CN1458930A - 噻唑烷二酮衍生物的酒石酸盐 - Google Patents
噻唑烷二酮衍生物的酒石酸盐 Download PDFInfo
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- CN1458930A CN1458930A CN01815682A CN01815682A CN1458930A CN 1458930 A CN1458930 A CN 1458930A CN 01815682 A CN01815682 A CN 01815682A CN 01815682 A CN01815682 A CN 01815682A CN 1458930 A CN1458930 A CN 1458930A
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- 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
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Abstract
一种新颖的药物化合物5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐或其溶剂化物,一种制备这种化合物的方法,一种包含这种化合物的药物组合物,以及这种化合物在医药方面的用途。
Description
本发明涉及新颖的药物,此药物的制法以及此药物在医学中的用途。
公开号为0306228的欧洲专利申请涉及一些据报导具有降低血糖和促使血清脂质减少的活性的噻唑烷二酮衍生物。EP0306228的实施例30的化合物是5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,3-二酮(以下称作“化合物(I)”)。
公开号为WO94/05659的国际专利申请披露了EP0306228的化合物的某些盐类,它们中的一种是酒石酸盐,WO94/05669的优选盐是马来酸盐。
现已发现,化合物(I)形成新颖的酒石酸盐(以下也称作“内消旋酒石酸盐”(“Meso-Tartrate”))。
此新颖的内消旋酒石酸盐是稳定的高熔点结晶物质,因此适于大规模制备和处理。此内消旋酒石酸盐能进行大规模药物加工,特别是在需要热或产生热的药物加工,例如研磨、流化床干燥、喷雾干燥、热熔融加工及用高压进行的消毒时。此内消旋酒石酸盐也能够用有效的、经济的和特别适于大规模制备的可再生产工艺来制备。
此新颖的内消旋酒石酸盐还具有有用的药物性能,而且特别是人们已指出,它对糖尿病、与糖尿病相关的疾病以及它的并发症的治疗和/或预防是有用的。
因此,本发明提供5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐或其溶剂化合物。
此内消旋酒石酸盐适用的是单酒石酸盐。
此单酒石酸盐还任选包括其他单价成盐离子例如碱金属阳离子或铵阳离子。
在一个优选方面,此内消旋酒石酸盐具有与图1基本上一致的红外光谱。
在一个优选方面,此内消旋酒石酸盐具有与图2基本上一致的拉曼光谱。
在一个优选方面,此内消旋酒石酸盐具有与表1或图3基本上一致的X-射线粉末衍射图(XRPD)。
在一个优选方面,此内消旋酒石酸盐具有与图4基本上一致的固态13CNMR谱。
在一个优选方面,此内消旋酒石酸盐的熔点在147-157℃的范围内,例如在148-155℃的范围内,如148℃,153℃及155℃。
在优选方面,本发明提供5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,3-二酮内消旋酒石酸盐,其特征在于它具有:
(i)基本上与图1一致的红外光谱;
(ii)基本上与图2一致的拉曼光谱;
(iii)基本上与表1或图3一致的X-射线粉末衍射图(XRPD);以及
(iv)基本上与图4一致的固态13CNMR谱。
本发明包括分离成纯形式的内消旋酒石酸盐或它的溶剂化物或与其他物质的混合物。因此,在一方面,本发明提供处于分离形式的内消旋酒石酸盐或它的溶剂化合物。
另一方面,本发明提供处于纯形式的内消旋酒石酸盐或它的溶剂化物。
在又一方面,本发明提供处于结晶形式的内消旋酒石酸盐或它的溶剂化物。
此外,本发明提供处于固体药物上可接受形式的内消旋酒石酸盐或它的溶剂化物,例如固体剂型,特别当用于作口服时。
另外,本发明也提供处于药物上可接受形式的内消旋酒石酸盐或它的溶剂化物,特别是处于松散形式,这种形式特别易于进行药物加工,特别是在需要热或产生热的药物加工例如研磨;例如热干燥特别是流化床干燥或喷雾干燥;例如热熔加工;例如热消毒如高压消毒。
再有,本发明提供药物上可接受形式特别是松散形式,以及特别是处于于在需要热或产生热的制备过程中已经加工过的形式的内消旋酒石酸盐或其溶剂化物,例如处于已磨形式;例如处于已热干燥形式,特别是已流化床干燥形式或已喷雾干燥形式;例如处于已热熔加工过的形式;例如处于被例如高压消毒的已热消毒形式。
适合的溶剂化物是水合物。
本发明也提供制备内消旋酒石酸盐或其溶剂化物的方法,其特征在于将优选分散于或溶解于合适溶剂中的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(化合物(I))或其盐,与内消旋酒石酸根离子源反应,然后,如果需要,制备所得到的内消旋酒石酸盐的溶剂化物;以及回收此内消旋酒石酸盐或其溶剂化物。
适合的反应溶剂是酮如丙酮,或醚如四氢呋喃,烷醇如丙醇-2,烃如甲苯,酯如乙酸乙酯,腈如乙腈,或卤代烃如二氯甲烷,或水,或有机酸如乙酸;或它们的混合物。
内消旋酒石酸根离子源可方便地是内消旋酒石酸。优选将内消旋酒石酸以固体加入或在溶液中加入,例如在水中或在低级醇如甲醇、乙醇或丙醇-2中,或在溶剂混合物中加入。内消旋酒石酸的适用可溶碱性盐如内消旋酒石酸铵,或者胺如乙胺或二胺的内消旋酒石酸盐,可被用作内消旋酒石酸根离子的替代源。
化合物(I)的浓度优选在2-25%重量/体积的范围内,更优选在5~20%的范围内。内消旋酒石酸溶液的浓度优选在5~125%重量/体积的范围内。
反应通常在室温或高温下进行,例如在溶剂的回流温度下进行,虽然也可以采用任何能生成所需产物的合适温度。
此内消旋酒石酸盐的溶剂化物例如水合物根据通常的方法制备。
所需化合物的回收通常包括从合适溶剂或溶剂混合物,方便的是从反应溶剂中结晶出来,通常通过冷却予以促进。例如,此内消旋酒石酸盐可以从酮如丙酮,或从醚如四氢呋喃,或从水,或从它们的混合物中结晶出来。通过蒸发出去部分或全部溶剂,或通过在高温下结晶随后控制冷却,任选分步进行,可以高产率地获得此盐。可以采用仔细控制沉淀温度的方法以改善产物的再生产率。
结晶也可以用内消旋酒石酸盐或其溶剂化物的结晶进行接种而开始,但这并不必需。
当此单酒石酸盐包括其他单价成盐离子如碱金属或铵阳离子时,通过将单酒石酸盐与所选择的单价成盐离子例如金属或铵离子的溶液反应而方便地形成该离子。作为代替,化合物(I)可以用该单价成盐离子的单酒石酸盐进行处理。
化合物(I)按照公知的方法制备,例如按照在EP0306228和WO94/05659中公开的那些方法制备。EP0306228和WO94/05659的公开在这里引用作参考文献。
内消旋酒石酸是商业提供的化合物。
当这里使用术语“T开始”时,它通常用差示扫描量热法测出,而且具有本技术领域都理解的意义,例如在Ford及Timmins,1989所著的《药物热分析,方法及应用》(Pharmaceutical Thermal Analysis,Techniques andApplications)中以“相应于前转变基线与外推的转变前沿的交叉点的温度”所表示的意义。
当这里就某些化合物而使用术语“良好的流动性能”时,它合适地表征为该化合物的Hausner比为小于或等于1.5,特别是小于或等于1.25。
“Hausner比”是本技术领域接受的术语。
当这里使用术语“与糖尿病相关的疾病的预防”时,它包括治疗那些疾病,如耐胰岛素性,受削弱的糖耐量,血内胰岛素过多症,及妊娠糖尿病。
糖尿病优选指II型糖尿病。
与糖尿病相关的疾病包括血糖过多及耐胰岛素性和肥胖症。此外,与糖尿病相关的疾病还包括高血压,心血管疾病特别是动脉粥样硬化,某些饮食疾病,特别是患与饮食不足相关的疾病如神经性食欲缺乏,及患与过食相关的疾病如肥胖症和厌食贪食症的患者的食欲调节和摄取量调节。与糖尿病相关的其他疾病还包括多囊卵巢综合症和甾体导致的耐胰岛素性。
这里包括的与糖尿病相关的疾病的并发症包括肾脏疾病,特别是与II型糖尿病发展相关的肾病,这包括糖尿病肾病变,肾小球性肾炎,肾小球硬化症,肾病综合症,高血压肾硬化,及最后阶段肾病。
如上所述,本发明的化合物具有有用的治疗性能:因此本发明提供了用作活性治疗物质的所述内消旋酒石酸盐或其溶剂化物。
更具体地说,本发明提供了用于治疗和/或预防糖尿病、与糖尿病相关的疾病以及其某些并发症的所述内消旋酒石酸盐或其溶剂化物。
此内消旋酒石酸盐或其溶剂化物本身即可给药,或者它优选以还包含药物上可接受的载体的药物组合物给药。配制此内消旋酒石酸盐或其溶剂化物的合适方法通常是在上述出版物中关于化合物(I)所公开的那些方法。
因此,本发明也提供一种包含所述内消旋酒石酸盐或其溶剂化物以及药物上可接受的载体的药物组合物。
此内消旋酒石酸盐或其溶剂化物一般以单位剂量形式给药。
此活性化合物可以以任何合适途径给药,但通常是经口或胃肠外途径给药。为了这种用法,此化合物通常与药物载体、稀释剂和/或赋形剂一起以药物组合物的形式使用,虽然此药物组合物的准确形式将自然取决于给药方式。
此组合物用混合制备,适用于口服、胃肠外或局部给药,为此制成片剂、胶囊,口服液体制剂,粉末、粒剂,锭剂,软锭剂,可恢复的粉末,可注射的或可输注的溶液或悬浮液,栓剂和经皮使用的装置。口服组合物是优选的,特别是成形的口服组合物,因为它们更适合于普通用法。
口给药的片剂或胶囊通常以单位剂量提供,并含有常用的赋形剂如粘结剂,填料,稀释剂,成片剂,润滑剂,崩解剂,着色剂,芳香剂,及润湿剂。这些片剂可以按本技术领域公知的方法包覆。
所用合适填料包括纤维素,甘露糖醇,乳糖及其他相似物。适用的崩解剂包括淀粉,聚乙烯吡咯烷酮及淀粉衍生物如淀粉乙醇酸钠。适用的润滑剂包括例如硬脂酸镁。适用的药物上可接受的润滑剂包括月桂基硫酸钠。
可以采用通常用的掺混、填充、压片等方法制造固体口服组合物。可以采用重复掺混的操作法把活性剂分散到使用了大量填料的组合物中。当然,这种操作在本技术领域是常用的。
口服液体制剂的形式可以是例如水悬浮液或油悬浮液,溶液,乳液,糖浆,或酏剂,或者它可以以干产物提供,这种干产物可以在使用前用水或其他合适媒介物进行再溶解。这种液体制剂可以含有常用添加剂例如悬浮剂如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂,乳化剂如卵磷脂、脱水山梨醇单油酸酯或阿拉伯胶;非水媒介物(它可包括食用油)如杏仁油、分级椰子油、油性酯如甘油酯、丙二醇酯或乙醇酯;防腐剂如对羟基苯甲酸甲酯或丙酯、或山梨酸;而如果需要还可含通用的芳香剂或着色剂。
为了胃肠外给药,制备了含本发明化合物及无菌媒介物的液体单元剂量剂形式。根据媒介物及浓度,可将此化合物悬浮或溶解。胃肠外用的溶液通常通过将此活性化合物溶在媒介物中、在灌入合适小玻璃瓶或安瓿之前将过滤器消毒、以及封口而制取。将辅剂如局部麻醉剂、防腐剂及缓冲剂也溶于媒介物中也是有好处的。为提高稳定性,在灌入小玻璃瓶并在真空下除去水之后,可将此组合物冷冻。
胃肠外用的悬浮液用基本相同方法制备,只是将此活性化合物悬浮于媒介物中而不是使之溶解和在悬浮于消毒媒介物中之前曝露于环氧乙烷中使之消毒。在组合物中包括表面活性剂或润湿剂以使活性化合物均匀分布,是有益的。的或印刷的使用方法。
这里所用的术语“药物上可接受的”包括既可人用,也可兽用的化合物、组合物及各成分:例如术语“药物上可接受的盐”包括兽药上可接受的盐。
本发明还提供治疗和/或预防人或非人的哺乳动物的糖尿病、与糖尿病相关的疾病以及其某些并发症的方法,此方法包括给予需要的人或非人哺乳动物有效的无毒量的所述内消旋酒石酸盐或其溶剂化物。
此活性组份方便地以上面定义的药物组合物给药,这构成本发明的一个特别方面。
另一方面,本发明提供了此内消旋酒石酸盐及其溶剂化物在制造药物方面的用途,这种药物用于治疗和/或预防糖尿病、与糖尿病相关的疾病以及其某些并发症。
在治疗和/或预防糖尿病、与糖尿病相关的疾病以及其某些并发症时,内消旋酒石酸盐及其溶剂化物的使用量应使得能提供合适剂量的化合物(I),例如EP0306,228,WO94/05659或WO98/55122中所公开的。
对于本发明的化合物来说,在上述治疗中未发现有害的毒理作用。
下列实施例将解释本发明,但无论如何不是限制本发明。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-2,4-二酮内消旋酒石酸盐
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(8.0克)及四氢呋喃(160毫升)的混合物搅拌并加热至50℃,加入内消旋酒石酸(3.84克)在水(20毫升)之中的溶液,将此混合物在50℃搅拌15分钟,过滤,并把此清亮滤液冷至21℃。于40℃在减压下将溶剂蒸发,加入丙酮(40毫升),并把此混合物在21℃搅拌,得到白色悬浮液。过滤收集产物,用丙酮洗涤,并在真空下干燥,得白色结晶固体5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐(10.6克)。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-2,4-二酮内消旋酒石酸盐
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(3.0克,8.4毫摩尔),丙酮(40毫升)及四氢呋喃(5毫升)的混合物在搅拌下于回流下加热2.5小时。往其中加入内消旋酒石酸单水合物(1.41克,8.4毫摩尔)在水(2毫升)中的溶液。将此混合物在搅拌下于回流下加热2.5小时,然后冷至21℃,并在21℃搅拌16小时。过滤收集白色固体,用丙酮(40毫升)洗涤,然后在减压下在21℃干燥2.5小时,得到白色结晶固体5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐(3.25克)。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-2,4-二酮内消旋酒石酸盐
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(10.0克,28毫摩尔),丙酮(120毫升)及四氢呋喃(15毫升)的混合物在搅拌下于回流下加热50分钟。往其中加入内消旋酒石酸单水合物(4.7克,28毫摩尔)在水(6.0毫升)中的溶液。将此混合物在搅拌下于回流下加热1小时,然后冷至21℃,并在21℃搅拌16小时。过滤收集白色固体,用丙酮(50毫升)洗涤,然后在减压下在21℃干燥3小时,得到到白色结晶固体5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐(11.7克)。
记录的实施例1产物的特征数据
用Nicolet 710 FT-IR光谱仪在2cm-1分辨率下测得此产物在矿物油中的分散物的红外吸收光谱(图1)。以1cm-1间隔将这些数据进行数字化。在下列各处观察吸收谱带:3405,1738,1694,1629,1556,1537,1505,1459,1436,1418,1330,1268,1249,1223,1182,1167,1143,1104,1074,1057,1033,1000,949,916,887,853,818,771,717,668,619,568,528,515cm-1。
用装有通用ATR附件的Perkin-Elmer Spectrum One FT-IR谱仪记录此固体产物的红外光谱。在下列各处观察吸收带:3407,2937,2750,1739,1693,1628,1555,1535,1504,1476,1459,1412,1388,1358,1330,1261,1248,1222,1182,1167,1143,1101,1074,1056,1033,999,948,916,887,853,818,771,744,717,667cm-1。
采用Nicolet 960 E.S.P.FT-Raman谱仪,在4cm-1分辨率下,用输出功率为400mw的Nd:V04激光仪(1064nm)激发,使用NMR管中的样品,记录下产物的拉曼光谱(图2)。在下列各处观察吸收谱带:3101,3059,2952,2922,2877,1739,1604,1544,1458,1438,1394,1331,1270,1222,1203,979,887,827,739,668,638,605,472,344cm-1。
采用下列捕获条件记录产物的X-射线衍射图(图3):管状阴极:Cu,发生器电压:40Ky,发生器电流:40mA,起始角:2.0°2θ,终止角:35.0°2θ,步宽:0.02°2θ,每步时间:2.5秒。特征XRPD角及相对强度记录在表1中
表1
角 | 相对强度 |
2θ° | % |
4.9 | 11.4 |
9.3 | 12.4 |
9.9 | 3.1 |
12.2 | 1.9 |
14.3 | 3.3 |
14.9 | 7 |
15.2 | 19 |
15.9 | 23.8 |
16.2 | 13.9 |
17.0 | 8.6 |
17.3 | 17.5 |
18.1 | 25.9 |
18.5 | 31.3 |
19.1 | 10.7 |
19.9 | 18.4 |
20.4 | 100 |
21.6 | 26 |
22.2 | 23.7 |
22.7 | 6.1 |
23.6 | 23.1 |
24.5 | 5.7 |
25.2 | 23 |
25.8 | 9.2 |
26.2 | 17.8 |
26.8 | 11.5 |
27.4 | 14.7 |
28.1 | 6.8 |
28.4 | 8.7 |
29.7 | 5.7 |
30.2 | 9.7 |
30.6 | 9.3 |
31.1 | 23.6 |
31.4 | 13.4 |
32.2 | 14 |
32.6 | 19.7 |
32.9 | 15.2 |
33.6 | 11.4 |
33.8 | 12.4 |
34.4 | 8.7 |
34.7 | 9 |
将产物的固态NMR谱(图4)记录在于90.55MHz之下操作的BrukerAMX360仪上:将此固体装入安装有Kel-F盖子的4毫米氧化锆MAS转动体中,而转动体以约10KHz旋转。通过从Hartmann-Hahn匹配的质子的交叉极化(CP接触时间3毫秒,重复时间15秒)而获得13C MAS谱,而在用双脉冲相调制(TPPM)的复合程序进行的搜索过程中将质子去偶。将化学位移相对于TMS在176.4ppm处外部参比甘氨酸的羧酸根信号,在下列各处进行观察:183.0,177.2,175.4,173.0,160.0,159.0,151.8,144.2,138.9,134.3,130.8,128.2,123.6,113.7,112.8,77.4,76.7,74.5,55.5,53.5,50.0,42.4,36.6,33.8ppm。此内消旋酒石酸盐的性能记录的实施例1产物的内消旋酒石酸的固体稳定性
此药物的固体稳定性,将在玻璃瓶中的大约1.0克此物质在下列情况下测定的:a)在40℃/相对湿度(RH)75%,打开瓶子,1个月,b)在50℃,塞好瓶子,1个月。用HPLC测定在这两种情况下此物质的最终含量和降解产物。
a)40℃/75%RH:未观察到明显的降解(HPLC测出含起始物97%)。
b)50℃:未观察明显的降解(HPLC测出含起始物98%)。此内消旋酒石酸盐的熔点
使用Buchi545熔点仪,按照美国药典,USP23,1995,<741>“熔点范围或温度,第Ia类方法”,测定此内消旋酒石酸盐的熔点。
实施例1的产物,熔点:149℃
实施例2的产物,熔点:153℃
实施例3的产物,熔点:155℃此内消旋酒石酸盐的T开始
用Perkin-Elmer DSC仪器以差示扫描量热法测定此药物的T开始。
实施例1的产物,T开始(10℃/分钟,闭盘):146℃
实施例2的产物,T开始(10℃/分钟,开盘):153℃
实施例3的产物,T开始(10℃/分钟,开盘):154℃
Claims (12)
1.一种化合物5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐或其溶剂化物。
2.根据权利要求1的化合物,其特征在于它具有:
(i)基本上与图1一致的红外光谱;
(ii)基本上与图2一致的拉曼光谱;
(iii)基本上与表1或图3一致的X-射线粉末衍射图(XRPD);或
(iv)基本上与图4一致的固态13CNMR谱。
3.根据权利要求1的化合物,其特征在于它具有下列特征中的两个或更多个:
(i)基本上与图1一致的红外光谱;
(ii)基本上与图2一致的拉曼光谱;
(iii)基本上与表1或图3一致的X-射线粉末衍射图(XRPD);以及
(iv)基本上与图4一致的固态13CNMR谱。
4.根据权利要求1~3任一项的化合物,它处于已提纯形式。
5.根据权利要求1~3任一项的化合物,它处于固体剂量形式。
6.根据权利要求1~3任一项的化合物,它处于在需要热或产生热的制备过程中能进行药物加工的形式,这种加工过程例如是研磨;例如是热干燥,特别是流化床干燥或喷雾干燥;例如是热熔加工;例如是热消毒如高压消毒。
7.根据权利要求1~3任一项的化合物,它处于在需要热或产生热的制备过程中已经加工过的形式之中,例如处于已研磨形式;例如处于已热干燥形式特别是已流化床干燥形式或已喷雾干燥形式;例如处于已热熔加工过的形式;例如处于已被如高压消毒的热消毒形式。
8.根据权利要求1~3任一项的化合物,它处于具有良好流动性能的药物上可接受的形式。
9.一种制备上述的内消旋酒石酸盐或其溶剂化物的方法,其特征在于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(化合物I)或其盐与内消旋酒石酸根离子源反应,然后,如果需要,制备所得到的内消旋酒石酸盐的溶剂化物;以及回收此内消旋酒石酸盐或其溶剂化物。
10.一种包含5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐或其溶剂化物以及药物上可接受的载体的药物组合物。
11.一种用作活性治疗物质的化合物5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐或其溶剂化物。
12.5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮内消旋酒石酸盐或其溶剂化物在制备于治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些并发症的药物的用途。
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AU2001276508A1 (en) | 2002-02-18 |
BG107605A (bg) | 2003-09-30 |
WO2002012233A1 (en) | 2002-02-14 |
BR0112984A (pt) | 2003-06-10 |
EP1307448A1 (en) | 2003-05-07 |
EA200300231A1 (ru) | 2003-06-26 |
NO20030508D0 (no) | 2003-01-31 |
IL154277A0 (en) | 2003-09-17 |
ECSP034468A (es) | 2003-03-31 |
MA25830A1 (fr) | 2003-07-01 |
SK1452003A3 (en) | 2004-05-04 |
HUP0300770A2 (hu) | 2003-11-28 |
KR20030022356A (ko) | 2003-03-15 |
JP2004505971A (ja) | 2004-02-26 |
ZA200300962B (en) | 2003-10-29 |
MXPA03001086A (es) | 2003-05-27 |
CZ2003314A3 (cs) | 2004-02-18 |
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