CN101490007B - 具有芷香酮亚结构的vr1香草素受体拮抗剂 - Google Patents

具有芷香酮亚结构的vr1香草素受体拮抗剂 Download PDF

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CN101490007B
CN101490007B CN2007800259461A CN200780025946A CN101490007B CN 101490007 B CN101490007 B CN 101490007B CN 2007800259461 A CN2007800259461 A CN 2007800259461A CN 200780025946 A CN200780025946 A CN 200780025946A CN 101490007 B CN101490007 B CN 101490007B
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thiazolinyl
acrylamide
isoquinoline
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P·G·巴拉尔迪
P·A·博雷亚
P·杰佩蒂
M·G·帕瓦尼
F·弗鲁塔罗罗
M·特雷维萨尼
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Abstract

本发明涉及式(I)化合物，其中Y、R、n和X如说明书所定义，它们的制备方法和包含它们的药物组合物。式(I)化合物抑制在炎症后痛觉过敏的发展中起关键作用的瞬时受体电位香草酸亚型1(TRPV1)，因而它们可用作止痛和抗炎的药物。

Description

具有芷香酮亚结构的VR1香草素受体拮抗剂
发明领域
本发明涉及香草素受体拮抗剂，特别是TRPV1拮抗剂。
发明背景
瞬时受体电位香草酸亚型1(TRPV1)在炎症后的痛觉过敏的发展中起关键作用；因而，TRPV1配体在临床上可用作镇痛和抗炎药。
从天然产物中得到的且被称为辣椒碱类和Resiniferonoids的化合物是已知的TRPV1配体。其中，Retvanil(维甲酸的香草酰胺)是一种有效的激动剂1
Figure G2007800259461D00011
Ber.der Deutschen Chem.Gesellschaft，70卷，1009-1012页中公开了下列化合物的合成：
但是没有提及它们的生物学性质。
WO 03/024920提到了维甲类在治疗关节炎和炎性皮肤病中的用途。
Chem.Pharm.Bull.43(1)100-107(1995)中公开了特别是下列化合物：
Figure G2007800259461D00021
其中R是H且R’是H或甲基，
以及它们的维甲酸活性(retinoidal activity)。
WO 03/049702、JOC 48卷，第1期，2005，71-90页和Neuropharmacology，46卷，第1期，2004，133-149页中公开了N-芳基肉桂酰胺，其包含一个可表示为如下的基团：
Figure G2007800259461D00022
其中A是被取代的芳基。这些化合物是香草素受体的拮抗剂并可用于治疗许多炎性病症。
发明描述
本发明涉及式(I)的TRPV1抑制剂
Figure G2007800259461D00023
其中：
Y是下式的基团：
Figure G2007800259461D00024
其中：
R’选自氢、卤素、羟基、(C1-C6)烷基、(C2-C6)链烯基、(C3-C6)炔基、(C1-C6)烷氧基、(C1-C6)烷基氨基、苯基、萘基、苯氧基、萘氧基或苯基氨基，其中的芳环任选地被一个或多个卤素、羟基、(C1-C4)烷基、(C1-C4)烷氧基和三氟甲基取代；
R是甲基或氢；
n是0或1；
X选自苯基、吡啶基、萘基、喹啉基和异喹啉基，其任选地被一个或多个选自卤素、羟基、(C1-C4)烷基、(C1-C4)烷氧基和三氟甲基的基团取代；其中不包括下列化合物：
依据第一个优选的实施方案，本发明涉及式(I)化合物，其中n是0且X是5-异喹啉基。其中，特别优选的是其中R是氢且Y是下式的基团的化合物：
Figure G2007800259461D00032
其中R’如上文所定义，更优选地是氢、甲氧基或如上文所示的任选地被取代的苯氧基。
式(I)化合物的实例如下：
(2E)-N-(4-氯苯基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-N-(4-氯苄基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-N-(异喹啉-5-基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-N-(4-氯苯基)-3-(2，6，6-三甲基环己-2-烯基)丙烯酰胺；
(2E)-3-(2，6，6-三甲基环己-1-烯基)-N-(萘-1-基)丙烯酰胺；
(2E)-N-(4-氯苯基)-3-(2，6，6-三甲基-3-苯氧基环己-1-烯基)丙烯酰胺；
(2E)-N-(3-甲氧基苯基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-N-(5-氯吡啶-2-基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-N-(4-氯苯基)-3-(2，6，6-三甲基环己-1，3-二烯基)丙烯酰胺；
(2E)-N-(4-(三氟甲基)苯基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-3-(2，6，6-三甲基环己-1-烯基)-N-(喹啉-3-基)丙烯酰胺；
(2E)-3-(2，6，6-三甲基环己-1-烯基)-N-(喹啉-5-基)丙烯酰胺；
(2E)-N-(异喹啉-5-基)-3-(3-甲氧基-2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-N-(异喹啉-5-基)-3-(2，6，6-三甲基-3-苯氧基环己-1-烯基)丙烯酰胺；
(2E)-N-(异喹啉-5-基)-3-(3-(3-甲氧基苯基)-2，6，6-三甲基环己-1-烯基)丙烯酰胺；
(2E)-3-(3-(4-氯苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺；
(2E)-3-(3-(4-氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺；
(2E)-3-(3-(3-氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺；
(2E)-3-(3-(3，4-二氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺。
式(I)化合物可用常规方法制备，例如通过式(II)化合物
Figure G2007800259461D00041
其中Y和R如上文所定义且使羧基适当地活化以进行酰胺化反应与商购可得的式(III)化合物的反应来制备
X(CH2)nNH2
(III)
其中X如上文所定义。
本发明将通过下列实施例和方案来阐明。
实施例
所有商购可得的化合物均购自Aldrich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F254 Merck板)监测，使用紫外灯检测斑点并用KMnO4水溶液显色。快速色谱使用Merck硅胶(230-240目)完成。1H-NMR谱以TMS为内标通过Varian 400MHz波谱仪记录。质谱通过Waters-Micromass ZMD波谱仪获得。熔点通过Buchi-Tottoli仪器确定且未经校正。
实施例1(2E)-N-(异喹啉-5-基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺Ia(方 案1)
通过文献2中所述的卤仿反应用商购可得的β-芷香酮制备酸1。将1.0mmol(194mg)的酸1溶于8ml的无水DMF中。将EDCI(1.2当量，1.2mmol，230mg)、HOBt(1.2当量，1.2mmol，162mg)和5-氨基异喹啉(1.2当量，1.2mmol，173mg)在0℃依次加入。在室温将反应混合液搅拌20小时。减压蒸发溶剂并将残余物溶于50ml乙酸乙酯中。用水(2×20ml)和饱和的氯化钠溶液(1×10ml)洗涤有机相，经硫酸钠干燥并在真空下浓缩。残余物粗品经柱色谱(硅胶，3/7乙酸乙酯/己烷随后用乙酸乙酯洗脱)纯化，最后从乙醚中重结晶得到150mg浅褐色固体。收率＝47％。Mp：(乙醚)131-133℃。1H NMR(CDCl3，400MHz)δ1.10(6H，s)，1.49(2H，m)，1.62(2H，m)，1.81(3H，s)，2.05(2H，m)，6.18(1H，d)，7.62(2H，m)，7.70(2H，m)，7.81(1H，d)，8.38(1H，bs)，8.53(1H，d，J＝5.6Hz)，9.25(1H，s)；[M+1]321.7(C21H24N2O计算值320.43)。
实施例2(2E)-N-(异喹啉-5-基)-3-(3-甲氧基-2，6，6-三甲基环己-1-烯基)丙烯 酰胺Ib(方案2)
制备例1
(2E)-3-(3-甲氧基-2，6，6-三甲基环己-1-烯基)丙烯酸甲酯3的合成3
将酯2(8mmol，1.66g)和N-溴代琥珀酰亚胺(1.1当量，8.8mmol，1.56g)在CCl4(30ml)中的悬浮液回流1小时。经硅藻土过滤后，蒸发溶剂。将残余物溶于MeOH(20ml)并使反应回流过夜。蒸发溶剂并将粗产物溶于乙醚(30ml)并用水(1×20ml)洗涤。使有机相经硫酸钠干燥并在真空下浓缩。经色谱柱(使用1/9乙酸乙酯/石油醚作为洗脱液)纯化残余物粗品得到715mg的无色油状物。收率＝37.5％(两步)。1H NMR(CDCl3，400MHz)δ1.02(3H，s)，1.04(3H，s)，1.38(2H，m)，1.62(2H，m)，1.79(3H，s)，3.37(3H，s)，3.51(1H，m)，3.75(3H，s)，5.84(1H，d，J＝16Hz)，7.33(1H，d，J＝16Hz)；[M+1]239.1(C14H22O3计算值238.32)。
(2E)-3-(3-甲氧基-2，6，6-三甲基环己-1-烯基)丙烯酸4的合成
在0℃将LiOH(5当量，630mg)加入酯3(3mmol，715mg)在3∶1∶1THF/MeOH/水(15ml)中的溶液中并在室温将该混合液搅拌过夜。减压除去溶剂并用水(20ml)稀释残余物。通过加入10％HCl使酸析出并用AcOEt(3×15ml)萃取。经Na2SO4干燥合并的有机相，并在真空下蒸发得到600mg的油状产物。收率＝89％。1H NMR(CDCl3，400MHz)δ1.03(3H，s)，1.05(3H，s)，1.39(2H，m)，1.62(2H，m)，1.80(3H，s)，3.38(3H，s)，3.52(1H，m)，5.86(1H，d，J＝16Hz)，7.45(1H，d，J＝16Hz)；[M+1]225.5(C13H20O3计算值224.3)。
制备例2
将1.0mmol(224mg)的酸4溶于10ml无水DMF。在0℃依次加入EDCI(1.2当量，1.2mmol，230mg)、HOBt(1.2当量，1.2mmol，162mg)和5-氨基异喹啉(1.2当量，1.2mmol，173mg)。在室温下将该反应混合液搅拌20小时。减压蒸发溶剂并将残余物溶于50ml乙酸乙酯。用水(3×20ml)和饱和的氯化钠溶液(1×10m1)洗涤有机相，经硫酸钠干燥并在真空下浓缩。经色谱柱(硅胶，乙酸乙酯)纯化残余物粗品，最后从乙醚中重结晶得到160mg的黄色无定形固体。收率＝45％。1H NMR(CDCl3，400MHz)δ1.07(6H，s)，1.42(2H，m)，1.66(2H，m)，1.86(3H，s)，3.40(3H，s)，3.48(1H，m)，6.18(1H，d)，7.51(1H，m)，7.65(3H，m)，7.84(1H，d)，8.38(1H，bs)，8.55(1H，d，J＝6Hz)，9.26(1H，s)；[M+1]351.2(C22H26N2O2计算值350.45)。
实施例3(2E)-N-(异喹啉-5-基)-3-(2，6，6-三甲基-3-苯氧基环己-1-烯基)丙烯 酰胺Ic(方案3)
制备例1
(2E)-3-(2，6，6-三甲基-3-苯氧基环己-1-烯基)丙烯酸甲酯5c 4的合成
将酯2(3.12mmol，650mg)和N-溴代琥珀酰亚胺(1.1当量，3.43mmol，611mg)在CCl4(15ml)中的悬浮液回流1小时。经硅藻土过滤后，蒸发溶剂。将残余物溶于MeOH(5ml)并将其滴加到苯酚钠(6.24mmol)的甲醇(10ml)溶液中。将得到的混合液在室温下搅拌过夜。将反应物倾至冷的5％氢氧化钠水溶液(15ml)中并用乙醚(2×20ml)萃取产物。用水(1×10ml)和盐水(1×5ml)洗涤有机层，经无水硫酸钠干燥并在真空下浓缩。经色谱柱(使用1/9乙酸乙酯/石油醚作为洗脱液)纯化粗产物得到350mg的无色油状物。收率＝37.5％(两步)。1H NMR(CDCl3，400MHz)δ1.07(3H，s)，1.12(3H，s)，1.42(2H，m)，1.78(2H，m)，1.86(3H，s)，3.78(3H，s)，4.57(1H，m)，5.92(1H，d，J＝16.4Hz)，6.95(3H，m)，7.29(2H，m)，7.44(1H，d，J＝16.4Hz)；[M+1]301.2(C19H24O3计算值300.39)。
(2E)-3-(2，6，6-三甲基-3-苯氧基环己-1-烯基)丙烯酸6c的合成
在0℃将LiOH(5当量，243mg)加入酯5(1.16mmol，350mg)在3∶1∶1THF/MeOH/水(12.5ml)中的溶液中并在室温下将该混合液搅拌过夜。减压蒸发溶剂并用水(20ml)稀释残余物。通过加入10％HCl使酸析出并用AcOEt(3×15ml)萃取。经Na2SO4干燥合并的有机层并在真空下蒸发得到300mg的白色固体。收率＝90％。1H NMR(CDCl3，400MHz)δ1.08(3H，s)，1.13(3H，s)，1.44(2H，m)，1.78(2H，m)，1.87(3H，s)，4.58(1H，m)，5.94(1H，d，J＝16.4Hz)，6.96(3H，m)，7.29(2H，m)，7.52(1H，d，J＝16.4Hz)；[M+1]287.5(C18H22O3计算值286.37)。
制备例2
将0.5mmol(143mg)的酸6c溶于5ml无水DMF。在0℃依次加入EDCI(1.2当量，0.6mmol，115.2mg)、HOBt(1.2当量，0.6mmol，81mg)和5-氨基异喹啉(1.2当量，0.6mmol，86.51mg)。在室温下将该反应混合液搅拌20小时。减压蒸发溶剂并将残余物溶于30ml乙酸乙酯。用水(2×10ml)和饱和氯化钠溶液(1×10ml)洗涤有机相，经硫酸钠干燥并在真空下浓缩。经柱色谱(硅胶，乙酸乙酯/石油醚8∶2)纯化固体粗品，最后从乙醚中重结晶得到100mg的白色固体。收率＝48.5％。Mp：(乙醚)141-143℃。1HNMR(CDCl3，400MHz)δ1.14(3H，s)，1.17(3H，s)，1.47(2H，m)，1.78(2H，m)，1.95(3H，s)，4.60(1H，m)，6.41(1H，d)，6.97(2H，d，J＝7.2Hz)，7.26(4H，m)，7.59(1H，d，J＝16Hz)，7.80(1H，t，J＝8Hz)，7.92(1H，d，J＝8Hz)，8.17(1H，m)，8.37(1H，m)，8.52(1H，bs)，9.26(1H，s)；[M+1]413.6(C27H28N2O2计算值412.52)。
实施例4(2E)-3-(3-(4-氯苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基) 丙烯酰胺Id(方案3)
依据制备例2从0.5mmol的酸6d起始得到了150mg白色固体状的化合物Id。收率＝67％。Mp：(乙醚)168℃。1H NMR(CDCl3，400MHz)δ1.11(3H，s)，1.14(3H，s)，1.45(2H，m)，1.66(2H，m)，1.86(3H，s)，4.76(1H，m)，6.61(1H，d)，7.06(2H，d，J＝8.8Hz)，7.31(2H，m)，7.34(2H，d，J＝8.8Hz)，7.69(1H，t，J＝8Hz)，7.95(1H，d，J＝8Hz)，8.04(1H，m)，8.27(1H，bs)，8.58(1H，d，J＝6Hz)，9.33(1H，s)；[M+1]448.4(C27H27ClN2O2计算值446.97)。
实施例5(2E)-3-(3-(4-氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基) 丙烯酰胺Ie(方案3)
依据制备例2从0.5mmol的酸6e起始得到了100mg白色固体状的化合物Ie。收率＝46％。Mp：(乙醚)135-137℃。1H NMR(CDCl3，400MHz)δ1.11(3H，s)，1.15(3H，s)，1.44(2H，m)，1.71(2H，m)，1.92(3H，s)，4.50(1H，m)，6.21(1H，d)，6.91(2H，m)，6.98(2H，m)，7.54(1H，d，J＝15.6Hz)，7.72(3H，m)，7.87(1H，d)，8.41(1H，bs)，8.55(1H，d，J＝6.4Hz)，9.28(1H，s)；[M+1]431.6(C27H27FN2O2计算值430.51)。
实施例6(2E)-3-(3-(3-氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基) 丙烯酰胺If(方案3)
依据制备例2从0.5mmol的酸6f起始得到了90mg白色固体状的化合物If。收率＝42％。Mp：(乙醚)147℃。1H NMR(CDCl3，200MHz)δ1.11(3H，s)，1.14(3H，s)，1.57(2H，m)，1.71(2H，m)，1.88(3H，s)，4.56(1H，m)，6.20(1H，d)，6.70(4H，m)，7.58(1H，d，J＝15.6Hz)，7.65(3H，m)，7.85(1H，d)，8.38(1H，bs)，8.59(1H，d，J＝5.8Hz)，9.29(1H，s)；[M+1]431.5(C27H27FN2O2计算值430.51)。
(2E)-3-(3-(3，4-二氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯 酰胺Ig(方案3)
依据制备例2从0.5mmol的酸6g起始得到了90mg白色固体状的化合物Ig。收率＝40％。Mp：(乙醚)155℃。1H NMR(CDCl3，200MHz)δ1.11(3H，s)，1.14(3H，s)，1.53(2H，m)，1.75(2H，m)，1.89(3H，s)，4.55(1H，m)，6.20(1H，d)，6.68(3H，m)，7.50(1H，d，J＝15.6Hz)，7.65(3H，m)，7.85(1H，d)，8.40(1H，bs)，8.60(1H，d，J＝5.8Hz)，9.29(1H，s)；[M+1]449.7(C27H26F2N2O2计算值448.51)。
方案1
Figure G2007800259461D00091
试剂：i)EDCI，HOBt，5-氨基异喹啉，DMF，室温
方案2
试剂：i)NBS/CCl4；ii)MeOH，回流；iii)LiOH，THF/MeOH/水，室温；iv)EDCI，HOBt，5-氨基异喹啉，DMF，室温
方案3
Figure G2007800259461D00102
试剂：i)NBS/CCl4；ii)R”PhONa，EtOH，室温；iii)LiOH，THF/MeOH/水，室温；iv)EDCI，HOBt，5-氨基异喹啉，DMF，室温
生物学试验
使用新生和成年的Sprague-Dawley大鼠(～250g)(意大利，Harlam)。所有试验都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
使用试验时体重在250-350g之间的雄性Sprague-Dawley大鼠。对于结合试验而言，将麻醉的大鼠断头处死，取出脊髓，并在含5mM KCl、5.8mM NaCl、0.75mM CaCl2、2mM MgCl2、320mM蔗糖、10mM Hepes的冰冷的缓冲液(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分钟并将上清液在4℃以35000xg再离心30分钟(Beckman Avanti J25)。将沉淀物在上述同样的缓冲液中重悬并用于结合试验中。在饱和试验中，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，将膜与[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的存在下确定非特异性结合。孵育后将反应混合液在0℃冷却并与牛α1-酸糖蛋白(200μg每管)共同孵育15分钟以减少非特异性RTX结合。通过将样品以18500xg离心15分钟使膜结合的RTX与游离RTX分离。切下微量离心管带沉淀的尖端部分并通过闪烁计数(Packard 2500TR)测定其放射性活度。依据Bio-Rad方法以牛血清白蛋白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。
培养的大鼠三叉神经节中的Ca2+荧光测定
将两日龄的新生大鼠末梢麻醉并断头处死。取出三叉神经节并迅速放入冷的磷酸盐缓冲溶液(PBS)中，然后转移至胶原酶/分散酶(以1mg/ml溶于无Ca2+-Mg2+的PBS)于37℃放置35分钟7。酶处理后用无Ca2+-Mg2+的PBS将所述神经节清洗三次，然后置于2ml冷的补充有10％胎牛血清(FBS，热灭活的)、2mM L-谷氨酰胺、100U/ml青霉素和100μg/ml链霉素的DMEM中。通过用一系列注射器针头(由23G降至25G)吹打若干次，将神经节分离成单个细胞。最后通过40μm滤器过滤培养基和神经节以滤去碎片，向其中注满8ml DMEM培养基并离心(200xg 5分钟)。将最终的细胞沉淀在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]中重悬。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至8天。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、HEPES 10和BSA(0.1％)，pH 7.4]中使铺好的神经细胞负载Fura-2-AM-ester(3μM)，于37℃放置40分钟。然后将铺好的神经细胞用Ca2+缓冲液洗涤两次并转移至Nikon Eclipse TE300倒置显微镜台上的槽中。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)记录F340/F380比值以指示相对[Ca2+]i变化，将铺好的神经细胞转移至槽中后，在该实验开始前使其达到(至少10分钟)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和式(I)化合物预处理对由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
在用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)。在辣椒碱注射前两小时经口施用化合物Id(10mg/kg)。辣椒碱刺激90分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)、SB-366791(1mM)和式(I)化合物的储备液浓度。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结合位点。[3H]-RTX的竞争结合试验表明化合物Ia、Ib、Ic、Id、Ie、If、Ig和对照化合物(E)-3-(4-氯苯基)-N-3-甲氧基苯基)丙烯酰胺(SB-366791)的Ki值分别为66(56-78)nM、26.2(21.1-32.6)nM、4.93(3.40-7.16)nM、27(23-32)nM、14.8(10.2-21.5)nM、8.14(6.87-9.65)nM、10.3(7.9-13.4)nM和36(30-43)nM。
Ca2+荧光
在大多数(95％)大鼠三叉神经元细胞中辣椒碱(0.1μM)均引起[Ca2+]增加，由此可确定这些三叉神经元为TRPV1表达神经元。抑制由辣椒碱诱导的[Ca2+]i活化的Ia、Ib、Ic、Id、Ie、If和Ig的IC50值分别为44(11-184)nM、28.4(25.2-31.9)nM、2.12(1.44-2.82)nM、18.2(4-98)nM、5.25(4.11-6.70)nM、0.38(0.36-0.40)和0.65(0.62-0.68)nM。抗辣椒碱和SB-366791(对照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。结果表示为平均值和95％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Id显示了对辣椒碱的促异常性疼痛作用有显著的预防作用。
参考文献
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Claims (6)

1.式(I)化合物：
Figure FSB00000382381900011
其中：
Y是下式的基团
Figure FSB00000382381900012
其中：
R’选自氢、C1-C6烷氧基或苯氧基，其中的芳环任选地被一个或多个卤素取代；
R是氢；
n是0；
X选自异喹啉基。
2.根据权利要求1的化合物，其中X是5-异喹啉基。
3.根据权利要求2的化合物，其中R’选自氢、甲氧基或如权利要求1所述任选地被取代的苯氧基。
4.化合物，其选自：
(2E)-N-(异喹啉-5-基)-3-(2，6，6-三甲基环己-1-烯基)丙烯酰胺、
(2E)-N-(异喹啉-5-基)-3-(3-甲氧基-2，6，6-三甲基环己-1-烯基)丙烯酰胺、
(2E)-N-(异喹啉-5-基)-3-(2，6，6-三甲基-3-苯氧基环己-1-烯基)丙烯酰胺、
(2E)-3-(3-(4-氯苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺、
(2E)-3-(3-(4-氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺、
(2E)-3-(3-(3-氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺、
(2E)-3-(3-(3，4-二氟苯氧基)-2，6，6-三甲基环己-1-烯基)-N-(异喹啉-5-基)丙烯酰胺。
5.包含根据权利要求1至4中任意一项的化合物和一种或多种载体和/或赋形剂的药物组合物。
6.权利要求1至4中任意一项的化合物在制备止痛和/或抗炎的药物中的用途。
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