NO782357L - PROCEDURE FOR MAKING BICYCLIC THIA-DIAZA COMPOUNDS - Google Patents
PROCEDURE FOR MAKING BICYCLIC THIA-DIAZA COMPOUNDSInfo
- Publication number
- NO782357L NO782357L NO782357A NO782357A NO782357L NO 782357 L NO782357 L NO 782357L NO 782357 A NO782357 A NO 782357A NO 782357 A NO782357 A NO 782357A NO 782357 L NO782357 L NO 782357L
- Authority
- NO
- Norway
- Prior art keywords
- salts
- phenyl
- compounds
- thiazole
- imidazo
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 47
- 238000000034 method Methods 0.000 title claims description 22
- 150000003839 salts Chemical class 0.000 claims description 34
- -1 methoxy or halogen Chemical class 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- OYJGEOAXBALSMM-UHFFFAOYSA-N 2,3-dihydro-1,3-thiazole Chemical compound C1NC=CS1 OYJGEOAXBALSMM-UHFFFAOYSA-N 0.000 claims description 9
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- 239000005977 Ethylene Substances 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 241000534944 Thia Species 0.000 claims description 3
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical group C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- JLBQKIKVJYJZME-UHFFFAOYSA-N 5,6-bis(3-chlorophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole Chemical compound ClC1=CC=CC(C2C(N3CCSC3=N2)C=2C=C(Cl)C=CC=2)=C1 JLBQKIKVJYJZME-UHFFFAOYSA-N 0.000 claims 1
- XRILYHALWKQWIC-UHFFFAOYSA-N 5,6-diphenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole Chemical compound N1=C2SCCN2C(C=2C=CC=CC=2)C1C1=CC=CC=C1 XRILYHALWKQWIC-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 239000000052 vinegar Substances 0.000 description 4
- 235000021419 vinegar Nutrition 0.000 description 4
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 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
- 238000001816 cooling Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- BJCIJTYQFAOPCE-UHFFFAOYSA-N 2-bromo-1,2-bis(4-methoxyphenyl)ethanone Chemical compound C1=CC(OC)=CC=C1C(Br)C(=O)C1=CC=C(OC)C=C1 BJCIJTYQFAOPCE-UHFFFAOYSA-N 0.000 description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- PJLOGZZDKDUMFU-VIFPVBQESA-N (2s)-2-(benzenesulfonamido)pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NS(=O)(=O)C1=CC=CC=C1 PJLOGZZDKDUMFU-VIFPVBQESA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SZSPKBXYQNXXBH-UHFFFAOYSA-N 1-(2-bromo-4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone Chemical compound C1=CC(OC)=CC=C1CC(=O)C1=CC=C(OC)C=C1Br SZSPKBXYQNXXBH-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- JHXOAXMCYMGJLQ-UHFFFAOYSA-N 2,3-dihydro-1,3-thiazol-2-amine Chemical compound NC1NC=CS1 JHXOAXMCYMGJLQ-UHFFFAOYSA-N 0.000 description 1
- QQGYDWWMCCPYNZ-UHFFFAOYSA-N 2-(2-imino-1,3-thiazol-3-yl)-1,2-diphenylethanone Chemical compound N=C1SC=CN1C(C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 QQGYDWWMCCPYNZ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- IPVFCRUKTBYITA-UHFFFAOYSA-N 4,5-bis[(4-methoxyphenyl)methyl]-1,3-dihydroimidazole-2-thione Chemical compound C1=CC(OC)=CC=C1CC1=C(CC=2C=CC(OC)=CC=2)NC(S)=N1 IPVFCRUKTBYITA-UHFFFAOYSA-N 0.000 description 1
- DNQAQWCFLJOCNU-UHFFFAOYSA-N 4,5-bis[(4-methoxyphenyl)methyl]imidazolidine-2-thione Chemical compound C1=CC(OC)=CC=C1CC1C(CC=2C=CC(OC)=CC=2)NC(=S)N1 DNQAQWCFLJOCNU-UHFFFAOYSA-N 0.000 description 1
- HJYSGEJLUSZCTF-UHFFFAOYSA-N 4,5-diphenylimidazolidine-2-thione Chemical compound N1C(S)=NC(C=2C=CC=CC=2)C1C1=CC=CC=C1 HJYSGEJLUSZCTF-UHFFFAOYSA-N 0.000 description 1
- ALYNCZNDIQEVRV-PZFLKRBQSA-N 4-amino-3,5-ditritiobenzoic acid Chemical compound [3H]c1cc(cc([3H])c1N)C(O)=O ALYNCZNDIQEVRV-PZFLKRBQSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- LGRQUXHYJBFGTM-UHFFFAOYSA-N 4H-imidazole Chemical compound C1C=NC=N1 LGRQUXHYJBFGTM-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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Description
Fremgangsmåte til fremstilling av bicykliske tia-diaza-forbindelser. Process for the preparation of bicyclic thia-diaza compounds.
Oppfinnelsen vedrører nye bicykliske tia-diaza-forbindelser, spesielt 1,3-diaza-cyklopent-2-eno-/2,1-b/(1-tia-3-aza-cykloalkaner) med den generelle formel i (I): The invention relates to new bicyclic thia-diaza compounds, in particular 1,3-diaza-cyclopent-2-eno-/2,1-b/(1-thia-3-aza-cycloalkanes) with the general formula in (I):
hvis 1,3-diaza-cyklopent-2-en-ring kan ha en ytterligere dobbeltbinding, Alk betyr laverealkylen, som adskiller tia- fra aza-atomet ved 2-4 karbonatpmer, Ar^og Ar2betyr uavhengig av hverandre eventuelt substituert fenyl, pyridyl eller tienyl, og n = if 1,3-diaza-cyclopent-2-ene ring can have an additional double bond, Alk means lower alkylene, which separates thia- from the aza atom by 2-4 carbon atoms, Ar^ and Ar2 independently of each other mean optionally substituted phenyl, pyridyl or thienyl, and n =
0, 1 eller 2, med den forholdsregel at.minst en av restene Ar^0, 1 or 2, with the precaution that at least one of the residues Ar^
og A^ er forskjellig fra fenyl, når Alk betyr etylen og [1,3-diaza-cyklopent-2-en-ringen er en imidazolring, samt deres salter, samt fremgangsmåte til deres fremstilling, videre farmasøytiske preparater inneholdende disse forbindelser og deres anvendelse fortrinnsvis i form av farmasøytiske preparater. and A^ is different from phenyl, when Alk means ethylene and the [1,3-diaza-cyclopent-2-ene ring is an imidazole ring, as well as their salts, as well as methods for their preparation, further pharmaceutical preparations containing these compounds and their use preferably in the form of pharmaceutical preparations.
De i forbindelse med foreliggende beskrivelse med "lavere" betegnede rester og forbindelser inneholder fortrinnsvis inntil 7 og i første rekke inntil 4 karbonatomer. The residues and compounds designated as "lower" in connection with the present description preferably contain up to 7 and primarily up to 4 carbon atoms.
Laverealkylen Alk er fortrinnsvis uforgrenet men også forgrenet laverealkylen med 2-4 karbonatomer i kjeden mellom svovel-og nitrogenatomet. The lower alkylene Alk is preferably unbranched but also branched lower alkylene with 2-4 carbon atoms in the chain between the sulfur and nitrogen atoms.
Pyridyl er en 2-, 3- eller 4-pyridyl og tienyl en 3-eller spesielt 2-tienyl. Pyridyl is a 2-, 3- or 4-pyridyl and thienyl a 3- or especially 2-thienyl.
Substituert fenyl, pyridyl eller thienyl er f.eks.Substituted phenyl, pyridyl or thienyl are e.g.
en gang, to ganger eller også fleire ganger substituert. Substip tuenter, spesielt ved fenylresten er bl.a. laverealkyl, laverealkoksy, halogen, trifluormetyl, laverealkylsulfonyl eller nitro. Substi-teunter på pyridyl- eller thienyl-resten er fortrinnsvis laverealkyl, halogen eller trifluormetyl. once, twice or even several times substituted. Substip tuents, especially at the phenyl residue are i.a. lower alkyl, lower alkoxy, halogen, trifluoromethyl, lower alkylsulfonyl or nitro. Substituents on the pyridyl or thienyl residue are preferably lower alkyl, halogen or trifluoromethyl.
Ovenfor som i det følgende kan generelle begreperAbove as in the following may general terms
ha følgende betydning:have the following meaning:
laverealkyl er f.eks. metyl, etyl, nppropyl, isopropyl, n-butyl, isobutyl, sec.-butyl, eller tert.-butyl, videre n-pentyl, n-hexyl, isohexyl eller npheptyl. lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, or tert.-butyl, further n-pentyl, n-hexyl, isohexyl or n-heptyl.
Laverealkylen er etylen, samt 1,3-propylen, 1,4-butylen, kan imidlertid også være 1,2-propylen, 1,2- eller 2,3-butylen, 1,3- eller 2,4-pentylen eller 1,4-pentylen. The lower alkylene is ethylene, as well as 1,3-propylene, 1,4-butylene, but can also be 1,2-propylene, 1,2- or 2,3-butylene, 1,3- or 2,4-pentylene or 1 ,4-pentylene.
Laverealkoksy er f.eks. metoksy, etoksy, n-propyloksy, isopropyloksy, n-butyloksy eller tert.-butyloksy. Low-area coke is e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or tert-butyloxy.
Halogen er slik med atomnummer til og'med 35 og betyr Halogen is like this with atomic numbers up to and including 35 and means
fluor eller brom, fortrinnsvis klor.fluorine or bromine, preferably chlorine.
Laverealkylsulfonyl betyr f.eks. metylsulfonyl, Lower alkylsulfonyl means e.g. methylsulfonyl,
etylsulfonyl eller n-propylsulfonyl.ethylsulfonyl or n-propylsulfonyl.
Forbindelsen ifølge' oppfinnélsen har verdifulle farma-kologiske egenskaper, spesielt betennelseshemmende og antireumatiske virkninger, slik det lar seg vise i dyreforsøk, f.eks. i kaolin-poteødemprøve (Helv.Physiol. Acta 25(1967) 156) på rotte ved en peroralt inngitt dose på ca. 10 mg/kg eller i terpentin-pleuritis-prøven (Helv.Physiol.Acta 26 (1969)287) på rotte peroralt gitt ved en dose fra 30 til 100 mg/kg viser de en antiinflammatorisk resp. anti"-eksudativ virkning* Spesielt de umettede forbindelser viser også i adjuvans-arthritis-prøven (Pharmacology 2 (1969) 288) på rotte ved en peroral dose på 10-30 mg/kg en utmerket virkning. The compound according to the invention has valuable pharmacological properties, especially anti-inflammatory and anti-rheumatic effects, as can be shown in animal experiments, e.g. in the kaolin paw edema test (Helv.Physiol. Acta 25(1967) 156) on rats at a perorally administered dose of approx. 10 mg/kg or in the turpentine pleuritis test (Helv.Physiol.Acta 26 (1969)287) on rats given orally at a dose from 30 to 100 mg/kg they show an anti-inflammatory resp. anti"-exudative effect* Especially the unsaturated compounds also show an excellent effect in the adjuvant arthritis test (Pharmacology 2 (1969) 288) on rats at an oral dose of 10-30 mg/kg.
De nye forbindelser er også analgetisk.virksomme,The new compounds are also analgesically effective,
slik det lar seg vise i fényl-p-benzokinon-prøven på mus (Proe. Soc.Exp.Biol. 95 (1957) 729) ved doser fra 30 til 100 mg/kg, gitt peroralt. as shown in the phenyl-p-benzoquinone test on mice (Proe. Soc.Exp.Biol. 95 (1957) 729) at doses from 30 to 100 mg/kg, given orally.
Videre er hemmevirkningen av de nye preparater på prostaglandin-syntetase in vitro (Prostaglandins, 7 (1974) 123) å nevne i konsentrasjoner fra 0,05 til 20 yg/ml. Dessuten viser de en verdifull antitrombotisk effekt, nemlig en beskyttelse mot døde-lig lungeemboli på kaniner (Pharmacology 14 (1976) 522) i perorale "doser på 0,03-3 mg/kg. Furthermore, the inhibitory effect of the new preparations on prostaglandin synthetase in vitro (Prostaglandins, 7 (1974) 123) is worth mentioning in concentrations from 0.05 to 20 µg/ml. Moreover, they show a valuable antithrombotic effect, namely a protection against fatal pulmonary embolism in rabbits (Pharmacology 14 (1976) 522) in peroral doses of 0.03-3 mg/kg.
Tetrahydro-forbindelsene viser i tillegg dertil en forsterkende virkning i pertussisoedem-prøven ( Agents and Actions, vol. 6, 613, 1976) ved 5-50 mg/kg/rotte. The tetrahydro compounds also show an enhancing effect in the pertussis edema test (Agents and Actions, vol. 6, 613, 1976) at 5-50 mg/kg/rat.
De nye forbindelser kan derfor anvendes som anti-flogistika f.eks. til behandling av reumatiske, artritiske og andre med betennelse forbundne sykdommer, spesielt reumatisk arthritis eller som analgetika, f.eks. til behandling av smertetilstander. The new compounds can therefore be used as anti-phlogistics, e.g. for the treatment of rheumatic, arthritic and other diseases associated with inflammation, especially rheumatic arthritis or as analgesics, e.g. for the treatment of pain conditions.
Oppfinnelsen vedrører spesielt forbindelser medThe invention relates in particular to connections with
foicmel I, hvori Arog Ar 2 uavhengig av hverandre betyr en eventuelt med lavere alkyl, laverealkoksy, halogen eller, trif luormetyl substituert fenylrest, en pyridyl-, som en 2-, 3- eller 4-pyridyl-eller tienyl-, spesielt en 2-tienylrest, Alk betyr en laverealkylenrest, som forbinder svovel- .og. nitrogenatomet med hverandre over 2-3 karbonatomer i første rekke en uforgrenet laverealkylenrest og n betyr spesielt 0, videre også 1 eller 2, samt deres salter. foicmel I, in which A and Ar 2 independently of each other mean an optionally with lower alkyl, lower alkoxy, halogen or, trifluoromethyl substituted phenyl radical, a pyridyl-, such as a 2-, 3- or 4-pyridyl- or thienyl-, especially a 2 -thienyl residue, Alk means a lower alkylene residue, which connects sulfur- .and. the nitrogen atom with each other over 2-3 carbon atoms primarily an unbranched lower alkylene residue and n in particular means 0, further also 1 or 2, as well as their salts.
Oppfinnelsen vedrører i første rekke forbindelser med formel II The invention primarily relates to compounds of formula II
hvori Ar-^og Ar2uavhengig av hverandre betyr en eventuelt med laverealkoksy, som metoksy eller halogen, spesielt klor substituert fenylrest og m betyr i første rekke 1, videre også 2,sa mt deres salter. Oppfinnelsen vedrører imidlertid spesielt også forbindelser med formel III in which Ar-^ and Ar2, independently of each other, mean a phenyl radical optionally substituted with lower alkoxy, such as methoxy or halogen, especially chlorine, and m means primarily 1, further also 2, as with their salts. However, the invention also particularly relates to compounds of formula III
^hvori Ar^ og Ar 2 uavhengig av hverandre betyr en eventuelt med lavere alkoksy, som metoksy eller halogen, spesielt klor substituert fenylrest og m betyr i første rekke 1, videre også 2, samt deres salter. ^wherein Ar^ and Ar 2 independently of each other mean an optionally lower alkoxy, such as methoxy or halogen, especially chlorine substituted phenyl residue and m means primarily 1, further also 2, as well as their salts.
Spesielt vedrører oppfinnelsen de nye forbindelser In particular, the invention relates to the new compounds
omtalt, i eksemplene.discussed, in the examples.
De nye forbindelser lar seg fremstille etter i og for seg kjente metoder. The new compounds can be produced according to methods known per se.
Således kan man f.eks. ringslutte forbindelser med formel IV Thus, one can e.g. ring-closed compounds of formula IV
hvori X betyr en reaksjonsdyktig forestret hydroksygruppe, og hvis ønsket i eventuelt dannede forbindelser, hvori n =0, oksyderer tia-atomet til sulfinyl- eller sulfonylgruppen, og/eller hvis ønsket overfører dannede frie forbindelser i deres salter, eller omdanner dannede salter i de frie forbindelser og/eller adskiller en fremgangsmåtenressig dannet isomerblanding i de enkelte isomere. in which X means a reactive esterified hydroxy group, and if desired in any compounds formed, in which n =0, the thia atom oxidizes to the sulfinyl or sulfonyl group, and/or if desired transfers formed free compounds into their salts, or converts formed salts into the free compounds and/or separates a procedurally formed isomer mixture into the individual isomers.
Reaksjonsdyktig forestret hydroksy er spesielt jReactive esterified hydroxy is particularly j
'en hydroksylgruppe forestret med'en sterk uorganisk syre, f.eks. halogenhydrogen, spesielt klorhydrogen eller svovelsyre, eller med en sterk organisk syre, som med en laverealkansulfonsyre, f.eks. metan- eller etansulfonsyre eller en eventuelt ved laverealkyl, laverealkoksy eller halogen substituert benzensulfonsyre, f.eks. p-toluensulfonsyre eller p-brombenzensulfonsyre. a hydroxyl group esterified with a strong inorganic acid, e.g. hydrogen halide, especially hydrogen chloride or sulfuric acid, or with a strong organic acid, such as with a lower alkanesulfonic acid, e.g. methane or ethanesulfonic acid or a benzenesulfonic acid optionally substituted by lower alkyl, lower alkoxy or halogen, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid.
Ringslutningen gjennomføres fortrinnsvis under syre-avspaltende betingelser. Derved arbeider man i første rekke i et lavtkokende oppløsningsmiddel, som dimetylformamid eller aceton, en alkohol, f.eks. metanol eller etanol, hvis ønsket, i nærvær av en base, f.eks. en uorganisk base som et alkali- eller jordalkali-hydridy -hydroksyd eller -karbonat, i første rekke natriumhydrid, natriumhydroksyd eller natriumkarbonat, eller en .organisk base fortrinnsvis en nitrogenbase, som trilaverealkylamin, f.eks. tri-metylamin, trietylamin, dimetyl-isopropylamin eller pyridin. The cyclization is preferably carried out under acid-cleaving conditions. Thereby, one works primarily in a low-boiling solvent, such as dimethylformamide or acetone, an alcohol, e.g. methanol or ethanol, if desired, in the presence of a base, e.g. an inorganic base such as an alkali or alkaline earth hydride hydroxide or carbonate, primarily sodium hydride, sodium hydroxide or sodium carbonate, or an organic base, preferably a nitrogen base, such as tri-lower alkylamine, e.g. trimethylamine, triethylamine, dimethyl-isopropylamine or pyridine.
Utgangsstoffene lar seg oppnå når man omsetter en tilsvarende diaza-2-merkapto-forbindelse med et dihydroksyalkylen, med hverandre, hvori minst av de to hydroksygrupper er reaksjonsdyktig forestret, eventuelt oksyderer merkaptogruppen til sulfinyl-eller sulfonylgruppen, og deretter, hvis nødvendig forestrer reak sjonsdyktig den andre hydroksygruppen. De reaksjonsdyktige for-estrede hydroksygrupper tilsvarer de ovennevnte som også betingel-sene for kondensasjon. Ved denne reaksjon kan spesielt når begge hydroksylgruppene er reaksjonsdyktig forestret, utgangsstoffer med formel IV fåes in situ som i samme reaksjon sluttes til ring. The starting materials can be obtained when one reacts a corresponding diaza-2-mercapto compound with a dihydroxyalkylene, with each other, in which at least the two hydroxy groups are reactively esterified, possibly oxidizing the mercapto group to the sulfinyl or sulfonyl group, and then, if necessary, reactively esterifying the second hydroxy group. The reactive esterified hydroxy groups correspond to the above as well as the conditions for condensation. In this reaction, especially when both hydroxyl groups are reactively esterified, starting substances of formula IV can be obtained in situ which in the same reaction are joined to form a ring.
De nye forbindelser med formel I, som inneholder en ytterligere dobbeltbinding, kan også fåes når man ringslutter forbindelser med formel Va resp. Vb: The new compounds of formula I, which contain an additional double bond, can also be obtained when ring-closing compounds of formula Va or Vb:
ell er deres tautomere, og hvis ønsket i eventuelt dannede forbindelser, hvori*~n"~= oksyderer tia-atomet. tilssulf inyl- eller sulfonylgruppen og/eller hvis ønsket overfører dannede frie forbindelser i deres salter eller dannede salter i de frie forbindelser og/ el^r oppdeler en dannet i^ome^r^la^djLng i de enkelte isomere. ell are their tautomers, and if desired in possibly formed compounds, in which *~n"~= oxidizes the thia atom. to the sulfinyl or sulfonyl group and/or if desired transfers formed free compounds into their salts or formed salts into the free compounds and / el^r divides a formed i^ome^r^la^djLng into the individual isomers.
Ringslutningen foregår under vannavspaltende betingelser som ved oppvarming, f.eks. fra ca. 50°C.til ca. 150°C, fortrinnsvis i nærvær av et oppløsningsmiddel som acetonitril eller en alkohol,.f.eks. metanol eller etanol. The ring closure takes place under water-splitting conditions such as during heating, e.g. from approx. 50°C to approx. 150°C, preferably in the presence of a solvent such as acetonitrile or an alcohol, e.g. methanol or ethanol.
Utgangsstoffene lar seg oppnå når man.på i og for seg kjent måte omsetter en forbindelse med- -formel VI, The starting materials can be obtained when, in a manner known per se, reacting a compound with- -formula VI,
med en forbindelse med formel VII with a compound of formula VII
eller deres tautomere. or their tautomers.
Reaksjonsdyktig forestréde hydroksygrupper X er spesielt de ovennevnte., Reactively esterified hydroxy groups X are especially those mentioned above.,
Foretas denne omsetning også under yannavspaltende betingelser, f.eks. ved oppvarming i et oppløsningsmiddel som acetonitril eller en alkohol, kan utgangsstoffene med formel Va resp. Vb fåes in situ, som ringslutter seg under disse reak-sjonsbetingelser. If this transaction is also carried out under yannavsavvning conditions, e.g. by heating in a solvent such as acetonitrile or an alcohol, the starting materials of formula Va or Vb is obtained in situ, which forms a ring under these reaction conditions.
Oksydasjonen av t-i-a-atomet- til sulfinyl- eller sulfonylgruppen lar seg gjennomføre på i og for seg kjent måte, f.eks. med peroksyder, som hydrogenperoksyd, eller persyrer, f.eks. en : eventuelt med laverealkyl, laverealkoksy, halogen eller en ytterligere karboksylgruppe substituert benzbpersyre, som benzopersyre selv eller ftalmonopersyre, eller en alkanperkarboksylsyre, som pereddiksyre eller et perjodat, som natriumperjodat. Denne reaksjon foretas for det meste ved lavere temperaturer i et oppløs-ningsmiddel som iseddik eller aceton. The oxidation of the t-i-a atom to the sulfinyl or sulfonyl group can be carried out in a manner known per se, e.g. with peroxides, such as hydrogen peroxide, or peracids, e.g. a: optionally with lower alkyl, lower alkoxy, halogen or a further carboxyl group substituted benzperic acid, such as benzoperic acid itself or phthalmonoperic acid, or an alkane percarboxylic acid, such as peracetic acid or a periodate, such as sodium periodate. This reaction is mostly carried out at lower temperatures in a solvent such as glacial acetic acid or acetone.
De nye forbindelser kan fåes i form av syreaddisjons-salter, spesielt farmasøytisk anvendbare ikke-toksiske salter, f.eks. med organiske syrer, som klorhydrogen-, bromhydrogen-, svovel- eller fosforsyre, eller med organiske, som alifatiske, cykloalifatiske, cykloalifatisk-alifatiske, aromatiske, aralifa-tiske, heterocykliske eller heterocykllsk-alifatiske karboksyl-eller sulfonsyrer, f.eks. eddiksyre, propionsyre, ravsyre, glykol-syre, melkesyre, eplesyre, vinsyre, sitronsyre, ascorbinsyre, maleinsyre, fenyleddiksyre, benzosyre, 4-aminobenzosyre, antranil-syre, 4-hydroksybenzosyre, salicylsyre, aminosalicylsyre, embon-syre eller nikofcinsyre, samt metansulfonsyre, etansulfonsyre, 2-hydroksyetansulfonsyre- etylensulfonsyre, benzensulfonsyre, p-toluensulfonsyre, naftalinsulfonsyre, sulfanilsyre eller cyklo-hexylsulfaminsyre. Salter av denne type kan f.eks. fåes ved behandling av de frie forbindelser med syrene eller med egnede an-ionutvekslerharpikser. The new compounds can be obtained in the form of acid addition salts, especially pharmaceutically usable non-toxic salts, e.g. with organic acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acid, or with organic, such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic or sulphonic acids, e.g. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, aminosalicylic acid, embonic acid or nicofcic acid, as well as methanesulfonic acid , ethanesulfonic acid, 2-hydroxyethanesulfonic acid-ethylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfamic acid. Salts of this type can e.g. obtained by treating the free compounds with the acids or with suitable anion exchange resins.
På grunn av det snevre forhold mellom de nye forbindelser i fri form og i form av deres salter er det i det fore-gående og følgende med frie forbindelser eller salter også eventuelt å forstå tilsvarende salter resp. frie forbindelser. Due to the narrow relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compounds or salts are also possibly understood as corresponding salts or free connections.
De nye forbindelser kan foreligge som isomerblandinger som racemater eller diasteroisomerblandinger, eller i form av de rene isomere, som optisk aktive komponenter. Oppdelingen av det dannede isomerblandinger i de rene isomere kan foregå etter kjente metoder. Racemater lar seg f.eks. oppdele på grunn av fysikalsk-kjemiske forskjeller som f.eks. slike.i oppløselighet,i deres diasteromere sålter eller ved fraksjonert krystallisering fra et optisk aktivt oppløsningsmiddel eller ved kromatografi, spesielt tynnsjiktkromatografi på et optisk aktivt. bæremateriale i de optisk aktive antipoder. Derved isolerer man fortrinnsvis den farmakologisk mest virksomme og minst toksiskerene isomer, spesielt den mes£ virksomme og minst toksiske aktive antipode. The new compounds can exist as isomeric mixtures such as racemates or diastereoisomer mixtures, or in the form of the pure isomers, as optically active components. The separation of the isomer mixtures formed into the pure isomers can be carried out according to known methods. Racemate can e.g. divide due to physico-chemical differences such as e.g. such.in solubility, in their diastereomeric salts or by fractional crystallization from an optically active solvent or by chromatography, especially thin layer chromatography on an optically active. carrier material in the optically active antipodes. Thereby, the pharmacologically most effective and least toxic isomer is preferably isolated, especially the most effective and least toxic active antipode.
De ovennevnte reaksjoner gjennomføres på vanlig måte i nærvær eller fravær av fortynnings-, kondensasjons-■og/eller The above-mentioned reactions are carried out in the usual way in the presence or absence of dilution, condensation and/or
katalytiske midler, hvis nødvendig ved nedsatt eller forhøyet temperatur, i lukket kar og/eller i en inert atmosfære, catalytic agents, if necessary at reduced or elevated temperature, in a closed vessel and/or in an inert atmosphere,
j j
Fremgangsmåten omfatter også de utførelsésformer ifølge som mellomprodukt dannede forbindelser anvendes som utgangs-stof fer og de resterende fremgangsmåtetrinn gjennomføres med disse, eller fremgangsmåten avbrytes på ett eller annet trinn, videre kan utgangsstoffer anvendes i form av derivater eller dannes under reaksjonen. The method also includes the embodiments according to which compounds formed as intermediates are used as starting materials and the remaining method steps are carried out with these, or the method is interrupted at one or another step, starting materials can also be used in the form of derivatives or formed during the reaction.
Fortrinnsvis anvendes slike utgangsstoffer og reak-sjonsbetingelsene velges således at man kommer til de innlednings-vis som spesielt foretrukne oppførte forbindelser. Such starting materials are preferably used and the reaction conditions are chosen so that the compounds listed at the outset as particularly preferred are reached.
Oppfinnelsen vedrører også de som mellomprodukter opp-nåelige nye forbindelser med de generelle formler Va resp. Vb The invention also relates to the new compounds obtainable as intermediates with the general formulas Va or Vb
44
eller deres tautomere,„hvori Alk betyr laverealkylen, som adskiller tia- fra aza-atomet, med 2-4 karbonatomer, Ar1og Ar2 betyr uavhengig, av hweraridre eventuelt substituert fenyl, pyridyl eller tienyl, og n betyr 0, 1 eller 2, samt deres salter. I de ovennevnte biologiske prøveanordninger er de omtrent like virksomme som dihydro-forbindelsene med formel I og kan anvendes som antiinflammatorika, f.eks. til behandling sv reumatisk arthritis. or their tautomers, in which Alk means the lower alkylene, which separates thia- from the aza-atom, with 2-4 carbon atoms, Ar1 and Ar2 means independently, optionally substituted by hweraridre phenyl, pyridyl or thienyl, and n means 0, 1 or 2, and their salts. In the above-mentioned biological test devices, they are approximately as effective as the dihydro compounds of formula I and can be used as anti-inflammatories, e.g. for the treatment of rheumatoid arthritis.
De nye forbindelser ifølge oppfinnelsen kan f.eks. anvendes til fremstilling av farmasøytiske preparater, som inneholder en virksom mengde av det aktive stoff sammen eller i blanding med uorganiske eller organiske, faste eller flytende, farmasøytiske anvendbare bærestoffer, som egner seg til enteral eller parenteral administrering. Således anvender man tabletter eller gelatinkapsler som inneholder det virksomme stoff sammen med fortynningsmidler, f.eks. laktose, dextrose, sukrose, mannitol, sbrbitol, cellulose og/eller'glycerol, og. smøremidler f.eks. kisel-jord, talkum, stearinsyre eller salter derav, som magnesium- The new compounds according to the invention can e.g. is used for the production of pharmaceutical preparations, which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutical usable carriers, which are suitable for enteral or parenteral administration. Thus, tablets or gelatin capsules are used which contain the active substance together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sbrbitol, cellulose and/or'glycerol, and. lubricants e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium
eller kalsiumstearat og/eller polyetyienglykolj... tabletter inneholder likeledes bindemiddel, f.eks. magnesiumaluminiumsilikat, stivelser som mais-, hvetey ris-, eller pilrotstivelse, gelatiner, tragant, metylcellulose, natriumkarboksymetylcellulose og/eller polyvinylpyrrolidon, og hvis ønsket sprengmidler, f.eks. stivelse, agar, alginsyre eller et salt herav, som natriumalginat og/eller bruseblandinger eller adsorbsjonsmiddel, farvestoffer, smaksstoffer og søtningsmidler. Videre kan man anvende de nye farmakologisk virksomme forbindelser i form av injiserbare, f.eks. intravenøst administrerbare preparater eller av infusjonsoppløsninger. Slike oppløsninger er fortrinnsvis isotonisk vandige oppløsninger eller suspensjoner, idet disse f.eks. kan fremstilles av lyofiliserte preparater før brukt, hvilke preparater inneholder det virksomme stoff alene eller sammen med et bæremateriale, f.eks. mannitfor calcium stearate and/or polyethylene glycolj... tablets also contain a binder, e.g. magnesium aluminum silicate, starches such as corn, wheat, rice, or arrowroot starch, gelatins, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and if desired explosives, e.g. starch, agar, alginic acid or a salt thereof, such as sodium alginate and/or fizzy mixes or adsorbents, colourings, flavorings and sweeteners. Furthermore, the new pharmacologically active compounds can be used in the form of injectables, e.g. intravenously administrable preparations or of infusion solutions. Such solutions are preferably isotonically aqueous solutions or suspensions, as these e.g. can be prepared from lyophilized preparations before use, which preparations contain the active substance alone or together with a carrier material, e.g. mantf
De farmasøytiske preparater kan være sterilisert og/eller inneholde hjelpestoffer, f.eks. konserverings-, stabiliserings-, fukte- og/ eller emulgeringsmidler, oppløselighetsformidlere, salter til regulering av osmotisk trykk og/eller puffere. De foreliggende farmasøytiske preparater som hvis ønsket kant inneholde ytterligere farmakologisk verdifulle stoffer, fremstilles på i og for seg kjent måte, f.eks. ved-hjelp av vanlig blande-, granfiilerings-, dragérings-, oppløsnings- eller lyofiliseringsfremgangsmåte og inneholder fra. ca. 0,1% til 100%,.spesielt fra ca. 1% til ca. 50% lyo-filisater inntil 100% av det aktive stoff. Enkeltdosen'for et yarmblodsdyr på ca. 70 kg utgjør mellom 0,1 og 0,75 g, dagsdosen utgjør mellom 0,2 og 1,0 g. The pharmaceutical preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting agents and/or emulsifiers, solubility mediators, salts for regulating osmotic pressure and/or buffers. The present pharmaceutical preparations, which if desired contain additional pharmacologically valuable substances, are produced in a manner known per se, e.g. by means of ordinary mixing, fine-filing, coating, dissolving or lyophilizing methods and contains from. about. 0.1% to 100%, especially from approx. 1% to approx. 50% lyophilisates up to 100% of the active substance. The single dose' for a warm-blooded animal of approx. 70 kg is between 0.1 and 0.75 g, the daily dose is between 0.2 and 1.0 g.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler.. The invention will be explained in more detail with the help of some examples.
E ksempel 1Example 1
En blanding av 5 g a-brom-desoksyanisoin, 3 g 2-aminotiazolin og 30 ml etanol omrøres 4 timer ved 60°C, deretter to timer under tilbakeløp og deretter dessuten 12 timer ved værelsetemperatur. De derved utfelte krystaller frasuges og ettervaskes med etanol og dietyleter. Man får således rå 5,6-di-(p-metoksyfenyl)-imidazo/2/l-lj/dihydro-tiazol. Smp. etter omkrystallisering fra toluen-petroleter 152-154°C. A mixture of 5 g of α-bromo-desoxyanisoin, 3 g of 2-aminotiazoline and 30 ml of ethanol is stirred for 4 hours at 60° C., then for two hours under reflux and then also for 12 hours at room temperature. The thereby precipitated crystals are suctioned off and washed with ethanol and diethyl ether. One thus obtains crude 5,6-di-(p-methoxyphenyl)-imidazo/2/1-1/dihydro-thiazole. Temp. after recrystallization from toluene-petroleum ether 152-154°C.
Eksempel 2Example 2
En suspensjon av 7 ml 1,2-dibrometan, 7 g natriumkarbonat og 55 ml isopropanol omrøres ved værelsetemperatur og blandes iløpet av en time med suspensjonen av 4,7 g 4,5-difenyl-imidazolidin-2-tion i 110 ml 1,5%-ig natronlut. Reaksjonsblandingen kokes 7 timer under tilbakeløp, deretter fjernes isopropanol og dibrometan rotasjonsfordamper og den gjenblivende suspensjon ekstraheres med toluen. Toluénekstraktet vaskes med solen, A suspension of 7 ml of 1,2-dibromoethane, 7 g of sodium carbonate and 55 ml of isopropanol is stirred at room temperature and mixed during one hour with the suspension of 4.7 g of 4,5-diphenyl-imidazolidin-2-thione in 110 ml of 1, 5% caustic soda. The reaction mixture is boiled for 7 hours under reflux, then isopropanol and dibromoethane are removed in a rotary evaporator and the remaining suspension is extracted with toluene. The toluene extract is washed with the sun,
tørkes over natriumsulfat og inndampes. Residuet kromatograferes på silikagel. Etter adskillelse av upolare forurensninger med etylacetat elueres cis-5,6-difenyl-2,3,5,6-tetrahydro-imidazo/2,l-b/ tiazol med en blanding av etylacetat:metanol = 99:1 som farveløs olje. Det krystalliseres spontant til hvite krystaller ved smp. 110-113 C (sintertemp. 103 o Cf. dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel. After separation of non-polar impurities with ethyl acetate, cis-5,6-diphenyl-2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole is eluted with a mixture of ethyl acetate:methanol = 99:1 as a colorless oil. It crystallizes spontaneously into white crystals at m.p. 110-113 C (sinter temp. 103 o Cf.
Eksempel 3Example 3
En suspensjon av 3,5 ml 1,2-dibrometan, 3,5 g natriumkarbonat og 30 ml isopropanol blandes under omrøring ved værelsetemperatur iløpet av 1 time med suspensjonen av 3 g 4,5-di-anisyl-2-merkapto-imidazol i 50 ml 1,5%-ig natronlut. Reaksjonsblandingen kokes 6 timer under tilbakeløp, deretter fjernes isopropanol og dibrometan på rotasjonsfordamper og den gjenblivende suspensjon b-låndes med 10 ml 20%-ig kalilut og ekstraheres med etylacetat. A suspension of 3.5 ml of 1,2-dibromoethane, 3.5 g of sodium carbonate and 30 ml of isopropanol is mixed with stirring at room temperature during 1 hour with the suspension of 3 g of 4,5-di-anisyl-2-mercapto-imidazole in 50 ml 1.5% caustic soda. The reaction mixture is boiled for 6 hours under reflux, then isopropanol and dibromoethane are removed on a rotary evaporator and the remaining suspension is diluted with 10 ml of 20% potassium hydroxide and extracted with ethyl acetate.
De organiske faser vaskes med sol, tørkes med natriumsulfat og inndampes. Fra residuet får man etter omkrystallisering fra toluen-petroleter 5,6-di-(p-metoksy-fenyl)-imidazo/2,1-b/dihydro-tiazol ved smp. 152-154°C. The organic phases are washed with sunlight, dried with sodium sulphate and evaporated. From the residue, after recrystallization from toluene-petroleum ether, 5,6-di-(p-methoxy-phenyl)-imidazo/2,1-b/dihydro-thiazole is obtained at m.p. 152-154°C.
Eksempel 4Example 4
14,8 g 4,5-di-(p-metoksy-fenyl)-2-g-hydroksy-etyl-merkapto-imidazol oppløses i 50 ml absolutt pyridln og dryppes under omrøring ved ca. -5°C indre temperatur til en oppløsning av 15,8 g benzensulfoklorid i 60 ml absolutt pyridin. Deretter ut-rører man 60 timer ved 0°C.. Reaksjonsblandingen helles på isvann og ekstraheres med diklormetan. De med.vann 3 ganger'vaskede og forenede diklormetanekstrakter mørkes over natriumsulfat og inndampes til tørrhet. Den viskose olje krystalliseres fra toluen-petroleter. Det fåes 5,6-di-(p-metoksyfenyl)-imidazo/2,1-b/dihydro-tiazol med smp, 152-154°C. 14.8 g of 4,5-di-(p-methoxy-phenyl)-2-g-hydroxy-ethyl-mercapto-imidazole are dissolved in 50 ml of absolute pyridyl and added dropwise while stirring at approx. -5°C internal temperature to a solution of 15.8 g of benzene sulfochloride in 60 ml of absolute pyridine. The mixture is then stirred for 60 hours at 0°C. The reaction mixture is poured onto ice water and extracted with dichloromethane. The combined dichloromethane extracts, washed 3 times with water, are darkened over sodium sulphate and evaporated to dryness. The viscous oil is crystallized from toluene-petroleum ether. 5,6-di-(p-methoxyphenyl)-imidazo/2,1-b/dihydro-thiazole with m.p. 152-154°C is obtained.
Utgangsmaterialet kan f.eks. fremstilles på følgende måte: 2,5 g natrium oppløses i 220 ml etanol. Hertil har man 35 g 4,5-dianisyl-imidazolin-2-tion. Man får en.suspensjon. Iløpet av 2 minutter dryppes hertil ved værelsetemperatur under omrøring 15,7 ml 2-kloretanol. Man omrører 1 time ved 6 0^C og fire timer,under tilbakeløp. Deretter inndampes den svake suspensjon til.tørrhet. Residuet renses fra aceton/vann. The starting material can e.g. is prepared as follows: dissolve 2.5 g of sodium in 220 ml of ethanol. 35 g of 4,5-dianisyl-imidazolin-2-thione are added to this. You get a suspension. Over the course of 2 minutes, 15.7 ml of 2-chloroethanol are added dropwise at room temperature while stirring. The mixture is stirred for 1 hour at 60°C and four hours under reflux. The weak suspension is then evaporated to dryness. The residue is cleaned from acetone/water.
Eksempel 5Example 5
En blanding av 60 g N-etylrdiisopropylamin, 70 g 2-aminodihydrotiazol, 150 g a-brom-desoksyanisoin' og 800 ml acetb-nitril omrøres-48 timer ved værelsetemperatur. Det derved' dannede 5,6-di-(p-metoksy-fenyl)-imidazo/2,1-b/dihydro-tiazolin frasuges A mixture of 60 g of N-ethylrdiisopropylamine, 70 g of 2-aminodihydrothiazole, 150 g of α-bromo-deoxyanisoin' and 800 ml of acetb-nitrile is stirred for 48 hours at room temperature. The thereby formed 5,6-di-(p-methoxy-phenyl)-imidazo/2,1-b/dihydro-thiazoline is filtered off
og ettervaskes med acetonitril. Ved inndampning av filtratet' og fordeling av det således for oppløsningsmiddel befridde residu mellom etylacetat og vann får man ytterligere 50. g råprodukt. Ved omkrystallisering av råproduktet fra toluen, fåe man 5,6-di-(p-metoksy-fenyl) -imidazo/2 , l-b7dihydro-tiazol ved smp. 152-154°C. and washed with acetonitrile. By evaporating the filtrate and distributing the residue thus freed from solvent between ethyl acetate and water, a further 50 g of crude product is obtained. By recrystallization of the crude product from toluene, 5,6-di-(p-methoxy-phenyl)-imidazo[2,1-b]dihydro-thiazole is obtained at m.p. 152-154°C.
Eksempel 6Example 6
Til en oppløsning av 23 g p-toluensulfoklorid i 80 ml pyridin haes ved 0°C under omrøring' oppløsningen av 20' g 2-(2-hydroksy-etyl-tio)-4(5)-3'-pyridyl-5(4)-fenyl-imidazol. Reaksjonsblandingen omrøres 16 timer ved 0°C, helles på is og ekstraheres med eter. Fra eterekstraktene får man etter"vasking med vann og tørking over natriumsulfat et inndampningsresidu som etter kromatografering på silikagel med toluen og eddikester og etter omkrystallisering av.de tilsvarende fraksjoner fra eddikester gir isomerblandingen 5(6)-(3-pyridyl)-6(5)-fenyl-imidazo/2,1-b/dihydro-tiazol som hvite krystaller med smp. 150-151°C. To a solution of 23 g of p-toluenesulfochloride in 80 ml of pyridine is added at 0°C with stirring the solution of 20' g of 2-(2-hydroxy-ethyl-thio)-4(5)-3'-pyridyl-5( 4)-phenyl-imidazole. The reaction mixture is stirred for 16 hours at 0°C, poured onto ice and extracted with ether. From the ether extracts, after washing with water and drying over sodium sulfate, an evaporation residue is obtained which, after chromatography on silica gel with toluene and ethyl acetate and after recrystallization of the corresponding fractions from ethyl acetate, gives the isomer mixture 5(6)-(3-pyridyl)-6(5 )-phenyl-imidazo/2,1-b/dihydro-thiazole as white crystals with mp 150-151°C.
Utgangsmaterialet lar seg fremstille som følger:The starting material can be produced as follows:
10,8 g benzylpyridyl(3)-keton omrøres sammen med10.8 g of benzylpyridyl(3)-ketone are stirred together with
40 ml pyridin og en oppløsning av 8 g hydroksylaminhydroklorid i40 ml of pyridine and a solution of 8 g of hydroxylamine hydrochloride i
15 ml pyridin i 6" timer ved 100°C. Reaksjonsblandingen helles på is/vann og videreomrøres 15 minutter. De utfelte krystaller fra-. suges, vaskes med vann og tørkes i høyvakuum. Man får benzyl-pyridyl (3) -keton-oksim med smp. 122-126°C. 15 ml of pyridine for 6 hours at 100°C. The reaction mixture is poured onto ice/water and further stirred for 15 minutes. The precipitated crystals are suctioned off, washed with water and dried in high vacuum. Benzyl pyridyl (3) ketone is obtained oxime with mp 122-126°C.
Til en wed -10°C omrørt oppløsning av 8,5 g benzyl-pyridyl (3 ) -keton-oksim i 20 ml pyridin tildryppes ijfeøpet av 5 minutter oppløsningen av 7,7 g p-toluensulfoklorid i 15 ml pyridin. Reaksjonsblandingen oppbevares 24 timer i kjøleskap og helles deretter på is/vann. Etter lengere omrøring og utrivning stivner den utfelte. olje til krystaller.' Disse suges fra, vaskes med vann og tørkes i høyvakuum. Man får 11,6 g av et råprodukt med smp. 87-92°C, som ifølge tynnsjiktkromatografien imidlertid inneholder edukt. To a stirred solution of 8.5 g of benzyl-pyridyl (3)-ketone oxime in 20 ml of pyridine at -10°C, the solution of 7.7 g of p-toluenesulfochloride in 15 ml of pyridine is added dropwise over 5 minutes. The reaction mixture is stored for 24 hours in a refrigerator and then poured onto ice/water. After longer stirring and straining, the precipitate hardens. oil to crystals.' These are sucked off, washed with water and dried in a high vacuum. You get 11.6 g of a crude product with m.p. 87-92°C, which according to thin-layer chromatography, however, contains educt.
Det anvendes direkte i neste trinn.It is used directly in the next step.
11,6 g råprodukt (benzyl-pyridyl(3^-keton-oksim-p-toluensulfoester)•suspenderes i 90 ml absolutt etanol og ved 0°C tildryppes under omrøring oppløsningen av 3,7 g kalium-tert.-butylat i 30 ml absolutt etanol. Reaksjonsblandingen omrøres 2 timer ved 0°C. Suspensjonen frasuges og filtratet anvendes med en gang i heste trinn. 11.6 g of crude product (benzyl-pyridyl(3^-ketone-oxime-p-toluenesulfoester)•are suspended in 90 ml of absolute ethanol and at 0°C the solution of 3.7 g of potassium tert.-butylate in 30 ml of absolute ethanol. The reaction mixture is stirred for 2 hours at 0° C. The suspension is suctioned off and the filtrate is used at once in four steps.
3,6 g natriumtiocyanat oppløses i 60 ml etanol og blandes med 4,5 ml konsentrert saltsyre. 3.6 g of sodium thiocyanate are dissolved in 60 ml of ethanol and mixed with 4.5 ml of concentrated hydrochloric acid.
Suspensjonen frasuges og filtratet holdes sammen med den alkoholiske oppløsning av det dannede a-amino-benzyl-pyridyl(3)-keton i 18 timer under tilbakeløp. Etter avkjøling lar det seg fra reaksjonsblandingen frasuge 2,8 g rått 4-fenyl-5-pyridyl(3)-2-merkapto-imidazol. Filtratet inneholder ytterligere mengder av produktet. Etter omkrystallisering fra dimetylformamid-vann smelter det ved 290-300°C. The suspension is suctioned off and the filtrate is kept together with the alcoholic solution of the formed α-amino-benzyl-pyridyl(3)-ketone for 18 hours under reflux. After cooling, 2.8 g of crude 4-phenyl-5-pyridyl(3)-2-mercapto-imidazole can be suctioned off from the reaction mixture. The filtrate contains additional amounts of the product. After recrystallization from dimethylformamide-water it melts at 290-300°C.
0,8 g natrium oppløses i 200 ml etanol. Oppløsningen blandes med 8 g l-fenyl-5-pyridyl(3)-2-merkaptoimidazol og oppvarmes til tilbakeløp. Etterat det er dannet en klar oppløsning, tildryppes 2,3 ml 2-kloretanol og reaksjonsblandingen kokes i 16 timer under tilbakeløp. Oppløsningsmidlet avdampes under vakuum og residuet fordeles mellom vann og eddikester. De organiske faser vaskes 0.8 g of sodium is dissolved in 200 ml of ethanol. The solution is mixed with 8 g of 1-phenyl-5-pyridyl(3)-2-mercaptoimidazole and heated to reflux. After a clear solution has formed, 2.3 ml of 2-chloroethanol is added dropwise and the reaction mixture is boiled for 16 hours under reflux. The solvent is evaporated under vacuum and the residue is distributed between water and vinegar. The organic phases are washed
med vann og sol, tørkes med natriumsulfat og inndampes. Som residu får man krystallinsk 2-(2-hydroksy-etyl-tio)-4(5)-3'-pyridyl-5(4)-fenyl-imidazol. Dét.smelter etter omkrystallisering fra eddikester/etanol ved 157-159°C. with water and sun, dried with sodium sulphate and evaporated. As a residue, crystalline 2-(2-hydroxy-ethyl-thio)-4(5)-3'-pyridyl-5(4)-phenyl-imidazole is obtained. It melts after recrystallization from ethyl acetate/ethanol at 157-159°C.
På analog måte fåes det følgende forbindelser, idetIn an analogous way, the following compounds are obtained, in that
det gåes ut fra tilsvarende utgangsstoffer: 5,6-di-(p-metyl-fenyl)-2,3,5,6-tetrahydroimidaao/2 ,1-bJ tiazol 5,6-di-(p-klor-fenyl)-2,3,5,6-tetrahydro-imidazo/2 ,1-b/tiazol 5.6- di-(m-klor-fenyl)-2,3,5,6-tetrahydro-imidazo/2,1-b/tiazol 5 , 6-di- (p-metoksyfenyl) ) -3-metyl-2 ,3,5, e-tetrahydro-imidazo/^ , l-b_7-tiazol eller it is assumed from corresponding starting substances: 5,6-di-(p-methyl-phenyl)-2,3,5,6-tetrahydroimidaao/2,1-bJ thiazole 5,6-di-(p-chloro-phenyl) -2,3,5,6-tetrahydro-imidazo/2,1-b/thiazole 5,6-di-(m-chloro-phenyl)-2,3,5,6-tetrahydro-imidazo/2,1-b/ thiazole 5 , 6-di-(p-methoxyphenyl) )-3-methyl-2 ,3,5, ε-tetrahydro-imidazo/^ , 1-b_7-thiazole or
6.7- di-(p-metoksy-fenyl)-2,3,4,5,6,7-hexa-hydro-imidazo/2,l-b/- tiazin. 6.7-di-(p-methoxy-phenyl)-2,3,4,5,6,7-hexa-hydro-imidazo/2,1-b/- thiazine.
Eksempel 7.Example 7.
14,3 g 2-/N-(1,2-bis-p-metoksy-fenyl-2-hydroksyetyl7-åmino-tiazolin oppløses i 24,3 ml konsentrert svovelsyre og omrøres en time ved værelsetemperatur. Reaksjonsblandingen'helles på is, gjøjjes alkalisk med 2-n sodaoppløsning og ekstraheres med eddikester. De organiske faser vaskes med vann, tørkes over natriumsulfat og.inndampes. Fra residuet får man ved omkrystallisering fra toluen-petroleter 5,6-trans-di-(p-metoksyfenyl)-2,3,5,6-tetrahydro- | 4H-imidazol/2 , l-bJ?-tiazol med smp. 125-126°C. r Det anvendte utgan gsmaté"riale lar seg f .eks. fremstille'som følger: 45 g brom-desoksy-anisoin suspenderes i .17.0. ml..acetonitril. Suspensjonen blandes, med 23 ml. N-etyl-diisopropylamin og 15,4 g 2-aminotiazolin, omrøres 2 timer ved værelsetemperatur, frasuges og filtergodset ettervaskes med litt eddikester. Man får således 2-/fo-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-amino-tiazolin resp. 2-iLmino-3- (1, 2-bis-p-metoksy-fenyl-2-6kso-etyl) -tiazolin med smp. 95-98°C. 14.3 g of 2-/N-(1,2-bis-p-methoxy-phenyl-2-hydroxyethyl7-amino-thiazoline) are dissolved in 24.3 ml of concentrated sulfuric acid and stirred for one hour at room temperature. The reaction mixture is poured onto ice, made alkaline with 2-n soda solution and extracted with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and evaporated. From the residue, recrystallization from toluene-petroleum ether gives 5,6-trans-di-(p-methoxyphenyl)- 2,3,5,6-tetrahydro-|4H-imidazole/2,1-bJ?-thiazole with melting point 125-126°C. The starting material used can, for example, be prepared as follows: 45 g of bromo-deoxy-anisoin are suspended in 17.0 ml of acetonitrile. The suspension is mixed with 23 ml of N-ethyl-diisopropylamine and 15.4 g of 2-aminotiazoline, stirred for 2 hours at room temperature, aspirated off and the filter material washed with a little acetic ester. One thus obtains 2-[fo-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-amino-thiazoline or 2-imino-3-(1,2-bis-p-methoxy- phenyl-2-6xo-ethyl)-thiazoline with mp 95-98°C.
På analog måte får man: 2-/N-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-amino-5-metyl-tiazolin resp. 2-imino-5-metyl-3-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-tiazolin eller deres tautomere, In an analogous way, one obtains: 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-amino-5-methyl-thiazoline resp. 2-imino-5-methyl-3-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-thiazoline or their tautomers,
2-/N-(1,2-bis-pemetoksyfenyl-2-okso-etyl)-amino-4-metyl- 2-/N-(1,2-bis-pemethoxyphenyl-2-oxo-ethyl)-amino-4-methyl-
tiazolin resp. 2-amino-4-metyl-3-(l,2-bis-p-metoksyfenyl-2-okso-etyl)-tiazolin eller deres tautomere, thiazoline or 2-amino-4-methyl-3-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-thiazoline or their tautomers,
2-/N-(1,2-bis-fenyl-2-okso-etyl)-amino-tiazolin2-[N-(1,2-bis-phenyl-2-oxo-ethyl)-amino-thiazoline
resp. 2-imino-3-(1,2-bis-fenyl-2-okso-etyl)-tiazolin eller deres tautomere med smp. 121-123°C eller respectively 2-imino-3-(1,2-bis-phenyl-2-oxo-ethyl)-thiazoline or their tautomers with m.p. 121-123°C or
2-/N-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-amino-5,6-dihydro-4H-tiazin resp. 2-imino-3-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-5,6-dihydro-4H-tiazin eller deres tautomere. 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-amino-5,6-dihydro-4H-thiazine resp. 2-imino-3-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-5,6-dihydro-4H-thiazine or their tautomers.
31,5 g 2-/N-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-aminogtiazolin eller dets isomere oppløses i 350 ml metanol og blandes porsjonsvis med 4,26 g natriumborhydrid. Suspensjonen omrøres' 2 timer ved værelsetemperatur, frasuges deretter og ettervaskes med metanol. Man får,således.2-/af-(1,2-bis-p-metoksy-fenyl-2-hydroksy-etyl)-amino-tiazolin med smp. 185-187°C. 31.5 g of 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-aminothiazoline or its isomers are dissolved in 350 ml of methanol and mixed in portions with 4.26 g of sodium borohydride. The suspension is stirred for 2 hours at room temperature, then suctioned off and washed with methanol. Thus, 2-[alpha]-(1,2-bis-p-methoxy-phenyl-2-hydroxy-ethyl)-amino-thiazoline with m.p. 185-187°C.
Idet det gåes ut fra tilsvarende tiazolinforbindelser lar det seg på analog måte fremstille følgende forbindelser:• Starting from corresponding thiazoline compounds, the following compounds can be prepared in an analogous way:•
5- fenyl-6-p-klorfenyl-2,3,5,6-tetrahydroimidazo/2,l-b/-tiazol 6- fenyl-5-p-klorfenyl-2,3,5,6-tetrahydroimidazo/2 ,l-b7~tiazol 5 ,6-di- (p-metoksyfenyl) -2-metyl-2 ,3,5, e-tetrahydroimidazo^ , 1-bJ7-tiazol eller 5-phenyl-6-p-chlorophenyl-2,3,5,6-tetrahydroimidazo/2,1-b/-thiazole 6-phenyl-5-p-chlorophenyl-2,3,5,6-tetrahydroimidazo/2,l- b7~thiazole 5,6-di-(p-methoxyphenyl)-2-methyl-2,3,5,e-tetrahydroimidazo^ , 1-bJ7-thiazole or
5,6-di-(p-metoksyfenyi-3-metyl-2,3,5,6-tetrahydro-imidazo/2,l-b/-tiazol. 5,6-Di-(p-Methoxyphenyl-3-methyl-2,3,5,6-tetrahydro-imidazo[2,1-b]-thiazole.
Eksempel 8Example 8
2 g 5,6-di-p-metoksyfenyl-2,3-dihydro-4H-imidazo-Cl,1-b/tiazol suspesnderes i 33 ml etanol og blandes iløpet av 5 minutter med 7,91 ml 30%-ig hydrogenperoksyd. Reaksjonsblandingen holdes 90 minutter under tilbakeløp, avkjøles, helles på 200 ml isvann og ekstraheres med eddikester. Fra inndampnings-residuet av de med vann vaskede og over natriumsulfat tørkede organiske faser får man ved omkrystaliisering 5,6-di-p-metoksy fenyl-imidazo/2,l-b/2,3-dihydro-tiazol-sulfoksyd med smp. 176-177°C. 2 g of 5,6-di-p-methoxyphenyl-2,3-dihydro-4H-imidazo-Cl,1-b/thiazole are suspended in 33 ml of ethanol and mixed during 5 minutes with 7.91 ml of 30% hydrogen peroxide . The reaction mixture is refluxed for 90 minutes, cooled, poured into 200 ml of ice water and extracted with vinegar. From the evaporation residue of the organic phases washed with water and dried over sodium sulfate, 5,6-di-p-methoxy is obtained by recrystallization phenyl-imidazo/2,1-b/2,3-dihydro-thiazole sulfoxide with m.p. 176-177°C.
Eksempel 9Example 9
0,69 g natrium oppløses i 60 ml etanol og blandes med 9,36 g 2-merkapto-4,5-di-p-metbksyfenyl-imidazol. Reaksjonsblandingen omrøres 30 minutter, blandes med 3,1 g 3-klor-l-propanol, holdes 2 timer under tilbakeløp, avkjøles, klarfiltreres og inn- 0.69 g of sodium is dissolved in 60 ml of ethanol and mixed with 9.36 g of 2-mercapto-4,5-di-p-methoxyphenyl-imidazole. The reaction mixture is stirred for 30 minutes, mixed with 3.1 g of 3-chloro-1-propanol, held under reflux for 2 hours, cooled, filtered clear and in-
dampes til tørrhet. Residuet, det rå 2-(3-hydroksy-propyl-tio)-4,5-di-p-metoksyfenyl-imidazol holdes under tilbakeløp i 3 0 min. evaporate to dryness. The residue, the crude 2-(3-hydroxy-propyl-thio)-4,5-di-p-methoxyphenyl-imidazole is refluxed for 30 min.
i 50 ml tionylklorid. Overskytende tionylklorid avdampes, av-drives ved avdestillering av 100 ml dessuten tilsatt kloroform, in 50 ml of thionyl chloride. Excess thionyl chloride is evaporated, driven off by distilling off 100 ml of additionally added chloroform,
og residuet holdes sammen med 100 ml etanol og 50 ml 4 0%-ig kalilut i 4 timer under tilbakeløp. Deretter inndampes reaksjonsblandingen på rotasjonsfordamper, blandes med isvann og ekstraheres med eddikester. De organiske_faser vaskes med vann, tørkes og inndampes. Residuet kromatograferes med toluen:eddikester 1:1 and the residue is kept together with 100 ml of ethanol and 50 ml of 40% potassium hydroxide for 4 hours under reflux. The reaction mixture is then evaporated on a rotary evaporator, mixed with ice water and extracted with vinegar. The organic_phases are washed with water, dried and evaporated. The residue is chromatographed with toluene:acetic ester 1:1
på silikagel. Ved omkrystallisering av de tilsvarende fraksjoner fra aceton får man 6,7-di-p-metoksyfenyl-2,3,4,5-tetrahydro-imidazo/2,l-b_7(l,3)-tiazin med smp. 189-191.°C. on silica gel. Recrystallization of the corresponding fractions from acetone yields 6,7-di-p-methoxyphenyl-2,3,4,5-tetrahydro-imidazo/2,1-b_7(1,3)-thiazine with m.p. 189-191°C.
Eksempel" 10. _jExample" 10. _j
Analogt Eksempel 9 blir det av 2-merkapto-4,5-di-p-klorfenyl-imidazol med 2-kloretanol fremstilt 2-(2-hydroksy-etyl-tio)-4,5-di-p-klorfenyl-imidazol med smp. 197-199°C og herav ved cyklisering med tionylklorid 5 , 6-di-'p-klorfenyl-imidazo/2 , l-b7di-hydro-tiazol med smp. 199-204°C. Analogously to Example 9, 2-(2-hydroxy-ethyl-thio)-4,5-di-p-chlorophenyl-imidazole is prepared from 2-mercapto-4,5-di-p-chlorophenyl-imidazole with 2-chloroethanol with m.p. 197-199°C and from this by cyclization with thionyl chloride 5 , 6-di-'p-chlorophenyl-imidazo/2 , 1-b7 dihydro-thiazole with m.p. 199-204°C.
Analogt kan man også fremstille 5,6-di-p-metoksyfenyl-4H-imidazo/!>, l-b_7dihydro-tiazo. Analogously, 5,6-di-p-methoxyphenyl-4H-imidazo/!>, 1-b_7dihydro-thiazo can also be prepared.
Eksempel 11Example 11
0,5 g 5,6-di-p-metoksyfenyl-2,3-dihydro-4H-imidazo/2 ,l-b^7tiazol suspenderes i 1,5 ml iseddik og blandes med 0,9 ml 30%-ig hydrogenperoksyd. Reaksjonsblandingen omrøres 7 timer ved 60°C, helles deretter på is-vann bg ekstraheres med eddikester. 0.5 g of 5,6-di-p-methoxyphenyl-2,3-dihydro-4H-imidazo[2,1-b]thiazole is suspended in 1.5 ml of glacial acetic acid and mixed with 0.9 ml of 30% hydrogen peroxide. The reaction mixture is stirred for 7 hours at 60°C, then poured onto ice-water and extracted with vinegar.
De organiske faser vaskes med l-n natronlut inntil ekstraktene forblir basiske, nøytralvasker deretter med vann og sol, tørkes over natriumsulfat og inndampes. Residuet krystalliseres, fra eddikester og omkrystalliseres fra eddikester-petroleter. Man får således 5 ,6-di-p-metoksyfenyl-imidazb/5 , l-b_7-dihydro-tiazol-sulfon med smp. 186-187°C. The organic phases are washed with l-n caustic soda until the extracts remain basic, then neutral washed with water and sun, dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate and recrystallized from ethyl acetate-petroleum ether. One thus obtains 5,6-di-p-methoxyphenyl-imidazb/5,1-b_7-dihydro-thiazole-sulfone with m.p. 186-187°C.
Eksempel 12Example 12
35 g 2-/N-(1,2-bis-p-metoksyfenyl-2-okso-etyl)-aminotiazolin (sml. Eksempel 7) holdes sammen med 250 ml isopropanol og 1 ml bromhydrogen (48%-ig) i 2 timer under tilbakeløp. Ved av-kjøling i isbad og frasugning av produktet får man 5,6-di-(p-metoksy- 35 g of 2-/N-(1,2-bis-p-methoxyphenyl-2-oxo-ethyl)-aminotiazoline (cf. Example 7) are kept together with 250 ml of isopropanol and 1 ml of hydrogen bromide (48%-ig) in 2 hours during reflux. By cooling in an ice bath and suctioning off the product, 5,6-di-(p-methoxy-
fenyl)-imidazol/*2,1-b/dihydro-tiazol med smp. 155-156°C.phenyl)-imidazole/*2,1-b/dihydro-thiazole with m.p. 155-156°C.
Fra moderluten lar det seg utvinne hydrobromidet av 5,6-di-(p-metoksyfenyl)-imidazo/2,1-b/dihydro-tiazol, smp. 200-210°C. From the mother liquor it is possible to recover the hydrobromide of 5,6-di-(p-methoxyphenyl)-imidazo/2,1-b/dihydro-thiazole, m.p. 200-210°C.
Eksempel 13Example 13
Til en suspensjon av 11,8 g 5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo/2,l-b7tiazol i 30 ml vann haes 17 ml l-n saltsyre og 5 g N-benzensulfonyl-L(+)-glutaminsyre. Blandingen oppløses ved oppvarming, og bringes til krystallisasjon ved av-kjøling. L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo/2,1-b/- tiazol N-benzen-sulfonyl L(+)—glutamat frasuges, vaskes med litt vann, suspenderes i vann og spaltes med fortynnet natronlut. 17 ml of 1-n hydrochloric acid and 5 g of N -benzenesulfonyl-L(+)-glutamic acid. The mixture is dissolved by heating, and brought to crystallization by cooling. L-5,6-di-p-anisyl-2,3,5,6-tetrahydro-4H-imidazo/2,1-b/-thiazole N-benzenesulfonyl L(+)-glutamate is suctioned off, washed with a little water, suspend in water and decompose with dilute caustic soda.
Av dette ekstraheres L-5,6-di-p-anisyl-2,3,5>6-tetrahydro-4H-imidazo/2, l-b_7tiazol med etylacetat. From this L-5,6-di-p-anisyl-2,3,5>6-tetrahydro-4H-imidazo/2,1-b_7thiazole is extracted with ethyl acetate.
Eksempel 14Example 14
Farmasøytiske preparater inneholdende:Pharmaceutical preparations containing:
Bestanddelene siktes, blandes godt og blandingen fylles i hårdgelatinkapsler. The ingredients are sieved, mixed well and the mixture is filled into hard gelatin capsules.
Eksempel 15Example 15
Tabletter inneholdende:Tablets containing:
Saccarosen, kalsium-dihydratet og det virksomme stoff blandes og granuleres med en 10%-ig gelatinoppløsning. The sucrose, calcium dihydrate and the active substance are mixed and granulated with a 10% gelatin solution.
Det fuktige granulat siktes, tørkes, blandes med stivelse, talkum og stearinsyre, siktes og presses til tabletter. The moist granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and pressed into tablets.
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LU77703A LU77703A1 (en) | 1977-07-07 | 1977-07-07 | METHOD FOR PRODUCING BICYCLIC THIA-DIAZA COMPOUNDS |
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EP (3) | EP0019688A1 (en) |
JP (1) | JPS5416470A (en) |
AR (2) | AR222309A1 (en) |
AU (1) | AU3778878A (en) |
DD (2) | DD138212A5 (en) |
DK (1) | DK305578A (en) |
ES (4) | ES471458A1 (en) |
FI (1) | FI782132A (en) |
GR (1) | GR64978B (en) |
IL (1) | IL55086A0 (en) |
IT (1) | IT8149647A0 (en) |
LU (1) | LU77703A1 (en) |
NO (1) | NO782357L (en) |
NZ (1) | NZ187789A (en) |
PL (1) | PL116596B1 (en) |
PT (1) | PT68246A (en) |
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DE2963572D1 (en) * | 1978-04-11 | 1982-10-21 | Ciba Geigy Ag | Mercapto-imidazole derivatives, their preparation, mercapto-imidazole derivatives for the treatment of inflammatory diseases and their pharmaceutical compositions |
DE2823197A1 (en) * | 1978-05-24 | 1979-11-29 | Schering Ag | NEW IMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM |
US4175127A (en) * | 1978-09-27 | 1979-11-20 | Smithkline Corporation | Pyridyl substituted 2,3-dihydroimidazo[2,1-b]thiazoles |
FI800005A (en) * | 1979-01-05 | 1980-07-06 | Ciba Geigy Ag | FRAMEWORK FOR BICYCLING THREAD SALES |
US4636516A (en) * | 1981-02-19 | 1987-01-13 | Yamanouchi Pharmaceutical Co., Ltd. | 3,5-di-tert-butyl-4-hydroxyphenyl-substituted heterocyclic compounds |
IL78834A (en) * | 1985-05-23 | 1992-07-15 | Smithkline Beckman Corp | 2,3-dihydro-5-(1,4-dihydropyridin-4-yl)-6-phenylimidazo(2,1-b)thiazoles and 6,7-dihydro-3-(1,4-dihydropyridin-4-yl)-2-phenyl-5h-imidazo(2,1-b)(1,3)thiazines and their use as intermediates in a process for preparing the corresponding pyridyl-substituted imidazo(2,1-b)thiazoles and 5h-imidazo(2,1-b)(1,3)thiazines |
US5008390A (en) * | 1985-05-23 | 1991-04-16 | Smithkline Beckman Corporation | Compounds for preparing 6-phenyl-2,3-dihydroimidazo[2,1-b]-thiazoles and corresponding thiazines |
US4803279A (en) * | 1985-05-23 | 1989-02-07 | Smithkline Beckman Corporation | 1.4-dihydro-4-pyridyl-substituted imidazo (2,1-b) thiazoles and the corresponding thiazines. |
ZW24186A1 (en) * | 1985-12-12 | 1987-07-08 | Smithkline Beckman Corp | Inhibition of the 5-lipoxygenase pathway |
US4719218A (en) * | 1985-12-12 | 1988-01-12 | Smithkline Beckman Corporation | Pyrrolo[1,2-a]imidazole and pyrrolo[1,2-a]pyridine derivatives and their use as 5-lipoxygenase pathway inhibitor |
AU6355190A (en) * | 1989-06-13 | 1991-01-17 | Smithkline Beecham Corporation | Inhibition of interleukin-1 and tumor necrosis factor production by monocytes and/or macrophages |
GB9005966D0 (en) * | 1990-03-16 | 1990-05-09 | May & Baker Ltd | New compositions of matter |
GB9019838D0 (en) * | 1990-09-11 | 1990-10-24 | Smith Kline French Lab | Compounds |
US5240918A (en) * | 1992-03-24 | 1993-08-31 | Egis Gyogyszergyar | 2-(substituted imino)-thiazolidines and process for the preparation thereof |
US5552422A (en) * | 1995-01-11 | 1996-09-03 | Merck Frosst Canada, Inc. | Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents |
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US2981739A (en) * | 1958-01-27 | 1961-04-25 | Diamond Alkali Co | Certain alpha-haloaldehyde addition products of ethylenethioureas and process |
NL131034C (en) * | 1964-05-11 | |||
US3297708A (en) * | 1965-10-06 | 1967-01-10 | American Cyanamid Co | Method of preparing thiazolidines |
US3455924A (en) * | 1967-02-08 | 1969-07-15 | Upjohn Co | Dianisylimidazoles |
NL164285C (en) * | 1968-01-09 | 1980-12-15 | Rhone Poulenc Sa | PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION CONTAINING AN IMIDAZOŸ2.1-BŸTHIAZOLE DERIVATIVE, THE PREPARED PHARMACEUTICAL PREPARATIONS AND A METHOD FOR PREPARING THIS IMIDAZOŸ2.1-BŸTHIAZOLDER |
BE788792A (en) * | 1971-09-30 | 1973-03-13 | Ici Ltd | METHODS AND COMPOSITIONS FOR ANTI-BACTERIAL USE |
US3842097A (en) * | 1973-01-22 | 1974-10-15 | Searle & Co | 2-(phenoxyalkylthio)imidazoles and congeners |
SE428686B (en) * | 1975-08-11 | 1983-07-18 | Du Pont | PROCEDURE FOR PREPARING ANTI-INFLAMMATORALLY ACTIVE IMIDAZOLS |
GB1541321A (en) * | 1976-03-10 | 1979-02-28 | Metabio | 2,3-dihydroimidazo(2,1-b)thiazole derivatives and process for their preparation |
US4064260A (en) * | 1976-07-29 | 1977-12-20 | E. I. Du Pont De Nemours And Company | Anti-inflammatory diarylimidazothiazoles and their corresponding S-oxides |
US4263311A (en) * | 1976-09-27 | 1981-04-21 | Smithkline Corporation | 5,6-Phenyl-2,3-dihydroimidazo [2,1-b] thiazoles |
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1977
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1978
- 1978-06-29 EP EP80101323A patent/EP0019688A1/en not_active Ceased
- 1978-06-29 EP EP78100272A patent/EP0000353A3/en not_active Withdrawn
- 1978-06-29 EP EP80101322A patent/EP0020858A1/en not_active Withdrawn
- 1978-07-03 PT PT68246A patent/PT68246A/en unknown
- 1978-07-03 FI FI782132A patent/FI782132A/en not_active Application Discontinuation
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- 1978-07-05 IL IL55086A patent/IL55086A0/en unknown
- 1978-07-05 ES ES471458A patent/ES471458A1/en not_active Expired
- 1978-07-05 AU AU37788/78A patent/AU3778878A/en active Pending
- 1978-07-06 ZA ZA00783898A patent/ZA783898B/en unknown
- 1978-07-06 JP JP8153378A patent/JPS5416470A/en active Pending
- 1978-07-06 NO NO782357A patent/NO782357L/en unknown
- 1978-07-06 DK DK783055A patent/DK305578A/en unknown
- 1978-07-06 DD DD78206565A patent/DD138212A5/en unknown
- 1978-07-06 SU SU782632647A patent/SU873886A3/en active
- 1978-07-06 NZ NZ187789A patent/NZ187789A/en unknown
- 1978-07-06 DD DD78214990A patent/DD145538A5/en unknown
- 1978-07-07 PL PL1978208253A patent/PL116596B1/en unknown
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1979
- 1979-03-05 ES ES478296A patent/ES478296A1/en not_active Expired
- 1979-05-18 SU SU792763599A patent/SU893134A3/en active
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- 1979-09-20 ES ES484327A patent/ES484327A1/en not_active Expired
- 1979-10-23 SU SU792831085A patent/SU850007A3/en active
- 1979-12-03 AR AR279136A patent/AR224381A1/en active
- 1979-12-20 SU SU792855458A patent/SU873887A3/en active
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1981
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Also Published As
Publication number | Publication date |
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AR222309A1 (en) | 1981-05-15 |
SU850007A3 (en) | 1981-07-23 |
IT8149647A0 (en) | 1981-11-06 |
ZA783898B (en) | 1979-07-25 |
DK305578A (en) | 1979-01-08 |
EP0000353A2 (en) | 1979-01-24 |
SU893134A3 (en) | 1981-12-23 |
EP0019688A1 (en) | 1980-12-10 |
ES484327A1 (en) | 1980-05-16 |
AR224381A1 (en) | 1981-11-30 |
GR64978B (en) | 1980-06-11 |
NZ187789A (en) | 1981-03-16 |
PL208253A1 (en) | 1979-06-04 |
ES471458A1 (en) | 1979-10-01 |
PT68246A (en) | 1978-08-01 |
FI782132A (en) | 1979-01-08 |
PL116596B1 (en) | 1981-06-30 |
DD138212A5 (en) | 1979-10-17 |
ES478296A1 (en) | 1979-05-16 |
DD145538A5 (en) | 1980-12-17 |
EP0020858A1 (en) | 1981-01-07 |
ES484033A1 (en) | 1980-04-16 |
LU77703A1 (en) | 1979-03-26 |
EP0000353A3 (en) | 1979-06-13 |
AU3778878A (en) | 1980-01-10 |
JPS5416470A (en) | 1979-02-07 |
SU873886A3 (en) | 1981-10-15 |
SU873887A3 (en) | 1981-10-15 |
IL55086A0 (en) | 1978-09-29 |
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