CN101985438A - 取代苯基哌嗪芳烷酮衍生物及其在制备镇痛药物中的应用 - Google Patents
取代苯基哌嗪芳烷酮衍生物及其在制备镇痛药物中的应用 Download PDFInfo
- Publication number
- CN101985438A CN101985438A CN2009100555447A CN200910055544A CN101985438A CN 101985438 A CN101985438 A CN 101985438A CN 2009100555447 A CN2009100555447 A CN 2009100555447A CN 200910055544 A CN200910055544 A CN 200910055544A CN 101985438 A CN101985438 A CN 101985438A
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- China
- Prior art keywords
- phenyl
- piperazine
- trifluoromethyl
- ketone
- ethyl ketone
- 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.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
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Abstract
本发明公开了一类取代苯基哌嗪芳烷酮衍生物及其在制备镇痛药物中的应用,本发明所述的衍生物为具有以下结构通式化合物的游离碱或盐。药理试验表明本发明化合物为非阿片类镇痛剂,具有良好的镇痛作用,以及较小的毒副作用。结构通式如下:
Description
技术领域
本发明涉及一种取代苯基哌嗪芳烷酮衍生物以及在制备镇痛药物中的应用。
背景技术
严重的急慢性疼痛是指各种损伤性刺激引起伤害性感受器兴奋,通过伤害性信息传递信使的冲动,传入到中枢神经系统引起伤害性感受和痛觉。严重的急慢性疼痛包括肿瘤疼痛、术后疼痛、各种反复发作的急慢性疼痛等,困扰着数以千万计的患者,是目前临床一大难题。
临床使用的镇痛药物大致可分为以下三类:1)非甾体消炎镇痛药2)阿片类镇痛药3)辅助镇痛药,包括:局部麻醉药,抗抑郁药,抗癫痫药等。
目前,针对急性疼痛和癌症疼痛临床主要应用阿片类镇痛药。阿片类镇痛药物的成瘾性及呼吸抑制,胃蠕动减少等副作用,限制了它的广泛使用。在各种慢性非癌症疼痛和神经性疼痛的治疗方面,阿片类镇痛药或非甾体消炎镇痛药的治疗效果很难令人满意。因此,寻找既能保持强镇痛效应,又能克服阿片类镇痛药和非甾体消炎镇痛药的诸多副作用,安全用于临床的广谱镇痛药物,已经成为镇痛领域的主要研究目标和创新药研究热点方向。
近年来,国外的一些大制药公司,如默克公司,辉瑞公司等纷纷投巨资开发新型非成瘾性中枢镇痛剂,也取得了一定的进展。例如:2005年美国FDA批准钙离子通道拮抗剂(Ziconotide)上市,用于治疗其他药物无效或耐受的严重慢性疼痛,该药物存在易引起体位性低血压等副作用。但现有的药物还远远不能满足不同临床患者疼痛控制的要求,尤其是对于某些癌症疼痛、严重的慢性疼痛以及一些神经性疼痛,目前还没有合适的,安全有效的镇痛药物,因此需要不断地开发化学结构新颖的,毒副作用小,治疗范围广,安全用于临床的非成瘾性镇痛类药物,以满足不同疼痛患者的需要。同时,非阿片类镇痛药物具有日益发展的巨大市场,如有新颖的镇痛药物问世,亦将产生很大的社会效益和经济效益。
本发明人在专利ZL 02111786.1中公开了芳烷酮哌嗪衍生物及其在制备镇痛、镇静药物中的应用,其结构通式如下:
在后续研究中发现,当n=0时所得到的取代苯基哌嗪芳烷酮衍生物在动物模型中具有较强的镇痛作用,而镇静作用较小。
发明内容
本发明需要解决的技术问题之一是公开一类取代苯基哌嗪芳烷酮衍生物,克服现有镇痛药物具有成瘾性及呼吸抑制、胃蠕动减少和镇静等副作用的缺陷,以解决临床难题。
本发明需要解决的技术问题之二是公开所述取代苯基哌嗪芳烷酮衍生物在制备治疗镇痛药物中的应用。
本发明需要解决的技术问题之三是公开所述取代苯基哌嗪芳烷酮衍生物在制备治疗中枢神经系统紊乱性疾病药物中的应用。
本发明所述的取代苯基哌嗪芳烷酮衍生物为具有式(I)所示化合物的游离碱或盐,盐为盐酸盐、溴氢酸盐、硫酸盐、三氟醋酸盐或甲磺酸盐等,优选的盐为盐酸盐、溴氢酸盐,其盐可含0.5-3分子的结晶水:
(I)
其中:
R代表C1-C5的直链或支链的烷基,其中烷基上的氢原子任选被1-3个氟原子、氨基、羟基、C1-C3的烷氧基或C1-C4的烷胺基取代;
R1,R2,R3分别代表氢、卤素、C1-C3的烷基或C1-C3的烷氧基,烷基部分的氢原子可以任选被1-3个氟原子取代,且R1,R2和R3不同时为氢原子;
A代表:
其中:
R4代表:氢、卤素、羟基、C1-C3的烷氧基、三氟甲氧基、C1-C3的烷基、硝基、甲璜酰基、氨基、乙酰胺基、甲磺胺基、甲基亚磺酰胺基或C1-C4的烷胺基取代;
优选的,所述的取代苯基哌嗪芳烷酮衍生物包括:
I-1 1-(4-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-2 1-(3-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-3 1-(2-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-4 1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-5 1-(3-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-6 1-(2-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-7 1-o-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-8 1-m-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-9 1-p-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-10 1-(4-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-11 1-(3-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-12 1-(2-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-13 1-(4-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-14 1-(3-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-15 1-(2-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-16 1-(2-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-17 1-(3-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-18 1-(4-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-19 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙-1-酮、
I-20 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁-1-酮、
I-21 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮、
I-22 1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮、
I-23 2-(4-(3-甲氧基苯基)哌嗪-1-基)-1-苯乙酮、
I-24 1-(4-甲氧基苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮、
I-25 1-(4-氟苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮、
I-26 1-(3-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙-1-酮、
I-27 1-环己基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-28 1-(噻吩-2-基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮或
I-29 2-(4-(2-甲氧基苯基)哌嗪-1-基)-1-苯乙酮
最优选的化合物为:
I-4 1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-6 1-(2-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-13 1-(4-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-20 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁-1-酮、
I-21 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮或
I-29 2-(4-(2-甲氧基苯基)哌嗪-1-基)-1-苯乙酮。
具体化学结构式如下表所示:
本发明的化合物可采用如下的方法进行合成:
合成路线:
以芳烷酮化合物1为起始原料,在溴化铜作用下,发生a-溴化反应,得相应的a-溴化芳烷酮化合物2,再与取代的苯基哌嗪3进行缩合反应制备目标化合物(I)。
本发明中所使用的芳烷酮化合物1均有市售;取代的苯基哌嗪3可以参照文献(Tetrahedron Letters,38,39,1997,6875-6876)报道的方法,以取代的苯胺和氮芥为原料,在微波作用下制得,或采用市售产品。
本发明发现取代苯基哌嗪芳烷酮系列新化合物在小鼠化学品致痛药理模型上,多数化合物显示较强的抗疼痛扭体反应作用,具有镇痛活性。小鼠的热板药理模型试验也表明化合物具有镇痛作用。
动物模型研究结果表明,I-4等6个优选化合物具有明显镇痛作用,口服吸收较好。多次用药后不显耐药性,药物依赖性潜力很低,治疗指数较大,具备作为新型非成瘾性镇痛剂开发的潜在价值。
本发明人发现,本发明的衍生物毒性较低,神经副反应小。
因此,本发明所述取代苯基哌嗪芳烷酮衍生物可用于制备镇痛剂。
本发明所述取代苯基哌嗪芳烷酮衍生物还可能用于制备其它中枢神经系统紊乱性疾病的药物。例如:用于治疗神经性疼痛、躁狂症、焦虑症、各种抑郁症、精神分裂症、帕金森病(PD)、亨廷顿舞蹈病(HD)、阿尔茨海默氏病、老年性痴呆、阿尔茨海默氏型痴呆、记忆障碍、执行功能丧失、血管性痴呆和其它痴呆,以及与智力、学习或记忆相关的功能障碍性疾病等药物。
本发明的衍生物可以组合物的形式通过口服、注射等方式施用于需要这种治疗的患者。给药日剂量一般为0.1~3mg/kg(口服)或0.02~2mg/kg(注射),可根据临床实验结果及患者的病情、年龄等由医师决定。
所述组合物包括治疗有效量的所述取代苯基哌嗪芳烷酮衍生物和医学上可接受的载体。
所述载体是指药学领域常规的载体,例如:稀释剂、赋形剂如水等;粘合剂如纤维素衍生物、明胶、聚乙烯吡咯烷酮等;填充剂如淀粉等;崩裂剂如碳酸钙、碳酸氢钠;润滑剂如硬脂酸钙或硬脂酸镁等。另外,还可以在组合物中加入其他辅助剂如香味剂和甜味剂。用于口服时,可将其制备成常规的固体制剂如片剂、粉剂或胶囊等;用于注射时,可将其制备成注射液。
本发明的组合物的各种剂型可以采用医学领域常规的方法进行制备,其中活性成分的含量为0.1%~99.5%(重量比)。
本发明所述的取代苯基哌嗪芳烷酮衍生物及其生理上可接受的盐对各种类型的疼痛具有镇痛作用,包括各种伤害感受性疼痛、急性疼痛、慢性疼痛、神经性疼痛、精神性疼痛和混合性疼痛等。它特别包括但不限于:手术后疼痛、神经原性疼痛、中枢性痛、躯体痛、内脏痛、慢性后背痛、颈和腰痛、癌症痛、炎症疼痛、糖尿病性神经痛、坐骨神经痛、紧张性头痛、丛集性头痛、每日慢性头痛、疱疹神经痛、面部和口腔神经痛以及肌筋膜痛综合征、假性肢痛、残肢痛和截瘫痛、牙痛、耐阿片样物质疼痛、包括心脏手术和乳房切除术在内的术后疼痛、心绞痛、骨盆疼痛、膀胱炎以及阴道前庭炎和睾丸痛在内的泌尿生殖道疼痛、月经前期疼痛综合症。中风后疼痛、过敏性肠综合征、劳累和分娩疼痛、分娩后疼痛、因烧伤和化学损伤或日晒导致的疼痛和骨损伤性疼痛。
本专利结构类型化合物具有如下优点:
1.在小鼠醋酸扭体和热板模型中均显示较强的镇痛作用;
2.与阿片受体三个亚型均无高亲和力,表明该类型化合物为非阿片镇痛剂;
3.镇静作用较小,可以开发成专一性的镇痛剂;
4.毒副作用小,安全指数高;
5.成药性较好,具有作为新型非阿片镇痛剂的潜在价值。
本发明涉及的新型的取代苯基哌嗪芳烷酮衍生物及其生理上可接受的盐具有非常有用的药学性质及良好的耐受性,尤其是作为新型镇痛药物的应用。该类化合物为具有非成瘾性的中枢镇痛剂,动物试验无明显镇静作用,具有很小的毒副作用和较高的安全指数。
具体实施方式
通法:
1-取代苯基-2-(取代苯基哌嗪基)烷基-1-酮(I)盐酸盐的制备:
1)a-溴代苯烷酮的制备
芳烷酮0.1mol溶解于200ml的氯仿和乙酸乙酯的混合溶剂中(体积比1∶1),室温搅拌下,加入固体溴化铜0.2mol,回流反应12小时。冷却反应液至室温,过滤,滤液浓缩至干,剩余油状物用石油醚(2x100ml)热抽提,去除不溶物,合并石油醚相,蒸干得油状物,收率:40~94%。
2)1-取代苯基-4-芳甲酰烷基哌嗪盐酸盐的制备
取代苯基哌嗪(0.01mol)和a-溴代芳烷酮(0.012mol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(4.15g,0.03mol),升温回流反应5小时。冷却反应液,过滤,滤液蒸干,加入乙酸乙酯150ml,用水(1x50ml)洗涤,饱和食盐水水(1x50ml)洗涤,干燥,过滤,滤液用HCl/C2H5OH(5N)调pH=2,过滤析出的固体,乙醇/水或乙醇/乙酸乙酯重结晶,得1-取代苯基-4-芳甲酰烷基哌嗪的盐酸盐,收率10~80%。
实施例1
1-(4-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-1)的制备
以对甲氧基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代对甲氧基苯乙酮。取a-溴代对甲氧基苯乙酮(0.66g,2.86mmol)和3-三氟甲基苯基哌嗪(0.60g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.86g,收率79.26%。熔点:216.7-218.7℃,MS(m/s):379.0[M+1]+。
1HNMR(DMSO-d6):δ3.33-3.96(m,8H,哌嗪-H),3.87(s,3H,-OCH3),5.12(s,2H,-CH2-),7.12-7.98(m,8H,Ar-H)。
实施例2
1-(3-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-2)的制备
以3-甲氧基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-3-甲氧基苯乙酮。取a-溴代-3-甲氧基苯乙酮(0.66g,2.86mmol)和3-三氟甲基苯基哌嗪(0.60g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(3-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.82g,收率75.93%。熔点:219.9-222.3℃,MS(m/s):379.1[M+1]+。
1HNMR(DMSO-d6):δ3.36-3.96(m,8H,哌嗪-H),3.84(s,3H,-OCH3),5.22(s,2H,-CH2-),7.14-7.59(m,8H,Ar-H)。
实施例3
1-(2-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-3)的制备
以2-甲氧基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-2-甲氧基苯乙酮。取a-溴代-2-甲氧基苯乙酮(0.66g,2.86mmol)和3-三氟甲基苯基哌嗪(0.60g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(2-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.53g,收率49.07%。熔点:218.9-220.1℃,MS(m/s):379.2[M+1]+。
1HNMR(DMSO-d6):δ3.29-3.95(m,8H,哌嗪-H),3.97(s,3H,-OCH3),4.88(s,2H,-CH2-),7.11-7.89(m,8H,Ar-H)。
实施例4
1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-4)的制备
以对氟苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代对氟苯乙酮。取a-溴代对氟苯乙酮(0.62g,2.86mmol)和3-三氟甲基苯基哌嗪(0.60g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.78g,收率73.90%。熔点:227.8-229.3℃,MS(m/s):366.9[M+1]+。
1HNMR(DMSO-d6):δ3.36-3.95(m,8H,哌嗪-H),5.21(s,2H,-CH2-),7.14-8.10(m,8H,Ar-H)。
实施例5
1-(2-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-6)的制备
以2-氟苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-2-氟苯乙酮。取a-溴代-2-氟苯乙酮(0.52g,2.4mmol)和3-三氟甲基苯基哌嗪(0.50g,2.2mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(0.90g,6.5mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(2-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.21g,收率22.11%。熔点:189.3-191.8℃,MS(m/s):367.8[M+1]+。
1HNMR(DMSO-d6):δ3.43-3.95(m,8H,哌嗪-H),4.98(s,2H,-CH2-),7.14-8.02(m,8H,Ar-H)。
实施例6
1-o-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-7)的制备
以2-甲基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-2-甲基苯乙酮。取a-溴代-2-甲基苯乙酮(0.61g,2.86mmol)和3-三氟甲基苯基哌嗪(0.60g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-o-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.60g,收率53.10%。熔点:195.6-197.0℃,MS(m/s):363.1[M+1]+。
1HNMR(DMSO-d6):δ2.51(s,3H,-CH3),3.16-3.95(m,8H,哌嗪-H),5.12(s,2H,-CH2-),7.12-7.92(m,8H,Ar-H)
实施例7
1-p-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-9)的制备
以4-甲基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-4-甲基苯乙酮。取a-溴代-4-甲基苯乙酮(0.51g,2.4mmol)和3-三氟甲基苯基哌嗪(0.50g,2.4mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(0.91g,6.6mmol),升温回流反应5小时。按通法中的后处理操作,得到1-p-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.43g,收率49.60%。熔点:224.7-226.5℃,MS(m/s):363.1[M+1]+。
1HNMR(DMSO-d6):δ2.41(s,3H,Ph-CH 3 ),3.32-3.93(m,8H,哌嗪-H),5.11(s,2H,-CH2-),7.15-7.91(m,8H,Ar-H)。
实施例8
1-(4-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-10)的制备
以4-硝基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-4-硝基苯乙酮。取a-溴代-4-硝基苯乙酮(0.58g,2.4mmol)和3-三氟甲基苯基哌嗪(0.50g,2.4mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(0.91g,6.6mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.13g,收率12.87%。熔点:12.87%。m.p=172.0-174.1℃,MS(m/s):394.0[M+1]+。
1HNMR(DMSO-d6):δ3.22-3.93(m,8H,哌嗪-H),5.21(s,2H,-CH2-),7.14-8.45(m,8H,Ar-H)。
实施例9
1-(4-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-13)的制备
以4-甲磺酰基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-4-甲磺酰基苯乙酮。取a-溴代-4-甲磺酰基苯乙酮(0.79g,2.9mmol)和3-三氟甲基苯基哌嗪(0.60g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.62g,收率55.86%。熔点:204.1-206.3℃,MS(m/s):427.1[M+1]+。
1HNMR(DMSO-d6):δ3.14-3.94(m,8H,哌嗪-H),3.31(s,3H,-SO2CH3),5.26(s,2H,-CH2-),7.12-8.28(m,8H,Ar-H)。
实施例10
1-(4-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-18)的制备
以4-氯苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代-4-氯苯乙酮。取a-溴代-4-氯苯乙酮(0.41g,1.8mmol)和3-三氟甲基苯基哌嗪(0.37g,1.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(0.67g,4.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.44g,收率60.27%。熔点:195.8-198.1℃,MS(m/s):383.0[M+1]+。
1HNMR(DMSO-d6):δ3.35-3.92(m,8H,哌嗪-H),5.16(s,2H,-CH2-),7.14-8.02(m,8H,Ar-H)。
实施例11
1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁-1-酮盐酸盐(I-20)的制备
以苯丁酮为原料,按通法中的合成及后处理方法制备a-溴代苯丁酮。取a-溴代苯丁酮(0.65g,2.86mmol)和3-三氟甲基苯基哌嗪(0.6g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁-1-酮盐酸盐0.46g,收率39.32%。熔点:187.2-188.8℃,MS(m/s):377.2[M+1]+。
1HNMR(DMSO-d6):δ0.78(t,3H,-CH3,J=14.88),2.07(m,2H,-CH-CH 2 -),3.18-3.70(m,8H,哌嗪-H),5.57(t,H,-CH-),7.14-8.13(m,9H,Ar-H)
实施例12
1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮盐酸盐(I-21)的制备
以苯戊酮为原料,按通法中的合成及后处理方法制备a-溴代苯戊酮。取a-溴代苯戊酮(0.69g,2.86mmol)和3-三氟甲基苯基哌嗪(0.6g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮盐酸盐0.5g,收率45.05%。熔点:180.5-182.4℃,MS(m/s):391.2[M+1]+。
1HNMR(DMSO-d6):δ0.944(t,3H,-CH3,J=14),0.962-1.353(m,2H,-CH-CH 2 -),1.733-1.948(dd,2H,-CH 2 -CH3),2.75-3.20(m,8H,哌嗪-H),4.13(t,H,-CH-),6.99-8.07(m,9H,Ar-H)。
实施例13
1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮盐酸盐(I-22)的制备
以4-氟苯戊酮为原料,按通法中的合成及后处理方法制备a-溴代-4-氟苯戊酮。取a-溴代-4-氟苯戊酮(2.12g,8.2mmol)和3-三氟甲基苯基哌嗪(1.71g,7.4mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(3.08g,22.3mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮盐酸盐1.72g,收率52.12%。熔点:203.1-205.5℃,MS(m/s):379.0[M+1]+。
1HNMR(DMSO-d6):δ0.794(t,3H,-CH3,J=14.8),1.028-1.196(m,2H,-CH-CH 2 -),1.927-1.980(dd,2H,-CH 2 -CH3),3.322-3.652(m,8H,哌嗪-H),5.358(t,H,-CH-),7.14-8.19(m,8H,Ar-H)。
实施例14
2-(4-(3-甲氧基苯基)哌嗪-1-基)-1-苯乙酮盐酸盐(I-23)的制备
取a-氯代苯乙酮(0.44g,2.86mmol)和3-甲氧基苯基哌嗪(0.5g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到2-(4-(3-甲氧基苯基)哌嗪-1-基)-1-苯乙酮盐酸盐0.75g,收率83.15%。熔点:224.9-226.2℃,MS(m/s):311.1[M+1]+。
1HNMR(DMSO-d6):δ3.53-3.89(m,8H,哌嗪-H),3.72(s,3H,-OCH3),5.22(s,2H,-CH2-),6.36-8.10(m,9H,Ar-H)。
实施例15
1-(4-甲氧基苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮盐酸盐(I-24)的制备
以对甲氧基苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代对甲氧基苯乙酮。取a-溴代对甲氧基苯乙酮(0.66g,2.86mmol)和3-甲氧基苯基哌嗪(0.5g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-甲氧基苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮盐酸盐0.82g,收率83.67%。熔点:201.0-203.1℃,MS(m/s):341.1[M+1]+。
1HNMR(DMSO-d6):δ3.22-3.83(m,8H,哌嗪-H),3.72(s,3H,-OCH3),3.87(s,3H,-OCH3),5.11(m,H,-CH-),6.43-7.98(m,8H,Ar-H)
实施例16
1-(4-氟苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮盐酸盐(I-25)的制备
以对氟苯乙酮为原料,按通法中的合成及后处理方法制备a-溴代对氟苯乙酮。取a-溴代对氟苯乙酮(0.62g,2.86mmol)和3-甲氧基苯基哌嗪(0.5g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-(4-氟苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮盐酸盐0.73g,收率76.84%。熔点:206.8-209.3℃,MS(m/s):329.1[M+1]+。
1HNMR(DMSO-d6):δ3.31-3.84(m,8H,哌嗪-H),3.72(s,3H,-OCH3),5.21(s,2H,-CH2-),6.05-8.01(m,8H,Ar-H)。
实施例17
1-环己基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-27)的制备
以1-环己基乙酮为原料,按通法中的合成及后处理方法制备2-溴-1-环己基乙酮。取2-溴-1-环己基乙酮(0.59g,2.86mmol)和3-三氟甲基苯基哌嗪(0.6g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-环己基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.73g,收率83.33%。熔点:236.1-238.3℃,MS(m/s):355.2[M+1]+。
1HNMR(DMSO-d6):δ1.14-1.85(m,10H,-C5H10),3.23-3.47(m,8H,哌嗪-H),3.89(m,H,-COCH-),4.55(s,2H,-CH2-),7.13-7.48(m,4H,Ar-H)。
实施例18
1-(噻吩-2-基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐(I-28)的制备
以1-(噻吩-2-基)乙酮为原料,按通法中的合成及后处理方法制备2-溴-1-(噻吩-2-基)乙酮。取2-溴-1-(噻吩-2-基)乙酮(0.59g,2.86mmol)和3-三氟甲基苯基哌嗪(0.6g,2.6mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(1.08g,7.8mmol),升温回流反应5小时。按通法中的后处理操作,得到1-环己基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮盐酸盐0.7g,收率68.63%。熔点:213.0-214.2℃,MS(m/s):355.0[M+1]+。
1HNMR(DMSO-d6):δ3.34-3.94(m,8H,哌嗪-H),5.10(s,2H,-CH2-),7.14-8.21(m,7H,Ar-H)。
实施例19
2-(4-(2-甲氧基苯基)哌嗪-1-基)-1-苯乙酮盐酸盐(I-29)的制备
取a-氯代对氟苯乙酮(1.86g,12mmol)和2-甲氧基苯基哌嗪(1.92g,10mmol),溶解于50ml丙酮溶剂中,加入无水碳酸钾(4.4g,32mmol),升温回流反应5小时。按通法中的后处理操作,得到2-(4-(2-甲氧基苯基)哌嗪-1-基)-1-苯乙酮盐酸盐0.85g,收率26.0%。熔点:206.8-209.3℃,MS(m/s):311.1[M+1]+。
1HNMR(DMSO-d6):δ3.39-3.58(m,8H,哌嗪-H),3.82(s,3H,-OCH3),5.00(s,2H,-CH2-),7.01-7.95(m,9H,Ar-H)。
实施例20
片剂:实施例1-19的衍生物 25mg
蔗糖 155mg
玉米淀粉 65mg
硬脂酸镁 5mg
制备方法:将活性成分与蔗糖、玉米淀粉混合,加水湿润,搅拌均匀,干燥,粉碎过筛,加入硬脂酸镁,混合均匀,压片。每片重250mg,活性成分含量为25mg。
实施例21
针剂:实施例1-19的衍生物 10mg
注射用水 990mg
制备方法:将活性成分溶解于注射用水,混合均匀,过滤,将所获得的溶液在无菌条件下分装于安瓿瓶中,每瓶100mg,活性成分含量为1mg/瓶。
实施例22
化合物小鼠醋酸扭体法体内镇痛作用
1.实验动物:
健康昆明种小鼠,清洁级KM小鼠购自南京青龙山动物养殖中心,普通环境内饲养。
2.实验给药方式:
将化合物用注射用水配制成4mg/ml、2mg/ml、1mg/ml溶液,对照组及给药组均采用动物经颈部皮下注射给药。
3.实验给药剂量:
给药组采用三种不同剂量给药,分别为:10mg/kg、20mg/kg、40mg/kg。
4.实验方法:
以阿斯匹林为阳性对照药物,采用醋酸扭体法进行实验。
5.具体实验操作:
取小鼠30只,雌雄各半,体重在18-23克之间。将其分为五组,分别为:阴性对照组、阳性对照组、低剂量组、中剂量组和高剂量组,具体如下:
阴性对照组 生理盐水 0.2ml
阳性对照组 阿斯匹林 200mg/kg
低剂量组 受试药物 10mg/kg
中剂量组 受试药物 20mg/kg
高剂量组 受试药物 40mg/kg
小鼠先经灌胃给药测试样品(10mg/kg,20mg/kg,40mg/kg),阴性对照组口服生理盐水(20ml/kg),阳性对照组口服阿斯匹林(200mg/kg),1小时后各组小鼠分别ip 0.7%乙酸10ml/kg,间隔5min后记录各组小鼠在15min内出现的扭体反应次数,按下列公式计算各给药组的扭体反应抑制率。
6.部分化合物多剂量给药实验结果:详见表2
注:*表示P值<0.05,**表示P值<0.01
实施例23
化合物小鼠热板法体内镇痛作用
1.实验动物:
健康昆明种小鼠,清洁级KM小鼠购自南京青龙山动物养殖中心,普通环境内饲养。
2.实验给药方式:
将化合物用注射用水配制成4mg/ml、2mg/ml、1mg/ml溶液,对照组及给药组均采用动物经颈部皮下注射给药。
3.实验给药剂量:
给药组采用三种不同剂量给药,分别为:10mg/kg、20mg/kg、40mg/kg。
4.实验方法:
以吗啡为阳性对照药物,采用热板法进行实验。
5.具体实验操作:
取小鼠30~40只,雌雄各半,体重在18-23克之间。首先,分别将小鼠置于55.5℃的热板上测试2~3次基础痛阈值,基础痛阈值5~30s为合格,淘汰不合格的小鼠。取30只合格小鼠将其分为五组,分别为:阴性对照组、阳性对照组、低剂量组、中剂量组和高剂量组,具体如下:
阴性对照组 直接测试基础痛阈值
阳性对照组 吗啡 0.2mg/ml 0.2ml
低剂量组 受试药物1mg/ml 0.2ml
中剂量组 受试药物2mg/ml 0.2ml
高剂量组 受试药物4mg/ml 0.2ml
小鼠经颈部皮下注射测试样品溶液(10mg/kg,20mg/kg,40mg/kg),阳性对照组皮下注射吗啡(2mg/kg),1小时后各组小鼠分别测痛阈值作为给药后痛阈值。按下面的公式计算痛阈提高率:
6.部分化合物实验结果:详见表3
表3.化合物小鼠热板法筛选结果
注:*表示P值<0.05,**表示P值<0.01
实施例24
化合物与阿片受体亚型μ、δ、κ的竞争性结合实验
应用放射性配体结合实验测定化合物对阿片受体亚型μ、δ、κ的竞争结合能力,来验证该类化合物的镇痛途径属非阿片类。
受体竞争实验分为总结合管、非特异性结合管及试样管。总结合管中加入30μg膜蛋白、[3H]Diprenorphine(终浓度为0.4nM),用50mM Tris-HCl(pH7.4)调节终体积至200μL;相对应的非特异结合管中另加10μM Naloxone;试样管分别加入待测化合物(终浓度为10-5M),37℃温育30min,然后置冰浴终止反应。在Millipore样品收集器上经GF/C(Whatman)玻璃纤维滤纸负压抽滤。用冰冷的50mM Tris-HCl(pH7.4)冲洗滤纸三次,每次4ml,滤纸烘干后置于0.5ml Eppendorf管,加0.5ml亲脂闪烁液,BeckmanLS6500多功能液体闪烁计数仪测定放射性强度。每一浓度为三复管,每一独立实验重复3-4次。各试样管特异性结合CPM值=各试样管总结合CPM值-非特异性管CPM值。[待测化合物对阿片受体不同亚型的竞争结合抑制率(%)=(100%-试样管特异性结合(CPM值)/溶剂组特异性结合(CPM值))×100%。各试药每次试验做双三复管取均值,重复实验2次以上,数据以mean±SE表示,用方差分析法作统计学比较。测定的6个化合物对阿片受体三种不同亚型均无高亲和力,实验结果见表4。
表4.化合物与阿片受体亚型μ、δ、κ的竞争性结合实验结果
实施例25
化合物I-13、I-21和I-29急性毒性研究:
化合物I-21和I-29进行序贯法之限度实验,小鼠po的LD50剂量大于2000mg/kg。
I-13采用Bliss法统计,小鼠po的LD50为785mg/kg。
上述结果表明,I-13、I-21和I-29具有明显镇痛作用,口服吸收较好。与阿片受体亚型μ、δ、κ无明显亲和作用,属非阿片类镇痛途径;两者治疗指数较大,具备作为新型非阿片类镇痛新药研究开发的潜在价值。
Claims (12)
2.根据权利要求1所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,R代表C1-C5的直链或支链的烷基,其中烷基上的氢原子任选被1-3个氟原子、氨基、羟基、C1-C3的烷氧基或C1-C4的烷胺基取代。
3.根据权利要求1所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,R1,R2,R3分别代表氢、卤素、C1-C3的烷基或C1-C3的烷氧基,烷基部分的氢原子任选被1-3个氟原子取代。
4.根据权利要求2所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,R1,R2,R3分别代表氢、卤素、C1-C3的烷基或C1-C3的烷氧基,烷基部分的氢原子任选被1-3个氟原子取代。
5.根据权利要求1所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,所述的盐为盐酸盐、溴氢酸盐、硫酸盐、三氟醋酸盐或甲磺酸盐。
6.根据权利要求5所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,所述的盐为盐酸盐、溴氢酸盐。
7.根据权利要求1所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,所述的盐含0.5-3分子的结晶水。
8.根据权利要求1所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,所述的取代苯基哌嗪芳烷酮衍生物包括:
I-1 1-(4-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-2 1-(3-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-3 1-(2-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-4 1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-5 1-(3-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-6 1-(2-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-7 1-o-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-8 1-m-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-9 1-p-甲苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-10 1-(4-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-11 1-(3-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-12 1-(2-硝基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-13 1-(4-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-14 1-(3-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-15 1-(2-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-16 1-(2-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-17 1-(3-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-18 1-(4-氯苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-19 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙-1-酮、
I-20 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁-1-酮、
I-21 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮、
I-22 1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮、
I-23 2-(4-(3-甲氧基苯基)哌嗪-1-基)-1-苯乙酮、
I-24 1-(4-甲氧基苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮、
I-25 1-(4-氟苯基)-2-(4-(3-甲氧基苯基)哌嗪-1-基)乙酮、
I-26 1-(3-甲氧基苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙-1-酮、
I-27 1-环己基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-28 1-(噻吩-2-基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮或
I-29 2-(4-(2-甲氧基苯基)哌嗪-1-基)-1-苯乙酮。
9.根据权利要求1所述的取代苯基哌嗪芳烷酮衍生物,其特征在于,所述的取代苯基哌嗪芳烷酮衍生物为:
I-4 1-(4-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-6 1-(2-氟苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-13 1-(4-(甲磺酰基)苯基)-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙酮、
I-20 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁-1-酮、
I-21 1-苯基-2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)戊-1-酮或
I-29 2-(4-(2-甲氧基苯基)哌嗪-1-基)-1-苯乙酮。
10.一种药物组合物,其特征在于,包括治疗有效量的权利要求1~8任一项所述的取代苯基哌嗪芳烷醇衍生物和医学上可接受的载体。
11.权利要求1~8任一项所述的取代苯基哌嗪芳烷酮衍生物在制备治疗镇痛药物中的应用。
12.权利要求1~8任一项所述的取代苯基哌嗪芳烷酮衍生物在制备治疗中枢神经系统紊乱性疾病药物中的应用。
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CN111410647A (zh) * | 2019-01-04 | 2020-07-14 | 中国人民解放军军事科学院军事医学研究院 | μ阿片受体偏向性激动剂及其医药用途 |
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CN111410647A (zh) * | 2019-01-04 | 2020-07-14 | 中国人民解放军军事科学院军事医学研究院 | μ阿片受体偏向性激动剂及其医药用途 |
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