CN1122019C - 芳环上带有苯基取代基的四氢萘和它们在治疗癫痫，中风和脑或脊柱创伤中的应用 - Google Patents

芳环上带有苯基取代基的四氢萘和它们在治疗癫痫，中风和脑或脊柱创伤中的应用 Download PDF

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CN1122019C
CN1122019C CN96193739A CN96193739A CN1122019C CN 1122019 C CN1122019 C CN 1122019C CN 96193739 A CN96193739 A CN 96193739A CN 96193739 A CN96193739 A CN 96193739A CN 1122019 C CN1122019 C CN 1122019C
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R·斯沃波达
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Abstract

本发明涉及游离碱或酸加成盐形式的式(I)化合物，其中R1和R2独立地是氢，(C1-4)烷基，(C1-4)烷氧基，(C1-4)烷硫基，卤素，三氟甲基，三氟甲氧基，氰基，(C2-5)烷酰基，(C1-4)烷基磺酰基或氨磺酰基；R3是氢，羟基，(C1-4)烷基，(C1-4)烷氧基，卤素，氰基，(C2-5)烷酰基，氨基甲酰基，(C1-4)烷基磺酰氧基或三氟甲基磺酰氧基；R4和R5独立地是氢，(C1-4)烷基，羟基(C2-4)烷基或苯基(C1-4)烷基，或与它们所连接的氮原子一起形成吡咯烷基，哌啶子基或哌嗪基。式(I)化合物可用于治疗癫痫，中风和脑或脊柱创伤。

Description

芳环上带有苯基取代基的四氢萘和它们 在治疗癫痫，中风和脑或脊 柱创伤中的应用
本发明涉及新的氨基四氢萘(四氢化萘胺)，它们的制备方法，以及它们作为药物的用途和含有它们的药用组合物。
按本发明，首要方面它提供了芳香环上带有苯基取代基的1，2，3，4-四氢-2-萘胺和它们的酸加成盐。
苯基取代基优选在2-萘胺的5位上。
苯基取代基可带有其它取代基，例如在下述式I中的情况。
其它的取代基也可适宜地存在，但不限于在芳环上，例如，在5位上有苯基取代的2-萘胺的8位上。
本发明更具体地提供了游离碱或酸加成盐形式的式I化合物。
Figure C9619373900051
其中R1和R2独立地是氢，(C1-4)烷基，(C1-4)烷氧基，(C1-4)烷硫基，卤素，三氟甲基，三氟甲氧基，氰基，(C2-5)烷酰基，(C1-4)烷基磺酰基或氨磺酰基，R3是氢，羟基，(C1-4)烷基，(C1-4)烷氧基，卤素，氰基，(C2-5)烷酰基，氨基甲酰基，(C1-4)烷基磺酰氧基或三氟甲磺酰氧基，且R4和R5独立地是氢，(C1-4)烷基，羟(C2-4)烷基或苯基(C1-4)烷基，或与它们所连接的氮原子一起形成吡咯烷基，哌啶子基或哌嗪基，
卤素是氟，氯，溴或碘，优选氟或氯。
烷基，烷氧基和烷硫基均优选是直链基。它们优选含有1-3个碳原子，更优选它们是甲基，甲氧基和甲硫基。
下述的含意和它们的组合是优选的：R1和R2独立地是氢，(C1-4)烷基，(C1-4)烷氧基，卤素或三氟甲基，R3是氢，羟基，(C1-4)烷氧基，氰基或氨基甲酰基，R4和R5独立地是氢或(C1-4)烷基，或与它们所连接的氮原子一起形成哌啶子基。
在一组特定的式I化合物中，R1和R2独立地是氢、(C1-4)烷基、(C1-4)烷氧基、(C1-4)烷硫基、卤素、三氟甲基、氰基或(C2-5)烷酰基，R3的定义如上，R4和R5独立地是氢、(C1-4)烷基或苯基(C1-4)烷基，或与它们所连接的氮原子一起形成吡咯烷基、哌啶子基或哌嗪基。
本发明化合物在2位上有一个不对称碳原子。因此，它们可能以旋光形式或旋光异构体混合物(如外消旋混合物)的形式存在。所有的旋光异构体及其混合物，包括外消旋混合物，部是本发明的一部分。
如果本发明化合物是以旋光形式存在，则优选R构型。
在另一方面，本发明提供了制备本发明化合物的方法，按照该方法，将芳环上带有卤素的1，2，3，4-四氢-2-萘胺与任选取代的苯基硼酸进行反应，并将生成的产物以游离碱或其酸加成盐的形式收集。
更具体地说，本发明提供了制备本发明化合物的方法，该方法是由式II化合物与式III化合物反应，并以游离碱或其酸加成盐形式收集产物，
Figure C9619373900061
其中R3，R4和R5如上定义，Hal是卤素，其中R1和R2如上定义。
本反应可按已知的方式进行，优选经过渡金属催化的芳基-芳基偶联反应，例如象实施例1所描述的。Hal优选为溴或碘，尤其是溴。
按已知的方法将按上述方法得到的反应混合物进行处理，并将所获得的化合物纯化。
按已知的方式从其游离碱制备酸加成盐，反之亦然。适合根据本发明使用的可药用的酸加成盐包括例如盐酸盐，马来酸氢盐富马酸氢盐和丙二酸氢盐。
本发明外消旋化合物可从外消旋的起始原料制备。旋光异构体可从旋光性的起始原料或从其外消旋体制备。从外消旋体通过已知的方法可制备其对映体，例如，经过非对映异构体的盐分步结晶，例如与(+)-二-O，O′-对甲苯酰基-D-酒石酸或(-)-二-O，O′-对甲苯酰基-L-酒石酸所成盐的分步结晶。
式II化合物的起始原料可以按已知的方法(如实施例1中所述)，经过式IV化合物的卤化反应制备，
Figure C9619373900071
其中R3，R4和R5如上定义。
起始原料式III和式IV是已知的或可按与已知方法类似的方式制备
本发明化合物，例如式1化合物和它们的药学上适用的酸加成盐(在下文称作本发明剂)显示了药理活性，因此适合作为药用。
本发明剂按口服约1-100mg/kg剂量和腹膜内约0.32-32mgkg剂量给药对由最大限度电休充诱导的鼠的惊厥可提供长时间持续的保护作用〔参见E.A.Swinyard《美国药学会会志，科学版(J.Am.Pharm.Assoc.Sci.Ed.)》 38，201(1949)和《药理学与实验治疗学杂志》(J.Pharmacol.Exptl.Therap， 106，319(1952)〕。
因此，本发明剂用于治疗癫痫和其它某些惊厥症，如高压神经综合征
另外，本发明剂在大鼠的大脑中动脉(MCA)闭塞模型中按1-30mg/kg剂量经腹膜内，静脉和口服给药降低了局部缺血诱导的神经元损伤和由此导致的病症〔参见A.Tamura等《大脑血流与代谢杂志》(J.Cereb.Blood Flow Metabol.) 1，53-60(1981)，A，Sauter，M.Rudin，《中风》(Stroke) 17，1228-1234(1986)〕。
所以本发明剂适用于治疗涉及大脑缺氧，氧不足和/或局部缺血的任何临床病症，例如，对灰质和白质的局部缺血性的损害、中风、蛛网膜下出血、脑和脊柱损伤/创伤、高颅内压、多发梗塞性痴呆或血管性痴呆等，还适用于可能会造成大脑缺氧、氧不足和/或局部缺血的任何外科手术(例如，心脏旁通术、脑外血管手术)。
本发明药剂对藜芦碱I敏感的钠通道显示出亲合作用，其IC50值约0.1～约100μM。关于其亲和的方式参见J.B Brown，《神经科学杂志》(Journal of Neuroscience) 6，2064-2070(1986)中的举例说明。浓度约为0.1～1μM的本发明剂在鼠的海马切片标本中封阻藜芦碱I诱导的谷氨酸盐的释放。该实验按照M.J.Leach等在《癫痫》(Epilepsia)27，490～497(1986)和《中风》(stroke) 24，1063-1067(1993)中的改良方法用外源性的谷氨酸盐进行。
因此，本发明剂适合治疗其病因涉及谷氨酸释放的任何病理、失调或临床症状，包括精神疾病(如精神分裂痘，抑郁症，焦虑症，恐慌发作，注意力不集中和识别障碍，社交冷漠)，激素症状(生长激素分泌过剩〔例如，糖尿病、血管病和肢端肥大症的治疗〕或促黄体激素分泌过剩〔前列腺肥大，绝经综合征〕，在应激反应中皮质酮分泌过剩)，代谢诱导的脑损伤(低血糖，非酮症高血糖〔甘氨酸脑病〕，亚硫酸盐氧化酶缺乏，与肝功能衰竭有关的肝性脑病)，呕吐，痉挛状态，耳鸣，疼痛(例如，癌痛，关节炎痛)和药物(酒精，鸦片制剂〔包括具有类似于鸦片疗效的合成药，例如，哌替啶，美沙酮等〕，可卡固，苯丙胺，巴比妥类药物和其它镇静剂，苯并二氮杂类)的滥用和戒除等。
此外，本发明剂适合治疗涉及神经元损伤的任何病状，例如神经变性疾病如阿耳茨海默氏病，杭廷顿氏舞蹈病或帕金森氏病，病毒(包括人类免疫缺陷病毒)诱导的神经变性，肌萎缩性脊髓侧索硬化(ALS)，神经核上麻痹，橄榄体脑桥小脑萎缩(OPCA)，和环境的外源性神经毒素的作用。
对于上述病症，其适合的剂量自然依赖于，例如，所使用的化合物，宿主，给药方式和病情的性质和程度的不同而改变。然而，一般按约0.1-约100，优选约0.5-约100mg/kg动物体重的日剂量给药可获得满意的结果。对于较大的哺乳动物，例如人，按常规给药，例如一天分四次剂量或控释形式给药，所需要的日给药剂量约为1-约500，优选约1-约300mg的本发明药剂。
治疗上述所有病症的优选化合物是(R)-1，2，3，4-四氢-8-甲氧基-N，N-二甲基-5-〔4-(三氟甲基)苯基〕-2-萘胺，它是实施例21化合物。在上述提到的电休克模型实例中已测定了该化合物对最大电休克诱导的惊厥所提供的保护作用，以阈剂量10mg/kg口服给药后可持续8小时。在MCA闭塞模型试验中，闭塞后立刻腹膜内施用该化合物，发现该化合物在3.2、10和32mg/kg的剂量下能与剂量有关地减小梗塞的尺寸(分别减小19，43和53％)。在藜芦碱I诱导的谷氨酸释放试验中，已发现封阻释放的IC50值为0.5μM，这与它对藜芦碱I结合部位的亲合力相一致(IC50＝125nM)。
在MCA闭塞模型试验中实施例21化合物优于标准的Lifarizine(腹膜内按10mg/kg剂量给药后梗塞体积的减小43％对25％)。在藜芦碱I诱导的各氨酸释放试验中发现与Lifarizine等效，但比标准的利鲁唑和拉莫三嗪更有效IC50分别为0.51μM与5μM和20μM)。
优选的病症是癫痫，中风和脑与脊柱创伤。
本发明药剂可按任何常规途径给药，尤其是肠道给药，优选口服，例如片剂和胶囊剂，或非肠道给药，例如注射溶液剂或悬浮液剂。
由上所述，本发明也提供了一种药用发明剂，例如，它用于治疗癫痫，中风和脑和脊柱创伤。
此外，本发明提供了药用组合物，包括本发明剂及至少一种药物载体或稀释剂。该组合物可按常规方法制备。单位剂型含有例如，约0.25-约150，优选0.25-约25mg的本发明化合物。
此外本发明也提供了本发明剂在制造药物方面的应用，该药物可用于治疗上述任何病症，如癫痫，中风和脑或脊柱创伤。
另一方面，本发明还提供了一种方法，用于治疗需要这种治疗的患者的任何上述病症，例如癫痫、中风和脑或脊柱创伤，该法包括给该患者有效治疗量的本发明剂。
下述的实施例说明了本发明。温度为摄氏度并且未校正。
实施例1：(+/-)-1，2，3，4-四氢-5-(4-氯苯基)-8-甲氧基-N，N-二甲基-2-萘胺
将(+/-)-1，2，3，4-四氢-5-溴-8-甲氧基-N，N-二甲基-2-萘胺0.57g(2mMol)溶于8ml的甲苯中。加入4-氯苯硼酸0.55g(3.54mMol)，三(邻-甲苯基)膦0.07g(0.23mMol)，2N碳酸钠水溶液3ml和甲醇0.7ml。脱气后体系中充入氩气，加入醋酸钯(II)0.031g(0.14mMol)并将该混合物于80℃搅拌过夜。分出水相并用乙酸乙酯萃取。合并的有机相用2N醋酸萃取，酸性的萃取液用氨水碱化后再次用乙酸乙酯萃取。用硫酸钠干燥后，过滤并蒸去有机溶剂，得到的亮棕色的油状物用富马酸在甲基叔丁醚中处理。将生成的盐从异丙醇中重结晶，得到标题化合物的富马酸氢盐的白色结晶，m.p.213-216°。
可按下述的方法制备起始原料：
将(+/-)-1，2，3，4-四氢-8-甲氧基-N，N-二甲基-2-萘胺4.1g(20mMol)溶于50ml的醋酸中并加入醋酸钠1.8g(22mMol)。室温下用30分钟时间滴入1.02ml(20mMol)溴在5ml醋酸中的溶液。有无色沉降物生成。过夜搅拌后减压蒸去溶剂，残渣用水溶解后用乙酸乙酯萃取。剩余的水相用氨水碱化并用乙酸乙酯萃取。有机相用硫酸钠干燥，过滤并蒸发至干。将剩余的油状物在球-球蒸馏装置(bulb tobulb distillation apparatus)中蒸馏得到浅黄色的油状物，在0.04毫巴下b.p.170～180°。
下列化合物按类似于实施例1的方法制备。
                             表1
实例 R1 R2 R3 R4 R5 构型 熔点(盐)
2 H H OMe Me Me +/- 171-174°(1)
3 2-Cl ＂ ＂ ＂ ＂ ＂ 186-190°(1)
4 2-Me ＂ ＂ ＂ ＂ ＂ 190-196°(1)
5 2-OMe ＂ ＂ ＂ ＂ ＂ 252-263°(2)
6 H ＂ OH ＂ ＂ ＂ 223-229°(3)
7 ＂ ＂ H ＂ ＂ ＂ 130-133°(1)
8 4-Me ＂ OM ＂ ＂ ＂ 205-209°(4)
9 4-CF3 ＂ ＂ ＂ ＂ ＂ 202-207°(4)
10 2-Cl 4-Cl ＂ ＂ ＂ ＂ 250-257°(2)
11 2-F H ＂ ＂ ＂ ＂ 200-209°(4)
12 3-Cl ＂ ＂ ＂ ＂ ＂ 187-190°(1)
13 2-Cl ＂ ＂ ＂ ＂ (-)-(S) 200-225°(4)
14 ＂ ＂ ＂ ＂ H ＂ 219-224°(4)
15 ＂ ＂ ＂ ＂ Me (+)-(R) 221-226°(4)
16 ＂ ＂ ＂ ＂ H ＂ 216-223°(4)
17 H ＂ ＂ 哌啶子基 +/- 239-245°(4)
18 2-Cl ＂ ＂ ＂ ＂ 204-210°(4)
19 H ＂ ＂ 正丙基 正丙基 ＂ 130-145°(1)
20 4-CF3 ＂ ＂ Me Me (-)-(S) 212-215°(4)
21 ＂ ＂ ＂ ＂ ＂ (+)-(R) 209-216°(4)75-82°(3)
22 ＂ ＂ OH ＂ ＂ ＂ 224-263°(2)*
23 2-Et ＂ OMe ＂ ＂ +/- 189-197°(4)
24 2-Cl ＂ CN ＂ ＂ ＂ 209-215°(4)
25 ＂ 4-F OMe ＂ ＂ ＂ 236-240°(2)
26 2-F ＂ ＂ ＂ ＂ ＂ 172-178°(1)
                                续表1
27 2-OMe 4-OMe ＂ ＂ ＂ ＂ 182-189°(4)
28 2-F 3-F ＂ ＂ ＂ ＂ 193-211°(4)
29 2-OMe 3-OMe ＂ ＂ ＂ ＂ 213-229°(4)
30 2-Me 5-Me ＂ ＂ ＂ ＂ 212-220°(4)
31 2-Cl 3-Cl ＂ ＂ ＂ ＂ 198-208°(4)
32 2-F 5-F ＂ ＂ ＂ ＂ 189-195°(1)
33 2-Me 4-Me ＂ ＂ ＂ ＂ 232-238°(2)
34 2-Cl H CONH2 ＂ ＂ ＂ 186-189°(3)
35 4-CF3 ＂ OMe ＂ H (+)-R 205-208°(4)
36 H ＂ ＂ ＂ Me ＂ 198-211°(4)
37 4-Me ＂ ＂ ＂ ＂ ＂ 194-202°(4)
38 4-Cl ＂ ＂ ＂ ＂ ＂ 196-203°(4)
39 4-OMe ＂ ＂ ＂ ＂ ＂ 235-239°(4)
40 4-F ＂ ＂ ＂ ＂ ＂ 199-212°(1)
41 4-CF3 ＂ ＂ (CH2)2-OH ＂ ＂ 185-112°(4)
42 ＂ ＂ H Me ＂ ＂ 140-143°(5)
Me＝甲基Et＝乙基*分解点(1)马来酸氢盐(2)盐酸盐(3)游离碱(4)富马酸氢盐(5)丙二酸氢盐

Claims (7)

1.以游离碱或酸加成盐形式存在的式I化合物
Figure C9619373900021
其中R1和R2独立地是氢，(C1-4)烷基，(C1-4)烷氧基，(C1-4)烷硫基，卤素，三氟甲基，三氟甲氧基，氰基，(C2-5)烷酰基，(C1-4)烷基磺酰基或氨磺酰基，R3是氢，羟基，(C1-4)烷基，(C1-4)烷氧基，卤素，氰基，(C2-5)烷酰基，氨基甲酰基，(C1-4)烷基磺酰氧基或三氟甲磺酰氧基，和R4和R5独立地是氢，(C1-4)烷基，羟基(C2-4)烷基或苯基(C1-4)烷基，或与它们所连接的氮原子一起形成吡咯烷基，哌啶子基或哌嗪基。
2.以游离碱或酸加成盐的形式存在的权利要求1的化合物，其中R1和R2独立地是氢，(C1-4)烷基，(C1-4)烷氧基，卤素，三氟甲基，氰基，(C2-5)烷酰基或(C1-4)烷硫基，R3是氢，羟基，(C1-4)烷基，(C1-4)烷氧基，卤素，氰基，(C2-5)烷酰基，氨基甲酰基，(C1-4)烷基磺酰氧基或三氟甲基磺酰氧基，和R4和R5独立地是氢，(C1-4)烷基或苯基(C1-4)烷基，或与它们所连接的氮原子一起形成吡咯烷基，哌啶子基或哌嗪基。
3.选自式I化合物的旋光或外消旋形式的权利要求1的化合物，它们以游离碱或酸的加成盐形式存在，其中：R1＝4-Cl，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝H，       R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Me，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-OMe，   R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝H，       R2＝H，    R3＝OH，     R4＝Me，    R5＝Me，R1＝H，       R2＝H，    R3＝H，      R4＝Me，    R5＝Me，R1＝4-Me，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝4-CF3，  R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝4-Cl， R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-F，     R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝3-Cl，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝H，R1＝H，       R2＝H，    R3＝OMe，    R4+R5＝哌啶子基，R1＝2-Cl，    R2＝H，    R3＝OMe，    R4+R5＝哌啶子基，R1＝H，       R2＝H，    R3＝OMe，    R4＝正丙基，R5＝正丙基，R1＝4-CF3，  R2＝H，    R3＝OH，     R4＝Me，    R5＝Me，R1＝2-Et，    R2＝H，    R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝H，    R3＝CN，     R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝4-F，  R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-F，     R2＝4-F，  R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-OMe，   R2＝4-OMe，R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-F，     R2＝3-F，  R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-OMe，   R2＝3-OMe，R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Me，    R2＝5-Me， R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝3-Cl， R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-F，     R2＝5-F，  R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Me，    R2＝4-Me， R3＝OMe，    R4＝Me，    R5＝Me，R1＝2-Cl，    R2＝H，    R3＝CONH2， R4＝Me，    R5＝Me，R1＝4-CF3，  R2＝H，    R3＝OMe，    R4＝Me，    R5＝H，R1＝4-OMe，  R2＝H，    R3＝OMe，   R4＝Me，     R5＝Me，R1＝4-F，    R2＝H，    R3＝OMe，   R4＝Me，     R5＝Me，R1＝4-CF1， R2＝H，    R3＝OMe，   R4＝Et-OH，  R5＝Me，和R1＝4-CF1， R2＝H，    R3＝H，     R4＝Me，     R5＝MeMe是甲基，和Et是乙基。
4.权利要求1的化合物，该化合物是(R)-1，2，3，4-四氢-8-甲氧基-N，N-二甲基-5-〔4-(三氟甲基)苯基〕-2-萘胺，以游离碱或酸加成盐形式存在。
5.一种制备如权利要求1定义的游离碱或其酸加成盐形式的式I化合物的方法，该方法是通过式II化合物与式III化合物反应，并将生成的化合物以游离碱或酸加成盐形式回收，
Figure C9619373900041
其中R3，R4和R5如权利要求1所定义，Hal是卤素，其中R1和R2如权利要求1所定义。
6.一种药物组合物，其中含有权利要求1-4中任何一项的以游离碱或其可药用酸加成盐形式存在的化合物，及其药物载体或稀释剂。
7.权利要求1-4中任何一项的以游离碱或其可药用酸加成盐形式存在的化合物在制造用于治疗癫痫，中风和脑或脊柱创伤的药物中的应用。
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