CN108864132B - 一类冬凌草甲素衍生物及其制备方法和用途 - Google Patents
一类冬凌草甲素衍生物及其制备方法和用途 Download PDFInfo
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- CN108864132B CN108864132B CN201810902802.XA CN201810902802A CN108864132B CN 108864132 B CN108864132 B CN 108864132B CN 201810902802 A CN201810902802 A CN 201810902802A CN 108864132 B CN108864132 B CN 108864132B
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- oridonin derivative
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- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical class C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims description 41
- -1 hydroxy, carbonyl Chemical group 0.000 claims description 37
- 150000001875 compounds Chemical class 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000000376 reactant Substances 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 150000003973 alkyl amines Chemical class 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
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- 201000007270 liver cancer Diseases 0.000 claims description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
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- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本发明公开了一类由以下通式(1)表示的冬凌草甲素衍生物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物及其制备方法和用途。根据本发明的由以下通式(1)表示的冬凌草甲素衍生物水溶性良好，且生物利用度更高。体外生物学实验证明本发明的冬凌草甲素衍生物具有更高的抗肿瘤活性，对自身免疫性疾病具有良好的效果。
Description
技术领域
本发明属于化学医药领域，具体而言，涉及一种冬凌草甲素衍生物及其制备方法和用途。
背景技术
冬凌草甲素(Oridonin)是从香茶菜属(Rabdosia)植物中分离出的一种贝壳杉烯二商类(ent-kaurene diterpenoid)天然有机化合物，如下式1所示：
冬凌草甲素是冬凌草的主要有效成分，具有清热解毒、活血化痕、抗菌消炎、抗肿瘤等功效。研究发现，冬凌草甲素具有确切的体内体外抗肿瘤活性，其抗瘤谱也广，如对人体食管癌109细胞系及人体肝癌BEL-7402细胞株均有明显的细胞毒作用，对小鼠艾氏腹水癌、肝癌的腹水型和实体型以及肉瘤S180均有抗肿瘤作用。临床用于治疗原发性肝癌、食管癌和贡门癌等(见刘晨江，赵志j鸣。中国药学杂志，1998,33,577)。冬凌草甲素为二萜类成分，几乎不溶于水，限制了它在临床的应用。人们对冬凌草甲素进行结构修饰，试图找到药理活性更好的化合物，日本学者Fujita小组(见Fujita E,Nagao Y,Kaneko K,etal.Chem.Pharm.Bull,1976,24(9):2118；Fujita E,Nagao Y,Kohno T,eta1.Chem.Pharm.Bull.,1981,29(11):3208；Node M,Sai M,Fuji K,eta1.Chem.Pharm.Bull.,1983,31(4):1433.)对冬凌草甲素的14位进行了结构改造研究，发现14位毗化后的衍生物活性较冬凌草甲素提高了30％。
目前为止冬凌草甲素有关的结构改造主要集中在对羟基和羰基的取代修饰，例如CN 1255502A、CN105418627A等专利申请文件中所示，但对1位的碳碳双键普遍认为是影响其药理性质的结构而未尝改变。
而本申请的发明人经过研究发现对1位的碳碳双键进行修饰可以很好地提高药理学活性，改善冬凌草甲素其衍生物抗肿瘤活性和水溶性等性质，基于此本发明的发明人开发了一系列的冬凌草甲素的衍生化合物，其可以作为进一步开发为新药使用。
发明内容
根据本发明的一个方面，提供了一类由以下通式(1)表示的冬凌草甲素衍生物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物：
其中，所述取代基R1和R2各自独立为氢、C1–6直链或支链烷基、C2–6直链或支链烯基、C2–6直链或支链炔基、C3–6环烷基；
或者取代基R1和R2通过连接基团彼此连接形成四元至八元含有1至3个杂原子的杂环基，所述连接基团为含有0至3个杂原子的C1–6亚烷基。
优选地，所述四元至八元含有1至3个杂原子的杂环基中的杂原子选自N、O或S。
优选地，所述取代基R1和R2各自独立为氢、C1–3直链或支链烷基、C2–4直链或支链烯基、C2–4直链或支链炔基。
进一步优选地，所述取代基R1和R2各自独立为氢、甲基、乙基、丙基、异丙基、丙烯基、丁烯基、丙炔基、丁炔基、环丙基或环丁基。
进一步优选地，所述取代基R1和R2各自独立为甲基、乙基或丙基。
优选地，当取代基R1和R2通过连接基团彼此连接形成四元至八元含有1至3个杂原子的杂环基时，所述连接基团为含有0至2个杂原子的C1–4亚烷基。
取代基R3选自以下基团中的任意一种：C1–3直链或支链烷基、C2–4直链或支链烯基、C2–4直链或支链炔基、C3–6环烷基、硝基、氰基、羟基、卤素。
或者取代基R3为选自N、O或S的原子，并与其连接的碳原子形成双键。
取代基R4和R5各自独立地选自C1–6直链或支链烷基、C2–6直链或支链烯基、C2–6直链或支链炔基、C1–6直链或支链烷氧基、硝基、氰基、取代或未取代的羟基、羰基、卤素、取代或未取代的磺酸基、取代或未取代的磷酸酯基；
其中所述取代的羟基中的取代基选自C1–6直链或支链烷基、C1–6直链或支链烷基羰基、含有1至3个C1–4烷基的苯基、由1至3个苯基取代的C1–4烷基；
所述取代的磺酸基中的取代基选自C1–6直链或支链烷基、C1–6直链或支链烷基羰基、含有1至3个C1–4烷基的苯基、由1至3个苯基取代的C1–4烷基；
所述取代的磷酸酯基中的取代基选自C1–6直链或支链烷基、C1–6直链或支链烷基羰基、含有1至3个C1–4烷基的苯基、由1至3个苯基取代的C1–4烷基。
或者取代基R4和R5通过-(CR6R7)n-彼此连接，其中n为1、2或3的正整数；取代基R6和R7各自独立为C1–6直链或支链烷基、C2–6直链或支链烯基、C2–6直链或支链炔基、C1–6直链或支链烷氧基、硝基、氰基、卤素。
优选地，所述取代基R4和R5各自独立地选自C1–4直链或支链烷基、C2–4直链或支链烯基、C2–4直链或支链炔基、C1–4直链或支链烷氧基、硝基、氰基、取代或未取代的羟基、羰基、取代或未取代的磺酸基、取代或未取代的磷酸酯基；
优选地，其中所述取代的羟基中的取代基选自C1–4直链或支链烷基、C1–4直链或支链烷基羰基、含有1或2个C1–4烷基的苯基、由1或2个苯基取代的C1–4烷基；
所述取代的磺酸基中的取代基选自C1–6直链或支链烷基、C1–6直链或支链烷基羰基、含有1至3个C1–4烷基的苯基、由1或2个苯基取代的C1–4烷基；
所述取代的磷酸酯基中的取代基选自C1–6直链或支链烷基、C1–6直链或支链烷基羰基、含有1至3个C1–4烷基的苯基、由1或2个苯基取代的C1–4烷基。
优选地，所述取代基R4和R5各自独立地选自甲基、乙基、正丙基、异丙基、环丙基、乙烯基、烯丙基、正丁基、仲丁基、异丁基、叔丁基、环丁基、C1–4直链或支链烷氧基、硝基、取代或未取代的羟基、羰基、取代或未取代的磺酸基、取代或未取代的磷酸酯基；
优选地，其中所述取代的羟基中的取代基选自甲基、乙基、正丙基、异丙基、环丙基、乙烯基、烯丙基、正丁基、仲丁基、异丁基、叔丁基、环丁基、C1–3直链或支链烷基羰基、含有1或2个C1–3烷基的苯基、由1或2个苯基取代的C1–3烷基；
所述取代的磺酸基中的取代基选自甲基、乙基、正丙基、异丙基、环丙基、乙烯基、烯丙基、正丁基、仲丁基、异丁基、叔丁基、环丁基、C1–3直链或支链烷基羰基、含有1或2个C1–3烷基的苯基、由1或2个苯基取代的C1–3烷基；
所述取代的磷酸酯基中的取代基选自甲基、乙基、正丙基、异丙基、环丙基、乙烯基、烯丙基、正丁基、仲丁基、异丁基、叔丁基、环丁基、C1–3直链或支链烷基羰基、含有1或2个C1–3烷基的苯基、由1或2个苯基取代的C1–3烷基。
优选地，所述取代基R4和R5通过-(CR6R7)n-彼此连接，其中n为1或2的正整数；取代基R6和R7各自独立地选自C1–4直链或支链烷基、C2–4直链或支链烯基、C2–4直链或支链炔基、C1–4直链或支链烷氧基、硝基、羟基、氰基、卤素。
优选地，所述取代基R4和R5通过-(CR6R7)n-彼此连接，其中n为1或2的正整数；取代基R6和R7各自独立地选自C1–3直链或支链烷基、C2–3直链或支链烯基、C2–3直链或支链炔基、C1–3直链或支链烷氧基、硝基、羟基、卤素。
优选地，所述取代基R4和R5通过-(CR6R7)n-彼此连接，其中n为1或2的正整数；取代基R6和R7各自独立地选自甲基、乙基、正丙基、异丙基、环丙基、乙烯基、烯丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、环丙氧基、硝基、羟基。
优选地，所述卤素选自氟、氯或溴。
优选地，根据本发明的所述由通式(1)表示的冬凌草甲素衍生物选自以下化合物中：
所述通式(1)表示的冬凌草甲素衍生物的药学上可接受的盐为所述通式(1)表示的冬凌草甲素衍生物与有机酸或无机酸形成的药学上可接受的盐，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等。或者通式(1)表示的冬凌草甲素衍生物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式(1)表示的冬凌草甲素衍生物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者通式(1)表示的冬凌草甲素衍生物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
根据本发明的另一个方面，提供了一种冬凌草甲素衍生物的制备方法，所述制备方法的反应式如下并包括以下步骤：
1)用氮气置换反应器中气氛三次，将通式(2)的化合物和催化剂加入反应器中，然后加入适量溶剂，搅拌使通式(2)的化合物溶解，其中通式(2)的化合物可以根据现有技术的制备方法得到；
将反应物烷基胺HNR1R2溶解于适量溶剂中，然后滴加入反应器中，同时将温度升高至20至50℃，反应约3至6小时，得到通式(3)表示的产物；
待反应完成后，将反应体系冷却至室温，然后通过减压蒸馏除去溶剂，然后通过高效制备液相色谱法(以甲醇与水或者乙腈与水为流动相)分离产品通式(3)表示的化合物；
2)用氮气置换反应器中气氛三次，将通式(3)的化合物和相应的反应物按照摩尔比1:1至1:3的比例加入反应器中，然后加入适量溶剂，加热回流反应0.5h至3h，冷却至室温，加入碱性溶液，氯仿提取，干燥，蒸干有机层得粗产物，乙酸乙酯-石油醚重结晶，得到产品通式(1)表示的化合物。
其中步骤1)中所述催化剂选自氢氧化钠、甲醇钠、乙醇钠、叔丁醇钾、三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯(DBU)、碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的任意一种或多种。所述催化剂的用量为通式(2)的化合物重量的5wt％至10wt％。
优选地，所述催化剂的用量为通式(2)的化合物重量的6wt％至8wt％。
优选地，所述反应物烷基胺HNR1R2中的取代基R1和R2与上面通式(1)中的定义相同。
优选地，所述通式(2)的化合物中的取代基R3与上面通式(1)中的定义相同。
优选地，所述反应物烷基胺HNR1R2与通式(2)的化合物的摩尔比为1:1至20:1，优选为2:1至15:1，更优选为5:1至8:1。
优选地，所述溶剂选自醇、酮、醚或酯中的一种或几种；所述醇选自甲醇、乙醇、异丙醇、叔丁醇中的一种或几种；所述酮选自丙酮、甲乙酮中的一种或几种；所述醚选自乙醚、二氧六环、异丙醚、甲基叔丁基醚、四氢呋喃中的一种或几种；并且所述酯选自乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸丁酯中的一种或几种。
优选地，步骤2)中所述碱性溶液为碳酸氢钠溶液、碳酸钠溶液或碳酸钾溶液等
根据本发明的另一个方面，提供了一种由通式(1)表示的冬凌草甲素衍生物在制备抗肿瘤药物中的用途。
根据所述由通式(1)表示的冬凌草甲素衍生物及其盐在制备抗肿瘤药物中的用途，其中所述肿瘤包括(但不限于)脑胶质瘤、前列腺癌、肺癌、子宫癌、、肝癌、乳腺癌、宫颈癌、食管癌绒毛膜癌、直肠癌：皮肤癌症(如黑色素瘤)、肾癌、睾丸癌、淋巴系统癌症、消化道癌症、脾癌、卵巢癌、结肠癌、头颈部癌、口腔癌、咽喉癌、鼻咽癌、胰腺癌、膀胱癌、神经母细胞瘤等。
所述由通式(1)表示的冬凌草甲素衍生物及其盐在自身免疫性疾病药物中的应用，所述自身免疫性疾病包括系统性红斑狼疮、银屑病。
根据本发明的另一个方面，提供了一种药物组合物，所述药物组合物包括治疗有效量的由通式(1)表示的冬凌草甲素衍生物和至少一种赋形剂、稀释剂或载剂。
有益效果
本发明的冬凌草甲素衍生物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物水溶性良好，且生物利用度更高。体外生物学实验证明本发明的冬凌草甲素衍生物具有更高的抗肿瘤活性，对自身免疫性疾病具有良好的效果。
附图说明
图1为表示红斑狼疮治疗效果实验中小鼠生存率的图。
具体实施方式
以下，将详细地描述本发明。在进行描述之前，应当理解的是，在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义，而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上，根据与本发明的技术方面相应的含义和概念进行解释。因此，这里提出的描述仅仅是出于举例说明目的的优选实例，并非意图限制本发明的范围，从而应当理解的是，在不偏离本发明的精神和范围的情况下，可以由其获得其他等价方式或改进方式。
本发明所提供的由通式(1)表示的冬凌草甲素衍生物和包含该冬凌草甲素衍生物的药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位剂量中包含0.05-200mg通式(1)的冬凌草甲素衍生物，优选地，制剂配方的单位剂量中包含0.1mg-100mg通式(1)冬凌草甲素衍生物。
本发明的由通式(1)表示的冬凌草甲素衍生物和药物组合物可对哺乳动物临床使用，包括人和动物，可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200mg/kg体重，一次性服用，或0.01-100mg/kg体重分次服用。不管用何种服用方法，个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始，逐渐增加剂量一直到找到最适合的剂量。
本发明中，术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化，如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。
典型的配方是通过混合本发明的通式(1)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的，包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂，将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言，安全的溶剂是无毒性含水溶剂诸如水，以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物以可被接受的形式制造或使用。
本发明所述的如式(1的冬凌草甲素衍生物与至少一种其它药物的组合使用时，两种药物或多种药物可以分开使用也可以组合使用，优选以药学组合物的形式给药。本发明的如式(1)的冬凌草甲素衍生物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式，分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中，本发明的冬凌草甲素衍生物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质，或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等；粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等；溶液阻滞剂如石蜡等；吸收促进剂如季铵化合物等；吸附剂如高岭土、膨润土等；润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下，该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料，其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的冬凌草甲素衍生物或其组合物之外，该液态剂型可含有本领域中常用的惰性稀释剂，诸如水或其他溶剂；增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺；油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等)；甘油；四氢糠基醇；聚乙二醇与脱水山梨糖醇的脂肪酸酯；或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外，该组合物也可包括赋形剂，诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言，除了本发明的由通式(1)表示的冬凌草甲素衍生物或组合物之外，可进一步含有载剂诸如悬浮剂，如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶，或这些物质中几种的混合物等。
本发明的由通式(1)表示的冬凌草甲素衍生物或药物组合物可采用其它局部给药剂型给药，包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液，亦意欲涵盖于本发明的范围内。
以下实施例仅是作为本发明的实施方案的例子列举，并不对本发明构成任何限制，本领域技术人员可以理解在不偏离本发明的实质和构思的范围内的修改均落入本发明的保护范围。除非特别说明，以下实施例中使用的试剂和仪器均为市售可得产品。
实施例
实施例1：化合物1的制备
在单口烧瓶中将冬凌草甲素200mg(0.55mmol)溶于15ml无水甲醇中,在搅拌状态下，逐滴加入33％二甲胺水溶液，室温搅拌2小时，TLC监控反应完成后，反应液在40～50℃减压旋干，得白色固体213.5mg,产率95.2％1H NMR(DMSO-d6)δppm:6.14(s,1H),5.90(d,J＝11.6Hz,1H),5.55(s,1H),4.79(s,1H),3.87(dd,J＝10.4,8.0Hz,1H),3.52～3.74(m,4H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.51～2.71(m,3H),2.26(s,6H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.42～1.62(m,3H),1.23(d,J＝11.6Hz,1H),1.15(s,6H)；MS-EI m/z(％):410(M+1,100).
实施例2：化合物2的制备
在单口烧瓶中将冬凌草甲素200mg(0.55mmol)溶于15ml无水甲醇中,在搅拌状态下，逐滴加入1.1mmol二乙胺，室温搅拌4小时，TLC监控反应完成后，反应液在40～50℃减压旋干，剩余物溶于二氯甲烷，饱和盐水洗三次，无水硫酸钠干燥，旋干，得白色固体218.7mg,产率91.4％。1HNMR(DMSO-d6)δppm:6.11(s,1H),5.93(d,J＝11.6Hz,1H),5.45(s,1H),4.79(s,1H),3.87(dd,J＝10.4,8.0Hz,1H),3.52～3.73(m,4H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.55～2.71(m,3H),2.40(q,J＝8.4Hz,4H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.40～1.62(m,3H),1.33(t,J＝8.4Hz,6H),1.23(d,J＝11.6Hz,1H),1.13(s,6H)；MS-EI m/z(％):438(M+1,100).
实施例3：化合物3的制备
在单口烧瓶中将冬凌草甲素200mg(0.55mmol)溶于15ml无水甲醇中,在搅拌状态下，逐滴加入1.1mmol哌嗪，40℃搅拌3小时，TLC监控反应完成后，反应液在40～50℃减压旋干，剩余物加入二氯甲烷溶解，以5％稀盐酸洗，饱和盐水洗，无水硫酸钠干燥，旋干，得白色固体210.4mg,产率85.2％。1H NMR(DMSO-d6)δppm:6.20(s,1H),5.91(d,J＝11.6Hz,1H),5.50(s,1H),4.83(s,1H),3.82(dd,J＝10.4,8.0Hz,1H),3.51～3.72(m,4H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.73～2.85(m,8H),2.52～2.74(m,3H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.42～1.62(m,3H),1.23(d,J＝11.6Hz,1H),1.18(s,6H)；MS-EIm/z(％):451(M+1,100).
实施例4：化合物4的制备
将100mg(0.24mmol)化合物1加入10mL丙酮中，加入0.3mL(2.5mmol)二甲氧基丙烷、8.6mg(0.05mmol)对甲基苯磺酸，加热回流反应1h。加入0.5mo l/L碳酸钠溶液，氯仿提取，干燥，蒸干有机层得粗产物，乙酸乙酯-石油醚重结晶，得白色固体84.4mg，收率75.2％。1HNMR(DMSO-d6)δppm:6.11(s,1H),5.92(d,J＝11.6Hz,1H),5.50(s,1H),4.79(s,1H),3.82(dd,J＝10.4,8.0Hz,1H),3.51～3.72(m,2H),3.43～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.5～2.7(m,3H),2.26(s,6H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.62(s,3H),1.42～1.62(m,3H),1.32(s,3H),1.23(d,J＝11.6Hz,1H),1.11(s,6H)；MS-EI m/z(％):450(M+1,100).
实施例5：化合物5的制备
将100mg(0.23mmol)化合物2加入10mL丙酮中，加入0.3mL(2.5mmol)二甲氧基丙烷、8.6mg(0.05mmol)对甲基苯磺酸,加热回流反应1h。加入0.5mol/L碳酸钠溶液，氯仿提取，干燥，蒸干有机层得粗产物，乙酸乙酯-石油醚重结晶，得白色固体82.9mg，收率76.3％。1HNMR(DMSO-d6)δppm:6.13(s,1H),5.90(d,J＝11.6Hz,1H),5.44(s,1H),4.79(s,1H),3.87(dd,J＝10.4,8.0Hz,1H),3.52～3.73(m,2H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.55～2.71(m,4H),2.40(q,J＝8.4Hz,4H),2.36(s,6H)，1.90～2.00(m,2H),1.67～1.83(m,3H),1.40～1.62(m,3H),1.33(t,J＝8.4Hz,6H),1.23(d,J＝11.6Hz,1H),1.11(s,6H)；MS-EI m/z(％):478(M+1,100).
实施例6：化合物6的制备
在25ml圆底烧瓶中，加入100mg(0.24mmol)化合物1和10ml甲苯，搅拌下加入0.5g3,4-二甲氧基苯甲醛和0.02g对甲苯磺酸，80℃反应4小时。停止反应，用水和乙酸乙酯萃取，有机相用饱和碳酸氢钠溶液，饱和氯化铵溶液洗涤，加入无水硫酸钠干燥过夜，过滤，滤液减压浓缩后得白色固体，过硅胶柱层析，用石油醚－丙酮(6:1)洗脱，得无色针状晶体0.65g，产率92％。1H NMR(DMSO-d6)δppm:7.25(d,J＝8.2Hz,2H),6.98(d,J＝8.2Hz,2H),6.11(s,1H),6.00(s,1H),5.92(d,J＝11.6Hz,1H),5.50(s,1H),4.79(s,1H),3.92(s,3H),3.82(dd,J＝10.4,8.0Hz,1H),3.5～3.7(m,2H),3.43～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.5～2.7(m,3H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.62(s,3H),1.42～1.62(m,3H),1.32(s,3H),1.23(d,J＝11.6Hz,1H),1.11(s,6H)；MS-EI m/z(％):528.3(M+1,100).
实施例7：化合物7的制备
在25ml圆底烧瓶中，加入100mg(0.24mmol)化合物1和0.5ml吡啶，搅拌下滴加0.3ml乙酸酐，回流4小时后，加入2ml 5％稀盐酸溶液，反应0.5小时。停止反应，用水和乙酸乙酯萃取，有机相用饱和碳酸氢钠溶液，饱和氯化铵溶液洗涤，加入无水硫酸钠干燥过夜，过滤，滤液减压浓缩后得白色固体，过硅胶柱层析，用石油醚－丙酮(6:1)洗脱，得无色针状晶体56.4mg，产率50.1％。1H NMR(DMSO-d6)δppm:6.15(s,1H),6.09(d,J＝10.4Hz,1H),5.83(s,1H),4.33,4.09(d,J＝11.2Hz,1H),3.78(dd,J＝10.4,3.8Hz,1H),3.49～3.51(m,1H),3.21(d,J＝9.9Hz,1H),2.48(m,2H),2.28(m,1H)2.26(s,6H),2.05(s,3H)，1.12(s,6H)；MS-EI m/z(％):452(M+1,100).
实施例8：化合物8的制备
在25ml圆底烧瓶中，加入100.0mg(0.24mmol)化合物1，15.0ml二氯甲烷和0.2ml三乙胺，搅拌下加入0.3g对甲苯磺酰氯，0℃反应4小时后，加入少量水淬灭反应，用水和乙酸乙酯萃取，有机相用饱和碳酸氢钠溶液，饱和氯化铵溶液洗涤，加入无水硫酸钠干燥过夜，过滤，滤液减压浓缩后得白色固体，用石油醚－丙酮重结晶得无色针状晶体129.5mg，产率92.1％。1H NMR(DMSO-d6)δppm:7.75(d,J＝8.2Hz,2H),7.46(d,J＝8.2Hz,2H),6.15(s,1H),6.09(d,J＝10.4Hz,1H),5.82(s,1H),4.33,4.09(d,J＝11.2Hz,1H),3.76(dd,J＝10.4,3.8Hz,1H),3.49～3.51(m,1H),3.23(d,1H,J＝9.9Hz),2.48(m,2H),2.34(s,3H),2.28(m,1H)2.26(s,6H),1.10(s,6H)；MS-EI m/z(％):452(M+1,100).
实施例9：化合物9的制备
在50ml圆底烧瓶中加入100.0mg(0.24mmol)化合物1，15ml丙酮，0℃搅拌下缓慢滴加0.5ml Jone's试剂，室温反应2小时后，加入0.2ml异丙醇，反应0.5小时，加入0.5g碳酸氢钠，反应0.5小时，加入15ml乙酸乙酯稀释，过滤，滤液减压浓缩后得白色固体，用石油醚－丙酮重结晶得无色针状晶体64.3mg，产率63.2％。1H NMR(DMSO-d6)δppm:6.12(s,1H),5.91(d,J＝11.6Hz,1H),5.53(s,1H),4.77(s,1H),3.87(dd,J＝10.4,8.0Hz,1H),3.51～3.72(m,3H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.52～2.74(m,3H),2.26(m,8H),1.67～1.83(m,3H),1.42～1.62(m,3H),1.23(d,J＝11.6Hz,1H),1.13(s,6H)；MS-EI m/z(％):408(M+1,100).
实施例10：化合物10的制备
在50ml圆底烧瓶中加入100.0mg(0.23mmol)化合物2，15ml丙酮，0℃搅拌下缓慢滴加0.5ml Jone's试剂，室温反应2小时后，加入0.2ml异丙醇，反应0.5小时，加入0.5g碳酸氢钠，反应1小时，加入15ml乙酸乙酯稀释，过滤，滤液减压浓缩后得白色固体，用石油醚－丙酮重结晶得无色针状晶体58.03mg，产率58.3％。1H NMR(DMSO-d6)δppm:6.10(s,1H),5.90(d,J＝11.6Hz,1H),5.47(s,1H),4.75(s,1H),3.83(dd,J＝10.4,8.0Hz,1H),3.52～3.73(m,3H),3.42～3.46(m,1H),3.06(d,J＝9.2Hz,1H),2.55～2.71(m,5H),2.40(q,J＝8.4Hz,4H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.40～1.62(m,3H),1.33(t,J＝8.4Hz,6H),1.23(d,J＝11.6Hz,1H),1.13(s,6H)；MS-EI m/z(％):436(M+1,100).
实施例11：化合物11的制备
将100mg(0.25mmol)化合物8加入10mL丙酮中，加入0.3mL(2.5mmol)二甲氧基丙烷、8.6mg(0.05mmol)对甲基苯磺酸,加热回流反应1.5h。加入0.5mol/L碳酸钠溶液,氯仿提取，干燥，蒸干有机层得粗产物，乙酸乙酯-石油醚重结晶，得白色固体80.8mg，收率72.3％。1HNMR(DMSO-d6)δppm:6.14(s,1H),5.91(d,J＝11.6Hz,1H),5.45(s,1H),4.76(s,1H),3.82(dd,J＝10.4,8.0Hz,1H),3.51～3.70(m,2H),3.43～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.53～2.74(m,3H),2.28(m,8H),1.67～1.83(m,3H),1.62(s,3H),1.42～1.62(m,3H),1.32(s,3H),1.23(d,J＝11.6Hz,1H),1.10(s,6H)；MS-EI m/z(％):448(M+1,100).
实施例12：化合物12的制备
将100mg(0.23mmol)化合物10加入10mL丙酮中，加入0.3mL(2.5mmol)二甲氧基丙烷、8.6mg(0.05mmol)对甲基苯磺酸，加热回流反应1.5h。加入0.5mol/L碳酸钠溶液，氯仿提取，干燥，蒸干有机层得粗产物，乙酸乙酯-石油醚重结晶，得白色固体82.6mg，收率75.6％。1HNMR(DMSO-d6)δppm:6.13(s,1H),5.90(d,J＝11.6Hz,1H),5.44(s,1H),4.79(s,1H),3.87(dd,J＝10.4,8.0Hz,1H),3.52～3.73(m,2H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.55～2.71(m,3H),2.40(q,J＝8.4Hz,4H),2.36(s,6H)，1.90～2.00(m,2H),1.67～1.83(m,3H),1.40～1.62(m,3H),1.33(t,J＝8.4Hz,6H),1.23(d,J＝11.6Hz,1H),1.11(s,6H)；MS-EI m/z(％):476(M+1,100)。
实施例13：化合物13的制备
在50ml圆底烧瓶中，加入100mg(0.24mmol)化合物1，10ml CH3CN和10ml DMF，氩气保护下，-10℃下滴加0.3ml CCl4，搅拌10min后，滴入0.3ml DIPEA和3mg DMAP。5min后，缓慢滴加0.5ml P(H)(O)(OBn)2。-10℃反应4h后，加入0.5mol/L的KH2PO4溶液10ml终止反应，反应液用乙酸乙酯萃取，有机相用无水硫酸钠干燥过夜，过滤，滤液减压浓缩后得白色固体，过硅胶柱层析，用石油醚－丙酮(4:1)洗脱，得白色固体144.7mg，产率90.1％。1H NMR(DMSO-d6)δppm:7.26～7.36(m,10H),6.14(s,1H),5.90(d,J＝11.6Hz,1H),5.55(s,1H),5.13(d,J＝7.88Hz,4H),4.79(s,1H),3.87(dd,J＝10.4,8.0Hz,1H),3.52～3.74(m,2H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.51～2.71(m,3H),2.26(s,6H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.42～1.62(m,3H),1.23(d,J＝11.6Hz,1H),1.11(s,6H)；MS-EI m/z(％):670(M+1,100).
实施例14：化合物14的制备
将化合物12(140mg)溶于10ml二氯甲烷中，氩气保护下，0℃下滴加0.3ml TMSBr，搅拌1h后，减压蒸馏除去溶剂，丙酮/水重结晶，得白色固体95.2mg，产率93.0％。1H NMR(DMSO-d6)δppm:6.18(s,1H),5.94(d,J＝11.6Hz,1H),5.50(s,1H),4.79(s,1H),3.83(dd,J＝10.4,8.0Hz,1H),3.52～3.74(m,4H),3.44～3.48(m,1H),3.06(d,J＝9.2Hz,1H),2.51～2.71(m,3H),2.26(s,6H),1.90～2.00(m,2H),1.67～1.83(m,3H),1.42～1.62(m,3H),1.23(d,J＝11.6Hz,1H),1.11(s,6H)；MS-EI m/z(％):490(M+1,100).
实施例15：化合物1盐酸盐的制备：
将100mg化合物1溶于5ml乙醚中，通入氯化氢气体，有白色固体析出，抽滤固体，乙醚洗涤，干燥，得化合物1的盐酸盐107.5mg,产率98.5％。HPLC纯度：99.7％。
实验实施例1
根据本发明的冬凌草甲素衍生物抗肿瘤活性测试
细胞采用人肺癌细胞A549，乳腺癌细胞MCF-7，人肝癌细胞BEL7402，宫颈癌细胞Hela。
四种细胞分别经过消化、计数分别制成5×104个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔5×103个细胞)，置于37℃，5％CO2培养箱中培养24小时，用培养基稀释药物至所需浓度(浓度为10μmol/L),每孔加入100μL含药培养基，同时设阴性对照组和阳性对照组。96孔板置于37℃，5％CO2培养箱中培养72小时。然后，每孔加入20μL MTT(5mg/mL)染色，继续培养4小时，弃去培养基，每孔加入150μLDMSO溶解，λ＝490nm测OD值，计算IC50值，见表1。
表1：根据本发明的冬凌草甲素衍生物的抗肿瘤活性测试数据
实验实施例2
水溶解度的测定：采用HPLC方法测定化合物的水溶解度
色谱柱:Diamonsil C 18(250mm×4.6mm，5μm)，流动相：甲醇-水(体积比为55∶45)，检测波长:238nm，流速：1.0mL·min-1，柱温：40℃。
将过量的冬凌草甲素及其衍生物加入10mL具塞玻璃试管中,分别加入2mL水、不同pH值的磷酸盐缓冲液，于25℃摇床振摇72h，离心，取上清液用甲醇适当稀释后取20μL注入高效液相色谱仪，记录峰面积，代入标准曲线计算冬凌草甲素及其衍生物在各种溶剂中的平衡溶解度，见表2。
表2：冬凌草甲素及其衍生物的水溶解度
实验实施例3
红斑狼疮治疗效果实验
雌性MRL/lpr小鼠根据初始蛋白尿及体重随机分成5组：模型组(ddH2O，n＝11)；醋酸泼尼松(Prednisone，PNS)阳性对照组(2mg/kg，n＝10)；化合物15高剂量组(5mg/kg，n＝11)；化合物15中剂量组(2.5mg/kg，n＝11)；化合物15低剂量组(1.25mg/kg，n＝11)。9周龄开始，一天2次口服给药，至27周龄。给药期间每周记录小鼠生存率(见附图1)。实验证明化合物15可以有效提高小鼠的生存率。
Claims (18)
1.一类由以下通式(1)表示的冬凌草甲素衍生物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐：
其中，所述取代基R1和R2各自独立为氢、C1–6直链或支链烷基；或者取代基R1和R2通过连接基团彼此连接形成四元至八元含有1至3个选自N、O或S的杂原子的杂环基；
取代基R3为羰基或羟基；
取代基R4和R5各自独立地选自羟基、羰基、磺酸酯基、由含有1至3个C1–4烷基的苯基取代的磺酸酯基、磷酸酯基、由1至3个苯基取代的C1–4烷基取代的磷酸酯基；或者取代基R4和R5通过-(CR6R7)n-彼此连接，其中n为1或2的正整数；取代基R6和R7各自独立地选自甲基、乙基、正丙基、异丙基、环丙基。
2.根据权利要求1所述的由通式(1)表示的冬凌草甲素衍生物，其特征在于，取代基R1和R2各自独立为氢、C1–3直链或支链烷基。
3.根据权利要求1所述的由通式(1)表示的冬凌草甲素衍生物，其特征在于，取代基R1和R2各自独立为氢、甲基、乙基、丙基、异丙基。
4.根据权利要求1所述的由通式(1)表示的冬凌草甲素衍生物，其特征在于，取代基R1和R2各自独立为甲基、乙基或丙基。
5.一类冬凌草甲素衍生物，其特征在于，所述冬凌草甲素衍生物、其对映异构体、非对映异构体、外消旋体及其混合物、以及其药学上可接受的盐，选自以下化合物中：
6.根据权利要求1至4中任意一项所述的由通式(1)表示的冬凌草甲素衍生物，其特征在于，所述通式(1)表示的冬凌草甲素衍生物的药学上可接受的盐为所述通式(1)表示的冬凌草甲素衍生物与有机酸或无机酸形成的药学上可接受的盐，所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸，以及所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸；或者通式(1)表示的冬凌草甲素衍生物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式(1)表示的冬凌草甲素衍生物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐；或者通式(1)表示的冬凌草甲素衍生物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸和乙磺酸形成的对应的有机酸盐。
7.一种根据权利要求1至4中任意一项所述的由通式(1)表示的冬凌草甲素衍生物的制备方法，所述制备方法的反应式如下并包括以下步骤：
1)用氮气置换反应器中气氛三次，将通式(2)的化合物和催化剂加入反应器中，然后加入适量溶剂，搅拌使通式(2)的化合物溶解，其中通式(2)的化合物可以根据现有技术的制备方法得到；
将反应物烷基胺HNR1R2溶解于适量溶剂中，然后滴加入反应器中，同时将温度升高至20至50℃，反应3至6小时，得到通式(3)表示的产物；
待反应完成后，将反应体系冷却至室温，然后通过减压蒸馏除去溶剂，然后通过高效制备液相色谱法分离产品通式(3)表示的化合物；
2)用氮气置换反应器中气氛三次，将通式(3)的化合物和相应的反应物按照摩尔比1:1至1:3的比例加入反应器中，然后加入适量溶剂，加热回流反应0.5h至3h，冷却至室温，加入碱性溶液，氯仿提取，干燥，蒸干有机层得粗产物，乙酸乙酯-石油醚重结晶，得到产品通式(1)表示的化合物。
8.根据权利要求7所述的制备方法，其特征在于，步骤1)中所述催化剂选自氢氧化钠、甲醇钠、乙醇钠、叔丁醇钾、三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯(DBU)、碳酸铯、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的任意一种或多种；所述催化剂的用量为通式(2)的化合物重量的5wt％至10wt％。
9.根据权利要求7所述的制备方法，其特征在于，所述催化剂的用量为通式(2)的化合物重量的6wt％至8wt％。
10.根据权利要求7所述的制备方法，其特征在于，所述反应物烷基胺HNR1R2中的取代基R1和R2与权利要求1中通式(1)中的定义相同。
11.根据权利要求7所述的制备方法，其特征在于，所述通式(2)的化合物中的取代基R3与权利要求1中通式(1)中的定义相同。
12.根据权利要求7所述的制备方法，其特征在于，所述反应物烷基胺HNR1R2与通式(2)的化合物的摩尔比为1:1至20:1。
13.根据权利要求12所述的制备方法，其特征在于，所述反应物烷基胺HNR1R2与通式(2)的化合物的摩尔比为2:1至15:1。
14.根据权利要求13所述的制备方法，其特征在于，所述反应物烷基胺HNR1R2与通式(2)的化合物的摩尔比为5:1至8:1。
15.根据权利要求7所述的制备方法，其特征在于，所述溶剂选自醇、酮、醚或酯中的一种或几种；所述醇选自甲醇、乙醇、异丙醇、叔丁醇中的一种或几种；所述酮选自丙酮、甲乙酮中的一种或几种；所述醚选自乙醚、二氧六环、异丙醚、甲基叔丁基醚、四氢呋喃中的一种或几种；并且所述酯选自乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸丁酯中的一种或几种。
16.根据权利要求7所述的制备方法，其特征在于，步骤2)中所述碱性溶液为碳酸氢钠溶液、碳酸钠溶液或碳酸钾溶液。
17.一种根据权利要求1至5中任意一项所述冬凌草甲素衍生物、其对映异构体、非对映异构体、外消旋体及其混合物、以及其药学上可接受的盐在制备抗肿瘤药物或自身免疫性疾病药物中的用途，
所述肿瘤为肺癌、子宫癌、肝癌、乳腺癌，所述自身免疫性疾病为系统性红斑狼疮、银屑病。
18.一种药物组合物，其特征在于，所述药物组合物包括治疗有效量的根据权利要求1至5中任意一项所述冬凌草甲素衍生物、其对映异构体、非对映异构体、外消旋体及其混合物、以及其药学上可接受的盐和至少一种赋形剂、稀释剂或载剂。
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