CN1602311A - 2－氨基－4－吡啶基甲基－二氢噻唑衍生物作为诱导型no－合酶抑制剂的用途 - Google Patents
2－氨基－4－吡啶基甲基－二氢噻唑衍生物作为诱导型no－合酶抑制剂的用途 Download PDFInfo
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- CN1602311A CN1602311A CNA028246934A CN02824693A CN1602311A CN 1602311 A CN1602311 A CN 1602311A CN A028246934 A CNA028246934 A CN A028246934A CN 02824693 A CN02824693 A CN 02824693A CN 1602311 A CN1602311 A CN 1602311A
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- pyridin
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Abstract
本发明涉及式(I)的2－氨基－4－吡啶基甲基－二氢噻唑衍生物或其药学上可接受的盐作为诱导型NO－合酶抑制剂的用途，其中：R1＝R2＝Cl，或(C1－C4)烷基，或羟基，或(C1－C4)烷氧基，或至少R1和R2两者之一是氢且另一个是(C1－C4)烷基、羟基、(C1－C4)烷氧基或氯。
Description
本发明涉及式(I)的2-氨基-4-吡啶基甲基-二氢噻唑衍生物，
或其药学上可接受的盐作为诱导型NO-合酶抑制剂的用途。
本发明的主题是式(I)的2-氨基-4-吡啶基甲基-二氢噻唑衍生物和其药学上可接受的盐在制备药物组合物中的用途，所述组合物用于预防及治疗其中涉及因诱发诱导型NO-合酶(NOS-2或iNOS)而导致的一氧化氮(NO)异常产生的疾病；含有新型2-氨基-4-吡啶基甲基-二氢噻唑衍生物及其药学上可接受的盐的药物组合物；以及新型2-氨基-4-吡啶基甲基-二氢噻唑衍生物及其药学上可接受的盐。
一氧化氮(NO)是与多种生理和病理过程有关的扩散型基团，其通过氧化L-精氨酸而合成，此反应由称为一氧化氮合酶或NO-合酶(NOS)的一族酶催化，其国际酶类命名法编号为E.C.1.14.13.39。
已知三种NOS同工酶，其中两种为组成型，一种为诱导型：
-神经元型NOS(NOS-1或nNOS)最初自神经组织分离并复制，其在所述神经组织中为组成酶。NOS-1根据基于钙和钙调蛋白的机制对各种生理刺激如膜受体激活起反应而产生NO。
-诱导型NOS(NOS-2或iNOS)可对免疫刺激如例如各种细胞中的细胞因子或细菌抗原做出反应而被诱导，这些细胞如例如巨噬细胞、内皮细胞、肝细胞、神经胶质细胞，以及许多其它类型的细胞。此等同工酶活性不受钙的调节，因此一经诱导，就会在延长的时间内产生大量的NO。
-内皮型NOS(NOS-3或eNOS)属于钙和钙调蛋白依赖性组成酶，这种NOS最初在血管内皮细胞中确认，其中，它对生理刺激如膜受体激活起反应而产生NO。
由神经元型和内皮型组成型同工酶(NOS-1和NOS-3)产生的NO通常与细胞间的信号传输功能有关。例如：血管内壁上的内皮细胞通过产生NO而诱导下面的平滑肌细胞舒张，从而有助于调节动脉压。
由诱导型NOS-2同工酶大量产生的NO尤其涉及与多种组织和器官的急性和慢性炎症相关的病理现象。
由此，因诱导NOS-2而过多产生NO在神经系统变性病变中发挥一定的作用，这些病变如例如多发性硬化症、局灶性或全脑缺血、脑或脊髓创伤、帕金森氏病、亨廷顿舞蹈病、阿尔茨海默氏病、肌萎缩性侧索硬化症、偏头痛、抑郁症、精神分裂症、焦虑症、癫痫病。与此类似，除中枢神经系统外，NOS-2的诱导也与多种具有炎性因素的病变有关，如例如糖尿病、动脉粥样硬化症、心肌炎、关节炎、关节病、哮喘、肠易激综合征、克罗恩氏病、腹膜炎、胃食管反流、葡萄膜炎、吉-巴综合征、肾小球肾炎、红斑狼疮和银屑病。NOS-2还涉及某些形式的肿瘤生长，如例如上皮瘤、腺癌或肉瘤，并涉及革兰氏阳性或革兰氏阴性细胞内或细胞外细菌感染。
过多产生NO的所有情况均是有害的，因此通过施用能够抑制NOS-2的物质来减少NO的产生应该是可取的。然而，鉴于组成型同工酶NOS-3所发挥的重要生理作用、特别是在调节动脉压方面的作用，抑制同工酶NOS-2时必须尽量减少对同工酶NOS-3的影响。事实上，已知施用非选择性NOS同工酶抑制剂会导致血管收缩和动脉压上升(Moncada，S.、Palmer，R.M.J.和Higgs，E.A.，“自L-精氨酸生物合成一氧化氮：一种调节细胞功能和通讯的途径”，Biochem.Pharmacol.，1989，38：1709-1715)。这些对心血管系统的影响是有害的，因为会减少向组织的养分供应。因此，本发明涉及对NOS-2抑制作用显著高于对NOS-3抑制作用的化合物。
基于二氢噻唑的NOS抑制剂在专利申请WO94/12165、WO95/11231和WO96/14842中特别述及。
本发明涉及式(I)的2-氨基-4-吡啶基甲基-二氢噻唑衍生物在制备用于预防或治疗疾病的有用的药品中的用途，所述疾病涉及因诱发诱导型NO-合酶(NOS-2或iNOS)而导致的一氧化氮(NO)异常产生，其中：
R1和R2相同且代表羟基、(C1-C4)烷基、氯或(C1-C4)烷氧基；
或者至少R1或R2之一是氢且另一个是(C1-C4)烷基、(C1-C4)烷氧基、羟基或氯。
在上述及以下定义中，(C1-C4)烷基和(C1-C4)烷氧基在直链或支链中含有1至4个碳原子。
式(I)化合物含有一个或多个不对称碳，因此其可以是外消旋形式或对映异构体和非对映异构体形式，这些以及其混合物也构成本发明的一部分。
此外，式(I)化合物可以是互变异构形式(Ia)：
这些互变异构体也构成本发明的一部分。
根据本发明有用的式(I)化合物中，可提及以下化合物：
4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，
4-(2-氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，
4-(2，6-二氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，其外消旋物、对映异构体、非对映异构体和其互变异构体，以及其药学上可接受的盐，更特别地是以下化合物：
(+)-4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，
4-(2-氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，
4-(2，6-二氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，其互变异构体以及其药学上可接受的盐。
根据本发明有用的且特别优选的式(I)化合物中，可以提及以下化合物：
4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，其外消旋物、对映异构体和其互变异构体，以及其药学上可接受的盐，最特别地是以下化合物：
(+)-4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，其互变异构体以及其药学上可接受的盐。
本发明还涉及药物组合物，其含有作为活性成分的式(I)衍生物，其中R1和R2相同且代表羟基、(C1-C4)烷基、氯或(C1-C4)烷氧基，或至少R1或R2之一是氢且另一个是(C1-C4)烷基、(C1-C4)烷氧基、羟基或氯，以及其外消旋物、对映异构体、非对映异构体及其混合物、其互变异构体和其药学上可接受的盐。
式(I)化合物可通过将式(II)衍生物环化而制备，
其中R1和R2具有与式(I)中相同的含义。
该环化通常在约100℃的温度下、在水性介质中用酸如盐酸进行。优选使用6N盐酸。
式(II)衍生物可根据以下反应方案获得：
这些通式中，Ra是胺功能保护基团，如那些T.W.GREENE，“有机合成中的保护基”，J.Wiley-Interscience Publication(1991)中所述的保护基，优选乙酰基或叔丁氧羰基，Rb是(C1-C4)烷基或烷氧羰基，优选甲基、乙基或异丁氧羰基，Hal是卤原子，优选氯、溴或碘。
反应a通常在(C1-C4)醇钠(优选乙醇钠)存在下、在相应的醇中、在10℃至反应介质沸点之间的温度下进行。
反应b通常在惰性溶剂如二甲基甲酰胺中、在碘化锂存在下、在100℃至反应介质沸点之间的温度下进行；或者在(C1-C4)脂肪醇中、在氢氧化钠存在下、在10℃至30℃的温度下进行，然后用盐酸水溶液(优选6N至12N)中和，之后在反应介质的沸点温度下于溶剂如二氧杂环己烷或(C1-C4)脂肪醇中加热。
反应b’优选在约100℃的温度下、使用12N盐酸进行。
为得到其中Rb为烷基的衍生物，反应b”通常在50℃至反应介质沸点之间的温度下、在无机酸如硫酸存在下，通过(C1-C4)脂肪醇(优选甲醇或乙醇)的作用进行。为得到Rb为异丁氧羰基的衍生物，此反应通常是在-20℃至0℃的温度下、在惰性溶剂如四氢呋喃中、在碱如三乙胺存在下通过氯甲酸异丁酯的作用进行。
还原反应c优选使用氢化物如硼氢化钠或氢化铝锂、在(C1-C4)脂肪醇或四氢呋喃中、于10℃至30℃的温度下进行。
其中Ra是胺功能保护基团的化合物的脱保护反应d是通过任何本领域技术人员已知的脱保护方法进行，特别是T.W.GREENE，“有机合成中的保护基”，J.Wiley-Interscience Publication(1991)中所述的那些方法。优选地，若保护基团是乙酰基，此反应使用盐酸水溶液、在约100℃的温度下进行。若保护基团是叔丁氧羰基，此反应使用盐酸、在二氧杂环己烷中、在约20℃的温度下进行。
反应e是在20℃至反应介质沸点之间的温度下、在惰性溶剂如(C1-C4)脂肪醇(优选甲醇或乙醇)中、任选在叔胺如三乙胺存在下，通过异硫氰酸叔丁酯的作用进行。
其中R1和R2是OH的式(II)化合物可通过同样的作用自式(III)化合物制备，式(III)中Z是甲硅烷基、优选叔丁基二甲基甲硅烷基，该制备方法在Synthesis 1994，486和Tetrahedron 1986，42，2725中述及。
其中R1是OH且R2是氢的式(I)化合物可根据以下反应方案制备：
这些通式中，Ra是胺功能保护基团，如那些T.W.GREENE，“有机合成中的保护基”，J.Wiley-Interscience Publication(1991)中所述的保护基，优选乙酰基或叔丁氧羰基，且Rb是(C1-C4)烷基或烷氧羰基，优选甲基、乙基或异丁氧羰基。Rc是醇功能保护基团，如那些T.W.GREENE，“有机合成中的保护基”，J.Wiley-Interscience Publication(1991)中所述的保护基，优选甲硅烷基且最特别地是叔丁基二甲基甲硅烷基。
反应a通常在10℃至反应介质沸点之间的温度下、在(C1-C4)醇钠(优选乙醇钠)存在下、在相应的醇中进行。
反应b通常在100℃至反应介质沸点之间的温度下、在碘化锂存在下、于惰性溶剂如二甲基甲酰胺中进行；或者在10℃至30℃的温度下、在氢氧化钠存在下于(C1-C4)脂肪醇中进行，然后用6N盐酸水溶液中和，之后在反应介质的沸点温度下、在惰性溶剂如二氧杂环己烷或醇如乙醇中加热。
反应b’优选在约100℃的温度下使用12N盐酸进行。
为得到其中Rb为烷基的衍生物，反应b”通常是在50℃至反应介质沸点之间的温度下、在无机酸如硫酸存在下，通过(C1-C4)脂肪醇(优选甲醇、乙醇)的作用进行。为得到其中Rb为异丁氧羰基的衍生物，此反应通常是在-20℃至0℃的温度下、在惰性溶剂如四氢呋喃中、在碱如三乙胺存在下，通过氯甲酸异丁酯的作用进行。
还原反应c优选在约10℃至约30℃的温度下、使用氢化物如硼氢化钠或氢化铝锂在(C1-C4)脂肪醇和/或四氢呋喃中进行。
保护反应d是通过任何迄今已知的醇功能保护方法进行，如那些T.W.GREENE，“有机合成中的保护基”，J.Wiley-IntersciencePublication(1991)中所述的方法，优选在约0℃至约30℃的温度下、使用叔丁基二甲基甲硅烷基氯、在碱如叔胺(优选二异丙基乙胺)存在下、在溶剂如二氯甲烷中进行。
反应e是在0℃至反应介质沸点之间的温度下、在3-氯-过苯甲酸存在下于溶剂如二氯甲烷中进行。
反应f是在10℃至反应介质沸点之间的温度下、在对甲苯磺酰氯存在下、在碱如叔胺(优选三乙胺)存在下、在溶剂如醇(优选甲醇)中进行。
其中Ra是胺功能保护基团且Rc是醇功能保护基团的化合物的脱保护反应g是通过任何本领域技术人员已知的脱保护方法进行，特别是那些T.W.GREENE，“有机合成中的保护基”，J.Wiley-Interscience Publication(1991)中所述的方法。优选地，若保护基团Ra是乙酰基且保护基团Rc是甲硅烷基且最特别地为叔丁基二甲基甲硅烷基，则此反应是在反应介质沸点温度下使用盐酸水溶液(优选6N HCl)进行。
反应h是在20℃至反应介质沸点之间的温度下、在惰性溶剂如(C1-C4)脂肪醇(优选甲醇、乙醇)中、任选在叔胺如三乙胺存在下，通过异硫氰酸叔丁酯的作用进行。
反应i通常是在反应介质的沸点温度下、使用酸如盐酸、在水性介质中进行。优选使用6N盐酸。
其中R1是OAlk且R2是氢或R1和R2均为OAlk的式(I)化合物，可分别自其中R1是OH且R2是氢或R1和R2均为OH的式(I)化合物、通过用结构为Hal-Alk的化合物进行烷基化制备。Hal代表卤原子(优选氯、溴或碘)，Alk具有与式(I)中相同的含义。此反应通常在20℃至反应介质沸点之间的温度下、在酸受体如三烷基胺(例如三乙胺)、碱金属氢氧化物(例如氢氧化钠、氢氧化钾)或碱金属氢化物(例如氢化钠)存在下、在惰性溶剂如二甲基甲酰胺、二甲亚砜、二氧杂环己烷、四氢呋喃中进行。
将式(I)化合物分离，并可通过常规已知方法、例如结晶、层析或萃取进行纯化。
式(I)化合物的对映异构体可通过拆分外消旋混合物而获得，例如按照PIRCKLE W.H.等人，“不对称合成”，第1卷，Academic Press(1983)中的手性柱层析法进行，或者通过形成盐或自手性前体合成。其非对映异构体可按照已知的常规方法(结晶、层析或自手性前体)制备。
在有机溶剂如醇、酮、醚或氯化溶剂中通过无机酸或有机酸的作用可任选将式(I)化合物转化为无机酸或有机酸的加成盐。这些盐也构成本发明的一部分。
可提及的药学上可接受的盐的实例有：苯磺酸盐、氢溴酸盐、盐酸盐、柠檬酸盐、乙磺酸盐、延胡索酸盐、葡萄糖酸盐、碘酸盐、羟乙基磺酸盐、马来酸盐、甲磺酸盐、亚甲基双-β-萘酚酸盐(methylenebis-β-oxynaphthoate)、硝酸盐、草酸盐、双羟萘酸盐、磷酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、茶碱乙酸盐(theophyllinacetate)和对甲苯磺酸盐。
式(I)化合物是诱导型NO-合酶或2型NO-合酶(NOS-2)的抑制剂，因此可用于预防及治疗与一氧化氮产生过多相关的疾病，如多发性硬化症、局灶性或全脑缺血、脑或脊髓创伤、帕金森氏病、亨廷顿舞蹈病、阿尔茨海默氏病、肌萎缩性侧索硬化症、偏头痛、抑郁症、精神分裂症、焦虑症、癫痫病、糖尿病、动脉粥样硬化症、心肌炎、关节炎、关节病、哮喘、过肠易激综合征、克罗恩氏病、腹膜炎、胃食管反流、葡萄膜炎、吉-巴综合征、肾小球肾炎、红斑狼疮和银屑病，某些形式的肿瘤如例如上皮瘤、腺癌或肉瘤的生长，以及革兰氏阳性或革兰氏阴性细胞内或细胞外细菌感染。
这些化合物作为NOS-2和NOS-3抑制剂的活性是通过测定[3H]-L-精氨酸转化为[3H]-L-瓜氨酸的转化率来确定，分别采用自脂多糖预处理(在采集组织前6小时i.p.10mg/kg)的大鼠或小鼠肺中提取的NOS-2酶级分和重组牛NOS-3市售制剂。在37℃下将化合物于HEPES缓冲液(50mM，pH6.7)中温育20至30分钟，所述缓冲液中存在5μM(当测量NOS-2活性时)或10μM(当测量NOS-3活性时)[3H]-L-精氨酸、1mM NADPH、15μM四氢生物蝶呤(tetrabiopterine)、1μM FAD、0.1mM DTT，当测定NOS-3活性时还含有10μg/ml钙调蛋白和1.25mM CaCl2。加入含有10mM EGTA的冷HEPES缓冲液(100mM，pH5.5)中止温育，并加入500mg阳离子型离子交换树脂(AG50W-X8，反离子：Na+)以从[3H]-L-瓜氨酸中分离[3H]-L-精氨酸。放置5分钟使各相分离后，用闪烁计数器在合适的闪烁液存在下测定液相中保留的放射性。使用L-[脲基-14C]-瓜氨酸作为外标，能够估算所形成的L-[3H]-瓜氨酸的回收率。
NOS-2或NOS-3的活性以反应介质中含有的每毫克蛋白每分钟所形成的[3H]-L-瓜氨酸的皮摩尔数表示。
在对NOS-2酶进行的该试验中，式(I)化合物的IC50值小于或等于10μM。
选择性是通过IC50 NOS-3/IC50 NOS-2的比值测定，化合物的选择性大于45。
式(I)化合物是低毒性的，其经皮途径施用于小鼠测得的LD50大于40mg/kg。
下列实施例说明了本发明，但并未包括全部内容。
实施例1：
(+)-4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-噻唑-2-基胺
将0.4g N-(叔丁基)-N’-[2-羟基-1-(3-甲氧基-吡啶-4-基甲基)乙基]-硫脲在4mL 6N盐酸水溶液中的混悬液在约100℃下加热18小时。然后在约40℃的温度兼减压(2kPa)条件下浓缩反应介质。将所得残余物用25mL蒸馏水处理，并用20mL二氯甲烷将混合物洗涤两次。在约40℃的温度兼减压(2kPa)条件下蒸发水相，用15mL乙醇将残余物处理两次，并根据上述条件浓缩，然后在烘箱中在约40℃的温度兼减压(10kPa)条件下干燥4小时。获得约0.31g外消旋4-(2-氨基-4，5-二氢-噻唑-4-基甲基)-1H-吡啶-2-酮盐酸盐，为浅黄色固体形式，熔点为124℃。将该产物通过CHIRALCEL OD 20μ柱、用庚烷-乙醇-三乙胺混合物(体积比为80/20/0.1)进行层析纯化。收集含有预期产物的级分并在约40℃的温度兼减压(1kPa)条件下浓缩，然后在烘箱中在约40℃的温度兼减压(10kPa)条件下干燥残余物。获得约0.0131g(+)-4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-噻唑-2-基胺，(0.5％DMSO中的αD 20＝+12.1+/-0.7)。[1H NMR谱(300MHz，(CD3)2SO d6，δ(ppm))：2.73(dd，J＝13.5和7Hz，1H)；2.80(dd，J＝13.5和7Hz，1H)；3.27(dd，J＝11.5和5.5Hz，1H)；3.62(dd，J＝11.5和7.5Hz，1H)；4.53(mt，1H)；6.13(dd，J＝6.5和1.5Hz，1H)；6.24(s大，1H)；7.34(d，J＝6.5Hz，1H)；自8.90至9.40(mf甚宽，2H)；自9.60至10.40(mf甚宽，1H)]。
N-(叔丁基)-N’-[2-羟基-1-(3-甲氧基-吡啶-4-基甲基)乙基]-硫脲
将约0.337mL异硫氰酸叔丁酯加入0.3g 2-氨基-3-(3-甲氧基-吡啶-4-基)-1-丙醇的50mL无水乙醇溶液中，然后在约20℃兼惰性气氛下将反应介质搅拌18小时。再加入0.337mL异硫氰酸叔丁酯，并在约60℃的温度下将反应混合物加热4小时。冷却后，在约40℃的温度兼减压(2kPa)条件下浓缩反应介质。得到的油在氩压力(50kPa)下用硅胶柱(粒径40-63μm，直径4cm，高22cm)层析纯化，用20％二氯甲烷/甲醇/氨水混合物(体积比为90/10/0.5)洗脱，得到10mL级分。收集含有预期产品的级分并在约40℃的温度兼减压(2kPa)条件下浓缩。得到约0.4g N-(叔丁基)-N’-[2-羟基-1-(3-甲氧基-吡啶-4-基-甲基)乙基]-硫脲，为黄色油状物形式。[红外光谱CH2Cl2：3620；3411；2972；1614；1561；1532；1400；1319；1161；1041和815cm-1]。
2-氨基-3-(3-甲氧基-吡啶-4-基)-1-丙醇
在约100℃的温度下将1.2g N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(3-甲氧基-吡啶-4-基)乙基]-乙酰胺在60ml 6N盐酸水溶液中的混合物加热30分钟。在约20℃的温度下冷却后，滴入足量的30％氢氧化钠水溶液，将pH调至约10。然后用100mL乙酸乙酯将混合物萃取三次，将有机萃取液合并，用硫酸镁干燥，然后在约40℃的温度兼减压(2kPa)条件下浓缩。得到约0.3g 2-氨基-3-(3-甲氧基-吡啶-4-基)-1-丙醇，为黄色油状物形式。[红外光谱CH2Cl2：3628；3335；2948；1614；1561；1400；1319；1162；1044和815cm-1]。
N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(3-甲氧基-吡啶-4-基)乙基]-乙酰
胺
向5.12g N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(1-氧基-吡啶-4-基)乙基]-乙酰胺在150mL无水甲醇中的混合物中加入约6g对甲苯磺酰氯，然后加入8.9mL三乙胺。在约60℃的温度下将反应介质加热96小时，然后在约40℃的温度兼减压(2kPa)条件下浓缩。用200mL二氯甲烷处理残余物，并用150mL蒸馏水和100mL氯化钠饱和水溶液洗涤三次。有机相用硫酸镁干燥、过滤，然后在约40℃的温度兼减压(2kPa)条件下浓缩。残余物在氩压力(50kPa)下用硅胶柱(粒径40-63μm，直径7cm，高30cm)层析纯化，用20％二氯甲烷/甲醇/氨水混合物(体积比为95/5/0.5)洗脱，得到10mL级分。合并含有预期产物的级分，并在约40℃的温度兼减压(2kPa)条件下浓缩。得到约1.24g N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(3-甲氧基-吡啶-4-基)-乙基]-乙酰胺，为黄色油状物形式。[红外光谱CCl4：3446；2954；2930；2858；1684；1614；1562；1499；1399；1255；1117；1043和837cm-1]。
N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(1-氧基-吡啶-4-基)-乙基]-乙酰胺
在惰性气氛、搅拌下，缓慢将约9.4g 3-氯-过苯甲酸加入21g N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(吡啶-4-基)-乙基]-乙酰胺在250mL二氯甲烷中的混合物中，然后在约40℃的温度下加热30分钟。之后，将反应介质冷却，并用200mL饱和碳酸氢钠溶液洗涤三次、再用150mL蒸馏水洗涤。有机相用硫酸镁干燥，然后在约40℃的温度兼减压(2kPa)条件下浓缩。得到的油在氩压力(50kPa)下用硅胶柱(粒径40-63μm，直径7cm，高37cm)层析纯化，相继用20％二氯甲烷/甲醇/氨水(体积比为97/3/0.5、95/5/0.5、90/10/0.5)洗脱，得到50mL级分。将含有预期产物的级分合并，并在约40℃的温度兼减压(2kPa)条件下浓缩。由此获得4.5g N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(1-氧基-吡啶-4-基)-乙基]-乙酰胺，为黄色油状物形式。[1HNMR谱(300MHz，(CD3)2SO d6，δ(ppm))；0.07(s，6H)；0.90(s，9H)；1.65(s，3H)；2.57(dd，J＝13.5和9.5Hz，1H)；2.85(dd，J＝13.5和4.5Hz，1H)；自3.40至3.60(mt，2H)；3.96(mt，1H)；7.22(d，J＝7Hz，2H)；7.73(d，J＝8Hz，1H)；8.12(d，J＝7Hz，2H)。
N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(吡啶-4-基)-乙基]-乙酰胺
在搅拌下，向25g N-(1-羟甲基-2-(吡啶-4-基)-乙基)-乙酰胺在700mL二氯甲烷中的混悬液中加入约87g叔丁基二甲基甲硅烷，然后滴加112mL二异丙基乙胺。在约20℃的温度下将反应介质搅拌24小时，然后加入蒸馏水。静置使各相分离后，有机相用250mL蒸馏水和200mL氢氧化钠饱和水溶液洗涤三次。然后用硫酸镁干燥，过滤并在约40℃的温度兼减压(2kPa)条件下浓缩。得到的油在氩压力(50kPa)下用硅胶柱(粒径40-63μm，直径11cm，高40cm)层析纯化，用20％二氯甲烷/甲醇/氨水混合物(体积比为95/15/0.5)洗脱，得到100mL级分。将含有预期产物的级分合并，并在约40℃的温度兼减压(2kPa)条件下浓缩。得到21g N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(吡啶-4-基)-乙基]-乙酰胺，为白色固体形式。[质谱DCIm/z＝309MH+]。
N-(1-羟甲基-2-(吡啶-4-基)-乙基)-乙酰胺
在惰性气氛、搅拌下，向21.5g 2-(乙酰基氨基)-3-(4-吡啶基)丙酸乙酯的800mL无水甲醇溶液中缓慢加入约8.7g硼氢化钠，温度维持在30℃以下。加完之后，继续在约20℃的温度下将反应介质搅拌24小时，然后在约30℃的温度兼减压(2kPa)条件下浓缩。残余物用450mL水处理，再用150mL二氯甲烷萃取四次。在约50℃的温度兼减压(2kPa)条件下浓缩水相，残余物在氩压力(50kPa)下用硅胶柱(粒径40-63μm，直径7.5cm，高40cm)层析纯化，用20％二氯甲烷/甲醇/氨混合物(体积比为90/10/0.5)洗脱，得到50mL级分。将含有预期产物的级分合并，并在约40℃的温度兼减压(2kPa)条件下浓缩。由此得到2.6g N-(1-羟甲基-2-(吡啶-4-基)-乙基)-乙酰胺，为固体油形式。[红外光谱(KBr)：3279；3200；2865；1647；1609；1560；1374；1080；1057；1005；907；806；566和517cm-1]。
2-(乙酰基氨基)-3-(4-吡啶基)-丙酸乙酯
将约51.2mL 5N氢氧化钠水溶液滴加至49.4g 2-(乙酰基氨基)-2-(4-吡啶基甲基)-丙二酸二乙基的600mL无水乙醇溶液中。在约20℃的温度下将混合物搅拌1小时，然后滴加21.3mL 12N盐酸水溶液，并在约70℃的温度下将反应介质加热5小时。在约20℃的温度下冷却后，在约50℃的温度兼减压(2kPa)条件下浓缩反应介质。用200mL冷乙醇处理残余物，由此形成的沉淀用30mL冷乙醇洗涤两次。按照上述条件蒸发滤液。重复以上操作几次，以从反应介质中除去氢氧化钠。由此得到43.1g 2-(乙酰基氨基)-3-(4-吡啶基)丙酸乙酯，为桔黄色油的形式。[质谱EI m/z＝236M+；m/z＝178M-NHAc；m/z＝121 C7H9N2 +；m/z＝93 C6H7N+；基峰值m/z＝43C2H3O+]。
2-(乙酰基氨基)-2-(4-吡啶基甲基)-丙二酸二乙酯
在惰性气氛、搅拌下，向750mL乙醇滴加约9g氢氧化钠。加入氢氧化钠后，将反应混合物的温度维持在约20℃，缓慢加入42g乙酰氨基丙二酸二乙酯，然后在约20℃的温度下将混合物搅拌1小时30分钟。然后，快速加入61.5g 4-溴甲基-吡啶氢溴酸盐在250mL乙醇中的混悬液，将所得混悬液在约20℃的温度下搅拌18小时。然后在约40℃的温度兼减压(2kPa)条件下浓缩反应介质。用200mL蒸馏水处理残余物，并用1N盐酸水溶液中和直至pH等于7。在约0℃温度下冷却所得混悬液，过滤，用50mL冰冷的水将不溶物洗涤两次，然后在烘箱中在约40℃的温度兼减压(10kPa)条件下干燥18小时。由此得到49.4g 2-(乙酰基氨基)-2-(4-吡啶基甲基)丙二酸二乙酯，为淡粉红色固体形式。[红外光谱CH2Cl2：3409；2895；1741；1681；1603；1496；1302；1198；1057；855；557和524cm-1]。
4-溴甲基-吡啶氢溴酸盐
在惰性气氛、搅拌下，向140g溴化三苯基膦在750mL二氯甲烷中的混悬液中加入30g 4-吡啶基-甲醇的250mL二氯甲烷溶液，将混合物的温度维持在27℃以下。在约20℃的温度下将反应介质搅拌4小时，然后将所得不溶物过滤，并用100mL二氯甲烷冲洗，旋转过滤。由此得到61.5g 4-溴甲基-吡啶氢溴酸盐，为白色固体形式。[质谱EI m/z＝171 M+；m/z＝92 C6H6N；基峰值m/z＝65 C5H5 +]。
本发明的药物组合物由式(I)化合物或该化合物的异构体或互变异构体或盐以纯物质形式或以与任何其它药学相容的可为惰性或生理活性的产品混合的组合物形式组成。本发明的药品可经口服、经肠胃外、经直肠或局部使用。
可以使用的用于口服施用的固体组合物包括片剂、丸剂、粉剂(明胶胶囊剂、扁囊剂)或颗粒剂。在这些组合物中，本发明的有效成分在氩气流下与一种或多种惰性稀释剂如淀粉、纤维素、蔗糖、乳糖或二氧化硅混合。这些组合物还可包含除稀释剂外的物质，例如一种或多种润滑剂如硬脂酸镁或滑石粉、染料、包衣物(糖衣)或光泽剂。
可以使用的用于口服施用的液体组合物包括药学上可接受的溶液剂、混悬剂、乳剂、糖浆剂和酏剂，含有惰性稀释剂如水、乙醇、甘油、植物油或液态石蜡。这些组合物还可包含除稀释剂外的物质，例如湿润产品、甜味剂、增稠剂、调味剂或稳定剂。
用于肠胃外施用的无菌组合物可优选是水性或非水性溶液剂、混悬剂或乳剂。可使用的溶剂或赋形剂包括水、丙二醇、聚乙二醇、植物油、特别是橄榄油、可注射有机酯例如油酸乙酯，或其它适宜的有机溶剂。这些组合物还可包含辅助剂，特别是润湿剂、等张剂、乳化剂、分散剂和稳定剂。灭菌可以以几种方式进行，例如通过无菌过滤、在组合物中加入灭菌剂、通过辐射或通过加热进行。它们还可制成无菌固体组合物形式，其使用时可溶于无菌水或任何其它可注射的无菌介质中。
用于直肠施用的组合物为栓剂或直肠胶囊，其除了含有活性产物外，还含有赋形剂如可可油、半合成甘油酯或聚乙二醇。
用于局部施用的组合物可以是例如乳膏剂、洗剂、滴眼剂、漱口剂、滴鼻剂或气雾剂。
对人类疾病的治疗中，本发明的化合物特别可用于治疗和/或预防多发性硬化症、局灶性或全脑缺血、脑或脊髓创伤、帕金森氏病、亨廷顿舞蹈病、阿尔茨海默氏病、肌萎缩性侧索硬化症、偏头痛、抑郁症、精神分裂症、焦虑症、癫痫病、糖尿病、动脉粥样硬化症、心肌炎、关节炎、关节病、哮喘、肠易激综合征、克罗恩氏病、腹膜炎、胃食管反流、葡萄膜炎、吉-巴综合征、肾小球肾炎、红斑狼疮、银屑病、某些形式的肿瘤如例如上皮瘤、腺癌或肉瘤的生长，以及革兰氏阳性或革兰氏阴性细胞内或细胞外细菌感染。
剂量取决于所需的效果、治疗持续时间和所使用的施用途径；通常成人一天的口服量为1mg至100mg，单位剂量含0.5mg至50mg活性物质。
一般而言，医生会根据待治疗个体的年龄、体重和所有其它个体情况确定合适的剂量。
下列实施例说明了本发明的组合物：
实施例A
根据常规技术制得含有50mg活性产物且具有以下组成的凝胶胶囊：
-式(I)化合物 ………………………………………………50mg
-纤维素………………………………………………………18mg
-乳糖…………………………………………………………55mg
-胶态二氧化硅………………………………………………1mg
-羧甲基淀粉钠………………………………………………10mg
-滑石粉………………………………………………………10mg
-硬脂酸镁………………………………………………1mg
实施例B
根据常规技术制得含有50mg活性产物且具有以下组成的片剂：
-式(I)化合物 ………………………………………… 50mg
-乳糖…………………………………………………… 104mg
-纤维素………………………………………………… 40mg
-聚维酮………………………………………………… 10mg
-羧甲基淀粉钠………………………………………… 22mg
-滑石粉………………………………………………… 10mg
-硬脂酸镁……………………………………………… 2mg
-胶态二氧化硅………………………………………… 2mg
-羟甲基纤维素、甘油、二氧化钛混合物(72-3.5-24.5)适量1片薄膜包衣成品片剂的重量为245mg。
实施例C
含有10mg活性产物且具有以下组成的注射液：
-式(I)化合物 ………………………………………… 10mg
-苯甲酸………………………………………………… 80mg
-苄醇…………………………………………………… 0.06ml
-苯甲酸钠……………………………………………… 80mg
-95％乙醇……………………………………………… 0.4ml
-氢氧化钠……………………………………………… 24mg
-丙二醇………………………………………………… 1.6ml
-水……………………………………………………… 适量4ml
本发明还涉及预防和治疗其中涉及因诱发诱导型NO-合酶(NOS-2或iNOS)而导致的一氧化氮(NO)异常生成的疾病的方法，其通过施用式(I)化合物、其外消旋混合物、对映异构体、非对映异构体以及其混合物、其互变异构体和其药学上可接受的盐进行。
Claims (18)
1.式(I)化合物，
其中：
R1和R2相同且代表羟基、(C1-C4)烷基、氯或(C1-C4)烷氧基；
或者至少R1或R2之一是氢且另一个是(C1-C4)烷基、(C1-C4)烷氧基、羟基或氯；
其中(C1-C4)烷基和(C1-C4)烷氧基在直链或支链中含有1至4个碳原子；
其外消旋物、对映异构体、非对映异构体及其混合物、其互变异构体和其药学上可接受的盐。
2.权利要求1的化合物，其中式(I)化合物选自以下化合物：
4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-噻唑-2-基胺，
4-(2-氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，和
4-(2，6-二氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，其外消旋物、对映异构体、非对映异构体及其混合物、其互变异构体和其药学上可接受的盐。
3.权利要求1或2的化合物，其中式(I)化合物选自以下化合物：
(+)-4-(2-羟基-吡啶-4-基甲基)-4，5-二氢-噻唑-2-基胺，
4-(2-氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，和
4-(2，6-二氯-吡啶-4-基甲基)-4，5-二氢-1，3-噻唑-2-基胺，其互变异构体以及其药学上可接受的盐。
4.权利要求1至3的化合物，其用作药品。
5.药物组合物，其含有处于药学上可接受的介质中的权利要求1至3所定义的化合物。
6.权利要求4的药品，其中所述药品包含至少一种权利要求1至3所定义的化合物，医治性应用于治疗其中涉及因诱发诱导型NO-合酶(NOS-2)而导致的一氧化氮(NO)异常生成的疾病。
7.权利要求4的药品，其中所述药品包含至少一种权利要求1至3所定义的化合物，医治性应用于治疗帕金森氏病。
8.制备如权利要求1中所定义的式(I)化合物的方法，其中将式(II)衍生物环化，
其中R1和R2具有与权利要求1中相同的含义，并任选将其转化为药学上可接受的盐。
9.权利要求8的制备方法，其中的环化在约100℃的温度下、在酸性介质中进行。
10.权利要求9的制备方法，其中酸性介质优选为6N盐酸。
11.制备如权利要求8所定义的且其中R1和R2具有与权利要求1中相同的含义的式(II)化合物的方法，包括以下步骤：使式(IIa)化合物，
其中Ra是氢原子或胺功能保护基团如CO2tBu或Ac，且Rb是烷基或烷氧羰基，
受到还原剂的作用，以便获得式(IIb)化合物，
使式(IIb)化合物受到脱保护剂的作用，以便获得式(IIc)化合物，
使式(IIc)化合物受到异硫氰酸叔丁酯的作用，以便获得式(II)化合物，
12.制备如权利要求1中所定义的其中R1是OH且R2是H的式(I)化合物的方法，包括将式(IV)衍生物环化的步骤，
并任选将产物转化为药学上可接受的盐。
13.权利要求12的制备方法，其中的环化在约100℃的温度下、在酸性介质中进行。
14.权利要求13的制备方法，其中酸性介质优选为6N盐酸。
15.制备权利要求12的式(IV)化合物的方法，包括以下步骤：在碱存在下、在醇溶剂中使式(V)化合物，
其中Ra和Rc是氢或胺和醇功能保护基团，如Ra是COMe或COOtBu且Rc是叔丁基二甲基甲硅烷基，
受到对甲苯磺酰氯的作用，以便获得式(VI)化合物，
使式(VI)化合物受到脱保护剂的作用，以便获得式(VII)化合物，
使式(VII)化合物受到异硫氰酸叔丁酯的作用，以便获得如权利要求12所定义的式(IV)化合物。
16.如权利要求15所定义的式IV、V、VI、VII化合物。
17.如权利要求11所定义的式II、IIa、IIb、IIc化合物，2-乙酰基氨基-3-(2-乙氧基-吡啶-4-基)-丙酸乙酯除外。
18.化合物，其为
N-(叔丁基)-N’-[2-羟基-1-(3-甲氧基-吡啶-4-基-甲基)乙基]-硫脲；
2-氨基-3-(3-甲氧基-吡啶-4-基)-1-丙醇；
N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(3-甲氧基-吡啶-4-基)乙基]-乙酰胺；和
N-[1-(叔丁基-二甲基-甲硅烷氧基甲基)-2-(1-氧基-吡啶-4-基)-乙基]-乙酰胺。
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| FR01/14508 | 2001-11-09 | ||
| FR0114508A FR2832150B1 (fr) | 2001-11-09 | 2001-11-09 | Utilisation de derives de 2-amino-4-pyridylmethyl-thiazoline comme inhibiteurs de no-synthase inductible |
| US35297802P | 2002-01-30 | 2002-01-30 | |
| US60/352,978 | 2002-01-30 |
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| ES2572263T3 (es) * | 2005-10-25 | 2016-05-31 | Shionogi & Co | Derivados de dihidrooxazina y tetrahidropirimidina como inhibidores de BACE 1 |
| EP2147914B1 (en) | 2007-04-24 | 2014-06-04 | Shionogi&Co., Ltd. | Aminodihydrothiazine derivatives substituted with cyclic groups |
| EP2151435A4 (en) | 2007-04-24 | 2011-09-14 | Shionogi & Co | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALZHEIMER'S DISEASE |
| KR101324426B1 (ko) | 2008-06-13 | 2013-10-31 | 시오노기세야쿠 가부시키가이샤 | β 세크레타제 저해 작용을 갖는 황 함유 복소환 유도체 |
| EP2360155A4 (en) | 2008-10-22 | 2012-06-20 | Shionogi & Co | 2-AMINOPYRIDIN-4-ON AND 2-AMINOPYRIDINE DERIVATIVE WITH BACE1-HEMDERING EFFECT |
| CN102834384A (zh) | 2009-12-11 | 2012-12-19 | 盐野义制药株式会社 | *嗪衍生物 |
| WO2012057248A1 (ja) | 2010-10-29 | 2012-05-03 | 塩野義製薬株式会社 | ナフチリジン誘導体 |
| US9018219B2 (en) | 2010-10-29 | 2015-04-28 | Shionogi & Co., Ltd. | Fused aminodihydropyrimidine derivative |
| EP2703399A4 (en) | 2011-04-26 | 2014-10-15 | Shionogi & Co | OXAZINE DERIVATIVE AND BACE-1 HEMMER THEREOF |
| WO2014065434A1 (en) | 2012-10-24 | 2014-05-01 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having bace1 inhibitory activity |
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| AU4149696A (en) * | 1994-11-15 | 1996-06-06 | Merck & Co., Inc. | Substituted heterocycles as inhibitors of nitric oxide synthase |
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| HRP20040402A2 (en) | 2004-10-31 |
| HUP0402033A2 (hu) | 2005-02-28 |
| DE60234117D1 (de) | 2009-12-03 |
| IL161843A (en) | 2011-08-31 |
| NO20033131L (no) | 2003-08-27 |
| JP2005517634A (ja) | 2005-06-16 |
| MXPA04004213A (es) | 2004-07-08 |
| SI1450750T1 (sl) | 2010-02-26 |
| PT1450750E (pt) | 2010-01-18 |
| CA2465877C (fr) | 2009-12-29 |
| MA27143A1 (fr) | 2005-01-03 |
| CN1288153C (zh) | 2006-12-06 |
| EP1450750A2 (fr) | 2004-09-01 |
| JP4342309B2 (ja) | 2009-10-14 |
| IL161843A0 (en) | 2005-11-20 |
| DK1450750T3 (da) | 2010-03-08 |
| WO2003039446A2 (fr) | 2003-05-15 |
| US6762196B2 (en) | 2004-07-13 |
| CA2465877A1 (fr) | 2003-05-15 |
| CY1110284T1 (el) | 2015-01-14 |
| PL370267A1 (en) | 2005-05-16 |
| WO2003039446A3 (fr) | 2003-11-27 |
| EP1450750B1 (fr) | 2009-10-21 |
| ES2335090T3 (es) | 2010-03-22 |
| RU2004117531A (ru) | 2005-04-10 |
| NO20033131D0 (no) | 2003-07-08 |
| BR0206368A (pt) | 2004-02-10 |
| US20030153605A1 (en) | 2003-08-14 |
| ATE446295T1 (de) | 2009-11-15 |
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