CN102558270A - 20(S) and 20(R)-dammarane-3beta,12beta,20,25-tetrol derivative and preparation method and application thereof - Google Patents

20(S) and 20(R)-dammarane-3beta,12beta,20,25-tetrol derivative and preparation method and application thereof Download PDF

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CN102558270A
CN102558270A CN2012100610338A CN201210061033A CN102558270A CN 102558270 A CN102558270 A CN 102558270A CN 2012100610338 A CN2012100610338 A CN 2012100610338A CN 201210061033 A CN201210061033 A CN 201210061033A CN 102558270 A CN102558270 A CN 102558270A
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dammarane
salts
derivatives
tetrol
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孙宝山
王朋
赵余庆
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辽宁新中现代医药有限公司
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The invention belongs to the field of medicine, and relates to a 20(S) and 20(R)-dammarane-3beta,12beta,20,25-tetrol derivative with anti-tumor activity and a preparation method and application thereof. The derivative has a structural formula (I) shown in the specifications, wherein R1 and R2 are mono-substituted or bis-substituted or can be substituted simultaneously; and R1 and R2 are acylation substituted amino acid, amino protected amino acid and oligopeptide, amino protected oligopeptide and polypeptide, amino protected polypeptide, or a base pair which forms deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), and a derivative of the base pair. The anti-tumor activity of the derivative and salt thereof is higher than that of 20(S) and 20(R)-protopanaxadiol, the activity of other anti-tumor medicines can be more obviously enhanced, and the toxic and side effects of the medicines are reduced.

Description

OH20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐的通式(I)320 (S)和20 (R)-达玛烷-3 β ' 12 β ' 20' 25-四醇衍生物及其制备方法和应用[0001] 技术领域:本发明属于医药技术领域,提供具有抗肿瘤活性的20(s)和20 (R)-达玛烧-3 β,12 β,20,25-四醇衍生物及其制备方法和应用,还涉及该化合物及以该化合物作为活性成分的组合物在抗肿瘤方面的用途。 OH20 (S) and 20 (R) - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts of formula (I) 320 (S) and 20 (R) - Dammarane -3 β '12 β' 20 '25- tetrol derivatives and their preparation and application [0001] technical field: the present invention belongs to the field of medical technology, there is provided having anti-tumor activity of 20 (s) and 20 (R) - dammar burning -3 β, 12 β, 20,25- tetrol derivatives and their preparation and use, and to the use of said compounds and to the compounds as active ingredients in antitumor compositions terms. [0002] 背景技术:20 (R)-达玛烷-3β,12Β, 20,25-四醇[20 (R) - 25-0H-PPD]具有较强的抗癌活性,能抑制人肿瘤细胞(人乳腺癌、人小细胞肺癌、人胃癌、人结肠癌、人神经胶质癌、人黑色素瘤、人宫颈癌、人肝癌、早幼粒白血病、肉瘤S-180、肝癌腹水型、小鼠宫颈癌-14及艾氏腹水癌等) 生长与增殖,诱导肿瘤细胞分化、凋亡,抑制肿瘤新生血管生成、抑制肿瘤的浸润和转移、±曾强机体免疫力和降低化疗药物毒副作用等抗肿瘤活性。 [0002] BACKGROUND: 20 (R) - Dammarane -3β, 12Β, 20,25- tetraol [20 (R) - 25-0H-PPD] has stronger anti-cancer activity, can inhibit human tumor cells (human breast cancer, human small cell lung carcinoma, human gastric cancer, human colon cancer, human glial carcinoma, human melanoma, human cervical carcinoma, human hepatocellular carcinoma, promyelocytic leukemia, sarcoma S-180, ascites hepatoma, mouse cervical and -14) growth and proliferation Ehrlich ascites carcinoma, induce tumor cell differentiation and apoptosis, inhibiting angiogenesis, inhibiting tumor invasion and metastasis, ± had strong immunity and reduce side effects of chemotherapy and other anti tumor activity. 比目前在国内广泛用于抗癌药物的人参皂苷衍生物收3对肿瘤的生长抑制活性高5-15倍。 Ratio of ginsenoside derivatives are widely used in the domestic yield of three pairs of anti-cancer drugs to tumor growth inhibition activity 5-15 times higher. 25-0H-PPD还能以剂量依存的方式诱导肺癌细胞系H838 (p53野生型)和H358 (p53缺失型)的凋亡和抑制细胞增殖,并能使细胞周期阻滞在Gl期,不同浓度的该化合物均显示出比其他人参皂苷更强的活性。 25-0H-PPD in a dose-dependent manner but also human lung cancer cell lines H838 (p53 wild type) and H358 (p53 deletion type) inhibition of cell proliferation and apoptosis, and cell cycle arrest in Gl can of different concentrations this compound showed a stronger activity than other ginsenosides. 此外,25-0H-PPD (在50μΜ和ΙΟΟμΜ时)有效降低前列腺癌细胞系LNCaP (ρ53野生型)和PC3 (Ρ53缺失型)的存活率,但不影响成纤维细胞;该化合物还能诱导这两种细胞的凋亡,抑制细胞的增殖,并使细胞周期阻滞在Gl期。 Further, 25-0H-PPD (at 50μΜ and ΙΟΟμΜ) reduce prostate cancer cell line LNCaP (ρ53 wild type) and PC3 (Ρ53 deletion) survival, but not fibroblasts; the compound which can induce the two cell apoptosis, inhibit cell proliferation, and cell cycle arrest in Gl phase. 在25-0H-PPD处理过的LNCaP和PC3细胞中,抑癌基因ρ21、ρ27和Bax的表达提高,而原癌基因MDM2、Bcl2、E2Fl、cdk2、CDK4和Cyclin Dl 的表达均降低。 25-0H-PPD in treated LNCaP and PC3 cells, tumor suppressor genes ρ21, ρ27, and increased expression of Bax, and proto-oncogene MDM2, expression of Bcl2, E2Fl, cdk2, CDK4 and Cyclin Dl were lower. 25-0H-PPD具有较强的抗癌生物活性,但是存在水溶性差、生物利用度低等不足,严重影响了临床上的应用。 25-0H-PPD has a strong anti-cancer biological activity, but there is poor water solubility, low bioavailability inadequate, seriously affecting the clinical applications. 氨基酸、肽类化合物、基因碱基等对细胞及核酸具有良好的亲和性,将其引入到药物分子中,有利于药物到达细胞组织内而有效地发挥作用。 Amino acid, peptide compounds, and the like having the nucleotide cells and nucleic good affinity, which is incorporated into the molecule drugs, favor the drug to reach the tissue to function effectively. 本专利通过对其结构进行修饰,以克服上述缺点,发现高效、低毒的新化合物实体。 This patent is modified by its structure, in order to overcome the above disadvantages, found that efficient, low toxicity of new chemical entities. [0003] 发明内容:本发明提供具有抗肿瘤活性的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其制备方法。 [0003] Disclosure of the Invention: The present invention provides anti-tumor activity of 20 (S) and 20 (R) - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and their preparation. [0004] 本发明提供的通式(I)的20⑶和20 (R)-达玛烷_3 β,12 β,20,25-四醇衍生物及其盐:其中,RU R2可为单取代、双取代,或同时取代;Rl、R2可为酰化取代的氨基酸、氨基保护的氨基酸、寡肽、多肽,或是组成DNA、RNA的碱基对及其衍生物等。 [0004] The present invention provides general formula (I), 20⑶ and 20 (R) - Dammarane _3 β, 12 β, 20,25- tetrol derivatives and salts thereof: wherein, RU R2 may be mono-substituted , disubstituted, or simultaneously substituted; Rl, R2 may be a substituted amino acylated amino, protected amino, oligopeptide, polypeptide, or the composition of the DNA, RNA, base pairs and their derivatives. [0005] 本发明提供的通式(I)的20⑶和20 (R)-达玛烷_3 β,12 β,20,25-四醇衍生物及其盐,其中:所述的盐为钾盐、钠盐、铵盐、镁盐、钙盐或盐酸盐。 [0005] The present invention provides general formula (I), 20⑶ and 20 (R) - Dammarane _3 β, 12 β, 20,25- tetrol derivatives and salts thereof, wherein: the salt is potassium salt, sodium, ammonium, magnesium, calcium, or hydrochloride salt. [0006] 本发明提供的20 (S)和20 (R)-达玛烷_3 β,12 β,20,25-四醇衍生物及其盐中: 所述的氨基酸是20种蛋白质氨基酸,包括;丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、谷氨酸等;所述的碱基对包括腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶、胸腺嘧啶及其衍生物等; 所述的氨基酸的构型为D型和L型; 所述寡肽是2〜20个氨基酸残基通过肽键连接形成的肽; 所述多肽由20个以上的氨基酸残基组成的肽。 [0006] The present invention provides 20 (S) and 20 (R) - Dammarane _3 β, 12 β, 20,25- tetrol derivative or its salt: 20 amino acids of the proteins of amino acids, comprising; alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine, cysteine, tyrosine, days asparagine, glutamine, lysine, arginine, histidine, aspartate, glutamate and the like; the base pairs adenine, guanine, cytosine, uracil, thymine and derivatives thereof; configuration of the amino acid is D and L forms; 2~20 said oligopeptide is a peptide of amino acid residues joined by peptide bonds formed; the polypeptide consists of more than 20 amino acid residues the group consisting of a peptide. [0007] 所述的保护基是叔丁氧羰基(Boc-)、苄氧羰基(CBz-)、芴甲氧羰基(Fmoc-)等。 Said protective group [0007] is tert-butoxycarbonyl group (Boc-), benzyloxycarbonyl (CBz-), fluorenyl methoxy carbonyl (Fmoc-) and the like. [0008] 其中Rl、R2可单取代、也可双取代。 [0008] wherein Rl, R2 can be monosubstituted, disubstituted also. [0009] 本发明的式(I)化合物可按如下方法制备:20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物是相应的氨基酸、寡肽和多肽在催化作用下与20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇进行酰化反应、脱保护反应而制得。 [0009] Preparation of a method according to the invention a compound of formula (I) can be: 20 (S) and 20 (R) - Dammarane -3 β, 12 β, 20,25- tetrol derivatives are the corresponding amino acid, oligopeptides and polypeptides with 20 (S) and 20 (R) under the catalysis - acylation dammarane -3 β, 12 β, 20,25- tetraol, prepared deprotection reaction. 反应的溶剂可以是四氢呋喃、二甲基甲酰胺、苯、甲苯、二氯甲烷、二甲基亚砜等, 反应温度可以是0-1500C,可用的脱水剂可为二环己基碳二亚胺(DCC)、1- (3- 二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)等,可用的催化剂可为4-二甲氨基吡啶(DMAP)U-羟基苯并三唑(HOBT)、三乙胺等,可用脱保护方法有三氟乙酸(TFA)、硅胶催化、溶液法等。 The reaction solvent may be tetrahydrofuran, dimethylformamide, benzene, toluene, methylene chloride, dimethyl sulfoxide and the like, the reaction temperature may be 0-1500C, usable dehydrating agents may be dicyclohexyl carbodiimide ( DCC), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and the like, may be used as a catalyst 4-dimethylaminopyridine (DMAP) U- hydroxybenzotriazole triazole (HOBT), triethylamine, etc., the deprotection method can be used with a trifluoroacetic acid (TFA), catalytic silica gel, solution and the like. [0010] 合成路线I :4 [0010] Scheme I: 4

Figure CN102558270AD00051

各氨基酸(b)可为丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、谷氨酸及其氨基保护的相应氨基酸,寡肽、多肽等衍生物。 Each amino acid (b) may be alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine, cysteine, derivatives of tyrosine, asparagine, glutamine, lysine, arginine, histidine, corresponding amino acid aspartic acid, glutamic acid and protected amino, oligopeptides, polypeptides and the like. [0011] 合成路线II: [0011] Scheme II:

Figure CN102558270AD00061

所述的碱基对(Ml)包括腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶、胸腺嘧啶及其衍生物,如氟尿嘧啶、尿嘧啶氮芥等。 The base pairs (of Ml) including adenine, guanine, cytosine, uracil, thymine and derivatives thereof, such as fluorouracil, uracil mustard and the like. [0012] 20 (S)和20 (R)-达玛烷_3 β,12 β,20,25-四醇二元羧酸及无机酸衍生物的盐是用相应的氢氧化物的水溶液调ΡΗ,然后用有机溶剂沉淀而得。 [0012] 20 (S) and 20 (R) - Dammarane _3 β, salt 12 β, 20,25- tetrol dicarboxylic acid and an inorganic acid derivative with the corresponding hydroxide aqueous solution was ΡΗ, then precipitate was obtained by using an organic solvent. 例如用氢氧化钠,氨水调ρΗ 至中性,然后用丙酮沉淀,得相应的盐。 For example with sodium hydroxide, aqueous ammonia ρΗ to neutral, then precipitated with acetone, to give the corresponding salt. [0013] 本发明结构通式(I)是通过对20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇进行修饰,引入一些新的基团,特别是引入含有水溶性极性基团如含胺基取代的氨基酸衍生物,将提高衍生物的溶解度和生物利用度,并增强该类化合物的抗肿瘤活性。 [0013] structural formula (I) of the present invention is obtained by 20 (S) and 20 (R) - Dammarane -3 β, 12 β, 20,25- tetraol be modified to introduce some new group, particular into a water-soluble polar groups such substituted amino acid derivative containing an amine, to increase solubility and bioavailability of the derivatives, and to enhance the antitumor activity of such compounds. [0014] 在本发明提供了结构通式(I)化合物在制备抗肿瘤药物制剂中的应用。 [0014] Providing the general formula (I) use of a compound in the preparation of anti-tumor drugs in the formulations of the present invention. [0015] 本发明提供了含有上述20(¾和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐的药物,将上述衍生物及其盐与常规的药用辅剂混合而制成制剂。所述制剂可为颗粒剂、胶囊剂、片剂、注射剂、输液或栓剂。本发明的药物可用于治疗肿瘤。[0016] 结构通式(I)所述的化合物可用于治疗各种肿瘤的生长和转移,肿瘤主要包括有: 肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道癌、乳房癌、前列腺癌、睾丸癌、结肠癌、 卵巢癌、膀胱癌、子宫颈癌、黑色素癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊状腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、威尔姆斯癌、胶质细胞癌、星形细胞癌、成神经管细胞癌、颅咽管癌、室管膜瘤、松果体瘤、成血细胞瘤 [0015] The present invention provides the above 20 (¾ and 20 (R) comprising - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and pharmaceutically acceptable salts of the above-mentioned derivatives and salts thereof and conventional pharmaceutical adjuvants and formulated. the formulation may be a granule, a capsule, tablet, injection, infusion or suppositories. medicaments of the invention may be used to treat tumors. [0016] structural formula (I) the compounds useful in the treatment of various tumors growth and metastasis, tumors mainly include: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, stomach cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, bladder cancer, cystic carcinoma , medullary carcinoma, bronchogenic carcinoma, osteocyte carcinoma, epithelial carcinoma, bile duct carcinoma, choriocarcinoma, embryo carcinoma, seminoma, Wilms cancer, glial cell carcinoma, carcinoma astrocytoma, medulloblastoma carcinoma, carcinoma craniopharyngioma, ependymoma, pinealoma, tumor cells into blood 声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、 绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、股纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、 Vocal cord neuroma, meningioma, neuroblastoma, optic nerve cells into the tumor, neurofibroma, fibrosarcoma, fibroblasts, fibroma, fibroadenoma, chondroma, fibrous sac tumor, fibrous myxoma, bone fibers tumors, myxosarcoma fibers, fiber papilloma, myxosarcoma, bursal tumor, osteochondroma mucus, mucous chondrosarcoma, fibrosarcoma mucous cartilage, mucus adenoma, mucous cells into tumors, liposarcoma, lipoma, adenoma fat, adipogenic cell tumor, osteochondroma fat, fat fibroma, hemangioma fat, mucous lipoma, chondrosarcoma, chondroma, chondrosarcoma fibroids, chordoma, chorionic adenoma, villous epithelial tumor, choriocarcinoma cell tumor, osteosarcoma tumor, bone tumor, osteochondroma fibroma, chondrosarcoma, osteochondroma, bone cysts, bone dentin tumor, fibrous tumors, shares fibrosarcoma, angiosarcoma, hemangioma, lipoma, vascular chondroma , hemangioblastoma, horny vascular tumors, vascular glioma, hemangioendothelioma, angiofibroma, vascular fibroids, angiolipoma, vascular lymphangioma, 管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、 淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、 横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、 红细胞增多症、淋巴瘤、多发性骨髓瘤。[0017] 本发明提供的含有达玛烷-3112120,25-四醇衍生物及其盐不仅比达玛烷-3 β,12 β,20,25-四醇具有更强的抗病毒、抗癌活性,同时还可更明显的增强其它抗病毒、抗癌药物的活性和降低这些药物毒性。 Fat pipe leiomyoma, angiomyolipoma, vascular muscle neuroma, angiomyxoma, vascular tumors reticuloendothelial, lymphatic sarcoma, lymphatic granulomas, lymphangioma, lymphoma, lymphoid myxoma, lymphosarcoma, lymphatic fibroma, lymphoma, lymphoid neoplasia, lymphoblastoma, endothelial tumor, tumor endothelial cells, synovioma, synovial sarcoma, mesothelioma, connective tissue tumors, Ewing's tumor, leiomyoma, leiomyosarcoma , as leiomyoma, fibroma, rhabdomyosarcoma, rhabdomyosarcoma, myxoma rhabdomyosarcoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic cells, polycythemia vera, lymphoma, multiple myeloma. [0017] The present invention provides -3112120,25- tetraol containing derivatives and salts thereof not only Bi Dama dammarane alkoxy -3 β, 12 β, 20,25- tetraol having a stronger antiviral, anticancer activity, but can also more other significantly enhanced anti-viral, anti-cancer activity of these drugs and reduce toxicity. [0018] 本发明的主要优点在于,在天然产物20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇的3位或12位引入含有氨基酸、寡肽、多肽和各种碱基基团,合成衍生物,增强抗肿瘤活性。 [0018] The main advantage of the present invention is that, in the natural product 20 (S) and 20 (R) - Dammarane -3 β, 12 β, 3 or 12 20,25- tetraol containing amino acid is introduced, the oligonucleotide peptides, polypeptides and various alkali radicals, synthetic derivatives, enhance the anti-tumor activity. [0019] 在天然产物20 (S)和20 (R)-达玛烷_3β,12β,20,25-四醇3位或12位引入含有药学上可接受的与碱或酸中和形成的盐,合成的衍生物提高了水溶性。 [0019] Natural Products 20 (S) and 20 (R) - Dammarane _3β, 12β, 20,25- tetrol 3 or 12 is introduced is formed with pharmaceutically acceptable bases or acids are contained and derivative salt, water-soluble synthetic improved. [0020] 附图说明:图1为3 β -N-叔丁氧羰基-L-丙氨酰基-达玛烷-12 β,20,25-三醇核磁共振氢谱; 图2为3 β -N-叔丁氧羰基-L-丙氨酰基-达玛烷-12 β,20,25-三醇核磁共振碳谱; 图3为3 β -L-丙氨酰基-达玛烷-12 β,20,25-三醇核磁共振氢谱; 图4为3 β -L-丙氨酰基-达玛烷-12 β,20,25-三醇核磁共振碳谱; 图5为3 β -N-叔丁氧羰基-硝基-L-精氨酰基-达玛烷-12 β,20,25-三醇核磁共振氢谱;图6为3 β -N-叔丁氧羰基-硝基-L-精氨酰基-达玛烷-12 β,20,25-三醇核磁共振碳谱;图7为3 β -L-甘氨酰基-达玛烷-12 β,20,25-三醇核磁共振氢谱; 图8为3 β -L-甘氨酰基-达玛烷-12 β,20,25-三醇核磁共振碳谱; 图9为化合物l-3、25-0H-PPD对MCF-7细胞系的抑制率; 图10为化合物l-3、25-0H-PPD对A549细胞系的抑制率; 图11为化合物l-3、25-0H-PPD对Lovo细胞系的抑制率。 [0020] BRIEF DESCRIPTION OF DRAWINGS: FIG. 1 is a 3 β -N- tert-butoxycarbonyl group -L- alanyl - Dammarane -12 β, 20,25- triol H NMR; FIG. 2 is a 3 β - N- t-butoxycarbonyl -L-alanyl - dammarane -12 β, 20,25- triol C NMR; FIG. 3 is a 3 β -L- alanyl - dammarane -12 β, 20,25- triol H NMR; FIG. 4 is a 3 β -L- alanyl - dammarane -12 β, 20,25- triol C NMR; FIG. 5 is a 3 β -N- t butoxycarbonyl - nitro -L- arginyl - dammarane -12 β, 20,25- triol H NMR; FIG. 6 is a 3 β -N- tert-butoxycarbonyl group - nitro fine -L- aminoacyl - dammarane -12 β, 20,25- triol C NMR; FIG. 7 is a 3 β -L- glycyl - dammarane -12 β, 20,25- triol H NMR ; FIG. 8 is a 3 β -L- glycyl - dammarane -12 β, 20,25- triol C NMR; FIG. 9 is a l-3,25-0H-PPD compound of MCF-7 cell line inhibition rate; FIG. 10 is a l-3,25-0H-PPD compound inhibitory rate of A549 cell lines; FIG. 11 is a l-3,25-0H-PPD compound inhibitory rate of Lovo cell line. 具体实施方式[0021] 下面结合具体实施例,进一步阐述本发明。 DETAILED DESCRIPTION [0021] The following embodiments with reference to specific embodiments, further illustrate the present invention. 应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。 It should be understood that these embodiments are illustrative only and the present invention is not intended to limit the scope of the invention. 下列实施例中未注明具体条件的试验方法,通常按照常规条件或按照制造厂商所建议的条件。 Test Method no specific conditions in the examples below, are performed under routine conditions, or according to conditions recommended by the manufacturer. [0022] 制备实施例1制备3 β -N-叔丁氧羰基-L-丙氨酰基-达玛烷-12 β,20, 25-三醇称取0.3g达玛烷-3 β,12 β,20,25-四醇溶于15ml无水CH2Cl2中,加入DCC 0. 87g, BOC-L-甘氨酸DMAP 0. 03g,Boc-L-丙氨酸0. Mg,室温反应Mh。 [0022] Preparation Example 1 3 β -N- tert-butoxycarbonyl group -L- alanyl embodiment - Dammarane -12 β, 20, 25- triol weighed 0.3g Dammarane -3 β, 12 β , 20,25- four dissolved in 15ml of anhydrous CH2Cl2 was added DCC 0. 87g, BOC-L- glycine DMAP 0. 03g, Boc-L- alanine 0. Mg, room temperature Mh. 反应毕,过滤,取滤液减压回收试剂得总产物。 Completion of the reaction, was filtered, the filtrate under reduced pressure to give the overall product recovery agent. 总产物溶液30mL乙酸乙酯中,5%NaHC03萃取(20mLX 3),有机层用无水MgSO4干燥,过滤取滤液,减压回收试剂得粗品产物。 30mL total product solution in ethyl acetate, 5% NaHC03 and extracted (20mLX 3), the organic layer was dried over anhydrous MgSO4, filtered and the filtrate under reduced pressure to give crude product recovery agent. 经硅胶柱色谱,用石油醚:乙酸乙酯(1 : 1)洗脱,得到三个组分,其中组分3为3 β -N-叔丁氧羰基-L-丙氨酰基-达玛烷-12 β,20, 25-三醇(51. 5%)ο[0023] 3 β -N-叔丁氧羰基-L-丙氨酰基-达玛烷-12 β,20,25-三醇核磁数据(附图1、 2):1H-WRGSHz, C,D,N) : δ 4. 53 (1Η, Η-3), δ 3. 58 (1Η, td, Η-12), δ 2. 04 (3Η, s ; CH,),δ 1. 44 (3Η, s; CH3): δ 0. 91(3H, s;CH3),δ 1. 41 (6Η, s, 2 X CH3), δ 1. 11 (3Η, s, CH3), δ 0. 99 (3Η, s, CH3), δ 0. 88 (3Η, s ; CH3), δ 0. 85 (3Η, s ; CH3) ; 13C-NMR (CDCl3, 300MHz): δ 81. 8 (C-3), 71. 0 (C-12), 74. 1 (C—20), 70. 6 (C—25),51. 5 (C—17),155. 0 (N- C=O), 173. 0 (-C0-)。 Silica gel column chromatography, eluting with petroleum ether: ethyl acetate (1: 1) to give three fractions, wherein Component 3 is a 3 β -N- tert-butoxycarbonyl group -L- alanyl - Dammarane -12 β, 20, 25- triol (51. 5%) ο [0023] 3 β -N- tert-butoxycarbonyl group -L- alanyl - dammarane -12 β, 20,25- triol NMR data (figures 1, 2): 1H-WRGSHz, C, D, N): δ 4. 53 (1Η, Η-3), δ 3. 58 (1Η, td, Η-12), δ 2. 04 (3Η, s; CH,), δ 1. 44 (3Η, s; CH3): δ 0. 91 (3H, s; CH3), δ 1. 41 (6Η, s, 2 X CH3), δ 1. 11 (3Η, s, CH3), δ 0. 99 (3Η, s, CH3), δ 0. 88 (3Η, s; CH3), δ 0. 85 (3Η, s; CH3); 13C-NMR (CDCl3 , 300MHz):. δ 81. 8 (C-3), 71. 0 (C-12), 74. 1 (C-20), 70. 6 (C-25), 51 5 (C-17), 155. 0 (N- C = O), 173. 0 (-C0-). [0024] 制备实施例2制备3 β -L-丙氨酰基-达玛烷-12 β,20, 25-三醇称取3 β -N-叔丁氧羰基-L-丙氨酰基-达玛烷-12 β,20, 25-三醇0. Ig加至25mL圆底烧瓶中,加IOmL甲苯溶解,加入0. Ig硅胶,加热回流6小时,反应结束后冷却至室温,过滤,用甲醇清洗硅胶,将滤液蒸干后,得粗产物。 Take 3 β -N- t-butoxycarbonyl -L-alanyl Dammarane -12 β, 20, 25- triol said - - dharma Example [0024] Preparation 2 Preparation of 3 β -L- alanyl alkoxy -12 β, 20, 25- triol 0. Ig was added to a 25mL round bottom flask, add IOmL dissolved in toluene, 0. Ig of silica gel was added, refluxed for 6 hours. after the reaction was cooled to room temperature, filtered, washed with methanol after silica gel, and the filtrate was evaporated to dryness to give a crude product. 经硅胶柱色谱,用二氯甲烷:甲醇(25:1)洗脱,得到终产物:浅黄色粉末3 β -L-丙氨酰基-达玛烷-12 β,20, 25-三醇(57. 3%)。 Silica gel column chromatography, using dichloromethane: methanol (25: 1) to give the final product: pale yellow powder 3 β -L- alanyl - Dammarane -12 β, 20, 25- triol (57 . 3%). [0025] 3 β -L-丙氨酰基-达玛烷-12 β,20,25-三醇核磁数据(附图3、4):1H-NMR (75Hz, C5D5N) : δ 5. 75 (NH) , δ 4. 43 (1Η, Η-3), δ 3. 52(1Η, td, Η-12), δ 2. 09 (3Η, s; CH3), δ 1. 44 (3Η, s ; CH3), δ 1. 03 (3Η, s, CH3), δ 0. 93 (3Η, s, CH3), δ 0. 89 (3Η, s ; CH3), δ 0. 88 (3Η, s ; CH3), δ 0. 83 (3Η, s ; CH3) ; 13C-NMR (CDCl3, 300MHz): δ 80. 2 (C-3), 69. 7(C-12), 72.3(C_20), 69.0(025),51.1 (C—17), 22. 9(C-21), 44. 7 (C-22), 38. 8 (CI), 28. 1 (C-2), 38. 1 (C-4), 55. 1 (C-5), 18. 5 (C-6),40. 2 (C-8), 49. 7 (C-9), 37. 7(C-10), 32. 2(C-Il), 49. 5(C-13); 31. 2(C-15), 26. 7(C-16), 16. 3(C-18), 16. 8(C-19), 18.7 (C-23): 30. 0(C-26), 30. 2(C-27), 14. 1 (C-28), 15. 9 (C—29),17. 4 (C-30)35. 1 (C-7), 51. 8(C-14); 45. 6(C-24): 175. 4 (-C0-)。 [0025] 3 β -L- alanyl - Dammarane -12 β, 20,25- triol NMR data (figures 3,4): 1H-NMR (75Hz, C5D5N): δ 5. 75 (NH ), δ 4. 43 (1Η, Η-3), δ 3. 52 (1Η, td, Η-12), δ 2. 09 (3Η, s; CH3), δ 1. 44 (3Η, s; CH3 ), δ 1. 03 (3Η, s, CH3), δ 0. 93 (3Η, s, CH3), δ 0. 89 (3Η, s; CH3), δ 0. 88 (3Η, s; CH3), δ 0. 83 (3Η, s; CH3); 13C-NMR (CDCl3, 300MHz): δ 80. 2 (C-3), 69. 7 (C-12), 72.3 (C_20), 69.0 (025), 51.1 (C-17), 22. 9 (C-21), 44. 7 (C-22), 38. 8 (CI), 28. 1 (C-2), 38. 1 (C-4), 55. 1 (C-5), 18. 5 (C-6), 40. 2 (C-8), 49. 7 (C-9), 37. 7 (C-10), 32. 2 (C -Il), 49. 5 (C-13); 31. 2 (C-15), 26. 7 (C-16), 16. 3 (C-18), 16. 8 (C-19), 18.7 (C-23):. 30. 0 (C-26), 30. 2 (C-27), 14. 1 (C-28), 15. 9 (C-29), 17 4 (C-30) 35. 1 (C-7), 51. 8 (C-14); 45. 6 (C-24): 175. 4 (-C0-). [0026] 制备实施例3制备3 β -N-叔丁氧羰基-硝基-L-精氨酰基-达玛烷-12 β,20, 25-三醇称取0.3g 达玛烷-3 β,12 β,20,25-四醇溶于15ml 无水CH2Cl2,加入DCC 0. 87g,DMAP 0. 03g, Boc-NO2-L-精氨酸0.40g,室温反应Mh。 [0026] Preparation Example 3 Preparation of 3 β -N- tert-butoxycarbonyl group - nitro -L- arginyl - Dammarane -12 β, 20, 25- triol weighed 0.3g Dammarane -3 β , 12 β, 20,25- four dissolved in 15ml of anhydrous CH2Cl2, was added DCC 0. 87g, DMAP 0. 03g, Boc-NO2-L- arginine 0.40g, rt Mh. 反应毕,过滤,取滤液减压回收试剂得总产物。 Completion of the reaction, was filtered, the filtrate under reduced pressure to give the overall product recovery agent. 总产物溶液30mL乙酸乙酯中,5%NaHC03萃取(20mLX 3),有机层用无水MgSO4干燥, 过滤取滤液,减压回收试剂得粗品产物。 30mL total product solution in ethyl acetate, 5% NaHC03 and extracted (20mLX 3), the organic layer was dried over anhydrous MgSO4, filtered and the filtrate under reduced pressure to give crude product recovery agent. 经硅胶柱色谱,用石油醚:丙酮(1:1)洗脱,得到三个组分:组分3为3 β -N-叔丁氧羰基-硝基-L-精氨酰基-达玛烷-12 β,20, 25-三醇(63. 5%)ο[0027] 3 β -N-叔丁氧羰基-硝基-L-精氨酰基-达玛烷-12 β,20, 25-三醇核磁数据(附图5、6):1H-NMR (75Hz, C5D5N) : δ 4. 53 (1Η, Η-3) , δ 3. 58 (1Η, td, ; H-12), δ 4. 28 (1Η, CH-C0) ; 13C-NMR (CDCl3, 300MHz) : δ 82. 6 (C_3),71. O (C—12) ,74.2 (C-20),70. 6 (C-25),60. 3(NC-CO),155. O(N- C=O),172. 1(-CO-)。 Silica gel column chromatography, eluting with petroleum ether: acetone (1: 1) to give three fractions: component 3 of 3 β -N- tert-butoxycarbonyl group - nitro -L- arginyl - Dammarane -12 β, 20, 25- triol (63. 5%) ο [0027] 3 β -N- tert-butoxycarbonyl group - nitro -L- arginyl - dammarane -12 β, 20, 25- NMR data triol (figures 5,6): 1H-NMR (75Hz, C5D5N): δ 4. 53 (1Η, Η-3), δ 3. 58 (1Η, td,; H-12), δ 4 . 28 (1Η, CH-C0); 13C-NMR (CDCl3, 300MHz):.. δ 82. 6 (C_3), 71 O (C-12), 74.2 (C-20), 70 6 (C-25 ), 60. 3 (NC-CO), 155. O (NC = O), 172. 1 (-CO-). [0028] 制备实施例4制备3 β -N-叔丁氧羰基-D-甘氨酰基-达玛烷-12 β,20, 25-三醇称取0.3g达玛烷-3 β,12 β,20,25-四醇溶于15ml无水CH2C12,加入DCC 0. 87g, DMAP 0.03g,Boc-L-甘氨酸0.22g,室温反应Mh。 [0028] Preparation Example 4 Preparation of 3 β -N- tert-butoxycarbonyl group -D- glycyl - Dammarane -12 β, 20, 25- triol weighed 0.3g Dammarane -3 β, 12 β , 20,25- four dissolved in 15ml of anhydrous CH2C12, was added DCC 0. 87g, DMAP 0.03g, Boc-L- glycine 0.22g, rt Mh. 反应毕,过滤,取滤液减压回收试剂得总产物。 Completion of the reaction, was filtered, the filtrate under reduced pressure to give the overall product recovery agent. 总产物溶液30mL乙酸乙酯中,5%NaHC03萃取(20mLX 3),有机层用无水MgS04干燥, 过滤取滤液,减压回收试剂得粗品产物。 30mL total product solution in ethyl acetate, 5% NaHC03 and extracted (20mLX 3), the organic layer was dried over anhydrous MgS04, filtered and the filtrate under reduced pressure to give crude product recovery agent. 经硅胶柱色谱,用石油醚:乙酸乙酯(1:1)洗脱,得到三个组分,其中组分3为3 β -N-叔丁氧羰基-L-甘氨酰基-达玛烷-12 β,20,25-三醇(46. 5%) ο[0029] 3 β -N-叔丁氧羰基-L-甘氨酰基-达玛烷-12 β,20, 25-三醇核磁数据: 1H-WRGSHz, C5D5N) : δ 4. 56 (1Η, Η-3), δ 3. 61 (1Η, td;H_12), δ 2. 05 (3Η, s ; CH3),δ 1. 44 (3Η, s; CH3), δ 1. 43 (6Η, s, 2 X CH3), δ 1. 03 (3Η, s, CH3) ; 13C-NMR (CDCl3, 300ΜΗζ): δ 81. 8 (C—3),71. 0 (C—12) ,74.1 (C-20), 70. 6 (C-25), 155. 1 (N- C=O), 172. 9(-C0-)。 Silica gel column chromatography, eluting with petroleum ether: ethyl acetate (1: 1) to give three fractions, wherein Component 3 is a 3 β -N- -L- tert-butoxycarbonyl glycyl - Dammarane -12 β, 20,25- triol (46. 5%) ο [0029] 3 β -N- -L- tert-butoxycarbonyl glycyl - dammarane -12 β, 20, 25- triol NMR data: 1H-WRGSHz, C5D5N): δ 4. 56 (1Η, Η-3), δ 3. 61 (1Η, td; H_12), δ 2. 05 (3Η, s; CH3), δ 1. 44 ( 3Η, s; CH3), δ 1. 43 (6Η, s, 2 X CH3), δ 1. 03 (3Η, s, CH3); 13C-NMR (CDCl3, 300ΜΗζ): δ 81. 8 (C-3 ), 71. 0 (C-12), 74.1 (C-20), 70. 6 (C-25), 155. 1 (N- C = O), 172. 9 (-C0-). [0030] 制备实施例5制备3 β -D-甘氨酰基-达玛烷-12 β,20, 25-三醇称取3 β -N-叔丁氧羰基-D-甘氨酰基-达玛烷-12 β,20, 25-三醇0. Ig加至25mL圆底烧瓶中,加IOmL甲苯溶解,加入0. Ig硅胶,加热回流6小时,反应结束后冷却至室温,过滤,用甲醇清洗硅胶,将滤液蒸干后,得粗产物。 [0030] Preparation Example 5 3 β -D- prepared glycyl - Dammarane -12 β, 20, 25- triol weighed 3 β -N- tert-butoxycarbonyl group -D- glycyl - dharma alkoxy -12 β, 20, 25- triol 0. Ig was added to a 25mL round bottom flask, add IOmL dissolved in toluene, 0. Ig of silica gel was added, refluxed for 6 hours. after the reaction was cooled to room temperature, filtered, washed with methanol after silica gel, and the filtrate was evaporated to dryness to give a crude product. 经硅胶柱色谱,用二氯甲烷:甲醇(25:1)洗脱,得到终产物:浅黄色粉末3 β -L-丙氨酰基-达玛烷-12 β, 20, 25-三醇(52. 6. 3%)。 Silica gel column chromatography, using dichloromethane: methanol (25: 1) to give the final product: pale yellow powder 3 β -L- alanyl - Dammarane -12 β, 20, 25- triol (52 . 6.3%). [0031] 3 β -D-甘氨酰基-达玛烷-12 β,20, 25-三醇核磁共振谱数据:1H-NMR (75Hz, C5D5N) : δ 5. 75 (NH), δ 4. 45 (1Η, Η-3), δ 3. 52(1Η, Η-12), δ 2. 08 (3Η, s ; CH3),δ 0. 88 (3Η, s ; CH3), δ 0. 83 (3Η, s ; CH3) ; 13C-NMR (CDCl3, 300MHz): δ 80. 2 (C-3), 69. 7(C-12), 72. 3 (C-20), 69. 0 (C-25) ; 51. 5(C-17), 22. 9(C-21), 44. 1(C-22), 38. 6 (CI), 28. 1(C-2), 38. 1(C-4), 55. 1(C-5), 18. 5(C-6),40. 1(C-8), 49. 9 (C-9), 37. 2(C-IO), 32. 2(C-Il), 49. 5(C-13); 31. 5(C-15), 26. 7(C-16), 16. 3(C-18), 16. 8(C-19), 18.7 (C-23); 30. 0(C-26), 30. 2(C-27), 14. 1 (C-28), 15. 9 (C-29), 17.4(C_30):〖、12 β-N-叔丁氧羰35. 1 (C-7), 51. 8(C-14): 45. 6(C-24) 173. 9 (-C0-)。 [0031] 3 β -D- glycyl - Dammarane -12 β, 20, 25- triol NMR spectral data: 1H-NMR (75Hz, C5D5N): δ 5. 75 (NH), δ 4. 45 (1Η, Η-3), δ 3. 52 (1Η, Η-12), δ 2. 08 (3Η, s; CH3), δ 0. 88 (3Η, s; CH3), δ 0. 83 ( 3Η, s; CH3); 13C-NMR (CDCl3, 300MHz): δ 80. 2 (C-3), 69. 7 (C-12), 72. 3 (C-20), 69. 0 (C- 25); 51. 5 (C-17), 22. 9 (C-21), 44. 1 (C-22), 38. 6 (CI), 28. 1 (C-2), 38. 1 ( C-4), 55. 1 (C-5), 18. 5 (C-6), 40. 1 (C-8), 49. 9 (C-9), 37. 2 (C-IO), 32. 2 (C-Il), 49. 5 (C-13); 31. 5 (C-15), 26. 7 (C-16), 16. 3 (C-18), 16. 8 (C -19), 18.7 (C-23); 30. 0 (C-26), 30. 2 (C-27), 14. 1 (C-28), 15. 9 (C-29), 17.4 (C_30 ): 〖, 12 β-N- tert-butoxycarbonyl 35. 1 (C-7), 51. 8 (C-14): 45. 6 (C-24) 173. 9 (-C0-). [0032] 制备实施例6制备3 β -N-叔丁氧羰基-L-缬氨酸基-达玛烷-12 β,20, 25- _ 基-L-缬氨酰基-达玛烷-3 β,20, 25-三醇称取0.3g达玛烷-3 β,12 β,20,25-四醇溶于15ml无水CH2Cl2,加入DCC 0. 87g, BOC-L-甘氨酸DMAP 0.03g,Boc-L-缬氨酸0.27g,室温反应Mh。 Example [0032] Preparation 6 Preparation of 3 β -N- tert-butoxycarbonyl group -L- valine - Dammarane -12 β, 20, 25- _ group -L- valyl - Dammarane -3 β, 20, 25- triol weighed 0.3g dammarane -3 β, 12 β, 20,25- four dissolved in 15ml of anhydrous CH2Cl2, was added DCC 0. 87g, BOC-L- glycine DMAP 0.03g, boc-L- valine 0.27g, rt Mh. 反应毕,过滤,取滤液减压回收试剂得总产物。 Completion of the reaction, was filtered, the filtrate under reduced pressure to give the overall product recovery agent. 总产物溶液30mL乙酸乙酯中,5%NaHC03萃取(20mLX 3),有机层用无水MgSO4干燥,过滤取滤液,减压回收试剂得粗品产物。 30mL total product solution in ethyl acetate, 5% NaHC03 and extracted (20mLX 3), the organic layer was dried over anhydrous MgSO4, filtered and the filtrate under reduced pressure to give crude product recovery agent. 经硅胶柱色谱,用石油醚:乙酸乙酯(1 : 1)洗脱,得到三个组分,其中组分2为白色固体12 β -N-叔丁氧羰基-L-缬氨酰基-达玛烷-3 β,20, 25-三醇(22. 8%),组分3为3 β -N-叔丁氧羰基-L-缬氨酰基-达玛烷-12β,20, 25-三醇(58. 5%)。 Silica gel column chromatography, eluting with petroleum ether: ethyl acetate (1: 1) to give three fractions, wherein component 2 as a white solid 12 β -N- tert-butoxycarbonyl group -L- valyl - up Ma alkoxy -3 β, 20, 25- triol (22.8%), 3 β -N- component 3 is tert-butoxycarbonyl group -L- valyl - dammarane -12β, 20, 25- three alcohol (58.5%). [0033] 3 β -N-叔丁氧羰基-L-缬氨酰基-达玛烷-12 β,20, 25-三醇核磁数据: 1H-NMR (75Hz, C5D5N) : δ 5. 03 (NH), δ 4. 56 (1Η, H-3), δ 3. 59(1Η, ;Η-12),δ 0. 89 (3Η, s ; CH3), δ 0. 88 (3Η, s ; CH3), δ 0. 83 (3Η, s ; CH3) ; 13C-NMR (CDCl3, 300MHz): δ 82. 1 (C-3), 71.0 (C-12), 74.2 (C—20), 70. 7 (C—25),79. 6(CO), 155. 8(N- C=O), 172. 7 (-C0-)。 [0033] 3 β -N- tert-butoxycarbonyl group -L- valyl - Dammarane -12 β, 20, 25- triol NMR data: 1H-NMR (75Hz, C5D5N): δ 5. 03 (NH ), δ 4. 56 (1Η, H-3), δ 3. 59 (1Η,; Η-12), δ 0. 89 (3Η, s; CH3), δ 0. 88 (3Η, s; CH3) , δ 0. 83 (3Η, s; CH3); 13C-NMR (CDCl3, 300MHz): δ 82. 1 (C-3), 71.0 (C-12), 74.2 (C-20), 70. 7 ( C-25), 79. 6 (CO), 155. 8 (N- C = O), 172. 7 (-C0-). [0034] 12 β -N-叔丁氧羰基-L-缬氨酰基-达玛烷-12 β,20, 25-三醇核磁数据: 1H-NMR (75Hz, C5D5N) : δ 5. 34 (NH), δ 4. 56 (1Η, Η-3), δ 3. 47(1Η, ;Η-12),δ 0. 89 (3Η, s ; CH3), δ 0. 88 (3Η, s ; CH3), δ 0. 83 (3Η, s ; CH3) ; 13C-NMR (CDCl3, 300MHz): δ 78. 7 (C-3), 76. 6 (C-12), 73.7 (C—20), 71. 1 (C—25), 79. 6(CO), 155. 8(N- C=O), 172. 5 (-C0-)。 [0034] 12 β -N- tert-butoxycarbonyl group -L- valyl - Dammarane -12 β, 20, 25- triol NMR data: 1H-NMR (75Hz, C5D5N): δ 5. 34 (NH ), δ 4. 56 (1Η, Η-3), δ 3. 47 (1Η,; Η-12), δ 0. 89 (3Η, s; CH3), δ 0. 88 (3Η, s; CH3) , δ 0. 83 (3Η, s; CH3); 13C-NMR (CDCl3, 300MHz): δ 78. 7 (C-3), 76. 6 (C-12), 73.7 (C-20), 71. 1 (C-25), 79. 6 (CO), 155. 8 (N- C = O), 172. 5 (-C0-). [0035] 制备实施例7制备:5-氟尿嘧啶-1-基乙酸合成将5-氟尿嘧啶(5. 20g, 0. 04mol)溶于40mL0. 5mol/L的NaOH溶液中。 Preparation Example 7 [0035] Preparation: 5-Fluorouracil-1-yl acetic acid 5-fluorouracil (5. 20g, 0. 04mol) was dissolved 40mL0 5mol / L NaOH solution. 控制温度40-50°C,搅拌下缓慢滴加氯乙酸(5. 64g,0.06mol)溶液30mL,40分钟滴完。 Controlling the temperature of 40-50 ° C, was slowly added dropwise with stirring acid (5. 64g, 0.06mol) was 30mL, 40 minutes dropwise. 控制此温度下反应,薄层色谱跟踪反应,大约6小时5-FU原料反应完全。 Under control of the reaction temperature, the reaction was followed by thin layer chromatography, 5-FU for about 6 hours the reaction was complete feed. 将混合液冷却至室温,用盐酸调节PH至1-2,于冰箱中冷藏过夜。 The mixture was cooled to room temperature, adjusted PH to 1-2 with hydrochloric acid, in the refrigerator overnight. 过滤,沉淀物用冷水洗涤,烘干得化合物5-氟尿嘧啶-1-基乙酸(5-FUAA),收率拟%。 Filtered and the precipitate was washed with cold water, dried to give compound l-yl acetate, 5-fluorouracil (5-FUAA), Quasi% yield. [0036] 制备实施例8制备:20(1?)-3 0-5'-氟尿嘧啶-1,-基-乙酰基-达玛烷-12β,20,25-三醇的合成称取25-0H-PPD 0. 9g (1. 883mmol)加至50mLDMF 中,然后加入BOC-L-丙氨酸071g(3. 766mmol),振摇使溶解,于冰水浴中加入DCC 1. 164g(3. 766mmol)、 DMAP 0. 5g(4. 093mmol),室温反应Mh,过滤,滤液减压回收溶剂至干,干法上硅胶柱(2. OX 50cm)层析,以乙酸乙酯-甲醇(50:1洗脱),分离得到化合物4 ( 51%)。 [0036] Preparation Example 8 Preparation Example: 20 (1?) --3 0-5'- fluorouracil -1 - yl - acetyl - Dammarane -12β, 20,25- triol synthesized weighed 25-0H -PPD 0. 9g (1. 883mmol) was added to a 50mLDMF then added BOC-L- alanine 071g (3. 766mmol), shake to dissolve, in an ice-water bath was added DCC 1. 164g (3. 766mmol) , DMAP 0. 5g (. 4 093mmol), Mh room temperature, filtered and the filtrate under reduced pressure to recover the solvent to dryness, the dry silica gel column (2. OX 50cm) chromatographed with ethyl acetate - methanol (50: 1 wash off), compound 4 was isolated (51%). [0037] 20 (R)-3 β-5,-氟尿嘧啶_1,-基-乙酰基-达玛烷-12 β,20,25-三醇核磁数据(附图7、8) =1H-WR (75Hz, C5D5N) : δ 10. 02 (1Η, s), ^7. 3 (1H, s), δ 4. 58 (1Η, H-3), δ 3. 59(1Η; Η-12), δ 0. 89 (3Η, s ; CH3), δ 0. 88 (3Η, s ; CH3), δ 0. 83 (3Η, s ; CH3); 13C-NMR (CDCl3, 300ΜΗζ): δ 83.6 (C-3), 71. 1 (C-12), 74. 3 (C—20), 70. 5 (C—25), δ 166. 8(C=O)、δ 149. 6(C=O)、δ 157. 5(C=O)。 [0037] 20 (R) -3 β-5, - _1 fluorouracil, - group - acetyl - Dammarane -12 β, 20,25- triol NMR data (figures 7,8) = 1H-WR . (75Hz, C5D5N): δ 10. 02 (1Η, s), ^ 7 3 (1H, s), δ 4. 58 (1Η, H-3), δ 3. 59 (1Η; Η-12), δ 0. 89 (3Η, s; CH3), δ 0. 88 (3Η, s; CH3), δ 0. 83 (3Η, s; CH3); 13C-NMR (CDCl3, 300ΜΗζ): δ 83.6 (C- 3), 71. 1 (C-12), 74. 3 (C-20), 70. 5 (C-25), δ 166. 8 (C = O), δ 149. 6 (C = O), δ 157. 5 (C = O). [0038] 活性测试达玛烷-3 β,12 β,20,25-四醇衍生物抗肿瘤活性测试采用经典的MTT法进行抗肿瘤活性测试,对我们合成的达玛烷-3 β,12 β,20,25-四醇衍生物和对照化合物氟尿嘧啶(5-Fu),如人乳腺癌细胞MCF-7,人肺癌细胞A549,人结肠癌细胞Lovo,人子宫颈癌细胞株HeLa、大肠癌HCT116、脑胶质瘤U87、人大肠癌HD9等多数衍生物具有广谱抗肿瘤作用,并确定了IC5tl值。 [0038] Activity testing Dammarane -3 β, 12 β, 20,25- tetraol derivative Antitumor Activity Test method classic MTT test anti-tumor activity, our synthetic Dammarane -3 β, 12 β, 20,25- tetrol derivative and control compound fluorouracil (5-Fu), such as human breast cancer cell line MCF-7, human lung cancer cells A549, human colon cancer cells Lovo, human cervical cancer cell line HeLa, colorectal cancer HCT116, U87 glioma, colorectal cancer, etc. most HD9 derivatives having broad-spectrum anti-tumor effect, and to determine the value IC5tl. [0039] 主要试剂与主要设备:RMPI 1640培养液(购自Gibco) ;DMEM高糖培养液(购自Gibco) ;DMEM低糖培养液(购自Gibco);小牛血清(购自Hyclone);胎牛血清(TBD公司);四甲基偶氮唑盐(MTT)美国Sigma (St. Louis, MO);胰蛋白酶(Biosharp) ;DMS0 (沈阳化学试剂厂);NaCl (沈阳化学试剂厂);KC1 (沈阳化学试剂厂);KH2P03 (沈阳化学试剂厂);Na2HP03(沈阳化学试剂厂);NaHC03 (沈阳化学试剂厂);酶标仪(奥地利TECAN); 96孔细胞培养板(Costar公司)。 [0039] Reagents and major equipment: RMPI 1640 medium (available from Gibco); DMEM high glucose medium (available from Gibco); DMEM low glucose medium (available from Gibco); calf serum (purchased from Hyclone); Tire bovine serum (TBD Corporation); tetrazolium salt (MTT) U.S. Sigma (St. Louis, MO); trypsin (Biosharp); DMS0 (Shenyang Chemical Reagent Factory); NaCI (Shenyang Chemical Reagent Factory); The KC1 (Shenyang Chemical Reagent Factory); KH2P03 (Shenyang Chemical Reagent Factory); Na2HP03 (Shenyang Chemical Reagent Factory); or NaHCO3 in (Shenyang Chemical Reagent Factory); microplate reader (Austria TECAN); 96-well cell culture plates (Costar Corporation). [0040] 实验方法:人结肠癌细胞Lovo细胞株、人子宫颈癌细胞株HeLa细胞株、人肺癌细胞A549细胞株的培养条件均为RMPI 1640培养液,10%胎牛血清,人乳腺癌细胞MCF-7细胞株、大肠癌HCT116细胞株、脑胶质瘤U87细胞株、人大肠癌HD9细胞株的培养条件为低糖DMEM培养液10%胎牛血清。 [0040] Experimental method: human colon cancer cell line Lovo cells, human cervical cancer cell line HeLa cells, culture conditions of the human lung cancer cell line A549 cells were RMPI 1640 medium, 10% fetal calf serum, human breast cancer cells MCF-7 cell line, HCT116 colorectal carcinoma cell lines, glioma cell line U87, culture conditions HD9 colorectal cancer cell lines for sugar in DMEM with 10% FBS. 以上细胞株均培养于5% C02,37°C的培养箱中。 Above cell lines were cultured in an incubator in 5% C02,37 ° C in. 使用DMSO 溶解,配成浓度为lOmmol/L的母液,储存于_20°C。 DMSO was used to dissolve, dubbed the concentration lOmmol / L mother liquor, stored at _20 ° C. [0041 ] 细胞株使用无血清的RMPI 1640培养液将药物的母液稀释成lOOOumol/L, 300umol/L, 1 OOumo 1/L, 10umol/L,每孔加入IOuL,使得药物的终浓度为1 OOumol/L, 30umol/L,10umol/L,lumol/L。 [0041] The cell line serum-free RMPI 1640 culture medium diluted mother liquor medicament into lOOOumol / L, 300umol / L, 1 OOumo 1 / L, 10umol / L, added to each well IOuL, so that the drug final concentration of 1 OOumol / L, 30umol / L, 10umol / L, lumol / L. [0042] 如图9所示,3i3-L_丙氨酰基-达玛烷-12β,20,25_三醇(化合物1)作用于乳腺癌细胞系MCF-7的剂量反应曲线,培养48小时的IC5Q=2. 9μΜ,明显低于20 (R)-达玛烷-3 β,12 β,20,25-四醇IC5Q=48. 9μΜ,即是先导化合物活性的16倍。 [0042] As shown in FIG 9, 3i3-L_ alanyl - Dammarane -12β, 20,25_ triol (Compound 1) acting on the breast cancer cell line MCF-7 dose-response curves, and cultured for 48 hours . the IC5Q = 2 9μΜ, significantly lower than the 20 (R) -. dammarane -3 β, 12 β, 20,25- tetrol IC5Q = 48 9μΜ, i.e. 16 times the activity of the lead compound. 3 β -N-叔丁氧羰基-硝基-L-精氨酰基-达玛烷-12 β,20, 25-三醇(化合物2)、20 (R)-3 β -5' -氟尿嘧啶-1,-基-乙酰基-达玛烷-12 β,20,25-三醇(化合物3)作用于MCF-7的IC5tl分别为6. 8μΜ、38. ΐμΜ,均低于先导化合物25-0H-PPD。 3 β -N- tert-butoxycarbonyl group - nitro -L- arginyl - Dammarane -12 β, 20, 25- triol (Compound 2), 20 (R) -3 β -5 '- fluorouracil - 1, - yl - acetyl - dammarane -12 β, 20,25- triol (compound 3) acts on IC5tl MCF-7, respectively 6. 8μΜ, 38 ΐμΜ, lead compounds are less than 25-0H. -PPD. [0043] 同样,化合物1-3对于人肺癌细胞Α549细胞株48小时的IC5tl分别为2. 8、 10. 2,38. 9μΜ,抗肿瘤活性有显著提高(图10)。 [0043] Similarly, compounds 1-3 for 48 hours IC5tl Α549 cell line was human lung cancer cells were 2. 8, 10. 2,38. 9μΜ, anti-tumor activity was significantly improved (FIG. 10). 对于人结肠癌细胞Lovo细胞株48小时的IC5tl分别为9.9、0.5、35.2口11,抗肿瘤活性均强于25-0!1^^0 (图11)。 For human colon cancer cell line Lovo cells were 48 hours IC5tl 9.9,0.5,35.2 port 11, the antitumor activity stronger than 25-0! ^^ 0 1 (FIG. 11). 与此同时,发现具有通式(I)的化合物具有选择性杀伤肿瘤细胞的特点,并且活性多强于20 (R)-达玛烷-3 β,12 β,20,25-四醇。 At the same time, we found that compounds having the formula (I) having a characteristic selectively kill tumor cells, and the activity was stronger than multi-20 (R) - Dammarane -3 β, 12 β, 20,25- tetraol. [0044] 制剂实施例1 片剂每片含有化合物3 β -L-丙氨酰基-达玛烷-12 β,20,25-三醇(制备实施例2) 5mg的片剂是按以下配方制备。 [0044] Formulation Example 1 Tablets each containing Compound 3 β -L- alanyl - Dammarane -12 β, 20,25- triol (Preparation Example 2) 5mg tablets are prepared according to the following formula . 将以下组份均勻混合,用常规方法压成每片重170mg的片剂。 The following components were uniformly mixed and compressed to form tablets each weighing 170mg by conventional methods. [0045] 制剂实施例2硬胶囊每粒含有化合物3 β -L-丙氨酰基-达玛烷-12 β,20, 25-三醇(制备实施例2) 5mg的硬胶囊是按以下配方,均勻混合,装入硬胶囊。 Example 2 Hard capsules [0045] Formulation each containing compound 3 β -L- alanyl - Dammarane -12 β, 20, 25- triol (Preparation Example 2) Hard capsules according to the following formulation is 5mg, uniformly mixed, and filled into hard capsules.

Figure CN102558270AD00121

[0046] 制剂实施例3 [0046] Formulation Example 3

Figure CN102558270AD00122

散剂每粒含有化合物3 β -L-丙氨酰基-达玛烷-12 β,20, 25-三醇(制备实施例2) 5mg的散剂是按以下配方,均勻混合,每袋装1. Og散剂。 Powders each containing compound 3 β -L- alanyl - Dammarane -12 β, 20, 25- triol (Preparation Example 2) 5mg of powder according to the following formulation is uniformly mixed, per bag 1. Og powder. [0047] 制剂实施例4注射剂每毫升注射液含有化合物3 β -L-丙氨酰基-达玛烷-12 β,20, 25-三醇盐酸盐(制备实施例2) 5mg的注射剂是按以下配方,用无菌蒸馏水配制。 Example 4 Injection [0047] Formulation per ml injection containing compound 3 β -L- alanyl - Dammarane -12 β, 20, 25- triol hydrochloride (Preparation Example 2) is based on injection of 5mg the following recipe, prepared with sterile distilled water. 3p-L,_f[_ 基-达玛烷-12(5,20,25-三醇 0..5g 3p-L, _f [_ yl - Dammarane 12 (5,20,25- triols 0..5g

Figure CN102558270AD00123

[0048] 以上实施例可更详细说明本发明,但不以任何形式限制本发明。 [0048] The above embodiments of the present invention may be described in more detail, but do not limit the present invention in any way. 12 12

Claims (8)

1.具有通式(I)的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐: 20 (S) and 20 (R) 1. having the formula (I) - A Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof:
Figure CN102558270AC00021
其中,RU R2为单取代、双取代,或同时取代;Rl、R2为酰化取代的氨基酸、氨基保护的氨基酸、寡肽、多肽,或是组成DNA、RNA的碱基对及其衍生物。 Wherein, RU R2 is monosubstituted, disubstituted, or simultaneously substituted; bases Rl, R2 to the acylated amino acid substitution, amino-protected amino acid, oligopeptide, polypeptide, or the composition of DNA, RNA and derivatives of.
2.权利要求1所述的通式(I)的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐,其中:所述的盐为钾盐、钠盐、铵盐、镁盐、钙盐或盐酸盐。 20 (S) and 20 (R) of the general formula according to claim 1 (I) - A Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof, wherein: the salts are potassium, sodium, ammonium, magnesium, calcium, or hydrochloride salt.
3.权利要求1所述的通式(I)的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐,其中:所述的氨基酸选自丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、谷氨酸。 20 (S) and 20 (R) according to formula 1 (I) 3. claims - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof, wherein: an amino acid selected from alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine, cysteine, tyrosine , asparagine, glutamine, lysine, arginine, histidine, aspartic acid, glutamic acid.
4.权利要求1所述的通式(I)的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐,其中:所述寡肽是2-20个氨基酸残基通过肽键连接形成的肽;所述多肽由20个以上的氨基酸残基组成的肽。 20 (S) and 20 (R) according to formula 1 (I) 4. claims - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof, wherein: oligopeptide is a peptide of 2-20 amino acid residues joined by peptide bonds formed; peptide of the polypeptide consists of more than 20 amino acid residues.
5.权利要求1所述的通式(I)的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐,其中:所述的氨基酸的构型为D型或L型;所述的氨基保护的氨基酸的保护基选自叔丁氧羰基、苄氧羰基、芴甲氧羰基;所述的碱基对选自腺嘌呤、鸟嘌呤、胞嘧啶、尿嘧啶、胸腺嘧啶及其衍生物。 20 (S) and 20 (R) according to formula 1 (I) 5. claims - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof, wherein: the amino acid configuration is a D or L; protecting the amino protecting group selected from t-butoxycarbonyl, benzyloxycarbonyl, fluorenyl methoxycarbonyl amino acids; the base pair is selected from adenine, birds purine, cytosine, uracil, thymine, and derivatives thereof.
6.权利要求1所述的通式(I)的20 (S)和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐,其中:R1、R2为单取代或双取代。 20 (S) and 20 (R) according to the formula of claim 1 (I) - A Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof, wherein: R1, R2 is a mono- or di-substituted.
7. 一种组合物,包括有效量的权利要求1-6任何一项所述的20(¾和20 (R)-达玛烷-3 β,12 β,20,25-四醇衍生物及其盐和其药学上可接受的载体。 A composition comprising an effective amount of any one of claims 1-6 20 (¾ and 20 (R) - Dammarane -3 β, 12 β, 20,25- tetrol derivatives and salts thereof and a pharmaceutically acceptable carrier.
8.权利要求1-6中任何一项所述的20 (S)和20 (R)-达玛烷_3 β,12 β,20,25-四醇衍生物及其盐和权利要求7所述的组合物在制备治疗抗肿瘤药物中的应用。 Dammarane _3 β, 12 β, 20,25- tetrol derivatives and salts thereof as claimed in claim 7 and - any 20 (S) and 20 (R) according to one of claim 1-6 application of antineoplastic compositions described in the preparation of the treatment.
CN2012100610338A 2012-03-09 2012-03-09 20(S) and 20(R)-dammarane-3beta,12beta,20,25-tetrol derivative and preparation method and application thereof CN102558270A (en)

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