CN101003550B - 8-卤代腺嘌呤类核苷化合物、合成方法和其药物用途 - Google Patents
8-卤代腺嘌呤类核苷化合物、合成方法和其药物用途 Download PDFInfo
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Abstract
本发明公开了通式I所代表的化合物8-卤代-9-(2-特戊酰氧甲氧基膦酰甲氧基)乙基-腺嘌呤，8-卤代-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)丙基-腺嘌呤，及其有机酸盐II和它们的制备方法。其中X为F、Cl，、Br：R为H、CH3；(R)指当R为甲基时手性碳的构型为R型；R1为H，-CH2OCOC(CH3)3，-CH2OCOOCH(CH3)2；当R为H时，R1为-CH2OCOCH(CH3)3；当R为CH3时，R1为-CH2OCOOCH(CH3)2；有机酸为富马酸、延胡索酸、柠檬酸等。化合物I、II可用于治疗HIV、HBV等病毒感染药物的开发。
Description
技术领域
本发明涉及系列类核苷化合物，尤其涉及8-卤代腺嘌呤类核苷化合物、合成方法及其药物用途。
背景技术
阿德福韦(adefovir，ADV)由Gilead Sciences公司开发的抗病毒药物，临床证明有抗HBV活性(包括对拉米夫定耐药性HBV)。ADV化学结构为腺嘌呤-9-乙氧基甲基磷酸，口服利用度低，变态反应重。阿德福韦酯(adefovir dipivoxiil)是ADV的前体药物，亲脂性提高，比ADV的肠上皮穿透能力增加10倍，生物利用度有所提高。
泰诺福韦(Tenofovir，PMPA)是一种腺嘌呤非环核苷类抗病毒化合物，对逆转录酶病毒有强抑制作用，并且与临床上使用的其他核甘类抗病毒药物没有交叉耐药性。但是，泰诺福韦的强亲水性影响其临床药物应用。为减小泰诺福韦的亲水性，人们将其改造为磷酸酯前药，泰诺福韦的双异丙氧羰氧甲酯(PMPA-2POC)正是这一前体药物，其与富马酸形成的盐已被FDA于2001年批准用作治疗HIV感染的药物。这是迄今为止抗病毒活性较强的HIV逆转录酶拟制剂类的抗艾滋病感染药物。
然而，上述阿德福韦酯、泰诺福韦双异丙氧羰氧甲酯仍然可以通过对嘌呤碱基的修饰，进一步提高其脂溶性能，改善生物利用度。
发明内容
为进一步改善阿德福韦酯、泰诺福韦脂的脂溶性，本发明提供一类新的具有抗病毒活性的8-卤代腺嘌呤类核苷化合物及其合成方法和其应用，至目前还未见报道。
本发明以腺嘌呤无环核苷为先导化合物，对分子结构中腺嘌呤碱基的8位进行卤代修饰，得到一类新型8-卤代腺嘌呤无环核苷，并与有机酸反应生成有机酸盐，得到一类新型8-卤代腺嘌呤无环核苷及其有机酸盐。
8-卤代腺嘌呤无环核苷及其有机酸盐结构分别为通式(I)、(II)：
其中X为F，、Cl或Br；
R为H或CH3；
(R)为当R为CH3时，手性碳构型；
R1为H，-CH2OCOC(CH3)3，-CH2OCOOCH(CH3)2；
当R为H时，R1为-CH2OCOC(CH3)3；
当R为CH3时，R1为-CH2OCOOCH(CH3)2；
有机酸为富马酸、延胡索酸、柠檬酸等有机酸。
其具体可为下列化合物，但是并不局限于下列化合物：
本发明所提供化合物具有较好的脂溶性，在反向液相色谱图上，脂溶性提高表现为保留时间增加。化合物5，6的保留时间较相应的未溴代物增加，未溴代物保留时间为4.19分钟，化合物5，6的保留时间为6.37分钟。
本发明提供化合物及其有机酸盐的合成路线如下：
X2为Br2、Cl2或F2；
即化合物腺嘌呤无环核苷在醋酸中进行8位卤代反应生成8-卤代腺嘌呤无环核苷，然后与有机酸反应形成8-卤代腺嘌呤无环核苷盐。
该合成路线具体包括如下步骤：将化合物腺嘌呤无环核苷溶于有机酸或醇中，或溶于有机酸和醇的混合溶剂中，优选醋酸、甲醇、乙醇；在有机酸碱金属盐、季銨氢氧化物等碱性物质例如醋酸钠，氢氧化四乙基銨等存在下，于0-100℃优选室温下，加入溴素Br2或氯气Cl2或由惰性气体稀释的氟气F2/He，生成结构式(I)所代表的化合物即8-卤代腺嘌呤无环核苷。
化合物(I)溶于有机溶剂中，于温度20-80℃、优选40-70℃下与有机酸反应，冷却、结晶，得到结构式(II)所代表的化合物。其中有机溶剂为醇、酯、酮、醚、卤代烃、甲苯、乙腈等及由其组成的混合溶剂，优选甲醇、乙醇、异丙醇；有机酸为脂肪族酸和芳香族酸，优选柠檬酸、富马酸、山梨酸、苯甲酸等，更优选富马酸；有机酸与化合物(I)的摩为0.5∶1～2∶1，优选1∶1。
采取细胞培养法测定了本发明化合物的抗HIV病毒活性，采用MT-4细胞培养，HIV-1IIIB实验病毒株感染，加入药物，测定药物半数有毒浓度(CC50)，半数有效浓度(EC50)。结果表明化合物对HIV有较强的抗HIV-1活性。
药物在细胞培养内的抗HIV活性：
TDF：Tenofovir disoproxil fumarate；
EC50：半数有效浓度；
CC50：半数有毒浓度；SI：选择指数；
ND：未测定。
本发明提供的上述化合物含有8-卤代腺嘌呤无环核苷-富马酸结构，表现出良好的抗HIV-1、抗HBV活性，可用于抗病毒药物的制备。该抗病毒药物剂型可以是按照药学领域常规生产的方法制备，使活性药物成分与一种或多种载体混合，制成口服剂型，其含有0.5％-99.5％的本发明所合成的化合物活性成分，优选5％-95％。
本发明的药物组合物组成可由如下配比构成：
本发明合成化合物5-95％
乳糖 1-60％
淀粉 0-20％
微晶纤维素 1-40％
羧甲淀粉钠 1-5％
聚乙二醇(PEG6000) 0-10％
羟丙基甲基纤维素 1-5％
硬脂酸镁 1-5％
该药物组合物可以制成片剂、包衣片剂或胶囊剂等适于口服给药的剂型。口服片剂或胶囊剂的粘合剂可选用微晶纤维素、甲基纤维素、羟乙基纤维素羟丙基纤维素、羟丙基甲基纤维素、羧甲基淀粉钠、羧甲基纤维素钠、羧甲基纤维素钙、聚乙烯吡咯烷酮(PVP)、糊精等。表面活性剂可选用硬脂酸钙、硬脂酸镁、十二烷基硫酸钠、单硬脂酸甘油酯、单油酸甘油酯、泊洛沙姆(Poloxamer)、聚乙二醇(PEG)、吐温80等。糖或多糖可选乳糖、蔗糖、葡萄糖、淀粉、微晶纤维素、糊精等，但均不局限于此。
本发明有益效果在于：1、本发明对腺嘌呤碱基的8位进行卤代修饰，得到一系列8-卤代腺嘌呤无环核苷化合物，并与有机酸反应生成盐，使具有抗病毒活性的8-卤代腺嘌呤类核苷化合物具有很好的脂溶性，为此类药物的开发提供了较好的应用前景；2、该合成路线经济、可行。
附图说明
图为在色谱条件：SOD-C18柱，15cm；流动相：0.04mol/L磷酸三乙胺水溶液∶乙腈＝55∶45；流量：1.00ml/min下，本发明合成出的化合物6和未溴代化合物6的高效液相色谱图。
具体实施方式
为对本发明进行更好的说明，举实施例如下：
实施例1.8-溴-9-(2-二特戊酰氧甲氧基膦酰甲氧基)-乙基-腺嘌呤(化合物11)：
取9-(2-二特戊酰氧甲氧基膦酰甲氧基)-乙基-腺嘌呤(3.0克，6.0mmol)，溶于30ml醋酸中，加醋酸钠(3g)，加Br20.5mL，9.7mmol).搅拌2小时，原料点消失，依次加乙酸乙酯(150ml)、水120ml，搅拌下加饱和亚硫酸氢钠(NaHSO3)至混合物成无色，静止，分出有机相，水相调节PH至8.0-8.5，用乙酸乙酯萃取(2×100mL)，合并有机相，并用饱和氯化钠水溶液洗涤、无水硫酸钠干燥后，蒸出有机溶剂得标题化合物3.10g。mp.99℃，FAB HRMS[M+H+]calcd for C20H32BrN5O8P 581.3740.found 581.3747。
实施例2.8-溴-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤-富马酸(化合物6)：
(1)8-溴-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤(化合物5)：
取9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤(3.3克，6.3mmol)，溶于30ml醋酸中，加醋酸钠(1.0g)，加Br2(0.50mL，9.7mmol).搅拌2小时，原料点消失，依次加加乙酸乙酯(180ml)、水(150ml)，搅拌下加饱和亚硫酸氢钠(NaHSO3)至混合物成无色，静止，分出有机相，水相调节PH至8.0-8.5，用乙酸乙酯萃取(280mL)，合并有机相，并用饱和氯化钠水溶液洗涤、无水硫酸钠干燥，蒸出有机溶剂得粘稠状化合物5。1H NMR(CD3OD)δppm8.19(s，1H)，6.75(s，2H，CH2)，5.56-5.40(m，4H，2CH2)，4.48(s，4H)，4.27(m，2H，CH2)，4.15-3.90(m，2H，)，3.85-3.75(m，1H)，1.31-1.28(m，15H，5CH3).FABHRMS[M+H+]calcd.for C19H29BrN5O10P 599.3462.found 599.3480。
(2)8-溴-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤-富马酸(化合物6)：
取8-溴-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤(1.2g)及富马酸(0.235g)，加甲醇100ml，加热回流，保温20分钟，冷却、结晶，抽滤，石油醚洗涤滤饼，干燥，得白色固体。mp.126℃，Anal.Calcd.forC23H33BrN5O14P：C，38.67；H，4.66.Found：C，38.73；H，4.70。
实施例3.8-氯-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤-富马酸
(1)8-氯-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤
取9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤(3.0克)，溶于50ml醋酸中，加醋酸钠(3.0g)，搅拌下通入氯气，搅拌2小时，TLC检测至原料点消失，依次加加乙酸乙酯(100ml)、水150ml，搅拌下加5％亚硫酸氢钠(NaHSO3)至混合物用淀粉碘化钾试纸检测不变蓝，静止分层，分出有机相，水相调节PH至8.0-8.5，用乙酸乙酯萃取(2×60mL)，合并有机相，并用饱和氯化钠水溶液洗涤、无水硫酸钠干燥后，蒸出有机溶剂得标题化合物。FABHRMS[M+H+]calcd.for C20H32ClN5O8P 554.8952.found 554.8961。
(2)8-氯-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤-富马酸：
取8-氯-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤(1.0g，1.8mmol)及富马酸(0.21g，1.8mmol)，加甲醇30ml，加热回流，保温15-20分钟，冷却、结晶、抽滤、石油醚洗涤滤饼，干燥，得白色固体。Anal.Calcd forC23H33ClN5O14P：C，41.23；H，4.96.Found：C，41.24；H，5.01。
实施例4.8-氟-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤-富马酸
(1)8-氟-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)丙基-腺嘌呤
取9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)丙基-腺嘌呤(3.0克)，溶于50ml乙腈中，加醋酸钠(3.0g)，搅拌下通入浓度为1％的氟气-氦混合气体(F2-He)，至原料消失，依次加乙酸乙酯(100ml)、水(150ml)，充分混合后静止，分出有机相，将水相调节PH至8.0-8.5，用乙酸乙酯萃取(2×50mL)，合并有机相，并用饱和氯化钠水溶液洗涤、无水硫酸钠干燥后，蒸出有机溶剂得标题化合物。FAB HRMS[M+H+]calcd.for C19H29FN5O10P 538.4406.found 538.4415。
(2)8-氟-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤-富马酸：
取8-氟-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)-丙基腺嘌呤(0.5g)及富马酸(0.11g)，加甲醇15ml，加热回流，保温20分钟，冷却、结晶、抽滤，石油醚洗涤滤饼，干燥，得白色固体。Anal.Calcd for C23H33FN5O14P：C，42.27；H，5.09.Found：C，42.34；H，5.12。
实施例5.本发明的药物组合物可按通用的口服药物制剂制备方法制成片剂或胶囊，300mg剂量的化合物6的片剂或胶囊单位含量如下(mg/片，mg/粒)：
化合物6 300mg
乳糖 200mg
淀粉 50mg
微晶纤维素 20mg
羧甲淀粉钠 20mg
硬脂酸镁 10mg。
Claims (10)
1.8-卤代腺嘌呤类核苷化合物，其特征在于，具有通式I所示结构：其代表8-卤代-9-(2-二特戊酰氧甲氧基膦酰甲氧基)乙基-腺嘌呤或8-卤代-9-(2-(R)-二异丙氧羰氧甲氧基膦酰甲氧基)丙基-腺嘌呤化合物，
其中X为F、Cl或Br；
R为H或CH3；
(R)为手性碳构型；
R1为-CH2OCOC(CH3)3或-CH2OCOOCH(CH3)2；
当R为H时，R1为-CH2OCOC(CH3)3，(R)不存在；
当R为CH3时，R1为-CH2OCOOCH(CH3)2。
2.如权利要求1所述的8-卤代腺嘌呤类核苷化合物，其特征在于，具体为下列化合物：
3.如权利要求1所述的8-卤代腺嘌呤类核苷化合物的盐，其特征在于，具有通式II所示结构：
其中X为F、Cl或Br；
R为H或CH3；
(R)为当R为CH3时，手性碳构型；
R1为-CH2OCOC(CH3)3或-CH2OCOOCH(CH3)2；
当R为H时，R1为-CH2OCOC(CH3)3，(R)不存在；
当R为CH3时，R1为-CH2OCOOCH(CH3)2；
有机酸为富马酸、延胡索酸、柠檬酸。
4.如权利要求3所述的8-卤代腺嘌呤类核苷化合物的盐，其特征在于，具体为下列化合物：
5.如权利要求1所述的8-卤代腺嘌呤类核苷化合物的合成方法，其特征在于，其包括如下步骤：
将化合物腺嘌呤无环核苷溶于有机酸或醇中，或有机酸和醇的混合溶剂中，在有机酸碱金属盐或季銨氢氧化物存在下，于0-100℃加入溴素Br2或氯气Cl2或由惰性气体He稀释的氟气，生成化合物I。
6.如权利要求5所述的8-卤代腺嘌呤类核苷化合物的合成方法，其特征在于，有机酸为醋酸；醇为甲醇或乙醇；有机酸碱金属盐为醋酸钠；季銨氢氧化物为氢氧化四乙基銨；温度为室温。
7.如权利要求3所述的8-卤代腺嘌呤类核苷化合物盐的合成方法，其特征在于，其包括如下步骤：
将8-卤代-腺嘌呤无环核苷化合物I溶于有机溶剂中，于20-80℃与有机酸反应得到8-卤代-腺嘌呤无环核苷盐，即化合物II。
8.如权利要求7所述的8-卤代腺嘌呤类核苷化合物盐的合成方法，其特征在于，有机酸为脂肪族酸和芳香族酸；有机酸与化合物I的摩尔比为0.5∶1～2∶1；反应温度为40-70℃。
9.如权利要求7或8所述的8-卤代腺嘌呤类核苷化合物盐的合成方法，其特征在于，有机酸为柠檬酸、富马酸、延胡索酸、山梨酸、苯甲酸；有机酸与化合物I的摩尔比为1∶1。
10.如权利要求3所述的8-卤代腺嘌呤类核苷化合物盐的应用，其特征在于，用作制备抗病毒药物。
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| CN1465582A (zh) * | 2002-07-01 | 2004-01-07 | 中国人民解放军军事医学科学院放射医 | 核苷酸类似物、含它的药物组合物及其用途 |
| CN1634943A (zh) * | 2004-11-05 | 2005-07-06 | 中国医学科学院医药生物技术研究所 | 一组非环核苷酸类似物及其合成方法和在抗病毒中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1465582A (zh) * | 2002-07-01 | 2004-01-07 | 中国人民解放军军事医学科学院放射医 | 核苷酸类似物、含它的药物组合物及其用途 |
| CN1634943A (zh) * | 2004-11-05 | 2005-07-06 | 中国医学科学院医药生物技术研究所 | 一组非环核苷酸类似物及其合成方法和在抗病毒中的应用 |
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