CN1208033A - 有抗炎和肌肉松弛活性的秋水仙碱和硫代秋水仙碱衍生物 - Google Patents
有抗炎和肌肉松弛活性的秋水仙碱和硫代秋水仙碱衍生物 Download PDFInfo
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Abstract
本发明涉及通式(Ⅰ)的3-去甲基—硫代秋水仙碱衍生物,式中
R可以是-CH2-、HOCH2-CHOH-CH2,H2NCH2CHOHCH2-、HOOCCH2-、OH-CH2-CHCl-CH2-,涉及其制备方法,涉及含有它们的药物组合物并涉及它们用于具有肌肉松弛和抗炎活性的药物的制备。
Description
肌肉松驰药物具有减轻肌肉紧张,例如肌肉挛缩的共同的特性。
肌肉挛缩是运动器官若干病理学的一个特征,并且它是导致相关的疼痛状况持续的主要作用因素之一。肌肉挛缩也发生于炎性-风湿和变质性矫形外科病理学方面;当受到感染时,除了疼痛之外,它还引起僵硬,后者限制关节端的相互移动性,从而限制相关部位的功能性。由于这些原因,非常关注具有显著的肌肉松驰和镇痉性质特征的药物分子。
已知秋水仙碱是一种似生物碱,广泛地和相当长期地用于治疗痛风。在治疗中同样广泛使用的是3-去甲基-硫代秋水仙碱葡糖苷,又称硫代秋水仙苷,在针对骨胳肌炎症的治疗中作为镇痉药(Ortopedia eTraumatologia Oggi Xll,n 4,1992)。最近已经证实硫代秋水仙苷的活性与它和对马钱子碱敏感的甘氨酸受体之间的相互作用有关系,因此,具有拟甘氨酸活性的化合物由于其肌肉松驰特性能够用于风湿病学-矫形外科领域。
现在已经发现,用不论在体内还是在体外的研究来评价,通式(Ⅰ)的硫代秋水仙碱衍生物都能够比那些贯用的类似已知物质以更为有利的剂量发挥有效的肌肉松驰作用。
在结合试验中,本发明的化合物显示出比结构类似的化合物,即硫代秋水仙苷更高的对甘氨酸受体的亲和力(表Ⅰ)。
表Ⅰ化合物 浓度(μM) 置换%硫代秋水仙苷 0.1 200.5 451 70化合物Ⅰ 0.1 401 85化合物Ⅱ 0.1 351 65化合物Ⅲ 0.1 501 75
与受体的相互作用按照A.B.Young和S.H.Snyder在Proc.Natl.Acad.Sci U.S.A.71,4002,1974报告的方法作了评价。
在体内实验中已经研究了兔子由马钱子引起的多突触反射的抑制作用。
使用这种方式,本发明的化合物以1mg/kg的剂量肌肉注射,能够减少多突触反射的50%(化合物Ⅰ)、60%(化合物Ⅱ)和65%(化合物Ⅲ),并且能够完全除去相同剂量的马钱子-引发反射的效力;已使用5mg/kg的最小剂量的对照分子硫代秋水仙苷用于获得可比较的效果。
此外,分子式(Ⅰ)的化合物具有比硫代秋水仙苷小得多的急性毒性。实际上,在小鼠的静脉内,化合物Ⅰ-Ⅲ的DL50大于30mg/kg,硫代秋水仙苷的DL50是7.5mg/kg。
在乳腺癌细胞上和其它肿瘤细胞上的体外细胞毒性实验表明,本发明的化合物在浓度高达5000nM以上仍无细胞毒性,而母体硫代秋水仙苷甚至在0.6nM浓度时就有细胞毒性了。
结论是,本发明的化合物是安全的,在治疗上是有优势的。
化合物Ⅰ-Ⅴ可以从3-去甲基硫代秋水仙碱素出发,按照下面的总反应流程,使用传统的反应剂和合成工艺来制备。
为了治疗使用,化合物Ⅰ-Ⅴ可以适当地使用药物学可接受的赋形剂和载体配制成例如胶囊、片剂、颗粒、栓剂、乳膏、注射液、油膏、凝胶和其它的形式,更为一般化的按照传统技术,例如在“Remington’sPharmaceutical Sciences Handbook”(Mack PublishingCompany,New York,U.S.A,17thEd.1985)中所述的那些形式。
因此本发明还涉及含有通式Ⅰ化合物的药物组合物,用于作为肌肉松驰剂,镇痉剂、消炎药、抗痛风药、更为一般地用于风湿病学-矫形外科领域中。
以下的实施例具体说明本发明。
实施例Ⅰ
合成3-去甲基-3-缩水甘油基硫代秋水仙碱
将3-去甲基硫代秋水仙碱(200mg,0.5mmol)悬浮于CH3CN(10ml)中。回流该混合物,然后加入1,8-二氮杂二环[5,4,0]十一碳-7-烯(DBU153μl,1mmol)。产物马上溶解,溶液颜色变暗。此后,再加入(±)-表氯醇(3mmol,190μl)。通过TLC(CCH2Cl2-MeOH 9-1)监测反应。7小时后,原料全部反应完毕。将溶剂蒸发掉,反应粗产物采用重量分析色谱法在硅胶上,用CH2Cl2-MeOH 100-2混合物洗脱纯化。生成的油状产物(160mg,0.35mmol,产率:70%)从丙酮中结晶,并根据1H-13C-NMR,COSY和NOESY色谱进行鉴别。
形成的产物是两种非对映体(2’R,7S,aS)和(2’S,7S,aS)的混合物。
m.p.:241-241.5℃.
1H-NMR:(CDCl3)7.84-7.79(m,1H),7.42(s,1H),7.31
(d,1H,J10.3),7.08(d,1H,J10.3),6.57,6.56(2s,
1H),4.66-4.61(m,1H),4.37-4.28(m,1H),4.10-3.98(m,
1H),3.94(s,3H),3.65(s,3H),3.44-3.37(m,1H),
2.96-2.91(m,1H),2.82-2.76(m,1H),2.43(s,3H),
2.48-1.85(m,4H),1.97(s,3H).
13C-NMR:(CDCl3)162.5,170.2,158.4,152.7,152.0,
151.4,142.3,138.6,135.0,134.5,128.4,126.8,126.7,
109.6,109.5,70.4,70.1,61.7,61.5,52.4,50.3,44.7,
36.4,29.9,22.9,15.2.
实施例Ⅱ
合成3-去甲基-3-(2,3-二羟丙基)硫代秋水仙碱
将3-去甲基-3-缩水甘油基硫代秋水仙碱(300mg,0.67mmol)溶于二噁烷-H2O(1-1.5ml)混合物中并用催化剂量的0.2N的H2SO4处理,然后加热回流。这个反应用TLC(CH2Cl2-MeOH 9-1)监测。5小时后将溶剂蒸发掉,并将反应粗产物采用重量分析色谱法,在硅胶上用CH2Cl2-MeOH 100-3混合物洗脱纯化。获得所希望的产物(根据其光谱特征鉴别:1H-13C-NMR和COSY)的产率为73%(228mg,0.48mmol),是两各种非对映体(2’R,7S,aS)和(2’S,7S,aS)的混合物。m.p.:149-150℃,分解1H-NMR:(CDCl3)7.28(d,1H,J9.8),7.26(s,1H),7.06(d,1H,J9.8),6.58(s,1H),6.48(d,1H,J8.5),4.71-4.60(m,1H),4.20-4.11(m,4H),3.94(s,3H),3.85-3.82(m,1H),3.65(s,3H),2.60-1.92(m,4H),2.44(s,3H),1.99(s,3H).13C-NMR:(CDCl3)182.5,170.0,158.5,152.6,151.5,142.2,138.2,134.8,134.7,128.4,126.8,126.7,109.6,92.5,71.7,70.2,63.8,61.7,52.3,36.6,29.9,23.0,15.3.
实施例Ⅲ
合成3-去甲基-3-(3-氨基-2-羟丙基)硫代秋水仙碱
将3-去甲基-3-缩水甘油基秋水仙碱(300mg,0.67mmol)溶于氨饱和的EtOH中并加热至60℃。1小时后反应完成,将溶剂蒸发掉,得到纯态的目的产物,产率为83%(261mg,0.55mmol),为两种非对映体(2’R,7S,aS)和(2’s,7S,aS)的混合物。产物根据其光谱特性鉴别:1H-NMR。m.p.:144.8-145.5℃,分解1H-NMR:(CDCl3)7.28(d,1H,J10.6),7.26(s,1H),7.06(d,1H,J10.6),4.72-4.58(m,1H),4.12-3.90(m,4H),3.94(s,3H),3.65(s,3H),3.05-1.5(m,5H),2.44(s,3H),1.99(s,3H).
实施例Ⅳ
合成2-(3-去甲基硫代秋水仙碱)乙酸
将3-去甲基硫代秋水仙碱(401mg,1mmol)在室温下悬浮于无水CH3CN(10ml)中。滴加1,8-二氮杂二环[5,4,0]十一碳-7-烯(DBU)(192ml,1.3mmol):混合物呈溶状并颜色变暗。在这次加入之后,再加入溴乙酸乙酯(161ml,1.3mmol),由此溶液颜色缓慢变浅。大约2小时后,再加入60ml的DBU和70ml的这种酯。反应混合物在室温放置10小时。TLC:CH2ClZ-MeOH=9/1。
在减压下将溶剂蒸发掉,得到的粗产物采用极性梯度的(polaritygradient)重量分析色谱法用CH2ClZ-MeOH混合物洗脱纯化。以84%的产率得到所需要的酯(410mg)。产物根据其光谱特性鉴别。m.p.:115℃1H NMR(CDCl3):1.31(t,J7.1,3H,Me),1.97(s,3H,MeCO),1.8-2.5(m,4H,H-5,H-6),2.43(s,3H,SMe),3.66,3.98(two s,6H,OMe),4.25(q,J7.1,2H,OCH2Me),4.58-4.70(m,1H,H-7),4.72(s,2H,OCH2),6.46(s,1H,H-4),7.08(d,J10.6,1H,H-11),7.29(d,J10.6,1H,H-12),7.27(s,1H,H-8),7.85(d,J6.9,1H,NH).
将NaOH颗粒(32mg,0.8mmol)溶于5%的EtOH(10ml)水溶液中。加入2-(3-去甲基硫代秋水仙碱)乙酸乙酯(300mg,0.62mmol),反应在室温。在磁力搅拌下进行。1小时后(TLC:CH2Cl2-MeOH=9/1),将溶剂蒸发,将剩余物溶于HCl稀水溶液中。沉淀出一种黄色产物,该产物再在硅胶上采用色谱法,用CH2ClZ-MeOH 9-1混合物洗脱纯化。得到2-(3-去甲基硫代秋水仙碱)乙酸(260mg),产率是92%。
m.p.:189-190℃分解(丙酮)
1H NMR(CDCl3):1.95(s,3H,MeCO),1.75-2.58(m,4H,H-
5,H-6),2.44(s,3H,SMe),3.03(s,1H,COOH)3.64,
3.97(two s,6H,OMe),4.51-4.70(m,1H,H-7),4.73(s,
2H,OCH2),6.61(s,1H,H-4),7.12(d,J10.7,1H,H-11),
7.31(d,J10.7,1H,H-12 and NH),7.50(s,1H,H-8).
按照与上述实施例相同的工艺已得到了3-去甲基-3-(2-氯-3-羟丙基)硫代秋水仙碱。
m.p.:118-119分解(丙酮,i-Pr2O)
1H NMR(CDCl3):1.99(s,3H,MeCO),1.75-2.58(m,4H,H-
5,H-6),2.44(s,3H,SMe),3.07(t,1H,OH,
deuterable),3.66,3.94(two s,6H,OMe),3.77-3.87,
4.15-4.32(two m,2+3H,CH2CHCH2),4.57-4.70(m,1H,H-
7), 6.58(s,1H,H-4),7.14(d,J10.6,1H,H-11),7.29
(d,J10.6,H-12),7.35(m,1H,NH),7.37(s,1H,H-8).
实施例Ⅴ
将式(Ⅰ)的化合物配制成小瓶装形式的制剂实施例。
小瓶装的
化合物(Ⅱ) 5mg
氯化钠 15.8mg
注射制剂用水适量加至 2ml
实施例Ⅵ
将式(Ⅰ)的化合物配制成胶囊形式的制剂实施例。
硬明胶胶囊
化合物(Ⅱ) 10mg
乳糖 212.3mg
淀粉 1.3mg
硬脂酸镁 2.4mg
实施例Ⅶ
将式(Ⅰ)的化合物配制成乳膏形式的制剂实施例。
乳膏
化合物(Ⅱ) 0.5g
对羟基苯甲酸甲酯 0.14g
对羟基苯甲酸乙酯 0.035g多氧乙烯-20-脱水山梨醇单油酸酯 5g
月桂基硫酸钠 2g
鲸蜡 5g
鲸蜡醇 7g
氢化羊毛脂 12.5g
硬脂酸 8g
藻酸钠 0.5g
熏衣草油 1g
纯化水适量加至 100g
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IT000845A/97 | 1997-04-11 | ||
IT97MI000845A IT1291550B1 (it) | 1997-04-11 | 1997-04-11 | Derivati della colchicina e della tiocolchicina ad attivita' antinfiammatoria e miorilassante |
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CN102741223A (zh) * | 2010-01-22 | 2012-10-17 | 共有药物有限公司 | 硫代秋水仙碱和秋水仙碱类似物、其制备方法和使用方法 |
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US6720323B2 (en) | 2000-07-07 | 2004-04-13 | Angiogene Pharmaceuticals Limited | Colchinol derivatives as angiogenesis inhibitors |
US6624317B1 (en) | 2000-09-25 | 2003-09-23 | The University Of North Carolina At Chapel Hill | Taxoid conjugates as antimitotic and antitumor agents |
US6825236B2 (en) * | 2003-04-14 | 2004-11-30 | California Pacific Medical Center | Colchicine derivatives |
US20070179143A1 (en) | 2003-06-25 | 2007-08-02 | Je Il Pharmaceutical Co., Ltd. | Tricyclic derivatives or pharmaceutically acceptable salts thereof, their preparations and pharmaceutical compositions containing them |
ITMI20051418A1 (it) * | 2005-07-22 | 2007-01-23 | Indena Spa | Analoghi del tiocolchicoside ad attivita'miorilassante e antiinfiammatoria |
JP5435995B2 (ja) * | 2009-01-30 | 2014-03-05 | 出光興産株式会社 | 環状化合物の製造方法 |
EP2924022A1 (en) * | 2014-03-27 | 2015-09-30 | INDENA S.p.A. | Amorphous form of a thiocolchicine derivative |
WO2020000109A1 (en) * | 2018-06-29 | 2020-01-02 | Alberta Health Services | Methods and uses of colchicine derivatives |
RU2740530C1 (ru) * | 2020-06-11 | 2021-01-15 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Способ профилактики развития постперикардиотомного синдрома и пароксизмов фибрилляции предсердий у кардиохирургических больных |
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US2820029A (en) * | 1954-02-10 | 1958-01-14 | U C L A F | New thio-derivatives of colchiceine compounds and a process of making same |
FR1344474A (fr) * | 1962-10-18 | 1963-11-29 | Roussel Uclaf | Dérivés de la colchicine et de la thiocolchicine et procédé de préparation |
EP0356137B1 (en) * | 1988-08-24 | 1994-10-26 | Advance Biofactures Corporation | Carbonates of 3-demethylthiocolchicine and N-acyl analogs |
IT1276996B1 (it) * | 1995-06-27 | 1997-11-04 | Indena Spa | Derivati della colchicina, loro uso e formulazioni che li contengono |
-
1997
- 1997-04-11 IT IT97MI000845A patent/IT1291550B1/it active IP Right Grant
-
1998
- 1998-04-06 KR KR1019980012058A patent/KR100559526B1/ko not_active IP Right Cessation
- 1998-04-06 DK DK98106236T patent/DK0870761T3/da active
- 1998-04-06 SI SI9830614T patent/SI0870761T1/xx unknown
- 1998-04-06 ES ES98106236T patent/ES2216197T3/es not_active Expired - Lifetime
- 1998-04-06 EP EP98106236A patent/EP0870761B1/en not_active Expired - Lifetime
- 1998-04-06 DE DE1998621815 patent/DE69821815T2/de not_active Expired - Lifetime
- 1998-04-06 PT PT98106236T patent/PT870761E/pt unknown
- 1998-04-06 AT AT98106236T patent/ATE260252T1/de active
- 1998-04-07 US US09/056,365 patent/US5973204A/en not_active Expired - Lifetime
- 1998-04-08 RU RU98106625/04A patent/RU2190598C2/ru not_active IP Right Cessation
- 1998-04-09 CN CN98109694A patent/CN1089336C/zh not_active Expired - Fee Related
- 1998-04-09 JP JP10112841A patent/JP2916470B2/ja not_active Expired - Fee Related
- 1998-04-09 AU AU60733/98A patent/AU738857B2/en not_active Ceased
- 1998-04-09 CA CA002234480A patent/CA2234480C/en not_active Expired - Fee Related
-
1999
- 1999-06-30 HK HK99102778A patent/HK1017880A1/xx not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102448930A (zh) * | 2009-05-27 | 2012-05-09 | 共有药物有限公司 | 硫代秋水仙碱衍生物、其制造方法和使用方法 |
CN102741223A (zh) * | 2010-01-22 | 2012-10-17 | 共有药物有限公司 | 硫代秋水仙碱和秋水仙碱类似物、其制备方法和使用方法 |
Also Published As
Publication number | Publication date |
---|---|
KR100559526B1 (ko) | 2006-06-28 |
US5973204A (en) | 1999-10-26 |
CN1089336C (zh) | 2002-08-21 |
AU6073398A (en) | 1998-10-15 |
EP0870761A1 (en) | 1998-10-14 |
AU738857B2 (en) | 2001-09-27 |
RU2190598C2 (ru) | 2002-10-10 |
CA2234480C (en) | 2006-12-12 |
JPH1121277A (ja) | 1999-01-26 |
JP2916470B2 (ja) | 1999-07-05 |
SI0870761T1 (en) | 2004-06-30 |
HK1017880A1 (en) | 1999-12-03 |
CA2234480A1 (en) | 1998-10-11 |
DE69821815D1 (de) | 2004-04-01 |
EP0870761B1 (en) | 2004-02-25 |
ATE260252T1 (de) | 2004-03-15 |
DE69821815T2 (de) | 2005-01-13 |
ITMI970845A1 (it) | 1998-10-11 |
IT1291550B1 (it) | 1999-01-11 |
KR19980081125A (ko) | 1998-11-25 |
DK0870761T3 (da) | 2004-06-28 |
ES2216197T3 (es) | 2004-10-16 |
PT870761E (pt) | 2004-05-31 |
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