CN1218046A - 酰胺衍生物 - Google Patents
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Abstract
本发明涉及医药,特别是具有钙释放依赖性钙通道阻滞作用的以下通式(I′)表示的酰胺衍生物及以其为有效成分的医药组合物,尤其是钙释放依赖性钙通道阻滞剂。式中符号的含义如下:D:可带有1至3个作为取代基的可被卤素取代或无取代的低级烷基的吡唑基,B:亚苯基或亚噻吩基,X:式-NH-CO-或式-CO-NH-表示的基团,A:可被卤素取代的苯基、可被低级烷基取代的5~6元单杂环芳基。
Description
本发明涉及医药,特别是具有钙释放依赖性钙通道阻滞作用的酰胺衍生物,以及以此为有效成分的医药组合物,还特别涉及钙释放依赖性钙通道阻滞剂。
以往,人们就知道各种细胞活化过程中作为细胞内传递机制的钙离子(Ca2+)的重要性。即使在炎症细胞中Ca2+作为重要的调节因子也起一定作用。但是,以往作为Ca2+拮抗剂的硝苯吡啶(nifedipine)等膜电位依赖性Ca2+通道(以下略称为VOCC)阻滞剂对炎症细胞活化没有抑制作用,这就表明在炎症细胞中存在VOCC以外的Ca2+流入机制。
Hoth等报道在肥大细胞和淋巴细胞中存在由于Ca2+贮藏枯竭而引起的从具有选择性的细胞外导入Ca2+的Ca2+流入机制,即钙释放依赖性钙通道(Ca2+releaseactivated Ca2+ channel;以下略称为CRACC;也可称为钙贮藏依赖性钙通道(Store-dependent Ca2+ channel)),以及肥大细胞和淋巴细胞对膜电位无感应性(PflugersArch.,430,p315-22(1995))。人们都知道CRACC存在于肥大细胞、淋巴细胞、星形细胞(J.Biol.Chem.,270,p29-32(1995))等几乎所有的炎症细胞中,对细胞因子的产生及脂质介质的游离等有很大的影响(J.Immunol.,155,p285-96(1995)及Br.J.Pharmacol.,144,p598-601(1995))。
近年,由于明确了作为慢性类风湿性关节炎治疗剂的tenidap的作用机制之一是对CRACC的阻滞作用(Cell Calcium 14,p1-16(1993)),所以,CRACC阻滞剂在临床上可能对慢性类风湿性关节炎等慢性炎症有用。
此外,CRACC也存在于内皮细胞(Am.J.Physiol.,269,C733-8(1995))及上皮细胞(J.Biol.Chem.,270,p169-75(1995))中。内皮细胞受到自由基损伤与持续的钙流入有关(Am.J.Physiol.,261,C889-896(1991)),CRACC阻滞剂对与内皮细胞有关的组织损伤具有保护作用。
而且,有报道认为抑制钙的流入还可抑制细胞增殖和白细胞介素-2(IL-2)的产生(Br.J.Pharmmacol.,133,p861-8(1994)),CRACC阻滞剂作为恶性肿瘤等增殖性或进行性疾病、自身免疫疾病的预防.治疗剂有用,作为移植时排斥反应的抑制剂也有用。
另一方面,已知代表平滑肌细胞和神经细胞的兴奋性细胞通过VOCC调节细胞内的钙,与CRACC无关。所以,相对于VOCC而言,对CRACC具有选择性的钙通道阻滞剂对血管平滑肌和中枢神经没有显现出不良作用,可作为对各种炎症性疾病、变应性疾病、自身免疫疾病、组织损伤、增殖性疾病等的预防或治疗有用的药物使用。
近年,还报道了一些具有CRACC阻滞作用的化合物,例如,德国公开公报4404249号揭示了环烷基-哌嗪乙醇衍生物、WO94/00435号公报揭示了2-(3,4-二氢-1-异喹啉基)乙酰胺衍生物。此外,文献(J.Pharm.Exp.Ther.,257,p967-971(1991))揭示了具有CRACC阻滞作用的5-氨基-1-[[3,5-二氯-4-(4-氯苯甲酰)苯基]-甲基]-1H-1,2,3-***-4-羧酰胺。但是,没有报道对VOCC具有CRACC选择性的化合物。
另一方面,德国公开公报2525024号揭示了显现抗炎作用的5-(杂环氨基苯基)-1-苯基吡唑衍生物。但是,既没有揭示也没有暗示它具有CRACC阻滞作用和抑制IL-2产生的作用。
WO95/18097号公报揭示了具有环GMP磷酸二脂酶抑制作用的下式表示的氨茴酸衍生物。式中,R1至R4表示可被H、卤素、…取代的吡唑基、…,n表示0~6,W表示N或CH,Y表示O或S、…(详细情况参考该公报)。
本发明者们对具有良好CRACC阻滞作用的化合物进行认真研究的结果是,发现结构与以往报道的具有CRACC阻滞作用的化合物完全不同的酰胺衍生物具有良好的CRACC阻滞作用。而且,还发现这些化合物对VOCC具有很高的CRACC选择性,从而完成了本发明。
即,本发明涉及以下通式(Ⅰ)表示的新颖的酰胺衍生物或其制药学上允许的盐。
(式中符号的含义如下:
D:可带有1至3个作为取代基的可被卤素取代或无取代的低级烷基的吡唑基,
B:亚苯基或亚噻吩基,
X:式-NH-CO-或式-CO-NH-表示的基团,
A:可被卤素取代的苯基、可被低级烷基取代的5~6元单杂环芳基;
但是,4-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]-1,2,3-噻二唑-5-羧酰替酰胺(以下用化合物A表示)和4′-氯-5-(1-甲基-5-三氟甲基)-1H-吡唑-3-基)噻吩-2-羧酰替酰胺(以下用化合物B表示)除外。以下相同。)
此外,化合物A和化合物B在MAYBRIDGE公司试剂目录(UK,Cornwall,1995年8月发行)中作为SEW04225及KM02940记载,是公知的化合物。但是,对其用途,无论是医药方面的用途或其他用途都没有任何报道。
本发明的通式(Ⅰ)表示的较好的化合物是D为至少可被1个三氟甲基取代的吡唑基或1-甲基-3-三氟甲基-1H-比唑-5-基或3,5-双(三氟甲基)-1H-吡唑-1-基,A为可被卤原子取代的苯基或可被低级烷基取代的选自噻唑基、噻二唑基、噻吩基及吡啶基的5~6元单杂环芳基的酰胺衍生物或其制药学上允许的盐。
本发明还涉及包含化合物A及化合物B的以下通式(Ⅰ′)表示的酰胺衍生物或其制药学上允许的盐和制药学上允许的载体的医药组合物。特别是钙释放依赖性钙通道阻滞用医药组合物。较好的是IL-2产生抑制剂,变应性、慢性炎症性或自身免疫疾病的预防或治疗剂、支气管哮喘或慢性类风湿性关节炎的预防或治疗剂。
(式中符号的含义如下:
D:可带有1~3个作为取代基的可被卤素取代或无取代的低级烷基的吡唑基,
B:亚苯基或亚噻吩基,
X:式-NH-CO-或式-CO-NH-表示的基团,
A:可被卤素取代的苯基、可被低级烷基取代的5~6元单杂环芳基;以下相同)
本说明书中对“低级”没有特别的限定,表示碳原子数为1~6的直链或支链碳链。“低级烷基”较好的是甲基、乙基和丙基。“5~6元单杂环芳基”表示含有1~4个选自氮原子、硫原子和氧原子的杂原子的5~6元单杂环芳基,较好的是噻吩基、噻唑基、噻二唑基、吡啶基。“亚苯基”较好的是1,4-亚苯基,“亚噻吩基”较好的是2,5-亚噻吩基。
“卤原子”较好的是F和Cl。“可被卤原子取代的低级烷基”较好的是三氟甲基。
本发明的取代基有时存在几何异构体和互变异构体,本发明包括从这些异构体中分离出来的单体或昆合物。而且,本发明的化合物有时具有手性碳,存在以此为基础的(R)体、(S)体旋光异构体。本发明包括全部光学异构体的混合物及分离出来的单体。
本发明的化合物(Ⅰ)或(Ⅰ′)还包括酸加成盐或由于取代基的不同而与碱形成的盐。这些盐为制药学上允许的盐,较好的是与盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、天冬氨酸、谷氨酸等有机酸形成的酸加成盐;与钠、钾、镁、钙、铵等无机碱,甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等有机碱形成的盐或铵盐等。
此外,本发明还包括本发明化合物(Ⅰ)或(Ⅰ′)及其盐的各种水合物和溶剂合物及多晶型物质。
(制备方法)
利用本发明的化合物及其制药学上允许的盐的基本骨架或以取代基的种类为基础的特征,通过各种公知的合成方法能够制备本发明的化合物及其制药学上允许的盐。此时,根据官能团的种类有时用下列手段可在制备技术上获得效果,即在原料至中间体阶段将官能团用适当的保护基保护起来,也就是转变为可容易地转换为该官能团的基团。然后,如有必要可除去保护基,获得所希望的化合物。这类官能团包括羟基和羧基等。这类保护基包括Greene和Wuts著《(ProtectiveGroups in Organic Synthesis》第2版中记载的保护基,只要符合反应条件即可使用。
以下,对本发明化合物的具有代表性的制备方法进行说明。
本制备方法如前述反应式所示,使通式(Ⅱ)或(Ⅴ)表示的酰胺衍生物和通式(Ⅲ)或(Ⅳ)表示的羧酸衍生物进行酰胺化反应,就可获得本发明化合物(Ⅰ-1)或(Ⅰ-2)。
可在制备方法1中使用的羧酸衍生物(Ⅲ)或(Ⅳ)为游离羧酸或其反应性衍生物,作为反应性衍生物包括酰氯、酰溴等酰卤化物,酰基叠氮,用甲醇、乙醇、苄醇、可被取代的苯酚、1-羟基苯并***、N-羟基琥珀酰亚胺等调制成的活性酯,对称酸酐,与烷基碳酸、对甲苯磺酸等的混合酸酐等。这些反应性衍生物可使用市售产品,也可通过常用的方法制备。
酰胺化反应可按照常用方法进行。
在使用游离羧酸时,较好的是在反应时使用N,N′-二环己基碳二亚胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(WSCD)等缩合剂或1,1′-羰基二咪唑、N,N′-二琥珀酰亚胺基碳酸酯、二苯基磷酰迭氮、磷酰氯、三氯化磷、三苯膦/N-溴琥珀酰亚胺等羧酸的活化剂。
使用等摩尔或其中之一过量的通式(Ⅱ)或(Ⅴ)表示的酰胺衍生物和通式(Ⅲ)或(Ⅳ)表示的羧酸衍生物,在对反应无影响的有机溶剂,例如,吡啶、四氢呋喃(THF)、二噁烷、***、苯、甲苯、二氯甲烷、1,2-二氯乙烷(DCE)、氯仿、二甲基甲酰胺(DMF)、乙酸乙酯、乙腈等溶剂中进行反应。反应温度可根据反应衍生物的种类作适当的选择。
(式中,Ra和Rb表示H或低级烷基。)
本制备方法就是使与通式(Ⅵ)表示的化合物的酮相连的碳原子三氟乙酰化后,使其与肼衍生物反应环化而获得本发明化合物(Ⅰ-3)。
步骤1的三氟乙酰化可在甲醇钠、乙醇钠、碱金属六甲基二甲硅烷基胺、氢化钠、烷基锂、三乙胺等碱存在下,在-78℃使三氟乙酰化剂(例如,三氟乙酸乙酯、三氟乙酸酐等)在甲醇、乙醇、1,3-二甲基咪唑烷基-2-酮(DMI)、THF、DMF等溶剂中加热回流而反应。
步骤2的环化反应是在乙酸、盐酸等酸或异丙醇钛(Ⅳ)、氯化钛(Ⅳ)、三氟化硼-***配位化合物等路易斯酸存在下或非存在状态下,在甲醇、乙醇等溶剂中或无溶剂状态下使步骤1获得的化合物和肼衍生物反应。该反应可在冷却下至加热回流条件下进行。
(原料化合物的制备方法)
上述制备方法中的原料化合物可使用市售产品,也可通过本领域技术人员公知的方法合成。
通过上述各制备方法获得的反应生成物可作为游离化合物、其盐、其水合物或各种溶剂合物而分离精制。盐可通过常用的成盐反应获得。分离精制可使用萃取、浓缩、蒸馏、结晶化、过滤、重结晶、各种色谱法等常用化学方法。各种异构体可利用异构体间的物理化学性质差通过常用方法分离。例如,旋光异构体可通过一般的消旋拆分法,如分别结晶化或色谱法等被分离。此外,旋光异构体也可由具备适当光学活性的游离化合物合成。
本发明化合物作为医药组合物的活性成分有用。由于特别具有CRACC阻滞作用和抑制IL-2产生的作用,所以,作为CRACC阻滞剂或IL-2产生抑制剂有用。
特别是作为与CRACC和IL-2的产生有关的变应性、慢性炎症性或自身免疫疾病的预防治疗剂有用。变应性、慢性炎症性或自身免疫疾病是指支气管哮喘、牛皮癣、包括特应性皮炎在内的特应性疾病、包括克罗恩病在内的炎症性大肠疾病、消化性溃疡、肾炎、肝炎、胰腺炎、胶原性疾病、慢性类风湿性关节炎、变形性关节炎、移植时的排斥反应等,包括与CRACC或IL-2产生有关的各种疾病。
通过后述的CRACC阻滞作用和IL-2产生抑制作用等体外试验结果,以及使用作为支气管哮喘的代表性疾病模型的抗原诱发气管内嗜酸细胞浸润模型,与T细胞活化有关的疾病模型及小鼠胶原性关节炎模型等动物疾病模型的各种试验结果,可明确本发明化合物对上述疾病的作用。此外,本发明化合物还具有抑制IL-4和IL-5产生的作用、抑制MMP-1产生的作用、抑制TNFα产生的作用等,从这些结果也可说明对上述疾病的作用。
另一方面,由于CRACC阻滞剂对细胞增殖具有抑制作用,所以,对恶性肿瘤、动脉硬化、多脏器硬化症、各种纤维化疾病及烧伤后瘢痕等增殖性或进行性疾病的预防或治疗有用。此外,由于CRACC阻滞剂还能够抑制肥大细胞、炎症细胞或星形细胞这些外周或中枢组织中与炎症反应有关的细胞的活化,所以,对缺血再回流损伤、头部外伤、脑梗塞和心肌梗塞这些组织损伤有保护作用。
特别是相对于VOCC,具有选择性CRACC阻滞作用的本发明化合物可显现出CRACC阻滞作用,但不会因阻滞VOCC而对中枢神经或血管平滑肌产生不良作用,所以十分有用。
以下是为了证明本发明化合物的药理作用而进行的试验及其结果。
(1)CRACC阻滞作用
将载有钙指示荧光色素fura-2(1μM)的PCI2-h5大鼠成神经细胞(Jurkat细胞,6×106/ml)悬浮液100μl分别注入96孔微量测定板的各个孔内。在各个孔中再添加包含最终浓度2倍浓度的受试药物和2μM钙泵抑制剂サプシガルギン(最终浓度为1μM)的Hanks平衡盐溶液100μl,使サプシガルギン刺激细胞内钙浓度上升,添加30分钟后获得激发波长340nm/500nm和激发波长380nm/500nm的荧光强度,由这两个荧光强度可算出荧光强度比(R)。计算该荧光强度比时,事先用不存在细胞的体系,以同样的方法测定受试药物自身的荧光性,校正自身荧光对fura-2荧光的影响。
从25μMイォノマイシン刺激获得的最大反应荧光强度比(Rmax)、5μMイォノマイシン+1mMEGTA刺激获得的最小反应荧光强度比(Rmin)、激发波长为380nm时的钙结合色素的荧光率(Sb2)和激发波长为380nm时的钙解离色素的荧光率(Sf2)算出细胞内的钙浓度。
计算式:细胞内钙浓度(nM)=224×[(R-Rmin)/(Rmax-R)]×[Sf2/Sb2]。
从在所得各浓度受试药物存在下的细胞内钙浓度和仅由溶剂获得的对照组的细胞内钙浓度,可算出各浓度受试药物对钙流入细胞内的阻滞(CRACC阻滞)率,算出表示50%CRACC阻滞的浓度(IC50值)。
实施例1~6的化合物的IC50值在0.51~0.050μM的范围内。
(2)对VOCC阻滞作用的选择性
将载有钙指示荧光色素fura-2(1μM)的PC12-h5大鼠成神经细胞(Jurkat细胞,2×106/ml)悬浮液100μl分别注入96孔微量测定板的各个孔内。在各个孔中再添加包含最终浓度2倍浓度的受试药物和100mM KCl(最终浓度为50mM)的Hanks平衡盐溶液l00μl,使高浓度氯化钙刺激细胞内钙浓度上升,添加30分钟后获得激发波长340nm/500nm和激发波长380nm/500nm的荧光强度,由这两个荧光强度算出荧光强度比(R)。计算该荧光强度比时,事先用不存在细胞的体系,以同样的方法测定受试药物自身的荧光性,校正自身荧光对fura-2荧光的影响。
与前述CRACC阻滞作用相同,算出VOCC阻滞作用的IC50值,并进行比较。
实施例1~6的化合物的VOCC阻滞作用比各自的CRACC阻滞作用弱16倍以上。
(3)抑制IL-2产生的作用
使用PC12-h5大鼠成神经细胞(Jurkat细胞),按照S.Clare Chung等在Br.J.Pharmacol.,113:861-868,1994中记载的方法测试抑制IL-2产生的活性,求出IC50值。
本发明化合物显示1μM以下的IC50值。
(4)对TNCB诱发接触性过敏症(TNCB-induced Contact Hypersensitivity)的作用
使用5周龄的雄性ICR小鼠,采用与记载在Current Protocol inImmunology(John Wiley & Sons,Inc.1994)上相同的方法测试本发明化合物对TNCB诱发接触性过敏症的效果。
(5)对ConA诱发小鼠肝病模型的保肝作用
使用4~5周龄的Balb/c小鼠(SLC),采用与G.Tiegs等在J Clin.Invest.1992.90:196-203上记载的相同方法进行试验。其结果是本发明化合物显现出剂量依赖性的保肝效果。
(6)对类风湿性关节炎模型的抗关节炎作用
使用5周龄的雄性DBA/1J小鼠(日本チヤ-ルスリバ-),以记载在FumioNishikaku and Yoshihiko Koga,Immunopharmacology,25,65-74(1993)和FuminoriKato,Masanao Nomura and Kyoko Nakamura,Annal of the Rheumatic Disease 55,535-539(1996)上的方法为基准,测试抗关节炎作用。本发明的化合物显现出明显的抗关节炎作用。
(7)对嗜酸性细胞浸润的抑制作用(抗原引起的大鼠呼吸道嗜酸性细胞增多)
使用4周龄的雄性BN大鼠,采用与W.Elwood等在Inflamm.Res.,44:83-86,1995上记载的相同方法,测试对嗜酸性细胞浸润的抑制作用。此外,静脉给药在抗原暴露30分钟前进行,经口给药在抗原暴露1小时前和3小时后进行。
本试验中,本发明化合物使白细胞总数和嗜酸性细胞数减少,对嗜酸性细胞的浸润有抑制作用。
包括本发明化合物(Ⅰ′)或其盐和制药学上允许的载体的医药组合物可由1种或2种以上通式(Ⅰ′)表示的化合物或其盐,利用制剂化时常用的药剂用载体、赋形剂、其他添加剂,通过常用方法调制而得。给药时可采用片剂、丸剂、胶囊剂、颗粒剂、散剂、溶液剂等经口给药,或静注、肌注等注射剂、栓剂、经皮等非经口给药的任何一种方式。
本发明经口给药的固体组合物包括片剂、散剂、颗粒剂等。这些固体组合物中混合了1种或1种以上的活性物质和至少1种惰性稀释剂,如乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、硅铝酸镁。根据常用方法,组合物中还可包含惰性稀释剂以外的添加剂,如硬脂酸镁等润滑剂和纤维素乙醇酸钙等崩解剂,乳糖等稳定剂,谷氨酸或天冬氨酸等助溶剂。如有必要,还可在片剂或丸剂外包裹蔗糖、明胶、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯等糖衣或胃溶性、肠溶性薄膜。
经口给药的液体组合物包括药剂学上允许的乳浊剂、溶液剂、混悬剂、糖浆剂和酏剂等,其中包含常用的惰性稀释剂,如精制水、乙醇等。这种组合物中除了惰性稀释剂以外还可包含湿润剂、悬浮剂等助剂,甜味剂,矫味剂,芳香剂和防腐剂。
非经口给药的注射剂包括无菌水性或非水性溶液剂,混悬剂,乳浊剂。水性溶液剂和混悬剂中包含注射用蒸馏水和生理盐水。非水性溶液剂和混悬剂中包含丙二醇,聚乙二醇,橄榄油等植物油,乙醇等醇类,吐温80等。这些组合物中还可包含防腐剂,湿润剂,乳化剂,分散剂,稳定剂(例如乳糖),助溶剂(例如谷氨酸、天冬氨酸)等助剂。它们可通过滤菌薄膜过滤,配合使用灭菌剂或通过照射达到无菌化目的。或将它们制成无菌固体组合物,在使用前用无菌水或无菌注射用溶剂溶解。
通常经口给药时1天的药量相对于体重约为0.001~10mg/kg,可1次或分为2~4次给药。静脉注射时1天的给药量相对于体重约为0.0001~1mg/kg,可1次或分为数次给药。给药量可根据症状、年龄、性别等的情况作适当选择。
以下,以实施例为基础对本发明进行更为详细的说明。本发明化合物并不仅限于实施例中记载的化合物。
实施例1
在室温下彻夜搅拌4-甲基噻唑-5-羧酸(108mg)、4-[3,5-双(三氟甲基)-1H-吡唑-1-基]苯胺(223mg)、WSCD盐酸盐(152mg)和DCE(5ml)的混合物。在反应液中添加水(10ml),用***(5ml)和乙酸乙酯(10ml)的混合溶剂萃取生成物。然后依次用1当量的盐酸、饱和碳酸氢钠水溶液、饱和食盐水洗涤萃取液。用无水硫酸镁干燥有机层后,在减压条件下浓缩。所得残渣用硅胶柱色谱法(洗脱液:正己烷∶乙酸乙酯=2∶1)精制后,用乙酸乙酯和正己烷的混合溶剂重结晶,获得为无色针状结晶的4-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]噻唑-5-羧酰替苯胺(143mg)。
实施例2
在2-氯苯胺(68mg)、吡啶(42mg)和二氯甲烷(2ml)的混合物中添加5-(1-甲基-3-三氟甲基-1H-吡唑-5-基)噻吩-2-酰氯(150mg)和二氯甲烷(1.5ml)的混合物,在室温下搅拌30分钟。然后在反应液中添加饱和碳酸氢钠水溶液,用乙酸乙酯萃取生成物后,用饱和食盐水洗涤萃取液。用无水硫酸镁干燥有机层后,在减压条件下浓缩。所得残渣用乙醇重结晶,获得为无色结晶的2′-氯-5-(1-甲基-3-三氟甲基-1H-吡唑-5-基)噻吩-2-羧酰替苯胺(80mg)。此外,使5-(1-甲基-3-三氟甲基-1H-吡唑-5-基)噻吩-2-羧酸和草酰氯反应,获得为褐色固体的上述原料化合物5-(1-甲基-3-三氟甲基-1H-吡唑-5-基)噻吩-2-酰氯。
实施例3
在冰冷却条件下,在4′-乙酰基-4-氯苯甲酰替苯胺(1.00g)和DMI(10ml)的混合物中添加甲醇钠(257mg),在室温下搅拌2小时。然后在反应液中添加三氟乙酸乙酯(0.522ml),于60℃搅拌2天。接着在反应液中添加水(50ml)和1当量盐酸(10ml),用乙酸乙酯萃取生成物后,依次用水、饱和食盐水洗涤萃取液。用无水硫酸镁干燥有机层后,在减压下浓缩。然后在室温下搅拌所得残渣和甲基肼(0.206ml)、乙酸(2ml)和乙醇(20ml)的混合物,历时21小时。在减压下浓缩反应液后,在所得残渣中添加乙酸乙酯(100ml),依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤。用无水硫酸镁干燥有机层后,在减压下浓缩。所得残渣用硅胶柱色谱法(洗脱液:正己烷∶乙酸乙酯=3∶1)精制后,用乙酸乙酯和正己烷的混合溶剂重结晶,获得为无色粉末状结晶的4-氯-4′-(1-甲基-3-三氟甲基-1H-吡唑-5-基)苯甲酰替苯胺(440mg)。
与实施例1同样操作,能够分别获得后述表1的实施例4(4-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]-1,2,3-噻二唑-5-羧酰替苯胺)、实施例5(3-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]噻吩-2-羧酰替苯胺)及实施例6(4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]吡啶-3-羧酰替苯胺)的化合物。
实施例化合物的结构和物理化学性质如表1所示。表中Ex表示实施例编号,Str表示结构式,Dat表示物理化学性质,mp表示熔点,NMR表示核磁共振谱(DMSO-d6,TMS内标)δppm。
Claims (9)
1.酰胺衍生物或其制药学上允许的盐,其特征在于,由以下通式(Ⅰ)表示,
式中符号的含义如下:
D:可带有1至3个作为取代基的可被卤素取代或无取代的低级烷基的吡唑基,
B:亚苯基或亚噻吩基,
X:式-NH-CO-或式-CO-NH-表示的基团,
A:可被卤素取代的苯基、可被低级烷基取代的5~6元单杂环芳基;
但是,4-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]-1,2,3-噻二唑-5-羧酰替酰胺和4′-氯-5-(1-甲基-5-三氟甲基)-1H-吡唑-3-基)噻吩-2-羧酰替酰胺除外。
2.如权利要求1所述的酰胺衍生物或其制药学上允许的盐,其中的D为可被至少1个三氟甲基取代的吡唑基。
3.如权利要求1所述的酰胺衍生物或其制药学上允许的盐,其中的D为1-甲基-3-三氟甲基-1H-吡唑-5-基或3,5-双(三氟甲基)-1H-吡唑-1-基,A为可被卤原子取代的苯基或可被低级烷基取代的选自噻唑基、噻二唑基、噻吩基和吡啶基的5~6元单杂环芳基。
5.如权利要求4所述的医药组合物,其特征还在于,它是一种IL-2产生抑制剂。
6.如权利要求5所述的医药组合物,其特征还在于,它是变应性、慢性炎症性或自身免疫疾病的预防或治疗剂。
7.如权利要求6所述的医药组合物,其特征还在于,它是支气管哮喘的预防或治疗剂。
8.如权利要求6所述的医药组合物,其特征还在于,它是慢性类风湿性关节炎的预防或治疗剂。
9.如权利要求4~8的任一项所述的医药组合物,其中包含选自4-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]噻唑-5-羧酰替苯胺、2′-氯-5-(1-甲基-3-三氟甲基-1H-吡唑-5-基)噻吩-2-羧酰替苯胺、4-氯-4′-(1-甲基-3-三氟甲基-1H-吡唑-5-基)苯甲酰替苯胺、4-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1基]-1,2,3-噻二唑-5-羧酰替苯胺、3-甲基-4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]噻吩-2-羧酰替苯胺及4′-[3,5-双(三氟甲基)-1H-吡唑-1-基]吡啶-3-羧酰替苯胺的酰胺衍生物或其制药学上允许的盐。
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KR (1) | KR100589868B1 (zh) |
CN (1) | CN1107671C (zh) |
AR (1) | AR016957A1 (zh) |
AT (1) | ATE360618T1 (zh) |
AU (2) | AU751139B2 (zh) |
BR (1) | BR9803883A (zh) |
CA (1) | CA2304979A1 (zh) |
DE (1) | DE69837675T2 (zh) |
ES (1) | ES2285784T3 (zh) |
HU (1) | HUP9802310A1 (zh) |
NO (1) | NO317417B1 (zh) |
PL (1) | PL192411B1 (zh) |
PT (1) | PT1024138E (zh) |
RU (1) | RU2185381C2 (zh) |
TW (1) | TW495498B (zh) |
WO (1) | WO1999019303A1 (zh) |
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CN106905311A (zh) * | 2010-08-27 | 2017-06-30 | 钙医学公司 | 调节细胞内钙的化合物 |
CN110627724A (zh) * | 2009-10-08 | 2019-12-31 | 理森制药股份公司 | 吡唑衍生物钙释放激活钙通道调节剂及非小细胞肺癌的治疗方法 |
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- 1998-10-12 HU HU9802310A patent/HUP9802310A1/hu unknown
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8598355B2 (en) | 2008-05-14 | 2013-12-03 | Astellas Pharma Inc. | Amide compound |
CN102026961B (zh) * | 2008-05-14 | 2014-04-09 | 安斯泰来制药株式会社 | 酰胺化合物 |
CN110627724A (zh) * | 2009-10-08 | 2019-12-31 | 理森制药股份公司 | 吡唑衍生物钙释放激活钙通道调节剂及非小细胞肺癌的治疗方法 |
CN106905311A (zh) * | 2010-08-27 | 2017-06-30 | 钙医学公司 | 调节细胞内钙的化合物 |
Also Published As
Publication number | Publication date |
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TW495498B (en) | 2002-07-21 |
AU751139B2 (en) | 2002-08-08 |
AU9459398A (en) | 1999-05-03 |
HUP9802310A1 (hu) | 2000-03-28 |
NO20001907D0 (no) | 2000-04-12 |
ES2285784T3 (es) | 2007-11-16 |
KR19990037018A (ko) | 1999-05-25 |
DE69837675T2 (de) | 2008-01-10 |
PL329150A1 (en) | 1999-04-26 |
US6958339B2 (en) | 2005-10-25 |
HU9802310D0 (en) | 1998-12-28 |
BR9803883A (pt) | 2000-05-16 |
US20010011090A1 (en) | 2001-08-02 |
KR100589868B1 (ko) | 2006-10-24 |
DE69837675D1 (en) | 2007-06-06 |
PT1024138E (pt) | 2007-08-01 |
US7247635B2 (en) | 2007-07-24 |
US20060264430A1 (en) | 2006-11-23 |
WO1999019303A1 (fr) | 1999-04-22 |
AR016957A1 (es) | 2001-08-01 |
NO317417B1 (no) | 2004-10-25 |
EP1024138A4 (en) | 2002-02-06 |
US7285554B2 (en) | 2007-10-23 |
EP1024138A1 (en) | 2000-08-02 |
ATE360618T1 (de) | 2007-05-15 |
CN1107671C (zh) | 2003-05-07 |
CA2304979A1 (en) | 1999-04-22 |
RU2185381C2 (ru) | 2002-07-20 |
NO20001907L (no) | 2000-06-09 |
US20050234055A1 (en) | 2005-10-20 |
AU8713998A (en) | 1999-04-29 |
EP1024138B1 (en) | 2007-04-25 |
PL192411B1 (pl) | 2006-10-31 |
US6348480B1 (en) | 2002-02-19 |
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