DE3906357A1 - NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTS - Google Patents
NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTSInfo
- Publication number
- DE3906357A1 DE3906357A1 DE3906357A DE3906357A DE3906357A1 DE 3906357 A1 DE3906357 A1 DE 3906357A1 DE 3906357 A DE3906357 A DE 3906357A DE 3906357 A DE3906357 A DE 3906357A DE 3906357 A1 DE3906357 A1 DE 3906357A1
- Authority
- DE
- Germany
- Prior art keywords
- hydrogen
- methyl
- compounds
- radical
- azido
- 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.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 12
- 239000002777 nucleoside Substances 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 230000000840 anti-viral effect Effects 0.000 title description 3
- 229940126601 medicinal product Drugs 0.000 title 1
- 150000003833 nucleoside derivatives Chemical class 0.000 title 1
- -1 acyclic nucleoside Chemical class 0.000 claims abstract description 78
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims abstract description 32
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 229940104302 cytosine Drugs 0.000 claims abstract description 16
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 14
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 9
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims abstract description 8
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims abstract description 8
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940113082 thymine Drugs 0.000 claims abstract description 8
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 150000004712 monophosphates Chemical class 0.000 claims abstract description 6
- 229930024421 Adenine Natural products 0.000 claims abstract description 5
- 229960000643 adenine Drugs 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 239000001177 diphosphate Substances 0.000 claims abstract description 5
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 5
- 235000011180 diphosphates Nutrition 0.000 claims abstract description 5
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229940035893 uracil Drugs 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 150000005840 aryl radicals Chemical group 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000001226 triphosphate Substances 0.000 claims description 4
- 235000011178 triphosphate Nutrition 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000006193 alkinyl group Chemical group 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- 125000003729 nucleotide group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 125000002015 acyclic group Chemical group 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- NFNOAHXEQXMCGT-UHFFFAOYSA-N 2-phenylmethoxyacetaldehyde Chemical compound O=CCOCC1=CC=CC=C1 NFNOAHXEQXMCGT-UHFFFAOYSA-N 0.000 description 3
- JXDZQJSQAMAXEL-UHFFFAOYSA-N 5-methyl-1,3-bis(trimethylsilyl)pyrimidine-2,4-dione Chemical compound CC1=CN([Si](C)(C)C)C(=O)N([Si](C)(C)C)C1=O JXDZQJSQAMAXEL-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- HRQGCQVOJVTVLU-UHFFFAOYSA-N bis(chloromethyl) ether Chemical compound ClCOCCl HRQGCQVOJVTVLU-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229940127073 nucleoside analogue Drugs 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KJBPYIUAQLPHJG-UHFFFAOYSA-N 1-phenylmethoxypropan-2-ol Chemical compound CC(O)COCC1=CC=CC=C1 KJBPYIUAQLPHJG-UHFFFAOYSA-N 0.000 description 2
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 2
- ANBUFJLGLGFVQO-UHFFFAOYSA-N 5-methyl-1-(1-phenylmethoxypropan-2-yloxymethyl)pyrimidine-2,4-dione Chemical compound C1=C(C)C(=O)NC(=O)N1COC(C)COCC1=CC=CC=C1 ANBUFJLGLGFVQO-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 206010001513 AIDS related complex Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 241000450599 DNA viruses Species 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 206010049025 Persistent generalised lymphadenopathy Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000007265 chloromethylation reaction Methods 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 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
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 201000003450 persistent generalized lymphadenopathy Diseases 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 125000005208 trialkylammonium group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 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 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- NLMDJJTUQPXZFG-UHFFFAOYSA-N 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane Chemical compound C1COCCOCCNCCOCCOCCN1 NLMDJJTUQPXZFG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BWACMFIZQAWINJ-UHFFFAOYSA-N 1-(1-hydroxypropan-2-yloxymethyl)-5-methylpyrimidine-2,4-dione Chemical compound OCC(C)OCN1C=C(C)C(=O)NC1=O BWACMFIZQAWINJ-UHFFFAOYSA-N 0.000 description 1
- IKJKWMZHARGQHY-UHFFFAOYSA-N 1-[(1-cyclohexyl-2-hydroxyethoxy)methyl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1COC(CO)C1CCCCC1 IKJKWMZHARGQHY-UHFFFAOYSA-N 0.000 description 1
- OIDPUZFPKYTECR-UHFFFAOYSA-N 1-[(1-cyclohexyl-2-phenylmethoxyethoxy)methyl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1COC(C1CCCCC1)COCC1=CC=CC=C1 OIDPUZFPKYTECR-UHFFFAOYSA-N 0.000 description 1
- ISQIHPIBRUCZDO-UHFFFAOYSA-N 1-[(2-hydroxy-1-phenylethoxy)methyl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1COC(CO)C1=CC=CC=C1 ISQIHPIBRUCZDO-UHFFFAOYSA-N 0.000 description 1
- ZXTKLQVROOZGGK-UHFFFAOYSA-N 1-[[1-(4,5-dihydro-1,3-thiazol-2-yl)-2-hydroxyethoxy]methyl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1COC(CO)C1=NCCS1 ZXTKLQVROOZGGK-UHFFFAOYSA-N 0.000 description 1
- HCFZACYZJLIELF-UHFFFAOYSA-N 1-cyclohexyl-2-phenylmethoxyethanol Chemical compound C1CCCCC1C(O)COCC1=CC=CC=C1 HCFZACYZJLIELF-UHFFFAOYSA-N 0.000 description 1
- QPTIFDOBDUXOJX-UHFFFAOYSA-N 1-phenyl-2-phenylmethoxyethanol Chemical compound C=1C=CC=CC=1C(O)COCC1=CC=CC=C1 QPTIFDOBDUXOJX-UHFFFAOYSA-N 0.000 description 1
- LBCWOJDBMOATOL-UHFFFAOYSA-N 2-(2-purin-9-ylethyl)propane-1,3-diol Chemical class N1=CN=C2N(CCC(CO)CO)C=NC2=C1 LBCWOJDBMOATOL-UHFFFAOYSA-N 0.000 description 1
- ZGJZMKWRUMQNNN-UHFFFAOYSA-N 2-(2H-pyrimidin-1-ylmethoxy)propane-1,3-diol Chemical compound OCC(CO)OCN1CN=CC=C1 ZGJZMKWRUMQNNN-UHFFFAOYSA-N 0.000 description 1
- UNJRGXHLXITKAM-UHFFFAOYSA-N 2-(chloromethoxy)propoxymethylbenzene Chemical compound ClCOC(C)COCC1=CC=CC=C1 UNJRGXHLXITKAM-UHFFFAOYSA-N 0.000 description 1
- VVWDAMFFNWHLNI-UHFFFAOYSA-N 2-(fluoromethyl)-4-hydroxy-3-[(5-methyl-2,4-dioxopyrimidin-1-yl)methoxy]butanenitrile Chemical compound CC1=CN(COC(CO)C(CF)C#N)C(=O)NC1=O VVWDAMFFNWHLNI-UHFFFAOYSA-N 0.000 description 1
- CREFCSPLSAGFBI-UHFFFAOYSA-N 2-[(6-aminopurin-9-yl)methoxy]-3-azidopropan-1-ol Chemical compound NC1=NC=NC2=C1N=CN2COC(CO)CN=[N+]=[N-] CREFCSPLSAGFBI-UHFFFAOYSA-N 0.000 description 1
- NBGYUNAGJYINAO-UHFFFAOYSA-N 3-[(2,4-dioxopyrimidin-1-yl)methoxy]-4-hydroxy-2,2-dimethylbutanamide Chemical compound NC(=O)C(C)(C)C(CO)OCN1C(=O)NC(=O)C=C1 NBGYUNAGJYINAO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- AKZAWZQUPQUXGL-UHFFFAOYSA-N 5-methyl-1-[(1-phenyl-2-phenylmethoxyethoxy)methyl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1COC(C=1C=CC=CC=1)COCC1=CC=CC=C1 AKZAWZQUPQUXGL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000589614 Pseudomonas stutzeri Species 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 208000010094 Visna Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- WMJMABVHDMRMJA-UHFFFAOYSA-M [Cl-].[Mg+]C1CCCCC1 Chemical compound [Cl-].[Mg+]C1CCCCC1 WMJMABVHDMRMJA-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000005107 alkyl diaryl silyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000005335 azido alkyl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002739 cryptand Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- FQGYCXFLEQVDJQ-UHFFFAOYSA-N mercury dicyanide Chemical compound N#C[Hg]C#N FQGYCXFLEQVDJQ-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Gegenstand der vorliegenden Erfindung sind neue acyclische Nucleosid-Analoga der allgemeinen Formel IThe present invention relates to new acyclic Nucleoside analogues of the general formula I
in welcher
R ein Wasserstoffatom, einen aliphatischen Acylrest,
eine Monophosphat-, Diphosphat- oder Triphosphatgruppe
darstellt,
R¹ einen Arylrest, einen gesättigten, ungesättigten oder
aromatischen heterocyclischen Fünf- oder Sechsring
mit einem oder mehreren Heteroatomen, einen Cycloalkyl-
oder Cycloalkenylrest, einen geradkettigen
oder verzweigten Alkinyl- bzw. Alkenylrest mit 2-7
Kohlenstoffatomen, einen Alkandienylrest, eine
Formyl-, Cyano-, Azido-, C₁-C₆-Alkoxycarbonyl-, C₁-C₆-
Alkylcarbonyl- oder Aminocarbonylgruppe,
oder den Restin which
R represents a hydrogen atom, an aliphatic acyl radical, a monophosphate, diphosphate or triphosphate group,
R¹ is an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a cycloalkyl or cycloalkenyl radical, a straight-chain or branched alkynyl or alkenyl radical with 2-7 carbon atoms, an alkanedienyl radical, a formyl or cyano -, Azido, C₁-C₆-alkoxycarbonyl, C₁-C₆- alkylcarbonyl or aminocarbonyl group,
or the rest
bedeutet, wobei R², R³ und R⁴ gleich oder verschieden
sein können und Wasserstoff, Amino, Azido, Cyano,
C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylcarbonyl-, Aminocarbonyl,
C₁-C₆-Alkylmercapto, C₁-C₆-Alkyl, Halogen-C₁-C₆-alkyl
oder Azido-C₁-C₆-alkyl sein können,
B für die Pyrimidin- und Purinbasen Thymin, Uracil,
Cytosin, Adenin, Hypoxanthin und Guanin steht, die in
1-, 7- oder 9-Stellung substituiert sind,
deren Tautomere, optisch aktive Formen oder physiologisch
verträgliche Salze anorganischer und organischer Säuren.
Außerdem betrifft die Erfindung Verfahren zur Herstellung
dieser Verbindungen sowie diese Verbindungen enthaltende
Arzneimittel.means, where R², R³ and R⁴ can be the same or different and hydrogen, amino, azido, cyano, C₁-C₆-alkoxycarbonyl, C₁-C₆-alkylcarbonyl-, aminocarbonyl, C₁-C₆-alkylmercapto, C₁-C₆-alkyl, halogen Can be -C₁-C₆-alkyl or azido-C₁-C₆-alkyl,
B represents the pyrimidine and purine bases thymine, uracil, cytosine, adenine, hypoxanthine and guanine, which are substituted in the 1-, 7- or 9-position,
their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids. The invention also relates to processes for the preparation of these compounds and medicaments containing these compounds.
Für den Fall, daß R¹ in der allgemeinen Formel I den RestIn the event that R¹ in the general formula I the rest
darstellt, und R² und R³ gleichzeitig Wasserstoff bedeuten und R⁴ ein Wasserstoffatom oder eine Azido- oder Isopropylmercaptogruppe darstellt, kann B nicht der Guanin- bzw. Adeninrest sein. Ausgenommen sind auch Verbindungen, in denen R² und R³ gleichzeitig Wasserstoff bedeuten und R⁴ eine Methylgruppe ist. represents, and R² and R³ are simultaneously hydrogen and R⁴ represents a hydrogen atom or an azido or isopropyl mercapto group B cannot be the guanine or Be adenine residue. Connections are also excluded, in which R² and R³ are both hydrogen and R⁴ is a methyl group.
Die erfindungsgemäßen Verbindungen können optisch aktiv oder in Form ihrer Racemate vorliegen. Die stereoisomeren Verbindungen können aus den racemischen Gemischen nach an sich bekannten Methoden über diastereomere Salze hergestellt werden. Zur Racematspaltung können z. B. Weinsäure, Äpfelsäure oder Campher-10-sulfonsäure verwendet werden.The compounds according to the invention can be optically active or in the form of their racemates. The stereoisomers Compounds can be prepared from the racemic mixtures known methods about diastereomeric salts will. For resolution, z. B. tartaric acid, Malic acid or camphor-10-sulfonic acid can be used.
Die antiviralen Eigenschaften acyclischer Nucleosid-Analoga sind bereits für eine Vielzahl von Verbindungen beschrieben.The antiviral properties of acyclic nucleoside analogues have already been described for a large number of compounds.
In Tetrahedron 1985, 41, 5965 ist der synthetische Zugang zu 2′,3′-Secopyrimidin-ribonucleosiden beschrieben. Weiterhin kennt man Seco-Nucleoside des Adenins als Inhibitoren der Adenosin-Deaminase (Biochem. 1972, 11, 2772) und insbesondere das Acyclovir und dessen N-substituierte Derivate als potente Inhibitoren der Herpes-Simplex-Virus-Replikation bei den Typen HSV-1 und HSV-2 (J. Med. Chem. 1988, 31, 1351 und dort zitierte Literatur).In Tetrahedron 1985, 41, 5965 is the synthetic approach to 2 ', 3'-secopyrimidine ribonucleosides described. Seco-nucleosides of adenine are also known as inhibitors adenosine deaminase (Biochem. 1972, 11, 2772) and especially the acyclovir and its N-substituted Derivatives as potent inhibitors of herpes simplex virus replication for types HSV-1 and HSV-2 (J. Med. Chem. 1988, 31, 1351 and literature cited there).
Eine antiherpetische Wirkung ist ebenfalls beschrieben für ringgeöffnete Analoga von Adeninnucleosiden (Helv. Chim. Acta 1987, 70, 219), für acyclische 2′-Deoxyguanosin-Analoga wie 9-[(3-Fluoro-1-hydroxy-2-propoxy)methyl]guanin sowie dessen 3-Azido-, 3-Chlor- und das in 3-Stellung unsubstituierte Derivat (J. Med. Chem. 1986, 29, 1384), für 1- [(1,3-Dihydroxy-2-propoxy)methyl]pyrimidine (J. Med. Chem. 1988, 31, 144) sowie das entsprechende Guanin (J. Med. Chem. 1985, 28, 358) und für 9-[4-Hydroxy-3-(hydroxymethyl)but-1-yl]purine sowie deren Ester (J. Med. Chem. 1987, 30, 1636). An anti-therapeutic effect is also described for ring-opened analogues of adenine nucleosides (Helv. Chim. Acta 1987, 70, 219), for acyclic 2'-deoxyguanosine analogues such as 9 - [(3-fluoro-1-hydroxy-2-propoxy) methyl] guanine and its 3-azido, 3-chloro and the 3-unsubstituted Derivative (J. Med. Chem. 1986, 29, 1384), for 1- [(1,3-Dihydroxy-2-propoxy) methyl] pyrimidine (J. Med. Chem. 1988, 31, 144) and the corresponding guanine (J. Med. Chem. 1985, 28, 358) and for 9- [4-hydroxy-3- (hydroxymethyl) but-1-yl] purines and their esters (J. Med. Chem. 1987, 30, 1636).
In der DE 36 27 024 A1 (1985) sind ebenfalls acyclische, in 6- und 9-Stellung substituierte 2-Aminopurine, wie das 9-[(3-Fluoro-1-hydroxy-2-propoxy)methyl]guanin - (vgl. Chem. Scr. 1986, 26, 179) - und dessen 3-Chloro-, 3-Bromo-, 3-Iodo- und 3-Isopropylthio-Derivat, mit Wirkung gegen HSV-1 beschrieben. Das 9-[(3-Azido-1-hydroxy-2-propoxy)methyl]adenin ist aus Can. J. Chem. 1984, 62, 241 bekannt. Die Inhibitor- und Substratspezifität von Deoxythymidinkinase (isoliert aus HSV-1) wurde mit acyclischen Nucleosid-Analoga von Pyrimidin- und Purinbasen untersucht (Biochem. Pharmacol. 1981, 30, 3071 und Mol. Pharmacol. 1983, 24, 316).DE 36 27 024 A1 (1985) are also acyclic, 2- and 9-substituted 2-aminopurines, such as that 9 - [(3-Fluoro-1-hydroxy-2-propoxy) methyl] guanine - (cf. Chem. Scr. 1986, 26, 179) - and its 3-chloro, 3-bromo, 3-iodo and 3-isopropylthio derivative, with action against HSV-1 described. The 9 - [(3-azido-1-hydroxy-2-propoxy) methyl] adenine is from Can. J. Chem. 1984, 62, 241. The inhibitor and substrate specificity of deoxythymidine kinase (isolated from HSV-1) was made with acyclic nucleoside analogs of pyrimidine and purine bases (Biochem. Pharmacol. 1981, 30, 3071 and Mol. Pharmacol. 1983, 24, 316).
Überraschenderweise wurde nun gefunden, daß die Verbindungen der allgemeinen Formel I die Vermehrung von DNA- bzw. RNA-Viren auf der Stufe der virusspezifischen DNA- bzw. RNA-Transkription hemmen. Die Substanzen können über die Inhibierung des Enzyms Reverse Transkriptase speziell die Vermehrung von Retroviren hemmen (vgl. dazu Proc. Natl. Acad. Sci. USA 1986, 83, 1911 und Nature 1987, 325, 773).Surprisingly, it has now been found that the compounds of the general formula I the multiplication of DNA or RNA viruses at the level of virus-specific DNA or inhibit RNA transcription. The substances can over the inhibition of the reverse transcriptase enzyme specifically inhibit the multiplication of retroviruses (cf. Proc. Natl. Acad. Sci. USA 1986, 83, 1911 and Nature 1987, 325, 773).
Aufgrund dieser Eigenschaften sind die erfindungsgemäßen Verbindungen der allgemeinen Formel I geeignet zur Therapie und Prophylaxe von Infektionen, die durch DNA-Viren - wie z. B. das Herpes-Simplex-Virus, Cytomegalo-Virus, Papova-Virus, Varicella-Zoster-Virus oder Epstein-Barr- Virus - oder RNA-Viren - wie Toga-Viren oder insbesondere Retroviren, wie die Onco-Viren HTLV-I und II sowie die Lentiviren Visna, (HIV-1 und -2) HTLV-III und IV - verursacht werden. Because of these properties, the invention Compounds of general formula I suitable for therapy and prophylaxis of infections caused by DNA viruses - such as B. the herpes simplex virus, cytomegalo virus, Papova virus, Varicella zoster virus or Epstein-Barr Virus - or RNA viruses - such as toga viruses or in particular Retroviruses, such as the onco viruses HTLV-I and II as well as the Lentiviruses Visna, (HIV-1 and -2) HTLV-III and IV - caused.
Besonders geeignet erscheinen die Verbindungen der Formel I zur Behandlung der klinischen Manifestationen der retroviralen HIV-Infektion beim Menschen, wie der anhaltenden generalisierten Lymphadenopathie (PGL), dem fortgeschrittenen Stadium des AIDS-verwandten Komplex (ARC) und dem klinischen Vollbild von AIDS.The compounds of the formula appear to be particularly suitable I treat the clinical manifestations of retroviral HIV infection in humans, such as persistent generalized lymphadenopathy (PGL), the advanced Stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
Zur Behandlung von AIDS-Patienten ist bis heute nur das AZT (3′-Azido-3′-deoxythymidin, DE 36 08 606 A1) zugelassen. Toxische Nebenwirkungen dieses Arzneimittels auf das Knochenmark machen jedoch bei etwa 50% der behandelten Patienten Bluttransfusionen erforderlich.To this day, this is the only treatment for AIDS patients AZT (3'-azido-3'-deoxythymidine, DE 36 08 606 A1) approved. Toxic side effects of this drug the bone marrow, however, make up about 50% of those treated Patients need blood transfusions.
Die Verbindungen der allgemeinen Formel I besitzen diese Nachteile nicht. Sie wirken antiviral, ohne in pharmakologisch relevanten Konzentrationen cytotoxisch zu sein.The compounds of the general formula I have them No disadvantages. They have an antiviral effect without being pharmacological relevant concentrations to be cytotoxic.
Steht R in der allgemeinen Formel I für einen aliphatischen Acylrest, so kann dieser geradkettig oder verzweigt, gesättigt oder ungesättigt sein und 1-20, vorzugsweise 1-10 Kohlenstoffatome enthalten. Besonders bevorzugt sind der Acetyl-, Propionyl-, Isopropionyl- und der tert.-Butyrylrest.R in the general formula I is an aliphatic Acyl radical, this can be straight-chain or branched, be saturated or unsaturated and 1-20, preferably Contain 1-10 carbon atoms. Particularly preferred are the acetyl, propionyl, isopropionyl and the tert-butyryl radical.
Bedeutet R¹ einen Arylrest, so ist darunter vorzugsweise der Phenylrest zu verstehen. Die Bedeutung heterocyclischer Fünf- oder Sechsring für R¹ umfaßt Ringe mit 1-4 bzw. 1-5 Heteroatomen, wobei die Heteroatome gleich oder verschieden sein können und Sauerstoff, Stickstoff oder Schwefel bedeuten, und die heterocyclischen Fünf- oder Sechsringe gewünschtenfalls an einem oder mehreren Stickstoffatomen ein Sauerstoffatom tragen können. If R¹ is an aryl radical, preference is given to it to understand the phenyl radical. The importance of heterocyclic Five or six rings for R1 include rings with 1-4 or 1-5 heteroatoms, the heteroatoms being equal to or can be different and oxygen, nitrogen or Mean sulfur, and the heterocyclic five or Six rings if desired on one or more nitrogen atoms can carry an oxygen atom.
Bevorzugte heterocyclische Fünfringe sind der Furanyl-, Thienyl-, Pyrrolyl-, Pyrazolyl-, Imidazolyl-, Thiazolyl-, Isothiazolyl-, Oxazolyl-, Isoxazolyl-, Oxadiazolyl-, Thiadiazolyl-, Triazolyl- und der Tetrazolylring sowie deren teilhydrierte Derivate.Preferred heterocyclic five-membered rings are the furanyl, Thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, Isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, Thiadiazolyl, triazolyl and the tetrazolyl ring and their partially hydrogenated derivatives.
Bedeutet R¹ einen heterocyclischen Sechsring, so sind in diesem Sinne bevorzugt der Pyridinyl-, Pyrimidinyl-, Pyrazinyl-, Pyridazinyl- und der Oxazinylring.If R¹ is a heterocyclic six-membered ring, then in In this sense, pyridinyl, pyrimidinyl, Pyrazinyl, pyridazinyl and the oxazinyl ring.
Steht R¹ für einen Cycloalkyl- oder Cycloalkenylrest, so sind darunter drei- bis siebengliedrige Ringe zu verstehen. Bevorzugt sind dabei der Cyclopropyl-, Cyclobutyl-, Cyclopentyl-, Cyclohexyl-, Cyclopentenyl- und der Cyclohexenylrest.R¹ is a cycloalkyl or cycloalkenyl radical, so are to be understood as three- to seven-membered rings. Cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cyclopentenyl and the cyclohexenyl radical.
Die bezeichneten Alkinylreste für R¹ mit 2-7, vorzugsweise 2-4 Kohlenstoffatomen, sind geradkettig oder verzweigt und stellen bevorzugt den Ethinyl- und Propinylrest dar.The designated alkynyl radicals for R¹ with 2-7, preferably 2-4 carbon atoms, are straight-chain or branched and preferably represent the ethynyl and propynyl radical.
Geradkettige oder verzweigte Alkenylreste mit 2-7, vorzugsweise 2-4 Kohlenstoffatome, sind bevorzugt der Vinyl-, Propenyl- oder 2-Methylpropenylrest.Straight-chain or branched alkenyl radicals with 2-7, preferably 2-4 carbon atoms, preferably the vinyl, Propenyl or 2-methylpropenyl.
Alkandienylreste können 4-8 Kohlenstoffatome enthalten, wobei der Butadienylrest besonders bevorzugt ist.Alkanedienyl residues can contain 4-8 carbon atoms, the butadienyl radical being particularly preferred.
Steht R¹ oder einer der Reste R², R³ bzw. R⁴ für einen C₁- C₆-Alkoxycarbonyl- oder C₁-C₆-Alkylcarbonylrest, so kann der Alkylteil geradkettig oder verzweigt sein und vorzugsweise 1-4 C-Atome aufweisen. Die Methyl-, Ethyl-, Isopropyl- und Isobutylreste sind dabei besonders bevorzugt. R¹ or one of the radicals R², R³ or R⁴ is a C₁- C₆-Alkoxycarbonyl- or C₁-C₆-alkylcarbonyl, so can the alkyl part may be straight-chain or branched and preferably Have 1-4 carbon atoms. The methyl, ethyl, isopropyl and isobutyl radicals are particularly preferred.
Die in der Definition der Substituenten R², R³ und R⁴ vorkommenden Alkylreste sowie die Alkylteile der genannten Alkylmercapto-, Halogenalkyl- und Azidoalkylgruppen können ebenfalls geradkettig oder verzweigt, gesättigt oder ungesättigt sein und 1-6, vorzugsweise 1-4 Kohlenstoffatome aufweisen.The in the definition of the substituents R², R³ and R⁴ occurring alkyl radicals and the alkyl parts of the above Alkyl mercapto, haloalkyl and azidoalkyl groups can also straight-chain or branched, saturated or unsaturated be and 1-6, preferably 1-4 carbon atoms exhibit.
Bevorzugt sind in diesem Fall der Methyl-, Ethyl-, Propyl-, Isopropyl-, Methylthio-, Azidomethyl-, Azidoethyl- und Halogenmethylrest, mit der Bedeutung Fluor, Chlor, Brom und Iod für Halogen, wobei die genannten Substituenten R², R³ und R⁴ gleich oder verschieden sein können.In this case, the methyl, ethyl, Propyl, isopropyl, methylthio, azidomethyl, azidoethyl and halomethyl radical, meaning fluorine, Chlorine, bromine and iodine for halogen, the said Substituents R², R³ and R⁴ may be the same or different can.
Wenn R¹ den RestIf R¹ does the rest
bedeutet, so sind besonders bevorzugtmeans, are particularly preferred
- a) Verbindungen, in denen R² und R³ gleich Wasserstoff sind und R⁴ für Formyl, Cyano oder Amino, bzw. den Methoxycarbonyl-, Ethoxycarbonyl-, Methylcarbonyl-, Ethylcarbonyl-, Aminocarbonyl-, Methylthio-, Ethylthio-, Fluormethyl-, Trifluormethyl-, Azidomethyl oder Azidoethylrest steht, a) Compounds in which R² and R³ are hydrogen are and R⁴ for formyl, cyano or amino, or the Methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, Ethylcarbonyl, aminocarbonyl, methylthio, ethylthio, Fluoromethyl, trifluoromethyl, azidomethyl or azidoethyl radical,
- b) Verbindungen mit R² gleich Wasserstoff, R³ gleich Methyl und R⁴ gleich Azido, Cyano, Amino oder dem Methoxycarbonyl-, Ethoxycarbonyl-, Methylcarbonyl-, Ethylcarbonyl-, Aminocarbonyl-, Methylthio-, Ethylthio-, Ethyl-, Propyl-, Fluormethyl-, Trifluormethyl- bzw. Azidomethylrest,b) compounds with R² equal to hydrogen, R³ equal to Methyl and R⁴ are azido, cyano, amino or the Methoxycarbonyl, ethoxycarbonyl, methylcarbonyl, Ethylcarbonyl, aminocarbonyl, methylthio, ethylthio, Ethyl, propyl, fluoromethyl, trifluoromethyl or azidomethyl radical,
- c) Verbindungen mit R² und R³ gleich Methyl und R⁴ mit der unter b) genannten Bedeutung.c) Compounds with R² and R³ are methyl and R⁴ with the meaning given under b).
Als mögliche Salze der Verbindungen der allgemeinen Formel I kommen vor allem Alkali-, Erdalkali- und Ammoniumsalze der Phosphatgruppen in Frage. Als Alkalisalze sind Lithium-, Natrium- und Kaliumsalze bevorzugt. Als Erdalkalisalze kommen insbesondere Magnesium- und Calciumsalze in Frage. Unter Ammoniumsalzen werden erfindungsgemäß Salze verstanden, die das Ammoniumion enthalten, das bis zu vierfach durch Alkylreste mit 1-4 Kohlenstoffatomen und/oder Aralkylreste, bevorzugt Benzylreste, substituiert sein kann. Die Substituenten können hierbei gleich oder verschieden sein.As possible salts of the compounds of the general formula I mainly come with alkali, alkaline earth and ammonium salts of the phosphate groups in question. As alkali salts are Lithium, sodium and potassium salts preferred. As alkaline earth salts come especially magnesium and calcium salts in question. Ammonium salts are used according to the invention Understand salts that contain the ammonium ion that up to four times through alkyl radicals with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals can be. The substituents can be the same or to be different.
Die Verbindungen der allgemeinen Formel I können basische Gruppen, insbesondere Amino-Gruppen enthalten, die mit geeigneten Säuren in Säureadditionssalze übergeführt werden können. Als Säuren kommen hierfür beispielsweise in Betracht: Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Milchsäure, Maleinsäure oder Methansulfonsäure. The compounds of general formula I can be basic Contain groups, especially amino groups, with suitable acids are converted into acid addition salts can be. As acids for this come in, for example Consideration: hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, fumaric acid, succinic acid, tartaric acid, Citric acid, lactic acid, maleic acid or methanesulfonic acid.
Zur Herstellung von Arzneimitteln werden die Substanzen der allgemeinen Formel I in an sich bekannter Weise mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Drageees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder Öl, wie z. B. Olivenöl, suspendiert oder gelöst. Die erfindungsgemäßen neuen Substanzen der allgemeinen Formel I und ihre Salze können in flüssiger oder fester Form enteral oder parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Zusätze, wie Stabilisierungsmittel, Lösungsvermittler oder Puffer enthält. Derartige Zusätze sind z. B. Tartrat- und Citratpuffer, Ethanol, Komplexbildner (wie Ethylendiamintetraessigsäure und deren nichttoxische Salze) und hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregulierung. Feste Trägerstoffe sind z. B. Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäuren, hochmolekulare Fettsäuren (wie Stearinsäure), Gelatine, Agar-Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette und feste hochmolekulare Polymere (wie Polyethylenglykole). Für orale Applikation geeignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe enthalten. The substances are used to manufacture drugs of the general formula I in a manner known per se suitable pharmaceutical carrier substances, aroma, Flavors and colors mixed and for example shaped as tablets or drageees or with addition appropriate auxiliaries in water or oil, such as. B. Olive oil, suspended or dissolved. The invention new substances of general formula I and their salts can be enteral or parenteral in liquid or solid form be applied. The preferred injection medium Water for use, which is the same for injection solutions usual additives, such as stabilizers, Contains solubilizers or buffers. Such additives are z. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic Salts) and high molecular weight polymers (such as liquid Polyethylene oxide) for viscosity regulation. Solid carriers are z. B. starch, lactose, mannitol, methyl cellulose, Talc, highly disperse silicas, high molecular weight Fatty acids (such as stearic acid), gelatin, agar, Calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as Polyethylene glycols). Preparations suitable for oral application can flavor and sweeteners if desired contain.
Die erfindungsgemäßen Verbindungen werden üblicherweise in Mengen von 0,1-100 mg, vorzugsweise 0,2-80 mg pro Tag und pro kg Körpergewicht appliziert. Bevorzugt ist es, die Tagesdosis auf 2-5 Applikationen zu verteilen, wobei bei jeder Applikation 1-2 Tabletten mit einem Wirkstoffgehalt von 0,5-1000 mg verabreicht werden. Die Tabletten können auch retardiert sein, wodurch sich die Anzahl der Applikationen pro Tag auf 1-3 vermindert. Der Wirkstoffgehalt der retardierten Tabletten kann 2-2000 mg betragen. Der Wirkstoff kann auch durch Injektion ein- bis achtmal pro Tag bzw. durch Dauerinfusion gegeben werden, wobei Mengen von 5-4000 mg pro Tag normalerweise ausreichen.The compounds according to the invention are usually described in Amounts of 0.1-100 mg, preferably 0.2-80 mg per day and applied per kg body weight. It is preferred that Distribute daily dose over 2-5 applications, with each application 1-2 tablets with an active ingredient content of 0.5-1000 mg can be administered. The tablets can also be delayed, which increases the number of Applications per day reduced to 1-3. The drug content the prolonged-release tablets can be 2-2000 mg be. The active ingredient can also be injected up to given eight times a day or by continuous infusion, amounts of 5-4000 mg per day are usually sufficient.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können nach verschiedenen, an sich bekannten Methoden hergestellt werden, wobei geeignete Schutzgruppen vorher eingeführt und später wieder abgespalten werden.The compounds of the general formula according to the invention I can by various methods known per se be prepared, with suitable protecting groups beforehand introduced and later split off again.
Die als Ausgangsstoffe verwendeten Purin- und Pyrimidinbasen sind bekannt und käuflich.The purine and pyrimidine bases used as starting materials are known and can be bought.
Als besonders zweckmäßig hat sich zur Herstellung der Verbindungen der allgemeinen Formel I ein Verfahren erwiesen, bei dem man eine Verbindung der allgemeinen Formel IIHas proven to be particularly useful for the preparation of the compounds of the general formula I, in which a compound of the general formula II
in der R¹ die oben angegebene Bedeutung hat, R⁵ eine geeignete Schutzgruppe wie z. B. die Trityl-, Acetyl-, Benzoyl-, Benzyl-, Trialkylsilyl-, Aryldialkylsilyl- oder Alkyldiarylsilylgruppe und Z eine reaktive Gruppe, wie Halogen, Acetoxy, Methylsulfonyloxy oder Toluolsulfonyloxy, vorzugsweise ein Chloratom darstellt, mit einer Pyrimidin- oder Purinbase zur Reaktion bringt und nach Abspaltung der Schutzgruppe R⁵ unter literaturbekannten Bedingungen die erfindungsgemäßen Verbindungen der Formel I mit R gleich Wasserstoff erhält.in which R¹ has the meaning given above, R⁵ a suitable one Protecting group such as B. the trityl, acetyl, Benzoyl, benzyl, trialkylsilyl, aryldialkylsilyl or Alkyldiarylsilyl group and Z is a reactive group, such as Halogen, acetoxy, methylsulfonyloxy or toluenesulfonyloxy, preferably represents a chlorine atom, with a Pyrimidine or purine base brings about and after Splitting off of the protective group R⁵ under literature Conditions of the compounds of the invention Formula I with R equal to hydrogen.
Setzt man dabei zweckmäßigerweise die mit Hexamethyldisilazan bis- bzw. trissilylierten Pyrimidin- oder Purinbasen mit einer Verbindung der allgemeinen Formel II, in der Z gleich Chlor ist, um, so erhält man nach Abspaltung der Trimethylsilyl-Schutzgruppen in bekannter Weise die in 9-Position substituierten Purin-Derivate bzw. die in 1-Stellung substituierten Pyrimidin-Derivate der Formel I. Wegen der Feuchtigkeitsempfindlichkeit der silylierten Purine und Pyrimidine empfiehlt sich die Verwendung eines Schutzgases im Reaktionsgefäß, wie z. B. Stickstoff oder Argon. Die Abspaltung der Silylschutzgruppe kann z. B. durch Kochen des Zwischenproduktes mit einem niederen Alkohol, wie Methanol oder Ethanol erfolgen, geschieht aber in der Regel schon während der wäßrigen Aufarbeitung. Vorteilhaft ist auch eine Methode, bei der man eine Verbindung der Formel II, in der R¹, R⁵ und Z die oben angegebene Bedeutung haben, unter Phasentransferbedingungen mit einer Pyrimidin- oder Purinbase umsetzt. It is expedient to use hexamethyldisilazane bis- or trissilylated pyrimidine or purine bases with a compound of general formula II, in the Z is chlorine, um, is obtained after cleavage the trimethylsilyl protecting groups in a known manner in 9-position substituted purine derivatives or those in the 1-position substituted pyrimidine derivatives of the formula I. Because of the moisture sensitivity of the silylated Purines and pyrimidines are recommended to use a Shielding gas in the reaction vessel, such as. B. nitrogen or Argon. The silyl protective group can be split off, for. B. by boiling the intermediate with a lower one Alcohol, such as methanol or ethanol, happens but usually already during the aqueous work-up. Also advantageous is a method in which you can connect of the formula II in which R¹, R⁵ and Z are the above have given meaning under phase transfer conditions reacted with a pyrimidine or purine base.
Unter Bedingungen der Phasentransferkatalyse werden die Basen in ein entsprechendes Anion überführt, beispielsweise durch 50%ige wäßrige Natronlauge. Das so entstandene Anion wird durch einen Phasentransferkatalysator, beispielsweise Tris[2-(2-methoxyethoxy)-ethyl]amin (TDA-1), hydrophobiert und in die organische Phase transportiert, in der es mit der reaktiven Verbindung der Formel II abreagiert.Under conditions of phase transfer catalysis the bases are converted into a corresponding anion, for example by 50% aqueous sodium hydroxide solution. That so Anion is formed by a phase transfer catalyst, for example tris [2- (2-methoxyethoxy) ethyl] amine (TDA-1), hydrophobized and in the organic Phase in which it reacts with the reactive compound of the formula II reacted.
Eine weitere vorteilhafte Methode zur Herstellung der Verbindungen der Formel I stellt das Fest-Flüssig-Phasentransfer-Verfahren unter Verwendung von festem, pulverförmigem Kaliumhydroxid, dem oben genannten Kryptanden, sowie einer Verbindung der Formel II und einer Pyrimidin- bzw. Purinbase in einem aprotischen Lösungsmittel dar (vgl. Seela et al., Helv. Chim. Acta 1988, 71,1; J. Chem. Soc. PTI 1988, 697).Another advantageous method of making the connections of the formula I represents the solid-liquid phase transfer process using solid, powdery Potassium hydroxide, the above cryptand, and a compound of the formula II and a pyrimidine or purine base in an aprotic solvent (see Seela et al., Helv. Chim. Acta 1988, 71.1; J. Chem. Soc. PTI 1988, 697).
Die Chlormethylether der allgemeinen Formel II mit Z gleich Chlor können außerdem direkt unter Verwendung von Tetrabutylammoniumiodid als Phasentransferkatalysator mit der Pyrimidin- bzw. Purinbase in einem inerten Lösungsmittel umgesetzt werden (vgl. Helv. Chim. Acta 1987, 70, 220) oder nach Versetzen mit Natriumacetat mit di- bzw. triacetylierten Pyrimidin- bzw. Purinbasen zur Reaktion gebracht werden (vgl. J. Med. Chem. 1986, 29, 1384) oder in einer Quecksilbercyanid-katalysierten Reaktion mit der silylierten Base kondensiert werden (vgl. J. Med. Chem. 1985, 28, 358). The chloromethyl ether of the general formula II with Z chlorine can also be used directly using Using tetrabutylammonium iodide as a phase transfer catalyst the pyrimidine or purine base in an inert solvent are implemented (cf. Helv. Chim. Acta 1987, 70, 220) or after adding sodium acetate with di- or triacetylated pyrimidine or purine bases for the reaction brought (see J. Med. Chem. 1986, 29, 1384) or in a mercury cyanide catalyzed reaction with the silylated base are condensed (cf. J. Med. Chem. 1985, 28, 358).
Die Umsetzungen nach den oben beschriebenen Verfahren werden zweckmäßig in einem inerten, aprotischen Lösungsmittel, z. B. Sulfolan, Toluol oder Xylol, durchgeführt. In Frage kommen ferner Dichlormethan, 1,2-Dichlorethan, Chlorbenzol, 1,2-Dimethoxyethan, Dioxan, Dimethylformamid und Acetonitril. Zum Abfangen des gebildeten Halogenwasserstoffs kann gegebenenfalls eine Base, wie Triethylamin, Pyridin oder N-Ethylmorpholin, zugesetzt werden. Die Reaktionszeiten liegen je nach Reaktionspartner und -temperatur zwischen 4 und 24 Stunden. Die Reaktionen werden allgemein bei Temperaturen zwischen 0 und 150°C, vorzugsweise Raumtemperatur und 100°C durchgeführt.The implementations according to the procedures described above are advantageously in an inert, aprotic solvent, e.g. B. sulfolane, toluene or xylene. In Question also come dichloromethane, 1,2-dichloroethane, Chlorobenzene, 1,2-dimethoxyethane, dioxane, dimethylformamide and acetonitrile. To trap the hydrogen halide formed a base such as triethylamine, Pyridine or N-ethylmorpholine can be added. The Response times vary depending on the reactant and -Temperature between 4 and 24 hours. The reactions are generally at temperatures between 0 and 150 ° C, preferably carried out at room temperature and 100 ° C.
Die Chlormethylether der allgemeinen Formel II mit Z gleich Chlor werden nach literaturbekannten Verfahren hergestellt, in dem man eine Verbindung der allgemeinen Formel IIIThe chloromethyl ether of the general formula II with Z become chlorine according to methods known from the literature prepared by connecting the general Formula III
in der R¹ und R⁵ die oben angegebene Bedeutung haben, mit Paraformaldehyd oder 1,3,5-Trioxan in Gegenwart von gasförmigem oder an Kieselgel adsorbiertem Chlorwasserstoff umsetzt und die Reaktionsprodukte ohne weitere Reinigung in die nächste Reaktion einsetzt (vgl. Helv. Chim. Acta 1987, 70, 219; J. Med. Chem. 1988, 31, 144 und 1986, 29, 1384).in which R¹ and R⁵ have the meaning given above, with Paraformaldehyde or 1,3,5-trioxane in the presence of gaseous or hydrogen chloride adsorbed on silica gel implements and the reaction products without further purification in the next reaction (cf. Helv. Chim. Acta 1987, 70, 219; J. Med. Chem. 1988, 31, 144 and 1986, 29, 1384).
Verbindungen der allgemeinen Formel III sind z. T. literaturbekannt oder werden in Anlehnung an diese Literatur dargestellt (vgl. oben zitierte Literatur sowie Tetrahedron Lett. 1988, 29, 2737 und 1988, 29, 2459; J. Org. Chem. 1988, 53, 4131; J. Am. Chem. Soc. 1978, 100, 1481; Tetrahedron Lett. 1984, 25, 3225).Compounds of the general formula III are e.g. T. known from the literature or are based on this literature (see literature cited above and tetrahedron Lett. 1988, 29, 2737 and 1988, 29, 2459; J. Org. Chem. 1988, 53, 4131; J. Am. Chem. Soc. 1978, 100, 1481; Tetrahedron Lett. 1984, 25, 3225).
Die Phosphatgruppen werden in Verbindungen der allgemeinen Formel I, in denen R Wasserstoff bedeutet, in bekannter Weise eingeführt. Die Monophosphate erhält man beispielsweise, indem man Verbindungen der Formel I mit R gleich Wasserstoff mit Phosphoroxychlorid in Trialkylphosphat vorzugsweise Trimethylphosphat, phosphoryliert. Die auf diesem Wege erhaltenen Triethylammoniumsalze können in bekannter Weise in andere Salze durch Umsalzen überführt werden. Die Di- bzw. Triphosphate der allgemeinen Formel I werden hergestellt, indem ein Trialkylammoniumsalz des Monophosphats der Formel I aktiviert und anschließend mit einem Trialkylammoniumphosphat bzw. -diphosphat kondensiert wird. Als Trialkylammoniumionen werden bevorzugt Tributylammoniumionen eingesetzt. Die Aktivierung erfolgt vorteilhafterweise unter wasserfreien Bedingungen mittels 1,1′-Carbonyldiimidazol bei Raumtemperatur in einem polaren, aprotischen Lösungsmittel, wie z. B. Dimethylformamid. Die Kondensation wird ebenfalls bei Raumtemperatur in einem polaren, aprotischen Lösungsmittel durchgeführt. Bevorzugt ist Dimethylformamid. Die Reaktionszeiten für Aktivierung und Kondensationsreaktion betragen jeweils 3 Stunden bis 3 Tage.The phosphate groups are found in compounds of the general Formula I, in which R is hydrogen, is known Way introduced. The monophosphates are obtained, for example, by making compounds of formula I equal to R. Hydrogen with phosphorus oxychloride in trialkyl phosphate preferably trimethyl phosphate, phosphorylated. The on Triethylammonium salts obtained in this way can be obtained in a known manner Converted into other salts by salting will. The di- or triphosphates of the general formula I are made by using a trialkylammonium salt of the monophosphate Formula I activated and then with a trialkylammonium phosphate or diphosphate condensed becomes. Preferred trialkylammonium ions are Tributylammonium ions used. The activation takes place advantageously under anhydrous conditions 1,1′-carbonyldiimidazole at room temperature in a polar, aprotic solvents, such as. B. Dimethylformamide. The condensation is also in at room temperature a polar, aprotic solvent. Dimethylformamide is preferred. The response times for Activation and condensation reaction are 3 each Hours to 3 days.
Der Erfolg der Phosphorylierung kann durch Dünnschichtchromatographie, -elektrophorese und ³¹P-NMR-Spektroskopie kontrolliert werden.The success of phosphorylation can be determined by thin layer chromatography, -electrophoresis and 31 P NMR spectroscopy to be controlled.
Vorzugsweise wird die Phosphorylierung bei niedriger Temperatur, besonders vorteilhaft bei 0-10°C durchgeführt. Die Reaktionszeit beträgt 5 Stunden bis 1 Tag, bevorzugt 7-15 Stunden.Preferably the phosphorylation is lower Temperature, particularly advantageously carried out at 0-10 ° C. The reaction time is 5 hours to 1 day, preferably 7-15 Hours.
Die Aufarbeitung erfolgt beispielsweise durch Hydrolyse der Reaktionsmischung mit Eis, anschließende Neutralisation und Isolierung des Produktes mittels Ionenaustauschchromatographie.Working up is carried out, for example, by hydrolysis the reaction mixture with ice, followed by neutralization and isolation of the product by means of ion exchange chromatography.
Die verschiedenen Salze der Di- und Triphosphate können ebenfalls nach bekannten Methoden hergestellt werden.The different salts of di- and triphosphates can can also be produced by known methods.
Die Phosphorylierung zum Triphosphat der allgemeinen Formel I kann auch als Eintopf-Variante durchgeführt werden. Die Darstellung erfolgt analog zu den Vorschriften von Ludwig (Acta Biochim. Biophys. Acad. Sci. Hung. 1981, 16, 131), Ruth/Cheng (Mol. Pharmcol. 1981, 20, 415) und Kovacs/Ötvös (Tetrahedron Lett. 1988, 29, 4525). The phosphorylation to the triphosphate of the general Formula I can also be carried out as a one-pot variant will. The presentation is analogous to the regulations by Ludwig (Acta Biochim. Biophys. Acad. Sci. Hung. 1981, 16, 131), Ruth / Cheng (Mol. Pharmcol. 1981, 20, 415) and Kovacs / Ötvös (Tetrahedron Lett. 1988, 29, 4525).
Bevorzugt im Sinne der vorliegenden Erfindung sind außer den in den Beispielen genannten Verbindungen und den durch Kombination aller in den Ansprüchen genannten Bedeutungen ableitbaren Verbindung die folgenden acyclischen Nucleosid-Analoga:Preferred for the purposes of the present invention are the compounds mentioned in the examples and by Combination of all meanings mentioned in the claims derivable compound the following acyclic Nucleoside analogues:
1-[[1-(3-Furyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Furyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(3-Thienyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Thienyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(1-Cyclopentenyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(Oxazolin-2-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(Thiazolin-2-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(Imidazol-2-yl)-2-hydroxyethoxy]methyl]cytosin
1-[[1-(Oxazol-4-yl)-2-hydroxyethoxy]methyl]cytosin
1-[[1-(Thiazol-4-yl)-2-hydroxyethoxy]methyl]cytosin
9-[[1-(1,2,3-Oxadizol-4-yl)-2-hydroxy-ethoxy]methyl]guanin
9-[[1-(1,2,3-Thiadiazol-4-yl)-2-hydroxy-ethoxy]methyl]adenin
1-[[1-(1,2,3-Triazol-4-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(Tetrazol-5-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Pyridyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(3-Pyridyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(4-Pyridyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(3-Furyl)-2-hydroxyethoxy]methyl]uracil
1-[(1-Cyclohexen-1-yl-2-hydroxyethoxy)methyl]thymin
1-[(1-Ethinyl-2-hydroxyethoxy]methyl]thymin
1-[(1-Propin-1-yl-2-hydroxyethoxy]methyl]thymin
1-[(1-Vinyl-2-hydroxyethoxy]methyl]thymin
1-[[1-(1-Bromvinyl)-2-hydroxyethoxy]methyl]cytosin
1-[[1-(1-Cyanovinyl)-2-hydroxyethoxy]methyl]cytosin
1-[(1-Propen-2-yl-2-hydroxyethoxy]methyl]thymin
1-[(1-Cyano-2-hydroxyethoxy]methyl]cytosin
1-[(1-Azido-2-hydroxyethoxy)methyl]cytosin
1-[(1-Methoxycarbonyl-2-hydroxyethoxy)methyl]cytosin
1-[(1-Aminocarbonyl-2-hydroxyethoxy)methyl]cytosin
1-[(1-Cyanomethyl-2-hydroxyethoxy)methyl]cytosin
1-[(1-Azidomethyl-2-hydroxyethoxy)methyl]cytosin
1-[(1-Methoxycarbonylmethyl-2-hydroxyethoxy)methyl]thymin
1-[(1-Aminocarbonylmethyl-2-hydroxyethoxy)methyl]thymin
1-[(1-Methylmercaptomethyl-2-hydroxyethoxy)methyl]thymin
1-[[1-(2-Fluorethyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Azidoethyl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(1-Cyanoethyl)-2-hydroxyethoxy]methyl]thymin
9-[[1-(2-Propyl)-2-hydroxyethoxy]methyl]guanin
1-[[1-(Methoxycarbonylethan-1-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(Aminocarbonylethan-1-yl]-2-hydroxyethoxy]methyl]thymin
9-[[1-(Methylmercaptoethan-1-yl)-2-hydroxyethoxy]methyl]adenin
1-[[1-(2-Fluor-1-azidoethan-1-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Fluor-1-cyanoethan-1-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Fluor-1-methoxycarbonylethan-1-yl)-2-hydroxyethoxy]methyl]t-hymin
9-[[1-(2-Fluor-1-aminocarbonylethan-1-yl)-2-hydroxyethoxy]methyl]gua-nin
1-[[1-(2-Fluor-1-methylmercaptoethan-1-yl)-2-hydroxyethoxy]methyl]th-ymin
1-[[1-(1-Azido-2,2,2-trifluorethan-1-yl)-2-hydroxyethoxy]methyl]thym-in
1-[[1-(1-Cyano-2,2,2-trifluorethan-1-yl)-2-hydroxyethoxy]methyl]thym-in
1-[[1-(1-Methoxycarbonyl-2,2,2-trifluorethan-1-yl)-2-hydroxyethoxy]m-ethyl]thymin
1-[[1-(1-Aminocarbonyl-2,2,2-trifluorethan-1-yl)-2-hydroxyethoxy]met-hyl]thymin
9-[[1-(1-Methylmercapto-2,2,2-trifluorethan-1-yl)-2-hydroxyethoxy]me-thyl]adenin
1-[[1-(2-Azidopropan-2-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Cyanopropan-2-yl)-2-hydroxyethoxy]methyl]thymin
9-[[1-(2-Methoxycarbonylpropan-2-yl)-2-hydroxyethoxy]methyl]guanin
1-[[1-(2-Aminocarbonylpropan-2-yl)-2-hydroxyethoxy]methyl]thymin
1-[[1-(2-Methylmercaptopropan-2-yl)-2-hydroxyethoxy]methyl]cytosin
1-[[1-(2-Aminocarbonylpropan-2-yl)-2-hydroxyethoxy]methyl]uracil
9-[[1-(2-Methoxycarbonylpropan-2-yl)-2-hydroxyethoxy]methyl]guanin1 - [[1- (3-furyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-furyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (3-thienyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-thienyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-Cyclopentenyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (Oxazolin-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (Thiazolin-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (Imidazol-2-yl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (Oxazol-4-yl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (Thiazol-4-yl) -2-hydroxyethoxy] methyl] cytosine
9 - [[1- (1,2,3-Oxadizol-4-yl) -2-hydroxyethoxy] methyl] guanine
9 - [[1- (1,2,3-Thiadiazol-4-yl) -2-hydroxy-ethoxy] methyl] adenine
1 - [[1- (1,2,3-Triazol-4-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (tetrazol-5-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-pyridyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (3-pyridyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (4-pyridyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (3-furyl) -2-hydroxyethoxy] methyl] uracil
1 - [(1-Cyclohexen-1-yl-2-hydroxyethoxy) methyl] thymine
1 - [(1-Ethynyl-2-hydroxyethoxy] methyl] thymine
1 - [(1-Propin-1-yl-2-hydroxyethoxy] methyl] thymine
1 - [(1-vinyl-2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-bromovinyl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (1-Cyanovinyl) -2-hydroxyethoxy] methyl] cytosine
1 - [(1-propen-2-yl-2-hydroxyethoxy] methyl] thymine
1 - [(1-Cyano-2-hydroxyethoxy] methyl] cytosine
1 - [(1-Azido-2-hydroxyethoxy) methyl] cytosine
1 - [(1-methoxycarbonyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-aminocarbonyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-cyanomethyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-Azidomethyl-2-hydroxyethoxy) methyl] cytosine
1 - [(1-methoxycarbonylmethyl-2-hydroxyethoxy) methyl] thymine
1 - [(1-aminocarbonylmethyl-2-hydroxyethoxy) methyl] thymine
1 - [(1-Methylmercaptomethyl-2-hydroxyethoxy) methyl] thymine
1 - [[1- (2-fluoroethyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Azidoethyl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-cyanoethyl) -2-hydroxyethoxy] methyl] thymine
9 - [[1- (2-propyl) -2-hydroxyethoxy] methyl] guanine
1 - [[1- (Methoxycarbonylethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (aminocarbonylethan-1-yl] -2-hydroxyethoxy] methyl] thymine
9 - [[1- (Methylmercaptoethan-1-yl) -2-hydroxyethoxy] methyl] adenine
1 - [[1- (2-Fluoro-1-azidoethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Fluoro-1-cyanoethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Fluoro-1-methoxycarbonylethan-1-yl) -2-hydroxyethoxy] methyl] t-hymine
9 - [[1- (2-Fluoro-1-aminocarbonylethan-1-yl) -2-hydroxyethoxy] methyl] guanine
1 - [[1- (2-Fluoro-1-methylmercaptoethan-1-yl) -2-hydroxyethoxy] methyl] th-ymin
1 - [[1- (1-Azido-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-Cyano-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (1-Methoxycarbonyl-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] m-ethyl] thymine
1 - [[1- (1-Aminocarbonyl-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] thymine
9 - [[1- (1-Methylmercapto-2,2,2-trifluoroethan-1-yl) -2-hydroxyethoxy] methyl] adenine
1 - [[1- (2-Azidopropan-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Cyanopropan-2-yl) -2-hydroxyethoxy] methyl] thymine
9 - [[1- (2-Methoxycarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] guanine
1 - [[1- (2-aminocarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] thymine
1 - [[1- (2-Methylmercaptopropan-2-yl) -2-hydroxyethoxy] methyl] cytosine
1 - [[1- (2-aminocarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] uracil
9 - [[1- (2-Methoxycarbonylpropan-2-yl) -2-hydroxyethoxy] methyl] guanine
15 g (0,1 mol) Benzyloxyacetaldehyd (vgl. Synth. Commun. 1988, 18, 359) in 70 ml abs. Ether wurden bei 0-10°C innerhalb von 30 Minuten mit dem aus 2,4 g (0,1 mol) Magnesium und 6,23 ml (0,1 mol) Methyliodid in 50 ml Ether hergestellten Methylmagnesiumiodid versetzt und nach vollständiger Zugabe 4 Stunden unter Rückfluß erhitzt. Nach dem Abkühlen wurden 150 ml gesättigte NH₄Cl-Lösung zugegeben, die organische Phase abgetrennt, über Na₂SO₄ getrocknet und das Lösungsmittel im Vakuum entfernt. Ausbeute 15,2 g (91% d. Th.), Rf 0,5 (Heptan/Methylethylketon 2/1).15 g (0.1 mol) benzyloxyacetaldehyde (cf. Synth. Commun. 1988, 18, 359) in 70 ml abs. At 0-10 ° C., the methylmagnesium iodide prepared from 2.4 g (0.1 mol) of magnesium and 6.23 ml (0.1 mol) of methyl iodide in 50 ml of ether was added to ether at 30 ° C. and after the addition was complete 4 Heated under reflux for hours. After cooling, 150 ml of saturated NH₄Cl solution were added, the organic phase was separated off, dried over Na₂SO₄ and the solvent was removed in vacuo. Yield 15.2 g (91% of theory), R f 0.5 (heptane / methyl ethyl ketone 2/1).
In eine Suspension aus 8,3 g (0,05 mol) 1-Benzyloxy-2-propanol und 3,0 g (0,1 mol) Paraformaldehyd in 100 ml abs. Dichlormethan wurde bei 0°C bis zur vollständigen Lösung des Niederschlages trockenes Chlorwasserstoffgas eingeleitet (1-3 Stunden) und die klare Lösung 8 Stunden bei 0°C gerührt. Dann wurde über MgSO₄ getrocknet, das Filtrat im Rotationsverdampfer vom Lösungsmittel befreit und das zurückbleibende Öl ohne weitere Reinigung in die nächste Reaktion eingesetzt, Rf 0,59 (Essigester/Heptan 1/1). In a suspension of 8.3 g (0.05 mol) of 1-benzyloxy-2-propanol and 3.0 g (0.1 mol) of paraformaldehyde in 100 ml of abs. Dichloromethane was passed in at 0 ° C. until the precipitate had completely dissolved dry hydrogen chloride gas (1-3 hours) and the clear solution was stirred at 0 ° C. for 8 hours. Then it was dried over MgSO₄, the filtrate was freed from solvent in a rotary evaporator and the remaining oil was used in the next reaction without further purification, R f 0.59 (ethyl acetate / heptane 1/1).
Das Rohprodukt des Chlormethylethers der letzten Reaktion wurde in 70 ml abs. Dichlormethan gelöst und bei Raumtemperatur unter Stickstoff innerhalb von 15 Minuten zu einer Lösung aus 13,5 g (0,05 mol) Bis-(trimethylsilyl)thymin in 70 ml abs. Dichlormethan getropft. Nach vollständiger Zugabe wurde 20 Stunden auf 50°C erhitzt. Dann wurden 100 ml Wasser zugegeben, die organische Phase abgetrennt, über Na₂SO₄ getrocknet und im Rotationsverdampfer eingeengt. Der Rückstand wurde durch Säulenchromatographie an Kieselgel mit Dichlormethan/Methanol 20/1 als Eluens gereinigt. Ausbeute über beide Schritte 8,2 g (54% d. Th.), hellgelbes Öl, Rf 0,56.The crude product of the chloromethyl ether of the last reaction was abs in 70 ml. Dissolved dichloromethane and at room temperature under nitrogen within 15 minutes to a solution of 13.5 g (0.05 mol) of bis (trimethylsilyl) thymine in 70 ml abs. Dripped dichloromethane. After the addition was complete, the mixture was heated to 50 ° C. for 20 hours. Then 100 ml of water were added, the organic phase separated, dried over Na₂SO₄ and concentrated in a rotary evaporator. The residue was purified by column chromatography on silica gel with dichloromethane / methanol 20/1 as the eluent. Yield over both steps 8.2 g (54% of theory), light yellow oil, R f 0.56.
3,8 g 1-[(1-Methyl-2-benzyloxyethoxy)methyl]thymin wurden in 300 ml abs. Methanol gelöst und nach Zugabe von 1,5 g Palladium auf Kohle bis zur Aufnahme der theoretischen Wasserstoffmenge bei Raumtemperatur und Normaldruck hydriert. Nach Abtrennen des Katalysators wurde das Filtrat eingedampft und der Rückstand durch Säulenchromatographie an Kieselgel 60 mit Dichlormethan/Methanol 20/1 als Eluens gereinigt. Ausbeute 1,85 g (69% d. Th.), Schmp. 104-109°C. 3.8 g of 1 - [(1-methyl-2-benzyloxyethoxy) methyl] thymine were in 300 ml abs. Dissolved methanol and after addition from 1.5 g palladium on carbon until the absorption of the theoretical amount of hydrogen at room temperature and Normal pressure hydrogenated. After removing the catalyst the filtrate was evaporated and the residue passed through Column chromatography on silica gel 60 with dichloromethane / methanol 20/1 cleaned as eluent. Yield 1.85 g (69% of theory), mp. 104-109 ° C.
Analog zu Bsp. 1 wurde durch Umsetzung von Benzyloxyacetaldehyd mit Phenyllithium bei -80°C in 59% Ausbeute 2-Benzyloxy-1-phenylethanol hergestellt. Chlormethylierung und Umsetzung mit Bis-(trimethylsilyl)thymin lieferte nach Säulenchromatographie an Kieselgel mit Essigester/Heptan 1/1 als Eluens in 53% Ausbeute das 1-[(2-Benzyloxy-1- phenylethoxy)methyl]thymin als weißen Feststoff vom Schmp. 104-106°C. Die Hydrierung an Palladium auf Kohle führte mit 74% Ausbeute zum 1-[(2-Hydroxy-1-phenylethoxy)methyl]thymin (Schmp. 114-116°C).Analogously to Example 1 was by reacting benzyloxyacetaldehyde with phenyllithium at -80 ° C in 59% yield 2-Benzyloxy-1-phenylethanol produced. Chloromethylation and reaction with bis (trimethylsilyl) thymine subsequently supplied Column chromatography on silica gel with ethyl acetate / heptane 1/1 as eluent in 53% yield the 1 - [(2-benzyloxy-1- phenylethoxy) methyl] thymine as a white solid of mp. 104-106 ° C. The hydrogenation on palladium on carbon resulted with 74% yield to 1 - [(2-hydroxy-1-phenylethoxy) methyl] thymine (Mp 114-116 ° C).
2-Benzyloxy-1-cyclohexylethanol wurde analog zu Bsp. 1 aus Benzyloxyacetaldehyd und Cyclohexylmagnesiumchlorid hergestellt und durch Säulenchromatographie an Kieselgel mit Essigester/Heptan 1/5 als Eluens gereinigt (68% Ausbeute, farbloses Öl). Chlormethylierung und Umsetzung mit Bis(trimethylsilyl)thymin führten nach Säulenchromatographie an Kieselgel mit Essigester/Heptan 2/1 als Eluens in 83% Ausbeute zum 1-[(2-Benzyloxy-1-cyclohexylethoxy)methyl]thymin. Aus dem Rohprodukt der Hydrierung an Palladium auf Kohle wurde nach der Säulenchromatographie an Kieselgel mit Essigester/Heptan 2/1 als Eluens das 1-[(1-Cyclohexyl- 2-hydroxyethoxy)methyl]thymin in 41% Ausbeute erhalten (Schmp. 124-127°C).2-Benzyloxy-1-cyclohexylethanol was made analogously to Example 1 Benzyloxyacetaldehyde and Cyclohexylmagnesiumchlorid prepared and by column chromatography on silica gel Ethyl acetate / heptane 1/5 purified as eluent (68% yield, colorless oil). Chloromethylation and reaction with bis (trimethylsilyl) thymine led to column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent in 83% Yield to 1 - [(2-benzyloxy-1-cyclohexylethoxy) methyl] thymine. From the crude hydrogenation product on palladium Charcoal was obtained after column chromatography on silica gel with ethyl acetate / heptane 2/1 as eluent the 1 - [(1-cyclohexyl 2-hydroxyethoxy) methyl] thymine obtained in 41% yield (Mp 124-127 ° C).
Claims (4)
R ein Wasserstoffatom, einen aliphatischen Acylrest, eine Monophosphat, Diphosphat- oder Triphosphatgruppe darstellt,
R¹ einen Arylrest, einen gesättigten, ungesättigten oder aromatischen heterocyclischen Fünf- oder Sechsring mit einem oder mehreren Heteroatomen, einen Cycloalkyl- oder Cycloalkenylrest, einen geradkettigen oder verzweigten Alkinyl- bzw. Alkenylrest mit 2-7 Kohlenstoffatomen, einen Alkandienylrest, eine Formyl-, Cyano-, Azido-, C₁-C₆- Alkoxycarbonyl-, C₁-C₆-Alkylcarbonyl- oder Aminocarbonylgruppe
oder den Rest bedeutet, wobei R², R³ und R⁴ gleich oder verschieden sein können und Wasserstoff, Amino, Azido, Cyano, C₁-C₆-Alkoxycarbonyl, C₁-C₆- Alkylcarbonyl-, Aminocarbonyl, C₁-C₆-Alkylmercapto, C₁-C₆-Alkyl, Halogen-C₁-C₆-alkyl oder Azido-C₁-C₆- alkyl sein können,
B für die Pyrimidin- und Purinbasen Thymin, Uracil, Cytosin, Adenin, Hypoxanthin und Guanin steht, die in 1-, 7- oder 9-Stellung substituiert sind,
deren Tautomere, optisch aktive Formen oder physiologisch verträgliche Salze anorganischer und organischer Säuren, mit der Maßgabe, daß für den Fall, daß R₂ und R₃ gleichzeitig Wasserstoff bedeuten, R₄ nicht eine Methylgruppe bedeuten kann, und für den Fall, daß R₂ und R₃ Wasserstoff, und R₄ Wasserstoff, eine Azido- oder Isopropylmercaptogruppe darstellt, B nicht den Guanin- oder Adeninrest bedeuten kann.1. Compounds of the general formula I in the
R represents a hydrogen atom, an aliphatic acyl radical, a monophosphate, diphosphate or triphosphate group,
R¹ is an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a cycloalkyl or cycloalkenyl radical, a straight-chain or branched alkynyl or alkenyl radical with 2-7 carbon atoms, an alkanedienyl radical, a formyl or cyano -, Azido, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkylcarbonyl or aminocarbonyl
or the rest means, where R², R³ and R⁴ may be the same or different and hydrogen, amino, azido, cyano, C₁-C₆-alkoxycarbonyl, C₁-C₆- alkylcarbonyl-, aminocarbonyl, C₁-C₆-alkylmercapto, C₁-C₆-alkyl, halogen Can be -C₁-C₆-alkyl or azido-C₁-C₆- alkyl,
B represents the pyrimidine and purine bases thymine, uracil, cytosine, adenine, hypoxanthine and guanine, which are substituted in the 1-, 7- or 9-position,
their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids, with the proviso that in the event that R₂ and R₃ are simultaneously hydrogen, R₄ cannot be a methyl group, and in the event that R₂ and R₃ are hydrogen, and R₄ represents hydrogen, an azido or isopropyl mercapto group, B cannot denote the guanine or adenine residue.
R ein Wasserstoffatom, einen aliphatischen Acylrest, eine Monophosphat-, Diphosphat- oder Triphosphatgruppe darstellt,
R¹ einen Arylrest, einen gesättigten, ungesättigten oder aromatischen heterocyclischen Fünf- oder Sechsring mit einem oder mehreren Heteroatomen, einen Cycloalkyl- oder Cycloalkenylrest, einen geradkettigen oder verzweigten Alkinyl- bzw. Alkenylrest mit 2-7 Kohlenstoffatomen, einen Alkandienylrest, eine Formyl-, Cyano-, Azido-, C₁-C₆- Alkoxycarbonyl-, C₁-C₆-Alkylcarbonyl- oder Aminocarbonylgruppe,
oder den Rest bedeutet, wobei R², R³ und R⁴ gleich oder verschieden sein können und Wasserstoff, Amino, Azido, Cyano, C₁-C₆-Alkoxycarbonyl, C₁-C₆-Alkylcarbonyl-, Aminocarbonyl, C₁-C₆-Alkylmercapto, C₁-C₆-Alkyl, Halogen-C₁-C₆-alkyl oder Azido-C₁-C₆-alkyl sein können,
B für die Pyrimidin- und Purinbasen Thymin, Uracil, Cytosin, Adenin, Hypoxanthin und Guanin steht, die in 1-, 7- oder 9-Stellung substituiert sind,
deren Tautomere, optisch aktive Formen oder physiologisch verträgliche Salze anorganischer und organischer Säuren, mit der Maßgabe, daß für den Fall, daß R₂ und R₃ gleichzeitig Wasserstoff bedeuten, R₄ nicht eine Methylgruppe bedeuten kann, und für den Fall, daß R₂ und R₃ Wasserstoff, und R₄ Wasserstoff, eine Azido- oder Isopropylmercaptogruppe darstellt, B nicht den Guanin- oder Adeninrest bedeuten kann, dadurch gekennzeichnet, daß man eine Verbindung der Formel II in der R¹ die oben angegebene Bedeutung hat, R⁵ eine für die Hydroxylfunktion geeignete Schutzgruppe und Z eine reaktive Gruppe darstellt, mit einer Pyrimidin- oder Purinbase zur Reaktion bringt und anschließend die Schutzgruppe R⁵ nach an sich bekannten Methoden abspaltet,
und gegebenenfalls anschließend die so erhaltenen Verbindungen der allgemeinen Formel I, in denen R ein Wasserstoffatom bedeutet, in die entsprechenden Mono-, Di- oder Triphosphate überführt.2. Process for the preparation of compounds of formula I. in the
R represents a hydrogen atom, an aliphatic acyl radical, a monophosphate, diphosphate or triphosphate group,
R¹ is an aryl radical, a saturated, unsaturated or aromatic heterocyclic five- or six-membered ring with one or more heteroatoms, a cycloalkyl or cycloalkenyl radical, a straight-chain or branched alkynyl or alkenyl radical with 2-7 carbon atoms, an alkanedienyl radical, a formyl or cyano -, Azido, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkylcarbonyl or aminocarbonyl,
or the rest means, where R², R³ and R⁴ can be the same or different and hydrogen, amino, azido, cyano, C₁-C₆-alkoxycarbonyl, C₁-C₆-alkylcarbonyl-, aminocarbonyl, C₁-C₆-alkylmercapto, C₁-C₆-alkyl, halogen Can be -C₁-C₆-alkyl or azido-C₁-C₆-alkyl,
B represents the pyrimidine and purine bases thymine, uracil, cytosine, adenine, hypoxanthine and guanine, which are substituted in the 1-, 7- or 9-position,
their tautomers, optically active forms or physiologically acceptable salts of inorganic and organic acids, with the proviso that in the event that R₂ and R₃ are simultaneously hydrogen, R₄ cannot be a methyl group, and in the event that R₂ and R₃ are hydrogen, and R₄ represents hydrogen, an azido or isopropyl mercapto group, B cannot denote the guanine or adenine residue, characterized in that a compound of the formula II in which R¹ has the meaning given above, R⁵ represents a protective group suitable for the hydroxyl function and Z represents a reactive group, causes a reaction with a pyrimidine or purine base and then splits off the protective group R⁵ by methods known per se,
and optionally subsequently converting the compounds of the general formula I thus obtained in which R represents a hydrogen atom into the corresponding mono-, di- or triphosphates.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3906357A DE3906357A1 (en) | 1989-03-01 | 1989-03-01 | NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTS |
| PCT/EP1990/000298 WO1990009998A1 (en) | 1989-03-01 | 1990-02-22 | Novel acyclic nucleoside analogues, process for their production and use of these compounds as anti-viral drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3906357A DE3906357A1 (en) | 1989-03-01 | 1989-03-01 | NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3906357A1 true DE3906357A1 (en) | 1990-09-06 |
Family
ID=6375168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE3906357A Withdrawn DE3906357A1 (en) | 1989-03-01 | 1989-03-01 | NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTS |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE3906357A1 (en) |
| WO (1) | WO1990009998A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994003467A2 (en) * | 1992-08-05 | 1994-02-17 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2119722T (en) | 2002-08-23 | 2016-12-12 | Illumina Cambridge Ltd | Labelled nucleotides |
| US11008359B2 (en) | 2002-08-23 | 2021-05-18 | Illumina Cambridge Limited | Labelled nucleotides |
| CN112778363B (en) * | 2019-11-05 | 2024-03-15 | 华创合成制药股份有限公司 | Nitroimidazole derivative and preparation method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4347360A (en) * | 1980-09-16 | 1982-08-31 | Ens Bio Logicals Inc. | Ring open nucleoside analogues |
| IE842642L (en) * | 1983-10-31 | 1985-04-30 | Harvard College | Purine Derivatives |
| JPH0625061B2 (en) * | 1984-07-03 | 1994-04-06 | ザ ウエルカム フアウンデ−シヨン リミテツド | Antiviral compound |
| DE3627024A1 (en) * | 1985-09-24 | 1987-04-02 | Hoechst Ag | 2-AMINOPURINS SUBSTITUTED IN 6 AND 9 POSITIONS, THEIR USE, MEDICINAL PRODUCTS CONTAINING THESE PURINES AND METHOD FOR THE PRODUCTION OF THE PURINS |
-
1989
- 1989-03-01 DE DE3906357A patent/DE3906357A1/en not_active Withdrawn
-
1990
- 1990-02-22 WO PCT/EP1990/000298 patent/WO1990009998A1/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994003467A2 (en) * | 1992-08-05 | 1994-02-17 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
| WO1994003467A3 (en) * | 1992-08-05 | 1994-06-23 | Inst Organic Chem Biochem | Antiretroviral enantiomeric nucleotide analogs |
| EP0897917A1 (en) * | 1992-08-05 | 1999-02-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Compounds for use in the preparation of antiretroviral enantiomeric nucleotide analogs |
| US6057305A (en) * | 1992-08-05 | 2000-05-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
| US6479673B1 (en) | 1992-08-05 | 2002-11-12 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
| US6653296B1 (en) * | 1992-08-05 | 2003-11-25 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990009998A1 (en) | 1990-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0545966B1 (en) | New phospholipid derivatives of nucleosides, their preparation and their use as antiviral drugs | |
| DE69406649T2 (en) | N-ALKYL-2 SUBSTITUTED ATP ANALOGS | |
| DE69232845T2 (en) | 1,3-oxathiolane nucleoside analog compounds | |
| DE2539963C2 (en) | Purine compounds, processes for their preparation and pharmaceutical preparations containing these compounds | |
| DE69704286T2 (en) | Phosphonate nucleotide compounds | |
| DE68926137T2 (en) | Pyrimidine nucleosides | |
| DE602005005240T2 (en) | 4'-C-substituted 2-haloadenosine derivatives | |
| EP0484333B1 (en) | Nucleoside derivatives and their use as medicaments | |
| DE60005502T2 (en) | 4'-C-ETHYNYL-PURINE-NUCLEOSIDES | |
| DE69204717T2 (en) | ATP analogs. | |
| EP0286028A2 (en) | Derivatives of disazapurine nucleosides, process for their preparation and their use in the sequence analysis of nucleic acids and as antiviral agents | |
| DE68922235T2 (en) | Aristeromycin or adenosine derivatives substituted by acetylene, cyan or allen. | |
| EP3183257B1 (en) | Di- and triphosphate prodrugs | |
| DE68918215T2 (en) | 2'-halomethylidene, 2'-ethenylidene and 2'-ethynyl adenosine derivatives. | |
| DE68923913T2 (en) | Neplanocin derivatives. | |
| DE3852008T2 (en) | Links. | |
| DE3906357A1 (en) | NEW ACYCLIC NUCLEOSIDE ANALOG, METHOD FOR THE PRODUCTION AND USE OF THESE COMPOUNDS AS ANTIVIRAL MEDICINAL PRODUCTS | |
| WO1993005047A1 (en) | New tricyclic thiazol and oxazol derivates with antiviral action | |
| WO2009129798A2 (en) | Diphosphate and triphosphate prodrugs, in particular nucleoside diphosphate and triphosphate prodrugs | |
| EP0521463A2 (en) | Substituted cyclic cycloalkyltriols, process, intermediates for their preparation and their use as antiviral and antiparasitic agents | |
| NO880606L (en) | NUCLEOTID ANALOGS AND PROCEDURES FOR THEIR PREPARATION. | |
| EP0614462B1 (en) | New method of preparing 2-fluoropurine derivatives | |
| EP0464642A1 (en) | Pyrimidine derivatives, their preparation and use as well as medicaments containing them | |
| WO1990008147A1 (en) | Purine nucleosides, process for producing them, and drugs containing these compounds | |
| WO1990009999A1 (en) | Seco-nucleoside derivatives and drugs containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8139 | Disposal/non-payment of the annual fee |