CN106496169A - 土木香内酯衍生物及其盐 - Google Patents
土木香内酯衍生物及其盐 Download PDFInfo
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- CN106496169A CN106496169A CN201610880931.4A CN201610880931A CN106496169A CN 106496169 A CN106496169 A CN 106496169A CN 201610880931 A CN201610880931 A CN 201610880931A CN 106496169 A CN106496169 A CN 106496169A
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- Prior art keywords
- acid
- compound
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- alantolactone
- derivant
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- PXOYOCNNSUAQNS-AGNJHWRGSA-N alantolactone Chemical compound C1[C@H]2OC(=O)C(=C)[C@H]2C=C2[C@@H](C)CCC[C@@]21C PXOYOCNNSUAQNS-AGNJHWRGSA-N 0.000 title claims description 21
- 241001597008 Nomeidae Species 0.000 title claims 10
- PXOYOCNNSUAQNS-UHFFFAOYSA-N alantolactone Natural products C1C2OC(=O)C(=C)C2C=C2C(C)CCCC21C PXOYOCNNSUAQNS-UHFFFAOYSA-N 0.000 title claims 10
- 150000003839 salts Chemical class 0.000 title abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 13
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 9
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims abstract description 6
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001530 fumaric acid Substances 0.000 claims abstract description 5
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims abstract description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims abstract description 4
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 3
- 239000004471 Glycine Substances 0.000 claims abstract description 3
- 239000005639 Lauric acid Substances 0.000 claims abstract description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 3
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 3
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- 239000011976 maleic acid Substances 0.000 claims abstract description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 3
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims abstract description 3
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims abstract description 3
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- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
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- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
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- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 7
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- NYYAUGSBUVAOHW-UHFFFAOYSA-N 2-methyl-1h-pyrrole;pyridine Chemical compound CC1=CC=CN1.C1=CC=NC=C1 NYYAUGSBUVAOHW-UHFFFAOYSA-N 0.000 claims 1
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Abstract
土木香内酯衍生物及其盐，提供了如一种如式(I)所示的土木香内酯衍生物；成盐的酸为无机酸或有机酸，所述的无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸，硼酸、亚硒酸、磷钼酸、亚磷酸、亚硫酸，所述有机酸选自柠檬酸、马来酸、D‑苹果酸、L‑苹果酸、DL‑苹果酸、L‑乳酸、D‑乳酸、DL‑酸、草酸、甲磺酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1‑萘磺酸、2‑萘磺酸、酞酸、酒石酸、丙二酸、丁二酸、富马酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、苯甲酸或取代苯甲酸。
Description
技术领域：
本发明属于涉及土木香内酯衍生物及其盐及其应用与制剂。
背景技术：
土木香(Inula helenium)为菊科(Compositae)旋覆花属植物，多年生草本，根供药用。有健脾和胃、调气解郁、止痛安胎功能，用于胸胁、脘腹胀痛，呕吐泻痢，胸胁挫伤，岔气作痛，胎动不安等症。土木香挥发油中含有土木香内酯、异土木香内酯等成分，其化学结构与山道年类似，对猪、犬、猫均有驱虫作用，其疗效较山道年优，且毒性较低。
土木香内酯(CAS：546-43-0，)属于倍半萜类化合物，亦是土木香药材中含量较高的主要有效成分。其结构如下所示近年来研究发现土木香中的倍半萜-土木香内酯类成分有抗肿瘤细胞增值的作用和抗结核分支杆菌等新作用。分别在1999年和2002年，Charles和Konishi等人在对土木香内酯类化合物的药理作用进行研究后，提出α-亚甲基-γ-内酯可能是该类化合物抗肿瘤细胞增值和抗结核分支杆菌的必须功能基团。但由于土木香内酯的水溶性较差，难于以常规给药途径作用于人体，且经过进一步实验发现土木香内酯的毒性较大。
中国专利CN2009100742161公开了一种异土木香内酯衍生物及其盐，并公开了将异土木香内酯的13位亚甲基改造成为胺基，使其具有较好的水溶性，口服生物利用度较高，在抗肿瘤活性方面，其药效较原化合物更高，毒性更小。但该文献仅公开了对肿瘤细胞进行体外抑瘤实验的数据，在动物实验中我们发现，该化合物的口服毒性较大，难于真正应用于临床，且本身水溶性并不理想，在进行毒性实验和动物体内抑瘤实验时的效果均不令人满意，没有临床应用的价值。因此在现有技术基础上，对土木香内酯进行结构改造，并提供一种新的土木香内酯衍生物以显著提高其用于癌症等疾病治疗时的效果，并降低其细胞毒性，并通过将该衍生物制备成为作为前体药物的衍生物盐，克服原药水溶性差，半衰期短，生物利用度低等缺点，成为现有技术中亟待解决的问题。
发明内容
为解决前述问题，本发明提供了一种土木香内酯衍生物及其盐，含有作为活性成分的土木香内酯衍生物盐及至少一种可药用载体的治疗癌症药物组合物，以及式(I)土木香内酯衍生物盐在制备治疗癌症药物中的应用。
为了实现本发明的上述目的，本发明提供如下的技术方案：
提供了一种如式(I)所示的土木香内酯衍生物，
式(I)中，其中Y为氧或单键；
R1和R2可以相同或不同，分别为氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；R1、R2和N原子形成环状结构，环优选为3-9元环，环状结构上可以被一个或多个取代基取代，包括氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基。其中R1和R2优选为氢或C1-C6的烷基或环烷基。更优选R1和R2均为甲基。
本发明还提供了一种如式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐，所述的无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸，硼酸、亚硒酸、磷钼酸、亚磷酸、亚硫酸，所述有机酸选自柠檬酸、马来酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-酸、草酸、甲磺酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、酒石酸、丙二酸、丁二酸、富马酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、苯甲酸或取代苯甲酸。优选为式(I)所述土木香内酯衍生物的富马酸盐。更优选为式(II)或式(III)化合物
本发明还提供了如式(I)所述土木香内酯衍生物及其无机酸盐或有机酸盐在制备治疗癌症药物中的应用。所述式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐为式(II)化合物或式(III)化合物
本发明还提供了如式(I)所述土木香内酯衍生物及其无机酸盐或有机酸盐在制备抗炎药物中的应用；所述式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐为为式(II)化合物或式(III)化合物。
本发明还提供了如式(I)所述土木香内酯衍生物及其无机酸盐或有机酸盐在制备治疗甲状腺炎药物中的应用；所述式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐为式(II)化合物或式(III)化合物。
本发明还提供了如式(I)所述土木香内酯衍生物及其无机酸盐或有机酸盐在制备治疗炎症性肠病药物中的应用；所述式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐为式(II)化合物或式(III)化合物。所述炎症性肠病为溃疡性结肠炎或克罗恩病。
本发明还提供了如式(I)所述土木香内酯衍生物及其无机酸盐或有机酸盐在制备治疗肺纤维化药物中的应用；所述式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐为式(II)化合物或式(III)化合物。
本发明还提供了一种药物组合物，其特征是含有作为活性成分的至少一种式(II)化合物或式(III)化合物和至少一种可药用的辅料的至少一种化合物和至少一种可药用的辅料。
本发明通过土木香内酯进行结构改造，提供了新型土木香内酯衍生物及其无机酸盐或有机酸盐，在药理实验中我们发现，本发明提供的新型土木香内酯衍生物及其盐，在具有较高体外抗癌活性的基础上，在荷瘤小鼠的抑瘤实验中表现出了优异的性能。尤其是本发明优选的化合物(I-II)、化合物(I-III)及作为其前体药物的化合物(II)、化合物(II)，不但具有较高的抑瘤率，更重要的是大幅度的提高了实验动物的生存期。从而可以在制备抗癌药物中得到应用。同时在其他动物实验中本发明提供的土木香内酯衍生物及其盐还表现出对肺纤维化及炎症性肠病、甲状腺炎等自身免疫性炎症疾病的良好效果。
具体实施方式
为了理解本发明，下面以实施例进一步说明本发明，但不意于限制本发明的保护范围。
实施例1：
化合物(II)的制备
1)化合物(I-II)的制备
土木香内酯(300.0mg,1.29mmol)溶解在二氯甲烷(50mL)中，依次向上述混合体系中加入二甲胺盐酸盐(1.6g,19.4mmol)和碳酸钾(5.2g,37.4mmol)，体系加热回流反应3小时，过滤除去固体，滤液用水洗，干燥浓缩，柱层析纯化(石油醚：乙酸乙酯＝1:1)得到化合物(I-II)(白色固体，236.0g，产率：50％)。
2)化合物(II)的制备，将步骤1)得到化合物(I-II)(200.0mg,0.72mmol)溶解在甲醇(7mL)中，向上述混合体系中加入富马酸(86.7mg,0.74mmol)，搅拌反应0.5小时，旋除溶剂，加乙酸乙酯溶解，过滤得化合物(II)(白色固体，246.4mg，产率：87.3％)
元素分析测定化合物(II)分子式：C21H31NO6
HMR数据：1HNMR(400MHz,CDCl3):δ6.69(s,2H),5.25(d,J＝2.8Hz,1H),3.56(dd,J＝14.7,6.9Hz,1H),3.41(dd,J＝13.4,6.4Hz,1H),3.33–3.27(m,3H),2.91(s,6H),2.60–2.50(m,1H),2.12(dd,J＝15.0,3.3Hz,1H),1.90–1.77(m,1H),1.66–1.55(m,4H),1.44(m,1H),1.22(d,J＝8.8Hz,3H),1.17(t,J＝6.0Hz,4H)；13C NMR(100MHz,CDCl3)δ180.6,173.7,156.2,138.7,117.8,82.0,58.0,46.8,46.0,45.9,45.7,42.6,41.8,36.7,36.5,31.7,25.8,20.4.
实施例2：
化合物(III)的制备
1)化合物(I-III)的制备
土木香内酯(2.0g,8.6mmol)溶解在二氯甲烷(10mL)中，向上述体系中缓慢滴加过氧苯甲酸(2.1g,10.3mmol)的二氯甲烷(20mL)溶液，室温下反应3小时，饱和硫代硫酸钠水溶液淬灭反应，有机层用饱和碳酸氢钠水溶液洗涤(20mL×3)，干燥浓缩，柱层析纯化(石油醚：乙酸乙酯＝5：2)得化合物(I-III)(白色固体，2.0g，收率94％)
2)化合物(III)的制备
将上步得到的化合物(I-III)(300.0mg,1.29mmol)溶解在二氯甲烷(50mL)中，依次向上述混合体系中加入二甲胺盐酸盐(1.6g,19.4mmol)和碳酸钾(5.2g,37.4mmol)，体系加热回流反应3小时，过滤除去固体，滤液用水洗，干燥浓缩，得到的粗品溶解在甲醇(7mL)中，向上述混合体系中加入富马酸(130.1mg,1.11mmol)，搅拌反应0.5小时，旋除溶剂，加乙酸乙酯溶解，过滤得化合物(III)(白色固体，369.6mg，产率：87.3％)
元素分析测定化合物(III)分子式：C22H35NO7
NMR谱图数据：1HNMR(400MHz,CDCl3):δ6.26(s,2H),4.59–4.53(m,1H),3.06(dd,J＝14.7,6.9Hz,1H),2.64(t,J＝12.5Hz,1H),2.46(d,J＝4.3Hz,1H),2.28(s,6H),2.60–2.50(m,1H),2.12(dd,J＝15.0,3.3Hz,1H),1.90–1.77(m,1H),1.66–1.55(m,4H),1.09–1.01(m,4H),0.89(d,J＝8.8Hz,3H),0.88(s,3H)；13C NMR(100MHz,DMSO)δ177.0,167.6,135.0,75.4,67.6,57.1,56.3,45.0,38.9,38.0,37.9,35.7,34.5,32.0,29.8,24.1,17.8,16.6.
实施例3：
土木香内酯衍生物盐的体外癌细胞抑制作用
采用四甲基偶氮唑蓝(MTT)比色法检测土木香内酯衍生物盐对癌细胞的抑制作用。
MTT比色法实验步骤：将处于对数生长期的癌细胞按照每毫升5×104细胞数的密度接种至96孔细胞培养板中，调零孔为不含细胞的正常培养基。12小时后更换含不同浓度梯度土木香内酯衍生物的培养基，调零孔更换正常培养基，每个浓度梯度设置5个复孔，置于37℃，5％CO2培养箱中培养。24小时后显微镜下观察细胞状态及生长变化。48小时后每孔加入四甲基偶氮唑蓝(凯基生物，5mg/mL)溶液,继续在37℃，5％CO2培养箱中培养，4小时后吸走培养基，每孔加入DMSO 100μL，使用酶标仪在570纳米波长下测量吸光度值，使用Graphpad软件进行数据统计分析，计算半数有效浓度(IC50，单位：μM)。抑制效果见表1。
表1土木香内酯衍生物盐对各种癌细胞的抑制活性(IC50)
其中，MDA-MB-231、B16、Hela、A375、A549、Panc1、PLC、HepG2、MHCC-97H、C6、U937、Hep2、HCT-116、MGC-803、sk-ov-3分别表示人乳腺癌细胞、小鼠黑色素瘤细胞、人宫颈癌细胞、人肺癌细胞、人胰腺癌细胞、人肝癌细胞、人高转移肝癌细胞、大鼠胶质瘤细胞、淋巴瘤细胞、人喉癌细胞、人结肠癌细胞、人胃癌细胞、人卵巢癌细胞。
通过表1可知：所筛选的化合物对受试细胞均有一定的抑制作用。
药理实施例1：土木香内酯衍生物及其盐的肿瘤抑制和延长动物生存期作用
试验对象：本试验选用动物品系为C57BL/6小鼠，雌性，18～22g，SPF级别。
试验接种内容：LLC实体瘤。使用肿瘤二次移植法，将实体肿瘤切分成小块，逐一接种到小鼠背部腋下处。待种瘤部位观察到明显瘤体后重新分组，保证瘤体大小以及体重均匀分布于各组之中，造模成功后的荷瘤小鼠分为模型对照组及实验组1～6，每组20只小鼠，其中模型对照组每天给予0.1mL生理盐水，实验组1为阳性对照组，以环磷酰胺为阳性对照药，剂量为20mg/kg。实验组2～6中各化合物的给药剂量为150mg/kg,均采用灌胃给药治疗，化合物(IV)分子式为化合物(IV)的制备方法如中国专利申请CN2009100742161中所述，具体分组与给药情况见表2。每天测定小鼠肿瘤的直径,计算小鼠的肿瘤体积，每天称量小鼠的体重。
连续给药两周。两周后每组处死10只小鼠并剥离肿瘤。解剖后称量肿瘤重量，计算抑瘤率(means肿瘤，n＝10)。然后将剩余小鼠饲养至全部死亡，计算其平均生存期(means饲养，n＝10)。
抑瘤率抑瘤率＝(对照组平均肿瘤质量-实验组动物肿瘤质量)/对照组平均肿瘤质量×量照组％
表2土木香内酯衍生物盐对肿瘤的抑制作用
通过表2可知：与模型对照组(生理盐水组)相比，化合物(I-II)、化合物(I-III)、化合物(II)和化合物(III)组均对肿瘤有抑制作用，且均能够显著提高荷瘤小鼠的生存期，其中化合物(II)和化合物(III)因成盐后水溶性和生物利用度更高，其抑瘤效果和延长荷瘤小鼠生存期的效果更为明显。而化合物(IV)没有明显的抑瘤和延长荷瘤小鼠生存期的效果。
药理实施例2：对溃疡性炎性肠病急性期动物模型的治疗
1.实验方法
本试验选用动物品系为C57BL/6小鼠，雌性，18～22g，SPF级别，每组10只。实验采用3％DSS(葡聚糖硫酸钠)诱导溃疡性炎性肠病急性期模型。在适应期时，给予小鼠自由进食和饮水，实验开始即将饮用水换成3％的DSS溶液(正常对照组除外)，给小鼠自由饮用。每只小鼠日饮水量按6mL计算，次日再补充足量DSS溶液，DSS溶液共给予8天。初次给予DSS24h后，将出现软便、腹泻或血便现象的小鼠作为造模成功动物并随即对小鼠进行灌胃给药，正常对照组以及模型对照组小鼠每天给予0.1mL双蒸水，阳性对照组小鼠每天给予0.1mL柳氮磺胺吡啶(SASP，300mg/kg)，待测药品组每天给药0.1mL(50mg/kg)。给药7天后颈椎脱臼法处死小鼠。
给药期间，每天观察小鼠的一般生活状态，粪便性状及腹泻和血便情况，拍照记录，每天称量小鼠体重。并于给药完成后进行DAI(疾病活动指数)评分，评分标准如下表
处死小鼠后，解剖并剖取结直肠并测量长度，沿肠系膜方向将结直肠纵向剪开，生理盐水清洗粪便，用10％中性福尔马林溶液进行固定。取严重溃疡处作病理检查，依次进行脱水、石蜡包埋、切片、苏木素-伊红染色，显微镜下观察组织病变情况并进行评分。组织病变评分(HI)标准见下表(将两个指标的得分相加即为组织病变评分)
土木香内酯衍生物及其盐对DSS诱导的溃疡性炎性肠病急性期治疗效果情况见下表3(means±s，n＝10)
通过表3可知：化合物(II)对DSS诱导的溃疡性炎性肠病急性期的影响比较显著，有一定的治愈效果，与模型组相比具有显著差异性。化合物(III)、化合物(I-II)和化合物(I-III)对溃疡性炎性肠病有一定的缓解作用。
药理实施例3：对高碘水诱导的桥本甲状腺炎疾病模型动物的治疗
1.实验方法
选用SPF级昆明种雌性小鼠，体重28-32g，采用高碘水(0.64g碘化钠溶于1L自来水)。将猪甲状腺球蛋白100mg溶解于灭菌双蒸水50mL中(2mg/mL)，取10mL与等体积完全弗氏佐剂充分混合成油包水状。皮肤消毒后，取0.1mL(100μg)给模型组组小鼠进行皮下多点(足趾皮下、背部皮下、腹部皮下、颈部皮下)注射作为初次免疫。实验第12天,取猪甲状腺球蛋白10mL(2mg/mL)与不完全弗氏佐剂10mL充分混合成油包水状后，取0.1mL(100μg)给模型组小鼠多点皮下注射进行加强免疫，再间隔12天进行一次免疫后进行建模评价。建模成功后将高碘水撤去，给以正常水饮用。
小鼠建模成功后开始给药治疗(给药前称重)，将造模成功的实验动物随机分组，每组10只，另取10只正常小鼠作空白组，分组与给药情况见下表：
2.实验结果
给药结束后，分别测量各组实验动物的体重，并监测实验动物血液中TPOAb(抗甲状腺过氧化物酶抗体)及TGAb(甲状腺球蛋白抗体)含量的变化
监测结果见下表
| 实验分组 | 体重(g) | TGAb(ng/L) | TGAb(IU/ml) |
| 空白组 | 28.6±1.40 | 31.7±10.8 | 34.2±7.4 |
| 模型组 | 19.9±1.99 | 80.7±17.9 | 65.5±24.8 |
| 地塞米松组 | 27.4±1.67 | 39.7±11.0 | 42.4±8.5 |
| 化合物(II)组 | 25.1±2.11 | 54.2±8.7 | 59.6±10.6 |
| 化合物(III)组 | 27.3±1.57 | 41.3±8.2 | 48.1±7.6 |
| 化合物(I-II)组 | 23.5±1.98 | 46.6±7.2 | 60.6±9.4 |
| 化合物(I-III)组 | 24.7±1.68 | 45.1±6.2 | 53.9±8.0 |
给药结束后，与空白组相比，模型组小鼠体重显著降低；而化合物(II)、化合物(III)、化合物(I-II)和化合物(I-III)组的体重增长情况均好于模型组，表明化合物(II)及化合物(III)能明显改善小鼠体重情况。与空白组相比，模型组小鼠TPOAb及TGAb显著升高，分别为空白组小鼠的255％、192％，而化合物(II)组TPOAb及TGAb分别为空白组的171％、174％，化合物(III)组的TPOAb及TGAb分别为空白组的130％、141％，与模型组相比小鼠的TPOAb及TGAb均显著降低。化合物(I-II)和化合物(I-III)组的小鼠的TPOAb及TGAb与模型组相比也有所降低。
以上结果表明化合物(II)、化合物(III)、化合物(I-II)和化合物(I-III)均对桥本甲状腺炎具有一定得治疗作用。
药理实施例4：对百草枯诱导小鼠肺纤维化模型的治疗
1.实验方法
随机将70只小鼠分为2组，空白组10只，建模组60只，雌雄各半。建模组小鼠在建模前禁食16h，灌胃给予剂量100mg/Kg百草枯溶液，空白组用同体积生理盐水灌胃，建模当天记为第1天。
第7天(根据预实验对建模时间的探索结果，小鼠建模7天出现肺纤维化症状。)将建模组的60只小鼠随机分为6组，分别为：模型组10只、阳性药地塞米松组10只、化合物(II)组、化合物(III)组、化合物(I-II)组、化合物(I-III)组(每组10只)，雌雄各半。第8天小鼠给药治疗(给药前称重)，化合物(II)、化合物(III)、化合物(I-II)及化合物(I-III)按一定剂量灌胃给药治疗；阳性药地塞米松组按0.45mg/Kg剂量灌胃给药治疗，空白组及模型组小鼠按体重灌胃给予相应体积的生理盐水。每天上、下午各观察一次小鼠的一般状态，每天称重并给药一次，给药时间为28天。
2.实验结果
实验结束后，检测各组实验小鼠的体重、肺系数、羟脯氨酸及胶原含量，实验结果见下表(means±s，n＝10)
2.1体重监测结果：给药结束后，与空白组相比，模型组小鼠体重显著降低；而化合物(II)、化合物(III)、化合物(I-II)及化合物(I-III)体重增长情况均好于模型组，表明化合物(II)、化合物(III)、化合物(I-II)及化合物(I-III)均能改善小鼠体重情况，其中化合物(II)、化合物(III)效果更为明显。
2.2肺系数影响：与空白组相比，模型组小鼠肺系数显著升高，为空白组小鼠肺系数的124％，化合物(II)及化合物(II)组的小鼠肺系数分别为空白组小鼠肺系数的104％、102％，与模型组相比小鼠肺系数均显著减小。以上结果表明化合物(II)及化合物(III)可降低百草枯诱导肺纤维化小鼠的肺系数，能显著改善肺纤维化状态，化合物(I-II)及化合物(I-III)也能够一定程度上降低肺系数，改善肺纤维化状态。
2.3羟脯氨酸及胶原含量影响：与空白组相比，模型组小鼠肺组织羟脯氨酸及胶原百分比明显升高，羟脯氨酸及胶原含量均为空白组小鼠的131％。化合物(II)组小鼠的肺组织羟脯氨酸及胶原百分含量为空白组小组的117％，化合物(III)组小鼠的肺组织羟脯氨酸及胶原百分含量均为空白组小组的111％，与模型组比，化合物(II)、化合物(III)化合物(I-II)及化合物(I-III)的肺组织羟脯氨酸及胶原百分含量均显著降低。实验结果表明化合物(II)、化合物(III)化合物(I-II)及化合物(I-III)可降低百草枯诱导肺纤维化小鼠的羟脯氨酸及胶原百分含量。
综上所述：化合物(II)、化合物(III)、化合物(I-II)及化合物(I-III)均能改善肺纤维化小鼠肺部的胶原沉积，对肺纤维化有一定得治疗效果，有望开发为治疗肺纤维化的药物。
Claims (10)
1.一种如式(I)所示的土木香内酯衍生物，
式(I)中，其中Y为氧或单键；
R1和R2可以相同或不同，分别为氢、烷基、环烷基、羟基取代烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基、杂环基、三氟甲基、多氟取代烷基、腈基、腈基甲基、酰基、氨基甲酰基、磺酰基、磺酰胺基或芳氧烷基；R1、R2和N原子形成环状结构，环优选为3-9元环，环状结构上可以被一个或多个取代基取代，包括氢、烷基、环烷基、烯基、炔基、芳基、烷基芳基、芳基烷基、芳基烯基、芳基炔基或杂环基。
2.如权利要求1所述的土木香内酯衍生物，其特征是R1和R2为氢或C1-C6的烷基或环烷基。
3.如权利要求2所述的土木香内酯衍生物，其特征是R1和R2均为甲基。
4.如权利要求1～3任一所述的土木香内酯衍生物的无机酸盐或有机酸盐，其特征是所述的无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸，硼酸、亚硒酸、磷钼酸、亚磷酸、亚硫酸，所述有机酸选自柠檬酸、马来酸、D-苹果酸、L-苹果酸、DL-苹果酸、L-乳酸、D-乳酸、DL-酸、草酸、甲磺酸、戊酸、油酸、月桂酸、对甲基苯磺酸、1-萘磺酸、2-萘磺酸、酞酸、酒石酸、丙二酸、丁二酸、富马酸、乙醇酸、硫醇酸、甘氨酸、肌氨酸、磺酸、烟酸、甲基吡啶酸、异烟酸、苯甲酸或取代苯甲酸。
5.如权利要求4所述的土木香内酯衍生物的无机酸盐或有机酸盐，其特征是无机酸盐或有机酸盐为富马酸盐，
6.如权利要求4所述的土木香内酯衍生物的无机酸盐或有机酸盐，其特征是所述土木香内酯衍生物的无机酸盐或有机酸盐为式(II)或式(III)化合物。
7.如权利要求1～3任一所述的土木香内酯衍生物在制备治疗癌症药物中的应用。
8.如权利要求4～6任一所述的土木香内酯衍生物的无机酸盐或有机酸盐在制备治疗癌症药物中的应用。
9.如权利要求8所述的应用，其特征为所述式(I)所述土木香内酯衍生物的无机酸盐或有机酸盐为式(II)化合物或式(III)化合物。
10.一种药物组合物，其特征是含有作为活性成分的至少一种式(II)化合物或式(III)化合物和至少一种可药用的辅料。
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