JPH01199991A - 2', 3'-dideoxy-4-thio-uridine derivative, production thereof and antiviral agent using said derivative - Google Patents
2', 3'-dideoxy-4-thio-uridine derivative, production thereof and antiviral agent using said derivativeInfo
- Publication number
- JPH01199991A JPH01199991A JP63103892A JP10389288A JPH01199991A JP H01199991 A JPH01199991 A JP H01199991A JP 63103892 A JP63103892 A JP 63103892A JP 10389288 A JP10389288 A JP 10389288A JP H01199991 A JPH01199991 A JP H01199991A
- Authority
- JP
- Japan
- Prior art keywords
- group
- derivative
- thio
- dideoxy
- uridine
- 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.)
- Granted
Links
- HFUKRBLAIFTSMI-POYBYMJQSA-N 1-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-4-sulfanylidenepyrimidin-2-one Chemical class O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=S)C=C1 HFUKRBLAIFTSMI-POYBYMJQSA-N 0.000 title claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 239000003443 antiviral agent Substances 0.000 title abstract 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000006239 protecting group Chemical group 0.000 claims abstract description 13
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 208000030507 AIDS Diseases 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims abstract description 6
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical group O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 230000003612 virological effect Effects 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000000840 anti-viral effect Effects 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 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 2
- 244000309464 bull Species 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012470 diluted sample Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- ZLOIGESWDJYCTF-UHFFFAOYSA-N 4-Thiouridine Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-UHFFFAOYSA-N 0.000 description 1
- ZLOIGESWDJYCTF-XVFCMESISA-N 4-thiouridine Chemical class O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-XVFCMESISA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- VKCLPVFDVVKEKU-UHFFFAOYSA-N S=[P] Chemical compound S=[P] VKCLPVFDVVKEKU-UHFFFAOYSA-N 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 229960000523 zalcitabine Drugs 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
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- 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〕
本発明は新規な２’、３’−ジデオキシ−４−チオ−ウ
リジン誘導体およびその製法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel 2',3'-dideoxy-4-thio-uridine derivative and a method for producing the same.
本発明の化合物は優れた抗ウィルス作用を呈し、例えば
ウィルス病であるエイズ治療薬としても極めて有用な化
合物である。The compound of the present invention exhibits an excellent antiviral effect and is an extremely useful compound as a therapeutic agent for AIDS, which is a viral disease.
本発明者等は、抗ウィルス作用を有し、かつ低毒性であ
る新規な化合物を鋭意検討した結果、２’、３’−ジデ
オキシ−４−チオ−ウリジンおよびその誘導体が優れた
抗ウィルス作用を発揮し、例えばエイズ治療薬として極
めて有用であることを見出した。As a result of intensive investigation into new compounds that have antiviral activity and low toxicity, the present inventors found that 2',3'-dideoxy-4-thio-uridine and its derivatives have excellent antiviral activity. It has been found that it is extremely useful, for example, as a therapeutic agent for AIDS.
本発明は、下記一般式［工］で表わされる２゛、３°−
ジデオキシ−４−チオ−ウリジン誘導体およびこれを有
効成分とする抗エイズウィルス剤並びにエイズ等のウィ
ルス病治療方法および治療薬に係る。The present invention provides 2゛, 3°-
The present invention relates to a dideoxy-4-thio-uridine derivative, an anti-AIDS virus agent containing the same as an active ingredient, and a method and drug for treating viral diseases such as AIDS.
（但しＲは水素またはアセチル基、ベンゾイル基、トリ
チル基等の保護基を示す）
更に本発明は下記一般式［ｎ］
ＯＨ
（但しＲ′はアセチル基、ベンゾイル基、トリチル阜等
の保護基を示す）
で表わされる２’、３’−ジデオキシウリジン誘導体に
ピリジン生方硫化リンを作用させることを特徴とする下
記一般式［■′ ］
（但しＲ′は前記に同じ）
で表わされる２°、３°−ジデオキシ−４−チオ−ウリ
ジン誘導体の製法並びに下記一般式［ＩＮ（但しＲ′は
アセチル塁、ベンゾイル基、トリチル基等の保護基を示
す）
で表わされる２°、３”−デオキシ−４−チオ−ウリジ
ン誘導体を加水分解することを特徴とする下記一般式［
Ｉ”］
で表わされる２°、３°−ジデオキシ−４−チオ−ウリ
ジンの製法を提供するものである。(However, R represents hydrogen or a protecting group such as an acetyl group, benzoyl group, or trityl group.) Furthermore, the present invention is applicable to the following general formula [n] OH (wherein R' represents a protecting group such as an acetyl group, benzoyl group, or trityl group). 2°, represented by the following general formula [■'] (where R' is the same as above), characterized in that 2',3'-dideoxyuridine derivative represented by Process for producing 3°-dideoxy-4-thio-uridine derivatives and 2°,3”-deoxy- expressed by the following general formula [IN (where R' represents a protecting group such as an acetyl group, benzoyl group, or trityl group)] The following general formula [which is characterized by hydrolyzing a 4-thio-uridine derivative]
The present invention provides a method for producing 2°,3°-dideoxy-4-thio-uridine represented by I''].
即ち本発明の化合物は、２°、３°−ジデオキシウリジ
ンを原料として、次の様な方法により容易に製造するこ
とかできる。That is, the compound of the present invention can be easily produced by the following method using 2°,3°-dideoxyuridine as a raw material.
即ち、２°、３゛−ジデオキシウリジンを原料として、
まず５゛位の水醸基をアセチル基、ベンゾイル基、トリ
チル塞等の適当な保護基で保護した後、ピリジン生方硫
化リンと反応させることにより、容易に対応する２゛、
３°−ジデオキシ−４−チオ−ウリジン誘導体へと変換
することができる。That is, using 2°, 3′-dideoxyuridine as a raw material,
First, the aqueous group at the 5゛ position is protected with an appropriate protecting group such as an acetyl group, benzoyl group, or trityl group, and then the corresponding 2゛,
It can be converted into a 3°-dideoxy-4-thio-uridine derivative.
この誘導体を常法に従って保護基を除去することにより
、本発明の化合物２°、３゛−ジデオキシ−４−チオ−
ウリジンが高収率で得られる。By removing the protective group from this derivative according to a conventional method, the compound of the present invention 2°,3′-dideoxy-4-thio-
Uridine is obtained in high yield.
本発明における原料物質の２°、３−ジデオキシウリジ
ン誘導体をピリジン溶液生方硫化リンと反応させる場合
、五硫化リンの量は２°、３°−ジデオキシウリジン誘
導体に対して０．５倍モル以上、好ましくは１〜２倍モ
ルが望ましい。更に反応収率をあげるためには、反応系
に水を添加することが好ましくその水の添加量は、五硫
化リンの０．５〜１倍モルが好ましい。反応は水を添加
しなくても進行するが、この場合反応液は黒褐色となり
タール状物質が生成し収率が数段低下する。反応は２〜
５時間の還流で完結する。反応終了後、ピリジン溶液を
濃縮ピリジンを留去し、残留物をクロロホルムで抽出し
目的とする２′、３°−ジデオキシ−４−チオ−ウリジ
ン誘導体を９５％以上の収率で容易に得ることができる
。次いで保護基を常法に従いアルカリあるいは酸で除去
することにより本発明の化合物２’、３’−ジデオキシ
−４−チオ−ウリジンを高収率で、しかも容易に製造す
ることができる。When the 2°,3-dideoxyuridine derivative of the raw material in the present invention is reacted with the pyridine solution organic phosphorus sulfide, the amount of phosphorus pentasulfide is 0.5 times or more in mole relative to the 2°,3°-dideoxyuridine derivative. , preferably 1 to 2 times the mole. In order to further increase the reaction yield, it is preferable to add water to the reaction system, and the amount of water added is preferably 0.5 to 1 mole of phosphorus pentasulfide. The reaction proceeds even without the addition of water, but in this case the reaction solution becomes blackish brown and a tar-like substance is produced, which lowers the yield by several stages. The reaction is 2~
Complete refluxing for 5 hours. After the reaction is completed, the pyridine solution is concentrated, the pyridine is distilled off, and the residue is extracted with chloroform to easily obtain the desired 2',3°-dideoxy-4-thio-uridine derivative with a yield of 95% or more. Can be done. Then, by removing the protecting group with an alkali or acid according to a conventional method, the compound 2',3'-dideoxy-4-thio-uridine of the present invention can be easily produced in high yield.
このようにして製造した本発明の化合物は、通常の精製
方法、例えばカラムクロマト法あるいは町結晶法あるい
はこれらを組み合わせることにより容易に精製すること
ができる。The compound of the present invention produced in this manner can be easily purified by a conventional purification method, such as a column chromatography method, a crystallization method, or a combination thereof.
又、原料である２“、３゛−ジデオキシウリジンあるい
はその誘導体はリボ核酸の構成成分であるウリジンから
既知の方法により容易に得ることができる。例えば、Ｃ
ｈｅｍ、 Ｐｈａｒｍ、 Ｂｕｌｌ、、１８（３）。In addition, the raw material 2'',3'-dideoxyuridine or its derivatives can be easily obtained from uridine, a constituent of ribonucleic acid, by known methods. For example, C
hem, Pharm, Bull, 18(3).
５５４〜５６０．１９７０の方法では「ノリジンをピリ
ジン溶液中塩化メタンスルホニルで処理し、２”、３’
。554-560.1970, ``Treatment of Norizine with methanesulfonyl chloride in pyridine solution, 2'', 3'
.
５−トリー〇−メタンスルホニルウリジンとし、これを
アセトアミドあるいはジメチルホルムアミド溶液中安息
香酸ナトリウムと反応さぜるこ゛とにより２，２′−ア
ンヒドロ−１−（３“−〇−ベンゾイルー３゛−○−メ
シル−β−アラビノシル）ウラシルとする。これを臭化
水素あるいは臭化アセチルと反応させることにより５’
−Ｑ−ベンゾイル−２°−ブロモ−２−デオキシ−５−
ｏ−メシルウリジンとした後、エタノール中水素雰囲気
下パラジウム炭素あるいはラネーニッケル触媒で処理す
ることにより５°−０−ベンゾイル−２°、３−ジデオ
キシウリジンを約６０％収率で得ることができる（Ｃｈ
ｅｍ、 Ｐｈａｒｍ、 Ｂｕｌｌ、、 １８（３Ｌ５５
４−５６０．１９７０）。5-tri〇-methanesulfonyluridine and reacted with sodium benzoate in acetamide or dimethylformamide solution to form 2,2'-anhydro-1-(3''-〇-benzoyl-3゛-○-mesyl -β-arabinosyl)uracil.By reacting this with hydrogen bromide or acetyl bromide, 5'
-Q-benzoyl-2°-bromo-2-deoxy-5-
After forming o-mesyluridine, 5°-0-benzoyl-2°,3-dideoxyuridine can be obtained in about 60% yield by treatment with palladium carbon or Raney nickel catalyst in hydrogen atmosphere in ethanol (Ch
em, Pharm, Bull, 18 (3L55
4-560.1970).
次にこの発明の実施例を示す。 Next, examples of this invention will be shown.
（１）製造例
５°−ベンゾイル−２゛、３−ジデオキシウリジン３□
１６ｇと蒸溜水０．２２９をピリジン５０ｄに溶解させ
、次いで室温撹拌下に五硫化リン２．６７３を加えて３
時間還流した。反応終了後、放冷析出した固形分を炉別
、固形分は少量のピリジンで洗浄した。１ｑられたピリ
ジン炉液は、濃縮乾固しクロロホルムで抽出分離し５′
−ベンゾイル−２°、３゛−ジデオキシ−４−チオ−ウ
リジン３．１５９ （収率９５％）を１ｑた。(1) Production example 5°-benzoyl-2′,3-dideoxyuridine 3□
16 g and 0.229 g of distilled water were dissolved in 50 d of pyridine, and then 2.673 g of phosphorus pentasulfide was added while stirring at room temperature.
Refluxed for an hour. After the reaction was completed, the solid content precipitated by cooling was separated into a furnace, and the solid content was washed with a small amount of pyridine. The 1q pyridine furnace solution was concentrated to dryness, extracted and separated with chloroform, and 5'
1 q of -benzoyl-2°,3'-dideoxy-4-thio-uridine (3.159%, yield 95%) was obtained.
次いで、これを２％ナトリウムメトキシドのメタノール
溶液４０ｒＩｄｌに溶し、１時間遠流した。反応終了後
酢酸で中和し、濃縮してカラムクロマトにより分離精製
した。得られた結晶は再度メタノールからの再結晶で精
製し、下記の物性値をもつ２′、３°−ジデオキシ−４
−チオ−ウリジン１．８４９ （収率８５％）を得た。Next, this was dissolved in 40 rIdl of a 2% sodium methoxide methanol solution and centrifuged for 1 hour. After the reaction was completed, it was neutralized with acetic acid, concentrated, and separated and purified by column chromatography. The obtained crystals were purified again by recrystallization from methanol to obtain 2',3°-dideoxy-4 having the following physical properties.
-Thio-uridine 1.849 (yield 85%) was obtained.
淡黄色針状結晶 融点１２１〜１２２°ＣＮＭＲスペク
トル（ＤＭＳＯ−δ６）：δ１．４０〜２．７０ （
４トＩ、 ｍ、 Ｃ２’ ａｎ（Ｉ Ｃ３’
−３．４０〜３．８０ （２ト１． ｍ、 Ｃ
５’ −Ｈ）３．８０〜４．３０ （１ト１．
ｍ、 Ｃ４’ −Ｈ）５．１０（１ト１．
ｔ、 Ｃｓ ’ −０ｆ−Ｌ、 Ｄ２
０添加により消失）
５．９０ （１Ｈ，Ｑ、、’ Ｃ１’ −Ｈ）
６．２５ （１１−１，ｄ 、 Ｃｓ −Ｈ＞７．９５
（１Ｈ，ｄ、 Ｃ６−Ｈ＞
１２．６０ （１ｆ−１，ｂｓ、 Ｎ−Ｈ，Ｄ２０添
加により消失）
元素分析 Ｃ９Ｆ１１２Ｎ２Ｓ０３として計算１直
Ｃ： ４７．３Ｂ 、 ト１ ： り、３０．
Ｎ ： １２．２７ 。Pale yellow needle crystals Melting point 121-122°C NMR spectrum (DMSO-δ6): δ1.40-2.70 (
4tI, m, C2' an(I C3'
-3.40~3.80 (2t 1.m, C
5'-H) 3.80-4.30 (1 to 1.
m, C4'-H) 5.10 (1 to 1.
t, Cs'-0f-L, D2
Disappeared by adding 0) 5.90 (1H,Q,,'C1'-H)
6.25 (11-1,d, Cs-H>7.95
(1H, d, C6-H> 12.60 (1f-1, bs, disappeared by addition of N-H, D20) Elemental analysis Calculated as C9F112N2S03 in one turn
C: 47.3B, T1: ri, 30.
N: 12.27.
３ ： １４．０５
実験値 Ｃ； ４７．４６ 、ト１ ； ５．３３．
Ｎ ： １２．１２ 。3: 14.05 Experimental value C: 47.46, T1: 5.33.
N: 12.12.
３ ： １４．０８
ＩＲ（ＫＢｒ）第１図の通り
ＩＪＶ （ＥｔＯＨ）第２図ノ通す
（２）抗ウイルス試験
例１゜
本発明の一般式［■′ ］の化合物の抗ウィルス作用は
、Ｒｏｗｅらの試験方法（Ｊ、 Ｗ。3: 14.08 IR (KBr) As shown in Figure 1, IJV (EtOH) Figure 2. The test method of et al. (J, W.
ＶｉｒｏｌｏｇＶ １９７０．４２．１１３６ ）に準
じて確認した。結果を表１に示した。It was confirmed according to Virolog V 1970.42.1136). The results are shown in Table 1.
ウィルス： Ｈｏｌｏｎｅｙ−ｍｕｒｉｎｅ ｌｅｕｋ
ｅｍｉａ ｖｉｒｕｓ細 胞：５Ｃ−１
族１．抗ウィルス効果
（注） Ｅ Ｄ ： Ｅｆｆｅｃｔｉｖｅ Ｄｏｓｅμ
Ｍ二マイクロモル
ＡＺＴ：３’−アジド−３°−デオキシ。Virus: Holoney-murine leuk
emia virus cells: 5C-1 group 1. Antiviral effect (Note) ED: Effective Doseμ
M2 micromolar AZT: 3'-azido-3°-deoxy.
チミジン
ＤＤＣ：２’、３°−ジデオキシシチジン例２．ラウス
肉腫ウィルス（Ｒ３Ｖ）に対する効果
初代培養細胞（Ｃｈｉｃｋ Ｅｍｂｒｙｏ Ｆｉｂｒｏ
ｆａｓｔ）を用いて、約３０分間Ｒ３Ｖ感染させた。そ
して段階的に希釈した試料を添加し、４〜７日後にＲ３
Ｖ感染による細胞の形質転換がどの段階において抑制さ
れたかを検鏡により判定した。Thymidine DDC: 2',3°-dideoxycytidine Example 2. Effect on Rous Sarcoma Virus (R3V) Primary cultured cells (Chick Embryo Fibro
fast) for about 30 minutes. Then, stepwise diluted samples were added, and after 4 to 7 days, R3
The stage at which cell transformation due to V infection was inhibited was determined by microscopy.
例３． ＨＩ Ｖ （ｔｌｕｍａｎ ｉｍｍｕｎｏｄｅ
ｆｉｃｉｅｎｃｙｖｉｒｕｓ）に対する効果
ＭＴ−４細胞を用いて、３７°Ｃで１時間ＨＩ■感染さ
せた。そして、段階的に希釈した試料を添加し、３日後
にＨＩＶ感染による細胞の形質転換がどの段階において
抑制されたかを検鏡により判定した。Example 3. H.I.V.
MT-4 cells were infected with HI for 1 hour at 37°C. Then, serially diluted samples were added, and three days later, it was determined by microscopy at which stage the transformation of cells due to HIV infection was suppressed.
表１〜３に示される通り、本発明化合物はＤＤＣと同様
の優れた抗ウィルス作用を示すことから、本発明化合物
がエイズ等のウィルス病治療薬として有効であることは
明らかである。As shown in Tables 1 to 3, the compounds of the present invention exhibit excellent antiviral effects similar to those of DDC, so it is clear that the compounds of the present invention are effective as therapeutic agents for viral diseases such as AIDS.
［発明の効果］
以上説明したように、この発明によれば、新規で抗ウィ
ルス作用の優れた化合物が提供される。例えば、エイズ
等のウィルス病治療薬として極めて有効である。[Effects of the Invention] As explained above, according to the present invention, a novel compound with excellent antiviral activity is provided. For example, it is extremely effective as a therapeutic agent for viral diseases such as AIDS.
第１図は本発明化合物のＩＲスペクトル図を、第２図は
本発明化合物のＵ■スペクトル図を夫々示す。
第２図
手続ネ「１１正書（自発）
昭和６３年８月８日FIG. 1 shows the IR spectrum of the compound of the present invention, and FIG. 2 shows the U⋯ spectrum of the compound of the present invention. Figure 2 Procedures ``11 Official Book (Spontaneous) August 8, 1986
Claims (5)
リチル基等の保護基を示す） で表わされる２’，３’−ジデオキシ−４−チオ−ウリ
ジン誘導体。(1) 2' represented by the following general formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R represents hydrogen or a protecting group such as an acetyl group, benzoyl group, or trityl group) , 3'-dideoxy-4-thio-uridine derivative.
の保護基を示す） で表わされる２’，３’−ジデオキシウリジン誘導体に
ピリジン中五硫化リンを作用させることを特徴とする下
記一般式［ I ′］ ▲数式、化学式、表等があります▼［ I ′］ （但しＲ′は前記に同じ） で表わされる２’，３’−ジデオキシ−４−チオ−ウリ
ジン誘導体の製法。(2) 2', 3' represented by the following general formula [II] ▲Mathematical formulas, chemical formulas, tables, etc.▼[II] (R' represents a protecting group such as an acetyl group, benzoyl group, trityl group, etc.) - The following general formula [ I ′] is characterized by the action of phosphorus pentasulfide in pyridine on a dideoxyuridine derivative ▲ There are numerical formulas, chemical formulas, tables, etc. A method for producing a 2',3'-dideoxy-4-thio-uridine derivative.
の保護基を示す） で表わされる２’，３’−ジデオキシ−４−チオ−ウリ
ジン誘導体を加水分解することを特徴とする下記一般式
［ I ″］ ▲数式、化学式、表等があります▼［ I ″］ で表わされる２’，３’−ジデオキシ−４−チオ−ウリ
ジンの製法。(3) The following general formula [ I ′] ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [ I ′] (However, R′ represents a protective group such as an acetyl group, benzoyl group, trityl group, etc.) 2', 2', 3'- represented by the following general formula [ I ″] ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [ I ″] which is characterized by hydrolyzing a 3'-dideoxy-4-thio-uridine derivative Method for producing dideoxy-4-thio-uridine.
リチル基等の保護基を示す） で表わされる２’，３’−ジデオキシ−４−チオ−ウリ
ジン誘導体を有効成分とする抗エイズウイルス剤等の抗
ウイルス剤。(4) The following general formula [ I ] ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [ I ] (In the formula, R represents hydrogen or a protecting group such as an acetyl group, benzoyl group, trityl group, etc.) 2' , 3'-dideoxy-4-thio-uridine derivatives as an active ingredient, such as anti-AIDS virus agents.
するエイズ等のウイルス病治療方法および治療薬。(5) A method and drug for treating viral diseases such as AIDS, which contain a derivative represented by the general formula [I] as an active ingredient.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63103892A JPH01199991A (en) | 1987-10-20 | 1988-04-28 | 2', 3'-dideoxy-4-thio-uridine derivative, production thereof and antiviral agent using said derivative |
| US07/200,903 US4954485A (en) | 1987-10-20 | 1988-06-01 | 2',3'-dideoxy-4-thio-uridine derivatives, process for their preparation and antivirus agents using them |
| DE3820588A DE3820588A1 (en) | 1987-10-20 | 1988-06-16 | 2 ', 3'-DIDESOXY-4-THIOURIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, AND ANTIVIRUS AGENTS CONTAINING THEM |
| GB8814973A GB2211185B (en) | 1987-10-20 | 1988-06-23 | Uridine derivatives and antiviral agents containing them |
| FR8809795A FR2621918B1 (en) | 1987-10-20 | 1988-07-20 | 2 ', 3'-DIDESOXY-4-THIO-URIDINES, PROCESS FOR THE PREPARATION OF SUCH SUBSTANCES AND MEDICINAL PRODUCTS CONTAINING SAME |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-265083 | 1987-10-20 | ||
| JP26508387 | 1987-10-20 | ||
| JP63103892A JPH01199991A (en) | 1987-10-20 | 1988-04-28 | 2', 3'-dideoxy-4-thio-uridine derivative, production thereof and antiviral agent using said derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01199991A true JPH01199991A (en) | 1989-08-11 |
| JPH0579073B2 JPH0579073B2 (en) | 1993-11-01 |
Family
ID=17412362
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63103892A Granted JPH01199991A (en) | 1987-10-20 | 1988-04-28 | 2', 3'-dideoxy-4-thio-uridine derivative, production thereof and antiviral agent using said derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01199991A (en) |
-
1988
- 1988-04-28 JP JP63103892A patent/JPH01199991A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0579073B2 (en) | 1993-11-01 |
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