USRE45004E1 - Bromo-phenyl substituted thiazolyl dihydropyrimidines - Google Patents
Bromo-phenyl substituted thiazolyl dihydropyrimidines Download PDFInfo
- Publication number
- USRE45004E1 USRE45004E1 US13/869,947 US200813869947A USRE45004E US RE45004 E1 USRE45004 E1 US RE45004E1 US 200813869947 A US200813869947 A US 200813869947A US RE45004 E USRE45004 E US RE45004E
- Authority
- US
- United States
- Prior art keywords
- compound
- salt
- formula
- hepatitis
- alkyl
- 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.)
- Active, expires
Links
- 125000004799 bromophenyl group Chemical group 0.000 title abstract description 3
- 125000000335 thiazolyl group Chemical group 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 25
- -1 thiazolyl dihydropyrimidine Chemical class 0.000 claims abstract description 22
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 6
- 229940121354 immunomodulator Drugs 0.000 claims abstract description 6
- 239000003443 antiviral agent Substances 0.000 claims abstract description 5
- 230000002584 immunomodulator Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 62
- 238000000034 method Methods 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 239000011737 fluorine Substances 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 9
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 8
- 108700024845 Hepatitis B virus P Proteins 0.000 claims description 7
- 229960001627 lamivudine Drugs 0.000 claims description 7
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 108010050904 Interferons Proteins 0.000 claims description 6
- 102000014150 Interferons Human genes 0.000 claims description 6
- 150000001409 amidines Chemical class 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 229940079322 interferon Drugs 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 4
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 3
- 150000007942 carboxylates Chemical group 0.000 claims description 3
- 230000007882 cirrhosis Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000000269 nucleophilic effect Effects 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000001299 aldehydes Chemical class 0.000 claims 2
- 231100000283 hepatitis Toxicity 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000003016 phosphoric acids Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 208000015181 infectious disease Diseases 0.000 abstract description 6
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 22
- 0 [1*]C1=C(C2N=C([6*])NC(CN3CCOCC3)=C2C([3*])=O)C=CC([2*])=C1 Chemical compound [1*]C1=C(C2N=C([6*])NC(CN3CCOCC3)=C2C([3*])=O)C=CC([2*])=C1 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 230000000840 anti-viral effect Effects 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 7
- OPZDXMCOWFPQPE-UHFFFAOYSA-N 2-bromo-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Br)=C1 OPZDXMCOWFPQPE-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 241000700721 Hepatitis B virus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- VZWOXDYRBDIHMA-UHFFFAOYSA-N CC1=NC=CS1 Chemical compound CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 description 4
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 4
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229940047124 interferons Drugs 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- FGCZYICKZZNEEU-VHEBQXMUSA-N n-[(e)-1-chloro-3-oxo-1-phenyl-3-piperidin-1-ylprop-1-en-2-yl]benzamide Chemical compound C=1C=CC=CC=1C(/Cl)=C(C(=O)N1CCCCC1)\NC(=O)C1=CC=CC=C1 FGCZYICKZZNEEU-VHEBQXMUSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 4
- 210000002845 virion Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- GFWWQGUAHZKPML-UHFFFAOYSA-N CC1=NC=C(F)C=C1F Chemical compound CC1=NC=C(F)C=C1F GFWWQGUAHZKPML-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000012228 culture supernatant Substances 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- 230000002085 persistent effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- NYJVPTKMDYSZDU-MRNVWEPHSA-N (2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-1-[2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]-3-carboxypropanoyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 NYJVPTKMDYSZDU-MRNVWEPHSA-N 0.000 description 2
- IMOLAGKJZFODRK-UHFFFAOYSA-N 2-phenylprop-2-enamide Chemical class NC(=O)C(=C)C1=CC=CC=C1 IMOLAGKJZFODRK-UHFFFAOYSA-N 0.000 description 2
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102000000588 Interleukin-2 Human genes 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 108020005202 Viral DNA Proteins 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- ZIGBVTIJGLEPKF-UHFFFAOYSA-N [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OC)=C1CN1CCOCC1 Chemical compound [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OC)=C1CN1CCOCC1 ZIGBVTIJGLEPKF-UHFFFAOYSA-N 0.000 description 2
- YULGRDBMLRHVRZ-UHFFFAOYSA-N [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OC)=C1CN1CCOCC1.[H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1CN1CCOCC1 Chemical compound [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OC)=C1CN1CCOCC1.[H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1CN1CCOCC1 YULGRDBMLRHVRZ-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 229960001614 levamisole Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940021747 therapeutic vaccine Drugs 0.000 description 2
- 229950001463 thymoctonan Drugs 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- MOIIOZOJYWYXEP-UHFFFAOYSA-N 1,3-thiazole-2-carboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=NC=CS1 MOIIOZOJYWYXEP-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- OSBLTNPMIGYQGY-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;boric acid Chemical compound OB(O)O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O OSBLTNPMIGYQGY-UHFFFAOYSA-N 0.000 description 1
- MBIJIMHXYNGPBO-UHFFFAOYSA-N 4-(2-bromo-4-fluorophenyl)-1,6-dimethyl-2-(1,3-thiazol-2-yl)-4H-pyrimidine-5-carboxylic acid Chemical compound CN1C(=NC(C(=C1C)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 MBIJIMHXYNGPBO-UHFFFAOYSA-N 0.000 description 1
- WEPPRLVWSAYDQM-UHFFFAOYSA-N 4-(2-bromo-4-fluorophenyl)-1-ethyl-6-(morpholin-4-ylmethyl)-2-(1,3-thiazol-2-yl)-4H-pyrimidine-5-carboxylic acid Chemical compound C(C)N1C(=NC(C(=C1CN1CCOCC1)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 WEPPRLVWSAYDQM-UHFFFAOYSA-N 0.000 description 1
- FYZKQYIJXAEPLU-UHFFFAOYSA-N 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-1-ethyl-2-(1,3-thiazol-2-yl)-4H-pyrimidine-5-carboxylic acid Chemical compound C(C)N1C(=NC(C(=C1CBr)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 FYZKQYIJXAEPLU-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
- 206010059193 Acute hepatitis B Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- JKZJKRJCEBEGFD-UHFFFAOYSA-N C(C)N1C(=NC(C(=C1C)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 Chemical compound C(C)N1C(=NC(C(=C1C)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 JKZJKRJCEBEGFD-UHFFFAOYSA-N 0.000 description 1
- YHNUOFBSOVOXQR-UHFFFAOYSA-N CN1C(=NC(C(=C1CBr)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 Chemical compound CN1C(=NC(C(=C1CBr)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 YHNUOFBSOVOXQR-UHFFFAOYSA-N 0.000 description 1
- GNXKRCBMHDKJQC-UHFFFAOYSA-N CN1C(=NC(C(=C1CN1CCOCC1)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 Chemical compound CN1C(=NC(C(=C1CN1CCOCC1)C(=O)O)C1=C(C=C(C=C1)F)Br)C=1SC=CN=1 GNXKRCBMHDKJQC-UHFFFAOYSA-N 0.000 description 1
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 239000003298 DNA probe Substances 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 241000724709 Hepatitis delta virus Species 0.000 description 1
- 208000037319 Hepatitis infectious Diseases 0.000 description 1
- 101000959794 Homo sapiens Interferon alpha-2 Proteins 0.000 description 1
- 102100040018 Interferon alpha-2 Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- BACYUWVYYTXETD-UHFFFAOYSA-N N-Lauroylsarcosine Chemical compound CCCCCCCCCCCC(=O)N(C)CC(O)=O BACYUWVYYTXETD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004353 Polyethylene glycol 8000 Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000008051 TBE buffer Substances 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 102400000800 Thymosin alpha-1 Human genes 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- QWXOJIDBSHLIFI-UHFFFAOYSA-N [3-(1-chloro-3'-methoxyspiro[adamantane-4,4'-dioxetane]-3'-yl)phenyl] dihydrogen phosphate Chemical compound O1OC2(C3CC4CC2CC(Cl)(C4)C3)C1(OC)C1=CC=CC(OP(O)(O)=O)=C1 QWXOJIDBSHLIFI-UHFFFAOYSA-N 0.000 description 1
- SLUQDVUBZBWZMD-UHFFFAOYSA-N [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1C Chemical compound [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1C SLUQDVUBZBWZMD-UHFFFAOYSA-N 0.000 description 1
- ACVCAKOXDIMMMW-UHFFFAOYSA-N [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1CBr Chemical compound [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1CBr ACVCAKOXDIMMMW-UHFFFAOYSA-N 0.000 description 1
- SQGRDKSRFFUBBU-UHFFFAOYSA-N [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1CN1CCOCC1 Chemical compound [H]N1C(C2=NC=CS2)=NC(C2=C(Br)C=C(F)C=C2)C(C(=O)OCC)=C1CN1CCOCC1 SQGRDKSRFFUBBU-UHFFFAOYSA-N 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- 208000037628 acute hepatitis B virus infection Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- SUYVUBYJARFZHO-UHFFFAOYSA-N dATP Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-UHFFFAOYSA-N 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- QDGZDCVAUDNJFG-FXQIFTODSA-N entecavir (anhydrous) Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)C1=C QDGZDCVAUDNJFG-FXQIFTODSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 229940094991 herring sperm dna Drugs 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 description 1
- 229940085678 polyethylene glycol 8000 Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 108700004121 sarkosyl Proteins 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the invention relates to a new bromo-phenyl substituted thiazolyl dihydropyrimidine, its preparation method and use as a medicament especially for treating and preventing hepatitis B infections.
- the invention also relates to a composition comprising the dihydropyrimidine, other antiviral agent and, when appropriate, an immunomodulator and a medicament comprising the composition especially for treating and preventing HBV infections such as hepatitis B infections.
- the hepatitis B virus belongs to the family of hepadna viruses. It can cause acute and/or persistent or progressive chronic diseases. Many other clinical manifestations in the pathological state are also caused by the hepatitis B virus—in particular chronic inflammation of the liver, cirrhosis of the liver and hepatocellular carcinoma. In addition, coinfection with the hepatitis delta virus may have adverse effects on the progress of the disease.
- the interferon and lamivudine are conventional medicaments approved to be used for treating chronic hepatitis.
- the interferon has just moderate activity but has an adverse side reaction.
- lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment is stopped.
- the IC 50 value of lamivudine (3-TC) is 300 nM (Science, 299 (2003), 893-896).
- U.S. Pat. No. 7,074,784 discloses 6-amidoalkyldihydropyrimidine and its use as a medicament especially for treating and preventing hepatitis B infection.
- R 1 is o-chlorine
- R 2 is p-chlorine
- R 6 is 3,5-difluoropyridin-2-yl
- X is —CH 2 —
- Z is morpholinyl.
- the compound can inhibit the growth of hepatitis B virus during cell culturing.
- the IC 50 value is 2 nM (tested by themselves).
- U.S. Pat. No. 7,074,784 B2 also discloses an example, wherein a difluoro residue is substituted for thiazol-2-yl (described in Example 45 of the patent).
- the derivative has a similar IC 50 value (2 nM) (see Table 1).
- This invention relates to a compound having formula (I) and its isomer (Ia),
- R 1 is o-bromine
- R 2 is p-fluorine
- R 3 is C 1 -C 4 alkyl
- R 6 is thiazol-2-yl
- X is methylene
- Z is morpholinyl.
- R 1 of the compound of the invention having formula (I) and (Ia) is o-bromine
- R 2 is p-fluorine
- R 3 is methyl or ethyl
- R 6 is thiazol-2-yl
- X is methylene
- Z is morpholinyl.
- This invention also relates to an enantiomer of the compound disclosed herein and a mixture thereof.
- the racemate can be separated by a known method, and fundamentally it is a homogeneous component in a stereoisomer mixture.
- the compounds of the invention comprise an isomer having formula (I) and (Ia) and a mixture thereof.
- the compound of the invention can also be in a form of a salt, preferably a physiologically acceptable salt.
- the physiologically acceptable salt can be an inorganic acid salt or organic acid salt.
- it is an inorganic acid salt such as chloride, bromide, phosphate or sulfate, etc., or a carboxylate or a sulfonate, such as acetate, maleate, fumarate, malate, citrate, tartarate, lactate, benzoate or methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate or naphthalenedisulfonate, etc.
- the physiologically acceptable salt can also be a metal salt or an ammonium salt of the compound of the invention.
- it is a sodium salt, potassium salt, magnesium salt or calcium salt, and an ammonium salt produced by ammonia or organic amine such as ethylamine, diethylamine or triethylamine, diethanolamine or triethanolamine, dicyclohexylamine, dimethylaminoethyl alcohol, arginine, lysine, ethylenediamine or 2-phenylethylamine, etc.
- the compound (I) of the invention can be prepared by the following methods:
- R 1 , R 2 , R 3 , X and Z are as defined herein, and then the benzylidene compound reacts with an amidine having formula (V) or a salt thereof (such as hydrochloride or acetate) with or without the addition of an alkali or an acid, and, when appropriate, in the presence of an inert organic solvent:
- R 6 is as defined herein; or [B] the ⁇ -ketoester having formula (III) reacts with the benzaldehyde having formula (II) and the amidine having formula (V) or a salt thereof (such as hydrochloride or acetate) with or without the addition of an alkali or an acid, and, when appropriate, in the presence of an inert organic solvent in one step; or [C] if X in formula (I) is methylene, a compound having formula (VI) reacts with morpholine having formula (VII) with or without the addition of an alkali, and, when appropriate, in the presence of an inert organic solvent,
- R 1 , R 2 , R 3 and R 6 are as defined herein and Y is a nucleophilic substituent, such as chloro, bromo, iodo, methylsulfonyl or toluenesulfonyl; or [D] the benzaldehyde having formula (II) reacts with a compound having formula (X) and the amidine having formula (V) with or without the addition of an alkali and, when appropriate, in an inert organic solvent,
- R 3 , X and Z are as defined herein.
- Compound of formula (VI) can be prepared by, for example, reacting a compound having formula (VIII)
- R 1 , R 2 , R 3 and R 6 are as defined herein, with a brominating agent such as N-bromosuccinimide, preferably in an inert organic solution, to produce a compound having formula (IX):
- R 3 is as defined herein.
- ⁇ -keto carboxylate (III) is well-known, or can be prepared by known methods published in the literature [for example, D. Baumann, “Um GmbH von Diketen mit mecanicen, Phenolen und Mercaptanen”, in “Methoden der organischen Chemie” (Houben-Weyl), vol. VII/4, 230 ff (1968); Y. Oikawa, K. Sugano und O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].
- the compound (V) is known and can be prepared according to the descriptions of WO-A-99/54326 and WO-A-99/54329.
- Morpholine (VII) is commercially available.
- the inert organic solvent is preferably an alcohol such as methanol, ethanol and isopropyl alcohol, an ether such as dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, a carboxylic acid such as acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine or hexamethyl phosphoric triamide.
- an alcohol such as methanol, ethanol and isopropyl alcohol
- an ether such as dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, a carboxylic acid such as acetic acid, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine or hexamethyl phosphoric triamide.
- the reaction temperature can be varied within quite a wide range. Usually the temperature is between 20° C. and 150° C. Preferably, the temperature is the boiling temperature of the selected solvent.
- the reaction can be carried out under the atmospheric pressure or under a high pressure. It is usually carried out under the atmospheric pressure.
- the reaction can be carried out with or without an acid or alkali. It is preferable to carry out the reaction in the presence of a weak acid such as acetic acid, formic acid or the like.
- a weak acid such as acetic acid, formic acid or the like.
- An embodiment of the invention relates to a composition
- a composition comprising A) at least one of the above dihydropyrimidines and B) at least one of other antiviral agents different from A).
- a certain embodiment of the invention relates to a composition
- a composition comprising A) the above dihydropyrimidine, B) an HBV polymerase inhibitor and, when appropriate, C) an immunomodulator.
- the immunomodulator C) is selected from, for example, all the interferons such as ⁇ -interferon, ⁇ -interferon and ⁇ -interferon, especially ⁇ -2a-interferon and ⁇ -2b-interferon, an interleukin such as interleukin-2, a polypeptide such as thymosin- ⁇ -1 and a thymoctonan, an imidazoquinoline derivative such as levamisole, an immunoglobulin and a therapeutic vaccine.
- interferons such as ⁇ -interferon, ⁇ -interferon and ⁇ -interferon, especially ⁇ -2a-interferon and ⁇ -2b-interferon, an interleukin such as interleukin-2, a polypeptide such as thymosin- ⁇ -1 and a thymoctonan, an imidazoquinoline derivative such as levamisole, an immunoglobulin and a therapeutic vaccine.
- this invention also relates to a composition for treating and preventing HBV infections and its use for treating diseases induced by HBV.
- the use of the combinations of the invention provides valuable advantages for the treatment of HBV-induced diseases compared with monotherapy with the individual compounds, namely principally a synergistic antiviral activity, but also good tolerability of the combinations of the invention in Tox-50 (the range of toxicity at which 50% of the cells survive).
- HBV polymerase inhibitors B for the purposes of the invention are those which, in the endogenous polymerase assay which was published by Ph. A. Furman et al. in Antimicrobial Agents and Chemotherapy, Vol. 36 (No. 12), 2688 (1992) and which is described hereinafter, lead to an inhibition of the formation of an HBV DNA double strand, so as to result in a maximum of 50% of the activity of the zero value.
- HBV polymerase inhibitors B for use in the invention are the substances disclosed in the endogenous polymerase experiment published in “Antimicrobial Agents and Chemotherapy” Vol. 36 (No. 12), 2688 (1992) by Ph. A. Furman, and the substances described below for inhibiting the formation of double-stranded HBV DNA thereby resulting in the maximum 50% activity value to be zero.
- HBV virions from culture supernatants incorporate nucleoside 5′-triphosphates into the plus strand of the HBV DNA in vitro.
- agarose gel electrophoresis By using agarose gel electrophoresis, the incorporation of [ ⁇ - 32 P]-deoxynucleoside 5′-triphosphate into the viral 3.2 kb DNA product is observed in the presence and absence of a substance potentially having HBV polymerase-inhibiting properties.
- HBV virions are obtained from the cell culture supernatant of HepG2.2.15 cells by precipitation with polyethyleneglycol and are concentrated. One part by volume of clarified cell culture supernatant is mixed with 1 ⁇ 4 by volume of an aqueous solution containing 50% by weight polyethylene glycol 8000 and 0.6 M sodium chloride.
- the virions are sedimented by centrifugation at 2500 ⁇ g/15 minutes.
- the sediments are resuspended in 2 ml of buffer containing 0.05 M tris-HCl (pH 7.5) and dialyzed against the same buffer containing 100 mM potassium chloride.
- the samples can be frozen at ⁇ 80° C.
- Each reaction mixture (100 ⁇ l) contains at least 105 HBV virions; 50 mM tris-HCl (pH 7.5); 300 mM potassium chloride; 50 mM magnesium chloride; 0.1% Nonident® P-40 (nonionic detergent from Boehringer Mannheim); 10 ⁇ M dATP, 10 ⁇ M dGTP, 10 ⁇ M dTTP; 10 ⁇ Ci [ 32 P]dCTP (3000 Ci/mmol; final concentration 33 nM) and 1 ⁇ M of the potential polymerase inhibitor in its triphosphorylated form.
- the samples are incubated at 37° C. for one hour and then the reaction is stopped by adding 50 mM EDTA.
- a 10% weight/volume SDS solution (containing 10 g of SDS per 90 ml of water) is added to a final concentration of 1% by volume (based on the total volume), and proteinase K is added to a final concentration of 1 mg/ml. After incubation at 37° C. for one hour, samples are extracted with the same volume of phenol/chloroform/isoamyl alcohol (ratio 25:24:1 by volume), and the DNA is precipitated from the aqueous phase with ethanol.
- Adefovir dipivoxil 9- ⁇ 2-[[bis[(pivaloyloxy)-methoxy]-phosphinyl]-methoxy]-ethyl ⁇ -a-denine, cf.
- Abacavir ( ⁇ )-(1S-cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, cf.
- FTC (2R-cis)-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-pyrimidin-2(1H)-one, cf.
- ⁇ -L-FDDC 5-(6-amino-2-fluoro-9H-purin-9-yl)-tetrahydro-2-furanmethanol, cf.
- L-FMAU 1-(2-deoxy-2-fluoro- ⁇ -L-arabinofuranosyl)-5-methyl-pyrimidine-2,4(1H,3H)-dione, cf. WO 99/05157, WO 99/05158 and U.S. Pat. No. 5,753,789.
- a further preferred embodiment of the invention relates to a composition
- a composition comprising A) the above dihydropyrimidines having formula (I) and (Ia); and B) lamivudine.
- HBV antiviral agents B comprise, for example, phenylpropenamides of the following formula:
- R 1 and R 2 are, each independently, C 1-4 alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and/or oxygen;
- R 3 to R 12 are each independently hydrogen, halogen, C 1-4 alkyl, optionally substituted C 1-4 alkoxy, nitro, cyano or trifluoromethyl;
- R 13 is hydrogen, C 1-4 alkyl, C 1-7 acyl or aralkyl and X is halogen or optionally substituted C 1-4 alkyl.
- AT-61 is the compound
- Preferred immunomodulators C) comprise, for example, all interferons such as ⁇ -, ⁇ - and ⁇ -interferons, in particular also ⁇ -2a- and ⁇ -2b-interferons, interleukins such as interleukin-2, polypeptides such asthymosin- ⁇ -1 and thymoctonan, imidazoquinoline derivatives such as Levamisole®, immunoglobulins and therapeutic vaccines.
- interferons such as ⁇ -, ⁇ - and ⁇ -interferons, in particular also ⁇ -2a- and ⁇ -2b-interferons, interleukins such as interleukin-2, polypeptides such asthymosin- ⁇ -1 and thymoctonan, imidazoquinoline derivatives such as Levamisole®, immunoglobulins and therapeutic vaccines.
- a further preferred embodiment of the invention relates to combinations of A) above dihydropyrimidines (I) and (Ia), B) lamivudine and, where appropriate, C) an interferon.
- the antiviral action of the compounds of the invention on hepatitis B virus is investigated by methods based on those described by M. A. Sells et al., Proc. Natl. Acad. Sci., 84, 1005-1009 (1987) and B. E. Korba et al., Antiviral Research 19, 55-70 (1992).
- the antiviral tests are carried out in 96-well microtiter plates.
- the first vertical row of the plate receives only growth medium and HepG2.2.15 cells. It serves as virus control.
- test compounds 50 mM
- DMSO dimethyl methoxysulfoxide
- test concentration 100 ⁇ M (1st test concentration) in each case into the second vertical test row of the microtiter plate and subsequently diluted in twofold steps 210 times in growth medium plus 2% by weight of fetal calf serum (volume 25 ⁇ l)
- Each well of the microtiter plate then contains 225 ⁇ l of HepG2.2.15 cell suspension (5 ⁇ 104 cells/ml) in growth medium plus 2% by weight of fetal calf serum.
- the test mixture is incubated at 37° C. and 5% CO2 (v/v) for 4 days.
- the supernatant is then aspirated off and discarded, and the wells receive 225 ⁇ l of freshly prepared growth medium.
- the compounds according to the invention are each added anew as 10-fold concentrated solution in a volume of 25 ⁇ l. The mixtures are incubated for a further 4 days
- the HepG2.2.15 cells are examined under the light microscope or by means of biochemical detection methods (for example Alamar Blue stain or Trypan Blue stain) for cytotoxic changes
- the supernatant and/or cells are then harvested and sucked by means of a vacuum onto 96-well dot-blot chambers covered with a nylon membrane (in accordance with the manufacturer's information).
- Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells are detected, for example, under the light microscope as changes in cell morphology. Such substance-induced changes in the HepG2.2.15 cells compare with untreated cells are visible, for example, as cytolysis, vacuolation or altered cell morphology.
- a 50% cytotoxicity (Tox.-50) means that 50% of the cells show a morphology comparable to the corresponding cell control.
- the tolerability of some of the compounds according to the invention is additionally tested on other host cells such as, for example, HeLa cells, primary human peripheral blood cells or transformed cell lines such as H-9 cells.
- the intra- or extracellular supernatants of the HepG2.2.15 cells are denatured (1.5 M NaCl/0.5 N NaOH), neutralized (3 M NaCl/0.5M Tris HCl, pH 7.5) and washed (2 ⁇ SSC).
- the DNA is then baked onto the membrane by incubating the filters at 120° C. for 2-4 hours.
- Detection of the viral DNA from the treated HepG2.2.15 cells on the nylon filters is usually carried out with nonradioactive, digoxigenin-labeled hepatitis B-specific DNA probes, each of which is labeled with digoxigenin, purified and employed for the hybridization in accordance with the manufacturer's information.
- the prehybridization and hybridization take place in 5 ⁇ SSC, 1 ⁇ blocking reagent, 0.1% by weight N-lauroylsarcosine, 0.02% by weight SDS and 100 ⁇ g of herring sperm DNA.
- the prehybridization takes place at 60° C. for 30 minutes, and the specific hybridization takes place with 20 to 40 ng/ml of the digoxigenized, denatured HBV-specific DNA (14 hours, 60° C.). The filters are then washed.
- the filters were washed and prehybridized in a blocking reagent (in accordance with the manufacturer's information). Hybridization was then carried out with an anti-DIG antibody coupled to alkaline phosphatase for 30 minutes. After a washing step, the substrate of alkaline phosphatase, CSPD, was added, incubated with the filters for 5 minutes, then packed in plastic film and incubated at 37° C. for a further 15 minutes. The chemiluminescence of the hepatitis B-specific DNA signals was visualized by exposing the filters to an X-ray film (incubation depending on signal strength: 10 minutes to 2 hours).
- the half-maximum inhibitory concentration (IC 50 , 50% inhibitory concentration) was determined as the concentration at which the intra- or extracellular hepatitis B-specific band was reduced by the compound according to the invention by 50% compared with an untreated sample.
- the compound of the invention exhibits an effective antiviral effect with an IC 50 less than 1 nM. Therefore, the compound of the invention is suitable for use in treating the diseases induced by viruses, especially acute and chronic persistent HBV infections.
- Chronic viral diseases induced by HBV can worsen the morbidity and the chronic hepatitis B virus infection can cause liver cirrhosis and/or hepatocellular carcinoma in many cases.
- Areas of indication which may be mentioned for the compounds of the invention are, for example: the treatment of acute and chronic viral infections which may lead to infectious hepatitis, for example infections with hepatitis B viruses.
- the compounds of the invention are particularly suitable for the treatment of chronic hepatitis B infections and the treatment of acute and chronic hepatitis B viral infections.
- the present invention includes pharmaceutical preparations which, besides nontoxic, inert pharmaceutically suitable carriers, comprise one or more compounds (I) or (Ia) or a combination of the invention or which consist of one or more active ingredients (I) or (Ia) or of a combination of the invention.
- the active ingredients (I) and (Ia) are intended to be present in the pharmaceutical preparations mentioned above in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight, of the complete mixture.
- compositions mentioned above may also comprise other active pharmaceutical ingredients apart from the compounds (I) and (Ia).
- the ratio of the amounts of the components A, B and, where appropriate, C in the compositions of the invention may vary within wide limits; it is preferably 5 to 500 mg of A/10 to 1000 mg of B, in particular 10 to 200 mg of A/20 to 400 mg of B.
- Component C which is also to be used where appropriate, may be used in amounts of, preferably, 1 to 10 million, in particular 2 to 7 million, I.U. (international units), about three times a week over a period of up to one year.
- the compounds or compositions of the invention are intended to be present in the pharmaceutical preparations mentioned above in general in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95, % by weight of the complete mixture.
- the pharmaceutical preparations mentioned above can be produced in a conventional way by known methods, for example by mixing the active ingredient(s) with the carrier(s).
- a single dose contains the active ingredient(s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg/kg of body weight.
- the invention therefore relates further to the compounds and compositions defined above for controlling diseases.
- the invention further relates to medicaments comprising at least one of the compounds or compositions defined above and, where appropriate, one or more other active pharmaceutical ingredient(s).
- the invention further relates to the use of the compounds and compositions defined above for producing a medicament for the treatment and prophylaxis of the diseases described above, preferably of viral diseases, in particular of hepatitis B.
- the percentage data in the following examples relate in each case to weight unless indicated otherwise.
- the ratios of solvents in solvent mixtures are in each case based on volume.
- the anti-HBV active compounds in the two examples are enantiomers having a relatively long retention time.
- the treatment of the hepatitis B virus-producing HepG2.2.15 cells with the compounds of the invention can lead to a reduction in intra- and/or extracellular viral DNA.
- the compounds disclosed herein exhibit an effective antiviral effect with the IC 50 less than 1 nM. Therefore, the compounds can be used for the treatment of a disease induced by viruses, especially acute and chronic persistent HBV infections according to the methods of the invention or any method known to a person skilled in the art.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
TABLE 1 |
Example 2 of U.S. Pat. No. 7,074,784 B2 |
Example | R1 | R2 | R3 | R6 | IC50 (nM) |
12 | Cl | Cl | CH3 |
|
2(self-tested) |
9 | Br | F | CH3 |
|
7 |
5 | Cl | F | CH3 |
|
2-4 |
45 | Cl | Cl | CH3 |
|
2 |
TABLE 2 |
Some Examples of this Invention |
|
Example | R1 | R2 | R3 | R6 | IC50 (nM) | ||
1 | Br | F | CH3 |
|
0.3 | ||
2 | Br | Cl | CH2CH3 |
|
0.2 | ||
wherein R1 is o-bromine, R2 is p-fluorine, R3 is C1-C4 alkyl, R6 is thiazol-2-yl, X is methylene and Z is morpholinyl.
wherein R1, R2, R3, X and Z are as defined herein, and then the benzylidene compound reacts with an amidine having formula (V) or a salt thereof (such as hydrochloride or acetate) with or without the addition of an alkali or an acid, and, when appropriate, in the presence of an inert organic solvent:
wherein R6 is as defined herein; or
[B] the β-ketoester having formula (III) reacts with the benzaldehyde having formula (II) and the amidine having formula (V) or a salt thereof (such as hydrochloride or acetate) with or without the addition of an alkali or an acid, and, when appropriate, in the presence of an inert organic solvent in one step; or
[C] if X in formula (I) is methylene, a compound having formula (VI) reacts with morpholine having formula (VII) with or without the addition of an alkali, and, when appropriate, in the presence of an inert organic solvent,
wherein R1, R2, R3 and R6 are as defined herein and Y is a nucleophilic substituent, such as chloro, bromo, iodo, methylsulfonyl or toluenesulfonyl; or
[D] the benzaldehyde having formula (II) reacts with a compound having formula (X) and the amidine having formula (V) with or without the addition of an alkali and, when appropriate, in an inert organic solvent,
wherein R1, R2, R3 and R6 are as defined herein, with a brominating agent such as N-bromosuccinimide, preferably in an inert organic solution, to produce a compound having formula (IX):
and reacting the compound having a nucleophilic substituent, directly or after the compound being further converted according to a conventional method as described in a literature, with the morpholine having formula (VII).
wherein R1 and R2 are, each independently, C1-4 alkyl or, together with the nitrogen atom on which they are located, form a ring having 5 to 6 ring atoms which comprise carbon and/or oxygen; R3 to R12 are each independently hydrogen, halogen, C1-4 alkyl, optionally substituted C1-4 alkoxy, nitro, cyano or trifluoromethyl; and R13 is hydrogen, C1-4 alkyl, C1-7 acyl or aralkyl and X is halogen or optionally substituted C1-4 alkyl.
Example No. | IC50 (nM) | ||
5 | 0.2 | ||
(—)-5 | 0.1 | ||
6 | 0.3 | ||
(—)-6 | 0.2 | ||
Claims (22)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/869,947 USRE45004E1 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200710119019 | 2007-06-18 | ||
CN200710119019 | 2007-06-18 | ||
US13/869,947 USRE45004E1 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
PCT/CN2008/001187 WO2008154817A1 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US12/664,392 US8236797B2 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE45004E1 true USRE45004E1 (en) | 2014-07-08 |
Family
ID=40155886
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/869,947 Active 2028-12-24 USRE45004E1 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US12/664,392 Ceased US8236797B2 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US13/550,601 Ceased US8343969B2 (en) | 2007-06-18 | 2012-07-17 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US13/869,981 Active USRE44987E1 (en) | 2007-06-18 | 2013-04-25 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/664,392 Ceased US8236797B2 (en) | 2007-06-18 | 2008-06-18 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US13/550,601 Ceased US8343969B2 (en) | 2007-06-18 | 2012-07-17 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US13/869,981 Active USRE44987E1 (en) | 2007-06-18 | 2013-04-25 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
Country Status (15)
Country | Link |
---|---|
US (4) | USRE45004E1 (en) |
EP (2) | EP2159224B1 (en) |
JP (2) | JP5361879B2 (en) |
KR (1) | KR101173892B1 (en) |
CN (2) | CN101328171A (en) |
AU (1) | AU2008265397C1 (en) |
BR (1) | BRPI0813237B8 (en) |
CA (1) | CA2691056C (en) |
DK (2) | DK2159224T3 (en) |
ES (2) | ES2391597T3 (en) |
HK (1) | HK1174035A1 (en) |
PL (2) | PL2514750T3 (en) |
PT (2) | PT2514750E (en) |
RU (1) | RU2443703C2 (en) |
WO (1) | WO2008154817A1 (en) |
Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101173892B1 (en) | 2007-06-18 | 2012-08-16 | 선샤인 레이크 파르마 컴퍼니 리미티드 | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
CN101744823B (en) * | 2008-12-17 | 2013-06-19 | 广东东阳光药业有限公司 | Solid dispersion of dihydropyrimidine compounds and preparation thereof for medical purpose |
WO2010069147A1 (en) * | 2008-12-17 | 2010-06-24 | 张中能 | Dihydropyrimidine derivatives, compositions thereof and their use |
CN101575318B (en) | 2009-06-25 | 2012-02-08 | 中国人民解放军军事医学科学院毒物药物研究所 | Novel dihydropyridine compound and application thereof on preparing drugs for curing and/or preventing virus diseases |
WO2013102655A1 (en) * | 2012-01-06 | 2013-07-11 | Janssen R&D Ireland | 4,4-disubstituted-1,4-dihydropyrimidines and the use thereof as medicaments for the treatment of hepatitis b |
US20130267517A1 (en) | 2012-03-31 | 2013-10-10 | Hoffmann-La Roche Inc. | Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
HUE034919T2 (en) * | 2012-08-24 | 2018-03-28 | Sunshine Lake Pharma Co Ltd | 2,4,5,6-Substituted 3,6-dihydropyrimidine derivatives as hepatitis B virus (HBV) polymerase inhibitors for the treatment of e.g. chronic hepatitis |
CN103664897B (en) * | 2012-09-01 | 2018-04-03 | 广东东阳光药业有限公司 | Dihydropyrimidines and its application in medicine |
CN103664925B (en) * | 2012-09-07 | 2018-01-23 | 广东东阳光药业有限公司 | The Dihydropyrimidines of heteroaryl substitution and its application in medicine |
WO2014037480A1 (en) * | 2012-09-10 | 2014-03-13 | F. Hoffmann-La Roche Ag | 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
CN103664899B (en) * | 2012-09-11 | 2017-06-16 | 广东东阳光药业有限公司 | The Dihydropyrimidines of heteroaryl substitution and its application in medicine |
CN103694234A (en) * | 2012-09-27 | 2014-04-02 | 广东东阳光药业有限公司 | Crystal form of dihydropyrimidine derivatives |
WO2014153459A2 (en) * | 2013-03-20 | 2014-09-25 | Indiana University Research And Technology Corporation | Fluorescent-hap: a diagnostic stain for hbv cores in cells |
WO2015074546A1 (en) | 2013-11-19 | 2015-05-28 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
RU2688193C1 (en) * | 2013-11-27 | 2019-05-21 | Саншайн Лейк Фарма Ко., Лтд. | Processes for preparing dihydropyrimidine derivatives and intermediate compounds thereof |
MY196243A (en) | 2014-03-28 | 2023-03-24 | Sunshine Lake Pharma Co Ltd | Dihydropyrimidine Compounds and Their Application In Pharmaceuticals |
AU2015255656A1 (en) * | 2014-05-09 | 2016-11-10 | Assembly Biosciences, Inc. | Methods and compositions for treating hepatitis B virus infections |
CN105859709B (en) | 2015-02-07 | 2018-12-04 | 广东东阳光药业有限公司 | The compound of dihydropyrimidine derivatives and its application in drug |
EP3370759A1 (en) | 2015-11-03 | 2018-09-12 | H. Hoffnabb-La Roche Ag | Combination therapy of an hbv capsid assembly inhibitor and an interferon |
CN109689059A (en) | 2016-08-24 | 2019-04-26 | 豪夫迈·罗氏有限公司 | The combination treatment of HBV Mouth Disease Virus Proteins inhibitor and nucleosides or nucleotide analog |
KR102085497B1 (en) | 2017-02-23 | 2020-03-05 | 푸젠 코선터 파마슈티컬 컴퍼니 리미티드 | Tricyclic Compounds and Their Applications |
CA3058111A1 (en) | 2017-03-31 | 2018-10-04 | Fujifilm Corporation | 4-pyridone compound or salt thereof, and pharmaceutical composition and formulation including same |
AU2018291688B2 (en) | 2017-06-27 | 2022-02-03 | Janssen Pharmaceutica Nv | Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections |
CN107501257B (en) * | 2017-08-17 | 2020-05-29 | 山东大学 | Dihydropyrimidine-triazole derivative and preparation method and application thereof |
CA3101373A1 (en) | 2018-05-25 | 2019-11-28 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | 2,3-dihydro-1h-pyrrolizine-7-formamide derivative and application thereof |
US11053235B2 (en) | 2018-08-09 | 2021-07-06 | Janssen Sciences Ireland Unlimited Company | Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases |
EP3854797B1 (en) | 2018-08-23 | 2023-03-15 | Fujian Akeylink Biotechnology Co., Ltd. | Crystal form of tri-cycle compound and application thereof |
WO2020255016A1 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and dihydropyrimidine derivatives as capsid assembly modulators |
CN114728973B (en) | 2019-11-22 | 2024-06-28 | 正大天晴药业集团股份有限公司 | Crystal form of nucleoprotein inhibitor and application thereof |
CN116888118A (en) | 2021-02-05 | 2023-10-13 | 和博医药有限公司 | Phenyl dihydropyrimidine compound and application thereof |
WO2022268154A1 (en) * | 2021-06-24 | 2022-12-29 | 上海齐鲁制药研究中心有限公司 | New anti-hepatitis b compound |
Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4822798A (en) | 1982-09-18 | 1989-04-18 | Bayer Aktiengesellschaft | Circulation-active 4-phenyl-6-substituted dihydropyrimidines |
WO2000058302A1 (en) | 1999-03-25 | 2000-10-05 | Bayer Aktiengesellschaft | Dihydropyrimidines and their use in the treatment of hepatitis b |
WO2001045712A1 (en) | 1999-12-22 | 2001-06-28 | Bayer Aktiengesellschaft | Combinations of medicaments for treating viral diseases |
WO2001068647A1 (en) | 2000-03-15 | 2001-09-20 | Bayer Aktiengesellschaft | Medicaments against viral diseases |
WO2001068639A1 (en) | 2000-03-17 | 2001-09-20 | Bayer Aktiengesellschaft | Dihydropyrimidine-5-carboxylic acid esters and use thereof as medicaments against viral diseases |
WO2001068641A1 (en) | 2000-03-17 | 2001-09-20 | Bayer Aktiengesellschaft | 6-aminoalkyl-dihydropyrimidines and the use thereof as medicaments against viral diseases |
WO2001088642A1 (en) | 2000-05-18 | 2001-11-22 | Inovacor Ab | Computer based system adapted to create a representation of the pumping action of a heart |
US6436943B1 (en) | 1998-04-18 | 2002-08-20 | Bayer Aktiengesellschaft | Use of dihydropyrimidines as medicaments, and novel substances |
US6503913B1 (en) | 1998-04-18 | 2003-01-07 | Bayer Aktiengesellschaft | 2-heterocyclically substituted dihydropyrimidines |
US6696451B1 (en) | 1998-04-18 | 2004-02-24 | Bayer Aktiengesellschaft | Dihydropyrimidines |
US7074784B2 (en) | 2000-03-16 | 2006-07-11 | Siegfried Goldmann | Medicaments against viral diseases |
WO2008009209A1 (en) | 2006-07-10 | 2008-01-24 | Beijing Molecule Science And Technology Co., Ltd | Dihydropyrimidine compounds and their uses in preparation of medicaments for treating and preventing antiviral diseases |
WO2008154818A1 (en) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Fluorophenyl-substituted thiazolyl dihydropyrimidines |
WO2008154820A1 (en) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Carbethoxy-substituted thiazolyl dihydropyrimidines |
WO2008154819A1 (en) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Carbethoxy-substituted thiazolyl dihydropyrimidines |
US20100004268A1 (en) | 2006-07-10 | 2010-01-07 | Song Li | Optically Pure Dihydropyrimidine Compounds and Their Uses for the Preparation of a Medicament for Treatment and Prevention of Viral Diseases |
US20100010013A1 (en) | 2007-01-16 | 2010-01-14 | Beijing Molecule Science And Technology Co., Ltd. | Dihydropyrimidine compounds and their uses in manufacture of a medicament for treatment and prevention of viral diseases |
US8236797B2 (en) | 2007-06-18 | 2012-08-07 | Sunshine Lake Pharma Co., Ltd. | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6458772B1 (en) | 1909-10-07 | 2002-10-01 | Medivir Ab | Prodrugs |
CS263951B1 (en) | 1985-04-25 | 1989-05-12 | Antonin Holy | 9-(phosponylmethoxyalkyl)adenines and method of their preparation |
CS263952B1 (en) | 1985-04-25 | 1989-05-12 | Holy Antonin | Remedy with antiviral effect |
US5047407A (en) | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
GB8815265D0 (en) | 1988-06-27 | 1988-08-03 | Wellcome Found | Therapeutic nucleosides |
MY104575A (en) | 1989-12-22 | 1994-04-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
US5700937A (en) | 1990-02-01 | 1997-12-23 | Emory University | Method for the synthesis, compositions and use of 2'-deoxy-5-fluoro-3'-thiacytidine and related compounds |
US6346627B1 (en) | 1990-02-01 | 2002-02-12 | Emory University | Intermediates in the synthesis of 1,3-oxathiolane nucleoside enantiomers |
US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
US5276151A (en) | 1990-02-01 | 1994-01-04 | Emory University | Method of synthesis of 1,3-dioxolane nucleosides |
US6642245B1 (en) | 1990-02-01 | 2003-11-04 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
EP0481214B1 (en) | 1990-09-14 | 1998-06-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
US5340816A (en) | 1990-10-18 | 1994-08-23 | E. R. Squibb & Sons, Inc. | Hydroxymethyl(methylenecyclopentyl) purines and pyrimidines |
US5206244A (en) | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
NZ241625A (en) | 1991-02-22 | 1996-03-26 | Univ Emory | 1,3-oxathiolane derivatives, anti-viral compositions containing such and method of resolving racemic mixture of enantiomers |
WO1992018517A1 (en) | 1991-04-17 | 1992-10-29 | Yale University | Method of treating or preventing hepatitis b virus |
TW374087B (en) | 1993-05-25 | 1999-11-11 | Univ Yale | L-2',3'-dideoxy nucleotide analogs as anti-hepatitis B(HBV) and anti-HIV agents |
US5627160A (en) | 1993-05-25 | 1997-05-06 | Yale University | L-2',3'-dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents |
US5753789A (en) | 1996-07-26 | 1998-05-19 | Yale University | Oligonucleotides containing L-nucleosides |
AU4090697A (en) | 1996-09-03 | 1998-03-26 | Bristol-Myers Squibb Company | Improved process for preparing the antiviral agent {1s-(1alpha, 3alpha, 4beta)}-2-amino-1,9-dihydro-9-{4-hydroxy-3-(hydroxymethyl)-2 -methylenecyclopentyl}-6h-purin-6-one |
AU5923998A (en) | 1997-01-31 | 1998-08-25 | Avid Therapeutics Inc. | 2-benzoylamino-3-phenylpropenamide derivatives and methods of using the same |
TW434252B (en) | 1997-07-23 | 2001-05-16 | Univ Georgia Res Found | Process for the preparation of 2'-fluoro-5-methyl-β-L-arabino-furanosyluridine |
US6636943B1 (en) * | 1999-07-30 | 2003-10-21 | Hewlett-Packard Development Company, L.P. | Method for detecting continuity modules in a direct Rambus DRAM subsystem |
DE10012824A1 (en) | 2000-03-16 | 2001-09-20 | Bayer Ag | New 6-hydroxyhydrocarbyl or 6-thiohydrocarbyl-dihydropyrimidine-5-carboxylic acid derivatives, useful for the treatment of viral infections, especially hepatitis B infections |
KR20060056338A (en) | 2003-07-22 | 2006-05-24 | 고꾸리쯔 다이가꾸호우징 도쿄노우코우다이가쿠 | Reflection type polarizer, laminate optical member and liquid crystal display unit |
-
2008
- 2008-06-18 KR KR1020107000850A patent/KR101173892B1/en active IP Right Review Request
- 2008-06-18 BR BRPI0813237A patent/BRPI0813237B8/en active IP Right Grant
- 2008-06-18 DK DK08757463.8T patent/DK2159224T3/en active
- 2008-06-18 JP JP2010512492A patent/JP5361879B2/en active Active
- 2008-06-18 PT PT121768618T patent/PT2514750E/en unknown
- 2008-06-18 EP EP08757463A patent/EP2159224B1/en active Active
- 2008-06-18 RU RU2010101212/04A patent/RU2443703C2/en active
- 2008-06-18 US US13/869,947 patent/USRE45004E1/en active Active
- 2008-06-18 CA CA2691056A patent/CA2691056C/en active Active
- 2008-06-18 CN CNA2008101257258A patent/CN101328171A/en not_active Withdrawn
- 2008-06-18 CN CN2008800208411A patent/CN102066369B/en active Active
- 2008-06-18 ES ES08757463T patent/ES2391597T3/en active Active
- 2008-06-18 US US12/664,392 patent/US8236797B2/en not_active Ceased
- 2008-06-18 DK DK12176861.8T patent/DK2514750T5/en active
- 2008-06-18 PT PT08757463T patent/PT2159224E/en unknown
- 2008-06-18 PL PL12176861T patent/PL2514750T3/en unknown
- 2008-06-18 EP EP12176861.8A patent/EP2514750B1/en active Active
- 2008-06-18 PL PL08757463T patent/PL2159224T3/en unknown
- 2008-06-18 AU AU2008265397A patent/AU2008265397C1/en active Active
- 2008-06-18 WO PCT/CN2008/001187 patent/WO2008154817A1/en active Application Filing
- 2008-06-18 ES ES12176861.8T patent/ES2442907T3/en active Active
-
2012
- 2012-07-17 US US13/550,601 patent/US8343969B2/en not_active Ceased
-
2013
- 2013-01-31 HK HK13101360.5A patent/HK1174035A1/en unknown
- 2013-04-25 US US13/869,981 patent/USRE44987E1/en active Active
- 2013-06-03 JP JP2013116979A patent/JP5970421B2/en active Active
Patent Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4822798A (en) | 1982-09-18 | 1989-04-18 | Bayer Aktiengesellschaft | Circulation-active 4-phenyl-6-substituted dihydropyrimidines |
US6503913B1 (en) | 1998-04-18 | 2003-01-07 | Bayer Aktiengesellschaft | 2-heterocyclically substituted dihydropyrimidines |
US6696451B1 (en) | 1998-04-18 | 2004-02-24 | Bayer Aktiengesellschaft | Dihydropyrimidines |
US6436943B1 (en) | 1998-04-18 | 2002-08-20 | Bayer Aktiengesellschaft | Use of dihydropyrimidines as medicaments, and novel substances |
WO2000058302A1 (en) | 1999-03-25 | 2000-10-05 | Bayer Aktiengesellschaft | Dihydropyrimidines and their use in the treatment of hepatitis b |
WO2001045712A1 (en) | 1999-12-22 | 2001-06-28 | Bayer Aktiengesellschaft | Combinations of medicaments for treating viral diseases |
WO2001068647A1 (en) | 2000-03-15 | 2001-09-20 | Bayer Aktiengesellschaft | Medicaments against viral diseases |
US7074784B2 (en) | 2000-03-16 | 2006-07-11 | Siegfried Goldmann | Medicaments against viral diseases |
WO2001068639A1 (en) | 2000-03-17 | 2001-09-20 | Bayer Aktiengesellschaft | Dihydropyrimidine-5-carboxylic acid esters and use thereof as medicaments against viral diseases |
WO2001068641A1 (en) | 2000-03-17 | 2001-09-20 | Bayer Aktiengesellschaft | 6-aminoalkyl-dihydropyrimidines and the use thereof as medicaments against viral diseases |
WO2001088642A1 (en) | 2000-05-18 | 2001-11-22 | Inovacor Ab | Computer based system adapted to create a representation of the pumping action of a heart |
WO2008009209A1 (en) | 2006-07-10 | 2008-01-24 | Beijing Molecule Science And Technology Co., Ltd | Dihydropyrimidine compounds and their uses in preparation of medicaments for treating and preventing antiviral diseases |
US20100004268A1 (en) | 2006-07-10 | 2010-01-07 | Song Li | Optically Pure Dihydropyrimidine Compounds and Their Uses for the Preparation of a Medicament for Treatment and Prevention of Viral Diseases |
US20100010013A1 (en) | 2007-01-16 | 2010-01-14 | Beijing Molecule Science And Technology Co., Ltd. | Dihydropyrimidine compounds and their uses in manufacture of a medicament for treatment and prevention of viral diseases |
WO2008154818A1 (en) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Fluorophenyl-substituted thiazolyl dihydropyrimidines |
WO2008154820A1 (en) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Carbethoxy-substituted thiazolyl dihydropyrimidines |
WO2008154819A1 (en) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Carbethoxy-substituted thiazolyl dihydropyrimidines |
US8236797B2 (en) | 2007-06-18 | 2012-08-07 | Sunshine Lake Pharma Co., Ltd. | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
US8343969B2 (en) | 2007-06-18 | 2013-01-01 | Sunshine Lake Pharma Co., Ltd. | Bromo-phenyl substituted thiazolyl dihydropyrimidines |
Non-Patent Citations (1)
Title |
---|
Huff, Joel R., "HIV Protease: A Novel Chemotherapeutic Target for AIDS," Journal of Medicinal Chemistry, Aug. 1991, pp. 2305-2314, vol. 34, No. 8. |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
USRE45004E1 (en) | Bromo-phenyl substituted thiazolyl dihydropyrimidines | |
US7074784B2 (en) | Medicaments against viral diseases | |
US6503913B1 (en) | 2-heterocyclically substituted dihydropyrimidines | |
WO2008154819A1 (en) | Carbethoxy-substituted thiazolyl dihydropyrimidines | |
US6436943B1 (en) | Use of dihydropyrimidines as medicaments, and novel substances | |
WO2008154820A1 (en) | Carbethoxy-substituted thiazolyl dihydropyrimidines | |
WO2008154818A1 (en) | Fluorophenyl-substituted thiazolyl dihydropyrimidines | |
DE10012549A1 (en) | New heterocyclic-substituted dihydropyrimidine derivatives useful for treatment of viral infections, especially hepatitis B infections | |
DE10012824A1 (en) | New 6-hydroxyhydrocarbyl or 6-thiohydrocarbyl-dihydropyrimidine-5-carboxylic acid derivatives, useful for the treatment of viral infections, especially hepatitis B infections | |
WO2001068639A1 (en) | Dihydropyrimidine-5-carboxylic acid esters and use thereof as medicaments against viral diseases | |
JP2003514896A (en) | Novel 5-pyrimidinecarboxamide derivatives and pharmaceutical compositions containing the derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ZHANG, ZHONGNENG, CHINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GOLDMANN, SIEGFRIED;REEL/FRAME:031133/0976 Effective date: 20100130 Owner name: ZHANG, ZHONGNENG, CHINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LIU, YI SONG;REEL/FRAME:031133/0888 Effective date: 20100205 Owner name: ZHANG, ZHONGNENG, CHINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LI, JING;REEL/FRAME:031133/0944 Effective date: 20100130 Owner name: SUNSHINE LAKE PHARMA CO., LTD., CHINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ZHANG, ZHONGNENG;REEL/FRAME:031133/0978 Effective date: 20130826 |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
AS | Assignment |
Owner name: NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SUNSHINE LAKE PHARMA CO., LTD.;REEL/FRAME:050781/0929 Effective date: 20190906 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 8 |
|
AS | Assignment |
Owner name: SUNSHINE LAKE PHARMA CO., LTD., CHINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED;REEL/FRAME:052921/0778 Effective date: 20200525 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 12 |