CN101062919A - 4-甲基-1h-二芳基吡唑衍生物及其作为药物的用途 - Google Patents
4-甲基-1h-二芳基吡唑衍生物及其作为药物的用途 Download PDFInfo
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- CN101062919A CN101062919A CN 200710102117 CN200710102117A CN101062919A CN 101062919 A CN101062919 A CN 101062919A CN 200710102117 CN200710102117 CN 200710102117 CN 200710102117 A CN200710102117 A CN 200710102117A CN 101062919 A CN101062919 A CN 101062919A
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- phenyl
- pyrazole
- chloro
- formamide
- methyl
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Abstract
本发明涉及通式I的4-甲基-1H-二芳基吡唑衍生物及其药用盐,其制备方法,含它们的药用组合物作为脑内大麻素I型(CB1)受体抑制剂特别是在治疗肥胖、改善记忆、戒烟方面的用途。
Description
发明领域
本发明涉及通式I的4-甲基-1H-二芳基吡唑衍生物及其药用盐,其制备方法,含它们的药用组合物及通式I化合物作为脑内大麻素I型(CB1)受体抑制剂在治疗与CB1受有关疾病或症状如肥胖、改善记忆、戒烟方面的用途。
背景技术
大麻类物质是最早被人类认识的成瘾性物质之一,大约有一千年的药用历史,其主要活性成分是Δ9-四氢大麻酚(delta-9-tetrahydro-cannabinol,Δ9-THC)。大麻类物质具有止痛、镇静、抗痉挛、抗呕吐、抗青光眼及抗高血压等多种药理作用,但易产生耐受性和成瘾性,限制了它们的使用(R.K.Razden,Pharmacol.Rew.,1986,38,75-149)。
大麻素(cannabinoid,CB)受体是指对大麻类物质如Δ9-THC有应答的受体。90年代初,大麻素的两种受体亚型被成功克隆:CB1(R.Mechoulam,et al.,Biochem.Pharmacol.,1995,50,83-90)和CB2(S.Munro,et al.,Nature,1993,365,61-65)。它们都属于G蛋白偶联受体的视紫质样家族A纲。基因克隆研究发现这两种受体完整的氨基酸序列有44%的同源性,跨膜区氨基酸序列有68%的同源性(L.A.Matsuda,et al.,Nature,1990,346,561-564)。氨基酸序列的分析显示,它们的结构中都包括七次亲酯跨膜α螺旋结构。两种大麻素受体可以激活多重细胞内信号转导通路,包括通过抑制腺苷酸环化酶、抑制钙通道、激活钾通道、激活MAP激酶通道来抑制cAMP的生成。且都对百日咳毒素(pertussis toxin)敏感,表明两种受体主要为Gi/o型G蛋白偶联受体(P.H.Reggio,Curr.Pharm.Des.,2003,9,1607-1633)。CB1受体主要存在于中枢神经系统,又名中枢型大麻素受体;CB2受体主要存在于外周神经元,又名外周型大麻素受体;功能之一都是阻止神经递质的释放。它们的主要区别在于其氨基酸序列、信号转导机制、器官分布及对某些激动剂和抑制剂敏感度的不同。
CB1受体是利用氚标记的CP55940,通过放射自显影技术和放射配体结合研究方法确证的受体。它包含473个氨基酸,由17个跨膜区组成,该受体在进化中有着高度保守性和重要性。人类与大鼠的CB1受体氨基酸序列有97.3%同源,分子量大约为52800左右。CB1受体主要位于脑、脊髓与外周神经系统中,脑内CB1受体主要分布于基底神经节(黑质、苍白球、外侧纹状体)、海马CA锥体细胞层,小脑和大脑皮层。CB1受体的这种分布可能与大麻素对记忆、认知、运动控制的调节有关。
研究证实,大麻素受体I型的内源性配体对食物摄取和能量消耗有双重调控作用,从而达到控制体重的目的(A.C.Howlett,et al.Pharmacol.Rev.,2002,54,161-202)。
大麻素受体激动剂大多没有特异性,均可以同时与两种大麻素受体结合。与激动剂不同的是,目前人工合成的几种大麻素受体抑制剂都表现出非常高的受体特异性。其中,大麻素受体I型抑制剂直接作用于中枢神经系统,表现出多种多样的活性。如抗肥胖、戒烟、改善记忆和认知障碍、治疗精神疾病和肿瘤化疗等。二芳基吡唑类化合物是最受瞩目的CB1受体抑制剂之一,它可高效选择性的与CB1受体结合,迅速的阻断或逆转CB1受体的调节作用,降低信号转导通路的活性(M.Rinaldi-Carmona,et al.,FEBS Lett,1994,350,240 244)。因此,寻找结构新颖的具有CB1抑制活性的二芳基吡唑类化合物是十分必要的。
发明内容
本发明的目的在于寻找并开发作用于CB1受体的新的二芳基吡唑类小分子抑制剂。
本发明人经过研究发现,具有下面通式(I)的化合物具有抑制CB1受体的作用,因此可以用于治疗与CB1受体有关的疾病或症状,如用于治疗肥胖、戒烟、改善记忆和认知障碍、治疗精神疾病和肿瘤化疗等各种疾病或症状。
本发明第一方面涉及通式(I)的化合物或其可药用的盐或水合物,
其中:R是H,C1-C15烷基,尤其是C1-C8的直链或支链烷基,C3-7环烷基,或是C6-C15的取代或未取代的芳香基,代表性芳香基如苯基、萘基、蒽基、芴基,或含N杂环如喹啉、吡咯、哌啶、哌嗪、吗啉、咪唑、吡唑、吗啉或其他杂环如噻唑、呋喃等;取代基选自卤素、氰基、硫氢基、甲酰基、羟基、磺酸酯、硝基、亚硝基、C1-C8取代或未取代烷氨基、C1-6烷硫基、C1-C8烷氧基、C1-C15烷基、尤其是C1-C8直链、支链或环状烷基。
根据本发明,优选的R是任意一取代或二取代的苯、芴、吡啶,取代基选自卤素、氨基、甲酰基、C1-6烷氧基、;R亦可以是哌啶、吗啉、呋喃、咪唑,取代基选自卤素、C1-6烷基、氨基;R亦可以是C1-8直链、支链或环状烷基。
本发明所用术语“C1-C15烷基”或“C1-C8烷基”是指含1-15个或1-8个碳原子的直链、支链或环状烷基,包括但并不局限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、新戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
本发明所用术语“卤素”是指由元素氟、氯、溴、碘所衍生的原子团
本发明所用术语“环烷基”是指含有3-7个碳原子的环烷基,包括但是并不局限于环丙基、环戊基、环己基等。
根据本发明,本发明涉及的通式(I)化合物或其可药用的盐或水合物优选下面的化合物:
(1)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-9H-芴基)-4-甲基-1H-吡唑-3-甲酰胺
(2)N-(4-溴苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺
(3)1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(3-吡啶基)-1H-吡唑-3-甲酰胺
(4)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-环戊基-4-甲基-1H-吡唑-3-甲酰胺
(5)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(甲基环己基)-4-甲基-1H-吡唑-3-甲酰胺
(6)1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-甲基-1-哌嗪基)-1H-吡唑-3-甲酰胺
(7)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-呋喃-甲基)-4-甲基-1H-吡唑-3-甲酰胺
(8)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(4-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺
(9)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺
(10)N-(4-甲氧基苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺
(11)1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(3-吡啶基-甲基)-1H-吡唑-3-甲酰胺
(12)1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-吡啶基-甲基)-1H-吡唑-3-甲酰胺
(13)N-[3-(1-1H-咪唑基)-丙基]-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺
(14)1-(2,4-二氯苯基)-5-(4-氯苯基)-N-[4-(二甲基氨基)苯基]-4-甲基-1H-吡唑-3-甲酰胺
及其可药用盐或水合物。
根据本发明,本发明涉及如通式I所示化合物或其立体异构体的合适的可药用盐或水合物,其中可药用的盐包括但是并不局限于通式I化合物与无机酸如盐酸、硫酸、磷酸、亚磷酸、氢溴酸和硝酸所成的盐以及与各种有机酸,如马来酸、苹果酸、延胡索酸、琥珀酸、酒石酸、柠檬酸、乙酸、乳酸、甲磺酸、对甲苯磺酸、棕榈酸等所成的盐。本发明中的一些化合物可能用水或各种有机溶剂结晶或重结晶,在这种情况下,可能形成各种溶剂化物。本发明包括那些化学计量的溶剂化物,包括水合物,也包括在用低压升华干燥法制备时形成的包含可变量水的化合物。
根据本发明,本发明式I化合物的立体异构体指本发明中部分化合物可能以光学异构体或互变异构体的形式存在,本发明包括其所有存在形式,特别是纯异构体的形式。不同的异构体形式可以以各种常规的手段与其它形式的异构体分离或拆分开,或者某种异构体可以各种常规的合成方法或立体专一或不对称合成的方法得到。既然通式I化合物是以药用为目的的,可以理解它们最好以纯的形式提供,例如至少60%的纯度,更合适的75%,更好的85%,最好至少98%的纯度(%是指重量百分比)。不纯化合物的制备方法可用来用于药用组合物中更纯的形式。这些不够纯的产物中至少含有1%,更适合的5%,更好的至少10%的如通式I所示的化合物或其可药用的衍生物。
本发明另一方面涉及制备通式I化合物的方法。通式I的化合物可以从已知的或可购得的化合物为原料,经过人工合成的方法制备。如果原料不能购得,则这里提供它们的制备方法,或它们可以通过文献报道的方法制备。
通式(I)的化合物的制备方法包括:
(i)将式II5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酸和氯化亚砜反应,得到5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯。
(ii)将5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯与取代胺NHR反应得到通式(I)化合物
其中R的定义同如前所述。
式(II)的合成方法在相关文献如Design and synthesis of theCB1 selective cannabinoid antagonist AM281:A Potential HumanSPECT ligand,R.Lan,Q.Lu and P.Fan,(AAPS Pharmsci 1999,1(3),article 4)和The synthesis and pharmacological evaluationof the cannabinoid antago--nist SR141716A,A.K.Dutta,et al.,(Med Chem Res 1994,5,54-62)中已有详尽的论述。
通式(I)化合物可以用常规方法单个合成,亦可用组合化学的混-分方法或平行合成的方法以库(每个库中至少含两个,或5-1000个,最好是10-100个化合物)为单位合成,即可以在液相中合成也可以用固相合成方法。
关于制备通式(I)化合物更详尽的资料见实施例
本发明还涉及药物组合物,其包括至少一种式I化合物和至少一种药用载体或赋形剂。通式I的化合物或其可药用的盐可以单独使用,或与可药用的载体或赋形剂一起以药物组合物的形式使用,当以药物组合物的形式使用时,通常将有效剂量的本发明通式I化合物或其可药用盐或水合物以及一种或多种可药用载体或稀释剂结合制成适当的施用形式或剂量形式,这一程序包括通过合适的方式将组分混合、粒化、压缩或溶解。
本发明药用组合物可以以下方面的任意方式施与:口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入,或借助一种外植的储器用药,其中优选口服、肌注、腹膜内或静脉内用药方式。
本发明的药物组合物中含有的药用载体包括但不局限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,缓冲物质如磷酸盐,甘油,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛酯等。载体在药物组合物中的含量可以是1重量%-98重量%,通常大约占到80重量%。为方便起见,局部麻醉剂,防腐剂,缓冲剂等可直接溶于载体中。
口服制剂如口服片剂和胶囊可以含有赋形剂如粘合剂,如糖浆,阿拉伯胶,山梨醇,黄芪胶,或聚乙烯吡咯烷酮,填充剂,如乳糖,蔗糖,玉米淀粉,磷酸钙,山梨醇,氨基乙酸,润滑剂,如硬脂酸镁,滑石,聚乙二醇,硅土,崩解剂,如马铃薯淀粉,或可接受的增润剂,如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液形式的本发明药物组合物可以制成水和油的悬浮液,溶液,乳浊液,糖浆或酏剂,也可以制成干品,用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂,如悬浮剂,山梨醇,纤维素甲醚,葡萄糖糖浆,凝胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶,氢化的食用油脂,乳化剂,如卵磷脂,山梨聚醣单油酸盐,阿拉伯树胶;或非水载体(可能包含可食用油),如杏仁油,油脂如甘油,乙二醇,或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯,山梨酸。如需要可添加调味剂或着色剂。
栓剂可包含常规的栓剂基质,如可可黄油或其它甘油酯。
非肠道给药,液态剂型通常由化合物和至少一种消毒或无菌的载体制成。载体首选水。依照所选载体和药物浓度的不同,化合物既可溶于载体中也可制成悬浮溶液,在制成注射用溶液时先将化合物溶于水中,过滤消毒后装入封口瓶或安瓿中。
当皮肤局部施用时,本发明化合物可以制成适当的软膏,洗剂,或霜剂的形式,其中活性成分悬浮或溶解于一种或多种的载体中。其中软膏制剂可以使用的载体包括但不局限于:矿物油,液体凡士林,白凡士林,丙二醇,聚氧化乙烯,聚氧化丙烯,乳化蜡和水;洗剂和霜剂可使用的载体包括但不限于:矿物油,脱水山梨糖醇单硬脂酸酯,吐温60,十六烷酯蜡,十六碳烯芳醇,2-辛基十二烷醇,苄醇和水。
依据给药方式的不同,组合物中可以含有重量比0.1%,或更合适的重量比10-60%的活性组分。但组合物为单位剂型时,每个单位最好包含50-500毫克活性成分。依据给药途径和给药频率的不同,用于成人的适宜治疗剂量,举例讲可为每天100-3000毫克,如每天1500毫克。这一剂量对应于1.5-50毫克/公斤/天,合适的剂量是5-20毫克/公斤/天。
必须认识到,通式I化合物的最佳给药剂量和间隔是由疾病或症状的严重程度、化合物性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等条件决定的,而这一最佳给药剂量可由临床医生来确定。
本发明还涉及式I化合物或其立体异构体或它们的药用盐或它们的水合物在制备用于治疗与CB1受体有关疾病或症状的药物中的用途。
具体实施方案
下面的具体实施例是本发明的优选实施方案,其不应理解为对本发明构成任何限制。
化合物的熔点由RY-1熔点仪测定,温度计未较正。质谱由Micromass ZabSpec高分辨率质谱仪(分辨率1000)测定。1H NMR由JNM-ECA-400超导NMR仪测定,工作频率1HNMR 400MHz。
实施例
实施例1 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-9H-芴基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
步骤1 5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备。
取0.5g 5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酸,用10ml甲苯溶解,加入0.29ml氯化亚砜,加热至回流,4小时后,蒸出氯化亚砜和甲苯,再分三次加入各10ml甲苯,蒸馏,得0.4g红棕色油状物。直接投料下步反应。
步骤2 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-9H-芴基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
将上步所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.23g2-氨基芴和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应9小时。用石油醚∶乙酸乙酯=2∶1柱层析分离,得到0.388g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-9H-芴基)-4-甲基-1H-吡唑-3-甲酰胺,mp:212.9-214.5℃,两步总收率54.34%,
1H-NMR(DMSO,δppm):2.32(s,3H),3.92(s,2H),7.27(dd,1H),7.36(t,1H),7.48(m,2H),7.55(d,1H),7.61(dd,1H),7.78-7.84(m,4H),8.18(s,1H),10.25(s,1H).FAB-MS(m/e):545.1(M+)。
实施例2 N-(4-溴苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.215g对溴苯胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应9小时。用石油醚∶乙酸乙酯=2∶1柱层析分离,得到0.327g的N-(4-溴苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺,mp:157.6-159.3℃,两步总收率46.58%,
1H-NMR(DMSO,δppm):2.29(s,3H),7.26(dd,2H),7.47-7.51(m,5H),7.79-7.83(m,4H),10.35(s,1H)。FAB-MS(m/e):536.0(M+)。
实施例3 1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(3-吡啶基)-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.141g对溴苯胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应6.5小时。用石油醚∶乙酸乙酯=1∶3柱层析分离,得到0.311g的1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(3-吡啶基)-1H-吡唑-3-甲酰胺mp:162.8-164.1℃,两步总收率51.86%,
1H-NMR(DMSO,δppm):2.31(s,3H),7.27-7.38(m,3H),7.47(d,2H),7.60(dd,1H),7.80-7.84(m,2H),8.22-8.30(m,2H),8.98(d,1H),10.47(s,1H).FAB-MS(m/e):457.0(M+)。
实施例4 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-环戊基-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.256g环戊胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应5.5小时。用石油醚∶乙酸乙酯=8∶1柱层析分离,得到0.398g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-环戊基-4-甲基-1H-吡唑-3-甲酰胺,mp:146.9-148.7℃,两步总收率67.69%,1H-NMR(DMSO,δppm):1.50-1.66(m,6H),1.80-1.88(m,2H),2.24(s,3H),4.20-4.24(m,1H),7.21-7.24(d,2H),7.44-7.59(m,3H),7.74-7.76(m,2H),8.01(d,1H).FAB-MS(m/e):448.1(M+)。元素分析:C22H20Cl3N3O,计算值(%)C58.88,H4.49,N9.36,测定值(%)C58.98,H4.50,N9.49。
实施例5 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(甲基环己基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.22g氨甲基环戊烷和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应4.5小时。用石油醚∶乙酸乙酯=7∶1柱层析分离,得到0.250g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(甲基环己基)-4-甲基-1H-吡唑-3-甲酰胺,mp:110.4-111.9℃,两步总收率40%,1H-NMR(DMSO,δppm):0.87-1.68(m,10H),2.24(s,3H),3.05(t,1H),7.22(d,2H),7.45-7.60(m,3H),7.75-7.78(m,2H),8.20(t,1H).FAB-MS(m/e):476.2(M+)。
实施例6 1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-甲基-1-哌嗪基)-1H-吡唑-3-甲酰胺的制备
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.225g的1-氨基-4甲基哌嗪和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应4.5小时。用石油醚∶乙酸乙酯=7∶1柱层析分离,得到0.266g的1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-甲基-1-哌嗪基)-1H-吡唑-3-甲酰胺,mp:96.7-98.9℃,两步总收率42.42%,1H-NMR(DMSO,δppm):2.16-2.21(d,6H),2.50(s,4H),
2.81(t,4H),7.21(d,2H),7.44-7.48(d,2H),7.57-7.60(dd,1H),7.76-7.77(m,2H),9.22(s,1H).FAB-MS(m/e):478.2(M+)。
实施例7 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-呋喃-甲基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.189g的2-呋喃甲基胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应6小时。用石油醚∶乙酸乙酯=6∶1柱层析分离,得到0.415g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-呋喃-甲基)-4-甲基-1H-吡唑-3-甲酰胺,mp:154.7-156.1℃,两步总收率68.75%,1H-NMR(DMSO,δppm):2.25(s,3H),4.40(d,2H),6.22(d,1H),
6.38(m,1H),7.23(d,2H),7.45-7.60(m,4H),7.75-7.79(m,2H),8.69(t,1H).FAB-MS(m/e):462.1(M++1)。
实施例8 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(4-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.22g的4-氟苯胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应5小时。用石油醚∶乙酸乙酯=7∶1柱层析分离,得到0.398g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(4-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺,mp:174.7-176.3℃,两步总收率63.99%,1H-NMR(DMSO,δppm):2.30(s,3H),7.14-7.29(m,4H),7.46-7.63(m,3H),7.80-7.86(m,4H),10.30(s,1H).FAB-MS(m/e):474.1(M+)。
实施例9 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.22g的2-氟苯胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应5小时。用石油醚∶乙酸乙酯=7∶1柱层析分离,得到0.438g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺,mp:163.5-165.0℃,两步总收率70.42%,1H-NMR(DMSO,δppm):2.29(s,3H),7.20-7.31(m,5H),7.47-7.50(d,2H),7.60-7.63(dd,1H),7.74-7.84(m,3H),9.81(s,1H).FAB-MS(m/e):474.0(M+)。
实施例10 N-(4-甲氧基苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.268g的(4-甲氧基苯基)-甲基胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应6小时。用石油醚∶乙酸乙酯=6∶1柱层析分离,得到0.405g的N-(4-甲氧基苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺,mp:130.8-132.3℃,两步总收率61.74%,1H-NMR(DMSO,δppm):2.25(s,3H),3.72(s,3H),4.34(d,2H),6.86(d,2H),7.23(t,4H),7.45-7.59(m,3H),7.75-7.78(m,2H),8.75(t,1H).FAB-MS(m/e):500.0(M+)。
实施例11 1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-吡啶基-甲基)-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.211g的4-氨甲基吡啶和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应7小时。用石油醚∶乙酸乙酯=1∶1柱层析分离,得到0.263g的1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-吡啶基-甲基)-1H-吡唑-3-甲酰胺,mp:64.7-67.0℃,两步总收率42.55%,1H-NMR(DMSO,δppm):2.25(s,3H),4.42(d,2H),7.24-7.30(m,4H),7.46(d,2H),7.59(dd,1H),7.78-7.80(m,2H),8.49(m,2H),8.98(t,1H).FAB-MS(m/e):471.2(M+)。
实施例12 N-[3-(1-1H-咪唑基)-丙基]-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.244g的N-(3-氨基丙基)-咪唑和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应7小时。用氨水∶乙醇∶氯仿=1∶10∶200柱层析分离,得到0.42g的N-[3-(1-1H-咪唑基)-丙基]-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺,mp:184.5-186.8℃,两步总收率65.58%,1H-NMR(DMSO,δppm):1.93-1.95(m,2H),2.25(s,3H),3.21(dd,2H),3.96(t,2H),6.88(t,1H),7.21-7.25(m,3H),7.45(d,2H),7.57(dd,1H),7.67(s,1H),7.75-7.79(m,2H),8.43(t,1H).FAB-MS(m/e):488.0(M+)。
实施例14 1-(2,4-二氯苯基)-5-(4-氯苯基)-N-[4-(二甲基氨基)苯基]-4-甲基-1H-吡唑-3-甲酰胺的制备。
5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基吡唑-3-甲酰氯的制备方法参见实施例1。
将所得甲酰氯用4ml二氯甲烷溶解,0℃下,缓慢滴加入0.266g的N,N-二甲基对位苯胺和0.234ml三乙胺在5ml二氯甲烷的溶液中,室温下反应7小时。用石油醚∶乙酸乙酯=1∶3柱层析分离,得到0.443g的1-(2,4-二氯苯基)-5-(4-氯苯基)-N-[4-(二甲基氨基)苯基]-4-甲基-1H-吡唑-3-甲酰胺,mp:151.5-152.8℃,两步总收率67.65%,1H-NMR(DMSO,δppm):2.29(s,3H),2.86(s,6H),6.68(d,2H),7.25(d,2H),7.46(d,2H),7.59(dd,3H),7.79-7.81(m,2H),9.88(s,1H).FAB-MS(m/e):500.1(M+)。
实施例15 本发明化合物对大鼠小脑CB1受体的作用
实验方法
(1)大鼠小脑CB1受体膜蛋白的制备:
用Wistar大鼠,220~260g,雌雄不限,断头处死后,迅速分离出小脑,称量后加入10倍体积的Tris-HCl Buffer(50mM Tris HCl,5mM MgCl26.H20,1mM EDTA,0.5%(W/V)BSA,pH7.4),用匀浆器15000rpm/min进行匀浆,每次30秒,共5次。匀浆液经400×g离心10min,取上清液再用39000×g离心10min,收集沉淀,用原重量的10倍体积Tris-HCl Buffer pH7.4重新悬浮,再用39000×g离心10min,取沉淀用相同缓冲液洗涤,39000×g离心10min,最后将得到的沉淀用Tris-HCl Buffer悬浮,分装后(整个操作过程要在4℃进行)在-80℃保存备用。用Folin法测定蛋白质含量。
(2)CB1受体蛋白质含量的测定:
样品100μl,内含BSA 5~100μg(作标准曲线用)或待测样品,不足100μl者用H20补足,加试剂甲(①含4%碳酸钠及0.2%酒石酸钠(Na2C4 H906 2H20)的0.2N NaOH溶液,②4%硫酸铜(CuSO4.5H2O)水溶液,将①和②按100∶1的比例混合均匀,即为试剂甲,配制后一天内使用)100μl,混合后放在室温反应10分钟,再加试剂乙(Folin-酚试剂,最后浓度为1N)20μl,立即混匀,置50℃水浴中,孵温15分钟,取200μl用微量多道扫描光密度计,波长690nm,光程0.6cm,测光密度值,用H2O 100μl代替样品作空白对照。
(3)CB1受体与3H-SR141716A的饱和实验:
所有管中依次加30μg相同受体的蛋白量,在非特异结合管中加入25μl(10-4M)SR141716A,在30℃反应30分钟;全部试管依次加入不同的3H-SR141716A,用Tris-HCl Buffer补足所有反应管体积为300μl,在30℃反应1小时;然后点样于49型玻璃纤维滤纸上(滤纸预先用0.1mg/ml BSA湿润),经负压抽滤,再用冰冷的Tris-HClBuffer(50mM Tris-HCl Buffer,pH 7.4,1mM EDTA,5mM MgCL2)洗涤,每次2ml,共10次,抽干滤纸,将滤纸取出烘干后,放在闪烁瓶中,加1ml闪烁液,用LS6500型液闪计数器测定放射性强度。
(4)药物对CB1受体与3H-SR141716A结合竞争实验:
在30℃的反应条件中摆放试管,所有管中依次加入100μg受体蛋白量,测试管中依次加入20μl一定浓度的药物,非特异结合管中加入50μl非标配体(ACEA),非标配体终浓度为1mM,预先反应30分钟,全部试管依次加入30μl 3H-SR141716A(16nM),标记配体终浓度为2.4nM,用Buffer补足所有反应管体积为200μl,在30℃反应条件下反应1小时,然后点样于49型玻璃纤维滤膜上,经负压抽滤,再用冰冷的Buffer洗涤10次,每次2ml,抽干滤膜,将滤膜取出烘干后,放在闪烁瓶中,加1ml闪烁液,用LS6500型液闪计数器测定放射性强度。
实验结果
活性评价结果如下表所示:
表1
化合物 | 抑制百分比(%) | ||
1×10-5M | 1×10-7M | 1×10-9M | |
SR141716A | 100.0 | 100.0 | 92.2 |
1实施例1 | 100.0 | 95.8 | 84.2 |
2实施例2 | 100.0 | 69.8 | 1.5 |
3实施例3 | 100.0 | 75.6 | 56.6 |
7实施例4 | 100.0 | 96.6 | 50.6 |
9实施例5 | 100.0 | 74.0 | 40.1 |
10实施例6 | 87.3 | 57.4 | 27.8 |
11实施例7 | 100.0 | 84.2 | 50.1 |
12实施例8 | 100.0 | 84.8 | 30.1 |
13实施例9 | 100.0 | 81.2 | 40.3 |
14实施例10 | 100.0 | 82.8 | 24.0 |
16实施例11 | 100.0 | 100.0 | 14.4 |
20实施例12 | 100.0 | 98.9 | 17.2 |
21实施例13 | 100.0 | 64.0 | 31.2 |
根据初筛结果,对CB1受体亲和力较高的化合物,进一步测定其IC50(Log M)。SR141716为1.30×10-10,实施例1化合物为2.53×10-10。
实施例16 本发明化合物的药代动力学性质
方法
把所合成化合物组建一个ISISBase数据库,*.db格式的文件,用Concord 4.08程序将化合物从2D转化到3D,转为*.mo12格式,传入SYBYL给化合物以相应的电荷。在SYBYL中组建一个数据库,*.mdb格式,把所有分子导入,)用VolSurf3.010的GRID程序计算3D分子与水、疏水和羰基3个探针之间的相互作用场,分别计算Caco-2细胞吸收透膜模型、BBB血脑屏障透过性模型和药物蛋白结合模型的描述参数。
预测结果见下表
化合物 | BBB | Caco2 | 蛋白结合 |
1实施例12实施例23实施例37实施例49实施例510实施例611实施例712实施例813实施例914实施例1016实施例1120实施例1221实施例13SR141716 | -0.18-0.10-0.080.190.22-0.050.0400.01-0.17-0.17-0.30-0.050.13 | 1.170.770.540.951.020.680.770.790.820.620.550.651.010.91 | 109.8391.9082.2986.7392.9580.2186.4388.4087.5789.6487.1392.0099.0985.26 |
上表中,BBB透过性模型的预测结果:能穿透的为BBB+,不能穿透的为BBB-;Caco-2模建的结果,得分高者,透膜性高;蛋白结合模型的结果,得分者高,蛋白结合能力强。从表中可以看出,化合物实施例4、实施例5在三项预测中都有良好表现,优于对照化合物SR141716A,实施例1的透膜性也强于阳性对照药SR141716A。
Claims (7)
2.权利要求1的4-甲基-1H-二芳基吡唑衍生物,其选自下列化合物:
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-9H-芴基)-4-甲基-1H-吡唑-3-甲酰胺
N-(4-溴苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(3-吡啶基)-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-环戊基-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(甲基环己基)-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-甲基-1-哌嗪基)-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-呋喃-甲基)-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(4-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-(2-氟苯基)-4-甲基-1H-吡唑-3-甲酰胺
N-(4-甲氧基苯基)-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(3-吡啶基-甲基)-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-N-(4-吡啶基-甲基)-1H-吡唑-3-甲酰胺
N-[3-(1-1H-咪唑基)-丙基]-1-(2,4-二氯苯基)-5-(4-氯苯基)-4-甲基-1H-吡唑-3-甲酰胺
1-(2,4-二氯苯基)-5-(4-氯苯基)-N-[4-(二甲基氨基)苯基]-4-甲基-1H-吡唑-3-甲酰胺
3.一种药物组合物,其包含作为活性的成分,如权利要求1~2中任何一项所述的4-甲基-1H-二芳基吡唑衍生物,或其立体异构体或它们的可药用盐,或它们的水合物或溶剂化物及药用载体或赋形剂。
4.权利要求3的药物组合物一种用于治疗肥胖的药物组合物。
5.权利要求3的药物组合物,其是一种用于改善记忆的药物组合物。
6.权利要求3的药物组合物,其是一种用于戒烟的药物组合物。
7.通式I的4-甲基-1H-二芳基吡唑衍生物或其立体异构体或它们的可药用的盐或它们的水合物在制备具有治疗肥胖、改善记忆、戒烟活性的药物中的用途。
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CN102558058A (zh) * | 2012-01-19 | 2012-07-11 | 陕西理工学院 | 1-芳基-3-取代-5-取代氨基-4-吡唑甲酰胺类化合物及其应用 |
WO2012151958A1 (zh) * | 2011-05-12 | 2012-11-15 | Fan Rulin | 低毒性3-吡唑羧酸酰胺、其制备方法及其在制备作为cb1受体抑制剂药物中的应用 |
US8642597B2 (en) | 2007-08-27 | 2014-02-04 | Basf Se | Pyrazole compounds for controlling invertebrate pests |
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Family Cites Families (5)
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FR2713225B1 (fr) * | 1993-12-02 | 1996-03-01 | Sanofi Sa | N-pipéridino-3-pyrazolecarboxamide substitué. |
FR2789079B3 (fr) * | 1999-02-01 | 2001-03-02 | Sanofi Synthelabo | Derive d'acide pyrazolecarboxylique, sa preparation, les compositions pharmaceutiques en contenant |
FR2804604B1 (fr) * | 2000-02-09 | 2005-05-27 | Sanofi Synthelabo | Utilisation d'un antagoniste des recepteurs aux cannabinoides centraux pour la preparation de medicaments utiles pour faciliter l'arret de la consommation de tabac |
US6509367B1 (en) * | 2001-09-22 | 2003-01-21 | Virginia Commonwealth University | Pyrazole cannabinoid agonist and antagonists |
US6825209B2 (en) * | 2002-04-15 | 2004-11-30 | Research Triangle Institute | Compounds having unique CB1 receptor binding selectivity and methods for their production and use |
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CN102558058B (zh) * | 2012-01-19 | 2014-10-29 | 陕西理工学院 | 1-芳基-3-取代-5-取代氨基-4-吡唑甲酰胺类化合物及其应用 |
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