CN1183130C - 噻唑烷类衍生物及其医药用途 - Google Patents
噻唑烷类衍生物及其医药用途 Download PDFInfo
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- CN1183130C CN1183130C CNB991202503A CN99120250A CN1183130C CN 1183130 C CN1183130 C CN 1183130C CN B991202503 A CNB991202503 A CN B991202503A CN 99120250 A CN99120250 A CN 99120250A CN 1183130 C CN1183130 C CN 1183130C
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- thiazolidine
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- pyridyl
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- 150000003548 thiazolidines Chemical class 0.000 title description 4
- 239000003814 drug Substances 0.000 claims abstract description 5
- 201000001421 hyperglycemia Diseases 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910001415 sodium ion Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims 3
- 150000001875 compounds Chemical class 0.000 abstract description 29
- 150000001768 cations Chemical class 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- -1 alkaline earth metal cation Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000002902 bimodal effect Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 150000001457 metallic cations Chemical class 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000004445 quantitative analysis Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZITMXBBQIWULSF-UHFFFAOYSA-N B.C.C Chemical compound B.C.C ZITMXBBQIWULSF-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical class [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 150000005838 radical anions Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
式(I)化合物：其中M#[+]表示药物上可接收金属阳离子，n＝1-4的整数。此化合物的制备方法，含有此化合物的药物组合物及其在治疗和/或预防高血糖症上的应用。
Description
本发明涉及噻唑烷盐类衍生物，其制备方法，含有这些化合物的药物组合物及它们的降血糖作用。
PCT专利WO9405659描述了一些具有降血糖活性的通式(II)噻唑烷生物。
其中M-表示药物上可接受的酸根阴离子。
但从该文献披露的通式(II)化合物的马来酸盐的溶解度看，其在水溶液中的溶解度较低，不利于口服制剂的制备。
本发明的目的是寻找具有优良水溶性的新的噻唑烷盐类衍生物。
现在发现式(I)中的一组化合物在水溶液中具有优良的溶解度，同时显示出优良的降血糖作用。例如，在室温水溶液和中性生理缓冲溶液中，式(I)化合物的溶解度≥45mg/ml。再者式(I)中的化合物在固体条件下也显示了良好的稳定性。这些化合物易溶于水的性质和良好的固体稳定性提供了良好生物可利用度，从而可大量而有效地制备各种制剂。
因此，本发明提供了一类具有通式(I)的化合物：
其中M+表示药物上可接收的金属阳离子，n为1-4的整数。
优选的金属阳离子是碱金属或碱土金属阳离子。
优选的碱金属阳离子是钠或钾离子。
根据本发明，优选的式(I)化合物是5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐。
应当理解，本发明式(I)化合物盐也包括其适宜的药物上可接受的溶剂化物和水合物。
本发明还涉及用于预防或治疗高血糖症的药物组合物，其包括式I化合物及药用载体，
其中，M+表示药物上可接受的金属阳离子，n为1-4的整数。
根据本发明，本发明式I化合物可以单独使用或以药物组合物的形式使用。本发明药物组合物可通过口服、非肠道或局部给药途径给药。给药剂型举例有：片剂、胶囊、溶液、注射液、栓剂、贴剂、软膏等。
根据本发明，本发明的药物组合物可按本领域已知方法制备，例如将式I化合物与药用载体混合。
根据本发明，本发明的式I化合物可通过将5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮(其制备见Cantello，B.C.C，Cawthorne，M.A.，Cottam，G.P.，等人，药物化学杂志(J.Med.chem.)，1994，37：3977-85中所述)与碱金属或碱土金属醇盐如乙醇碱金属盐反应制备。
根据本发明，本发明化合物的溶解度可以用标准的溶解度测定方法测定。例如在室温水溶液和中性生理缓冲溶液中，式(I)化合物中钠盐的溶解度≥45mg/ml，而同样条件下式(II)化合物中马来酸盐的溶解度小于10mg/ml。因此式(I)化合物与式(II)化合物相比在水溶液和中性生理缓冲溶液中具有显著提高的溶解度，这一性质为式(I)化合物的生物可利用度，大量使用和有效制备制剂提供了优点。
根据本发明，本发明式I化合物具有良好的稳定性且该稳定性可以用常规的定量分析法测定。例如式I化合物稳定性可以用加速稳定性实验来测定，如在40摄氏度，75％相对湿度；40摄氏度，92.5％相对湿度；及80摄氏度，测定式I化合物的稳定性。分析可以用薄层色谱，差示扫描量热法，热解重量分析法和升温下的等温实验进行。实验化合物的定量分析是在贮藏期之前、贮藏期之间和贮藏期之后取样进行。
本发明还提供了用于治疗和/或预防高血糖症的式(I)化合物和/或其药物上可接受的溶剂化物或其水合物。
式(I)化合物可以用下列实施例合成、纯化，结晶和进行热稳定性及吸湿性分析，实施例用于说明本发明，但没有任何限制作用。
实施例1
5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐。
将32mg的金属钠溶解在5ml无水乙醇中，加热回流至钠消失，然后将上述制得的乙醇钠滴加到溶解在25ml无水乙醇中的500mg5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮中。开始保持反应温度为零度，滴加完毕将反应逐渐升温到室温，搅拌过夜，将母液浓缩，加入乙醚搅拌，过滤，用乙醚反复洗涤所得到的固体，真空干燥得到5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐，426mg(收率84.7％)，m.p.215℃(分解)。
1H NMR δ(ppm)(400MHZ，d6-DMSO)：3.0-3.3(2H，多重峰)，3.1(3H，单峰)，3.9(2H，三重峰)，4.1(2H，三重峰)，4.2(1H，多重峰)，6.5-6.7(2H，多重峰)，6.8(2H，双峰)，7.1(2H，双峰)，7.5(1H，三重峰)，8.1(1H，双峰)。
实施例2
5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐的热稳定性。
5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐样品放入80℃烘箱烘烤，分别在第0，3，8，15天取样，用HSGF-254硅胶板，CHCl3∶CH3OH＝10∶0.3展开剂，进行薄层色谱分析，在紫外254nm波长下，所有样品的Rf＝0.51，这表明样品组成无分解。
实施例3
5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐的吸湿稳定性。
5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐样品分别放入恒温40℃，置有饱和KNO3溶液(相对湿度92.5％)和饱和NaCl溶液(相对湿度75％)的干燥器中。放置在92.5％相对湿度中的样品分别在0，8，15天取样：放在75％相对湿度中的样品分别在0，8，15，45天取样，用HSGF-254硅胶板，CHCl3∶CH3OH＝10∶0.3展开剂，进行薄层色谱分析，在紫外254nm波长下，所有样品的Rf＝0.51，这表明样品组成无变化。
Claims (3)
1.式I的5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐，
其中M+为钠离子，n为1。
2.含有式I的5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐，
其中M+为钠离子，n为1，及药用载体的药物组合物。
3.式I的5-〔4-〔2-(N-甲基-N-(2-吡啶基)氨基)乙氧基〕苄基〕噻唑烷-2，4-二酮钠盐在制备用于治疗和/或预防高血糖症的药物中的应用，
其中M+为钠离子，n为1。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991202503A CN1183130C (zh) | 1999-09-24 | 1999-09-24 | 噻唑烷类衍生物及其医药用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991202503A CN1183130C (zh) | 1999-09-24 | 1999-09-24 | 噻唑烷类衍生物及其医药用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1253136A CN1253136A (zh) | 2000-05-17 |
| CN1183130C true CN1183130C (zh) | 2005-01-05 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB991202503A Expired - Lifetime CN1183130C (zh) | 1999-09-24 | 1999-09-24 | 噻唑烷类衍生物及其医药用途 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU225919B1 (en) * | 1999-12-18 | 2007-12-28 | Richter Gedeon Nyrt | Thiazolidine-derivatives, process for their preparation pharmaceutical and intermediates |
| GB0021865D0 (en) * | 2000-09-06 | 2000-10-18 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0023971D0 (en) * | 2000-09-29 | 2000-11-15 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0023970D0 (en) * | 2000-09-29 | 2000-11-15 | Smithkline Beecham Plc | Novel pharmaceutical |
| ES2174748B1 (es) * | 2001-01-31 | 2003-09-16 | Vita Lab | Nueva sal de tiazolidindiona y sus polimorfos como agentes antidiabeticos y procedimiento para la obtencion de los mismos. |
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1999
- 1999-09-24 CN CNB991202503A patent/CN1183130C/zh not_active Expired - Lifetime
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| Publication number | Publication date |
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| CN1253136A (zh) | 2000-05-17 |
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