CN1886366A - 环戊基衍生物 - Google Patents
环戊基衍生物 Download PDFInfo
- Publication number
- CN1886366A CN1886366A CNA2004800346593A CN200480034659A CN1886366A CN 1886366 A CN1886366 A CN 1886366A CN A2004800346593 A CNA2004800346593 A CN A2004800346593A CN 200480034659 A CN200480034659 A CN 200480034659A CN 1886366 A CN1886366 A CN 1886366A
- Authority
- CN
- China
- Prior art keywords
- compound
- benzylamino
- fluoro
- carboxylic acid
- oxygen base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
本发明涉及以下通式(I)的新的环戊基衍生物,其中X是亚甲基、氧、硫或NR7基团;R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;R2、R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;R4、R5、R6、R7独立地是氢或C1-C6烷基;和其药学上可接受的盐,它们具有作为钠和/或钾通道调控剂的活性,因此可用于预防、减轻和治愈各种病变,包括但不限于神经病学疾病、精神病学疾病、心血管疾病、炎性疾病、眼科疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中上述机理已被描述为发挥病理学作用。
Description
本发明涉及以下通式(I)的新的环戊基衍生物:
其中
X是亚甲基、氧、硫或NR7基团;
R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;
R2,R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;
R4,R5,R6,R7独立地是氢或C1-C6烷基;
和其药学上可接受的盐,它们具有作为钠和/或钾通道调控剂的活性,因此可用于预防、减轻和治愈各种病变,包括但不限于神经病学疾病、精神病学疾病、心血管疾病、炎性疾病、眼科疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中上述机理已被描述为发挥病理学作用。
发明背景
化学背景
DE 2624290描述了具有以下通式的2-氨基环烷烃羧酸和其衍生物以及它们作为镇痛剂、退热剂和麻醉剂的用途:
其中R1是羟基或NR4R5基团,R2和R3是氢、烷基、芳烷基、芳基或酰基,R4和R5是氢、C1-C8烷基、芳烷基、芳基或杂芳基。
生物学背景
众所周知,钠通道在神经元网络中发挥重要作用,它们在细胞和细胞网络各处迅速传递电脉冲,从而协调从运动到认知的高级过程。这些通道是大的跨膜蛋白质,它们能够在不同状态之间切换,使钠离子能够选择性地渗透。对于该过程而言,需要动作电位使膜去极化,因此这些通道是电压-门控的。在过去几年中,已经对钠通道有了更深入的了解,并且开发了与它们作用相互的药物。
已经清楚的是,许多作用机理未知的药物实际上通过调控钠通道电导来发挥作用,包括局部麻醉剂、I类抗心律失常剂和抗惊厥剂。已经发现神经元钠通道阻滞剂可用于治疗癫痫(苯妥英和卡马西平)、双相性精神障碍(拉莫三嗪)、预防神经变性和减轻神经性疼痛。各种使神经元兴奋性稳定的抗癫痫药对神经性疼痛是有效的(加巴喷丁)。
另外,在多种炎性疼痛模型中也已经观察到钠通道表达或活性的增加,提示了钠通道在炎性疼痛中的作用。
钙通道是跨膜多亚基蛋白质,其控制钙离子从细胞外液进入细胞。一般,钙通道是电压依赖性的,被称为电压敏感性钙通道(VSCC)。VSCC见于哺乳动物神经***各处,它们调节诸如细胞兴奋性、递质释放、细胞内代谢、神经分泌活动和基因表达等各种活动。动物中所有“可兴奋的”细胞例如中枢神经***(CNS)的神经元、外周神经细胞和包括骨骼肌、心肌和静脉与动脉平滑肌的细胞在内的肌肉细胞均具有电压依赖性钙通道。钙通道在调节细胞内钙离子水平上具有核心作用,而细胞内钙离子水平对细胞活力和功能而言是很重要的。细胞内钙离子浓度与动物的许多生命过程有关,例如神经递质释放、肌肉收缩、起博点活性和激素分泌。据信,钙通道与某些疾病状态有关。许多可用于治疗包括人在内的哺乳动物的各种心血管疾病的化合物被认为通过调控存在于心脏和/或血管平滑肌中的电压依赖性钙通道的功能来发挥它们的有益作用。对钙通道具有活性的化合物也已用于治疗疼痛。具体而言,负责神经递质调节的N-型钙通道(Cav2.2)被认为在伤害感受传递中发挥重要作用,这不仅是由于它们的组织分布,而且来自多种药理学研究的结果。这种假设已经在临床上被Zinocotide证实,Zinocotide是一种从海洋蜗牛—僧袍芋螺(Conus Magus)的毒液中得到的肽。这种肽的治疗用途的局限在于它在人中必须进行鞘内施用(BowersoxS.S.和Luther R.Toxicon,1998,36,11,1651-1658)。
所有这些发现共同表明,具有钠和/或钙通道阻滞作用的化合物在预防、减轻和治愈各种病变中具有高的治疗潜能,包括神经病学疾病、精神病学疾病、心血管疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中上述机理已被描述为发挥病理学作用。
有很多文章和专利描述了治疗或调控多种障碍的钠通道和/或钙通道调控剂或拮抗剂,例如它们用作局部麻醉剂、抗心律失常剂、止吐剂、抗躁狂抑郁剂、治疗单相性抑郁、心血管疾病、尿失禁、腹泻、炎症、癫痫、神经变性病症、神经细胞死亡的药物、抗惊厥剂、治疗神经性疼痛、偏头痛、急性痛觉过敏与炎症、肾病、***反应、哮喘、支气管痉挛、痛经、食道痉挛、青光眼、泌尿道障碍、胃肠蠕动障碍、早产(premature labour)、肥胖的药物。以下给出了非常不完全的列表。
在WO 03/057219(和其中的参考文献)中报道了广泛和充分的现有技术综述;在以下参考文献中报道了现有技术的其它选择:Alzheimer,C.Adv.Exp.Med.Biol.2002,513,161-181;Vanegas,H.;Schaible,H.Pain2000,85,9-18;美国专利5,051,403;美国专利5,587,454;美国专利5,863,952;美国专利6,011,035;美国专利6,117,841;美国专利6,362,174;美国专利6,380,198;美国专利6,420,383;美国专利6,458,781;美国专利6,472,530;美国专利6,518,288;美国专利6,521,647;WO 97/10210;WO03/018561。
发明内容
本发明涉及式(I)的新化合物
其中
X是亚甲基、氧、硫或NR7基团;
R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;
R2,R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;
R4,R5,R6,R7独立地是氢或C1-C6烷基;和其药学上可接受的盐。
本发明的化合物可用作钠和/或钙通道调控剂。
苯环中的取代基R1-X、R2和R3可以位于任何位置。式I化合物的药学上可接受的盐包括与无机酸或有机酸的酸加成盐,无机酸例如盐酸、氢溴酸、硫酸和磷酸,有机酸例如乙酸、丙酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、乙醇酸、乳酸、草酸、苹果酸、马来酸、丙二酸、富马酸、酒石酸、柠檬酸等。
本发明优选的化合物是这样的式I化合物,其中X是氧、亚甲基、NH或NCH3,R1是C1-C8烷基链,其任选地被CF3、苯基或苯氧基取代,其中R1中的芳族环任选地被一个或两个卤素或甲氧基或三氟甲基取代,R2和R3是氢、甲基、甲氧基、氟、氯或溴,R4、R5和R6是氢或甲基。
本发明的具体化合物的实例有:
2-(2-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(3-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(4-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基硫基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氨基)-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-溴-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-2-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;和其所有立体异构体和/或药学上可接受的盐。
本发明的化合物和其盐可以通过包括以下步骤的方法得到:
a)在还原剂的存在下,使式II化合物与式III化合物反应,
所述的式II化合物是
其中R1、R2、R3和X如上文所定义,
所述的式III化合物是
其中R4、R5和R6如上文所定义,
由此得到式I化合物;或者
b)使式IV化合物与式III化合物反应,
所述的式IV化合物是
其中R1、R2、R3和X如上文所定义,Y是卤素原子或O-EWG基团,其中EWG表示能够将它们所连接的氧转化为良好离去基团的吸电子基团,
例如甲磺酰基、甲苯磺酰基或三氟乙酰基,
由此得到式I化合物;或者
c)使式Ia化合物与式V或VI化合物反应,
所述的式Ia化合物是
其中R1、R2、R3、R5、R6和X如上文所定义,
所述的式V或VI化合物是
R4Y R8CHO
V VI
其中Y和R4如上文所定义,R8是氢或C1-C5烷基,
由此得到其中R4是C1-C6烷基的本发明化合物;
和如果需要的话,将一种本发明的化合物转化为另一种本发明的化合物,和/或如果需要的话,将本发明的化合物转化为药学上可接受的盐,和/或如果需要的话,将盐转化为游离化合物,和/或如果需要的话,将本发明的化合物的异构体混合物分离为单个的异构体。
化合物II、III、IV、V和VI是可商购获得的化合物或者是利用已知方法以可商购获得的化合物为原料制备的。
生成式I化合物的式II化合物与式III化合物的反应和式Ia化合物与式VI化合物的反应是还原性氨基化反应,其可以按照已知方法进行。根据本发明的一个优选实施方案,它可以如下进行:在氮气氛下,在适合的有机溶剂中,例如醇,例如低级链烷醇,特别是甲醇,或者乙腈,或者四氢呋喃,在约0℃至约80℃的温度下,在还原剂的存在下,最适当的是硼氢化钠或氰基硼氢化钠。有时可以向反应混合物中加入异丙醇钛IV和分子筛以促进反应。
在式IV和V化合物中,卤素优选地是溴或碘。式IV化合物与式III化合物的烷基化反应和式Ia化合物与式V化合物的烷基化反应可以如下进行:在适合的有机溶剂中,例如醇,例如甲醇、乙醇或异丙醇,特别是乙醇,在约0℃至约50℃的温度下。
当本发明的化合物和其中间产物中存在需要在进行上述反应之前加以保护的基团时,可以按照已知的方法在反应之前对它们进行保护、然后去保护。
药理学
在体外结合研究中使用选择性放射性配体证明了本发明的化合物对钙和/或钠通道结合位点显示出亲和性。
本发明的化合物是电压依赖性钠通道和/或钙通道的阻滞剂。因此这些化合物以高亲和性从钠通道的结合位点上置换3H-箭毒蛙碱(BTX),IC50在低μM或亚μM范围内。类似地,这些化合物从钙通道的结合位点上置换3H-尼群地平,IC50在低μM或最通常在亚μM范围内,以及抑制经由细胞去极化通过钙通道所诱导的钙内流。
当钠通道被阻滞时这类物质表现出“使用-依赖性”,即,仅在反复刺激钠通道之后才达到钠通道的最大阻滞。所以,这些物质优选地与被多次活化的钠通道结合。结果,这些物质能够优先在被病理性过度刺激的那些机体区域中发挥活性,正如膜片钳实验所示的那样(W.A.Catteral,TrendsPharmacol.Sci.,8,57-65;1987),该实验表明本发明的化合物以“使用-依赖性”方式阻滞电刺激的钠通道。
作为这些机理的结果,当在各种动物模型中以0.1至100mg/kg口服施用时,本发明的化合物具有体内活性,特别是MES电惊厥试验、持续性疼痛***模型和角叉菜胶炎症模型。
荧光钙内流测定法和电生理学研究已经证明了本发明化合物的钙和/或钠通道的电压依赖性阻滞作用。
通过基于荧光的钙内流测定法测定了通式I的环戊基衍生物的N-型钙通道调控活性。
在表达Na通道Nav1.3的离体非洲爪蟾***(xenopus oocyte)中,利用双电极电压钳(TEVC)技术通过电生理学测定法测定了通式I的环戊基衍生物的钠通道调控活性。
鉴于上述作用机理,本发明的化合物可用于治疗或预防神经性疼痛。神经性疼痛综合征包括但不限于:糖尿病性神经病;坐骨神经痛;非特异性下背部疼痛;多发性硬化疼痛;纤维肌痛;HIV-相关性神经病;神经痛,例如带状疱疹后神经痛和三叉神经痛;和由身体创伤、切断术、癌症、毒素或慢性炎性病症导致的疼痛。
本发明的化合物也可用于治疗慢性疼痛。慢性疼痛包括但不限于由炎症或炎性相关性病症、骨关节炎、类风湿性关节炎所导致的慢性疼痛或者作为疾病、急性损伤或创伤的后遗症的慢性疼痛,包括上背部疼痛或下背部疼痛(由全身、局部或原发性脊柱疾病(例如神经根病)所引起)、骨痛(由骨关节炎、骨质疏松、骨转移或未知原因引起)、骨盆痛、与脊髓损伤有关的疼痛、心脏性胸痛、非心脏性胸痛、中风后中枢性痛、肌筋膜痛、癌症疼痛、AIDS疼痛、镰状细胞性疼痛、老年病性疼痛或者由头痛、颞下颌关节综合征、痛风、纤维化或胸腔出口综合征所导致的疼痛。
本发明的化合物也可用于治疗急性疼痛(由急性损伤、疾患、运动医学损伤、腕管综合征、灼伤、肌肉骨骼扭伤与拉伤、肌腱拉伤、颈臂痛综合征、消化不良(dyspepsis)、胃溃疡、十二指肠溃疡、痛经、子宫内膜异位症或手术(例如心脏直视手术或旁路手术)所导致)、术后疼痛、肾结石疼痛、胆囊疼痛、胆结石疼痛、分娩疼痛或牙痛。
本发明的化合物也可用于治疗偏头痛例如紧张性头痛、变形偏头痛(transformed migraine)或进行性头痛(evolutive headache)、丛集性头痛,以及继发性头痛障碍例如由感染、代谢障碍或其它全身性疾患衍生的头痛障碍,和由上述原发性和继发性头痛的恶化所导致的其它急性头痛、发作性偏头痛等。
本发明的化合物也可用于治疗神经病学病症和认知障碍。神经病学病症包括但不限于诸如以下病症:癫痫(包括单纯性部分癫痫发作、复杂性部分癫痫发作、继发性泛化性癫痫发作,进一步包括癫痫小发作、肌阵挛性癫痫发作、阵挛性癫痫发作、强直性癫痫发作、强直性阵挛性癫痫发作和无张力性癫痫发作),退行性痴呆(包括老年性痴呆、阿尔茨海默病、皮-尼病、帕金森病)和血管性痴呆(包括多发性脑梗塞痴呆、中风和脑缺血),以及与颅内占位性病变、创伤、感染及相关病症(包括HIV感染)、代谢、毒素、缺氧和维生素缺乏有关的痴呆;和与衰老有关的轻微认知功能减退,特别是与年龄有关的记忆功能减退,运动障碍(脑炎后帕金森综合征、进行性核上麻痹、皮质基底节变性),发作性睡眠,注意缺陷多动症(ADHD),肌萎缩性侧索硬化,唐氏综合征。
本发明的化合物也可用于治疗精神病学障碍。精神病学障碍包括但不限于又称为双相性精神障碍的躁狂抑郁(例如I型双相性精神障碍、II型双相性精神障碍)、循环性情感障碍、快速循环、极快速循环(ultradiancycling)、双相性抑郁、急性躁狂、躁狂、混合躁狂、轻躁狂或单相性抑郁、精神***症、精神***样障碍、***情感性障碍、妄想性障碍、短时精神障碍、分享性精神障碍、由一般医学病症引起的精神病性精神障碍、精神作用物质-诱发的精神病性精神障碍或未另外指定的精神病性精神障碍、焦虑症以及吸烟和药物成瘾。
本发明的化合物也可用于治疗外周疾病,例如耳鸣、肌肉痉挛、肌肉硬化和其它障碍,包括但不限于心血管疾病(例如心律失常、心肌梗塞或心绞痛、高血压、缺氧、心肌缺血)、内分泌障碍(例如肢端肥大症或尿崩症)、其中其病理生理学涉及内源性物质(例如儿茶酚胺、激素或生长因子)的过量或过多分泌或其它不适当的细胞分泌的疾病。
本发明的化合物也可用于治疗肝病,例如炎性肝病,例如慢性病毒性乙型肝炎、慢性病毒性丙型肝炎、酒精性肝损伤、原发性胆汁性肝硬化、自身免疫性肝炎、非酒精性脂肪性肝炎和肝移植物排斥。
本发明的化合物抑制影响所有机体***的炎性过程。因此可用于治疗肌肉骨骼***的炎性过程,下面是实例列表,但不是所有目标障碍的全部:关节炎性病症,例如强直性脊柱炎、颈椎关节炎、纤维肌痛、痛风、幼年型类风湿关节炎、腰骶关节炎、骨关节炎、骨质疏松、银屑病性关节炎、风湿性疾病;影响皮肤和相关组织的障碍:湿疹、银屑病、皮炎和炎性病症如晒伤;呼吸***障碍:哮喘、变应性鼻炎和呼吸窘迫综合征、其中涉及炎症的肺障碍如哮喘和支气管炎;慢性阻塞性肺病;免疫与内分泌***障碍:结节性动脉外膜炎、甲状腺炎、再生障碍性贫血、硬皮病、重症肌无力、多发性硬化、结节病、肾炎综合征、贝赫切特综合征、多肌炎、龈炎。
本发明的化合物也可用于治疗胃肠(GI)道障碍,例如炎性肠病,包括但不限于溃疡性结肠炎、克隆病、回肠炎、直肠炎、乳糜泻、肠病、显微镜性结肠炎或胶原性结肠炎、嗜酸细胞性胃肠炎或者直肠结肠切除术后和回肠***吻合术(ileonatal anastomosis)后导致的隐窝炎,和肠易激惹综合征,包括任何与腹部疼痛和/或腹部不适有关的障碍,例如幽门痉挛、神经性消化不良、痉挛性结肠、痉挛性结肠炎、痉挛性肠、肠神经官能症(intestinal neurosis)、功能性结肠炎、粘液性结肠炎、轻泻性结肠炎和功能性消化不良;也用于治疗萎缩性胃炎、变形性胃炎(gastritis varialoforme)、溃疡性结肠炎、消化性溃疡、胃灼热(pyresis)和其它胃肠道损伤,例如幽门螺旋杆菌(Helicobacter pylori)引起的胃肠道损伤、胃食管反流病、胃轻瘫,例如糖尿病胃轻瘫;和其它功能性肠病,例如非溃疡性消化不良(NUD);呕吐、腹泻和内脏炎症。
本发明的化合物也可用于治疗泌尿-生殖道障碍,例如膀胱过度活动症、***炎(慢性细菌性和慢性非细菌性***炎)、***痛、间质性膀胱炎、尿失禁和良性***增生、子宫***、***、***炎和***炎。
本发明的化合物也可用于治疗眼科疾病,例如视网膜炎、视网膜病变、眼色素层炎和急性眼组织损伤、黄斑变性或青光眼、结膜炎。
本发明的化合物也可用于治疗肥胖。
本发明的化合物也可用于治疗所有其它由对电压门控钠通道和/或电压门控钙通道的抑制作用所介导的病症。
应当领会的是,本发明的化合物可以有利地与一种或多种其它治疗剂联合使用。适合用于辅助治疗的药物的实例包括5HT1B/1D激动剂,例如曲坦类(例如舒马普坦或那拉曲坦);腺苷A1激动剂;EP配体;NMDA调控剂,例如甘氨酸拮抗剂;P物质拮抗剂(例如NK1拮抗剂);***素;对乙酰氨基酚或非那西丁;5-脂氧化酶抑制剂;白三烯受体拮抗剂;DMARD(例如甲氨蝶呤);加巴喷丁和相关化合物;三环抗抑郁剂(例如阿米替林);神经元稳定性抗癫痫药;单胺能摄取抑制剂(例如文拉法辛);基质金属蛋白酶抑制剂;氧化氮合酶(NOS)抑制剂,例如iNOS或nNOS抑制剂;肿瘤坏死因子α释放或作用的抑制剂;抗体疗法,例如单克隆抗体疗法;抗病毒剂,例如核苷抑制剂(例如拉米夫定)或免疫***调控剂(例如干扰素);镇痛剂,例如环加氧酶-2抑制剂;局部麻醉剂;***,包括咖啡因;H2-拮抗剂(例如雷尼替丁);质子泵抑制剂(例如奥美拉唑);抗酸剂(例如氢氧化铝或氢氧化镁);抗胃肠气胀药(例如semethicone);减充血剂(例如去氧肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘甲唑林、赛洛唑啉、丙己君或左旋去氧麻黄碱、萘甲唑林、赛洛唑啉、丙己君或左旋去氧麻黄碱);镇咳剂(例如可待因、氢可酮、carmiphen、喷托维林或右旋甲吗喃);利尿剂;或者镇静性或非镇静性抗组胺剂。应当理解的是,本发明包括式(I)化合物或其药学上可接受的盐与一种或多种治疗剂组合的用途。
本发明的化合物可用于人和兽医学。应当理解的是,对治疗的称谓包括已有症状的治疗和预防性治疗,另有明确规定除外。
上文所定义的通式I的环戊基衍生物可以作为药学上可接受的组合物的“活性成分”被施用,所述组合物可以通过常规工艺制备,例如通过将活性成分与药学上可接受的、治疗上惰性的有机和/或无机载体物质相混合来制备。
包含上文所定义的环戊基衍生物的组合物可以以多种形式施用,例如以片剂、锭剂(troch)、胶囊剂、糖衣片或薄膜衣片、液体溶液剂、乳剂或混悬剂的形式口服施用;以栓剂形式直肠施用;胃肠外施用,例如通过肌内或静脉内注射或输注进行胃肠外施用;和透皮施用。
可用于制备这类组合物的适合的药学上可接受的、治疗上惰性的有机和/或无机载体物质包括例如水、明胶、***胶、乳糖、淀粉、纤维素、硬脂酸镁、滑石粉、植物油、聚亚烷基二醇等。包含上文所定义的式I的环戊基衍生物的组合物可以被灭菌,并且可以含有其它已知的组分,例如防腐剂、稳定剂、湿润剂或乳化剂,例如石蜡油、二缩甘露醇单油酸酯、调节渗透压的盐、缓冲剂等。
例如,除了活性成分以外,固体口服剂型还可以含有稀释剂,例如乳糖、葡萄糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅、滑石粉、硬脂酸、硬脂酸镁或硬脂酸钙,和/或聚乙二醇;粘合剂,例如淀粉、***胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂,例如淀粉、海藻酸、藻酸盐或淀粉羟乙酸钠;泡腾混合物;染料;甜味剂;湿润剂,例如卵磷脂、聚山梨醇酯、十二烷基硫酸盐;和一般而言,用在药物制剂中的无毒的与无药理活性的物质。所述药物制剂可以用已知方法制备,例如通过混合、造粒、压片、包糖衣或包薄膜衣方法制备。
口服制剂包含缓释制剂,其可以按常规方式制备,例如通过给片剂和颗粒涂敷肠溶衣来制备。
口服施用的液体分散物可以是例如糖浆剂、乳剂和混悬剂。
糖浆剂可以含有作为载体的例如蔗糖或蔗糖与甘油和/或甘露醇和/或山梨醇。
混悬剂和乳剂可以含有作为载体的例如天然树胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。除了活性化合物以外,肌内注射的混悬剂或溶液剂还可以含有药学上可接受的载体,例如无菌水、橄榄油、油酸乙酯、二醇类,例如丙二醇,和如果需要的话,适量盐酸利多卡因。静脉内注射或输注的溶液剂可以含有作为载体的例如无菌水,或者优选地它们可以是无菌、水性、等张盐水溶液的形式。
除了活性成分以外,栓剂还可以含有药学上可接受的载体,例如可可脂、聚乙二醇、聚氧乙烯脱水山梨醇脂肪酸酯表面活性剂或卵磷脂。
适合的治疗每天给予1、2或3次,这取决于清除率。因此,所需剂量可以以单剂量形式或者作为以适当时间间隔施用的多剂量形式给予,例如每天二至四个或更多个分剂量。
包含上文所定义的式I的环戊基衍生物的药物组合物每个剂量单元中将含有约0.1至约500mg活性成分,最优选含有1至10mg活性成分,所述的剂量单元例如胶囊剂、片剂、粉针剂、茶匙(teaspoonful)、栓剂等。
待施用的最佳治疗有效剂量可以由本领域技术人员容易地确定,并且基本上将因制剂的强度、施用方式和所治疗的病症或障碍的进展程度而异。另外,包括个体的年龄、体重、饮食和施用时间在内的与所治疗的特定个体有关的因素也将导致需要调整剂量至适当的治疗有效水平。
以下实施例进一步阐述了发明。
实施例1
顺式-2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺
将2M的2-氨基-环戊烷羧酸酰胺(0.75g,6.5mmol)在干燥THF中的溶液加入到1M的如实施例3所述制备的3-(2-氟-苄基氧基)-苯甲醛(1.64g,7.15mmol)在干燥THF中的溶液中。向该混合物中滴加2M的Ti(O-iPr)4(2.77g,9.75mmol)在干燥THF中的溶液,将反应混合物在室温、氮气下搅拌12小时。
加入0.75M的硼氢化钠(0.69g,18.2mmol)在无水乙醇中的溶液,将所得混合物在70℃下加热6小时。冷却后,加入8ml水猝灭反应,滤出所得白色沉淀。用SCX柱(强阳离子交换树脂)纯化粗化合物。用3%氨的甲醇溶液洗脱回收纯产物。在真空下蒸发溶剂后,得到标题化合物(2.08g),最后收率94%。
MS(ESI Pos Spray 3.5 kV;Skimmer 20 V;Probe 250℃):343[MH+]
1H-NMR(DMSO-d6)δ:7.55(m,1H),7.45(m,2H),7.25(m,3H),7.0(s,1H),6.88(m,2H),6.78(s,1H),5.1(s,2H),3.7(dd,2H),3.10(m,1H),2.65(m,1H),1.90-1.4(m,6H).
实施例2
顺式-2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺
将2M的2-氨基-环戊烷羧酸酰胺(0.75g,6.5mmol)在干燥THF中的溶液加入到1M的如实施例4所述制备的4-(2-氟-苄基氧基)-3,5-二甲基-苯甲醛(1.84g,7.15mmol)在干燥THF中的溶液中。向该混合物中滴加2M的Ti(O-iPr)4(2.77g,9.75mmol)在干燥THF中的溶液,将反应混合物在室温、氮气下搅拌12小时。
加入0.75M的硼氢化钠(0.69g,18.2mmol)在无水乙醇中的溶液,将所得混合物在70℃下加热6小时。冷却后,加入8ml水猝灭反应,滤出所得白色沉淀。用SCX柱(强阳离子交换树脂)纯化粗化合物。用3%氨的甲醇溶液洗脱回收纯产物。在真空下蒸发溶剂后,得到标题化合物(2.14g),最后收率89%。
MS(ESI Pos Spray 3.5 kV;Skimmer 20 V;Probe 250℃):371[MH+]
1H-NMR(DMSO-d6)δ:7.60(m,1H),7.48(m,2H),7.28(m,2H),6.95(s,2H),6.78(s,1H),4.80(s,2H),3.6(dd,2H),3.15(m,1H),2.68(m,1H),2.2(s,6H),1.85-1.51(m,6H).
实施例3
3-(2-氟-苄基氧基)-苯甲醛
将0.5M的1-溴甲基-2-氟-苯(1.50g,8.0mmol)在DMF中的溶液滴加到3-羟基-苯甲醛(0.89g,7.3mmol)、K2CO3(1.51g,11mmol)与KI(0.12g,0.73mmol)在100ml DMF中的混悬液中。将反应混合物在90℃下搅拌过夜。冷却至室温后,滤出固体残余物,在真空下蒸发溶剂。将残余物溶于乙酸乙酯,将有机层用1M NaOH洗涤两次,用Na2SO4干燥,蒸发至干。将残余物在硅胶上纯化,得到167mg标题化合物(定量收率)。
实施例4
4-(2-氟-苄基氧基)-3,5-二甲基-苯甲醛
将0.5M的1-溴甲基-2-氟-苯(1.50g,8.0mmol)在DMF中的溶液滴加到1.09g 4-羟基-3,5-二甲基-苯甲醛(7.3mmol)、1.51g K2CO3(11mmol)与120mg KI(0.73mmol)在100ml DMF中的混悬液中。反应按照与实施例3所述的相同方法进行。将残余物在硅胶上纯化,得到定量收率的标题化合物(1.88g)。
实施例5
大鼠脑膜中3H-箭毒蛙碱的体外结合
膜制备物(P2级分):在轻微麻醉下处死雄性Wistar大鼠(Harlan,意大利,175-200g),迅速取出脑,切下皮质,在10体积冰冷的0.25M蔗糖缓冲液(50mM Tris-HCl,pH 7.4)中匀化。将粗匀浆在3250rpm下离心10分钟,回收上清液。将沉淀再次匀化和离心,合并两份上清液,在+4℃、14750rpm下离心10分钟。将所得沉淀贮存在-20℃下备用。
结合测定:利用Polytron PT10将沉淀重新混悬在50mM pH 7.4的Hepes缓冲液中,其含有0.8mM MgSO4、5.4mM KCl、5.5mM葡萄糖和130mM胆碱。结合测定是在0.25ml终体积中进行的,其中含有50μl膜制备物(约200μg蛋白质)、50μl 3H-箭毒蛙碱配体(10nM)、50μl TTX(1μM)、50μl蝎毒素(37.5μg/ml)和50μl供试化合物或缓冲液或300μM藜芦定,以测定非特异性结合。在37℃下进行结合测定达30分钟,在真空下迅速通过Whatman GF/B玻璃纤维滤器过滤来终止测定。将滤器(预先用聚乙烯亚胺0.1%浸泡)用3×5ml冰冷的缓冲液洗涤,置于含有闪烁合剂(FilterCount,Packard)的微型瓶中。以45%的效率用液体闪烁谱测量法测量所结合的放射性。
数据分析:通过计算机程序LIGAND由置换曲线计算IC50(McPherson,J.Pharmacol.Methods,14,213.1985)。使用至少9种浓度得到置换曲线,各浓度均一式两份,覆盖100000倍范围。
实施例6
大鼠脑膜中3H-尼群地平的体外结合
膜制备物:在轻微麻醉下处死雄性Wistar大鼠(Harlan,意大利,175-200g),迅速取出脑,切下皮质,利用Polytron PT10在10体积冰冷的50mM pH 7.7的Tris·HCl中匀化。将粗匀浆在50000×g下离心10分钟。将沉淀在+4℃、50000×g下在新鲜缓冲液中匀化并离心10分钟,该操作进行两次。将所得沉淀贮存在-20℃下备用。
结合测定:利用Polytron PT10将沉淀重新混悬在50mM pH 7.7的Tris·HCl中。结合测定是在1ml终体积中进行的,其中含有900μl膜制备物(约700μg蛋白质)、50μl 3H-尼群地平(0.15nM)和50μl供试化合物或缓冲液或1μM尼群地平,以测定非特异性结合。在25℃下进行结合测定达45分钟,在真空下迅速通过Whatman GF/B玻璃纤维滤器过滤来终止测定。将滤器用3×5ml冰冷的缓冲液洗涤,置于含有闪烁合剂(Filter Count,Packard)的微型瓶中。以45%的效率用液体闪烁谱测量法测量所结合的放射性。
数据分析:通过计算机程序LIGAND由置换曲线计算IC50(McPherson,J.Pharmacol.Methods,14,213.1985)。使用至少9种浓度得到置换曲线,各浓度均一式两份,覆盖100000倍范围。
实施例7
钙内流测定
IMR32人神经母细胞瘤细胞在组成上具有L和N型通道。在分化条件下,IMR32优先在膜表面上表达N-型通道。利用选择性L型阻滞剂硝苯地平阻滞其余L-型钙通道。在这些实验条件下,仅能检测N-型通道。
在225cm2烧瓶中,使用1mM dibutyrril-cAMP和2.5μM溴脱氧尿苷使IMR32细胞分化8天(4次),然后分离,以200,00个细胞/孔接种在聚赖氨酸包被的96孔板上,在分化缓冲液的存在下进一步温育18-24小时,备用。
基于荧光钙指示剂485-535nm波长,使用Ca2+Kit Assay(MolecularDevices)。
将分化的细胞与染剂加载物一起在37℃下温育30分钟,然后单独加入硝苯地平(1μM)或者在存在ω-芋螺毒素或供试化合物的情况下加入,进一步温育15分钟。
在自动注入100mM KCl去极化溶液之前和之后(30-40秒),利用Victor读板器(Perkin Elmer)测量荧光(485-535nm)。
由5种浓度计算抑制曲线,各浓度均一式三份,利用线性回归分析确定IC50。
通式I的优选化合物抑制N-型钙通道,IC50值小于10μM。
实施例8
电生理学测定
用表达Na通道Nav1.3的离体非洲爪蟾***进行测定强直性阻滞的实验。利用双电极电压钳(TEVC)技术记录电流。
***制备:
将青蛙(非洲爪蟾(Xenopus laevis))用含3-氨基苯甲酸乙酯的溶液(1g/l)麻醉,25分钟后将其背朝下置于“冰床”上。切开皮肤和其它组织,拉出卵巢叶(ovarian lobe),保持在ND96Ca2+(NaCl 96mM,KCl 2mM,MgCl21mM,Hepes 10mM,用NaOH调至pH 7.85)中。
取出***后,分别缝合肌肉和皮肤。
将卵巢叶缩减至10/20***群,置于含胶原酶溶液(1mg/ml)的试管中,在温育器中保持运动约1小时。
此步骤结束时,***彼此完全分开,用ND96Ca2+冲洗三次,用NDE(ND96Ca2++CaCl 0.9mM,MgCl2 0.9mM,丙酮酸盐2.5mM,庆大霉素50mg/l)冲洗三次。
所得***处于不同的发育阶段。仅选择处于V或VI阶段的细胞用于RNA注入后的实验。
制备后的那天,用20ng Nav1.3 cRNA注入***(DrummondNanoject),供养在NDE中。
从mRNA注入后48小时开始,利用双微电极电压钳自动化工作站记录全细胞电流。
典型的微电极具有0.5至1MΩ电阻,填充有KCl 3M。
对照浴溶液含有(mM):NaCl 98,MgCl2 1,CaCl2,1.8,HEPES 5(pH7.6)。
制备化合物贮备液(20mM),溶于外部浴液至终浓度。
电流记录:
首先研究***中表现的Nav1.3电流的电流/电压(I/V)关系,目的是测定激发最大活化的膜电位。在0mV下Nav1.3显示最大活化,我们将其用作强直性阻滞研究的测试电位(Vtest)。
然后研究Nav1.3电流的稳态失活性质,目的是分别测定通道可用性为最大(Imax)的静息态膜电位(Vrest)和产生半数最大电流可用性(I)的半数最大失活膜电位(V)。然后利用这两种电压条件评价强直性阻滞的电压依赖性。
最后利用一个两步方案测定Nav1.3阻滞的电压依赖性:使***在-80mV下与膜片接触,通过100ms步进脉冲将电流分别从在-80mV(静息,Imax条件)和-40mV(去极化,I条件)下的3000ms的预调节电位(preconditioning potential)活化至0mV(Vtest)。
在不存在和存在不同浓度化合物的情况下记录两种条件下的电流振幅(在两次之间进行洗脱),目的是测定浓度-抑制作用曲线和去极化(半数最大电流可用性)条件下强直性阻滞的IC50值。
优选的通式I化合物抑制Nav1.3钠通道,IC50值低于参比钠通道阻滞剂ralfinamide。
实施例9
大鼠和小鼠最大电击试验
通过耳内夹电极使Wistar大鼠接受电击(160mA 0.2s,脉冲列60Hz,脉冲持续时间0.4ms;ECT单元模式7801,Ugo Basile,Comerio,意大利),在至少97%对照动物中足以产生后肢强直性伸肌反应。
小鼠接受28mA电击0.7s,脉冲列80Hz,脉冲持续时间0.4ms。在MES诱导之前对小鼠或大鼠施用多个剂量的供试化合物和标准AED,每个剂量组10至20只,施用体积5ml/kg,对于口服施用而言在MES诱导之前60分钟进行或者对于腹膜内施用而言在MES诱导之前30分钟进行,计算ED50值。癫痫发作的后肢强直性伸肌组分的完全抑制被视为抗惊厥活性的证据。
实施例10
小鼠***试验
按照Rosland等,(1990)的改进方案,向小鼠皮下(s.c.)注射20μl 2.7%***溶液至左后足足底表面内,立即置于透明的PVC观察室(23×12×13cm)内。通过对注射足的累积舔舐时间(秒)进行计数来量化疼痛行为。在***注射后早期(0-5min)和后期(30-40min)进行测量(Tjolsen等1992)。
在***注射前15分钟口服施用供试化合物,施用体积为10ml/kg体重,每个剂量组10只小鼠。对照组用载体处理。
实施例11
角叉菜胶炎症模型
使用175-200克的雄性Wistar大鼠。
向左后足注射100μl角叉菜胶(2%w/v在盐水中)。在角叉菜胶注射前1小时口服施用本发明化合物(30mg/kg)、吲哚美辛(5mg/kg)或对照载体(例如蒸馏水)。在角叉菜胶注射前即刻(基础值)和之后1、2、3、4和5小时,利用器官充满度测量器(Ugo Basile)测量足体积。
Claims (6)
1.式I化合物
其中
X是亚甲基、氧、硫或NR7基团;
R1是直链或支链的C1-C8烷基或C3-C8亚链烯基或C3-C8亚炔基链,其任选地被CF3、苯基、苯氧基或萘基取代,芳族环任选地被一个或多个C1-C4烷基、卤素、三氟甲基、羟基或C1-C4烷氧基取代;
R2,R3独立地是氢、C1-C3烷基链、卤素、三氟甲基、羟基或C1-C4烷氧基;
R4,R5,R6,R7独立地是氢或C1-C6烷基;
和其药学上可接受的盐。
2.根据权利要求1所述的式I化合物,其中X是氧、亚甲基、NH或NCH3,R1是C1-C8烷基链,其任选地被CF3、苯基或苯氧基取代,其中R1中的芳族环任选地被一个或两个卤素或甲氧基或三氟甲基取代,R2和R3是氢、甲基、甲氧基、氟、氯或溴,R4、R5和R6是氢或甲基。
3.选自下组的化合物:
2-(2-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(3-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-(4-苄基氧基-苄基氨基)-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[3-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基硫基)-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氨基)-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3-氟-苄基氨基]-环戊烷羧酸酰胺;
2-[2-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-氯-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-溴-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-2-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
(2-[4-(2-氟-苄基氧基)-3-甲氧基-苄基氨基]-环戊烷羧酸酰胺;
2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;
顺式-2-[4-(2-氟-苄基氧基)-3,5-二甲基-苄基氨基]-环戊烷羧酸酰胺;
和其所有立体异构体和/或药学上可接受的盐。
4.制备权利要求1中所定义的式I化合物或其药学上可接受的盐的方法,该方法包括:
a)在还原剂的存在下,使式II化合物与式III化合物反应,
所述的式II化合物是
其中R1、R2、R3和X如上文所定义,
所述的式III化合物是
其中R4、R5和R6如上文所定义,
由此得到式I化合物;或者
b)使式IV化合物与式III化合物反应,
所述的式IV化合物是
其中X、R1、R2和R3如上文所定义,Y是卤素原子或O-EWG基团,其中EWG表示能够将它们所连接的氧转化为良好离去基团的吸电子基团,
例如甲磺酰基、甲苯磺酰基或三氟乙酰基,
由此得到式I化合物;或者
c)使式Ia化合物与式V或VI化合物反应,
所述的式Ia化合物是
其中R1、R2、R3、R5、R6和X如上文所定义,
所述的式V或VI化合物是
R4Y R8CHO
V VI
其中Y和R4如上文所定义,R8是氢或C1-C5烷基,
由此得到其中R4是C1-C6烷基的本发明的化合物;
和如果需要的话,将一种本发明的化合物转化为另一种本发明的化合物,和/或如果需要的话,将本发明的化合物转化为药学上可接受的盐,和/或如果需要的话,将盐转化为游离化合物,和/或如果需要的话,将本发明的化合物的异构体混合物分离为单个的异构体。
5.药物组合物,其含有权利要求1中所定义的式I化合物或其药学上可接受的盐以及与之混合的适合的载体和/或稀释剂,还任选地含有其它治疗剂。
6.权利要求1中所定义的式I化合物或其药学上可接受的盐在制备药物中的用途,所述药物具有钠和/或钙通道调控活性,用于预防、减轻和治愈神经病学疾病、精神病学疾病、心血管疾病、炎性疾病、眼科疾病、泌尿系疾病、代谢疾病和胃肠疾病,其中在病理学过程中涉及钠和/或钙通道。
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