JPH03148278A - Novel nucleoside and production thereof - Google Patents
Novel nucleoside and production thereofInfo
- Publication number
- JPH03148278A JPH03148278A JP28483589A JP28483589A JPH03148278A JP H03148278 A JPH03148278 A JP H03148278A JP 28483589 A JP28483589 A JP 28483589A JP 28483589 A JP28483589 A JP 28483589A JP H03148278 A JPH03148278 A JP H03148278A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- dideoxy
- herpes
- formulas
- 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
- 239000002777 nucleoside Substances 0.000 title claims description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 claims abstract 2
- VZUXBJJSNWVHHB-NTSWFWBYSA-N 7-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-1h-imidazo[4,5-d]triazin-4-one Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NN=NC2=O)=C2N=C1 VZUXBJJSNWVHHB-NTSWFWBYSA-N 0.000 claims abstract 2
- 102000055025 Adenosine deaminases Human genes 0.000 claims abstract 2
- RSDSRGVCGAOGFK-NTSWFWBYSA-N [(2s,5r)-5-(4-aminoimidazo[4,5-d]triazin-7-yl)oxolan-2-yl]methanol Chemical compound C1=NC=2C(N)=NN=NC=2N1[C@H]1CC[C@@H](CO)O1 RSDSRGVCGAOGFK-NTSWFWBYSA-N 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 102000006267 AMP Deaminase Human genes 0.000 claims description 3
- 108700016228 AMP deaminases Proteins 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 125000003835 nucleoside group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003443 antiviral agent Substances 0.000 abstract description 5
- 230000003612 virological effect Effects 0.000 abstract description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 abstract description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 2
- 208000001688 Herpes Genitalis Diseases 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
- 201000004946 genital herpes Diseases 0.000 abstract description 2
- 230000001506 immunosuppresive effect Effects 0.000 abstract description 2
- 239000012442 inert solvent Substances 0.000 abstract description 2
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 abstract 1
- 208000007514 Herpes zoster Diseases 0.000 abstract 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 abstract 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 abstract 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 abstract 1
- 229950006790 adenosine phosphate Drugs 0.000 abstract 1
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 3
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 3
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 3
- 201000006966 adult T-cell leukemia Diseases 0.000 description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 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
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010072210 Genital herpes zoster Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 229960004150 aciclovir Drugs 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 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
- 238000000746 purification Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は例えば抗ウィルス剤などの医薬として期待され
る新規ヌクレオシドに関するものである。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel nucleoside that is expected to be used as a medicine such as an antiviral agent.
（従来の技術）
核酸関連物質には抗ウィルス作用を持つものが数多く知
られており、そのうちいくつかのものは有用々医薬品と
して臨床に供されている。(Prior Art) Many nucleic acid-related substances are known to have antiviral effects, and some of them are in clinical use as useful pharmaceuticals.
例えば抗ウィルス剤としてはピダラビン（Ｍ。For example, as an antiviral agent, pidarabine (M.
Ｐｒ１ｖａｔ ｄｅ Ｇａｒｉｌｈｅ ａｎｄ Ｊ、
ｄｅ Ｒｕｂｂｅｒ、 Ｃ−Ｒ−Ａｃａｄ、 Ｓｏｃ。Pr1vat de Garilhe and J,
de Rubber, C-R-Acad, Soc.
Ｄ（Ｐａｒｉｓ）２５９．２７２５（，１９６４））、
アシクロビｋ （Ｇ、 Ｂ−Ｅｌｉｏｎ ｅｔ ａｌ
、、 Ｐｒｏｃ、 Ｎａｔｌ、 Ａｃａｄ、 Ｓｃｉ、
ＵＳＡ＋７４．５７１６（２９７７））、 アジド
チミジン（Ｈ。D (Paris) 259.2725 (, 1964)),
Acyclovir K (G, B-Elion et al.
,, Proc, Natl, Acad, Sci,
USA+74.5716 (2977)), azidothymidine (H.
Ｍｉｔｓｕｙａ ｅｔ ａｌ、、 Ｐｒｏｃ、 Ｎａｔ
ｌ、 Ａｃａｄ、 ５ｃｉ−ＵＳＡ、 ８２゜７０９
６（１９８５））等が知られている。Mitsuya et al., Proc., Nat.
l, Acad, 5ci-USA, 82°709
6 (1985)) etc. are known.
（発明が解決しようとする課題）
しかしながら、上記抗ウィルス薬は適用範囲が狭く、ま
た溶解度、経口吸収性、代謝等の影響により投与方法が
限られる、また、骨髄前等の副作用のため長期投与が困
難である等問題点を多く残している。また、後天性免疫
不全症候群（ＡＩＤＳ）、成人Ｔ細胞白血病（ＡＴＬ）
等悪性なウィルス病が増加の傾向にあることから、新た
々抗ウイルス薬の開発が望まれている。(Problems to be Solved by the Invention) However, the above antiviral drugs have a narrow scope of application, and the administration methods are limited due to the effects of solubility, oral absorption, metabolism, etc., and long-term administration due to side effects such as pre-marrow Many problems remain, such as the difficulty of Also, acquired immunodeficiency syndrome (AIDS), adult T-cell leukemia (ATL)
Since the number of iso-malignant viral diseases is on the rise, the development of new antiviral drugs is desired.
（課題を解決するための手段） 本発明は、−紋穴 （式中ＲはＮＨｚまたはＯＨを示す。(Means for solving problems) The present invention is characterized by - (In the formula, R represents NHZ or OH.
）
で示される新規ヌクレオシド即ち、２１３−ジデオキシ
−２−アザアデノシンおよび２１３′−ジデオキシ−２
−アザイノシン及びそれら塩及びそれらの製造法に関す
るものである。), namely, 213-dideoxy-2-azaadenosine and 213'-dideoxy-2
- This invention relates to azainosine, salts thereof, and methods for producing them.
本発明の新規ヌクレオシドは公知化合物の２１３−ジデ
オキシアデノシン（ｄｄＡ）より次に示す工程により得
ることができる。The novel nucleoside of the present invention can be obtained from the known compound 213-dideoxyadenosine (ddA) by the following steps.
（ａ）
（ｄｄＡ）
（ｂ）
（Ｃ）
（ｄ）
（Ｉａ）
反応式（１）
（）
〈式中Ｒは、”１＝５’で示される基を意味する。）
即ち、−紋穴（ａ）で表わされるｄｄＡを、クロロアセ
トアルデヒドと反応させ、−紋穴（ｂ）で表わされる化
合物を合成することが出来る。また、−紋穴（ｂ）で表
わされる化合物を水酸化ナトリウムｔｌどのアルカリで
加水分解することにより一般式（Ｃ）で表わされる化合
物を合成することが出来る。さらに、−紋穴（Ｃ）で表
わされる化合物を亜硝酸などで処理することにより一般
式（ｄ）で表わされる化合物を合成することが出来る。(a) (ddA) (b) (C) (d) (Ia) Reaction formula (1) () (In the formula, R means a group represented by "1=5'.) That is, - Monana By reacting ddA represented by (a) with chloroacetaldehyde, it is possible to synthesize the compound represented by -Momone (b).Also, the compound represented by -Momone (b) can be synthesized with sodium hydroxide tl, etc. A compound represented by general formula (C) can be synthesized by hydrolysis with an alkali.Furthermore, by treating a compound represented by -Momonena (C) with nitrous acid etc., a compound represented by general formula (d) can be synthesized. The represented compounds can be synthesized.
さらに−紋穴（ｄ）で表わされる化合物を、臭素あるい
はＮ−ブロモこはく酸イミド（ＮＢＳ）などのハロゲン
化剤で処理することにより前記式（Ｉａ）で示される２
１３′−ジデオキシ−２−７ザアデノシンを得ることが
できる。Furthermore, by treating the compound represented by Monhole (d) with a halogenating agent such as bromine or N-bromosuccinimide (NBS), 2
13'-dideoxy-2-7zaadenosine can be obtained.
この化合物に、更にアデニル酸デアミナー七門
（Ａ１１４Ｐ−デアミナーゼ）またはアデノシンデアを
得ることができる。In addition to this compound, adenylate deaminase (A114P-deaminase) or adenosine dea can be obtained.
これらの反応は通常不活性溶媒中で、約−１０℃〜約５
０℃例えば最初の化合物（ｂ）を得る工程は約１０°Ｃ
〜約３０℃程度の室温で、第２及び第３の工程は化合物
（Ｃ）を単離することなく行うことができ、やはり通常
室温にて行うことができる。また（ｄ）から（Ｉａ）へ
の工程は通常約−１０℃〜約１０℃、例えば水冷下で行
うことができる。These reactions are usually carried out in an inert solvent at temperatures ranging from about -10°C to about 5°C.
0°C For example, the step of obtaining the first compound (b) is about 10°C
The second and third steps can be carried out without isolating compound (C) at a room temperature of about 30° C. to about 30° C., and can also usually be carried out at room temperature. Further, the step from (d) to (Ia) can be usually carried out at about -10°C to about 10°C, for example under water cooling.
次の（Ｉａ）から（Ｉｂ）への工程は０．１Ｍ 〜２．
０Ｍのリン酸緩衝液（ｐＨ約５．０〜約８．０）中反応
温度約り℃〜約５０℃にて行うことができる。The next step from (Ia) to (Ib) is 0.1M to 2.
The reaction can be carried out in 0M phosphate buffer (pH about 5.0 to about 8.0) at a reaction temperature of about 50°C to about 50°C.
（効 果）
以上の方法により、本発明の一般式（Ｉ）で表わされる
化合物は強い抗ウィルス作用を持つことが期待され、口
唇、性器ヘルペス、帯状庖疹、免疫抑制時の単純ヘルペ
スウィルス−１型、２型（Ｈ８Ｖ−Ｉ、 ＩＩ） 、バ
リセラシスターウィルス（ＶＺＶ）、サイトメガロウィ
ルス（ＣＭ■）、エプスタイン−パールウィルス（ＥＢ
Ｖ）感染症、ウィルス性肝炎、ウィルス性呼吸器疾患、
ウィルス性消化器疾患、ＡＩＤＳ、ＡＴＬ等の多くのウ
ィルス性疾患に有効であることが期待される。(Effect) According to the above method, the compound represented by the general formula (I) of the present invention is expected to have a strong antiviral effect, and is effective against cold sores, genital herpes, herpes zoster, and herpes simplex virus during immunosuppression. Type 1, type 2 (H8V-I, II), Valicella sister virus (VZV), cytomegalovirus (CM■), Epstein-Perle virus (EB
V) Infectious diseases, viral hepatitis, viral respiratory diseases,
It is expected to be effective against many viral diseases such as viral gastrointestinal diseases, AIDS, and ATL.
また、制癌剤としても期待される。It is also expected to be used as an anticancer agent.
（実施例）
次に、実施例を挙げて本発明化合物の製造について具体
的に説明する。(Example) Next, the production of the compound of the present invention will be specifically explained with reference to Examples.
実施例１゜
化合物（ｂ）の合成
２１３′−ジデオキシアデノシｙ（ｄｄＡ）（化合物（
ａ））て−夜撹拌した。反応終了後、飽和炭酸水素ナト
リウム水溶液を加えて中和し、ダイヤイオンＨＰ−２０
（５１１１／）のカラムに通塔し、水洗後、３０％メタ
ノール水溶液で溶出した。溶出液を濃縮乾固し、化合物
（ｂ）を２６．３■得た。Example 1゜Synthesis of compound (b) 213'-dideoxyadenosy (ddA) (compound (
a)) Stir overnight. After the reaction is completed, a saturated aqueous sodium bicarbonate solution is added to neutralize it, and Diaion HP-20
(5111/) column, washed with water, and eluted with a 30% methanol aqueous solution. The eluate was concentrated to dryness to obtain 26.3 μ of compound (b).
ＴＬＣ（シリカゲル）：ＲｆＯ，４８（酢酸エテル：メ
タノール：水＝７ ： ２ ： １ ）
ＭＳ（ＦＡＢ） ２６０（Ｍ＋Ｈ）”ＮＭＲ（ＤｍＯ
，ｐｐｍ） ８．９７（ｓ、ＩＨ）、８．４７（ｓ。TLC (silica gel): RfO, 48 (ethyl acetate: methanol: water = 7: 2: 1) MS (FAB) 260 (M+H)" NMR (DmO
, ppm) 8.97 (s, IH), 8.47 (s.
ＩＨ）、７．９３（ｄ、ＩＨ）、７．６０（ｄ、ＩＨ）
。IH), 7.93 (d, IH), 7.60 (d, IH)
.
・６．４７（ｔ、ＩＨ）、４．５６（ｍ、ＩＨ）、４．
００（ｍ。・6.47 (t, IH), 4.56 (m, IH), 4.
00 (m.
２Ｈ）、３．０〜２．０（ｍ、４Ｈ）
実施例２゜
化合物（ｄ）の合成
化合物（ｂ） ２６．３■を０．ＩＮ水酸化す） １７
ウム水溶液１ ｍｌに加えて室温で、−夜撹拌後、反応
液に酢酸を加えて中和し、ダイヤイオンＨＰ−２０（８
ｍｌ ）のカラムに通塔した。水洗した後、３０％メタ
ノール水溶液で溶出し、溶出液を濃縮乾固した。2H), 3.0 to 2.0 (m, 4H) Example 2゜Synthesis of compound (d) Compound (b) 26.3■ to 0. IN hydroxide) 17
After stirring overnight at room temperature, acetic acid was added to the reaction solution to neutralize it, and Diaion HP-20 (8
ml) column. After washing with water, elution was performed with a 30% methanol aqueous solution, and the eluate was concentrated to dryness.
次いで５０％酢酸水溶液４４０μｌに溶解し、水冷下、
亜硝酸す） ＩＪウム７，２■を加えて１０分撹拌した
。反応終了後、飽和炭酸水素ナトリウムで中和し、ダイ
ヤイオンＨＰ−２０（８ｍｌ ）のカラムにロマトグラ
フィー（２０ｍ／、クロロホルム−メタノール５：１）
により分離、精製を行い、化合物（ｄ）を４．４ｆｆｌ
！得た。Then, it was dissolved in 440 μl of 50% acetic acid aqueous solution and cooled with water.
7.2 ml of IJum (nitrous acid) was added and stirred for 10 minutes. After the reaction was completed, it was neutralized with saturated sodium bicarbonate and chromatographed on a Diaion HP-20 (8 ml) column (20 m/chloroform-methanol 5:1).
The compound (d) was separated and purified by 4.4 ffl
! Obtained.
ＴＬＣ（シリカゲル）：ＲｆＯ，７１（酢酸エテル：メ
タノール：水＝７ ： ２ ： １ ）
ＭＳ（ＦＡＢ）２６１（Ｍ＋Ｈ）”
ＮＭＲ（ＤｘＯ，ｐｐｍ） ８．６８（ｓ、ＩＨ）、
８．４４（ｄ。TLC (silica gel): RfO, 71 (ethyl acetate: methanol: water = 7:2:1) MS (FAB) 261 (M+H)" NMR (DxO, ppm) 8.68 (s, IH),
8.44 (d.
ＩＨ）、７．７３（ｄ、ＩＨ）、６．５９（ｔ、ＩＨ）
。IH), 7.73 (d, IH), 6.59 (t, IH)
.
４．３７（ｍ、 ＩＨ）、 ３．８〜３．６（ｍ、
２Ｈ）、 ２．６８（ｍ、 ２Ｈ）、 ２．
３〜１．９（ｍ、 ２Ｈ）実施例３゜
化合物（Ｉ）の合成
化合物（ｄ） ４．４ Ｑを１モル酢酸緩衝液（ｐＨ５
，１）３００μＩに溶解し、Ｎ−ブロモコハク酸イミド
１３．２■を加えて、水冷下、−夜撹拌した。反応終了
後、飽和炭酸水素ナトリウムで中和し、ダイヤイオンＨ
Ｐ−２０（８ｒｘｌ ）のカラムに通塔した。4.37 (m, IH), 3.8-3.6 (m,
2H), 2.68 (m, 2H), 2.
3-1.9 (m, 2H) Example 3゜Synthesis of compound (I) Compound (d) 4.4Q was dissolved in 1 molar acetate buffer (pH 5
, 1) 13.2 μl of N-bromosuccinimide was added to the solution, and the mixture was stirred overnight under water cooling. After the reaction is completed, it is neutralized with saturated sodium hydrogen carbonate and Diaion H
It was passed through a column of P-20 (8 rxl).
水洗後、３０％メタノール水溶液で溶出し、溶出液を濃
縮乾固後、シリカゲルカラムクロマトグラフィー（４ａ
ｕ、クロロホルム−メタノール５：１により、分離、精
製を行い、化合物（Ｊａ） ０．５６■を得た。After washing with water, elution was carried out with 30% methanol aqueous solution, the eluate was concentrated to dryness, and then subjected to silica gel column chromatography (4a
Separation and purification were performed using u, chloroform-methanol 5:1 to obtain Compound (Ja) 0.56.
ＴＬＣ（シリカゲル）：ＲｆＯ，６２（クロロホルム−
メタノール＝３ ： １ ）
ＭＳ（ＦＡＢ）２３７（Ｍ＋Ｈ）”
）
ＮＭＲ（Ｄ２０．Ｉ）ｐｍ） ８．５５（Ｓ、ＩＨ）
、６．４４（ｔ。TLC (silica gel): RfO,62 (chloroform-
Methanol = 3:1) MS (FAB) 237 (M+H)'') NMR (D20.I) pm) 8.55 (S, IH)
, 6.44 (t.
ＩＨ）Ｉ ４．３２（ｍｌ ＩＨ）、３．８〜３．５
（ｍ、２Ｈ）。IH) I 4.32 (ml IH), 3.8-3.5
(m, 2H).
２．５８（ｍ、２Ｈ）、２．：（−１，９（ｍ、２Ｈ）
実施例４６
化合物（Ｉｂ）の合成
化合物（ｉａ）３．３■を０．１ Ｍリン酸バッファー
（ｐＨ６，８） １ ｒｎｌに溶解し、ＡＭＰ−デアミ
ナーゼ■
（商品名：デアミナーゼ 天分製薬）４．２２メガユニ
ツトを加え、３２℃にて８７時間放置した。2.58 (m, 2H), 2. :(-1,9(m,2H)
Example 46 Synthesis of compound (Ib) Compound (ia) 3.3■ was dissolved in 0.1 M phosphate buffer (pH 6,8) 1 rnl, and AMP-deaminase■ (trade name: Deaminase Tenbun Seiyaku) 4 .22 megaunits were added and left at 32°C for 87 hours.
反応終了後、ダイヤイオンＨＰ−２０（８ｒｕｌ ）に
通塔し、２％食塩、水にて洗浄後、５０％含水メタノー
ルにて溶出した。溶出液を濃縮乾固して、化合物０を２
．６Ｍ＠得た。After the reaction was completed, the column was passed through a Diaion HP-20 (8 rul), washed with 2% sodium chloride and water, and eluted with 50% aqueous methanol. The eluate was concentrated to dryness to give compound 0 to 2
．． I got 6M@.
ＴＬＣ（シリカゲル）：ＲｆＯ，６４（クロロホルム−
メタノール＝３ ： １ ）
ＭＳ（ＦＡＢ） ２３８（Ｍ＋Ｈ）”ＮＭＲ（Ｄ２０
．ｐｐｍ） ８．５２（Ｓ、ＩＨ）、 ６．５ｏ（
ｔ。TLC (silica gel): RfO,64 (chloroform-
Methanol = 3:1) MS (FAB) 238 (M+H)” NMR (D20
．． ppm) 8.52 (S, IH), 6.5o (
t.
Claims (1)
新規ヌクレオシド及びその塩 ２、式 ▲数式、化学式、表等があります▼ で示される化合物に、ハロゲン化剤を作用させることを
特徴とする式 ▲数式、化学式、表等があります▼ で示される新規ヌクレオシド及びその塩の製造法 ３、式 ▲数式、化学式、表等があります▼ で示される２′，３′−ジデオキシ−２−アザアデノシ
ンまたはその塩に、アデニル酸デアミナーゼまたはアデ
ノシンデアミナーゼを作用させることを特徴とする下記
式 ▲数式、化学式、表等があります▼ で示される２′，３′−ジデオキシ−２−アザイノシン
の製造法[Claims] 1. A novel nucleoside represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R in the formula represents NH_2 or OH group) and its salts 2. Formula ▲ Numerical formulas, chemical formulas, tables, etc. There is a formula ▲ which is characterized by causing a halogenating agent to act on the compound represented by ▼ There are mathematical formulas, chemical formulas, tables, etc. ▼ Method 3 for producing novel nucleosides and their salts represented by formula ▲ Mathematical formula, chemical formula, There are tables, etc. ▼ The following formula is characterized by causing adenylate deaminase or adenosine deaminase to act on 2',3'-dideoxy-2-azaadenosine or its salt shown by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Production method of 2',3'-dideoxy-2-azainosine shown by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28483589A JPH03148278A (en) | 1989-11-02 | 1989-11-02 | Novel nucleoside and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28483589A JPH03148278A (en) | 1989-11-02 | 1989-11-02 | Novel nucleoside and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03148278A true JPH03148278A (en) | 1991-06-25 |
Family
ID=17683630
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28483589A Pending JPH03148278A (en) | 1989-11-02 | 1989-11-02 | Novel nucleoside and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03148278A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8742101B2 (en) | 2003-07-25 | 2014-06-03 | Idenix Pharmaceuticals, Inc. | Purine nucleoside analogues for treating flaviviridae including hepatitis C |
-
1989
- 1989-11-02 JP JP28483589A patent/JPH03148278A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8742101B2 (en) | 2003-07-25 | 2014-06-03 | Idenix Pharmaceuticals, Inc. | Purine nucleoside analogues for treating flaviviridae including hepatitis C |
| US9186369B2 (en) | 2003-07-25 | 2015-11-17 | Idenix Pharmaceuticals, Llc | Purine nucleoside analogues for treating flaviviridae including hepatitis C |
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