CN1046531A - 抗病毒化合物 - Google Patents
抗病毒化合物 Download PDFInfo
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- CN1046531A CN1046531A CN90103632A CN90103632A CN1046531A CN 1046531 A CN1046531 A CN 1046531A CN 90103632 A CN90103632 A CN 90103632A CN 90103632 A CN90103632 A CN 90103632A CN 1046531 A CN1046531 A CN 1046531A
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- 230000014509 gene expression Effects 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 12
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- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000002773 nucleotide Substances 0.000 claims description 5
- 125000003729 nucleotide group Chemical group 0.000 claims description 5
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- 125000003118 aryl group Chemical group 0.000 claims description 4
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 claims description 2
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- -1 Carbonyl Chemical group 0.000 description 14
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- FKQVBUIGFXQQPU-UHFFFAOYSA-N 1-dichlorophosphoryloxy-4-methylsulfonylbenzene Chemical compound CS(=O)(=O)C1=CC=C(OP(Cl)(Cl)=O)C=C1 FKQVBUIGFXQQPU-UHFFFAOYSA-N 0.000 description 5
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- 239000000463 material Substances 0.000 description 2
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 2
- 230000000865 phosphorylative effect Effects 0.000 description 2
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- KECCFSZFXLAGJS-UHFFFAOYSA-N 4-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=C(O)C=C1 KECCFSZFXLAGJS-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
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- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
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- 125000003277 amino group Chemical group 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
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- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
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- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical class N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
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- 229910052698 phosphorus Inorganic materials 0.000 description 1
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- 231100000614 poison Toxicity 0.000 description 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
I式化合物及其药理上可接受的盐具有有效的抗病毒活性:
Description
本发明涉及抗病毒化合物及其应用,此类化合物的制备方法和用于此方法中的中间体。
将抗病毒化合物叠氮胸苷(AZT)在临床上用于抵预人体免疫缺损病毒(HIV)是有缺陷的。例如对骨髓细胞有毒性,现已发现,本发明的化合物有降低此类毒性的前景。
本发明包括Ⅰ式化合物及其药理上可接受的盐(例如:盐酸盐):
其中R1表示脂肪烃基,例如烷基,特别是C1-C6烷基;
Ar表示取代的或未取代的芳环;
X表示-SO2-或-CO-;
R2和R3通常相同,但也可以不同。它们表示式(a),(b),(c),(d),(e),(f),(g),(h)或(i)的基团。
其中B表示式(A),(G),(C),(H)或(T)的核苷碱残基:
若当R2和R3同时表示未取代的式(a)基团时,B表示式(A),(G),(C)或(H)的核苷碱残基。(A),(G),(C),(H)和(T)分别表示腺苷,鸟嘌呤,胞嘧啶,次黄嘌呤和胸腺嘧啶基团是较好的。
一般来说,Ar表示苯环,基团R1X和磷酸脂取代基彼此相互处于苯环的对位上时,通常此苯环不再有另外的取代基。
而当Ar表示取代的芳环时,每个取代基的出现。通常能够使得该化合物能易于水解成相应的酚,即无过度毒性的R1XArOH。
虽然Ar表示未取代的苯环更可取,但也可表示为至多有四个取代基的环。这些取代基中特别有兴趣的是是卤素,例如氯,氟烷基,例如三氟甲基、二氟甲基、一氟甲基,烷氧基,例如C1-C4烷氧基,氟烷氧基,羰烷氧基,例如C1-C6羰烷氧基,氨基和酰氨基。烷基R1通常不是支链的,较典型的是甲基,而X表示磺酰基更可取。
基团R2和R3主要包括:(ⅰ)-(ⅹ),特别是((ⅰ),(ⅴ),(ⅵ)和(ⅸ)。
可见,化合物中的基团(ⅰ)-(ⅵ)是较好的,它们可以用缩写名称来表示:(ⅰ)AZT,(ⅱ)d4C,(ⅲ)d4A,(ⅳ)d2A,(ⅴ)d4T,(ⅵ)ddI。
另一方面本发明化合物可通过式Ⅲ的二卤代磷酸酯:R1XArOP(O)。Y2(其中Y表示卤素,例如氯)和式R2OH化合物(例如叠氮胸苷)或其衍生物,例如核苷碱基被保护的衍生物,象胞嘧啶的自由氨基被乙酰化的衍生物之间的反应而制得。上述反应通常在碱存在下进行,例如1-甲基咪唑,典型的是在非质子溶剂如乙腈中进行。
另外,当X为SO2时,按照本发明Ⅰ式化合物还可以通过氧化Ⅳ式化合物:R1SArOP(O)(OR2)(OR3)或式(Ⅴ)的化合物:R1SOArOP(O)(OR2)(OR3),来制得。典型的氧化反应是用过酸如3-氯过苯甲酸进行的。
本发明还包括式Ⅳ和式Ⅴ的中间体化合物。
本发明化合物已发现可用于治疗和预防人的还原病毒感染,特别是引起获得性免疫系统缺损综合征(AIDS)的人的免疫系统缺损病毒(HIV)的感染。
因之,本发明还包括Ⅰ式化合物在治疗上的应用及Ⅰ式化合物用于制备可治疗或预防人的还原病毒感染,特别是HIV或称为获得性免疫缺损综合征的的病毒感染的药物。
药物的剂型和剂量可参考已知的治疗或预防上的常规方法而确定,通常Ⅰ式化合物的剂量要低于相应的AZT的量,并在大约50到800mg的范围内。
当活性的Ⅰ式化合物及其药理上可以接受的盐能够单独服用时,那么将此活性化合物直接当作药物配方将是较为可取的。本发明用于药物上的配方包括:该活性化合物,一种或多种药理上可以接受的载体及其它一些组份,这些组份本身具有治疗作用,或与Ⅰ式化合物有协同作用。或是兼有两种作用的组份。载体必须是药理上可以接受的,也就是与配方中其它一些组分相匹配,且对受者无害。
本发明进一步提供了由Ⅰ式化合物(自由碱基或药物上可以接受的酸加成盐形式)与其药理上可以接受的载体组成的药物配方。
此配方包括那些适合于口服,直肠、皮表或非肠道的(包括皮下、肌肉和静脉内)给药的配方。
该配方可以方便地以单位剂形存在并且可通过药学领域中众所周知的方法制备。一般,所有的方法都包括将活性化合物与一载体相结合的步骤。此载体可含有一种或多种附加成分。配方制备方法通常是将活性化合物与一液体载体或一精细分散的固体的载体或上述两者均匀并紧密地结合。如果必要,也可将产物成形。
适合于口服的本发明的配方可以是不连续单元的形式,例如每一种都含有定量的活性化合物的胶囊、扁囊剂、片剂或锭剂,又如散剂或粒剂;或水的或非水的液体悬浮液,如糖浆、酏剂、乳剂或饮剂。活性化合物也可以作成药团,干药糖剂或糊剂。
片剂可通过压制或印模的方法制得,可任意含有一种或多种附加成分。压制的片剂可在合适的机器上将自由流动形式的活性化合物如散剂或粒剂任意地与粘合剂、润滑剂、惰性稀释剂、表面活性剂或分散剂相混合压制而成。印模制成的片剂可在合适的机器上将活性化合物的粉末和任何合适的载体组成的混合物用印模的方法制得。
糖浆可以通过将活性化合物加到浓的糖水(如蔗糖)溶液中的方法制得。其中可加入一些附加成分,这些附加成分包括:调味品,糖的析晶阻止剂或者增加其它成分溶解度的增溶剂,如多羟基醇象甘油或山梨醇。
直肠使用的配方通常是含有常用载体如可可脂的栓剂。
适于非肠道使用的配方最好是由无菌的与服药者血液等渗的活性化合物的水制剂。
除了前述的附加成分外,本发明的配方如软膏、乳膏等中还可包括的一种或多种附加成分均可选自于稀释剂、缓冲剂、调味剂、粘合剂、表面活性剂、增稠剂、润滑剂、防腐剂(包括抗氧化剂)等。
本发明通过以下实施例说明:
实施例1
4-(甲磺酰基)苯基-双-(3′-叠氮胸苷-5′-基)磷酸酯的制备。
A.4-(甲磺酰基)苯基二氯代磷酸酯
4-(甲硫代)苯基二氯代磷酸酯
向新蒸馏出的磷酰基氯(45ml,0.5mol)和1-甲基咪唑(0.15ml)的溶液中加入4-(甲基硫代)苯酚(14g,0.1mol),将溶液加热回流20小时,蒸馏除去过量的磷酰基氯,将残余物减压蒸馏,得产品(11g,产率42%),熔点135-142℃(2mmHg),1HNMR(CDCl3):δ2.39(3H,S,SCH3),7.22(4H,S,苯基)。
4-(甲磺酰基)苯酚
向4-(甲硫代)苯酚(7.0g,0.05mol)的30%甲醇水(100ml)的溶液中于0℃加入高碘酸钠(10.7g,0.05mmol)的溶液。将得到的悬浮液搅拌30分钟,然后加入水(500ml),过滤除去沉淀。滤液冷却至4℃,再加入另一部分高碘酸钠(10.7g,0.05mmol),得到的悬浮液搅拌48小时后再加入另一部分高碘酸钠(5.35g,0.025mmol),搅拌18小时后,过滤除去沉淀,滤液用乙醚提取,将乙醚蒸干,残余物于硅胶柱上纯化,以氯仿∶甲醇9∶1为洗脱剂,得标题化合物(2.75g,产率32%),分析结果:(C7H3O3S),C,H。
4-(甲磺酰基)苯基二氯代磷酸酯
将4-(甲硫代)苯酚(3.0g,17mmol)和新蒸馏出的磷酰基氯(13.35ml,87mmol)及1-甲基咪唑(0.05ml)加热回流20小时,蒸馏除去过量的磷酰基氯,残余物减压蒸馏得到标题化合物(熔点185℃,1mmHg)为黄色油状物,冷却后固化(500mg,产率10%),分析结果:(游离酸C7H9O6S)C,H。
B.4-(甲磺酰基)苯基-双-(3′-叠氮胸苷-5′-基)-磷酸酯
于室温、干燥氮气下,将4-(甲磺酰基)苯基二氯代磷酸酯(52mg,0.18mmol),1-甲基咪唑(0.08ml,0.92mmol)和无水乙腈(3ml)搅拌5分钟,接着加入1ml叠氮胸腺嘧啶脱氧核甙(80mg,0.3mmol)的无水乙腈溶液,得到的悬浮液于室温搅拌过夜。在CHCl3∶MeoH为9∶1时,反应混合物的薄层层析(TLC)显示出移动较慢的色点仅约点25%。此时加入另一份等量的4-(甲磺酰基)苯基二氯代磷酸酯和1-甲基咪唑的无水乙腈溶液,将反应混合物再搅拌48小时,TLC显示约90%转变成为移动较慢的组分。加入磷酸盐缓冲液(15ml,PH为6.0)后,混合物用氯仿(4×10ml)萃取,氯仿萃取液用水洗,然后用硫酸镁干燥。减压蒸掉氯仿,残余物预吸收于硅胶上,在短的硅胶柱(80g,7734型)上以氯仿∶甲醇9∶1洗脱,将合适的组分浓缩得一白色固体(115mg,52%)。
NMR:
(1H)δ(d6DMSO):11.36(2H,S,NH)7.95(2H,d,苯基)7.5S(2H,d,H-6)7.45(2H,d,苯基),6.14(2H,t,-H-11),4.4S(2H,m,H-31),
20 4.04(2H,m,H-41),3.42(4H,m,H-S1),3.21(3H,S,SO2CH3),2.44(4H,m,H-21),1.71(6H,S,CH3)
元素分析:
测定值:C,42.9;H,4.5;N,18.9;C27H31N10O12P5 计算值C,43.2;H,4.16;N,18.66。
25 Mass:
M/Z751(M+H)+.773(M+Na)+
实施例2
通过4-(甲硫代)苯基类似物制备4-(甲磺酰基)苯基-双-(3′-叠氮胸苷-5′-基)磷酸酯
将4-(甲硫代)苯基-双-(3′-叠氮胸苷-5′-基)磷酸酯(144mg,0.2mmol,由4-(甲硫代)苯基二氯代磷酸酯(实施例1A)和叠氮胸苷反应制得)溶解在无水乙醇中并冷却至0℃。搅拌下于15分钟内滴加3-氯代过苯甲酸(107mg,0.6mmol)的无水乙醇(15ml)溶液,将得到的溶液于5℃放置过夜后,TLC(氯仿δ-甲醇9∶1)显示转变成为移动较慢的组分的量约占90%。减压蒸除溶剂,残余物用硅胶预吸收,于硅胶柱(10g,9385型)上以氯仿-甲醇9∶1洗脱,将合适的组分浓缩,用色谱板(2mm薄板,相同的溶剂系统)进一步纯化,分离出的产品为白色固体(105mg,70%)。
化合物4-(甲磺酰基)苯基-双-(3′-叠氮胸苷-5′-基)磷酸酯样品通过HPLC的反相色谱分析显示含有4个组分:作为微量组分的叠氮胸苷(AZT),4-(甲磺酰基)苯基-双-3′-叠氮胸苷-5′-基磷酸酯,较后出现的在酯链上无侧链的化合物和一未确定组分。
此样品用于下述抗病毒试验的检定,其质量认为是合适的。
抗-HIV试验
检定试验是通过在96井微量滴定板内被HIV3B IOTCID50感染的MT4细胞系完成的。每个化合物的抗病毒活性和细胞毒性是同时检定的。在每一块板中,可以筛选3个化合物,除有其它说明外,每一化合物的试验浓度均为100.0,10.0,1.0和0.1μm,且每次检定中都含有作为正对照标准的AZT,其浓度为10.0,1.0,0.1和0.01μm。
在37℃恒温下维持5天后,通过与感染或未感染的对照标准相比较计算出活细胞的数目,可以测定出每一个化合物的抗病毒活性(感染细胞)和细胞毒性(未感染细胞)。活细胞的数目可以用加入四唑染料MTT的方法来确定。MTT被吸收并转变成兰色甲替(FOrmazan)衍生物是和活性细胞的数目成线性关系的。随着MTT的加入,细胞随酸化的异丙醇发生增溶,并可用分光光度法测出MTT转化的程度。
通过化合物保护细胞使其不受病毒引起细胞病作用的能力,说明了它的抗病毒活性是明显的。所记述的结果是在指定浓度下被保护细胞的百分数。
测定结果 下表中说明:
表1
保护百分数(%)
BTG1704的浓度:100 10 1.0 0.1 0.01 0.001μm MTC
抗病毒活性:13% 79% 91% 91% 21% 9% 100μm
从表1可以看出,当BTG1704的浓度介于0.1到10μm之间时,其保护MT4细胞使不受HIV-1细胞病作用的能力是显著的。药物的有毒浓度约为100μm,但这并非是有关细胞毒性的定量试验。
实施例3:
4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧胞苷-5′-基)磷酸酯
N4-乙酰基-2′,3′-二脱氢-2′,3′-二脱氧胞苷:
将悬浮于无水甲醇(10000ml)中的2′,3′-二脱氢-2′,3′-二脱氧胞苷(36.2mmol)加热回流,每小时加入4次无水的乙酸酐(10ml,106mmol;总量为40ml,0.42mol),最后在回流温度下将反应混合物搅拌6小时,然后于室温放置过夜,将沉淀的结晶滤出,用乙醇洗(产率73%)。
4-(甲硫代)苯基-双-(N4-乙酰基-2′,3′-二脱氢-2′,3′-二脱氧胞苷-5′-基)磷酸酯
将4-(甲硫代)苯基二氯代磷酸酯、干燥的1-甲基咪唑和无水乙腈剧烈搅拌5分钟,然后加入到N4-乙酰基-2′,3′-二脱氢-2′,3′-二脱氧胞苷的乙腈溶液中,于室温搅拌数小时后,加入磷酸盐缓冲液(PH为6.0),用氯仿萃取混合物,氯仿萃取液用水洗后用硫酸镁干燥。减压蒸除氯仿,残余物用硅胶预吸收,在短的硅胶柱上洗脱,得到的物质进一步用层析板纯化(2mm薄板),然后分离出产品。
4-(甲硫代)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧胞苷-5′-基)磷酸酯
于室温下,将4-(甲硫代)苯基-双-(N4-乙酰基-2′,3′-二脱氢-2′,3′-二脱氧胞苷-5′-基)磷酸酯和碳酸钾的甲醇溶液搅拌20小时,然后减压蒸除溶剂,残余物用硅胶预吸收,在短的硅胶柱上洗脱,分离出产品。
4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧胞苷-5′-基)磷酸酯
将4-(硫代苯基)-双-(2′,3′-二脱氢-2′,-3′-二脱氧胞苷-5′-基)磷酸酯溶解在无水乙醇中并冷却至0℃,在约10分钟内搅拌下滴加3-氯过苯甲酸溶液,混合物于5℃下放置15小时后,TLC显示出起始原料已全部转变成其中含有微少杂质的主要组分,减压蒸除溶剂,残余物用-2mm层析板在少量氯仿下展开,重复此纯化过程并分离出产品。
实施例4
4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧腺苷-5′-基)磷酸酯
将4-(甲磺酰基)苯基二氯代磷酸酯(86mg,0.3mmol),无水1-甲基咪唑(0.13ml,1.4mmol)和无水吡啶(20ml)搅拌5分钟,然后加入到2′,3′-二脱氢-2′,3′-二脱氧腺苷(100mg,0.4mmol)中,室温下,将反应混合物剧烈搅拌18小时,TLC显示起始原料转变成移动较慢的组分约占50%,再加入一份“磷酰化剂”(86mg,0.3mmol和0.13ml,1.4mmol 1-甲基咪唑)并搅拌24小时后,TLC显示转化成移动较慢的组分的量仍为约50%。将反应混合物减压蒸馏至干,残余物用硅胶预吸收,在硅胶柱上以氯仿∶甲醇10∶1洗脱,合并得到的组分并蒸干,然后溶解在微量氯仿中并加入环乙烷后研磨,得产品(23mg,产率16%)。
NMR:δ(d6DMSO)3.19(3H,S,SO2CH3)4.24(2H,S,2x H-5′),5.04(2H,S,2X H-4′),6.26(2H,t,2X H-1′),6.42(2H,s,2x H-3′),6.96(2H,s,2x H-2′),7.32(4H,d,2x NH2),7.22-7.77(4H,dd,苯基),8.07(2H,d,2x H-2),8.16(2H,s,2x H-8)
FAB Mass:m/z683〔M+H〕+
实施例5
4-(甲磺酰基)苯基-双-(2′,3′-二脱氧腺苷-5′-基)磷酸酯
将4-(甲磺酰基)苯基二氯代磷酸酯(87mg,0.3mmol),无水1-甲基咪唑(0.13ml,1.4mmol)和无水吡啶(20ml)搅拌5分钟,然后加入到2′,3′-二脱氧腺苷(120mg,0.5mmol)中。于室温通入氮气的条件下,将反应混合物搅拌16小时。TLC显示起始原料转变成移动较慢的组分的量约为40%。再加入另一份“磷酰化试剂”(87mg,0.3mmol和0.13ml,0.3mmol1-甲基咪唑)并将反应混合物再搅拌24小时,将反应混合物减压蒸干,残余物用硅胶预吸收,于硅胶柱层析上以二氯甲烷∶甲醇20∶3洗脱。
NMR:δ(d6DMSO)2.08(4H,m,2x H-2′),2.80(4H,m,2x H-3′),3.92(4H,m,2x H-5′),4.26(2H,s,2x H-4′),6.24(2H,m,2x H-1′)7.26(4H,s,2x NH2),7.31-7.84(4H,m,苯基),8.13(2H,s,2x H-2),8.27(2H,s,2x H-8).
FAB Mass:m/z 687〔M+H〕+
实施例6
4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧胸苷-5′-基)磷酸酯
将4-(甲磺酰基)苯基二氯代磷酸酯(58mg,0.2mmol),无水1-甲基咪唑(85μl,1.0mmol)和无水乙腈(5ml)剧烈搅拌5分钟,然后加入到2′,3′-二脱氢-2′,3′-二脱氧胸苷(70mg,0.3mmol)的无水乙腈(5ml)溶液中,于室温通氮气的条件下搅拌17小时,TLC(氯仿∶甲醇=10∶1)显示转变成移动较慢组分的量约为60%。再加入一份“磷酰化剂”(22mg,0.1mmol和0.4ml,0.4mmol 1-甲基咪唑),搅拌26小时后,再加入一份“磷酸化剂”(13mg,0.05mmol和0.4ml,0.4mmol 1-甲基咪唑)在37℃将反应混合物搅拌18小时,但TLC显示60%的转化率并没有丝毫提高,当加入磷酸盐缓冲液(20ml,PH6.0)后,用氯仿萃取混合物,干燥有机层(硫酸镁),然后减压蒸馏至干,残余物经过硅胶柱层析以乙醚∶甲醇5∶1为洗脱剂而纯化,得产品(35mg,产率34%)。
NMR:δ(d6DMSO)1.65(6H,d,2x CH3)3.25(3H,s,SO2CH3),4.35(4H,m,2x H-5′),4.95(2H,s,2x H-4′),6.05(2H,m,2x H-3′),6.40(2H,m,2x H-2′),6.85(2H,s,2x H-1′),7.25-7.40(4H,dd,苯基),7.90(2H,m,2x H-6),11.35(2H,d,2x NH).
FAB Mass:m/z 665〔M+H〕+
元素分析:
测定值:C,48.9;H,4.6;N,8.5
C27H29O12N4PS计算值C,48.8;H4.4;N,8.4%
Claims (25)
2、根据权利要求1的化合物,其中Ar表示取代的或未取代的苯环。
3、根据权利要求2的化合物,其中R1X基和磷酸酯取代基处在对位上。
4、根据权利要求1的化合物,其中Ar表示取代的芳环,并可使Ⅰ式化合物容易水解成相应的无过度毒性的酚R1XArOH。
5、根据权利要求1的化合物,其中Ar表示一取代或多取代的苯环,其可以是下列相同或不相同的取代基:卤素,氟烷基,烷氧基,氟烷氧基,羰烷氧基,氨基或酰氨基。
6、根据权利要求1的化合物,其中X表示磺酰基。
7、根据在前的任何一项权利要求的化合物,其中R2和R3各自表示式(a),(b),(d)或(f)基团。
8、根据权利要求7的化合物,其中R2和R3各自表示如在上文定义的式(f)基团。
9、根据权利要求7的化合物,其中R2和R3各自表示式(ⅰ)到(Ⅹ)的任何基团:
10、根据权利要求9的化合物,其中R2和R3各自表示式(ⅰ),(ⅴ),(ⅵ)或(ⅸ)。
11、4-(甲磺酰基)苯基-双-(3′叠氮胸苷-5′-基)磷酸酯。
12、4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧胞苷-5′-基)磷酸酯。
13、4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧腺苷-5′-基)磷酸酯。
14、4-(甲磺酰基)苯基-双-(2′,3′-二脱氧腺苷-5′-基)磷酸酯。
15、4-(甲磺酰基)苯基-双-(2′,3′-二脱氢-2′,3′-二脱氧胸苷-5′-基)磷酸酯。
16、制备Ⅰ式化合物的方法,其中包括将Ⅲ式二卤代磷酸酯:R1XArOP(O)Y2
其中R1表示脂肪烃基;
X表示-SO2-或-CO-;
Y表示卤素
与式R2OH化合物反应,R2如上文定义,或与R2中的核苷碱被保护的R2OH的衍生物反应。
17、根据权利要求16的方法,其中R2中的核苷碱基是乙酰化胞嘧啶。
18、根据权利要求16或17的方法,其中反应是在碱存在下进行。
19、根据权利要求18的方法,其中的碱是1-甲基咪唑。
20、制备Ⅰ式化合物的方法,其中将式ⅣR1SArOP(O)(OR2)(OR3)或式ⅤR1SOArOP(O)(OR2)(OR3)化合物氧化,其中的R1Ar,R2和R3如上文定义。
21、根据权利要求20的方法,其中的氧化作用使用过酸。
22、如上文定义的式Ⅳ的中间体化合物。
23、如上文定义的式Ⅴ的中间体化合物。
24、如上文定义的Ⅰ式化合物在治疗上的应用。
25、如上文定义的Ⅰ式化合物用于制备治疗或预防人的还原-病毒感染的药物。
26、治疗或预防人的还原病毒感染的方法,其中包括让被病毒感染的个体服用抑制或阻止病毒复制有效量的Ⅰ式化合物。
27、治疗或预防人的还原病毒感染的方法,其中包括用效量的可抑制或阻止病毒复制的Ⅰ式化合物来治疗被病毒感染的血液。
28、根据权利要求26或27的方法,其中的病毒是人的免疫系统缺损病毒(HIV)。
29、由Ⅰ式化合物及其药理上可以接受的载体构成的用于治疗或预防人的还原病毒感染的配方。
30、根据权利要求29的配方,是以剂型存在的。
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GB898908355A GB8908355D0 (en) | 1988-04-18 | 1989-04-13 | Output apparatus antiviral compounds |
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JP (1) | JPH03505880A (zh) |
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GB (1) | GB2230266B (zh) |
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OA (1) | OA09553A (zh) |
PT (1) | PT93743A (zh) |
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US6903224B2 (en) | 1988-04-11 | 2005-06-07 | Biochem Pharma Inc. | Substituted 1,3-oxathiolanes |
US7119202B1 (en) | 1989-02-08 | 2006-10-10 | Glaxo Wellcome Inc. | Substituted-1,3-oxathiolanes and substituted-1,3-dioxolanes with antiviral properties |
US5270315A (en) * | 1988-04-11 | 1993-12-14 | Biochem Pharma Inc. | 4-(purinyl bases)-substituted-1,3-dioxlanes |
US6350753B1 (en) | 1988-04-11 | 2002-02-26 | Biochem Pharma Inc. | 2-Substituted-4-substituted-1,3-dioxolanes and use thereof |
UA45942A (uk) * | 1989-02-08 | 2002-05-15 | Біокем Фарма, Інк. | 1,3-оксатіолан, його похідні, спосіб (варіанти) його одержання та фармацевтична композиція |
MY104575A (en) * | 1989-12-22 | 1994-04-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
US5204466A (en) * | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
US6642245B1 (en) | 1990-02-01 | 2003-11-04 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
US5728575A (en) | 1990-02-01 | 1998-03-17 | Emory University | Method of resolution of 1,3-oxathiolane nucleoside enantiomers |
US5276151A (en) * | 1990-02-01 | 1994-01-04 | Emory University | Method of synthesis of 1,3-dioxolane nucleosides |
US6703396B1 (en) | 1990-02-01 | 2004-03-09 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers |
GB9009861D0 (en) | 1990-05-02 | 1990-06-27 | Glaxo Group Ltd | Chemical compounds |
US6228860B1 (en) | 1990-11-13 | 2001-05-08 | Biochem Pharma Inc. | Substituted 1,3-oxathiolanes with antiviral properties |
US6369066B1 (en) | 1990-11-13 | 2002-04-09 | Biochem Pharma, Inc. | Substituted 1,3-oxathiolanes with antiviral properties |
US5587480A (en) * | 1990-11-13 | 1996-12-24 | Biochem Pharma, Inc. | Substituted 1,3-oxathiolanes and substituted 1,3-dithiolanes with antiviral properties |
US5444063A (en) * | 1990-12-05 | 1995-08-22 | Emory University | Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity |
US5925643A (en) * | 1990-12-05 | 1999-07-20 | Emory University | Enantiomerically pure β-D-dioxolane-nucleosides |
AU1254892A (en) * | 1990-12-18 | 1992-07-22 | Sloan-Kettering Institute For Cancer Research | Novel synthesis of 2'-"up" fluorinated 2''-deoxy-arabinofuranosylpurines |
IL100502A (en) * | 1991-01-03 | 1995-12-08 | Iaf Biochem Int | PHARMACEUTICAL PREPARATIONS CONTAINING CIS-4-AMINO-1-) 2-HYDROXIMETHIL-1,3-OXETYOLEN-5-IL (- |
US6812233B1 (en) | 1991-03-06 | 2004-11-02 | Emory University | Therapeutic nucleosides |
US5817667A (en) * | 1991-04-17 | 1998-10-06 | University Of Georgia Research Foudation | Compounds and methods for the treatment of cancer |
GB9110874D0 (en) * | 1991-05-20 | 1991-07-10 | Iaf Biochem Int | Medicaments |
ZA923641B (en) * | 1991-05-21 | 1993-02-24 | Iaf Biochem Int | Processes for the diastereoselective synthesis of nucleosides |
FR2685331A1 (fr) * | 1991-12-12 | 1993-06-25 | Centre Nat Rech Scient | Phosphotriesters de la ddu, leur preparation et leur application en therapeutique. |
US5679652A (en) * | 1992-02-13 | 1997-10-21 | Schott; Herbert | Amphiphilic nucleosidephosphate analogues |
US6444656B1 (en) | 1992-12-23 | 2002-09-03 | Biochem Pharma, Inc. | Antiviral phosphonate nucleotides |
US6005107A (en) | 1992-12-23 | 1999-12-21 | Biochem Pharma, Inc. | Antiviral compounds |
GB9226879D0 (en) * | 1992-12-23 | 1993-02-17 | Iaf Biochem Int | Anti-viral compounds |
US20020120130A1 (en) | 1993-09-10 | 2002-08-29 | Gilles Gosselin | 2' or 3' -deoxy and 2', 3' -dideoxy-beta-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti- viral agents |
US5587362A (en) * | 1994-01-28 | 1996-12-24 | Univ. Of Ga Research Foundation | L-nucleosides |
HUT76331A (en) * | 1994-07-15 | 1997-08-28 | Lepetit Spa | Dinucleoside-5',5'-pyrophosphates |
IL115156A (en) | 1994-09-06 | 2000-07-16 | Univ Georgia | Pharmaceutical compositions for the treatment of cancer comprising 1-(2-hydroxymethyl-1,3-dioxolan-4-yl) cytosines |
US5703058A (en) | 1995-01-27 | 1997-12-30 | Emory University | Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent |
US6391859B1 (en) | 1995-01-27 | 2002-05-21 | Emory University | [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides |
US5808040A (en) * | 1995-01-30 | 1998-09-15 | Yale University | L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides |
AU722214B2 (en) | 1995-06-07 | 2000-07-27 | Centre National De La Recherche Scientifique (Cnrs) | Nucleosides with anti-hepatitis B virus activity |
US5753789A (en) * | 1996-07-26 | 1998-05-19 | Yale University | Oligonucleotides containing L-nucleosides |
WO2001012644A1 (en) * | 1999-08-17 | 2001-02-22 | Adani, Alexander | Dinucleoside 5',5'-tetraphosphates as inhibitors of viral reverse transcriptases and viruses |
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CA1330794C (en) * | 1987-03-27 | 1994-07-19 | Phillip Frost | Anti-viral compounds, dosage forms and methods |
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JPH03505880A (ja) | 1991-12-19 |
KR920700217A (ko) | 1992-02-19 |
CA2028151A1 (en) | 1990-10-14 |
DE69021242D1 (de) | 1995-09-07 |
ES2077643T3 (es) | 1995-12-01 |
PT93743A (pt) | 1990-11-20 |
GB2230266B (en) | 1992-08-12 |
GB9008105D0 (en) | 1990-06-06 |
WO1990012023A1 (en) | 1990-10-18 |
NZ233197A (en) | 1991-11-26 |
ZA902784B (en) | 1991-12-24 |
FI906113A0 (fi) | 1990-12-12 |
GB2230266A (en) | 1990-10-17 |
AU5407890A (en) | 1990-11-05 |
EP0392791A1 (en) | 1990-10-17 |
EP0392791B1 (en) | 1995-08-02 |
DE69021242T2 (de) | 1996-01-11 |
ATE125817T1 (de) | 1995-08-15 |
OA09553A (en) | 1993-01-31 |
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