于简化而忽略的。例如,对于图中的第一个结构,暗示在嘧啶环的3-位,核糖3'位的氧上,和在核糖2'位的氨基甲酸酯的氮上有氢。另外,如本发明的范围公开的,说明与磷原子不双键键合的氧以离子化形式作为与抗衡离子的盐存在,或与氢原子键合。为了简便,图中的一些结构绘成盐形式,但不应理解成排除可能存在氢的可能性。
在图末尾包括了几种在呋喃糖羟基上无修饰的母体化合物Up4U、Ip4U、Up3U和Cp3U,以说明本发明的实用性。然而这些未修饰的专利化合物不抑制ADP-诱导的聚集,也不在本发明的范围内。
Claims (18)
1.P2Y12受体拮抗剂化合物的用途,其特征在于,用于制备预防或治疗与血小板聚集有关的疾病或病况的药物,所述P2Y12受体拮抗剂化合物是式I的单核苷酸化合物:
式I
其中:
X1、X2和X3分别是氧、亚甲基、或二氟亚甲基;
T1、T2、W和V是氧:
m=0,1或2;
n=0或1;
p=0,1,或2;
其中m+n+p之和是1-5;
M=H、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
A=M;
D1=O;
Y′=H、OH或OR1;
Z′=H、OH或OR2;条件是Y′和Z′中至少一个是OR1或OR2;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的相应的2′和/或3′氧;
C是碳原子;
R5和R6合起来作为与C双键键合的氧,R7是氨基或一或二取代的氨基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,这样式II的基团是氨基甲酸酯
式III
其中:
O是呋喃糖或碳环的2′和3′氧,呋喃糖或碳环的2′和3′氧与同一碳原子C连接,形成环状缩醛或环状缩酮;和
R8和R9分别是氢、芳烷基、芳基、取代的芳烷基、取代的芳基,或可以合起来形成由3-8个原子组成的同环,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,或
B′是通式IV和V的嘌呤或嘧啶残基,它分别通过碱基的9-或1-位与呋喃糖或碳环的1′位连接;
式IV
式V
其中:
R10和R14分别是氧代、氨基或酰基氨基;
J是碳;
R11是氢或不存在;
R15是氢或不存在;
R12是氢;
R13是氢、烷硫基;和
R16是氢。
2.P2Y12受体拮抗剂化合物的用途,其特征在于,用于制备预防或治疗与血小板聚集有关的疾病或病况的药物,所述P2Y12受体拮抗剂化合物是式I的二核苷酸化合物:
式I
其中:
X1、X2和X3分别是氧、亚甲基、或二氟亚甲基;
T1、T2、W和V分别是氧:
m=0,1或2;
n=0或1;
p=0,1,或2;
其中m+n+p之和是1-5;
M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
D1=O;
Y′=H、OH或OR1;
Z′=H、OH或OR2;条件是Y′和Z′中至少一个是OR1或OR2;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的相应的2′和/或3′氧;
C是碳原子;
R5和R6合起来作为与C双键键合的氧,R7是氨基或一或二取代的氨基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,这样式II的基团是氨基甲酸酯;或
式III
其中:
O是呋喃糖或碳环的2′和3′氧,呋喃糖或碳环的2′和3′氧与同一碳原子C连接,形成环状缩醛或环状缩酮
R8和R9分别是氢、芳烷基、芳基、取代的芳烷基、取代的芳基,或可以合起来形成由3-8个原子组成的同环,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,或
A是核苷残基,定义如:
其通过呋喃糖或碳环的5′位与磷酸链连接,
其中:
D2=O;
Z=H、OH或OR3;
Y′=H、OH或OR4;
R3和R4是通过通式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III所述的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接的残基;
B和B′是式IV和V的嘌呤或嘧啶残基,它分别通过碱基的9-或1-位与呋喃糖或碳环的1′位连接;
式IV
式V
其中:
R10和R14分别是氧代、氨基或酰基氨基;
J是碳;
R11是氢、或不存在;
R15是氢或不存在;
R12是氢;
R13是氢或烷硫基;和
R16是氢。
3.如权利要求1或2所述的用途,其特征在于,所述药物减少用于预防、治疗或处理血小板聚集疾病的其它治疗剂的与剂量有关的不良副作用的发生率。
4.如权利要求3所述的用途,其特征在于,所述与血小板聚集有关的疾病或病况是疾病或过程,其特征是血栓形成、动脉硬化疾病的原发性动脉血栓并发症、动脉粥样硬化疾病干预的血栓并发症、手术或机械损伤的血栓并发症、机械性诱导的血小板活化、分流堵塞、血管损伤和炎症继发性的血栓形成、弥散性血栓/血小板消耗性成分的适应症、静脉血栓形成、冠状动脉血栓形成、动脉粥样硬化和动脉硬化的病理作用、血液和血产品在储藏过程中的血小板聚集和凝块形成、超聚集性的慢性或急性状态、动脉或静脉在溶纤维蛋白治疗后的重新阻塞、与体外循环有关的血小板粘附、与溶栓治疗有关的血栓并发症、与冠状和其它血管成形术有关的血栓并发症、或与冠状动脉分流术有关的血栓并发症。
5.如权利要求4所述的用途,其特征在于,所述与血栓形成有关的疾病或过程是不稳定性心绞痛、冠状动脉血管成形术和心肌梗塞;所述动脉硬化的原发性动脉血栓并发症是血栓性中风、周围血管疾病和没有血栓溶解的心肌梗塞;所述动脉粥样硬化疾病干预的血栓并发症是血管成形术、动脉内膜切除术、支架放置、冠状和其它血管移植手术;所述手术或机械损伤的血栓并发症是手术或偶然创伤后的组织补救,重建性手术包括皮瓣,和“还原性”手术;所述机械性诱导的血小板活化是导致微血栓栓塞的心肺分流术和血制品储藏;所述分流堵塞是肾透析和血浆置换;所述血管损伤和炎症继发性的血栓形成是血管炎、动脉炎、肾小球肾炎和器官移植排斥;所述弥散性血栓/血小板消耗性成分的适应症是播散性血管内凝结、血栓性血小板减少性紫癜、溶血性尿毒症综合征、肝素诱导的血小板减少症和先兆子痫/子痫;所述静脉血栓形成是深静脉血栓、静脉栓塞疾病、血液学病况以及偏头痛;和所述冠状动脉血栓形成是与不稳定性心绞痛、冠状动脉血管成形术和急性心肌梗塞有关。
6.如权利要求5所述的用途,其特征在于,所述血液学病况是血小板增多症和红细胞增多症。
7.如权利要求5所述的用途,其特征在于,所述动脉硬化和动脉粥样硬化的所述病理学作用是动脉粥样硬化、急性中风和慢性不稳定性心绞痛、不稳定性心绞痛、短暂性局部缺血发作和中风、周围血管疾病、动脉血栓形成、先兆子痫、栓塞、血管成形术、颈动脉内膜切除术和血管移植吻合术后的再狭窄或突然闭合;所述超聚集性的慢性或急性状态是由于弥散性血管内凝血、败血症、手术或感染性休克、手术后和产后创伤、心肺分流术、不兼容输血、胎盘早期脱离、血栓性血小板减少性紫癜、蛇毒和免疫疾病导致的。
8.如权利要求1所述的用途,其特征在于,所述化合物对个体全身性给药。
9.如权利要求8所述的用途,其特征在于,所述全身性给药选自:注射所述化合物的可注射形式;通过口施用所述化合物的口服形式;在皮肤上贴上含有所述化合物的透皮贴片或透皮垫;通过鼻部滴剂或鼻部喷雾施用所述化合物的液/液悬浮剂;对口腔或鼻咽气道施用所述化合物的喷雾化的液体;直肠施用所述化合物的栓剂形式;以含有常规无毒性药物学上可接受的载体、佐剂和载体的单剂制剂阴道施用所述化合物;玻璃体内施用所述化合物;和通过手术内滴注施用所述化合物的凝胶、霜、粉末、泡沫、结晶、脂质体、喷雾或液体悬液形式;这样所述化合物的治疗有效量通过全身性吸收和循环接触所述病人的目标血小板。
10.如权利要求8所述的用途,其特征在于,所述全身性给药包括通过选自:泵导管系统和连续或选择性释放装置的装置将所述化合物输注给目标血小板。
11.一种化合物,其特征在于,该化合物具有式Ib:
式Ib
其中:
D1=O;
n和p=0,1,或2,这样n+p之和是0-3;
A=M;其中M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
X1和X2分别是O、CH2、或CF2,条件是当n=1时,X1和X2不是O,当n=0时,X1不是0;
T1、V和W分别是O;
Y′=H、OH或OR1,
Z′=H、OH或OR2,其中R1和R2符合通式II或III的定义;条件是Y′和Z′的至少一个分别是OR1或OR2;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的相应的2′和/或3′氧;
C是碳原子;
R5和R6合起来作为与C双键键合的氧,R7是氨基或一或二取代的氨基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,这样式II的基团是氨基甲酸酯;
式III
其中:
O是呋喃糖或碳环的2′和3′氧,呋喃糖或碳环的2′和3′氧与同一碳原子(C)连接,形成环状的缩醛、环状的缩酮;
R8和R9分别是氢、芳烷基、芳基、取代的芳烷基、取代的芳基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,或可以合起来形成由3-8个原子组成的同环;
B′是式IV的嘌呤残基,通过9-位连接,或式V的嘧啶残基,通过1-位连接:
式IV
式V
其中:
R10和R14分别是氧代、氨基、酰基氨基;
J是碳;
R11是氢或不存在;
R15是氢或不存在;
R12是氢;
R13是氢;
R16是氢;
条件是当R10=NH2或O,和当R5和R6合起来作为与C双键键合的氧时,R7不等于邻甲基氨基苯基。
12.如权利要求11所述的化合物,其特征在于,该化合物选自:2′或3′苯基氨基甲酸酯UTP、2′,3′-二苯基氨基甲酸酯UTP、2′,3′苯基乙醛缩醛ADP、或2-(3-三氟甲基丙基)硫代-6-(2-甲硫基)乙基氨基-2′,3′-(苄基)亚甲基二氧嘌呤核糖核苷5′-α,β-二氟亚甲基二磷酸酯。
13.式Ia的化合物:
式Ia
其中:
D1和D2分别是O;
m和p=0,1或2;n=0或1;这样m+n+p的和是1-5;
X1、X2和X3=分别是O、CH2、CF2;
T1、T2、V和W分别是O;
M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
Y′=H、OH或OR1;
Z′=OH或OR2;
Z=OH或OR3;
Y=H、OH或OR4,其中R1、R2、R3和R4符合通式II或III的定义,条件是Y′、Z′、Z和Y中至少一个是OR1、OR2、OR3或OR4;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的相应的2′和/或3′氧;
C是碳原子;
R5和R6合起来作为与C双键键合的氧,R7是氨基或一或二取代的氨基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,这样式II的基团是氨基甲酸酯;或
式III
其中:
O是呋喃糖或碳环的2′和3′氧,呋喃糖或碳环的2′和3′氧与同一碳原子C连接,形成环状缩醛、环状缩酮;和
R8和R9分别是氢、芳烷基、芳基、取代的芳烷基、取代的芳基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,或可以合起来形成由3-8个原子组成的同环,或
B和B′分别是式V的嘧啶残基,通过1-位连接;
式V
其中:
R14是氧代、氨基;或酰基氨基;
R15是氢或不存在;或
R16是氢。
14.如权利要求13所述的化合物,其特征在于,该化合物选自:二[3′(苯基氨基甲酸酯)dUp2dU],2′3′苯基乙醛缩醛Up3U、二2′3′苯基乙醛缩醛Up3U、2′3′苯基乙醛缩醛Up4U、2′3′苯基乙醛缩醛Up4dC、四苯基氨基甲酸酯Up4U、二2′,3′苯甲醛缩醛Up4U、2′,3′苯甲醛缩醛Up4U、二2′,3′苯基乙醛缩醛Cp4U、2′,3′苯基乙醛缩醛Cp4U、2′,3′苯基乙醛缩醛Up4C,2′,3′苯基乙醛缩醛Up4T、二2′,3′苯甲醛缩醛Cp4U、2′,3′苯甲醛缩醛Up4U、2′,3′苯甲醛缩醛Up4dC、2′3′苯甲醛缩醛Cp4U、2′3′苯甲醛缩醛Up4C、2′,3′苯基丙醛缩醛Up4U、二2′,3′苯基丙醛缩醛Up4U、2′,3′苯甲醛缩醛Cp4C、二MANT Up4U、Mant Up4U、二2′/3′苄基缩醛Up4U、单2′/3′苄基缩醛Up4U、三苯基氨基甲酸酯Up4U、2′3′苯基氨基甲酸酯Up4U和一苯基氨基甲酸酯Up4U。
15.一种化合物,其特征在于,该化合物具有式Ia:
式Ia
其中:
D1和D2分别是O;
m和p=0,1或2;n=0或1;这样m+n+p的和是1-5;
X1、X2和X3=分别是O、CH2、CF2;
T1、T2、V和W分别是O;
M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
Y′=H、OH或OR1;
Z′=OH或OR2;
Z=OH或OR3;
Y=H、OH或OR4,其中R1、R2、R3和R4符合通式II或III的定义,条件是Y、Z′、Z和Y′中至少一个是OR1、OR2、OR3或OR4;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的相应的2′和/或3′氧;
C是碳原子;
R5和R6合起来作为与C双键键合的氧,R7是氨基或一或二取代的氨基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,这样式II的基团是氨基甲酸酯;
式III
其中:
O是呋喃糖或碳环的2′和3′氧,呋喃糖或碳环的2′和3′氧与同一碳原子C连接,形成环状缩醛、环状缩酮,R8和R9分别是氢、芳烷基、芳基、取代的芳烷基、取代的芳基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,或可以合起来形成由3-8个原子组成的同环;和
B是通过9-位连接的式IV中的嘌呤残基;
B′是通过1-位连接的式V中的嘧啶残基;
式IV
式V
其中:
R10和R14是氧代、氨基或酰基氨基;
J是碳;
R11是氢或不存在;
R15是氢或不存在;或
R12是氢;
R13是氢、烷硫基;
R16是氢。
16.如权利要求15所述的化合物,其特征在于,该化合物选自:2′3′苯基乙醛缩醛Up4A、2′3′苯基乙醛缩醛AP4U、二2′3′苯基乙醛缩醛AP4U、2′3′苯基乙醛缩醛Ip4U、二2′3′苯甲醛缩醛Ip4U、2′,3′苯甲醛缩醛Ip4U、或P1-[2-(3-三氟甲基丙基)硫代-6-(2-甲硫基)乙基氨基2′,3′-(苄基)亚甲基二氧嘌呤核糖核苷]-p4-(2′,3′-(苄基)亚甲基二氧尿苷)四磷酸酯。
17.一种化合物,其特征在于,该化合物物具有式Ia:
式Ia
其中:
D1和D2分别是O;
m和p=0,1或2;n=0或1;这样m+n+p的和是1-5;
X1、X2和X3=分别是O、CH2、CF2;
T1、T2、V和W分别是O;
M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
Y′=H、OH或OR1;
Z′=OH或OR2;
Z=OH或OR3;
Y=H、OH或OR4,其中R1、R2、R3和R4符合通式II或III的定义,条件是Y′、Z′、Z和Y中至少一个是OR1、OR2、OR3或OR4;
R1和R2是通过式II的碳原子与呋喃糖或碳环的2′和/或3′羟基直接连接的残基,或通过式III的同一碳原子与呋喃糖或碳环的2′和3′羟基中的两个直接连接,
式II
其中:
O是呋喃糖或碳环的对应的2′和/或3′氧;
C是碳原子;
R5和R6合起来作为与C双键键合的氧,R7是氨基或一或二取代的氨基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,这样式II的基团是氨基甲酸酯;或
式III
其中:
O是呋喃糖或碳环的2′和3′氧,呋喃糖或碳环的2′和3′氧与同一碳原子C连接,形成环状缩醛、环状缩酮;和
R8和R9分别是氢、芳烷基、芳基、取代的芳烷基、取代的芳基,其中取代基选自羟基、硝基、甲氧基、氟、氯、溴、碘、甲基、乙基、丙基、丁基、烷硫基、烷氧基、羧基、氰基、氨基、三氟甲基、苯基、环丙基、环戊基和环己基,或可以合起来形成由3-8个原子组成的同环,
B和B′分别是通过9-位连接的式IV中的嘌呤残基;
式IV
其中:
R10是氧代、氨基,J是碳;
R11是氢或不存在;
R12是氢;
R13是氢;
条件是当R10=NH2,和当R5和R6合起来作为与C双键键合的氧时,R7不等于邻甲基氨基苯基。
18.一种化合物,其特征在于,该化合物具有式Ia′:
式Ia′
其中:
D1=O;
D2=O;
B和B’分别是通式IV或V的嘌呤或嘧啶残基,条件是B和B′中的至少一个是通式IV的嘌呤残基;
m和p=0,1或2;n=0或1;这样m+n+p之和是1-5;
X1,X2和X3分别是O,CH2,或CF2;
T1,T2,V和W分别是O;
M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
Y’=H或OH;
Z’=OH;
Z=OH;
Y=H或OH;
式IV
其中J是N;R12不存在;
式V
其中:
R10和R14是氧代、氨基、酰基氨基;
R11是氢,或不存在;
R13是氢;
R15是氢或不存在;和
R16是氢。
19.一种化合物,其特征在于,该化合物具有式Ia":
式Ia”
其中:
D1=O;
D2=O;
m和p=0,1或2;n=0或1;这样m+n+p的和是1-5;
X1,X2,和X3分别是O,CH2,CF2;
T1,T2,V,和W分别是O;
M=氢、碱金属离子、碱土金属离子、铵或NX4 +,其中X是C1-4烷基;
Y’=H或OH;
Z’=OH;
Z=OH;
Y=H或OH;
B和B′分别是式IV中的嘌呤残基,通过9-位连接,或式V的嘧啶残基,通过1-位连接,条件是B和B′中的至少一个是通式IV的嘌呤残基;
式IV
式V
其中:
R10是氧代,R14是氧代、氨基或酰基氨基;
J是碳;
R11是氢,或不存在;
R12是氢;
R13是氢;
R15是氢或不存在;和
R16是氢。
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US09/643,138 US7018985B1 (en) | 2000-08-21 | 2000-08-21 | Composition and method for inhibiting platelet aggregation |
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CN100465186C true CN100465186C (zh) | 2009-03-04 |
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US (2) | US7018985B1 (zh) |
EP (1) | EP1311525A2 (zh) |
JP (1) | JP2004521074A (zh) |
KR (1) | KR20040014934A (zh) |
CN (1) | CN100465186C (zh) |
AR (1) | AR032631A1 (zh) |
AU (2) | AU2001285470B2 (zh) |
BR (1) | BR0113402A (zh) |
CA (1) | CA2420179A1 (zh) |
MX (1) | MXPA03001518A (zh) |
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AU8547001A (en) | 2002-03-04 |
US20020052337A1 (en) | 2002-05-02 |
WO2002016381B1 (en) | 2002-08-15 |
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WO2002016381A3 (en) | 2002-05-10 |
CA2420179A1 (en) | 2002-02-28 |
US7018985B1 (en) | 2006-03-28 |
MXPA03001518A (es) | 2004-07-30 |
WO2002016381A2 (en) | 2002-02-28 |
TWI265931B (en) | 2006-11-11 |
AU2001285470B2 (en) | 2007-01-25 |
AR032631A1 (es) | 2003-11-19 |
CN1501940A (zh) | 2004-06-02 |
EP1311525A2 (en) | 2003-05-21 |
US7101860B2 (en) | 2006-09-05 |
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