CN1304408A - 对5-ht受体具有亲和力的n-苯并二噁烷基甲基-1-哌啶基-甲胺化合物 - Google Patents
对5-ht受体具有亲和力的n-苯并二噁烷基甲基-1-哌啶基-甲胺化合物 Download PDFInfo
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Abstract
本发明描述了式Ⅰ化合物、包括其中R表示H或F的可药用盐,其制备方法,以及它们在治疗下列疾病中的应用:抑郁、焦虑、精神病、怕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症和厌食、心血管和脑血管病、偏头痛、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大、药物引起的锥体束外综合征和痉挛状态。
Description
本发明涉及对5-HT1A和/或α1和/或D2受体具有亲和力的新的治疗剂,其制备方法,含有这些治疗剂的药物组合物以及它们在治疗下列疾病中的应用,所述疾病是中枢神经系统疾病例如抑郁、焦虑、精神病(例如精神分裂症)、迟发性运动障碍、帕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症(eating disorders)和厌食、心血管和脑血管病、偏头痛、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大、药物引起的锥体束外综合征和痉挛状态。
在WO93/17017中描述了具有血管收缩活性的[(苯并二噁烷基、苯并呋喃基和苯并吡喃基)烷氨基]烷基取代的2-嘧啶基化合物。要求了这些化合物用于治疗与血管舒张有关的疾病。
在WO95/07274中公开了下式Ⅰ化合物及其可药用盐具有治疗下列疾病的应用:中枢神经系统疾病例如抑郁、焦虑、精神病(例如精神分裂症)、迟发性运动障碍、帕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症和厌食、心血管和脑血管病、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大和痉挛状态,其中A是亚甲基或-O-;B是亚甲基或-O-;g是0、1、2、3或4;R1表示卤素、任选取代的烷基、任选取代的烷氧基、任选取代的烷硫基、羟基、酰氧基、羟甲基、氰基、链烷酰基、烷氧羰基、任选N-取代的氨基甲酰基、氨基甲酰基甲基、氨磺酰基或氨磺酰基甲基、任选被一或两个烷基取代的氨基、或者两个毗邻的R1基团与和其相连的碳原子一起形成稠合苯并环;R2是H、烷基或烷氧基;R3和R4彼此相同或不同,是H或烷基;U是任选被一个或多个烷基取代的亚烷基链;Q表示式Ⅱa、Ⅱb或Ⅱc的二价基团其中V是一个键或任选被一个或多个烷基取代的亚烷基链;VN是任选被一个或多个烷基取代的亚烷基链;X是一个键或亚烷基链,并且X′是亚烷基链,条件是X和X′中碳原子的总数为3或4;R5是H或烷基;并且T表示任选取代的芳基,其中任选含有一个或多个N原子,条件是当A是-O-时,T不是2-嘧啶基。
出人意料地发现,选自WO95/07274中一般公开的、而非具体命名或其中例举的某些化合物具有增加的活性,并且与WO95/07274中例举的化合物具有增加的选择性。
本发明提供了式Ⅰ化合物,包括其中R表示H或F的可药用盐本发明的具体化合物是(S)-(-)-1-[1-(4-氟-2-甲氧基苯基)哌啶-4-基]-N-(7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基)甲胺
和(S)-(-)-1-[1-(2-甲氧基苯基)哌啶-4-基]-N-(7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基)甲胺及其可药用盐。
本发明化合物具有超出本领域已知化合物的优点,因为它们在受体结合分析中具有选择性并且具有优越的口服活性。
式Ⅰ化合物可以以其与可药用酸的盐形式存在。所述盐的实例包括盐酸盐、氢溴酸盐、硫酸盐、甲磺酸盐、硝酸盐、马来酸盐、乙酸盐、柠檬酸盐、富马酸盐、酒石酸盐[例如(+)-酒石酸盐、(-)-酒石酸盐或其混合物,包括外消旋混合物]、琥珀酸盐、苯甲酸盐以及与氨基酸例如谷氨酸的盐。式Ⅰ化合物及其盐可以以其溶剂化物(例如水合物)的形式存在。
某些式Ⅰ化合物及其盐可以以多于一种结晶形式存在,并且本发明包括每种结晶形式及其混合物。某些式Ⅰ化合物及其盐还可以以溶剂化物例如水合物的的形式存在,本发明包括每种溶剂化物及其混合物。
本发明还包括药物组合物,其中含有治疗有效量的式Ⅰ化合物或其盐以及可药用稀释剂或载体。
下文所用术语活性化合物是指式Ⅰ化合物或其盐。在治疗应用中,活性化合物可以经口、直肠、非肠道或局部给药,优选口服给药。因此,本发明的治疗组合物可以是任何已知的供口服、直肠、非肠道或局部给药的药物组合物形式。适用于该组合物的可药用载体是药学领域公知的。本发明的组合物可以含有0.1-99%(重量)的活性化合物。通常将本发明组合物制备成单位剂型。优选的活性成分的单位剂量是1-500mg。制备这些组合物所用的赋形剂是药学领域已知的赋形剂。
口服给药的组合物是优选的本发明组合物,并且这些口服给药的组合物是以此种方式给药的已知药物形式,例如片剂、胶囊、糖浆和水或油悬浮液。制备这些组合物所用的赋形剂是药学领域已知的赋形剂。通过将活性化合物与惰性稀释剂如磷酸钙在崩解剂如玉米淀粉和润滑剂如硬脂酸镁存在下混合、并按已知方法压片,可以制备片剂。可以采用本领域专业人员已知的方式制备片剂,以使其持续释放本发明化合物。如果需要,该片剂可以用常规方法包肠溶衣,例如使用乙酸邻苯二甲酸纤维素包衣。同样地,可以采用常规方法制备含有活性化合物的胶囊,例如硬或软明胶胶囊,其中加有或不加赋形剂,并且如果需要,用已知方法包肠溶衣。每片或每粒胶囊通常含有1-500mg活性化合物。其他口服给药组合物包括例如水悬浮液,其中在无毒悬浮剂例如羧甲基纤维素钠存在下、在含水基质中含有活性化合物,以及油悬浮液,其中在合适的植物油例如花生油中含有本发明化合物。
可以将活性化合物配制成含有或不含其他赋形剂的颗粒剂。颗粒剂可以由患者直接吞服,或者可以在吞服前加入适当的液体载体(例如水)中。该颗粒剂可以含有崩解剂(例如由酸和碳酸盐或碳酸氢盐形成的可药用泡腾对)以便分散于液体基质中。
适于直肠给药的本发明组合物是用于该形式给药的已知药物剂型,例如含有可可脂或聚乙二醇基质的栓剂。
适于非肠道给药的本发明组合物是用于该形式给药的已知药物剂型,例如在适当溶剂中的无菌悬浮液或者无菌溶液。
局部给药组合物可以含有使本发明药物活性化合物分散于其中的基质,以使该化合物保持与皮肤接触,从而经皮施用该化合物。适宜的经皮给药组合物可以通过下述方法制备:将药物活性化合物与局部赋形剂例如矿物油、凡士林和/或蜡例如石蜡或蜂蜡以及可能的透皮吸收促进剂例如二甲基亚砜或丙二醇混合。或者,将活性化合物分散于可药用乳膏或油膏基质中。局部制剂中活性化合物的含量应当是在局部制剂预期在皮肤上停留期间释放治疗有效量化合物的量。
本发明化合物还可以经连续输注给药,连续输注可以是外源的例如静脉内输注,或是置于体内的化合物来源。内部来源包括可输注的植入缓释剂,其中含有例如通过渗透连续释放的化合物,可以是(a)液体或(b)固体形式的植入物,液体形式的植入物是例如在以例如极小水溶性的衍生物(如十二烷酸盐或酯)的形式输注的该化合物在可药用油中的悬浮液或溶液,用于所输注化合物的固体植入物是以植入载体的形式出现,例如合成树脂或蜡状物质形式的。该载体可以是含有所有化合物的单一物理实体,或是分别含有部分所释放化合物的数个物理实体。内源形式中活性化合物的含量应为在长期治疗过程中释放治疗有效量化合物的量。
在某些制剂中,以非常小的粒度(例如通过液能(fluid energy)研磨获得)使用本发明化合物是有益的。
在本发明组合物中,如果需要,可以将该活性化合物与其他相容的药理活性成分结合。
含有治疗有效量式Ⅰ化合物或其盐的该药物组合物可用于治疗人的抑郁、焦虑、精神病(例如精神分裂症)、迟发性运动障碍、帕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症、厌食、心血管和脑血管病、偏头痛、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大、药物引起的锥体束外综合征和痉挛状态。但是,在治疗这些疾病中活性化合物的准确给药量取决于多种因素,例如患者的年龄、疾病的严重程度和既往治疗史,并且总是处于给药医生合理的考虑范围之内,活性化合物每天的用量为1-1000mg,优选5-500mg,以单次剂量或多次剂量在一天中分一至多次给药。
通过下列试验证明了式Ⅰ化合物与5-羟色胺(5-HT)受体相互反应的能力,由此证实了该化合物抑制氚代配体在体外与5-HT受体、特别是5-HT1A受体结合的能力。
将取自150-250克重的雄性Charles River CD大鼠脑中的海马组织在冰冷的50mM Tris-HCl缓冲液(pH7.7)(在25℃测定时为1∶40 w/v)中打成匀浆,并在4℃、以30,000g的转速离心10分钟。将沉淀物再于相同的缓冲液中打成匀浆,在37℃保温10分钟,并在4℃、以30,000g的转速离心10分钟。将最终的沉淀物再悬浮于含有4mM氯化钙、0.1%L-抗坏血酸和10μM帕吉林盐酸盐的50mMTris-HCl缓冲液(pH7.7)中(相当于6.25mg湿重组织/毫升),并立即用于结合分析。将等分量的该悬浮液(400μl;相当于2.5mg湿重组织/管)分别加至含有配体(50μl;2nM)和蒸馏水(50μl;总体结合)或5-HT(50μl;10μM;非特异性结合)或试验化合物(50μl;10-6M的单一浓度或者从10-11至10-3M的10种浓度)的试管中。配体是[3H]8-羟基-2-(二异丙基氨基)-1,2,3,4-四氢化萘([3H]8-OH-DPAT),将该混合物在25℃保温30分钟,然后迅速过滤终止保温。
过滤物用冰冷的Tris-HCl缓冲液洗涤并干燥。将过滤物冲压到小瓶中,加入闪烁液体,并通过液体闪烁计数法测定放射活性。对单一浓度(10-6M)试验化合物的氚代配体特异性结合的置换百分数进行计算。对在10-6M浓度时氚代配体特异性结合置换≥50%的化合物,用化合物的浓度范围绘制置换曲线。由该曲线得出特异性结合50%抑制的浓度(IC50)。使用下列公式计算抑制系数Ki其中[配体]是所用氚代配体的浓度,KD是配体的平衡解离常数。
通过下列试验证明了式Ⅰ化合物与肾上腺素受体结合位点相互反应的能力,由此证实了该化合物抑制氚代配体在体外与肾上腺素受体、特别是α1-肾上腺素受体结合的能力。
将取自150-250克重的雄性Charles River CD大鼠脑中的全皮质组织在冰冷的50mM Tris-HCl缓冲液(pH7.6)(在25℃测定时为1∶40w/v)中打成匀浆,并在4℃、以1,000g的转速离心10分钟。将上清液在4℃、以30,000g的转速离心10分钟。将沉淀物再于50mM Tris-HCl缓冲液(pH7.6)(1∶40 w/v)中打成匀浆,并在4℃、以30,000g的转速离心10分钟。将最终的沉淀物再悬浮于50mMTris-HCl缓冲液(pH7.6)中(相当于12.5mg湿重组织/毫升),并立即用于结合分析。将等分量的该悬浮液(400μl;相当于5mg湿重组织/管)分别加至含有配体(50μl;0.1nM)和蒸馏水(50μl;总体结合)或酚妥拉明(50μl;5μM;非特异性结合)或试验化合物(50μl;10-6M的单一浓度或者从10-11至10-3M的10种浓度)的试管中。配体是[7-甲氧基-3H]哌唑嗪,将该混合物在30℃保温30分钟,然后迅速过滤终止保温。
过滤物用冰冷的Tris-HCl缓冲液洗涤并干燥。将过滤物冲压到小瓶中,加入闪烁液体,并通过液体闪烁计数法测定放射活性。对单一浓度(10-6M)试验化合物的氚代配体特异性结合的置换百分数进行计算。对在10-6M浓度时氚代配体特异性结合置换≥50%的化合物,用化合物的浓度范围绘制置换曲线。由该曲线得出特异性结合50%抑制的浓度(IC50)。使用下列公式计算抑制系数Ki其中[配体]是所用氚代配体的浓度,KD是配体的平衡解离常数。
通过下列试验证明了式Ⅰ化合物与多巴胺受体相互反应的能力,由此证实了该化合物抑制氚代配体在体外与多巴胺受体、特别是D2多巴胺受体结合的能力。
将取自140-250克重的雄性Charles River CD大鼠脑中的纹状体组织在冰冷的50mM Tris-HCl缓冲液(pH 7.7)中打成匀浆(在25℃测定),并以40,000g的转速离心10分钟。将沉淀物再悬浮于Tris盐缓冲液(含有120mM氯化钠、5mM氯化钾、2mM氯化钙和1mM氯化镁以及6mM抗坏血酸的50mM Tris-HCl缓冲液;pH7.7,在25℃测定)中,并再以40,000g的转速离心10分钟。将最终的沉淀物贮存在-80℃。每次试验前,将沉淀物再悬浮于Tris盐缓冲液(相当于2mg湿重组织/毫升)中。然后将等分量的该悬浮液(720μl;相当于1.44mg湿重组织/管)分别加至含有配体(40μl;1nM)和Tris盐缓冲液(40μl;总体结合)或螺环哌啶酮(40μl;10nM;非特异性结合)或试验化合物(40μ1;10-6M的单一浓度或者从10-11至10-4M的6种浓度)的试管中。配体是氚代(S)-舒必利,将该混合物在4℃保温40分钟,然后迅速过滤终止保温。
过滤物用冰冷的Tris-HCl缓冲液洗涤并干燥。将过滤物冲压到小瓶中,加入闪烁液体并放置约20小时,然后通过闪烁分光光度测定法计数。对单一浓度(10-6M)试验化合物的氚代配体特异性结合的置换百分数进行计算。对在10-6M浓度时氚代配体特异性结合置换≥50%的化合物,用化合物的浓度范围绘制置换曲线。由该曲线得出特异性结合50%抑制的浓度(IC50)。使用下列公式计算抑制系数Ki其中[配体]是所用氚代配体的浓度,KD是配体的平衡解离常数。
对实施例1、2和比较实施例A的每一最终产物进行的上述5-HT1A、α1和D2结合试验所得Ki值列于下表1中。由这些数据清楚地表明,与先前描述的化合物相比,本发明化合物对α1肾上腺素受体具有显著低的亲和性。这是非常重要的,因为正如本领域已知,α1受体拮抗作用引起一系列严重的副作用例如高血压、镇静和性功能障碍。因此,这些化合物优先与D2和5-HT1A受体相互作用、而几乎不与α1受体相互作用是有利的。
表1
阿朴吗啡引起的小鼠攀登拮抗作用
实施例编号 | 下列受体的Ki值(nM) | ||
5-HT1A | D2 | α1 | |
1 | 23 | 65 | 183 |
2 | 31 | 54 | 404 |
A | 22 | 44 | 53 |
经腹膜内注射用试验化合物或对照赋形剂处理重18-35克(最大范围10克)的雄性小鼠,小鼠分为10只一组。30分钟后,给小鼠皮下注射阿朴吗啡(0.88mg/kg)。在注射阿朴吗啡后,立即将小鼠放进试验笼中,以0-2的简单评分标准对每只小鼠的攀登行为进行10-20分钟的估价。
计算试验化合物的ED50值(引起50%对照评分的剂量)和95%置信限度。以游离碱等同物计算ED50值,并与比较实施例A的结果一起列于表2中。与先前描述的化合物相比,本发明化合物口服更为有效。更有效的化合物是有利的,因为它们不太可能对非治疗靶的器官引起系统性毒性。
表2
实施例 | ED50(mg/kg) |
1 | 1 |
2 | 1.8 |
A | 5 |
下面将描述式Ⅰ化合物的制备方法。这些方法构成本发明的另一方面。该方法优选在大气压下,在0-200℃、优选20-150℃的温度范围内进行。除非另外指明,取代基如上面对式Ⅰ所定义。
通过下列实施例举例说明本发明。对这些实施例中的每一最终产物均通过下列一种或多种方法测定其性质:气-液色谱;高效液相色谱;元素分析;核磁共振光谱和红外光谱。
实施例1
部分Aa)在搅拌和氮气氛下,用1小时,向氢化钠(7.0g,在矿物油中的60%分散物)在无水二甲基甲酰胺(250ml)中的悬浮液中滴加5-氟-2-硝基酚(25.0g)在无水二甲基甲酰胺(100ml)中的溶液。将该混合物搅拌1小时,然后向该混合物中滴加碘甲烷(10.0ml)。将该混合物在蒸汽浴中搅拌并加热3.5小时。再加入碘甲烷(2.5ml),并在95-100℃搅拌该混合物1小时,然后使其冷却过夜。滴加浓氨水溶液(15.0ml;S.G.0.880),并搅拌该混合物15分钟。将该混合物倒入用氢氧化钠水溶液(5M)碱化的水(1.5升)中,用二氯甲烷(4×400ml)萃取。合并的有机提取液用水、盐水洗涤,干燥,过滤并蒸发,得到液体,将该液体溶于乙醚(500ml),用水、盐水洗涤,干燥,过滤并蒸发,得到油,将该油再溶解于乙醚中,重复先洗涤、后干燥的步骤,得到油,该油用沸点为60-80℃的石油醚研制,并放置过夜。过滤收集固体产物并真空干燥,得到4-氟-2-甲氧基硝基苯。通过1H NMR测定结构。b)在室温、用10%披钯木炭作为催化剂,将4-氟-2-甲氧基硝基苯(23.7g)在工业甲基化酒精(400ml)中的溶液氢化。在氢理论上吸收后,将该混合物过滤,以除去催化剂,蒸发滤液,得到油状的4-氟-2-甲氧基苯胺。c)将4-氟-2-甲氧基苯胺(5.7g)和氯化4-氨基甲酰基-1-(2,4-二硝基苯基)吡啶(22.4g,采用WO95/07274所述方法制备)和甲醇(350ml)的混合物搅拌,并煮沸回流2小时。将该混合物在冰水浴中冷却并过滤。减压蒸发滤液得到固体,该固体用沸丙酮(900ml)研制。使该混合物冷却,过滤收集产物,并用丙酮洗涤,得到氯化4-氨基甲酰基-1-(4-氟-2-甲氧基苯基)吡啶。d)将c)的产物(13.2g)、甲酸铵(26.6g)和10%披钯木炭(6.6g)在氮气氛下搅拌,同时加入工业甲基化酒精(250ml)。剧烈搅拌该混合物,并在氮气氛下煮沸回流3.5小时,升华的甲酸铵用水洗涤回反应瓶中。使该混合物冷却,然后经过滤助剂过滤,用工业甲基化酒精、乙酸乙酯和水洗涤。减压蒸发滤液,残余物在水(1升)和乙酸乙酯(500ml)之间分配。用5M氢氧化钠溶液使该混合物强碱化。分离水层,用乙酸乙酯(3×500ml)萃取。将合并的乙酸乙酯萃取液干燥,过滤并蒸发,得到1-(4-氟-2-甲氧基苯基)哌啶-4-甲酰胺。e)将d)的产物(10.4g)悬浮在四氢呋喃(300ml)中,并在冰水浴中、在氮气氛和搅拌下,将该混合物分批加至氢化锂铝(3.4g)在四氢呋喃(100ml)中的悬浮液中。将该混合物在冰水浴中搅拌1.5小时,然后在室温搅拌19小时。向反应混合物中小心地加入水(20ml),然后加入5M氢氧化钠溶液(20ml)和水(40ml)。搅拌该混合物1小时,然后经过滤助剂过滤,过滤助剂用乙醚(700ml)洗涤。分离滤液,将有机相干燥,过滤并蒸发,得到胶状物质,该胶状物质用二氯甲烷(100ml)研制并过滤以除去某些固体。蒸发滤液,得到油,所得油经二氧化硅闪式柱色谱纯化,用甲醇、然后用甲醇/三乙胺(10∶1)作为流动相。收集合适的馏分,合并并蒸发,得到1-(4-氟-2-甲氧基苯基)哌啶-4-甲胺。
部分Ba)将六亚甲基四胺(47.5g)分批加入搅拌着的4-三氟甲基酚(50g)在三氟乙酸(680ml)中的溶液中,并将该混合物加热回流24小时。冷却后,加入水(355ml),然后加入硫酸水溶液(50%v/v,190ml),并在室温搅拌反应物4小时。酸性水相用乙醚(3×500ml)萃取。合并的有机提取液用盐酸(5M,3×500ml)和水(500ml)洗涤,并用硫酸镁干燥。减压蒸发有机溶剂,残余物经二氧化硅柱色谱纯化,用石油醚(沸点40-60℃)与乙酸乙酯的4∶1混合物洗脱。收集合适的馏分,减压蒸发溶剂,得到5-三氟甲基-2-羟基苯甲醛(25g),为淡粉色固体。b)将4-甲苯磺酸(R)-缩水甘油酯(24g)、5-三氟甲基-2-羟基苯甲醛(20g)和碳酸钾(16g)在二甲基甲酰胺(550ml)中的混合物搅拌,并在60℃加热72小时。冷却后,加入盐水(1.51),所得混合物用乙醚(4×500ml)萃取。合并的乙醚提取液用盐水(2×500ml)、水(500ml)洗涤,并用硫酸镁干燥。残余物经二氧化硅闪式柱色谱纯化,用石油醚(沸点40-60℃)和乙酸乙酯的3∶1混合物洗脱,得到(R)-5-三氟甲基-2-(2,3-环氧丙氧基)苯甲醛(18.7g),为黄色油。c)将前一反应产物(18.7g)与3-氯过苯甲酸(57-86%,48.7g)在二氯甲烷(1升)中的混合物加热回流24小时,然后冷却至室温。该混合物用饱和碳酸氢钠水溶液(3×700ml)、水(2×700ml)和盐水(700ml)洗涤,然后用硫酸镁干燥。蒸发溶剂,得到粗产物(R)-5-三氟甲基-2-(2,3-环氧丙氧基苯基甲酸酯(16.7g)。d)将前一反应产物(16.7g)、四氢呋喃(220ml)和饱和碳酸钾水溶液(175ml)的混合物在室温剧烈搅拌24小时。加入水(500ml),除去有机相。水相用乙酸乙酯(3×300ml)萃取,合并的有机提取液用硫酸镁干燥。减压除去溶剂,残余物经二氧化硅闪式柱色谱纯化,用石油醚(沸点40-60℃)和乙酸乙酯的4∶1至1∶1混合物梯度洗脱。合并合适的馏分并减压除去溶剂,得到(S)-7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲醇(12g),为黄色油。e)在0-5℃,将4-甲苯磺酰氯(9.6g)在二氯甲烷(60ml)中的溶液滴加至前一反应产物(10.7g)和4-二甲基氨基吡啶(6.7g)在二氯甲烷(90ml)中的溶液中。在室温搅拌该混合物4小时,然后放置18小时。该溶液用稀盐酸(5M,2×300ml)洗涤,用硫酸镁干燥,并减压除去溶剂,得到(R)-7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基4-甲苯磺酸酯(15.5g),为白色固体。
部分C
将部分B(e)的4-甲苯磺酸酯(4.3g)、部分A(e)的甲胺(2.4g)、碳酸钾(2.4g)、甲苯(80ml)和二甲基甲酰胺(30ml)搅拌并煮沸回流24小时。使该混合物冷却,倒入水(1.5升)中,然后用乙酸乙酯(3×350ml)萃取。合并的有机提取液用5M盐酸(3×250ml)萃取。合并的酸性提取液用5M氢氧化钠溶液碱化,并用乙酸乙酯(3×250ml)萃取,将有机提取液干燥,过滤并蒸发,得到油。将该油溶于乙醚(100ml)中,用碳酸钾干燥。将该混合物过滤并蒸发,得到油,该油经二氧化硅闪式柱色谱纯化,用乙酸乙酯/石油醚(沸点60-80℃)(9∶1)作流动相。收集合适的馏分、合并并蒸发,得到橙色油,将该油溶于乙醚(100ml)中,向该溶液中通氯化氢气15分钟。过滤收集所形成的沉淀,并在80℃真空干燥23小时,得到(S)-(-)-1-[1-(4-氟-2-甲氧基苯基)哌啶-4-基]-N-(7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基)甲胺二盐酸盐,熔点230-231℃。
实施例2
将1-[1-(2-甲氧基苯基)哌啶-4-基]甲胺(3.3g,按照WO95/07274所述方法制备)、(R)-7-三氟甲基-1,4-苯并二噁烷-2-基甲基4-甲苯磺酸酯(3.0g)、碳酸钾(2.5g)、甲苯(22ml)和二甲基甲酰胺(10ml)的混合物在搅拌下煮沸回流18小时。使该混合物冷却,倒入水(100ml)中,并用乙酸乙酯萃取。合并的有机提取液用稀盐酸(2×200ml)洗涤,酸性提取液用浓氢氧化钠溶液碱化,然后用乙酸乙酯(200ml)萃取。将合并的有机提取液干燥、过滤并蒸发,得到油,该油经二氧化硅闪式柱色谱纯化,用乙酸乙酯/甲醇(95∶5)作流动相,得到油,所得油如实施例1所述用氯化氢气处理,得到(S)-(-)-1-[1-(2-甲氧基苯基)哌啶-4-基]-N-(7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基)甲胺二盐酸盐,熔点243-245℃(分解)。比较实施例A
按照WO95/07274所述方法制备(S)-(-)-N-(7-氯-1,4-苯并二噁烷-2-基甲基)-1-(1-(2-甲氧基苯基)哌啶-4-基)甲胺(也称作(S)-(-)-N-(7-氯-2,3-二氢-1,4-苯并二噁英-2-基甲基)-1-(1-(2-甲氧基苯基)哌啶-4-基)甲胺)。
Claims (11)
1.式Ⅰ化合物,包括其中R表示H或F的可药用盐
2.权利要求1的化合物,是(S)-(-)-1-[1-(4-氟-2-甲氧基苯基)哌啶-4-基]-N-(7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基)甲胺及其可药用盐。
3.权利要求1的化合物,是(S)-(-)-1-[1-(2-甲氧基苯基)哌啶-4-基]-N-(7-三氟甲基-2,3-二氢-1,4-苯并二噁英-2-基甲基)甲胺及其可药用盐。
4.药物组合物,其中含有治疗有效量的权利要求1-3中任何一项的式Ⅰ化合物以及可药用稀释剂或载体。
5.下列疾病的治疗方法:抑郁、焦虑、精神病、帕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症、厌食、心血管和脑血管病、偏头痛、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大、药物引起的锥体束外综合征或痉挛状态,包括对需要治疗的患者使用治疗有效量的权利要求1-3中任何一项的式Ⅰ化合物。
6.权利要求5的方法,用于治疗精神分裂症。
7.权利要求5的方法,用于治疗焦虑。
8.用作药物的权利要求1-3中任何一项的式Ⅰ化合物。
9.用作治疗下述疾病的药物的权利要求1-3中任何一项的式Ⅰ化合物:抑郁、焦虑、精神病、迟发性运动障碍、帕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症、厌食、心血管和脑血管病、偏头痛、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大、药物引起的锥体束外综合征或痉挛状态。
10.权利要求1-3中任何一项的式Ⅰ化合物在制备治疗下述疾病的药物中的应用:抑郁、焦虑、精神病、迟发性运动障碍、帕金森氏病、肥胖、高血压、图雷特氏综合征、性功能障碍、药物成瘾、药物滥用、认知性疾病、阿尔茨海默氏病、老年性痴呆、强迫观念与行为的举止、恐慌发作、贪食症、厌食、心血管和脑血管病、偏头痛、非胰岛素依赖型糖尿病、血糖过多、便秘、心律失常、神经内分泌系统紊乱、应激反应、前列腺肥大、药物引起的锥体束外综合征或痉挛状态。
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AU2001267421A1 (en) * | 2000-05-12 | 2001-11-20 | Solvay Pharmaceuticals B.V. | Use of compounds having combined dopamine d2, 5-ht1a and alpha adrenoreceptor agonistic action for treating cns disorders |
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JP2002517392A (ja) | 2002-06-18 |
NO20006041D0 (no) | 2000-11-29 |
CO5021190A1 (es) | 2001-03-27 |
SK17602000A3 (sk) | 2001-08-06 |
AR018622A1 (es) | 2001-11-28 |
PL344594A1 (en) | 2001-11-05 |
BG104988A (bg) | 2001-11-30 |
HUP0102233A2 (hu) | 2002-05-29 |
WO1999062902A1 (en) | 1999-12-09 |
IL139552A0 (en) | 2002-02-10 |
CA2333756A1 (en) | 1999-12-09 |
NO20006041L (no) | 2000-11-29 |
BR9910927A (pt) | 2001-02-20 |
GB9811879D0 (en) | 1998-07-29 |
EP1087964A1 (en) | 2001-04-04 |
HRP20010005A2 (en) | 2001-12-31 |
TR200003569T2 (tr) | 2001-04-20 |
KR20010052526A (ko) | 2001-06-25 |
ID27067A (id) | 2001-02-22 |
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