CN1692100A - 4-[哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺衍生物及其在治疗疼痛、脊椎损伤或胃肠疾病方面的应用 - Google Patents
4-[哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺衍生物及其在治疗疼痛、脊椎损伤或胃肠疾病方面的应用 Download PDFInfo
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- CN1692100A CN1692100A CNA028195825A CN02819582A CN1692100A CN 1692100 A CN1692100 A CN 1692100A CN A028195825 A CNA028195825 A CN A028195825A CN 02819582 A CN02819582 A CN 02819582A CN 1692100 A CN1692100 A CN 1692100A
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- methyl
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- benzamide
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Abstract
本申请公开并要求保护通式(I)化合物及其可药用盐和含有该新化合物的药物组合物,以及它们在治疗、特别是治疗疼痛中的应用。在式(I)中,R1是选自苯基、吡啶基、噻吩基、呋喃基、咪唑基、吡咯基和***基的任何基因,其中各R1苯基环和R1杂芳香环可以任选地和独立地被选自直链和直链的C1-C6烷基、NO2、CF3、C1-C6烷氧基、氯、氟、溴和碘的1、2或3个取代基进一步取代。在苯基环上和杂芳香环上的取代可以在该系的任何位置发生。
Description
技术领域
本发明涉及新的化合物,其制备方法,应用和含有该新化合物的药物组合物。该新化合物可用于治疗,特别是用于治疗疼痛。
背景技术
δ受体已被确认在多种身体功能(例如循环***和疼痛***)中起作用。因此,δ受体的配体可能会有作为止痛药和/或抗高血压药的潜在用途。δ受体的配体还已显示出具有免疫调制活性。
现已确认了至少三种不同的阿片样物质受体群体(μ、δ和κ),所有这三种群体在很多物种(包括人)的中枢及外周神经***中都明显存在。在许多动物模型中当这些受体中的一种或几种被激活时都观察到痛觉缺失。
除了少数例外,目前可用的选择性阿片样δ配体本质上都是肽类,不适合通过全身途径给药。非肽型δ-激动剂的一个实例是SNC 80(BilskyE.J.et al.,Journal of pharmacology and ExperimentalTherapeutics,273(1),pp.359-366(1995))。然而,仍然需要不仅选择性提高、而且副作用改进的选择性δ-激动剂。
因此,构成本发明的基础的问题是找到新的止痛药,与目前的μ激动剂相比,它们的止痛作用提高,副作用改善,并且具有改进的全身给药效力。
已被确认并在先有技术中出现的止痛药有很多缺点:它们的药物动力学差,并且在以全身途径给药时不止痛。另外,已有报道说,先有技术中描述的优选的δ激动剂化合物在以全身途径给药时显示出显著的致惊厥作用。
我们现在发现,包括在WO 98/28275范围内但并非其专门公开的某些化合物,具有令人吃惊的改进的δ-激动剂性质和活体内效力。
发明内容
本发明的新化合物由式I定义
其中
R1是选自下列基团中的任何一个:
(ii)吡啶基
(iii)噻吩基
(iv)呋喃基
(v)咪唑基
(vi)***基
(viii)噻唑基
各R1苯基环和R1杂芳香环可以任选地和独立地再被独立地选自直链和支链C1-C6烷基、NO2、CF3、C1-C6烷氧基、氮、氟、溴和碘的1、2或3个取代基取代。在苯基环和杂芳香环上的取代可以在该环系的任何位置上发生。
特别是,本发明的新化合物由式I定义,其中R1是选自下述任何基团:
(i)苯基
(ii)吡啶基
(iii)噻吩基
和
式I化合物的盐和对映异构体也在本发明的范围内。
若是苯基环和杂芳香环是被取代的,优选的取代基独立地选自CF3、甲基、碘、溴、氟和氯中的任何一种。
本发明的新化合物可用于治疗,尤其是用于治疗各种疼痛症状,例如慢性疼痛、神经痛、急性疼痛、癌症疼痛、类风湿性关节炎引起的疼痛、偏头痛、内脏痛等。然而此名单不应被认为是详尽无遗的。
本发明化合物可作为免疫调制剂使用,尤其是用于自身免疫病,例如关节炎,用于皮肤移植、器官移植和类似的手术需要,用于胶原病、各种过敏病,用于作为抗肿瘤药和抗病毒药。
本发明化合物可用于其中存在或涉及到阿片样物质受体的变性或机能失调的疾病状态。这可能涉及本发明化合物的同位素标记的变体在诊断技术中的应用以及成像用途,例如用于正电子发射断层扫描术(PET)。
本发明化合物可用于治疗腹泻、抑郁、焦虑、尿失禁、各种精神病、咳嗽、肺水肿、各种胃肠障碍、脊椎损伤和药物瘾,包括治疗滥用酒精、尼古丁、阿片和其它药物,以及交感神经***障碍,例如高血压。
本发明化合物可作为止痛药使用,用于全身麻醉和受监的麻醉护理。常常使用具有不同性质的药物的组合来实现为保持麻醉状态所需的各种作用(例如忘记缺失、痛觉缺失、肌肉松弛和镇静)的平衡。在这种组合里包含着吸入型***、催眠药、抗焦虑药、神经肌肉阻断剂和阿片类物质。
任何以上式I化合物在制造用于治疗上述任何病症的药物中的应用也属于本发明的范围。
本发明的另一方面是一种治疗患有上述任何病症的治疗对象的方法,根据该方法,向需要这种治疗的患者施用有效数量的以上式I化合物。
本发明的又一方面是通式II的中间体
其中PG是氨基甲酸酯保护基团,例如丁氧羰基或苄氧羰基,或是苄基或取代苄基保护基,例如2,4-二甲氧基苄基。
制备方法
实施例
现在按照以下实验方案和实施例更详细地描述本发明,它们不应看作是对本发明的限制。
方案1:本发明化合物的合成路线
N,N-二乙基-4-[N-丁氧羰基哌啶-4-亚基(3-羧苯基)甲基]苯甲酰胺(2a)
将4-[溴-(4-二乙基氨基甲酰苯基)亚甲基]哌啶-1-羧酸甲丁酯(1a,451mg,1.0mmol)、3-羧苯基硼酸(330mg,2.0mmol)、2M Na2CO3(3mL)和四(三苯膦)合钯(0)25mg在甲苯(脱气,10mL)和乙醇(脱气,10mL)中的混合物在90℃于N2气下回流4小时。然后该反应混合物在冷至0℃后用NH4Cl水溶液猝灭反应,用乙酸乙酯(2×50mL)萃取。合并的有机相用盐水洗,用MgSO4干燥,蒸发后得到粗产物,将其用快速硅胶柱纯化,得到所要化合物2a(345mg,70%):1H NMR(CDCl3)δ1.15(3H,br m,CH3CH2-),1.23(3H,br m,CH3CH2-),1.47(9H,s,C(CH3)3),2.31(2H,m,哌啶C
H-),2.35(2H,m,哌啶C
H-),3.30(2H,br m,CH3CH2N-),3.48(4H,m,哌啶C
H-),3.54(2H,br m,CH3CH2N-),7.14(2H,d,J=8.0Hz,Ar
H),7.24(1H,m,Ar
H),7.33(2H,d,J=8.0Hz,Ar
H),7.42(1H,t,J=7.6Hz,Ar
H),7.86(1H,s,Ar
H),7.97(1H,d,J=7.6Hz,Ar
H).IR(NaCl)2976,1718,1691,1598,1430,1233,1166cm-1.
N,N-二乙基-4-[1-苄基哌啶-4-亚基-(3-羧苯基)甲基]苯甲酰胺(2b)
按照对于2a的方法,使用1b(441mg,1.0mmol)和3-羧苯基硼酸(330mg,2.0mmol)得到2b(325mg,67%):1H NMR(CDCl3)δ1.11(3H,br m,CH3CH2-),1.22(3H,br m,CH3CH2-),2.63(4H,m,哌啶C
H-),2.90(4H,m,哌啶C
H-),3.26(2H,br m,CH3CH2N-),3.52(2H,br m,CH3CH2N-),4.00(2H,s,CH2N-),7.11(2H,d,J=8.0Hz,Ar
H),7.16(1H,m,ArH),7.30(6H,m,Ar
H),7.42(2H,m,Ar
H),7.84(1H,s,Ar
H),7.96(1H,d,J=7.6Hz,Ar
H).
N,N-二乙基-4-[1-苄基哌啶-4-亚基(3-氨基甲酰苯基)甲基]苯甲酰胺(3b)
将241mg(0.5mmol)N,N-二乙基-4-[哌啶-4-亚基(3-羧苯基)甲基]苯甲酰胺(2b)、780mg(1.5mmol)PyBOP和200mg(1.5mmol)HoBt溶于4mL DMF中。依次加入0.58mL(4mmol)DIPEA和50mg(10.0mmol)NH4Cl。室温下搅拌0.5小时后,反应混合物用水和***猝停反应。收集白色沉淀物为所要的产物(3b,152mg,63%):1H NMR(CDCl3)δ1.10(3H,br m,CH3CH2-),1.21(3H,br m,CH3CH2-),2.62(4H,m,哌啶C
H-),2.89(4H,m,哌啶C
H-),3.26(2H,br m,CH3CH2N-),3.52(2H,br m,CH3CH2N-),4.00(2H,s,CH2N-),7.11(2H,d,J=8.0Hz,Ar
H),7.16(1H,m,ArH),7.30(6H,m,Ar
H),7.42(2H,m,Ar
H),7.84(1H,s,Ar
H),7.96(1H,d,J=7.6Hz,Ar
H);元素分析理论值C31H35N3O2 6.0HCl:C,53.16%;H,5.90%;计算值:C,53.07%;H,5.54%。
N,N-二乙基-4-[哌啶-4-亚基(3-氨基甲酰苯基)甲基]苯甲酰胺(4)
按照对于3b的方法,使用2a(150mg,0.30mmol)得到3a(105mg,70%):1H NMR(CDCl3)δ1.14(3H,br m,CH3CH2-),1.22(3H,br m,CH3CH2-),1.46(9H,s,C(CH3)3),2.28(2H,m,哌啶C
H-),2.33(2H,m,哌啶C
H-),3.30(2H,br m,CH3CH2N-),3.46(4H,m,哌啶C
H-),3.55(2H,br m,CH3CH2N-),7.13(2H,d,J=8.0Hz,Ar
H),7.30(3H,m,Ar
H),7.39(1H,t,J=7.6Hz,Ar
H),7.61(1H,s,Ar
H),7.68(1H,d,J=7.6Hz,Ar
H).
上述产物(3a)在室温下用4.0M HCl/二噁烷(10mL)处理4小时。蒸发后将残余物溶在水(10mL)中,用乙酸乙酯(2×20mL)萃取杂质。水相用NH4OH碱化,用乙酸乙酯(3×20mL)萃取。合并的有机相用盐水洗,用MgSO4干燥后蒸发,以定量产率得到4:1H NMR(CDCl3)δ1.15(3H,br m,CH3CH2-),1.23(3H,br m,CH3CH2-),1.90(2H,br,NH2),2.31(2H,m,哌啶C
H-),2.34(2H,m,哌啶C
H-),2.92(4H,m,哌啶C
H-),3.32(2H,br m,CH3CH2N-),3.55(2H,br m,CH3CH2N-),7.13(2H,d,J=8.0Hz,Ar
H),7.30(3H,m,Ar
H),7.38(1H,t,J=7.6Hz,Ar
H),7.58(1H,s,Ar
H),7.66(1H,d,J=7.6Hz,Ar
H).IR(NaCl)3307,2973,1668,1615,1435,1383,1289cm-1;元素分析理论值C24H29N3O2 2.8HCl:C,58.40%;H,6.49%;实验值:C,58.46%;H,6.57%。
N,N-二乙基-4-[1-(2-噻吩)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5a)
向N,N-二乙基-4-[哌啶-4-亚基(3-氨基甲酰苯基)甲基]苯甲酰胺(4,196mg,0.5mmol)、2-噻吩甲醛(112mg,1.0mmol)、乙酸(0.1mL)在MeOH(10mL)中的混合物中分批加入NaBH3(CN)(200mg)。将反应混合物在室温下搅拌4小时,然后用NH4Cl水溶液猝灭反应,用CH2Cl2(3×50mL)萃取。合并的有机相用盐水洗,用MgSO4干燥,蒸发,得到粗产物,将其用快速硅胶柱纯化,得到所要的产物(5a,216mg,89%)。1H NMR(CDCl3)δ1.13(3H,br m,CH3CH2-),1.22(3H,br m,CH3CH2-),2.36(2H,m,哌啶C
H-),2.42(2H,m,哌啶C
H-),2.54(4H,m,哌啶C
H-),3.26(2H,br m,CH3CH2N-),3.52(2H,br m,CH3CH2N-),3.76(2H,s,CH2N-),5.60(1H,br,NH),6.06(1H,br,NH),6.91(1H,s,ArH),6.94(1H,m,ArH),7.12(2H,d,J=8.0Hz,Ar
H),7.26(1H,m,ArH),7.30(3H,m,Ar
H),7.37(1H,t,J=7.6Hz,Ar
H),7.56(1H,s,Ar
H),7.64(1H,d,J=7.6Hz,Ar
H).IR(NaCl)3352,2973,1668,1614,1434,1290cm-1;元素分析理论值C29H33N3O2S 2.3HCl:C,60.95%;H,6.23%;实验值:C,60.96%;H,6.42%。
N,N-二乙基-4-[1-(2-呋喃基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5b)
按照用于5a的方法,使用4(196mg,0.5mmol)和2-呋喃甲醛(96mg,1.0mmol)得到5b(158mg,67%):1H NMR(CDCl3)δ1.12(3H,br m,CH3CH2-),1.22(3H,br m,CH3CH2-),2.41(4H,m,哌啶C
H-),2.83(4H,m,哌啶C
H-),3.27(2H,br m,CH3CH2N-),3.52(2H,br m,CH3CH2N-),3.88(2H,s,CH2N-),6.18(1H,br,NH),6.35(1H,m,ArH),6.42(1H,m,ArH),6.86(1H,m,NH),7.12(2H,d,J=8.0Hz,Ar
H),7.27(3H,m,ArH),7.32(1H,m,Ar
H),7.41(1H,s,Ar
H),7.61(1H,s,Ar
H),7.69(1H,d,J=7.6Hz,Ar
H);元素分析理论值C29H33N3O3 3.0HCl:C,59.95%;H,6.25%;实验值:C,59.68%;H,5.98%。
N,N-二乙基-4-[1-(3-呋喃基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5c)
按照用于5a的方法,使用4(196mg,0.5mmol)和3-呋喃甲醛(96mg,1.0mmol)得到5c(143mg,61%):1H NMR(CDCl3)δ1.13(3H,br m,CH3CH2-),1.25(3H,br m,CH3CH2-),2.42(4H,m,哌啶C
H-),2.70(4H,m,哌啶C
H-),3.26(2H,br m,CH3CH2N-),3.52(2H,br m,CH3CH2N-),3.62(2H,s,CH2N-),5.80(1H,br,NH),6.42(1H,br,NH),6.46(1H,s,ArH),7.12(2H,d,J=8.0Hz,Ar
H),7.28(3H,m,Ar
H),7.36(1H,t,J=7.6Hz,Ar
H),7.42(2H,m,ArH),7.59(1H,s,Ar
H),7.66(1H,d,J=7.6Hz,Ar
H);元素分析理论值C29H33N3O3 3.1HCl:C,59.58%;H,6.22%;实验值:C,59.44%;H,6.45%.
N,N-二乙基-4-[1-(2-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5d)
按照用于5a的方法,使用4(196mg,0.5mmol)和2-吡啶甲醛(107mg,1.0mmol)得到5d(35mg,15%):1H NMR(CDCl3)δ1.13(3H,br m,CH3CH2-),1.24(3H,br m,CH3CH2-),2.38(2H,m,哌啶C
H-),2.42(2H,m,哌啶C
H-),2.56(4H,m,哌啶C
H-),3.26(2H,brm,CH3CH2N-),3.54(2H,br m,CH3CH2N-),3.68(2H,s,CH2N-),5.64(1H,br,NH),6.12(1H,br,NH),7.14(3H,m,Ar
H),7.31(3H,m,ArH),7.35(1H,m,Ar
H),7.38(1H,m,Ar
H),7.56(1H,s,Ar
H),7.65(2H,m,Ar
H),8.58(1H,m,ArH).
N,N-二乙基-4-[1-(3-噻吩)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5e)
按照用于5a的方法,使用4(196mg,0.5mmol)和3-噻吩甲醛(112mg,1.0mmol)得到5e(185mg,76%):1H NMR(CDCl3)δ1.13(3H,br m,CH3CH2-),1.24(3H,br m,CH3CH2-),2.46(4H,m,哌啶C
H-),2.84(4H,m,哌啶C
H-),3.26(2H,br m,CH3CH2N-),3.52(2H,br m,CH3CH2N-),3.91(2H,s,CH2N-),5.72(1H,br,NH),6.44(1H,br,NH),7.13(3H,m,Ar
H),7.26(3H,m,ArH),7.36(3H,m,Ar
H),7.61(1H,s,Ar
H),7.68(1H,d,J=7.6Hz,Ar
H);元素分析理论值C29H33N3O2S 2.5HCl:C,60.18%;H,6.18%;实验值:C,60.16%;H,6.49%。
N,N-二乙基-4-[1-(2-噻唑)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5f):
向N,N-二乙基-4-[哌啶-4-亚基(3-氨基甲酰苯基)甲基]苯甲酰胺(4,300mg,0.8mmol)在1,2-二氯乙烷(15mL)中的溶液加入2-噻唑甲醛(94μL,1.1mmol)和三乙酰氧基硼氢化钠(228mg,1.1mmol)。室温下搅拌反应混合物20小时,然后用NaHCO3水溶液猝灭反应。水相用CH2Cl2(2×20mL)萃取,合并的有机相用MgSO4干燥,过滤和蒸发。粗产物用快速色谱法纯化,得到产物(5f),为黄色泡沫体(234mg,63%产率)。
将该产物溶于二氯甲烷(5mL),加入HCl的***溶液(1N,1.4mL,3eq.)。30分钟后将悬浮液浓缩并将固体干燥。
1H NMR(CDCl3)δ1.10(3H,t,J=7Hz,CH3);1.21(3H,t,J=7Hz,CH3);2.64(4H,br s,CH2);3.27-3.31(4H,m,CH2);3.48-3.53(2H,m,CH2);3.67(2H,br s,CH2);4.77(2H,s,NCH2Ar);7.27(2H,d,J=8.5Hz,Ar-H);7.33-7.37(3H,m,Ar-H);7.44(1H,t,J=7.5Hz,Ar-H);7.68-7.69(1H,m,Ar-H);7.75-7.78(2H,m,Ar-H);7.94(1H,d,J=3.5Hz,Ar-H).元素分析理论值C28H32N4O2S×2.5HCl:C,58.00%;H,6.00%;N,9.66%;实验值:C,58.00%;H,5.95%;N,9.43%.
N,N-二乙基-4-[1-(3-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5g)。
按照用于5f的方法,使用4(176mg,0.45mmol)和3-吡啶甲醛(60μL,0.6mmol)得到5g(91.5mg,42%):1H NMR(CDCl3)δ1.09(3H,t,J=7Hz,CH3);1.21(3H,t,J=7Hz,CH3);2.68-2.75(4H,m,CH2);3.26-3.28(4H,m,CH2);3.43-3.60(4H,m,CH2);4.65(2H,s,NCH2Ar);7.27(2H,d,J=8.5Hz,Ar-H);7.32-7.36(3H,m,Ar-H);7.43(1H,t,J=8Hz,Ar-H);7.70-7.71(1H,m,Ar-H);7.75-7.78(1H,m,Ar-H);8.19(1H,dd,J=6,8Hz,Ar-H);8.88(1H,d,J=8Hz,Ar-H);8.98(1H,d,J=6Hz,Ar-H);9.21(1H,s,Ar-
H);元素分析理论值C30H34N4O2×3.1HCl×0.4H2O:C,59.77%;H,6.34%;N,9.29%;实验值:C,59.70%;H,6.36%;N,9.17%.
N,N-二乙基-4-[1-(2-吡咯)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5h)
按照用于5f的方法,使用4(261mg,0.7mmol)和2-吡咯甲醛(89mg,0.9mmol)得到5h(118.5mg,38%):1H NMR(CDCl3)δ1.09(3H,t,J=7Hz,CH3);1.21(3H,t,J=7Hz,CH3);2.46-2.53(2H,m,CH2);2.65-2.77(2H,m,CH2);2.97-3.04(2H,m,CH2);3.26-3.30(2H,m,CH2);3.46-3.52(4H,m,CH2);4.30(2H,s,NCH2Ar);6.33-6.34(1H,m,Ar-H);6.85-6.86(1H,m,Ar-H);7.24-7.26(2H,m,Ar-H);7.30-7.36(4H,m,Ar-H);7.40-7.45(1H,m,Ar-H);7.67-7.68(1H,m,Ar-H);7.75-7.77(1H,m,Ar-H).元素分析理论值C29H34N4O2×1.1HCl×1.8H2O:C,64.13%;H,7.18%;N,10.32%;实验值:C,64.26%;H,7.15%;N,9.94%.
N,N-二乙基-4-[1-(4-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5i)
按照用于5f的方法,使用4(329mg,0.8mmol)和4-吡啶甲醛(112μL,1.2mmol)得到5i(217mg,54%):1H NMR(CDCl3)δ1.12(3H,t,J=7Hz,CH3);1.24(3H,t,J=7Hz,CH3);2.67-2.82(4H,m,CH2);3.22-3.34(4H,m,CH2);3.49-3.65(4H,m,CH2);4.72(2H,s,NCH2Ar);7.29(2H,d,J=8.5Hz,Ar-H);7.33-7.40(3H,m,Ar-H);7.46(1H,t,J=8Hz,Ar-H);7.72-7.73(1H,m,Ar-H),7.78-7.80(1H,m,Ar-H),8.37(2H,d,J=7Hz,Ar-H);9.00(2H,d,J=7Hz,Ar-H).
N,N-二乙基-4-[1-(4-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺(5j)
按照用于5f的方法,使用4(313mg,0.8mmol)和4-咪唑甲醛(108mg,1.1mmol)得到5j(68.2mg,18%):1H NMR(CDCl3)δ1.12(3H,t,J=7Hz,CH3);1.23(3H,t,J=7Hz,CH3);2.63(2H,t,J=6Hz,CH2);2.68(2H,t,J=6Hz,CH2);3.26-3.36(6H,m,CH2);3.54(2H,q,J=7Hz,CH2);4.45(2H,s,NCH2Ar);7.28(2H,d,J=8Hz,Ar-H);7.32-7.40(3H,m,Ar-H);7.45(1H,t,J=8Hz,Ar-H);7.66(1H,s,Ar-H);7.71(1H,t,J=2Hz,Ar-H);7.76-7.82(1H,m,Ar-H);8.61(1H,s,Ar-H).
药物组合物
本发明的新化合物可以口服、肌内、皮下、局部、鼻内、腹腔内、胸内、静脉内、硬膜外、鞘内、脑室内给药,以及注射到关节内给药。
一种优选的给药途径是口服、静脉内或肌内给药。
剂量将取决于给药途径、疾病的严重程度、患者的年龄和体重,以及责任医师在对具体的患者确定最合适的个别治疗方案和剂量水平时通常要考虑的其它因素。
为了由本发明化合物制备药物组合物,可药用的惰性载体可以是固体或液体。固体形式的制剂包括粉剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。
固体载体可以是一种或多种物质,它们也可以起稀释剂、矫味剂、增溶剂、润滑剂、悬浮剂、粘合剂或片剂崩解剂的作用;它还可以是一种包封材料。
在粉剂中,载体是与细分的活性组分混合的细分固体。在片剂中,活性组分与具有必要的粘合性的载体以适当的比例混合并压成所要的形状和尺寸。
为制备栓剂组合物,先将低熔点蜡例如脂肪酸甘油酯和可可脂的混合物熔化,将活性成分通过例如搅拌分散于其中。然后将这种熔化的均匀混合物倒入合适尺寸的模具中并令其冷却和固化。
合适的载体是碳酸镁、硬脂酸镁、滑石、乳糖、糖、果胶、糊精、淀粉、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。
盐则包括但不限于可药用的盐。本发明范围内的可药用的盐的实例包括:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、乙酸钙、樟脑磺酸盐、碳酸盐、氯化物、檬檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、羟基乙酰氨苯胂酸盐、己基间苯二酚盐、哈胺(Hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、羟乙磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、双羟萘酸盐(恩波酸盐)、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、单宁酸盐、酒石酸盐、茶氯酸盐。属于本发明范围内的不可药用的盐的实例包括:氢碘酸盐、高氯酸盐和四氟硼酸盐。
优选的可药用盐是盐酸盐、硫酸盐和酒石酸氢盐。
特别优选的是盐酸盐和硫酸盐。
组合物一词打算包括活性组分与作为载体的包封材料形成的制剂,这样得到一种胶囊,其中该活性组分(含或不含基它载体)被一种与其结合的载体所包围。类似地,扁囊剂也包括在内。片剂、粉剂、扁囊剂和胶囊剂可以作为适合口服的固体剂型使用。
液体形式组合物包括溶液剂、混悬剂和乳剂。活性化合物在无菌水或水/丙二醇中的溶液可以作为适合肠道外给药的液体制剂的实例。液体组合物也可以配制在聚乙二醇水溶液中。
口服用的水溶液可以通过将活性组分溶于水中并根据需要加入合适的着色剂、矫味剂、稳定剂及增稠剂来制备。用于口服的含水混悬剂的制备可以是将细分的活性组分与一种粘性物质例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠及药物配制领域已知的其它悬浮剂一起分散在水中。
药物组合物优选是单位剂型。这种形式的组合物被分成包含适量活性组分的单位剂量。这类单位剂型可以是包装好的制剂,包装内含有分立数量的制剂,例如,被包起来的片剂、胶囊剂和在小瓶或安瓿内的粉剂、单位剂型也可以是胶囊、扁胶囊或药片本身,或者可以是适当数量的任何这些包装形式。
生物学评价
体外模型
细胞培养
A.表达克隆的人类μ、δ和κ受体和新霉素抗性的人293S细胞在37℃和5%CO2下于摇荡器烧瓶内的悬浮液中生成,烧瓶内含有无钙DMEM,10%FBS,5%BCS,0.1%Pluronic F-68和600μg/mL遗传霉素。
B.将小鼠和大鼠的脑称重并在冰冷的PBS(含2.5mM EDTA,pH7.4)中冲洗。将脑在冰冷的裂解缓冲液(50mM Tris,pH7.0,2.5mM EDTA,使用前由在DMSO:乙醇的0.5M储备液中加入苯基甲基磺酰氟至0.5mM)中用Polytron均化15秒(小鼠)或30秒(大鼠)。
膜制备
将细胞成粒状沉淀并重新悬浮在裂解缓冲液(50mM Tris,pH7.0,2.5mM EDTA,使用前由0.1M的乙醇储备溶液中加入PMSF至0.1mM)中,在冰上培养15分,然后用Polytron均化30秒。将悬浮液在4℃下于1000g(最高)离心10分钟。将上清液保存在冰上,沉淀象以前一样重新悬浮和离心。将两次离心的清液合并,在46000g(最高)下离心30分。沉淀物再悬浮于冷的Tris缓冲液(50mM Tris/Cl,pH7.0)中,再次离心。将最终的沉淀物重新悬浮于膜缓冲液(50mM Tris,0.32M蔗糖,pH7.0)中。将一份(1mL)液体在聚丙烯管中于干冰/乙醇中冷冻并在-70℃下贮存直至使用。使用改良的Lowry法用十二烷基硫酸钠确定蛋白质浓度。
结合试验
将膜37℃解冻,在冰上冷却,通过25号针3次,稀释到结合缓冲液(50mM Tris,3mM MgCl2,1mg/mL BSA(Sigma A-7888),pH7.4,经0.22m滤膜过滤后在4℃储存,其中刚加入5μg/mL抑蛋白酶肽、10μM苯丁抑制素、10μM diprotin A,无DTT)中。将每份100μL的溶液加到冰冷的12×75mm的聚丙烯管中,管中装有μL合适的放射性配体和100μL各种浓度的试验化合物。在10μM纳洛酮存在或不存在的情况下分别测定总结合(TB)和非特异性结合(NS)。将试管滑动并在25℃下培养60-75分,随后将内容物快速真空过滤,并用约12mL/每管的冰冷洗涤缓冲液(50mM Tris,pH7.0,3mM MgCl2)经过GF/B滤膜(Whatman)洗,该滤膜预先在0.1%聚乙烯亚胺中浸泡至少2小时。将滤膜在含6-7mL闪烁液的微形瓶中浸泡至少12小时后,用β计数器测定滤膜上保留的放射性(dpm)。如果此试验是在96深孔板中进行,则在96孔位预浸PEI的单板过滤器上过滤,用3×1mL洗涤缓冲液洗,在烘箱中于55℃干燥2小时。加入每孔50μL的MS-20闪烁液后,在TopCount(Packard)上对滤板计数。
功能试验
通过确定化合物受体复合物激活GTP与受体所偶合的G-蛋白的结合的程度,测定化合物的激动剂活性。在GTP结合试验中,GTP[γ]35S与试验化合物和膜结合,该膜是得自表达克隆的人阿片样物质受体的HEK-293S细胞,或得自均化的大鼠或小鼠的脑。激动剂激发这些膜中的GTP[γ]35S结合。由剂量一响应曲线确定化合物的EC50和Emax值。δ拮抗剂纳屈吲哚使剂量响应曲线右移,证实了激动剂活性是经由δ受体调制的。
数据分析
将异性结合(SB)作为TB-NS计算,在各种试验化合物存在下的SB则表示成对照SB的百分数。配体在顶替特异结合的放射性配体方面的IC50值及Hill系数(nH)由分对数图或曲线拟合程序例如Ligand,GraphPad Prism,SigmaPlot或ReceptorFit计算。Ki值由Cheng-Prussoff公式计算。对于至少三条顶替曲线中的试验配体报道了IC50、Ki和nH的平均值±平均值标准偏差。生物学数据列在以下各页的表1中。
表1:生物学数据
受体饱和度
放射性配体Kδ值通过用浓度为估计的Kδ值的0.2-5倍(如果所需的放射性配体数量是做得到的,最高达10倍)的合适的放射性配体对细胞进行结合试验来测定。特异性放射性配体结合表示成pmole/mg膜蛋白。各个实验的Kδ和Bmax值是由各个特异结合的(B)对于nM自由的(F)放射性配体按照单位点模型进行非线性拟合得到的。
利用Von Frey试验测定机械性痛觉超敏
采用Chaplan等(1994)所述的方法在8:00至16:00时之间进行试验。将大鼠放在具有线网底的有机玻璃笼内,该线网底允许接近鼠爪,该鼠习惯10-15分钟。所试验的部位是左后爪中部足底,避开不太敏感的爪垫。用一系列刚度按对数增加的8只Von Frey毛状丝(0.41、0.69、1.20、2.04、3.63、5.50、8.51和15.14g,Stoelting,Ill,USA)接触鼠爪。Von Frey丝是由线网底面的下方沿垂直于足底表面的方向以足够的力施用,致使它顶着鼠爪有轻微弯曲,并保持约6-8秒。如果爪迅速抽回,则记下为正响应。在拿走丝后立即退缩也认为是正响应。移动被认为是模糊的响应,在这种情形应重复刺激。
试验方案
在手术后第1天试验FCA处理组的动物。利用Dixon(1980)的升降法测定50%抽回阈值。试验开始时使用该系列中间的2.04g丝。不管上升或下降,总是以依次相连的方式进行刺激。在对于最初选择的丝没有爪回抽响应时,改用更强的刺激;在爪回抽的情形,则选用紧邻的较弱刺激。用此方法计算最佳阈值需要在50%阈值的附近有6次响应,并且当响应首次发生改变时,即第一次跨过阈值时,开始计数这6次响应。如果阈值是在刺激范围之外,则分别指定数值为15.14(正常敏感)或0.41(最大痛觉超敏)。所得到的正和负响应情况用常规方法列表,X=无回抽,O=回抽,用以下公式内插得出50%回抽阈值:
50%g阈值=10(Xf+kδ)/10,000
其中xf=最后使用的Von Frey丝的值(log单位);K=对于正/负响应情况的表列值(得自Chaplan等(1994));δ=刺激之间的平均差值(log单位)。这里δ=0.224。
按照Chaplan等(1994)的方法,将Von Frey阈值转化成最大可能效果的百分数(%MPE)。使用以下公式计算%MPE:
试验物质的给药
在Von Frey试验之前对大鼠注射(皮下、腹腔内、静脉内或口服)试验物质,施用试验物质与Von Frey试验之间的时间随试验化合物而变。
扭体试验
在腹腔内施用乙酸时会引起小鼠的腹部收缩。随后将以一种典型方式伸展其身体。如果腹用止痛药物,所描述的这一运动被观察到的机会较少,则选择的药物是可能的好候选药物。
仅仅当存在以下情形时才考虑完全和典型的扭体反射试验:动物不移动;腰部轻微下降;两爪的足底情况均可观察。在此试验中,本发明化合物在口服给药1-100μmol/kg后显示出对扭体响应的明显的抑制作用。
(1)溶液剂制备
乙酸(AcOH):将120μl乙酸加到19.88mL蒸馏水中以便达到最终体积为20mL,AcOH最终浓度为0.6%。然后将该溶液混合(涡动),准备注射。
化合物(药物):准备各种药物,按标准步骤溶在最合适的载液中。
(2)溶液剂施用
在试验前20、30或40分钟(根据化合物种类及其特点)、径口、腹腔内(i.p.)、皮下(s.c)或静脉内(i.v.)按10mL/kg(考虑小鼠平均体重)施用化合物(药物)。当化合物以中枢途径心室内(i.c.v.)或鞘内(i.t)给药时,施用体积为5μl。
AcOH是在试验前的即刻,在两个部位按10mL/kg(考虑小鼠平均体重)腹腔内(i.p.)给药。
观察动物(小鼠)20分钟,记下发生(扭体反射)的次数,在实验结束时汇集整理。小鼠在带有接触衬垫的各个“鞋盒”笼内饲养。同一时刻通常观察总计4只小鼠:1只对照和3只用药的鼠。
Claims (17)
3.权利要求1的化合物,其中各R1苯基环和R1杂芳香环可以任选地和独立地进一步被独立选自甲基、CF3、氯、氟、溴和碘的1、2或个取代基取代。
4.权利要求1的化合物,该化合物是选自以下化合物的任何一种:
N,N-二乙基-4-[哌淀-4-亚基(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(2-噻吩)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(2-呋喃基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(3-呋喃基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(2-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(3-噻吩)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(2-噻唑)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(3-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(2-吡咯)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;
N,N-二乙基-4-[1-(4-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺;和
N,N-二乙基-4-[1-(4-吡啶)甲基哌啶-4-亚基-(3-氨基甲酰苯基)甲基]苯甲酰胺。
5.权利要求1的化合物,该化合物为其盐酸盐、二盐酸盐、硫酸盐、酒石酸盐、双三氟乙酸盐或柠檬酸盐形式。
6.权利要求1-5中任一项的化合物用于治疗。
7.权利要求6的化合物,其中的治疗是治疗疼痛。
8.权利要求6的化合物,其中的治疗是针对胃肠障碍。
9.权利要求6的化合物,其中的治疗是针对脊椎损伤。
10.权利要求6的化合物,其中的治疗涉及交感神经***障碍。
11.权利要求1的式1化合物在制造用于治疗疼痛的药物方面的应用。
12.权利要求1的式1化合物在制造用于治疗胃肠障碍的药物方面的应用。
13.权利要求1的式1化合物在制造用于治疗脊椎损伤的药物方面的应用。
14.一种药物组合物,其中含有作为活性组分的权利要求1的式1化合物以及可药用的载体。
15.一种治疗疼痛的方法,其中对需要疼痛治疗的患者施用有效数量权利要求1的式I化合物。
16.一种治疗胃肠障碍的方法,其中对患有胃肠障碍的患者施用有效数量的权利要求1的式1化合物。
17.一种治疗脊椎损伤的方法,其中对患有脊椎损伤的患者施用有效数量的权利要求I的式化合物。
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WO2016099394A1 (en) * | 2014-12-19 | 2016-06-23 | Pharmnovo Ab | Novel selective delta-opioid receptor agonists useful for the treatment of pain, anxiety and depression. |
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US2898339A (en) * | 1957-07-29 | 1959-08-04 | Wm S Merrell Co | N-substituted benzhydrol, benzhydryl, and benzhydrylidene piperidine |
US4581171A (en) * | 1983-07-27 | 1986-04-08 | Janssen Pharmaceutica, N.V. | [[Bis(aryl)methylene]-1-piperidinyl]alkyl-pyrimidinones useful for treating psychotropic disorders |
US4816586A (en) * | 1987-07-29 | 1989-03-28 | Regents Of The University Of Minnesota | Delta opioid receptor antagonists |
US5140029A (en) * | 1989-01-09 | 1992-08-18 | Janssen Pharmaceutica N.V. | 2-aminopyrimidinone derivatives |
US4939137A (en) * | 1989-06-28 | 1990-07-03 | Ortho Pharmaceutical Corporation | Ring-fused thienopyrimidinedione derivatives |
US5683998A (en) * | 1991-04-23 | 1997-11-04 | Toray Industries, Inc. | Tricyclic triazolo derivatives, processes for producing the same and the uses of the same |
GB9202238D0 (en) | 1992-02-03 | 1992-03-18 | Wellcome Found | Compounds |
US5574159A (en) * | 1992-02-03 | 1996-11-12 | Delta Pharmaceuticals, Inc. | Opioid compounds and methods for making therefor |
SE9504661D0 (sv) | 1995-12-22 | 1995-12-22 | Astra Pharma Inc | New compounds |
TW548271B (en) | 1996-12-20 | 2003-08-21 | Astra Pharma Inc | Novel piperidine derivatives having an exocyclic double bond with analgesic effects |
CA2316341A1 (en) | 1997-12-24 | 1999-07-08 | Ortho-Mcneil Pharmaceutical, Inc. | 4-[aryl(piperidin-4-yl)] aminobenzamides which bind to the delta-opioid receptor |
SE0001208D0 (sv) | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
SE0001207D0 (sv) * | 2000-04-04 | 2000-04-04 | Astrazeneca Canada Inc | Novel compounds |
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- 2002-10-02 KR KR10-2004-7004780A patent/KR20040039469A/ko not_active Application Discontinuation
- 2002-10-02 CN CNA028195825A patent/CN1692100A/zh active Pending
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107531670A (zh) * | 2014-12-19 | 2018-01-02 | 菲勒诺沃公司 | 二芳基亚甲基哌啶衍生物及其作为δ阿片受体激动剂的用途 |
CN107531670B (zh) * | 2014-12-19 | 2020-12-15 | 菲勒诺沃公司 | 二芳基亚甲基哌啶衍生物及其作为δ阿片受体激动剂的用途 |
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CO5580822A2 (es) | 2005-11-30 |
SE0103313D0 (sv) | 2001-10-03 |
AR036649A1 (es) | 2004-09-22 |
NO20041964L (no) | 2004-04-27 |
CA2460168A1 (en) | 2003-04-10 |
EP1440060A1 (en) | 2004-07-28 |
HUP0401915A2 (hu) | 2005-01-28 |
WO2003029215A1 (en) | 2003-04-10 |
US7205317B2 (en) | 2007-04-17 |
PL368804A1 (en) | 2005-04-04 |
KR20040039469A (ko) | 2004-05-10 |
JP2005505583A (ja) | 2005-02-24 |
US20050020629A1 (en) | 2005-01-27 |
IS7203A (is) | 2004-03-31 |
MXPA04003056A (es) | 2004-07-05 |
ZA200402514B (en) | 2005-01-24 |
BR0212959A (pt) | 2004-10-13 |
IL160889A0 (en) | 2004-08-31 |
RU2004107854A (ru) | 2005-09-10 |
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