CN1414854B - 膦酸酯化合物 - Google Patents
膦酸酯化合物 Download PDFInfo
- Publication number
- CN1414854B CN1414854B CN00818111.XA CN00818111A CN1414854B CN 1414854 B CN1414854 B CN 1414854B CN 00818111 A CN00818111 A CN 00818111A CN 1414854 B CN1414854 B CN 1414854B
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- Prior art keywords
- virus
- phosphonate
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- ester
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Abstract
本发明涉及膦酸酯化合物、含有它们的组合物、得到它们的方法及其用于治疗多种医学疾病,如骨质疏松和其它骨代谢疾病、癌、病毒感染等的用途。
Description
发明领域
本发明涉及膦酸酯化合物,含有它们的组合物,生产它们的方法及其用于治疗多种医学疾病,如骨质疏松和其它骨代谢疾病、癌、病毒感染等的用途。
发明背景
早已知膦酸酯化合物提供多种治疗学优点。一个具体种类的治疗学有用的膦酸酯化合物为双膦酸酯,即焦磷酸酯类似物,其中,焦磷酸酯键的中心氧原子被碳代替。多种取代基可以连接到该中心碳原子上以产生具有多种药效程度的衍生的双膦酸酯化合物。这些衍生物具有通式:
其中,Ra和Rb可以独立地选自羟基、氨基、巯基、卤素,或各种烷基或芳基,或这些基团的组合,这些基团可以被进一步取代。实例包括依替膦酸酯(etidronate),其中Ra为CH3,而Rb为OH;氯屈膦酸酯(clodronate),二氯亚甲基二磷酸(Cl2MDP),其中,Ra和Rb为Cl;帕米膦酸酯(pamidronate),3-氨基-1-羟基亚丙基双膦酸,其中,Ra为乙基氨基,而Rb为羟基;阿仑膦酸酯(alendronate),4-氨基-1-羟基亚丁基双膦酸,其中,Ra为丙基氨基,而Rb为羟基;奥帕膦酸酯(olpadronate),3-二甲基氨基-1-羟基亚丙基双膦酸,其中,Ra为二甲基氨基乙基,而Rb为羟基;和氨基-奥帕膦酸酯(olpadronate)(IG-9402),3-(N,N-二甲基氨基)-1-氨基亚丙基双 膦酸酯,其中,Ra为N,N-二甲基氨基乙基,而Rb为NH2。
双膦酸酯及其取代的衍生物具有固有的抑制体内骨吸收的性质。双膦酸酯还通过抑制成骨细胞凋亡(程序性细胞死亡)而起作用。其应用的适应症包括治疗和预防骨质疏松,治疗佩吉特氏病、转移性骨癌、甲状旁腺机能亢进、类风湿性关节炎、痛性营养障碍、胸-胁-锁骨肥厚、高歇氏病、骨干发育异常和某些非骨骼性病症(PaDapoulos,S.E.,在Osteoporosis(骨质疏松),R.Marcus,D.Feldman和J.Kelsey,eds.,Academic Press(学院出版社),SanDiego(圣地亚哥),1996.第1210页,表1)。
虽然双膦酸酯具有治疗学有用性质,它们仍受损于其作为口服试剂的药学缺点。一个缺点是低口服利用度:小至0.7%-5%的口服剂量被胃肠道吸收。口服吸收还在与食物共同摄入时减小。而且已知,目前可获得的一些双膦酸酯,如FOSAMAX(Merck;阿仑膦酸钠),SKELID(Sanofi,替鲁膦酸酯(tiludronate))和ACTONE(Procter和Gamble,利司膦酸酯(risedronate))具有局部毒性,导致食管刺激和溃疡。其它的双膦酸酯,如氨基-奥帕膦酸酯(olpadronate),缺乏抗吸收作用(Van Beek,E.等人,J.Bone MinerRes 11(10):1492-1497(1996),但抑制骨细胞凋亡,并能够刺激净骨形成(Plotkin,L.等人,JClin Invest 104(10):1363-1374(1999)和美国专利5,885,973)。因此研制出保持或增强母化合物药学活性,同时消除或减少其不良副作用的化学改性的双膦酸酯衍生物是有用的。
除了双膦酸酯,还已知单膦酸酯提供治疗作用。一类治疗学有用的单膦酸酯是抗病毒核苷酸膦酸酯,如西多福韦(cidofovir)、环西多福韦(cidofovir)、阿的福韦(adefovir)、泰诺福韦(tenofovir)等等,以及叠氮胸苷、更昔洛韦(ganciclovir)、阿昔洛韦(acyclovir)等等的5’-膦酸酯和亚甲基膦酸酯。在这种类型的化合物中,糖部分的5’-羟基,或不含有完全糖部分的无环核苷(更昔洛韦(ganciclovir)、喷昔洛韦(penciclovir)、阿昔洛韦(acyclovir)) 上的等同物被磷-碳键代替。在亚甲基膦酸酯的情况下,亚甲基代替5’-羟基或其等同物,从而使碳原子依次共价连接到膦酸酯上。各种AZT结构如以下所示,包括考虑用于实施本发明的化合物。AZT本身显示在左边。化合物A为AZT-单磷酸酯,它在糖和磷酸盐之间具有普通的磷酸二酯键。相比之下,在化合物B(AZT 5’-膦酸酯)和C(AZT 5’-亚甲基膦酸酯)中,3’-叠氮基、2’,3’-二脱氧核糖的5’-羟基不存在,并被磷-碳键(AZT膦酸酯)或被由磷-碳键连接的亚甲基(AZT亚甲基膦酸酯)代替。化合物B和C为用于实施本发明的化合物的实例。
这种类型的化合物可能具有作为抗增殖或抗病毒核苷酸的活性。在细胞代谢时,发生额外的两种磷酸化作用以形成代表核苷三磷酸盐等同物的核苷酸膦酸酯二磷酸酯。抗病毒核苷酸膦酸酯二磷酸酯是病毒RNA或DNA聚合酶或逆转录酶的选择性抑制剂。也就是说,它们对病毒聚合酶的抑制活性远远大于它们对哺乳动物细胞DNA聚合酶α、β和γ或哺乳动物RNA聚合酶的抑制程度。相反,抗增殖核苷酸膦酸酯二磷酸酯抑制癌细胞DNA和RNA聚合酶,并可能表现出远远低于正常细胞DNA和RNA聚合酶的选择性。由于核苷酸膦酸酯通过胃肠道的吸收较差,它们经常需要肠道外给药(如西多福韦(cidofovir))。而且,带负电的膦酸酯部分可能会干扰细胞渗入,导致抗病毒或抗增殖活性降低。本发明的化合物可以令人惊奇地克服这类试剂的缺点。
抗病毒膦酸酯的药理学活性试剂是已知的;以下的美国专利描 述了核苷酸膦酸酯类似物的其它方法:5,672,697(核苷-5’-亚甲基膦酸酯)、5,922,695(抗病毒膦酰基甲氧基核苷酸类似物)、5,977,089(抗病毒膦酰基甲氧基核苷酸类似物)、6,043,230(抗病毒膦酰基甲氧基核苷酸类似物)、6,069,249。以前已公开了共价连接到含有具有氨基、羧基、羟基或巯基官能团的药物的不含有膦酸酯的烷基甘油磷酸酯的制备和应用。这些前药可选择地包含连接基基团或者在药物和烷基甘油磷酸酯之间的一种或两种其它的磷酸酯(美国专利5,411,947和美国专利申请08/487,081)。氯甲烷二膦酸的部分酯是已知的(美国专利5,376,649),并已报道了氯屈膦酸酯(clodronate)的二酐(Ahlmark等人,医学化学(JMed Chem)42:1473-1476(1999))。但是,发现部分酯不通过化学或生物转化释放活性双膦酸酯(Niemi,R.等人,JChrom B 701:97-102(1997))。还已公开了包含连接到抗病毒核苷(美国专利5,223,263)或膦酰基-羧酸酯(美国专利5,463,092)上的烷基甘油磷酸酯残基的前药。
因此,不断需要毒性较小,更为有效的药剂用于治疗各种疾病,如由病毒感染和不适当的细胞增殖引起的疾病,例如癌。因此,本发明目的在于研制化学改性的膦酸酯衍生物药理学活性试剂,如抗病毒和抗肿瘤药学试剂。这些改性的衍生物在给予需要的受试者时,增大了母化合物效力,同时使有害的副作用最小化。
发明简述
本发明提供了膦酸酯化合物的类似物。考虑用于本发明的膦酸酯化合物包括减少骨吸收或者抑制成骨细胞或骨细胞凋亡的膦酸酯化合物,以及改善用于治疗癌、各种病毒感染等等的核苷酸膦酸酯类似物的生物活性、选择性或生物利用度的膦酸酯化合物。本发明化合物包括共价连接(直接或间接通过连接基分子)到取代的或未取代的烷基甘油、烷基丙二醇、烷基乙二醇或相关部分的膦酸酯。本发明另一方面提供了含有本文所述的膦酸酯化合物的类似物的药剂。
本发明另一方面还提供了各种治疗方法,如用于治疗或预防哺乳动物骨吸收的方法、用于通过预防成骨细胞和骨细胞凋亡而增加骨形成的方法、用于增加骨质量和强度的方法、用于治疗病毒感染的方法、用于治疗由于不适当的细胞增殖而引起的疾病如癌的方法,等等。
附图描述
图1概述了本发明化合物,1-O-十六烷氧基丙烷阿仑膦酸酯(alendronate)对地塞米松诱导的MLO-Y4骨细胞凋亡的效果。条棒代表3次独立测定的平均值±SD。空白条棒代表不使用地塞米松,而黑色条棒代表使用10-4M地塞米松。
图2概述了本发明化合物,1-O-十六烷氧基丙烷阿仑膦酸酯(alendronate)对地塞米松诱导的颅盖细胞的凋亡的效果。条棒代表3个独立测定的平均值±SD。灰色条棒代表不使用地塞米松,而黑色条棒代表使用10-4M地塞米松。
发明详述
本发明的膦酸酯化合物具有结构:
其中:
R1和R1’独立地为-H、可选择性取代的-O(C1-C24)烷基、-O(C1-C24)链烯基、-O(C1-C24)酰基、-S(C1-C24)烷基、-S(C1-C24)链烯基或-S(C1-C24)酰基,其中,至少一个R1和R1’不为-H,且其中该链烯基或酰基可选择具有1-6个双键;
R2和R2’独立地为-H、可选择性取代的-O(C1-C7)烷基、-O(C1-C7)链烯基、-S(C1-C7)烷基、-S(C1-C7)链烯基、-O(C1-C7)酰基、-S(C1-C7) 酰基、-N(C1-C7)酰基、-NH(C1-C7)烷基、-N((C1-C7)烷基)2、氧代、卤素、-NH2、-OH或-SH;
R3为与可选择的连接基L上的官能团或Cα上可利用的氧原子连接的药学活性膦酸酯、双膦酸酯或药学活性化合物的膦酸酯衍生物;
X,当存在时,为:
m为0-6的整数;
而n为0或1。
在优选的实施方案中,m=0、1或2。在这些优选的实施方案中,R2和R2’优选为H,而前药为治疗的膦酸酯的乙二醇、丙二醇或丁二醇的衍生物。优选的乙二醇膦酸酯类物质具有结构:
其中,R1、R1’、R3、L和n如以上定义。
优选的丙二醇类物质具有结构:
其中,m=1,而R1、R1’、R3、L和n如在通式中定义。
优选的甘油类物质具有结构:
其中,m=1,R2=H,R2’=OH,Cα上R2和R2’同时为-H。甘油为光学活性分子。采用甘油的立体定向性编号惯例,sn-3位是被甘油激酶磷酸化的位置。在具有甘油残基的本发明化合物中,-(L)n-R3部分可以在甘油的sn-3或sn-1位结合。
在所有种类的本发明的药理学活性试剂中,R1优选为具有式-O-(CH2)t-CH3的烷氧基,其中,t为0-24。更优选t为11-19。更优选t为15或17。
优选的R3基团包括已知具有临床用途的双膦酸酯,例如,化合物:
依替膦酸酯(etidronate):1-羟基亚乙基双膦酸(EDHP);
氯屈膦酸酯(clodronate):二氯亚甲基二磷酸(Cl2MDP);
替鲁膦酸酯(tiludronate):氯-4-苯基硫代亚甲基双膦酸;
帕米膦酸酯(pamidronate):3-氨基-1-羟基亚丙基双膦酸(ADP);
阿仑膦酸酯(alendronate):4-氨基-1-羟基亚丁基双膦酸;
奥帕膦酸酯(olpadronate):3-二甲基氨基-1-羟基亚丙基双膦酸(二甲基-APD);
伊班膦酸酯(ibandronate):3-甲基戊基氨基-1-羟基亚丙基双膦酸(BM 21.0955);
EB-1053:3-(1-吡咯烷基)-1-羟基亚丙基双膦酸;
利司膦酸酯(risedronate):2-(3-吡啶基)-1-羟基-亚乙基双膦酸;
氨基-奥帕膦酸酯(olpadronate):3-(N,N-二甲基氨基-1-氨基亚丙基)双膦酸酯(IG9402),等等。
R3还可以选自各种含膦酸酯的核苷酸(或者可能被衍生至其对应的膦酸酯的核苷),还考虑将它用于本发明。优选的核苷包括用于治疗由不适当的细胞增殖引起的疾病的核苷,如2-氯-脱氧腺苷、1-β-D-阿拉伯呋喃糖基-胞苷(阿糖孢苷,ara-C)、氟尿苷、5-氟脱氧尿嘧啶核苷(或5-氟脱氧尿苷)、吉西他宾(gemcitabine)、克拉利宾(cladribine)、氟达拉滨(fludarabine)、喷司他丁(pentostatin)(2’-脱氧助间型霉素),6-巯基嘌呤、6-硫鸟嘌呤和取代的或未取代的1-β-D-阿拉伯呋喃糖基-鸟嘌呤(ara-G)、1-β-D-阿拉伯呋喃糖基-腺苷(ara-A)、1-β-D-阿拉伯呋喃糖基-尿苷(ara-U)等等。
用于治疗病毒感染的核苷还可以被转化成其对应的用作R3官能团的5’-膦酸酯。这些膦酸酯类似物一般含有用于取代抗病毒核苷的5’-羟基的膦酸酯(-PO3H2)或亚甲基膦酸酯(-CH-2PO3H2)基团。某些通过-PO3H2取代5’-羟基而得到的抗病毒膦酸酯的实例为:
某些通过-CH2-PO3H2取代5’羟基而得到的抗病毒膦酸酯的实例为:
其它优选的考虑用于实施本发明的抗病毒核苷酸膦酸酯类似地来源于抗病毒核苷,包括ddA、ddI、ddG、L-FMAU、DXG、DAPD、L-dA、L-dI、L-(d)T、L-dC、L-dG、FTC、喷昔洛韦(penciclovir)等等。
此外,抗病毒膦酸酯如西多福韦(cidofovir)、环西多福韦(cidofovir)、阿的福韦(adefovir)、泰诺福韦(tenofovir)等等,可以用作本发明的R3基团。
本发明的某些化合物在糖部分具有一个或多个手性中心,并可能因此存在旋光活性形式。类似地,当此化合物含有链烯基或不饱和烷基或酰基部分时,存在此化合物的顺式和反式同分异构形式的可能性。在取代基如烷基上可能存在其它不对称碳原子。R-和S-异构体及其混合物,包括外消旋混合物以及顺式和反式异构体的混合物考虑用于本发明。所有这些异构体及其混合物考虑在本发明的范围内。如果要求一种具体的立体异构体,则它的制备可以通过现有技术中已知的方法,采用含有不对称中心并已被解析的原料的立体特异性反应;或者可选择地,通过由已知方法产生立体异构体的混合物并进行解析的方法。
存在许多可以根据本发明进行衍生以改进其药理学活性或增加其口服吸收的膦酸酯化合物,例如,这些化合物公开在以下专利中,本文全部引用其中的每一篇作为参考:美国专利3,468,935(依替膦酸酯(etidronate))、4,327,039(帕米膦酸酯(pamidronate))、4,705,651(阿仑膦酸酯(alendronate))、4,870,063(双膦酸衍生物)、4,927,814(双膦酸酯)、5,043,437(叠氮基二脱氧核苷的膦酸酯)、5,047,533(无环嘌呤膦酸酯核苷酸类似物)、5,142,051(嘧啶和嘌呤碱基的N-膦酰基甲氧基烷基衍生物)、5,183,815(骨作用试剂)、5,196,409(双膦酸酯)、5,247,085(抗病毒嘌呤化合物)、5,300,671(偕二膦酸)、5,300,687(三氟甲基苄基膦酸酯)、5,312,954(双和四膦酸酯)、5,395,826(胍烷基-1,1-双膦酸衍生物)、5,428,181(双膦酸酯衍生物)、5,442,101(亚甲基双膦酸衍生物)、5,532,226(三氟甲基苄基膦酸酯)、5,656,745(核苷酸类似物)、5,672,697(核苷-5’-亚甲基膦酸酯)、5,717,095(核苷酸类似物)、5,760,013(胸苷酸类似物)、5,798,340(核苷酸类似物)、5,840,716(膦酸酯核苷酸化合物)、5,856,314(硫取代的、含氮、杂环膦酸酯化合物)、5,885,973(奥帕膦酸酯 (olpadronate))、5,886,179(核苷酸类似物)、5,877,166(对映体纯的2-氨基嘌呤膦酸酯核苷酸类似物)、5,922,695(抗病毒膦酰基甲氧基核苷酸类似物)、5,922,696(嘌呤的烯和丙二烯膦酸酯衍生物)、5,977,089(抗病毒膦酰基甲氧基核苷酸类似物)、6,043,230(抗病毒膦酰基甲氧基核苷酸类似物)、6,069,249(抗病毒膦酰基甲氧基核苷酸类似物);比利时专利672205(氯屈膦酸酯(clodronate));欧洲专利753523(氨基-取代的双膦酸);欧洲专利申请186405(偕二膦酸酯)等等。
某些双膦酸酯化合物能够抑制角鲨烯合酶并降低哺乳动物,包括人的血清胆固醇水平。
例如,在Pauls等人的美国专利5,441,946和5,563,128,Phosphonate derivatives of lipophilic amines(亲脂性胺的膦酸酯衍生物)中公开了这些双膦酸酯的实施例,本文全部引用这二者作为参考。本发明的这些角沙烯合酶抑制化合物的类似物,及其在治疗人类脂类疾病的用途在本发明的保护范围之内。可以口服或局部应用本发明的双膦酸酯以预防或治疗牙周疾病,如在美国专利5,270,365中所述,本文引用其全部作为参考。
本文所用的术语“烷基”指1-24个碳原子的一价直链或支链或环基,包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基等等。
本文所用的术语“取代的烷基”包括还含有一种或多种选自以下基团的取代基的烷基:羟基、烷氧基(低级烷基)、巯基(低级烷基)、环烷基、取代的环烷基、杂环基、取代的杂环基、芳基、取代的芳基、杂芳基、取代的杂芳基、芳氧基、取代的芳氧基、卤素、三氟甲基、氰基、硝基、氮羰基、氨基、酰氨基、-C(O)H、酰基、氧酰基、羧基、氨基甲酰基、磺酰基(sulfonyl)、氨磺酰基、磺酰基(sulfuryl)等等。
本文所用的“链烯基”指具有一个或多个碳-碳双键并具有2-24个碳原子的直链或支链烃基,而“取代的链烯基”指还含有一个或 多个上述取代基的链烯基。
本文所用的“芳基”指具有6-14个碳原子的芳基,而“取代的芳基”指还含有一个或多个上述取代基的芳基。
本文所用的“杂芳基”指含有一个或多个杂原子(如N、O、S等等)作为部分环结构,并具有3-14个碳原子的芳基,而“取代的杂芳基”指还含有一个或多个上述取代基的杂芳基。
本文所用的术语“键”或“价键”指由电子对组成的原子间的连接。
本文所用的术语“药学上可接受的盐”指酸和碱加成盐。
本文所用的术语“前药”指这样的药学活性化合物的衍生物:它具有可被化学或代谢分解的基团,并且通过溶剂分解或在体内生理条件下成为药学活性化合物。
膦酸酯类似物,包括通过羟基共价连接到1-O-烷基甘油、3-O-烷基甘油、1-S-烷基硫代甘油或烷氧基-链烷醇上的治疗学有效膦酸酯(或治疗学有效化合物的膦酸酯衍生物),比母化合物在胃肠道更有效地被吸收。口服剂量的此类似物从哺乳动物的胃肠道完整地吸收,并在体内通过内源性酶的作用释放出活性药物。本发明的膦酸酯类似物还具有比对应的未衍生的化合物更高程度的生物利用度。
本发明的化合物是现有技术中描述的烷基甘油磷酸酯前药的改进,因为含膦酸酯部分直接与烷基甘油或烷氧基链烷醇部分连接,还因为膦酸键的存在阻止了酶转化为游离药物。这些基团之间的其它连接可以存在于改进的类似物中。例如,具有式-O-(CH2)n-C(O)O-的双官能团连接,其中的n为1-24,可以将膦酸酯连接到烷氧基-链烷醇或烷基甘油部分的羟基上。
前述使本发明的膦酸酯实现了更高程度的口服吸收。而且,细胞酶,但不是血浆或消化道酶将此轭合物转化成游离的膦酸酯。烷氧基-链烷醇膦酸酯的进一步的优点是大大减少或消除了同时给予食物降低或消除了膦酸酯吸收的趋势,导致更高的血浆水平和更好地被患者接受。
可以口服给药的本发明化合物的剂型有片剂、胶囊、溶液、乳液或悬浮液、吸入液体或固体颗粒、微胶囊颗粒,作为喷雾剂,通过器械如透皮贴片穿透皮肤,或直肠给药,如栓剂的形式。本发明的亲脂性衍生物特别适于透皮吸收给药和转运体系,并还可以用于牙膏。还可以注射液的形式进行肠道外给药。
可以将此组合物制成常规剂型,如胶囊、片剂、气雾剂、溶液、悬浮液,或者与载体一起用于局部应用。含有本发明化合物的药剂可以通过常规技术制备,如在Remington’sPharmaceuticalSciences,1985中所述。
所用的药学载体或稀释剂可以是常规的固体或液体载体。固体载体的实例为乳糖、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸或纤维素的低级烷基醚。液体载体的实例为糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧化乙烯或水。载体或稀释剂包括现有技术中已知的任何持续释放物质,如甘油单硬脂酸或二硬脂酸酯,单独或与蜡混合在一起。
如果将固体载体用于口服给药,则将制剂压片或以粉末或小丸的形式放在硬明胶胶囊中。固体载体的含量变化很大,但一般约为25mg-1g。如果使用液体载体,则制剂可以是糖浆、乳液、软明胶胶囊或无菌注射液体,如含水或非水液体悬浮液或溶液。
通过将活性成分(即一种或多种本发明化合物)与药学惰性的无机或有机载体、稀释剂和/或赋形剂混合而制得片剂。可以用于片剂的赋形剂的实例是乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐。用于明胶胶囊的适宜的赋形剂的实例植物油、蜡、脂肪、半固体和液体多元醇。还可以将双膦酸酯前药制成微囊包着的形式。
对于鼻内投药,制剂可以含有溶于或悬浮于液体载体,特别是含水载体中的本发明化合物。对于气雾剂应用,载体可以含有增溶剂如丙二醇,表面活性剂,吸收增强剂如卵磷脂或环糊精,或者防腐剂。
用于肠道外注射的本发明药物组合物包括药学上可接受的无菌 含水或非水液体、分散体、悬浮液或乳液,以及用于在使用前重组为无菌注射液或分散体的无菌粉末。
用于制备溶液和糖浆的适宜的赋形剂为水、多元醇、蔗糖、转化糖、葡萄糖等等。用于制备注射液的适宜的赋形剂为水、醇、多元醇、甘油、植物油等等。
这些药品还可以包含任何多种加入的组分,如防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、矫味剂、缓冲剂、包衣剂、抗氧剂、稀释剂等等。
可选择地,本发明的药物组合物可以包含此通式的化合物与一种或多种表现出不同活性的化合物,如抗生素或其它药理学活性物质的组合。这些组合在本发明的保护范围之内。
本发明提供了治疗与骨代谢、病毒感染、不适当的细胞增殖等等有关的哺乳动物疾病的方法。这些方法具体包括给予需要治疗的人或其它哺乳动物治疗学有效量的本发明的前药。适于这种治疗的适应症包括老年性、绝经后或类固醇诱导的骨质疏松、佩吉特氏病、转移性骨癌、甲状旁腺机能亢进、类风湿性关节炎、痛性营养障碍、胸-肋锁骨肥厚、高歇氏病、骨干发育异常、某些非骨胳性疾病和牙周疾病、人免疫缺陷病毒(HIV)、流行性感冒、单纯疱疹病毒(HSV)、人疱疹病毒6、巨细胞病毒(CMV)、肝炎B病毒、非洲淋巴细胞瘤病毒(EBV)、带状疱疹病毒、淋巴瘤、血液学疾病如白血病等等。
本发明的一方面提供了用于预防或治疗哺乳动物,特别是人的骨丢失的方法,所述方法包括给予人或哺乳动物治疗学有效量的本发明的化合物。骨吸收抑制本发明的双膦酸酯前药在其中来自制备的前药的双膦酸酯有效的条件下治疗对抗破骨细胞调节的吸收或正常骨丢失。适于这种治疗的症状包括骨质疏松,特别是经绝后的妇女的骨质疏松,这种骨质疏松与长期的糖皮质激素治疗和骨的佩吉特氏病相伴。还已发现双膦酸酯化合物氯屈膦酸酯(clodronate)(Ostac,Boehringer-曼海姆,曼海姆,德国)降低处于远距转移瘤的高度风险下的乳癌患者的骨和内脏转移瘤(Diel,I. J.等人,(1998)New Engl.J.Med.339(60357-363)。可以根据与母化合物相同的方法评价本发明双膦酸酯前药的效力。它们包括对比测定腰脊、股骨颈、髋骨、前臂和全身的骨矿质密度,以及测定脊椎骨折、脊柱变形和骨质疏松的高度,骨扫描或放射鉴定转移性疾病中的骨损伤等等。
本发明另一方面提供了以下用于增加哺乳动物,特别是人的骨质量和强度的方法:给予抑制成骨细胞和骨细胞凋亡的本发明骨合成代谢促进化合物,导致更大净比率的骨形成,同时基本上不改变破骨细胞功能(Plotkin等人,J Clin Invest 104:1363-1374(1999)和Van Beek等人,J骨Min Res 11:1492(1996))。
本发明另一个方面还提供了用于治疗由病毒感染引起的疾病的方法。这种治疗的指征包括易受病毒感染,如人免疫缺陷病毒(HIV)、流行性感冒、单纯疱疹前病毒(HSV)、人疱疹病毒6、巨细胞病毒(CMV)、肝炎B和C病毒、非洲淋巴细胞瘤病毒(EBV)、带状疱疹病毒、由正痘病毒属(如重型和轻型天花、牛痘(vaccinia)、天花(smallpox)、牛痘(cowpox)、骆驼痘、猴痘等等)、埃博拉病毒、乳头瘤病毒等等引起的疾病。
本发明另一方面还提供了用于治疗由不适宜的细胞增殖,例如用于治疗癌,如黑瘤、肺癌、胰腺癌、胃、结肠和直肠癌、前列腺和乳癌、白血病和淋巴瘤等等而引起的疾病的方法。可以转化成用作本发明化合物的核苷酸膦酸酯的抗癌化合物包括但不限于阿糖孢苷(ara-C)、氟尿苷、氟脱氧尿苷(fluorodeoxyuridine或floxuridine)、gemcitibine、克拉利宾(cladribine)、氟达拉滨(fludarabine)、喷司他丁(pentostatin)(2’-脱氧助间型霉素)、6-巯基嘌呤和6-硫代鸟嘌呤和取代的或未取代的ara-腺苷(ara-A),ara-鸟苷(ara-G)和ara-尿苷(ara-U)。本发明的抗癌化合物可以单独使用或与其它抗代谢物或其它类抗癌药如生物碱、拓扑异构酶抑制剂、烷基化试剂、抗肿瘤抗生素等等联合使用。
本发明的前药可以口部、肠道外、局部、直肠和通过其它途径,以所需的适宜剂量给药。
本文所用的术语“肠道外”指皮下、静脉内、动脉内、肌内或玻璃体内注射,或输注技术。
术语“局部”包括直肠给药和吸入喷雾,以及更为普遍的口和鼻的皮肤和粘膜途径,以及在牙膏中。
用于本发明的膦酸酯前药的术语“有效量”是预防或逆转上述疾病的用量。具体对于与骨代谢有关的疾病而言,有效量是预防、减弱或逆转异常或过量骨吸收或在年老,特别是绝经后女性中存在的骨吸收,或者预防或对抗乳癌的骨转移和内脏转移。
关于与病毒感染或不适当的细胞增殖有关的疾病如癌,根据抗病毒或抗癌母化合物的建议剂量来确定“有效量”。选择的剂量将取决于所选择的化合物、给药途径、治疗病症的严重性、受治疗患者的病症和前病史。但是,在本领域技术的范围内,可以开始使用低于取得目标治疗效果所需水平的剂量,并逐渐增大剂量直至实现目标效果。如果需要的话,可以为了给药目的而将有效的日剂量分成多次剂量,如每天2-4次剂量。但是,应该理解用于具体患者的具体的剂量水平将取决于多种因素,包括体重、健康状况、饮食、时间、给药途径、与其它药物的组合和治疗疾病的严重性。
一般来说,分散在单元剂型中的本发明的化合物包含1%-100%的活性成分。当作为药物给予患者如人时,治疗剂量的范围约为0.01-1,000mg/kg/天,优选约0.10mg/kg/天-100mg/kg/天。本发明药物组合物中的活性成分的实际剂量水平可以改变以将有效地实现特定患者期望的治疗学反应的用量的活性化合物进行给药。
大量的动物实验已表明双膦酸酯在设计模拟相关临床疾病的实验条件下的预防骨损失的效力。根据这些研究,可以获得许多小动物模型体系用于评价双膦酸酯的效果。这些试验还用于测定本发明双膦酸酯前药的对比功效。双膦酸酯治疗的评价一般要求测定股骨灰分重量和骨质量,例如在治疗和未治疗动物试验组之间测定小粱 状骨体积。Thompson,D.等人(1990)J.Bone和Mineral Res.5(3):279-286,公开了用于评价用氨基羟基丁烷双膦酸酯处理的固定的大鼠上的骨丢失抑制。Yamamoto,M.等人(1993)Calcif Tissue Int53:278-282诱导了大鼠的甲状腺功能亢进症以产生与甲状腺机能亢进的人患者类似的骨变化,并根据骨钙素的测定和通过组织形态学分析,包括松质骨体积的差别,骨部分的类骨质、破骨细胞和成骨细胞表面的组织学比较,比较了双膦酸酯-治疗和未治疗小组的生物化学。Seedor,J.G.等人(1991)J.Bone和Mineral Res.6(4):339-346通过股骨灰分重量和小粱状胫骨体积的组织形态学分析,描述了阿仑膦酸酯(alendronate)在对抗过度活跃大鼠的骨丢失中的效果。包括成长大鼠的骺组织检查的Schenk试验还可以用作筛选试验。实施例14提供了例举性的筛选试验,用于评价本发明化合物对由各种策略造成的实验性大鼠骨质减少的骨吸收对抗效果。
本发明化合物可通过各种方法制备,如在图解I-VI中所述。提供以下一般的膦酸酯酯化方法仅仅用于举例,而不应将其理解为以任何方式对本发明进行限定。实际上,已研制出许多用于直接缩合膦酸和醇的方法(如参见R.C.Larock,Comprehensive OrganicTransformations(综合有机转化),VCH,New York,1989,p.966及其引用的参考文献)。如果需要,可以任何适宜的分离或纯化方法,如过滤、萃取、蒸馏、快速柱色谱法、薄层色谱法、蒸馏或这些方法的组合。适宜的制备和分离方法的具体例子在以下实施例中。当然还可以使用其它等同的制备和分离方法。
图解I罗列了含有伯氨基的双膦酸酯前药如帕米膦酸酯(pamidronate)或阿仑膦酸酯(alendronate)的合成。实施例1提供了用于合成1-O-十六烷氧基丙基-阿仑膦酸酯(alendronate)(HDP-阿仑膦酸酯(alendronate))或1-O-十六烷氧基丙基-帕米膦酸酯(pamidronate)(HDP-帕米膦酸酯(pamidronate))的条件。在该方法中,用三乙胺处理在吡啶溶液中的4-苯二酰亚氨基丁酰基膦酸二甲酯(1b,如美国专利5,039,819所述制备)和亚磷酸十六烷氧基丙 基甲基酯(2)的混合物得到双膦酸四酯3b,用硅胶色谱法对其进行纯化。通过如在Kers,A.,Kers,I.,Stawinski,J.,Sobkowski,M.,Kraszewski,A.Synthesis,1995年四月,427-430中所述的亚磷酸二苯基酯酯交换法得到中间产物2。这样,首先用十六烷氧基丙-1-醇处理在吡啶溶液中的亚磷酸二苯基酯,然后用甲醇处理得到化合物2。
图解I
5a n=2:1-O-十六烷基丙二醇-3-帕米膦酸酯
5b n=3:1-O-十六烷基丙二醇-3-阿仑膦酸酯
这种方法的一个重要的方面是其它长链醇可以用于代替十六烷氧基丙-1-醇以产生本发明的各种化合物。用在乙腈中的溴代三甲基硅烷处理中间产物3b,选择性地分离甲酯得到单酯4b。用在混合溶剂体系(20%甲醇/80%1,4-二噁烷)中的肼处理4b,除去所示的苯二酰亚氨基保护基团。通过过滤收集目标阿仑膦酸酯(alendronate)前药,并通过氨的甲醇溶液处理而将其转化成三铵。
图解II例举了缺少伯氨基的双膦酸酯类似物的的合成。在这种情况下,这些方法步骤与图解I类似,除了不必用苯二酰亚氨基进 行保护和随后的肼解去保护。
图解II
可以采用图解III所示的修正方法将具有1-氨基的双膦酸酯,如氨基-奥帕膦酸酯(olpadronate),转化成本发明前药的类似物。
图解III
用无水HCl处理化合物2和3-(二甲基氨基)丙腈的混合物,然后加入亚磷酸二甲酯得到四酯3,然后用溴代三甲基硅烷将其脱甲 基,得到十六烷氧基丙基-氨基-奥帕膦酸酯(olpadronate)。
图解IV例举了其中的脂类基团结合到母化合物的伯氨基而不是作为膦酸酯的双膦酸酯类似物的合成。
图解IV
图解V例举了西多福韦(cidofovir)、环西多福韦(cidofovir)和其它膦酸酯的烷基甘油或烷基丙二醇类似物的一般合成。用在二甲基甲酰胺中的NaH处理2,3-异亚丙基甘油,1,然后与甲磺酸烷基酯反应得到烷基酯,2。通过乙酸的处理除去异亚丙基,然后与在吡啶中的三苯甲基氯反应得到中间产物3。用卤化烷将中间产物3烷化得到化合物4。用80%乙酸水溶液除去三苯甲基得到O,O-二烷基甘油,5。将化合物5溴化,然后与环西多福韦(cidofovir)或其它含膦酸酯的核苷酸的钠盐反应得到目标膦酸酯加合物,7。通过与氢氧化钠水溶液的反应将环状加合物开环。可以通过用1-O-烷基丙烷-3-醇取代图解V中的化合物5而合成优选的丙二醇类物质。可以 用这些核苷酸膦酸酯取代图解V反应(f)中的cCDV而合成泰诺福韦(tenofovir)和阿的福韦(adefovir)类似物。类似地,可以这种方式形成本发明的其它核苷酸膦酸酯。
图解V
试剂:a)NaH、R1OSO2Me、DMF;b)80%乙酸水溶液;c)三苯甲基氯、吡啶;d)NaH、R2-Br、DMF;e)CBr1、三苯基膦、THF;f)环西多福韦(cidofovir)(DCMC盐)、DMF;g)0.5N NaOH
图解VI例举了使用1-O-十六烷氧基丙基-阿的福韦(adefovir)作为例子,合成本发明核苷酸膦酸酯的一般方法。加入悬浮在无水吡啶中的核苷酸膦酸酯(5mmol)和烷氧基链烷醇或烷基甘油衍生物(6mmol)以及1,3-二环己基碳化二亚胺(DCC,10mmol)。将混合物加热至回流,并剧烈搅拌直至薄层色谱法监测到缩合反应完成。然后将混合物冷却并过滤。减压浓缩滤液,将残余物吸附在硅胶上,并用快速柱色谱法进行纯化(用大约9∶1二氯甲烷/甲醇洗脱)得到对应的膦酸一酯。
图解VI
现在参照以下非限制性的实施例更为详细地描述本发明。
实施例1
1-O-十六烷基丙二醇-3-阿仑膦酸酯(alendronate)的合成
A.亚磷酸十六烷氧基丙基甲基酯(b)
采用在Kers,A.,Kers,I.,Stawinski,J.,Sobkowski,M.,Kraszewski,A.Synthesis,1995年4月,427-430中描述的方法制备十六烷氧基丙基甲基亚磷酸酯。往保持在0℃的处在吡啶(50mL)中的亚磷酸二苯酯(14g,60mmol)溶液中缓慢加入在吡啶(25mL)中的十六烷氧基丙-1-醇(6.0g,20mmol)溶液。搅拌混合物1小时,然后加入无水甲醇(10mL)。再搅拌1小时后,蒸发溶剂,将残余物吸附在硅胶上并进行色谱处理,使用梯度洗脱(己烷至20%乙酸乙酯/80%己烷),得到纯化合物2,为一种蜡状、低熔点固体(4.5g,60%产率)。1HNMR(CDCl3)δ6.79(d,1H,J=696Hz),4.19(q,2H),3.78(d,3H),3.51(t,3H),3.40(t,2H),1.95(pent,2H),1.25(broads,28H),0.88(t,3H)
B.十六烷氧基丙基三甲基4-苯二酰亚氨基丁酰基膦酸酯(3b)
将三乙胺(0.2g,2mmol)加到在吡啶(50mL)中的二甲基4-苯二酰亚氨基丁酰基膦酸酯(1b,3.0g,7.9mmol,如在美国专利 5,039,819中所述制备)和十六烷氧基丙基甲基亚磷酸酯(2,2.9g,9mmol)的混合物。室温下搅拌混合物5小时,然后真空下除去溶剂。将残余物吸附在硅胶上,并进行色谱处理得到化合物3b(3.5g,63%),为一种粘油。1HNMR(CDCl3)δ7.84(d,2H),7.72(d,2H),4.45(m,1H),4.27(m,4H),4.15(q,2H),3.68(s,3H),3.84(s,3H),3.71(t,2H),3.51(m,2H),3.38(t,2H),2.04(m,2H),1.94(五重峰,2H),1.54(m,2H),1.25(宽峰s,28H),0.88(t,3H). 31PNMR(22.54(二重峰),21.22(四重峰))。
C.4-苯二酰亚氨基丁酰基膦酸十六烷基丙基酯(4b)
将以上化合物(3.0g,4.3mmol)溶于无水乙腈(50mL),并冷却至0℃。缓慢加入在乙腈(25mL)中的溴代三甲基硅烷(3.9g,25.5mmol)溶液,然后将溶液再搅拌2小时。随后缓慢地将混合物倒到碎冰上。真空过滤收集形成的沉淀,并真空干燥得到1.2g4b(42%产率)。1HNMR(DMSO-d6)7.86(m,4H),3.99(q,2H),3.66-3.55(m,1H),3.54(m,2H),3.35(t,2H),3.27(t,2H),1.89-1.80(m,),1.72(pent.,2H),1.53-1.40(m,2H),1.22(宽峰s,28H),0.85(t,3H).31PNMR(21.51(二重峰),19.50(二重峰))。
D.1-O-十六烷基丙二醇-3-阿仑膦酸酯(alendronate)(5b)
将化合物4b(300mg,0.45mmol)溶于1,4-二噁烷(20mL)和甲醇(5mL)的混合物中。然后加入无水肼,并在室温下将混合物搅拌4小时。真空过滤收集分离出的沉淀,并用1,4-二噁烷清洗。然后将固体悬浮在乙醇中,并加入氨的甲醇溶液(3mL)。搅拌10分钟后,过滤收集所得的固体,用乙醇清洗并真空干燥得到220mg HDP-阿仑膦盐(alendronate)(5b),为三铵盐。FT-IR法分析表明除去了苯二酰亚氨基保护基团。电雾化MS m/e532(MH+),530(MH-)。
实施例2
1-O-十六烷基丙二醇-3-帕米膦酸酯(pamidronate)(5a)的合成
以类似的方式(根据图解1)制备1-O-十六烷基丙二醇-3-帕米膦酸酯(pamidronate),除了使用3-苯二酰亚氨基丙酸制备二甲基3-苯二酰亚氨基丙酮基膦酸酯(1a)。将化合物1a与2缩合得到双膦酸三甲酯3a。如在以上步骤C和D中的去保护得到所示的HDP-帕米膦酸酯(pamidronate)。
实施例3
1-O-十八烷基-2-O-甲基sn-甘油-3-阿仑膦酸酯(alendronate)的合成
在实施例1的步骤A中,通过用各种长链醇取代十六烷氧基丙-1-醇而制备具有亲脂性基团而非十六烷氧基丙基的前药。例如,1-O-十八烷基-2-O-甲基-sn-甘油与在吡啶中的亚磷酸二苯酯反应,然后用甲醇处理得到1-O-十八烷基-2-O-甲基-sn-甘油基甲基亚磷酸酯。将此亚磷酸二烷基酯与膦酸酯1b缩合,然后在步骤C和D中去保护,得到1-O-十八烷基-2-O-甲基-sn-甘油-3-阿仑膦酸酯(alendronate)。图解2例举了在侧链上不具有伯氨基的其它双膦酸酯轭合物的合成。在这种情况下,用苯二酰亚氨基进行保护和通过肼解进行去保护是不必要的。
实施例4
HDP-氨基-奥帕膦酸酯(olpadronate)的合成
图解3例举了1-氨基双膦酸酯轭合物的合成。采用来自实施例1,3-(二甲基氨基)丙腈的化合物2,和在Orlovskii,V.V.;Vovsi,B.A.J.Gen Chem.USSR(Engl.Transl.)1976,46:294-296中描述的方法,制备双膦酸三甲酯3。用如在实施例1的步骤C中所述的溴代三甲基硅烷脱甲基,得到HDP-氨基-奥帕膦酸酯(olpadronate)。
实施例5
1-O-十六烷基丙二醇-3-琥珀酰基-阿仑膦酸酯(alendronate)
图解4例举了双膦酸酯轭合物的合成,其中,脂类基团连接到母化合物的氨基上。将四甲基-(4-苯二酰亚氨基-1-氢化亚丁基)双膦酸酯(2.0g,4.4mmol)溶于0.2M肼的甲醇溶液(100mL),并在室温下将溶液搅拌3天。当固体开始分离时,将混合物浓缩至其体积的一半。滤出固体并将滤液浓缩至干。质子NMR表明此化合物为四甲基-(4-氨基-1-羟基亚丁基)双膦酸酯。50℃下用五氧化磷将它干燥过夜。往在吡啶(25mL)和N,N-二甲基甲酰胺(25mL)的混合物中的1.2g此化合物的悬浮液中加入3-琥珀酰基-1-十六烷氧基丙烷(1.76g,4.4mmol)。加入二环己基碳化二亚胺(2.52g,12.21mmol),并在室温下搅拌此混合物2天。过滤混合物,将滤液吸附在硅胶上,并用在二氯甲烷(0%-20%)中增加梯度的甲醇进行快速色谱处理得到琥珀酰化的化合物。用在乙腈中的三甲基甲硅溴解封此化合物得到标题化合物,从甲醇中将此化合物结晶纯化。
实施例6
阿的福韦(adefovir)十六烷氧基丙基和1-O-十八烷基-sn-甘油酯的合成
将DCC(2.06g,10mmol)加到在无水吡啶中的阿的福韦(adefovir)(1.36g,5mmol)和3-十六烷氧基-1-丙醇(1.8g,6mmol)的混合物中。将混合物加热至回流,并搅拌18小时,然后冷却和过滤。减压下浓缩滤液,并将残余物应用于硅胶短柱上。用9∶1二氯甲烷/甲醇洗脱柱得到十六烷氧基丙基-阿的福韦(adefovir)(HDP-ADV),为一种白色粉末。
将DCC(2.06g,10mmol)加到在无水吡啶(30mL)中的阿的福韦(adefovir)(1.36g,5mmol)和1-O-十八烷基-sn-甘油(2.08g, 6mmol)的混合物中。将混合物加热至回流,并搅拌过夜,然后冷却和过滤。减压下浓缩滤液,并将残余物应用于硅胶柱上。用9∶1二氯甲烷/甲醇洗脱柱得到1-O-十八烷基-sn-甘油基-3-阿的福韦(adefovir)。
实施例7
AZT-膦酸十六烷氧基丙基酯的合成
采用公开的方法:Hakimelahi,G.H.;Moosavi-Movahedi,A.A.;Sadeghi,M.M.;Tsay,S-C.;Hwu,J.R.Journal of MedicinalChemistry,199538,4648-4659,合成AZT(3’-叠氮基-3’-5’-二脱氧胸苷-5’-膦酸)的膦酸酯类似物。
将AZT膦酸酯(1.65g,5mmol)悬浮在无水吡啶(30mL)中,然后加入3-十六烷氧基-1-丙醇(1.8g,6mmol)和DCC(2.06g,10mmol),将混合物加热至回流并搅拌6小时,将残余物施加于硅胶柱上。用9∶1二氯甲烷/甲醇洗脱柱得到3’-叠氮基-3’-5’-二脱氧胸苷-5’-膦酸,十六烷氧基丙基酯。
实施例8
环西多福韦(cidofovir)的十六烷氧基丙基、十八烷氧基丙基、十八烷氧基乙基和十六烷基酯的合成
将N,N-二环己基-4-吗啉甲酰胺(DCMC,1.0g,3.5mmol)加到在N,N-DMF(25mL)中的西多福韦(cidofovir)(1.0g,3.17mmol)的搅拌的悬浮液中。将混合物搅拌过夜以溶解西多福韦(cidofovir)。然后将此澄清溶液装到另一个漏斗上,并缓慢(30分钟)加到搅拌的1,3-二环己基碳化二亚胺(1.64g,7.9mmol)的热吡啶溶液中。在100℃下搅拌反应混合物16小时,然后冷却至室温,减压下除去溶剂。将残余物吸附在硅胶上,并采用快速色谱法,使用梯度洗脱(CH2Cl2+MeOH)进行纯化。最终用5∶5∶1 CH2Cl2/MeOH/H2O洗脱UV活性产物。蒸发溶剂得到860mg白色固体。 1H和31PNMR光谱表明此产物为环西多福韦(cidofovir)的DCMC盐(产率=44%)。
往处在无水DMF(35mL)中的环西多福韦(cidofovir)(DCMC盐)(0.5g,0.8mmol)的溶液加入1-溴-3-十六烷氧基丙烷(1.45g,4mmol),搅拌此混合物,并在80℃下加热6小时。然后真空浓缩此溶液,将残余物吸附在硅胶上,并采用快速色谱法,使用梯度洗脱(CH2Cl2+EtOH)进行纯化。用90∶10CH2Cl2/EtOH洗脱烷基化产物。将含有纯产物的部分蒸发,得到260mg HDP-环西多福韦(cidofovir)(55%产率)。
往处在无水DMF(35mL)中的环西多福韦(cidofovir)(DCMC盐)(1.0g,3.7mmol)溶液加入1-溴-3-十八烷氧基丙烷(2.82g,7.2mmol),搅拌此混合物,并在85℃下加热5小时。然后真空浓缩此溶液,将残余物吸附在硅胶上,并采用快速色谱法,使用梯度洗脱(CH2Cl2+MeOH)进行纯化。用9∶1CH2Cl2/MeOH洗脱烷基化产物。将含有纯产物的部分蒸发,得到450mg ODP-环西多福韦(cidofovir)。
往处在无水DMF(35mL)中的CDV(DCMC盐)(1.0g,3.7mmol)溶液加入1-溴-3-十八烷氧基乙烷(3.0g,7.9mmol),搅拌此混合物,并在80℃下加热4小时。然后真空浓缩此溶液,将残余物吸附在硅胶上,并采用快速色谱法,使用梯度洗脱(CH2Cl2+MeOH)进行纯化。用9∶1CH2Cl2/MeOH洗脱烷基化产物。将含有纯产物的部分蒸发得到320mg十八烷氧基乙基-cCDV。
往处在无水DMF(35mL)中的环西多福韦(cidofovir)(DCMC盐)(0.5g,0.8mmol)溶液加入1-溴-十六烷(1.2g,4mmol),搅拌此混合物,并在80℃下加热6小时。然后真空浓缩此溶液,将残余物吸附在硅胶上,并采用快速色谱法,使用梯度洗脱(CH2Cl2+MeOH)进行纯化。用9∶1CH2Cl2/MeOH洗脱烷基化产物。将含有纯产物的部分蒸发得到160mg十六烷基-cCDV。
实施例9
西多福韦(cidofovir)的十六烷氧基丙基、十八烷氧基丙基、十八烷氧基乙基十六烷基酯的合成
将以上的十六烷氧基丙基-环CDV溶于0.5M NaOH,并在室温下搅拌1.5小时。然后滴加50%乙酸以调节PH至大约9。过滤分离出沉淀的HDP-CDV,用水清洗并干燥,然后重结晶(3∶1对二噁烷/水)得到HDP-CDV。
类似地,用0.5MNaOH将十八烷氧基丙基-、十八烷氧基乙基-和十六烷基-cCDV酯水解,并纯化得到对应的西多福韦(cidofovir)二酯。
实施例10
环更昔洛韦(ganciclovir)膦酸十六烷氧基丙基酯的合成
采用公开的方法(Reist,E.J.;Sturm,P.A.;Pong,R.Y.;Tanga,M.J.和Sidwell,R.W.Synthesis of acyclonucleosidephosphonates for evaluation as antival agents(用于评价作为抗病毒的无环核苷膦酸酯的合成),17-34页.In J,C.Martin(ed.),Nucleotide Analogues as antiviral Agents(作为抗病毒剂的核苷酸类似物),American Chemical Society,Washington,D.C.)制备更昔洛韦(ganciclovir)的环膦酸酯类似物。在DMF中转化成DCMC盐后,用1-溴-3-十六烷氧基丙烷处理cGCV膦酸酯,并将混合物加热到80℃持续6小时。通过快速色谱法分离烷基化产物得到HDP-环GCV膦酸酯。
实施例11
更昔洛韦(ganciclovir)膦酸十六烷氧基丙基酯的合成
将以上的HDP-cyclicGCV膦酸酯溶于0.5M NaOH并在室温下搅拌使其转化为无环二酯。用50%乙酸水溶液将此溶液中和以沉淀产物,在3∶1对二噁烷/水中重结晶此产物。
实施例12
1-O-十六烷氧基丙烷阿仑膦酸酯(alendronate)抑制地塞米松诱导的MLO-Y4骨细胞凋亡
用指示浓度的1-O-十六烷氧基丙烷阿仑膦酸酯(alendronate)(HDP-阿仑膦酸酯(alendronate))对MLO-Y4骨细胞进行预处理1小时,然后在地塞米松(10-4M最终浓度)存在或不存在下培养细胞6小时。由台盼蓝更新测定死细胞百分率(Plotkin等人,J Clin Invest 104:1363-1374,1999)。结果如图1所示。条棒表示3个独立测定的平均值±SD。通过单一方法ANOVA(Student-Keuls-Newman试验)分析数据。*p<0.05。HDP阿仑膦酸酯(alendronate)抑制10-8-10-5M的地塞米松诱导的凋亡。
实施例13
1-O-十六烷氧基丙烷阿仑膦酸酯(alendronate)抑制地塞米松诱导的颅盖细胞凋亡
从新生C57BL/6J小鼠得到颅盖细胞,并传代于细胞培养物上。用指示浓度的HDP-阿仑膦酸酯(alendronate)预处理细胞1小时,然后在地塞米松(10-4M最终浓度)存在或不存在下培养细胞6小时。由台盼蓝更新测定死细胞百分率(Plotkin等人,J Clin Invest104:1363-1374,1999)。结果如图2所示。条棒表示3个独立测定的平均值±SD。通过单一方法ANOVA(Student-Keuls-Newman试验)分析数据。*p<0.05。用10-8或更高的HDP-阿仑膦酸酯(alendronate)预处理细胞消除了地塞米松诱导的死细胞增长%(p=<0.05)。与0.05 pM DEVD(一种凋亡的肽抑制剂)接触,然后与地塞米松接触的细胞没有表现出死细胞%增长,这表明DEVD阻断了地塞米松诱导的凋亡。
实施例14
1-O-十六烷基丙烷阿仑膦酸酯(alendronate)对切除卵巢大鼠的骨吸收的抑制
在4-12周的期间内,以0mg/kg/天-8mg/kg/天的梯度浓度皮下注射4-氨基-1-羟基亚丁基-1,1-双膦酸,二钠盐或1-O十六烷基丙二醇-3-阿仑膦酸酯(alendronate),来治疗已经过双侧卵巢切除术的雌性Sprague-Dawley大鼠(250gm-280gm)的小组成员。在12周将大鼠,包括对照组成员处死并将各动物的股骨灰化。可选择地,给药方法可以是口服。测定各个体的股骨灰分重量,比较各组的值作为骨质量的指标以确定治疗方案中的相对骨损失抑制作用。1-O-十六烷基丙烷阿仑膦酸酯(alendronate)治疗的动物表现出骨损失小于切除卵巢的对照组。
实施例15
1-O-十八烷氧基丙基-阿仑膦酸酯(alendronate)对患骨质疏松的人的骨吸收的抑制
用安慰剂或1-O十八烷氧基丙基-阿仑膦酸酯(alendronate),以0.1mg/kg/天-100mg/kg/天的口服剂量对两组绝经后妇女治疗2-3年的时间。在治疗期间不断监测治疗组成员的骨矿质密度、椎骨骨折的发生率、根据放射照相检查的椎骨畸形的发展和体重损失。在各治疗组之间比较测量值以确定治疗组中阿仑膦酸酯(alendronate)治疗形式的效力。用1-O-十八烷氧基丙基阿仑膦酸酯(alendronate)治疗的小组比安慰剂组具有较少的骨折和较低的骨密度降低比率。
实施例16
1-O-十八烷氧基丙基-氨基-奥帕膦酸酯(olpadronate)对患有类固醇诱导的骨质疏松的人的骨形成的刺激
以0.1mg/kg/天-100mg/kg/天的口服剂量的1-O-十八烷氧基丙基-氨基-奥帕膦酸酯(olpadronate)或安慰剂对类固醇诱导的骨质疏松患者小组治疗1个月至1年的时间。在治疗期间,连续监测治疗组成员的骨矿质密度,椎骨骨折的发生率、根据放射照相检查的椎骨畸形和椎高丧失的进展。在各治疗组之间比较测量值以确定治疗组中1-O-十八烷氧基丙基-氨基-奥帕膦酸酯(olpadronate)的效力。与安慰剂治疗相比,1-O-十八烷氧基丙基-氨基-奥帕膦酸酯(olpadronate)治疗的患者的骨密度增大而骨折减少。
实施例17
膦酸酯核苷酸类似物抗人巨细胞病毒(HCMV)的抗病毒活性和选择性
HCMV抗病毒试验:如Dankner,W.M.,Scholl,D.,Stanat,S.C.,Martin,M.,Souke,R.L.和Spector,S.A.,J.Virol.Methods21:293-298,1990所报道,通过DNA杂交完成HCMV DNA的抗病毒试验。简单地说,用含有2%FBS和抗生素的不同浓度的Eagle极限必需培养基(E-MEM)对在24孔培养基中的亚融合MRC-5细胞预处理24小时。移出培养基,并加入一定稀释度的HCMV菌株导致5天内无药物孔中的细胞发生3-4+病理效果(CPE)。37℃下吸收病毒1小时,抽吸并用药物稀释液代替。培养5天后,采用核酸杂交法,使用购自Diagnostic Hybrids公司(雅典,OH)的CMV抗病毒易感试验试剂盒对HCMV DNA进行一式三份定量。移出培养基,并根据制造商的说明溶解细胞。在吸收溶解产物后,在60℃下将HybriwixTM过滤器杂交过夜。73℃下清洗HybriwixTM30分钟,并在γ计数器上计算。结果表示为EC50(50%抑制浓度)。
在西多福韦(cidofovir)和阿的福韦(adefovir)的1-O-十六烷 基丙二醇(HDP)衍生物上进行最初的实验,如表1所示。
表1
如表1的结果所示,1-O-十六烷基丙二醇-3-环CDV(HDPcCDV)的活性较CDV或环CDV大900倍。而更多的细胞毒素,在快速分化的细胞中对抗HCMV的选择性指数为>59,000相对于未衍生的CDV’s的1,900至>2,100。根据这些乐观的初始结果,采用其它的本发明化合物进行进一步的实验。这些进一步的实验描述如下。
受试化合物的体外细胞毒性:用添加2%牛胎儿血清和抗生素的E-MEM(Gibco BRL,Grand Island,NY)稀释的药物处理在24孔平板中的亚融合人肺成纤维细胞(MRC-5,美国模式培养物保藏所,Rockville,MD)。37℃下培养5天后,在放大下视力检查单细胞层,并评价导致细胞数量50%减少的药物浓度。
这些实验所得的数据如表2所示。
表2
根据DNA减少测得的对MRC-5人肺成纤维细胞中人CMV复制的抑制
EC50-50%有效浓度;CC50-50%细胞毒素浓度;选择性指数-CC50/EC50。EC50结果是3-6次测定的平均值,除了ADV是在一式两份中完成的单一重复。
从表2所示的结果看出,本发明的化合物一律比未衍生的西多福韦(cidofovir)、环西多福韦(cidofovir)和阿的福韦(adefovir)更具有活性和选择性。
实施例18
HDP-cCDV对痘病毒复制的体外作用
通过测定剂量依赖性细胞病理效果(CPE)的减小,测定西多福韦(cidofovir)(CDV)、环西多福韦(cidofovir)(cCDV)和1-O-十六烷基丙二醇-3-cCDV(HDP-cCDV)对被疫苗病母和牛痘病毒感染的人包皮成纤维细胞的抗病毒活性。在人包皮成纤维(HFF)细胞的CPE 减少试验中测得原始的疫苗和牛痘的EC50。值。如此得到的数据表示在表3中。
表3
如表3所示,HDP-cCDV具有IC50值为0.11M的高度的抗疫苗病毒活性,而cCDV和CDV分别为0.97和1.8μM。HDP-cCDV在牛痘感染的细胞HDP-cCDV中极其有效,IC50值为<0.03μM,而cCDV和CDV则分别为0.72和2.1。根据这些乐观的数据,研究了本发明西多福韦(cidofovir)类似物对其它正痘病毒属复制的效果。
痘病毒抗病毒细胞病理效果(CPE)试验:在每一种药物浓度下,用1000pfu/孔的正痘病毒属感染含有Vero细胞的三个孔,而其它三个孔保持不被感染以用于毒性测定。检测平板并在感染病毒的,未处理的细胞表现出4+CPE之后进行染色。将中性红加到介质中并通过540nm下的中性红吸收来评价CPE。根据剂量反应图测定50%抑制(EC50)和细胞毒素浓度(CC50)。结果如表4所示。
表4
EC50μM
EC50-50%有效浓度;CC50-50%Vero细胞中的细胞毒素浓度;选择性指数-CC50/EC50。缩写如表2。结果为3次测定平均值。
如表4所示,本发明的化合物实际上比未衍生的CDV或cCDV更具有抗疫苗、牛痘和各种天花菌株的活性。
实施例19
1-O-十六烷基丙二醇-3-阿的福韦(adefovir)(HDP-ADV)对HIV-1复制的体内效果
如下进行本发明化合物对HIV-1复制的抑制作用的初步实验。如以上由Larder等人,Antimicrobial Agents & Chemotherapy,34:436-441,1990所述进行药物试验。将感染HIV-1LAI的HT4-6C细胞与所指示的药物接触,并在37℃下培养3天。将细胞与结晶紫混合以目测检验噬菌斑。抗病毒活性以药物治疗样品中的对照噬菌斑(无药物)的百分数评估。EC50。为将噬菌斑数减少50%的微摩尔浓度。在感染HIV-1的HT4-6C细胞上比较阿的福韦(adefovir)与AZT(齐多夫定(zidovudine))和1-O-十六烷基丙二醇-3-阿的福韦(adefovir)(HDP-ADV)的活性。结果如表5所示。
表5
阿的福韦(adefovir)具有中等活性,其EC50为16μM。根据这些乐观的初步结果,预期AZT具有高度活性(ECSO 0.007M),但HDP-ADV在三种化合物中活性最大,其EC50为0.0001μM,比阿的福 韦(adefovir)本身的活性大105以上,进一步的实验如下进行。
HIV-1抗病毒试验:采用噬菌斑减少试验(Larder,B.A.,Chesebro,B.和Richman,D.D.Antimirob.Agents Chemother.,34:436-441,1990)测定抗病毒化合物对表达CD4的HeLa HT4-6C细胞的HIV复制效果。简言之,在24孔微稀释平板中,每孔用100-300个噬菌斑形成单元(PFU)的病毒感染单层HT4-6C细胞。如上述,将各种浓度的药物加到含有5%FBS和抗生素的Dulbecco’s改良的Eagle培养基中。37℃下3天后,用10%甲醛磷酸盐缓冲液(PBS)将此单层细胞固定,并用0.25%结晶紫染色以目测检验病毒噬菌斑。用药物治疗样品中测定的与对照噬菌斑的百分率来评价。采用Hostetler等人,Antiviral Research(抗病毒研究),31:59-67,1996的方法评价细胞毒性。结果如表6所示。
表6
通过噬菌斑减少对HT4-6C细胞中HIV复制的抑制作用
EC50-50%有效浓度;CC50-50%细胞毒素浓度;选择性指数-CC50/EC50。EC50值为4个实验的平均值。
表6显然表明,本发明化合物1-O-十六烷基丙二醇-3-ADV比阿的福韦(adefovir)更具有活性和选择性。
实施例21
西多福韦(cidofovir)类似物对疱疹病毒复制的效果
HSV1抗病毒试验:通过以下方法在24孔培养基中接种亚融合MRC-5细胞:除去培养基,并加入一定稀释度的HSV-1病毒,该稀 释度导致20-24小时内无药物孔中的3-4+CPE。37℃将它吸收1小时,抽出并用各种浓度的处在含有2%FBS和抗生素的E-MEM中的药物代替。大约接种24小时后,采用核酸杂交法,使用购自Diagnostic Hybrids公司(雅典,OH)的HSV抗病毒易感性试验试剂盒对HSV-DNA进行一式三份定量。根据制造商的说明除去培养基并将细胞溶解。吸收溶解产物,然后在60℃下用HybriwixTM滤器杂交过夜。73℃下将Hybriwix清洗30分钟,并在γ计数器上计数。如在实施例17中所述评价细胞毒性。由此得到的EC50和CC50值如表7所示。
表7
根据DNA减少测得的对MRC-5人肺成纤维细胞中人HSV复制的抑制
缩写如表2。EC50-50%有效浓度;CC50-50%细胞毒素浓度;选择性指数-CC50/EC50。EC50值是两次测定的平均值,除了HDP-CDV是在式两份中的单一测定。
如表7所示,所有的本发明化合物比未衍生的核苷酸膦酸酯,西多福韦(cidofovir)或环西多福韦(cidofovir)更具有抗HSV-1活性。
虽然通过举例和用于澄清和理解目的的实施例较详细地描述了上述的发明,但对于本领域技术人员来说,显然可以在本发明的教 导下对其作某些改变和修正,同时不背离本发明的构思和保护范围。
Claims (24)
1.具有以下结构的膦酸酯化合物:
其中:
R1和R1’独立地为-H、选择性取代的-O(C1-C24)烷基、-O(C1-C24)链烯基、-S(C1-C24)烷基或-S(C1-C24)链烯基,其中,至少R1和R1’中一个不为-H,且其中所述的链烯基可选择具有1-6个双键;
R2和R2’独立地为-H、选择性取代的-O(C1-C7)烷基、-O(C1-C7)链烯基、-S(C1-C7)烷基、-S(C1-C7)链烯基、-O(C1-C7)酰基、-S(C1-C7)酰基、-N(C1-C7)酰基、-NH(C1-C7)烷基、-N((C1-C7)烷基)2、氧代、卤素、-NH2、-OH或-SH;
R3为选自阿的福韦、西多福韦、环西多福韦、泰诺福韦和叠氮胸苷磷酸酯的抗病毒核苷膦酸酯;或通过用-PO3H2取代所述核苷的5’-羟基得到的抗病毒核苷膦酸酯;
或选自下列的化合物:
1-羟基亚乙基双膦酸;
二氯亚甲基二磷酸;
氯-4-苯基硫代亚甲基双膦酸;
3-氨基-1-羟基亚丙基双膦酸;
4-氨基-1-羟基亚丁基双膦酸;
3-二甲基氨基-1-羟基亚丙基双膦酸;
3-甲基戊基氨基-1-羟基亚丙基双膦酸;
3-(1-吡咯烷基)-1-羟基亚丙基双膦酸;
2-(3-吡啶基)-1-羟基-亚乙基双膦酸;和
3-(N,N-二甲基氨基-1-氨基亚丙基)双膦酸酯;
或含膦酸酯的核苷,其中所述核苷选自2-氯-脱氧腺苷、1-β-D-阿拉伯呋喃糖基-胞苷、阿糖胞苷、5’-氟脱氧尿嘧啶核苷、吉西他宾、克拉利宾、取代的或未取代的1-β-D-阿拉伯呋喃糖基-鸟嘌呤、1-β-D-阿拉伯呋喃糖基-腺苷和1-β-D-阿拉伯呋喃糖基-尿苷;
其与可选择的连接基L上的官能团或Cα上可利用的氧原子连接;
L为价键或式的双官能团连接分子,其中,t为1-24的整数,J和G独立地为-O-、-S-、-C(O)O-或-NH-,而R为-H、取代或未取代的烷基或者链烯基;
m为0-6的整数;
而n为0或1。
2.根据权利要求1所述的膦酸酯化合物,其中,所述R3是1-羟基亚乙基双膦酸、二氯亚甲基二磷酸、氯-4-苯基硫代亚甲基双膦酸、3-氨基-1-羟基亚丙基双膦酸、4-氨基-1-羟基亚丁基双膦酸、3-二甲基氨基-1-羟基亚丙基双膦酸、3-甲基戊基氨基-1-羟基亚丙基双膦酸、3-(1-吡咯烷基)-1-羟基亚丙基双膦酸、2-(3-吡啶基)-1-羟基-亚乙基双膦酸或3-(N,N-二甲基氨基-1-氨基亚丙基)双膦酸酯。
3.根据权利要求1所述的膦酸酯化合物,其中
R3是西多福韦或泰诺福韦;
n是0;
R1’、R2和R2’每个是氢;
m是1;和
R1是-O(C1-C24)烷基。
4.根据权利要求3所述的膦酸酯化合物,其中R1是-O(CH2)15-CH3或-O-(CH2)17-CH3。
5.根据权利要求3所述的膦酸酯化合物,其中R3是西多福韦,和R1是未取代的-O(CH2)15-CH3。
6.根据权利要求3所述的膦酸酯化合物,其中R3是泰诺福韦,和R1是未取代的-O(CH2)15-CH3。
7.一种药物组合物,它包含如权利要求1所述的膦酸酯化合物及其药学上可接受的载体。
8.根据权利要求1所述的膦酸酯化合物在制备用于治疗哺乳动物的骨质疏松的药物中的用途。
9.根据权利要求1所述的膦酸酯化合物在制备用于增加哺乳动物的骨矿质密度的药物中的用途。
10.根据权利要求1所述的膦酸酯化合物在制备用于预防哺乳动物的成骨细胞和骨细胞凋亡的药物中的用途。
11.根据权利要求1所述的膦酸酯化合物在制备用于治疗哺乳动物的病毒感染的药物中的用途。
12.根据权利要求1所述的瞵酸酯化合物在制备用于治疗哺乳动物的生长性肿瘤的药物中的用途。
13.根据权利要求1所述的膦酸酯化合物在制备用于调节哺乳动物的细胞增殖的药物中的用途。
14.组合物,其包括在药学上可接受的载体中的权利要求3-6中任一项所述的膦酸酯化合物。
15.根据权利要求1所述膦酸酯化合物在制备用于治疗病毒疾病的药物中的用途,其中所述病毒疾病选自人免疫缺陷病毒、流行性感冒、单纯疱疹病毒、人疱疹病毒6、巨细胞病毒、肝炎B和C病毒、非洲淋巴细胞瘤病毒、带状疱疹病毒、正痘病毒、埃博拉病毒和乳头瘤病毒。
16.根据权利要求15所述的用途,其中所述病毒是正痘病毒,选自重型和轻型天花、牛痘、天花、牛痘、骆驼痘和猴痘。
17.根据权利要求15所述的用途,其中所述病毒是人免疫缺陷病毒。
18.根据权利要求15所述的用途,其中所述病毒是流行性感冒病毒。
19.根据权利要求15所述的用途,其中所述病毒是人疱疹病毒6。
20.根据权利要求15所述的用途,其中所述病毒是巨细胞病毒。
21.根据权利要求15所述的用途,其中所述病毒是肝炎B或肝炎C病毒。
22.根据权利要求15所述的用途,其中所述病毒是非洲淋巴细胞瘤病毒。
23.根据权利要求15所述的用途,其中所述病毒是带状疱疹病毒。
24.根据权利要求15所述的用途,其中所述病毒是乳头瘤病毒。
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