CN103183723B - 新颖的尿苷肽类抗生素及其用途 - Google Patents
新颖的尿苷肽类抗生素及其用途 Download PDFInfo
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- CN103183723B CN103183723B CN201210579561.2A CN201210579561A CN103183723B CN 103183723 B CN103183723 B CN 103183723B CN 201210579561 A CN201210579561 A CN 201210579561A CN 103183723 B CN103183723 B CN 103183723B
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- sansanmycin
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Abstract
本发明涉及新颖的尿苷肽类抗生素及其用途。具体地,本发明提供了以下式I化合物或其药学可接受的盐或溶剂合物,其中各取代基如说明书所述。本发明还提供了式I化合物的制备方法以及它们作为药物特别是作为抗菌药物例如抗结核病药物方面的应用。
Description
技术领域
本发明属于医药化学领域,具体涉及一类新的可作为细菌抑制剂的化合物,特别涉及一类具有抗菌活性的Sansanmycin类尿苷肽抗生素及其制备方法,以及此类化合物在作为药物特别是作为抗菌药物例如抗结核病药物方面的应用。
背景技术
结核病(TB)是由结核分枝杆菌引起的传染性疾病,近年来其流行重新加重。我国是全球22个TB高负担国家之一,患病率高,耐药率也高。据世界卫生组织(WHO)统计,我国约5.5亿人感染了结核菌,其中耐药患者超过40万,是世界上新增结核病例最多、多药耐药结核病发生率最高的国家之一。因此,TB重新成为全球、特别是我国十分关注的公共卫生和社会问题。目前,临床广泛使用的抗TB药物仍然是上世纪70年代前研发的药物,如异烟肼(INH)、利福平(RFP)、吡嗪酰胺和乙胺丁醇等,因其有效的抗TB作用一直是临床TB治疗的一线用药。然而,由于此类药物的长期使用以及TB患者的用药疗程长等缘故,已不可避免地产生了日趋严重的耐药问题;同时这些药物还存在肝肾功能损伤、胃肠道反应等毒副作用,部分限制了此类药物的临床使用。尤其我国是一个TB高发国家,面临的问题更加严峻。自上个世纪七十年代中期,RNA聚合酶抑制剂——利福平成功用于临床以来,近40年来没有一种专门用于TB治疗的药物开发成功;也未见新结构骨架的抗结核候选物出现。因此,研究新靶点、新作用机制或新化学实体的抗TB新药,以克服“TB治疗药物的耐药”这一全球性难题,近年来已成为全球科学家研究的重点与热点之一。
人们已经获得并表征了一种具有抗结核分支杆菌活性的尿苷肽类抗生素Sansanmycin A,在本文中可缩写为SSA。例如文献(Yunying Xie,et al.A NewNucleosidyl-peptide Antibiotic,Sansanmycin,The Journal of Antibiotics.2007,60(2):158-161)中详细公开了SSA这种尿苷肽类抗生素的制备、结构分析、表征以及对某些细菌(例如结核分支杆菌、绿脓杆菌、金黄色葡萄球菌和大肠杆菌)的抗菌活性。Sansanmycin A的化学结构式如下:
人们仍然期待有新颖而有效的抗菌药例如抗结核病的药物用于临床。
发明内容
本发明的目的是寻找具有有效的抗菌新化合物。本发明人令人惊奇的发现,具有式I结构的取代尿苷肽类抗生素具有令人期待的效果。本发明基于此发现而得以完成。
为此,本发明第一方面提供了以下式I化合物:
或其药学可接受的盐或溶剂合物,其中
R1选自以下基团g70、g11和g12:
其中R11选自0-2个选自下列的基团:卤素、OH、NH2、NO2、C1-6烷基、C1-6烷氧基,R12是0-4个与环碳原子连接的C1-6烷基;
R2选自以下基团g3至g6:
R3选自以下基团g1和g2:
根据本发明第一方面的化合物,其中R1选自以下基团g70、g11和g12:
其中R11选自0-2个选自下列的基团:卤素、OH、NH2、NO2、C1-4烷基,R12是1-2个与环碳原子连接的C1-4烷基。在一个实施方案中,R11是0或1个OH。在一个实施方案中,R12是0、1或2个C1-4烷基。
根据本发明第一方面的化合物,其中基团g70是选自以下g7、g8、g9、g10的基团:
根据本发明第一方面的化合物,其中所述的C1-6烷基包括它的任意子基团,在一个实施方案中,C1-6烷基是选自下列的烷基:C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、己基。在一个实施方案中C1-4烷基是选自下列的烷基:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基。
根据本发明第一方面的化合物,其中所述的卤素选自:氟、氯、溴、碘。在一个实施方案中,所述的卤素选自:氟、氯、溴。
根据本发明第一方面的化合物,其中R1不为基团g11、R2不为基团g3、并且R3不为基团g2。
根据本发明第一方面的化合物,其中R1不为基团g11、R2不为基团g6、并且R3不为基团g2。
根据本发明第一方面的化合物,其为以下式I化合物:
或其药学可接受的盐或溶剂合物,其中R1、R2、R3分别是如下表所述的基团:
No. | 化合物编号 | R1 | R2 | R3 |
1 | SSH | g11 | g3 | g1 |
2 | SSI | g7 | g3 | g1 |
3 | SSJ | g8 | g3 | g1 |
4 | SSK | g7 | g3 | g2 |
5 | SSL | g8 | g3 | g2 |
6 | SSM | g9 | g3 | g2 |
7 | SSN | g10 | g4 | g2 |
8 | SSO | g10 | g5 | g2 |
9 | SSP | g11 | g5 | g2 |
10 | SSQ | g12 | g3 | g2 |
11 | SSR | g7 | g5 | g2 |
12 | SSS | g8 | g5 | g2 |
本发明第二方面提供了制备本发明第一方面所述化合物的方法,其是使用本申请人/发明人的菌株CGMCC No.1764经发酵培养分离处理得到。在一个实施方案中,本发明化合物是参考CN 101153052A所记载的方法制备的。在一个实施方案中,本发明化合物是参考CN 101153052A中实施例1所记载的方法制备的。
根据本发明第二方面的方法,其基本上参考CN 101153052A所记载的方法,例如所用发酵培养基和菌种与CN 101153052A中的相同,发酵时间4-8天,最优6天,发酵后离心或过滤除去菌丝体,上清或滤液上4006大孔吸附树脂,10%、20%、30%丙酮水溶液分步洗脱,收集活性部分,过Toyopear DEAE-650M弱阴离子交换树脂,用Tris-HCl洗脱,分步收集,HPLC检测各个部分,按峰合并,用制备HPLC进行制备,条件:色谱柱:Shim-pack PREP-ODS柱(Shim-pack,Kyoto,Japan),250×20mm,10μm;洗脱:不同浓度MeOH的0.1%(w/v)(NH4)2CO3)溶液洗脱,流速:5ml/min;检测波长254nm,柱温:40℃。通过此方法得到本发明式I化合物,例如示例性的12个化合物,即Sansanmycin H-S,其中Sansanmycin H可以缩写为SSH,SansanmycinI可以缩写为SSI,Sansanmycin S可缩写为SSS。
根据本发明第二方面的方法,其还包括使所得式I化合物进行纯化的步骤。在一个实施方案中,所述的是使用制备型液相色谱法纯化的。例如可以参考文献(例如Yunying Xie,et al.A New Nucleosidyl-peptide Antibiotic,Sansanmycin,The Journalof Antibiotics.2007,60(2):158-161中详细公开的)方法进行纯化。
本发明方法还可参考文献记载的方法(例如Yunying Xie,et al.The Journal ofAntibiotics.2007,60(2):158-161)进行,本发明方法可使用该文献中记载的由本发明人/申请人以保藏号CGMCC No.1764保藏的菌株Streptomyces sp SS进行。
在本发明第二方面的制备方法中,在必要情况下,在式I化合物制备过程中,为防止有些基团(如氨基、羟基等)发生不希望的反应,需要对这些基团予以保护,同时,在适当的时候予以去除保护基。这些实施例不胜枚举的,没有具体提及的保护基的使用和脱保护的方法也属于本发明的范围之内。
本发明第三方面涉及一种药物组合物,其包含本发明第一方面任一项所述的式I化合物,以及任选的一种或多种药学可接受的载体或赋形剂。
本发明第四方面涉及本发明第一方面任一项所述的式I化合物在制备用于治疗和/或预防哺乳动物(包括人)感染性疾病(例如由细菌感染引起的疾病,例如由结核杆菌感染引起的疾病,例如结核病)的药物中的用途。
本发明第五方面涉及一种在有需要的哺乳动物中治疗和/或预防哺乳动物(包括人)感染性疾病(例如由细菌感染引起的疾病,例如由结核杆菌感染引起的疾病,例如结核病)的方法,该方法包括给有需要的哺乳动物施用治疗有效量的本发明第一方面任一项所述的式I化合物。
本发明第六方面涉及用于治疗和/或预防哺乳动物(包括人)感染性疾病(例如由细菌感染引起的疾病,例如由结核杆菌感染引起的疾病,例如结核病)的药物组合物,该药物组合物包含本发明第一方面任一项所述的式I化合物,以及任选的一种或多种药学可接受的载体或赋形剂。
本发明第七方面还涉及用于治疗和/或预防哺乳动物(包括人)感染性疾病(例如由细菌感染引起的疾病,例如由结核杆菌感染引起的疾病,例如结核病)的本发明第一方面任一项所述的式I化合物。
本发明的任一方面的任一实施方案,可以与其它实施方案进行组合,只要它们不会出现矛盾。此外,在本发明任一方面的任一实施方案中,任一技术特征可以适用于其它实施方案中的该技术特征,只要它们不会出现矛盾。
下面对本发明作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。
在本发明合成式I化合物的方法中,反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者,本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其它式I化合物。
本发明的式I化合物可以与其它活性成分组合使用,只要它不产生其他不利作用,例如过敏反应。
本发明式I所示的活性化合物可作为唯一的抗菌药物使用,或者可以与一种或多种其他抗菌药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
本文所用的术语“组合物”意指包括包含指定量的各指定成分的产品,以及直接或间接从指定量的各指定成分的组合产生的任何产品。在本发明中,术语“组合物”可以与“药物组合物”互换使用。
本发明的化合物可以以衍生自无机酸或有机酸的药学可接受的盐的形式使用。词语“药学可接受的盐”指在可靠的医学判断范围内,适合用于与人类和低等动物的组织接触而不出现过度的毒性、刺激、过敏反应等,且与合理的效果/风险比相称的盐。药学可接受的盐是本领域公知的。例如,S.M.Berge,et al.,J.Pharmaceutical Sciences,1977,66:1中对药学可接受的盐进行了详细描述。所述盐可通过使本发明化合物的游离碱官能度与合适的有机酸反应,在本发明化合物的最终分离和纯化过程中原位制备或者单独制备。代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(异硫代硫酸盐,isothionate)、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐和十一烷酸盐。同样,碱性含氮基团可用以下物质季铵化:低级烷基卤化物如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯如硫酸二甲酯、二乙酯、二丁酯和二戊酯;长链卤化物如癸基、十二烷基、十四烷基和十八烷基的氯化物、溴化物和碘化物;芳基烷基卤化物如苄基溴和苯乙基溴及其他。因此得到可溶于或分散于水或油的产品。可用来形成药学可接受的酸加成盐的酸实例包括无机酸如盐酸、氢溴酸、硫酸和磷酸,以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。
碱加成盐可通过使本发明化合物的含羧酸部分与合适的碱反应,在本发明化合物的最终分离和纯化过程中原位制备,所述的碱例如药学可接受的金属阳离子的氢氧化物、碳酸盐和碳酸氢盐,或者氨或有机伯胺、仲胺或叔胺。
药学可接受的盐包括但不限于基于碱金属或碱土金属的阳离子如锂、钠、钾、钙、镁和铝盐等,以及无毒的季铵和胺阳离子,包括铵、四甲基铵、四乙基铵、甲基铵、二甲基铵、三甲基铵、三乙基铵、二乙基铵和乙基铵等。可用于形成碱加成盐的其他代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等。
本发明式I化合物还包括其异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物、和酯,本发明式I化合物以及它的异构体、消旋体、对映体、非对映体、对映体富集物、溶剂合物、和酯还可以形成溶剂合物,例如水合物、醇合物等。上述化合物还可以是前药或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。一般来说,对于本发明的目的,与药学可接受的溶剂如水、乙醇等的溶剂合物形式与非溶剂合物形式相当。
以式I表示的本发明的一些示例性的化合物的结构及其抗结核分支杆菌H37Rv的活性(MIC)列于下面,其中的抗菌活性测定方法见实施例部分。
本发明一些示例化合物对结核分支杆菌的活性(MIC,μg/mL)列于下面:
注*:得自中国结核病患者的结核分支杆菌菌株2199是利福平和异烟肼耐药株。
可改变本发明药物组合物中各活性成分的实际剂量水平,以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病况和既往病史来选定。但是,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。
当用于上述治疗和/或预防或其他治疗和/或预防时,治疗和/或预防有效量的一种本发明化合物可以以纯形式应用,或者以药学可接受的酯或前药形式(在存在这些形式的情况下)应用。或者,所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂的药物组合物给药。词语“治疗和/或预防有效量”的本发明化合物指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到,本发明化合物和组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者,具体的治疗有效剂量水平须根据多种因素而定,所述因素包括所治疗的障碍和该障碍的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;所采用的具体化合物的给药时间、给药途径和排泄率;治疗持续时间;与所采用的具体化合物组合使用或同时使用的药物;及医疗领域公知的类似因素。例如,本领域的做法是,化合物的剂量从低于为得到所需治疗效果而要求的水平开始,逐渐增加剂量,直到得到所需的效果。一般说来,本发明式I化合物用于哺乳动物特别是人的剂量可以介于0.001~1000mg/kg体重/天,例如介于0.01~100mg/kg体重/天,例如介于0.01~10mg/kg体重/天。
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发明化合物的药物组合物。因此本发明还提供包含与一种或多种无毒药物可接受载体配制在一起的本发明化合物的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
所述的药物组合物可配制成许多剂型,便于给药,例如,口服制剂(如片剂、胶囊剂、溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射水可立即使用)。所述的药物组合物中载体包括:口服制剂使用的粘合剂(如淀粉,通常是玉米、小麦或米淀粉、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮),稀释剂(如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素,和/或甘油),润滑剂(如二氧化硅、滑石、硬脂酸或其盐,通常是硬脂酸镁或硬脂酸钙,和/或聚乙二醇),以及如果需要,还含有崩解剂,如淀粉、琼脂、海藻酸或其盐,通常是藻酸钠,和/或泡腾混合物,助溶剂、稳定剂、悬浮剂、无色素、矫味剂等,可注射的制剂使用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可以将其配制成肠衣片剂。
更具体地说,本发明的药物组合物可通过口服、直肠、胃肠外、池内、阴道内、腹膜内、局部(如通过散剂、软膏剂或滴剂)、口颊给予人类和其他哺乳动物,或者作为口腔喷雾剂或鼻腔喷雾剂给予。本文所用术语“胃肠外”指包括静脉内、肌肉内、腹膜内、胸骨内、皮下和关节内注射和输液的给药方式。
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非水溶液剂、分散剂、混悬剂或乳剂,及供重构成无菌可注射溶液剂或分散剂的无菌散剂。合适的含水或非水载体、稀释剂、溶剂或媒介物的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、植物油(如橄榄油)、可注射有机酯如油酸乙酯及它们的合适混合物。
这些组合物也可含有辅料,如防腐剂、湿润剂、乳化剂和分散剂。通过各种抗细菌剂和抗真菌剂,例如尼泊金酯类、三氯叔丁醇、苯酚、山梨酸等,可确保防止微生物的作用。还期望包括等渗剂,例如糖类、氯化钠等。通过使用能延迟吸收的物质,例如单硬脂酸铝和明胶,可达到可注射药物形式的延长吸收。
混悬剂中除活性化合物外还可含有悬浮剂,例如乙氧基化异十八醇、聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶或者这些物质的混合物等。
在一些情况下,为延长药物的作用,期望减慢皮下或肌内注射药物的吸收。这可通过使用水溶性差的晶体或无定形物质的液体混悬剂来实现。这样,药物的吸收速度取决于其溶解速度,而溶解速度又可取决于晶体大小和晶型。或者,胃肠外给药的药物形式的延迟吸收通过将该药物溶解于或悬浮于油媒介物中来实现。
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚乙交酯(polylactide-polyglycolide)中形成药物的微胶囊基质来制备。可根据药物与聚合物之比和所采用的具体聚合物的性质,对药物释放速度加以控制。其他生物可降解聚合物的实例包括聚原酸酯类(poly(orthoesters))和聚酐类(poly(anhydrides))。可注射贮库制剂也可通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。
可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,所述固体组合物可在临用前溶解或分散于无菌水或其他无菌可注射介质。
本发明化合物或其组合物可用口服方法或非胃肠道给药方式。口服给药可以是片剂、胶囊剂、包衣剂,肠道外用药制剂有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟悉的方法制备的。为了制造片剂、胶囊剂、包衣剂所用的辅料是常规用的辅料,例如淀粉、明胶、阿拉伯胶,硅石,聚乙二醇,液体剂型所用的溶剂如水、乙醇、丙二醇、植物油(如玉米油、花生油、橄榄油等)。含有本发明化合物的制剂中还有其它辅料,例如表面活性剂,润滑剂,崩解剂,防腐剂,矫味剂和色素等。在片剂、胶囊剂、包衣剂、注射剂和栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物量计算的。在单元剂型中本发明式I化合物一般含量为0.01-5000mg,优选的单元剂型含有0.1-500mg,更优选的单元剂型含有1-300mg。具体地说,本发明可以提供的供口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在此类固体剂型中,活性化合物可与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和/或以下物质混合:a)填充剂或增量剂如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯树胶;c)保湿剂如甘油;d)崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶液阻滞剂如石蜡;f)吸收加速剂如季铵化合物;g)湿润剂如鲸蜡醇和甘油单硬脂酸酯;h)吸附剂如高岭土和膨润土以及i)润滑剂如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠和它们的混合物。在胶囊剂、片剂和丸剂的情况下,所述剂型中也可包含缓冲剂。
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇等,也可用作软胶囊和硬胶囊中的填充物。
片剂、糖衣丸剂(dragees)、胶囊剂、丸剂和颗粒剂的固体剂型可与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。这些固体剂型可任选含有遮光剂,且其组成还可使其只是或优先地在肠道的某个部位任选以延迟方式释放活性成分。可以使用的包埋组合物的实例包括高分子物质和蜡类。如果适合,活性化合物也可与一种或多种上述赋形剂配成微囊形式。
供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、糖浆剂和酏剂。液体剂型除含有活性化合物外还可含有本领域常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇(tetrahydrofurfuryl alcohol)、聚乙二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。口服组合物除包含惰性稀释剂外还可包含辅料,例如湿润剂、乳化剂和悬浮剂、甜味剂、矫味剂和香味剂。
供直肠或阴道给药的组合物优选是栓剂。栓剂可通过将本发明化合物与合适的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂蜡混合来制备,它们在室温下为固体,但在体温下则为液体,因此可在直肠腔或阴道腔内熔化而释放出活性化合物。
本发明的化合物及其组合物还考虑用于局部给药。供局部给予本发明化合物的剂量形式包括散剂、喷雾剂、软膏剂和吸入剂。在无菌条件下将活性化合物与药学可接受的载体和任何所需的防腐剂、缓冲剂或推进剂混合。眼用制剂、眼软膏剂、散剂和溶液剂也被考虑在本发明范围内。
本发明化合物也可以脂质体形式给药。如本领域所公知,脂质体通常用磷脂或其他脂类物质制得。脂质体由分散于含水介质中的单层或多层水化液晶所形成。任何能够形成脂质体的无毒、生理上可接受和可代谢的脂质均可使用。脂质体形式的本发明组合物除含有本发明化合物外,还可含有稳定剂、防腐剂、赋形剂等。优选的脂类是天然和合成的磷脂和磷脂酰胆碱(卵磷脂),它们可单独或者一起使用。形成脂质体的方法是本领域公知的。参见例如Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y.(1976),p.33。
本发明人发现,结构式I所示的尿苷肽类抗生素对结核分支杆菌(例如H37Rv)有抑制作用。因此,本发明的化合物可用于治疗和/或预防哺乳动物(包括人)感染性疾病(例如由细菌感染引起的疾病,例如由结核杆菌感染引起的疾病,例如结核病)。
附图说明
图1、Sansanmycin H的1HNMR谱图(D2O)。
图2、Sansanmycin H的13CNMR谱图(D2O)。
图3、Sansanmycin I的1H-NMR谱图(D2O)。
图4、Sansanmycin I的13C-NMR谱图(D2O)。
图5、Sansanmycin J的1H-NMR谱图(D2O)。
图6、Sansanmycin J的13C-NMR谱图(D2O)。
图7、Sansanmycin L的1HNMR谱图(D2O)。
图8、Sansanmycin L的13C-NMR谱图(D2O)。
图9、Sansanmycin M的1HNMR谱图(D2O)。
图10、Sansanmycin M的13C-NMR谱图(D2O)。
图11、Sansanmycin N的1HNMR谱图(D2O)。
图12、Sansanmycin N的13C-NMR谱图(D2O)。
图13、Sansanmycin O的1HNMR谱图(D2O)。
图14、Sansanmycin O的13C-NMR谱图(D2O)。
图15、Sansanmycin P的1HNMR谱图(D2O)。
图16、Sansanmycin P的13C-NMR谱图(D2O)。
图17、Sansanmycin R的1HNMR谱图(D2O)。
图18、Sansanmycin R的13C-NMR谱图(D2O)。
图19、Sansanmycin S的1HNMR谱图(D2O)。
图20、Sansanmycin S的13C-NMR谱图(D2O)。
具体实施方式
下面通过具体的制备实施例和生物学试验例进一步说明本发明,但是,应当理解为,这些实施例和试验例仅仅是用于更详细具体地说明之用,而不应理解为用于以任何形式限制本发明。
本发明对试验中所使用到的材料以及试验方法进行一般性和/或具体的描述。虽然为实现本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所用材料和操作方法是本领域公知的。
A、实施例部分
参考CN 101153052A(ZL 200610141075.7)所记载的方法,例如所用发酵培养基和菌种与CN 101153052A中的相同,发酵时间4-8天,最优6天,发酵后离心或过滤除去菌丝体,上清或滤液上4006大孔吸附树脂,10%,20%,30%丙酮水溶液分步洗脱,收集活性部分,过Toyopear DEAE-650M弱阴离子交换树脂,用Tris-HCl洗脱,分步收集,HPLC检测各个部分,按峰合并,用制备HPLC进行制备,条件:色谱柱:Shim-pack PREP-ODS柱(Shim-pack,Kyoto,Japan),250×20mm,10μm;洗脱:不同浓度MeOH的0.1%(w/v)(NH4)2CO3)溶液洗脱,流速:5ml/min;检测波长254nm,柱温:40℃。通过此方法共得到12个新组分Sansanmycin H-S。
结构解析:
Sansanmycin H(在本发明中可缩写为SSH,下文类似表述具有类似含义):白色无定形粉末;256,200;ESI-MS m/z 841.3[M+H]+,HR-ESI-MS m/z841.31850[M+H]+(计算值C38H49O12N8S,841.31852)
将Sansanmycin H的分子离子峰[M+H]+的MS/MS谱(见以下结构式标示的)与Sansanmycin A(Yunying Xie,et al.A New Nucleosidyl-peptide Antibiotic,Sansanmycin,The Journal of Antibiotics.2007,60(2):158-161)的进行比对,发现其存在m/z 660的碎片峰,说明两者差异可能只存在于C-末端的氨基酸,由M-660可推测C-末端可能为羟基苯丙氨酸。从NMR图谱中确定C-末端为酪氨酸。通过与Sansanmycin A相比,我们发现Sansanmycin H的13C-NMR谱中无色氨酸碳信号峰,1H-NMR谱多一个酪氨酸的氢信号δ7.09(d,J=9.6Hz,2H),6.80(d,J=9.0Hz,2H),2.83(m,1H),3.02(m,1H),4.24(m,1H),其他片段的碳信号峰和氢信号峰几乎相同。由此我们进一步推测Sansanmycin H与Sansanmycin A的差别只在于C-端氨基酸不同,前者为酪氨酸而后者为色氨酸。我们通过DEPT、1H-1H COSY和HMBC谱对1H-NMR和13C-NMR(图1,2)信号峰进行了归属(如表1),最终确定了Sansanmycin H的结构如下(结构式中678、503、634、660等数值以及标示它们的线条或箭头标示的是MS/MS结果,本发明其它结构式中亦有相同含义):
表1 Sansanmycin H的1H NMR(500MHz)和13C NMR(125MHz)数据
该光谱是在D2O中记录的。化学位移(δ)以ppm单位给出。
*结构单元的缩写为:m-Tyr=m-酪氨酸,Trp=色氨酸,AMBA=2-氨基-3-甲基氨基丁酸,Met=甲硫氨酸。
Sansanmycin I:白色无定形粉末;254,198;ESI-MS m/z 853.3[M+H]+,HR-ESI-MS m/z 853.31869[M+H]+(计算值C39H49O12N8S,853.31852)。
Sansanmycin I比Sansanmycin H多12个质量数,根据这类化合物N-末端可以为四氢异喹啉的特点(Yunying Xie,et al.Two novel nucleosidyl-peptide antibiotics:Sansanmycin F and G produced by Streptomyces sp SS.The Journal of Antibiotics.2010,63(3):143-146中详细公开的),推测可能是N-末端氨基成环,形成了四氢异喹啉衍生物;MS/MS分析如以下结构式中标示的,证实了上述这一推测。四氢异喹啉芳环上的氢信号δ6.54(s,1H),6.72(d,J=8.9Hz,1H),6.99(d,J=8.4Hz,1H)表明其为6位羟基取代,并且通过1H-1H COSY、HSQC和HMBC谱对1H-NMR和13C-NMR(图3,4)信号峰进行了归属(如表2),进一步确证了Sansanmycin I的结构如下所示。
表2 Sansanmycin I的1H NMR(600MHz)和13C NMR(150MHz)数据
该光谱是在微碱性D2O中记录的。化学位移(δ)以ppm单位给出。
*结构单元的缩写为:Tyr=酪氨酸,Trp=色氨酸,AMBA=2-氨基-3-甲基氨基丁酸,TIC=6-羟基-1,2,3,4-四氢-3-异喹啉甲酸
Sansanmycin J:白色无定形粉末;261,199;ESI-MS m/z 853.3[M+H]+,HR-ESI-MS m/z 853.31859[M+H]+(计算值C39H49O12N8S,853.31852).
Sansanmycin J质量数与Sansanmycin I相同,MS/MS分析(如以下结构式中标示的)显示其碎片离子也与Sansanmycin I相同。比较两者的1H-NMR谱图,发现只有N-末端的四氢异喹啉的芳环氢信号不同,Sansanmycin I的为δ6.54(s,1H),6.72(d,J=8.9Hz,1H),6.99(d,J=8.4Hz,1H),为6位羟基取代,而Sansanmycin L的为δ6.51(d,J=7.7Hz,1H),6.67(d,J=7.7Hz,1H),7.06(m,1H),为8位羟基取代,并且通过1H-1H COSY、HSQC和HMBC谱对1H-NMR和13C-NMR(图5,6)信号峰进行了归属(如表3),进一步确证了Sansanmycin J的结构如下所示。
表3 Sansanmycin J的1H NMR(600MHz)和13C NMR(150MHz)数据
该光谱是在微碱性D2O(pD 8)中记录的。化学位移(δ)以ppm单位给出。
*结构单元的缩写为:Tyr=酪氨酸,Trp=色氨酸,AMBA=2-氨基-3-甲基氨基丁酸,TIC=8-羟基-1,2,3,4-四氢-3-异喹啉甲酸
Sansanmycin K:白色无定形粉末;263,220,199;ESI-MS m/z876.3[M+H]+,HR-ESI-MS m/z 876.33463[M+H]+(计算值C41H50O11N9S,876.33450)。
Sansanmycin K比Sansanmycin A(Yunying Xie,et al.A New Nucleosidyl-peptideAntibiotic,Sansanmycin,The Journal of Antibiotics.2007,60(2):158-161中公开的)多12个质量数,根据这类化合物N-末端可以为四氢异喹啉的特点(Yunying Xie,et al.Two novel nucleosidyl-peptide antibiotics:Sansanmycin F and G produced byStreptomyces sp SS.The Journal of Antibiotics.2010,63(3):143-146中详细公开的),推测可能是N-末端氨基成环形成了四氢异喹啉,将Sansanmycin K的分子离子峰[M+H]+的MS/MS图谱与Sansanmycin A(Yunying Xie,et al.A NewNucleosidyl-peptide Antibiotic,Sansanmycin,The Journal of Antibiotics.2007,60(2):158-161中公开的)的进行比对,发现其存在m/z 701的碎片峰,进一步说明两者差异只存在于N-末端的氨基酸。从NMR图谱中确定N-末端为四氢异喹啉,从1H-NMR低场处的氢信号δ6.51(s,1H),6.70(d,J=7.8Hz,1H)6.99(d,J=7.8Hz,1H)可以确定为6位羟基取代四氢异喹啉,通过DEPT、1H-1H COSY、HSQC和HMBC谱对1H-NMR和13C-NMR信号峰进行了归属(如表4),最终确定了Sansanmycin K的结构如下。
表4 Sansanmycin K的1H NMR(600MHz)和13C NMR(150MHz)数据
*结构单元的缩写为:Trp=色氨酸,AMBA=2-氨基-3-甲基氨基丁酸,Met=甲硫氨酸,TIC=6-羟基-1,2,3,4-四氢-3-异喹啉甲酸
Sansanmycin L:白色无定形粉末;259,220,199;ESI-MS m/z876.3[M+H]+,HR-ESI-MS m/z 876.33453[M+H]+(计算值C41H50O11N9S,876.33450)。
Sansanmycin L质量数与Sansanmycin K相同,MS/MS分析(如以下结构式中标示的)显示其碎片离子也与Sansanmycin K相同。比较两者的1H-NMR谱图,发现只有N-末端的四氢异喹啉的芳环氢信号不同,Sansanmycin K的为δ6.51(s,1H),6.70(d,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),为6位羟基取代,而Sansanmycin L的为δ6.54(d,J=7.2Hz,1H),6.70(d,J=8Hz,1H),7.05(t,J=7.8Hz,1H),为8位羟基取代,其1H-NMR和13C-NMR如图7,8。通过分析MS/MS结果(如下结构式),进一步确证Sansanmycin L的结构如下所示。
Sansanmycin M:白色无定形粉末;263,221,197;ESI-MS m/z890.3[M+H]+,HR-ESI-MS m/z 890.35013[M+H]+(计算值C42H52O11N9S,890.35015)。
Sansanmycin M比Sansanmycin K多14个质量数,与Sansanmycin K的1H-NMR谱比较,前者多了一个-CH3信号δ1.41(d,J=6.5Hz,5H),并且四氢异喹啉1位由Sansanmycin K的两个氢信号δ3.84(d,J=16.2Hz,1H),δ3.93(d,J=16.2Hz,1H),变为一个氢信号δ3.96(q,J=6.1Hz,1H),说明甲基连接在四氢异喹啉的1位,从1H-1HCOSY图谱可以看到-CH3信号δ1.41与CH信号δ3.96相关,进一步确定甲基连接在四氢异喹啉的1位。其1H-NMR和13C-NMR如图9,10。通过分析ESI-MS/MS结果(如下结构式),进一步证实了Sansanmycin M的结构如下所示。
Sansanmycin N:白色无定形粉末;258,220,201;ESI-MS m/z920.4[M+H]+,HR-ESI-MS m/z 920.36078[M+H]+(计算值C43H54O12N9S,920.36072).
Sansanmycin N比Sansanmycin F(Yunying Xie,et al.A New Nucleosidyl-peptideAntibiotic,Sansanmycin,The Journal of Antibiotics.2007,60(2):158-161中详细公开的)多16个质量数,即多一个氧原子,并且甲硫氨酸上-S-CH3信号由δ2.02向低场位移到δ2.78,由此推测甲硫氨酸上的S原子被氧化成亚砜基。四氢异喹啉芳环上的氢信号δ6.46(d,J=2.2Hz,1H),6.73(dd,J=8.5,2.3Hz,1H),7.18(d,J=8.4Hz,1H)表明其为6位羟基取代。其1H-NMR和13C-NMR如图11,12。通过分析ESI-MS/MS结果如下,进一步确证Sansanmycin N的结构如下所示。
Sansanmycin O:白色无定形粉末;257,219,200;ESI-MS m/z920.4[M+H]+,HR-ESI-MS m/z 920.39371[M+H]+(计算值C47H54O11N9,920.30373).
Sansanmycin O与Sansanmycin N分子量相同,ESI-MS/MS分析(如以下结构式中标示的)表明其与Sansanmycin N具有相同的碎片离子,但在HPLC上保留时间明显长于Sansanmycin N,苯丙氨酸有与甲硫亚砜相同的分子量,因此推测SansanmycinO中苯丙氨酸残基取代的了Sansanmycin N结构中的甲硫亚砜残基;分析Sansanmycin O的1H-NMR发现其在δ2.0左右没有甲硫亚砜的信号峰,进一步确定其不含甲硫亚砜,在低场δ6.4-7.7间有14个H信号峰,比Sansanmycin N多了5个H信号峰,及一个自旋系统δ7.12(m,2H),7.26(m,2H),因此进一步确定SansanmycinO中苯丙氨酸残基取代了Sansanmycin N结构中的甲硫亚砜残基。四氢异喹啉芳环上的氢信号δ6.46(d,J=2.2Hz,1H),6.74(dd,J=8.4,2.3Hz,1H),7.16(d,J=8.7Hz,1H)表明其为6位羟基取代。其1H-NMR和13C-NMR如图13,14。通过分析ESI-MS/MS结果如下,进一步确证Sansanmycin O的结构如下所示。
Sansanmycin P:白色无定形粉末;258,219,201;ESI-MS m/z880.4[M+H]+,HR-ESI-MS m/z 880.36243[M+H]+(计算值C44H50O11N9,880.36243)。
Sansanmycin P与Sansanmycin C(Yunying Xie,et al.Sansanmycins B and C,new components of sansanmycins.The Journal of Antibiotics.2008,61(4):237-240中详细公开的)分子量相同,ESI-MS/MS分析(如以下结构式中标示的)表明其与Sansanmycin C具有相同的碎片离子,但在HPLC上保留时间明显长于SansanmycinC,因此推测类似于Sansanmycin O,结构中可能含有苯丙氨酸残基;分析SansanmycinP的1H-NMR发现其在δ2.0左右没有甲硫亚砜的信号峰,进一步确定其不含甲硫亚砜,在低场δ6.4-7.7间有15个H信号峰,比Sansanmycin C多了5个H信号峰,及一个自旋系统δ7.25(m,2H),7.09(m,2H),因此进一步确定Sansanmycin P结构含有苯丙氨酸残基。其1H-NMR和13C-NMR如图15,16。通过分析ESI-MS/MS结果如下,进一步确证Sansanmycin P结构如下所示。
Sansanmycin Q:白色粉末,白色无定形粉末;258,219,199;ESI-MS m/z 921.0[M+H]+,HR-ESI-MS m/z 921.35594[M+H]+(计算值C42H53O12N10S,921.35596)。
Sansanmycin Q与Sansanmycin A(Yunying Xie,et al.A New Nucleosidyl-peptideAntibiotic,Sansanmycin,The Journal of Antibiotics.2007,60(2):158-161)相比多57个质量数,并且与Sansanmycin A的NMR相比,多了δ-CH2 46.1和δ-CO 177.3两个碳信号,以及一个δ-CH2 3.26的氢信号,因此推测Sansanmycin Q可能比A多了一个甘氨酸残基NH2-CH2-CO-;与Sansanmycin A相比,Hm-Tyr-2的化学位移由δ4.04向低场位移至δ4.94,因此推断甘氨酸残基连接在N-末端;ESI-MS/MS分析结果(如以下结构式中标示的),通过分析DEPT、1H-1H COSY、HSQC和HMBC谱对SansanmycinQ的1H-NMR及13C-NMR信号进行了归属,结果见表5,进一步确证了SansanmycinQ的结构如下所示。
表5 Sansanmycin Q的1H NMR(600MHz)和13C NMR(150MHz)数据
*结构单元的缩写为:m-Tyr=m-酪氨酸,Trp=色氨酸,AMBA=2-氨基-3-甲基氨基丁酸,Gly=glycine,Met=甲硫氨酸
Sansanmycin R:白色无定形粉末;259,200;ESI-MS m/z 892.4[M+H]+,HR-ESI-MS m/z 892.36253[M+H]+(计算值C45H50O11N9,892.36243).
Sansanmycin R比Sansanmycin K多16个质量数,根据这类化合物的特点推测Sansanmycin R可能比K多一个氧或者类似于Sansanmycin O,结构中含有苯丙氨酸;在HPLC上保留时间明显长于Sansanmycin K,因此推测类似于Sansanmycin O,结构中含有苯丙氨酸;分析Sansanmycin R的1H-NMR发现其在2.0ppm左右没有甲硫亚砜或甲硫氨酸的信号峰,进一步确定其不含甲硫亚砜或甲硫氨酸,在低场δ6.4-7.7间有14个H信号峰,比Sansanmycin K多了5个H信号峰,及一个自旋系统δ7.27(m,2H),7.13(m,2H),因此进一步确定Sansanmycin R结构中含有苯丙氨酸残基。其1H-NMR和13C-NMR如图17,18。通过分析ESI-MS/MS结果(如下),进一步确定了Sansanmycin的结构如下所示。
Sansanmycin S:白色无定形粉末;258,219,199;ESI-MS m/z892.4[M+H]+,HR-ESI-MS m/z 892.36254[M+H]+(计算值C45H50O11N9,892.36243)。
Sansanmycin S质量数与Sansanmycin R相同,MS/MS分析(如以下结构式中标示的)显示其碎片离子也与Sansanmycin R相同。比较两者的1H-NMR谱图,发现只有N-末端的四氢异喹啉的芳环氢信号不同,Sansanmycin R的为δ6.49(s,1H),6.70(d,J=7.8Hz,1H),6.97(d,J=8.4Hz,1H),为6位羟基取代,而Sansanmycin S的为δ6.52(d,J=7.5Hz,1H),6.70(d,J=8.0Hz,1H),7.06(t,J=7.8Hz 1H),为8位羟基取代,其1H-NMR和13C-NMR如图19,20。通过分析ESI-MS/MS结果(如下),进一步确证了Sansanmycin S的结构如下所示。
本发明部分示例性的化合物的1HNMR谱图和13CNMR谱图见图1至图20。
Claims (7)
1.选自以下编号SSH至SSS的12种化合物或其药学可接受的盐,所述12种化合物具有以下式I的结构:
所述12种化合物各自的取代基R1、R2、R3分别是如下表所述的基团:
其中,
R1的各取代基g7、g8、g9、g10、g11、g12分别为:
R2的各取代基g3、g4、g5分别为:
R3的各取代基g1、g2分别为:
2.一种药物组合物,其包含权利要求1所述化合物,以及任选的一种或多种药学可接受的载体或赋形剂。
3.权利要求1所述化合物在制备用于治疗和/或预防哺乳动物感染性疾病的药物中的用途。
4.权利要求3的用途,所述哺乳动物是人。
5.权利要求3的用途,所述感染性疾病是由细菌感染引起的疾病。
6.权利要求3的用途,所述感染性疾病是由结核杆菌感染引起的疾病。
7.权利要求3的用途,所述感染性疾病是结核病。
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