CN1243740C - 乙酰替苯胺衍生物的α型或β型结晶 - Google Patents
乙酰替苯胺衍生物的α型或β型结晶 Download PDFInfo
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Abstract
本发明提供了作为糖尿病治疗剂的制造原料有用的新结晶。涉及(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶及β型结晶。该α型结晶不显现出吸湿性,具有可作为医药品使用的稳定性,工业生产上能够大量合成。β型结晶显现出弱吸湿性,作为α型结晶的制造中间体有用。
Description
技术领域
本发明涉及作为糖尿病治疗剂有用的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶或β型结晶以及含有上述结晶的医药品,特别是糖尿病治疗剂。
背景技术
本发明者报道,以下的化学结构式表示的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的二盐酸盐兼具胰岛素分泌促进作用和胰岛素敏感性增强作用,还具有基于选择性的β3受体刺激作用的抗肥胖作用及抗高脂血症作用,是对糖尿病的治疗有用的化合物(国际公开WO99/20607号,实施例41)。
但是,该二盐酸盐具有较强的吸湿性,且不稳定,所以作为医药品使用目前还存在问题。
医药品除了要求对湿度、温度和光等长期稳定之外,还要求在制剂过程中的稳定。医药品如果具有较强的吸湿性,则物理化学性质会发生变化,不同批号会出现水分量不同这样的不良情况,所以需长期保存在干燥室内,或需设置干燥步骤,不利于工业使用。
发明的揭示
在上述技术水平下,本发明者对国际公开WO 99/20607号的实施例41中记载的上述化合物进行了认真研究,找到了新颖的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶(以下简称为“α型结晶”)或β型结晶(以下简称为“β型结晶”)。这2种新颖的结晶都为游离体,可通过粉末X射线衍射光谱及DSC分析区分。先前获得的二盐酸盐结晶在相对湿度80%以上时,其吸湿性急剧上升,在相对湿度90%时保持了约14%的水分,具有较强的吸湿性,是不稳定的结晶。
对应于此,本发明的“α型结晶”在相对湿度5%~95%的范围内,水分保持量在0.2%以下,是无吸湿性的稳定型结晶,可作为医药品使用。此外,“β型结晶”从相对湿度约20%开始重量有所增加,保持了约3%的水分,具有较弱的吸湿性,是一种亚稳定型结晶,也可作为医药品使用。“β型结晶”可作为“α型结晶”的制造中间体使用。
α型结晶及β型结晶分别通过下述粉末X射线衍射光谱的晶格间隔[2θ(°)]及DSC分析的热吸收峰赋予特征。粉末X射线衍射中,在数据的性质上和结晶的同一性认定方面,晶格间隔和整体的图形是非常重要的,相对强度因为结晶成长的方向、颗粒的大小和测定条件可多少有所变化,不能严密地解释。
表1(α型结晶)
晶格间隔 | 相对强度 | 晶格间隔 | 相对强度 |
5.32 | 强 | 19.04 | 较强 |
8.08 | 强 | 20.20 | 较强 |
15.28 | 较强 | 23.16 | 较强 |
17.88 | 较强 | 24.34 | 较强 |
表2(β型结晶)
晶格间隔 | 相对强度 | 晶格间隔 | 相对强度 |
9.68 | 中等程度 | 22.10 | 中等程度 |
19.76 | 较强 | 23.52 | 中等程度 |
20.72 | 中等程度 |
此外,DSC分析中,确认α型结晶在142~146℃、β型结晶在90~110℃及142~146℃分别具有热吸收峰。
粉末X射线衍射的测定中,采用MAC Science MXP18TAHF22型,以管球:Cu、管电流:40mA、管电压:40kV、试样宽:0.020°、扫描速度:3°/分钟、波长:1.54056埃、测定衍射角范围(2θ):5~40°的条件进行测定。
热分析(DSC及TGA)分别在以下条件下测定。
DSC:Perkin-Elmer Pyris 1型、25℃~250℃(10℃/分钟)、N2(20ml/分钟)、铝制试样盘。TGA:Perkin-Elmer TGA 7型、25℃~250℃(10℃/分钟)、N2(20ml/分钟)、铂制试样盘。
核磁共振谱(NMR)使用JEOL JNM-LA400型及JEOL JNM-A500型进行测定,作为内标使用四甲基硅烷(TMS)。
质谱分析使用JEOL DX-300型及JEOL LX-2000型进行测定。
本发明还涉及含有(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶或β型结晶的医药品,特别涉及兼具抗肥胖作用及抗高脂血症作用的糖尿病治疗剂。
以本发明的结晶为医药品的制造原料的医药品可以是片剂、丸剂、胶囊剂、颗粒剂、散剂等经口给药或吸入剂等非经口给药的形式。作为经口给药的固体组合物,可采用片剂、散剂和颗粒剂等。这种固体组合物由1种或1种以上的活性物质与至少1种惰性赋形剂,例如,乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、硅铝酸镁等混合而成。组合物中可根据常规方法含有惰性添加剂,例如,硬脂酸镁等润滑剂、羧甲基淀粉钠等崩解剂及助溶剂。片剂或丸剂根据需要还可包裹糖衣或胃溶性或肠溶性的包衣。给药量可考虑症状、给药对象的年龄和性别等根据不同情况决定,通常经口给药时成人1天为0.01mg/kg~100mg/kg左右,可以1次给药,也可分2~4次给药。
(制造方法)
在(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶中加入重结晶溶剂(乙醇水溶液37%~50%),在约70~80℃加热溶解后,以1小时约冷却10℃的速度慢慢冷却获得α型结晶。工业生产时大规模制造中易晶析,α型结晶通过接种能够优先析出。
室温下,在(R)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐、2-氨基噻唑-4-基乙酸、浓盐酸及水的混合液中加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺一盐酸盐,中和其酸性溶液,能够获得β型结晶的湿饼(湿饼表示结晶被溶剂润湿的状态)。
在该β型结晶中加入重结晶溶剂(乙醇水溶液37%~50%),在约70~80℃加热溶解后,将外温设定为20℃,急剧冷却,也能够获得β型结品。此外,β型结晶也可通过接种优先析出。
如上所述,分离的β型结晶加热溶解后能够再次转变为α型结晶,所以β型结晶作为α型结晶的制造中间体有用。
实施发明的最佳方式
以下,通过实施例1~4对本发明进行具体说明,但它们并不限制本发明的范围。将通过与国际公开WO 99/20607号记载的方法不同的方法制得的原料化合物作为参考例1~3。以下图示为参考例1~3及实施例1~4的合成路线。比较参考例为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的二盐酸盐结晶的制造方法。
合成路线
参考例1
在5.90kg的4-硝基苯基乙胺一盐酸盐、4.43kg的(R)-苦杏仁酸、2.94kg的三乙胺及22L的N,N-二甲基甲酰胺的混合物中加入3.93kg的羟基苯并三唑及5.58kg的1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺一盐酸盐(EDC),室温附近搅拌2小时。再加入0.28kg的EDC,室温附近彻夜搅拌。然后,用110L的水稀释反应液,用乙酸乙酯(60L,30L)萃取。有机层依次用1M盐酸60L、20%碳酸钾水溶液60L及水(60L,60L)洗涤后,于10~19℃减压浓缩。残渣用35L的甲苯加热溶解(87℃)后冷却,于20℃彻夜搅拌。滤取生成的结晶,用10L的甲苯洗涤。真空干燥,获得7.66kg呈淡黄色结晶的(R)-2-羟基-N-[2-(4-硝基苯基)乙基]-2-苯基乙酰胺。
1H-NMR(DMSO-d6,400MHz)δ(ppm)=2.87(2H,t,J=7.2Hz),3.30~3.46(2H,m)4.85(1H,d,J=4.8Hz),6.12(1H,d,J=4.8Hz),7.20~7.33(5H,m),7.40(2H,d,J=8.0Hz),8.04~8.12(3H,m),FAB-MS m/z:301(M+H)+。
(另一方法)使用4-硝基苯基乙胺1/2硫酸盐的制造方法
在9.77g的4-硝基苯基乙胺1/2硫酸盐、6.00g的(R)-苦杏仁酸、4.70g的碳酸钾及60ml的N,N-二甲基甲酰胺的混合物中加入6.14g的羟基苯并三唑及8.70g的1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺一盐酸盐(EDC),室温附近搅拌2小时。再加入0.87g的EDC,室温附近彻夜搅拌。用水稀释反应液后,用乙酸乙酯萃取。有机层用1M的盐酸、20%碳酸钾水溶液及水依次洗涤后,减压浓缩。残渣用甲苯重结晶,获得10.4g呈淡黄色结晶的(R)-2-羟基-N-[2-(4-硝基苯基)乙基]-2-苯基乙酰胺。
参考例2
将7.51kg的(R)-2-羟基-N-[2-(4-硝基苯基)乙基]-2-苯基乙酰胺、23L的1,3-二甲基-2-咪唑烷酮及23L的四氢呋喃的混合物冷却至-18℃后,在-7℃以下滴加49.4kg的1M甲硼烷-四氢呋喃溶液。然后,升温至70℃,搅拌5小时。反应混合物冷却至-12℃,在5℃以下添加2.9kg的甲醇和5.9kg的浓盐酸。于68℃搅拌1小时后,减压浓缩至内容量为50L。加入60kg的30%的K2CO3水溶液及6L的水,用75L的乙酸乙酯萃取。有机层用75L洗涤后减压浓缩。在残渣中加入75L的异丙醇,于40℃溶解,再加入浓盐酸2.46kg结晶化,于23℃彻夜搅拌。滤取结晶,用38L的异丙醇洗涤。真空干燥,获得7.29kg的(R)-2-[[2-(4-硝基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐。
1H-NMR(DMSO-d6,400MHz)δ(ppm)=3.00~3.08(1H,m),3.15~3.30(5H,m),5.00~5.05(1H,m),6.23(1H,d,J=4.0Hz),7.29~7.35(1H,m),7.36~7.43(4H,m),7.57(2H,d,J=8.4Hz),8.21(2H,d,J=8.4Hz),9.12(2H,br),FAB-MS m/z:287(M+H)+。
参考例3
在氢氛围气中,对11.0kg的(R)-2-[[2-(4-硝基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐、110L的甲醇及1.20kg湿的10%钯-碳(湿润率54.2%)的混合物进行搅拌直至氢的吸入停止。过滤反应液,对滤液进行减压浓缩。在残渣中加入40L的甲醇,于40℃溶解,再加入220L的二异丙醚结晶化,于20℃彻夜搅拌。滤取结晶,用30L的二异丙醚洗涤。真空干燥,获得9.43kg的(R)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐。
(另一方法)作为晶析溶剂使用乙酸乙酯的方法
在氢氛围气中,对15.0g的(R)-2-[[2-(4-硝基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐、90ml的甲醇及655mg湿的10%钯-碳(湿润率54.2%)的混合物进行搅拌直至氢的吸入停止。过滤反应液,加热滤液,使甲醇溶液浓缩的同时断续加入乙酸乙酯,使其淤浆化。滤取生成的结晶,用乙酸乙酯洗涤。真空干燥,获得12.9g的(R)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐。
1H-NMR(DMSO-d6,400MHz)δ(ppm)=2.76~2.90(2H,m),2.95~3.16(4H,m),4.95~5.11(3H,m),6.20(1H,d,J=4.0Hz),6.53(2H,d,J=8.4Hz),6.89(2H,d,J=8.4Hz),7.28~7.43(5H,m),8.97(1H,br),9.29(1H,br),FAB-MSm/z:257(M+H)+。
实施例1(β型结晶的制造)
室温下,在8.00g的(R)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐、4.32g的2-氨基噻唑-4-基乙酸、2.64g的浓盐酸及120ml水的混合液中加入5.76g的1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺一盐酸盐(EDC),搅拌1小时。然后在反应液中滴加2.40g氢氧化钠及40ml水的混合液,进行结晶化。滤取生成的结晶,用水洗涤后真空干燥,获得9.93g的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶。
实施例2(经由β型结晶的湿饼制造β型结晶)
于15℃在13.50kg的(R)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐、7.29kg的2-氨基噻唑-4-基乙酸、4.46kg的浓盐酸及270L水的混合液中加入9.73kg的1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺一盐酸盐(EDC),搅拌1小时。然后在反应液中滴加4.10kg氢氧化钠及110L水的混合液,进行结晶化。滤取生成的结晶,用水洗涤后,获得26.2kg的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶的湿饼。该结晶以湿润状态直接用于重结晶。
在26.2kg的β型结晶的湿饼中加入180L的水和140L的乙醇,在约80℃加热溶解后,将外温设定为20℃,急剧冷却。滤取生成的结晶后干燥,获得15.40kg的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶。
β型结晶的粉末X射线衍射图及热分析图如图1和图2所示。
(另一方法)(通过β型结晶的接种进行重结晶)
加热溶解7.54g的β型结晶、60ml乙醇和90ml水的混合物后冷却,于45℃加入380mg的β型结晶。然后,在冰冷却下搅拌15分钟。过滤结晶后干燥,获得6.93g的β型结晶。
实施例3(由β型结晶制备α型结晶)
在约80℃加热溶解15.30kg的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶、180L水及120L乙醇的混合物后冷却,于50℃加入15.0g的α型结晶。然后冷却至20℃,过滤结晶后干燥,获得14.24kg的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶。α型结晶的粉末X射线衍射图如图3所示。
实施例4(由β型结晶的湿饼制备α型结晶)
与实施例2同样,由6.66kg的(R)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯基乙醇一盐酸盐获得23.42kg的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶的湿饼。在该湿饼中加入92L水和76L乙醇,在约80℃加热溶解后,以1小时约10℃的比例冷却,于55℃加入8.4g的α型结晶。然后冷却至20℃,过滤结晶后干燥,获得6.56kg的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶。α型结晶的粉末X射线衍射图及热分析图如图4及图5所示。
1H-NMR(DMSO-d6,500MHz)δ(ppm)=1.60(1H,s),2.59~2.66(4H,m),2.68~2.80(2H,m),3.45(2H,s),4.59(1H,br),5.21(1H,br),6.30(1H,s),6.89(2H,s),7.11(2H,d,J=8.5Hz),7.19~7.23(1H,m),7.27~7.33(4H,m),7.49(2H,d,J=8.5Hz),9.99(1H,s),FAB-MS m/z:397(M+H)+。
比较参考例(二盐酸盐的制造)
将20.0g的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺溶于1,4-二噁烷,再加入8.41ml的浓盐酸。滤取生成的结晶,获得25.0g的(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺二盐酸盐。二盐酸盐结晶的粉末X射线衍射图如图6所示。
1H-NMR(DMSO-d6,400MHz)δ(ppm)=2.90~3.08(3H,m),3.10~3.21(3H,m),3.75(2H,s),4.99~5.03(1H,m),6.69(1H,s),7.20(2H,d,J=8.8Hz),7.28~7.43(5H,m),7.59(2H,d,J=8.8Hz),8.94(1H,brs),9.17(2H,br),9.40(1H,brs),FAB-MS m/z:397(M+H)+。
产业上利用的可能性
本发明的α型结晶不显现出吸湿性,且稳定,所以能够作为医药品使用,作为医药品有用。本发明的β型结晶虽然显现出较弱的吸湿性,但也较稳定,可作为α型结晶的制造中间体使用。这些结晶兼具胰岛素分泌促进作用及胰岛素敏感性增强作用,对糖尿病的治疗有用。这些结晶作为医药品的有用性通过以下的吸湿性试验及降血糖试验确认。
1.吸湿性试验
吸湿性测定采用VTI SGA-100型,在温度:25℃、测定范围:相对湿度5~95%、测定间隔:相对湿度5%的条件下进行。
其结果是,(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺二盐酸盐结晶从相对湿度约80%开始重量急剧增加,在相对湿度90%保持约14%的水分,显现出强吸湿性(参考图7)。另一方面,本发明的α型结晶在相对湿度5%~95%的范围内,水分保持量在0.2%以下,未显现出吸湿性(参考图9)。此外,确认β型结晶从相对湿度约20%开始重量增加,保持约3%的水分,显现出较弱的吸湿性(参考图8)。
上述(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺二盐酸盐结晶显现出较强的吸湿性,结晶的物理化学性质和物性发生了变化,不稳定。对应于此,本发明的α型结晶未显现出吸湿性,稳定性良好,可作为医药品的制造原料使用。β型结晶虽然具有较弱的吸湿性,但也是一种亚稳定型结晶,所以能够作为医药品使用。
2.kk小鼠(胰岛素抗性模型:肥胖,高血糖)中的降血糖试验
采用雄性kk小鼠(血糖值200mg/dl以上),摄食下测定血糖值后,随机分组。1天1次共7天给小鼠强制口服试验药物,将最后给药15~18小时后的血糖值与给药前的血糖值作比较(n=6)。从小鼠的尾静脉用玻璃毛细管(用肝素进行过处理)采血,进行除蛋白质处理后,用葡萄糖氧化酶法对上清液中的葡萄糖量(mg/dl)进行比色定量。使血糖值比服用试验药物前的值减少30%的用量以ED30值表示。
其结果是,α型结晶的经口给药的ED30值在3.5mg/kg/天以下,显现出较强活性。
3.β型结晶作为制造中间体的有用性
β型结晶可作为α型结晶的制造中间体使用。β型结晶在工业生产中通过急冷可切实且简便地得到。与α型结晶相比,由于其在重结晶溶剂(乙醇水溶液37%~50%)中的溶解性较高,所以使β型结晶重结晶,能够容易地获得α型结晶。
对附图的简单说明
图1为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶的粉末X射线衍射图。(本发明结晶)
图2为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶的热分析图。(本发明结晶)
图3为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶的粉末X射线衍射图。(本发明结晶)
图4为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶的粉末X射线衍射图。(本发明结晶)
图5为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶的热分析图。(本发明结晶)
图6为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺二盐酸盐结晶的粉末X射线衍射图。
图7为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺二盐酸盐结晶的吸湿性曲线图。
图8为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶的吸湿性曲线图。(本发明结晶)
图9为(R)-2-(2-氨基噻唑-4-基)-4’-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶的吸湿性曲线图。(本发明结晶)
图中,Intensity表示强度,Temperature表示温度,Heat Flow Endo Up表示吸热,Weight表示重量,Adsorption表示吸附,Desorption表示脱附,Isotherm表示曲线,RH表示相对湿度。
Claims (8)
1.(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶,其特征在于,粉末X射线衍射中,在2θ(°)5.32、8.08、15.28、17.88、19.04、20.20、23.16及24.34附近具有主峰。
2.如权利要求1所述的(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶,其特征在于,DSC分析中,在142~146℃具有热吸收峰。
3.医药组合物,其特征在于,含有权利要求1所述的(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶和制药学上允许的载体。
4.糖尿病治疗剂,其特征在于,含有权利要求1所述的(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的α型结晶和制药学上允许的载体。
5.(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶,其特征在于,粉末X射线衍射中,在2θ(°)9.68、19.76、20.72、22.10及23.52附近具有主峰。
6.如权利要求5所述的(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶,其特征在于,DSC分析中,在90~110℃及142~146℃具有热吸收峰。
7.医药组合物,其特征在于,含有权利要求5所述的(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶和制药学上允许的载体。
8.糖尿病治疗剂,其特征在于,含有权利要求5所述的(R)-2-(2-氨基噻唑-4-基)-4′-[2-[(2-羟基-2-苯基乙基)氨基]乙基]乙酰替苯胺的β型结晶和制药学上允许的载体。
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