CN115894600A - 别白桦醇衍生物及其制备方法、药物组合物和应用 - Google Patents
别白桦醇衍生物及其制备方法、药物组合物和应用 Download PDFInfo
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- CN115894600A CN115894600A CN202111168844.3A CN202111168844A CN115894600A CN 115894600 A CN115894600 A CN 115894600A CN 202111168844 A CN202111168844 A CN 202111168844A CN 115894600 A CN115894600 A CN 115894600A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 title description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 18
- BZNIIOGSANMIET-HWNNWUPFSA-N allobetulinol Chemical class C([C@@]12C)C[C@H](O)C(C)(C)[C@@H]1CC[C@]([C@]1(C)CC3)(C)[C@@H]2CC[C@@H]1[C@H]1[C@H]2OC[C@]13CCC2(C)C BZNIIOGSANMIET-HWNNWUPFSA-N 0.000 claims abstract description 12
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- -1 5-6 membered heterocyclic radicals Chemical class 0.000 claims description 132
- 150000001875 compounds Chemical class 0.000 claims description 90
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 210000004027 cell Anatomy 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 17
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- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- DSNLMYRCHYFVDO-UHFFFAOYSA-N [5a,5b,8,8,11a-pentamethyl-9-(oxan-2-yloxy)-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysen-3a-yl]methyl 4-methylbenzenesulfonate Chemical compound C1CC(C2(CCC3C(C)(C)C(OC4OCCCC4)CCC3(C)C2CC2)C)(C)C2C2C(C(=C)C)CCC21COS(=O)(=O)C1=CC=C(C)C=C1 DSNLMYRCHYFVDO-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
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- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 8
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- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims description 5
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- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- 206010019695 Hepatic neoplasm Diseases 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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Abstract
本发明属于医药领域，具体提供一种式(I)所示的别白桦醇衍生物其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药：
Description
技术领域
本发明属于医药领域，具体涉及别白桦醇衍生物及其制备方法、药物组合物和应用。
背景技术
自然界中存在着各种各样的三萜类化合物，这类化合物由于其具有独特的生物活性以及低毒性使得人们进行了很多研究，齐墩果烷型五环三萜就是其中具有重要生物活性的一种。别白桦醇(allobetulin)及其衍生物也是齐墩果烷型五环三萜中的一种。
Allobetulin(别白桦醇)和28-oxoallobetulin(28-氧代别桦木脑，28-氧代别白桦醇)是一种天然存在的比较稀少的五环三萜，属于齐墩果烷型。与大多数齐墩果烷型五环三萜相比，该类化合物的C-18是α-构型而不是β-构型，属于18α-oleanane(18α-齐墩果烷型)。虽然五环三萜通常具有各种不同的生物活性，但是母体化合物一般都有两个缺点，一是低浓度下生物活性极低；二是药理特性不佳，在水中的低溶解度会造成体外高活性化合物在体内筛选失败以及给药困难。而且，该类化合物如同白桦醇和白桦脂酸一样，也存在水溶性差等缺点。
因此，有必要开发活性更好、生物利用度更高或高效低毒的新化合物。
发明内容
为改善上述技术问题，本发明提供了一种式(I)所示的别白桦醇衍生物，其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药：
其中，
不存在或为双键，当
为双键时，B选自O或S，当
不存在时，B也不存在；
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，所述别白桦醇衍生物具有式(I-1)或式(I-2)所示的结构：
其中，X、Y、Z、B、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，B选自O，当
不存在时，B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，所述别白桦醇衍生物具有式(I-3)或式(I-4)所示的结构：
其中，X、Y、Z、B、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，B选自O，当
不存在时，B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，所述别白桦醇衍生物选自如下化合物：
本发明还提供所述别白桦醇衍生物的制备方法，包括将式(1)化合物与式(2)化合物反应，得到式(I)所示的别白桦醇衍生物：
其中，Het1、Het2、B、Z、
独立地具有上文所述的定义。
根据本发明的实施方案，所述反应可以在溶剂中进行；所述溶剂可以为有机溶剂或水与有机溶剂的混合溶剂；所述有机溶剂可以为甲醇、乙醇、异丙醇、正丁醇、叔丁醇、四氢呋喃、二氧六环、N,N-二甲基甲酰胺；
根据本发明的实施方案，所述反应在催化剂存在下进行，所述催化剂在反应过程中会形成一价铜离子，例如为Cu和CuSO4的组合、CuCl、CuI；
根据本发明的实施方案，所述反应中化合物1与催化剂的摩尔比为1:0.1-1，例如为1:0.2-0.8；
根据本发明的实施方案，所述反应中化合物1与化合物2的摩尔比为1:0.5-2，例如为1:0.8-1.2。
本发明还提供一种药物组合物，其包含治疗有效量的所述别白桦醇衍生物、其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药。
根据本发明的实施方案，所述药物组合物还包括一种或多种药学上可接受的辅料，例如载体或赋形剂。
根据本发明的实施方案，所述药物组合物还可以进一步含有或不含有一种或多种额外的治疗剂。
根据本发明的实施方案，所述药物组合物还包括赋形剂，通过所述赋形剂将药物组合物稀释或装入例如胶囊、小药囊、纸或其它容器形式的这种载体内。当赋形剂用作稀释剂时，它可以是固体、半固体或液体物质，用作溶媒、载体或活性成分的介质。因此，所述药物组合物可以是以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒)；例如含高达10％重量活性成分的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。
优选地，所述适宜赋形剂选自乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆和甲基纤维素。
本发明还提供所述别白桦醇衍生物，其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药在制备药物中的用途，其中所述药物为抗肿瘤药物。
根据本发明的实施方案，所述肿瘤为肝肿瘤或胃肿瘤。
根据本发明的实施方案，所述药物可以用于抑制肿瘤细胞生长，所述肿瘤细胞可以为癌细胞，如选自肝癌细胞、胃癌细胞，其实例可以为选自下列的细胞：Luc7721、HepG2、MNK-45、SW620、MCF-7、A549。
本发明还提供一种预防或治疗肿瘤(例如癌症)的方法，包括向有此需要的患者施用治疗有效量的所述别白桦醇衍生物，其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药。
根据本发明的实施方案，所述癌症可以为肝癌、胃癌。
有益效果
发明人意外地发现，本发明提供的别白桦醇化合物具有优异的抗肿瘤活性。并且，本发明提供合成方法简便可行，收率较高，将其应用于制备抗肿瘤的药物，具有较好的应用价值。
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。
实施例1：化合物的制备
制备化合物xiv采用如下方法：
a.先用Lewis酸将白桦醇重排为化合物2。
b.用氧化剂将化合物2中的-OH氧化成酮得到化合物3。
c.使用溴代丙炔与步骤b中制备的化合物3反应得到化合物4。
d.采用硼氢化钠将步骤c中制备的化合物4中的羰基还原成羟基，制备得到化合物5。
e.通过click反应将4’-叠氮尿苷加入到步骤d中制备的化合物5中合成齐墩果烷衍生物xiv。
具体合成路线如下：
化合物2的合成：将白桦脂醇(化合物1,2.0g,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2(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).13C NMR(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3的合成：化合物2(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3(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4的合成：将化合物3(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4(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5的合成：将化合物4(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5(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5(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.
参考合成化合物xiv的方法合成了化合物i-xiii、xv-xviii。
对于化合物i-ix，区别在于，将步骤c中得到的化合物4与相应的叠氮核苷(4’-叠氮尿苷、4’-叠氮胞苷、4’-叠氮脱氧尿苷、4’-叠氮脱氧胞苷、4’-叠氮-2’-脱氧-2’-氟尿苷、4’-叠氮-2’-脱氧-2’-氟胞苷、齐多夫定等)进行步骤e的click反应；
对于化合物x-xiii和xv-xviii，区别在于，将步骤d中得到的化合物5与相应的叠氮核苷(4’-叠氮胞苷、4’-叠氮脱氧尿苷、4’-叠氮脱氧胞苷、4’-叠氮-2’-脱氧-2’-氟尿苷、4’-叠氮-2’-脱氧-2’-氟胞苷、齐多夫定等)进行步骤e的click反应；
化合物i，白色固体，收率63％。1H NMR(DMSO-d6,400MHz)δ:7.86(d,J＝7.2Hz,1H),7.81(s,1H),7.24(brs,2H),6.60(t,J＝5.0Hz,1H),5.85(br,1H),5.62(t,J＝5.8Hz,1H),5.49(d,J＝5.3Hz,1H),4.68(m,1H),4.21(dd,J＝12.1,5.7Hz,1H),3.95(dd,J＝12.0,5.9Hz,1H),3.63(d,J＝7.8Hz,1H),3.40(s,1H),3.34(d,J＝7.8Hz,1H),3.16(m,1H),3.07(dd,J＝14.9,4.5Hz,1H),2.48(dd,J＝14.9,7.9Hz,1H),2.20-2.35(m,2H),2.01(dd,J＝12.8,5.4Hz,1H),1.05(s,3H),1.02(s,3H),0.99(s,3H),0.96(s,3H),0.88(s,3H),0.84(s,3H),0.76(s,3H).13C NMR(DMSO-d6,100MHz)δ:215.7,165.7,154.7,144.0,141.5,121.9,109.5,99.3,86.7,86.1,70.5,70.2,62.3,56.7,49.7,47.7,46.2,46.1,41.2,40,8,40.3,40.1,37.7,37.0,36.0,35.9,33.7,33.1,32.4,28.7,25.9,25.8,25.8,25.1,24.2,21.3,20.7,18.7,15.9,15.4,13.2.
化合物ii，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).13C NMR(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.
化合物iii，白色固体，收率48％。1H NMR(MeOH-d4,400MHz)δ:7.94(d,J＝8.1Hz,1H),7.92(s,1H),6.41(dd,J＝18.6,2.4Hz,1H),5.75(d,J＝8.1Hz,1H),5.38(ddd,J＝53.4,5.3,2.5Hz,1H),5.00(dd,J＝18.8,5.3Hz,1H),4.28(d,J＝12.2Hz,1H),4.05(d,J＝12.2Hz,1H),3.79(d,J＝7.9Hz,1H),3.55(s,1H),3.48(d,J＝7.8Hz,1H),3.25-3.09(m,2H),2.70-2.56(m,1H),2.09(dd,J＝12.9,5.2Hz,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).13C NMR(MeOH-d4,100MHz)δ:218.7,166.1,152.0,146.5,143.8,124.1,103.4,100.4,93.4(d,J＝189.6Hz),92.7(d,J＝35.7Hz),89.7,72.3(d,J＝15.7Hz),72.3,64.8,59.0,52.0,49.6,48.2,48.1,43.5,42.7,42.1,42.0,38.8,37.6,37.3,35.7,34.9,33.9,29.3,27.6,27.5,27.2,27.0,25.7,24.9,22.5,22.1,20.4,16.9,16.4,14.0.
化合物iv，白色固体，收率45％。1H NMR(MeOH-d4,400MHz)δ:8.35(d,J＝7.9Hz,1H),7.93(s,1H),6.46(dd,J＝17.4,1.4Hz,1H),6.15(d,J＝7.9Hz,1H),5.36(ddd,J＝53.3,5.2,1.6Hz,1H),4.97(dd,J＝20.5,5.2Hz,1H),4.33(d,J＝12.2Hz,1H),4.06(d,J＝12.1Hz,1H),3.79(d,J＝7.8Hz,1H),3.54(s,1H),3.48(d,J＝7.9Hz,1H),3.25-3.08(m,2H),2.71-2.56(m,1H),2.09(dd,J＝12.7,5.0Hz,1H),1.15(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).13C NMR(MeOH-d4,100MHz)δ:218.7,161.8,148.8,147.1,146.7,124.1,100.7,95.4,93.5(d,J＝191.1Hz,1H),92.9(d,J＝35.5Hz),89.7,72.3,71.8(d,J＝16.2Hz,1H),64.3,59.0,52.0,49.6,48.2,48.1,43.5,42.7,42.1,42.0,38.8,37.6,37.3,35.7,34.9,33.8,29.3,27.6,27.5,27.2,27.0,25.7,24.9,22.5,22.1,20.4,16.9,16.4,13.9.
化合物v，白色固体，收率70％。1H NMR(MeOH-d4,400MHz)δ:8.03(d,J＝8.1Hz,1H),7.90(s,1H),6.33(d,J＝5.1Hz,1H),5.79(d,J＝8.1Hz,1H),4.65-4.56(m,2H),4.44(d,J＝11.9Hz,1H),3.96(d,J＝11.9Hz,1H),3.79(d,J＝7.8Hz,1H),3.55(s,1H),3.47(d,J＝7.8Hz,1H),3.27-3.09(m,2H),2.61(dd,J＝14.3,6.9Hz,1H),2.10(dd,J＝13.0,5.2Hz,1H),1.14(s,3H),1.08(s,3H),1.06(s,3H),1.06(s,3H),0.95(s,3H),0.91(s,3H),0.82(s,3H).13C NMR(MeOH-d4,100MHz)δ:218.6,166.0,152.6,146.2,142.8,124.1,103.7,101.0,91.3,89.7,74.5,74.0,72.3,66.0,59.0,52.0,49.6,48.3,48.1,43.5,42.7,42.1,42.0,38.8,37.6,37.3,35.7,34.9,33.8,29.4,27.6,27.5,27.2,27.1,25.7,25.0,22.6,22.1,20.4,16.9,16.4,14.0.
化合物vi，白色固体，收率68％。1H NMR(MeOH-d4,400MHz)δ:8.00(d,J＝7.4Hz,1H),7.95(s,1H),6.32(d,J＝4.9Hz,1H),5.98(brs,1H),4.68-4.53(m,2H),4.43(d,J＝11.9Hz,1H),3.98(d,J＝11.9Hz,1H),3.79(d,J＝7.9Hz,1H),3.55(s,1H),3.47(d,J＝7.8Hz,1H),3.29-3.07(m,2H),2.60(dd,J＝14.2,7.1Hz,1H),2.10(dd,J＝12.9,5.1Hz,1H),1.14(s,3H),1.08(s,3H),1.06(s,3H),1.06(s,3H),0.95(s,3H),0.91(s,3H),0.82(s,3H).13C NMR(MeOH-d4,100MHz)δ:218.6,167.8,158.6,146.1,143.7,124.2,101.0,97.0,93.3,89.7,74.3,73.9,72.3,65.9,59.0,52.0,49.6,48.3,48.1,43.6,42.7,42.1,42.0,38.8,37.7,37.3,35.7,34.9,33.9,29.3,27.6,27.5,27.2,27.1,25.7,24.9,22.6,22.1,20.4,16.9,16.4,14.0.
化合物vii，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).13C NMR(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.
化合物viii，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.
化合物ix，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.
化合物x，白色固体，收率60％。1H NMR(MeOH-d4,400MHz)δ:8.05(d,J＝7.5Hz,1H),7.87(s,1H),6.69(t,J＝5.9Hz,1H),5.95(brs,1H),4.84(t,J＝6.8Hz,1H),4.40(d,J＝12.0Hz,1H),4.12(d,J＝12.1Hz,1H),3.77(d,J＝7.9Hz,1H),3.54(s,1H),3.46(d,J＝7.8Hz,1H),3.17(dd,J＝14.1,2.5Hz,1H),2.83(d,J＝10.8Hz,1H),2.60-2.39(m,3H),2.05-1.89(m,1H),1.71(dd,J＝13.0,2.9Hz,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),0.63(t,J＝12.7Hz,1H).13CNMR(MeOH-d4,100MHz)δ:167.8,158.1,146.6,143.1,123.8,101.8,96.6,89.7,89.0,83.1,73.0,72.3,64.6,57.2,52.5,48.2,46.3,42.8,42.0,41.9,40.5,39.6,38.6,37.7,37.3,37.3,35.7,35.1,33.9,29.8,29.3,29.1,27.6,27.6,27.2,24.9,22.3,19.7,17.8,17.1,16.3,14.0.
化合物xi，白色固体，收率63％。1H NMR(MeOH-d4,400MHz)δ:7.99(d,J＝8.1Hz,1H),7.85(s,1H),6.70(dd,J＝7.1,5.2Hz,1H),5.75(d,J＝8.1Hz,1H),4.85(m,1H),4.38(d,J＝12.1Hz,1H),4.11(d,J＝12.1Hz,1H),3.78(d,J＝7.8Hz,1H),3.54(s,1H),3.46(d,J＝7.8Hz,1H),3.17(dd,J＝14.3,3.1Hz,1H),2.83(d,J＝10.8Hz,1H),2.67-2.49(m,2H),2.45(dt,J＝13.8,7.0Hz,1H),2.03-1.87(m,1H),1.71(dd,J＝13.0,3.3Hz,1H),0.99(s,3H),0.98(s,3H),0.94(s,3H),0.91(s,3H),0.84(s,3H),0.82(s,3H),0.81(s,3H),0.74(d,J＝9.1Hz,1H),0.63(t,J＝12.6Hz,1H).13C NMR(MeOH-d4,100MHz)δ:166.3,152.3,146.6,143.1,123.7,103.2,101.6,89.7,88.0,83.1,73.1,72.3,64.6,57.2,52.5,48.2,46.3,42.8,42.0,41.9,40.5,38.9,38.5,37.7,37.3,37.3,35.7,35.1,33.9,29.8,29.3,29.1,27.6,27.6,27.2,24.9,22.3,19.7,17.8,17.1,16.3,14.0.
化合物xii，白色固体，收率54％。1H NMR(MeOH-d4,400MHz)δ:7.95(s,1H),7.94(d,J＝8.2Hz,1H),6.41(dd,J＝18.6,2.0Hz,1H),5.75(d,J＝8.1Hz,1H),5.39(ddd,J＝53.4,5.1,2.3Hz,1H),5.01(dd,J＝18.7,5.3Hz,1H),4.29(d,J＝12.2,Hz,1H),4.07(d,J＝12.2Hz,1H0,3.78(d,J＝7.8Hz,1H),3.53(s,1H),3.46(d,J＝7.7hz,1H),3.19(dd,J＝14.1,2.7Hz,1H),2.83(d,J＝10.8Hz,1H),2.53(dd,J＝14.5,9.1Hz,1H),2.02-1.86(m,1H),1.72(dd,J＝13.0,2.9Hz,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),0.75(d,J＝9.2Hz,1H),0.63(t,J＝12.5Hz,1H).13C NMR(MeOH-d4,100MHz)δ:166.0,152.0,146.8,143.8,124.0,103.5,100.4,93.4(d,J＝190.1Hz),92.7(d,J＝35.4Hz),89.7,83.1,72.3,72.3(d,J＝16.2Hz),64.9,57.2,52.5,48.2,46.3,42.8,42.0,41.9,40.5,38.6,37.7,37.4,37.3,35.7,35.1,33.9,29.8,29.3,29.1,27.6,27.6,27.2,25.0,22.3,19.7,17.8,17.1,16.3,14.0.
化合物xiii，白色固体，收率51％。1H NMR(MeOH-d4,400MHz)δ:7.96(s,1H),7.95(d,J＝7.4Hz,1H),6.38(dd,J＝19.0,1.7Hz,1H),5.94(d,J＝7.6Hz,1H),5.32(ddd,J＝53.9,5.1,2.0Hz,1H),5.01(dd,J＝19.7,5.3Hz,1H),4.29(d,J＝12.2Hz,1H),4.10(d,J＝12.1Hz,1H),3.77(d,J＝7.9Hz,1H),3.54(s,1H),3.46(d,J＝7.8Hz,1H),3.18(dd,J＝14.4,3.1Hz,1H),2.83(d,J＝10.8Hz,1H),2.54(dd,J＝14.4,8.9Hz,1H),2.02-1.88(m,1H),1.72,(dd,J＝13.1,3.3Hz,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＝9.5Hz,1H),0.63(t,J＝12.7Hz,1H).13C NMR(MeOH-d4,100MHz)δ:168.2,157.9,146.7,144.5,124.0,100.4,96.8,94.12(d,J＝35.1Hz),93.78(d,J＝189.4Hz),89.7,83.1,72.4(d,J＝17.5Hz),72.3,65.0,57.2,52.5,48.2,46.3,42.8,42.0,41.9,40.5,38.5,37.7,37.3,37.3,35.7,35.1,33.9,29.8,29.3,29.1,27.6,27.6,27.2,25.0,22.3,19.7,17.8,17.1,16.3,14.0.
化合物xv，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.
化合物xvi，白色固体，收率60％。1H NMR(MeOH-d4,400MHz)δ:7.92(d,J＝8.3Hz,1H),7.89(s,1H),6.81(dd,J＝10.2,5.5Hz,1H),5.76(d,J＝8.1Hz,1H),5.41(dt,J＝54.5,5.3Hz,1H),4.86(dd,J＝22.4,5.0Hz,1H),4.30(s,2H),3.77(d,J＝7.8Hz,1H),3.54(s,1H),3.46(d,J＝7.8Hz,1H),3.24-3.11(m,1H),2.83(d,J＝10.7Hz,1H),2.54(dd,J＝14.2,9.0Hz,1H),2.06-1.88(m,1H),1.70(dd,J＝12.9,2.8Hz,1H),0.98(s,6H),0.93(s,3H),0.91(s,3H),0.83(s,3H),0.82(s,3H),0.81(s,3H),0.74(d,J＝9.3Hz,1H),0.62(t,J＝12.6Hz,1H).13C NMR(MeOH-d4,100MHz)δ:165.9,152.0,147.0,143.1,123.8,102.8,98.3(d,J＝8.6Hz),96.22(d,J＝193.9Hz),89.6,85.4(d,J＝16.7Hz),83.1,76.2(d,J＝25.1Hz,1H),72.3,62.9,57.2,52.4,48.1,46.3,42.7,41.9,41.9,40.5,38.5,37.7,37.3,37.2,35.7,35.1,33.9,29.8,29.4,29.1,27.6,27.6,27.2,25.0,22.3,19.7,17.8,17.1,16.4,14.1.
化合物xvii，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.
化合物xviii，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.
实施例2化合物的制备
制备化合物xxiii采用如下方法：
a.先用Jone’s试剂将白桦醇氧化为白桦脂酮酸(化合物6)。
b.如实施例1中用Lewis酸将化合物6重排得到化合物7。
c.使用溴代丙炔与步骤b中制备的化合物7反应得到化合物8。
e.通过click反应将4’-叠氮尿苷加入到步骤c中制备的化合物8中合成齐墩果烷衍生物xxiii。
具体合成路线如下：
化合物6的合成：将白桦醇(20.0g,45.2mmol)溶于丙酮(400mL)，冰浴搅拌下缓慢滴加新配置的Jones’试剂(200mL)，滴加完毕后0℃搅拌20分钟，撤去冰浴继续反应2小时。TLC检测反应完毕后，加入甲醇(300mL)粹灭反应，再加入水(300mL)搅拌30分钟。减压蒸去溶剂后，水相用乙酸乙酯萃取(3×200mL)，合并有机相，无水Na2SO4干燥，蒸干溶剂柱分离得到白色固体化合物6(12.2g,26.8mmol,59.3％),mp 191-193℃.1H NMR(DMSO-d6,400MHz)δ:12.10(s,1H),4.69(s,1H),4.57(s,1H),2.95(td,J＝11.1,5.2Hz,1H),2.48-2.30(m,2H),2.26(td,J＝12.6,3.2Hz,1H),2.15-2.06(m,1H),1.89-1.73(m,3H),1.65(s,3H),1.67-1.60(m,1H),1.54(t,J＝11.3Hz,1H),1.48-1.00(m,14H),1.02-0.96(m,1H),0.98(s,3H),0.95(s,3H),0.93(s,3H),0.90(s,3H),0.85(s,3H).13C NMR(DMSO-d6,100MHz)δ：218.5,177.2,150.3,109.7,55.4,53.8,49.0,48.4,46.6,46.5,42.1,40.1,38.8,37.7,36.4,36.3,33.6,33.1,31.6,30.1,29.2,26.4,25.1,21.0,20.7,19.2,19.0,15.7,15.4,14.3.
化合物7的合成：将白桦脂酮酸(化合物6,2.0g,4.40mmol)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7(1.68g,产率84.0％)。1H NMR(CDCl3,400MHz)δ：3.93(s,1H),2.57-2.34(m,2H),1.92(ddd,J＝12.6,7.6,4.6Hz,1H),1.88-1.83(m,1H),1.80(d,J＝11.1Hz,1H),1.06(s,3H),1.01(s,3H),1.01(s,3H),0.94(s,3H),0.93(s,3H),0.92(s,6H),0.87(s,3H).
化合物8的合成：将化合物7(1.68g,3.69mmol)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4(1.18g,2.39mmol,产率65％)。1H NMR(CDCl3,400MHz)δ:3.91(s,1H),2.91-2.77(m,1H),2.59(ddt,J＝17.1,4.4,2.5Hz,1H),2.39-2.28(m,1H),2.19(ddt,J＝17.1,8.6,2.4Hz,1H),1.12(s,3H),1.04(s,3H),1.02(s,3H),1.00(s,3H),0.95(s,3H),0.93(s,3H),0.84(s,3H).13C NMR(CDCl3,100MHz)δ:215.4,179.7,85.9,82.9,69.4,57.3,50.7,48.2,46.6,46.0,41.1,40.6,40.0,37.4,35.9,33.5,33.4,32.2,31.8,28.7,27.8,26.3,25.4,24.9,23.9,21.5,21.1,19.4,19.0,16.4,15.6,13.5.
化合物xxiii的合成：在50mL圆底烧瓶中,将化合物8(147.8mg，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xxiii(96.0mg，0.12mmol，产率62％).1HNMR(MeOH-d4,400MHz)δ:8.02(d,J＝8.1Hz,1H),7.90(s,1H),6.33(d,J＝5.2Hz,1H),5.79(d,J＝8.1Hz,1H),4.65-4.54(m,2H),4.43(d,J＝11.9Hz,1H),4.01(s,1H),3.95(d,J＝11.9Hz,1H),3.26-3.08(m,2H),2.61(dd,J＝14.2,6.8Hz,1H),2.10(dd,J＝12.8,5.1Hz,1H),1.91(d,J＝11.1Hz,1H),1.14(s,3H),1.07(s,3H),1.05(s,3H),1.00(s,3H),0.98(s,6H),0.91(s,3H).13C NMR(MeOH-d4,100MHz)δ:218.5,182.3,166.0,152.6,142.8,124.1,103.7,101.0,91.3,87.9,74.6,74.0,66.0,59.0,54.9,52.1,49.6,48.3,47.9,47.6,43.5,41.9,41.3,38.8,37.7,34.7,34.6,33.6,32.8,29.2,29.1,27.4,27.1,26.6,25.7,24.1,22.4,22.1,20.3,17.0,16.2,14.1.
实施例3化合物的制备
制备化合物xxxvii采用如下方法
a.将实施例1中的化合物5与2,2’-二甲基琥珀酸酐反应得到化合物9。
b.通过click反应将4’-叠氮脱氧胞苷加入到步骤a制备的化合物9中合成齐墩果烷衍生物xxxvii。
具体合成路线如下：
化合物9的合成：将化合物5(480mg,1mmol)溶于20mL无水吡啶，加入2,2-二甲基琥珀酸酐(1g,7.8mmol)和DMAP(122mg,1mmol)搅拌回流过夜。反应完毕后蒸干溶剂，柱色谱分离得到白色固体化合物9(260mg,0.427mmol,产率42.7％)。1H NMR(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),2.89(d,J＝14.5Hz,1H),2.38(d,J＝14.2Hz,1H),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),1.31(s,3H),1.22(s,3H),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:87.9,83.0,81.4,71.3,70.0,55.5,51.0,48.0,46.8,46.2,44.9,41.5,40.8,40.6,39.1,37.4,36.7,36.3,34.8,34.1,33.8,32.7,29.0,28.8,28.8,28.3,26.4,26.3,24.5,22.3,21.0,18.4,17.3,16.2,15.7,13.5.
化合物xxxvii的合成：在50mL圆底烧瓶中,将化合物9(182mg，0.30mmol)、叠氮核苷化合物4’-叠氮脱氧胞苷(67.0mg,0.25mmol)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(4:1)分离得到白色固体化合物xxxvii(122.8mg，0.14mmol，产率56.0％)。1H NMR(MeOH-d4,400MHz)δ:8.05(d,J＝7.5Hz,1H),7.87(s,1H),6.69(t,J＝5.9Hz,1H),5.95(brs,1H),4.84(t,J＝6.8Hz,1H),4.40(d,J＝12.0Hz,1H),4.12(d,J＝12.1Hz,1H),3.77(d,J＝7.9Hz,1H),3.54(s,1H),3.46(d,J＝7.8Hz,1H),3.17(dd,J＝14.1,2.5Hz,1H),2.92(d,J＝14.5Hz,1H),2.83(d,J＝10.8Hz,1H),2.60-2.39(m,3H),2.38(d,J＝14.2Hz,1H),2.05-1.89(m,1H),1.71(dd,J＝13.0,2.9Hz,1H),1.33(s,3H),1.25(s,3H),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),0.63(t,J＝12.7Hz,1H).13C NMR(MeOH-d4,100MHz)δ:167.8,158.1,146.6,143.1,123.8,101.8,96.6,89.7,89.0,83.1,73.0,72.3,64.6,57.2,52.5,48.2,46.3,46.1,45.9,42.8,42.0,41.9,40.5,39.6,38.6,37.7,37.3,37.3,35.7,35.1,33.9,29.8,29.3,29.1,29.0,28.8,27.6,27.6,27.2,24.9,22.3,19.7,17.8,17.1,16.3,14.0.
参考合成化合物xxxvii的方法合成了化合物xxxvii-xxxxii。
实施例4：生物活性测试
2.1本发明化合物对人肝癌细胞Luc7721和HepG2、人胃腺癌细胞MNK-45、人结肠癌细胞SW620、人乳腺癌细胞MCF-7、人肺癌细胞A549的抑制活性测试
本实验用不同浓度的受试化合物分别作用于上述细胞48小时，通过MTT法检测细胞生长抑制率，来检测化合物对不同肿瘤细胞的抑制程度。
实验方法：
将受试溶解于一定体积的DMSO中，配成浓度为10mmol/L的母液4℃保存，使用的时候取母液稀释为一定倍数的溶液。
具体操作步骤如下：
(1)取处于对数生长期的Luc7721、HepG2、MNK-45、SW620、MCF-7和A549细胞，离心、重悬，调整细胞悬液密度至8×104cell/mL，接种于96孔培养板中，每孔加入100μL细胞悬液，然后放置细胞培养箱中37℃，5％CO2常规培养。
(2)孵育24h后，显微镜下观察各孔细胞单层贴壁均匀生长，实验组孔内分别加入不同浓度的受试化合物溶液1μL，使化合物终浓度均分别为1.5、3、6.25、12.5、25、50、75、100μmol/L，每个浓度均设4个复孔；同时设空白组(只加入培养基不加细胞悬液)、阴性对照组(只加入细胞悬液)。
(3)放置培养箱培养48h后，每孔加入20μL MTT溶液，在培养箱中继续培养4h。然后小心弃去上层培养基，每孔加入150μl DMSO，至于摇床上37℃恒温震荡10min，使结晶物充分溶解。在酶联免疫检测仪490nm波长下检测各孔吸光度OD值。
(4)计算样品对细胞的抑制作用，公式如下：
抑制率(％)＝(细胞对照孔OD值－给药孔OD值)/(细胞对照孔OD值－空白孔OD值)×100％
根据所计算的抑制率，求出各受试化合物抑制细胞生长的半数抑制浓度IC50值。
表1：受试化合物的IC50值(μmol/L)
由表1可以看出，本发明化合物样品均对多种癌细胞存在不同程度的抑制作用，某些化合物对不同细胞还体现出优异的广谱抑制作用或选择性抑制作用。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种式(I)所示的别白桦醇衍生物，其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药：
其中，
不存在或为双键，当
为双键时，B选自O或S，当
不存在时，B也不存在；
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。
2.根据权利要求1所述的别白桦醇衍生物，其特征在于，具有式(I-1)或式(I-2)所示的结构：
其中，X、Y、Z、B、Rm、
独立地具有权利要求1所述的定义。
3.根据权利要求1或2所述的别白桦醇衍生物，其特征在于，
不存在或为双键，当
为双键时，B选自O，当
不存在时，B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。
4.根据权利要求1-3任一项所述的别白桦醇衍生物，其特征在于，所述别白桦醇衍生物具有式(I-3)或式(I-4)所示的结构：
其中，X、Y、Z、B、Rm、
独立地具有权利要求1-3任一项所述的定义。
5.根据权利要求1-4任一项所述的别白桦醇衍生物，其特征在于，
不存在或为双键，当
为双键时，B选自O，当
不存在时，B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。
6.根据权利要求1-5任一项所述的别白桦醇衍生物，其特征在于，所述别白桦醇衍生物选自如下化合物：
7.权利要求1-6任一项所述别白桦醇衍生物的制备方法，其特征在于，所述制备方法包括将式(1)化合物与式(2)化合物反应，得到式(I)所示的别白桦醇衍生物：
其中，Het1、Het2、B、Z、
独立地具有权利要求1-6任一项所述的定义。
8.根据权利要求7所述的制备方法，其特征在于，所述反应在溶剂中进行；所述溶剂为有机溶剂或水与有机溶剂的混合溶剂；所述有机溶剂为甲醇、乙醇、异丙醇、正丁醇、叔丁醇、四氢呋喃、二氧六环、N,N-二甲基甲酰胺；
优选地，所述反应在催化剂存在下进行，所述催化剂在反应过程中会形成一价铜离子，所述催化剂例如为Cu和CuSO4的组合、CuCl、CuI；
优选地，所述反应中化合物1与催化剂的摩尔比为1:0.1-1，例如为1:0.2-0.8；
优选地，所述反应中化合物1与化合物2的摩尔比为1:0.5-2，例如为1:0.8-1.2。
9.一种药物组合物，其包含治疗有效量的权利要求1-6任一项所述别白桦醇衍生物、其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药。
10.权利要求1-6任一项所述别白桦醇衍生物，其药学上可接受的盐、互变异构体、立体异构体、氮氧化物、水合物或前药在制备药物中的用途，其中所述药物优选为抗肿瘤药物；
优选地，所述肿瘤为肝肿瘤或胃肿瘤；
优选地，所述药物用于抑制肿瘤细胞生长，所述肿瘤细胞为癌细胞，如选自肝癌细胞、胃癌细胞，例如选自下列细胞：Luc7721、HepG2、MNK-45、SW620、MCF-7、A549。
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