JPH0567619B2 - - Google Patents
Info
- Publication number
- JPH0567619B2 JPH0567619B2 JP22388088A JP22388088A JPH0567619B2 JP H0567619 B2 JPH0567619 B2 JP H0567619B2 JP 22388088 A JP22388088 A JP 22388088A JP 22388088 A JP22388088 A JP 22388088A JP H0567619 B2 JPH0567619 B2 JP H0567619B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- acid
- nmr
- melting point
- 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 - Lifetime
Links
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- -1 methylene, Ethylene, trimethylene, 1-methylmethylene Chemical group 0.000 description 35
- 238000002844 melting Methods 0.000 description 32
- 230000008018 melting Effects 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000000354 decomposition reaction Methods 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 230000000704 physical effect Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-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
- 239000005457 ice water Substances 0.000 description 6
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 150000003568 thioethers Chemical class 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000007514 bases Chemical class 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- TXNSZCSYBXHETP-UHFFFAOYSA-N 2-chloro-n-(hydroxymethyl)acetamide Chemical compound OCNC(=O)CCl TXNSZCSYBXHETP-UHFFFAOYSA-N 0.000 description 2
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical class OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-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
- NPFYZDNDJHZQKY-UHFFFAOYSA-N 4-Hydroxybenzophenone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC=CC=C1 NPFYZDNDJHZQKY-UHFFFAOYSA-N 0.000 description 2
- ZSBDGXGICLIJGD-UHFFFAOYSA-N 4-phenoxyphenol Chemical compound C1=CC(O)=CC=C1OC1=CC=CC=C1 ZSBDGXGICLIJGD-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N CD3OD Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-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
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 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
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 2
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical compound C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- FRYHCSODNHYDPU-UHFFFAOYSA-N ethanesulfonyl chloride Chemical compound CCS(Cl)(=O)=O FRYHCSODNHYDPU-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- ZXRCAYWYTOIRQS-UHFFFAOYSA-N hydron;phenol;chloride Chemical compound Cl.OC1=CC=CC=C1 ZXRCAYWYTOIRQS-UHFFFAOYSA-N 0.000 description 2
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 150000004967 organic peroxy acids Chemical class 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229960001922 sodium perborate Drugs 0.000 description 2
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 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
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QPPJJQOUDGSRPN-UHFFFAOYSA-N (3-amino-4-hydroxyphenyl)-phenylmethanone Chemical compound C1=C(O)C(N)=CC(C(=O)C=2C=CC=CC=2)=C1 QPPJJQOUDGSRPN-UHFFFAOYSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KPRZOPQOBJRYSW-UHFFFAOYSA-N 2-(aminomethyl)phenol Chemical class NCC1=CC=CC=C1O KPRZOPQOBJRYSW-UHFFFAOYSA-N 0.000 description 1
- JTXMVXSTHSMVQF-UHFFFAOYSA-N 2-acetyloxyethyl acetate Chemical compound CC(=O)OCCOC(C)=O JTXMVXSTHSMVQF-UHFFFAOYSA-N 0.000 description 1
- KELKWZKNBJTIRP-UHFFFAOYSA-N 2-amino-4-benzylphenol Chemical compound C1=C(O)C(N)=CC(CC=2C=CC=CC=2)=C1 KELKWZKNBJTIRP-UHFFFAOYSA-N 0.000 description 1
- IGIDZGNPFWGICD-UHFFFAOYSA-N 2-amino-4-phenylphenol Chemical compound C1=C(O)C(N)=CC(C=2C=CC=CC=2)=C1 IGIDZGNPFWGICD-UHFFFAOYSA-N 0.000 description 1
- NLZGZZGWVCEQTQ-UHFFFAOYSA-N 2-amino-4-phenylsulfanylphenol Chemical compound C1=C(O)C(N)=CC(SC=2C=CC=CC=2)=C1 NLZGZZGWVCEQTQ-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- CDMGNVWZXRKJNS-UHFFFAOYSA-N 2-benzylphenol Chemical compound OC1=CC=CC=C1CC1=CC=CC=C1 CDMGNVWZXRKJNS-UHFFFAOYSA-N 0.000 description 1
- KDTZBYPBMTXCSO-UHFFFAOYSA-N 2-phenoxyphenol Chemical compound OC1=CC=CC=C1OC1=CC=CC=C1 KDTZBYPBMTXCSO-UHFFFAOYSA-N 0.000 description 1
- VMKYTRPNOVFCGZ-UHFFFAOYSA-N 2-sulfanylphenol Chemical compound OC1=CC=CC=C1S VMKYTRPNOVFCGZ-UHFFFAOYSA-N 0.000 description 1
- IDKCKPBAFOIONK-UHFFFAOYSA-N 3,4-dimethylbenzenethiol Chemical compound CC1=CC=C(S)C=C1C IDKCKPBAFOIONK-UHFFFAOYSA-N 0.000 description 1
- DFMDAJMTLJGKFW-UHFFFAOYSA-N 3-chloro-2-nitrophenol Chemical compound OC1=CC=CC(Cl)=C1[N+]([O-])=O DFMDAJMTLJGKFW-UHFFFAOYSA-N 0.000 description 1
- LADOBJZJEARFJO-UHFFFAOYSA-N 4-(4-methylphenyl)sulfanylphenol Chemical compound C1=CC(C)=CC=C1SC1=CC=C(O)C=C1 LADOBJZJEARFJO-UHFFFAOYSA-N 0.000 description 1
- HJSPWKGEPDZNLK-UHFFFAOYSA-N 4-benzylphenol Chemical compound C1=CC(O)=CC=C1CC1=CC=CC=C1 HJSPWKGEPDZNLK-UHFFFAOYSA-N 0.000 description 1
- XAYCNCYFKLSMGR-UHFFFAOYSA-N 4-phenylsulfanylphenol Chemical compound C1=CC(O)=CC=C1SC1=CC=CC=C1 XAYCNCYFKLSMGR-UHFFFAOYSA-N 0.000 description 1
- VCHSXYHBMFKRBK-UHFFFAOYSA-N 4771-47-5 Chemical compound OC(=O)C1=CC=CC(Cl)=C1[N+]([O-])=O VCHSXYHBMFKRBK-UHFFFAOYSA-N 0.000 description 1
- MZDBQSFPAMTTIS-UHFFFAOYSA-N 5-chloro-2-nitrophenol Chemical compound OC1=CC(Cl)=CC=C1[N+]([O-])=O MZDBQSFPAMTTIS-UHFFFAOYSA-N 0.000 description 1
- QQVVAVSPGWOFKT-UHFFFAOYSA-N 5-chloro-4-fluoro-2-nitrophenol Chemical compound OC1=CC(Cl)=C(F)C=C1[N+]([O-])=O QQVVAVSPGWOFKT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004381 Choline salt Substances 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
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-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
- 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
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000033115 angiogenesis Effects 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
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000003146 anticoagulant 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
- 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
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 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
- WEDIIKBPDQQQJU-UHFFFAOYSA-N butane-1-sulfonyl chloride Chemical compound CCCCS(Cl)(=O)=O WEDIIKBPDQQQJU-UHFFFAOYSA-N 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
- 201000011510 cancer Diseases 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- NBBWLOJCZSYDAD-UHFFFAOYSA-N ethyl 4-sulfanylbenzoate Chemical compound CCOC(=O)C1=CC=C(S)C=C1 NBBWLOJCZSYDAD-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 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
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- AEHJDQSLTMFLQO-UHFFFAOYSA-N hexane-1-sulfonyl chloride Chemical compound CCCCCCS(Cl)(=O)=O AEHJDQSLTMFLQO-UHFFFAOYSA-N 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
- 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
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000004966 inorganic peroxy acids Chemical class 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 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
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 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
- 150000003248 quinolines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000000725 suspension 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
産業上の利用分野
本発明は、薬理作用を有するスルホンアミド誘
導体及びその塩に関する。
従来の技術
本発明に係わる化合物は、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、後記するように医薬品として有用な
化合物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
本発明によれば、下記一般式(1)で表わされるス
ルホンアミド誘導体及びその塩が提供される。
INDUSTRIAL APPLICATION FIELD The present invention relates to sulfonamide derivatives and salts thereof having pharmacological effects. Prior Art The compound according to the present invention is a novel compound that has not been described in any literature. Problems to be Solved by the Invention The present invention aims to provide a compound useful as a pharmaceutical, as described later. Means for Solving the Problems According to the present invention, a sulfonamide derivative represented by the following general formula (1) and a salt thereof are provided.
本明細書において、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、ヘキシル基等の炭素数１〜６の直鎖又は分枝
鎖上アルキル基を例示できる。
低級アルキレン基としては、例えばメチレン、
エチレン、トリメチレン、１−メチルメチレン、
テトラメチレン、２−メチルトリメチレン、ペン
タメチレン、ヘキサメチレン基等の炭素数１〜６
の直鎖又は分枝鎖状アルキレン基を例示できる。
ハロゲン原子としては、弗素、塩素、臭素及び
沃素原子を例示できる。
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、ブトキ
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炭素数１〜６の直
鎖又は分枝鎖状アルコキシ基を例示できる。
低級アシルアミノ基としては、例えばアセチル
アミノ、プロピオニルアミノ、ブチリルアミノ、
イソブチリルアミノ、バレリルアミノ、イソバレ
リルアミノ、ピバロイルアミノ、ヘキサノイルア
ミノ基などの炭素数１〜６の直鎖又は分枝鎖状ア
シルアミノ基を例示できる。
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、イソプロポキシカルボニル、
ブトキシカルボニル、tert−ブトキシカルボニ
ル、ペンチルオキシカルボニル、ヘキシルオキシ
カルボニル基等の炭素数１〜６の直鎖又は分枝鎖
状アルコキシカルボニル基を例示できる。
上記一般式(1)で表わされる本発明化合物及びそ
の塩は、動物、特に哺乳動物に対して例えば抗炎
症、抗リウマチ、抗喘息、抗アレルギー、解熱、
鎮痛、血小板凝集阻止、血管新生阻害作用等の薬
理作用を示し、例えば抗炎症剤、抗リウマチ剤、
抗喘息剤、抗アレルギー剤、解熱剤、鎮痛剤、抗
血栓剤、血管新生阻害剤等の医薬品として有用で
ある。尚、上記「血管新生阻害」とは、血管の新
生、即ち、例えば腫瘍増殖、網膜症、乾癬等の病
態時或いは創傷治癒過程において盛んに起こるこ
との知られている新しい血管の形成を阻害するこ
とを意味しており、従つて血管新生阻害剤には、
悪性腫瘍、網膜症、乾癬等の疾患の治療剤が包含
される。
本発明のスルホンアミド誘導対は、各種の方法
により製造することができる。その具体例を下記
反応工程式に示す。
＜反応工程式−１＞
In this specification, the lower alkyl group is
Examples include straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups. Examples of lower alkylene groups include methylene,
Ethylene, trimethylene, 1-methylmethylene,
1 to 6 carbon atoms such as tetramethylene, 2-methyltrimethylene, pentamethylene, hexamethylene group, etc.
Examples include straight chain or branched alkylene groups. Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms. Examples of lower alkoxy groups include methoxy,
Examples include straight chain or branched alkoxy groups having 1 to 6 carbon atoms such as ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy groups. Examples of lower acylamino groups include acetylamino, propionylamino, butyrylamino,
Examples include straight-chain or branched acylamino groups having 1 to 6 carbon atoms, such as isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, and hexanoylamino groups. Examples of lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
Examples include straight-chain or branched alkoxycarbonyl groups having 1 to 6 carbon atoms, such as butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl groups. The compound of the present invention represented by the above general formula (1) and its salts are useful for animals, especially mammals, such as anti-inflammatory, anti-rheumatic, anti-asthmatic, anti-allergic, antipyretic, etc.
It exhibits pharmacological effects such as analgesia, platelet aggregation inhibition, and angiogenesis inhibition, such as anti-inflammatory agents, anti-rheumatic agents,
It is useful as a pharmaceutical agent such as an anti-asthmatic agent, an anti-allergic agent, an antipyretic agent, an analgesic agent, an antithrombotic agent, and an angiogenesis inhibitor. The above-mentioned "inhibition of angiogenesis" refers to the inhibition of angiogenesis, that is, the formation of new blood vessels that is known to occur actively during pathological conditions such as tumor growth, retinopathy, and psoriasis, or during the wound healing process. This means that angiogenesis inhibitors include
This includes therapeutic agents for diseases such as malignant tumors, retinopathy, and psoriasis. The sulfonamide-derived couples of the present invention can be produced by a variety of methods. A specific example thereof is shown in the reaction scheme below. <Reaction scheme-1>
【化】[ka]
上記反応工程式−１に示す方法によれば、アミ
ン誘導体(2)のＮ−スルホニル化反応により、本発
明化合物（1a）を製造できる。
上記において、原料化合物として使用するアミ
ン誘導体(2)の内アミノフエノール類は公知であ
り、例えば特開昭58−113152号公報、WO85／
01289号、特開昭60−94973号公報、特開昭62−
201861号公報等に記載されている。また、アミノ
メチルフエノール類は、例えばジヤーナル オブ
メデイシナル ケミストリー〔J.Med.Chem.、
23、1414（1980）〕に記載のジー．イー．ストツカ
ー（G.E.Stokker）らの方法に準じて製造するこ
とができる。
上記反応工程式−１に示すＮ−スルホニル化反
応は、アミン誘導体(2)に、不活性有機溶媒中で、
塩基性化合物の存在下に適当なスルホニル化剤を
反応させることにより実施できる。ここで、不活
性有機溶媒としては、例えば塩化メチレン、クロ
ロホルム、１，２−ジクロロエタン等のハロゲン
化炭化水素類、ジエチルエーテル、テトラヒドロ
フラン、ジオキサン等のエーテル類、塩基性化合
物を兼ねたピリジン等を有利に使用できる。塩基
性化合物としては、上記ピリジンの他、例えばト
リエチルアミン、Ｎ，Ｎ−ジメチルアニリン等を
使用できる。またスルホニル化剤としては、例え
ば塩化メタンスルホニル、塩化エタンスルホニ
ル、塩化１−ブタンスルホニル、塩化１−ヘキサ
ンスルホニル等のハロゲン化低級アルカンスルホ
ニル及び塩化ベンゼンスルホニル等を例示でき
る。之等スルホニル化剤の使用量は、通常化合物
(2)に対して１〜1.2倍モル量の範囲から選択され
るのが適当である。反応は、一般に０〜100℃、
好ましくは０〜30℃の温度範囲条件下に、約１〜
20時間で良好に進行する。
また、原料化合物(2)においてアミノ基の反応性
が低く、且つR2a置換基に悪影響を与えない場合
は、上記スルホニル化剤を２〜10倍モル量用い
て、同様の反応条件を採用することによつて、原
料化合物(2)のＮ，Ｏ−ジスルホニル化反応を実施
し、次いでアルカリ加水分解により、脱Ｏ−スル
ホニル化反応を行なつて、本発明化合物（1a）
を製造することもできる。
上記アルカリ加水分解反応は、通常の方法に従
い、例えばメタノール、エタノール、tert−ブタ
ノール等のアルコール系溶媒中で、２〜10倍モル
量の水酸化ナトリウム、水酸化カリウム等のアル
カリ金属水酸化物を用いて、0.1〜20時間程度、
室温〜溶媒の沸点温度で加熱することにより行な
うことができる。
＜反応工程式−２＞
According to the method shown in Reaction Scheme-1 above, the compound (1a) of the present invention can be produced by the N-sulfonylation reaction of the amine derivative (2). In the above, among the amine derivatives (2) used as raw material compounds, aminophenols are known, for example, JP-A-58-113152, WO85/
No. 01289, JP-A-60-94973, JP-A-62-
It is described in Publication No. 201861, etc. In addition, aminomethylphenols can be used, for example, in the Journal of Medicinal Chemistry [J.Med.Chem.
23, 1414 (1980)]. E. It can be produced according to the method of GESTokker et al. In the N-sulfonylation reaction shown in the above reaction scheme-1, the amine derivative (2) is added to the amine derivative (2) in an inert organic solvent.
This can be carried out by reacting a suitable sulfonylating agent in the presence of a basic compound. Here, as the inert organic solvent, for example, halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and pyridine which also serves as a basic compound are preferably used. Can be used for As the basic compound, in addition to the above-mentioned pyridine, for example, triethylamine, N,N-dimethylaniline, etc. can be used. Examples of the sulfonylating agent include lower alkanesulfonyl halides such as methanesulfonyl chloride, ethanesulfonyl chloride, 1-butanesulfonyl chloride, and 1-hexanesulfonyl chloride, and benzenesulfonyl chloride. The amount of sulfonylating agent used is usually
It is appropriate to select from a range of 1 to 1.2 times the molar amount of (2). The reaction is generally carried out at 0 to 100°C.
Preferably under a temperature range of 0 to 30°C, from about 1 to
Progresses well in 20 hours. In addition, if the reactivity of the amino group in the starting compound (2) is low and it does not adversely affect the R 2a substituent, the same reaction conditions can be adopted using 2 to 10 times the molar amount of the above sulfonylating agent. Particularly, the starting compound (2) is subjected to an N,O-disulfonylation reaction, and then a de-O-sulfonylation reaction is performed by alkaline hydrolysis to obtain the compound (1a) of the present invention.
can also be manufactured. The above-mentioned alkaline hydrolysis reaction is carried out in accordance with a conventional method, for example, by adding 2 to 10 times the molar amount of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an alcoholic solvent such as methanol, ethanol, or tert-butanol. For about 0.1 to 20 hours,
This can be carried out by heating at room temperature to the boiling point temperature of the solvent. <Reaction scheme-2>
【化】[ka]
【化】[ka]
【化】[ka]
上記反応工程式−２に示す方法によれば、スル
ホンアミド誘導体（1b）中のホルミルイミノ基
及び低級アシルアミノ基を酸加水分解反応させる
ことによつて、またスルホンアミド誘導体（1d）
中の低級アルコキシカルボニル基のアルカリ加水
分解反応による開裂によつて、それぞれ対応する
基としてアミノ基及びカルボキシル基を有する本
発明化合物（1c）及び（1e）を製造することがで
きる。
上記酸加水分解反応は、無溶媒又はメタノー
ル、エタノール、酢酸等の適当な不活性有機溶媒
中で、化合物（1b）に塩酸、臭化水素酸等の適
当な酸を、室温〜溶媒の沸点温度範囲で作用させ
ることにより実施できる。化合物（1b）に対す
る酸の使用割合は、とくに限定はないが、通常触
媒量〜約50倍モル量程度とするのがよい。また上
記アルカリ加水分解反応は、前記反応工程式−１
に示した方法と同様にして実施できる。
＜反応工程式−３＞
According to the method shown in Reaction Scheme-2 above, by subjecting the formylimino group and lower acylamino group in the sulfonamide derivative (1b) to an acid hydrolysis reaction, the sulfonamide derivative (1d)
Compounds (1c) and (1e) of the present invention, each having an amino group and a carboxyl group as corresponding groups, can be produced by cleavage of the lower alkoxycarbonyl group in the alkali hydrolysis reaction. The above acid hydrolysis reaction is carried out by adding an appropriate acid such as hydrochloric acid or hydrobromic acid to compound (1b) without a solvent or in an appropriate inert organic solvent such as methanol, ethanol, or acetic acid at a temperature ranging from room temperature to the boiling point of the solvent. It can be carried out by acting within a range. The ratio of the acid to compound (1b) is not particularly limited, but it is usually from a catalytic amount to about 50 times the molar amount. In addition, the above-mentioned alkaline hydrolysis reaction is carried out using the above-mentioned reaction scheme-1.
This can be carried out in the same manner as the method shown in . <Reaction scheme-3>
上記反応工程式−３に示す方法によれば、スル
フイド誘導体（1f）の酸化反応によつて、スルホ
キシド誘導体（1g）又はスルホニル誘導体（1h）
を製造することができ、またスルホキシド誘導体
（1g）の酸化反応によつてスルホニル誘導体
（1h）を製造することができる。
上記酸化反応は、いずれも例えばジクロロメタ
ン、クロロホルム、１，２−ジクロロエタン、酢
酸、水等及び之等の混合溶媒等の適当な不活性溶
媒中で実施できる。スルフイド誘導体（1f）から
のスルホキシド誘導体（1g）の製造反応は、よ
り詳しくは、例えばｍ−クロロ過安息香酸、過酢
酸等の有機過酸又は過酸化水素、過ホウ素酸ナト
リウム等の無機過酸を、化合物（1f）に対して等
モル量程度用いて有利に行ない得る。またスルフ
イド誘導体（1f）又はスルホキシド誘導体（1g）
からのスルホン誘導体（1h）の製造反応は、上
記と同様にして、有機過酸又は過ホウ素酸ナトリ
ウム等を原料化合物に対して約２〜５倍モル量の
範囲で用いることによつて実施できる。上記合反
応工程式に示す反応による得られる本発明化合物
は、慣用の分離手段による容易に単離精製でる。
該分離手段としては、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を例示できる。
またかくして得られる本発明化合物は、これに
常法に従い適当な塩基性化合物を付加反応させる
ことにより、容易に医薬的に許容される塩とする
ことができ、該塩は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、本発明に包含され
る。上記塩としては、例えばコリン塩、ジエタノ
ールアミン塩、エタレンジアミン塩、Ｎ−メチル
−Ｄ−グルカミン塩、トリス（ヒドロキシメチ
ル）アミノメタン塩等の有機塩類及びリチウム
塩、ナトリウム塩、カリウム塩等の無機塩を例示
できる。
更に本発明化合物中には、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
薬的に許容される酸付加塩とすることができるも
のも存在し、該酸付加塩も同様の薬理活性を有
し、本発明に包含される。上記酸付加塩を形成す
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、メタンスルホン酸、ベンゼンスルホン酸等の
有機酸を例示できる。
実施例
以下、本発明を更に詳しく説明するため本発明
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−アミノメチル−４−（フエニルチオ）フエ
ノール・塩酸塩の製造
工程−１
４−（フエニルチオ）フエノール4.74ｇの酢酸
２ml溶液とＮ−（ヒドロキシメチル）クロロアセ
トアミド2.89ｇとを、氷冷下に、酢酸−97％硫酸
（９：１）の溶液23ml中に加え、室温で27時間攪
拌した。反応混合物を氷水にあけ、酢酸エチルで
抽出した。有機層を飽和食塩水で洗浄し、硫酸マ
グネシウムで乾燥した後、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
（展開溶媒；ジエチルエーテル：ヘキサン＝２：
３）で精製し、更にヘキサンで洗浄して、Ｎ−
［２−ヒドロキシ−５−（フエニルチオ）ベンジ
ル］クロロアセトアミド2.54ｇを淡赤色固体とし
て得た。
融点：87〜88℃1
H−NMR（CDCl3）：δ
4.11（ｓ、2H）
4.38（ｄ、Ｊ＝6.6Hz、2H）
6.94（ｄ、Ｊ＝8.4Hz、1H）
7.1−7.3（ｍ、5H）
7.28（ｄ、Ｊ＝2.3Hz、1H）
7.35（dd、Ｊ＝8.4Hz、2.3Hz、1H）
8.98（ｓ、1H）
工程−２
Ｎ−［２−ヒドロキシ−５−（フエニルチオ）ベ
ンジル］クロロアセトアミド1.50ｇをエタノール
10mlと36％塩酸５mlとの混合溶液に加え、３時間
加熱還流した。反応混合物の室温に冷却し、濃縮
して生成する固体を取し、ジエチルエーテルで
洗浄して、目的化合物1.35ｇを無色固体として得
た。
融点：228〜228.5℃（分解）1
H−NMR［（CD3）2SO］：δ
3.9−4.0（ｍ、2H）
7.02（ｄ、Ｊ＝8.4Hz、1H）
7.1−7.4（ｍ、5H）
7.36（dd、Ｊ＝8.4Hz、2.3Hz、1H）
7.53（ｄ、Ｊ＝2.3Hz、1H）
参考例 ２〜６
参考例１と工程−１と同様にして、４−（４−
メチルフエニルチオ）フエノール、４−フエニル
フエノール、４−ベンジルフエノール、４−フエ
ノキシフエノール及び４−ヒドロキシベンゾフエ
ノンのいずれかと、Ｎ−（ヒドロキシメチル）ク
ロロアセトアミドとから、それぞれ下記のＮ−
（２−ヒドロキシベンジル）クロロアセトアミド
誘導体を得た。
次いで、之等各化合物をそれぞれ参考例１の工
程−２と同様に加水分解反応させて、下記参考例
２〜６の各化合物を得た。
参考例 ２
Γ２−アミノメチル−４−（４−メチルフエニル
チオ）フエノール・塩酸塩
融点：231〜233℃（分解）1
H−NMR［CDCl3−CD3OD］：δ
2.30（ｓ、3H）、4.03（ｓ、2H）
6.91（ｄ、Ｊ＝8.9Hz、1H）
7.07（ｄ、Ｊ＝8.4Hz、2H）
7.13（ｄ、Ｊ＝8.4Hz、2H）
7.3−7.4（ｍ、2H）
ΓＮ−［２−ヒドロキシ−５−（４−メチルフエニ
ルチオ）ベンジル］クロロアセトアミド
融点：73〜78℃1
H−NMR［CDCl3］：δ
2.31（ｓ、3H）、4.10（ｓ、2H）
4.37（ｄ、Ｊ＝6.6Hz、2H）
6.91（ｄ、Ｊ＝8.4Hz、1H）
7.07（ｄ、Ｊ＝8.3Hz、2H）
7.14（ｄ、Ｊ＝8.3Hz、2H）
7.22（ｄ、Ｊ＝2.3Hz、1H）
7.29（dd、Ｊ＝8.4Hz、2.3Hz、1H）
7.36（broad ｓ、1H）
8.88（ｓ、1H）
参考例 ３
Γ２−アミノメチル−４−フエニルフエノール・
塩酸塩
融点：237〜238℃（分解）1
H−NMR［（CD3）2SO］：δ
4.01（ｄ、Ｊ＝4.5Hz、2H）
7.03（ｄ、Ｊ＝8.4Hz、1H）
7.2−7.5（3H）
7.53（dd、Ｊ＝8.4Hz、2.3Hz、1H）
7.5−7.7（ｍ、2H）
7.69（ｄ、Ｊ＝2.3Hz、1H）
ΓＮ−（２−ヒドロキシ−５−フエニルベンジル）
クロロアセトアミド
融点：153〜154℃1
H−NMR［CDCl3］：δ
4.12（ｓ、2H）
4.49（ｄ、Ｊ＝6.6Hz、2H）
7.02（ｄ、Ｊ＝8.4Hz、1H）
7.2−7.6（ｍ、8H）
8.70（ｓ、1H）
参考例 ４
Γ２−アミノメチル−４−ベンジルフエノール・
塩酸塩
融点：224〜225℃（分解）1
H−NMR［（CD3）2SO］：δ
3.82（ｓ、2H）、3.88（ｓ、2H）
6.86（ｄ、Ｊ＝8.2Hz、1H）
7.05（dd、Ｊ＝8.2Hz、2.1Hz、1H）
7.1−7.3（ｍ、6H）
ΓＮ−（２−ヒドロキシ−５−ヘンジルベンジル）
クロロアセトアミド
融点：75〜76℃1
H−NMR［CDCl3］：δ
3.89（ｓ、2H）、4.08（ｓ、2H）
4.36（ｄ、Ｊ＝6.6Hz、2H）
6.87（ｄ、Ｊ＝8.3Hz、1H）
9.92（ｄ、Ｊ＝2.3Hz、1H）
7.07（dd、Ｊ＝8.3Hz、2.3Hz、1H）
7.1−7.4（ｍ、6H）
7.47（ｓ、1H）
参考例 ５
Γ２−アミノメチル−４−フエノキシフエノー
ル・塩酸塩
融点：190〜192℃1
H−NMR［CDCl3−CD3OD］：δ
4.05（ｓ、2H）
6.8−7.4（ｍ、8H）
ΓＮ−（２−ヒドロキシ−５−フエノキシベンジ
ル）クロロアセトアミド
融点：128〜131℃1
H−NMR［CDCl3−CD3OD］：δ
4.05（ｓ、2H）、4.39（ｓ、2H）
6.8−7.4（ｍ、8H）
参考例 ６
Γ３−アミノメチル−４−ヒドロキシベンゾフエ
ノン・塩酸塩
融点：202〜208℃1
H−NMR［CDCl3−CD3OD］：δ
4.14（ｓ、2H）
7.04（ｄ、Ｊ＝8.4Hz、1H）
7.4−7.9（ｍ、7H）
ΓＮ−（５−ヘンゾイル−２−ヒドロイシベンジ
ル）クロロアセトアミド
融点：165〜171℃1
H−NMR［CDCl3−CD3OD］：δ
4.06（ｓ、2H）、4.47（ｓ、2H）
6.93（ｄ、Ｊ＝8.4Hz、1H）
7.4−7.8（ｍ、7H）
参考例 ７
２−アミノ−５−（フエニルチオ）ベンジルア
ルコールの製造
工程−１
５−クロロ−２−ニトロ安息香酸25ｇ、チオフ
エノール25ml及び炭酸カリウム38ｇを、Ｎ，Ｎ−
ジメチルホルムアミド（DMF）150mlに加え、
100℃で４時間加熱攪拌した。反応混合物を室温
に冷却し、氷水にあけ、酢酸エチルで洗浄した。
水層を36％塩酸で酸性とし、酢酸エチルで抽出し
た。有機層を飽和食塩水で洗浄し、硫酸マグネシ
ウムで乾燥後、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（クロロホル
ム：メタノール＝10：１）で精製して、２−ニト
ロ−５−（フエニルチオ）安息香酸28ｇを淡褐色
固体として得た。
融点：130〜131℃1
H−NMR［（CD3）2SO］：δ
7.36（ｄ、Ｊ＝7.7Hz、1H）
7.40（ｄ、Ｊ＝1.3Hz、1H）
7.4−7.6（ｍ、5H）
7.95（dd、Ｊ＝7.7Hz、1.3Hz、1H）
工程−２
２−ニトロ−５−（フエニルチオ）安息香酸4.9
ｇを、テトラヒドロフラン（THF）49mlに溶解
させ、これにハイドロサルフアイナトリウム18ｇ
の水150ml溶液加え、室温で１時間撹拌した。反
応混合物をクエン酸でPH４とし、酢酸エチルで抽
出した。有機層を飽和食塩水で洗浄し、硫酸マグ
ネシウム乾燥後、濃縮した。得られた粗生成物を
ジエチルエーテル−ヘキサンで洗浄して、２−ア
ミノ−５−（フエニルチオ）安息香酸3.0ｇを淡黄
色固体として得た。
融点：210〜212℃1
H−NMR［（CD3）2SO］：δ
6.83（ｄ、Ｊ＝8.8Hz、1H）
6.9−7.4（ｍ、6H）
7.85（ｄ、Ｊ＝2.4Hz、1H）
工程−３
水素化アルミニウムリチウム0.15ｇをTHF5ml
に懸濁させ、これに室温下攪拌しながら、２−ア
ミノ−５−（フエニルチオ）安息香酸0.32ｇを加
え、更に２時間攪拌した。反応混合物を氷浴で冷
却しながら、水次いで15％水酸化ナトリウム水溶
液を加えた。不溶物を過して除き、液を濃縮
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（クロロホルム：メタノール＝
33：１）で精製して、目的化合物0.24ｇを無色結
晶として得た。
融点：92〜93℃1
H−NMR（CDCl3）：δ
1.61（ｓ、2H）、4.64（ｓ、2H）
6.69（ｄ、Ｊ＝8.2Hz、1H）
7.0−7.3（ｍ、6H）
7.29（dd、Ｊ＝8.2Hz、２，２Hz、1H）
参考例 ８
２−アミノ−５−（４−ヒドロキシフエニルチ
オ）フエノール・塩酸塩の製造
工程−１
５−クロロ−２−ニトロフエノール5.0ｇ、４
−ヒドロキシチオフエノール3.6ｇ及び炭酸カリ
ウム4.0ｇを、DMF43mlに加え、100℃で2.5時間
加熱攪拌した。反応混合物を室温に冷却し、氷水
にあけ、36％塩酸で酸性とし、酢酸エチルで抽出
した。有機層を飽和食塩水で洗浄し、硫酸マグネ
シウムで乾燥後、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（ジエチル
エーテル：ヘキサン＝１：４）で精製し、更にヘ
キサンで洗浄して、５−（４−ヒドロキシフエニ
ルチオ）−２−ニトロフエノール5.2ｇを淡黄色固
体として得た。
融点：143〜144℃1
H−NMR［CDCl3］：δ
6.60（ｄ、Ｊ＝2.0Hz、1H）
6.64（dd、Ｊ＝8.9Hz、２，０Hz、1H）
6.64（ｄ、Ｊ＝8.0Hz、2H）
7.44（ｄ、Ｊ＝8.0Hz、2H）
7.92（ｄ、Ｊ＝8.9Hz、1H）
工程−２
５−４−（ヒドロキシフエニルチオ）−２−ニト
ロフエノール2.0ｇをTHF23mlと25％アンモニア
水23mlとの混合液に溶解させ、これにハイドロサ
ルフアイナトリウム13ｇの水49ml溶液を加え、室
温で15分間攪拌した後、酢酸エチルで抽出した。
有機層を飽和食塩水で洗浄し、硫酸マグネシウム
で乾燥後、濃縮した。得られた粗生成物をアセト
ニトリル20mlに溶解させ、これに4N塩化水素の
ジオキサン溶液２mlを加え、析出した固体を取
し、乾燥して、目的化合物1.7ｇを淡黄色固体と
して得た。
融点：214〜215℃（分解）1
H−NMR［（CD3）2SO］：δ
6.60（dd、Ｊ＝8.1Hz、２，０Hz、1H）
6.66（ｄ、Ｊ＝2.0Hz、1H）
6.87（ｄ、Ｊ＝8.6Hz、2H）
7.19（ｄ、Ｊ＝8.1Hz、1H）
7.31（ｄ、Ｊ＝8.6Hz、2H）
参考例 ９〜11
参考例８の工程−１と同様にして、５−クロロ
−２−ニトロフエノール及び５−クロロ−４−フ
ルオロ−２−ニトロフエノールのいずれかと、チ
オフエノール、３，４−ジメチルチオフエノール
及び４−メルカプト安息香酸エチルのいずれかと
から、それぞれ下記のニトロフエノール誘導体を
得た。
次いで、之等各化合物をそれぞれ参考例８の工
程−２と同様の還元反応に付して、下記参考例９
〜11の各化合物を得た。
参考例 ９
Γ４−（４−アミノ−３−ヒドロキシフエニルチ
オ）安息香酸エチル
融点：137〜139.5℃（分解）1
H−NMR［CDCl3］：δ
1.30（ｔ、Ｊ＝7.1Hz、3H）
３，93（broad、1H）
4.33（ｑ、Ｊ＝7.1Hz、2H）
6.75（ｄ、Ｊ＝7.9Hz、1H）
6.90（ｄ、Ｊ＝2.0Hz、1H）
6.96（dd、Ｊ＝7.9Hz、２，０Hz、1H）
7.04（ｄ、Ｊ＝8.9Hz、2H）
7.81（ｄ、Ｊ＝8.9Hz、2H）
Γ４−（３−ヒドロキシ−４−ニトロフエニルチ
オ）安息香酸エチル
融点：113〜114.5℃1
H−NMR［CDCl3］：δ
1.42（ｔ、Ｊ＝7.2Hz、3H）
4.42（ｑ、Ｊ＝7.2Hz、2H）
6.73（dd、Ｊ＝9.2Hz、２，０Hz、1H）
6.79（ｄ、Ｊ＝2.0Hz、1H）
7.58（ｄ、Ｊ＝8.5Hz、2H）
7.97（ｄ、Ｊ＝9.2Hz、1H）
8.10（ｄ、Ｊ＝8.5Hz、2H）
10.71（ｓ、1H）
参考例 10
Γ２−アミノ−５−（３，４−ジメチルフエニル
チオ）フエノール・塩酸塩
融点：179〜182℃（分解）1
H−NMR［（CD3）2SO］：δ
2.21（ｓ、3H）、2.23（ｓ、3H）
6.71（dd、Ｊ＝8.1Hz、1.9Hz、1H）
6.81（ｄ、Ｊ＝1.9Hz、1H）
7.1−7.3（ｍ、4H）
Γ５−（３，４−ジメチルフエニルチオ）−２−ニ
トロフエノール
融点：85〜86℃1
H−NMR［CDCl3］：δ
2.29（ｓ、3H）、2.32（ｓ、3H）
6.64（ｄ、Ｊ＝2.0Hz、1H）
6.66（dd、Ｊ＝8.7Hz、２，０Hz、1H）
7.2−7.4（ｍ、3H）
7.91（ｄ、Ｊ＝8.7Hz、1H）
10.77（ｓ、1H）
参考例 11
Γ２−アミノ−４−フルオロ−５−（フエニルチ
オ）フエノール・塩酸塩
融点：185℃以上（分解）1
H−NMR［（CD3）2SO］：δ
6.86（ｄ、Ｊ＝6.8Hz、1H）
7.19（ｄ、Ｊ＝9.7Hz、1H）
7.2−7.5（ｍ、5H）
Γ４−フルオロ−２−ニトロ−５−（フエニルチ
オ）フエノール
融点：92〜93℃1
H−NMR［（CD3）2SO］：δ
6.49（ｄ、Ｊ＝6.6Hz、1H）
7.5−7.7（ｍ、5H）
7.88（ｄ、Ｊ＝9.9Hz、1H）
参考例 12
Ｎ−（３−アミノ−４−ヒドロキシジフエニア
ミン）ホルムアミドの製造
工程−１
Ｎ−（４−ヒドロキシジフエニルアミン）ホル
ムアミド12.0ｇを酢酸54mlに溶解させ、これに氷
水下に61％硝酸6.4ｇを加え、３時間攪拌した。
反応混合物を氷水にあけ、生成する固体を取
し、水で洗浄後、乾燥させた。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（クロロ
ホルム：ヘキサン＝１：１）で精製して、Ｎ−
（４−ヒドロキシ−３−ニトロジフエニアミン）
ホルムアミド11.7ｇを橙色固体として得た。
融点：102〜140℃1
H−NMR［CDCl3］：δ
7.1−7.6（ｍ、7H）
7.98、8.06（各ｄ、各Ｊ＝2.7Hz、2.5Hz、1H）
8.63（ｓ、1H）
10.56、10.57（各ｓ、1H）
工程−２
Ｎ−４−（ヒドロキシ−３−ニトロジフエニル
アミン）ホルムアミドを、参考例８の工程−２と
同様の還元反応に付して、目的化合物を得た。
性状：油状物質1
H−NMR［CDCl3］：δ
6.3−6.7（ｍ、3H）
7.1−7.4（ｍ、5H）
8.52、8.62（各ｓ、1H）
参考例 13
参考例12の工程−１と同様にして、２−ベンジ
ルフエノールと硝酸とから、下記ニトロフエノー
ル誘導体を得た。
Γ２−ベンジル−６−ニトロフエノール
融点：58〜59℃1
H−NMR［CDCl3］：δ
4.06（ｓ、dH）
6.8−7.0（ｍ、1H）
7.2−7.4（ｍ、6H）
7.98（dd、Ｊ＝8.6Hz、1.3Hz、1H）
次いで上記化合物を、参考例８の工程−２と同
様の還元反応に付して、下記目的化合物を得た。
Γ６−アミノ−２−ベンジルフエノール・塩酸塩
融点：232〜234℃（分解）1
H−NMR［（CD3）2SO］：δ
4.03（ｓ、2H）
6.8−6.9（ｍ、1H）
7.0−7.1（ｍ、1H）
7.1−7.3（ｍ、6H）
参考例 14
２−アミノ−５−（４−メチルフエノキシ）フ
エノールの製造
工程−１
カリウムtert−ブトキシド6.6ｇをDMF100mlに
懸濁させ、これに室温でｐ−クレゾール6.3ｇを
加え、30分攪拌した。次いで５−クロロ−２−ニ
トロニソール10.0ｇを加え、100℃で18時間加熱
攪拌した。反応混合物を室温に冷却し、氷水にあ
け、酢酸エチルで抽出した。有機層を2N水酸化
ナトリウム、次いで飽和食塩水で洗浄し、硫酸マ
グネシウムで乾燥し、濃縮した。得られた粗生成
物をジエチルエーテル−ヘキサンで再結晶して、
５−（４−メチルフエノキシ）−２−ニトロアニソ
ール10.9ｇを黄色結晶として得た。
融点：125〜127℃1
H−NMR［CDCl3］：δ
2.38（ｓ、3H）、3.89（ｓ、3H）
6.46（dd、Ｊ＝9.1Hz、2.5Hz、1H）
6.63（ｄ、Ｊ＝2.5Hz、1H）
6.97（ｄ、Ｊ＝8.5Hz、2H）
7.22（ｄ、Ｊ＝8.5Hz、2H）
7.93（ｄ、Ｊ＝9.1Hz、1H）
工程−２
５−（４−メチルフエノキシ−２−ニトロアニ
ソール8.0ｇをジクロロメタン160mlに溶解させ、
ドライアイス−アセトン浴で冷却し、これに三臭
化ホウ素8.5ｇのジクロロメタン10ml溶液を加え、
20分間攪拌した。反応混合物を水にあけ、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、硫酸マグネシウムで乾燥した後、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（クロロホルム：ヘキサン＝１：２）で
精製して、５−（４−メチルフエノキシ）２−ニ
トロフエノール6.8ｇを黄色固体として得た。
融点：109〜110℃1
H−NMR［CDCl3］：δ
2.38（ｓ、3H）
6.48（ｄ、Ｊ＝2.7Hz、1H）
6.57（dd、Ｊ＝9.4Hz、2.7Hz、1H）
6.98（ｄ、Ｊ＝8.5Hz、2H）
7.23（ｄ、Ｊ＝8.5Hz、2H）
8.06（ｄ、Ｊ＝9.4Hz、1H）
10.89（ｓ、1H）
工程−３
５−（４−メチルフエノキシ）−２−ニトロフエ
ノールを参考例８の工程−２と同様に還元反応に
付して、目的化合物を得た。
融点：133〜135℃（分解）1
H−NMR［CDCl3］：δ
2.30（ｓ、3H）
6.4−6.5（ｍ、2H）
6.73（ｄ、Ｊ＝8.7Hz、1H）
6.85（ｄ、Ｊ＝8.5Hz、2H）
7.08（ｄ、Ｊ＝8.5Hz、2H）
参考例 15
参考例14の工程−２と同様にして、公知の５−
（２，４−ジフルオロフエノキシ）−２−ニトロア
ニソールと三臭化ホウ素とから、下記ニトロフエ
ノール誘導体を得た。
Γ５−（２，４−ジフルオロフエノキシ）−２−ニ
トロフエノール
融点：74〜76℃1
H−NMR［CDCl3］：δ
6.47（ｄ、Ｊ＝2.7Hz、1H）
6.60（dd、Ｊ＝9.4Hz、2.7Hz、1H）
6.9−7.3（ｍ、3H）
8.10（ｄ、Ｊ＝9.4Hz、1H）
10.88（ｓ、1H）
次いでこの化合物を参考例８の工程−２と同様
の還元反応に付して、下記目的化合物を得た。
Γ２−アミノ−５−（２，４−ジフルオロフエノ
ール）フエノール
融点：140〜142℃（分解）1
H−NMR［CDCl3−CD3CD］：δ
6.33（dd、Ｊ＝8.7Hz、2.7Hz、1H）
6.49（ｄ、Ｊ＝2.7Hz、1H）
6.68（ｄ、Ｊ＝8.7Hz、1H）
6.7−7.0（ｍ、3H）
実施例 １
Ｎ−［２−ヒドロキシ−５−（４−メチルフエニ
ルチオ）フエニル］メタンスルホンアミド［化
合物１］の製造
２−アミノ−４−（４−メチルフエニルチオ）
フエノール・塩酸塩1.6ｇ及びピリジン1.5ｇを、
ジクロロメタン30mlに加え、これに氷冷下で塩化
メタンスルホニル0.73ｇのジクロロメタン溶液10
mlを滴下し、2.5時間攪拌した。反応混合物を希
塩酸にあけ、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、硫酸マグネシウムで乾燥
後、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＝５：１）で精製し、更にジエチルエーテ
ル−ヘキサン（３：４）で洗浄して、目的化合物
1.6ｇを無色固体として得た。
得られた化合物の構造及び物性（融点及び1H
−NMR値）を第１表に示す。
実施例 ２
Ｎ−［２−ヒドロキシ−５−（フエニルチオ］ベ
ンジル］メタンスルホンアミド［化合物２］の
製造
２−アミノメチル−４−（フエニルチオ）フエ
ノール・塩酸塩（参考例１で得たもの）1.0ｇ及
びピシジン6.7mlを、シクロロメタン20mlに加え、
これに氷冷下で塩化メタンスルホニル0.64mlを滴
下し、室温で17時間攪拌した。反応混合物を希塩
酸にあけ、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、硫酸マグネシウムで乾燥
後、濃縮した。得られた生成製物をエタノール
7.5mlに溶解させ、3N水酸化ナトリウム水溶液7.5
mlを加えて30分間加熱還流した。反応混合物を室
温に冷却し、希塩酸にあけ、酢酸エチレで抽出し
た。有機層を飽和食塩水で洗浄し、硫酸マグネシ
ウムで乾燥後、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（クロロホル
ム：酢酸エチル＝４：１）で精製して、目的化合
物0.75ｇを無色固体として得た。
得られた化合物の構造及び物性を第１表に示
す。
実施例 ３〜33
化合物３〜化合物33の製造
実施例１又は２と同様にして、公知の２−アミ
ノ−４−（フエニルチオ）フエノール、２−アミ
ノ−５−（フエニルチオ）フエノール誘導体、２
−アミノア−４−フエニルフエノール、２−アミ
ノ−４−ベンジルフエノール、２−アミノ−４−
フエノキシフエノール、３−アミノ−４−ヒドロ
キシベンゾフエノン及び参考例２〜15で得た各化
合物のいずれかと、塩化メタンスルホニル、塩化
エタンスルホニル及び塩化ベンゼンスルホニルの
いずれかとから、本発明化合物を得た。
得られた化合物の構造及び物性を第１表に示
す。
実施例 34
Ｎ−［２−ヒドロシキ−５−（フエニルアミノ）
フエニル］メタンスルホンアミド［化合物34］
の製造
Ｎ−（４−ヒドロキシ−３−メチルスルホニル
アミノジフエニルアミン）ホルムアミド（実施例
26で製造したもの）1.5ｇを、エタノール30mlと
36％塩酸15mlに加え、20分間加熱還流した。反応
混合物を室温に冷却し、濃縮して生成する体を
取し、ジエチルエーテルで洗浄して、目的化合物
1.1ｇを淡褐色固体として得た。
得られた化合物の構造及び物性を第１表に示
す。
実施例 35
化合物35の製造
実施例34と同様にして、実施例12で製造した化
合物12と塩酸から、本発明化合物を製造した。
得られた化合物の構造及び物性を第１表に示
す。
実施例 36
４−（３−ヒドロキシ−４−メチルスルホニル
アミノフエニルチオ）安息香酸［化合物36］の
製造
４−（３−ヒドロキシ−４−メチルスルホニル
アミノフエニルチオ）安息香酸エチル（実施例13
で製造したもの）1.21ｇをメタノール15mlに溶解
させ、水酸化ナトリウム1.41ｇの水10ml溶液を加
え、３時間加熱還流した。反応混合物を室温に冷
却し、36％塩酸で酸性とした。生成する固体を
取し、水次いでジエチルエーテルで洗浄して、目
的化合物0.87ｇを無色固体として得た。
得られた化合物の構造及び物性を第１表に示
す。
実施例 37
Ｎ−［２−ヒドロキシ−４−（フエニルスルフイ
ニル）フエニル］メタンスルホンアミド［化合
物37］の製造
Ｎ−［２−ヒドロキシ−４−（フエニルチオ）フ
エニル］メタスルホンアミド（実施例３で製造し
たもの）1.55ｇをジクロロメタン100mlに溶解さ
せ、室温で70％ｍ−クロロ過安息香酸1.3ｇを少
量ずつ加え、30分間攪拌した。反応混合物を飽和
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、硫酸マグネシウムで乾
燥後、濃縮した。得られた粗生成物をジクロロメ
タン−メタノールから再結晶して、目的化合物
0.9ｇを無色結晶として得た。
得られた化合物の構造及び物性を第１表に示
す。
実施例 38
Ｎ−［２−ヒドロキシ−４−（フエニルスルホニ
ル）フエニル］メタンスルホンアミド［化合物
38］の製造
Ｎ−［２−ヒドロキシ−４−（フエニルチオ）フ
エニル］メタスルホンアミド（実施例３で製造し
たもの）1.1ｇをジクロロメタン50mlに溶解させ、
室温で70％ｍ−クロロ過安息香酸1.9ｇを加え、
３時間攪拌した。反応混合物を飽和重曹水、次い
で飽和食塩水で洗浄し、硫酸マグネシウムで乾燥
後、濃縮した。得られた粗生成物をシリカゲルカ
ルムクロマトグラフイー（クロロホルム）で精製
して、目的化合物0.5ｇを淡黄色固体として得た。
得られた化合物の構造及び物性を第１表に示
す。
According to the method shown in the above reaction scheme-3, the sulfoxide derivative (1g) or the sulfonyl derivative (1h) is produced by the oxidation reaction of the sulfide derivative (1f).
can be produced, and the sulfonyl derivative (1h) can also be produced by oxidation reaction of the sulfoxide derivative (1g). All of the above oxidation reactions can be carried out in a suitable inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, acetic acid, water, etc., and a mixed solvent thereof. More specifically, the production reaction of the sulfoxide derivative (1g) from the sulfide derivative (1f) is carried out using organic peracids such as m-chloroperbenzoic acid and peracetic acid, or inorganic peracids such as hydrogen peroxide and sodium perborate. This can be carried out advantageously by using approximately equimolar amount of compound (1f). Also sulfide derivative (1f) or sulfoxide derivative (1g)
The reaction for producing the sulfone derivative (1h) from can be carried out in the same manner as above, using an organic peracid or sodium perborate in an amount of about 2 to 5 times the molar amount of the starting compound. . The compound of the present invention obtained by the reaction shown in the above synthesis reaction scheme can be easily isolated and purified by conventional separation means.
Examples of the separation means include solvent extraction, recrystallization, column chromatography, and the like. Further, the compound of the present invention thus obtained can be easily converted into a pharmaceutically acceptable salt by subjecting it to an addition reaction with a suitable basic compound according to a conventional method, and the salt is a salt of the compound of the present invention in a free form. It has the same pharmacological activity as, and is included in the present invention. Examples of the above-mentioned salts include organic salts such as choline salt, diethanolamine salt, ethylene diamine salt, N-methyl-D-glucamine salt, and tris(hydroxymethyl)aminomethane salt, and inorganic salts such as lithium salt, sodium salt, and potassium salt. An example is salt. Furthermore, some of the compounds of the present invention can be converted into pharmaceutically acceptable acid addition salts by addition reaction with a suitable acidic compound according to a conventional method, and the acid addition salts can also be converted into pharmaceutically acceptable acid addition salts. It has pharmacological activity and is included in the present invention. Examples of acidic compounds that form the acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid; Examples include organic acids such as benzenesulfonic acid. Examples Hereinafter, in order to explain the present invention in more detail, production examples of raw material compounds for producing the compounds of the present invention will be given as reference examples, and then production examples of the compounds of the present invention will be given as examples. Reference Example 1 Production process of 2-aminomethyl-4-(phenylthio)phenol/hydrochloride-1 A 2 ml solution of 4.74 g of 4-(phenylthio)phenol in acetic acid and 2.89 g of N-(hydroxymethyl)chloroacetamide were cooled on ice. The mixture was added to 23 ml of acetic acid-97% sulfuric acid (9:1) solution and stirred at room temperature for 27 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated. The obtained crude product was subjected to silica gel column chromatography (developing solvent: diethyl ether: hexane = 2:
3), further washed with hexane, and N-
2.54 g of [2-hydroxy-5-(phenylthio)benzyl]chloroacetamide was obtained as a pale red solid. Melting point: 87-88℃ 1 H-NMR (CDCl 3 ): δ 4.11 (s, 2H) 4.38 (d, J = 6.6Hz, 2H) 6.94 (d, J = 8.4Hz, 1H) 7.1-7.3 (m, 5H) 7.28 (d, J = 2.3Hz, 1H) 7.35 (dd, J = 8.4Hz, 2.3Hz, 1H) 8.98 (s, 1H) Step-2 N-[2-hydroxy-5-(phenylthio)benzyl] 1.50g of chloroacetamide in ethanol
The mixture was added to a mixed solution of 10 ml and 5 ml of 36% hydrochloric acid, and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, concentrated, and the resulting solid was collected and washed with diethyl ether to obtain 1.35 g of the target compound as a colorless solid. Melting point: 228-228.5℃ (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 3.9-4.0 (m, 2H) 7.02 (d, J = 8.4Hz, 1H) 7.1-7.4 (m, 5H) 7.36 (dd, J = 8.4Hz, 2.3Hz, 1H) 7.53 (d, J = 2.3Hz, 1H) Reference Examples 2 to 6 In the same manner as Reference Example 1 and Step-1, 4-(4-
Methylphenylthio)phenol, 4-phenylphenol, 4-benzylphenol, 4-phenoxyphenol and 4-hydroxybenzophenone, and N-(hydroxymethyl)chloroacetamide, each of the following N −
A (2-hydroxybenzyl)chloroacetamide derivative was obtained. Next, each of these compounds was subjected to a hydrolysis reaction in the same manner as in Step-2 of Reference Example 1 to obtain each of the compounds of Reference Examples 2 to 6 below. Reference example 2 Γ2-aminomethyl-4-(4-methylphenylthio)phenol hydrochloride Melting point: 231-233°C (decomposition) 1 H-NMR [CDCl 3 - CD 3 OD]: δ 2.30 (s, 3H ), 4.03 (s, 2H) 6.91 (d, J=8.9Hz, 1H) 7.07 (d, J=8.4Hz, 2H) 7.13 (d, J=8.4Hz, 2H) 7.3−7.4 (m, 2H) ΓN -[2-Hydroxy-5-(4-methylphenylthio)benzyl]chloroacetamide Melting point: 73-78°C 1 H-NMR [CDCl 3 ]: δ 2.31 (s, 3H), 4.10 (s, 2H) 4.37 (d, J=6.6Hz, 2H) 6.91 (d, J=8.4Hz, 1H) 7.07 (d, J=8.3Hz, 2H) 7.14 (d, J=8.3Hz, 2H) 7.22 (d, J=2.3 Hz, 1H) 7.29 (dd, J = 8.4Hz, 2.3Hz, 1H) 7.36 (broad s, 1H) 8.88 (s, 1H) Reference example 3 Γ2-aminomethyl-4-phenylphenol.
Hydrochloride melting point: 237-238℃ (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 4.01 (d, J = 4.5 Hz, 2H) 7.03 (d, J = 8.4 Hz, 1H) 7.2-7.5 (3H) 7.53 (dd, J = 8.4Hz, 2.3Hz, 1H) 7.5-7.7 (m, 2H) 7.69 (d, J = 2.3Hz, 1H) ΓN-(2-hydroxy-5-phenylbenzyl)
Chloroacetamide melting point: 153-154°C 1 H-NMR [CDCl 3 ]: δ 4.12 (s, 2H) 4.49 (d, J = 6.6Hz, 2H) 7.02 (d, J = 8.4Hz, 1H) 7.2-7.6 ( m, 8H) 8.70 (s, 1H) Reference example 4 Γ2-aminomethyl-4-benzylphenol.
Hydrochloride melting point: 224-225℃ (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 3.82 (s, 2H), 3.88 (s, 2H) 6.86 (d, J = 8.2Hz, 1H) 7.05 (dd, J=8.2Hz, 2.1Hz, 1H) 7.1-7.3 (m, 6H) ΓN-(2-hydroxy-5-henzylbenzyl)
Chloroacetamide melting point: 75-76°C 1 H-NMR [CDCl 3 ]: δ 3.89 (s, 2H), 4.08 (s, 2H) 4.36 (d, J = 6.6Hz, 2H) 6.87 (d, J = 8.3Hz , 1H) 9.92 (d, J = 2.3Hz, 1H) 7.07 (dd, J = 8.3Hz, 2.3Hz, 1H) 7.1−7.4 (m, 6H) 7.47 (s, 1H) Reference example 5 Γ2-aminomethyl- 4-Phenoxyphenol hydrochloride Melting point: 190-192℃ 1 H-NMR [CDCl 3 -CD 3 OD]: δ 4.05 (s, 2H) 6.8-7.4 (m, 8H) ΓN-(2-hydroxy- 5-Phenoxybenzyl) chloroacetamide Melting point: 128-131°C 1H -NMR [ CDCl3 - CD3OD ]: δ 4.05 (s, 2H), 4.39 (s, 2H) 6.8-7.4 (m, 8H) Reference example 6 Γ3-aminomethyl-4-hydroxybenzophenone hydrochloride Melting point: 202 to 208°C 1 H-NMR [CDCl 3 - CD 3 OD]: δ 4.14 (s, 2H) 7.04 (d, J = 8.4 Hz, 1H) 7.4-7.9 (m, 7H) ΓN-(5-henzoyl-2-hydroysibenzyl)chloroacetamide Melting point: 165-171°C 1H -NMR [ CDCl3- CD3OD ]: δ 4.06 (s , 2H), 4.47 (s, 2H) 6.93 (d, J = 8.4Hz, 1H) 7.4-7.8 (m, 7H) Reference example 7 Production process of 2-amino-5-(phenylthio)benzyl alcohol-1 5- 25 g of chloro-2-nitrobenzoic acid, 25 ml of thiophenol and 38 g of potassium carbonate were mixed with N,N-
In addition to 150 ml of dimethylformamide (DMF),
The mixture was heated and stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature, poured into ice water, and washed with ethyl acetate.
The aqueous layer was made acidic with 36% hydrochloric acid and extracted with ethyl acetate. 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 (chloroform:methanol=10:1) to obtain 28 g of 2-nitro-5-(phenylthio)benzoic acid as a light brown solid. Melting point: 130-131℃ 1 H-NMR [(CD 3 ) 2 SO]: δ 7.36 (d, J = 7.7 Hz, 1H) 7.40 (d, J = 1.3 Hz, 1H) 7.4-7.6 (m, 5H) 7.95 (dd, J=7.7Hz, 1.3Hz, 1H) Step-2 2-nitro-5-(phenylthio)benzoic acid 4.9
Dissolve g in 49 ml of tetrahydrofuran (THF), and add 18 g of sodium hydrosulfate to this.
150 ml of water was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 4 with citric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was washed with diethyl ether-hexane to obtain 3.0 g of 2-amino-5-(phenylthio)benzoic acid as a pale yellow solid. Melting point: 210-212℃ 1 H-NMR [(CD 3 ) 2 SO]: δ 6.83 (d, J = 8.8 Hz, 1H) 6.9-7.4 (m, 6H) 7.85 (d, J = 2.4Hz, 1H) Step-3 0.15g of lithium aluminum hydride and 5ml of THF
To this was added 0.32 g of 2-amino-5-(phenylthio)benzoic acid while stirring at room temperature, and the mixture was further stirred for 2 hours. While cooling the reaction mixture in an ice bath, water and then 15% aqueous sodium hydroxide solution were added. Insoluble matter was removed by filtration, and the liquid was concentrated. The obtained crude product was subjected to silica gel column chromatography (chloroform:methanol=
33:1) to obtain 0.24 g of the target compound as colorless crystals. Melting point: 92-93℃ 1 H-NMR (CDCl 3 ): δ 1.61 (s, 2H), 4.64 (s, 2H) 6.69 (d, J = 8.2Hz, 1H) 7.0-7.3 (m, 6H) 7.29 ( dd, J = 8.2Hz, 2,2Hz, 1H) Reference example 8 2-amino-5-(4-hydroxyphenylthio)phenol hydrochloride manufacturing process-1 5-chloro-2-nitrophenol 5.0g, 4
-3.6 g of hydroxythiophenol and 4.0 g of potassium carbonate were added to 43 ml of DMF, and the mixture was heated and stirred at 100°C for 2.5 hours. The reaction mixture was cooled to room temperature, poured into ice water, acidified with 36% hydrochloric acid, and extracted with ethyl acetate. 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 (diethyl ether:hexane = 1:4) and further washed with hexane to obtain 5.2 g of 5-(4-hydroxyphenylthio)-2-nitrophenol. was obtained as a pale yellow solid. Melting point: 143-144℃ 1 H-NMR [CDCl 3 ]: δ 6.60 (d, J = 2.0Hz, 1H) 6.64 (dd, J = 8.9Hz, 2,0Hz, 1H) 6.64 (d, J = 8.0Hz , 2H) 7.44 (d, J = 8.0Hz, 2H) 7.92 (d, J = 8.9Hz, 1H) Step-2 5-4-(Hydroxyphenylthio)-2-nitrophenol 2.0g with THF 23ml and 25% The mixture was dissolved in a mixture with 23 ml of aqueous ammonia, and a solution of 13 g of sodium hydrosulfite in 49 ml of water was added thereto, stirred at room temperature for 15 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 dissolved in 20 ml of acetonitrile, and 2 ml of 4N hydrogen chloride in dioxane was added thereto, and the precipitated solid was collected and dried to obtain 1.7 g of the target compound as a pale yellow solid. Melting point: 214-215℃ (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 6.60 (dd, J = 8.1Hz, 2.0Hz, 1H) 6.66 (d, J = 2.0Hz, 1H) 6.87 (d, J=8.6Hz, 2H) 7.19 (d, J=8.1Hz, 1H) 7.31 (d, J=8.6Hz, 2H) Reference Examples 9 to 11 In the same manner as Step-1 of Reference Example 8, 5 - From either chloro-2-nitrophenol or 5-chloro-4-fluoro-2-nitrophenol and from either thiophenol, 3,4-dimethylthiophenol and ethyl 4-mercaptobenzoate, the following nitro A phenol derivative was obtained. Next, each of these compounds was subjected to a reduction reaction similar to Step-2 of Reference Example 8 to obtain the following Reference Example 9.
~11 of each compound were obtained. Reference example 9 Ethyl Γ4-(4-amino-3-hydroxyphenylthio)benzoate Melting point: 137-139.5°C (decomposition) 1 H-NMR [CDCl 3 ]: δ 1.30 (t, J = 7.1Hz, 3H) 3,93 (broad, 1H) 4.33 (q, J = 7.1Hz, 2H) 6.75 (d, J = 7.9Hz, 1H) 6.90 (d, J = 2.0Hz, 1H) 6.96 (dd, J = 7.9Hz, 2,0Hz, 1H) 7.04 (d, J = 8.9Hz, 2H) 7.81 (d, J = 8.9Hz, 2H) Ethyl Γ4-(3-hydroxy-4-nitrophenylthio)benzoate Melting point: 113-114.5 ℃ 1 H-NMR [CDCl 3 ]: δ 1.42 (t, J = 7.2 Hz, 3H) 4.42 (q, J = 7.2 Hz, 2H) 6.73 (dd, J = 9.2 Hz, 2,0 Hz, 1H) 6.79 ( d, J=2.0Hz, 1H) 7.58 (d, J=8.5Hz, 2H) 7.97 (d, J=9.2Hz, 1H) 8.10 (d, J=8.5Hz, 2H) 10.71 (s, 1H) Reference example 10 Γ2-amino-5-(3,4-dimethylphenylthio)phenol hydrochloride Melting point: 179-182℃ (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 2.21 (s, 3H) , 2.23 (s, 3H) 6.71 (dd, J = 8.1Hz, 1.9Hz, 1H) 6.81 (d, J = 1.9Hz, 1H) 7.1-7.3 (m, 4H) Γ5-(3,4-dimethylphenylene) ruthio)-2-nitrophenol Melting point: 85-86°C 1 H-NMR [CDCl 3 ]: δ 2.29 (s, 3H), 2.32 (s, 3H) 6.64 (d, J = 2.0Hz, 1H) 6.66 (dd , J = 8.7Hz, 2,0Hz, 1H) 7.2-7.4 (m, 3H) 7.91 (d, J = 8.7Hz, 1H) 10.77 (s, 1H) Reference example 11 Γ2-amino-4-fluoro-5- (Phenylthio)phenol hydrochloride Melting point: 185℃ or higher (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 6.86 (d, J = 6.8 Hz, 1H) 7.19 (d, J = 9.7 Hz, 1H ) 7.2-7.5 (m, 5H) Γ4-fluoro-2-nitro-5-(phenylthio)phenol Melting point: 92-93°C 1 H-NMR [(CD 3 ) 2 SO]: δ 6.49 (d, J = 6.6 Hz, 1H) 7.5-7.7 (m, 5H) 7.88 (d, J = 9.9Hz, 1H) Reference example 12 Manufacturing process of N-(3-amino-4-hydroxydipheniamine) formamide-1 N-(4 12.0 g of -hydroxydiphenylamine) formamide was dissolved in 54 ml of acetic acid, and 6.4 g of 61% nitric acid was added to the solution under ice water, followed by stirring for 3 hours.
The reaction mixture was poured into ice water, and the resulting solid was collected, washed with water, and then dried. The obtained crude product was purified by silica gel column chromatography (chloroform:hexane=1:1) to obtain N-
(4-hydroxy-3-nitrodipheniamine)
11.7 g of formamide was obtained as an orange solid. Melting point: 102-140℃ 1H -NMR [ CDCl3 ]: δ 7.1-7.6 (m, 7H) 7.98, 8.06 (each d, each J = 2.7Hz, 2.5Hz, 1H) 8.63 (s, 1H) 10.56, 10.57 (each s, 1H) Step-2 N-4-(hydroxy-3-nitrodiphenylamine)formamide was subjected to the same reduction reaction as in Step-2 of Reference Example 8 to obtain the target compound. Properties: Oily substance 1 H-NMR [CDCl 3 ]: δ 6.3-6.7 (m, 3H) 7.1-7.4 (m, 5H) 8.52, 8.62 (each s, 1H) Reference example 13 Step-1 of reference example 12 Similarly, the following nitrophenol derivative was obtained from 2-benzylphenol and nitric acid. Γ2-Benzyl-6-nitrophenol Melting point: 58-59℃ 1 H-NMR [CDCl 3 ]: δ 4.06 (s, dH) 6.8-7.0 (m, 1H) 7.2-7.4 (m, 6H) 7.98 (dd, J=8.6Hz, 1.3Hz, 1H) Next, the above compound was subjected to a reduction reaction similar to Step-2 of Reference Example 8 to obtain the following target compound. Γ6-amino-2-benzylphenol hydrochloride Melting point: 232-234℃ (decomposition) 1 H-NMR [(CD 3 ) 2 SO]: δ 4.03 (s, 2H) 6.8-6.9 (m, 1H) 7.0- 7.1 (m, 1H) 7.1-7.3 (m, 6H) Reference Example 14 Manufacturing process of 2-amino-5-(4-methylphenoxy)phenol-1 6.6 g of potassium tert-butoxide was suspended in 100 ml of DMF, and the suspension was heated to room temperature. Then 6.3 g of p-cresol was added and stirred for 30 minutes. Next, 10.0 g of 5-chloro-2-nitronisole was added, and the mixture was heated and stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 2N sodium hydroxide and then with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was recrystallized from diethyl ether-hexane,
10.9 g of 5-(4-methylphenoxy)-2-nitroanisole was obtained as yellow crystals. Melting point: 125-127°C 1 H-NMR [CDCl 3 ]: δ 2.38 (s, 3H), 3.89 (s, 3H) 6.46 (dd, J = 9.1Hz, 2.5Hz, 1H) 6.63 (d, J = 2.5 Hz, 1H) 6.97 (d, J = 8.5Hz, 2H) 7.22 (d, J = 8.5Hz, 2H) 7.93 (d, J = 9.1Hz, 1H) Step-2 5-(4-Methylphenoxy-2-nitro Dissolve 8.0g of anisole in 160ml of dichloromethane,
Cool in a dry ice-acetone bath, add a solution of 8.5 g of boron tribromide in 10 ml of dichloromethane,
Stir for 20 minutes. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated.
The obtained crude product was purified by silica gel column chromatography (chloroform:hexane=1:2) to obtain 6.8 g of 5-(4-methylphenoxy)2-nitrophenol as a yellow solid. Melting point: 109-110℃ 1 H-NMR [CDCl 3 ]: δ 2.38 (s, 3H) 6.48 (d, J = 2.7Hz, 1H) 6.57 (dd, J = 9.4Hz, 2.7Hz, 1H) 6.98 (d , J=8.5Hz, 2H) 7.23 (d, J=8.5Hz, 2H) 8.06 (d, J=9.4Hz, 1H) 10.89 (s, 1H) Step-3 5-(4-methylphenoxy)-2-nitro Phenol was subjected to a reduction reaction in the same manner as in Step-2 of Reference Example 8 to obtain the target compound. Melting point: 133-135℃ (decomposed) 1 H-NMR [CDCl 3 ]: δ 2.30 (s, 3H) 6.4-6.5 (m, 2H) 6.73 (d, J = 8.7Hz, 1H) 6.85 (d, J = 8.5Hz, 2H) 7.08 (d, J = 8.5Hz, 2H) Reference Example 15 In the same manner as Step-2 of Reference Example 14, the known 5-
The following nitrophenol derivative was obtained from (2,4-difluorophenoxy)-2-nitroanisole and boron tribromide. Γ5-(2,4-difluorophenoxy)-2-nitrophenol Melting point: 74-76°C 1H -NMR [ CDCl3 ]: δ 6.47 (d, J = 2.7Hz, 1H) 6.60 (dd, J = 9.4Hz, 2.7Hz, 1H) 6.9-7.3 (m, 3H) 8.10 (d, J = 9.4Hz, 1H) 10.88 (s, 1H) Next, this compound was subjected to a reduction reaction similar to Step-2 of Reference Example 8. The following target compound was obtained. Γ2-amino-5-(2,4-difluorophenol) phenol Melting point: 140-142°C (decomposition) 1 H-NMR [CDCl 3 -CD 3 CD]: δ 6.33 (dd, J = 8.7Hz, 2.7Hz, 1H) 6.49 (d, J = 2.7Hz, 1H) 6.68 (d, J = 8.7Hz, 1H) 6.7-7.0 (m, 3H) Example 1 N-[2-hydroxy-5-(4-methylphenylene) Production of methane sulfonamide [compound 1] 2-amino-4-(4-methylphenylthio)
1.6g of phenol hydrochloride and 1.5g of pyridine,
Add to 30 ml of dichloromethane, and add a dichloromethane solution of 0.73 g of methanesulfonyl chloride to this under ice cooling.
ml was added dropwise and stirred for 2.5 hours. The reaction mixture was poured into dilute hydrochloric acid 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 (dichloromethane: ethyl acetate = 5:1), and further washed with diethyl ether-hexane (3:4) to obtain the target compound.
1.6 g was obtained as a colorless solid. Structure and physical properties of the obtained compound (melting point and 1H
-NMR values) are shown in Table 1. Example 2 Production of N-[2-hydroxy-5-(phenylthio]benzyl]methanesulfonamide [Compound 2] 2-Aminomethyl-4-(phenylthio)phenol hydrochloride (obtained in Reference Example 1) 1.0 Add g and 6.7 ml of picidine to 20 ml of cyclomethane,
0.64 ml of methanesulfonyl chloride was added dropwise to this under ice cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained product is ethanol
Dissolve in 7.5ml 3N sodium hydroxide aqueous solution 7.5
ml and heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, poured into dilute hydrochloric acid, and extracted with ethylene acetate. 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 (chloroform:ethyl acetate=4:1) to obtain 0.75 g of the target compound as a colorless solid. The structure and physical properties of the obtained compound are shown in Table 1. Examples 3 to 33 Production of compounds 3 to 33 In the same manner as in Example 1 or 2, known 2-amino-4-(phenylthio)phenol, 2-amino-5-(phenylthio)phenol derivatives, 2
-amino-4-phenylphenol, 2-amino-4-benzylphenol, 2-amino-4-
The compound of the present invention is prepared from phenoxyphenol, 3-amino-4-hydroxybenzophenone, any of the compounds obtained in Reference Examples 2 to 15, and any of methanesulfonyl chloride, ethanesulfonyl chloride, and benzenesulfonyl chloride. Obtained. The structure and physical properties of the obtained compound are shown in Table 1. Example 34 N-[2-hydroxy-5-(phenylamino)
Phenyl] methanesulfonamide [Compound 34]
Preparation of N-(4-hydroxy-3-methylsulfonylaminodiphenylamine)formamide (Example
1.5g (manufactured in 26) with 30ml of ethanol.
The mixture was added to 15 ml of 36% hydrochloric acid and heated under reflux for 20 minutes. The reaction mixture was cooled to room temperature, concentrated, the resulting product was collected, and washed with diethyl ether to obtain the target compound.
1.1 g was obtained as a light brown solid. The structure and physical properties of the obtained compound are shown in Table 1. Example 35 Production of Compound 35 In the same manner as in Example 34, the compound of the present invention was produced from Compound 12 produced in Example 12 and hydrochloric acid. The structure and physical properties of the obtained compound are shown in Table 1. Example 36 Production of 4-(3-hydroxy-4-methylsulfonylaminophenylthio)benzoic acid [Compound 36] Ethyl 4-(3-hydroxy-4-methylsulfonylaminophenylthio)benzoate (Example 13)
1.21 g (produced in ) was dissolved in 15 ml of methanol, a solution of 1.41 g of sodium hydroxide in 10 ml of water was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and acidified with 36% hydrochloric acid. The resulting solid was collected and washed with water and diethyl ether to obtain 0.87 g of the target compound as a colorless solid. The structure and physical properties of the obtained compound are shown in Table 1. Example 37 Preparation of N-[2-hydroxy-4-(phenylsulfinyl)phenyl]methanesulfonamide [Compound 37] N-[2-hydroxy-4-(phenylthio)phenyl]methanesulfonamide (Example 3 1.55 g of the product prepared in ) was dissolved in 100 ml of dichloromethane, 1.3 g of 70% m-chloroperbenzoic acid was added little by little at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into saturated 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 recrystallized from dichloromethane-methanol to obtain the target compound.
0.9 g was obtained as colorless crystals. The structure and physical properties of the obtained compound are shown in Table 1. Example 38 N-[2-hydroxy-4-(phenylsulfonyl)phenyl]methanesulfonamide [compound
38] Dissolve 1.1 g of N-[2-hydroxy-4-(phenylthio)phenyl]methasulfonamide (produced in Example 3) in 50 ml of dichloromethane,
Add 1.9 g of 70% m-chloroperbenzoic acid at room temperature,
Stirred for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and then with saturated brine, dried over magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform) to obtain 0.5 g of the target compound as a pale yellow solid. The structure and physical properties of the obtained compound are shown in Table 1.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
Claims (1)
す。ｍ及びｎは同一又は異なつて０〜６を示す。
Ａは硫黄原子、イミノ基、２個のベンゼン環を結
ぶ炭素−炭素結合、スルフイニル基、スルホニル
基、低級アルキレン基、ホルミルイミノ基、酸素
原子又はカルボニル基を示す。Ｘは水素原子又は
ハロゲン原子を示す。R2は水素原子、ハロゲン
原子、低級アルキル基、低級アルコキシ基、アミ
ノ基、ヒドロキシル基、低級アシルアミノ基、低
級アルコキシカルボニル基又はカルボキシル基を
示す。R3は水素原子、ハロゲン原子又は低級ア
ルキル基を示す。〕 で表わされるスルホンアミド誘導体及びその塩。[Claims] 1 General formula: [In the formula, R 1 represents a lower alkyl group or a phenyl group. m and n are the same or different and represent 0 to 6.
A represents a sulfur atom, an imino group, a carbon-carbon bond connecting two benzene rings, a sulfinyl group, a sulfonyl group, a lower alkylene group, a formylimino group, an oxygen atom, or a carbonyl group. X represents a hydrogen atom or a halogen atom. R 2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, a hydroxyl group, a lower acylamino group, a lower alkoxycarbonyl group, or a carboxyl group. R 3 represents a hydrogen atom, a halogen atom, or a lower alkyl group. ] A sulfonamide derivative represented by these and its salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22388088A JPH0272150A (en) | 1988-09-06 | 1988-09-06 | Sulfonamide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP22388088A JPH0272150A (en) | 1988-09-06 | 1988-09-06 | Sulfonamide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0272150A JPH0272150A (en) | 1990-03-12 |
| JPH0567619B2 true JPH0567619B2 (en) | 1993-09-27 |
Family
ID=16805157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP22388088A Granted JPH0272150A (en) | 1988-09-06 | 1988-09-06 | Sulfonamide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0272150A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5545669A (en) * | 1994-06-02 | 1996-08-13 | Adams; Jerry L. | Anti-inflammatory compounds |
| TW523506B (en) | 1996-12-18 | 2003-03-11 | Ono Pharmaceutical Co | Sulfonamide or carbamide derivatives and drugs containing the same as active ingredients |
| GB9702194D0 (en) * | 1997-02-04 | 1997-03-26 | Lilly Co Eli | Sulphonide derivatives |
| FR2788770B1 (en) | 1999-01-21 | 2001-02-16 | Oreal | NOVEL CATIONIC 2-SULFONYLAMINOPHENOLS, THEIR USE AS A COUPLER FOR OXIDATION DYE, COMPOSITIONS COMPRISING THE SAME AND DYEING METHODS |
| KR100751899B1 (en) * | 2006-04-03 | 2007-08-23 | 경상대학교산학협력단 | Novel chalcone derivatives, pharmaceutically acceptable salts, method for preparation and composition containing thereof as an active ingredient for prevention and treatment of diseases induced by glycosidase |
-
1988
- 1988-09-06 JP JP22388088A patent/JPH0272150A/en active Granted
Also Published As
| Publication number | Publication date |
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| JPH0272150A (en) | 1990-03-12 |
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