JPH0555510B2 - - Google Patents
Info
- Publication number
- JPH0555510B2 JPH0555510B2 JP87289983A JP28998387A JPH0555510B2 JP H0555510 B2 JPH0555510 B2 JP H0555510B2 JP 87289983 A JP87289983 A JP 87289983A JP 28998387 A JP28998387 A JP 28998387A JP H0555510 B2 JPH0555510 B2 JP H0555510B2
- Authority
- JP
- Japan
- Prior art keywords
- chlorophenyl
- thieno
- diazepine
- ethyl
- triazolo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 69
- -1 [1,4] diazepine compound Chemical class 0.000 description 59
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- 150000001875 compounds Chemical class 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000003756 stirring Methods 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 32
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 28
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000002844 melting Methods 0.000 description 21
- 230000008018 melting Effects 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 20
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 19
- 108010003541 Platelet Activating Factor Proteins 0.000 description 19
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 19
- 238000001914 filtration Methods 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- 239000000203 mixture Substances 0.000 description 16
- 235000011054 acetic acid Nutrition 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 13
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000013078 crystal Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 7
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WUJWIURYYPJUEM-UHFFFAOYSA-N 4-(2-chlorophenyl)-2-[2-(4-methoxyphenyl)ethyl]-9-methyl-6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine Chemical compound C1=CC(OC)=CC=C1CCC1=CC(C(=NCC2=NN=C(C)N22)C=3C(=CC=CC=3)Cl)=C2S1 WUJWIURYYPJUEM-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- VMZUTJCNQWMAGF-UHFFFAOYSA-N Etizolam Chemical compound S1C(CC)=CC2=C1N1C(C)=NN=C1CN=C2C1=CC=CC=C1Cl VMZUTJCNQWMAGF-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 210000003169 central nervous system 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
- 239000008120 corn starch Substances 0.000 description 3
- 229940099112 cornstarch Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000007280 thionation reaction Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- FGNAJWFZOBYZLR-UHFFFAOYSA-N 3h-[1,2,4]triazolo[4,3-a][1,4]diazepine Chemical compound N1=CC=CN2CN=NC2=C1 FGNAJWFZOBYZLR-UHFFFAOYSA-N 0.000 description 2
- UNRYNEUZUOGHCV-UHFFFAOYSA-N 4-(2-chlorophenyl)-2-(2-(4-isobutylphenyl)ethyl)-9-methyl-6h-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine Chemical compound C1=CC(CC(C)C)=CC=C1CCC1=CC(C(=NCC2=NN=C(C)N22)C=3C(=CC=CC=3)Cl)=C2S1 UNRYNEUZUOGHCV-UHFFFAOYSA-N 0.000 description 2
- RDYBWHSOCLQMNH-UHFFFAOYSA-N 5-(2-chlorophenyl)-7-(2-phenylethyl)-1,3-dihydrothieno[2,3-e][1,4]diazepine-2-thione Chemical compound ClC1=C(C=CC=C1)C=1C2=C(NC(CN1)=S)SC(=C2)CCC2=CC=CC=C2 RDYBWHSOCLQMNH-UHFFFAOYSA-N 0.000 description 2
- YPXQSGWOGQPLQO-UHFFFAOYSA-N 5-nitro-1,3-dihydrobenzimidazole-2-thione Chemical compound [O-][N+](=O)C1=CC=C2N=C(S)NC2=C1 YPXQSGWOGQPLQO-UHFFFAOYSA-N 0.000 description 2
- OGAZEYYREIOAKI-UHFFFAOYSA-N 7-(2-chlorophenyl)-13-ethyl-4-[2-[4-(2-methylpropyl)phenyl]ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene Chemical compound S1C=2N3C(CC)=NN=C3CN=C(C=3C(=CC=CC=3)Cl)C=2C=C1CCC1=CC=C(CC(C)C)C=C1 OGAZEYYREIOAKI-UHFFFAOYSA-N 0.000 description 2
- VQKVRMMQKKRJAC-UHFFFAOYSA-N 7-(2-chlorophenyl)-13-methyl-4-(2-phenylethyl)-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene Chemical compound S1C=2N3C(C)=NN=C3CN=C(C=3C(=CC=CC=3)Cl)C=2C=C1CCC1=CC=CC=C1 VQKVRMMQKKRJAC-UHFFFAOYSA-N 0.000 description 2
- UGSHFXMQGVBNJG-UHFFFAOYSA-N 7-(2-chlorophenyl)-13-methyl-4-[2-(4-methylphenyl)ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene Chemical compound S1C=2N3C(C)=NN=C3CN=C(C=3C(=CC=CC=3)Cl)C=2C=C1CCC1=CC=C(C)C=C1 UGSHFXMQGVBNJG-UHFFFAOYSA-N 0.000 description 2
- UMJHGTPDFURMHS-UHFFFAOYSA-N 7-(2-chlorophenyl)-13-methyl-4-[2-(4-phenylphenyl)ethyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene Chemical compound S1C=2N3C(C)=NN=C3CN=C(C=3C(=CC=CC=3)Cl)C=2C=C1CCC(C=C1)=CC=C1C1=CC=CC=C1 UMJHGTPDFURMHS-UHFFFAOYSA-N 0.000 description 2
- CDIYYRPFIXXTEL-UHFFFAOYSA-N 7-(2-chlorophenyl)-13-methyl-4-[4-[4-(2-methylpropyl)phenyl]butyl]-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene Chemical compound C1=CC(CC(C)C)=CC=C1CCCCC1=CC(C(=NCC2=NN=C(C)N22)C=3C(=CC=CC=3)Cl)=C2S1 CDIYYRPFIXXTEL-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241001061127 Thione Species 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- KYAWBGDNKNBOJF-UHFFFAOYSA-N chembl442259 Chemical compound C1=CC(CCCC)=CC=C1CCC1=CC(C(=NCC2=NN=C(C)N22)C=3C(=CC=CC=3)Cl)=C2S1 KYAWBGDNKNBOJF-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960004404 etizolam Drugs 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- RMSWMRJVUJSDGN-UHFFFAOYSA-N israpafant Chemical compound C1=CC(CC(C)C)=CC=C1CCC1=CC(C(=NC(C)C2=NN=C(C)N22)C=3C(=CC=CC=3)Cl)=C2S1 RMSWMRJVUJSDGN-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 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 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 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 2
- LZTYEEBQWUSNDU-UHFFFAOYSA-N thieno[2,3-e][1,4]diazepine-2-thione Chemical compound S=C1C=NC=C2C=CSC2=N1 LZTYEEBQWUSNDU-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-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
- 238000002834 transmittance Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- VKKMDKZVKMTEJG-UHFFFAOYSA-N thieno[2,3-e][1,4]diazepin-2-one Chemical compound O=C1C=NC=C2C=CSC2=N1 VKKMDKZVKMTEJG-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Description
〔産業上の利用分野〕
本発明は新規かつ医薬として有用なチエノトリ
アゾロジアゼピン誘導体およびその薬理学的に許
容される酸付加塩に関する。
〔従来の技術〕
米国特許第3904641号明細書に記載されている
ように、６−（ｏ−クロロフエニル）−８−エチル
−１−メチル−4H−ｓ−トリアゾロ〔３，４−
ｃ〕チエノ〔２，３−ｅ〕〔１，４〕ジアゼピン
〔以下、エチゾラム〔国際一般的名称（INN）〕
と称する〕で代表されるある種ののｓ−トリアゾ
ロ〔３，４−ｃ〕チエノ〔２，３−ｅ〕〔１，４〕
ジアゼピン化合物が抗不安活性、抗痙攣活性など
の中枢神経系に対する有用な薬理活性を示すこと
が知られている。
ジヤパニーズ・ジヤーナル・オブ・フアーマコ
ロジー（Japanese Journal of Pharmacology）、
第44巻、381〜391ページ（1987年）にはエチゾラ
ムが血小板活性化因子（plateletactivating
factor；以下PAFと称する）に対して拮抗活性を
示すことが、さらにEP−A194416号明細書には
ｓ−トリアゾロ〔３，４−ｃ〕チエノ〔２，３−
ｅ〕〔１，４〕ジアゼピン−カルボン酸アミド化
合物がPAF拮抗活性を示すことがそれぞれ記載
されている。
〔発明が解決しようとする問題点〕
1972年、Benvenisteらはうさぎの好塩基球か
ら血小板を強力に凝集させる因子を見出し、血小
板活性化因子（PAF）と命名した。1980年に至
りHanahanらにより、この因子が２位にアセチ
ル基を有するアルキルエーテル型のホスホグリセ
リド、すなわち１−Ｏ−ヘキサデシルあるいはオ
クタデシル−２−アセチル−sn−グリセリル−３
−ホスホリルコリンであることが同定された。
爾来、PAFの生理的役割の解明が進み、生体
内での血小板の凝集、血圧のの低下、即時型アレ
ルギー反応、平滑筋収縮、炎症、痛み、浮腫、な
らびに呼吸器系、血臓血管系および静脈系の変調
を含めた種々の生理的反応の要因となつているこ
とが知られてきた。
従つて、PAF拮抗作用を有する化合物は炎症
性疾患、アレルギー疾患、アナフイラキシーシヨ
ツク、敗血症性シヨツク、DICなどの血管系疾
患、心筋系の病気、喘息、肺浮腫あるいは成人性
呼吸系疾患などの、PAFによつて惹起される多
くの疾患に極めて有用であると考えられる。
上述したように、最近ある種のｓ−トリアゾロ
〔３，４−ｃ〕チエノ〔２，３−ｅ〕〔１，４〕ジ
アゼピン化合物がPAF拮抗作用を有することが
示されてきた。しかしながら、そのような化合物
は中枢神経系に対する作用との分離、活性強度、
経口投与での有効性あるいは作用の持続性などの
面で必ずしも十分とはいいがたい。従つて、経口
投与で有効で、作用持続が長く、しかも中枢神経
系に対する抑制的作用の少ない、強力なPAF拮
抗作用を示すチエノトリアゾロジアゼピン化合物
を提供することが望まれる。
〔問題点を解決するための手段〕
本発明は、２位にアラルキル側鎖が置換した
PAF拮抗作用を有する一連の新規チエノ〔３，
２−ｆ〕〔１，２，４〕トリアゾロ〔４，３−ａ〕
〔１，４〕ジアゼピン化合物を提供することにあ
り、該化合物は経口投与で有効で、作用持続が長
く、さらに鎮静作用、筋弛緩作用などの中枢抑制
的作用が少ない。
すなわち、本発明は一般式
（式中、Arはピリジル、フエニルまたは置換基
としてハロゲン、水酸基、炭素数１〜５個の直鎖
または分枝鎖状アルキルおよび炭素数１〜５個の
直鎖または分枝鎖状アルコキシから任意に選ばれ
る１〜３個を有するフエニル、Ａは炭素数１〜８
個のアルキレンまたは炭素数１〜５個の直鎖また
は分枝鎖状アルキルで置換された炭素数１〜８個
のアルキレンを、R1，R2，R3は同一または異な
つて、水素または炭素数１〜５個の直鎖または分
枝鎖状アルキルを、R4，R5，R6は同一または異
なつて、水素、ハロゲン、水酸基、炭素数１〜８
個の直鎖または分枝鎖状アルキル、炭素数１〜８
個の直鎖または分枝鎖状アルコキシ、フエニル、
フエノキシ、アラルキル、アラルキルオキシまた
は芳香環上にハロゲン、水酸基、炭素数１〜５個
の直鎖または分枝鎖状アルキルおよび炭素数１〜
５個の直鎖または分枝鎖状アルコキシから任意に
選ばれる１〜３個の置換基を有しているフエニ
ル、フエノキシ、アラルキルまたはアラルキルオ
キシを示す。）
で表わされるチエノトリアゾロジアゼピン誘導体
およびその薬理学的に許容される酸付加塩に関す
る。
上記各記号の定義中、ハロゲンとは塩素、臭
素、フツ素、ヨウ素を、炭素数１〜５個の直鎖ま
たは分枝鎖状アルキルとはメチル、エチル、ｎ−
プロピル、イソプロピル、ｎ−ブチル、イソブチ
ル、第３級ブチル、ｎ−ペンチル、イソペンチ
ル、第３級ペンチル、１−メチルブチルなどを、
炭素数１〜５個の直鎖または分枝鎖状アルコキシ
とはメトキシ、エトキシ、ｎ−プロポキシ、イソ
プロポキシ、ｎ−ブトキシ、イソブトキシ、第３
級ブトキシ、ｎ−ペンチルオキシ、イソペンチル
オキシ、第３級ペンチルオキシ、１−メチルブチ
ルオキシなどを、ピリジルとは２−ピリジル、３
−ピリジル、４−ピリジルを、炭素数１〜８個の
アルキレンとは直鎖状アルキレンを意味し、メチ
レン、エチレン、トリメチレン、テトラメチレ
ン、ペンタメチレン、ヘキサメチレン、ヘプタメ
チレン、オクタメチレンを、炭素数１〜５個の直
鎖または分枝鎖状アルキルで置換された炭素数１
〜８個のアルキレンとは同一炭素上もしくは異な
る炭素上に炭素数１〜５個のアルキルで置換され
たアルキレンを意味し、メチルメチレン、プロピ
レン、メチルトリメチレン、ジメチルエチレン、
ジメチルテトラメチレン、エチルエチレン、ジメ
チルトリメチレンなどを、炭素数１〜８個の直鎖
または分枝鎖状アルキルとはメチル、エチル、ｎ
−プロピル、イソプロピル、ｎ−ブチル、イソブ
チル、第３級ブチル、ｎ−ペンチル、イソペンチ
ル、１−メチルブチル、ｎ−ヘキシル、１−メチ
ルペンチル、ｎ−ヘプチル、４−メチルヘキシ
ル、１−エチルペンチル、１，４−ジメチルペン
チル、ｎ−オクチル、６−メチルヘプチル、２−
エチルヘキシルなどを、炭素数１〜８個の直鎖ま
たは分枝鎖状アルコキシとはメトキシ、エトキ
シ、ｎ−プロポキシ、イソプロポキシ、ｎ−ブト
キシ、イソブトキシ、第３級ブトキシ、ｎ−ペン
チルオキシ、イソペンチルオキシ、ｎ−ヘキシル
オキシ、ｎ−ヘプチルオキシ、１−プロピルブト
キシ、ｎ−オクチルオキシ、５−メチルヘキシル
オキシ、２−エチルヘキシルオキシ、１，６−ジ
メチルヘキシルオキシなどを、アラルキルとはベ
ンジル、１−フエニルエチル、２−フエニルエチ
ル、３−フエニルプロピル、４−フエニルブチル
などを、アラルキルオキシとはベンジルオキシ、
２−フエニルエトキシ、３−フエニルプロポキ
シ、４−フエニルブトキシなどを、芳香環上にハ
ロゲン、水酸基、炭素数１〜５個の直鎖または分
枝鎖状アルキルおよび炭素数１〜５個の直鎖また
は分枝鎖状アルコキシから任意に選ばれる１〜３
個の置換基を有しているフエニル、フエノキシ、
アラルキルまたはアラルキルオキシとは２−クロ
ロフエニル、２−ブロモフエニル、３−フルオロ
フエニル、２，３−ジクロロフエニル、４−ヒド
ロキシフエニル、２−メチルフエニル、４−メチ
ルフエニル、３−エチルフエニル、４−プロピル
フエニル、４−イソプロピルフエニル、４−ブチ
ルフエニル、４−第３級ブチルフエニル、４−ペ
ンチルフエニル、２，４−ジメチルフエニル、２
−メトキシフエニル、４−メトキシフエニル、３
−エトキシフエニル、２−プロポキシフエニル、
４−ブトキシフエニル、２，４−ジメトキシフエ
ニル、３，４，５−トリメトキシフエニル、２−
クロロフエノキシ、２，３−ジクロロフエノキ
シ、４−ヒドロキシフエノキシ、２−メチルフエ
ノキシ、４−ブチルフエノキシ、２，４−ジメチ
ルフエノキシ、２−メトキシフエノキシ、４−メ
トキシフエノキシ、２，４−ジメトキシフエノキ
シ、３，４，５−トリメトキシフエノキシ、２−
クロロベンジル、２，３−ジクロロベンジル、４
−ヒドロキシベンジル、２−メチルベンジル、４
−メトキシベンジル、３，４，５−トリメトキシ
ベンジル、２−（２−クロロフエニル）エチル、
２−クロロベンジルオキシ、２，４−ジメチルベ
ンジルオキシ、３，４，５−トリメトキシベンジ
ルオキシ、２−（２−クロロフエニル）エトキシ、
２−（２，４−ジメチルフエニル）エトキシなど
を示す。
一般式（）の化合物の医薬上許容しうる酸付
加塩としては塩酸、硫酸、リン酸、臭化水素酸、
硝酸などの無機酸との塩、またはマレイン酸、フ
マール酸、リンゴ酸、酒石酸、コハク酸、クエン
酸、酢酸、乳酸、メタンスルホン酸、パラトルエ
ンスルホン酸、パモ酸などの有機酸との塩があげ
られる。
本発明化合物が１個またはそれ以上の不斉炭素
原子を有する場合にはラセミ体、ジアステレオ異
性体および個々の光学異性体が存在し得るが、本
発明はそれらすべてを包含する。
本発明の好ましい化合物としては、４−（２−
クロロフエニル）−２−〔２−（４−イソブチルフ
エニル）エチル〕−９−メチル−6H−チエノ
〔３，２−ｆ〕〔１，２，４〕トリアゾロ〔４，３
−ａ〕〔１，４〕ジアゼピン、４−（２−クロロフ
エニル）−２−〔２−（４−メチルフエニル）エチ
ル〕−９−メチル−6H−チエノ〔３，２−ｆ〕
〔１，２，４〕トリアゾロ〔４，３−ａ〕〔１，
４〕ジアゼピン、４−（２−クロロフエニル）−２
−〔４−（４−イソブチルフエニル）ブチル〕−９
−メチル−6H−チエノ〔３，２−ｆ〕〔１，２，
４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼ
ピン、４−（２−クロロフエニル）−２−〔２−（４
−メトキシフエニル）エチル〕−９−メチル−6H
−チエノ〔３，２−ｆ〕〔１，２，４〕トリアゾ
ロ〔４，３−ａ〕〔１，４〕ジアゼピン、４−（２
−クロロフエニル）−２−〔２−（４−ｎ−ブチル
フエニル）エチル〕−９−メチル−6H−チエノ
〔３，２−ｆ〕〔１，２，４〕トリアゾロ〔４，３
−ａ〕〔１，４〕ジアゼピン、４−（２−クロロフ
エニル）−２−〔２−（４−フエニルフエニル）エ
チル〕−９−メチル−6H−チエノ〔３，２−ｆ〕
〔１，２，４〕トリアゾロ〔４，３−ａ〕〔１，
４〕ジアゼピン、４−（２−クロロフエニル）−２
−（２−フエニルエチル）−９−メチル−6H−チ
エノ〔３，２−ｆ〕〔１，２，４〕トリアゾロ
〔４，３−ａ〕〔１，４〕ジアゼピン、４−（２−
クロロフエニル）−２−（４−イソブチルベンジ
ル）−９−メチル−6H−チエノ〔３，２−ｆ〕
〔１，２，４〕トリアゾロ〔４，３−ａ〕〔１，
４〕ジアゼピン、４−（２−クロロフエニル）−２
−〔３−（４−イソブチルフエニル）プロピル〕−
９−メチル−6H−チエノ〔３，２−ｆ〕〔１，
２，４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジ
アゼピン、４−（２−クロロフエニル）−９−エチ
ル−２−〔２−（４−イソブチルフエニル）エチ
ル〕−6H−チエノ〔３，２−ｆ〕〔１，２，４〕
トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼピン、
４−（２−クロロフエニル）−２−〔２−（４−イソ
ブチルフエニル）エチル〕−６，９−ジメチル−
６−Ｈ−チエノ〔３，２−ｆ〕〔１，２，４〕ト
リアゾロ〔４，３−ａ〕〔１，４〕ジアゼピン、
４−（２−クロロフエニル）−２−〔２−（４−ｎ−
ブチルフエニル）エチル〕−６，９−ジメチル−
6H−チエノ〔３，２−ｆ〕〔１，２，４〕トリア
ゾロ〔４，３−ａ〕〔１，４〕ジアゼピンなどが
あげられる。
本発明の一般式（）化合物は、一般式
（式中、各記号は前記と同義である。）
で表わされる化合物にチオン化試薬を反応させ、
一般式
（式中、各記号は前記と同義である。）
で表わされる化合物を得、ついでこのの一般式
（）の化合物と一般式
R3CONHNH2 （）
（式中、R3は前記と同義である。）
で表される化合物とを反応させることによつて製
造されるか、または一般式（）の化合物にヒド
ラジン水和物を反応させて得られる一般式
（式中、各記号前記と同義である。）
で表わされる化合物に一般式
R3COOH （）
（式中、R3は前記と同義である。）
で表わされる化合物もしくはそ反応性誘導体、ま
たは一般式
R3C（OR7）3 （）
〔式中、R7は炭素数１〜５個のアルキル（メチ
ル、エチルなど）を示し、R3は前記と同義であ
る。〕
で表わされる化合物を反応させることにり製造さ
れる。
上記方法中、チオン化試薬としては五硫化リ
ン、Lawesson試薬〔２，４−ビス（４−メトキ
シフエニル）−１，３，２，４−ジチアジホスフ
エタン−２，４−ジスルフイツド〕などが挙げら
れ、一般式（）の化合物の反応性誘導体として
は、酸ハライド、酸無水物、混合酸無水物、炭素
数１〜５個のアルキルエステル、ベンジルエステ
ルなどが挙げられる。
一般式（）の化合物とチオン化試薬との反応
は、通常反応に不活性な溶媒（ピリジン、ジメチ
ルアニリン、ベンゼン、トルエン、キシレン、テ
トラヒドロフラン、クロロホルム、ジオキサンな
ど、またはその混合溶媒）中、30〜100℃で３分
から５時間で進行する。
一般式（）の化合物と一般式（）の化合物
との反応は、通常反応に不活性な溶媒（ベンゼ
ン、トルエン、キシレン、テトラヒドロフラン、
ジオキサンなど、またはその混合溶媒）中、有機
酸（酢酸、プロピオン酸など）、無機酸（塩酸、
硫酸など）またはシリカゲルの存在下に室温から
用いた溶媒の還流温度で30分から５時間で進行す
る。
一般式（）の化合物とヒドラジン水和物との
反応は、通常反応に不活性な溶媒（メタノール、
エタノール、プロパノール、イソプロピルアルコ
ール、ブタノールなど）中、０℃〜40℃、５分か
ら３時間程度で進行する。
一般式（）の化合物と、一般式（）の化合
物もしくはその反応性誘導体または一般式（）
の化合物との反応は、反応に不活性な溶媒（ベン
ゼン、トルエン、キシレン、テトラヒドロフラ
ン、ジオキサンなど、またはその混合溶媒）中、
有機酸（酢酸、プロピオン酸など）、無機酸（塩
酸、硫酸など）またはシリカゲルの存在下に室温
から用いた溶媒の還流温度で30分から６時間で進
行する。
一般式（）の化合物においてR4，R5，R6の
うち少なくとも１個が水酸基である化合物または
Arが水酸基で置換された化合物は一般式（）
においてR4，R5，R6の少なくとも１個が前記で
定義されたアルコキシである化合物またはArが
アルコキシで置換された化合物を脱アルキル化す
ることによつても製造される。
脱アルキル化剤としては臭化水素酸−酢酸、塩
化アルミニウム、メチオニン−メタンスルホン
酸、低級アルキルジスルフイド−塩化アルミニウ
ムなどが挙げられ、反応は反応に不活性な溶媒
（酢酸、塩化メチレン、クロロホルム、ジロロエ
タン、メタンスルホン酸など）中、室温から用い
た溶媒の還流温度下に１〜24時間で進行する。
また一般式（）の化合物においてR4，R5，
R6の少なくとも一つが水酸基である化合物に一
般式
R8−Ｘ （）
〔式中、R8はR4，R5，R6で定義したアルキルあ
るいはアラルキルを、Ｘはハロゲン（塩素、臭素
など）、メタンスルホニルオキシ、スルホニルオ
キシを表わす。〕
で表わされる化合物を作用させて相当するアルコ
キシ、アラルキルオキシとすることもできる。反
応は好適には炭酸水素アルカリ、炭酸アルカリ、
水酸化アルカリ、水素化ナトリウム、ナトリウム
アミド、トリエチルアミンなどの塩基の存在下、
不活性な溶媒（エタノール、メタノール、ジメチ
ルホルムアミド、ジオキサン、２−メトキシエタ
ノールなど）中、０℃から用いた溶媒の還流温度
下に、30分から24時間で進行する。
このようにして得られた一般式（）の化合物
は再結晶、クロマトグラフイーなど、それ自体公
知の方法により、反応混合物から分離、精製する
ことができる。
一般式（）の化合物は常法により無機酸また
は有機酸と処理することにより、前記した製薬上
許容されうる塩にすることができる。
本発明化合物中、不斉炭素原子を有する場合に
は、通常ラセミ体として得られる。ラセミ体は常
法により光学異性体に分割することができる。そ
のような光学異性体は光学活性な出発化合物を使
用することによつても製造することができる。個
個のジアステレオ異性体は分別再結晶またははク
ロマトグラフイーによつて精製できる。
本発明に包含される化合物は以下の表に例示し
た通りである。
[Industrial Field of Application] The present invention relates to novel and pharmaceutically useful thienotriazolodiazepine derivatives and pharmacologically acceptable acid addition salts thereof. [Prior Art] As described in U.S. Pat. No. 3,904,641, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-
c] Thieno [2,3-e] [1,4] diazepine [hereinafter referred to as etizolam [International Nonproprietary Name (INN)]
Certain s-triazolo[3,4-c]thieno[2,3-e][1,4]
It is known that diazepine compounds exhibit useful pharmacological activities on the central nervous system, such as anxiolytic and anticonvulsant activities. Japanese Journal of Pharmacology,
Volume 44, pp. 381-391 (1987) states that etizolam is a platelet activating factor.
EP-A194416 further states that s-triazolo[3,4-c]thieno[2,3-
e][1,4]Diazepine-carboxylic acid amide compounds have been described to exhibit PAF antagonistic activity. [Problems to be solved by the invention] In 1972, Benveniste et al. discovered a factor that strongly aggregates platelets from rabbit basophils and named it platelet activating factor (PAF). In 1980, Hanahan et al. discovered that this factor was an alkyl ether type phosphoglyceride with an acetyl group at the 2-position, namely 1-O-hexadecyl or octadecyl-2-acetyl-sn-glyceryl-3.
- was identified as phosphorylcholine. Since then, progress has been made in elucidating the physiological role of PAF, and it has been shown to be involved in platelet aggregation, lowering of blood pressure, immediate allergic reactions, smooth muscle contraction, inflammation, pain, edema, and the respiratory system, blood vasculature, and blood vessels in the body. It has been known that it is a factor in various physiological responses including modulation of the venous system. Therefore, compounds with PAF antagonistic effects may be used to treat inflammatory diseases, allergic diseases, anaphylactic shots, septic shots, vascular diseases such as DIC, myocardial diseases, asthma, pulmonary edema, and adult respiratory diseases. , is considered to be extremely useful for many diseases caused by PAF. As mentioned above, it has recently been shown that certain s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine compounds have PAF antagonistic activity. However, such compounds lack separation of effects on the central nervous system, intensity of activity,
It cannot be said that oral administration is necessarily sufficient in terms of effectiveness or duration of action. Therefore, it is desired to provide a thienotriazolodiazepine compound that is effective when administered orally, has a long duration of action, has little depressant effect on the central nervous system, and exhibits a strong PAF antagonistic effect. [Means for Solving the Problems] The present invention provides an aralkyl side chain substituted at the 2-position.
A series of novel thienos with PAF antagonism [3,
2-f] [1,2,4] Triazolo [4,3-a]
The object of the present invention is to provide a [1,4] diazepine compound, which is effective when administered orally, has a long duration of action, and has less central depressant effects such as sedative and muscle relaxant effects. That is, the present invention is based on the general formula (In the formula, Ar is pyridyl, phenyl, or any substituent selected from halogen, hydroxyl group, straight-chain or branched alkyl having 1 to 5 carbon atoms, and straight-chain or branched alkoxy having 1 to 5 carbon atoms) phenyl having 1 to 3 selected from, A has 1 to 8 carbon atoms
or an alkylene having 1 to 8 carbon atoms substituted with a linear or branched alkyl having 1 to 5 carbon atoms, R 1 , R 2 , and R 3 are the same or different, and hydrogen or carbon 1 to 5 linear or branched alkyl, R 4 , R 5 , R 6 are the same or different, hydrogen, halogen, hydroxyl group, carbon number 1 to 8
straight or branched alkyl, having 1 to 8 carbon atoms
linear or branched alkoxy, phenyl,
Phenoxy, aralkyl, aralkyloxy or halogen on the aromatic ring, hydroxyl group, straight chain or branched alkyl having 1 to 5 carbon atoms, and 1 to 5 carbon atoms
It represents phenyl, phenoxy, aralkyl, or aralkyloxy having 1 to 3 substituents arbitrarily selected from 5 straight-chain or branched alkoxy groups. ) and its pharmacologically acceptable acid addition salts. In the definitions of each symbol above, halogen refers to chlorine, bromine, fluorine, and iodine, and linear or branched alkyl having 1 to 5 carbon atoms refers to methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, tertiary pentyl, 1-methylbutyl, etc.
Linear or branched alkoxy having 1 to 5 carbon atoms refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tertiary
Butoxy, n-pentyloxy, isopentyloxy, tertiary pentyloxy, 1-methylbutyloxy, etc., pyridyl refers to 2-pyridyl, 3
- Pyridyl, 4-pyridyl, alkylene with 1 to 8 carbon atoms means linear alkylene, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, carbon number 1 carbon number substituted with 1 to 5 straight or branched alkyl
~8 alkylene means alkylene substituted with an alkyl having 1 to 5 carbon atoms on the same carbon or different carbons, and includes methylmethylene, propylene, methyltrimethylene, dimethylethylene,
Dimethyltetramethylene, ethylethylene, dimethyltrimethylene, etc. are defined as linear or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, 1-methylbutyl, n-hexyl, 1-methylpentyl, n-heptyl, 4-methylhexyl, 1-ethylpentyl, 1 , 4-dimethylpentyl, n-octyl, 6-methylheptyl, 2-
Ethylhexyl, etc., and linear or branched alkoxy having 1 to 8 carbon atoms are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tertiary butoxy, n-pentyloxy, isopentyl. oxy, n-hexyloxy, n-heptyloxy, 1-propylbutoxy, n-octyloxy, 5-methylhexyloxy, 2-ethylhexyloxy, 1,6-dimethylhexyloxy, etc. Aralkyl refers to benzyl, 1- Phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc., aralkyloxy means benzyloxy,
2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, etc. are combined with halogen, hydroxyl group, straight-chain or branched alkyl having 1 to 5 carbon atoms, and straight-chain alkyl having 1 to 5 carbon atoms on the aromatic ring. 1 to 3 arbitrarily selected from chain or branched alkoxy
phenyl, phenoxy, having 4 substituents,
Aralkyl or aralkyloxy means 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl. enyl, 4-isopropylphenyl, 4-butylphenyl, 4-tertiary butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2
-methoxyphenyl, 4-methoxyphenyl, 3
-ethoxyphenyl, 2-propoxyphenyl,
4-butoxyphenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-
Chlorophenoxy, 2,3-dichlorophenoxy, 4-hydroxyphenoxy, 2-methylphenoxy, 4-butylphenoxy, 2,4-dimethylphenoxy, 2-methoxyphenoxy, 4-methoxyphenoxy , 2,4-dimethoxyphenoxy, 3,4,5-trimethoxyphenoxy, 2-
Chlorobenzyl, 2,3-dichlorobenzyl, 4
-Hydroxybenzyl, 2-methylbenzyl, 4
-methoxybenzyl, 3,4,5-trimethoxybenzyl, 2-(2-chlorophenyl)ethyl,
2-chlorobenzyloxy, 2,4-dimethylbenzyloxy, 3,4,5-trimethoxybenzyloxy, 2-(2-chlorophenyl)ethoxy,
2-(2,4-dimethylphenyl)ethoxy, etc. Pharmaceutically acceptable acid addition salts of the compound of general formula () include hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid,
Salts with inorganic acids such as nitric acid, or salts with organic acids such as maleic acid, fumaric acid, malic acid, tartaric acid, succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, pamoic acid, etc. can give. When the compounds of the present invention have one or more asymmetric carbon atoms, racemates, diastereoisomers and individual optical isomers may exist, all of which are encompassed by the present invention. Preferred compounds of the present invention include 4-(2-
chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3
-a][1,4]Diazepine, 4-(2-chlorophenyl)-2-[2-(4-methylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, 4-(2-chlorophenyl)-2
-[4-(4-isobutylphenyl)butyl]-9
-Methyl-6H-thieno[3,2-f][1,2,
4] Triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-2-[2-(4
-methoxyphenyl)ethyl]-9-methyl-6H
-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2
-chlorophenyl)-2-[2-(4-n-butylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3
-a][1,4]Diazepine, 4-(2-chlorophenyl)-2-[2-(4-phenylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, 4-(2-chlorophenyl)-2
-(2-phenylethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-
chlorophenyl)-2-(4-isobutylbenzyl)-9-methyl-6H-thieno[3,2-f]
[1,2,4] Triazolo [4,3-a] [1,
4] Diazepine, 4-(2-chlorophenyl)-2
-[3-(4-isobutylphenyl)propyl]-
9-Methyl-6H-thieno[3,2-f][1,
2,4]triazolo[4,3-a][1,4]diazepine, 4-(2-chlorophenyl)-9-ethyl-2-[2-(4-isobutylphenyl)ethyl]-6H-thieno[ 3,2-f] [1,2,4]
triazolo[4,3-a][1,4]diazepine,
4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-
6-H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,
4-(2-chlorophenyl)-2-[2-(4-n-
butylphenyl)ethyl]-6,9-dimethyl-
Examples include 6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine. The compound of the general formula () of the present invention has the general formula (In the formula, each symbol has the same meaning as above.) Reacting a compound represented by the above with a thionation reagent,
general formula (In the formula, each symbol has the same meaning as above.) A compound represented by this is obtained, and then a compound of the general formula () and the general formula R 3 CONHNH 2 () (wherein R 3 has the same meaning as above) is obtained. ), or a compound of the general formula () obtained by reacting a compound of the general formula () with hydrazine hydrate. (In the formula, each symbol has the same meaning as above.) A compound represented by the general formula R 3 COOH () (In the formula, R 3 has the same meaning as above) or a reactive derivative thereof, or General formula R 3 C(OR 7 ) 3 () [In the formula, R 7 represents an alkyl having 1 to 5 carbon atoms (methyl, ethyl, etc.), and R 3 has the same meaning as above. ] It is manufactured by reacting the compound represented by the following. In the above method, phosphorus pentasulfide, Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphethane-2,4-disulfide], etc. are used as the thionation reagent. Examples of reactive derivatives of the compound of general formula () include acid halides, acid anhydrides, mixed acid anhydrides, alkyl esters having 1 to 5 carbon atoms, and benzyl esters. The reaction between the compound of general formula () and the thionation reagent is usually carried out in a solvent inert to the reaction (pyridine, dimethylaniline, benzene, toluene, xylene, tetrahydrofuran, chloroform, dioxane, etc., or a mixed solvent thereof) for 30 to 30 minutes. The process proceeds from 3 minutes to 5 hours at 100°C. The reaction between the compound of general formula () and the compound of general formula () is usually carried out using a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran,
organic acids (acetic acid, propionic acid, etc.), inorganic acids (hydrochloric acid,
sulfuric acid, etc.) or silica gel at room temperature to the reflux temperature of the solvent used for 30 minutes to 5 hours. The reaction between the compound of general formula () and hydrazine hydrate is usually carried out using a solvent inert to the reaction (methanol,
The process proceeds for about 5 minutes to 3 hours at 0°C to 40°C in ethanol, propanol, isopropyl alcohol, butanol, etc.). Compounds of general formula () and compounds of general formula () or reactive derivatives thereof or general formula ()
The reaction with the compound is carried out in a solvent inert to the reaction (benzene, toluene, xylene, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof).
The process proceeds from room temperature to the reflux temperature of the solvent used in the presence of an organic acid (acetic acid, propionic acid, etc.), an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or silica gel for 30 minutes to 6 hours. A compound of general formula () in which at least one of R 4 , R 5 , and R 6 is a hydroxyl group, or
Compounds in which Ar is substituted with a hydroxyl group have the general formula ()
It is also produced by dealkylating a compound in which at least one of R 4 , R 5 , and R 6 is alkoxy as defined above or a compound in which Ar is substituted with alkoxy. Examples of dealkylating agents include hydrobromic acid-acetic acid, aluminum chloride, methionine-methanesulfonic acid, and lower alkyl disulfide-aluminum chloride. , dilorethane, methanesulfonic acid, etc.) from room temperature to the reflux temperature of the solvent used for 1 to 24 hours. Also, in the compound of general formula (), R 4 , R 5 ,
A compound in which at least one of R 6 is a hydroxyl group has the general formula R 8 -X () [In the formula, R 8 is an alkyl or aralkyl defined as R 4 , R 5 , R 6 , and X is a halogen (chlorine, bromine, etc.). ), methanesulfonyloxy, and sulfonyloxy. ] The corresponding alkoxy or aralkyloxy can also be obtained by reacting the compound represented by the following. The reaction is preferably carried out using an alkali hydrogen carbonate, an alkali carbonate,
In the presence of a base such as alkali hydroxide, sodium hydride, sodium amide, triethylamine,
The reaction proceeds in an inert solvent (ethanol, methanol, dimethylformamide, dioxane, 2-methoxyethanol, etc.) from 0°C to the reflux temperature of the solvent used for 30 minutes to 24 hours. The compound of general formula () thus obtained can be separated and purified from the reaction mixture by methods known per se, such as recrystallization and chromatography. The compound of general formula () can be converted into the above-mentioned pharmaceutically acceptable salt by treating with an inorganic or organic acid in a conventional manner. When the compound of the present invention has an asymmetric carbon atom, it is usually obtained as a racemate. Racemates can be resolved into optical isomers by conventional methods. Such optical isomers can also be prepared by using optically active starting compounds. Individual diastereoisomers can be purified by fractional recrystallization or chromatography. Compounds included in the present invention are exemplified in the table below.
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
【表】【table】
本発明化合物のPAF拮抗作用について、家兎
血小板のPAF誘発による凝集に対する拮抗作用
を、in vitro，ex vivoで、またはPAF誘発のマ
ウス・シヨツク死、およびラツト足浮腫に対する
抑制効果などで調べた。
試薬に用いた化合物は次の通りである。
化合物Ａ：４−（２−クロロフエニル）−２−〔２
−（４−イソブチルフエニル）エチル〕−９−メ
チル−6H−チエノ〔３，２−ｆ〕〔１，２，
４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジア
ゼピン
化合物Ｂ：４−（２−クロロフエニル）−２−〔２
−（４−メチルフエニル）エチル〕−９−メチル
−6H−チエノ〔３，２−ｆ〕〔１，２，４〕ト
リアゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
化合物Ｃ：４−（２−クロロフエニル）−２−〔４
−（４−イソブチルフエニル）ブチル〕−９−メ
チル−6H−チエノ〔３，２−ｆ〕〔１，２，
４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジア
ゼピン
化合物Ｄ：４−（２−クロロフエニル）−２−〔２
−（４−メトキシフエニル）エチル〕−９−メチ
ル−6H−チエノ〔３，２−ｆ〕〔１，２，４〕
トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼピ
ン
化合物Ｅ：４−（２−クロロフエニル）−２−〔２
−（４−ｎ−ブチルフエニル）エチル〕−９−メ
チル−6H−チエノ〔３，２−ｆ〕〔１，２，
４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジア
ゼピン
化合物Ｆ：４−（２−クロロフエニル）−２−〔２
−（４−フエニルフエニル）エチル〕−９−メチ
ル−6H−チエノ〔３，２−ｆ〕〔１，２，４〕
トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼピ
ン
化合物Ｇ：４−（２−クロロフエニル）−２−（２
−フエニルエチル）−９−メチル−6H−チエノ
〔３，２−ｆ〕〔１，２，４〕トリアゾロ〔４，
３−ａ〕〔１，４〕ジアゼピン
化合物Ｈ：４−（２−クロロフエニル）−２−（４
−イソブチルベンジル）−９−メチル−6H−チ
エノ〔３，２−ｆ〕〔１，２，４〕トリアゾロ
〔４，３−ａ〕〔１，４〕ジアゼピン
化合物Ｉ：４−（２−クロロフエニル）−２−〔３
−（４−イソブチルフエニル）プロピル〕−９−
メチル−6H−チエノ〔３，２−ｆ〕〔１，２，
４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジア
ゼピン
化合物Ｊ：４−（２−クロロフエニル）−９−エチ
ル−２−〔２−（４−イソブチルフエニル）エチ
ル〕−6H−チエノ〔３，２−ｆ〕〔１，２，４〕
トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼピ
ン
化合物Ｋ：４−（２−クロロフエニル）−２−〔２
−（４−イソブチルフエニル）エチル〕−６，９
−ジメチル−6H−チエノ〔３，２−ｆ〕〔１，
２，４〕トリアゾロ〔４，３−ａ〕〔１，４〕
ジアゼピン
化合物Ｌ：４−（２−クロロフエニル）−２−〔２
−（４−ｎ−ブチルフエニル）エチル〕−６，９
−ジメチル−6H−チエノ〔３，２−ｆ〕〔１，
２，４〕トリアゾロ〔４，３−ａ〕〔１，４〕
ジアゼピン
実施例 １
ウサギ血小板凝集抑制作用（試験管内試験）
ウサギから１／10量の3.8％クエン酸ナトリウ
ム溶液を加えた血液を採取し、200×ｇで10分間
遠心分離し、血小板に富んだ血漿（以下、PRP
という。）を調製した。さらに、1000×ｇで10分
間遠心分離し、血小板の乏しい血漿（以下PPP
という。）を調製した。
凝集能の測定はJ.Physiology、第168巻、178ペ
ージ（1963年）に記載のボーン（BORN，G.V.
R.）の混濁測定法にしたがつて、６チヤンネ
ル・NKKヘマトレーサー１（PAT−6A）で測定
した。PRPおよびPPPで０〜100％の光透過を調
節した。1000rpmで撹拌しながら、PRP0.3mlに
試験化合物溶液または溶媒3μを加え、37℃で
２分間保持したのち、PAF（Serdary Research
Lab.）3μを最終濃度が1.8×10-7Mになるよう
に加え、５分間光透過度を記録した。
すべての実験において、PAFは濃度が100μ
ｇ／mlになるようにエタノールに溶解し、使用時
に0.9％生理食塩水で希釈して用いた。
試験化合物による血小板凝集の抑制率は、下記
式のように、試験化合物存在下と非存在下での最
大光透過度により求めた。
抑制％＝（１−試験化合物存在下での最大凝集／試験化
合物非存在下での最大凝集）×100
この抑制％と用量との曲線から、IC50値（μ
ｇ／ml、50％抑制濃度）を求め、結果を第１表に
まとめた。
Regarding the PAF antagonizing effect of the compounds of the present invention, the antagonizing effect on PAF-induced aggregation of rabbit platelets was investigated in vitro, ex vivo, and the inhibitory effect on PAF-induced mouse shock death and rat paw edema. The compounds used as reagents are as follows. Compound A: 4-(2-chlorophenyl)-2-[2
-(4-isobutylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,
4] Triazolo[4,3-a][1,4]diazepine compound B: 4-(2-chlorophenyl)-2-[2
-(4-methylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine compound C: 4-( 2-chlorophenyl)-2-[4
-(4-isobutylphenyl)butyl]-9-methyl-6H-thieno[3,2-f][1,2,
4] Triazolo[4,3-a][1,4]diazepine compound D: 4-(2-chlorophenyl)-2-[2
-(4-methoxyphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]
Triazolo[4,3-a][1,4]diazepine compound E: 4-(2-chlorophenyl)-2-[2
-(4-n-butylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,
4] Triazolo[4,3-a][1,4]diazepine compound F: 4-(2-chlorophenyl)-2-[2
-(4-phenylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]
Triazolo[4,3-a][1,4]diazepine compound G: 4-(2-chlorophenyl)-2-(2
-phenylethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,
3-a] [1,4] diazepine compound H: 4-(2-chlorophenyl)-2-(4
-isobutylbenzyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine compound I: 4-(2-chlorophenyl) -2-[3
-(4-isobutylphenyl)propyl]-9-
Methyl-6H-thieno[3,2-f][1,2,
4] Triazolo[4,3-a][1,4]diazepine compound J: 4-(2-chlorophenyl)-9-ethyl-2-[2-(4-isobutylphenyl)ethyl]-6H-thieno[ 3,2-f] [1,2,4]
Triazolo[4,3-a][1,4]diazepine compound K: 4-(2-chlorophenyl)-2-[2
-(4-isobutylphenyl)ethyl]-6,9
-dimethyl-6H-thieno[3,2-f][1,
2,4] Triazolo [4,3-a] [1,4]
Diazepine compound L: 4-(2-chlorophenyl)-2-[2
-(4-n-butylphenyl)ethyl]-6,9
-dimethyl-6H-thieno[3,2-f][1,
2,4] Triazolo [4,3-a] [1,4]
Diazepine Example 1 Inhibitory effect on platelet aggregation in rabbits (in vitro test) Blood was collected from rabbits with 1/10 volume of 3.8% sodium citrate solution added and centrifuged at 200 x g for 10 minutes to extract platelet-rich plasma. (hereinafter referred to as PRP
That's what it means. ) was prepared. Furthermore, the platelet-poor plasma (hereinafter PPP) was centrifuged at 1000 x g for 10 minutes.
That's what it means. ) was prepared. The aggregation ability was measured using the BORN, GV
Measurement was performed using a 6-channel NKK hematotracer 1 (PAT-6A) according to the turbidity measurement method of R. Light transmission was adjusted from 0 to 100% with PRP and PPP. While stirring at 1000 rpm, add 3 μ of test compound solution or solvent to 0.3 ml of PRP, hold at 37°C for 2 minutes, and add PAF (Serdary Research
Lab.) was added to a final concentration of 1.8 x 10 -7 M, and the optical transmittance was recorded for 5 minutes. In all experiments, PAF was used at a concentration of 100μ
It was dissolved in ethanol to a concentration of g/ml and diluted with 0.9% physiological saline before use. The inhibition rate of platelet aggregation by the test compound was determined by the maximum light transmittance in the presence and absence of the test compound, as shown in the following formula. % inhibition = (1 - maximum aggregation in the presence of test compound / maximum aggregation in the absence of test compound) x 100 From this % inhibition versus dose curve, the IC 50 value (μ
g/ml, 50% inhibitory concentration), and the results are summarized in Table 1.
【表】【table】
【表】
実験例 ２
ウサギ血小板凝集抑制作用（生体外試験）
実験例１の試験管内試験のようにPRP中に試
験化合物を添加することにかえて、あらかじめウ
サギに試験化合物を経口投与し、経時的にクエン
酸加血液（3.8％クエン酸ナトリウム１容に血液
９容）を採取した。以降、この血液を用い、実験
例１に準じて試験化合物の投与１、３、６および
24時間後の抑制効果を検定し第２表に示した。[Table] Experimental Example 2 Inhibitory effect on rabbit platelet aggregation (in vitro test) Instead of adding the test compound to PRP as in the in vitro test of Experimental Example 1, the test compound was orally administered to rabbits in advance, and the test compound was administered orally to rabbits over time. Citrated blood (9 volumes of blood in 1 volume of 3.8% sodium citrate) was collected separately. Thereafter, using this blood, administration of test compounds 1, 3, 6, and 1 according to Experimental Example 1 was carried out.
The inhibitory effect after 24 hours was tested and shown in Table 2.
【表】
実験例 ３
PAR誘発マウス・シヨツク死に対する作用
実験はプロスタグランジンズ
（Prostaglandins）、第30巻、545ページ（1985年）
に記載のヤング（Young）らの方法にしたがつ
て行つた。体重25〜30ｇの雄性ICRマウス（チヤ
ールスリバー）を１群９〜15匹用いた。試験化合
物を経口投与（0.1ml／10ｇ）して１時間後、
PAF（Serdary Research Lab.）80μｇ／Kgを尾
静脈から投与した。PAFを投与後、24時間観察
し、結果は生存動物数／試験動物数および生存率
（％）で表わし、第３表に示した。[Table] Experimental example 3 Effect on PAR-induced mouse shot death The experiment was conducted in Prostaglandins, Vol. 30, p. 545 (1985)
This was done according to the method of Young et al. described in . Groups of 9 to 15 male ICR mice (Charles River) weighing 25 to 30 g were used. One hour after oral administration of the test compound (0.1 ml/10 g),
PAF (Serdary Research Lab.) 80 μg/Kg was administered through the tail vein. After administration of PAF, the animals were observed for 24 hours, and the results were expressed as number of surviving animals/number of tested animals and survival rate (%), and are shown in Table 3.
【表】
実験例 ４
PAF edemaに対する作用
実験はエイジエンツ・アンド・アクシヨンズ
（Agents and Actions）、第18巻、359ページ
（1986年）に記載のスウイングル（Swingle）ら
の方法に準じて行つた。体重150ｇ前後の雄性
Donryuラツトを１群５匹用いた。試験化合物の
経口投与（25ml／Kg）１時間後、PAF（Serdary
Research Lab.）5μｇ／0.05mlをラツト右後肢足
蹠皮下に注射し、さらにに１時間後足容積を測定
した。結果は、起炎剤投与前の足容積に対する増
加率を算出し、対照群に対する抑制率で表わし、
第４表に示した。[Table] Experimental Example 4 Effect on PAF edema The experiment was conducted according to the method of Swingle et al. described in Agents and Actions, Vol. 18, p. 359 (1986). Male weighing around 150g
Five Donryu rats were used in each group. One hour after oral administration (25ml/Kg) of the test compound, PAF (Serdary
Research Lab.) 5 μg/0.05 ml was subcutaneously injected into the right hind paw pad of rats, and the hind paw volume was further measured for 1 hour. The results were calculated by calculating the rate of increase in foot volume before administration of the inflammatory agent, and expressed as the inhibition rate relative to the control group.
It is shown in Table 4.
出発化合物は新規であり、ジヤーナル・オブ・
メデイシナル・ケミストリー（J.Med.Chem.）、
第16巻、214ページ（1973年）に記載の方法に従
つて得ることができる。出発化合物の詳細な調製
方法を以下に例をあげて説明する。
出発化合物の製造例
ａ） ２−アミノ−３−（２−クロロベンゾイル）
−５−〔２−（４−イソブチルフエニル）エチ
ル〕−チオフエン
２−クロロシアノアセトフエノン29ｇ、硫黄
4.9ｇをジメチルホルムアミド50mlに懸濁し、撹
拌下、トリエチルアミン18.5ｇを加える。次い
で、４−（４−イソブチルフエニル）ブチルアル
デヒド30ｇをエタノール10mlに溶解して加え、撹
拌下60℃で３時間反応する。反応液を氷水にあ
け、400mlのクロロホルムににて抽出する。水洗
後、無水硫酸マグネシウムで乾燥する。濾別後、
濾液を減圧濃縮すると表記の油状アミノ化合物70
ｇを得る。
ｂ） ２−クロロアセチルアミノ−３−（２−ク
ロロベンゾイル）−５−〔２−（４−イソブチル
フエニル）エチル〕−チオフエン
上記ａ）の化合物70ｇをクロロホルム500mlに
溶解し、クロロアセチルクロリド20ｇを加え、撹
拌下、２時間加熱還流する。冷後、炭酸水素ナト
リウム水、食塩水にて洗浄する。無水硫酸マグネ
シウムで乾燥し、濾別後、減圧濃縮する。残留物
を簡易シリカゲルクロマトグラフイーに付し、粗
成油状の表記クロロアセチルアミノ化合物45ｇを
得る。
ｃ） ２−アミノアセチルアミ−３−（２−クロ
ロベンゾイル）−５−〔２−（４−イソブチルフ
エニル）エチル〕−チオフエン
上記ｂ）のクロロアセチルアミノ化合物45ｇ、
ヨウ化ナトリウム16ｇをテトラヒドロフラン200
mlに懸濁し、撹拌下、２時間加熱還流する。放冷
後、ドライアイス−メタノールにて−20℃に冷却
し、液体アンモニア約30mlを撹拌下に加える。反
応液は２時間かけて徐々に室温まで昇温する。ア
スピレーターで脱アンモニア後、減圧濃縮し、残
留物を500mlのクロロホルムに溶解する。水洗後、
無水硫酸マグネシウムで乾燥する。濾別後、減圧
濃縮すると表記の油状粗成アミノ化合物50ｇを得
る。
ｄ） ５−（２−クロロフエニル）−７−〔２−（４
−イソブチルフエニル）エチル〕−１，３−ジ
ヒドロ−2H−チエノ〔２，３−ｅ〕−１，４−
ジアゼピン−２−オン
上記ｃ）の化合物50ｇをイソプロピルアルコー
ル300mlに溶解後、酢酸8.5ｇを加え、撹拌下６時
間加熱還流する。反応液を減圧濃縮し、残留物を
クロロホルム500mlに溶解する。炭酸水素ナトリ
ウム水、食塩水にて洗浄後、無水硫酸マグネシウ
ムで乾燥する。濾別後、減圧濃縮し、残留物を簡
易シリカゲルクロマトグラフイーに付し、クロロ
ホルム−メタノール（100：１〜100：３）で溶出
する。目的画分を減圧濃縮し、イソプロピルエー
テルから結晶化すると、融点179〜181℃の表記の
無色結晶チエノジアゼピン10ｇを得る。
以下、実施例をあげて本発明を具体的に説明す
るが、本発明は何らこれらに限定されるものでな
い。
実施例 １
４−（２−クロロフエニル）−２−〔２−（４−イ
ソブチルフエニル）エチル〕−９−メチル−6H
−チエノ〔３，２−ｆ〕〔１，２，４〕トリア
ゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
５−（２−クロロフエニル）−７−〔２−（４−イ
ソブチルフエニル）エチル〕−１，３−ジヒドロ
−2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピ
ン−２−オン9.8ｇおよびLawesson試薬5.5ｇを
トルエン200mlに懸濁させ、40〜43℃にて１時間
撹拌する。反応液を減圧濃縮し、残留物をシリカ
ゲルクロマトグラフイーに付し、クロロホルム−
メタノール（100：１〜100：２）で溶出する。目
的画分を減圧濃縮すると、融点180〜182℃（分
解）の５−（２−クロロフエニル）−７−〔２−（４
−イソブチルフエニル）エチル〕−１，３−ジヒ
ドロ−2H−チエノ〔２，３−ｅ〕−１，４−ジア
ゼピン−２−チオン9.6ｇを得る。
５−（２−クロロフエニル）−７−〔２−（４−イ
ソブチルフエニル）エチル〕−１，３−ジヒドロ
−2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピ
ン−２−チオン9.6ｇをメタノール100mlに懸濁さ
せ、100％ヒドラジン・ヒドラート3.5ｇを氷冷下
加え、30分間撹拌する。反応終了後、メタノール
を30〜40℃で完全に留去後、クロロホルム100ml
を加え、溶解し無水硫酸マグネシウムにて乾燥す
る。濾別後、濾液を減圧濃縮すると５−（２−ク
ロロフエニル）−７−〔２−（４−イソブチルフエ
ニル）エチル〕−１，３−ジヒドロ−2H−チエノ
〔２，３−ｅ〕−１，４−ジアゼピン−２−ヒドラ
ゾン８ｇを油状物として得る。
それをトルエン100mlに溶解後、氷冷、撹拌下、
無水酢酸５ｇを加え、約30分間撹拌する。この反
応液に酢酸６ｇを加え、撹拌下、１時間加熱還流
後、減圧濃縮する。残留物をクロロホルムに溶解
後、炭酸水素ナトリウム水、食塩水で洗浄し、無
水硫酸マグネシウムで乾燥する。濾別後、濾液を
減圧濃縮し、得られた残留物をシリカゲルクロマ
トグラフイーに付し、クロロホルム−メタノール
（100：１〜100：３）で溶出する。目的画分を減
圧濃縮し、酢酸エチルから結晶化すると、融点
118〜121℃の無色結晶として４−（２−クロロフ
エニル）−２−〔２−（４−イソブチルフエニル）
エチル〕−９−メチル−6H−チエノ〔３，２−
ｆ〕〔１，２，４〕トリアゾロ〔４，３−ａ〕
〔１，４〕ジアゼピン4.2ｇを得る。
同様にチオン体と前記ヒドラジン・ヒドラート
の代わりに酢酸ヒドラジドを反応させることによ
り該目的物が得られる。
実施例 ２
４−（２−クロロフエニル）−２−〔２−（４−メ
チルフエニル）エチル〕−９−メチル−6H−チ
エノ〔３，２−ｆ〕〔１，２，４〕トリアゾロ
〔４，３−ａ〕〔１，４〕ジアゼピン
融点195〜197℃の５−（２−クロロフエニル）−
７−〔２−（４−メチルフエニル）エチル〕−１，
３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，
４−ジアゼピン−２−オン3.9ｇおよびLawesson
試薬2.5ｇをトルエン50mlに懸濁させ、40〜43℃
にて１時間撹拌する。反応液を減圧濃縮し、残留
物をシリカゲルクロマトグラフイーに付し、クロ
ロホルム−メタノール（100：１〜100：２）で溶
出する。目的画分を減圧濃縮すると、融点190〜
191℃（分解）の５−（２−クロロフエニル）−７
−〔２−（４−メチルフエニル）エチル〕−１，３
−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，４
−ジアゼピン−２−チオン４ｇを得る。
５−（２−クロロフエニル）−７−〔２−（４−メ
チルフエニル）エチル〕−１，３−ジヒドロ−2H
−チエノ〔２，３−ｅ〕−１，４−ジアゼピン−
２−チオン５ｇをメタノール50mlに懸濁させ、
100％ヒドラジン・ヒドラート２ｇを氷冷下に加
え、30分間撹拌する。次いで、メタノールを30〜
40℃で完全に留去後、残留物にクロロホルム100
mlを加え溶解し、無水硫酸マグネシウムで乾燥す
る。濾別後、減圧濃縮し、残留物をトルエン100
mlに溶解する。氷冷、撹拌下、無水酢酸３ｇを加
え、30分間反応を行う。次いで、酢酸4.4ｇを加
え、撹拌下、１時間加熱還流する。減圧濃縮後、
残留物をクロロホルムに溶解し、炭酸水素ナトリ
ウ、食塩水にて洗浄後、無水硫酸マグネシウムで
乾燥する。濾別後、減圧濃縮を行い、残留物をシ
リカゲルクロマトグラフイーに付し、クロロホル
ム−メタノール（100：１〜100：３）で溶出す
る。目的画分を減圧濃縮し、酢酸エチルから結晶
化すると、融点160〜162℃の無色結晶として４−
（２−クロロフエニル）−２−〔２−（４−メチルフ
エニル）エチル〕−９−メチル−6H−チエノ
〔３，２−ｆ〕〔１，２，４〕トリアゾロ〔４，３
−ａ〕〔１，４〕ジアゼピン0.7ｇを得る。
実施例 ３
４−（２−クロロフエニル）−２−〔４−（４−イ
ソブチルフエニル）ブチル〕−９−メチル−6H
−チエノ〔３，２−ｆ〕〔１，２，４〕トリア
ゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
融点133〜135℃の５−（２−クロロフエニル）−
７−〔４−（４−イソブチルフエニル）ブチル〕−
１，３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−
１，４−ジアゼピン−２−オン8.9ｇおよび
Lawesson試薬4.7ｇをトルエン100mlに懸濁させ、
38〜40℃にて１時間撹拌する。反応液を減圧濃縮
し、残留物をシリカゲルクロマトグラフイーに付
し、クロロホルム−メタノール（100：１〜100：
２）で溶出する。目的画分を減圧濃縮すると、融
点169〜171℃（分解）の５−（２−クロロフエニ
ル）−７−〔４−（４−イソブチルフエニル）ブチ
ル〕−１，３−ジヒドロ−2H−チエノ〔２，３−
ｅ〕−１，４−ジアゼピン−２−チオン８ｇを得
る。
５−（２−クロロフエニル）−７−〔４−（４−イ
ソブチルフエニル）ブチル〕−１，３−ジヒドロ
−2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピ
ン−２−チオン８ｇをメタノール100mlに懸濁し、
氷冷撹拌下、100％ヒドラジン・ヒドラート2.8ｇ
を加え、30分間反応する。減圧濃縮し、残留物を
クロロホルム100mlに溶解後、無水硫酸マグネシ
ウムで乾燥する。濾別後、減圧濃縮すると油状ヒ
ドラゾノ体８ｇを得る。ヒドラゾノ体をトルエン
100mlに溶解し、撹拌下、無水酢酸４ｇを加え、
30分間撹拌する。酢酸６ｇを加え、撹拌下、１時
間加熱還流する。減圧濃縮後、残留物をクロロホ
ルム100mlに溶解し、炭酸水素ナトリウム水、食
塩水で洗浄後、無水硫酸マグネシウムで乾燥す
る。濾別後、減圧濃縮し、残留物をシリカゲルク
ロマトグラフイーに付し、クロロホルム−メタノ
ール（100：１〜100：３）で溶出する。日的画分
を減圧濃縮すると油状の４−（２−クロロフエニ
ル）−２−〔４−（４−イソブチルフエニル）ブチ
ル〕−９−メチル−6H−チエノ〔３，２−ｆ〕
〔１，２，４〕トリアゾロ〔４，３−ａ〕〔１，
４〕ジアゼピン3.8ｇを得る。
実施例 ４
４−（２−クロロフエニル）−２−〔２−（４−メ
トキシフエニル）エチル〕−９−メチル−6H−
チエノ〔３，２−ｆ〕〔１，２，４〕トリアゾ
ロ〔４，３−ａ〕〔１，４〕ジアゼピン
融点196〜198℃の５−（２−クロロフエニル）−
７−〔２−（４−メトキシフエニル）エチル〕−１，
３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，
４−ジアゼピン−２−オン７ｇおよびLawesson
試薬５ｇをトルエン100mlに懸濁させ、45〜48℃
にて１時間撹拌する。反応液を減圧濃縮し、残留
物をシリカゲルクロマトグラフイーに付し、クロ
ロホルム−メタノール（100：１〜100：２）で溶
出する。目的画分を減圧濃縮すると、点185〜186
℃（分解）の５−（２−−クロロフエニル）−７−
〔２−（４−メトキシフエニル）エチル〕−１，３
−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，４
−ジアゼピン−２−チオン７ｇを得る。
５−（２−クロロフエニル）−７−〔２−（４−メ
トキシフエニル）エチル〕−１，３−ジヒドロ−
2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピン
−２−チオン７ｇをメタノール100mlに懸濁させ、
100％ヒドラジン・ヒドラート2.7ｇを加加え、約
30分間撹拌する。反応液を30〜40℃にて濃縮し、
クロロホルム100mlを加えて溶解後、無水硫酸マ
グネシウムで乾燥する。有機層を濃縮乾固し、残
査を乾燥トルエン100mlに溶解し、無水酢酸５ｇ
を加え、室温下、約30分間撹拌する。ひきつづき
この溶液に酢酸2.9ｇを加え、１時間、撹拌下、
加熱還流した後、濃縮乾固する。残査にクロロホ
ルム、水を加え炭酸水素ナトリウムで中和後、ク
ロロホルム層を食塩水で洗浄し、無水硫酸マグネ
シウムで乾燥後、濾過する。濾液を濃縮後、残査
をシリカゲルクロマトグラフイーに付し、クロロ
ホルム−メタノール（100：１〜100：３）で溶出
する。目的画分を濃縮後、ヘキサン−酢酸エチル
から結晶化すると、融点100〜105℃で無色結晶と
して、４−（２−クロロフエニル）−２−〔２−（４
−メトキシフエニル）エチル〕−９−メチル−6H
−チエノ〔３，２−ｆ〕〔１，２，４〕トリアゾ
ロ〔４，３−ａ〕〔１，４〕ジアゼピン４ｇを得
る。
実施例 ５
４−（２−クロロフエニル）−２−〔２−（４−ヒ
ドロキシフエニル）エチル〕−９−メチル−6H
−チエノ〔３，２−ｆ〕〔１，２，４〕トリア
ゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
実施例４で得たチエノトリアゾロジアゼピン
1.5ｇをメタンスルホン酸100mlに溶解し、DL−
メチオニン５ｇを加え、室温下、24時間放置す
る。これを氷水約300mlにあけ、炭酸水素ナトリ
ウムで中和後、酢酸エチル抽出を行い、有機層を
飽和食塩水で洗浄する。無水硫酸マグネシウムで
乾燥後、濾別し、濾液を濃縮すると無色結晶が析
出する。結を濾取し、イソプロピルエーテルで洗
浄後、乾燥すると、融点100〜102℃の４−（２−
クロロフエニル）−２−〔２−（４−ヒドロキシフ
エニル）エチル〕−９−メチル−6H−チエノ
〔３，２−ｆ〕〔１，２，４〕トリアゾロ〔４，３
−ａ〕〔１，４〕ジアゼピン0.9ｇを得る。
実施例 ６
４−（２−クロロフエニル）−２−〔２−（４−イ
ソプロポキシフエニル）エチル〕−９−メチル
−6H−チエノ〔３，２−ｆ〕〔１，２，４〕ト
リアゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
実施例５で得たチエノトリアゾロジアゼピン
0.5ｇを２−メトキシエタノール20mlに溶解し、
水酸化カリウム0.2ｇ、ヨウ化イソプロピル0.62
ｇを加え、撹拌下、90℃で４時間反応させる。反
応液を濃縮乾固し、残査をクロロホルム50mlに溶
解後、水洗し、無水硫酸マグネシウムで乾燥す
る。濾別後、減圧濃縮し、イソプロピルエーテル
−酢酸エチルから結晶化すると、融点121〜124℃
の無色結晶として４−（２−クロロフエニル）−２
−〔２−（４−イソプロポキシフエニル）エチル〕
−９−メチル−6H−チエノ〔３，２−ｆ〕〔１，
２，４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジ
アゼピン0.3ｇを得る。
実施例 ７
４−（２−クロロフエニル）−２−〔２−（４−ｎ
−ブチルフエニル）エチル〕−９−メチル−6H
−チエノ〔３，２−ｆ〕〔１，２，４〕トリア
ゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
融点152〜154℃の５−（２−クロロフエニル）−
７−〔２−（４−ｎ−ブチルフエニル）エチル〕−
１，３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−
１，４−ジアゼピン−２−オン５ｇおよび
Lawesson試薬2.8ｇをトルエン100mlに懸濁させ、
40〜45℃にて１時間撹拌する。反応液を減圧濃縮
し、残留物をシリカゲルクロマトグラフイーに付
し、クロロホルム−メタノール（100：１〜100：
２）で溶出する。目的画分を減圧濃縮すると、融
点186〜188℃（分解）の５−（２−クロロフエニ
ル）−７−〔２−（４−ｎ−ブチルフエニル）エチ
ル〕−１，３−ジヒドロ−2H−チエノ〔２，３−
ｅ〕−１，４−ジアゼピン−２−チオン3.8ｇを得
る。
５−（２−クロロフエニル）−７−〔２−（４−ｎ
−ブチルフエニル）エチル〕−１，３−ジヒドロ
−2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピ
ン−２−チオン3.8ｇをメタノール50mlに懸濁さ
せ、氷冷、撹拌下、100％ヒドラジン・ヒドラー
ト1.4ｇを加え、30分間反応させる。反応液を30
〜40℃にて濃縮乾固し、クロロホルム100mlを加
えて溶解後、無水硫酸マグネシウムにて乾燥す
る。濾別後、クロロホルムを留去し、残査を乾燥
トルエン75mlに溶解する。撹拌下、無水酢酸2.1
ｇを加え、30分間反応を行う。その後、酢酸３ｇ
を加え撹拌下、２時間加熱還流し、冷後反応液を
濃縮乾固する。残査にクロロホルム100mlを加え、
溶解し炭酸水素ナトリウム水で中和する。クロロ
ホルム層を食塩水で洗浄後、無水硫酸マグネシウ
ムで乾燥し、濾別後、濾液を濃縮する。残査をシ
リカゲルクロマトグラフイーに付し、クロロホル
ム−メタノール（100：１〜100：３）で溶出す
る。目的画分を濃縮後、酢酸エチルから結晶化す
ると、融点119〜121℃の無色結晶として４−（２
−クロロフエニル）−２−〔２−（４−ｎ−ブチル
フエニル）エチル〕−９−メチル−6H−チエノ
〔３，２−ｆ〕〔１，２，４〕トリアゾロ〔４，３
−ａ〕〔１，４〕ジアゼピン１ｇを得る。
実施例 ８
４−（２−クロロフエニル）−２−〔２−（４−フ
エニルフエニル）エチル〕−９−メチル−6H−
チエノ〔３，２−ｆ〕〔１，２，４〕トリアゾ
ロ〔４，３−ａ〕〔１，４〕ジアゼピン
融点187〜189℃の５−（２−クロロフエニル）−
７−〔２−（４−フエニルフエニル）エチル〕−１，
３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，
４−ジアゼピン−２−オン7.2ｇおよびLawesson
試薬3.9ｇをトルエン100mlに懸濁させ、58〜60℃
にて１時間撹拌する。反応液を減圧濃縮し、残留
物をシリカゲルクロマトグラフイーに付し、クロ
ロホルム−メタノール（100：１〜100：２）で溶
出する。目的画分を減圧濃縮すると、融点190〜
191℃（分解）の５−（２−クロロフエニル）−７
−〔２−（４−フエニルフエニル）エチル〕−１，
３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，
４−ジアゼピン−２−チオン６ｇを得る。
５−（２−クロロフエニル）−７−〔２−（４−フ
エニルフエニル）エチル〕−１，３−ジヒドロ−
2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピン
−２−チオン６ｇをメタノール100mlに懸濁させ、
氷冷、撹拌下、100％ヒドラジン・ヒドラート2.1
ｇを加え、１時間反応させる。析出した結晶を濾
別後、乾燥してヒドラゾノ体5.4ｇを得る。ヒド
ラゾノ体をトルエン75mlに懸濁し、無水酢酸1.4
ｇを加え１時間反応後、酢酸4.2ｇを添加し、水
抜きをしながら撹拌下、１時間加熱還流を行う。
冷後、濃縮乾固し100mlのクロロホルムに溶解す
る。水を加え炭酸水素ナトリウムで中和し、水洗
乾燥する。濾別後、濾液を濃縮し、残査をシリカ
ゲルクロマトグラフイーに付し、クロロホルム−
メタノール（100：１〜100：３）で溶出する。目
的画分を濃縮後、酢酸エチルから結晶化すると、
融点163〜165℃の無色結晶として４−（２−クロ
ロフエニル）−２−〔２−（４−フエニルフエニル）
エチル〕−９−メチル−6H−チエノ〔３，２−
ｆ〕〔１，２，４〕トリアゾロ〔４，３−ａ〕
〔１，４〕ジアゼピン2.8ｇを得る。
実施例 ９
４−（２−クロロフエニル）−２−ベンジル−９
−メチル−6H−チエノ〔３，２−ｆ〕〔１，
２，４〕トリアゾロ〔４，３−ａ〕〔１，４〕
ジアゼピン
５−（２−クロロフエニル）−７−ベンジル−
１，３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−
１，４−ジアゼピン−２−オンおよび５硫化リン
1.2ｇをピリジン50mlに懸濁し、82℃にて３時間
撹拌する。反応液を撹拌下、氷水100mlにあけ、
析出した結晶を濾取し、水洗後、乾燥すると、融
点188〜189℃（分解）の５−（２−クロロフエニ
ル−７−ベンジル−１，３−ジヒドロ−2H−チ
エノ〔２，３−ｅ〕−１，４−ジアゼピン−２−
チオン４ｇを得る。
５−（２−クロロフエニル）−７−ベンジル−
１，３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−
１，４−ジアゼピン−２−チオン14ｇをメタノー
ル50mlに懸濁し、氷冷、撹拌下下100％ヒドラジ
ン・ヒドラート1.8ｇを加え、室温で30分間反応
させる。30℃でメタノールを留去し、残査をクロ
ロホルム100mlに溶解する。飽和食塩水で洗浄後、
無水硫酸マグネシウムで乾燥する。濾別後、濾液
を濃縮乾固し、残査をトルエン50mlに溶解し、無
水酢酸1.3ｇ、酢酸3.8ｇを加え、4.5時間、撹拌
下、加熱還流する。反応液を濃縮乾固し、残査を
クロロホルムに溶解し、炭酸水素ナトリウムで中
和後、水洗し無水硫酸マグネシウムで乾固する。
濾別後、濾液を濃縮し、残査をシリカゲルクロマ
トグラフイーに付し、クロロホルム−メタノール
（100：１〜100：３）で溶出する。目的画分を濃
縮乾固し、イソプロピルエーテル−酢酸エチルか
ら結晶化すると、融点161〜163℃の淡黄色結晶と
して、４−（２−クロロフエニル）−２−ベンジル
−９−メチル−6H−チエノ〔３，２−ｆ〕〔１，
２，４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジ
アゼピン1.5ｇを得る。
実施例 10
４−（２−クロロフエニル）−２−（２−フエニ
ルエチル）−９−メチル−6H−チエノ〔３，２
−ｆ〕〔１，２，４〕トリアゾロ〔４，３−ａ〕
〔１，４〕ジアゼピン
融点175〜176℃の５−（２−クロロフエニル）−
７−（２−フエニルエチル）−１，３−ジヒドロ−
2H−チエノ〔２，３−ｅ〕−１，４−ジアゼピン
−２−オン7.5ｇおよびLawesson試薬4.8ｇをト
ルエン150mlに懸濁させ、40〜45℃にて１時間撹
拌する。反応液を減圧濃縮し、残留物をシリカゲ
ルクロマトグラフイーに付し、クロロホルム−メ
タノール（100：１〜100：２で）溶出する。目的
画分を減圧濃縮すると、５−（２−クロロフエニ
ル）−７−（２−フエニルエチル）−１，３−ジヒ
ドロ−2H−チエノ〔２，３−ｅ〕−１，４−ジア
ゼピン−２−チオン9.8ｇを得る。
５−（２−クロロフエニル）−７−（２−フエニ
ルエチル）−１，３−ジヒドロ−2H−チエノ
〔２，３−ｅ〕−１，４−ジアゼピン−２−チオン
9.8ｇをメタノール40mlに懸濁し、室温にて撹拌
下、100％ヒドラジン・ヒドラート3.3ｇを加え、
室温下に30分間撹拌する。減圧濃縮し、油状物を
クロロホルム20mlに溶解後、無水硫酸マグネシウ
ムで乾燥、濾別する。再度、減圧濃縮して油状物
13ｇを得る。油状物のヒドラゾノ体をトルエン80
mlに懸濁し、撹拌下、無水酢酸6.4mlを加え、さ
らに酢酸6.9mlを加えて、加熱撹拌下、45分還流
する。この反応液を減圧濃縮し、酢酸エチル100
mlに溶解し、炭酸水素ナトリウム水、食塩水で洗
浄後、無水硫酸マグネシウムで乾燥して減圧濃縮
すると、油状物6.5ｇを得る。この油状物をシリ
カゲルクロマトグラフイーに付し、クロロホルム
−メタノール（100：１〜100：３）で溶出する。
目的画分を減圧濃縮し、イソプロピルエーテル−
酢酸エチルから結晶化すると、融点106〜108℃の
無色結晶として、４−（２−クロロフエニル）−２
−（２−フエニルエチル）−９−メチル−6H−チ
エノ〔３，２−ｆ〕〔１，２，４〕トリアゾロ
〔４，３−ａ〕〔１，４〕ジアゼピン２ｇを得る。
実施例 11
４−（２−クロロフエニル）−２−〔２−（４−ク
ロロフエニル）エチル〕−９−メチル−6H−チ
エノ〔３，２−ｆ〕〔１，２，４〕トリアゾロ
〔４，３−ａ〕〔１，４〕ジアゼピン
融点201〜203℃の５−（２−クロロフエニル）−
７−〔２−（４−クロロフエニル）エチル〕−１，
３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，
４−ジアゼピン−２−オン8.2ｇおよびLawesson
試薬4.9ｇをトルエン160mlに懸濁させ、40〜45℃
にて１時間撹拌する。反応液を減圧濃縮し、残留
物をシリカゲルクロマトグラフイーに付し、クロ
ロホルム−メタノール（100：１〜100：２）で溶
出する。目的画分を減圧濃縮すると、５−（２−
クロロフエニル）−７−〔２−（４−クロロフエニ
ル）エチル〕−１，３−ジヒドロ−2H−チエノ
〔２，３−ｅ〕−１，４−ジアゼピン−２−チオン
4.5ｇを得る。
５−（２−クロロフエニル）−７−〔２−（４−ク
ロロフエニル）エチル〕−１，３−ジヒドロ−2H
−チエノ〔２，３−ｅ〕−１，４−ジアゼピン−
２−チオン4.5ｇをメタノール20mlに懸濁し、氷
冷撹拌下、100％ヒドラジン・ヒドラート1.7ｇを
加え、室温下15分間撹拌する。減圧濃縮後、残査
をクロロホルム50mlに溶解し、無水硫酸マグネシ
ウムで乾燥後、再度減圧濃縮して、油状物5.1ｇ
を得る。油状ヒドラゾノ体をトルエン40mlに懸濁
し、撹拌下、無水酢酸3.4ml、酢酸3.7mlを加え
て、撹拌下、45分間加熱還流する。反応液を減圧
濃縮し、残査を酢酸エチル50mlに溶解し、炭酸水
素ナトリウム水、食塩水で洗浄後、無水硫酸マグ
ネシウムで乾燥して、減圧濃縮すると油状物3.6
ｇを得る。これをイソプロピルエーテル−酢酸エ
チルから結晶化し、晶出した結晶を濾取し、イソ
プロピルエーテル−酢酸エチルから再結晶する
と、融点162〜164℃の無色結晶として４−（２−
クロロフエニル）−２−２−（４−クロロフエニ
ル）エチル〕−９−メチル−6H−チエノ〔３，２
−ｆ〕〔１，２，４〕トリアゾロ〔４，３−ａ〕
〔１，４〕ジアゼピン1.3ｇを得る。
実施例 12
４−（２−クロロフエニル）−２−〔２−（４−ｎ
−ヘキシルフエニル）エチル〕−９−メチル−
6H−チエノ〔３，２−ｆ〕〔１，２，４〕トリ
アゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
融点149〜151℃の５−（２−クロロフエニル）−
７−〔２−（４−ｎ−ヘキシルフエニル）エチル〕
−１，３−ジヒドロ−2H−チエノ〔２，３−ｅ〕
−１，４−ジアゼピン−２−オン６ｇおよび
Lawesson試薬5.2ｇをトルエン100mlに懸濁させ、
40〜42℃にて１時間撹拌する。反応液を減圧濃縮
し、残留物をシリカゲルクロマトグラフイーに付
し、クロロホルム−メタノール（100：１〜100：
２）で溶出する。目的画分を減圧濃縮すると、融
点140〜145℃（分解）の５−（２−クロロフエニ
ル）−７−〔２−（４−ｎ−ヘキシルフエニル）エ
チル〕−１，３ジヒドロ−2H−チエノ〔２，３−
ｅ〕−１，４−ジアゼピン−２−チオン６ｇを得
る。
５−（２−クロロフエニル）−７−〔２−（４−ｎ
−ヘキシルフエニル）エチル〕−１，３−ジヒド
ロ−2H−チエソ〔２，３−ｅ〕−１，４−ジアゼ
ピン−２−チオン６ｇを、メタノール50mlに懸濁
し、氷冷撹拌下、100％ヒドラジン・ヒドラート
２ｇを加え、30分間反応させる。反応液を減圧濃
縮し、残査をクロロホルム100mlに溶解する。無
水硫酸マグネシウムで乾燥後、再度減圧濃縮し、
油状物７ｇを得る。油状のヒドラゾノ体をトルエ
ン100mlに懸濁し、撹拌下、無水酢酸3.8ｇ、酢酸
2.5ｇを加え、６時間撹拌下に加熱還流する。反
応液を減圧濃縮し、残査をクロロホルム100mlに
溶解し、炭酸水素ナトリウム水で水洗後、無水硫
酸マグネシウムで乾燥して、減圧濃縮すると油状
物７ｇを得る。この油状物をシリカゲルクロマト
グラフイーに付し、クロロホルム−メタノール
（100：１〜100：３）で溶出する。目的画分を減
圧濃縮し、４−（２−クロロフエニル）−２−〔２
−（４−ｎ−ヘキシルフエニル）エチル〕−９−メ
チル−6H−チエノ〔３，２−ｆ〕〔１，２，４〕
トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
２ｇを得る。
実施例 13
４−（２−クロロフエニル）−〔２−（４−イソブ
チルフエニル）エチル〕−６，９−ジメチル−
6H−チエノ〔３，２−ｆ〕〔１，２，４〕トリ
アゾロ〔４，３−ａ〕〔１，４〕ジアゼピン
融点188〜191℃の５−（２−クロロフエニル）−
７−〔２−（４−イソブチルフエニル）エチル〕−
３−メチル−１，３−ジヒドロ−2H−チエノ
〔２，３−ｅ〕−１，４−ジアゼピン−２−オン２
ｇおよびLawesson試薬1.04ｇをトルエン37mlに
懸濁させ、40〜45℃にて１時間撹拌する。反応液
を減圧濃縮し、残留物をシリカゲルクロマトグラ
フイーに付し、クロロホルム−メタノール
（100：１〜100：２）で溶出する。目的画分を減
圧濃縮すると、５−（２−クロロフエニル）−７−
〔２−（４−イソブチルフエニル）エチル〕−３−
メチル−１，３−ジヒドロ−2H−チエノ〔２，
３−ｅ〕−１，４−ジアゼピン−２−チオン1.2ｇ
を得る。
５−（２−クロロフエニル）−７−〔２−（４−イ
ソブチルフエニル）エチル〕−３−メチル−１，
３−ジヒドロ−2H−チエノ〔２，３−ｅ〕−１，
４−ジアゼピン−２−チオン9.1ｇをテトラヒド
ロフラン150mlに溶解し、氷冷下、100％ヒドラジ
ン・ヒドラート3.1ｇを加え、室温で２時間反応
させる。減圧下、テトラヒドロフランを留去し、
残査をクロロホルム200mlに溶解する。無水硫酸
マグネシウムで乾燥し、濾別後、減圧濃縮する。
残査にオルト酢酸エチル50mlを加え、70〜72℃で
１時間加温する。反応液を減圧濃縮し、残査をシ
リカゲルクロマトグラフイーに付し、クロロホル
ム−メタノール（100：１〜100：３）で溶出す
る。目的画分を濃縮後、イソプロピルエーテルか
ら結晶化すると、融点129.5〜131.5℃の無色結晶
として、４−（２−クロロフエニル）−２−〔２−
（４−イソブチルフエニル）エチル〕−６，９−ジ
メチル−6H−チエノ〔３，２−ｆ〕〔１，２，
４〕トリアゾロ〔４，３−ａ〕〔１，４〕ジアゼ
ピン4.3ｇを得る。
製剤処方例
(1) 錠剤
実施例１の化合物を0.5部、乳糖25部、結晶セ
ルロース35部およびコーンスターチ３部とをよく
混和したのち、コーンスターチ２部で製した結合
剤とよく練合した。この練合物を16メツシユで篩
過し、オーブン中50℃で乾燥後、24メツシユで篩
過した。ここに得た練合粉体とコーンスターチ８
部、結晶セルロース11部およびタルク９部とをよ
く混合した後、圧搾打錠し、１錠あたり有効成分
0.5mg含有の錠剤を得た。
(2) １％散剤
実施例１の化合物を１部と乳糖90部をよく混和
し、適当量のメチルセルロースより製した結合剤
とよく練合する。これを16メツシユで篩過し、オ
ーブン中50℃で乾燥する。乾燥顆粒末を32メツシ
ユで圧篩過し、適量のシリコンジオキシドとよく
混和して、１％散剤を得た。
本発明を上述の明細書およびそれに包含される
実施例で十分に説明したが、これらは本発明の精
神と範囲に反することなく種々に変更、修飾する
ことができる。
The starting compound is new and the Journal of
Medicinal Chemistry (J.Med.Chem.),
It can be obtained according to the method described in Vol. 16, p. 214 (1973). The detailed preparation method of the starting compound will be explained below by giving an example. Example of preparation of starting compounds a) 2-amino-3-(2-chlorobenzoyl)
-5-[2-(4-isobutylphenyl)ethyl]-thiophene 2-chlorocyanoacetophenone 29g, sulfur
Suspend 4.9 g in 50 ml of dimethylformamide, and add 18.5 g of triethylamine while stirring. Next, 30 g of 4-(4-isobutylphenyl)butyraldehyde dissolved in 10 ml of ethanol was added, and the mixture was reacted at 60° C. for 3 hours with stirring. Pour the reaction solution into ice water and extract with 400 ml of chloroform. After washing with water, dry with anhydrous magnesium sulfate. After filtering,
When the filtrate is concentrated under reduced pressure, the indicated oily amino compound 70 is obtained.
get g. b) 2-chloroacetylamino-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl)ethyl]-thiophene Dissolve 70 g of the compound in a) above in 500 ml of chloroform, and dissolve 20 g of chloroacetyl chloride. and heated under reflux for 2 hours while stirring. After cooling, wash with sodium bicarbonate water and saline solution. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The residue was subjected to simple silica gel chromatography to obtain 45 g of a crude oily chloroacetylamino compound. c) 2-Aminoacetylamino-3-(2-chlorobenzoyl)-5-[2-(4-isobutylphenyl)ethyl]-thiophene 45 g of the chloroacetylamino compound of b) above,
16 g of sodium iodide and 200 g of tetrahydrofuran
ml and heated under reflux for 2 hours while stirring. After cooling, cool to -20°C with dry ice-methanol, and add about 30 ml of liquid ammonia while stirring. The reaction solution is gradually heated to room temperature over 2 hours. After removing ammonia using an aspirator, concentrate under reduced pressure and dissolve the residue in 500 ml of chloroform. After washing with water,
Dry with anhydrous magnesium sulfate. After filtration, the mixture is concentrated under reduced pressure to obtain 50 g of the oily crude amino compound described above. d) 5-(2-chlorophenyl)-7-[2-(4
-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-
Diazepin-2-one After dissolving 50 g of the compound c) above in 300 ml of isopropyl alcohol, 8.5 g of acetic acid was added, and the mixture was heated under reflux for 6 hours with stirring. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 500 ml of chloroform. After washing with sodium bicarbonate water and saline, dry with anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the residue was subjected to simple silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). The target fraction is concentrated under reduced pressure and crystallized from isopropyl ether to obtain 10 g of colorless crystalline thienodiazepine having a melting point of 179-181°C. EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these in any way. Example 1 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-9-methyl-6H
-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl) 9.8 g of ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one and 5.5 g of Lawesson's reagent were suspended in 200 ml of toluene and heated at 40 to 43°C. Stir for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, and chloroform-
Elute with methanol (100:1-100:2). When the target fraction was concentrated under reduced pressure, 5-(2-chlorophenyl)-7-[2-(4
9.6 g of -isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione 9.6 g in 100 ml of methanol, add 3.5 g of 100% hydrazine hydrate under ice cooling, and stir for 30 minutes. After the reaction is complete, methanol is completely distilled off at 30-40℃, and 100ml of chloroform is added.
Add, dissolve and dry over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1. , 8 g of 4-diazepine-2-hydrazone are obtained as an oil. After dissolving it in 100ml of toluene, cooling on ice and stirring,
Add 5 g of acetic anhydride and stir for about 30 minutes. Add 6 g of acetic acid to this reaction solution, heat under reflux for 1 hour while stirring, and then concentrate under reduced pressure. The residue is dissolved in chloroform, washed with aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). The desired fraction was concentrated under reduced pressure and crystallized from ethyl acetate, resulting in a melting point of
4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl) as colorless crystals at 118-121°C.
ethyl]-9-methyl-6H-thieno[3,2-
f] [1,2,4] triazolo [4,3-a]
Obtain 4.2 g of [1,4] diazepine. Similarly, the desired product can be obtained by reacting the thione compound with acetic acid hydrazide instead of the hydrazine hydrate. Example 2 4-(2-chlorophenyl)-2-[2-(4-methylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3] -a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 195-197℃
7-[2-(4-methylphenyl)ethyl]-1,
3-dihydro-2H-thieno[2,3-e]-1,
4-Diazepin-2-one 3.9g and Lawesson
Suspend 2.5g of reagent in 50ml of toluene and heat at 40-43℃.
Stir for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:2). When the desired fraction is concentrated under reduced pressure, the melting point is 190~
5-(2-chlorophenyl)-7 at 191℃ (decomposition)
-[2-(4-methylphenyl)ethyl]-1,3
-dihydro-2H-thieno[2,3-e]-1,4
-4 g of diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[2-(4-methylphenyl)ethyl]-1,3-dihydro-2H
-thieno[2,3-e]-1,4-diazepine-
Suspend 5 g of 2-thione in 50 ml of methanol,
Add 2 g of 100% hydrazine hydrate under ice cooling and stir for 30 minutes. Then add methanol to 30~
After complete distillation at 40℃, add 100% chloroform to the residue.
ml, dissolve, and dry over anhydrous magnesium sulfate. After filtration, concentrate under reduced pressure and dissolve the residue in toluene 100%
Dissolve in ml. Add 3 g of acetic anhydride under ice-cooling and stirring, and react for 30 minutes. Next, 4.4 g of acetic acid was added, and the mixture was heated under reflux for 1 hour while stirring. After vacuum concentration,
The residue was dissolved in chloroform, washed with sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). The target fraction was concentrated under reduced pressure and crystallized from ethyl acetate to give 4-
(2-chlorophenyl)-2-[2-(4-methylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3
-a] 0.7 g of [1,4] diazepine is obtained. Example 3 4-(2-chlorophenyl)-2-[4-(4-isobutylphenyl)butyl]-9-methyl-6H
-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 133-135°C
7-[4-(4-isobutylphenyl)butyl]-
1,3-dihydro-2H-thieno[2,3-e]-
8.9 g of 1,4-diazepin-2-one and
Suspend 4.7g of Lawesson's reagent in 100ml of toluene,
Stir for 1 hour at 38-40°C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography using chloroform-methanol (100:1-100:
Elute in 2). When the target fraction was concentrated under reduced pressure, 5-(2-chlorophenyl)-7-[4-(4-isobutylphenyl)butyl]-1,3-dihydro-2H-thieno[ 2,3-
e] 8 g of -1,4-diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[4-(4-isobutylphenyl)butyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione 8 g Suspended in 100ml of methanol,
2.8 g of 100% hydrazine hydrate under ice-cooling and stirring
Add and react for 30 minutes. Concentrate under reduced pressure, dissolve the residue in 100 ml of chloroform, and dry over anhydrous magnesium sulfate. After filtration, the mixture is concentrated under reduced pressure to obtain 8 g of an oily hydrazonomer. Hydrazonoform toluene
Dissolve in 100ml, add 4g of acetic anhydride while stirring,
Stir for 30 minutes. Add 6 g of acetic acid, and heat to reflux for 1 hour while stirring. After concentration under reduced pressure, the residue is dissolved in 100 ml of chloroform, washed with aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). When the daily fraction was concentrated under reduced pressure, an oily 4-(2-chlorophenyl)-2-[4-(4-isobutylphenyl)butyl]-9-methyl-6H-thieno[3,2-f] was obtained.
[1,2,4] Triazolo [4,3-a] [1,
4] Obtain 3.8 g of diazepine. Example 4 4-(2-chlorophenyl)-2-[2-(4-methoxyphenyl)ethyl]-9-methyl-6H-
Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 196-198°C
7-[2-(4-methoxyphenyl)ethyl]-1,
3-dihydro-2H-thieno[2,3-e]-1,
4-Diazepin-2-one 7g and Lawesson
Suspend 5g of reagent in 100ml of toluene and heat at 45-48℃.
Stir for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:2). When the target fraction is concentrated under reduced pressure, points 185 to 186 are obtained.
5-(2--chlorophenyl)-7- at °C (decomposition)
[2-(4-methoxyphenyl)ethyl]-1,3
-dihydro-2H-thieno[2,3-e]-1,4
-7 g of diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[2-(4-methoxyphenyl)ethyl]-1,3-dihydro-
7 g of 2H-thieno[2,3-e]-1,4-diazepine-2-thione was suspended in 100 ml of methanol,
Add 2.7g of 100% hydrazine hydrate, approx.
Stir for 30 minutes. Concentrate the reaction solution at 30-40℃,
Add 100 ml of chloroform to dissolve, then dry with anhydrous magnesium sulfate. The organic layer was concentrated to dryness, the residue was dissolved in 100 ml of dry toluene, and 5 g of acetic anhydride was added.
and stir at room temperature for about 30 minutes. Subsequently, 2.9 g of acetic acid was added to this solution, and the mixture was stirred for 1 hour.
After heating to reflux, the mixture is concentrated to dryness. After adding chloroform and water to the residue and neutralizing with sodium bicarbonate, the chloroform layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. After concentrating the filtrate, the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). After concentrating the desired fraction, crystallization from hexane-ethyl acetate yields 4-(2-chlorophenyl)-2-[2-(4
-methoxyphenyl)ethyl]-9-methyl-6H
4 g of -thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine are obtained. Example 5 4-(2-chlorophenyl)-2-[2-(4-hydroxyphenyl)ethyl]-9-methyl-6H
-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine Thienotriazolodiazepine obtained in Example 4
Dissolve 1.5g in 100ml of methanesulfonic acid and add DL-
Add 5 g of methionine and leave at room temperature for 24 hours. Pour this into about 300 ml of ice water, neutralize with sodium bicarbonate, extract with ethyl acetate, and wash the organic layer with saturated brine. After drying over anhydrous magnesium sulfate, it is filtered and the filtrate is concentrated to precipitate colorless crystals. The precipitate is collected by filtration, washed with isopropyl ether, and dried to give 4-(2-
chlorophenyl)-2-[2-(4-hydroxyphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3
-a] 0.9 g of [1,4] diazepine is obtained. Example 6 4-(2-chlorophenyl)-2-[2-(4-isopropoxyphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[ 4,3-a][1,4]diazepine Thienotriazolodiazepine obtained in Example 5
Dissolve 0.5g in 20ml of 2-methoxyethanol,
Potassium hydroxide 0.2g, isopropyl iodide 0.62
g and reacted at 90°C for 4 hours with stirring. The reaction solution is concentrated to dryness, and the residue is dissolved in 50 ml of chloroform, washed with water, and dried over anhydrous magnesium sulfate. After filtration, concentration under reduced pressure and crystallization from isopropyl ether-ethyl acetate gives a melting point of 121-124°C.
4-(2-chlorophenyl)-2 as colorless crystals of
-[2-(4-isopropoxyphenyl)ethyl]
-9-methyl-6H-thieno[3,2-f][1,
0.3 g of 2,4]triazolo[4,3-a][1,4]diazepine is obtained. Example 7 4-(2-chlorophenyl)-2-[2-(4-n
-butylphenyl)ethyl]-9-methyl-6H
-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 152-154°C
7-[2-(4-n-butylphenyl)ethyl]-
1,3-dihydro-2H-thieno[2,3-e]-
1,4-diazepin-2-one 5g and
Suspend 2.8g of Lawesson's reagent in 100ml of toluene,
Stir for 1 hour at 40-45°C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography using chloroform-methanol (100:1-100:
Elute in 2). The target fraction was concentrated under reduced pressure to obtain 5-(2-chlorophenyl)-7-[2-(4-n-butylphenyl)ethyl]-1,3-dihydro-2H-thieno[ with a melting point of 186-188°C (decomposed). 2,3-
e] 3.8 g of -1,4-diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[2-(4-n
3.8 g of -butylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione was suspended in 50 ml of methanol, and cooled on ice and stirred at 100% Add 1.4 g of hydrazine hydrate and react for 30 minutes. 30% reaction solution
Concentrate to dryness at ~40°C, add 100 ml of chloroform to dissolve, and dry over anhydrous magnesium sulfate. After filtration, chloroform is distilled off and the residue is dissolved in 75 ml of dry toluene. Under stirring, acetic anhydride 2.1
g and react for 30 minutes. Then 3g of acetic acid
was added and heated under reflux for 2 hours with stirring, and after cooling, the reaction solution was concentrated to dryness. Add 100ml of chloroform to the residue,
Dissolve and neutralize with sodium bicarbonate water. The chloroform layer is washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated. The residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). After concentrating the target fraction, crystallization from ethyl acetate yields 4-(2
-chlorophenyl)-2-[2-(4-n-butylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3
-a] 1 g of [1,4] diazepine is obtained. Example 8 4-(2-chlorophenyl)-2-[2-(4-phenylphenyl)ethyl]-9-methyl-6H-
Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 187-189°C
7-[2-(4-phenylphenyl)ethyl]-1,
3-dihydro-2H-thieno[2,3-e]-1,
7.2 g of 4-diazepin-2-one and Lawesson
Suspend 3.9g of reagent in 100ml of toluene and heat at 58-60℃.
Stir for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:2). When the desired fraction is concentrated under reduced pressure, the melting point is 190~
5-(2-chlorophenyl)-7 at 191℃ (decomposition)
-[2-(4-phenylphenyl)ethyl]-1,
3-dihydro-2H-thieno[2,3-e]-1,
6 g of 4-diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[2-(4-phenylphenyl)ethyl]-1,3-dihydro-
6 g of 2H-thieno[2,3-e]-1,4-diazepine-2-thione was suspended in 100 ml of methanol,
Ice-cold, stirring, 100% hydrazine hydrate 2.1
g and react for 1 hour. The precipitated crystals are filtered and dried to obtain 5.4 g of hydrazonomer. Suspend the hydrazonomer in 75 ml of toluene and add 1.4 ml of acetic anhydride.
After reacting for 1 hour, 4.2 g of acetic acid was added, and the mixture was heated under reflux for 1 hour while stirring while draining water.
After cooling, concentrate to dryness and dissolve in 100 ml of chloroform. Add water and neutralize with sodium bicarbonate, wash with water and dry. After filtration, the filtrate was concentrated, the residue was subjected to silica gel chromatography, and chloroform-
Elute with methanol (100:1-100:3). After concentrating the target fraction and crystallizing it from ethyl acetate,
4-(2-chlorophenyl)-2-[2-(4-phenylphenyl)] as colorless crystals with a melting point of 163-165°C.
ethyl]-9-methyl-6H-thieno[3,2-
f] [1,2,4] triazolo [4,3-a]
Obtain 2.8 g of [1,4] diazepine. Example 9 4-(2-chlorophenyl)-2-benzyl-9
-Methyl-6H-thieno[3,2-f][1,
2,4] Triazolo [4,3-a] [1,4]
Diazepine 5-(2-chlorophenyl)-7-benzyl-
1,3-dihydro-2H-thieno[2,3-e]-
1,4-diazepin-2-one and phosphorus pentasulfide
Suspend 1.2 g in 50 ml of pyridine and stir at 82°C for 3 hours. Pour the reaction solution into 100ml of ice water while stirring.
The precipitated crystals are collected by filtration, washed with water, and dried to give 5-(2-chlorophenyl-7-benzyl-1,3-dihydro-2H-thieno[2,3-e] with a melting point of 188-189°C (decomposed)). -1,4-diazepine-2-
Obtain 4 g of thione. 5-(2-chlorophenyl)-7-benzyl-
1,3-dihydro-2H-thieno[2,3-e]-
Suspend 14 g of 1,4-diazepine-2-thione in 50 ml of methanol, add 1.8 g of 100% hydrazine hydrate under ice-cooling and stirring, and react for 30 minutes at room temperature. Methanol is distilled off at 30°C, and the residue is dissolved in 100 ml of chloroform. After washing with saturated saline,
Dry with anhydrous magnesium sulfate. After filtration, the filtrate is concentrated to dryness, the residue is dissolved in 50 ml of toluene, 1.3 g of acetic anhydride and 3.8 g of acetic acid are added, and the mixture is heated under reflux with stirring for 4.5 hours. The reaction solution is concentrated to dryness, and the residue is dissolved in chloroform, neutralized with sodium bicarbonate, washed with water, and dried over anhydrous magnesium sulfate.
After filtration, the filtrate is concentrated, and the residue is subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). The desired fractions were concentrated to dryness and crystallized from isopropyl ether-ethyl acetate to give 4-(2-chlorophenyl)-2-benzyl-9-methyl-6H-thieno as pale yellow crystals with a melting point of 161-163°C. 3,2-f] [1,
1.5 g of 2,4]triazolo[4,3-a][1,4]diazepine is obtained. Example 10 4-(2-chlorophenyl)-2-(2-phenylethyl)-9-methyl-6H-thieno[3,2
-f] [1,2,4] triazolo [4,3-a]
[1,4]Diazepine 5-(2-chlorophenyl)- with a melting point of 175-176℃
7-(2-phenylethyl)-1,3-dihydro-
7.5 g of 2H-thieno[2,3-e]-1,4-diazepin-2-one and 4.8 g of Lawesson's reagent are suspended in 150 ml of toluene and stirred at 40-45°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:2). The target fraction was concentrated under reduced pressure to yield 5-(2-chlorophenyl)-7-(2-phenylethyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione. Obtain 9.8g. 5-(2-chlorophenyl)-7-(2-phenylethyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione
Suspend 9.8g in 40ml of methanol, add 3.3g of 100% hydrazine hydrate while stirring at room temperature,
Stir for 30 minutes at room temperature. Concentrate under reduced pressure, dissolve the oil in 20 ml of chloroform, dry over anhydrous magnesium sulfate, and filter. Concentrate under reduced pressure again to obtain an oily substance.
Get 13g. Toluene 80% of oily hydrazonomer
ml, add 6.4 ml of acetic anhydride with stirring, then add 6.9 ml of acetic acid, and reflux for 45 minutes with stirring. This reaction solution was concentrated under reduced pressure, and 100% ethyl acetate was added.
ml, washed with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 6.5 g of an oily substance. This oil was chromatographed on silica gel and eluted with chloroform-methanol (100:1 to 100:3).
The target fraction was concentrated under reduced pressure and diluted with isopropyl ether.
Crystallization from ethyl acetate gives 4-(2-chlorophenyl)-2 as colorless crystals with a melting point of 106-108°C.
2 g of -(2-phenylethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine are obtained. Example 11 4-(2-chlorophenyl)-2-[2-(4-chlorophenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 -a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 201-203℃
7-[2-(4-chlorophenyl)ethyl]-1,
3-dihydro-2H-thieno[2,3-e]-1,
8.2 g of 4-diazepin-2-one and Lawesson
Suspend 4.9g of reagent in 160ml of toluene and heat at 40-45℃.
Stir for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:2). When the target fraction is concentrated under reduced pressure, 5-(2-
chlorophenyl)-7-[2-(4-chlorophenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione
Obtain 4.5g. 5-(2-chlorophenyl)-7-[2-(4-chlorophenyl)ethyl]-1,3-dihydro-2H
-thieno[2,3-e]-1,4-diazepine-
Suspend 4.5 g of 2-thione in 20 ml of methanol, add 1.7 g of 100% hydrazine hydrate while stirring on ice, and stir for 15 minutes at room temperature. After concentration under reduced pressure, the residue was dissolved in 50 ml of chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure again to obtain 5.1 g of oil.
get. The oily hydrazonomer is suspended in 40 ml of toluene, 3.4 ml of acetic anhydride and 3.7 ml of acetic acid are added under stirring, and the mixture is heated under reflux for 45 minutes while stirring. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oily substance (3.6 ml).
get g. This was crystallized from isopropyl ether-ethyl acetate, the crystals were collected by filtration, and recrystallized from isopropyl ether-ethyl acetate as colorless crystals with a melting point of 162-164°C.
chlorophenyl)-2-2-(4-chlorophenyl)ethyl]-9-methyl-6H-thieno[3,2
-f] [1,2,4] triazolo [4,3-a]
Obtain 1.3 g of [1,4] diazepine. Example 12 4-(2-chlorophenyl)-2-[2-(4-n
-hexylphenyl)ethyl]-9-methyl-
6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 149-151°C
7-[2-(4-n-hexylphenyl)ethyl]
-1,3-dihydro-2H-thieno[2,3-e]
-1,4-diazepin-2-one 6 g and
Suspend 5.2g of Lawesson's reagent in 100ml of toluene,
Stir for 1 hour at 40-42°C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography using chloroform-methanol (100:1-100:
Elute in 2). The target fraction was concentrated under reduced pressure to obtain 5-(2-chlorophenyl)-7-[2-(4-n-hexylphenyl)ethyl]-1,3dihydro-2H-thieno[2] with a melting point of 140-145°C (decomposition). ,3-
e] 6 g of -1,4-diazepine-2-thione are obtained. 5-(2-chlorophenyl)-7-[2-(4-n
-hexylphenyl)ethyl]-1,3-dihydro-2H-thieso[2,3-e]-1,4-diazepine-2-thione (6 g) was suspended in 50 ml of methanol, and while stirring under ice cooling, 100% hydrazine. Add 2 g of hydrate and react for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 ml of chloroform. After drying with anhydrous magnesium sulfate, concentrate again under reduced pressure.
7 g of oil are obtained. The oily hydrazonomer was suspended in 100 ml of toluene, and while stirring, 3.8 g of acetic anhydride and acetic acid were added.
Add 2.5 g and heat to reflux while stirring for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 100 ml of chloroform, washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 7 g of an oil. This oil was chromatographed on silica gel and eluted with chloroform-methanol (100:1 to 100:3). The target fraction was concentrated under reduced pressure to obtain 4-(2-chlorophenyl)-2-[2
-(4-n-hexylphenyl)ethyl]-9-methyl-6H-thieno[3,2-f][1,2,4]
2 g of triazolo[4,3-a][1,4]diazepine are obtained. Example 13 4-(2-chlorophenyl)-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-
6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 5-(2-chlorophenyl)- with melting point 188-191°C
7-[2-(4-isobutylphenyl)ethyl]-
3-Methyl-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one 2
g and 1.04 g of Lawesson's reagent are suspended in 37 ml of toluene and stirred at 40-45°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:2). When the target fraction was concentrated under reduced pressure, 5-(2-chlorophenyl)-7-
[2-(4-isobutylphenyl)ethyl]-3-
Methyl-1,3-dihydro-2H-thieno[2,
3-e]-1,4-diazepine-2-thione 1.2g
get. 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-3-methyl-1,
3-dihydro-2H-thieno[2,3-e]-1,
Dissolve 9.1 g of 4-diazepine-2-thione in 150 ml of tetrahydrofuran, add 3.1 g of 100% hydrazine hydrate under ice cooling, and react at room temperature for 2 hours. Tetrahydrofuran was distilled off under reduced pressure.
Dissolve the residue in 200 ml of chloroform. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure.
Add 50 ml of ethyl orthoacetate to the residue and heat at 70-72°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with chloroform-methanol (100:1 to 100:3). After concentrating the target fraction, crystallization from isopropyl ether yields 4-(2-chlorophenyl)-2-[2-
(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H-thieno[3,2-f][1,2,
4] Obtain 4.3 g of triazolo[4,3-a][1,4]diazepine. Formulation Example (1) Tablets 0.5 parts of the compound of Example 1, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of cornstarch were thoroughly mixed, and then thoroughly kneaded with a binder prepared from 2 parts of cornstarch. This mixture was passed through a 16-mesh sieve, dried in an oven at 50°C, and then passed through a 24-mesh sieve. Kneaded powder obtained here and cornstarch 8
1 part of crystalline cellulose and 9 parts of talc are thoroughly mixed, compressed into tablets, and each tablet contains the active ingredients.
Tablets containing 0.5 mg were obtained. (2) 1% powder 1 part of the compound of Example 1 and 90 parts of lactose are thoroughly mixed, and the mixture is thoroughly kneaded with an appropriate amount of a binder made from methylcellulose. This is passed through a 16 mesh sieve and dried in an oven at 50°C. The dried granule powder was pressure sieved through a 32-mesh filter and thoroughly mixed with an appropriate amount of silicon dioxide to obtain a 1% powder. Although the present invention has been fully described in the above specification and the examples contained therein, various changes and modifications may be made thereto without departing from the spirit and scope of the present invention.
Claims (1)
としてハロゲン、水酸基、炭素数１〜５個の直鎖
または分枝鎖状アルキルおよび炭素数１〜５個の
直鎖または分枝鎖状アルコキシから任意に選ばれ
る１〜３個を有するフエニルを、Ａは炭素数１〜
８個のアルキレンまたは炭素数１〜５個の直鎖ま
たは分枝鎖状アルキルで置換された炭素数１〜８
個のアルキレンを、R1，R2，R3は同一または異
なつて、水素または炭素数１〜５個の直鎖または
分枝鎖状アルキルを、R4，R5，R6は同一または
異なつて、水素、ハロゲン、水酸基、炭素数１〜
８個の直鎖または分枝鎖状アルキル、炭素数１〜
８個のの直鎖または分枝鎖状アルコキシ、フエニ
ル、フエノキシ、アラルキル、アラルキルオキシ
または芳香環上にハロゲン、水酸基、炭素数１〜
５個の直鎖または分枝鎖状アルキルおよび炭素数
１〜５個の直鎖または分枝鎖状アルコキシから任
意に選ばれる１〜３個の置換基を有しているフエ
ニル、フエノキシ、アラルキルまたはアラルオキ
シを示す。） で表わされるチエノトリアゾロジアゼピン誘導体
およびその薬理学的に許容される酸付加塩。[Claims] 1. General formula (In the formula, Ar is pyridyl, phenyl, or any substituent selected from halogen, hydroxyl group, straight-chain or branched alkyl having 1 to 5 carbon atoms, and straight-chain or branched alkoxy having 1 to 5 carbon atoms) A is phenyl having 1 to 3 carbon atoms selected from
1 to 8 carbon atoms substituted with 8 alkylene or straight or branched alkyl of 1 to 5 carbon atoms
R 1 , R 2 , R 3 are the same or different and represent hydrogen or a straight or branched alkyl having 1 to 5 carbon atoms, R 4 , R 5 , R 6 are the same or different Hydrogen, halogen, hydroxyl group, carbon number 1~
8 straight or branched alkyls, 1 to 1 carbon atoms
8 linear or branched alkoxy, phenyl, phenoxy, aralkyl, aralkyloxy or aromatic rings with halogen, hydroxyl group, or carbon number 1 to
Phenyl, phenoxy, aralkyl or having 1 to 3 substituents arbitrarily selected from 5 straight chain or branched alkyls and straight chain or branched alkoxy having 1 to 5 carbon atoms; Indicates araloxy. ) Thienotriazolodiazepine derivatives and pharmacologically acceptable acid addition salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62289983A JPH01156982A (en) | 1986-11-17 | 1987-11-17 | Thienotriazolodiazepine derivative |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61-273395 | 1986-11-17 | ||
| JP27339586 | 1986-11-17 | ||
| JP62-94058 | 1987-04-15 | ||
| JP62-222721 | 1987-09-04 | ||
| JP62289983A JPH01156982A (en) | 1986-11-17 | 1987-11-17 | Thienotriazolodiazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01156982A JPH01156982A (en) | 1989-06-20 |
| JPH0555510B2 true JPH0555510B2 (en) | 1993-08-17 |
Family
ID=26550646
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62289983A Granted JPH01156982A (en) | 1986-11-17 | 1987-11-17 | Thienotriazolodiazepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01156982A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998053828A1 (en) * | 1997-05-27 | 1998-12-03 | Senju Pharmaceutical Co., Ltd. | Israpafant-containing water-base preparations |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW219935B (en) * | 1991-12-25 | 1994-02-01 | Mitsubishi Chemicals Co Ltd | |
| AU2939000A (en) * | 1999-03-12 | 2000-10-04 | Welfide Corporation | Preventive or therapeutic agents for inflammatory dermatoses |
-
1987
- 1987-11-17 JP JP62289983A patent/JPH01156982A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998053828A1 (en) * | 1997-05-27 | 1998-12-03 | Senju Pharmaceutical Co., Ltd. | Israpafant-containing water-base preparations |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01156982A (en) | 1989-06-20 |
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