JPH02124898A - Novel compound containing purine base, use thereof and intermediate - Google Patents
Novel compound containing purine base, use thereof and intermediateInfo
- Publication number
- JPH02124898A JPH02124898A JP1076455A JP7645589A JPH02124898A JP H02124898 A JPH02124898 A JP H02124898A JP 1076455 A JP1076455 A JP 1076455A JP 7645589 A JP7645589 A JP 7645589A JP H02124898 A JPH02124898 A JP H02124898A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- oxetanyl
- expressed
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 55
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000003443 antiviral agent Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 2
- LMJVXGOFWKVXAW-OXOINMOOSA-N oxetanocin A Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H]1CO LMJVXGOFWKVXAW-OXOINMOOSA-N 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 231100000636 lethal dose Toxicity 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZTWYAIASAJSBMA-UHFFFAOYSA-N 8-azido-7h-purin-6-amine Chemical compound NC1=NC=NC2=C1NC(N=[N+]=[N-])=N2 ZTWYAIASAJSBMA-UHFFFAOYSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 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
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- DVGWFQILDUEEGX-UUOKFMHZSA-N (2r,3r,4s,5r)-2-(6,8-diaminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound NC1=NC2=C(N)N=CN=C2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O DVGWFQILDUEEGX-UUOKFMHZSA-N 0.000 description 1
- PFUVOLUPRFCPMN-UHFFFAOYSA-N 7h-purine-6,8-diamine Chemical compound C1=NC(N)=C2NC(N)=NC2=N1 PFUVOLUPRFCPMN-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 241000004176 Alphacoronavirus Species 0.000 description 1
- 241000712891 Arenavirus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 108010059712 Pronase Proteins 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- -1 acetoxymethyl Chemical group 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001512 anti-cytomegaloviral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000003438 effect on compound Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明の新規化合物は、抗ウィルス作用を有し医薬品と
して期待される。[Detailed Description of the Invention] [Industrial Application Field] The novel compound of the present invention has antiviral activity and is expected to be used as a pharmaceutical.
プリンヌクレオシドであるアデノシンから、８、−アジ
ドおよび８−アミノアデノシンを合成する方法（Ｊ、
Ａｍ、 Ｃｈｅｗ、 Ｓａｃ、、 ８７．１７７２ （
１９６５））が知られている。Method for synthesizing 8,-azide and 8-aminoadenosine from adenosine, a purine nucleoside (J,
Am, Chew, Sac,, 87.1772 (
1965)) is known.
ウィルス怒染症分野においては、その性質が千差万別で
あるため、その治療には常に新規物質が要望されている
。In the field of viral infectious diseases, there is a wide variety of properties, so new substances are always needed for the treatment.
（課題を解決するための手段〕
本発明者らは種々研究した結果、式（１）（式中、Ｒは
アジド基またはアミノ基を示す、）で表されるプリン塩
基を存する新規化合物及びその薬理学上許容される塩が
抗ウィルス作用を有し、抗ウィルス剤の有効成分となる
ことを見出し本発明を完成した。(Means for Solving the Problems) As a result of various studies, the present inventors have discovered a novel compound containing a purine base represented by formula (1) (wherein R represents an azido group or an amino group) and its The present invention was completed by discovering that a pharmacologically acceptable salt has an antiviral effect and can be used as an active ingredient of an antiviral agent.
（式中、Ｘは臭素、塩素等のハロゲン原子を、Ｙはアセ
チル基等のアシル基を示す）で表される化合物に関する
。(wherein, X represents a halogen atom such as bromine or chlorine, and Y represents an acyl group such as an acetyl group).
化合物（１）は酸と塩を形成するが、塩を形成するため
の酸としては、薬理学上許容される酸であればよ（、例
えば、塩酸、硫酸、リン酸などが好ましい。Compound (1) forms a salt with an acid, and the acid for forming the salt may be any pharmacologically acceptable acid (for example, hydrochloric acid, sulfuric acid, phosphoric acid, etc. are preferable).
本発明化合物（１）は、アデニン塩基を有する化合物（
２）（特開昭６１−２９３９９２号参照）を原料として
、例えば下記に示す反応経路を経て合成することができ
る。The compound (1) of the present invention is a compound having an adenine base (
2) (see JP-A-61-293992) as a raw material, it can be synthesized, for example, through the reaction route shown below.
−〉
即ち、化合物（２）をトリエチルアミン存在下で無水酢
酸と反応させて化合物（３）を得、次いでクロロホルム
中Ｎ−ブロムアセトアミドで臭素化して本発明化合物（
４）を得る。-> That is, compound (2) is reacted with acetic anhydride in the presence of triethylamine to obtain compound (3), which is then brominated with N-bromoacetamide in chloroform to obtain the compound of the present invention (
4) is obtained.
次にエタノール中アジ化ナトリウムを反応させて化合物
（５）とした後、メタノール中アンモニアを反応させて
水酸基の保護基を除去することにより、本発明化合物の
１つである化合物（１ａ）を得ることができる。もう１
つの本発明化合物（１ｂ）は、化合物（１ａ）を水−メ
タノール中、パラジウム−炭素触媒存在下、水素ガスで
還元することにより得ることができる。Next, after reacting with sodium azide in ethanol to obtain compound (5), ammonia in methanol is reacted to remove the hydroxyl protecting group to obtain compound (1a), which is one of the compounds of the present invention. be able to. One more
Compound (1b) of the present invention can be obtained by reducing compound (1a) with hydrogen gas in water-methanol in the presence of a palladium-carbon catalyst.
なお、上記反応は一興体例として挙げたが、化合１７１
（２）の水酸基は常法どおりアシル化して保護基を導入
し、更に８位をハロゲン化することにより本発明化合物
（４′）を得ることが出来、これを更に同様に反応させ
ると化合物（ｌａ） 、（ｌｂ）を得ることが出来る。Note that the above reaction was given as an example of a compound, but compound 171
The hydroxyl group of (2) is acylated in a conventional manner to introduce a protecting group, and the 8-position is further halogenated to obtain the compound (4') of the present invention, which is further reacted in the same manner to obtain the compound (4'). la) and (lb) can be obtained.
この様にして得られた化合物（１）（以下、その塩も含
む）は、後記の如く抗ウィルス作用を有する医薬品とし
て極めて有用である。医薬品として使用する場合の製剤
化および投与方法は従来公知の種々の方法が適用できる
。即ち、投与方法としては注射、経口、直腸投与などが
可能である。The compound (1) thus obtained (hereinafter also including its salt) is extremely useful as a pharmaceutical having antiviral action as described below. When used as a pharmaceutical, various conventionally known methods can be used for formulation and administration. That is, possible administration methods include injection, oral administration, and rectal administration.
製剤形態としては注射剤、粉末剤、顆粒剤、錠剤、坐剤
などの形態がとり得る。The formulation may be in the form of injections, powders, granules, tablets, suppositories, etc.
製剤化の際には化合物（１）に悪影響を与えない限り、
医薬用に用いられる種々の補助剤、即ち、担体やその他
の助剤、例えば安定剤、防腐剤、無痛化荊、乳化剤等が
必要に応じて使用されうる。When formulating, as long as it does not have an adverse effect on compound (1),
Various auxiliaries used in medicine, ie, carriers and other auxiliaries, such as stabilizers, preservatives, soothing agents, emulsifiers, etc., may be used as necessary.
製剤において、化合物（１）の含量は製剤形態等により
広範囲に変えることが可能であり、一般には化合物（り
を０．０１〜１００％（重量）、好ましくは０．１〜７
０％（重量）含有し、残りは通常医薬用に使用される担
体その他の補助剤からなる。In the formulation, the content of compound (1) can be varied widely depending on the formulation form, etc., and generally the content of compound (1) is 0.01 to 100% (by weight), preferably 0.1 to 7.
It contains 0% (by weight), and the rest consists of carriers and other auxiliaries commonly used for pharmaceutical purposes.
化合物（１）の投与量は症状等により異なるが、成人１
人１日当り０．０１〜８００ ｒｒｔ程度である。遠投
を必要とする場合には用量をおさえることが好ましい。The dosage of compound (1) varies depending on symptoms, etc., but for adults 1
It is about 0.01 to 800 rrt per person per day. When long-distance casting is required, it is preferable to reduce the dose.
化合物（１）の製剤化には通常、塩酸塩や硫酸塩などの
医薬用に許容される塩の形で用いられる。Compound (1) is usually used in the form of pharmaceutically acceptable salts such as hydrochloride and sulfate.
本発明の抗ウィルス剤は次のようなウィルスに対し使用
できる。The antiviral agent of the present invention can be used against the following viruses.
ポックスウィルス
ヘルペスウィルス（サイトメガロウィルスなど）アデノ
ウィルス
バボバウイルス
ヘパドナウィルス（Ｂ型肝炎ウィルスなど）パルボウイ
ルス
ラブドウィルス
バラミクソウィルス
アレナウイルス
レトロウィルス（ＨＩ Ｖウィルスなど）コロナウィル
ス
プニャウイルス
トガウィルス
ピコルナウィルス
レオウィルス
〔作用〕
次に本発明化合物（１）の抗ウィルス活性及び急性致死
量について示す。Poxviruses Herpesviruses (such as Cytomegalovirus) Adenovirus Babovavirus Hepadnavirus (such as Hepatitis B virus) Parvovirus Rhabdovirus Balamyxovirus Arenavirus Retrovirus (such as HIV virus) Coronavirus Punyavirus Togavirus Picornavirus Reovirus [Effect] Next, the antiviral activity and acute lethal dose of the compound (1) of the present invention will be shown.
（１）サイトメガロウィルス抑制作用
人胎児線維芽細胞の単層を存する３５ｍ５＋デイシエ（
ｄｉｓｈ）にサイドメガロンウィルス（ＡＯ１６９株）
！００Ｐ Ｆ Ｕ （Ｐｌａｑｕｅ ＦｏｒｍｌｎｇＵ
ｎｉｔ）を感染させ、１時間吸着後、各）】度の化合物
（１）を含む培地〔０，５％アガロース（ａｇａｒｏｓ
ｅ）、２％生胎児血清（ｆｅｔａｌｃａｌｆ ｓｅｒｕ
ｍ） ）で重層し、３７℃、５％（ｖ／ｖ）の炭酸ガス
フ卵器中にてｌＯ日間培養した後プラーク（Ｐｌａｑｕ
ｅ）形成を測定し、５０％抑制値（ＩＣｓ’）を求めた
。その結果を表１に示した。(1) Cytomegalovirus inhibitory effect 35m5+ Dacie containing a monolayer of human fetal fibroblasts (
side megalon virus (AO169 strain) in dish)
! 00P F U (Plaque Formng U
nit), and after adsorption for 1 hour, a medium containing compound (1) [0.5% agarose
e), 2% live fetal serum (fetalcalf serum)
After culturing for 10 days at 37°C in an incubator with 5% (v/v) carbon dioxide gas, plaque
e) Formation was measured and 50% inhibition values (ICs') were determined. The results are shown in Table 1.
表１ 化合物（１）の抗サイトメガロウィルス活性
（２）Ｂ型肝炎ウィルス抑制作用
活性Ｂ型肝炎ウィルスを産生放出する培養肝細胞株ＨＢ
６１１（Ｐｒｏｃ、 Ｎａｔｌ、 Ａｃａｄ、 Ｓｃｌ
、 ＵＳＡ、 ８４゜４４４ （１９８７））をＤａｌ
ｂｅｃｃｏに従い−ｏｄｉｆｉｅｄ Ｉｌ：ａｇｌｅ培
地（ＧＩＢＧＯ）中にて１０％子牛脂児血清、２００
μｇ／ｄ０４１Ｂ、ペニシリンおよびストレプトマイシ
ン（各１００ μ／−）存在下に３７℃、５坏ＣＯ，を
用いて培養する。６穴プレートに５ Ｘ ｌｏ’ｃｅｌ
ｌ／穴（３５１１１）となるよう接種し、１〜２日後５
０％コンフルエントとなったところで各濃度の化合物（
１）を加えて培養、以降３日毎に同じ濃度に薬剤を含む
培地と交換しつつ１５日間培養を続けた後培地を除去す
る。Table 1 Anti-cytomegalovirus activity of compound (1) (2) Hepatitis B virus inhibitory activity Cultured liver cell line HB that produces and releases hepatitis B virus
611 (Proc, Natl, Acad, Scl
, USA, 84°444 (1987)) by Dal
10% calf fat serum in agle medium (GIBGO), 200 g
Pg/d041B, penicillin and streptomycin (100 μ/− each) are cultured at 37° C. and CO2. 5 x lo'cel in 6-well plate
1/hole (35111), 1-2 days later 5
At 0% confluence, each concentration of compound (
1) was added and cultured. Afterwards, the culture medium was continued for 15 days, replacing the medium with a medium containing the drug at the same concentration every 3 days, and then the medium was removed.
細胞を０，５−のリシスバ７ バー （ＬＹ！ｌｓ ｂ
ｕｆｆｅｒ）（１０ｓＭ Ｔｒｌｓ ＨＣＩ ｐＨ７，
８１５ｍＭ ＮａｔＥＤＴＡ 、 １％５ＯＳ１０、
ＩＱｒ／ ｍｌ Ｐｒｏｎａｓｅ Ｋ） にて３７℃
ｌｈｒ処理して溶解し、得られたＤＮＡをＲＮａｓｅ処
理、フェノール・クロロホルム処理エタノール沈澱法に
より純化した４次いで５μ、 ＤＮＡをＨｉｎｄ ｍ処
理し、サザン法ニヨって２１ｐ −標ｆｉＢ型肝炎ウィ
ルスＤＮＡをプローブとしてＤＮＡのパターンを分析し
た。Cells are 0,5-resis bar 7 bar (LY!ls b
buffer) (10sM Trls HCI pH7,
815mM NatEDTA, 1%5OS10,
IQr/ml Pronase K) at 37°C
The resulting DNA was purified by RNase treatment, phenol/chloroform treatment, and ethanol precipitation. The DNA pattern was analyzed as a probe.
その結果を表２に示した。The results are shown in Table 2.
表２
化合物（１
の抗Ｂ型肝炎ウイルス活性
（３）急性致死量
雌性ＣＤＦ 、マウス（体重２２−２５ｇ）を用い、化
合物（ｌａ）、化合物（１ｂ）の腹腔内投与における急
性致死量を求めた。Table 2 Anti-hepatitis B virus activity of compound (1) (3) Acute lethal dose Acute lethal dose of compound (la) and compound (1b) determined by intraperitoneal administration using female CDF and mice (body weight 22-25 g) Ta.
両物質を２０％に希釈した溶媒（体積比３５：６５のＤ
ＭＳＯとＴｗｅｅｎ ８０の混和溶液）に溶解し、それ
ぞれ公比２で１５０■／ｋｇから１２００■／ｋｇまで
の投与量を単回投与し、１４日目間観察した結果、化合
物（１ａ）では３００ｇ／ｋｉｒ以下に、化合物（１ｂ
）では６００ ｔｔ ／ ｋ＋ｒ以下に死亡を認めなか
った。A solvent in which both substances were diluted to 20% (D
Compound (1a) was dissolved in a mixed solution of MSO and Tween 80) and administered in a single dose from 150 μ/kg to 1200 μ/kg at a common ratio of 2, and observed for 14 days. /kir or less, the compound (1b
), no deaths were observed below 600 tt/k+r.
上記の結果から明らかなように本発明の式（１）で示さ
れる化合物は抗ウィルス活性を有し、又、低毒性であり
、かつ従来の核酸系抗生物質とその化学構造を異にする
ことから、新たな作用機作を有する新規抗ウィルス剤と
して期待されるものである。As is clear from the above results, the compound represented by formula (1) of the present invention has antiviral activity, has low toxicity, and has a chemical structure different from that of conventional nucleic acid antibiotics. Therefore, it is expected to be a new antiviral agent with a new mechanism of action.
以下に本発明の実施例を挙げて具体的に説明するが、本
発明はこれらに限定されるものではない。EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited thereto.
実施例１
９− （（２’Ｒ，３’Ｒ，４’Ｓ）−３’、４’−ビ
ス（ヒドロキシメチル）−２′−オキセタニル］８−ア
ジドアデニン〔化合物（ｌａ） ）の合成９− （（２
’Ｒ，３’Ｒ，４’Ｓ）−３’、４’−ビス（アセトキ
シメチル）−２′−オキセタニル〕８−アジドアデニン
〔化合物（５））０．４ｇをアンモニア飽和メタノール
２０−に溶解させ室温で１６時間攪拌した０反応終了後
、反応液を濃縮し残渣をシリカゲルカラムクロマトグラ
フィーで精製した。Example 1 Synthesis of 9-((2'R,3'R,4'S)-3',4'-bis(hydroxymethyl)-2'-oxetanyl]8-azidoadenine [compound (la)) 9 - ((2
Dissolve 0.4 g of 'R,3'R,4'S)-3',4'-bis(acetoxymethyl)-2'-oxetanyl]8-azidoadenine [compound (5)) in 20-methanol saturated with ammonia. After the reaction was completed and stirred at room temperature for 16 hours, the reaction solution was concentrated and the residue was purified by silica gel column chromatography.
クロロホルム／メタノール＝９ 溶出部より化合物（ｌ
ａ） を０．２９ｇ得た。Chloroform/methanol=9 The compound (l
0.29g of a) was obtained.
腸、ｐ、 １８２℃（分解）
ＩＲ（Ｋｌｌｒ、ｃｍ−’） ３４１０． ３３２５
． ３１２５． ２１７０． １６５７゜１６０Ｂ、
１５１５． １４０Ｏ
ＮＭＲ（ＣＤｓＯＤ、Ｐｐｌｍ） ８．１４（ｓ、Ｉ
Ｈ）、 ６．２９（ｄ、ＬＨ）。Intestine, p, 182°C (decomposition) IR (Kllr, cm-') 3410. 3325
．． 3125. 2170. 1657°160B,
1515. 140O NMR (CDsOD, Pplm) 8.14(s, I
H), 6.29 (d, LH).
４．６４（ｍ、ＬＨ）、 ４．２３（ｍ＋ＩＨ）、
３．９６（ｍ、２Ｈ）。4.64 (m, LH), 4.23 (m+IH),
3.96 (m, 2H).
３．７６（ｄ、２Ｈ）
ＭＳ（ＦＡＢ） ２９３（門＋１ｌ）−、２６７、
１５１実施例２
９− （（２’Ｒ，３’Ｒ，４’Ｓ）−３’、４’−ビ
ス（ヒドロキシメチル）−２′−オキセタニル〕８−ア
ミノアデニン〔化合物（ｌｂ） ）の合成化合物（ｌａ
） ０．１７ｇを５０％メタノ〜ル水溶液６〇−に溶解
し、１０％パラジウム−炭素０．１ｇを加えて室温で水
素ガスを１時間吹込んだ０反応終了後、反応液を濃縮し
残渣をシリカゲル薄層クロマトグラフィー（展開溶媒：
クロロホルム／メタノール−２，Ｒｆ−０，２３）で精
製し化合物（１ｂ）を０．１１ｇ得た。3.76 (d, 2H) MS (FAB) 293 (gate + 1l) -, 267,
151 Example 2 Synthesis of 9-((2'R,3'R,4'S)-3',4'-bis(hydroxymethyl)-2'-oxetanyl]8-aminoadenine [compound (lb)) Compound (la
) 0.17 g was dissolved in 50% aqueous methanol solution, 0.1 g of 10% palladium-carbon was added, and hydrogen gas was blown in at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated to form a residue. Silica gel thin layer chromatography (developing solvent:
It was purified with chloroform/methanol-2, Rf-0,23) to obtain 0.11 g of compound (1b).
曽、ｐ、 １９６〜１９７ ℃
Ｉ Ｒ（ＫＢｒ、ｃ＋ｍ−’） ３４２５（ｓｈ）、
３３２５．３１８５．１６４５゜１５６０、 １４０５
ＮＭＲ（ＣＤｓＯ［１，ｐｐｍ） ７．９９（ｓ、Ｌ
Ｈ）、 ６．５１（ｄ、ＩＨ）。Zeng, p, 196-197 °C IR (KBr, c+m-') 3425 (sh),
3325.3185.1645°1560, 1405 NMR (CDsO [1, ppm) 7.99 (s, L
H), 6.51(d, IH).
４．６５（ｄｔ、ＩＢ）、 ４．１４（ｍ、ＩＢ）、
３．９６（ｄｄ、ＩＨ）３．７８（ｎ＋、２８）、
３．３１（ｍ、ＩＨ）ＭＳ（ＦＡＢ） ２６７（
Ｍ＋１” 、 １５１実施例３
（Ａ） ９− （（２’Ｒ，３’Ｒ，４’Ｓ）−３’、
４’−ビス（アセトキシメチル）−２′−オキセタニル
〕−アデニン〔化合物（３）〕の合成
９− （（２’Ｒ，３’Ｒ，４’Ｓ）−３’、４’−ビ
ス（ヒドロキシメチル）−２′−オキセタニル〕アデニ
ン〔化合物（２） ） ２．５１ｇ、 ４−ジメチルア
ミノピリジン０．０９ｇ、 ）リエチルアミン２．６
ｇおよび無水酢酸２．４ｇをアセトニトリル１４０ｄ中
に加えて室温で３時間攪拌した０反応終了後、反応液を
濃縮し残渣をシリカゲルカラムクロマトグラフィーで精
製し、クロロホルム／メタノール−４９溶出部より化合
物（３）を３゜３４ｇ得た。4.65 (dt, IB), 4.14 (m, IB),
3.96 (dd, IH) 3.78 (n+, 28),
3.31 (m, IH) MS (FAB) 267 (
M+1", 151 Example 3 (A) 9- ((2'R, 3'R, 4'S)-3',
Synthesis of 4'-bis(acetoxymethyl)-2'-oxetanyl]-adenine [compound (3)] 9-((2'R,3'R,4'S)-3',4'-bis(hydroxy methyl)-2'-oxetanyl]adenine [compound (2)) 2.51 g, 4-dimethylaminopyridine 0.09 g, ) ethylamine 2.6
After the completion of the reaction, the reaction solution was concentrated and the residue was purified by silica gel column chromatography, and the compound ( 3.34 g of 3) was obtained.
鋼、ｐ、 ８０〜８２℃
ＩＲ（ＫＢｒ、ｃｍ−’） ３４５０（ｓｈ）、 ３３
２０．３１７５．１７４５１６Ｂ０． １６４０． １
６０５． １２４ＯＮＭＲ（ＣＤＣ１ｚ、ｐｐｍ）８．
３７（ｓ、ＩＨ）、 ８．２０（ｓ、１）１）。Steel, p, 80-82℃ IR (KBr, cm-') 3450 (sh), 33
20.3175.174516B0. 1640. 1
605. 124ONMR (CDC1z, ppm)8.
37 (s, IH), 8.20 (s, 1) 1).
６．４６（ｄ、ＩＨ）、 ５．８４（ｂｒ、ｓ、２Ｈ
）、 ４．７９（ｓ、ＬＨ）。6.46 (d, IH), 5.84 (br, s, 2H
), 4.79 (s, LH).
４．５３（ｄｄ、２Ｈ）、 ４．４３（ｄｄ、０１）
、 ４．３３（ｄｄ、１）１）。4.53 (dd, 2H), 4.43 (dd, 01)
, 4.33 (dd, 1) 1).
３．９８（ｍ、１８）、 ２．１７（ｓ、３Ｈ）、
２．１１（ｓ、３８）ＭＳ（ＦＡＢ） ３３６（
Ｍ＋Ｈ）４ １３６（Ｂ） ９− （（２’Ｒ，３’
Ｒ，４’５）−３’、４’−ビス（アセトキシメチル）
−２′−オキセタニル〕−８−ブロムアデニン〔化合物
（４）〕の合成化合物（３） ３．３ｇおよびＮ−ブロ
ムアセトアミド４．５ｇをクロロホルム５０１Ｒ１中で
１６時間還流した０反応終了後、反応液を濃縮し残渣を
酢酸エチル１５〇−に溶解して、１０％ハイドロサルフ
ァイドナトリウム水溶液、次いで飽和炭酸水素ナトリウ
ム水溶液で洗浄後無水ｆｉ？酸ナトリウムで乾燥した。3.98 (m, 18), 2.17 (s, 3H),
2.11 (s, 38) MS (FAB) 336 (
M+H)4 136(B) 9- ((2'R,3'
R,4'5)-3',4'-bis(acetoxymethyl)
Synthesis of -2'-oxetanyl]-8-bromaadenine [compound (4)] 3.3 g of compound (3) and 4.5 g of N-bromoacetamide were refluxed in chloroform 501R1 for 16 hours. After completion of the reaction, the reaction mixture was was concentrated, the residue was dissolved in 150 ml of ethyl acetate, washed with a 10% aqueous sodium hydrosulfide solution, then with a saturated aqueous sodium bicarbonate solution, and then anhydrous fi? dried with sodium chloride.
溶媒を留去して得られた残渣をシリカゲルカラムクロマ
トグラフィーで精製し、クロロホルム／メタノール−９
９溶出部より化合物（４）を２．７ｇ得た。The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and chloroform/methanol-9
2.7 g of compound (4) was obtained from the 9 eluted portion.
ＴＲ（ＫＢｒ、ｃｍ−’） ３４２０．１？４２．１６
４０．１５９７．１２４ＯＮＭＲ（ＣＤＣ１ｓ、 ｐｐ
ｍ） ８．３６（ｓ、ＬＨ）、 ６．４１（ｄ、Ｉ
Ｈ）。TR (KBr, cm-') 3420.1?42.16
40.1597.124ONMR (CDC1s, pp
m) 8.36 (s, LH), 6.41 (d, I
H).
５．８８（ｂｒ、ｓ、２Ｈ）、 ５．００（ｍ、ＬＨ）
、 ４．８５（Ｉｌ、ＩＨ）。5.88 (br, s, 2H), 5.00 (m, LH)
, 4.85 (Il, IH).
４．７２（ｍ、ＩＨ）、 ４．６２（ｄｄ、ＩＨ）、
４．３８（ｄｄ、ＩＨ）。4.72 (m, IH), 4.62 (dd, IH),
4.38 (dd, IH).
４．３０（ｄｄ、ＩＨ）、２．１２（ｓ、３Ｈ）、２．
０８（ａ、３Ｈ）月５（ＦＡＢ） ４１６，４１４
（月十Ｈ）′″ 、２１６，２１４（Ｃ） ９−
（（２’Ｒ，３’Ｒ，４’Ｓ）−３’ 、４’−ビス（
アセトキシメチル）−２′−オキセタニル〕−８−アジ
ドアデニン〔化合物（５）〕の合成化合物（４） １．
３６ｇをエタノール４ｏ−に溶解し、アジ化ナトリウム
０．２２ｇの水０．５−溶液を加えて２４時間還流後、
溶媒を留去した。残渣をクロロホルムに溶解して水洗後
、無水硫酸ナトリウムで乾燥した。溶媒を濃縮して得ら
れた残渣をシリカゲルカラムクロマトグラフィーで精製
し、クロロホルム／メタノール−９９溶出部より化合物
（５）を０．９ｇ得た。4.30 (dd, IH), 2.12 (s, 3H), 2.
08 (a, 3H) Month 5 (FAB) 416,414
(Monday 10H)''', 216,214 (C) 9-
((2'R, 3'R, 4'S)-3', 4'-bis(
Synthesis of acetoxymethyl)-2'-oxetanyl-8-azidoadenine [compound (5)] Compound (4) 1.
36g was dissolved in ethanol 4o-, a 0.5-aqueous solution of 0.22g of sodium azide was added, and after refluxing for 24 hours,
The solvent was distilled off. The residue was dissolved in chloroform, washed with water, and then dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent was purified by silica gel column chromatography, and 0.9 g of compound (5) was obtained from the chloroform/methanol-99 eluate.
翔、ｐ、 １２９〜１３１ ℃
ＩＲ（ＫＢｒ、ｃｍ−’） ３４２０．３３２０．３１
８０．２１６０．１？４０゜１６４５、１５２３．１３
８２．１２５ＯＮＭＲ（Ｃ［１Ｃ１ｓ、 ｐｐｍ） ８
．３１（ｓ、 ＩＨ）、 ６．２４（ｄ、 ＬＨ）。Sho, p, 129-131 °C IR (KBr, cm-') 3420.3320.31
80.2160.1?40°1645, 1523.13
82.125ONMR (C[1C1s, ppm) 8
．． 31 (s, IH), 6.24 (d, LH).
５．４１（ｂｒ、ｓ、２Ｈ）、 ４．７９（ｄｄ、 １
Ｍ）、４．６９（＋、２Ｈ）。5.41 (br, s, 2H), 4.79 (dd, 1
M), 4.69 (+, 2H).
４．５８（ｄｃｌ、ＩＨ） ４．２９（ｓ、２１（）。4.58 (dcl, IH) 4.29(s, 21().
２．１２（ｓ、３Ｈ）。2.12 (s, 3H).
２．０９（ｓ、３Ｈ） ＭＳ（ＦＡＢ） ３７７ （Ｍ ＋ Ｈ）”2.09 (s, 3H) MS(FAB) 377 (M + H)”
Claims (1)
れるプリン塩基を有する新規化合物及びその薬理学上許
容される塩。 ２、第１項記載の新規化合物又はその薬理学上許容され
る塩を有効成分とする抗ウィルス剤。 ３、式 ▲数式、化学式、表等があります▼ （式中、Ｘはハロゲン原子を、Ｙはアシル基を示す）で
表される化合物。[Claims] ▲Includes mathematical formulas, chemical formulas, tables, etc.▼ A novel compound having a purine base represented by (wherein R represents an azido group or an amino group) and a pharmacologically acceptable salt thereof . 2. An antiviral agent containing the novel compound described in item 1 or a pharmacologically acceptable salt thereof as an active ingredient. 3. A compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom and Y represents an acyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1076455A JPH02124898A (en) | 1988-04-28 | 1989-03-30 | Novel compound containing purine base, use thereof and intermediate |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-103789 | 1988-04-28 | ||
| JP10378988 | 1988-04-28 | ||
| JP63-180232 | 1988-07-21 | ||
| JP1076455A JPH02124898A (en) | 1988-04-28 | 1989-03-30 | Novel compound containing purine base, use thereof and intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02124898A true JPH02124898A (en) | 1990-05-14 |
Family
ID=26417596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1076455A Pending JPH02124898A (en) | 1988-04-28 | 1989-03-30 | Novel compound containing purine base, use thereof and intermediate |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02124898A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5494912A (en) * | 1991-06-26 | 1996-02-27 | Merrell Pharmaceuticals Inc. | 9-purinyl phosphonic acid derivitives for treating gout |
| US5527803A (en) * | 1990-07-04 | 1996-06-18 | Merrell Pharmaceuticals Inc. | 9-purinyl phosphonic acid derivatives |
-
1989
- 1989-03-30 JP JP1076455A patent/JPH02124898A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5527803A (en) * | 1990-07-04 | 1996-06-18 | Merrell Pharmaceuticals Inc. | 9-purinyl phosphonic acid derivatives |
| US5538978A (en) * | 1990-07-04 | 1996-07-23 | Merrell Pharmaceuticals Inc. | 9-purinyl phosphonic acid derivatives |
| US5494912A (en) * | 1991-06-26 | 1996-02-27 | Merrell Pharmaceuticals Inc. | 9-purinyl phosphonic acid derivitives for treating gout |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPS63239294A (en) | Novel adenosine derivative and medicinal composition containing said compound as active ingredient | |
| JPH069680A (en) | 2'-fluoro-2',3'-dideoxypyrimidinenucleoside | |
| JP2002525374A (en) | Antiviral purine derivatives | |
| JPH02503312A (en) | chemical compound | |
| JPH07500317A (en) | 1,3-oxathiolane nucleoside analogs | |
| PT88930B (en) | METHOD FOR THE PREPARATION OF NEW ANALYSES OF NUCLEOSIDES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| JPH08510747A (en) | L-2 ', 3'-dideoxynucleoside analogues as anti-hepatitis B (HBV) and anti-HIV agents | |
| US5132291A (en) | Antivirals and methods for increasing the antiviral activity of azt | |
| SE450251B (en) | XANTATE SOCIETIES FOR THERAPEUTICAL USE, NEW XANTATE SOCIETIES, AND THERAPEUTIC COMPOSITIONS CONTAINING THESE SOCIETIES | |
| JPH01283285A (en) | Novel acetylene, cyano and allenarysteromycin/ adenosine derivatives | |
| JPH01308267A (en) | Novel aristelomycin/adenosine derivatives | |
| JP2967998B2 (en) | New neplanosin derivatives | |
| US5574149A (en) | Method of treating HIV infections with 2',3'-dideoxy-3'-fluoro-5-chlorouridine | |
| JPH02160769A (en) | Novel 2'-halomethylidene, 2'-ethenylidene and | |
| EP0236227B1 (en) | Nitrate derivatives and their use as vasodilators | |
| NZ547907A (en) | 4'-Substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity | |
| JPH07504666A (en) | Antiviral phosphonic acid derivatives of purine analogs | |
| TW200813066A (en) | Novel compounds | |
| PT91489B (en) | PROCESS FOR THE PREPARATION OF 3'-FLUORO NUCLEOSIDE ANALOGUES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM | |
| TW564249B (en) | New arabinosyl adenine derivatives | |
| JPH02124898A (en) | Novel compound containing purine base, use thereof and intermediate | |
| EP0936911B1 (en) | Adenosine deaminase inhibitors | |
| CN114573651A (en) | N4-hydroxycytidine lipid prodrug and preparation method and application thereof | |
| JP3025557B2 (en) | 2-alkynyl adenosine derivatives | |
| JPH06234753A (en) | Isoxazole compound and its salt |