CN101341125B - 作为缓激肽拮抗剂的菲啶衍生物 - Google Patents
作为缓激肽拮抗剂的菲啶衍生物 Download PDFInfo
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- CN101341125B CN101341125B CN200680048197XA CN200680048197A CN101341125B CN 101341125 B CN101341125 B CN 101341125B CN 200680048197X A CN200680048197X A CN 200680048197XA CN 200680048197 A CN200680048197 A CN 200680048197A CN 101341125 B CN101341125 B CN 101341125B
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- Prior art keywords
- dihydro
- phenanthridines
- chloro
- benzenesulfonyls
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
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- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
本发明涉及式(I)的新的菲啶衍生物,其中的变量如说明书中所定义,涉及生产它们的方法,涉及含有它们的药理学组合物,以及涉及它们在治疗或预防疼痛和炎性过程中的应用。
Description
发明领域
本发明涉及式(I)的新的菲啶衍生物和其旋光对映体或外消旋体和/或盐和/或水合物和/或溶剂化物,它们可以用于治疗或预防疼痛和炎症过程。本发明也涉及生产式(I)化合物的方法和含有它们的药理学组合物。
发明背景
激肽是应答组织损伤或感染,在激肽释放酶催化切割激肽原后在血浆和外周组织中形成的内源肽。激肽在伴随疼痛和炎症的病理生理学过程中起重要作用。它们的生物学作用由表示为B1和B2的2种G-蛋白偶联的膜受体介导。已经克隆了B1和B2受体[Biochem.Biophys.Res.Commun.,184(1992)260-268和J.Biol.Chem.,269(1994)21583-21586],调节它们的表达、自我维护和信号转导功能的机理正在集中研究中[Pharmacol.Rev.,57(2005)27-77]。
第一组激肽即缓激肽(BK)和血管舒张素(LysBK)优先通过刺激广泛分布于许多组织中的组成型表达的且快速脱敏的B2受体起作用。另一方面,它们的有活性的羧肽酶代谢产物即第二组激肽desArg9BK(DABK)和LysdesArg9BK(LysDABK)会激活在非病理条件下罕见表达的诱导型且非脱敏的B1受体。通常,B1受体在不同性质的损伤(组织创伤,感染等)后快速出现。因而,B1受体上调似乎是全身反应的一部分,后者包括酶、受体、自身活性物质、细胞因子和趋化因子的局部共表达(最终上调),众所周知它们在组织对不同类型的损伤的早期和晚期应答中起关键作用。
在动物模型中已经证实,在慢性炎症状态中存在从B2至B1的功能优势转换。B2受体涉入炎症和疼痛应答的急性期,而B1受体则参 与该应答的慢性期。激肽受体在炎症和疼痛转导中的涉入,已经得到了在缺乏缓激肽B1受体的小鼠上进行的研究结果的支持。B1受体缺陷型小鼠在感觉功能方面不同于野生型小鼠,表现出对有害化学物质和热刺激的止痛阈值增加,和多形核白细胞在炎症位点积聚的急剧减少[PNAS,97(2000)8140-8145和Neuropharmacology 41(2201)1006-1012]。此外,在B1受体缺陷型小鼠中的最原始发现是,中枢激肽受体在伤害感受中的作用的直接证据,表明在B1-受体敲除的小鼠中观察到的痛觉减退部分地归因于脊髓中减少的中枢敏化。但是,除了上述变化以外,B1敲除的小鼠表面上是正常的,没有任何明显的病理学变化。
除了B1受体在外周的基础表达的证据以外,最近越来越多的证据表明,B1受体在有些神经元元件中组成型地“中枢”表达,包括脊髓和有些高级结构。这些受体的功能尚不清楚,但是它们已经涉入疼痛传递和痛觉过敏。因此,认为B1受体拮抗剂可以用于减轻疼痛,这不仅通过外周位点,而且如果它们也会阻断中枢B1受体的话,可能会具有更广谱的镇痛作用[NeuroReport 11(2000)4003-4005;NeuroReport,12(2001)2311-2313;Neuroscience 107(2001)665-673和Neuroscience Letters 294(2000)175-178]。
在科学数据的基础上,缓激肽受体以几种途径参与疼痛和痛觉过敏的介导。B1受体拮抗剂可能具有不同的作用模式。它们具有(1)对伤害性感受器的间接(′外周′)作用,这是通过抑制其它产生疼痛的介质(前列腺素,细胞因子和氧化亚氮)从除感觉神经元以外的细胞(巨噬细胞,成纤维细胞或内皮细胞)释放;(2)对表达B1受体(组成型)的伤害性感受器的直接(′外周′)作用,或经诱导(3)对脊髓浅表背角中的疼痛处理的“中枢”作用。
因此,口服活性的非肽缓激肽B1受体拮抗剂可以是治疗慢性炎性疼痛的潜在治疗剂。
发明概述
我们已经发现了一类菲啶衍生物,它们具有对缓激肽B1受体的高亲和力和相对于缓激肽B2受体的选择性。该选择性是特别重要的,因为化合物的不希望的副作用不显著得多。
本发明涉及式(I)的新的菲啶衍生物
其中
R1是氢原子或C1-C4烷基;
R2选自(1)氢原子;条件是,R1和R2不能同时是氢原子;(2)-(CH2)n-NRaRb,(3)-(CH2)n-CO-NRaRb,(4)-(CH2)m-X-Q,(5)-CHRc-NRaRb;
或
R1和R2与它们结合的氮原子一起形成含有1-3个选自O、S和N的杂原子的4-7元杂环;其中所述环可选地被下述取代基取代:-CO-NRaRb,C1-C4烷基,4-(4,5-二氢-1H-咪唑-2-基)-苄基或4-(1,4,5,6-四氢-嘧啶-2-基)-苄基;
R3,R4,R5,R6和R7彼此独立地是氢原子,卤素原子,三氟甲基,C1-C4烷基,C1-C4烷氧基,或乙酰基;
n是1-4的整数;
Ra和Rb是氢原子,可选被取代的C1-C4烷基,或Ra、Rb和它们二者结合的氮原子一起形成含有1-3个选自O、S和N的杂原子的饱和的、部分不饱和的或芳族4-7元环;其中所述环可选地被下述取代基取代:1-哌啶基,2-哌啶基,4-哌啶基,2-吡啶基或4-吡啶基;
Rc是甲基,羟甲基,苄基或苯基;
m是0-6的整数;
X是单键,O或S;
Q是苯基,它可选地被下述取代基取代:[1,4′]联哌啶-1′-基,4,5-二氢-1H-咪唑-2-基,-(CH2)n-NH-(C=NH)-NH2或-(CH2)m-(C=NH)-NH2基团;或4-哌啶基,它可选地被下述取代基取代:4-哌啶基;或C5-C7环烷基,它可选地被下述取代基取代:-(CH2)m-NRaRb 基团,
和其旋光对映体或外消旋体和/或盐和/或水合物和/或溶剂化物。
本发明也涉及药物组合物,其含有式(I)化合物或其旋光对映体或外消旋体或盐或水合物或溶剂化物作为活性成分。
此外,本发明的目的是,式(I)化合物的合成,和含有这些化合物的药物的化学和制药生产,以及使用这些化合物的治疗方法,这是指,给待治疗的哺乳动物(包括人)施用有效量的本发明的式(I)化合物本身或作为药物。
发明详述
本发明涉及式(I)的新的缓激肽B1受体拮抗剂菲啶衍生物
其中
R1是氢原子或C1-C4烷基;
R2选自(1)氢原子;条件是,R1和R2不能同时是氢原子;
(2)-(CH2)n-NRaRb,(3)-(CH2)n-CO-NRaRb,(4)-(CH2)m-X-Q,(5)-CHRc-NRaRb;
或
R1和R2与它们结合的氮原子一起形成含有1-3个选自O、S和N的杂原子的4-7元杂环;其中所述环可选地被下述取代基取代:-CO-NRaRb,C1-C4烷基,4-(4,5-二氢-1H-咪唑-2-基)-苄基或4-(1,4,5,6-四氢-嘧啶-2-基)-苄基;
R3,R4,R5,R6和R7彼此独立地是氢原子,卤素原子,三氟甲基,C1-C4烷基,C1-C4烷氧基,或乙酰基;
n是1-4的整数;
Ra和Rb是氢原子,可选被取代的C1-C4烷基,或Ra、Rb和它们二者结合的氮原子一起形成含有1-3个选自O、S和N的杂原子的饱和的、部分不饱和的或芳族4-7元环;其中所述环可选地被下述取代基取代:1-哌啶基,2-哌啶基,4-哌啶基,2-吡啶基或4-吡啶基;
Rc是甲基,羟甲基,苄基或苯基;
m是0-6的整数;
X是单键,O或S;
Q是苯基,它可选地被下述取代基取代:[1,4′]联哌啶-1′-基,4,5-二氢-1H-咪唑-2-基,-(CH2)n-NH-(C=NH)-NH2或-(CH2)m-(C=NH)-NH2基团;或4-哌啶基,它可选地被下述取代基取代:4-哌啶基;或C5-C7环烷基,它可选地被下述取代基取代:-(CH2)m-NRaRb 基团,
和其旋光对映体或外消旋体和/或盐和/或水合物和/或溶剂化物。
本发明也涉及药物组合物,其含有式(I)化合物或其旋光对映体或外消旋体或盐或水合物或溶剂化物作为活性成分。
此外,本发明的目的是,式(I)化合物的合成,和含有这些化合物的药物的化学和制药生产,以及使用这些化合物的治疗方法,这是指,给待治疗的哺乳动物(包括人)施用有效量的本发明的式(I)化合物本身或作为药物。
术语“卤素”取代基表示氟、氯、溴或碘原子。在本说明书中使用的术语C1-C4烷基表示甲基,乙基,正丙基和异丙基和不同的丁 基。这些C1-C4烷基可以是在C1-C4烷氧基和C1-C4烷氧基羰基中。
在R1和R2的含义中,4-7元杂环可以是例如哌啶,吡咯烷,哌嗪,高哌嗪,吗啉,硫代吗啉等。
在Ra和Rb的含义中,C1-C4烷基可以被例如4-哌啶基、1-吡咯烷基或哌嗪基取代。
在Ra和Rb的含义中,饱和的、部分不饱和的或芳族4-7元环可以是例如哌啶,吡咯烷,哌嗪,高哌嗪,吗啉,硫代吗啉等。
本发明也涉及式(I)化合物与酸或碱形成的盐。
有机和无机酸都可以用于酸加成盐的形成。适合的无机酸可以是例如盐酸、硫酸和磷酸。一价有机酸的代表可以是例如甲酸、乙酸、三氟乙酸、丙酸和不同的丁酸、戊酸和癸酸。二价有机酸的代表可以是例如草酸、丙二酸、马来酸、富马酸和琥珀酸。也可以使用其他有机酸,例如羟基酸,例如柠檬酸、酒石酸,或者芳族羧酸,例如苯甲酸或水杨酸,以及脂族和芳族磺酸,例如甲磺酸和对甲苯磺酸。尤其有价值的酸加成盐组是其中酸组分本身在所应用的剂量不具有治疗效果,或者它对活性成分的效应不具有不利的影响。这些酸加成盐是药学上可接受的酸加成盐。不属于药学上可接受的酸加成盐的酸加成盐也属于本发明,其原因是在既定的情况下它们能够有利于所需化合物的纯化和分离。
在与碱形成的盐中,特别重要的是与碱金属(例如钠、钾)、碱土金属(例如钙和镁)以及与氨或有机胺形成的盐。后面的碱可以具有进一步的取代基,例如羟基或胺基,其可以影响例如产物的溶解度和操作处理。与碱形成的盐是药学可接受的碱加成盐。
根据本发明,可以如下合成式(I)化合物:
在有催化剂、优选四(三苯膦)-钯(0)存在下,使式(II)的硼酸衍生物
其中R6和R7的含义如上所定义
与式(III)的2-溴苯胺反应
然后将这样得到的式(IV)氨基-联苯衍生物
其中R6和R7的含义如上所定义,
用式(V)磺酰氯衍生物磺酰化
其中R3,R4和R5的含义如上所定义,
根据文献[J.Org.Chem.63(1998)5211-5215]所述的方法,对形成的式(VI)磺酰胺衍生物进行环化反应
其中R3,R4,R5,R6和R7的含义如上所定义,
将所得到的式(VII)菲啶乙酸酯衍生物在有碱存在下水解
其中R3,R4,R5,R6和R7的含义如上所定义,且R是C1-C4烷基以提供式(VIII)的菲啶乙酸衍生物
其中R3,R4,R5,R6和R7的含义如上所定义,
然后使后者与式(IX)的胺衍生物反应
其中R1和R2的含义如上所定义,
通过引入新的取代基和/或修饰或去除现有的取代基,和/或成盐 和/或从盐释放出化合物,可以将给定情况中所得到的式(I)菲啶衍生物转化成其它式(I)化合物。
磺酰化反应优选地在合适溶剂中进行,优选在有碱存在下。反应后进行薄层色谱。必要的反应时间是6-20h。通过不同的方法,可以进行反应混合物的后处理。
a)浓缩反应混合物,通过结晶或萃取分离产物。如果粗产物不够纯,则可以使用柱色谱来进行纯化。柱色谱在正相上进行,使用Kieselgel 60作为吸附剂,使用不同的溶剂系统例如正己烷/乙酸乙酯、氯仿/甲醇、二氯甲烷/乙酸乙酯或氯仿/丙酮作为洗脱剂,或在反相上进行,使用YMC-Pack ODS-AQ型填料(packing)(YMC生产),使用乙腈/水/三氟乙酸作为洗脱剂。
b)将反应混合物倒入冰-水中,通过过滤或萃取分离产物。将粗产物结晶或通过如上所述的柱色谱纯化。通过IR、NMR和质谱,测定产物的结构。
优选地,通过从式(VIII)的羧酸制备活性衍生物,使其优选地在碱存在下与式(IX)的胺反应,形成酰胺键。
在酰胺键形成期间,在适当的溶剂(例如二甲基甲酰胺、乙腈、氯代烃类或烃类)中,羧酸可在原位转化为活性衍生物。活性衍生物可以是酰氯(例如用亚硫酰氯从羧酸制备)、混合酐(例如在碱例如三乙胺存在下,用氯甲酸异丁酯从羧酸制备)、活性酯(例如在碱例如三乙胺存在下,用羟基苯并三唑(HOBt)和二环己基碳二亚胺(DCC)或O-苯并三唑-1-基-N,N,N′,N′-四甲基脲六氟磷酸盐(HBTU)从羧酸制备)、酰基叠氮(例如从羧酸酰肼制备)。活性衍生物可以在0℃到室温的温度范围制备。出于释放胺的需要,在碱例如三乙胺存在下,向这样得到的溶液或悬浮液中加入作为碱或作为与无机酸形成的盐的适当的式(IX)的胺。缩合反应后进行薄层色谱。必要的反应时间是6-20小时。可通过不同方法进行反应混合物的后处理。
当反应混合物是悬浮液时,滤出沉淀,用水和/或用有机溶剂洗涤,且从适当溶剂中重结晶,以得到纯产物。如果结晶没有产生纯产 物,那么为了纯化产物可使用柱色谱。使用Kieselgel 60作为吸附剂,使用不同的溶剂系统例如甲苯/甲醇、氯仿/甲醇、或甲苯/丙酮作为洗脱剂,在正相上进行柱色谱;或在反相上进行,使用YMC-PackODS-AQ型填料(YMC生产),使用乙腈/水/三氟乙酸作为洗脱剂。如果反应混合物在酰胺键形成反应结束时是溶液,将其浓缩,且将残余物结晶或用适当有机溶剂萃取,并在给定情况中通过如上所述的柱色谱纯化。产物的结构通过IR、NMR和质谱法分析确定。
所得的式(I)的酰胺衍生物(从制备方法独立得到)在给定情况中下可以通过引入进一步的取代基和/或修饰和/或除去现存的取代基,和/或通过用酸形成盐,和/或通过以碱处理从获得的酸加成盐释放式(I)苯酰胺衍生物,转化为另一种式(I)化合物,和/或通过用碱处理可以将式(I)的游离磺酰胺衍生物转化为盐。
式(II)的硼酸和式(V)的磺酰氯可商业上得到。大多数式(IX)的胺可以通过不同的已知方法来合成。在实施例中描述了有些新的式(IX)的胺的合成。遵循这些操作,也可以制备式(IX)的其它胺。
本发明化合物以及它们的药学可接受的盐或水合物或溶剂化物可以原样使用,或合适地以药物组合物形式使用。这些组合物(药物)可以是固体、液体或半液体形式,且可以加入通常在实践中使用的药物辅剂和辅助材料,例如载体、赋形剂、稀释剂、稳定剂、湿润或乳化剂、pH和渗透压调节剂、调味剂或加香剂以及促进配制或提供制剂的添加剂。
在各特定情形下起到治疗作用所需要的剂量可根据以下情况在宽限度内改变并将适合个体需要:疾病的阶段、待治疗患者的状况和体重,以及患者对活性成分的敏感性、给药途径和每天治疗的次数。待使用的活性成分的实际剂量可以由了解待治疗的患者的拥有本领域技能的主治医生来安全地确定。
含本发明活性成分的药物组合物通常在单个剂量单位中包含0.01-100mg活性成分。当然,在一些组合物中的活性成分量有可能超出上面定义的上限或下限。
固体形式的药物组合物可以是例如片剂、糖锭剂、胶囊剂、丸剂或用于制备注射剂的冻干粉安瓿。液体组合物是可注射的和可输注的组合物、流体药物、包装液和滴剂。半液体组合物可以是软膏剂、香脂剂、乳膏剂、震荡合剂和栓剂。
为了给药简单,药物组合物合适地包括含一定量的活性成分的剂量单位,所述量有待一次或几次给药,或其二分之一或三分之一或四分之一部分。这样的剂量单位是例如片剂,该片剂能够用促进对分或四分片剂的沟来粉碎,以便精确施用所需量的活性成分。
片剂可以包有酸溶解层,以确保在离开胃之后释放活性成分内含物。这样的片剂是肠包衣的。通过将活性成分装入胶囊,也能得到类似效应。
口服给药的药物组合物可以含有例如乳糖或淀粉作为赋形剂,羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷或淀粉糊作为粘合剂或粒化剂。加入马铃薯淀粉或微晶纤维素作为崩解剂,但也可使用超支链淀粉或甲醛酪蛋白。滑石粉、胶体硅酸、硬脂精、硬脂酸钙或硬脂酸镁可用作防粘剂或润滑剂。
片剂可以例如通过湿法粒化之后压制来制造。在适当的设备中,将混合的活性成分和赋形剂以及在给定情况中一部分崩解剂与粘合剂的水溶液、醇溶液或水醇溶液粒化,然后干燥颗粒。将其它崩解剂、润滑剂和防粘剂加入干燥的颗粒中,并将混合物压制成片剂。在给定情况中,片剂制有平分沟,以方便给药。
通过压制,可从活性成分和适当的辅料的混合物直接制备片剂。在给定情况中,片剂可以通过使用在制药实践中常用的添加剂进行包衣,例如稳定剂、调味剂、调色剂如糖、纤维素衍生物(甲基纤维素或乙基纤维素、羧甲基纤维素钠等)、聚乙烯吡咯烷酮、磷酸钙、碳酸钙、食品调色剂、食用酒精(food laces)、香味剂、氧化铁颜料等。在胶囊剂情况下,将活性成分和辅料的混合物装入胶囊中。
液体口服组合物,例如悬浮液、糖浆剂、酏剂,可用水、二醇类、油、醇、调色剂和调味剂制成。
为直肠给药,将组合物制备成栓剂或灌肠剂。栓剂除活性成分外可含称为前栓动物脂(adeps pro suppository)的载体。载体可以是植物油,例如氢化植物油,C12-C18脂肪酸甘油三酯(优选商标名Witepsol下的载体)。将活性成分与熔化的前栓动物脂均匀混合,并模制成栓剂。
为胃肠外给药,将组合物配制成注射液。为生产注射液,将活性成分溶解在蒸馏水和/或不同的有机溶剂中,例如乙二醇醚,在给定情况中存在增溶剂例如聚氧乙烯失水山梨糖醇单月桂酸酯、-单油酸酯或单硬脂酸酯(吐温20、吐温60、吐温80)。注射液还可包括不同的辅料,例如防腐剂例如乙二胺四乙酸,以及pH调节剂和缓冲液和给定情况中的局部麻醉药如利多卡因。在装入安瓿前将含本发明活性成分的注射液过滤,在装入后将其灭菌。
如果活性成分吸湿,那么通过冻干可使其稳定。
缓激肽B1受体拮抗剂描述在例如下述国际专利申请中:WO200075107,WO02076964,WO04054584,WO02099388,WO05004810。
用途
本发明的化合物是缓激肽受体拮抗剂,尤其是选择性的缓激肽B1受体拮抗剂,因此可以用于治疗或预防疼痛和炎性过程。所述化合物会有效地治疗疼痛,包括,例如,慢性疼痛,尤其炎性疼痛,痛觉过敏,骨和关节痛(骨关节炎),重复的运动性疼痛,肌筋膜痛(肌肉损伤,纤维肌痛),内脏痛(溃疡性结肠炎,胰腺炎,膀胱炎,葡萄膜炎),围手术期疼痛(普通外科,妇科),手术后痛(术后痛综合征),创伤后痛(例如扭伤或骨折),神经性疼痛(疱疹后神经痛,神经损伤,幻肢痛,单一神经病变,多发性神经病),牙痛,和癌性疼痛。此外,用于治疗与心绞痛、月经、糖尿病血管病变、后毛细管脆性有关的疼痛或与胰岛炎有关的糖尿病症状(例如高血糖症,多尿,蛋白尿和增加的亚硝酸盐和激肽释放酶尿排泄)、糖尿病性痛觉过敏。此外,所述化合物可以用于治疗血管性水肿,动脉粥样硬化,感染性休克,如用 作抗血容量减少剂和/或抗低血压剂,和脓毒病。它们可以用作平滑肌松弛剂,用于治疗胃肠道或子宫的痉挛。此外,本发明的化合物另外可以用于治疗炎性皮肤病症,例如银屑病和湿疹,和皮肤损伤包括烧伤和晒伤(紫外线红斑和疼痛)。所述化合物可以用于治疗不同起源的炎性疼痛(例如类风湿性关节炎,风湿病,腱鞘炎,肝病,过敏性肠综合征,炎性肠病,克罗恩病,肾炎,变应性鼻炎,血管运动性鼻炎,葡萄膜炎,龈炎),变态反应。这样的化合物可以在治疗上用于治疗炎性气道病,例如慢性阻塞性肺病,成人呼吸窘迫综合征,支气管炎,肺炎,哮喘。它们可以用于控制、限制或逆转哮喘中的气道高反应性,用于治疗内源性和外源性哮喘,包括变应性哮喘(特应性的或非特应性的),职业性哮喘,病毒或细菌加重的哮喘,其它非变应性哮喘,“喘鸣-婴儿综合征”,以及运动诱发的支气管收缩。它们可以有效地对抗尘肺,包括矾土肺,碳末沉着症,石棉沉着病,石末沉着病,驼鸟毛尘肺,肺铁末沉着症,硅肺病,烟草尘肺和棉尘肺。另外,它们在有些神经障碍中可能有效,例如对抗多发性硬化,阿尔茨海默氏病,癫痫,脑水肿,头痛包括丛集性头痛,偏头痛,包括预防性和急性应用,以及闭合性头部创伤。
生物学评价
在表达重组人B1或B2受体的细胞中,通过用平板读数荧光计测量胞质钙离子浓度,体外评价对B1和B2受体的拮抗剂效能
细胞培养
在含有10%胎牛血清(FCS)、100U/ml青霉素、0.1mg/ml链霉素、0.25μg/ml两性霉素B、1%极限必需培养基Eagle(MEM)、非必需氨基酸溶液、600μg/ml G418,1%丙酮酸(用于B2细胞系)的Dulbecco氏改良伊格尔培养基(DMEM)中,培养稳定表达重组人B1(CHO-B1,Euroscreen)或B2(CHO-B2,Perkin-Elmer)受体的中国仓鼠卵巢(CHO)细胞。将细胞保持在37℃、增湿培养箱中,在5%CO2/95% 空气气氛下,每周1∶4传代3次。以1.5-2.5×104细胞/孔,将细胞平板接种在标准的96-孔微量平板上,在细胞平板接种后1-2天,测量胞质钙离子浓度([Ca2+]i)。
胞质钙浓度的荧光测量
分别在稳定表达人B1和B2受体的CHO-B1和CHO-B2细胞上,测量[Ca2+]i。在标准的96-孔微量平板中培养细胞,在测量前,装载Ca2+-敏感的荧光染料fluo-4/AM(2μM):取出培养基后,向细胞加入染料(溶于试验缓冲液:145mM NaCl,5mM KCl,2mM MgCl2,2mM CaCl2,10mM HEPES,20mM D-葡萄糖,2mM丙磺舒,100μl/孔),在37℃、增湿培养箱中,在5%CO2/95%空气气氛下,培养细胞40-120min。为了终止染料装载,用试验缓冲液洗涤细胞2次。洗涤后,根据实验设置,向每个孔中加入不同浓度的实验化合物(从DMSO储备溶液在胞外介质中稀释,终DMSO浓度<0.1%)或缓冲液。在37℃温育20-25min后,用平板读数荧光计(Fluoroskan Ascent,Labsystems)逐列测量基线和激动剂诱发的[Ca2+]i变化。从平板的底部,进行激发和发射的检测。Fluo-4使用的滤光片:激发滤光片-485nm,发射滤光片-538nm。在37℃进行整个测量过程,用定制的软件控制。通过测量在有不同浓度的化合物存在下激动剂诱发的[Ca2+]i升高的降低,评价实验化合物的抑制效力。对于CHO-B1,激动剂是LysDABK,对于CHO-B2细胞,激动剂是缓激肽。应用EC80浓度的激动剂,EC80-值源自每天测定的剂量-响应曲线。将荧光数据表达为ΔF/F(将荧光变化相对于基线标准化)。在多个孔中测定对单个平板的所有处理。将同一处理的所有孔的数据平均化,将平均值用于分析。将在单一浓度点的化合物的抑制效力表达为对对照激动剂响应的抑制百分比。用S形浓度-抑制曲线拟合数据(源自至少3个独立实验),将IC50值确定为产生化合物导致的最大抑制的一半的浓度。
在表1中,列出了在该实验中测量的最有效的本发明化合物和有些检查的参照化合物。
表1
实施例编号 | B1功能 | 参照化合物代码 | B1功能 |
1 | +++ | 70002460 | ++ |
2 | +++ | 70003770 | + |
3 | +++ | 70004287 | +++ |
4 | +++ | 70004387 | ++ |
5 | +++ | ||
6 | +++ | ||
8 | ++ | ||
9 | +++ | ||
14 | +++ | ||
15 | +++ | ||
16 | +++ | ||
17 | +++ | ||
18 | +++ | ||
19 | ++ | ||
20 | +++ | ||
21 | +++ |
+IC50>0.5μM
++IC50是在0.1-0.5μM之间
+++IC50<0.1μM
参照化合物如下:
70002460:4-{2-[(2,2-二苯基-乙基)-氨基]-5-{[4-/(4-<1-甲基-乙基>-1-哌嗪基)-羰基/-1-哌啶基]-磺酰基}-苯甲酰基}-吗啉
70003770:(±)-N-[1-(4-氨基甲基-苄基)-2-氧-2-吡咯烷-1-基-乙基]-3-(萘-2-磺酰基氨基)-3-苯基-丙酰胺
70004287:2-[1-(3,4-二氯-苯磺酰基)-3-氧-1,2,3,4-四氢喹喔啉-2(R)-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺[专利号WO04054584]
受体结合试验
1.人重组缓激肽B1受体结合
根据Euroscreen技术数据表(目录号:ES-091),在人重组缓激肽1受体(在CHO细胞中表达)上进行结合试验。与作为放射性配体的[3,4-脯氨酰-3,4-3H(N)]-[Des-Arg10]血管舒张素一起温育20μg蛋白/试管。在有10μM Lys-des-Arg9-缓激肽存在下,测定非特异性结合。最终的温育体积是250μl。将样品在25℃温育15min,然后经过在0.5%PE I中预浸泡至少1h的GF/B过滤器快速真空过滤。通过液体闪烁谱学,测定放射性。
在表2中,列出了在该实验中测量的最有效的本发明化合物和有些检查的参照化合物。
表2
实施例编号 | B1结合 | 参照化合物代码 | B1结合 |
1 | +++ | 70002460 | +++ |
2 | +++ | 70003770 | + |
3 | +++ | 70004287 | +++ |
4 | +++ | 70004387 | +++ |
5 | +++ | ||
6 | +++ | ||
8 | +++ | ||
9 | +++ | ||
14 | +++ | ||
15 | +++ | ||
16 | +++ | ||
17 | +++ | ||
18 | +++ | ||
19 | +++ | ||
20 | +++ | ||
21 | +++ |
+Ki>0.5μM
++Ki是在0.1-0.5μM之间
+++Ki<0.1μM
参照化合物如下:
70002460:4-{2-[(2,2-二苯基-乙基)-氨基]-5-{[4-/(4-<1-甲基-乙基>-1-哌嗪基)-羰基/-1-哌啶基]-磺酰基}-苯甲酰基}-吗啉
70003770:(±)-N-[1-(4-氨基甲基-苄基)-2-氧-2-吡咯烷-1-基-乙基]-3-(萘-2-磺酰基氨基)-3-苯基-丙酰胺
70004287:2-[1-(3,4-二氯-苯磺酰基)-3-氧-1,2,3,4-四氢喹喔啉-2(R)-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺[专利号WO04054584]
70004387:(±)-N-[4-(1,4′-联哌啶)-1′-基-苯基]-N′-[2,3-二氢-5-(4-甲基-苯基)-2-氧-1-丙基-1H-1,4-苯并二氮杂 -3-基]-脲[专利号WO 02099388]
2.人重组缓激肽B2受体结合
根据受体生物学技术数据表(目录号:RBHB2M),经过微小改进,在人重组缓激肽2受体(在CHO细胞中表达)上进行结合试验。与作为放射性配体的[2,3,-脯氨酰-3,4-3H(N)]-缓激肽一起温育8.4μg蛋白/试管。在有5μM缓激肽存在下,测定非特异性结合。最终的温育体积是200μl。将样品在4℃温育90min,然后经过在0.5%PEI中预浸泡至少1h的GF/B过滤器快速真空过滤。通过液体闪烁谱学,测定放射性。
根据功能和结合试验,所述化合物表现出对人B1受体超过人B2受体的高亲和力和选择性(>50倍)。
下面的非限制性实施例,解释了根据本发明的化合物的合成和药物组合物。
参照实施例1
2-(4-吡啶-4-基-哌嗪-1-基)-乙胺
a)2-[2-(4-吡啶-4-基-哌嗪-1-基)-乙基]-异吲哚-1,3-二酮
将1-吡啶-4-基-哌嗪[Org.Lett.4(2002)737-740](1.0g,6.12mmol)、N-(2-溴乙基)-酞酰亚胺(1.71g,6.74mmol)、碳酸钾(0.85g,6.12mmol)、碘化钾(1.02g,6.12mmol)和二甲基甲酰胺(10mL)的混合物在70℃搅拌24h,然后浓缩。将残余物溶于水中, 用二氯甲烷萃取,有机层经硫酸钠干燥,过滤,并浓缩。使用Kieselgel60(0.040-0.063mm)(Merck)作为吸附剂,使用氯仿∶甲醇∶NH4OH=10∶1∶0.1作为洗脱剂,通过柱色谱纯化粗产物,产生1.52g(74%)标题化合物,为白色固体。
b)2-(4-吡啶-4-基-哌嗪-1-基)-乙胺
将搅拌的2-[2-(4-吡啶-4-基-哌嗪-1-基)-乙基]-异吲哚-1,3-二酮(1.52g,4.52mmol)、乙醇(47.5mL)、水(2.5mL)和水合肼(98%,0.438mL,9.04mmol)的混合物回流3h,然后冷却,用二乙醚(100mL)稀释。滤出沉淀的晶体,用二乙醚洗涤,浓缩滤液。将残余物溶于N氢氧化钠(25mL),用二氯甲烷(4×25mL)萃取,用盐水(25mL)洗涤合并的有机层,经硫酸钠干燥,过滤并浓缩,产生0.58g(62%)标题化合物,为无色油。
参照实施例2
2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐
a)4-[2-(1,3-二氧-1,3-二氢-异吲哚-2-基)-乙基]-苄腈
在氩气下,将4-(2-羟基-乙基)-苄腈[Helv.Chim.Acta 64(1981)1688-1703](4.49g,30.5mmol)、酞酰亚胺(4.94g,33.55mmol)、三苯膦(8.8g,33.55mmol)和二甲基甲酰胺(100mL)的溶液在0℃搅拌20分钟,然后在0℃逐滴加入偶氮二羧酸二乙酯(7.59mL,48.8mmol)。将这样得到的反应混合物在室温搅拌过夜,然后倒入冰-水(740mL)。滤出沉淀的产物,用水洗涤,并干燥。从2-丙醇重结晶粗产物,产生7.83g(93%)标题化合物,为黄色固体。
b)2-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-异吲哚-1,3-二酮
将干燥的氯化氢气体鼓泡通过冰冷的4-[2-(1,3-二氧-1,3-二氢-异吲哚-2-基)-乙基]-苄腈(7.83g,28.3mmol)于乙醇(400mL)中的溶液3h,然后将这样得到的混合物保持在8℃过夜。真空浓缩反应混合物,将残余物溶于无水乙醇(400mL),加入乙二胺(2.0mL,29.7mmol),将反应混合物在室温搅拌过夜。真空浓缩混合物,将残余物在 二氯甲烷(400mL)和浓氨水(400mL)之间分配,分离相,用二氯甲烷(2×200mL)萃取水相。合并的有机层经硫酸钠干燥,过滤并浓缩。从2-丙醇重结晶粗产物,产生5.58g(62%)标题化合物,为白色固体。
c)2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐
将2-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-异吲哚-1,3-二酮(5.58g,17.47mmol)、乙醇(140mL)和水合肼(98%,6.57mL,135.4mmol)的混合物在室温搅拌2h,然后真空浓缩。将残余物在二氯甲烷(250mL)和N氢氧化钠(250mL)之间分配,分离相,用二氯甲烷(6×250mL)萃取水相。合并的有机层经硫酸钠干燥,过滤并浓缩。将粗产物溶于甲醇(15mL),通过加入氯化氢的甲醇溶液,将溶液的pH调节至5,然后将混合物在室温搅拌1h。加入二乙醚(200mL)后,将悬浮液在0℃搅拌2h,滤出沉淀的晶体,用二乙醚洗涤,干燥,产生4.11g(90%)标题化合物,为白色固体。
参照实施例3
(3-[1,4′]联哌啶-1′-基)-丙胺三盐酸盐
a)(3-[1,4′]联哌啶-1′-基-丙基)-氨基甲酸叔丁基酯
将4-哌啶子基哌啶(Aldrich)(2.0g,11.88mmol)、(3-溴-丙基)-氨基甲酸叔丁基酯[Eur.J.Med.Chem.Chim.Ther.37(2002)573-584](3.96g,16.63mmol)、二甲基甲酰胺(130mL)和碳酸钾(1.64g,11.88mmol)的混合物在室温搅拌过夜,然后真空浓缩。将残余物溶于水(150mL),用二氯甲烷(3×150mL)萃取,用盐水(150mL)洗涤合并的有机层,经硫酸钠干燥,过滤并浓缩。对粗产物进行柱色谱,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,使用氯仿∶甲醇∶NH4OH=10∶1∶0.1作为洗脱剂,产生2.27g(59%)标题化合物,为油。
b)3-[1,4′]联哌啶-1′-基)-丙胺三盐酸盐
将(3-[1,4′]联哌啶-1′-基-丙基)-氨基甲酸叔丁基酯(2.15g,6.6mmol)、无水二噁烷(40mL)和6.5N于二噁烷中的氯化氢(22mL)的混合物在室温搅拌过夜,然后用二乙醚稀释,在0℃搅拌1h。滤 出沉淀的晶体,用二乙醚洗涤,并干燥,产生2.03g(92%)标题化合物,为米黄色固体。
参照实施例4
反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐
a)反式-2-{1-[4-(N-叔丁氧基羰基)-氨基]-环己基}-乙醇
将反式-2-{1-[4-(N-叔丁氧基羰基)-氨基]-环己基}-乙酸甲基酯[J.Med.Chem.43(2000)1878-1885](28.5g,105.2mmol)于无水四氢呋喃(500mL)中的溶液冷却至-2℃,分部分加入氢化铝锂(5.4g,142mmol),将混合物在-2℃搅拌60分钟。将反应混合物冷却至-10℃,用乙酸乙酯(15mL)淬灭,然后在0℃向混合物中缓慢加入盐水(43ml)。过滤沉淀的盐,用乙酸乙酯洗涤。真空浓缩滤液。从二异丙基醚(100ml)重结晶残余物,产生23.7g(93%)标题化合物,为白色粉末。
b)甲磺酸反式-2-(4-叔丁氧基羰基氨基-环己基)-乙基酯
在0℃,向搅拌的反式-2-{1-[4-(N-叔丁氧基羰基)-氨基]-环己基}-乙醇(15g,62mmol)、和三乙胺(10.5mL,75mmol)于无水二氯甲烷(150mL)中的溶液中,逐滴加入于二氯甲烷(25mL)中的甲磺酰氯(5.7mL,73.4mmol)。在0℃搅拌30分钟后,用水萃取溶液3次。有机溶液经硫酸钠干燥,并真空浓缩,产生13.0g(65%)标题化合物。
c)反式-[4-(2-吡咯烷-1-基-乙基)-环己基]-氨基甲酸叔丁基酯
将甲磺酸反式-2-(4-叔丁氧基羰基氨基-环己基)-乙基酯(3.2g,10mmol)、碳酸钾(1.4g,10mmol)和吡咯烷(1.25mL,15mmol)于乙腈(40mL)中的混合物在60℃搅拌2小时。将混合物冷却至室温,倒入水(200mL)中。滤出沉淀的白色晶体,用水洗涤,产生1.9g(64%)标题化合物。
d)反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐
根据参照实施例3/b所述的方法,从反式-[4-(2-吡咯烷-1-基-乙基)-环己基]-氨基甲酸叔丁基酯制备标题化合物。
参照实施例5
2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐
a)2-(4-吡啶-2-基-哌嗪-1-基)-乙醇三盐酸盐
将搅拌的1-(2-吡啶基)-哌嗪(Aldrich)(4.6mL,30mmol)、2-溴乙醇(2.5mL,35mmol)、碳酸钾(4.8g,35mmol)和1-丁醇(60mL)的混合物回流过夜,然后加入进一步量的2-溴乙醇(2.5mL,35mmol),将混合物回流24h。冷却至室温后,滤出沉淀的盐,用乙酸乙酯洗涤,浓缩滤液。将残余物溶于乙酸乙酯(150mL),用水(150mL)萃取。有机层经硫酸钠干燥,过滤并浓缩。将残余物溶于二乙醚(100mL),通过加入氯化氢在乙酸乙酯中的溶液,将溶液的pH调节至5,然后将混合物在室温搅拌1h。加入二乙醚(150mL)后,将悬浮液在0℃搅拌2h,滤出沉淀的晶体,用二乙醚洗涤并干燥,产生4.8g(50%)标题化合物。
b)2-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-异吲哚-1,3-二酮
根据参照实施例2/a所述的方法,从2-(4-吡啶-2-基-哌嗪-1-基)-乙醇(用10%氢氧化钠溶液从三盐酸盐释放,用二氯甲烷萃取)制备标题化合物。
c)2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐
根据参照实施例2/c所述的方法,从2-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-异吲哚-1,3-二酮制备标题化合物。
参照实施例6
4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶
a)(4-氰基-苄基)-磷酸二乙基酯
在配有Dean-Stark阱的烧瓶中,在150℃搅拌4-氰基-苄基溴(41.8g,0.213mol)和三乙基亚磷酸酯(42mL,0.244mol)的混合物6h,然后对反应混合物进行真空蒸馏,产生52.2g(97%)标题化合物。
b)4-(1-苄基-哌啶-4-亚基甲基)-苄腈
在氩气下,向搅拌的N-苄基-4-哌啶酮(Aldrich)(26.0g,0.137mol)和(4-氰基-苄基)-磷酸二乙基酯(36.6g,0.1445mol)于二甲基 甲酰胺(260mL)中的混合物中,在0℃加入氢化钠(60%,7.8g,0.195mol)。将反应混合物在室温搅拌过夜,然后逐滴加入乙醇(10mL),将这样得到的混合物倒入水(300mL)中,用二乙醚(3×300mL)萃取。有机层经硫酸钠干燥,浓缩。残余物经柱色谱纯化,使用Kieselgel60(0.040-0.063mm)(Merck)作为吸附剂,使用正己烷∶乙酸乙酯=2∶1作为洗脱剂,产生34.65g(87%)标题化合物,为油。
c)4-(1-苄基-哌啶-4-亚基甲基)-苯甲亚胺酸(benzimidic acid)乙基酯
将4-(1-苄基-哌啶-4-亚基甲基)-苄腈(14g,48.6mmol)、氯仿(10mL)和6M于乙醇中的氯化氢(300mL)的混合物在室温搅拌48小时。真空浓缩溶液,将剩余的固体重复溶于乙醇(400mL),并真空浓缩,产生16.4g(92.4%)标题化合物,其不经进一步纯化,用于下面的步骤。
d)1-苄基-4-[4-(4,5-二氢-1H-咪唑-2-基)-苯亚甲基]-哌啶
向4-(1-苄基-哌啶-4-亚基甲基)-苯甲亚胺酸乙基酯(6.8g,18.3mmol)于乙醇(250mL)中的溶液中,加入乙二胺(2.45mL,36.6mmol),将混合物在室温搅拌过夜。滤出沉淀的固体,真空浓缩滤液。将残余物重复溶于乙醇(100mL),真空浓缩。通过快速柱色谱纯化粗产物,使用Kieselgel 60(0.015-0.040mm)作为吸附剂(Merck),使用氯仿∶甲醇∶NH4OH=9∶2∶0.1作为洗脱剂,产生2.7g(44.6%)标题化合物。
e)4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶
向搅拌的1-苄基-4-[4-(4,5-二氢-1H-咪唑-2-基)-苯亚甲基]-哌啶(0.1g,0.3mmol)于乙醇(20mL)中的溶液中,加入甲酸铵(0.19g,3mmol)和10%Pd/C(20mg),将混合物回流8小时。滤出催化剂,真空浓缩滤液。通过柱色谱纯化剩余的粗物质,使用碱式氧化铝(150目,Aldrich)作为吸附剂,使用在氯仿中的10%甲醇作为洗脱剂,产生68mg(92%)标题化合物。
参照实施例7
2-(4-哌啶-4-基甲基-苯基)-1,4,5,6-四氢-嘧啶
a)2-[4-(1-苄基-哌啶-4-亚基甲基)-苯基]-1,4,5,6-四氢-嘧啶
根据参照实施例6/d所述的方法,从4-(1-苄基-哌啶-4-亚基甲基)-苯甲亚胺酸乙基酯和1,2-二氨基-丙烷制备标题化合物。
b)2-(4-哌啶-4-基甲基-苯基)-1,4,5,6-四氢-嘧啶
根据参照实施例6/e所述的方法,从2-[4-(1-苄基-哌啶-4-亚基甲基)-苯基]-1,4,5,6-四氢-嘧啶制备标题化合物。
参照实施例8
2-(4-吡啶-4-基-哌嗪-1-基)-丙胺
a)2-[2-(4-吡啶-4-基-哌嗪-1-基)-丙基]-异吲哚-1,3-二酮
根据参照实施例1/a所述的方法,从1-吡啶-4-基-哌嗪[Org.Lett.4(2002)737-740]和N-(2-溴丙基)-酞酰亚胺制备标题化合物。
b)2-(4-吡啶-4-基-哌嗪-1-基)-丙胺
根据参照实施例1/b所述的方法,从2-[2-(4-吡啶-4-基-哌嗪-1-基)-丙基]-异吲哚-1,3-二酮制备标题化合物。
实施例1
2-[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
a)4′-氟-联苯-2-基胺
向搅拌的2-溴苯胺(1.72g,10.0mmol)于二甘醇二甲醚(30mL)中的溶液中,加入四(三苯膦)-钯(0)(0.13g,0.3mmol)和2.0M碳酸钠水溶液(15mL,30.0mmol)。在一个分开的烧瓶中,将4-氟苯基硼酸(2.23g 16.0mmol)溶于乙醇(8mL),将含有2-溴苯胺的混合物加入该硼酸溶液。在80℃加热所得到的褐色反应混合物6小时,然后冷却,用乙酸乙酯稀释,用饱和氯化铵溶液洗涤。有机层经硫酸钠干燥,过滤并浓缩。残余物通过快速柱色谱纯化,使用Kieselgel60(0.015-0.040mm)作为吸附剂(Merck),使用正己烷∶乙酸乙酯=2∶1作为洗脱剂,从乙醇重结晶后产生1.8g(60%)标题化合物,为白 色晶体。
b)3,4-二氯-N-(4′-氟-联苯-2-基)-苯磺酰胺
向搅拌的4′-氟-联苯-2-基胺(2.17g 11.6mmol)和4-二甲氨基吡啶(13mg,0.11mmol)于吡啶(20mL)中的溶液中,在0℃加入3,4-二氯-苯磺酰氯(4.23g 17.4mmol)。将反应混合物在室温搅拌过夜,然后浓缩。将残余物在氯仿(50mL)和水(50mL)之间分配。分离含水层,用氯仿(2×50mL)萃取。用饱和碳酸氢钠水溶液(20mL)和盐水(20mL)洗涤合并的有机萃取物,经硫酸钠干燥,过滤并浓缩。从2-丙醇结晶产物,产生3.58g(78%)标题化合物,为白色晶体。
c)[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-乙酸甲基酯
在100mL双颈烧瓶中,在150℃真空干燥乙酸钠(370mg,4.5mmol)2小时,然后加入乙酸钯(100.8mg 0.45mmol)、乙酸铜(II)水合物(90.0mg,0.45mmol)、3,4-二氯-N-(4′-氟-联苯-2-基)-苯磺酰胺(3.58g,9mmol)、丙烯酸甲酯(2.32g,27mmol)、4 分子筛(3.6g)和二甲基甲酰胺(45mL),在120℃搅拌所得到的混合物16小时。冷却后,浓缩反应混合物,然后用水(50mL)稀释,用二乙醚(2×30mL)萃取,经硫酸钠干燥,过滤并浓缩。残余物通过快速柱色谱纯化,使用Kieselgel 60(0.015-0.040mm)作为吸附剂(Merck),使用正己烷∶乙酸乙酯=4∶1作为洗脱剂,产生1.91g(44%)标题化合物,为白色晶体。
d)[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-乙酸
向搅拌的[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-乙酸甲基酯(0.48g,1mmol)于四氢呋喃和水的1∶1混合物(30mL)中的溶液中,加入氢氧化锂一水合物(105mg,2.5mmol)。将反应混合物在室温搅拌2小时,然后浓缩。将残余物溶于乙酸乙酯(25mL)和水(25mL)的混合物中,用1N盐酸溶液酸化。分离含水相,用乙酸乙酯(2×25mL)萃取。合并的有机萃取物经硫酸钠干燥,过滤并浓缩,产生0.46g(98%)标题化合物,为白色晶体。
e)2-[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
将[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-乙酸(210mg,0.45mmol)、三乙胺(0.07mL,1.5mmol)和N-(3-二甲氨基丙基)-N′-乙基碳二亚胺盐酸盐(0.19g,0.5mmol)于无水二甲基甲酰胺(5mL)中的溶液在室温搅拌5分钟,然后加入2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)(131mg,0.5mmol)。通过加入三乙胺,将反应混合物的pH调节至8,这样得到的混合物在室温搅拌过夜,然后真空浓缩。通过制备型薄层色谱法(二氯甲烷∶甲醇∶NH4OH=5∶1∶0.1),纯化残余物,产生382mg(75%)标题化合物,为白色晶体。
MS(EI)638.1(MH+)。
实施例2
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
a)N-联苯-2-基-3,4-二氯-苯磺酰胺
根据实施例1b所述的方法,从2-氨基联苯(Aldrich)制备标题化合物。
b)[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从N-联苯-2-基-3,4-二氯-苯磺酰胺制备标题化合物。
c)[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
d)2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。MS(EI)620.5(MH+)。
实施例3
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[2-(4-吡啶-4-基-哌嗪-1-基)-乙基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和2-(4-吡啶-4-基-哌嗪-1-基)-乙胺(参照实施例1)制备标题化合物。MS(EI)637.3(MH+)。
实施例4
反式-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参照实施例4)制备标题化合物。MS(EI)627.2(MH+)。
实施例5
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-1-{4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶-1-基}-乙酮
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶(参照实施例6)制备标题化合物。MS(EI)674.3(MH+)。
实施例6
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-1-{4-[4-(1,4,5,6-四氢-嘧啶-2-基)-苄基]-哌啶-1-基}-乙酮
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和2-(4-哌啶-4-基甲基-苯基)-1,4,5,6-四氢-嘧啶(参照实施例7)制备标题化合物。MS(EI)688.3(MH+)。
实施例7
N-[2-(4-氰基-苯基)-乙基]-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和4-(2-氨基-乙基)-苄腈[J.Am.Chem.Soc.125(2003)7516-7517]制备标题化合物。MS(EI)577.2(MH+)。
实施例8
N-(4-[1,4′]联哌啶-1′-基-苯基)-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和4-[1,4′]联哌啶-1′-基-苯基胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)690.3(MH+)。
实施例9
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和3-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参照实施例8)制备标题化合物。MS(EI)651.2(MH+)。
实施例10
N-(3-[1,4′]联哌啶-1′-基-丙基)-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)和3-[1,4′]联哌啶-1′-基)-丙胺三盐酸盐(参照实施例3)制备标题化合物。MS(EI)655.68(MH+)。
实施例11
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-乙酰胺
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-5,6-二 氢-菲啶-6-基]-乙酸(实施例2c)和2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐(参照实施例5)制备标题化合物。MS(EI)637.3(MH+)。
实施例12
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{[(哌啶-4-基甲基)-氨甲酰基]-甲基}-乙酰胺盐酸盐
a){2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酸甲基酯
将[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸(实施例2c)(225mg,0.5mmol)、三乙胺(0.14mL,1mmol)和HBTU[O-苯并三唑-1-基-N,N,N′,N′-四甲基脲六氟磷酸盐](208mg,0.55mmol)于无水二甲基甲酰胺(5mL)中的溶液在室温搅拌5分钟,然后加入甘氨酸甲基酯盐酸盐(63mg,0.5mmol)。通过加入三乙胺,将反应混合物的pH调节至8,将这样得到的混合物在室温搅拌过夜,然后真空浓缩。通过制备型薄层色谱法(二氯甲烷∶甲醇∶NH4OH=15∶1∶0.1)纯化残余物,产生248mg(95%)标题化合物,为白色晶体。
b){2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酸
根据实施例1d所述的方法,从{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酸甲基酯制备标题化合物。
c)4-[(2-{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酰基氨基)-甲基]-哌啶-1-甲酸叔丁基酯
根据实施例1e所述的方法,从{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酸和4-氨基甲基-哌啶-1-甲酸叔丁基酯制备标题化合物。
d)2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{[(哌啶-4-基甲基)-氨甲酰基]-甲基}-乙酰胺盐酸盐
向4-[(2-{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酰基氨基)-甲基]-哌啶-1-甲酸叔丁基酯(140mg,0.2mmol)于乙酸乙酯(5mL)中的溶液中,加入在乙酸乙酯中的2.4M氯化 氢(4mL,9.6mmol)。将反应混合物在室温搅拌过夜,然后用二乙醚(25mL)稀释。滤出沉淀的产物,用二乙醚洗涤,产生127mg(87%)标题化合物,为白色晶体。MS(EI)602.2(MH+)。
实施例13
2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[(2-哌啶-4-基-乙基氨甲酰基)-甲基]-乙酰胺盐酸盐
a)4-[2-(2-{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酰基氨基)-乙基]-哌啶-1-甲酸叔丁基酯
根据实施例1e所述的方法,从{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酸(实施例12b)和4-(2-氨基-乙基)-哌啶-1-甲酸叔丁基酯制备标题化合物。
b)2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[(2-哌啶-4-基-乙基氨甲酰基)-甲基]-乙酰胺盐酸盐
根据实施例12d所述的方法,从4-[2-(2-{2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰基氨基}-乙酰基氨基)-乙基]-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)616.2(MH+)。
实施例14
N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐
a)N-联苯-2-基-4-甲基-苯磺酰胺
根据实施例1b所述的方法,从2-氨基联苯(Aldrich)和4-甲基-苯磺酰氯制备标题化合物。
b)[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从N-联苯-2-基-4-甲基-苯磺酰胺制备标题化合物。
c)[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
d)N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐
根据实施例1e所述的方法,从[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。MS(EI)565.7(MH+)。
实施例15
N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐
a)N-联苯-2-基-2,4,4-三甲基-苯磺酰胺
根据实施例1b所述的方法,从2-氨基联苯(Aldrich)和2,4,6-三甲基-苯磺酰氯制备标题化合物。
b)[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从N-联苯-2-基-2,4,6-三甲基-苯磺酰胺制备标题化合物。
c)[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
d)N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺
根据实施例1e所述的方法,从[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。
实施例16
N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐
a)N-联苯-2-基-4-甲氧基-苯磺酰胺
根据实施例1b所述的方法,从2-氨基联苯(Aldrich)和4-甲氧基-苯磺酰氯制备标题化合物。
b)[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从N-联苯-2-基-4-甲氧基-苯磺酰胺制备标题化合物。
c)[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
d)N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐
根据实施例1e所述的方法,从[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。MS(EI)581.6(MH+)。
实施例17
2-[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
a)2′-甲氧基-联苯-2-基胺
根据实施例1a所述的方法,从2-甲氧基苯基硼酸制备标题化合物。
b)3,4-二氯-N-(2′-甲氧基-联苯-2-基)-苯磺酰胺
根据实施例1b所述的方法,从2′-甲氧基-联苯-2-基胺制备标题化合物。
c)[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从3,4-二氯-N-(2′-甲氧基-联苯-2-基)-苯磺酰胺制备标题化合物。
d)[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
e)2-[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。
实施例18
2-[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
a)2′,4′-二氟-联苯-2-基胺
根据实施例1a所述的方法,从2,4-二氟苯基硼酸制备标题化合物。
b)3,4-二氯-N-(2′,4′-二氟-联苯-2-基)-苯磺酰胺
根据实施例1b所述的方法,从2′,4′-二氟-联苯-2-基胺制备标题化合物。
c)[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从3,4-二氯-N-(2′,4′-二氟-联苯-2-基)-苯磺酰胺制备标题化合物。
d)[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
e)2-[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
根据实施例1e所述的方法,从[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2- 基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。MS(EI)656.1(MH+)。
实施例19
2-[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
a)4′-乙酰基-联苯-2-基胺
根据实施例1a所述的方法,从4-乙酰基苯基硼酸制备标题化合物。
b)N-(4′-乙酰基-联苯-2-基)-3,4-二氯-苯磺酰胺
根据实施例1b所述的方法,从4′-乙酰基-联苯-2-基胺制备标题化合物。
c)[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从N-(4′-乙酰基-联苯-2-基)-3,4-二氯-苯磺酰胺制备标题化合物。
d)[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
e)2-[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
根据实施例1e所述的方法,从[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参照实施例2)制备标题化合物。MS(EI)662.3(MH+)。
实施例20
N-[2-(4-甲脒基(carbamimidoyl)-苯基)-乙基]-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺
将N-[2-(4-氰基-苯基)-乙基]-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺(实施例7)(200mg,0.35mmol)在于乙醇溶液中的9M氯化氢(10mL)中的溶液,在室温静置过夜,然后真空浓缩混合物。将残余物溶于乙醇(10mL),加入碳酸铵(335mg,3,5mmol)。将反应混合物在室温搅拌过夜,然后真空浓缩。通过制备型薄层色谱法(二氯甲烷∶甲醇∶NH4OH=5∶1∶0.1)纯化残余物,产生113mg(55%)标题化合物,为白色晶体。MS(EI)594.1(MH+)。
实施例21
反式-2-[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-N-[4-(2-吡咯烷-1-基乙基)-环己基]-乙酰胺
将[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-乙酸(实施例17/d)(0.163g,0.34mmol)、三乙胺(0.3mL,2.1mmol)和O-苯并三唑-1-基-N,N,N′,N′-四甲基脲六氟磷酸盐(HBTU)(0.152g,0.4mmol)于无水二甲基甲酰胺(10mL)中的溶液在室温搅拌5分钟,然后加入反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参照实施例4)(0.09g,0.34mmol)。通过加入三乙胺,将反应混合物的pH调节至8,这样得到的混合物在室温搅拌过夜,然后真空浓缩。用饱和碳酸氢钠溶液(30mL)处理残余物,滤出沉淀的晶体,用水洗涤,并干燥。通过柱色谱纯化粗产物,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,使用氯仿∶甲醇∶NH4OH=9∶1∶0.1作为洗脱剂。用二乙醚结晶产物,产生0.135g(60%)标题化合物。MS(EI)657.2(MH+)。
实施例22
反式-2-[5-(3,4-二氯-苯磺酰基)-8,10-二甲氧基-5,6-二氢-菲啶-6-基]-N-[4-(2-吡咯烷-1-基乙基)-环己基]-乙酰胺
a)2′,4′-二甲氧基-联苯-2-基胺
根据实施例1a所述的方法,从2,4-二甲氧基苯基硼酸制备标题化合物。
b)3,4-二氯-N-(2′,4′-二甲氧基-联苯-2-基)-苯磺酰胺
根据实施例1b所述的方法,从2′,4′-二甲氧基-联苯-2-基胺制备标题化合物。
c)[5-(3,4-二氯-苯磺酰基)-8,10-二甲氧基-5,6-二氢-菲啶-6-基]-乙酸甲基酯
根据实施例1c所述的方法,从3,4-二氯-N-(2′,4′-二甲氧基-联苯-2-基)-苯磺酰胺制备标题化合物。
d)[5-(3,4-二氯-苯磺酰基)-8,10-二甲氧基-5,6-二氢-菲啶-6-基]-乙酸
根据实施例1d所述的方法,从[5-(3,4-二氯-苯磺酰基)-8,10-二甲氧基-5,6-二氢-菲啶-6-基]-乙酸甲基酯制备标题化合物。
e)2-[5-(3,4-二氯-苯磺酰基)-8,10-二甲氧基-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐
根据实施例21所述的方法,从[5-(3,4-二氯-苯磺酰基)-8,10-二甲氧基-5,6-二氢-菲啶-6-基]-乙酸和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参照实施例4)制备标题化合物。MS(EI)687.2(MH+)。
实施例23
药物组合物的制备:
a)片剂:
将0.01-50%的式(I)的活性成分,15-50%的乳糖,15-50%的马铃薯淀粉,5-15%的聚乙烯吡咯烷酮,1-5%的滑石粉,0.01-3%的硬脂酸镁,1-3%的胶体二氧化硅和2-7%的过支链淀粉混合,然后通过湿法制粒并压制成片剂。
b)糖衣片,薄膜包衣片:
将按照上述方法制备的片剂用由肠或胃溶薄膜组成的,或由糖或滑石粉组成的层包衣。糖衣片用蜂蜡和carnuba腊的混合物抛光。
c)胶囊:
将0.01-50%的式(I)活性成分,1-5%的十二烷基硫酸钠,15-50%的淀粉,15-50%的乳糖,1-3%的胶体二氧化硅和0.01-3%的硬脂酸镁充分混合,将混合物过筛并填充至硬明胶胶囊中。
d)混悬液:
成分:0.01-15%的式(I)活性成分,0.1-2%的氢氧化钠,0.1-3%的柠檬酸,0.05-0.2%的尼泊金(4-羟基苯甲酸甲酯钠),0.005-0.02%的对羟基苯甲酸丙酯,0.01-0.5%的聚羧乙烯(聚丙烯酸),0.1-5%的96%乙醇,0.1-1%的矫味剂,20-70%的山梨醇(70%水溶液)和30-50%的蒸馏水。
在剧烈搅拌下,按小份将聚羧乙烯加至在20ml蒸馏水中的尼泊金和柠檬酸溶液中,并将溶液放置10-12h。然后在搅拌下加入在1ml蒸馏水中的氢氧化钠,山梨醇水溶液,并最终加入乙醇覆盆子香精。往载体中按小份加入活性成分并使用浸渍匀浆机悬浮。最后用蒸馏水将该悬浮剂加至所需最终体积,且将该悬浮糖浆过胶体研磨设备。
e)栓剂:
对每种栓剂,将0.01-15%的式(I)活性成分和1-20%的乳糖充分混合,然后将50-95%的前栓动物脂(例如Witepsol 4)熔化并冷却至35℃,用匀化器将活性成分和乳糖的混合物在其中混合。将所得混合物冷却塑模。
f)冻干粉安瓿组合物:
以注射用双蒸水制成5%的甘露醇或乳糖溶液,将该溶液过滤以获得无菌溶液。0.01-5%式(I)活性成分的水溶液也以注射用双蒸水制成,并将此溶液过滤以获得无菌溶液。在无菌条件下将这两种溶液混合,以1ml部分装入安瓿中,将安瓿内容物冻干,且将安瓿在氮气下密封。在施用前,将安瓿内容物溶解在无菌水或0.9%(生理的)无菌氯化钠水溶液中。
Claims (4)
1.式(I)的缓激肽B1受体拮抗剂菲啶衍生物和/或其盐,
(I)
其中
R1是氢原子;
R2选自(1)-(CH2)n-NRaRb、(2)-(CH2)m-Q,或
R1和R2与它们结合的氮原子一起形成含有1~3个氮原子的4-7员杂环;其中,所述环任选被4-(4,5-二氢-1H-咪唑-2-基)-苄基或4-(1,4,5,6-四氢-嘧啶-2-基)-苄基取代;
R3,R4和R5彼此独立地是氢原子,卤素原子、C1-C4烷基或C1-C4烷氧基;
R6和R7各自独立地是氢原子、卤素原子、C1-C4烷氧基或乙酰基;
n是1~4的整数;
Ra和Rb与它们结合的氮原子一起形成含有1-3个氮原子的饱和4-7员环,其中,所述环任选被2-吡啶基或4-吡啶基取代;
m是0~6的整数;
Q是苯基,任选被[1,4’]联哌啶基-1’-基、4,5-二氢-1H-咪唑-2-基或-(CH2)m-(C=NH)-NH2基团取代;或C5-C7环烷基,任选被-(CH2)m-NRaRb基团取代。
2.化合物,其选自:2-[5-(3,4-二氯-苯磺酰基)-8-氟-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐,2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐,2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[2-(4-吡啶-4-基-哌嗪-1-基)-乙基]-乙酰胺,反式-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-乙酰胺,2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-1-{4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶-1-基}-乙酮,2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-1-{4-[4-(1,4,5,6-四氢-嘧啶-2-基)-苄基]-哌啶-1-基}-乙酮,N-(4-[1,4′]联哌啶-1′-基-苯基)-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺,2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-乙酰胺,N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(甲苯-4-磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐,N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(2,4,6-三甲基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐,N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-2-[5-(4-甲氧基-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺盐酸盐,2-[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐,2-[5-(3,4-二氯-苯磺酰基)-8,10-二氟-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐,2-[8-乙酰基-5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-乙酰胺盐酸盐,N-[2-(4-甲脒基-苯基)-乙基]-2-[5-(3,4-二氯-苯磺酰基)-5,6-二氢-菲啶-6-基]-乙酰胺或反式-2-[5-(3,4-二氯-苯磺酰基)-10-甲氧基-5,6-二氢-菲啶-6-基]-N-[4-(2-吡咯烷-1-基乙基)-环己基]-乙酰胺。
3.药物组合物,其包含治疗有效量的权利要求1所述的式(I)化合物或其药学可接受的盐和一种或多种药学可接受的赋形剂。
4.权利要求1所述的式(I)化合物或其药学可接受的盐用于生产药物的用途,所述药物用于预防和/或治疗需要抑制缓激肽B1受体的病症。
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HU0501169A HU230518B1 (hu) | 2005-12-20 | 2005-12-20 | Bradykinin B1 receptor szelektív antagonista hatással rendelkező új fenatridin származékok, eljárás előállításukra, és az ezeket tartalmazó gyógyszerkészítmények |
HUP0501169 | 2005-12-20 | ||
PCT/HU2006/000120 WO2007072092A2 (en) | 2005-12-20 | 2006-12-19 | New phenanthridine derivatives as bradykinin antagonists |
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HUP0600809A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New phenylsulfamoyl-benzamide derivatives as bradykinin antagonists, process and intermediates for their preparation and pharmaceutical compositions containing them |
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WO2009053763A1 (en) * | 2007-10-27 | 2009-04-30 | Richter Gedeon Nyrt. | New non-peptide derivatives as bradykinin bl antagonists |
US20110190348A1 (en) * | 2008-08-21 | 2011-08-04 | Pradeep Banerjee | Methods for treating cns disorders |
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TW202202495A (zh) | 2020-03-26 | 2022-01-16 | 匈牙利商羅特格登公司 | 作為gamma-胺基丁酸A受體次單元alpha 5受體調節劑之㖠啶及吡啶并〔3,4-c〕嗒𠯤衍生物 |
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EP1966142A2 (en) | 2008-09-10 |
HU0501169D0 (en) | 2006-02-28 |
NZ568864A (en) | 2011-07-29 |
AU2006327896B2 (en) | 2012-05-31 |
US8034827B2 (en) | 2011-10-11 |
CA2632941C (en) | 2012-05-08 |
WO2007072092A3 (en) | 2007-11-01 |
KR101027623B1 (ko) | 2011-04-06 |
AU2006327896A1 (en) | 2007-06-28 |
NO20083201L (no) | 2008-09-18 |
CA2632941A1 (en) | 2007-06-28 |
WO2007072092A8 (en) | 2008-03-20 |
IL191601A0 (en) | 2008-12-29 |
JP2009520013A (ja) | 2009-05-21 |
TW200837058A (en) | 2008-09-16 |
GEP20115216B (en) | 2011-05-25 |
UA99707C2 (en) | 2012-09-25 |
EA200801549A1 (ru) | 2008-10-30 |
ZA200805295B (en) | 2009-05-27 |
HUP0501169A3 (en) | 2008-03-28 |
EA015419B1 (ru) | 2011-08-30 |
HU230518B1 (hu) | 2016-10-28 |
KR20080076971A (ko) | 2008-08-20 |
US20090270411A1 (en) | 2009-10-29 |
CN101341125A (zh) | 2009-01-07 |
MX2008008200A (es) | 2008-11-14 |
HUP0501169A2 (en) | 2007-09-28 |
WO2007072092A2 (en) | 2007-06-28 |
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