WO1997000879A1 - Method for preparing sulphate esters effective in the treatment of hiv (human immunodeficiency virus) infections, and aids - Google Patents
Method for preparing sulphate esters effective in the treatment of hiv (human immunodeficiency virus) infections, and aids Download PDFInfo
- Publication number
- WO1997000879A1 WO1997000879A1 PCT/SE1996/000824 SE9600824W WO9700879A1 WO 1997000879 A1 WO1997000879 A1 WO 1997000879A1 SE 9600824 W SE9600824 W SE 9600824W WO 9700879 A1 WO9700879 A1 WO 9700879A1
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- WIPO (PCT)
- Prior art keywords
- acetyl
- sulphate
- mono
- tri
- derivative
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 150000003467 sulfuric acid derivatives Chemical class 0.000 title abstract description 6
- 241000725303 Human immunodeficiency virus Species 0.000 title description 3
- 208000015181 infectious disease Diseases 0.000 title description 2
- 229910021653 sulphate ion Inorganic materials 0.000 claims abstract description 11
- 150000002402 hexoses Chemical class 0.000 claims abstract description 7
- 150000002972 pentoses Chemical class 0.000 claims abstract description 7
- YYHPEVZFVMVUNJ-UHFFFAOYSA-N n,n-diethylethanamine;sulfur trioxide Chemical compound O=S(=O)=O.CCN(CC)CC YYHPEVZFVMVUNJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical group O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical class CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000003729 nucleotide group Chemical group 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical class CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 2
- 150000001413 amino acids Chemical group 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- 239000002773 nucleotide Chemical group 0.000 claims description 2
- 229920001184 polypeptide Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 108090000765 processed proteins & peptides Chemical group 0.000 claims description 2
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N 2-Amino-2-Deoxy-Hexose Chemical compound NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- 229930182830 galactose Natural products 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 150000008278 pentosamines Chemical class 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- KWDXXNWKTRGMDM-IYWGXSQHSA-N n-acetylgalactosamine 4,6-disulfate Chemical compound CC(=O)N[C@H]1C(O)O[C@H](COS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@@H]1O KWDXXNWKTRGMDM-IYWGXSQHSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 3
- BCGMHUJYDACFAF-SMTKFLNTSA-N (2R,3R,4S,5S)-5-acetamido-3,4,6-trihydroxy-2-(hydroxymethyl)oxane-3,4-disulfonic acid Chemical compound S(=O)(=O)(O)[C@]1([C@H](C(O)O[C@@H]([C@@]1(O)S(=O)(=O)O)CO)NC(C)=O)O BCGMHUJYDACFAF-SMTKFLNTSA-N 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000008273 hexosamines Chemical class 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- -1 sulphate ester derivatives of N-acetyl-D-galactosamine Chemical class 0.000 description 2
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- WHCJUIFHMJFEFZ-IYWGXSQHSA-N N-Acetylgalactosamine 4-sulfate Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](OS(O)(=O)=O)[C@@H]1O WHCJUIFHMJFEFZ-IYWGXSQHSA-N 0.000 description 1
- OVRNDRQMDRJTHS-YTWDBIDXSA-N N-[(3S,4S,5S,6S)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1C(O)O[C@@H](CO)[C@@H](O)[C@H]1O OVRNDRQMDRJTHS-YTWDBIDXSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- WHCJUIFHMJFEFZ-UIAUGNHASA-N N-acetyl-beta-D-galactosamine 4-sulfate Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS(O)(=O)=O)[C@@H]1O WHCJUIFHMJFEFZ-UIAUGNHASA-N 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- UACKMRBTWRKKRF-KEWYIRBNSA-N [(2r,3s,4r,5r)-5-acetamido-6-hydroxy-3,4-disulfooxyoxan-2-yl]methyl hydrogen sulfate Chemical compound CC(=O)N[C@H]1C(O)O[C@H](COS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@@H]1OS(O)(=O)=O UACKMRBTWRKKRF-KEWYIRBNSA-N 0.000 description 1
- YQKFJYBRZVNXKQ-UHFFFAOYSA-N [Na].BC#N Chemical compound [Na].BC#N YQKFJYBRZVNXKQ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical group S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 150000008272 galactosaminides Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
Definitions
- the present invention relates to a method for preparing mono-, di-, tri-or tetra-sulphate esters of pentoses and hexoses and their salts, see formulas (I) .
- R 1 is hydrogen, C j ,-C ⁇ -alkyl, benzyl, amino acid, nucleotide, or polypeptide;
- R 2 is OH, S0 4 ' or NHR 3 ;
- R 3 is hydrogen, acetyl or C 2 -C 24 -acyl, aminoacyl or sulphonyl;
- X 3 is OH or S0 4 " ;
- X 4 is OH or SO « " ;
- X s is OH or S0 4 " ; is OH or SOpole “ ;
- , is H, Na, K, Ca, Zn, Mg, Li, Ba, Mn, Hg, Ag or Au.
- the general method for preparing sulphated pentoses and hexoses according to the invention include sulphation with sulphur trioxide-triethylamine complex of hydroxyl- protected sugars in a polar solvent, such as N,N-dimethyl formamide at 20-80 * C, preferably 30-70'C, most preferably 40- 60 * C.
- This reaction step is very effective and yield almost quantitative yields in mild conditions, it is also very efficient in producing specially de ⁇ igned sulphate esters.
- the sulphation method according to the invention also include catalytic hydrogenation in presence of a catalyst, such as palladium hydroxide, to give compounds with formulas (I) .
- One embodiment of the present invention is the method for preparation of sulphate ester derivatives of N-acetyl-D-galactosamine.
- the method comprises treatment of N-acetyl-D-galactosamine with benzyl alcohol and Amberiite ® IR 120 to yield benzyl-N-acetyl-D- galactosaminide.
- the hydroxyl groups of benzyl-N-acetyl- D-galactosaminide was protected and treated with sulphur trioxide-triethylamine complex in N,N-dimethyl formamide at 20-80 * C.
- reaction yielded mono-, di- or tri-sulphate substituted benzyl-N-acetyl-D-galactosaminide.
- the sulph ⁇ ated galactosaminide was catalytically hydrogenated with palladium hydroxide and was commonly worked up to give 50-99% of mono-, di- or tri-sulphate substituted N-ace- tyl-D-galactosamine.
- a further embodiment of the present invention is a method for preparation of sulphate ester derivatives of N-acetyl-D-glucosamine.
- the preparation procedure follo ⁇ wed the same route as described above and yielded after common workup procedures 50-99% of mono-, di- or tri- sulphate substituted N-acetyl-D-glucosamine.
- the 6-O-benzyl derivative (278mg, 85%) was O-sulphated as described in example 1 to give 3,4-di-sulpho-N-acetyl-D- galactosamine (75mg, 91%) . SO calc. 50.65% found 49.0%.
- the benzylidene group was removed by treatment of the product (400mg) with 60% acetic acid in water (10ml) with stirring at 60 C for 3 hours, then cooled, and concentrated. The acetic acid was removed by repeated evaporation with toluene and 295 mg (90%) of 3-0-benzyl derivative was obtained.
- This compound was O-sulphated a ⁇ described in example 1 and gave 74,8 mg (83%) of 4,6-di- O-sulpho-N-acetyl-D-galactosamine. SO calcd. 50.65%, Found 49.5%.
- Benzyl-N-acetyl-D-galactosaminide 300 mg was stirred with trityl chloride (300 mg) and silver nitrate (250 mg) in pyridine (5 ml) at room temperature for 24 hours.
- the reaction mixture was partitioned between dichloromethane and water and the organic layer was concentrated. Column chromatography of the residue (dichloromethane-methanol (9:1)) gave 6-0-trityl derivative (373mg, 70%) .
- the product was benzylated as described earlier to obtain 3, 4-di-O-benzyl derivative.
- this derivative was treated with trifluoro acetic acid (10 ml 1 % in dichloromethane) at room temperature for 20 hours.
- Column chromatography of the residue on silica gel gave 3,4-di-0-benzyl-6-OH derivati ⁇ ve (284mg, 90%) .
- the 3, 4-di-0-benzyl-6-OH derivative was O-sulphated as described in example 1 to give 6-0- ⁇ ulpho- N-acetyl-D-galacto ⁇ amine (177mg, 92%) . SO calc. 32.0% found 30.3%.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method for preparing sulphate esters of pentoses and hexoses and their salts, together with sulphur trioxide-triethylamine complex to form a mono-, di-, tri- or tetra-sulphate ester of the pentose or hexose.
Description
Method for preparing sulphate esters effective in the treatment of HIV (Human Immuno Deficiency Virus ) infections , and AIDS.
The present invention relates to a method for preparing mono-, di-, tri-or tetra-sulphate esters of pentoses and hexoses and their salts, see formulas (I) .
Where R1 is hydrogen, Cj,-Cε-alkyl, benzyl, amino acid, nucleotide, or polypeptide;
R2 is OH, S04 ' or NHR3; R3 is hydrogen,
acetyl or C2-C24-acyl, aminoacyl or sulphonyl;
X3 is OH or S04 "; X4 is OH or SO« "; Xs is OH or S04 "; is OH or SO„"; , is H, Na, K, Ca, Zn, Mg, Li, Ba, Mn, Hg, Ag or Au.
Background of the Invention Sulphate esters of hexosamines have been prepared by direct sulphation of hexosamines with chlorosulphonic acid. Previously, Lloyd, A.G. (1962) Biochem. J. 83, 455-460 and Suzuki, S. and Strominger, J.L. (1960) J. Biol. Chem. 235, 267-273 showed that sulphate esters prepared by the direct sulphation of N-acetyllgalactosamine with chlo- rosulfonic acid consists of mixtures of mono-and bisulphate esters of the sugar. In a later publication Kazuhiko Ishihara et al. Biochim. Biophys. Acta, 437 (1979) 416-430, synthesised N-acetylgalactosamine-4, 6-disulphate. UDP-GalNAc- 4-sulphate was treated with chlorosulfonic acid, the disulphated nucleotide thus prepared was hydrolysed with 0.01 M HCl to result in N-acetylgalactosamine-4, 6-disulphate. In
CONFIRMATION OPY
an other paper Yasuo Nakanis i et al. J. of Biol. Chem. vol. 256 No. 11 (1981) 5443-5449, sulphate was introduced into position 6 of the nonreducing terminal N-acetylgalactosamine- 4-sulphate by a terminal 6-sulphotransferase.
Description of the Invention
The general method for preparing sulphated pentoses and hexoses according to the invention include sulphation with sulphur trioxide-triethylamine complex of hydroxyl- protected sugars in a polar solvent, such as N,N-dimethyl formamide at 20-80*C, preferably 30-70'C, most preferably 40- 60*C. This reaction step is very effective and yield almost quantitative yields in mild conditions, it is also very efficient in producing specially deεigned sulphate esters. The sulphation method according to the invention also include catalytic hydrogenation in presence of a catalyst, such as palladium hydroxide, to give compounds with formulas (I) .
One embodiment of the present invention is the method for preparation of sulphate ester derivatives of N-acetyl-D-galactosamine. The method comprises treatment of N-acetyl-D-galactosamine with benzyl alcohol and Amberiite® IR 120 to yield benzyl-N-acetyl-D- galactosaminide. The hydroxyl groups of benzyl-N-acetyl- D-galactosaminide was protected and treated with sulphur trioxide-triethylamine complex in N,N-dimethyl formamide at 20-80*C. Depending on which hydroxyl groups were protected the reaction yielded mono-, di- or tri-sulphate substituted benzyl-N-acetyl-D-galactosaminide. The sulph¬ ated galactosaminide was catalytically hydrogenated with palladium hydroxide and was commonly worked up to give 50-99% of mono-, di- or tri-sulphate substituted N-ace- tyl-D-galactosamine.
A further embodiment of the present invention is a method for preparation of sulphate ester derivatives of N-acetyl-D-glucosamine. The preparation procedure follo¬ wed the same route as described above and yielded after
common workup procedures 50-99% of mono-, di- or tri- sulphate substituted N-acetyl-D-glucosamine.
The following examples are given by way of ex¬ ample the invention only and not by way of limitation thereof.
Example 1
3,4, 6-tri-O-sulpho-N-acetyl-D-galactosamine
A solution of benzyl-N-acetyl-D-galactosaminide (155mg) was stirred in N,N-dimethyl formamide (2 ml) for 15 hours at 50*C in presence of sulphur trioxide-triethy¬ lamine complex (380mg) . The mixture was cooled and met¬ hanol (1 ml) was added. The mixture was chromatographed on a silica gel (30 g) column with ethylacetate: yridine- :acetic acid:water (8:5:1:3) to yield a pure fraction, this was solved in methanol (1 ml) and was further elua¬ ted from a Sephadex® SP 25 (Na+-form 2x25 cm) column with methanol:water (1:9) to afford the 3,4, 6-tri-O-sulpho- derivative ( 220 mg, 80%) . The benzyl-groups were removed in a solution of ethanol:water (2:1) and catalytic hydro¬ genation in presence of palladium hydroxide (20% Pd) for 1 day. The suspension was filtered and concentrated, finally lyophilised. SO calc. 64.86% found 63.5%.
Example 2
3,4-di-sulpho-N-acetyl-D-galactosamine
A solution of benzyl 4, 6-0-benzylidene-N-acetyl- D-galactosaminide (1 mmol) and sodium cyanoborhydride (9 mmol) in dry THF (15 ml) containing powdered 3A molecular sieves was cooled to O'C. Hydrogen chloride in diethyl ether was added dropwise until the solution was acidic (pH paper, gas evolution) . The mixture was monitored with TLC and when completed (after 10 min. at O'C) it was poured into ice-water. The product was extracted with dichloromethane and purified on a silica gel column. The 6-O-benzyl derivative (278mg, 85%) was O-sulphated as described in example 1 to give 3,4-di-sulpho-N-acetyl-D-
galactosamine (75mg, 91%) . SO calc. 50.65% found 49.0%.
Example 3
4, 6-di-D-sulpho-N-acetyl-D-galactosamine A solution of benzyl-4, 6-0-benzylidene-N-acetyl-
D-galactosaminide (400 mg) in dry N,N-dimethylformamide (6 ml) was stirred at O'C in presence of barium oxide (845,5 mg) , barium hydroxide 8 H20 (261 mg) and benzyl bromide (232 μl) waε added. After completion of the reaction (TLC, dichloromethane.-methanol (95:5)) the excess of benzyl bromide was quenched with methanol (150 μl) . The mixture was diluted with chloroform, washed with water, dried (Na2S04) and concentrated. The residue was crystallized from ethanol yielding 472 mg (70%) of product. The benzylidene group was removed by treatment of the product (400mg) with 60% acetic acid in water (10ml) with stirring at 60 C for 3 hours, then cooled, and concentrated. The acetic acid was removed by repeated evaporation with toluene and 295 mg (90%) of 3-0-benzyl derivative was obtained. This compound was O-sulphated aε described in example 1 and gave 74,8 mg (83%) of 4,6-di- O-sulpho-N-acetyl-D-galactosamine. SO calcd. 50.65%, Found 49.5%.
Example 4
4-O-sulpho-N-acetyl-D-galactosamine
A solution of benzyl-4, 6-0-benzylidene-N-acetyl- D-galactosaminide (400 mg) was treated as described in example 3. The di-O-benzyl derivative was O-sulphated as described in example 1 to give 4-0-sulpho-N-acetyl-D- galactoεamine (180mg, 91%) . NMR data: 2,1 ppm s N-Ac,* 3,6-4 ppm m skeleton H; 4,1-4,2 ppm m C6-H; 4,6 ppm d C4- H; 5,2 ppm d anomer H. The NMR spectra were recorded on a Brucker 200 instrument. SO calc. 32.0% found 30.6%.
Example 5
3-sulpho-N-acetyl D-galactosamine
Benzyl-N-acetyl-D-galactosaminide (400 mg) was treated with benzaldehyde dimethylacetal to give 450 mg (88%) of 4, 6-O-benzylidene derivative. O-Sulphation was achieved with the sulphur trioxide-triethylamine complex in N,N-dimethylformamide yielding 431,3 mg (90%) of 3-0- sulpho-derivative from 400 mg of starting material . The product (350 mg) was catalytically hydrogenated in ethanol-water in presence of palladium hydroxide giving 200 mg (91%) of 3-0-sulpho--N-acetyl-galactosamine. SO calcd. 32%, found 30,2%.
Example 6 6-0-sulpho-N-acetyl-D-galactosamine
Benzyl-N-acetyl-D-galactosaminide (300 mg) was stirred with trityl chloride (300 mg) and silver nitrate (250 mg) in pyridine (5 ml) at room temperature for 24 hours. The reaction mixture was partitioned between dichloromethane and water and the organic layer was concentrated. Column chromatography of the residue (dichloromethane-methanol (9:1)) gave 6-0-trityl derivative (373mg, 70%) .
The product was benzylated as described earlier to obtain 3, 4-di-O-benzyl derivative. To remove the 6-O- trityl group this derivative was treated with trifluoro acetic acid (10 ml 1 % in dichloromethane) at room temperature for 20 hours. Column chromatography of the residue on silica gel gave 3,4-di-0-benzyl-6-OH derivati¬ ve (284mg, 90%) . The 3, 4-di-0-benzyl-6-OH derivative was O-sulphated as described in example 1 to give 6-0-εulpho- N-acetyl-D-galactoεamine (177mg, 92%) . SO calc. 32.0% found 30.3%.
Claims
1. A method for preparing mono-, di-, tri-or tetra- sulphate esters of pentoses and hexoses, and salts there of, according to formulas (I)
R2 is OH, S04 ~ or NHR3; R3 is hydrogen, 
acetyl or C2-C24-acyl, aminoacyl or sulphonyl,-
X3 is OH or S04 "; X4 is OH or S04 "; Xs is OH or S04 "; is OH or S04 ";
Y+, Y2 is H, Na, K, Ca, Zn, Mg, Li, Ba, Mn, Hg, Ag or
Au,
characterized in that the sulphation step include treatment with sulphur trioxide-triethylamine complex.
2. A method according to claim 1, characterized in that the solvent used in the sulphation step is N,N- dimethylformamide.
3. A method according to claim 1 or 2, characteri¬ zed in that the reaction temperature of the sulphation step is in the range from 20 to 80"C, preferably from 30 to 70*C, most preferably from 40 to 60*C.
4. A method according to any of the claims 1-3, characterized in that the method comprises a catalytic hydrogenation step.
5. A method according to claim 4, characterized in that the catalyst is palladium hydroxide.
6. A method according to claim 5, characterized in that method comprises a protection step, wherein hydroxyl groups of the sugar is protected before the sulphation step.
7. A method according to any of the claims 1-6, characterized in that the pentoses and hexoses are selected from the group consisting of ribose, xylose, arabinose, galactose, glucose or mannose.
8. A method according to any of the claims 1-7, characterized in that the pentoses and hexoses have an amine-group in position 2.
9. A method according to claim 8, characterized in that the prepared hexosamine is a mono-, di-or tri- sulphate substituted N-acetyl-D-galactosamine derivative.
10. A method according to claim 8, characterized in that the prepared hexosamine is a mono-, di-or tri- sulphate substituted N-acetyl-D-glucosamine derivative.
11. A method according to claim 8, characterized in that the prepared pentosamine is a mono-or di-sulphate substituted N-acetyl-D-ribosamine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU62478/96A AU6247896A (en) | 1995-06-21 | 1996-06-20 | Method for preparing sulphate esters effective in the treatment of hiv (human immunodeficiency virus) infections, and aids |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9502264-6 | 1995-06-21 | ||
| SE9502264A SE9502264D0 (en) | 1995-06-21 | 1995-06-21 | Method for preparing sulphate esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997000879A1 true WO1997000879A1 (en) | 1997-01-09 |
Family
ID=20398703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE1996/000824 WO1997000879A1 (en) | 1995-06-21 | 1996-06-20 | Method for preparing sulphate esters effective in the treatment of hiv (human immunodeficiency virus) infections, and aids |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6247896A (en) |
| SE (1) | SE9502264D0 (en) |
| WO (1) | WO1997000879A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004007515A1 (en) * | 2002-07-10 | 2004-01-22 | Seikagaku Corporation | Sulfotransferase inhibitors |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992533A (en) * | 1988-09-29 | 1991-02-12 | Rikagaku Kenkyusho | Sulfated oligosaccharides and derivatives thereof |
| US5116821A (en) * | 1990-11-20 | 1992-05-26 | The Procter & Gamble Company | Sulfated glyceroglucolipids as inhibitors of bacterial adherence |
| US5385891A (en) * | 1991-08-29 | 1995-01-31 | Tanabe Seiyaku Co., Ltd. | Polysulfate of β-cyclodextrin derivative and process for preparing the same |
-
1995
- 1995-06-21 SE SE9502264A patent/SE9502264D0/en unknown
-
1996
- 1996-06-20 AU AU62478/96A patent/AU6247896A/en not_active Abandoned
- 1996-06-20 WO PCT/SE1996/000824 patent/WO1997000879A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4992533A (en) * | 1988-09-29 | 1991-02-12 | Rikagaku Kenkyusho | Sulfated oligosaccharides and derivatives thereof |
| US5116821A (en) * | 1990-11-20 | 1992-05-26 | The Procter & Gamble Company | Sulfated glyceroglucolipids as inhibitors of bacterial adherence |
| US5385891A (en) * | 1991-08-29 | 1995-01-31 | Tanabe Seiyaku Co., Ltd. | Polysulfate of β-cyclodextrin derivative and process for preparing the same |
Non-Patent Citations (2)
| Title |
|---|
| CARBOHYDR. CHEM., Volume 7, No. 3, 1988, I.G. LEDER, "Synthesis of the 3-0, 4-0 and 6-0 Sulfates of Methyl 2-Amino-2-Deoxy-alpha-D-Glucopyranoside", page 583 - page 592. * |
| CARBOHYDR. RES., Volume 93, 1981, P.J. ARCHBALD et al., "13C-NMR Studies of D-Glucose and D-Galactose Monosulphates", page 177 - page 190. * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004007515A1 (en) * | 2002-07-10 | 2004-01-22 | Seikagaku Corporation | Sulfotransferase inhibitors |
| JPWO2004007515A1 (en) * | 2002-07-10 | 2005-11-10 | 生化学工業株式会社 | Sulfate transferase inhibitor |
| JP4549185B2 (en) * | 2002-07-10 | 2010-09-22 | 生化学工業株式会社 | Sulfate transferase inhibitor |
| US8288139B2 (en) | 2002-07-10 | 2012-10-16 | Seikagaku Corporation | Sulfotransferase inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| SE9502264D0 (en) | 1995-06-21 |
| AU6247896A (en) | 1997-01-22 |
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