CN116057046A - 用于抑制疱疹病毒的组合物 - Google Patents
用于抑制疱疹病毒的组合物 Download PDFInfo
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- CN116057046A CN116057046A CN202180024303.5A CN202180024303A CN116057046A CN 116057046 A CN116057046 A CN 116057046A CN 202180024303 A CN202180024303 A CN 202180024303A CN 116057046 A CN116057046 A CN 116057046A
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Abstract
本文公开内容提供了式I‑V化合物,其可用于抑制对象的病毒疾病。在一些实施方式中,式I‑V的化合物可以用于抑制疱疹病毒。
Description
相关申请的交叉引用
本申请要求2020年1月24日提交的美国申请号62/965,755的权益,其公开内容通过引用全文纳入本文。
序列表
本申请包含以ASCII格式电子提交的序列表,并通过引用全文纳入本文。2021年1月22日创建的所述ASCII拷贝命名为2635-000IWO0I_Sequence Listing_ST25.txt,并且大小为1KB。
政府权益的声明
本发明是在政府支持下由国家卫生研究院(National Institutes of Health)授予的基金号1R0IDC013550资助完成。政府对本发明拥有一定的权利。
发明背景
感染人类巨细胞病毒(HCMV,其是疱疹病毒家族的一员)在人类中很常见。超过80岁的个体中血清阳性率达到90%1。虽然感染通常是无症状的,但HCMV仍然对移植受体和艾滋病患者有严重威胁。它也是全世界最常见的先天性感染,导致儿童听力丧失、全面性障碍(global disabilities)和中枢神经系统损伤2-6。
核苷类似物更昔洛韦(GCV)及其口服制剂val-GCV通过减少HCMV复制和疾病的后遗症显著改善了移植效果7,8。GCV还显示可防止先天感染儿童的听力恶化9。然而,GCV或val-GCV疗程延长会导致严重的骨髓毒性10-13。对先天性感染婴儿口服val-GCV的III期临床试验得出结论,6个月的治疗可能比6周具有更好的神经效果,但出现了耐GCV突变体14。类似地,移植受者中出现了耐GCV突变体15-16。当出现GCV耐药性时,有限的治疗替代品膦甲酸(foscarnet)和西多福韦(cidofovir)具有高度肾毒性,并且只能静脉内给予。其在耐药性或难治性HCMV病例中的使用与高发病率和死亡率相关13。一些新药已进入FDA批准和临床试验。末端酶抑制剂来特莫韦(letermovir)最近被批准用于造血骨髓移植后的HCMV预防17。报道了细胞培养中的UL56突变的快速选择16和患者对来特莫韦的耐药性18。病毒UL97激酶抑制剂马里巴韦(Maribavir)正在进行临床试验19。
新疱疹病毒抑制剂的识别是药物开发的一个重要领域。尽管有多种药物可用,但考虑到可用药物的毒性和进行性耐药突变体选择(ongoing selection of drugresistant mutants),显然需要改进现有药物。
发明概述
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式I化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式II化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基。在一些实施方式中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式III化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括给予式IV化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式V化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是氢、C1-C6直链或支链烷基或C3-C6环烷基;并且R2为未取代或被R3或OR3取代的苯基,其中R3为氢、C1-C6直链或支链烷基或C3-C6环烷基。在一些实施方式中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。在一些实施方式中,所述化合物是
在一些实施方式中,本文公开的方法还包括给予超过一种生物活性剂,例如,两种、三种、四种或更多种生物活性剂。
在一些实施方式中,所述疱疹病毒选自人类疱疹病毒1型(HHV-1)、人类疱疹病毒2型(HHV2)、人类疱疹病毒3型(HHV3)、人类疱疹病毒4型(HHV4)、人类疱疹病毒5型(HHV5)、人类疱疹病毒6型(HHV6)、人类疱疹病毒7型(HHV7)和人类疱疹病毒8型(HHV8)。在一些实施方式中,疱疹病毒是HHV-5。
本文公开了一种药物组合物,其包含式I的化合物或其盐、溶剂化物或立体异构体:
其中,R1是任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开了一种药物组合物,其包含式II的化合物或其盐、溶剂化物或立体异构体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基。在一些实施方式中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开药物组合物,其包含式III的化合物或其盐、溶剂化物或立体异构体以及药学上可接受的运载体:
本文公开了药物组合物,其包含式IV的化合物或其盐、溶剂化物或立体异构体以及药学上可接受的运载体:
本文公开了药物组合物,其包含式V的化合物或其盐、溶剂化物或立体异构体以及药学上可接受的运载体:
其中,R1是氢、C1-C6直链或支链烷基或C3-C6环烷基;并且R2为未取代或被R3或OR3取代的苯基,其中R3为氢、C1-C6直链或支链烷基或C3-C6环烷基。在一些实施方式中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。在一些实施方式中,所述化合物是
本文公开了式I的化合物或其盐、溶剂化物或立体异构体:
其中,R1是任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接,条件是所述化合物不能是化合物A:
在化合物或其盐、溶剂化物或立体异构体的一些实施方式中,所述化合物选自:
本文公开了式II的化合物或其盐、溶剂化物或立体异构体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基,条件是所述化合物不能是选自下组的化合物:
在一些实施方式中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。
本文公开了式V的化合物或其盐、溶剂化物或立体异构体:
其中,R1是氢、C1-C6直链或支链烷基或C3-C6环烷基;并且R2为未取代或被R3或OR3取代的苯基,其中R3为氢、C1-C6直链或支链烷基或C3-C6环烷基。在一些实施方式中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。在一些实施方式中,所述化合物是
本文公开了抑制或治疗对象中的人类疱疹病毒的方法,所述方法包括:向对象给予治疗有效量的药学上可接受的组合物,所述组合物包含一种或多种上述化合物和药学上可接受的运载体。
本文还公开了抑制或治疗对象中的人类疱疹病毒的方法,所述方法包括:向对象给予治疗有效量的药学上可接受的组合物,所述组合物包含一种或多种上述化合物、至少一种其它生物活性剂和药学上可接受的运载体。
本文还公开了本文所公开的化合物或组合物用于治疗对象中人类疱疹病毒的用途。本文还公开了本文所公开的化合物或组合物用于治疗对象中人类疱疹病毒。本文还公开了本文所公开的化合物或组合物用于制造用于治疗对象中人类疱疹病毒的药剂。
附图简要说明
图1:高通量筛选(HTS)的流程图。
图2:五种化合物的化学结构和分子量(MW)。
图3:MLS8969抑制HCMV复制,图3A:HFF感染HCMV Towne pp28(MOI=l),然后用MLS8999或GCV处理。在72hpi下测量荧光素酶活性。图3B:HFF感染HCMV TB40(100PFU/孔),并用MLS8969或GCV处理。10天后对斑块进行染色并计数。图3C:HFF用8969或GCV预处理24小时,然后以MOI 1、0.1和0.01感染HCMV Towne。在72hpi下测量荧光素酶活性。图3D、图3E:HFF用指示浓度的MLS8969或GCV预处理24小时,然后以100PFU/孔感染HCMV TB40(图3D)或耐GCV的HCMV Towne(图3E)。10天后对斑块进行染色并计数。图3A-3E:数据是代表性实验的三个值的平均值±SD。图3F:HFF进行预处理或在处理后感染。在MOI 1、0.1和0.01下进行感染(Towne)。在72hpi下测量来自细胞裂解物的病毒蛋白的表达。WB数据来自代表性实验。
图4:MLS8969是HCMV的进入抑制剂。HFF用3μM MLS8999预处理24小时,然后感染HCMV Towne(MOI=1,0.1,0.01)。肝素(30μM)用作阻断病毒进入细胞的阳性对照,并且GCV预处理(5μM)用作阴性对照。用于HCMV编码pp65的IFA在2hpi下进行,以确定不同条件下定位在细胞核中的pp65的量。实验独立重复三次,显示了来自代表性实验的图像。
图5:NFU1827是HCMV复制的即早早期抑制剂(immediate early-earlyinhibitor)。图5A:HFF感染HCMV TB40(100PFU/细胞),并用指示浓度的化合物NFU1827处理。斑块以8dpi进行染色并计数。实验重复三次,并且所示数据为代表性实验的三个值的平均值±SD。图5B:HFF感染耐GCV的HCMV Towne(MOI=0.1PFU/细胞),并用指示浓度的NFU1827处理。在72hpi下测量细胞裂解物中的荧光素酶活性。所示数据是代表性实验的三个值的平均值±SD。图5C、5D:HFF感染HCMV Towne(MOI=1PFU/细胞),并且感染后(0、6、12、24、48和72小时)添加或去除化合物。在72hpi下测量细胞裂解物中的荧光素酶活性。所示数据是代表性实验的三个值的平均值±SD。图5E:HFF感染HCMV Towne(MOI=1PFU/细胞),并在72hpi下测定病毒蛋白和细胞β-肌动蛋白的表达。实验重复两次,WB数据来自代表性实验。图5F、5G:HFF感染HCMV TB40(MOI=0.1),并用NFU1827(5μM)或GCV(5μM)处理。在指定的时间点裂解细胞以分离DNA。通过实时PCR来测量细胞中的病毒DNA复制(图5F)和上清液中的病毒DNA载量(图5G)。实验重复三次,并且所示数据为代表性实验的一式三份值的平均值±SD。
图6:MLS8554是HCMV复制的即早早期抑制剂。图6A:HFF以100PFU/孔感染TB40,并用指示浓度的MLS8554处理。斑块以8dpi进行染色并计数。实验重复三次,显示来自代表性实验的数据。图6B:HFF感染耐GCV的HCMV Towne(MOI=0.1),并用指示浓度的MLS8554处理。在72hpi下测量细胞裂解物中的荧光素酶活性。所示数据是单个实验的三个值的平均值±SD。图6C、6D:HFF感染HCMV Towne(MOI=1),并在感染后的指定时间点添加或去除化合物。在72hpi下测量细胞裂解物中的荧光素酶活性。实验独立重复两次,并且显示来自单个实验的代表性数据。图6E:HFF感染HCMV Towne(MOI=1),并在3天后测定病毒蛋白和细胞β-肌动蛋白的表达。WB数据来自代表性实验。图6F、6G:HFF感染HCMV Towne(MOI=0.1),并用MLS8554(2μM)或GCV(5μM)处理。收集上清液,并且在指定的时间点裂解细胞以分离DNA。通过实时PCR来测定细胞中的病毒DNA复制(图6F)和上清液中的病毒DNA载量(图6G)。所示数据是两个独立实验的四个值的平均值±SD。
图7:MLS8091在早晚期抑制HCMV复制。图7A:HFF感染HCMV TB40(100PFU/孔),并用指示浓度的MLS8091处理。斑块以8dpi进行染色并计数。实验独立重复三次,显示来自单个代表性实验的数据。图7B:HFF感染耐GCV的HCMV Towne(MOI=0.1),并用指示浓度的MLS8091处理。在72hpi下检测细胞裂解物中的荧光素酶活性。所示数据是单个实验的三个值的平均值±SD。图7C、7D:HFF感染HCMV Towne(MOI=1),并且在感染后的不同时间点(0、6、24、48和72小时)添加或去除化合物。在72hpi下测量细胞裂解物中的荧光素酶活性。实验独立重复两次,并且显示来自单个实验的代表性数据。图7E:HFF感染HCMV Towne(MOI=1),并在72hpi下测定病毒蛋白和细胞β-肌动蛋白的表达。WB数据来自代表性实验。图7F、7G:HFF感染HCMV(MOI=0.1),并用MLS8091(1.5μM)或GCV(5μM)处理。收集上清液,并且在指定的时间点裂解细胞以分离DNA。通过实时PCR来测定细胞中的病毒DNA复制(图7F)和上清液中的病毒DNA载量(图7G)。实验独立重复两次。所示数据是单个实验的三个值的平均值±SD。
图8:NCGC2955是HCMV复制的早晚期抑制剂(early-late inhibitor)。图8A:HFF感染HCMV TB40(100PFU/孔),并用指示浓度的NCGC2955处理。斑块以8dpi进行染色并计数。实验独立重复三次,显示来自单个代表性实验的数据。图8B:HFF感染耐GCV的HCMV Towne(100PFU/孔),并用指示浓度的NCGC2955处理。斑块以8dpi进行染色并计数。所示数据是单个实验的三个值的平均值±SD。图8C、8D:HFF感染HCMV Towne(MOI=1),并且在感染后的不同时间(0、6、24、48和72小时)添加或去除化合物。在72hpi下测量细胞裂解物中的荧光素酶活性。所示数据是三个独立实验的平均值(平均值±SD)。图8E:HFF感染HCMV Towne(MOI=1),并在72hpi下测定病毒蛋白的表达。实验独立重复三次,显示来自单个代表性实验的数据。图8F、8G:HFF感染HCMV Towne(MOI=0.1),并用2955(3μM)或GCV(5μM)处理。收集上清液,并且在指定的时间点裂解细胞以分离DNA。通过实时PCR来测定细胞中的病毒DNA复制(图8F)和上清液中的病毒DNA载量(图8G)。所示数据是两个独立实验的四个值的平均值±SD。
图9:新识别的HCMV抑制剂和GCV的组合是添加物。(图9A-9E)HFF感染HCMV Towne(MOI=1),并用单独的各化合物、不同剂量的各化合物与GCV组合进行处理。对于药物组合,HCMV感染细胞用单个化合物EC50值两倍的起始药物浓度和两倍连续稀释物处理。在72hpi下检测细胞裂解物中的荧光素酶活性,并通过Bliss模型计算药物组合中化合物的抗病毒活性。实线表示观察到的HCMV抑制(剂量响应),并且虚线表示药物组合各剂量的预期HCMV抑制。图9A-9D:实验单独重复三次。显示来自单个代表性实验的数据。图9E:所示数据是单个实验的三个值的平均值±SD。
图10:新识别的HCMV抑制剂与HCMV末端酶抑制剂来特莫韦(Letermovir)的组合是添加物。(图10A-10E)HFF感染TB40(100PFU/孔),并用单独的各化合物、不同剂量的各化合物与来特莫韦的组合进行处理。对于药物组合,HCMV感染细胞用单个化合物EC50值两倍的起始药物浓度处理,随后用两倍连续稀释物处理。在10dpi下计数各种情况下的斑块数量,并使用Bliss模型计算化合物的抗病毒活性。实线表示观察到的HCMV抑制(剂量响应),并且虚线表示药物组合各剂量的预期HCMV抑制。所示数据是单个实验的三个值的平均值±SD。
图11:目录图表:HCMV复制期间五种新抑制剂和GCV的最大活性时间。如“材料和方法”部分所述,对五种化合物中的每一种进行了另加和去除试验,并各化合物显示于图5-8C&D。当添加时和去除时,计算各化合物的荧光素酶活性降低75%的时间,并以独特的颜色表示。图5、6、7、8C和8D中提供了单独的另加和去除试验。
发明详述
需要改进现在可用的疱疹病毒药物。为此目的,使用高度敏感的pp28-荧光素酶HCMV报告子和多个化学库集合20进行了约400,000种化合物的大规模筛选活动。
本文公开了预防和治疗有需要对象中的人类疱疹病毒的化合物和药物组合物。
本文所述的化合物在以有效量给予细胞或细胞群时能抑制人类疱疹。在某些实施方式中,细胞或细胞群在宿主生物体或对象中。
如本文所用,术语“人类疱疹病毒”是指已知能感染人类的疱疹病毒科DNA病毒。疱疹病毒科(Herpesviridae)物种的示例包括:引起面部冷疮的(HHV-1)HSV-1、HSV-2(生殖器疱疹)(HHV-2)、引起水痘和带状疱疹的水痘-带状疱疹病毒(HHV-3)、引起单核细胞增多症的爱泼斯坦-巴尔病毒(HHV4)、HCMV或人巨细胞病毒(CMV或HHV-5)、玫瑰色病毒(HHG-6A)、疱疹淋巴营养病毒(HHHV-6B)、玫瑰糠疹(HHV-7)、以及卡波西肉瘤相关疱疹病毒(Kaposi'ssarcoma-associated herpesvirus,HHV-8)。
本文公开了式I-V的化合物,其可用于抑制病毒疾病。在一些实施方式中,式I-V的化合物可用于抑制有需要对象的疱疹病毒感染,包括哺乳动物,如人类,如婴儿、儿童和成人,包括40岁及以上的成人。
本文还公开了包含式I-V的化合物和药物运载体的药物组合物,其可用于抑制病毒疾病。在一些实施方式中,药物组合物可用于抑制哺乳动物(包括人类)的疱疹病毒感染。
根据一个或多个实施方式中,本文还公开了包含式I-V的化合物、至少一种额外的生物活性剂和药物运载体的药物组合物,其可用于抑制病毒疾病。在一些实施方式中,药物组合物可用于抑制哺乳动物(包括人类)的疱疹病毒感染。
根据一个或多个实施方式,本文公开了抑制对象中的人类疱疹病毒的方法,所述方法包括:向对象给予治疗有效量的式I-V的化合物或包含I-V的化合物和药学上可接受的运载体的药学上可接受的组合物。
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式I化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式II化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基。在一些实施方式中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式III化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括给予式IV化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
本文公开了抑制有需要的对象中的人类疱疹病毒的方法,所述方法包括向所述对象给予式V化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是氢、C1-C6直链或支链烷基或C3-C6环烷基;并且R2为未取代或被R3或OR3取代的苯基,其中R3为氢、C1-C6直链或支链烷基或C3-C6环烷基。在一些实施方式中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。在一些实施方式中,所述化合物是
在一些实施方式中,本文所公开的方法还包括给予超过一种生物活性剂。
在一些实施方式中,所述疱疹病毒选自:人类疱疹病毒1型(HHV-1)、人类疱疹病毒2型(HHV2)、人类疱疹病毒3型(HHV3)、人类疱疹病毒4型(HHV4)、人类疱疹病毒5型(CMV或HHV5)、人类疱疹病毒6型(HHV6)、人类疱疹病毒7型(HHV7)和人类疱疹病毒8型(HHV8)。在一些实施方式中,疱疹病毒是HHV-5。
本文公开了一种药物组合物,其包含式I的化合物或其盐、溶剂化物或立体异构体:
其中,R1是任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开了一种药物组合物,其包含式II的化合物或其盐、溶剂化物或立体异构体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基。在一些实施方式中,R2是任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。在一些实施方式中,所述化合物选自下组:
本文公开药物组合物,其包含式III的化合物或其盐、溶剂化物或立体异构体以及药学上可接受的运载体:
本文公开了药物组合物,其包含式IV的化合物或其盐、溶剂化物或立体异构体以及药学上可接受的运载体:
本文公开了药物组合物,其包含式V的化合物或其盐、溶剂化物或立体异构体以及药学上可接受的运载体:
其中,R1是氢、C1-C6直链或支链烷基或C3-C6环烷基;并且R2为未取代或被R3或OR3取代的苯基,其中R3为氢、C1-C6直链或支链烷基或C3-C6环烷基。在一些实施方式中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。在一些实施方式中,所述化合物是
本文公开了式I的化合物或其盐、溶剂化物或立体异构体:
其中,R1是任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接,条件是所述化合物不能是化合物A:
在化合物或其盐、溶剂化物或立体异构体的一些实施方式中,所述化合物选自:
本文公开了式II的化合物或其盐、溶剂化物或立体异构体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基,条件是所述化合物不能是选自下组的化合物:
在一些实施方式中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。
本文公开了式V的化合物或其盐、溶剂化物或立体异构体:
其中,R1是氢、C1-C6直链或支链烷基或C3-C6环烷基;并且R2为未取代或被R3或OR3取代的苯基,其中R3为氢、C1-C6直链或支链烷基或C3-C6环烷基。在一些实施方式中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。在一些实施方式中,所述化合物是
术语“脂肪族”是本领域公认的术语,包括直链、支链和环状烷烃、烯烃或炔烃。在某些实施方式中,脂肪族基团是直链或支链的,并且具有1至约20个碳原子。
术语“烷基”是本领域公认的,并且包括饱和脂肪族基团,所述饱和脂肪族基团包括直链烷基、支链烷基、环烷基(脂环族基团)、烷基取代的环烷基和环烷基取代的烷基。在某些实施方式中,直链或支链烷基在其骨架中具有约30个或更少的碳原子(例如,对于直链为C1-C30,对于支链为C3-C30),或者约20个或更少的碳原子。类似地,环烷基在其环结构中具有约3至约10个碳原子,或者在环结构中有约5、6或7个碳原子。
此外,术语“烷基”(或“低级烷基”)包括“未取代的烷基”和“经取代的烷基”,后者是指在烃骨架的一个或多个碳上具有取代氢的取代基的烷基部分。此类取代基可包括例如卤素、羟基、羰基(例如羧基、烷氧羰基、甲酰基或酰基)、硫羰基(如硫酯、硫代乙酸根或硫代甲酸根)、烷氧基、磷酰基、膦酸根、次膦酸根、氨基、脒、亚胺、氰基、硝基、叠氮基、巯基、烷硫基、硫酸根、磺酸根、氨磺酰基、磺酰胺基、磺酰基、杂环基、芳烷基或芳族或杂芳族部分。本领域技术人员将理解,如果合适,烃链上被取代的部分本身可以被取代。例如,经取代的烷基的取代基可以包括取代和未取代形式的氨基、叠氮基、亚氨基、酰胺基、磷酰基(包括膦酸根和次膦酸根)、磺酰基(包括硫酸根、磺酰胺基、氨磺酰基和磺酸根)和甲硅烷基,以及醚、烷硫基、羰基(包括酮、醛、羧酸根和酯),-CF3、-CN等。示例性的经取代的烷基如下文所述。环烷基可进一步被烷基、烯基、烷氧基、烷硫基、氨基烷基、羰基取代的烷基、-CF3、-CN等取代。
术语“芳烷基”是本领域公认的,并且包括芳基基团(例如芳族或杂芳族基团)。
术语“烯基”和“炔基”是本领域公认的,分别指含有至少一个双键或三键的部分。
术语“芳基”是本领域公认的,并且包括5元、6元和7元的可以包含0至4个杂原子的单环芳族基团,例如苯、吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、三唑、吡唑、吡啶、吡嗪、哒嗪和嘧啶等。术语“杂原子”通常包括除碳或氢之外任何元素的原子。说明性杂原子包括硼、氮、氧、磷、硫和硒。环结构中具有杂原子的芳基也可称为“芳基杂环”或“杂芳族”。芳族环可以在一个或多个环位置上被上述取代基取代,例如卤素、叠氮化物、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、氨基、硝基、巯基、亚氨基、酰胺基、膦酸根、次膦酸根、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、磺酰胺基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CF3、-CN等。术语“芳基”还包括具有两个或更多个环的多环体系,其中,两个或更多个碳是两个相邻环共有的(环是“稠环”),其中,至少一个环是芳香环,例如,其他环可以是环烷基、环烯基、环炔基、芳基和/或杂环基,或由非环部分连接的环。
术语“邻位”、“间位”和“对位”是本领域公认的,分别适用于1,2-、1,3-和1,4-二取代苯环。例如,名称1,2-二甲苯和邻二甲苯是同义的。
术语“杂环基”或“杂环烷基”是本领域公认的,并且包括约3至约10元环结构,例如3元环至约7元环,其环结构中包括1至4个杂原子。杂环也可以是多环。杂环基团包括例如噻吩、噻蒽、呋喃、吡喃、异苯并呋喃、色烯、呫吨、吩噁噻(phenoxanthin)、吡咯咪唑、吡唑、异噻唑、异噁唑、吡啶、吡嗪、嘧啶、哒嗪、吲哚嗪、异吲哚、吲哚、吲唑、嘌呤、喹嗪、异喹啉、喹啉、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、咔唑、咔啉、菲啶、吖啶、嘧啶、菲罗啉、吩嗪、吩吡嗪、吩噻嗪、呋咱、吩噁嗪、吡咯烷、氧杂环戊烷、四氢噻吩(thiolane)、噁唑、哌啶、哌嗪、吗啉、内酯、内酰胺(如氮杂环丁酮和吡咯烷酮)、磺内酰胺(sultams)、磺内酯(sultones)等。杂环环可以在一个或多个位置上被上述取代基取代,例如卤素、烷基、芳烷基、炔基、环烷基、羟基、氨基、硝基、巯基、亚氨基、酰胺基、膦酸根、次膦酸根、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CD3、-CN等。
术语“多环基”和“多环基团”是本领域公认的,并且包括具有两个或更多个环(例如,环烷基、环烯基、环炔基、芳基和/或杂环基)的结构,其中,两个或更多个碳是两个相邻环共有的,例如,环是“稠环”。通过非相邻原子连接的环,例如,三个或更多原子相对于两个环是公共的,则称为“桥接”环。多环的各环可以被上述取代基取代,例如卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚氨基、酰胺基、膦酸根、次膦酸根、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CD3、-CN等。
本文所用术语“碳环”是本领域公认的,并且包括芳族或非芳族环,其中,环的各原子是碳。下述本领域公认的术语具有下述含义:“硝基”是指-NO2;术语“卤素”表示-F、-Cl、-Br或-I;术语“巯基”是指-SH;术语“羟基”或“羟基基团”是指-OH;术语“磺酰基“是指-SO2-。
术语“胺”和“氨基”是本领域公认的,并且包括未取代的胺和经取代的胺。伯胺带两个氢,仲胺带一个氢和另一取代基,并且叔胺的两个氢被取代。例如,一个或两个氢的取代基可以是烷基、烯基和芳基、环烷基、环烯基、杂环、多环等。如果两个氢都被羰基取代,羰基围绕氮就会形成酰亚胺。
术语“烷基胺”包括如上所限定的胺基团,其上连接有经取代或未取代的烷基。
术语“酰胺基”在本领域公认为氨基取代的羰基。
术语“烷硫基”是本领域公认的,并且包括如上所限定的烷基,其上连接有硫自由基。在某些实施方式中,“烷硫基”部分表示为-S-烷基、-S-烯基、-S-炔基等。代表性烷硫基包括甲硫基、乙硫基等。
术语“羰基”是本领域公认的,并且包括C=O结构。羰基包括在酯;羧基;甲酸根;硫代羰基;硫酯;硫代羧酸;硫代甲酸根;酮;和醛中。
术语“烷氧基”和“烷氧基基团”是本领域公认的,并且包括如上所限定的烷基,其上连接有氧自由基。代表性烷氧基包括甲氧基、乙氧基、丙氧基、叔丁氧基等。
“醚”是通过氧共价连接的两个烃。因此,使该烷基成为醚的烷基取代基是烷氧基或类似于烷氧基,例如由-O-烷基、-O-烯基、-O-炔基等之一表示。
术语“磺酸根”是本领域公认的,并且包括其中硫原子携带两个双键氧和一个单键氧的部分。
术语“硫酸根”是本领域公认的,并且包括类似于磺酸根但包含两个单键氧的部分。
术语“磺酰胺”、“氨磺酰基”、“磺酰基”、和“亚砜”(sulfoxido)是本领域公认的,并且各自包含如本文所述的各种R基团取代基。
术语“亚磷酰胺”和“亚磷亚酰胺”(phophonamidite)是本领域公认的。
术语“硒烷基(selenoalkyl)”是本领域公认的,并且包括具有其上连接有取代硒基的烷基。烷基上可以进行取代的示例性“硒醚”选自如下中的一种:-Se-烷基、-Se-烯基、-Se-炔基等。
取代可以对烯基和炔基进行,以产生例如氨基烯基、氨基炔基、酰胺基烯基、亚氨基烯基、亚氨基炔基、硫烯基、硫炔基、羰基取代的烯基或炔基。
烃是本领域公认的术语,并且包括具有至少一个氢原子和一个碳原子的所有允许的化合物。例如,允许的烃包括可以取代或未取代的非环状和环状、支化和未支化、碳环和杂环、芳族和非芳族有机化合物。
术语“保护基团”是本领域公知的,并且包括保护潜在反应性官能团免受不希望发生的化学转化的临时取代基。该保护基团的示例分别包括羧酸的酯、醇的甲硅烷基醚、醛和酮的缩醛和缩酮。已对保护基团化学领域进行了综述,例如Greene等人,《有机合成中的保护基团》(Protective Groups in Organic Synthesis)第二版,威利出版社(Wiley),纽约,(1991年)。
除非另有明确说明或上下文另有规定,否则当在任何结构中出现不止一次时,每个表达式(例如烷基、芳基等)的限定意为与同一结构中其他地方的限定无关。
术语三氟甲磺酰基(triflyl)、甲苯磺酰基(tosyl)、甲磺酰基(mesyl)和九氟丁磺酰基(nonaflyl)是本领域公认的,并且分别指三氟甲磺酰基基团、甲苯磺酰基基团、甲磺酰基基团和九氟丁磺酰基基团。术语三氟甲磺酸根(triflate)、甲苯磺酸根(tosylate)、甲磺酸根(mesylate)和九氟丁磺酸根(nonaflate)是本领域公认的,分别指三氟甲磺酸酯、甲苯磺酸酯、甲磺酸酯和九氟丁磺酸酯官能团和含有所述基团的分子。
缩写Me、Et、Ph、Tf、Nf、Ts和Ms是本领域公认的,分别表示甲基、乙基、苯基、三氟甲磺酰基、九氟丁磺酰基、甲苯磺酰基和甲磺酰基。具有本领域普通技术的有机化学工作者所用缩写的更详尽的列表可参见有机化学杂志(Journal of Organic Chemistry)每卷第一期;该列表一般以标题为“标准缩写列表”的表格形式出现。
因此,本文所公开的化合物中包括所公开化合物的互变异构形式(包括对映体、立体异构体和非对映异构体的异构形式),以及其药学上可接受的盐。术语“药学上可接受的盐”包括通常用于形成碱金属盐和形成游离酸或游离碱加成盐的盐。可用于形成药学上可接受的酸加成盐的酸的示例包括无机酸(如盐酸、硫酸和磷酸)和有机酸(如马来酸、琥珀酸和柠檬酸)。其他药学可接受的盐包括含有碱金属或碱土金属(如钠、钾、钙和镁)的盐,或含有有机碱(例如二环己胺)的盐。例如,所公开化合物的合适的药学上可接受的盐包括酸加成盐,例如,其可通过混合本文所公开化合物溶液与药学上可接受的酸的溶液来形成,所述酸为例如盐酸、硫酸、甲磺酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸或磷酸。所有这些盐可以通过常规方法制备,例如,通过适当的酸或碱与本文所公开的相应化合物反应。
用游离羧基形成的盐还可源自无机碱例如钠、钾、铵、钙、或铁的氢氧化物,和有机碱例如异丙胺、三甲胺、2-乙基氨基乙醇、组氨酸、普鲁卡因等。
对于在药物中使用,本文公开的化合物的盐应为药学上可接受的盐。然而,其它盐也可用于制备本文所公开化合物或其药学上可接受的盐。
此外,本文所公开实施方式包括本文所公开化合物的水合物。术语“水合物”包括但不限于半水合物、一水合物、二水合物、三水合物等。本文所公开化合物的水合物可以通过使化合物与水在合适条件下接触以产生所选水合物来制备。
本文公开的实施方式还包括用于制备包含化合物的药物产品的方法。术语“药物产品”是指本文限定的适用于医药用途的组合物(药物组合物)。包含本文所公开化合物的为了特定应用而配制的药物组合物视为其实施方式。
本文所公开的组合物可以包含运载体。术语“运载体”(carrier)是指与治疗物与其一起给予的稀释剂、佐剂、赋形剂或载剂(vehicle)。
相对于本文所述的药物组合物,药学上可接受的运载体可以是常规使用的任意运载体,并且仅受物理化学因素限制(例如溶解度和与活性化合物没有反应性),以及受给药途径限制。本文所述的药学上可接受的运载体,如载剂、佐剂、赋形剂和稀释剂,是本领域技术人员众所周知的,并且是公众容易获得的。药学上可接受的运载体的示例包括可溶性运载体,例如生理上可以接受的已知缓冲液(例如磷酸盐缓冲液)以及固体组合物,例如固态运载体或胶乳珠。药学上可接受的运载体优选为对活性剂呈化学惰性的那些以及在使用条件下没有或几乎没有有害副作用的那些。
本文所用的运载体或稀释剂可以是用于固体制剂的固体运载体或稀释剂、用于液体制剂的液体运载体或稀释剂或它们的混合物。
固体运载体或稀释剂包括但不限于:树胶、淀粉(例如玉米淀粉、预糊化淀粉)、糖(例如乳糖、甘露醇、蔗糖、右旋糖)、纤维素材料(例如,微晶纤维素)、丙烯酸酯(例如聚甲基丙烯酸酯)、碳酸钙、氧化镁、滑石或它们的混合物。
对于液体制剂,药学上可接受的运载体可以是例如水溶液或非水溶液、悬浮液、乳液或油。非水溶剂的示例是丙二醇,聚乙二醇、可注射有机共溶剂、表面活性剂和可注射有机酯如油酸乙酯。水运载体包括:例如,水、醇溶液/水溶液、环糊精、乳液或悬浮液,包括盐水和缓冲介质。
油的示例是石油、动物、植物或合成来源的油,例如花生油、大豆油、矿物油、橄榄油、葵花籽油、鱼肝油、芝麻油、棉籽油、玉米油、橄榄(olive)、矿脂和矿物油(mineral)。用于胃肠道外制剂的合适脂肪酸包括:例如,油酸、硬脂酸和异硬脂酸。油酸乙酯和肉豆蔻酸异丙酯是合适脂肪酸酯的示例。
胃肠道外运载体(用于皮下注射、静脉注射、动脉注射或肌肉注射)包括:例如,氯化钠溶液、盐水溶液、林格氏右旋糖、右旋糖和氯化钠、乳酸林格溶液或固定油。适于胃肠道外给予的制剂包括:例如,水溶液和非水溶液、等渗无菌注射溶液,其可以包含使该制剂与预期接受者的血液等渗的抗氧化剂、缓冲液、抑菌剂和溶质;以及含有悬浮剂、增溶剂、增稠剂、稳定剂和防腐剂的水性和非水性无菌悬浮剂。
静脉内载剂包括:例如,流体和营养补充剂、电解质补充剂如基于林格氏右旋糖的那些等。示例为:添加或不添加表面活性剂和其他药学上可接受的佐剂的无菌液体,例如水和油。一般来说,水、盐水、右旋糖水溶液和相关糖溶液,以及二醇如丙二醇或聚乙二醇可以是液体运载体,特别是对于注射溶液。
此外,在一些实施方式中,本文所述的化合物还可以包括:例如,粘合剂(例如,阿拉伯胶(acacia)、玉米淀粉、明胶、卡波姆、乙基纤维素、瓜尔胶、羟丙基纤维素、羟丙甲基纤维素、聚烯吡酮);崩解剂(例如,玉米淀粉、马铃薯淀粉、海藻酸、二氧化硅、交联羧甲纤维素钠(croscarmelose sodium)、交联聚维酮(crospovidone)、瓜尔胶、淀粉乙醇酸钠);不同pH值和离子强度的缓冲液(例如,Tris-HCl(三羟甲基氨基甲烷盐酸盐)、乙酸盐、磷酸盐);添加剂,如白蛋白或明胶,以防止吸附至表面;洗涤剂(如吐温20、吐温80、Pluronic F68、胆酸盐);蛋白酶抑制剂;表面活性剂(如十二烷基硫酸钠);渗透促进剂、增溶剂(例如,聚氧乙烯氢化蓖麻油(cremophor)、甘油、聚乙二醇、苯扎氯铵(benzlkoniumchloride)、苯甲酸苄酯、环糊精、山梨聚糖酯、硬脂酸);抗氧化剂(例如,抗坏血酸、焦亚硫酸钠、丁基羟基茴香醚);稳定剂(例如,羟丙基纤维素、羟丙基甲基纤维素);增粘剂(例如卡波姆、胶体二氧化硅、乙基纤维素、瓜尔胶);甜味剂(例如,阿巴斯甜、柠檬酸);防腐剂(例如硫柳汞、苯甲醇、对羟基本甲酸酯(parabens));润滑剂(例如,脂酸、硬脂酸镁、聚乙二醇、十二烷基硫酸钠);助流剂(例如,胶体二氧化硅);增塑剂(例如,邻苯二甲酸二乙酯、柠檬酸三乙酯);乳化剂(例如,卡波姆、羟丙基纤维素、十二烷基硫酸钠);聚合物包衣(例如,泊洛沙姆(poloxamers)或泊洛沙胺(poloxamines));包衣和成膜剂(例如乙基纤维素、丙烯酸酯、聚甲基丙烯酸酯);和/或佐剂。
运载体的选择将部分由具体化合物以及用于给予化合物的具体方法确定。因此,存在本所公开的药物组合物的多种合适制剂。以下用于胃肠道外、皮下、静脉内、肌肉内、动脉内、鞘内和腹膜内给予的制剂是示例性的,并且不是限制性的。可以使用超过一种途径来给予化合物,在某些情况下,特定途径可以提供比另一种途径更直接、更有效的响应。在一些实施方式中,在本文所公开的方法中,本文公开的化合物或药物组合物口服给予,例如,以片剂、胶囊、悬浮液给予,或者静脉内给予。
用于胃肠道外制剂的合适的皂可包括:例如,脂肪碱金属、铵和三乙胺盐,且合适的去垢剂包括:例如,(a)阳离子型去垢剂,例如,二甲基二烷基卤化铵和卤化烷基吡啶嗡,(b)阴离子型去垢剂,例如,烷基、芳基和烯烃磺酸盐,烷基、烯烃、醚和单甘油磺酸盐,以及磺基琥珀酸酯,(c)非离子型去垢剂,例如,脂肪胺氧化物、脂肪酸烷醇酰胺和聚氧乙烯-聚丙烯共聚物,(d)两性去垢剂,例如烷基-b-氨基丙酸盐和2-烷基咪唑啉季铵盐,以及(e)它们的混合物。
在溶液中,胃肠道外制剂通常含有约0.5重量%至约25重量%的化合物。可以使用防腐剂和缓冲液。为使注射位点处的刺激最小化或消除注射位点处的刺激,这类组合物可含有一种或多种非离子型表面活性剂,例如,具有约12至约17的亲水-亲油平衡值(HLB)。这类制剂中表面活性剂的量通常为约5重量%至约15重量%。例如,合适的表面活性剂包括:聚乙二醇山梨糖醇酐脂肪酸酯,例如失水山梨醇单油酸酯和由环氧丙烷与丙二醇缩合形成的环氧乙烷与疏水性碱的高分子量加合物。
胃肠道外制剂可存在于单位剂量或多剂量密封容器中,例如安瓿和药瓶,并且可冷冻干燥(冻干)条件进行保存,临使用前只需要加入注射用无菌液体赋形剂(如水)即可。即席注射溶液和悬浮液可以由无菌粉末、颗粒和片剂进行制备。
可注射制剂符合本文的公开内容。本领域技术人员熟知用于可注射组合物的有效药物运载体的要求(参见Pharmaceutics and Pharmacy Practice(《药理学和药剂学实践》),JBL公司(J.B.Lippincott Co.),宾夕法尼亚州费城,Banker和Chalmers编,第238-250页(1982),以及ASHP Handbook on Injectable Drugs(《可注射药物的ASHP手册》),Toissel,第4版,第622-630页(2009)。
如上所述式I、II、III、IV和V化合物中任何一种的化合物、盐、溶剂化物或立体异构体的给予量或剂量应足以在合理的时间范围内在对象内产生例如治疗或预防反应。剂量将由特定化合物的功效和人的病情以及待治疗人的体重来确定。
如上所述式I、II、III、IV和V化合物中任何一种的化合物、盐、溶剂化物或立体异构体的剂量还将由给予特定化合物可能伴随的任何不良副作用的存在、性质和程度确定。通常,主治医师将考虑多种因素,如年龄、体重、总体健康、饮食、性别、将给予的化合物、给予途径和治疗的病情严重程度,来确定用于治疗每个个体患者的化合物剂量。例如但并非意图限制本文的公开内容,化合物的剂量可约为0.001至约1000mg/kg待治疗对象体重/天。
在一些实施方式中,术语“给予/给药”是指将本文所公开的化合物引入对象,例如,接受疾病治疗的对象,并且允许该化合物与体内一种或多种疾病相关细胞或细胞群接触。在一些实施方式中,宿主中的宿主细胞或宿主细胞群可以是通过结合至上述式I、II、III、IV和V化合物的抗原可进行选择性结合的任何细胞或细胞群。本领域技术人员应理解,宿主细胞可以是感染病毒的细胞。
根据一些实施方式,本文的公开内容提供了用于抑制对象中的人类疱疹病毒的方法,所述方法包括:向对象给予治疗有效量的药学上可接受的组合物,所述组合物包含一种或多种上述化合物和药学上可接受的运载体。
根据一些实施方式,本文的公开内容提供了用于治疗对象医疗病症(包括但不限于抑制人类疱疹病毒)的方法,所述方法包括:向对象给予治疗有效量的药学上可接受的组合物,所述组合物包含一种或多种上述化合物、药学上可接受的运载体和至少一种其它生物活性剂。
根据一些实施方式,本文的公开内容提供了用于抑制或治疗对象中的人类疱疹病毒的方法,所述方法包括:向对象给予治疗有效量的药学上可接受的组合物,所述组合物包含一种或多种上述化合物和药学上可接受的运载体。
根据一些实施方式,本文的公开内容提供了用于抑制或治疗对象中的人类疱疹病毒(例如,抑制人类疱疹病毒复制)的方法,所述方法包括:向对象给予治疗有效量的药学上可接受的组合物,所述组合物包含一种或多种上述化合物、至少一种生物活性剂和药学上可接受的运载体。
“抑制疱疹病毒”或“疱疹病毒的抑制”是指减少或防止病毒复制、治疗病毒感染所引起的症状(例如肝炎或肺炎),减少血液或血浆中的病毒载量,和/或减少持续性病毒血症。
“进行治疗”或“治疗”是本领域公认的术语,其包括治愈以及减轻任何病情或疾病的至少一种症状。治疗包括降低易感疾病、病症或病情、但尚未被诊断为患有该疾病、病症或病情的动物发生该疾病、病症或病情的可能性;抑制疾病、病症或病情,例如阻碍其进展;以及缓解疾病、病症或病情,例如导致疾病任何程度的退化;抑制疾病、病症或病情,例如阻碍其进展;以及缓解疾病、病症或病情,即使潜在的病理生理方面没有受到影响或其他症状保持在相同水平。
在一些实施方式中,本文公开的药物组合物可用于治疗对象的病毒感染。在一些实施方式中,病毒感染是疱疹病毒感染,例如,CMV感染。
在一些实施方式中,本文所公开的药物组合物可以与一种或多种额外的生物活性剂(包括例如抗病毒剂)组合。
“预防/预防性”或“治疗/治疗性”治疗是本领域公认的,包括向宿主给予一种或多种主题组合物。如果在不想要的病情(例如,宿主动物的疾病或其他不想要的状态)有临床表现之前给予,则治疗是预防性的,即,其保护宿主防止不想要的病情发展,而如果在不想要的病情显现之后给予,则该治疗是治疗性的(即,其目的是减少、减轻或稳定现有的不想要的病情或其副作用)。
生物活性剂可以根据组合物的预期用途而千差万别。术语“活性”是本领域公认的,是指在对象体内局部或全身发挥作用的生物、生理或药学上的活性物质的任何部分。可称为“药物”的生物活性剂的示例在众所周知的文献中进行了描述,例如,Merck Index(默克指数)、Physicians'Desk Reference(医生案头参考)和Pharmacological Basis ofTherapeutics(治疗学的药理学基础),并且其包括但不限于:药物(medicaments);维生素;矿物质补充剂;用于治疗、预防、诊断、治愈或减轻疾病或病的物质;影响身体结构或功能的物质;或前药,其在位于生理环境后变得具有生物活性或更具活性。可以使用各种形式的生物活性剂,这些生物活性剂能够在给予至对象后使主题组合物释放到例如相邻组织或流体中。在一些实施方式中,生物活性剂可用于交联聚合物基质中,例如,从而促进软骨形成。在其它实施方式中,生物活性剂可用于交联聚合物基质中,以治疗、减轻、抑制或预防疾病或症状,例如,与促进软骨形成配合。
生物活性剂的进一步示例包括但不限于:酶、受体拮抗剂或激动剂、激素、生长因子、自体骨髓、抗生素、抗微生物剂和抗体。术语“生物活性剂”还意图涵盖可以掺入本文所公开化合物和组合物的各种细胞类型和基因。
在某些实施方式中,主题组合物可以占总组合物约1重量%至约75重量%或更高,或者包含约2.5%、5%、10%、20%、30%、40%、50%、60%或70%的生物活性剂。
生物活性剂的非限制性示例包括如下:肾上腺素阻断剂(adrenergic blockingagents)、同化剂(anabolic agents)、雄激素类固醇(androgenic steroids)、抗酸剂(antacids)、抗哮喘剂(anti-asthmatic agents)、抗过敏材料(antiallergenicmaterials)、降胆固醇降脂药(anti-cholesterolemic and anti-lipid agents)、抗胆碱药(anti-cholinergics)和拟交感神经药(sympathomimetics)、抗凝血剂(anti-coagulants)、抗惊厥剂(anti-convulsants)、止泻剂(anti-diarrheal)、止吐剂(anti-emetics)、抗高血压剂(antihypertensive agents)、抗感染剂(anti-infective agents)、抗炎药(anti-inflammatory agents)如类固醇、非甾族抗炎药(nonsteroidal anti-inflammatory agents)、抗疟疾药(anti-malarials)、抗躁狂药(anti-manic agents)、止恶心药(anti-nauseants)、抗肿瘤药(antineoplastic agents)、减肥药(anti-obesityagents)、抗帕金森病药(anti-parkinsonian agents)、退热止痛药(anti-pyretic andanalgesic agents)、解痉剂(anti-spasmodic agents)、抗血栓药(anti-thromboticagents)、降尿酸药(anti-uricemic agents)、防心绞痛药(anti-anginal agents)、抗组胺药(antihistamines)、止咳药(anti-tussives)、食欲抑制剂(appetite suppressants)、苯并菲啶类生物碱(benzophenanthridine alkaloids)、生物制剂(biologicals)、心脏作用剂(cardioactive agents)、脑扩张剂(cerebral dilators)、冠状动脉扩张剂(coronarydilators)、减充血剂(decongestants)、利尿剂(diuretics)、诊断剂(diagnosticagents)、促红细胞生成剂(erythropoietic agents)、雌激素(estrogens)、祛痰剂(expectorants)、胃肠道镇静剂(gastrointestinal sedatives)、药剂(agents)、促血糖升高剂(hyperglycemic agents)、安眠剂(hypnotics)、降血糖药(hypoglycemic agents)、离子交换树脂(ion exchange resins)、泻药(laxatives)、矿物质补充剂(mineralsupplements)、有丝分裂剂(mitotics)、化痰药(mucolytic agents)、生长因子、神经肌肉药物(neuromuscular drugs)、营养物质(nutritional substances)、外周血管扩张剂(peripheral vasodilators)、促孕剂(progestational agents)、前列腺素(prostaglandins)、心力加强剂(psychic energizers)、精神药物品(psychotropics)、镇静剂(sedatives)兴奋剂(stimulants)、甲状腺药和抗甲状腺药(thyroid and anti-thyroid agents)、安定剂(tranquilizers)、子宫松弛剂(uterine relaxants)、维生素、抗原材料(antigenic materials)和前药。
上述类别的可用生物活性剂的具体示例包括:(a)抗肿瘤药,如雄激素抑制剂(androgen inhibitors)、抗代谢药(antimetabolites)、细胞毒性药物(cytotoxicagents)和免疫调节剂(immunomodulators);(b)止咳药,如右美沙芬(dextromethorphan)、氢溴酸盐(hydrobromide)、诺司卡品(noscapine)、柠檬酸喷托维林(carbetapentanecitrate)和盐酸氯苯达诺(chlophedianol hydrochloride);(c)抗组胺药(antihistamine),如扑尔敏酒石酸苯茚胺(chlorpheniramine phenindamine tartrate)、吡拉明琥珀酸多西拉明(pyrilamine doxylamine succinate)和柠檬酸苯妥洛敏(phenyltoloxamine citrate);(d)减充血剂,如盐酸(hydrochloride)、盐酸苯丙醇胺(phenylpropanolamine hydrochloride)、盐酸伪麻黄碱(pseudoephedrinehydrochloride)和麻黄碱(ephedrine);(e)各种生物碱,如磷酸可待因(codeinephosphate)、硫酸可待因(codeine sulfate)和吗啡(morphine);(f)矿物补充剂,如氯化钾、氯化锌、碳酸钙、氧化镁和其他碱金属和碱土金属盐;(g)离子交换树脂,例如N-乙酰普鲁卡因胺(N-acetylprocainamide);(i)退热药(antipyretics)和镇痛剂(analgesics),如扑热息痛(acetaminophen)、阿司匹林(aspirin)和布洛芬(ibuprofen);食欲抑制剂(appetite suppressant),如苯基丙醇胺(phenyl-propanol amine)或咖啡因(caffeine);(k)祛痰剂,如愈创甘油醚(guaifenesin);(l)抗酸剂,如氢氧化铝和氢氧化镁;生物制品,如肽、多肽、蛋白质和氨基酸、激素(hormones)、干扰素(interferons)或细胞因子(cytokines)以及其他生物活性肽化合物,如降血钙素(calcitonin)、ANF、EPO和胰岛素;(n)抗感染剂,如抗真菌药、抗病毒药、防腐剂和抗生素;以及(m)脱敏剂和抗原材料,例如用于疫苗应用的材料。
更具体地说,可用的生物活性剂的非限制性示例包括以下治疗类别:镇痛剂,例如,非甾体抗炎药(nonsteroidal anti-inflammatory drugs)、阿片激动剂(opiateagonists)和水杨酸盐(salicylates);抗组胺药(antihistamines),例如,H1阻断剂(H1-blockers)和H2阻断剂(H2-blockers);抗感染剂,例如,如抗寄生虫药(antihelmintics)、抗厌氧菌药(antianaerobics)、抗生素(antibiotics)、氨基糖苷类抗生素(aminoglycoside antibiotics)、抗真菌抗生素(antifungal antibiotics)、头孢菌素类抗生素(cephalosporin antibiotics)、大环内酯类抗生素(macrolide antibiotics)、其它抗生素(miscellaneous antibiotics)、青霉素类抗生素(penicillin antibiotics)、喹诺酮类抗生素(quinolone antibiotics)、磺胺类抗生素(sulfonamide antibiotics)、四环素类抗生素(tetracycline antibiotics)、抗分枝杆菌剂(antimycobacterials)、抗结核抗分枝杆菌剂(antituberculosis antimycobacterials)、抗原生菌剂(antiprotozoals)、抗疟抗原生动物剂(antimalarial antiprotozoals)、抗病毒药(antiviral agents)、抗逆转录病毒药(anti-retroviral agents)、杀疥剂(scabicides)和泌尿道抗感染剂(urinary anti-infectives);抗肿瘤药,如烷基化剂(alkylatingagents)、氮芥烷基化剂(nitrogen mustard alkylating agents)、亚硝基脲烷基化剂(nitrosourea alkylating agents)、抗代谢药(antimetabolites)、嘌呤类似物抗代谢药(purine analog antimetabolites)、;嘧啶类似物抗代谢药(pyrimidine analogantimetabolites);激素类抗肿瘤药(hormonal antineoplastics)、天然抗肿瘤药(natural antineoplastics)、抗生素类天然抗肿瘤药(antibiotic naturalantineoplastics)和长春花生物碱天然抗肿瘤药(vinca alkaloid naturalantineoplastics);自主神经系统作用物(autonomic agents),如抗胆碱能药(anticholinergics)、抗肌氨酸抗胆碱能药物(antimuscarinic anticholinergics)、麦角生物碱(ergot alkaloids)、拟副交感神经药(parasympathomimetics)、胆碱能激动剂拟副交感神经药(cholinergic agonist parasympathomimetics)、胆碱酯酶抑制剂拟副交感神经药(cholinesterase inhibitor parasympathomimetics)、抗交感神剂(sympatholytics)、α-阻滞剂抗交感神剂(a-blocker sympatholytics)、抗交感神剂(sympatholytics)、拟交感神经药(sympathomimetics)和肾上腺素能激动剂拟交感神经药(adrenergic agonist sympathomimetics);心血管药(cardiovascular agents),如抗心绞痛药(antianginals)、抗心绞痛药(antianginals)、钙通道阻滞剂抗心绞痛药(calciumchannel blocker antianginals)、硝酸盐抗心绞痛药(nitrate antianginals)、抗心律失常药(antiarrhythmics)、心肌糖苷抗心律失常药(cardiac glycosideantiarrhythmics)、I类抗心律失常药(class I antiarrhythmics)、II类抗心律失常药、III类抗心律失常药、IV类抗心律失常药、降压药(antihypertensive agents)、α-阻滞剂降压药(a-blocker antihypertensives)、血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitor)(ACE抑制剂)降压药、13-阻滞剂降压药(13-blockerantihypertensives)、钙通道阻滞剂抗高血压药(calcium-channel blockerantihypertensives)、中枢作用肾上腺素能降压药(central-acting adrenergicantihypertensives)、利尿降压药(diuretic antihypertensive agents)、外周血管扩张剂降压药(peripheral vasodilator antihypertensives)、降脂药(antilipemics)、胆汁酸隔离剂降脂剂(bile acid sequestrant antilipemics)、还原酶抑制剂降血脂剂(reductase inhibitor antilipemics)、肌力药物(inotropes)、强心甙(cardiacglycoside inotropes)和溶栓药(thrombolytic agents);皮肤病药(dermatologicalagents),如抗组胺药(antihistamines)、抗炎药(anti-inflammatory agents)、皮质类固醇抗炎药(corticosteroid anti-inflammatory agents)、麻醉药(anesthetics)、局部抗感染药(topical anti-infectives)、局部抗感染药(topical anti-infectives)、抗病毒局部抗感染药(antiviral topical anti-infectives)和局部抗肿瘤药(topicalantineoplastics);电解质和肾脏制剂(electrolytic and renal agents),如酸化剂(acidifying agents)、碱化剂(alkalinizing agents)、利尿剂(diuretics)、碳酸酐酶抑制剂利尿剂(carbonic anhydrase inhibitor diuretics)、袢利利尿剂(loopdiuretics)、渗透性利尿剂(osmotic diuretics)、保钾利尿剂(potassium-sparingdiuretics)、噻嗪类利尿剂(thiazide diuretics)、电解液替代品(electrolytereplacements)和尿酸剂(uricosuric agents);酶,如胰腺酶(pancreatic enzymes)和溶栓酶(thrombolytic enzymes);胃肠道药(gastrointestinal agents),如止泻药(antidiarrheals)、止吐药(antiemetics)、胃肠道抗炎药(gastrointestinal anti-inflammatory agents)、水杨酸胃肠道抗炎性药物(salicylate gastrointestinalanti-.inflammatory agents)、抗酸抗溃疡药物(antacid anti-ulcer agents)、胃酸泵抑制剂抗溃疡药(gastric acid-pump inhibitor anti-ulcer agents)、胃粘膜抗溃疡剂(gastric mucosal anti-ulcer agents)、H2-阻滞剂抗溃疡剂(H2-blocker anti-ulceragents)、胆石溶解剂(cholelitholytic agents)、助消化剂(digestants)、催吐剂(emetics)、泻药(laxatives)和大便软化剂(stool softeners),以及胃肠动力药(prokinetic agents);全身麻醉药(general anesthetic),例如吸入麻醉药(inhalationanesthetics)、卤化吸入麻醉药(halogenated inhalation anesthetics)、静脉麻醉药(intravenous anesthetics)、巴比妥类静脉麻醉药(barbiturate intravenousanesthetics)、苯二氮卓静脉麻醉药(benzodiazepine intravenous anesthetics)和阿片激动剂静脉麻醉药(opiate agonist intravenous anesthetics);血液学药物(hematological agents),如抗贫血药(antianemia agents)、造血抗贫血剂(hematopoietic antianemia agents)、凝血剂(coagulation agents)、抗凝剂(anticoagulants)、止血凝血剂(hemostatic coagulation agents)、血小板抑制凝血剂(platelet inhibitor coagulation agents)、溶栓酶凝血剂(thrombolytic enzymecoagulation agents)和血浆容量扩增剂(plasma volume expanders);激素和激素调节剂,如堕胎药(abortifacients)、肾上腺药(adrenal agents)、皮质类固醇肾上腺药(corticosteroid adrenal agents)、雄激素(androgens)、抗雄激素(anti-androgens)、降糖药(antidiabetic agents)、磺酰脲类降糖药(sulfonylurea antidiabetic agents)、抗低血糖药(antihypoglycemic agents)、口服避孕药(oral contraceptives)、孕激素避孕药(progestin contraceptives)、雌激素(estrogens)、生育药(fertility agents)、催产药(oxytocics)、甲状旁腺药(parathyroid agents)、垂体激素(pituitary hormones)、孕激素(progestins)、抗甲状腺药(antithyroid agents)、甲状腺激素(thyroid hormones)、和催产药(tocolytics);免疫生物制剂,如免疫球蛋白(immunoglobulins)、免疫抑制剂(immunosuppressives)、类毒素(toxoids)和疫苗(vaccines);局部麻醉药(localanesthetics),例如,酰胺类局部麻醉药(amide local anesthetics)和酯类局部麻醉剂(ester local anesthetics);肌肉骨骼药物(musculoskeletal agents),如抗痛风抗炎药(anti-gout anti-inflammatory agents)、皮质类固醇抗炎药(corticosteroid anti-inflammatory agents)、金复合抗炎药(gold compound anti-inflammatory agents)、免疫抑制抗炎药(immunosuppressive anti-inflammatory agents)、非甾体抗炎药(nonsteroidal anti-·inflammatory drugs)、水杨酸抗炎药(salicylate anti-inflammatory agents)、骨骼肌松弛剂(skeletal muscle relaxants)、神经肌肉阻滞剂骨骼肌松弛剂(neuromuscular blocker skeletal muscle relaxants)和反向神经肌肉阻滞剂骨骼肌松弛剂(reverse neuromuscular blocker skeletal muscle relaxants);神经药物(neurological agents),如抗惊厥剂(anticonvulsants)、巴比妥类抗惊厥剂(barbiturate anticonvulsants)、苯二氮卓类抗惊厥剂(benzodiazepineanticonvulsants)、抗偏头痛药(anti-migraine agents)、抗帕金森病药(anti-parkinsonian agents)、抗眩晕药(anti-vertigo agents)、阿片激动剂(opiateagonists)和阿片拮抗剂(opiate antagonists);眼科药物(ophthalmic agents),如抗青光眼药(anti-glaucoma agents)、抗青光眼药(anti-glaucoma agents)、有丝分裂剂(mitotics)、抗青光眼药物(anti-glaucoma agents)、散瞳药(mydriatics)、肾上腺素能激动剂散瞳剂(adrenergic agonist mydriatics)、抗毒蕈碱散瞳药物(antimuscarinicmydriatics)、眼科麻醉药(ophthalmic anesthetics)、眼部抗感染药(ophthalmic anti-infectives)、眼部氨基糖苷类抗感染剂(ophthalmic aminoglycoside anti-infectives)、眼部大环内酯类抗感染药(ophthalmic macrolide anti-infectives)、眼部喹诺酮类抗感染药物(ophthalmic quinolone anti-infectives)、眼部磺胺酰胺类抗感染药品(ophthalmic sulfonamide anti-infectives)、眼部四环素抗感染药(ophthalmictetracycline anti-infectives)、眼部抗炎药(ophthalmic anti-inflammatoryagents)、眼部皮质类固醇抗炎药(ophthalmic corticosteroid anti-·inflammatoryagents)和眼部非甾体抗炎药(ophthalmic nonsteroidal anti-inflammatory drugs);精神药物(psychotropic agents),如抗抑郁药(antidepressants)、杂环抗抑郁药(heterocyclic antidepressants)、单胺氧化酶抑制剂选择性血清素再吸收抑制剂三环类抗抑郁药(monoamine oxidase inhibitors selective serotonin re-uptakeinhibitors tricyclic antidepressants)、抗麻醉药(antimanics)、抗精神病药(anti-psychotics)、吩噻嗪类抗精神病药物(phenothiazine antipsychotics)、抗焦虑药(anxiolytics)、镇静药(sedatives)和安眠药(hypnotics)、巴比妥类镇静药和安眠药,苯二氮卓类抗焦虑药(benzodiazepine anxiolytics)、镇静剂(sedatives)和安眠药(hypnotics),以及精神刺激药(psychostimulants);呼吸道药物(respiratory agents),如镇咳药(antitussives)、支气管扩张剂(bronchodilators)、肾上腺素能激动剂支气管扩张剂(adrenergic agonist bronchodilators)、抗毒蕈碱支气管扩张药(antimuscarinicbronchodilators)、祛痰药(expectorants)、化痰药(mucolytic agents)、呼吸道抗炎药(respiratory anti-inflammatory agents)和呼吸道皮质类固醇抗炎药(respiratorycorticosteroid anti-inflammatory agents);毒理学药剂(toxicology agents),如解毒剂(antidotes)、重金属剂((heavy agents))、药物滥用药剂(substance abuse agents)、威慑性药物滥用药剂(deterrent substance abuse agents)和戒断性药物滥用剂(withdrawal substance abuse agents);矿物质;和维生素,例如,维生素A、维生素B、维生素C、维生素D、维生素E、和K。
来自上述类别的其它类别生物活性剂包括:(1)一般镇痛剂,例如利多卡因(lidocaine,)、其他“凯恩”(caine)镇痛剂或其衍生物,以及非甾体抗炎药(NSAID)镇痛剂,包括双氯芬酸(diclofenac)、布洛芬(ibuprofen)、酮洛芬(ketoprofen)和萘普生(naproxen);(2)阿片类激动剂镇痛剂(opiate agonist analgesics),如可待因(codeine)、芬太尼(fentanyl)、氢化吗啡酮(hydromorphone)和吗啡(morphine);(3)水杨酸类镇痛剂,如阿司匹林(ASA)(肠溶ASA);(4)H1-阻滞剂抗组胺药,如氯马斯汀(clemastine)和特非那定(terfenadine);(5)H2-阻滞剂抗组胺药,如西咪替丁(cimetidine)、法莫替丁(famotidine)、尼扎替丁(nizadine)和雷尼替丁(ranitidine);(6)抗感染药,如莫匹罗星(mupirocin);(7)抗厌氧菌抗感染药(antianaerobic anti-infectives),如氯霉素(chloramphenicol)和克林霉素(clindamycin);(8)抗真菌抗生素抗感染药(antifungal antibiotic anti-infectives),如两性霉素b(amphotericin b)、克霉唑(clotrimazole)、氟康唑(fluconazole)和酮康唑(ketoconazole);(9)大环内酯类抗生素抗感染药(macrolide antibiotic anti-infectives),如阿奇霉素(azithromycin)和红霉素(erythromycin);(10)其它抗生素抗感染药(miscellaneous antibiotic anti-infectives),如亚胺培南(imipenem);青霉素(penicillin),(11)抗生素抗感染药(antibiotic anti-infectives),如萘夫西林(nafcillin)、苯唑西林(oxacillin)、青霉素G和青霉素V;(12)喹诺酮类抗生素抗感染药(quinolone antibiotic anti-infectives),如环丙沙星(ciprofloxacin)和诺氟沙星(norfloxacin);(13)四环素类抗生素抗感染药(tetracycline antibiotic anti-infectives),如强力霉素(doxycycline)、米诺环素(minocycline)和四环素(tetracycline);(14)抗结核抗生素抗感染药(antituberculosisantimycobacterial anti-infectives),如异烟肼(isoniazid)和利福平(rifampin);(15)抗原生菌抗感染药(antiprotozoal anti-infectives),如阿托瓦松(atovaquone)和氨苯砜(dapsone);(16)抗疟抗原生动物抗感染药(antimalarial anti-protozoal anti-infectives),如氯喹(chloroquine)和乙胺嘧啶(pyrimethamine);(17)抗逆转录病毒抗感染药(anti-retroviral anti-infectives),如利托那韦(ritonavir)和齐多夫定(zidovudine);(18)抗病毒抗感染药,如无环鸟苷(acyclovir)、更昔洛韦(ganciclovir)、干扰素-y(ganciclovir)和金刚乙胺(rimantadine);(19)烷基化抗肿瘤药(alkylatingantineoplastic agents),如卡铂(carboplatin)和顺铂(cisplatin);(20)亚硝基脲烷基化抗肿瘤药(nitrosourea alkylating antineoplastic agents),如卡莫司汀(carmustine)(BCNU);(21)抗代谢抗肿瘤药(antimetabolite antineoplastic agents),如甲氨蝶呤(methotrexate);(22)嘧啶类似物抗代谢抗肿瘤药(pyrimidine analogantineoplastic agents),如氟尿嘧啶(fluorouracil)(S-FU)和吉西他滨(gemcitabine);(23)激素类抗肿瘤药(hormonal antineoplastics),如戈舍瑞林(goserelin)、亮丙瑞林(leuprolide)和他莫昔芬(tamoxifen);(24)天然抗肿瘤药(natural antineoplastics),例如,阿地白介素(aldesleukin)、白细胞介素-2(interleukin-2)、多西他赛(docetaxel)、依托泊苷(etoposide)、干扰素(interferon);紫杉醇(paclitaxel)、其他紫杉烷衍生物(taxane derivatives)和维甲酸(tretinoin)(ATRA);(25)抗生素类天然抗肿瘤药(antibiotic natural antineoplastics),如博莱霉素(bleomycin)、更生霉素(dactinomycin)、道诺霉素(daunorubicin)、阿霉素(doxorubicin)和丝裂霉素(mitomycin);(26)长春花生物碱天然抗肿瘤药(vinca alkaloid naturalantineoplastics),如长春碱和长春新碱;(27)自主神经系统作用物(autonomic agents),例如,烟碱(nicotine);(28)抗胆碱能自主神经系统作用物(anticholinergic autonomicagents),如苯托品(benztropine)和三己苯基(rihexyphenidyl);(29)抗肌氨酸自主神经系统作用物(anticholinergic autonomic agents),如阿托品(atropine)和奥昔布宁(oxybutynin);(30)麦角生物碱自主神经系统作用物(ergot alkaloid autonomicagents),例如,溴隐亭(bromocriptine);(31)胆碱能激动剂拟副交感神经药(cholinergicagonist parasympathomimetics),例如毛果芸香碱(pilocarpine);(32)胆碱酯酶抑制剂拟副交感神经药(cholinesterase inhibitor parasympathomimetics),例如吡啶斯的明(pyridostigmine);(33)α-阻滞剂抗交感神剂(α-blocker sympatholytics),例如,哌唑嗪(prazosin);(34)D-阻滞剂抗交感神剂(D-blocker sympatholytics),例如,阿替洛尔(atenolol);(35)肾上腺素能拟交感神经药(adrenergic sympathomimetics),例如沙丁胺醇(albuterol)和多巴酚丁胺(dobutamine);(36)心血管药(cardiovascular agents),如阿司匹林(ASA)(肠溶ASA);(37)D-阻滞剂抗心绞痛药(D-blocker antianginals),例如,阿替洛尔(atenolol)和普萘洛尔(propranolol);(38)钙通道阻滞剂抗心绞痛药(calciumchannel blocker antianginals),例如,硝苯地平(nifedipine)和维拉帕米(verapamil);(39)硝酸盐抗心绞痛药(nitrate antianginals),例如,二硝酸异山梨酯(ISDN);(40)心肌糖苷抗心律失常药(cardiac glycoside antiarrhythmics),例如,(41)I类抗心律失常药(class I antiarrhythmics),例如,利多卡因(lidocaine)、美西律(mexiletine)、苯妥英(phenytoin)、普鲁卡因胺(procainamide)和奎尼丁(quinidine);(42)II类抗心律失常药(class II antiarrhythmics),例如,阿替洛尔(atenolol)、美托洛尔(metoprolol)、普萘洛尔(propranolol)和噻吗洛尔(timolol);(43)III类抗心律失常药(class III antiarrhythmics),例如,乙胺碘呋酮(amiodarone);(44)IV类抗心律失常药(class IV antiarrhythmics),例如,地尔硫卓(diltiazem)和维拉帕米(verapamil);(45)降压药(antihypertensives),例如,哌唑嗪(prazosin);(46)血管紧张素转换酶抑制剂(ACE抑制剂)降压药(angiotensin-converting enzyme inhibitor(ACE inhibitor)antihypertensives),例如,卡托普利(captopril)和依那普利(enalapril);(47)降压药(antihypertensives),例如,阿替洛尔(atenolol)、美托洛尔(metoprolol)、纳多洛尔(nadolol)和普萘洛尔(propranolol);(48)钙通道阻滞剂抗高血压药(calcium-channelblocker antihypertensive agents),例如,地尔硫卓(diltiazem)和硝苯地平(nifedipine);(49)中枢作用肾上腺素能降压药(central-acting adrenergicantihypertensives),例如,氯压定(clonidine)和甲基多巴(methyldopa);(50)利尿降压药(diuretic antihypertensive agents),例如,阿米洛利(amiloride)、呋塞米(furosemide)、氢氯噻嗪(hydrochlorothiazide)(HCTZ)和螺内酯(spironolactone);(51)外周血管扩张剂降压药(peripheral vasodilator antihypertensives),例如,米诺地尔(minoxidil);(52)降脂药(antilipemics),例如,吉非罗齐(gemfibrozil)和普罗布考(probucol);(53)胆汁酸隔离剂降脂剂(bile acid sequestrant antilipemics),例如,胆甾胺(cholestyramine);(54)还原酶抑制剂降血脂剂(reductase inhibitorantilipemics),例如,洛伐他汀(lovastatin)和普伐他汀(pravastatin);(55)肌力药物(inotropes),例如,氨力农(amrinone)、多巴酚丁胺(dobutamine)和多巴胺(dopamine);(56)强心甙(cardiac glycoside inotropes),例如,(57)溶栓药(thrombolytic agents),例如,阿替普酶(alteplase)、阿尼普酶(anistreplase)、链激酶(streptokinase)和尿激酶(urokinase);(58)皮肤病药(dermatological agents),如秋水仙素(colchicine)、异维甲酸(isotretinoin)、甲氨蝶呤(methotrexate)、米诺地尔(minoxidil)、维甲酸(tretinoin),(59)皮质类固醇抗炎药(dermatological corticosteroid anti-inflammatory agents),如倍他米松(betamethasone)和地塞米松(dexamethasone);(60)抗真菌局部抗感染药(antifungal topical anti-infectives),如两性霉素(amphotericin)、克霉唑(clotrimazole)、咪康唑(miconazole)和制霉菌素(nystatin);(61)抗病毒局部抗感染药(antiviral topical anti-infectives),如无环鸟苷(acyclovir);(62)局部抗肿瘤药(topical antineoplastics),例如,(63)电解质和肾脏制剂(electrolytic and renal agents),如乳果糖(lactulose);(64)袢利利尿剂(loopdiuretics),例如,呋塞米(furosemide);(65)保钾利尿剂(potassium-sparingdiuretics),例如,氨苯蝶啶(triamterene);(66)噻嗪类利尿剂(thiazide diuretics),例如,氢氯噻嗪(hydrochlorothiazide)(HCTZ);(67)尿酸剂(uricosuric agents),例如,丙磺舒(probenecid);(68)酶和(69)溶栓酶(thrombolytic enzymes),例如,阿替普酶(alteplase)、阿尼普酶(anistreplase)、链激酶(streptokinase)和尿激酶(urokinase);(70)止吐药(antiemetics),例如,普鲁氯哌嗪(prochlorperazine);(71)水杨酸胃肠道抗炎性药物(salicylate gastrointestinal anti-inflammatory agents),例如,柳氮磺吡啶(sulfasalazine)(72)胃酸泵抑制剂抗溃疡药(gastric acid-pump inhibitor anti-ulcer agents),例如,奥美拉唑(omeprazole);(73)H2-阻滞剂抗溃疡剂(H2-blockeranti-ulcer agents),如西咪替丁(cimetidine)、法莫替丁(famotidine)、尼扎替丁(nizadine)和雷尼替丁(ranitidine);(74)助消化剂(digestants),例如,胰脂肪酶(pancrelipase);(75)胃肠动力药(prokinetic agents),例如,红霉素(erythromycin);(76)阿片激动剂静脉麻醉药(opiate agonist intravenous anesthetics),例如,芬太尼(fentanyl);(77)造血抗贫血剂(hematopoietic antianemia agents),如(G-CSF)和(GM-CSF);(78)凝血剂(coagulation agents),例如,因子1-10(AlIF 1-10);(79)抗凝剂(anticoagulants),例如,华法林(warfarin);(80)溶栓酶凝血剂(thrombolytic enzymecoagulation agents),例如,阿替普酶(alteplase)、阿尼普酶(anistreplase)、链激酶(streptokinase)和尿激酶(urokinase);(81)激素和激素调节剂,例如,溴隐亭(bromocriptine);(82)堕胎药(abortifacients),例如,甲氨蝶呤(methotrexate);(83)降糖药(antidiabetic agents),例如,胰岛素(insulin);(84)口服避孕药(oralcontraceptives),例如,雌激素(estrogen)和孕激素(progestin);(85)孕激素避孕药(progestin contraceptives),例如,左炔诺孕酮(levonorgestrel)和甲基炔诺酮(norgestrel);(86)雌激素(estrogens),例如,共轭雌激素(conjugated estrogens)、己烯雌酚(diethylstilbestrol)(DES)、雌激素(雌二醇(estradiol)、雌酮(estrone)和硫酸雌酮哌嗪(estropipate));(87)生育药(fertility agents),例如,克罗米酚(clomiphene)、人绒毛膜促性腺激素(human chorionic gonadotropin)(HCG)和尿促性素(menotropins);(88)甲状旁腺药(parathyroid agents),例如,降钙素(calcitonin);(89)垂体激素(pituitary hormones),例如,去氨加压素(desmopressin)、戈舍瑞林(goserelin)、催产素(oxytocin)和加压素(vasopressin)(ADH);(90)孕激素(progestins),例如,甲孕酮(medroxyprogesterone)、炔诺酮(norethindrone)和孕酮(progesterone);(91)甲状腺激素(thyroid hormones),例如,左甲状腺素(levothyroxine);(92)免疫生物制剂(immunobiologic agents),例如,干扰素β-1b和干扰素γ-1b;(93)免疫球蛋白(immunoglobulins),例如,免疫球蛋白1M、IMIG、IGIM和免疫球蛋白IVIG;(94)酰胺类局部麻醉药(amide local anesthetics),例如,利多卡因(lidocaine);(95)酯类局部麻醉剂(ester local anesthetics),例如,苯佐卡因(benzocaine)和普鲁卡因(procaine);(96)肌肉骨骼皮质类固醇抗炎药(musculoskeletal corticosteroid anti-inflammatoryagents),如倍氯米松(beclomethasone)、倍他米松(betamethasone)、可的松(cortisone)、地塞米松(dexamethasone)、氢化可的松(hydrocortisone)和泼尼松(prednisone);(97)肌肉骨骼抗炎免疫抑制剂(musculoskeletal anti-inflammatory immunosuppressives),如硫唑嘌呤(azathioprine)、环磷酰胺(cyclophosphamide)和甲氨蝶呤(methotrexate);(98)肌肉骨骼非甾体抗炎药(musculoskeletal nonsteroidal anti-inflammatorydrugs),如双氯芬酸(diclofenac)、布洛芬(ibuprofen)、酮洛芬(ketoprofen)、酮咯酸(ketorlac)和萘普生(naproxen);(99)骨骼肌松弛剂(skeletal muscle relaxants),例如,安定(diazepam);(100)反向神经肌肉阻滞剂骨骼肌松弛剂(reverse neuromuscularblocker skeletal muscle relaxants),例如,吡啶斯的明(pyridostigmine);(101)神经药物(neurological agents),例如,尼莫地平(nimodipine)、利鲁唑(riluzole)、他克林(tacrine)和噻氯匹定(ticlopidine);(102)抗惊厥剂(anticonvulsants),例如,卡马西平(carbamazepine)、加巴喷丁(gabapentin)、拉莫三嗪(lamotrigine)、苯妥英(phenytoin)和丙戊酸(valproic acid);(103)巴比妥类抗惊厥剂(barbiturate anticonvulsants),例如,苯巴比妥(phenobarbital)和普利米酮(primidone);(104)苯二氮卓类抗惊厥剂(benzodiazepine anticonvulsants),例如,氯硝西泮(clonazepam)、地西泮(diazepam)和劳拉西泮(lorazepam);(105)抗偏头痛药(anti-migraine agents),例如,溴隐亭(bromocriptine)、左旋多巴(levodopa)、卡比多巴(carbidopa)和培高利特(pergolide);(106)抗眩晕药(anti-vertigo agents),如敏可静(meclizine);(107)阿片激动剂(opiateagonists),如可待因(codeine)、芬太尼(fentanyl)、氢化吗啡酮(hydromorphone)、美沙酮(methadone)和吗啡(morphine);(108)阿片拮抗剂(opiate antagonists),例如,纳诺酮(naloxone);(109)抗青光眼药(anti-glaucoma agents),如噻吗洛尔(timolol);(110)有丝分裂抗青光眼药(mitotic anti-glaucoma agents),如毛果芸香碱(pilocarpine);(111)眼部氨基糖苷类抗感染剂(ophthalmic aminoglycoside anti-infectives),例如,庆大霉素(gentamicin)、新霉素(neomycin)和妥布霉素(tobramycin);(112)眼部喹诺酮类抗感染药物(ophthalmic quinolone anti-infectives),如环丙沙星(ciprofloxacin)、诺氟沙星(norfloxacin)和氧氟沙星(ofloxacin);(113)眼部皮质类固醇抗炎药(ophthalmiccorticosteroid anti-·inflammatory agents),如地塞米松(dexamethasone)和泼尼松龙(prednisolone);(114)眼部非甾体抗炎药(ophthalmic nonsteroidal anti-inflammatory drugs),如双氯芬酸(diclofenac);(115)抗精神病药(anti-psychotics),例如氯氮平(clozapine)、氟哌啶醇(haloperidol)和利培酮(risperidone);(116)苯二氮卓类抗焦虑药、镇静剂和安眠药(benzodiazepine anxiolytics,sedatives andhypnotics),例如,氯硝西泮(clonazepam)、地西泮(diazepam)、劳拉西泮(lorazepam)、去甲羟安定(oxazepam)和普拉西泮(prazepam);(117)精神刺激药(psychostimulants),例如,哌甲酯(methylphenidate)和培莫林(pemoline);(118)例如,可待因(codeine);(119)支气管扩张剂(bronchodilators),例如,(120)肾上腺素能激动剂支气管扩张剂(adrenergic agonist bronchodilators),例如,沙丁胺醇(albuterol);(121)呼吸道皮质类固醇抗炎药(respiratory corticosteroid anti-inflammatory agents),例如,地塞米松(dexamethasone);(122)解毒剂(antidotes),例如,氟马西尼(flumazenil)和纳诺酮(naloxone);(123)重金属剂(heavy metal agents),例如,青霉胺(penicillamine);(124)威慑性药物滥用药剂(deterrent substance abuse agents),例如,二硫仑(disulfiram)、纳曲酮(naltrexone)和烟碱(nicotine);(125)戒断性药物滥用剂(withdrawal substanceabuse agents),例如,溴隐亭(bromocriptine);(126)矿物质,例如,铁、钙和镁;(127)维生素B化合物,如氰钴胺(cyanocobalamin)(维生素B12)和烟酸(维生素B3);(128)维生素C化合物,如抗坏血酸(ascorbic acid);和(129)维生素D,如骨化三醇。
此外,可以使用重组或细胞衍生蛋白质,例如重组β-葡聚糖;牛免疫球蛋白浓缩物;牛超氧化物歧化酶;含有氟尿嘧啶、肾上腺素和牛胶原蛋白的制剂;重组水蛭素(r-Hir)、HIV-1免疫原;重组人生长激素重组EPO(recombinant human growth hormonerecombinant EPO,r-EPO);基因活化EPO(GA-EPO);重组人血红蛋白(r-Hb);重组人美卡舍明(recombinant human mecasermin)(r-1GF-1);重组干扰素α;来格司亭(lenograstim)(G-CSF);奥氮平(olanzapine);重组促甲状腺激素(r-TSH);和拓扑替康(topotecan)。
此外,还可以使用下面列出的肽、蛋白质和其他大分子,例如白介素(interleukins)1至18,包括突变体和类似物;干扰素a、y,可用于软骨再生、激素释放激素(hormone releasing hormone)(LHRH)和类似物、促性腺激素释放激素转化生长因子(gonadotropin releasing hormone transforming growth factor)(TGF);纤维母细胞生长因子(fibroblast growth factor)(FGF);肿瘤坏死因子-α);神经生长因子(NGF);生长激素释放因子(GHRF)、表皮生长因子(EGF)、结缔组织活化成骨因子、成纤维细胞生长因子同源因子(FGFHF);肝细胞生长因子(HGF);胰岛素生长因子(IGF);侵袭抑制因子-2(IIF-2);骨形态生成蛋白(bone morphogenetic proteins)1-7(BMP 1-7);生长抑素;胸腺肽-a-y-球蛋白;超氧化物歧化酶(SOD);和补体因子,以及这些因子(例如生长因子)的生物活性类似物、片段和衍生物。
转化生长因子(TGF)超基因家族的成员是多功能调节蛋白,可以掺入聚合物基质中。TGF超基因家族的成员包括β-转化生长因子(例如TGF-131、TGF-132、TGF-133);骨形态生成蛋白(例如,BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素结合生长因子(例如,纤维母细胞生长因子(FGF)、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、胰岛素样生长因子(IGF))(例如,抑制素A、抑制素B)、生长分化因子(例如GDF-1);和激活素(例如,激活素A、激活素B、激活素AB)。生长因子可以从天然或自然来源分离,例如从哺乳动物细胞分离,也可以通过合成方法制备,例如通过重组DNA技术或各种化学过程制备。此外,可以使用这些因子的类似物、片段或衍生物,只要其呈现出天然分子的至少一些生物活性。例如,类似物可以通过表达通过位点特异性突变或其他基因工程技术改变的基因来制备。
本文所公开的方法、药物组合物和化合物可以进行结合以提供一种、两种或更多种本文公开的化合物,其可选地与例如马里巴韦(maribavir)、膦甲酸、GCV和/或来特莫韦(letermovir)。
可以使用各种形式的生物活性剂。这些生物活性剂包括但不限于:无电荷分子、分子复合物、盐、醚、酯、酰胺、前药形式等形式,当植入、注射或以其他方式置于对象体内时被生物活化。
包括以下示例,以指导本领域普通技术人员实践本公开主题的代表性实施方式。根据本公开以及本领域的一般技能水平,本领域技术人员能够理解以下实施例仅用于示例,并且可采用多种改变、修改以及变化,而不偏离本公开的范围。以下合成描述和具体实施例仅用于说明的目的,不应解释为以任何方式限制通过其他方法制备本公开的化合物。
实施例
实施例1
材料和方法
化合物:这些化合物是由高通量筛选(HTS)识别出来的,然后使用多种HCMV株、多种抗病毒检测和新型化合物制备进行验证。除了从筛选时所用的库中获得的化合物外,NFU1827在威斯康星医学院化学生物学专业生物化学系(Department of Biochemistry,Program in Chemical Biology at the Medical College of Wisconsin)合成,MLS8091购自普林斯顿生物分子研究公司(Princeton Biomolecular Research,Inc.),MLS8969购自加利福尼亚州圣地亚哥ChemBridge公司,ML S8554购自InterBioScreen STOCK1N-59867,NCGC2955由约翰·霍普金斯大学医学院化学中心(Chemistry Core,Johns HopkinsUniversity School of Medicine)合成。使用Phenomenex Luna C 183.0x75mm色谱柱,在含0.05%v/vTFA的H2O中以4-100%ACN的7分钟梯度,或使用希金斯分析股份有限公司(Higgins Analytical,Inc.)Targa C l8 5μm 4.6x150mm柱,在含0.01%TFA的H2O中以0-100%ACN的30分钟梯度,并且在254nm处进行吸光度检测或蒸发光散射检测,通过HPLC来测定用于生物试验的所有合成和购买化合物的纯度。生物试验中使用的所有化合物的NMR和MS数据与其结构一致,并且通过HPLC测定的纯度>95%。
将化合物溶解在二甲基亚砜(DMSO)中,并将50和10mM的储备溶液储存在-80℃下。更昔洛韦(Ganciclovir)购自西格玛奥德里奇公司(Sigma Aldrich)(密苏里州圣路易斯),在ddH2O中制备10mM储备溶液。
NCGC2955的合成:4-(异丙基氨甲酰基)哌啶-1-羧酸叔丁酯(1)。向含1-(叔丁氧羰基)哌啶-4-羧酸35(3.94g,17.2mmol,1.0当量)的CH2Cl2(39mL)溶液中添加N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(3.46g,18.0mmol,1.05当量)、1-羟基苯并三唑一水合物(2.83g,18.5mmol,1.075当量)和异丙胺(5.1mL,60.15mmol、3.5当量)。在室温下搅拌21h后,反应用CH2Cl2稀释,并用5%HCl水溶液洗涤。用CH2Cl2(3x20mL)萃取水性层。合并有机层,用无水MgSO4干燥,并在真空中浓缩。通过快速色谱法(0至100%EtOAc/己烷)纯化,以63%的产率提供2.95g固体化合物1。1H NMR(500MHz,CDCl3)δ5.28(d,J=6.45Hz,lH),4.01-4.25(m,3H),2.73(br.s.,2H),2.16(tt,J=3.69,11.63Hz,lH),1.79(d,J=11.32Hz,2H),1.61(dq,J=4.24,12.42Hz,2H),1.45(s,9H),1.14(d,J=6.60Hz,6H)。
N-异丙基哌啶-4-甲酰胺三氟乙酸盐(2)。在室温下,向含化合物1(2.95g,10.9mmol)的CH2Cl2(5mL)溶液中加入三异丙基硅烷(250μL)和三氟乙酸(3mL)。在室温下搅拌24小时后,在真空中去除挥发物,提供粘性浆料,而无需进一步纯化即可使用。lH NMR(500MHz,CDC13)δ4.06(qd,J=6.86,13.38Hz,lH),3.57(d,J=12.89Hz,2H),3.10(br.s.,2H),2.45-2.63(m,lH),2.05-2.16(m,4H),1.18(d,J=6.60Hz,6H)。
4-(4-氯苄基)-4H-噻吩并[3,2-b]吡咯-5-羧酸甲酯(3)。在室温下向无水DMF(10mL)中的4H-噻吩并[3,2-b]吡咯-5-羧酸甲酯36(1.44g,7.99mmol,1.0当量)和碳酸铯(3.91g,12.0mmol,1.5当量)的悬浮液中一次性添加4-氯苄基溴化物(1.97g,9.59mmol,1.2当量)。在室温下搅拌直至完成(约4小时)后,反应用水稀释,并用EtOAc(3x20 mL)萃取。合并有机层,用盐水洗涤,用无水MgSO4干燥,并在真空中浓缩。通过快速色谱法(3m 0%,6m梯度0至50%,2m 50%EtOAc/己烷)纯化,以98%的产率提供2.40g淡黄色固体的甲基酯3。lHNMR(500MHz,CDC13)δ7.33(d,J=5.34Hz,1H),7.21-7.29(m,3H),7.05(d,J=8.17Hz,2H),6.85(d,J=5.50Hz,lH),5.71(s,2H),3.83(s,3H)。
4-(4-氯苄基)-4H-噻吩并[3,2-b]吡咯-5-羧酸(4)。向THF(1252mL)和MeOH(12mL)中的甲基酯3(3.58g,11.7mmol,1.0当量)的混合物中一次性添加水中的一水合氢氧化锂溶液(12mL)。在室温下快速磁力搅拌2天后,起始材料被消耗,并在真空中去除有机溶剂。用水(约20mL)稀释剩余水溶液,并在强烈的磁力搅拌下,用浓HCl水溶液将pH调节为pH=1。在酸化期间形成沉淀物,通过真空过滤收集,用水洗涤并在真空下干燥,以98%的产率提供3.34g化合物4。1H NMR(500MHz,DMSO-d6)δ12.57(br.s.,IH),7.56(d,J=5.19Hz,1H),7.29-7.43(m,J=8.49Hz,2H),7.17-7.29(m,2H),7.05-7.17(m,J=8.49Hz,2H),5.76(s,2H)。
1-(4-(4-氯苄基)-4H-噻吩并[3-b]吡咯-5-羰基)-N-异丙基哌啶-4-甲酰胺(NCGC2955)。向CH2Cl2(1.7mL)中的化合物4(51.9mg,0.177mmol,1.0当量)的混合物中添加N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(37.5mg,0.19mmol,1.1当量)、1-羟基苯并三唑一水合物(31.0mg,0.204mmol,1.15当量)和二异丙基乙胺(123μL,0.71mmol、4当量)。在室温下搅拌5分钟后,添加TFA盐2(60.7mg,0.21mmol,1.2当量)作为CH2Cl2中的溶液(0.2mL,加上0.2mL漂洗),并在室温下搅拌反应。24小时后,反应用CH2Cl2稀释,并用5%HCl水溶液洗涤。用EtOAc(3x10mL)萃取水层。合并有机层,用无水MgSO4干燥,并在真空中浓缩。通过快速色谱法(0至100%EtOAc/己烷)纯化,以62%的产率提供48.9mg白色固体NCGC2955。1H NMR(500MHz,CDCl3)δ7.24(d,J=8.33Hz,2H),7.18(d,J=5.19Hz,lH),7.08(d,J=8.33Hz,2H),6.83(d,J=5.19Hz,lH),6.58(s,lH),5.43(s,2H),5.19(d,J=8.02Hz,lH),4.44(d,J=12.89Hz,2H),4.08(qd,J=6.77,13.34Hz,lH),2.92(t,J=12.34Hz,2H),2.24(tt,J=3.62,11.08Hz,lH),1.80(d,J=14.93Hz,2H),1.43-1.63(m,6H),1.15(d,J=6.60Hz,6H)。
NFU1827的合成:4-(4-甲氧基苯基)-7-硫杂-2,5-二氮杂三环[6.4.0.02,6]十二碳-1(8),3,5,9,11-五烯-10-羧酸(5)。将2-氨基苯并噻唑-6-羧酸(2.0g,10.30mmol,1.0当量)和2-溴-4'-甲氧基苯乙酮(2.60g,11.33mmol,1.1当量)填装入压力瓶并悬浮于2-甲氧基乙醇(50mL)中。悬浮液加热至40℃,120小时,并且在140℃加热19小时。允许反应冷却至室温并在真空中浓缩。粗制化合物通过快速柱色谱(5至75%EtOAc/己烷)纯化,以55%的产率提供1.83g化合物6。1H NMR(500MHz,DMSO-d6)δ13.17(broads,lH),8.69(s,lH),8.63(d,J=1.2Hz,lH),8.10(dd,J=1.6,8.3Hz,lH),8.01(d,J=8.4Hz,lH),7.78(d,J=8.7Hz,lH),6.99(d,J=8.8Hz,lH),3.77(s,3H)。
N-[3-(4-乙基哌嗪-1-基)丙基]-4-(4-甲氧基苯基)-7-硫杂-2,5-二氮杂三环[6.4.0.02,6]十二碳-1(8),3,5,9,11-五烯-10-甲酰胺(NFU1827)。将化合物5(100mg,0.308mmol)、N-(3-二甲基氨基丙基)-N'-乙基碳化二亚胺盐酸盐(118.2mg,0.617mmol)和1-羟基苯并三唑水合物(83.3mg,0.617mmol)溶解于DMF中,并在室温下搅拌1小时。然后反应用3-(4-乙基哌嗪-1-基)丙-1-胺(0.2269mL,211.2mg,1.23mmol)处理,并在室温下搅拌18小时。然后将反应倒入H2O(20mL)中。其用EtOAc(3x20mL)萃取。合并的萃取物用H2O(4x20mL)洗涤,随后用盐水(1x20mL)洗涤。有机层进行干燥(Na2SO4),过滤,并以真空除去溶剂。粗制化合物通过快速柱色谱,使用EtOAc/己烷(90:10至0:100的梯度洗脱)纯化,以41%的产率提供60mg NFU1827。lH NMR(500MHz,CDCl3)δ8.71(s,lH),8.21(s,lH),7.99(d,J=8.4Hz,lH),7.91(s,lH),7.80(d,J=8.7Hz,2H),7.62(d,J=8.4Hz,lH),6.96(d,J=8.7Hz,2H),3.85(s,3H),3.60(q,J=5.2Hz,2H),2.63(t,J=5.5Hz,2H),2.46(q,J=7.3Hz,2H),1.82(m,2H),1.78(broads,8H),1.10(t,J=7.2Hz,3H)。13CNMR(126MHz,CDCl3)δ162.72,156.34,145.14,130.89,128.49,127.24,123.49,123.25,122.78,120.26,111.13,109.09,102.92,57.32,55.69,52.27,50.25,49.91,49.39,38.42,26.62,20.55,17.98,11.12.C26H31N5O2S[M+H]+的HRMS(ESI+)m/z计算为478.2272,实测为478.2271。
细胞:人包皮成纤维细胞(HFFs),第12-16代;(ATCC,CRL-2088)在37℃下在5%的CO2培养箱中,在含有10%胎牛血清(FBS)的达尔伯克氏改良伊格尔培养基(Dulbecco'smodified Eagle medium)(DMEM)(加利福尼亚卡尔斯巴德Gibco公司)中生长。用小鼠胚胎成纤维细胞(MEF,ATCC,CRL-1658)感染小鼠CMV。Vero细胞从约翰·霍普金斯大学医学院加里·海沃德博士的实验室获得。
细胞毒性试验:MTT试验按照制造商的说明(西格玛奥德里奇公司)所述进行。未感染细胞用化合物处理72小时或10天(抗病毒试验的相同时间点),并向各孔中添加20μL/孔的MTT[3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-溴化四唑,5mg/mL磷酸盐缓冲盐水(PBS)溶液]。在150rpm下振摇5分钟后,板在37℃下培养2-3小时。黄色溶液通过活细胞线粒体脱氢酶转化为深蓝色甲(formazan)通过测量560nm处的吸光度来进行定量。
病毒和抗病毒试验:报道了在UL99(pp28)晚期启动子控制下表达荧光素酶的重组pp28荧光素酶Towne HCMV株,为药物筛选提供了高度敏感的可重复报告基因(reproducible reporter)20。报道了一种在UL97中含有C607Y突变的耐GCV的HCMV pp28荧光素酶37。HCMV TB40菌株获取自ATCC(VR-1578)。人类疱疹病毒1型和2型(HSV1、HSV2)的临床分离物从约翰·霍普金斯微生物实验室收集,没有能够将其与特定患者联系起来的标识。小鼠CMV(MCMV)Smith株(ATCC VR-1399)用于MEF感染。
荧光素酶活性:如前所述,在72hpi下收集细胞裂解物,并使用Glomax Multi+检测系统(威斯康星州麦迪逊市普洛麦格公司(Promega))来测定荧光素酶活性20。
斑块减少试验:将HFF接种到12孔板中(2x105个细胞/孔),并以约100个斑块/孔感染HCMV TB40。90分钟后,对培养基进行抽气,将含有0.5%羧甲基纤维素(CMC)、4%胎牛血清(FBS)和药物的DMEM添加到两个复孔中。在37℃下培养10-12天后,去除覆盖层,并在结晶紫染色后对斑块进行计数。对于Vero细胞中的HSV1和HSV2复制,吸附时间为60分钟,36小时后对斑块进行计数。3天后完成MEF中的斑块试验。
裂解EB病毒(EBV)复制的抑制:用100μg/ml山羊抗人IgG(西格玛公司(Sigma))诱导潜伏感染EBV的Akata细胞(24孔板0.5xl06/孔)。在添加人IgG后,立即将化合物和GCV对照添加到三个孔中。裂解诱导48小时后收集细胞用于DNA定量。使用Wizard SV Genomic试剂盒(威斯康星州麦迪逊市普洛麦格公司)来纯化细胞DNA。这些化合物对EBV裂解诱导的影响通过EBV DNA聚合酶基因BALF538的实时PCR进行分析。
另加和去除试验:进行这些试验以识别HCMV复制期间化合物具有最高活性的阶段。在另加组中,在0、6、24和48hpi将化合物添加到感染的HFF中,并在72hpi测量荧光素酶活性。在去除组中,在病毒感染后立即添加化合物,然后在0、6、24和48小时后去除;在72hpi测定荧光素酶。
DNA分离和实时定量(qPCR):使用Wizard SV基因组DNA分离试剂盒(威斯康星州麦迪逊市普洛麦格公司)从未感染的对照和HCMV感染的HFF中分离出总DNA。为了确定上清液中的病毒载量,使用BioRobot M48仪器(加利福尼亚州巴伦西亚凯杰公司(Qiagen))上的自动DNA提取从上清液分离出总DNA。使用了针对来自CMV基因组的高度保守US 17区域的151bp的US 17实时PCR试验39。US 17的引物和探针为:
正向5'-GCGTGCTTTTTAGCCTCTGCA-3'(SEQ ID NO:1),
反向5'-AAAAGTTTGTGCCCCAACGGTA-3'(SEQ ID NO:2),和
US17探针FAM 5'-TGATCGGGCGTTATCGCGTTCT-3'(SEQ ID NO:3)。
HCMV进入和间接免疫荧光试验:使用MLS8969、GCV和肝素对照来测定HCMV进入的抑制。化合物在无血清培养基中稀释,并在感染前24小时添加到接种在载玻片上的HFF中。在感染(MOI 1或0.1PFU/细胞)2小时后,用100%冷冻甲醇固定细胞,用磷酸盐缓冲盐水(PBS)、5%血清、0.3%Triton X-100封闭细胞1小时。然后细胞与1:50小鼠单克隆抗pp65抗体(加利福尼亚伯林盖姆载体实验室公司(Vector Laboratories))在37℃的加湿室中培养1小时,用TBST(0.1%)洗涤三次,用1:500罗丹明偶联抗小鼠IgG(西格玛公司)在37℃下在加湿室内培养1小时,并用TBST(0.1%)洗涤。在用蔡司ZI荧光显微镜可视化之前,向载玻片中加入含有DAPI的镜油(加州圣克鲁斯市圣克鲁斯生物技术公司(Santa CruzBiotechnology))液滴。以40倍放大率拍摄图像。
SDS聚丙烯酰胺凝胶电泳和免疫印迹分析:将含有等量蛋白质的细胞裂解物与等体积的样品缓冲液(125mM Tris-HCL,pH 6.8,4% SDS,20%甘油和5%β-巯基乙醇)混合,并在100℃下沸腾10分钟。变性蛋白质在Tris-三甘氨酸聚丙烯酰胺凝胶(8-10%)中解析,并通过电印迹法转移到聚偏二氟乙烯(PVDF)膜(加利福尼亚州赫拉克勒斯市伯乐实验室(Bio-Rad Laboratories))。膜在封闭溶液[5%w/v脱脂奶粉和含0.1%吐温-20的PBS(PBST)]中培养1小时,用PBST洗涤,并在4℃下与一抗培养过夜。膜用PBST清洗,并在室温下用PBST中的辣根过氧化物酶偶联二抗培养1小时。用PBST洗涤后,使用SuperSignal WestDura和Pico试剂(伊利诺斯州罗克富德的皮尔斯化学公司(Pierce Chemical))通过化学发光使蛋白质条带显示。
抗体:使用以下抗体——小鼠单克隆抗HCMV IEl和IE2(MAB810,马萨诸塞州比尔里卡的密理博公司(Millipore))、小鼠单克隆抗-HCMV UL83(pp65,加利福尼亚伯林盖姆载体实验室公司)、小鼠单克隆抗体HCMV UL44、小鼠单克隆抗-HCMV UL84和小鼠抗-肌动蛋白抗-小鼠IgG(加州圣克鲁斯市的圣克鲁斯生物技术公司)。辣根过氧化物酶(HRP)偶联的抗小鼠IgG来自GE医疗公司(GE Healthcare)(威斯康星州沃基肖)。辣根过氧化物酶(HRP)偶联的抗兔IgG来自细胞信号公司(Cell Signaling)(马萨诸塞州贝弗利)。
药物组合与分析:这些实验按照之前报告40的来进行。使用pp28荧光素酶测试GCV和各化合物的组合。简而言之,2x106 HFF/板接种在96孔板中,并感染pp28荧光素酶TowneHCMV株(MOI=1)。首先,分别为各药物单独生成剂量-反应曲线,以确定其EC50。然后,药物以其EC50的两倍组合,用4%FBS在DMEM中稀释,然后进行连续稀释,并在感染后一起添加。组合和各药物单独的荧光素酶活性在72hpi定量。使用TB40通过斑块试验测试来特莫韦和各新型化合物的组合。同样的原理适用于药物组合效果的试验,并且在8dpi对斑块进行计数。使用Bliss模型计算各药物组合对pp28荧光素酶活性和斑块减少的影响。在该模型中,药物组合表示两个概率独立事件的乘积,如以下等式所述41:
其中D是药物浓度,m是斜率,EC50是导致50%病毒抑制的有效浓度。两种抑制剂(Fu,未受影响分数)的组合效果计算为两种抑制剂Fu1和Fu2的单独效果的乘积。如果观察到的抑制倍数除以预期抑制倍数的比率大于1,则化合物是协同的。如果比率小于1,则组合被视为是拮抗的,如果等于1,则组合是相加的。
统计学分析:使用Sigmaplot(加利福尼亚州圣何塞Systat Software公司)和GraphPad Prism(加利福尼亚拉霍拉GraphPad-Software公司)进行斯氏t检验。使用单向ANOVA将所有样本组与对照组进行比较。对P值进行调整用于多重比较。在所有附图中,遵循了以下惯例。*表示p值<0.05,**表示p值<0.01,***表示p值<0.001。曲线拟合工具箱、MATLAB软件(v7.10)、MathWorks(Natick,MA)用于通过四参数逻辑回归确定EC50和CC50值。
实施例2
用于HCMV抑制剂的高通量筛选:pp28-HCMV荧光素酶已被证明为用化合物抑制HCMV提供了高度可重复且敏感的结果,用于筛选370000种化合物的MLSMR收集、65000种化合物的NCGC多样性收集以及批准和研究的药物的NCGC药物收集。使用感染前镀覆的2种化合物剂量进行筛选,并在感染后72小时(hpi)检测裂解物的荧光素酶活性。使用公布的化合物剂量-反应曲线算法21,选出总计2215个HCMV荧光素酶抑制剂。进行二次筛选以去除在人包皮成纤维细胞(HFF)中显示出毒性的化合物,产生847个经证实的无毒HCMV抑制剂(图1)。
通过HCMV的pp28重组Towne和pp28耐GCV Towne菌株的荧光素酶活性(72hpi)以及使用HCMV Towne或TB40的斑块减少(10天)来测量HCMV抑制。病毒蛋白表达通过Western印迹分析进行测定。在未感染的HFF中进行比色MTT试验,以与感染性试验平行确定细胞毒性,即在72小时和10天时,并且表示为CC50。所有5种化合物在亚μM至低μM浓度下对所有使用的HCMV菌株都具有活性。基于斑块减少,MLS8969对HCMV的活性最好,其次是MLS8091、MLS8554、NCGC2955和NFU1827(表1)。
表1. 5种化合物对不同HCMV菌株的抗HCMV活性、毒性和斜率
*=预处理,随后进行斑块减少试验
**=斑块减少试验
计算各化合物的斜率参数(类似于希尔系数)。1的斜率表示一个结合位点或非协同性。当一个位点处的结合增加了另一个位点处配体结合的亲和力时,存在正协同性(斜率>1)。如果一个位点处的结合使另一位点处配体的亲和力降低,则化合物表现出负协同性(斜率<1)。对于其他慢性病毒感染,如HIV,发现斜率不仅是区分药物类别和已知作用机制的重要因素,而且还有助于降低抗病毒活性,甚至耐药病毒突变体22、23的EC50不变。基于斑块减少试验,除MLS8969外,所有化合物的斜率均为1。
实施例3
其它疱疹病毒的抑制:用这五种化合物测试对单纯性疱疹病毒1和2(HSV1、HSV2)、EB病毒(EBV)和小鼠CMV(MCMV)的抑制。斑块减少试验用于HSV1、HSV2和MCMV。IgG诱导后,通过实时PCR检测AKATA细胞中裂解EBV复制的抑制。只有MLS8554对HS1I、HSV2和MCMV有活性(表2)。
表2.五种化合物对其它疱疹病毒的活性;NA-没有活性;CI-临床分离物
NCGC2955对MCMV有活性(EC50为1μM,表2),但在10μM和更高浓度下观察到对MEF的毒性。NFU1827显示出对EBV的活性(EC50-1.92±0.1μM)。其它化合物具有对HCMV的特异性活性,但并未抑制HSV1或MCMV。
实施例4
HCMV抑制的时间:进行另加和去除试验。化合物在0、6、12、24、36和48hpi添加或去除,并在72hpi测量荧光素酶活性。基于这些试验,各化合物具有特定的最大活性时间,基于最大病毒抑制的时间在记录为如下。
实施例5
HCMV进入的抑制:化合物MLS8969在以1PFU/细胞的MOI感染后,首先在72hpi使用荧光素酶试验进行测试,但观察到荧光素酶酶活性的最小降低(图3A)。.然而,斑块试验显示出MLS8969的良好抗HCMV活性(图3B)。
因为在高通量筛选中,HFF在感染前用化合物进行处理(预处理),并且我们的斑块试验(感染后添加MLS8969)显示出EC50为0.12±0.02μM(表1),我们怀疑荧光素酶活性抑制缺乏可能代表MOI依赖性现象,因此暗示进入抑制24。因此,试验使用0.01、0.1和1PFU/细胞的MOI(图3C)进行,并在感染前添加MLS8969。观察到荧光素酶活性的MOI依赖性抑制(图3C)。在斑块减少试验中,用MLS8969预处理也抑制了TB40和耐GCV的HCMV Towne(图3D、3E)。Western印迹分析证实了这些数据并未显示出在1PFU/细胞的MOI后处理或预处理下的病毒蛋白表达抑制,而在低MOI(0.01)感染后的预处理导致IEl/2、pp65、UL84和UL44蛋白水平降低(图3F)。通过HCMV pp65的间接免疫荧光试验(IFA)获得MLS8969为进入抑制剂的进一步证据(图4)。MLS8969仅在0.1的MOI时抑制HCMV进入;无论MOI如何,GCV均不影响pp65核染色(图4)。肝素(阳性对照)抑制HCMV进入。
实施例6
HCMV复制的即早早期阶段(immediate early-to early stage)的抑制剂:两种化合物在0至24hpi显示出抗HCMV活性(NFU1827和MLS8554)。NFU1827仅对HCMV和GCV-R HCMV具有活性,EC50分别为0.85±0.1和0.84±0.1μM(表1,图5A和B),但对MCMV或HSV1没有活性(表2)。另加和去除试验表示活性的即早早期时间。当24小时后添加到感染的细胞中时,其失去了抑制HCMV的能力。6小时后去除NFU1827已经实现了显著的HCMV抑制(图5C&D)。NFU1827降低了IE1和IE2的水平(图5E)。根据其即早早期活性,上清液中的病毒DNA复制和DNA产量显著降低(图5F&G)。
MLS8554在所有抑制HCMV、GCV-R HCMV,MCMV和HSV1的抗病毒试验中有活性(图6,表1和表2)。在感染后的即早早期时间测定其最大活性。.当在24hpi或之后添加时,其活性显著降低,当在6小时去除时,HCMV抑制已接近完成(图6C&D)。72hpi的Western印迹分析显示出IE2、UL44、UL84和pp65的表达降低(图6E)。与减少IE1和IE2两者的NFU1827相比,MLS8554主要减少IE2表达。病毒DNA复制和DNA上清液产量均降低(图6F&G)。
实施例7
HCMV复制早晚期(early-to late stage)的抑制剂:MLS8091显示了对HCMV和耐GCV的HCMV的剂量反应,并且EC50分别为0.39±0.5和0.26±0.02μM(表1,图7),但对HSV1或MCMV没有活性(表2)。在另加试验中,其活性时间与GCV的活性时间重叠,但在去除试验中,MLS8091显示出更早的效果(图7C&D)。在72hpi观察所有病毒蛋白的抑制(图7E)。尽管对DNA产量的影响与GCV没有显著差异,但病毒DNA复制的抑制大于GCV(图7F和7G)。
NCGC2955抑制HCMV和GCV-R HCMV(图8A和8B)。对于该化合物,优选斑块试验,因为其没有显示出采用荧光素酶试验的全剂量反应。在另加试验中,NCGC2955活性时间与GCV重叠,但在去除试验中,NCGC2955显示出比GCV更久的活性(图8C&D)。在72hpi,存在包括IE1和IE2的病毒蛋白表达的显著降低(图8E)。尽管通过斑块试验抑制病毒子代并抑制病毒蛋白表达,但NCGC2955对病毒DNA复制和病毒DNA产量的影响不大(图8F和8G),表明通过不涉及DNA复制机制的机制进行抑制。
实施例8
具有与GCV和来特莫韦的药物组合模式:在HCMV感染的HFF中测试各化合物单独使用或与GCV或来特莫韦组合使用的效果。对于所有五种试剂,观察到与GCV(图9)或来特莫韦(图10)的相加或轻度协同效果。观察到的抑制倍数除以预期抑制倍数的比率>1被认为是药物协同效果,<1被认为是药物拮抗效果,=1被认为是相加效果。药物组合的Bliss系数如表3所示。对于来特莫韦及其与五种化合物中的每一种的组合,EC50基于斑块试验来测定。通过斑块试验测试GCV和2955的组合。所有其他组合和Bliss系数用pp28-荧光素酶测定。所有Bliss系数均接近1,表明化合物之间的相加效果。
表3.药物组合的Bliss系数
实施例9
讨论和结论:我们报道了使用我们的pp28荧光素酶HCMV针对HCMV抑制剂进行的迄今为止最大的HTS的结果。该报告子病毒在该筛选中显示出高灵敏度和可重复性20。其优点是HCMV编码的pp28是真正的晚期基因(true late gene),因此其活化代表HCMV复制接近完整的周期。
筛选活动可能会导致假阳性命中,需要认真验证。我们使用多个HCMV菌株和多个详细抗病毒试验的组合方法导致五种不同命中(hit)的识别和表征,各命中都有其独特的特征。对于五种命中,MLS8969抑制HCMV进入,MLS8554和NFU1827抑制HCMV-复制的即早早期期(但对其他疱疹病毒的影响彼此不同),MLS8091和NCGC2955在早晚期具有活性,但NCGC2955并未对病毒DNA复制有强烈抑制。当与GCV或蜡特莫韦组合使用时,所有五种化合物均表现出相加效果或轻微协同作用。在所有药物组合实验中均未发现拮抗作用。此外,五种化合物对耐GCV的HCMV具有活性,表明其机制与病毒DNA聚合酶不同。未来的研究应提供对五种化合物的作用机制的深入了解。根据这里提供的数据,我们预期各化合物都具有独特的HCMV抑制机制。
使用包含有限数量小分子、不同HCMV菌株、细胞类型和治疗时间的库进行筛选。基于荧光强度多种激酶抑制剂阻断HCMV复制,将三株重组HCMV应用于细胞激酶库(具有80种化合物)作为试点筛选,所述三株重组HCMV携带增强型黄色荧光蛋白(EYFP),与即早期病毒蛋白2(IE-2)、ppUL32(ppl50)和ppUL83(pp65)融合25。该筛选在感染时使用了10μM的固定药物浓度,并且有限数量的命中没有明显的细胞毒性。已生成报告子细胞系以筛选抗HCMV化合物26、27。在一种使用荧光素酶报告子细胞系的方法中,启动子提供IE蛋白活化;因此,无法评估在感染较晚期抑制HCMV的化合物27。用HCMV菌株AD169对187种化合物的格雷激酶抑制剂库(Gray Kinase Inhibitor library)进行了成功筛选,并且细胞用抗体染色以检测HCMV抗原pp28。三种激酶抑制剂识别为IE2生产的抑制剂28。最近的药物再利用筛选使用Micro Discovery System公司的2560种化合物的光谱集29,30。Mercorelli使用基于机制的筛选,旨在识别干扰IE2反式激活活性的化合物。表型试验测量了融合至IE231或UL9932的EGFP的表达。HTS的主要成功在于从化合物库33的筛选中识别来特莫韦(AIC246),其在随后的研究中被证明具有抑制HCMV的新作用机制34。
总之,我们的研究提供了在亚μM至低μM浓度下抑制HCMV复制的几种新型化合物。这些化合物中的每一种都是未来机理研究和药物开发的良好候选。
本文引用的所有参考文献(包括出版物、专利申请和专利)如同各文献单独引入并明确表示通过引用纳入且在本文中完整阐述的相同程度通过引用纳入本文。描述本文公开内容使得上下文(特别是在所附权利要求的上下文中)使用的术语“一个”和“一种”和“该”等类似表达应解释为涵盖单数和复数,除非另有说明或者上下文明确另有所指。术语“包含”、“具有”、“包括”以及“含有”应解释为开放式术语(即,表示“包括,但不限于”),除非另有说明。除非本文中另有说明,本文中对数值范围的引用仅仅是一种简约表示方法,单独表示落在该范围内的每个独立的值,且每个独立的值均被纳入说明书内中,如同在本文中单独陈述。本文所述的所有方法可以任何合适的顺序进行,除非本文另有说明或者与上下文明显矛盾。除非另外指出,本文提供的任何和所有实施例和示例或者示例性语言(例如,“例如/如/诸如”)的使用仅仅是为了更好地阐述本文公开内容,而不是对公开内容范围的限制。说明书中的所有语言都不应解释为指示对本文公开内容实践所必需的非权利要求的要素。
本文公开内容包括适用法律允许的所附权利要求中记载的主题的所有修改和等同物。此外,除非本文另外指出或与上下文明显矛盾,否则本文公开内容涵盖上述要素的所有可能变化形式的任何组合。
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19.Papanicolaou,G.A;Silveira,F.P.;Langston,A A;Pereira,M.R.;Avery,R.K.;Uknis,M.;Wijatyk,A;Wu,J.;Boeckh,M.;Marty,F.M.;Villano,S.Maribavir forRefractory or Resistant Cytomegalovirus Infections in Hematopoietic-cell orSolid-organ Transplant Recipients:A Randomized,Dose-ranging,Double-blind,Phase 2Study(马里巴韦治疗造血细胞或实体器官移植受者难治或耐药巨细胞病毒感染:随机、剂量范围、双盲、2期研究).Clin Infect Dis 2018,68,1255-1264。
20.He,R.;Sandford,G.;Hayward,G.S.;Burns,W.H.;Posner,G.H.;Forman,M.;AravBoger,R.Recombinant luciferase-expressing human cytomegalovirus(CMV)forevaluation of CMV inhibitors(表达人巨细胞病毒(CMV)的重组荧光素酶用于评估CMV抑制剂).Virol.J 20ll,8,40。
21.Inglese,J.;Auld,D.S.;Jadhav,A;Johnson,R.L.;Simeonov,A;Yasgar,A;Zheng,W.;Austin,C.P.Quantitative high-throughput screening:a titration-basedapproach that efficiently identifies biological activities in large chemicallibraries(定量高通量筛选:一种基于滴定的方法,可有效识别大型化学库中的生物活性).Proc Natl Acad Sci USA 2006,103,11473-8。
22.Shen,L.;Peterson,S.;Sedaghat,A.R.;McMahon,M.A;Callender,M.;Zhang,H.;Zhou,Y.;Pitt,E.;Anderson,K.S.;Acosta,E.P.;Siliciano,R.F.Dose-responsecurve slope sets class-specific limits on inhibitory potential of anti-HIVdrugs(剂量-反应曲线斜率设定了抗HIV药物抑制潜力的类别特定限值).Nat.Med2008,14,762-766。
23.Sampah,M.E.;Shen,L.;Jilek,B.L.;Siliciano,R.F.Dose-response curveslope is a missing dimension in the analysis of HIV-1drug resistance(剂量-反应曲线斜率是HIV-1耐药性分析中的缺失维度).Proc.Natl.Acad Sci.U S.A 2011,108,7613-7618。
24.Jacobson,J.G.;Renau,T.E.;Nassiri,M.R.;Sweier,D.G.;Breitenbach,J.M.;Townsend,L.B.;Drach,J.C.Nonnucleoside pyrrolopyrimidines with a uniquemechanism of action against human cytomegalovirus(具有独特作用机制的非核苷吡咯嘧啶抗人巨细胞病毒).Antimicrob.Agents Chemother 1999,43,1888-1894。
25.Straschewski,S.;Warmer,M.;Frascaroli,G.;Hohenberg,H.;Mertens,T.;Winkler,M.Human cytomegaloviruses expressing yellow fluorescent fusionproteins--characterization and use in antiviral screening(表达黄色荧光融合蛋白的人巨细胞病毒的特性及其在抗病毒筛选中的应用).PLoS.One 2010,5,e9174。
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34.Goldner,T.;Hewlett,G.;Ettischer,N.;Ruebsamen-Schaeff,H.;Zimmermann,H.;Lischka,P.The novel anticytomegalovirus compound AIC246(Letermovir)inhibits human cytomegalovirus replication through a specificantiviral mechanism that involves the viral terminase(新型抗巨细胞病毒化合物AIC246(来特莫韦)通过涉及病毒终末酶的特定抗病毒机制抑制人类巨细胞病毒复制).JVirol201l,85,10884-93。
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36.Srinivasan,S.;Schuster,G.B.A conjoined thienopyrrole oligomerformed by using DNA as a molecular guide(以DNA为分子导向形成的连合噻吩吡咯低聚物).Org Lett 2008,10,3657-60。
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序列表
<110> BOGER, Ravit
<120> 用于抑制疱疹病毒的组合物
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Claims (27)
3.一种抑制有需要的对象中的人类疱疹病毒的方法,包括向所述对象给予式II化合物或其药物组合物或其盐、溶剂化物或立体异构体,所述药物组合物包含药学上可接受的运载体:
其中,R1是H,并且R2独立地是H或任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的烷基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接;或者
R1和R2一起形成任选被一个或多个脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子;并且R3是H或任选被一个或多个卤素、CF3、CN和NO2部分所取代的环烷基、杂环烷基、芳基或杂芳基。
4.如权利要求3所述的方法,其中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。
9.如权利要求8所述的方法,其中,R1是C1-C4直链或支链烷基;并且R2是被OR3取代的苯基,其中R3为C1-C4直链或支链烷基。
11.如权利要求1至10中任一项所述的方法,其中,所述疱疹病毒选自人类疱疹病毒1型(HHV-1)、人类疱疹病毒2型(HHV2)、人类疱疹病毒3型(HHV3)、人类疱疹病毒4型(HHV4)、人类疱疹病毒5型(HHV5)、人类疱疹病毒6型(HHV6)、人类疱疹病毒7型(HHV7)和人类疱疹病毒8型(HHV8)。
12.如权利要求11所述的方法,其中,所述疱疹病毒是HHV-5。
13.如权利要求12所述的方法,其中,HHV-5抗更昔洛韦。
14.如权利要求1-13中任一项所述的方法,所述方法还包括给予超过一种生物活性剂。
15.如权利要求1-14中任一项所述的方法,所述方法还包括给予更昔洛韦或来特莫韦。
19.如权利要求18所述的药物组合物,其中,R2是任选被一个或多个烷基、脒基、胍基、磷酸根、硫酸根、四唑、3-羟基异噁唑、仲酰胺、磺酰胺、磺酰脲、酰基脒、酰基胍取代的C1-C6杂环烷基或C1-C6杂芳基,其具有1至10个碳原子并通过C1-C3烷基连接。
24.如权利要求23所述的药物组合物,其中,R1是C1-C4直链或支链烷基;并且
R2是被OR3取代的苯基,其中,R3是C1-C4直链或支链烷基。
26.如权利要求16-25中任一项所述的药物组合物,所述药物组合物还包含超过一种生物活性剂。
27.如权利要求26所述的药物组合物,所述组合物还包含更昔洛韦或来特莫韦。
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