EP1235804A1 - Novel 3-nitropyridine derivatives and the pharmaceutical compositions containing said derivatives - Google Patents
Novel 3-nitropyridine derivatives and the pharmaceutical compositions containing said derivativesInfo
- Publication number
- EP1235804A1 EP1235804A1 EP00981887A EP00981887A EP1235804A1 EP 1235804 A1 EP1235804 A1 EP 1235804A1 EP 00981887 A EP00981887 A EP 00981887A EP 00981887 A EP00981887 A EP 00981887A EP 1235804 A1 EP1235804 A1 EP 1235804A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- derivatives
- group
- compounds
- nitropyridine
- 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- Withdrawn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
- QLILRKBRWXALIE-UHFFFAOYSA-N 3-nitropyridine Chemical class [O-][N+](=O)C1=CC=CN=C1 QLILRKBRWXALIE-UHFFFAOYSA-N 0.000 title abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 239000003814 drug Substances 0.000 claims abstract description 21
- 208000030507 AIDS Diseases 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 4
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims abstract 3
- 230000003449 preventive effect Effects 0.000 claims abstract 3
- 238000002360 preparation method Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 239000004615 ingredient Substances 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- XBTOSRUBOXQWBO-UHFFFAOYSA-N 1h-indazol-5-amine Chemical compound NC1=CC=C2NN=CC2=C1 XBTOSRUBOXQWBO-UHFFFAOYSA-N 0.000 claims description 2
- DVRGUTNVDGIKTP-UHFFFAOYSA-N 2-chloro-6-methoxy-3-nitropyridine Chemical class COC1=CC=C([N+]([O-])=O)C(Cl)=N1 DVRGUTNVDGIKTP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 2
- KEJFADGISRFLFO-UHFFFAOYSA-N 1H-indazol-6-amine Chemical compound NC1=CC=C2C=NNC2=C1 KEJFADGISRFLFO-UHFFFAOYSA-N 0.000 claims 1
- WUPLOZFIOAEYMG-UHFFFAOYSA-N 2-methoxy-5-nitropyridine Chemical class COC1=CC=C([N+]([O-])=O)C=N1 WUPLOZFIOAEYMG-UHFFFAOYSA-N 0.000 claims 1
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 22
- 230000035755 proliferation Effects 0.000 abstract description 17
- 230000002401 inhibitory effect Effects 0.000 abstract description 15
- 208000002672 hepatitis B Diseases 0.000 abstract description 12
- 241000700721 Hepatitis B virus Species 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 230000000694 effects Effects 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 108700024845 Hepatitis B virus P Proteins 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 241000700605 Viruses Species 0.000 description 14
- 239000012265 solid product Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000002777 nucleoside Substances 0.000 description 13
- -1 indazol-6-yl Chemical group 0.000 description 11
- 108020004414 DNA Proteins 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000010839 reverse transcription Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 238000011161 development Methods 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 230000010076 replication Effects 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 230000009471 action Effects 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 238000003752 polymerase chain reaction Methods 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 101710132601 Capsid protein Proteins 0.000 description 5
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 5
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- BPYHGTCRXDWOIQ-UHFFFAOYSA-N 3-nitropyridin-2-amine Chemical compound NC1=NC=CC=C1[N+]([O-])=O BPYHGTCRXDWOIQ-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000003992 Peroxidases Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 230000000840 anti-viral effect Effects 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
- 238000004140 cleaning Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000005361 D2 NMR spectroscopy Methods 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 2
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 2
- 241000588724 Escherichia coli Species 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
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 101710086987 X protein Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000008856 allosteric binding Effects 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000002489 hematologic effect Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 125000004537 indazol-5-yl group Chemical group N1N=CC2=CC(=CC=C12)* 0.000 description 2
- 125000004357 indazolylamino group Chemical group N1N=C(C2=CC=CC=C12)N* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 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
- 230000003612 virological effect Effects 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
- 229960002555 zidovudine Drugs 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JMHSCWJIDIKGNZ-UHFFFAOYSA-N 4-carbamoylbenzoic acid Chemical class NC(=O)C1=CC=C(C(O)=O)C=C1 JMHSCWJIDIKGNZ-UHFFFAOYSA-N 0.000 description 1
- 150000000565 5-membered heterocyclic compounds Chemical class 0.000 description 1
- 150000000644 6-membered heterocyclic compounds Chemical class 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 108010006785 Taq Polymerase Proteins 0.000 description 1
- 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 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000332 continued effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical class 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 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
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- GXPPOJFAQOXIBE-UHFFFAOYSA-N n-(6-methoxy-3-nitropyridin-2-yl)-1h-indazol-5-amine Chemical compound COC1=CC=C([N+]([O-])=O)C(NC=2C=C3C=NNC3=CC=2)=N1 GXPPOJFAQOXIBE-UHFFFAOYSA-N 0.000 description 1
- DLDSQMMFDXRBIW-UHFFFAOYSA-N n-(6-methoxy-3-nitropyridin-2-yl)-1h-indazol-6-amine Chemical compound COC1=CC=C([N+]([O-])=O)C(NC=2C=C3NN=CC3=CC=2)=N1 DLDSQMMFDXRBIW-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel 3-n ⁇ tropyr ⁇ dme
- This invention also relates to the
- Ri is methoxy or R_ .
- R 3 is h, hydroxy, dialkylammo group with C 2 ⁇ C 6 , straight
- R 3 may or may not contain asymmetrical carbons
- R is H, straight or branched alkyl group with C ⁇ C 4 , or
- R 3 and R 4 both may consist of 5 or 6 membered heterocyclic
- R 2 is mdazol-5-yl, or indazol-6-yl ;
- n is an integer between 0 and 3.
- HBV Hepatitis B virus
- liver hepatitis causes acute or chronic hepatitis, which may progress to liver
- HBV genome consists of genes for polymerase (P) , surface
- pre-Sl pre-S2 and S
- core protein pre-C and C
- polymerase, surface protein, and core protein are structural
- the gene for HBV polymerase comprises 80% of the whole
- This polypeptide includes sequences responsible for
- HBV enters liver when antigenic protein on virion surface
- liver cell DNAs are synthesized by HBV polymerase action
- nucleic acids which is responsible for facile encapsidation.
- nucleoside compounds such as lamivudme and
- AIDS AIDS
- herpes zoster herpes zoster
- nucleoside compounds are considered a poor cnoice
- AIDS is a disease inducing dramatic decrease in immune
- HIV Human immunodeficiency virus
- HIV responsible for AIDS
- attack helper T cells which is one of the T cells with regulatory
- helper T cells function in the immune system.
- HIV have been most widely used for the treatment of AIDS.
- the present invention provides novel 3-nitropyridine
- present invention inhibit proliferation of hepatitis B virus
- invention provides novel 3-nitropyridine derivatives
- Ri is methoxy or
- R 3 is H, hydroxy, dialkylamino group with C 2 ⁇ C 6 , straight
- R 3 may or may not have asymmetrical carbons
- R 4 is H, straight or branched alkyl group with C ⁇ C 4 , or
- R 3 and R both may consist of 5 or 6 membered heterocyclic
- R 2 is indazol-5-yl, or indazol-6-yl ; n is an integer between 0 and 3
- R 3 and R 4 are represented as a 5 or 6 me oered
- heterocyclic compounds with 1 to 3 heteroatoms selected from
- This heterocyclic ring may be
- Both inorganic and organic acids may be used as free acids in
- hydrobromic acid, sulfuric acid, and phosphoric acid may be used.
- organic acids citric acid, acetic acid, lactic acid,
- glutamic acid and aspartic acid may be used.
- the present invention also provides the process for
- X is Cl or OCH 3 ;
- R 2 , R 3 , R 4 and n are as defined
- the present invention includes the method of
- amme compounds of formula 7 are commercially available and
- step 1 m the synthetic product
- an organic base may be used and common tertiary amines
- pyridme are preferable.
- Preferable reaction time and temperature are 4 ⁇ 15 hrs and
- reaction is a single or a mixture of
- solvents selected from chloroform, methylene chloride,
- acetonit ⁇ le and alcohols such as methanol and ethanol .
- step 1 one with chloro group at 6 position is used m tne following reaction of step 2
- Preferable solvent is a single or a mixture of solvents selected
- the present invention also provides the pnarmaceutical compositions of therapeutics for preventing and treating AIDS,
- compositions of the present invention compounds of formula 1
- the solid product was dried at 50 ° C m va cuo to obtain the desired
- the solid product was dried at 50-60 ° C m va cuo
- reaction mixture was cooled and stirred at 25 ° C for 1 hr.
- peroxidase enzyme recognize the polymerized substrates.
- Biotm-UTP 46 mM T ⁇ s-HCl, 266 mM KC1, 27.5 mM MgCl 2 , 9.2 mM
- HBV polymerase catalyzes
- HBV and proliferation of HBV and may be useful as therapeutics for
- the cell concentration was adjusted to 1 10 5 cells mi and
- test compounds were adoe ⁇ to the final concentrations of 0.01, 0.1,
- PCR polymerase chain reaction
- DNA polymerized by PCR was electrophorese ⁇ on Agarose gel
- the present invention on the reduction of HBV proliferation.
- non-nucleosides may not have problems such as toxicity and early development of resistant virus strains ooserved in the use of
- the present invention may be used m parallel with nucleoside
- control HBV proliferation and may be useful as therapeutics for
- reaction mixture containing matrix-primer hybrid poly (A) oligo (dT) i 5 , DIG (digoxigenm) -dUTP, biot -dUTP, and
- HIV reverse transcriptase was calculated using the group without
- transcriptase having more than 70% reduction at the
- control HIV proliferation and may be useful as therapeutics for
- compounds of formula 1 have acute toxicity m rats .
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR9953295U | 1999-11-27 | ||
KR1019990053295A KR100566193B1 (en) | 1999-11-27 | 1999-11-27 | Novel 3-nitropyridine derivatives and pharmaceutical compositions thereof |
KR9964402U | 1999-12-29 | ||
KR1019990064402A KR100566189B1 (en) | 1999-12-29 | 1999-12-29 | Novel 5-pyrimidinecarboxamide derivatives and pharmaceutical compositions thereof |
PCT/KR2000/001365 WO2001038306A1 (en) | 1999-11-27 | 2000-11-27 | Novel 3-nitropyridine derivatives and the pharmaceutical compositions containing said derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1235804A1 true EP1235804A1 (en) | 2002-09-04 |
Family
ID=26636373
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00981887A Withdrawn EP1235804A1 (en) | 1999-11-27 | 2000-11-27 | Novel 3-nitropyridine derivatives and the pharmaceutical compositions containing said derivatives |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1235804A1 (en) |
AU (1) | AU1899501A (en) |
WO (1) | WO2001038306A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR0313000A (en) * | 2002-07-19 | 2005-07-12 | Memory Pharm Corp | Compounds, pharmaceutical composition and method for inhibiting pde4 enzyme, enhancing cognition and / or treating psychosis in a patient |
US7135575B2 (en) | 2003-03-03 | 2006-11-14 | Array Biopharma, Inc. | P38 inhibitors and methods of use thereof |
JP4617299B2 (en) | 2003-03-03 | 2011-01-19 | アレイ バイオファーマ、インコーポレイテッド | p38 inhibitors and methods of use thereof |
JP5131990B2 (en) | 2006-01-31 | 2013-01-30 | アレイ バイオファーマ、インコーポレイテッド | Kinase inhibitors and methods of use thereof |
KR20100067047A (en) * | 2008-12-10 | 2010-06-18 | 동화약품주식회사 | The new 2, 6-substituted 3-nitropyridine derivatives, the preparation thereof and pharmaceutical composition comprising the same |
US20220106265A1 (en) * | 2018-12-11 | 2022-04-07 | Duke University | Compositions and methods for the treatment of cancer |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4210942A1 (en) * | 1992-04-02 | 1993-10-07 | Bayer Ag | 7-Oxo-7H-pyrido [1,2,3-d, e] [1,4] benzoxacin-6-carboxylic acids and esters |
KR200162458Y1 (en) * | 1996-12-31 | 1999-12-15 | 정몽규 | Air exhaust grill structure of a car |
-
2000
- 2000-11-27 EP EP00981887A patent/EP1235804A1/en not_active Withdrawn
- 2000-11-27 AU AU18995/01A patent/AU1899501A/en not_active Abandoned
- 2000-11-27 WO PCT/KR2000/001365 patent/WO2001038306A1/en active Search and Examination
Non-Patent Citations (1)
Title |
---|
See references of WO0138306A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2001038306A1 (en) | 2001-05-31 |
AU1899501A (en) | 2001-06-04 |
WO2001038306A9 (en) | 2003-06-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100713137B1 (en) | Novel 2,4-difluorobenzamide derivatives | |
KR100798579B1 (en) | Novel methoxy-1,3,5-triazine derivatives and the pharmaceutical compositions containing said derivatives | |
US20200399216A1 (en) | Endocyclic thiamidinoamide-arylamide compound and use thereof for treating hepatitis b | |
JP6549109B2 (en) | Sulfoximine substituted quinazolines and their use as MNK1 and / or MNK2 kinase inhibitors | |
JP2002509140A (en) | Triazine antiviral compounds | |
US6608058B2 (en) | 6-methylnicotinamide derivatives as antiviral agents | |
MX2012011379A (en) | Non-nucleoside reverse transcriptase inhibitors. | |
WO2005042530A1 (en) | Rsv polymerase inhibitors | |
WO2013033003A1 (en) | Hiv replication inhibitors | |
EP1235804A1 (en) | Novel 3-nitropyridine derivatives and the pharmaceutical compositions containing said derivatives | |
KR102650441B1 (en) | Internally cyclic sulfiamidine amide-aryl amide compounds and their use for the treatment of hepatitis B | |
WO2017148290A1 (en) | Substituted adenine compound and pharmaceutical composition thereof | |
WO2004014873A1 (en) | 4-substituted quinazoline-8-carboxyamide derivative and pharmaceutically acceptable addition salt thereof | |
CN102834381A (en) | Derivatives of pyridoxine for inhibiting HIV integrase | |
US6743795B1 (en) | 3-nitropyridine derivaives and the pharmaceutical compositions containing said derivatives | |
KR100566193B1 (en) | Novel 3-nitropyridine derivatives and pharmaceutical compositions thereof | |
CN112759549B (en) | 3-substituted amino-4- ((substituted pyridinyl) amino) cyclobut-3-ene-1, 2-dione compounds | |
KR100566194B1 (en) | Novel 3-nitropyridine derivatives and pharmaceutical compositions thereof | |
KR100566188B1 (en) | Novel 5-pyrimidinecarboxamide derivatives and pharmaceutical compositions thereof | |
US6762189B1 (en) | 5-pyrimidinecarboxamide derivatives and the pharmaceutical compositions containing said derivatives | |
EP1235806A1 (en) | Novel 5-pyrimidinecarboxamide derivatives and the pharmaceutical compositions containing said derivatives | |
CN112189009A (en) | Chromene derivatives as inhibitors of TCR-NCK interaction | |
KR100661081B1 (en) | 6-Methylnicotinamide derivatives as antiviral agents | |
KR100566189B1 (en) | Novel 5-pyrimidinecarboxamide derivatives and pharmaceutical compositions thereof | |
KR100609490B1 (en) | 6-Methylnicotinamide derivatives as antiviral agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20020625 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Free format text: AL;LT;LV;MK;RO;SI |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: KIM, NAM, DOO Inventor name: LEE, GEUN, HYUNG Inventor name: PARK, SANG, JIN Inventor name: PARK, YONG, KYUN, C/O WON INTERN. PATENT&LAW FIRM Inventor name: YOON, SUNG, JUNE Inventor name: LEE, SANG, WOOK Inventor name: PARK, HEE, JEOUNG Inventor name: KIM, JONG, WOO |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Effective date: 20030401 |
|
RBV | Designated contracting states (corrected) |
Designated state(s): AT BE CH CY DE DK FR GB IT LI SE |