CN101528681B - 作为缓激肽拮抗剂的磺酰胺衍生物 - Google Patents
作为缓激肽拮抗剂的磺酰胺衍生物 Download PDFInfo
- Publication number
- CN101528681B CN101528681B CN2007800400106A CN200780040010A CN101528681B CN 101528681 B CN101528681 B CN 101528681B CN 2007800400106 A CN2007800400106 A CN 2007800400106A CN 200780040010 A CN200780040010 A CN 200780040010A CN 101528681 B CN101528681 B CN 101528681B
- Authority
- CN
- China
- Prior art keywords
- chloro
- phenyl sulfamoyl
- sulfamoyl base
- benzamide
- phenyl
- 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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Abstract
本发明涉及式(I)的新磺酰胺衍生物及其旋光对映体或外消旋物和/或盐和/或水合物和/或溶剂合物,其中R1-R5和Z如权利要求中所定义,其是缓激肽B1的选择性拮抗剂,本发明还涉及制备这些化合物的方法,包含这些化合物的药理学组合物,以及涉及它们在治疗或预防疼痛性状况或炎性状况中的用途。
Description
技术领域
本发明涉及式(I)的新磺酰胺衍生物及其旋光对映体或外消旋物和/或盐和/或水合物和/或溶剂合物,其可用于治疗或预防疼痛性过程和炎性过程。本发明还涉及制备式(I)的化合物的方法以及涉及包含式(I)的化合物的药理学组合物。
背景技术
激肽是响应组织损伤或感染在由激肽释放酶进行激肽原催化裂解之后在血浆和周围组织中形成的内源性肽。激肽在伴随疼痛和炎症的病理生理过程中起重要作用。它们的生物作用通过两种由B1和B2表示的G蛋白偶联膜受体介导。B1和B2受体二者都已被克隆[Biochem.Biophys.Res.Commun.,184(1992)260-268和J.Biol.Chem.,269(1994)21583-21586]并且正深入地研究了调节其表达、自动维持和信号传导功能的机制[Pharmacol.Rev.,57(2005)27-77]。
第一组激肽,缓激肽(BK)和胰激肽(LysBK)优先地通过刺激组成型表达和迅速脱敏的B2受体起作用,所述B2受体广泛地分布在许多组织中。另一方面,它们的活性羧肽酶代谢物,第二组激肽,即,desArg9BK(DABK)和LysdesArg9BK(LysDABK)激活诱导型和非脱敏性B1受体,该受体在非病理学条件下很少被表达。通常,B1受体在许多性质的损伤(组织创伤,感染等)之后迅速地出现。因此,B1受体上调似乎是普遍性应答的一部分,该普遍性应答包括酶、受体、自身有效物质、细胞因子和趋化因子的局部共同表达(最终是上调),它们在组织对各种类型的损伤的早期和晚期应答中显著扮演关键角色。
在动物模型中,已经证明在慢性炎性状态中存在从B2到B1功能优势的转换。尽管B2受体牵涉炎性应答和疼痛应答的急性期,但是B1受体牵涉这一应答的慢性期。激肽受体在炎症和疼痛转导方面的牵涉已经得到了对缺乏缓激肽B1受体的小鼠的研究结果的支持。B1受体缺乏型小鼠与野生型小鼠在感觉功能方面是不同的,对有害的化学刺激和热刺激表现出增加的止痛阈,和在炎症部位处的多形核白细胞的积累大幅度减少[PNAS,97(2000)8140-8145和Neuropharmacology41(2001)1006-1012]。另外,在B1受体缺乏型小鼠中大多数的最初发现是中枢激肽受体在伤害感受中作用的直接证据,暗示了在B1受体敲除小鼠中观察到的痛觉减退部分地是由于在脊髓内中枢敏化作用降低所致。然而,除了以上所述变化,B1敲除小鼠显然是正常的,没有任何明显的病理变化。
除了B1受体在外周的基础表达的证据,最近越来越多的证据显示了B1受体在一些神经元构件中“中枢”被组成性表达,所述神经元构件也包括脊髓和一些更高级结构在内。这些受体的作用尚不清楚,但是它们已牵涉疼痛传递和痛觉过敏。因此,B1受体拮抗剂被认为可用于缓解疼痛,不仅通过外周部位,而且,如果它们也阻断中枢B1受体的话,可能具有广谱止痛效果[NeuroReport 11(2000)4003-4005;NeuroReport,12(2001)2311-2313;Neuroscience 107(2001)665-673和Neuroscience Letters 294(2000)175-178]。
根据科技数据,缓激肽受体以若干种方式牵涉疼痛和痛觉过敏的介导。B1受体拮抗剂可具有多种作用方式。它们具有(1)通过抑制其它产生疼痛的介质的释放而对伤害感受器的间接(‘外周’)作用。在炎性诱导时出现在与感觉神经元邻接的细胞(巨噬细胞、成纤维细胞或内皮细胞)上的N.B.B1受体牵涉释放使伤害感受器敏化或激活的介质(前列腺素、细胞因子和氧化氮)。(2)对表达B1受体(组成型表达)的伤害 感受器的或当诱导时直接(‘外周’)作用,和(3)对脊髓的背浅角中的疼痛加工的“中枢”作用。
因此,口服有效的非肽类缓激肽B1受体拮抗剂在治疗慢性炎性疼痛中可以是潜在的治疗剂。
若干专利和专利申请描述了具有不同化学结构的缓激肽B1受体拮抗剂。这些文献例如为以下的国际专利申请:WO200075107、WO02076964、WO04054584、WO02099388、WO05004810。
发明概述
本发明人已发现了一类苯甲酰胺衍生物,其对缓激肽B1受体具有高亲和性并且相对于缓激肽B2受体对缓激肽B1受体具有高选择性。这一选择性特别重要,因为化合物表现出少得多的不需要的副作用。
本发明涉及式(I)的新磺酰胺衍生物,
其中
R1为氢原子或C1-C4烷基;
R2选自(1)氢原子;条件是,R1和R2不能同时为氢原子;(2)-(CH2)n-NRaRb,(3)-(CH2)m-X-Q,或
R1和R2连同与它们连接的氮原子一起形成包含0-3个选自O、S和N的杂原子(除了与R1和R2连接的氮原子以外)的4-7元杂环;其 中所述环任选地被C1-C4烷基、-(CH2)q-Y-P、氧代、4-(4,5-二氢-1H-咪唑-2-基)-苄基、4-(1,4,5,6-四氢-嘧啶-2-基)-苄基或4-基甲基-苄脒基团取代;
R3、R4和R5彼此独立地为氢原子、卤素原子、氰基、氨基或被一个或多个C1-C4烷基取代的氨基、C1-C4烷氧基、三氟甲基、三氟甲氧基、C1-C4烷基、羟基、C1-C4烷氧基羰基或-C(=O)-NH2基团;
Z选自(1)单键;(2)氧原子;(3)CH2基团;(4)CO基团;(5)NRc基团;(6)S原子;(7)SO2基团;
n为1至4的整数;
m为0或2至6的整数;
q为0至4的整数;
Ra和Rb为(1)氢原子、(2)直链或支链C1-C6烷基;
Rc为氢原子或C1-C4烷基;
X为单键、-CO-或-CO-NH-或-NH-CO-基团;
Y为单键、-CO-或-CONRa基团;
P为(1)-N(C1-C4烷基)2基团;(2)-NH-(CH2)n-Het基团;(3)饱和的、部分不饱和的或芳香族的包含1-3个选自O、S和N的杂原子的4-7元环;其中所述环任选地被氧代或C1-C4烷基取代;
Q为(1)饱和的、部分不饱和的或芳香族的包含1-3个选自O、S和N的杂原子的4-7元环;其中所述环任选地被氧代、-(CH2)n-Het、1-哌啶基、1-(C1-C4-烷基)-4-哌啶基、4-哌啶基、2-嘧啶基、2-吡嗪基、2-吡啶基、4-甲基-2-吡啶基、6-甲基-2-吡啶基或4-吡啶基取代;(2)苯基,其任选地被-(CH2)n-Het、-(CH2)n-NH-C(=NH)-NH2、4,5-二氢-1H-咪唑-2-基或[1,4’]联哌啶-1’-基取代;(3)C5-C7环烷基,其任选地被-(CH2)n-Het基团取代;(4)苄基,其任选地被-(CH2)n-Het、-(CH2)n-NH-C(=NH)-NH2或4,5-二氢-1H-咪唑-2-基取代;(5)-(CH2)n-Het基团;
Het为包含1-3个选自O、S、SO2和N的杂原子的4-7元杂环,其任选地被(1)氧代;(2)一个或多个C1-C4烷基取代;
及其旋光对映体或外消旋物和/或盐和/或水合物和/或溶剂合物。
本发明还涉及药物组合物,其包括式(I)的化合物或其旋光对映体或外消旋物或盐或水合物或溶剂合物作为活性成分。
本发明的另一个目的是式(I)化合物的合成,和包含这些化合物的药剂的化学和药物制造,以及使用这些化合物的治疗方法,该方法意指对包括人在内的待治疗哺乳动物给予有效量的本发明的式(I)的化合物,该化合物本身被给予或者作为药剂被给予。
发明详述
本发明涉及式(I)的新的缓激肽B1受体拮抗剂磺酰胺衍生物,
其中
R1为氢原子或C1-C4烷基;
R2选自(1)氢原子;条件是,R1和R2不能同时为氢原子;(2)-(CH2)n-NRaRb,(3)-(CH2)m-X-Q,或
R1和R2连同与它们连接的氮原子一起形成包含0-3个选自O、S和N的杂原子(除了与R1和R2连接的氮原子以外)的4-7元杂环;其中所述环任选地被C1-C4烷基、-(CH2)q-Y-P、氧代、4-(4,5-二氢-1H-咪唑-2-基)-苄基、4-(1,4,5,6-四氢-嘧啶-2-基)-苄基或4-基甲基-苄脒基团取代;
R3、R4和R5彼此独立地为氢原子、卤素原子、氰基、氨基或被 一个或多个C1-C4烷基取代的氨基、C1-C4烷氧基、三氟甲基、三氟甲氧基、C1-C4烷基、羟基、C1-C4烷氧基羰基或-C(=O)-NH2基团;
Z选自(1)单键;(2)氧原子;(3)CH2基团;(4)CO基团;(5)NRc基团;(6)S原子;(7)SO2基团;
n为1至4的整数;
m为0或2至6的整数;
q为0至4的整数;
Ra和Rb为(1)氢原子、(2)直链或支链C1-C6烷基;
Rc为氢原子或C1-C4烷基;
X为单键、-CO-或-CO-NH-或-NH-CO-基团;
Y为单键、-CO-或-CONRa基团;
P为(1)-N(C1-C4烷基)2基团;(2)-NH-(CH2)n-Het基团;(3)饱和的、部分不饱和的或芳香族的包含1-3个选自O、S和N的杂原子的4-7元环;其中所述环任选地被氧代或C1-C4烷基取代;
Q为(1)饱和的、部分不饱和的或芳香族的包含1-3个选自O、S和N的杂原子的4-7元环;其中所述环任选地被氧代、-(CH2)n-Het、1-哌啶基、1-(C1-C4-烷基)-4-哌啶基、4-哌啶基、2-嘧啶基、2-吡嗪基、2-吡啶基、4-甲基-2-吡啶基、6-甲基-2-吡啶基或4-吡啶基取代;(2)苯基,其任选地被-(CH2)n-Het、-(CH2)n-NH-C(=NH)-NH2、4,5-二氢-1H-咪唑-2-基或[1,4’]联哌啶-1’-基取代;(3)C5-C7环烷基,其任选地被-(CH2)n-Het基团取代;(4)苄基,其任选地被-(CH2)n-Het、-(CH2)n-NH-C(=NH)-NH2或4,5-二氢-1H-咪唑-2-基取代;(5)-(CH2)n-Het基团;
Het为包含1-3个选自O、S、SO2和N的杂原子的4-7元杂环,其任选地被(1)氧代;(2)一个或多个C1-C4烷基取代;
及其旋光对映体或外消旋物和/或盐和/或水合物和/或溶剂合物。
本发明还涉及药物组合物,其包括式(I)的化合物或其旋光对映体或外消旋物或盐或水合物或溶剂合物作为活性成分。
本发明的另外的目的是式(I)化合物的合成,和包含这些化合物的药剂的化学和药物制造,以及使用这些化合物的治疗方法,该方法意指对包括人在内的待治疗哺乳动物给予有效量的本发明的式(I)的化合物,该化合物本身被给予或者作为药剂被给予。
术语“卤素”取代基表示氟、氯、溴或碘原子。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、以及不同的丁基。这些C1-C4烷基可以是C1-C4烷氧基和C1-C4烷氧基羰基。
R1和R2含义中的4-7元杂环可以是例如哌啶、吡咯烷、哌嗪、高哌嗪(homopiperazine)、吗啉、硫代吗啉等。
Het基团可以是例如哌啶、吡咯烷、哌嗪、高哌嗪、吗啉、硫代吗啉、吡啶、嘧啶、吡嗪等。
P和Q含义中的饱和的、部分不饱和的或芳香族的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、咪唑、吡啶等。
本发明还涉及式(I)的化合物与酸或碱形成的盐。
可使用有机酸和无机酸形成酸加成盐。适当的无机酸可以是例如盐酸、硫酸和磷酸。单价有机酸的典型实例可以是例如甲酸、乙酸、三氟乙酸、丙酸以及不同的丁酸、戊酸和癸酸。二价有机酸的典型实例可以是例如草酸、丙二酸、马来酸、富马酸和琥珀酸。还可使用其它的有机酸,诸如羟基酸如枸橼酸、酒石酸,或芳香族羧酸如苯甲酸或水杨酸,以及脂肪族和芳香族磺酸如甲磺酸和对甲苯磺酸。特别有价值的酸加成盐的组是其中酸组分自身在施用剂量下不具有治疗效果 或者其对活性成分的效果没有不利的影响。这些酸加成盐是可药用的酸加成盐。不属于可药用的酸加成盐属于本发明的酸加成盐的原因是,在给定情况下它们在所需化合物的纯化和分离中是有利的。
在与碱形成的盐中,特别重要的是与碱金属如钠、钾,碱土金属如钙和镁,以及与氨或有机胺形成的盐。后者碱可以具有另外的取代基,例如羟基或氨基,其可以影响产物的溶解性和处理性。与碱形成的盐是可药用的碱加成盐。
根据本发明,式(I)的化合物可以如下合成:使式(II)的胺衍生物
-其中R3、R4和R5的含义如上对式(I)所述,
与式(III)的磺酰氯反应,
然后使如此获得的式(IV)的苯基氨磺酰基苯甲酸,
-其中R3、R4和R5的含义如上所定义,
与式(V)的胺衍生物反应,
-其中R1和R2的含义如上所定义,并且在给定情况下,获得的式(I)的苯基氨磺酰基苯甲酰胺衍生物可以通过引入新的取代基和/或修饰或除去已有的取代基,和/或成盐和/或从盐中释放化合物而被转化为式(I)的其它化合物。
磺酰化反应优选在适当的溶剂中,优选在碱存在的条件下进行。该反应之后进行薄层色谱法。必要的反应时间是6-20小时。反应混合物的后处理可以通过不同的方法进行。
a)将反应混合物浓缩并且通过结晶或提取分离出产物。如果粗产物不够纯,则然后可使用柱色谱法用于其纯化。柱色谱法以正相采用Kieselgel 60作为吸附剂和不同的溶剂体系例如正己烷/乙酸乙酯、氯仿/甲醇、二氯甲烷/乙酸乙酯或氯仿/丙酮作为洗脱剂进行,或者以反相采用YMC-Pack ODS-AQ型填料(由YMC生产)和乙腈/水/三氟乙酸或乙腈/水/乙酸作为洗脱剂进行。
b)将反应混合物倾入到冰-水中,并通过过滤或提取分离出产物。粗产物如上所述进行结晶或通过柱色谱法纯化。产物的结构通过IR、 NMR和质谱学测定。
酰胺键形成优选如下进行:从式(IV)的羧酸制备活性衍生物,其在碱存在的条件下与式(V)的胺反应。
羧酸转化为活性衍生物可以在酰胺键形成期间在适当的溶剂(例如二甲基甲酰胺、乙腈、氯代烃或烃或其混合物)中原位进行。活性衍生物可以是酰基氯(例如从羧酸与亚硫酰氯制备),混合酐(例如从羧酸与氯甲酸异丁酯在碱例如三乙胺存在的条件下制备),活性酯(例如从羧酸与羟基苯并三唑(HOBt)和二环己基碳二亚胺(DCC)或O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(HBTU)在碱例如三乙胺存在的条件下制备)。活性衍生物可以在0℃到室温的温度下被制备。将碱形式或与无机酸形成的盐形式的适当的式(V)的胺在碱例如三乙胺(需要其来释放胺)存在的条件下加入到如此获得的溶液或悬浮液中。浓缩反应,然后进行薄层色谱法。必要的反应时间是6-20小时。反应混合物的后处理通过不同的方法进行。
当反应混合物是悬浮液时,过滤出沉淀物,用水和/或有机溶剂洗涤,得到纯产物。如果反应混合物是溶液,则在酰胺键形成反应结束时:
(a)将反应混合物浓缩,残余物经过结晶或用适当的有机溶剂提取,并且在给定情况下通过柱色谱法纯化。以正相采用Kieselgel 60作为吸附剂和不同的溶剂体系例如甲苯/甲醇、氯仿/甲醇或甲苯/丙酮作为洗脱剂或以反相采用YMC-Pack ODS-AQ型填料(由YMC生产)和采用乙腈/水/三氟乙酸或乙腈/水/乙酸作为洗脱剂进行柱色谱法。
b)反应混合物如上所述直接通过柱色谱法纯化,得到纯产物。
产物的结构通过IR、NMR和质谱学测定。
获得的式(I)的苯甲酰胺衍生物(其独立地得自制备方法),在给定情况下,可以如下被转化为另外的式(I)的化合物:引入另外的取代 基和/或修饰和/或除去已有的取代基,和/或与酸成盐和/或从获得的酸加成盐用碱处理而释放式(I)的苯甲酰胺衍生物和/或游离的式(I)的磺酰胺衍生物可用碱处理而被转化为盐。
例如,包含游离羟基的式(I)的化合物用不同的酰化试剂或磺酰化试剂可被转化为酰氧基或磺酰氧基(sulfoxy)衍生物。该反应可以例如在氯代烃中,使用酰基氯或酸酐作为酰化试剂,在碱(例如三乙胺或碳酸钠)存在的条件下进行。包含硝基的式(I)的磺酰胺衍生物可以通过还原被转化为胺,并且该胺可以进一步反应以得到酸酰胺,如关于羟基的酰化所述的,或可以合成氨基甲酸酯衍生物。酯基团可以被水解,并且获得的游离羧酸可以通过与适当的胺衍生物反应而被转化为酰胺。N-(叔丁氧羰基)基团可以被有机酸或无机酸(如三氟乙酸或氯化氢)所裂解。氰基可被转化为酰胺、N-羟基-脒或不同的含氮杂环基团。
大部分的式(V)的胺和式(III)的磺酰氯可以是市售的,或者可根据不同的已知方法被合成。一些式(V)的新的胺的合成在实施例中被描述。根据这些过程,还可制备其它的式(V)的胺。
本发明的化合物及其可药用盐或水合物或溶剂合物本身可以被使用或者以药物组合物的形式被适当地使用。这些组合物(药物)可以是固体、液体或半液体形式,并且可以加入在实践中常用的药物佐剂和辅助材料,诸如载体、赋形剂、稀释剂、稳定剂、润湿剂或乳化剂,pH调节剂和渗透压调节剂,调味剂或芳香剂,以及促进配制或提供制剂的添加剂。
为发挥治疗效果所需的剂量可以变化幅度较大并且适于在每一特定情况下的单独要求,这取决于疾病的阶段、待治疗患者的状况和体重、以及患者对活性成分的敏感性、给药途径和日治疗的次数。待用活性成分的实际剂量可以由本领域的主治医师在对待治疗患者了解的 情况下安全地被确定。
包含本发明的活性成分的药物组合物通常在单个剂量单位中包含0.01到100毫克的活性成分。当然在一些组合物中,活性成分的量可能超过上面所限定的上限或下限。
药物组合物的固体形式可以是例如片剂、糖衣丸(dragée)、胶囊、丸剂或可用于制备注射剂的冻干粉末安瓿。液体组合物是可注射的和可输注的组合物,流体药品、填充液和滴剂。半液体组合物可以是软膏剂、香膏剂(balsams)、霜剂、振摇混合物和栓剂。
为了给药简单的原因,药物组合物包括的剂量单位包含以一次或数次或以其一半、三分之一或四分之一部分给药的量的活性成分是适当的。这种剂量单位例如是片剂,其具有有助于片剂二等分或四等分的凹痕,可以被制成粉末,从而准确地给予所需量的活性成分。
用酸溶性层将片剂包衣以确保在离开胃之后释放活性成分内容物。该片剂可具有肠溶包衣。通过囊封活性成分也可以实现相似的效果。
用于口服给药的药物组合物可包含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成粒剂。马铃薯淀粉或微晶纤维素作为崩解剂被加入,但是也可使用超支链淀粉(ultraamylopectin)或甲醛酪蛋白。滑石、胶体硅酸、硬脂、硬脂酸钙或硬脂酸镁可用作抗粘着剂和润滑剂。
片剂可以通过湿法造粒,然后压缩被制造。混合的活性成分和赋形剂以及在给定情况下与一部分的崩解剂用粘合剂的水溶液、醇溶液或水醇溶液在适当的设备中造粒,然后将粒子干燥。可加入另外的崩解剂、润滑剂和抗粘着剂到经干燥的颗粒中,并将混合物压缩成片。 在给定的情况下,片剂被制成带有二等分凹痕以便于给药。
片剂可以从活性成分与适当的助剂的混合物通过压缩直接制备。在给定情况下,片剂可以采用药学实践中常用的添加剂进行包衣,例如,稳定剂,调味剂,着色剂,诸如糖,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),聚乙烯基吡咯烷酮,磷酸钙,碳酸钙,食品级着色剂,食物修饰剂(food laces),芳香剂,氧化铁色素等。在胶囊的情况中,活性成分与助剂的混合物被填充在胶囊内。
液体口服组合物,例如,悬浮剂,糖浆剂,酏剂,可以采用水、二醇类、油类、醇类、着色剂和娇味剂来制备。
对于直肠给药,组合物被配制成栓剂或灌肠剂。栓剂除了活性成分之外还可包含载体,所谓的adeps pro栓剂。载体可以是植物油,诸如氢化植物油,C12-C18脂肪酸甘油三酯(优选商品名为Witepsol的载体)。活性成分与熔融的adeps pro栓剂均一混合并将栓剂模压成型。
对于非肠道给药,组合物被配制成注射液。对于制备注射液,将活性成分溶解在蒸馏水和/或不同的有机溶剂诸如二醇醚中,在给定的情况下,存在增溶剂,例如聚氧乙烯失水山梨醇一月桂酸酯、聚氧乙烯失水山梨醇一油酸酯或聚氧乙烯失水山梨醇一硬脂酸酯(吐温20、吐温60、吐温80)。注射液还可包含不同的助剂,诸如防腐剂如乙二胺四乙酸盐,以及pH调整剂和缓冲剂,并且在给定情况中,包含局部麻醉剂如利多卡因。包含本发明的活性成分的注射液在其被填充到安瓿内之前经过过滤,并且在填充后进行杀菌。
如果活性成分是吸湿性的,则然后通过冻干使其稳定。
实用性
本发明的化合物是缓激肽受体拮抗剂,特别是选择性缓激肽B1受体拮抗剂,因此可用于治疗或预防疼痛过程和炎性过程。化合物可有效地用于治疗疼痛,所述疼痛包括例如慢性疼痛,特别是炎性疼痛,痛觉过敏,骨和关节疼痛(骨关节炎),反复性运动痛,肌筋膜疼痛(肌肉损伤,纤维肌痛),内脏疼痛(溃疡性结肠炎,胰腺炎,膀胱炎,葡萄膜炎),围术期疼痛(普通外科,妇科),术后疼痛(术后疼痛综合征),创伤后疼痛(例如扭伤或骨折),神经性疼痛(带状疱疹神经痛,神经损伤,幻肢痛,单神经病,多神经病),牙齿疼痛,和癌疼痛。另外用于治疗与以下疾病有关的疼痛:心绞痛,月经,糖尿病性血管病变,毛细血管后阻力或与胰岛炎有关的糖尿病症状(例如高血糖,多尿,蛋白尿,和亚硝酸盐和激肽释放酶尿排泄增加),糖尿病性疼痛过敏。另外,该化合物可用于治疗血管神经性水肿,动脉粥样硬化,脓毒性休克(例如,用作抗循环血容量降低剂和/或抗血压降低剂)以及脓毒症。它们可用作平滑肌松弛药用于治疗胃肠道或子宫的痉挛。另外,本发明的化合物可另外用于治疗炎性皮肤病,诸如牛皮癣和湿疹,和包括烧伤和晒伤(UV-红斑和疼痛)在内的皮肤损伤。该化合物可用于治疗不同起源的炎性疼痛(例如类风湿性关节炎,风湿性疾病,腱鞘炎,肝病,肠易激综合征,炎症性肠病,克隆病,肾炎,变应性鼻炎,血管舒缩性鼻炎,葡萄膜炎,龈炎),过敏症。这类化合物可治疗性地用于治疗炎性气道病,诸如慢性阻塞性肺病,成人呼吸窘迫综合征,支气管炎,肺炎,哮喘。它们可用于控制、限制或逆转哮喘中的气道高反应性,用于治疗包括变应性哮喘(特发的或非特发的)、职业性哮喘、病毒或细菌加重的哮喘、其它非变应性哮喘、“婴幼儿喘息综合征”、以及运动诱导的支气管收缩在内的内源性哮喘和外源性哮喘。它们可有效对抗尘肺病,包括铝尘肺,碳硅末沉着病,石棉肺,石末沉着病,驼鸟毛尘肺,铁尘肺,矽肺病,烟尘肺和棉尖肺。另外,它们在一些神经病学病症中是有效的,例如可有效对抗多发性硬化,阿尔茨海默病,癫痫症,脑水肿,包括集束性头痛在内的头痛,包括预防性应用和急性应用的偏头痛,以及闭合性头创伤。
生物学评价
功能试验:
在表达重组人B1或B2受体的细胞中,使用读板荧光计,通过体外测量胞质钙离子浓度,来评价在B1和B2受体上的拮抗剂效力
细胞培养
将稳定表达重组人B1(CHO-B1,Euroscreen)或B2(CHO-B2,Perkin-Elmer)受体的中国仓鼠卵巢(CHO)细胞在Dulbecco氏改进伊格尔培养基(DMEM)中培养,该培养基包含10%的胎牛血清(FCS),100U/ml青霉素,0.1mg/ml的链霉素,0.25μg/ml的两性霉素B,1%的伊格尔极限必需培养基(MEM),非必需氨基酸溶液,600μg/mlG418,1%丙酮酸盐(用于B2细胞系)。细胞在湿润的培养箱中和在5%CO2/95%空气的气氛中保持在37℃下并以1∶4传代,每周三次。将细胞以1.5-2.5×104个细胞/孔铺板在标准的96孔微量培养板中,在细胞铺板后1-2天进行胞质钙离子浓度([Ca2+]i)的测量。
胞质钙浓度的荧光测量
在分别稳定表达人B1受体和B2受体的CHO-B1和CHO-B2细胞上进行[Ca2+]i的测量。细胞在标准96孔微量培养板中生长,然后装载发荧光的Ca2+-敏感性染料fluo-4/AM(2μM):取出培养基后,将染料加入到细胞中(溶解于试验缓冲液:145mM NaCl,5mM KCl,2mMMgCl2,2mM CaCl2,10mM HEPES,20mM右旋葡萄糖,2mM丙磺舒,100μl/孔),将细胞在37℃下在湿润培养箱中在5%CO2/95%空气的气氛中培养40-120分钟。为使其停止,用试验缓冲液洗涤装载染料的细胞两次。洗涤之后,将各种浓度的供试化合物(从DMSO储备溶液被稀释到细胞外介质中,最终DMSO浓度<0.1%)或缓冲液被加入到每个孔中,根据实验设计的不同而异。在37℃下培养20-25分钟后,使用读板荧光计(Fluoroskan Ascent,Labsystems)逐行测量 [Ca2+]i的基线变化和由激动剂引起的变化。从板的底部进行激发和检测发射。用于Fluo-4的滤波器:激发滤波器-485纳米,发射滤波器-538纳米。整个测量过程在37℃下进行并通过定制软件控制。通过测量在不同浓度化合物存在的条件下对由激动剂引起的[Ca2+]i升高的降低来测量供试化合物的抑制效力。激动剂对于CHO-B1细胞是LysDABK,对于CHO-B2细胞是缓激肽。激动剂以EC80浓度被施加,EC80值得自每日测定的剂量-反应曲线。荧光数据用ΔF/F表示(归一化到基线的荧光变化)。在单个板上的所有处理在多个孔内进行测量。得自使用相同处理的所有孔的数据取平均值并且将平均值用于分析。在单个浓度点下的化合物的抑制效力用对照激动剂应答的抑制百分数来表示。将S形浓度抑制曲线拟合到该数据(得自至少三次独立实验)并且测定IC50值作为产生由化合物引起的最大抑制的一半的浓度。
在功能试验和结合试验中测量的检查的参考化合物如下所示:
1)4-{2-[(2,2-二苯基-乙基)-氨基]-5-{4-[4-[(4-甲基-1-哌嗪基)-羰基]-1-哌啶基]-磺酰基}-苯甲酰基}-morfoline(NVP-SAA1 64,Br.J.Pharmacol.144(2005)889-899);Ki 8nM;IC50:33nM;
2)(R)-N-[2,3-二氢-2-氧代-5-(2-苯基-乙基)-1-丙基-1H-1,4-苯并二氮杂 -3-基]-N’-{4-[4-(4-吡啶基)-1-哌嗪基]-苯基}-脲(J.Med.Chem.46(2003)1803-1806);Ki 0.59nM;IC50 1.9nM;
3)N-[4-(,4’-联哌啶)-1’-基苯基]-N’-[(3R)-2,3-二氢-5-(4-甲基-苯基)-2-氧代-1-丙基-1H-1,4-苯并二氮杂 -3-基]-脲(J.Med.Chem.46(2003)1803-1806);Ki 13.4nM;IC50 64.5nM。
由本发明人测量的关于参考化合物的Ki和IC50数据与文献中所给出的数据非常一致。
在表1中列出了在功能试验中测定的本发明最有效的化合物。
表1
实施例编号 | B1功能 | 实施例编号 | B1功能 |
1 | ++++ | 64 | +++ |
2 | ++++ | 66 | ++++ |
3 | ++++ | 76 | +++ |
4 | ++++ | 87 | ++ |
5 | ++++ | 99 | +++ |
6 | ++++ | 101 | +++ |
7 | ++++ | 102 | ++++ |
8 | +++ | 105 | ++++ |
9 | +++ | 111 | ++++ |
10 | +++ | 114 | ++++ |
11 | +++ | 116 | ++++ |
20 | +++ | 121 | +++ |
22 | ++++ | 127 | ++++ |
23 | ++ | 129 | +++ |
24 | ++++ | 132 | +++ |
28 | ++++ | 135 | +++ |
29 | +++ | 137 | +++ |
30 | +++ | 147 | +++ |
33 | +++ | 152 | +++ |
36 | +++ | 157 | ++++ |
37 | +++ | 159 | +++ |
54 | +++ | 166 | +++ |
56 | +++ | 167 | +++ |
58 | ++++ | 169 | ++++ |
62 | ++++ | 170 | ++++ |
+IC50>0.5μM +++IC50为20到100nM
++IC50为0.1到0.5μM ++++IC50<20nM
受体结合试验
1.人重组缓激肽B1受体结合
根据Euroscreen Technical Data Sheet(Cat.No.: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。将20μg蛋白/管与作为放射性配体的[3,4-脯氨酰基-3,4-3H(N)]-[Des-Arg10]胰激肽培养。在10μM Lys-des-Arg9-缓激肽存在的条件下测定非特异性结合。最终培养体积为250微升。样品在25℃下培养15分钟,然后迅速地通过GF/B过滤器进行真空过滤,该过滤器预浸渍在0.5%PEI中至少1小时,通过液体闪烁光谱法测定放射性。
在表2中列出了在结合试验中测定的本发明最有效的化合物。
表2
实施例编号 | B1结合 | 实施例编号 | B1结合 |
1 | ++++ | 64 | +++ |
2 | ++++ | 66 | ++++ |
3 | ++++ | 76 | +++ |
4 | ++++ | 87 | ++ |
5 | ++++ | 99 | +++ |
6 | ++++ | 101 | +++ |
7 | ++++ | 102 | ++++ |
8 | ++++ | 105 | ++++ |
9 | ++++ | 111 | ++++ |
10 | ++++ | 114 | ++++ |
11 | +++ | 116 | ++++ |
20 | +++ | 121 | +++ |
22 | ++++ | 127 | +++ |
23 | +++ | 129 | +++ |
[0122]
24 | ++++ | 132 | ++++ |
28 | ++++ | 135 | +++ |
29 | +++ | 137 | +++ |
30 | +++ | 147 | +++ |
33 | +++ | 152 | +++ |
36 | ++++ | 157 | ++++ |
37 | +++ | 159 | +++ |
54 | +++ | 166 | +++ |
56 | ++++ | 167 | +++ |
58 | ++++ | 169 | ++++ |
62 | ++++ | 170 | ++++ |
+Ki>0.5μM +++Ki为20到100nM
++Ki为0.1到0.5μM ++++Ki<20nM
2.人重组缓激肽B2受体结合
根据具有微小改进的Receptor Biology Technical Data Sheet(Cat.No.:RBHB2M)在人重组缓激肽2受体(在CHO细胞中表达)上进行结合试验。将8.4μg蛋白/管与作为放射性配体的[2,3-脯氨酰基-3,4-3H(N)]-缓激肽培养。在5μM缓激肽存在的条件下测定非特异性结合。最终培养体积为200微升。样品在+4℃下培养90分钟,然后迅速地通过GF/B过滤器进行真空过滤,该过滤器预浸渍在0.5%PEI中至少1小时,通过液体闪烁光谱法测定放射性。
根据功能试验和结合试验,化合物对人B1受体比对人B2受体表现出更高的亲合性和选择性(>50倍)。
本发明的化合物和药物组合物的合成通过以下的非限制性实施例进行说明。
参考例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)-邻苯二甲酰亚胺(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24小时,然后浓缩。残余物溶解于水,用二氯甲烷提取,有机层用硫酸钠干燥,过滤并且浓缩。粗产物通过柱色谱法纯化,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,和使用氯仿∶甲醇∶氢氧化铵=10∶1∶0.1作为洗脱剂,得到1.52g(74%)的标题化合物,为白色固体。
b)2-(4-吡啶-4-基-哌嗪-1-基)乙胺
使搅拌的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3小时,然后冷却并用乙醚(100mL)稀释。将沉淀的晶体过滤出,用乙醚洗涤并将滤液浓缩。将残余物溶解于N氢氧化钠(25mL),用二氯甲烷提取(4×25mL),合并的有机层用盐水(25mL)洗涤,用硫酸钠干燥,过滤并且浓缩,得到0.58g(62%)的标题化合物,为无色油状物。
参考例2
2-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-乙胺二盐酸盐
a)4-[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙基]-苯甲腈
在氩气下,将4-(2-羟基-乙基)-苯甲腈[Helv.Chim.Acta 64(1981)1688-1703](4.49g,30.5mmol)、邻苯二甲酰亚胺(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℃滴加偶氮二羧酸二乙酯(7.59mL,48.8mmol)。 如此得到的反应混合物在室温搅拌过夜,然后倾倒在冰-水(740mL)中。将沉淀的产物过滤出,用水洗涤并且干燥。粗产物从2-丙醇重结晶,得到7.83g(93%)的标题化合物,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
使无水氯化氢气体鼓泡通过4-[2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙基]-苯甲腈(7.83g,28.3mmol)在乙醇(400mL)中的冰冷的溶液达3小时,然后将如此得到的混合物在8℃保持过夜。将反应混合物真空浓缩,残余物溶解于无水乙醇(400mL),加入乙二胺(2.0mL,29.7mmol)并将反应混合物在室温搅拌过夜。将混合物真空浓缩,残余物在二氯甲烷(400mL)和浓氢氧化铵(400mL)之间分配,将各相分开并将水相用二氯甲烷提取(2×200mL)。合并的有机层用硫酸钠干燥,过滤并且浓缩。粗产物从2-丙醇重结晶,得到5.58g(62%)的标题化合物,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2小时,然后真空浓缩。残余物在二氯甲烷(250mL)和N氢氧化钠(250mL)之间分配,将各相分开并将水相用二氯甲烷提取(6×250mL)。合并的有机层用硫酸钠干燥,过滤并且浓缩。粗产物溶解于甲醇(15mL),通过加入氯化氢甲醇溶液将溶液的pH调节到5,然后将混合物在室温搅拌1小时。在添加乙醚(200mL)之后,将悬浮液在0℃搅拌2小时,将沉淀的晶体过滤出,用乙醚洗涤并且干燥,得到4.11g(90%)的标题化合物,为白色固体。
参考例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。残余物溶解于水(150mL),用二氯甲烷提取(3×150mL),合并的有机层用盐水(150mL)洗涤,用硫酸钠干燥,过滤并且浓缩。粗产物经过柱色谱法纯化,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,和使用氯仿∶甲醇∶氢氧化铵=10∶1∶0.1作为洗脱剂,得到2.27g(59%)的标题化合物,为油状物。
b)3-[1,4’]联哌啶-1’-基-丙胺三盐酸盐
(3-[1,4’]联哌啶-1’-基-丙基)-氨基甲酸叔丁基酯(2.15g,6.6mmol)、无水二氧杂环己烷(40mL)和含6.5N氯化氢的二氧杂环己烷(22mL)的混合物在室温搅拌过夜,然后用乙醚稀释并且在0℃搅拌1小时。将沉淀的晶体过滤出,用乙醚洗涤并且干燥,得到2.03g(92%)的标题化合物,为米色固体。
参考例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-叔丁氧羰基)氨基]-环己基}-乙醇
将反式-2-{1-[4-(N-叔丁氧羰基)-氨基]-环己基}-乙酸甲酯[J.Med.Chem.43(2000)1878-1885](28.5g,105.2mmol)在无水四氢呋喃(500mL)中的溶液冷却到-2℃,分批加入氢化铝锂(5.4g,142mmol)并将混合物在-2℃搅拌60分钟。将反应混合物冷却到-10℃并且用乙酸乙酯(15mL)淬灭,然后在0℃向混合物缓慢加入盐水(43ml)。将沉淀的盐过滤,并且用乙酸乙酯洗涤。将滤液真空浓缩。残余物从二异丙基醚(100ml)重结晶,得到23.7g(93%)的标题化合物,为白色粉末。
b)甲磺酸反式-2-(4-叔丁氧羰基氨基-环己基)-乙酯
在0℃向搅拌的反式-2-{1-[4-(N-叔丁氧羰基)-氨基]-环己基}-乙醇(15g,62mmol)和三乙胺(10.5mL,75mmol)在无水二氯甲烷(150mL)中的溶液中滴加含甲磺酰氯(5.7mL,73.4mmol)的二氯甲烷(25mL)。在0℃搅拌30分钟之后,溶液用水提取三次。有机溶液用硫酸钠干燥并且真空浓缩,得到13.0g(65%)的标题化合物。
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-叔丁氧羰基氨基-环己基)-乙酯(3.2g,10mmol)、碳酸钾(1.4g,10mmol)和吡咯烷(1.25mL,15mmol)在乙腈(40mL)中的混合物在60℃搅拌2小时。将混合物冷却到室温并且倾倒在水(200mL)中。沉淀的白色晶体过滤出并且用水洗涤,得到1.9g(64%)的标题化合物。
d)反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐
根据参考例3/b中所述的方法从反式-[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。
参考例5
(4-甲基-哌嗪-1-基)-哌啶-4-基-甲酮盐酸盐
a)4-(4-甲基-哌嗪-1-羰基)-哌啶-1-甲酸叔丁基酯
将1-(叔丁氧羰基)-4-哌啶甲酸(Aldrich)(21.88g,95.4mmol)、三乙胺(13.3mL,95.4mmol)和HBTU[O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(Advanced Chem.Tech.)](38.36g,101.0mmol)在无水二甲基甲酰胺(100mL)中的溶液在室温搅拌5分钟,之后加入N-甲基-哌嗪(10.6mL,95.5mmol)。通过添加三乙胺将反应混合物的pH调节到8,如此得到的混合物在室温搅拌过夜,然后真空浓缩。残余物用饱和碳酸氢钠溶液(350mL)处理,用乙酸乙酯(3×250mL)提取,合并的有机层用饱和碳酸氢钠溶液、水和盐水洗涤,用硫酸钠干燥,过滤并且浓缩。残余物经过柱色谱法纯化,使用Kieselgel 60 (0.040-0.063mm)(Merck)作为吸附剂,和使用氯仿∶甲醇=9∶1作为洗脱剂,得到25.8g(87%)的标题化合物,为油状物。
b)(4-甲基-哌嗪-1-基)-哌啶-4-基-甲酮盐酸盐
根据参考例3/b中所述的方法从4-(4-甲基-哌嗪-1-羰基)-哌啶-1-甲酸叔丁基酯制备标题化合物。
参考例6
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,然后加入另外量的2-溴乙醇(2.5mL,35mmol)并将混合物回流24小时。在冷却到室温之后,将沉淀的盐过滤出,用乙酸乙酯洗涤并将滤液浓缩。残余物溶解于乙酸乙酯(150mL)并且用水(150mL)提取。有机层用硫酸钠干燥,过滤并且浓缩。残余物溶解于乙醚(100mL),通过加入氯化氢的乙酸乙酯溶液调节溶液的pH到5,然后将混合物在室温搅拌1小时。在添加乙醚(150mL)之后,将悬浮液在0℃搅拌2小时,将沉淀的晶体过滤出,用乙醚洗涤并且干燥,得到4.8g(50%)的标题化合物。
b)2-[2-(4-吡啶-2-基-哌嗪-1-基)乙基]-异吲哚-1,3-二酮
根据参考例2/a中所述的方法从2-(4-吡啶-2-基-哌嗪-1-基)-乙醇(使用10%氢氧化钠溶液从三盐酸盐释放出来,并且用二氯甲烷提取)制备标题化合物。
c)2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐
根据参考例2/c中所述的方法从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。
参考例7
N-(4-氨基甲基-苄基)-胍二盐酸盐
a)(4-(N,N’二叔丁氧羰基-胍基甲基-苄基))-氨基甲酸叔丁基酯
将(4-氨基甲基-苄基)-氨基甲酸叔丁基酯(Aldrich)(0.47g,2mmol)、1-甲基-二叔丁氧基-硫脲[J.Org.Chem.52(1987)1700-1703](0.6g,2mmol)、HgCl2(0.56g,2mmol)和二甲基甲酰胺(10mL)的混合物在室温搅拌48小时。将沉淀的盐过滤出并将滤液真空浓缩。将剩余的油状物溶解于氯仿(70mL),用水洗涤(3×40mL),用硫酸钠干燥并且浓缩,得到0.65g(68%)的标题化合物。
b)N-(4-氨基甲基-苄基)-胍二盐酸盐
根据参考例3/b中所述的方法从(4-(N,N’-二叔丁氧羰基-胍基甲基-苄基))-氨基甲酸叔丁基酯制备标题化合物。
参考例8
4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶
a)(4-氰基-苄基)-膦酸二乙酯
将4-氰基-苄基溴(41.8g,0.213mol)和亚磷酸三乙酯(42mL,0.244mol)的混合物在装备有Dean-Stark气水分离器的烧瓶中在150℃搅拌6小时,然后使反应混合物经过真空蒸馏,得到52.2g(97%)的标题化合物。
b)4-(1-苄基-哌啶-4-亚基甲基)苯甲腈
在氩气下,在0℃,向搅拌的N-苄基-4-哌啶酮(Aldrich)(26.0g,0.137mol)和(4-氰基-苄基)-膦酸二乙酯(36.6g,0.1445mol)在二甲基甲酰胺(260mL)中的混合物中加入氢化钠(60%,7.8g,0.195mol)。将反应混合物在室温搅拌过夜,然后滴加乙醇(10mL),将如此得到的混合物倾倒在水(300mL)中,并且用乙醚提取(3×300mL)。有机层用硫 酸钠干燥并且浓缩。残余物通过柱色谱法纯化,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,和使用正己烷∶乙酸乙酯=2∶1作为洗脱剂,得到34.65g(87%)的标题化合物,为油状物。
c)4-(1-苄基-哌啶-4-亚基甲基)-苯甲亚胺酸乙酯
将4-(1-苄基-哌啶-4-亚基甲基)-苯甲腈(14g,48.6mmol)、氯仿(10mL)和含6M氯化氢的乙醇(300mL)的混合物在室温搅拌48小时。将溶液真空浓缩,残余的固体反复地溶解于乙醇(400mL)并且真空浓缩,得到16.4g(92.4%)的标题化合物,其不经进一步纯化用于下一个步骤。
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)-苯甲亚胺酸乙酯(6.8g,18.3mmol)的乙醇(250mL)溶液中加入乙二胺(2.45mL,36.6mmol)并将混合物在室温搅拌过夜。将沉淀的固体过滤出并将滤液真空浓缩。残余物反复地溶解于乙醇(100mL)并且真空浓缩。粗产物通过急骤色谱法纯化,使用氯仿∶甲醇∶氢氧化铵=9∶2∶0.1作为洗脱剂,得到2.7g(44.6%)的标题化合物。
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)的乙醇(20mL)溶液中加入甲酸铵(0.19g,3mmol)和10%Pd/C(20mg)并且将混合物回流8小时。将催化剂过滤出并将滤液真空浓缩。剩余的粗物质通过柱色谱法纯化,使用碱性氧化铝(150目,Aldrich)作为吸附剂和使用含10%甲醇的氯仿作为洗脱剂,得到68mg(92%)的标题化合物。
参考例9
4-哌啶-4-基甲基-苄脒
a)4-(1-苄基-哌啶-4-亚基甲基)苄脒
根据参考例8/d中所述的方法从4-(1-苄基-哌啶-4-亚基甲基)-苯甲亚胺酸乙酯和含氨的甲醇制备标题化合物。
b)4-哌啶-4-基甲基-苄脒
根据参考例8/e中所述的方法从4-(1-苄基-哌啶-4-亚基甲基)-苄脒制备标题化合物。
参考例10
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
根据参考例8/d中所述的方法从4-(1-苄基-哌啶-4-亚基甲基)-苯甲亚胺酸乙酯和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
根据参考例8/e中所述的方法从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。
参考例11
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
根据参考例1/a中所述的方法从1-吡啶-4-基-哌嗪[Org.Lett.4(2002)737-740]和N-(2-溴丙基)-邻苯二甲酰亚胺制备标题化合物。
b)2-(4-吡啶-4-基-哌嗪-1-基)-丙胺
根据参考例1/b中所述的方法从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。
参考例12
4-(4-氨基-丁基)哌啶-1-甲酸叔丁基酯
a)4-(3-甲烷磺酰基氧基-丙基)哌啶-1-甲酸叔丁基酯
在0℃向4-(3-羟基丙基)-哌啶-1-甲酸叔丁基酯(2.12g,8.7mmol)的二氯甲烷(10mL)溶液中加入三乙胺(1.33mL,9.57mmol)和甲磺酰氯(0.74mL,9.57mmol)并将反应混合物在这个温度搅拌1小时。在通过添加甲醇(1mL)将反应淬灭之后,将混合物用水、饱和碳酸氢钠溶液和水洗涤,用硫酸钠干燥,过滤并且浓缩,得到2.73g(97%)的标题化合物。
b)4-(3-氰基-丙基)-哌啶-1-甲酸叔丁基酯
向4-(3-甲烷磺酰基氧基-丙基)-哌啶-1-甲酸叔丁基酯(1.35g,4.2mmol)的二甲基甲酰胺(30mL)溶液中加入氰化钾(0.33g,5.1mmol)并将反应混合物在80℃搅拌20小时。在真空浓缩之后,将残余物用水处理并且用乙酸乙酯提取(3×50mL)。合并的有机层用水和盐水洗涤,用硫酸钠干燥,过滤并且浓缩,得到0.919g(87%)的标题化合物。
c)4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯
向搅拌的4-(3-氰基-丙基)-哌啶-1-甲酸叔丁基酯(0.896g,3.55mmol)和氢氧化锂水合物(0.447g,10.65mmol)在二氧杂环己烷(56mL)和水(14mL)的混合物中的溶液中加入10%Pd/C(90mg)和阮内镍(0.42g)。反应混合物在50℃氢化3小时,然后将催化剂过滤出并且将滤液浓缩。残余物通过柱色谱法纯化,使用Kieselgel 60(0.015-0.040mm)(Merck)作为吸附剂,和使用甲醇∶氢氧化铵=10∶1作为洗脱剂,得到0.493g(54%)的标题化合物。MS(EI)257.2(MH+)。
参考例13
4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯
a)4-(3-叠氮基-丙基)-哌啶-1-甲酸叔丁基酯
向4-(3-甲烷磺酰基氧基-丙基)-哌啶-1-甲酸叔丁基酯(参考例 13/a)(1.35g,4.2mmol)的二甲基甲酰胺(30mL)溶液中加入叠氮化钠(0.33g,5.1mmol)并将反应混合物在80℃搅拌20小时。在真空浓缩之后,残余物用水处理并且用乙酸乙酯提取(3×50mL)。合并的有机层用水和盐水洗涤,用硫酸钠干燥,过滤并且浓缩,得到1.08g(96%)的标题化合物。MS(EI)291.3(M+Na+)。
b)4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯
向4-(3-叠氮基-丙基)-哌啶-1-甲酸叔丁基酯(1.738g,6.48mmol)的无水四氢呋喃(50mL)溶液中加入水(0.49mL)和三苯膦(3.4g,12.96mmol)。将反应混合物在室温搅拌过夜,然后浓缩。残余物通过柱色谱法纯化,使用Kieselgel 60(0.015-0.040mm)(Merck)作为吸附剂,和使用甲醇∶氢氧化铵=10∶1作为洗脱剂,得到1.498g(95%)的标题化合物。MS(EI)243.2(MH+)。
参考例14
2-(1’-甲基-[1,4’]联哌啶-4-基)-乙胺三-三氟乙酸盐
a)[2-(1’-甲基-[1,4’]联哌啶-4-基)-乙基]-氨基甲酸叔丁基酯
向三乙胺(44mg,0.44mmol)的无水乙醇(5mL)溶液中加入(2-哌啶-4-基-乙基)-氨基甲酸叔丁基酯[Bioorg.Med.Chem.Lett.;11(2001)2325-2330](300mg,0.44mmol)、异丙醇钛(IV)(125mg,0.44mmol)和N-甲基-哌啶酮(50mg,0.44mmol)。将反应混合物在25℃搅拌20小时,然后加入硼氢化钠(17mg,0.44mmol),并将得到的混合物进一步在25℃搅拌20小时。然后通过将混合物倾倒在2N氨水(0.66mL)中将反应淬灭,将得到的无机沉淀物过滤出并且用二氯甲烷洗涤,并将含水的滤液用二氯甲烷提取。合并的提取液用硫酸钠干燥,过滤并且真空浓缩。残余物通过柱色谱法纯化,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,和使用氯仿∶甲醇∶氢氧化铵=10∶1∶0.1作为洗脱剂,得到77mg(54%)的标题化合物,为带黄色的油状物。MS(EI)326.3(MH+)。
b)2-(1’-甲基-[1,4’]联哌啶-4-基)-乙胺三-三氟乙酸盐
向搅拌的[2-(1’-甲基-[1,4’]联哌啶-4-基)-乙基]-氨基甲酸叔丁基酯(77mg,0.236mmol)在二氯甲烷(5mL)中的冰冷的溶液中加入三氟乙酸(0.15mL)并将反应混合物在室温搅拌过夜,然后真空浓缩,得到127mg(95%)的标题化合物。MS(EI)226.4(MH+)。
参考例15
2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙胺
a)(4-吡啶-2-基甲基-哌嗪-1-基)-乙腈
向搅拌的1-(2-吡啶基甲基)哌嗪(EMKA-Chemie)(309mg,1.69mmol)的乙醇(10mL)溶液中加入氯-乙腈(306mg,4.06mmol)和碳酸钠(718mg,6.77mmol)并将混合物回流4小时。然后将沉淀的无机盐过滤出,用乙醇洗涤并将滤液真空浓缩,得到340mg(93%)的标题化合物,为带黄色的油状物。MS(EI)217.2(MH+)。
b)2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙胺
在氩气气氛下,向氢化铝锂(125mg,3.37mmol)在无水四氢呋喃(15mL)中的悬浮液中加入(4-吡啶-2-基甲基-哌嗪-1-基)-乙腈(340mg,1.57mmol)的四氢呋喃(15mL)溶液并将反应混合物在室温搅拌3小时。然后通过加入10%氢氧化钠溶液(0.2mL)和水(0.75mL)将反应淬灭,并将混合物在室温搅拌过夜。将不溶性物质过滤出,用四氢呋喃洗涤并将滤液真空浓缩,得到338mg(98%)的标题化合物,为带黄色的固体。MS(EI)221.2(MH+)。
参考例16
2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙胺
a)(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙腈
根据参考例17/a中所述的方法从1-(2-吡嗪基甲基)哌嗪 (EMKA-Chemie)制备标题化合物。MS(EI)204.2(MH+)。
b)2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙胺
根据参考例17/b中所述的方法从(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙腈制备标题化合物。MS(EI)208.2(MH+)。
参考例17
4-(4-氨基甲基-苄基)-哌啶-1-甲酸叔丁基酯
a)4-哌啶-4-基甲基-苯甲腈
向搅拌的4-(1-苄基-哌啶-4-亚基甲基)-苯甲腈(参考例8/b)(17.4g,60mmol)的甲醇(100mL)溶液中加入10%Pd/C(1.7g)并将反应混合物氢化3天,然后将催化剂过滤出并将滤液浓缩。残余物通过柱色谱法纯化,使用Kieselgel 60(0.015-0.040mm)(Merck)作为吸附剂,和使用氯仿∶甲醇∶氢氧化铵=4∶1∶0.1作为洗脱剂,得到3.6g(30%)的标题化合物。
b)4-(4-氰基-苄基)-哌啶-1-甲酸叔丁基酯
向4-哌啶-4-基甲基-苯甲腈(3.6g,18mmol)在二氧杂环己烷(105mL)和水(52mL)中的溶液中加入二碳酸二叔丁酯(5.44g,25mmol)并将反应混合物在室温搅拌过夜。在浓缩之后,残余物在水和氯仿之间分配,有机层用硫酸钠干燥,过滤并且真空浓缩,得到4.0g(74%)的标题化合物,为带黄色的油状物,其在静置时固化。MS(EI)323.1(M+Na+)。
c)4-(4-氨基甲基-苄基)-哌啶-1-甲酸叔丁基酯
根据参考例13/c中所述的方法从4-(4-氰基-苄基)-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)305.3(MH+)。
实施例1
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-吡啶-4-基-哌嗪-1-基)-乙基]-苯甲酰胺二盐酸盐
a)2,4-二氯-1-(2-硝基-苯氧基)-苯
将1-氟-2-硝基苯(4.8mL,45.42mmol)、碳酸钾(13.8g,0.1mol)和2,4-二氯-苯酚(8.16g,50.06mmol)在无水二甲基甲酰胺(70mL)中的混合物在100℃搅拌2小时。将固体过滤出,并将滤液真空浓缩。残余物在乙醚和1N氢氧化钠之间分配,有机层用1N氢氧化钠、水和盐水洗涤,用硫酸钠干燥,过滤并且真空浓缩,得到11.69g(91%)的标题化合物,为带黄色的油状物,其在静置时固化。MS(EI)285.2(MH+)。文献[Chem.Heterocycl.Compd.(Engl.Transl.)11(1975)1356-1358]
b)2-(2,4-二氯-苯氧基)-苯胺[Chem.Abstr.84(1976)164313q]
向搅拌的2,4-二氯-1-(2-硝基-苯氧基)-苯(3.5g,12.32mmol)的乙酸乙酯(60mL)溶液中加入二氯化锡二水合物(13.89g,61.6mmol)并将混合物回流2小时,之后将其用饱和碳酸氢钠溶液(192mL)淬灭。将有机相分离并将水相用乙酸乙酯洗涤几次。合并的提取液用硫酸钠干燥,过滤并且真空浓缩,得到3.1g(99%)的标题化合物,为带黄色的油状物:MS(EI)255.2(MH+)。
c)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸
在氩气气氛下向用冰冷却的2-(2,4-二氯-苯氧基)-苯胺(0.5g,1.97mmol)的无水吡啶(5mL)溶液中分批加入4-氯磺酰基苯甲酸(0.45g,1.97mmol)。将反应混合物在室温搅拌过夜。将混合物真空蒸发,残余物用1N盐酸(20mL)处理,并且用乙酸乙酯提取(3×50mL)。合并的有机层用1N盐酸、水和盐水洗涤,用硫酸钠干燥,过滤并且真空浓缩。残余物经过急骤柱色谱法纯化,使用Kieselgel 60(0.015-0.040mm)作为吸附剂(Merck)和使用氯仿∶甲醇∶乙酸=294∶6∶1作为洗脱剂,得到0.6g(70%)的标题化合物,为浅粉红色固体,其从乙醚-石油醚结晶。 MS(EI)439.3(MH+)。
d)4-[2-(2,4-二氯-苯氧基)苯基氨磺酰基]-N-{2-[4-吡啶-4-基-哌嗪-1-基)-乙基]-苯甲酰胺二盐酸盐
将4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(0.2g,0.45mmol)、三乙胺(0.07mL,0.5mmol)和HBTU[O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸盐(Advanced Chem.Tech.)](0.19g,0.5mmol)在无水二甲基甲酰胺(5mL)中的溶液在室温搅拌5分钟,之后,加入2-(4-吡啶-4-基)-哌嗪-1-基)-乙胺(参考例1)(0.11g,0.5mmol)。通过添加三乙胺将反应混合物的pH调节到8,将如此得到的混合物在室温搅拌过夜,然后真空浓缩。残余物用饱和碳酸氢钠溶液(10mL)处理,用乙酸乙酯提取(3×25mL),合并的有机层用饱和碳酸氢钠溶液、水和盐水洗涤,用硫酸钠干燥,过滤并且浓缩。残余物经过急骤柱色谱法纯化,使用Kieselgel 60(0.015-0.040mm)作为吸附剂(Merck)和使用氯仿∶甲醇∶氢氧化铵=95∶5∶1作为洗脱剂,然后转化为二盐酸盐形式,得到0.078g(25%)的标题化合物,为带浅黄色的无定形固体。MS(EI)627.5(MH+)。
实施例2
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺三氟乙酸盐
将4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)(0.35g,0.8mmol)、三乙胺(0.36mL,2.56mmol)和HBTU(0.34g,0.88mmol)在无水二甲基甲酰胺(8mL)中的溶液在室温搅拌5分钟,之后加入2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参考例2)(0.23g,0.88mmol)。通过添加三乙胺调节反应混合物的pH到8,将如此得到的混合物在室温搅拌过夜,然后真空浓缩。残余物经过反相HPLC,使用YMC-Pack ODS-AQ型填料(由YMC生产)和乙腈/水/三氟乙酸作为洗脱剂。在将适合的级分浓缩之后,残余物与乙醚研磨,过滤并且 干燥,得到0.33g(57%)的标题化合物,为白色无定形固体。MS(EI)610.5(MH+)。
实施例3
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(2,4-二氯-苯氧基)苯基氨磺酰基]-苯甲酰胺
根据实施例1/d从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和3-[1,4’]联哌啶-1’-基-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)646.5(MH+)。
实施例4
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺
a)4-[2-(3,4-二氯-苯氧基)苯基氨磺酰基]-苯甲酸
向搅拌的2-(3,4-二氯-苯氧基)-苯胺[Chem.Pharm.Bull.33(1985)4409-4421](0.2g,0.787mmol的无水吡啶(5mL)溶液中加入4-氯磺酰基苯甲酸(0.2g,0.9mmol)。将反应混合物在室温搅拌过夜,然后倾倒在冰-水(50mL)中。将沉淀的晶体过滤出,用水洗涤并且干燥,得到0.3g(87%)的标题化合物。
b)4-[2-(3,4-二氯-苯氧基)苯基氨磺酰基]-N-(2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺
将4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(0.11g,0.25mmol)、三乙胺(0.07mL,0.5mmol)和HBTU(0.11g,0.29mmol)在无水二甲基甲酰胺(5mL)中的溶液在室温搅拌5分钟,之后加入2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参考例2)(0.11g,0.5mmol)。通过添加三乙胺调节反应混合物的pH到8,将如此得到的混合物在室温搅拌过夜,然后真空浓缩。残余物用饱和碳酸氢钠溶液(30mL)处理,将沉淀的晶体过滤出,用水洗涤并且干燥。粗产物通 过柱色谱法纯化,使用Kieselgel 60(0.040-0.063mm)(Merck)作为吸附剂,和使用氯仿∶甲醇∶氢氧化铵=9∶1∶0.1作为洗脱剂。产物用乙醚结晶,得到0.65g(42%)的标题化合物。
实施例5
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和3-[1,4’]联哌啶-1’-基-丙胺三盐酸盐(参考例3)制备标题化合物。
实施例6
4-[2-(4-氯-苯氧基)-苯基氨磺酰基-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)苯基]-乙基}-苯甲酰胺
a)4-[2-(4-氯-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例4/a中所述的方法从2-(4-氯-苯氧基)-苯胺[Collect.Czech.Chem.Commun.65(2000)862-880]制备标题化合物。
b)4-[2-(4-氯-苯氧基)苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺
根据实施例4/b中所述的方法从4-[2-(4-氯-苯氧基)-苯基氨磺酰基]-苯甲酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参考例2)制备标题化合物。
实施例7
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基)-苯甲酰胺
a)4-[2-(4-溴-苯氧基)苯基氨磺酰基]-苯甲酸
根据实施例4/a中所述的方法从2-(4-溴-苯氧基)-苯胺[J.Chem.. Soc.(1930)1202,1206]制备标题化合物。
b)4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺
根据实施例4/b中所述的方从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参考例2)制备标题化合物。
实施例8
N-(4-[1,4’]-联哌啶-1’-基-苯基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺
将4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)(0.3g,0.68mmol)、HOBt[1-羟基苯并三唑](0.093g,0.68mmol)和EDC盐酸盐[N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺](0.132g,0.68mmol)在无水二甲基甲酰胺(5mL)中的溶液在0℃搅拌10分钟,之后加入4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806](0.178g,0.68mmol)并将反应混合物在室温搅拌过夜。将混合物真空浓缩,残余物用饱和碳酸氢钠溶液(10mL)处理,并且用氯仿提取(3×10mL)。合并的有机层用硫酸钠干燥,过滤,并且真空浓缩。残余物从氯仿重结晶,得到0.115g(25%)的标题化合物,为黄色无定形固体。MS(EI)680.6(MH+)。
实施例9
反式-4-[2-(2,4-二氯-苯氧基)苯基氨磺酰基]-N-[4-(2-吡略烷-1-基乙基)-环己基]-苯甲酰胺
根据实施例4/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和反式-4-(2-吡咯烷-1-基乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)617.6(MH+)。
实施例10
3-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-4-基-哌嗪-1-基)-乙基]-苯甲酰胺二盐酸盐
a)3-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基-苯甲酸
根据实施例1/c中所述的方法从2-(2,4-二氯-苯氧基)-苯胺(实施例1/b)和3-氯磺酰基苯甲酸制备标题化合物。MS(EI)439.3(MH+)。
b)3-[2-(2,4-二氯苯氧基)-苯基氨磺酰基]-N-{2-[4-吡啶-4-基-哌嗪-1-基)-乙基]-苯甲酰胺二盐酸盐
根据实施例1/d中所述的方法从3-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸和2-(4-吡啶-4-基)-哌嗪-1-基)-乙胺(参考例1)制备标题化合物。MS(EI)627.5(MH+)。
实施例11
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-4-基乙基)-苯甲酰胺三氟乙酸盐
a)4-(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-(2-氨基-乙基)-哌啶-1-甲酸叔丁基酯[Bioorg.Med.Chem.Lett.13(2003)2167-2172]制备标题化合物。MS(EI)672.6(M+Na+)。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-4-基乙基)-苯甲酰胺三氟乙酸盐
向冰冷的4-(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-哌啶-1-甲酸叔丁基酯(0.26g,0.4mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(0.4mL)并将反应混合物在室温搅拌过夜,然后浓缩。残余物与乙醚研磨,过滤并且干燥,得到0.22g(83%)的标题 化合物,为白色无定形固体。MS(EI)549.4(MH+)。
实施例12
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(2-二甲基氨基-乙基)-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和N,N-二甲基乙二胺(Aldrich)制备标题化合物。MS(EI)509.4(MH+)。
实施例13
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-N-甲基-苯甲酰胺三氟乙酸盐
a)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(4-氰基-苄基)-N-甲基-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和N-甲基-4’-氰基-苄胺[J.Med.Chem.26(1983)309-312]制备标题化合物。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-N-甲基-苯甲酰胺三氟乙酸盐
将无水氯化氢气体鼓泡通过4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(4-氰基-苄基)-N-甲基-苯甲酰胺(0.51g,0.9mmol)在无水乙醇(50mL)中的冰冷的溶液一小时,然后将如此得到的混合物在8℃保持过夜。将反应混合物真空浓缩,将残余物溶解于无水乙醇(15mL),加入乙二胺(67μL,0.99mmol)并将反应混合物在室温搅拌过夜。将混合物真空浓缩,残余物经过反相HPLC,使用YMC-Pack ODS-AQ型填料(由YMC生产)和乙腈/水/三氟乙酸作为洗脱剂。在将适当的级分浓缩之后,残余物与乙醚研磨,过滤并且干燥,得到0.347g(53%)的标题化合物,为白色固体。MS(EI)610.5(MH+)。
实施例14
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-哌啶-4-基甲基-苯甲酰胺三氟乙酸盐
a)4-({4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-甲基)-哌啶-1-甲酸叔丁基酯
根据实施例4/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-氨基甲基-哌啶-1-甲酸叔丁基酯(Fluka)制备标题化合物。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-哌啶-4-基甲基-苯甲酰胺三氟乙酸盐
根据实施例11/b中所述的方法从4-({4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-甲基)-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)535.5(MH+)。
实施例15
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4,5-二氢-1H-咪唑-2-基)-乙基]-苯甲酰胺
a)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(丙腈-3-基)-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和3-氨基丙腈(Fluka)制备标题化合物。MS491.4(EI)(MH+)。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4,5-二氢-1H-咪唑-2-基)-乙基]-苯甲酰胺
根据实施例13/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(丙腈-3-基)-苯甲酰胺制备标题化合物。
实施例16
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-哌啶-4-基-苯甲酰胺三氟乙酸盐
a)4-(4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-哌啶-1-甲酸叔丁基酯
根据实施例4/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-氨基-哌啶-1-甲酸叔丁基酯盐酸盐(Fluka)制备标题化合物。MS(EI)643.5(M+Na+)。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-哌啶-4-基-苯甲酰胺三氟乙酸盐
根据实施例11/b中所述的方法从4-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-哌啶-1-甲酸叔丁基酯制备标题化合物。
实施例17
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-甲基-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和甲胺(1.61M的二甲苯溶液)制备标题化合物。MS 452.3(EI)(MH+)。
实施例18
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(4-甲基-哌嗪-1-羰基)-哌啶-1-羰基]-苯磺酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和(4-甲基-哌嗪-1-基)-哌啶-4-基-甲酮盐酸盐(参考例5)制备标题化合物。MS 632.5(EI)(MH+)。
实施例19
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(2-二甲基氨基-乙基)-N-甲基-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和N,N,N’-三甲基-乙二胺(Aldrich)制备标题化合物。MS 523.3(EI)(MH+)。
实施例20
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺三氟乙酸盐
根据实施例2中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-(4-吡啶-2-基-哌嗪-1-基)-乙胺(参考例6)制备标题化合物。
实施例21
4-([1,4’]联哌啶-1’-羰基)-N-[2-(2,4-二氯-苯氧基)-苯基]-苯磺酰胺
根据实施例8中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4,4’-联哌啶制备标题化合物。
实施例22
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺
a)4-溴-2-氯-1-(2-硝基-苯氧基)-苯
根据实施例1/a中所述的方法从4-溴-2-氯-苯酚制备标题化合物。MS(EI)329.3(MH+)。
b)2-(4-溴-2-氯-苯氧基)-苯胺
根据实施例1/b中所述的方法从4-溴-2-氯-1-(2-硝基-苯氧基)-苯制备标题化合物。MS(EI)300.2(MH+)。
c)4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例1/c中所述的方法从2-(4-溴-2-氯-苯氧基)-苯胺制备标题化合物。MS(EI)483.4(MH+)。
d)4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺
根据实施例2中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸和2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙胺二盐酸盐(参考例2)制备标题化合物。MS 655(EI)(MH+)。
实施例23
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-(4-胍基甲基-苄基)-苯甲酰胺盐酸盐
根据实施例2中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和N-(4-氨基甲基-苄基)-胍二盐酸盐(参考例7)制备标题化合物。
实施例24
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(1’-甲基-[1,4’]联哌啶-4-基)-乙基]-苯甲酰胺
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-(1’-甲基-[1,4’]联哌啶-4-基)-乙胺三-三氟乙酸盐(参考例14)制备标题化合物。MS(EI)646.3(MH+)。
实施例25
N-[2-(4-溴-苯氧基)-苯基]-4-{4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶-1-羰基}-苯磺酰胺
根据实施例2中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶(参考例8)制备标题化合物。
实施例26
4-(1-{4-[2-(4-氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-基甲基)-苄脒
根据实施例2中所述的方法从4-[2-(4-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例6/a)和4-哌啶-4-基甲基-苄脒(参考例9)制备标题化合物。
实施例27
N-[2-(4-氯-苯氧基)-苯基]-4-{4-[4-(1,4,5,6-四氢-嘧啶-2-基)-苄基]-哌啶-1-羰基}-苯磺酰胺
根据实施例2中所述的方法从4-[2-(4-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例6/a)和2-(4-哌啶-4-基甲基-苯基)-1,4,5,6-四氢-嘧啶(参考例10)制备标题化合物。
实施例28
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺
根据实施例2中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参考例11)制备标题化合物。
实施例29
哌啶-4-甲酸(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-酰胺盐酸盐
a)(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-氨基甲酸叔丁基酯
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和(2-氨基-乙基)-氨基甲酸叔丁基酯(Aldrich) 制备标题化合物。MS(EI)603.2(M+Na+)。
b)N-(2-氨基-乙基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺盐酸盐
向搅拌的(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-氨基甲酸叔丁基酯(0.41g,0.71mmol)的二氯甲烷(5mL)溶液加入含9M氯化氢的乙醇(0.4mL)并将反应混合物在室温静置2小时。然后将混合物用乙醚(20mL)稀释,将沉淀的产物过滤,用乙醚洗涤并且干燥,得到0.28g(77%)的标题化合物,为白色固体。MS(EI)481.2(MH+)。
c)4-(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基氨基甲酰基)-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从N-(2-氨基-乙基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺和哌啶-1,4-二甲酸单-叔丁基酯(Aldrich)制备标题化合物。MS(EI)692.1(MH+)。
d)哌啶-4-甲酸(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-酰胺盐酸盐
根据实施例29/b中所述的方法从4-(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基氨基甲酰基)-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)592.1(MH+)。
实施例30
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺盐酸盐
向搅拌的4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)(41mg,0.085mmol)在二氯甲烷(2mL)和二甲基甲酰胺(0.2mL)的混合物中的溶液中加入4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯(参考 例13)(24mg,0.1mmol)、HBTU(46mg,0.12mmol)和三乙胺(60μL,0.4mmol)。将混合物在室温搅拌24小时,然后通过柱色谱法纯化,使用Kieselgel 60(0.015-0.040mm)作为吸附剂(Merck)和使用从100%A洗脱剂开始并且在20分钟时间内进行到100%B洗脱剂的梯度洗脱(洗脱剂A:正己烷;洗脱剂B:乙酸乙酯)。将纯化的化合物溶解于乙酸乙酯(0.5mL),加入含2.5M氯化氢的乙酸乙酯(2.0mL)并将混合物在室温搅拌24小时。将沉淀的产物过滤,用乙醚洗涤并且真空干燥,得到35mg(64%)的标题化合物。MS(EI)608.1(MH+)。
实施例31
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-(2-苯氧基-苯基氨磺酰基)-苯甲酰胺
a)4-(2-苯氧基-苯基氨磺酰基)-苯甲酸
根据实施例4/a中所述的方法从2-苯氧基-苯胺(Aldrich)制备标题化合物。MS(EI)370.2(MH+)。
b)N-(4-[1,4’]联哌啶-1’-基-苯基)-4-(2-苯氧基-苯基氨磺酰基)-苯甲酰胺
向搅拌的4-(2-苯氧基-苯基氨磺酰基)-苯甲酸(31mg,0.085mmol)在二氯甲烷(2mL)和二甲基甲酰胺(0.2mL)的混合物中的溶液中加入4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806](26mg,0.1mmol)、HBTU(46mg,0.12mmol)和三乙胺(30μL,0.2mmol)。将混合物在室温搅拌24小时,然后通过柱色谱法纯化,使用Kieselgel60(0.015-0.040mm)作为吸附剂(Merck)和使用从100%A洗脱剂开始并且在15分钟的时间内进行到70%A和30%B洗脱剂的混合物的梯度洗脱(洗脱剂A:氯仿;洗脱剂B:包含5%氢氧化铵的甲醇),得到24.8mg(48%)的标题化合物。MS(EI)611.3(MH+)。
实施例32
1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-甲酸(哌啶-4-基甲基)-酰胺乙酸盐/盐酸盐混合盐
a)1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-甲酸乙酯
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和哌啶-4-甲酸乙酯(Aldrich)制备标题化合物。MS(EI)578.2(MH+)。
b)1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-甲酸
向搅拌的1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-甲酸乙酯(0.24g,0.42mmol)在四氢呋喃(2.5mL),水(1.25mL)和甲醇(1.25mL)的混合物中的溶液中加入氢氧化锂一水合物(0.044g,1.0mmol)并将反应混合物在室温搅拌2小时。将混合物浓缩,将残余物溶解于水,用1M盐酸酸化,将沉淀的固体过滤出,用水洗涤并且干燥,得到0.18g(79%)的标题化合物。MS(EI)550.2(MH+)。
c)4-{[(1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-羰基)-氨基]-甲基}-哌啶-1-甲酸叔丁基酯
根据实施例2中所述的方法从1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-甲酸和4-(氨基甲基)-Boc-哌啶(Fluka)制备标题化合物。MS(EI)746.2(MH+)。
d)1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-甲酸(哌啶-4-基甲基)-酰胺乙酸盐/盐酸盐混合盐
根据实施例29/b中所述的方法从4-{[(1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌啶-4-羰基)-氨基]-甲基}-哌啶-1-甲酸叔丁基酯制备标题化合物。粗产物经过反相HPLC,使用YMC-PackODS-AQ型填料(由YMC生产)和乙腈/水/乙酸作为洗脱剂,得到标题 化合物。MS(EI)646.2(MH+)。
实施例33
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(哌啶-4-基氨基甲酰基)-乙基]-苯甲酰胺乙酸盐
a)3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸乙酯
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和β-丙氨酸乙酯盐酸盐(Aldrich)制备标题化合物。MS(EI)538.2(MH+)。
b)3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸
根据实施例32/b中所述的方法从3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸乙酯制备标题化合物。MS(EI)510.1(MH+)。
c)4-(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酰基氨基)-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸和4-氨基-哌啶-1-甲酸叔丁基酯(Fluka)制备标题化合物。MS(EI)692.2(MH+)。
d)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(哌啶-4-基氨基甲酰基)-乙基]-苯甲酰胺乙酸盐
根据实施例29/b中所述的方法从4-(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酰基氨基)-哌啶-1-甲酸叔丁基酯制备标题化合物。粗产物经过反相HPLC,使用YMC-Pack ODS-AQ型填料(由YMC生产)和乙腈/水/乙酸作为洗脱剂,得到标题化合物。MS(EI)592.2(MH+)。
实施例34
(S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-甲酸(哌啶-4-基甲基)-酰胺盐酸盐
a)(S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-甲酸苄基酯
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和L-脯氨酸苄基酯盐酸盐(Aldrich)制备标题化合物。MS(EI)626.3(MH+)。
b)(S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-甲酸
根据实施例32/b中所述的方法从(S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-甲酸苄基酯制备标题化合物。MS(EI)536.2(MH+)。
c)4-{[((S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-羰基)-氨基]-甲基}-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从(S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-甲酸和4-氨基甲基-哌啶-1-甲酸叔丁基酯(Fluka)制备标题化合物。MS(EI)754.2(M+Na+)。
d)(S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-甲酸(哌啶-4-基甲基)-酰胺盐酸盐
根据实施例29/b中所述的方法从4-{[((S)-1-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-吡咯烷-2-羰基)-氨基]-甲基}-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)632.1(MH+)。
实施例35
4-[2-(4-溴-苯氧基)-苯基氨磺酰基-N-{2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)651.2(MH+)。
实施例36
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例8中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)641.2(MH+)。
实施例37
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[(哌啶-4-基甲基)-氨基甲酰基]-乙基}-苯甲酰胺乙酸盐/盐酸盐混合盐
a)4-[(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酰基氨基)-甲基]-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸(实施例33/b)和4-(氨基甲基)-Boc-哌啶(Fluka)制备标题化合物。MS(EI)706.2(MH+)。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[(哌啶-4-基甲基)-氨基甲酰基]-乙基}-苯甲酰胺乙酸盐/盐酸盐混合盐
根据实施例29/b中所述的方法从4-[(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酰基氨基)-甲基]-哌啶-1-甲酸叔丁基酯制备标题化合物。粗产物经过反相HPLC,使用YMC-Pack ODS-AQ 型填料(由YMC生产)和乙腈/水/乙酸作为洗脱剂,得到标题化合物。MS(EI)606.2(MH+)。
实施例38
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(3-哌啶-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)632.2(MH+)。
实施例39
N-[2-(2,4-二氯-苯氧基)-苯基-4-[4-(3-吡咯烷-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(3-吡咯烷-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)618.2(MH+)。
实施例40
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(3-二甲基氨基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和二甲基(3-哌嗪-1-基-丙基)-胺(EMKA-Chemie)制备标题化合物。MS(EI)592.2(MH+)。
实施例41
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(1-甲基-哌啶-3-基甲基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(1-甲基-哌啶-3-基甲基)-哌嗪 (EMKA-Chemie)制备标题化合物。MS(EI)618.2(MH+)。
实施例42
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-吡咯烷-1-基-乙基)-哌啶-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-(2-吡咯烷-1-基-乙基)-哌啶(EMKA-Chemie)制备标题化合物。MS(EI)603.2(MH+)。
实施例43
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-吡啶-2-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(2-吡啶-2-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)612.2(MH+)。
实施例44
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(3-吗啉-4-基-丙基)-[1,4]二氮杂环庚烷-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(3-吗啉-4-基-丙基)-高哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)648.2(MH+)。
实施例45
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-二甲基氨基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和二甲基-(2-哌嗪-1-基-乙基)-胺(EMKA-Chemie)制备标题化合物。MS(EI)578.2(MH+)。
实施例46
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-氧代-2-哌啶-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-哌嗪-1-基-哌啶-1-基-乙酮(EMKA-Chemie)制备标题化合物。MS(EI)632.0(MH+)。
实施例47
N-[2-(2,4-二氯-苯氧基)-苯基]-4-(4-吡啶-2-基甲基-哌嗪-1-羰基)-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-吡啶-2-基甲基-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)598.2(MH+)。
实施例48
N-[2-(2,4-二氯-苯氧基)-苯基]-4-(4-吡啶-3-基甲基-哌嗪-1-羰基)-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-吡啶-3-基甲基-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)598.2(MH+)。
实施例49
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-二乙基氨基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和二乙基-(2-哌嗪-1-基-乙基)-胺(EMKA-Chemie)制备标题化合物。MS(EI)606.2(MH+)。
实施例50
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-吡啶-4-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(2-吡啶-4-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)612.2(MH+)。
实施例51
N-[2-(2,4-二氯-苯氧基)-苯基]-4-(4-吡啶-4-基甲基-哌嗪-1-羰基)-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-吡啶-4-基甲基-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)598.2(MH+)。
实施例52
2-(4-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌嗪-1-基)-N-甲基-N-苯基-乙酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和N-甲基-N-苯基-2-哌嗪-1-基-乙酰胺(EMKA-Chemie)制备标题化合物。MS(EI)654.2(MH+)。
实施例53
2-(4-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌嗪-1-基)-N-吡啶-3-基-乙酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-哌嗪-1-基-N-吡啶-2-基-乙酰胺(EMKA-Chemie)制备标题化合物。MS(EI)641.2(MH+)。
实施例54
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例8中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)641.2(MH+)。
实施例55
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和2-哌嗪-1-基-吡咯烷-1-基-乙酮(EMKA-Chemie)制备标题化合物。MS(EI)618.2(MH+)。
实施例56
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基-N-[2-(2-哌啶-4-基-乙基氨基甲酰基)-乙基]-苯甲酰胺盐酸盐
a)4-[2-(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酰基氨基)-乙基]-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸(实施例33/b)和4-(2-氨基-乙基)-哌啶-1-甲酸叔丁基酯[Bioorg.Med.Chem.Lett.;13(2003)2167-2172.]制备标题化合物。MS(EI)742.1(M+Na+)。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(2-哌啶-4-基-乙基氨基甲酰基)-乙基]-苯甲酰胺盐酸盐
根据实施例29/b中所述的方法从4-[2-(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酰基氨基)-乙基]-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)620.1(MH+)。
实施例57
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺三氟乙酸盐
a)4-(3-{4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙基)-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯(参考例14)制备标题化合物。MS(EI)696.1(M+Na+)。
b)4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺三氟乙酸盐
根据实施例11/b中所述的方法从4-(3-{4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙基)-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)573.2(MH+)。
实施例58
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酰胺
a)4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸
在氩气气氛下向用冰冷却的2-(4-溴-苯氧基)-5-氟-苯胺[YakugakuZasshi;87(1967)591,594;Chem.Abstr.;67(1967)73282](0.43g,1.52mmol)在无水吡啶(10mL)中的溶液中分批加入4-氯磺酰基苯甲酸(0.34g,1.52mmol)。将反应混合物在室温搅拌过夜。将混合物真空浓缩,残余物用1N盐酸(15mL)处理,并且用乙酸乙酯提取(3×20mL)。合并的有机层用1N盐酸、水和盐水洗涤,用硫酸钠干燥,过滤并且真空浓缩。残余物与乙醚研磨,过滤,用乙醚洗涤并且干燥,得到0.31g(43%)的标题化合物,为浅粉色固体。MS(EI)467.9(MH+)。
b)N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)707.7(MH+)。
实施例59
N-[2-(3,4-二氯-苯氧基)-苯基]-4-(4-吡啶-3-基甲基-哌嗪-1-羰基)-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-吡啶-3-基甲基-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)598.1(MH+)。
实施例60
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-吡啶-4-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(2-吡啶-4-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)612.0(MH+)。
实施例61
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(2-吡咯烷-1-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)604.2(MH+)。
实施例62
N-(3-[1,4’]联哌啶-1’-基-3-氧代-丙基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺三氟乙酸盐
根据实施例8中所述的方法从3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙酸(实施例33/b)制备标题化合物。粗产物经过反相HPLC,使用YMC-Pack ODS-AQ型填料(由YMC生产)和乙腈/水/三氟乙酸作为洗脱剂,得到标题化合物。
实施例63
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)680.2(MH+)。
实施例64
反式-4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)617.2(MH+)。
实施例65
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐(参考例6)制备标题化合物。MS(EI)627.2(MH+)。
实施例66
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参考例11)制备标题化合物。MS(EI)641.2(MH+)。
实施例67
2-(4-{4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌嗪-1-基)-N-吡啶-2-基-乙酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-哌嗪-1-基-N-吡啶-2-基-乙酰胺(EMKA-Chemie)制备标题化合物。MS(EI)641.2(MH+)。
实施例68
2-(4-{4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌嗪-1-基)-N-吡啶-3-基-乙酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-哌嗪-1-基-N-吡啶-3-基-乙酰胺(EMKA-Chemie)制备标题化合物。MS(EI)641.2(MH+)。
实施例69
N-[2-(3,4-二氯-苯氧基)-苯基]-4-(4-吡啶-4-基甲基-哌嗪-1-羰基)-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-吡啶-4-基甲基-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)598.2(MH+)。
实施例70
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)641.2(MH+)。
实施例71
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)641.2(MH+)。
实施例72
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)628.2(MH+)。
实施例73
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-吗啉-4-基-丙基)-[1,4]二氮杂环庚烷-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(3-吗啉-4-基-丙基)-高哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)648.2(MH+)。
实施例74
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-吗啉-4-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和4-(3-哌嗪-1-基-丙基)-吗啉(EMKA-Chemie)制备标题化合物。MS(EI)634.2(MH+)。
实施例75
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-二甲氨基乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和二甲基-(2-哌嗪-1-基-乙基)-胺(EMKA-Chemie)制备标题化合物。MS(EI)578.2(MH+)。
实施例76
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)563.1(MH+)。
实施例77
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(2-吡咯烷-1-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)604.2(MH+)。
实施例78
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(3-吗啉-4-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-(3-哌嗪-1-基-丙基)-吗啉(EMKA-Chemie)制备标题化合物。MS(EI)633.3(MH+)。
实施例79
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-哌啶-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(2-哌啶-1-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)618.2(MH+)。
实施例80
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-吗啉-4-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-(2-哌嗪-1-基-乙基)-吗啉(EMKA-Chemie)制备标题化合物。MS(EI)620.2(MH+)。
实施例81
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(3-吡咯烷-1-基-丙基)-[1,4]二氮杂环庚烷-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-(3-吡咯烷-1-基-丙基)-高哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)632.1(MH+)。
实施例82
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和1-吗啉-4-基-2-哌嗪-1-基-乙酮(EMKA-Chemie)制备标题化合物。MS(EI)634.1(MH+)。
实施例83
4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)563.3(MH+)。
实施例84
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-吡啶-2-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(2-吡啶-2-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)612.2(MH+)。
实施例85
N-[2-(3,4-二氯-苯氧基)-苯基]-4-(4-吡啶-2-基甲基-哌嗪-1-羰基)-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-吡啶-2-基甲基-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)598.1(MH+)。
实施例86
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-二乙基氨基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨 磺酰基]-苯甲酸(实施例4/a)和二乙基-(2-哌嗪-1-基-乙基)-胺(EMKA-Chemie)制备标题化合物。MS(EI)606.2(MH+)。
实施例87
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(3-哌啶-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)633.2(MH+)。
实施例88
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-吡咯烷-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(3-吡咯烷-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)619.1(MH+)。
实施例89
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-二甲基氨基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和二甲基-(3-哌嗪-1-基-丙基)-胺(EMKA-Chemie)制备标题化合物。MS(EI)593.1(MH+)。
实施例90
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(1-甲基-哌啶-3-基甲基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(1-甲基-哌啶-3-基甲基)-哌嗪 (EMKA-Chemie)制备标题化合物。MS(EI)618.0(MH+)。
实施例91
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-吡咯烷-1-基-乙基)-哌啶-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和4-(2-吡咯烷-1-基-乙基)-哌啶(EMKA-Chemie)制备标题化合物。MS(EI)603.0(MH+)。
实施例92
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-哌啶-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(2-哌啶-1-基-乙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)618.0(MH+)。
实施例93
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-氧代-2-吡咯烷-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-哌嗪-1-基-吡咯烷-1-基-乙酮(EMKA-Chemie)制备标题化合物。MS(EI)618.0(MH+)。
实施例94
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-吗啉-4-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和4-(2-哌嗪-1-基-乙基)-吗啉(EMKA-Chemie)制备标题化合物。MS(EI)620.0(MH+)。
实施例95
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-氧代-2-哌啶-1-基-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和2-哌嗪-1-基-1-哌啶-1-基-乙酮(EMKA-Chemie)制备标题化合物。MS(EI)632.0(MH+)。
实施例96
2-(4-{4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基}-哌嗪-1-基)-N-甲基-N-苯基-乙酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和N-甲基-N-苯基-2-哌嗪-1-基-乙酰胺(EMKA-Chemie)制备标题化合物。MS(EI)654.0(MH+)。
实施例97
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(2-吗啉-4-基-2-氧代-乙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-吗啉-4-基-2-哌嗪-1-基-乙酮(EMKA-Chemie)制备标题化合物。MS(EI)634.0(MH+)。
实施例98
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)651.2(MH+)。
实施例99
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙胺(参考例15)制备标题化合物。MS(EI)651.2(MH+)。
实施例100
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)638.2(MH+)。
实施例101
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)587.2(MH+)。
实施例102
N-3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和3-[1,4’]联哌啶-1’-基-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)674.2(MH+)。
实施例103
反式-4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)645.2(MH+)。
实施例104
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐(参考例6)制备标题化合物。MS(EI)654.2(MH+)。
实施例105
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和2-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参考例11)制备标题化合物。MS(EI)669.2(MH+)。
实施例106
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-{2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)669.2(MH+)。
实施例107
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-{2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙胺[Arzneim.Forsch.;24(1974)1964-1970]制备标题化合物。MS(EI)669.2(MH+)。
实施例108
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙胺(参考例15)制备标题化合物。MS(EI)669.2(MH+)。
实施例109
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)656.2(MH+)。
实施例110
4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酸(实施例58/a)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)605.2(MH+)。
实施例111
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)656.2(MH+)。
实施例112
反式-4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)627.2(MH+)。
实施例113
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和2-(4-吡啶-2-基-哌嗪-1-基)-乙胺四盐酸盐(参考例6)制备标题化合物。MS(EI)637.2(MH+)。
实施例114
4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例7/a)和2-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参考例11)制备标题化合物。MS(EI)651.2(MH+)。
实施例115
N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-吡咯烷-1-基-丙基)-[1,4]二氮杂环庚烷-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例4/a)和1-(3-吡咯烷-1-基-丙基)-高哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)633.1(MH+)。
实施例116
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酰胺
a)2-氯-4-氟-1-(2-硝基-苯氧基)-苯
根据实施例1/a中所述的方法从2-氯-4-氟-苯酚制备标题化合物。
b)2-(2-氯-4-氟-苯氧基)-苯胺
根据实施例1/b中所述的方法从2-氯-4-氟-1-(2-硝基-苯氧基)-苯制备标题化合物。
c)4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例4/a中所述的方法从2-(2-氯-4-氟-苯氧基)-苯胺制备标题化合物。MS(EI)422.1(MH+)。
d)N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-[2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)629.2(MH+)。
实施例117
4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例116/c)和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)546.1(MH+)。
实施例118
4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-1-基-乙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例116/c)和2-哌啶-1-基-乙胺(EMKA-Chemie)制备标题化合物。MS(EI)532.1(MH+)。
实施例119
4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例116/c)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)611.1(MH+)。
实施例120
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例116/c)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)663.2(MH+)。
实施例121
反式-4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例116/c)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)600.2(MH+)。
实施例122
4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-1-基-乙基)-苯甲酰胺
a)2-(4-氯-2-甲氧基-苯氧基)-苯胺
根据实施例1/b中所述的方法从4-氯-2-甲氧基-1-(2-硝基-苯氧基)-苯[J.Chem.Soc.(1934)867]制备标题化合物。
b)4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例1/c中所述的方法从2-(4-氯-2-甲氧基-苯氧基)-苯胺制备标题化合物。MS(EI)434.2(MH+)。
c)4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-1-基-乙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸和2-哌啶-1-基-乙胺(EMKA-Chemie)制备标题化合物。MS(EI)544.2(MH+)。
实施例123
4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)558.2(MH+)。
实施例124
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)675.2(MH+)。
实施例125
4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)623.2(MH+)。
实施例126
4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-[2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙胺(参考例16)制备标题化合物。MS(EI)623.2(MH+)。
实施例127
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
a)4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例4/a中所述的方法从2-(4-三氟甲基-苯氧基)-苯胺[J.Chem.Soc.Perkin Trans.1.(1976)1279-1285]制备标题化合物。 MS(EI)438.0(MH+)。
b)N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)680.2(MH+)。
实施例128
N-(3-哌啶-1-基-丙基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例127/a)和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)562.2(MH+)。
实施例129
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例127/a)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)645.2(MH+)。
实施例130
反式-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例127/a)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)616.2(MH+)。
实施例131
N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例127/a)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)627.2(MH+)。
实施例132
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)641.2(MH+)。
实施例133
反式-4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)612.2(MH+)。
实施例134
4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例122/b)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)572.2(MH+)。
实施例135
4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例116/c)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)560.2(MH+)。
实施例136
N-[4-哌啶-4-基-丁基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例127/a)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)576.1(MH+)。
实施例137
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺三氟乙酸盐
a)4-[3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙基)-哌啶-1-甲酸叔丁基酯
根据实施例1/d中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯(参考例13)制备标题化合物。MS(EI)685.2(M+Na+)。
b)4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺三氟乙酸盐
根据实施例11/b中所述的方法从4-(3-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-丙基)-哌啶-1-甲酸叔丁基酯制备标题化合物。MS(EI)563.2(MH+)。
实施例138
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
a)4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例4中所述的方法从2-(4-三氟甲氧基-苯氧基)-苯胺[J.Med.Chem.13(1970)295-297]制备标题化合物。MS(EI)454.1(MH+)。
b)N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸和3-[1,4’]联哌啶-1’-基-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)661.2(MH+)。
实施例139
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例138/a)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)695.2(MH+)。
实施例140
N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例138/a)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)643.2(MH+)。
实施例141
N-[2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙基]-4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例138/a)和2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙胺(参考例16)制备标题化合物。MS(EI)643.3(MH+)。
实施例142
4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
a)2-氯-4-甲氧基-1-(2-硝基-苯氧基)-苯
根据实施例1/a中所述的方法从2-氯-4-甲氧基-苯酚制备标题化合物。
b)2-(2-氯-4-甲氧基-苯氧基)-苯胺
根据实施例1/b中所述的方法从2-氯-4-甲氧基-1-(2-硝基-苯氧基)-苯制备标题化合物。
c)4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例4/a中所述的方法从2-(2-氯-4-甲氧基-苯氧基)-苯胺制备标题化合物。MS(EI)434.1(MH+)。
d)4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)558.2(MH+)。
实施例143
4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)572.2(MH+)。
实施例144
N-(4-哌啶-4-基-丁基)-4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-三氟甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例138/a)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)592.2(MH+)。
实施例145
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)675.2(MH+)。
实施例146
4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-1-基-乙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和2-哌啶-1-基-乙胺(EMKA-Chemie)制备标题化合物。MS(EI)544.2(MH+)。
实施例147
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)641.2(MH+)。
实施例148
反式-4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)612.2(MH+)。
实施例149
4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)623.2(MH+)。
实施例150
4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-N-[2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例142/c)和2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙胺(参考例16)制备标题化合物。MS(EI)623.3(MH+)。
实施例151
4-(2-苯氧基-苯基氨磺酰基)-N-(2-哌啶-1-基-乙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-(2-苯氧基-苯基氨磺酰基)-苯 甲酸(实施例31/a)和2-哌啶-1-基-乙胺(EMKA-Chemie)制备标题化合物。MS(EI)480.2(MH+)。
实施例152
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-(2-苯氧基-苯基氨磺酰基)-苯甲酰胺
根据实施例31/b中所述的方法从4-(2-苯氧基-苯基氨磺酰基)-苯甲酸(实施例31/a)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)577.2(MH+)。
实施例153
反式-4-(2-苯氧基-苯基氨磺酰基)-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-(2-苯氧基-苯基氨磺酰基)-苯甲酸(实施例31/a)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)548.3(MH+)。
实施例154
4-(2-苯氧基-苯基氨磺酰基)-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-(2-苯氧基-苯基氨磺酰基)-苯甲酸(实施例31/a)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)559.2(MH+)。
实施例155
4-(2-苯氧基-苯基氨磺酰基)-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-(2-苯氧基-苯基氨磺酰基)-苯甲酸(实施例31/a)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制 备标题化合物。MS(EI)508.2(MH+)。
实施例156
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)608.1(MH+)。
实施例157
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)691.1(MH+)。
实施例158
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)673.0(MH+)。
实施例159
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-[2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)和2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙胺(参考例16)制备标题化合物。MS(EI)673.0(MH+)。
实施例160
4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
a)3-二乙基氨基-1-(2-硝基-苯氧基)-苯
根据实施例1/a中所述的方法从3-二乙基氨基-苯酚制备标题化合物。MS(EI)287.1(MH+)。
b)2-(3-二乙基氨基-苯氧基)-苯胺
根据实施例1/b中所述的方法从3-二乙基氨基-1-(2-硝基-苯氧基)-苯制备标题化合物。
c)4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酸
根据实施例1/c中所述的方法从2-(3-二乙基氨基-苯氧基)-苯胺制备标题化合物。MS(EI)441.1(MH+)。
d)4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酸和3-哌啶-1-基-丙胺(EMKA-Chemie)制备标题化合物。MS(EI)565.3(MH+)。
实施例161
N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3-二乙基氨基-苯氧基)-苯 基氨磺酰基]-苯甲酸(实施例160/c)和3-[1,4’]联哌啶-1’-基)-丙胺三盐酸盐(参考例3)制备标题化合物。MS(EI)648.3(MH+)。
实施例162
反式-4-[2-(3-二乙氨基-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例160/c)和反式-4-(2-吡咯烷-1-基-乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)619.3(MH+)。
实施例163
4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-N-[2-(4-嘧啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3-二乙氨基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例160/c)和2-(4-嘧啶-2-基-哌嗪-1-基)-乙胺[Bioorg.Med.Chem.;12(2004)3965-3970]制备标题化合物。MS(EI)630.3(MH+)。
实施例164
4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例160/c)和4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯(参考例13)制备标题化合物。MS(EI)565.3(MH+)。
实施例165
4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基甲基-苄基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(3-二乙基氨基-苯氧基)-苯基 氨磺酰基]-苯甲酸(实施例160/c)和4-(4-氨基甲基-苄基)-哌啶-1-甲酸叔丁基酯(参考例17)制备标题化合物。MS(EI)627.3(MH+)。
实施例166
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基甲基-苄基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例160/c)和4-(4-氨基甲基-苄基)-哌啶-1-甲酸叔丁基酯(参考例17)制备标题化合物。MS(EI)670.2(MH+)。
实施例167
4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)622.1(MH+)。
实施例168
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(3-二乙基氨基-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例160/c)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med.Chem.46(2003)1803-1806]制备标题化合物。MS(EI)682.3(MH+)。
实施例169
N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例22/c)和4-[1,4’]联哌啶-1’-基-苯胺[J.Med. Chem.46(2003)1803-1806]制备标题化合物。MS(EI)725.1(MH+)。
实施例170
4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)576.2(MH+)。
实施例171
N-(2-苯甲酰基-苯基)-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
a)4-(2-苯甲酰基-苯基氨磺酰基)-苯甲酸
根据实施例1/c中所述的方法从2-氨基-二苯酮制备标题化合物。MS(EI)382.2(MH+)。
b)N-(2-苯甲酰基-苯基)-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例1/d中所述的方法从4-(2-苯甲酰基-苯基氨磺酰基)-苯甲酸和1-(3-哌啶-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)575.2(MH+)。
实施例172
N-[2-(2,4-二氯-苯氧基)-苯基]-4-[4-(3-哌啶-4-基-丙基)-哌啶-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酸(实施例1/c)和4,4’-三亚甲基二哌啶(Aldrich)制备标题化合物。MS(EI)631.2(MH+)。
实施例173
N-(2-苯甲酰基-苯基)-4-[4-(3-吡咯烷-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-(2-苯甲酰基-苯基氨磺酰基)-苯甲酸(实施例171/a)和1-(3-吡咯烷-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)575.2(MH+)。
实施例174
N-[2-(2,4-二氯-苯甲酰基)-苯基]-4-[4-(3-吡咯烷-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
a)4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸
根据实施例1/c中所述的方法从(2-氨基-苯基)-(2,4-二氯-苯基)-甲酮[Synthesis,(1980)677-688]和4-氯磺酰基-苯甲酸制备标题化合物。MS(EI)451(MH+)。
b)N-[2-(2,4-二氯-苯甲酰基)-苯基]-4-[4-(3-吡咯烷-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸和1-(3-吡咯烷-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)630.4(MH+)。
实施例175
N-[2-(2,4-二氯-苯甲酰基)-苯基]-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸(实施例174/a)和1-(3-吡咯烷-1-基-丙基)-哌嗪(EMKA-Chemie)制备标题化合物。MS(EI)644.3(MH+)。
实施例176
反式-4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸(实施例174/a)和反式-4-(2-吡咯烷-1-基乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)629.2(MH+)。
实施例177
4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸(实施例174/a)和2-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参考例11)制备标题化合物。MS(EI)653.2(MH+)。
实施例178
N-[2-(2,4-二氯-苯甲酰基)-苯基]-4-[4-(3-哌啶-4-基-丙基)-哌啶-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸(实施例174/a)和4,4’-三亚甲基二哌啶(Aldrich)制备标题化合物。MS(EI)643.2(MH+)。
实施例179
反式-4-(2-苯甲酰基-苯基氨磺酰基)-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺
根据实施例31/b中所述的方法从4-(2-苯甲酰基-苯基氨磺酰基)-苯甲酸(实施例171/a)和反式-4-(2-吡咯烷-1-基乙基)-环己胺二盐酸盐(参考例4)制备标题化合物。MS(EI)560.5(MH+)。
实施例180
4-(2-苯甲酰基-苯基氨磺酰基)-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺
根据实施例31/b中所述的方法从4-(2-苯甲酰基-苯基氨磺酰基)-苯甲酸(实施例171/a)和2-(4-吡啶-4-基-哌嗪-1-基)-丙胺(参考例11)制备标题化合物。MS(EI)584.4(MH+)。
实施例181
4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸(实施例174/a)和4-(3-氨基-丙基)-哌啶-1-甲酸叔丁基酯(参考例13)制备标题化合物。MS(EI)575.3(MH+)。
实施例182
4-(2-苯甲酰基-苯基氨磺酰基)-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐
根据实施例30中所述的方法从4-[2-(2,4-二氯-苯甲酰基)-苯基氨磺酰基]-苯甲酸(实施例171/a)和4-(4-氨基-丁基)-哌啶-1-甲酸叔丁基酯(参考例12)制备标题化合物。MS(EI)520.4(MH+)。
实施例183
N-(2-苯甲酰基-苯基)-4-[4-(3-哌啶-4-基-丙基)-哌啶-1-羰基]-苯磺酰胺
根据实施例31/b中所述的方法从4-(2-苯甲酰基-苯基氨磺酰基)-苯甲酸(实施例171/a)和4,4’-三亚甲基二哌啶(Aldrich)制备标题化合物。MS(EI)574.2(MH+)。
实施例184
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%的聚乙烯基吡咯烷酮,1-5%的滑石,0.01-3%的硬脂酸镁,1-3%的胶体二氧化硅和2-7%的超支链淀粉混合,然后通过湿法造粒进行制粒并压缩成片。
b)糖衣丸,薄膜包衣的片剂:
将根据如上所述方法制备的片剂用由肠溶薄膜或胃溶薄膜组成或由糖和滑石组成的层进行包衣。糖衣丸用蜂蜡和巴西棕榈蜡的混合物进行抛光。
c)胶囊:
将0.01-50%的式(I)的活性成分,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在硬明胶胶囊中。
d)悬浮剂:
成分:0.01-15%的式(I)的活性成分,0.1-2%的氢氧化钠,0.1-3%的枸橼酸,0.05-0.2%的尼泊金(4-羟基苯甲酸甲酯钠),0.005-0.02%的对羟苯甲酸丙酯,0.01-0.5%的卡波普(聚丙烯酸),0.1-5%的96%乙醇,0.1-1%的娇味剂,20-70%的山梨醇(70%的水溶液)和30-50%的蒸馏水。
向尼泊金和枸橼酸在20毫升的蒸馏水中的溶液中在强烈搅拌下分小份加入卡波普,将溶液放置10-12小时。然后在搅拌下加入在1毫升蒸馏水中的氢氧化钠,山梨醇的水溶液,最后加入乙醇木莓调味剂。向该载体中分小份加入活性成分,使用浸渍均化器进行悬浮。最后,用蒸馏水将悬浮液填充到所需的最终体积,并使得悬浮液糖浆通过胶体磨设备。
e)栓剂:
对于每个栓剂,将0.01-15%的式(I)的活性成分和1-20%的乳糖充分混合,然后使50-95%的adeps pro栓剂(例如Witepsol 4)熔融,冷却到35℃,使用均化器将活性成分和乳糖的混合物混合到其中,所得的混合物被模压成型为冷却形式。
f)冻干粉末安瓿组合物:
使用双蒸馏注射用水制备5%的甘露醇或乳糖溶液,将溶液过滤,以便成为无菌溶液。还使用双蒸馏注射用水制备了0.01-5%的式(I)的活性成分的溶液,将该溶液过滤,以便成为无菌溶液。将这两种溶液在无菌条件下混合,以1毫升小份填充在安瓿中,将安瓿的内容物冻干,并在氮气下密封安瓿。在给药前,将安瓿的内容物溶解在无菌水或0.9%(生理)无菌氯化钠水溶液中。
Claims (7)
1.式(I)的缓激肽B1受体拮抗剂磺酰胺衍生物,及其旋光对映体或外消旋物和/或盐,
其中
R1为氢原子或C1-C4烷基;
R2选自(1)氢原子;条件是,R1和R2不能同时为氢原子;(2)-(CH2)n-NRaRb,(3)-(CH2)m-X-Q,或者
R1和R2连同与它们连接的氮原子一起形成4-7元杂环,该环除了包含与R1和R2连接的氮原子以外还包含0-3个选自O、S和N的杂原子;其中所述环任选地被C1-C4烷基、-(CH2)q-Y-P、氧代、4-(4,5-二氢-1H-咪唑-2-基)-苄基、4-(1,4,5,6-四氢-嘧啶-2-基)-苄基或4-基甲基-苄脒基团取代;
R3、R4和R5彼此独立地为氢原子、卤素原子、氰基、氨基或被一个或多个C1-C4烷基取代的氨基、C1-C4烷氧基、三氟甲基、三氟甲氧基、C1-C4烷基、羟基、C1-C4烷氧基羰基或-C(=O)-NH2基团;
Z选自(1)单键;(2)氧原子;(3)CH2基团;(4)CO基团;(5)NRc基团;(6)S原子;(7)SO2基团;
n为1至4的整数;
m为0或2至6的整数;
q为0至4的整数;
Ra和Rb为(1)氢原子,(2)直链或支链C1-C6烷基;
Rc为氢原子或C1-C4烷基;
X为单键、-CO-或-CO-NH-或-NH-CO-基团;
Y为单键、-CO-或-CONRa基团;
P为(1)-N(C1-C4烷基)2基团;(2)-NH-(CH2)n-Het基团;(3)饱和的、部分不饱和的或芳香族的包含1-3个选自O、S和N的杂原子的4-7元环;其中所述环任选地被氧代或C1-C4烷基取代;
Q为(1)饱和的、部分不饱和的或芳香族的包含1-3个选自O、S和N的杂原子的4-7元环;其中所述环任选地被氧代、-(CH2)n-Het、1-哌啶基、1-(C1-C4-烷基)-4-哌啶基、4-哌啶基、2-嘧啶基、2-吡嗪基、2-吡啶基、4-甲基-2-吡啶基、6-甲基-2-吡啶基或4-吡啶基取代;(2)苯基,其任选地被-(CH2)n-Het、-(CH2)n-NH-C(=NH)-NH2、4,5-二氢-1H-咪唑-2-基或[1,4’]联哌啶-1’-基取代;(3)C5-C7环烷基,其任选地被-(CH2)n-Het基团取代;(4)苄基,其任选地被-(CH2)n-Het、-(CH2)n-NH-C(=NH)-NH2或4,5-二氢-1H-咪唑-2-基取代;(5)-(CH2)n-Het基团;
Het为包含1-3个选自O、S、SO2和N的杂原子的4-7元杂环,其任选地被(1)氧代;(2)一个或多个C1-C4烷基取代;
排除化合物3-[([1,1′-联苯基]-2-基氨基)磺酰基]-N-[2-(2-吡啶基)-乙基]苯甲酰胺。
2.权利要求1的化合物,其选自以下化合物:4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]N-{2-[4-吡啶-4-基-哌嗪-1-基)-乙基]-苯甲酰胺二盐酸盐,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺三氟乙酸盐,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(4-氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺,4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺,N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺,反式-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺,3-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-4-基-哌嗪-1-基)-乙基]-苯甲酰胺二盐酸盐,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(2-哌啶-4-基-乙基)-苯甲酰胺三氟乙酸盐,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺三氟乙酸盐,4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4,5-二氢-1-H-咪唑-2-基)-苯基]-乙基}-苯甲酰胺,4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-(4-胍基甲基-苄基)-苯甲酰胺盐酸盐,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(1’-甲基-[1,4’]联哌啶-4-基)-乙基]-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺,哌啶-4-甲酸(2-{4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰基氨基}-乙基)-酰胺,4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺盐酸盐,N-(4-[1,4’]联哌啶-1’-基-苯基)-4-(2-苯氧基-苯基氨磺酰基)-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(哌啶-4-基氨基甲酰基)-乙基苯]-甲酰胺乙酸盐,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[(哌啶-4-基甲基)-氨基甲酰基]-乙基}-苯甲酰胺盐酸盐,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(4-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(2-哌啶-4-基-乙基氨基甲酰基)-乙基]-苯甲酰胺盐酸盐,N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-3-氧代-丙基)-4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺三氟乙酸盐,4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺,4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基-哌嗪-1-基)-乙基]-苯甲酰胺,4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺,4-[2-(3,4-二氯-苯氧基)-苯基氨磺酰基]-N-{2-[4-(6-甲基-吡啶-2-基)-哌嗪-1-基]-乙基}-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-1-基-丙基)-苯甲酰胺,N-[2-(3,4-二氯-苯氧基)-苯基]-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺,4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[2-(4-吡啶-2-基甲基-哌嗪-1-基)-乙基]-苯甲酰胺,4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-苯甲酰胺,4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺,4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺,4-[2-(4-溴-苯氧基)-5-氟-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(4-溴-苯氧基)-苯基氨磺酰基]-N-[3-(4-吡啶-4-基-哌嗪-1-基)-丙基]-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-N-[4-(2-吡咯烷-1-基-乙基)-环己基]-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-氯-2-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(2-氯-4-氟-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐,N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-三氟甲基-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(3-哌啶-4-基-丙基)-苯甲酰胺盐酸盐,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(2-氯-4-甲氧基-苯氧基)-苯基氨磺酰基]-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-(2-苯氧基-苯基氨磺酰基)-苯甲酰胺,N-(3-[1,4’]联哌啶-1’-基-丙基)-4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-[2-(2,3,5,6-四氢-[1,2’]联吡嗪-4-基)-乙基]-苯甲酰胺,4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基甲基-苄基)-苯甲酰胺盐酸盐,4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐,N-(4-[1,4’]联哌啶-1’-基-苯基)-4-[2-(4-溴-2-氯-苯氧基)-苯基氨磺酰基]-苯甲酰胺,4-[2-(2,4-二氯-苯氧基)-苯基氨磺酰基]-N-(4-哌啶-4-基-丁基)-苯甲酰胺盐酸盐或N-(2-苯甲酰基-苯基)-4-[4-(3-哌啶-1-基-丙基)-哌嗪-1-羰基]-苯磺酰胺。
4.式(V)的化合物,其选自以下化合物:N-(4-氨基甲基-苄基)-胍二盐酸盐、4-[4-(4,5-二氢-1H-咪唑-2-基)-苄基]-哌啶和4-哌啶-4-基甲基-苄脒。
5.药物组合物,其包含治疗上有效量的权利要求1的式(I)的化合物或其旋光对映体或外消旋物或可药用盐以及一种或多种可药用的赋形剂。
6.权利要求的式(I)的化合物或其旋光对映体或外消旋物或可药用盐在制备用于预防和/或治疗需要抑制缓激肽受体的病况的药物中的用途。
7.权利要求6的用途,其中所述缓激肽受体是缓激肽B1受体。
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HUP0600808A3 (en) * | 2006-10-27 | 2008-09-29 | Richter Gedeon Nyrt | New benzamide derivatives as bradykinin antagonists, process for their preparation and pharmaceutical compositions containing them |
JP2011500782A (ja) * | 2007-10-27 | 2011-01-06 | リヒター ゲデオン ニルバーノシャン ミーケデーレスベニュタールシャシャーグ | ブラジキニンb1拮抗剤としての新規非ペプチド誘導体 |
CN102159210A (zh) * | 2008-08-21 | 2011-08-17 | 吉瑞工厂 | 用于治疗cns障碍的方法 |
CN102159077A (zh) * | 2008-08-21 | 2011-08-17 | 吉瑞工厂 | 用于治疗神经性疼痛的方法 |
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- 2007-10-27 WO PCT/HU2007/000104 patent/WO2008050168A1/en active Application Filing
- 2007-10-27 KR KR1020097008095A patent/KR20090076927A/ko not_active Application Discontinuation
- 2007-10-27 US US12/447,132 patent/US20100075978A1/en not_active Abandoned
- 2007-10-27 EP EP07824996.8A patent/EP2074083B1/en active Active
- 2007-10-27 GE GEAP200711270A patent/GEP20125437B/en unknown
- 2007-10-27 CA CA2667285A patent/CA2667285C/en not_active Expired - Fee Related
- 2007-10-27 NZ NZ575762A patent/NZ575762A/en not_active IP Right Cessation
- 2007-10-27 EA EA200900606A patent/EA018046B1/ru not_active IP Right Cessation
- 2007-10-27 MX MX2009004527A patent/MX2009004527A/es active IP Right Grant
- 2007-10-27 JP JP2009533966A patent/JP2010507644A/ja active Pending
- 2007-10-27 BR BRPI0718495-6A patent/BRPI0718495A2/pt not_active IP Right Cessation
- 2007-10-27 AU AU2007310588A patent/AU2007310588B2/en not_active Ceased
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Also Published As
Publication number | Publication date |
---|---|
MX2009004527A (es) | 2009-07-02 |
CU23840B1 (es) | 2012-10-15 |
NO20092050L (no) | 2009-07-17 |
EP2074083B1 (en) | 2013-06-19 |
EP2074083A1 (en) | 2009-07-01 |
CA2667285A1 (en) | 2008-05-02 |
WO2008050168A1 (en) | 2008-05-02 |
AU2007310588B2 (en) | 2012-08-23 |
WO2008050168A8 (en) | 2009-04-09 |
IL198345A0 (en) | 2010-02-17 |
NZ575762A (en) | 2011-12-22 |
TN2009000107A1 (en) | 2010-08-19 |
GEP20125437B (en) | 2012-03-26 |
HU0600810D0 (en) | 2006-12-28 |
CA2667285C (en) | 2012-09-25 |
HUP0600810A3 (en) | 2008-09-29 |
CU20090070A7 (es) | 2011-05-27 |
BRPI0718495A2 (pt) | 2013-12-03 |
AU2007310588A1 (en) | 2008-05-02 |
CN101528681A (zh) | 2009-09-09 |
JP2010507644A (ja) | 2010-03-11 |
HUP0600810A2 (en) | 2008-08-28 |
MA30911B1 (fr) | 2009-11-02 |
EA200900606A1 (ru) | 2009-08-28 |
MY148076A (en) | 2013-02-28 |
KR20090076927A (ko) | 2009-07-13 |
US20100075978A1 (en) | 2010-03-25 |
EA018046B1 (ru) | 2013-05-30 |
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