CN100348605C - 秋水仙碱苷类似物 - Google Patents
秋水仙碱苷类似物 Download PDFInfo
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- UXAFRQPVHYZDED-ZZEDUEFDSA-N Colchicoside Chemical class C1([C@@H](NC(C)=O)CCC2=C3)=CC(=O)C(OC)=CC=C1C2=C(OC)C(OC)=C3O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UXAFRQPVHYZDED-ZZEDUEFDSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 229960002708 antigout preparations Drugs 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 7
- 239000005864 Sulphur Chemical group 0.000 claims description 4
- 239000003158 myorelaxant agent Substances 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 10
- PKYOHQGXPPVIGD-HNNXBMFYSA-N n-[(7s)-3-hydroxy-1,2-dimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound O=C1C(SC)=CC=C2C3=C(OC)C(OC)=C(O)C=C3CC[C@H](NC(C)=O)C2=C1 PKYOHQGXPPVIGD-HNNXBMFYSA-N 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 8
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical class C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 abstract description 5
- 210000003205 muscle Anatomy 0.000 abstract description 4
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- JRRUSQGIRBEMRN-HNNXBMFYSA-N n-[(7s)-3-hydroxy-1,2,10-trimethoxy-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical group O=C1C(OC)=CC=C2C3=C(OC)C(OC)=C(O)C=C3CC[C@H](NC(C)=O)C2=C1 JRRUSQGIRBEMRN-HNNXBMFYSA-N 0.000 abstract description 3
- 229940045695 antineooplastic colchicine derivative Drugs 0.000 abstract 1
- 230000002040 relaxant effect Effects 0.000 abstract 1
- 229910052717 sulfur Chemical group 0.000 abstract 1
- 239000011593 sulfur Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 10
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical class CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- 238000012544 monitoring process Methods 0.000 description 3
- -1 peracetic acid salt Chemical class 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
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- 208000025747 Rheumatic disease Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N boron trifluoride etherate Substances FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
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- 229910052731 fluorine Inorganic materials 0.000 description 2
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- 230000007170 pathology Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
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- 231100000419 toxicity Toxicity 0.000 description 2
- WHVNYMMWPUHYES-CZBDKTQLSA-N (3s,4r,5s)-2-fluorooxane-3,4,5-triol Chemical compound O[C@H]1COC(F)[C@@H](O)[C@@H]1O WHVNYMMWPUHYES-CZBDKTQLSA-N 0.000 description 1
- QVBTZFANYYOOEQ-CZBDKTQLSA-N C1([C@@H](O)[C@H](O)[C@@H](O)CO1)[F+2] Chemical compound C1([C@@H](O)[C@H](O)[C@@H](O)CO1)[F+2] QVBTZFANYYOOEQ-CZBDKTQLSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000011714 Glycine Receptors Human genes 0.000 description 1
- 108010076533 Glycine Receptors Proteins 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- KFSLWBXXFJQRDL-UHFFFAOYSA-N peroxyacetic acid Substances CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229930001910 pseudoalkaloid Natural products 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/248—Colchicine radicals, e.g. colchicosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明涉及秋水仙碱衍生物，特别是通式(I)的3-去甲基-和3-去甲基硫代-秋水仙碱(见右图)，其中X是氧或硫，涉及其制备方法和含有它们的药物组合物。式(I)化合物具有肌肉松弛、抗炎和抗痛风活性。
Description
发明领域
本发明涉及秋水仙碱衍生物，特别是具有肌肉松弛、抗炎和抗痛风活性的3-去甲基-和3-去甲基硫代-秋水仙碱衍生物。
技术背景
松弛药减小肌肉张力，用于治疗挛缩和肌肉痉挛。肌肉痉挛是慢性疼痛的主要原因之一；其以运动器官的多种病变以及炎性-风湿性和变性矫形病变为特征；当它影响关节、进而引起疼痛时，导致僵硬，这使受累部位的关节灵活性和屈曲性降低。由于这些原因，对具有肌肉松弛和解痉性质的分子的研究仍然具有显著的临床意义。
已知秋水仙碱是一种长期以来已经广泛用于治疗痛风的伪生物碱。3-去甲基-硫代秋水仙碱苷、硫代秋水仙碱苷也广泛用于治疗影响肌肉系统的挛缩和炎性病症(Ortopedia e traumatologia Oggi XII，n.4，1992)。最近已经证明硫代秋水仙碱苷的活性是由于其具有与马钱子碱敏感性甘氨酸受体相互作用的能力；因此，具有拟甘氨酸活性的化合物由于其肌肉松弛性质而可以用于风湿性-矫形领域。
发明内容
本发明涉及通式(I)的秋水仙碱衍生物：
其中X为氧或硫。
就本发明的目的而言，其中X为氧的化合物称为(Ia)，而其中X为硫的式(I)化合物称为(Ib)。式(I)化合物包括D和L异构体。特别优选化合物(Ib)的D和L异构体-3-O-β-D-吡喃木糖基-3-O-去甲基硫代秋水仙碱和3-O-β-L-吡喃木糖基-3-O-去甲基硫代秋水仙碱。
按照EP 0 789 028中所公开的通用方法通过使D-或L-吡喃木糖基-氟与3-O-去甲基秋水仙碱(IIa)和3-O-去甲基硫代秋水仙碱(IIb)反应制备本发明的化合物：
更详细地，使3-O-去甲基秋水仙碱(IIa)或3-O-去甲基硫代秋水仙碱(IIb)与D-或L-吡喃木糖基-氟(III)或其保护形式反应，优选其过乙酸盐/酯。该反应在极性非质子溶剂中进行，所述极性非质子溶剂优选选自乙腈和氯化溶剂；反应温度为0℃至溶剂的沸腾温度，优选室温；反应于碱存在下进行，优选1，1，3，3-四甲基胍。该反应通常在10分钟至2小时的时间内反应完全。可以不回收中间体而进行保护基团的水解。
特别地，已经观察到化合物(Ib)的β-D异构体具有明显的肌肉松弛活性，该活性比相应的硫代秋水仙碱苷异构体的活性更高，还具有明显的抗炎和抗痛风活性。
用转棒(rota-rod)试验对肌肉松弛活性进行了评价。在试验前30分钟用化合物(Ib)的β-D异构体以1-3-10 mg/kg的剂量腹膜内处理体重为20-25g的瑞士雄性小鼠。通过检测小鼠对以2至50r.p.m.递增速度旋转的转盘刺激的耐受力评价了对横纹肌的松弛活性。下表中所报告的结果表明本发明的化合物比用作参比化合物的硫代秋水仙碱苷活性更高。
表1
| 处理 | 剂量(mg/Kg腹膜内) | 耐受时间(秒M±S.E.) | DE50mg/Kg |
| 对照 | 400±27 | ||
| 化合物(Ib)β-D异构体 | 1 | 270±19 | |
| 3 | 175±14 | 2.23(1.84-2.82) | |
| 10 | 80±10 | ||
| 硫代秋水仙碱苷β-D异构体 | 1 | 345±20 | |
| 3 | 265±17 | 4.47(3.16-7.01) | |
| 10 | 110±12 |
另外，本发明的化合物的毒性明显更低。事实上，它的DL50是80(63-94)mg/kg腹膜内，而硫代秋水仙碱苷的DL50是20mg/kg。这些结果表明本发明的化合物具有更高的活性，其毒性/活性剂量比明显比硫代秋水仙碱苷更有利。
表2
| 处理 | DE50 mg/Kg腹膜内 | DL50mg/Kg腹膜内 | DL50/DE50 |
| 化合物(Ib)β-D异构体 | 2.23 | 80 | 35.87 |
| 硫代秋水仙碱苷β-D异构体 | 4.47 | 20 | 4.47 |
本发明的化合物可以采用常规的赋形剂和方法如Remington’sPharmaceutical Siences Handbook，第XVII版，Mack Pub.，纽约，美国中所报道的那些赋形剂和方法掺入用于口服、静脉内、肌内、透皮和局部施用的药物制剂中。在可用于制备胃肠外或局部施用的脂质体形式的赋形剂中，特别优选天然的和合成的磷脂。根据疾病和施用途径的不同，剂量可以从每天5至50mg不等。
现在通过一些实施例更详细地阐述本发明。
实验部分
熔点用Buchi 510仪器测定。NMR光谱用Bruker AC 200测定。
实施例1 3-O-(2’，3’，4’-O-三乙酰基-β-D-吡喃木糖基)-3-O-去甲基硫代秋水仙碱
在氮气和搅拌下，将3-O-去甲基硫代秋水仙碱(IIb)(0.5mmol)和按照Hayashi等(Chemistry Lett.1984，1747)制备的2，3，4-O-三乙酰基-α-D-吡喃木糖基氟(0.75mmol)混悬在在室温下的干燥乙腈(10ml)中。加入1，1，3，3-四甲基胍(1.5mmol)，混悬液变为澄清的红色。加入三氟化硼乙醚合物(4mmol)，之后溶液变为无色。通过TLC(CH2Cl2∶MeOH 9∶1)监测反应。当起始物消失后(30分钟)，加入饱和碳酸氢钠溶液(10ml)使反应停止。分离各相，用乙酸乙酯(3×10ml)萃取水相。将合并的有机相用饱和硫酸氢钾溶液(15ml)、盐水(15ml)洗涤，用硫酸镁干燥。蒸发溶剂后，用硅胶色谱法分离反应产物。或者，将粗品直接进行去保护。
1H-NMR(CDCl3)-δ(ppm)7.06(NH，d，7.4Hz)，7.06(H12，d，10.3Hz)，7.27(H11.d，10.3Hz)，7.33(H8，s)，6.71(H4，s)，4.71-4.55(H7，m)，2.60-1.90(H5-H6，m)，3.90(2-OMe，s)，3.66(1-OMe，s)，2.44(SMe，s)，2.00(乙酰胺)，5.28-5.18，5.08-4.98(H1’，H2’H3’，H4’，m)，4.30(H5′a，ddd，4.3，7.0，12.1Hz)，3.58(H5′b，ddd 4.3，7.0，12.1Hz)，2.12(OAc)，2.11(OAc)，2.10(OAc)。
实施例2 3-O-(2’，3’，4’-O-三乙酰基-β-L-吡喃木糖基)-3-O-去甲基硫代秋水仙碱
在氮气和搅拌下，将3-O-去甲基硫代秋水仙碱(IIb)(0.5mmol)和按照Takanashi等(Liebigs Ann.Chem.1997，1081)制备的2，3，4-O-三乙酰基-α-L-吡喃木糖基氟(0.75mmol)混悬在在室温下的干燥乙腈(10ml)中。加入1，1，3，3-四甲基胍(1.5mmol)，混悬液变为澄清的红色。加入三氟化硼乙醚合物(4mmol)后，溶液变为无色。通过TLC(CH2Cl2∶MeOH 9∶1)监测反应。
当起始原料消失后(2小时)，加入饱和碳酸氢钠溶液(10ml)使反应停止。分离各相，用乙酸乙酯(3×10ml)萃取水相。将合并的有机相用饱和硫酸氢钾溶液(15ml)、盐水(15ml)洗涤，用硫酸镁干燥。蒸发溶剂后，用硅胶色谱法分离反应产物。或者，将粗品直接进行去保护。
1H-NMR(CDCl3)-δ(ppm)7.34(NH，d，7.9Hz)，7.07(H12，d，10.7Hz)，7.30(H11，d 10.7Hz)，7.37(H8，s)，6.71(H4，s)，4.71-4.55(H7，m)，2.60-1.80(H5-H6，m)，3.88(2-OMe，s)，3.64(1-OMe，s)，2.44(SMe，s)，2.00(乙酰胺)，5.28-5.18 e 5.10-4.90(H1’，H2’，H3’，H4′m)，4.25(H5′a，ddd，4.3，4.4，12.1Hz)，3.58(H5′b，ddd 4.3，4.4，12.1Hz)，2.14(OAc)，2.11(OAc)，2.10(OAc)。
实施例3在乙醇中去保护的通用方法
在室温下，将实施例1或2制备的粗产物(理论量0.5mmol)溶解在乙醇(4ml)和1N NaOH(2ml)中。通过TLC监测反应。起始物消失后，蒸除溶剂，将残余物用硅胶色谱法处理。可以将产物用甲醇/异丙醇进一步结晶。实施例4在丙酮中去保护的通用方法
将由实施例1或2制备的粗产物(理论量1mmol)与碳酸钾一起混悬在丙酮(30ml)和水(10ml)中。将混合物进行回流，直至起始物消失。蒸除溶剂，用色谱法回收产物。可以将产物用甲醇和二异丙醚进一步结晶。
实施例5 3-O-β-D-吡喃木糖基-3-O-去甲基硫代秋水仙碱
按照实施例3或4的去保护方法在用硅胶色谱法(用CH2Cl2/MeOH梯度洗脱)处理后以45％的收率得到该产物。
熔点193℃；[α]D 22-201(c 1，MeOH)；
1NMR(CDCl3)：ppm 8.64(NH，d，7.6 Hz)，7.15(H12，d，10.6Hz)，7.28(H11，d，10.6Hz)，7.03(H8，s)，6.85(H4，s)4.37-4.25(H7，m)，2.60-1.80(H5-H6，m)，3.84(2-OMe，s)，3.55(1-OMe，s)，2.42(SMe，s)，1.86(乙酰胺)，4.97(H1’，6.6Hz)，3.20-3.90(H2′，H3′，H4′，H5′，m)，4.40-5.60(OH)。
实施例6 3-O-β-L-吡喃木糖基-3-O-去甲基硫代秋水仙碱
按照实施例3或4的去保护方法在用硅胶色谱法(用CH2Cl2/MeOH梯度洗脱)处理后以45％的收率得到该产物。
熔点220℃；[α]D 22-176(c 1，MeOH)；
1H-NMR(CDCl3)：ppm 8.64(NH，d，7.3 Hz)，7.17(H12，d，10.2 Hz)，7.29(H11，d，10.2Hz)，7.03(H8，s)，6.87(H4，s)4.23-4.41(H7，m)，2.70-1.90(H5-H6，m)，3.84(2-OMe，s)，3.55(1-OMe，s)，2.42(SMe，s)，1.86(乙酰胺)，5.02(H1’，6.9Hz)，3.20-3.90(H2’，H3’，H4’，H5’，m)，4.90-5.60(OH)。
Claims (11)
1.通式(I)的化合物：
其中X是氧或硫。
2.权利要求1中所述的化合物，其中X是氧。
3.权利要求1中所述的化合物，其中X是硫。
4.一种化合物，其选自：3-O-β-D-吡喃木糖基-3-O-去甲基硫代秋水仙碱和3-O-β-L-吡喃木糖基-3-O-去甲基硫代秋水仙碱。
5.权利要求1-4中任一项的化合物在制备肌肉松弛药中的用途。
6.权利要求1-4中任一项的化合物在制备抗炎药中的用途。
7.权利要求1-4中任一项的化合物在制备抗痛风药中的用途。
8.药物组合物，其含有权利要求1-4中任一项的化合物以及与之混合的合适的赋形剂和/或载体。
9.权利要求8中所述的药物组合物，其是用于局部使用的药物组合物。
10.权利要求8中所述的药物组合物，其是用于胃肠外使用的药物组合物。
11.权利要求9或10中所述的药物组合物，其中赋形剂选自天然的和合成的磷脂。
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| IT001144A ITMI20031144A1 (it) | 2003-06-06 | 2003-06-06 | Analoghi del colchicoside. |
| ITMI2003A001144 | 2003-06-06 |
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| ITMI20051418A1 (it) * | 2005-07-22 | 2007-01-23 | Indena Spa | Analoghi del tiocolchicoside ad attivita'miorilassante e antiinfiammatoria |
| EP2076525A2 (en) | 2006-10-06 | 2009-07-08 | Wisconsin Alumni Research Foundation | Colchicine neoglycosides and methods for their synthesis and use |
| DE602008004113D1 (de) * | 2008-05-28 | 2011-02-03 | Indena Spa | Verfahren zur Glycosidierung von Colchicin und Thiocolchicin |
| US8722205B2 (en) | 2009-03-23 | 2014-05-13 | Universal Display Corporation | Heteroleptic iridium complex |
| WO2010138670A2 (en) * | 2009-05-27 | 2010-12-02 | Mutual Pharmaceutical Company, Inc. | Thiocolchicine derivatives, method of making and methods of use thereof |
| WO2013149109A1 (en) * | 2012-03-30 | 2013-10-03 | Takeda Pharmaceuticals U.S.A., Inc. | Colchicine formulations; methods of making; and methods of use thereof |
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| CN1063486A (zh) * | 1990-12-25 | 1992-08-12 | 有限会社尾源研究所 | 脱乙酰基秋水仙素衍生物 |
| JPH04330045A (ja) * | 1990-12-25 | 1992-11-18 | Bigen Kenkyusho:Kk | デアセチルコルヒチンの製造方法 |
| EP0789028A2 (en) * | 1996-02-08 | 1997-08-13 | INDENA S.p.A. | A process for the glycosidation of colchicine derivatives and products obtained |
| CN1188482A (zh) * | 1995-06-27 | 1998-07-22 | 因迪纳有限公司 | 秋水仙碱衍生物,其应用及含它们的制剂 |
| CN1208003A (zh) * | 1997-08-08 | 1999-02-17 | 韩财元 | 摆翼式直升飞机 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB773729A (en) * | 1955-06-10 | 1957-05-01 | Roussel Uclaf | New derivatives of n-deacetylalkylthiocolchiceines and process for their production |
| CH341831A (fr) * | 1955-06-10 | 1959-10-31 | Uclaf Societe Anonyme | Procédé de préparation de produits de condensation de saccharides sur l'azote des N-désacétyl-alcoylthiocolchicéines |
| JPS5619357B2 (zh) * | 1972-05-02 | 1981-05-07 | ||
| IT1270124B (it) * | 1994-10-05 | 1997-04-28 | Indena Spa | Derivati della colchicina e loro impiego terapeutico |
| IT1285777B1 (it) * | 1996-10-07 | 1998-06-18 | Indena Spa | Processo di biotrasformazione di composti colchicinoidi nei corrispondenti 3-glicosilderivati |
| FR2779147B1 (fr) * | 1998-05-27 | 2000-06-30 | Synthelabo | Derive de thiocolchicoside sa preparation et son application en therapeutique |
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|---|---|---|---|---|
| CN1063486A (zh) * | 1990-12-25 | 1992-08-12 | 有限会社尾源研究所 | 脱乙酰基秋水仙素衍生物 |
| JPH04330045A (ja) * | 1990-12-25 | 1992-11-18 | Bigen Kenkyusho:Kk | デアセチルコルヒチンの製造方法 |
| CN1188482A (zh) * | 1995-06-27 | 1998-07-22 | 因迪纳有限公司 | 秋水仙碱衍生物,其应用及含它们的制剂 |
| EP0789028A2 (en) * | 1996-02-08 | 1997-08-13 | INDENA S.p.A. | A process for the glycosidation of colchicine derivatives and products obtained |
| CN1208003A (zh) * | 1997-08-08 | 1999-02-17 | 韩财元 | 摆翼式直升飞机 |
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