CN102040556B - 茚喹诺啉的光学异构体、其制备方法及其医药用途 - Google Patents
茚喹诺啉的光学异构体、其制备方法及其医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及茚喹诺啉的光学异构体、其制备方法及其医药用途,本发明的光学异构体的结构式为I、II、III、IV,药理试验证明,本发明的光学异构体对κ-受体的亲和力和选择性强于消旋体MB-1c,其镇痛活性最强比消旋体MB-1c强9~10倍。
Description
技术领域
本发明涉及药物化学领域,具体涉及κ-阿片受体激动剂茚喹诺啉的光学异构体及其制备方法。
背景技术
茚喹诺啉,化学名为5-氯-3-[-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮,是发明人前期研究发明的一种高活性和高选择性的κ-阿片受体激动剂(CN1887872和WO/2008/009215)。结构式如下:
茚喹诺啉
发明人前期通过一系列药理研究表明,茚喹诺啉作为选择性的κ-阿片受体激动剂,具有良好的成药性,值得进行深入的开发。但茚喹诺啉含有两个手性碳,可产生四个光学异构体。由于这四个光学异构体与κ-阿片受体之间的结合有可能存在差异,所以有可能产生不同的生物活性和(或)毒副作用。因此,合成茚喹诺啉的四个光学异构体,并对它们进行生物活性、毒性和副作用的研究,对于茚喹诺啉的成药性研究具有重要的指导意义。
发明内容
本发明的目的是提供高光学纯度的茚喹诺啉的光学异构体,本发明公开了我们合成茚喹诺啉的四个光学异构体,结构式如下:
化合物I的化学名为5-氯-(3R)-3-[(1R)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮;化合物II的化学名为5-氯-(3S)-3-[(1R)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮;化合物III的化学名为5-氯-(3R)-3-[(1S)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮;化合物IV的化学名为5-氯-(3S)-3-[(1S)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮。
本发明还包括上述四个化合物的药学上可接受的盐,用于与化合物I、II、III和IV形成盐的酸有:盐酸、氢溴酸、硫酸、碳酸、柠檬酸、酒石酸、苹果酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或精氨酸。
本发明优选结构式III和IV的化合物。更优选结构式III的化合物。
本发明还公开了制备化合物I、II、III和IV的两个新的中间体,结构式加下:
中间体V的制备方法,包括:
其中:
去酸剂A为K2CO3、Na2CO3或(Et)3N,4-二甲氨基吡啶;
溶剂A为丙酮、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N二甲基乙酰胺或二甲亚砜;
溶剂B为异丙醇与选自丙酮、异丙醚或乙醚中任一种溶剂的混合溶剂;
去酸剂B为NaOH、KOH、LiOH、K2CO3、Na2CO3、NaOCH3或NaOEt;
溶剂C为冰醋酸、N,N-二甲基甲酰胺和盐酸、N,N-二甲基甲酰胺和冰醋酸或四氢呋喃和冰醋酸;
L-(-)-DTTA为L-(-)-二对甲基二苯甲酰酒石酸。
中间体V优选的制备方法如下:
将消旋的1-(四氢吡咯-1-甲基)-1,2,3,4-四氢异喹啉与氯甲酸苄酯在溶剂丙酮和去酸剂碳酸钾存在下中反应得到消旋的1-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉,再与L-(-)-二对甲基二苯甲酰酒石酸溶于异丙醇成盐,并用异丙醇和异丙醚混合溶剂重结晶,析出固体再用丙酮重结晶,所得精制品用NaOH水溶液处理后,以乙醚萃取,蒸干溶剂得无色油状物,将无色油状物溶于乙酸水溶液中,加入Pd-C后进行氢解脱苄基后得中间体V。
中间体VI的制备方法,包括:
其中:
去酸剂A为K2CO3、Na2CO3或(Et)3N,4-二甲氨基吡啶;
溶剂A为丙酮、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N二甲基乙酰胺或二甲亚砜;
溶剂B为异丙醇与选自丙酮、异丙醚或乙醚中任一种溶剂的混合溶剂;
去酸剂B为NaOH、KOH、LiOH、K2CO3、Na2CO3、NaOCH3或NaOEt;
溶剂C为冰醋酸、N,N-二甲基甲酰胺和盐酸、N,N-二甲基甲酰胺和冰醋酸或四氢呋喃和冰醋酸;
D-(+)-DTTA为D-(+)-二对甲基二苯甲酰酒石酸。
中间体VI优选的制备方法如下:
将消旋的1-(四氢吡咯-1-甲基)-1,2,3,4-四氢异喹啉与氯甲酸苄酯在溶剂丙酮和去酸剂碳酸钾存在下中反应得到消旋的1-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉,再与D-(+)-二对甲基二苯甲酰酒石酸溶于异丙醇成盐,并用异丙醇和异丙醚混合溶剂重结晶,析出固体再用丙酮重结晶,所得精制品用NaOH水溶液处理后,以乙醚萃取,蒸干溶剂得无色油状物,将无色油状物溶于乙酸水溶液中,加入Pd-C后进行氢解脱苄基后得中间体VI。
本发明的化合物I、II、III、IV的制备方法,包括:
其中当缩合剂为二环己基碳二亚胺时,催化剂为4-二甲氨基吡啶;
当缩合剂为1-乙基-3-(3-二甲胺基丙基)碳二亚胺盐酸盐时,催化剂为1-羟基苯并三唑;
溶剂为二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜。
V和VI互为对映体,VII和VIII也互为对映体。
其中VII的结构式如下:
VII的制备方法如下:
将消旋的间氯苯基琥珀酸和(R)-(+)-α-苯乙胺溶于乙醇,成盐,冷却,过滤得(R)-(-)-间氯苯基琥珀酸(R)-(+)-α-苯乙胺盐粗品,乙醇重结晶得精品,将精品溶于NaOH水溶液中,加入二氯甲烷,混合,取水层,用浓盐酸酸化,析出固体,过滤得(R)-(-)-间氯苯基琥珀酸,将(R)-(-)-间氯苯基琥珀酸加入氯化亚砜中回流制成酰氯,冷却后加入无水二氯甲烷和无水三氯化铝反应,反应液倒入冰水中,处理得到(R)-(-)-6-氯-2,3-二氢-茚-3-酮-1-羧酸(VII)。
VIII的结构式如下
VIII的制备方法如下:
将消旋的间氯苯基琥珀酸和(S)-(-)-α-苯乙胺溶于乙醇,成盐,冷却,过滤得(S)-(+)-间氯苯基琥珀酸(S)-(-)-α-苯乙胺盐粗品,乙醇重结晶得精品,将精品溶于NaOH水溶液中,加入二氯甲烷,混合,取水层,用浓盐酸酸化,析出固体,过滤得(S)-(+)-间氯苯基琥珀酸,将(S)-(+)-间氯苯基琥珀酸加入氯化亚砜中回流制成酰氯,冷却后加入无水二氯甲烷和无水三氯化铝反应,反应液倒入冰水中,处理得到(S)-(+)-6-氯-2,3-二氢-茚-3-酮-1-羧酸(VIII)。
上述反应中,根据不同的目的物选用不同的反应原料,如制备化合物I,则选用V和VII;如果制备化合物II,则选用V和VIII;如果制备化合物III,则选用VI和VII;如果制备化合物IV,则选用VI和VIII。
经放射性配体结合实验和初步的动物体内镇痛试验显示,本发明的四个光学异构体对κ-受体具有不同程度的亲和性和选择性。在小鼠热板法和扭体法镇痛试验中,四个光学异构体显示出不同程度的镇痛活性。其中化合物III和IV对κ-受体选择性和镇痛效果明显优于化合物I和II。尤其是化合物III,其镇痛效果优于化合物IV。
下面是部分药理学试验和结果:
一、放射性配体受体结合实验:
实验分总结合管和非特异结合管,另设几组样品管加不同浓度竞争配体。总结合管加相当于20μg的表达的膜受体蛋白和[3H]diprenorphine(0.5nM)(1.44Pbq.mol-1广谱阿片拮抗剂,Amersham公司),相对应的非特异结合管另加1μM的纳络酮(广谱阿片拮抗剂,Sigma公司),样品管加不同浓度待筛选的化合物,用50mM Tris(Amresco公司)-HCl(pH 7.4)调节至终体积100μl。在30℃孵育30min,然后置冰水中终止反应。在Millipore样品收集器上经GF/(Whatman)玻璃纤维滤纸负压抽滤。用冰冷的50mM Tris-HCl(pH 7.4)冲洗三次,每次4ml,滤纸烘干后,置于0.5ml Eppendorff管,加0.5ml亲脂闪烁液(上海试剂一厂),Beckman LS 6500多功能液体闪烁计数仪测定放射性强度,计算抑制率,每一浓度为三复管,每一次独立实验3-4次。
计算方法:
IC50值用Prism 4.0软件计算。
Ki=IC50/(1+[L]/Kd),([L]为所加标记配体的浓度,Kd为放射性配体的平衡解离参数)。
表1.化合物对μ-阿片受体的亲和力(μ-Ki)和κ-受体的亲和力(κ-Ki)值及受体选择性μKi/κKi值
代号 | μ-Ki(nM) | κ-Ki(nM) | μKi/κKi |
I | NA | 18.20±4.72 | - |
II | NA | 17.50±2.30 | - |
III | 486.0±38.3 | 0.049±0.007 | 9918 |
IV | 205.1±7.7 | 0.0059±0.001 | 34762 |
茚喹诺啉 | 698±92 | 0.033±0.008 | 21151 |
NA:在1μM下未见结合。
由表1可知,化合物III和IV均对κ-受体有较强的亲和力和选择性,而化合物I和II对κ-受体的亲和力较弱。其中化合物IV对κ-受体的亲和力和选择性强于消旋体茚喹诺啉。
二、小鼠热板法镇痛试验:
正常小鼠(昆明种小鼠,雌性,18~22g,中科院上海动物中心提供)挑选:实验室温度控制在22℃左右,测痛仪(型号GJ-8402,浙江宁海白石电子医药仪器厂)热板温度调节至55℃,记录小鼠自投入热板至出现舔后足时间作为该小鼠的痛域值,共测2次,每次间隔20分钟,以平均值不超过30秒为合格小鼠。
实验组小鼠:将合格小鼠随机分组,每组10只。皮下注射给予化合物I,II,III,IV。各组均在给药后5,15,30,5,60分钟测定小鼠痛反应时间一次,超过1分钟认为该药有效。
上述动物镇痛实验方法依据经典的小鼠热板法(徐叔云主编.药理实验方法学(第二版)[M].人民卫生出版社,1991.)
试验结果见表2.
三、小鼠扭体法镇痛试验:
实验组小鼠:昆明种小鼠(18~22g,雌雄各半,中科院上海动物中心提供)。
方法:将小鼠随机分组,每组10只,雌雄各半。
对照组:生理盐水组。0.2ml/只,皮下注射给予化合物I,II,III,IV。15分钟后腹腔给0.6%醋酸溶液,0.2ml/只,记录15分钟内小鼠扭体的次数。
实验组:药物配成低、中、高三组剂量。分别在给药后15分钟(选择药物起效的高峰时间)后腹腔给0.6%醋酸溶液,0.2ml/只,记录15分钟内小鼠扭体的次数。
试验结果见表2.
表2.化合物在小鼠不同镇痛模型中镇痛能力的比较
由表2可知,化合物III和IV的镇痛活性明显强于化合物I和II。其中化合物III的镇痛活性最强,比化合物IV强1倍,比消旋体茚喹诺啉强9~10倍。
具体实施方式
熔点测定用RY-1型熔点仪,温度计未校正;IR谱用Nicolet Impact 410型红外光谱仪测定,KBr压片;1H-NMR用BRUKER ACF-300型核磁共振仪和AM-500型核磁共振仪完成,内标TMS;MS用HP1100型质谱仪和Agilent 1100系列LC/MSD Trap SL测定;元素分析仪为Carlo Erba 1106型。
实施例1
(±)-1-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉(2)
化合物1-(四氢吡咯-1-甲基)-1,2,3,4-四氢异喹啉(1)11.16g(51.67mmol)溶于160ml丙酮中,加入50%K2CO3 12.7ml,于室温中向反应液中滴加氯甲酸苄酯10.6g(62.17mmol),滴毕反应2h,蒸干溶剂,以乙醚/水萃取,取乙醚层。乙醚层用稀盐酸处理,以乙醚/水萃取,取水层。水层再用稀NaOH调至碱性,再次用乙醚/水萃取,取乙醚层。无水NaSO4干燥过夜,减压蒸去溶剂,得桔黄色油状物。柱层析纯化(石油醚∶三乙胺=1∶0.1洗脱),得桔黄色油状物(2)13.42g,收率74.5%。
MS(ESI(+)70V,m/z):351.3([M+H]+,basepeak);1H-NMR(500MHz,CDCl3),δ(ppm):7.08~7.37(9H,m,ArH),5.08~5.35(3H,m,OCH2,H1),4.09~4.30(1H,m,H3),3.29~3.43(1H,m,H3’),2.87~2.98(2H,m,H9,H9’),2.44~2.74(6H,m,H4,H4’,H11,H11’,H14,H14’),1.65~1.74(4H,m,H12,H12’,H13,H13’).
R-(+)-1-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉L-(-)-二对甲基苯甲酰酒石酸盐(3)
在500ml茄瓶中加入化合物(2)17.5g(50mmol),L-(-)-二对甲基苯甲酰酒石酸(L-(-)-DTTA)19.3g(50mmol)以及异丙醇120ml,加热煮沸,回流1小时后冷却,加入异丙醚30ml,再加热回流2小时后,倒入100ml丙酮中,静置冷却析晶,得白色晶体10.2g,收率27%。所得晶体再用丙酮重结晶3次,得晶体(3)4.1g,收率40.1%,m.p.145~147℃,旋光[α]20 D=-37.5(c=1,MeOH)。
R-(+)-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉(4)
将上述晶体(3)2g(2.7mmol)用20mlNaOH(1M)溶液处理后,以乙醚萃取,蒸干溶剂得无色油状物(4)0.86g,收率90%。旋光[α]20 D=+66.7(c=1,MeOH)。
MS(ESI(+)70V,m/z):351.2([M+H]+,base peak);1H-NMR(300MHz,CDCl3),δ(ppm):7.07~7.35(9H,m,ArH),5.07~5.36(3H,m,OCH2,H1),4.09~4.30(1H,m,H3),3.28~3.41(1H,m,H3’),2.87~2.97(2H,m,H9,H9’),2.45~2.72(6H,m,H4,H4’,H11,H11’,H14,H14’),1.64~1.73(4H,m,H12,H12’,H13,H13’).
R-(-)-(四氢吡咯-1-甲基)-1,2,3,4-四氢异喹啉(V)
在100ml茄瓶中加入化合物(4)1g(2.85mmol),40ml 90%的醋酸水溶液,并小心加入10%的Pd/C 0.2g,于常温下剧烈搅拌催化氢化过夜。反应毕,减压蒸去溶剂及副产物甲苯,小心加入饱和NaHCO3,以CH2Cl2萃取,无水Na2SO4干燥,过滤,低温减压蒸去溶剂后得无色油状物(V)0.6g,收率几乎定量。旋光[α]20 D=-33.0(c=1,MeOH).
MS(ESI(+)70V,m/z):217.2([M+H]+,basepeak);1H-NMR(300MHz,CDCl3),δ(ppm):7.07~7.25(4H,m,ArH),4.07(1H,dd,J1=3.2Hz,J2=10.1Hz,H1),3.17~3.22(1H,m,H3),2.92~3.00(2H,m,H3’,H9),2.80~2.82(2H,m,H9’,H4),2.70(1H,bs,NH),2.65~2.67(2H,m,H11,H14),2.57~2.60(1H,m,H4’),2.48~2.50(2H,m,H11’,H14’),1.75~1.79(4H,m,H12,H12’,H13,H13’).
实施例2
S-(-)-1-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉D-(+)-二对甲基苯甲酰酒石酸盐(5)
以化合物2和D-(+)-二对甲基苯甲酰酒石酸为原料,参照实施例1中化合物(3)相关操作,得到白色晶体(5)。m.p.145~147℃,旋光[α]20 D=+38.7(c=1,MeOH)。
S-(-)-(四氢吡咯-1-甲基)-2-(苄氧羰基)-1,2,3,4-四氢异喹啉(6)
以化合物(5)为原料,参照实施例1中化合物(4)相关操作,得到无色油状物(6),收率90%。旋光[α]20 D=-64.0(c=1,MeOH)。
S-(+)-(四氢吡咯-1-甲基)-1,2,3,4-四氢异喹啉(VI)
以化合物(6)为原料,参照实施例1中化合物(V)相关操作,得到无色油状物(VI),收率几乎定量。旋光[α]20 D=+36.6(c=1,MeOH).
MS(ESI(+)70V,m/z):217.2([M+H]+,base peak);1H-NMR(300MHz,CDCl3),δ(ppm):7.07~7.25(4H,m,ArH),4.07(1H,dd,J1=3.2Hz,J2=10.1Hz,H1),3.17~3.22(1H,m,H3),2.92~3.00(2H,m,H3’,H9),2.80~2.82(2H,m,H9’,H4),2.70(1H,bs,NH),2.65~2.67(2H,m,H11,H14),2.57~2.60(1H,m,H4’),2.48~2.50(2H,m,H11’,H14’),1.75~1.79(4H,m,H12,H12’,H13,H13’).
实施例3
(R)-(-)-间氯苯基琥珀酸(R)-(+)-α-苯乙胺盐(7)
间氯苯基琥珀酸10.0g(43.74mmol)和(R)-(+)-α-苯乙胺10.86g(89.62mol)于140ml乙醇中加热溶解,静置过夜,析晶,过滤得白色晶体12.3g,将该晶体溶于热乙醇95ml中,静置过夜,析晶,得到白色晶体7.5g,继续用乙醇重结晶两次,得白色晶体(7)3.9g,m.p.180-183℃,收率18.7%。
(R)-(-)-间氯苯基琥珀酸(8)
取此晶体(7)3.5g(7.43mmol)置于2.5mol/L的NaOH溶液35ml中,加入二氯甲烷100ml,搅拌30min,分出水层,水层用二氯甲烷(50ml)洗涤一次,水层用浓盐酸酸化至pH1-2,析出固体,抽滤,水洗,干燥得白色固体(8)1.45g,收率85.2%,m.p.174-175℃,[α]D 20=-110.1(c=1,MeOH),手性毛细管电泳测定ee%=96.3%。
1H-NMR(500MHz,DMSO-d6),δ(ppm):12.50(2H,bs,COOH),7.32~7.38(3H,m,ArH4,ArH5,ArH6),7.26~7.27(1H,m,ArH7),3.91~3.95(1H,dd,J1=5.4Hz,J2=9.8Hz,dd,H2),2.92~2.98(1H,dd,J1=9.8Hz,J2=16.9Hz,H3a),2.56~2.60(1H,dd,J1=5.4Hz,J2=16.9Hz,H3b)
MS(ESI(-)70V,m/z):226.8([M-H]-,base peak)
Anal.Calcd.For C10H9ClO4:C 52.53,H 3.97;Found:C 52.22,H 4.33
(R)-(-)-6-氯-2,3-二氢-茚-3-酮-1-羧酸(VII)
在100ml三颈瓶中加入化合物(8)3g(13.12mol),二氯亚砜5ml,电磁搅拌下,升温至回流反应0.5h,稍冷后加入无水二氯甲烷30ml,无水AlCl33g,室温下继续反应3h。然后小心地往溶液中滴加10%盐酸50ml,待水解完毕往溶液中加入5ml氯仿。过滤,固体用75ml乙酸乙酯溶解,分出其中的水层,再用少量水洗涤。所得有机层用饱和碳酸钠溶液提取3次,每次15ml,合并提取液,缓慢滴加10%盐酸至pH1-2,析出固体,过滤得白色固体。干燥得产品(VII)1.6g,收率57.9%,m.p.146-148℃,[α]D 20=-33.8(c=1,MeOH)。
1H-NMR(300MHz,DMSO-d6),δ(ppm):13.05(1H,bs,COOH),7.76(1H,s,ArH),7.64~7.67(1H,d,J=8.1Hz,ArH),7.54~7.57(1H,d,J=8.1Hz,ArH),4.31~4.34(1H,m,H1),2.88~2.90(2H,m,H2)MS(ESI(-)70V,m/z):208.7([M-H]-)
Anal.Calcd.For C10H7ClO3:C 57.03,H 3.35;Found:C 57.34,H 3.32
实施例4
(S)-(+)-间氯苯基琥珀酸(S)-(-)-α-苯乙胺盐(9)
以间氯苯基琥珀酸和(S)-(-)-α-苯乙胺为原料,参照实施例3中化合物(7)的操作,得到白色晶体(9),收率21.1%,m.p.180-183℃。
(S)-(+)-间氯苯基琥珀酸(10)
以化合物(9)为原料,同实施例3中化合物(8)的操作,得化合物(10),收率79.5%,白色固体,m.p.174-175℃,[α]D 20=+114.4(c=1,MeOH),手性毛细管电泳测定ee%=94.3%。
1H-NMR(300MHz,DMSO-d6),δ(ppm):12.44(2H,bs,COOH),7.35~7.38(3H,m,ArH4,ArH5,ArH6),7.26~7.27(1H,m,ArH7),3.91~3.95(1H,dd,J1=5.4Hz,J2=9.8Hz,H2),2.92~2.98(1H,dd,J1=9.8Hz,J2=16.9Hz,H3a)2.56~2.60(1H,dd,J1=5.4Hz,J2=16.9Hz,H3b)
MS(ESI(-)70V,m/z):226.8([M-H]-,base peak)
Anal.Calcd.For C10H9ClO4:C 52.53,H 3.97;Found:C 52.19,H 4.13
(S)-(+)-6-氯-2,3-二氢-茚-3-酮-1-羧酸(VIII)
以化合物(10)为原料,同实施例3中化合物(VII)的操作,得到白色固体(VIII),收率54.3%,m.p.146~148℃,[α]D 20=+34.2(c=1,MeOH)。
1H-NMR(300MHz,DMSO-d6),δ(ppm):13.06(1H,bs,COOH),7.76(1H,s,ArH),7.64~7.67(1H,d,J=8.1Hz,ArH),7.54~7.57(1H,d,J=8.1Hz,ArH),4.31~4.34(1H,m,H1),2.88~2.90(2H,m,H2).MS(ESI(-)70V,m/z):208.7([M-H]-).
Anal.Calcd.For C10H7ClO3:C 57.03,H 3.35;Found:C 57.25,H 3.29
实施例5
5-氯-(3R)-3-[(1R)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮(I)
在50ml三颈瓶中加入化合物R-(-)-(四氢吡咯-1-甲基)-1,2,3,4-四氢异喹啉(V)0.63g(3.0mmol),化合物R-(-)-6-氯-2,3-二氢-茚-3-酮-1-羧酸(VII)0.74g(3.5mmol),催化量的4-二甲氨基吡啶(DMAP),CH2Cl2 20ml,冰浴控温0℃搅拌0.5小时,滴加N,N′-二环己基碳酰亚胺(DCC)0.83g(4.2mmol)溶于CH2Cl2 10ml所得的溶液,滴毕,氮气保护下室温搅拌过夜。反应液成桔红色浊液,过滤除去1,3-二环己基脲(DCU),浓缩,残留物柱层析(石油醚∶乙酸乙酯∶三乙胺=4∶1∶0.1),得白色固体(I)0.55g,收率45%,m.p.120~122℃,旋光[α]20 D=-25(c=1,MeOH)。
1H-NMR(300MHz,CDCl3),δ(ppm):7.66~7.70(2H,m,ArH20, 20 ),7.60/6.97(2H,s/s,ArH 22 ,22),7.40~7.42/7.31~7.33(2H,dd/dd,ArH 19 ,19),7.14~7.29(8H,d,ArH7, 7 ,8, 8 ,5, 5 ,6, 6 ),5.80~5.83/5.37~5.39(2H,dd/dd,H 1 ,1),4.91~4.93/4.63~4.66(2H,dd/dd,H16, 16 ),4.74~4.78/4.25~4.28(2H,m/m,H3, 3 ),3.94~4.00(1H,m,H 9 ),3.29~3.33/3.22~3.26(2H,m/m,H3’, 3’ ),2.44~3.20(15H,m,H9,9’, 9’ ,H17, 17 ,17’, 17’ ,H4, 4 ,4’, 4’ ,H11,1 1’,H14,14’),2.42~2.45/2.59~2.62(4H,m,H 11 , 11’ ,H 14 , 14’ ),1.54~1.79(8H,m,H12, 12 ,12’, 12’ ,H13, 13 ,13’, 13’ )
(注:本化合物存在两组氢,比例约为10∶7)
IR(cm-1):3471,3413,2964,2929,2790,1716(C=O),1639(C=O),1596,1440,825,744MS(ESI(+)70V,m/z):409.2([M+H]+,base peak)
Anal.Calcd.for C24H25ClN2O2:C 70.49,H 6.16,N 6.85;Found:C 70.29,H 6.49,N 6.75
实施例6
5-氯-(3S)-3-[(1R)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮(II)
以化合物(V)与(VIII)为原料,同实施例3中化合物(I)操作得白色固体(II),收率46%,m.p.122℃,旋光[α]20 D=-32.6(c=1,MeOH)。
1H-NMR(300MHz,CDCl3),δ(ppm):7.61~7.70(2H,m,ArH20, 20 ),7.59/6.98(2H,s/s,ArH 22 ,22),7.41~7.43/7.32~7.33(2H,dd/dd,ArH 19 ,19),7.13~7.35(8H,d,ArH7, 7 ,8, 8 ,5, 5 ,6, 6 ),5.75~5.85/5.32~5.43(2H,dd/dd,H 1 ,1)4.89~4.93/4.63~4.70(2H,dd/dd,H16, 16 ),4.75~4.77/4.30~4.35(2H,m/m,H3, 3 ),3.90~4.02(1H,m,H 9 ),3.34~3.39/3.23~3.29(2H,m/m,H3’, 3’ ),2.43~3.20(15H,m,H9,9’, 9’ ,H17, 17 ,17’, 17’ ,H4, 4 ,4’, 4’ ,H11,11’,H14,14’),2.4 2~2.45/2.59~2.62(4H,m,H 11 , 11’ ,H 14 , 14’ ),1.54~1.79(8H,m,H12, 12 ,12’, 12’ ,H13, 13 ,13’, 13’ )
(注:本化合物存在两组氢,比例约为10∶7)
IR(cm-1):3471,3413,2964,2929,2790,1716(C=O),1639(C=O),1596,1440,825,744MS(ESI(+)70V,m/z):409.2([M+H]+,base peak)
Anal.Calcd.for C24H25ClN2O2:C 70.49,H 6.16,N 6.85;Found:C70.26,H6.36,N 6.77
实施例7
5-氯-(3R)-3-[(1S)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮(III)
以化合物(VI)与(VII)为原料,同实施例3中化合物(I)操作得白色固体(III),收率40%,m.p.122℃,旋光[α]20 D=+49(c=1,MeOH)。
1H-NMR(300MHz CDCl3)δ(ppm):7.55~7.75(2H,m,ArH20, 20 ),7.50/6.97(2H,s/s,ArH 22 ,22),7.39~7.44/7.31~7.33(2H,dd/dd,ArH 19 ,19),7.12~7.32(8H,d,ArH7, 7 ,8, 8 ,5, 5 ,6, 6 ),5.80~5.85/5.30~5.40(2H,dd/dd,H 1 ,1),4.85~4.95/4.60~4.71(2H,dd/dd,H16, 16 ),4.70~4.80/4.20~4.25(2H,m/m,H3, 3 ),3.84~4.03(1H,m,H 9 ),3.20~3.33/3.24~3.26(2H,m/m,H3’, 3’ ),2.44~3.20(15H,m,H9,9’, 9’ ,H17, 17 ,17’, 17’ ,H4, 4 ,4’, 4’ ,H11,11’,H14,14’),2.4 0~2.47/2.59~2.64(4H,m,H 11 , 11’ ,H 14 , 14’ ),1.54~1.79(8H,m,H12, 12 ,12’, 12’ ,H13, 13 ,13’, 13’ )
(注:本化合物存在两组氢,比例约为10∶7)
IR(cm-1):3471,3413,2964,2929,2790,1716(C=O),1639(C=O),1596,1440,825,744MS(ESI(+)70V,m/z):409.2([M+H]+,base peak)
Anal.Calcd.for C24H25ClN2O2:C 70.49,H 6.16,N 6.85;Found:C70.16,H6.42,N 6.63
实施例8
5-氯-(3S)-3-[(1S)-1-(四氢吡咯-1-甲基)-3,4-二氢-1H-异喹啉-2-羰基]-2,3-二氢-1H-茚-1-酮(IV)
以化合物(VI)和(VIII)为原料,同实施例3中化合物(I)操作得白色固体(IV),收率44%,m.p.122℃,旋光[α]20 D=+23.7(c=1,MeOH)。
1H-NMR(500MHz,CDCl3),δ(ppm):7.65~7.73(2H,m,ArH20, 20 ),7.60/6.90(2H,s/s,ArH 22 ,22),7.38~7.42/7.32~7.35(2H,dd/dd,ArH 19 ,19),7.10~7.29(8H,d,ArH7, 7 ,8, 8 ,5, 5 ,6, 6 ),5.78~5.86/5.33~5.41(2H,dd/dd,H 1 ,1),4.89~4.95/4.60~4.70(2H,dd/dd,H16, 16 ),4.71~4.78/4.20~4.31(2H,m/m,H3, 3 ),3.90~4.03(1H,m,H 9 ),3.26~3.39/3.20~3.23(2H,m/m,H3’, 3’ ),2.49~3.20(15H,m,H9,9’, 9’ ,H17, 17 ,17’, 17’ ,H4, 4 ,4’, 4’ ,H11,11’,H14,14’),2.4 8~2.50/2.59~2.62(4H,m,H 11 , 11’ ,H 14 , 14’ ),1.54~1.79(8H,m,H12, 12 ,12’, 12’ ,H13, 13 ,13’, 13’ )
(注:本化合物存在两组氢,比例约为10∶7)
IR(cm-1):3471,3413,2964,2929,2790,1716(C=O),1639(C=O),1596,1440,825,744MS(ESI(+)70V,m/z):409.2([M+H]+,base peak)
Anal.Calcd.for C24H25ClN2O2:C 70.49,H 6.16,N 6.85;Found:C 70.33,H6.39,N 6.75
Claims (8)
2.权利要求1的化合物或其药学上可接受的盐,其中化合物结构式为:
。
3.权利要求1的药学上可接受的盐是化合物III或IV与下列酸形成的盐:盐酸、氢溴酸、硫酸、碳酸、柠檬酸、酒石酸、苹果酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或精氨酸。
6.一种药物组合物,其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
7.权利要求1的化合物或其药学上可接受的盐用于制备预防或治疗与κ-阿片受体激动剂有关的疾病的药物的用途。
8.权利要求7的用途,其中κ-阿片受体激动剂有关的疾病是疼痛。
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