WO1998056803A1 - Nouveau derive de nucleoside optiquement actif, son procede de production et agent anti-hbv le contenant - Google Patents

Nouveau derive de nucleoside optiquement actif, son procede de production et agent anti-hbv le contenant Download PDF

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WO1998056803A1
WO1998056803A1 PCT/KR1998/000149 KR9800149W WO9856803A1 WO 1998056803 A1 WO1998056803 A1 WO 1998056803A1 KR 9800149 W KR9800149 W KR 9800149W WO 9856803 A1 WO9856803 A1 WO 9856803A1
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Prior art keywords
dideoxy
furanosyl
fluoroapio
compound
optically active
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PCT/KR1998/000149
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English (en)
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Chung Ii Hong
Jung Woo Kim
Sang Joon Lee
Koo Hun Chung
Soon Kil Ahn
Jae Wook Lee
Byeong Seon Jeong
Hoe Joo Son
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Chong Kun Dang Corp.
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Priority to AU77897/98A priority Critical patent/AU7789798A/en
Publication of WO1998056803A1 publication Critical patent/WO1998056803A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification

Definitions

  • Novel optically active nucleoside derivative its manufacturing method and anti-HBV agent containing the derivative thereof
  • This invention relates to a novel optically active compound of the nucleoside derivative expressed by the following formula 1, its manufacturing method and anti-HBV agent containing the compound:
  • Ri is hydrogen, phosphate, phosphonate, alkyl or acyl group; R 2 is substituted or non-substituted pyrimidine or purine base.
  • Hepatitis B virus is a lethal virus, which causes acute/chronic Hepatitis in human body, and finally develops the disease into liver cancer.
  • a remedy for treating the viral disease does not exist though vaccines against the virus have been developed.
  • Ara-A, interferon or the like has been used in treatment of Hepatitis B, however, there are many problems in view of effectiveness and safety.
  • nucleoside compounds having anti-HBV activity have been reported.
  • 2',3'-dideoxy-3'-thiacytidine Proc. Natl. Acad. Sci. USA, 88, 8495(1991)]
  • 5-fluoro-2',3'-dideoxy- 3'-thiacytidine Proc. Natl. Acad. Sci. USA, 88, 8495(1991)]
  • 2',3'- dideoxy- ⁇ -L-5-fluoro-cytidine Biochem. Pharm., 47, 171(1994)
  • 2',3'-dideoxy- ⁇ -L-5-cytidine Biochem. Pharm., 47, 171(1994)
  • etc. are reported as showing anti-HBV activity.
  • An object of this invention is to provide a optically active compound of the nucleoside derivative expressed by the formula 1.
  • Another object of this invention is to provide a process of manufacturing an optically active compound of the nucleoside derivative expressed by the formula 1. Further object of this invention is to provide an antiviral agent containing an optically active compound of the nucleoside derivative expressed by the formula 1. More specifically, the object of this invention is to provide an anti-HBV agent containing an optically active compound of the nucleoside derivative expressed by the formula 1.
  • This invention relates to a novel optically active compound of the nucleoside derivative expressed by the following formula 1, its manufacturing method and anti-HBV agent containing the derivative:
  • Ri is hydrogen, phosphate, phosphonate, alkyl or acyl group; R 2 is substituted or non-substituted pyrimidine or purine base.
  • a compound expressed by the formula 1 has more than two asymmetric carbon atoms, it may be represented by the following compound expressed by formula la, lb, lc and Id:
  • Rj and R 2 are same as defined as above.
  • Rj is hydrogen, phosphonate or phosphate;
  • R 2 is selected from the following groups:
  • R 3 is hydrogen, methyl, hydroxymethyl, methoxymethyl, methylthiomethyl, trifluoromethyl, ethyl, propyl, cyclopropyl, vinyl, 2-bromovinyl, fluoro, chloro, bromo, or iodo
  • R- 4 is hydrogen, methyl, ethyl, hydroxy, methoxy or acyl of Cj ⁇ C 6
  • R 5 is hydrogen, cyano, carboxyl, alkoxycarbonyl, carbamoyl, or thiocarbamoyl
  • R ⁇ and R 7 are independently hydrogen, hydroxy, amino, fluoro, chloro, bromo or iodo.
  • An optically active compound of the nucleoside derivative expressed by the following formula 1 according to this invention includes l-(2,3-dideoxy-3-fluoroapio- ⁇ -L-furanosyl)uracil, l-(2,3-dideoxy-3-fluoroapio- ⁇ -D-furanosyl)uracil, l-(2,3-dideoxy-3-fluoroapio- ⁇ -L-furanosyl)uracil, l-(2,3-dideoxy-3-fluoroapio- ⁇ -D-furanosyl)uracil, l-(2, 3-dideoxy-3-fluoroapio- ⁇ -L-furanosyl)thymine, l-(2,3-dideoxy-3-fluoroapio- ⁇ -D-furanosyl)thymine, l-(2,3-dideoxy-3-fluoroapio- -L-furanosyl)thymine, l-(2,3-d
  • an optically active compound of the nucleoside derivative expressed by the formula 1 may be prepared by the following three methods: 1) Asymmetric synthesis
  • the inventors have prepared an optically active compound of the nucleoside derivative expressed by the formula 1 by the above three methods.
  • apiose derivatives having an absolute structure of the following formula 2 or 3 are condensed with appropriate bases, and are separated on column:
  • R 8 and R 9 are hydrogen, hydroxyl protecting group, preferably alkyl group, acyl group or substituted silyl group, more preferably benzyl group, triphenylmethyl group, acetyl group, benzoyl group, trimethylsilyl group, tertiary butyldimethylsilyl group, or tertiary butyldiphenylsilyl group, respectively;
  • L is acyloxy, halide group or alkoxy group and among them, acetoxy group is preferred.
  • optically active compound wherein R, is hydrogen is obtained by the deprotecting reaction of the above-obtained optically active compound.
  • the optically active compound wherein R, is phosphate or phosphonate can be obtained by the reaction with phosphate or phosphonate compound of the optically active compound wherein Rx. is hydrogen, obtained above.
  • optically active compound of the nucleoside derivative expressed by formula 1, can be obtained by the procedure that comprises the condensation of the compound expressed by formula 2 or 3 with silyl-protected base in the presence of Lewis acid catalyst.
  • Preferred solvents of the condensation reaction include dichloromethane, 1,2- dichloroethane and acetonitrile.
  • Preferred Lewis acid is selected from silyl compounds, such as tin chloride, titanium tetrachloride and trimethylsilyl triplate.
  • an optically active compound expressed by the formula 2 or 3 is also a novel one designed to use as an intermediate in the manufacture of optically active compound of the nucleoside derivative expressed by the formula 1.
  • This compound can be prepared according to the following reaction scheme 1 : &C
  • R 8 , R-g and L are same as defined above, and R 8 and R 9 is not same with each other.
  • a process for obtaining an optically active compound of the nucleoside derivative expressed by the formula 1 is conducted in such a manner that: primary alcohol of the well known compound 4 is selectively protected to give a compound 5; the compound 5 is fluorinated by fluorination reagents such as DAST (diethylaminosulfurtrifluoride) to give a compound 6; the protecting group of two primary alcohols from the compound 6 is selectively deprotected to give a compound 7a and 7b; the compound 7a and 7b is cleavaged in the presence of ozone to give lactol 8a and 8b; and the lactol 8 is acylated, alkylated or halogenated to give intermediates 2 and 3.
  • fluorination reagents such as DAST (diethylaminosulfurtrifluoride)
  • This optical resolution method is based on the principle that, from the D or the L form composing racemic compound, only one optical isomer can be esterificated or de-esterificated selectively by specific enzyme.
  • the above lipase or esterase may be obtaind in any one selected from the group consisting of Aspergillus, Mucor, Rhizopus, Penicillium, Candida, Pseudomonas, hog's pancreas (PPL), etc., while esterification reagents include vinyl ester of carboxylic acid having C ⁇ C 20 -
  • a substrate used for the selective de-esterification includes acyl ester of C, ⁇ C 20 derived from racemic compound expressed by the formula 1.
  • the solvents used for this enzymatic reaction include water, organic solvent or co-solvent consisting of water and organic solvent.
  • optically active compound of the nucleoside derivative expressed by the formula 1 may be prepared in such a manner that a racemic compound of the nucleoside derivative expressed by the formula 1 is reacted with an optical resolution reagent to give a diastereoisomer salt or complex; the compound is separated by fractional crystallization or column chromatography; and the optical resolution reagent is removed using acid or base.
  • the optical resolution reagents include an optically active amino acid or its derivative, optically active tartaric acid, optically active mandelic acid, an optically active malic acid, camphosulfonic acid and an optically active alkaloids (e.g., quinine, cinchonine and strychnine).
  • a solvent water or organic solvent may be used.
  • some pharmaceutically acceptable salt may be obtained in such a manner that after dissolving the above compound, so obtained, in an appropriate solvent, the mixture is reacted with acid or base and its preferred salt is a hydrochloride salt.
  • An object of the present invention is to provide an anti-HBV agent containing an optically active compound of the nucleoside derivative expressed by the formula 1.
  • the optically active compound of the nucleoside derivative expressed by the formula 1 has 10-500 mg of daily adult dose.
  • the anti-HBV agent of this invention may be administered orally or parenterally to the body by general method.
  • Example 1 Synthesis of (2R)-2-hydroxy-2-(benzyloxymethyl)-4- pentene-1-yl-benzoate To a solution of (2S)-2-hydroxy-2-(benzyloxymethyl)-4- penten-1-ol (290 mg) in dichloromethane (4 ml), dimethylaminopyridine (32 mg), triethylamine (0.3 ml), and benzoic anhydride (443 mg) were added and the mixture was stirred at room temperature for 2 hours. The resultant mixture was diluted with dichloromethane and washed with IN hydrochloric acid, saturated sodium bicarbonate solution and brine, successively. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 7 Synthesis of (-)-N 4 -acetyI-l-(3'-0-benzyl-2,3-dideoxy- 3-fluoroapio- ⁇ -L-furanosyl) cytosine and (+)-N 4 -acetyl-l-(3'-0- benzyl-2,3-dideoxy-3-fluoroapio- a -L-furanosyl) cytosine
  • This suspension was cooled in an ice/water bath to 5 °C , and treated with trimethylsilyltrifluoromethane sulfonate (0.23 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (5 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 8 Synthesis of (+)-N 4 -acetyI-l-(3'-0-benzoyl-2,3- dideoxy-3-fluoroapio- ⁇ -D-furanosyl) cytosine and (-)-N 4 -acetyl- l-(3'-0-benzoyl-2,3-dideoxy-3-fluoroapio- a -D-furanosyl) cytosine
  • N 4 -acetylcytosine 178 mg
  • ammonium sulfate catalytic amount
  • Example 9 Synthesis of (-)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -L- furanosyl) cytosine To a solution of (-)-N 4 -acetyl-l-(3'-0-benzyl-2,3-dideoxy-3- fluoroapio- ⁇ -L-furanosyl) cytosine (72 mg) in dichloromethane (5 ml), borontrichloride (1.0M solution in dichloromethane, 1 ml) was added at -78 ° C and the mixture was stirred at the same temperature for 1 hour.
  • Example 10 Synthesis of (+)-l-(2,3-dideoxy-3-fluoroapio- a -L- furanosyl) cytosine
  • the title compound (39 mg, 87.6%>) as a white solid was obtained in the same manner as described in Example 9, using (+)-N 4 - acetyl-l-(3'-0-benzyl-2,3-dideoxy-3-fluoroapio- a -L-furanosyl) cytosine (70 mg) obtained in Example 7 instead of (-)-N 4 -acetyl-l-(3'- 0-benzyl-2,3-dideoxy-3-fluoroapio- ⁇ -L-furanosyl) cytosine. [ +110.87 ° (c 0.18, CH 3 OH )
  • This suspension was cooled in an ice/water bath to 5 °C , and treated with trimethylsilyltrifluoromethanesulfonate (0.17 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (5 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 14 Synthesis of (+)-N 4 -benzoyl-l-(3'-0-benzoyl-2,3- dideoxy-3-fluoroapio- ⁇ -D-furanosyl)-5-fluorocytosine and (-)-N 4 - benzoyl-l-(3'-0-benzoyl-2,3-dideoxy-3-fluoroapio- a -D- furanosyl)-5-fluorocytosine
  • This suspension was cooled in an ice/water bath to 5 °C , and treated with trimethylsilyltrifluoromethanesulfonate (0.41 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (5 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • the titled compound (28 mg, 71.6%) as a white solid was obtained in the same manner as described in Example 15, except using (+)-N 4 -benzoyl-l-(3'-0-benzyl-2,3-dideoxy-3-fluoroapio- a -L- furanosyl)-5-fluorocytosine (70 mg) obtained in Example 13 instead of (-)-N 4 -benzoyl-l -(3'-0-benzyl-2,3-dideoxy-3-fluoroapio- ⁇ -L- furanosyl)-5-fluorocytosine.
  • N 4 -benzoyl-l-(3'-0-benzyl-2,3-dideoxy-3-fluoroapio- -D- furanosyl)-5-fluorocytosine (210 mg) obtained in Example 14 instead of (+)-N 4 -benzoyl-l-(3'-0-benzoyl-2,3-dideoxy-3-fluoroapio- ⁇ -D- furanosyl)-5-fluorocytosine.
  • Example 19 Synthesis of (+)-l-(3'-0-benzyl-2,3-dideoxy-3- fluoroapio- ⁇ -L-furanosyl) thymine and (+)-l-(3'-0-benzyl-2,3- dideoxy-3-fluoroapio- a -L-furanosyl) thymine
  • This suspension was cooled in an ice/water bath to 5 °C , and treated with trimethylsilyltrifluoromethane sulfonate (0.76 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 20 Synthesis of (-)-l-(3'-0-benzoyl-2,3-dideoxy-3- fluoroapio- ⁇ -D-furanosyl) thymine and (-)-l-(3'-0-benzoyl-2,3- dideoxy-3-fluoroapio- a -D-furanosyl) thymine
  • This suspension was cooled in an ice/water bath to 5 °C , and treated with trimethylsilyltrifluoromethane sulfonate (1.42 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • the titled compound (120 mg, 71.4%) as a white solid was obtained in the same manner as described in Example 21 , using (+)- 1 - (3'-0-benzyl-2,3-dideoxy-3-fluoroapio- a -L-furanosyl) thymine (230 mg) obtained in Example 19 instead of (+)-l-(3'-0-benzyl-2,3- dideoxy-3-fluoroapio- ⁇ -L-furanosyl) thymine.
  • Example 25 Synthesis of (+)-l-(3'-0-benzyl-2,3-dideoxy-3- fluoroapio- ⁇ -L-furanosyl)-5-ethyluracil and (+)-l-(3'-0-benzyl- 2,3-dideoxy-3-fluoroapio- a -L-furanosyl)-5-ethyluracil
  • ⁇ -iorm ⁇ NMR (CDC1 3 ) ⁇ : 9.42 (s, IH), 7.37 - 7.26 (m, 5H), 7.06 (s, IH), 6.20 (t, IH), 4.60 (s, 2H), 4.33 -4.12 (m, 2H), 3.75 - 3.71 (m, 2H), 2.78 -2.67 (m, IH), 2.44 -2.32 (m, IH), 2.32 -2.27 (m, 2H), 1.08 (t, 3H) ff -form : ⁇ NMR (CDC1 3 ) ⁇ : 9.75 (s, IH), 7.37 - 7.31 (m, 6H), 6.28 (dd, IH), 4.59 (dd, 2H), 4.43 -4.34 (m, IH), 3.97 (dd, IH), 3.75 -3.61 (m, 2H), 2.
  • Example 26 Synthesis of (-)-l-(3'-0-benzoyI-2,3-dideoxy-3- fluoroapio- ⁇ -D-furanosyl)-5-ethyluracil and (-)-l-(3'-0-benzoyl- 2,3-dideoxy-3-fluoroapio- -D-furanosyl)-5-ethyluracil
  • This suspension was cooled in an ice/water bath to 5 ° C , and treated with trimethylsilyltrifluoromethane sulfonate (0.25 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with chloroform, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 27 Synthesis of (+)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -L- furanosyl)-5-ethyluraciI
  • (+)-l-(3'-0-benzyl-2,3-dideoxy-3-fluoroapio- ⁇ -L-furanosyl)-5-ethyluracil 37 mg
  • borontrichloride 1.M solution in dichloromethane, 0.85 ml
  • Example 28 Synthesis of (+)-l-(2,3-dideoxy-3-fluoroapio- a -L- furanosyI)-5-ethyluracil
  • the titled compound (40 mg, 60%>) as a white solid was obtained in the same manner as described in Example 27, using (+)-l- (3'-0-benzyl-2,3-dideoxy-3-fluoroapio- a -L-furanosyl)-5-ethyluracil (90 mg) obtained in Example 25 instead of (+)-l-(3'-0-benzyl-2,3- dideoxy-3-fluoroapio- ⁇ -L-furanosyl)-5-ethyluracil.
  • the titled compound (65.8 mg, 89%) as a white solid was obtained in the same manner as described in Example 29, using (-)-l- (3'-0-benzoyl-2,3-dideoxy-3-fluoroapio- a -D-furanosyl)-5- ethyluracil (100 mg) obtained in Example 26 instead of (-)-l-(3'-0- benzoy 1-2 ,3 -dideoxy-3 -fluoroapio- ⁇ -D-furanosy l)-5 -ethy luracil .
  • Example 31 Synthesis of (+)-l-(3'-0-benzyl-2,3-dideoxy-3- fluoroapio- ⁇ -L-furanosyl)-5-iodouracil and (-)-l-(3'-0-benzyl- 2,3-dideoxy-3-fluoroapio- a -L-furanosyl)-5-iodouracil
  • This suspension was cooled in an ice/water bath to 5 °C , and treated with trimethylsilyltrifluoromethane sulfonate (0.54 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 32 Synthesis of (-)-l-(3'-0-benzoyl-2,3-dideoxy-3- fluoroapio- ⁇ -D-furanosyl)-5-iodouracil and (+)-l-(3'-0-benzoyI- 2,3-dideoxy-3-fluoroapio- a -D-furanosyl)-5-iodouraciI
  • This suspension was cooled in an ice/water bath to 5 ° C , and treated with trimethylsilyltrifluoromethane sulfonate (0.4 ml). The reaction mixture was stirred for 30 minutes. Saturated sodium bicarbonate solution (10 ml) was added to the mixture and the mixture was allowed to warm to room temperature and stir for 20 minutes. The solution was diluted with dichloromethane, and the organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
  • Example 35 Synthesis of (-)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -D- furanosyl)-5-iodouracil
  • (-)-l-(3'-0-benzoyl-2,3-dideoxy-3- fluoroapio- ⁇ -D-furanosyl)-5-iodouracil 58 mg
  • sodium methoxide 25wt% solution in methanol, 0.1 ml
  • (+)-l-(3'-0-benzoyl-2,3-dideoxy-3-fluoroapio- a -D-furanosyl)-5- iodouracil (120 mg) obtained in Example 32 instead of (-)-l-(3'-0- benzoyl-2,3-dideoxy-3-fluoroapio- ⁇ -D-furanosyl)-5-iodouracil.
  • Example 37 Preparation of (-)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -L- furanosyl) cytosine by enzymatic optical resolution
  • the titled compound (30 mg) was obtained in the same manner as described in the 1st method, using Amano-PS (20 mg) instead of Amano-AK. 3 rd method
  • the titled compound (32 mg) was obtained in the same manner as described in the 1st method, using pseudomonas fluorescence lipase (26.5 mg) instead of Amano-AK.
  • the titled compound (42 mg) was obtained in the same manner as described in the 1st method, using acetonitrile (6 ml) instead of t-butylalcohol.
  • Example 38 Preparation of (+)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -D- furanosyl) cytosine by enzymatic optical resolution
  • Example 39 Preparation of (-)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -L- furanosyl) cytosine by an optical resolution reagent 1 st method
  • the titled compound (102 mg) was obtained in the same manner as described in the 1st method, using L-mandelic acid (390 mg) as an optical resolution reagent instead of (-)-N-acetyl- phenylglycine.
  • Example 40 Preparation of (+)-l-(2,3-dideoxy-3-fluoroapio- ⁇ -D- furanosyl) cytosine by an optical resolution reagent
  • Antiviral assay was performed by the following method. D form compound obtained in Example 24, L form compound obtained in Example 22 and racemic compound thereof were used respectively as a test compound, and lamivudine was used as a reference compound.
  • HBV DNA was then analyzed in a quantitative and qualitative manner for overall levels of HBV DNA.
  • Acute oral toxicity test was performed by the following method. Five male ICR mice aged with 4 weeks and weighing between 20 and 25 g were used as a group. 250 mg/kg, 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg, as single dose, of L form compound obtained in Example 22 were administered to four test groups, respectively. All mice were fasted during 16 h prior to compound administration. The test compound was suspended in corn oil to make 20 ml/kg of administration volume regardless dose, and the suspension was administered orally to the test groups separately. The observations of clinical symptoms were performed during 2 weeks from drug administration. The results were recorded daily, and body weights were determined at least three times. After 2 weeks, that is, observation period, autopsy was performed.
  • mice The organs and the tissues of mice were observed with naked eyes, and the results were recorded. As a result, it was observed that LD 50 of the test compound, calculated from the result, was at least 2,000 mg/kg. And abnormal phenomena were not observed in the clinical symptoms and in the result of autopsy. At the test doses, the mortality rates were 0%.

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Abstract

L'invention concerne un nouveau dérivé de nucléoside optiquement actif, représenté par la formule (1), dans laquelle R1 est hydrogène, phosphate ou un groupe alkyle ou acyle; et R2 est une base pyrimidique ou purique substituée ou non substituée; ainsi que son procédé de production et un agent anti-HBV le contenant.
PCT/KR1998/000149 1997-06-10 1998-06-09 Nouveau derive de nucleoside optiquement actif, son procede de production et agent anti-hbv le contenant WO1998056803A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU77897/98A AU7789798A (en) 1997-06-10 1998-06-09 Novel optically active nucleoside derivative, its manufacturing method and anti-hbv agent containing the derivative thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR19970023863 1997-06-10
KR1997/23863 1997-06-10

Publications (1)

Publication Number Publication Date
WO1998056803A1 true WO1998056803A1 (fr) 1998-12-17

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PCT/KR1998/000149 WO1998056803A1 (fr) 1997-06-10 1998-06-09 Nouveau derive de nucleoside optiquement actif, son procede de production et agent anti-hbv le contenant

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Country Link
KR (1) KR19990006811A (fr)
AU (1) AU7789798A (fr)
ID (1) ID20944A (fr)
WO (1) WO1998056803A1 (fr)
ZA (1) ZA984796B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011510090A (ja) * 2008-01-22 2011-03-31 ダウ アグロサイエンシィズ エルエルシー ５−フルオロピリミジン誘導体

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03161488A (ja) * 1989-11-21 1991-07-11 Takeda Chem Ind Ltd 光学活性シクロペンタン誘導体およびその製造法
WO1994014456A1 (fr) * 1992-12-24 1994-07-07 Biochem Pharma Inc. Utilisation d'analogues de nucleosides didesoxy dans le traitement d'infections virales

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03161488A (ja) * 1989-11-21 1991-07-11 Takeda Chem Ind Ltd 光学活性シクロペンタン誘導体およびその製造法
WO1994014456A1 (fr) * 1992-12-24 1994-07-07 Biochem Pharma Inc. Utilisation d'analogues de nucleosides didesoxy dans le traitement d'infections virales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 105, No. 3, 21 July 1986, (Columbus, Ohio, USA), page 670, Abstract No. 24554w, DYATKINA N.B. et al., "Nucleosides of Fluoro Sugars. XV. Synthesis of 2'-3'-Dideoxy-3'-Fluoro-D-Ribofuranosyl Benzimidazole - A New Fluorosugar Purine Nucleoside Analog"; & Z. CHEM., 1985, 25(5), 180 (Ger). *
CHEMICAL ABSTRACTS, Vol. 115, No. 21, 25 November 1991, (Columbus, Ohio, USA), page 1009, Abstract No. 232777e, FUKASE H. et al., "Preparation of 2'-3'-Dideoxy-3'-Fluoro Carbocyclic Purine Nucleoside Analogs as Virucides"; & JP,A,03 161 488. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011510090A (ja) * 2008-01-22 2011-03-31 ダウ アグロサイエンシィズ エルエルシー ５−フルオロピリミジン誘導体
US9174970B2 (en) 2008-01-22 2015-11-03 Dow Agrosciences Llc 5-fluoro pyrimidine derivatives
US9204653B2 (en) 2008-01-22 2015-12-08 Dow Agrosciences Llc 5-fluoro pyrimidine derivatives

Also Published As

Publication number Publication date
ZA984796B (en) 1998-12-29
KR19990006811A (ko) 1999-01-25
ID20944A (id) 1999-04-01
AU7789798A (en) 1998-12-30

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