CN115844903B - 白桦醇衍生物在制备抑制细菌药物中的用途 - Google Patents
白桦醇衍生物在制备抑制细菌药物中的用途 Download PDFInfo
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- CN115844903B CN115844903B CN202310062218.9A CN202310062218A CN115844903B CN 115844903 B CN115844903 B CN 115844903B CN 202310062218 A CN202310062218 A CN 202310062218A CN 115844903 B CN115844903 B CN 115844903B
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供式(I‑8)所示的白桦醇衍生物在制备抑制细菌药物中的用途。所述白桦醇衍生物或其药学上可接受的盐对多种细菌均表现出较好的抑菌效果，可用于制备抗菌药物：
Description
技术领域
本发明属于医药领域，具体涉及白桦醇衍生物在制备抑制细菌药物中的用途。
背景技术
细菌(Bacteria)是指生物的主要类群之一，属于细菌域，也是所有生物中数量最多的一类。细菌是许多疾病的病原体，可以通过各种方式，如接触、消化道、呼吸道、昆虫叮咬等在正常人体间传播疾病，具有较强的传染性，对人体健康危害较大。
白桦醇又名白桦醇酯、桦木醇，属于羽扇豆烷类五环三萜，是一种广泛存在于各种植物中的天然产物。因此，开发白桦醇及其衍生物的新的药物用途具有重要意义。但截至目前，尚未发现有文献对此类衍生物的抗细菌活性进行研究和报道。
发明内容
本发明提供了一种式(I)所示的白桦醇衍生物或其药学上可接受的盐在制备抗菌药物中的用途：
其中，
不存在或为双键，当
为双键时，A选自O或S，当
不存在时，A也不存在；
M不存在或者选自
Het1选自被1个、2个或更多个Rm取代的5-6元杂环基，例如
Het2选自被1个、2个或更多个Rn取代的
Het1通过其成环的碳原子或氮原子与Het2中的成环碳原子或氮原子键合；
Het1通过其成环的碳原子或氮原子基团与三氮唑基团的N原子键合；
X、Y相同或不同，彼此独立地选自H、卤素、OH、SH、CN、OH，无取代或任选被一个、两个或更多个Ra取代的下列基团：C1-40烷基、C3-20环烷基、C1-40烷氧基、3-20元杂环基、C6-20芳基、5-20元杂芳基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、NH2、-C(O)OR1、-OC(O)R2、-OP(O)(OR3)2、-OS(O)2R4；
Z选自O、S、卤素、OH、SH、CN、无取代或任选被一个、两个或更多个Rb取代的下列基团：C1-40烷基、C3-20环烷基、C1-40烷氧基、3-20元杂环基、C6-20芳基、5-20元杂芳基、3-20元杂环基氧基、C6-20芳基氧基、5-20元杂芳基氧基、NH2、-C(O)OR1、-OC(O)R2、-OP(O)(OR3)2、-OS(O)2R4；其中，当
为双键时，Z选自O或S；当
为单键时，Z选自上文定义的除O和S之外的其他基团；
每一个R1、R2、R3、R4相同或不同，彼此独立地选自H、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-40烷基、C3-20环烷基、3-20元杂环基、C6-20芳基、5-20元杂芳基、C6-20芳基-C1-40烷基；
Rm、Rn相同或不同，彼此独立地选自H、卤素、OH、SH、CN，无取代或任选被一个、两个或更多个Rd取代的下列基团：C1-40烷基或C1-40烷氧基；
Ra、Rb、Rc、Rd相同或不同，彼此独立地选自卤素、OH、CN、NO2、氧代(＝O)、硫代(＝S)、C1-40烷基、C2-40烯基、C2-40炔基、C3-40环烷基、C3-40环烯基、C3-40环炔基、C6-20芳基、5-20元杂芳基、3-20元杂环基、C1-40烷基氧基、C2-40烯基氧基、C2-40炔基氧基、C3-40环烷基氧基、C3-40环烯基氧基、C3-40环炔基氧基、C6-20芳基氧基、5-20元杂芳基氧基、3-20元杂环基氧基、C1-40烷基硫基、C2-40烯基硫基、C2-40炔基硫基、C3-40环烷基硫基、C3-40环烯基硫基、C3-40环炔基硫基、C6-20芳基硫基、5-20元杂芳基硫基、3-20元杂环基硫基、NH2、-C(O)C1-40烷基、-C(O)NH2、-C(O)NHC1-40烷基、-C(O)-NH-OH、-COOC1-40烷基、-COOH、-OC(O)C1-40烷基、-OC(O)H、-S(O)2C1-40烷基、S(O)2H、-S(O)2OC1-40烷基、-OS(O)2C1-40烷基、-P(O)(OH)2、-B(OH)2。
根据本发明的实施方案，所述白桦醇衍生物具有式(I-1)、式(I-2)或式(I-3)所示的结构：
其中，X、Y、Z、A、Rm、
独立地具有上文所述的定义。
根据本发明的实施方案，
不存在或为双键，当
为双键时，A选自O，当
不存在时，A也不存在；
X、Y相同或不同，彼此独立地可以选自H、卤素、OH、OH、NH2、C1-6烷基、C3-8环烷基、C1-6烷氧基；
Z可以选自O、卤素、OH、SH、CN、无取代或任选被一个、两个或更多个Rb取代的C1-6烷基、C1-6烷氧基、-OC(O)R2，当
为双键时，Z选自O；当
为单键时，Z选自上文定义的除O之外的其他基团；R2可以选自H、无取代或任选被一个、两个或更多个Rc取代的下列基团：C1-6烷基、C6-14芳基、C6-14芳基-C1-6烷基；
Rm可以选自H、卤素、OH，无取代或任选被一个、两个或更多个Rd取代的下列基团：C1-6烷基或C1-6烷氧基；
Rb、Rc、Rd可以选自卤素、OH、CN、NO2、C1-6烷基、C3-8环烷基、C1-6烷氧基、3-8元杂环基、C6-14芳基、5-14元杂芳基、3-8元杂环基氧基、C6-14芳基氧基或5-14元杂芳基氧基。
根据本发明的实施方案，所述白桦醇衍生物具有式(I-4)、式(I-5)或式(I-6)所示的结构：
其中，X、Y、Z、A、Rm、
独立地具有上文所述的定义。
根据本发明的实施方案，
不存在或为双键，当
为双键时，A选自O，当
不存在时，A也不存在；
X可以选自H、甲基、F、Cl、Br；
Y可以选自OH、NH2；
Z可以选自O、F、Cl、Br、OH、CN、C1-6烷基、C1-6烷氧基、-OC(O)R2，当
为双键时，Z为O；当
为单键时，Z选自F、Cl、Br、OH、CN、C1-6烷基、C1-6烷氧基、-OC(O)R2；R2可以选自H、甲基、
Rm可以选自H、F、Cl、Br、OH。
作为实例，所述白桦醇衍生物具有式(I-8)所示的结构：
其中，Y选自OH或NH2；
Rm选自H、F、Cl、Br或OH。
作为选择，当Rm选自F、Cl、Br或OH时，与Rm相连接的碳原子可以选自R构型或S构型。作为实例，所述白桦醇衍生物选自如下化合物：
本发明还提供一种式(I)所示的化合物或其药学上可接受的盐作为抗细菌药物的应用。
本发明还提供一种治疗细菌感染的方法，包括给予患者治疗有效量的式(I)所示的化合物或其药学上可接受的盐，从而治疗细菌感染。
根据本发明的实施方案，所述细菌可以选自革兰氏阴性菌，如沙门氏菌、大肠杆菌；或选自革兰氏阳性菌，如金黄色葡萄球菌。
本发明还提供一种抗菌、灭菌或抑菌的方法，包括给予患者治疗有效量的式(I)所示的化合物或其药学上可接受的盐。
本发明还提供一种式(I)所示的化合物或其药学上可接受的盐，其具有抗菌活性。
根据本发明的实施方案，所述菌可以为细菌，例如选自革兰氏阴性菌，如沙门氏菌、大肠杆菌；或选自革兰氏阳性菌，如金黄色葡萄球菌。
本发明还提供一种抗菌药物组合物，包括式(I)所示的化合物或其药学上可接受的盐中的至少一种。
根据本发明的实施方案，所述抗菌药物组合物还包括至少一种药学上可接受的载体。
有益效果
本发明提供的白桦醇衍生物化合物具有抗菌活性，对多种细菌均表现出较好的抑菌效果，可用于制备抗菌药物。
术语定义与说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-40”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10，以及数值范围“11-40”中的每一个整数数值即11、12、13、14、15、......、35、36、37、38、39、40。此外，当某些数值范围被定义为“数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
应当理解，本文在描述1、2个或更多个中，“更多个”应当是指大于2，例如大于等于3的整数，例如3、4、5、6、7、8、9或10。
术语“卤素”表示氟、氯、溴和碘。
术语“C1-40烷基”应理解为表示具有1～40个碳原子的直链或支链饱和一价烃基。例如，“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C2-40烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2～40个碳原子，优选“C2-10烯基”。“C2-10烯基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，例如，具有2、3、4、5或6个碳原子(即，C2-6烯基)，具有2或3个碳原子(即，C2-3烯基)。应理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C2-40炔基”应理解为表示直连或支链的一价烃基，其包含一个或多个三键并且具有2～40个碳原子，优选“C2-10炔基”。术语“C2-10炔基”应理解为优选表示直连或支链的一价烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子，例如，具有2、3、4、5或6个碳原子(即，“C2-6炔基”)，具有2或3个碳原子(“C2-3炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地，所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C3-20环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃，其具有3～20个碳原子，优选“C3-10环烷基”。术语“C3-10环烷基”应理解为表示饱和的一价单环、双环烃环或桥环烷烃，其具有3、4、5、6、7、8、9或10个碳原子。所述C3-10环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃，其包含1-5个独立选自N、O和S的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团，优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环、双环烃环或桥环烷烃，其包含1-5个，优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，所述杂环基可以包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是苯并稠合的。所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。根据本发明，所述杂环基是无芳香性的。所述3-20元杂环基与其它基团相连构成本发明的化合物时，可以为3-20元杂环基上的碳原子与其它基团相连，也可以为3-20元杂环基环上杂环原子与其它基团相连。例如当3-20元杂环基选自哌嗪基时，可以为哌嗪基上的氮原子与其它基团相连。或当3-20元杂环基选自哌啶基时，可以为哌啶基环上的氮原子和其对位上的碳原子与其它基团相连。
术语“C6-20芳基”应理解为优选表示具有6～20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，优选“C6-14芳基”。术语“C6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C6-14芳基”)，特别是具有6个碳原子的环(“C6芳基”)，例如苯基；或联苯基，或者是具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基，或者是具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基，或者是具有13个碳原子的环(“C13芳基”)，例如芴基，或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。当所述C6-20芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5～20个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时，可以为5-20元杂芳基环上的碳原子与其它基团相连，也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明，杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式，例如其位置异构体。因此，对于一些说明性的非限制性实例，可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式，包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基；噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基；吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
除非另有说明，本文中术语的定义同样适用于包含该术语的基团，例如C1-40烷基的定义也适用于C1-40烷氧基等。
本领域技术人员可以理解，式I所示化合物可以以各种药学上可接受的盐的形式存在。如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。酸加成盐包括但不限于：盐酸盐、氢氟酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、焦硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、氨基磺酸盐、2-萘磺酸盐、甲酸盐、乙酰乙酸、丙酮酸、月硅酸酯、肉桂酸酯、苯甲酸盐、醋酸盐、二羟乙酸盐、三氟乙酸盐、三甲基乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一酸盐、硬脂酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、草酸盐、水杨酸盐、琥珀酸盐、葡萄糖酸盐、奎尼酸盐、双羟萘酸盐、甘醇酸盐、酒石酸盐、乳酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、环戊烷丙酸盐、二葡糖酸盐、3-羟基-2-萘甲酸盐、烟酸盐、扑酸盐、果胶酯酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、衣康酸盐、三氟甲磺酸盐、十二烷基硫酸盐、对甲苯磺酸盐、萘二磺酸盐、丙二酸盐、己二酸盐、藻酸盐、扁桃酸盐、葡庚酸盐、甘油磷酸盐、磺基水杨酸盐、半硫酸或硫氰酸盐、天冬氨酸盐等；碱加成盐例如碱金属盐、碱土金属盐和铵盐等，具体包括但不限于：钠盐、锂盐、钾盐、铵盐、铝盐、镁盐、钙盐、钡盐、铁盐、亚铁盐、锰盐、亚锰盐、锌盐、铵盐(包括与NH3和有机胺形成的盐(NH4盐)、甲铵盐、三甲铵盐、二乙铵盐、三乙铵盐、丙铵盐、三丙铵盐、异丙铵盐、叔丁铵盐、N,N'-二苄基乙二铵盐、二环己铵盐、1,6-己二铵盐、苄铵盐、乙醇铵盐、N,N-二甲基乙醇铵盐、N,N-二乙基乙醇铵盐、三乙醇铵盐、氨丁三醇盐、赖氨酸盐、精氨酸盐、组氨酸盐、葡糖铵盐、N-甲基葡糖铵盐、二甲基葡糖铵盐、乙基葡糖铵盐、葡甲铵盐、甜菜碱盐、咖啡因盐、氯普鲁卡因盐、普鲁卡因盐、利多卡因盐、吡啶盐、甲基吡啶盐、哌啶盐、吗啉盐、哌嗪盐、嘌呤盐、可可碱盐、胆碱盐)等。
根据其分子结构，本发明的化合物是手性的，因此可能存在各种对映异构体形式。因而这些化合物可以以消旋体形式或光学活性形式存在。本发明的化合物或其中间体可以通过本领域技术人员公知的化学或物理方法分离为对映异构体化合物，或者以此形式用于合成。在外消旋的胺的情况中，通过与光学活性的拆分试剂反应，从混合物制得非对映异构体。适当的拆分试剂的示例是光学活性的酸，例如R和S形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸、适当的N-保护的氨基酸(例如N-苯甲酰脯氨酸或N-苯磺酰基脯氨酸)或各种光学活性的樟脑磺酸。借助光学活性的拆分试剂(例如固定在硅胶上的二硝基苯甲酰基苯基甘氨酸、三乙酸纤维素或其它碳水化合物的衍生物或手性衍生化的异丁烯酸酯聚合物)，也可有利地进行色谱对映体拆分。用于此目的的适当的洗脱剂是含水或含醇的溶剂混合物，例如，己烷/异丙醇/乙腈。
术语“互变异构体”(tautomerism)包括本领域技术人员已知的那些互变异构形式，例如选自烯醇式-酮式、酰胺式-亚胺酸式、内酰胺式-内酰亚胺式、烯胺式-亚胺烯胺式-烯胺式等的互变异构体。
可以根据已知的方法，例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
本文中使用的短语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
制备例1：化合物1-8的制备
本发明中所涉及的化合物1-8的制备参考化合物xiv的制备例所示，其中，化合物xiv的制备过程中，制备得到化合物5(化合物b)和化合物6(化合物c)：
(1)先用Lewis酸将白桦醇a重排为化合物b。
(2)用氧化剂将步骤(1)中制备的化合物b中的-OH氧化成酮得到化合物c。
(3)使用溴代丙炔与步骤(2)中制备的化合物c反应得到化合物d。
(4)采用硼氢化钠将步骤(3)中制备的化合物d中的羰基还原成羟基，制备得到化合物e。
(5)通过click反应将4’-叠氮尿苷加入到步骤(4)中制备的化合物e中合成化合物xiv。
具体合成路线如下：
化合物b的合成：将白桦脂醇(化合物a,2.0g,4.52mmol)和对甲苯磺酸(TsOH,2.0g,11.61mmol)在二氯甲烷中加热回流搅拌过夜。反应完成后，通过柱色谱纯化产物，得到白色固体化合物b(1.8g,产率90％)。1H NMR(CDCl3,400MHz)δ：3.77(d,J＝7.8Hz,1H),3.52(s,1H),3.43(d,J＝7.8Hz,1H),3.19(dd,J＝11.1,5.1Hz,1H),1.71(dt,J＝13.1,3.6Hz,1H),0.97(s,6H),0.92(s,3H),0.91(s,3H),0.84(s,3H),0.79(s,3H),0.76(s,3H),0.69(d,J＝9.4Hz,1H).13CNMR(CDCl3,100MHz)δ：87.9,78.9,71.2,55.5,51.0,46.8,41.4,40.7,40.6,38.9,38.9,37.2,36.7,36.2,34.1,33.9,32.7,28.8,28.0,27.4,26.4,26.4,26.2,24.5,21.0,18.2,16.5,15.7,15.4,13.5.
化合物c的合成：化合物b(1.8g,4.06mmol)溶于丙酮(Acetone,100mL)，冰浴搅拌下缓慢滴入琼斯试剂(Jones reagent,18mL)，待滴完后冰浴下反应2h，TLC检测反应完毕后，加入甲醇35mL，搅拌20min，再加入水35mL，搅拌20min。减压蒸发除去甲醇和丙酮，水相用CH2Cl2萃取，收集有机相，用无水Na2SO4固体干燥，过滤，真空减压蒸发除去溶剂，即可得到化合物c(1.68g,产率94％)。1H NMR(CDCl3,400MHz)δ：3.78(d,J＝7.8Hz,1H),3.53(s,1H),3.45(d,J＝7.8Hz,1H),2.57-2.36(m,2H),1.94(ddd,J＝12.5,7.6,4.6Hz,1H),1.66(d,J＝12.4Hz,1H),1,22(dd,J＝13.3,4.9Hz,1H),1.08(s,3H),1.03(s,3H),1.01(s,3H),0.94(s,3H),0.93(s,3H),0.92(s,6H),0.79(s,3H).13C NMR(CDCl3,100MHz)δ：218.2,87.9,71.2,55.0,50.4,47.3,46.8,41.4,40.7,40.5,39.8,37.0,36.7,36.3,34.2,34.1,33.2,32.7,28.8,26.7,26.4,26.4,26.2,24.5,21.5,21.0,19.6,16.3,15.5,13.4.
化合物d的合成：将化合物c(1.68g,3.81mmol)溶于乙二醇二甲醚(DME,80mL)，加入双(三甲基硅烷基)氨基钾的四氢呋喃溶液(KN(SiMe3)2,25mL，25mmol)，搅拌30min后加入1mol/L Et3B的四氢呋喃溶液(27mL,238.34mmol)，继续搅拌1.5h后加入溴代丙炔(3.8mL,48.55mmol)，搅拌过夜。TLC检测反应完毕后，加入稀盐酸将溶液调至酸性，反应液用乙酸乙酯萃取，收集有机相并用饱和碳酸氢钠溶液洗，无水Na2SO4干燥，过滤，减压除去溶剂。柱色谱分离(乙酸乙酯:石油醚＝1:20)，得到化合物d(1.18g,2.46mmol,产率64％)。1H NMR(CDCl3,400MHz)δ:3.78(d,J＝7.1Hz,1H),3.53(s,1H),3.45(d,J＝7.8Hz,1H),2.88(ddt,J＝10.0,8.4,5.2Hz,1H),2.62(ddd,J＝17.1,4.4,2.7Hz,1H),2.37(dd,J＝12.9,5.6Hz,1H),2.21(ddd,J＝17.1,8.3,2.6Hz,1H),1.97(t,J＝2.7Hz,1H),1.15(s,3H),1.07(s,3H),1.06(s,3H),1.04(s,3H),0.94(s,3H),0.91(s,3H),0.80(s,3H).13C NMR(CDCl3,100MHz)δ:215.7,87.9,83.0,71.2,69.4,57.4,50.6,48.3,46.8,46.7,41.4,41.3,40.8,40.7,37.5,36.7,36.2,34.1,33.6,32.7,28.8,26.4,26.3,26.2,25.0,24.5,21.6,21.3,19.5,19.2,16.5,15.8,13.4.
化合物e的合成：将化合物d(1.18g,2.46mmol)中加入甲醇100ml，再缓慢加入NaBH4(186.12mg,4.92mmol)，室温搅拌过夜。冰浴下滴加稀盐酸中和NaBH4，减压蒸馏除去甲醇，乙酸乙酯萃取，合并有机相用饱和碳酸氢钠溶液洗，无水Na2SO4干燥，过滤，减压除去溶剂。柱色谱分离(乙酸乙酯:石油醚＝1:15)，得到化合物e(638.64mg,1.33mmol,产率54％)。1HNMR(CDCl3,400MHz)δ:3.77(d,J＝7.8Hz,1H),3.53(s,1H),3.44(d,J＝7.7Hz,1H),3.03(d,J＝10.5Hz,1H),2.46-2.31(m,2H),2.01(t,J＝2.7Hz,1H),1.86(dd,J＝12.8,3.8Hz),1.83-1.73(m,1H),1.69-1.61(m,1H),1.16-1.06(m,1H),0.99(s,3H),0.98(s,3H),0.93(s,3H),0.92(s,3H),0.89(s,3H),0.80(s,3H),0.70(s,3H).13C NMR(CDCl3,100MHz)δ:87.9,83.0,81.4,71.3,70.0,55.5,51.0,46.8,44.9,41.5,40.8,40.6,39.1,37.4,36.7,36.3,34.8,34.1,33.8,32.7,28.8,28.3,26.4,26.3,24.5,22.3,21.0,18.4,17.3,16.2,15.7,13.5.
化合物xiv的合成：在50mL圆底烧瓶中,将化合物e(144.2mg，0.30mmol)、叠氮核苷化合物4’-叠氮尿苷(57.0mg,0.20mmol)溶解到15mL的乙醇中，再加入1mol/L的CuSO4溶液200μL，Cu粉(0.1mmol)，45℃反应48h，待反应结束(TLC监测)，蒸干溶剂后直接柱层析分离，二氯甲烷/甲醇(6:1)分离得到白色固体化合物xiv(80.0mg，0.10mmol，产率52.22％).1HNMR(MeOH-d4,400MHz)δ:8.03(d,J＝8.1Hz,1H),7.93(s,1H),6.36(d,J＝5.5Hz,1H),5.79(d,J＝8.1Hz,1H),4.66-4.56(m,2H),4.46(d,J＝11.9Hz,1H),3.98(d,J＝11.9Hz,1H),3.77(d,J＝7.8Hz,1H),3.54(s,1H),3.46(d,J＝7.8Hz,1H),3.24-3.12(m,1H),2.83(d,J＝10.7Hz,1H),2.52(dd,J＝14.2,9.1Hz,1H),2.05-1.87(m,1H),1.79-1.67(m,1H),0.99(s,6H),0.94(s,3H),0.91(s,3H),0.84(s,3H),0.82(s,3H),0.81(s,3H),0.74(d,J＝9.4Hz,1H),0.64(t,J＝12.7Hz,1H).13C NMR(MeOH-d4,100MHz)δ:166.0,152.6,142.8,103.7,101.1,91.3,89.7,83.0,74.6,74.0,72.3,65.9,57.2,52.4,48.1,46.4,42.7,41.9,41.9,40.6,38.5,37.7,37.3,37.3,35.7,35.1,33.9,29.9,29.4,29.1,27.6,27.6,27.2,25.0,22.3,19.7,17.9,17.2,16.3,14.1.
参考上述化合物xiv的方法合成了下列化合物(化合物1、化合物2、化合物3、化合物4、化合物7以及化合物8)，不同之处在于将步骤(3)中得到的化合物d与相应的叠氮核苷进行步骤(5)的click反应，或者将步骤(4)中得到的化合物e与相应的叠氮核苷进行步骤(5)的click反应，所得化合物(化合物1、化合物2、化合物3、化合物4、化合物7以及化合物8)的表征数据如下：
(1)化合物1
表征数据：白色固体，收率78％。1H NMR(MeOH-d4,400MHz)δ:7.92(d,J＝1.2Hz,1H),7.87(brs,1H),6.47(t,J＝6.4Hz,1H),5.40(dt,J＝8.5,5.5Hz,1H),4.34(dt,J＝5.6,3.0Hz,1H),3.90(dd,J＝12.2,3.0Hz,1H),3.78(d,J＝6.5Hz,1H),3.77(dd,J＝15.4,3.1Hz,1H),3.55(s,1H),3.47(d,J＝7.9Hz,1H),3.27-3.18(m,1H),3.13(dd,J＝14.4,5.0Hz,1H),2.97-2.84(m,1H),2.72(ddd,J＝14.2,8.5,6.3Hz,1H),2.60(dd,J＝14.2,5.8Hz,1H),2.11(dd,J＝12.9,5.1Hz,1H),1.90(d,J＝1.1Hz,3H),1.16(s,3H),1.07(s,3H),1.06(s,3H),1.04(s,3H),0.94(s,3H),0.91(s,3H),0.82(s,3H).13C NMR(MeOH-d4,100MHz)δ:218.3,166.4,152.3,147.9,146.2,138.3,124.1,111.7,89.6,86.7,86.5,72.2,62.2,60.9,59.0,52.0,49.6,48.7,48.1,43.4,42.7,42.1,42.0,39.1,38.9,37.7,37.3,35.7,34.9,33.9,29.4,27.6,27.5,27.2,25.7,25.0,22.6,22.1,20.4,17.0,16.5,14.0,12.7.
(2)化合物2
表征数据：白色固体，收率78％。1H NMR(MeOH-d4,400MHz)δ:7.91(s,1H),7.87(s,1H),6.48(t,J＝6.4Hz,1H),5.40(dt,J＝8.5,5.6Hz,1H),4.35(dt,J＝5.7,3.0Hz,1H),3.91(dd,J＝12.2,2.9Hz,1H),3.78(d,J＝7.5Hz,1H),3.77(dd,J＝12.3,3.2Hz,1H),3.54(s,1H),3.47(d,J＝7.8Hz,1H),3.19(dd,J＝14.5,2.6Hz,1H),2.93(dt,J＝12.5,6.4Hz,1H),2.82(d,J＝10.8Hz,1H),2.74(ddd,J＝14.3,8.5,6.2Hz,1H),2.51(dd,J＝14.5,9.2Hz,1H),1.91(s,3H),1.70(dd,J＝13.1,3.3Hz,1H),0.99(s,3H),0.99(s,3H),0.94(s,3H),0.91(s,3H),0.84(s,3H),0.82(s,3H),0.81(s,3H),0.75(d,J＝9.1Hz,1H),0.65(t,J＝12.7Hz,1H).13C NMR(MeOH-d4,100MHz)δ:166.5,152.4,148.2,138.4,123.8,111.8,89.7,86.8,86.5,83.1,72.3,62.2,60.9,57.2,52.5,48.2,46.5,42.8,42.0,41.9,40.5,39.1,38.5,37.7,37.4,37.3,35.7,35.1,33.9,29.9,29.3,29.1,27.6,27.6,27.2,24.9,22.4,19.7,17.8,17.1,16.3,14.0,12.6.
(3)化合物3
表征数据：白色固体，收率59％。1H NMR(MeOH-d4,400MHz)δ:7.99(d,J＝8.1Hz,1H),7.83(s,1H),6.68(dd,J＝7.2,5.2Hz,1H),5.75(d,J＝8.1Hz,1H),4.86(m,1H),4.37(d,J＝12.1Hz,1H),4.09(d,J＝12.1Hz,1H),3.79(d,J＝7.9Hz,1H),3.55(s,1H),3.47(d,J＝7.8Hz,1H),3.25-3.09(m,2H),2.68-2.52(m,2H),2.43(dt,J＝13.8,7.0Hz,1H),2.08(dd,J＝12.9,5.3Hz,1H),1.14(s,3H),1.08(s,3H),1.07(s,3H),1.06(s,3H),0.95(s,3H),0.91(s,3H),0.82(s,3H).13CNMR(MeOH-d4,100MHz)δ:218.7,166.2,152.2,146.4,143.1,123.9,103.2,101.7,89.7,87.9,73.1,72.3,64.6,59.0,52.0,48.2,48.1,43.6,42.7,42.1,42.0,38.9,38.8,37.7,37.3,35.7,34.9,33.9,29.3,27.6,27.5,27.2,27.1,25.7,24.9,22.6,22.1,20.4,16.9,16.4,14.0.
(4)化合物4
表征数据：白色固体，收率57％。1H NMR(DMSO-d6,400MHz)δ:7.82(d,J＝7.5Hz,1H),7.79(s,1H),7.33(brs,1H),7.29(brs,1H),6.22(d,J＝5.7Hz,1H),5.81(d,J＝7.4Hz,1H),5.69(t,J＝5.9Hz,1H),5.42(d,J＝8.4Hz,1H),5.40(d,J＝9.3Hz,1H),4.54(d,J＝6.7Hz,1H),4.44-4.36(m,2H),4.25(dd,J＝11.8,6.3Hz,1H),3.83(dd,J＝11.8,5.5Hz,1H),3.62(d,J＝7.9Hz,1H),3.38(s,1H),3.31(d,J＝7.9Hz,1H),3.21-3.11(m,1H),2,71(dd,J＝10.5,6.9Hz,1H),2.26(dd,J＝14.4,9.8Hz,1H),1.88-1.74(m,1H),1.66(dd,J＝12.9,2.6Hz,1H),0.91(s,3H),0.89(s,3H),0.87(s,3H),0.84(s,3H),0.76(s,3H),0.74(s,3H),0.71(s,3H),0.54(t,J＝12.4Hz,1H).13C NMR(DMSO-d6,100MHz)δ:165.6,155.3,144.4,142.0,121.9,98.4,94.8,90.0,86.7,80.5,72.5,71.7,70.2,64.1,55.2,50.3,46.1,44.5,40.8,40.2,40.1,39.0,36.7,36.0,35.8,35.7,33.7,33.3,32.4,28.7,28.6,28.5,25.9,25.8,25.8,24.2,20.5,18.1,16.9,16.6,15.4,13.3.
(5)化合物7
表征数据：白色固体，收率52％。1H NMR(MeOH-d4,400MHz)δ:7.91(dd,J＝8.2,1.1Hz,1H),7.87(s,1H),6.79(dd,J＝10.5,5.5Hz,1H),5.76(d,J＝8.1Hz,1H),5.38(dt,J＝54.2,5.2Hz,1H),4.84(dd,J＝22.2,4.9Hz,1H),4.34-4.22(m,2H),3.79(d,J＝7.8Hz,1H),3.55(s,1H),3.48(d,J＝7.8Hz,1H),3.26-3.10(m,2H),2.64(dd,J＝14.4,7.0Hz,1H),2.08(dd,J＝12.9,5.2Hz,1H),1.15(s,3H),1.08(s,3H),1.07(s,3H),1.05(s,3H),0.95(s,3H),0.91(s,3H),0.82(s,3H).13CNMR(MeOH-d4,100MHz)δ:218.6,165.9,152.0,146.8,143.1,124.0,102.8,98.4(d,J＝8.8Hz),96.2(d,J＝193.7Hz),89.7,85.4(d,J＝16.9Hz),76.3(d,J＝24.8Hz),72.3,63.0,59.0,52.0,49.6,48.3,48.1,43.5,42.7,42.1,42.0,38.8,37.7,37.3,35.7,34.9,33.9,29.3,27.6,27.5,27.2,27.0,25.7,24.9,22.5,22.1,20.4,16.9,16.4,13.9.
(6)化合物8
表征数据：白色固体，收率55％。1H NMR(MeOH-d4,400MHz)δ:7.93(d,J＝7.4Hz,1H),7.88(s,1H),6.81(dd,J＝12.1,4.4Hz,1H),5.99(brs,1H),5.34(dt,J＝54.0,4.6Hz,1H),4.77(dd,J＝20.4,4.2Hz,1H),4.33(d,J＝12.6Hz,1H),4.24(d,J＝12.2Hz,1H),3.79(d,J＝7.7Hz,1H),3.55(s,1H),3.47(d,J＝7.8Hz,1H),3.26-3.10(m,2H),2.63(dd,J＝14.3,6.8Hz,1H),2.08(dd,J＝13.0,5.0Hz,1H),1.15(s,3H),1.08(s,3H),1.07(s,3H),1.05(s,3H),0.95(s,3H),0.91(s,3H),0.82(s,3H).13C NMR(MeOH-d4,100MHz)δ:218.7,167.9,157.9,146.7,143.4,124.1,99.0(d,J＝6.6Hz),96.4(d,J＝193.2Hz),89.7,86.7(d,J＝15.7Hz),76.4(d,J＝25.4Hz),72.3,63.4,59.0,52.0,49.6,48.2,48.1,43.6,42.7,42.1,42.0,38.8,37.7,37.3,35.7,34.9,33.9,29.3,27.6,27.5,27.2,27.0,25.7,24.9,22.5,22.1,20.4,16.9,16.4,13.9.
(7)对照化合物9
表征数据：白色固体，收率58％。1H NMR(DMSO-d6,400MHz)δ:7.90(s,1H),7.77(d,J＝7.4Hz,1H),7.33(brs,1H),7.30(brs,1H),6.76(dd,J＝7.3,5.6Hz,1H),6.23(d,J＝5.0Hz,1H),5.85(t,J＝5.6Hz,1H),5.80(d,J＝7.3Hz,1H),5.32(dt,J＝55.3,5.6Hz,1H),4.72(dt,J＝25.0,4.6Hz,1H),4.58(d,J＝6.4Hz,1H),4.23-4.06(m,2H),3.62(d,J＝7.5Hz,1H),3.39(s,1H),3.33(d,J＝7.5Hz,1H),3.16(d,J＝12.8Hz,1H),2.71(dd,J＝10.2,6.5Hz,1H),2.29(dd,J＝14.4,9.8Hz,1H),1.90-1.75(m,1H),1.63(d,J＝11.7Hz,1H),0.91(s,3H),0.89(s,3H),0.87(s,3H),0.84(s,3H),0.75(s,3H),0.75(s,3H),0.72(s,3H),0.52(t,J＝12.8Hz,1H).13C NMR(DMSO-d6,100MHz)δ:165.6,154.7,144.9,141.8,122.1,95.5(d,J＝10.2Hz),94.7(d,J＝191.4Hz),94.2,86.7,83.0,80.4,74.2(d,J＝24.8Hz),70.2,60.9,55.2,50.4,46.1,44.4,40.9,40.2,40.1,39.0,36.8,36.0,35.9,35.4,33.7,33.3,32.4,28.8,28.5,28.5,25.9,25.9,25.8,24.2,20.5,18.1,16.9,16.6,15.4,13.3.
实施例1抑菌活性测定
1.1材料
离心管(2mL，15mL)、锥形瓶(250mL)、牛津杯(内径6.0mm，高10.0mm，外径8.0mm)、比色皿。
1.2试剂
蛋白胨、酵母粉、NaCl、琼脂粉、二甲基亚砜(DMSO)。
1.3培养基配制
(1)LB液体培养基：胰蛋白胨10g，酵母提取物5g，氯化钠10g，加入1000mL ddH2O完全溶解后，调pH值至7.3±0.1，121℃灭菌20min，固体培养基加入1-2％的琼脂。
(2)素琼脂：称取1.6g琼脂粉于100mL蒸馏水中，121℃灭菌20min，备用。
1.4指示菌菌悬液的准备
(1)菌株：大肠杆菌CICC 10389、金黄色葡萄球菌CICC 21600和沙门氏菌CICC21513。
(2)指示菌稀释：取斜面培养基新鲜培养物，吸取5.0mL培养液加入斜面试管内，反复吹吸，洗下菌苔。随后将洗液移至另一无菌试管中，用电动混合器混合(振荡)20s，以使细菌悬浮均匀。先用细菌浓度比浊测定法粗测其含菌浓度，然后以培养液稀释为0.5麦氏比浊标准。此时菌液浓度在1.5×108CFU/mL左右。
1.5待测样品前处理
将受试化合物分别用DMSO稀释至200μg/mL待用，以200μg/mL沙拉沙星为阳性对照，DMSO溶液为阴性对照。
1.6抑菌试验
(1)于超净工作台内，向每个灭菌培养皿中倾注约10mL的素琼脂进行铺底，每个培养皿厚度均一，待素琼脂冷却凝固，备用。
(2)吸取调制好的指示菌菌液1mL加入到100mL恒温至50℃左右的LB固体培养基中，轻轻摇匀(避免起泡，此时指示菌在培养基中的浓度为106CFU/mL)，向每个培养皿倒10mL，将该层均匀铺平，待其冷却凝固。
(3)在平板背面做好浓度梯度标记，将灭菌好的牛津杯置于菌层培养基之上。
(4)吸取150μL的样液加入到相应的牛津杯内。
(5)将加过样的培养皿放入4℃的冰箱中预扩散4小时。
(6)将上述培养皿移入培养箱中37℃过夜培养。
(7)培养结束后，用镊子去掉牛津杯，然后用游标卡尺测量抑菌圈直径，测量时通过圆心，并记录测量结果。
1.7受试化合物的抑菌效果
由表1可知，大肠杆菌、沙门氏菌普遍对化合物1-8高敏，金黄色葡萄球菌普遍对化合物1-8中敏。上述化合物有广泛的抑菌活性，且活性优于对照化合物9。
表1：化合物1-8及对照化合物9的拮抗病原菌抑菌圈直径(mm)
注：牛津杯直径8mm，抑菌圈直径10mm以下为低敏，10-14mm为中敏，15-20mm为高敏，20mm以上为极敏。
实施例2：最低抑菌浓度(MIC)测定
1.1试验菌株
大肠杆菌CICC 10389、金黄色葡萄球菌CICC 21600和沙门氏菌CICC 21513。
1.2操作步骤
(1)MIC板制备：将用培养液倍比稀释后不同浓度的抗菌药物溶液分别加到灭菌的96孔聚苯乙烯板中，第1至第11孔加药液，每孔100μL，第12孔不加药作为生长对照。
(2)接种物制备：取斜面培养基新鲜培养物，吸取5.0mL培养液加入斜面试管内，反复吹吸，洗下菌苔。随后将洗液移至另一无菌试管中，用电动混合器混合(振荡)20s，以使细菌悬浮均匀。先用细菌浓度比浊测定法粗测其含菌浓度，然后以培养液稀释为0.5麦氏比浊标准。经培养液1∶1000稀释后，取100μL菌悬液接种于含抗(抑)菌剂的MIC板，作为试验组样本。此时，第1孔至第11孔药物浓度分别为128、64、32、16、8、4、2、1、0.5、0.25、0.125μg/mL。
(3)细菌培养：将MIC板放置36℃培养箱中，培养24h；观察结果。
1.3受试化合物的测试结果
当阳性对照有微生物生长(混浊)，阴性对照无菌生长(透明)时，试验组无菌生长的最高稀释度所对应的抗(抑)菌剂浓度，为该样品对受试菌的MIC。
由表2可知，多数受试化合物对大肠杆菌和沙门氏菌的MIC值比金黄色葡萄球菌更低，且效果优于对照化合物9。
表2：最小抑菌浓度MIC(μg/mL)
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。
Claims (3)
1.式(I-8)所示的白桦醇衍生物或其药学上可接受的盐在制备抑制细菌药物中的用途，其中所述细菌选自大肠杆菌或沙门氏菌：
其中，Y选自OH或NH2；
Rm选自H、F、Cl、Br或OH。
2.根据权利要求1所述的用途，其特征在于，Rm选自F、Cl、Br或OH，与Rm相连接的碳原子选自R构型或S构型。
3.根据权利要求1所述的用途，其特征在于，式(I-8)所示的白桦醇衍生物选自如下化合物：
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