CN107007608B - I型和ii型糖尿病的治疗 - Google Patents
I型和ii型糖尿病的治疗 Download PDFInfo
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- CN107007608B CN107007608B CN201610988112.1A CN201610988112A CN107007608B CN 107007608 B CN107007608 B CN 107007608B CN 201610988112 A CN201610988112 A CN 201610988112A CN 107007608 B CN107007608 B CN 107007608B
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Abstract
本发明提供苯氧基嘧啶酮化合物或其药学可接受的盐在制备用于增强胰岛素诱导的血糖降低应答或者增强并延长胰岛素作用的药物中的用途。
Description
本申请是2012年12月12日提交的发明名称为“I型和II型糖尿病的治疗”的第201280069531.5号中国专利申请的分案申请。
技术领域
本公开涉及治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向所述哺乳动物给药胰岛素以及苯氧基嘧啶酮(phenoxypyrimidinone)化合物或其药学可接受的盐,并且涉及其制剂。
背景技术
糖尿病是最常见的内分泌系统病症,并且在体内的血糖水平始终保持在正常之上时发生。其仅在美国就影响超过23,000,000人。糖尿病是身体不能产生胰岛素(I型糖尿病)或身体不能对胰岛素的效应应答(II型糖尿病)所带来的疾病。其还可以在妊娠期间出现。胰岛素是调节血糖水平的主要激素之一,并且允许身体使用糖作为能量。一旦II型糖尿病发展,症状包括不寻常的口渴、尿频、视力模糊或极度疲劳。I型糖尿病出现是因为胰腺产生胰岛素的细胞β细胞被免疫系统破坏。患有I型糖尿病的人不产生胰岛素,并且必须使用胰岛素注射液以控制他们的血糖。I型糖尿病最常在20岁以下的人中开始,但是可以在任何年龄出现。因此,显然需要可以用来治疗I型和/或II型糖尿病的化合物和组合物。
发明内容
本公开提供治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素和有效量的式I的化合物或其药学可接受的盐:
其中:R1为烷基;X为卤素;Y为O、S或NH;Z为O或S;n为0-5的整数且m为0或1,其中m+n小于或等于5。
本公开还提供治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素和有效量的式II的化合物或其药学可接受的盐:
其中:R1为烷基;X为卤素;并且n为0-5的整数且m为0或1,其中m+n小于或等于5。
本公开还提供治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素和有效量的式III的化合物或其药学可接受的盐:
其中:R1为烷基;并且n为0-5的整数。
本公开还提供治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素和有效量的式IV的化合物或其药学可接受的盐:
其中:X为卤素;并且m为0或1。
本公开还提供治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素和有效量的下式的化合物或其药学可接受的盐:
本公开还提供治疗哺乳动物的I型或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素和有效量的下式的化合物或其药学可接受的盐:
本公开还提供用于以片剂、软胶囊剂或胶囊剂形式口服给药的制剂,其包含胰岛素以及约1mg-约1000mg的下式的化合物或其药学可接受的盐:
其中所述用于口服给药的制剂是用于治疗或预防I型或II型糖尿病。
本公开还提供用于以片剂、软胶囊剂或胶囊剂形式口服给药的制剂,其包含胰岛素以及约1mg-约1000mg的下式的化合物或其药学可接受的盐:
其中所述用于口服给药的制剂是用于治疗或预防I型或II型糖尿病。
本公开还提供一种用于治疗哺乳动物的I型糖尿病或II型糖尿病的组合物,其包含上述苯氧基嘧啶酮化合物中的任一种或多种或其药学可接受的盐以及胰岛素。
本公开还提供一种用于制备治疗哺乳动物的I型糖尿病或II型糖尿病的药物的组合物,其包含上述苯氧基嘧啶酮化合物中的任一种或多种或其药学可接受的盐以及胰岛素。
本公开还提供上述苯氧基嘧啶酮化合物中的任一种或多种或者其药学可接受的盐以及胰岛素在治疗哺乳动物的I型糖尿病或II型糖尿病中的用途。
本公开还提供上述苯氧基嘧啶酮化合物中的任一种或多种或者其药学可接受的盐以及胰岛素在制备用于治疗哺乳动物的I型糖尿病或II型糖尿病的药物中的用途。
附图说明
图1示出式IV的化合物与胰岛素的共给药增强胰岛素降低血糖的应答的结果。*p<0.05;比较胰岛素与胰岛素/化合物共给药。
图2示出式IV的化合物与胰岛素的共给药增强胰岛素降低血糖的应答的结果。*p<0.05;**p<0.01,比较胰岛素与胰岛素/化合物共给药。
图3示出式IV的化合物的给药增强并延长胰岛素介导的血糖降低。当与胰岛素单独处理相比时*p<0.05。当与胰岛素单独处理相比时***p<0.001。数据表示为平均值±SEM。通过双向ANOVA然后post-hoc Bonferroni测试分析数据。
具体实施方式
除非另有定义,所有技术和科学术语均具有与公开的实施方案所属领域的技术人员通常理解相同的意义。
如本文所用,除非上下文另有明确指示,术语“一个(a)”或“一个(an)”表示“至少一个”或者“一个或多个”。
如本文所用,术语“约”表示数值近似,并且小的变化不会显著影响公开的实施方案的实施。当使用数值限定时,除非上下文另有指示,“约”表示数值可以变化±10%并保持在公开的实施方案的范围内。
如本文所用,术语“烯基”表示具有一个或多个碳-碳双键以及2-20个碳原子的直链或支化的烷基,包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。在一些实施方案中,烯基链长度为2-10个碳原子,长度为2-8个碳原子,长度为2-6个碳原子,或者长度为2-4碳原子。
如本文所用,术语“烷氧基”表示1-20个碳原子的直链或支化的-O-烷基,包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基等。在一些实施方案中,烷氧基链长度为1-10个碳原子,长度为1-8个碳原子,长度为1-6个碳原子,长度为1-4个碳原子,长度为2-10个碳原子,长度为2-8个碳原子,长度为2-6个碳原子,或者长度为2-4个碳原子。
如本文所用,术语“烷基”表示直链或支化的饱和烃基。烷基可以包含1-20、2-20、1-10、2-10、1-8、2-8、1-6、2-6、1-4、2-4、1-3或者2或3个碳原子。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、叔丁基、异丁基)、戊基(例如,正戊基、异戊基、新戊基)、己基、异己基、庚基、4,4-二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2-甲基-1-戊基、2,2-二甲基-1-丙基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基等。
如本文所用,术语“炔基”表示具有一个或多个碳-碳三键以及2-20个碳原子的直链或支化的烷基,包括但不限于乙炔基、1-丙烯基、2-丙烯基等。在一些实施方案中,炔基链长度为2-10个碳原子,长度为2-8个碳原子,长度为2-6个碳原子,或者长度为2-4碳原子。
如本文所用,术语“动物”包括但不限于人和非人脊椎动物如野生、驯养和农场动物。
如本文所用,术语“芳基”表示单环、双环或多环(例如,具有2、3或4个稠环)芳香烃。在一些实施方案中,芳基具有6-20个碳原子或6-10个碳原子。芳基的实例包括但不限于苯基、萘基、蒽基(anthracenyl)、菲基(phenanthrenyl)、二氢化茚基、茚基、四氢萘基等。
如本文所用,术语“芳氧基”表示-O-芳基,其中芳基如本文所定义。芳氧基可以是未取代的,或者被一个或两个合适的取代基取代。芳氧基的芳环可以是单环,其中所述环包含6个碳原子,在本文中称作“(C6)芳氧基”。
如本文所用,术语“苄基”表示-CH2-苯基。
如本文所用,术语“碳环”表示5-或6-元饱和或不饱和的环,任选地包含O、S或N原子作为环的一部分。碳环的实例包括但不限于环戊基、环己基、环戊-1,3-二烯以及上文列举的任何杂环。
如本文所用,术语“载体”表示与化合物一起给药的稀释剂、佐剂或赋形剂。药物载体可以为液体,如水和油,包括石油、动物、植物或合成来源的油,如花生油、大豆油、矿物油、芝麻油等。药物载体还可以为盐水、阿拉伯树胶、明胶、淀粉糊、滑石、角蛋白、胶态二氧化硅、尿素等。此外,可以使用助剂、稳定剂、增稠剂、润滑剂和着色剂。
如本文所用,术语“化合物”表示本文所述化合物的所有立体异构体、互变异构体和同位素。
如本文所用,术语“包含(comprising)”(以及包含的任何形式,如“包含(comprise)”、“包含(comprises)”和“包含(comprised)”)、“具有(having)”(以及具有的任何形式,如“具有(have)”和“具有(has)”)、“包括(including)”(以及包括的任何形式,如“包括(includes)”和“包括(include)”)或“含有(containing)”(以及含有的任何形式,如“含有(contains)”和“含有(contain)”)是包括性或开放性的,并且不排除额外的未列举的元件或方法步骤。
如本文所用,术语“环烷基”表示非芳香环烃,包括含有多达20个环形成碳原子的环化烷基、烯基和炔基。环烷基可以包括单环或多环系统如稠环系统、桥环系统和螺环系统。在一些实施方案中,多环系统包括2、3或4个稠环。环烷基可以包含3-15、3-10、3-8、3-6、4-6、3-5或者5或6个环形成碳原子。环烷基的环形成碳原子可以任选地被氧代或硫代取代。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、降冰片基(norbornyl)、降菔基(norpinyl)、降胆烷基(norcarnyl)、金刚烷基等。环烷基的定义中还包括具有稠和(具有共同的键)至环烷基环的一个或多个芳环的部分,例如戊烷、戊烯、己烷等的苯并或噻吩基衍生物(例如,2,3-二氢-1H-茚-1-基或1H-茚-2(3H)-酮-1-基)。
如本文所用,术语“糖尿病”包括“I型糖尿病”和“II型糖尿病”,并且常伴随有相关并发症,包括例如肥胖和高胆固醇。
如本文所用,术语“卤代”表示卤素基团,包括但不限于氟、氯、溴和碘。
如本文所用,术语“杂芳基”表示具有多达20个环形成原子(例如,C)且具有至少一个杂原子环成员(环形成原子)如硫、氧或氮的芳香杂环。在一些实施方案中,杂芳基具有至少一个或多个杂原子环形成原子,每个独立地为硫、氧或氮。在一些实施方案中,杂芳基具有3-20个环形成原子、3-10个环形成原子、3-6个环形成原子或3-5个环形成原子。在一些实施方案中,杂芳基包含2-14个碳原子、2-7个碳原子或者5或6个碳原子。在一些实施方案中,杂芳基具有1-4个杂原子、1-3个杂原子或者1或2个杂原子。杂芳基包括单环和多环(例如,具有2、3或4个稠环)系统。杂芳基的实例包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基(如吲哚-3-基)、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、苯并噻吩基、嘌呤基、咔唑基、苯并咪唑基、二氢吲哚基、吡喃基、噁二唑基、异噁唑基、三唑基、噻蒽基、吡唑基、中氮茚基、异吲哚基、异苯并呋喃基、苯并噁唑基、呫吨基、2H-吡咯基、吡咯基、3H-吲哚基、4H-喹嗪基、酞嗪基、二氮杂萘基、喹唑啉基、菲啶基、吖啶基、咟啶基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咕基、吩噁嗪基等。合适的杂芳基包括1,2,3-三唑、1,2,4-三唑、5-氨基-1,2,4-三唑、咪唑、噁唑、异噁唑、1,2,3-噁二唑、1,2,4-噁二唑、3-氨基-1,2,4-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、吡啶和2-氨基吡啶。
如本文所用,术语“杂环”或“杂环环”表示5-至7-元单环或双环或者7-至10-元双环杂环系统,其任何环可以是饱和或不饱和的,并且其由碳原子以及选自N、O和S的1-3个杂原子组成,其中N和S杂原子可以任选地被氧化,N杂原子可以任选地被季铵化,并且包括其中任何上文定义的杂环稠和至苯环的任何双环基团。特别有用的是包含一个氧或硫、1-3个氮原子,或者一个氧或硫连同一个或两个氮原子的环。杂环可以连接在导致产生稳定结构的任何杂原子或碳原子。杂环基团的实例包括但不限于哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基(2-oxopyrrolodinyl)、2-氧代氮杂基、氮杂基、吡咯基、4-哌啶酮基、吡咯烷基、吡唑基、吡唑烷基、咪唑基、咪唑啉基、咪唑烷基、吡啶基、吡嗪基、嘧啶基、哒嗪基、噁唑基、噁唑烷基、异噁唑基、异噁唑烷基、吗啉基、噻唑基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、吲哚基、喹啉基、异喹啉基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、苯并噁唑基、呋喃基、四氢呋喃基、四氢吡喃基、噻吩基、苯并噻吩基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜和噁二唑基。吗啉代与吗啉基相同。
如本文所用,术语“杂环烷基”表示具有多达20个环形成原子的非芳香杂环,包括环化的烷基、烯基和炔基基团,其中环形成碳原子中的一个或多个被杂原子如O、N或S原子代替。杂环烷基可以为单环或多环(例如,稠和、桥接或螺环系统)。在一些实施方案中,杂环烷基具有1-20个碳原子或3-20个碳原子。在一些实施方案中,杂环烷基包含3-14个环形成原子、3-7个环形成原子或者5或6个环形成原子。在一些实施方案中,杂环烷基具有1-4个杂原子、1-3个杂原子或者1或2个杂原子。在一些实施方案中,杂环烷基包含0-3个双键。在一些实施方案中,杂环烷基包含0-2个三键。杂环烷基的实例包括但不限于吗啉代、硫代吗啉代、哌嗪基、四氢呋喃基、四氢噻吩基、2,3-二氢苯并呋喃基、1,3-苯并噁唑、苯并-1,4-二噁烷、哌啶基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、吡唑烷基、噻唑烷基、咪唑烷基、吡咯烷-2-酮-3-基等。此外,杂环烷基的环形成碳原子和杂原子可以任选地被氧代或硫代(sulfido)取代。例如,环形成S原子可以被1或2个氧代取代(形成S(O)或S(O)2)。对于另一实例,环形成C原子可以被氧代取代(形成羰基)。杂环烷基的定义中还包括具有稠和至非芳香杂环(与非芳香杂环共有键)的一个或多个芳香环的部分,包括但不限于吡啶基、噻吩基、苯邻二甲酰亚胺基、萘二甲酰基亚胺基(naphthalimidyl)以及杂环的苯并衍生物如吲哚(indolene)、异吲哚(isoindolene)、异吲哚啉-1-酮-3-基、4,5,6,7-四氢噻吩并[2,3-c]吡啶-5-基、5,6-二氢噻吩并[2,3-c]吡啶-7(4H)-酮-5-基和3,4-二氢异喹啉-1(2H)-酮-3基基团。杂环烷基的环形成碳原子和杂原子可以任选地被氧代或硫代取代。
如本文所用,可交换使用的术语“个体”或“患者”表示任何动物,包括哺乳动物,如小鼠、大鼠、其他啮齿动物、兔、狗、猫、猪、牛、羊、马或灵长类如人。
如本文所用,短语“有需要”表示动物或哺乳动物已鉴定为需要特定方法或治疗。在一些实施方案中,鉴定可以通过诊断的任何方式。在本文所述的任何方法和治疗中,动物或哺乳动物可以是有需要的。
如本文所用,短语“1-5的整数”表示1、2、3、4或5。
如本文所用,术语“分离”表示如通过常规技术将本文所述的化合物与(a)天然来源如植物或细胞,如细菌培养物,或者(b)合成有机化学反应混合物的其他组分分开。
如本文所用,术语“哺乳动物”表示啮齿动物(即,小鼠、大鼠或豚鼠)、猴、猫、狗、奶牛、马、猪或人。在一些实施方案中,哺乳动物为人。
如本文所用,术语“n-元”(其中n为整数)通常描述部分中环形成原子的数量,其中环形成原子的数量为n。例如,吡啶为6-元杂芳基环的实例,而噻吩为5-元杂芳基环的实例。
如本文所用,短语“任选地取代”表示取代是任选存在的,因此包括未取代和取代的原子和部分。“取代的”原子或部分表示指定原子或部分上的任何氢可以被来自所示取代基基团的选择代替,只要不超过指定原子或部分的正常价,并且取代导致稳定的化合物。例如,如果甲基是任选地取代的,则碳原子上的3个氢原子可以被取代基基团代替。
如本文所用,短语“药学可接受的”表示在良好的医学判断范围内的、适合用于与人和动物的组织接触的那些化合物、材料、组合物和/或剂型。在一些实施方案,“药学可接受的”表示联邦或州政府的监管机构批准或者美国药典或其他公认的药典列出用于动物,更特别是用于人。
如本文所用,短语“药学可接受的盐”包括但不限于酸性或碱性基团的盐。性质为碱性的化合物能够与各种无机酸和有机酸形成各种盐。可以用来制备这类碱性化合物的药学可接受的酸加成盐的酸是形成无毒的酸加成盐的那些酸,即包含药理学可接受的阴离子的盐包括但不限于硫酸盐、硫代硫酸盐、柠檬酸盐、马来酸盐、乙酸盐、草酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、亚硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、硼酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酸式柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡萄糖酸盐、葡糖醛酸盐、糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐(methanesulfonate)、乙磺酸盐(ethanesulfonate)、苯磺酸盐(benzenesulfonate)、对甲苯磺酸盐、碳酸氢盐、丙二酸盐、甲磺酸盐(mesylate)、乙磺酸盐(esylate)、萘二磺酸盐(napsydisylate)、甲苯磺酸盐(tosylate)、苯磺酸盐(besylate)、正磷酸盐、三氟乙酸盐、和双羟萘酸盐(即1,1′-亚甲基-双-(2-羟基-3-萘甲酸盐))。除了上文提到的酸,包括氨基部分的化合物可以与各种氨基酸形成药学可接受的盐。性质为酸性的化合物能够与各种药理学可接受的阳离子形成碱盐。这类盐的实例包括但不限于碱金属或碱土金属盐,具体地,钙、镁、铵、钠、锂、锌、钾和铁盐、本发明还包括本文所述化合物的季铵盐,其中所述化合物具有一个或多个叔胺部分。
如本文所用,术语“苯基”表示-C6H5。苯基可以是未取代的,或者被1、2或3个合适的取代基取代。
如本文所用,术语“防止”或“预防”表示减少获得特定疾病、疾病状况或病症的风险。
如本文所用,术语“纯化的”表示当分离时,分离物包含分离物重量的至少90%、至少95%、至少98%或至少99%的本文所述的化合物。
如本文所用,短语“季铵盐”表示所公开的具有一个或多个叔胺部分的化合物的衍生物,其中通过烷基化如甲基化或乙基化将叔胺部分转化为季铵阳离子(并且通过阴离子如Cl-、CH3COO-和CF3COO-平衡所述阳离子)来修饰至少一个母体化合物中的叔胺部分。
如本文所用,短语“基本上分离的”表示至少部分或基本上分离自其形成或检测的环境的化合物。
如本文所用,术语“合适的取代基”或“取代基”表示不使本文所述的化合物或可用于制备它们的中间体的合成或药物功用失效的基团。合适的取代基的实例包括但不限于C1-C6烷基、C1-C6烯基、C1-C6炔基、C5-C6芳基、C1-C6烷氧基、C3-C5杂芳基、C3-C6环烷基、C5-C6芳氧基、-CN、-OH、氧代、卤代、卤代烷基、-NO2、-CO2H、-NH2、-NH(C1-C8烷基)、-N(C1-C8烷基)2、-NH(C6芳基)、-N(C5-C6芳基)2、-CHO、-CO(C1-C6烷基)、-CO((C5-C6)芳基)、-CO2((C1-C6)烷基)和-CO2((C5-C6)芳基)。本领域技术人员可以基于本文所述的化合物的稳定性以及药理学和合成活性容易地选择合适的取代基。
如本文所用,短语“治疗有效量”表示在组织、系统、动物、个体或人中引起研究者、兽医、医生或其他临床医师所寻求的生物学或医学反应的活性化合物或药剂的量。疗效取决于治疗的病症或期望的生物学效应。因此,疗效可以是与病症相关的症状的严重程度的减少和/或病症发展的抑制(部分或完全),或者改善的病症的治疗、治愈、防止或消除,或者改善的副作用。引起治疗反应所需的量可以基于个体的年龄、健康、大小和性别来确定。最佳量还可以基于监测个体对治疗的反应来确定。
如本文所用,术语“治疗(treat)”、“治疗(treated)”或“治疗(treating)”表示治疗性处理以及预防或防范措施,其中目的是防止或减缓(减轻)不期望的生理状况、病症或疾病,或者获得有益或期望的临床结果。为了本发明的目的,有益或期望的临床结果包括但不限于症状的缓解;疾病状况、病症或疾病程度的减少;疾病状况、病症或疾病的稳定(即,不恶化)状态;疾病状况、病症或疾病发展的发生延迟或减慢;疾病状况、病症或疾病状态的改善或者缓解(无论部分或全部),无论可检测或不可检测;至少一个可测量的物理参数的改善,不必可由患者辨别;或者疾病状况、病症或疾病的增强或改善。治疗包括引起临床上显著的反应而没有过高水平的副作用。治疗还包括与如果不接受治疗的预期存活期相比延长存活期。
本公开的化合物在本文中通过它们的化学结构和/或化学名来鉴定。当化合物通过化学结构和化学名来称呼,并且化学结构和化学名互相冲突时,化学结构决定化合物的性质。
在本说明书的不同地方,化合物的取代基可以以组或范围公开。具体地,本发明旨在包括这类组和范围的成员的各个和每个单独亚组合。例如,术语“C1-6烷基”具体地旨在单独地公开甲基、乙基、丙基、C4烷基、C5烷基和C6烷基,线性和/或支化的。
对于其中变量看来超过一个的化合物,每个变量可以是选自定义该变量的马库什组的不同部分。例如,当描述结构具有同时存在于相同化合物上的两个R基团时,这两个R基团可以代表选自定义R的马库什组的不同部分。在另一实例中,当任选存在的多取代基以形式指定时,例如,
还应当理解为了清楚而在不同实施方案的上下文中描述的本公开的某些特征也可以在单一实施方案中组合提供。相反地,为了简洁而在单一实施方案中描述的本公开的各种特征也可以单独或以任何合适的亚组合提供。
应当理解本公开涵盖在适用时,本公开的化合物的立体异构体、非对映体和光学立体异构体的用途,以及它们的混合物。此外,应当理解本公开的化合物的立体异构体、非对映体和光学立体异构体以及它们的混合物在本公开的范围内。通过非限制性实例的方式,混合物可以是外消旋物,或者混合物可以包含与其他立体异构体不等比例的一种特定立体异构体。此外,化合物可以提供为基本上纯的立体异构体、非对映体和光学立体异构体(如差向异构体)。
本文所述的化合物可以是不对称的(例如,具有一个或多个立体中心)。除非另有说明,所有立体异构体如对映体和非对映体均意图包括在本公开的范围内。包含不对称的取代的碳原子的化合物可以以旋光或外消旋形式分离。从旋光起始材料制备旋光形式的方法是本领域已知的,例如通过外消旋混合物的拆分或通过立体选择性合成。许多烯烃的几何异构体、C=N双键等也可以存在于本文所述的化合物中,并且本公开考虑所有这样稳定的异构体。化合物的顺式和反式立体异构体也包括在本公开的范围内,并且可以分离为异构体的混合物或者分开的异构体形式。当能够立体异构或几何异构的化合物以其结构或名称命名而没有提到具体的R/S或顺式/反式构型时,意图考虑所有这样的异构体。
化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种进行,包括例如分级重结晶,利用手性拆分酸,其为旋光的盐形成有机酸。合适的分级重结晶方法的拆分剂包括但不限于旋光酸如酒石酸的D和L形式、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸以及各种旋光樟脑磺酸如β-樟脑磺酸。适合分级结晶方法的其他拆分剂包括但不限于α-甲基苄基胺的立体异构纯形式(例如,S和R形式,或者非对映体纯形式)、2-苯甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1,2-二氨基环己烷等。外消旋混合物的拆分还可以通过在装有旋光拆分剂(例如,二硝基苯甲酰基苯基甘氨酸)的柱上洗脱来进行。合适的洗脱溶剂组合物可以由本领域技术人员确定。
化合物还可以包括互变异构形式。互变异构形式由单键与相邻双键的交换连同伴随的质子迁移所致。互变异构形式包括质子异变的互变异构体,其为具有相同实验式和总电荷的同分异构质子化状态。质子异变的互变异构体的实例包括但不限于酮-烯醇对、酰胺-亚氨酸对、内酰胺-内酰亚胺对、酰胺-亚氨酸对、烯胺-亚胺对,以及其中质子可以占据杂环系统的两个或更多个位置的环形式,包括但不限于1H-和3H-咪唑,1H-、2H-和4H-1,2,4-三唑,1H-和2H-异吲哚以及1H-和2H-吡唑。互变异构形式可以平衡或者通过适当的取代空间上锁定为一种形式。
化合物还包括水合物和溶剂合物,以及无水和非溶剂化形式。
化合物还可以包括中间体或最终化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。例如,氢的同位素包括氚和氘。
在一些实施方案中,化合物或其药学可接受的盐是基本上分离的。部分分离可以包括例如富含本公开的化合物的组合物。基本上分离可以包括这样的组合物,其包含至少约50重量%、至少约60重量%、至少约70重量%、至少约80重量%、至少约90重量%、至少约95重量%、至少约97重量%或至少约99重量%的本公开的化合物或其药学可接受的盐。分离化合物和它们的盐的方法是本领域常规的。
虽然公开的化合物是合适的,可以将其他官能团加入化合物,预期结果相似。具体地,预期硫代酰胺和硫酯具有非常相似的特性。芳香环之间的距离可以影响化合物的几何模式,并且这个距离可以通过加入不同长度的脂肪链来改变,所述脂肪链可以是任选取代的,或者可以包括氨基酸、二羧酸或二胺。化合物内单体之间的距离和单体的相对方向还可以通过用具有额外原子的替代物代替酰胺键来改变。因此,用二羰基代替羰基改变单体之间的距离和二羰基单元的倾向以采用两个羰基部分的反排列并改变化合物的周期性。苯均四酸酐代表简单的酰胺键的另一可选物,其可以改变化合物的构象和物理特性。固相有机化学的现代方法(E.Atherton and R.C.Sheppard,Solid Phase Peptide Synthesis APractical Approach IRL Press Oxford 1989)现在允许合成具有达到5,000道尔顿的分子量的均匀分散化合物。其他取代模式同样有效。
本文所述的化合物还包括称作前药的衍生物,其可以通过以这样的方式修饰化合物中存在的官能团来制备,所述修饰在常规操作中或体内从母体化合物切割。前药的实例包括如本文所述的化合物,其包含附加至化合物的羟基、氨基、巯基或羧基的一个或多个分子部分,并且当向患者给药时,在体内切割以分别形成游离的羟基、氨基、巯基或羧基。前药的实例包括但不限于本文所述化合物中醇和胺官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物。前药的制备和使用在T.Higuchi et al.,“Pro-drugs as Novel Delivery Systems,”Vol.14of the A.C.S.Symposium Series,和Bioreversible Carriers in Drug Design,ed.Edward B.Roche,American Pharmaceutical Association and Pergamon Press,1987中讨论,两者均整体援引加入本文。
包含胺官能的化合物还可以形成N-氧化物。在本文中提到包含胺官能的化合物还包括N-氧化物。当化合物包含几个胺官能时,可以将一个或一个以上氮原子氧化以形成N-氧化物。N-氧化物的实例包括叔胺或含氮杂环的氮原子的N-氧化物。可以通过用氧化剂如过氧化氢或过酸(例如,过氧羧酸(peroxycarboxylic acid))处理相应的胺形成N-氧化物(参见,Advanced Organic Chemistry,by Jerry March,4th Edition,WileyInterscience)。
本发明提供式V的化合物或其药学可接受的盐:
其中R1、R2、R3、R4、R5、R6和R7各自独立地为合适的取代基;或者其中R1、R2、R3、R4、R5、R6和R7各自独立地为氢、烷氧基、烷基、烯基、炔基、芳基、芳氧基、苄基、环烷基、卤素、杂芳基、杂环烷基、-CN、-OH、-NO2、-CF3、-CO2H、-CO2烷基或-NH2;
R8为烷基或氢;
X为O、S、NH或N-烷基;并且
Z为O或S。
在一些实施方案中,R8为烷基,如甲基。在一些实施方案中,R8为氢。
在一些实施方案中,X为氧。
在一些实施方案中,Z为氧。
在一些实施方案中,R2-R6中至少一个为烷基,如甲基。在一些实施方案中,R2-R6中至少一个为卤素,如氯。在一些实施方案中,R2-R6中至少一个为-CN。在一些实施方案中,R2-R6中至少一个为-OH。在一些实施方案中,R2-R6中至少一个为-NO2。在一些实施方案中,R2-R6中至少一个为-CF3。在一些实施方案中,R2-R6中至少一个为-CO2H。在一些实施方案中,R2-R6中至少一个为-NH2。在一些实施方案中,R2-R6中至少一个为-烷氧基。
在一些实施方案中,R2为烷基,如甲基;R1和R3-R8各自为氢,并且X和Z为O。在一些实施方案中,R2为卤素,如氯;R1和R3-R8各自为氢;并且X和Z为O。在一些实施方案中,R3为烷基,如甲基;R1、R2和R4-R8各自为氢;并且X和Z为O。
在一些实施方案中,R3为卤素,如氯;R1、R2和R4-R8各自为氢;并且X和Z为O。
在一些实施方案中,R4为烷基,如甲基;R1-R3和R5-R8各自为氢;并且X和Z为O。
在一些实施方案中,R4为卤素,如氯;R1-R3和R5-R8各自为氢;并且X和Z为O。
在一些实施方案中,R5为-CF3;R1-R4和R6-R8各自为氢;并且X和Z为O。在一些实施方案中,R5为-NH2;R1-R4和R6-R8各自为氢;并且X和Z为O。
在一些实施方案中,R6为-CF3;R1-R5和R7-R8各自为氢;并且X和Z为O。在一些实施方案中,R6为-NH2;R1-R5和R7-R8各自为氢;并且X和Z为O。
本公开还提供式I的化合物或其药学可接受的盐:
其中:
R1为烷基;
X为卤素;
Y为O、S或NH;
Z为O或S;
n为0-5的整数,并且m为0或1,其中m+n小于或等于5。
在一些实施方案中,烷基为甲基,并且n为1。
在一些实施方案中,卤素为氯,并且m为1。
在一些实施方案中,Y为O。
在一些实施方案中,Z为O。
在一些实施方案中,R1为甲基,Y为O,Z为O,n为1,并且m为0。在一些实施方案中,R1在间位。
在一些实施方案中,X为氯,Y为O,Z为O,n为0,并且m为1。在一些实施方案中,X在间位。
本公开还提供式II的化合物或其药学可接受的盐:
其中:
R1为烷基;
X为卤素;并且
n为0-5的整数,并且m为0或1,其中m+n小于或等于5。
在一些实施方案中,烷基为甲基,并且n为1。
在一些实施方案中,卤素为氯,并且m为1。
在一些实施方案中,R1为甲基,n为1,并且m为0。在一些实施方案中,R1在间位。
在一些实施方案中,X为氯,n为0,并且m为1。在一些实施方案中,X在间位。
本公开还提供式III的化合物或其药学可接受的盐:
其中:
R1为烷基;并且
n为0-5的整数。
在一些实施方案中,R1为烷基,n为1。在一些实施方案中,R1在间位。
本公开还提供式IV的化合物或其药学可接受的盐:
其中:
X为卤素;并且
m为0-1的整数。
在一些实施方案中,X为氯,并且m为1。在一些实施方案中,X在间位。
式I-IV涵盖且可用于本文所述方法的化合物的说明性实例包括但不限于:
其还已知为托利咪酮、CP-26154和2(1H)-嘧啶酮、5-(3-甲基苯氧基)。
本文所述的化合物可以通过本领域技术人员已知的有机化学技术合成,例如美国专利号3,922,345所述,其整体援引加入本文。
本公开的化合物存在于包含胰岛素的组合物中,并且与其给药至哺乳动物。合适的胰岛素包括但不限于注射胰岛素、经皮胰岛素、吸入胰岛素或它们的任何组合。作为胰岛素的另一种选择,可以使用胰岛素衍生物、促分泌剂、敏化剂或模拟物。与本公开的化合物组合使用的胰岛素促分泌剂包括但不限于毛喉素、二丁酰基(dibutryl)cAMP和异丁基甲基黄嘌呤(IBMX)。
有4种类型的胰岛素,通过它们的起效和作用持续时间来区分。速效胰岛素(例如优泌乐)具有快速起效(在15分钟内)和长达5小时的作用持续时间,并且在注射时覆盖对摄入的膳食的需要。短效胰岛素(例如优泌林)也具有快速起效,覆盖对给药1小时内深入的膳食的需要,并且具有长达8小时的作用持续时间。中效胰岛素(例如NPH)具有延迟起效(1-2小时)以及长达24小时的作用持续时间。长效胰岛素(例如来得时、Levemir)具有延迟起效与给药后长达36小时的作用时间。这些胰岛素通常以各种组合给药以调节血糖水平。
本文所述的化合物可以以任何常规方式通过其中它们有活性的任何途径给药。给药可以全身、局部或口服。例如,给药可以但不限于肠胃外、皮下、静脉内、肌肉内、腹腔内、经皮、口服、口腔、舌下或眼部途径,或者阴道内,通过吸入、通过贮存注射或通过植入。给药模式可以取决于靶向的病原体或微生物。给药的具体路线的选择可以由临床医生根据临床医生已知的方法进行调整以获得期望的临床反应。
在一些实施方案中,在需要治疗的区域局部给药一种或多种化合物或其药学可接受的盐是可取的。这可以这样实现,例如且不限于在手术期间通过局部灌注,体表施用,例如手术之后与创伤敷料联合,通过注射,通过导管,通过栓剂,或者通过植入物,其中所述植入物为多孔、无孔或胶状物质,包括膜如sialastic膜,或纤维。
在一些实施方案中,本公开的化合物可以与胰岛素和至少一种其他治疗剂用于联合治疗。本公开的化合物、胰岛素和治疗剂可以叠加或协同作用。在一些实施方案中,将包含本公开的化合物的组合物与胰岛素和另一治疗剂的给药同时或连续给药,所述胰岛素和另一治疗剂可以是与本公开的化合物相同的组合物的一部分,或者可以是不同的组合物。在另一实施方案中,在给药胰岛素和另一治疗剂之前或之后给药包含本公开的化合物的组合物。因为许多本公开的化合物可用于治疗的病症为慢性病症,在一实施方案中,联合疗法包括交替给药包含本公开的化合物的组合物、胰岛素和包含另一治疗剂的组合物,例如以最小化与特定治疗剂相关的毒性。每种药物或治疗剂的给药持续时间可以为例如1个月、3个月、6个月或一年。在某些实施方案中,当本公开的组合物与胰岛素和可能产生不良副作用(包括但不限于毒性)的另一治疗剂同时给药时,所述治疗剂可以有利地以引发不良副作用的阈值以下的剂量给药。在一些实施方案中,化合物可以与胰岛素以及另一糖尿病药物、血压药物和/或胆固醇药物联合给药。
本公开的组合物可以与他汀一起给药。与本公开的化合物和胰岛素联合使用的他汀包括但不限于阿托伐他汀、普伐他汀、氟伐他汀、洛伐他汀、辛伐他汀和西立伐他汀。
本公开的组合物还可以与PPAR激动剂如噻唑烷二酮或贝特一起给药。与本公开的化合物和胰岛素联合使用的噻唑烷二酮包括但不限于吡格列酮、环格列酮、5-((4-(2-(甲基-2-吡啶基氨基)乙氧基)苯基)甲基)-2,4-噻唑烷二酮、曲格列酮、WAY-120,744、恩格列酮、AD 5075、达格列酮和罗格列酮。与本公开的化合物和胰岛素联合使用的贝特包括但不限于吉非贝齐、非诺贝特、氯贝特或环丙贝特。如先前所提到的,治疗有效量的贝特或噻唑烷二酮常具有毒性副作用。因此,在一些实施方案中,当本公开的组合物与胰岛素和PPAR激动剂联合给药时,PPAR激动剂的剂量低于伴随有毒性副作用的剂量。
本公开的组合物还可以与胆汁酸结合树脂一起给药。与本公开的化合物和胰岛素联合使用的胆汁酸结合树脂包括但不限于消胆胺和盐酸考来替泊。
本公开的组合物还可以与烟碱酸或烟酸一起给药。
本公开的组合物还可以与RXR激动剂一起给药。与本公开的化合物和胰岛素联合使用的RXR激动剂包括但不限于LG 100268、LGD 1069、9-顺式视黄酸、2-(1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)-环丙基)-吡啶-5-羧酸或4-((3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)2-羰基)-苯甲酸。
本公开的组合物还可以与减肥药一起给药。与本公开的化合物和胰岛素联合使用的减肥药包括但不限于β-肾上腺素能受体激动剂如β-3受体激动剂、西布曲明、安非他酮、氟西汀和芬特明。
本公开的组合物还可以与激素一起给药。与本公开的化合物和胰岛素联合使用的激素包括但不限于甲状腺激素和雌激素。
本公开的组合物还可以与tyrophostine或其类似物一起给药。与本公开的化合物和胰岛素联合使用的Tyrophostine包括但不限于tryophostine 51。
本公开的组合物还可以与基于磺酰脲的药物一起给药。与本公开的化合物和胰岛素联合使用的基于磺酰脲的药物包括但不限于格列派特、格列本脲、醋磺己脲、氯磺丙脲、格列波脲、甲苯磺丁脲、妥拉磺脲、格列吡嗪、格列齐特、格列喹酮、格列己脲、苯磺丁脲和甲磺环己脲(tolcyclamide)。
本公开的组合物还可以与双胍一起给药。与本公开的化合物和胰岛素联合使用的双胍包括但不限于二甲双胍、苯乙双胍和丁福明。
本公开的组合物还可以与α-葡糖苷酶抑制剂一起给药。与本公开的化合物和胰岛素联合使用的α-葡糖苷酶抑制剂包括但不限于阿卡波糖和米格列醇。
本公开的组合物还可以与apo A-I激动剂一起给药。在一实施方案中,apo A-I激动剂为apo A-I的Milano形式(apo A-IM)。在一些实施方案中,与本公开的化合物和胰岛素联合给药的apo A-IM通过Abrahamsen的U.S.Pat.No.5,721,114的方法制备。在一些实施方案中,apo A-I激动剂为肽激动剂。在一些实施方案中,与本公开的化合物和胰岛素联合给药的apo A-I肽激动剂为U.S.Pat.No.6,004,925或6,037,323的肽。
本公开的组合物还可以与载脂蛋白E(apo E)一起给药。在一些实施方案中,与本公开的化合物和胰岛素联合给药的apoE通过U.S.Pat.No.5,834,596的方法制备。
在一些实施方案中,本公开的组合物可以与HDL-提高药物;HDL增强剂;或者载脂蛋白A-I、载脂蛋白A-IV和/或载脂蛋白基因的调节剂一起给药。
本公开的组合物可以与已知的心血管药物一起给药。与本公开的化合物和胰岛素联合使用以防止或治疗心血管疾病的心血管药物包括但不限于外周抗肾上腺素能药物、中枢抗高血压药物(例如,甲基多巴、甲基多巴HCl)、抗高血压直接血管扩张剂(例如,二氮嗪、肼屈嗪HCl)、影响肾素-血管紧张素系统的药物、外周血管扩张剂、酚妥拉明、抗心绞痛药物、强心苷、变力扩血管药(inodilator)(例如,氨力农、米力农、依诺昔酮、fenoximone、伊马唑旦、硫马唑)、抗心律失常药物、钙内流阻滞剂、ranitine、波生坦和瑞泽林。
本公开的组合物可以与辐照治疗或者一种或多种化疗剂一起给药。对于辐照治疗,辐照可以为γ射线或X-射线。对于辐照疗法的总体概述,参见Hellman,Chapter 12:Principles of Radiation Therapy Cancer,in:Principles and Practice ofOncology,DeVita et al.,eds.,2nd.Ed.,J.B.Lippencott Company,Philadelphia。可用的化疗剂包括甲氨蝶呤、红豆杉醇、巯嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素、达卡巴嗪、procarbizine、依托泊苷、campathecins、博来霉素、多柔比星、伊达比星、柔红霉素、放线菌素D、普卡霉素、米托蒽醌、天冬酰胺酶、长春碱、长春新碱、长春瑞滨、紫杉醇和多西他赛。在一些实施方案中,本发明的组合物还包含一种或多种化疗剂和/或与辐射疗法同时给药。在一些实施方案中,化疗或辐射疗法在给药本公开的组合物之前或之后给药,如在给药本公开的组合物之后1小时、5小时、12小时、1天、1周、1个月或几个月(例如,长达3个月)。
给药的化合物、胰岛素和另一治疗剂的量是治疗有效的量。给药的剂量取决于治疗的个体的特征,例如,治疗的具体动物、年龄、体重、健康、同时治疗的类型(如果存在)、以及治疗的频率,并且可以由本领域技术人员(例如,由临床医生)容易地确定。特定剂量方案的选择可以由临床医生根据临床医生已知的方法进行选择或调整或滴定以获得期望的临床反应。
在特定疾病、疾病状况或病症的治疗和/或预防中有效的本文所述的化合物、胰岛素和其他治疗剂的量取决于疾病、疾病状况或病症的性质和程度,并且可以通过标准临床技术确定。此外,体外或体内测定可以任选地用来帮助鉴定最佳剂量范围。组合物中采用的精确剂量还取决于给药途径和病症的严重性,并且应当根据执业医生的判断和每个患者的情况决定。但是,合适的口服给药的剂量范围一般为约0.001毫克-约200毫克/千克体重、约0.01毫克-约100毫克/千克体重、约0.01毫克-约70毫克/千克体重、约0.1毫克-约50毫克/千克体重、0.5毫克-约20毫克/千克体重或者约1毫克-约10毫克/千克体重。在一些实施方案中,口服剂量为约5毫克/千克体重。
在一些实施方案中,合适的静脉内(i.v.)给药的剂量范围为约0.01mg-约500mg/kg体重、约0.1mg-约100mg/kg体重、约1mg-约50mg/kg体重或者约10mg-约35mg/kg体重。合适的其他给药模式的剂量范围可以基于本领域技术人员已知的上述剂量进行计算。例如,皮内、肌肉内、腹腔内、皮下、硬膜外、舌下、大脑内、阴道内、经皮给药或通过吸入给药的推荐剂量在约0.001mg-约200mg/kg体重、约0.01mg-约100mg/kg体重、约0.1mg-约50mg/kg体重或者约1mg-约20mg/kg体重的范围内。有效剂量可以从源自体外或动物模型测试系统的剂量-反应曲线推断。合适的动物模型和系统是本领域公知的。
本文所述的化合物可以配制用于通过注射如通过团注射或连续输注肠胃外给药。所述化合物可以通过在约15分钟至约24小时的时间中皮下连续输注来给药。用于注射的制剂可以存在于单位剂型中,如在安瓿或多剂量容器中,具有添加的防腐剂。组合物可以采用这样的形式如油性或水性媒介物中的悬浮液、溶液或乳液,并且可以包含配制辅剂(formulatory agent)如悬浮剂、稳定剂和/或分散剂。在一些实施方案中,注射剂为短效、长效形式,或者皮下或肌肉内注射的植入物或颗粒形式。在一些实施方案中,肠胃外剂型为溶液剂、混悬剂、乳剂或干粉形式。
对于口服给药,本文所述的化合物可以通过将化合物与本领域公知的药学可接受的载体组合来配制。合适的载体使得能够将化合物配制为片剂、丸剂、糖锭剂、胶囊剂、乳剂、液体、凝胶、糖浆、药囊(cache)、团粒、散剂、颗粒剂、浆、锭剂、水性或油性混悬剂等,用于待治疗的患者口服摄入。口服使用的药物制品可以这样获得,例如添加固体赋形剂,任选地研磨所得的混合物,并且如果期望,在添加合适的助剂之后加工颗粒的混合物以获得片剂或糖锭剂核心。合适的赋形剂包括但不限于填充剂如糖,包括但不限于乳糖、蔗糖、甘露醇和山梨醇;纤维素制品例如但不嫌我玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄蓍树胶、甲基纤维素、羟基丙基甲基-纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮(PVP)。如果期望,可以添加崩解剂,例如但不限于交联的聚乙烯吡咯烷酮、琼脂、或者海藻酸或其盐如藻酸钠。
口服给药的组合物可以包含一种或多种任选存在的物质,例如,甜味剂如果糖、阿斯巴甜或糖精;增香剂如薄荷、冬青油或樱桃;着色剂;以及防腐剂,以便提供药学美味的制品。此外,当为片剂或丸剂形式时,可以将组合物包衣以延迟在胃肠道中的崩解和吸收,从而在延长的时间中提供持续作用。渗透活性驱动的化合物周围的选择性透性膜也适合口服给药的化合物。口服组合物可以包括标准媒介物如甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。这类媒介物适合为医药级。
糖锭剂核心可以提供有合适的包衣。为了这个目的,可以使用浓缩的糖溶液,其可以任选地包含阿拉伯树胶、滑石、聚乙烯吡咯烷酮、卡波普胶、聚乙二醇和/或二氧化钛、漆溶液以及合适的有机溶剂或溶剂混合物。可以将染料或色素添加至片剂或糖锭剂包衣用于识别或表征活性化合物剂量的不同组合。
可以口服使用的药物制品包括但不限于由明胶组成的推入(push-fit)胶囊,以及由明胶和增塑剂如甘油或山梨醇组成的软的密封胶囊。推入胶囊可以包含活性成分,混合填充剂如乳糖、粘合剂如淀粉和/或润滑剂如滑石或硬脂酸镁以及任选存在的稳定剂。在软胶囊中,可以将活性化合物溶于或悬浮于合适的液体中,例如脂肪油、液体石蜡或液体聚乙二醇。此外,可以添加稳定剂。
对于口腔给药,组合物可以采用例如以常规方式配制的片剂或锭剂形式。
对于通过吸入给药,本文所述的化合物可以以气溶胶喷雾外观的形式从加压包或喷雾剂递送,使用合适的抛射剂如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其他合适的气体。在加压气溶胶的情况下,剂量单位可以通过提供阀以递送计量的量来确定。用于吸入器或吹入器的如明胶的胶囊或筒可以配制为包含化合物以及合适的粉末基质如乳糖或淀粉的粉末混合物。
本文所述的化合物还可以配制为直肠组合物如栓剂或保留灌肠,如包含常规栓剂基质如可可脂或其他甘油酯。本文所述的化合物还可以配制为阴道组合物如阴道霜剂、栓剂、子宫托、阴道环和子宫内避孕器。
在经皮给药中,化合物可以应用于膏药(plaster),或者可以通过因此提供给生物体的经皮、治疗系统施用。在一些实施方案中,化合物存在于霜剂、溶液剂、散剂、流体乳剂、流体混悬剂、半固体、软膏剂、糊剂、凝胶剂、胶状物和泡沫中,或者包含上述任一种的贴剂中。
本文所述的化合物还可以配制为贮存制品。这类长效制剂可以通过植入(例如皮下或肌肉内)或者通过肌肉内注射给药。贮存注射可以以约1-约6个月或更长的间隔给药。因此,例如,化合物可以与合适的聚合或疏水材料一起配制(例如作为可接受的油中的乳剂)或离子交换树脂,或者为难溶性衍生物,例如为难溶性盐。
在另一实施方案中,化合物可以在控释系统中递送。在一实施方案中,可以使用泵(参见Langer,supra;Sefton,CRC Crit.Ref.Biomed.Eng.,1987,14,201;Buchwald etal.,Surgery,1980,88,507Saudek et al.,N.Engl.J.Med.,1989,321,574)。在另一实施方案中,可以使用聚合材料(参见Medical Applications of Controlled Release,Langerand Wise(eds.),CRC Pres.,Boca Raton,Fla.(1974);Controlled DrugBioavailability,Drug Product Design and Performance,Smolen and Ball(eds.),Wiley,New York(1984);Ranger et al.,J.Macromol.Sci.Rev.Macromol.Chem.,1983,23,61;see,also Levy et al.,Science,1985,228,190;During et al.,Ann.Neurol.,1989,25,351;Howard et al.,J.Neurosurg.,1989,71,105)。在另一实施方案中,可以将控释系统放置于接近本文所述化合物的靶标,如肝,因此仅需要全身剂量的部分(参见,例如,Goodson,in Medical Applications of Controlled Release,supra,vol.2,pp.115-138(1984))。可以使用Langer,Science,1990,249,1527-1533)的综述中讨论的其他控释系统。
本领域还已知化合物可以包含在这样的制剂中,所述制剂具有药学可接受的稀释剂、填充剂、崩解剂、粘合剂、润滑剂、表面活性剂、疏水媒介物、水溶性媒介物、乳化剂、缓冲剂、湿润剂、增湿剂、增溶剂、防腐剂等。药物组合物还可以包含合适的固相或凝胶相载体或赋形剂。这类载体或赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物、明胶和聚合物如聚乙二醇。在一些实施方案中,本文所述的化合物可以与以下物质一起使用,包括但不限于局部镇痛剂(例如,利多卡因)、屏障装置(例如,GelClair)或漂洗液(例如,Caphosol)。
在一些实施方案中,本文所述的化合物可以在囊泡,特别是脂质体中递送(参见,Langer,Science,1990,249,1527-1533;Treat et al.,in Liposomes in the Therapy ofInfectious Disease and Cancer,Lopez-Berestein and Fidler(eds.),Liss,New York,pp.353-365(1989);Lopez-Berestein,ibid.,pp.317-327;see generally ibid.)。
合适的组合物包括但不限于口服不吸收的组合物。合适的组合物还包括但不限于盐水、水、环糊精溶液和pH 3-9的缓冲溶液。
本文所述的化合物或其药学可接受的盐可以与许多赋形剂一起配制,所述赋形剂包括但不限于净化水、丙二醇、PEG 400、甘油、DMA、乙醇、苄醇、柠檬酸/柠檬酸钠(pH3)、柠檬酸/柠檬酸钠(pH5)、三(羟基甲基)氨基甲烷HCl(pH7.0)、0.9%盐水和1.2%盐水以及它们的任何组合。在一些实施方案中,赋形剂选自丙二醇、净化水和甘油。
在一些实施方案中,可以将制剂冻干为固体并在使用之前用例如水重建。
当向哺乳动物(例如,为了兽医用途向动物或为了临床用途向人)给药时,化合物可以以分离形式给药。
当向人给药时,化合物可以是无菌的。当化合物静脉内给药时,水是合适的载体。盐水溶液以及葡萄糖和甘油水溶液也可以用作液体载体,特别是用于可注射溶液。合适的药物载体包括赋形剂如淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酰酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水和乙醇等。如果期望,本公开的组合物还可以包含最小量的湿润剂或乳化剂,或者pH缓冲剂。
本文所述的组合物可以采用以下形式:溶液剂、混悬剂、乳剂、片剂、丸剂、团粒、胶囊剂、包含液体的胶囊剂、散剂、缓释制剂、栓剂、气溶胶、喷雾剂或适合使用的任何其他形式。合适的药物载体的实例描述于Remington’s Pharmaceutical Sciences,A.R.Gennaro(Editor)Mack Publishing Co。
在一实施方案中,按照常规方法将化合物配制为适合向人给药的药物组合物。通常,化合物为无菌等渗水性缓冲液中的溶液。在必要时,组合物还可以包括增溶剂。静脉内给药的组合物可以任选地包括局部镇痛剂如利多卡因以减轻注射部位的疼痛。一般来说,成分单独提供,或者在单位剂型中混合在一起,例如作为密封容器如安瓿中的干的冻干粉或不含水的浓缩物,或者指示活性剂的量的药囊(sachette)。当化合物通过输注给药时,其可以例如用包含无菌药品级水或盐水的输注瓶配药。当化合物通过注射给药时,可以提供注射用无菌水或盐水的安瓿,成分可以在给药之前混合。
药物组合物可以为单位剂型。在这样的形式中,可以将组合物分为包含适当量的活性组分的单位剂量。单位剂型可以为包装制品,包含离散量的制品的包装,例如成包的片剂、胶囊剂以及小瓶或安瓿中的散剂。单位剂型还可以是胶囊剂、扁囊剂或片剂本身,或者其可以是适当数量的任何这些包装形式。
在一些实施方案中,本发明的组合物为液体形式,其中活性剂(即,本文公开的表面两亲性聚合物或低聚物之一)存在于溶液中、悬浮液中、作为乳剂或者作为溶液/悬浮液。在一些实施方案中,液体组合物为凝胶形式。在其他实施方案中,液体组合物为水性的。在其他实施方案中,组合物为软膏剂形式。
合适的防腐剂包括但不限于包含汞的物质如苯基汞化卤(例如,乙酸苯汞、硼酸苯汞和硝酸苯汞)和硫柳汞;稳定的二氧化氯;季铵化合物如苯扎氯铵、十六烷基三甲溴铵和西吡氯铵;咪唑烷基尿素;对羟基苯甲酸酯如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯和对羟基苯甲酸丁酯,以及它们的盐;苯氧基乙醇;氯苯氧基乙醇;苯氧基丙醇;氯代丁醇;氯甲酚;苯基乙基醇;EDTA二钠;以及山梨酸及其盐。
当需要时,组合物中可以包括任选存在的一种或多种稳定剂以增加化学稳定性。合适的稳定剂包括但不限于螯合剂或络合剂,例如钙络合剂乙二胺四乙酸(EDTA)。例如,组合物中可以包括适当量的EDTA或其盐如二钠盐以在储存期间络合过量的钙离子并防止凝胶形成。可以适当地包括约0.01%-约0.5%量的EDTA或其盐。在那些包含除EDTA以外的防腐剂的实施方案中,EDTA或其盐,更特别是EDTA二钠可以以约0.025重量%-约0.1重量%的量存在。
组合物中还可以包括一种或多种抗氧化剂。合适的抗氧化剂包括但不限于抗坏血酸、焦亚硫酸钠、亚硫酸氢钠、乙酰半胱氨酸、聚季铵盐-1、苯扎氯铵、硫柳汞、氯代丁醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯基乙基醇、依地酸二钠、山梨酸或本领域技术人员已知的其他物质。通常以约0.001重量%-约1.0重量%的水平采用这类防腐剂。
在一些实施方案中,通过可接受的增溶剂至少部分溶解化合物。某些可接受的非离子表面活性剂如聚山梨酯80可以用作增溶剂,如可接受的乙二醇,聚乙二醇,例如聚乙二醇400(PEG-400),以及乙二醇醚。
用于溶液和溶液/混悬液组合物的合适的增溶剂为环糊精。合适的环糊精选自α-环糊精、β-环糊精、γ-环糊精、烷基环糊精(例如,甲基-β-环糊精、二甲基-β-环糊精、二乙基-β-环糊精)、羟基烷基环糊精(例如,羟基乙基-β-环糊精、羟基丙基-β-环糊精)、羧基-烷基环糊精(例如,羧基甲基-β-环糊精)、磺烷基醚环糊精(例如,璜丁基醚-β-环糊精)等。环糊精的应用已在Rajewski et al.,Journal of Pharmaceutical Sciences,1996,85,1155-1159中综述。可接受的环糊精可以任选地以约1-约200mg/ml、约5-约100mg/ml或者约10-约50mg/ml的浓度存在于组合物中。
在一些实施方案中,组合物任选地包含悬浮剂。例如,在其中组合物为水性悬浮液或溶液/悬浮液的那些实施方案中,组合物可以包含一种或多种聚合物作为悬浮剂。可用的聚合物包括但不限于水溶性聚合物如纤维素聚合物,例如羟丙基甲基纤维素,以及水不溶性聚合物如交联的包含羧基的聚合物。但是,在一些实施方案中,组合物的确不含大量的固体颗粒物质,无论是抗微生物聚合物或低聚物活性剂、赋形剂或者两者,因为如果存在,固体颗粒物质可以引起治疗的眼的不适和/或刺激。
组合物中可以包括一种或多种可接受的pH调节剂和/或缓冲剂,包括酸如乙酸、硼酸、柠檬酸、乳酸、磷酸和盐酸;碱如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠和三-羟基甲基氨基甲烷;以及缓冲剂如柠檬酸盐/葡萄糖、碳酸氢钠和氯化铵。包括将组合物的pH维持在可接受的范围内所需要的量的这类酸、碱和缓冲剂。
组合物中可以包括任选存在的一种或多种可接受的表面活性剂,优选非离子表面活性剂,或者助溶剂以增加组合物的组分的溶解性或赋予物理稳定性,或者为了其他目的。合适的非离子表面活性剂包括但不限于聚氧乙烯脂肪酸甘油酯和植物油,例如,聚氧乙烯(60)氢化蓖麻油;以及聚氧乙烯烷基醚和烷基苯基醚,例如,辛苯昔醇10、辛苯昔醇40;聚山梨酯20、60和80;聚氧乙烯/聚氧丙烯表面活性剂(例如, F-68、F84和P-103);环糊精;或者本领域技术人员已知的其他物质。通常,在组合物中以约0.01重量%-约2重量%的水平采用这类助溶剂或表面活性剂。
组合物中还可以任选地包括一种或多种润滑剂以促进流泪或作为“干眼”药物。这类物质包括但不限于聚乙烯醇、甲基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮。应当理解在本发明中促进流泪仅在流泪天然缺陷时是有益的,以便恢复正常程度的泪液分泌。当过量流泪出现时,可以减少组合物在眼中的停留时间。
本公开还提供药物包或试剂盒,其包含装有本文所述的一种或多种化合物或组合物的一个或多个容器。与这类容器任选相关的可以是管理药物或生物产品的生产、使用或销售的政府机构所规定形式的提示,该提示反映用于人给药治疗本文所述的疾病状况、疾病或病症的生产、使用或销售的机构的批准。在一些实施方案中,试剂盒包含一种以上本文所述的化合物或组合物。在一些实施方案中,试剂盒包含本文所述的化合物和胰岛素,以及任选存在的另一治疗剂,在单一可注射剂型中,例如可注射装置如带针头注射器内的单一剂量。
本公开还提供治疗哺乳动物的I型和/或II型糖尿病的方法,所述方法包括向有此需要的哺乳动物给药有效量的胰岛素以及可接受量的上述一种或多种化合物或其药学可接受的盐。在一些实施方案中,哺乳动物可以在治疗之前预诊断患有I型或II型糖尿病或者糖尿病前期。在一些实施方案中,可以未进行正式诊断;在这类实施方案中,可以怀疑哺乳动物患有I型或II型糖尿病或者糖尿病前期,认为治疗对其是可取的。在一些实施方案中,所述方法可以用来治疗肥胖和糖尿病的并发症如高胆固醇血症、高血压、冠心病;糖尿病性神经病、糖尿病性视网膜病变、勃起功能障碍和肾疾病。
在一些实施方案中,本文所述的化合物可以与胰岛素同时或连续给药。因此,在一些实施方案中,首先给药胰岛素,然后给药式I-V中任一个的本文所述的化合物。在一些实施方案中,首先给药式I-V中任一个的本文所述的化合物,然后给药胰岛素。在一些实施方案中,胰岛素和式I-V中任一个的本文所述的化合物同时给药。当同时给药时,胰岛素和式I-V中任一个的本文所述的化合物可以存在于不同的药物组合物中,或者可以组合在单一药物组合物中,例如本文所述的许多药物组合物中的任一种。在一些实施方案中,目前的胰岛素给药方案可以用于胰岛素和本文所述的式I-V中任一种的化合物的给药。
在一些实施方案中,式I-V的化合物中任一种的有效量为约0.1mg/kg-约100mg/kg、约0.5mg/kg-约50mg/kg、约1mg/kg-约25mg/kg或者约5mg/kg-约20mg/kg。
胰岛素注射的剂量水平和频率根据糖尿病的类型(I型或II型)、胰岛素受体敏感性的状态、年龄和血糖水平而变化,并且针对单独的患者。胰岛素的起始剂量如下:速效胰岛素如优泌乐以0.5U/kg/天的起始剂量给药;短效胰岛素如优泌林以0.5U/kg/天的起始剂量给药;中效胰岛素如NPH和长效胰岛素如来得时以0.2U/kg/天的起始剂量给药。
在一些实施方案中,以约0.05U/kg/天-约5U/kg/天、约0.1U/kg/天-约2.5U/kg/天或者约0.3U/kg/天-约0.8U/kg/天的起始剂量给药速效胰岛素如优泌乐或短效胰岛素如优泌林(与式I-V的化合物一起)。在一些实施方案中,以约0.5U/kg/天的起始剂量给药速效胰岛素如优泌乐或短效胰岛素如优泌林(与式I-V的化合物一起)。
在一些实施方案中,以约0.01U/kg/天-约3U/kg/天、约0.05U/kg/天-约0.6U/kg/天或者约0.1U/kg/天-约0.3U/kg/天的起始剂量给药中效胰岛素如NPH和长效胰岛素如来得时(与式I-V的化合物一起)。在一些实施方案中,以约0.02U/kg/天的起始剂量给药中效胰岛素如NPH和长效胰岛素如来得时(与式I-V的化合物一起)。
为了可以更有效地理解本公开,下文提供实施例。应当理解这些实施例仅为了说明的目的而不应理解为以任何方式限制要求保护的实施方案。在这些实施例中,除非另有说明,根据Maniatis et al.,Molecular Cloning-A Laboratory Manual,2nd ed.,ColdSpring Harbor Press(1989)中所述的方法,利用可商购的试剂进行分子克隆反应和其他标准重组DNA技术。
实施例
实施例1:Db/db研究1
在本研究中,使用约16周龄的雄性DbDb Lep-缺陷小鼠(Harlan Laboratories)。实验设计如表1所示。
表1实验设计研究1
方法:将小鼠分为4组,6只小鼠/组。利用Accu-Chek Aviva血糖仪(RocheDiagnostics)测量血糖水平。在给药后长达72小时测量血糖的时间。每次研究之前校准血糖仪。通过剪尾获得血液(5μL)并直接用于葡萄糖试纸。葡萄糖水平报道为mg/dL。
在研究1中,在给药受试物品之前将动物禁食4小时,然后连续禁食至8小时时间点。然后向动物随意提供食物直至28小时时间点前4小时,在28小时时间点将它们禁食直至最后的血糖测量时间点。
数据表示为平均值±SEM。通过双向ANOVA然后post-hoc Bonferroni测试分析数据。N=6/组。
结果:在研究1中,16周龄的db/db小鼠表现出平均482mg/dL的禁食血糖水平。给药后3小时胰岛素降低血糖水平至平均166.5mg/dL。在胰岛素处理的动物中,血糖水平8小时返回基线水平。给药化合物102在给药后的任何时间点均不显著影响血糖水平。但是,化合物102与胰岛素的共给药延长胰岛素反应,直至给药后至少52小时均观察到显著的血糖降低。来自这个实验室的历史数据显示与7周龄db/db小鼠中约10ng/mL的胰岛素峰值水平相比,16周龄db/db小鼠具有低于或等于1ng/mL的胰岛素水平,并且在非糖尿病的瘦对照中胰岛素水平平均为约2-5ng/mL。结果如图1所示。
化合物102与胰岛素的共给药增强胰岛素血糖降低反应。*p<0.05;比较胰岛素与胰岛素/化合物102共给药。在化合物102处理组中微小但统计上不显著的血糖降低预期是老年db/d/b小鼠中剩余的低水平胰岛素生成的结果。
实施例2:Db/db研究2
在本研究中,使用约18周龄的雄性DbDb Lep-缺陷小鼠(Harlan Laboratories)。实验设计如表2所示。
表2实验设计研究2
方法:将小鼠分为4组,6只小鼠/组。利用Accu-Chek Aviva血糖仪(RocheDiagnostics)测量血糖水平。在给药后长达72小时测量血糖的时间。每次研究之前校准血糖仪。通过剪尾获得血液(5μL)并直接用于葡萄糖试纸。葡萄糖水平报道为mg/dL。
在研究2中,在每个血糖测量时间点之前将动物禁食4小时,然后返回自由获取食物。
数据表示为平均值±SEM。通过双向ANOVA然后post-hoc Bonferroni测试分析数据。N=6/组
结果:进行第二研究以重复在24-72小时时间窗口中化合物102影响胰岛素作用的发现,特别是关注胰岛素/化合物102组合效果直至其返回正常水平(即,媒介物处理的动物的水平)。在第二研究中,与第一研究有3个差异:1)在研究时小鼠为18周龄,2)将胰岛素剂量-水平降低至3-1.5U/kg,以及3)测量血糖水平直至给药后72小时。
在这个研究中,禁食血糖水平平均为420mg/dL。单独胰岛素给药或单独化合物102给药后24小时,血糖水平与媒介物对照没有不同。但是,胰岛素与化合物102的共给药在24、36和48小时时间点引起显著血糖降低。在胰岛素/化合物102共给药的动物中,血糖水平72小时返回基线水平。结果如图2所示。
化合物102与胰岛素的共给药增强胰岛素血糖降低反应。*p<0.05;**p<0.01,比较胰岛素与胰岛素/化合物102共给药。胰岛素处理组未表现出血糖降低,因为胰岛素活性通常在2-4小时之间导致其完全程度的血糖降低,并且在8小时完成;这个研究未检测该时间点。在胰岛素处理组中于24和36小时时间点略微升高的血糖是在胰岛素处理的动物中经常观察到的“反弹”效应。
实施例3:链佐星研究
在本研究中,使用约8周龄的雄性CD-1:ICR小鼠(Charles River)。实验设计如表3所示。向小鼠给药链佐星破坏胰腺β-细胞并用于产生I型糖尿病的模型。对丧失胰腺β-细胞应答,小鼠变得高血糖。这些小鼠是胰岛素反应的。
表3实验设计STZ研究
方法:
链佐星给药:通过标准方法进行向小鼠给药链佐星。简单地说,在第1、3和8天以70mg/kg的剂量-水平向小鼠给药STZ。每次给药之前禁食18小时。在第2和9天向小鼠给药胰岛素(0.5U)。在第11天,测量血糖水平。将具有低于300mg/dL的血糖水平的小鼠从研究排除。将小鼠随机分至处理组。
在初始STZ给药后第14天在胰岛素耐受测试上测试小鼠。向小鼠给药胰岛素(0.35U s.c.),然后30分钟后给药化合物102(100mg/kg i.p.)。
化合物102或媒介物给药之后5、15、30、60、90、120、180、240、360和480分钟测量血糖。通过剪尾采集血液,并且通过血糖仪(Accu-Chek Aviva Glucometers;RocheDiagnostics)测量血滴的葡萄糖水平。
数据表示为平均值±SEM。通过双向ANOVA然后post-hoc Bonferroni测试分析数据。N=6/组
结果:链佐星给药使血糖水平增加至大于500mg/dL。这个水平的葡萄糖表明胰腺β-细胞被完全破坏。给药化合物102在给药后长达6小时的任何时间点均不影响血糖水平。胰岛素给药在给药后90分钟将血糖水平从546mg/dL(基线)降低至263mg/dL。在给药后4.5小时,血糖水平返回至基线水平。
与胰岛素组合,化合物102增强胰岛素效果。在胰岛素给药之后30分钟给药化合物102。化合物102使胰岛素介导的血糖减少增加至157mg/dL(与单独胰岛素的263mg/dL相比)。此外,在给药后长达6小时血糖水平仍降低。
这些数据显示化合物102在I型糖尿病小鼠中增强并延长胰岛素的作用。
对于在链佐星I型糖尿病小鼠中媒介物处理或化合物102处理,在时间0向小鼠给药化合物102或媒介物。在给药后长达6小时测量血糖水平。在胰岛素耗尽的小鼠中化合物102不影响血糖水平。对于胰岛素与化合物102组合,在化合物102之前30分钟给药胰岛素。在时间0给药化合物102。在给药后长达6小时测量血糖水平。给药化合物102增强并延长胰岛素介导的血糖降低。当与胰岛素单独处理相比时*p<0.05。当与胰岛素单独处理相比时***p<0.001。数据表示为平均值±SEM。通过双向ANOVA然后post-hoc Bonferroni测试分析数据。结果如图3所示。
在这些研究中,在db/db小鼠中化合物102与胰岛素共给药引起显著延长的胰岛素介导的血糖降低反应。此外,向胰岛素处理的I型糖尿病小鼠给药化合物102增强并延长胰岛素的作用。
这些数据表明化合物102可以用作胰岛素的辅助疗法以延长晚期II糖尿病和I型糖尿病中的胰岛素活性。
除了本文所述的那些修改,从上文的描述,本发明的各种修改对于本领域技术人员是明显的。这类修改意图也在所附权利要求书的范围内。本申请中引用的每个参考文献(包括但不限于杂志文章、美国和非美国专利、专利申请公开、国际专利申请公开、基因文库登录号等)整体援引加入本文。
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CN201610988112.1A Active CN107007608B (zh) | 2011-12-12 | 2012-12-12 | I型和ii型糖尿病的治疗 |
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US10863264B2 (en) | 2017-01-23 | 2020-12-08 | David Sampson | Vibration inducing tactile apparatus |
BR112020013924A2 (pt) * | 2018-01-11 | 2020-12-01 | Bukwang Pharmaceutical Co., Ltd. | método para preparar tolimidona, e, composição farmacêutica |
Citations (2)
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WO2009015133A1 (en) * | 2007-07-23 | 2009-01-29 | Melior Discovery, Inc. | Methods of activating irs-1 and akt |
WO2011150300A1 (en) * | 2010-05-28 | 2011-12-01 | Melior Pharmaceuticals I, Inc. | Prevention of pancreatic beta cell degeneration |
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US3922345A (en) | 1971-10-29 | 1975-11-25 | Pfizer | Pyrimidinones and hydroxy pyrimidines |
SE9203753D0 (sv) | 1992-12-11 | 1992-12-11 | Kabi Pharmacia Ab | Expression system for producing apolipoprotein ai-m |
SE9500778D0 (sv) | 1995-03-03 | 1995-03-03 | Pharmacia Ab | Process for producing a protein |
US6037323A (en) | 1997-09-29 | 2000-03-14 | Jean-Louis Dasseux | Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders |
US6004925A (en) | 1997-09-29 | 1999-12-21 | J. L. Dasseux | Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders |
US20030198666A1 (en) * | 2002-01-07 | 2003-10-23 | Richat Abbas | Oral insulin therapy |
US7985422B2 (en) * | 2002-08-05 | 2011-07-26 | Torrent Pharmaceuticals Limited | Dosage form |
US20070025953A1 (en) * | 2005-07-27 | 2007-02-01 | Jones Michael R | Co-therapy for diabetic conditions |
KR101452518B1 (ko) | 2005-08-22 | 2014-10-21 | 멜리어 파마슈티칼스 아이, 인코포레이티드 | Lyn 키나제 활성의 조절 및 관련된 장애의 치료를 위한방법 및 제제 |
RU2316339C1 (ru) * | 2006-09-13 | 2008-02-10 | Общество С Ограниченной Ответственностью "Концерн О3" | Способ получения препарата инсулина для перорального применения |
JP2010518860A (ja) * | 2007-02-20 | 2010-06-03 | メリオール・ファーマスーティカルズ・ワン・インコーポレイテッド | Lynキナーゼの活性化剤の同定方法 |
MX2011006073A (es) * | 2008-12-12 | 2011-06-24 | Merck Patent Gmbh | Combinacion de insulina con derivados de triazina y su uso para tratar diabetes. |
CN110785170B (zh) * | 2017-04-10 | 2023-03-28 | 梅里奥尔医药I公司 | 脂肪细胞的治疗 |
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Patent Citations (2)
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WO2009015133A1 (en) * | 2007-07-23 | 2009-01-29 | Melior Discovery, Inc. | Methods of activating irs-1 and akt |
WO2011150300A1 (en) * | 2010-05-28 | 2011-12-01 | Melior Pharmaceuticals I, Inc. | Prevention of pancreatic beta cell degeneration |
Also Published As
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HK1202819A1 (zh) | 2015-10-09 |
CN104271140A (zh) | 2015-01-07 |
CN104271140B (zh) | 2016-11-23 |
WO2013090319A3 (en) | 2014-12-04 |
KR20140107416A (ko) | 2014-09-04 |
IL233004A0 (en) | 2014-07-31 |
US20200215068A1 (en) | 2020-07-09 |
SG10201604828QA (en) | 2016-07-28 |
JP2015513310A (ja) | 2015-05-07 |
CN107007608A (zh) | 2017-08-04 |
EP2790704A2 (en) | 2014-10-22 |
CA2859156A1 (en) | 2013-06-20 |
BR112014014289A8 (pt) | 2017-06-13 |
EP2790704B1 (en) | 2019-04-03 |
ZA201404738B (en) | 2016-10-26 |
RU2646475C2 (ru) | 2018-03-05 |
EP2790704A4 (en) | 2015-09-02 |
MX2014006990A (es) | 2015-02-05 |
BR112014014289A2 (pt) | 2017-06-13 |
KR102069395B1 (ko) | 2020-01-22 |
RU2014128528A (ru) | 2016-02-10 |
SG11201403207WA (en) | 2014-09-26 |
AU2012352480A1 (en) | 2014-07-17 |
IL233004B (en) | 2020-01-30 |
US20150190396A1 (en) | 2015-07-09 |
AU2017204652B2 (en) | 2018-08-16 |
JP6152387B2 (ja) | 2017-06-21 |
WO2013090319A2 (en) | 2013-06-20 |
CA2859156C (en) | 2020-10-06 |
AU2017204652A1 (en) | 2017-07-27 |
MX359171B (es) | 2018-09-18 |
NZ626495A (en) | 2016-03-31 |
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