CN102099360A - 作为黑色素浓集激素受体-1拮抗剂的羟基取代的噻吩并嘧啶酮 - Google Patents
作为黑色素浓集激素受体-1拮抗剂的羟基取代的噻吩并嘧啶酮 Download PDFInfo
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Abstract
本发明提供具有下式IA和IB的化合物,其可用作MCHR 1拮抗剂,且包括其前药和可药用盐:
Description
技术领域
本发明涉及噻吩并嘧啶酮非碱性黑色素浓集激素受体-1(MCHR1)拮抗剂、含有MCHR 1拮抗剂的药物组合物、制备所述MCHR 1拮抗剂的方法及采用所述MCHR 1拮抗剂治疗糖尿病、肥胖症和相关疾病的方法。
背景技术
几个系列的药理学证据和遗传学证据支持黑色素浓集激素受体-1(Melanin Concentrating Hormone Receptor-1)(下文称为“MCHR1”)作为食物摄取和体重调节剂的作用。对黑色素浓集激素(MCH)进行中枢给药增加了大鼠和小鼠的食物摄取和体重。对MCH进行长期ICV输注在小鼠中引起了增加的食物摄取和最终的肥胖症,而对MCH肽拮抗剂进行输注在饮食诱导的肥胖小鼠中阻断了MCH诱导的食物摄取并导致了体重减轻和进食减少。
MCH肽和受体的表达都是由营养状况调节的。MCH mRNA在饮食过多的(hyperphagic)肥胖小鼠(ob/ob)和禁食的动物中都被上调。对MCH肽的基因进行靶向断裂导致了饮食过少(hypophagia)和贫弱(1eanness)。MCHR1基因的断裂导致了贫弱、改变的代谢和轻度饮食过多所伴随的运动过多(hyperlocomotion)。相反地,MCH肽的过表达导致了饮食过多、肥胖症和糖尿病。在啮齿动物体重和进食模型中已显示小分子的MCHR1拮抗剂在口服给药和腹膜内给药后导致了体重减轻(Eur.J.Pharmaco1.,438:129-135(2002)、Nat.Med.,8:825-830(2002)和Eur.J.Pharmacol.,497:41-47(2004))。
也已报导MCHR1在急性实验性结肠炎和可能的人类IBD(炎性肠病)的发病机制中具有关键作用。已显示免疫中和是针对TNBS诱导结肠炎的有效治疗。Kokkotou,E.等人,“Melanin-concentrating hormone as a mediator ofintestinal inflammation”,PNAS,105(30):10613-10618(2008年7月29日)。
此外,也已报导MCH和MCHR1在对应激的内分泌和行为反应中发挥作用。用MCHR拮抗剂治疗大鼠和小鼠产生较强抗抑郁和抗焦虑效应。(JPETDOI:10.1124/jpet.108.143362)
已经披露了多种非肽的MCHR1拮抗剂。每种类别的范围都反映了有关识别配体为MCHR1激动剂所需标准的共同认知。有关MCHR1专利披露的最近综述通过以下描述强调了这些结构的共性:“Ubiquitous throughout theMCH patentliterature are molecules consisting of a central scaffold to whichlinkers to an aryl or heteroarylgroup and a basic amino functionality areattached”(T.J.Kowalski,T.J.et a1.,Exp.Opin.Invest.Drugs,13:1113-1122(2004))。这些类别的药效团模型一致地提出了拮抗剂配体的碱性胺中心和受体的天冬氨酸123之间假定的必要静电相互作用,认为所述作用大概模拟了MCH肽激动剂的精氨酸14与MCHR1受体的天冬氨酸123之间的强制性相互作用(Ulven,T.et al.,J.Med.Chem.,48:5684-5697(2005))。然而,在MCHR1拮抗剂中引入这种碱性胺基本增加了与非靶标离子通道(off-target ion-channel)和生物胺受体(biogenic amine receptor)结合的可能性。
2007年4月26日公开的美国专利公开2007/0093509A1披露一系列式A的新颖高亲和力选择性MCHR 1拮抗剂:
其中,
A是苯基或单环杂芳基;
D是CH2或直接键;
R1独立地选自氢、卤素、低级烷基、低级环烷基、CF3、OR6或SR6;
R2是氢或低级烷基;
R4是羟基或G-D2-Zn;
n是1至3的整数;
R5是氢、卤素、低级烷基、低级环烷基、CF3、SR6、低级烷氧基、低级环烷氧基、CN、CONR7R7、SOR6、SO2R6、NR7COR7、NR7CO2R7、CO2R6、杂芳基、NR7SO2R6或COR6;
G是O、S或CR7R7;
D2是直接键、低级烷基、低级环烷基或4至6元非碱性杂环基团;
Z是氢、羟基、低级烷氧基、低级环烷氧基、OCONR7R7、CN、CONR7R7、SOR6、SO2R6、NR7COR7、NR7CO2R7、CO2R6、杂芳基、NR6SO2R6或COR6;
R6独立地选自低级烷基或低级环烷基;且
R7独立地选自氢、低级烷基或低级环烷基,其中两个R7及其所连接的原子可任选形成4至7个原子的环。
发明内容
本发明涉及MCHR 1拮抗剂,其具有极优良的药效、药物代谢动力学和安全性分布(profiles),例如具有下式IA或IB(包括其所有立体异构体)的那些或其前药或可药用盐:
式IA的优选前药为选自乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯、磷酸酯和氨基酸酯的其前药酯或盐的形式;或者为选自磷酸酯缩醛(phosphateacetal)和O-葡萄糖苷的其前药醚或盐的形式。
一些优选前药酯基团具有下式:
其中R为烷基或氢且Ra为H、烷基或苄基。
根据本发明的一个方面,提供具有以下结构(包括其立体异构体)中的一种结构的化合物:
包括任一上述结构的可药用盐。
根据本发明的一个方面,提供具有以下结构IB(包括其所有立体异构体)的化合物或其前药或可药用盐:
式IB化合物的优选前药为选自乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯、磷酸酯和氨基酸酯的其酯或盐的形式;或者为选自磷酸酯缩醛和O-葡萄糖苷的其前药醚或盐的形式。
根据本发明的一个方面,式IB的前药酯为以下中的一种:
其中R为烷基或氢且Ra为H、烷基或苄基。
优选的式IB化合物具有以下结构(包括其立体异构体)中的一种结构:
或可为任一上述结构的可药用盐。
根据本发明的一个方面,提供药物组合物,其包含至少一种本申请所述的式IA或IB化合物,且可任选包括至少一种选自以下的额外治疗药剂:抗肥胖症药、抗糖尿病药、食欲抑制剂、胆固醇/脂质降低药和HDL升高药;以及至少一种可药用稀释剂或载体。
根据本发明的一个方面,提供药物组合,其包含至少一种式IA或IB化合物和至少一种选自以下的额外治疗药剂:抗肥胖症药、抗糖尿病药、食欲抑制剂、胆固醇/脂质降低药和HDL升高药。
本发明的优选药物组合包含式IA或IB化合物或其前药或其盐,以及抗糖尿病药或抗肥胖症药。
本发明也涉及具有式IA或IB的化合物(或其前药)在制造可用于治疗肥胖症、糖尿病、焦虑症、抑郁症或炎性肠病的药物中的用途。
本发明另外涉及具有下式中的一种的化合物:
本发明另外涉及将下述结构的酮经酶促还原为以下结构的醇的方法,该方法包含使所述酮与酮还原酶反应以将所述酮转化为醇
实施例1的B部分的酮
实施例1C部分的(R)-醇。
根据本发明的一个方面,提供制备式IA化合物的方法
以形成以下结构的(R)-醇
且使上述(R)-醇在有机溶剂存在下与以下结构的化合物缩合
以形成式IA化合物。
具体实施方案
定义
除非另有说明,本申请单独使用或作为另一个基团的部分使用的术语“低级烷基”包括含有1至8个碳的直链和支链烃,以及本申请单独使用或作为另一个基团的部分使用的术语“烷基”和“烷(alk)”包括在正链中含有1至20个碳优选1至10个碳更优选1至8个碳的直链和支链烃,例如甲基、乙基、丙基、异丙基、丁基、叔丁基、异丁基、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、它们的各种支链异构体等以及包括1至4个取代基的上述基团,所述取代基如卤素(例如F、Br、Cl或I)或CF3、烷基、烷氧基、芳基、芳基氧基、芳基(芳基)或联芳基、芳基烷基、芳基烷基氧基、烯基、炔基、环烷基、环烯基、环烷基烷基、环烷基烷基氧基、羟基、羟基烷基、酰基、烷酰基、杂芳基、杂芳基氧基、杂环烷基、芳基杂芳基、芳基烷氧基羰基、杂芳基烷基、杂芳基烷氧基、芳基氧基烷基、芳基氧基芳基、烷基氨基(alkylamido)、烷酰基氨基(alkanoylamino)、芳基羰基氨基、硝基、氰基、巯基、卤代烷基、三卤代烷基和/或烷基硫基。
除非另有说明,本申请单独使用或作为另一个基团的部分使用的术语“环烷基”包括含有1至3个环的饱和或部分不饱和(含有1或2个双键)的环烃基,所述1至3个环中的任何一个可任选为取代的螺环烷基(spirosubstituted cycloalkyl),所述环烃基包括单环烷基、二环烷基和三环烷基,其含有总共3至20个成环碳原子,优选3至10个成环碳原子,并且所述环烃基可与1或2个就芳基所述的芳族环稠合,所述环烃基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基、所述基团中的任何一个可任选被1至4个取代基取代,所述取代基如卤素、烷基、烷氧基、羟基、芳基、芳基氧基、芳基烷基、环烷基、烷基氨基、烷酰基氨基、氧代、酰基、芳基羰基氨基、硝基、氰基、巯基和/或烷基硫基和/或所述烷基取代基中的任何取代基。
本申请单独使用或作为另一个基团的部分使用的术语“卤素”或“卤代”是指氯、溴、氟以及碘和CF3,其中优选为氯或氟。
术语“金属离子”是指碱金属离子如钠、钾或锂和碱土金属离子如镁和钙、以及锌和铝。
术语“前药”涵盖术语“前药酯”和术语“前药醚”且可包括其可药用盐。本申请所用术语“前药酯”包括通过以下方式形成的酯和碳酸酯:采用本领域技术人员已知的操作使本发明化合物的一个或多个羟基与烷基、烷氧基或芳基取代的酰化剂或磷酸化剂反应以生成乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯、氨基酸酯和磷酸酯等。
所述前药酯的实施例包括
术语“前药醚”包括磷酸酯缩醛和O-葡萄糖苷。所述前药醚的代表性实例包括
在上式中,R为烷基或H,且Ra为H、烷基或苄基。
盐和立体异构体
本发明化合物(包括化合物IA和IB)在呈前药形式时可按盐形式存在,所述盐也在本发明范围内。优选为可药用(即无毒性,生理上可接受)盐。如果本发明化合物具有例如至少一个碱性中心,则其可形成酸加成盐。所述酸加成盐例如用无机强酸来形成,例如矿物酸,例如硫酸、磷酸或氢卤酸;用有机羧酸来形成,例如具有1至4个碳原子的烷羧酸,例如乙酸,其未经取代或经例如卤素取代为氯乙酸,例如饱和或不饱和二羧酸(例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸),例如羟基羧酸(例如抗坏血酸、羟基乙酸、乳酸、苹果酸、酒石酸或柠檬酸),例如氨基酸(例如天冬氨酸或谷氨酸或赖氨酸或精氨酸)、或苯甲酸;或用有机磺酸来形成,例如未经取代或经例如卤素取代的(C1-C4)烷基或芳基磺酸,例如甲基磺酸或对甲苯磺酸。如果希望,也可形成存在另一碱性中心的相应酸加成盐。具有至少一个酸性基团(例如COOH)的本发明化合物也可与碱形成盐。与碱形成的适合的盐例如为金属盐,例如碱金属盐或碱土金属盐,例如钠、钾或镁盐;或与氨或有机胺形成的盐,例如吗啉、硫吗啉、哌啶、吡咯烷、单低级烷基胺、二低级烷基胺或三低级烷基胺,例如乙胺、叔丁胺、二乙胺、二异丙胺、三乙胺、三丁胺或二甲基丙胺,或单羟基低级烷基胺、二羟基低级烷基胺或三羟基低级烷基胺,例如单乙醇胺、二乙醇胺或三乙醇胺。此外可形成相应内盐。本发明也包括不适于药物用途但可用于例如本发明游离化合物或其可药用盐的分离或纯化的盐。
本发明化合物的含有碱性基团的优选盐包括单氢氯化物、硫酸氢盐、甲烷磺酸盐、磷酸盐、硝酸盐或乙酸盐。
本发明化合物的含有酸性基团的优选盐包括钠、钾和镁盐以及可药用有机胺。
本发明涵盖本发明化合物的所有立体异构体,其呈混合物形式或呈纯或基本纯的形式。本发明化合物可在包括任何取代基在内的任何碳原子处具有不对称中心。因此,本发明化合物可按对映异构或非对映异构形式或按其混合物存在。制备方法可采用外消旋体、对映异构体或非对映异构体作为起始原料。在制备非对映异构或对映异构产物时,可通过常规方法将其分离,例如色谱法或分级结晶。
药物组合物和组合
根据本发明的一些实施例,提供药物组合物,其包含至少一种本申请所述化合物和至少一种可药用稀释剂或载体。本发明药物组合物可任选包括至少一种选自以下的额外治疗药剂:抗肥胖症药、抗糖尿病药、抗抑郁药剂、抗焦虑药、抗炎药、食欲抑制剂、胆固醇/脂质降低药和HDL升高药和本申请所定义的其它治疗药剂。
本发明也涉及药物组合,其包含至少一种本发明化合物和至少一种选自以下的额外治疗药剂:抗肥胖症药、抗糖尿病药、抗抑郁药剂、抗焦虑药、抗炎药、食欲抑制剂、胆固醇/脂质降低药和HDL升高药和本申请所定义的其它治疗药剂。
根据本发明的一个实施方案,所述抗糖尿病药选自:促胰岛素分泌剂、胰岛素敏化剂、葡糖激酶抑制剂、糖皮质激素拮抗剂、果糖1,6-二磷酸酶抑制剂、AMP激酶活化剂、肠降血糖素调节剂、葡糖苷酶抑制剂、醛糖还原酶抑制剂、PPAR γ激动剂、PPARα激动剂、PPAR δ拮抗剂或激动剂、PPARα/γ双重激动剂、11-β-HSD-1抑制剂、二肽基肽酶IV(DP4)抑制剂、SGLT2抑制剂如达利清(dapagliflozin)、胰岛素、胰高血糖素样肽-1(GLP-1)、GLP-1激动剂和PTP-1B抑制剂。
根据本发明的一个实施方案,额外治疗药剂为抗肥胖症药。与本发明化合物组合使用的适合抗肥胖症药的实例包括黑皮质素受体(MC4R)激动剂、大麻素受体调节剂、内源性大麻素合成调节剂、GPR119激动剂、脂肪吸收抑制剂、生长激素促分泌素受体(GHSR)拮抗剂、甘丙肽(galanin)受体调节剂、食欲肽(orexin)拮抗剂、SGLT2抑制剂、DPP4抑制剂、三重单胺再摄取抑制剂、CCK激动剂、GLP-1激动剂和其它前胰高血糖素原衍生的肽;NPY1或NPY5拮抗剂、NPY2和NPY4调节剂、促肾上腺皮质素释放因子调节剂、组胺受体-3(H3)调节剂、aP2抑制剂、PPARγ调节剂、PPAR δ调节剂、乙酰CoA羧化酶(ACC)抑制剂、硬脂酰Co-A去饱和酶-1(SCD-1)抑制剂、11-β-HSD-1抑制剂、脂联素受体调节剂;β3肾上腺素能激动剂、甲状腺受体β调节剂、脂酶抑制剂、5-羟色胺受体激动剂、单胺再摄取抑制剂或释放剂、厌食药、CNTF(睫状神经营养因子)、BDNF(脑源性神经营养因子)、瘦蛋白(leptin)和瘦蛋白受体调节剂、大麻素-1受体反激动剂/中性拮抗剂、DGAT抑制剂、阿片拮抗剂和支链淀粉(amylin)受体调节剂。
优选抗肥胖症药包括SGLT2抑制剂,例如美国专利6,414,126中所披露的那些。最优选的抗肥胖症药包括达利清和脂酶抑制剂,例如奥利司他(orlistat);或单胺再摄取抑制剂或释放剂,例如芬氟拉明(fenfluramine)、右芬氟拉明(dexfenfluramine)、氟伏沙明(fluvoxamine)、氟西汀(fluoxetine)、帕罗西汀(paroxetine)、舍曲林(sertraline)、对氯苯丁胺(chlorphentermine)、氯福雷司(cloforex)、氯特胺(clortermine)、匹西雷司(picilorex)、西布曲明(sibutramine)、右旋安非他命(dexamphetamine)、芬特明(phentermine)、苯丙醇胺(phenylpropanolamine)或马吲哚(mazindol)。
使用方法
根据本发明的一个实施方案,提供在需要治疗的患者中治疗肥胖症的方法,其包括单独给予或与一种或多种额外抗肥胖症药组合给予治疗有效量的至少一种本发明化合物,其中该肥胖症药剂选自本申请所述的那些。
根据本发明的一个实施方案,提供在需要治疗的患者中治疗糖尿病、尤其II型糖尿病的方法,其包括单独给予或与一种或多种额外抗糖尿病药组合给予治疗有效量的至少一种本发明化合物,其中该糖尿病药剂如本申请所述。
根据本发明的一个实施方案,提供在患者中治疗抑郁症的方法,其包括给予治疗有效量的至少一种本发明化合物。
根据本发明的一个实施方案,提供在需要治疗的患者中治疗焦虑症的方法,其包括给予治疗有效量的本发明化合物。
根据本发明的一个实施方案,提供治疗炎性肠病的方法,其包括给予治疗有效量的至少一种本发明化合物。
用途
可将本发明化合物给予哺乳动物(优选人类)以治疗各种病症和障碍,包括(但不限于)代谢和进食障碍以及与代谢障碍有关的病症(例如肥胖症、糖尿病、动脉硬化、高血压、多囊卵巢病、心血管疾病、骨关节炎、皮肤病、葡萄糖稳态受损、胰岛素抵抗、高胆固醇血症、高甘油三酯血症、胆结石(choletithiasis)、血脂障碍病症(dislipidemic conditions)、神经性贪食和强迫性进食障碍);睡眠障碍;和精神障碍,例如抑郁症、焦虑症、精神分裂症、精神性药物滥用(substance abuse)、认知增强和帕金森病(Parkinson′s disease)。
本发明描述的化合物可用于增强认知增强药的作用,这些认知增强药如乙酰胆碱酯酶抑制剂(例如他克林)、毒蕈碱受体-1激动剂(例如米拉美林(milameline))、烟碱性激动剂、谷氨酸受体(AMPA和NMDA)调节剂和亲神经性药物(neurotropic agent)(例如吡拉西坦(piracetam)、左乙拉西坦(levetiracetam))。用于与本发明化合物组合来治疗阿尔兹海默病和认知障碍的合适疗法的实例包括多奈哌齐、他克林、利凡斯的明(revastigraine)、5HT6、γ分泌酶抑制剂、β分泌酶抑制剂、SK通道阻断剂、Maxi-K阻断剂和KCNQ阻断剂。
本发明描述的化合物可用于增强用于治疗帕金森病的药物的作用。用于治疗帕金森病的药物的实例包括含有或不含有COMT抑制剂的左旋多巴、抗谷氨酸能药(antiglutamatergic drug)(金刚烷胺、利鲁唑(riluzole))、α-2肾上腺素能拮抗剂(如咪唑克生(idazoxan))、阿片拮抗剂(如纳曲酮(naltrexone))、其它多巴胺激动剂或运载体调节剂(transporter modulator)(如罗匹尼罗(ropinirole)或普拉克索(pramipexole))或神经营养因子(neurotrophic factor)(如神经胶质细胞衍生的神经营养因子(glial derived neurotrophicfactor(GDNF)))。
剂型
本发明化合物可按口服剂型来给药。用于所述药物组合物的剂型包括这样的口服剂型,如颗粒剂、粉末剂、片剂、胶囊剂、糖浆剂、乳剂、混悬剂等,以及用于所述药物组合物的剂型包括这样的非口服剂型,如注射剂(例如皮下注射剂、静脉内注射剂、肌内注射剂或腹膜内注射剂)、点滴输注剂(dripinfusion)、外用形式(例如鼻喷雾制剂、透皮制剂、软膏剂等)以及栓剂(例如直肠栓剂和阴道栓剂)。
这些剂型可通过药学操作中常规使用的本身已知的技术来制备。具体的制备操作如下。
为了制备口服剂型,例如将赋形剂(例如乳糖、蔗糖、淀粉、甘露醇等)、崩解剂(例如碳酸钙、羧甲基纤维素钙等)、粘合剂(例如α-淀粉、阿拉伯胶、羧甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素等)和润滑剂(例如滑石、硬脂酸镁、聚乙二醇6000等)加到一种或多种活性组分中,然后对得到的组合物进行压制。当需要时,通过本身已知的技术对经压制的产物进行包衣,用于掩味或肠溶或持续释放。可使用的包衣材料包括例如乙基纤维素、羟甲基纤维素、聚乙二醇、乙酸邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素和丙烯酸树脂(Rohm&Haas,Germany)(甲基丙烯酸(酯)-丙烯酸(酯)共聚物)。
注射剂通常可经由以下操作来制备。将一种或多种活性组分与以下物质一起溶解、混悬或乳化于水性媒介物(例如蒸馏水、生理盐水、林格溶液(Ringer’s solution)等)或油性媒介物(例如植物油(如橄榄油、芝麻油、棉籽油、玉米油等)或丙二醇)中,所述物质为分散剂(例如吐温80(Atlas Powder,U.S.A.)、HCO 60(Nikko Chemicals)、聚乙二醇、羧甲基纤维素、海藻酸钠等)、防腐剂(例如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苄醇、三氯叔丁醇、苯酚等)、等渗剂(例如氯化钠、甘油、山梨醇、葡萄糖、转化糖(inverted sugar)等)和其它添加剂。当期望时,也可加入增溶剂(例如水杨酸钠、乙酸钠等)、稳定剂(例如人血清白蛋白)、无痛剂(soothing agent)(例如苯扎氯铵、盐酸普鲁卡因等)和其它添加剂。
用于外用的剂型可如下制备:将一种或多种活性组分加工成固体、半固体或液体组合物。为了制备固体组合物,例如将一种或多种活性组分按原样或与以下物质在一起的混合物的形式加工成粉末剂,所述物质为赋形剂(例如乳糖、甘露醇、淀粉、微晶纤维素、蔗糖等)、增稠剂(例如天然胶、纤维素衍生物、丙烯酸(酯)聚合物等)等。液体组合物可按与上文提及的注射剂基本相同的方式来制备。半固体组合物优选按水性或油性凝胶剂形式或软膏剂形式提供。这些组合物可任选含有pH控制剂(例如碳酸、磷酸、枸橼酸、盐酸、氢氧化钠等)和防腐剂(例如对羟基苯甲酸酯、三氯叔丁醇、苯扎氯铵等)以及其它添加剂。
栓剂可如下制备:将一种或多种活性组分加工成油性或水性组合物,所述组合物为固体、半固体或液体。可使用的油性基质包括例如高级脂肪酸甘油酯[例如可可脂、Witepsols(Dinamit-Nobel)等]、中链脂肪酸[例如Migriols(Dinamit-Nobel)等]、植物油(例如芝麻油、大豆油、棉籽油等)等。水溶性基质包括例如聚乙二醇、丙二醇等。亲水性基质包括例如天然胶、纤维素衍生物、乙烯基聚合物(vinyl polymer)和丙烯酸(酯)聚合物等。
剂量
本发明药物组合物的剂量可参考各活性组分的推荐剂量来适当地确定,并可根据以下因素来适当地选择:接受者、接受者的年龄和体重、目前的临床状态、给药时间、剂型、给药方法和活性组分的组合以及其它因素。例如,胰岛素敏感度增强剂的成人剂量可选自以下剂量:0.01至30mg/kg体重(优选0.05至10mg/kg体重和更优选0.05至5mg/kg体重)的临床口服剂量范围或0.005至10mg/kg体重(优选0.01至10mg/kg体重和更优选0.01至1mg/kg体重)的临床肠胃外剂量范围。联用的具有不同作用模式的其它一种或多种活性组分也可按通过参考各推荐临床剂量范围而选择的剂量范围来使用。
本发明药物组合物中活性组分的比例可根据接受者、接受者的年龄和体重、目前的临床状态、给药时间、剂型、给药方法和活性组分的组合以及其它因素来适当地选择。
药物联用
本发明在其范围内包括药物组合物,所述药物组合物含有单独的或与药物载体或稀释剂组合的作为活性成分的治疗有效量的至少一种本发明化合物。任选地,本发明化合物可单独使用,或与可用于治疗上述病症的其它合适的治疗药物联用,所述其它合适的治疗药物包括抗肥胖症药、抗糖尿病药、食欲抑制剂、胆固醇/脂质降低药、HDL升高药、认知增强药、用于治疗神经变性的药物、用于治疗呼吸系统病症的药物、用于治疗肠病的药物、抗炎药、抗焦虑药、抗抑郁药、抗高血压药、强心苷(cardiac glycoside)和抗肿瘤药。
可通过将各活性组分一起或独立地与生理上可接受的载体、赋形剂、粘合剂、稀释剂等混合来组合或分开配制本发明药物组合。当独立配制活性组分时,可使用稀释剂等将各制剂临时混合并给予,或可在同时或在交错时间将其彼此独立地给予相同个体。因此,可在给予本发明黑色素浓集激素受体(MCHR)拮抗剂之前、同时、或之后给予所述其它一种或多种治疗药剂。
与本申请化合物联用的合适抗肥胖症药的实例包括:黑皮质素受体(MC4R)激动剂,大麻素受体调节剂,生长激素促分泌素受体(GHSR)拮抗剂,甘丙肽受体调节剂,食欲肽拮抗剂,CCK激动剂,GLP-1激动剂以及其它前胰高血糖素原衍生的肽,NPY1或NPY5拮抗剂,NPY2和NPY4调节剂,促肾上腺皮质激素释放因子激动剂,组胺受体-3(H3)调节剂,aP2抑制剂,PPARγ调节剂,PPARδ调节剂,乙酰辅酶A羧化酶(ACC)抑制剂,11-β-HSD-1抑制剂,脂联素受体调节剂,β3肾上腺素能激动剂,如AJ9677(Takeda/Dainippon)、L750355(Merck)或CP331648(Pfizer)或在美国专利5,541,204、5,770,615、5,491,134、5,776,983和5,488,064中披露的其它已知β3激动剂,甲状腺受体β调节剂,如在WO97/21993(U.Cal SF)、WO99/00353(KaroBio)和WO 00/039077(KaroBio)中披露的甲状腺受体配体,脂酶抑制剂,如奥利司他或ATL-962(Alizyme),5-羟色胺受体激动剂(例如BVT-933(Biovitrum)或氯卡色林(lorcaserin)(Arena)),单胺再摄取抑制剂或释放剂,如芬氟拉明、右芬氟拉明、氟伏沙明、氟西汀、帕罗西汀、舍曲林、对氯苯丁胺、氯福雷司、氯特胺、匹西雷司、西布曲明、右旋苯丙胺、芬特明、苯丙醇胺或马吲哚,厌食药,如托吡酯(topiramate)(Johnson&Johnson),CNTF(睫状体神经营养因子)/(Regeneron),BDNF(脑源性神经营养因子),瘦蛋白和瘦蛋白受体调节剂,大麻素-1受体反激动剂/中性拮抗剂,如SR-141716(Sanofi)或SLV-319(Solvay)和DGAT抑制剂如在WO2006/134317(A1)(Astra Zeneca)、WO 2006/044775(A2)(Bayer)、WO2006/06019020(A1)(Sankyo)、WO 2006/082010(A1)(Roche)、WO2004/047755(A2)(Japan Tobacco,Tularik)和WO 2005/0727401(A2)(Amgen,Japan Tobacco)中所述的那些。
与本发明化合物联用的合适抗糖尿病药的实例包括促胰岛素分泌剂或胰岛素敏化剂,其可包括双胍类、磺脲类、葡萄糖苷酶抑制剂、醛糖还原酶抑制剂、PPARγ激动剂(如噻唑烷二酮类)、PPARα激动剂(如苯乙酸衍生物(fibric acid derivative))、PPARδ拮抗剂或激动剂、PPARα/γ双重激动剂、11-β-HSD-1抑制剂、二肽基肽酶IV(DP4)抑制剂(包括saxagliptin、维格列汀(vildagliptin)和西他立叮(sitagliptin))、SGLT2抑制剂(包括dapagliflozin和serglifozin)、糖原磷酸化酶抑制剂和/或氯茴苯酸类以及胰岛素和/或胰高血糖素样肽-1(GLP-1)、GLP-1激动剂、SIRT活化剂(白藜芦醇)和/或PTP-1B抑制剂(蛋白质酪氨酸磷酸酶-1B抑制剂)。
所述抗糖尿病药可以是口服抗高血糖症药物,优选为双胍类如二甲双胍或苯乙双胍或它们的盐,优选为盐酸二甲双胍。当所述抗糖尿病药为双胍类时,所使用的本发明化合物与双胍类的重量比可在约0.001∶1至约10∶1优选约0.01∶1至约5∶1的范围内。
所述抗糖尿病药还可优选为磺脲类如格列本脲(glyburide)(也称为格列本脲(glibenclamide))、格列美脲(披露于美国专利4,379,785中)、格列吡嗪、格列齐特、氯磺丙脲、其它已知的磺脲类或作用于β细胞中ATP依赖性通道的其它抗高血糖药物,其中格列本脲和格列吡嗪是优选的,其可按同一口服剂型或分开口服剂型的形式给药。口服抗糖尿病药也可以是葡萄糖苷酶抑制剂如阿卡波糖(披露于美国专利4,904,769中)或米格列醇(披露于美国专利4,639,436中),其可按同一口服剂型或分开口服剂型的形式给药。
本发明化合物可与PPARγ激动剂联用,所述PPARγ激动剂如噻唑烷二酮类口服抗糖尿病药或其它胰岛素敏化剂(其在NIDDM患者中具有胰岛素敏感度作用),如罗格列酮(SKB)、吡格列酮(Takeda)、Mitsubishi的MCC-555(披露于美国专利5,594,016中)、Glaxo-Wellcome的GL-262570、恩格列酮(CP-68722,Pfizer)、达格列酮(CP-86325,Pfizer)、伊格列酮(isaglitazone)(MIT/J&J)、JTT-501(JPNT/P&U)、L-895645(Merck)、R-119702(Sankyo/WL)、NN-2344(Dr.Reddy/NN)或YM-440(Yamanouchi),优选为罗格列酮和吡格列酮。
本发明化合物可与PPARα/γ双重激动剂联用,所述PPARα/γ双重激动剂如MK-767/KRP-297(Merck/Kyorin)(如在K.Yajima,et al.,Am.J.Physiol.Endocrinol.Metab.,284:E966-E971(2003)中所述)、AZ-242(tesaglitazar;Astra-Zeneca)(如在B.Ljung,et al.,J.Lipid Res.,43:1855-1863(2002)中所述)、莫格他唑(muraglitazar)或美国专利6,414,002中披露的化合物。
本申请化合物可与抗高脂血症药物(anti-hyperlipidemia agent)或用于治疗动脉硬化的药物联用。降血脂药(hypolipidemic agent)的实例可以是HMGCoA还原酶抑制剂,其包括但不限于在美国专利3,983,140中披露的美伐他汀和相关化合物、在美国专利4,231,938中披露的洛伐他汀(美维诺林(mevinolin))和相关化合物、在美国专利4,346,227中披露的普伐他汀和相关化合物以及在美国专利4,448,784和4,450,171中披露的辛伐他汀和相关化合物。本申请可使用的其它HMG CoA还原酶抑制剂包括但不限于在美国专利5,354,772中披露的氟伐他汀、在美国专利5,006,530和5,177,080中披露的西立伐他汀(cerivastatin)、在美国专利4,681,893、5,273,995、5,385,929和5,686,104中披露的阿托伐他汀、在美国专利5,011,930中披露的匹伐他汀(pitavastatin)(Nissan/Sankyo的尼伐他汀(nisvastatin)(NK-104)或伊伐他汀)、在美国专利5,260,440中披露的Shionogi-Astra/Zeneca的罗苏伐他汀(维沙他汀(ZD-4522))以及在美国专利5,753,675中披露的相关他汀类化合物、在美国专利4,613,610中披露的甲羟戊酸内酯衍生物的吡唑类似物、在PCT申请WO86/03488中披露的甲羟戊酸内酯衍生物的茚类似物、在美国专利4,647,576中披露的6-[2-(取代的吡咯-1-基)-烷基)吡喃-2-酮及其衍生物、Searle的SC-45355(3-取代的戊二酸衍生物)二氯乙酸酯、在PCT申请WO 86/07054中披露的甲羟戊酸内酯的咪唑类似物、在法国专利2,596,393中披露的3-羧基-2-羟基-丙烷-膦酸衍生物、在欧洲专利申请0221025中披露的2,3-二取代的吡咯衍生物、2,3-二取代的呋喃衍生物和2,3-二取代的噻吩衍生物、在美国专利4,686,237中披露的甲羟戊酸内酯的萘基类似物、在美国专利4,499,289中披露的八氢萘类、在欧洲专利申请0142146A2中披露的美维诺林(洛伐他汀)的酮基类似物以及在美国专利5,506,219和5,691,322中披露的喹啉衍生物和吡啶衍生物。此外,适用于本申请的可用于抑制HMG CoA还原酶的膦酸化合物披露于GB 2205837中。
适于在本申请中使用的角鲨烯合成酶抑制剂包括但不限于在美国专利5,712,396中披露的α-膦酰基-磺酸酯类、Biller et al.,J.Med.Chem.,31,1869-1871(1998)所披露的物质(包括类异戊二烯(膦基-甲基)膦酸酯)以及其它已知的角鲨烯合成酶抑制剂(例如在美国专利4,871,721和4,924,024以及Biller,S.A.et al.,Curr.Pharm.Des.,2:1-40(1996)中披露的物质)。
此外,适于在本申请中使用的其它角鲨烯合成酶抑制剂包括Ortiz deMontellano,P.et al.,J.Med.Chem.,20:243-249(1977)所披露的萜类焦磷酸酯、Corey et al.,J.Am.Chem.Soc.,98:1291-1293(1976)所披露的法尼基二磷酸酯类似物A和前角鲨烯焦磷酸酯(PSQ-PP)类似物、McClard,R.W.et al.,J.Am.Chem.Soc.,109:5544(1987)所报道的膦基磷酸酯和Capson,T.L.,Ph.D.dissertation,Dept.Med.Chem.Univ.Utah,Abstract,Table of Contents,pp.16,17,40-43,48-51,Summary(June 1987)所报道的环丙烷类。
适于在本申请中使用的其它降血脂药包括但不限于苯乙酸衍生物,如非诺贝特、吉非贝齐、氯贝丁酯、苯扎贝特、环丙贝特、克利贝特等、在美国专利3,674,836中披露的普罗布考和相关化合物(优选为普罗布考和吉非贝齐)、胆汁酸多价螯合剂(例如考来烯胺、考来替泊和DEAE-葡聚糖凝胶(Policexide)和考来胶(Sankyo/Geltex))以及(Rhone-Poulenc)、E-5050(N-取代的乙醇胺衍生物)、伊马昔尔(HOE-402)、四氢抑脂素(tetrahydrolipstatin)(THL)、istigmastanylphos-phorylcholine(SPC,Roche)、氨基环糊精(Tanabe Seiyoku)、AjinomotoAJ-814(薁衍生物)、甲亚油酰胺(Sumitomo)、Sandoz 58-035、American Cyanamid CL-277,082和CL-283,546(二取代的脲衍生物)、烟酸、阿昔莫司、阿昔呋喃、新霉素、对氨基水杨酸、阿司匹林、在美国专利4,759,923中披露的聚(二烯丙基甲基胺)衍生物、季胺聚(二烯丙基二甲基氯化铵)和在美国专利4,027,009中披露的紫罗烯类以及其它已知的血清胆固醇降低药物。
其它降血脂药可以是如在以下文献中披露的ACAT抑制剂(其也具有抗动脉粥样硬化活性)或TS-962(Taisho Pharmaceutical Co.Ltd)以及F-1394、CS-505、F-12511、HL-004、K-10085和YIC-C8-434:Drugs of the Future,24:9-15(1999)(Avasimibe(阿伐麦布));Nicolosi et a1.,“The ACAT inhibitor,Cl-1011is effective in the prevention and regression of aortic faty streak area inhamsters”,Atherosclerosis(Shannon,Irel.),137(1):77-85(1998);Ghiselli,G.,“The pharmacological profile of FCE 27677:a hovel ACAT inhibitor with potenthypolipidemic activity mediated by selective suppression of the hepatic secretionofApoB100-containing lipoprotein”,Cardiovasc.Drug Rev.,16(1):16-30(1998);Smith,C.et al.,“RP 73163:a bioavailable alkylsulfinyl-diphenylimidazoleACAT inhibitor”,Bioorg.Med.Chem.Lett.,6(1):47-50(1996);Krause,B.R.etal.,Chapter 6:“ACAT Inhibitors:Physiologic Mechanisms for Hypolipidemicand Anti-Atherosclerotic Activities in Experimental Animals”,Inflammation:Mediators and Pathways,CRC Press,Inc.,publ.,Ruffolo,Jr.,R.R.et al.,eds.,pp.173-198(1995);Sliskovic et al.,“ACAT inhibitors:potential anti-atheroscleroticagents”,Curr.Med.Chem.,1(3):204-225(1994);和Stout et al.,“Inhibitors ofacyl-CoA:cholesterol O-acyl transferase(ACAT)as hypocholesterolemic agents.6.The first water-soluble ACAT inhibitor with lipid-regulating activity.Inhibitors ofacyl-CoA:cholesterol acyltransferase(ACAT).7.Development of a series ofsubstituted N-phenyl-N-[(1-phenylcyclopentyl)-methyl]ureas with enhancedhypocholesterolemic activity”,Chemtracts:Org.Chem.,8(6):359-362(1995)。
降血脂药可以是LDL受体活性的上调剂,例如MD-700(TaishoPharmaceutical Co.Ltd)和LY295427(Eli Lilly)。降血脂药可以是胆固醇吸收抑制剂,优选为Schering-Plough的SCH48461(依泽替米贝(ezetimibe))以及在Atherosclerosis,115:45-63(1995)和J.Med.Chem.,41:973(1998)中披露的物质。
其它脂质药物或脂质调节药物可以是胆固醇基转移蛋白(cholesteryltransfer protein)抑制剂(CETP),如Pfizer的CP-529,414以及WO/0038722以及EP 818448(Bayer)和EP 992496中披露的物质和Pharmacia的SC-744和SC-795以及CETi-1和JTT-705。
降血脂药可以是回肠Na+/胆汁酸协同转运蛋白抑制剂,如Drugs oftheFuture,24:425-430(1999)中披露的物质。可与本发明联用的ATP枸橼酸裂解酶(ATP citrate lyase)抑制剂可包括例如美国专利5,447,954中披露的物质。
其它脂质药物还包括植物雌激素化合物,如WO 00/30665中披露的物质,包括经分离的大豆蛋白、浓缩大豆蛋白(soy protein concentrate)或大豆粉(soy flour),以及异黄酮,如染料木黄酮(genistein)、黄豆苷元(daidzein)、大豆黄素(glycitein)或牛尿酚(equol),或WO 00/015201中披露的植物甾醇(phytosterol)、植物甾烷醇(phytostanol)或生育三烯酚(tocotrienol),如EP675714中披露的β-内酰胺胆固醇吸收抑制剂,HDL上调剂,如LXR激动剂、PPARα激动剂和/或FXR激动剂,如EP 1022272中披露的LDL分解代谢促进剂,如DE 19622222中披露的钠-质子交换抑制剂,如美国专利5,698,527和GB 2304106中披露的LDL受体诱导剂或甾体糖苷(steroidal glycoside),抗氧化剂,如WO 94/15592中披露的β-胡萝卜素、抗坏血酸、α-生育酚或视黄醇(retinol),以及维生素C,和抗高半胱氨酸药(antihomocysteine agent),如叶酸、叶酸盐(酯)、维生素B6、维生素B12和维生素E,WO 97/35576中披露的异烟肼,WO 97/48701中披露的胆固醇吸收抑制剂、HMG-CoA合成酶抑制剂或羊毛甾醇脱甲基酶抑制剂(lanosterol demethylase inhibitor),用于治疗血脂障碍的PPARδ激动剂,或WO 2000/050574中披露的固醇调节元件结合蛋白-1(sterol regulating element binding protein-1)(SREBP-1),例如鞘脂,如神经酰胺,或中性鞘磷脂酶(neutral sphingomyelenase,N-SMase)或其碎片。优选的降血脂药是普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀、匹伐他汀、罗苏伐他汀和依泽替米贝以及烟酸和/或考来胶。
本发明化合物还可与抗高血压药联用。与本发明化合物联用的合适抗高血压药的实例包括β肾上腺素能阻断剂、钙通道阻断剂(L-型和/或T-型)(例如地尔硫维拉帕米、硝苯地平、氨氯地平和mybefradil)、利尿剂(例如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟噻嗪、苄氟噻嗪、甲基氯噻嗪、三氯噻嗪、泊利噻嗪、苄噻嗪、依他尼酸、替尼酸、氯噻酮、呋塞米、musolimine、布美他尼、triamtrenene、阿米洛利、螺内酯)、肾素抑制剂、ACE抑制剂(例如卡托普利、佐芬普利、福辛普利、依那普利、ceranopril、西拉普利(cilazopril)、地拉普利、喷托普利、喹那普利、雷米普利、赖诺普利)、AT-1受体拮抗剂(例如氯沙坦、厄贝沙坦和缬沙坦)、ET受体拮抗剂(例如西他生坦(sitaxsentan)、阿曲生坦(atrsentan)和在美国专利5,612,359和6,043,265中披露的化合物)、双重ET/AII拮抗剂(例如在WO 00/01389中披露的化合物)、中性肽链内切酶(NEP)抑制剂、血管肽酶(vasopepsidase)抑制剂(双重NEP-ACE抑制剂)(例如奥马曲拉和gemopatrilat)以及硝酸脂。
MCHR1拮抗剂可用于治疗与肥胖症相关的其它疾病,包括睡眠障碍。因此,本发明描述的化合物可与治疗睡眠障碍的疗法联用。与本发明化合物联用的用于治疗睡眠障碍的合适疗法的实例包括褪黑激素类似物(melatoninanalog)、褪黑激素受体拮抗剂、ML1B激动剂、GABA受体调节剂、NMDA受体调节剂、组胺-3(H3)受体调节剂、多巴胺激动剂和食欲肽受体调节剂。
MCHR1拮抗剂可减少或缓解精神性药物滥用或成瘾性病症(addictivedisorder)。因此,大麻素受体调节剂与用于治疗成瘾性病症的药物的组合可降低剂量需要或改善目前成瘾性病症疗法的功效。用于治疗精神性药物滥用或成瘾性病症的药物的实例为选择性5-羟色胺再摄取抑制剂(SSRI)、美沙酮、丁丙诺啡(buprenorphine)、尼古丁和丁氨苯丙酮(bupropion)。
MCHR1拮抗剂可减少焦虑或抑郁,因此本发明描述的化合物可与抗焦虑药或抗抑郁药联用。与本发明化合物联用的合适抗焦虑药的实例包括苯并二氮杂类(benzodiazepine)(例如地西泮、劳拉西泮、奥沙西泮、阿普唑仑、氯氮、氯硝西泮、氯氮盐(酯)(chlorazepate)、哈拉西泮和普拉西泮)、5HT1A受体激动剂(例如丁螺环酮、氟辛克生(flesinoxan)、吉哌隆和伊沙匹隆)以及促肾上腺皮质激素释放因子(CRF)拮抗剂。
与本发明化合物联用的合适类别的抗抑郁药的实例包括去甲肾上腺素再摄取抑制剂(叔胺三环和仲胺三环)、选择性5-羟色胺再摄取抑制剂(SSRI)(氟西汀、氟伏沙明、帕罗西汀和舍曲林)、单胺氧化酶抑制剂(MAOI)(异卡波肼、苯乙肼、反苯环丙胺、司来吉兰)、单胺氧化酶的可逆性抑制剂(RIMA)(吗氯贝胺(moclobemide))、5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRI)(文拉法辛)、促肾上腺皮质激素释放因子(CRF)受体拮抗剂、α-肾上腺素受体拮抗剂和非典型抗抑郁药(丁氨苯丙酮、锂剂、奈法唑酮、曲唑酮和维洛沙嗪)。
常规抗精神病药与MCHR1拮抗剂的组合也可在治疗精神病或躁狂症中使症状降低作用得以增强。此外,这样的组合能引起快速的症状降低作用,这减少了对用抗精神病药进行长期治疗的需要。这样的组合也可降低对有效抗精神病剂量的需要,这使发展成通常由长期抗精神病治疗引起的运动功能障碍的可能性得以降低。
与本发明化合物联用的合适抗精神病药的实例包括以下类别的抗精神病药:吩噻嗪类(氯丙嗪、美索达嗪、硫利达嗪、醋奋乃静、氟奋乃静、奋乃静和三氟拉嗪)、硫代黄嘌呤类(thioxanthine)(氯普噻吨、替沃噻吨(thiothixene))、杂环二苯并氮杂蕈类(氯氮平、奥氮平和阿立哌唑)、丁酰苯类(氟哌啶醇)、二苯基丁基哌啶类(匹莫齐特)和吲哚酮类(molindolone)。与本发明化合物组合的具有潜在治疗价值的其它抗精神病药包括洛沙平、舒必利和利培酮。
本发明化合物与常规抗精神病药的组合就治疗如以上就躁狂症所述的精神分裂性障碍而言也可提供增强的治疗作用。本发明使用的精神分裂性障碍包括偏执型精神分裂症(paranoid schizophrenia)、错乱型精神分裂症(disorganized schizophrenia)、紧张型精神分裂症(catatonic schizophrenia)、混合型精神分裂症(undifferentiated schizophrenia)、残留型精神分裂症(residualschizophrenia)、精神分裂症样精神障碍(schizophreniform disorder)、情感分裂性精神障碍(schizoaffective disorder)、妄想性精神障碍(delusional disorder)、短时精神障碍和未指明的精神障碍(psychotic disorder not specified)。与本申请化合物组合的合适抗精神病药的实例包括上文提及的抗精神病药以及多巴胺受体拮抗剂、毒蕈碱性受体激动剂、5HT2A受体拮抗剂和5HT2A/多巴胺受体拮抗剂或部分激动剂(例如奥氮平、阿立哌唑、利培酮、齐拉西酮)。
制备方法
如方案1中所概述,通过式1A和1B的结构表示的本发明化合物可通过以下方法在一个步骤中制备:在有机溶剂如热EtOH或优选熔融苯酚中使式2化合物与式3化合物缩合来生成本发明化合物。
方案1
式2化合物可根据以引用方式全文并入本发明中的WO2003/033476中所述通过加热式4化合物与二甲基甲酰胺二甲基缩醛来制备。
式4化合物的制备描述于WO1998/49899中,将其全部内容通过引用方式并入本文。
式3的苯胺可通过以下方法制备:通过在溶剂如EtOH、MeOH中或在乙酸乙酯-醇共溶剂中使用催化剂如Pd/C催化氢化,还原式5a或5b硝基芳族化合物(方案1)。
或者,其中R1为环烷基环且虚线以及R2和R3都不存在的式5b化合物可通过以下方式来制备:例如使用酮还原酶如酮还原酶(KRED)112或酮还原酶(KRED)113(Biocatalytics,Inc.)对酮8实施酶促还原,或例如使用念珠菌SC16117(第56511号)对酮8实施微生物转化来产生醇5b。
或者,可通过在溶剂如EtOAc中用SnCl2还原式5a或5b化合物来生成式3的苯胺。
最容易地,其中R1为环烷基环且虚线以及R2和R3都不存在的式5b化合物可通过依序实施烷基化和还原自式6化合物来制备:其中需要在溶剂如DMF中,在碱如Cs2CO3或K2CO3存在下,用适当烷基化剂(例如式7所示的α-卤代酮)使化合物6烷基化,然后还原中间体酮8。还原可在非手性条件下采用试剂如NaBH4在溶剂如EtOH中实现,然后实施拆分;或者可选择地,可在手性条件下采用酶或手性试剂通过本领域技术人员容易获知的操作来实现。
可选择地,其中R1不存在且存在由虚线表示的取代碳环以及R2和R3的式5a化合物可通过以下方式直接制备:在介于100-180℃的温度,在溶剂(其含有充足NaH2PO4以在反应进行时缓冲pH)如85%MeCN/H2O中,以加热方式或通过微波来加热式6化合物的碱金属盐(Na或K)与式9环氧化物。
式9的环氧化物可商购或可采用本领域技术人员易于获知的操作容易地制备。
应理解,尽管在本发明中已根据具体描述的具体实施方案描述了本发明,但所述实施方案表现为对本发明一般原理的描述,且本发明并不受限于所述实施方案。一些不背离本发明真实主旨和范围的对任一给定物质、方法步骤或化学式的修改和改变对本领域技术人员而言容易显而易见,且所有所述修改和改变皆应视为在下文权利要求的范围内。
缩写
本发明采用以下缩写:
Ph=苯基
Bn=苄基
t-Bu=叔丁基
Me=甲基
Et=乙基
TMS=三甲基甲硅烷基
TBS=叔丁基二甲基甲硅烷基
THF=四氢呋喃
Et2O=乙醚
EtOAc=乙酸乙酯
DMF=二甲基甲酰胺
MeOH=甲醇
EtOH=乙醇
i-PrOH=异丙醇
HOAc或AcOH=乙酸
TFA=三氟乙酸
i-Pr2NEt=二异丙基乙胺
Et3N=三乙胺
DMAP=4-二甲基氨基吡啶
NaBH4=硼氢化钠
n-BuLi=正丁基锂
Pd/C=钯/碳
KOH=氢氧化钾
NaOH=氢氧化钠
LiOH=氢氧化锂
K2CO3=碳酸钾
NaHCO3=碳酸氢钠
Ar=氩气
N2=氮气
min=分钟
h或hr=小时
L=升
mL=毫升
μL=微升
g=克
mg=毫克
mol=摩尔
mmol=毫摩尔
meq=毫当量
RT=室温
sat或sat′d=饱和的
aq.=水溶液
TLC=薄层色谱
HPLC=高效液相色谱
LC/MS=高效液相色谱/质谱
MS或Mass Spec=质谱
NMR=核磁共振
mp=熔点
实施例
以下实施例用于更好地说明而非限制本发明一些优选实施方案。
在可能的情况下,采用模块收敛方法(modular convergent approach)来制备以下实施例,其中需要合成适当的苯胺,与甲酰胺缩合以生成生物活性噻吩并嘧啶酮,然后进行修饰以将醇部分转化为前药。
实施例1
A.2-溴-1-环丙基乙酮
遵循Calverley,M.J.等人在Tetrahedron Lett.,43:4609(1987)中描述的操作,在0℃,历时5min将Br2(21.72mL,422mmol)添加至1-环丙基乙酮(35.44g,421mmol)在MeOH(250mL)中的溶液。在低于10℃将所得深橙色溶液搅拌50min,此时发生褪色。在移除冰浴后,在20℃将混合物另外搅拌0.5h;随后添加30ml水。另外搅拌15min后,用90ml水稀释反应混合物,然后用200mL Et2O(4x)实施萃取。依序用1M Na2CO3(150ml)和盐水(100ml)洗涤合并的有机层,然后经无水MgSO4干燥。在过滤和使用旋转蒸发器浓缩后,得到呈无色油状物形式的粗产物。随后在13mm Hg实施蒸馏,得到40.9g 2-溴-1-环丙基乙酮,其为沸点为58-62℃的无色油状物。1H NMR(500MHz,CDCl3)δppm 0.95-1.03(m,2H),1.08-1.15(m,2H),2.13-2.21(m,1H),4.00(s,2H)。
B.1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙酮
将4-硝基愈创木酚钾盐水合物(31.7g,153mmol)和A部分中制备的2-溴-1-环丙基乙酮(29.4g,180mmol)在DMF(310mL)中的橙色悬浮液在80℃加热1h。LC-MS分析显示已完全转化为产物。将所得黄色反应混合物用水(932ml)稀释并搅拌4hr,同时所述混合物冷却至20℃。随后过滤得到黄色滤饼,将所述黄色滤饼用150mL H2O洗涤3遍并风干,得到34.6g 1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙酮,其为淡黄色固体。M.P.112-113℃1HNMR(400MHz,CDCl3):δppm 0.95-1.03(m,2H),1.13-1.18(m,2H),2.15-2.23(m,1H),3.95(s,3H)、4.86(s,2H),6.73(d,J=8.7Hz,1H),7.75(d,J=2.7Hz,1H),7.82(dd,J=8.7,2.7Hz,1H)。13C NMR(100MHz,CDCl3)δppm 205.2,152.7,149.1,117.3,111.6,106.9,73.5,56.3,17.1,12.0。HPLC:5.8min保留时间,98.7%API;柱SB C184.6×75mm;流速2.5ml/min;梯度溶剂系统:100%A:0%B至0%A:100%B,历时8min(溶剂A:10%MeOH-90%H2O+0.2%H3PO4;溶剂B:90%MeOH-10%H2O+0.2%H3PO4),在220nm检测。LC/MS:m/e 252.3(M+H);4min梯度;保留时间2.35min。
C.(R)-1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙醇(C部分(R)-醇)
C.制备(1)
在0℃,历时15min,向B部分中制备的1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙酮(34.6g,138mmol)在EtOH(356mL)中的黄色悬浮液添加NaBH4(3.1g,82mmol)。在移除冰浴后,使温度不超过20℃,同时再搅拌反应混合物35分钟。在此期间颜色逐渐变为更深的黄色。使用冰浴将搅拌着的反应混合物冷却至约10℃,然后小心地缓慢添加HOAc(12mL,210mmol),以使H2气逸出速率最小化。在气体逸出停止后搅拌0.5h,然后在真空下使用旋转蒸发器浓缩黄色悬浮液,以除去约300mL EtOH。进行过滤,在用H2O洗涤并风干后,得到淡黄色固体(28.7g)。随后进一步浓缩滤液,以除去大部分EtOH,从而导致形成更多沉淀,其在如上所述的过滤后,相当于另外4.9g期望产物。将两部分合并,得到33.6g外消旋1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙醇。
通过手性色谱法拆分,使用AD-H(3×25cm,5μm)柱,在手性SFC条件下拆分在2/1MeCN/i-PrOH(451mL)中的外消旋1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙醇(45.1g,mmol)。该色谱条件采用在35℃的CO2/i-PrOH的85/15混合物作为流动溶剂,流速为130mL/min,BPR压力保持在100巴且检测器波长为234nM。每次0.7mL注射液需要7min的运行时间。在234nm,基于SFC/UV面积%,使用分析性SFC条件测定R对映异构体的手性纯度大于99.9%。在真空下使用旋转蒸发器浓缩所得洗脱液,得到(R)-1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙醇,其为黄色油状物。随后将其溶于150ml EtOH中并再次浓缩,得到呈黄色油状物形式的标题化合物,其在高真空下干燥过夜后,固化形成淡黄色固体(20.9g)。M.P.77℃1HNMR(400MHz,CDCl3):δppm 0.30-0.37(m,1H),0.42-0.50(m,1H),0.55-0.69(m,2H),0.97-1.08(m,1H),2.40-2.70(bs,1H),3.41(ddd,J=8.3,8.3,2.7Hz,1H)、3.93(s,3H),4.10(dd,J=9.3,8.0Hz,1H),4.23(dd,J=9.3,2.7Hz,1H)、6.95(d,J=8.8Hz,1H),7.74(d,J=2.2Hz,1H),7.89(dd,J=8.8,2.2Hz,1H)。13CNMR(100MHz,CDCl3)ppm 153.7,149.2,141.7,117.6,111.5,106.7,74.4,73.5,56.2,13.4,2.7,2.0。HPLC:6.26min保留时间,98.7%API;柱SB C184.6×75mm;流速2.5ml/min;梯度溶剂系统:100%A:0%B至0%A:100%B,历时8min(溶剂A:10%MeOH-90%H2O+0.2%H3PO4;溶剂B:90%MeOH-10%H2O+0.2%H3PO4),在220nm检测。LC/MS:m/e=254.3(M+H)。
手性HPLC:通过HPLC色谱法,在35℃使用AD-H,25×4.6mm ID;5μm柱来评价光学纯度,其中流动相为CO2/异丙醇的80/20混合物,在100巴,流速为2mL/min。在这些条件下,在第7分钟时洗脱出期望的R对映异构体,然后在第8.5min时洗脱出S对映异构体。
C.制备(2)
采用得自Biocatalytics,Inc.的两种可商购酮还原酶(即KRED-112和KRED-113)将B部分的酮还原为对应的C部分的(R)-醇。反应在30℃于pH7.5的100mM磷酸盐缓冲液中进行,底物输入量为4-10mg/mL且酶输入量为2-5mg/mL。使用异丙醇和NADP再生还原过程所需的辅因子NADPH。也使用葡萄糖脱氢酶、NADP和葡萄糖再生此还原所需的辅因子NADPH。建立了反相和手性HPLC方法,以测定底物和产物浓度以及产物的对映体过量。
对于期望的C部分(R)-醇,两种酮还原酶KRED 112和KRED 113实现97-99%的产率和99.5%的对映体过量。结果如下表中所示:
B部分酮还原至C部分(R)-醇
(IPA-200μL,pH 7.5,30℃)
对于(S)-醇,采用上述操作,得自Julich Enzyme,Inc.的两种酮还原酶(即ADH试剂盒部件5/9和ADH试剂盒部件6/9)实现44-48%的产率和100%的对映体过量。
HPLC法
测定对映体过量的反相手性HPLC:
溶剂:溶剂A和B的梯度
A:0.05%TFA/水-甲醇(80∶20)
B:0.05%TFA/乙腈-甲醇(80∶20)
始于30%B,在25min时55%B,在30min时100%B,在40min时100%B
总时间40min,流速:0.5ml/min,室温
UV检测240和340nm。02.22
保留时间为:
(S)-醇保留时间:26.74min
(R)-醇保留时间:24.9min
B部分酮峰位于32.74min处
C.制备(3):选择性酶促还原过程
使用念珠菌(SC16117)还原B部分酮:使用念珠菌(SC16117)(第56511号)将B部分酮还原为对应的C部分(R)-醇。在28℃于含有2%葡萄糖、2%麦芽提取物、1%酵母提取物和0.5%蛋白胨的培养基中使培养物生长48小时。通过离心收集细胞,并以10%(w/v)细胞浓度使细胞悬浮于pH 7.0的50mM磷酸钾缓冲液中。向细胞补充5mg/mL底物、50mg/mL葡萄糖、5mg/mL NADP和5单位葡萄糖脱氢酶以再生此还原所需的NADPH。在28℃使反应进行24小时。通过HPLC来测定产物浓度和产物对映体过量。
念珠菌SC16117(第56511号)以67%产率和97%对映体过量产生期望(R)-醇。从细胞提取物将得自念珠菌SC16117的酮还原酶纯化至匀质。纯化蛋白将B部分酮还原为对应的具有100%对映体过量的C部分(R)-醇。使用葡萄糖、葡萄糖脱氢酶和NADP再生还原过程所需的辅因子NADPH。
D.(R)-2-(4-氨基-2-甲氧基苯氧基)-1-环丙基乙醇
向C部分中制备的(R)-1-环丙基-2-(2-甲氧基-4-硝基苯氧基)乙醇(20.90g,83mmol)在EtOH(546ml)中的溶液添加5%Pd/C(折干计算,Degussa类型,50%水含量(3.0g,0.705mmol))。在20℃使悬浮液氢化(1大气压H2,气球)2.5h;然后LC/MS分析显示反应完成。在通过垫过滤反应混合物且随后用EtOH洗涤滤饼后,在真空下使用旋转蒸发器浓缩滤液,得到(R)-2-(4-氨基-2-甲氧基苯氧基)-1-环丙基乙醇,其为棕色固体。M.P.71℃(18.34g,100%)。1H NMR(400MHz,CDCl3):δppm 0.18-0.27(m,1H)、0.38-0.43(m,1H),0.45-0.61(m,2H),0.82-0.92(m,1H),3.21(ddd,J=8.8,8.8,2.6Hz,1H)、3.80(s,3H),3.86(dd,J=10.1,8.8Hz,1H),4.09(dd,J=10.1,2.6Hz,1H),6.21(dd,J=8.3,2.7Hz,1H),6.29(d,J=2.7Hz,1H),6.78(d,J=8.3Hz,1H)。13C NMR(100MHz,CDCl3)δppm 151.2,142.1,140.8,118.7,106.9,100.5,76.5,74.4,55.7,12.9,2.5,1.6。HPLC:6.28min保留时间,98.5%API;柱SB C184.6×75mm;流速2.5ml/min;梯度溶剂系统:100%A:0%B至0%A:100%B,历时8min(溶剂A:10%MeOH-90%H2O+0.2%H3PO4;溶剂B:90%MeOH-10%H2O+0.2%H3PO4),在220nm检测。LC/MS:m/e 224.5(M+H);4min梯度。
E.(E)-5-(4-氯苯基)-3-(2-(二甲基氨基)亚甲基氨基)噻吩-2-甲酸甲酯
向可商购3-氨基-5-(4-氯苯基)噻吩-2-甲酸甲酯(75g,279mmo1)在EtOH(450mL)中的混合物添加1,1-二甲氧基-N,N-二甲基甲胺(56mL,420mmol)。将搅拌着的反应混合物加热至回流;然后悬浮液在30min内变为澄清溶液。LC/MS分析显示反应在4hr后完成。将混合物冷却至室温,然后在真空下使用旋转蒸发器浓缩,得到黄绿色油状物。在添加Et2O(100mL)后搅拌混合物,同时添加晶种。连续搅拌导致快速形成沉淀,通过过滤收集沉淀。在真空下干燥过夜后,得到74.9g淡黄色固体。浓缩滤液得到另外4.5g产物,从而得到总产率为79.4g(88%)的5-(4-氯苯基)-3-(2-(二甲基氨基)亚甲基氨基)噻吩-2-甲酸甲酯。1H NMR(400MHz,CDCl3):δppm 3.06(s,3H)、3.08(s,3H),3.81(s,3H),6.98(s,1H),7.33-7.38(m,2H),7.51-7.56(m,2H),7.68(s,1H)。13C NMR(100MHz,CDCl3)δppm 163.2,159.1,156.0,145.7,134.4,132.2,129.1,126.9,122.3,112.4,51.4,40.2,34.3。HPLC:6.14min保留时间,85.1%API;柱SB C184.6×75mm;流速2.5ml/min;梯度溶剂系统:100%A:0%B至0%A:100%B,历时8min(溶剂A:10%MeOH-90%H2O+0.2%H3PO4;溶剂B:90%MeOH-10%H2O+0.2%H3PO4),在220nm检测。LC/MS:m/e 323.3(M+H);4min梯度。
F.(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)-噻吩并[3,2-d]嘧啶-4(3H)-酮
将E部分中制备的5-(4-氯苯基)-3-((二甲基氨基)亚甲基氨基)噻吩-2-甲酸甲酯(85g,263mmol)、D部分中制备的苯胺(52g,233mmol)和苯酚(230g,2444mmol)的混合物在130℃加热30min。使所得黑色粘稠浆料冷却至室温,然后用Et2O(300mL)稀释。将所得混合物在室温搅拌20min,然后过滤。在用Et2O(600mL)洗涤滤饼后,HPLC指示产物含有6%苯酚。此外,一些产物保留在黑色滤液中。使滤饼溶于CH2Cl2(200mL)中生成橙色溶液,其在用Et2O(400mL)稀释并搅拌后生成沉淀。通过过滤收集所得固体并在烘箱中于40℃干燥,得到期望标题化合物,其为灰白色固体(81g,产率74.2%)。MP178-179℃1H NMR(400MHz,DMSO-d6)δppm 0.29-0.45(m,4H),0.91-1.01(m,1H),3.34-3.39(m,1H),3.79(s,3H),3.96-4.05(m,2H),7.04(dd,1H),7.13(d,J=8.2Hz,1H),7.19(s,1H),7.58(d,J=8.8Hz,2H),7.92(d,J=8.2Hz,2H),7.97(s,1H),8.40(s,1H)。13C NMR(100MHz,DMSO-d6)δppm 1.33,1.66,14.11,55.79,71.16,73.18,111.86,112.81,119.61,121.71,122.04,127.84,129.27,129.68,131.22,134.27,148.61,148.99,149.48,149.78,156.09,157.40。HPLC:8.29min保留时间,>99%API;柱SB C184.6×75mm;流速2.5ml/min;梯度溶剂系统:100%A:0%B至0%A:100%B,历时8min(溶剂A:10%MeOH-90%H2O+0.2%H3PO4;溶剂B:90%MeOH-10%H2O+0.2%H3PO4),在220nm检测。LC/MS:m/e 469.3(M+H);4min梯度。
手性HPLC:通过HPLC色谱法,在25℃使用OD,250×4.6mm ID;10μm柱来评价光学纯度,其中流动相为60%异丙醇和40%庚烷,流速为3mL/min。在这些条件下于第13.2分钟洗脱出期望的R对映异构体,然后在第19.7分钟洗脱出S对映异构体。
实施例2
6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮
A.3,3-二氟-N,N-二甲基环丁烷甲酰胺
在0℃将草酰氯(21.74mL,248mmol)滴加至3,3-二氟环丁烷羧酸(26g,191mmol;如以下文献中所述制备:Elend,D.等人,Syn.Comm.,35:657(2005))在CH2Cl2(500mL)和DMF(0.5mL)中的搅拌着的溶液中。使反应混合物达到室温并在室温搅拌1h,然后在室温使用旋转蒸发器以约50mm Hg的真空进行浓缩。在将THF(300mL)添加至所得残余物中后,使搅拌着的溶液冷却至0℃,然后添加Me2NH(478mL,955mmol)在THF中的2M溶液。在室温搅拌反应混合物0.5h后,在乙醚(ether)和5%Na2CO3水溶液之间分配混合物。有机层经MgSO4干燥并在室温真空浓缩。在CH2Cl2和水之间分配残余物,然后有机层经MgSO4干燥并在室温真空浓缩,得到3,3-二氟-N,N-二甲基环丁烷甲酰胺(24g,147mmol,产率77%),其为棕色半固体,以原样用于下一步骤中。1H NMR(400MHz,CDCl3)δppm 2.82-3.13(9H,m),2.62-2.79(2H,m)。
B.1-(3,3-二氟环丁基)-N,N-二甲基甲胺
在0℃将A部分中制备的3,3-二氟-N,N-二甲基环丁烷甲酰胺(24g,147mmol)在THF(500mL)中的溶液添加至氢化锂铝(7.5g,198mmol)在500mLTHF中的搅拌着的悬浮液中。使混合物达到室温。在室温搅拌反应混合物18h后,通过在搅拌下缓慢添加5℃的10mL 6N NaOH和5mL水使其淬灭。将混合物在室温搅拌0.5h,经Na2SO4干燥并过滤。通过使用Vigreux柱小心蒸馏大部分THF,将滤液浓缩至约30mL。在稍低压力下(约100-200mmHg)蒸馏剩余物质;该级份(20mL,沸点70-90℃)含有混杂有THF的标题化合物。用温和氮气流小心吹扫残余THF,得到1-(3,3-二氟环丁基)-N,N-二甲基甲胺(12g,80mmol,产率54.7%)。1H NMR(400MHz,CDCl3)δppm2.46-2.94(2H,m),2.38(2H,d,J=6.55Hz),2.16-2.28(9H,m)。
C.1-(3,3-二氟环丁基)-N,N-二甲基甲胺氧化物水合物
参考文献Cope,A.C.等人,Org.Syn.Coll.,IV:612-615;Doering等人,J.Am.Chem.Soc.,89(17):4534(1967)。
在5至22℃,历时2h将30%H2O2水溶液(18mL)滴加至B部分中制备的1-(3,3-二氟环丁基)-N,N-二甲基甲胺(12g,80mmol)在甲醇(100mL)中的搅拌着的溶液中。在室温搅拌20h后,另外添加30%H2O2(18mL)。3h后,以小份将在水(3mL)中的Pd黑浆料(150mg)添加至搅拌着的反应混合物中,使得可用冷却浴将温度维持在5至25℃之间。在室温将反应混合物搅拌1h,直至O2逸出停止。在过滤后,真空浓缩滤液,得到1-(3,3-二氟环丁基)-N,N-二甲基甲胺氧化物水合物(15g,半固体),其为浓稠无色油状物。1H NMR(400MHz,CD3OD)δppm 3.47(2H,d,J=5.29Hz),3.16(6H,s),2.75-2.92(3H,m),2.42-2.58(2H,m)。
D.1,1-二氟-3-亚甲基环丁烷
为了从样品除去大部分水,使用具有冷却至-78℃的收集瓶的蒸馏装置,在真空下(10mm)于100℃加热C部分中制备的1-(3,3-二氟环丁基)-N,N-二甲基甲胺氧化物水合物(15g,91mmol)。在除去水后,使温度逐渐升高至165℃。在约1h后,大部分起始原料已被热解(少量深棕色物质保留在蒸馏瓶中)。然后依序用5%HCl水溶液(3×3mL)和饱和NaHCO3(5ml)洗涤收集瓶的内容物。通过Na2SO4过滤有机层(烯烃),得到1,1-二氟-3-亚甲基环丁烷(5.5g,52.8mmol,产率58.2%),其为无色油状物。1H NMR(400MHz,CDCl3)ppm5.10(2H,quin,J=2.52Hz),2.77-3.57(4H,m)。
E.5,5-二氟-1-氧杂螺[2.3]己烷
在室温以小份将间氯过氧苯甲酸(74.6g,303mmol)添加至D部分中制备的1,1-二氟-3-亚甲基环丁烷(21.0g,202mmol)在CH2Cl2(600mL)中的搅拌着的溶液中。在添加期间用水浴冷却反应混合物。在约1h后开始轻微放热,因此需使用冰水混合物进一步冷却。历时3h使反应混合物达到室温。在室温搅拌16h后,添加另外的m-CPBA(10g)。将反应混合物在室温搅拌24h,然后在冰箱中于4℃储存过夜以沉淀出一些酸。在过滤后,用10%Na2CO3洗涤滤液。将有机层干燥(Na2SO4),使用Vigreux柱浓缩至约170mL。在约10mm将此物质快速蒸馏至-78℃阱中(采用两个串联阱以将损失最小化)。使用Vigreux柱将馏出液浓缩至约50mL的体积,得到CH2Cl2:5,5-二氟-1-氧杂螺[2.3]己烷的3∶1混合物(80g,200mmol,产率99%,通过NMR测量)。此物质不经进一步纯化就用于下一步骤中。1H NMR(400MHz,CDCl3δppm2.91-3.16(4H,m),2.88(2H,s)。
F.3,3-二氟-1-((2-甲氧基-4-硝基苯氧基)甲基)环丁醇
将E部分中制备的5,5-二氟-1-氧杂螺[2.3]己烷+3当量CH2Cl2(22.52g,0.06mol)、2-甲氧基-4-硝基苯酚钾(12.43g,0.060mol)和NaH2PO4·H2O(7.45g,0.054mol)在50mL MeCN-水(85∶15)中的混合物在130℃于钢弹(steel bomb)中加热3.5h。将反应混合物用EtOAc稀释,用5%Na2CO3洗涤,干燥(MgSO4)并浓缩。将粗产物从约150mL MTBE重结晶,得到3,3-二氟-1-((2-甲氧基-4-硝基苯氧基)甲基)环丁醇(11.2g,0.039mol,产率64.5%),其为淡黄色固体。在将母液浓缩至约50mL后,获得另外1.2g纯度稍低的期望产物。1HNMR(400MHz,CDCl3)δppm 7.89(1H,dd,J=8.94,2.64Hz),7.76(1H,d,J=2.77Hz),6.95(1H,d,J=9.06Hz),4.16(2H,s),3.94(3H,s),3.36(1H,s),2.73-2.92(4H,m)。
G.1-((4-氨基-2-甲氧基苯氧基)甲基)-3,3-二氟环丁醇
在50psi H2下将F部分中制备的3,3-二氟-1-((2-甲氧基-4-硝基苯氧基)甲基)环丁醇(32.0g,111mmol)和10%Pd/C(2.0g,1.879mmol)在700mLMeOH中的混合物搅拌1.5h。在过滤后浓缩滤液,得到1-((4-氨基-2-甲氧基苯氧基)甲基)-3,3-二氟环丁醇(28.9g,111mmol,定量产率),其为淡紫色固体。1H NMR(400MHz,CD3OD)δppm 6.68(1H,d,J=8.56Hz),6.35(1H,d,J=2.52Hz),6.16(1H,dd,J=8.31,2.52Hz),4.77(3H,br.s.),3.78(2H,s),3.68(3H,s),2.68-2.82(2H,m),2.38-2.56(2H,m)。
H.6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮
将实施例1的E部分中制备的(E)-5-(4-氯苯基)-3-((二甲基氨基)亚甲基-氨基)噻吩-2-甲酸甲酯(33.9g,105mmol)和G部分中制备的1-((4-氨基-2-甲氧基-苯氧基)甲基)-3,3-二氟环丁醇(27.2g,105mmol)和苯酚(200g)的搅拌着的混合物在135-140℃加热45min,同时通过LC监测反应。将混合物用甲醇(700mL)稀释,在室温搅拌15min并在室温静置过夜。将沉淀产物通过过滤分离,用冷冻甲醇洗涤并在真空下干燥,得到6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮(37g,73.3mmol,产率69.8%),其为白色固体。用Et2O和己烷稀释母液沉淀出更多固体,将其与MeOH一起研磨,得到1.8g第二批期望产物。MP 198-199℃1HNMR(400MHz,CDCl3)δppm 8.14(1H,s),7.66(2H,d,J=8.56Hz),7.54(1H,s),7.45(2H,d,J=8.56Hz),7.08(1H,d,J=8.56Hz),6.99(1H,d,J=2.27Hz),6.95(1H,dd,J=8.31,2.27Hz),4.14(2H,s),3.89(3H,s),2.72-2.93(4H,m)。13CNMR(126MHz,CDCl3)δppm 157.3,156.7,151.8,150.4,148.60(1C,s),148.0,135.7,131.4,131.4,129.4,127.6,123.1,120.8,119.4,115.7,117.6(dd,J=282,269.Hz),111.4,75.5,64.6(dd,J=18,8Hz),56.0,46.0(t,J=22.89Hz)。
实施例3至11
制备实施例1和2化合物的前药,以改良溶解性和暴露。采用标准条件生成所述两种醇的氨基酸酯。二元酸如草酸、丙二酸、琥珀酸和戊二酸各自半酯的制备例示于实施例7和11中。实施例3和8例示单磷酸酯的制备。
实施例3
二氢磷酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基酯
A.双(2-(三甲基甲硅烷基)乙基)二异丙基亚磷酰胺
在N2下,在配有温度探头和加料漏斗的250mL三颈烧瓶中使二异丙基亚磷酰胺二氯化物(diisopropylphosphoramidous dichloride)(10.8g,50.78毫摩尔)在Et2O(53mL)中的溶液冷却至0至-2℃。历时27-28分钟将2-(三甲基甲硅烷基)乙醇(12.6g;106.55毫摩尔)和Et3N(15.4g;152.19毫摩尔)在Et2O(84mL)中的溶液滴加至搅拌着的二异丙基亚磷酰胺二氯化物溶液中。温和放热(+1-2℃),并伴有浓稠白色悬浮液的形成。在20℃搅拌过夜后,过滤混合物。用Et2O将所得滤饼洗涤两次(每次30mL)。将合并的滤液用饱和NaHCO3水溶液洗涤(2×100mL),然后用盐水洗涤(40mL)。在经MgSO4干燥并在真空下于室温浓缩至干后,得到双(2-(三甲基甲硅烷基)乙基)二异丙基亚磷酰胺(18.12g;49.56毫摩尔;产率97.60%),其为透明无色液体。1H NMR δ(400MHz,CDCl3):3.90-3.78(m,4H),3.77-3.68(m,2H),1.31(d,J=6.6Hz,12H),1.17-1.12(m,4H),0.15(s,18H)。13C NMR δ(100MHz,CDCl3):60.7(2,d,JC-P=19.1Hz,2C),42.7(1,d,JC-P=12.7Hz,2C),24.6(3,d,JC-P=7.6Hz,4C),20.1(2,d,JC-P=7.6Hz,2C),-1.4(3,6C)。31P NMR δ(162MHz,CDCl3):143.5(s)。LC/MS:m/e(M+H);4min梯度;min保留时间。
B.双(2-(三甲基甲硅烷基)乙基)磷酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基酯
在20℃向配有回流冷凝器和温度探头并用N2吹洗的250mL三颈圆底烧瓶添加(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)-噻吩并[3,2-d]嘧啶-4(3H)-酮(6.33g;13.50毫摩尔)(在实施例1中制备)、1H-1,2,4-三唑(1.89g;27.02毫摩尔)和无水CH2Cl2(65mL)。向所得浓稠白色悬浮液中添加A部分中制备的双(2-(三甲基甲硅烷基)乙基)二异丙基亚磷酰胺(9.8g;26.80毫摩尔)。在N2下将搅拌着的反应混合物加热至回流(40℃内温),历时18hr。在18.25hr(HPLC显示在17.5hr后完全转化)后,使反应混合物冷却至-3至-4℃。随后滴加H2O2(8.8mL;100.14毫摩尔)导致高放热,其仅在停止添加时减弱。注意,放热仅发生在添加最初1.3-1.5mL期间;历时15分钟添加剩余H2O2根本不放热。在添加完成后,在0-5℃将反应物搅拌2hr,然后HPLC分析显示反应完成且反应相当彻底(约92.9-93AP)。通过历时12-15分钟滴加60mL 1N Na2S2O5淬灭反应。注意,由于最初15-20mL淬灭物产生放热,导致温度升高至17-18℃,因此需要冷却浴;剩余添加是吸热性的。在10-15℃将混合物搅拌20分钟,然后分离各相。(在有机层中未检测到过氧化物)。依序用70mL 1N HCl、65mL H2O和50mL盐水洗涤有机层,然后经4.5g MgSO4干燥。在通过过滤除去干燥剂后,在25托和低于30℃的浴下,使用旋转蒸发器将体积降低至约30mL。使残余物重溶解在65mL MTBE中;再次浓缩至约30-35mL,产生轻度混浊的残余物。用另外35mL MTBE和45mL己烷以15mL/份加以稀释,生成固体。在浓缩至40mL期间,转动促进白色半透明粒子的形成。进一步将残余物浓缩至干,得到24.5g混杂有MTBE的白色固体。在40mL己烷中滴定该固体,产生看起来相当均匀的悬浮液,在用40mL己烷+5mL MTBE进一步稀释后通过过滤收集。用95∶5己烷/MTBE将滤饼洗涤两次(每次21mL)并在具有真空抽吸的过滤器上风干1hr。在真空下室温干燥后,得到具有96.64AP的双(2-(三甲基甲硅烷基)乙基)磷酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基酯(9.64g;12.86毫摩尔;产率95.30%),其为纯白色晶体产物。1H NMR δ(400MHz,CDCl3):8.10(s,1H),7.64(d,J=8.8Hz,2H),7.51(s,1H),7.42(d,J=8.8Hz,2H),7.05(d,J=8.8Hz,1H),6.94(d,J=2.7Hz,1H),6.90(dd,J=8.8,2.7Hz,1H),4.31-4.20(m,2H),4.21-4.08(m,4H),4.08-4.00(m,1H),3.85(s,3H),1.30-1.18(m,1H),1.13-1.04(m,4H),0.70-0.60(m,3H),0.47-0.38(m,1H),0.02(2s,18H)。13C NMR δ(C100MHz,DCl3):157.4,156.8,151.7,150.3,149.1,148.2,135.7,131.6,130.5,129.5,127.7,123.2,120.1,119.2,114.3,111.4,81.1(d,JC-P=5.1Hz),71.8(d,JC-P=5.1Hz),66.1(d,JC-P=6.4Hz,2C),56.2,19.6(2d,JC-P=6.4Hz),13.1(d,JC-P=5.1Hz),3.6,3.0,-1.5。31P NMR δ(162MHz,CDCl3):-1.11(m,JP-H 7.4Hz)。HPLC:96.64%API。MS(电喷雾,+离子)m/z 749,751。
C.二氢磷酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基酯
在配有机械搅拌器、温度计入口、氮/真空转换入口、加料漏斗和回流冷凝器的500mL夹套式反应器(二醇(glycol))内将B部分中制备的双(2-(三甲基甲硅烷基)乙基)磷酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基-乙基酯(35.27g,47.06毫摩尔)和无水CH2Cl2(315mL)的混合物在20℃搅拌至完全溶解;然后使内温降至-2℃。在温度稳定后,将TFA(30.2mL;399.40毫摩尔)滴加至搅拌着的溶液中,导致温度上升1.6℃。使反应温度维持在-0.5℃和1℃之间(内温),同时定时取出等分试样,以通过HPLC分析监测反应进程。在TFA添加完成后,立即进行HPLC分析,显示组成为9.29%起始双酯、44.78%单去保护物、42.2%期望产物、1.21%(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)-噻吩并[3,2-d]嘧啶-4(3H)-酮和1.25%主要副产物。在64min后,组成为0.0%起始酯、0.62%单去保护物、94.36%期望产物、1.52%(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)-噻吩并[3,2-d]嘧啶-4(3H)-酮和2.69%主要副产物。在95分钟后,使反应物冷却至-3℃,然后历时5min添加MeOH(28.5mL)。在搅拌30min后,在50mm Hg和15℃将反应混合物浓缩至约134mL的剩余体积。使溶液温度升高至19℃,然后缓慢添加120mL MTBE(历时约12min)。尽管在添加约30mL MTBE后开始引晶,但在开始形成白色沉淀之前添加约42-45mL MTBE。在19-20℃搅拌2小时后,通过过滤收集固体。用120mL MTBE/CH2Cl22.5∶1v/v将反应器和滤饼洗涤两次。用真空抽吸将高度砂质的白色/灰白色物质风干15min,然后在真空烘箱中于45℃干燥过夜,得到25.58g粗产物。通过以下方法将这种物质(通过F NMR测定含有一些TFA)重结晶:在夹套式反应器中,将在200mL THF和16mL水中的24.3g粗产物在搅拌下加热至55-57℃,以实现完全溶解。在60℃将溶液另外加热15min,历时10min冷却至45℃;然后历时约5min添加50mL丙酮,同时在整个添加过程中使温度保持在44℃以上。在添加完成后,用先前结晶产物对略微混浊的溶液实施引晶。在快速结晶开始后,立即历时30分钟添加另外245mL丙酮,且在整个添加过程中使温度维持在42.5℃以上。将所得浓稠浆液历时约60分钟冷却至22℃(夹套),且在20-21℃搅拌90min,然后通过过滤收集固体。将反应器和滤饼首先用120mL丙酮/THF 3∶1v/v洗涤,然后用丙酮(110mL)洗涤。在用真空抽吸风干40min后,在真空烘箱中于50℃将固体干燥18hr,得到18.96g二氢磷酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基酯(对映体过量99.2%,纯度99.4%,产率73%)。M.P.166℃1H NMR(500MHz,DMSO-d6)δppm 0.41(m,2H),0.52(m,2H),1.26(m,1H),3.82(m,1H),4.20(d,2H,J=4.29Hz),3.80(s,3H),7.06(dd,1H,J=8,57,J=2.34Hz),7.15(d,1H,J=8.57Hz),7.22(d,1H,J=2.34Hz)、7.58(d,2H,J=8.57Hz),7.93(2H,J=8.57Hz),7.98(s,1H),8.40(s,1H)。13H NMR(126MHz,DMSO-d6)δppm 2.4,3.1,13.1,56.0,71.0,77.9,112.2,113.1,119.8,121.9,122.1,128.0,129.4,130.1,131.3,134.4,148.4,149.1,149.6,149.9,156.2,157.5。31P NMR δ(162MHz,DMSO-d6):-0.75。HPLC:95.4%API;0.69%。LC/MS:m/e 549.1(M+H);4min梯度。高分辨率质谱:C24H23O7N2ClPS计算值549.06522;实验值549.06531。
手性HPLC:通过HPLC色谱法,在20℃使用OJ-RH,150×4.6mm ID;5μm柱评价光学纯度,其中流动相为100%甲醇和0.1%磷酸且流速为0.5mL/min。在这些条件下在第8分钟洗脱出S对映异构体,然后在第10min洗脱出期望的R对映异构体。
实施例4
(S)-2-氨基-3-甲基丁酸((R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基)酯
将实施例1中所述的(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)-噻吩并[3,2-d]嘧啶-4(3H)-酮(1.3g,2.33mmol)、二异丙基碳二亚胺(0.88g,6.99mmol)、4-二甲基氨基吡啶(142mg,1.16mmol)和N-(叔丁氧基羰基)-L-缬氨酸(1.52g,6.99mmol)在CH2Cl2(10mL)中的混合物在室温搅拌19h。通过LCMS分析确定,无起始醇残留。将悬浮液用CH2Cl2稀释并用NaHCO3水溶液洗涤。在用CH2Cl2萃取水层后,将合并的有机层依序用水和盐水洗涤,经Na2SO4干燥,过滤并在减压下浓缩滤液。残余物经快速色谱法(硅胶,EtOAC/己烷0-40%梯度)纯化,得到标题化合物(1.12g),其为白色固体。1H NMR(CDCl3)δ0.41-0.46(m,1H),0.49-0.53(m,1H),0.58-0.63(m,1H),0.64-0.68(m,1H),0.925(d,J=7Hz),3H),0.99(d,J=7Hz),1.16-1.19(m,1H),1.44(s,9H),2.19-2.23(m,1H),3.86(s,3H),4.23-4.32(m,3H),4.67-4.71(m,1H),5.06(d,J=2Hz,1H),6.92-6.95(m,2H),7.04(d,J=2Hz,1H),7.26(s,2H),7.45(d,J=2Hz),7.54(s,1H),7.66(d,J=2Hz,2H),8.16(s,1H)。LCMS(ES):m/z=669[M+H]。
B
将A部分的BOC缬氨酸酯(1.12g,1.67mmol)溶于TFA/CH2Cl2的1∶2混合物中(17mL)。1hr后,通过在20℃的HPLC分析确定反应已完成,然后在真空下除去挥发性物质。在将残余物溶于CH2Cl2中后,用NaHCO3/Na2CO3水溶液洗涤两遍,然后用盐水洗涤,随后经Na2SO4干燥。在浓缩后,得到900mg(94%)标题化合物。通过快速色谱法(硅胶,MeOH/CH2Cl2,0-10%梯度)进一步纯化,得到标题化合物(0.87g),其为白色固体。1H NMR(CDCl3)δ0.41-0.45(m,1H),0.50-0.54(m,1H),0.58-0.63(m,1H),0.64-0.67(m,1H),0.94(d,J=7Hz),3H),1.01(d,J=7Hz),1.16-1.19(m,1H),2.07-2.10(m,1H),3.36(d,J=1Hz,1H),3.87(s,3H),4.24-4.31(m,2H),4.68-4.72(m,1H),6.92-6.95(m,2H),7.03(d,J=2Hz,1H),7.26(s,2H),7.44(d,J=2Hz),7.53(s,1H),7.66(d,J=2Hz,2H),8.14(s,1H)。LCMS(ES):m/z 569[M+H]+。
实施例5
2-氨基乙酸(R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基-苯氧基)-1-环丙基乙基酯盐酸盐
在25℃向实施例1中所述的(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)-噻吩并[3,2-d]嘧啶-4(3H)-酮(300mg,0.640mmol)、2-(叔丁氧基羰基氨基)乙酸(168mg,0.960mmol)和DMAP(65mg,0.532mmol)在CH2Cl2(20mL)中的混合物滴加二异丙基碳二亚胺(150μL,0.963mmol)。在25℃将所得混合物搅拌2h。进行蒸发,然后实施快速色谱法(120g,0%-100%EtOAc-己烷),得到期望的N-Boc甘氨酸酯(477mg,0.762mmol,产率119%),其为无色固体,含有15摩尔%二异丙基脲。HPLC方法:梯度溶剂系统100%A:0%B至0%A:100%B(A=90%H2O/10%MeOH+0.2%H3PO4;B=90%MeOH/10%H2O+0.2%H3PO4),历时4min;在220nm检测。YMC S3ODS4.6×50mm Ballistic柱;保留时间=3.61min,100%。
不经进一步纯化就将N-Boc甘氨酸酯(379mg,0.605mmol)添加至4NHCl/二烷(10mL,40.0mmol)中。在搅拌3h后,将混合物用MeOH(5mL)稀释并过滤。用Et2O(50mL)洗涤滤饼,得到标题化合物的HCl盐(291mg,0.52mmol,产率85%),其为灰白色固体。M.P.218-220℃1H NMR(DMSO-d6,400MHz):δ0.38-0.48(m,1H),0.49-0.64(m,3H),1.18-1.30(m,1H),3.3-3.42(m,2H),3.77(s,3H),3.78-4.0(m,2H),4.2-4.32(m,2H),4.65-4.74(m,1H),7.06(dd,J=8.85,2.64Hz,1H),7.15(d,J=8.8Hz,1H),7.22(d,J=2.2Hz,1H),7.58(d,J=8.35Hz,2H),7.93(d,J=8.8Hz,2H),7.99(s,1H)。LC-MS:526.1[M+H]+。HPLC:SunFire C183.5μM,4.6×150mm,以10%-100%运行10min且随后以100-100%运行5min;流速=1mL/min;溶剂A=0.05%TFA/H2O∶CH3CN(95∶5),溶剂B=0.05%TFA/H2O∶CH3CN(5∶95)。Rt=7.46min,纯度>99%。
实施例6
(S)-2-氨基丙酸((R)-2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙基)酯盐酸盐
以与实施例5中所述类似的方式制备标题化合物,不同的是使用Boc-L-丙氨酸代替Boc-甘氨酸。1H NMR(甲醇-d4,400MHz):δ0.45-0.58(m,2H),0.6-0.75(m,2H),1.22-1.34(m,1H),1.58(d,J=7.5Hz,3H),3.87(s,3H),4.07(br q,J=7.0Hz,2H),4.35-4.42(m,2H),4.72-4.80(m,1H),7.04(dd,J=8.6,2.4Hz,1H),7.14-7.20(m,2H),7.52(d,J=8.35Hz,2H),7.73(s,1H),7.83(d,J=8.35Hz,2H),8.39(s,1H)。LC-MS:540.4[M+H]+。HPLC:SunFire C183.5μM,4.6×150mm,以10%-100%运行10min且随后以100-100%运行5min;流速=1mL/min;溶剂A=0.05%TFA/H2O∶CH3CN(95∶5),溶剂B=0.05%TFA/H2O∶CH3CN(5∶95)。Rt=7.62min,纯度=98.7%(检测器I)。
实施例7
(R)-5-(2-(4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)-1-环丙基乙氧基)-5-氧代戊酸
将戊二酸酐(73.0mg,0.640mmo1)、实施例1中制备的(R)-6-(4-氯苯基)-3-(4-(2-环丙基-2-羟基乙氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮(60mg,0.128mmol)和4-吡咯烷子基吡啶(4-pyrrolidinopyridine)(18.96mg,0.128mmol)在CH2Cl2(4mL)中的混合物在40℃搅拌25小时。LC-MS指示转化约35%。添加戊二酸酐(130mg)和4-吡咯烷吡啶(20mg)的另外部分。在40℃另外搅拌16h后,根据HPLC确定转化完成。将混合物冷却至室温,用CH2Cl2(10mL)稀释,用1N HCl、盐水洗涤,干燥(Na2SO4),过滤并蒸发,得到白色固体,其经制备性HPLC(Luna Axia 5μC1830×100mm;10min梯度,40%A:60%B至0%A:100%B(A=90%H2O/10%MeOH+0.1%TFA);(B=90%MeOH/10%H2O+0.1%TFA);在220nm检测)纯化,得到不纯标题化合物(58mg,78%),其为白色固体。通过制备性HPLC,使用CH3CN-系统(Luna Axia 5μC18 30×100mm;10min梯度,40%A:60%B至0%A:100%B(A=90%H2O/10%CH3CN+0.1%TFA);(B=90%CH3CN/10%H2O+0.1%TFA);在220nm检测)进一步纯化产物,得到标题化合物(40mg,0.069mmol,产率53.6%),其为白色固体。1HNMR(CDCl3,400MHz):δ0.33-0.43(m,1H),0.45-0.55(m,1H),0.55-0.68(m,2H),1.06-1.18(m,1H),1.85-1.95(m,2H),2.30-2.45(m,4H),3.86(s,3H),4.23-4.35(m,2H),4.64-4.73(m,1H),6.87-6.96(m,2H),7.03(d,J=7.9Hz,2H),7.44(d,J=8.35Hz,2H),7.53(s,1H),7.65(d,J=8.35Hz,2H),8.24(s,1H)。LC-MS,[M+H]+=583.5。HPLC方法:梯度溶剂系统,100%A:0%B至0%A:100%B(A=90%H2O/10%MeOH+0.2%H3PO4;B=90%MeOH/10%H2O+0.2%H3PO4),历时4min;在220nm检测。YMC S3ODS 4.6×50mm Ballistic柱;保留时间=4.35min。
实施例8
二氢磷酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯
A.磷酸二苄基酯·1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯
在回流温度加热实施例2中所述的6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮(1.01g,2.000mmol)、二苄基二异丙基亚磷酰胺(2.073g,6.00mmol)和1H-1,2,4-三唑(0.414g,6.00mmol)在1,2-二氯乙烷(30mL)中的混合物。在1h后,使混合物冷却至室温;然后添加2mL 50%H2O2。在室温搅拌15分钟后,将混合物用CH2Cl2稀释,依序用水、5%硫代硫酸钠水溶液和水洗涤。有机层经MgSO4干燥,浓缩并对粗产物实施快速色谱法(硅胶/己烷-EtOAc 100∶0至0∶100梯度),得到磷酸二苄基酯·1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(1.3g,1.699mmol,产率85%)。1HNMR(400MHz,氯仿-d)δppm 8.10(1H,s),7.66(2H,d,J=8.56Hz),7.54(1H,s),7.45(2H,d,J=8.56Hz),7.28-7.40(10H,m),6.95(1H,d,J=8.56Hz),6.92(1H,d,J=2.27Hz),6.87(1H,dd,J=8.31,2.27Hz),5.08(4H,dd,J=7.81,1.26Hz),4.32(2H,s),3.76(3H,s),2.89-3.30(4H,m)。
B.二氢磷酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯
将A部分中制备的磷酸二苄基酯·1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(1.3g,1.699mmol)溶于5mL纯TFA中。在室温3h后,将反应混合物浓缩并使用旋转蒸发器从MeOH(3x)再次浓缩。从EtOH研磨残余物,得到白色固体二氢磷酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并-[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(0.985g,1.684mmol,产率9%)。M.P.219℃1HNMR(400MHz,DMSO-d6)δ8.40(1H,s),7.98(1H,s),7.92(2H,d,J=8.3Hz),7.57(2H,d,J=8.3Hz),7.23(1H,d,J=1.8Hz),7.15(1H,d,J=8.8Hz),7.07(1H,d,J=8.1Hz),4.27(2H,s),3.79(3H,s),3.21(2H,q,J=14.4Hz),2.94-3.10(2H,m)。13C NMR(126MHz,CDCl3)δppm 157.41,156.05,149.81,149.42,149.30,148.08,131.2,130.63,129.27,127.83,122.0,121.72,119.73,118.21(t,J=270.9Hz),114.1,112.28,72.2(m),69.32(ddd,J=18.5,12.0,6.9Hz),56.0,44.32(m)LCMS:585(M+H)。
实施例9
2-氨基乙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯
将1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(3.80g,19.80mmol)添加至实施例2中制备的6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)-甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮(2.0g,3.96mmol)、Boc-甘氨酸(3.47g,19.80mmo1)和4-(吡咯烷-1-基)吡啶(2.94g,19.80mmol)在CH2Cl2(50mL)中的混合物中。将混合物在搅拌下回流15min,用CH2Cl2稀释,依序用冷10%H2SO4水溶液和饱和NaHCO3洗涤。将有机层干燥(MgSO4)并浓缩,得到白色固体(3.8g)。在溶于CH2Cl2(30mL)中并添加TFA(15mL)后,在室温将溶液保持15min。然后将反应混合物浓缩,在CH2Cl2和5%Na2CO3水溶液之间分配。将有机层干燥(MgSO4)并在真空下浓缩。对粗产物实施快速色谱法(硅胶/CH2Cl2-iPrOH 100∶0至80∶20梯度),得到2-氨基乙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(2.2g)。1H NMR(400MHz,氯仿-d)δppm 8.13(1H,s),7.66(2H,d,J=8.56Hz),7.53(1H,s),7.45(2H,d,J=8.56Hz),7.03(1H,d,J=8.56Hz),6.97(1H,d,J=2.52Hz),6.92(1H,dd,J=8.31,2.27Hz),4.44(2H,s),3.88(3H,s),3.43(2H,s),3.06-3.36(2H,m),2.85-3.07(2H,m)。LCMS:562(M+H)。
实施例10
(S)-2-氨基丙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯盐酸盐
A.(S)-2-(叔丁氧基羰基氨基)-丙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯
在密封管中将Boc-丙氨酸(94mg,0.495mmol)、得自实施例2的6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮(50mg,0.099mmol)、4-吡咯烷子基吡啶(14.68mg,0.099mmol)和N,N′-二异丙基碳二亚胺(0.077mL,0.495mmol)在CH2Cl2(4mL)中的混合物在40℃搅拌18小时。在冷却至室温并在真空下除去挥发性物质后,对粗产物实施梯度色谱法(硅胶/EtOAc/己烷0-30%),得到(S)-2-(叔丁氧基羰基氨基)丙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(59mg,0.087mmol,产率88%),其为灰白色固体。1H NMR(400MHz,CDCl3)δppm 8.13(1H,s),7.66(2H,d),7.54(1H,s),7.46(2H,d),6.87-7.06(3H,m),4.96(1H,br.s.),4.34-4.48(2H,m),4.20-4.34(1H,m),3.87(3H,s),3.09-3.24(2H,m),2.97(2H,宽s.),1.45(9H,s),1.38(3H,d,J=7.30Hz)。LC-MS:2.72min 677(M+H)。Luna 5u C1830×4.6mm ID,流速=4ml/min.,梯度=0%A至100%B运行2min.,A=90%H2O/10%MeOH/0.1%TFA,B=10%H2O/90%MeOH/0.1%TFA)。
B(S)-2-氨基丙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯盐酸盐
将来自A部分的(S)-2-(叔丁氧基羰基氨基)-丙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(59mg,0.087mmol)在25%TFA/CH2Cl2(4mL)中的混合物在室温搅拌30min。在真空下除去挥发性物质后,粗产物经制备性HPLC(Axia,Luna 5micron 30×100mm,流速=40ml/min.,梯度=0%A至100%B,运行10min.,A=90%H2O/10%MeOH/0.1%TFA,B=10%H2O/90%MeOH/0.1%TFA)纯化。将期望级份浓缩并在高真空下干燥,然后添加饱和NaHCO3水溶液(6ml)并用CH2Cl2(2×10ml)萃取。合并的CH2Cl2层经Na2SO4干燥并浓缩,然后通过溶于CH2Cl2(2ml)中并在-30℃添加1.0M HCl(0.079mL,0.079mmol)/MeOH(2ml)将游离碱(42mg,0.073mmol)转化为HCl盐。然后浓缩HCl盐并在高真空下干燥,得到(S)-2-氨基丙酸1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁基酯(41.94mg,0.073mmol,产率83%),其为白色固体。1H NMR(400MHz,MeOD)δppm 8.27(1H,s),7.73(2H,d),7.63(1H,s),7.43(2H,d),7.02-7.15(2H,m),6.94(1H,dd,J=8.56,2.52Hz),4.41(2H,d,J=3.02Hz),3.91-4.02(1H,m),3.78(3H,s),2.87-3.18(4H,m),1.44(3H,d,J=7.30Hz)。LC-MS:2.33min576(M+H)。Luna 5u C1830×4.6mm ID,流速=4ml/min.,梯度=0%A至100%B,运行2min.,A=90%H2O/10%MeOH/0.1%TFA,B=10%H2O/90%MeOH/0.1%TFA。
实施例11
5-(1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁氧基)
-5-氧代戊酸钠盐
将戊二酸酐(56.5mg,0.495mmol)、来自实施例2的6-(4-氯苯基)-3-(4-((3,3-二氟-1-羟基环丁基)甲氧基)-3-甲氧基苯基)噻吩并[3,2-d]嘧啶-4(3H)-酮(50mg,0.099mmol)和4-吡咯烷子基吡啶(14.68mg,0.099mmol)在CH2Cl2(4mL)中的混合物在40℃搅拌18小时。在冷却并在真空下除去挥发性物质后,粗产物经制备性HPLC(Axia,Luna 5micron30×100mm,流速=40ml/min.,梯度=0%A至100%B,运行10min.,溶剂A=90%H2O/10%MeCN/0.1%TFA,溶剂B=10%H2O/90%MeCN/0.1%TFA)纯化。将期望级份合并,浓缩并在高真空下干燥,得到纯游离酸(37mg,0.60mmol)。
如果希望,可通过将0.5M NaHCO3水溶液(0.131mL,0.065mmol)添加至含有该酸(37mg,0.60mmol)的THF溶液(2mL)中来生成相应钠盐。然后将溶液浓缩并在高真空下干燥,得到5-(1-((4-(6-(4-氯苯基)-4-氧代噻吩并[3,2-d]嘧啶-3(4H)-基)-2-甲氧基苯氧基)甲基)-3,3-二氟环丁氧基)-5-氧代戊酸钠(37.59mg,0.061mmol,产率61.3%),其为灰白色固体。1H NMR(400MHz,MeOD)δppm 8.28(1H,s),7.67-7.81(2H,m),7.62(1H,s),7.37-7.47(2H,m),7.01-7.11(2H,m),6.92(1H,dd,J=8.44,2.39Hz),4.33(2H,s),3.78(3H,s),2.94-3.11(2H,m),2.78-2.95(2H,m),2.27(2H,t,J=7.55Hz),2.13(2H,t,J=7.43Hz),1.68-1.84(2H,m)。LC-MS:2.59min 619(M+H)。Luna 5u C1830×4.6mm ID,流速=4ml/min.,梯度=0%A至100%B,运行2min.,A=90%H2O/10%MeOH/0.1%TFA,B=10%H2O/90%MeOH/0.1%TFA。
分析和生物学评估
首先在体外结合测定中对本发明化合物(即本发明化合物IA和IB)和化合物a至f(如2007年4月26日公开的美国专利公开2007/0093509A1中所述制备)进行表征,以测定拮抗肽激动剂与人黑色素浓集激素受体(MCHR1)结合的Ki或能力。
用于评价MCHR1活性的放射性配体结合测定
来自稳定转染的表达突变(E4Q,A5T)hMCHR1受体的HEK-293细胞的膜通过杜恩斯匀浆化(dounce homogenization)和差速离心来制备。结合实验用0.5-1.0μg膜蛋白进行,所述膜蛋白以0.2ml的总体积在25mM HEPES(pH7.4)(其含有10mM MgCl2、2mM EGTA和0.1%BSA)(结合缓冲液)中孵育90分钟。为了进行竞争性结合测定,在0.06-0.1nM[Phe13,[125I]Tyr19]-MCH和浓度增加的未标记的测试分子的存在下进行反应。反应如下终止:用96孔GFCUnifilter板(其预涂覆有含有1%BSA的0.075ml结合缓冲液,并用含有0.01%TX-100的0.4ml磷酸缓冲盐水(pH 7.4)洗涤3次)进行快速真空过滤。对滤器进行干燥,将0.05ml Microscint 20加到每个孔中,随后通过在微量板闪烁计数器(Packard)上进行闪烁计数来对放射性活性进行定量。抑制常数通过使用四参数逻辑方程(four parameter logistic equation)的非线性最小二乘法分析来确定。
选择所表现Ki值为20nM或更低的化合物,用于进一步表征代谢稳定性和细胞色素P450酶介导的大鼠微粒体氧化降解的函数关系。在大鼠PK(药物代谢动力学)模型中进一步评价表现小于10%降解的化合物,以测定其口服生物利用度和进入CNS的能力。对于本发明化合物IA和IB以及化合物a至f,除非以前药形式(在此评价中前药为氨基酸酯,即分别为缬氨酸和甘氨酸)给予化合物(IA和IB以及a至f),否则溶解度受限吸收显著降低口服暴露。在含有IA、c、d和e的亚组的情况中,采用L-缬氨酸酯前药来实施比较性体内研究;对于含有IB、a、b和f的亚组,使用甘氨酸酯前药。在向大鼠口服给予10mg/kg剂量的前药酯后,进一步评价的标准是脑与血浆浓度比为0.2至3,且8hr AUC大于生物活性物质的3微摩尔*hr。随后在四天的效力模型中评价符合此标准的化合物亚组,其中需要每天向生长中的年轻雄性大鼠给予酯前药。使用从大鼠、犬、灵长类和人类获得的肝细胞对在以30mg/kg或更低剂量给予时产生超过5%体重减轻的剂量依赖性体重减轻的化合物实施进一步表征,以确定相对清除率并确定何种物种可最佳地预测人类清除。在确定犬对人类PK具有最佳预测性后,使用在犬中的半衰期预计活性化合物的临床半衰期。
所测试化合物
对MCHR 1拮抗剂实施表征的流程图
尽管与化合物IA和IB(本发明化合物)具有结构类似性,但上述化合物a至f仍不能满足所有标准。
仅本发明化合物IA和IB满足对所有这些测定所选择的标准。对于化合物f,犬和人类的肝细胞清除率极低。随后在犬中实施的全面PK研究披露,在犬中的半衰期超过200hr。假定预期在人类中的半衰期等长(即使没有更长),则f系列化合物被视为不理想,这是由于在临床研究期间半衰期超过一周的化合物可使情况显著变复杂并增加开支,以及会引发安全性问题。
此外,随后以30mg/kg历时一个月向大鼠给予化合物f的研究披露,动物发生阻塞性肝胆损伤。其它调查证实,毒性药剂是源自含有化合物f中叔原醇部分的烷基链的体内氧化羟基化的代谢产物。当以高达300mg/kg的剂量历时一个月给予大鼠时,化合物IA和化合物IB均未诱导胆道损伤形成,这是由于不能发生相当的代谢转化。
化合物IA和IB也表现与犬类似的人肝细胞清除率;然而,在犬中的半衰期在20hr以下。因此,经预测,这两种化合物的预计人半衰期为20-40hr。因此,化合物IA和IB表现极佳药效、药物代谢动力学和安全性分布。
前药的评价
所述前药提高暴露(生物利用度)的相对能力在8小时PK研究中评价,所述研究使用经插管的SPRAGUE(CD,Charles River BreedingLaboratory)大鼠。所述化合物(母体化合物和前药酯)以口服10mg/kg的剂量按在0.5%甲基纤维素/0.1%吐温80/水中的混悬液的形式以2.0ml/kg口服(p.o.)给药(The compounds(parent and prodrug esters)were administered p.o.at 2.0ml/kg as a suspension in 0.5%methyl cellulose,0.1%Tween 80in water at 10mg/kg p.o.)。在1、2、4和8小时采集血液样品。确定母体化合物浓度后,计算8小时研究的AUC。
在成长中的年轻大鼠中评价MCHR体内活性
将重约240克的雄性SPRAGUE(CD,Charles River BreedingLaboratory)大鼠置于单独的带有垫料(bedding)的塑料笼中。将房间维持在72°F和50%湿度,且维持12/12亮暗循环(light dark cycle),其中在1600小时熄灯(light out)。使大鼠调整5天,然后开始具有食物选择的研究。标准口粮(normal chow)(2018)含有18%蛋白质、5%脂肪和73%糖类,高脂肪高糖饮食(Research Diets(D2327))含有20%蛋白质、40%脂肪和40%糖类,其中所述糖类全部为蔗糖,且所述脂肪为大豆油和椰子油。研究表明大鼠显示出对高脂肪椰子油的高度偏爱。研究表明大鼠显示出对高脂肪/高蔗糖饮食的高度偏爱(80%偏爱)。每天对体重和两种食物消耗和水摄入进行测量。水在整个研究过程中是随意可得到的。将食物消耗表示为每天的卡路里消耗,其为口粮克数乘以Kcal(千卡)/克(3.5)加上高脂肪高糖饮食克数乘以Kcal/克(4.59)的和。
在研究的第0天,基线体重在药物处置前测量。基线食物消耗为第一次药物处置前3天的平均值。在1500小时,药物每天以口服3.0mg/kg、10mg/kg和30mg/kg的剂量按在0.5%甲基纤维素/0.1%吐温80/水中的混悬液的形式以2.0ml/kg口服(p.o.)给药,其中开始于第0天,并继续每天给药至第4天(Drugwas administered daily p.o.at 2.0ml/kg at 1500hours beginning on day 0andcontinuing daily through day 4as a suspension in 0.5%methyl cellulose,0.1%Tween 80in water at 3.0,10and 30mg/kg p.o.)。使用ANOVA和Fishers PLSD统计学评价所有数据。
生物学数据
在成年肥胖大鼠中评价MCHR体内活性
将得自Charles River Laboratories的重250-300g的雄性大鼠单独饲养于塑料笼中,且实施在下午1点熄灯的12小时亮/12小时暗循环。使动物房维持在72°F和50%湿度。通过使大鼠同时获得两种不同饮食HARLAN大鼠口粮(标准口粮)和研究性饮食D12327(高脂肪高糖类高适口性饮食)来使大鼠变肥胖。研究性饮食口粮包括40%植物脂肪、40%糖类(蔗糖)和20%蛋白质。Harlan饮食包括5%脂肪(豆油)、67%糖类(淀粉)和22%蛋白质。所用正常Harlan大鼠饮食含有3.4千卡/克饮食,研究性饮食#12327含有4.59千卡/克。对大鼠实施选择饮食制度10周以诱导肥胖。一旦开始实施选择饮食制度,在研究持续期间根据该制度来饲养大鼠。收集基线进食和体重,并使用基线进食和体重将动物分为多个治疗组。在选择饮食开始时平均大鼠体重为250克。在慢性给药开始时大鼠的平均体重为661.7±6.3(平均值±平均标准偏差)克。
在暗循环开始前一小时对大鼠实施口服给药。每天在给药时测量体重和食物消耗。将食物消耗转换为千卡消耗。总千卡消耗通过以下方法确定:使每种饮食的千卡消耗相加,这通过使每种饮食消耗的克数乘以千卡/克来确定。
在研究第2天使用得自Columbus Instruments,Columbus,Ohio的Opto-M3系统来测定动物的运动活性。此测量在第2天的间接量热评价后立即实施。在晚上监测活性,在下午3点开始并持续16小时。将光束随时间的中断分为若干个60分钟的区段(Photobeam breaks over time were collapsedinto 60minute bins)。
通过间接量热法,使用得自Columbus Instruments,Columbus,Ohio的Oxymax系统来测量呼吸商数(Respiratory quotient,RQ)和耗氧量(vO2)。在研究第2天和第15天实施测量。对大鼠实施给药且将其置于单独室中。对每只大鼠实施六次测量,测量之间间隔45分钟。在上午10:00点开始测量,在下午1点开始暗循环。将数据标准化为体表面积(kg0.75)。重复测量ANOVA,然后实施简单效应分析,由此分析耗氧量和呼吸商数的统计显著性。使用得自Echo Medical Systems,Houston,Texas的回波MRI(echo MRI)来测定身体组成。在研究第29天测量身体脂肪%。测定身体脂肪%变化;使用ANOVA且经由Fischers PLSD实施事后比较来确定统计显著性。
生物学数据
Claims (16)
2.如权利要求1的化合物,所述化合物呈选自以下的其前药酯或盐的形式:乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯、磷酸酯和氨基酸酯;或呈选自磷酸酯缩醛和O-葡萄糖苷的其前药醚或盐的形式。
6.如权利要求5的化合物,所述化合物呈选自以下的其前药酯或盐的形式:乙酸酯、新戊酸酯、甲基碳酸酯、苯甲酸酯、磷酸酯和氨基酸酯;或呈选自磷酸酯缩醛和O-葡萄糖苷的其前药醚或盐的形式。
9.一种药物组合物,其包含至少一种根据权利要求1的化合物或根据权利要求5的化合物和任选的至少一种选自以下的额外治疗药剂:抗肥胖症药、抗糖尿病药、食欲抑制剂、胆固醇/脂质降低药和HDL升高药;以及至少一种可药用稀释剂或载体。
10.一种药物组合,其包含至少一种根据权利要求1的化合物或根据权利要求5的化合物和至少一种选自以下的额外治疗药剂:抗肥胖症药、抗糖尿病药、食欲抑制剂、胆固醇/脂质降低药和HDL升高药。
11.如权利要求10的药物组合,其中所述额外治疗药剂为抗糖尿病药或抗肥胖症药。
12.如权利要求1或5的化合物在制造可用于治疗肥胖症、糖尿病、焦虑症、抑郁症或炎性肠病的药物中的用途。
13.一种具有以下结构的化合物
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-
2009
- 2009-05-27 PE PE2009000744A patent/PE20091928A1/es not_active Application Discontinuation
- 2009-05-28 AR ARP090101925A patent/AR075260A1/es unknown
- 2009-05-28 WO PCT/US2009/045452 patent/WO2009146365A1/en active Application Filing
- 2009-05-28 EP EP09755726A patent/EP2310394A1/en not_active Withdrawn
- 2009-05-28 US US12/473,346 patent/US7989433B2/en active Active
- 2009-05-28 JP JP2011511814A patent/JP2011521962A/ja not_active Withdrawn
- 2009-05-28 CN CN2009801280666A patent/CN102099360A/zh active Pending
- 2009-05-28 KR KR1020107029384A patent/KR20110021988A/ko not_active Application Discontinuation
- 2009-05-28 BR BRPI0913197A patent/BRPI0913197A2/pt not_active Application Discontinuation
- 2009-05-28 MX MX2010012803A patent/MX2010012803A/es not_active Application Discontinuation
- 2009-05-28 CA CA2726264A patent/CA2726264A1/en not_active Abandoned
- 2009-05-28 EA EA201001882A patent/EA201001882A1/ru unknown
- 2009-05-28 AU AU2009251331A patent/AU2009251331A1/en not_active Abandoned
- 2009-06-01 TW TW098118073A patent/TW201000487A/zh unknown
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2010
- 2010-11-16 IL IL209354A patent/IL209354A0/en unknown
- 2010-11-24 ZA ZA2010/08451A patent/ZA201008451B/en unknown
- 2010-11-30 CO CO10151012A patent/CO6280492A2/es not_active Application Discontinuation
Also Published As
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ZA201008451B (en) | 2012-04-25 |
AR075260A1 (es) | 2011-03-23 |
CO6280492A2 (es) | 2011-05-20 |
TW201000487A (en) | 2010-01-01 |
CA2726264A1 (en) | 2009-12-03 |
JP2011521962A (ja) | 2011-07-28 |
EP2310394A1 (en) | 2011-04-20 |
AU2009251331A1 (en) | 2009-12-03 |
BRPI0913197A2 (pt) | 2016-01-12 |
WO2009146365A1 (en) | 2009-12-03 |
MX2010012803A (es) | 2010-12-07 |
KR20110021988A (ko) | 2011-03-04 |
US20090298794A1 (en) | 2009-12-03 |
US7989433B2 (en) | 2011-08-02 |
EA201001882A1 (ru) | 2011-06-30 |
IL209354A0 (en) | 2011-01-31 |
PE20091928A1 (es) | 2009-12-31 |
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