CN1980894A - 作为ppar调节剂的化合物和组合物 - Google Patents
作为ppar调节剂的化合物和组合物 Download PDFInfo
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- CN1980894A CN1980894A CNA2005800196459A CN200580019645A CN1980894A CN 1980894 A CN1980894 A CN 1980894A CN A2005800196459 A CNA2005800196459 A CN A2005800196459A CN 200580019645 A CN200580019645 A CN 200580019645A CN 1980894 A CN1980894 A CN 1980894A
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- alkyl
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- disease
- inhibitor
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Classifications
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Abstract
本发明提供了化合物、包含这类化合物的药物组合物和使用这类化合物来治疗或预防与过氧化物酶体增殖物激活受体(PPAR)家族活性、特别是PPARδ活性有关的疾病或疾患的方法。
Description
相关申请的交叉参考
本申请要求2004年5月14日提交的美国临时专利申请No.60/571,004的优先权。该申请的全部公开内容完整地引入本文作为参考并用于所有目的。
发明背景
发明领域
本发明提供了化合物、包含这类化合物的药物组合物和使用这类化合物治疗或预防与过氧化物酶体增殖物激活受体(PPAR)家族活性、特别是PPARδ活性有关的疾病或疾患的方法。
背景
过氧化物酶体增殖物激活受体(PPAR)是核激素受体超家族的成员,该家族是调节基因表达的配体-活化转录因子。某些PPAR与大量疾病状态有关,包括血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、动脉粥样化形成、高甘油三酯血症、心力衰竭、心肌梗塞、血管疾病、心血管疾病、高血压、肥胖、炎症、关节炎、癌症、阿尔茨海默氏病、皮肤疾患、呼吸系统疾病、眼部疾患、IBD(易激性肠病)、溃疡性结肠炎和节段性回肠炎。因此,调节PPAR、特别是PPARδ的活性的分子可用作这些疾病治疗中的治疗剂。
发明概述
在一方面,本发明提供了式I化合物及其N-氧化物衍生物、前药衍生物、被保护的衍生物、单一异构体及其异构体混合物;以及该化合物的可药用盐和溶剂化物(如水合物),
其中:
m是选自1、2和3的整数;
Z1、Z2和Z3是独立地选自CH和N的成员;
L1选自-XOX-和-XS(O)0-2X-;其中X独立地选自价键和C1-4亚烷基;其中L1的任意亚烷基可任选被1至3个选自卤代、C1-6烷基、C1-6烷氧基、卤代-C1-6烷基和卤代-C1-6烷氧基的基团取代;
R6和R7独立地选自-R10和-YR10;其中Y选自C1-6亚烷基、C2-6亚烯基和C2-6亚炔基;且R10选自C3-12环烷基、C3-8杂环烷基、C6-10芳基和C5-13杂芳基;
其中R10的任意芳基、杂芳基、环烷基和杂环烷基任选被1至3个基团取代,所述基团独立地选自卤代、硝基、氰基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基、卤代-C1-6烷氧基、-XS(O)0-2XR11、-XS(O)0-2XR12、-X-NR11R11、-XNR11XR12和-XOXR12;其中X是价键或C1-4亚烷基;R11选自氢和C1-6烷基;且R12选自C3-12环烷基、C3-8杂环烷基、C6-10芳基和C5-10杂芳基;其中R12的任意芳基、杂芳基、环烷基和杂环烷基任选被1至3个基团取代,所述基团独立地选自卤代、硝基、氰基、C1-6烷基、C1-6烷氧基、卤代-C1-6烷基和卤代-C1-6烷氧基;
R8选自卤代、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基、卤代-C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-12环烷基和C3-8杂环烷基;其中R8的任意芳基、杂芳基、环烷基和杂环烷基任选被1至3个基团取代,所述基团独立地选自卤代、硝基、氰基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基和卤代-C1-6烷氧基;
R9选自-XOXC(O)OR11和-XC(O)OR11;其中X是价键或C1-4亚烷基;且R11选自氢和C1-6烷基。
第二方面,本发明提供了药物组合物,它含有式I化合物或其N-氧化物衍生物、单一异构体和异构体混合物;或其可药用盐,与一种或多种适宜的赋形剂混合。
第三方面,本发明提供了治疗动物疾病的方法,其中PPAR活性、特别是PPARδ的调节能够预防、抑制或改善该疾病的病理学和/或症状学,该方法包含对该动物给予治疗有效量的式I化合物或其N-氧化物衍生物、单一异构体和异构体混合物,或其可药用盐。
第四方面,本发明提供了式I化合物在制备用于治疗动物疾病的药物中的用途,其中PPAR活性、特别是PPARδ活性对该疾病的病理学和/或症状学有作用。
第五方面,本发明提供了制备式I化合物及其N-氧化物衍生物、前药衍生物、被保护的衍生物、单一异构体和异构体混合物及其可药用盐的方法。
发明详述
定义
“烷基”作为基团及作为其它基团(例如卤代-烷基和烷氧基)的结构要素,可以是直链或支链的。C1-6烷氧基包括甲氧基、乙氧基等。卤代-烷基包括三氟甲基、五氟乙基等。
“芳基”表示含有6至10个环碳原子的单环或稠合的二环芳族环系。例如,芳基可以是苯基或萘基,优选苯基。“亚芳基”表示从芳基衍生的二价基团。
“杂芳基”如芳基所定义,其中一个或多个环成员是杂原子。例如,杂芳基包括吡啶基、吲哚基、吲唑基、喹喔啉基、喹啉基、苯并呋喃基、苯并吡喃基、苯并噻喃基、苯并[1,3]二氧杂环戊烯、咪唑基、苯并咪唑基、嘧啶基、呋喃基、唑基、异唑基、三唑基、四唑基、吡唑基、噻吩基等。“C6-10芳基C0-4烷基”表示经由亚烷基连接的如上所述的芳基。例如,C6-10芳基C0-4烷基包括苯乙基、苄基等。
“环烷基”表示饱和或部分不饱和的单环、稠合二环或桥连多环环系,含有所示数目的环原子。例如,C3-10环烷基包括环丙基、环丁基、环戊基、环己基等。
“杂环烷基”表示如本申请所定义的环烷基,其条件是所示一个或多个环碳被选自如下的部分所代替:-O-、-N=、-NR-、-C(O)-、-S-、-S(O)-或-S(O)2-,其中R是氢、C1-4烷基或氮保护基团。例如,在本申请中用于描述本发明化合物的C3-8杂环烷基包括吗啉代基、吡咯烷基、哌嗪基、哌啶基、哌啶酮基、1,4-二氧杂-8-氮杂-螺[4.5]癸-8-基等。
“卤素”(或卤代)优选代表氯或氟,但是还可以是溴或碘。
“治疗”表示缓和或减轻疾病和/或其伴随症状的方法。
优选实施方案的说明
本发明提供了化合物、组合物和治疗疾病的方法,其中PPARδ活性的调节能够预防、抑制或改善该疾病的病理学和/或症状学,该方法包含对动物给予治疗有效量的式I化合物。
在一个实施方案中,对于式I化合物,m是选自1至3的整数;Z1、Z2和Z3是独立地选自CH和N的成员;L1选自-XOX-和-XSX-;其中X独立地选自价键和G1-4亚烷基;R6和R7独立地选自-R10和-YR10;其中Y选自C1-6亚烷基和C2-6亚烯基;且R10选自C6-10芳基和C5-13杂芳基;其中R10的任意芳基或杂芳基任选被1至3个基团取代,所述基团独立地选自卤代、氰基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基、卤代-C1-6烷氧基、-XS(O)0-2XR11、-XNR11R11和XOXR12;其中X是价键或C1-4亚烷基;R11选自氢和C1-6烷基;且R12是C6-10芳基;R8是C1-6烷基;且R9是-XOXC(O)OR11;其中X是价键或C1-4亚烷基;且R11选自氢和C1-6烷基。
在一个实施方案中,本发明提供了式Ia化合物:
其中:
Z1、Z2和Z3是独立地选自CH和N的成员;
L1选自-CH2O-、-OCH2-和-SCH2-;
R6和R7独立地选自-R10和-YR10;其中Y是亚丙烯基;且R10选自苯基、联苯基、萘基、苯并[b]呋喃基、吡啶基、嘧啶基、二苯并呋喃-2-基、呋喃基、苯并[b]噻吩、噻吩基和喹啉基;其中R10的任意芳基或杂芳基任选被1至3个基团取代,所述基团独立地选自卤代、氰基、甲基、羟基-甲基、甲硫基、甲氧基、三氟甲基、三氟甲氧基、苯氧基、乙磺酰基和二甲基氨基。
在一个实施方案中,本发明提供了式Ib化合物:
其中:
R6选自-R10和-YR10;其中Y是亚丙烯基;且R10选自苯基、联苯基、萘基、苯并[b]呋喃基、吡啶基、嘧啶基、二苯并呋喃-2-基、呋喃基、苯并[b]噻吩、噻吩基和喹啉基;其中R10的任意芳基或杂芳基任选被1至3个基团取代,所述基团独立地选自卤代、氰基、甲基、羟基-甲基、甲硫基、甲氧基、三氟甲基、三氟甲氧基、苯氧基、乙磺酰基和二甲基氨基;且R13选自甲氧基、三氟甲基和三氟甲氧基。
优选的式I化合物是下文实施例详述的那些。
药理学和效用
本发明化合物调节PPAR的活性,因此可用于治疗疾病或疾患,其中PPAR对该疾病的病理学和/或症状学有作用。本发明进一步提供了用在治疗疾病或疾患的药物制备中的本发明化合物,其中PPAR、特别是PPARδ对该疾病的病理学和/或症状学有作用。
这类化合物因此可以用于治疗或预防血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、动脉粥样化形成、高甘油三酯血症、心力衰竭、高胆固醇血症、心肌梗塞、血管疾病、心血管疾病、高血压、肥胖、恶病质、HIV消瘦综合征、炎症、关节炎、癌症、阿尔茨海默氏病、食欲缺乏、神经性食欲缺乏、食欲过盛、皮肤疾患、呼吸系统疾病、眼部疾患、IBD(易激性肠病)、溃疡性结肠炎和节段性回肠炎。优选治疗或预防血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、动脉粥样化形成、高甘油三酯血症、心血管疾病、高血压、肥胖、炎症、癌症、皮肤疾患、IBD(易激性肠病)、溃疡性结肠炎和节段性回肠炎。
本发明化合物还可以用于治疗长期危重疾病,增加肌肉质量和/或肌肉强度,增加瘦体重,维持老年人的肌肉强度和功能,增强肌肉耐力和肌肉功能,和逆转或预防老年人的衰弱。
进而,本发明化合物可以用作哺乳动物降血糖剂,用于治疗和预防其中牵涉有葡萄糖耐量降低、高血糖和抗胰岛素性的病症,例如1型与2型糖尿病、葡萄糖代谢降低(IGM)、葡萄糖耐量降低(IGT)、禁食葡萄糖降低(IFG)和X综合征。优选1型与2型糖尿病、葡萄糖代谢降低(IGM)、葡萄糖耐量降低(IGT)和禁食葡萄糖降低(IFG)。
按照上述,本发明进一步提供了在需要这类治疗的受治疗者中预防或治疗任意上述疾病或疾患的方法,该方法包含对所述受治疗者给予治疗有效量(见下文“给药和药物组合物”)的本发明化合物或其可药用盐。就任意上述用途而言,所需剂量将因给药方式、所治疗的特定病症和所需效果而异。本发明还涉及:i)用作药物的本发明化合物或其可药用盐;和ii)本发明化合物或其可药用盐在制备药物的用途,该药物用于预防或治疗任意上述疾病或疾患。
给药和药物组合物
一般而言,本发明化合物将以治疗有效量经由本领域已知的任意常用的和可接受的方式单独或者与一种或多种治疗剂组合给药。治疗有效量可以因疾病严重性、受治疗者的年龄与相对健康、所用化合物的效力及其它因素而异。一般而言,以日剂量约0.03至2.5mg/kg体重全身给药被指示获得令人满意的结果。大型哺乳动物、例如人类的指示日剂量为约0.5mg至约100mg,方便地以例如多达每天四次的分开剂量或者以延迟形式给予。适于口服给药的单元剂型包含约1至50mg活性成分。
本发明化合物可以作为药物组合物经任意常规途径、特别是肠内方式(例如口服,例如以片剂或胶囊形式)或者胃肠道外方式(例如注射溶液或混悬液形式)、局部方式(例如以洗剂、凝胶、软膏或霜剂,或者鼻用或栓剂形式)施用。通过混合、造粒或包衣方法,可以按照常规方式制备包含游离或可药用盐形式的本发明化合物以及至少一种可药用载体或稀释剂的药物组合物。例如,口服组合物可以是片剂或明胶胶囊,包含活性成分以及a)稀释剂,例如乳糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇、纤维素和/或甘氨酸;b)润滑剂,例如二氧化硅、滑石粉、硬脂酸、硬脂酸镁或硬脂酸钙和/或聚乙二醇;就片剂而言,还有c)粘合剂,例如硅酸铝镁、淀粉糊、明胶、西黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要的话还有d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐或泡腾混合物;和/或e)吸收剂、着色剂、矫味剂和甜味剂。可注射组合物可以是含水等张溶液或混悬液,栓剂可以由脂肪乳液或混悬液制备。组合物可以被灭菌和/或含有助剂,例如防腐剂、稳定剂、润湿剂或乳化剂、溶解促进剂、调节渗透压的盐和/或缓冲剂。另外,它们还可以含有其它治疗用物质。适于透皮应用的制剂包括有效量的本发明化合物和载体。载体可以包括可吸收的药理学可接受的溶剂,以帮助穿过宿主的皮肤。例如,透皮装置是绷带剂的形式,包含背衬膜、含有化合物和任选的载体的贮库、任选的速率控制屏障(历经延长了的时间以受控和预定的速率递送化合物至宿主皮肤)和固定该装置于皮肤的手段。还可以使用基质透皮制剂。适于局部应用、例如用于皮肤和眼睛的制剂优选是本领域熟知的水溶液、软膏、霜剂或凝胶。这类制剂可以含有增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。
本发明还涉及药物组合物,包含治疗有效量的如本文所述的化合物与一种或多种可药用载体的组合。
本发明化合物可以以治疗有效量与一种或多种治疗剂组合给药(药物组合)。
因而,本发明还涉及药物组合,例如组合制剂或药物组合物(固定组合),包含:1)如上所定义的本发明化合物或其可药用盐;和2)至少一种选自如下的活性成分或其各自的可药用盐,和任选的可药用载体:
a)抗糖尿病剂,例如胰岛素、胰岛素衍生物和模拟物;胰岛素促分泌剂,例如磺脲类,例如格列吡嗪、格列本脲和亚莫利阿玛尔;促胰岛素磺脲受体配体,例如格列奈类,例如那格列奈和瑞格列奈;胰岛素敏化剂,例如蛋白酪氨酸磷酸酶-1B(PTP-1B)抑制剂,例如PTP-112;GSK3(糖原合成酶激酶-3)抑制剂,例如SB-517955、SB-4195052、SB-216763、NN-57-05441和NN-57-05445;RXR配体,例如GW-0791和AGN-194204;钠依赖性葡萄糖协同转运蛋白抑制剂,例如T-1095;糖原磷酸化酶A抑制剂,例如BAY R3401;双胍类,例如甲福明;α-糖苷酶抑制剂,例如阿卡波糖;GLP-1(高血糖素样肽-1)、GLP-1类似物(例如Exendin-4)和GLP-1模拟物;DPPIV(二肽基肽酶IV)抑制剂,例如DPP728、LAF237(vildagliptin-WO 00/34241的实施例1)、MK-0431、saxagliptin、GSK23A;AGE断裂剂(breaker);噻唑烷酮衍生物(格列酮),例如吡格列酮、罗格列酮或(R)-1-{4-[5-甲基-2-(4-三氟甲基-苯基)-唑-4-基甲氧基]-苯磺酰基}-2,3-二氢-1H-吲哚-2-甲酸(在专利申请WO 03/043985中被描述为实施例4的化合物19),非格列酮型PPARγ激动剂,例如GI-262570;
b)降血脂剂,例如3-羟基-3-甲基-戊二酰辅酶A(HMG-CoA)还原酶抑制剂,例如洛伐他汀、匹伐他汀、辛伐他汀、普伐他汀、西立伐他汀、美伐他汀、维洛他汀(velostatin)、氟伐他汀、达伐他汀、阿托伐他汀、罗苏伐他汀和利伐他汀(rivastatin);角鲨烯合成酶抑制剂;FXR(法呢醇X受体)和LXR(肝X受体)配体;考来烯胺;贝特类;烟酸和阿司匹林;
c)抗肥胖剂或食欲调节剂,例如芬特明、来普汀(leptin)、溴隐亭、右旋苯丙胺、苯丙胺、氟苯丙胺、右旋氟苯丙胺、西布曲明、奥利司他、右芬氟拉明、吗吲哚、芬特明、苯甲曲秦、安非拉酮、氟西汀、安非他酮、托吡酯、安非拉酮、苄非他明、苯丙醇胺或依考匹泮、麻黄碱、伪麻黄碱或大麻素受体拮抗剂;
d)抗高血压剂,例如髓袢利尿剂,例如依他尼酸、呋塞米和托塞米;利尿剂,例如噻嗪衍生物、氯噻嗪、氢氯噻嗪、阿米洛利;血管紧张素转化酶(ACE)抑制剂,例如贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、莫昔普利、培哚普利、喹那普利、雷米普利和群多普利;Na-K-ATP酶膜泵抑制剂,例如地高辛;中性内肽酶(NEP)抑制剂,例如thiorphan、terteo-thiorphan、SQ29072;ECE抑制剂,例如SLV306;ACE/NEP抑制剂,例如奥马曲拉、山帕曲拉和法西多曲;血管紧张素II拮抗剂,例如坎地沙坦、依普罗沙坦、厄贝沙坦、氯沙坦、替米沙坦和缬沙坦,特别是缬沙坦;肾素抑制剂,例如阿利吉仑、特拉吉仑、地替吉仑、RO 66-1132、RO-66-1168;β-肾上腺素能受体阻滞剂,例如醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、美托洛尔、纳多洛尔、普萘洛尔、索他洛尔和噻吗洛尔;影响收缩力的物质,例如地高辛、多巴酚丁胺和米力农;钙通道阻滞剂,例如氨氯地平、苄普地尔、地尔硫革、非洛地平、尼卡地平、尼莫地平、硝苯地平、尼索地平和维拉帕米;醛甾酮受体拮抗剂;和醛甾酮合成酶抑制剂;
e)增加HDL的化合物;
f)胆固醇吸收调节剂,例如Zetia和KT6-971;
g)Apo-A1类似物和模拟物;
h)凝血酶抑制剂,例如希美加群(Ximelagatran);
i)醛甾酮抑制剂,例如阿那曲唑、法倔唑、依普利酮;
j)血小板聚集抑制剂,例如阿司匹林、氯吡格雷硫酸氢盐;
k)雌激素、睾酮、选择性雌激素受体调节剂、选择性雄激素受体调节剂;
l)化学治疗剂,例如芳香酶抑制剂,例如弗隆,抗雌激素剂,拓扑异构酶I抑制剂,拓扑异构酶II抑制剂,微管活化剂,烷化剂,抗肿瘤抗代谢物,铂配合物,降低蛋白激酶活性的化合物,例如PDGF受体酪氨酸激酶抑制剂,优选伊马替尼(N-{5-[4-(4-甲基-哌嗪子基-甲基)-苯甲酰氨基]-2-甲基苯基}-4-(3-吡啶基)-2-嘧啶胺),其在欧洲专利申请EP-A-0 564409中被描述为实施例21,或者4-甲基-N-[3-(4-甲基-咪唑-1-基)-5-三氟甲基-苯基]-3-(4-吡啶-3-基-嘧啶-2-基氨基)-苯甲酰胺,其在专利申请WO04/005281中被描述为实施例92;和
m)与5-HT3受体相互作用的物质和/或与5-HT4受体相互作用的物质,例如替加色罗(在美国专利No.5510353中被描述为实施例13)、替加色罗马来酸氢盐、西沙必利、西兰司琼。
最优选的组合伴侣是替加色罗、伊马替尼、vildagliptin、甲福明、噻唑烷酮衍生物(格列酮)(例如吡格列酮、罗格列酮或(R)-1-{4-[5-甲基-2-(4-三氟甲基-苯基)-唑-4-基甲氧基]-苯磺酰基}-2,3-二氢-1H-吲哚-2-甲酸)、磺脲受体配体、阿利吉仑、缬沙坦、奥利司他或他汀类(例如匹伐他汀、辛伐他汀、氟伐他汀或普伐他汀)。
优选药物组合含有治疗有效量的如上所定义的本发明化合物与治疗有效量的上述其它治疗剂的组合,例如各自采用如本领域所报道的有效治疗剂量。组合伴侣(1)和(2)可以在一个组合单元剂型中或在两个分开的单元剂型中一起、依次或分别给药。单元剂型还可以是固定组合。
由通用名或商品名所确定的活性成分的结构可从标准著作“默克索引”或“医师案头参考”(Physician′s Desk Reference)的现行版本或者从数据库(例如Patents International(例如IMS World Publications)或Current Drugs)中获知。其相应内容引入本文作为参考。任何本领域技术人员完全能够确定这些活性成分,并且基于这些参考文献,同样能够制备并在体外和体内标准测试模型中测试药物的适应症和性质。
在另一优选的方面,本发明涉及药物组合物(固定组合),包含治疗有效量的本文所述化合物与治疗有效量的至少一种选自上述a)至m)的活性成分或各自的可药用盐的组合。
本文所述的药物组合物或组合用于制备治疗下列疾病的药物:血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、高甘油三酯血症、心力衰竭、心肌梗塞、血管疾病、心血管疾病、高血压、肥胖、炎症、关节炎、癌症、阿尔茨海默氏病、皮肤疾患、呼吸系统疾病、眼部疾患、炎性肠病、IBD(易激性肠病)、溃疡性结肠炎、节段性回肠炎,以及其中牵涉有葡萄糖耐量降低、高血糖和抗胰岛素性的病症,例如1型与2型糖尿病、葡萄糖代谢降低(IGM)、葡萄糖耐量降低(IGT)、禁食葡萄糖降低(IFG)和X综合征。
这类治疗剂包括雌激素、睾酮、选择性雌激素受体调节剂、选择性雄激素受体调节剂、胰岛素、胰岛素衍生物和模拟物;胰岛素促分泌剂,例如磺脲类,例如格列吡嗪和亚莫利阿玛尔;促胰岛素磺脲受体配体,例如格列奈类,例如那格列奈和瑞格列奈;胰岛素敏化剂,例如蛋白酪氨酸磷酸酶-1B(PTP-1B)抑制剂;GSK3(糖原合成酶激酶-3)抑制剂或RXR配体;双胍类,例如甲福明;α-糖苷酶抑制剂,例如阿卡波糖;GLP-1(高血糖素样肽-1)、GLP-1类似物(例如Exendin-4)和GLP-1模拟物;DPPIV(二肽基肽酶IV)抑制剂,例如异亮氨酸-噻唑烷(isoleucin-thiazolidide);DPP728和LAF237;降血脂剂,例如3-羟基-3-甲基-戊二酰辅酶A(HMG-CoA)还原酶抑制剂,例如洛伐他汀、匹伐他汀、辛伐他汀、普伐他汀、西立伐他汀、美伐他汀、维洛他汀、氟伐他汀、达伐他汀、阿托伐他汀、罗苏伐他汀、fluindostatin和利伐他汀;角鲨烯合成酶抑制剂;FXR(法呢醇X受体)和LXR(肝X受体)配体;考来烯胺;贝特类;烟酸和阿司匹林。本发明化合物可以与其它活性成分同时、之前或之后通过相同或不同的给药途径单独给药或者在同一药物制剂中一起给药。
本发明还提供了药物组合,例如药盒,包含:a)第一药物,它是本文公开的游离或可药用盐形式的本发明化合物,和b)至少一种共同药物。药盒可以包含其用药指导。
用于本文的术语“共同给药”或“组合给药”等意欲涵盖对单一患者施用所选择的治疗剂,并且还意欲包括其中各药物不必借助相同给药途径或者同时给药的治疗方案。
本文所用的术语“药物组合”表示混合或组合一种以上活性成分所得的产品,包括活性成分的固定与非固定组合。术语“固定组合”意味着活性成分、例如式I化合物和共同药物以单一实体或剂型同时对患者给药。术语“非固定组合”意味着活性成分、例如式I化合物和共同药物作为单独的实体同时、共同或依次对患者给药,没有具体的时间限制,其中这类给药在患者机体中提供了两种化合物的治疗有效水平。后者还适用于合剂疗法,例如三种或三种以上活性成分的给药。
制备本发明化合物的方法
本发明还包括本发明化合物的制备方法。在所述反应中,可能有必要保护反应活性官能团,例如羟基、氨基、亚氨基、硫羟基或羧基(其中它们在终产物中是需要的)以避免它们不被希望地参与反应。按照标准实践可以使用常规保护基团,例如参见T.W.Greene和P.G.M.Wuts的″Protective Groups in Organic Chemistry″,John Wiley and Sons,1991。
式I化合物可按照下述反应流程图1所述来制备:
反应流程图1
其中m、L1、R6、R7、R8、R9、Z1、Z2和Z3如发明概述中式I中所定义,且Q是卤代(如Cl、Br、I等)。式I化合物通过使式2化合物与式3和4化合物在适宜催化剂(如Pd(PPh3)4等)和适宜溶剂(如二烷、乙醇等)存在下反应来制备。该反应在约150℃至约200℃温度范围内进行(微波化),并且进行长达20分钟至完全。
式I中间体可按照下述反应流程图2a和2b所述来制备:
反应流程图2a
其中R6、R7、Z1、Z2和Z3如发明概述中式I中所定义,且Q是卤代(如Cl、Br、I等)。式6化合物通过使式5化合物与式3和4化合物在适宜催化剂(如Pd(PPh3)4等)和适宜溶剂(如二烷、乙醇等)存在下反应来制备。该反应在约150℃至约200℃温度范围内进行(微波化),并且进行长达20分钟至完全。式6化合物在适宜催化剂(如N-溴琥珀酰亚胺(NBS)等)和适宜溴化剂(如偶氮二异丁腈(AIBN)等)存在下进一步反应生成式7化合物。
其中L1是-OCH2-的式I化合物可按照下述反应流程图2b所述来制备:
反应流程图2b
其中m、R6、R7、R8、R9、Z1、Z2和Z3如发明概述中式I中所定义。式I化合物通过使式5化合物与式6化合物在适宜溶剂(如乙腈等)和适宜碱(如碳酸铯等)存在下反应来制备。反应在氮气下进行,并且进行长达30小时至完全。反应可任选通过用例如LiOH等皂化来完成。
其它制备本发明化合物的方法
使游离碱形式的化合物与可药用无机或有机酸反应,可以制备本发明化合物的可药用酸加成盐。或者,使游离酸形式的化合物与可药用无机或有机碱反应,可以制备本发明化合物的可药用碱加成盐。或者,使用原料或中间体的盐可以制备本发明化合物的盐形式。
从相应的碱加成盐或酸加成盐形式可以分别制备本发明化合物的游离酸或游离碱形式。例如,用适宜的碱(例如氢氧化铵溶液、氢氧化钠等)处理,可以将本发明化合物的酸加成盐形式转化为相应的游离碱。用适宜的酸(例如盐酸等)处理,可以将本发明化合物的碱加成盐形式转化为相应的游离酸。
在适宜的惰性有机溶剂(例如乙腈、乙醇、含水二烷等)中,在0至80℃下,用还原剂(例如硫、二氧化硫、三苯膦、硼氢化锂、硼氢化钠、三氯化磷、三溴化磷等)处理,可以从本发明化合物的N-氧化物制备本发明化合物的未氧化形式。
借助本领域普通技术人员已知的方法可以制备本发明化合物的前药衍生物(例如,关于进一步细节参见Saulnier等人,(1994),Bioorganic andMedicinal Chemistry Letters,第4卷,第1985页)。例如,使未衍生化的本发明化合物与适宜的氨甲酰化剂(例如1,1-酰氧基烷基碳酰氯(carbanochloridate)、碳酸对硝基苯基酯等)反应,可以制备适当的前药。
借助本领域普通技术人员已知的手段可以制备本发明化合物的被保护的衍生物。可用于产生和除去保护基团的技术的详细说明可以参见T.W.Greene,“Protecting Groups in Organic Chemistry”,第3版,JohnWiley and Sons,Inc.,1999。
本发明化合物可以适宜被制成或者在本发明方法期间生成溶剂化物(例如水合物)。使用有机溶剂如二烯、四氢呋喃或甲醇,从水性/有机溶剂混合物中重结晶,可以适宜地制备本发明化合物的水合物。
使化合物的外消旋混合物与旋光活性拆分剂反应生成一对非对映异构化合物,分离非对映异构体并回收旋光纯的对映异构体,可以将本发明化合物制成它们的单一立体异构体。尽管使用本发明化合物的共价非对映异构体衍生物可以进行对映异构体的拆分,不过可离解的配合物是优选的(例如结晶性非对映异构体盐)。非对映异构体具有不同的物理性质(例如熔点、沸点、溶解度、反应活性等),利用这些不同可以容易地分离。非对映异构体可以借助色谱法分离,或者优选通过基于溶解度差异的分离/拆分技术来分离。然后借助任意不会导致外消旋化的实用手段回收旋光纯的对映异构体以及拆分剂。可用于从外消旋混合物中拆分化合物的立体异构体的技术的更详细说明可以参见Jean Jacques,Andre Collet,Samuel H.Wilen,“Enantiomers,Racemates and Resolutions”,John Wiley and Sons,Inc.,1981。
总之,制备式I化合物的方法可包括:
(a)反应流程1或2的方法;和
(b)任选将本发明化合物转化为可药用盐;
(c)任选将本发明化合物的盐形式转化为非盐形式;
(d)任选将本发明化合物的未氧化形式转化为可药用的N-氧化物;
(e)任选将本发明化合物的N-氧化物形式转化为其未氧化形式;
(f)任选从异构体混合物中拆分出本发明化合物的单一异构体;
(g)任选将未衍生化的本发明化合物转化为可药用的前药衍生物;和
(h)任选将本发明化合物的前药衍生物转化为其未衍生化的形式。
只要没有具体描述原料的生产,这些化合物是已知的或者可以类似于本领域已知的方法或如下文实施例的公开加以制备。
本领域技术人员将领会到,上述转化仅仅是本发明化合物的制备方法的示例,其它已知方法可类似地被采用。
实施例
下列中间体和实施例进一步例证但不限制本发明,它们阐述根据本发明的式I化合物的制备。
中间体4:(4-羟基-2-甲基-苯氧基)-乙酸甲酯
步骤A:将4’-羟基-3’-甲基苯乙酮1(25g,166.4mmol)和溴乙酸甲酯(25.5g,166.4mmol)溶于MeCN(600mL)。加入Cs2CO3(117.8g,332.9mmol),将混合物于室温搅拌过夜。将不溶性盐过滤和用MeCN洗涤后,除去溶剂,将剩余物溶于EtOAc,依次用1M HCl(3×500mL)和H2O(2×500mL)洗涤。将有机层干燥(MgSO4),过滤,浓缩,得到2,为白色固体。
步骤B:将(4-乙酰基-2-甲基-苯氧基)-乙酸甲酯2(33g,151.3mmol)、77%mCPBA(54.9g,264.8mmol)与p-TsOH(2.9g,15.1mmol)的DCM(650mL)溶液回流加热48小时。然后将反应混合物用1M KI(2×500mL)和NaHSO3(2×500mL)洗涤。将有机层干燥(MgSO4),过滤,浓缩,得到3,为褐色浆状物。
步骤C:将(4-乙酰氧基-2-甲基-苯氧基)-乙酸甲酯3(25g,105.0mmol)的无水MeOH(400mL)溶液与0.5M NaOMe的MeOH溶液(210mL,105.0mmol)合并,于室温搅拌1小时。将溶液用1M HCl中和,用H2O洗涤(2×500mL)。将有机层干燥(MgSO4),过滤,浓缩,得到4,为褐色固体:1H-NMR(400MHz,CD3OD)δ=6.65-6.51(m,3H),4.60(s,2H),3.75(s,3H),2.19 (s,3H).MS C10H13O4(M+H+)计算值197.1,实测值197.2
中间体6.(4-巯基-2-甲基-苯氧基)-乙酸乙酯
步骤A:将500mL三颈圆底烧瓶中加入氯磺酸(25mL,373.9mmol),用氮气净化,冷却至0℃。在氮氛围和剧烈搅拌下,滴加(2-甲基苯氧基)乙酸乙酯1(40g,206.2mmol)。将混合物于0℃搅拌90分钟,然后倾入冰-水(200mL)中。将混合物于室温另外搅拌45分钟后,过滤白色沉淀,用冰水洗涤,真空干燥,得到5,为白色固体。
步骤B:将(4-氯磺酰基-2-甲基-苯氧基)-乙酸乙酯5(25g,85.4mmol)和锡(50.8g,427mmol)混悬于EtOH中,冷却至0℃。滴加4 N HCl在二烷中的溶液(107mL,427mmol)后,将所得混合物回流加热3小时。然后将混合物真空浓缩,残余物溶于氯仿中,过滤。滤液真空浓缩,得到黄色油状物,将其经色谱法(二氧化硅,Hex/EtOAc梯度)纯化,得到6,为无色油状物:1H-NMR(400MHz,CDCl3)δ=7.14(m,1H),7.07-7.10(m,1H),6.59(m,1H),4.60(s,2H),4.25(q,J=7.1Hz,2H),3.33(s,1H),2.24(s,3H),1.29(t,J=7.1Hz,3H).MS C11H14O3S(M+H+)计算值227.1,实测值227.4
中间体8.(3-氯-4-羟基-苯基)-乙酸甲酯
步骤A:将3-氯-4-羟基-苯基)-乙酸7(20g,107mmol)溶于含有催化量浓H2SO4(2.5mL)的MeOH(250mL)中。将溶液回流加热过夜。蒸发溶剂,残余物溶于DCM中,用H2O(3×200mL)洗涤。有机层干燥(MgSO4),过滤并浓缩,得到8,为浅黄色固体:1H-NMR(400MHz,CD3OD)δ=7.21(d,J=2.1Hz,1H),7.01(dd,J=2.1Hz,J=8.3,IH),6.84(d,J=8.3Hz,1H),3.67(s,3H),3.54(s,2H).MS C9H10ClO3(M+H+)计算值201.0,实测值201.2
中间体11.(3-氯-4-巯基-苯基)-乙酸甲酯
步骤A:将3-(氯-4-羟基-苯基)-乙酸甲基酯8(4.1g,21.4mmol)、二甲基硫代氨基甲酰氯(3.2g,25.6mmol)、Et3N(5.9mL,42.8mmol)和DMAP(261mg,2.14mmol)溶于无水二烷(30mL)中,在氮气中回流加热16小时。将反应混合物冷却至室温,用EtOAc稀释,用H2O(3×50mL)洗涤。将有机层干燥(MgSO4)、过滤并浓缩,得到9,为无色油状物。
步骤B:将(3-氯-4-二甲基硫代氨基甲酰基氧基-苯基)-乙酸甲酯9(5.2g,18.1mmol)转移至配有温度计的250mL三颈圆底烧瓶中。加入十四烷(45mL),将混合物回流加热(250℃)过夜。冷却至室温后,滗出溶剂,残余的油状物用己烷洗涤数次,经色谱法(二氧化硅,Hex/EtOAc梯度)纯化,得到10,为棕色油状物。
步骤C:将(3-氯-4二甲基氨基甲酰基硫基-苯基)-乙酸甲酯10(3.1g,10.8mmol)溶于0.5M NaOMe的MeOH溶液中。将混合物回流加热4小时,然后用1M HCl酸化。蒸发有机溶剂,残余物萃取入EtOAc(50mL)中,用H2O(2×50mL)洗涤。将有机层干燥(MgSO4)、过滤并浓缩,纯化(二氧化硅,己烷/EtOAc梯度),得到11,为淡黄色油状物:1H-NMR(400MHz,CDCl3)δ=7.30-7.26(m,2H),7.06-7.03(m,1H)3.87(s,1H),3.69(s,3H),3.55(s,2H).MS C9H10ClO2S(M+H+)计算值217.0,实测值217.3
中间体13.[4-(3,5-二溴-苄氧基)-2-甲基-苯氧基]-乙酸甲酯
将4-羟基-2-甲基-苯氧基)-乙酸甲酯4(0-36g,1.8mmol)溶于无水乙腈(3mL)中。加入碳酸铯(1.31g,4mmol),然后加入3,5-二溴苄基溴12(0.78g,2.37mmol)。将混合物在氮氛围下搅拌18小时。过滤所得红色混悬液,固体再用乙腈洗涤,将所得澄清红色溶液浓缩至油状物。进行硅胶色谱法(10%至25%乙酸乙酯的己烷溶液),得到13,为油状物,其缓慢固化为灰白色结晶物质。1H-NMR(400MHz,CDCl3)δ=7.58(d,J=2Hz,1H),7.47(d,J=2Hz,2H),6.77(s,1H),6.64(m,2H),4.91(s,2H),4.58(s,2H),3.77(s,3H),2.26(s,3H).MS C17H17Br2O4(M+H+)计算值442.95,实测值442.9
中间体15.[4-(5-溴-4′-甲氧基-联苯-3-基甲氧基)-2-甲基-苯氧基]-乙酸甲酯
将4-(3,5-二溴-苄氧基)-2-甲基-苯氧基]-乙酸甲酯13(1.26g,2.8mmol)溶于二烷(2mL)中。加入4-甲氧基苯基硼酸14(0.45g,3mmol),然后加入水(0.2mL)、乙醇(0.2mL)、碳酸钾(0.48g,3.5mmol)和四(三苯膦)钯(0.2g,0.17mmol)。将混合物在氮氛围下搅拌并接受微波处理(170℃,6分钟)。过滤所得橙色混悬液,固体再次用二烷洗涤,将所得溶液采用反相HPLC纯化(C18柱子,50%至100%梯度ACN/水,含0.05%TFA),得到15,为油状物。1H-NMR(400MHz,CDCl3)(存在旋转异构体)δ=7.61-7.46(m,5H),6.96(m,2H),6.9-6.6(m,3H),5.06,4.98,和4.90(3s,总计达2H),4.56(s,2H),3.83(m,3H),3.77(s,3H),2.25(s,3H).MS C24H24BrO5(M+H+)计算值471.08,实测值471.3
中间体17.[4-(5-溴-4′-三氟甲基-联苯-3-基甲氧基)-2-甲基-苯氧基]-乙酸甲
酯
采用类似于合成15的方法来制备17,为固体。1H-NMR(400MHz,CDCl3)δ=7.71-7.65(m,5H),7.61(s,1H),7.56(s,1H),6.84(d,J=2.8Hz,1H),6.72(dd,J=8.8,2.8Hz,1H),6.67(d,J=8.8Hz,1H)5.03(s,2H),4.61(s,2H),3.80(s,3H),2.29(s,3H).MS C23H19BrF3O4(M+H+)计算值509.06,实测值509.0。
中间体18.[4-(3,5-二溴-苄基硫基)-2-甲基-苯氧基]乙酸乙酯
将4-巯基-2-甲基-苯氧基)-乙酸乙酯6(0.23g,1.02mmol)溶于无水乙腈(3mL)中。加入碳酸铯(0.47g,1.44mmol),然后加入3,5-二溴苄基溴12(0.38g,1.16mmol)。将混合物于室温在氮氛围下搅拌18小时。将所得红色混悬液倾入1N HCl水溶液(20mL)中。用二氯甲烷萃取,经MgSO4干燥,真空浓缩,得到油状物。进行硅胶色谱法(5%至25%乙酸乙酯的己烷溶液),得到18,为油状物。1H-NMR(400MHz,CDCl3)δ=7.51(s,1H),7.23(s,2H),7.12(d,J=2Hz,1H),7.06(dd,J=8.4,2.0Hz,1H),6.60(d,J=8.4Hz,1H),4.62(s,2H),4.26(q,J=6.8Hz,2H),3.85(s,2H),2.25(s,3H),1.29(t,J=6.8Hz,3H).MS C18H18Br2O3S(M+H+)计算值472.9,实测值472.9
中间体19.[3-氯-4-(3,5-二溴-苄氧基)-苯基]-乙酸甲酯
采用类似于合成中间体18的方法制备19。1H-NMR(400MHz,CDCl3)δ=7.63(s,1H),7.55(s,2H),7.34(d,J=2Hz,1H),7.11(dd,J=8.4,2.0Hz,1H),6.86(d,J=8.4Hz,1H),5.06(s,2H),3.70(s,3H),3.55(s,2H).MSC16H14Br2ClO3(M+H+)计算值446.9,实测值446.9
中间体20.[3-氯-4-(3,5-二溴-苄基硫基)-苯基]乙酸甲酯
采用类似于合成中间体18的方法制备20。1H-NMR(400MHz,CDCl3)δ=7.54(s,1H),7.35(m,3H),7.16(d,J=8.0Hz,1H),7.09(dd,J=8.0,1.2Hz,1H),4.02(s,2H),3.70(s,3H),3.57(s,2H).MS C16H14Br2ClO3(M+H+)计算值462.9,实测值462.8
实施例A1.[4-(3,5-双(4-三氟甲基苯基)-苄氧基)-2-甲基苯氧基]-乙酸
步骤A:将[4-(3,5-二溴-苄氧基)-2-甲基-苯氧基]-乙酸甲酯13(0.0375g,0.088mmol)溶于二烷(1mL)中。加入4-三氟甲基苯基硼酸(0.0514g,0.27mmol),然后加入水(0.01mL)、乙醇(0.01mL)、碳酸钾(0.0557g,0.4mmol)和四-(三苯膦)钯(0.117g,0.01mmol)。将混合物在氮氛围下搅拌并接受微波处理(170℃,10分钟)。将所得橙色混悬液过滤,固体再次用二烷洗涤,浓缩所得溶液,经硅胶色谱法(10%至25%乙酸乙酯的己烷溶液)纯化,得到[4-(3,5-双(4-三氟甲基苯基)-苄氧基)-2-甲基-苯氧基]-乙酸甲酯,为油状物。1H-NMR(400MHz,CDCl3)δ=7.77-7.64(m,8H),7.52(s,2H),7.34(s,1H),6.88(d,J=2.8Hz,1H),6.76(dd,J=9.0,2.8Hz,1H),6.68(d,J=9.2Hz,1H),5.14(s,2H),4.61(s,2H),3.80(s,3H),2.95(s,3H).19F-NMR(376MHz,CDCl3)δ=-62.4
步骤B:将上述步骤A的[4-(3,5-双(4-三氟甲基苯基)-苄氧基)-2-甲基-苯氧基]-乙酸甲酯粗品溶于二烷(2mL)中。加入固体氢氧化锂一水合物(18mg,0.44mmol,过量),然后加入水(0.2mL)。1小时后,将混合物浓缩至干。经反相HPLC纯化,得到[4-(3,5-双(4-三氟甲基苯基)-苄氧基)-2-甲基-苯氧基]-乙酸A1,为固体。1H-NMR(400 MHz,CDCl3)δ=7.67(m,9H),7.61(s,2H),6.82(d,J=2.8Hz,1H),6.72(dd,J=9.0,2.Hz,1H),6.64(d,J=9.2Hz,1H),5.08(s,2H),4.58(s,2H),2.22(s,3H).19F-NMR(376 MHz,CDCl3)δ=-62.4。未获得MS。
实施例A2.[4-(4-甲氧基-4″-三氟甲氧基-[1,1′;3′,1″]三联苯-5′-基甲氧
基)-2-甲基-苯氧基]-乙酸
将5-溴-3-(4-乙氧基-3-甲基-苯氧基甲基)-4′-甲氧基-联苯15(50mg,0.11mmol)和4-三氟甲氧基苯基硼酸(30mg,0.15mmol,1.3当量)溶于二烷(0.5mL)中。加入碳酸钾(38mg,0.27mmol)、水(0.05mL)和乙醇(0.05mL),然后加入四(三苯膦)钯(15.6mg,0.13mmol)。将混合物在氮氛围下搅拌并接受微波处理(170℃,10分钟).冷却,加入0.25mL 1N氢氧化锂水溶液,并于室温搅拌3小时,然后进行反相纯化,得到[4-(4-甲氧基-4″-三氟甲氧基-[1,1′;3′,1″]三联苯-5′-基甲氧基)-2-甲基-苯氧基]-乙酸A2.1H-NMR(400MHz,CDCl3)δ=7.50(m,3H),7.42(m,4H),7.17(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,2H),6.75(d,J=2.8Hz,1H),6.65(dd,J=8.8,2.8Hz,1H),6.58(d,J=8.8Hz,1H),5.17(s,2H),4.50(s,2H),3.73(s,3H),2.16(s,3H).19F-NMR(376 MHz,CDCl3)δ=-57.8.MS C30H26F3O6(M+H+)计算值539.17,实测值539.0
实施例A3.[2-甲基-4-(4″-三氟甲氧基-4-三氟甲基-[1,1′;3′,1″]三联苯-5′-基
甲氧基)-苯氧基]-乙酸
将4-(5-溴-4′-三氟甲基-联苯-3-基甲氧基)-2-甲基-苯氧基]-乙酸甲酯17(25mg,0.05mmol)和4-三氟甲氧基苯基硼酸(15mg,0.07mmol)溶于二烷(0.5mL)中。加入碳酸钾(15mg,0.11mmol)、水(0.05mL)和乙醇(0.05mL),然后加入四(三苯膦)钯(10mg,0.009mmol)。将混合物在氮氛围下搅拌并接受微波处理(170℃,10分钟)。冷却,加入0.25mL 1N氢氧化锂水溶液,并于室温搅拌3小时,然后进行反相纯化,得到[2-甲基-4-(4″-三氟甲氧基-4-三氟甲基-[1,1′;3′,1″]三联苯-5′-基甲氧基)-苯氧基]-乙酸A3。1H-NMR(400 MHz,CDCl3)δ=7.61(m,5H),7.52(m,4H),7.19(d,J=8.8Hz,2H),6.76(d,J=2.8Hz,1H),6.65(dd,J=8.8,2.8Hz,1H),6.58(d,J=8.8Hz,1H),5.00(s,2H),4.51(s,2H),2.16(s,3H).19F-NMR(376 MHz,CDCl3)δ=-57.8(s,3F),-62.4(s,3F).MS C30H22F6NaO5(M+Na+)计算值599.1,实测值598.8
重复上述实施例中所述的方法,采用适宜的原料,获得下表1中确定的式I化合物。
表1
实施例B1.{4-[4,6-双-(4-甲氧基-苯基)-嘧啶-2-基甲氧基]-2-甲基-苯氧基}-
乙酸
步骤A:将4,6-二羟基-2-甲基嘧啶21(1.03g,8.1mmol)混悬于2.5mL三氯氧化磷(27.3mmol)中。将混合物于95℃加热18小时。冷却,将混合物用二氯甲烷(100mL)稀释并过滤。然后将其用水、饱和碳酸氢钠水溶液和盐水洗涤,然后浓缩,得到4,6-二氯-2-甲基嘧啶22,为白色粉末。
1H-NMR(400MHz,CDCl3)δ=7.45(s,1H),2.77(s,3H).MS C5H5Cl2N2(M+H+)计算值162.99,实测值163.2
步骤B:将4,6-二氯-2-甲基嘧啶22(0.10g,0.6mmol)溶于二烷(1mL)中。加入4-甲氧基-苯基硼酸(0.32g,2.1mmol),然后加入水(0.01mL)、乙醇(0.01mL)、碳酸钾(0.40g,2.9mmol)和四(三苯膦)钯(0.13g,0.11mmol)。将混合物在氮氛围下搅拌并进行微波处理(170℃,5分钟)。将所得橙色混悬液过滤,固体再用二烷洗涤,过滤所得溶液,经硅胶色谱法(5%至25%乙酸乙酯的己烷溶液)纯化,得到4,6-双-(4-甲氧基-苯基)-2-甲基-嘧啶23,为油状物。1H-NMR(400MHz,CDCl3)δ=8.03(d,J=8.8 Hz,2H),7.70(s,1H),6.95(d,J=8.8 Hz,2H),3.82(s,6H),2.77(s,3H).MS C19H19N2O2(M+H+)计算值306.15,实测值306.9
步骤C:将4,6-双-(4-甲氧基-苯基)-2-甲基-嘧啶23(0.21g,0.7mmol)溶于4mL四氯化碳中。加入N-溴-琥珀酰亚胺(0.10g,0.56mmol),将混合物于75℃搅拌加热。加入固体2,2′-偶氮二异丁腈(AIBN)(0.01g,0.06mmol),将混合物于75℃搅拌24小时。冷却,用二氯甲烷稀释,用水、饱和NaHCO3水溶液和盐水洗涤,然后经固体Na2SO4干燥并浓缩,得到2-溴甲基-4,6-双-(4-甲氧基-苯基)-嘧啶24,为油状物。其未经进一步纯化用于下一步骤。1H-NMR(400MHz,CDCl3)δ=8.02(d,J=8.8Hz,2H),7.69(s,1H),6.94(d,J=8.8Hz,2H),3.82(s,2H)
步骤D:将(4-羟基-2-甲基-苯氧基)-乙酸甲酯4(0.13g,0.66mmol)溶于无水乙腈(3mL)中。加入碳酸铯(0.40g,1.2mmol),然后加入上述步骤C的2-溴甲基-4,6-双-(4-甲氧基-苯基)-嘧啶24。将混合物在氮氛围下于室温搅拌18小时。所得混悬液过滤,固体再用乙腈洗涤,浓缩所得澄清溶液,得到{4-[4,6-双-(4-甲氧基-苯基)-嘧啶-2-基甲氧基]-2-甲基-苯氧基}-乙酸甲酯25粗品,为油状物。MS C29H29N2O6(M+H+)计算值500.19,实测值500.1
步骤E:将上述步骤D的{4-[4,6-双-(4-甲氧基-苯基)-嘧啶-2-基甲氧基]-2-甲基-苯氧基}-乙酸甲酯25(0.14g,0.28mmol)溶于二烷(2mL)中。加入固体氢氧化锂一水合物(80mg,2.0mmol),然后加入水(0.2mL)。于室温搅拌5小时后,将混合物浓缩至干。经反相HPLC纯化,得到{4-[4,6-双(4-甲氧基-苯基)-嘧啶-2-基甲氧基]-2-甲基-苯氧基}-乙酸B1,为固体。MS C28H27N2O6(M+H+)计算值487.18,实测值487.2
实施例B2.{4-[2,6-双-(4-甲氧基-苯基)-嘧啶-4-基甲氧基]-2-甲基-苯氧基}-
乙酸
将类似于实施例B1的方法用于制备实施例B2,采用2,4-二氯-6-甲基嘧啶代替中间体22作为原料。1H-NMR(400 MHz,CDCl3)δ=8.49(d,J=8.8Hz,2H),8.19(d,J=8.8Hz,2H),7.71(s,1H),7.01(d,J=8.8Hz,4H),6.88(d,J=2.8Hz,1H),6.74(dd,J=8.8,2.8Hz,1H),6.67(d,J=8.8Hz,1H),5.19(s,2H),4.60(s,2H),3.89(s,6H),2.26(s,3H).MS C28H27N2O6(M+H+)计算值487.18,实测值487.2
重复上述实施例中所述的方法,采用适宜的原料,获得下表2中确定的化合物。
表2
转录测定
利用转染测定评估本发明化合物调节PPAR转录活性的能力。简言之,向哺乳动物细胞经瞬时转染引入嵌合蛋白的表达载体以及报道基因质粒(其中荧光素酶基因处于GAL4结合位点的控制之下),所述嵌合蛋白含有与PPARδ、PPARα或PPARγ的配体结合结构域(LBD)融合的酵母GAL4的DNA结合结构域。一旦暴露于PPAR调节剂,PPAR转录活性改变,借助荧光素酶水平可以监测这一点。如果转染细胞暴露于PPAR激动剂,则PPAR-依赖性转录活性增加且荧光素酶水平上升。
在实验开始前一天,将293T人胚胎肾细胞(8×106)接种在175cm2烧瓶中的10%FBS、1%青霉素/链霉素/两性霉素、DMEM培养基中。通过用PBS(30mL)洗涤、然后用胰蛋白酶(0.05%;3mL)分离来收获细胞。加入测定培养基(DMEM,CA-葡聚糖胎牛血清(5%)),使胰蛋白酶失活。将细胞自旋,重新悬浮至170,000个细胞/mL。制备GAL4-PPAR LBD表达质粒(1μg)、UAS-荧光素酶报道基因质粒(1μg)、Fugene(3∶1比率;6μL)与无血清培养基(200μL)的转染混合物,于室温温育15-40分钟。向细胞加入转染混合物,得到0.16M细胞/mL,然后将细胞(50μL/孔)平板接种到384孔白色实底的经过TC-处理的平板中。将细胞在37℃和5.0%CO2下进一步温育5-7小时。制备每种供试化合物在DMSO中的12点系列稀释液(3倍系列稀释),起始化合物浓度为10μM。向测定平板中的每孔细胞加入供试化合物(500nL),将细胞在37℃和5.0%CO2下温育18-24小时。向每孔加入细胞溶解产物/荧光素酶测定缓冲液Bright-GloTM(25%;25μL;Promega)。进一步于室温温育5分钟后,测量荧光素酶活性。
通过将原始荧光值除以各平板上的DMSO对照值对其进行标准化。分析标准化数据,采用Prizm图形拟合程序拟合剂量-响应曲线。EC50被定义为化合物引起最大与最小值之间的半数响应的浓度。将由化合物引起的响应与参比PPAR调节剂所得最大值进行比较,计算相对功效(或功效百分比)。
游离或可药用盐形式的式I化合物表现出宝贵的药理性质,例如本申请所述的体外试验所示。本发明化合物优选具有小于1μM、更优选小于500nM、更优选小于100nM的PPARδEC50。本发明化合物对PPARδ的选择性比PPARγ高至少100倍。
不言而喻,本文所述的实施例和实施方案仅供阐述目的,各种鉴于此的修改和变化将对本领域技术人员有所启示,并且包括在本申请的宗旨和范围以及所附权利要求的范围之内。本文引用的所有出版物、专利和专利申请出于各种目的引入本文作为参考。
Claims (13)
1、式I化合物及其可药用盐、水合物、溶剂化物、异构体和前药:
其中
m是选自0、1、2和3的整数;
Z1、Z2和Z3是独立地选自CH和N的成员;
L1选自-XOX-和-XS(O)0-2X-;其中X独立地选自价键和G1-4亚烷基;其中L1的任意亚烷基任选被1至3个选自卤代、C1-6烷基、C1-6烷氧基、卤代-C1-6烷基和卤代-C1-6烷氧基的基团取代;
R6和R7独立地选自-R10和-yR10;其中Y选自C1-6亚烷基、C2-6亚烯基和C2-6亚炔基;且R10选自C3-12环烷基、C3-8杂环烷基、C6-10芳基和C5-13杂芳基;
其中R10的任意芳基、杂芳基、环烷基和杂环烷基任选被1至3个基团取代,所述基团独立地选自卤代、硝基、氰基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基、卤代-C1-6烷氧基、-XS(O)0-2XR11、-XS(O)0-2XR12、-X-NR11R11、-XNR11XR12和-XOXR12;其中X是价键或C1-4亚烷基;R11选自氢和C1-6烷基;且R12选自C3-12环烷基、C3-8杂环烷基、C6-10芳基和C5-10杂芳基;其中R12的任意芳基、杂芳基、环烷基和杂环烷基任选被1至3个基团取代,所述基团独立地选自卤代、硝基、氰基、C1-6烷基、C1-6烷氧基、卤代-C1-6烷基和卤代-C1-6烷氧基;
R8选自卤代、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基、卤代-C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-12环烷基和C3-5杂环烷基;其中R8的任意芳基、杂芳基、环烷基和杂环烷基任选被1至3个基团取代,所述基团独立地选自卤代、硝基、氰基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基和卤代-C1-6烷氧基;
R9选自-XOXC(O)OR11和-XC(O)OR11;其中X是价键或C1-4亚烷基;且R11选自氢和C1-6烷基。
2、权利要求1的化合物,其中:
m是选自0-3的整数;
Z1、Z2和Z3是独立地选自CH和N的成员;
L1选自-XOX-和-XSX-;其中X独立地选自价键和C1-4亚烷基;
R6和R7独立地选自-R10和-YR10;其中Y选自C1-6亚烷基和C2-6亚烯基;且R10选自C6-10芳基和C5-13杂芳基;其中R10的任意芳基或杂芳基任选被1至3个基团取代,所述基团独立地选自卤代、氰基、C1-6烷基、C1-6烷氧基、羟基-C1-6烷基、卤代-C1-6烷基、卤代-C1-6烷氧基、-XS(O)0-2XR11、-XNR11R11和-XOXR12;其中X是价键或C1-4亚烷基;R11选自氢和C1-6烷基;且R12是C6-10芳基;
R8是C1-6烷基;且
R9是-XOXC(O)OR11;其中X是价键或C1-4亚烷基;且R11选自氢和C1-6烷基。
3、权利要求2的化合物,具有式Ia结构:
其中:
Z1、Z2和Z3是独立地选自CH和N的成员;
L1选自-CH2O-、-OCH2-、-CH2S-和-SCH2-;
R6和R7独立地选自-R10和-YR10;其中Y是亚丙烯基;且R10选自苯基、联苯基、萘基、苯并[b]呋喃基、吡啶基、嘧啶基、二苯并呋喃-2-基、呋喃基、苯并[b]噻吩、噻吩基和喹啉基;其中R10的任意芳基或杂芳基任选被1至3个基团取代,所述基团独立地选自卤代、氰基、甲基、羟基-甲基、甲硫基、甲氧基、三氟甲基、三氟甲氧基、苯氧基、乙磺酰基和二甲基氨基。
4、权利要求3的化合物,具有式Ib结构:
其中:
R6选自-R10和-YR10;其中Y是亚丙烯基;且R10选自苯基、联苯基、萘基、苯并[b]呋喃基、吡啶基、嘧啶基、二苯并呋喃-2-基、呋喃基、苯并[b]噻吩、噻吩基和喹啉基;其中R10的任意芳基或杂芳基任选被1至3个基团取代,所述基团独立地选自卤代、氰基、甲基、羟基-甲基、甲硫基、甲氧基、三氟甲基、三氟甲氧基、苯氧基、乙磺酰基和二甲基氨基;且
R13选自甲氧基、三氟甲基和三氟甲氧基。
5、治疗动物疾病或疾患的方法,其中PPARδ活性的调节能够预防、抑制或改善该疾病的病理学和/或症状学,该方法包含对该动物给予治疗有效量的权利要求1的化合物。
6、权利要求5的方法,其中该疾病或疾患选自血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、动脉粥样化形成、高甘油三酯血症、心力衰竭、心肌梗塞、血管疾病、心血管疾病、高血压、肥胖、恶病质、炎症、关节炎、癌症、食欲缺乏、神经性食欲缺乏、食欲过盛、阿尔茨海默氏病、皮肤疾患、呼吸系统疾病、眼部疾患、易激性肠病、溃疡性结肠炎、节段性回肠炎、1型糖尿病、2型糖尿病和X综合征的治疗或预防。
7、权利要求5的方法,其中该疾病或疾患选自HIV消瘦综合征、长期危重疾病、肌肉质量和/或肌肉强度降低、瘦体重下降、老年人肌肉强度和功能的维持、肌肉耐力和肌肉功能下降以及老年人衰弱。
8、权利要求1至4任一项的化合物在制备用于治疗动物疾病的药物中的用途,所述疾病中PPARδ活性对该疾病的病理学和/或症状学有作用。
9、药物组合物,包含治疗有效量的权利要求1至4任一项的化合物与一种或多种可药用赋形剂的组合。
10、药物组合,尤其是药物组合物,包含:1)权利要求1至4任一项的化合物或其可药用盐;和2)至少一种选自如下的活性成分或其各自的可药用盐;和任选的可药用载体:
a)抗糖尿病剂,例如胰岛素、胰岛素衍生物和模拟物;胰岛素促分泌剂,例如磺脲类,例如格列吡嗪、格列本脲和亚莫利阿玛尔;促胰岛素磺脲受体配体,例如格列奈类,例如那格列奈和瑞格列奈;胰岛素敏化剂,例如蛋白酪氨酸磷酸酶-1B(PTP-1B)抑制剂,例如PTP-112;GSK3(糖原合成酶激酶-3)抑制剂,例如SB-517955、SB-4195052、SB-216763、NN-57-05441和NN-57-05445;RXR配体,例如GW-0791和AGN-194204;钠依赖性葡萄糖协同转运蛋白抑制剂,例如T-1095;糖原磷酸化酶A抑制剂,例如BAY R3401;双胍类,例如甲福明;α-糖苷酶抑制剂,例如阿卡波糖;GLP-1(高血糖素样肽-1)、GLP-1类似物如Exendin-4和GLP-1模拟物;二肽基肽酶IV抑制剂,例如DPP728、vildagliptin、MK-0431、saxagliptin、GSK23A;AGE断裂剂;噻唑烷酮衍生物(格列酮),例如吡格列酮、罗格列酮或(R)-1-{4-[5-甲基-2-(4-三氟甲基-苯基)-唑-4-基甲氧基]-苯磺酰基}-2,3-二氢-1H-吲哚-2-甲酸,非格列酮型PPARγ激动剂,例如GI-262570;
b)降血脂剂,例如3-羟基-3-甲基-戊二酰辅酶A(HMG-CoA)还原酶抑制剂,例如洛伐他汀、匹伐他汀、辛伐他汀、普伐他汀、西立伐他汀、美伐他汀、维洛他汀、氟伐他汀、达伐他汀、阿托伐他汀、罗苏伐他汀和利伐他汀;角鲨烯合成酶抑制剂;FXR(法呢醇X受体)和LXR(肝X受体)配体;考来烯胺;贝特类;烟酸和阿司匹林;
c)抗肥胖剂或食欲调节剂,例如芬特明、来普汀、溴隐亭、右苯丙胺、苯丙胺、芬氟拉明、右芬氟拉明、西布曲明、奥利司他、右芬氟拉明、吗吲哚、芬特明、苯甲曲秦、安非拉酮、氟西汀、安非他酮、托吡酯、安非拉酮、苄非他明、苯丙醇胺或依考匹泮、麻黄碱、伪麻黄碱或大麻素受体拮抗剂;
d)抗高血压剂,例如髓袢利尿剂,例如依他尼酸、呋塞米和托塞米;利尿剂,例如噻嗪衍生物、氯噻嗪、氢氯噻嗪、阿米洛利;血管紧张素转化酶(ACE)抑制剂,例如贝那普利、卡托普利、依那普利、福辛普利、赖诺普利、莫昔普利、培哚普利、喹那普利、雷米普利和群多普利;Na-K-ATP酶膜泵抑制剂,例如地高辛;中性内肽酶(NEP)抑制剂,例如thiorphan、terteo-thiorphan、SQ29072;ECE抑制剂,例如SLV306;ACE/NEP抑制剂,例如奥马曲拉、山帕曲拉和法西多曲;血管紧张素II拮抗剂,例如坎地沙坦、依普罗沙坦、厄贝沙坦、氯沙坦、替米沙坦和缬沙坦,特别是缬沙坦;肾素抑制剂,例如阿利吉仑、特拉吉仑、地替吉仑、RO 66-1132、RO-66-1168;β-肾上腺素能受体阻滞剂,例如醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、美托洛尔、纳多洛尔、普萘洛尔、索他洛尔和噻吗洛尔;影响收缩力的物质,例如地高辛、多巴酚丁胺和米力农;钙通道阻滞剂,例如氨氯地平、苄普地尔、地尔硫、非洛地平、尼卡地平、尼莫地平、硝苯地平、尼索地平和维拉帕米;醛甾酮受体拮抗剂;和醛甾酮合成酶抑制剂;
e)增加HDL的化合物;
f)胆固醇吸收调节剂,例如Zetia和KT6-971;
g)Apo-A1类似物和模拟物;
h)凝血酶抑制剂,例如希美加群;
i)醛甾酮抑制剂,例如阿那曲唑、法倔唑、依普利酮;
i)血小板聚集抑制剂,例如阿司匹林、氯吡格雷硫酸氢盐;
k)雌激素、睾酮、选择性雌激素受体调节剂、选择性雄激素受体调节剂;
l)化学治疗剂,例如芳香酶抑制剂,例如弗隆、抗雌激素剂、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、微管活化剂、烷化剂、抗肿瘤抗代谢物、铂配合物、降低蛋白激酶活性的化合物,例如PDGF受体酪氨酸激酶抑制剂,优选伊马替尼或4-甲基-N-[3-(4-甲基-咪唑-1-基)-5-三氟甲基-苯基]-3-(4-吡啶-3-基-嘧啶-2-基氨基)-苯甲酰胺;和
m)与5-HT3受体相互作用的药物和/或与5-HT4受体相互作用的药物,例如替加色罗、替加色罗马来酸氢盐、西沙必利、西兰司琼。
11、治疗或预防下列疾病的根据权利要求9的药物组合物或根据权利要求11的组合:血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、高甘油三酯血症、心力衰竭、心肌梗塞、血管疾病、心血管疾病、高血压、肥胖、炎症、关节炎、癌症、阿尔茨海默氏病、皮肤疾患、呼吸系统疾病、眼部疾患、炎性肠病、IBD(易激性肠病)、溃疡性结肠炎、节段性回肠炎、其中牵涉有葡萄糖耐量降低、高血糖和抗胰岛素性的病症,例如1型与2型糖尿病、葡萄糖代谢降低(IGM)、葡萄糖耐量降低(IGT)、禁食葡萄糖降低(IFG)和X综合征。
12、用作药物的根据权利要求1至4任一项的化合物或根据权利要求10的药物组合物或根据权利要求11的组合。
13、根据权利要求1至4任一项的化合物或根据权利要求10的药物组合物或根据权利要求11的组合在制备药物中的用途,所述药物用于治疗或预防血脂异常症、高脂血症、高胆固醇血症、动脉粥样硬化、高甘油三酯血症、心力衰竭、心肌梗塞、血管疾病、心血管疾病、高血压、肥胖、炎症、关节炎、癌症、阿尔茨海默氏病、皮肤疾患、呼吸系统疾病、眼部疾患、炎性肠病、IBD(易激性肠病)、溃疡性结肠炎、节段性回肠炎、其中牵涉有葡萄糖耐量降低、高血糖和抗胰岛素性的病症,例如1型与2型糖尿病、葡萄糖代谢降低(IGM)、葡萄糖耐量降低(IGT)、禁食葡萄糖降低(IFG)和X综合征。
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US8080658B2 (en) | 2007-07-10 | 2011-12-20 | Idemitsu Kosan Co., Ltd. | Material for organic electroluminescent element and organic electroluminescent element employing the same |
EP2184277B1 (en) * | 2007-07-25 | 2015-07-01 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | Aryl pyrimidine derivatives, preparation methods and pharmaceutical uses thereof |
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CA2724737A1 (en) * | 2008-05-19 | 2009-11-26 | The University Of Tennessee Research Foundation | Pyrimidine non-classical cannabinoid compounds and related methods of use |
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BR112012019973B1 (pt) | 2010-02-09 | 2019-02-05 | Bayer Cropscience Ag | Derivados de ácido antranílico hidrazina-substituídos, misturas, compostos precursores,composições agroquímicas, processos para preparação dos referidos compostos e composições, uso dos compostos, das misturas ou das composições, e método para o controle de pragas animais |
KR20130087495A (ko) | 2010-06-15 | 2013-08-06 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | 안트라닐산 유도체 |
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FR2665159B1 (fr) * | 1990-07-24 | 1992-11-13 | Rhone Poulenc Sante | Nouveaux derives de la pyridine et de la quinoleine, leur preparation et les compositions pharmaceutiques qui les contiennent. |
JPH08333287A (ja) * | 1995-06-02 | 1996-12-17 | Fuji Yakuhin Kogyo Kk | 芳香環置換アルキルカルボン酸及びアルカノール誘導体とそれらを含有する抗血栓剤 |
CA2395298A1 (en) * | 2000-01-28 | 2001-08-02 | Novo Nordisk A/S | Propionic acid derivatives and their use in the treatment of diabetes and obesity |
US6555577B1 (en) | 2000-01-28 | 2003-04-29 | Novo Nordisk A/S | Compounds, their preparation and use |
JP2004525139A (ja) * | 2001-03-23 | 2004-08-19 | 中外製薬株式会社 | Flt−1リガンド、および血管形成により調節可能な疾患の治療におけるそれらの使用 |
US6875780B2 (en) * | 2002-04-05 | 2005-04-05 | Warner-Lambert Company | Compounds that modulate PPAR activity and methods for their preparation |
CA2503280A1 (en) * | 2002-10-28 | 2004-05-06 | Novo Nordisk A/S | Allyloxy and allylsulfanyl compounds and use thereof as ppar modulators |
US7968723B2 (en) * | 2004-05-05 | 2011-06-28 | High Point Pharmaceuticals, Llc | Compounds, their preparation and use |
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- 2005-05-13 MX MXPA06013195A patent/MXPA06013195A/es not_active Application Discontinuation
- 2005-05-13 KR KR1020067023755A patent/KR20070026503A/ko not_active Application Discontinuation
- 2005-05-13 US US11/596,598 patent/US7745445B2/en not_active Expired - Fee Related
- 2005-05-13 AU AU2005245418A patent/AU2005245418B2/en not_active Ceased
- 2005-05-13 CN CNA2005800196459A patent/CN1980894A/zh active Pending
- 2005-05-13 RU RU2006144121/04A patent/RU2006144121A/ru not_active Application Discontinuation
- 2005-05-13 WO PCT/US2005/016747 patent/WO2005113506A1/en active Application Filing
- 2005-05-13 JP JP2007513391A patent/JP2007537289A/ja active Pending
- 2005-05-13 CA CA002564365A patent/CA2564365A1/en not_active Abandoned
- 2005-05-13 BR BRPI0510024-0A patent/BRPI0510024A/pt not_active IP Right Cessation
- 2005-05-13 EP EP05751010A patent/EP1756062A4/en not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110914248A (zh) * | 2017-07-18 | 2020-03-24 | 菲尼克斯-Fxr股份有限公司 | 含有胺或(硫代)酰胺的lxr调节剂 |
Also Published As
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EP1756062A1 (en) | 2007-02-28 |
JP2007537289A (ja) | 2007-12-20 |
US7745445B2 (en) | 2010-06-29 |
EP1756062A4 (en) | 2008-01-02 |
AU2005245418B2 (en) | 2008-11-27 |
BRPI0510024A (pt) | 2007-09-25 |
AU2005245418A1 (en) | 2005-12-01 |
KR20070026503A (ko) | 2007-03-08 |
MXPA06013195A (es) | 2007-02-14 |
CA2564365A1 (en) | 2005-12-01 |
US20070259890A1 (en) | 2007-11-08 |
RU2006144121A (ru) | 2008-06-20 |
WO2005113506A1 (en) | 2005-12-01 |
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