JPS63112574A - 4-trisubstituted phenyl-2(3h)-thiazolone derivative - Google Patents
4-trisubstituted phenyl-2(3h)-thiazolone derivativeInfo
- Publication number
- JPS63112574A JPS63112574A JP26007486A JP26007486A JPS63112574A JP S63112574 A JPS63112574 A JP S63112574A JP 26007486 A JP26007486 A JP 26007486A JP 26007486 A JP26007486 A JP 26007486A JP S63112574 A JPS63112574 A JP S63112574A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- compound
- mono
- thiazolone
- 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.)
- Pending
Links
- ZQPJESBQCMTNHF-UHFFFAOYSA-N 3-phenyl-1,3-thiazol-2-one Chemical class O=C1SC=CN1C1=CC=CC=C1 ZQPJESBQCMTNHF-UHFFFAOYSA-N 0.000 title claims description 3
- -1 cyano, formyl Chemical group 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 17
- 125000000217 alkyl group Chemical group 0.000 abstract description 14
- 239000003960 organic solvent Substances 0.000 abstract description 10
- 238000001816 cooling Methods 0.000 abstract description 7
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 4
- 150000001340 alkali metals Chemical class 0.000 abstract description 4
- YJZOPBSZDIBXBG-UHFFFAOYSA-N 2-methylthiophene-3-carboxylic acid Chemical compound CC=1SC=CC=1C(O)=O YJZOPBSZDIBXBG-UHFFFAOYSA-N 0.000 abstract description 3
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract description 3
- 230000001754 anti-pyretic effect Effects 0.000 abstract description 3
- 239000002221 antipyretic Substances 0.000 abstract description 3
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 239000003435 antirheumatic agent Substances 0.000 abstract description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 abstract 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract 1
- 229940124605 anti-osteoporosis drug Drugs 0.000 abstract 1
- 229940124347 antiarthritic drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000000921 elemental analysis Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012024 dehydrating agents Substances 0.000 description 5
- 125000004663 dialkyl amino group Chemical group 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 150000002923 oximes Chemical class 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 230000022244 formylation Effects 0.000 description 3
- 238000006170 formylation reaction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-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
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000006263 metalation reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 2
- 229940116357 potassium thiocyanate Drugs 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- YIYKUVVECCMODI-UHFFFAOYSA-N 2-methylpropyl hydrogen carbonate hydrochloride Chemical compound Cl.CC(C)COC(O)=O YIYKUVVECCMODI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UXIWLHNMLDJWMF-UHFFFAOYSA-N 4-phenyl-3h-1,3-thiazol-2-one Chemical compound S1C(O)=NC(C=2C=CC=CC=2)=C1 UXIWLHNMLDJWMF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000486679 Antitype Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-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
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-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
- 230000005856 abnormality Effects 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 238000003287 bathing Methods 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
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006309 butyl amino group Chemical group 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
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 1
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 125000004914 dipropylamino group Chemical group C(CC)N(CCC)* 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- QRNIUENDZLBQKI-UHFFFAOYSA-N ethyl hydrogen carbonate hydrobromide Chemical compound Br.CCOC(O)=O QRNIUENDZLBQKI-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005932 isopentyloxycarbonyl group Chemical group 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([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
- 125000000468 ketone group Chemical group 0.000 description 1
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 description 1
- 229910001641 magnesium iodide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 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
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- GPPYYOFCUVXNNH-UHFFFAOYSA-N methyl hydrogen carbonate;hydrochloride Chemical compound Cl.COC(O)=O GPPYYOFCUVXNNH-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([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
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005933 neopentyloxycarbonyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 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
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004894 pentylamino group Chemical group C(CCCC)N* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical group CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 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
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 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
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は下記一般式（Ｉ）で示される新規な４−トリ置
換フェニル−２（３Ｈ）−チアゾロン誘導体及びその塩
に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel 4-trisubstituted phenyl-2(3H)-thiazolone derivative represented by the following general formula (I) and a salt thereof.
（式中の記号は以下の意味を有する。(The symbols in the formula have the following meanings.
Ｒ１及びＲ３；同−又は異って、）・ロゲン原子又は炭
素数が１乃至３個のアルキル基。R1 and R3; the same or different, ), a rogene atom or an alkyl group having 1 to 3 carbon atoms;
Ｒ２；水酸基、低級アルコキシ基、アミノ基。R2; hydroxyl group, lower alkoxy group, amino group.
モノ若しくはジ低級アルキルアミノ基。Mono- or di-lower alkylamino group.
又はモノ若しくはジ低級アルカノイル アミノ基。or mono- or di-lower alkanoyl Amino group.
Ｒ４：水素原子、ンアノ基、ホルミル基、ヒドロキシイ
ミノメチル基、低級アルコ
キシイミノメチル基、カルボキシ基。R4: hydrogen atom, ano group, formyl group, hydroxyiminomethyl group, lower alkoxyiminomethyl group, carboxy group.
低級アルコキシカルボニル基、カルバ
モイル基、又はモノ若してはジ低級ア
ルキルアミノカルボニル基）
（従来の技術）
本発明者らは、先に抗炎症剤、解熱剤、鎮痛剤、抗関接
炎剤、抗リウマチ剤及び免疫機能調整剤として有用な４
− （３，５−ジーｔｅｒｔ−ブチルー４−ヒドロキシ
フェニル）−２（３Ｈ）−チアゾロン誘導体又はその塩
を見出し、特許出願を行った（特願昭６０−２７２７６
２号）。(lower alkoxycarbonyl group, carbamoyl group, or mono- or di-lower alkylaminocarbonyl group) (Prior art) 4 Useful as a rheumatism agent and immune function regulator
- Discovered (3,5-di-tert-butyl-4-hydroxyphenyl)-2(3H)-thiazolone derivative or its salt and filed a patent application (Japanese Patent Application No. 60-27276
No. 2).
従来、４位にフェニル基を有する２ （３Ｈ）−チアゾ
ロン誘導体の合成例は極めて少ない。わずかに４−炭素
環アリール−５−置換又は未置換アミノアルキル−２（
３Ｈ）−チアゾロン化合物が特公昭５２−６９９２号公
報に開示されており。Conventionally, there have been very few examples of synthesis of 2(3H)-thiazolone derivatives having a phenyl group at the 4-position. Slightly 4-carbocyclic aryl-5-substituted or unsubstituted aminoalkyl-2 (
3H)-thiazolone compounds are disclosed in Japanese Patent Publication No. 52-6992.
この化合物は、抗炎症性、抗アドレナリン性。This compound has anti-inflammatory and anti-adrenergic properties.
抗潰瘍性活性を有することが報告されている。It has been reported to have anti-ulcer activity.
本発明は、これら先願あるいは公知化合物とは、その置
換基を異にする点に化学構造上の特徴を有する新規化合
物を提供するものである。The present invention provides a novel compound that has chemical structural characteristics that differ from these prior applications or known compounds in that its substituents are different.
（解決するための手段） 本発明者らは１種々の新規化合物を創製し。(Means to solve) The present inventors have created various new compounds.
特にリウマチ、関節炎、骨粗鬆症による骨の胃常を改善
する薬理活性を有する化合物をスクリーニングした結果
、中でも頭記一般式（Ｉ）で示される化合物及びその塩
が、優れた薬理活性を有することをつきとめ９本発明に
至った。As a result of screening for compounds that have pharmacological activity to improve bone problems caused by rheumatism, arthritis, and osteoporosis, we found that the compound represented by general formula (I) and its salts have excellent pharmacological activity. 9 The present invention has been achieved.
すなわち９本発明は２頭記一般式（Ｉ）で示される化合
物及びその塩を構成とする。That is, the present invention comprises a compound represented by the general formula (I) and a salt thereof.
本発明化合物（Ｉ）について詳細に説明すると。The compound (I) of the present invention will be explained in detail.
以下の通りである。It is as follows.
本明細書の一般式の定義において、特に断わらない現り
、「低級」なる用語は炭素数が１乃至６個の直鎖又は分
岐状の炭素鎖を意味する。In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.
従って、「低級アルキル基」としては、具体的には例え
ばメチル基、エチル基、プロピル基。Therefore, the "lower alkyl group" specifically includes, for example, a methyl group, an ethyl group, and a propyl group.
イソプロピル基、ブチル基、イソブチル基、 ５ｅｅ−
ブチル基、 ｔｅｒｔ−ブチル基、ペンチル基、イソ
ペンチル基、ネオペンチルｘ、 ｔｅｒｔ−ペンチル
基、１−メチルブチル基、２−メチルブチル基、１，２
−ジメチルプロピル基、ヘキシル基。Isopropyl group, butyl group, isobutyl group, 5ee-
Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl x, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2
-dimethylpropyl group, hexyl group.
イソヘキシル基、■−メチルペンチル基、２−メチルペ
ンチル基、３−メチルペンチル基、 １゜１−ジメチル
ブチル基、１，２−ジメチルブチル基、２，２−ジメチ
ルブチル基、１，３−ジメチルブチル基、２，３−ジメ
チルブチル基、３，３−ジメチルブチル基、１−エチル
ブチル基、２−エチルブチル基、１．Ｌ２−）ジメチル
プロピル基。Isohexyl group, ■-Methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1゜1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl Butyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1. L2-) dimethylpropyl group.
１．２．２− ト’Ｊ メチルプロピル基、１−エチル
−１−メチルプロピル基、１−エチル−２−メチルプロ
ピル基等が挙げられる。1.2.2-t'J Methylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, and the like.
また、「低級アルコキシ基」としては、メトキシ基、エ
トキシ基、プロポキシ基、イソプロポキシ基、ブトキシ
基、イソブトキシ基、 ５ｅｃ−ブトキシ基、 ｔ
ｅｒｔ−ブトキシ基、ペンチルオキシ基、イソペンチル
オキシ基、ネオペンチルオキシ基、 ｔｅｒｔ−ペン
チルオキシ基、ヘキシルオキシ基環炭素数１乃至６個の
直鎖又は分岐状のアルコキシ基が挙げられる。In addition, examples of the "lower alkoxy group" include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, 5ec-butoxy group, t
Examples include ert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, and linear or branched alkoxy groups having 1 to 6 ring carbon atoms.
また、「モノ−若しくはジー低級アルキルアミノ基」は
、アミノ基の一つ又は二つの水素原子が前記「低級アル
キル基」で置換された基を意味する。具体的にはメチル
アミン基、エチルアミノ基、プロピルアミン基、イソプ
ロピルアミノ基、ブチルアミノ基、イソブチルアミノ基
、ペンチルアミノ基、イソペンチルアミノ基、ヘキシル
アミノ基等炭素数が１乃至６個の直鎖又は分岐状のアル
キル基で置換されたモノアルキルアミノ基、ジメチルア
ミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジイ
ンプロピルアミノ基、ジブチルアミノ基、ジアルキルア
ミノ基。Moreover, "mono- or di-lower alkylamino group" means a group in which one or two hydrogen atoms of an amino group are substituted with the above-mentioned "lower alkyl group". Specifically, straight groups having 1 to 6 carbon atoms such as methylamine group, ethylamino group, propylamine group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group, isopentylamino group, hexylamino group, etc. A monoalkylamino group, dimethylamino group, diethylamino group, dipropylamino group, diimpropylamino group, dibutylamino group, dialkylamino group substituted with a chain or branched alkyl group.
ジヘキシルアミノ基等炭素数が１乃至６個の直鎖又は分
岐状のアルキル基でジ置換された対称型のジアルキルア
ミノ基、エチルメチルアミノ基、メチルプロピルアミノ
基、エチルプロピルアミノ基、ブチルメチルアミノ基、
ブチルエチルアミノ基、ブチルプロピルアミノ基等炭素
数カ一■乃至６個の直鎖又は分岐状のアルキル基のうち
相異なるアルキル基でジ置換された非対称型のジアルキ
ルアミノ基が挙げられる。Symmetrical dialkylamino group di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms such as dihexylamino group, ethylmethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group basis,
Examples include asymmetric dialkylamino groups di-substituted with different alkyl groups among linear or branched alkyl groups having 1 to 6 carbon atoms, such as butylethylamino and butylpropylamino groups.
また、低級アルカノイル基としては炭素数が２乃至６個
の直鎖又は分岐状のアルキルカルボニル基が挙げられ、
具体的にはアセチル基、プロピオニル基、ブチリル基、
インブチリル基。In addition, examples of lower alkanoyl groups include linear or branched alkylcarbonyl groups having 2 to 6 carbon atoms,
Specifically, acetyl group, propionyl group, butyryl group,
Imbutyryl group.
バレリル基、インバレリル基、ピバロ’ｆ Ａ４１ヘキ
サノイル基等である。These include valeryl group, invaleryl group, pivalo'f A41 hexanoyl group, and the like.
従って「モノ若しくはジ低級アルカノイルアミノ基」は
、アミン基の一つ又は二つの水素原子が前記「低級アル
カノイル基」で置換された基を意味する。好適にはモノ
低級アルカノイルアミノ基であり、具体的にはアセトア
ミド基。Therefore, "mono- or di-lower alkanoylamino group" means a group in which one or two hydrogen atoms of the amine group are substituted with the above-mentioned "lower alkanoyl group". Preferably it is a mono-lower alkanoylamino group, specifically an acetamido group.
プロピオンアミド基、ブチリルアミノ基、イソブチリル
アミノ基、ビバロイルアシノ基、ヘキサノイルアミノ基
等が挙げられる。Examples include a propionamide group, a butyrylamino group, an isobutyrylamino group, a bivaloylacino group, a hexanoylamino group, and the like.
「低級アルコキシイミノメチル基」は、ヒドロキシイミ
ノメチル基のヒドロキシ基の水素原子が前記「低級アル
キル基」で置換した基であり、具体的には、メトキンイ
ミノメチル基、エトキシイミノメチル基、プロポキンイ
ミノメチル基、イソプロポキシイミノメチル基、ブトキ
シイミノメチル基、 ｔｅｒｔ−ブトキシイミノメチ
基、ペンチルオキシイミノメチル基、ヘキシルオキシイ
ミノメチル基等の直鎖又は分岐状の低級アルキル基で置
換したヒドロキシイミノメチル基が例示される。A "lower alkoxyiminomethyl group" is a group in which the hydrogen atom of the hydroxyl group of a hydroxyiminomethyl group is substituted with the above-mentioned "lower alkyl group". Hydroxyimino substituted with a linear or branched lower alkyl group such as quiniminomethyl group, isopropoxyiminomethyl group, butoxyiminomethyl group, tert-butoxyiminomethyl group, pentyloxyiminomethyl group, hexyloxyiminomethyl group, etc. A methyl group is exemplified.
さらに、「低級アルコキシカルボニル基」トしては、メ
トキシカルボニル基、エトキシカルボニル基、プロポキ
シカルボニル基、イソプロポキシカルボニル基、ブトキ
シカルボニル基。Furthermore, the "lower alkoxycarbonyl group" includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, and a butoxycarbonyl group.
インブトキシカルボニル基、 ５ｅｅ−ブトキシ力／ｌ
／ ホ＝ル、Ｓ 、 ｔｅｒｔ −フ）キシカルボニ
ル基、ペンチルオキシカルボニル基、イソペンチルオキ
シカルボニル基、ネオペンチルオキシカルボニルｇ、ｔ
ｅｒｔ−ヘンチルオキシカルボニル基、ヘキシルオキシ
カルボニル基等カルボキシ基と炭素数が１乃至６個の直
鎖又は分岐状の低級アルコールとエステル形成された基
が挙げられる。Imbutoxycarbonyl group, 5ee-butoxy power/l
/ hole, S, tert-f)oxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl g, t
Examples include groups in which an ester is formed between a carboxy group and a linear or branched lower alcohol having 1 to 6 carbon atoms, such as ert-hentyloxycarbonyl group and hexyloxycarbonyl group.
また、「モノ若しくはジ低級アルキルアミノカルボニル
基」はカルバモイル基の一つ又は二つの水素原子が前記
「低級アルキル基」での置換した基を意味し、具体的に
は、メチルアミノカルボニル基、エチルアミノカルボニ
ル基、プロピルアミノカルボニル基、イソプロピルアミ
ノカルボニル基、ブチルアミノカルボニル基。In addition, "mono- or di-lower alkylaminocarbonyl group" means a group in which one or two hydrogen atoms of a carbamoyl group are substituted with the above-mentioned "lower alkyl group", and specifically, methylaminocarbonyl group, ethyl Aminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group.
ペンチルアミノカルボニル基、ヘキシルアミノカルボニ
ル基等のカルボニル基とモノアルキルアミノ基とがアミ
ド結合したモノアルキルアミノカルボニル基；ジメチル
アミノカルボニル基。A monoalkylaminocarbonyl group in which a carbonyl group such as a pentylaminocarbonyl group or a hexylaminocarbonyl group and a monoalkylamino group are bonded through an amide bond; a dimethylaminocarbonyl group.
ジエチルアミノカルボニル基、ジプロピルアミノカルボ
ニル基、ジブチルアミノカルボニル基。Diethylaminocarbonyl group, dipropylaminocarbonyl group, dibutylaminocarbonyl group.
ジペンチルアミノカルボニル基、ジヘキシルアミノカル
ボニル基等のカルボニル基と対称型のジアルキルアミノ
基とがアミド結合した対称型シアルギルアミノカルボニ
ル基；ヤ、エチルメチルアミノカルボニル基、ブチルプ
ロピルアミノカルボニル基、エチルプロピルアミノカル
ボニル基、ブチルメチルアミノカルボニル基、ブチルエ
チルアミノカルボニル基、ブチルプロピルアミノカルボ
ニル基等のカルボニル基と非対称型のジアルキルアミノ
基とがアミド結合した非対称型ジアルキルアミノカルボ
ニル基が挙ケラれる。A symmetrical sialgylaminocarbonyl group in which a carbonyl group such as a dipentylaminocarbonyl group or a dihexylaminocarbonyl group and a symmetrical dialkylamino group are bonded through an amide bond; Y, ethylmethylaminocarbonyl group, butylpropylaminocarbonyl group, ethylpropylamino Examples include asymmetric dialkylaminocarbonyl groups in which an amide bond is formed between a carbonyl group and an asymmetric dialkylamino group, such as a carbonyl group, a butylmethylaminocarbonyl group, a butylethylaminocarbonyl group, a butylpropylaminocarbonyl group, and the like.
「ハロゲン原子」としては、具体的には塩素原子、臭素
原子等が挙げられる。Specific examples of the "halogen atom" include a chlorine atom, a bromine atom, and the like.
本発明化合物（Ｉ）においては、ケト型、エノール型の
互変異性体が、またイミノメチル基や低級アルコキシイ
ミノメチル基であるときは。In the compound (I) of the present invention, when the keto type or enol type tautomer is an iminomethyl group or a lower alkoxyiminomethyl group.
ｓｙｎ型、 ａｎｔｉ型の異性体が存在する。Syn-type and anti-type isomers exist.
また２本発明化合物（Ｉ）は、不整炭素原子を含む置換
基で置換した化合物である場合には。Further, in the case where the compound (I) of the present invention is a compound substituted with a substituent containing an asymmetric carbon atom.
光学異性体が存在する。Optical isomers exist.
本発明には本発明化合物（Ｉ）の各種の立体異性体及び
その混合物の全てが含まれる。The present invention includes all various stereoisomers of the compound (I) of the present invention and mixtures thereof.
上記一般式（Ｉ）で示される本発明化合物は塩を形成す
る。本発明には化合物（Ｉ）の塩も含まれ、このような
塩としては塩酸、臭化水素酸。The compound of the present invention represented by the above general formula (I) forms a salt. The present invention also includes salts of compound (I), such as hydrochloric acid and hydrobromic acid.
硫酸、硝酸やリン酸などの無機酸や、ギ酸、酢酸、シュ
ウ酸、クエン酸、コハク酸、フマール酸、マレイン酸、
酒石酸、メタンスルホン酸。Inorganic acids such as sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, oxalic acid, citric acid, succinic acid, fumaric acid, maleic acid,
Tartaric acid, methanesulfonic acid.
エタンスルホン酸などの有機酸との酸付加塩などが挙げ
られる。Examples include acid addition salts with organic acids such as ethanesulfonic acid.
本発明化合物（Ｉ）は種々の方法により合成することが
できる。代表的な製造法を以下に例示する。Compound (I) of the present invention can be synthesized by various methods. Typical manufacturing methods are illustrated below.
（ａ）環化
Ｍ−８ＣＮ （Ｉｎ）
又はアルカリ金属を意味する）
本発明化合物中Ｒ４が水素原子である化合物は、一般式
（ＩＩ）で示されるアセトフェノン類と、一般式（ｍ）
で示されるチオシアン酸類とを反応させるか、または式
（ＩＶ）で示されるアンモニウムチオカーバメートとを
反応させることにより製造される。(a) Cyclized M-8CN (In) or an alkali metal) The compounds of the present invention in which R4 is a hydrogen atom include acetophenones represented by the general formula (II) and acetophenones represented by the general formula (m).
It is produced by reacting with a thiocyanic acid represented by the formula (IV) or an ammonium thiocarbamate represented by the formula (IV).
ここに、Ｘが示すハロゲン原子としてはヨウ素原子、臭
素原子、塩素原子等が９Ｍが示すアルカリ金属としては
ナトリウム、カリウム等が挙げられる。Here, examples of the halogen atom represented by X include iodine atom, bromine atom, chlorine atom, etc., and examples of the alkali metal represented by 9M include sodium, potassium, etc.
反応は、化合物（ＩＴＴ）の有機溶媒（例えばアセトン
、メチルエチルケトン、メタノール。The reaction is carried out using a compound (ITT) in an organic solvent (eg acetone, methyl ethyl ketone, methanol).
エタノール等の）溶液に、チオシアン酸アルカリ水溶液
、チオシアン酸と塩基との混合物。(e.g., ethanol), an aqueous alkaline thiocyanate solution, and a mixture of thiocyanate and a base.
又はアンモニウムチオカーバメートのアルコール溶液を
加え、室温下又は加熱下に実施される。Alternatively, an alcoholic solution of ammonium thiocarbamate is added and the reaction is carried out at room temperature or under heating.
用いられる塩基としてはナトリウム、カリウムなどのア
ルカリ金属アルコラード、水酸化ナトリウム、水酸化カ
リウムが好適である。Suitable bases to be used are alkali metal alcoholides such as sodium and potassium, sodium hydroxide, and potassium hydroxide.
（ｂ） ホルミル化
（式中Ｒ１、Ｒ２及びＲ３は前記の意味を有する。）一
般式（Ｉｂ）で示されるホルミル化合物は、化化合物（
Ｉａ）にオキシ塩化リン、オキザリルクロホルミル基を
導入するヴイルスマイアー（Ｖｉ ｌｓｍｅ ｉｅｒ
）反応により合成することができる。(b) Formylation (wherein R1, R2 and R3 have the above-mentioned meanings) The formyl compound represented by the general formula (Ib) is a formyl compound (
Vilsmeier introduces phosphorus oxychloride and oxalylchloroformyl groups into Ia).
) can be synthesized by reaction.
反応はｒチルホルムアミド等にオキシ塩化リン等を冷却
下に加えた後、化合物（Ｉａ）を加えるかあるいは化合
物（Ｉａ）＃チルホルムアミド等に溶解し、これにオキ
シ塩化リン等を滴下して行うのが好適である。The reaction is carried out by adding phosphorus oxychloride, etc. to r-chillformamide, etc. under cooling, then adding compound (Ia), or dissolving compound (Ia) in #chillformamide, etc., and dropping phosphorus oxychloride, etc. thereto. is preferable.
Ｒ１悶−
一タ慢チルホルムアミドは溶媒をも兼ねることができる
が、さらに反応に不活性な他の有機溶媒例えばジクロロ
メタン、クロロホルム、ベンゼンやジクロロベンゼン等
を用いることもできる。Although R1 chloride-chillformamide can also serve as a solvent, other organic solvents that are inert to the reaction, such as dichloromethane, chloroform, benzene, and dichlorobenzene, can also be used.
反応温度は室温乃至加温下に設定するのが望ましい。The reaction temperature is desirably set at room temperature or under heating.
（ｃ） オキシム化
（式中Ｒ１、Ｒ２及びＲ３は前記の意味を有し、Ｒ５は
水素原子又は低級アルキル基を意味する）一般式（Ｉｃ
）で示されるオキシムは、一般式（Ｉｂ）で示されるア
ルデヒドに一般式（Ｖ）で示されるヒドロキシルアミン
類を作用させることに製造することができる。(c) Oxime formation (in the formula, R1, R2 and R3 have the above-mentioned meanings, and R5 means a hydrogen atom or a lower alkyl group) general formula (Ic
The oxime represented by ) can be produced by reacting an aldehyde represented by general formula (Ib) with a hydroxylamine represented by general formula (V).
反応は、化合物（Ｉｂ）と、化合物（Ｉｂ）に対して；
−−＼
ルホルムアミド、ジクロロメタン、ジクロロニータン、
クロロホルム、ヒリシン、ベンゼン、酢酸エチル、アセ
トニトリル、エーテル、メタノール、エタノール等の反
応に不活性な有機溶媒中、塩基の存在下９通常室温下に
行うのが好ましい。The reaction is for compound (Ib) and compound (Ib);
--＼ Formamide, dichloromethane, dichloronitane,
The reaction is preferably carried out in an organic solvent inert to the reaction, such as chloroform, hisricin, benzene, ethyl acetate, acetonitrile, ether, methanol, ethanol, etc., in the presence of a base, usually at room temperature.
用いられる塩基としては、ピリジン、ピコリン、ルチジ
ン、 Ｎ、Ｎ−ジメチルアニリン、水酸化ナトリウム、
水酸化カリウム等カー挙げられる。Bases used include pyridine, picoline, lutidine, N,N-dimethylaniline, sodium hydroxide,
Examples include potassium hydroxide.
ピリジンは溶媒を兼ねることができる。Pyridine can also serve as a solvent.
（ｄ） シアン化
（Ｔｄ）
（式中、Ｒ’ｌＲ２及びＲ３は前記と同じ意味を有する
。(d) Cyanide (Td) (wherein R'lR2 and R3 have the same meanings as above.
一般式（Ｉｄ）で示されるニトリル化合物は一般式（Ｉ
ｅ’）で示されるオキシム化合物に脱水剤を作用させる
ことにより製造される。The nitrile compound represented by the general formula (Id) is a nitrile compound represented by the general formula (Id).
It is produced by treating the oxime compound represented by e') with a dehydrating agent.
反応は、ジクロロメタン、ジクロロエタン。The reaction is dichloromethane and dichloroethane.
クロロホルム、ヒリシン、ベンゼン、酢酸エチル、アセ
トニトリル、エーテル、ジオキサン等の有機溶媒中、化
合物（Ｉｃ’）に、オキザリルクロリド、塩化チオニル
等の脱水剤を加え、室温乃至加温下に実施するのが有利
である。ピリジン。A dehydrating agent such as oxalyl chloride or thionyl chloride is added to compound (Ic') in an organic solvent such as chloroform, hisricin, benzene, ethyl acetate, acetonitrile, ether, or dioxane, and the reaction is carried out at room temperature or under heating. It's advantageous. Pyridine.
ピコリン、ルチジン、 Ｎ、Ｎ−ジメチルアニリン等
の塩基を添加して実施することもできる。It can also be carried out by adding a base such as picoline, lutidine, N,N-dimethylaniline and the like.
なお、このニトリル化合物（Ｉｄ）は、一般式（Ｉｂ
）で示されるホルミル化合物にヒドロキシルアミン鉱酸
塩を、オキシム化及び脱水反応に共通の有機溶媒中、脱
水剤の存在下で反応させることにより、特にオキシム化
合物を単離することなく、直接製造することができる。In addition, this nitrile compound (Id) has the general formula (Ib
) is directly produced without isolating the oxime compound by reacting the hydroxylamine mineral salt with the formyl compound in the presence of a dehydrating agent in an organic solvent common to oxime formation and dehydration reactions. be able to.
この反応においてピリジン含有有機溶媒を用いるときは
、特に脱水剤を必要としない。When a pyridine-containing organic solvent is used in this reaction, no dehydrating agent is particularly required.
また、このニトリル化合物（Ｉｄ）は、オキザリルクロ
リドや温化チオニル等がホルミル化における縮合剤と脱
水反応の脱水剤を兼ねることができ、ホルミル化、オキ
シム化、脱水反応に共通の有機溶媒を用いピリジンを添
加し、かつヒドロキシルアミン鉱酸塩を用いるときは、
ホルミル化合物やオキシム化合物を特に単離することな
く化合物（Ｉａ）より、直接製造することカー可能であ
る。In addition, this nitrile compound (Id), such as oxalyl chloride and warmed thionyl, can serve as a condensing agent in formylation and a dehydrating agent in dehydration reactions, and can be used as an organic solvent common to formylation, oxime formation, and dehydration reactions. When adding pyridine and using hydroxylamine mineral salt,
It is possible to directly produce formyl compounds and oxime compounds from compound (Ia) without particularly isolating them.
（ｅ） エーテルの開裂
（Ｔｅ） （Ｔｆ）（式中、
Ｒ’ｌ Ｒ２＋ Ｒ３及びＲ４は前記の意味を有し。(e) Cleavage of ether (Te) (Tf) (wherein,
R'l R2+ R3 and R4 have the meanings given above.
Ｒ６は低級アルキル基を意味する）
一般式（Ｉｆ）で示されろ４−ヒドロキシフエニこの反
応は化合物（Ｉｅ）にピリジン塩酸塩、臭化水素、ヨウ
化水素（赤リン共存下を含む）、トリフルオロ酢酸、濃
塩酸、ヨウ化マグネシウムエーテラート、塩化アルミニ
ウム、臭化アルミニウムなどを常温乃至加熱下に作用さ
せることにより行われる。(R6 means a lower alkyl group) This reaction is shown by the general formula (If). 4-Hydroxyphenylene is added to compound (Ie) with pyridine hydrochloride, hydrogen bromide, and hydrogen iodide (including in the presence of red phosphorus). , trifluoroacetic acid, concentrated hydrochloric acid, magnesium iodide etherate, aluminum chloride, aluminum bromide, etc., at room temperature or under heating.
（ｆ） 直接メタル化によるカルボキシ化合物の合成
（Ｔａ） （Ｔ
ｇ）（式中ＨＲ’＋Ｒ２及びＲ３は前記の意味を有する
）一般式（Ｉｇ）で示されるカルボキシ化合物は。(f) Synthesis of carboxy compounds by direct metalation (Ta) (T
g) A carboxy compound represented by the general formula (Ig) (wherein HR'+R2 and R3 have the above-mentioned meanings).
化合物（Ｉａ）の直接メタル化により合成することがで
きる。It can be synthesized by direct metalation of compound (Ia).
反応は、化合物（Ｉｇ）を反応に不活性な有機溶媒９例
えばエーテル、テトラヒドロフラン、１゜２−ジメトキ
シエタン等中でｎ−ブチルリチウムやフェニルリチウム
等のアルキルまたはアリリチウムと反応させ９次いで二
酸化炭素を用させることにより行われる。The reaction is carried out by reacting compound (Ig) with an alkyl or alilithium such as n-butyllithium or phenyllithium in an inert organic solvent such as ether, tetrahydrofuran, 1.2-dimethoxyethane, etc.9 and then adding carbon dioxide. This is done by using
反応は通常冷却下に行うのが好適である。なお、化合物
（Ｉｇ）は、化合物（Ｉｂ）や（Ｉｄ）を通常の方法に
よって酸化して製造することもできる。The reaction is usually preferably carried out under cooling. Note that compound (Ig) can also be produced by oxidizing compound (Ib) or (Id) by a conventional method.
（ｇ） アミド化Ａ法 （Ｔｈ） （式中Ｊ Ｒ’＋Ｒ２及びＲ３は前記の意味を有し。(g) Amidation method A (Th) (In the formula, J R'+R2 and R3 have the above meanings.
Ｒ７及びＲ８は同−又は異なって、水素原子。R7 and R8 are the same or different and are hydrogen atoms.
低級アルキルキ基又は低級アルカノイル基を意味する）
本発明化合物中一般式（Ｉｈ）で示される化合物は、一
般式（Ｉｇ）で示されるカルボン酸又はその反応性誘導
体と一般式（■）で示されるアミン類とを反応させるこ
とにより製造される。Among the compounds of the present invention, the compound represented by the general formula (Ih) is a compound represented by the general formula (Ig) or a reactive derivative thereof, and the compound represented by the general formula (■). Manufactured by reacting with amines.
化合物（Ｉｇ）の反応性誘導体としては、酸クロライド
、酸ブロマイド等の酸ハライド；酸アジド；Ｎ−ヒドロ
キシベンゾトリアゾールのエステル、ｐ−ニトロフェニ
ルエステル、ｐ−クロルフェニルエステル等の活性エス
テル；対称型酸無水物；混合酸無水物例例えばイソブチ
ル炭酸クロライド、メチル炭酸クロライド、エチル炭酸
ブロマイドの如きアルキル炭酸ハライドと化合物（Ｉｇ
）を反応させて得られるアルキル炭酸混合酸無水物等で
ある。Reactive derivatives of compound (Ig) include acid halides such as acid chloride and acid bromide; acid azides; active esters such as N-hydroxybenzotriazole esters, p-nitrophenyl esters, and p-chlorophenyl esters; symmetrical types; Acid anhydride; Mixed acid anhydride, such as alkyl carbonate halide such as isobutyl carbonate chloride, methyl carbonate chloride, ethyl carbonate bromide, and compound (Ig
) is an alkyl carbonic acid mixed acid anhydride obtained by reacting.
化合物（Ｉｇ）を遊離のカルボン酸で反応させるときは
、喝クツクロヘキシルカルポジイド、ｌ、１−カルボニ
ルジイミダゾール等の縮合剤の存在下に実施するのが有
利である。When compound (Ig) is reacted with a free carboxylic acid, it is advantageous to carry out the reaction in the presence of a condensing agent such as cyclohexylcarpodiide, 1,1-carbonyldiimidazole, or the like.
また２反応性誘導体を作用させるときは１反応を促進さ
せるためにトリエチルアミン、ピリジン、ピコリン、ル
チジン、 Ｎ、Ｎ−ジメチルアニリン如き有機塩基、あ
るいは炭酸カリウム。In addition, when using two-reactive derivatives, an organic base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, or potassium carbonate is used to promote one reaction.
炭酸ナトリウム、水酸化ナトリウム、水酸化カリウムの
如き塩基の存在下に行うのが有利な場合力′−ある。It may be advantageous to carry out the reaction in the presence of a base such as sodium carbonate, sodium hydroxide, potassium hydroxide.
溶媒や温度条件等は用いられる反応性誘導体の種類など
によって適宜選択され、設定される。The solvent, temperature conditions, etc. are appropriately selected and set depending on the type of reactive derivative used.
エーテル、テトラヒドロフラン、クロロホルム。Ether, tetrahydrofuran, chloroform.
ジクロルメタン、ジクロルエタン等の有機溶媒あるいは
これらの混合溶媒が挙げられる。Examples include organic solvents such as dichloromethane and dichloroethane, and mixed solvents thereof.
（ｈ） アミド化Ｂ法
（Ｒ１、Ｒ３及びＲ４は前記の意味を有し Ｒ９及びＲ
Ｉ Ｏは同−又は異って、低級アルキル基を意味する）
一般式（■ｊ）や（Ｉｋ）で示される化合物は、一般式
（Ｉｉ）の化合物と、一般式（■）の化合物又はその反
応性誘導体とを反応させ９次いで一般式（）■）で示さ
れるカルボン酸又はその反応性誘導体をさらに作用させ
ることにより製造される。(h) Amidation method B (R1, R3 and R4 have the above meanings, R9 and R
The compounds represented by the general formula (■j) or (Ik) are the compound of the general formula (Ii) and the compound of the general formula (■) or It is produced by reacting with a reactive derivative thereof, and then further reacting with a carboxylic acid represented by the general formula (2) or a reactive derivative thereof.
反応は前記（Ｉｇ）法と同様に実施できる。The reaction can be carried out in the same manner as the method (Ig) above.
その他の製造法
Ｒ２がモノ若しくはジ低級アルキルアミノ基である化合
物やＲ４がモノ若しくはジ低級アルキルアミノカルボニ
ル基である化合物は、一般的なＮ−アルキル化反応によ
り合成することができる。反応に関与する基が別に存在
するときや。Other Production Methods Compounds in which R2 is a mono- or di-lower alkylamino group and compounds in which R4 is a mono- or di-lower alkylaminocarbonyl group can be synthesized by a general N-alkylation reaction. When there are other groups involved in the reaction.
副反応を抑制するために保護基を用いて実施するのネ有
利である。It is advantageous to carry out the reaction using protective groups in order to suppress side reactions.
上記に例示した種々の製造法により製造された本発明化
合物は遊離のまま、塩として製造されろときは塩のまま
あるいは遊離化合物を常法によりその塩となし単離され
精製される。The compounds of the present invention produced by the various production methods exemplified above are isolated and purified either as free compounds, or when produced as salts, as salts, or by converting the free compounds into salts by conventional methods.
単離、精製は戸数、抽出、再結晶、各種カラムクロマト
グラフィー等通常用いられる化学操作を適用してなされ
る。Isolation and purification are performed by applying commonly used chemical operations such as extraction, recrystallization, and various column chromatography.
（発明の効果）
本発明によって提供される化合物（Ｉ）及びその塩は、
優れた抗炎症作用、解熱鎮痛作用、あるいはりウマチ、
関節炎、骨粗懸症等による骨の異常を改善する作用を有
するので、抗炎症剤。(Effect of the invention) Compound (I) and its salt provided by the present invention are:
Excellent anti-inflammatory effect, antipyretic and analgesic effect, and rheumatoid arthritis,
An anti-inflammatory agent because it has the effect of improving bone abnormalities caused by arthritis, osteoporosis, etc.
解熱剤、鎮痛剤、抗リウマチ剤、抗関節炎剤。Antipyretic, analgesic, antirheumatic, antiarthritic.
抗骨粗鬆剤として有用である。It is useful as an anti-osteoporosis agent.
本発明化合物（Ｉ）及びその塩は、そのままもしくは自
体公知の薬学的に許容されうる担体。The compound (I) of the present invention and its salts may be used as such or in a known pharmaceutically acceptable carrier.
賦形剤などと混合した医薬組成物として使用に供される
。投与は錠剤、カプセル剤、散剤、顆粒剤、丸剤等の経
口投与、注射剤、ンロンブ剤。It is used as a pharmaceutical composition mixed with excipients and the like. Administration is by oral administration such as tablets, capsules, powders, granules, pills, injections, and tablets.
軟膏剤、坐剤等の非経口投与のいずれであってもよい。Parenteral administration such as ointments and suppositories may be used.
投与量は投与対象、投与ルート、症状等によって異なる
が通常成人１日当り１〜５００■、好ましくは１０〜１
００ ｍｇであり、これを１日２〜４回に分げて経口又
は非経口投与する。The dosage varies depending on the subject, route of administration, symptoms, etc., but is usually 1 to 500 μl per day for adults, preferably 10 to 1 μl per day.
00 mg, which is administered orally or parenterally in 2 to 4 divided doses a day.
（実施例）
つぎに、実施例により本発明の化合物及びその製造法を
説明する。(Example) Next, the compound of the present invention and its manufacturing method will be explained with reference to Examples.
実施例１
５−シアノ−４−（４−メトキシ−３，５−ジメチルフ
ェニル）−２（３Ｈ）−チアゾロンルムアミド１０ｇと
１．２−ジクロロエタン２ｍ７の混−′−液を滴下する
。滴下終了後室温にて３０分間攪拌する。４−フェニル
−２（３Ｈ）−チアゾロン１．８ｇを熱還流する。反応
液を冷却後、１０％炭酸カリウム水溶液５０ｍ１に分散
し、１５〜２０分間攪拌する。希塩酸で酸性とした後ク
ロロホルムで抽出する。抽出液７０．６５ ｇを得た。Example 1 A mixed solution of 10 g of 5-cyano-4-(4-methoxy-3,5-dimethylphenyl)-2(3H)-thiazolonelumamide and 2 m7 of 1,2-dichloroethane was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. 1.8 g of 4-phenyl-2(3H)-thiazolone is heated to reflux. After cooling the reaction solution, it is dispersed in 50 ml of 10% aqueous potassium carbonate solution and stirred for 15 to 20 minutes. After acidifying with dilute hydrochloric acid, extract with chloroform. 70.65 g of extract was obtained.
融点 １９４−１９６℃（エタノール）元素分析値（Ｃ
ｌ５ＨＩ２Ｎ２０２Ｓ ： ２６０．３１６として）Ｃ
（％） Ｈ（％） Ｎ（％）理論値 ５９
．９８ ’４．６５ １０．７６実験値 ５９
．７７ ４．７４ １０．６５実施例２
実施例１と同様にして以下の化合物を得た。Melting point 194-196℃ (ethanol) Elemental analysis value (C
l5HI2N202S: 260.316)C
(%) H (%) N (%) Theoretical value 59
．． 98 '4.65 10.76 Experimental value 59
．． 77 4.74 10.65 Example 2 The following compound was obtained in the same manner as in Example 1.
５−シアノ−４−（３，５−ジイソプロピル−４−ヒド
ロキシフェニル） −２（３Ｈ）−チアゾロン融点 ２
６６−２６７℃（クロロホルム）元素分析値（Ｃｌ６Ｈ
１８Ｎ２０Ｓとして）Ｃ（％） Ｈ（％） Ｎ
（％）理論値 ６３，５５ ６．００ ９．２６
実験値 ６３．４３ ６．０８ ９．１１実施例３
４−（３，５−ジメチル−４−ヒドロキシフェニル）中
で油温１６０℃の油浴中にて２〜３時間攪拌する。5-cyano-4-(3,5-diisopropyl-4-hydroxyphenyl)-2(3H)-thiazolone Melting point 2
66-267℃ (chloroform) elemental analysis value (Cl6H
As 18N20S) C (%) H (%) N
(%) Theoretical value 63,55 6.00 9.26
Experimental value 63.43 6.08 9.11 Example 3 Stir in 4-(3,5-dimethyl-4-hydroxyphenyl) in an oil bath at an oil temperature of 160°C for 2 to 3 hours.
冷却後水を加えた後、酢酸エチルで抽出する。抽出液を
１規定水酸化ナトリウムで抽出する。水層を希塩酸で酸
性とする。生じた沈殿を戸数する。After cooling, add water and extract with ethyl acetate. Extract the extract with 1N sodium hydroxide. Acidify the aqueous layer with dilute hydrochloric acid. Count the resulting precipitate.
を得た。I got it.
融点 １９７−１９８°Ｃ（クロロホルム）元素分析値
（ＣｏＨｏＯ３： ２２１．２８０として）Ｃ（％）
Ｈ（％） Ｎ（％）理論値 ５９，７１
５．０１ ６．３３実験値 ５９．６９ ５，
０３ ６．２０実施例４
実施例３と同様にして以下の化合物を得た。Melting point 197-198°C (chloroform) Elemental analysis value (as CoHoO3: 221.280) C (%)
H (%) N (%) Theoretical value 59,71
5.01 6.33 Experimental value 59.69 5,
03 6.20 Example 4 The following compound was obtained in the same manner as in Example 3.
５−シアノ−４−（３，５−ジメチル−４−ヒドロキシ
フェニル）−２（３Ｈ）−チアゾロン融点 〉３００°
Ｃ（メタノール）
Ｃ（％） Ｈ（％） Ｎ（％）理論値 ５５
，２９ ４．４８ １０．７５実験値 ５’５，
２１ ４．２１ １０．７５実施例５
４−（３，５−ジメチル−４−メトキシフェニル）−２
（３Ｈ）−チアゾロン
２−プロモー３’、５’−ジメチル−４′−メトキシ−
アセトフェノ７４ｇをアセトン３０ｍ１に溶解する。チ
オシアン酸カリウム１．５３ｇを水３ｍｌに溶解した溶
液を滴下する。滴下終了後１〜１．５時間室温で攪拌す
る。反応液を減圧濃縮し、残渣にエタノール３０ｍ１゜
濃塩酸３ｍｌを加え、６〜１０時間加熱還流する。冷却
後、生じた沈殿を戸取する。沈殿をエタノールより再結
晶して ４−（３，５−ジメチル−４−メトキシフェニ
ル）−２（３Ｈ）−チアゾロン１．０ｇヲ４だ。5-Cyano-4-(3,5-dimethyl-4-hydroxyphenyl)-2(3H)-thiazolone Melting point 〉300°
C (methanol) C (%) H (%) N (%) Theoretical value 55
,29 4.48 10.75Experimental value 5'5,
21 4.21 10.75 Example 5 4-(3,5-dimethyl-4-methoxyphenyl)-2
(3H)-thiazolone 2-promo 3',5'-dimethyl-4'-methoxy-
Dissolve 74 g of acetopheno in 30 ml of acetone. A solution of 1.53 g of potassium thiocyanate dissolved in 3 ml of water is added dropwise. After the dropwise addition is completed, the mixture is stirred at room temperature for 1 to 1.5 hours. The reaction solution is concentrated under reduced pressure, 30 ml of ethanol and 3 ml of concentrated hydrochloric acid are added to the residue, and the mixture is heated under reflux for 6 to 10 hours. After cooling, collect the resulting precipitate. The precipitate was recrystallized from ethanol to yield 1.0 g of 4-(3,5-dimethyl-4-methoxyphenyl)-2(3H)-thiazolone.
融点 ２２６−２２７°Ｇ（エタノール）元素分析イ真
（Ｃ，２Ｈ３３Ｎ０２Ｓ：２３５．３０７として）Ｃ（
％） Ｈ（％） Ｎ（％）理論値 ６１，
２５ ５．５７ ５．９５実験値 ６１．２０
５，５８ ５．９２実施例６〜７
実施例５と同様にして以下の化合物を得た。Melting point: 226-227°G (ethanol) Elemental analysis (as C, 2H33N02S: 235.307) C (
%) H (%) N (%) Theoretical value 61,
25 5.57 5.95 Experimental value 61.20
5,58 5.92 Examples 6 to 7 The following compounds were obtained in the same manner as in Example 5.
４−（３，５−ジブロモ−４−アニリノ） −２（３Ｈ
）−チアゾロン
融点 ２４６℃（分解）（アセトン）
元素分析値（ＣｇＨ６Ｎ２０ＳＢｒ、、 Ｈ４Ｃ３Ｈａ
Ｏとして）Ｃ（％） Ｈ（％） Ｎ（％） Ｓ（％）
Ｂｒ（％）理論値 ３１．６９ ２．２２７，７８
８．８９ ４４．４８実験値 ３１．３５ １．８３
７，６９ ９．１９ ４４．６１実施例７
４−（３−アセチルアミノ−２，４−ジエチルフェニル
）−２（３Ｈ）−チアゾロン
融点 ２５３−２５５°Ｃ（アセトン）元素分析値（Ｃ
Ｉ５Ｈ１８Ｎ２０２Ｓとして）Ｃ（％） Ｈ（％）
Ｎ（％）Ｓ（％）理論値 ６２，０４ ６．２５ ９
．６’５ １１．０４実験値 ６２．００ ６．２３
９．２７ １１．０３実施例８
臭素１．２ ｍｌを滴下する。ＴＬＣで原料の消失を確
認した後、減圧濃縮する。残渣をアセトン５０に溶解す
る。チオシアン酸カリウム２．３ｇを３ｍｌに溶解した
溶液を滴下する。室温で一時間攪拌した後、生じた沈殿
を戸数する。涙液を減圧濃縮する。残渣にエタノール５
０ｍ７及び濃塩酸５＋＋＋ｔを加え終夜加熱還流する。4-(3,5-dibromo-4-anilino)-2(3H
)-thiazolone Melting point 246℃ (decomposition) (acetone) Elemental analysis value (CgH6N20SBr, H4C3Ha
(as O) C (%) H (%) N (%) S (%)
Br (%) theoretical value 31.69 2.227,78
8.89 44.48 Experimental value 31.35 1.83
7,69 9.19 44.61 Example 7 4-(3-acetylamino-2,4-diethylphenyl)-2(3H)-thiazolone Melting point 253-255°C (acetone) Elemental analysis value (C
As I5H18N202S) C (%) H (%)
N (%) S (%) Theoretical value 62.04 6.25 9
．． 6'5 11.04 Experimental value 62.00 6.23
9.27 11.03 Example 8 Add 1.2 ml of bromine dropwise. After confirming the disappearance of the raw materials by TLC, the mixture is concentrated under reduced pressure. Dissolve the residue in 50% acetone. A solution of 2.3 g of potassium thiocyanate dissolved in 3 ml is added dropwise. After stirring for one hour at room temperature, the resulting precipitate was collected. Concentrate tear fluid under reduced pressure. Add 5 ethanol to the residue
Add 0 m7 and 5++t of concentrated hydrochloric acid, and heat under reflux overnight.
減圧濃縮後、残渣をシリカゲルクロマトに付ス。クロロ
ホルム−メタノールにて浴出し粗製物３４０ｇを得た。After concentration under reduced pressure, the residue was subjected to silica gel chromatography. 340 g of a crude product was obtained by bathing with chloroform-methanol.
さらにベンゼンより再結晶し。Furthermore, it is recrystallized from benzene.
４−（３，５−ジイソプロピル−４−ヒドロキシフェニ
ル）−２（３Ｈ）−チアゾロン１．５ｇを得た。1.5 g of 4-(3,5-diisopropyl-4-hydroxyphenyl)-2(3H)-thiazolone was obtained.
融点 １８７ｊ１８８°Ｃ（ベンゼン）元素分析値（Ｃ
ｌ５ＨＩＱＮ ０２Ｓとして）Ｃ（％） Ｈ（％）Ｎ
（％＞ Ｓ（％）理論値 ６４．．９４ ６，９０
５．０５ １１．５６実験値 ６４，９６ ６．９０
４．９０ １１．５５実施例９
４−（３−アセチルアミノ−２，４−ジエチルフェニル
−２（３Ｈ）−チアゾロン２．０ｇと濃塩酸３０ｍ１の
混液を封管にて１２０−１３０°Ｃの油浴で３時間加熱
する。冷却後水を加える。生じた沈殿を戸数する。沈殿
をエタノールで再結晶し、４−（３−アミノ−２，４−
ジエチルフェニル）−２（３Ｈ）−チアゾロン塩酸塩０
．７ｇを得た。Melting point 187j188°C (benzene) Elemental analysis value (C
l5HIQN As 02S) C (%) H (%) N
(%> S(%) Theoretical value 64..94 6,90
5.05 11.56 Experimental value 64,96 6.90
4.90 11.55 Example 9 A mixture of 2.0 g of 4-(3-acetylamino-2,4-diethylphenyl-2(3H)-thiazolone and 30 ml of concentrated hydrochloric acid) was heated at 120-130°C in a sealed tube. Heat in an oil bath for 3 hours. Add water after cooling. Separate the resulting precipitate. Recrystallize the precipitate from ethanol to obtain 4-(3-amino-2,4-
Diethylphenyl)-2(3H)-thiazolone hydrochloride 0
．． 7g was obtained.
Claims (1)
炭素数が１乃至３個のアルキル基、 Ｒ＾２；水酸基、低級アルコキシ基、アミノ基、モノ若
しくはジ低級アルキルアミノ基、 又はモノ若しくはジ低級アルカノイル アミノ基、 Ｒ＾４；水素原子、シアノ基、ホルミル基、ヒドロキシ
イミノメチル基、低級アルコ キシイミノメチル基、カルボキシ基、 低級アルコキシカルボニル基、カルバ モイル基、又はモノ若しくはジ低級ア ルキルアミノカルボニル基） で示される４−トリ置換フェニル−２（３Ｈ）−チアゾ
ロン誘導体又はその塩。[Claims] 1. General formula▲ Numerical formula, chemical formula, table, etc.▼ (Symbols in the formula have the following meanings. R^1 and R^3; Same or different, halogen atom or carbon Alkyl group having 1 to 3 atoms, R^2; hydroxyl group, lower alkoxy group, amino group, mono- or di-lower alkylamino group, or mono- or di-lower alkanoylamino group, R^4; hydrogen atom, cyano group, 4-trisubstituted phenyl-2(3H)-thiazolone represented by formyl group, hydroxyiminomethyl group, lower alkoxyiminomethyl group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, or mono- or di-lower alkylaminocarbonyl group) Derivative or salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26007486A JPS63112574A (en) | 1986-10-30 | 1986-10-30 | 4-trisubstituted phenyl-2(3h)-thiazolone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP26007486A JPS63112574A (en) | 1986-10-30 | 1986-10-30 | 4-trisubstituted phenyl-2(3h)-thiazolone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63112574A true JPS63112574A (en) | 1988-05-17 |
Family
ID=17342942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP26007486A Pending JPS63112574A (en) | 1986-10-30 | 1986-10-30 | 4-trisubstituted phenyl-2(3h)-thiazolone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63112574A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0513379A1 (en) * | 1990-11-30 | 1992-11-19 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
-
1986
- 1986-10-30 JP JP26007486A patent/JPS63112574A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0513379A1 (en) * | 1990-11-30 | 1992-11-19 | Teijin Limited | 2-arylthiazole derivative and pharmaceutical composition containing the same |
| US5614520A (en) * | 1990-11-30 | 1997-03-25 | Teijin Limited | 2-arylthiazole derivatives and pharmaceutical composition thereof |
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