CN101104604B - 光学纯二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 - Google Patents
光学纯二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 Download PDFInfo
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- CN101104604B CN101104604B CN2006100986459A CN200610098645A CN101104604B CN 101104604 B CN101104604 B CN 101104604B CN 2006100986459 A CN2006100986459 A CN 2006100986459A CN 200610098645 A CN200610098645 A CN 200610098645A CN 101104604 B CN101104604 B CN 101104604B
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- 239000000539 dimer Substances 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 235000021317 phosphate Nutrition 0.000 description 1
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- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 239000004302 potassium sorbate Substances 0.000 description 1
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- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
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- 230000002285 radioactive effect Effects 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
本发明涉及通式(I)光学纯化合物或其可药用的盐或水合物。本发明还涉及通式(I)光学纯化合物的制备方法，以及通式(I)光学纯化合物或其可药用盐或水合物的作为药物的用途，尤其是作为用于治疗和预防乙型肝炎的药物的用途。
Description
技术领域
本发明涉及通式(I)的光学纯的二氢嘧啶类化合物及其制备方法，包含上述化合物的药物组合物，以及该类化合物或其可药用盐或水合物作为药物的用途，尤其是作为用于治疗和预防乙型肝炎的药物的用途。
背景技术
慢性乙型肝炎是由乙型肝炎病毒(HBV)引起的，世界范围内广泛流行的一种严重传染病，与肝硬化和肝癌的发生密切相关。我国是乙型肝炎高发区，1992-1995年全国病毒性肝炎血清流行病学调查结果表明，我国人群乙型肝炎病毒表面抗原(HBsAg)携带率为9.7％，估计约1.3亿人为HBV携带者。对我国病毒性肝炎流行现状的研究发现，乙型肝炎年报告发病率从1990年的21.9/10万升高到2003年的53.3/10万，呈明显上升趋势(王晓军，张荣珍，胡苑笙等疾病监测，2004，19(8)：290-292)。慢性乙型肝炎不仅严重影响人体健康，而且给家庭、社会造成沉重的经济负担，慢性乙型肝炎已成为我国重大的公共卫生问题之一。
用于治疗慢性乙肝的药物主要有两类——免疫调节剂和核苷类DNA聚合酶抑制剂(Loomba R.，Liang T.J.，Antivir.Ther.，2006，11(1)：1-15)。前者包括：干扰素-α2b(IFN-α2b，Intron 
)和聚乙二醇干扰素-α2a(peg-IFN-α2a， 
)；后者包括：拉米夫定(Lamivudine， 
)、阿德福韦酯(Adefovir Dipivoxil， 
)和恩替卡韦(Entecavir， )。相比较而言可供临床应用的用于治疗乙肝的药物种类和数量还很少，因此不断研究开发新的安全有效的抗病毒药物，尤其是具有全新作用机制的药物具有 十分重要的意义。
Deres等报道了以Bay41-4109、Bay39-5493为代表的杂芳环取代的二氢嘧啶类(HAP)化合物，该类化合物能够通过阻止正常核衣壳的形成起到抑制HBV复制的作用，该类化合物同核心蛋白的结合具有结构特异性。(Deres K.，Schroder C.H.，Paessens A.，et al.Science，2003，299(5608)：893-896)。对其作用机制研究发现，HAP通过与核心蛋白的113-143氨基酸残基作用，改变了形成核衣壳的二聚体之间的夹角，导致形成不稳定的膨胀的核衣壳，加速核心蛋白的降解(Hacker H.J.，Deres K.，Mildenberger M.，et al.，Biochem.Pharmacol.2003，66(12)：2273-2279)。WO99/54326和WO99/54329中分别公开了2-吡啶基和2-噻唑基取代的二氢嘧啶类化合物。
发明内容
本发明涉及了通式(I)光学纯的二氢嘧啶类化合物
(I)
或其可药用盐或水合物，
其中
R1代表氢、(C1-C4)-烷基、(C2-C4)-链烯基、(C1-C6)-酰基、芳酰基、芳磺酰基，
R2代表选择性被选自下述相同或不同取代基取代最高可达5次的苯基、噻唑基、咪唑基：卤素、羟基、氰基、三氟甲基、硝基、苄基、(C1-C6)-烷基、(C1-C6)-烷氧基、(C1-C6)-烷硫基、(C1-C6)-烷氧羰基、(C1-C6)-酰氧基、氨基、(C1-C6)-烷基氨基或(C1-C6)-二烷基氨基，(C1-C6)-酰基氨基，
R3代表苯基、呋喃基、噻吩基、三唑基、吡啶基、具有3-6个碳原子的环烷基，
其中上述环系可任选被选自下述基团的相同或不同取代基单取代或多取代：卤素、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、(C1-C6)-烷氧基、(C1-C6)-烷氧羰基和(C1-C6)-烷基，其中所述烷基可被具有6-10个碳原子的芳基、卤素、或-S-R5、NR6R7、CO-NR8R9和-A-CH2-R10所示基团取代，
其中
R5代表可任选被卤素取代的苯基，
R6、R7、R8和R9相同或不同，并分别代表氢、苯基、羟基取代苯基、羟基、(C1-C6)-酰基或(C1-C6)-烷基，其中所述烷基可被羟基、(C1-C6)-烷氧基羰基、苯基或羟基取代苯基取代，
A代表O、S、SO或SO2，
R10代表可任选被选自下述基团相同或不同取代基单取代或多取代的苯基：卤素、硝基、三氟甲基、(C1-C6)-烷基和(C1-C6)-烷氧基，
R4代表式-OR11或式
其中
R11代表氢，直链、支链或环状饱和或不饱和(C1-C8)-烃基，其中所述烃基可任选含有1个或2个选自O、CO、NH、-NH(C1-C4)-烷基、-N((C1-C4)-烷基)2、S和SO2的相同或不同杂链单元，并且可任选被卤素、硝基、氰基、烷氧基、具有6-10个碳原子的芳基、芳烷基、杂芳基或式-NR15R16所示基团取代，
其中
R15和R16相同或不同，并分别代表氢、苄基或(C1-C6)-烷基，
R12、R13、R14代表分别选自下述基团的不同取代基：氢、卤素、硝基、氰基、C1-6烷氧羰基、芳基、直链，支链或环状饱和或不饱和(C1-C8)-烃基，其中所述烃基可任选被卤素、硝基、氰基、C1-6烷氧基、C1-6烷氧羰基、具有6-10个碳原子的芳基、芳基C1-6烷基、杂芳基取代。
本发明说明书中，(C2-C6)-链烯基是指具有2-6个碳原子的直链或支链烯基，优选3-5个碳原子的直链或支链烯基，包括但是并不局限于乙烯基、丙烯基、正戊烯基、正己烯基。
本发明说明书中，(C1-C6)-酰基是指具有1-6个碳原子的直链或支链酰基，优选具有2-4个碳原子的直链或支链酰基，包括但是并不局限于甲酰基、乙酰基。
本发明说明书中，芳基通常是指5-14元的取代的或非取代的芳环系统，或可能包含稠合的双环或三环的芳环系统，包括但是并不局限于苯基和萘基。
本发明说明书中，(C1-C6)-烷基是指直链或支链的含有1-6个碳原子的基团，包括但并不局限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基和叔丁基等。
本发明说明书中，(C1-C6)-烷氧基是指含有1-6个碳原子的直链或支链烷氧基，优选具有1-4个碳原子的直链或支链烷氧基，包括但并不局限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基和叔丁氧基等。
本发明说明书中，(C1-C6)-烷硫基是指含有1-6个碳原子的直链或支链烷硫基，优选具有1-4个碳原子的直链或支链烷硫基。
本发明说明书中，(C1-C6)-烷氧羰基是指具有1-6个碳原子的直链或支链烷氧羰基，优选具有1-4个碳原子的直链或支链烷氧羰基，包括但并不局限于甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基和叔丁氧羰基等。
本发明说明书中，手性伯氨是指分子中至少含一个手性中心的伯氨，可以为R构型或S构型。包括但并不局限于(R)或(S)-1-苯基乙胺、(R)或(S)-1-苯基丙胺、(R)或(S)-1-(2-萘基)乙胺、D或L型的天然或非天然氨基酸。
本发明化合物可以以立体异构体形式存在。
本发明化合物包括通式I及其异构体Ia和它们的混合物。如果R1为氢，异构体I和Ia以互变异构体平衡存在：
本发明化合物还可以成盐的形式。
其中可药用的优选的盐包括但是并不局限于与无机酸如盐酸、硫酸、磷酸、亚磷酸、氢溴酸和硝酸所成的盐以及与各种有机酸，如马来酸、富马酸、苹果酸、延胡索酸、琥珀酸、酒石酸、柠檬酸、乙酸、乳酸、苯甲酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、棕榈酸等所成的盐。
其可药用的盐还包括但并不局限于本发明化合物的金属盐如钠盐、钾盐、镁盐或钙盐，或与氨或有机胺如乙胺、二乙胺、三乙胺、二乙醇胺、三乙醇胺、二环己基胺、二甲基氨基乙醇、精氨酸、赖氨酸、乙二胺、或2-苯基乙胺等成的铵盐。
本发明中的一些化合物可能用水或各种有机溶剂结晶或重结晶，在这种情况下，可能形成各种溶剂化物。本发明包括那些化学计量的溶剂化物，包括水合物，也包括在用低压升华干燥法制备时形成的包含可变量水的化合物。
定义如下的通式(I)化合物及它们的盐或水合物是优选的，
其中：
R1代表氢、甲基、甲酰基、乙酰基、芳酰基、芳磺酰基，
R2代表被选自卤代最高达5次的苯基、或选自下述基团的相同或不同取代基取代最高达3次的噻唑基、咪唑基：氟、氯、溴、苄基、(C1-C4)-烷基、(C1-C4)-烷氧基、氨基、(C1-C4)-酰基氨基，
R3代表苯基、呋喃基、噻吩基、吡啶基、环戊基或环己基，
其中上述环系可任选被选自下述基团的相同或不同取代基单取代或多取代：卤素、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、羟基、甲氧基羰基和式-CONHCH2C(CH3)3、-CONH(CH2)2OH、 -CONHCH2C6H5、-CONHC6H5、-OCH2C6H5或-S-pCl-C6H4所示基团，
R4代表式-OR11或式
其中
R11代表氢、(C1-C4)-链烯基或(C1-C4)-烷基，其中所述基团可任选被卤素、吡啶基、氰基、苯氧基、烷氧基、三氟乙基、苄基或式-NR15R16所示基团取代，
其中
R15和R16相同或不同，并分别代表氢、苄基或(C1-C4)-烷基，
R12、R13、R14代表分别选自下述基团的不同取代基：氢、氟、氯、硝基、氰基、烷氧羰基、芳基、直链，支链或环状饱和或不饱和(C1-C6)-烃基，其中所述烃基可任选被卤素、硝基、氰基、烷氧基、烷氧羰基、具有6-10个碳原子的芳基、芳烷基、杂芳基取代。
定义如下的通式(I)化合物及它们的盐或水合物是特别优选的，其中：
R1代表氢、甲基、甲酰基、乙酰基、苯甲酰基、苯磺酰基、对甲苯磺酰基，
R2代表被选自氟代最高达5次的苯基、或选自下述基团的相同或不同取代基取代最高达2次的噻唑基、咪唑基：氟、氯、溴、苄基、(C1-C3)-烷基、(C1-C3)-烷氧基、氨基、(C1-C3)-酰基氨基，
R3代表苯基、呋喃基、噻吩基、吡啶基、环戊基或环己基，
其中上述环系可任选被选自下述基团的相同或不同取代基取代最高达3次：氟、氯、溴、碘、羟基、三氟甲基、三氟甲氧基、三氟甲磺酰基、硝基、氰基、羧基、甲氧基羰基和式-CONHCH2C(CH3)3、-CONH(CH2)2OH、-CONHCH2C6H5、-CONHC6H5、-OCH2C6H5或-S-pCl-C6H4所示基团，
R4代表式-OR11或式
其中
R11代表氢、(C1-C3)-链烯基或(C1-C4)-烷基，其中所述基团可任选被卤素、吡啶基、氰基、苯氧基、烷氧基、三氟乙基、苄基或式-NR15R16所示基团取代，
其中
R15和R16相同或不同，并分别代表氢、苄基或甲基，
R12、R13、R14代表分别选自下述基团的不同取代基：氢、烷氧羰基、取代或非取代苯基、萘基、苄基、直链或支链(C1-C3)-烃基。
定义如下的通式(I)化合物及它们的盐或水合物是非常特别优选的，
其中：
R1代表氢或乙酰基，
R2代表被选自氟代最高达3次的苯基、或选自下述基团的相同或不同取代基取代最高达2次的2-噻唑基、4-噻唑基、5-噻唑基、2-咪唑基：氟、氯、甲基、苄基、氨基、乙酰基氨基，
R3代表可任选被选自下述基团的相同或不同取代基取代最高达3次的苯基：氟、氯、溴、羟基、硝基、甲氧基、甲基，
R4代表式-OR11或式
其中
R11代表具有最高达3个碳原子的直链或支链烷基，所述烷基可被氟或氯原子取代。
R12、R13、R14代表分别选自下述基团的不同取代基：氢、甲基、乙基、丙基、甲氧羰基、乙氧羰基、苯基，
本发明特别优选的通式(I)化合物或其可药用盐或水合物为下面的化合物：
1.(R，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸酰胺
2.(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸乙酯
3.(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸三氟乙酯
4.(R，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(2，4，6-三氟苯基)-1，4-二氢嘧啶-5-甲酸酰胺
5.(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2，4，6-三氟苯基)-1，4-二氢嘧啶-5-甲酸乙酯
6.(S，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(5-噻唑基)-1，4-二氢嘧啶-5-甲酸酰胺
7.(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(5-噻唑基)-1，4-二氢嘧啶-5-甲酸乙酯。
本发明化合物通式(I)可通过下述方法制备：
1)在加入或不加入碱或酸的情况下，在适当的惰性溶剂中，通式(II)脒类或其盐
其中R2定义同上，
与通式(III)醛
其中R3定义同上，
以及通式(IV)反应，
CH3COCH2CONHCR12R13R14(IV)
其中R12、R13、R14定义同上，
得到通式(V)的化合物
或者，
在加入或不加入碱或酸的情况下，于20-150℃，在适当的惰性溶剂中，通式(VI)或(VII)
其中R3、R12、R13、R14定义同上，
与上述通式(II)反应
或者，
在铵盐存在下，将上述通式(III)醛与通式(IV)化合物以及通式(VIII)亚氨基醚反应，
其中R2定义同上，且R′为C1-C4烷基。
2)通式(V)在适当的溶剂中进行酰基化，得通式(IX)
其中R1为(C1-C6)-酰基、芳酰基或芳磺酰基，R2，R3，R12、R13、R14定义同上，
3)通式(IX)在酸性或碱性条件下，适当的溶剂中进行亚硝基化，然后与醇钠R11ONa反应得通式(I)化合物
其中R1为氢，R2，R3，R4，R11定义同上，
利用下述反应方案来举例说明本发明方法：
1.对A、B、C反应方案而言，反应步骤1适用的溶剂是所有的惰性有机溶剂。这些溶剂优选包括醇类如乙醇、甲醇、异丙醇，醚类如二氧杂环己烷、乙醚、四氢呋喃、乙二醇一甲醚、乙二醇二甲醚或冰醋酸、二甲基甲酰胺、二甲基亚砜、乙腈、吡啶和六甲基磷酰胺。
反应温度可在较宽的范围内变化。通常该反应在20-150℃进行，优选在各溶剂的沸点进行。
该反应可在常压，但也可在升高的压力下进行。通常该反应在常压下进行。
该反应可在加入或不加入碱或酸的条件下进行，但本发明反应优选在相对弱的酸如乙酸或甲酸的存在下进行。
用作起始物质的通式(II)的脒在某些情况下是已知的，或者可以按照文献中记载的已知方法由相应的氰基化合物制备(参见Diana，G.D.，Yarinsky，A.，Zalay，E.S.，et al.J.Med.Chem.1969，12(9)：791-793；Garigipati，R.S.Tetrahedron.Lett.1990，31(14)：1969-1972；Boere，R.J.，Oakley，R.T.，Read，R.V.JOrganometal.Chem.1987，331：161-167；Judkins，B.D.，Allen，D.G.，Cook，T.A.Synth.Commun.1996，26(23)：4351-4367； Tommasi，R.A.，Macchia，W.M.，Parker，D.T.Tetrabedron.Lett.1998，39：5947-5950)。
用作起始物质的通式(III)的醛是已知的，或者可以按照文献中记载的已知方法制备(T.D.Harris和G.P.Roth，J.Org.Chem.1979，44，146；DE 2165260，July 1972；DE 2401665，July 1974；Mijanoet.al.CA 1963，59，13929c；E.Adler，H.D.Bccker，Chem.Scand.1961，15，849；E.P.Papadopoulos，M.Mardin，Ch.Issidoridis，J.Org.Chem.Soc.1956，78，2543)。
用作起始物质的通式(IV)的化合物CH3COCH2CONHR12由分子结构中含手性中心的伯氨R12NH2与双乙烯酮或双乙烯酮丙酮加成物，在加入碱或不加入碱的条件下，于惰性溶剂中反应制备。通常该反应在50-150℃进行，优选在80-100℃进行。
用作起始物质通式(VI)或通式(VII)化合物可按文献记载的已知方法由通式(IV)化合物CH3COCH2CONHR12与通式(III)的醛在惰性溶剂中，加入或不加入酸和碱的条件下制备(参见G.Jones，“诺文葛耳缩合”，有机反应，第XV卷，第204页起(1967))。
用作起始物质的通式(VIII)的亚氨基醚是已知的，或者可以按文献记载的已知方法制备(参见S.A.Glckman，A.C.Cope，J.Am.Chem.Soc.1945，67，1017)。
2.反应步骤2的酰基化反应适用的溶剂是所有的惰性非质子性有机溶剂。这些溶剂优选包括醚类如二氧杂环己烷、乙醚、四氢呋喃、乙二醇二甲醚或二甲基甲酰胺、二甲基亚砜、乙腈、吡啶和六甲基磷酰胺。
反应温度可在较宽的范围内变化。通常该反应在-20-100℃进行，但优选在室温进行。
该反应通常在碱性条件下进行，可应用的碱优选但不局限于无机碱如碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾、醋酸钠或有机碱如三乙胺、吡啶、六氢吡啶、N，N-二甲基氨基吡啶、吗啉等。
3.步骤3的亚硝化产物通常在酸性条件如醋酸、盐酸或硫酸存 在下与亚硝酸钠反应或在碱性条件如醋酸钠、吡啶、六氢吡啶、N，N-二甲基氨基吡啶存在下与NO2BF4或NOBF4反应制备。
亚硝化反应适用的溶剂是惰性的有机溶剂，优选但并不局限于二氧杂环己烷、乙醚、乙腈、二氯甲烷、硝基甲烷、四氢呋喃、乙二醇一甲醚、乙二醇二甲醚、冰醋酸、二甲基甲酰胺、二甲基亚砜、吡啶和六甲基磷酰胺。
反应通常在惰性气体保护下，于-50-50℃进行，但优选在0℃进行。
亚硝基化产物一般不经纯化，直接同醇钠R11ONa反应得到产物。醇钠可由相应的醇与金属钠制备得到。
关于制备通式I化合物更详尽的资料见实施例。
本发明化合物的抗病毒作用按Sells等人(M.A.Sells，M.L.Chen，G.Proc.Natl.Acad.Sci.1987，84，1005-1009)和Korba等(B.E.Korba，J.L.Gerin Antiviral Research 1992，19，55-70)描述的方法测定。
在96孔微量滴定板中进行抗病毒试验。该板的第一竖行只含生长培养基和HepG 2.2.15细胞，用作空白对照。
首先将试验化合物的贮备液(50毫摩尔)溶解在DMSO中，用HepG2.2.15细胞生长培养基制备进一步稀释液。通常将本发明的化合物以100μg/ml的试验浓度(第1试验浓度)吸移到微量滴定板第二竖试验排的各孔中，然后用生长培养基加2％胎牛血清(25μl)进行稀释，每次稀释2倍，稀释最高达210倍。
然后将225μl HepG 2.2.15细胞在生长培养基加2％胎牛血清中的悬浮液(5×104个细胞/ml)加到该96孔微量滴定板的每个孔中。
该试验混合物在37℃，5％CO2条件下培育4天。然后吸出上清液并弃去，在各孔中加入225μl新制备的生长培养基。再次加入本发明化合物，溶液体积25μl。将该混合物再培育4天。
在收获上清液测定抗病毒效果之前用光学显微镜技术或生物化学检测方法(如Alamar Blue染色或Trypan Blue染色)考察HepG 2.2.15细胞毒性变化。
然后收集上清液，并用真空将其吸收到用尼龙膜盖住的96孔斑点印迹室中(按生产商的使用说明)。
细胞毒性测定
由物质诱发的在HepG 2.2.15细胞中的细胞毒性或抑制细胞的变化可采用例如光学显微镜技术来测定，并以细胞形态的变化表示。这类在HepG 2.2.15细胞中由物质诱发的变化与未经处理的细胞相比是明显的，例如细胞溶解、空泡形成或细胞形态改变。以观察细胞病变为指标，8天显微镜下观察细胞病变，完全破坏为4；75％为3；50％为2；25％为1；无病变为0。计算各浓度下平均细胞病变程度和抑制百分数。按Reed&Muench法计算半数有毒浓度(TC50)，最大无毒浓度(TC0)。
TC50是指50％的细胞具有与相应的细胞对照相似的形态时的本发明化合物的浓度。
抗病毒活性测定
将上清液转移到斑点装置(参见上文)的尼龙膜上之后，将HepG2.2.15细胞的上清液变性(1.5M NaCl/0.5M NaOH)、中和(3M NaCl/0.5M Tris HCl，pH 7.5)和洗涤(2xSSC)。然后将滤膜在120℃保温2-4小时使DNA被烘烤到该膜上。
DNA杂交
通常采用非放射活性地高辛配基标记的乙型肝炎特异性DNA探针来测定尼龙滤膜上处理后的HepG 2.2.15细胞的病毒DNA。其中，每次都是依据生产商的使用说明将所述探针用地高辛配基标记、纯化和杂交。
简单地说，预杂化和杂化是在5×SSC、1×封闭剂、0.1％N-月桂酰肌氨酸、0.02％SDS和100μg青鱼精子DNA中进行预杂交和杂交。在60℃进行30分钟预杂交，用20-40ng/ml地高辛配基化的变性HBV特异性DNA进行特异性杂交(14小时，60℃)。然后将过滤膜进行洗涤，进行HBV DNA的地高辛配基抗体检测。
地高辛配基标记的DNA的免疫学检测按生产商的说明进行。
简单地说，该滤膜用封闭剂进行洗涤和预杂交(按制造商的说明)，然后用事先偶联到碱性磷酸酶上的抗-DIG抗体进行杂交30分钟。洗涤后，加入碱性磷酸酯酶底物CSPD，与滤器一起培养5分钟，然后包在塑料薄膜中，并在37℃再培养15分钟。将过滤器暴露于x-射线膜上测量乙型肝炎特定DNA的化学发光信号(根据信号强度培养10分钟至2小时)，计算半数抑制浓度(IC50)。
半数抑制浓度(IC50)是指与未处理样品相比，使乙型肝炎特异性带减少50％时本发明化合物的浓度。
本发明的化合物显示出较强的抗病毒作用。这类化合物对乙型肝炎(HBV)具有出乎预料的抗病毒活性，因此适于用来治疗病毒引起的各种疾病，尤其是急性和慢性持久性HBV病毒感染引起的疾病。由HBV引起的慢性病毒性疾病可以导致各种不同严重程度的综合症状，众所周知，慢性乙型肝炎病毒感染可导致肝硬化和(或)肝细胞癌。
可用本发明化合物治疗的适应症的实例有：
治疗可导致感染性肝炎的急性和慢性病毒感染的，例如乙型肝炎病毒感染。特别优选的是慢性乙型肝炎感染的治疗和急性乙型肝炎病毒感染的治疗。
本发明化合物的药物组合物，可以以下方面的任意方式施与：口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入，或借助一种外植的储器用药，其中优选口服、肌注、腹膜内或静脉内用药方式。
本发明化合物或含有本发明化合物的药物组合物可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂等。
本发明的药物组合物中还可以含有常用的载体，这里所述可药用 载体包括但不局限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血清蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛酯等。载体在药物组合物中的含量可以是1％-98％重量，通常大约占到80％重量。为方便起见，局部麻醉剂，防腐剂，缓冲剂等可直接溶于载体中。
口服片剂和胶囊可以含有赋形剂如粘合剂，如糖浆，阿拉伯胶，山梨醇，黄芪胶，或聚乙烯吡咯烷酮，填充剂，如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇，氨基乙酸，润滑剂，如硬脂酸镁，滑石，聚乙二醇，硅土，崩解剂，如马铃薯淀粉，或可接受的增润剂，如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂，山梨醇，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝凝胶，氢化的食用油脂，乳化剂，如卵磷脂，山梨聚醣单油酸盐，阿拉伯胶；或非水载体(可能包含可食用油)，如杏仁油，油脂如甘油，乙二醇或乙醇；防腐剂如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。
栓剂可包含常规的栓剂基质，如可可黄油或其它甘油酯。
对胃外投药，液态剂型通常由化合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同，化合物既可溶于载体中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的载体中。其中软膏制剂可以使用的载体包括但不局限于：矿物油，液体凡士林， 白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂和霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。
在上述药物制剂中通式(I)的活性化合物的存在浓度应为该混合物总重量的约0.1～99.5％，优选约0.5～95％(重量)。
上述药物制剂除了包含通式(I)的化合物外，还可进一步包含其它的药物活性化合物。
一般而言，已经证明有利的是无论在人体医药还是在兽医药中，本发明活性化合物的给药总量每24小时为约0.5-500mg，优选1-100mg/kg体重，如果合适的话，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为约1-80mg，更优选为1-50mg/kg体重，但也可以不按照上述的剂量，即取决于治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。
具体实施方式
下面的具体实施例是本发明的优选实施方案，其不应理解为对本发明构成任何限制。
化合物的熔点由RY-1熔点仪测定，温度计未较正。质谱由Micromass ZabSpec高分辨率质谱仪(分辨率1000)测定。1H NMR由JNM-ECA-400超导NMR仪测定，工作频率1H NMR 400MHz，13C NMR100MHz。
实施例
实施例1(R，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸酰胺
步骤1 (R)-α-甲基苄胺6.06克(50mmol)，双乙烯酮丙酮加成物7.11克(50mmol)置于单口的250ml圆底烧瓶中，加入N，N二甲基甲酰胺100ml，三乙胺6.01克(60mmol)，于80-100℃反应2小时，停止反应。加入200ml水，用4N的盐酸中和到中性，乙酸乙酯萃取，有机相用饱和氧化钠水溶液洗涤，无水硫酸钠干燥，过滤，浓缩得化合物19.33克，收率91％。
步骤2 化合物14.5克(22.05mmol)、2-氯-4-氟苯甲醛3.5克(22.05mmol)、2-噻唑甲脒醋酸盐4.5克(22.05mmol)和无水醋酸钠1.0克(22.05mmol)，加入无水乙醇100ml，回流反应16小时，浓缩除去溶剂，所得固体加入乙酸乙酯40ml和水40ml，分液，水相用乙酸乙酯20ml*2进行萃取，合并有机相，用饱和氯化钠水溶液进行洗涤，无水硫酸钠干燥，过滤，浓缩，快速柱层析分离得颗粒状淡黄色细针状固体(化合物2)2.93克，收率45％。mp 224-226℃。 1H-NMR(400MHz，DMSO-d6)δ1.30-1.34(3H，m)；2.01(3H，s)；4.84-4.88(1H，m)；5.97(1H，s)；7.03-7.05(2H，m)；7.12-7.24(4H，m)；7.36-7.39(1H，m)；7.49-7.53(1H，m)；7.87-7.88(1H，d)；7.93-7.96(1H，m)；8.17-8.19(1H，d)；9.35(1H，s)；MS(EI)454.0(M+)
实施例2(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸乙酯
化合物2 0.91克(2mmol)溶于无水N，N-二甲基甲酰胺20ml中，加入0.3三乙胺03克(3mmol)，滴入乙酰氯0.16ml(2.4mmol)，室温反应6小时。加入水20ml，乙酸乙酯15ml*6进行萃取。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，快速柱层析分离得化合物30.746克，收率75％。1H-NMR(400MHz，DMSO-d6)δ1.23-1.41(3H，m)；1.98(3H，s)；2.17(3H，s)；4.96-5.0(1H，m)；6.59(1H，s)；7.07-7.42(8H，m)；7.98-7.99(1H，d)；8.02-8.03(1H，d)8.63-8.64(1H，d)；MS(EI)496.1(M+)
氮气保护下，将化合物30.5克(1mmol)置于25ml的三口圆底烧瓶中，加入醋酸5ml溶解，冰浴冷却，于0℃加入亚硝酸钠0.14克(2mmol)。反应6小时，加入水30ml，冷却的二氯甲烷15ml*3快速萃取。有机相用饱和氯化钠水溶液洗涤，无水硫酸钠干燥。过滤浓缩得0.521克，不经纯化直接进行反应。
将0.521克上述产物加入无水乙醇15ml中，冰浴冷却，加入乙醇钠0.135g，于0℃反应50分钟。停止反应加入15ml水，用4N盐酸调节PH到中性，浓缩，乙酸乙酯与水进行分液，水相再用乙酸乙酯10ml*3进行萃取。有机相用无水硫酸钠干燥。柱层析分离得化合物40.296克，收率78％。1H-NMR(400MHz，DMSO-d6)δ1.01-1.07(3H，m)；2.46(3H，s)；3.90-3.95(2H，m)；5.99(1H，s)；7.17-7.22(1H，m)；7.90-7.91(1H，d)；7.97-7.98(1H，d)；9.96(1H，s)；MS(EI)379.0(M+)
[a]D＝-54.6(c＝1％，CH3OH)
实施例3(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸三氟乙酯
采用实施例2的制备方法，将乙醇钠改为三氟乙醇钠得黄色无定型固体化合物50.296克，收率78％。1H-NMR(400MHz，DMSO-d6)δ4.60-4.64(2H，m)；6.01(1H，s)；7.16-7.21(1H，m)；7.34-7.43(2H，m)；7.92-7.93(1H，d)；7.98-7.99(1H，d)；10.23(1H，s)；MS(EI)432.1(M+)
[a]D＝-80.1(c＝1％，CH3OH)
实施例4(R，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(2，4，6-三氟苯基)-1，4-二氢嘧啶-5-甲酸酰胺
2-氯-4-氟苯甲醛1.58g(10mmol)，化合物12.04g(10mmol)，溶于乙醇40ml中，室温搅拌2d.，然后加入2，4，6-三氟苯甲脒醋酸盐2.34g(10mmol)，回流反应过夜，蒸除溶剂，加入乙酸乙酯和水分液，乙酸乙酯层用无水硫酸钠干燥，过滤，浓缩，柱层析分离得混合物4.7g，溶于乙酸乙酯，析出固体化合物6，50％乙醇重结晶得无色细针状固体2.2g。1H-NMR(400MHz，DMSO-d6)δ1.3-1.33(3H，m)；1.97(3H，s)；4.81-4.88(1H，m)；5.96(1H，s)；7.04-7.39(9H，m)；7.57-7.61(1H，m)；8.11-8.13(1H，d)；9.25(1H，s)；MS(EI)501(M+)
实施例5(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2，4，6-三氟苯基)-1，4-二氢嘧啶-5-甲酸乙酯
采用实施例2的方法，由化合物6制备得到化合物7无色细针状结晶。1H-NMR(400MHz，DMSO-d6)δ1.39-1.41(3H，d，J＝7.0)；2.07(3H，s)；2.10(3H，s)；4.95-4.99(1H，m)；6.47(1H，s)；7.08-7.30(8H，m)；7.45-7.51(2H，m)；8.70-8.72(1H，d，J＝8.12)；MS(EI)543(M+)。
由化合物7得到化合物8。无色针状结晶，mp 162-165℃； 1H-NMR(400MHz，DMSO-d6)δ1.02-1.05(3H，t，J＝7.0Hz)；2.32(3H，s)；3.92-3.96(2H，m，J＝7.0Hz)；5.97(1H，s)；7.21-7.45(5H，m)；9.86(1H，s)；MS(EI)426(M+)；[α]D＝-92.38(c＝1％，甲醇)。
实施例6(S，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(5-噻唑基)-1，4-二氢嘧啶-5-甲酸酰胺
采用实施例1的制备方法，由(S)-α-甲基苄胺6.1g(50mmol)， 得到化合物99.6g(产率95％)。
化合物92.9g(14.2mmol)，2-氯-4-氟苯甲醛2.2g(14.2mmol)，溶于无水乙醇50ml中，加入醋酸和六氢吡啶各7滴，室温反应24hr，浓缩，柱层析分离得白色固体10 4.1g，乙酸乙酯/石油醚重结晶。 1H-NMR(400MHz，CDCl3)δ1.42-1.44(3H，d)；2.45(3H，s)；5.18-5.21(1H，m)；6.07-6.09(1H，d)；6.72-6.76(1H，m)；7.12-7.47(9H，m)；7.75(1H，s)；
化合物103.4g(10mmol)，5-噻唑甲脒醋酸盐1.9(10mmol)，醋酸钠1.0(12mmol)溶于无水乙醇50ml中，加热回流20hr，浓缩除去溶剂，所得固体加入乙酸乙酯和水，分液，水相用乙酸乙酯进行萃取，合并有机相，用饱和氯化钠水溶液进行洗涤，无水硫酸钠干燥，过滤，浓缩，柱层析分离得淡黄色固体(化合物11)1.9克，收率41％。 1H-NMR(400MHz，DMSO-d6)δ1.22-1.25(3H，m)；2.11(3H，s)；4.85-4.88(1H，m)；5.96(1H，s)；7.14-7.43(8H，m)；8.10-8.12(1H，d)；8.49(1H，s)；9.09(1H，s)；9.17(1H，s)；MS(EI)454.0(M+)
实施例7(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(5-噻唑基)-1，4-二氢嘧啶-5-甲酸乙酯
采用实施例2的方法，由化合物11制备化合物12得黄色泡沫样固体。1H-NMR(400MHz，DMSO-d6)δ1.34-1.36(3H，d)；2.08(3H，s)；2.18(3H，s)；4.97-5.01(1H，m)；6.56(1H，s)；7.11-7.37(7H，m)；7.50-7.53(1H，dd)；7.93(1H，s)；8.72-8.74(1H，d)；9.23(1H，s)；MS(EI)496.1(M+)
由化合物12得到化合物13。1H-NMR(400MHz，DMSO-d6)δ1.0-1.06(3H，t，J＝7.0Hz)；2.44(3H，s)；3.92-3.94(2H，m，J＝7.0Hz)；5.93(1H，s)；7.36-7.39(3H，m)；8.54(1H，s)；9.11(1H，s)；9.60(1H，s)；
MS(EI)379.0(M+)；[α]D＝-65.0(c＝1％，甲醇)。
实施例8化合物的细胞毒性及抗病毒活性测定
照说明书描述的方法测定本发明化合物的细胞毒性及抗病毒活性，结果见表1
表1化合物对HBV DNA的抑制作用
| 实施例编号 | IC50μM | TD50μM |
| 2 | ＜0.8 | ＞62.9 |
| 3 | 5.1 | 37.4 |
| 5 | 1.3 | 13.8 |
| 7 | 1.8 | ＞12.5 |
Claims (4)
1.通式(Ⅰ)光学纯化合物的制备方法，
其中
R1代表氢，
R2代表选择性被选自下述基团的相同或不同取代基取代的苯基、噻唑基：卤素，
R3代表苯基、
其中上述环系可任选被选自下述基团的相同或不同取代基单取代
或多取代：卤素，
R4代表式
其中
R12、R13、R14代表分别选自下述基团的不同取代基：氢、卤素、直链、支链或环状饱和或不饱和(C1-C8)-烃基，其中所述烃基可任选被卤素取代，
其包括如下步骤：
1)在加入或不加入碱或酸的情况下，在适当的惰性溶剂中，通式(Ⅱ)脒类或其盐
其中R2定义同上，
与通式(Ⅲ)醛
其中R3定义同上，
以及通式(Ⅳ)反应，
CH3COCH2CONHCR12R13R14(Ⅳ)
其中R12、R13、R14定义同上，
得到通式(Ⅴ)的化合物
或者，
在加入或不加入碱或酸的情况下，于20-150℃，在适当的惰性溶剂中，通式(Ⅵ)或(Ⅶ)
其中R3、R12、R13、R14定义同上，
与上述通式(Ⅱ)反应，得到式(Ⅴ)化合物。
2.通式(Ⅰ)光学纯化合物的制备方法，
其中
R1代表氢，
R2代表选择性被选自下述基团的相同或不同取代基取代的苯基、噻唑基：卤素，
R3代表苯基、
其中上述环系可任选被选自下述基团的相同或不同取代基单取代或多取代：卤素，
R4代表式-OR11
其中
R11代表氢，直链、支链或环状饱和或不饱和(C1-C8)-烃基，其中所述烃基可任选含有1个或2个选自O、CO、NH、-NH(C1-C4)-烷基、-N((C1-C4)-烷基)2、S和SO2的相同或不同杂链单元，并且可任选被卤素、硝基、氰基取代，
其包括如下步骤：
1)在加入或不加入碱或酸的情况下，在适当的惰性溶剂中，通式(Ⅱ)脒类或其盐
其中R2定义同上，
与通式(Ⅲ)醛
其中R3定义同上，
以及通式(Ⅳ)反应，
CH3COCH2CONHCR12R13R14 (Ⅳ)
其中R12、R13、R14代表分别选自下述基团的不同取代基：氢、卤素、直链、支链或环状饱和或不饱和(C1-C8)-烃基，其中所述烃基可任选被卤素取代，
得到通式(Ⅴ)的化合物
或者，
在加入或不加入碱或酸的情况下，于20-150℃，在适当的惰性溶剂中，通式(Ⅵ)或(Ⅶ)
其中R3、R12、R13、R14定义同上，
与上述通式(Ⅱ)反应，得到式(Ⅴ)化合物，
2)通式(Ⅴ)在适当的溶剂中进行酰基化，得通式(Ⅸ)
其中R1′为(C1-C6)-酰基、芳酰基或芳磺酰基，R2，R3，R12、R13、R14定义同上，
3)通式(Ⅸ)在酸性或碱性条件下，适当的溶剂中进行亚硝基化，然后与醇钠R11ONa反应得通式(Ⅰ)光学纯化合物
其中R1为氢，R2，R3定义同上，R4定义为OR11，R11定义同上。
3.权利要求1的方法，其中所制备的光学纯化合物选自：
(R，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸酰胺
(R，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(2，4，6-三氟苯基)-1，4-二氢嘧啶-5-甲酸酰胺
(S，R)-N-(1-苯基乙基)-4-(2-氯-4-氟苯基)-6-甲基-2-(5-噻唑基)-1，4-二氢嘧啶-5-甲酸酰胺。
4.权利要求2的方法，其中所制备的光学纯化合物选自：
(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸乙酯
(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2-噻唑基)-1，4-二氢嘧啶-5-甲酸三氟乙酯
(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(2，4，6-三氟苯基)-1，4-二氢嘧啶-5-甲酸乙酯
(R)-4-(2-氯-4-氟苯基)-6-甲基-2-(5-噻唑基)-1，4-二氢嘧啶-5-甲酸乙酯。
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| CN2006100986459A CN101104604B (zh) | 2006-07-10 | 2006-07-10 | 光学纯二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 |
| PCT/CN2007/002099 WO2008009210A1 (fr) | 2006-07-10 | 2007-07-09 | Composés de dihydropyrimidine optiquement purs et leurs utilisations dans la fabrication d'un médicament pour traiter ou prévenir des viroses |
| EP07764007.6A EP2048141B1 (en) | 2006-07-10 | 2007-07-09 | Optically pure dihydropyrimidine compounds and their uses for the preparation of a medicament for treatment and prevention of viral diseases. |
| JP2009518703A JP4988841B2 (ja) | 2006-07-10 | 2007-07-09 | 光学的に純粋なジヒドロピリミジン化合物類、及びウイルス性疾患の治療及び予防のための医薬調製のためのこれらの使用 |
| US12/373,101 US8329902B2 (en) | 2006-07-10 | 2007-07-09 | Optically pure dihydropyrimidine compounds and their uses for the preparation of a medicament for treatment and prevention of viral diseases |
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| CN2006100986459A CN101104604B (zh) | 2006-07-10 | 2006-07-10 | 光学纯二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 |
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| CN101104617B (zh) * | 2006-07-10 | 2010-06-23 | 北京摩力克科技有限公司 | 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 |
| USRE45004E1 (en) * | 2007-06-18 | 2014-07-08 | Sunshine Lake Pharma Co., Ltd. | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
| CN101575318B (zh) | 2009-06-25 | 2012-02-08 | 中国人民解放军军事医学科学院毒物药物研究所 | 二氢嘧啶类化合物及其用于制备治疗和/或预防病毒性疾病的药物的用途 |
| US20130267517A1 (en) | 2012-03-31 | 2013-10-10 | Hoffmann-La Roche Inc. | Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
| MY182403A (en) | 2012-08-24 | 2021-01-25 | Sunshine Lake Pharma Co Ltd | Dihydropyrimidine compounds and their application in pharmaceuticals |
| BR112015004113A2 (pt) | 2012-09-10 | 2017-07-04 | Hoffmann La Roche | 6-aminoácido heteroarila diidropirimidinas para o tratamento e profilaxia da infecção pelo vírus da hepatite b |
| US9498479B2 (en) | 2013-11-19 | 2016-11-22 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
| MY172391A (en) * | 2013-11-27 | 2019-11-22 | Sunshine Lake Pharma Co Ltd | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
| MY196243A (en) | 2014-03-28 | 2023-03-24 | Sunshine Lake Pharma Co Ltd | Dihydropyrimidine Compounds and Their Application In Pharmaceuticals |
| WO2016124126A1 (en) | 2015-02-07 | 2016-08-11 | Sunshine Lake Pharma Co., Ltd. | Complexes and salts of dihydropyrimidine derivatives and their application in pharmaceuticals |
| KR20220123124A (ko) | 2020-03-30 | 2022-09-05 | 케이와 인코포레이티드 | 광학 시트, 백라이트 유닛, 액정 표시 장치 및 정보 기기 |
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- 2007-07-09 EP EP07764007.6A patent/EP2048141B1/en not_active Not-in-force
- 2007-07-09 US US12/373,101 patent/US8329902B2/en not_active Expired - Fee Related
- 2007-07-09 JP JP2009518703A patent/JP4988841B2/ja not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| EP2048141A4 (en) | 2011-11-16 |
| WO2008009210A8 (fr) | 2009-01-08 |
| JP2009542730A (ja) | 2009-12-03 |
| EP2048141B1 (en) | 2017-06-14 |
| US8329902B2 (en) | 2012-12-11 |
| JP4988841B2 (ja) | 2012-08-01 |
| WO2008009210A1 (fr) | 2008-01-24 |
| EP2048141A1 (en) | 2009-04-15 |
| US20100004268A1 (en) | 2010-01-07 |
| CN101104604A (zh) | 2008-01-16 |
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