CN101490006B - 作为香草素-1受体调节剂的联芳基甲酸芳基酰胺 - Google Patents
作为香草素-1受体调节剂的联芳基甲酸芳基酰胺 Download PDFInfo
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及式(I)化合物,其中A和Z如说明书中所定义,还涉及制备这些衍生物的方法以及它们用于治疗炎性疾病如神经性疼痛的用途。
Description
发明领域
本发明涉及香草素受体调节剂,特别是涉及TRPV1拮抗剂。
背景技术
瞬时受体电位香草酸亚型1(TRPV1)与温度和机械性痛觉过敏的发生密切相关,且已提出其在包括神经性疼痛和泌尿障碍的不同的病理状况中起关键作用。
包含联芳基部分的香草素受体拮抗剂是已知的;其中,在WO2004/0567741中公开了以下被取代的联芳基-4-甲酸芳基酰胺:
发明描述
现在已发现通过用异喹啉-5-基环替换以上化合物中的吡啶基可得到具有改良的特性的TRPV1拮抗剂。
相应地,本发明提供了改良的通式(I)的香草素-1受体调节剂
其中:
A是CH或N;
Z是苯基或吡啶基环,其任选地被1或2个R基团取代,所述R基团彼此可以相同或不同且选自C1-C4烷基(优选地是甲基、异丙基或叔丁基)、C1-C4卤代烷基(优选地是三氟甲基)或卤素。
在本说明书中,卤素是指选自氟、氯、溴和碘的卤原子,优选地是氯。
本发明优选的第一组化合物是式(Ia)的化合物,
其中Z如上文所定义。
本发明优选的第二组化合物是式(Ib)的化合物,
其中Z如上文所定义。
在式(Ia)和式(Ib)的化合物中,Z优选地是在对位被除氢以外、优选地是氯的R基团取代的苯环。本发明最优选的化合物是N-(4-氯苯基)-6-(异喹啉-5-基)吡啶-3-甲酰胺(下文用V394表示)。
式(I)化合物可用常规方法制备,如通过将式(II)化合物,
其中A如上文所定义且将羧基活化为酰氯,
和式(III)化合物反应来制备,
Z-NH2
(III)
其中Z如上文所定义。
优选地,式(I)化合物可通过将式(IV)化合物,
其中A和Z如上文所定义且X是选自碘和溴的卤素,
和硼酸(V)进行Suzuki反应2来得到
例如,将6-溴-或6-氯-N-(4-氯苯基)吡啶-3-甲酰胺和异喹啉-5-基-5-硼酸进行Suzuki反应可方便地制备化合物V394。
式(I)化合物调节TRPV1受体;优选的化合物V394在大鼠脊髓中的Ki值为15nM(13-17),且在培养的大鼠背根神经节神经元中的IC50值为0.83nM(0.74-0.93)。因此,本发明的化合物可用于制备治疗炎性状态(如慢性疼痛和炎性痛觉过敏)的药物组合物。这些制剂可以通过常规的方法和赋形剂来制备,例如在Remington’s药学手册(Pharmaceutical ScienceHandbook),XVII版,Mack Pub.,N.Y.,U.S.A.中所公开的内容。
将通过以下实施例在下文中阐明本发明。
实施例
材料和方法
所有可商购的化合物均从Aldrich购得且未经进一步纯化直接使用。反应进程通过硅胶薄层色谱(预涂覆F254Merck板)监测,斑点用紫外光检测并用KMnO4水溶液显色。快速色谱使用Merck硅胶(230-240目)进行。1H-NMR谱以TMS为内标通过Varian 400MHz波谱仪记录。质谱通过Waters-Micromass ZMD质谱仪获得。熔点通过Buchi-Tottoli仪器确定且未经校正。
实施例N-(4-氯苯基)-6-(异喹啉-5-基)吡啶-3-甲酰胺(V394)
步骤a)6-氯-N-(4-氯苯基)吡啶-3-甲酰胺
将商购可得的6-氯-烟酰氯(56.8mmol,10g)溶于50ml无水CH2Cl2中,并在0℃将其滴加到二异丙基胺(DIEA)(1.2当量,68.2mmol,11.67ml)和4-氯苯胺(1.2当量,68.2mmol,8.70g)的50ml CH2Cl2溶液中。在室温下将该混合液搅拌20小时,然后用CH2Cl2(200ml)稀释并用水(1x200ml)和盐水(1x100ml)洗涤。用硫酸钠干燥有机层并将其浓缩。使粗产物从乙醚中结晶,得到13g白色固体。收率=86%。1H NMR(CDCl3,200MHz)δ7.35(2H,d,J=8.8Hz),7.47(1H,d,J=8.2Hz),7.58(2H,d,J=8.8Hz),7.88(1H,bs),8.16(1H,dd,J=8.4Hz,J’=2.8Hz),8.84(1H,d,J=2.4Hz)。
步骤b)异喹啉-5-基-5-硼酸
将冷却至-78℃的n-BuLi(1.2当量,3mmol,1.2ml)在20ml新蒸馏THF中的2.5M的溶液加入到5-溴异喹啉(2.5mmol,520mg)的5ml THF溶液中。使得到的混合液在此温度下反应45分钟。然后加入硼酸三异丙酯(1.2当量,3mmol,0.7ml)的溶液并在相同温度下搅拌混合液5分钟,然后使其升至室温并再搅拌一个小时。通过缓慢加入5%NaOH溶液(30ml)淬灭混合液。分离水层并在0℃加入10%HCl将其酸化至pH值5/6。用乙酸乙酯萃取,蒸发有机相,并使其从乙醚中结晶,得到250mg白色固体。收率=58%。1H NMR(d6-DMSO,200MHz)δ7.66(1H,t,J=7.2Hz),8.07(1H,d,J=5.8Hz),8.13(1H,d,J=8.0Hz),8.34(1H,d),8.47(1H,d),8.50(2H,bs),9.29(1H,s);[M+1]174.1(C9H8BNO2计算值172.98)。
步骤c)N-(4-氯苯基)-6-(异喹啉-5-基)吡啶-3-甲酰胺(Suzuki反应)
将异喹啉-5-基-5-硼酸(1.5当量,8.4mmol,1.46g)、6-氯-N-(4-氯苯基)吡啶-3-甲酰胺(5.6mmol,1.5g)、醋酸钯(4%mol,48mg)、三苯基膦(2当量,2.94g)、15%Na2CO3(4ml)、EtOH(4ml)和甲苯(50ml)的混合液在80℃加热16小时。蒸发后,加入饱和的碳酸氢钠溶液并滤出沉淀的固体,然后用乙酸乙酯洗涤。使残余物从甲醇中重结晶,得到1.4g白色固体状的化合物V394。熔点(乙醚)=258℃。收率=69%。1H NMR(d6-DMSO,400MHz)δ7.471(2H,d,J=8.8Hz),7.838(1H,m),7.852(2H,d,J=8.8Hz),7.953(1H,d,J=8.0Hz),8.049(1H,dd,J=7.2Hz,J’=0.8Hz),8.085(1H,d,J=6.0Hz),8.290(1H,d,J=8.4Hz),8.490(1H,dd,J=8.4Hz,J’=2.2Hz),8.543(1H,d,J=6.0Hz),9.300(1H,d,J=1.6Hz),9.438(1H,s),10.695(1H,s);[M+1]360.4(C21H14ClN3O计算值359.81)。
生物学试验
使用新生和成年的Sprague-Dawley大鼠(~250g)(意大利,Harlam)。所有试验均遵循国家指南并经地区伦理委员会批准。
放射性配体结合试验
使用试验时重量在250至350g之间的雄性Sprague-Dawley大鼠。对于结合试验而言,断头处死麻醉的大鼠,取出脊髓,并将其在冰冷的包含5mM KCl、5.8mM NaCl、0.75mM CaCl2、2mM MgCl2、320mM蔗糖、10mM Hepes的缓冲液(pH 8.6)中用Polytron组织匀浆机进行破碎5。将匀浆过的组织在4℃以1000xg离心10分钟,将上清液在4℃以35000xg再离心30分钟(Beckman Avanti J25)。将沉淀物用上述同样的缓冲液重悬并用于结合试验中。在饱和实验中,将来自膜悬浮液的150μg蛋白质/样品与[3H]-仙人掌毒素([3H]-RTX)(0.003-3nM)在包含0.25mg/ml无脂肪酸牛血清白蛋白的试验缓冲液中在37℃孵育60分钟。在竞争试验中,将膜、[3H]RTX(0.4nM)和浓度增加(从0.1nM至3μM)的测试化合物在37℃孵育60分钟。
在1μM RTX的存在下评价非特异性结合。孵育后将反应混合液在0℃冷却,并与牛α1-酸糖蛋白(200μg每管)孵育15分钟以减少非特异性RTX结合。通过将样品在18500xg离心15分钟使膜结合的RTX与游离RTX分离。切下微量离心管带有沉淀的离心管的尖端部分,并通过闪烁计数(Packard 2500 TR)测量其放射性活度。依据Bio-Rad方法以牛血清白蛋白作为标准参照物测定蛋白质浓度(Bradford,1976)。用Ligand程序分析饱和与竞争试验6。
培养的大鼠背根神经节神经元中的Ca2+荧光测定
将成年大鼠末梢麻醉并断头处死。取出背根神经节并将其置于冷的磷酸盐缓冲液(PBS)中,然后转移至胶原酶(10mg/ml)、胰蛋白酶(5mg/ml)和DNAse(1mg/ml)中于37℃放置35分钟。通过用一系列注射器针头(由23G降至25G)吹打若干次,将放置在冷的DMEM(补充有10%胎牛血清、2mM L-谷氨酰胺、100U/ml青霉素和100μg/ml链霉素)中的神经节分离成单个细胞。过滤培养基和神经节以除去组织碎片,向其中注满8mlDMEM培养基并离心(200xg 5分钟)。将最终的细胞沉淀重悬于DMEM培养基(补充有100ng/ml小鼠神经生长因子(小鼠-NGF-7S)和胞嘧啶-β-d-阿糖胞苷游离碱(ARA-C)2.5μM)中。将细胞铺于涂覆聚L-赖氨酸(8.3μM)和层粘连蛋白(5μM)的25mm的盖玻片上,在37℃于充有5%CO2和空气的加湿培养箱中培养5-8天,然后加入在Ca2+缓冲液(具有以下成分(mM):CaCl2 1.4、KCl 5.4、MgSO4 0.4、NaCl 135、D-葡萄糖5、HEPES10含BSA(0.1%),pH 7.4)中的Fura-2-AM-ester(3μM),于37℃放置40分钟。然后用Ca2+缓冲液洗涤细胞两次并转移至Nikon Eclipse TE300倒置显微镜的台上的槽中。在340nM和380nM激发Fura-2-AM-ester,通过用动态图像分析系统(Laboratory Automation 2.0,RCS,意大利,佛罗伦萨)计录F340/F380比值以指示相对[Ca2+]i变化,在该实验开始前使细胞(至少10分钟)达到稳定的荧光。用含Fura-2-AM-ester和确定浓度的游离Ca2+的缓冲液制作标准曲线。然后用该曲线将由F340/F380比值得到的数据转化为[Ca2+]i(nM)8。研究用抗辣椒碱(CPZ)、SB366791和V394进行预处理对由0.1μM辣椒碱产生的[Ca2+]i增加的影响。
大鼠中由辣椒碱-诱导的继发的异常性疼痛
在乙醚麻醉的大鼠右爪光滑皮肤的跖面注射辣椒碱(20nmols/50μl/爪)(Chaplan等人,1994)。在注射辣椒碱前两小时口服施用化合物V394(30μmol/kg)。辣椒碱刺激90分钟后评价触觉异常性疼痛。
药物和试剂
药物和试剂从所标明的公司购得:[3H]-仙人掌毒素(Perkin Elmer,Boston,MA)、SB-366791(Tocris,UK)、辣椒碱、抗辣椒碱、离子霉素、层粘连蛋白、聚L-赖氨酸、P物质(Sigma,意大利);小鼠NGF-7S和胶原酶/分散酶(Roche Diagnostics,意大利);达尔伯克改良伊格尔培养基(DMEM)、热灭活的胎牛血清(FBS)、L-谷氨酰胺(200mM)、青霉素/链霉素(10,000IU/ml±10,000UG/ml)(Gibco,意大利);Fura-2-AM-ester(SocietàItaliana Chimici,意大利)。在50%DMSO和50%吐温80中配制辣椒碱(10mM)、抗辣椒碱(10mM)、(E)-3-(4-氯苯基)-N-(3-甲氧基苯基)丙烯酰胺(称为SB-366791)(1mM)和V394的储备液浓度。将Fura-2-AM-ester和离子霉素溶于100%的DMSO。将所有其它药物溶于蒸馏水。然后在Krebs缓冲液中配制到适合的稀释度。
结果
放射性配体结合试验
[3H]-RTX对大鼠脊髓表达的TRPV1的饱和曲线显示KD值为0.21(0.16-0.27)且Bmax值为57(53-62)fmol/mg蛋白质。斯卡查德图基本上呈线性且对数据进行的计算机分析表明只存在一类的高亲和性的结合位点。[3H]-RTX的竞争结合试验表明V394和对照SB-366791的Ki值分别为15(13-17)nM和36(30-43)nM。
Ca2+荧光
在绝大多数(95%)的背根神经节神经元中辣椒碱(0.1μM)均引起[Ca2+]增加,由此可确定这些背根神经节神经元为TRPV1表达神经元。抑制由辣椒碱诱导的[Ca2+]i活化的V394的IC50值为0.83nM(0.74-0.93)。抗辣椒碱和SB-366791(对照的TRPV1拮抗剂)抑制辣椒碱响应的IC50值分别为948(676-1330)nM和8.7(3.4-17.3)nM。该结果表示为平均值和95%的置信区间。
大鼠中由辣椒碱-诱导的继发的异常性疼痛
辣椒碱刺激90分钟后,化合物V394对辣椒碱的促异常性疼痛作用有显著的预防作用(55%)。
参考文献
1.Bakthavatchalam,R.;Blum,C.A.;Brielmann,H.;Darrow,J.W.;DeLombaert,S.;Yoon,T.;Zheug,X.Neurogen Corporation WO2004/056774,170pp。
2.Shieh,W.C.;Carlson,J.A.J.Org.Chem.1992,57,379-381。
3.Zhang,J.;Assodi,J.;Charter,C.;L′hermite,N.;Weston,J.Tetrahedron Lett.2001,42,6683-6686。
4.Meier,P.;Legraverant,S.;Mueller,S.;Schaub,J.Synthesis 2003,4,551-554。
5.a)Szallasi A.和Blunberg P.M.Neurosciences 1992,8,368。b)Szallasi A.和Blunberg P.M.Naunyn Schmiedeberg’s Arch Pharmacol.1993,347,84-91。
6.Munson,P.J.;Rodbard,D.Anal.Biochem.1980,107,220-239。
7.Rigoni,M.;Trevisani,M.;Gazzieri,D.;Nadaletto,R.;Tognetto,M.;Creminon,C.;Davis,J.B.;Campi,B.;Amatesi,S.;Geppetti,P.;Harrison,S.Br.J.Pharmacol.2003,138,977-985。
8.Kudo,Y.;Ozaki,K.;Miyakawa,A.;Amano,T.;Ogura,A.Jap.J.Pharmacol.1986,41,345-351。
Claims (8)
2.根据权利要求1的化合物,其中R选自甲基、异丙基、叔丁基或三氟甲基。
6.权利要求1至5中任意一项的化合物在制备用于治疗炎性疾病和泌尿障碍的药物中的用途。
7.根据权利要求6的用途,其中炎性疾病是神经性疼痛。
8.包含权利要求1至5中任意一项的化合物和可药用载体和/或赋形剂的药物组合物。
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