CN1289082C - 用于治疗糖尿病的药物组合物 - Google Patents
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Abstract
药物组合物,其中含有胰岛素敏感性增强剂并同时含有与所述增强剂作用机理不同的其它抗糖尿病药,该组合物对糖尿病性高血糖表现出强大的抑制作用并可用于预防和治疗糖尿病。
Description
本发明涉及一种药物组合物,它含有胰岛素敏感性增强剂并同时含有一种或多种其它在作用机理上不同于所述增强剂的抗糖尿病药。
近几年来,糖尿病的病理学过程已越来越为人们所了解,同时,对相应的病理阶段特异的药物也已开发出来。相应地,一个接一个地出现了多种具有新的作用机理的药物。
已知胰岛素敏感性增强剂还可用作胰岛素抵抗性去阻滞剂,这是因为它们具有恢复受损伤的胰岛素受体功能的作用,在这几年,它们引起了人们较多的关注。
参照这样的胰岛素敏感性增强剂,已开发出了一些非常有用的化合物,例如Pioglitazone[Fujita et al.,Diabetes,32,804-810,1983,JP-A S55(1980)-22636(EP-A 8203),JP-AS61(1986)-267580(EP-A 193256)]。Pioglitazone可恢复损伤的胰岛素受体的功能以使不正常的下述因素正常,如细胞内葡萄糖载体的分布,与糖代谢有关的主要酶系,例如葡萄糖激酶,及与脂质代谢相关的酶系,例如脂蛋白脂酶。结果,解除了胰岛素抑制性以改善葡萄糖耐受性,降低中性脂质和游离脂肪酸的血浆浓度。由于Pioglitazone这些作用相对比较缓慢,且长期服药产生的副作用的风险也较低,这一化合物适用于那些预计为高度胰岛素耐受的肥胖患者。
同样,已有报道胰岛素敏感性增强剂如CS-045,噻唑烷二酮衍生物和取代的噻唑烷二酮衍生物可与胰岛素合用[JP-A H4(1992)-66579,JP-A H4(1992)-69383,JP-A H5(1993)-202042]。然而,具有本发明特定组合的药物组合物还未见报道。
糖尿病是一种具有多种病理表现的慢性疾病,同时伴有脂质代射紊乱、循环失调和糖代谢紊乱。结果,在许多情况下,糖尿病易发展为多种并发症。因此,有必要针对每个人的病情选择出适用于占主导地位的疾病阶段的药物。然而,这一选择在临床实施时通常是较难的,这是因为单独使用一种药物在某些疾病状态时不能产生足够的疗效,同时,增加剂量或长期服药会带来多种问题,如副作用。
根据上文所述的技术,本发明的发明人作了许多研究工作以开发抗糖尿病药,该药即使在长期给药的情况下也不会引起副反应,且对于大量的糖尿病人群有效。结果,发现上述目的可通过下面的方法实现,即使用一种胰岛素敏感性增强剂,例如上文所述的药物,同时结合使用作用机理不同于所述增强剂的其它抗糖尿病药,这样就完善了本发明。
因此,本发明涉及:
1)药物组合物,其中含有一种胰岛素敏感性增强剂并同时含有至少下述中的一种,其中包括,α-葡萄糖激酶抑制剂,醛糖还原酶抑制剂,双胍,抑制素化合物,鲨烯合成抑制剂,非贝特(fibrate)化合物,LDL分解代谢增强剂及血管紧张肽转化酶抑制的化合物;
2)按照1)的药物组合物,其中所述胰岛素敏感性增强剂为由下述结构式代表的化合物:
其中R代表任选的取代烃基或杂环基;Y代表由-CO-,-CH(OH)-或NR3(其中R3代表任选的取代烷基)代表的基团;m为0或1;n为0,1或2;X代表CH或N;A代表一化学键或C1-7二价脂肪族烃基;Q代表氧原子或硫原子:R1代表氢原子或烷基;环E可任选具有1至4个取代基,取代基可任选与R1结合以形成个环;L和M分别代表氢原子,或L和M任选相互结合形成一化学键;或它们的药理学可接受的盐;
3)按照2)的药物组合物,其中结构式(I)代表的化合物为pioglitazone;
4)按照1)的药物组合物,其中含有一种胰岛素敏感性增强剂并同时含有一种α-葡萄糖激酶抑制剂;
5)按照4)的药物组合物,其中所述α-葡萄糖激酶抑制剂为voglibose;
6)按照4)的药物组合物,其中所述胰岛素敏感性增强剂为pioglitazone且α-葡萄糖激酶抑制剂为voglibose;
7)按照1)的药物组合物,该组合物用于预防或治疗糖尿病;
8)药用组合物,其中含有下述结构式代表的化合物:
其中R′代表任选的取代烃基或杂环基;Y代表由-CO-,-CH(OH)-或-NR3(其中R3代表任选的取代烷基)代表的基团;m为0或1;n为0,1或2;X代表CH或N;A代表一化学键或C1-7二价脂肪族烃基;Q代表氧原子或硫原子;R1代表氢原子或烷基;环E可任选具有1至4个取代基,取代基可任选与R1结合以形成一个环;L和M分别代表氢原子,或L和M任选相互结合形成一化学键;一个限制条件是当m和n为0,X代表CH,A代表一化学键,Q代表硫原子,R1,L和M代表氢原子且环E不具有其它取代基时R1不代表苯并吡喃基;或它们的药理学可接受的盐并同时含有胰岛素分泌增强剂和/或胰岛素制品;
9)按照8)的药物组合物,其中由结构式(II)代表的化合物为由下面结构式代表的化合物:
10)按照8)的药物组合物,其中由结构式(II)代表的化合物为pioglitazone;
11)按照8)的药物组合物,其中所述胰岛素分泌增强剂为优降糖;
12)按照8)的药物组合物,其中所述其中由结构式(II)代表的化合物为pioglitazone,胰岛素分泌增强剂为优降糖;
13)按照8)的药物组合物,该组合物用于预防或治疗糖尿病。
本说明书中使用的术语″胰岛素敏感性增强剂″指任意和所有可恢复受损的胰岛素受体功能以解除胰岛素抑制并因此提高胰岛素敏感性的药物。作为胰岛素敏感性增强剂的例子,可以是结构式(I)代表的化合物或其药理学可接受的盐。
在结构式(I)中,作为R所代表的任选的取代烃基,可以是脂族烃基,脂环烃基,脂环-脂族烃基,芳族脂族烃基和芳族烃基。这些烃基中碳原子的数目优选1至14。
脂族烃基优选具有1至8个碳原子的。作为脂族烃基,可以是C1-8饱和脂族烃基(例如烷基),例如甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,戊基,异戊基,新戊基,叔戊基,己基,异己基,庚基和辛基,还可是不饱合脂族烃基(例如,链烯基,链二烯基,炔基,链二炔基),例如,乙烯基,1-丙烯基,2-丙烯基,1-丁烯基,2-丁烯基,3-丁烯基,2-甲基-1-丙烯基,1-戊烯基,2-戊烯基,3-戊烯基,4-戊烯基,3-甲基-2-丁烯基,1-己烯基,3-己烯基,2,4-己二烯基,5-己烯基,1-庚烯基,1-辛烯基,乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,2-丁炔基,3-丁炔基,1-戊炔基,2-戊炔基,3-戊炔基,4-戊炔基,1-己炔基,3-己炔基,2,4-己二炔基,5-己炔基,1-庚炔基和1-辛炔基。
脂环烃基优选具有3至7个碳原子的。作为脂环烃基,可以是C3-7饱和脂环烃基(例如环烷基),例如环丙基、环丁基、环戊基、环己基和环庚基,还可以是C5-7不饱合脂环烃基(例如环烯基、环二烯基),例如1-环戊烯,2-环戊烯,3-环戊烯,1-环己烯,2-环己烯,3-环己烯,1-环庚烯基,2-环庚烯基,3-环庚烯基和2,4-环庚二烯基。
作为脂环-脂族烃基,可以是那些通过将上述环脂族烃基与脂族烃基连接起来的基团(例如环烷基-烷基,环烯基-烷基),具有4至9个碳原子的这样的基团如环丙甲基,环丙乙基,环丁甲基,环戊甲基,2-环戊烯基甲基,3-环戊烯基甲基,环己基甲基,2-环己烯基甲基,3-环己烯基甲基,环己基乙基,环己基丙基,环庚基甲基和环庚基乙基。
芳香脂肪烃基优选那些具有7至13个碳原子的(例如芳烷基),作为芳香脂肪烃基,可以是C7-9的苯烷基,例如苄基,苯乙基,1-苯乙基,3-苯丙基,2-苯丙基和1-苯丙基,也可以是C11-13萘烷基,例如α-萘甲基,α-萘乙基,3萘甲基和β-萘乙基。
作为芳香烃基,可以具有6至14个碳原子,例如苯基,萘基(α-萘基,β-萘基)。
在结构式(I)中。作为R所代表的任选取代杂环基中的杂环基,可以是例如5-7元杂环基,包括环中含有1至4个杂原子的杂环,杂原子选自氧原子,硫原子和氮原子,还可以是稠合环基。作为稠环,可以是,例如,这些5至7元杂环基与含有一或两个氮原子的6元环,苯环或含有一个硫原子的5元环稠合。
这些杂环基的例子包括2-吡啶基,3-吡啶基,4-吡啶基,2-嘧啶基,4-嘧啶基,5-嘧啶基,6-嘧啶基,3-哒嗪基,4-哒嗪基,2-吡嗪基,2-吡咯啉基,3-吡咯啉基,2-咪唑基,4-咪唑基,5-咪唑基,3-吡唑基,4-吡唑基,异噻唑基,异唑基,2-噻唑基,4-噻唑基,5-噻唑基,2-唑基,4-唑基,5-唑基,1,1,4-二唑-5-基,1,2,4-三唑-3-基,1,2,4-三唑-4-基,四唑-5-基,苯并咪唑-2-基,吲哚-3-基,1H-吲唑-3-基,1H-吡咯并[2,3-b]吡嗪-2-基,1H-吡咯并[2,3-b]吡啶-6-基,1H-咪唑并[4,5-b]吡啶-2-基,1H-咪唑并[4,5-c]吡啶-2-基,1H-咪唑并[4,5-b]吡嗪-2-基和苯并吡喃基。其中,优选吡啶基,唑基或噻唑基。
在结构式(I)中,R所代表的烃基和杂环基可在任意取代点任选具有1至5个,优选1至3个取代基。这样的取代基的例子包括脂肪烃基,脂环烃基,芳基,芳杂环基,非芳族杂环基,卤原子,硝基,任意取代的氨基,任意取代的酰基,任意取代的羟基,任意取代的硫醇基,任意酯化的羧基,脒基,氨基甲酰基,氨磺酰基,磺基,氰基,叠氮基和亚硝基。
脂肪烃基的例子包括C1-15直链或支链脂肪烃基,例如烷基,烯基和炔基。
烷基的优选例子包括C1-10烷基,例如甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,叔丁基,戊基,异戊基,新戊基,叔戊基,1-乙基丙基,己基,异己基,1,1-二甲基丁基,2,2-二甲基丁基,3,3-二甲基丁基,2-乙基丁基,己基,庚基,辛基,壬基和癸基。
链烯基的优选的例子包括C2-10链烯基,例如乙烯基,烯丙基,异丙烯基,1-丙烯基,2-甲基-1-丙烯基,1-丁烯基,2-丁烯基,3-丁烯基,2-乙基-1-丁烯基,3-甲基-2-丁烯基,1-戊烯基,2-戊烯基,3-戊烯基,4-戊烯基,4-甲基-3-戊烯基,1-己烯基,2-己烯基,3-己烯基,4-己烯基和5-己烯基。
炔基的优选的例子包括C2-10炔基,例如乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,2-丁炔基,3-丁炔基,1-戊炔基,2-戊炔基,3-戊炔基,4-戊炔基,1-己炔基,2-己炔基,3-己炔基,4-己炔基和5-己炔基。
作为脂环烃基,可以是C3-12饱合或不饱合脂环烃基,例如环烷基,环烯基和环二烯基。
环烷基的优选的例子包括C3-10环烷基,例如环丙基,环丁基,环戊基,环己基,环庚基,环辛基。二环[2,2,1]庚基,二环[2,2,2]辛基,二环[3,2,1]辛基,二环[3,2,2]壬基,二环[3,3,1]壬基,二环[4,2,1]壬基和二环[4,3,1]癸基。
环烯基的优选的例子包括C3-10环烯基,例如2-环戊烯-1-基,3-环戊烯-1-基,2-环己烯-1-基和3-环己烯-1-基。
优选的环二烯基的例子包括C4-10环二烯基例如2,4-环戊二烯-1-基,2,4-环己二烯-1-基和2,5-环己二烯-1-基。
优选的芳基的例子包括C6-14芳基,例如苯基,萘基(1-萘基,2-萘基),蒽基,菲基和苊基。
优选的芳香杂环基的例子包括芳香单杂环基,例如呋喃基,噻行基,吡咯基,唑基,异唑基,噻唑基,异噻唑基,咪唑基,吡唑基,1,2,3-二唑基,1,2,4-二唑基,1,3,4-二唑基,呋咱基,1,2,3-噻二唑基,1,2,4-噻二唑基,1,3,4-噻二唑基,1,2,3-三唑基,1,2,4-三唑基,四唑基,吡啶基,哒嗪基,嘧啶基,吡嗪基和三嗪基;及芳香稠杂环基,例如苯并呋喃基,异苯并呋喃基,苯并[b]噻吩基,吲哚基,异吲哚基1H-吲唑基,苯并咪唑基,苯并唑基,1,2-苯并异唑基,苯并噻唑基,1,2-苯并异噻唑基,1H-苯并三唑基,喹啉基,异喹啉基,噌啉基,喹唑啉基,喹喔啉基,2,3-二氮杂萘基,亚萘基,嘌呤基,喋啶基,咔唑基,α-咔啉基,3-咔啉基,γ-咔啉基,吖啶基,吩嗪基,吩噻嗪基,吩嗪基,吩氧硫杂环己二烯基(phenoxathiinyl),噻嗯基,啡啶基,菲咯啉基,中氮茚基,吡咯并[1,2-b]哒嗪基,吡唑并[1,5-a]吡啶基,咪唑并[1,2-a]吡啶基,咪唑并[1,5-a]吡啶基,咪唑并[1,2-b]哒嗪基,咪唑并[1,2-a]咪啶基,1,2,4-三唑并[4,3-a]吡啶基和1,2,4-三唑并[4,3-b]哒嗪基。
优选的非芳香族杂环基包括环氧乙烷基,氮杂环丁烷基,oxetanyl,thietanyl,吡咯烷基,四氢呋喃基,thiolanyl,哌啶基,四氢吡喃基、吗啉基、硫代吗啉基,pyrrolidino,哌啶子基,吗啉代和硫吗啉代。
卤素原子的例子包括氟、氯、溴和碘。
作为任意取代的取代氨基,可以是N-单取代氨基和N,N-二取代氨基。取代氨基的例子包括选自如下取代基的具有一或两个取代基的氨基其中有C1-10烷基,C2-10链烯基,C2-10炔基,芳香基,杂环基和C1-10酰基(例如甲基胺,二甲胺,乙基胺,二乙胺,二丁胺,二烯丙基胺,环己胺,苯胺,N-甲基-N-苯基胺,乙酰胺,丙酰胺,苯甲酰胺和烟酰胺。
作为酰基,可以是C1-13酰基,例如C1-10链烷酰基,C3-10链烯酰基,C4-10环烷基酰基,C4-10环烯基酰基和C6-12芳基羧基。
优选的C1-10链烷酰基的例子包括甲酰基,乙酰基,丙酰基,丁酰基,异丁酰基,戊酰基,异戊酰基,新戊酰基,己酰基,庚酰基和辛酰基。优选的C3-10链烯酰基包括丙烯酰基,甲基丙烯酰基,丁烯酰基和异丁烯酰基。优选的C4-10环烷基酰基的例子包括环丁烷酰基,环戊烷酰基环己烷酰基和环庚烷酰基。优选的C4-10环烯基酰基包括2-环己烯基酰基。优选的C6-12芳香酰基的例子包括苯甲酰基,萘甲酰基和烟酰基。作为取代酰基中的取代基,可以是,例如C1-3烷基,C1-3烷氧基,卤素原子(例如氯,氟,溴等),硝基,羟基和氨基。
作为任意取代的羟基,可以是,例如烷氧基,环烷氧基,链烯氧基,环烯氧基,芳烷氧基,酸基和芳氧基。
优选的烷氧基的例子包括C1-10烷氧基,例如甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,仲丁氧基,叔丁氧基,戊氧基,异戊氧基,新戊氧基,己氧基,庚氧基和壬氧基。优选的环烷氧基的例子包括C3-10环烷氧基例如环丁氧基,环戊氧基和环己氧基。优选的链烯氧基的例子包括C2-10链烯氧基,例如烯丙氧基,丁邻烯氧基,2-戊烯氧基和3-己烯氧基。优选的环烯氧基的例子包括C3-10环烯氧基,例如2-环戊烯氧基和2-环己烯氧基。优选的芳烷氧基的例子包括C7-10芳氧基,例如苯基-C1-4烷氧基(例如苄氧基和苯乙氧基)。优选的酸基的例子包括C2-13酸基,更优选C2-4烷酰氧基(例如,乙酰氧基,丙酰氧基,丁酰氧基和异丁酰氧基)。优选的芳氧基的例子包括C6-14芳氧基,例如苯氧基和萘氧基。芳氧基可任选具有一个或两个取代基,例如卤素原子(例如氯,氟,溴)。取代芳氧基的例子包括4-氯苯氧基。
作为任意取代的硫醇基,可以是烷基硫基,环烷基硫基,烯基硫基,环烯基硫基,芳烷基硫基,酰基硫基和芳基硫基。
优选的烷基硫基的例子包括C1-10烷基硫基,例如甲基硫基,乙基硫基,丙基硫基,异丙基硫基,丁基硫基,异丁基硫基,仲丁基硫基,叔丁基硫基,戊基硫基,异戊基硫基,新戊基硫基,己基硫基,庚基硫基和壬基硫基。优选的环烷基硫基的例子包括C3-10环烷基硫基,例如环丁基硫基,环戊基硫基和环己基硫基。优选的烯基硫基的例子包括C2-10烯基硫基,例如烯丙基硫基,丁邻烯硫基,2-戊基硫基和3-己基硫基。优选的环烯基硫基的例子包括C3-10环烯基硫基,例如2-环戊基硫基和2-环己基硫基优选的芳基硫基的例子包括C7-10芳硫基,例如苯基-C1-4烷基硫基(例如苄基硫基和苯乙基硫基)。优选的酰基硫基的例子包括C2-13酰基硫基,更优选C2-4烷酰基硫基(例如,乙酰基硫基,丙酰基硫基,丁酰基硫基和异丁酰基硫基)。
优选的芳硫基的例子包括C6-14芳硫基,例如苯硫基和萘硫基。芳硫基可任选具有一个或两个取代基,例如卤素原子(例如氯,氟,溴)。取代的芳基硫基的例子包括4-氯苯基硫基。
作为任意酯化的羧基,可以是,例如烷氧基羰基,芳烷氧基羰基和芳氧基羰基。
优选的烷氧基羰基的例子包括C2-5烷氧基羰基,例如甲氧基羰基,乙氧基羰基,丙氧基羰基和丁氧基羰基。优选的芳烷氧基羰基的例子包括C8-10芳烷氧基羰基,例如苄氧基羰基。优选的芳氧基羰基的例子包括C7-15芳氧基羰基,例如苯氧基羰基和P-甲基苯氧基羰基。
在R所代表的烃基和杂环基上的取代基中,优选C1-10烷基,芳杂环基和C6-14芳基,尤其优选C1-3烷基,呋喃基,噻吩基,苯基和萘基。
在结构式(I)中,R所代表的烃基和杂环基上的取代基在为脂环烃基,芳基,芳杂环基或非芳香族杂环基时可以具有一个或多个,优选1至3个合适的取代基。这些取代基的例子包括C1-6烷基,C2-6链烯基,C2-6炔基,C3-7环烷基,C6-14芳基,芳族杂环基(例如,噻吩基,呋喃基,吡啶基,唑基和噻唑基),非芳族杂环基(例如,四氢呋喃基,吗啉代,硫吗啉代,哌啶子基,pyrrolidino和哌嗪基),C7-9芳烷基,氨基,N-单-C1-4烷基氨基,N,N-二-C1-4烷基氨基,C2-8酰胺基(例如,乙酰胺基,丙酰氨基和苯甲酰胺基),脒基,C2-8酰基(例如C2-8烷基酰基),氨基甲酰基,N-单-C1-4烷基氨基甲酰基,N,N-二-C1-4烷基氨基甲酰基,磺酰基,N-单一C1-4烷基磺酰基,N,N-二-C1-4烷基磺酰基,羧基,C2-8烷氧基羰基,羟基,C1-4烷氧基,C2-5链烯氧基,C3-7环烷氧基,C7-9芳烷氧基,C6-14芳氧基,巯基,C1-4烷基硫基,C7-9芳烷基硫基,C6-14芳基硫基,磺基,氰基,叠氮基,硝基,亚硝基和卤素原子。
在结构式(I)中,R优选为任意取代的杂环基。R更优选为吡啶基,唑基或噻唑基,它们任选被1至3个取代基取代,取代基选自C1-3烷基,呋喃基,噻吩基,苯基和萘基。
结构式(II)中的R′与R定义相同,除了R′在m和n为0时不代表苯并吡喃基;X代表CH;A代表化学键;Q代表硫原子;R1,L和M代表氢原子;并且环E不带有其它取代基。
在结构式(I)和(II)中,Y代表-CO-,-CH(OH)-或-NR3-(其中R3代表任意取代的烷基),优选-CH(OH)-,或-NR3。作为R3所代表的任意取代的烷基,可以是,例如,C1-4烷基,如甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基和叔丁基。取代基的例子包括卤素(例如,氟,氟,溴和碘),C1-4烷氧基(例如甲氧基,乙氧基,丙氧基,丁氧基,异丁氧基,仲丁氧基和叔丁氧基),羟基,硝基和C1-4酰基(例如甲酰基,乙酰基和丙酰基)。
符号m为0或1,优选0。
符号n为0、1或2,优选0或1。
X代表CH或N,优选CH。
在结构式(I)和(II)中,A代表化学键或C1-7二价脂族烃基。该脂族烃基可以是直链或支链,饱合或不饱合,该脂族烃基特定的例子包括饱合的[例如,-CH2-,-CH(CH3)-,-(CH2)2,-CH(C2H5)-,-(CH2)3-,-(CH2)4-,-(CH2)5-,-(CH2)6-和-(CH2)7-]和不饱合的[-CH=CH-,-C(CH3)=CH-,-CH=CH-CH2-,-C(C2H5)=CH-,-CH2-CH=CH-CH2-,-CH2-CH2-CH=CH-CH2-,-CH=CH-CH=CH-CH2-和-CH=CH-CH=CH-CH=CH-CH2-。A优选为一化学键或C1-4二价脂族烃基,该脂族烃基优选为饱合的。A更优选为一化学键或-(CH2)2-。
作为R1所代表的烷基,基本为与上述R3基团中的烷基相同的。R1优选为氢原子。
在结构式(I)和(II)中,部分结构式:
环E可在任意可取代位置具有1至4个取代基。这样的取代基的例子包括烷基,任意取代的羟基,卤素原子,任意取代的酰基和任意取代的氨基。这些取代基基本与那些R代表的烃基和杂环基的取代基相同。
环E,即部分结构式:
优选代表结构式:
其中R2代表氢原子,烷基,任意取代的羟基,卤素原子,任意取代的酰基,硝基或任意取代的氨基。
作为R2所代表的烷基,任意取代的羟基,卤素原子,任意取代的酰基和任意取代的氨基,可以是R所代表的烃基和杂环基的取代基。R2优选为氢原子,任意取代的羟基或卤素原子,更优选氢原子或任意取代的羟基,尤其优选氢原子或C1-4烷氧基。
在结构式(I)和(II)中,L和M代表氢原子,或任选彼此接合形成化学键。L和M优选为氢原子。
在L和M彼此接合形成化学键的化合物中,相对于唑烷二酮(azolidinedione)环5位的双键存在(E)-和(Z)-型异构体。
而且,在L和M分别代表氢原子的化合物中由于唑烷二酮环中5位不对称的碳,存在(R)-和(S)-光学异构体。本发明化合物包括这些(R)-和(S)-光学异构体和外消旋异构体。
优选的结构式(I)或(II)所代表的化合物的例子包括那些R为吡啶,唑和噻唑基的,它们任选具有1至3个取代基,取代基选自C1-3烷基、呋喃基,噻吩基,苯基和萘基;m为0;n为0或1;X为CH;A为一化学键或-(CH2)2-;R1为氢原子;环E,即部分结构式:
R2为氢原子或C1-4烷氧基;L和M均为氢原子。
优选的结构式(I)所代表的化合物的例子包括:
(1)结构式(III)所代表的化合物,例如5-[4-[2-(3-乙基-2-吡啶基)乙氧基]苄基]-2,4-噻唑烷二酮;5-[4-[2-(4-乙基-2-吡啶基)乙氧基]-苄基]-2,4-噻唑烷二酮;5-[4-[2-(5-乙基-2-吡啶基)乙氧基]-苄基]-2,4-噻唑烷二酮(通用名:pioglitazone);和5-[4-[2-(6-乙基-2-吡啶基)乙氧基]-苄基]-2,4-噻唑烷二酮;
(2)(R)-(+)-5-[3-[4-[2-(2-呋喃基)-5-甲基-4-唑基甲氧基]-3-甲氧基苯基]丙基]-2,4-唑烷二酮;和
(3)5[[4-[(3,4-二氢-6-羟基-2,5,7,8-四甲基-2H-1-苯并吡喃-2-基)甲氧基]苯基]甲基]-2,4-噻唑烷二酮(通用名:troglitazone/CS-045)。
结构式(I)所代表的化合物尤为优选pioglitazone。
结构式(II)所代表的化合物优选结构式(III)所代表的化合物和(R)-(+)-5-[3-[4-[2-(2-呋喃基)-5-甲基-4-唑基甲氧基]-3-甲氧基苯基]丙基]-2,4-唑烷二酮,更优选pioglitazone;
结构式(I)或(II)或代表化合物的药理学可接受的盐例如与无机碱形成的盐,与有机碱形成的盐,与无机酸形成的盐,与有机酸形成的盐,及与碱性或酸性氨基酸所形成的盐。
优选的与无机碱形成的盐的例子包括与碱金属,例如钠,钾等所形成的盐,与碱土金属例如钙,镁等所形成的盐,及与铝,铵等所形成的盐。
优选的与有机碱所形成的盐的例子包括与三甲胺,三乙胺,吡啶,皮考啉,乙醇胺,二乙醇胺,三乙醇胺,二环己胺,N,N-二苄基乙烯基二胺等所形成的盐。
优选的与无机酸所形成的盐的例子包括与盐酸,氢溴酸,硝酸,硫酸,磷酸等所成的盐。
优选的与有机酸所形成的盐的例子包括与甲酸,乙酸,三氟乙酸,富马酸,草酸,酒石酸,马来酸,柠檬酸,琥珀酸,苹果酸,甲磺酸,苯磺酸,P-甲基苯磺酸等所成的盐。
优选的与碱性氨基酸所成的盐的例子包括与精氨酸,赖氨酸,鸟氨酸等所成的盐,优选的与酸性氨基酸所成的盐的例子包括与天冬氨酸,谷氨酸等所成的盐。
结构式(III)所代表的化合物的药理学可接受的盐优选与无机酸所形成的盐,更优选与盐酸所形成的盐。尤其是,pioglitazone优选以与盐酸与成的盐的形式使用。
结构式(I)或(II)所代表的化合物或其盐可按下述方法制备,例如,JPA S55(1980)-22636(EP-A 8203),JPA S60(1985)-208980(EP-A 155845),JPA S61(1986)-286376(EP-A 208420),JPA S61(1986)-85372(EP-A 177353),JPA S61(1986)-267580(EPA-A 193256),JPA H5(1993)-86057(WO 92/18501),JPA H7(1995)-82269(EP-A 605228),JPA H7(1995)-101945(EP-A 612743),EP-A 643050,EP-A 710659等中所描述的方法或与此类似的方法。
胰岛素敏感性增强剂包括5-[[3,4-二氢-2-(苯基甲基)-2H-1-苯并吡喃-6-基]甲基]-2,4-噻唑烷二酮(通用名:englitazone)或其钠盐;5-[[4-[3-(5-甲基-2-苯基-4-唑基)-1-氧丙基]苯基]甲基]-2,4-噻唑烷二酮(通用名:darglitazone/CP-86325)或其钠盐;5-[2-[5-甲基-2-苯基-4-唑基甲基)苯并呋喃-5-基甲基]-2,4-唑烷二酮(CP-92768);5-(2-萘磺酰基)-2,4-噻唑烷二酮(AY-31637);4-[(2-萘基)甲基]-3H-1,2,3,5-噻二唑(oxathiadiazol)-2-氧化物(AY-30711);和5-[[4-[2-(甲基-2-吡啶基胺基)乙氧基]苯基]-甲基]-2,4-噻唑烷二酮(BRL-49653)等,另外还有上文所述的化合物。
本发明中,与上文所述胰岛素敏感性增强剂合用的药物的例子包括α-葡萄糖激酶抑制剂,醛糖还原酶抑制剂,双胍,抑制素化合物,鲨烯合成抑制剂,非贝特化合物,LDL分解代谢增强剂和血管紧张肽转化酶抑制剂。
α-葡萄糖激酶抑制剂是这样一类药物,它们可抑制消化酶,例如淀粉酶,麦芽糖酶,α-糊精酶,蔗糖酶等,从而迟滞淀粉和蔗糖的消化。α-葡萄糖激酶抑制剂的例子包括阿卡波糖,N-(1, 3-二羟基-2-丙基)valiolamine(通用名:voglibose),米格列醇(miglitol)等,优选voglibose。
醛糖还原酶抑制剂为这样一类药物,它们可以抑制多元醇代谢过程中的一级速度限制酶以预防或阻止糖尿病综合症。在糖尿病的高血糖状态时,在多元醇代谢过程中葡萄糖的利用率提高了而且过剩的山梨醇在细胞内积聚,从而成为组织毒素,因此引起了一些综合症,例如糖尿病性神经病、视网膜病和肾病,醛糖还原酶抑制剂的例子包括tolurestat;依帕司地;3,4-二氢-2,8-二异丙基-3-硫代-2H-1,4-苯并嗪-4-乙酸;2,7-二氟-螺(9H-芴-9,4′-咪唑烷)-2′,5′-二酮(通用名:imirestat);3-[(4-溴-2-氟苯基)甲基]-7-氯-3,4-二氢-2,4-二氧-1(2H)-喹唑啉乙酸(通用名:zenarestat);6-氟-2,3-二氢-2′,5′-二氧-螺[4H-1-苯并吡喃基-4,4′-咪唑烷基]-2-甲酰胺(SNK-860);zopolrestat;索比尼尔和1-[(3-溴-2-苯并呋喃基)磺酰基]-2,4-咪唑烷二酮(M-16209)等。
双胍是具有这样一些作用的药物。它们可以激动有氧糖酵解,提高外周组织中对胰岛素的敏感性,抑制胃肠道吸收葡萄糖,抑制肝脏糖元异生作用,抑制脂肪酸氧化,双胍的例子包括苯二胍(phenformin),二甲双胍,丁二胍等。
抑制素化合物是具有这样一些作用的药物,它们可通过抑制羟甲基glutalyl CoA(HMG-CoA)还原酶而降低血液中胆固醇浓度。
抑制素化合物的例子包括pravastatin及其钠盐,西瓦特,洛伐他丁,atorvastatin,氟伐地丁等。
鲨烯合成抑制剂是具有通过抑制鲨烯合成而降低血液胆固醇浓度作用的药物。
鲨烯合成抑制剂的例子包括(S)-α[双[2,2-二甲基-1-氧丙氧基)甲氧基]氧膦基]-3-苯氧基苯基丁磺酸单钾盐(BMS-188494)。
非贝特化合物是具有降低血液中胆固醇浓度的作用的药物,这种作用是通过抑制肝中甘油三酯的合成和分泌同时激活一种脂蛋白脂酶而完成的。非贝特化合物的例子包括苯扎贝特,苄氯贝特,比尼贝特,ciplofibrate,克利贝特,氯贝丁酯,clofibric acid、etofibrate,苯非贝特,诺衡,nicofibrate,pirifibrate,ronifibrate,双贝特,益多脂等。
LDL分解代谢增强剂是具有降低血液中胆固醇浓度作用的药物,这种作用通过增加LDL(低密度脂蛋白)受体数目完成。
LDL分解代谢增强剂的例子包括在JPA H7(1995)-316144中描述的化合物,其结构式如下:
其中R4,R5,R6,和R7是相同或不相同的,代表氢原子,卤素原子,低级烷基或低级烷氧基;r是0-2;s为2-4;p为1-2;或它的盐;尤其是N-[2-[4-双(4-氟苯基)甲基-1-哌嗪基]乙基]-7,7-二苯基-2,4,6-庚三烯酸酰胺。
上面提到的抑制素化合物,鲨烯合成抑制剂,非贝特化合物和LDL分解代谢增强剂能被其他具有降低血液胆固醇和甘油三酯浓度特性的药物所代替。这些药物的例子包括烟酸衍生物如尼可莫尔和戊四烟酯;抗氧化剂如丙丁酚;及离子交换树脂如消胆胺。
血管紧张素转换酶是具有部分地降低血液葡萄糖浓度同时具有降低血压作用的药物,这是通过抑制血管紧张素转换酶完成的。血管紧张素转换酶抑制剂的例子包括卡托普利,依那普利,阿拉普利,地拉普利,雷米普利,利诺普利,咪哒普利,贝那普利,西洛普利,西拉普利,依那普利拉,福辛普利,莫替普利,哌道普利,喹那普利,斯哌普利,temocapril,川多普利。
本发明中,特别优选包含有胰岛素敏感性增强剂和α-葡萄苷酶抑制剂的药物组合物。胰岛素敏感性抑制剂首选pioglitazone,α-葡萄苷酶抑制剂首选voglibose。
本发明中,与结构式(II)所代表的化合物或其药理学可接受的盐共同使用的药物例子包括胰岛素分泌增强剂和/或胰岛素制品。
胰岛素分泌增强剂是具有促进胰腺3细胞分泌胰岛素特性的药物。胰岛素分泌增强剂例子包括磺酰脲(SU)。磺酰脲(SU)是促进胰腺β细胞分泌胰岛素的药物,这种作用通过经由细胞膜内的SU受体传递胰岛素分泌信号而实现。SU的例子包括甲糖宁;氯磺丙脲;甲磺氮脲;乙酰苯磺酰环己脲;4-氯-N-[(1-吡咯烷胺)羧基]-苯磺酰胺通用名:吡喃葡萄糖胺)或它的铵盐;优降糖;甲磺吡脲;1-丁基-3-间氨基苯磺酰脲;磺胺丁脲;glibonuride;格列吡嗪;gliquidone;glisoxepid;glybuthiazole;glibuzole;环己降糖;嘧啶降糖;glypinamide;phenbutamide;tolycyclamide等。
胰岛素分泌增强剂除上文提到的化合物外还包括N-[[4-(1-甲基乙基)环己基)羰基]-D-苯丙氨酸(AY-4166);钙(2S)-2-苄基-3(顺-六氢化-2-异二氢氮茚基羰基)丙酸盐二水合物(KAD-1229);和glimepiride(Hoe 490)等。胰岛素分泌增强剂优选优降糖。
胰岛素制品包括动物胰岛素制品通常从牛或猪胰腺提取以及人胰岛素制品-通过遗传工程技术合成,通常使用大肠杆菌或酵母菌。由于可得到多种类型的胰岛素制品,如直接作用的,双峰作用的,中介作用的,和长期作用的,所以可依据病人的情况,选择合适类型给药。
本发明优选的药物组合物包含结构式(II)所代表的化合物或其药理学可接受的盐结合胰岛素分泌增强剂。由结构式(II)代表的化合物或其药理学可接受的盐优选pioglitazone,胰岛素分泌增强剂优选降糖。
由本发明提供的两个药物组合物—其一包含有胰岛素敏感性增强剂及从α-葡萄苷酶抑制剂,醛糖还原酶抑制剂,双胍,抑制素化合物,鲨烯合成抑制剂,非贝特化合物,LDL代谢增强剂和血管紧张肽转化酶抑制剂中选择的至少一种物质;其二包含由结构式(II)所代表的化合物或其药理学可接受的盐及胰岛素分泌增强剂和/或胰岛素制品—可分别通过下述方式使用:分别将各自的活性成分全部或单独与生理学可接受的载体,赋形剂,粘合剂,稀释剂等相混合然后将混合物作为药物组合物以口服或非口服方式给药。当将活性成分单独配制时,各制剂可在临用前与稀释剂或类似物混合并可单独服用,对同一个病人可同时或间隔服用每一种混合物。
所述药物组合物的剂型包括口服制剂如颗粒剂、散剂、片剂、胶囊剂、糖浆剂、乳剂、混悬剂等,及非口服制剂如注射剂(如皮下注射,静脉注射,肌注和腹膜内注射制剂),滴注,外用剂型(如鼻腔喷雾剂,透皮制剂,油膏剂等),及栓剂(例如直肠及阴道栓剂)。
这些剂型可通过公知的用于药物生产的传统工艺制作。特定的生产过程如下:
为制作口服剂型,向一种或多种活性成分中加入例如赋形剂(如乳糖,蔗糖,淀粉,甘露醇等),崩解剂(如碳酸钙,羧甲基纤维素钙等),粘合剂(如α-淀粉,阿拉伯胶,羧甲基纤维素,聚乙烯吡咯烷酮,烃丙基纤维素等),及润滑剂(如滑石粉,硬脂酸镁,聚乙二醇6000等),然后将所得的组合物压制。必要时,将压制产品以公知的技术包衣,以掩盖其味道或使其在小肠溶解或达到缓释的目的。可使用的包衣材料包括,例如乙基纤维素、羟甲基纤维素,聚氧乙烯醇,醋酸纤维素邻苯二甲酸酯,羟丙基甲基纤维素邻苯二甲酸酯,及Eudragit(Rohm & Haas,德国,甲基丙烯酸-丙烯酸共聚物)。
注射剂一般可通过下列步骤生产。将活性成分在水性载体(如蒸馏水,生理盐水,Ringer′s溶液等)或油性载体(例如植物油如橄榄油,芝麻油,棉籽油,玉米油等或丙烯醇)中与分散剂(如Tween 80(Atlas Powder,U.S.A),HCO 60(Nikko Chemicals)聚乙二醇,羧甲基纤维素,藻酸钠等),防腐剂(如p-羟基苯甲酸甲酯,p-羟基苯甲酸丙酯,苄醇,氯丁醇,苯酚等),等渗剂(如氯化钠,甘油,山梨醇,葡萄糖,转化糖),及其他添加物一起溶解,悬浮或乳化。如果需要,也可加入助溶剂(如水杨酸钠,乙酸钠等),稳定剂(如人血清白蛋白),镇痛剂(如benzalkoniumchloride,盐酸普鲁卡因等)及其他添加剂。
外用制剂可通过:将一种或多种活性物质制成固体,半固体或液体组合物的方法制备。制备固体组合物时,可采用的方法如:将一种或多种活性成分单独或与赋形剂(如乳糖,甘露醇,淀粉,微晶纤维素,蔗糖等),增稠剂(如天然胶,纤维素衍生物,丙烯酸聚合物等)等相混合并制成散剂。液体组合物可通过与上文所述注射剂大体相同的方法制备。半固体组合物优选制成水或油脂胶体的形式或油膏的形式。这些组合物可任选含有PH控制剂(如碳酸、磷酸、柠檬酸、盐酸、氢氧化钠等)和防腐剂(如p-羟基苯甲酸酯,氯丁醇,benzalkonium chloride等)。
栓剂可通过将一种或多种活性成分制成油性或水性固体、半固体或液体组合物的方法制备。油性基质可包括例如高级脂肪酸甘油酯[如可可脂,Witepsols(Dinamit-Nobel)等],中等链长脂肪酸[如Migriols(Dinamit-Nobel)等],植物油(例如芝麻油、大豆油,棉籽油等)等。水溶性基质可包括例如聚乙二醇,丙二醇等。亲水性基质包含例如天然胶,纤维素衍生物,乙烯聚合物和丙烯酸聚合物等。
本发明的药物组合物毒性低,可以安全地用于哺乳动物(如人,小鼠,鼠,兔,狗,猫,牛,马,猪,猴)。
本发明的药物组合物的剂量可参照对各种性成分的推荐剂量而适当确定,并可依据病人,病人的年龄和体重,当时临床状况,给药时间、剂型、给药方式及活性成分的组合等因素适当地选择。例如,胰岛素敏感性增强剂,其对一个成年人来说可选择的临床口服剂量范围是0.01到10mg/kg体重(优选0.05至10mg/kg体重,更优选的是0.05到5mg/kg体重),而临床非肠道剂量范围是0.005到10mg/kg体重(优选0.01到10mg/kg体重,更优选的是0.01到1mg/kg体重)。其余结合使用并具有不同作用方式的活性成分也可以参考各自推荐的临床剂量范围来选择使用合适的剂量范围。优选的给药频度为每天1到3次。
本发明的药物组合物中活性成分的比率可依据病人,病人年龄和体重,当时临床状况,给药时间,剂型,给药方式以及活性成分的组合各个因素而适当选择。例如,当胰岛素敏感性增强剂以结构式(I)代表的化合物或其药理学可接受的盐(如pioglitazone)与α-葡萄糖苷酶抑制剂Viglibose结合给药于病人时,Voglibose所使用的比率通常为大约0.0001到0.2份(重量),优选约0.001到0.02份(重量),对1份(重量)的化合物或其盐。再比如,当结构式(II)所代表的化合物或其药理学可接受的盐与胰岛素分泌增强剂优降糖结合给药于病人时,优降糖所使用的比率通常为重量份比0.002到5份,优选约0.025到0.5份,对1重量份的化合物或其药理学可接受的盐。
本发明的药物组合物与两种活性成分单独给药相比显示出明显的协同作用。例如,与将每一种活性成分单独给药于伴有遗传性肥胖的糖尿病Wistar肥鼠相比较,这些活性成分的结合给药明显提高了对高血糖和葡萄糖减少的耐受性。这样,本发明的药物组合物比服用单一成分药物更能有效地降低糖尿病患者血液中葡萄糖的浓度,因此,可更好地用于糖尿病综合症的预防和治疗。
而且,由于与单独服用任何一种活性成分相比较,本发明的药物组合物能以降低了的剂量获得足够的药效,所以可降低各成分的副作用(如胃肠失调如腹泻等)。
下面的应用实施例和实验实施例仅用来更详细地闸述本发明,不能解释为限定了本发明的范围。
本发明的药物组合物可依据下述配方制备。
应用实施例1
胶囊
(1)盐酸pioglitazone 30mg
(2)voglibose 0.2mg
(3)乳糖 60mg
(4)微晶纤维素 79.8mg
(5)硬脂酸镁 10mg
总共180mg
将(1)、(2)、(3)和(4)的全量与(5)的半量混匀并以常规方法制粒。然后,加入(5)的余量,混合后将全部组合物装入一个明胶硬胶囊壳中。
应用实施例2
片剂:
(1)盐酸pioglitazone 10mg
(2)优降糖 1.25mg
(3)乳糖 86.25mg
(4)玉米淀粉 20mg
(5)聚乙二醇 2.5mg
(6)羟丙基纤维素 4mg
(7)Carmellose Calcium 5.5mg
(8)硬脂酸镁 0.5mg
130mg(每片)
(1)、(2)、(3)、(4)和(5)的全量与(6)和(7)的2/3,及(8)的1/2混匀并以常规方法制粒。然后,将(6)、(7)和(8)的余量加入到颗粒中,混匀,将全部组合物用压片机压片。成人剂量为3片/天,分成1至3次给药。
应用实施例3
胶囊:
(1)盐酸pioglitazone 10mg
(2)依帕司地 50mg
(3)乳糖 55mg
(4)微晶纤维素 55mg
(5)硬脂酸镁 10mg
总共180mg
将(1)、(2)、(3)和(4)的全量以及(5)的1/2量混匀并以常规方法制粒。然后,加入(5)的余量并把全部组合物装入明胶胶囊壳中。成人剂量为3个胶囊/天,分为1-3次服用。
实验实施例1
盐酸pilglitazone与α-葡糖苷抑制剂的结合服用在遗传性肥胖且患糖尿病的Wistar肥鼠中的效应。
将14-19周龄的雄性Wistar肥鼠分成4组,每组5-6只,服用盐酸pioglitazone(1mg/kg体重/天,口服)和/或Voglibose(α-葡萄苷酶抑制剂)(0.31mg/kg体重/天;以5ppm的比率混在市售饲料中服用)14天。从尾静脉取血,使用一种商品试剂盒(NC-ROPET,Nippon Chemiphar CO.)以酶法分别测定血浆葡萄糖和血红蛋白A1。结果表示为每组(n=5-6)的平均值±标准偏差并以Dunnett′s检验分析,在表1中给出。使用1%的显著性水平。
[表1]
组 | 血浆葡萄糖(mg/dl) | 血红蛋白A1(%) |
对照 | 345±29 | 5.7±0.4 |
Pioglitazone | 215±50* | 5.2±0.3 |
Voglibose | 326±46 | 6.0±0.6 |
Pioglitazone+voglibose | 114±23* | 4.5±0.4* |
*:P<0.01与对照组相比
表1中很清楚地表明,与单独服用任一单一成分药物相比,pioglitazone与voglibose的联合服用很明显地降低了血液葡萄糖和血红蛋白A1的浓度。
实验实施例2
盐酸pilglitazone与一种胰岛素分泌增强剂的联合服用在遗传性肥胖并患糖尿病的Wistar肥鼠中的效应。
将13-14周龄的雄性肥鼠分成4组,一组5只,服用盐酸pioglitazone(3mg/kg/天,口服)和/或优降糖(一种胰岛素分泌增强剂)(3mg/kg/天,口服)7天。禁食过夜之后马上进行口服葡萄糖负荷试验(2g葡萄糖/kg/5ml,口服)。在葡萄糖负荷试验之前和试验之后的120及240分钟,由尾静脉收集血液并以酶法(EncoreChemical System;Baker)分析血浆葡萄糖。结果以每组(n=5)平均值±SD并以Dunnett′s检验分析,在表2中给出。
[表2]
组 | 血浆葡萄糖(mg/dl) | ||
0min | 120min | 240min | |
对照 | 119±9 | 241±58 | 137±10 |
Pioglitazone | 102±12 | 136±17* | 102±9* |
优降糖 | 118±12 | 222±61 | 106±24* |
Pioglitazone+优降糖 | 108±3 | 86±10* | 60±5* |
*:与对照组相比P<0.01
表2很清楚地表明,与单独服用任一单一成分药物相比,pioglitazone与优降糖的联合使用很明显地抑制了葡萄糖负荷试验之后的血糖升高。
本发明的药物组合物显示出对糖尿病性高血糖有强抑制效果,并可用于糖尿病的预防和治疗。而且,此药物组合物还可用于糖尿病综合症如糖尿病性神经病,肾病,视网膜病,大血管病和骨质稀少症。另外,根据临床症状,通过选择合适的药物成分,给药途径,剂量等可以在长期治疗中达到维持稳定低血糖的效果,同时副作用非常小。
Claims (8)
1、预防或治疗糖尿病、糖尿病综合症、由于糖尿病引起的糖代谢紊乱或由于糖尿病引起的脂质代谢紊乱的药物组合物,其中含有伏格列波糖和选自吡格列酮或其药理学上可接受的盐的胰岛素敏感性增强剂。
2、按照权利要求1的药物组合物,其中所述胰岛素敏感性增强剂是吡格列酮或其盐酸盐。
3、伏格列波糖和选自吡格列酮或其药理学上可接受的盐的胰岛素敏感性增强剂在制备用于预防或治疗糖尿病的药物组合物中的应用。
4、伏格列波糖和选自吡格列酮或其药理学上可接受的盐的胰岛素敏感性增强剂在制备用于预防糖尿病综合症的药物组合物中的应用。
5、伏格列波糖和选自吡格列酮或其药理学上可接受的盐的胰岛素敏感性增强剂在制备用于预防由于糖尿病引起的糖代谢紊乱的药物组合物中的应用。
6、伏格列波糖和选自吡格列酮或其药理学上可接受的盐的胰岛素敏感性增强剂在制备用于预防由于糖尿病引起的脂质代谢紊乱的药物组合物中的应用。
7、按照权利要求3-6任一项的应用,其中所述胰岛素敏感性增强剂是吡格列酮或其盐酸盐。
8、根据权利要求3-6任一项的应用,其中所述胰岛素敏感性增强剂与伏格列波糖独立配制。
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