JPH07242647A - Thiazoline derivative - Google Patents
Thiazoline derivativeInfo
- Publication number
- JPH07242647A JPH07242647A JP7002241A JP224195A JPH07242647A JP H07242647 A JPH07242647 A JP H07242647A JP 7002241 A JP7002241 A JP 7002241A JP 224195 A JP224195 A JP 224195A JP H07242647 A JPH07242647 A JP H07242647A
- Authority
- JP
- Japan
- Prior art keywords
- group
- compound
- formula
- thiazoline
- mixture
- 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.)
- Granted
Links
- 150000003549 thiazolines Chemical class 0.000 title claims abstract description 7
- -1 cyano, carbamoyl Chemical group 0.000 claims abstract description 90
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004423 acyloxy group Chemical group 0.000 claims description 7
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 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
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 65
- 230000003042 antagnostic effect Effects 0.000 abstract description 9
- 108010012088 Fibrinogen Receptors Proteins 0.000 abstract description 8
- 230000021164 cell adhesion Effects 0.000 abstract description 4
- 206010003210 Arteriosclerosis Diseases 0.000 abstract description 2
- 208000007536 Thrombosis Diseases 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 abstract description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 206010008118 cerebral infarction Diseases 0.000 abstract description 2
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 2
- 150000004820 halides Chemical class 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract description 2
- 208000023589 ischemic disease Diseases 0.000 abstract description 2
- 208000010125 myocardial infarction Diseases 0.000 abstract description 2
- 208000031229 Cardiomyopathies Diseases 0.000 abstract 1
- 206010027476 Metastases Diseases 0.000 abstract 1
- 230000002862 amidating effect Effects 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 230000009401 metastasis Effects 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 125000005415 substituted alkoxy group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000002844 melting Methods 0.000 description 42
- 230000008018 melting Effects 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 239000013078 crystal Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 238000000034 method Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 5
- 108010049003 Fibrinogen Proteins 0.000 description 5
- 102000008946 Fibrinogen Human genes 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940012952 fibrinogen Drugs 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 238000007429 general method Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 210000004027 cell Anatomy 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
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- 101000829980 Homo sapiens Ral guanine nucleotide dissociation stimulator Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 102100023320 Ral guanine nucleotide dissociation stimulator Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 238000010306 acid treatment Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- 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
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- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 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
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Chemical group 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- 229960001134 von willebrand factor Drugs 0.000 description 1
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は新規なチアゾリン誘導体
に関し、更に詳しくは、フィブリノーゲン受容体拮抗作
用、細胞接着因子拮抗作用を有する新規なチアゾリン誘
導体に関する。FIELD OF THE INVENTION The present invention relates to a novel thiazoline derivative, and more particularly to a novel thiazoline derivative having fibrinogen receptor antagonistic action and cell adhesion factor antagonistic action.
【０００２】[0002]
【従来の技術】血小板は各種血小板凝集惹起物質の刺激
により、血小板膜糖蛋白ＧＰＩＩｂ／ＩＩＩａ複合体上
にフィブリノーゲンの結合部位が発現し、その結果血小
板が相互にフィブリノーゲンを介して結合し凝集すると
いわれている。またフィブリノーゲンの受容体との結合
部位であるといわれているＡｒｇ−Ｇｌｙ−Ａｓｐを含
むＡｒｇ−Ｇｌｙ−Ａｓｐ−Ｓｅｒ（以下、ＲＧＤＳと
略記する。）等のペプチド誘導体［Thrombosys，Re
s．，第５６巻，第６号，第６８７ページ（１９８９
年）］や分子内にアミジノ基を有する化合物（特開平２
−２２３５４３号公報）などがフィブリノーゲン受容体
に対する拮抗作用を有し、血小板凝集抑制作用を有する
ことが知られている。しかし未だその作用は充分ではな
い。2. Description of the Related Art It is said that platelets express a fibrinogen binding site on the platelet membrane glycoprotein GPIIb / IIIa complex upon stimulation with various platelet aggregation-inducing substances, and as a result, platelets mutually bind via fibrinogen and aggregate. ing. In addition, peptide derivatives such as Arg-Gly-Asp-Ser (hereinafter abbreviated as RGDS) including Arg-Gly-Asp which is said to be a binding site for fibrinogen receptor [Thrombosys, Re.
s. , Volume 56, Issue 6, Page 687 (1989)
Year)] or a compound having an amidino group in the molecule (JP-A-2
No. 223543) and the like have an antagonistic action on the fibrinogen receptor and an inhibitory action on platelet aggregation. However, its action is not yet sufficient.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は、優れ
たフィブリノーゲン受容体拮抗作用、細胞接着因子拮抗
作用を有する化合物を提供することにある。An object of the present invention is to provide a compound having excellent fibrinogen receptor antagonistic action and cell adhesion factor antagonistic action.
【０００４】[0004]
【課題を解決するための手段】本発明者らは鋭意検討し
た結果、フィブリノーゲン受容体拮抗作用、細胞接着因
子拮抗作用剤として有用な新規な含硫複素環誘導体を見
出し、本発明を完成した。Means for Solving the Problems As a result of intensive studies by the present inventors, the inventors have found a novel sulfur-containing heterocyclic derivative useful as a fibrinogen receptor antagonistic agent and a cell adhesion factor antagonistic agent, and completed the present invention.
【０００５】本発明は、式（Ｉ） The present invention has the formula (I)
【０００６】（式中、Ｒ1はシアノ基、カルバモイル
基、チオカルバモイル基、低級アルキルチオイミドイル
基、アミジノ基、窒素原子上の水素原子がアラルキル基
もしくはアルコキシカルボニル基の一個以上で置換され
たアミジノ基、モルホリノチオカルボニル基、ヒドロキ
シメチル基または式（ＩＩ） (Wherein R 1 is a cyano group, a carbamoyl group, a thiocarbamoyl group, a lower alkylthioimidoyl group, an amidino group, or an amidino group in which a hydrogen atom on a nitrogen atom is substituted with one or more aralkyl groups or alkoxycarbonyl groups. Group, morpholinothiocarbonyl group, hydroxymethyl group or formula (II)
【０００７】（式中、Ｒ13は低級アルキル基を示す。）
を示し、Ｒ2は低級アルキル基を示し、Ｒ3は水素原子ま
たは低級アルキル基を示し、ｎは１〜５の整数を示し、
Ｒ4は 水酸基、アミノ基、低級アルコキシ基または複
素環、低級アルカノイルオキシ基、低級アルコキシ基、
低級アルコキシアルコキシ基もしくはアミノ基で置換さ
れたアルコキシ基、Ｎ，Ｎ−ジ低級アルキルアミノ基を
示す。）で表されるチアゾリン誘導体およびその塩。(In the formula, R 13 represents a lower alkyl group.)
R 2 represents a lower alkyl group, R 3 represents a hydrogen atom or a lower alkyl group, n represents an integer of 1 to 5,
R 4 is a hydroxyl group, amino group, lower alkoxy group or heterocycle, lower alkanoyloxy group, lower alkoxy group,
A lower alkoxyalkoxy group, an alkoxy group substituted with an amino group, or an N, N-dilower alkylamino group is shown. ) The thiazoline derivative and its salt represented by.
【０００８】以下式［Ｉ］で表される化合物を本発明化
合物と称する。The compound represented by the formula [I] is hereinafter referred to as the compound of the present invention.
【０００９】本発明において、低級アルキル基とは炭素
原子数１〜４個の直鎖または分枝したアルキル基（例え
ば、メチル基、エチル基、プロピル基、イソプロピル
基、ブチル基、イソブチル基または第３ブチル基）を示
し、低級アルコキシ基とは炭素原子数１〜４個の直鎖ま
たは分枝したアルコキシ基（例えば、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、イソブトキシ基または第３ブトキシ基）を示し、製
薬学的に許容される塩とは、アルカリ金属類、アルカリ
土類金属類、アンモニア、アルキルアミン類、鉱酸、カ
ルボン酸、スルホン酸などとの塩であり、例えば、ナト
リウム塩、カリウム塩、カルシウム塩、アンモニウム
塩、アルミニウム塩、トリエチルアンモニウム塩、塩酸
塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、
燐酸塩、酢酸塩、フマル酸塩、マレイン酸塩、メタンス
ルホン酸塩が挙げられる。In the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group or 3 butyl group), and the lower alkoxy group means a linear or branched alkoxy group having 1 to 4 carbon atoms (for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group or The third butoxy group), and a pharmaceutically acceptable salt is a salt with an alkali metal, an alkaline earth metal, ammonia, an alkylamine, a mineral acid, a carboxylic acid, a sulfonic acid, or the like, For example, sodium salt, potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, hydrochloride, hydrobromide, and iodine salt. Hydrobromide, sulfate, nitrate,
Examples thereof include phosphate, acetate, fumarate, maleate and methanesulfonate.
【００１０】本発明化合物は、以下に示す方法によって
製造することができる。The compound of the present invention can be produced by the following method.
【００１１】すなわち本発明化合物は、式（ａ） That is, the compound of the present invention has the formula (a)
【００１２】（式中、Ｒ5はシアノ基、モルホリノチオ
カルボニル基またはヒドロキシメチル基を示し、Ｒ6は
低級アルキル基を示す）で表わされる化合物と式Ｒ2Ｘ
（式中Ｒ2は前記と同意義であり、Ｘはハロゲン原子で
ある）で表わされるハロゲン化物（例えばヨウ化メチ
ル、ベンジルクロリドである。）、Ｒ2 2ＳＯ4（式中Ｒ2
は前記と同意義である。）で表わされるジアルキル硫酸
（例えば、ジメチル硫酸である。）、Ｒ7ＳＯ3Ｒ2（式
中、Ｒ7は任意のアルキル基またはアリール基であり、
Ｒ2は前記と同意義である。）で表わされるスルホン酸
エステル（例えば、メタンスルホン酸メチルである。）
などのアルキル化剤を塩基の存在下に反応させて、式
（ｂ） (Wherein R 5 represents a cyano group, a morpholinothiocarbonyl group or a hydroxymethyl group, and R 6 represents a lower alkyl group) and a compound represented by the formula R 2 X
(In the formula, R 2 has the same meaning as described above, and X is a halogen atom) and a halide (for example, methyl iodide or benzyl chloride), R 2 2 SO 4 (R 2 in the formula
Is as defined above. ) Dialkyl sulfuric acid (for example, dimethyl sulfuric acid), R 7 SO 3 R 2 (wherein R 7 is any alkyl group or aryl group,
R 2 has the same meaning as described above. ) Sulfonic acid ester represented by (for example, methyl methanesulfonate)
By reacting an alkylating agent such as
【００１３】（式中Ｒ2，Ｒ5及びＲ6は前記と同意義で
ある。）の化合物に導き、更にエステル部分を通常用い
られる方法を用いて加水分解して、式（ｃ） (Wherein R 2 , R 5 and R 6 have the same meanings as defined above), and the ester moiety is hydrolyzed by a commonly used method to give a compound of formula (c)
【００１４】（式中、Ｒ2及びＲ5は前記と同意義であ
る。）で表わされる化合物またはそれらの塩類とした
後、式（ｄ） Ｈ2Ｎ−（ＣＨ2）n−Ｃ（＝Ｏ）Ｒ4 ・・・・・・（ｄ） （式中ｎ，Ｒ4は前記と同意義である。）で示されるア
ミン類もしくはそれらの塩を用いて、アミド結合を形成
する通常の方法によりアミド化することによって、Ｒ3
が水素原子であり、Ｒ1がシアノ基、モルホリノチオカ
ルボニル基あるいはヒドロキシメチル 基である本発明
化合物を製造することができる。(Wherein R 2 and R 5 have the same meanings as defined above) or a salt thereof, and then the compound of formula (d) H 2 N- (CH 2 ) n -C (= O) R 4 ··· (d) A general method for forming an amide bond using an amine represented by the formula (n and R 4 are as defined above) or a salt thereof. By amidation with R 3
Is a hydrogen atom, and R 1 is a cyano group, a morpholinothiocarbonyl group or a hydroxymethyl group.
【００１５】また、更にこれらの化合物を塩基の存在
下、式（ｅ） Ｒ8Ｘ ・・・・・・・・・（ｅ） （式中、Ｒ8は低級アルキル基を示し、Ｘは、前記と同
意義である。）で示されるアルキルハライドと反応する
ことによって、Ｒ3が低級アルキル基であり、Ｒ1がシア
ノ基、モルホリノチオカルボニル基あるいはヒドロキシ
メチル 基である本発明化合物を製造することができ
る。Further, in the presence of a base, these compounds are further subjected to the formula (e) R 8 X ... (E) (wherein R 8 represents a lower alkyl group, and X is The same meaning as above.) To produce a compound of the present invention in which R 3 is a lower alkyl group and R 1 is a cyano group, a morpholinothiocarbonyl group or a hydroxymethyl group. be able to.
【００１６】別法として本発明化合物は、例えばＯｒ
ｇ．Ｓｙｎｔｈ．Ｃｏｌｌ．第３巻第７３５頁に記載さ
れた方法によって得た式（ｆ） Alternatively, the compound of the present invention may be, for example, Or
g. Synth. Coll. Formula (f) obtained by the method described in Vol. 3, page 735.
【００１７】（式中、Ｒ2およびＲ5は前記と同意義であ
る。）と式（ｇ） ＣＨ3ＣＯＣＨ（Ｃｌ）ＣＯ2Ｒ6・・・・・（ｇ） （式中、Ｒ6は前記と同意義である。）で表わされる化
合物を塩基の存在下もしくは非存在下溶媒中もしくは無
溶媒中で加熱下に反応させて式（ｂ）の化合物へと導
き、引続き上記と同様の操作によって製造することがで
きる。(Wherein R 2 and R 5 have the same meanings as described above) and the formula (g) CH 3 COCH (Cl) CO 2 R 6 (g) (wherein R 6 Has the same meaning as described above.) The compound represented by the formula (b) is reacted by heating in the presence or absence of a base in a solvent or without a solvent to give a compound of the formula (b). It can be manufactured by operation.
【００１８】さらにＲ1がシアノ基である本発明化合物
をたとえば塩基を触媒として用いて硫化水素と反応させ
る方法、ＮａＢＨ2Ｓ3と反応させる方法等によってＲ1
がチオカルバモイル基である本発明化合物に導くことが
できる。更にここで得られた本発明化合物の硫黄原子を
式（ｈ） Ｒ9Ｘ ・・・・・・・・・（ｈ） （式中Ｒ9は低級アルキル基であり、Ｘは前記と同意義
である。）で表わされる低級アルキルハライドで処理し
てＲ1が低級アルキルチオイミドイル基である本発明の
化合物に導くことができ、更にアンモニア、アラルキル
アミンもしくはこれらの塩で処理することによって、Ｒ
1がアミジノ基もしくは窒素原子上の水素原子が１個以
上のアラルキル基で置換されたアミジノ基である本発明
化合物に導くことができる。[0018] R 1 further method wherein R 1 is reacted with hydrogen sulfide using the present invention compounds such base is a cyano group as a catalyst, by a method such as reaction with NaBH 2 S 3
Can be derived to a compound of the present invention in which is a thiocarbamoyl group. Furthermore, the sulfur atom of the compound of the present invention obtained here is represented by the formula (h) R 9 X ... (H) (wherein R 9 is a lower alkyl group, and X is as defined above). Can be converted to a compound of the present invention in which R 1 is a lower alkylthioimidoyl group, and further treated with ammonia, aralkylamine or a salt thereof to give R
The compound of the present invention in which 1 is an amidino group or an amidino group in which a hydrogen atom on a nitrogen atom is substituted with one or more aralkyl groups can be introduced.
【００１９】また、Ｒ1がカルバモイル基である本発明
化合物は、Ｒ1がシアノ基である本発明化合物を塩基性
条件下過酸化水素と反応させる方法等によって導くこと
ができる。The compound of the present invention in which R 1 is a carbamoyl group can be derived by a method of reacting the compound of the present invention in which R 1 is a cyano group with hydrogen peroxide under basic conditions.
【００２０】さらにＲ1が窒素原子上の水素原子が低級
アルコキシカルボニル基で置換されたアミジノ基である
本発明化合物は、Ｒ1がアミジノ基または窒素原子がア
ラルキル基で置換されたアミジノ基である本発明化合物
を式（ｉ） Ｒ10Ｏ（Ｃ＝Ｏ）Ｘ ・・・・・・（ｉ） もしくは 式（ｊ） Ｒ11Ｏ（Ｃ＝Ｏ）Ｏ（Ｃ＝Ｏ）ＯＲ11 ・・・・（ｊ） （式ｉ,ｊ中、Ｒ10、Ｒ11は低級アルキル基を示し、Ｘ
は前記と同意義である。）で表わされる化合物で塩基の
存在下に処理することによって製造することが出来る。Furthermore the present invention compounds in which R 1 is a hydrogen atom on the nitrogen atom is the amidino group substituted with a lower alkoxycarbonyl group is a amidino group R 1 is an amidino group or a nitrogen atom is substituted with an aralkyl group The compound of the present invention is represented by the formula (i) R 10 O (C═O) X ... (i) or the formula (j) R 11 O (C═O) O (C═O) OR 11 (J) (In the formulas i and j, R 10 and R 11 represent a lower alkyl group, and X
Is as defined above. It can be produced by treating with a compound represented by the formula (1) in the presence of a base.
【００２１】Ｒ1がアミジノ基もしくは窒素原子がアラ
ルキル基の１個以上で置換されたアミジノ基である本発
明化合物はＲ1がシアノ基である本発明化合物から、例
えば、イミノクロリドやイミノエーテルを経由するシア
ノ基をアミジノ基に変換する一般的な方法を用いて合成
することもできる。The compound of the present invention in which R 1 is an amidino group or an amidino group in which the nitrogen atom is substituted with one or more aralkyl groups is a compound of the present invention in which R 1 is a cyano group, for example, imino chloride or imino ether. It can also be synthesized using a general method for converting a cyano group passing through to an amidino group.
【００２２】Ｒ4が水酸基である本発明化合物またはそ
の塩を製造する場合、Ｒ4がアミノ基または水酸基以外
であるの本発明化合物からエステルの加水分解行う事に
よりそれぞれの本発明化合物に導くことができる。エス
テルの加水分解はアルカリ処理、鉱酸処理等の一般的な
方法を用いることができる。In the case of producing the compound of the present invention in which R 4 is a hydroxyl group or a salt thereof, the compound of the present invention in which R 4 is other than an amino group or a hydroxyl group is introduced into each compound of the present invention by hydrolysis of an ester. You can For hydrolysis of the ester, general methods such as alkali treatment and mineral acid treatment can be used.
【００２３】Ｒ4がアミノ基である本発明化合物は、Ｒ4
が水酸基または複素環、低級アシルオキシ基、低級アル
コキシ基、低級アルコキシアルコキシ基またはアミノ基
で置換されたアルコキシ基である本発明化合物から、溶
媒中アンモニアと反応する等のエステルあるいはカルボ
ン酸からアミドを形成する一般的な方法により導くこと
ができる。The invention compounds wherein R 4 is amino group, R 4
From a compound of the present invention in which is a hydroxyl group or a heterocycle, a lower acyloxy group, a lower alkoxy group, a lower alkoxyalkoxy group or an alkoxy group substituted with an amino group, forms an amide from an ester or a carboxylic acid that reacts with ammonia in a solvent Can be derived by a general method of
【００２４】また、Ｒ4が複素環、低級アシルオキシ
基、低級アルコキシ基、低級アルコキシアルコキシ基ま
たはアミノ基で置換されたアルコキシ基である本発明化
合物は、Ｒ4が水酸基である本発明化合物またはその塩
と式（ｋ） Ｒ12ＯＨ ・・・・・・・・（ｋ） （式中、Ｒ12は複素環、低級アシルオキシ基、低級アル
コキシ基、低級アルコキシアルコキシ基またはアミノ基
で置換されたアルキル基を示し、Ｘは前記と同意義であ
る。）または Ｒ12Ｘ ・・・・・・・・（ｋ） （式中、Ｒ12は複素環、低級アシルオキシ基、低級アル
コキシ基、低級アルコキシアルコキシ基またはアミノ基
で置換されたアルキル基を示し、Ｘは前記と同意義であ
る。）で表わされる化合物とをたとえば４−ジメチルア
ミノピリジン存在下にジシクロヘキシルカルボジイミド
で処理する等の一般的なカルボン酸のエステル化の条件
で反応する事によって製造することができる。The compound of the present invention in which R 4 is a heterocycle, a lower acyloxy group, a lower alkoxy group, a lower alkoxyalkoxy group or an alkoxy group substituted with an amino group is a compound of the present invention in which R 4 is a hydroxyl group or a compound thereof. Salt and Formula (k) R 12 OH ... (k) (In the formula, R 12 is alkyl substituted with a heterocycle, a lower acyloxy group, a lower alkoxy group, a lower alkoxyalkoxy group or an amino group. A group, X is as defined above, or R 12 X ..... (k) (In the formula, R 12 is a heterocycle, a lower acyloxy group, a lower alkoxy group, a lower alkoxyalkoxy. Group or an alkyl group substituted with an amino group, and X has the same meaning as described above.) With a compound represented by, for example, dicyclohexyl in the presence of 4-dimethylaminopyridine. It can be prepared by reacting a general esterification of a carboxylic acid conditions such as treatment with a carbodiimide.
【００２５】また、Ｒ4が複素環、低級アシルオキシ
基、低級アルコキシ基、低級アルコキシアルコキシ基ま
たはアミノ基で置換されたアルコキシ基である本発明化
合物は酸処理等の一般的なエステル交換の条件を用いる
事によって相互に変換することによって製造することが
できる。The compound of the present invention in which R 4 is a heterocycle, a lower acyloxy group, a lower alkoxy group, a lower alkoxyalkoxy group or an alkoxy group substituted with an amino group is subjected to general transesterification conditions such as acid treatment. It can be manufactured by converting each other by using.
【００２６】上記の反応で塩基を用いる場合の塩基とし
ては、例えば、水酸化ナトリウム、水酸化カリウム、ジ
ムシルナトリウム、水素化ナトリウム、ナトリウムアミ
ド、第３ブチルカリウム、酢酸ナトリウム等のアルカリ
金属塩類、トリエチルアミン、ジイソプロピルエチルア
ミン、ピリジンのアミン類等を用いることができ、アミ
ン類の塩とは、例えば、酢酸アンモニウム等の有機酸塩
を用いることができる。 反応溶媒としては水、メタノ
ール、エタノール、イソプロピルアルコール、第三ブチ
ルアルコール等のアルコール類、ジオキサン、テトラヒ
ドロフラン等のエーテル類、ジメチルホルムアミド、ジ
メチルスルホキシド、ピリジン、塩化メチレン、クロロ
ホルム、アセトン、酢酸等の反応に不活性な溶媒を用い
ることができる。When a base is used in the above reaction, examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, sodium dimucil, sodium hydride, sodium amide, tertiary butyl potassium, sodium acetate, and the like. Triethylamine, diisopropylethylamine, pyridine amines and the like can be used. As the amine salt, for example, an organic acid salt such as ammonium acetate can be used. As a reaction solvent, water, alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone, acetic acid and the like An inert solvent can be used.
【００２７】[0027]
【発明の効果】このようにして得た式Ｉの化合物は、血
小板上のフィブリノーゲン受容体（ＧｐＩＩｂ／ＩＩＩ
ａ）に対するフィブリノーゲン、フィブロネクチン、フ
ォンヴィルブラント因子等の各種粘着性タンパク質の結
合を阻害し、血小板の凝集、粘着に対する抑制作用を有
する。また式Ｉの化合物は各種細胞表面への上記粘着性
タンパク質及びヴィトロネクチン、コラーゲン等の細胞
間マトリックスを形成する粘着性タンパク質の結合を阻
害し、細胞間の相互作用、細胞−細胞間マトリックス間
の相互作用に作用する。INDUSTRIAL APPLICABILITY The compound of formula I thus obtained is a fibrinogen receptor (GpIIb / III) on platelets.
It inhibits the binding of various adhesive proteins such as fibrinogen, fibronectin, von Willebrand factor to a), and has the action of suppressing platelet aggregation and adhesion. In addition, the compound of the formula I inhibits the binding of the above-mentioned adhesive proteins to various cell surfaces and the adhesive proteins forming the intercellular matrix such as vitronectin and collagen, and the interaction between cells, cell-cell matrix Affect the interaction of.
【００２８】従って本発明の化合物は血栓症、脳梗塞、
心筋梗塞等の虚血性疾患、動脈硬化症等の疾患の予防よ
び治療剤、悪性腫瘍の転移抑制剤などに用いることがで
きる。Accordingly, the compounds of the present invention are suitable for thrombosis, cerebral infarction,
It can be used as a preventive and therapeutic agent for ischemic diseases such as myocardial infarction, diseases such as arteriosclerosis, and a metastasis inhibitor for malignant tumors.
【００２９】この目的のためには、式Ｉの化合物を常用
の増量剤、結合剤、崩壊剤、ｐＨ調節剤、溶解剤などを
添加し、常用の製剤技術によって錠剤、丸剤、カプセル
剤、顆粒剤、粉剤、液剤、乳剤、懸濁剤、注射剤などに
調製することができる。For this purpose, the compound of formula I is added with conventional fillers, binders, disintegrants, pH adjusters, solubilizers, etc., and tablets, pills, capsules, It can be prepared into granules, powders, solutions, emulsions, suspensions, injections and the like.
【００３０】式Ｉの本発明化合物は、成人の患者に対し
て、通常経口投与の場合、１〜１０００ｍｇ、非経口投
与の場合０．０１〜１００ｍｇを１日１回または数回に
分けて投与することができる。この投与量は疾病の種
類、患者の年齢、体重、症状により適宜増減することが
できる。The compound of the present invention of formula I is usually administered to an adult patient in an amount of 1 to 1000 mg when orally administered, and 0.01 to 100 mg when parenterally administered, once a day or in several divided doses. can do. This dose can be appropriately increased or decreased depending on the type of disease, the age, weight and symptoms of the patient.
【００３１】以下、試験例を挙げて式Ｉの化合物のフィ
ブリノーゲン受容体拮抗作用を説明する。The fibrinogen receptor antagonism of the compound of formula I will be described below with reference to test examples.
【００３２】試験例１［ヒト血小板 フィブリノーゲン
結合試験］ 試験開始２週間前より血小板の機能に影響を及ぼすこと
が知られている薬剤の服用を行っていない健常人の肘静
脈よりクエン酸採血（３.１３％クエン酸ナトリウム液
１容：血液９容）を行い、この血液を室温で１２０ｇで
１５分間遠沈して得た上清を多血小板血漿（ＰＲＰ）と
した。Test Example 1 [Human Platelet Fibrinogen Binding Assay] Citric acid blood sampling (3) from a cubital vein of a healthy person who has not taken a drug known to affect platelet function 2 weeks before the start of the test. A 13% sodium citrate solution (1 volume: 9 volumes of blood) was applied, and the blood was spun down at 120 g for 15 minutes to obtain a supernatant as platelet-rich plasma (PRP).
【００３３】上記のＰＲＰに１／５量のＡＣＤ溶液（Ａ
ＣＤ溶液：クエン酸／クエン酸ナトリウム／デキストロ
ース）を加え、１２００ｇで１５分間遠沈した。沈澱物
をタイロード液（２０％ウシ胎児血清、２ｍＭ，Ｍ
ｇ2+）に懸濁した後セファロース２Ｂカラムを用いてゲ
ル濾過を行いフィブリノーゲン除去血小板懸濁液（１×
１０9個／ｍｌ）を得た。このフィブリノーゲン除去血
小板懸濁液に被験薬として式１の化合物をジメチルスル
ホキシドに溶解し、生理食塩水で所要濃度に調整した液
及びＡＤＰ（終濃度１０μＭ）と125Ｉでラベルしたヒ
トフィブリノーゲンを用いて結合実験を行い被検薬の結
合阻害率を算出した。A 1/5 volume of the ACD solution (A
CD solution: citric acid / sodium citrate / dextrose) was added, and the mixture was spun down at 1200 g for 15 minutes. Precipitate the Tyrode's solution (20% fetal calf serum, 2 mM, M
g 2+ ) and then gel filtration using Sepharose 2B column to remove fibrinogen-removed platelet suspension (1 x
10 9 cells / ml) were obtained. Using a solution of the compound of formula 1 dissolved in dimethylsulfoxide as a test drug in this fibrinogen-depleted platelet suspension and ADP (final concentration 10 μM) and human fibrinogen labeled with 125 I as physiological saline A binding experiment was performed to calculate the binding inhibition rate of the test drug.
【００３４】また、比較薬としてＲＧＤＳ（シグマ社
製）、及び ３−［３−（４−アミジノベンゾイル）ベ
ンズアミド］プロピオン酸（特開平２−２２３５４３に
記載された化合物、以下 対照薬と記す）を用い、前記
と同様に試験液を調整し、これについて前記と同様の試
験を行った。RGDS (manufactured by Sigma) as a comparative drug, and 3- [3- (4-amidinobenzoyl) benzamido] propionic acid (the compound described in JP-A-2-223543, hereinafter referred to as a control drug). A test liquid was prepared in the same manner as described above, and the same test as above was conducted for this.
【００３５】その結果を表１に示した。ただし、表中の
化合物番号は実施例に示す化合物番号と同一である。The results are shown in Table 1. However, the compound numbers in the table are the same as the compound numbers shown in the examples.
【００３６】[0036]
【表１】 [Table 1]
【００３７】[0037]
【実施例】以下、実施例を挙げて本発明を更に詳細に説
明する。表２，３に化合物番号および実施例と式Ｉにお
ける置換基の相関を示す。EXAMPLES The present invention will be described in more detail with reference to examples. Tables 2 and 3 show the compound numbers and the correlation between the examples and the substituents in formula I.
【００３８】[0038]
【表２】 [Table 2]
【００３９】[0039]
【表３】 [Table 3]
【００４０】実施例１ （１）６０％油性水素化ナトリウム（０.８４ｇ）のＮ,
Ｎ−ジメチルホルムアミド（以下ＤＭＦと略す）（３０
０ｍｌ）懸濁液に、氷冷下 ２−（４−シアノベンゾイ
ルアミノ）−４−メチルチアゾール−５−カルボン酸エ
チルエステル（２２. ０７ｇ）を加え、室温で１時間攪
拌した。Example 1 (1) 60% oily sodium hydride (0.84 g) in N,
N-dimethylformamide (hereinafter abbreviated as DMF) (30
To the suspension (0 ml) was added 2- (4-cyanobenzoylamino) -4-methylthiazole-5-carboxylic acid ethyl ester (22.07 g) under ice cooling, and the mixture was stirred at room temperature for 1 hour.
【００４１】反応混合物にヨウ化メチル（４.８ｍｌ）
のＤＭＦ（５０ｍｌ）溶液を滴下し、さらに室温で１時
間攪拌した。反応混合物を３％塩酸にあけ、析出した結
晶を濾取し、得られた粗結晶を塩化メチレンとメタノー
ルの混液で再結晶して ２−（４−シアノベンゾイルイ
ミノ）−３,４−ジメチル−３Ｈ−チアゾリン−５−カ
ルボン酸エチル（１５.９７ｇ）を得た。Methyl iodide (4.8 ml) was added to the reaction mixture.
DMF (50 ml) solution of was added dropwise, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was poured into 3% hydrochloric acid, the precipitated crystals were collected by filtration, and the obtained crude crystals were recrystallized with a mixed solution of methylene chloride and methanol to give 2- (4-cyanobenzoylimino) -3,4-dimethyl-. Ethyl 3H-thiazoline-5-carboxylate (15.97 g) was obtained.
【００４２】融点 ２４４〜２４５℃。Melting point 244-245 ° C.
【００４３】（２）２−（４−シアノベンゾイルイミ
ノ）−３,４−ジメチル−３Ｈ−チアゾリ ン−５−カル
ボン酸エチル（９.８８ｇ）、塩化メチレン（２５０ｍ
ｌ）、メタノール（２５０ｍｌ）の混合物に１０％水酸
化ナトリウム水溶液（４８ｍｌ）を加え、室温で１７時
間攪拌した。(2) Ethyl 2- (4-cyanobenzoylimino) -3,4-dimethyl-3H-thiazolin-5-carboxylate (9.88 g), methylene chloride (250 m
A 10% aqueous sodium hydroxide solution (48 ml) was added to a mixture of l) and methanol (250 ml), and the mixture was stirred at room temperature for 17 hours.
【００４４】反応混合物を減圧濃縮して析出した結晶を
濾取して ２−（４−シアノベンゾイルイミノ）−３,
４−ジメチル−３Ｈ−チアゾリン−５−カルボン酸ナト
リウム塩（１０.０ｇ）を得た。The reaction mixture was concentrated under reduced pressure and the precipitated crystals were collected by filtration to give 2- (4-cyanobenzoylimino) -3,
4-Dimethyl-3H-thiazoline-5-carboxylic acid sodium salt (10.0 g) was obtained.
【００４５】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6，δ）；２.
６６（３Ｈ,ｓ），３.７５（３Ｈ,ｓ），７.９１（２
Ｈ,ｄ,Ｊ＝８Ｈｚ），８.３３（２Ｈ,ｄ,Ｊ＝８Ｈ
ｚ）。 （３）２−（４−シアノベンゾイルイミノ）−３,４−
ジメチル−３Ｈ−チアゾリン−５−カルボン酸ナトリウ
ム塩（９.８５ｇ）のＤＭＦ懸濁液に攪拌下β−アラニ
ンメチルエステル塩酸塩（４.６８ｇ）、１−ヒドロキ
シベンゾトリアゾール一水和物（９.３４ｇ）、１−エ
チル−３−［３−（ジメチルアミノ）プロピル］−カル
ボジイミド塩酸塩（６.４３ｇ）を順次加え室温で１４
時間攪拌した。反応混合物 を水にあけ、析出した結晶
を濾取、塩化メチレンとヘキサンの混合液で再結晶して
Ｎ−（２−メトキシカルボニルエチル）−２−（４−
シアノベンゾイルイミノ）−３,４−ジメチル−３Ｈ−
チアゾリン−５−カルボキサミド（化合物１）（９.９
ｇ）を得た。 1 H-NMR (DMSO-d 6 , δ); 2.
66 (3H, s), 3.75 (3H, s), 7.91 (2
H, d, J = 8Hz), 8.33 (2H, d, J = 8H
z). (3) 2- (4-cyanobenzoylimino) -3,4-
Β-alanine methyl ester hydrochloride (4.68 g) and 1-hydroxybenzotriazole monohydrate (9.85 g) in a DMF suspension of dimethyl-3H-thiazoline-5-carboxylic acid sodium salt (9.85 g) with stirring. 34 g) and 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (6.43 g) were sequentially added, and the mixture was stirred at room temperature for 14
Stir for hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized from a mixed solution of methylene chloride and hexane to give N- (2-methoxycarbonylethyl) -2- (4-
Cyanobenzoylimino) -3,4-dimethyl-3H-
Thiazoline-5-carboxamide (Compound 1) (9.9
g) was obtained.
【００４６】融点 １８７.５〜１８９.５℃。Melting point 187.5-189.5 ° C.
【００４７】実施例２ 化合物１（９.６６ｇ）、ピリジン（５００ｍｌ）、ト
リエチルアミン（８．７ｍｌ）の混合物に攪拌下室温で
硫化水素を３時間通じた後１６時間放置した。反応混合
物を溶媒留去し、得られた粗結晶を酢酸エチルで洗浄し
て Ｎ−（２−メトキシカルボニルエチル）−２−（４
−チオカルバモイルベンゾイルイミノ）−３，４−ジメ
チル−３Ｈ−チアゾリン−５−カルボキサミド（化合物
２）（１０. ５６ｇ） を得た。Example 2 Hydrogen sulfide was passed through a mixture of Compound 1 (9.66 g), pyridine (500 ml) and triethylamine (8.7 ml) at room temperature for 3 hours with stirring, and then the mixture was allowed to stand for 16 hours. The solvent was distilled off from the reaction mixture, and the obtained crude crystals were washed with ethyl acetate to give N- (2-methoxycarbonylethyl) -2- (4
-Thiocarbamoylbenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 2) (10.56 g) was obtained.
【００４８】融点 ２１５.５〜２１６.５℃。Melting point 215.5-216.5 ° C.
【００４９】実施例３ 化合物２（６.３１ｇ）のアセトン（１６００ｍｌ）懸
濁液に加熱還流下ヨウ化メチル２８ｍｌを４回に分けて
３０分間隔で加え、４時間攪拌した。反応混合物を減圧
濃縮して析出した結晶を濾取してＮ−（２−メトキシカ
ルボニルエチル）−２−［４−（メチルチオイミドイ
ル）ベンゾイルイミノ］−３,４−ジ メチル− ３Ｈ−
チアゾリン−５−カルボキサミド ヨウ化水素酸塩（化
合物３ ）（７.６９ ｇ）を得た。Example 3 To a suspension of the compound 2 (6.31 g) in acetone (1600 ml), 28 ml of methyl iodide was added under heating and refluxing in 4 portions at 30 minute intervals, and the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were collected by filtration and N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3,4-dimethyl-3H-.
Thiazoline-5-carboxamide hydroiodide (Compound 3) (7.69 g) was obtained.
【００５０】融点 ２０３.５〜２０４℃。Melting point 203.5-204 ° C.
【００５１】実施例４ 化合物３（７.３１ｇ）、酢酸アンモニウム（４.０
ｇ）、メタノール（１５０ｍｌ）の混合物を加熱還流下
７０分攪拌した。反応混合物を減圧濃縮して析出した結
晶を濾取して Ｎ−（２−メトキシカルボニルエチル）
−２−（４−アミジノベ ンゾイルイミノ）−３,４−ジ
メチル−３Ｈ−チアゾリン−５−カルボキサミド酢酸塩
（化合物４）（４.９６ｇ）を得た。Example 4 Compound 3 (7.31 g), ammonium acetate (4.0
A mixture of g) and methanol (150 ml) was stirred with heating under reflux for 70 minutes. The reaction mixture was concentrated under reduced pressure and the precipitated crystals were collected by filtration and N- (2-methoxycarbonylethyl).
2- (4-Amidinobenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide acetic acid salt (Compound 4) (4.96 g) was obtained.
【００５２】融点 ２２３〜２２４.５℃。Melting point 223-224.5 ° C.
【００５３】実施例５ 化合物４（３７１ｍｇ）、２−メトキシエタノール（５
ｍｌ）、メタンスルホン酸（０．１ｍｌ）の混合物を５
０℃で１時間攪拌した後、室温で１時間半攪拌した。析
出した結晶を濾取して Ｎ−２−［（２−メトキシエト
キシカルボニル）エチル］−２−（４−アミジノベンゾ
イルイミノ）−３,４−ジメチル−３Ｈ−チアゾ リン−
５−カルボキサミド メタンスルホン酸塩（化合物５）
（１６６ｍｇ）を得た。Example 5 Compound 4 (371 mg), 2-methoxyethanol (5
ml) and methanesulfonic acid (0.1 ml) mixed with 5
After stirring at 0 ° C. for 1 hour, the mixture was stirred at room temperature for 1.5 hours. The precipitated crystals were collected by filtration to give N-2-[(2-methoxyethoxycarbonyl) ethyl] -2- (4-amidinobenzoylimino) -3,4-dimethyl-3H-thiazoline-
5-carboxamide methanesulfonate (Compound 5)
(166 mg) was obtained.
【００５４】融点 ２１３〜２１５℃。Melting point 213-215 ° C.
【００５５】実施例６ 化合物４、２−（２−メトキシエトキシ）エタノールを
用いて、実施例５と同様の反応操作を行いＮ−｛２−
［２−（２−メトキシエトキシ）エトキシカルボニル］
エチル｝−２−（４−アミジノベンゾイルイミノ）−
３,４−ジメチル−３Ｈ− チアゾリン−５−カルボキサ
ミド メタンスルホン酸塩（化合物６）を得た。Example 6 Using compound 4, 2- (2-methoxyethoxy) ethanol, the same reaction procedure as in Example 5 was carried out to obtain N- {2-.
[2- (2-methoxyethoxy) ethoxycarbonyl]
Ethyl} -2- (4-amidinobenzoylimino)-
There was obtained 3,4-dimethyl-3H-thiazoline-5-carboxamide methanesulfonate (Compound 6).
【００５６】融点 １８３．５〜１８６℃。Melting point 183.5-186 ° C.
【００５７】実施例７ 化合物１（３．００ｇ）、塩化メチレン（３０ｍｌ）、
ジオキサン（３０ｍｌ）、水（３０ｍｌ）の混合物に、
１０％水酸化ナトリウム水溶液３．１２ｍｌを加え、８
０℃で２時間半攪拌した。反応混合物を減圧濃縮し、得
られた残渣のＤＭＦ１００ｍｌ懸濁液にヨウ化ピバロイ
ルオキシメチル（３．６３ｇ）のＤＭＦ２０ｍｌ溶液を
滴下し、室温で１６時間攪拌した。反応混合物を水にあ
け、析出した結晶を濾取し塩化メチレンで洗浄して Ｎ
−（２−ピバロイルオキシメトキシカルボニルエチル）
−２−（４−シアノベンゾイルイミノ）−３,４− ジメ
チル−３Ｈ−チアゾリン−５−カルボキサミド（化合物
７）（６５８ｍｇ）を得た。Example 7 Compound 1 (3.00 g), methylene chloride (30 ml),
Into a mixture of dioxane (30 ml) and water (30 ml),
Add 3.12 ml of 10% sodium hydroxide aqueous solution, and add 8
The mixture was stirred at 0 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of pivaloyloxymethyl iodide (3.63 g) in 20 ml of DMF was added dropwise to a suspension of the obtained residue in 100 ml of DMF, and the mixture was stirred at room temperature for 16 hours. The reaction mixture is poured into water, and the precipitated crystals are collected by filtration and washed with methylene chloride to give N
-(2-pivaloyloxymethoxycarbonylethyl)
2- (4-Cyanobenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 7) (658 mg) was obtained.
【００５８】融点 １１３〜１１５℃。Melting point 113-115 ° C.
【００５９】実施例８ 化合物７を用いて、実施例２〜３と同様の反応操作を行
い以下の化合物を得た。Example 8 Using compound 7, the same reaction procedure as in Examples 2 to 3 was carried out to obtain the following compound.
【００６０】Ｎ−（２−ピバロイルオキシメトキシカル
ボニルエチル）−２−（４−チオカルバモイルベンゾイ
ルイミノ）−３,４−ジメチル−３Ｈ−チアゾリン−５
−カルボ キサミド（化合物８） 融点 １９４．５〜１９８℃。N- (2-pivaloyloxymethoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3,4-dimethyl-3H-thiazoline-5
-Carboxamide (Compound 8) Melting point 194.5-198 ° C.
【００６１】Ｎ−（２−ピバロイルオキシメトキシカル
ボニルエチル）−２−［４−（メチルチオイミドイル）
ベンゾイルイミノ］−３,４−ジメチル−３Ｈ−チア ゾ
リン−５−カルボキサミド ヨウ化水素酸塩（化合物
９） 融点 １７３〜１７３．５℃。N- (2-pivaloyloxymethoxycarbonylethyl) -2- [4- (methylthioimidoyl)
Benzoylimino] -3,4-dimethyl-3H-thiazolin-5-carboxamide hydroiodide (Compound 9), melting point 173-1735C.
【００６２】実施例９ 化合物１（５.００ｇ）、塩化メチレン（２０ｍｌ）、
メタノール（２０ｍｌ）の混合物に１０％水酸化ナトリ
ウム水溶液（２０ｍｌ）を加え、室温で２時間攪拌し
た。Example 9 Compound 1 (5.00 g), methylene chloride (20 ml),
A 10% aqueous sodium hydroxide solution (20 ml) was added to a mixture of methanol (20 ml), and the mixture was stirred at room temperature for 2 hours.
【００６３】反応混合物を溶媒留去したのち３％塩酸を
加え、析出した結晶を濾取して Ｎ−（２−カルボキシ
エチル）−２−（４−シアノベンゾイルイミノ）−３,
４−ジメチル−３Ｈ−チアゾリン−５−カルボキサミド
（化合物１０）（４．６５ｇ）を得た。After distilling off the solvent from the reaction mixture, 3% hydrochloric acid was added, and the precipitated crystals were collected by filtration to give N- (2-carboxyethyl) -2- (4-cyanobenzoylimino) -3,
4-Dimethyl-3H-thiazoline-5-carboxamide (Compound 10) (4.65 g) was obtained.
【００６４】融点 ２４７〜２４７．５℃（分解）。Melting point 247-247.5 ° C. (decomposition).
【００６５】実施例１０ 化合物１０（２.００ｇ）のＤＭＦ懸濁液に攪拌下Ｎ，
Ｎ−ジメチルエタノールアミン（０．５９ｍｌ）、１−
エチル−３−｛３−（ジメチルアミノ）プロピル｝−カ
ルボジイミド塩酸塩（１．１３ｇ）、４−ジメチルアミ
ノピリジン（０．１２ｇ）を順次加え室温で１４時間攪
拌した。反応混合物を水にあけ酢酸エチルで抽出した。
酢酸エチル層を飽和食塩水洗浄、無水硫酸マグネシウム
乾燥後減圧濃縮した。残渣をシリカゲルカラムクロマト
グラフィー（メタノール−塩化メチレン）に付し、Ｎ−
［２−（Ｎ，Ｎ−ジメチルアミノエチルオキシ）カルボ
ニルエチル］−２−（４−シアノベンゾイルイミノ）−
３,４−ジメチル−３Ｈ−チアゾリン−５−カルボキサ
ミド（化合物１１）（１．０１ｇ）を得た。Example 10 A suspension of Compound 10 (2.00 g) in DMF was stirred under N,
N-dimethylethanolamine (0.59 ml), 1-
Ethyl-3- {3- (dimethylamino) propyl} -carbodiimide hydrochloride (1.13 g) and 4-dimethylaminopyridine (0.12 g) were sequentially added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methanol-methylene chloride), N-
[2- (N, N-Dimethylaminoethyloxy) carbonylethyl] -2- (4-cyanobenzoylimino)-
There was obtained 3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 11) (1.01 g).
【００６６】融点 １３１〜１３３.５℃。Melting point 131-133.5 ° C.
【００６７】実施例１１ 化合物１０（２．０ｇ）、４−（２−ヒドロキシエチ
ル）モルホリン（０．７２ｍｌ）を用いて、実施例１０
および２と同様の反応操作を行い以下の化合物を得た。Example 11 Using Compound 10 (2.0 g) and 4- (2-hydroxyethyl) morpholine (0.72 ml), Example 10
The same reaction procedure as in and 2 was performed to obtain the following compound.
【００６８】Ｎ−［２−（２−モルホリノエトキシカル
ボニル）エチル］−２−（４−シアノベンゾイルイミ
ノ）−３,４−ジメチル−３Ｈ−チアゾリン−５−カル
ボキサミド （化合物１２） 融点 １０７〜１０９℃。N- [2- (2-morpholinoethoxycarbonyl) ethyl] -2- (4-cyanobenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 12) Melting point 107-109 ° C .
【００６９】Ｎ−［２−（２−モルホリノエトキシカル
ボニル）エチル］−２−（４−チオカルバモイルベンゾ
イルイミノ）−３,４−ジメチル−３Ｈ−チアゾリン−
５−カル ボキサミド（化合物１３）1 Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6、δ）；２．４０（４Ｈ，
ｔ，Ｊ＝６Ｈｚ），２．５４（２Ｈ，ｔ，Ｊ＝６Ｈ
ｚ），２．５７（２Ｈ，ｔ，Ｊ＝６Ｈｚ），２．６０
（３Ｈ，ｓ），３．４５（２Ｈ，ｑ，Ｊ＝６Ｈｚ），
３．５４（２Ｈ，ｔ，Ｊ＝６Ｈｚ），３．６６（２Ｈ，
ｔ，Ｊ＝６Ｈｚ），３．８３（３Ｈ，ｓ），４．１４
（２Ｈ，ｔ，Ｊ＝６Ｈｚ），７．９５（２Ｈ，ｄ，Ｊ＝
８Ｈｚ），８．２２（２Ｈ，ｄ，Ｊ＝８Ｈｚ），８．３
０（１Ｈ，ｔ，Ｊ＝６Ｈｚ），９．６１（１Ｈ，ｂｒ
ｓ），９．９９（１Ｈ，ｂｒｓ）。N- [2- (2-morpholinoethoxycarbonyl) ethyl] -2- (4-thiocarbamoylbenzoylimino) -3,4-dimethyl-3H-thiazoline-
5-Carboxamide (Compound 13) 1 H-NMR (DMSO-d 6 , δ); 2.40 (4H,
t, J = 6 Hz), 2.54 (2H, t, J = 6H
z), 2.57 (2H, t, J = 6Hz), 2.60
(3H, s), 3.45 (2H, q, J = 6Hz),
3.54 (2H, t, J = 6Hz), 3.66 (2H,
t, J = 6 Hz), 3.83 (3H, s), 4.14
(2H, t, J = 6Hz), 7.95 (2H, d, J =
8 Hz), 8.22 (2H, d, J = 8 Hz), 8.3
0 (1H, t, J = 6Hz), 9.61 (1H, br
s), 9.99 (1H, brs).
【００７０】実施例１２ ６０％油性水素化ナトリウム（０.３８４ｇ）のＤＭＦ
（３０ｍｌ）懸濁液に、氷冷下 化合物１（３.０９
ｇ）を加え、室温で１時間攪拌した。反応混合物にヨウ
化メチル（０.６０ｍｌ）を加え、さらに室温で４０分
間攪拌した。Example 12 60% oily sodium hydride (0.384 g) in DMF
In a (30 ml) suspension, the compound 1 (3.09 under ice cooling) was added.
g) was added, and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.60 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 40 minutes.
【００７１】反応混合物を水にあけ、析出した結晶を濾
取し、得られた粗結晶をシリカゲルカラムクロマトグラ
フィー（酢酸エチル）に付し、塩化メチレンとヘキサン
の混液で再結晶して Ｎ−メチル−Ｎ−（２−メトキシ
カルボニルエチル）−２−（４−シアノ ベンゾイルイ
ミノ）−３,４−ジメチル−３Ｈ−チアゾリン−５−カ
ルボキサミド（ 化合物１４）（１５.９７ｇ）を得た。The reaction mixture was poured into water, the precipitated crystals were collected by filtration, the obtained crude crystals were subjected to silica gel column chromatography (ethyl acetate), and recrystallized with a mixed solution of methylene chloride and hexane to give N-methyl. -N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 14) (15.97 g) was obtained.
【００７２】融点 １９５．５〜１９７．５℃。Melting point 195.5-197.5 ° C.
【００７３】実施例１３ 化合物１４を用いて、実施例２〜４と同様の反応操作を
行い以下の化合物を得た。Example 13 Using the compound 14, the same reaction operation as in Examples 2 to 4 was carried out to obtain the following compound.
【００７４】Ｎ−メチル−Ｎ−（２−メトキシカルボニ
ルエチル）−２−（４−チオカルバモイルベンゾイルイ
ミノ）−３,４−ジメチル−３Ｈ−チアゾリン−５−カ
ルボキサミド （化合物１５） 融点 ２１９〜２２０℃。N-methyl-N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 15) Melting point 219-220 ° C .
【００７５】Ｎ−メチル−Ｎ−（２−メトキシカルボニ
ルエチル）−２−［４−（メチルチオイミドイル）ベン
ゾイルイミノ］−３,４−ジメチル−３Ｈ−チアゾリン
−５−カル ボキサミド ヨウ化水素酸塩（化合物１
６）。N-Methyl-N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3,4-dimethyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 1
6).
【００７６】1Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6、δ）；２．
３３（３Ｈ，ｓ），２．６６（３Ｈ，ｔ，Ｊ＝６Ｈ
ｚ），２．８４（３Ｈ，ｓ），２．９９（３Ｈ，ｓ），
３．６０（３Ｈ，ｓ），３．６６（２Ｈ，ｔ，Ｊ＝６Ｈ
ｚ），３．８３（３Ｈ，ｓ），７．９７（２Ｈ，ｄ，Ｊ
＝８Ｈｚ），８．４２（２Ｈ，ｄ，Ｊ＝８Ｈｚ）。 1 H-NMR (DMSO-d 6 , δ); 2.
33 (3H, s), 2.66 (3H, t, J = 6H
z), 2.84 (3H, s), 2.99 (3H, s),
3.60 (3H, s), 3.66 (2H, t, J = 6H
z), 3.83 (3H, s), 7.97 (2H, d, J
= 8 Hz), 8.42 (2H, d, J = 8 Hz).
【００７７】Ｎ−メチル−Ｎ−（２−メトキシカルボニ
ルエチル）−２−（４−アミジノベンゾ イルイミノ）
−３,４−ジメチル−３Ｈ−チアゾリン−５−カルボキ
サミド 酢酸塩（化合物１７） 融点 ２０２〜２０３℃。N-methyl-N- (2-methoxycarbonylethyl) -2- (4-amidinobenzoylimino)
-3,4-Dimethyl-3H-thiazoline-5-carboxamide acetate (Compound 17) Melting point 202-203 ° C.
【００７８】実施例１４ 化合物１７（０.５ｇ）、水（２．０ｍｌ）、４７％臭
化水素酸水溶液（１.５ｍｌ）の混合物を８０℃で１時
間攪拌した。反応混合物を氷冷して析出した結晶を濾取
して Ｎ−メチル−Ｎ−（２−カルボキシエチル）−２
−（４−アミジノベン ゾイルイミノ）−３,４−ジメチ
ル−３Ｈ−チアゾリン−５−カルボキサミド・臭化 水
素酸塩（化合物１８）（０.１４ｇ）を得た。Example 14 A mixture of compound 17 (0.5 g), water (2.0 ml) and 47% aqueous hydrobromic acid solution (1.5 ml) was stirred at 80 ° C. for 1 hour. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration and N-methyl-N- (2-carboxyethyl) -2.
There was obtained-(4-amidinobenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide hydrobromide (Compound 18) (0.14 g).
【００７９】融点 ２１５〜２２３℃。Melting point 215-223 ° C.
【００８０】実施例１５ （１）４−ヒドロキシメチル安息香酸メチル（２．０
ｇ）、メタノール（５ｍｌ）、１０％水酸化ナトリウム
水溶液（４．８ｍｌ）の混合物を室温で２０時間攪拌し
た。反応混合物を溶媒留去し、得られた残渣のＤＭＦ
（５０ｍｌ）懸濁液に攪拌下２−アミノ−４−メチルチ
アゾール−５−カルボン酸エチルエステル（２．９４
ｇ）、１−ヒドロキシベンゾトリアゾール一水和物
（３.６８ｇ）、１− エチル−３−［３−（ジメチルア
ミノ）プロピル］−カルボジイミド塩酸塩（２.５ ３
ｇ）を順次加え８０℃で６時間攪拌した。反応混合物を
３％塩酸にあけ、析出した結晶を濾取して ２−（４−
ヒドロキシメチルベンゾイルアミド）−４−メチルチア
ゾール−５−カルボン酸エチル（２.８７ｇ）を得た。Example 15 (1) Methyl 4-hydroxymethylbenzoate (2.0
A mixture of g), methanol (5 ml) and 10% aqueous sodium hydroxide solution (4.8 ml) was stirred at room temperature for 20 hours. The solvent was distilled off from the reaction mixture, and the obtained residue was DMF.
2-Amino-4-methylthiazole-5-carboxylic acid ethyl ester (2.94) was added to the suspension (50 ml) with stirring.
g), 1-hydroxybenzotriazole monohydrate (3.68 g), 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (2.53).
g) was sequentially added and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was poured into 3% hydrochloric acid, and the precipitated crystals were collected by filtration and 2- (4-
Obtained ethyl hydroxymethylbenzoylamide) -4-methylthiazole-5-carboxylate (2.87 g).
【００８１】融点 ２００〜２０２℃。Melting point 200-202 ° C.
【００８２】（２）２−（４−ヒドロキシメチルベンゾ
イルアミド）−４−メチルチアゾール−５−カルボン酸
エチルを用いて、実施例１と同様の反応操作を行い２−
（４−ヒドロキシメチルベンゾイルイミノ）−３，４−
ジメチル−３Ｈ−チアゾリン−５−カルボン酸エチルを
得た。(2) Using ethyl 2- (4-hydroxymethylbenzoylamide) -4-methylthiazole-5-carboxylate, the same reaction procedure as in Example 1 was carried out.
(4-Hydroxymethylbenzoylimino) -3,4-
Obtained ethyl dimethyl-3H-thiazoline-5-carboxylate.
【００８３】融点 １９３〜１９４℃。Melting point 193-194 ° C.
【００８４】（３）２−（４−ヒドロキシメチルベンゾ
イルイミノ）−３，４−ジメチル−３Ｈ−チアゾリン−
５−カルボン酸エチル（１.０ｇ）、塩化メチレン（２
０ｍｌ）、メタノール（２０ｍｌ）の混合物に１０％水
酸化ナトリウム水溶液（４．８ｍｌ）を加え、室温で１
３時間攪拌した。反応混合物を溶媒留去して３％塩酸を
加え析出した結晶を濾取した。この結晶のＤＭＦ懸濁液
に攪拌下β−アラニンメチルエステル塩酸塩（０.４２
ｇ）、トリエチルアミン（０．４２ｍｌ）、１−ヒドロ
キシベンゾトリアゾール一水和物（０.９２ｇ）、１−
エチル−３−｛３−（ジ メチルアミノ）プロピル｝−
カルボジイミド塩酸塩（０.５７ｇ）を順次加え室温で
６８時間攪拌した。(3) 2- (4-hydroxymethylbenzoylimino) -3,4-dimethyl-3H-thiazoline-
Ethyl 5-carboxylate (1.0 g), methylene chloride (2
0 ml) and a mixture of methanol (20 ml), 10% aqueous sodium hydroxide solution (4.8 ml) was added, and the mixture was stirred at room temperature for 1 hour.
Stir for 3 hours. The reaction mixture was evaporated, 3% hydrochloric acid was added, and the precipitated crystals were collected by filtration. A β-alanine methyl ester hydrochloride (0.42) was added to a suspension of the crystals in DMF with stirring.
g), triethylamine (0.42 ml), 1-hydroxybenzotriazole monohydrate (0.92 g), 1-
Ethyl-3- {3- (dimethylamino) propyl}-
Carbodiimide hydrochloride (0.57 g) was sequentially added, and the mixture was stirred at room temperature for 68 hours.
【００８５】反応混合物を３％塩酸にあけ酢酸エチルで
抽出し、酢酸エチル層を飽和炭酸水素ナトリウム水溶液
および飽和食塩水洗浄、無水硫酸マグネシウム乾燥後減
圧濃縮した。The reaction mixture was poured into 3% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
【００８６】得られた残渣を塩化メチレンとヘキサンの
混液で再結晶して Ｎ−（２−メトキシカルボニルエチ
ル）−２−（４−ヒドロキシメチルベンゾイルイミノ）
−３,４−ジメチル−３Ｈ−チアゾリン−５−カルボキ
サミド（化合物１９）（０.94 ｇ）を得た。The obtained residue was recrystallized from a mixed solution of methylene chloride and hexane to give N- (2-methoxycarbonylethyl) -2- (4-hydroxymethylbenzoylimino).
-3,4-Dimethyl-3H-thiazoline-5-carboxamide (Compound 19) (0.94 g) was obtained.
【００８７】融点 ２０７〜２０８.５℃。Melting point 207-208.5 ° C.
【００８８】実施例１６ 化合物１９（０．５ｇ）のメタノール（１０ｍｌ）溶液
に１０％水酸化ナトリウム水溶液（２．０ｍｌ）を加
え、８０℃で１時間攪拌した。反応混合物を溶媒留去し
て３％塩酸を加え析出した結晶を濾取して Ｎ−（２−
カルボキシエチル）−２−（４−ヒドロキシメチルベン
ゾイルイミノ）−３,４−ジメチル− ３Ｈ−チアゾリン
−５−カルボキサミド（化合物２０）（０．４２２ｇ）
を得た。 融点 ２０４〜２０６℃。Example 16 To a solution of the compound 19 (0.5 g) in methanol (10 ml) was added 10% aqueous sodium hydroxide solution (2.0 ml), and the mixture was stirred at 80 ° C. for 1 hour. The solvent was distilled off from the reaction mixture, 3% hydrochloric acid was added, and the precipitated crystals were collected by filtration to give N- (2-
Carboxyethyl) -2- (4-hydroxymethylbenzoylimino) -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 20) (0.422g)
Got Melting point 204-206 ° C.
【００８９】実施例１７ ジ−ｔｅｒｔ−ブチルジカーボネート（２．１２ｇ）、
テトラヒドロフラン（５０ｍｌ）、化合物４（３．０
ｇ）の混合物に、氷冷下トリエチルアミン（１．８ｍ
ｌ）、水（５０ｍｌ）を加え、室温で３時間攪拌した。
反応混合物を溶媒留去し析出した結晶を濾取して Ｎ−
（２−メトキシカルボニルエチル）−２−［４− （Ｎ
−ｔｅｒｔ−ブチルカルボニルアミジノ）ベンゾイルイ
ミノ］−３,４−ジメ チル−３Ｈ−チアゾリン−５−カ
ルボキサミド（化合物２１）（３．１２ｇ）を得た。Example 17 Di-tert-butyl dicarbonate (2.12 g),
Tetrahydrofuran (50 ml), compound 4 (3.0
g), a mixture of triethylamine (1.8 m) under ice cooling.
1) and water (50 ml) were added, and the mixture was stirred at room temperature for 3 hours.
The solvent was distilled off from the reaction mixture, and the precipitated crystals were collected by filtration to give N-
(2-Methoxycarbonylethyl) -2- [4- (N
-Tert-Butylcarbonylamidino) benzoylimino] -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 21) (3.12 g) was obtained.
【００９０】融点 ２０２〜２０３℃。Melting point 202-203 ° C.
【００９１】実施例１８ 化合物２１（１．０ｇ）のメタノール（１０ｍｌ）溶液
に１０％水酸化ナトリウム水溶液（０．９５ｍｌ）を加
え、７０℃で２時間攪拌した。反応混合物を溶媒留去し
て析出した結晶を濾取して Ｎ−（２−カルボキシエチ
ル）−２−［４−（ Ｎ−ｔｅｒｔ−ブチルカルボニル
アミジノ）ベンゾイルイミノ］−３,４−ジメチ ル−３
Ｈ−チアゾリン−５−カルボキサミド ナトリウム塩
（化合物２２）（０．９８ｇ）を得た。Example 18 To a solution of compound 21 (1.0 g) in methanol (10 ml) was added 10% aqueous sodium hydroxide solution (0.95 ml), and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was evaporated and the precipitated crystals were collected by filtration to give N- (2-carboxyethyl) -2- [4- (N-tert-butylcarbonylamidino) benzoylimino] -3,4-dimethyl-. Three
H-thiazoline-5-carboxamide sodium salt (Compound 22) (0.98 g) was obtained.
【００９２】１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ6、δ）；
１．４５（９Ｈ，ｓ），２．０９（２Ｈ，ｔ，Ｊ＝６Ｈ
ｚ），２．６２（３Ｈ，ｓ），３．４３（２Ｈ，ｑ，Ｊ
＝６Ｈｚ），３．８３（３Ｈ，ｓ），８．０３（２Ｈ，
ｄ，Ｊ＝８Ｈｚ），８．２６（２Ｈ，ｄ，Ｊ＝８Ｈ
ｚ），９．００（１Ｈ，ｔ，Ｊ＝８Ｈｚ），９．１２
（２Ｈ，ｂｒｓ）。 1 H-NMR (DMSO-d 6 , δ);
1.45 (9H, s), 2.09 (2H, t, J = 6H
z), 2.62 (3H, s), 3.43 (2H, q, J
= 6 Hz), 3.83 (3H, s), 8.03 (2H,
d, J = 8 Hz), 8.26 (2H, d, J = 8H)
z), 9.00 (1H, t, J = 8Hz), 9.12.
(2H, brs).
【００９３】実施例１９ 化合物２２（０．８７ｇ）、ＤＭＦ（１５ｍｌ）、ヨウ
化ナトリウム（０．２８ｇ）の混合物に２−クロロ−
Ｎ，Ｎ−ジメチルアセトアミド（０．１９ｍｌ）を加
え、室温で５時間攪拌した。反応混合物を水にあけ、析
出した結晶を濾取して Ｎ−［２−（Ｎ，Ｎ−ジメチル
カルバモイルメトキシカルボニル）エチル］−２−［４
−（Ｎ−ｔｅｒｔ−ブチルカルボニルアミジノ）ベンゾ
イルイミノ］−３,４−ジメチル−３Ｈ−チアゾリン−
５−カルボキサミド （化合物２ ３）（０．８３ｇ）
を得た。Example 19 2-Chloro-in a mixture of compound 22 (0.87 g), DMF (15 ml) and sodium iodide (0.28 g).
N, N-Dimethylacetamide (0.19 ml) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give N- [2- (N, N-dimethylcarbamoylmethoxycarbonyl) ethyl] -2- [4
-(N-tert-butylcarbonylamidino) benzoylimino] -3,4-dimethyl-3H-thiazoline-
5-carboxamide (Compound 23) (0.83 g)
Got
【００９４】融点 １６７〜１６９℃。Melting point 167-169 ° C.
【００９５】実施例２０ 化合物２３（０．７５ｇ）の塩化メチレン（５ｍｌ）溶
液にトリフルオロ酢酸（７ｍｌ）を加え、室温で２時間
攪拌した。Example 20 Trifluoroacetic acid (7 ml) was added to a solution of compound 23 (0.75 g) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 2 hours.
【００９６】反応混合物に水を加え、析出した結晶を濾
取して Ｎ−［２−（Ｎ，Ｎ−ジメチルカルバモイルメ
トキシカルボニル）エチル］−２−（４−アミジノベン
ゾイルイミノ）−３,４−ジメチル−３Ｈ−チアゾリン
−５−カルボキサミドトリフルオロ酢酸塩（化合物２
４）（０．７５４ｇ）を得た。Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give N- [2- (N, N-dimethylcarbamoylmethoxycarbonyl) ethyl] -2- (4-amidinobenzoylimino) -3,4-. Dimethyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (compound 2
4) (0.754g) was obtained.
【００９７】融点 ２１８〜２１９℃。Melting point 218-219 ° C.
【００９８】実施例２１ 化合物２２を用いて、実施例１９、２０と同様の反応操
作を行い、以下の化合物を得た。Example 21 Using compound 22, the same reaction procedure as in examples 19 and 20 was carried out to obtain the following compound.
【００９９】Ｎ−［２−（Ｎ，Ｎ−ジエチルカルバモイ
ルメトキシカルボニル）エチル］−２−［４−（Ｎ−ｔ
ｅｒｔ−ブチルカルボニルアミジノ）ベンゾイルイミ
ノ］−３,４−ジメチル−３Ｈ−チアゾリン−５−カル
ボキサミド （化合物２５ ） 融点 １５４〜１５６℃。N- [2- (N, N-diethylcarbamoylmethoxycarbonyl) ethyl] -2- [4- (Nt)
ert-Butylcarbonylamidino) benzoylimino] -3,4-dimethyl-3H-thiazoline-5-carboxamide (Compound 25) Melting point 154-156 ° C.
【０１００】Ｎ−［２−（Ｎ，Ｎ−ジエチルカルバモイ
ルメトキシカルボニル）エチル］−２−（４−アミジノ
ベンゾイルイミノ）−３,４−ジメチル−３Ｈ−チアゾ
リン−５−カルボキサミド トリフルオロ酢酸塩（化合
物２６） 融点 ２０６．５〜２０７．５℃。N- [2- (N, N-diethylcarbamoylmethoxycarbonyl) ethyl] -2- (4-amidinobenzoylimino) -3,4-dimethyl-3H-thiazo
Phosphorus-5-carboxamide trifluoroacetic acid salt (Compound 26) Melting point 206.5-207.5 ° C.
【０１０１】Ｎ−［２−（５−メチル−２−オキソ−
１，３−ジオキソレン−４−イルメトキシカルボニル）
エチル］−２−［４−（Ｎ−ｔｅｒｔ−ブチルカルボニ
ルアミジノ）ベンゾイルイミノ］−３,４−ジメチル−
３Ｈ−チアゾリン−５−カルボキサミド（化合物２７） 融点 １０５．５〜１０７．５℃。N- [2- (5-methyl-2-oxo-
1,3-dioxolen-4-ylmethoxycarbonyl)
Ethyl] -2- [4- (N-tert-butylcarbonylamidino) benzoylimino] -3,4-dimethyl-
3H-thiazoline-5-carboxamide (Compound 27) Melting point 105.5-107.5 ° C.
【０１０２】実施例２２ （１）テレフタルアルデヒド酸メチル（１１．５ｇ）、
硫黄（２．２８ｇ）、モルホリン（１４０ｍｌ）の混合
物を加熱還流下２０分攪拌した。反応混合物を冷却した
後析出した結晶を濾取し、メタノール−水で再結晶する
ことにより ４−（モルホリノチオカルボニル）安息香
酸メチル（１５．７ｇ）を得た。Example 22 (1) Methyl terephthalaldehyde (11.5 g),
A mixture of sulfur (2.28 g) and morpholine (140 ml) was stirred with heating under reflux for 20 minutes. After cooling the reaction mixture, the precipitated crystals were collected by filtration and recrystallized from methanol-water to obtain methyl 4- (morpholinothiocarbonyl) benzoate (15.7 g).
【０１０３】融点 １２３．５〜１２５℃。Melting point 123.5-125 ° C.
【０１０４】（２）４−（モルホリノチオカルボニル）
安息香酸メチル（６．１ｇ）、１０％水酸化ナトリウム
水溶液（１８ｍｌ）、メタノール（１００ｍｌ）の混合
物を加熱還流下２時間攪拌した。反応混合物を減圧濃縮
し、３％塩酸で酸性にした後析出した結晶を濾取してカ
ルボン酸を得た。このカルボン酸と、１−ヒドロキシベ
ンゾトリアゾール一水和物（６．０９ｇ）、１−エチル
−３−［３−（ジメチルアミノ）プロピル］−カルボジ
イミド塩酸塩（４．２２ｇ）、２−アミノ−４−メ チ
ル−５−チアゾールカルボン酸エチル（４．８３ｇ）、
ＤＭＦ（１００ｍｌ）、トリエチルアミン（３．１ｍ
ｌ）の混合物を６０℃で６時間攪拌した。反応混合物を
３％塩酸にあけ、析出した結晶を濾取し、２−［４−
（モルホリノチオカルボニル）ベンゾイルアミノ］−４
−メチル−５−チアゾールカルボン酸エチル（８．３４
ｇ）を得た。(2) 4- (morpholinothiocarbonyl)
A mixture of methyl benzoate (6.1 g), 10% aqueous sodium hydroxide solution (18 ml) and methanol (100 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, acidified with 3% hydrochloric acid, and the precipitated crystals were collected by filtration to give a carboxylic acid. This carboxylic acid, 1-hydroxybenzotriazole monohydrate (6.09 g), 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (4.22 g), 2-amino-4. -Ethyl methyl-5-thiazolecarboxylate (4.83 g),
DMF (100 ml), triethylamine (3.1 m
The mixture of l) was stirred at 60 ° C. for 6 hours. The reaction mixture was poured into 3% hydrochloric acid, and the precipitated crystals were collected by filtration, 2- [4-
(Morpholinothiocarbonyl) benzoylamino] -4
Ethyl -methyl-5-thiazolecarboxylate (8.34
g) was obtained.
【０１０５】融点 ２６５℃（分解）。Melting point 265 ° C (decomposition).
【０１０６】（３）６０％油性水素化ナトリウム（０．
７９ｇ）のＤＭＦ（１００ｍｌ）懸濁液に、氷冷下 ２
−［４−（モルホリノチオカルボニル）ベンゾイルアミ
ノ］−４−メチル−５−チアゾールカルボン酸エチル
（５．９１ｇ）を加え、室温で１時間攪拌した。反応混
合物にヨウ化メチル（２．５５ｇ）のＤＭＦ（４０ｍ
ｌ）溶液を滴下し、さらに室温で２時間攪拌した。反応
混合物を３％塩酸にあけ、析出した結晶を濾取し、得ら
れた粗結晶を酢酸エチルで抽出し、溶媒留去して２−
［４−（モルホリノチオカルボニル）ベンゾイルイミ
ノ］−３、４−ジメチル−３Ｈ−チアゾリン−５−カル
ボン酸エチル（４．２６ｇ）を得た。(3) 60% oily sodium hydride (0.
79 g) in a DMF (100 ml) suspension under ice cooling 2
Ethyl-[4- (morpholinothiocarbonyl) benzoylamino] -4-methyl-5-thiazolecarboxylate (5.91 g) was added, and the mixture was stirred at room temperature for 1 hr. Methyl iodide (2.55 g) in DMF (40 m) was added to the reaction mixture.
l) The solution was added dropwise, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was poured into 3% hydrochloric acid, the precipitated crystals were collected by filtration, the obtained crude crystals were extracted with ethyl acetate, and the solvent was distilled off to give 2-
Ethyl [4- (morpholinothiocarbonyl) benzoylimino] -3,4-dimethyl-3H-thiazoline-5-carboxylate (4.26 g) was obtained.
【０１０７】融点 ２６３〜２６６℃（分解）。Melting point 263-266 ° C (decomposition).
【０１０８】（４）２−［４−（モルホリノチオカルボ
ニル）ベンゾイルイミノ］−３、４−ジメチル−３Ｈ−
チアゾリン−５−カルボン酸エチル（３．９０ｇ）、１
０％水酸化ナトリウム水溶液（１４．４ｍｌ）、メタノ
ール（５０ｍｌ）、塩化メチレン（５０ｍｌ）の混合物
を室温で２時間攪拌した。反応混合物を３％塩酸にあ
け、析出した結晶を濾取してカルボン酸を得た。このカ
ルボン酸と、β−アラニンメチルエステル（２．５１
ｇ）、１−ヒドロキシベンゾトリアゾール一水和物
（５．５１ｇ）、１−エチル−３−［３−（ジメチルア
ミノ）プロピル］−カルボジ イミド塩酸塩（３．４５
ｇ）、トリエチルアミン（２．５ｍｌ）、ＤＭＦ（１０
０ｍｌ）の混合物を室温で３２時間攪拌した。反応混合
物を３％塩酸にあけ、析出した結晶を濾取して Ｎ−
（２−メトキシカルボニルエチル）−２−［４−（モル
ホリノチオカルボニル）ベンゾイルイミノ］−３、４−
ジメチル−３Ｈ−チアゾリン−５−カルボキサミド（化
合物２８）（３．７４ｇ）を得た。 融点 ２２７．５〜２３１℃。(4) 2- [4- (morpholinothiocarbonyl) benzoylimino] -3,4-dimethyl-3H-
Thiazoline-5-carboxylate ethyl (3.90 g), 1
A mixture of 0% aqueous sodium hydroxide solution (14.4 ml), methanol (50 ml) and methylene chloride (50 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into 3% hydrochloric acid, and the precipitated crystals were collected by filtration to give a carboxylic acid. This carboxylic acid and β-alanine methyl ester (2.51
g), 1-hydroxybenzotriazole monohydrate (5.51 g), 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (3.45).
g), triethylamine (2.5 ml), DMF (10
(0 ml) was stirred at room temperature for 32 hours. The reaction mixture was poured into 3% hydrochloric acid, and the precipitated crystals were collected by filtration and N-
(2-Methoxycarbonylethyl) -2- [4- (morpholinothiocarbonyl) benzoylimino] -3,4-
Dimethyl-3H-thiazoline-5-carboxamide (Compound 28) (3.74 g) was obtained. Melting point 227.5-231 [deg.] C.
【０１０９】実施例２３ 化合物２８（０．４ｇ）のアセトン（１０ｍｌ）懸濁液
に、ヨウ化メチル（１．２４ｍｌ）を加え、加熱還流下
２．５時間攪拌した。反応混合物を冷却し、析出した結
晶を濾取して ヨウ化 α−メチルチオ−４−〔｛５−
［２−（メトキシカルボニル）エチルアミノカルボニ
ル］−３，４−ジメチル−３Ｈ−チアゾリン−２−デ
ン｝アミノカルボニル〕ベンジリデンモルホリニウム
（０．３９ｇ）（化合物２９）を得た。Example 23 Methyl iodide (1.24 ml) was added to a suspension of compound 28 (0.4 g) in acetone (10 ml), and the mixture was stirred for 2.5 hours with heating under reflux. The reaction mixture was cooled, and the precipitated crystals were collected by filtration to give i-α-methylthio-4-[{5-
[2- (Methoxycarbonyl) ethylaminocarbonyl] -3,4-dimethyl-3H-thiazoline-2-den} aminocarbonyl] benzylidenemorpholinium (0.39 g) (Compound 29) was obtained.
【０１１０】融点 ２１６〜２１９℃（分解）。Melting point 216-219 ° C (decomposition).
【０１１１】実施例２４ （１）１−（４−シアノベンゾイル）−３−イソプロピ
ルチオ尿素（１．４ｇ）、２−クロロアセト酢酸エチル
（２．２１ｇ）、トルエン（２０ｍｌ）の混合物を加熱
還流下２時間攪拌した。反応混合物を冷却して析出した
結晶を濾取し、得られた粗結晶をヘキサンで洗浄し、ト
ルエンで再結晶することにより ２−（４−シアノベン
ゾイルイミノ）−３−イソプロピル−４−メチル−３Ｈ
−チアゾリン−５−カルボン酸エチル（２．０ｇ）を得
た。Example 24 (1) A mixture of 1- (4-cyanobenzoyl) -3-isopropylthiourea (1.4 g), ethyl 2-chloroacetoacetate (2.21 g) and toluene (20 ml) was heated under reflux. Stir for 2 hours. The reaction mixture was cooled, and the precipitated crystals were collected by filtration, the obtained crude crystals were washed with hexane and recrystallized from toluene to give 2- (4-cyanobenzoylimino) -3-isopropyl-4-methyl-. 3H
Obtained ethyl thiazoline-5-carboxylate (2.0 g).
【０１１２】融点 ２０７．５〜２０９℃。Melting point 207.5-209 ° C.
【０１１３】（２）２−（４−シアノベンゾイルイミ
ノ）−３−イソプロピル−４−メチル−３Ｈ−チアゾリ
ン−５−カルボン酸エチルを用い、実施例１と同様の操
作を行なって、Ｎ−（２−メトキシカルボニルエチル）
−２−（４−シアノベンゾイルイミノ）−３−イソプロ
ピル−４−メチル−３Ｈ−チアゾリン−５−カルボキサ
ミド（化合物３０）を得た。(2) Using ethyl 2- (4-cyanobenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxylate, the same procedure as in Example 1 was repeated to obtain N- ( 2-methoxycarbonylethyl)
2- (4-Cyanobenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide (Compound 30) was obtained.
【０１１４】融点 １３９．５〜１４１℃。Melting point 139.5-141 ° C.
【０１１５】実施例２５ Ｎ−（２−メトキシカルボニルエチル）−２−（４−シ
アノベンゾイルイミノ）−３−イソプロピル−４−メチ
ル−３Ｈ−チアゾリン−５−カルボキサミドを原料に用
い、実施例２と同様の操作を行なって、Ｎ−（２−メト
キシカルボニルエチル）−２−（４−チオカルバモイル
ベンゾイルイミノ）−３−イソプロピル−４−メチル−
３Ｈ−チアゾリン−５−カルボキサミド（化合物３１）
を得た。 融点 １７２．５〜１７４℃。Example 25 N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide was used as a starting material, and By performing the same operation, N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-isopropyl-4-methyl-
3H-thiazoline-5-carboxamide (compound 31)
Got Melting point 172.5-174 [deg.] C.
【０１１６】実施例２６ 化合物３１を用いて、実施例１４と同様の反応操作によ
りＮ−（２−カルボキシエチル）−２−（４−チオカル
バモイルベンゾイルイミノ）−３−イソプロピル−４−
メチル−３Ｈ−チアゾリン−５−カルボキサミド（化合
物３２）を得た。Example 26 Using compound 31, N- (2-carboxyethyl) -2- (4-thiocarbamoylbenzoylimino) -3-isopropyl-4- was prepared according to the same reaction procedure as in Example 14.
Methyl-3H-thiazoline-5-carboxamide (compound 32) was obtained.
【０１１７】融点 １７５〜１７６℃（分解）。Melting point 175-176 ° C (decomposition).
【０１１８】実施例２７ ２−（４−シアノベンゾイルイミノ）−３−イソプロピ
ル−４−メチル−３Ｈ−チアゾリン−５−カルボン酸ナ
トリウム塩と対応する原料を用い、実施例１と同様の操
作を行なって、Ｎ−（３−メトキシカルボニルプロピ
ル）−２−（４−シアノベンゾイルイミノ）−３−イソ
プロピル−４−メチル−３Ｈ−チアゾリン−５−カルボ
キサミド（化合物３３）を得た。Example 27 2- (4-Cyanobenzoimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxylic acid sodium salt and the corresponding starting material were used, and the same operation as in Example 1 was carried out. To give N- (3-methoxycarbonylpropyl) -2- (4-cyanobenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide (Compound 33).
【０１１９】融点 １３８〜１３９℃。Melting point 138-139 ° C.
【０１２０】実施例２８ 化合物３３を用いて、実施例２と同様の操作を行なっ
て、Ｎ−（３−メトキシカルボニルプロピル）−２−
（４−チオカルバモイルベンゾイルイミノ）−３−イソ
プロピル−４−メチル−３Ｈ−チアゾリン−５−カルボ
キサミド（化合物３４）を得た。Example 28 Using compound 33 and following the same procedure as in example 2, N- (3-methoxycarbonylpropyl) -2-
(4-Thiocarbamoylbenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide (Compound 34) was obtained.
【０１２１】融点 １０６〜１０７．５℃。Melting point 106-107.5 ° C.
【０１２２】実施例２９ ２−（４−シアノベンゾイルイミノ）−３−イソプロピ
ル−４−メチル−３Ｈ−チアゾリン−５−カルボン酸ナ
トリウム塩と対応する原料を用い、実施例１及び２と同
様の反応操作を行い、以下の化合物を得た。Example 29 2- (4-Cyanobenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxylic acid sodium salt and the corresponding starting materials were used to carry out the same reaction as in Examples 1 and 2. Operation was performed to obtain the following compound.
【０１２３】Ｎ−（５−メトキシカルボニルペンチル）
−２−（４−シアノベンゾイルイミノ）−３−イソプロ
ピル−４−メチル−３Ｈ−チアゾリン−５−カルボキサ
ミド（化合物３５） 融点 １５８．５〜１６０．５℃。N- (5-methoxycarbonylpentyl)
2- (4-Cyanobenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide (Compound 35) Melting point 158.5-160.5 ° C.
【０１２４】Ｎ−（５−メトキシカルボニルペンチル）
−２−（４−チオカルバモイルベンゾイルイミノ）−３
−イソプロピル−４−メチル−３Ｈ−チアゾリン−５−
カルボキサミド（化合物３６） 融点 １１９．５〜１２０．５℃。N- (5-methoxycarbonylpentyl)
-2- (4-thiocarbamoylbenzoylimino) -3
-Isopropyl-4-methyl-3H-thiazoline-5-
Carboxamide (Compound 36) Melting point 119.5-120.5 ° C.
【０１２５】実施例３０ 化合物３０（０．２ｇ）、塩化メチレン（６ｍｌ）、メ
タノール（６ｍｌ）の混合物に６Ｎ水酸化ナトリウム水
溶液（０．１２ｍｌ）を加え、室温で３日間攪拌したの
ち、３％過酸化水素水（０．２３ｍｌ）を加え、室温で
４時間攪拌した。Example 30 A 6N aqueous sodium hydroxide solution (0.12 ml) was added to a mixture of compound 30 (0.2 g), methylene chloride (6 ml) and methanol (6 ml), and the mixture was stirred at room temperature for 3 days and then 3%. Hydrogen peroxide solution (0.23 ml) was added, and the mixture was stirred at room temperature for 4 hours.
【０１２６】反応混合物に５％チオ硫酸ナトリウム水溶
液を加え、溶媒留去した後３％塩酸を加えて析出した結
晶を濾取して Ｎ−（２−カルボキシエチル）−２−
（４−カルバモイルベンゾイルイミノ）−３−イソプロ
ピル−４−メチル−３Ｈ−チアゾリン−５−カルボキサ
ミド（化合物３７）を得た。A 5% aqueous sodium thiosulfate solution was added to the reaction mixture, the solvent was distilled off, 3% hydrochloric acid was added, and the precipitated crystals were collected by filtration and N- (2-carboxyethyl) -2-
(4-carbamoylbenzoylimino) -3-isopropyl-4-methyl-3H-thiazoline-5-carboxamide (Compound 37) was obtained.
【０１２７】融点 ２４１〜２４３℃。Melting point 241-243 ° C.
【０１２８】実施例３１ 化合物３０（０．２ｍｇ）の塩化メチレン（２ｍｌ）溶
液に２Ｍアンモニア／メタノール溶液（１０ｍｌ）を加
え、室温で３日間攪拌した。反応混合物を溶媒留去し、
得られた残渣のメタノール溶液（１０ｍｌ）に、６Ｎ水
酸化ナトリウム水溶液（０．２５ｍｌ）、３％過酸化水
素水（０．２３ｍｌ）を加え室温で２時間半攪拌した。
反応混合物に３％塩酸を加えて溶媒留去し、アセトンと
塩化メチレンの混合液から結晶化させてＮ−（２−カル
バモイルエチル）−２−（４−カルバモイルベンゾイル
イミノ）−３−イソプロピル−４−メチル−３Ｈ−チア
ゾリン−５−カルボキサミド（化合物３８）を得た。Example 31 A 2M ammonia / methanol solution (10 ml) was added to a solution of the compound 30 (0.2 mg) in methylene chloride (2 ml), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off from the reaction mixture,
A 6N aqueous sodium hydroxide solution (0.25 ml) and 3% aqueous hydrogen peroxide (0.23 ml) were added to a methanol solution (10 ml) of the obtained residue, and the mixture was stirred at room temperature for 2 hours and a half.
To the reaction mixture was added 3% hydrochloric acid, the solvent was distilled off, and the mixture was crystallized from a mixed solution of acetone and methylene chloride to give N- (2-carbamoylethyl) -2- (4-carbamoylbenzoylimino) -3-isopropyl-4. -Methyl-3H-thiazoline-5-carboxamide (Compound 38) was obtained.
【０１２９】融点 ２０４〜２０８℃。Melting point 204-208 ° C.
フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/535 ＡＤＵ ＡＥＤ (72)発明者 川島 豊 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内 (72)発明者 畑山 勝男 東京都豊島区高田３丁目24番１号 大正製 薬株式会社内Continuation of front page (51) Int.Cl. 6 Identification number Office reference number FI Technical indication location A61K 31/535 ADU AED (72) Inventor Yutaka Kawashima 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. In-house (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.
Claims (1)
バモイル基、低級アルキルチオイミドイル基、アミジノ
基、窒素原子上の水素原子がアラルキル基もしくはアル
コキシカルボニル基の一個以上で置換されたアミジノ
基、モルホリノチオカルボニル基、ヒドロキシメチル基
または式 （式中、Ｒ13は低級アルキル基を示す。）を示し、Ｒ2
は低級アルキル基を示し、Ｒ3は水素原子または低級ア
ルキル基を示し、ｎは１〜５の整数を示し、Ｒ4は水酸
基、アミノ基、低級アルコキシ基または複素環、低級ア
ルカノイルオキシ基、低級アルコキシ基、低級アルコキ
シアルコキシ基もしくはアミノ基で置換されたアルコキ
シ基、Ｎ，Ｎ−ジ低級アルキルアミノ基を示す。）で表
されるチアゾリン誘導体およびその塩。1. A formula (In the formula, R 1 represents a cyano group, a carbamoyl group, a thiocarbamoyl group, a lower alkylthioimidoyl group, an amidino group, an amidino group in which a hydrogen atom on a nitrogen atom is substituted with one or more aralkyl groups or alkoxycarbonyl groups, Morpholinothiocarbonyl group, hydroxymethyl group or formula (Wherein R 13 represents a lower alkyl group), and R 2
Represents a lower alkyl group, R 3 represents a hydrogen atom or a lower alkyl group, n represents an integer of 1 to 5, R 4 represents a hydroxyl group, amino group, lower alkoxy group or heterocycle, lower alkanoyloxy group, lower An alkoxy group, a lower alkoxyalkoxy group, an alkoxy group substituted with an amino group, or an N, N-dilower alkylamino group is shown. ) The thiazoline derivative and its salt represented by.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP00224195A JP3750143B2 (en) | 1994-01-14 | 1995-01-10 | Thiazoline derivative |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP258894 | 1994-01-14 | ||
| JP6-2588 | 1994-08-05 | ||
| JP00224195A JP3750143B2 (en) | 1994-01-14 | 1995-01-10 | Thiazoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07242647A true JPH07242647A (en) | 1995-09-19 |
| JP3750143B2 JP3750143B2 (en) | 2006-03-01 |
Family
ID=26335594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP00224195A Expired - Fee Related JP3750143B2 (en) | 1994-01-14 | 1995-01-10 | Thiazoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3750143B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003058A1 (en) * | 1995-07-07 | 1997-01-30 | Taisho Pharmaceutical Co., Ltd. | 4-alkylthiazoline derivatives |
-
1995
- 1995-01-10 JP JP00224195A patent/JP3750143B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003058A1 (en) * | 1995-07-07 | 1997-01-30 | Taisho Pharmaceutical Co., Ltd. | 4-alkylthiazoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3750143B2 (en) | 2006-03-01 |
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