JP2527917B2 - 治療薬 - Google Patents
治療薬Info
- Publication number
- JP2527917B2 JP2527917B2 JP5511397A JP51139793A JP2527917B2 JP 2527917 B2 JP2527917 B2 JP 2527917B2 JP 5511397 A JP5511397 A JP 5511397A JP 51139793 A JP51139793 A JP 51139793A JP 2527917 B2 JP2527917 B2 JP 2527917B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- alkyl group
- compound
- hydrogen
- 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.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 182
- 239000001257 hydrogen Substances 0.000 claims abstract description 109
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 109
- -1 alkoxycarbonyalkenyl Chemical group 0.000 claims abstract description 69
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000002723 alicyclic group Chemical group 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims abstract description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 150000002431 hydrogen Chemical class 0.000 claims description 38
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 21
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 16
- 238000010438 heat treatment Methods 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 208000025747 Rheumatic disease Diseases 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- AQZNKLJRHSWVOV-UHFFFAOYSA-N ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2N=C(C)C(OCC)=CC2=C1NC1=CC=C(OC)C=C1 AQZNKLJRHSWVOV-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- KHVFTTVPXONUEK-UHFFFAOYSA-N 4-[(6-ethoxy-7-methyl-1,8-naphthyridin-4-yl)amino]-2,6-dimethylphenol Chemical compound C1=CN=C2N=C(C)C(OCC)=CC2=C1NC1=CC(C)=C(O)C(C)=C1 KHVFTTVPXONUEK-UHFFFAOYSA-N 0.000 claims description 2
- MFQRHPQDMCQXGL-UHFFFAOYSA-N 6-ethoxy-n-(4-methoxyphenyl)-7-methyl-1,8-naphthyridin-4-amine Chemical compound C1=CN=C2N=C(C)C(OCC)=CC2=C1NC1=CC=C(OC)C=C1 MFQRHPQDMCQXGL-UHFFFAOYSA-N 0.000 claims description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 239000012380 dealkylating agent Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- VSJPYMWRSVBITD-UHFFFAOYSA-N ethyl 6-ethoxy-4-[4-(2-hydroxyethoxy)anilino]-7-methyl-1,8-naphthyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2N=C(C)C(OCC)=CC2=C1NC1=CC=C(OCCO)C=C1 VSJPYMWRSVBITD-UHFFFAOYSA-N 0.000 claims description 2
- WPMPEBNPWUMGRJ-UHFFFAOYSA-N ethyl 7-ethoxy-4-(4-methoxyanilino)-1,8-naphthyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2N=C(OCC)C=CC2=C1NC1=CC=C(OC)C=C1 WPMPEBNPWUMGRJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 137
- 238000000034 method Methods 0.000 abstract description 36
- 239000003435 antirheumatic agent Substances 0.000 abstract description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 8
- 125000001475 halogen functional group Chemical group 0.000 abstract 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 abstract 1
- 125000004414 alkyl thio group Chemical group 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 125000005019 carboxyalkenyl group Chemical group 0.000 abstract 1
- 125000004181 carboxyalkyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 238000002844 melting Methods 0.000 description 42
- 230000008018 melting Effects 0.000 description 42
- 239000000243 solution Substances 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 239000007787 solid Substances 0.000 description 33
- 238000010992 reflux Methods 0.000 description 30
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 238000009835 boiling Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 125000001246 bromo group Chemical group Br* 0.000 description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 235000019271 petrolatum Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 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 7
- 241000699670 Mus sp. Species 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- YVLDREWBMDHQGN-UHFFFAOYSA-N chloro hypochlorite phosphoric acid Chemical compound ClOCl.OP(O)(O)=O YVLDREWBMDHQGN-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- AQSRRZGQRFFFGS-UHFFFAOYSA-N 2-methylpyridin-3-ol Chemical compound CC1=NC=CC=C1O AQSRRZGQRFFFGS-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 6
- 239000004264 Petrolatum Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 230000003628 erosive effect Effects 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 201000008482 osteoarthritis Diseases 0.000 description 6
- 229940066842 petrolatum Drugs 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 206010003246 arthritis Diseases 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
- UCYSCIJWSTXBHG-UHFFFAOYSA-N ethyl 6-ethoxy-7-methyl-4-oxo-1h-1,8-naphthyridine-3-carboxylate Chemical compound N1=C(C)C(OCC)=CC2=C(O)C(C(=O)OCC)=CN=C21 UCYSCIJWSTXBHG-UHFFFAOYSA-N 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- JJCODSWKMAHWBP-UHFFFAOYSA-N ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate Chemical compound N1=C(C)C(OCC)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 JJCODSWKMAHWBP-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 description 3
- BATUATIMONERQY-UHFFFAOYSA-N 5-ethoxy-6-methylpyridin-2-amine Chemical compound CCOC1=CC=C(N)N=C1C BATUATIMONERQY-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 3
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 230000005484 gravity Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 108010077055 methylated bovine serum albumin Proteins 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 229920000137 polyphosphoric acid Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 201000004595 synovitis Diseases 0.000 description 3
- UKMSWIQIYDTDBK-UHFFFAOYSA-N 2,6-dichloro-4-[(6-ethoxy-7-methyl-1,8-naphthyridin-4-yl)amino]phenol Chemical compound C1=CN=C2N=C(C)C(OCC)=CC2=C1NC1=CC(Cl)=C(O)C(Cl)=C1 UKMSWIQIYDTDBK-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- BJEZWGZDQXAODC-UHFFFAOYSA-N 3-bromo-6-ethoxy-n-(4-methoxyphenyl)-7-methyl-1,8-naphthyridin-4-amine Chemical compound BrC1=CN=C2N=C(C)C(OCC)=CC2=C1NC1=CC=C(OC)C=C1 BJEZWGZDQXAODC-UHFFFAOYSA-N 0.000 description 2
- YUHXVWQQUNUOGH-UHFFFAOYSA-N 3-ethoxy-2-methylpyridine Chemical compound CCOC1=CC=CN=C1C YUHXVWQQUNUOGH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ADHVKJKRZSDQSU-UHFFFAOYSA-N 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine Chemical compound C1=CN=C2N=C(C)C(OCC)=CC2=C1Cl ADHVKJKRZSDQSU-UHFFFAOYSA-N 0.000 description 2
- GMWZPVNIMVUDTO-UHFFFAOYSA-N 6-bromo-7-methyl-1h-1,8-naphthyridin-4-one Chemical compound C1=CC(O)=C2C=C(Br)C(C)=NC2=N1 GMWZPVNIMVUDTO-UHFFFAOYSA-N 0.000 description 2
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- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- SBVDIWCCBXDGEC-UHFFFAOYSA-N trifluoromethyl 1,8-naphthyridine-3-carboxylate Chemical compound FC(F)(F)OC(=O)C=1C=NC2=NC=CC=C2C1 SBVDIWCCBXDGEC-UHFFFAOYSA-N 0.000 description 1
- MQAYPFVXSPHGJM-UHFFFAOYSA-M trimethyl(phenyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)C1=CC=CC=C1 MQAYPFVXSPHGJM-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9127252.6 | 1991-12-23 | ||
| GB919127252A GB9127252D0 (en) | 1991-12-23 | 1991-12-23 | Therapeutic agents |
| PCT/EP1992/002901 WO1993013097A1 (en) | 1991-12-23 | 1992-12-12 | Anti-rheumatic naphthyridine derivatives |
| CN93109454A CN1096784A (zh) | 1991-12-23 | 1993-06-22 | 含取代4(5)-氨基-1,8-二氨杂萘的治疗剂 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07502280A JPH07502280A (ja) | 1995-03-09 |
| JP2527917B2 true JP2527917B2 (ja) | 1996-08-28 |
Family
ID=36822317
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5511397A Expired - Fee Related JP2527917B2 (ja) | 1991-12-23 | 1992-12-12 | 治療薬 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5464781A (OSRAM) |
| EP (1) | EP0618916B1 (OSRAM) |
| JP (1) | JP2527917B2 (OSRAM) |
| CN (1) | CN1096784A (OSRAM) |
| AT (1) | ATE171452T1 (OSRAM) |
| AU (1) | AU656832B2 (OSRAM) |
| BG (1) | BG98813A (OSRAM) |
| CA (1) | CA2125858A1 (OSRAM) |
| CZ (1) | CZ153594A3 (OSRAM) |
| DE (1) | DE69227125T2 (OSRAM) |
| FI (1) | FI943019A7 (OSRAM) |
| GB (1) | GB9127252D0 (OSRAM) |
| HR (1) | HRP921455A2 (OSRAM) |
| HU (1) | HUT66971A (OSRAM) |
| IL (1) | IL104169A0 (OSRAM) |
| IN (1) | IN174405B (OSRAM) |
| MX (1) | MX9207494A (OSRAM) |
| NO (1) | NO942376L (OSRAM) |
| NZ (1) | NZ246156A (OSRAM) |
| SI (1) | SI9200408A (OSRAM) |
| SK (1) | SK75094A3 (OSRAM) |
| WO (1) | WO1993013097A1 (OSRAM) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9312891D0 (en) * | 1993-06-22 | 1993-08-04 | Boots Co Plc | Therapeutic agents |
| GB9318931D0 (en) * | 1993-09-14 | 1993-10-27 | Boots Co Plc | Therapeutic agents |
| GB9420168D0 (en) * | 1994-10-06 | 1994-11-23 | Boots Co Plc | Therapeutic agents |
| AR004010A1 (es) | 1995-10-11 | 1998-09-30 | Glaxo Group Ltd | Compuestos heterociclicos |
| CA2263479A1 (en) | 1996-09-25 | 1998-04-02 | Zeneca Limited | Quinoline derivatives inhibiting the effect of growth factors such as vegf |
| RS49779B (sr) | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
| US6166069A (en) * | 1998-05-12 | 2000-12-26 | American Home Products Corporation | Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
| US6933299B1 (en) | 1999-07-09 | 2005-08-23 | Smithkline Beecham Corporation | Anilinoquinazolines as protein tyrosine kinase inhibitors |
| DE60037020T2 (de) | 1999-07-09 | 2008-08-21 | Glaxo Group Ltd., Greenford | Anilinochinazoline als protein-tyrosin-kinasehemmer |
| CN1240688C (zh) | 2000-04-07 | 2006-02-08 | 阿斯特拉曾尼卡有限公司 | 喹唑啉化合物 |
| US6534656B2 (en) * | 2001-05-31 | 2003-03-18 | North Carolina State University | Short synthesis of pyridine-based pharmaceutical intermediates |
| JP2003329989A (ja) * | 2002-03-06 | 2003-11-19 | Nippon Telegr & Teleph Corp <Ntt> | 光送信装置 |
| GB0230018D0 (en) | 2002-12-23 | 2003-01-29 | Syngenta Ltd | Fungicides |
| US8309562B2 (en) * | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
| US7618975B2 (en) | 2003-07-03 | 2009-11-17 | Myriad Pharmaceuticals, Inc. | 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| WO2005063739A1 (en) | 2003-12-23 | 2005-07-14 | Pfizer Inc. | Novel quinoline derivatives |
| US8258145B2 (en) * | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
| CA2592900A1 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
| EP1971611B1 (en) * | 2005-12-21 | 2012-10-10 | Abbott Laboratories | Anti-viral compounds |
| CA2633760A1 (en) * | 2005-12-21 | 2007-07-05 | Abbott Laboratories | Anti-viral compounds |
| NZ569817A (en) * | 2005-12-21 | 2011-10-28 | Abbott Lab | Anti-viral compounds |
| TW200738707A (en) * | 2005-12-21 | 2007-10-16 | Abbott Lab | Anti-viral compounds |
| EP2345652A1 (en) | 2005-12-21 | 2011-07-20 | Abbott Laboratories | Antiviral compounds |
| US8236950B2 (en) | 2006-12-20 | 2012-08-07 | Abbott Laboratories | Anti-viral compounds |
| BRPI0914936A2 (pt) * | 2008-07-03 | 2015-10-20 | Merck Patent Gmbh | naftiridininonas como inibidores de aurora quinase |
| ES2432070T3 (es) | 2009-02-24 | 2013-11-29 | Respiratorius Ab | Diazaheteroarilos broncodilatadores novedosos |
| WO2011063398A1 (en) * | 2009-11-23 | 2011-05-26 | Cylene Pharamaceuticals, Inc. | Polymorphs and salts of a kinase inhibitor |
| RU2605549C2 (ru) | 2010-04-02 | 2016-12-20 | Синомикс, Инк. | Производные 3-карбокси-4-аминохинолина, полезные как модификаторы сладкого вкуса |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4466965A (en) * | 1982-07-26 | 1984-08-21 | American Hospital Supply Corporation | Phthalazine compounds, compositions and use |
| NO174506B (no) * | 1984-10-30 | 1994-02-07 | Usv Pharma Corp | Analogifremgangsmaate ved fremstilling av terapeutisk aktive forbindelser |
| EP0222839A4 (en) * | 1985-05-17 | 1988-11-09 | Univ Australian | ANTI-MALARIA COMPOUNDS. |
| JPS6368568A (ja) * | 1986-09-10 | 1988-03-28 | Otsuka Pharmaceut Factory Inc | ｐ−アミノフエノ−ル誘導体 |
| DE3644825A1 (de) * | 1986-12-31 | 1988-07-14 | Basf Ag | Substituierte 1,8-naphthyridin-derivate und diese enthaltende fungizide |
| JPH07116187B2 (ja) * | 1987-07-22 | 1995-12-13 | シェリング・コーポレーション | 二環式化合物、それらを薬剤として使用すること、それらの製法、およびそれらの製造に有用な中間体 |
| GB8804443D0 (en) * | 1988-02-25 | 1988-03-23 | Smithkline Beckman Intercredit | Compounds |
| US4978661A (en) * | 1988-09-29 | 1990-12-18 | Innocenzo Caruso | Use of 6-halo-4-quinolone compounds and pharmaceutical compositions thereof for the preparation of a medicament for the therapeutical application in rheumatoid arthritis |
| GR900100380A (el) * | 1989-05-20 | 1991-10-10 | Fisons Plc | Μέ?οδος παρασκευής αντι-φλεγμονωδών παραγώγων αμινοφενόλης. |
| AU634561B2 (en) * | 1989-07-27 | 1993-02-25 | Eli Lilly And Company | Naphthyridine derivatives |
| JP2988739B2 (ja) * | 1990-04-16 | 1999-12-13 | 協和醗酵工業株式会社 | １，８−ナフチリジン−２−オン誘導体 |
| JP3157077B2 (ja) * | 1994-02-16 | 2001-04-16 | 内山工業株式会社 | ベアリングシール |
-
1991
- 1991-12-23 GB GB919127252A patent/GB9127252D0/en active Pending
-
1992
- 1992-10-12 US US08/244,369 patent/US5464781A/en not_active Expired - Lifetime
- 1992-12-12 WO PCT/EP1992/002901 patent/WO1993013097A1/en not_active Ceased
- 1992-12-12 HU HU9401877A patent/HUT66971A/hu unknown
- 1992-12-12 DE DE69227125T patent/DE69227125T2/de not_active Expired - Fee Related
- 1992-12-12 AT AT93900052T patent/ATE171452T1/de not_active IP Right Cessation
- 1992-12-12 NZ NZ246156A patent/NZ246156A/en unknown
- 1992-12-12 CZ CZ941535A patent/CZ153594A3/cs unknown
- 1992-12-12 AU AU31587/93A patent/AU656832B2/en not_active Ceased
- 1992-12-12 SK SK750-94A patent/SK75094A3/sk unknown
- 1992-12-12 EP EP93900052A patent/EP0618916B1/en not_active Expired - Lifetime
- 1992-12-12 CA CA002125858A patent/CA2125858A1/en not_active Abandoned
- 1992-12-12 JP JP5511397A patent/JP2527917B2/ja not_active Expired - Fee Related
- 1992-12-17 IN IN758MA1992 patent/IN174405B/en unknown
- 1992-12-18 IL IL104169A patent/IL104169A0/xx unknown
- 1992-12-22 MX MX9207494A patent/MX9207494A/es unknown
- 1992-12-22 HR HR921455A patent/HRP921455A2/hr not_active Application Discontinuation
- 1992-12-22 SI SI19929200408A patent/SI9200408A/sl unknown
-
1993
- 1993-06-22 CN CN93109454A patent/CN1096784A/zh active Pending
-
1994
- 1994-05-31 BG BG98813A patent/BG98813A/bg unknown
- 1994-06-22 FI FI943019A patent/FI943019A7/fi not_active Application Discontinuation
- 1994-06-22 NO NO942376A patent/NO942376L/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07502280A (ja) | 1995-03-09 |
| NO942376D0 (OSRAM) | 1994-06-22 |
| AU656832B2 (en) | 1995-02-16 |
| AU3158793A (en) | 1993-07-28 |
| NO942376L (no) | 1994-06-22 |
| US5464781A (en) | 1995-11-07 |
| CZ153594A3 (en) | 1995-02-15 |
| SK75094A3 (en) | 1995-04-12 |
| BG98813A (bg) | 1995-05-31 |
| DE69227125T2 (de) | 1999-02-18 |
| EP0618916B1 (en) | 1998-09-23 |
| HUT66971A (en) | 1995-01-30 |
| CA2125858A1 (en) | 1993-07-08 |
| HRP921455A2 (en) | 1994-12-31 |
| NZ246156A (en) | 1996-01-26 |
| MX9207494A (es) | 1993-07-01 |
| ATE171452T1 (de) | 1998-10-15 |
| DE69227125D1 (de) | 1998-10-29 |
| IL104169A0 (en) | 1993-05-13 |
| EP0618916A1 (en) | 1994-10-12 |
| FI943019A0 (fi) | 1994-06-22 |
| IN174405B (OSRAM) | 1994-11-26 |
| GB9127252D0 (en) | 1992-02-19 |
| WO1993013097A1 (en) | 1993-07-08 |
| HU9401877D0 (en) | 1994-09-28 |
| SI9200408A (en) | 1993-09-30 |
| FI943019A7 (fi) | 1994-06-22 |
| CN1096784A (zh) | 1994-12-28 |
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Legal Events
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| R250 | Receipt of annual fees |
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