CN1455777A - 四氢噻唑二酮衍生物的酒石酸盐 - Google Patents
四氢噻唑二酮衍生物的酒石酸盐 Download PDFInfo
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- 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
一种新的药物化合物5-(4-(2-(N-甲基-N-(2-吡啶基)氨基)乙氧基)苄基)四氢噻唑-2,4-二酮L(+)酒石酸盐或其溶剂化物,一种制备这种化合物的方法,一种含有这种化合物的药物组合物以及这种化合物在医疗中的用途。
Description
本发明涉及新的药物组合物、制备该药物的方法和该药物的医疗用途。
欧洲专利申请公开号0,306,228涉及某些具有降血糖和降血脂活性的四氢噻唑二酮衍生物。EP 0,306,228的实施例30化合物是5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮(以下也称为″化合物(I)″)。
国际专利申请公开号WO94/05659公开了EP 0,306,228该化合物的某些盐,其中一种是酒石酸盐。WO94/05659中优选的盐是马来酸盐。
现已发现,化合物(I)形成一种特别稳定的并因此适用于大批生产和处理的新的酒石酸盐(以下也称″L(+)酒石酸盐″)。该L(+)酒石酸盐还具有高的熔点并具有良好的整体流动性能。因此该L(+)酒石酸盐出乎意料地能改进大规模的制药工艺过程,特别是能大规模地进行搅拌磨制。
该新形式的盐能用有效、经济和可重复的方法制备,特别适合于大规模生产。
该新的L(+)酒石酸盐还具有有用的药学性能,特别是它显示出可用于治疗和/或预防糖尿病、与糖尿病有关的疾病及其某些并发症。
因此,本发明提供了5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮,L(+)酒石酸盐或其溶剂化物。
适宜的L(+)酒石酸盐是单酒石酸盐。
单酒石酸盐也可任选地包含单价的成盐离子,如碱金属或铵阳离子。
在一种有利的情况中,该L(+)酒石酸盐提供一种基本上与图1一致的红外光谱。
在一种有利的情况中,该L(+)酒石酸盐提供一种基本上与图2一致的拉曼光谱。
在一种有利的情况中,该L(+)酒石酸盐提供一种基本上与图表1或图3一致的X射线粉末衍射图(XRPD)。
在一种有利的情况中,该L(+)酒石酸盐提供一种基本上与图4一致的固态13C NMR谱。
在一种有利的情况中,该L(+)酒石酸盐的熔点在180-185℃范围内,如180-183℃,例如182.1℃。
一个优选的情况是,本发明提供了5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮,L(+)酒石酸盐,其特征在于它具有:
(i)一种基本上与图1一致的红外光谱;和
(ii)一种基本上与图2一致的拉曼光谱;和
(iii)一种基本上与表1或图3一致的X射线粉末衍射图(XRPD);和
(iii)一种基本上与图4一致的固态13C NMR谱。
本发明包含了分离成纯形式的或与别的物质混合的L(+)酒石酸盐或其溶剂化物。因此本发明一方面提供了分离形式的L(+)酒石酸盐或其溶剂化物。
本发明另一方面提供了纯形式的L(+)酒石酸盐或其溶剂化物。
本发明又一方面提供了结晶形式的L(+)酒石酸盐或其溶剂化物。
本发明也提供了固态的药学上可接受的形式例如固体剂型的L(+)酒石酸盐或其溶剂化物,特别是当采用口服给药时。
而且,本发明还提供了药学上可接受的形式特别是松散状的L(+)酒石酸盐或其溶剂化物,这样的形式特别能被粉碎。因此本发明也提供了粉碎形式的L(+)酒石酸盐或其溶剂化物。
还有,本发明还提供了药学上可接受的形式特别是松散状的L(+)酒石酸盐或其溶剂化物,这样的形式具有良好的流动性,特别是有良好的整体流动性。
合适的溶剂化物是水合物。
本发明也提供了制备该L(+)酒石酸盐或其溶剂化物的方法,其特征在于:使5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮(化合物(I))或其盐优选溶解或分散在适当的溶剂中,使其与原料L(+)酒石酸盐离子反应,并且然后如果需要,将生成的该L(+)酒石酸盐再制成溶剂化物;以及回收该L(+)酒石酸盐或其溶剂化物。
合适的溶剂是链烷醇如丙-2-醇,或烃如甲苯,酮如丙酮,酯如乙酸乙酯,醚如四氢呋喃,腈如乙腈,或卤代烃如二氯甲烷,或水,或有机酸如乙酸;或者它们的混合物。
通常,L(+)酒石酸盐的离子源为L(+)酒石酸。加入的L(+)酒石酸优选为固体或溶液的形式,例如在水或一种诸如甲醇、乙醇或丙-2-醇的低级醇中,或者在混合溶剂中。一种可替代的L(+)酒石酸盐离子源为一种适宜的可溶性L(+)酒石酸的碱盐如L(+)酒石酸铵,或者一种胺例如乙胺或二乙胺的L(+)酒石酸盐。
化合物(I)的浓度优选在2至25%重量/体积的范围内,更优选在5至20%的范围内。酒石酸溶液的浓度优选在5至130%重量/体积的范围内。
该反应可在环境温度下进行或在高温下例如在溶剂的回流温度下进行,但也可以采用生产所需要产品的任何方便的温度。
L(+)酒石酸盐的溶剂化物,如水合物,可按照常用方法制备。
所需化合物的回收一般包括从一种适当的溶剂或溶剂混合物(便于反应的溶剂)中结晶,通常辅以冷却。例如,这种L(+)酒石酸盐可从一种醇如乙醇或丙-2-醇、或腈如乙腈、或者它们的混合物中结晶出来。通过蒸发一些或全部溶剂,或者在升高的温度下结晶,然后进行受控冷却,任选地分阶段进行,从而可得到高收率的该盐。仔细地控制沉淀析出温度可以用于提高此产品形式的再现性。
结晶还可以通过接种这种L(+)酒石酸盐或其一种溶剂化物的晶种而开始,但这不是必需的。
当这种单酒石酸盐包括另一种单价成盐离子如碱金属或铵阳离子时,所述的离子可通过将此单酒石酸盐与所选择的单价成盐离子(例如一种金属或铵离子)的溶液反应而方便地形成。或者,可以用所述单价成盐离子的单酒石酸盐处理化合物(I)。
按照已知的方法如EP 0,306,228和WO94/05659中公开的那些方法制备化合物(I)。EP 0,306,228和WO94/05659的公开说明书在此作为参考文献引用。
L(+)酒石酸是一种市场上可买到的化合物。
本发明用的″T开始″这一参数通常是用差分扫描量热法测定的,并具有本领域通用的含义,如Ford and Timmins1989的“药物热分析、技术和应用”中所表达的意思是“相应于转变之前的基线与推定的转变前沿外推线相交点的温度”。
本发明对于某些化合物所用的“良好的流动性能”这一术语是Hausner比小于或等于1.5,特别是小于或等于1.25的该化合物所具有的特征。
″Hausner比″是常用的术语。
本发明所用的“与糖尿病有关的疾病的预防”这一术语也包括有些疾病如胰岛素抗性、葡萄糖耐量降低和妊娠期糖尿病的治疗。
糖尿病主要是指II型糖尿病。
与糖尿病有关的疾病包括高血糖和胰岛素抗性和肥胖症。其它与糖尿病有关的疾病包括高血压、心血管病特别是动脉粥样硬化、某些食欲障碍特别是患者食欲的控制和食物吸收由于饥饿而受到障碍(例如神经性厌食)以及由于饮食过量而产生的失调(例如肥胖和贪食症)。另外与糖尿病有关的疾病包括多囊性卵巢综合征和类固醇诱发的胰岛素抗性。
本发明所包含的与糖尿病有关的并发症包括肾病特别是与II型糖尿病的发展有关的肾病,包括糖尿病性肾病、肾小球肾炎、肾小球硬化、肾病综合征、高血压性肾硬化和晚期肾病。
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L(+)酒石酸盐或其溶剂化物。
更具体地说,本发明提供了用作治疗和/或预防与糖尿病有关的疾病及其某些并发症的L(+)酒石酸盐及其溶剂化物。
L(+)酒石酸盐及其溶剂化物本身可作为药物被服用,或者优选的是服用另外还包含药学上可接受载体的药物组合物。配制该L(+)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用于化合物(I)所公开的那些方法。
因此,本发明还提供了一种含有L(+)酒石酸盐或其溶剂化物和其药学上可接受的载体的药物组合物。
该L(+)酒石酸盐或其溶剂化物通常是以单位剂量形式服用。
活性化合物的服用可以通过任何合适的途径,但通常是口服或非肠道给药。对于这种应用来说,通常是以该化合物与药学上可接受的载体、稀释剂和/或赋形剂结合的形式来使用,但是该药物组合物的正确形式自然取决于用药的方式。
组合物是通过混合制备的并且该组合物适用于口服、非肠胃道或局部给药,因而这样的组合物可以是片剂、胶囊、口服液体制剂、粉剂、颗粒剂、糖锭、软锭、临用前可重新配制的粉末剂、可注射或可注输的溶液或悬浮液、栓剂和透皮贴剂。口服给药的组合物是优选的,特别是成形的口服组合物,因为它们使用更方便。
口服的片剂和胶囊通常以单位剂型存在,并且含有常用的赋型剂如粘结剂、填充剂、稀释剂、成片剂、润滑剂、崩解剂、着色剂、香味剂、和湿润剂。该片剂可用现有技术中已知的方法包衣。
适用的填充剂包括纤维素、甘露醇、乳糖和其它类似的试剂。合适的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物如羟基乙酸淀粉钠。合适的润滑剂包括例如硬酯酸镁。合适的药学上可接受的湿润剂包括十二烷基硫酸钠。
固体口服组合物可通过共混、填充、压片等的常规方法来制备。可以用反复共混的操作方法将活性剂分布在那些采用大量填充剂的整个组合物中。当然,这样的操作也是现有技术中常用的。
口服液体制剂的剂型可以是水性或油性的悬浮液、溶液、乳液、糖浆或酏剂,或者可以是在使用前与水或其它合适的载体重新兑勾的干燥产物。这样的液体制剂可以含有常规的添加剂,例如悬浮剂如山梨糖醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬酯酸铝胶或氢化可食用脂肪,乳化剂如卵磷脂、脱水山梨糖醇单油酸酯、或阿拉伯树胶;非水载体(它可包括可食用油)如杏仁油、分馏的椰子油、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对羟基苯甲酸丙酯或山梨酸,以及如果需要还可含常规的香味剂或着色剂。
对于非肠胃道给药,制成含本发明化合物和无菌载体的液体的单位剂型。根据载体和浓度的不同,该化合物可以是混悬的或溶解的。非肠胃道用的溶液通常是通过将活性化合物溶解在载体和填充剂中来制备的,该载体和填充剂在填充到适当的小瓶或安瓿和封口之前先进行灭菌。最好将局部麻醉剂、防腐剂和缓冲剂等的辅剂也溶于载体中。为了提高稳定性,可将组合物在填充到小瓶之后加以冷冻和在真空下除水。
非肠胃道用的混悬剂是基本上按相同方法制备的,只是活性化合物是悬浮不是溶解在载体中,并且在无菌载体中悬浮之前将其先暴露在环氧乙烷中灭菌。最好是将表面活性剂或湿润剂包含在组合物中以便该活性化合物能均匀分布。
在实践中,这些组合物通常都附有医疗用的书写或打印的说明书。
这里所用的‘药学上可接受的’这一术语是概括了人用和兽用化合物、组合物和组份:例如‘药学上可接受的盐’也包括了兽医药可接受的盐。
本发明还提供了治疗和/或预防人或非人动物的糖尿病、与尿病有关的疾病及其某些并发症的方法,该方法包括给有此需要的人或非人动物服用有效且无毒量的L(+)酒石酸盐或其溶剂化物。
通常,可以服用活性组分作为前面所定义的药物组合物,这形成了本发明的一个具体的方面。
另一方面,本发明还提供了L(+)酒石酸盐或其溶剂化物在制备用治疗和/或预防糖尿病、与尿病有关的疾病及其某些并发症的药物中的应用。
在治疗和/或预防糖尿病、与尿病有关的疾病及其某些并发症中该L(+)酒石酸盐或其溶剂化物的服用量是要提供适当剂量的化合物(I),该剂量如EP 0,306,228、WO94/05659或WO98/55122所述。
在上述用本发明化合物的治疗中没有出现毒副作用。
以下实施例是举例说明本发明而不是以任何方式限制本发明的范围。
实施例1 5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮L(+)酒石酸盐
将5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4二酮(3.82g)和变性乙醇(120ml)的混合物搅拌并加热回流至出现澄清的溶液。将该溶液冷却到70℃,加L(+)酒石酸(1.6g)。加热回流10分钟后大约经过1小时该混合物冷却到21℃。过滤收集产品并在21℃下真空干燥3个小时,得到5[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮L(+)酒石酸盐(4.93g),一种白色结晶固体。
实施例2 5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4二酮L(+)酒石酸盐
将5-[4-[2-(N-甲基N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4二酮(2.0g)、L(+)酒石酸(0.84g)、丙酮(90ml)和去离子水(5ml)的混合物搅拌并加热回流至出现澄清的溶液。将该反应混合物冷却到21℃并减压蒸发溶剂。加甲苯(100ml)并搅拌混合物,减压蒸发该溶剂。在残余物中加变性乙醇(20ml)和乙腈(20ml)并将该混合物搅拌和温热到60℃,然后冷却到21℃。过滤收集产品并真空干燥,得到5[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮L(+)酒石酸盐(4.93g),一种白色结晶固体。
1H NMR(d6-DMSO):与该L(+)酒石酸盐一致。
实施例3 5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4二酮L(+)酒石酸盐
将5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮(5.0g)和丙烷-2-醇(100mL)的混合物搅拌并加热回流10分钟,此时出现澄清的溶液。将L(+)酒石酸盐(2.1g)在丙烷-2-醇(30mL)中的溶液在60至70℃下加到反应混合物中,搅拌并加热回流5分钟。将该反应混合物经90分钟冷却到21℃。过滤收集产品,用丙烷-2-醇(50mL)洗涤,并在真空下干燥,得到5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮L(+)酒石酸盐为白色结晶固体(6.7g)。
实施例4 5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮L(+)酒石酸盐
将L(+)酒石酸盐(8.4g)在丙烷-2-醇(70mL)中的溶液加到回流搅拌的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮(20.0g)在丙烷-2-醇(400mL)中的悬浮液中。将该反应混合物搅拌并回流至出现澄清的溶液,然后冷却到21℃。过滤收集白色固体,用丙烷-2-醇(100mL)洗涤然后在21℃真空干燥2小时,得到5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]四氢噻唑-2,4-二酮L(+)酒石酸盐(27.0g,95%),白色结晶固体。
对实施例2产物记录的特征数据
该产物在矿物油中分散液的红外吸收光谱是用Nicolet 710 FT-IR光谱仪在2cm-1分辨率下得到的(图1)。使数据以1cm-1带间数字化,所观察到的谱带如下:3384,1751,1699,1646,1621,1544,1512,1465,1415,1377,1357,1304,1267,1233,1168,1076,1059,1032,998,927,901,835,773,752,716,688,618,589,556,527,506cm-1
固体产物的红外光谱是用Perkin-Elmer Spectrum One FT-IR光谱仪记录的,该光谱仪用通用的ATR仪表调准。所观察到的谱带如下:3385,3133,2935,2786,1750,1692,1645,1619,1609,1544,1510,1466,1415,1384,1357,1303,1267,1232,1210,1167,1153,1141,1074,1058,1032,998,926,898,830,750,714,685,658cm-1
产物的拉曼光谱(图2)是用NMR管中的样品使用Nicolet 960 E.S P.FT-拉曼光谱仪在4cm-1分辨率下记录的,用输出功率为400mW的Nd:V04激光器(1064nm)激发。所观察到的谱带如下:3101,3065,3042,2920,1747,1699,1610,1584,1545,1471,1439,1389,1357,1319,1293,1235,1207,1176,1146,1035,982,930,901,828,773,741,659,637,620,604,506,468,431,397,348,281,99cm-1
产物的X-射线粉末衍射图(图3)是用下列接收条件记录的:管阳极:Cu,发生器强度:40kV,发生器电流:40mA,起始角:2.0°2θ,终止角:35.0°2θ,阶跃度:0.02°2θ,每个阶跃的时间:2.5秒。特征XRPD角和相对强度记录在表1中。
表1
角度 | 相对强度 |
2θ° | % |
6.4 | 8.8 |
7.8 | 11.6 |
9.7 | 3.3 |
10.6 | 5 |
12.2 | 12.5 |
12.8 | 11.3 |
13.1 | 7.4 |
14.0 | 5.5 |
14.7 | 5 |
15.9 | 24.4 |
16.5 | 100 |
17.5 | 31.5 |
17.9 | 10.6 |
18.2 | 11.9 |
18.6 | 39.7 |
19.4 | 26.4 |
21.3 | 20.4 |
21.6 | 23.2 |
22.6 | 76.3 |
23.3 | 7.5 |
23.7 | 16.7 |
24.3 | 49.5 |
25.2 | 32.6 |
25.7 | 40.5 |
26.4 | 11.9 |
27.2 | 24.8 |
27.4 | 21.3 |
28.3 | 13.3 |
29.2 | 28 |
29.7 | 10.3 |
30.4 | 9 |
30.7 | 14.9 |
31.1 | 13.7 |
31.6 | 12.9 |
32.2 | 10.9 |
33.3 | 15.7 |
33.9 | 16.2 |
产物的固态NMR谱(图4)用Bruker AMX360仪器记录,操作频率90.55MHz。该固体填充在配有Kel-F盖的4mm氧化锆MAS旋光器内,旋光器在大约10kHz下自旋。通过正交偏振从Hartmann-Hahn匹配的质子(CP接触时间3ms,重复时间15s)收13CMAS谱图并在接收过程中使用双脉冲相调节(TPPM)组合次序来使质子去偶合。化学移位是外部参照甘氨酸的羧酸根在176.4ppm上相对于TMS的信号并观察到的移位是:181.0,179,177.2,174.7,173.0,158.2,150.3,144.7,141.6,139.2,136.1,131.7,118.1,113.8,111,110,74.6,73.7,73.0,64.6,55.8,50.7,40.5,38.7,36.7,34.9ppm
对实施例4的产物L(+)酒石酸盐所记录的性能
L(+)酒石酸盐的固态稳定性
该药物的固态稳定性的测定方法是将大约1.0克该物质在a)40℃/75%相对湿度(RH)的玻璃瓶子中贮存一个月,打开暴露一个月,和b)在50℃中封闭一个月。在以下两种情况下用HPLC测定该物质的最终含量和降价产物
a)40℃/75%RH:没有观察到明显的降价(HPLC测定97%开始值)。
b)50℃:没有观察到明显的降价(HPLC测定98%开始值)。
L(+)酒石酸盐的流动性能
L(+)酒石酸盐的整体密度与带分体密度之比(Hausner Ratio)是用标准方法测定的(见“制药学-剂型设计”″,editor M.Aulton,1988,由ChurchillLivingstone出版)。
Hausner Ratio:1.2
L(+)酒石酸盐的熔点
用一种Buchi 545熔点测量仪,根据美国药典USP23,1995,<741>的“熔化范围或温度,Ia类的规程”描述的方法测定此L(+)酒石酸盐的熔点。
熔点:182.1℃
L(+)酒石酸盐的T开始
这种药物的T开始是用Perkin-Elmer DSC7仪器通过差分扫描量热法(Differential Scanning Calorimetry)测定的。
T开始(10℃/分,封闭的锅):187℃
Claims (11)
1.一种化合物5-(4-(2-(N-甲基-N-(2-吡啶基)氨基)乙氧基)苄基)四氢噻唑-2,4-二酮L(+)酒石酸盐或其溶剂化物。
2.权利要求1的化合物,其特征在于它提供:
(i)一种基本上与图1一致的红外光谱;
(ii)一种基本上与图2一致的拉曼光谱;
(iii)一种基本上与表1或图3一致的X射线粉末衍射图(XRPD);或
(iv)一种基本上与图4一致的固态13C NMR谱。
3.权利要求1的化合物,其特征在于它具有以下的两个或多个的特性:
(i)一种基本上与图1一致的红外光谱;和
(ii)一种基本上与图2一致的拉曼光谱;和
(iii)一种基本上与表1或图3一致的X射线粉末衍射图(XRPD);和
(iii)一种基本上与图4一致的固态13C NMR谱。
4.根据权利要求1-3中任一项的化合物,是纯形式的。
5.根据权利要求1-3中任一项的化合物,是固体剂型。
6.根据权利要求1-3中任一项的化合物,是药学上可接受的能被磨碎的形式。
7.根据权利要求1-3中任一项的化合物,是药学上可接受的具有良好流动性的形式。
8.一种制备L(+)酒石酸盐或其溶剂化物的方法,其特征在于使5-(4-(2-(N-甲基-N-(2-吡啶基)氨基)乙氧基)苄基)四氢噻唑-2,4-二酮(化合物(I))或其盐与L(+)酒石酸盐离子的原料反应,并且如果需要,然后将所得的该L(+)酒石酸盐制成其溶剂化物;以及收取该L(+)酒石酸盐或其溶剂化物。
9.一种药物组合物,含有5-(4-(2-(N-甲基-N-(2-吡啶基)氨基)乙氧基)苄基)四氢噻唑-2,4-二酮L(+)酒石酸盐或其溶剂化物,和其药学上可接受的载体。
10.一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)四氢噻唑-2,4-二酮L(+)酒石酸盐或其溶剂化物。
11. 5-(4-(2-(N-甲基-N-(2-吡啶基)氨基)乙氧基)苄基)四氢噻唑-2,4-二酮L(+)酒石酸盐或其溶剂化物在制备用于治疗和/或预防糖尿病、与糖尿病有关的疾病及其并发症的药物中的应用。
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