NO321985B1 - Dihydropyrimidinforbindelser, fremgangsmater for fremstilling av slike, samt fremgangsmate for fremstilling av farmasoytiske preparater og anvendelse av forbindelsene i farmasoytiske preparater for behandling av virussykdommer, saerlig hepatitt B - Google Patents

Dihydropyrimidinforbindelser, fremgangsmater for fremstilling av slike, samt fremgangsmate for fremstilling av farmasoytiske preparater og anvendelse av forbindelsene i farmasoytiske preparater for behandling av virussykdommer, saerlig hepatitt B Download PDF

Info

Publication number: NO321985B1
Authority: NO; Norway
Prior art keywords: general formula; compounds; alkyl; amino; differently
Prior art date: 1998-04-18

Application number

NO20005215A

Other languages

English (en)

Norwegian (no)

Other versions

NO20005215L (no

NO20005215D0 (no

Inventor

Arnold Paessens

Juergen Stoltefuss

Siegfried Goldmann

Thomas Kramer

Ulrich Niewohner

Karl-Heinz Schlemmer

Olaf Weber

Erwin Graef

Stefan Lottmann

Kark Deres

Jorn Stolting

Original Assignee

Bayer Ag

Priority date (The priority date 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 date listed.)

1998-04-18

Filing date

2000-10-17

Publication date

2006-07-31

2000-10-17 Application filed by Bayer Ag filed Critical Bayer Ag

2000-10-17 Publication of NO20005215D0 publication Critical patent/NO20005215D0/no

2000-12-13 Publication of NO20005215L publication Critical patent/NO20005215L/no

2006-07-31 Publication of NO321985B1 publication Critical patent/NO321985B1/no

Links

150000001875 compounds Chemical class 0.000 title claims description 54
238000000034 method Methods 0.000 title claims description 22
238000011282 treatment Methods 0.000 title claims description 10
239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
201000010099 disease Diseases 0.000 title claims description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 7
230000003612 virological effect Effects 0.000 title claims description 4
208000002672 hepatitis B Diseases 0.000 title description 7
WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 title description 2
-1 trifluoromethoxy, carboxyl Chemical group 0.000 claims description 22
150000003839 salts Chemical class 0.000 claims description 18
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
125000004432 carbon atom Chemical group C* 0.000 claims description 13
239000000460 chlorine Substances 0.000 claims description 13
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
239000002253 acid Substances 0.000 claims description 10
229910052801 chlorine Inorganic materials 0.000 claims description 10
239000001257 hydrogen Substances 0.000 claims description 10
229910052739 hydrogen Inorganic materials 0.000 claims description 10
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
239000011737 fluorine Substances 0.000 claims description 9
229910052731 fluorine Inorganic materials 0.000 claims description 9
125000004076 pyridyl group Chemical group 0.000 claims description 9
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
238000004519 manufacturing process Methods 0.000 claims description 8
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
239000004480 active ingredient Substances 0.000 claims description 7
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
150000001409 amidines Chemical class 0.000 claims description 6
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
229910052794 bromium Inorganic materials 0.000 claims description 6
229910052736 halogen Inorganic materials 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
125000001424 substituent group Chemical group 0.000 claims description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
230000001154 acute effect Effects 0.000 claims description 5
125000000217 alkyl group Chemical group 0.000 claims description 5
230000001684 chronic effect Effects 0.000 claims description 5
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
150000003863 ammonium salts Chemical class 0.000 claims description 4
125000003118 aryl group Chemical group 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
239000003960 organic solvent Substances 0.000 claims description 4
125000004430 oxygen atom Chemical group O* 0.000 claims description 4
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
239000000969 carrier Substances 0.000 claims description 3
208000016350 chronic hepatitis B virus infection Diseases 0.000 claims description 3
239000003814 drug Substances 0.000 claims description 3
150000002463 imidates Chemical class 0.000 claims description 3
239000001301 oxygen Substances 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
238000002360 preparation method Methods 0.000 claims description 3
229920006395 saturated elastomer Polymers 0.000 claims description 3
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
206010059193 Acute hepatitis B Diseases 0.000 claims description 2
208000037628 acute hepatitis B virus infection Diseases 0.000 claims description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
125000001153 fluoro group Chemical group F* 0.000 claims description 2
150000003840 hydrochlorides Chemical class 0.000 claims description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 3
229940126601 medicinal product Drugs 0.000 claims 3
125000001183 hydrocarbyl group Chemical group 0.000 claims 1
239000000546 pharmaceutical excipient Substances 0.000 claims 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
210000004027 cell Anatomy 0.000 description 20
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
239000000243 solution Substances 0.000 description 11
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
229960000583 acetic acid Drugs 0.000 description 7
239000006228 supernatant Substances 0.000 description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
108020004414 DNA Proteins 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
238000006243 chemical reaction Methods 0.000 description 6
SOGUCWFOKBJAQO-UHFFFAOYSA-N methyl 2-[(2-chloro-4-fluorophenyl)methylidene]-3-oxobutanoate Chemical compound COC(=O)C(C(C)=O)=CC1=CC=C(F)C=C1Cl SOGUCWFOKBJAQO-UHFFFAOYSA-N 0.000 description 6
ATUOLSDAAPMVJJ-UHFFFAOYSA-N 3,5-dichloropyridine-2-carbonitrile Chemical compound ClC1=CN=C(C#N)C(Cl)=C1 ATUOLSDAAPMVJJ-UHFFFAOYSA-N 0.000 description 5
WDLIDNANRSUVFL-UHFFFAOYSA-N 3,5-difluoropyridine-2-carboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=NC=C(F)C=C1F WDLIDNANRSUVFL-UHFFFAOYSA-N 0.000 description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
150000001299 aldehydes Chemical group 0.000 description 5
230000000840 anti-viral effect Effects 0.000 description 5
235000019439 ethyl acetate Nutrition 0.000 description 5
239000001963 growth medium Substances 0.000 description 5
239000012071 phase Substances 0.000 description 5
238000010992 reflux Methods 0.000 description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
239000002585 base Substances 0.000 description 4
238000001816 cooling Methods 0.000 description 4
238000001514 detection method Methods 0.000 description 4
SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
238000009396 hybridization Methods 0.000 description 4
239000000203 mixture Substances 0.000 description 4
NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
239000000047 product Substances 0.000 description 4
239000011734 sodium Substances 0.000 description 4
239000007858 starting material Substances 0.000 description 4
LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 4
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 3
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
239000004677 Nylon Substances 0.000 description 3
208000036142 Viral infection Diseases 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
230000037396 body weight Effects 0.000 description 3
231100000433 cytotoxic Toxicity 0.000 description 3
230000001472 cytotoxic effect Effects 0.000 description 3
239000012528 membrane Substances 0.000 description 3
150000007522 mineralic acids Chemical class 0.000 description 3
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
229920001778 nylon Polymers 0.000 description 3
239000012074 organic phase Substances 0.000 description 3
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
239000002904 solvent Substances 0.000 description 3
239000000126 substance Substances 0.000 description 3
230000009385 viral infection Effects 0.000 description 3
238000005160 1H NMR spectroscopy Methods 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
125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
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 2
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
241000700721 Hepatitis B virus Species 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
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125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
125000004414 alkyl thio group Chemical group 0.000 description 2
230000000903 blocking effect Effects 0.000 description 2
239000003153 chemical reaction reagent Substances 0.000 description 2
DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
125000000753 cycloalkyl group Chemical group 0.000 description 2
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
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150000002148 esters Chemical class 0.000 description 2
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230000002401 inhibitory effect Effects 0.000 description 2
238000002844 melting Methods 0.000 description 2
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VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
229910052757 nitrogen Inorganic materials 0.000 description 2
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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238000000926 separation method Methods 0.000 description 2
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238000010186 staining Methods 0.000 description 2
BRKFQVAOMSWFDU-UHFFFAOYSA-M tetraphenylphosphanium;bromide Chemical compound [Br-].C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BRKFQVAOMSWFDU-UHFFFAOYSA-M 0.000 description 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
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CELKOWQJPVJKIL-UHFFFAOYSA-N 3-fluoropyridine Chemical compound FC1=CC=CN=C1 CELKOWQJPVJKIL-UHFFFAOYSA-N 0.000 description 1
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PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
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XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
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238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
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239000004472 Lysine Substances 0.000 description 1
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BACYUWVYYTXETD-UHFFFAOYSA-N N-Lauroylsarcosine Chemical compound CCCCCCCCCCCC(=O)N(C)CC(O)=O BACYUWVYYTXETD-UHFFFAOYSA-N 0.000 description 1
UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
150000001204 N-oxides Chemical class 0.000 description 1
239000004353 Polyethylene glycol 8000 Substances 0.000 description 1
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239000007983 Tris buffer Substances 0.000 description 1
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239000003513 alkali Substances 0.000 description 1
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WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
238000009835 boiling Methods 0.000 description 1
244000309464 bull Species 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
159000000007 calcium salts Chemical class 0.000 description 1
229910002091 carbon monoxide Inorganic materials 0.000 description 1
150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
230000006037 cell lysis Effects 0.000 description 1
239000006285 cell suspension Substances 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
208000019425 cirrhosis of liver Diseases 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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229960002887 deanol Drugs 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
229960005156 digoxin Drugs 0.000 description 1
LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
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238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000004821 distillation Methods 0.000 description 1
229940079593 drug Drugs 0.000 description 1
239000003480 eluent Substances 0.000 description 1
CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
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238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 description 1
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239000011888 foil Substances 0.000 description 1
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239000007789 gas Substances 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
238000003306 harvesting Methods 0.000 description 1
208000005252 hepatitis A Diseases 0.000 description 1
206010073071 hepatocellular carcinoma Diseases 0.000 description 1
231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
229940094991 herring sperm dna Drugs 0.000 description 1
125000000623 heterocyclic group Chemical group 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
150000002431 hydrogen Chemical class 0.000 description 1
230000001900 immune effect Effects 0.000 description 1
239000012442 inert solvent Substances 0.000 description 1
208000015181 infectious disease Diseases 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium 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
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
238000000386 microscopy Methods 0.000 description 1
238000002156 mixing Methods 0.000 description 1
239000004570 mortar (masonry) Substances 0.000 description 1
125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
150000002825 nitriles Chemical class 0.000 description 1
ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
238000006053 organic reaction Methods 0.000 description 1
210000004976 peripheral blood cell Anatomy 0.000 description 1
150000002978 peroxides Chemical class 0.000 description 1
230000002085 persistent effect Effects 0.000 description 1
239000003444 phase transfer catalyst Substances 0.000 description 1
RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
235000019446 polyethylene glycol 8000 Nutrition 0.000 description 1
229940085678 polyethylene glycol 8000 Drugs 0.000 description 1
229920000151 polyglycol Polymers 0.000 description 1
239000010695 polyglycol Substances 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
235000015320 potassium carbonate Nutrition 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
239000000523 sample Substances 0.000 description 1
108700004121 sarkosyl Proteins 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
241000894007 species Species 0.000 description 1
238000003756 stirring Methods 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
HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
230000007306 turnover Effects 0.000 description 1
230000002477 vacuolizing effect Effects 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
210000002845 virion Anatomy 0.000 description 1
238000005406 washing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
- 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
- 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
- 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
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
- 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
- C07D401/14—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 three or more hetero rings

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Communicable Diseases (AREA)
Engineering & Computer Science (AREA)
Oncology (AREA)
Virology (AREA)
Gastroenterology & Hepatology (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Pyridine Compounds (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Saccharide Compounds (AREA)

NO20005215A 1998-04-18 2000-10-17 Dihydropyrimidinforbindelser, fremgangsmater for fremstilling av slike, samt fremgangsmate for fremstilling av farmasoytiske preparater og anvendelse av forbindelsene i farmasoytiske preparater for behandling av virussykdommer, saerlig hepatitt B NO321985B1 (no)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
DE19817264A DE19817264A1 (de)	1998-04-18	1998-04-18	Neue Dihydropyrimidine
PCT/EP1999/002344 WO1999054326A1 (de)	1998-04-18	1999-04-07	Dihydropyrimidine

Publications (3)

Publication Number	Publication Date
NO20005215D0 NO20005215D0 (no)	2000-10-17
NO20005215L NO20005215L (no)	2000-12-13
NO321985B1 true NO321985B1 (no)	2006-07-31

Family

ID=7864972

Family Applications (2)

Application Number	Title	Priority Date	Filing Date
NO20005215A NO321985B1 (no)	1998-04-18	2000-10-17	Dihydropyrimidinforbindelser, fremgangsmater for fremstilling av slike, samt fremgangsmate for fremstilling av farmasoytiske preparater og anvendelse av forbindelsene i farmasoytiske preparater for behandling av virussykdommer, saerlig hepatitt B
NO20045259A NO329020B1 (no)	1998-04-18	2004-12-01	Difluorpyridiner

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
NO20045259A NO329020B1 (no)	1998-04-18	2004-12-01	Difluorpyridiner

Country Status (36)

Country	Link
US (3)	US6696451B1 (2)
EP (1)	EP1080086B1 (2)
JP (2)	JP4590097B2 (2)
KR (1)	KR100636771B1 (2)
CN (1)	CN1159311C (2)
AR (1)	AR018187A1 (2)
AT (1)	ATE223401T1 (2)
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DK1080086T3 (da)	2002-12-23
CZ293482B6 (cs)	2004-05-12
GT199900056A (es)	2000-10-07
RU2245881C9 (ru)	2006-02-10
NZ507569A (en)	2002-04-26
WO1999054326A8 (de)	1999-12-29
SK286407B6 (sk)	2008-09-05
PE20000427A1 (es)	2000-06-25
BRPI9917862B8 (pt)	2021-05-25
KR20010042788A (ko)	2001-05-25
SV1999000047A (es)	2000-06-23
CU23049A3 (es)	2005-06-24
CZ20003871A3 (cs)	2001-01-17
EP1080086B1 (de)	2002-09-04
ZA200005136B (en)	2001-03-02
PL193898B1 (pl)	2007-03-30
BRPI9917862B1 (pt)	2013-05-07
JP2002512243A (ja)	2002-04-23
PL343481A1 (en)	2001-08-27
CO5021127A1 (es)	2001-03-27
US6696451B1 (en)	2004-02-24
TW548274B (en)	2003-08-21
BG104812A (en)	2001-06-29
AR018187A1 (es)	2001-10-31
JP4590097B2 (ja)	2010-12-01
DE19817264A1 (de)	1999-10-21
BRPI9917862A2 (2)	2010-12-07
WO1999054326A1 (de)	1999-10-28
CA2328780A1 (en)	1999-10-28
DE59902573D1 (en)	2002-10-10
US7514565B2 (en)	2009-04-07
US20040167135A1 (en)	2004-08-26
ATE223401T1 (de)	2002-09-15
TR200003011T2 (tr)	2001-01-22
SK15652000A3 (sk)	2001-04-09
ES2183548T3 (es)	2003-03-16
BG64649B1 (bg)	2005-10-31
AU740318B2 (en)	2001-11-01
CN1159311C (zh)	2004-07-28
JP2010241837A (ja)	2010-10-28
SI1080086T1 (en)	2003-02-28
IL138584A0 (en)	2001-10-31
AU3813399A (en)	1999-11-08
EP1080086A1 (de)	2001-03-07
MY126527A (en)	2006-10-31
NO20005215L (no)	2000-12-13
KR100636771B1 (ko)	2006-10-23
NO20005215D0 (no)	2000-10-17
NO329020B1 (no)	2010-07-26
UA63998C2 (uk)	2004-02-16
CN1305471A (zh)	2001-07-25
BR9909730A (pt)	2000-12-19
JP5237332B2 (ja)	2013-07-17
BR9909730B1 (pt)	2012-09-04
HUP0102372A2 (hu)	2001-12-28
IL138584A (en)	2006-09-05
HK1039119A1 (en)	2002-04-12
US20070117812A1 (en)	2007-05-24
RU2245881C2 (ru)	2005-02-10
CA2328780C (en)	2008-09-23
HUP0102372A3 (en)	2003-01-28
NO20045259L (no)	2000-12-13
PT1080086E (pt)	2002-12-31
ID27263A (id)	2001-03-22

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2013-06-17	CHAD	Change of the owner's name or address (par. 44 patent law, par. patentforskriften)	Owner name: BAYER INTELLECTUAL PROPERTY GMBH, DE
2019-05-13	MK1K	Patent expired

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US6696451B1 (en)	2004-02-24	Dihydropyrimidines
US6436943B1 (en)	2002-08-20	Use of dihydropyrimidines as medicaments, and novel substances
RU2443703C2 (ru)	2012-02-27	Бром-фенил замещенные тиазолилдигидропиримидины
EP0579496B1 (en)	2001-11-14	4-Aminoquinazoline derivatives, and their use as medicine
US20030232842A1 (en)	2003-12-18	Medicaments against viral diseases
EP1877396B1 (de)	2009-02-18	Dipyridyl-dihydropyrazolone und ihre verwendung 4- (pyridin-3-yl) -2- (pyridin-2-yl) -1,2-dihydro-3h-pyrazol-3-on derivate als spezifische hemmstoffe der hif-prolyl-4-hydroxylasen zur behandlung kardiovaskulärer und hämatologischer erkrankungen
WO2000058302A1 (de)	2000-10-05	Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b
KR20050047128A (ko)	2005-05-19	신규 피리미딘아미드 유도체 및 그의 용도
CN113105394A (zh)	2021-07-13	一种含芳杂环结构的联苯二芳基嘧啶类衍生物及其制备方法和应用
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