FI95708B - Analogiförfarande för framställning av ett 1,4-diazepinderivat och dess farmaceutiskt godtagbara salt - Google Patents
Analogiförfarande för framställning av ett 1,4-diazepinderivat och dess farmaceutiskt godtagbara salt Download PDFInfo
- Publication number
- FI95708B FI95708B FI894867A FI894867A FI95708B FI 95708 B FI95708 B FI 95708B FI 894867 A FI894867 A FI 894867A FI 894867 A FI894867 A FI 894867A FI 95708 B FI95708 B FI 95708B
- Authority
- FI
- Finland
- Prior art keywords
- group
- formula
- compound
- methyl
- tetrahydro
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims description 31
- 150000004911 1,4-diazepines Chemical class 0.000 title description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 22
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Chemical group 0.000 claims abstract description 6
- 150000002367 halogens Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 164
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 127
- -1 thioamide compound Chemical class 0.000 claims description 86
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 150000001721 carbon Chemical group 0.000 claims description 8
- 229910052717 sulfur Chemical group 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000011593 sulfur Chemical group 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 3
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims 4
- 150000002366 halogen compounds Chemical class 0.000 claims 2
- 208000026935 allergic disease Diseases 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- 238000005160 1H NMR spectroscopy Methods 0.000 description 116
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 113
- 239000002904 solvent Substances 0.000 description 110
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 90
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 82
- 239000000243 solution Substances 0.000 description 79
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 73
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 56
- 238000010898 silica gel chromatography Methods 0.000 description 51
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 235000017557 sodium bicarbonate Nutrition 0.000 description 36
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 36
- 239000012156 elution solvent Substances 0.000 description 34
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 33
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 31
- HNDGEYCCZGRMTN-UHFFFAOYSA-N thieno[3,2-f:4,5-f]bis[1]benzothiophene Chemical compound S1C2=CC=3SC=CC=3C=C2C2=C1C=C(SC=C1)C1=C2 HNDGEYCCZGRMTN-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 29
- 238000001816 cooling Methods 0.000 description 28
- 239000000203 mixture Substances 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 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 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 23
- 208000009144 Pure autonomic failure Diseases 0.000 description 22
- 238000001035 drying Methods 0.000 description 22
- 239000013312 porous aromatic framework Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000000605 extraction Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- 238000004821 distillation Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 235000011121 sodium hydroxide Nutrition 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- ONOBXDPYDHTSBQ-UHFFFAOYSA-N 2,3,4,7-tetrahydro-1h-diazepine Chemical compound C1CC=CCNN1 ONOBXDPYDHTSBQ-UHFFFAOYSA-N 0.000 description 10
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000008096 xylene Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- ILLHORFDXDLILE-UHFFFAOYSA-N 2-bromopropanoyl bromide Chemical compound CC(Br)C(Br)=O ILLHORFDXDLILE-UHFFFAOYSA-N 0.000 description 7
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 7
- 238000009739 binding Methods 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 description 6
- PFBUKDPBVNJDEW-UHFFFAOYSA-N dichlorocarbene Chemical group Cl[C]Cl PFBUKDPBVNJDEW-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 5
- 125000003541 2-chlorobenzoyl group Chemical group ClC1=C(C(=O)*)C=CC=C1 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229940102396 methyl bromide Drugs 0.000 description 5
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- UFGRQTFDXZTUMM-UHFFFAOYSA-N (3-but-1-ynylphenyl) hydrogen carbonate Chemical compound CCC#CC1=CC=CC(OC(O)=O)=C1 UFGRQTFDXZTUMM-UHFFFAOYSA-N 0.000 description 3
- KQBUUAMEELZUED-UHFFFAOYSA-N 2-chloro-3-oxo-3-phenylpropanenitrile Chemical compound N#CC(Cl)C(=O)C1=CC=CC=C1 KQBUUAMEELZUED-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- CKHDBDHHJXIWRP-UHFFFAOYSA-N [2-(2-cyanopropan-2-yl)phenyl] hydrogen carbonate Chemical compound N#CC(C)(C)C1=CC=CC=C1OC(O)=O CKHDBDHHJXIWRP-UHFFFAOYSA-N 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 3
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 230000009871 nonspecific binding Effects 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- OCQAXYHNMWVLRH-ROUUACIJSA-N (2s,3s)-2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical compound O=C([C@](O)(C(=O)O)[C@@](O)(C(O)=O)C(=O)C=1C=CC=CC=1)C1=CC=CC=C1 OCQAXYHNMWVLRH-ROUUACIJSA-N 0.000 description 2
- OTZXZTJDUFZCNC-ONEGZZNKSA-N (e)-3-cyclopropylprop-2-enoic acid Chemical compound OC(=O)\C=C\C1CC1 OTZXZTJDUFZCNC-ONEGZZNKSA-N 0.000 description 2
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 2
- QUDZELMKHAGEGK-UHFFFAOYSA-N 1-[2-amino-3-(2-chlorobenzoyl)-5,7-dihydro-4h-thieno[2,3-c]pyridin-6-yl]ethanone Chemical compound C1N(C(=O)C)CCC2=C1SC(N)=C2C(=O)C1=CC=CC=C1Cl QUDZELMKHAGEGK-UHFFFAOYSA-N 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- URXAFLNNQPPVFC-UHFFFAOYSA-N 2-amino-n-[3-(2-chlorobenzoyl)-6-(cyclopropanecarbonyl)-5,7-dihydro-4h-thieno[2,3-c]pyridin-2-yl]propanamide Chemical compound CC(N)C(=O)NC=1SC=2CN(C(=O)C3CC3)CCC=2C=1C(=O)C1=CC=CC=C1Cl URXAFLNNQPPVFC-UHFFFAOYSA-N 0.000 description 2
- YENKKCASHWWLSZ-UHFFFAOYSA-N 2-bromo-n-[3-(2-chlorobenzoyl)-6-(cyclopropanecarbonyl)-5,7-dihydro-4h-thieno[2,3-c]pyridin-2-yl]propanamide Chemical compound CC(Br)C(=O)NC=1SC=2CN(C(=O)C3CC3)CCC=2C=1C(=O)C1=CC=CC=C1Cl YENKKCASHWWLSZ-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- PPZZCMKWRAVJDS-UHFFFAOYSA-N 3-cyclopropylpropanoic acid Chemical compound OC(=O)CCC1CC1 PPZZCMKWRAVJDS-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- 229910014033 C-OH Inorganic materials 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- 229910014570 C—OH Inorganic materials 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- JKAAZNVFUBIILJ-UHFFFAOYSA-N [2-amino-3-(2-chlorobenzoyl)-5,7-dihydro-4h-thieno[2,3-c]pyridin-6-yl]-cyclopropylmethanone Chemical compound NC=1SC=2CN(C(=O)C3CC3)CCC=2C=1C(=O)C1=CC=CC=C1Cl JKAAZNVFUBIILJ-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003125 aqueous solvent 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
- 239000012148 binding buffer Substances 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 description 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- PGYJQTDVXDWHTC-UHFFFAOYSA-N cyclopropyl-(4-hydroxypiperidin-1-yl)methanone Chemical compound C1CC(O)CCN1C(=O)C1CC1 PGYJQTDVXDWHTC-UHFFFAOYSA-N 0.000 description 2
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 2
- OLUQSRNJDSQETR-UHFFFAOYSA-N n-[6-acetyl-3-(2-chlorobenzoyl)-5,7-dihydro-4h-thieno[2,3-c]pyridin-2-yl]-2-aminopropanamide Chemical compound CC(N)C(=O)NC=1SC=2CN(C(C)=O)CCC=2C=1C(=O)C1=CC=CC=C1Cl OLUQSRNJDSQETR-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 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
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 1
- NOCRHJOLVFAFED-DKWTVANSSA-N (2s)-2-aminopropanoyl chloride;hydrochloride Chemical compound Cl.C[C@H](N)C(Cl)=O NOCRHJOLVFAFED-DKWTVANSSA-N 0.000 description 1
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 1
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- GOFIUEUUROFVMA-UHFFFAOYSA-N 1-(1h-indol-5-yl)ethanone Chemical compound CC(=O)C1=CC=C2NC=CC2=C1 GOFIUEUUROFVMA-UHFFFAOYSA-N 0.000 description 1
- WOWAAVPJNOLUDA-UHFFFAOYSA-N 1-(cyclopropanecarbonyl)piperidin-4-one Chemical compound C1CC(=O)CCN1C(=O)C1CC1 WOWAAVPJNOLUDA-UHFFFAOYSA-N 0.000 description 1
- QBFLUDJWIFUEJA-UHFFFAOYSA-N 1-cyanopropyl phenyl carbonate Chemical compound CCC(C#N)OC(=O)OC1=CC=CC=C1 QBFLUDJWIFUEJA-UHFFFAOYSA-N 0.000 description 1
- SFCWOICEQYPTBM-UHFFFAOYSA-N 14-(2-chlorophenyl)-5-(cyclopropanecarbonyl)-12-methyl-8-thia-5,10,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),13-trien-11-one Chemical compound N1C(=O)C(C)N=C(C=2C(=CC=CC=2)Cl)C(C=2CC3)=C1SC=2CN3C(=O)C1CC1 SFCWOICEQYPTBM-UHFFFAOYSA-N 0.000 description 1
- PMJJTEUWGHAVGT-UHFFFAOYSA-N 14-(2-chlorophenyl)-5-(cyclopropanecarbothioyl)-12-methyl-8-thia-5,10,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),13-triene-11-thione Chemical compound N1C(=S)C(C)N=C(C=2C(=CC=CC=2)Cl)C(C=2CC3)=C1SC=2CN3C(=S)C1CC1 PMJJTEUWGHAVGT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- LIZMZWFDPKUAOD-UHFFFAOYSA-N 2-cyanoethyl carbamate Chemical compound NC(=O)OCCC#N LIZMZWFDPKUAOD-UHFFFAOYSA-N 0.000 description 1
- BKQZFPHZFSLMNE-UHFFFAOYSA-N 2-cyanopropan-2-yl 4-hydroxypiperidine-1-carboxylate Chemical compound N#CC(C)(C)OC(=O)N1CCC(O)CC1 BKQZFPHZFSLMNE-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- AYEGPMGNMOIHDL-UHFFFAOYSA-N 2-methylcyclopropane-1-carboxylic acid Chemical compound CC1CC1C(O)=O AYEGPMGNMOIHDL-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- SJGNPEZYXVEDED-UHFFFAOYSA-N 3-chloropyridine Chemical compound ClC1=CC=C=N[CH]1 SJGNPEZYXVEDED-UHFFFAOYSA-N 0.000 description 1
- BDUBTLFQHNYXPC-UHFFFAOYSA-N 3-methylbut-2-enoyl chloride Chemical compound CC(C)=CC(Cl)=O BDUBTLFQHNYXPC-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- BAQQRABCRRQRSR-UHFFFAOYSA-N 4-hydroxybutylnitrile Chemical compound OCCCC#N BAQQRABCRRQRSR-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- SRIQFCJARAPHRI-UHFFFAOYSA-N Alginin Natural products COc1cc(O)c2C(=O)C(=C(Oc2c1O)c3ccc(OC4OC(C(O)C(O)C4O)C(=O)O)cc3)O SRIQFCJARAPHRI-UHFFFAOYSA-N 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OQHIOKDKKJFXHR-UHFFFAOYSA-N C1=CC(OC)=CC=C1P1(=S)SP(=S)S1 Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)S1 OQHIOKDKKJFXHR-UHFFFAOYSA-N 0.000 description 1
- ZYIMBCMGCRVTPS-UHFFFAOYSA-N C1CC2=C(NC1)SC(=C2)C(=O)C3=CC=CC=C3Cl Chemical compound C1CC2=C(NC1)SC(=C2)C(=O)C3=CC=CC=C3Cl ZYIMBCMGCRVTPS-UHFFFAOYSA-N 0.000 description 1
- CKKXJIOQICWXKF-UHFFFAOYSA-N C1N=NC2=CC=CC=NN21 Chemical compound C1N=NC2=CC=CC=NN21 CKKXJIOQICWXKF-UHFFFAOYSA-N 0.000 description 1
- DVINITOBOMDGFM-UHFFFAOYSA-N CC(C)(C#N)OC(=O)N1CCC2=C(C1)SC(=C2)C(=O)C3=CC=CC=C3Cl Chemical compound CC(C)(C#N)OC(=O)N1CCC2=C(C1)SC(=C2)C(=O)C3=CC=CC=C3Cl DVINITOBOMDGFM-UHFFFAOYSA-N 0.000 description 1
- UBVQZPMYJSYIHI-UHFFFAOYSA-N CCC(C)OC(=O)N1CCC(=O)CC1 Chemical compound CCC(C)OC(=O)N1CCC(=O)CC1 UBVQZPMYJSYIHI-UHFFFAOYSA-N 0.000 description 1
- PUKPYXNAMAKTOE-UHFFFAOYSA-N CCC(C)OC(=O)N1CCC(O)CC1 Chemical compound CCC(C)OC(=O)N1CCC(O)CC1 PUKPYXNAMAKTOE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical compound O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- CUFOWOODCBSVRL-UHFFFAOYSA-N but-3-ynyl 14-(2-chlorophenyl)-12-methyl-11-oxo-8-thia-5,10,13-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2(7),13-triene-5-carboxylate Chemical compound S1C=2CN(C(=O)OCCC#C)CCC=2C2=C1NC(=O)C(C)N=C2C1=CC=CC=C1Cl CUFOWOODCBSVRL-UHFFFAOYSA-N 0.000 description 1
- FADJINBQXDIIOB-UHFFFAOYSA-N but-3-ynyl 2-amino-3-(2-chlorobenzoyl)-5,7-dihydro-4h-thieno[2,3-c]pyridine-6-carboxylate Chemical compound NC=1SC=2CN(C(=O)OCCC#C)CCC=2C=1C(=O)C1=CC=CC=C1Cl FADJINBQXDIIOB-UHFFFAOYSA-N 0.000 description 1
- ANFXWVSMEBPCBH-UHFFFAOYSA-N but-3-ynyl 4-hydroxypiperidine-1-carboxylate Chemical compound OC1CCN(C(=O)OCCC#C)CC1 ANFXWVSMEBPCBH-UHFFFAOYSA-N 0.000 description 1
- DAVFUOQIWNMXHQ-UHFFFAOYSA-N but-3-ynyl 4-oxopiperidine-1-carboxylate Chemical compound C#CCCOC(=O)N1CCC(=O)CC1 DAVFUOQIWNMXHQ-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-UHFFFAOYSA-N 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- NTBIYBAYFBNTCD-KBPBESRZSA-N dibenzoyl (2s,3s)-2,3-dihydroxybutanedioate Chemical compound O=C([C@@H](O)[C@H](O)C(=O)OC(=O)C=1C=CC=CC=1)OC(=O)C1=CC=CC=C1 NTBIYBAYFBNTCD-KBPBESRZSA-N 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HXBCPBSHJYHXQV-AATRIKPKSA-N ethyl (e)-3-cyclopropylprop-2-enoate Chemical compound CCOC(=O)\C=C\C1CC1 HXBCPBSHJYHXQV-AATRIKPKSA-N 0.000 description 1
- JLMMMEDWRUVCEW-UHFFFAOYSA-N ethyl 2-(oxan-4-yl)acetate Chemical compound CCOC(=O)CC1CCOCC1 JLMMMEDWRUVCEW-UHFFFAOYSA-N 0.000 description 1
- HXBCPBSHJYHXQV-UHFFFAOYSA-N ethyl 3-cyclopropylprop-2-enoate Chemical compound CCOC(=O)C=CC1CC1 HXBCPBSHJYHXQV-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000002912 morpholin-4-ylsulfonyl group Chemical group O1C([H])([H])C([H])([H])N(S(=O)(=O)[*])C([H])([H])C1([H])[H] 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- XMZMVWOWQFMIKI-UHFFFAOYSA-N n-[6-acetyl-3-(2-chlorobenzoyl)-5,7-dihydro-4h-thieno[2,3-c]pyridin-2-yl]-2-bromopropanamide Chemical compound CC(Br)C(=O)NC=1SC=2CN(C(C)=O)CCC=2C=1C(=O)C1=CC=CC=C1Cl XMZMVWOWQFMIKI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 102000030769 platelet activating factor receptor Human genes 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 206010039722 scoliosis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- AHDDRJBFJBDEPW-DTWKUNHWSA-N trans-2-Phenylcyclopropanecarboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H]1C1=CC=CC=C1 AHDDRJBFJBDEPW-DTWKUNHWSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Claims (15)
1. Analoglmetod för att framställa triatsolo-l,4-diazepinderi-vat eller dess farmaseutiskt acceptabla salt, enligt föijande formel (I) R’ R3 R1 och R2 är samma eller olika och är väte eller en lägre al-kylgrupp, R3 är väte eller en halogen, R4 är väte eller en lägre alkylgrupp, X är: o (a) en grupp med formeln · V O (b) grupp med formeln -N-c- / där R5 är R5 väte eller en lägre alkylgrupp, 0 (c) grupp med formeln , OR° (d) grupp med formeln -0-P- , där R€ är II o en lägre alkylgrupp), O II (e) en grupp med formeln -s- , II o n är ett heltal 0 eller 1 95708 140 och Y ars (1) en cycloalkylgrupp, som kan ha en substituent eller substi-tuenter, (2) cycloalkylalkyl, (3) alkynylgrupp, R7 (4) grupp med formeln Cll3-C-(CH2) r / väri R7 är CN väte eller metyl och r är 0, 1 eller 2, (5) grupp enligt formeln NC-(CHa)P- , (väri p är ett heltal 1-6), (6) grupp enligt formeln a-(CHs),,- där A är en grupp, som valts bland pyridylgrupp, pyranylgrupp och morfolinogrupp och q är helhetstalet 0-6), (7) alkynylgrupp, som har 1-6 kolatomer, och vari fenylgruppen eller cycloalkylgruppen är förenad med vilken som heist kol-atom), (8) grupp med formeln NC / (9) grupp med formeln r 2^ N SO^-u- f (i vilken R8 och R9 är samma eller olika och är väte, lägre alkylgrupp, pyridy-lmetylgrupp eller cycloalkylgrupp, eller R8 och R9 kan vara fö-renade med nitrogen för ringformning, och B är fenylengrupp eller lägre alkylengrupp, med 1-3 kolatomer, (10) grupp med formeln CH-c-ch,-h/~\ o (11) grupp med formeln oQ. -CH,-?-0 -c -ch, - o (12) grupp med formeln 0Qi-?-o-ch,-c-c-cn,- (13) grupp med formeln ^r\-cH=c«- (14) grupp med formeln ^Vc-c- 95708 141 (15) lägre alkylgrupp, eller (16) cycloalkylalkylengrupp, r~\ (17) \_^-0-(01)2)8- , väri s är 1 eller 2, J \ (18) \_/-(CH2)t- , väri t är 1 eller. 2, (19) °0“CH' (20) aryläiky1, (21) arylalkenyl, \-(E) u— (22) I , väri R10 är väte eller RIO RH fenyl, R11 är väte eller en lägre alkyl, E on alkenylen och u är 0 eller 1, eller (23) O- , väri G är alkenylen eller -.1-(0¾)^ J är syre eller svavel, k är 0, 1 eller 2, under förutsättning att da X är
0 O
0 H 0 H (a) Il / (b) -N-C- ' (®) H eller (e) -S- / -0-C- | -C- I) R3 0 Y är vald ur grupperna (1)-(14) och (16)-(23) och da X är 0R° (d) -0-p- , Y är grupp (15) och da n = 0, Y är II 0 enligt grupp (3) en alkynylgrupp, kännetecknad av, att: en tioamidförening enligt den allmänna formeln (IX) hydro-liseras, för att fä en förening enligt formeln (III): s ^ νΛΛ X*· (1X) >=« i S/' 95708 142 cöö<: väri substituenterna är desamma som föregäende, och 1) för framställning föreningen enligt formeln (I), väri O o X enligt formeln (a) -o-C- eller formeln (b) -N-C- R° och n = 1, föreningar enligt formeln (II) och formeln (III) kondenseras, för att framställa en förening enligt formeln (I ): Y - x - 0 -/Λ W (II) 4 \ N ^ .s >=» 8’ Q-V (III) • ✓ '--ovi<·· ... C)=N R2 H’ 95708 143 väri substituenterna är samma som föregäende, 2) » för att f rams täi la föreningar enligt formeln (I), väri X är en förening enligt formeln q \\ -C- och n = 1, kondenseras karboxylsyra enligt formeln (IV) eller dess reakti-va syraderivat och förening enligt formeln (III), för att framställa en förening enligt formeln (I''): 0 jj Y-c-OH <VI> + Γ k <ΓΙ11 D-v ^ n < .]
0 K -f* N i (I"> £>r3 väri substituenterna är samma som föregäende, 3) för att framställa föreningar enligt formeln (I), där X är en förening enligt formeln 0Re och n = 1, t; il o 95708 144 tilläts halogenföreningen enligt den allmänna formeIn (VII) och föreningen enligt formeln (III) reagera, för att framställa en förening enligt formeln (I") 0R6 | ' (VII) Y -o -p - Hai I! 0 + R1 —-(5== N x Γ n S (riI> “OUC k1, >=N R2 J- R3 R " CS5= N N OR6 Γ ,N ! S <r"> l-°TOUr kfi' o _y=r R2 £jh R3 väri substituenterna är samma som föregäende och Hai är en halogen, för framställning av en förening enligt formeln (I), väri n = 0, tilläts halogenföreningen enligt den allmänna formeln (VIII) reagera med föreningen enligt den allmänna formeln (I-II), för att tillverka en förening enligt formeln (I""), 95708 145 Y — Hal (VIII) + R<-^=NX Γ N hOm \r (iii> Q- R3 Φ R,~~rNv (I····) _ S N '-Cm: )<' >=N RJ €>«a väri substituenterna är samma som föregäende, och Hai är halogen
2. Förfarande enligt krav 1, kännetecknat av, att X är (a), (b) eller (c).
3. Förfarande enligt krav 1, kännetecknat av, att X är (c) -CO-.
4. Förfarande enligt krav 1, kännetecknat av, att Y är nägon av grupperna (1) - (16).
5. Förfarande enligt krav 1, kännetecknat av, att X är (c) -CO- och n är 1.
6. Förfarande enligt krav 1, kännetecknat av, att X är (a) -COO- och n är 1. 95708 146
7. Förfarande enligt krav 1, kännetecknat av, att X är (b) -NRs-CO- och n är 1.
8. Förfarande enligt vilket som heist tidigare krav 1-7, kännetecknat av, att Y är en cycloalkyl.
9. Förfarande enligt vilket som heist tidigare krav 1-7, kännetecknat av, att Y är en cycloalkyl med 3-7 kolatomer.
10. Förfarande enligt vilket som heist tidigare krav 1-7, kännetecknat av, att Y är en cyclopropyl.
11. Förfarande enligt vilket som heist tidigare krav 1-7, kännetecknat av, att R1 är väte och R2 är metyl.
12. Förfarande enligt vilket som heist enligt tidigare krav 1-7, kännetecknat av, att R1 är väte, R2 är metyl och Y är cycloalkyl.
13. Förfarande enligt krav 1, kännetecknat av, att Y är nägon av grupperna (4), (3), (16) och (2).
14. Förfarande enligt krav 1, kännetecknat av, att Y är HC=c-C(CH3)2-.
15. Förfarande enligt krav 1, kännetecknat av, att R3 är klor, R1 är väte, R4 är metyl, n är 1, och Y-X- och R2 är definierade enligt nigon av följande kombinationer: 147 „ 95708 ch3 o 1 11 H HC-C-O-C- H ch3 ch3 o I II rH NC-C-O-C- L 3 ch3 0 ' Il ^/CH=CH-C- h O K H /^CH=CH-C- H O K li / ( CH 2)a ~C- H O — CH^NHC - h O II ch = c-ch2ch2q-c - CH3 o II NCCHaCHaCHaOC - ch3 O r\ 11 D>— c - H o‘- o-l- O 11 - C - CH-
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27546088 | 1988-10-31 | ||
| JP27546088 | 1988-10-31 | ||
| JP29706888 | 1988-11-24 | ||
| JP29706888 | 1988-11-24 | ||
| JP31801688 | 1988-12-16 | ||
| JP31801688 | 1988-12-16 | ||
| JP33162288 | 1988-12-28 | ||
| JP33162288 | 1988-12-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI894867A0 FI894867A0 (sv) | 1989-10-13 |
| FI95708B true FI95708B (sv) | 1995-11-30 |
| FI95708C FI95708C (sv) | 1996-03-11 |
Family
ID=27479049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI894867A FI95708C (sv) | 1988-10-31 | 1989-10-13 | Analogiförfarande för framställning av ett 1,4-diazepinderivat och dess farmaceutiskt godtagbara salt |
Country Status (15)
| Country | Link |
|---|---|
| EP (3) | EP0367110B1 (sv) |
| JP (1) | JP2756004B2 (sv) |
| KR (1) | KR910009332B1 (sv) |
| CN (1) | CN1036520C (sv) |
| AT (3) | ATE213247T1 (sv) |
| AU (1) | AU621413B2 (sv) |
| CA (1) | CA2000985C (sv) |
| DE (3) | DE68929455T2 (sv) |
| DK (1) | DK540689A (sv) |
| FI (1) | FI95708C (sv) |
| HU (1) | HU217127B (sv) |
| NO (1) | NO175259C (sv) |
| NZ (1) | NZ231188A (sv) |
| PH (1) | PH27461A (sv) |
| PT (1) | PT92153B (sv) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH30676A (en) * | 1986-07-22 | 1997-09-16 | Boehringer Ingelhein Kg | Hetrazepine compounds which have useful pharmaceutical utility |
| GB8907257D0 (en) * | 1989-03-31 | 1989-05-17 | Rech Et D Applic Scient Scras | New derivatives of hetrazepine as anti-paf and anti-ischemic agents |
| GB8907256D0 (en) * | 1989-03-31 | 1989-05-17 | Rech Et D Applic Scient Scras | New derivatives of hetrazepine as anti-asthmatic anti-allergic and gastro-intestinal protectors |
| AT394563B (de) * | 1990-05-09 | 1992-05-11 | Scras | Verfahren zur herstellung von thieno-triazolodiazepinderivaten |
| DE4027470A1 (de) * | 1990-08-30 | 1992-03-05 | Boehringer Ingelheim Kg | Neue hetrazepinoide amide |
| DE4107521A1 (de) * | 1991-03-08 | 1992-09-10 | Boehringer Ingelheim Kg | Neue acylaminosubstituierte hetrazepine |
| ATE191345T1 (de) * | 1991-12-11 | 2000-04-15 | Yoshitomi Pharmaceutical | Arzneimittel zur behandlung von autoimmunerkrankungen |
| TW219935B (sv) * | 1991-12-25 | 1994-02-01 | Mitsubishi Chemicals Co Ltd | |
| US5639782A (en) * | 1992-03-04 | 1997-06-17 | Center For Innovative Technology | Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors |
| US5530141A (en) * | 1992-03-04 | 1996-06-25 | Center For Innovative Technology | 2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; and 2,5-diaryl-1,3-oxathiolanes for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
| US5648486A (en) * | 1992-07-13 | 1997-07-15 | Cytomed, Inc. | Compounds and methods for the treatment of inflammatory and immune disorders |
| EP0650485B1 (en) | 1992-07-13 | 2000-10-11 | Cytomed, Inc. | 2,5-diaryl tetrahydro-thiophenes, -furans and analogs for the treatment of inflammatory and immune disorders |
| US5463083A (en) * | 1992-07-13 | 1995-10-31 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
| US5434151A (en) * | 1992-08-24 | 1995-07-18 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
| US5358938A (en) * | 1992-07-13 | 1994-10-25 | Cytomed, Inc. | Compounds and methods for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase |
| ES2061406B1 (es) * | 1993-05-07 | 1995-06-01 | Uriach & Cia Sa J | Nuevos derivados de la 2-(quinolina) con actividad farmacologica. |
| JP2523259B2 (ja) * | 1993-06-30 | 1996-08-07 | エスオーエンジニアリング株式会社 | フォ―ハ―ス内のガラス温度制御方法 |
| US5703093A (en) * | 1995-05-31 | 1997-12-30 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
| US5750565A (en) * | 1995-05-25 | 1998-05-12 | Cytomed, Inc. | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
| US5792776A (en) * | 1994-06-27 | 1998-08-11 | Cytomed, Inc., | Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders |
| CA2294139A1 (en) * | 1997-06-25 | 1998-12-30 | Nikken Chemicals Co., Ltd. | Triazolo-1,4-diazepine compounds and medicinal composition containing the same |
| FR2779652B1 (fr) * | 1998-06-15 | 2001-06-08 | Sod Conseils Rech Applic | Utilisation de diazepines pour la preparation de medicaments destines a traiter les etats pathologiques ou les maladies dans lesquels un des recepteurs de la somatostatine est implique |
| SG109000A1 (en) | 2003-07-16 | 2005-02-28 | Asml Netherlands Bv | Lithographic apparatus and device manufacturing method |
| US7977336B2 (en) | 2006-12-28 | 2011-07-12 | Banyu Pharmaceutical Co. Ltd | Aminopyrimidine derivatives as PLK1 inhibitors |
| US9249161B2 (en) | 2010-12-02 | 2016-02-02 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| AR084070A1 (es) | 2010-12-02 | 2013-04-17 | Constellation Pharmaceuticals Inc | Inhibidores del bromodominio y usos de los mismos |
| US9422292B2 (en) | 2011-05-04 | 2016-08-23 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| WO2012174487A2 (en) | 2011-06-17 | 2012-12-20 | Constellation Pharmaceuticals, Inc. | Bromodomain inhibitors and uses thereof |
| US9624244B2 (en) | 2012-06-06 | 2017-04-18 | Constellation Pharmaceuticals, Inc. | Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof |
| TWI602820B (zh) | 2012-06-06 | 2017-10-21 | 星宿藥物公司 | 溴域抑制劑及其用途 |
| US10092574B2 (en) | 2012-09-26 | 2018-10-09 | Valorisation-Recherche, Limited Partnership | Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof |
| DK3157928T3 (da) | 2014-06-20 | 2019-05-20 | Constellation Pharmaceuticals Inc | Krystallinske former af 2-((4s)-6-(4-chlorphenyl)-1-methyl-4h-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamid |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3435973A1 (de) * | 1984-10-01 | 1986-04-10 | Boehringer Ingelheim KG, 6507 Ingelheim | Diazepine enthaltende pharmazeutische zusammensetzungen mit paf-antagonistischer wirkung |
| DE3502392A1 (de) * | 1985-01-25 | 1986-07-31 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue thieno-triazolo-1,4-diazepino-2- carbonsaeureamide, verfahren zu ihrer herstellung und pharmazeutische zusammensetzungen |
| ES2037013T3 (es) | 1986-01-21 | 1993-06-16 | Boehringer Ingelheim Kg | Procedimiento para preparar tieno-1,4-diazepinas. |
| DE3724031A1 (de) | 1986-07-22 | 1988-01-28 | Boehringer Ingelheim Kg | Neue hetrazepine und verfahren zu ihrer herstellung |
| PH30676A (en) | 1986-07-22 | 1997-09-16 | Boehringer Ingelhein Kg | Hetrazepine compounds which have useful pharmaceutical utility |
| ES2039408T3 (es) * | 1986-11-17 | 1993-10-01 | Yoshitomi Pharmaceutical Industries, Ltd. | Un procedimiento para preparar un compuesto de tienotriazolodiazepina. |
| EP0368175A1 (de) * | 1988-11-06 | 1990-05-16 | Boehringer Ingelheim Kg | 3S,7S-3-(Morpholinocarbonyl)-5-(2-chlorphenyl)-7,10-dimethyl-3,4-dihydro-2H,7H-cyclopenta[4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin. |
| GB8911030D0 (en) * | 1989-05-13 | 1989-06-28 | Scras | Hetrazepine derivatives |
| YU133090A (sh) * | 1989-07-12 | 1993-10-20 | Boehringer Ingelheim Kg. | Novi heteroazepini s paf-antaganostičnim učinkom in postopek za njihovo pripravo |
| AT394563B (de) * | 1990-05-09 | 1992-05-11 | Scras | Verfahren zur herstellung von thieno-triazolodiazepinderivaten |
-
1989
- 1989-10-13 FI FI894867A patent/FI95708C/sv not_active IP Right Cessation
- 1989-10-18 CA CA002000985A patent/CA2000985C/en not_active Expired - Fee Related
- 1989-10-18 PH PH39380A patent/PH27461A/en unknown
- 1989-10-26 AT AT95111206T patent/ATE213247T1/de not_active IP Right Cessation
- 1989-10-26 EP EP89119910A patent/EP0367110B1/en not_active Expired - Lifetime
- 1989-10-26 EP EP95111206A patent/EP0677524B1/en not_active Expired - Lifetime
- 1989-10-26 AT AT94101416T patent/ATE234306T1/de not_active IP Right Cessation
- 1989-10-26 DE DE68929455T patent/DE68929455T2/de not_active Expired - Fee Related
- 1989-10-26 AU AU43761/89A patent/AU621413B2/en not_active Ceased
- 1989-10-26 EP EP94101416A patent/EP0606103B1/en not_active Expired - Lifetime
- 1989-10-26 AT AT89119910T patent/ATE183187T1/de active
- 1989-10-26 DE DE68929049T patent/DE68929049T2/de not_active Expired - Fee Related
- 1989-10-26 DE DE68929372T patent/DE68929372T2/de not_active Expired - Fee Related
- 1989-10-27 NO NO894287A patent/NO175259C/no not_active IP Right Cessation
- 1989-10-27 NZ NZ231188A patent/NZ231188A/xx unknown
- 1989-10-27 JP JP1281300A patent/JP2756004B2/ja not_active Expired - Lifetime
- 1989-10-30 DK DK540689A patent/DK540689A/da not_active Application Discontinuation
- 1989-10-30 HU HU895609A patent/HU217127B/hu not_active IP Right Cessation
- 1989-10-30 PT PT92153A patent/PT92153B/pt not_active IP Right Cessation
- 1989-10-31 KR KR1019890015723A patent/KR910009332B1/ko not_active IP Right Cessation
-
1994
- 1994-01-17 CN CN94100504A patent/CN1036520C/zh not_active Expired - Fee Related
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI95708B (sv) | Analogiförfarande för framställning av ett 1,4-diazepinderivat och dess farmaceutiskt godtagbara salt | |
| KR101901044B1 (ko) | 비시클릭-융합된 헤테로아릴 또는 아릴 화합물 및 ｉｒａｋ４ 억제제로서의 그의 용도 | |
| CA2741934C (en) | Thienotriazolodiazepine derivatives active on apo a | |
| KR102677015B1 (ko) | Bet 억제제로서의 헤테로시클릭 화합물 | |
| CA2907912A1 (en) | C-linked heterocycloalkyl substituted pyrimidines and their uses | |
| CA2812363A1 (en) | Substituted polycyclic carbamoyl pyridone derivative prodrug | |
| JP2009545569A (ja) | ピラゾロピリミジン、それらの製造方法および医薬品としてのそれらの使用 | |
| CA2934011A1 (en) | Pyrazole derivatives and uses thereof as inhibitors of dlk | |
| WO2007129111A1 (en) | Diazepine derivatives as 5-ht2a antagonists | |
| US8962859B2 (en) | Spiro-amino-imidazo-fused heterocyclic compounds as beta-secretase modulators and methods of use | |
| WO1994021612A1 (en) | Carbostyril derivatives as matrix metalloproteinases inhibitors | |
| SK17022001A3 (sk) | Deriváty a analógy galantamínu | |
| US20140031340A1 (en) | 5-Amino-Oxazepine and 5-Amino-Thiazepane Compounds as Beta Secretase Antagonists and Methods of Use | |
| TW202334167A (zh) | 作為ｅｒｂｂ２抑制劑之稠合四環喹唑啉衍生物 | |
| US5594006A (en) | Carbostyril derivatives as matrix metalloproteinases inhibitors | |
| MXPA02004474A (es) | Agentes antibacterianos de acido carboxilico de naftiridina y quinolina. | |
| HUT54151A (en) | Process fopr producing new (r)-(-)-3-quinuclidinone derivatives and pharmaceutical compositions comprising such compounds | |
| JP2971901B2 (ja) | トリアゾロ―１，４―ジアゼピン系化合物 | |
| RU2117670C1 (ru) | Производные триазоло[1,4]диазепина и способы их получения | |
| DK171644B1 (da) | 2-Biheterocyklothiopenemderivater samt mellemprodukt til disses fremstilling | |
| FI83085B (fi) | Foerfarande foer framstaellning av terapeutiskt anvaendbara pyridazo/1,2-a//1,2/diazepinderivat. | |
| US20220213089A1 (en) | Inhibiting cyclic amp-responsive element-binding protein (creb) | |
| NO301072B1 (no) | Analogifremgangsmåte for fremstilling av terapeutisk aktive triazolo-1,4-diazepinforbindelser | |
| CA3160368A1 (en) | Substituted imidazolecarboxamide as bruton's tyrosine kinase inhibitors | |
| DD293587A5 (de) | Verfahren zur herstellung von triazol-1,4-diazepinverbindungen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| BB | Publication of examined application | ||
| FG | Patent granted |
Owner name: EISAI CO., LTD. |
|
| MA | Patent expired |