CN101961333A - 噻唑烷二酮衍生物及其作为抗糖尿病药的用途 - Google Patents
噻唑烷二酮衍生物及其作为抗糖尿病药的用途 Download PDFInfo
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- CN101961333A CN101961333A CN2010100046806A CN201010004680A CN101961333A CN 101961333 A CN101961333 A CN 101961333A CN 2010100046806 A CN2010100046806 A CN 2010100046806A CN 201010004680 A CN201010004680 A CN 201010004680A CN 101961333 A CN101961333 A CN 101961333A
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- Prior art keywords
- potassium salt
- thiazolidine
- benzyl
- methyl
- diketone
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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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- A—HUMAN NECESSITIES
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Abstract
化合物5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐或其可药用的溶剂化物,包含所述化合物的药物组合物和所述化合物在药物,尤其是在治疗糖尿病中的应用。
Description
本申请是中国发明申请(发明名称:噻唑烷二酮衍生物及其作为抗糖尿病药的用途;申请日:2001年09月28日;申请号:01816563.X(国际申请号:PCT/GB01/04346))的分案申请。
技术领域
本发明涉及新药物、制备该药物的方法和该药物在药品中的应用。
背景技术
公开号为0,306,228的欧洲专利申请涉及某些公开为具有低血糖(hypoglycaemic)和促使血清脂质减少的(hypolipidaemic)活性的噻唑烷二酮衍生物。EP 0,306,228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-2,4-二酮(下文也称为“化合物(I)”)。
公开号为WO 94/05659的国际专利申请披露了EP 0,306,228的化合物的某些盐。WO 94/05659的优选盐是马来酸盐。
发明内容
现已经发现,化合物(I)形成新钾盐(下文也称为“钾盐”),新钾盐是特别稳定的,因此适用于大量制备和处理。钾盐还具有高熔点且显示出特别好的水溶性。因此,令人惊奇的是钾盐能经受大规模的药物加工,特别是大规模的研磨。可以通过特别适用于大规模制备的高效、经济和可再现的方法制备该新盐。
该新的钾盐也具有有用的药物性能且特别是其可用于治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些特定的并发症。
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]噻唑烷-2,4-二酮钾盐,或其溶剂化物。
在一个优选的方面,钾盐提供了基本上如图1的红外光谱。
在一个优选的方面,钾盐提供了基本上如图2的拉曼光谱。
在一个优选的方面,钾盐提供了基本上如表1或图3的X-射线粉末衍射图谱(XRPD)。
在一个优选的方面,钾盐提供了基本上如图4的固态13C NMR波谱。
在一个优选的方面,本发明提供了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,钾盐,或其溶剂化物,其特征在于它提供:
(i)基本上如图1的红外光谱;
(ii)基本上如图2的拉曼光谱;
(iii)基本上如表1或图3的X-射线粉末衍射图谱(XRPD);和
(iv)基本上如图4的固态13C NMR波谱。
本发明包括以纯净形式离析或与其它物质掺混的钾盐或其溶剂化物。因此,在一个方面,提供了离析形式的钾盐或其溶剂化物。
在另一个方面,提供了纯化形式的钾盐或其溶剂化物。
在再一个方面,提供了结晶形式的钾盐或其溶剂化物。
并且,本发明提供了固体可药用盐形式如固体剂型,特别是适用于口服的钾盐或其溶剂化物。
并且,本发明还提供了可药用形式、特别是松散形式(bulk form)的钾盐或其溶剂化物,所述形式特别能够进行研磨。本发明还提供来研磨形式的钾盐。
合适的溶剂化物是水合物。
具体地,本发明涉及以下方面:
1.化合物5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐或其可药用的溶剂化物,其特征在于它提供下列一种或多种特征:
(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-射线粉末衍射图谱(XRPD);
(iv)基本上与图4一致的固态13C NMR波谱;和
(v)熔点范围为194~201℃。
项2.根据项1的化合物,其特征在于它提供下列两种或多种特征:
(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-射线粉末衍射图谱(XRPD);和
(iv)基本上与图4一致的固态13C NMR波谱。
项3.根据项1的化合物,呈固态剂型。
项4.根据项1或2的化合物,呈松散的研磨的形状。
项5.药物组合物,包含以上所述的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐(钾盐)或其可药用的溶剂化物及其可药用的载体,其中该钾盐的存在量提供了1,2,3,4,4~8或8~12mg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。
项6.根据项5的药物组合物,包含钾盐或其可药用的盐,其量为提供1,2,3或4mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
项7.根据项5的药物组合物,包含钾盐或其可药用的盐,其量为提供2mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
项8.根据项5的药物组合物,包含钾盐或其可药用的盐,其量为提供4mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
项9.根据项5的药物组合物,其量为提供8mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
项10.药物组合物,包含5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐或其可药用的盐以及一种或多种其它抗糖尿病药和任选的其可药用的载体。
项11.治疗和/或预防人类或非人类哺乳动物中的糖尿病、与糖尿病相关的疾病及其某些特定的并发症的方法,包括向需要治疗的人类或非人类哺乳动物给药有效的、非毒性量的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐或其可药用的盐,其中钾盐的存在量为提供1,2,3,4,4~8或8~12mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
项12.治疗和/或预防人类或非人类哺乳动物中的糖尿病、与糖尿病相关的疾病及其某些特定的并发症的方法,包括给药有效的、非毒性量的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐或其可 药用的盐以及一种或多种其它抗糖尿病药。
项13.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-2,4-二酮钾盐或其可药用的盐,其中钾盐的存在量为提供1,2,3,4,4~8或8~12mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
项14.5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐或其溶剂化物在生产治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些特定的并发症的药物中的应用,其中钾盐的存在量为提供1,2,3,4,4~8或8~12mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
本发明还提供了制备钾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,优选分散或溶解在合适的溶剂中,与钾离子源进行反应,然后,如果需要,制备所得的钾盐的溶剂化物;以及回收钾盐或其溶剂化物。
合适的反应溶剂是链烷醇如丙-2-醇,或烃如甲苯,酮如丙酮,酯如乙酸乙酯,醚如四氢呋喃,腈如乙腈或卤化烃如二氯甲烷,或水;或其混合物。
方便的钾离子源是氢氧化钾。氢氧化钾优选以固体或溶液例如在水或低级醇如甲醇、乙醇或丙-2-醇,或溶剂的混合物中的形式加入。可供选择的钾离子源是醇钾盐如叔丁醇钾。
化合物(I)的浓度范围优选是2~25%重量/体积,更优选是5~20%。氢氧化钾溶液的浓度范围优选是2~110%重量/体积。
反应通常在环境温度或高温如在溶剂的回流温度下进行,尽管可以使用提供所需产物的任何适宜温度。
根据常规方法制备钾盐的溶剂化物如水合物。
所需化合物的回收通常包括从合适的溶剂、合适地是反应溶剂中结晶,通常在冷却的帮助下进行。例如,可以从醇如丙-2-醇,酮如丙酮,酯如乙酸乙酯,醚如四氢呋喃,或水,或其混合物中将钾盐进行结晶。通过蒸发一些或所有溶剂或通过在高温下结晶随后进行受控的冷却,任选分阶段进行而改进盐的收率。可以通过小心控制沉淀温度和放入晶种(seeding)来改进产品形式的再现性。
也可以通过用钾盐或其溶剂化物的晶体作为晶种来开始结晶,但这并非是必要的。
根据已知的方法如EP 0,306,228和WO 94/05659披露的方法来制备化合物(I)。将EP 0,306,228和WO 94/05659的公开内容引入本发明作为参考。
氢氧化钾和叔丁醇钾是市场上可买到的化合物。
用于本发明中的术语“T起始”通常通过差示扫描量热法测定且具有本领域通常理解的含义,如在Pharmaceutical Thermal Analysis,Techniques andApplications,Ford and Timmins,1989中表示为“相当于预跃迁基线和跃迁的外推前边的交叉点的温度”。
用于本发明中的术语“预防与糖尿病相关的疾病”包括治疗疾病如胰岛素耐受(insulin resistance)、葡萄糖耐量降低(impaired glucose tolerance)、血胰岛素过多症(hyperinsulinaemia)和妊娠糖尿病(gestational diabetes)。
“糖尿病”优选指II型糖尿病。
与糖尿病相关的疾病包括高血糖症(hyperglycaemia)、胰岛素耐受(insulin resistance)和肥胖症。与糖尿病相关的其它疾病包括高血压、心血管疾病,特别是动脉粥样硬化症,某些进食障碍疾患(eating disorder),特别是调节患者的食欲和食物摄入,上述患者患有与饮食不足(under-eating)相关的失调如神经性食欲缺乏,和与饮食过量相关的失调如肥胖症和厌食易饿(anorexia bulimia)相关的失调。与糖尿病相关的其它疾病包括多囊卵巢综合征和类固醇诱发的胰岛素耐受(steroid induced insulin resistance)。
包括在本发明中的与糖尿病相关的疾病并发症包括肾病,尤其是与II型糖尿病的进展相关的肾病包括糖尿病性肾病(diabetic nephropathy)、血管球性肾炎、肾小球硬化症(glomerular sclerosis)、肾病综合征(nephroticsyndrome),高血压性肾硬化(hypertensive nephrosclerosis)和晚期肾病(endstage renal disease)。
如上文所述,本发明的化合物具有有用的治疗性能:本发明因此提供了用作活性治疗物质的钾盐或其溶剂化物。
更具体的是,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及其某些特定的并发症的钾盐或其溶剂化物。
钾盐或其溶剂化物可以直接给药,或优选作为还包含可药用的载体的药物组合物的形式给药。适用于配制钾盐或其溶剂化物的方法通常披露在 上述公开化合物(I)的公开文件中。
因此,本发明也提供了包含钾盐或其溶剂化物及其可药用的载体的药物组合物。
钾盐或其溶剂化物通常以单位剂型给药。
可以通过任何合适的路径但通常通过口服或胃肠外路径给药活性化合物。对于这类用途来说,通常以与药物载体、稀释剂和/或赋形剂联合使用的药物组合物的形式来使用化合物,但是组合物的精确形状通常取决于给药方式。
通常以掺混物的形式制备组合物,且该组合物适用于口服、胃肠外或局部给药,且因此可以呈片剂、胶囊剂、口服液体制剂、粉剂、颗粒剂、锭剂(lozenges)、锭剂(pastilles)、可重构的粉末、可注射和可灌输的溶液或悬浮液、栓剂和经皮制剂。口服给药的组合物是优选的,特别是成形的口服组合物,因为它们更适用于通常用途。
口服给药的片剂和胶囊剂通常以单剂存在,且含有常规的赋形剂如粘结剂、填料、稀释剂、成片剂(tabletting agents)、润滑剂、崩解剂(disintegrants)、着色剂、调味剂和润湿剂。可以根据本领域公知的方法对片剂进行包衣。
使用的合适的填料包括纤维素、甘露醇、乳糖和其它类似的试剂。合适的崩解剂包括淀粉、聚乙烯基吡咯烷酮和淀粉衍生物如淀粉乙醇酸钠。合适的润滑剂包括例如硬脂酸镁。合适的可药用的润湿剂包括月桂基硫酸钠。
可以通过共混、填充、成片等的常规方法制备固体口服组合物。可以使用重复的共混操作来将活性试剂分布在那些使用大量填料的整个组合物中。这类操作当然是本领域中常用的。
口服液体制剂可以呈例如水性或油性悬浮液、溶液、乳液、糖浆或酊剂(elixirs)形式,或者可以作为在使用前用水或其它合适的载体重构的干产品的形式存在。这类液体制剂可以包含常规添加剂如悬浮剂如山梨醇、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的可食用脂肪、乳化剂如卵磷脂、脱水山梨醇单油酸酯或阿拉伯树胶;非水性载体(可包括可食用的油),例如,杏仁油、分馏的椰子油、油性酯如甘油、丙二醇或乙醇的酯;防腐剂如对羟基苯甲酸甲酯或丙酯或山梨酸,以及需要的常规调味剂或着色剂。
对于胃肠外给药来说,制备包含本发明的化合物和消毒的载体的流体单剂型。取决于载体和浓度,化合物可以悬浮或溶解。胃肠外溶液通常是通过将活性化合物溶解在载体中,并在填充到合适的小瓶或安瓿中之前过滤消毒,并密封而制备。有利的是,将佐剂如局部麻醉剂、防腐剂和缓冲剂也溶解在载体中。为了增强稳定性,可以在填充到小瓶中后将组合物冷冻并在真空下除去水。
以基本上相同的方式制备胃肠外悬浮液,不同之处是将活性化合物悬浮在载体中而不是在悬浮在消毒载体中之前溶解并通过暴露于环氧乙烷而消毒。有利的是,将表面活性剂或润湿剂包含在组合物中以方便活性化合物的均匀分布。
通常的实践是,组合物通常伴随有用于相关的医学治疗的书面或印刷指导。
用于本发明中的术语“可药用的”包括人用和兽医用的化合物、组合物和组分:例如“可药用的盐”包括兽医学上可接受的盐。
本发明还提供了治疗和/或预防人类或非人类哺乳动物中的糖尿病、与糖尿病相关的疾病及其某些特定的并发症的方法,包括向需要治疗的人类或非人类哺乳动物给药有效、非毒性量的钾盐或其溶剂化物。
合适的是,活性组分可以作为前面定义的药物组合物的形式给药,且这构成了本发明的一个具体的方面。
在另一个方面,本发明提供了钾盐或其溶剂化物在生产治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些特定(certain)的并发症的药物中的应用。
在治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些特定的并发症中,钾盐或其溶剂化物可以以提供合适剂量的化合物(I)的量摄入,如EP0,306,228,WO 94/05659或WO 98/55122中所披露的量。
本发明的单剂组合物包含钾盐或其可药用的溶剂化物,其量为提供多至12mg,包括1-12mg如2-12mg的化合物(I),尤其是2-4mg,4-8mg或8-12mg的化合物(I),例如1,2,3,4,5,6,7,8,9,10,11或12mg的化合物(I)。因此,具体是,提供了包含钾盐或其溶剂化物及其可药用的载体的药物组合物,其中钾盐或其可药用的溶剂化物的存在量为提供1,2,4,8,4~8或8~12mg的化合物(I),如1mg的化合物(I),如2mg的化合物(I);如4mg的化合物(I); 如8mg的化合物(I);如12mg的化合物(I)的量。
本发明还提供了包含钾盐或其可药用的溶剂化物联合使用一种或多种其它抗糖尿病药以及任选的可药用的载体的药物组合物。
本发明还提供了治疗和/或预防人类或非人类哺乳动物中的糖尿病、与糖尿病相关的疾病及其某些特定的并发症的方法,包括给药有效、非毒性量钾盐或其可药用的溶剂化物以及一种或多种其它抗糖尿病药。
在另一个方面,本发明提供了钾盐或其可药用的溶剂化物联合使用一种或多种其它抗糖尿病药在生产治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些特定的并发症的药物中的应用。
在前面提到的治疗中,给药钾盐或其可药用的溶剂化物和其它一种或多种抗糖尿病药包括同时给药或顺序给药活性试剂。
合适的是,在前面提到的组合物包括单剂,或治疗中,钾盐或可药用的溶剂化物的存在量为提供多至12mg,包括1-12mg,如2-12mg的化合物(I),尤其是2-4mg,4-8mg或8-12mg的化合物(I),例如1,2,3,4,5,6,7,8,9,10,11或12mg的化合物(I)或4-8或8-12mg的化合物(I)。因此,例如,在前面提到的组合物(包括单剂)或治疗中,钾盐或可药用的溶剂化物的存在量为提供1mg的化合物(I);钾盐或可药用的溶剂化物的存在量为提供2mg的化合物(I);钾盐或可药用的溶剂化物的存在量为提供3mg的化合物(I);钾盐或可药用的溶剂化物的存在量为提供4mg的化合物(I);钾盐或可药用的溶剂化物的存在量为提供8mg的化合物(I)。
其它抗糖尿病药合适地选自双胍(biguanides)、磺脲(sulphonylureas)和α-葡糖苷酶抑制剂。其它抗糖尿病药优选是双胍。其它抗糖尿病药优选是磺脲。其它抗糖尿病药优选是α-葡糖苷酶抑制剂。合适的抗糖尿病药披露在WO 98/57649、WO 98/57634、WO 98/57635、WO 98/57636、WO 99/03477和WO 99/03476中。将前面提到的公开文件的内容引入本发明中作为参考。
在前面提到的治疗中,本发明的化合物没有显示出不利的毒副作用。
附图说明
现参考附图,更详细地描述本发明。
图1为本发明钾盐的红外光谱;
图2为本发明钾盐的拉曼光谱;
图3为本发明钾盐的的X-射线粉末衍射图谱(XRPD);
图4为本发明钾盐的固态13C NMR波谱。
下列实施例用于说明本发明,但决不限制本发明。
具体实施方式
实施例
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,钾盐
在50℃下,将氢氧化钾(0.56g)在水(5ml)中的溶液加入到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(3.0g)在四氢呋喃(30ml)中的搅拌溶液中。在约1小时内,在搅拌下,将该溶液冷却到21℃并在减压下蒸发掉溶剂以得到作为结晶固体的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,钾盐(2.90g)。
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,钾盐
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(3.0g)在丙酮(30ml)中的搅拌悬浮液加热至回流,然后加入氢氧化钾(0.56g)在水(5ml)中的溶液。5分钟后,形成透明溶液,在约1小时内将搅拌溶液的温度冷却到21℃。在减压下蒸发掉溶剂,得到作为结晶固体的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,钾盐(3.25g)。
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,钾盐
将氢氧化钾(0.56g)在水(1ml)中的溶液加入回流下的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(3.0g)在丙-2-醇(30ml)的搅拌悬浮液中。在5分钟内,溶液变成透明,然后开始形成沉淀。在约90分钟内将搅拌的混合物冷却到21℃。通过过滤收集固体沉淀物,用丙-2-醇(10ml)洗涤并在真空下干燥16小时,得到作为白色结晶固体的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,钾盐(3.14g)。
实测值(%):C:54.44,H:4.53,N:10.45;预期值:C:54.52,H:4.83,N:10.60。
通过离子色谱法测定的钾离子含量为9.9%重量(预期值:9.9%)。
水含量(Karl-Fisher):0.2%重量。
实施例4 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,钾盐
将叔丁醇钾(1.41g)加入回流下的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(3.0g)在乙酸乙酯(30ml)的搅拌悬浮液中。将搅拌的混合物在回流下保持15分钟,然后在约1小时内冷却到21℃。通过过滤收集固体,用乙酸乙酯(10ml)洗涤并在真空下在50℃下干燥72小时,得到作为白色结晶固体的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,钾盐(3.30g)。
实施例5 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,钾盐
将氢氧化钾(4.71g)在水(5.0ml)中的溶液加入回流下的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(25.0g)在丙-2-醇(250ml)的搅拌悬浮液中。将搅拌的混合物在回流下保持15分钟,然后在约1小时内冷却到21℃。通过过滤收集固体,用丙-2-醇(50ml)洗涤并在真空下在60℃下干燥16小时,得到作为白色结晶固体的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,钾盐(26.6g)。
实施例3的产物记录的表征数据
使用Nicolet 710 FT-IR光谱仪在2cm-1分辨率下得到产物的矿物油分散液的红外吸收光谱(图1)。以1cm-1间隔将数据数字化。在1668,1605,1596,1559,1537,1512,1504,1424,1311,1263,1247,1224,1206,1199,1178,1156,1061,1008,977,964,896,830,783,764,746,731,692,663,559,510,479cm-1处观察到谱带。
使用配置有通用的ATR附件的Perkin-Elmer Spectrum One FT-IR光谱仪记录固体产物的红外光谱。在2924,2867,1667,1595,1557,1534,1501,1462,1438,1422,1389,1364,1309,1262,1244,1220,1206,1197,1178,1155,1106,1080,1060,1007,977,963,922,896,829,782,764,746,729,692,662cm-1处观察到谱带。
使用Nicolet 960 E.S.P.FT-Raman光谱仪,在4cm-1分辨率下由功率输出为400mW的Nd:V04激光(1064nm)激发而记录NMR管中的样品的拉 曼光谱(图2)。在3068,3055,3012,2925,2900,2868,1663,1611,1560,1463,1439,1424,1387,1313,1275,1206,1179,1158,1099,1057,977,923,897,842,783,750,726,663,633,480,405,347cm-1处观察到谱带。
使用下列获取条件来记录产品的X-射线粉末衍射图案(图3):阳极管:Cu,发电机电压:40kV,发电机电流:40mA,起始角度:2.0°2θ,最终角度:35.0°2θ,步长:0.02°2θ,每步时间:2.5秒。表征性的XRPD角度和相对强度记录在表1中。
表1
角度 | 相对角度 |
2θ° | % |
3.1 | 100 |
6.2 | 13 |
9.3 | 13.2 |
12.1 | 0.8 |
12.5 | 3.1 |
12.9 | 1 |
13.5 | 1.3 |
14.3 | 8 |
15.2 | 35.9 |
15.6 | 2.9 |
16.3 | 1.4 |
17.4 | 0.9 |
18.5 | 3.6 |
18.8 | 10.5 |
19.8 | 2.9 |
20.1 | 2.9 |
20.5 | 2.4 |
21.1 | 6.2 |
21.7 | 1.3 |
22.4 | 9.3 |
23.3 | 11.3 |
23.8 | 7.3 |
24.2 | 8.4 |
24.9 | 2.9 |
25.5 | 3.2 |
26.6 | 4.4 |
27.1 | 9.9 |
28.0 | 5.8 |
[0116]
28.4 | 4.5 |
29.6 | 4.3 |
29.9 | 2.6 |
30.9 | 6.1 |
32.1 | 10.1 |
32.8 | 2.5 |
33.2 | 7.3 |
34.5 | 3.1 |
在90.55MHz下运行的Bruker AMX360仪器上记录产品的固态NMR波谱(图4):将固体包装在装有Kel-F帽的4mm氧化锆MAS转子中,且转子在约10kHz下旋转。通过Hartmann-Hahn匹配的质子的交叉极化(cross-polarisation)(CP接触时间3ms,反复时间15s)获取13C MAS光谱,且在获取期间通过使用两脉冲相调制(TPPM)的复合顺序将质子去耦。将化学位移与相对于四甲基硅烷(TMS)的176.4ppm处的甘油的羧酸酯信号外部对照,在38.8,49.7,64.3,66.7,103.9,110.9,118.1,129.1,131.1,132.4,136.2,148.3,158.6,191.1,196.3ppm处观察到化学位移。
钾盐的性质,所记录的是实施例5的产品
钾盐的固态稳定性
在a)40℃/75%相对湿度(RH)下,开放暴露1个月,和b)50℃,封闭,1个月下,通过将约1.0g物质储存在玻璃瓶中而测定药物的固态稳定性。通过HPLC分析两种情况下物质的最终含量和变质情况。
a)40℃/75%RH:没有观察到明显的变质(HPLC分析101%起始物质)。
b)50℃:没有观察到明显的变质(HPLC分析99%起始物质)。
钾盐的溶解度
通过将1~1000ml的等份试样的水加入约100mg的药物中直到粉末溶解而测定物质的溶解度。通过HPLC分析饱和溶液而确认目视溶解度。
溶解度:>100mg/ml。
钾盐的熔点范围
根据U.S.Pharmacopoeia,USP 23,1995,<741>“Melting range ortemperature,Procedure for Class Ia”,使用Buchi 545熔点仪器所述的方法测定钾盐的熔点范围。
熔点范围:196.4~200.6℃。
钾盐的T起始
使用Perkin-Elmer DSC7仪器通过差示扫描量热法测定药物的T起始。
T起始(10℃/分钟,封闭盘(closed pan)):205℃。
Claims (7)
1.药物组合物,包含5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐及其可药用的载体,
其中5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐的特征在于它提供下列一种或多种特征:
(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-射线粉末衍射图谱(XRPD);
(iv)基本上与图4一致的固态13CNMR波谱;和
(v)熔点范围为194~201℃,以及
其中该钾盐的存在量提供了1,2,3,4,4~8或8~12mg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。
2.根据权利要求1的药物组合物,包含该钾盐或其可药用的盐,其量为提供1,2,3或4mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
3.根据权利要求1的药物组合物,包含该钾盐或其可药用的盐,其量为提供2mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
4.根据权利要求1的药物组合物,包含该钾盐或其可药用的盐,其量为提供4mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
5.根据权利要求1的药物组合物,其量为提供8mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
6.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-2,4-二酮钾盐或其可药用的盐,
其中5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐的特征在于它提供下列一种或多种特征:
(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-射线粉末衍射图谱(XRPD);
(iv)基本上与图4一致的固态13C NMR波谱;和
(v)熔点范围为194~201℃,以及
其中钾盐的存在量为提供1,2,3,4,4~8或8~12mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
7.化合物5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐在生产治疗和/或预防糖尿病、与糖尿病相关的疾病及其某些特定的并发症的药物中的应用,
其中5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮钾盐的特征在于它提供下列一种或多种特征:
(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-射线粉末衍射图谱(XRPD);
(iv)基本上与图4一致的固态13C NMR波谱;和
(v)熔点范围为194~201℃,以及
其中该钾盐的存在量为提供1,2,3,4,4~8或8~12mg的5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮的量。
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HU225919B1 (en) * | 1999-12-18 | 2007-12-28 | Richter Gedeon Nyrt | Thiazolidine-derivatives, process for their preparation pharmaceutical and intermediates |
HUP0800755A2 (en) | 2008-12-11 | 2010-09-28 | Richter Gedeon Nyrt | Crystalline forms of rosiglitazone |
Family Cites Families (8)
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US5521201A (en) * | 1987-09-04 | 1996-05-28 | Beecham Group P.L.C. | Method for treatment of atherosclerosis |
ATE186724T1 (de) * | 1987-09-04 | 1999-12-15 | Beecham Group Plc | Substituierte thiazolidindionderivate |
GB9124513D0 (en) * | 1991-11-19 | 1992-01-08 | Smithkline Beecham Plc | Novel process |
GB9308487D0 (en) * | 1993-04-23 | 1993-06-09 | Smithkline Beecham Plc | Novel compounds |
GB9712866D0 (en) * | 1997-06-18 | 1997-08-20 | Smithkline Beecham Plc | Novel method of treatment |
GB9723295D0 (en) * | 1997-11-04 | 1998-01-07 | Smithkline Beecham Plc | Novel process |
CN1183130C (zh) * | 1999-09-24 | 2005-01-05 | 中国人民解放军军事医学科学院毒物药物研究所 | 噻唑烷类衍生物及其医药用途 |
HU225919B1 (en) * | 1999-12-18 | 2007-12-28 | Richter Gedeon Nyrt | Thiazolidine-derivatives, process for their preparation pharmaceutical and intermediates |
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2000
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2001
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- 2001-09-28 EP EP01972254A patent/EP1325000B1/en not_active Revoked
- 2001-09-28 AT AT01972254T patent/ATE368038T1/de active
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2003
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2007
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