CN101228157A - 罗格列酮的氨基酸盐 - Google Patents
罗格列酮的氨基酸盐 Download PDFInfo
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- rosiglitazone
- amino acid
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- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical class C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960004586 rosiglitazone Drugs 0.000 title claims abstract description 38
- -1 Amino acid salts Chemical class 0.000 title claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 229960001231 choline Drugs 0.000 claims description 15
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000030814 Eating disease Diseases 0.000 claims description 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 235000014632 disordered eating Nutrition 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 201000001421 hyperglycemia Diseases 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000009897 systematic effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 9
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- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 7
- 229930182817 methionine Natural products 0.000 description 7
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- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
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- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- 229960003271 rosiglitazone maleate Drugs 0.000 description 2
- SUFUKZSWUHZXAV-BTJKTKAUSA-N rosiglitazone maleate Chemical compound [H+].[H+].[O-]C(=O)\C=C/C([O-])=O.C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O SUFUKZSWUHZXAV-BTJKTKAUSA-N 0.000 description 2
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- YASAKCUCGLMORW-HNNXBMFYSA-N (-)-rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1C[C@@H]1SC(=O)NC1=O YASAKCUCGLMORW-HNNXBMFYSA-N 0.000 description 1
- HMBHAQMOBKLWRX-UHFFFAOYSA-N 2,3-dihydro-1,4-benzodioxine-3-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)COC2=C1 HMBHAQMOBKLWRX-UHFFFAOYSA-N 0.000 description 1
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 241000978776 Senegalia senegal Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
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- 229940075419 choline hydroxide Drugs 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 239000003797 essential amino acid Substances 0.000 description 1
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- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
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- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
本发明涉及罗格列酮(系统命名：5－(4－/2－(N－甲基－N－(2－吡啶基)氨基)乙氧基/苄基)－2，4－噻唑烷二酮)的外消旋形式或对映体或互变异构形式的新的氨基酸盐以及所述盐的溶剂化物。
Description
本发明涉及罗格列酮(rosiglitazone)的新盐，即罗格列酮的氨基酸盐及其溶剂化物，涉及包含这种盐或溶剂化物的药物制剂，涉及其治疗某些疾病的用途，以及涉及制备这种盐的方法。具体地，本发明涉及罗格列酮的外消旋形式或对映体或互变异构形式的胆碱酸盐、赖氨酸盐和精氨酸盐，优选胆碱酸盐，因为其良好的水溶性。
罗格列酮是对于5-(4-/2-(N-甲基-N-(2-吡啶基)氨基)乙氧基/苄基)-2，4-噻唑烷二酮的INN命名，且在EP-B 0 306 228 B1中详细描述。其适于治疗和预防高血糖症，特别是II型糖尿病、高脂血症、高血压、心血管疾病和某些进食障碍疾病。认为马来酸盐比游离碱更易溶，其具有良好的稳定性且因为其改进的选择性尤其适用于II型糖尿病。其描述于EP 0 658 161 B1。WO94/05659还公开了酒石酸盐。WO02/12232公开了DL酒石酸盐，认为其不同于D酒石酸盐和L酒石酸盐，且具有有益的特性。罗格列酮的盐酸盐是WO02/20519的主题物质且其磷酸盐公开于WO05/023803。其将具有高水溶性，但这仍不太令人满意。因此，需要寻找罗格列酮的新盐以拓宽其使用范围。该新盐将尤其具有良好的水溶性，特别是在生理条件下。
罗格列酮新盐的可能应用的标准是，可能具有不利或甚至有害性质的物质不被药物非活性的阴离子带进体内，认为该阴离子能改变药物活性碱的某些副性状。因此，该阴离子不应是从体外得来的，如果可能的话，至少应是存在于体内的物质或甚至其供给是有利的。
现已发现氨基酸对于形成罗格列酮盐是有益的。氨基酸甚至是人体的必需组成部分，即，没有源自体外的物质，且通常其供给是实际所需的。因此，根据本发明的氨基酸盐是良好耐受的且显示低毒性。它们也具有良好的水溶性。该水溶性取决于pH。当pH为9.0，罗格列酮胆碱酸盐的水溶性为20.0mg/ml，罗格列酮赖氨酸盐的水溶性为9.4mg/ml，且罗格列酮马来酸盐的水溶性为5.9mg/ml而罗格列酮磷酸盐的水溶性仅为2.4mg/ml。当pH为6.5，罗格列酮胆碱酸盐的水溶性为11.7mg/ml，其超过罗格列酮马来酸盐水溶性(＜0.1mg/ml)100倍。令人惊讶的是，根据本发明的盐实际上是不吸湿的并显示优异的稳定性。就本发明在此描述的罗格列酮而言，本发明适用于罗格列酮的对映体和互变异构形式。
目前尤其优选罗格列酮与胆碱的盐。
胆碱是很多代谢功能的重要组分且用作治疗剂。此外，它是多种维生素制剂的组分且包含于许多食物中。摄取通常的量其实际是无毒的且因此是良好相容的。
赖氨酸为必需氨基酸且存在于几乎所有蛋白中。其药物相容性已经测试过多次。赖氨酸用作尤其是营养食品的食品添加剂。
精氨酸为非必需氨基酸，其同样存在于几乎所有蛋白中。其用作食品添加剂和治疗剂组分。
氨基酸盐可通过将罗格列酮碱溶解于沸腾乙醇或甲醇中并添加固体氨基酸或溶于温水的氨基酸溶液而容易地制备。罗格列酮胆碱酸盐也可通过将罗格列酮悬浮于无水乙醇，用胆碱溶液混合之，并用乙酸乙酯和乙醚沉淀该盐而适当地获得。该产物以晶体沉淀且优选在0℃过滤。
根据本发明的盐可用通常已知的方法配制成用于哺乳动物优选人的药物制剂。该药物制剂包含根据本发明的盐并混合药用有机或无机载体，该载体适于肠内或胃肠外给药。尤其优选口服给药本发明的盐，通过片剂、胶囊、粉剂或液体形式，如悬浮液、在溶液中以乳剂或糖浆形式。
当配制片剂时，使用通常的药物载体，如柠檬酸钠、乳糖、微晶纤维素和淀粉，润滑剂如无水硅石、氢化蓖麻油、硬脂酸镁、月桂基硫酸钠和滑石，以及粘合剂如淀粉糊、葡萄糖、乳糖、阿拉伯胶、甘露醇、三硅酸镁和滑石。当本发明的盐以液体给药时，可以使用常用液体载体。
还优选如在技术中已知和在相关标准著作中描述的用于注射和输液的制剂。
根据本发明的盐也可以通常已知方法配制成长效制剂或具有缓慢或持续释放的药物。
实施例
实施例1
在水浴加热温度50℃下将3.5g罗格列酮溶解于15ml的THF中。将2.65g的45％的胆碱的甲醇(methanolic choline hydroxide)溶液添加至该溶液。搅拌5分钟后，在搅拌下逐渐添加75ml乙酸乙酯。将晶种添加至轻微浑浊的溶液中并移去加热浴。将该批量在室温放置过夜。产物以细白针状物沉淀。通过真空过滤分离晶体，用10ml THF/乙酸乙酯1∶3的混合物清洗并在真空干燥24小时。
产量：3g
熔点：101.5-103.8℃
1H光谱：组合物胆碱/罗格列酮1∶1，几乎无溶剂可见
测试产物的粉末X射线光谱如图1所示。2θ值标绘于x轴，强度标绘于y轴。所得多晶型形式的特征为在2θ值为8.76，15.90，17.59，18.75，19.73和22.24的主峰，具体是以下峰数据：
粉末X射线衍射
| 峰位置2θ(°) | 峰强度 |
| 8.76 | 571.3 |
| 9.89 | 283.3 |
| 12.49 | 119.9 |
| 14.12 | 206.7 |
| 15.90 | 804.3 |
| 17.59 | 4529.8 |
| 17.92 | 319.2 |
| 18.34 | 290.5 |
| 18.75 | 669.7 |
| 19.73 | 952.5 |
| 20.72 | 369.8 |
| 21.22 | 265.5 |
| 22.06 | 309.9 |
| 22.24 | 463.8 |
| 23.41 | 161.8 |
| 24.68 | 189.6 |
| 29.56 | 184.1 |
| 31.07 | 187.3 |
| 32.01 | 201.0 |
| 34.57 | 184.4 |
在室温和常压用标准方法像通常一样进行测量。对于每个2θ值可以规定0.2作为误差范围。
实施例2
将5g罗格列酮悬浮于25ml无水乙醇中，在室温添加3.87g胆碱溶液，搅拌混合物10分钟并最终过滤。将100ml乙酸乙酯和100ml乙醚添加至滤液中，然后将滤液放置于冰箱5℃过夜。产物沉淀，为细白针状物。通过真空过滤分离晶体，并用10ml乙醚清洗。产物在室温20mbar下干燥5天。
产量：4.5g(70％)
实施例3
在加热沸腾下将4g罗格列酮溶解于130ml无水乙醇中。将1.642g赖氨酸溶解于5ml温水中并添加至热罗格列酮溶液中。将形成的澄清溶液加热沸腾5分钟。移去加热浴，并将该批量在室温放置。在室温放置3小时后，将其放置在冰箱5℃过夜。产物通过真空过滤分离，用20ml乙醇清洗并在50℃真空干燥几天。
产量：5.4g
实施例4
将1g罗格列酮和411mg赖氨酸溶解于10ml沸腾甲醇(无水)中，并在加热沸腾下将其添加至12ml异丙醇中。约5分钟后，移去加热浴并将该批量在室温放置过夜。产物通过真空过滤分离，用异丙醇和乙醚清洗，然后在50℃真空干燥16小时。
1H光谱：组合物赖氨酸/罗格列酮1∶1，约6％摩尔异丙醇。
实施例5
将1.05g罗格列酮和426mg赖氨酸溶解于10ml沸腾甲醇(无水)中，并在加热沸腾下将其添加至18ml乙酸乙酯中。约5分钟后，除去加热浴并将该批量在室温放置过夜。产物通过真空过滤分离，用乙酸乙酯清洗，并在50℃真空干燥16小时。
产量：1g
1H光谱：组合物赖氨酸/罗格列酮1∶1，约8％摩尔乙醇
实施例6
将2g罗格列酮和976mg精氨酸在70ml乙醇中加热至沸腾半小时。所得溶液在室温放置过夜。产物通过真空过滤分离，用乙醇清洗，并在50℃真空干燥2天。
产量：2.4g
实施例7
测定实施例1和3制备的罗格列酮盐的溶解度并与马来酸盐和游离碱的溶解度比较。
使用以下缓冲液：
pH 1.5 2％磷酸
pH 3.0 188mg KH2PO4溶于200ml水(aqua purificata)中并用1.0nHCl调节
pH 8.9 188mg KH2PO4溶于200ml水中并用1.0n NaOH调节
pH 12.0 250mg K2HO4溶于200ml水中并用1.0n HCl调节
在每种情况下添加约100mg待测物质的10ml(具有良好的溶解度，如pH11.8相应小些)上述相应缓冲液，并通过1.0n HCl或1.0n NaOH调节至相应的pH。之后，悬浮液在超声波浴中处理1分钟，检测pH，且当需要时，分别再调节至以下所给的值。然后，该溶液以0.45μm规格的过滤器过滤。
在345nm测量所制备的溶液的吸收。待测溶液用磷酸均匀调节至pH1.5以用于检测。游离碱作为校准物。
结果总结于表1。其尤其公开了，在生理pH范围，氨基酸盐的溶解度显著大于碱和马来酸盐的溶解度，尤其是胆碱酸盐在pH 6.5显示超过100倍的溶解度。
表1：罗格列酮的氨基酸盐与马来酸盐和游离碱的溶解度比较.
| 溶解度在 | 胆碱酸盐 | 赖氨酸盐 | 马来酸盐 | 碱 |
| pH 4.6 | 1.1mg/ml | 1.2mg/ml | 0.6mg/ml | 0.2mg/ml |
| pH 6.5 | 11.7mg/ml | 0.2mg/ml | ＜0.1mg/ml | 0.1mg/ml |
| pH 9.0 | 20.0mg/ml | 9.4mg/ml | 5.9mg/ml | 5.9mg/ml |
| pH 11.8 | ＞50mg/ml | ＞50mg/ml | 19.2mg/ml | ＞50mg/ml |
Claims (8)
1.罗格列酮外消旋形式或对映体或互变异构形式的氨基酸盐和所述盐的溶剂化物。
2.根据权利要求1的氨基酸盐，即罗格列酮胆碱酸盐及其溶剂化物。
3.根据权利要求1的氨基酸盐，即罗格列酮赖氨酸盐及其溶剂化物。
4.根据权利要求1的氨基酸盐，即罗格列酮精氨酸盐及其溶剂化物。
5.罗格列酮胆碱酸盐的多晶型形式，其特征为具有2θ值在8.76、15.90、17.59、18.75、19.73和22.24的粉末X射线衍射图。
6.药物，其包含根据权利要求1-5任一项的氨基酸盐或溶剂化物，和任选的一种或多种药物相容的载体和/或赋形剂。
7.根据权利要求1-5任一项的氨基酸盐或溶剂化物在制备用于治疗或预防高血糖症，特别是II型糖尿病、高脂血症、高血压、心血管疾病和/或进食障碍疾病的药物中的用途。
8.制备根据权利要求1-5任一项的氨基酸盐或溶剂化物的方法，其中将罗格列酮的外消旋形式或对映体或互变异构形式与氨基酸反应，或将罗格列酮与氨基酸的盐转化为另一种盐。
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| CN107789352A (zh) * | 2017-10-25 | 2018-03-13 | 桂林浩新科技服务有限公司 | 一种复方药物制剂及在制备治疗高血糖、高血脂的药物中的应用 |
| CN109053717A (zh) * | 2018-08-09 | 2018-12-21 | 天津理工大学 | 一种罗格列酮龙胆酸盐及其制备方法 |
| CN109053718A (zh) * | 2018-08-09 | 2018-12-21 | 天津理工大学 | 一种罗格列酮糖精盐及其制备方法 |
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| WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
| EA031116B1 (ru) | 2009-04-03 | 2018-11-30 | Ф. Хоффманн-Ля Рош Аг | КРИСТАЛЛИЧЕСКИЕ ПОЛИМОРФНЫЕ ФОРМЫ {3-[5-(4-ХЛОРФЕНИЛ)-1H-ПИРРОЛО[2,3-b]ПИРИДИН-3-КАРБОНИЛ]-2,4-ДИФТОРФЕНИЛ}АМИДА ПРОПАН-1-СУЛЬФОНОВОЙ КИСЛОТЫ |
| TW201041888A (en) | 2009-05-06 | 2010-12-01 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
| US8329724B2 (en) | 2009-08-03 | 2012-12-11 | Hoffmann-La Roche Inc. | Process for the manufacture of pharmaceutically active compounds |
| MX2012005284A (es) | 2009-11-06 | 2012-06-28 | Plexxikon Inc | Compuestos y metodos para la modulacion de cinasas. e indicaciones para ello. |
| PT2672967T (pt) | 2011-02-07 | 2018-12-07 | Plexxikon Inc | Compostos e métodos de modulação da quinase e suas indicações |
| US9030870B2 (en) * | 2011-08-26 | 2015-05-12 | Micron Technology, Inc. | Threshold voltage compensation in a multilevel memory |
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| WO2015042495A2 (en) * | 2013-09-22 | 2015-03-26 | Jiva Pharma, Inc. | Metformin salts to treat type2 diabetes |
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| KR20040062965A (ko) * | 2001-11-21 | 2004-07-09 | 스미스클라인비이참피이엘시이 | 로시글리타존 에디실레이트 및 항당뇨제로서의 그의 용도 |
| JP2005513038A (ja) * | 2001-11-21 | 2005-05-12 | スミスクライン ビーチャム パブリック リミテッド カンパニー | ５−［４−［２−（ｎ−メチル−ｎ−（２−ピリジル）アミノ）エトキシ］ベンジル］チアゾリジン−２，４−ジオンベンゼンスルホン酸塩；その製造方法；多形体ｉ、ｉｉおよびｉｉｉ；および医薬上活性な成分としてのその使用 |
| GB0129851D0 (en) * | 2001-12-13 | 2002-01-30 | Smithkline Beecham Plc | Novel compounds |
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| WO2003050112A1 (en) * | 2001-12-13 | 2003-06-19 | Smithkline Beecham Plc | Toluenesulfonate hydrates of a thiazolidinedione derivative |
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| WO2003050116A1 (en) * | 2001-12-13 | 2003-06-19 | Smithkline Beecham Plc | A 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione (i) 10-camphorsulphonic acid salt and use against diabetes mellitus |
| WO2003053962A1 (en) * | 2001-12-20 | 2003-07-03 | Smithkline Beecham Plc | 5- (4- (2- (n-methyl-n- (2-pyridyl) amino) ethoxy) benzyl) thiazolidine-2, 4-dione malic acid salt and use against diabetes mellitus |
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| WO2005023803A1 (en) * | 2003-09-10 | 2005-03-17 | Biocon Limited | Phosphoric acid salt of 5-[[4-[2-(methyl-2-pyridinylamino) ethoxy] phenyl] methyl]- 2,4-thiazolidinedione |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107789352A (zh) * | 2017-10-25 | 2018-03-13 | 桂林浩新科技服务有限公司 | 一种复方药物制剂及在制备治疗高血糖、高血脂的药物中的应用 |
| CN109053717A (zh) * | 2018-08-09 | 2018-12-21 | 天津理工大学 | 一种罗格列酮龙胆酸盐及其制备方法 |
| CN109053718A (zh) * | 2018-08-09 | 2018-12-21 | 天津理工大学 | 一种罗格列酮糖精盐及其制备方法 |
Also Published As
| Publication number | Publication date |
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| EP1907386B1 (de) | 2010-06-02 |
| AU2006271863A1 (en) | 2007-01-25 |
| WO2007009799A1 (de) | 2007-01-25 |
| ATE469896T1 (de) | 2010-06-15 |
| NZ565159A (en) | 2010-01-29 |
| ZA200800184B (en) | 2009-02-25 |
| US20080207700A1 (en) | 2008-08-28 |
| IL188661A0 (en) | 2008-08-07 |
| NO20080704L (no) | 2008-02-07 |
| DE102005034406A1 (de) | 2007-02-01 |
| DE502006007113D1 (de) | 2010-07-15 |
| KR20080032108A (ko) | 2008-04-14 |
| UA92354C2 (en) | 2010-10-25 |
| EA200800065A1 (ru) | 2008-08-29 |
| BRPI0613686A2 (pt) | 2011-01-25 |
| CA2616031A1 (en) | 2007-01-25 |
| JP2009502760A (ja) | 2009-01-29 |
| EA012594B1 (ru) | 2009-10-30 |
| ES2344662T3 (es) | 2010-09-02 |
| EP1907386A1 (de) | 2008-04-09 |
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