CN1183765A - 对5-ht1a受体具高度亲和力的苯氧乙胺衍生物,其制备方法、作为药物的用途及含有它们的药物组合物 - Google Patents

对5-ht1a受体具高度亲和力的苯氧乙胺衍生物,其制备方法、作为药物的用途及含有它们的药物组合物 Download PDF

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CN1183765A
CN1183765A CN96193757A CN96193757A CN1183765A CN 1183765 A CN1183765 A CN 1183765A CN 96193757 A CN96193757 A CN 96193757A CN 96193757 A CN96193757 A CN 96193757A CN 1183765 A CN1183765 A CN 1183765A
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ethyl
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D·比格
J·波米尔
C·马丁
P·罗伯特
J－P·狄法尤克斯
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Ipsen Pharma SAS
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Abstract

对5－HT1A受体具有高亲合性的通式(Ⅰ)苯氧乙胺衍生物,其制备方法,含它们的药物组合物,它们的用途,尤其是作为胃酸分泌抑制剂或作为止吐剂。通式(Ⅰ)或其盐中,Ar为由一或多个取代基取代的苯基;和R为表示含1至10个碳原子的烃基,选自直链或支链烷基、链烯基或链炔基,单环或多环、饱和或不饱和环烷基、环烷基烷基或烷基环烷基;吡啶基或异喹啉基;可被一个或多个取代基取代的苯基。

Description

对5-HT1A受体具高度亲和力的苯氧乙胺衍生物， 其制备方法、作为药物的用途及含有它们的药物组合物
神经介质血清素(5-羟色胺，5-HT)在病因学及一些疾病的治疗中举足轻重(R.A.Glennon，J.Med.Chem.，30，1[1987])。很多5-HT受体已被确认并对5-HT能(serotoninergic)功能的选择性控制起积极作用。亚型5-HT1A因作用于其受体的化合物可用来治疗焦虑、抑郁、睡眠问题或心血管疾病而在某种程度来说特别引人注目(脑5-HT1A受体：行为和神经化学药理；Editors：C.T.Dourish，S.Ahlenius，P.H.Huston；Ellis Horwood，Ltd.，Chichester[1987])。5-HT1A拮抗剂也可用作止吐药(U.Wells，M.Ravenscroft，P.Bhandari，P.L.R.Andrews，Med.Sci.Symp.，Ser.5，179[1993])；F.Okada，Y.Torii，H.Saito，N.Matsuki，Ipn.药理杂志，64，109[1994])或作为抗分泌剂(J.S.Gidda，J.M.Schaus，EP455510 A2；D.C.Evans，J.S.Gidda，Gastroenterolgy，104，A76[1993])。
本发明涉及对5-HT1A具高度亲和力的苯氧乙胺的新的衍生物、其制备方法、含有它们的药物组合物，并涉及它们作为特异性胃酸分泌抑制剂或作为止吐药的用途。
通式I产物及这些产物的盐也是本发明的目的：
Figure A9619375700061
其中Ar表示被一个或多个取代基取代的苯基；R表示含1至10个碳原子的烃基，选自直链或支链烷基、链烯基或链炔基，单环或多环、饱和或不饱和环烷基、环烷基烷基或烷基环烷基；吡啶基或异喹啉基；可被一个或多个取代基取代的苯基。
本发明的目的更具体地讲是限定如上的通式I的产物，其特征是Ar表示的苯基的取代基(一种或多种)选自卤素、低级烷基、低级烷氧基、氰基、硝基、羟基、C(O)NR1R2、C(O)NHOR3、NHC(O)R4、NHC(O)NHR5、CH2NHC(O)NHR6、CH2OR7、CH2NHC(O)R8、CO2R9、NHCO2R10、C(O)R11和SR12基团。
其中R1、R2、R3、R4、R5、R6、R7和R8独立地是氢原子或低级烷基，而R9、R10、R11和R12独立地是低级烷基；R代表苯基的取代基(一种或多种)选自低级烷基、低级烷氧基、卤素、羟基、硝基、氨基或酰氨基。
上述定义中，术语卤素表示氟原子、氯原子、溴原子或碘原子，优选氟或碘。术语低级烷基表示优选含1至6个碳原子的直链或支链烷基，特别是含1至4个碳原子的烷基如甲基、乙基、丙基、丁基、异丁基、仲丁基及叔丁基。
在链烯基中，包括乙烯基、烯丙基和丁烯基。链炔基中包括；乙炔基或炔丙基。
在酰氨基中包括乙酰氨基及丙酰氨基。
低级烷氧基可以相应于上述烷基。优选甲氧基、乙氧基或异丙氧基。
饱和单环环烷基可以选自含3至7个碳原子的基团如环丙基、环丁基、环戊基、环己基或环庚基。
单或多不饱和环烷基可以选自环丁烯、环戊烯、环己烯、环戊二烯或环己二烯基。
多环环烷基的例子有双环-[2，2，1]-庚基或金刚烷基。
式I产物可以与酸，特别是药用酸，形成加成盐。
盐的例子在下面的实验部分中给出。
本发明特别的目的是上述通式I化合物，其特征是Ar表示的是苯基，它被如下取代基取代：羟基、甲氧基、-C(O)NHMe、-NHC(O)Me、-NHCOR10(R10表示甲基或乙基)、-NHCONH2、-C(O)NHOH，而R表示环戊基、环己基、环庚基、环庚基甲基、金刚烷基、叔丁基、新戊基、苯基或氟代苯基。
Ar表示的苯基的取代基优选在2或3位。
具体地讲，本发明的目的是在下述实施例中描述的产物，特别是与下式相应的产物及这些化合物与有机或无机酸形成的盐：-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]苯甲酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]金刚烷酰胺；-N[4-(2-(2-甲氨基羰基苯氧基)乙基)氨基)丁基]苯甲酰胺；-N[4-(2-(2-羟基苯氧基)乙基)氨基丁基]苯甲酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]环己酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]环庚酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]2-双环[2，2，1]庚酰胺；
本发明的目的也包括制备限定如上的、通式I产品的制备方法，其特征是：A)其中Ar定义如上的产品式II与其中X表示卤素或假卤素的产品式III反应得到产品式IV，
Figure A9619375700083
产品式IV除去苯邻二甲酰亚胺基得到产品式V。
Figure A9619375700091
用酰化试剂处理产品式V得到产品式VI，酰化试剂衍生自RCO2H酸，其中R的定义如上或者B)产品式VII与下式的N-苄基乙醇胺反应得到产品式
Figure A9619375700095
将其转变为产品式IX其中Y表示卤素或假卤素，式产品IX通过与式ArOH的酚衍生物反应转变为上述产品式VI，而产品式VI通过苄基的裂解转变为产品式I，如果需要，则通过相应的酸的作用将产品式I转变为酸加成盐。
                      反应路线1
Figure A9619375700111
在此反应路线中，Ar和R限定如上，X表示起始基团如氯、溴、碘、甲磺酰氧基、苯磺酰氧基或对甲苯磺酰氧基，换言之，卤素或假卤素。
通式II的化合物与通式III的化合物制备通式IV的化合物的反应在极性溶剂如乙腈或二甲基甲酰胺中在酸性中和剂如碳酸钾或碳酸钠的存在下加热很容易完成。通式IV的苯邻二甲酰亚胺可以按照常规方法转变为式V的伯胺，例如通过与肼的水合物优选在溶剂如乙醇中加热。这样得到的通式V的伯胺通过与酸RCO2H衍生物反应转变为式VI的酰胺，其中酸衍生物可以是适当的酰氯或酸酐或其它活化酸衍生物如通常在肽偶合反应中所用的。反应在惰性溶剂如乙醚、四氢呋喃或二氯甲烷中进行，且一般在酸性中和剂如叔胺如三乙胺或二异丙基乙胺的存在下进行。
                      反应路线    2：
Figure A9619375700131
在此反应路线中，Ar和R的限定如上，而Y与X相同或不同，表示起始基团如氯、溴、碘、甲磺酰氧基、苯甲磺酰氧基或对甲苯磺酰氧基，换言之，卤素或假卤素。
可以通过将通式VII的化合物与N-苄基乙醇胺在极性溶剂如乙醇中在酸性中和剂如叔胺或无机碱如碳酸钠或碳酸钾的存在下加热制备通式VIII的化合物。或者，可以简单地在溶剂的存在下，优选在氮气氛中将通式VII的化合物与过量的N-苄基乙醇胺加热至60至90℃制备通式VII的化合物。可以通过与甲磺酰氯在惰性溶剂如二氯甲烷中在有机碱如三乙胺或二-异丙基乙胺的存在下将这样制得的通式VIII的化合物转变为如通式IX(Y＝Cl)的氯化物。可通过将通式IX的化合物与由适当的ArOH酚用碱如氢氧化钠、氢氧化钾或氢化钠制备的苯氧基阴离子反应来制备通式VI的化合物。此反应在质子惰性的溶剂并优选在偶极质子惰性溶剂如二甲基甲酰胺中进行。
按照脱苄基的已知的一般方法，例如，催化氢化或与氯甲酸酯如氯甲酸乙烯基酯或氯甲酸α-氯乙酯反应后进行水解或甲醇解反应，通过通式VV的化合物脱保护来制备通式I的化合物。脱苄基的其它方法如“Protective Groups in Organic Synthesis”(T.W.Green，P.G.M.Wuts；第二版，J.Wiley and Sons，Inc，364-66[1991])所述也可使用，该方法应与通式VI的芳基核(一个或多个)相容。
也可按照在下面的实验部分给出的常规方法进行式I产物的任何成盐作用。
本发明的化合物具有有用的药理性质。因此，已发现本发明的化合物对5HT1A受体具有高度亲和性。
因此，本发明的化合物可以具多种医疗用途。
此化合物可以抑制胃酸分泌和顺铂等引起的呕吐。因此，本发明的化合物可以用作止吐药或用来治疗需要此治疗的或需要降低胃酸分泌的疾病，如胃或十二指肠溃疡或胃炎、胃食管反流、胃性消化不良、左林格-埃利森综合征或恶心。
本发明的化合物也对胃排空和小肠蠕动有作用。例如，它们可以用来治疗便秘、术后张力缺乏或胃轻瘫。
它们也可以治疗某些神经系统疾病如焦虑、抑郁、睡眠问题如失眠、药物依赖、阿尔茨海默病、食欲紊乱如食欲缺乏或头晕。本发明的这些化合物也可以用于治疗心血管系统疾病，特别是高血压。
下面的实验部分给出了本发明化合物的药理性质。
这些性质使式I产物适于药用。定义如上的式I产物及其与有机或无机酸形成的酸加成盐、以及含有此活性组份的药物组合物、上述药物的至少一种，也是本申请的药物方面的目的。
本发明也涉及含本发明化合物或其药用酸加成盐与药用载体结合的药物组合物。该药物组合物可以是固体，例如，散剂、颗粒剂、片剂、凝胶或栓剂。适当的固体载体可以是如磷酸钙、硬脂酸镁、滑石、蔗糖、乳糖、糊精、淀粉、明胶、纤维素、甲基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷和蜡。
含本发明化合物的药物组合物也可以是液体，例如，溶液剂、乳剂、混悬剂或糖浆。适宜的液体载体可以是如水、有机溶剂如甘油或乙二醇及其在水中以不同比例加入到油或药用脂肪中的混合物。灭菌液体化合物可以用于肌肉、腹膜内或皮下注射，灭菌化合物也可静脉内给药。
定义如上的式I产物在制备止吐药、降低胃酸分泌药、加速胃排空药、加速小肠运送药、治疗焦虑、抑郁或睡眠问题药物及心血管疾病药中的用途也是本发明的目的。
本发明的目的还有新的工业产品，尤其是制备如上定义的式I，式IV，V，VI，VIII和IX得的新的工业产物。
本发明的起始物质，特别是式II、III和VII产物的起始物，是已知的产物，或可以通过已知的产物制备。例如，N-苄基乙醇胺是由ACROS公司市售的产品。
式II的产物可以通过经典方法由相应的苯氧基乙胺制备，例如通过苯甲酰胺中间体被氢化锂铝还原或等同的方法。或者，可以按照常规方法使用还原胺化作用。
苯氧乙基乙胺可以按照常规方法制备，例如苯酚与氯乙腈在碱性介质中反应后用氢化锂铝将腈还原，见Chim.Ther.8(3)259-270(1973)。
式III的化合物为市售产品或可以通过本领域技术人员已知的方法制备。X表示溴原子的式III的产物由ACROS公司经售。
X表示其它卤原子如氯或碘或者假卤素如甲磺酰基、甲苯磺酰基或苯磺酰基的式III的产物，可以通过常规方法由Maybridge公司销售的相应的醇制备。
式V的产物可以按照由醇形成甲磺酰基酯的已知方法由ω-羟基丁酰胺制备，见J.Org.Chem.35(9)，3195-6(1970)。
下列实施例用来说明上述方法，在任何情况下，都不必看作是对本发明范围的限制。实验部分：实施例1N-[4-{2-(2-甲氧基苯基)乙基}氨基丁基]苯甲酰胺(I，Ar＝2-甲氧基苯基，R＝苯基：表1，化合物1)步骤1：N-[4-{苄基[2-(2-甲氧基苯氧基)乙基]氨基}丁基]苯邻二甲酰亚胺(IV，Ar＝2-甲氧基苯基)
将N-(4-溴丁基)苯邻二甲酰亚胺(9.87g，0.035mol)的乙腈(200ml)溶液加到N-苄基[2-(2-甲氧基苯氧基)乙基]胺(8.5g，0.033mol)的、含碳酸钾(9.1g，0.0066mol)的乙腈(170ml)热(60℃)溶液中，见此混合物搅拌并加热回流6小时，然后将其冷却至室温、过滤、减压蒸除溶剂。将残余物溶于二氯甲烷(500ml)中，用水(3×50ml)洗涤并用硫酸镁干燥。过滤并蒸除溶剂得到油状物，通过闪式色谱在硅胶柱上用乙酸乙酯/庚烷洗脱液(1/4，然后3/7)进行纯化，得到7.2g(48％)化合物IV，为油状物。NMR(CDCl3)，δ：1.5-1.7(m，4H)，2.54-2.67(t，2H)，2.84-2.97(t，2H)，3.59-3.73(m，4H)，3.83(s，3H)，3.99-4.15(m，2H)，6.79-6.89(m，4H)，7.20-7.32(m，5H)，7.64-7.88(m，4H)步骤2：N-苄基-N-[2-(2-甲氧基苯氧基)乙基]1，4-丁二胺(V，Ar＝2-甲氧苯基)
将肼水合物(0.83ml，0.017mol)的乙醇(20ml)溶液加到N-[4-{苄基[2-(2-甲氧基苯氧基)乙基]氨基}丁基]苯邻二甲酰亚胺(7.2g，0.016mol)的乙醇(70ml)溶液中，并搅拌此溶液，加热回流3小时。冷却至室温后，减压蒸除溶剂并将残余油状物用1N盐酸(40ml)处理。过滤移出沉淀物，在水中洗涤，将滤液和洗涤液用碳酸钾(16g)调为碱性。用二氯甲烷(3×80ml)提取分离后的油并用硫酸镁干燥提取物。过滤并减压蒸除溶剂得到4.4g(86％)油状化合物。用氯化氢气体在乙醚中的饱和溶液处理此游离碱的醚化溶液，得到N-苄基-N-[2-(2-甲氧基苯氧基)乙基]-1，4-丁二胺二盐酸盐；由乙醇中重结晶后，mp200-202℃。步骤3N-[4-{苄基[2-(2-甲氧基苯氧基)乙基]氨基}丁基]苯甲酰胺(VI，Ar＝2-甲氧基苯基，R＝苯基)
搅拌并冷却(5-10℃)的同时，将苯甲酰氯(0.9ml，0.0076mol)的四氢呋喃(25ml)溶液加到三乙胺(1.05ml，0.0076mol)的四氢呋喃(25ml)溶液中。在10℃保持30分钟后，在室温保持1小时，减压蒸除溶剂。将残余物溶于二氯甲烷中。用水洗涤此溶液并用硫酸镁干燥。过滤并减压蒸除溶剂得到油状物，通过闪式色谱在硅胶上用乙酸乙酯/己烷(1/1然后3/2)作洗脱液纯化此油状物，得到油状所要化合物2g(61％)。NMR(CDCl3)，δ：1.58-1.85(m，4H)，2.60-2.66(m，2H)，2.85-2.97(t，2H)，3.39-3.45(m，2H)，3.66(s，2H)，3.8(s，3H)，3.99-4.12(t，2H)，6.42(larges，1H)，6.76-6.90(m，4H)，7.21-7.46(m，8H)，7.66-7.77(m，2H).步骤4N-[4-{2-(2-甲氧基苯氧基)乙基}氨基丁基]苯甲酰胺(I，Ar＝2-甲氧基苯基，R＝苯基：表1中化合物1)
将钯碳催化剂(0.8g，10％)加到N-[4-{苄基[2-(2-甲氧基苯氧基)乙基]氨基}丁基]苯甲酰胺(2g，0.0046mol)的甲醇(30ml)溶液中，此混合物在1.5帕斯卡下在室温氢化。当氢被吸收彻底后(约3小时)，过滤除去催化剂并减压蒸除溶剂得到1.2g(76％)油状化合物I。用氯化氢气体的饱和乙醚溶液处理此游离碱的乙醚化溶液得到1.0g(59％)化合物1的二盐酸盐，为白色结晶，mp118-120℃。实施例2N-[4-{2-(2-甲氧基苯氧基)乙基}氨基丁基]-1-金刚烷酰胺(I，Ar＝2-甲氧基苯基，R＝1-金刚烷基：表1中化合物2)步骤1N-[4-{苄基[2-(2-甲氧基苯氧基]乙基]氨基}丁基]-1-金刚烷酰胺(VI，Ar＝2-甲氧基苯基，R＝1-金刚烷基)
将1-金刚烷羰基氯(2.14g，0.011mol)分批加到冷却的(5℃)N-苄基-N-[2-(2-甲氧基苯氧基)乙基]-1，4-丁二胺(按照实施例1描述的方法制备)和三乙胺(1.54ml，0.0011mol)的四氢呋喃(40ml)溶液中。30分钟后，将此反应混合物再加热至室温，1小时后，减压蒸除溶剂。将残余物溶解在二氯甲烷中，用水洗涤，并用硫酸镁干燥。过滤并减压蒸除溶剂得到油状物，通过闪式色谱在硅胶上用乙酸乙酯/己烷(1/2然后3/4)作洗脱液纯化得到3g(61％)标题化合物，为油状物。NMR(CDCl3)，δ：1.24-1；29(m，2H)，1.53-1.67(m，4H)，1.67-1.94(m，14H)，2.5-2.7(m，2H)，2.93-2.96(t，2H)，3.21-3.23(m，2H)，3.71(s，2H)，3.85(s，3H)，4.07-4.10(t，2H)，6.82-6.92(m，4H)，7.24-7.37(m，5H).步骤2N-[4-{2-(2-甲氧基苯氧基)乙基}氨基丁基]-1-金刚烷酰胺(I，Ar＝2-甲氧基苯基，R＝1-金刚烷基：表1中化合物2)
将钯碳催化剂(1.5g，10％)加到N-[4-{苄基[2-(2-甲氧基苯氧基)乙基]氨基}丁基]-1-金刚烷酰胺(2.85g，0.058mol)的甲醇(30ml)溶液中，此混合物在1.5帕斯卡下在室温氢化。当氢被吸收彻底后(约3小时)，过滤除去催化剂并减压蒸除溶剂得到2g(87％)油状化合物I。用富马酸(0.17g)的丙酮溶液处理此游离碱(0.6g)的丙酮溶液得到0.5g化合物2的富马酸盐，为白色结晶，mp122-124℃。实施例3N-[4-{2-(2-硝基苯氧基)乙基]氨基}丁基]苯甲酰胺(I，Ar＝2-硝基苯基，R＝苯基：表1中化合物8)步骤1：N-[4-{苄基(2-羟基苯氧基)乙基]氨基]丁基]苯甲酰胺(VIII，R＝苯基)
在氮气氛下，将N-苄氨基乙醇(60.5g，56.8m1，0.4mol)和N-[4-(甲磺酰氧基)丁基]苯甲酰胺(51.5g，0.19mol)的混合物在75-80℃加热2小时。冷却此反应混合物，将其溶解在二氯甲烷(400ml)中，用水(3×100ml)洗涤此溶液，然后用硫酸镁干燥。过滤此溶液并减压蒸除溶剂得到油状物，用二异丙基醚结晶得到51.5g(83％)化合物VIII，为白色结晶，mp61-62℃。步骤2：N-[4-{苄基(2-氯乙基)氨基}丁基]苯甲酰胺(IX，R＝苯基，Y＝Cl)
将甲磺酰基氯(14.8g，10ml，0.13mol)滴加到冷却的(5℃)N-[4-{苄基(2-羟基)乙基]氨基}本原则丁基]苯甲酰胺(35g，0.11mol)的二氯甲烷(300ml)溶液中，同时搅拌。将此溶液的温度升至室温，1.5小时后加入三乙胺(13g，18ml，0.13mol)并继续搅拌1.5小时。在冰水(150ml)和饱和盐水(2×100ml)中洗涤此反应混合物并用硫酸镁干燥。过滤并减压蒸除溶剂得到36.6g(99％)标题化合物，为淡棕色油状物，当将其保持在4℃时出现结晶。NMR(CDCl3)，δ：1.58-1.67(m，4H)，2.58(m，2H)，2.83(t，2H，J＝6，8Hz)，3.40-3.45(q，2H，J＝6，5Hz)，3.51(t，2H，J＝6，8Hz)，3.66(s，2H)，6.19(s，1H)，7.24-7.48(m，8H)，7.73-7.175(m，2H)步骤3N-[4-{苄基[2-(2-硝基苯氧基)乙基]氨基}丁基]苯甲酰胺
(VI，Ar＝2-硝基苯基，R＝苯基)
在氮气氛下，将2-硝基苯酚(0.56g，0.004mol)分批加入搅拌的氢化钠(在60％油中的分散液160mg，0.004mol)的无水二甲基甲酰胺(10ml)悬液中。当无氢气放出后，搅拌的同时，向其中滴加N-[4-{苄基(2-氯乙基)氨基}丁基]苯甲酰胺(1.6g，0.0046mol)的无水二甲基甲酰胺(5ml)溶液。将此反应混合物在65-70℃加热1.5小时后，冷却至室温，并将其到入碎冰中。用乙醚(50ml)提取此混合物。分离有机相并用水(3×20ml)洗涤，用硫酸镁干燥。过滤并减压蒸除溶剂得到1.3g油状物，通过闪式色谱在硅胶上用乙酸乙酯/庚烷(3/1)的混合物作洗脱液纯化。得到油状标题化合物(0.94g，52％)。NMR(CDCl3)，δ：1.59-1.65(m，4H)，2.62(t，2H，J＝0，65Hz)，2.92(t，2H，J＝0，55Hz)，3.42-3.45(m，2H)，3.67(s，2H)，4.09(t，2H，J＝0，55Hz)，6.45(s，1H)，6.95-6.98(m，2H)，7.20-7.32(m，5H)，7.38-7.46(m，4H)，7.76-7.79(m，3H)步骤4N-[4-{2-(2-硝基苯氧基)乙基}氨基丁基]苯甲酰胺(I，Ar＝2-硝基苯基，R＝苯基：表1中化合物8)
在氮气氛中，在冰浴冷却下，将氯甲酸α-氯乙酯(0.28g，0.002mol)的无水二氯甲烷(1.8ml)溶液滴加到N-[4-{苄基[2-(2-硝基)乙基]氨基}丁基]苯甲酰胺(0.82g，0.18mol)的无水二氯甲烷(9ml)溶液中。2小时后，减压蒸除溶剂。用甲醇(10ml)溶解此残余物并加热回流1小时。减压浓缩溶剂并加入乙酸乙酯(10ml)。过滤收集形成的沉淀，用乙酸乙酯和乙醚洗涤并干燥得到0.55g(76％)化合物I的盐酸盐，mp159.5-160℃。实施例4N-[4-{2-(2-甲基氨基羰基苯氧基)乙基]氨基}丁基]苯甲酰胺(I，Ar＝2-MeNHC(O)C6H4，R＝苯基：表1中化合物18)步骤1：N-[4-{苄基[2-(2-甲基氨基羰基苯氧基)乙基]氨基}丁基]苯甲酰胺(VI，Ar＝2-MeNHC(O)C6H4，R＝苯基)
将按照实施例3描述的方法制备的N-[4-{苄基[2-(2-氯苯氧基)乙基]氨基}丁基]苯甲酰胺(8.1g，0.023mol)的二甲基甲酰胺(50ml)溶液加到就地制备的搅拌的2-甲基氨基羰基苯酚钠溶液中。后者由2-甲基氨基羰基苯酚(3.0g，0.002mol)、氢氧化钠(0.8g，0.02mol)和水(4ml)在二甲基甲酰胺(50ml)溶液中制备。将此混合物在85℃加热4小时，冷却至室温，并将混合物到入冰水中。用乙酸乙酯(250ml)提取此混合物，有机相用2％氢氧化钠水溶液(100ml)和盐水(3×50ml)洗涤并用硫酸镁干燥。过滤并减压蒸除溶剂得到黄色油状物，用闪式色谱在硅胶上以乙酸乙酯作洗脱液纯化得到5.2g(57％)油状化合物VI。NMR(CDCl3)，δ：1.35-1.80(m，4H)，2.40-2.65(m，2H)，2.84-2.94(m，4H)，3.34-3.44(m，2H)，3.65(s，2H)，4.16(t，2H，J＝5，5Hz)，6.30-6.65(m，1H)，6.84-7.09(m，2H)，7.26-7.48(m，8H)，7.72-7.82(m，2H)，8.13-8.23(m，2H)步骤2：N-[4-{2-(2-甲基氨基羰基苯氧基)乙基]氨基}丁基]苯甲酰胺(I，Ar＝2-MeNHC(O)C6H4，R＝苯基：表1中化合物18)
将含有钯碳(10％)和失活水的催化剂加到N-[4-{苄基[2-(2-甲基氨基羰基苯氧基)乙基]氨基}丁基]苯甲酰胺(6.6g，0.015mol)的甲醇(200ml)溶液中，在常压下室温将此混合物氢化。当氢气吸收彻底后(约3小时)，过滤除去催化剂并减压蒸发滤液。在丙酮(15ml)中收集此残余物并用富马酸(1.04g，0.009mol)的丙酮(100ml)溶液处理。向沉淀收集到的油状固体中加入异丙醇(50ml)结晶。过滤收集白色结晶产物，用丙酮洗涤并干燥得到2.7g(38％)化合物18的半富马酸盐，mp159-161℃。
上述方法得到本发明化合物的游离碱或酸加成盐。如果本发明化合物是以与酸的加成盐的形式得到的，则可以用碱将酸加成盐的溶液碱化得到游离碱。反之，如果产物是游离碱，这可以通过在适宜的有机溶剂中溶解此游离碱并按照用游离碱与酸制备加成盐的常规方法用酸处理此溶液制备与酸形成的酸加成盐，特别是与药用酸形成的酸加成盐。
与之形成酸加成盐的酸的例子包括无机酸如硫酸、盐酸、氢溴酸或磷酸，或者有机酸如酒石酸、富马酸、马来酸、枸橼酸、辛酸、草酸、苯甲酸、甲磺酸、对甲苯磺酸、苯磺酸、琥珀酸或乙酸。
含不对称中心、外消旋混合物基个体光学活性异构体的本发明化合物也在本发明的范围内。
下表1给出了按照上述方法制备的主要化合物，它只是举例说明而不限制本发明的范围。化合物1、2、8和18相应于上述实施例1、2、3和4。其它产品可以通过相同的方法制备。
表1
化合物编号     Ar     R     盐   mp(℃)
    12345678910111213141516171819202122232425262728293031323334     2-MeO.C6H42-MeO.C6H42-MeO.C6H42-MeO.C6H42-iPrO.C6H42-H2NC(O).C6H42-MeO.C6H42-O2N.C6H42-NC.C6H42-HOCH2.C6H42-MeS.C6H42-MeO.C6H42-MeO.C6H42-MeO.C6H42-MeO.C6H42-MeC(O).C6H42-MeO.C6H42-MeNHC(O).C6H43-H2NC(O).C6H42-HO.C6H42-MeC(O)NH.C6H42-MeO.C6H42-MeO.C6H42-F.C6H43-MeO.C6H42-MeO.C6H42-Me.C6H42，3-(MeO)2.C6H32-MeO.C6H42-MeO.C6H43-MeNHC(O).C6H42-Me2NC(O).C6H42-MeO.C6H42-MeO.C6H4     C6H51-金刚烷基2-吡啶基2-异喹啉基C6H5C6H52-MeC(O)NH.C6H4C6H5C6H5C6H5C6H52-HO.C6H42-MeO.C6H43-MeO.C6H44-MeCH(OH).C6H4C6H54-MeO.C6H4C6H5C6H5C6H5C6H54-O2N.C6H44-F.C6H4C6H5C6H5叔丁基C6H5C6H52，6-Me2.C6H33-I.C6H4C6H5C6H5CH2 tBu环己基     盐酸盐富马酸盐二盐酸盐二盐酸盐盐酸盐盐酸盐盐酸盐盐酸盐盐酸盐盐酸盐盐酸盐半富马酸盐富马酸盐富马酸盐半富马酸盐盐酯盐半富马酸盐半富马酸盐盐酸盐盐酸盐游离碱盐酸盐盐酸盐盐酸盐盐酸盐富马酸盐盐酸盐盐酸盐富马酸盐盐酸盐盐酸盐富马酸盐富马酸盐富马酸盐     118-120122-124152-154166-168108-110128-13292-94159.5-160168-168.5144-145.5140-140.5140-142120-12268-70152-154187-192.5135-137159-161264-266.5252-254.574-78162.5-163.5119-120.5167-168174-175.5149-151162-163141.5-142123-125121-121.5227-229126-128.5130-132134-136
    3536373839404142434445464748495051525354555657585960616263646566676869     2-MeO.C6H42-HONH(CO).C6H42，6-(MeO)2.C6H32-H2NC(O)NH.C6H42-MeO.C6H42-MeNHC(O)NHCH2.C6H42-MeO.C6H42-MeO.C6H42-MeO.C6H42-MeO2C.C6H42-MeO.C6H42-MeO.C6H42-MeNHC(O).C6H43-MeNHC(O).C6H43-MeC(O)NH.C6H42-MeO.C6H42-MeNHC(O).C6H43-MeNHC(O).C6H42-MeO.C6H42-MeO.C6H43-MeO.C6H42-MeO.C6H43-EtO2CNH.C6H42-MeNHC(O).C6H42-MeO.C6H43-H2NC(O)NH.C6H42-MeNHC(O).C6H43-MeNHC(O).C6H43-MeC(O)NH.C6H42-EtO.C6H42-HONC(O).C6H43-EtO2CNH.C6H43-MeO2C.C6H43-H2NC(O)NH.C6H42-MeO.C6H4     异丙基C6H5C6H5C6H5(CH2)4MeC6H5CH(nPr)2CH2CH(Me)2环戊基C6H51-甲基环己基环庚基CH2 tButButBu2-二环[2，2，1]庚基tBuCH2 tBuCH(Et)2C(Et)Me2 tRu4-甲基环己基C6H54-F.C6H4CH2环戊基C6H5环己基环己基CH2 tButBu环己基环己基CH2 tBuCH2 tBu环丙基   富马酸盐草酸盐草酸盐盐酸盐富马酸盐草酸盐富马酸盐富马酸盐富马酸盐盐酸盐富马酸盐富马酸盐半富马酸盐盐酸盐盐酸盐富马酸盐富马酸盐半富马酸盐丰富马酸盐富马酸盐(0.75)富马酸盐富马酸盐(0.75)草酸盐半富马酸盐富马酸盐草酸盐草酸盐草酸盐半富马酸盐富马酸盐盐酸盐盐酸盐盐酸盐盐酸盐富马酸盐     120-122147-148.5166-167.5193-194110-112170-171.5118-120134-136122-124103-106120-122125-126137-138169-171.5164-165.5130-131134-135.5145-146134-135115-116148.5-149127-128175-177154.5-156118-119141-143180-182171-173166-167131.5-133179-180204.5-205157-158144-14690-92
通过使用上述方法，也可制备下列产品，它们也是本发明的一部分并且它们构成了优选的产品：
    化合物     Ar     R
    ABCDEFGHIJKLMNOPQRSTUVWXYZAAABACAD     2-HONHC(O).C6H42-HONHC(O).C6H42-HONHC(O).C6H42-HONHC(O).C6H42-HONHC(O).C6H42-HONHC(O).C6H42-HONHC(O).C6H42-MeNHC(O).C6H42-MeNHC(O).C6H42-MeNHC(O).C6H42-MeNHC(O).C6H42-HO.C6H42-HO.C6H42-HO.C6H42-HO.C6H42-HO.C6H42-HO.C6H42-HO.C6H42-HO.C6H43-H2NC(O)NH.C6H43-H2NC(O)NH.C6H43-H2NC(O)NH.C6H43-H2NC(O)NH.C6H43-H2NC(O)NH.C6H43-H2NC(O)NH.C6H43-H2NC(O)NH.C6H43-EtO2CNH.C6H43-EtO2CNH.C6H43-EtO2CNH.C6H43-EtO2CNH.C6H4     4-F.C6H4环庚基环戊基环戊基CH2金刚烷基叔丁基叔丁基CH2环庚基环戊基环戊基CH2金刚烷基4-F.C6H4环庚基环己基环戊基环戊基CH2金刚烷基叔丁基叔丁基CH24-F.C6H4环庚基环己基环戊基环戊基CH2金刚烷基叔丁基4-F.C6H4环庚基环戊基环戊基CH2
    AEAFAGAHAIAJAKALAMANAOAPAQARASATAUAVAWAXAYAZBA     3-EtO2CNH.C6H43-EtO2CNH.C6H43-EtO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeO2CNH.C6H43-MeC(O)NH.C6H43-MeC(O)NH.C6H43-MeC(O)NH.C6H43-MeC(O)NH.C6H43-MeC(O)NH.C6H43-MeC(O)NH.C6H43-MeC(O)NH.C6H43-MeNHC(O).C6H43-MeNHC(O).C6H43-MeNHC(O).C6H43-MeNHC(O).C6H43-MeNHC(O).C6H4     金刚烷基叔丁基叔丁基CH24-F.C6H4C6H5环庚基环己基环戊基环戊基CH2金刚烷基叔丁基4-F.C6H4C6H5环庚基环己基环戊基环戊基CH2金刚烷基4-F.C6H4环庚基环戊基环戊基CH2金刚烷基
本发明产物的药理学研究1)本发明化合物对5-HT1A受体的亲和力
按照Perutka等(J.Neurochem.，47，529[1986])的方法，通过检测与鼠大脑皮层有关的[3H]8-羟基-2(二正丙基氨基)四氢化萘([3H]8-OH-DPAT)的抑制来测定化合物对5-HT1A5-羟色胺能受体的亲和力。
在50mM Tris-HCl(pH7.4)中将雄性Sprague Dawley鼠的大脑皮层均化并在4℃以40000g离心10分钟。将小丸到入相同缓冲液的悬液中并在37℃孵育10分钟并将均浆再在4℃以40000g离心10分钟。
与浓度为100pM至100μM的、未标记的竞争物进行三次[3H]8-OH-DPATA的结合竞争抑制实验。在25℃将鼠大脑皮层(10mg/ml，湿润)和[3H]8-OH-DPAT(1nM)在含4mM氯化钙、10μM pargylin和0.1％抗坏血酸的Tris-HCl(50mM，pH7.4)中孵育30分钟。
通过Whatman GF/B纤维玻璃过滤器用Brandel细胞收集器立即过滤结合的[3H]8-OH-DPAT。用相同的缓冲液在0-4℃将过滤器洗涤三次并通过闪烁分光仪测定它们的放射性。
通过从总结合物中减掉在1μM[3H]8-OH-DPAT存在下的结合得到特异的结合。由计算机用Ligand程序(Munston and Rodbard，Anal.Biochem.107，220[1980])通过非线性回归的相互作用分析来分析结合特性。
本发明的典型化合物的结果在表2中给出。临床使用的5-HT1A拮抗剂丁螺旋酮用作对照。
                        表2
化合物编号                             Ki(nM)
1                                      0.20
2                                      0.10
3                                      1.4
11                                     0.71
14                                     1.6
20                                     0.23
23                                     0.33
30                                     0.44
33                                   0.33
34                                   0.087
45                                   0.14
46                                   0.094
50                                   0.071
59                                   0.65
64                                   0.77
丁螺旋酮                             202)胃抗分泌活性
按照Shay等描述的方法(H.Shay，D.C.Sun，M.Gruenstein，Gastroenterology，26，906[1954])实验本发明化合物的胃抗分泌活性。重约200g的雄性Sprague Dawley鼠在实验前禁食24小时，期间它们可以自由地饮水。在乙醚麻醉下将它们的幽门结扎并同时将被试化合物通过腹膜内(i.p)或十二指肠内(i.d)给药。再将它们的腹部缝合，4小时后将它们处死。收集胃分泌液并以1500g离心15分钟，测量上清液的体积并用0.05N氢氧化钠自动滴定测定其酸度。每个实验都有对照组。
按照Lichtfield和Wilcoxon描述的方法(J.T.Lichtfield，F.A.Wilcoxon，J.Pharmacol.96，99[1949])计算抑制50％酸分泌(X浓度盐酸的体积)的需要量(ED50)。所得到的本发明代表性化合物的结果见表3，并与临床使用的参考化合物：哌吡二氮杂(抗胆碱药)、雷尼替丁(组胺H2受体拮抗剂)和奥美拉唑(质子泵抑制剂)比较。
                        表3
化合物编号                         ED50(mg/kgi.d.)
1                                     3.7
2                                     3.6
18                                    3.2
20                                    3.1
  哌吡二氮杂                                   14
    雷尼替丁                                     22
    奥美抗唑                                     4.63)本发明化合物的止吐活性--对顺铂引起呕吐的抑制
按照Barnes等描述的方法(J.M.Barnes，N.M.Barnes，B.costall，R.J.Naylor，F.D.tattersall，Neuropharmacology，27[8]783[1988])的改进方式在白鼬中评价对顺铂引起呕吐的抑制。将重约0.5kg至1.5kg的、雌或雄性白化白鼬或欧洲鸡貂用戊巴比妥(30-40mg/kgi.p)麻醉并将聚乙烯注射管插进颈静脉。两天后，在使用顺铂(30mg/kg，i.v)前30分钟，静脉注射被试化合物。观察6小时并记录呕吐的次数。每个实验都包括对照组。
本发明有代表性化合物的结果见表4。并且与临床使用的参考化合物蒽丹色创(5-HT1A拮抗剂)和甲氧氯普胺(D2拮抗剂)比较。
                        表4
    化合物编号     (mg/kg i.v.)     抑制率(％)
    118蒽丹色创甲氧氯普胺     1.01.00.51     40626215
4)本发明化合物对小肠转运的作用
按照A.F.Green描述的方法(Br.J.Pharmacol，14，26-34[1959])测定本发明化合物对小肠转运的作用。给要禁食的重约200g的雄性SpragueDawley鼠口服(p.o.)溶解于100ml蒸馏水中的碳(10g)和阿拉伯树胶(2.5g)。15分钟后将动物处死并测量碳的转运时间。
在服用碳前30分钟，进行被试化合物的皮下给药(s.c.)。表5中列出了化合物18的结果。
                        表5
  化事物编号   剂量  (mg/kgs.c.)   与对照组比较碳的转运时间
18     0.31.0     +16％+20％
5)本发明化合物对胃排空的作用
按照C.Scarpignato等描述的方法(Arch.Int.Pharmacodyn.，246，286-294[1980])实验本发明化合物对胃排空的作用。给已禁食的、重约200g的Sprague Dewley鼠口服含酚红(0.5mg/ml)的1.5％甲基纤维素溶液1.5ml。15分钟后处死动物并将幽门解开。用装有含苏打溶液(0.1N100ml)的特氟隆烧杯收集胃的内容物。向5ml均化物中加入20％三氟乙酸水溶液0.5ml使蛋白质沉淀。离心后，升至上部的溶液被分离并加到4.5ml0.5N苏打水溶液中，用分光光度计在波长560nM测定酚红的含量。
给动物皮下注射(s.c.)被试化合物15分钟后，服用酚红。
化合物18得到的结果见表6。
                            表6
化合物编号 剂量(mg/kgs.c.)     与对照组相比对胃排空时间的作用
18     0.31.03.0     +8％+18％+26％

Claims (15)

1.通式I的化合物及这些产物的盐：
其中
Ar表示被一个或多个取代基取代的苯基；
R表示含1至10个碳原子的烃基，其选自直链或支链烷基、链烯基或链炔基，单环或多环、饱和或不饱和环烷基、环烷基烷基或烷基环烷基；
吡啶基或异喹啉基；
可被一个或多个取代基取代的苯基。
2.权利要求1所述的通式I的化合物，其特征是Ar表示的苯基的一种或多种取代基选自卤素、低级烷基、低级烷氧基、氰基、硝基、羟基、C(O)NR1R2、C(O)NHOR3、NHC(O)R4、NHC(O)NHR5、CH2NHC(O)NHR6、CH2OR7、CH2NHC(O)R8、CO2R9、NHCO2R10、C(O)R11和SR12基团；其中R1、R2、R3、R4、R5、R6、R7和R8独立地是氢原子或低级烷基，而R9、R10、R11和R12独立地是低级烷基；R代表苯基的一种或多种取代基选自低级烷基、低级烷氧基、卤素、羟基、硝基、氨基或酰氨基。
3.权利要求1或2所述的通式I的化合物，其特征是Ar表示被羟基、甲氧基、-C(O)NHMe、-NHC(O)Me、-NHCO2R′10、-NHCONH2、-C(O)NHOH，其中R′10表示甲基或乙基，而R表示环戊基、环己基、环庚基、环庚基甲基、金刚烷基、叔丁基、新戊基、苯基或氟代苯基。
4.权利要求1至3所述的通式I的化合物并相应于下式中的任何一个及这些化合物与无机或有机酸形成的盐：-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]苯甲酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]金刚烷酰胺；-N[4-(2-(2-甲氨基羰基苯氧基)乙基)氨基丁基]苯甲酰胺；-N[4-(2-(2-羟基苯氧基)乙基)氨基丁基]苯甲酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]环己酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]环庚酰胺；-N[4-(2-(2-甲氧基苯氧基)乙基)氨基丁基]2-双环[2，2，1]庚酰胺。
5.制备权利要求1所述的通式I化合物的方法，其特征在于：
A)其中Ar定义如权利要求1的产品式II
Figure A9619375700031
与其中X表示卤素或假卤素的产品式III反应得到产品式IV；
Figure A9619375700033
产品式IV除去苯邻二甲酰亚胺基得到产品式V；用酰化试剂处理产品式V得到产品式VI，酰化试剂衍生自RCO2H酸，其中R的定义如权利要求1；或者B)产品式VII与下式的N-苄基乙醇胺反应
Figure A9619375700043
得到产品式VIII；
Figure A9619375700044
将其转变为产品式IX
Figure A9619375700045
其中Y表示卤素或假卤素，产品式IX通过与式ArOH的酚衍生物反应转变为上述产品式VI，而产品式VI通过苄基的裂解转变为产品式I，如果需要，则通过相应的酸的作用将产品式I转变为酸加成盐。
6.药物，其含权利要求1所述的产品式I、所述产品式I与无机或有机酸形成的药用加成盐。
7.药物，其含权利要求2至4中任一权项所述的产品式I、及所述产品式I与无机或有机酸形成的药用加成盐。
8.含权利要求6或7所述的至少一种药物作为活性成分的药物组合物。
9.权利要求1至4中任一权项所述产品式I在制备止吐药中的用途。
10.权利要求1至4中任一权项所述产品式I在制备降低胃分泌药中的用途。
11.权利要求1至4中任一权项所述产品式I在制备加速胃排空药中的用途。
12.权利要求1至4中任一权项所述产品式I在制备加速小肠转运药中的用途。
13.权利要求1至4中任一权项所述产品式I在制备治疗焦虑、抑郁或睡眠紊乱药药中的用途。
14.权利要求1至4中任一权项所述产品式I在制备治疗心血管疾病，特别是高血压药中的用途。
15.新的工业产品，权利要求5所述的式IV、V、VI、VIII和IX化合物。
CN96193757A 1995-04-07 1996-04-05 对5-ht1a受体具高度亲和力的苯氧乙胺衍生物,其制备方法、作为药物的用途及含有它们的药物组合物 Pending CN1183765A (zh)

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