CN101166524B - 氨基酸衍生物 - Google Patents
氨基酸衍生物 Download PDFInfo
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- CN101166524B CN101166524B CN2006800141982A CN200680014198A CN101166524B CN 101166524 B CN101166524 B CN 101166524B CN 2006800141982 A CN2006800141982 A CN 2006800141982A CN 200680014198 A CN200680014198 A CN 200680014198A CN 101166524 B CN101166524 B CN 101166524B
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- acid
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- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Abstract
本发明涉及使用式(I)的化合物治疗疼痛的方法,式中R1、R2、R3和R4如说明书中所定义。本发明还涉及式(I)的某些新颖的衍生物。
Description
本发明涉及α-氨基酸衍生物。更特别的是,本发明涉及α,α-二取代的-α-氨基酸衍生物并且涉及制备该衍生物的方法、该衍生物制备中使用的中间体、包含该衍生物的组合物和该衍生物的用途。
本发明的化合物为α-2-δ(α2δ)受体配体(也被称为α-2-δ配体),且本身适用于治疗许多不同的疾病。α-2-δ受体配体为与人钙通道α-2-δ亚基的任何亚型结合的分子。钙通道α-2-δ亚基包含许多已在文献中描述过的亚型(例如1型,J.Biol.Chem.,1996,271(10),5768-76;2型及3型,J.Membr.Biol.,2001,184(1),35-43及Mol.Pharmacol.,2001,59(5),1243-1248,2001;以及4型,Mol.Pharmacol.,2002,62(3),485-496)。α-2-δ受体配体有时也被称为GABA类似物。
在已知的α-2-δ配体当中,有已上市销售的药物例如加巴喷丁(以Neurontin为商标销售)及普加巴林(以Lyrica为商标销售)。加巴喷丁为一种抗惊厥剂,其已上市销售用于治疗癫痫。普加巴林已上市销售用于治疗神经病性疼痛。
总是存在提供新药的需求,该新药潜在地具有改进的性质(例如,更大的效力、更大的选择性、从胃肠道中更好的吸收、更大的代谢稳定性及更有利的药物动力学性质)。其它可能的优点包括更大或更少的血脑屏障的渗透,根据目标疾病,更低的毒性以及副作用的发生率减少。
因此,本发明提供式(I)的化合物或其药学上可接受的盐或溶剂化物在制造用于治疗疼痛的药剂中的用途,作为实施方案A:
其中
R1为C1-C6烷基,该C1-C6烷基任选被一个或多个卤素、-R5、-OR5或-SR5基团取代;
R2为甲基,其任选被一个或多个氟基团取代;
R3为H、(C1-C6烷基)、芳基、茚满基或(C1-C6烷基)氧基羰基氧基(C1-C6烷基);
R4为H、(C1-C6烷基)C(O)-、芳基C(O)-或经由其羧基连接而形成酰胺的天然α-氨基酸残基;
R5为C1-C6烷基、C1-C6卤代烷基、C3-C8环烷基或芳基;
芳基为苯基或萘基,各自任选被一个或多个选自卤素、-NR6R6,C1-C6烷基、C3-C8环烷基、C1-C6烷氧基及氰基的取代基取代;并且
R6为H、C1-C6烷基或C3-C8环烷基。
本发明进一步提供式(II)的化合物或其药学上可接受的盐或溶剂化物,作为实施方案B:
其中R7为:
(a)支链C6-C10烷基,除了4-甲基戊-1-基及1-甲基戊-1-基以外;
(b)被一个或多个氟基团取代的C2-C6烷基,除了1-氟乙-1-基、七氟丙基、2,2-二三氟甲基乙-1-基、五氟乙基、2-氟乙-1-基、2-氟戊-1-基及2-氟-3-甲基丁-1-基以外;
(c)被一个C3-C8环烷基取代的C1-C6烷基,除了环己基甲基以外;
(d)被一个芳基取代的乙基,除了芳基为苯基或被-NH2、碘或甲氧基取代的苯基(不管其它的取代)以外;
(e)被芳基取代的C3-C4烷基,除了芳基为苯基、3,4-二羟基苯基或3,4-二甲氧基苯基以外;
(f)被芳基取代的C5-C6烷基;
(g)被C5-C6烷氧基取代的C1-C2烷基;
(h)被C1-C6烷氧基取代的C3-C6烷基;
(i)被C3-C8环烷氧基取代的C1-C6烷基;
(j)被芳氧基取代的C1-C6烷基,除了(2-甲氧基苯基)氧基甲基、(4-甲氧基苯基)氧基甲基、(4-氯苯基)氧基甲基、(2,6-二甲基苯基)氧基甲基、(2-甲氧基-5-氯苯基)氧基甲基、(2-甲氧基-5-氟苯基)氧基甲基及(2-甲氧基-4-氯苯基)氧基甲基以外;
(k)被己硫基取代的甲基或被C1-C6烷硫基取代的C4-C6烷基;
(l)被C3-C8环烷硫基取代的C1-C6烷基,除了环己基硫基甲基以外;或
(m)被芳硫基取代的C1-C6烷基,除了苯基硫基甲基、(4-氯苯基)硫基甲基、(4-氟苯基)硫基甲基、2-(苯硫基)乙基、(4-氯苯基)硫基乙基、(4-甲氧基苯基)硫基甲基及(4-甲氧基苯基)硫基乙基以外;
R8为甲基,其任选被一个或多个氟基团取代;
芳基为苯基或萘基,各自任选被一个或多个选自卤素、-NR9R9、C1-C6烷基、C3-C8环烷基、C1-C6烷氧基及氰基的取代基取代;并且
R9为H、C1-C6烷基或C3-C8环烷基。
在上述定义中,卤素意指氟、氯或溴且优选是氟或氯。除非另外详细指明,包含必需碳原子数目的烷基及烷氧基可以是未分枝的链或支链。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基及叔丁基。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基及叔丁氧基。环烷基的实例包括环丙基、环丁基、环戊基、环己基及环庚基。
在实施方案Aa中,本发明提供式(I)的化合物或其药学上可接受的盐或溶剂化物在制造用于治疗疼痛的药剂中的用途,其中R3及R4二者都是H且R1及R2如上述实施方案A中所定义。
在实施方案Ab中,本发明提供式(I)的化合物或其药学上可接受的盐或溶剂化物在制造用于治疗疼痛的药剂中的用途,其中R3及R4如上述实施方案A或实施方案Aa中所定义,R1如实施方案A中所定义及R2为甲基。
在实施方案Ac中,本发明提供式(I)的化合物或其药学上可接受的盐或溶剂化物在制造用于治疗疼痛的药剂中的用途,其中R3及R4如上述实施方案A或实施方案Aa中所定义,R2如上述实施方案A或实施方案Ab中所定义并且R1为:
(a)C1-C2烷基,该C1-C2烷基任选被一个或多个卤素、-R5、-OR5或-SR5基团取代,R5如实施方案A中所定义;或
(b)未被取代的C5-C7烷基或被一个选自C3-C8环烷基、芳基或芳氧基的基团取代的C1-C2烷基,芳基如实施方案A中所定义;
(c)分枝的未被取代的C5-C7烷基或被一个选自C3-C8环烷基、芳基或芳氧基的基团取代的C1-C2烷基,芳基如实施方案A中所定义;
(d)乙基丁基、二甲基丁基、乙基戊基、甲基戊基、甲基丁基、环戊基甲基、环丁基甲基、环丙基乙基、苯氧基乙基或氯苯基甲基;或
(e)2-乙基-丁-1-基、3,3-二甲基丁-1-基、3-乙基戊-1-基、3-甲基戊-1-基、2-甲基丁-1-基、3-甲基丁-1-基、4-甲基戊-1-基、环戊基甲基、环丁基甲基、2-环丙基乙-1-基、2-(苯氧基)乙-1-基或(3-氯苯基)甲基。
在实施方案Ba中,本发明提供式(II)的化合物,或其药学上可接受的盐或溶剂化物,其中R7如上述实施方案B中所定义并且R8为甲基。
在实施方案Bb中,本发明提供式(II)的化合物,或其药学上可接受的盐或溶剂化物,其中R8如上述实施方案B或实施方案Ba中所定义并且R7为:
(a)支链C6-C7烷基,除了4-甲基戊-1-基及1-甲基戊-1-基以外;被一个C3-C8环烷基取代的C1-C2烷基,除了环己基甲基以外;被芳氧基取代的C1-C2烷基,除了(2-甲氧基苯基)氧基甲基、(4-甲氧基苯基)氧基甲基、(4-氯苯基)氧基甲基、(2,6-二甲基苯基)氧基甲基、(2-甲氧基-5-氯苯基)氧基甲基、(2-甲氧基-5-氟苯基)氧基甲基及(2-甲氧基-4-氯苯基)氧基甲基以外;2-甲基丁基;或氯苯基甲基;或
(b)2-乙基-丁-1-基、3,3-二甲基丁-1-基、3-乙基戊-1-基、3-甲基戊-1-基、2-甲基丁-1-基、4-甲基戊-1-基、环戊基甲基、环丁基甲基、2-环丙基乙-1-基、2-(苯氧基)乙-1-基或(3-氯苯基)甲基。
根据本发明的特定优选化合物是在下面实施例部分中列出的那些及其药学上可接受的盐及溶剂化物。
用于本发明中的化合物的进一步实例有:
3-氯-α-甲基-L-苯丙氨酸;
4-苯氧基-L-异缬氨酸;
2,5-二甲基-L-正亮氨酸;及
(2S)-2-氨基-4-环丙基-2-甲基丁酸;
及其药学上可接受的盐及溶剂化物。
应注意的是,式(II)的化合物全部也是式(I)的化合物,为本身是新颖的那些式(I)的化合物。因此,应该了解,下文对式(I)化合物的全部提及也是对式(II)化合物的提及。
式(I)的化合物的药学上可接受的盐包括酸加成及其碱盐。
适合的酸加成盐是由形成无毒盐的酸形成的。实例包括乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸/氯化物、氢溴酸/溴化物、氢碘酸/碘化物、羟乙磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、糖质酸盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐及三氟乙酸盐。
适合的碱盐是由形成无毒盐的碱形成的。实例包括铝盐、精氨酸盐、二苄基乙二胺盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、甲葡胺盐、乙醇胺盐、钾盐、钠盐、缓血酸胺盐及锌盐。
也可以形成酸及碱的半盐,例如半硫酸盐及半钙盐。
关于适合的盐的综述,参见史多尔(Stahl)及窝马斯(Wermuth)的药物盐的手册:性质、选择及使用(Handbook of Pharmaceutical Salts: Properties,Selection,and Use)(Wiley-VCH,Weinheim,德国,2002)。
可利用下列三种方法的一种或多种来制备式(I)化合物的药学上可接受的盐:
(i)通过使式(I)的化合物与想要的酸或碱反应;
(ii)通过从式(I)化合物的合适前体中去除酸不稳定或碱不稳定的保护基团,或通过使用想要的酸或碱使适合的环状前体,例如,内酯或内酰胺开环;或
(iii)通过与适当的酸或碱反应或用适合的离子交换柱,将式(I)化合物的一种盐转换成另一种盐。
典型地在溶液中进行全部三种反应。所产生的盐可沉淀出来且利用过滤来收集或可通过蒸发溶剂来回收。在所产生盐中的离子化程度可从完全离子化变化至几乎非离子化。
R3及R4为H的式(I)化合物具有碱性氨基及酸性羧基,且在生理pH下将以两性离子形式存在。
式(I)的化合物可以非溶剂化形式及溶剂化形式二者存在。本文中使用术语“溶剂化物”来描述分子络合物,其包含式(I)的化合物与化学计算量的一种或多种药学上可接受的溶剂分子(例如,乙醇)。当所述的溶剂为水时,使用术语“水合物”。
包含在本发明范围内的络合物有络合物例如包合物、药物宿主包合络合物(其中,与前文提及的溶剂化物对比,该药物及宿主以化学计算量或非化学计算量存在)。本发明还包括含有二种或更多种有机和/或无机组分(其可以化学计算量或非化学计算量存在)的药物的络合物。所产生的络合物可以是离子化的、部分离子化的或非离子化的。关于这类络合物的综述,参见哈雷布瑞安(Haleblian)的J.Pharm.Sci.,64(8),1269-1288 (1975年8月)。
在下文中,对式(I)化合物的全部提及包括对其盐、溶剂化物和络合物以及对其盐的溶剂化物及络合物的提及。
如在上文中所定义的,式(I)的化合物可以一种或多种结晶(多晶型)形式或异构形式(包括旋光异构体、几何异构体及互变异构体)、同位素标记的形式或前药的形式存在。所有这类结晶/异构形式及前药全部在本发明的范围内,且在下文进一步描述。应该相应地解释对式(I)化合物的全部全部提及。
在本发明的范围内包括式(I)的化合物,其中R3和/或R4为在将该化合物给予哺乳动物(优选人类)后被转换成H的基团。将这类化合物称为前药。因此,当将这些衍生物(其本身可能具有很少或没有药理学活性)施用到机体中或机体上时,它们可转被换成R3及R4二者都是H的式(I)化合物,该化合物具有想要的作为α-2-δ配体的活性。例如,通过水解裂解可转化该前药。
典型地,R3为烷基,优选为C1-C6烷基。适合的烷基的特定实例是乙基、异丙基及正丁基。或者,R3可为芳基(其中芳基如上文中所定义),例如苯基或茚满基。在其它适合的实施方案中,R3可为烷氧羰基氧基烷基, 例如-CH2OC(O)OtBu、 -CH(CH3)OC(O)OEt或-CH(CH3)OC(O)OiPr(参见药理学及实验治疗剂杂志(Journal ofPharmcology and Experimental Therapeutics)),311,1,324-335)或经由亚甲基连接的环状碳酸酯。
典型地,R4为酰胺形成性基团,例如-CO(C1-C6烷基)或-CO(芳基)(其中芳基如上文中所定义)。特定的实例是甲基羰基、异丙基羰基及苯基羰基。或者,R4可为通过其羧基连接以形成酰胺的α-氨基酸残基。优选天然存在的氨基酸,特别是甘氨酸、丙氨酸及缬氨酸。
可使用许多体外试验及体内动物模型来准确评估特定的化合物是否作为前药起作用并且在体内水解裂解成活性化合物。可使用包括简单匀浆及微粒体在内的一系列组织部分,来体外表征前药体外水解:参见,例如,药理学及实验治疗剂杂志,294,2,580-587;Life Sci.,62,14,1231-124;国际药剂学杂志(International Journal ofPharmaceutics),166,1,45-53;及Toxicol. Lett.,82-83,439-445。就这一点来说,大鼠肝微粒体匀浆特别有用。也可使用体内试验来研究前药性质。活性成分及前药二者的静脉内及口服药物动力学提供关于该前药的相对生物利用度、机体水解该前药的能力及水解成活性物质的速率的信息(参见Antimicrob.Agents.Chemother.42,3,647-653)。在最近的综述中,已给出了所建议的用于测定前药的筛选策略(现代药物代谢(Current Drug Metabolism),2003,第4册,案号6,p 483)。
可在前药作为新颖的给药系统(Pro-drugs as Novel Delivery Systems),第14册,ACS研讨会系列(ACS Symposium Series)(T.Higuchi及W.Stella);及药物设计中的生物可逆载体(Bioreversible Carriers in Drug Design),佩加蒙出版社(Pergamon Press),1987(ed.E.B.罗趣(Roche),美国制药协会(American PharmaceuticalAssociation))中发现关于前药使用的进一步信息。
式(I)化合物的前药(除了包括R3及R4基团的那些以外)也在本发明的范围内,且可例如以本领域的技术人员已知为“前部分(pro-moieties)”的某些部分,置换存在于式(I)化合物中的合适官能度,来制造它们,例如,如在H.Bundgaard的前药设计(Design of Prodrugs)(爱尔斯维尔(Elsevier),1985)中所描述的。
根据本发明的其它前药的某些实例包括,当(I)的化合物包含伯氨基或仲氨基官能度(-NH2或-NHR,其中R≠H)时,其酰胺,例如,其中(该情况可以是)式(I)化合物的氨基官能度的一个或二个氢被(C1-C10)烷酰基置换的化合物。
再者,某些式(I)的化合物它们本身可用作其它式(I)的化合物的前药。
在本发明的范围内还包括式(I)化合物的代谢产物,亦即,在给予该药物后在体内形成的化合物。根据本发明的代谢产物的某些实例包括:
(i)当式(I)的化合物包含甲基时,其羟甲基衍生物(-CH3->-CH2OH):
(ii)当式(I)的化合物包含烷氧基时,其羟基衍生物(-OR->-OH);
(iii)当式(I)的化合物包括叔氨基时,其仲氨基衍生物(-NR1R2->-NHR1或-NHR2);
(iv)当式(I)的化合物包含仲氨基时,其伯衍生物(-NHR1->-NH2);
(v)当式(I)的化合物包括苯基部分时,其酚衍生物(-Ph->-PhOH);及
包含进一步不对称碳原子的式(I)化合物可以非对映异构体的形式存在。当该结构异构体经由低能量障碍可互变时,则可产生互变异构的异构体现象(“互变异构现象”)。互变异构现象可采用质子互变异构现象或所谓的价互变异构现象。可见单一化合物可存在多种类型的同分异构现象。
在本发明的范围内包括式(I)化合物的全部非对映异构体及互变体形式,包括表现出多种类型的同分异构体现象的化合物,及其一种或多种的混合物。还包括其中抗衡离子是光学活性的(例如,d-乳酸盐或l-赖氨酸),或外消旋的(例如,dl-酒石酸盐或dl-精氨酸)的酸加成盐或碱盐。
可通过本领域的技术人员所熟知的常规技术,例如,色谱法及分级结晶,来分离非对映异构体。
式(I)的化合物是在α-碳原子上具有所定义的立体化学的α-氨基酸。制备/分离个别对映体的常规技术包括由适合的光学纯前体的手性合成,或使用例如手性高压液相色谱法(HPLC)拆分外消旋体(或者盐或衍生物的外消旋体)。
或者,可以使外消旋体(或外消旋前体)与适合的光学活性化合物反应。可利用色谱法和/或分级结晶来分离所产生的非对映异构混合物,并且利用本领域的技术人员所熟知的方法将该非对映异构体的一种或二者转换成相应的纯对映体。
也可以使用色谱法(典型地为HPLC),在不对称树脂上,使用由烃(典型地为庚烷或己烷)组成的流动相(包含0至50体积%的异丙醇,典型地从2%至20体积%,以及0至5体积%的烷基胺,典型地0.1%的二乙胺),来获得富集对映异构体的化合物。浓缩该洗脱液提供所述富集的混合物。
可通过本领域的技术人员所熟知的常规技术来分离立体异构体的聚集物,参见,例如,E.L.Eliel及S.H.Wilen的有机化合物的立体化 学(Stereochemistry of Organic Compounds)(威利,纽约,1994)。
适合于包含在本发明化合物中的同位素实例包括氢的同位素,例如2H及3H;碳的同位素,例如11C、13C及14C;氯的同位素,例如36Cl;氟的同位素,例如18F;碘的同位素,例如123I及125I;氮的同位素,例如13N及15N;氧的同位素,例如15O、17O及18O;磷的同位素,例如32P;及硫的同位素,例如35S。
某些经同位素标记的式(I)化合物(例如,结合了放射性同位素的那些)在药物和/或底物组织分布研究中是有用的。鉴于放射性同位素氚(即,3H)及碳-14(即,14C)容易结合及现有的检测手段,它们特别适用于此目的。
以较重的同位素(例如氘,即,2H)取代可提供某些治疗优点(这是由较大的代谢稳定性所导致的),例如,体内半生期增加或剂量需求减少,并且因此在某些情况下是优选的。
以正电子发射性同位素(例如,11C、18F、15O及13N)取代可适用于正子成像术(PET)研究,用于检查底物受体的占据性。
通常可利用本领域的技术人员所熟知的常规技术,或利用类似于在伴随的实施例及制备例中所描述的那些方法,使用合适的经同位素标记的试剂替代先前使用的非标记的试剂,来制备经同位素标记的式(I)化合物。
根据本发明的药学上可接受的溶剂化物包括其中结晶溶剂可被同位素取代(例如D2O、d6-丙酮、d6-DMSO)的那些。
为α-2-δ受体配体的式(I)化合物可潜在地用于治疗广泛范围的病症。治疗疼痛,特别是神经病性疼痛是优选的用途。
生理性疼痛是一种重要的保护机理,其被设计用于警戒来自外部环境的潜在伤害性刺激的危险。系统通过一组特异性初级感觉神经元发挥作用,并经由外周转导机理被有害刺激活化(关于综述,参见Millan,1999,Prog.Neurobiol.,57,1-164)。这些感觉纤维被称为伤害感受器,是传导速率慢的特征性地小直径轴突。伤害感受器编码有害刺激的强度、持续时间和特性,并且凭借它们向脊髓的局部解剖组织投射,还编码刺激的定位。在伤害感受神经纤维上发现有伤害感受器,该伤害感受神经纤维有两种主要类型,A-δ纤维(有髓鞘的)和C纤维(无髓鞘的)。由伤害感受器输入所生成的活动在后角中的复杂加工之后直接或者经由脑干交接(relay)核转移到前底(ventrobasal)丘脑,然后到皮质,在那里生成疼痛的感觉。
疼痛一般可以分为急性的或慢性的。急性疼痛突然开始,并且是短暂存在的(通常在十二周内或更少)。它通常与具体的原因有关,例如具体的损伤,并且经常是急剧的和严重的。它是发生在由手术、牙齿处理、劳损或扭伤所致具体损伤之后的一类疼痛。急性疼痛一般不导致任何持续性心理应答。相反,慢性疼痛是长期疼痛,通常持续三个月以上,引起显著的心理和情绪问题。慢性疼痛的常见实例是神经病性疼痛(例如疼痛性糖尿病性神经病、疱疹后神经痛)、腕管综合征、背部疼痛、头痛、癌症疼痛、关节炎疼痛和慢性手术后疼痛。
当机体组织经由疾病或创伤发生实质性损伤时,伤害感受器活化的特征被改变,在伤害感受器终止的外周、损伤局部周围和中央存在敏感化。这些效应引起疼痛的感觉强化。在急性疼痛中,这些机理可以适用于促进保护行为,其可更好地能够使修复过程发生。正常的预期将是一旦损伤已经愈合,敏感性恢复正常。不过,在很多慢性疼痛状态中,敏感性过高远比愈合过程长久,并且经常是由神经系统损伤引起的。这种损伤经常引起与适应障碍和异常活性有关的感觉神经纤维的异常(Woolf & Salter,2000,Science,288,1765-1768)。
当在患者的症状中有不适和异常敏感性特征时,呈现临床疼痛。患者趋于是相当异质的,并且可以呈现各种疼痛症状。这类症状包括:1)自发性疼痛,其可以是迟钝性、烧灼性或刺痛;2)夸大的响应于有害刺激的疼痛(痛觉过敏);3)由正常无害刺激产生的疼痛(异常性疼痛-Meyer等,1994,Textbook of Pain,13-44)。尽管患有各种形式急性与慢性疼痛的患者可以具有相似的症状,不过基础性机理可以是不同的,因此可能需要不同的治疗策略。因此疼痛也可以根据不同的病理生理学分为许多不同的亚型,包括伤害感受性、炎性和神经病性疼痛。
伤害感受性疼痛是由组织损伤或者由具有导致损伤潜力的强烈刺激所诱发的。伤害感受器在损伤部位转导刺激而活化疼痛传入神经,在它们末端的水平上活化脊髓中的神经元。然后这上行脊束交接至脑,在那里感知疼痛(Meyer等,1994,Textbook of Pain,13-44)。伤害感受器的活化活化两种类型的传入神经纤维。有髓鞘的A-δ纤维迅速传送,负责急剧的和刺痛的疼痛感觉,而无髓鞘的C纤维以较缓慢的速率传送,传达钝痛或酸痛。中等至严重的急性伤害感受性疼痛是由如下状况引起的疼痛的突出特性:中枢神经系统创伤、劳损/扭伤、灼伤、心肌梗塞和急性胰腺炎、手术后疼痛(任意类型外科手术之后的疼痛)、创伤后疼痛、肾绞痛、癌症疼痛和背部疼痛。癌症疼痛可以是慢性疼痛,例如肿瘤相关的疼痛(例如骨疼痛、头痛、面疼痛或内脏疼痛)或者与癌症疗法有关的疼痛(例如化疗后综合征、慢性术后疼痛综合征或放射后综合征)。癌症疼痛也可以响应于化疗、免疫疗法、激素疗法或放射疗法而发生。背部疼痛可以是由椎间盘突出或破裂或者腰面(lumber facet)关节、骶髂关节、脊旁肌肉或后纵韧带的异常引起的。背部疼痛可以自然消散,但是在有些持续12周的患者中,它变为可能是特别衰弱性的慢性病况。
神经病性疼痛目前被定义为由神经系统的原发性损伤或功能障碍所引发或导致的疼痛。创伤和疾病可以导致神经损害,因而术语“神经病性疼痛”涵盖多种病因的很多障碍。它们包括但不限于外周神经病、糖尿病性神经病、疱疹后神经痛、三叉神经痛、背部疼痛、癌症神经病、HIV神经病、幻肢疼痛、腕管综合征、中枢性中风后疼痛和与慢性酒精中毒、甲状腺机能减退、尿毒症、多发性硬化、脊髓损伤、帕金森氏病、癫痫和维生素缺乏有关的疼痛。神经病性疼痛是病理性的,因为它没有保护作用。它经常存在于最初原因已经消失之后良久,普遍持续数年,显著降低患者的生活质量(Woolf和Mannion,1999,Lancet,353,1959-1964)。神经病性疼痛的症状是难以治疗的,因为它们经常是异质的,即使在患有相同疾病的患者之间也是如此(Woolf& Decosterd,1999,Pain Supp.,6,S141-S147;Woolf和Mannion,1999,Lancet,353,1959-1964)。它们包括自发性疼痛,其可以是连续性的和阵发性的或者异常发作的疼痛,例如痛觉过敏(对有害刺激的敏感性增加)和异常性疼痛(对正常无害刺激的敏感性)。
炎性过程是一系列复杂的生化与细胞事件,响应于组织损伤或外来物质的存在而活化,其导致肿胀和疼痛(Levine和Taiwo,1994,Textbook of Pain,45-56)。关节炎疼痛是最常见的炎性疼痛。类风湿病是发达国家最常见的慢性炎性病症之一,类风湿性关节炎是残疾的常见原因。类风湿性关节炎的确切病因是未知的,但是目前的假设提示,遗传和微生物学因素可能都是重要的(Grennan & Jayson,1994,Textbook of Pain,397-407)。根据估计,大约一千六百万美国人患有症状性骨关节炎(OA)或变性性关节疾病,其中大多数年龄在60岁以上,并且预计随着人口年龄的增长这会增加到四千万,使其成为重大的公共健康问题(Houge & Mersfelder,2002,Ann Pharmacother.,36,679-686;McCarthy等,1994,Textbook of Pain,387-395)。大多数骨关节炎患者由于伴随的疼痛寻求医学关注。关节炎对心理社会和身体功能具有显著的影响,已知其是晚年生活能力丧失的主导原因。关节强硬性脊椎炎也是一种风湿性疾病,它导致脊柱和骶髂关节的关节炎。它从终生发生的背部疼痛的间歇性发作,变化为攻击脊柱、外周关节和其他机体器官的严重的慢性疾病。
另一种类型的炎性疼痛是内脏疼痛,它包括与炎性肠疾病(IBD)有关的疼痛。内脏疼痛是与内脏有关的疼痛,涵盖腹腔的器官。这些器官包括性器官、脾脏和部分消化系统。与内脏有关的疼痛可以分为消化性内脏疼痛和非消化性内脏疼痛。普遍遇到的引起疼痛的胃肠(GI)障碍包括功能性肠障碍(FBD)和炎性肠疾病(IBD)。这些GI障碍包括在目前仅被适度控制的广泛范围的疾病状态,就FBD来说,包括胃-食管反流、消化不良、肠易激综合征(IBS)和功能性腹部疼痛综合征(FAPS),就IBD来说,包括克罗恩氏病、回肠炎和溃疡性结肠炎,它们全部都经常都引起内脏疼痛。其他类型的内脏疼痛包括与痛经、膀胱炎和胰腺炎有关的疼痛和骨盆疼痛。
应当注意,有些类型的疼痛具有多种病因,因而可以分在多个领域中,例如背部疼痛和癌症疼痛既具有伤害感受性组元(component)又具有神经病性组元。
其他类型的疼痛包括:
·肌肉-骨骼障碍,包括肌痛、纤维肌痛、脊椎炎、血清-阴性(非类风湿性)关节病、非关节风湿病、营养不良病、糖原分解、多肌炎和脓性肌炎引起的疼痛;
·心脏与血管疼痛,包括由心绞痛、心肌梗塞、二尖瓣狭窄、心包炎、雷诺氏现象、硬化病和骨骼肌缺血导致的疼痛;
·头部疼痛,例如偏头痛(包括有先兆的偏头痛和没有先兆的偏头痛)、簇性头痛、紧张型疼痛混合型头痛以及与血管障碍有关的头痛;以及
·口面部疼痛,包括牙痛、耳痛、烧灼性口综合征和颞下颌肌筋膜疼痛。
式(I)的化合物潜在地可用于治疗所有种类的疼痛,但是特别适用于治疗神经病性疼痛。
除了疼痛以外,式(I)的化合物潜在地适用于治疗可用α-2-δ配体治疗的任何疾病或病症。该病症包括癫痫、胃肠障碍、早泄、烧灼性口腔综合征、膀胱障碍(例如,膀胱活动过度)、晕厥发作、纤维肌痛、运动机能减退、颅障碍、热潮红、特发性震颤、化学品依赖性及成瘾、与依赖性或成瘾相关的戒断症状、成瘾行为、痉挛、关节炎、炎性障碍(例如,类风湿性关节炎、骨关节炎、牛皮癣)、多尿、月经前综合征、月经前烦躁不安障碍、耳鸣、胃损伤、唐氏(Down’s)综合征、脱髓鞘性疾病(例如,多发性硬化及肌萎缩性侧索硬化症(amylolateralsclerosis)、由于急性或慢性脑血管损伤引起的脑血管障碍(例如,脑栓塞、蛛网膜下出血或脑水肿)、头部创伤、脊髓损伤及神经元损伤(例如,在中风期间、在心脏旁路手术中、在颅内出血事件中、在围产期窒息中、在心动停止中及在癫痫状态下发生)。α-2-δ配体也可适用于治疗谵妄、痴呆症及遗忘症及其它认知或神经变性病(例如,帕金森氏病、亨廷顿舞蹈病、阿尔兹海默氏病、老年痴呆、记忆障碍、血管性痴呆)。它们可适用于治疗运动疾病,例如运动不能、运动障碍、痉挛、图雷特(Tourette’s)综合征、史卡特(Scott)综合征、瘫痪、运动不能-僵硬综合征及锥体外运动疾病。它们也可适用于治疗睡眠障碍、心境障碍、抑郁症、抑郁性障碍、双相性精神障碍、焦虑症、恐慌症、边缘性人格障碍、精神分裂症、精神病障碍、与智力迟钝相关的行为紊乱、自闭症及行为障碍。
可通过常规的途径,例如通过在下文显现的一般方法中描述的程序,或通过在实施例部分及制备例部分中描述的特定方法,或通过与其类似的方法,来制备所有的式(I)化合物。本发明也包括任何一种或多种这些用来制备式(I)化合物的方法,以及其中使用的任何新颖的中间体。
除非另有描述,在下面的一般方法中,R1、R2、R3及R4如先前关于式(I)的化合物所定义并且Ph为苯基。
根据第一方法(A),可通过式(III)化合物的氢解去保护来制备其中R3及R4为H的式(I)化合物:
其中R1及R2如上所定义。典型使用氢源,例如氢气、环己二烯或甲酸铵(优选氢气)与过渡金属催化剂,例如钯、铂或铑催化剂(优选钯催化剂),来进行氢化。也可使用酸,例如,盐酸或三氟乙酸)来增加反应速率。在优选的程序中,以碳上钯及盐酸处理式(III)化合物在合适溶剂(例如乙醇)中的溶液,于约414kPa(60psi)下氢化。
可通过用下式的化合物:
R2M1 (V)
式中R2如上所定义并且M1为适合的金属,任选携带一个或多个其它的配体,处理式(IV)的亚胺:
式中R1如上所定义;或者通过用下式的化合物:
R1M1 (VII)
其中R1及M1如上所定义,处理式(VI)的亚胺:
其中R2如上所定义,来制备式(III)的化合物。在该亚胺加成反应中,式(V)或(VII)的有机金属试剂典型地为有机锂或有机镁衍生物。优选其中M1为MgX(X为卤化物)的有机镁(格利雅)试剂。在适合的惰性溶剂(例如,四氢呋喃或二乙醚)中,于低温(典型在0至-78℃之间)下进行该反应。在优选的程序中,在-50℃和在三氟化硼合乙醚存在下,分别以适合的式(V)或(VII)的格利雅试剂处理式(IV)或(VI)化合物在合适溶剂(例如,四氢呋喃)中的溶液。
可通过将下式的化合物:
分别与下式的化合物(式中R1如上所定义及X为C1-C6烷基):
或式(X)的化合物(式中R2如上所定义及X为C1-C6烷基):
缩合,来制备式(IV)和(VI)的化合物。可在碱性、中性或酸性条件下进行该缩合,且其通常需要高温和/或延长的反应时间。在典型的程序中,在约80℃下,在脱水剂(例如,4分子筛)存在下,加热式(VIII)化合物与式(IX)或(X)化合物在合适溶剂(例如三氟乙醇)中的溶液。
式(X)、(IX)及(VIII)的化合物可商业购得,或使用本领域技术人员所熟知的标准方法容易地制得,其中该标准方法或来自公知常识(例如,参见Richard Larock的“综合有机转换(Comprehensive OrganicTransformations)”(1999,VCH出版公司(Publishers Inc.))或参考特定的已公开的程序。
可从其中R3和/或R4为H的式(I)化合物,通过技术人员所熟知的简单化学转换,来制备其中R3和/或R4不是H的式(I)化合物。可在上文引用的综合有机转换中发现适合于该酰胺及酯形成反应的条件。
或者,根据第二方法(B),可通过式(IIIa)的开环化合物的氢解去保护来制备其中R3及R4为H的式(I)的化合物:
其中R1及R2如上所定义。典型地使用氢源,例如氢气、环己二烯或甲酸铵(优选氢气)及过渡金属催化剂,例如钯、铂或铑催化剂(优选钯催化剂),来进行该氢化。也可使用酸,例如盐酸或三氟乙酸,来增加反应速率。在优选的程序中,以碳上钯处理式(IIIa)化合物在合适溶剂(例如丙-2-醇及水)中的溶液,且在约414kPa(60psi)下氢化。
可通过以式(V)或(VII)的化合物处理式(IV)或(VI)的亚胺,接着以适合的酸或碱处理,来制备式(IIIa)的化合物。适合于该亚胺加成反应的条件如上关于方法(A)所述。在优选的程序中,首先在-78℃下,在三氟化硼四氢呋喃络合物存在下,以适合的式(VII)的格利雅试剂处理式(VI)化合物在合适溶剂(例如四氢呋喃)中的溶液,接着以适合的酸(例如,盐酸水溶液)处理。
或者,根据第三方法(C),可通过水解式(XI)的腈来制备其中R3及R4二者都是H的式(I)的化合物:
其中R1及R2如上所定义。典型地在水性溶剂中,在高温下,用酸性或碱性催化来完成该水解。在典型的程序中,以6摩尔浓度的盐酸处理式(XI)化合物的水溶液且将其加热至约100℃。
可通过将氰化物加成至式(XII)的化合物来制备式(XI)的化合物:
其中R1及R2如上所定义。用于该加成的优选氰化物源为其中M2为金属阳离子的式M2CN的化合物,其任选携带其它的配体。最优选的是氰化二烷基铝,例如氰化二乙基铝。以在适合的惰性溶剂(例如四氢呋喃、二氯甲烷或二乙醚)中的溶液来进行该反应。在优选的程序中,在-78至-20℃的温度下,以氰化二乙基铝处理式(XII)化合物在异丙醇与四氢呋喃的混合物中的溶液。
可通过在脱水条件下,使式(XIII)的化合物:
与式(XIV)的化合物(其中R1及R2如上所定义):
反应,来制备式(XII)的化合物。典型地用路易斯酸(例如,四乙醇钛)催化该反应。在优选的程序中,在约50℃的温度下,以四乙醇钛处理式(XIII)化合物与式(XIV)化合物在适合的溶剂(例如四氢呋喃)中的溶液。
式(XIII)及(XIV)的化合物可商业购得,或使用本领域的技术人员所熟知的标准方法容易地制得,其中该标准方法来自公知常识(例如,参见Richard Larock的“综合有机转换”(1999,VCH出版公司)),或参考特定的已公开的程序。
或者,根据第四方法(D),可通过水解式(XV)的酯来制备其中R3及R4二者都是H的式(I)的化合物:
其中R1及R2如上所定义。可在酸性或碱性条件下进行该水解。在典型的程序中,在回流下加热式(XV)化合物在盐酸水溶液中的溶液16小时。
可通过式(XVI)化合物的甲醇分解来制备式(XV)的化合物:
其中R1及R2如上所定义,且Y1及Y2各自选自C1-C6烷基。可以酸或碱催化来进行该反应。在典型的程序中,在室温下,搅拌式(XVI)化合物在甲醇的盐酸中的溶液约72小时。
可通过以式R2L1的化合物(其中R2如上所定义并且L1为适合的离去基团)烷基化式(XVII)的化合物,来制备式(XVI)的化合物:
其中R1、Y1及Y2如上所定义。L1优选为卤素(特别是溴)、三氟甲烷磺酸盐或甲烷磺酸盐。典型地,以碱(例如丁基锂),在惰性溶剂(例如二乙醚或四氢呋喃)中,于低温(通常在-78至-20℃的范围内)下使式(XVII)的化合物去质子化。然后,加入烷基化剂在惰性溶剂中的溶液。在优选的程序中,于-78℃下,以正丁基锂处理式(XVII)化合物在四氢呋喃中的溶液,然后加入过量的烷基化剂。
可通过式(XVIII)化合物的双烷基化来制备式(XVII)的化合物:
其中R1如上所定义。典型地,在惰性溶剂(例如,四氢呋喃或二乙醚)中使用碱(例如,叔丁醇钾、六甲基二硅氨化(hexamethyldisilazide)钾或氢化钠)使式(XVIII)的化合物去质子化。然后,在-20℃至室温的温度下,加入适合的烷基化剂,例如烷基卤(特别是烷基溴)或磺酸烷酯(例如,甲磺酸烷酯)。在优选的程序中,使用过量的四氟硼酸三甲基氧盐(trimethoxonium)作为烷基化剂。
可通过环化式(XIX)的化合物来制备式(XVIII)的化合物:
其中R1如上所定义。在典型的程序中,在回流下加热式(XIX)化合物在合适溶剂(例如,甲苯)中的溶液。
可通过还原式(XX)的化合物来制备式(XIX)的化合物:
其中R1如上所定义。典型地使用氢及氢化催化剂(例如,钯、铂或铑催化剂)来完成该还原。在优选的程序中,在室温下,以氢处理式(XX)化合物在合适溶剂(例如,乙醇的盐酸水溶液)中的溶液。
可通过使式(XXI)的胺:
与式(XXII)的酸(其中R1如上所定义)偶联,来制备式(XX)的化合物。
首先通过将其转换成相应的酰基氯或以适合的肽偶联剂处理,来活化所述酸。若使用酰基氯,则预先形成它,然后在碱(例如,三乙胺)存在下,使其与胺(为在适合的惰性溶剂(例如,二氯甲烷或四氢呋喃)中的溶液)反应。或者,以碱(例如,三乙胺)及偶联剂(例如,碳二亚胺)处理所述酸与胺在合适溶剂(例如二氯甲烷或四氢呋喃)中的溶液。
式(XXI)及(XXII)的化合物可商业购得,或使用本领域的技术人员所熟知的标准方法容易地制得,其中该标准方法来自公知常识(例如,参见Richard Larock的“综合有机转换”(1999,VCH出版公司)),或参考特定的已公开的程序。
或者,根据第五方法(E),可通过拆分式(Ia)的外消旋化合物来制备式(I)的化合物(其中R3及R4二者都是H,R1及R5未被卤素或氰基取代并且R2为甲基)。
可通过本领域的技术人员所熟知的许多方法,包括手性色谱法、形成非对映衍生物(例如,酯类、醚类或盐类)或化学或酶动力学拆分,来进行拆分。典型地,在适合的有机溶剂中以手性碱或酸处理式(Ia)的化合物,以形成非对映盐,且通过结晶最少可溶的非对映体达到分离。适合的拆分剂包括酒石酸衍生物、扁桃酸、樟脑磺酸、鹰爪豆碱、α-甲基苄胺、伪麻黄碱及氨基醇类。也可使用非对映盐拆分来增加式(I)的非外消旋化合物的对映体过量。
可通过式(XXIII)化合物的氢解去保护来制备式(Ia)的化合物,其中Ra为芳基,其任选被氨基、(C1-C6)烷基氨基、羟基、(C1-C6)烷氧基、磺酸盐、磺酰胺、磺酰基、三氟甲基、硝基、(C1-C6)酰基或腈取代,并且Rb为氢、(C1-C6)烷基或Ra。
该氢解去保护条件如上关于方法(A)所述。
或者,可从式(XXIII)的化合物,通过拆分式(XXIII)的化合物,接着氢解去保护,来制备式(I)的化合物。
可通过用如上所定义的式(VII)化合物处理式(XXIV)的化合物,来制备式(XXIII)的化合物。
适合于该亚胺加成反应的条件如上关于方法(A)所定义。优选其中M1为MgX(X为卤化物)的有机镁(格利雅)试剂。在优选的程序中,在低温(典型地在0至-78℃的温度)下及在三氟化硼合乙醚或三氟化硼四氢呋喃络合物存在下,用适合的式(VII)的格利雅试剂处理式(XXIV)化合物在合适溶剂(例如,四氢呋喃)中的溶液。
可通过于适合的催化剂存在下,缩合式(X)的酯化合物(如在方法(A)中所定义)与式(XXV)的胺化合物,来制备式(XXIV)的化合物。
条件如关于方法(A)所述。式(XXV)的化合物可商业购得。
或者,根据第六方法(F),可通过式(XXVI)化合物的去保护来制备式(I)的化合物(其中R3及R4二者都是H、R1及R5未被卤素或氰基取代并且R2为甲基):
其中Ra及Rb如关于方法(E)所定义并且Rc为适合的手性酯基团,例如甲基或伪麻黄碱基(pseudoephidrinyl)。可在酸性或碱性条件(典型地为盐酸水溶液及二乙醚或柠檬酸水溶液及四氢呋喃)下进行该去保护。
可如在四面体(Tetrahedron);不对称(Asymmetry),1992,3,591-594及四面体快迅(Tetrahedron Letters),1982,23,4259-4262中所述,制备式(XXVI)的化合物。
或者,可通过类似的方法(其中Rc为非手性酯基团,例如C1-6烷基或苄基)来制备式(Ia)的外消旋化合物。
可通过在碱性条件下,使式(XXVII)的化合物与式(XXVIII)的亲电子试剂反应,来制备式(XXVI)的化合物:
其中LG为适合的离去基团,例如Cl、Br、I或RdSO2O(其中Rd为C1-C6烷基、CF3或任选被C1-C6烷基或硝基取代的芳基),优选Br或三氟甲磺酰基。另外,可使用添加剂(例如碘化钾)来就地形成更具反应性的亲电子试剂。典型地,使用无机碱(例如,碳酸钾或氢氧化钠)或有机碱(例如,磷氮烯碱),任选在相转移催化剂存在下,在有机溶剂(例如,二氯甲烷、四氢呋喃或甲苯)中,在-78℃至室温的温度下进行该反应。
可如四面体,2004,60,5919-5930及四面体快迅,1998,39,8775-8778中描述,来制备式(XXVII)的化合物。
也可通过类似于描述在方法(E)中的方法异构化式(XXIV)的化合物(其自身可从式(XXV)的胺化合物制备),来制备式(XXVII)的化合物。
或者,可通过甲基化式(XXIX)的化合物来制备式(XXVI)的化合物。
典型的条件包括在-78℃至室温的温度下,任选在相转移催化剂存在下,在有机溶剂(例如,二氯甲烷、四氢呋喃或甲苯)中,以适合的亲电子试剂(例如,碘甲烷、硫酸二甲酯、四氟硼酸三甲基氧盐或三氟甲磺酸甲酯)与无机碱(例如,碳酸钾或氢氧化钠)或有机碱(例如,磷氮烯碱),处理式(XXIX)的化合物。
可通过如上关于方法(F)所述,在碱性条件下,使式(XXX)的化合物与式(XXVIII)的亲电子试剂反应,来制备式(XXIX)的化合物。
或者,可如在四面体,2004,60,5919-5930及四面体快迅,1998,39,8775-8778中所述,来制备式(XXIX)的化合物。
可如在J.Org.Chem.,1982,47,2663-2666中所述,制备式(XXX)的化合物。
或者,根据第七方法(G),可通过缩合式(XXXI)的化合物与铵源或胺及氰化物源,接着水解所产生的氨基腈或乙内酰脲,来制备式(Ia)的外消旋化合物(其中R3及R4二者都是H、R1及R5未被卤素或氰基取代并且R2为甲基)。
可使用氨源(例如,乙酸铵或碳酸铵、或胺ReNH2(其中Re为C1-C6烷基、苄基或任选经氨基、(C1-C6烷基)氨基、羟基、C1-C6烷氧基、磺酸盐、磺酰氨基、磺酰基、CF3、硝基、C1-C6酰基或腈取代的芳基)及酰基阴离子同效物(例如,氰化物盐)进行该缩合。典型的水解条件包括在水性溶剂系统中,以酸或碱处理所产生的氨基腈或乙内酰脲。典型地,在室温至100℃下的温度下,以含水盐酸、氢溴酸、硫酸或磷酸、或包含6至12%过氧化氢的氢氧化钾或氢氧化钠水溶液处理该氨基腈或乙内酰脲。
或者,可在手性催化剂(例如镧-BINOL衍生的催化剂或环己基二胺衍生的催化剂)或式(XXXI)化合物的手性酮衍生物(例如手性亚胺或亚磺酰基亚胺)存在下,在酮或在适合的酮衍生物(例如,氧膦基亚胺)上进行该缩合步骤,可使用其以立体选择方式提供式(I)的化合物。
或者,根据第八方法(H),可通过式(XXXII)化合物的霍夫曼(Hoffmann)重排来制备式(I)的化合物(其中R3及R4二者都是H、R1及R5未被卤素或氰基取代并且R2为甲基):
其中Rf为H、C1-C10烷基、苄基或经取代的苄基。可合适地使用次溴酸钠或含水氢氧化钠与溴的混合物,来进行该霍夫曼重排。或者,在室温下,在乙腈与水的混合物中的苯基亚碘酰基双(三氟甲磺酸酯)将实现此转换。
可通过式(XXXIII)化合物(其中Rf如上所定义):
或式(XXXV)化合物的去对称化,来制备式(XXXII)的化合物:
可通过使所述酯基团之一与氨或氨源(例如氯化铵)或经合适保护的胺选择性反应,接着去保护,来进行该去对称化。或者,可通过将所述酯基团之一水解成羧酸,接着例如,在室温下,于乙腈中使用1,1’-羰基二咪唑及氨进行酰胺偶联,来实现该去对称化,以提供式(XXXII)的化合物(参见安吉汪达化学(Angewandte Chemie),国际版(2004),43(47),6493-6496)。可使用酶(例如,脂肪酶,例如猪肝酯酶或南极洲念珠菌(Candida Antarctica),在以水或氨为基础的溶剂系统中)或化学地(例如,使用α-甲基苄胺,接着使用碳上钯及氢在醇性溶剂中,在室温或高于室温下氢解;或使用手性催化剂及适合的胺或氨源),进行该去对称化。
可从商业可购得的式(XXXIV)的化合物,通过如方法F中所述的在碱性条件下与适合的式(XXVIII)的亲电子试剂反应,来制备式(XXXIII)及(XXXV)的化合物:
其中Rg为H、C1-C10烷基、苄基或经取代的苄基;或二个Rg基团连在一起为C(CH3)2。
或者,可从商业可购得的式(XXXVI)的化合物(其中Rg如上所定义):
通过在碱性条件下,与适合的式(XXVIII)的亲电子试剂反应,接着以适合的试剂甲基化(如在方法F中所述),来制备式(XXXIII)及(XXXV)的化合物。
或者,可通过(XXXIIa)化合物(其中Rf如上所定义)的霍夫曼重排来制备式(Ia)的化合物。
条件如上关于方法(H)所描述。
可从式(XXXIII)或(XXXV)的化合物,使用上文关于方法(H)所述的条件来制备式(XXXIIa)的外消旋化合物,但是不用对映选择性催化剂或手性试剂。
也可使用上述描述用来建构其中R1或R2已部分形成的化合物的反应,然后通过官能团操控完成该合成,来制备式(I)的化合物。例如,基团可以保护形式进行合成并且在最后步骤中去保护。希欧多拉格林尼(Theodora Greene)及彼得瓦刺(Peter Wuts)的“有机合成的保护基团”(第三版,1999,约翰威利及宋斯(John Wiley and Sons))中描述了适合的保护基团。理查德拉若克的“综合有机转换”(1999,VCH出版公司)中描述了适合的官能团转换。
式(I)的化合物可以结晶或无定形产物给药。可通过例如沉淀、结晶、冷冻干燥、喷雾干燥或蒸发干燥等方法获得它们,例如为固体塞、粉末或薄膜。为此目的,可使用微波或射频干燥。
它们可单独给药,或与一种或多种其它式(I)的化合物组合给药,或与一种或多种其它药物(或作为其任何组合)组合给药。通常来说,它们将以与一种或多种药学上可接受的赋形剂结合的制剂来给药。在本文中,使用术语“赋形剂”来描述式(I)化合物以外的任何成分。该赋形剂的选择在很大程度上将取决于多种因素,例如特定的给药方式、赋形剂对溶解度及稳定性的作用及剂型的属性。
对本领域的技术人员来说,适合于递送式(I)化合物的药物组合物及其制备方法将是非常明显的。可例如在雷明顿氏药物科学 (Remington’s Pharmaceutical Sciences),第19版(马克出版公司(MackPublishing Company),1995)中发现该组合物及其制备方法。
式(I)的化合物可口服给药。口服给药可包括吞,以便该化合物进入胃肠道,或可使用颊或舌下给药,通过该给药该化合物直接从口中进入血流。
适合于口服给药的制剂包括固体制剂,例如片剂、包含颗粒、液体、粉末的胶囊、锭剂(包括填充液体的锭剂)、咀嚼剂、多颗粒及纳米颗粒、凝胶剂、固溶体、脂质体、薄膜、卵状小体、喷雾剂及液体制剂。
液体制剂包括悬浮液、溶液、糖浆及酏剂。这类制剂可用作在软或硬胶囊中的充填剂,并且典型地包含载体(例如,水、乙醇、聚乙二醇、丙二醇、甲基纤维素或适合的油)及一种或多种乳化剂和/或悬浮剂。液体制剂也可通过固体(例如,从小药囊)的再构成来制备。
式(I)的化合物也可以快速溶解、快速崩解剂型使用,例如描述在梁(Liang)及陈(Chen)的治疗专利中的专家主张(Expert Opinion inTherapeutic Patents)(11(6),981-986,(2001))中的那些。
对于片剂剂型来说,可根据剂量,使式(I)的化合物构成该剂型的1重量%至80重量%,更典型地构成该剂型的5重量%至60重量%。除了式(I)的化合物以外,片剂通常包含崩解剂。崩解剂的实例包括淀粉羟乙酸钠、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲纤维素钠、交聚维酮、聚乙烯吡咯烷酮、甲基纤维素、微晶纤维素、经低级烷基取代的羟丙基纤维素、淀粉、预胶化淀粉及藻酸钠。通常来说,该崩解剂将包含该剂型的1重量%至25重量%,优选5重量%至20重量%。
通常使用粘合剂来对片剂制剂赋予粘附性质。适合的粘合剂包括微晶纤维素、明胶、糖、聚乙二醇、天然及合成胶、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基纤维素及羟丙基甲基纤维素。片剂也可包含稀释剂,例如乳糖(例如,一水合物、喷雾干燥的一水合物或无水形式)、甘露醇、木糖醇、右旋糖、蔗糖、山梨糖醇、微晶纤维素、淀粉及磷酸氢钙二水合物。
片剂也可任选包含表面活性剂,例如月桂基硫酸钠及聚山梨酯80;及助流剂,例如二氧化硅及滑石粉。当存在时,表面活性剂的含量可为片剂的0.2重量%至5重量%,并且助流剂的含量可为片剂的0.2重量%至1重量%。
片剂也通常包含润滑剂,例如硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酰富马酸钠,以及硬脂酸镁与月桂基硫酸钠的混合物。润滑剂的含量通常为片剂的0.25重量%至10重量%,优选为0.5重量%至3重量%。
其它可能的成分包括抗氧化剂、着色剂、调味剂、防腐剂及味道遮蔽剂。
示范性的片剂包含最高约80%的式(I)化合物,约10重量%至约90重量%的粘合剂,约0重量%至约85重量%的稀释剂,约2重量%至约10重量%的崩解剂及约0.25重量%至约10重量%的润滑剂。
片剂掺合物可直接压紧或用滚筒压紧来形成片剂。或者,片剂掺合物或掺合物的部分可在制片前经湿法制粒、干法制粒或熔融法制粒、熔化凝结或挤压。最后制剂可包含一层或多层且可经包衣或未经包衣;其甚至可装入胶囊中。
在H.莱伯门(Lieberman)及L.拉趣门(Lachman)的药物剂型:片剂 (Pharmaceutical Dosage Forms:Tablets),第1册(马赛尔蝶克(Marcel Dekker),纽约,1980)中讨论了片剂的制剂。
用于人类或兽医用途的可消耗口服薄膜典型为柔软可溶于水或水可膨胀的薄膜剂型,其可快速溶解或粘膜粘附,且典型地包含式(I)的化合物、薄膜形成性聚合物、粘合剂、溶剂、湿润剂、增塑剂、稳定剂或乳化剂、粘度改进剂及溶剂。该制剂的某些组分可发挥多种功能。
用在薄膜中的式(I)化合物可以是溶于水的或不溶于水的。可溶于水的化合物典型地包含该溶质的1重量%至80重量%,更典型地为20重量%至50重量%。较不溶的化合物可包含组合物的较大比例,典型地最高为该溶质的88重量%。或者,式(I)的化合物可以多颗粒珠的形式使用。
薄膜形成性聚合物可选自天然多糖、蛋白质或合成的水胶体,且典型地在0.01至99重量%,更典型地在30至80重量%的范围内存在。
该薄膜中的其它可能的成分包括抗氧化剂、着色剂、调味剂、调味增强剂、防腐剂、唾液刺激剂、冷却剂、共溶剂(包括油类)、润肤剂、膨胀剂、消泡剂、表面活性剂及味道遮蔽剂。
典型地通过蒸发干燥涂布到可剥离的背衬载体或纸上的薄含水膜来制备根据本发明的薄膜。这可在干燥烤箱或通道(典型在组合的涂布干燥器)中,或通过冷冻干燥或抽真空来进行。
用于口服给药的固体制剂可被配制成即释和/或调释。调释制剂包括延迟释放制剂、持续释放制剂、脉冲释放制剂、受控释放制剂、靶向释放制剂和程序化释放制剂。
美国专利第6,106,864号中描述了用于本发明的目的的合适调释制剂。在弗马(Verma)等人的在线制药技术(Pharmaceutical Technology On-line),25(2),1-14(2001)中将发现其它适合的释放技术的细节(例如,高能量分散体及渗透及经涂布的颗粒)。WO-A-00/35298中描述了使用口香糖来达到受控释放。
也可以将式(I)的化合物直接施用到血流、肌肉或内部器官中。用于肠胃外给药的适合途径包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内及皮下递送。适合于肠胃外给药的手段包括针头(包括微针头)注射器、无针注射器及输液技术。
肠胃外制剂典型地为水溶液,其可包含赋形剂,例如盐、碳水化合物及缓冲剂(优选pH为3至9),但是,对于某些应用来说,它们可更适合被配制成无菌的非水溶液或与合适介质(例如无菌、无热原的水)结合使用的干燥形式。
可使用本领域的技术人员所熟知的标准制药技术,容易地完成肠胃外制剂在无菌状态下(例如,通过冷冻干燥法)的制备。
通过使用适当的制剂技术,例如掺入溶解度提高剂,可增加在制备肠胃外制剂中使用的式(I)化合物的溶解度。
用于肠胃外给药的制剂可被配制成即释和/或调释。调释制剂包括延迟释放制剂、持续释放制剂、脉冲释放制剂、受控释放制剂、靶向释放制剂和程序化释放制剂。因此,式(I)的化合物可被配制成固体、半固体或触变性液体,用于以提供活性化合物的调释的植入储库形式给药。该制剂的实例包括已涂布药物的支架(stent)及聚(dl-乳酸-共乙醇酸)(PGLA)微球体。
也可以将式(I)的化合物局部给药至皮肤或粘膜(即,真皮或透皮肤)。用于此目的的典型制剂包括凝胶剂、水凝胶剂、洗剂、溶液、乳膏、软膏、撒布粉、敷料、泡沫剂、薄膜、皮肤贴剂、糯米纸囊剂、植入物、海绵、纤维、绷带及微乳液。也可以使用脂质体。典型的载体包括醇、水、矿物油、液状石蜡、白凡士林、甘油、聚乙二醇及丙二醇。可掺入渗透增强剂,—参见,例如,菲宁(Finnin)及摩根(Morgan)的J.Pharm.Sci.,88(10),955-958(1999年10月)。
其它局部给药的方法包括利用电穿孔法、离子电渗疗法、音波透入法(phonophoresis)、音波透入法(sonophoresis)及微针头或无针头(例如,粉末杰特(Powderject)TM、拜欧杰特(Bioject)TM等等)注射来递送。
用于局部给药的制剂可被配制成即释和/或调释。调释制剂包括延迟释放制剂、持续释放制剂、脉冲释放制剂、受控释放制剂、靶向释放制剂和程序化释放制剂。
也可以将式(I)的化合物鼻内给药或通过吸入给药,典型地从干粉吸入器中以干粉形式(单独、作为混合物(例如,与乳糖干燥混合)、或作为混合的组分颗粒(例如,与磷脂类(例如,卵磷脂)混合);或以气溶胶喷雾形式从加压的容器、泵、喷洒器、雾化器(优选使用电流体力学产生细雾的雾化器)或喷雾器来给药,其使用或不使用适合的推进剂(例如,1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷)。对于鼻内使用来说,所述粉末可包含生物粘着剂,例如,脱乙酰壳多糖或环糊精。
所述加压的容器、泵、喷洒器、雾化器或喷雾器包括式(I)化合物的溶液或悬浮液,其包含例如乙醇、含水乙醇、或适合于分散、增溶或延长活性物释放的可替代的药剂、作为溶剂的推进剂及任选的表面活性剂(例如,三油酸山梨坦、油酸或寡乳酸)。
在以干粉或悬浮液制剂使用之前,可将药物产品微粉化成适合于通过吸入递送的尺寸(典型地小于5微米)。这可利用任何适当的研粉方法,例如螺旋喷射式研磨、流化床喷射式研磨、形成纳米粒子的超临界流体加工、高压均化或喷雾干燥来达到。
可配制用于吸入器或吹入器中的胶囊(例如,由明胶或羟丙基甲基纤维素制得)、泡眼包装和药筒,以包含式(I)的化合物、适合的粉末基质(例如乳糖或淀粉)及性能改进剂(例如l-亮氨酸、甘露醇或硬脂酸镁)的粉末混合物。乳糖可以是无水的或单水合物的形式,优选后者。其它适合的赋形剂包括葡聚糖、葡萄糖、麦芽糖、山梨糖醇、木糖醇、果糖、蔗糖及海藻糖。
适合于用在利用电流体力学产生细雾的雾化器中的溶液制剂每次揿动可以含有1μg至20mg本发明化合物,揿动体积可以从1μl至100μl不等。典型的制剂可以包含式(I)化合物、丙二醇、无菌的水、乙醇和氯化钠。可以用于代替丙二醇的可替代溶剂包括甘油和聚乙二醇。
可以向打算用于吸入/鼻内给药的那些制剂中加入适合的矫味剂,例如薄荷醇和左薄荷醇,或者甜味剂,例如糖精或糖精钠。
例如使用PGLA,可以将用于吸入/鼻内给药的制剂配制成即释和/或调释。调释制剂包括延迟释放制剂、持续释放制剂、脉冲释放制剂、受控释放制剂、靶向释放制剂和程序化释放制剂。
在干粉吸入剂和气溶胶的情况下,用递送计量的量的阀门测定剂量单位。根据本发明的单位通常被安排给予计量的剂量或“喷雾”。总的日剂量将在全天中以单一剂量或者更通常以分开的剂量形式给予。
式(I)的化合物可以经直肠或阴道给药,例如以栓剂、子宫托或灌肠剂的形式。可可脂是传统的栓剂基质,但是需要时可以使用各种代用品。
用于直肠/阴道给药的制剂可以被配制成即释和/或调释。调释制剂包括延迟释放制剂、持续释放制剂、脉冲释放制剂、受控释放制剂、靶向释放制剂和程序化释放制剂。
也可以将式(I)的化合物直接给药至眼睛或耳朵,典型地以在等渗、pH调整的、无菌盐水中微粉化悬浮液或溶液的滴剂形式。其它适合于眼睛及耳朵给药的制剂包括软膏、生物可降解(例如,可吸收的凝胶海绵、胶原)及非生物可降解(例如,聚硅氧烷)的植入物、糯米纸囊剂、镜片及颗粒或小囊系统(例如,泡囊(niosomes)或脂质体)。可以与防腐剂(例如,苯扎氯铵)一起掺入聚合物例如交联的聚丙烯酸、聚乙烯醇、透明质酸、纤维素聚合物例如羟丙基甲基纤维素、羟乙基纤维素或甲基纤维素或杂多糖聚合物(例如,结兰胶(gelan gum))。也可通过离子电渗疗法递送该制剂。
用于眼睛/耳朵给药的制剂可被配制成即释和/或调释。调释制剂包括延迟释放制剂、持续释放制剂、脉冲释放制剂、受控释放制剂、靶向释放制剂或程序化释放制剂。
可以将式(I)的化合物与可溶性大分子实体(例如,环糊精或其适合的衍生物或含聚乙二醇的聚合物)组合,以便改善其在任何前述给药方式中的溶解度、溶出速率、味道遮蔽、生物利用度和/或稳定性。
例如,现已发现药物-环糊精络合物一般可用于大多数的剂型和给药途径。可以使用包合和非包合的络合物。作为与药物直接络合的替代选择,环糊精可以用作辅助添加剂,也就是作为载体、稀释剂或增溶剂。最常用于这些目的的是α-、β-与γ-环糊精,其实例可以在国际专利申请No.WO-A-91/11172、WO-A-94/02518和WO-A-98/55148中找到。
就对人类患者给药而言,式(I)化合物的总日剂量通常在1mg至1000mg的范围内,当然这取决于给药的方式和所选化合物的效力。总日剂量可以单次剂量或分开的剂量给予并且可由医生决定落在本文中给出的典型范围之外。
这些剂量是基于体重约60kg至70kg的普通人类受治疗者而言。医生将轻易地能够确定对于体重落在该范围之外的受治疗者,例如婴儿和老人的剂量。
为了避免疑问,本文对“治疗”的提及包括对治愈、缓和以及预防性治疗的提及。
可以基于J.Biol.Chem.,1996,271(10),5768-5776中所给出的方法,使用[3H]加巴喷丁及来自猪脑组织的α2δ亚基,在放射性配体结合试验中测量本发明的α-2-δ配体的生物活性。现将该试验再现如下。
[3H]加巴喷丁结合试验
脑膜的制备
在整个试验过程中,将全部溶液维持在4℃。在10体积的缓冲液A(0.32M的蔗糖/1mM的EDTA/1mM的EGTA/10mM的Hepes/KOH,pH7.4)中,通过六冲程(strokes)的玻璃/特氟隆均化器,以600r.p.m均质化猪脑皮质(最多50克)(新鲜或冷冻的)。去除1000g×10分钟沉淀小粒后,以40,000g离心上层液20分钟,且将所产生的粒状沉淀再悬浮于10体积的缓冲液B(1mM的EDTA/1mM的EGTA/10mM的Hepes/KOH,pH7.4)中。在连续搅拌30分钟后,在最后再悬浮于大约3体积的储存缓冲液(1.25mM的EDTA/1.25mM的EGTA/25%甘油/12.5mM的Hepes/KOH,pH7.4)中前,用缓冲液B通过离心如上使膜成为粒状沉淀两次,以提供每毫升含约3毫克蛋白质的浓度。将等分样贮存在-80℃下直到需要为止。
结合试验方案:
在22℃下,在10mM的Hepes/KOH(pH7.4)中,进行[3H]加巴喷丁与猪大脑皮质膜结合60分钟。将非特异结合(nsb)定义为在10μM普加巴林存在下所获得的结合。使用250微升的试验体积,其包含200微升的膜、25微升的试验化合物/缓冲液/nsb、25微升的[3H]加巴喷丁(最后试验浓度~10nM)。可使用2×1毫升的冷50mM的Tris/HCl(pH7.4),通过在真空下快速过滤通过已浸渍过冷50mM的Tris/HCl(pH7.4)的GF/B单过滤板,来实现未结合的放射性配体的分离。在加入50微升/孔的微闪烁液(microscint)-40前,放置所述板至干燥,使用脱普康(TopCount)闪烁计数器测定结合的放射性的量。结果可以IC50表示(就μM或nM来说)。
在该α-2-δ试验中测试了下面描述的全部实施例,且已发现其具有1μM或更小的结合亲和性(IC50)。例如,(2S)-2-氨基-4-乙基-2-甲基己酸(实施例1)的结合亲和性为21 nM。
可以有用地将α-2-δ受体配体与另一种药理活性化合物,或者与两种或更多种其他药理活性化合物组合,特别是在疼痛的治疗中。例如,可以与一种或多种药剂联合同时、依次或分开给予如上定义的α-2-δ受体配体,特别是式(I)的化合物或者其药学上可接受的盐或溶剂化物,所述药剂选自:
·阿片类镇痛剂,例如吗啡、海洛因、氢吗啡酮、羟吗啡酮、左吗啡、左洛啡烷、美沙酮、哌替啶、芬太尼、可卡因、可待因、二氢可待因、羟可酮、氢可酮、丙氧芬、纳美芬、纳洛芬、纳洛酮、纳曲酮、丁丙诺啡、布托啡诺、纳布啡或喷他佐辛;
·非甾族抗炎药(NSAID),例如阿司匹林、双氯芬酸、二氟尼柳、依托度酸、芬布芬、非诺洛芬、氟苯柳、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、甲氯芬那酸、甲芬那酸、萘丁美酮、萘普生、丙嗪、保泰松、吡罗昔康、舒林酸、托美丁或佐美酸;
·巴比妥类镇静剂,例如异戊巴比妥、阿普比妥、布塔巴比妥、布塔比妥、甲苯比妥、美沙比妥、美索比妥、戊巴比妥、苯巴比妥、司可巴比妥、他布比妥、theamylal或硫喷妥;
·具有镇静作用的H1拮抗剂,例如苯海拉明、吡拉明、异丙嗪、氯苯那敏或氯环利嗪;
·镇静剂,例如格鲁米特、甲丙氨酯、甲喹酮或氯醛比林;
·骨骼肌松弛剂,例如巴氯芬、卡立普多、氯唑沙宗、环苯扎林、美索巴莫或奥芬那君;
·NMDA受体拮抗剂,例如右甲吗喃((+)-3-羟基-N-甲基吗啡喃)或其代谢产物右啡烷((+)-3-羟基-N-甲基吗啡喃)、氯胺酮、美金刚、吡咯并喹啉苯醌或顺-4-(膦酰甲基)-2-哌啶甲酸;
·α-肾上腺素能剂,例如多沙唑嗪、坦索洛新、可乐定或4-氨基-6,7-二甲氧基-2-(5-甲磺酰氨基-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉;
·三环类抗抑郁剂,例如地昔帕明、丙米嗪、阿米替林或去甲替林;
·抗惊厥剂,例如卡马西平或丙戊酸盐;
·速激肽(NK)拮抗剂,特别是NK-3、NK-2或NK-1拮抗剂,例如(αR,9R)-7-[3,5-双(三氟甲基)苄基]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮芳辛并[2,1-g][1,7]-萘啶-6,13-二酮(TAK-637)、5-[[(2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基)苯基]乙氧基-3-(4-氟苯基)-4-吗啉基]-甲基]-1,2-二氢-3H-1,2,4-三唑-3-酮(MK-869)、拉奈匹坦、达匹坦或3-[[2-甲氧基-5-(三氟甲氧基)苯基]-甲氨基]-2-苯基-哌啶(2S,3S);
·毒蕈碱性拮抗剂,例如奥昔布宁、托特罗定、丙哌维林、曲司氯铵或达非那新;
·选择性COX-2抑制剂,例如塞来考昔、罗非考昔或伐地考昔;
·非选择性COX抑制剂(优选具有GI保护作用),例如硝基氟吡洛芬(HCT-1026);
·煤焦油镇痛剂,特别是对乙酰氨基酚;
·精神安定剂,例如氟哌利多;
·香草素受体激动剂(例如仙人掌毒素(resinferatoxin))或拮抗剂(例如抗辣椒碱);
·β-肾上腺素能剂,例如普萘洛尔;
·局部麻醉剂,例如美西律;
·皮质类固醇,例如地塞米松;
·5-HT受体激动剂或拮抗剂,特别是5-HT1B/1D激动剂,例如依来曲普坦、舒马曲坦、那拉曲坦、佐米曲普坦或利扎曲普坦;
·胆碱能(烟碱)镇痛剂;
·曲马朵(Tramadol)(商标);
·PDEV抑制剂,例如西地那非、伐地那非、taladafil、5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁烷基)-2,6-二氢-7H-吡唑并[4,3-d]-嘧啶-7-酮、1-{6-乙氧基-5-(3-乙基-6,7-二氢-2-(2-甲氧基乙基)-7-氧代-2H-吡唑并[4,3-d]嘧啶-5-基]-3-吡啶基磺酰基}-4-乙基哌嗪或N-[1-(2-乙氧基乙基)-5-(N-乙基-N-甲氨基)-7-(4-甲基吡啶-2-基氨基)-1H-吡唑并[4,3-d]嘧啶-3-羰基]甲磺酰胺;
·大麻素;
·代谢型谷氨酸1亚型受体(mGluR1)拮抗剂;
·5-羟色胺再摄取抑制剂,例如舍曲林;
·去甲肾上腺素再摄取抑制剂,特别是选择性去甲肾上腺素再摄取抑制剂,例如(S,S)-瑞波西汀;
·诱导型氧化氮合酶(iNOS)抑制剂,例如S-[2-[(1-亚氨基乙基)氨基]乙基]-2-甲基-L-半胱氨酸或(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚烯酸;
·乙酰胆碱酯酶抑制剂,例如多内佩齐;
·2型多巴胺(D2拮抗剂)例如齐拉西酮(ziprazidone);
·前列腺素E2 4亚型(EP4)拮抗剂,例如N-[({2-[4-(2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基)苯基]乙基}氨基)羰基]-4-甲基苯磺酰胺或4-[(1S)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]苯甲酸;
及其药学上可接受的盐和溶剂化物。
当将要给予活性化合物的组合时,可以方便地以适合于组合物共同给药的药盒(kit)形式,组合两种或更多种药物组合物。
这类药盒包含两种或更多种单独的药物组合物(其中至少一种含有α-2-δ受体拮抗剂,特别是式(I)的化合物),以及单独容纳该组合物的工具,例如容器、分离的瓶或分离的箔包装。这样的药盒的实施例是熟悉的用于包装片剂、胶囊等的泡眼包装。
这样的药盒特别适合于给予不同的剂型,例如口服和肠胃外制剂,用于以不同的剂量间隔给予单独的组合物,或者用于滴定独立的组合物。为了有助于顺应性,该药盒通常包含给药的指导,并且可以提供有所谓的记忆辅助装置。
将理解的是,本发明提供的和将要求保护的是如下方案:
(i)式(II)的化合物或其药学上可接受的盐或溶剂化物;
(ii)制备式(I)化合物或其药学上可接受的盐或溶剂化物的方法;
(iii)药物组合物,其包含式(II)的化合物或其药学上可接受的盐或溶剂化物,以及药学上可接受的赋形剂;
(iv)用作药剂的式(II)化合物或其药学上可接受的盐、溶剂化物或组合物;
(v)式(I)的化合物或其药学上可接受的盐、溶剂化物或组合物在制备用于治疗为α-2-δ受体配体的适应症的药剂中的用途;
(vi)式(I)的化合物或其药学上可接受的盐、溶剂化物或组合物在制备用于治疗疼痛的药剂中的用途;
(vii)用α-2-δ受体配体治疗哺乳动物(包括人类)的方法,其包括用有效量的式(I)化合物或用其药学上可接受的盐、溶剂化物或组合物治疗该哺乳动物;
(viii)治疗哺乳动物(包括人类)疼痛的治疗方法,其包括用有效量的式(I)的化合物或用其药学上可接受的盐、溶剂化物或组合物治疗该哺乳动物;
(ix)本文中公开的某些新颖中间体;以及
(x)式(I)或(II)的化合物与一种或多种其它药理学活性化合物的组合。
下面的实施例举例说明了式(I)化合物的制备。
在全部情况中,1H核磁共振(NMR)光谱与所提出的结构一致。以每百万分之份数偏移四甲基硅烷的低磁场给出特征化学位移(δ),使用常规缩写来指出主要峰:例如s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰;br,宽峰。使用电喷雾离子化(ESI)或大气压化学电离(APCI)来记录质谱(MS)。对于常见的溶剂,使用下列缩写:CDCl3,氘代氯仿;D6-DMSO,氘代二甲亚砜;CD3OD,氘代甲醇;THF,四氢呋喃。“氨”是指浓的氨水溶液,其具有0.88的比重。若使用薄层色谱法(TLC)时,其是指使用硅胶60 F254板的硅胶TLC,Rf为在TLC板上,化合物所移动的距离除以前端溶剂所移动的距离。使用功率范围在15至300瓦的机器,在2.45GHz处进行微波辐射,在反应过程中所提供的实际功率发生变化,以维持恒定的温度。LCMS表示液相色谱法质谱法(Rt=保留时间)。
实施例1
(2S)-2-氨基-4-乙基-2-甲基己酸
方法A
将皮尔曼催化剂(0.15克)添加到乙醇(5毫升)及1摩尔浓度盐酸水溶液(1毫升)中的(3S,5S)-3-(2-乙基丁基)-3-甲基-5-苯基吗啉-2-酮(0.15克,0.54毫摩尔,制备例1)溶液中。在氢气(414千帕,60psi)中,于室温下搅拌该反应24小时。通过Arbocel将该反应混合物过滤且以乙醇(20毫升)清洗。在减压下蒸发液体且将残余物分配在二氯甲烷(50毫升)与水(20毫升)之间。去除有机层,且以更多的二氯甲烷(50毫升)来萃取水相。在减压下蒸发水相,以提供黄色固体。利用离子交换色谱法,在都瓦克斯(Dowex)50 WX8树脂上,以0.88的氨水溶液∶水(2∶98至14∶86)洗脱,纯化该物质,获得标题化合物,为白色结晶固体(30毫克)。
1H NMR(CD3OD,400MHz)δ:0.83-0.89(m,6H),1.29-1.43(m,8H),1.58-1.62(dd,1H),1.81-1.86(dd,1H)。
LRMS(ESI):m/z 174[M+H+],172[M-H-]。
方法B
将20重量%的碳上氢氧化钯(1.0克;50重量%水湿润)添加到丙-2-醇及水(4∶1;200毫升)中的4-乙基-2-(2-羟基-1-苯基-乙氨基)-2-甲基-己酸(制备例10,10.0克;34.0毫摩尔)悬浮液中。以氮气然后以氢气清洗该容器三次,然后于氢气环境(60psi)下,在80℃下搅拌该悬浮液4小时。然后,将所得到的溶液通过Arbocel过滤且以丙-2-醇及水(4∶1;20毫升)清洗。加入丙-2-醇及水(4∶1;100毫升),然后在减压下蒸馏,收集260毫升溶剂。加入另外部分的丙-2-醇(100毫升),且在减压下通过蒸馏去除另外100毫升的溶剂。加入第三部分的丙-2-醇(100毫升),且在减压下通过蒸馏去除另外40毫升溶剂。然后,观察到粘性白色於浆,将其冷却至22℃。在22℃下搅拌所产生的於浆30分钟,然后,过滤分离出固体。以丙-2-醇(20毫升)来清洗滤饼,且在45℃在真空中干燥过夜,以获得该标题化合物(3.5克的粗产物重量,纯度98%,20.2毫摩尔,收率60%);1H-NMR(CD3OD,300MHz)δ:0.86(6H,q),1.28-1.40(5H,m),1.44(3H,s),1.57-1.63(1H,dd),1.80-1.87(1H,dd)。
实施例1.1
(2S)-2-氨基-4-乙基-2-甲基己酸苯磺酸盐
将在乙腈(50毫升)中的苯磺酸(9.5克)溶液添加到乙腈(175毫升)中的(2S)-2-氨基-4-乙基-2-甲基己酸(10克,0.057摩尔,实施例1)悬浮液中,且加热该混合物直到溶解。热过滤该溶液,且让其冷却过夜以提供标题化合物,为细白色针状物(16.5克,86%)。
1H NMR(CD3OD,400MHz)δ:0.87(m,6H),1.36(m,4H),1.41(m,1H),1.54(m,3H),1.75(m,1H),1.88(m,1H),7.42(m,3H),7.83(m,2H),4个可交换的未看见。
实施例1.2
(2S)-2-氨基-4-乙基-2-甲基己酸对甲苯磺酸盐
将乙腈(1毫升)中的对甲苯磺酸(54毫克,0.28毫摩尔)溶液添加到乙腈(1毫升)中的(2S)-2-氨基-4-乙基-2-甲基己酸(50毫克,0.28毫摩尔,实施例1)悬浮液中,且加热该混合物直到溶解。热过滤该溶液且让其冷却过夜,以获得标题化合物,为细白色针状物(69毫克,70%)。
1H NMR(CD3OD,400MHz)δ:0.88(m,6H),1.36(m,5H),1.54(s,3H),1.75(m,1H),1.90(m,1H),2.36(s,3H),7.22(d,2H),7.70(d,2H),4个可交换的未看见。
实施例1.3
(2S)-2-氨基-4-乙基-2-甲基己酸盐酸盐
通过将乙酰氯(0.04毫升)小心加入甲醇(1毫升)来制备HCl的甲醇溶液。将经冷却的溶液添加到甲醇(1毫升)中的(2S)-2-氨基-4-乙基-2-甲基己酸(100毫克,0.56毫摩尔,实施例1)悬浮液中,温热该混合物直到溶解,然后在减压下蒸发。从甲醇/乙腈中再结晶所产生的盐酸盐,以获得白色固体(63毫克,52%)。
1H NMR(CD3OD,400MHz)δ:0.87(m,6H),1.36(m,4H),1.43(m,1H),1.55(s,3H),1.75(m,1H),1.90(m,1H),4个可交换的未看见。
实施例2
2,5,5-三甲基-L-正亮氨酸
根据在实施例1中所概述的程序,从(3S,5S)-3-(3,3-二甲基丁基)-3-甲基-5-苯基吗啉-2-酮(0.394克,1.43毫摩尔,制备2)来制备标题化合物。获得白色结晶固体形式的产物(0.138克)。
1H NMR(CD3OD,400MHz)δ:0.91(s,9H),1.17-1.25(m,1H),1.28-1.36(m,1H),1.44(s,3H),1.59-1.67(m,1H),1.83-1.91(m,1H)。
LRMS(ESI):m/z 174[M+H+],172[M-H-]。
实施例3
(2S)-2-氨基-3-环戊基-2-甲基丙酸
根据在实施例1中所概述的程序,从(3S,5S)-3-(环戊基甲基)-3-甲基-5-苯基吗啉-2-酮(0.426克,1.56毫摩尔,制备例3)来制备标题化合物。获得白色结晶固体形式的产物(0.157克)。
1H NMR(CD3OD,400MHz)δ:1.08-1.22(m,2H),1.44(s,3H),1.48-1.68(m,4H),1.74-2.00(m,5H)。
LRMS(ESI):m/z 174[M+H+],172[M-H-]。
实施例4
(2S)-2-氨基-5-乙基-2-甲基庚酸
根据在实施例1中所概述的程序,从(3S,5S)-3-(3-乙基戊基)-3-甲基-5-苯基吗啉-2-酮(制备例4)来制备标题化合物。获得白色结晶固体形式的产物。
1H NMR(CD3OD,400MHz)δ:0.85-0.92(m,6H),1.16-1.48(m,7H),1.56(s,3H),1.72-1.99(m,2H)。
LRMS(ESI):m/z 188[M+H+],186[M-H-]。
实施例5
(2S)-2-氨基-3-环丁基-2-甲基丙酸
将皮尔曼催化剂(0.5克)添加到乙醇(1 5毫升)、水(2毫升)与三氟乙酸(0.5毫升)中的(3S,5S)-3-(环丁基甲基)-3-甲基-5-苯基吗啉-2-酮(0.445克,1.7毫摩尔,制备例5)溶液中。在氢气(414千帕,60psi)下,于室温下搅拌该反应24小时。将该反应混合物通过Arbocel过滤,且以乙醇(20毫升)清洗。在减压下蒸发液体,且将残余物分配在二氯甲烷(50毫升)与水(50毫升)之间。去除有机层,并以更多的二氯甲烷(50毫升)来萃取水相。在减压下蒸发水层,获得黄色固体。利用离子交换色谱法,在Dowex 50 WX8树脂上,以0.88氨水溶液∶水(2∶98至14∶86)洗脱,来纯化产物,以获得标题化合物(0.034克),为白色固体。
1H NMR(CD3OD,400MHz)δ:1.40(s,3H),1.69-1.84(m,6H),2.04-2.17(m,2H),2.41-2.54(m,1H)。
LRMS(ESI):m/z 158[M+H+],156[M-H-]。
实施例6
(2S,5R)-2-氨基-2,5-二甲基庚酸
在回流下,加热二烷(3毫升)与6N盐酸水溶液(15毫升)中的制备例8的化合物(1.10克)溶液16小时。然后让该溶液冷却至室温,蒸发溶剂且将残余物再溶解于2毫升的水中。以250毫升的去离子水来清洗DOWEX-50X8-200(25克)柱。然后负载该粗产物,且以250毫升的去离子水然后以250毫升10%的氨水溶液洗脱柱。蒸发基本级分以获得标题化合物(0.18克),为白色固体。
1H NMR(CD3OD,400MHz)δ:0.89(6H,m),1.08-1.24(2H,m),1.26-1.49(6H,m),1.56-1.65(1H,m),1.87-1.96(1H,m)。
LRMS(APCI):m/z 174[M+H+]。
实施例7
(4S)-2,4-二甲基-L-正亮氨酸
根据在实施例1中所概述的程序,从(3S,5S)-3-甲基-3-[(2S)-2-甲基丁基]-5-苯基吗啉-2-酮(0.586克,2.24毫摩尔,制备例9)来制备标题化合物,获得白色结晶固体形式的产物(0.018克)。
1H NMR(CD3OD,400MHz)δ:0.90-0.92(m,3H),0.94-0.95(m,3H),1.17-1.40(m,2H),1.45(s,3H),1.50-1.58(bs,1H),1.69-1.81(m,1H),1.70-1.83(m,1H)。
LRMS(ESI):m/z 262[M+H+]。
下列制备例显示了在上述实施例的制备中所使用的中间体它们本身是如何被合成的。
制备例1
(3S,5S)-3-(2-乙基丁基)-3-甲基-5-苯基吗啉-2-酮
在-78℃下,将三氟化硼合乙醚(5.85毫升,46毫摩尔)缓慢地添加到四氢呋喃中的(5S)-3-甲基-5-苯基-5,6-二氢-2H-1,4-嗪-2-酮(4.35克,23毫摩尔,参见WO-A-02/051983)溶液中。搅拌该溶液50分钟,然后历经40分钟加入格利雅试剂的乙醚(250毫升)溶液(从3-(溴甲基)戊烷(10.9克,66毫摩尔)与镁碎屑(2.5克,99毫摩尔)制备该格利雅试剂)。在-78℃下进一步搅拌该反应混合物75分钟,然后将其温至-20℃,且以饱和的氯化铵水溶液(100毫升)猝灭。加入更多的四氢呋喃(100毫升),且分离有机层与水层。干燥(MgSO4)有机层并在减压下浓缩。利用柱色谱法在硅胶上使用戊烷至戊烷∶乙醚(30∶70)的洗脱梯度,纯化残余物,以获得标题化合物,为白色固体(3.21克)。
1H NMR(CDCl3,400MHz)δ:0.79(q,6H),1.26-1.35(m,5H),1.41(s,3H),1.63(dd,1H),1.91(dd,1H),4.17-4.26(m,1H),4.28-4.35(m,2H),7.25-7.36(m,5H)。
LRMS(ESI):m/z 276[M+H+]。
制备例2
(3S,5S)-3-(3,3-二甲基丁基)-3-甲基-5-苯基吗啉-2-酮
历经二十分钟,将Rieke镁(343毫克,14.1毫摩尔)在四氢呋喃(13.7毫升)中的悬浮液添加到1-碘-3,3-二甲基丁烷在二乙醚(50毫升)中的溶液中,在室温下搅拌该反应40分钟。根据制备例1的方法,使用格利雅试剂溶液及(5S)-3-甲基-5-苯基-5,6-二氢-2H-1,4-嗪-2-酮(1克,5.28毫摩尔,参见WO-A-02/051983)来产生标题化合物。所合成的化合物总量为0.394克。
1H NMR(CDCl3,400MHz)δ:0.91(s,9H),1.13-1.31(m,3H),1.42(s,3H),1.67-1.77(bs,1H),2.02-2.10(m,1H),4.31-4.43(m,3H),7.34-7.46(m,5H)。
LRMS(ESI):m/z 276[M+H+]。
制备例3
(3S,5S)-3-(环戊基甲基)-3-甲基-5-苯基吗啉-2-酮
根据在制备例1中所概述的程序,使用(5S)-3-甲基-5-苯基-5,6-二氢-2H-1,4-嗪-2-酮(1克,5.28毫摩尔,参见WO-A-02/051983)及(碘代甲基)环戊烷来制备该化合物。所合成的化合物的总量为0.426克。
1H NMR(CDCl3,400MHz)δ:1.12-1.22(m,2H),1.43-1.65(m,8H),1.78-1.94(m,4H),2.13-2.18(m,1H),4.23-4.42(m,3H),7.31-7.45(m,5H)。
LRMS(ESI):m/z 274[M+H+]。
制备例4
(3S,5S)-3-(3-乙基戊基)-3-甲基-5-苯基吗啉-2-酮
根据在制备例1中所概述的程序,从(5S)-3-甲基-5-苯基-5,6-二氢-2H-1,4-嗪-2-酮(0.454克,2.39毫摩尔,参见WO-A-02/051983)及1-溴-3-乙基戊烷(参见Bull.Soc.Chim.Fr.,1975,201-205)来制备标题化合物。所合成的化合物的总量为0.07克。
1H NMR(CDCl3,400MHz)δ:0.91(s,9H),1.13-1.31(m,3H),1.42(s,3H),1.67-1.77(bs,1H),2.02-2.10(m,1H),4.31-4.43(m,3H7.34-7.46(m,5H)。
LRMS(ESI):m/z 276[M+H+]。
制备例5
(3S,5S)-3-(环丁基甲基)-3-甲基-5-苯基吗啉-2-酮
根据在制备例1中所概述的程序,从(5S)-3-甲基-5-苯基-5,6-二氢-2H-1,4-嗪-2-酮(1克,5.28毫摩尔,参见WO-A-02/051983)及(溴代甲基)环丁烷来制备标题化合物。所合成的化合物总量为0.445克。
1H NMR(CDCl3,400MHz)δ:1.43(s,3H),1.73-1.82(m,2H),1.86-1,92(m,2H),2.02-2.12(m,2H),2.14-2.19(m,1H),2.43-2.52(m,1H),4.22-4.27(m,1H),4.33-4.37(m,2H),7.31-7.43(m,5H)。
LRMS(ESI):m/z 260[M+H+]。
制备例6
(5R)-5-甲基庚-2-酮
将二环己基碳二亚胺(9.51克,46.1毫摩尔)、N,N’-二甲基-4-氨基吡啶(1.13克,9.2毫摩尔)及三乙胺(6.4毫升,46.1毫摩尔)添加到Meldrum酸(6.64克,46.1毫摩尔)在二氯甲烷(150毫升)中的溶液中。加入(4R)-4-甲基己酸(6克,46.1毫摩尔),且搅拌该反应混合物过夜。过滤该反应混合物,并以二氯甲烷(2×100毫升)来清洗固体。合并滤液及洗液,且在减压下蒸发,以获得橙色油。加入乙酸(50毫升)及水(50毫升),并在回流下加热该反应过夜。在该溶液冷却至室温后,以戊烷(100毫升)萃取它。干燥(MgSO4)有机萃取物及蒸发以提供残余物,使用柱色谱法,在硅胶上使用戊烷至戊烷∶二乙醚为19∶1的洗脱梯度来纯化该残余物,以获得标题化合物(2.8克),如淡黄色的油。
1H NMR(CDCl3,400MHz)δ:0.82-0.88(6H,m),1.07-1.19(1H,m),1.25-1.41(3H,m),1.54-1.64(1H,m),2.12(3H,s),2.34-2.47(2H,m)。
制备例7
N-[(1E,4R)-1,4-二甲基亚己基]-(S)-2-甲基丙烷-2-亚磺酰胺
将(5R)-5-甲基庚-2-酮(3克,23.4毫摩尔)在四氢呋喃(10毫升)中的溶液添加到(S)-2-甲基丙烷-2-亚磺酰胺及四乙醇钛(9.8毫升,46.8毫摩尔)在四氢呋喃中的溶液中。在50℃下搅拌该溶液20小时。让该反应混合物冷却至室温,以乙酸乙酯(50毫升)来稀释,然后将其倾入盐水(100毫升)中。剧烈搅拌层2分钟,然后过滤。分离有机层与水层且干燥(MgSO4)。在减压下蒸发溶剂,且利用柱色谱法,在硅胶上,使用1∶9的乙酸乙酯∶戊烷,然后使用3∶17的乙酸乙酯∶戊烷的洗脱梯度,来纯化残余物。该操作获得标题化合物,为淡黄色的油(3.6克)。
1H NMR(CDCl3,400MHz)δ:0.82-0.91(6H,m),1.10-1.23(10H,m),1.29-1.43(3H,m),1.54-1.65(1H,m),2.15(0.6H,s),2.30(2.4H,s),2.32-2.72(2H,m)。
LRMS;m/z ESI 232[M+H+]。
制备例8
N-[(1S,4R)-1-氰基-1,4-二甲基己基]-2-甲基丙烷-(S)-2-亚磺酰胺
将异丙醇(0.63毫升,8.2毫摩尔)添加到氰化二乙基铝在甲苯(12.3毫升)和四氢呋喃(5毫升)中的1摩尔浓度溶液的混合物中。在室温下搅拌该混合物10分钟,然后将其冷却至-78℃。历经2分钟,逐滴加入制备例7的化合物(1.9克,8.2毫摩尔)在四氢呋喃(20毫升)中的溶液。然后,在-78℃下搅拌该反应5分钟,且在室温下搅拌90分钟。然后将该反应混合物冷却至-20℃,且倾倒到已充分搅拌的乙酸乙酯(100毫升)与水(100毫升)的混合物上。将该混合物通过Arbocel过滤,且分离出乙酸乙酯层及干燥(MgSO4)。在减压下蒸发溶剂,并利用柱色谱法,在硅胶上,使用1∶4的乙酸乙酯∶戊烷,然后使用3∶7的乙酸乙酯∶戊烷的洗脱梯度,来纯化残余物。该操作获得白色固体形式的标题化合物(1.10克)。
1H NMR(CDCl3,400MHz)δ:0.86-0.93(6H,m),1.13-1.26(10H,m),1.29-1.44(3H,m),1.48-1.57(2H,m),1.64(3H,s),1.81-1.98(2H,m),3.41(1H,s)。
LRMS(APCI):m/z 259[M+H+]。
制备例9
(3S,5S)-3-甲基-3-[(2S)-2-甲基丁基]-5-苯基吗啉-2-酮
根据在制备例1中所概述的程序,从(5S)-3-甲基-5-苯基-5,6-二氢-2H-1,4-嗪-2-酮(1克,5.28毫摩尔,参见WO-A-02/051983)及(2S)-1-碘-2-甲基丁烷来制备标题化合物。所合成的化合物的总量为0.586克。
1H NMR(CDCl3,400MHz)δ:0.85-0.88(m,3H),0.94-0.96(m,3H),1.17-1.40(m,3H),1.46(s,3H),1.60(bs,1H),1.73-1.78(m1H),1.88-1.93(m,1H),4.22-4.42(m,3H),7.28-7.42(m,5H)。
LRMS(ESI):m/z[M+H+]。
制备例10
4-乙基-2-(2-羟基-1-苯基-乙氨基)-2-甲基-己酸
在-78℃下,在氮气中搅拌的同时,向(5S)-3-甲基-5-苯基-5,6-二氢-2H-[1,4]嗪-2-酮(5克,26.4毫摩尔,参见WO-A-02/051983)在无水2-甲基四氢呋喃(50毫升)中的溶液中,加入三氟化硼四氢呋喃络合物(5.8毫升,52.8毫摩尔)。然后在-78℃下搅拌所产生的溶液1小时。然后加入溴化(2-乙基丁基)镁在四氢呋喃(170毫升,0.16M,27.7毫摩尔)中的溶液,在加入期间,将温度维持在低于-60℃。在-78℃下,进一步搅拌所产生的溶液2小时。然后加入乙酸(0.6毫升10.6毫摩尔)且将该溶液温热至22℃。然后加入饱和的氯化铵水溶液(50毫升),接着加入水(100毫升)。分离相,且保留有机相。然后,在真空下蒸馏所产生的溶液至干燥。然后加入甲苯(75毫升),以水(25毫升)然后以饱和的氯化钠水溶液(25毫升)清洗该有机溶液,分离相及保留有机相。然后加入盐酸水溶液(100毫升,1.5M),且将所产生的二相性混合物温热至30℃及搅拌2小时。分离相及保留水相。然后加入氢氧化钠水溶液(47%w/w,6毫升,然后2M,16毫升),使pH为5(利用pH纸)。在22℃下搅拌所产生的於浆30分钟,然后通过过滤来分离出固体。以水(25毫升)清洗滤饼且在真空中60℃下干燥过夜,以提供标题化合物(4.1克的粗产物重量,纯度95%,14.0毫摩尔,收率53%):mp 149℃;1H-NMR(CD3OD,300MHz)δ:0.83(3H,t),0.90(3H,t),1.06(3H,s),1.31-1.54(5H,m),1.73(2H,d),4.40(1H,t),7.46-7.50(5H,m);LRMS(ES):m/z 293[M]+。
Claims (13)
1.式(II)的化合物:
或其药学上可接受的盐,其中
R7为:
(a)支链C6-C10烷基,除了4-甲基戊-1-基及1-甲基戊-1-基以外;或者
(b)被一个C3-C8环烷基取代的C1-C6烷基,除了环己基甲基以外;并且
R8为甲基,其任选被一个或多个氟基团取代。
2.根据权利要求1的式(II)的化合物或其药学上可接受的盐,其中R8为甲基。
3.根据权利要求1或权利要求2的式(II)的化合物或其药学上可接受的盐,其中R7为
(a)支链C6-C7烷基,除了4-甲基戊-1-基及1-甲基戊-1-基以外;或者
(b)被一个C3-C8环烷基取代的C1-C2烷基,除了环己基甲基以外。
4.根据权利要求1或权利要求2的式(II)的化合物或其药学上可接受的盐,其中R7为2-乙基-丁-1-基、3,3-二甲基丁-1-基、3-乙基戊-1-基、3-甲基戊-1-基、环戊基甲基、环丁基甲基或2-环丙基乙-1-基。
5.化合物,其选自如下化合物:
2,5,5-三甲基-L-正亮氨酸;
(2S)-2-氨基-3-环戊基-2-甲基丙酸;
(2S)-2-氨基-5-乙基-2-甲基庚酸;
(2S)-2-氨基-3-环丁基-2-甲基丙酸;以及
(2S,5R)-2-氨基-2,5-二甲基庚酸;
或其药学上可接受的盐。
6.化合物,其选自:(2S)-2-氨基-4-乙基-2-甲基己酸或其药学上可接受的盐。
7.根据权利要求6的化合物,其中该化合物是(2S)-2-氨基-4-乙基-2-甲基己酸。
8.根据权利要求6的化合物,其中该化合物是(2S)-2-氨基-4-乙基-2-甲基己酸苯磺酸盐。
9.根据权利要求6的化合物,其中该化合物是(2S)-2-氨基-4-乙基-2-甲基己酸对甲苯磺酸盐。
10.根据权利要求6的化合物,其中该化合物是(2S)-2-氨基-4-乙基-2-甲基己酸盐酸盐。
11.药物组合物,其包含权利要求1至10任何一项中所定义的式(II)的化合物或其药学上可接受的盐,以及药学上可接受的赋形剂。
12.一种组合物,其包含权利要求1至10任何一项中所定义的式(II)的化合物,或其药学上可接受的盐,以及另一种药理学活性化合物。
13.权利要求1至10任何一项中所定义的式(II)的化合物或其药学上可接受的盐在制备用于治疗疼痛的药物中的用途。
Applications Claiming Priority (3)
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US67602505P | 2005-04-28 | 2005-04-28 | |
US60/676,025 | 2005-04-28 | ||
PCT/IB2006/001086 WO2006114707A1 (en) | 2005-04-28 | 2006-04-19 | Amino acid derivatives |
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CN101166524A CN101166524A (zh) | 2008-04-23 |
CN101166524B true CN101166524B (zh) | 2010-12-22 |
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CN2006800141982A Expired - Fee Related CN101166524B (zh) | 2005-04-28 | 2006-04-19 | 氨基酸衍生物 |
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US (1) | US7612226B2 (zh) |
EP (1) | EP1879567A1 (zh) |
JP (2) | JP4173909B1 (zh) |
KR (1) | KR100925900B1 (zh) |
CN (1) | CN101166524B (zh) |
AP (1) | AP2007004161A0 (zh) |
AR (1) | AR054441A1 (zh) |
AU (1) | AU2006238933B2 (zh) |
BR (1) | BRPI0609879A2 (zh) |
CA (1) | CA2606353C (zh) |
CR (1) | CR9472A (zh) |
DO (1) | DOP2006000095A (zh) |
EA (1) | EA200701852A1 (zh) |
GT (1) | GT200600178A (zh) |
HK (1) | HK1116417A1 (zh) |
IL (1) | IL185790A0 (zh) |
MA (1) | MA29408B1 (zh) |
MX (1) | MX2007010978A (zh) |
NL (1) | NL1031705C2 (zh) |
NO (1) | NO20076000L (zh) |
PE (1) | PE20061435A1 (zh) |
SV (1) | SV2008002512A (zh) |
TN (1) | TNSN07400A1 (zh) |
TW (1) | TW200719889A (zh) |
UY (1) | UY29498A1 (zh) |
WO (1) | WO2006114707A1 (zh) |
ZA (1) | ZA200707678B (zh) |
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CN101195583B (zh) * | 2006-12-04 | 2012-07-04 | 四川抗菌素工业研究所有限公司 | 一种光学纯米那普仑及其盐的制备方法 |
KR20180001582A (ko) * | 2008-09-09 | 2018-01-04 | 에프. 호프만-라 로슈 아게 | 아실 설폰아미드의 다형체 |
JP2012176902A (ja) * | 2011-02-25 | 2012-09-13 | Tosoh F-Tech Inc | 新規な光学活性含フッ素化合物、その製造方法及びそれを用いた光学活性3,3,3−トリフルオロアラニンの製造方法 |
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