JPH0567142B2 - - Google Patents
Info
- Publication number
- JPH0567142B2 JPH0567142B2 JP6698986A JP6698986A JPH0567142B2 JP H0567142 B2 JPH0567142 B2 JP H0567142B2 JP 6698986 A JP6698986 A JP 6698986A JP 6698986 A JP6698986 A JP 6698986A JP H0567142 B2 JPH0567142 B2 JP H0567142B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- lower alkyl
- alkyl group
- formula
- compound
- 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 description 76
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 10
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 4
- -1 methoxy, Ethoxy, propoxy, isopropoxy Chemical group 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000000034 method Methods 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 150000004057 1,4-benzoquinones Chemical class 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 150000003927 aminopyridines Chemical class 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000000704 physical effect Effects 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RDQSIADLBQFVMY-UHFFFAOYSA-N 2,6-Di-tert-butylbenzoquinone Chemical compound CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O RDQSIADLBQFVMY-UHFFFAOYSA-N 0.000 description 4
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 4
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- KGIJOOYOSFUGPC-CABOLEKPSA-N 5-HETE Natural products CCCCC\C=C/C\C=C/C\C=C/C=C/[C@H](O)CCCC(O)=O KGIJOOYOSFUGPC-CABOLEKPSA-N 0.000 description 2
- KGIJOOYOSFUGPC-MSFIICATSA-N 5-Hydroxyeicosatetraenoic acid Chemical compound CCCCCC=CCC=CCC=C\C=C\[C@@H](O)CCCC(O)=O KGIJOOYOSFUGPC-MSFIICATSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000003435 antirheumatic agent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 238000006170 formylation reaction Methods 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- MBGSRKHDEJNWED-UHFFFAOYSA-N methyl 5-aminopyridine-3-carboxylate Chemical compound COC(=O)C1=CN=CC(N)=C1 MBGSRKHDEJNWED-UHFFFAOYSA-N 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AMQCWFKKFGSNNA-UHFFFAOYSA-N 2-butylcyclohexa-2,5-diene-1,4-dione Chemical compound CCCCC1=CC(=O)C=CC1=O AMQCWFKKFGSNNA-UHFFFAOYSA-N 0.000 description 1
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- HIYAVKIYRIFSCZ-CVXKHCKVSA-N Calcimycin Chemical compound CC([C@H]1OC2([C@@H](C[C@H]1C)C)O[C@H]([C@H](CC2)C)CC=1OC2=CC=C(C(=C2N=1)C(O)=O)NC)C(=O)C1=CC=CN1 HIYAVKIYRIFSCZ-CVXKHCKVSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 description 1
- LGULNFOANTYHKH-UHFFFAOYSA-N N1=CC=CC=C1.NC1=C(C=CC=C1)O Chemical class N1=CC=CC=C1.NC1=C(C=CC=C1)O LGULNFOANTYHKH-UHFFFAOYSA-N 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000001315 anti-hyperlipaemic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001518 anti-nephritic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- HIYAVKIYRIFSCZ-UHFFFAOYSA-N calcium ionophore A23187 Natural products N=1C2=C(C(O)=O)C(NC)=CC=C2OC=1CC(C(CC1)C)OC1(C(CC1C)C)OC1C(C)C(=O)C1=CC=CN1 HIYAVKIYRIFSCZ-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- WQPDQJCBHQPNCZ-UHFFFAOYSA-N cyclohexa-2,4-dien-1-one Chemical compound O=C1CC=CC=C1 WQPDQJCBHQPNCZ-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 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
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
産業上の利用分野
本発明は、薬理学的作用を有する新規なピリジ
ルアミノフエノール誘導体及びその塩並びに之等
の製造方法に関する。
従来の技術
本発明のピリジルアミノフエノール誘導体は、
文献未載の新規化合物である。
発明が解決しようとする問題点
本発明は、後記するように価値ある薬理作用を
有するピリジンアミノフエノール誘導体を提供す
ることを目的とする。
問題点を解決するための手段
本発明は、一般式
INDUSTRIAL APPLICATION FIELD The present invention relates to novel pyridylaminophenol derivatives and salts thereof having pharmacological effects, and methods for producing the same. PRIOR ART The pyridylaminophenol derivative of the present invention is
This is a new compound that has not been published in any literature. Problems to be Solved by the Invention An object of the present invention is to provide a pyridine aminophenol derivative having valuable pharmacological effects as described below. Means for Solving the Problems The present invention is based on the general formula
で表わされるピリジルアミノフエノール誘導体及
びその薬理的に許容される塩並びに之等化合物の
製造方法に係わる。
上記一般式(1)において低級アルキル基として
は、例えばメチル、エチル、プロピル、イソプロ
ピル、ブチル、イソブチル、tert−ブチル、ペン
チル、ヘキシル基等の直鎖又は分枝鎖状アルキル
基を例示できる。
低級アルコキシ基としては、例えばメトキシ、
エトキシ、プロポキシ、イソプロポキシ、sec−
ブトキシ、tert−ブトキシ、ペンチルオキシ、ヘ
キシルオキシ基等の直鎖又は分枝鎖状アルコキシ
基を例示できる。
低級アルコキシカルボニル基としては、例えば
メトキシカルボニル、エトキシカルボニル、プロ
ポキシカルボニル、1−メチル−1−エトキシカ
ルボニル、ブトキシカルボニル、2−メチル−1
−プロポキシカルボニル、1,1−ジメチル−1
エトキシカルボニル、ペンチルオキシカルボニ
ル、ヘキシルオキシカルボニル基等を例示でき
る。
低級アルコキシカルボニル低級アルキル基とし
ては、例えばメトキシカルボニルメチル、2−
(メトキシカルボニル)エチル、1−(メトキシカ
ルボニル)エチル、エトキシカルボニルメチル、
2−(エトキシカルボニル)エチル、1−(エトキ
シカルボニル)エチル、3−(メトキシカルボニ
ル)プロピル、1−(メトキシカルボニル)プロ
ピル基等を例示できる。
低級アルキルアミノ基としては、例えばメチル
アミノ、エチルアミノ、プロピルアミノ、イソプ
ロピルアミノ、ブチルアミノ、イソブチルアミ
ノ、tert−ブチルアミノ、ペンチルアミノ、ヘキ
シルアミノ基等を例示できる。
低級アルキルカルボニルアミノ基としては、例
えばメチルカルボニルアミノ、エチルカルボニル
アミノ、プロピルカルボニルアミノ、1−メチル
−1−エチルカルボニルアミノ、ブチルカルボニ
ルアミノ、2−メチル−1−プロピルカルボニル
アミノ、1,1−ジメチル−1−エチルカルボニ
ルアミノ、ペンチルカルボニルアミノ、ヘキシル
カルボニルアミノ基等を例示できる。
フエニル低級アルコキシ基としては、例えばベ
ンジルオキシ、2−フエニルエトキシ、3−フエ
ニルプロポキシ、4−フエニルブトキシ、2−フ
エニル−2,2−ジメチルエトキシ、5−フエニ
ルペンチルオキシ、6−フエニルヘキシルオキシ
基等を例示できる。
低級アルキルチオ基としては、例えばメチルチ
オ、エチルチオ、プロピルチオ、イソプロピルチ
オ、ブチルチオ、tert−ブチルチオ、ペンチルチ
オ、ヘキシルチオ基等を例示できる。
ハロゲン原子としては、例えば弗素、塩素、臭
素、沃素原子を例示できる。
カルボキシ低級アルキル基としては、例えばカ
ルボキシメチル、2−カルボキシエチル、3−カ
ルボキシプロピル、2−カルボキシ−1−メチル
エチル、4−カルボキシブチル、2−カルボキシ
1,1−ジメチルエチル、5−カルボキシペンチ
ル、6−カルボキシヘキシル基等を例示できる。
上記一般式(1)で表わされる本発明のピリジルア
ミノフエノール誘導体及びその塩は、プロスタグ
ランジン類、ロイコトリエン類の生合成の阻害作
用や調節作用及び脂質低下作用を有し、動物とり
わけ哺乳動物に対して抗炎症、抗リウマチ、抗腎
炎、抗喘息、抗アレルギー、解熱、鎮痛、血小板
凝集阻止、動脈硬化改善及び抗高脂血症作用を示
す。従つて本発明化合物は、抗炎症剤、抗リウマ
チ剤、腎疾患治療剤、抗喘息剤、抗アレルギー
剤、解熱剤、鎮痛剤、抗血栓剤、心筋硬塞治療剤
及び抗高脂血症剤等の医薬品として有用である。
本発明の一般式(1)で表わされる化合物は、例え
ば下記反応工程式−1〜−4に示す方法により製
造することができる。
<反応工程式−1>
The present invention relates to a pyridylaminophenol derivative represented by the above formula, a pharmacologically acceptable salt thereof, and a method for producing the same. Examples of the lower alkyl group in the above general formula (1) include linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl. Examples of lower alkoxy groups include methoxy,
Ethoxy, propoxy, isopropoxy, sec-
Examples include straight-chain or branched-chain alkoxy groups such as butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methyl-1-ethoxycarbonyl, butoxycarbonyl, 2-methyl-1
-propoxycarbonyl, 1,1-dimethyl-1
Examples include ethoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. Examples of the lower alkoxycarbonyl lower alkyl group include methoxycarbonylmethyl, 2-
(methoxycarbonyl)ethyl, 1-(methoxycarbonyl)ethyl, ethoxycarbonylmethyl,
Examples include 2-(ethoxycarbonyl)ethyl, 1-(ethoxycarbonyl)ethyl, 3-(methoxycarbonyl)propyl, and 1-(methoxycarbonyl)propyl groups. Examples of lower alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, and hexylamino groups. Examples of lower alkylcarbonylamino groups include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, 1-methyl-1-ethylcarbonylamino, butylcarbonylamino, 2-methyl-1-propylcarbonylamino, 1,1-dimethyl Examples include -1-ethylcarbonylamino, pentylcarbonylamino, and hexylcarbonylamino groups. Examples of phenyl lower alkoxy groups include benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 2-phenyl-2,2-dimethylethoxy, 5-phenylpentyloxy, 6-phenylhexyl. Examples include oxy groups. Examples of lower alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, and hexylthio groups. Examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms. Examples of carboxy lower alkyl groups include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 2-carboxy1,1-dimethylethyl, 5-carboxypentyl, Examples include 6-carboxyhexyl group. The pyridylaminophenol derivatives of the present invention represented by the above general formula (1) and their salts have inhibitory and regulatory effects on the biosynthesis of prostaglandins and leukotrienes, and lipid-lowering effects on animals, especially mammals. It exhibits anti-inflammatory, anti-rheumatic, anti-nephritis, anti-asthmatic, anti-allergic, antipyretic, analgesic, platelet aggregation inhibition, arteriosclerosis improvement, and antihyperlipidemic effects. Therefore, the compounds of the present invention can be used as anti-inflammatory agents, anti-rheumatic agents, renal disease therapeutic agents, anti-asthmatic agents, anti-allergy agents, antipyretics, analgesics, antithrombotic agents, myocardial infarction therapeutic agents, antihyperlipidemic agents, etc. It is useful as a medicine. The compound represented by the general formula (1) of the present invention can be produced, for example, by the methods shown in the following reaction schemes -1 to -4. <Reaction scheme-1>
【化】[ka]
【化】[ka]
上記反応工程式−1に示す方法によれば、一般
式(2)のベンゾキノン誘導体と一般式(3)のアミノピ
リジン誘導体との縮合反応及びこれに引続く還元
操作により、一般式(1a)の本発明化合物を収
得できる。
ここで原料であるベンゾキノン誘導体(2)及びア
ミノピリジン誘導体(3)は、公知化合物であるか又
は公知の方法により得ることができる。例えばア
ミノピリジン誘導体(3)は、ザ ケミストリー オ
ブ ヘテロサイクリツク コンパウンズ〔E.
Klingsberg編、The Chemistry of
Heterocyclic Compounds、14巻(Part3)、1962
年、John Wiley&Sons社及びR.A.Abramovitch
編、同本、第14巻(Supplement Part 3)、1974
年、同社〕に記載の方法に従い製造することがで
きる。
上記反応工程式−1に示す縮合反応は、ハロゲ
ン化物系ルイス酸、例えば塩化アルミニウム、塩
化第二鉄、四塩化チタン、塩化第二錫、塩化亜鉛
等の存在下に、ベンゾキノン誘導体(2)と脱酸剤を
兼ねたアミノピリジン誘導体(3)とを、不活性有機
溶媒、例えば1,2−ジクロロエタン、クロロホ
ルム、トルエン、ベンゼン等の溶媒中、室温〜約
120℃の温度で反応させることにより実施され、
この反応により化合物(4)が得られる。上記反応の
際には、脱酸剤として、例えばピリジン、トリエ
チルアミン等の不活性有機塩基を用いることもで
きる。ベンゾキノン誘導体(2)とアミノピリジン誘
導体(3)との使用割合は、特に限定はないが、通常
化合物(2)に対して化合物(3)を約1〜10倍モル量、
好ましくは約1〜3倍モル量用いるのがよい。
なお、上記において四塩化チタンを用いる反応
は、ジヤーナル オブ オーガニツク ケミスト
リー〔J.Org.Chem.、32巻、3246頁(1967年)〕
に記載されたワインガルデン(Weingarten)ら
の方法に準じて実施できる。
また、上記縮合反応は、上記したハロゲン化物
系ルイス以外のルイス酸、例えば三弗化硼素・エ
チルエーテル等を、テトラヒドロフラン、ジオキ
サン等の溶媒中で用いて、ベンゾキノン誘導体(2)
とアミノピリジン誘導体(3)とを、室温〜約100℃
の温度で反応させせることによつても実施でき、
これによつても化合物(4)を製造できる。この反応
は、フイグエラス(Figueras)らの方法〔J.Org.
Chem.、36巻、3497頁(1971)〕に従つて実施で
きる。
更に、上記化合物(4)は、ベンゾキノン誘導体(2)
とアミノピリジン誘導体(3)とを、約100〜200℃に
加熱して反応させることによつても製造できる。
この方法は、ライカー(Reiker)とケスラー
(Kessler)により、テトラヘドロン
(Tetrahedron、23巻、3723頁(1967)〕に詳しく
記載されている。
上記のごとくして得られる化合物(4)は、反応系
内より単離して引続く還元反応に供することがで
きるが、単離することなく引続く反応に供しても
よい。
還元反応は、通常の方法、例えばハイドロサル
フアイトナトリウム、亜鉛と酢酸を用いることに
より実施でき、これにより本発明化合物(1a)
が得られる。また上記還元反応は、例えばパラジ
ウム炭素、白金等の触媒の存在下に水素ガスを用
いても実施できる。
<反応工程式−2>
According to the method shown in Reaction Scheme-1 above, a condensation reaction between a benzoquinone derivative of general formula (2) and an aminopyridine derivative of general formula (3), followed by a reduction operation, results in a reaction of general formula (1a). The compound of the present invention can be obtained. The benzoquinone derivative (2) and aminopyridine derivative (3), which are the raw materials here, are known compounds or can be obtained by known methods. For example, aminopyridine derivatives (3) are available from The Chemistry of Heterocyclic Compounds [E.
Klingsberg, ed., The Chemistry of
Heterocyclic Compounds, Volume 14 (Part 3), 1962
John Wiley & Sons and R.A. Abramovitch
ed., same volume, Volume 14 (Supplement Part 3), 1974
It can be manufactured according to the method described in 2011, published by the same company. The condensation reaction shown in the above reaction scheme-1 is carried out with benzoquinone derivative (2) in the presence of a halide Lewis acid such as aluminum chloride, ferric chloride, titanium tetrachloride, tin chloride, zinc chloride, etc. The aminopyridine derivative (3), which also serves as a deoxidizing agent, is mixed in an inert organic solvent such as 1,2-dichloroethane, chloroform, toluene, benzene, etc. at room temperature to approx.
carried out by reacting at a temperature of 120°C,
Compound (4) is obtained by this reaction. In the above reaction, an inert organic base such as pyridine or triethylamine can also be used as a deoxidizing agent. The ratio of benzoquinone derivative (2) and aminopyridine derivative (3) to be used is not particularly limited, but usually about 1 to 10 times the molar amount of compound (3) to compound (2),
It is preferable to use about 1 to 3 times the molar amount. The above reaction using titanium tetrachloride is described in the Journal of Organic Chemistry [J.Org.Chem., Vol. 32, p. 3246 (1967)].
It can be carried out according to the method of Weingarten et al. described in . In addition, the above condensation reaction can be carried out by using a Lewis acid other than the above-mentioned halide Lewis acids, such as boron trifluoride/ethyl ether, in a solvent such as tetrahydrofuran or dioxane, to form a benzoquinone derivative (2).
and the aminopyridine derivative (3) at room temperature to about 100°C.
It can also be carried out by reacting at a temperature of
Compound (4) can also be produced by this method. This reaction was carried out by the method of Figueras et al. [J.Org.
Chem., vol. 36, p. 3497 (1971)]. Furthermore, the above compound (4) is a benzoquinone derivative (2)
It can also be produced by heating and reacting aminopyridine derivative (3) to about 100 to 200°C.
This method is described in detail by Reiker and Kessler in Tetrahedron (1967). Compound (4) obtained as described above is It can be isolated from the system and subjected to the subsequent reduction reaction, but it may also be subjected to the subsequent reaction without isolation.The reduction reaction can be carried out by a conventional method, for example, using sodium hydrosulfite, zinc and acetic acid. This can be carried out by
is obtained. The above reduction reaction can also be carried out using hydrogen gas in the presence of a catalyst such as palladium on carbon or platinum. <Reaction scheme-2>
【化】[ka]
上記反応工程式−2に示すアルキル化反応は、
オーガニツク リアクシヨン(M.L.Moore、
Organic Reaction、5頁、301頁(1957年)〕に
記載の方法に準じて実施できる。即ち、化合物
(1a′)に炭素数1〜6の脂肪族アルデヒドと蟻酸
とを、約50〜100℃の温度で作用させることによ
り、化合物(1b)を得ることができる。
<反応工程式−3>
The alkylation reaction shown in the above reaction scheme-2 is:
Organic Reaction (MLMoore,
Organic Reaction, p. 5, p. 301 (1957)]. That is, compound (1b) can be obtained by reacting compound (1a') with an aliphatic aldehyde having 1 to 6 carbon atoms and formic acid at a temperature of about 50 to 100°C. <Reaction scheme-3>
【化】[ka]
上記反応工程式−3に示すホルミル化反応は、
化合物(1a′)に蟻酸を、約50〜100℃の温度で作
用させることにより実施され、このホルミル化反
応により、化合物(1b′)を収得できる。
<反応工程式−4>
The formylation reaction shown in the above reaction scheme-3 is
This reaction is carried out by reacting compound (1a') with formic acid at a temperature of about 50 to 100°C, and through this formylation reaction, compound (1b') can be obtained. <Reaction scheme-4>
【化】[ka]
上記反応工程式−4に示す加水分解反応は、エ
リール(Eliel)らの方法〔Organic Syntheses、
巻、169頁(1963)〕に準じて実施できる。即
ち、無溶媒又は酢酸等の適当な溶媒中、化合物
(1a″)に塩酸、臭化水素酸等の適当な酸を、室温
〜約120℃の温度で作用させることにより化合物
(1c)を収得できる。化合物(1a″)に対する酸の
使用割合は、特に限定はないが、通常触媒量〜約
10倍モル量とするのが好ましい。
上記各反応工程式に示す方法により得られる本
発明の化合物(1)は、慣用される分離手段、例えば
溶媒抽出法、再結晶法、カラムクロマトグラフイ
ー等により容易に単離、精製することができる。
また、本発明化合物(1)は、これに常法に従い適
当な酸性化合物を付加反応させることにより、医
薬的に許容される塩とすることができる。上記塩
を形成し得る酸性化合物としては、例えば塩酸、
硫酸、リン酸、臭化水素酸等の無機酸及びマレイ
ン酸、フマール酸、リンゴ酸、酒石酸、クエン
酸、安息香酸、ベンゼンスルホン酸等の有機酸を
例示できる。更に本発明化合物中、遊離のカルボ
キシル基を有するものは、常法に従い容易にナト
リウム塩、カリウム塩等のアルカリ金属塩やカル
シウム塩、マグネシウム塩等の医薬的に許容され
る塩とすることができる。かくして得られる酸付
加塩及び金属塩も遊離形態の本発明化合物と同様
の薬理活性を有しており、本発明はかかる塩をも
包含するものである。
実施例
以下、本発明化合物の製造のための原料化合物
の製造例を参考例として挙げ、次いで本発明化合
物の製造例を実施例として挙げる。
参考例 1
2,6−ジ−tert−ブチル−4−〔(5−メトキ
シカルボニル−3−ピリジル)イミノ〕−2,
5−シクロヘキサジエン−1−オンの製造
〔 法〕
ピリジン7.4mlをジクロロエタン300mlに溶解
し、これに四塩化チタン2.5mlを加え、15分間加
熱還流させた。次いで2,6−ジ−tert−ブチル
−1,4−ベンゾキノン10g及び3−アミノ−5
−メトキシカルボニルピリジン7.0gを加え、20
時間加熱還流させた。反応混合物を室温に冷却
し、セライトを通して過し、不溶物をジクロロ
で洗浄した。液を濃縮して得られる粗生成物
を、シリカゲルカラムクロマトグラフイー(エー
テル:ヘキサン=1:9)で精製して、目的化合
物10.5gを淡黄色物質として得た。
〔 法〕
ピリジン0.81mlをジクロロエタン30mlに溶解
し、これに塩化アルミニウム粉末0.44gを加え、
15分間加熱還流した。次いで2,6−ジ−tert−
ブチル−1,4−ベンゾキノン1.10g及び3−ア
ミノ−5−メトキシカルボニルピリジン0.76gを
加え、15時間加熱還流した。反応混合物を室温に
冷却し、セライトを通して過し、不溶物をジク
ロロメタンで洗浄した。液を濃縮して得られる
粗生成物を、シリカゲルカラムクロマトグラフイ
ー(エーテル:ヘキサン=1:9)で精製して、
目的化合物1.25gを得た。
〔 法〕
2,6−ジ−tert−ブチル−1,4−ベンゾキ
ノン2.20gと3−アミノ−5−メトキシカルボニ
ルピリジン1.52gとを、攪拌しながら150℃で2
時間加熱した。反応混合物を室温に冷却し、シリ
カゲルカラムクロマトグラフイー(エーテル:ヘ
キサン=1:9)で精製して、目的化合物1.41g
を得た。
得られた化合物の物性(融点及び 1H−NMR
値)を第1表に示す。
参考例 2〜23
参考例1の法、法又は法のいずれかと同
様にして第1表に示す各化合物を製造した。
The hydrolysis reaction shown in reaction scheme-4 above is carried out by the method of Eliel et al. [Organic Syntheses,
Vol., p. 169 (1963)]. That is, compound (1c) is obtained by reacting a suitable acid such as hydrochloric acid or hydrobromic acid with compound (1a'') without a solvent or in a suitable solvent such as acetic acid at a temperature of room temperature to about 120°C. The ratio of acid to compound (1a″) is not particularly limited, but it usually ranges from a catalytic amount to approx.
It is preferable to use a 10-fold molar amount. The compound (1) of the present invention obtained by the method shown in each of the above reaction schemes can be easily isolated and purified by commonly used separation means such as solvent extraction, recrystallization, column chromatography, etc. can. Furthermore, the compound (1) of the present invention can be converted into a pharmaceutically acceptable salt by subjecting it to an addition reaction with a suitable acidic compound according to a conventional method. Examples of acidic compounds that can form the above salts include hydrochloric acid,
Examples include inorganic acids such as sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and benzenesulfonic acid. Further, among the compounds of the present invention, those having a free carboxyl group can be easily converted into alkali metal salts such as sodium salts and potassium salts, and pharmaceutically acceptable salts such as calcium salts and magnesium salts according to conventional methods. . The acid addition salts and metal salts thus obtained also have the same pharmacological activity as the free form of the compound of the present invention, and the present invention also encompasses such salts. Examples Hereinafter, production examples of raw material compounds for producing the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples. Reference example 1 2,6-di-tert-butyl-4-[(5-methoxycarbonyl-3-pyridyl)imino]-2,
Production of 5-cyclohexadien-1-one [Method] 7.4 ml of pyridine was dissolved in 300 ml of dichloroethane, 2.5 ml of titanium tetrachloride was added thereto, and the mixture was heated under reflux for 15 minutes. Then 10 g of 2,6-di-tert-butyl-1,4-benzoquinone and 3-amino-5
-Add 7.0g of methoxycarbonylpyridine,
The mixture was heated to reflux for an hour. The reaction mixture was cooled to room temperature, filtered through Celite, and insoluble materials were washed with dichloro. The crude product obtained by concentrating the liquid was purified by silica gel column chromatography (ether:hexane=1:9) to obtain 10.5 g of the target compound as a pale yellow substance. [Method] Dissolve 0.81 ml of pyridine in 30 ml of dichloroethane, add 0.44 g of aluminum chloride powder,
The mixture was heated to reflux for 15 minutes. Then 2,6-di-tert-
1.10 g of butyl-1,4-benzoquinone and 0.76 g of 3-amino-5-methoxycarbonylpyridine were added, and the mixture was heated under reflux for 15 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and insoluble materials were washed with dichloromethane. The crude product obtained by concentrating the liquid was purified by silica gel column chromatography (ether:hexane = 1:9),
1.25 g of the target compound was obtained. [Method] 2.20 g of 2,6-di-tert-butyl-1,4-benzoquinone and 1.52 g of 3-amino-5-methoxycarbonylpyridine were mixed at 150°C with stirring.
heated for an hour. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (ether:hexane=1:9) to obtain 1.41 g of the target compound.
I got it. Physical properties of the obtained compound (melting point and 1 H-NMR
values) are shown in Table 1. Reference Examples 2 to 23 Each compound shown in Table 1 was produced in the same manner as the method, method, or method of Reference Example 1.
【表】【table】
【表】【table】
【表】【table】
【表】
実施例 1
2,6−ジ−tert−ブチル−4−〔(5−メトキ
シカルボニル−3−ピリジル)アミノ〕フエノ
ールの製造
2,6−ジ−tert−ブチル−4−〔(5−メトキ
シカルボニル−3−ピリジル)イミノ〕−2,5
−シクロヘキサジエン−1−オン(参考例1で製
造したもの)6.0gを、テトラヒドロフラン100ml
に溶解し、室温でハイドロサルフアイトナトリウ
ム60gを水500ml溶液を加え、室温で30分間攪拌
した後、酢酸エチルで抽出いた。有機層を飽和食
塩水で洗浄し、硫酸マグネシウム上で乾燥し、濃
縮した。得られた粗生成物を酢酸エチル−n−ヘ
キサン(2:1)から再結晶して目的化合物5.6
gを無色結晶として得た。
得られた化合物の物性(融点及び 1H−NMR
値)を第2表に示す。
実施例 2〜23
実施例1と同様にして、参考例2〜23で得た各
化合物からそれぞれ対応する本発明化合物を製造
した。之等の化合物の物性を後記第2表に示す。
実施例 24
2,6−ジ−tert−ブチル−4−[(N−(6−
メトキシ−3−ピリジル)−N−メチル〕アミ
ノ]フエノールの製造
2,6−ジ−tert−ブチル−4−〔(6−メトキ
シ−3−ピリジル)アミノ〕フエノール(実施例
12で製造したもの)3.3g、37%ホルムアルデヒ
ド水溶液1.0g及び蟻酸3.0gの混合物を90〜100
℃で3.5時間加熱した。反応混合物を室温に冷却
し、5%重曹水にあけ、ジクロロメタンで抽出し
た。有機層を飽和食塩水で洗浄し、硫酸マグネシ
ウム上で乾燥し、濃縮した。得られた粗生成物を
シリカゲルカラムクロマトグラフイーで精製し、
更にヘキサンから再結晶して、目的化合物0.3g
を無色結晶として得た。
得られた化合物の物性(融点及び 1H−NMR
値)を第2表に示す。
実施例 25
2,6−ジ−tert−ブチル−4−[〔N−ホルミ
ル−N−(6−メトキシ−3−ピリジル)〕アミ
ノ]フエノールの製造
2,6−ジ−tert−ブチル−4−〔(6−メトキ
シ−3−ピリジル)アミノ〕フエノール(実施例
12で製造したもの)4.4gを蟻酸40mlに溶解し、
これを90〜100℃で1時間加熱した。反応混合物
を室温に冷却し、水にあけ、ジクロロメタンで抽
出した。有機層を5%重曹水、次いで飽和食塩水
で洗浄し、硫酸マグネシウム上で乾燥し、濃縮し
た。得られた粗生成物をシリカゲルカラムクロマ
トグラフイー(ジクロロメタン・酢酸エチル=
3:1)で精製し、更に酢酸エチル−エーテル
(1:20)から再結晶して、目的化合物3.7gを無
色結晶として得た。
得られた化合物の物性(融点及び 1H−NMR
値)を第2表に示す。
実施例 26
2,6−ジ−tert−ブチル−4−〔(5−カルボ
キシ−2−ピリジル)アミノ〕フエノール・塩
酸塩の製造
2,6−ジ−tert−ブチル−4−〔(5−メトキ
シカルボニル−2−ピリジル)アミノ〕フエノー
ル(実施例2で製造したもの)1.0g、36%塩酸
3ml及び酢酸6mlの混合物を50℃で24時間加熱し
た。反応混合物を減圧下に濃縮し、得られる粗生
成物を酢酸エチルから再結晶して、目的化合物
0.69gを淡黄色結晶として得た。
得られた化合物の物性(融点及び 1H−NMR
値)を第2表に示す。
実施例 27
実施例26と同様にして、実施例3で得た化合物
から対応する本発明化合物を製造した。得られた
化合物の物性を下記第2表に示す。[Table] Example 1 Production of 2,6-di-tert-butyl-4-[(5-methoxycarbonyl-3-pyridyl)amino]phenol 2,6-di-tert-butyl-4-[(5- Methoxycarbonyl-3-pyridyl)imino]-2,5
- 6.0 g of cyclohexadien-1-one (produced in Reference Example 1) was added to 100 ml of tetrahydrofuran.
A solution of 60 g of sodium hydrosulfite in 500 ml of water was added at room temperature, stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was recrystallized from ethyl acetate-n-hexane (2:1) to obtain the target compound 5.6.
g was obtained as colorless crystals. Physical properties of the obtained compound (melting point and 1 H-NMR
values) are shown in Table 2. Examples 2 to 23 In the same manner as in Example 1, corresponding compounds of the present invention were produced from the compounds obtained in Reference Examples 2 to 23, respectively. The physical properties of these compounds are shown in Table 2 below. Example 24 2,6-di-tert-butyl-4-[(N-(6-
Preparation of methoxy-3-pyridyl)-N-methyl]amino]phenol 2,6-di-tert-butyl-4-[(6-methoxy-3-pyridyl)amino]phenol (Example
12), a mixture of 1.0 g of 37% formaldehyde aqueous solution and 3.0 g of formic acid at 90-100 g.
Heated at ℃ for 3.5 hours. The reaction mixture was cooled to room temperature, poured into 5% aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography,
Further recrystallization from hexane yielded 0.3g of the target compound.
was obtained as colorless crystals. Physical properties of the obtained compound (melting point and 1 H-NMR
values) are shown in Table 2. Example 25 Preparation of 2,6-di-tert-butyl-4-[[N-formyl-N-(6-methoxy-3-pyridyl)]amino]phenol 2,6-di-tert-butyl-4- [(6-methoxy-3-pyridyl)amino]phenol (Example
12) was dissolved in 40 ml of formic acid,
This was heated at 90-100°C for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium bicarbonate and then with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was subjected to silica gel column chromatography (dichloromethane/ethyl acetate =
3:1) and further recrystallized from ethyl acetate-ether (1:20) to obtain 3.7 g of the target compound as colorless crystals. Physical properties of the obtained compound (melting point and 1 H-NMR
values) are shown in Table 2. Example 26 Production of 2,6-di-tert-butyl-4-[(5-carboxy-2-pyridyl)amino]phenol hydrochloride 2,6-di-tert-butyl-4-[(5-methoxy A mixture of 1.0 g of carbonyl-2-pyridyl)amino]phenol (prepared in Example 2), 3 ml of 36% hydrochloric acid and 6 ml of acetic acid was heated at 50 DEG C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was recrystallized from ethyl acetate to obtain the target compound.
0.69 g was obtained as pale yellow crystals. Physical properties of the obtained compound (melting point and 1 H-NMR
values) are shown in Table 2. Example 27 In the same manner as in Example 26, the corresponding compound of the present invention was produced from the compound obtained in Example 3. The physical properties of the obtained compound are shown in Table 2 below.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】
薬理試験
5−リポキシゲナーゼ阻害作用
細胞の調整及び5−リポキシゲナーゼ活性の測
定は、ボツコホ[Bokoch]らの方法[J.Biol.
Chem.、256、4156(1981)]及び越智らの方法
[J.Biol.Chem.、258、5754(1983)]に準じて行な
つた。
即ち、モルモツトに2%カゼインを腹腔内投与
し、14〜16時間後に放血死させ、腹腔内を洗浄し
て湿潤細胞を採取した。1mMCaCl2及び5.5mM
グルコースを含むリン酸緩衝液に上記細胞を2.5
×107セル/mlの濃度で懸濁させた。この細胞懸
濁液を30℃で2分間インキユベーシヨンした後、
10μMの供試化合物溶液を加え、更に2分間イン
キユベーシヨンした。その後、10μMイオノフオ
アA23187、続いて10μM14C−アラキドン酸を加
えた。3分間インキユベーシヨン後、0.2Mクエ
ン酸を加えて反応を停止し、生成物を酢酸エチル
で抽出した。抽出物を薄層板にスポツトし、展開
後、アラキドン酸、5−HETE及びその他の部
分をかき取り、14Cをシンチレーターで計数した。
供試化合物の5−リポキシゲナーゼ阻害活性は、
コントロールの5−HETE生成率に対する抑制
率で表わした。
結果を下表に示す。[Table] Pharmacological test 5-Lipoxygenase inhibitory effect Cell preparation and measurement of 5-lipoxygenase activity were performed by the method of Bokoch et al. [J.Biol.
Chem., 256, 4156 (1981)] and Ochi et al. [J. Biol. Chem., 258, 5754 (1983)]. That is, guinea pigs were intraperitoneally administered with 2% casein, 14 to 16 hours later, they were bled to death, and the peritoneal cavity was washed to collect wet cells. 1mM CaCl2 and 5.5mM
2.5 mL of the above cells in phosphate buffer containing glucose
The cells were suspended at a concentration of ×10 7 cells/ml. After incubating this cell suspension at 30°C for 2 minutes,
A 10 μM test compound solution was added and the mixture was further incubated for 2 minutes. Then 10 μM ionophore A23187 was added followed by 10 μM 14 C-arachidonic acid. After incubation for 3 minutes, the reaction was stopped by adding 0.2M citric acid and the product was extracted with ethyl acetate. The extract was spotted on a thin plate, and after development, arachidonic acid, 5-HETE and other parts were scraped off, and 14 C was counted using a scintillator.
The 5-lipoxygenase inhibitory activity of the test compound is
It was expressed as the inhibition rate relative to the control 5-HETE production rate. The results are shown in the table below.
【表】
上記表から、本発明の化合物は、優れた5−リ
ポキシゲナーゼ阻害活性を示し、抗アレルギー剤
として気管支喘息やアレルギー性鼻炎等のアレル
ギー疾患の予防及び治療に有効な化合物であるこ
とが判る。
カラゲニン誘発足浮腫抑制作用
S.D.系雄性ラツト(170〜190g、絶食)1群5
匹を使用し、シー・エー・ウインター(C.A.
Winter)らの方法[Proc.Soc.Exp.Biol.Med.、
111、544(1962)]に準じて本試験を行なつた。
即ち、5%アルビアゴム水溶液に懸濁させた供
試化合物を100mg/Kg経口投与し、1時間後に1
%カラゲニン溶液0.1mlを右足蹠皮下に注射した。
3時間後における足容積を測定し、カラゲニン処
置前の体積に対する増加率(浮腫率)を求め、こ
れを対照群の増加率と比較して抑制率(%)を求
めた。
結果を下表に示す。[Table] From the above table, it can be seen that the compound of the present invention exhibits excellent 5-lipoxygenase inhibitory activity and is an effective compound as an antiallergic agent for the prevention and treatment of allergic diseases such as bronchial asthma and allergic rhinitis. . Suppressive effect on carrageenan-induced paw edema SD male rats (170-190g, fasted) 1 group 5
C.A. Winter (CA
Winter) et al. [Proc.Soc.Exp.Biol.Med.,
111, 544 (1962)]. That is, 100 mg/Kg of the test compound suspended in a 5% aqueous gum albia solution was orally administered, and 1 hour later, 1
% carrageenan solution was injected subcutaneously into the right footpad.
The paw volume after 3 hours was measured, the increase rate (edema rate) with respect to the volume before carrageenin treatment was determined, and this was compared with the increase rate of the control group to determine the inhibition rate (%). The results are shown in the table below.
【表】
上記表から、本発明の化合物は、優れた浮腫抑
制活性を示し、抗炎症剤として関節炎やリウマチ
等の各種炎症性疾患の予防及び治療に有効な化合
物であることが判る。[Table] From the above table, it can be seen that the compound of the present invention exhibits excellent edema-suppressing activity and is an effective compound as an anti-inflammatory agent for the prevention and treatment of various inflammatory diseases such as arthritis and rheumatism.
Claims (1)
水素原子又は低級アルキル基を、R4は水素原子
又は低級アルキル基を、R5は低級アルコキシカ
ルボニル基、低級アルコキシカルボニル低級アル
キル基、アミノ基、低級アルキルアミノ基、ピペ
リジノ基、モルホリノ基、低級アルキルカルボニ
ルアミノ基、低級アルコキシ基、フエニル低級ア
ルコキシ基、低級アルキルチオ基、フエニルチオ
基、ハロゲン原子、低級アルキル基、カルボキシ
ル基又はカルボキシ低級アルキル基を、またR6
は水素原子、低級アルキル基又はホルミル基を示
す。但し、R3及びR4が同時に水素原子の場合及
びいずれか一方が水素原子で他方が低級アルキル
基の場合には、R5が低級アルキル基で且つR6が
水素原子であつてはならない。〕 で表わされるピリジルアミノフエノール誘導体及
びその薬理的に許容される塩。 2 一般式 【式】 〔式中R1及びR2は各々低級アルキル基を示す。〕 で表わされる化合物と一般式 【式】 〔式中R3は水素原子又は低級アルキル基を、R4
は水素原子又は低級アルキル基を、R5′は低級ア
ルコキシカルボニル基、低級アルコキシカルボニ
ル低級アルキル基、アミノ基、低級アルキルアミ
ノ基、ピペリジノ基、モルホリノ基、低級アルキ
ルカルボニルアミノ基、低級アルコキシ基、フエ
ニル低級アルコキシ基、低級アルキルチオ基、フ
エニルチオ基、ハロゲン原子又は低級アルキル基
を示す。但し、R3及びR4が同時に水素原子の場
合及びいずれか一方が水素原子で他方が低級アル
キル基の場合には、R5′は低級アルキル基であつ
てはならない。〕 で表わされる化合物とを、不活性溶媒中、ルイス
酸の存在下に縮合反応させて、一般式 【式】 〔式中R1、R2、R3、R4及びR5′は上記に同じ。〕 で表わされる化合物を得、次いで該化合物を還元
して一般式 【化】 〔式中R1、R2、R3、R4及びR5′は上記に同じ。〕 で表わされる化合物を得、 更に該化合物(1a)のR5′が低級アルコキシカ
ルボニル基、低級アルコキシカルボニル低級アル
キル基、ピペリジノ基、モルホリノ基、低級アル
キルカルボニルアミノ基、低級アルコキシ基、フ
エニル低級アルコキシ基、低級アルキルチオ基、
フエニルチオ基、ハロゲン原子又は低級アルキル
基の場合には、該化合物に一般式 R7CHO 〔R7は水素原子又は低級アルキル基を示す。〕 で表わされる化合物と蟻酸とを作用させることに
より又は蟻酸を作用させることにより、一般式 【化】 〔式中R1、R2、R3及びR4は上記に同じ。R5″は
低級アルコキシカルボニル基、低級アルコキシカ
ルボニル低級アルキル基、ピペリジノ基、モルホ
リノ基、低級アルキルカルボニルアミノ基、低級
アルコキシ基、フエニル低級アルコキシ基、低級
アルキルチオ基、フエニルチオ基、ハロゲン原子
又は低級アルキル基を、またR6は低級アルキル
基又はホルミル基を示す。〕 で表わされる化合物を得、 また上記化合物(1a)のR5′が低級アルコキシ
カルボニル基又は低級アルコキシカルボニル低級
アルキル基の場合には、該化合物を加水分解し
て、一般式 【化】 〔式中R1、R2、R3及びR4は上記に同じ。R5は
カルボキシル基又はカルボキシ低級アルキル基を
示す。〕 で表わされる化合物を得る ことを特徴とするピリジルアミノフエノール誘導
体及びその薬理的に許容される塩の製造方法。 3 一般式 【式】 〔式中R1及びR2は各々低級アルキル基を示す。〕 で表わされる化合物と、一般式 【式】 〔式中R3は水素原子又は低級アルキル基を、R4
は水素原子又は低級アルキル基を、またR5′は低
級アルコキシカルボニル基、低級アルコキシカル
ボニル低級アルキル基、アミノ基、低級アルキル
アミノ基、ピペリジノ基、モルホリノ基、低級ア
ルキルカルボニルアミノ基、低級アルコキシ基、
フエニル低級アルコキシ基、低級アルキルチオ
基、フエニルチオ基、ハロゲン原子又は低級アル
キル基を示す。但し、R3及びR4は同時に水素原
子の場合及びいずれか一方が水素原子で他方が低
級アルキル基の場合には、R5は低級アルキル基
であつてはならない。〕 で表わされる化合物とを、100〜200℃で縮合反応
させて、一般式 【式】 〔式中R1、R2、R3、R4及びR5′は上記に同じ。〕 で表わされる化合物を得、次いで該化合物を還元
して一般式 【化】 〔式中R1、R2、R3、R4及びR5′は上記に同じ。〕 で表わされる化合物を得、 更に該化合物(1a)のR5′が低級アルコキシカ
ルボニル基、低級アルコキシカルボニル低級アル
キル基、ピペリジノ基、モルホリノ基、低級アル
キルカルボニルアミノ基、低級アルコキシ基、フ
エニル低級アルコキシ基、低級アルキルチオ基、
フエニルチオ基、ハロゲン原子又は低級アルキル
基の場合には、該化合物に一般式 R7CHO 〔R7は水素原子又は低級アルキル基を示す。〕 で表わされる化合物と蟻酸とを作用させることに
より又は蟻酸を作用させることにより、一般式 【化】 〔式中R1、R2、R3及びR4は上記に同じ。R5″は
低級アルコキシカルボニル基、低級アルコキシカ
ルボニル低級アルキル基、ピペリジノ基、モルホ
リノ基、低級アルキルカルボニルアミノ基、低級
アルコキシ基、フエニル低級アルコキシ基、低級
アルキルチオ基、フエニルチオ基、ハロゲン原子
又は低級アルキル基を、またR6は低級アルキル
基又はホルミル基を示す。〕 で表わされる化合物を得、 また上記化合物(1a)のR5′が低級アルコキシ
カルボニル基又は低級アルコキシカルボニル低級
アルキル基の場合には、該化合物を加水分解し
て、一般式 【化】 〔式中R1、R2、R3及びR4は上記に同じ。R5は
カルボキシル基又はカルボキシ低級アルキル基を
示す。〕 で表わされる化合物を得る ことを特徴とするピリジルアミノフエノール誘導
体及びその薬理的に許容される塩の製造方法。[Claims] 1 General formula [Formula] [In the formula, R 1 and R 2 each represent a lower alkyl group, R 3 represents a hydrogen atom or a lower alkyl group, R 4 represents a hydrogen atom or a lower alkyl group, R 5 is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, an amino group, a lower alkylamino group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, a lower alkyl group, a carboxyl group or a carboxy lower alkyl group, and R 6
represents a hydrogen atom, a lower alkyl group or a formyl group. However, when R 3 and R 4 are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R 5 must not be a lower alkyl group and R 6 must not be a hydrogen atom. ] A pyridylaminophenol derivative represented by these and a pharmacologically acceptable salt thereof. 2 General Formula [Formula] [In the formula, R 1 and R 2 each represent a lower alkyl group. ] Compounds represented by the general formula [Formula] [In the formula, R 3 is a hydrogen atom or a lower alkyl group, R 4
is a hydrogen atom or a lower alkyl group, R 5 ' is a lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, amino group, lower alkylamino group, piperidino group, morpholino group, lower alkylcarbonylamino group, lower alkoxy group, phenyl Indicates a lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group. However, when R 3 and R 4 are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R 5 ' must not be a lower alkyl group. [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 ′ are as defined above] same. ] A compound represented by the formula is obtained, and then the compound is reduced to form a compound represented by the general formula: [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 ' are the same as above. ] A compound represented by is obtained, and R 5 ' of the compound (1a) is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group. group, lower alkylthio group,
In the case of a phenylthio group, a halogen atom, or a lower alkyl group, the compound has the general formula R 7 CHO [R 7 represents a hydrogen atom or a lower alkyl group. ] By reacting the compound represented by with formic acid or by reacting with formic acid, a compound of the general formula [Formula R 1 , R 2 , R 3 and R 4 are the same as above]. R 5 ″ is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group and R 6 represents a lower alkyl group or a formyl group.] In addition, when R 5 ' of the above compound (1a) is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group, The compound is hydrolyzed to produce a compound represented by the general formula: [In the formula, R 1 , R 2 , R 3 and R 4 are the same as above. R 5 represents a carboxyl group or a carboxy lower alkyl group] A method for producing a pyridylaminophenol derivative and a pharmacologically acceptable salt thereof, characterized in that it obtains a compound represented by the general formula [Formula] [wherein R 1 and R 2 each represent a lower alkyl group] and the general formula [Formula] [In the formula, R 3 is a hydrogen atom or a lower alkyl group, R 4
is a hydrogen atom or a lower alkyl group, and R 5 ' is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, an amino group, a lower alkylamino group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group,
Indicates a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group. However, when R 3 and R 4 are both hydrogen atoms, or when one of them is a hydrogen atom and the other is a lower alkyl group, R 5 must not be a lower alkyl group. ] A condensation reaction is carried out at 100 to 200°C with a compound represented by the formula [Formula] [wherein R 1 , R 2 , R 3 , R 4 and R 5 ' are the same as above. ] A compound represented by the formula is obtained, and then the compound is reduced to form a compound represented by the general formula: [In the formula, R 1 , R 2 , R 3 , R 4 and R 5 ' are the same as above. ] A compound represented by is obtained, and R 5 ' of the compound (1a) is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group. group, lower alkylthio group,
In the case of a phenylthio group, a halogen atom, or a lower alkyl group, the compound has the general formula R 7 CHO [R 7 represents a hydrogen atom or a lower alkyl group. ] By reacting the compound represented by with formic acid or by reacting with formic acid, a compound of the general formula [Formula R 1 , R 2 , R 3 and R 4 are the same as above]. R 5 ″ is a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a piperidino group, a morpholino group, a lower alkylcarbonylamino group, a lower alkoxy group, a phenyl lower alkoxy group, a lower alkylthio group, a phenylthio group, a halogen atom, or a lower alkyl group , and R 6 represents a lower alkyl group or a formyl group.] In addition, when R 5 ' of the above compound (1a) is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group, The compound is hydrolyzed to produce a compound represented by the general formula: [In the formula, R 1 , R 2 , R 3 and R 4 are the same as above. R 5 represents a carboxyl group or a carboxy lower alkyl group] 1. A method for producing a pyridylaminophenol derivative and a pharmacologically acceptable salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6698986A JPS62223173A (en) | 1986-03-25 | 1986-03-25 | Pyridylaminophenol derivative and production thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP6698986A JPS62223173A (en) | 1986-03-25 | 1986-03-25 | Pyridylaminophenol derivative and production thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS62223173A JPS62223173A (en) | 1987-10-01 |
JPH0567142B2 true JPH0567142B2 (en) | 1993-09-24 |
Family
ID=13331932
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP6698986A Granted JPS62223173A (en) | 1986-03-25 | 1986-03-25 | Pyridylaminophenol derivative and production thereof |
Country Status (1)
Country | Link |
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JP (1) | JPS62223173A (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5369078A (en) * | 1991-11-14 | 1994-11-29 | Dai Nippon Printing Co., Ltd. | Thermal transfer sheet |
FR2791674A1 (en) * | 1999-04-02 | 2000-10-06 | Sod Conseils Rech Applic | 2-Amino pyridines substituted by a group trapping free radicals, for treatment of e.g. cardiovascular, nervous system and inflammatory disorders |
FR2780971B1 (en) * | 1998-07-08 | 2001-09-28 | Sod Conseils Rech Applic | NOVEL 2-AMINOPYRIDINE DERIVATIVES, THEIR APPLICATION AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
AR019190A1 (en) * | 1998-07-08 | 2001-12-26 | Sod Conseils Rech Applic | DERIVATIVES OF 2-AMINOPIRIDINES, INTERMEDIATE PRODUCTS FOR THEIR PREPARATION, DRUGS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE TO PREPARE DRUGS |
AU2003211427A1 (en) * | 2002-02-18 | 2003-09-04 | Ishihara Sangyo Kaisha, Ltd. | Pyridine derivatives or salts thereof and cytokine production inhibitors containing the same |
AR051248A1 (en) | 2004-10-20 | 2007-01-03 | Applied Research Systems | DERIVATIVES OF 3-ARILAMINO PIRIDINA |
-
1986
- 1986-03-25 JP JP6698986A patent/JPS62223173A/en active Granted
Also Published As
Publication number | Publication date |
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JPS62223173A (en) | 1987-10-01 |
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