CN102145005A - 阳离子类固醇抗微生物剂组合物及其使用方法 - Google Patents
阳离子类固醇抗微生物剂组合物及其使用方法 Download PDFInfo
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Abstract
本发明提供了减少或抑制体外,间接体内或体内细胞的人免疫缺陷病毒(HIV)感染或发病,与体外,间接体内或体内的人免疫缺陷病毒(HIV)感染或发病(例如,疾病)相关的症状或病变,或是体外,间接体内或体内的人免疫缺陷病毒(HIV)感染或发病(例如,疾病)的不良副作用的方法。在一种实施方式中,本发明的方法包括通过发明化合物(例如,阳离子类固醇抗微生物剂或CSA)治疗对象。
Description
本申请是申请日为2007年01月31日、申请号为200780004321.7、名称为“阳离子类固醇抗微生物剂组合物及其使用方法”的发明申请的分案。
技术领域
本发明涉及减少或抑制体外,间接体内(Ex vivo)或体内细胞的人免疫缺陷病毒(HIV)感染或发病(例如,疾病),与体外,间接体内或体内的人免疫缺陷病毒(HIV)感染或发病(例如,疾病)相关的症状或病变,或是体外,间接体内或体内的人免疫缺陷病毒(HIV)感染或发病(例如,疾病)的不良副作用的方法。在一种实施方式中,本发明的方法包括通过发明化合物(例如,阳离子类固醇抗微生物剂或CSA)治疗对象。
背景技术
HIV感染可导致CD4(+)T淋巴细胞的严重下降,多种白细胞亚群的调节障碍以及全面免疫激活,且具有伺机性感染和恶性肿瘤等后续进展。
高效抗逆转录病毒疗法(HAART)的施用曾成功减少了HIV血浆病毒血症;然而,HAART恢复免疫功能的能力并不完全,特别是对于患有慢性和晚期疾病的患者。对HIV感染替代或补充疗法的开发,特别是那些能够弥补HAART的局限性的疗法将引起极大兴趣。
综述
阳离子类固醇抗微生物剂(CSAs)作为LL-37等内源肽抗生素功能性模拟物进行开发。现已开发得到一系列CSAs,且CSAs对包括人免疫缺陷病毒(HIV)在内的特定的脂包膜病毒具有很高的活性。多个CSAs的抗病毒活性已得到检测,且对活性和失活形式进行了鉴定。
附图说明
图1显示了本发明的化合物。
图2显示了化合物CSA-26和CSA-46。
图3显示了化合物134。
图4显示了化合物CSA-10。
图5显示了化合物140。
图6显示了化合物CSA-31。
图7显示了化合物352-354。
图8显示了化合物341-343和324-327。
图9显示了化合物358。
图10显示了本发明的各种化合物(CSAs)。
图11为HIV病毒核蛋白p24的ELISA研究,其代表了细胞HIV-VSV-G感染的四个独立研究。
图12为CSA与Hut细胞(实心方块),激活原代CD4+T细胞(实心圆),HEK-293T细胞(空心方块),HeLa细胞(空心圆)以及HIV孵育后的流式细胞仪细胞活性研究。
图13为CSAs与传染性HIV-VSV-G和Hut细胞孵育的研究。以感染对数据进行归一化并表示为一个代表性研究中三个重复样品的平均值。GFP表达(实心方块)和流式细胞仪测得的T细胞活性(空心方块)。误差棒显示了标准偏差。
发明详述
本发明的一个方面涉及阳离子类固醇抗微生物剂(CSA)在用于向对象提供对人免疫缺陷病毒(HIV)感染或发病的保护的药物制备中的用途。
本发明的另一个方面涉及阳离子类固醇抗微生物剂(CSA)在用于对需要人免疫缺陷病毒(HIV)感染或发病治疗的对象进行治疗的药物制备中的用途。
本发明的另一个方面涉及阳离子类固醇抗微生物剂(CSA)在用于降低对象对人免疫缺陷病毒(HIV)感染或发病易感性的药物制备中的用途。
在一个实施方式中,其中在该患有,暴露至或接触HIV的对象感染前,感染时或感染后施用该CSA。
在一个实施方式中,其中在急性或慢性HIV感染的症状发展前,发展时或发展后施用该CSA。
在一个实施方式中,其中该HIV包括了药物耐受的HIV型,组,亚型或分离物。
在一个实施方式中,其中该HIV包括了HIV-1或HIV-2。
在一个实施方式中,其中该HIV-1包括了组M,N或O组。
在一个实施方式中,其中该HIV-1包括了A,B,A/B,A/E,A/G,C,D,F,G,H,J或K亚型或者其混合物。
在一个实施方式中,其中该CSA选自图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54和CSA-59。
在一个实施方式中,其中该CSA在位置C24不带有带电基团。
在一个实施方式中,其中该CSA在位置C24带有疏水部分。
在一个实施方式中,其中在位置C24的该疏水部分包括脂质。
在一个实施方式中,其中该CSA在位置C7带有带电基团。
在一个实施方式中,其中该CSA包含多聚物。
在一个实施方式中,其中该CSA多聚物包含二聚物,三聚物或四聚物。
在一个实施方式中,其中与图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54或CSA-59的接枝长度相比,该CSA在类固醇支架和胺基团之间的接枝长度更短。
在一个实施方式中,其中该CSA包含药学可接受的载体或赋形剂。
在一个实施方式中,其中该CSA包括无菌制剂。
在一个实施方式中,其中该CSA包含具有一种或多种附加生物活性成分的组合物。
在一个实施方式中,其中该对象的CD4+T细胞数量少于500细胞/微升血液,少于200细胞/微升血液,或该对象的CD4+T细胞的百分比少于所有淋巴细胞的15%。
在一个实施方式中,其中针对HIV感染或发病,或由HIV感染或发病引起的症状向该对象提供了部分或完全保护。
在一个实施方式中,其中该药物减少,降低,抑制,改善或预防与对象HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或可能性。
在一个实施方式中,其中该症状选自:发烧,疲劳,头痛,咽喉痛,淋巴结肿大,体重减轻,腹泻,皮疹,疮,疣,鹅口疮,带状疱疹,慢性或急性盆腔炎(PID),干咳,呼吸急促,瘀伤,出血,麻木或瘫痪,肌肉无力,伺机性紊乱,神经损伤,脑病,痴呆和死亡。
在一个实施方式中,其中该伺机性紊乱选自细菌,病毒,真菌和寄生虫感染。
在一个实施方式中,其中该伺机性紊乱选自:支气管,气管,肺部或食道的念珠菌病,子宫颈癌,球孢子菌病,隐球菌病,隐孢子虫病,杆菌血管瘤病,巨细胞病毒(CMV),巨细胞病毒性视网膜炎,疱疹病毒,肝炎病毒,乳头状瘤病毒,组织胞浆菌,等孢子球虫病,卡波西氏肉瘤,伯基特淋巴瘤,免疫淋巴母细胞性瘤,鸟分枝杆菌病,结核分枝杆菌病,卡氏肺孢子虫病,肺炎,进行性多灶性脑白质病(PML),沙门氏菌病,弓形虫病,消耗综合征以及淋巴间质性肺炎/肺淋巴型。
在一个实施方式中,其中该药物预防或抑制HIV感染或与HIV感染或发病相关的一种或多种症状的恶化或进展。
在一个实施方式中,其中该药物稳定HIV感染或与HIV感染或发病相关的一种或多种症状。
在一个实施方式中,其中该药物减少或降低HIV滴度,病毒载量,病毒复制,病毒增殖,或病毒蛋白,或者抑制或防止HIV滴度,病毒载量,病毒复制,病毒增殖,或病毒蛋白的增加。
在一个实施方式中,其中该药物减少或降低对象对HIV感染或与HIV感染或发病相关的一种或多种症状的易感性。
在一个实施方式中,其中该药物增加或稳定对象体内CD4+T细胞的数量。
在一个实施方式中,其中该对象未曾感染或暴露至HIV。
在一个实施方式中,其中该对象已接种HIV疫苗。
在一个实施方式中,其中该对象已感染或暴露至HIV。
在一个实施方式中,其中该对象已诊断为HIV+。
在一个实施方式中,其中该对象患有免疫低下。
在一个实施方式中,其中该对象是免疫抑制剂治疗的候选人或已接受免疫抑制剂治疗。
在一个实施方式中,其中该对象是组织或器官移植的候选人或已接受组织或器官移植。
在一个实施方式中,其中该对象为新生儿,婴儿,幼儿或儿童。
在一个实施方式中,其中该对象年龄为50岁或以上。
在一个实施方式中,进一步包括向患者施用附加的CSA或其它治疗。
在一个实施方式中,其中该治疗针对HIV,由HIV治疗引发的副作用或由HIV感染或HIV治疗引发的伺机性紊乱。
在一个实施方式中,其中该治疗包含蛋白酶抑制剂,逆转录酶抑制剂,病毒融合抑制剂或病毒侵入抑制剂。
在一个实施方式中,其中该治疗包括施用:AK602,AMD070,APV,ATV,ATZ,AVX754,AZT,阿巴卡韦,无环鸟苷,阿德福韦酯,阿霉素,安普那韦,阿地白介素,阿洛夫定,两性霉素B脂质体注射剂,氨多索韦,注射用两性霉素B,两性霉素B粉针剂,两性霉素B,聚肌胞,安普那韦,睾酮透皮吸收贴片,睾酮凝胶,替拉那韦,阿扎那韦,阿奇霉素,BMS-488043,复方新诺明片,博路定,克拉霉素,缓冲凝胶,C31G,CD4-IgG2,CPV,CS,卡拉脑立德A,卡普韦林,卡波普974P,角叉菜胶,角叉菜凝胶,硫酸纤维素,克拉霉素,卡贝滋,利巴韦林,磺胺甲基异恶唑,佳息患,蓝藻蛋白-N,赛美维,DAPD,DLV,DPC 817,DS,地拉韦啶,Depo-睾丸激素,硫酸葡聚糖,去羟肌苷,大扶康,都可喜,多柔比星,屈大麻酚,EFV,依非韦伦,艾夫他滨,茚曲他滨,恩曲他滨,恩夫韦地,恩地卡韦,拉米夫定,依泊汀阿尔法,怡泼津,拉米夫定+阿巴卡韦复方制剂,凡毕复(磷酸盐),依托泊苷,艾特拉维呤,氟康唑,沙奎那韦软凝胶剂,膦沙那韦,两性霉素B,福泽昂,GSK-873,140(阿普拉维洛克),GW433908,γ-球蛋白-P(Gammar-P),更昔洛韦,生长激素,人生长激素,HEC,阿迪福韦,扎西他滨,羟乙基纤维素,IDV,IGIV,白介素-2(IL-2),INH,免疫球蛋白,茚地那韦,干扰素alfa-2,内含子A(2b),沙奎那韦,异烟肼,伊曲康唑,KP-1461,洛匹那韦+利托那韦复方制剂,L-000870810,LPV/RTV,拉米夫定,福沙那伟钙,屈大麻酚,美可治,甲地孕酮,利福布丁,NFV,NVP,萘二磺酸钠聚合物,喷他脒气雾剂,奈非那韦,葡萄糖醛酸三甲曲沙粉针剂,奈韦拉平,聚-L-乳酸,利托那韦,异烟肼,紫杉醇,PA-457,PMPA,PRO 2000,PRO 542,紫杉醇,紫杉醇,派罗欣(2a),潘他米丁,肽T,聚(I)-聚(C 12U),聚-L-乳酸,Polygam S/D,阿法依泊汀,普留净注射剂,RCV,RTV,RVT,拉西韦,利巴韦林,地拉韦啶,立妥威,立沃塞,阿扎那韦硫酸盐,利巴韦林,利福布汀,利福定,利福平,利福平,利托那韦,罗荛愫-A(2a),SCH-C,SCH-D(Vicriviroc),SQV,沙奎那韦,C31G凝胶,聚-L-乳酸,复方新诺明,雪兰思定,生长激素,斯皮仁诺,司他夫定,磺胺甲基异恶唑,睾丸素,依发韦仑,T-20,TDF,THC,TMCl14,TMCl25,TNX-355,紫杉醇,替诺福韦,延胡索酸替诺福韦酯,睾丸激素,替拉那韦,拓扑杀,甲氧苄啶,曲美沙特,三协维,特鲁瓦达,UC-781,UK-427,857(马拉维若),硫酸纤维素凝胶,缬更昔洛韦,缬更昔洛韦,丙戊酸,维乐命,病毒唑,替诺福韦酯,更昔洛韦,ZDV,扎西他宾,赛瑞特,阿巴卡韦,齐多夫定,希舒美,阿昔洛韦,D4T,ddC,β-LFddC,P-LFd4C,DDI,f-APV,3TC或人促红细胞生成素(EPO)。
在一个实施方式中,其中该治疗包含细胞因子,趋化因子,干扰素或白介素。
在一个实施方式中,其中该治疗针对肿瘤或癌症。
在一个实施方式中,其中该肿瘤或癌症治疗包括内部或外部放射治疗,手术切除治疗,高热疗法,或化疗剂。
在一个实施方式中,其中该治疗包含与HIV蛋白结合的抗体。
在一个实施方式中,其中该HIV蛋白选自:包膜蛋白gp160,gp120或gp41,gag蛋白,pol蛋白,p7,p17,p24,tat,rev,nef,vif,vpr,vpu,逆转录酶,整合酶和蛋白酶。
在一个实施方式中,其中该抗体为人,人源化或嵌合抗体。
在一个实施方式中,其中该抗体为单克隆或多克隆抗体。
本发明的另一方面涉及一种在HIV+对象体内提高或稳定CD4+T细胞数量的方法,其包括施用足量的阳离子类固醇抗微生物剂(CSA)以提高或稳定HIV+对象体内CD4+T细胞数量。
本发明的另一方面涉及一种在体外或体内减少或抑制细胞的HIV感染的方法,其包括施用包含了足量阳离子类固醇抗微生物剂(CSA)的组合物以抑制细胞的HIV感染。
在一个实施方式中,其中该细胞为哺乳动物细胞。
在一个实施方式中,其中该细胞为人细胞。
本发明的另一方面涉及图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54或CSA-59在用于向对象提供针对HIV感染或发病的保护的药物制备中的用途。
本发明的另一方面涉及图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54或CSA-59在用于给需要HIV感染或发病治疗的对象进行治疗的药物制备中的用途。
本发明的另一方面涉及图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54或CSA-59在用于降低对象对HIV感染或发病的易感性的药物制备中的用途。
本发明的另一方面涉及图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54或CSA-59在用于减少,降低,抑制,改善或预防与对象HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或可能性的药物制备中的用途。
本发明的另一方面涉及一种试剂盒,所述试剂盒包括包装材料,阳离子类固醇抗微生物剂(CSA)和说明书,所述说明书包括施用所述CSA从而:
a)向对象提供针对HIV感染或发病的保护;
b)治疗对象的HIV感染或发病;
c)降低对象对HIV感染或发病的易感性;或者
d)降低,抑制,改善或预防与对象HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或可能性。
本发明的另一方面涉及一种治疗对象的HIV感染或发病的候选药剂的鉴定方法,其包括:
a)提供受试药剂,所述受试药剂包含阳离子类固醇抗微生物剂(CSA);
b)将所述受试药剂与HIV接触并确定该受试药剂是否抑制HIV感染或发病,其中经鉴定可以抑制HIV感染或发病的受试药剂为治疗对象的HIV感染或发病的候选药剂。
本发明的另一方面涉及一种降低对象对HIV感染或发病易感性的候选药剂的鉴定方法,其包括:
a)提供受试药剂,所述受试药剂包含阳离子类固醇抗微生物剂(CSA);
b)将所述受试药剂与HIV接触并确定该受试药剂是否抑制HIV感染或发病,其中经鉴定可以抑制HIV感染或发病的受试药剂为降低对象对HIV感染或发病易感性的候选药剂。
本发明的另一方面涉及一种降低,抑制,改善或预防与对象HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或可能性的候选药剂的鉴定方法,其包括:
a)提供受试药剂,所述受试药剂包含阳离子类固醇抗微生物剂(CSA);
b)将所述受试药剂施用至感染或暴露至HIV的对象并确定该受试药剂是否降低,抑制,改善或预防与HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或可能性,其中可以降低,抑制,改善或预防与HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或可能性的受试药剂可鉴定为候选药剂。
在一个实施方式中,其中该对象包含哺乳动物。
在一个实施方式中,其中该对象包含灵长动物。
在一个实施方式中,其中该哺乳动物或灵长动物包括HIV感染或发病的动物模型。
本发明提供了减少或抑制体外,间接体内或体内细胞的人免疫缺陷病毒(HIV)感染或发病(例如,疾病),与体外,间接体内或体内的人免疫缺陷病毒(HIV)感染或发病(例如,疾病)相关的症状或病变,或是体外,间接体内或体内的人免疫缺陷病毒(HIV)感染或发病(例如,疾病)的不良副作用的方法。在一个实施方式中,本发明的方法包括通过发明的化合物(例如,阳离子类固醇抗微生物剂或CSA)治疗对象,其中该对象由于CSA的抗HIV活性或功能而需要接受该种治疗,从而向该对象提供有益的效果或改善。在另一实施方式中,本发明的方法包括通过施用数量足以向对象提供针对HIV感染或发病的保护的阳离子类固醇抗微生物剂(CSA)以向对象提供针对HIV感染或发病的保护。在更进一步的实施方式中,本发明的方法包括通过施用数量足以治疗对象的HIV感染或发病的阳离子类固醇抗微生物剂(CSA)以治疗对象的HIV感染或发病。在另一实施方式中,本发明的方法包括通过施用数量足以降低对象对HIV感染或发病易感性的阳离子类固醇抗微生物剂(CSA)以降低对象对HIV感染或发病的易感性。本发明的方法包括在对象与HIV接触或暴露至HIV之前,与之同时或之后施用CSA;以及在与HIV感染有关或由其引起的症状或病变形成之前,形成时或形成后施用CSA。在不同的方面,本发明的化合物(例如,CSA)在对象感染或暴露至HIV之前(预防),同时或之后(治疗)进行施用。
因此本发明的治疗方法包括了治疗和预防方法。可在HIV暴露或接触,HIV感染,或HIV感染有关或由其引起的症状或病变形成之前,同时或之后向该对象接触,间接体内施用或体内传递本发明的化合物(例如,CSA)。
术语“治疗”及其语法变化指该对象受HIV感染,例如,该对象显示了此处列举或本领域已知的与HIV感染或发病(例如,疾病)相关或由其引发的一种或多种症状或病变。术语“治疗”还包括了暴露至HIV或与之接触,但未显示此处列举或本领域已知的与HIV感染或发病(例如,疾病)相关或由其引发的一种或多种症状或病变的对象。
“预防”及其语法变化指在已知对HIV的接触或暴露之前向对象接触,施用或体内传递。当未知对象是否接触或暴露至HIV时,在与HIV感染或发病相关或由其引发的症状显现或发作前向对象接触,施用或体内传递化合物。在该方法中,接触,施用或体内传递本发明化合物(例如,CSA)可以消除,预防,抑制,下降或减少形成HIV感染或发病(例如,疾病)或与HIV感染或发病(例如,疾病)相关或由其引发的症状或病变的概率或易感性。
此处所用的术语“相关”在涉及HIV的症状,病变或不良副作用的关系时指由HIV感染或发病引发的症状,病变或不良副作用,或是HIV感染或发病的次生效应。因此对象的症状,病变或不良副作用可由HIV感染或发病(例如,疾病)直接导致或引发,或至少部分由对象对HIV感染或发病(例如,疾病)的响应或应答(例如,免疫应答)引起。例如,HIV感染或发病时产生的症状或发病可能部分由该对象的免疫应答引起。
在本发明的化合物和方法的特定实施方式中,CSA选自图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54和CSA-59。在另一实施方式中,CSA在位置C24没有带电基团或CSA在位置C24带有疏水部分(例如,脂质)。在附加的实施方式中,CSA在位置C7带有带点基团。在更进一步的实施方式中,CSA包含了多聚体形式(例如,二聚物,三聚物,四聚物,五聚物,或更高的多聚物形式)。在另一实施方式中,与图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54或CSA-59的位置C3,C7或C12的任意胺基团和类固醇支架之间的接枝长度相比,该CSA在类固醇支架和位置C3,C7或C12的任意胺基团之间的接枝长度更短。
本发明的方法,包括,例如,通常适用于HIV的预防和治疗方法,以及减少或防止HIV不良副作用的方法。HIV包括HIV的任意菌株或分离物或亚型或种类,或HIV的菌株或分离物或亚型或种类的组合。HIV-1和HIV-2为特定的范例。HIV-1组的特定非限制范例包括M,N和O组。其它的范例为药物耐受型HIV型,组,亚型或分离物。HIV-1的特定非限制性范例包括A,B,A/B,A/E,A/G,C,D,F,G,H,J和K亚型及其组合。
本发明的方法包括可形成有益效果的治疗方法。有益效果的具体的非限制性范例包括向对象提供针对HIV感染或发病(例如,疾病),或由HIV感染或发病引起的症状的部分或完全的保护(例如,抑制或减少针对疾病的概率或易感性)。有益效果的特定非限制性范例还包括减少,降低,抑制,延缓或阻止HIV感染或发病,以及减少,降低,抑制,改善或预防与HIV感染或发病有关的一种或多种症状或病变的发作,严重性,持续时间,进展,频率或可能性。有益效果的其它非限制性范例还包括对HIV滴度或载量上升,增殖或复制的数量减少,下降或抑制,延缓或预防。有益效果的进一步非限制性特定范例包括减少,降低,抑制,延缓,改善或预防对象对HIV感染或发病(例如,疾病)的发作,进展,严重性,持续时间,频率,概率或易感性,或者加速,促进或加快对象由HIV感染或发病或一种或多种相关症状,病变或不良副作用的恢复。
因此本发明的方法包括向对象提供有益的或治疗效果,例如,减少,降低,抑制,延缓,改善或预防HIV感染或发病或一种或多种与HIV感染或发病相关的症状,病变或不良副作用的发作,进展,严重性,持续时间,频率或概率;减少,降低,抑制,延缓或预防一种或多种HIV菌株或分离物或亚型的HIV滴度,病毒载量,复制,增殖或病毒蛋白数量上升。本发明方法的各种实施方式还包括了稳定感染或其症状或病变,或预防,抑制或延缓感染或与HIV感染或发病相关或由之引起的症状或病变的恶化或进展,或潜在的HIV感染的进展。
其发作,进展,严重性,频率,持续时间或概率可被减少,下降,抑制,延缓,改善或预防的与HIV感染或发病(例如,疾病)相关或由之引起的症状和病变的特定范例包括,例如,发烧,疲劳,头痛,咽喉痛,淋巴结肿大,体重减轻,腹泻,皮疹,疮,疣,鹅口疮,带状疱疹,慢性或急性盆腔炎(PID),干咳,呼吸急促,瘀伤,出血,麻木或瘫痪,肌肉无力,伺机性紊乱,神经损伤,脑病,痴呆和死亡。
其发作,进展,严重性,频率,持续时间或概率可被减少,下降,抑制,延缓,改善或预防的与HIV感染或发病(例如,疾病)相关或由之引起的症状和病变的特定范例还包括,例如,伺机性紊乱(例如,细菌,病毒,真菌和寄生虫感染)。伺机性紊乱的非限制性范例包括支气管,气管,肺部或食道的念珠菌病,子宫颈癌,球孢子菌病,隐球菌病,隐孢子虫病,杆菌血管瘤病,巨细胞病毒(CMV),巨细胞病毒性视网膜炎,疱疹病毒,肝炎病毒,乳头状瘤病毒,组织胞浆菌,等孢子球虫病,卡波西氏肉瘤,伯基特淋巴瘤,免疫淋巴母细胞性瘤,鸟分枝杆菌,结核分枝杆菌,卡氏肺孢子虫,肺炎,进行性多灶性脑白质病(PML),沙门氏菌病,弓形虫病,消耗综合征以及淋巴间质性肺炎/肺淋巴型。HIV感染或发病(例如,疾病)的其它症状和病变已为本领域所知,并提供了依据本发明对其进行的治疗。
可进行改善的其它的症状包括提高CD4+T细胞的数量,或稳定CD4+T细胞的数量(例如,大于500或200细胞/微升血液)。可进行改善的其它症状包括提高CD4+T细胞相对其它淋巴细胞的百分比,或稳定CD4+T细胞相对其它淋巴细胞的百分比(例如,大于15%)。
因此本发明方法还包括提高或稳定HIV+对象中CD4+T细胞的数量。在一个实施方式中,该方法包括在HIV+对象中施用充分量的CSA以提高或稳定CD4+T细胞的数量。在不同的方面,可以在对象中提高或稳定少于500细胞/微升血液的CD4+T细胞数,提高或稳定少于200细胞/微升血液的CD4+T细胞数,或者提高或稳定少于15%总淋巴细胞的CD4+T百分比。
除了其它方法外,本发明的方法包括向对象提供针对HIV感染或发病的预防,针对HIV感染或发病或与HIV感染或发病相关或由之引起的症状或病变的治疗,或降低对象对HIV感染或发病易感性,从而可以改善该对象的状况。因此改善是对与HIV感染或发病相关或由之引起的一种或多种症状或病变的发作,进展,严重性,持续时间,频率或概率,或病毒滴度,病毒载量,复制,增殖或病毒蛋白数量的任意主观或客观的减少,下降,抑制,延缓,改善或预防。改善还可包括减少,抑制或预防一种或多种HIV菌株或分离物或亚型或种类的病毒滴度,病毒载量,复制,增殖或病毒蛋白数量的增加。改善可进一步包括稳定与HIV感染或发病相关或由之引起的症状或病变,或者抑制,下降,延缓或预防与HIV感染或发病相关或由之引起的症状或病变的恶化或进展,或者潜在HIV感染的进展。因此,改善可以在任意程度或任意时间范围内(小时,天,周,月,年或治愈),例如,针对发烧,疲劳,头痛,咽喉痛,淋巴结肿大,体重减轻,腹泻,皮疹,疮,疣,鹅口疮,带状疱疹,慢性或急性盆腔炎(PID),干咳,呼吸急促,瘀伤,出血,麻木或瘫痪,肌肉无力,伺机性紊乱,神经损伤,脑病,痴呆,死亡,CD4+T细胞数量或CD4+T细胞相对总淋巴细胞的百分比,
改善还可包括减少或取消其它治疗(例如用于治疗具有HIV感染或发病或与HIV感染或发病相关或由之引起的症状或病变的抗病毒药物或其它药剂)的需求,剂量或频率。因此,针对HIV感染或发病,与HIV相关或由其引起的症状或病变,或由HIV引起的不良副作用的其它治疗数量的减少可认为提供了有益效果,因此,可认为在本发明方法的范围之内。可被取消或通过降低剂量或施用频率进行的非限制性示范HIV治疗包括蛋白酶抑制剂,逆转录酶抑制剂,病毒融合抑制剂和病毒侵入抑制剂。其它的非限制性示范HIV治疗包括AK602,AMD070,APV,ATV,ATZ,AVX754,AZT,阿巴卡韦,无环鸟苷,阿德福韦酯,阿霉素,安普那韦(Agenerase),阿地白介素,阿洛夫定,两性霉素B脂质体注射剂(AmBisome),氨多索韦,注射用两性霉素B(Amphocin),两性霉素B粉针剂,两性霉素B,聚肌胞,安普那韦,睾酮透皮吸收贴片(Androderm),睾酮凝胶,替拉那韦,阿扎那韦,阿奇霉素,BMS-488043,复方新诺明片,博路定,克拉霉素,缓冲凝胶(BufferGel),C31G,CD4-IgG2,CPV,CS,卡拉脑立德A(CalanolideA),卡普韦林,卡波普974P,角叉菜胶,角叉菜凝胶(Carraguard),硫酸纤维素,克拉霉素,卡贝滋,利巴韦林,磺胺甲基异恶唑,佳息患,蓝藻蛋白-N,赛美维,DAPD,DLV,DPC 817,DS,地拉韦啶,Depo-睾丸激素,硫酸葡聚糖,去羟肌苷,大扶康,都可喜,多柔比星,屈大麻酚,EFV,依非韦伦,艾夫他滨,茚曲他滨,恩曲他滨(商品名:Emtriva),恩夫韦地,恩地卡韦,拉米夫定,依泊汀阿尔法,怡泼津,拉米夫定+阿巴卡韦复方制剂,凡毕复(磷酸盐),依托泊苷,艾特拉维呤(Etravirine),氟康唑,沙奎那韦软凝胶剂,膦沙那韦,两性霉素B(Fungizone),福泽昂,GSK-873,140(阿普拉维洛克(Aplaviroc)),GW433908,Γ-球蛋白-P(Gammar-P),更昔洛韦,生长激素,人生长激素,HEC,阿迪福韦,扎西他滨,羟乙基纤维素,IDV,IGIV,白介素-2(IL-2),INH,免疫球蛋白,茚地那韦,干扰素alfa-2,内含子A(2b),沙奎那韦(Invirase),异烟肼,伊曲康唑,KP--1461,洛匹那韦+利托那韦复方制剂,L-000870S 10,LPV/RTV,拉米夫定,福沙那伟钙,屈大麻酚,美可治,甲地孕酮,利福布丁,NFV,NVP,萘二磺酸钠聚合物,喷他脒气雾剂,奈非那韦,葡萄糖醛酸三甲曲沙粉针剂,奈韦拉平,聚-L-乳酸(商品名:New-Fill),利托那韦,异烟肼,紫杉醇(商品名:Onxol),PA-457,PMPA,PRO 2000,PRO 542,紫杉醇,紫杉醇(商品名:Paxene),派罗欣(2a),潘他米丁,肽T,聚(I)-聚(C 12U),聚-L-乳酸,PolygamS/D,阿法依泊汀,普留净注射剂,RCV,RTV,RVT,拉西韦(Racivir),利巴韦林,地拉韦啶(商品名:Rescriptor),立妥威,立沃塞(Reverset),阿扎那韦硫酸盐(Reyataz),利巴韦林,利福布汀,利福定,利福平,利福平(商品名:Rimactane),利托那韦,罗荛愫-A(2a),SCH-C,SCH-D(CCR5拮抗剂(Vicriviroc)),SQV,沙奎那韦,C31G凝胶(Savvy),聚-L-乳酸(Sculptra),复方新诺明,雪兰思定,生长激素,斯皮仁诺,Stavudirie,磺胺甲基异恶唑,睾丸素,依发韦仑,T-20,TDF,THC,TMCl 14,TMCl 125,TNX355,紫杉醇(商品名:Taxol),替诺福韦,延胡索酸替诺福韦酯,睾丸激素,替拉那韦,拓扑杀,甲氧苄啶,曲美沙特,三协维,特鲁瓦达,UC-781,UK-427,857(马拉维若),硫酸纤维素凝胶(Ushercell),缬更昔洛韦(商品名:Valcyte),缬更昔洛韦,丙戊酸,维乐命,病毒唑,替诺福韦酯(Viread),更昔洛韦(VitraSert),ZDV,扎西他宾,赛瑞特,阿巴卡韦(Ziagen),齐多夫定,希舒美,阿昔洛韦,D4T,ddC,β-LFddC,P-LFd4C,DDI,f-APV,3TC或人促红细胞生成素(EPO)。其它的非限制性示范HIV治疗包括细胞因子,趋化因子,干扰素和白介素。其它的非限制性示范HIV治疗HIV或HIV蛋白,结合HIV蛋白的抗体(例如,包膜蛋白gp160,gp120或gp41,gag蛋白,pol蛋白,p7,p17,p24,tat,rev,nef,vif,vpr,vpu,逆转录酶,整合酶和蛋白酶)免疫。
治疗或改善无需完全消除任意特定的感染,发病(例如,疾病),症状,病变或不良副作用,或者所有与HIV感染或发病(例如,疾病)相关或由之引起的感染,症状,病变或不良副作用,或者对HIV免疫。相反地,治疗可以是任意客观或主观的可测量或可检测的抗病毒作用或对治疗对象的改善。因此,减少,抑制,降低,消除,延缓,停止或预防感染或发病(例如,疾病),感染或发病(例如,疾病)的症状或病变,或是由疫苗接种引起的不良副作用便是令人满意的结果。例如,本发明的化合物(例如,CSA)可减少,延缓或稳定发烧,但对疲劳,头痛,咽喉痛,淋巴结肿大,体重减轻,腹泻,皮疹,疮,疣,鹅口疮,带状疱疹,慢性或急性盆腔炎(PID),干咳,呼吸急促,瘀伤,出血,麻木或瘫痪,肌肉无力,伺机性紊乱,神经损伤,脑病,痴呆和死亡不具有任何作用。在另一实施例中本发明的化合物减少疲劳和头痛,但对一种或多种其它症状或病变没有可检测的改善。因此,当在较短或较长的时间内(小时,天,周,月,年,或治愈)对象的状况有渐进的改善,或者部分减少或稳定HIV感染,发病(例如,疾病)或其症状,病变或不良副作用,或者抑制或预防HIV感染,发病或其症状,病变或不良副作用的恶化或进展(稳定一种或多种症状或病变)时,便达到了令人满意的临床终点。
在本发明的具有预期结果的方法中,例如,在对HIV感染或发病(例如,疾病),与HIV相关或由之引起的症状或病变,或是由HIV引起的不良副作用提供客观或主观改善的治疗或预防方法中,本发明的化合物(例如,CSA)可以充分量或有效量进行施用。此处所用的“充分量”或“有效量”指在以单剂量或多剂量施用,单用或与一种或多种其它化合物,治疗,药剂(例如,药物)或治疗方案联用时,能够向给定对象提供任意程度或任意期限(例如,分钟,小时,天,月,年或治愈)的长期或短期可检测或可测量改善或有益效果的数量。
因此“充分量”或“有效量”包括对HIV感染或发病(例如,疾病),与HIV感染或发病(例如,疾病)相关或由之引起的一种或多种症状,或是HIV的不良副作用,可以降低,减少,抑制,预防或延缓其发作;降低,减少,抑制,延缓或预防其进展或恶化;或者降低,接触,改善或缓和其严重性,频率,持续时间,易感性或概率。此外,能加快对象从HIV感染或发病,与HIV感染或发病相关或由之引起的一种或多种症状,或HIV的不良副作用的恢复可认为是充分或有效量。
各种有益效果以及治疗和预防受益的指标在此列举并已为本领域技术人员所知。
充分量或有效量可以(但并非必须)在单次施用中提供且可以(但并非必须)单独施用(即,没有第二药物,药剂,治疗剂或治疗方案)或与其它化合物,药剂,治疗剂或治疗方案联用。此外,如果在以没有第二化合物,治疗,药剂或治疗方案时单剂量或多剂量给用时充分量或有效量不需要充分或有效,因为还可在该剂量之外采用其它的施用剂量,数量,频率或时间期限,或采用附加化合物,药剂,治疗剂或治疗方案以达到对给定对象的充分和有效。
充分量或有效量无需对每一个对象有效,或对给定组或群内大部分对象有效。因此,充分量或有效量指对特定对象充分或有效,而非对组或一般群充分或有效。如该类方法中通常所见,部分对象将比其它对象对本发明的方法显示出更大或更小的应答。
当数量,频率或时间期限可引起其它化合物,药剂,治疗剂或治疗方案的数量,频率或时间期限的取消或减少时,可认为该数量,频率或时间期限是充分和有效的,因而是有益的。例如,如果接触,施用或体内传递本发明化合物可引起治疗感染,发病,症状或病变,或不良副作用所使用的其它化合物,药剂,治疗剂或治疗方案更少的用量,频率或时间期限,则可认为本发明的化合物具有有益或治疗效果。
任意具有有益,附加,增效或补充活性或效果的化合物,药剂,治疗或其它治疗方案可与本发明的化合物(例如,CSAs)联合制剂或使用。在不同的实施方式中,该化合物,药剂,治疗剂或治疗方案用于向对象提供针对HIV感染或发病(例如,疾病)的保护;治疗对象的HIV感染或发病(例如,疾病);降低对象对HIV感染或发病(例如,疾病)的易感性;治疗与HIV感染或发病相关或由之引起的伺机性紊乱;或降低或预防由HIV感染或发病或HIV治疗引起的不良副作用。因此,本发明的组合物包括CSA与其它CSAs的组合物,CSA与其它药剂或治疗剂(例如,抗HIV药物,例如蛋白酶抑制剂,逆转录酶抑制剂,病毒融合抑制剂,以及病毒侵入抑制剂,活或减毒HIV,HIV蛋白,HIV抗体等)的组合物,本发明的方法包括接触,体外或体内施用另一适用于待治疗症状的化合物(例如,另一CSA),药剂,治疗剂或治疗方案。该适用的化合物(例如,另一CSA),药剂,治疗剂或治疗方案可参照此处列举的预防和治疗方法,以及用于治疗与HIV感染或发病相关或由之引起的伺机性紊乱,或降低或预防与HIV感染或发病或HIV治疗相关或由之引起的不良副作用的方法,在本发明的化合物(例如,CSA)体外或体内接触或施用之前,同时或之后进行使用。
该种联用组合物和方法的范例包括蛋白酶抑制剂,逆转录酶抑制剂,病毒融合抑制剂和病毒侵入抑制剂,活或减毒HIV,HIV蛋白和结合HIV蛋白的抗体。蛋白酶抑制剂,逆转录酶抑制剂,病毒融合抑制剂和病毒侵入抑制剂,活或减毒HIV,HIV蛋白和结合HIV蛋白的抗体(例如,单克隆或多克隆)的集合可与本发明的化合物联用或在本发明化合物施用之前,同时或之后单独施用。其它联用组合物和方法的范例包括HIV以及其它治疗剂,例如AK602,AMD070,APV,ATV,ATZ,AVX754,AZT,阿巴卡韦,无环鸟苷,阿德福韦酯,阿霉素,安普那韦(Agenerase),阿地白介素,阿洛夫定,两性霉素B脂质体注射剂,氨多索韦,注射用两性霉素B(Amphocin),两性霉素B粉针剂,两性霉素B,聚肌胞,安普那韦,睾酮透皮吸收贴片(Androderm),睾酮凝胶,替拉那韦,阿扎那韦,阿奇霉素,BMS-488043,复方新诺明片,博路定,克拉霉素,缓冲凝胶(BufferGel),C31G,CD4-IgG2,CPV,CS,卡拉脑立德A(Calanolide A),卡普韦林,卡波普974P,角叉菜胶,角叉菜凝胶(Carraguard),硫酸纤维素,克拉霉素,卡贝滋,利巴韦林,磺胺甲基异恶唑,佳息患,蓝藻蛋白-N,赛美维,DAPD,DLV,DPC 817,DS,地拉韦啶,Depo-睾丸激素,硫酸葡聚糖,去羟肌苷,大扶康,都可喜,多柔比星,屈大麻酚,EFV,依非韦伦,艾夫他滨,茚曲他滨,恩曲他滨(商品名:Emtriva),恩夫韦地,恩地卡韦,拉米夫定,依泊汀阿尔法,怡泼津,拉米夫定+阿巴卡韦复方制剂,凡毕复(磷酸盐),依托泊苷,艾特拉维呤(Etravirine),氟康唑,沙奎那韦软凝胶剂,膦沙那韦,两性霉素B(Fungizone),福泽昂,GSK-873,140(阿普拉维洛克(Aplaviroc)),GW433908,γ-球蛋白-P(Gammar-P),更昔洛韦,生长激素,人生长激素,HEC,阿迪福韦,扎西他滨,羟乙基纤维素,IDV,IGIV,白介素-2(IL-2),INH,免疫球蛋白,茚地那韦,干扰素alfa-2,内含子A(2b),沙奎那韦(Invirase),异烟肼,伊曲康唑,KP--1461,洛匹那韦+利托那韦复方制剂,L-000870S 10,LPV/RTV,拉米夫定,福沙那伟钙,屈大麻酚,美可治,甲地孕酮,利福布丁,NFV,NVP,萘二磺酸钠聚合物,喷他脒气雾剂,奈非那韦,葡萄糖醛酸三甲曲沙粉针剂,奈韦拉平,聚-L-乳酸(商品名:New-Fill),利托那韦,异烟肼,紫杉醇(商品名:Onxol),PA-457,PMPA,PRO 2000,PRO 542,紫杉醇,紫杉醇(商品名:Paxene),派罗欣(2a),潘他米丁,肽T,聚(I)-聚(C 12U),聚-L-乳酸,Polygam S/D,阿法依泊汀,普留净注射剂,RCV,RTV,RVT,拉西韦(Racivir),利巴韦林,地拉韦啶(商品名:Rescriptor),立妥威,立沃塞(Reverset),阿扎那韦硫酸盐(Reyataz),利巴韦林,利福布汀,利福定,利福平,利福平(商品名:Rimactane),利托那韦,罗荛愫-A(2a),SCH-C,SCH-D(CCR5拮抗剂(Vicriviroc)),SQV,沙奎那韦,C31G凝胶(Savvy),聚-L-乳酸(Sculptra),复方新诺明,雪兰思定,生长激素,斯皮仁诺,Stavudirie,磺胺甲基异恶唑,睾丸素,依发韦仑,T-20,TDF,THC,TMCl14,TMCl125,TNX355,紫杉醇(商品名:Taxol),替诺福韦,延胡索酸替诺福韦酯,睾丸激素,替拉那韦,拓扑杀,甲氧苄啶,曲美沙特,三协维,特鲁瓦达,UC-781,UK-427,857(马拉维若),硫酸纤维素凝胶(Ushercell),缬更昔洛韦(商品名:Valcyte),缬更昔洛韦,丙戊酸,维乐命,病毒唑,替诺福韦酯(Viread),更昔洛韦(VitraSert),ZDV,扎西他宾,赛瑞特,阿巴卡韦(Ziagen),齐多夫定,希舒美,阿昔洛韦,D4T,ddC,β-LFddC,P-LFd4C,DDI,f-APV,3TC或人促红细胞生成素(EPO)。
其它的非限制性示范HIV和其它治疗剂包括细胞因子,趋化因子,干扰素和白介素。
其它的附加示范性HIV和其它治疗剂包括HIV蛋白(例如,存在于HIV-1或HIV-2上的一种或多种蛋白,如包膜蛋白gp160,gp120或gp41,gag蛋白,pol蛋白,p7,p17,p24,tat,rev,nef,vif,vpr,vpu,逆转录酶,整合酶或蛋白酶),或结合HIV蛋白的抗体(例如,存在于HIV-1或HIV-2上的一种或多种蛋白,如包膜蛋白gp160,gp120或gp41,gag蛋白,pol蛋白,p7,p17,p24,tat,rev,nef,vif,vpr,vpu,逆转录酶,整合酶或蛋白酶)。HIV蛋白和结合抗体包括存在于HIV-1(例如,M,N和O组,或是包括A,B,A/B,A/E,A/G,C,D,F,G,H,J和K亚型及其组合)或HIV2,药物耐受型HIV型,组,亚型或分离物或与之结合的HIV蛋白和结合抗体。
联用组合物和方法的其它范例包括增强免疫系统和抗细胞增殖的治疗(肿瘤或癌症)。特定的非限制性范例包括细胞因子,趋化因子,干扰素和白介素,内部或外部放射治疗,手术切除治疗,高热疗法,以及化疗剂。
抗体包括分别通过重和轻链可变区(VH和VL)与其它分子(抗原)结合的蛋白。抗体为任意多克隆或单克隆免疫球蛋白分子或其混合物,例如,IgM,IgG,IgA,IgE,IgD及其任意亚类,例如IgG1,IgG2,IgG3,IgG4等。单克隆抗体指由单个克隆(包括任意真核,原核或噬菌体克隆)产生或获得的抗体。除非另行指明,抗体还包括功能性(或结合)片段或子序列,例如,Fab,Fab′,F(ab′)2,Fv,Fd,scFv和sdFv。
抗体包括与HIV蛋白或同源物特异性或选择性结合的抗体。即,与非HIV蛋白或同源物的结合不明显干扰对HIV蛋白或同源物的检测,除非该种他类蛋白具有与该HIV抗体识别的HIV蛋白或同源物的表位相类似或相同的表位。选择性结合可通过本领域已知的竞争性和非竞争性的特异性,亲和性和其它结合测定与非选择性结合相区分。
抗体包括“人源”形式,即完全人源或者在人源抗体中可以或确实存在的抗体的氨基酸序列。非人源抗体可通过以可以或确实存在于人源抗体的氨基酸残基取代非人源氨基酸残基来完全人源化。在人源抗体中存在的氨基酸残基,CDR区域图和人源抗体共有残基已为本领域所知(例如,参见Kabat,Sequences of Proteins of Immunological Interest.4th Ed.US Department of Health and HumanServices.Public Health Service(1987);Chothia和Lesk J.Mol.Biol.186:651(1987);Padlan Mol.Immunol.31:169(1994);以及PadlanMol.Immunol 28:489(1991))。
抗体包括“非人源”形式,即在与受体人免疫球蛋白分子中的目标抗原特异性结合的一个或多个决定簇互补区(CDRs)中具有非人源氨基酸残基(例如,小鼠,大鼠,山羊,兔等),在Fv框架区(FR)(即在CDRs侧翼的氨基酸残基)具有一个或多个人源氨基酸残基的抗体的氨基酸序列。除受体人免疫球蛋白分子和框架区氨基酸残基除任意人源残基外还可以是灵长动物氨基酸残基(例如,猿,长臂猿,大猩猩,黑猩猩,猕猴)之外,本领域中抗体的“灵长源化”在“人源化”的含义之内。
抗体包括“嵌合”形式,即抗体的氨基酸序列包含来自于两种或多种物种或者由其获取或分离的一个或多个部分。即,例如,抗体的一部分为人源(例如,恒定区)而抗体的其它部分为非人源(例如,鼠重或轻链可变区)。因此,嵌合抗体为抗体中不同部分来自于不同物种的分子。与人源化抗体不同,嵌合抗体可在抗体的任意区域具有不同种类的序列。
术语“对象”指动物,通常为哺乳动物,例如但不限于非人类灵长动物(猿,长臂猿,大猩猩,黑猩猩,猩猩,猕猴),驯养动物(狗和猫),畜牧动物(鸡,鸭,马,牛,山羊,绵羊,猪),实验动物(小鼠,大鼠,兔子,豚鼠)和人。对象包括动物模型,例如,HIV感染模型(例如,灵长动物SIV模型)。对象包括天然存在或非天然存在的突变的或是非人类遗传改造(例如,转基因或敲除)动物。对象进一步包括患有慢性或急性HIV感染或发病,HIV感染或发病的症状,或是由HIV引起的不良副作用,或者具有患病风险的动物。对象可处在任意年龄。例如,对象(例如,人)可以是新生儿,婴儿,幼儿,儿童,少年或成人,例如,50岁或以上。
对象包括对本发明的方法有需求的对象,例如,需要进行治疗性或预防性治疗。当本发明的方法可能向对象提供益处时,可认为该对象对该方法有需求。针对HIV感染,发病(例如,疾病),与HIV感染或发病(例如,疾病)相关或由之引起的症状或病变,以及由HIV引起的不良副作用向对象提供的各种益处已在此处列举并已为本领域所知。
适于进行治疗的对象包括患有HIV感染或发病或倦游与HIV有关或由之引起的症状或病变的对象。因此目标对象包括已感染HIV,已诊断为HIV+,或已形成与HIV感染或发病(例如,疾病)相关或由之引起的症状或病变的对象,且与病毒类型,任意感染,发病(例如,疾病),症状,病变或不良副作用的发作的时间和程度,进展,严重性,频率,时间期限无关。对象进一步包括与年龄,性别,人种等相匹配对象相比CD4+T细胞数量减少的对象。例如,需要治疗的对象可包括HIV+对象以及CD4+T细胞数量少于500细胞/微升血液,少于200细胞/微升血液,或CD4+T细胞的百分比少于所有淋巴细胞的15%的对象。
适于进行治疗的对象还包括具有HIV感染或发病风险或具有形成HIV感染风险的对象。因此候选对象包括暴露至或接触HIV的对象,或具有暴露至或接触HIV的风险的对象,且与暴露或接触的类型,时机或程度无关。因此本发明适用于具有HIV感染或发病风险,但未暴露至或接触HIV的对象。因此包括了预防方法。如此处列举和本领域已知,进行预防的对象可具有增长的HIV感染或发病风险(概率或易感性)。
适于治疗的有风险对象包括暴露至其它患有HIV对象的对象,或HIV感染风险会由于病毒传染性或细胞嗜性,免疫易感性(例如,免疫功能低下的对象),或环境风险的变化而上升。因此适于治疗的有风险对象包括了暴露至其它患有HIV感染的人员(例如,诊断为HIV+)或具有对其暴露的风险的人类对象。
同样适于治疗的对象还包括对HIV接种疫苗或将要接种疫苗的对象(例如,以活或减毒HIV,HIV蛋白或与HIV蛋白结合的抗体进行疫苗接种)。因此对象包括了未曾或已经暴露至或接触HIV的接种疫苗的对象,以及未曾或已经暴露至或接触HIV的接种疫苗的候选对象,且与暴露或接触的类型,时机或程度无关。
在各种实施方式中,对象已针对HIV接种疫苗或将要接种疫苗(例如,以活或减毒HIV,HIV蛋白或与HIV蛋白结合的抗体进行疫苗接种)。在不同的方面,可在针对HIV的疫苗接种之前,同时或之后(例如,疫苗接种后0-2,2-4,4-12或12-24小时之内)施用本发明的化合物(例如,CSA)。
对象进一步包括由于免疫紊乱(例如,自身免疫)或疾病,或免疫抑制治疗剂(例如,环磷酰胺)而免疫功能低下的对象。对象还包括暴露至HIV或诊断为HIV+的对象。对象进一步包括接受或将要接受组织或器官移植的对象。
本发明的化合物(包括CSAs)可结合在药物组合物或制剂之中。该种药物组合物/制剂可用于在体外或间接体内施用于对象。
药物组合物和制剂包括用于向对象施用的载体或赋形剂。此处所用的术语“药学可接受”和“生理可接受”指适用于一种或多种给药,体内传递或接触途径的生物相容的制剂,气体,液体或固体,或其混合物。制剂的相容性指它不破坏其活性成分(例如,CSA)的活性,或者不会引发超过预防或治疗效果或受益的不良副作用。
该种剂型包括与药物施用或体内接触或传递相容的溶剂(水或非水),溶液(水或非水),乳剂(例如,水包油或油包水),悬浮液,糖浆,酏剂,分散剂和悬浮介质,涂层,等张和吸收促进或减缓剂。水和非水溶剂,溶液和悬浮液可包括悬浮剂和增厚剂。药学可接受的载体包括片(涂层或未涂层),胶囊(硬或软),微珠,粉末,颗粒和晶体。补充活性化合物(例如,防腐,抗菌,抗病毒和抗真菌剂)也可包含在组合物中。
为便利起见,可将剂型作为单位剂型进行制备或提供。制备技术包括将活性成分(例如,CSA)和药学载体或赋形剂相结合。一般而言,可通过将活性成分与液体载体或细颗粒的固体载体或同时与两者混合,并在必要时为产品赋予形状来制备制剂。例如,可通过压缩或模制制备片剂。压缩片剂可通过在适当的机器内对粉末或颗粒状的自由流动形式的,与粘合,润滑,惰性稀释,防腐,表面活性或分散剂选择性混合的活性成分(例如,CSA)进行压缩制备。模制片可通过在适当的设备内对采用惰性液体稀释剂润湿的粉末状化合物(例如,CSA)的混合物模制得到。片剂可选择性地带涂层或刻痕,并可通过制剂使其活性成分缓释或控释。
制剂中还可添加助溶剂和佐剂。助溶剂的非限制性范例包含羟基基团或其它剂型基团,例如,醇,如异丙醇;二醇,如丙二醇,聚乙二醇,聚丙二醇,乙二醇醚,甘油;聚氧化乙烯醇和聚氧化乙烯脂肪酸酯。佐剂包括,例如,如大豆卵磷脂和油酸等表面活性剂;如失水山梨醇三油酸酯等山梨糖醇酯;以及聚乙烯吡咯烷酮。
补充活性化合物(例如,防腐,抗氧化,抗微生物剂包括如抗细菌,抗病毒和抗真菌剂等杀生剂和生物抑制剂)也可包含在组合物中。防腐剂和其它添加剂包括,例如,抗微生物剂,抗氧化剂,螯合剂和惰性气体(例如,氮)。因此药物组合物可包括防腐剂,抗微生物剂,抗氧化剂,螯合剂和惰性气体。
防腐剂可用于抑制微生物生长或提高活性成分的稳定性,从而延长药物制剂的保存期限。适用的防腐剂已为本领域所知,并包括,例如,EDTA,EGTA,苯扎氯铵或苯甲酸或苯甲酸盐,如苯甲酸钠。抗氧化剂包括,例如,抗坏血酸,维生素A,维生素E,生育酚,类似的维生素或维生素原。
抗菌药剂或化合物可直接或间接抑制,减少,延缓,停止,消除,阻止,阻抑由病原或非病原微生物的生长,传播,复制,增殖,繁殖所引起的污染。抗微生物剂的类别包括,抗细菌剂,抗病毒剂,抗真菌剂和抗寄生虫剂。抗微生物剂包括能杀死或破坏或抑制由微生物生长,传播,复制,增殖,繁殖引起的污染的药剂和化合物。
示范性抗细菌剂(抗生素)包括青霉素类(例如,青霉素G,氨苄西林,甲氧西林,苯唑西林,阿莫西林),头孢菌素类(例如,头孢羟氨苄,头孢雷特,头孢噻肟,头孢三嗪),四环素类(例如,强力霉素,金霉素,米诺环,和四环素),氨基糖苷类(例如,丁胺卡那霉素,庆大霉素,卡那霉素,新霉素,链霉素,奈替米星,巴龙霉素和妥布霉素),大环内酯类(例如,阿奇霉素,克拉霉素,红霉素),氟喹诺酮类(如环丙沙星,洛美沙星,诺氟沙星)以及包括氯霉素,克林霉素,环丝氨酸,异烟肼,利福平,万古霉素,氨曲南,克拉维酸,亚胺培南,多粘菌素,杆菌肽,两性霉素和制霉菌素的其它抗生素。
抗病毒剂的特定非限制性类别包括逆转录酶抑制剂;蛋白酶抑制剂;胸苷激酶抑制剂;糖或糖蛋白合成抑制剂;结构蛋白合成抑制剂;核苷类似物;以及病毒成熟抑制剂。抗病毒剂的特定非限制性范例包括上述列举内容,以及奈韦拉平,地拉韦啶,依法韦仑,沙奎那韦,利托那韦,茚地那韦,奈非那韦,安普那韦,齐多夫定(AZT),司他夫定(d4T),拉米夫定(3TC),去羟肌苷(DDI),扎西他滨(ddC),阿巴卡韦,阿昔洛韦,喷昔洛韦,伐昔洛韦,更昔洛韦,1-D-呋喃核糖基-1,2,4-三唑-3-酰胺,9->二羟基-乙氧基甲基鸟嘌呤,金刚胺,5-碘-2′-脱氧鸟苷,三氟胸苷,干扰素和阿糖腺苷。
示范性的抗真菌剂包括如苯甲酸,十一碳烯烷醇酰胺,环吡酮胺,多烯类,咪唑类,丙烯胺,thicarbamates,两性霉素B,羟苯丁酯,克林霉素,econaxole,amrolfine,布替萘芬,萘替芬,特比萘芬,酮康唑,二氯苯基咪唑二氧戊环,益康唑,econaxole,伊曲康唑,异康唑,咪康唑,硫康唑,克霉唑,抑霉唑,奥昔康唑,噻康唑,特康唑,布康唑,噻菌灵,伏立康唑,沙康唑,舍他康唑,芬替康唑,泊沙康唑,联苯苄唑,氟康唑,氟曲马唑,制霉菌素,匹马霉素,两性霉素B,氟胞嘧啶,纳他霉素,托萘酯,磺胺米隆,氨苯砜,卡泊芬净,actofunicone,灰黄霉素,碘化钾,龙胆紫,环哟酮胺,环吡酮胺,卤普罗近,酮康唑,十一烯酸盐,磺胺嘧啶银,十一烯酸,十一烯酸烷醇酰胺和碱性品红等药剂。
药物组合物可选择性地制成与特定施用途径相容的剂型。因此,药物组合物包括可通过各种途径施用并且局部、区域或全身传递的载体(赋形剂,稀释剂,溶媒或填充剂)。
本发明化合物(例如,CSA)可进行选择性制剂的用于接触或体内传递示范性施用途径包括吸入,呼吸,插管,肺内灌输,口服(口腔,舌下,粘膜),肺内,直肠,阴道,子宫,皮内,局部,皮肤,胃肠(例如,皮下,肌肉内,静脉,皮内,眼内,气管和硬膜外),鼻腔,鞘内,动脉内,腔内,透皮吸收,离子导入,眼部,视觉(例如,角膜),腺体内,器官内,淋巴内途径。
适于肠胃外施用的剂型包括该化合物的水和非水溶液,悬浮液或乳剂(可包括悬浮剂和增厚剂),其制剂通常无菌并与目标受体的血液等张。水载体的非限制性范例包括水,盐水(氯化钠溶液),右旋糖(例如,Ringer右旋糖),Ringer乳酸盐,果糖,乙醇,动物,植物或合成油脂。非水溶液的范例为丙二醇,聚乙烯乙二醇,植物油(例如橄榄油),以及可注射的有机酯(例如油酸乙酯)。静脉内载体包括液体和营养补充剂,电解质补充剂(例如基于Ringer右旋糖的电解质补充剂)。该制剂可制成单剂量或多剂量的试剂盒(例如,安瓿和小瓶),并可于使用前需要添加无菌液相载体(例如,注射用水)的冷冻干燥(冻干)条件下进行贮存。
对于透粘膜或透皮施用(例如,局部接触),该药物组合物中可包含渗透剂。渗透剂已在本领域公知,并包括,例如用于透粘膜施用的清洁剂,胆汁盐和夫西地酸衍生物。针对透皮施用,该活性剂可制成本领域公知的气雾剂,喷雾,软膏,油膏,凝胶,糊剂,洗剂,油剂,乳膏等。
对于皮肤等局部施用,药物组合物通常包括软膏,洗剂,糊剂,凝胶,喷雾,气雾剂或油。可采用的载体包括凡士林,羊毛脂,聚丙二醇,醇类,透皮吸收促进剂,及其组合。示范性的局部传递系统为包含活性成分(例如,CSA)的透皮铁剂。
对于口服施用,药物组合物包括作为粉末或颗粒的胶囊剂,扁囊剂,糖锭,片剂或锭剂。口服施用剂型还包括溶液或悬浮液(例如,水溶液或非水溶液;或者为水包油乳剂或油包水乳剂)。
对于呼吸道或鼻腔施用,药物组合物可制成用于传递的干粉,例如,例如通过呼吸道或鼻腔途径以吸入方式施用的颗粒大小在20至500微米范围内的精细或粗糙粉末。根据传递装置的效率,有效的干粉剂水平通常在约10至约100mg的范围内。载体为液体的用于施用(例如,鼻腔喷雾或鼻腔液滴)的适用剂型包括该活性成分的水或油溶液。
对于呼吸道或鼻腔施用,可采用定量吸入器(MDI),喷雾器(超声,电子及其它喷雾器),鼻腔喷雾器和干粉吸入器等气雾或喷雾传递系统和装置(也称为“气雾生成器”和“喷雾生成器”)。MDIs通常包括致动器,计量阀,以及包含悬浮液或溶液,推进剂,表面活性剂(如油酸,失水山梨醇三油酸酯,卵磷脂)的容器。致动器的激活可使预定量的药剂以气雾的形式从容器中分发,并由对象吸入。MDIs通常采用液体推进剂,并通常可产生直径为15至30微米的液滴,从而可优化传递剂量为1微克至10毫克的治疗剂。喷雾器是可通过覆盖嘴部和鼻子的面罩将药物转化为患者可吸入的细雾的设备。喷雾器可提供向上呼吸道和下呼吸道传递的微小液滴和大量输出。喷雾器通常可生成直径约为1微米的液滴。
干粉吸入器(DPT)可用于传递单独的本发明化合物或其与药学可接受载体的组合。DPIs可在患者通过该设备吸入时将活性成分传递进入呼吸道和肺部。DPIs通常不包含推进剂或其它成分,仅包含药物,但可选择性包含其它成分。DPIs通常为呼吸激活,但可采用空气或气压来协助传递。
对于直肠施用,药物组合物可包含在包括可可脂和水杨酸等成分的适用基质的栓剂中。对于阴道施用,药物组合物可包括除活性成分(例如,CSA)外包含了载体(适用载体的范例已为本领域所知)的阴道栓剂,卫生塞棉,乳膏,凝胶,糊剂,泡沫或喷雾。
适用于本发明的组合物和方法的药物制剂和传递系统已为本领域所知(例如,参见Remington:The Science and Practice of Pharmacy(2003)20th ed.,Mack Publishing Co.,Easton,PA;Remington′s Pharmaceutical Sciences(1990)18th ed.,Mack PublishingCo.,Easton,PA;The Merck Index(1996)12th ed.,Merck PublishingGroup,Whitehouse,NJ;
Pharmaceutical Principles of Solid Dosage Forms(1993),Technonic Publishing Co.,Inc.,Lancaster,Pa.;Ansel和Stoklosa,Pharmaceutical Calculations(2001)11th ed.,Lippincott Williams&Wilkins,Baltimore,MD;and Poznansky等人,Drug Delivery Systems(1980),R.L.Juliano,ed.,Oxford,N.Y.,pp.253-315)。
本发明的化合物(例如,CSAs)(包括药物制剂)可包装为单位剂型以便于施用和剂量一致。此处所用的“单位剂型”指配合待治疗对象的单位剂量的物理分散单位;每一个单位包含了选择性结合了药物载体(赋形剂,稀释剂,溶媒或填充剂)的预定数量的化合物,其在以单或多剂量施用时,可通过计算产生预期效果(例如,预防或治疗效果或受益)。单位剂型可包含所施用化合物(例如,CSA)的日剂量或单位,日亚剂量或其适当组分。单位剂型还包括,例如,胶囊剂,胶囊,锭剂,扁囊剂,糖锭,片剂,安瓿和小瓶,其包括了冷冻干燥或冻干状态的组合物;在体内施用或传递之前可添加无菌液相载体。单位剂型进一步包括,例如,具有此处披露的液相组合物的安瓿和小瓶。单位剂型进一步包括透皮施用的化合物,例如与对象的表皮接触较长或较短时间的“药膏”。单独剂型可包括在多剂量试剂盒或容器中。药物组合物可包装为单独或多重单位剂型以便于施用和剂量一致。
本发明的化合物(例如,CSAs)可以单丸剂或多重(例如,每小时,每天,每周,每月或每年或者介于1至10天,1至10周,1至10月,或者在适当长时间内一,二,三,四,五或更多次)剂量。示范性的频率为每日,每周或每月1-7次,1-5次,1-3次,2次或一次。接触,间接体内施用或体内传递的时机可由待治疗的感染,发病(例如,疾病),症状,病变或不良副作用所决定。例如,可在HIV感染,发病(例如,疾病)或疫苗接种的症状或不良副作用的发作基本同时,或在发作的1-60分钟或1-60小时之内向患者施用一定数量。
剂量可随多重因素变化,包括该治疗属于治疗性还是预防性,症状的发作,进展,严重性,频率,时间期限,概率或易感性,待治疗的病毒感染或发病(例如,疾病)的类型,预期的临床终点,之前,同时或后续的治疗,对象的总体健康,年龄,性别或人种,生物相容性,潜在的不良全身,区域或局部副作用,该对象中其它紊乱或疾病的存在,以及技术人员可以理解的其它因素(例如,医疗或家族史)。剂量,频率或时间期限可根据预期的临床效果,感染,症状或病变的状态,治疗或疗法的任何不良副作用进行增加或减少。本领域的技术人员将能理解提供足以产生预防或治疗效果或受益的量所需的剂量,频率和时间期限的影响因素。
对于治疗性的治疗,将尽早施用本发明的化合物(例如,CSA),通常可在对象暴露至,接触或感染HIV(例如,诊断为HIV+)后的0-72小时内或0-72天内,或在与HIV感染或发病(例如,发烧,疲劳,淋巴结肿大,CD4+细胞数量减少,伺机性感染等疾病)相关的一种或多种症状或病变形成后0-72小时内或0-72天内进行施用。
对于预防性治疗,本发明的化合物可在疑似接触HIV后立即或0-72小时内,或在预计或可能接触HIV之前0-4周(例如,1-3天或1-3周)进行施用。对于与对象的免疫/疫苗接种相关的预防性治疗,可在对象的免疫/疫苗接种之前,同时或之后施用化合物。
剂量可以根据目前现有的治疗方案,经验确定,利用动物疾病模型确定或选择性地根据人临床研究进行确定。例如,初始的研究剂量可根据动物(例如,灵长动物)研究确定,化合物施用的量可获得预防或治疗效果或受益。该剂量可根据对象的质量进行调整,且通常相对对象的体重在约0.1-1ug/kg,1-10ug/kg,10-25ug/kg,25-50ug/kg,50-100ug/kg,100-500ug/kg,500-1,000ug/kg,1-5mg/kg,5-10mg/kg,10-20mg/kg,20-50mg/kg,50-100mg/kg,100-250mg/kg,250-500mg/kg或更大的范伟内,每小时,每天,每周,每月或每年施用二,三,四或更多次。当然,剂量在适当的情况下可以更大或更小,例如,在给定时间段内(例如,1,2,3,4,5或更多小时,天,周,月,年)相对对象体重为0.00001mg/kg至约10,000.0mg/kg,约0.001mg/kg至约100mg/kg,约0.01mg/kg至约10mg/kg,或0.1mg/kg约至约1mg/kg。可以单丸剂或分次/定量剂量向患者施用,该剂量可根据此处列举以及本领域已知的各种考虑进行增加或减少。
给药量,频率或期限可根据HIV感染或发病(例如,疾病),相关的症状或病变,或HIV任意不良副作用的状态,或者HIV治疗或抗HIV疗法进行提高或降低。例如,一旦实现控制或达到特定的终点(例如,减少,降低,抑制,改善或预防与HIV感染或发病(例如,疾病)相关的一种或多种症状,或与HIV感染或发病相关或由之引起的一种或多种症状或病变的发作,严重性,持续时间,进展,频率或概率)时,可以减少给药量,频率或期限。
本发明提供了包括本发明化合物(例如,CSA),其联合组合物以及药物组合物/制剂并用适当包装材料进行包装的试剂盒。在一个实施方式中,试剂盒包括包装材料,阳离子类固醇抗微生物剂(CSA)及说明书。在各种方面,该说明书可用于施用该CSA以:向对象提供针对HIV感染或发病(例如,疾病)的保护;治疗对象的HIV感染或发病(例如,疾病);降低对象对HIV感染或发病(例如,疾病)的易感性;或是降低或预防与HIV或HIV治疗相关或由之引起的不良副作用。
术语“包装材料”指包容该试剂盒的成分的物理结构。该包装材料可维持该成分无菌,并可用常用于该种目的的材料(例如,纸,波纹纤维,玻璃,塑料,箔,安瓿,小瓶,管等)制作。试剂盒可包含多种成分,例如,两种或多种本发明的化合物或其与抗HIV药剂或治疗剂(例如,抗病毒剂,HIV蛋白或与该HIV蛋白结合的抗体)或药物的组合,可选择为无菌。
试剂盒可选择性包含带有成分描述(类型,数量,剂量等),体外,体内或间接体内的使用以及其中任意其它成分的说明书的标签或插页。标签或插页包括“印刷品”,例如,单独或粘帖至成分,试剂盒或包装材料(例如,箱子),或贴在包含试剂盒成分的安瓿,管子或小瓶的纸张或纸板。标签或插页可进一步包括计算机可读介质,例如磁碟(例如,软盘,硬盘,ZIP盘),如CD-或DVD-ROM/RAM,DVD,MP3等光碟,磁带,或RAM和ROM等电子存储介质或其复合体,如磁/光存储介质,FLASH介质或记忆类型卡。
标签或插页还可包括其中一种或多种成分的识别信息,剂量,活性成分的临床药理学(包括作用机制,药代动力学和药效学)。标签或插页可包括生产商,批次,生产商地址以及日期,过期日期的识别信息。
标签和插页可包含有关试剂盒成分可能针对的症状,紊乱或疾病(例如,病毒发病或感染)的信息。标签和插页可包含针对临床医师或对象在方法,治疗方案或治疗性/预防性方案(包括本发明的方法)中使用一种或多种试剂盒成分的说明书。说明书可包括化合物的数量,施用的频率或期限,以及开展此处所述的方法,治疗方案或预防性或治疗性方案的说明书。示范性的说明书包括,对治疗HIV感染或发病(例如,疾病)的说明。因此本发明的试剂盒可进一步包括针对实施本发明所述的任意方法(包括治疗,筛选或其它方法)的标签或说明书。因此,例如,试剂盒可包括如此处列举的具有一种或多种抗HIV活性的本发明的化合物(例如,CSA),以及对向需要该种治疗的对象在本发明的预防性或治疗性治疗方法中施用该化合物的说明书。示范性的说明书包括施用该CSA以:向对象提供针对HIV感染或发病(例如,疾病)的保护;治疗对象的HIV感染或发病(例如,疾病);降低对象对HIV感染或发病(例如,疾病)的易感性;降低,抑制,改善或预防与对象HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或概率;或是降低或预防与HIV或HIV治疗相关或由之引起的不良副作用。
标签或插页可包括试剂盒成分可能提供的任意作用或受益(例如,预防性或治疗性效果或受益)的信息。例如,标签或插页可提供对一种或多种可以改善的症状的描述,即,降低,抑制,改善或预防与对象HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或概率;或是降低或预防与HIV或HIV治疗相关或由之引起的不良副作用。HIV症状和病变已在此处列举或为本领域所知(例如,发烧,疲劳,头痛,咽喉痛,淋巴结肿大,体重减轻,腹泻,皮疹,疮,疣,鹅口疮,带状疱疹,慢性或急性盆腔炎(PID),干咳,呼吸急促,瘀伤,出血,麻木或瘫痪,肌肉无力,伺机性紊乱,神经损伤,脑病,痴呆,死亡等)。与HIV或抗HIV治疗相关的不良副作用在此处列举或为本领域所知。
标签或插页可包含有关治疗的潜在不良副作用的信息。标签或插页可进一步包括对临床医生或对象有关需要停止或减少特定试剂盒成分的使用的情形的警示。不良副作用可能在该对象曾经,将要或正在采用一种或多种可能与本发明的化合物不相容的其它药物时出现,或在该对象曾经,将要或正在接受与该化合物不相容的其它治疗方案时出现,因此,标签或插页可包括有关该种副作用或不相容性的信息。
本发明试剂盒可进一步在包含本发明化合物的药物制剂中包括缓冲剂,或防腐或稳定剂。该试剂盒的各个成分可封入单独的容器中,且所有不同的容器包含在单个包装中。本发明的试剂盒可冷冻保存。
本发明的试剂盒可包括用于实施本发明的方法或向对象间接体内或体内施用本发明的化合物(例如,CSA)的装置等成分。该装置可以是传递装置,例如,注射器,可压缩(例如,可压挤)管子或用于黏膜,皮肤/真皮或角膜传递的皮肤贴片,或者用于向肺部或呼吸道传递的喷雾传递设备。
可用于本发明的化合物已在此处以及美国专利6,350,738;6,486,148和6,767,904中(在此引用作为参考)作了一般和具体的描述。化合物包括类固醇延伸为,例如,显示了一种或多种抗HIV活性或功能的阳离子类固醇抗微生物剂(CSA)。本领域的技术人员将可认识到该化合物包含在此处列举的一般化学式中。具有一种或多种抗HIV活性或功能的本发明其它化合物也得到了描述,并可通过此处列举以及本领域的测定进行鉴别。
式I的化合物,也称为阳离子类固醇抗微生物剂(CSA),包含:
其中:
稠环A,B,C和D各自为饱和或者完全或部分不饱和环;且
R1至R4,R6,R7,R11,R12,R15,R16以及R17分别独立选自以下组合:氢,羟基,取代或未取代的(C1-C10)烷基,(C1-C10)羟烷基,(C1-C10)烷氧基-(C1-C10)烷基,(C1-C10)烷羧基-(C1-C10)烷基,(C1-C10)烷氨基-(C1-C10)烷基,(C1-C10)烷氨基-(C1-C10)烷氨基,(C1-C10)烷氨基-(C1-C10)烷氨基-(C1-C10)烷氨基,取代或未取代的(C1-C10)氨烷基,取代或未取代的芳基,取代或未取代的芳氨基-(C1-C10)烷基,(C1-C10)卤烷基,C2-C6烯基,C2-C6炔基,氧代,与第二类固醇结合的连接基团,取代或未取代的(C1-C10)氨基烷氧基,取代或未取代的(C1-C10)氨基烷氧基-(C1-C10)烷基,取代或未取代的(C1-C10)氨基烷羧基,取代或未取代的(C1-C10)-氨烷基氨羰基,取代或未取代的(C1-C10)氨烷基甲酰胺,H2N-HC(Q5)-C(O)-O-,H2N-HC(Q5)-C(O)-N(H)-,(C1-C10)叠氮烷氧基,(C1-C10)氰基烷氧基,P.G.-HN-HC(Q5)-C(O)-O-,(C1-C10)胍烷氧基,(C1-C10)季铵烷羧基以及(C1-C10)胍烷基羧基,其中Q5为任意氨基酸的侧链(包括甘氨酸的侧链,即,H),P.G.为氨基保护基团,且
R5,R8,R9,R10,R13及R14各自为:当稠环A,B,C或D之一不饱和时被去除以完整该位置的碳原子的化合价,或者
选自组合:氢,羟基,取代或未取代的(C1-C10)烷基,(C1-C10)羟烷基,(C1-C10)烷氧基-(C1-C10)烷基,取代或未取代的(C1-C10)氨烷基,取代或未取代的芳基,C1-C10卤烷基,C2-C6烯基,C2-C6炔基,氧代,与第二类固醇结合的连接基团,取代或未取代的(C1-C10)氨基烷氧基,取代或未取代的(C1-C10)氨基烷羧基,取代或未取代的(C1-C10)氨基烷氨基羰基,H2N-HC(Q5)-C(O)-O-,H2N-HC(Q5)-C(O)-N(H)-,(C1-C10)叠氮烷氧基,(C1-C10)氰基烷氧基,P.G.-HN-HC(Q5)-C(O)-O-,(C1-C10)胍烷氧基,以及(C1-C10)胍烷羧基,其中Q5为任意氨基酸的侧链,P.G.为氨基保护基团,且
假设R1至R14之中至少两个独立选自组合:取代或未取代的(C1-C10)氨基烷氧基,(C1-C10)烷羧基-(C1-C10)烷基,(C1-C10)烷氨基-(C1-C10)烷氨基,(C1-C10)烷氨基-(C1-C10)烷氨基-(C1-C10)烷氨基,取代或未取代的(C1-C10)氨基烷羧基,取代或未取代的芳氨基-(C1-C10)烷基,取代或未取代的(C1-C10)氨基烷氧基-(C1-C10)烷基,取代或未取代的(C1-C10)氨基烷氨基羰基,(C1-C10)季铵烷羧基,H2N-HC(Q5)-C(O)-O-,H2N-HC(Q5)-C(O)-N(H)-,(C1-C10)叠氮烷氧基,(C1-C10)氰基烷氧基,P.G.-HN-HC(Q5)-C(O)-O-,(C1-C10)胍烷氧基以及(C1-C10)胍烷羧基;或其药学可接受的盐。
此处所用的“环”可以是杂环或碳环。此处所用的术语“饱和”指式I的稠环上的各原子或者被氢化,或者被取代,从而使各原子的化合价饱和。此处所用的术语“不饱和”指式I的稠环上的各原子未被氢,或取代基饱和。例如,稠环中邻近的碳原子可以双键相互连接。不饱和还可包括删除以下基团对中的至少一对并以双键填补删除位置环碳原子的化合价;例如R5和R9;R8和R10;以及R13和R14。
此处所用的术语“未取代”指各个原子通过氢化使其化合价饱和的部分。
此处所用的术语“卤素”指氟,氯,溴或碘等卤素原子。
氨基酸侧链的范例包括但不限于H(甘氨酸),甲基(丙氨酸),-CH2-(C=O)-NH2(天冬酰胺),-CH2-SH(半胱氨酸),以及-CH(OH)CH3(苏氨酸)。
烷基基团可以是取代或未取代的支链或直链烃。支链烷基基团的范例包括异丙基,仲丁基,异丁基,叔丁基,仲戊基,异戊基,叔戊基,异己基。取代的烷基基团可具有一个,两个,三个或多个取代基,该取代基可相同或不同,分别替换一个氢原子。取代基为卤素(例如,F,Cl,Br和I),羟基,保护羟基,氨基,保护氨基,羧基,保护羧基,氰基,甲磺酰氨基,烷氧基,酰氧基,硝基以及低级卤烷基。
此处所用的术语“取代”指具有一个,两个,三个或多个取代基的部分,该取代基可相同或不同,分别替换一个氢原子。取代基的范例包括但不限于为卤素(例如,F,Cl,Br和I),羟基,保护羟基,氨基,保护氨基,羧基,保护羧基,氰基,甲磺酰氨基,烷氧基,酰氧基,硝基以及低级卤烷基。
芳基基团为C6-20的芳香环,其中该环由碳原子组成(例如,C6-C14,C6-10芳基基团)。卤烷基的范例包括氟甲基,二氯甲基,三氯甲基,1,1-二氟乙基以及2,2-二溴乙基。
芳烷基基团为至少具有一个芳基环并至少具有一个与该环相连的烷基或亚烃基链的包含6-20个碳原子的基团。芳烷基基团的范例为苯甲基基团。
连接基团为任何用于将该式的化合物与另一类固醇(式I的第二化合物)连接的二价部分。连接基团的范例为(C1-C10)烷氧基-(C1-C10)烷基。
氨基保护基团已为本领域的技术人员所知。一般而言,只要该保护基团在针对化合物其它位置的后续反应的条件下保持稳定,且能够在适当的位置去除而不对分子中的其余部分产生不利影响,则保护基团的种类并不重要。此外,当实质性合成转化完成后保护基团可被另一基团取代。显而易见的,当一种化合物与此处披露的化合物的区别仅在于披露化合物的一种或多种保护基团被不同的保护基团所取代时,该化合物在本发明范围内。进一步的范例和条件可参见T.W.Greene,Protective Groups in Organic Chemistry,(1st ed.,1981,2nd ed.,1991)。
本发明还包括了至少由4个稠环组成的环系统,其中各个环具有5-7个原子。该环系统具有两面,在相同面上连接了3条链。各条链包含了至少通过一个原子与环系统隔离的含氮基团;该含氮基团为氨基基团,例如,伯胺基基团,或胍基团。该化合物还可包含疏水基团,例如与类固醇骨架连接的取代的(C3-10)氨烷基基团,(C1-10)烷氧基(C3-10)烷基基团,或(C1-10)烷氨基(C3-10)烷基基团。
例如,该化合物可具有式V,其中具有含氮基团的三条链分别独立选自下文定义的R1至R4,R6,R7,R11,R12,R15,R10,R17以及R18。
V
其中:
稠环A,B,C和D各自为饱和或者完全或部分不饱和,假设A,B,C和D中至少两者饱和,其中A,B,C和D环形成环系统;
m,n,p和q分别独立为0或1;
R1至R4,R6,R7,R11,R12,R15,R16,R17及R18各自选自组合:氢,羟基,取代或未取代的(C1-C10)烷基,(C1-C10)羟烷基,(C1-C10)烷氧基-(C1-C10)烷基,(C1-C10)烷羧基-(C1-C10)烷基,(C1-C10)烷氨基-(C1-C10)烷基,(C1-C10)烷氨基-(C1-C10)烷氨基,(C1-C10烷氨基-(C1-C10)烷氨基-(C1-C10)烷氨基,取代或未取代的(C1-C10)氨烷基,取代或未取代的芳基,取代或未取代的芳氨基-(C1-C10)烷基,(C1-C10)卤烷基,C2-C6烯基,C2-C6炔基,氧代,与第二类固醇结合的连接基团,取代或未取代的(C1-C10)氨基烷氧基,取代或未取代的(C1-C10)氨基烷氧基-(C1-C10)烷基,取代或未取代的(C1-C10)氨基烷羧基,取代或未取代的(C1-C10)氨基烷氨基羰基,取代或未取代的(C1-C10)氨烷基甲酰胺,H2N-HC(Q5)-C(O)-O-,H2N-HC(Q5)-C(O)-N(H)-,(C1-C10)叠氮烷氧基,(C1-C10)氰基烷氧基,P.G.-HN-HC(Q5)-C(O)-O-,(C1-C10)胍烷氧基,(C1-C10)季铵烷羧基,以及(C1-C10)胍烷基羧基,其中Q5为任意氨基酸的侧链(包括甘氨酸的侧链,即,H)。P.G.为氨基保护基团,且
R5,R8,R9,R10,R13以及R14各自为:当稠环A,B,C或D之一不饱和时被去除以完整该位置的碳原子的化合价,或者选自组合:氢,羟基,取代或未取代的(C1-C10)烷基,(C1-C10)羟烷基,(C1-C10)烷氧基-(C1-C10)烷基,取代或未取代的(C1-C10)氨烷基,取代或未取代的芳基,C1-C10卤烷基,C2-C6烯基,C2-C6炔基,氧代,与第二类固醇结合的连接基团,取代或未取代的(C1-C10)氨基烷氧基,取代或未取代的(C1-C10)氨基烷羧基,取代或未取代的(C1-C10)氨基烷氨基羰基,H2N-HC(Q5)-C(O)-O-,H2N-HC(Q5)-C(O)-N(H)-,(C1-C10)叠氮烷氧基,(C1-C10)氰基烷氧基,P.G.-HN-HC(Q5)-C(O)-O-,(C1-C10)胍烷氧基以及(C1-C10)胍烷羧基,其中Q5为任意氨基酸的侧链,P.G.为氨基保护基团,
假设R1至R4,R6,R7,R11,R12,R15,R16,R17以及R18中至少三个在环系统的同一面上且各自选自组合:取代或未取代的(C1-C10)氨烷基,取代或未取代的(C1-C10)氨基烷氧基,(C1-C10)烷羧基-(C1-C10)烷基,(C1-C10)烷氨基-(C1-C10)烷氨基,(C1-C10)烷氨基-(C1-C10)烷氨基-(C1-C10)烷氨基,取代或未取代的(C1-C10)氨基烷羧基,取代或未取代的芳氨基-(C1-C10)烷基,取代或未取代的(C1-C10)氨基烷氧基-(C1-C10)氨基烷氨基羰基,取代或未取代的(C1-C10)氨基烷氨基羰基,取代或未取代的(C1-C5)氨烷基甲酰胺,(C1-C10)季铵烷羧基,H2N-HC(Q5)-C(O)-O-,H2N-HC(Q5)-C(O)-N(H)-,(C1-C10)叠氮烷氧基,(C1-C10)氰基烷氧基,P.G.-HN-HC(Q5)-C(O)-O-,(C1-C10)胍烷氧基以及(C1-C10)胍烷羧基;或其药学可接受的盐。在不同方面,m,n,p和q之中至少两个或至少三个为1。
此处列举的化合物保留了类固醇中发现的特定立体化学和电学特性。此处所用的术语“相同构型”指在融合类固醇上的取代基具有相同的立体化学取向。例如取代基R3,R7和R12均为β取代或α取代。
本发明的化合物包括但不限于具有与类固醇骨架或支架上的任意碳原子共价连接的胺或胍基团的化合物。在不同的实施方式中,可与该类固醇骨架或支架的C3,C7和C12中任意一个或多个位置共价连接基团。在其它实施方式中,该类固醇骨架或支架的C3,C7和C12中任意一个或多个位置缺失基团。
包含该基团的本发明的化合物可包含接枝,接枝具有可变的链长或大小。此处所用的术语“接枝”或“带接枝”在涉及本发明的化合物时指在类固醇骨架或支架以及末端氨基或胍基团之间的原子链。在不同实施方式中,在C3,C7和C12中任意一个或多个位置连接了接枝。在附加实施方式中,在C3,C7和C12中任意一个或多个位置缺失接枝。接枝长度可包括与该类固醇骨架共价连接的杂原子(O或N)。
也可采用其它环系统,例如,5元稠环。本发明还可包括具有5和6元环组合的骨架的化合物。胺或胍基团可通过至少一个,两个,三个或更多个原子与骨架隔离。该骨架可用于在类固醇的一面或平面为胺或胍基团取向。例如,下图显示了在骨架一面或平面具有伯胺基的化合物:
此处提供了式I的化合物的合成方法,其中R1至R14中至少两个基团各自选自由取代或未取代的(C1-C10)氨基烷氧基构成的组合。在一个实施方式中,该方法包括了接触式IV的化合物。
其中R1至R14中至少两个基团为羟基,且稠环A,B,C和D上剩余的部分如式I所定义,具有生成式IV烷基醚化合物的亲电体,其中R1至R14中至少两个基团为(C1-C10)烷氧基。该烷基醚化合物被转化成为氨基前体化合物,其中R1至R14中至少两个基团各自选自由(C1-C10)叠氮烷氧基和(C1-C10)氰基烷氧基构成的组合,且该氨基前体化合物被还原形成式I的化合物。
在方法中采用的亲电体包括但不限于2-(2-溴乙基)-1,3-二氧戊环,2-碘乙酰胺,2-氯乙酰胺,N-二(2-溴乙基)邻苯二甲酰亚胺,N-二(3-溴丙基)邻苯二甲酰亚胺,溴化烯丙酯。示范性亲电体为溴化烯丙酯。
本发明还包括了生成式I化合物的方法,其中R1至R14中至少两个基团为(C1-C10)胍烷氧基。在一个实施方式中,方法包括了将式IV化合物(其中R1至R14中至少两个基团为羟基)与生成式IV烷基醚化合物的亲电体相接触,其中R1至R14中至少两个基团为(C1-C10)烷氧基。该烯丙基醚化合物被转化成为氨基前体化合物,其中R1至R14中至少两个基团各自选自由(C1-C10)叠氮烷氧基和(C1-C10)氰基烷氧基构成的组合。该氨基前体化合物被还原生成氨烷基醚化合物,其中R1至R14中至少两个基团为(C1-C10)氨基烷氧基。该氨烷基醚化合物与胍接触生成亲电体以形成式I的化合物。
此处所用的术语“胍生成亲电体”指用于生成式I的胍化合物的亲电体。示范性的胍生成亲电体为HSO3-C(NH)-NH2。
本发明还包括了生成式I化合物的方法,其中R1至R14中至少两个基团为H2N-HC(Q5)-C(O)-O-且Q5为任意氨基酸的侧链。在一个实施方式中,方法包括了将式IV化合物(其中R1至R14中至少两个基团为羟基)与受保护的氨基酸接触生成式IV的受保护氨基酸化合物的步骤,其中R1至R14中至少两个基团为P.G.-HN-HC(Q5)-C(O)-O-且Q5为任意氨基酸的侧链,而P.G.为氨基保护基团。将受保护氨基酸化合物的保护基团去除以形成式I的化合物。
以下包括了制备本发明化合物的示范性非限制性合成路线图:
路线1显示了化合物1,2,4和5的制备
试剂(括号中为反应产率):a)LiAlH4,THF(98%)。b)三苯甲基氯Et3N,DMF(70%)。c)溴化烯丙酯,NaH,THF(96%)。d)O3,CH2Cl2,MeOH;Me2S;NaBH4(95%)。e)9-BBN,THF;H2O2,NaOH(80%)。F)MsCl,CH2Cl2,Et3N(78%,82%)。g)NaN3,DMSO(由20,19直接转化为23时为66%)。h)TsOH,MeOH(94%,总体来自于19时为94%)。i)MsCl,CH2Cl2,Et3N(99%,97%)。j)对苯甲基甲胺(95%,96%)。k)LiAlH4,THF(95%,99%)。l)NH2C(NH)SO3H,MeOH(91%,89%)。
路线2显示了化合物3的制备
试剂(括号中为反应产率):a)KCN,DMSO;MeOH,TsOH(92%)。b)MsCl,Et3N,CH2Cl2;BnMeNH(88%)。c)LiAlH4,AlCl3,THF(50%)。
路线3显示了化合物6和7的制备
试剂(括号中为反应产率):a)二环己基碳二亚胺,N-羟基琥珀酰亚胺,甲基苯胺,CH2Cl2,MeOH(85%)。b)LiAlH4,THF(82%)。c)二环己基碳二亚胺,二甲基氨基吡啶,Boc-甘氨酸,CH2Cl2(68%)。d)二环己基碳二亚胺,二甲基氨基吡啶,Boc-β-丙氨酸,CH2Cl2(72%)。e)二烷(约100%,约100%)
路线4显示了化合物8的合成
试剂(括号中为反应产率):a)DIAD,Ph3P,对硝基苯甲酸,THF(85%);NaOH,MeOH(85%)。b)溴化烯丙酯,NaN,THF(79%)。c)O3,CH2Cl2,MeOH;Me2S;NaBH4,(65%)。d)MsCl,CH2Cl2,Et3N(86%)。e)NaN3,DMSO(80%)。f)TsOH,MeOH(94%)。g)MsCl,CH2Cl2,Et3N;对苯甲基甲胺(93%)。g)LiAlH4,THF(94%)。
路线5显示了化合物CSA-7和CSA-8的合成
试剂(括号中为反应产率):a)NaH,溴辛烷,DMF(80%);LiAlH4,THF(60%)。b)LiAlH4,THF(60%)。
路线6显示了化合物CSA-11的合成
试剂(括号中为反应产率):a)乙烯乙二醇,对甲基苯磺酸,苯;NaOH,MeOH(96%)。b)溴化烯丙酯,NaH,THF(90%)。c)9-BBN,THF;NaOH,H2O2,H2O(54%)。d)吡啶对甲基苯磺酸盐,MeOH(98%)。e)甲烷磺酰氯,Et3N,CH2Cl2;NaN3,DMSO(88%)。f)LiAlH4,THF(69%)。
路线7显示了化合物CSA-10的合成
试剂(括号中为反应产率):a)甲烷磺酰氯,Et3N,CH2Cl2;NaBr,DMF(97%)。b)23,NaH,DMF(52%)。c)LiAlH4,THF(76%)。
路线8显示了化合物111,CSA-17,113和CSA-7的制备
对于23,116a-d,R=-(CH2)3N3
对于116a,111,R’=-CH3 对于116c和113,R’=-(CH2)4CH3
对于116b,CSA-17,R’=-(CH2)2CH3 对于116d和CSA-7,R’=-(CH2)7CH3
试剂(括号中为反应产率):a)NaH,DMF,CH3I,CH3(CH2)2Br,CH3(CH2)4Br或CH3(CH2)7Br(85-90%)。b)LiAlH4,THF(55-70%)。
路线9显示了化合物106的制备
试剂(括号中为反应产率):a)尿素-过氧化氢复合物,三氟醋酸酐,CH2Cl2(55%)。b)NaOH,MeOH;LiAl4,THF(43%)。
路线10显示了化合物108和109的制备
试剂(括号中为反应产率):a)O3,CH2Cl2,MeOH,Me2S;NaBH4(76%)。b)NaOH,MeOH;TrCl,Bt3N,DMAP,DMF;溴化烯丙酯,NaH,THF(64%)。c)9-BBN,THF;H2O2,NaOH(93%)。d)MsCl,Et3N,CH2Cl2;NaN3,DMSO;TsOH,MeOH,CH2Cl2(94%),e)LiAlH4,THF(71%)。f)o-NO2C6H4SeCN,Bu3P,THF;H2O2.(36%)。g)O3,CH2Cl2,MeOH;Me2S;LiAlH4,THF(68%)。
路线11显示了化合物202和203的制备
路线12显示了化合物209a-209c的制备
试剂(括号中为反应产率):a)BOC-甘氨酸,BOC-丙氨酸或二-BOC-赖氨酸,DGC,DMAP,CH2Cl2。b)LIOH,THF,MeOH(两步为71-85%),c)含于二烷的4M HCl(约100%)
路线13显示了化合物206的制备
试剂(括号中为反应产率):a)NH2OH.HCl,AcONa.,EtOH(97%)。b)NaBH4,TiCl4,甘醇二甲醚(33%)。
路线14显示了化合物324-326的合成
试剂(括号中为反应产率):a)苯甲醇,b)BOC-甘氨酸,BOC-β-丙氨酸或-BOC-γ-氨基丁酸,DCC,DMAP,CH2Cl2(68-78%)。c)H2,Pd/C(97-99%)。d)(CH3)2N(CH2)2OH,DCC,DMAP,CH2Cl2或THF(62-82%)。E)MeI,CH2Cl2。f)HCl,二烷(两步为83-90%)。
路线15显示了化合物341-343的合成
试剂(括号中为反应产率):a)辛醇,TsOH(73%)。b)Boc-甘氨酸,BOC-β-丙氨酸或-BOC-γ-氨基丁酸,DCC,DMAP,CH2Cl2(91-95%)。c)HCl,二烷(84-99%)。
路线16显示了化合物356的合成
试剂(括号中为反应产率):a)MsCl,NEt3,CH2Cl2(86%)。b)NH2(CH2)3NHBoc,THF(97%)。c)PPh3,THF/H2O,(86%)。d)HCl,2M含于乙基醚(89%)。
路线17显示了化合物CSA-54的合成
试剂(括号中为反应产率):a)MsCl,NEt,,CH2Cl2(86%)。b)NH2(CH2),OH,THF,然后步骤a(63%)。c)NH2(CH2)3NHBoc,THF,(83%)。d)PPh3,THF/H2O,(90%)。e)HCl,2M含于乙基醚,(94%)。
本发明的化合物以及如本发明所述的化合物前体可从如Sigm-Aldrich Co.,St.Louis;MO以及Research Plus,Inc.,Manasquan,NJ.等公司购得。如本发明所述的其它化合物可参照此处,美国专利6,350,738;6,486,148和6,767,904,以及本领域所披露的方法合成得到。
此处提供了用于治疗对象的HIV感染或发病,降低对象对HIV感染或发病的易感性以及降低,抑制,改善或预防与HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或概率的候选药剂的鉴定方法。在一种实施方式中,该方法包括了提供测试药剂(如阳离子类固醇抗微生物剂(CSA));将测试药剂与HIV接触并确定该药剂是否抑制HIV感染或发病。经鉴定可抑制HIV感染或发病的测试药剂为治疗对象HIV感染或发病的候选药剂。经鉴定可抑制HIV感染或发病的测试药剂同时还是降低对象对HIV感染或发病的易感性的候选药剂。经鉴定可抑制HIV感染或发病的测试药剂进一步为降低,抑制,改善或预防与HIV感染或发病相关的一种或多种症状的发作,严重性,持续时间,进展,频率或概率的候选药剂。经鉴定可抑制HIV感染或发病的测试药剂进一步为降低或预防由HIV或HIV治疗引起的不良副作用的候选药剂。在各个方面,该对象为哺乳动物(例如,灵长动物)。例如,哺乳动物可包含HIV感染或发病的动物模型(例如,SIV感染灵长动物)。
除非另行说明,此处所用的技术和科学术语的含义等同于本发明所属领域普通技术人员的普遍理解。尽管其它与此处所述类似或等同的方法和材料也可用于对本发明的实施或研究,此处描述了适用的方法和材料。
此处披露的所有特征均可以任何方式进行组合。本说明书披露的各个特征可由达到相同,相当或类似目的的特征进行替换。因此,除非另行指明,所披露的特征(例如,化合物结构)为相当或类似特征的一般范例。
此处引用的所有应用,出版物,专利及其它参考文献,GenBank引文以及ATCC引文均在此全文引用作为参考。在产生冲突的情况下,将受本说明书包括定义所支配。
除非上下文另行明确指出,此处所用的单数形式的“一种”和“该”包括复数含义。因此,例如,“一种化合物”包括了多个化合物而“一种抗HIV作用,活性或功能”可包括一种或多种作用,活性或功能,依次类推。
除非上下文另行明确指出,此处所用的所有数值或数值范围包括该范围内的整数以及该值或该范围内整数的分数。因此,举例说明,90-100%的范围包括91%,92%,93%,94%,95%,95%,97%等,以及91.1%,91.2%,91.3%,91.4%,91.5%等,92.1%,92.2%,92.3%,92.4%,92.5%等,并依次类推。0-72小时包括1,2,3,4,5,6,7小时等,以及1,2,3,4,5,6,7分钟等,并依次类推。0-72小时包括1,2,3,4,5,6,7小时等,以及1,1,3,4,5,6,7分钟等,并依次类推。剂量范围,例如0.1-1ug/kg,1-10ug/kg,10-25ug/kg,25-50ug/kg,50-100ug/kg,100-500ug/kg,500-1000ug/kg,1-5mg/kg,5-10mg/kg,10-20mg/kg,20-50mg/kg,50-100mg/kg,100-250mg/kg,250-500mg/kg,包括0.11-0.9ug/kg,2-9ug/kg,11.5-24.5ug/kg,26-49ug/kg,55-90ug/kg,125-400ug/kg,750-800ug/kg,1.1-4.9mg/kg,6-9mg/kg,11.5-19.5mg/kg,21-49mg/kg,55-90mg/kg,125-200mg/kg,275.5-450.1mg/kg等。
此处披露的本发明一般采用肯定性的语言描述多个实施方式。本发明还包括了完全或部分排除对象(例如,物质或材料,方法步骤和条件,方案或程序等)的实施方式。因此,尽管本发明一般不以本发明不包括什么来进行表示,本发明未明确排除的方面仍然在此披露。
本发明的一系列实施方式已得到描述。然而,本领域的技术人员可在不脱离本发明的精神和范围的情况下对本发明进行各种变化和修饰以使其适合各种用途和条件。例如,此处披露的本发明化合物的盐,酯,醚以及酰胺均在本发明的范围之内。相应地,下列实施例目的在于阐述,而非限制权利要求书中描述的本发明的范围。
具体实施方式
CSA化合物和中间体采用如下仪器进行鉴别:1H和13C NMR光谱记录于Varian Gemini 2000(200MHz),Varian Unity 300(300MHz)或Varian VXR 500(500MHz)光谱仪,并以TMS,残留CHCl3(1H)或CDCl3(13C),或是残留CHD2OD(1H)或CD3OD(13C)作为参考。IR光谱记录于Perkin Elmer 1600FTIR仪器。质谱数据来自于JOEL SX 102A光谱仪。THF在使用前采用Na/苯甲酮进行干燥,而CH2Cl2采用CaH2进行干燥。其它试剂和溶剂从市场购得并直接使用购得物品。
实施例1
本实施例包括了对一种或多种获取化合物1-5,13-20和22-27的示范性合成方法的描述。
化合物13:向1L圆底烧瓶添加含于干燥THF(600mL)的胆酸甲酯(30.67g,72.7mmol)以及LiAlH4(4.13g,109mmol)。回流48小时后,缓慢加入Na2SO4饱和水溶液(100mL),过滤所得沉淀并以热THF和MeOH进行洗涤。用MeOH重结晶得到13的无色晶体(28.0g,98%产率),m.p.236.5-238℃;IR(KBr)3375,2934,1373,1081cm-1;1H NMR(CDCl3/MeOH-d4,200MHz)δ3.98(bs,1H),3.83(bs,1H),3.60-3.46(m,2H),3.38(bs,5H),2.30-2.10(m,2H),2.05-1.05(多重态系列,22H),1.03(bs,3H),0.92(s,3H),0.71(s,3H);13CNMR(CDCl3/MeOH-d4,50MHz)δ73.89,72.44,68.99,63.51,48.05,47.12,42.49,40.37,39.99,36.62,36.12,35.58,35.40,32.77,30.69,30.04,29.02,28.43,27.27,23.96,23.08,18.00,13.02;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)417.2992(55.3%);计算417.2981。
化合物14:向圆底烧瓶添加含于DMF(300mL)的13(28.2g,71.7mmol),Et3N(20mL,143.4mmol),三苯甲基氯(25.98g,93.2mmol)以及DMAP(0.13g,1.07mmol)。在N2中于50℃下将混合物搅拌30小时,然后加入水(1000mL),并以EtOAc(5x200mL)萃取。用水和盐水洗涤合并的萃取相,并以MgSO4干燥。真空去除溶剂后,使用SiO2层析(以CH2Cl2,Et2O和MeOH为洗脱液)纯化残余物以得到浅黄色固体14(31.9g,70%产率),m.p.187℃.(分解);IR(KBr)3405,2935,1448,1075Gm-1;1H NMR(CDCl3,200MHz)δ7.46-7.42(m,6H),7.32-7.17(m,9H),3.97(bs,1H),3.83(bs,1H),3.50-3.38(m,1H),3.01(bs,1H),2.94(dd,J=14.2,12.2Hz,2H),2.64(bs,1H),2.51(bs,1H),2.36-2.10(m,2H),2.00-1.05(多重态系列,22H),0.96(d,J=5.8Hz,3H),0.87(s,3H),0.64(s,3H);13C NMR(CDCl3,50MHz)δ144.77,128.93,127.91,127.01,86.43,73.35,72.06,68.66,64.28,47.47,46.53,41.74,41.62,39.64,35.57,35.46,34.91,34.82,32.40,30.55,28.21,27.69,26.80,26.45,23.36,22.59,17.83,12.61;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)659.4069(100%);计算659.4076。
化合物15:向圆底烧瓶添加含于干燥THF(600mL)的14(20.0g,31.4mmol)以及NaH(60%含于矿物油,6.3g,157.2mmol)。将混合物在N2中回流30分钟,然后添加烯丙基溴(27mL,314mmol)。回流60小时后,添加NaH(3当量)和烯丙基溴(4当量)。再次回流50小时,缓慢加水(20mL),然后添加1%HCl直至水层呈中性。然后以乙醚(3x 100mL)萃取混合物,并以水(100mL)和盐水(2x 100mL)洗涤合并的萃取相。使用无水Na2SO4干燥乙醚溶液,去除溶剂后,使用SiO2层析(以1∶8的己烷和EtOAc/己烷作为洗脱液)纯化残留物以获得浅黄色玻璃15(22.76g,96%产率)。IR(近)2930,1448,1087cm-1;1H NMR(CDCl3,200MHz)δ7.48-7.30(m,6H),7.32-7.14(m,9H),6.04-5.80(m,3H),5.36-5.04(多重态系列,6H),4.14-3.94(m,4H),3.74(td,J=13.8,5.8Hz,2H),3.53(bs,1H),3.20-2.94(m,3H),3.31(bs,1H),2.38-1.90(m,4H),1.90-0.96(多重态系列,20H),0.90(d,J=5.4Hz,3H),0.89(s,3H),0.64(s,3H);13CNMR(CDCl3,50MHz)δ144.83,136.27,136.08,128.94,127.90,126.98,116.46,115.70,86.42,80.94,79.29,74.98,69.52,69.39,68.86,64.39,46.51,46.42,42.67,42.14,39.92,35.63,35.51,35.13,32.45,28.98,28.09,27.66,27.57,26.72,23.32,23.11,17.92,12.69;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)779.5013(86.1%);计算得到779.5015。
化合物16:向三口圆底烧瓶添加含于CH2Cl2(200mL)的15(3.34g,4.4mmol)以及甲醇(100mL)。向冷溶液(-78℃)吹入臭氧直至呈稳定蓝色。以氧气吹走过量臭氧。将混合物在干冰-丙酮浴中放置1小时。加入甲硫醚(2.4mL)15分钟后,在5%NaOH水溶液(10mL)/甲醇(10mL)中以NaBH4(1.21g,32mmol)处理该混合物,升温至室温。以盐水(3x50mL)洗涤混合物,以CH2Cl2(2x50mL)萃取合并的盐水洗液。以MgSO4干燥有机溶液。使用SiO2层析(含于CH2Cl2的MeOH(5%))纯化得到3.30g(95%产率)油状的16。IR(近)3358,2934,1448,1070cm-1;1H NMR(CDCl3,200MHz)δ7.50-7.42(m,6H),7.32-7.17(m,9H),3.80-2.96(多重态系列,20H),2.25-0.96(多重态系列,24H),0.89(bs,6H),0.65(s,3H);13C NMR(CDCl3,50MHz)5144.73,128.88,127.87,126.96,86.38,81.05,79.75,76.59,70.33,69.66,69.30,64.20,62.25,62.16,62.03,46.77,46.36,42.63,41.77,39.60,35.43,35.23,35.05,34.89,32.42,28.91,27.93,27.56,27.15,26.68,23.35,22.98,22.85,18.15,12.60;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)791.4860(100%),计算791.4863。
化合物17:在冰浴和N2中向圆底烧瓶添加含于干燥THF(30mL)的16(1.17g,1.55mmol),随后添加9-BBN/THF溶液(0.5M,10.2mL,5.51mmol)。将混合物在室温下搅拌12小时。顺序添加NaOH(20%)水溶液(2mL)和过氧化氢(30%)(2mL)。将混合物回流1小时,然后添加盐水(60mL)并以EtOAc(4x30mL)萃取。以无水Na2SO4干燥合并的萃取相。以SiO2层析(含于CH2Cl2的MeOH(5%))纯化得到无色油状的产物(1.01g,80%产率)。IR(近)3396,2936,1448,1365,1089cm-1;1H NMR(CDCl3,200MHz)δ7.50-7.42(m,6H),7.34-7.16(m,9H),3.90-3.56(m,13H),3.50(bs,1H),3.40-2.96(多重态系列,6H),2.30-0.94(多重态系列,30H),0.90(s,3H),0.88(d,J=5.4Hz,3H),0.64(s,3H);13C NMR(CDCl3,50MHz)δ144.73,128.88,127.85,126.94,86.36,80.52,78.90,76.36,66.82,66.18,65.77,64.22,61.53,61.41,6L34,46.89,46.04,42.60,41.59,39.60,35.37,35.27,34.88,32.75,32.44,32.31,28.82,27.65,27.48,27.13,26.77,23.35,22.74,22.38,18.08,12.48;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)833.5331(100%),计算833.5332。
化合物18:向圆底烧瓶添加含于CH2Cl2(150mL)的16(3.30g,4.29mmol)以及NEt3(2.09mL,15.01mmol)。将混合物置于冰浴和N2中,然后添加甲磺酰氯(1.10mL,14.16mmol)。30分钟后,添加水(30mL)和盐水(200mL)。以盐水(2x 50mL)洗涤CH2Cl2层并以无水Na2SO4干燥。以EtOAc(3x100mL)萃取合并的水相混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶1)纯化得到浅黄色油状的目标产物(3.35g,78%产率)。IR(近)2937,1448,1352,1174,1120,924cm-1;1H NMR(CDCl3,200MHz)δ7.52-7.40(m,6H),7.34-7.20,(m,9H),4.42-4.24(m,6H),3.90-3.64(m,4H),3.60-3.30(m,4H),3.24-3.00(m,3H),3.10(s,6H),3.05(s,3H),2.20-1.96(m,3H)1.96-1.60(m,8H),1.60-0.94(多重态系列,13H),0.91(bs,6H),0.65(s,3H);13C NMR(CDCl3,50MHz)δ114.68,128.85,127.85,126.96,86.37,81.37,79.58,76.58,69.95,69.43,69.34,66.52,66.31,65.59,64.11,46.80,46.20,42.65,41.48,39.35,37.82,37.48,35.36,34.92,34.73,32.37,28.66,28.01,27.44,27.03,26.72,23.17,22.91,22.72,18.13,12.50;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)1205.4176(81.5%),计算得到1205.4189。
化合物19:向圆底烧瓶添加含于CH2Cl2(50mL)的17(1.01g,1.25mmol)以及NEt3(0.608mL,4.36mmol)。将混合物置于冰浴和N2中,然后添加甲磺酰氯(0.318mL,4.11mmol)。30分钟后,添加水(10mL)和盐水(80mL)。以盐水(2x 20mL)洗涤CH2Cl2层并以无水Na2SO4干燥。以EtOAc(3x40mL)萃取合并的水相混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶1)纯化得到淡黄色油状的目标产物(1.07g,82%)。IR(近)2938,1356,1176,1112cm-1;1H NMR(CDCl3,300MHz)δ7.46-7.43,(m,6H),7.32-7.22(m,9H),4.40-4.31(m,6H),3.72-3.64(m,2H),3.55(dd,J=6.3,5.8Hz,2H),3.51(bs,3H),3.32-3J4(m,3H),3.14-2.92(m,3H),3.01(s,3H),3.01(s,3H),3.00(s,3H),2.10-1.92(m,10H),1.92-1.58(m,8H),1.56-0.92(多重态系列,12H),0.90(s,3H),0.89(d,J=5.4Hz,3H),0.64(s,3H);13C NMR(CDCl3,75MHz)δ144.67,128.85,127.85,126.96,86.42,81.06,79.83,76.81,68.12,68.06,68.02,64.26,64.06,63.42,46.76,46.38,42.73,41.87,39.73,37.44,37.32,37.29,35.52,35.48,35.32,35.06,32.53,30.55,30.28,30.02,29.15,27.96,27.69,27.61,26.75,23.52,23.02,18.17,12.64;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)1067.4672(100%),计算得到1067.4659。
化合物20:向圆底烧瓶添加含于干燥DMSO(20mL)的18(1.50g,1.50mmol)以及NaN3(0.976g,15mmol)。将混合物加热至80℃,并在N2下搅拌过夜,然后以水(100mL)稀释。以EtOAc(3x50mL)萃取所得的水相混合物,以盐水洗涤合并的萃取相并以无水Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶5)纯化得到的透明玻璃状的目标产物(0.83g,66%产率)。IR(近)2935,2106,1448,1302,1114cm-1;1H NMR(CDCl3,200MHz)δ7.50-7.42(m,6H),7.36-7.20(m,9H),3.84-3.70(m,2H),3.65(t,J=4.9Hz,2H),3.55(bs,1H),3.44-3.08(m,10H),3.02(t,J=6.4Hz,2H),2.38-0.96(多重态系列,24H),0.92(d,J=5.6Hz,3H),0.91(s,3H),0.65(s,3H);13C NMR(CDCl3,50MHz)δ114.84,128.97,127.92,126.99,86.42,81.24,80.12,76.59,67.84,67.29,66.66,64.36,51.67,51.44,51.18,46.53,46.23,42.21,41.93,39.73,35.66,35.36,35.06,34.78,32.40,28.95,27.76,27.39,26.87,23.45,22.98,22.92,17.98,12.53;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)866.5040(100%),计算得到866.5057。
化合物22:向圆底烧瓶添加含于MeOH(30mL)的20(830mg,0.984mmol)以及CH2Cl2(30mL)和对甲苯磺酸(9.35mg,0.0492mmol)。将该溶液在室温下搅拌2.5小时,然后添加NaHCO3饱和水溶液(10mL)。添加盐水(30mL),并以EtOAc(4x20mL)萃取混合物。以无水Na2SO4干燥合并的萃取相。以SiO2层析(EtOAc/己烷1∶2)纯化得到浅黄色油状的目标产物(0.564g,95%产率)。IR(近)3410,2934,2106,1301,1112cm-1;1H NMR(CDCl3,200MHz)δ3.80-3.54(m,7H),3.44-3.20(m,10H),2.35-0.96(多重态系列,24H),0.95(d,J=6.4Hz,3H),0.92(s,3H),0.68(s,3H);13C NMR(CDCl3,50MHz)δ81.10,80.01,76.60,67.75,67.16,66.56,63.63,51.57,51.34,51.06,46.29,46.12,42.12,41.81,39.60,35.55,35.23,34.94,34.66,31.75,29.48,28.81,27.72,27.66,27.29,23.32,22.86,22.80,17.85,12.39;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)624.3965(100%),计算得到624.3962。
化合物23:向圆底烧瓶添加19(1.07g,1.025mmol)和NaN3(0.666g,10.25mmol),随后添加干燥DMSO(15mL)。将混合物加热至80℃,在N2下过夜。加入H2O(200mL)后,以EtOAc(4x 40mL)萃取混合物,以盐水(2x 50mL)洗涤合并的萃取相并用无水Na2SO4干燥。去除溶剂后,将残留物溶解在MeOH(15mL)和CH2Cl2(15mL)中,然后添加催化量的对甲苯磺酸(9.75mg,0.051mmol)。将该溶液在室温下搅拌2.5小时,然后添加NaHCO3饱和水溶液(15mL)。添加盐水(60mL)后,以EtOAc(5x 30mL)萃取混合物。以盐水(50mL)洗涤合并的萃取相并以无水Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶2)纯化得到淡黄色油状的目标产物(0.617g,94%产率)。IR(近)3426,2928,2094,1456,1263,1107cm-1;1H NMR(CDCl3,300MHz)δ3.68-3.56(m,3H),3.56-3.34(多重态系列,10H),3.28-3.00(多重态系列,4H),2.20-2.00(m,3H),1.98-1.55(多重态系列,15H),1.55-0.96(多重态系列,13H),0.92(d,J=6.6Hz,3H),0.89(s,3H),0.66(s,3H);13C NMR(CDCl3,75MHz)δ80.63,79.79,76.04,64.99,64.45,64.30,63.72,49.01,48.94,48.74,46.49,46.39,42.70,41.98,39.80,35.65,35.42,35.28,35.08,31.99,29.78,29.75,29.70,29.49,29.06,27.87,27.79,27.65,23.53,23.04,22.85,18.05,12.59;HRFAB-MS(硫代甘油+Na基质)m/e:([M+Na]+)666.4415(100%),计算得到666.4431。
化合物24:向圆底烧瓶添加含于CH2Cl2(30mL)的22(0.564g,0.938mmol)以及NEt3(0.20mL,1.40mmol)。将混合物置于冰浴和N2中,然后添加甲磺酰氯(0.087mL,1.13mmol)。30分钟后,添加水(20mL)和盐水(100mL)。以盐水(2x 20mL)洗涤CH2Cl2层并以无水Na2SO4干燥。以EtOAc(3x30mL)萃取合并的水相混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶2)纯化得到浅黄色油状的目标产物(0.634g,99%产率)。IR(近)2935,2106,1356,1175,1113cm-1;1H NMR(CDCl3,300MHz)δ4.20(t,J=6.8Hz,2H),3.80-3.75(m,1H),3.70-3.64(m,3H),3.55(bs,1H),3.44-3.01(m,10H),3.00(s,3H),2.32-2.17(m,3H),2.06-2.03(m,1H),1.90-0.88(多重态系列,20H),0.95(d,J=6.6Hz,3H),0.91(s,3H),0.68(s,3H);13C NMR(CDCl3,75MHz)δ80.90,79.86,76.43,70.78,67.64,66.99,66.48,51.50,51.26,50.97,46.05,45.96,42.08,41.71,39.51,37.33,35.15,34.86,34.60,31.34,28.73,27.62,27.59,27.51,25.68,23.22,22.80,22.70,17.62,12.33;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)702.3741(100%),计算得到702.3737。
化合物25:向圆底烧瓶添加含于CH2Cl2(30mL)的23(0.617g,0.96mmol)以及NEt3(0.20mL,1.44mmol)。将混合物置于冰浴和N2中,然后添加甲磺酰氯(0.089mL,1.15mmol)。30分钟后,添加水(20mL)和盐水(120mL)。以盐水(2x 20mL)洗涤CH2Cl2层并以无水Na2SO4干燥。以EtOAc(3x100mL)萃取合并的水相混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。去除溶剂后得到浅黄色油状的目标产物(0.676g,97%产率)。IR(近)2934,2094,1454,1360,1174,1112cm-1;1H NMR(CDCl3,300MHz)δ4.17(t,J=6.6Hz,2H),3.65-3.28(series of multipJets,11H),3.64-3.00(多重态系列,4H),2.97(s,3H),2.18-1.96(多重态系列,16H),1.54-0.94(多重态系列,11H),0.89(d,J=6.6Hz,3H),0.86(s,3H),0.63(s,3H);13CNMR(CDCl3,15MHz)b 80.47,79.67,75.92,70.84,64.90,64.37,64.17,48.90,48.86,48.66,46.32,46.26,42.63,41.87,39.70,37.39,35.34,35.28,35.20,34.99,31.61,29.68,29.60,28.96,27.78,27.68,27.57,25.79,23.41,22.95,22.74,17.82,12.50;HRFAB-MS(硫代甘油基质)m/e:([M+H]+)722.4385(22.1%),计算得到722.4387。
化合物26:向50mL圆底烧瓶添加24(0.634g,0.936mmol)和对苯甲基甲胺(2mL)。将混合物在N2下加热至80℃过夜。真空去除过量对苯甲基甲胺,对残余物采用SiO2层析(EtOAc/己烷1∶2)。得到浅黄色油状的目标产物(0.6236g,95%产率)。IR(近)2935,2106,1452,1302,1116cm-1;1H NMR(CDCl3,200MHz)δ7.32-7.24(m,5H),3.80-3.76(m,1H),3.70-3.60(m,3H),3.54(bs,1H),3.47(s,2H),3.42-3.10(m,10H),2.38-2.05(m,5H),2.17(s,3H),2.02-0.88(多重态系列,23H),0.93(d,J=7.0Hz,3H),0.91(s,3H),0.66(s,3H);13CNMR(CDCI3,50MHz)δ139.60,129.34,128.38,127.02,81.22,80.10,76.71,67.85,67.29,66.65,62.45,58.38,51.65,51.44,51.16,46.50,46.21,42.40,42.20,41.93,39.72,35.80,35.34,35.05,34.76,33.65,28.93,27082,27.75,27.38,24.10,23.45,22.98,22.91,18.05,12.50;HRFAB-MS(硫代甘油+Na+基质)m/e:([M-H]+)703.4748(90.2%),计算得到703.4772;([M+H]+)705.4911(100%),计算得到705.4928;([M+Na]+)727.4767(1.5%),计算得到727.4748。
化合物27:向50mL圆底烧瓶添加25(0.676g,0.937mmol)和对苯甲基甲胺(2mL)。将混合物在N2下加热至80℃过夜。真空去除过量对苯甲基甲胺,对残余物采用SiO2层析(EtOAc/己烷1∶2)。得到浅黄色油状的目标产物(0.672g,96%产率)。IR(近)2934,2096,1452,1283,1107cm-1;1H NMR(CDCl3,300MHz)δ7.34-7.20(m,5H),3.68-3.37(多重态系列,13H),3.28-3.04(m,4H),2.33(t,J=7.0Hz,2H),2.18(s,3H),2.20-2.00(m,3H),1.96-1.56(多重态系列,14H),1.54-1.12(m,10H),1.10-0.96(m,3H),0.91(d,J=8.7Hz,3H),0.89(s,3H),0.65(s,3H);13C NMR(CDCl3,75MHz)δ139.48,129.23,128.30,126.96,80.66,79.81,76.08,65.00,64.46,64.34,62.50,58.37,49.02,48.95,48.75,46.65,46.40,42.69,42.43,42.00,39.83,35.86,35.45,35.30,35.10,33.83,29.81,29.78,29.72,29.09,27.88,27.81,27.66,24.19,23.57,23.06,22.87,18.15,12.62;HRFAB-MS(硫代甘油基质)m/e:([MH-H]+)747.5406(77.2%),计算得到747.5398。
化合物1:在N2下向圆底烧瓶添加含于干燥THF(30mL)的26(0.684g,0.971mmol)以及LiAlH4(313.7mg,3.0mmol)。将混合物在室温下搅拌12小时,然后缓慢添加Na2SO4.10H2O粉末(10g)。当灰色消失后,以Celite过滤混合物并以干THF洗涤。所得的产物(0.581g,95%产率)为无色玻璃状。IR(近)3372,2937,1558,1455,1362,1102cm-1;1H NMR(CDCl3,300MHz)δ734-7.20(m,5H),3.68-3.48(m,5H),3.47(s,2H),3.29(bs,1H),3.22-3.00(m,3H),2.96-2.80(m,6H),2.32(t,J=6.8,5.4Hz,2H),2.17(s,3H),2.20-2.00(m,3H),1.96-0.96(多重态系列,27H),0.93(d,J=6.8Hz,3H),0.90,(s,3H),0.67(s,3H);13C NMR(CDCl3,75MHz)δ139.50,129.22,128.31,126.96,80.76,79.85,76.10,70.90,70.33,70.24,62.48,58.27,46.55,46.45,42.72,42.58,42.33,41.99,39.77,35.78,35.37,35.01,33.73,29.07,27.95,27.71,24.06,23.46,22.99,18.14,12.55;HRFAB-MS(硫代甘油基质)m/e:([M+H]+)627.5211(100%),计算得到627.5213。
化合物1的盐酸盐:将化合物1溶解在最少量的CH2Cl2中,并添加过量HCl的醚溶液。真空去除溶剂和过量HCl,并获得非结晶白色粉末。1H NMR(甲醇-d4/15%(CDCl3,300MHz)δ7.61-7.57(m,2H),7.50-7.48(m,3H),4.84(bs,10H),4.45(bs,1H),4.30(bs,1H),3.96-3.82(m,2H),3.78-3.69(m,2H),3.66(bs,1H),3.59-3.32(多重态系列,4H),3.28-3.02(m,8H),2.81(s,3H),2.36-2.15(m,4H),2.02-1.68(m,8H),1.64-0.90(多重态系列,12H),1.01(d,J=6.35Hz,3H),0.96(s,3H),0.73(s,3H);13C NMR(甲醇-d4/15%(CDCl3,75MHz)δ132.31,131.20,130.92,130.40,83.13,81.09,78.48,65.54,64.98,64.11,60.87,57.66,47.51,46.91,43.52,43.00,41.38,41.19,41.16,40.75,40.30,36.37,36.08,36.00,35.96,33.77,29.68,29.34,28.65,28.37,24.42,24.25,23.33,21.51,18.80,13.04。
化合物2:在N2下向圆底烧瓶添加含于干燥THF(150mL)的27(0.82g,1.10mmol)以及LiAlH4(125mg,3.30mmol)。将混合物在室温下搅拌12小时,然后缓慢添加Na2SO4.10H2O粉末(10g)。当灰色消失后,以棉塞过滤混合物并以干THF洗涤。真空去除THF并将残留物溶解于CH2Cl2(50mL)。过滤后,获得无色玻璃状的目标产物(0.73g,99%产率)。IR(近)3362,2936,2862,2786,1576,1466,1363,1103cm-1;′H NMR(CDCI3,300MHz)δ7.32-7.23(m,5H),3.67-3.63(m,1H),3.60-3.57(m,IH),3.53(t,J=6.4Hz,2H),3.47(s,2H),3.46(bs,1H),3.24-3.17(m,2H),3.12-2.99(m,2H),2.83-2.74(多重态系列,6H),2.30(t,J=7.3Hz,2H),2.15(s,3H),2.20-2.00(m,3H),1.95-1.51(多重态系列,20H),1.51-1.08,(多重态系列,10H),1.06-0.80(m,3H),0.87(d,J=8.1Hz,3H),0.86(s,3H),0.61(s,3H);13C NMR(CDCl3,75MHz).
139.35,129.16,128.22,126.88,80.44,79.29,75.96,66.70,66.52,66.12,62.45,58.26,46.76,46.27,42.69,42.41,42.02,40.68,40.10,40.02,39.82,35.84,35.47,35.30,35.06,34.15,34.09,34.03,33.80,28.96,27.93,27.75,27.71,24.32,23.53,23.03,22.75,18.17,12.58;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)691.5504(38.5%),计算得到691.5502。
化合物2的盐酸盐:将化合物2溶解在最少量的CH2Cl2中,并添加过量HCl的醚溶液。去除溶剂和过量HCl以得到非结晶白色粉末。1H NMR(甲醇-d4/15%(CDCl 3,300MHz)δ7.60-7.59(m,2H)17.50-7.47(m,3H),4.82(bs,10H),4.43(bs,1H),4.32(bs,1H),3.85-3.79(m,1H),3.75-3.68(m,1H),3.64(t,J=5.74Hz,2H),3.57(bs,1H),3.36-3.28(m,2H),3.25-3.00(多重态系列,10H),2.82(s,3H),2.14-1.68(多重态系列,19H),1.65-1.15(多重态系列,11H)70.98(d,J=6.6Hz,3H),0.95(s,3H),0.72(s,3H);13C NMR(甲醇-d4/15%(CDCl3,75MHz)δ132.21,131.10,130.58,130.28,81.96,80.72,77.60,66.84,66.58,66.12,61.03,57.60,44.16,42.77,40.62,39.57,39.43,36.28,36.03,35.96,35.78,33.65,29.48,29.27,29.11,29.01,28.61,28.56,28.35,24.25,23.56,23.30,21.17,18.64,12.90。
化合物4:在室温下将1(79.1mg,0.126mmol)和三氧化硫脲(50.15mg,0.404mmol)在甲醇和氯仿中的悬浮液搅拌24小时,该悬浮液澄清。添加HCl的醚溶液(1M,1mL)后以N2气流去除溶剂。将残余物溶解于H2O(5mL)中,然后添加20%NaOH水溶液(0.5mL)。以CH2Cl2(4x 5mL)萃取所得的不透明混合物。以无水Na2SO4干燥合并的萃取相。去除溶剂得到白色粉末状的目标产物(90mg,95%),m.p.111-112℃。IR(近)3316,2937,1667,1650,1556,1454,1348,1102cm-1;1H NMR(5%甲醇-d4/CDCl3,300MHz)δ7.26-7.22(m,5H),4.37(bs,3H),3.71-3.51(多重态系列,5H),3.44(s,2H),3.39-3.10(多重态系列,10H),2.27(t,J=6.83Hz,2H),2.13(s,3H),2.02-0.94(多重态系列,33H),0.85(d,J=5.62Hz,3H),0.84(s,3H),0.61(s,3H);13C NMR(5%甲醇-d4/CDCl3,75MHz)δ158.54,158.48,158.43,138.27,129.47,128.32,127.19,81.89,80.30,77.34,69.02,68.46,67.21,62.36,58.00,47.36,46.18,43.26,43.00,42.73,42.18,41.48,39.32,35.55,34.97,34.89,34.67,33.63,28.93,28.28,27.53,27.16,23.96,23.28,23.16,22.77,18.36,12.58;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)753.5858(100%),计算得到753.5867。
化合物4的盐酸盐:将化合物4溶解在最少量的CH2Cl2和MeOH中,并添加过量HCl的醚溶液。以N2气流去除溶剂,残留物在高真空下过夜。所得目标产物为非结晶白色粉末。1H NMR(甲醇-d4/20%(CDCl3,300MHz)δ7.58(bs,2H),7.50-7.48(m,3H),4.76(bs,13H),4.45(d,J=I 2.9Hz,1H),4.27(dd,1H,J=I 2.9,5.4Hz),3.82-3.00(多重态系列,17H),2.81-2.80(m,3H),2.20-1.02(多重态系列,27H),0.98(d,J=6.59Hz,3H),0.95(s,3H),0.72(s,3H);13CNMR(甲醇-d4/20%CDCl3,75MHz)δ158.88,158.72,132.00,131.96,130.98,130.15,82.51,81.07,78.05,68.50,68.02,67.94,67.10,60.87,60.53,57.38,47.16,46.91,43.91,43.11,43.01,42.91,42.55,40.28,39.88,39.95,35.90,35.73,35.64,33.53,29.18,28.35,27.99,24.02,23.30,21.35,18.52,18.44,13.06。
化合物5:在室温下将2(113mg,0.169mmol)和三氧化硫脲(67.1mg,0.541mmol)在甲醇和氯仿中的悬浮液搅拌24小时。添加HCl的醚溶液(1M,1mL)后以N2气流去除溶剂。将残余物高真空过夜并溶解于H2O(5mL)中,然后添加20%NaOH溶液(1.0mL)。以CH2Cl2(5x 5mL)萃取所得的混合物。以无水Na2SO4干燥合并的萃取相。去除溶剂得到白色固体状的目标产物(90mg,95%产率),m.p.102-104℃。IR(近)3332,3155,2939,2863,1667,1651,1558,1456,1350,1100cm-1;1H NMR(5%甲醇-d4/CDCl3,300MHz)δ7.35-7.24(m,5H),3.75-3.64(m,1H),3.57(bs,5H),3.50(s,2H),3.53-3.46(m,1H),3.40-3.10(多重态系列,14H),2.34(t,J=7.31Hz,2H),2.19(s,3H),2.13-0.96(多重态系列,36H),0.91(bs,6H),0.66(s,3H);13C NMR(5%甲醇-d4/CDCl3,75MHz)δ157.49,157.31,157.23,138.20,129.52,128.34,127.23,81.17,79.19,76.42,65.63,65.03,64.70,62.36,58.02,47.23,46.24,42.89,42.18,41.45,39.45,39.40,39.30,38.71,35.61,35.55,35.02,34.82,33.69,29.87,29.59,29.42,28.84,27.96,27.56,23.95,23.40,22.82,22.64,18.28,12.54;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)795.6356(84.3%),计算得到795.6337。
化合物5的盐酸盐:将化合物5溶解在最少量的CH2Cl2和MeOH中,并添加过量HCl的醚溶液。以N2气流去除溶剂和过量HCl,残留物在高真空下过夜。所得目标产物为非结晶白色粉末。1H NMR(甲醇-d4/10%CDCl3,300MHz)δ7.62-7.54(m,2H),7.48-7.44(m,3H),4.84(bs,16H),4.46(d,J=12.7Hz,1H),4.26(dd,J=12.7,3.42Hz,1H),3.78-3.56(多重态系列,5H),3.38-3.05(多重态系列,13H),2.80(d,3H),2.19-2.04(m,3H),2.02-1.04(多重态系列,30H),0.98(d,J=6.35Hz,3H),0.95(s,3H),0.72(s,3H);13C NMR(甲醇-d4/10%CDCl3,75MHz)δ158.75,158.67,132.32,131.24,130.83,130.43,82.49,81.02,77.60,66.47,65.93,61.19,60.85,57.69,47.79,47.60,44.29,43.07,40.86,40.42,40.19,40.09,39.76,36.68,36.50,36.15,35.94,33.91,30.75,30.46,29.74,29.33,28.71,24.41,24.03,23.38,22.21,22.16,18.59,18.52,13.09。
化合物CSA-26可参照路线1和实施例1并采用7-脱氧胆酸替换胆酸和胆酸甲酯合成得到。
实施例2
本实施例包括了对一种或多种获取化合物3,28和29的示范性合成方法的描述。
化合物28:将19(0.641g,0.614mmol)和KCN(0.40g,6.14mmol)在无水DMSO(5mL)中的悬浮液于N2中80℃下搅拌过夜,然后添加H2O(50mL)。以EtOAc(4x 20mL)萃取水相混合物。以盐水洗涤合并的萃取相一次,以无水Na2SO4干燥并真空浓缩。将残留物溶解于CH2Cl2(3mL)和MeOH(3mL)中,并添加催化量的对甲苯磺酸(5.84mg,0.03mmol)。将该溶液在室温下搅拌3小时,然后添加NaHCO3饱和水溶液(10mL)。添加盐水(60mL)后,以EtOAc(4x 30mL)萃取混合物。以盐水洗涤合并的萃取相一次,以无水Na2SO4干燥并浓缩。经柱层析(硅胶,EtOAc/己烷2∶1)后由残留物得到浅黄色油状的目标产物(0.342g,92%产率)。IR(近)3479,2936,2864,2249,1456,1445,1366,1348,1108cm-1;1H NMR(CDCl3,300MHz)53.76-3.53(m,7H),3.32-3.06(多重态系列,4H),2.57-2.46(m,6H),2.13-1.00(多重态系列,31H),0.93(d,J=6.35Hz,3H),0.90(s,3H),0.67(s,3H);13C NMR(CDCl3,75MHz)δ119.91,119.89,80.75,79.65,76.29,65.83,65.37,65.19,63.63,46.57,46.44,42.77,41.79,39.71,35.63,35.26,35.02,32.00,29.46,29.03,27.96,27.74,26.64,26.42,26.12,23.56,22.98,22.95,18.24,14.65,14.54,14.30,12.60;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)618.4247(67.8%),计算得到618.4247。
化合物29:在N2中0℃下向含于干CH2Cl2(15mL)的28(0.34g,0.57mmol)溶液添加NEt3(119.5μL,0.857mmol),然后添加甲磺酰氯(53.1μL,0.686mmol)。在0℃下将混合物搅拌分钟,然后添加H2O(6mL)。添加盐水(60mL)后,以EtOAc(4x 20mL)萃取水相混合物。以盐水洗涤合并的萃取相一次,以无水Na2SO4干燥并浓缩。向残留液添加N-甲基苄胺(0.5mL),并将该混合物在N2中80℃下搅拌过夜。真空去除过量N-甲基苄胺,对残留物进行柱层析(硅胶,EtOAc/己烷2∶1,然后采用EtOAc)以获得浅黄色油状产物(0.35g,88%产率)。IR(近)2940,2863,2785,2249,1469,1453,1366,1348,1108cm-1;1H NMR(CDCl3,300MHz)δ7.34-7.21(m,5H),3.76-3.69(m,1H),3.64-3.50(m,4H),3.48(s,2H),3.31-3.05(多重态系列,4H),2.52-2.46(m,6H),2.33(t,J=7.32H,2Hz),2.18(s,3H),2.13-0.95(多重态系列,30H),0.91(d,J=6.80H,3Hz),0.90(s,3H),0.66(s,3H);13C NMR(CDCl3,75MHz)δ139.37,129.17,128.26,126.93,119.96,119.91,80.73,79.59,76.26,65.79,65.35,65.13,62.47,58.25,46.74,46.40,42.72,42.38,41.76,39.68,35.78,35.22,34.98,33.79,28.99,27.92,27.71,26.63,26.38,26.09,24.21,23.54,22.96,22.90,18.28,14.62,14.51,14.26,12.58;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)699.5226(100%),计算得到699.5213.
化合物3:向含于干THF(10mL)的AlCl3(0.1414g,1.06mmol)和LiAlH4(0.041g,1.06mmol)混合溶液中逐滴加入含于无水THF(10mL)的29(0.074g,0.106mmol)溶液。将悬浮液搅拌24小时,然后在冰浴温度下添加20%NaOH水溶液。向含水浆液中添加无水Na2SO4。过滤该溶液并以THF洗涤沉淀两次。去除溶剂后,对残留物进行柱层析(硅胶,MeOH/CH2Cl22∶1,然后采用MeOH/CH2CI2/NH3.H2O 4∶4∶1)以获得澄清油状产物(0.038g,50%产率)。IR(近)3362,2935,2863,2782,1651,1574,1568,1557,1471,1455,1103cm-1;1H NMR(CDCl3,300MHz)δ7.32-7.22(m,5H),3.60-3.02(宽多重态系统,18H),2.90-2.70(m,5H),2.33(t,J=7.20Hz,2H),2.24-2.04(m,3H),2.18(s,3H),1.96-0.96(多重态系列,30H),0.90(d,J=7.57Hz,3H),0.89(s,3H),0.64(s,3H);13C NMR(CDCl3,75MHz)δ139.44,129.24,128.31,126.97,80.63,79.65,75.97,68.44,68.00,67.96,62.54,58.40,46.77,46.30,42.73,42.43,42.07,41.92,41.74,41.72,39.81,35.82,35.48,35.07,33.84,31.04,30.30,30.10,29.03,28.11,27.82,27.81,27.74,27.67,27.64,24.31,23.50,23.04,22.93,18.22,12.63;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)711.6139(100%),计算得到711.6152;([M+Na]+)733.5974(46.1%),计算得到733.5972。
实施例3
本实施例包括了对一种或多种获取化合物6,7和30-33的示范性合成方法的描述。
化合物30:将胆酸(3.0g,7.3mmol)溶解于CH2Cl2(50mL)和甲醇(5mL)中。添加二环己基碳二亚胺(DCC)(1.8g,8.8mmol)后,再添加N-羟基琥珀酰亚胺(约100mg)和苯甲基甲胺(1.1g,8.8mmol)。将混合物搅拌2小时后过滤。浓缩滤出液并层析(SiO2,3%MeOH含于CH2Cl2)以获得3.0g白色固体(81%产率),m.p.184-186℃;IR(近)3325,2984,1678cm-1;1H NMR(CDCl3,200MHz)δ7.21(m,5H),4.51(m,2H),3.87(m,1H),3.74(m,2H),3.36(m,2H),2.84(s,3H),2.48-0.92(多重态系列,28H),0.80(s,3H),0.58(d,J=6.5Hz,3H);13C NMR(CDCl3,50MHz)δ174.30,173.94,137.36,136.63,128.81,128.46,127.85,127.50,127.18,126.28,72.96,71.76,68.35,53.39,50.65,48.77,46.91,46.33,41.44,39.36,39.18,35.76,35.27,34.76,33.87,31.54,34.19,31.07,30.45,28.11,27.63,26.14,25.59,24.92,23.26,17.51,12.41;FAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)512(100%),计算得到512。
化合物31:将化合物30(2.4g,4.7mmol)添加入于THF(50mL)中的LiAlH4(0.18g,4.7mmol)悬浮液。将混合物回流24小时,然而冷却至0℃。小心添加Na2SO4的水溶液,直至混合物的灰色消失。将盐过滤,真空浓缩滤除液以获得的2.1g白色固体(88%)。该产物被证明具有足够的纯度以进行进一步反应,m.p.70-73℃;IR(近)3380,2983,1502cm-1;1H NMR(CDCl3,300MHz)67.23(m,5H),3.98(bs,2H),3.81(m,3H),3.43(m,3H),2.74(m,2H),2.33(m,3H),2.25(s,3H),2.10-0.90(多重态系列,24H),0.98(s,3H),0.78(s,3H);13C NMR(CDCI3,75MHz)δ135.72,129.63,128.21,128.13,125.28,72.91,71.63,62.05,60.80,56.79,47.00,46.23,41.44,40.81,39.41,35.42,35.24,34.63,34.02,33.22,31.73,30.17,29.33,29.16,28.02,27.49,26.17,25.55,23.10,22.48,22.33,17.54,12.65;FAB-MS(硫代甘油基质)m/e:([M+H]+)498(100%),计算得到498。
化合物32:将化合物31(0.36g,0.72mmol)溶解于CH2Cl2(15mL)并添加Boc甘氨酸(0.51g,2.89mmol),DCC(0.67g,3.24mmol)和二甲基氨基吡啶(DMAP)(约100mg)。在N2下将混合物搅拌4小时后过滤。浓缩并层析(SiO2,5%MeOH含于CH2Cl2)后,可得到0.47g透明玻璃状的产物(68%)。1H NMR(CDCl3,300MHz)δ7.30(m,5H),5.19(bs,1H),5.09(bs,3H),5.01(bs,1H),4.75(m,1H),4.06-3.89(m,6H),2.33(m,2H),2.19(s,3H)2.05-1.01(多重态系列,26H),1.47(s,9H),1.45(s,18H),0.92(s,3H),0.80(d,J=6.4Hz,3H),0.72(s,3H).13C NMR(CDCl3,75MHz)δ170.01,169.86,169.69,155.72,155.55,139.90,129.05,128.17,126.88,79.86,76.53,75.09,72.09,62,35,57.88,47.78,45.23,43.12,42.79,42.16,40.81,37.94,35.51,34.69,34.57,34.36,33.30,31.31,29.66,28.80,28.34,27.22,26.76,25.61,24.02,22.83,22.47,17.93,12.19;FAB-MS(硫代甘油基质)m/e:([M+H]+)970(100%),计算得到970。
化合物33:将化合物31(0.39g,0.79mmol)溶解于CH2Cl2(15mL)并添加Boc-β-丙氨酸(0.60g,3.17mmol),DCC(0.73g,3.56mmol)和二甲基氨基吡啶(DMAP)(约100mg)。在N2下将混合物搅拌6小时后过滤。浓缩并层析(SiO2,5%MeOH含于CH2Cl2)后,可得到0.58g透明玻璃状的产物(72%)。IR(近)3400,2980,1705,1510cm-1;1H NMR(CDCl3,300MHz)δ7.27(m,5H),5.12(bs,4H),4.93(bs,]H),4.7](m,1H),3.40(m,12H),2.59-2.48(m,6H),2.28(m,2H),2.17(s,3H),2.05-1.01(多重态系列,26H),1.40(s,27H),0.90(s,3H),0.77(d,J=6.1Hz,3H),0.70(s,3H).13C NMR(CDCl3,75MHz)δ171.85,171.50,171.44,155.73,138.62,129.02,128.09,126.87,79.18,75.53,74.00,70.91,62.20,57.67,47.84,44.99,43.28,41.98,40.73,37.67,36.12,34.94,34.65,34.47,34.20,33.29,31.23,29.57,28.74,28.31,28.02,27.86,27.12,26.73,25.46,24.86,23.95,22.77,22.39,17.91,12.14;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)1011.6619(100%),计算得到1011.6634。
化合物6:将化合物32(0.15g,0.15mmol)与过量4N HCl在二烷中搅拌40分钟。真空去除二烷和HCl以得到0.12透明玻璃(约100%)。1H NMR(CD3OD,300MHz)δ7.62(bs,2H),7.48(bs,3H),5.30(bs,1H),5.11(bs,1H),4.72(bs(I H),4.46(m,1H),4.32(m,1H)4.05-3.91(m,4H),3.10(m,2H),2.81(s,3H),2.15-1.13(多重态系列,25H),1.00(s,3H),0.91(bs,3H),0.82(s,3H).13C NMR(CD3OD,125MHz)δ166.86,166.50,131.09,130.18,129.17,128.55,76.60,75.43,72.61,72.04,70.40,66.22,60.07,58.00,57.90,54.89,54.76,46.44,44.64,43.39,42.22,38.56,36.78,34.14,33.92,33.84,31.82,30.54,29.67,28.79,27.96,26.79,26.00,24.99,23.14,22.05,21.82,19.91,17.27,11.60;HRFAB-MS(硫代甘油+Na+基质)m/e:([M-4Cl-3H]+)669.4576(100%),计算得到669.4591。
化合物7:将化合物33(0.20g,0.20mmol)与过量4N HCl在二烷中搅拌40分钟。真空去除二烷和HCl以得到0.12透明玻璃(约100%)。1H NMR(CD3OD,500MHz)δ7.58(bs,2H),7.49(bs,3H),5.21(bs,1H),5.02(bs,1H),4.64(m,1H),4.44(m,1H),4.28(m,1H),3.30-2.84(m,14H),2.80(s,3H),2.11-1.09(多重态系列,25H),0.99(s,3H),0.89(d,J=4.1Hz,3H),0.80(s,3H);13C NMR(CD3OD,125MHz)δ171.92,171.56,171.49,132.44,131.32,131.02,130.51,78.13,76.61,61.45,57.94,46.67,44.80,42.36,40.85,39.33,37.03,36.89,36.12,36.09,35.79,35.63,33.81,33.10,32.92,32.43,30.28,28.43,28.04,26.65,24.02,22.86,21.98,18.70,12.68;HRFAB-MS(硫代甘油+Na+基质)m/e:([M-4C1-3H]+)711.5069(43%),计算得到711.5061。
实施例4
本实施例包括了对一种或多种获取化合物8,CSA-7,CSA-8和34-40的示范性合成方法的描述。
化合物34:向三苯基膦(1.60g,6.08mmol)的THF(100mL)溶液在0℃下添加偶氮二异丙基二羧酸(DIAD)(1.20mL,6.08mmol)并搅拌半小时,该过程中黄色溶液变成糊状。将化合物14(2.58g,4.06mmol)和对硝基苯甲酸(0.81g,4.87mmol)溶于THF(50mL)并添加入糊状物中。将所得混合物在环境温度下搅拌过夜。加入水(100mL),通过添加NaHCO3溶液使混合物略呈碱性,然后以EtOAc(3x50mL)萃取。以盐水洗涤合并的萃取相一次并以无水Na2SO4干燥。SiO2层析(Et2O/己烷1∶2)后得到白色粉末状的目标产物。m.p.207-209℃;IR(KBr)3434,3056,2940,2868,1722,1608,1529,1489,1448,1345cm-1;1H NMR(CDCl3,300MHz)δ8.30-8.26(m,2H),8.21-8.16(m,2H),7.46-7.42(m,6H),7.31-7.18(m,9H)5.33(bs,1H),4.02(bs,1H),3.90(bs,1H),3.09-2.97(m,2H),2.68(td,J=I 4.95,2.56Hz,1H),2.29-2.19(m,1H),2.07-1.06(多重态系列,24H),1.01(s,3H),0.98(d,J=6.6Hz,3H),0.70(s,3H);13C NMR(CDCl3,75MHz)δ164.21,150.56,144.70,136.79,130.77,128.88,127.86,126.98,123.70,86.47,73.24,73.00,68.70,64.22,47.79,46.79,42.15,39.76,37.47,35.52,35.34,34.23,33.79,32.46,31.12,28.74,27.71,26.85,26.30,25.16,23.41,17.98,12.77;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)808.4203(53.8%),计算得到808.4189。将硝基苯甲酸酯(2.75g,3.5mmol)溶解于CH2Cl2(40mL)和MeOH(20mL)中并添加20%NaOH水溶液(5mL)。将混合物加热至60℃维持24小时。加入水(100mL)并以EtOAc萃取。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。以SiO2层析(以3%MeOH含于CH2Cl2作为洗脱液)后得到白色固体状的目标产物(1.89g,85%产率)。m.p.105-106℃;IR(KBr)3429,3057,2936,1596,1489,1447,1376,1265,1034,704cm-1;1H NMR(CDCl3,300MHz)δ7.46-7.42(m,6H),7.32-7.19(m,9H),4.06(bs,1H),3.99(bs,1H),3.86(bd,J=2.44Hz,1H),3.09-2.97(m,2H),2.47(td,J=14.03,2.44Hz,1H),2.20-2.11(m,1H),2.04-1.04(多重态系列,25H),0.97(d,J=6.59Hz,3H),0.94(s,3H),0.68(s,3H);13C NMR(CDCl3,75MHz)δ144.70,128.88,127.86,126.97,86.45,73.31,68.84,67.10,64.23,47.71,46.74,42.10,39.70,36.73,36.73,36.15,35.53,35.45,34.45,32.46,29.93,28.67,27.86,27.71,26.87,26.04,23.43,23.16,17.94,12.75;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)659.4064(100%),计算得到659.4076。
化合物35:向圆底烧瓶添加34(2.0g,31.4mmol),NaH(60%含于矿物油,3.8g,31.4mmol)以及THF(150mL)。将悬浮液回流2小时,然后添加烯丙基溴(2.72mL,31.4mL)。回流28小时后,添加另外10当量的NaH和烯丙基溴。72小时后,添加另外10当量的NaH和烯丙基溴。115小时后,TLC显示几乎没有起始原料或中间体。向悬浮液中小心加入水(100mL),然后以EtOAc(5x50mL)萃取。以盐水洗涤合并的萃取相,并以无水Na2SO4干燥。SiO2层析(5%EtOAc/己烷)后得到浅黄色玻璃状的目标产物(1.81g,79%产率)。IR(近)3060,3020,2938,2865,1645,1596,H90,1448,1376,1076,705cm″-1;1H NMR(CDCl3,300MHz)δ7.46-7.42(m,6H),7.31-7.18(m,9H),6.06-5.85(m,3H),5.35-5.20(m,3H),5.15-5.06(m,3H),4.10-4.00(m,2H),3.93-3.90(m,2H),3.85-3.79(ddt,J=13.01,4.88,1.59Hz,1H),3.73-3.66(ddt,J=13.01,5.38,1.46Hz,1H),3.58(bs,1H),3.54(bs,1H),3.32(d,J=2.93Hz,1H),3.07-2,96(m,2H),2.36(td,J=13.67,2.68Hz,1H),2.24-2.10(m,2H),2.03-1.94(m,1H),1.87-0.86(多重态系列,20H),0.91(s,3H),0.90(d,J=6.83Hz,3H),0.64(s,3H);13C NMR(CDCl3,75MHz)δ144.77,136.29,136.21,136.13,128.90,127.86,126.94,116.13,115.51,115.42,86.44,81.11,75.65,73.92,69.40,68.81,64.43,46.68,46.54,42.93,39.93,36.98,35.66,35.14,35.14,32.83,32.54,30.48,28.51,27.72,27.64,26.82,24.79,23.65,23.43,23.40,18.07,12.80;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)757.5185(12.9%),计算得到757.5196。
化合物36:在-78℃下向含35(0.551g,0.729mmol)的CH2Cl2(40mL)和MeOH(20mL)溶液吹入臭氧,直至溶液呈深蓝色。以氧气吹走过量臭氧。添加甲基硫醚(1mL),然后添加含NaBH4(0.22g,5.80mmol)的5%NaOH溶液以及甲醇。将所得混合物在室温下搅拌过夜并以盐水洗涤。以EtOAc(3x 20mL)萃取该盐水。以Na2SO4干燥合并的萃取相。以SiO2层析(5%MeOH/CH2Cl2)纯化得到无色玻璃状的产物(0.36g,65%产率)。IR(近)3396,3056,2927,1596,1492,1462,1448,1379,1347,1264,1071cm-1;1H NMR(CDCl3,300MHz)δ7.46-7.42(m,6H),7.32-7.18(m,9H),3.77-3.57(多重态系列,10H),3.48-3.44(m,2H),3.36-3.30(m,2H),3.26-3.20(m,1H),3.04-2.99(m,2H),2.37-0.95(多重态系列,27H),0.92(s,3H),0.91(d,J=6.59Hz,3H),0.67(s,3H);13C NMR(CDCl3,75MHz)δ144.69,128.87,127.84,126.94,86.44,81.05,76.86,74.65,69.91,69.22,68.77,64.24,62.44,62.42,62.26,46.92,46.54,42.87,39.73,36.86,35.52,35.13,32.82,32.54,30.36,28.71,27.61,27.44,26.79,24.82,23.51,23.38,23.31,18.28,12.74;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)791.4844(96.4%),计算得到791.4863。
化合物37:在0℃和N2下将NEt3(0.23mL,1.66mmol)加入含36(0.364g,0.47mmol)的干CH2Cl2(30mL),然后加入甲磺酰氯(0.12mL,1.56mmol)。将混合物搅拌10分钟,加入H2O(10mL)以终止反应,然后以EtOAc(3x 30mL)萃取。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。通过SiO2层析(EtOAc/己烷1∶1)得到白色玻璃状的目标产物(0.411g,86%产率)。IR(近)3058,3029,2939,2868,1491,1461,1448,1349,1175,1109,1019cm-1;1H NMR(CDCl3,300MHz)57.46-7.42(m,6H),7.31-7.19(m,9H),4.35-4.26(m,6H),3.84-3.74(m,2H),3.64-3.56(m,4H),3.49-3.34(m,3H),3.06(s,3H),3.04(s,3H),3.02(s,3H),3.09-2.95(m,2H),2.28(bt,J=14.89Hz,1H),2.09-0.86(多重态系列,21H),0.92(s,3H),0.90(d,J=6.78Hz,3H),0.66(s,3H);13C NMR(CDCl3,75MHz)δ144.66,128.86,127.86,126.97,86.46,81.28,77.18,75.00,70.34,69.89,69.13,66.49,65.85,65.72,64.22,47.06,46.35,42.77,39.58,37.81,37.64,37.55,36.75,35.48,35.02,32.59,32.52,30.27,28.43,27.56,27.52,26.92,24.62,23.34,23.25,23.10,18.24,12.64;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)1025.4207(100%),计算得到1025.4189。
化合物38:将含于干DMSO(5mL)中的37(0.227g,0.227mmol)和NaN3(0.147g,2.27mmol)的悬浮液于80℃下搅拌过夜,以H2O(50mL)稀释,并以EtOAc(3x20mL)萃取。以盐水洗涤萃取相一次并以无水Na2SO4干燥。通过SiO2层析(EtOAc/己烷1∶8)得到黄色油状的目标产物(0.153g,80%产率)。IR(近)2929,2866,2105,1490,1466,1448,1107,705cm-1;1H NMR(CDCl3,300MHz)δ7.46-7.42(m,6H),7.32-7.19(m,9H),3.80-3.74(m,1H),3.70-3.55(多重态系列,5H),3.41-3.19(多重态系列,9H),3.04-2.98(m,2H),2.41(td,J=13.1,2.44Hz,1H),2.29-2.14(m,2H),2.04-0.86(多重态系列,20H),0.93(s,3H),0.91(d,J=6.60Hz,3H),0.66(s,3H);13C NMR(CDCI3,75MHz)8144.78,128.93,127.87,126.96,86.46,81.30,77.16,75.21,67.99,67.44,67.03,64.41,51.64,51.57,51,33,46.71,46.30,42.35,39.75,36.72,35.64,35.20,32.52,32.42,30.17,28.63,27.80,27.22,26.90,24.80,23.55,23.30,23.24,18.23,12.65;HRFAB-MS(硫代甘油+Na+基质)m/e:([Mn-Na]+)866.5049(96.9%),计算得到866.5057.
化合物39:将对甲苯磺酸(1.72mg)加入含于CH2Cl2(5mL)和MeOH(5mL)的38(0.153g,0.18mmol)的溶液,并将混合物搅拌2.5小时。加入饱和NaHCO3溶液(5mL),再加入盐水(30mL)。以EtOAc萃取水相混合物,以盐水洗涤合并的萃取相并以Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶3)得到浅黄色油状的目标产物(0.10g,92%产率)。IR(近)3426,2926,2104,1467,1441,1347,1107cm-1;1HNMR(CDCl3,300MHz)δ3.81-3.74(m,1H),3.71-3.54(m,7H),3.41-3.19(m,9H),2.41(td,J=13.61,2.32Hz,1H),2.30-2.14(m,2H),2.07-1.98(m,1H),1.94-0.95(多重态系列,21H),0.95(d,J=6.35Hz,3H),0.93(s,3H),0.69(s,3H);13C NMR(CDCl3,75MHz)δ81.22,77.08,75.13,67.94,67.36,66.97,63.76,51.59,51.51,51.26,46.51,46.24,42.31,39.68,36.64,35.58,35.12,32.34,31.92,30.11,29.55,28.54,27.82,27.16,24.75,23.47,23.23,23.18,18.15,12.56;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)624.3966(54.9%),计算得到624.3962。
化合物40:在0℃和N2下向含于CH2Cl2(8mL)的39(0.10g,0.166mmol)的溶液添加NEt3(34.8μL,0.25mmol),然后添加甲磺酰氯(15.5μL,0.199mmol)。将混合物搅拌15分钟。添加H2O(3mL)和盐水(20mL),然后以EtOAc(4x 10mL)萃取。以盐水洗涤合并的萃取相一次并以Na2SO4干燥。去除溶剂后,将残留物与对苯甲基甲胺(0.5mL)混合并加热至80℃,在N2下过夜。真空去除过量对苯甲基甲胺,对残留物进行SiO2层析(EtOAc/己烷1∶4)以得到黄色油状的产物(0.109g,93%产率)。IR(近)2936,2784,2103,1467,1442,1346,1302,1106,1027cm-1;1H NMR(CDCl3,300MHz)δ7.32-7.23(m,5H),3.81-3.74(m,1H),3.71-3.55(m,5H),3.47(s,2H),3.41-3.19(m,9H),2.46-2.11(m,5H),2.18(s,3H),2.03-0.85(多重态系列,20H),0.93(s,3H),0.93(d,J=6.35Hz,3H,),0.67(s,3H);13C NMR(CDCl3,75MHz)δ139.54,129.26,128.32,126.97,81.26,77.12,75.17,67.98,67.42,67.00,62.50,58.41,51.61,51.54,51.29,46.66,46.28,42.46,42.32,39.72,36.68,35.76,35.16,33.75,32.38,30.15,28.59,27.85,27.19,24.77,24.15,23.53,23.28,23.22,18.28,12.60;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)705.4929(100%),计算得到705.4928。
化合物8:将含于THF(20mL)的40(0.109g,0.155mmol)和LiAlH4(23.5mg,0.62mmol)的悬浮液在N2下搅拌过夜。小心添加Na2SO4.10H2O并搅拌,直至无灰色存在。加入无水Na2SO4,过滤白色沉淀,并以干THF洗涤。去除溶剂后,将残留物溶解于最少量的CH2Cl2并过滤。去除溶剂后得到无色油状的目标产物(0.091g,94%产率)。IR(近)3371,3290,3027,2938,2862,2785,1586,1493,1453,1377,1347,1098cm-1;1H NMR(CDCl3,300MHz)δ7.31-7.21(m,5H),3.65-3.53(m,4H),3.47(s,2H),3.42-3.34(m,2H),3.30(bs,1H),3.26-3.20(m,1H),3.14-3.09(m,1H),2.89-2.81(m,6H),2.39-2.27(m,3H),2.17(s,3H),2.15-0.88(多重态系列,29H),0.93(d,J=6.59Hz,3H),0.92(s,3H),0.67(s,3H);13C NMR(CDCl3,75MHz)δ139.34,129.16,128.24,126.90,80.75,76.44,74.29,70.58,69.88,69.75,62.47,58.27,46.66,46.47,42.75,42.63,42.51,42.35,39.77,36.87,35.73,35.04,33.77,32.90,30.38,28.71,27.70,27.32,24.89,24.09,23.53,23.36,23.25,18.24,12.62;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)627.5199(23.3%),计算得到627.5213。
化合物CSA-7:向含于干DMF(4mL)的23(0.18g,0.28mmol)的溶液添加NaH(0.224g,60%含于矿物油,5.60mmol)和溴代辛烷(0.48mL,2.80mmol)。将悬浮液在N2和65℃下搅拌过夜,然后加入H2O(60mL),以乙醚(4x20mL)萃取。以盐水洗涤合并的萃取相并以Na2SO4干燥。通过SiO2层析(己烷以及含于己烷的5%EtOAc)得到浅黄色油状的目标产物(0.169g,80%产率)。IR(近)2927,2865,2099,1478,1462,1451,1350,1264,1105cm-1;1H NMR(CDCl3,300MHz)δ3.69-3.35(多重态系列,15H),3.26-3.02(多重态系列,4H),2.19-2.02(m,3H),1.97-1.16(多重态系列,37H),1.12-0.99(m,2H),0.92-0.86(m,9H),0.65(s,3H);13C NMR(CDCI3,75MHz)δ80.69,79.84,76.13,71.57,71.15,65.07,64.49,64.39,49.08,48.99,48.80,46.68,46.45,42.72,42.05,39.88,35.74,35.49,35.36,35.14,32.42,32.03,30.01,29.85,29.81,29.76,29.67,29.48,29.14,27.92,27.80,27.70,26.58,26.42,23.59,23.09,22.92,22.86,18.11,14.31,12.65;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)778.5685(22.1%),计算得到778.5683。将三叠氮(0.169g,0.224mmol)和LiAlH4(0.025g,0.67mmol)悬浮于无水THF(10mL)并在N2和室温下搅拌过夜,然后小心加入Na2SO4水合物。灰色消失后,加入无水Na2SO4并搅拌。过滤得到白色沉淀并以THF洗涤。去除溶剂后,将残留物溶解于1M盐酸,并以乙醚(5mL)萃取水溶液一次。然后通过添加20%NaOH水溶液使该水溶液呈碱性,并以Et2O(4x 5mL)萃取。洗涤合并的萃取相,干燥并浓缩。对残留物进行SiO2层析(MeOH/CH2Cl2(1∶1)然后采用MeOH/CH2Cl2/NH3.H2O(4∶4∶1))以得到无色油状的目标产物(0.091g,60%产率)。IR(近)3361,2927,2855,1576,1465,1351,1105cm-1;1H NMR(CD3OD,300MHz)δ4.86(bs,6H),3.77-3.72(m,1H),3.70-3.61(m,1H),3.57-3.53(m,3H),3.43-3.38(m,4H),3.34-3.27(m,2H),3.18-3.10(m,2H),2.84-2.71(m,6H),2.22-2.07(m,3H),2.00-1.02(多重态系列,39H),0.97-0.88(m,9H),0.71(s,3H);13C NMR(CD3OD,75MHz)δ82.20,81.00,77.62,72.52,72.06,68.00,67.92,67.39,48.20,47.53,44.26,43.40,41.42,41.15,40.84,40.35,36.88,36.73,36.42,36.11,34.24,34.05,33.94,33.67,33.17,30.95,30.72,30.62,29.81,29.35,28.87,28.79,27.51,24.57,23.90,23.83,23.44,18.76,14.62,13.07;HRFAB-MS(硫代甘油基质)m/e:([M+H]+)678.6133(100%),计算得到678.6149。
化合物CSA-8:将含于THF(40mL)的23(0.126g,0.196mmol)和LiAlH4(0.037g,0.98mmol)的悬浮液在N2和室温下搅拌过夜,然后小心加入Na2SO4.10H2O。当悬浮液中的灰色消失后,加入无水Na2SO4并搅拌至有机相澄清。过滤得到白色沉淀并以THF洗涤两次。真空去除THF,对残留物进行SiO2层析(MeOH/CH2Cl2/NH3/H2O(4∶4∶1))以得到无色油状的目标产物(0.066g,60%产率)。IR(近)3365,2933,2865,1651,1471,1455,1339,1103cm-1;1H NMR(CDCl3/30%CD3OD,300MHz)δ4.43(bs,7H),3.74-3.68(m,1H),3.66-3.60(m,1H),3.57-3.50(m,5H),3.34-3.25(M,2H),3.17-3.06(M,2H),2.84-2.74(M,6H),2.19-2.01(M,3H),1.97-0.96(多重态系列,27H),0.94(d,J=7.2Hz,3H),0.92(s,3H),0.69(s,3H);13CNMR(CDCl3,75MHz)δ80.44,79.27,75.77,66.59,66.53,65.86,62.51,46.21,45.84,42.55,41.53,40.09,39.43,39.31,39.02,35.16,34.93,34.86,34.57,32.93,32.71,31.57,28.66,28.33,27.64,27.22,23.04,22.40,22.29,17.60,11.98;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)566.4889(8.9%),计算得到566.4897。
实施例5
本实施例包括了对一种或多种获取化合物CSA-11和43-47的示范性合成方法的描述。
化合物43:前体化合物41可通过D.H.R.Barton,J.Wozniak,S.Z.Zard,Tetrahedron,1989,vol.45,3741-3754中所报导的方法进行制备。将41(1.00g,2.10mmol),乙烯乙二醇(3.52mL,63mmol)和p-TsOH(20mg,0.105mmol)的混合物在苯中于N2下回流16小时。以Dean-Stark除湿器去除反应中形成的水分。以NaHCO3溶液(50mL)洗涤冷却的混合物并以Et2O(50mL,2x30mL)萃取。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。去除溶剂后得到白色玻璃状的产物(1.09g,100%)。IR(近)2939,2876,1735,1447,1377,1247,1074,1057,1039cm-1;1H NMR(CDCl3,300MHz)δ5.10(t,J=2.70Hz,1H),4.92(d,J=2.69Hz,1H),4.63-4.52(m,1H),3.98-3.80(m,4H),2.32(t,J=9.51Hz,1H),2.13(s,3H),2.08(s,3H),2.05(s,3H),2.00-1.40(多重态系列,15H),1.34-0.98(m,3H),1.20(s,3H),0.92(s,3H),0.82(s,3H);13C NMR(CDCl3,75MHz)δ170.69,170.63,170.47,111.38,75.07,74.23,70.85,64.95,63.43,49.85,44.73,43.39,41.11,37.37,34.84,34.80,34.52,31.42,29.18,27.02,25.41,24.16,22.72,22.57,22.44,21.73,21.63,13.40;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)521.3106(38.6%),计算得到521.3114。将三乙酸酯(1.09g,2.10mmol)溶解于MeOH(50mL)。向溶液中加入NaOH(0.84g,21mmol)。然后将悬浮液在N2下回流24小时。真空去除MeOH,将残留物溶解于Et2O(100mL),以H2O洗涤,然后用无水Na2SO4进行干燥。去除溶剂后得到白色固体状的目标产物(0.80g,96%产率),m.p.199-200℃。IR(近)3396,2932,1462,1446,1371,1265,1078,1055cm-1;1H NMR(10%CD3OD含于CDCl3,300MHz)54.08-3.83(多重态系列,9H),3.44-3.34(m,1H),2.41(t,J=9.28Hz,1H),2.22-2.10(m,2H),1.96-1.50(多重态系列,12H),1.45-0.96(多重态系列,4H),1.32(s,3H),0.89(s,3H),0.78(s,3H);13C NMR(10%CD3OD in CDCl3,75MHz)δ112.11,72.35,71.57,68.09,64.54,63.24,49.36,45.90,41.48,41.45,39.18,38.79,35.29,34.71,34.45,-29.90,27.26,26.60,23.65,22.54,22.44,22.35,13.46;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)417.2622(87.3%),计算得到417.2617。
化合物44:向圆底烧瓶添加含于干燥THF(100mL)的43(0.80g,2.03mmol)以及NaH(60%含于矿物油,0.81g,20.3mmol)。将悬浮液在N2下回流30分钟,然后添加烯丙基溴(1.75mL,20.3mmol)。回流48小时后,添加另外10当量的NaH和烯丙基溴。另48小时后,TLC显示无残留中间体。向冷却的悬浮液添加冷水(50mL)。以Et2O(60mL,2x 30mL)萃取所得的混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。通过SiO2柱层析(6%EtOAc含于己烷)得到浅黄色油状的目标产物(0.94g,90%产率)。IR(近)3076,2933,2866,1645,1446,1423,1408,1368,1289,1252,1226,1206,1130,1080,1057cm-1;1H NMR(CDCl3,300MHz)56.02-5.84(m,3H),5.31-5.04(m,6H),4.12-4.05(m,2H),4.01-3.81(m,7H),3.70(dd,J=I 2.94,5.62Hz,1H),3.55(t,J=2.56Hz,1H),3.33(d,J=2.93Hz,1H),3.18-3.08(m,1H),2.65(t,J=10.01Hz,1H),2.32-2.14(m,3H),1.84-1.45(多重态系列,10H),1.41-1.22(m,3H),1.27(s,3H),1.14-0.92(m,2H),0.89(s,3H),0.75(s,3H);13C NMR(CDCl3,75MHz)5136.38,136.07,136.00,116.31,115.54,115.38,112.34,80.07,79.22,75.05,69.83,69.34,68.82,65.14,63.24,48.80,45.96,42.47,42.15,39.40,35.55,35.16,35.15,29.04,28.22,27.52,24.21,23.38,23.11,22.95,22.58,13.79;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)537.3549(100%),计算得到537.3556。
化合物45:向含于干THF(50mL)的44(0.94g,1.83mmol)的溶液添加9-BBN(0.5M含于THF,14.7mL,7.34mmol),并于N2和室温下搅拌该混合物12小时,然后添加20%NaOH溶液(4mL)和30%H2O2溶液(4mL)。将混合物回流1小时,然后添加盐水(100mL)并以EtOAc(4x30mL)萃取。以无水Na2SO4干燥合并的萃取相。去除溶剂后,将残留物以SiO2柱层析(EtOAc然后采用10%MeOH溶于CH2Cl2)纯化得到无色油状的目标产物(0.559g,54%产率)。IR(近)3410,2933,2872,1471,1446,1367,1252,1086cm-1;1H NMR(CDCl3,300MHz)δ4.02-3.52(多重态系列,17H),3.41-3.35(m,1H),3.29(d,J=2.44Hz,1H),3.22-3.15(m,3H),2.58(t,J=I 0.01Hz,1H),2.27-1.95(m,3H),1.83-1.48(多重态系列,16H),1.40-0.93(多重态系列,5H),1.27(s,3H),0.90(s,3H),0.75(s,3H);13C NMR(CDCl3,75MHz)δ112.41,80.09,79.09,76.31,66.70,66.02,65.93,64.80,63.26,61.53,61.25,60.86,48.59,45.80,42.51,41.72,39.10,35.36,35.02,34.98,32.87,32.52,32.40,28.88,27.94,27.21,24.33,23.02,22.84(2C’s),22.44,13.69;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)591.3881(100%),计算得到591.3873。
化合物46:向含于丙酮(40mL)和水(4mL)的45(0.559g,0.98mmol)的溶液添加PPTS(0.124g,0.49mmol),并在N2下回流该溶液16小时。减压去除该溶剂。向残留物中加水(40mL),并以EtOAc(40mL,2x 20mL)萃取该混合物。以盐水洗涤合并的萃取相,干燥并蒸发至干燥。对残留物采用SiO2柱层析(8%MeOH含于CH2CI2)得到透明油状的目标产物(0.509g,98%产率)。IR(近)3382,2941,2876,1699,1449,1366,1099cm-1;1H NMR(CDCl3,300MHz)δ3.83-3.72(m,8H),3.66(t,J=5.62Hz,2H),3.54(bs,2H),3.43-3.28(m,4H),3.24-3.12(m,2H),2.26-2.00(m,4H),2.08(s,3H),1.98-1.50(多重态系列,15H),1.42-0.96(多重态系列,6H),0.90(s,3H),0.62(s,3H);13C NMR(CDCl3,75MHz)δ210.49,78.87(2C’s),76.30,66.86,66.18,65.69,61.74,61.43,60.71,55.31,48.05,43.02,41.58,39.53,35.28,35.09,34.96,32.77,32.70,32.31,31.12,28.72,27.88,27.14,23.47,22.75,22.47,22.34,13.86;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)547.3624(100%),计算得到547.3611。
化合物47:在0℃下向含于干CH2Cl2(10mL)的46(0.18g,0.344mmol)的溶液添加Et3N(0.168mL,1.20mmol),然后添加甲磺酰氯(0.088mL,1.13mmol)。10分钟后,添加H2O(3mL)和盐水(30mL)。以EtOAc(30mL,2x10mL)萃取混合物,以盐水洗涤萃取相,并以无水Na2SO4干燥。去除溶剂后,将残留物溶解于DMSO(5mL)和NaN3(0.233g,3.44mmol)中。将悬浮液加热至50℃,并在N2下维持12小时。向冷悬浮液添加H2O(50mL),以EtOAc(30mL,2x10mL)萃取混合物,以盐水洗涤萃取相并以无水Na2SO4干燥。通过SiO2柱层析(EtOAc/己烷1∶5)得到浅黄色油状的目标产物(0.191g,88%两步产率)。IR(近)2933,2872,2096,1702,1451,1363,1263,1102cm-1;1H NMR(CDCl3,300MHz)δ3.72-3.64(m,2H),3.55-3.24(多重态系列,11H),3.18-3.02(m,2H),2.22-2.02(m,4H),2.08(s,3H),1.95-1.46(多重态系列,15H),1.38-0.96(多重态系列,6H),0.89(s,3H),0.62(s,3H);13C NMR(CDCl3,75MHz)5210.36,79.69,79.22,75.98,65.08,64.80,64.53,55.31,48.93,48.86,48.76,48.06,43.03,41.91,39.66,35.44,35.31,35.12,31.04,29.77,29.69,29.67,28.99,28.10,27.65,23.60,22.99,22.95,22.50,14.00;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)622.3820(100%),计算得到622.3805。
化合物CSA-11:将化合物47(0.191g,0.319mmol)溶解于干THF(20mL),然后添加LiAlH4(60.4mg,1.59mmol)。将灰色悬浮液在N2和室温下搅拌12小时。小心添加Na2SO4.10H2O粉末。当悬浮液中的灰色消失后,加入无水Na2SO4并过滤得到沉淀物。去除溶剂后,通过柱层析(硅胶,MeOH/CH2Cl2/28%NH3.H2O 3∶3∶1)纯化残留物。从采集的组分中蒸发走大部分的溶剂后,加入5%HCl溶液(2mL)以溶解乳状残留物。然后以Et2O(2x10mL)萃取所得的澄清溶液。然后添加20%NaOH溶液,直至该溶液成为强碱性。然后使用CH2Cl2(20mL,2x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后去除溶剂以得到无色油状的目标产物(0.115g,69%产率)。由1H NMR可见该化合物比例约为9∶1的两种在C20的立体异构体混合物。该立体异构体并未分离,而是直接使用所得的混合物。由丰度最大的异构体所得的光谱:IR(近)3353,2926,2858,1574,1470,1366,1102cm-1;1H NMR(20%CDCl3in CD3OD,300MHz)δ4.69(bs,7H),3.76-3.69(m,1H),3.63-3.53(m,5H),3.50-3.40(m,1H),3.29(bs,1H),3.18-3.07(m,2H),2.94-2.83(m,1H),2.81-2.66(m,5H),2.23-2.06(m,4H),1.87-1.50(多重态系列,15H),1.39-0.96(多重态系列,6H),1.11(d,J=6.10Hz,3H),0.93(s,3H),0.75(s,3H);13C NMR(20%CDCl3溶于CD3OD,75MHz)δ81.46,80.67,77.32,70.68,67.90,67.66,67.18,50.32,47.17,43.30,43.06,40.74,40.64,40.38,40.26,36.31,36.28,35.93,34.30,34.02,33.29,29.63,29.31,28.43,26.10,24.67,24.09,23.96,23.50,13.30针对主要异构体;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)524.4431(64.2%),计算得到524.4427。
实施例6
本实施例包括了对一种或多种获取化合物CSA-10和48-49的示范性合成方法的描述。
化合物48:在0℃下向含于干CH2Cl2(10mL)的23(0.15g,0.233mmol)的溶液添加Et3N(48.8μL,0.35mmol),然后添加CH3SO2Cl(21.7μL,0.28mmol)。将混合物搅拌15分钟,然后加入H2O(3mL)。然后添加饱和NaCl溶液(20mL),以EtOAc(40mL,2x20mL)萃取该混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。旋转蒸发去除溶剂,并向残留物添加NaBr(0.12g,1.17mmol)和DMF(10mL)。将悬浮液加热至80℃,并在N2下维持2小时。真空去除DMF,对残留物进行硅胶层析(EtOAc/己烷1∶10)得到浅黄色油状的目标产物(0.191g,97%产率)。1H NMR(CDCl3,300MHz)δ3.69-3.35(多重态系列,13H),3.28-3.02(多重态系列,4H),2.18-2.04(m,3H),2.00-1.60(多重态系列,16H),1.58-0.96(多重态系列,11H),0.92(d,J=6.34Hz,3H),0.89(s,3H),0.66(s,3H);13C NMR(CDCl3,75MHz)δ80.62,79.81,76.08,65.07,64.50,64.34,49.03,48.98,48.79,46.49,46.46,42.73,42.02,39.85,35.47,35.34,35.12,34.79,34.72,29.82,29.80,29.74,29.11,27.91,27.78,27.69,23.55,23.07,22.88,18.10,12.62;HRFAB-MS(硫代甘油+Na+基质)m/e:([M-H]+)706.3609(63.1%),计算得到706.3591;704.3616(52.8%),计算得到704.3611。
化合物49:将化合物48(0.191g,0.269mmol)和23(0.295g,0.459mmol)溶解于DMF(3mL,在使用前于6mm Hg下对BaO进行蒸馏),然后添加NaH(0.054g,60%含于矿物油)。将悬浮液在N2和室温下搅拌24小时。添加H2O(100mL)以去除过量NaH,然后以Et2O(40mL,3x20mL)萃取混合物,以盐水洗涤萃取相并以无水Na2SO4干燥。以SiO2层析(EtOAc/己烷1∶6,然后为1∶2)得到浅黄色油状的目标产物(0.177g,基于化合物23的产率为52%)。IR(近)2940,2862,2095,1472,1456,1362,1263,1113cm-1;1HNMR(CDCl3,300MHz)δ3.68-3.35(多重态系列,26H),3.28-3.02(多重态系列,8H),2.20-2.04(m,6H),1.96-1.60(多重态系列,30H),1.52-0.98(多重态系列,12H),0.91(d,J=6.59Hz,6H),0.89(s,6H),0.65(s,6H);13C NMR(CDCl3,75MHz)δ80.68,79.83,76.13,71.71,65.06,64.48,64.39,49.08,48.98,48.80,46.64,46.44,42.71,42.04,39.88,35.73,35.49,35.36,35.14,32.41,29.84,29.81,29.76,29.14,27.92,27.78,27.69,26.58,23.59,23.08,22.92,18.12,12.64。
化合物CSA-10:将化合物49(0.219g,0.173mmol)溶解于干THF(10mL),然后添加LiAlH4(65mg,1.73mmol)。将灰色悬浮液在N2和室温下搅拌12小时。小心添加Na2SO4.10H2O粉末。当悬浮液中的灰色消失后,加入无水Na2SO4并过滤得到沉淀物。去除溶剂后,通过柱层析(硅胶,MeOH/CH2Cl2/28%NH3.H2O 2.5∶2.5∶1)纯化残留物。从采集的组分中蒸发走大部分的溶剂后,加入5%HCl溶液(2mL)以溶解乳状残留物。然后以Et2O(2x10mL)萃取所得的澄清溶液。然后添加20%NaOH溶液,直至该溶液成为强碱性。然后使用CH2Cl2(20mL,2x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后去除溶剂以得到无色玻璃状的目标产物(0.147g,76%产率)。IR(近)3364,32S7,2934,2861,1596,1464,1363,1105cm-1;1H NMR(20%CDCl3含于CD3OD,500MHz)δ4.74(bs,12H),3.75-3.70(m,2H),3.65-3.61(m,2H),3.57-3.52(m,6H),3.40(t,J=3.60Hz,4H),3.30(bs,4H),3.16-3.10(m,4H),2.84-2.73(m,12H),2.18-2.07(m,6H),1.97-1.61(多重态系列,30H),1.58-0.98(多重态系列,24H),0.95(d,3=6.84Hz,6H),0.94(s,6H),0.70(s,6H);13C NMR(20%CDCl3含于CD3OD,125MHz)δ81.70,80.52,77.09,72.34,67.75(2Cs),67.07,47.80,47.13,43.76,42.87,41.20,40.65,40.58,40.14,36.43,36.25,36.08,35.77,34.15,33.87(2Cs),33.18,29.55,28.92,28.47,28.42,27.25,24.27,23.54,23.41,18.70,13.07;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)1113.9625(68.8%),计算得到1113.9610。
实施例7
本实施例包括了对一种或多种获取化合物111-113和116a-d的示范性合成方法的描述。
化合物116a-d:代表性的方法:116b的制备。将NaH(0.06g,60%溶于矿物油,1.49mmol)和丙基溴(0.136mL,1.49mmol)加入化合物23的DMF溶液(其描述参见Li等人,J.Am.Chem.Soc.1998,120,2961)(0.096g,0.149mmol)。将悬浮液在N2下搅拌24小时。添加H2O(20mL),并以己烷(3x10mL)萃取混合物。以Na2SO4干燥合并萃取相,并在真空下浓缩。通过硅胶层析(10%EtOAc含于己烷)得到浅黄色油状的目标产物(92mg,90%产率)。1H NMR(CDCl3,500MHz)δ3.68-3.64(m,1H),3.61-3.57(m,1H),3.52(t,J=6.1Hz,2H),3.49(bs,1H),3.46-3.35(m,10H),3.25(d,J=2.4Hz,1H),3.23-3.19(m,1H),3.16-3.11(m,1H),3.09-3.03(m,1H),2.17-2.03(m,3H),1.95-1.55(m,17H),1.51-1.40(m,4H),1.38-1.17(m,5H),1.11-0.96(m,3H),0.93-0.89(m,9H),0.65(s,3H);13C NMR(CDCl3,75MHz)δ80.64,79.79,76.08,72.67,71.59,65.01,64.44,64.33,49.04,48.94,48.75,46.61,46.40,42.68,42.00,39.83,35.72,35.45,35.30,35.10,32.38,29.81,29.77,29.72,29.09,27.88,27.76,27.65,26.52,23.55,23.12,23.04,22.87,18.06,12.60,10.79;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)708.4910(23.5%),计算得到708.4920。
化合物111,CSA-17和113:代表性的方法:CSA-17的制备。将化合物116b(0.092g,0.134mmol)溶解于,然后添加LiAlH4(0.031g,0.81mmol)。将悬浮液在N2下搅拌12小时。然后小心添加Na2SO4.10H2O(约1g)。当悬浮液中的灰色消失后,加入无水Na2SO4并过滤得到沉淀物。浓缩并硅胶层析(CH2Cl2/MeOH/28%NH3.H2O12∶6∶1,然后为10∶5∶1)后得到溶解于1M HCl(2mL)的玻璃。以Et2O(2x 10mL)洗涤所得的透明溶液。向水相添加20%NaOH溶液,直至溶液呈强碱性。然后使用CH2Cl2(3x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后真空浓缩以得到无色玻璃状的目标产物(0.045g,55%产率)。1H NMR(约20%CDCl3含于CD3OD,500MHz)δ4.73(bs,6H),3.74-3.70(m,1H),3.65-3.61(m,1H),3.55(t,J=6.3Hz,2H),3.42-3.38(m,4H),3.33-3.30(m,2H),3.16-3.10(m,2H),2.83-2.73(m,6H),2.18-2.06(m,3H),1.96-1.20(多重态系列,26H),1.12-0.98(m,3H),0.95-0.92(m,9H),0.70(s,3H);13C NMR(约20%CDCl3含于CD3OD,75MHz)δ81.67,80.49,77.04,73.44,72.28,67.77,67.71,67.06,47.74,47.08,43.75,42.82,41.21,40.60,40.56,40.12,36.47,36.19,36.04,35.74,34.09,33.82,33.78,33.16,29.49,28.87,28.43,27.18,24.22,23.66,23.49,23.40,18.64,13.04,11.03;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)608.5348(100%),计算得到608.5330.111:1H NMR(约20%CDCl3含于CD3OD,500MHz)δ4.79(bs,6H),3.74-3.71(m,1H),3.66-3.62(m,1H),3.55(t,J=6.1Hz,2H),3.52(bs,1H),3.38-3.28(多重态系列,4H),3.33(s,3H),3.16-3.10(m,2H),2.83-2.72(m,6H),2.19-2.07(m,3H),1.97-1.62(多重态系列,15H),1.58-1.20(多重态系列,9H),1.13-0.98(m,3H),0.95(d,J=6.3Hz,3H),0.93(s,3H),0.70(s,3H);13C NMR(约20%CDCl3含于CD3OD,75MHz)δ81.82,80.65,77.20,74.43,67.85,67.18,58.90,47.80,47.22,43.91,43.01,41.31,40.78,40.69,40.22,36.63,36.35,36.18,35.86,34.27,33.97,33.26,29.60,29.03,28.58,28.53,27.14,24.33,23.61,23.45,18.68,13.06;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)602.4855(100%),计算得到602.4873。113:1H NMR(约50%CDCl3含于CD3OD,500MHz)δ4.08(bs,6H),3.71-3.67(m,1H),3.62-3.58(m,1H),3.53(t,J=6.3Hz,2H),3.49(bs,1H),3.43-3.38(m,4H),3.31-3.27(m,2H),3.14-3.07(m,2H),2.83-2.73(m,6H),2.16-2.03(m,3H),1.93-1.17(多重态系列,30H),1.10-0.96(m,3H),0.93-0.89(m,9H),0.67(s,3H);13C NMR(约50%CDCl3含于CD3OD,75MHz)δ80.51,79.35,75.85,71.29,70.83,66.73,66.62,65.96,46.68,45.98,42.59,41.63,40.20,39.53,39.43,39.21,35.34,35.04,35.00,34.71,33.11,32.90,32.82,32.00,29.15,28.49,28.15,27.75,27.35,26.22,23.18,22.60,22.45,22.34,17.77,13.75,12.22;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)636.5679(100%),计算得到636.5669。
实施例8
本实施例包括了对一种或多种获取化合物106和124的示范性合成方法的描述。
化合物124:将化合物47(0.256g,0.489mmol)溶解于CH2Cl2(10mL),并冷却至0℃,然后添加Na2HPO4(0.69g,4.89mmol)和尿素-过氧化氢复合物(UHP)(0.069g,0.733mmol)。然后逐滴添加三氟醋酸酐(TFAA)(0.138mL,0.977mmol)。将悬浮液搅拌12小时,并添加UHP(23mg,0.25mmol)和TFAA(0.069mL,0.49mmol)。继续12小时后,添加H2O(30mL),并以EtOAc(3x20mL)萃取所得混合物。以盐水(50mL)洗涤合并的萃取相一次,以无水Na2SO4干燥并真空浓缩。通过SiO2层析(EtOAc/己烷1∶5)得到无色油状的目标产物(0.145g,55%产率)。1H NMR(CDCl3,300MHz)δ5.21(dd,J=9.3and 7.3Hz,1H),3.70-3.57(m,2H),3.55(t,J=6.0Hz,2H),3.43-3.37(m,6H),3.32-3.25(m,3H),3.17-3.02(m,2H),2.28-2.05(m,4H),2.03(s,3H),1.86-1.19(多重态系列,19H),0.97(dd,J=I 4.5and 3.3Hz,1H),0.90(s,3H),0.78(s,3H);13C NMR(CDCl3,75MHz)δ171.08,79.71,78.03,75.72,75.53,65.41,65.04,64.53,48.79,48.70,46.49,41.92,39.44,37.81,35.45,35.22,35.10,29.73,29.63,28.89,28.33,27.50,27.34,23.39,22.97,22.92,21.28,12.72;HRFAB-MS(硫代甘油+Na+基质)m/e:([M-H]+)614.3798(24.5%),计算得到614.3778。
化合物106:将化合物124(0.145g,0.236mmol)溶解于CH2Cl2(2mL)和MeOH(1mL)中。添加20%NaOH溶液(0.2mL)。将混合物搅拌12小时,采用无水Na2SO4去除水分。真空浓缩后,以硅胶层析(EtOAc/己烷1∶3)纯化残留物以得到无色油状的目标产物(0.124g,92%产率)。1H NMR(CDCl3,300MHz)δ4.29(bs,1H),3.69-3.60(m,2H),3.52(t,J=6.0Hz,2H),3.45-3.32(m,8H),3.26(d,J=2.7Hz,1H),3.17-3.02(m,2H),2.19-1.94(m,4H),1.90-1.62(多重态系列,13H),1.57-1.20(多重态系列,7H),0.97(dd,J=14.3and 3.1Hz,1H),0.90(s,3H),0.73(s,3H);13C NMR(CDCl3,75MHz)δ79.69,78.03,75.47,73.38,65.46,65.00,64.47,48.87,48.68,46.83,41.93,39.71,37.87,35.43,35.20,35.09,29.96,29.69,29.59,29.53,28.89,28.44,27.48,23.72,22.91,22.71,11.77。将乙醇(0.124g,0.216mmol)溶解于干THF(20mL),然后添加LiAlH4(33mg,0.866mmol)。将灰色悬浮液在N2下搅拌12小时。小心添加Na2SO4.10H2O(约2g)。当悬浮液中的灰色消失后,加入无水Na2SO4并过滤得到沉淀物。去除溶剂后,通过柱层析(SiO2,MeOH/CH2Cl2/28%NH3.H2O2.5∶2.5∶1)纯化残留物。浓缩相关组分后,添加1M HCl (2mL)以溶解该乳状残留物。以Et2O(2x 10mL)洗涤所得的透明溶液。向水相添加20%NaOH溶液直至该溶液呈强碱性。然后使用CH2Cl2(20mL,2x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后去除溶剂以得到无色油状的目标产物(0.050g,47%产率)。1HNMR(20%CDCl3in CD3OD,300MHz)δ4.77(s,7H),4.25(t,J=8.5Hz,1H),3.75-3.68(m,1H),3.66-3.58(m,1H),3.55(t,J=6.1Hz,2H),3.48-3.41(m,1H),3.34(bs,1H),3.30(d,J=3.6Hz,1H),3.17-3.08(m,2H)32.86-2.70(m,6H),2.20-1.91(m,4H),1.88-1.16(多重态系列,19H),1.00(dd,J=14.2和3.0Hz,1H),0.93(s,3H),0.73(s,3H);13C NMR(20%CDCl3含于CD3OD,75MHz)δ80.62,79.12,76.74,73.77,68.50,67.79,67.17,47.69,43.04,40.76,40.64,40.62,40.22,39.01,36.32,36.25,35.94,34.27,33.97,33.72,30.13,29.53,28.43,24.48,23.58,23.40,12.38;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)496.4108(100%),计算得到496.4114。
实施例9
本实施例包括了对一种或多种获取化合物109和126-129的示范性合成方法的描述。
化合物126:将化合物125(2.30g,3.52mmol)溶解于CH2Cl2(100mL)和MeOH(50mL)中。添加少量Et3N,然后将溶液冷却至-78℃。向溶液吹入臭氧直至该溶液持续呈蓝色。添加Me2S(4mL),然后添加含NaBH4(0.266g,0.703mmol)的MeOH(10mL)。将所得溶液加温搅拌过夜。真空浓缩该溶液,添加盐水(60mL)。以EtOAc(40mL,2x30mL)萃取混合物,以盐水洗涤合并的萃取相,并以无水Na2SO4干燥。硅胶层析(EtOAc)以得到白色固体状的产物(1.24g,76%产率),m.p.219-220℃;1H NMR(CDCl3,300MHz)δ5.10(t,J=2.8Hz,1H),4.90(d,J=2.7Hz,1H),3.73-3.59(m,2H),3.56-3.44(m,1H),2.13(s,3H),2.09(s,3H),2.07-0.95(多重态系列,23H),0.91(s,3H),0.83(d,J=6.3Hz,3H),0.74(s,3H);13C NMR(CDCl3,75MHz)δ170.84,170.82,75.63,71.77,71.03,60.73,48.10,45.26,43.54,41.16,38.78,37.89,35.00,34.43,32.26,31.50,30.60,29.07,27.50,25.70,22.96,22.71,21.81,21.63,18.18,12.35;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)465.3197(20%),计算得到465.3216。
化合物127:将化合物126(1.24g,2.67mmol)溶解于MeOH(30mL)中,并添加NaOH(0.54g,13.4mmol)。。将悬浮液在N2下回流24小时。真空去除MeOH,然后添加H2O(50mL)。过滤沉淀,以H2O洗涤,然后真空干燥得到白色固体(1.02g)。将固体溶解于DMF(40mL),顺序添加NEt3(1.12mL,8.02mmol),DMAP(16.3mg,0.13mmol)和三苯甲基氯(1.49g,5.34mmol)。将悬浮液在N2下搅拌12小时,然后加热至50℃维持24小时。向冷却的悬浮液添加H2O(100mL),并以EtOAc(3x50mL)萃取混合物。以盐水(100mL)洗涤合并的萃取相,以无水Na2SO4干燥,并在真空下浓缩。硅胶层析(EtOAc)得到浅黄色玻璃状的产物(1.20g,72%产率)。向该玻璃添加干THF(80mL)和NaH(60%含于矿物油,0.77g,19.3mmol)。在N2下将悬浮液回流半小时,然后添加溴化烯丙酯(1.67mL,19.3mmol)。回流48小时后,添加另外10当量的NaH和溴化烯丙酯。继续48小时后,冷却反应混合物并缓慢添加H2O(100mL)。以己烷(3x50mL)萃取所得的混合物,以盐水(100mL)洗涤合并的萃取相,并以无水Na2SO4干燥。硅胶层析(5%EtOAc含于己烷)得到透明玻璃状的产物(1.27g,所有三步的产率为64%)。1H NMR(CDCl3,300MHz)δ7.46-7.43(m,6H),7.29-7.16(m,9H),5.98-5.81(m,3H),5.29-5.18(m,3H),5.14-5.03(m,3H),4.11-3.97(m,4H),3.75-3.67(m,2H),3.49(bs,1H),3.32-3.13(d,J=2.4Hz,1H),3.20-3.13(m,2H),3.00(m,1H),2.33-2.12(m,3H),2.03-0.92(多重态系列,19H),0.88(s,3H),0.78(d,J=6.6Hz,3H),0.65(s,3H);13C NMR(CDCl3,75MHz)δ144.71,136.08,136.04,135.94,128.80,127.76,126.86,116.30,115.57,86.53,80.77,79.20,74.96,69.42,69.34,68.81,62.00,46.87,46.48,42.67,42.11,39.90,36.15,35.50,35.14,35.10,33.23,28.99,28.09,27.75,27.56,23.36,23.32,23.12,18.24,12.66;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)765.4875(100%),计算得到765.4859。
化合物128:向127(1.27g,1.71mmol)的THF溶液(40mL)添加9-BBN(0.5M溶于THF,17.1mL)。将混合物搅拌12小时,然后添加NaOH(20%溶液,10mL)和H2O2(30%溶液,10mL)。将所得混合物回流1小时,然后添加盐水(100mL)并以EtOAc(4x30mL)萃取。以无水Na2SO4干燥合并萃取相,并在真空下浓缩。硅胶层析(5%MeOH含于CH2Cl2)得到透明玻璃状的产物(1.26g,93%产率)。1H NMR(5%CD3OD含于CDCl3,300MHz)δ7.46-7.43(m,6H),7.32-7.20(m,9H),3.94(s,3H),3.78-3.56(m,10H),3.48(bs,1H),3.32-3.26(m,2H),3.24-3.12(m,3H),3.00(dd,J=8.2and 6.1Hz,1H),2.23-1.96(m,3H),1.90-0.95(多重态系列,25H),0.90(s,3H),0.77(d,J=6.6Hz,3H),0.66(s,3H);13C NMR(5%CD3OD in CDCl3,75MHz)δ144.52,128.64,127.64,126.76,86.43,80.55,79.31,77.65,77.23,76.80,76.06,66.17,66.01,65.41,61.93,61.20,60.73,60.39,47.29,46.08,42.65,41.62,39.49,36.02,35.10,34.89,34.77,32.89,32.71,32.41,32.26,28.68,27.70,27.51,27.19,23.26,22.66,22.50,18.23,12.34;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)819.5169(100%),计算得到819.5099。
化合物129:向化合物128(1.26g,1.58mmol)的CH2Cl2溶液(50mL)在0℃下添加Et3N(0.92mL,6.60mmol),然后添加甲磺酰氯(0.47mL,6.05mmol)。15分钟后,先后添加H2O(10mL)和盐水(80mL)。以EtOAc(60mL,2x30mL)萃取混合物,并以无水Na2SO4干燥合并的萃取相。真空去除溶剂后,将残留物溶解于DMSO(10mL)并添加NaN3(1.192g,18.3mmol)。将悬浮液加热至60℃,在N2下过夜。添加H2O(100mL),并以EtOAc(3x40mL)萃取混合物。以盐水洗涤合并的萃取相并以无水Na2SO4干燥。真空去除溶剂以得到浅黄色油。将该油溶解于MeOH(10mL)和CH2Cl2(20mL)并添加TsOH(17.4mg,0.092mmol)。12小时后,添加饱和NaHCO3(20mL)和盐水(50mL),并以EtOAc(3x40mL)萃取该混合物。以盐水(50mL)洗涤合并的萃取相并以无水Na2SO4干燥。通过硅胶层析(EtOAc/己烷1∶3)得到浅黄色油状的目标产物(0.934,94%)。1H NMR(CDCl3,500MHz)δ3.75-3.70(m,1H),3.68-3.63(m,2H),3.62-3.57(m,1H),3.53(t,J=6.1Hz,2H),3.50(bs,1H),3.46-3.38(m,6H),3.26(d,J=2.4Hz,1H),3.24-3.20(m,1H),3.16-3.12(m,1H),3.10-3.04(m,1H),2.17-2.04(m,3H),1.96-1.63(m,14H),1.53-1.45(m,3H),1.35-1.20(m,7H),1.08-1.00(m,1H),0.97-0.88(m,1H),0.94(d,J=6.8Hz,3H),0.89(s,3H),0.67(s,3H);13C NMR(CDCl3,75MHz)δ80.64,79.81,76.06,65.05,64.49,64.34,61.03,49.02,48.98,48.78,46.93,46.53,42.76,42.01,39.83,39.14,35.46,35.33,35.12,32.97,29.79,29.73,29.10,27.90,27.68,23.56,23.06,22.88,18.24,12.60;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)652.4285(100%),计算得到652.4295。
化合物109:将化合物129(0.245g,0.391mmol)溶解于THF(30mL),然后添加LiAlH4(59mg,1.56mmol)。将灰色悬浮液在N2下搅拌12小时。小心添加Na2SO4.10H2O粉末(约1g)。当悬浮液中的灰色消失后,加入无水Na2SO4并过滤得到沉淀物。去除溶剂后,通过硅胶层析(CH2Cl2/MeOH/28%NH3.H2O 10∶5∶1,然后为10∶5∶1)纯化残留物。从相关组分中去除溶剂后,添加1M HCl(4mL)以溶解残留物。以Et2O(3x 10mL)萃取所得的透明溶液。添加20%NaOH溶液,直至该溶液成为强碱性。然后使用CH2Cl2(4x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后真空去除溶剂以得到无色油状的目标产物(0.15g,71%产率)。1H NMR(约20%CD3OD含于CDCl3,500MHz)δ4.73(bs,7H),3.74-3.70(m,1H),3.65-3.60(m,2H),3.56-3.52(m,4H),3.31-3.28(m,2H),3.16-3.09(m,2H),2.82-2.71(m,6H),2.19-2.06(m,3H),1.97-1.66(多重态系列,15H),1.58-1.48(m,3H),1.38-0.98(m,7H),0.96(d,J=6.8Hz,3H),0.93(s,3H),0.71(s,3H);13C NMR(约20%CD3OD含于CDCl3,75MHz)δ81.80,80.60,77.17,67.88,67.86,67.18,60.73,48.11,47.28,43.93,42.99,41.34,40.76,40.72,40.24,39.70,36.33,36.18,35.86,34.29,33.99,33.96,33.83,29.60,29.00,28.57,28.54,24.33,23.59,23.48,18.86,13.04;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)552.4756(100%),计算得到552.4772。
实施例10
本实施例包括了对一种或多种获取化合物108和130的示范性合成方法的描述。
化合物130:在0℃下于THF(5mL)中搅拌o-NO2C6H4SeCN(0.094g,0.21mmol)和Bu3P(0.095mL,0.38mmol)1/2小时,然后添加含于THF(2mL)的化合物129(0.10g,0.159mmol)。将悬浮液搅拌1小时,然后添加H2O2(30%水溶液,2mL)。将混合物搅拌12小时,然后以己烷(4x10mL)萃取。以无水Na2SO4干燥合并的萃取相。硅胶层析(10%EtOAc/己烷)后得到浅黄色油状的目标产物(0.035g,36%产率)。1H NMR(CDCl3,500MHz)δ5.73-5.66(ddd,J=17.1,10.2,8.3Hz,1H),4.90(dd,J=17.1,2.0Hz,1H),4.82(dd,J=I 0.2Hz,1.96Hz,1H),3.68-3.64(m,1H),3.62-3.58(m,1H),3.54-3.26(m,9H),3.25-3.22(m,2H),3.15-3.11(m,1H),3.10-3.04(m,1H),2.17-1.62(多重态系列,18H),1.51-1.43(m,2H),1.35-1.18(m,4H),1.06-0.91(m,2H),1.02(d,J=6.3Hz,3H),0.90(s,3H),0.68(s,3H);13C NMR(CDCl3,75MHz)δ145.50,111.72,80.60,79.82,76.09,65.06,64.50,64.45,49.05,48.97,48.79,46.43,46.13,42.76,42.03,41.30,39.84,35.49,35.34,35.15,29.82,29.80,29.75,29.11,28.00,27.84,27.68,23.56,23.08,22.95,19.79,12.87;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)634.4167(90.6%),计算得到634.4169。
化合物108:将化合物130(0.105g,0.172mmol)在-78℃下溶解于CH2Cl2(5mL)和MeOH(5mL)中。向该溶液吹入O3约20分钟,添加Me2S(1mL),并真空去除溶剂。将残留物溶解于THF(15mL),并添加LiAlH4(0.033g,0.86mmol)。搅拌悬浮液12小时。小心添加Na2SO4.10H2O(约2g)。当悬浮液中的灰色消失后,加入无水Na2SO4并过滤得到沉淀物。浓缩并硅胶层析(CH2Cl2/MeOH/28%NH3.H2O 10∶5∶1.5,然后为9∶6∶1.8)得到白色玻璃。向该原料添加1MHCl(4mL)。以Et2O(3x 10mL)洗涤所得的透明溶液。向水相添加20%NaOH溶液直至该溶液呈强碱性。然后使用CH2Cl2(4x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后去除溶剂以得到无色油状的目标产物(0.063g,68%产率)。1H NMR(约10%CD3OD含于CDCl3,500MHz)64.76(bs,7H),3.75-3.71(m,1H),3.66-3.62(m,1H),3.58-3.52(m,4H),3.33-3.29(m,2H),3.22(dd,J=10.5and 7.6Hz,1H),3.15-3.09(m,2H),2.81(t,J=6.8Hz,2H),2.76-2.71(m,4H),2.19-2.08(m,3H),2.00-1.66(多重态系列,14H),1.58-1.45(m,3H),1.40-1.08(m,5H),1.03(d,J=6.8Hz,3H),1.02-0.96(m,1H),0.93(s,3H),0.72(s,3H);13C NMR(约10%CD3OD含于CDCl3,75MHz)δ81.74,80.64,77.23,67.95,67.87,67.18,47.32,44.59,43.72,43.01,41.26,40.80,40.71,40.23,40.02,36.36,36.20,35.87,34.27,33.99,33.90,29.60,29.05,28.58,28.08,24.49,23.62,23.46,16.84,13.12;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)538.4578(4.7%),计算得到538.4584。
实施例11
本实施例包括了对一种或多种获取化合物CSA-21,133-134和CSA-15的示范性合成方法的描述。
化合物CSA-21:将化合物115(0.118g,0.183mmol)溶解于干CH2Cl2(10mL)中,并添加SO3吡啶复合物(0.035g,0.22mmol)。搅拌悬浮液12小时。真空去除溶剂以得到白色粉末。向该白色粉末添加1M HCl(10mL),并以CH2Cl2(4x 10mL)萃取所得的混合物。以无水Na2SO4干燥合并的萃取相。硅胶层析(10%MeOH含于CH2Cl2)后得到黄色油状的目标产物(0.11g,84%)。1H NMR(约10%CD3OD含于CDCl3,500MHz)84.03(t,J=6.8Hz,2H),3.69-3.65(m,1H),3.62-3.58(m,1H),3.55(t,J=6.1Hz,2H),3.51(bs,1H),3.46-3.38(m,6H),3.27(d,J=2.4Hz,1H),3.26-3.21(m,1H),3.18-3.07(m,2H),2.18-2.03(m,3H),1.95-1.47(多重态系列,19H),1.40-0.96(多重态系列,9H),0.92(d,J=6.8Hz,3H),0.91(s,3H),0.66(s,3H);13C NMR(约10%CD3OD含于CDCl3,75MHz)δ80.43,79.68,75.87,69.30,64.82,64.32,64.14,48.78,48.73,48.50,46.44,46.21,42.49,41.76,39.61,35.36,35.17,35.06,34.85,31.73,29.53,29.46,29.44,28.84,27.68,27.48,27.38,25.91,23.30,22.75,22.66,17.70,12.32;HRFAB-MS(硫代甘油+Na+基质)m/e:([M-H+2Na]+)768.3831(100%),计算得到768.3843。可通过在THF(10mL)和H2O(1mL)中以Ph3P(0.20g,0.77mmol)处理三叠氮(0.11g,0.15mrnol)来还原叠氮。将混合物搅拌3天。真空去除溶剂,然后以硅胶层析(CH2Cl2/MeOH/28%NH3.H2O 12∶6∶1,然后为10∶5∶1.5)纯化该残留物以得到玻璃状的目标产物(0.077g,78%产率)。向该玻璃添加含于Et2O(1M,0.5mL)的HCl以得到相应的盐酸盐。1H NMR(约10%CDCl 3含于CD3OD,500MHz)-δ4.81(s,10H),4.07-3.97(m,2H),3.82(bs,1H),3.71(bs,1H),3.65(t,J=5.2Hz,2H),3.57(bs,1H),3.37-3.30(m,2H),3.22-3.02(m,8H),2.12-1.71(多重态系列,17H),1.65-1.01(多重态系列,13H),0.97(d,J=6.8Hz,3H),0.94(s,3H),0.73(s,3H);13C NMR(约10%CDCl3含于CD3OD,75MHz)δ81.89,80.58,77.50,70.04,66.71,66.56,66.02,47.11,46.76,44.20,42.66,40.50,39.60,39.40,36.24,36.11,35.89,35.67,32.28,29.38,29.23,29.10,28.94,28.49,26.06,24.21,23.46,23.30,18.50,12.86;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)668.4271(100%),计算得到668.4258。
化合物CSA-13:将23(0.19g,0.264mmol)的甲磺酸盐与过量辛胺(2mL)在80℃下搅拌12小时。真空去除辛胺后,对残留物进行层析(硅胶,EtOAc/己烷1∶4以2%Et3N)得到浅黄色油状的目标产物(0.19g,95%产率)。1H NMR(CDCl3,300MHz)δ3.69-3.37(多重态系列,11H),3.26-3.00(m,4H),2.61-2.53(m,4H),2.20-2.02(m,3H),1.98-0.99(多重态系列,40H),0.92-0.85(m,9H),0.65(s,3H);13CNMR(CDCl3,75MHz)δ80.60,79.74,76.05,64.97,64.40,64.28,50.79,50.25,49.00,48.90,48.71,46.47,46.34,42.65,41.96,39.80,35.77,35.41,35.27,35.05,33.73,31.96,30.25,29.76,29.74,29.67,29.39,29.05,27.84,27.61,27.55,26.70,23.50,23.00,22.82,22.79,18.06,14.23,12.54;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)755.6012(100%),计算得到755.6024。将三叠氮(0.18g,0.239mmol)溶解于THF(10mL)和EtOH(10mL)。添加林德乐催化剂(44mg),将悬浮液在H2(50psi)下震荡12小时。真空去除溶剂后,通过硅胶层析(CH2Cl2/MeOH/28%NH3.H2O 10∶5∶1,然后为10∶5∶1.5)纯化残留物。向产物添加1M HCl(2mL),并以Et2O(2x 10mL)萃取所得的透明溶液。添加20%NaOH溶液,直至该溶液成为强碱性。然后使用CH2Cl2(20mL,2x 10mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后真空去除溶剂以得到透明油状的目标产物(0.114g,68%产率)。1H NMR(约20%CDCl3含于CD3OD,500MHz)δ4.79(bs,7H),3.74-3.70(m,1H),3.66-3.61(m,1H),3.56-3.51(m,3H),3.31-3.29(m,2H),3.16-3.09(m,2H),2.88-2.72(m,6H),2.59-2.51(m,4H),2.18-2.07(m,3H),1.97-1.66(多重态系列,14H),1.62-0.97(多重态系列,25H),0.95(d,J=6.3Hz,3H),0.93(s,3H),0.89(t,J=6.8Hz,3H),0.70(s,3H);13C NMR(约20%CDCl3含于CD3OD,75MHz)δ81.82,80.63,77.23,67.85,67.19,51.20,50.69,47.82,47.24,43.92,43.01,41.30,40.80,40.68,40.22,36.74,36.38,36.20,35.87,34.66,34.15,33.87,32.90,30.54,30.39,30.30,29.64,29.03,28.59,28.41,26.96,24.37,23.65,23.48,18.75,14.63,13.09;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)677.6309(46.6%),计算得到677.6309。
化合物CSA-46:化合物CSA-46可通过CSA-13的方法进行制备,其中以7-脱氧胆酸类固醇骨架前体替换胆酸。
化合物134:将化合物CSA-13(0.08g,0.12mmol)溶解于CHCl3(5mL)和MeOH(5mL),添加氨基亚胺磺酸(0.045g,0.36mmol),然后将悬浮液搅拌12小时。真空去除溶剂,然后将残留物溶解于1M HCl(6mL)和H2O(10mL)中。以Et2O(3x5mL)洗涤溶液,然后逐滴加入20%NaOH溶液直至该溶液呈强碱性。以CH2Cl2(4x5mL)萃取该碱性混合物。以无水Na2SO4干燥合并的萃取相,然后真空浓缩以得到无色玻璃状的目标产物(0.087g,91%产率)。1HNMR(约20%CDCl3含于CD3OD,500MHz)δ4.96(bs,13H),3.74-3.68(m,1H),3.65-3.50(m,4H),3.38-3.18(多重态系列,10H),2.60-2.50(m,4H),2.15-1.99(m,3H),1.88-1.72(m,14H),1.60-0.99(多重态系列,25H),0.94(bs,6H),0.89(t,J=6.6Hz,3H),0.71(s,3H);13C NMR(约20%CDCl3含于CD3OD,75MHz)δ159.00,158.87,158.72,81.68,79.93,76.95,66.59,65.93,65.45,50.82,50.40,47.64,46.94,43.67,42.27,40.18,39.25,36.19,35.66,35.40,34.21,32.45,30.51,30.26,30.18,30.10,29.86,29.35,28.71,28.15,28.00,26.87,23.94,23.44,23.23,23.12,18.61,14.42,12.98;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)803.6958(18.4%),计算得到803.6953。
化合物CSA-15:将23(0.092g,0.128mmol的甲磺酸盐溶解于DMSO(2mL),随后添加NaN3(0.0167g,0.256mmol)。将悬浮液加热至70℃并维持12小时。向冷却的悬浮液添加H2O(20mL),并以EtOAc/己烷(1∶1)(20mL,3x10mL)萃取混合物。以盐水(30mL)洗涤合并的萃取相,以无水Na2SO4干燥,在真空下浓缩得到浅黄色油状的产物(0.081g,95%产率)。1H NMR(CDCl3,300MHz)δ3.69-3.36(m,11H),3.25-3.02(m,6H),2.20-2.02(m,3H),1.97-1.60(m,15H),1.55-0.98(m,13H),0.92(d,J=6.3Hz,3H),0.89(s,3H),0.66(s,3H);13C NMR(CDCl3,75MHz)δ80.59,79.77,76.03,65.01,64.46,64.30,52.12,48.99,48.95,48.76,46.44,46.42,42.70,41.99,39.82,35.56,35.44,35.31,35.09,33.09,29.79,29.77,29.71,29.08,27.88,27.78,27.66,25.65,23.53,23.03,22.85,18.00,12.58;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)691.4512(100%),计算得到691.4496。将四叠氮(0.081g,0.12mmol)溶解于THF(5mL)和EtOH(10mL)。添加林德乐催化剂(30mg),将悬浮液在H2(50psi)下震荡12小时。真空去除溶剂后,通过硅胶层析(CH2Cl2/MeOH/28%NH3.H2O 5∶3∶1,然后为2∶2∶1)纯化残留物。向产物添加1M HCl(2mL),然后以Et2O(2x10mL)洗涤所得的溶液。向水相添加20%NaOH溶液直至该溶液呈强碱性。然后使用CH2Cl2(10mL,2x 5mL)萃取该碱性溶液。以无水Na2SO4干燥合并的萃取相,然后真空浓缩以得到无色油状的目标产物(0.044g,64%产率)。1H NMR(约20%CDCl3含于CD3OD,500MHz)δ4.79(bs,8H),3.74-3.70(m,1H),3.66-3.62(m,1H),3.56-3.52(m,3H),3.31-3.27(m,2H),3.16-3.10(m,2H),2.82-2.70(m,6H),2.64-2.54(m,2H),2.19-2.07(m,3H),1.99-1.66(多重态系列,14H),1.58-0.96(多重态系列,13H),0.96(d,J=6.6Hz,3H),0.93(s,3H),0.70(s,3H);13C NMR(约20%CDCl3含于CD3OD,75MHz)δ81.96,90.76,77.33,67.92,67.26,47.84,47.33,44.04,43.24,43.15,41.40,40.91,40.78,40.29,36.82,36.48,36.28,35.96,34.39,34.11,30.59,29.69,29.13,28.68,28.64,24.43,23.69,23.48,18.77,13.06;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+H]+)565.5041(100%),计算得到565.5057。
实施例12
本实施例包括了对一种或多种获取化合物203a-b,207a-c,209a-c,210a-b和CSA-31的示范性合成方法的描述。
化合物2O3a-b,207a-c,208a-c,209a-c以及210a-b:将BOC-甘氨酸与DCC,DMAP和胆酸衍生物201(路线图11)反应以较高产率得到三酯202a。在类似的反应中可成功采用BOC-β-丙氨酸生成202b。在二烷中使用HCl对202a和202b脱保护,然后纯化(SiO2层析,以CH2Cl2MeOH/NH4OH为洗脱液),以较高产率得到203a和203b。
通过相同的反应条件(路线图12)可得到甘氨酸和β-丙氨酸的三酰胺(分别为207a和207b)。同样可生成α-支链氨基酸的三酰胺。例如,在所述条件下,可生成具有二-BOC-赖氨酸侧链的三酰胺(化合物207c)。可以LiOH在THF中水解207a-c的C24酯得到醇208a-c。
在二烷中使用HCl脱保护(208a-c),可以较高产率得到三酰胺209a-c。此外,醇208a和208b可进行甲磺酸化并与甲基苄胺反应。在二烷中使用HCl脱保护所得的化合物可得到三酰胺210a和210b(路线图12)。化合物CSA-31的制备类似于化合物210a和210b。
实施例13
本实施例包括了对一种或多种获取化合物302,312-321,324-326,328-331和341-343的示范性合成方法的描述。
化合物302:化合物308(5β-胆烷酸3,7,12-三酮甲酯)可以通过胆酸甲酯和接近胆酸甲酯的吡啶重铬酸盐制备。化合物308的制备还可参见Pearson等人,J.Chem.Soc.Perkins Trans.11985,267;Mitra等人,J.Org.Chem.1968,33,175;以及Takeda等人,J.Biochem.(Tokyo)1959,46,1313。化合物308可在回流乙醇中以盐酸羟胺和醋酸钠处理12小时(如Hsieh等人,Bioorg.Med.Chem.1995,3,823所述),以97%的产率得到309。
在250ml三口烧瓶中加入甘醇二甲醚(100ml),并添加309(1.00g,2.16mmol)和氢硼化钠(2.11g,55.7mmol)。在0℃和氮气下向混合物缓慢添加TiCl4(4.0mL,36.4mmol)。将所得的绿色混合物在室温下搅拌24小时,然后再回流12小时。在冰浴中冷却烧瓶,并添加氢氧化铵(100mL)。将所得混合物在室温下搅拌6小时。缓慢加入浓盐酸(60mL),并将该酸性混合物搅拌8小时。加入固体KOH使所得的悬浮液成为碱性。过滤该悬浮液并以MeOH洗涤固体。合并滤出液和洗涤液并在真空下浓缩。将所得的固体悬浮在6%KOH水溶液(100mL)中并以CH2Cl2(4x75mL)萃取。以Na2SO4干燥合并的萃取相,真空去除溶剂以得到1.14g白色固体。在硅胶上层析(CH2Cl2/MeOH/NH4OH 12∶6∶1)该混合物以得到302(0.282g,33%产率),3(0.066g,8%产率),4(0.118g,14%产率)。
化合物302:m.p.200-202℃;1H NMR(约10%CDCl3含于CD3OD,300MHz)54.81(bs,7H),3.57-3.49(m,2H),3.14(t,J=3.2Hz,1H),2.97(bs,1H),2.55-2.50(m,1H),2.15-2.10(m,1H),1.95-1.83(m,3H),1.74-0.99(多重态系列,205H),1.01(d,J=6.4Hz,3H),0.95(s,3H),0.79(s,3H);13C NMR(10%CDCl3含于CD3OD,75MHz)δ63.28,55.01,52.39,49.20,48.69,47.00,43.24,42.77,41.03,40.27,36.82,36.35,35.75,35.12,32.77,31.36,30.10,28.54,27.88,26.96,24.35,23.38,18.18,14.23,HRFAB-MS(硫代甘油+Na+基质)m/e;([M+H]+)392.3627(100%);计算得到392.3641。
胆酸辛酯(328):将胆酸(3.14g,7.43mmol)和10-樟脑磺酸(0.52g,2.23mmol)溶解于辛醇(3.5mL,23.44mmol)。在油浴和真空(约13mm/Hg)下将该溶液加热至40-50℃。14小时后,在高真空下蒸发残留辛醇。通过层析(硅胶,5%MeOH含于CH2Cl2)纯化粗产品以得到白色粉末状的目标产物(2.81g,73%产率)。1H NMR(CDCl3,500MHz)δ4.06(t,J=6.7Hz,2H),3.98(s,1H),3.86(s,1H),3.48-3.44(m,1H),2.41-2.34(m,1H),2.28-2.18(m,3H),1.98-1.28(多重态系列,35H),0.99(d,J=3.3Hz,3H),0.90(s,3H),0.89(t,J=7Hz,3H),0.69(s,3H);13C NMR(CDCl3,75MHz)δ154.38,73.18,72.14,68.63,56.07,50.02,49.32,47.07,46.74,41.96,41.67,39.84,39.76,35.66,35.45,34.95,34.86,34.15,32.97,32.91,31.65,31.11,30.68,28.39,27.78,26.66,26.52,25.82,25.70,25.54,25.15,24.95,23.45,22.69,17.77,12.71;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)543.4015(100%),计算得到543.4026.
化合物329-331的代表性合成方法:在CH2Cl2(15mL)中将胆酸辛酯(328)(0.266g,0.511mmol),N-t-Boc-甘氨酸(0.403g,2.298mmol),DCC(0.474g,2.298mmol)以及DMAP(0.0624g,0.051mmol)混合3小时。过滤去除所得的白色沉淀。浓缩滤出液,通过层析(硅胶,EtOAc/己烷1∶2)纯化该产物以得到白色粉末状的目标产物(0.481g,95%产率)。化合物3291H NMR(CDCl3,300MHz)δ5.18(br,3H),5.01(s,1H),4.61(m,1H),4.04(t,J=6.5Hz,2H),3.97-3.88(多重态系列,6H),2.39-2.15(多重态系列,2H),2.06-1.02(多重态系列,35H),1.46(s,18H),1.45(s,9H),0.93(s,3H),0.88(t,J=6.7Hz,3H),0.81(d,J=6Hz,3H),0.74(s,3H);13C NMR(CDCl3,75MHz)6174.26,170.19,169.9,169.78,155.87,155.67,79.95,76.47,75.167,72.11,64.55,47.40,45.28,43.17,42.86,40.82,37.94,34.71,34.63,34.43,31.86,31.340,31.20,30.76,29.29,29.25,28.80,28.72,28.42,28.06,27.96,27.19,26.81,26.29,26.012,25.66,22.87,22.71,22.57,17.55,14.18,12.27;HRFAB-MS(硫代甘油+Na+基质)m/e:([Mn-Na]+)1014.6261(100%),计算得到1014.6242。化合物330:1HNMR(CDCl3,500MHz)δ5.10(s,1H),4.92(d,J=2.44Hz,1H),4.55(m,1H),4.00(t,J=6.8Hz,2H),3.39-3.33(多重态系列,6H),2.595-2.467(多重态系列,6H),2.31-2.12(多重态系列,2H),2.01-1.00(多重态系列,37H),1.39(s,27H),0.88(s,3H),0.84(t,J=6.8Hz,3H),0.76(d,J=6.3Hz,3H),0.69(s,3H);13C NMR(CDCl3,75MHz)δ174.16,172.10,171.78,171.67,155.95,79.45,75.67,74.21,71.10,64.63,47.79,45.27,43.52,40.97,37.92,36.35,35.14,35.05,34.90,34.71,34.46,31.91,31.45,30.95,29.35,29.31,28.96,28.78,28.56,28.55,27.22,26.98,26.269,25.71,23.00,22.77,22.64,17.75,14.24,12.39;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)1056.6702(100%),计算得到1056.6712。化合物331 13C NMR(CDCl3,125MHz)5174.00,172.75,172.41,172.30,156.03,79.00,75.28,73.79,70.77,64.39,47.43,45.04,43.21,40.76,40.00,39.93,37.78,34.74,34.62,34.23,32.19,32.01,31.70,31.24,30.77,29.13,29.10,28.67,38.58,28.38,25.86,25.37,22.56,22.38,17.51,14.05,12.13;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)1098.7181(100%),计算得到1098.7181。
化合物341-343的代表性合成方法:向化合物329(0.463g,0.467mmol)添加含于二烷(0.3mL,4.0M)中的HCl。将混合物搅拌39分钟后,真空去除过量HCl和溶剂。层析(硅胶,CH2Cl2/MeOH/NH3.H2O 10∶1.2∶0.1)后分离得到淡油状的产物(0.271g,84%)。341的三盐酸盐可通过添加含于二烷的HCl并真空蒸发过量HCl和二烷得到白色粉末进行制备。化合物341:1H NMR(CDCl3以及约10%CD3OD,500MHz)65.16(s,1H),4.99(t,J=3.6Hz,1H),4.61(m,1H),4.04(t,J=6.8Hz,2H),3.51-3.36(m,6H),2.34-2.15(m,2H),2.00-1.05(多重态系列,40H),0.93(s,3H),0.88(t,J=7.1Hz,3H),0.80(d,J=3.2Hz,3H),0.74(s,3H);13C NMR(CDCl3以及约10%CD3OD,75MHz)δ174.32,173.92,173.81,76.08,74.67,71.61,64.73,47.64,45.39,44.41,43.49,40.97,37.99,34.99,34.77,34.71,34.52,31.96,31.54,31.35,30.96,29.39,29.36,29.02,28.82,27.32,27.11,26.11,25.83,23.01,22.82,22.69,17.79,14.28,12.41;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)714.4651(100%),计算得到714.4669。化合物342:1H NMR(CDCl3以及约10%CD3OD,300MHz)δ5.142(s,1H),4.96(d,J=2.7Hz,1H),4.60,(m,1H),4.04(t,J=6.6Hz,2H),3.07-2.95(多重态系列,6H),2.56-2.43(多重态系列,6H),2.38-2.13(多重态系列,2H),2.07-1.02(多重态系列,36H),0.92(s,3H),0.88(t,J=6.6Hz,3H),0.82(d,J=6.6Hz,3H),0.73(s,3H);13C NMR(CDCl3and CD3OD,75MHz)δ174.29,172.29,171.98,171.92,75.52,74.09,70.98,64.67,47.78,45.26,43.52,40.98,38.73,38.62,38.35,38.07,38.03,37.99,35.01,34.81,34.77,34.49,31.92,31.50,31.40,30.99,29.36,29.33,28.93,28.80,27.43,26.96,26.08,25.56,23.07,22.79,22.62,17.73,14.25,12.34;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)714.4651(100%),计算得到714.4669。化合物343:1H NMR(CDCl3以及CD3OD,500MHz)δ5.12(s,1H)4.93(s,1H),4.59(m,1H),4.04(t,J=7Hz,2H),2.79-2.69(多重态系列,6H),2.4621-2.2999(多重态系列,6H),2.2033-1.0854(多重态系列,42H),0.94(s,2H),0.91(s,1H),0.88(t,J=7Hz,3H),0.82(d,J=6.4Hz,3H),0.75(s,3H);13C NMR(CDCl3以及CD3OD,75MHz)δ174.70,173.97,171.86,171.75,76.10,74.55,71.56,64.85,47.96,45.31,43.37,40.87,38.09,34.86,34.80,34.73,34.46,32.84,32.62,32.27,31.87,31.75,31.42,31.08,29.31,29.28,29.26,28.78,28.73,27.38,26.91,26.05,25.37,23.24,23.15,22.95,22.74,22.71,22.43,17.78,14.11,12.28;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)798.5624(100%),计算得到798.5609。
胆酸苄酯(312):将胆酸(4.33g,10.62mmol)和10-樟脑磺酸(0.493g,2.21mmol)溶解于苯辛醇(1.97mL,19.3mmol)。将悬浮液在油浴中加热至50℃,并在真空(约13mm/Hg)下搅拌16小时。真空去除过量苯甲醇,将粗产品层析(硅胶,5%MeOH含于CH2Cl2)得到白色粉末状的目标产物(4.23g,81%产率)。1H NMR(CDCl3,500MHz)δ7.34-7.33(m,5H),5.10(d,J=I.5Hz,2H),3.92(s,1H),3.81(s,1H),3.42(s,1H),3.40(br,m,3H),2.44-2.38(m,1H),2.31-2.25(m,1H),2.219(t,J=I 2Hz,2H),0.96(d,J=5.5Hz,3H),0.86(s,3H),0.63(s,3H);13C NMR(CDCl3,125MHz)δ174.25,136.30,128.66,128.63,128.32,128.28,128.24,73.18,71.98,68.54,66.18,47.14,46.56,41.69,39.65,35.51,35.37,34.91,34.84,31.49,31.08,30.50,28.31,27.62,26.47,23.35,22.65,22.60,17.42,12.63,12.57;HRFAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)521.3235(100%),计算得到521.3242。
化合物313-315的代表性合成方法:在CH2Cl2(15mL)中将胆酸苄酯(312)(0.248g,0.499mmol),N-t-Boc-甘氨酸(0.404g,2.30mmol),DCC(0.338g,1.49mmol)以及DMAP(0.051g,0.399mmol)混合16小时。过滤去除所得的白色沉淀,并浓缩滤出液。层析(硅胶,EtOAc/己烷0.6∶1)后得到白色粉末状的产物(0.329g,68%)。化合物313:1H NMR(CDCl3,300MHz)δ7.34-7.33(m,5H),5.16(s,1H),5.08(dd,J=22.5Hz,12.3Hz,4H),5.00(s,1H),4.60(m,1H),4.04-3.81(多重态系列,6H),2.43-1.01(多重态系列,25H),1.46(s,9H),1.44(s,18H),0.92(s,3H),0.797(d,J=5.7Hz,3H),0.69(s,1H);13C NMR(CDCl3,75MHz)δ173.99,170.25,170.05,169.85,155.73,136.19,128.69,128.45,128.35,80.06,77.65,77.23,76.80,76.53,75.24,72.19,66.29,47.46,45.35,43.24,42.91,40.89,38.00,34.79,34.66,34.49,31.43,31.25,30.77,28.88,28.40,27.23,26.89,25.74,22.94,22.65,17.61,12.32;FAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)992.5468(100%),计算得到992.5460。
化合物316-318的代表性合成方法:向MeOH(5mL)添加化合物313(0.505g,0.520mmol)和Pd(相对活性炭的质量百分比为5%,0.111g,0.0521mmol)。在H2(50psi)下将悬浮液搅拌20小时。过滤去除固体,并浓缩滤出液。通过层析(硅胶,5%MeOH含于CH2Cl2)的得到白色粉末状的纯化产物(0.450g,98%产率)。化合物336:1HNMR(CDC]3,500MHz)65.20(s,1H),5.12(br.,2H),4.92(s,1H),4.55(m,1H),3.98-3.83(多重态系列,6H),2.30-2.13(多重态系列,2H),1.96-0.98(多重态系列,30H),1.40(s,9H),1.39(s,18H),0.87(s,3H),0.76(d,J=6.3Hz,3H),0.68(s,3H);13C NMR(CDCl375MHz)8174.11,165.60,165.41,165.22,151.28,151.14,75.48,75.26,71.81,70.57,67.50,45.95,42.58,40.65,38.52,38.16,36.17,33.28,30.01,29.78,26.71,26.42,25.95,24.16,23.78,23.40,23.31,22.55,22.16,21.03,18.23,17.93,12.91,7.61;FAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)902.4997(21%),计算得到902.4990。
化合物319-321的代表性合成方法:向CH2Cl2(15mL)中添加化合物316(0.375g,0.427mmol),DCC(0.105g,0.512mmol)以及DMAP(0.062g,0.512mmol)和N,N-二甲乙醇胺(0.09ml,0.896mmol)。混合16小时后,真空去除溶剂和过量N,N-二甲乙醇胺。通过层析(硅胶,EtOAc/己烷/Et3N,12∶10∶0.6)得到白色粉末状的纯化产物(0.330g,82%产率)。1H NMR(CDCl3and about 10%CD3OD,500MHz)δ5.18(s,1H),5.00(s,1H),4.19(t,J=5.0Hz,2H),3.92(s,3H),3.81(s,3H),2.62(t,J=IO Hz,2H),2.30(s,6H),1.47(s,9H),1.47(s,1H),1.45(s,1H),2.12-1.05(多重态系列,27H),0.96(s,3H),0.84(d,J=I 0.5Hz,3H),0.78(s,3H);13C NMR(CDCl3and about10%CD3OD,125MHz)6174.19,170.05,169.87,156.21,79.36,79.27,76.06,76.90,71.80,61.19,57.04,46.88,44.87,44.67,44.53,42.78,42.15,42.01,40.43,37.47,34.32,34.11,33.92,33.35,33.25,30.74,30.56,30.16,28.40,27.67,27.62,26.73,26.19,25.18,25.10,24.72,24.49,22.29,21.8],16.76,11.56;FAB-MS(硫代甘油+Na+基质)m/e:([M+Na]+)973.5723(100%),计算得到973.5725。将前一反应的白色固体(0.680g,0.714mmol)与MeI(1M含于CH2Cl2,1.5mL)共同搅拌2小时真空去除溶剂和过量MeI得到白色固体(0.812g约100%)。该产物的使用可不经进一步纯化。
化合物324-326的代表性合成方法:将化合物319(0.812g,0.714mmol)溶解于CH2Cl2(5mL)和并添加三氟乙酸(0.5mL)。将混合物搅拌16分钟。真空去除溶剂和过量酸,对所得油进行层析(硅胶,CH2Cl2/MeOH/NH3.H2O 4∶4∶1)得到淡玻璃状的目标产物(0.437g,90%产率)。添加HCl(2M含于乙基醚,2.5mL)以得到淡黄色粉末状的324的三盐酸盐。化合物324:1H NMR(50%CDCl3,50%CD3OD,300MHz)55.43(s,1H),5.24(s,1H),4.84(m,1H),4.66(m,2H),4.16-3.96(多重态系列,6H),3.88(m,2H),3.37(s,9H),0.67(s,3H),0.59(d,J=6.3Hz,3H),0.56(s,3H);13C NMR(50%CDCI3,50%CD3OD,75MHz)D 173.47,167.06,167.01,166.70,78.01,76.49,73.78,64.98,57.67,53.36,47.49,46.99,45.61,43.28,40.83,40.23,40.10,37.69,34.80,34.48,34.28,31.03,30.63,30.44,28.94,27.05,26.56,25.50,22.53,21.56,16.95,11.37;FAB-MS(硫代甘油+Na+基质)m/e:([M-I]+)665.4475(85.6%),计算得到665.4489。经证明化合物325和326在用于纯化324的碱性洗脱液中十分不稳定,无法进行层析。因此,可通过使用HCl(2M含于二乙基醚)对320和321脱保护,然后以乙酸乙酯滴定制备325和326。该化合物的使用可无需进一步纯化。1H NMR光谱显示化合物325和326的纯度大于>95%。化合物325:1H NMR(50%CDCl3,50%CD3OD,500MHz)δ5.21(s,1H),5.02(d,J=4Hz,1H),4.64(m,1H),4.53(m,2H),3.74(m,2H),3.31-3.01(多重态系列,6H),3.23(s,9H),2.96-2.73(多重态系列s,6H),2.51-2.44(m,1H),2.35-2.29(m,1H),2.14-1.09(多重态系列,26H),0.99(s,3H),0.85(d,J=6.5Hz,3H),0.80(s,3H);13CNMR(50%CDCl3,50%CD3OD,125MHz)δ172.77,169.88,169.56,169.50,75.94,74.44,71.57,64.31,56.94,52.92,46.78,44.59,42.70,40.21,37.16,34.80,34.72,34.66,34.05,34.00,33.78,33.62,30.95,30.93,30.81,30.41,29.96,29.81,28.20,26.37,26.06,24.74,24.24,22.04,21.13,16.54,10.97;FAB-MS(硫代甘油+Na+基质)m/e:([M-I]+)707.4958(25.6%),计算得到707.4958。化合物326:1H NMR(50%CDCl3,50%CD3OD,500MHz)δ5.12(s,IH),4.94(d,J=2.5Hz,1H),4.56(m.1H),4.51(t,J=2.3Hz,2H),3.74(m,2H),3.23(s,9H),3.05-3.01(m,4H),2.98(t,J=7.5Hz,2H),2.63-2.43(多重态系列,6H),2.31-2.24(多重态系列,2H),2.07-1.87(多重态系列,12H),1.17-1.05(多重态系列,23H),0.94(s,3H),0.82(d,J=6.0Hz,3H),0.76(s,3H);13C NMR(50%CDCl3,50%CD3OD,125MHz)5171.87,169.79,169.59,169.50,76.12,74.70,71.65,65.57,65.08,64.40,57.68,53.74,52.78,45.33,43.54,41.04,39.12,37.92,43.85,34.72,34.56,34.34,32.30,31.47,31.27,30.87,30.58,29.03,27.053,26.84,25.51,24.95,24.91,22.87,22.82,22.65,21.93,17.31,11.81;FAB-MS(硫代甘油+Na+基质)m/e:([M-I]+)749.5432(100%),计算得到749.5436。
实施例14
本实施例包括了显示化合物352-354在酸性,中性和碱性条件下的稳定性的数据。
将化合物352-354以大约10mM的浓度溶解于50mM磷酸盐缓冲液(pH 2.0,7.0或12.0)。图9显示了化合物352-354的结构。通过HPLC(氰基-硅柱,0.15%TFA水-乙腈梯度洗脱)可观察到化合的分解。表15显示了化合物352-354于室温下在pH 2.0,pH 7.0和pH 12.0的磷酸盐缓冲液中的稳定性(半衰期)。这些化合物由于具有可促进通过HPLC设备中常用的吸收法测定分解的发色团,因而常被采用。
在低pH下,该胺将被质子化,该化合物显示相对的稳定性。在更高的pH下,该胺的质子化程度减少,并开始有酯水解。γ-氨基丁酸-衍生化合物特别易于水解,并预计可生成吡咯烷酮。一般认为根据特定的化合物,该类化合物可水解生成胆酸,胆碱或辛醇,以及甘氨酸,β-丙氨酸,或吡咯烷酮。
通过酯水解分解产生的化合物具有更低的极性,并更容易从起始原料中分离。最初仅观察到一种含苯分解产物;随反应继续,可观察到与后续酯水解相应的其它两种分解产物。
实施例15
本实施例包括生成式I化合物的附加示范性合成方法的描述。如Hsieh等人(Synthesis and DNA Binding Properties of C3-,C12-,and C24-Substituted Amino-Steroids Derived from Bile Acids,Biorganic and Medicinal Chemistry,1995,vol.6,823-838)所述,在一个实施例中,胆酸上的羟基基团可转化成为胺基团。
式I的化合物可按如下路线进行制备。
R基团对应任意氨基酸(D或L)组合
的侧链。
R基团对应任意氨基酸(D或L)组合
的侧链。
对类固醇起始原料的描述可参见Dictionary of Steroids,Hill,RR.;Kirk,D.N.;Makin,H.L.J;Murphy.G.M.,eds Chapman and Hall:New York,1991。
实施例16
本实施例描述了各种材料和方法。
细胞培养及原代细胞分离:外周血单核细胞(PBMC)可采用ficoll-hypaque密度梯度离心法由成年人血液分离得到。单核细胞和CD4+T细胞可采用AutoMACS由PBMC分离得到。可通过在添加了IL-4(R&D Systems,50μg/ml)和GM-CSF(R&D Systems,50μg/ml)的RPMI完全(10%胎牛血清(FBS),2mM L-谷氨酰胺,100U/ml青霉素G,100μg/ml链霉素)培养基中将CD14+单核细胞/ml培养5天,然后添加LPS(Sigma,100ng/ml)后续熟化1-2天得到DCs。通过以针对CD14,CD83,CD86和HLA-DR(均来自BD Biosciences)的抗体对细胞染色以评估成熟的DC产物。表达CCR5的Hut 78T细胞(Hut/CCR5)可参照前述制备和维持(OswaJd-Richter等人,Eur.J.Immunol.34:1705(2004);Oswald-Richter等人,PLoS Biol.2:E198(2004))。
病毒生产:可通过以包膜阴性前病毒质粒和VSV-G包膜质粒共转染HEK-293T细胞生成水疱性口炎病毒糖蛋白(VSV-G)-假型不可复制HIV颗粒(HDV-VSV-G)。可通过以NL4-3前病毒质粒转染HEK-293T细胞生成表达以CCR5作为共受体的HIV包膜BaL的可复制病毒(HIV-R5)。所有这些病毒均以EGFP(Clontech)替换了nef基因。采集上清液并对HUT细胞中的感染进行滴定以测定每毫升的感染单位(IFU)。
HIV感染和细胞活性测定:在不同的时间点和浓度的CSAs存在下培养病毒与通过与平板结合抗CD3抗体(OKT-3,ATCC)和可溶性抗CD28抗体(BD Biosciences)交联激活的Hut或原代CD4+T细胞。首先以抗小鼠IgG(10g/ml,Caltag)涂布平板,然后采用抗-CD3抗体。采用FACSCaliburTM四色细胞仪(BD Biosciences)和CELLQuestTM软件(BD Biosciences)在3天后通过GFP表达分析T细胞的感染。在肽处理后的不同时间点取出等份的细胞,并与碘化吡啶(PI,Sigma,25μg/ml)孵育。以PI排除作为活性指数通过流式细胞仪分析细胞。所有的数据均归一化至以对照处理的感染水平为各数据点的100%。
DC介导的感染测定:在MOI为2时以可复制HIV-R5脉动单核细胞衍生的DC。以2000rpm离心病毒-细胞混合物1小时,并继续培养2小时以使得DCs能够有效捕获病毒。用完全RPMI培养基洗涤DCs三次以去除非细胞相关病毒。向DC添加不同浓度的CSAs并孵育1小时。用完全RPMI培养基洗涤DCs三次并以1.5x104Hut/CCR5细胞孵育3天。收集细胞,以1%多聚甲醛固定,并用流式细胞仪分析GFP表达。在部分研究中,在CSA处理24小时候单独孵育DC并根据上文采用PI染色测定活性。
HIV p24测定:将HIV-VSV-G与不同浓度的CSAs或对照在完全RPMI培养基中孵育30分钟。然后通过ELISA测定培养基中病毒核蛋白p24的存在。以酶标仪(Molecular Devices)在405nm吸收下分析平板。总p24可通过线性回归分析由各平板中的标准计算得到。
实施例17
本实施例描述了各种CSAs存在下的HIV-VSV-G感染性研究。
将HIV-VSV-G(30,000感染单位)单独或与200μM CSA-8,50μM CSA-54,阳性对照肽(10μM的caerin 1.9)或稀释于RPMI中的水在完全RPMI培养基中孵育30分钟。然后通过ELISA测定培养基中病毒核蛋白p24的存在。以酶标仪(Molecular Devices)在405nm吸收下分析平板。数据代表了四次独立的研究(图11)。
实施例18
本实施例描述了以流式细胞仪进行的各种细胞的活性研究。
将CSAs与5x 105Hut细胞(实心方块),激活的原代CD4+T细胞(实心圆),HEK-293T细胞(空心方块)或HeLa细胞(空心圆)孵育1小时,从培养物中取出,以PI染色,并通过流式细胞仪分析活性(图12)。
实施例19
本实施例描述了以流式细胞仪进行的HIV-VSV-G感染的活性研究。
将CSAs与HIV-VSV-G(2x 105感染单位)和1x 105Hut细胞孵育5分钟,然后以完全RPMI培养基稀释4倍,并在37℃下孵育3天。收集细胞并进行GFP表达分析(实心方块)。数据归一化至水处理后的感染并表示为一个代表性研究中三个重复样本的平均值,误差棒显示了标准偏差(图13)。感染后24小时从培养物中取出1.5x 104T细胞,以PI染色,然后通过流式细胞仪分析活性(空心方块)。
Claims (10)
1.阳离子类固醇抗微生物剂(CSA)在用于向对象提供对人免疫缺陷病毒(HIV)感染或发病的保护的药物制备中的用途。
2.阳离子类固醇抗微生物剂(CSA)在用于对需要人免疫缺陷病毒(HIV)感染或发病治疗的对象进行治疗的药物制备中的用途。
3.阳离子类固醇抗微生物剂(CSA)在用于降低对象对人免疫缺陷病毒(HIV)感染或发病易感性的药物制备中的用途。
4.如权利要求1至3任意一项所述的用途,其中在该患有,暴露至或接触HIV的对象感染前,感染时或感染后施用该CSA。
5.如权利要求1至3任意一项所述的用途,其中在急性或慢性HIV感染的症状发展前,发展时或发展后施用该CSA。
6.如权利要求1至3任意一项所述的用途,其中该HIV包括了药物耐受的HIV型,组,亚型或分离物。
7.如权利要求1至3任意一项所述的用途,其中该HIV包括了HIV-1或HIV-2。
8.如权利要求1至3任意一项所述的用途,其中该HIV-1包括了组M,N或O组。
9.如权利要求1至3任意一项所述的用途,其中该HIV-1包括了A,B,A/B,A/E,A/G,C,D,F,G,H,J或K亚型或者其混合物。
10.如权利要求1至3任意一项所述的用途,其中该CSA选自图10所示的CSA-7,CSA-8,CSA-10,CSA-11,CSA-13,CSA-15,CSA-17,CSA-21,CSA-25,CSA-26,CSA-31,CSA-46,CSA-54和CSA-59。
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US6767904B2 (en) * | 1998-03-06 | 2004-07-27 | Bringham Young University | Steroid derived antibiotics |
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- 2007-01-31 EP EP07762971A patent/EP1978968A2/en not_active Withdrawn
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Cited By (9)
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US10676501B2 (en) | 2011-07-20 | 2020-06-09 | Brigham Young University | Hydrogel materials incorporating eluting ceragenin compound |
US11524015B2 (en) | 2013-03-15 | 2022-12-13 | Brigham Young University | Methods for treating inflammation, autoimmune disorders and pain |
US11739116B2 (en) | 2013-03-15 | 2023-08-29 | Brigham Young University | Methods for treating inflammation, autoimmune disorders and pain |
US11690855B2 (en) | 2013-10-17 | 2023-07-04 | Brigham Young University | Methods for treating lung infections and inflammation |
US11286276B2 (en) | 2014-01-23 | 2022-03-29 | Brigham Young University | Cationic steroidal antimicrobials |
CN106900172A (zh) * | 2014-06-26 | 2017-06-27 | 布莱阿姆青年大学 | 用于治疗真菌感染的方法 |
CN108136213A (zh) * | 2015-04-22 | 2018-06-08 | 布莱阿姆青年大学 | 塞拉集宁的合成方法 |
US11253634B2 (en) | 2016-03-11 | 2022-02-22 | Brigham Young University | Cationic steroidal antibiotic compositions for the treatment of dermal tissue |
US10959433B2 (en) | 2017-03-21 | 2021-03-30 | Brigham Young University | Use of cationic steroidal antimicrobials for sporicidal activity |
Also Published As
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AU2007211279A1 (en) | 2007-08-09 |
CN101378761A (zh) | 2009-03-04 |
ZA200805763B (en) | 2009-08-26 |
EP1978968A2 (en) | 2008-10-15 |
CN101378761B (zh) | 2013-10-16 |
CA2640584C (en) | 2015-12-01 |
AU2007211279B2 (en) | 2013-02-14 |
CA2640584A1 (en) | 2007-08-09 |
WO2007089907A3 (en) | 2007-11-01 |
WO2007089907A2 (en) | 2007-08-09 |
US20070190067A1 (en) | 2007-08-16 |
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