CN1043893C - 药品 - Google Patents
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Abstract
式(1)化合物及其药学上可接受的盐,以及它们作为药品治疗胃的疾病,心血管疾病和中枢神经***紊乱的用途。
Description
本发明涉及具药理活性的新化合物及其制备方法,以及它们作为药品的用途。
EP-A-429984(Nisshin flour Milling Co.,Ltd.)描述了具5-HT3受体拮抗活性的吲哚衍生物。
European Journal of Phrmarcology 146(1988),187-188及Naunyn-Schmiedeberg′s Arch.Pbarmacol.(1989)340:403-410描述了一个非经典的5-羟色胺受体,现在称其为5-HT4受体;以及ICS205-930,也是一个5-HT3受体拮抗剂,对该受体产生拮抗作用。
WO91/16045(Smithkline and French Laboratories Limited)描述了用心脏的5-HT4受体拮抗剂治疗房性心律失常和中风。
EP-A-501322(Glaxo Group Limited)描述了具5-HT4拮抗活性的吲哚衍生物。
现在发现了一类新的、结构独特的化合物具有5-HT4受体拮抗活性,这些化合物是1,2-烯氧取代的吲哚衍生物,分子中含氮杂环、稠合氮杂双环或氨烃基。
本发明提供式(Ⅰ)化合物,或其药学上可接受的盐,它们具有5-HT4受体拮抗活性:式中:
X是O,S,SO,SO2,CH2,CH或NR,其中R为氢或C1-6烷基;
A是2-4个碳原子的饱和或不饱和聚亚甲基链;
R1和R2为氢或C1-6烷基;
R3是氢,卤素,C1-6烷基,氨基,硝基或C1-6烷氧基;
R4是氢,卤素,C1-6烷基或C1-6烷氧基;
Y是O或NH;
n1为1,2,3或4;n2为0,1,2,3或4;n为2,3,4,或5;
q为0,1,2或3;p为0,1或2;m为0,1或2;
R5是氢,C1-12烷基,芳烷基或(CH2)2-R10,式中Z为2或3,
R10选自以下取代基:氰基,羟基,C1-6烷氧基,苯氧基,
C(O)C1-6烷基,COC6H5,-CONR11R12,NR11COR12,SO2NR11R12
或NR11SO2R12,其中R11和R12为氢或C1-6烷基;
R6,R7和R8均为氢或C1-6烷基,和
R9为氢或C1-10烷基;或者是CO-Y部分为杂环生物电子等排体所替代的式(1)化合物。
例如:烷基或含取代基的烷基包括适当的C1,C2,C3,C4,C5,C6,C7,C8,C9,C10,C11,或C12支链、直链或者环烷基;C1-4烷基包括甲基,乙基,正丙基和异丙基,正、异、仲、及叔丁基;环烷基包括环丙基,环丁基,环戊基,环己基,环庚基和环辛基。
芳基包括苯基和萘基,它们可以为下述一个或多个取代基取代:卤素,C1-6烷基及C1-6烷氧基。
卤素包括氟,氯,溴和碘。
虚线圆代表在该五元环的任何位置上有一个或两个双键,H,J和I均可以是氧,硫,氮或碳,但它们中至少要有一个不是碳,U代表氮或碳。
(d)的适当例子见EP-A-328200(Merck Sharp&Dohme Ltd.)描述X、Y和Z时所述,例如一个噁二唑部分。
X常为0。
A包括:-CH2-(CH2)5-CH2-,式中r是0,1或2,-CH2-CH=CH-;-C(CH3)=CH-;或当X是CH或N时,A可以是-(CH2)2-CH=或-CH=CH-CH=。A的其它例子将在下文的实施例中描述。
R1和R2常为氢,或者为偕二甲基。
r常为1。
R3最好是氢。
R4最好是氢或卤素,例如氟。
Y最好是0或NH。
Z为子式(a)时,若该氮杂环连在氮原子上,n1最好是2,3或4;若该氮杂环连到碳原子上,例如q为2时的4位,则n1最好是1。
Z为子式(b)时,连接该酯或酰胺的n2的碳原子数最好是2-4个。
Z为子式(c)时,n3最好是2,3或4。
R9和R10最好都是烷基,尤其是,其中之一为C4或C4以上的烷基。
本发明还提供了式(1)中带有侧链(ⅰ),(ⅱ),(ⅲ),(ⅳ),(ⅴ),(ⅵ)或(ⅶ)的新化合物;而且,(ⅰ)、(ⅱ)或(ⅲ)中的哌啶环可为吡咯烷基或氮杂环丁烷基替代;以及(或者)(ⅰ)或(ⅱ)中N取代基可为C3,或C3以上的烷基,或者取代苄基所替代。
式(ⅰ)或(ⅱ)中的N取代基可为如式(1)中定义的以及EP-A-501322的特定实例相应定义的(CH2)nR4替代。
式(1)化合物的药学上可接受的盐包括酸加成盐,所用的酸有常用酸,例如:盐酸、氢溴酸、硼酸、磷酸、硫酸以及药学上可接受的有机酸,例如:乙酸、酒石酸、马来酸、柠檬酸、琥珀酸、苯甲酸、抗坏血酸、甲磺酸、2-氧代戊二酸、2-甘油磷酸和葡糖-1-磷酸。
药学上可接受的盐的例子包括式(1)化合物的季铵衍生物;例如用化合物Rx-T将式(1)化合物季铵化,式中:Rx为C1-6烷基、苯基-C1-6烷基或C5-7环烷基,T是相应的酸根;适宜的Rx包括:甲基、乙基、正丙基和异丙基,苄基和苯乙基;适宜的T包括卤化物,例如氯化物,溴化物和碘化物。
药学上可接受的盐的例子还包括象N-氧化物这样的内盐。
式(1)化合物及其药学上可接受的盐(包括季铵衍生物及N-氧化物)也可以生成药学上可接受的溶剂化物,例如水合物,它包括本文涉及的式(1)化合物及其盐。
还应当明白,当Z为(b)时式(1)化合物中(CH2)n2部分相对于该偶合氮杂双环部分的构型可以采取α或β构型。
式(1)化合物可由该吲哚部分与Z按常规偶联法制备。GB2125398A(Sandoz Limited),GB1593146A和EP-A-36269(Beecham Group p.l.c.),EP-A-429984(Nisshin Flour Miling Co.)以及EP-A-328200(Merck Sharp&Dohme Limited)中描述了适宜的制备方法,亦可以参照EP-A-501322(Glaxo Group Limited)。应该知道含环的(CH2)r-或R3/R4可以在偶联前或偶联后引入(或修饰)。
氮杂(双)环侧链中间体是已知化合物,或可按PCT/GB92/01519和/01612(&mithkline Beecham p.l.c.)中描述的方法制备。
本发明化合物是5-HT4受体拮抗剂,因而人们相信,它们一般可以用于治疗或预防胃肠病,心血管疾和中枢神经***紊乱。
它们在治疗刺激性肠综合症(IBS)中具有潜在的用途,具体来说是对付IBS的胶泻,即这些化合物通过激活肠神经元来阻滞5-HT刺激肠蠕动的作用,这可以在IBS的动物模型中以降低排便率的方式方便地测出。它们也在治疗常与IBS相关的尿失禁中具有潜在的用途。
它们对其它胃肠疾病,例如与肠蠕动较快有关的胃肠疾病亦有潜在的用途,可以用作止吐剂。具体来说,它们对治疗胃食管反流病及消化不良所致的恶心及胃的症状方面具有潜在的用途。止吐活性在公知的由细胞毒剂或辐射所致呕吐的动物模型上测定。
独特的心脏5-HT4受体拮抗剂可预防与5-HT有关的心房纤维性颤动和其它的房性心律失常,预计还可以用于减少中风的发生(见A.J.Kaumann 1990,Naumyn-Schmiedeberg′s Arch.Pharmacol.342,619-622,给出了适宜的动物试验方法)。
人们认为,源自血小板的5-HT诱发加快心房纤维性颤动的房性心律失常以及与脑栓塞和全身性栓塞有关的房性疾病。脑栓塞是局部缺血性中风的最常见的病因,而该心脏是栓塞物质最常见的来源。需特别关注的是与心房纤维性颤动有关的栓塞频率。
抗焦虑活性可能是通过海马产生的(Dumuis et al 1988,MolPharmacol.,34,880-887)。活性可在标准动物模型上由群体相互作实验如X-迷宫实验来证实。
偏头痛患者在头痛发生前常处于焦虑和情绪紧张状态(sachs,1985,Migraine,Pan Books,London)。人们还观察到:在偏头痛发作期间的48小时内,脑脊液中的环AMP水平增高很多(Welch et al.1976,Neadache 16,160-167)。人们认为偏头痛,包括前驱症状时期及环AMP水平增高以后,与5-HT4受体兴奋有关。因此,服用5-HT4拮抗剂对减轻偏头痛发作具有潜在的益处。
本发明还提供药用组合物,它包括式(1)化合物或其药学上可接受的盐和药学上可接受的载体。
这样的组合物用混合的方法制备。通常采取肠道内给药方式,例如:口服、鼻内给药或直肠给药,或肠道外给药方式。剂型可以是片剂,胶囊,口服液体制剂,粉剂,颗粒剂,锭剂,可再生的粉剂,鼻喷雾剂,栓剂,可注射的及可输注的溶液或混悬液。预计还可以采取舌下给药或经皮肤给药的方式,可口服给药的组合物最好,因为它们更便于常规使用。
经口服给药的片剂和胶囊一般是一个单位剂量并含有常用赋形剂,例如粘合剂,填充剂,稀释剂,压片剂,润滑剂,崩解剂,着色剂,矫味剂和润湿剂。片剂可按本领域公知的方法包衣,例如肠溶包衣。
适用的填充剂包括:纤维素,甘露糖醇,乳糖及其类似物。适宜的崩解剂包括:淀粉,聚乙烯吡咯烷酮及淀粉的衍生物,如羟基乙酸淀粉钠。适宜的润滑剂包括如硬脂酸镁。
适宜的药学上可接受的润湿剂包括:十二烷基硫酸钠。口服液体制剂可为下述形式,诸如水或油的混悬剂,溶液,乳剂,糖浆或酏剂;或可为使用前能用水或其它媒介物再生的脱水产品。该液体制剂可以含通常的添加剂,诸如助悬剂,例如山梨醇,糖浆,甲基纤维素,明胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶或氢化食用脂肪;乳化剂,例如卵磷脂,脱水山梨醇一油酸酯或***胶;水不溶性媒介(包括食用油),例如杏仁油,分馏的椰子油,油酯,例如甘油酯、丙二醇酯或乙醇酯;防腐剂,如对羟基苯甲酸甲酯,对羟基苯甲酸丙酯或山梨酸,如果需要,可在制剂中加入通常的矫咪剂或着色剂。
口服液体制剂通常的形式为:水或油的混悬剂、溶液、乳剂、糖浆或酏剂,或可为使用前能用水或其它媒介物再生的脱水产品。该液体制剂可含通常的添加剂,例如助悬剂,乳化剂,水不溶性媒介(包括食用油),防腐剂和矫味剂或着色剂。
该口服组合物所以按常规方法生产:混合,灌装或压片。反复混合操作可将该活性成分全部离散到所用的大量的填充剂组合物中去。当然该操作按常规工艺进行。
对于肠道外给药,单位剂量液体制剂制成含本发明化合物和无菌媒介的形式。该化合物既可以混悬,又可以溶解于媒介中,这取决于该媒介和该制剂浓度。肠道外给药的溶液制剂的生产通常为:将该化合物溶解在媒介中,装入药瓶或安瓿前过滤灭菌,密封。有利的是,诸如局麻药、防腐剂及缓冲剂这样的辅料亦可溶于该媒介中。为增强稳定性,可将该组合物装瓶后冷冻,真空除水。
肠道外给药的混悬剂的生产方法实际上与溶液相间,只是将该化合物混悬于媒介中,而不是溶解,并在混悬于灭菌媒介中之前用环氧乙烷暴露灭菌。在该组合物中加入表面活性剂或润湿剂会有助于本发明化合物的均匀分散。
本发明进一步提供治疗哺乳动物应激性肠综合征,胃食管反流疾病,消化不良,房性心律失常和中风,焦虑和(或)偏头痛的方法。例如对于人类,包括给与有效量的式(1)化合物或其药学上可接受的盐。具体说,该方法包括:治疗IBS或房性心律失常如中风。
治疗上述疾病的有效剂量取决于本发明化合物相关效价,待治疾病的性质和严重程度以及该哺乳动物的体重。然而,70Kg体重成年人的单位剂量通常含本发明化合物0.05到1000mg,例如0.5到500mg。每日给药一次或几次,例如每日两次、三次或四次,每日一到三次更常见,即每日每公斤体重用量约在0.0001到50mg范围内,每日每公斤体重0.0002到25mg更普遍。
在上述的剂量范围内不产生任何毒性副作用。
本发明还提供将式(1)化合物或其药学上可接受的盐用作活性治疗物质,具体说,作为5-HT4受体拮抗剂治疗上述疾病。
本发明还提供式(1)化合物制造药物的用途,该药物用作5-HT4受体拮抗剂治疗上述疾病。
下列实施例描述式(1)化合物的制备;下列说明描述中间体的制备。
实施例
R1 R2 r R3 R4 X Y ZE1 H H 1 H H O O (ⅰ)E2 H H 1 H H O O (ⅵ)E3 H H 1 H H O NH (ⅰ)E4 H H 1 H H O O (ⅲ)E5 H H 1 H H O NH (ⅲ)E6 H H O H H O O (ⅰ)E7 (CH3)2 1 H H O O (ⅰ)E8 H H 1 H H S O (ⅰ)E9 H H 2 H H O O (ⅰ)E10 H H 1 H H CH2 O (ⅰ)E11 H H O H H CH2 O (ⅰ)E12 H H 2 H H CH2 O (ⅰ)E13 H H O H H CH2 NH (ⅰ)E14 H H O H H O NH (ⅰ)E15 H H 1 H H O O BzppmE16 H H 1 H H SO O (ⅰ)
实施例(续)
R1 R2 r R3 R4 X Y ZE17 H H Δ H H CH O (ⅰ)E18 H H Γ H H CH O (ⅰ)E19 H H 1 H H S NH (ⅰ)E20 H H 1 H H O NH BzppmE21 H H 1 H H O NH ppmE22 H H 1 H H O NH nC6H13ppmE23 H H 1 H H O NH (ⅱ)E24 H H 1 H H O NH EtppmE25 H H 1 H H O NH MeSO2aEtppmE26 H H 1 H H O NH (ⅵ)E27 H H 1 8-F H O O (ⅰ)E28 H H 1 B-F H O NH (ⅰ)E29 H H 1 H H NMe O (ⅰ)
实施例(续)
R1 R2 r R3 R4 X Y ZE30 - π - H H S O (ⅰ)E31 H H 0 H H S O (ⅰ)E32 - θ - H H S O (ⅰ)E33 - Λ - H H N O (ⅰ)E34 H H 0 H H S NH (ⅰ)E35 - θ - H H S NH (ⅰ)E36 H H 1 H H NH O (ⅰ)E37 H H 0 H H O O (ⅵ)E38 H H 2 H H O NH (ⅰ)E39 H H Γ H H N O (ⅰ)E40 H H 0 H H S O (ⅵ)
实施例(续)
R1 R2 r R3 R4 X Y ZE41 H H 0 H H S NH (ⅵ)E42 - θ - H H S O (ⅵ)E43 - θ - H H S NH (ⅵ)E44 H H 1 H H S O (ⅵ)E45 - Γ - H H NH NH (ⅰ)E46 H H 1 H H N NH (ⅰ)Δ-AR1R2是-(CH2)2-CH- Bz-苄基Γ-AR1R2是-CH=CH-CH= ppm-4-哌啶甲基π-AR1R2是-C(CH3)=CH- aEt-氨乙基-AR1R2是-CH=CH-Λ-AR1R2是-C(CH3)=CH-C(CH3)=
实施例1
3,4-二氢(化)-2H-[1,3]噁嗪并[3,2-a]吲哚-10-羧酸(1-正丁基-4-哌啶基)甲酯(E1)
a)将吲哚-3-羧酸(500mg,0.003mol)混悬于二氯甲烷(50ml)中,加入草酰氯(0.635g,0.005mol)和2滴二甲基甲酰胺,室温搅拌1.5小时,然后真空除去该溶剂,留下该酸的氯化物。
将1-丁基-4-哌啶甲醇,D6(513mg,0.003mol)溶于无水THF(10ml)溶液中,将该溶液在通氮气条件下在冰溶中冷却,滴加正丁基锂(1.88ml 1.6M的己烷溶液,0.003mol),得到的溶液于0℃搅拌15分钟。
将该酰基氯溶于无水THF(20ml)中,将该溶液于0℃滴加到该醇锂溶液中。
将该反应混合物加到至室温,搅拌3小时,真空除去溶剂,将残留物在氯仿和水中进行分配,分出氯仿层,用水洗涤几次,干燥和浓缩,得到1H-吲哚-3-羧酸(1-丁基-4-哌啶基)甲酯,为淡棕色胶状物。1HNMR(250MHz)CDCl3;δ:9.90(bs,1H),8.10-8.18(m,1H),7.78(d,1H),7.37-7.46(m,1H),7.16-7.28(m,2H),4.19(d,2H),3.05-3.15(bd,2H),2.40-2.49(m,2H),0.90(t,3H),1.20-2.18(m,11H).
6)将N-氯代琥珀酰亚胺(57mg,0.48mmol)混悬于氯仿(2ml)中,该混悬液用溶于氯仿(2ml)的吲哚-3-羟酸(1-正丁基-哌啶-4-基)甲酯(100mg,0.32mmol)溶液处理,室温搅拌2小时,该淡黄色溶液用3-溴代-1-丙醇(0.03ml,0.32mmol)处理,室温搅拌16小时;然后用10%的Na2CO3溶液碱化,用氯仿萃取,干燥和浓缩该萃取液,得黄色胶状物;将其溶于丙酮(6ml)中,用无水碳酸钾(130mg,0.94mmol)处理,室温搅拌18小时;该混合物用10%Na2CO3溶液处理,用乙酸乙酯萃取,干燥和浓缩该萃取液,得棕色油状物。将其进行色谱分离,首先用硅胶,氯仿/甲醇(97∶3)洗脱;然后用碱性氧化铝,乙酸乙酯洗脱,得无色油。该物以自色固体(11mg)从***/戊烷中析出,mp.117-119℃,即为该标题化合物(E1)。1H NMR(CDCl3)δ:7.97(d,1H),7.10-7.30(m,3H),4.55(t,2H),4.20(d,2H),4.11(t,2H),2.90-3.03(m,2H),2.25-2.40(m,4H),1.75-2.00(m,5H),1.22-1.55(m,6H),0.91(1,3H)MS(E1)M+370
实施例2
3,4-二氢(化)-2H-[1,3]噁嗪并[3,2-a]吲哚-10-羧酸eq-喹诺里西啶-2-基甲酯(E2)
a)用实施例1a所述方法,将eq-2-羟甲基喹诺里西啶(N.J.Leonard et al.,J.Org.Chem.1957,22.1445)与吲哚-3-羧酸氯化物反应,得到1-H-吲哚-3-羧酸eq-喹诺里西啶-2-基甲酯mp.154-157℃。1H NMR(CDCl3)δ:9.40(br.s,1H),8.10-8.20(m,1H),7.87(d,1H),7.35-7.45(m,1H),7.20-7.30(m,2H),4.20(d,2H),2.80-2.97(m,2H),1.43-2.20(m,11H),1.10-1.40(m,3H).
b)开始用N-氯代琥珀酰亚胺(1.5当量)处理1H-吲哚-3-羧酸eq-喹诺里西啶-2-基甲酯2小时,再用3-溴代-1-丙醇(2-当量)处理16小时。然后按实施例1b所述方法,在丙酮中用无水碳酸钾处理。该粗品用与实施1b相同的色谱条件纯化,得无色油(51%),即为该标题化合物。将它转化为其盐酸盐并从丙酮中析出,mp.164-167℃。1H NMR(HCl盐)(d6DMSO)δ:10.35(br.s,1H),7.85(d,1H),7.32(d,1H),7.07-7.20(m,2H),4.54(t,2H),4.13(t,2H),4.05(d,2H),3.25-3.43(m,2H),2.74-3.15(m,3H),2.20-2.33(m,2H),2.00-2.15(m,1H),1.35-1.95(m,10H).
实施例3
N-[(1-正丁基-4-哌啶基)甲基]-3,4-二氢-2H-[1,3]噁嗪并[3,2-a]吲哚-10-甲酰胺(E3)
方法1:用溶于氯仿(8ml)的N-[(1-正丁基哌啶-4-基)甲基]吲哚-3-甲酰胺,D1,(100mg,0.32mmol)溶液搅拌下处理溶于氯仿(3ml)的N-氯代琥珀酰亚胺(57mg,0.48mmol)溶液;室温搅拌2小时,然后用3-溴代-1-丙醇(0.03ml,0.32mmol)处理,搅拌16小时后,再加入3-溴代-1-丙醇10.03ml,0.32mmol);再于室温搅拌3小时,然后用过量的10%Na2CO3溶液处理,用氯仿萃取,萃取液用Na2SO4干燥,真空浓缩得黄色油状残留物。将该物溶于丙酮(10ml)中,用无水碳酸钾(130mg,0.96mmol)处理,室温搅拌16小时。将该混合物真空浓缩,残留物用10%Na2CO3溶液(10ml)处理,用氯仿萃取,萃取液用Na2SO4干燥,真空浓缩,得黄色油状残留物,用色谱法纯化;先用硅胶,氯仿/甲醇(19∶1)洗脱,然后用碱性氧化铝,用乙酸乙酯洗脱,得无色油;该物以白色固体(20mg,17%)从***中析出,mp.110-113℃,即为该标题化合物(E3)。1H NMR(CDCl3)δ:8.34(d,1H),7.05-7.30(m,3H),6.55(t,1H),4.53(t,2H),4.10(t,2H),3.33(t,2H),2.90-3.05(m,2H),2.25-2.45(m,4H),1.90-2.25(m,2H),1.20-1.85(m,9H),0.92(t,3H).MS(Cl)MH+370.
方法2:将新蒸出的3-溴代-1-丙醇(69ml,0.77mol)在通氮气以及室温搅拌下加到混悬于氯仿(2L)的N-1-[(正丁基-4-哌啶基)甲基]吲哚-3-甲酰胺(D1,120g,0.38mol)混悬液中,在5分钟内分批加入无水N-氯代琥珀酰亚胺(55g,0.42mol),所得的黄色溶液搅拌2.5小时,然后用1M HCl***溶液(15ml,0.015mol)处理。该反应适度放热,颜色变为橙色。进一步反应2小时后,用10%Na2CO3溶液(700ml)处理反应混合物,分出氯仿层,用Na2SO4干燥,真空浓缩,得粘稠的红色油状残留物。该物用丙酮(1.5L)和无水碳酸钾(130g,0.95mol)处理,然后室温搅拌18小时。将该反应混合物真空浓缩,残留物用水(1L)处理并用乙酸乙酯(1L)萃取。经放置,从该乙酸乙酯萃取液中析出固体。2小时后,于8℃滤出该固体,干燥,得51.7g该标题化合物(E3),为米色固体。该母液用1M盐酸(800ml)萃取,然后用K2CO3将该酸性萃取液碱化,用氯仿(2×700ml)萃取。合并氯仿萃取液,用Na2SO4干燥,真空浓缩,残留物用硅胶色谱纯化,用氯仿/甲醇(96∶4)洗脱,得黄色油状物。该物用***研磨,又得21.3g该标题化合物(E3),为白色固体。将它转化或盐酸,乙醇/60-80石油醚,重结晶,得白色固体,mp254-256℃(分解)。HCl盐-1H NMR(D2O)δ:7.90(d,1H),6.88-7.20(m,3H),4.35(bt,2H),3.70(bt,2H),3.40(bd,2H),3.20(bd,2H),2.9(bt,2H),2.65(bt,2H),2.12(bt,2H),1.20-1.90(m,9H),0.87(t,3H).
元素分析结果如下:
理论值 实测值碳 65.09 64.76, 64.75氢 7.95 7.73, 7.77氮 10.35 10.35, 10.36
说明说明1(关于实施例3,13,14,19如28的中间产物)a)N-(1-正丁基-4-哌啶基)甲胺
将溶于乙醇(700ml)的异-3-哌啶甲酰胺(70g,0.55mol)和1-溴丁烷(58.8ml,0.55mol)的溶液搅拌下用无水碳酸钾(152g,1.10mol)处理,加热回流3小时。将混合物冷却过滤,滤液真空浓缩。将油状残留物溶于氯仿(400ml)中,用水(1×300ml)洗涤,然后用Na2SO4干燥,真空浓缩,得黄色油状残留物(77.5g)。将该物与五氧化二磷(75g)充分混合,加热到160-180℃,通氮气,细心搅拌2.5小时。将反应混合物冷却,然后用水(500ml)处理,当用体物质溶解后,加入固体K2CO3碱化该溶液,用乙酸乙酯(2×400ml)萃取。合并萃取液,用Na2SO4干燥,真空浓缩,得棕色油状残留物(78g)。将该物溶于无水***(400ml)中,并在通氮气、0℃搅拌下滴加到混悬于***(200ml)中氢化铝锂(25g,0.66mol)混悬液中,该步骤在30分钟内完成。滴加完毕后,将该混合物加热至室温,搅拌18小时;再冷却到0℃,谨慎地用水(25ml),10%NaOH溶液(25ml)及再用水(75ml)处理,用硅藻土过滤,滤液真空浓缩,得棕色油状残留物,经真空蒸馏,得该标题化合物,为无色油(668,71%),bp96-99℃(在3mmHg下)。1H NMR(CDCl3)δ:2.90-3.02(m,2H),2.58(d,2H),2.25-2.38(m,2H),1.65-2.00(m,4H),1.08-1.58(m,9H),0.92(t,3H).
b)N-(1-正丁基-4-哌啶基甲基)引哚-3-甲酰胺
将草酰氯(0.81ml)和无水二甲基甲酰胺(3滴)在通氮气、0℃搅拌下加到溶于二氯甲烷(20ml)的吲哚-3-羧酸(1g)溶液中。3小时后,减压蒸出该溶剂。将残留的酰基氯(420mg)部分溶于二氯甲烷(112mg)中,滴加到溶于二氯甲烷(12ml)的N-正丁基-4-哌啶基甲胺(400mg)溶液中,再加入三乙胺(0.36ml)。室温搅拌过夜。该反应混合物用饱和NaHCO3溶液洗涤,该有机相用Na2SO4干燥,减压蒸除溶剂,残留物经乙酸乙酯重结晶,得该标题化合物(D1)(467mg,64%)。1H NMR(CDCl3)250 MHzδ:9.29(br s,1H),8.05-7.9(m,1H),7.81(d,1H),7.55-7.4(m,1H),7.39-7.2(m,2H),6.28(brs,1H),3.39(t,2H),3.0(brd,2H),2.45-2.25(m,2H),2.1-1.1(m,11H),0.9(t,3H).
5HT4受体拮抗剂活性
1)豚鼠结肠
用雄性豚鼠,体重250-400g。约3cm长的纵肠肌丛由该远侧结肠区获得。将该纵肠肌丛页重0.5g悬挂在含有克氏(Krebs)溶液的离析组织浴中,充入含5%CO2的O2,保持温度在37℃。在所有的实验中,该克氏溶液中还含有10-7Mmethiothepin和10-6Mgranisetron,以阻滞5-HT1,5-HT2和5-HT3受体。
以30s接触时间和15分钟一个给药周期,用5-HT画出一个简单的浓度-反应曲线,选出使该肌肉组织大约40-70%产生最大收缩的5-HT的浓度(大约10-7M)然后每隔15分钟交替给药:先给该浓度的5-HT,然后给大约等效浓度的烟碱受体激动剂,二甲基苯基哌嗪鎓(DMPP)。当对5-HT和DMPP的反应一致时,增加推定的5-HT受体拮抗剂的浓度,然后将其加到组织溶液中,以由5-HT或DMPP所致收缩降低的百分比测定该化合物的效应。从该数据中,所测出pIC50值,该值的定义为:降低收缩达50%时的拮抗剂的-log浓度。人们认为能降低对5-HT的反应而对DMPP无作用的化合物可作为5-HT4受体拮抗剂。
在大约pIC50=7或更高的浓度范围内,化合物一般有活性;尤其是当Y是O时,E1,E2,E3,E4,E5,E6,E8,E15和E27显示出良好的活性,当Y是NH时,E3、E20、E23和E28显示出良好的活性。
2)小猪心房
化合物在小猪自主博动屏上进行试验(Naunyn-Achmiedeberg′sArch.Pharmacol.342,619-622)。实施例3化合物的PKB(-log K)值为10.05。
3)鼠食管
按Baxter et al.Naunyn-Schmicdeberg′s Arch.Pharmacol.,343,439-446(1991)方法得到鼠食管膜粘膜肌层。分出粘膜层里面的平滑肌管,将其固定在37℃充氧(95%O2/5%CO2)的台罗德氏(Tyrodes)溶液中用于等张记录。所有的实验均在预先处理的优降宁制剂(100μM处理15分钟,然后洗净)中及在古柯碱(30μM)存在下进行。预先用碳酰胆碱(3μM)收缩该食管组织后可以得到对5-HT的松驰反应。
4)5-HT诱导的在狗胃囊中的能动性
化合物体内实验按下述文献提供方法进行:“用BRL 24924,一个新的胃原动力剂(prokinetic)刺激犬的能动性”,Bermudezet al.,J.Gastrointestinal motility,1990,2(4),281-286。
抗焦虑活性体内实验
鼠群相互作用实验
将鼠(雄性,Sprague Dawleys,Charles River,250-300g)8只一组安置在一个房间内呆5天。然后在该实验开始前将它们分开安置在与该实验室相邻的房间里呆4天。实验开始时,给鼠口服载体,试验化合物或苯并二氮)抗焦虑药,剂眠宁,二只鼠为一组(n=8-16),间隔15分钟。实验在上午10点开始。30分钟后,将它们按重量配对(第一次相遇)放入带有隔离间的群体相互作用箱内,每2只放入一个单间。该箱由自包的有机玻璃制成,54cm×37cm×26cm,前面是透明的有机玻璃,无盖,底被分成24个正方形,箱子内光照明亮(1151ux)。在其次的15分钟内,通过远离的电视监测,给主动的属体相互作用表现(刷毛,嗅,翻越或爬下,追逐,咬,爬的打斗)打分,得出相互作用的总成绩。每个鼠越过的隔离间数亦打分并计算总数。每个实验结束后,将该箱子仔细擦净。
E3增加相互作用的总成绩,口服剂量在0.01-10mg/Kg范围以上。
Claims (13)
2.按照权利要求1的化合物,其中Z为式(a)并且(CH2)n1与该氮杂环的碳原子相连。
3.按照权利要求2的化合物,其中Z为N-取代4-哌啶甲基。
4.按照权利要求3的化合物,其中N-取代基是C2-4的烷基或苄基。
5.按照权利要求1的化合物,其为N-[(1-正丁基-4-哌啶基)甲基]-3,4-二氢-2H-[1,3]噁嗪并[3,2-a]吲哚-10-甲酰胺或其可药用的盐。
6.按照权利要求1的化合物,其为N-[(1-正丁基-4-哌啶基)甲基]-3,4-二氢-2H-[1,3]噁嗪并[3,2-a]吲哚-10-甲酰胺盐酸盐。
7.一种药物组合物,它包含权利要求1-6中任一项的化合物和药学上可接受的载体。
8.按照权利要求1的化合物用作治疗活性物质的用途。
9.按照权利要求1的化合物在生产作为5-HT4受体拮抗剂的药物中的用途。
10.按照权利要求9的用途,其作为5-HT4拮抗剂在生产用于治疗或预防胃肠疾病、心血管疾病以及中枢神经***疾病的药物中的用途。
11.按照权利要求9的化合物的用途,其作为5-HT4拮抗剂在生产用于治疗应激性肠综合症的药物中的用途。
12.按照权利要求9的化合物的用途,其作为5-HT4拮抗剂在生产用于治疗尿失禁的药物中的用途。
13.按照权利要求9的化合物的用途,其作为5-HT4拮抗剂在生产用于治疗房性心律失常和中风的药物中的用途。
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GB9227045.3 | 1992-12-29 | ||
GB9218846.5 | 1992-12-29 | ||
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Families Citing this family (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5852014A (en) * | 1992-03-12 | 1998-12-22 | Smithkline Beecham P.L.C. | Condensed indole derivatives as 5HT4 -receptor antagonists |
GB9316195D0 (en) * | 1993-08-05 | 1993-09-22 | Smithkline Beecham Plc | Pharmaceuticals |
US5998409A (en) * | 1992-03-12 | 1999-12-07 | Smithkline Beecham Plc | Condensed indole derivatives as 5HT4 -receptor antagonists |
MX9305947A (es) * | 1992-09-29 | 1994-06-30 | Smithkline Beecham Plc | Compuestos antagonistas del receptor 5-ht4, procedimiento para su preparacion y composiciones farmaceuticas que las contienen. |
JPH08502283A (ja) * | 1992-10-16 | 1996-03-12 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 5−ht▲下4▼レセプターアンタゴニスト用の縮合環系n−アルキルピペリジニル−4−メチルカルボン酸エステル/アミド |
NZ257545A (en) * | 1992-11-05 | 1997-01-29 | Smithkline Beecham Plc | Heterocyclic (especially piperidine) derivatives and pharmaceutical compositions |
FR2699921B1 (fr) * | 1992-12-30 | 1995-02-10 | Synthelabo | Dérivés d'acide 2-(thien-2-yl)imidazo[2,1-b]benzothiazole-3-acétique, leur préparation et leur application en thérapeutique. |
GB9303340D0 (en) * | 1993-02-19 | 1993-04-07 | Smithkline Beecham Plc | Pharmaceuticals |
GB9310582D0 (en) * | 1993-05-22 | 1993-07-07 | Smithkline Beecham Plc | Pharmaceuticals |
GB9312348D0 (en) * | 1993-06-16 | 1993-07-28 | Smithkline Beecham Plc | Pharmaceuticals |
KR100219922B1 (ko) * | 1996-05-16 | 1999-09-01 | 이서봉 | 신규한 항바이러스성 6-아릴옥시 및 6-아릴카르보닐 2,4-피리미딘디온 유도체 및 그의 제조 방법 |
AU3464397A (en) * | 1996-07-02 | 1998-01-21 | Sang Sup Jew | Oxirane carboxylic acid derivative and its manufacturing method |
TR199900321T2 (xx) * | 1996-08-16 | 1999-04-21 | Smithkline Beecham P.L.C. | N-(1-nbutil - 4 - piperidil)metil) -3,4-dihidro -2H- (1,3) oksazino (3.2A) indol-10- Karboksamit haz�rlama prosesi ve prosesteki tuzlar ve ara �r�nler. |
US6100397A (en) * | 1996-08-16 | 2000-08-08 | Smithkline Beecham Plc | Process for the preparation of N-[(1-n butyl-4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a] indole-10-carboxamide and salts and intermediates in the process |
GB9618967D0 (en) * | 1996-09-11 | 1996-10-23 | Smithkline Beecham Plc | Pharmaceuticals |
GB9725933D0 (en) * | 1997-12-05 | 1998-02-04 | Smithkline Beecham Plc | Pharmaceuticals |
US6251893B1 (en) * | 1998-06-15 | 2001-06-26 | Nps Allelix Corp. | Bicyclic piperidine and piperazine compounds having 5-HT6 receptor affinity |
US20020091271A1 (en) | 1998-07-16 | 2002-07-11 | Smithkline Beecham Plc | Process for the preparation of an indole derivative |
GB9819035D0 (en) * | 1998-09-01 | 1998-10-28 | Cerebrus Res Ltd | Chemical compounds VII |
DE69935600T2 (de) * | 1998-09-10 | 2007-12-06 | F. Hoffmann-La Roche Ag | Dihydrobenzodioxincarbonsäureamid- und ketonderivate als 5-ht4-rezeptorantagonisten |
GB9820294D0 (en) * | 1998-09-17 | 1998-11-11 | Smithkline Beecham Plc | Pharmaceuticals |
US6545004B1 (en) | 1999-10-27 | 2003-04-08 | Cytokinetics, Inc. | Methods and compositions utilizing quinazolinones |
AU782870C (en) * | 2000-08-07 | 2007-03-15 | Glaxo Group Limited | The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions |
AU2005203196B9 (en) * | 2000-08-07 | 2009-04-09 | Glaxo Group Limited | The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions |
KR20030027010A (ko) * | 2000-08-07 | 2003-04-03 | 라보라뜨와르 글락소스미스클라인 | 심방 세동 예방 또는 치료용 의약의 제조에서의 5ht4수용체 길항제의 용도 |
AU782863C (en) * | 2000-08-07 | 2006-08-31 | Glaxo Group Limited | The use of 5HT4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions |
AU7655801A (en) * | 2000-08-08 | 2002-02-18 | Smithkline Beecham Plc | Pharmaceutical composition comprising condensed indole compound |
NZ535261A (en) * | 2000-08-08 | 2004-12-24 | Smithkline Beecham P | A tablet comprising the hydrochloride salt of N-(1-nbutyl-4-piperidinyl)methyl]-3,4-[1,3]oxazino[3,2-a] indole-10-carboxamide |
ATE329581T1 (de) * | 2002-02-14 | 2006-07-15 | Glaxo Group Ltd | Pharmazeutische formulierung, die n-((1-n-butyl-4-piperidinyl)menthyl)-3,4-dihydr -2h-(1, 3)oxazino(3,2-a)indol-10-carboxamid oder ein entsprechendes salz hiervon enthält, sowie deren herstellungsprozess, welcher trockengranulierung beinhaltet |
GB0211230D0 (en) | 2002-05-16 | 2002-06-26 | Medinnova Sf | Treatment of heart failure |
ITMI20031468A1 (it) | 2003-07-18 | 2005-01-19 | Acraf | Farmaco ativo nel dolore neuropatico |
ITMI20031467A1 (it) * | 2003-07-18 | 2005-01-19 | Acraf | Farmaco attivo nel dolore neuropatico |
CA2551171C (en) | 2003-12-23 | 2012-07-10 | Bio-Medisinsk Innovasjon As | Modulators of peripheral 5-ht receptors |
JP4612301B2 (ja) * | 2003-12-26 | 2011-01-12 | 広栄化学工業株式会社 | 1−アルキル−4−アミノメチルピペリジンの製造法 |
MX2009013815A (es) | 2007-06-22 | 2010-03-01 | Arqule Inc | Compuestos de quinazolinona y metodos de uso para los mismos. |
GB0905641D0 (en) * | 2009-04-01 | 2009-05-13 | Serodus As | Compounds |
WO2021116487A1 (en) | 2019-12-13 | 2021-06-17 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of niemann-pick c disease |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2557342A1 (de) * | 1975-12-19 | 1977-06-30 | Hoechst Ag | Basisch substituierte indolderivate und verfahren zu ihrer herstellung |
AU622330B2 (en) * | 1989-06-23 | 1992-04-02 | Takeda Chemical Industries Ltd. | Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides |
CA2030051C (en) * | 1989-11-17 | 2001-08-07 | Haruhiko Kikuchi | Indole derivatives |
US5189041A (en) * | 1990-11-16 | 1993-02-23 | Syntex (U.S.A.) Inc. | Tricyclic 5-ht3 receptor antagonists |
GB9103862D0 (en) * | 1991-02-25 | 1991-04-10 | Glaxo Group Ltd | Chemical compounds |
US5206382A (en) * | 1991-06-27 | 1993-04-27 | Fidia Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
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