SK283869B6 - Tricyklické triazolobenzazepínové deriváty, spôsob ich prípravy a antialergické prostriedky - Google Patents

Tricyklické triazolobenzazepínové deriváty, spôsob ich prípravy a antialergické prostriedky Download PDF

Info

Publication number: SK283869B6
Authority: SK; Slovakia
Prior art keywords: compound; formula; alkyl; substituted; alkoxy
Prior art date: 1997-09-29

Application number

SK425-2000A

Other languages

English (en)

Slovak (sk)

Other versions

SK4252000A3 (en

Inventor

Yasuo Ohtsuka

Toshio Nishizuka

Sohjiro Shiokawa

Seiji Tsutsumi

Mami Kawaguchi

Hideo Kitagawa

Hiromi Takata

Takashi Shishikura

Toyoaki Ishikura

Kenichi Fushihara

Yumiko Okada

Sachiko Miyamoto

Maki Shiobara

Original Assignee

Meiji Seika Kaisha, Ltd.

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1997-09-29

Filing date

1998-09-29

Publication date

2004-03-02

1998-09-29 Application filed by Meiji Seika Kaisha, Ltd. filed Critical Meiji Seika Kaisha, Ltd.

2000-10-09 Publication of SK4252000A3 publication Critical patent/SK4252000A3/sk

2004-03-02 Publication of SK283869B6 publication Critical patent/SK283869B6/sk

Links

238000000034 method Methods 0.000 title claims description 42
230000008569 process Effects 0.000 title claims description 16
238000004519 manufacturing process Methods 0.000 title claims 4
QDEVEJYEXBFIJD-UHFFFAOYSA-N triazolo[4,5-i][1]benzazepine Chemical class C1=CC2=CC=CC=NC2=C2C1=NN=N2 QDEVEJYEXBFIJD-UHFFFAOYSA-N 0.000 title abstract description 7
150000001875 compounds Chemical class 0.000 claims abstract description 312
125000000217 alkyl group Chemical group 0.000 claims abstract description 134
125000003545 alkoxy group Chemical group 0.000 claims abstract description 88
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 49
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 46
150000003839 salts Chemical class 0.000 claims abstract description 33
125000005843 halogen group Chemical group 0.000 claims abstract description 29
239000012453 solvate Substances 0.000 claims abstract description 28
239000001257 hydrogen Substances 0.000 claims abstract description 15
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
125000003342 alkenyl group Chemical group 0.000 claims abstract description 8
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 3
125000003884 phenylalkyl group Chemical group 0.000 claims abstract 2
-1 1-imidazolyl Chemical group 0.000 claims description 202
238000006243 chemical reaction Methods 0.000 claims description 66
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
229920006395 saturated elastomer Polymers 0.000 claims description 53
125000000623 heterocyclic group Chemical group 0.000 claims description 44
150000002367 halogens Chemical class 0.000 claims description 43
OSDBJMYIUDLIRI-UHFFFAOYSA-N oxo-[[1-[[4-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxy]cyclohexyl]oxymethyl]pyridin-4-ylidene]methyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1COC1CCC(OCN2C=CC(=C[NH+]=O)C=C2)CC1 OSDBJMYIUDLIRI-UHFFFAOYSA-N 0.000 claims description 39
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
MNLAVFKVRUQAKW-UHFFFAOYSA-N VR nerve agent Chemical compound CCN(CC)CCSP(C)(=O)OCC(C)C MNLAVFKVRUQAKW-UHFFFAOYSA-N 0.000 claims description 32
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
229910052799 carbon Inorganic materials 0.000 claims description 19
229910052736 halogen Inorganic materials 0.000 claims description 19
238000002360 preparation method Methods 0.000 claims description 17
125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 14
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
239000003814 drug Substances 0.000 claims description 13
229910052757 nitrogen Inorganic materials 0.000 claims description 12
125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
229910001516 alkali metal iodide Inorganic materials 0.000 claims description 7
238000011282 treatment Methods 0.000 claims description 7
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
208000026935 allergic disease Diseases 0.000 claims description 6
KPWJBEFBFLRCLH-UHFFFAOYSA-L cadmium bromide Chemical group Br[Cd]Br KPWJBEFBFLRCLH-UHFFFAOYSA-L 0.000 claims description 6
OKIIEJOIXGHUKX-UHFFFAOYSA-L cadmium iodide Chemical compound [Cd+2].[I-].[I-] OKIIEJOIXGHUKX-UHFFFAOYSA-L 0.000 claims description 6
229910052801 chlorine Inorganic materials 0.000 claims description 6
VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical group Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 6
UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical group I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 6
125000004093 cyano group Chemical group *C#N 0.000 claims description 5
150000007529 inorganic bases Chemical class 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
239000001301 oxygen Substances 0.000 claims description 5
125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000006239 protecting group Chemical group 0.000 claims description 5
125000004434 sulfur atom Chemical group 0.000 claims description 5
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
125000002947 alkylene group Chemical group 0.000 claims description 4
125000002619 bicyclic group Chemical group 0.000 claims description 4
229940124597 therapeutic agent Drugs 0.000 claims description 4
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
229940075417 cadmium iodide Drugs 0.000 claims description 3
125000001309 chloro group Chemical group Cl* 0.000 claims description 3
229910052802 copper Inorganic materials 0.000 claims description 3
239000010949 copper Substances 0.000 claims description 3
229910052744 lithium Inorganic materials 0.000 claims description 3
OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical group [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical group [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 3
229910001641 magnesium iodide Inorganic materials 0.000 claims description 3
229910052717 sulfur Inorganic materials 0.000 claims description 3
229940102001 zinc bromide Drugs 0.000 claims description 3
239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
125000001425 triazolyl group Chemical group 0.000 claims 1
229940002612 prodrug Drugs 0.000 abstract description 3
239000000651 prodrug Substances 0.000 abstract description 3
125000000547 substituted alkyl group Chemical group 0.000 abstract description 3
238000005160 1H NMR spectroscopy Methods 0.000 description 125
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
239000000243 solution Substances 0.000 description 117
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 115
239000000203 mixture Substances 0.000 description 99
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 77
238000002451 electron ionisation mass spectrometry Methods 0.000 description 58
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
230000015572 biosynthetic process Effects 0.000 description 51
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
238000003786 synthesis reaction Methods 0.000 description 50
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
239000000843 powder Substances 0.000 description 41
239000002904 solvent Substances 0.000 description 39
239000003921 oil Substances 0.000 description 35
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 33
239000000543 intermediate Substances 0.000 description 33
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
IHPFHZXEOBSXIH-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2h-triazole-4-carboxylate Chemical compound N1=NNC(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=C1C(=O)OCC IHPFHZXEOBSXIH-UHFFFAOYSA-N 0.000 description 25
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
230000002829 reductive effect Effects 0.000 description 24
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
238000010898 silica gel chromatography Methods 0.000 description 20
239000012044 organic layer Substances 0.000 description 19
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 18
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 17
239000006260 foam Substances 0.000 description 17
NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 16
KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 16
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
238000000926 separation method Methods 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
239000012300 argon atmosphere Substances 0.000 description 14
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 14
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
238000000746 purification Methods 0.000 description 13
229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
235000017557 sodium bicarbonate Nutrition 0.000 description 12
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
238000001816 cooling Methods 0.000 description 11
239000012043 crude product Substances 0.000 description 11
239000000047 product Substances 0.000 description 11
150000003852 triazoles Chemical class 0.000 description 11
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 10
238000003756 stirring Methods 0.000 description 10
125000001424 substituent group Chemical group 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 8
AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 8
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 8
NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
229910000027 potassium carbonate Inorganic materials 0.000 description 8
229930040373 Paraformaldehyde Natural products 0.000 description 7
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
239000000460 chlorine Substances 0.000 description 7
229940079593 drug Drugs 0.000 description 7
239000008187 granular material Substances 0.000 description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
239000000725 suspension Substances 0.000 description 7
IAKGGJYLHBHSQD-UHFFFAOYSA-N 1-(azidomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CN=[N+]=[N-])C=C1 IAKGGJYLHBHSQD-UHFFFAOYSA-N 0.000 description 6
125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 6
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
125000005842 heteroatom Chemical group 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
238000006396 nitration reaction Methods 0.000 description 6
AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 6
NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
239000011541 reaction mixture Substances 0.000 description 6
235000009518 sodium iodide Nutrition 0.000 description 6
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
206010020751 Hypersensitivity Diseases 0.000 description 5
239000002253 acid Substances 0.000 description 5
239000002585 base Substances 0.000 description 5
229910052794 bromium Inorganic materials 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
230000003111 delayed effect Effects 0.000 description 5
125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
238000001914 filtration Methods 0.000 description 5
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
238000006722 reduction reaction Methods 0.000 description 5
239000011734 sodium Substances 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
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 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 4
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
150000001540 azides Chemical class 0.000 description 4
239000013078 crystal Substances 0.000 description 4
238000010511 deprotection reaction Methods 0.000 description 4
KFTQWOBRKGHZAP-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(2-methylpropanoyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)C(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N KFTQWOBRKGHZAP-UHFFFAOYSA-N 0.000 description 4
SJAKKHIITAZTNR-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-1-[(4-methoxyphenyl)methyl]triazole-4-carboxylate Chemical compound C=1C(OC)=C(OC)C=C([N+]([O-])=O)C=1C(=O)C1=C(C(=O)OCC)N=NN1CC1=CC=C(OC)C=C1 SJAKKHIITAZTNR-UHFFFAOYSA-N 0.000 description 4
DJMDVHJVOTYDHB-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-3-[(4-methoxyphenyl)methyl]triazole-4-carboxylate Chemical compound CCOC(=O)C1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)N=NN1CC1=CC=C(OC)C=C1 DJMDVHJVOTYDHB-UHFFFAOYSA-N 0.000 description 4
150000002431 hydrogen Chemical class 0.000 description 4
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
229920002866 paraformaldehyde Polymers 0.000 description 4
239000002244 precipitate Substances 0.000 description 4
239000002243 precursor Substances 0.000 description 4
IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 4
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
230000009467 reduction Effects 0.000 description 4
238000007363 ring formation reaction Methods 0.000 description 4
229910052708 sodium Inorganic materials 0.000 description 4
229910000029 sodium carbonate Inorganic materials 0.000 description 4
239000003826 tablet Substances 0.000 description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 4
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APRBQIVWMKKOOQ-UHFFFAOYSA-N 4-o-ethyl 2-o-propan-2-yl 5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-2,4-dicarboxylate Chemical compound CCOC(=O)C1=NN(C(=O)OC(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O APRBQIVWMKKOOQ-UHFFFAOYSA-N 0.000 description 2
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125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
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BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
241000699670 Mus sp. Species 0.000 description 2
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
229920002472 Starch Polymers 0.000 description 2
YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
125000002339 acetoacetyl group Chemical group O=C([*])C([H])([H])C(=O)C([H])([H])[H] 0.000 description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
239000003377 acid catalyst Substances 0.000 description 2
150000001299 aldehydes Chemical class 0.000 description 2
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
125000003277 amino group Chemical group 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
239000000043 antiallergic agent Substances 0.000 description 2
239000012298 atmosphere Substances 0.000 description 2
208000010668 atopic eczema Diseases 0.000 description 2
150000008038 benzoazepines Chemical class 0.000 description 2
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
239000006227 byproduct Substances 0.000 description 2
125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 2
239000012141 concentrate Substances 0.000 description 2
235000008504 concentrate Nutrition 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
238000011161 development Methods 0.000 description 2
SFOCXODYDZTUOT-UHFFFAOYSA-N diethyl 1-[(4-methoxyphenyl)methyl]triazole-4,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C(=O)OCC)N=NN1CC1=CC=C(OC)C=C1 SFOCXODYDZTUOT-UHFFFAOYSA-N 0.000 description 2
229940043279 diisopropylamine Drugs 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
UZRLXARQFDGSTL-UHFFFAOYSA-N ethyl 2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate Chemical compound CCOC(=O)C(Br)C(Br)C(=O)C1=CC=C(OC)C(OC)=C1 UZRLXARQFDGSTL-UHFFFAOYSA-N 0.000 description 2
IWYHQRRWJCJBDL-UHFFFAOYSA-N ethyl 2-(4-chlorobutanoyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)CCCCl)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O IWYHQRRWJCJBDL-UHFFFAOYSA-N 0.000 description 2
VIAGMECHANXFFW-UHFFFAOYSA-N ethyl 2-(acetyloxymethyl)-5-(2-amino-4,5-dimethoxybenzoyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(C)=O)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N VIAGMECHANXFFW-UHFFFAOYSA-N 0.000 description 2
IWTHUZQDTVMCJY-UHFFFAOYSA-N ethyl 2-(butoxycarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCCCOC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 IWTHUZQDTVMCJY-UHFFFAOYSA-N 0.000 description 2
JORRLPLHHODMSY-UHFFFAOYSA-N ethyl 2-(chloromethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(CCl)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O JORRLPLHHODMSY-UHFFFAOYSA-N 0.000 description 2
ACMWIWSSYYKGOD-UHFFFAOYSA-N ethyl 2-[1-(1,3-diethoxypropan-2-yloxycarbonyloxy)-2-methylpropyl]-5-(4-methoxy-2-nitro-5-propan-2-yloxybenzoyl)triazole-4-carboxylate Chemical compound CCOCC(COCC)OC(=O)OC(C(C)C)N1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC(C)C)C=2)[N+]([O-])=O)=N1 ACMWIWSSYYKGOD-UHFFFAOYSA-N 0.000 description 2
DKJJVAFKNQRYKP-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(butoxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCCCOC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)=N1 DKJJVAFKNQRYKP-UHFFFAOYSA-N 0.000 description 2
HLHSZTSCYUYNKZ-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(chloromethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(CCl)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N HLHSZTSCYUYNKZ-UHFFFAOYSA-N 0.000 description 2
REUXKVMWLIOTHQ-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(dodecanoyloxymethyl)triazole-4-carboxylate Chemical compound CCCCCCCCCCCC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)=N1 REUXKVMWLIOTHQ-UHFFFAOYSA-N 0.000 description 2
IKDVDACKAACLSZ-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)=N1 IKDVDACKAACLSZ-UHFFFAOYSA-N 0.000 description 2
GDQLUNRELMXPTJ-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(ethoxymethyl)triazole-4-carboxylate Chemical compound CCOCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)=N1 GDQLUNRELMXPTJ-UHFFFAOYSA-N 0.000 description 2
WYXHMMJSKZUNAQ-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(hexadecanoyloxymethyl)triazole-4-carboxylate Chemical compound CCCCCCCCCCCCCCCC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)=N1 WYXHMMJSKZUNAQ-UHFFFAOYSA-N 0.000 description 2
LVAKCSQYHRPZPF-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(hexoxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCCCCCOC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)=N1 LVAKCSQYHRPZPF-UHFFFAOYSA-N 0.000 description 2
YESPBXGTYJEDSU-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(propan-2-yloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N YESPBXGTYJEDSU-UHFFFAOYSA-N 0.000 description 2
AHPSGKYZIXKRTN-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(1-pentan-3-yloxycarbonyloxypropyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(CC)OC(=O)OC(CC)CC)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O AHPSGKYZIXKRTN-UHFFFAOYSA-N 0.000 description 2
CLCKMZLARNBLHV-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(2-methylpropanoyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)C(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O CLCKMZLARNBLHV-UHFFFAOYSA-N 0.000 description 2
AKHCCWOLOOXHRC-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(3-methoxypentan-3-yl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(CC)(CC)OC)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O AKHCCWOLOOXHRC-UHFFFAOYSA-N 0.000 description 2
SDOIBUJUSQMAIJ-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(4-ethoxyheptan-4-yl)triazole-4-carboxylate Chemical compound CCCC(CCC)(OCC)N1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 SDOIBUJUSQMAIJ-UHFFFAOYSA-N 0.000 description 2
BFWDRMDPWOMBHE-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(dodecanoyloxymethyl)triazole-4-carboxylate Chemical compound CCCCCCCCCCCC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 BFWDRMDPWOMBHE-UHFFFAOYSA-N 0.000 description 2
HYWJFIRMGNLOMZ-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(ethoxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 HYWJFIRMGNLOMZ-UHFFFAOYSA-N 0.000 description 2
XYKVVCFCJLKCHT-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(hexadecanoyloxymethyl)triazole-4-carboxylate Chemical compound CCCCCCCCCCCCCCCC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 XYKVVCFCJLKCHT-UHFFFAOYSA-N 0.000 description 2
WEDORJKRRUGUKR-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(propan-2-yloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O WEDORJKRRUGUKR-UHFFFAOYSA-N 0.000 description 2
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125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
239000012230 colorless oil Substances 0.000 description 1
229940125904 compound 1 Drugs 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
239000006071 cream Substances 0.000 description 1
229960000265 cromoglicic acid Drugs 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
125000000753 cycloalkyl group Chemical group 0.000 description 1
RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
150000008508 dibenzocycloheptenes Chemical class 0.000 description 1
125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
239000007884 disintegrant Substances 0.000 description 1
VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 1
239000012374 esterification agent Substances 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical class CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 description 1
WWAQSVGFVNIDMS-UHFFFAOYSA-N ethyl 2,3-dibromo-4-(4,5-dimethoxy-2-nitrophenyl)-4-oxobutanoate Chemical compound CCOC(=O)C(Br)C(Br)C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O WWAQSVGFVNIDMS-UHFFFAOYSA-N 0.000 description 1
VHNIIYYKZAFDKF-UHFFFAOYSA-N ethyl 2-(1-chloroethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(C)Cl)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O VHNIIYYKZAFDKF-UHFFFAOYSA-N 0.000 description 1
SIFHWJYUSOUPMT-UHFFFAOYSA-N ethyl 2-(acetyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(C)=O)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O SIFHWJYUSOUPMT-UHFFFAOYSA-N 0.000 description 1
SAEFKHVNAALQSA-UHFFFAOYSA-N ethyl 2-(benzoyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound N1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)C(C(=O)OCC)=NN1COC(=O)C1=CC=CC=C1 SAEFKHVNAALQSA-UHFFFAOYSA-N 0.000 description 1
QNPDPTUQKZJXHS-UHFFFAOYSA-N ethyl 2-(cyclohexanecarbonyloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound N1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)C(C(=O)OCC)=NN1COC(=O)C1CCCCC1 QNPDPTUQKZJXHS-UHFFFAOYSA-N 0.000 description 1
OFWQMEIAVINULN-UHFFFAOYSA-N ethyl 2-(diethoxyphosphoryloxymethyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COP(=O)(OCC)OCC)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O OFWQMEIAVINULN-UHFFFAOYSA-N 0.000 description 1
WDPODKMALKHKFF-UHFFFAOYSA-N ethyl 2-[(4-aminobenzoyl)oxymethyl]-5-(2-amino-4,5-dimethoxybenzoyl)triazole-4-carboxylate Chemical compound N1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)C(C(=O)OCC)=NN1COC(=O)C1=CC=C(N)C=C1 WDPODKMALKHKFF-UHFFFAOYSA-N 0.000 description 1
HYQOKOHTDDAMMI-UHFFFAOYSA-N ethyl 2-[1-(1,3-diethoxypropan-2-yloxycarbonyloxy)-2-methylpropyl]-5-(3,4-dimethoxybenzoyl)triazole-4-carboxylate Chemical compound CCOCC(COCC)OC(=O)OC(C(C)C)N1N=C(C(=O)OCC)C(C(=O)C=2C=C(OC)C(OC)=CC=2)=N1 HYQOKOHTDDAMMI-UHFFFAOYSA-N 0.000 description 1
UVEPRDADPAKTSE-UHFFFAOYSA-N ethyl 2-[1-(1,3-diethoxypropan-2-yloxycarbonyloxy)-2-methylpropyl]-5-(4,5-dimethoxy-2-nitrobenzoyl)triazole-4-carboxylate Chemical compound CCOCC(COCC)OC(=O)OC(C(C)C)N1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 UVEPRDADPAKTSE-UHFFFAOYSA-N 0.000 description 1
DQJBEYQDAGBISH-UHFFFAOYSA-N ethyl 2-[1-(1,3-diethoxypropan-2-yloxycarbonyloxy)-2-methylpropyl]-5-(4-methoxy-3-propan-2-yloxybenzoyl)triazole-4-carboxylate Chemical compound CCOCC(COCC)OC(=O)OC(C(C)C)N1N=C(C(=O)OCC)C(C(=O)C=2C=C(OC(C)C)C(OC)=CC=2)=N1 DQJBEYQDAGBISH-UHFFFAOYSA-N 0.000 description 1
WXFQMQWBEXMWOA-UHFFFAOYSA-N ethyl 4-(3,4-dimethoxyphenyl)-4-oxobut-2-enoate Chemical compound CCOC(=O)C=CC(=O)C1=CC=C(OC)C(OC)=C1 WXFQMQWBEXMWOA-UHFFFAOYSA-N 0.000 description 1
HRKQNGUQJKPAIB-UHFFFAOYSA-N ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxobut-2-enoate Chemical compound CCOC(=O)C=CC(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O HRKQNGUQJKPAIB-UHFFFAOYSA-N 0.000 description 1
GGXHUOFQQHNZOK-UHFFFAOYSA-N ethyl 4-(4-methoxy-2-nitro-5-propan-2-yloxyphenyl)-4-oxobut-2-ynoate Chemical compound CCOC(=O)C#CC(=O)C1=CC(OC(C)C)=C(OC)C=C1[N+]([O-])=O GGXHUOFQQHNZOK-UHFFFAOYSA-N 0.000 description 1
ASEYTPDDGDRESF-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(1-chloroethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(C)Cl)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N ASEYTPDDGDRESF-UHFFFAOYSA-N 0.000 description 1
ARCOCRHVMWBEIH-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(2-methyl-1-propan-2-yloxycarbonyloxypropyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(OC(=O)OC(C)C)C(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N ARCOCRHVMWBEIH-UHFFFAOYSA-N 0.000 description 1
PCVPTZNGKIUBTK-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(3-methoxypentan-3-yl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(CC)(CC)OC)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N PCVPTZNGKIUBTK-UHFFFAOYSA-N 0.000 description 1
QDUXMJNBUIHRNM-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(4-chlorobutanoyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)CCCCl)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N QDUXMJNBUIHRNM-UHFFFAOYSA-N 0.000 description 1
FQWJUZUFUOPTIL-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(benzoyloxymethyl)triazole-4-carboxylate Chemical compound N1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)C(C(=O)OCC)=NN1COC(=O)C1=CC=CC=C1 FQWJUZUFUOPTIL-UHFFFAOYSA-N 0.000 description 1
PYOWQJDGMJGIAZ-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-(propan-2-yloxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)OC(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1N PYOWQJDGMJGIAZ-UHFFFAOYSA-N 0.000 description 1
YLOJPYNYPUUTCN-UHFFFAOYSA-N ethyl 5-(2-amino-4,5-dimethoxybenzoyl)-2-[[2-(4-methoxyphenyl)acetyl]oxymethyl]triazole-4-carboxylate Chemical compound N1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)N)C(C(=O)OCC)=NN1COC(=O)CC1=CC=C(OC)C=C1 YLOJPYNYPUUTCN-UHFFFAOYSA-N 0.000 description 1
BCCIDBQPLKZQSC-UHFFFAOYSA-N ethyl 5-(2-amino-4-methoxy-5-propan-2-yloxybenzoyl)-2-(2-methyl-1-propan-2-yloxycarbonyloxypropyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(OC(=O)OC(C)C)C(C)C)N=C1C(=O)C1=CC(OC(C)C)=C(OC)C=C1N BCCIDBQPLKZQSC-UHFFFAOYSA-N 0.000 description 1
HTYTXAGPUTZLEU-UHFFFAOYSA-N ethyl 5-(2-amino-4-methoxy-5-propan-2-yloxybenzoyl)-2-[1-(1,3-diethoxypropan-2-yloxycarbonyloxy)-2-methylpropyl]triazole-4-carboxylate Chemical compound CCOCC(COCC)OC(=O)OC(C(C)C)N1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC(C)C)C=2)N)=N1 HTYTXAGPUTZLEU-UHFFFAOYSA-N 0.000 description 1
HFLJBGRYKIVLHA-UHFFFAOYSA-N ethyl 5-(3,4-dimethoxybenzoyl)-1-[(4-methoxyphenyl)methyl]triazole-4-carboxylate Chemical compound C=1C=C(OC)C(OC)=CC=1C(=O)C1=C(C(=O)OCC)N=NN1CC1=CC=C(OC)C=C1 HFLJBGRYKIVLHA-UHFFFAOYSA-N 0.000 description 1
CPDZQJAZWCFEBD-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(2-methyl-1-propan-2-yloxycarbonyloxypropyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(OC(=O)OC(C)C)C(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O CPDZQJAZWCFEBD-UHFFFAOYSA-N 0.000 description 1
JPTAPOGSMWRIPY-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(2-methylpropoxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)OCC(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O JPTAPOGSMWRIPY-UHFFFAOYSA-N 0.000 description 1
QTPQKXMSCLOOFZ-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(ethoxymethyl)triazole-4-carboxylate Chemical compound CCOCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 QTPQKXMSCLOOFZ-UHFFFAOYSA-N 0.000 description 1
NEABHENBWMHAHJ-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(hexoxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCCCCCOC(=O)OCN1N=C(C(=O)OCC)C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)=N1 NEABHENBWMHAHJ-UHFFFAOYSA-N 0.000 description 1
KNNUIBNXACNTHF-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-(propan-2-yloxycarbonyloxymethyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(COC(=O)OC(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O KNNUIBNXACNTHF-UHFFFAOYSA-N 0.000 description 1
JOSHSKKQDYMEDW-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-[1-(1h-imidazole-2-carbonyloxy)propyl]triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(CC)OC(=O)C=2NC=CN=2)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O JOSHSKKQDYMEDW-UHFFFAOYSA-N 0.000 description 1
XHVAKIOSOUSFIQ-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-[1-[2-(2-methoxyethoxy)ethoxycarbonyloxy]-2-methylpropyl]triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(OC(=O)OCCOCCOC)C(C)C)N=C1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O XHVAKIOSOUSFIQ-UHFFFAOYSA-N 0.000 description 1
GYWJDCDXOAITJZ-UHFFFAOYSA-N ethyl 5-(4,5-dimethoxy-2-nitrobenzoyl)-2-[[2-(4-methoxyphenyl)acetyl]oxymethyl]triazole-4-carboxylate Chemical compound N1=C(C(=O)C=2C(=CC(OC)=C(OC)C=2)[N+]([O-])=O)C(C(=O)OCC)=NN1COC(=O)CC1=CC=C(OC)C=C1 GYWJDCDXOAITJZ-UHFFFAOYSA-N 0.000 description 1
HNCAOZXLNLYZHW-UHFFFAOYSA-N ethyl 5-(4-methoxy-2-nitro-5-propan-2-yloxybenzoyl)-2h-triazole-4-carboxylate Chemical compound N1=NNC(C(=O)C=2C(=CC(OC)=C(OC(C)C)C=2)[N+]([O-])=O)=C1C(=O)OCC HNCAOZXLNLYZHW-UHFFFAOYSA-N 0.000 description 1
JOOVEFZUMDHLFB-UHFFFAOYSA-N ethyl 5-(4-methoxy-3-propan-2-yloxybenzoyl)-2-(2-methyl-1-propan-2-yloxycarbonyloxypropyl)triazole-4-carboxylate Chemical compound CCOC(=O)C1=NN(C(OC(=O)OC(C)C)C(C)C)N=C1C(=O)C1=CC=C(OC)C(OC(C)C)=C1 JOOVEFZUMDHLFB-UHFFFAOYSA-N 0.000 description 1
VVFQKXBDILRLIL-UHFFFAOYSA-N ethyl 5-(4-methoxy-3-propan-2-yloxybenzoyl)-2h-triazole-4-carboxylate Chemical compound N1=NNC(C(=O)C=2C=C(OC(C)C)C(OC)=CC=2)=C1C(=O)OCC VVFQKXBDILRLIL-UHFFFAOYSA-N 0.000 description 1
HKKZLDQMWRNXOW-UHFFFAOYSA-N ethyl 5-[(4,5-dimethoxy-2-nitrophenyl)-hydroxymethyl]-1-[(4-methoxyphenyl)methyl]triazole-4-carboxylate Chemical compound C=1C(OC)=C(OC)C=C([N+]([O-])=O)C=1C(O)C1=C(C(=O)OCC)N=NN1CC1=CC=C(OC)C=C1 HKKZLDQMWRNXOW-UHFFFAOYSA-N 0.000 description 1
BGCXLCFAOUGMKG-UHFFFAOYSA-N ethyl 5-[hydroxy-(4-methoxy-2-nitro-5-propan-2-yloxyphenyl)methyl]-1-[(4-methoxyphenyl)methyl]triazole-4-carboxylate Chemical compound C=1C(OC(C)C)=C(OC)C=C([N+]([O-])=O)C=1C(O)C1=C(C(=O)OCC)N=NN1CC1=CC=C(OC)C=C1 BGCXLCFAOUGMKG-UHFFFAOYSA-N 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000003889 eye drop Substances 0.000 description 1
229940012356 eye drops Drugs 0.000 description 1
238000000434 field desorption mass spectrometry Methods 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
210000001035 gastrointestinal tract Anatomy 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
230000002140 halogenating effect Effects 0.000 description 1
ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 1
KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 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
239000012433 hydrogen halide Substances 0.000 description 1
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230000036046 immunoreaction Effects 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
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208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
229910052500 inorganic mineral Inorganic materials 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
238000006317 isomerization reaction Methods 0.000 description 1
150000007517 lewis acids Chemical class 0.000 description 1
239000007788 liquid Substances 0.000 description 1
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239000000314 lubricant Substances 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
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RHGZVXXMXLZIJI-UHFFFAOYSA-N methyl 4-(3,4-dimethoxybenzoyl)-3-[(4-methoxyphenyl)methyl]-1,2-dihydrotriazole-5-carboxylate Chemical compound N1NC(C(=O)OC)=C(C(=O)C=2C=C(OC)C(OC)=CC=2)N1CC1=CC=C(OC)C=C1 RHGZVXXMXLZIJI-UHFFFAOYSA-N 0.000 description 1
HWFBZCHUTWPZIH-UHFFFAOYSA-N methyl 4-(3,4-dimethoxyphenyl)-4-oxobut-2-enoate Chemical compound COC(=O)C=CC(=O)C1=CC=C(OC)C(OC)=C1 HWFBZCHUTWPZIH-UHFFFAOYSA-N 0.000 description 1
UDPCFPDALSEQFD-UHFFFAOYSA-N methyl 5-(3,4-dimethoxybenzoyl)-1-[(4-methoxyphenyl)methyl]triazole-4-carboxylate Chemical compound C=1C=C(OC)C(OC)=CC=1C(=O)C1=C(C(=O)OC)N=NN1CC1=CC=C(OC)C=C1 UDPCFPDALSEQFD-UHFFFAOYSA-N 0.000 description 1
DFYCWORLSDLMDV-UHFFFAOYSA-N methyl 5-(3,4-dimethoxybenzoyl)-2h-triazole-4-carboxylate Chemical compound N1=NNC(C(=O)C=2C=C(OC)C(OC)=CC=2)=C1C(=O)OC DFYCWORLSDLMDV-UHFFFAOYSA-N 0.000 description 1
NJEIEZKKLUYBGX-UHFFFAOYSA-N methyl 5-(4-methoxy-3-propan-2-yloxybenzoyl)-2h-triazole-4-carboxylate Chemical compound N1=NNC(C(=O)C=2C=C(OC(C)C)C(OC)=CC=2)=C1C(=O)OC NJEIEZKKLUYBGX-UHFFFAOYSA-N 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000011707 mineral Substances 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 description 1
210000004400 mucous membrane Anatomy 0.000 description 1
DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
GINQYTLDMNFGQP-UHFFFAOYSA-N n,n-dimethylformamide;methylsulfinylmethane Chemical compound CS(C)=O.CN(C)C=O GINQYTLDMNFGQP-UHFFFAOYSA-N 0.000 description 1
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
239000007923 nasal drop Substances 0.000 description 1
229940100662 nasal drops Drugs 0.000 description 1
229910052759 nickel Inorganic materials 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
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150000002902 organometallic compounds Chemical class 0.000 description 1
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125000004430 oxygen atom Chemical group O* 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
150000003016 phosphoric acids Chemical class 0.000 description 1
125000005544 phthalimido group Chemical group 0.000 description 1
230000036470 plasma concentration Effects 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
229910000105 potassium hydride Inorganic materials 0.000 description 1
230000002265 prevention Effects 0.000 description 1
238000012545 processing Methods 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
150000003222 pyridines Chemical class 0.000 description 1
ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
238000007873 sieving Methods 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000007787 solid Substances 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
238000013268 sustained release Methods 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000006188 syrup Substances 0.000 description 1
239000000454 talc Substances 0.000 description 1
229910052623 talc Inorganic materials 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000011701 zinc Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—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
- A61P11/06—Antiasthmatics
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- 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)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Pulmonology (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Engineering & Computer Science (AREA)
Molecular Biology (AREA)
Animal Behavior & Ethology (AREA)
Bioinformatics & Cheminformatics (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Biochemistry (AREA)
Immunology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

SK425-2000A 1997-09-29 1998-09-29 Tricyklické triazolobenzazepínové deriváty, spôsob ich prípravy a antialergické prostriedky SK283869B6 (sk)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
JP26461197		1997-09-29
JP5206398		1998-03-04
PCT/JP1998/004363 WO1999016770A1 (fr)	1997-09-29	1998-09-29	Derives de triazolobenzazepine tricyclique, leur procede de production et antiallergique

Publications (2)

Publication Number	Publication Date
SK4252000A3 SK4252000A3 (en)	2000-10-09
SK283869B6 true SK283869B6 (sk)	2004-03-02

Family

ID=26392670

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK425-2000A SK283869B6 (sk)	1997-09-29	1998-09-29	Tricyklické triazolobenzazepínové deriváty, spôsob ich prípravy a antialergické prostriedky

Country Status (25)

Country	Link
US (3)	US6372735B1 (fr)
EP (1)	EP1026167B1 (fr)
JP (1)	JP3188482B2 (fr)
KR (1)	KR100389140B1 (fr)
CN (2)	CN1155599C (fr)
AT (1)	ATE233764T1 (fr)
AU (1)	AU744636B2 (fr)
BR (1)	BR9814055B1 (fr)
CA (1)	CA2305307C (fr)
DE (1)	DE69811930T2 (fr)
DK (1)	DK1026167T3 (fr)
ES (1)	ES2191963T3 (fr)
HK (1)	HK1032782A1 (fr)
HU (1)	HUP0004020A3 (fr)
ID (1)	ID24101A (fr)
IL (1)	IL135303A0 (fr)
NO (2)	NO319542B1 (fr)
NZ (1)	NZ503601A (fr)
PL (1)	PL339544A1 (fr)
PT (1)	PT1026167E (fr)
RU (1)	RU2198885C2 (fr)
SK (1)	SK283869B6 (fr)
TR (1)	TR200000808T2 (fr)
TW (1)	TW510902B (fr)
WO (1)	WO1999016770A1 (fr)

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AU2002367110A1 (en) *	2001-12-26	2003-07-15	Meiji Seika Kaisha, Ltd.	Amorphous substance of tricyclic triazolobenzazepine derivative
DE60313124T2 (de)	2002-02-01	2007-08-23	Meiji Seika Kaisha Ltd.	Verfahren zur herstellung einer 1,2,3-triazolverbindung
CA2490972C (fr)	2002-07-09	2012-05-29	Bristol-Myers Squibb Company	Derives heterocycliques substitues utiles comme agents antidiabetique et anti-obesite et procede correspondant
EP1656368A4 (fr)	2002-07-09	2009-08-26	Bristol Myers Squibb Co	Derives heterocycliqes substitues utiles comme agents antidiabetique et antiabesite et leur procede de fabrication
JPWO2004113343A1 (ja) *	2003-06-19	2006-08-31	明治製菓株式会社	三環性トリアゾロベンゾアゼピン誘導体の新規結晶性物質
US20070167402A1 (en) *	2003-06-20	2007-07-19	Meiji Seika Kaisha, Ltd.	Product of coprecipitation of sparingly soluble substance and water-soluble polymer and process for producing the same
KR101792651B1 (ko)	2004-05-14	2017-11-20	밀레니엄 파머슈티컬스 인코퍼레이티드	아우로라 키나아제의 억제에 의해 유사분열 진행을 억제하기 위한 화합물 및 그 화합물을 포함하는 약학적 조성물
MX2008011178A (es) *	2006-03-02	2008-09-25	Meiji Seika Kaisha	Agente profilàctico o terapèutico para enfermedad oftàlmica alèrgica o enfermedad nasal alèrgica, que comprende derivado tricìclico de triazolobenzacepina.
JP5588172B2 (ja) *	2006-09-25	2014-09-10	フォルシュングフェアブントベルリンエー．ファウ．	プロリンが豊富なペプチドの構造的模倣薬およびその医薬用途
CL2007003244A1 (es)	2006-11-16	2008-04-04	Millennium Pharm Inc	Compuestos derivados de pirimido[5,4-d][2]benzazepina; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento del cancer.
ES2360461T3 (es)	2007-12-18	2011-06-06	Meiji Seika Kaisha Ltd.	Agente preventivo o terapéutico para enfermedad inflamatoria del intestino.
CN102264368B (zh)	2008-12-22	2014-09-10	米伦纽姆医药公司	极光激酶抑制剂与抗cd20抗体的组合
JO3635B1 (ar)	2009-05-18	2020-08-27	Millennium Pharm Inc	مركبات صيدلانية صلبة وطرق لانتاجها
JP6106437B2 (ja) *	2010-01-07	2017-03-29	アルカーメスファーマアイルランドリミテッド	複素芳香族化合物のプロドラッグ
CN102770024A (zh)	2010-02-19	2012-11-07	米伦纽姆医药公司	4-{[9-氯-7-(2-氟-6-甲氧基苯基)-5h-嘧啶并[5,4-d][2]苯并氮杂卓-2基]氨基}-2-甲氧基苯甲酸钠的结晶形式
US20130303519A1 (en)	2012-03-20	2013-11-14	Millennium Pharmaceuticals, Inc.	Methods of treating cancer using aurora kinase inhibitors
CN105209042B (zh)	2013-03-22	2019-03-08	米伦纽姆医药公司	催化性mtorc 1/2抑制剂与选择性极光a激酶抑制剂的组合
WO2017015316A1 (fr)	2015-07-21	2017-01-26	Millennium Pharmaceuticals, Inc.	Administration d'inhibiteur de kinase aurora et d'agents chimiothérapeutiques

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Publication number	Priority date	Publication date	Assignee	Title
EP0686636B1 (fr)	1993-12-28	2001-04-04	Meiji Seika Kabushiki Kaisha	Derives tricycliques de benzazepine et benzothiazepine
EP0834512A4 (fr) *	1995-06-15	2001-08-22	Meiji Seika Kaisha	Composes de benzazepine tricyclique
EP0888350A1 (fr) *	1996-03-08	1999-01-07	Zeneca Limited	Principes actifs neurologiques derives d'azolobenzazepine
US20070059533A1 (en) *	2005-09-12	2007-03-15	Burdette Steven R	Thermal reflow of glass and fused silica body

1998
- 1998-09-29 CN CNB98810735XA patent/CN1155599C/zh not_active Expired - Fee Related
- 1998-09-29 AT AT98944289T patent/ATE233764T1/de active
- 1998-09-29 CA CA002305307A patent/CA2305307C/fr not_active Expired - Fee Related
- 1998-09-29 SK SK425-2000A patent/SK283869B6/sk unknown
- 1998-09-29 DK DK98944289T patent/DK1026167T3/da active
- 1998-09-29 ES ES98944289T patent/ES2191963T3/es not_active Expired - Lifetime
- 1998-09-29 DE DE69811930T patent/DE69811930T2/de not_active Expired - Lifetime
- 1998-09-29 PT PT98944289T patent/PT1026167E/pt unknown
- 1998-09-29 JP JP51996999A patent/JP3188482B2/ja not_active Expired - Fee Related
- 1998-09-29 HU HU0004020A patent/HUP0004020A3/hu unknown
- 1998-09-29 CN CNB2003101047539A patent/CN1312135C/zh not_active Expired - Fee Related
- 1998-09-29 KR KR10-2000-7003362A patent/KR100389140B1/ko not_active IP Right Cessation
- 1998-09-29 BR BRPI9814055-8A patent/BR9814055B1/pt not_active IP Right Cessation
- 1998-09-29 TR TR2000/00808T patent/TR200000808T2/xx unknown
- 1998-09-29 IL IL13530398A patent/IL135303A0/xx unknown
- 1998-09-29 TW TW087116198A patent/TW510902B/zh not_active IP Right Cessation
- 1998-09-29 US US09/509,494 patent/US6372735B1/en not_active Expired - Lifetime
- 1998-09-29 ID IDW20000808A patent/ID24101A/id unknown
- 1998-09-29 WO PCT/JP1998/004363 patent/WO1999016770A1/fr not_active Application Discontinuation
- 1998-09-29 EP EP98944289A patent/EP1026167B1/fr not_active Expired - Lifetime
- 1998-09-29 RU RU2000111517/04A patent/RU2198885C2/ru not_active IP Right Cessation
- 1998-09-29 PL PL98339544A patent/PL339544A1/xx unknown
- 1998-09-29 AU AU91869/98A patent/AU744636B2/en not_active Ceased
- 1998-09-29 NZ NZ503601A patent/NZ503601A/en unknown
2000
- 2000-03-23 NO NO20001500A patent/NO319542B1/no unknown
2001
- 2001-05-22 HK HK01103502A patent/HK1032782A1/xx not_active IP Right Cessation
2002
- 2002-02-13 US US10/073,326 patent/US7022860B2/en not_active Expired - Fee Related
2004
- 2004-09-08 NO NO20043765A patent/NO20043765L/no not_active Application Discontinuation
2005
- 2005-11-09 US US11/269,828 patent/US7238812B2/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
DE69811930D1 (de)	2003-04-10
SK4252000A3 (en)	2000-10-09
US7022860B2 (en)	2006-04-04
US20020137739A1 (en)	2002-09-26
DE69811930T2 (de)	2003-12-18
CA2305307A1 (fr)	1999-04-08
ID24101A (id)	2000-07-06
WO1999016770A1 (fr)	1999-04-08
RU2198885C2 (ru)	2003-02-20
NO20001500L (no)	2000-05-18
NO20001500D0 (no)	2000-03-23
NO319542B1 (no)	2005-08-29
BR9814055B1 (pt)	2009-05-05
AU744636B2 (en)	2002-02-28
US20060074074A1 (en)	2006-04-06
NO20043765L (no)	2000-05-18
US6372735B1 (en)	2002-04-16
NZ503601A (en)	2002-02-01
HK1032782A1 (en)	2002-08-30
HUP0004020A2 (hu)	2001-09-28
PL339544A1 (en)	2000-12-18
HUP0004020A3 (en)	2002-12-28
TR200000808T2 (tr)	2000-08-21
ES2191963T3 (es)	2003-09-16
AU9186998A (en)	1999-04-23
TW510902B (en)	2002-11-21
CN1312135C (zh)	2007-04-25
EP1026167B1 (fr)	2003-03-05
EP1026167A4 (fr)	2001-07-11
CN1278262A (zh)	2000-12-27
CN1155599C (zh)	2004-06-30
US7238812B2 (en)	2007-07-03
CN1523019A (zh)	2004-08-25
EP1026167A1 (fr)	2000-08-09
JP3188482B2 (ja)	2001-07-16
CA2305307C (fr)	2004-11-30
KR100389140B1 (ko)	2003-06-25
DK1026167T3 (da)	2003-05-26
KR20010030784A (ko)	2001-04-16
ATE233764T1 (de)	2003-03-15
PT1026167E (pt)	2003-07-31
IL135303A0 (en)	2001-05-20
BR9814055A (pt)	2000-09-26

Publication	Publication Date	Title
US6372735B1 (en)	2002-04-16	Tricyclic triazolobenzazepine derivatives, process for producing the same, and antiallergic
SK281941B6 (sk)	2001-09-11	Deriváty kyseliny indol-2-karboxylovej, ich použitie, spôsob ich prípravy a farmaceutický prípravok s ich obsahom
EP2495243B1 (fr)	2016-12-28	Nouveau dérivé de 5-fluorouracile
WO1995008542A1 (fr)	1995-03-30	Inhibiteur de la farnesyl-transferase
IE912329A1 (en)	1992-01-15	9-purinyl phosphonic acid derivatives
US4816582A (en)	1989-03-28	Antimicrobial 2-oxo-1-azetidinesulphonic acids
DE102007061766A1 (de)	2009-06-25	4-(4-Cyano-2-thioaryl)-dihydropyrimidinone und ihre Verwendung
EP0695755A1 (fr)	1996-02-07	Pyrrolocarbazoles
WO2015150364A1 (fr)	2015-10-08	Acides benzotriazinonebutyriques substitués et leur utilisation
WO2002094829A1 (fr)	2002-11-28	Compose de carbapenem
FR2687677A1 (fr)	1993-08-27	Nouveaux derives de polyazaindenes antagonistes des recepteurs a l'angiotensine ii ; leurs procedes de preparation, compositions pharmaceutiques les contenant.
DE60027461T2 (de)	2006-09-28	Megluminsalz einer spezifischen Chinolinsäure-Verbindung mit NMDA Rezeptor-Aktivität
CN100387580C (zh)	2008-05-14	三环三唑并苯并氮杂䓬衍生物、用于制备该衍生物的方法和抗变态反应剂
DE69216124T2 (de)	1997-05-22	Chinon-Derivate
EP0583136B1 (fr)	1997-10-08	Composés pipéridino-3,4-dihydrocarbostyryl pour le traitement de désordres ischémiques
SK8642002A3 (en)	2002-12-03	Farnesyl transferase inhibitors, process for their preparation and pharmaceutical compositions containing them
MXPA00003047A (en)	2001-05-07	Tricyclic triazolobenzazepine derivatives, process for producing the same, and antiallergic
CZ20001145A3 (cs)	2000-10-11	Tricyklické triazolobenzazepinové deriváty
IE61325B1 (en)	1994-11-02	Crystalline salts of [3s(z)]-2[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1 -(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene] amino]oxy]acetic acid
WO1996032394A1 (fr)	1996-10-17	DERIVES DE PYRAZOLO[1,5-a]PYRIMIDINE
DD234005A5 (de)	1986-03-19	Verfahren zur herstellung neuer 1,2,4-triazacycloalkadienderivate
JP3739916B2 (ja)	2006-01-25	サイトカイン産生阻害剤
US5475000A (en)	1995-12-12	3-(substituted tetrazolyl)-4-oxo-4H-pyrido-[1,2-a]pyrimidines, salts thereof, pharmaceutical compositions containing them and process for preparing same
WO2004002956A2 (fr)	2004-01-08	Synthese asymetrique d'amino-pyrrolidinones et amino-pyrrolidinone cristallin a base libre
EP0646584A1 (fr)	1995-04-05	Derive de pyrazolotriazole