CN102408433B - 含嘧啶的肟类化合物、其制备方法和用途 - Google Patents
含嘧啶的肟类化合物、其制备方法和用途 Download PDFInfo
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- CN102408433B CN102408433B CN201110319829.4A CN201110319829A CN102408433B CN 102408433 B CN102408433 B CN 102408433B CN 201110319829 A CN201110319829 A CN 201110319829A CN 102408433 B CN102408433 B CN 102408433B
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Abstract
本发明属于医药技术领域,提供具有通式I结构的含嘧啶的肟类化合物及其药用盐,其中R1-R4如权利要求定义。本发明还涉及上述化合物的制备方法,并同时公开了以该类化合物或其药学上可接受的盐作为活性有效成分的药物组合物,以及它们在作为抗忧郁药物方面的应用。
Description
技术领域
本发明属于医药技术领域,更确切地说,是涉及一类具有抗抑郁的化合物及其制备方法、含有它们的药物组合物和作为抗抑郁药物的用途。
背景技术
随着社会竞争日趋激烈,生活节奏不断加快,人们的精神压力也逐渐增大,抑郁症已成为一种危害人类身心健康的主要精神疾病。2002年全球重症抑郁病患者已有8900多万人,而全球的抑郁症患者已达3.4亿。在年满18岁的成年人口中,抑郁症患者正以每年41.3%的速率增加。国际卫生组织预测2020年该病将成为全球第二大威胁人类健康的疾患。抑郁症在我国的情况也不容乐观,抑郁症患病率约为29%~35%左右,神经精神疾病在我国疾病总负担中排名首位,约占疾病总负担的70%。抑郁症对人类身心的危害已受到我国社会各界和人们的高度重视。
到目前为止,抗抑郁药的发展呈三个阶段,已开发出三代抗抑郁药物。1950~1980年代出现了第一代抗抑郁药物-三环类(吩噻嗪类)杂环抗抑郁药物,又称为传统抗抑郁药物。TCAs是单胺氧化酶再摄取抑制剂及非选择性5-羟色胺和去甲肾上腺素抑制剂。主要包括地昔帕明(desipramine)、咪帕明(imipramine)、氯咪帕明(clomipramine)、去甲替林(nortriptyline)、阿米替林(amitriptyline)、多塞平(doxepin)等。
二十世纪80年代末期以来出现第二代抗抑郁药物,即选择性5-羟色胺再摄取抑制剂(SSRIs),主要包括氟西汀(fluoxetine)、舍曲林(sertaline)、西酞普兰(citalopram)等。这类药物不良反应比三环类抗抑郁药物显著减小,安全性高,提高了治疗效果,在许多国家已经成为治疗抑郁症的首选药物,并已成为抗抑郁药市场上的主导产品。但由于抑制了5-HT的再摄取,使突触间隙处的5-HT增多,激动了5-HT3受体而产生焦虑、失眠、恶心、呕吐、食欲减退等副反应,且因为5-HT2受体被激动而性欲可能受到抑制,有的病人体重增加。但总的说来副反应程度较轻,不必做特殊处理。
随着对抑郁症基础理论的深入研究,为了克服抗抑郁药物的一些缺限,从20世纪90年代开始,出现了新作用机制的第三代抗抑郁药物,如5-HT/NA再摄取抑制剂,包括文拉法辛(venlaxine)、度洛西汀(duloxetine)、米纳普仑(milnacipran)、奈法唑酮(nefazodone);选择性单胺氧化酶抑制剂包括吗氯贝胺(moclobemide)、托罗莎酮(toloxatone);选择性NA再摄取抑制剂(selective NAreuptake inhibitors,NARIs)瑞波西汀(reboxetine);NA及特异性能5-HT抗抑郁剂如米氮平(mirtazapine)。这些药物与SSRIs类相比,在疗效、副作用及快速起效方面得到了改善,部分药物甚至只有1-2周的滞后期。
目前,国产药物主要是第一代三环类抗抑郁药,疗效低,副作用大,市场格局还是进口药品占据了主导地位。因此研制疗效高、毒副作用小的新型抗抑郁药就显得尤为重要。
发明内容
本发明的一个目的在于,公开一类含嘧啶的肟类化合物其药用盐。
本发明的另一个目的在于,公开一类含嘧啶的肟类化合物及其药用盐的制备方法。
本发明的再一个目的在于,公开以含嘧啶的肟类化合物及其药用盐为主要活性成分的药物组合物。
本发明还有一个目的在于,公开一类含嘧啶的肟类化合物及其药用盐作为抗抑郁药物方面的应用,特别是在用于制备预防或治疗情绪低落、心情郁郁寡欢、悲观、消极等抑郁症药物方面的用途。
现结合本发明目的,对本发明内容进行详细阐述。
本发明具体涉及通式I结构的化合物及其药学上可接受的盐:
其中:
R1、R3为:C1-C4直链或支链烷基。
R2为:氢,C1-C4直链或支链烷基。
优选以下化合物及其药学上可接受的盐:
I-1 5-((2-乙酰胺基-4,6-二氯嘧啶-5-基)(0-肟基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基乙酸酯
I-2 5-((2-丁酰胺基-4,6-二氯嘧啶-5-基)(0-甲基-肟基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基乙酸酯
I-3 5-((4,6-二氯-2-二氯嘧啶-5-基)(0-乙基-肟基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基乙酸酯
I-4 5-((4,6-二氯-2-戊酰胺基嘧啶-5-基)(0-丙基-肟基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基乙酸酯
I-5 5-((4,6-二氯-2-异丁基肟基-5-基)(0-异丙基-肟基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基丙酸酯
式I化合物药学上可接受的盐指:化合物与无机酸、有机酸所成的盐。其中优选:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐,对甲苯磺酸盐,马来酸盐,苯甲酸盐,琥珀酸盐,酒石酸盐,柠檬酸盐,富马酸盐,牛磺酸盐,葡萄糖酸盐,氨基酸盐。
通式I化合物的制备路线如下:
2-氨基-4,6-二氯-5-甲醛嘧啶(II),在四氢呋喃、DMF、丙酮、二氯甲烷、乙酸乙酯、苯、甲苯等溶剂中,与酰氯在三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠或氢氧化钾等缚酸剂的催化下,-30~30℃反应制得关键中间体III。中间体III在甲醇、乙醇或丙酮等溶剂中,与N-取代羟胺盐酸盐类化合物在三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠或氢氧化钾等缚酸剂的催化下,-30~85℃反应制得关键中间体IV。中间体IV再与溴、NBS或NCS等卤化剂在二氯甲烷、三氯甲烷或甲苯中-10~110℃反应,生成中间体V。中间体V与5,6,7,7a-四氢噻吩并[3,2-c]吡啶-2-(4H)-酮在氢氧化钾存在下,以三氯甲烷为溶剂,20~50℃反应制得中间体VI。中间体VI与酸酐在三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠或氢氧化钾存在下,以甲醇、乙醇、乙酸乙酯、二氯甲烷、三氯甲烷或甲苯为溶剂,25~120℃反应最终制得化合物I。
反应制得各种化合物或将所得产物溶于DMF、丙酮、甲醇、乙醇或DMSO中滴加无机酸、有机酸制成药学上可接受的盐。
具体是将所得产物溶于DMF、丙酮、甲醇、乙醇或DMSO中,滴加盐酸乙醇至pH2,制成盐酸盐。或将所得产物溶于DMF、丙酮、甲醇或乙醇,加入等摩尔牛磺酸,得其牛磺酸盐。也可将该化合物溶于DMF、丙酮、甲醇、乙醇或DMSO中,滴加浓硫酸的甲醇溶液,调pH2-3,制得其硫酸盐,等等。
此类化合物对于人类治疗抑郁是有效的。尽管本发明的化合物可以不经任何配制直接给药,但所述的各种化合物优选以药物制剂的形式使用,给药途径可以是非肠道途径(如静脉、肌肉给药)及口服给药。
本发明化合物的药物组合物制备如下:使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质,其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。
药物组合物以及单元剂型中含有的活性成份(本发明化合物)的量可以根据患者的病情、医生诊断的情况特定地加以应用,所用的化合物的量或浓度在一个较宽的范围内调节。通常,活性化合物的量范围为组合物的0.5~90%(重量),另一优选的范围为0.5~70%。
本发明的具有式I结构的化合物或其药学上可接受的盐,对抑郁症有明显的抑制作用。
下面通过药效学实验进一步说明本发明化合物的抗抑郁活性。
体重20~24g/只雄性昆明种小白鼠,在25cm×25cm×25cm悬尾箱顶板中心绳上连一夹子,夹小鼠尾尖1cm处使之倒悬,头部离箱底面4~5cm。实验前30min腹腔注射或实验前60min口服给予待测药物及阳性对照药氟西汀,悬尾6min,累计后4min小鼠不动时间。小鼠悬尾不动时间越短,抗抑郁作用越强。
表1对小鼠悬尾试验的影响(单次给药)
由以上药理实验可见,本发明的化合物对抑制抑郁有明显的效果。
具体实施方式
下面结合实施例对本发明做进一步的说明,实施例仅为解释性的,决不意味着它以任何方式限制本发明的范围。所述的化合物经高效液相色谱(HPLC),薄层色谱(TLC)进行检测。随后可以采用诸如红外光谱(IR),核磁共振谱(1H NMR,13C NMR),质谱(MS)等更进一步确证其结构。
参考实施例1:
中间体III-1的合成
在装有搅拌、冷凝器、温度计的反应瓶中加入19.2g 2-氨基-4,6-二氯-5-甲醛嘧啶(II),用35mL二氯甲烷将其溶解,加入三乙胺20.2g。-10~10℃下,将11.8g乙酰氯分批加入反应体系。加完后继续反应5h(板层显示反应完全)。将二氯甲烷蒸干,用3×40mL水洗涤反应液,用二氯甲烷萃取,无水硫酸钠充分干燥,过滤,减压蒸尽二氯甲烷,即得白色固体(HPLC:98.7%)。Rf=0.55[单点,展开剂:v(二氯甲烷)∶v(甲醇)=7∶1]。
参照参考实施例1的方法,即可合成中间体III-2~III-5。
表2中间体III-2~III-5列表
参考实施例2:
中间体IV-1的合成
在装有搅拌、冷凝器、温度计的反应瓶中加入11.7g中间体III-1,用35mL无水乙醇将其溶解,搅拌下加入氢氧化钠8.0g。将3.5g盐酸羟氨分批加入反应体系。加完,于室温下继续反应5h(板层显示反应完全)。将无水乙醇蒸干,用3×40mL水洗涤反应液,用二氯甲烷萃取,无水硫酸钠充分干燥,过滤,减压蒸尽二氯甲烷,即得浅灰色固体(HPLC:99.1%)。Rf=0.54[单点,展开剂:v(二氯甲烷)∶v(甲醇)=7∶1]。
参照参考实施例2的方法,即可合成中间体IV-2~IV-5。
表3中间体IV-2~IV-5列表
参考实施例3:
中间体V-1的合成
在装有搅拌、冷凝器、温度计的反应瓶中加入12.5g中间体III-1,用50mL二氯甲烷将其溶解,搅拌下加入NBS 9.0g。光照下室温反应6h(板层显示反应完全)。用3×30mL 35%Na2S2O3水溶液洗涤反应液,二氯甲烷层无水硫酸钠充分干燥,过滤,减压蒸尽二氯甲烷,即得浅黄色油状产物(HPLC:96.7%)。Rf=0.44[单点,展开剂:v(二氯甲烷)∶v(甲醇)=7∶1]。
参照参考实施例2的方法,即可合成中间体V-2~V-5。
表4中间体V-2~V-5列表
参考实施例4:
中间体VI-1的合成
在装有搅拌、冷凝器、温度计的反应瓶中加入16.4g中间体VI-1,用50mL三氯甲烷将其溶解,搅拌下加入氢氧化钾钾6.9g。将7.8g 5,6,7,7a-四氢噻吩并[3,2-c]吡啶-2-(4H)-酮分批加入反应体系。加完,于30-35℃继续反应3.5h(板层显示反应完全)。滤除固体物质,将无水甲醇蒸干,用3×30mL水洗涤反应液,用二氯甲烷萃取,无水硫酸钠充分干燥,过滤,减压蒸尽二氯甲烷,即得黑色油状物,柱分离[流动相:v(二氯甲烷)∶v(甲醇)=7∶1],Rf=0.30,得白色固体(HPLC:99.1%)。
参照参考实施例4的方法,即可合成中间体VI-2~VI-5。
表5中间体VI-2~VI-5列表
实施例1:
5-((2-乙酰胺基-4,6-二氯嘧啶-5-基)(0-肟基)甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶-2-基乙酸酯(化合物I-1)的合成
在装有搅拌、冷凝器、温度计的反应瓶中加入10.1g中间体V-1,用50mL二氯甲烷将其溶解,搅拌下加入三乙胺3.5g。将2.5g乙酸酐加入反应体系。加完后回流状态下反应3.5h(板层显示反应完全)。反应液冷却,用3×10mL水洗涤反应液,分取二氯甲烷层,无水硫酸钠充分干燥,过滤,减压蒸尽二氯甲烷,即得黄色油状物,柱分离[流动相:v(石油醚)∶v(乙酸乙酯)=2∶1],Rf=0.52,得白色固体(HPLC:99.5%)。
参照实施例1的方法,即可合成目标化合物I-2~I-4,用丙酸酐代替乙酸酐可制得化合物I-5。
表6化合物I-2~I-5列表
实施例2:
化合物I-2成盐酸盐:取化合物I-2白色固体产物1.5g,溶于10mL无水乙醇。冰水浴冷却至5℃,滴加11.1%盐酸乙醇溶液至pH为2,继续于冰水浴下搅拌约1h。过滤,真空干燥,得白色固体粉末。
实施例3:
化合物I-4成牛磺酸盐:取化合物I-4白色固体产物2.0g,溶于10mL丙酮。加热至回流后加入等摩尔牛磺酸,继续于回流下搅拌反应约1.5h。反应完毕,于室温下静置24h。析出白色结晶,过滤,真空干燥。
实施例4:
化合物I-5成硫酸盐:取化合物I-5白色固体产物1.2g,溶于15mL甲醇。冰水浴冷却至0℃,滴加10%硫酸甲醇溶液至pH为3,继续于冰水浴下搅拌约1h。过滤,得白色固体。
为了更充分地说明本发明的含嘧啶的肟类化合物的药物组合物,下面提供下列制剂实施例,所述实施例仅用于说明,而不是用于限制本发明的范围。所述制剂可以使用本发明化合物中的任何活性化合物及其盐,优选使用实施例1-4中所描述的化合物。
实施例5:
用下述成分制备硬明胶胶囊:
制备工艺:将原辅料预先干燥,过100目筛备用。按处方量将上述成分混合后,填充入硬明胶胶囊中。
实施例6:
用下述成分制备片剂:
制备工艺:将原辅料预先干燥,过100目筛备用。先将处方量的辅料充分混匀。将原料药以递增稀释法加到辅料中,每次加时充分混匀2-3次,保证药与辅料充分混匀,过20目筛,在55℃通风烘箱中干燥2h,干颗粒过16目筛整粒,测定中间体含量,混合均匀,在压片机上压片。
实施例7:
注射液的制备:
制备方法:取活性成分加入到已溶解聚山梨酯和丙二醇的注射用水中,加入药用碱调节pH值至4~8使其溶解。加入活性炭,搅拌吸附30min,除炭、精滤、灌封、灭菌。
实施例8:
注射用冻干粉的制备:
化合物I-4的牛磺酸盐 100mg
药用碱 0.1-7.0%
甘露醇 55-85%
制备方法:取活性成分加入注射用水,用药用碱调节pH值至4-8使其溶解。再加入甘露醇,按注射剂的要求进行高压灭菌,加入活性炭,采用微孔滤膜过滤,滤液进行分装,采用冷冻干燥法,制得疏松块状物,封口,即得。
Claims (7)
1.具有式Ⅰ结构的化合物及其药学上可接受的盐:
其中:
R1、R3为:C1-C4直链或支链烷基;
R2为:氢,C1-C4直链或支链烷基。
3.如权利要求1所述的化合物及其药学上可接受的盐,药学上可接受的盐指:化合物与无机酸、有机酸成盐。
4.如权利要求3所述的化合物及其药学上可接受的盐,药学上可接受的盐指:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、葡萄糖酸盐。
6.一种抗抑郁的药物组合物,它包含治疗有效量的权利要求1~2任一项的式Ⅰ化合物或其药学上可接受的盐及一种或多种药用载体。
7.权利要求1~2任一项的式Ⅰ化合物及其药学上可接受的盐在用于制备抗抑郁药物方面的应用。
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CN1984901A (zh) * | 2004-05-18 | 2007-06-20 | 先灵公司 | 用作pde4抑制剂的取代的2-喹啉基-唑 |
CN101402641A (zh) * | 2008-11-20 | 2009-04-08 | 天津药物研究院 | 含噻吩并吡啶的肟类衍生物、其制备方法和用途 |
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CN101402641A (zh) * | 2008-11-20 | 2009-04-08 | 天津药物研究院 | 含噻吩并吡啶的肟类衍生物、其制备方法和用途 |
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