CN101239970B - 联苯衍生物 - Google Patents
联苯衍生物 Download PDFInfo
- Publication number
- CN101239970B CN101239970B CN2008100741592A CN200810074159A CN101239970B CN 101239970 B CN101239970 B CN 101239970B CN 2008100741592 A CN2008100741592 A CN 2008100741592A CN 200810074159 A CN200810074159 A CN 200810074159A CN 101239970 B CN101239970 B CN 101239970B
- Authority
- CN
- China
- Prior art keywords
- subunit
- group
- compound
- benzene
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 107
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 12
- 208000006673 asthma Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 332
- 238000002360 preparation method Methods 0.000 claims description 257
- 229910052739 hydrogen Inorganic materials 0.000 claims description 102
- 125000000217 alkyl group Chemical group 0.000 claims description 99
- 239000001257 hydrogen Substances 0.000 claims description 99
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 73
- 239000008194 pharmaceutical composition Substances 0.000 claims description 46
- 238000011282 treatment Methods 0.000 claims description 42
- 125000001118 alkylidene group Chemical group 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000004429 atom Chemical group 0.000 claims description 17
- 201000008827 tuberculosis Diseases 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 9
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000003968 arylidene group Chemical group [H]C(c)=* 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract description 45
- 239000000048 adrenergic agonist Substances 0.000 abstract description 23
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 abstract description 22
- 239000003149 muscarinic antagonist Substances 0.000 abstract description 22
- 229940126157 adrenergic receptor agonist Drugs 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 18
- 102100039705 Beta-2 adrenergic receptor Human genes 0.000 abstract description 2
- 208000019693 Lung disease Diseases 0.000 abstract description 2
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 262
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
- 239000000203 mixture Substances 0.000 description 203
- 239000011541 reaction mixture Substances 0.000 description 170
- 238000003756 stirring Methods 0.000 description 167
- 239000000047 product Substances 0.000 description 159
- 239000000243 solution Substances 0.000 description 155
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
- 230000002829 reductive effect Effects 0.000 description 139
- -1 heterocyclic radical Chemical class 0.000 description 125
- 239000002904 solvent Substances 0.000 description 114
- 239000002253 acid Substances 0.000 description 109
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 103
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 95
- 238000006243 chemical reaction Methods 0.000 description 95
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 90
- 239000002585 base Substances 0.000 description 89
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 87
- 238000000034 method Methods 0.000 description 86
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 78
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 76
- 239000007787 solid Substances 0.000 description 76
- 238000005406 washing Methods 0.000 description 73
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 68
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 66
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 61
- 238000004128 high performance liquid chromatography Methods 0.000 description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 58
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 239000012044 organic layer Substances 0.000 description 51
- 229910052799 carbon Inorganic materials 0.000 description 48
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 48
- 239000007864 aqueous solution Substances 0.000 description 47
- 239000003795 chemical substances by application Substances 0.000 description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 46
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 229910052757 nitrogen Inorganic materials 0.000 description 40
- 229910052760 oxygen Inorganic materials 0.000 description 40
- 239000001301 oxygen Substances 0.000 description 36
- 229910052763 palladium Inorganic materials 0.000 description 33
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical group CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 239000010410 layer Substances 0.000 description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 29
- 238000001914 filtration Methods 0.000 description 29
- 239000011734 sodium Substances 0.000 description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 27
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 150000002431 hydrogen Chemical class 0.000 description 26
- 239000012141 concentrate Substances 0.000 description 25
- 235000008504 concentrate Nutrition 0.000 description 25
- 238000010438 heat treatment Methods 0.000 description 25
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 24
- 229910052794 bromium Inorganic materials 0.000 description 24
- 238000010790 dilution Methods 0.000 description 24
- 239000012895 dilution Substances 0.000 description 24
- 238000000746 purification Methods 0.000 description 24
- 125000003386 piperidinyl group Chemical group 0.000 description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 22
- 150000001721 carbon Chemical group 0.000 description 22
- 125000001072 heteroaryl group Chemical group 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 125000001400 nonyl group Chemical group [H]C([*])([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])[H] 0.000 description 21
- 239000003921 oil Substances 0.000 description 21
- 150000003254 radicals Chemical group 0.000 description 21
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 21
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 20
- 238000001035 drying Methods 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 19
- 239000012279 sodium borohydride Substances 0.000 description 19
- 229910000033 sodium borohydride Inorganic materials 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 229910052801 chlorine Inorganic materials 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 230000001737 promoting effect Effects 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 15
- 230000000903 blocking effect Effects 0.000 description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- 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 14
- 239000012266 salt solution Substances 0.000 description 14
- 125000000304 alkynyl group Chemical group 0.000 description 13
- 239000002245 particle Substances 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000011737 fluorine Substances 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- 125000004450 alkenylene group Chemical group 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 238000011097 chromatography purification Methods 0.000 description 11
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 11
- 108060003345 Adrenergic Receptor Proteins 0.000 description 10
- 102000017910 Adrenergic receptor Human genes 0.000 description 10
- 150000004646 arylidenes Chemical group 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 229940071648 metered dose inhaler Drugs 0.000 description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- 238000005507 spraying Methods 0.000 description 10
- 125000002769 thiazolinyl group Chemical group 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 description 9
- 125000004419 alkynylene group Chemical group 0.000 description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 238000011160 research Methods 0.000 description 9
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000000556 agonist Substances 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- 239000003701 inert diluent Substances 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 238000006386 neutralization reaction Methods 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 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 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 238000010926 purge Methods 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 235000009518 sodium iodide Nutrition 0.000 description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 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 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000002294 steroidal antiinflammatory agent Substances 0.000 description 6
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 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 5
- 239000002552 dosage form Substances 0.000 description 5
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
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- DPLOGSUBQDREOU-UHFFFAOYSA-N tert-butyl n-(5-aminopentyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCN DPLOGSUBQDREOU-UHFFFAOYSA-N 0.000 description 1
- FMTUFNCQKOLKON-UHFFFAOYSA-N tert-butyl n-[(4-amino-3-chlorophenyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(N)C(Cl)=C1 FMTUFNCQKOLKON-UHFFFAOYSA-N 0.000 description 1
- UXWQXBSQQHAGMG-UHFFFAOYSA-N tert-butyl n-[(4-aminophenyl)methyl]carbamate Chemical compound CC(C)(C)OC(=O)NCC1=CC=C(N)C=C1 UXWQXBSQQHAGMG-UHFFFAOYSA-N 0.000 description 1
- 150000003866 tertiary ammonium salts Chemical class 0.000 description 1
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- 239000010496 thistle oil Substances 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical group O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
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- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
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- ZRQJSWOPZOITNN-UHFFFAOYSA-N urea;dihydrochloride Chemical compound Cl.Cl.NC(N)=O ZRQJSWOPZOITNN-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims (12)
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US44784303P | 2003-02-14 | 2003-02-14 | |
US60/447,843 | 2003-02-14 | ||
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US60/467,035 | 2003-05-01 |
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CNB2004800065284A Division CN100378092C (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
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CN101239970A CN101239970A (zh) | 2008-08-13 |
CN101239970B true CN101239970B (zh) | 2011-07-20 |
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ID=36703992
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CN2008100741605A Expired - Lifetime CN101239971B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
CN2008100741592A Expired - Lifetime CN101239970B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
CN2008100741569A Expired - Lifetime CN101239968B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
CN2008100741573A Expired - Lifetime CN101239969B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
CNB2004800065284A Expired - Lifetime CN100378092C (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
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CN2008100741605A Expired - Lifetime CN101239971B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
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CN2008100741569A Expired - Lifetime CN101239968B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
CN2008100741573A Expired - Lifetime CN101239969B (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
CNB2004800065284A Expired - Lifetime CN100378092C (zh) | 2003-02-14 | 2004-02-13 | 联苯衍生物 |
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CN (5) | CN101239971B (zh) |
AR (1) | AR098785A2 (zh) |
ES (1) | ES2351392T3 (zh) |
ZA (1) | ZA200506215B (zh) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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US8263623B2 (en) * | 2008-07-11 | 2012-09-11 | Pfizer Inc. | Triazol derivatives useful for the treatment of diseases |
CN102395563B (zh) * | 2009-04-14 | 2015-05-20 | 葛兰素集团有限公司 | 联苯-2-基氨基甲酸酯的制备方法 |
RU2543716C2 (ru) * | 2009-04-23 | 2015-03-10 | Тереванс Рэспирэйтори Кампани Эл Эл Си | Диамидные соединения, обладающие активностью антагониста мускаринового рецептора и активностью агониста в2 адренергического рецептора |
AU2010242646A1 (en) * | 2009-04-30 | 2011-11-03 | Teijin Pharma Limited | Quaternary ammonium salt compound |
CN104876854B (zh) * | 2015-04-16 | 2017-03-01 | 御盛隆堂药业有限责任公司 | 羟基乙酸酯衍生物及其用途 |
WO2016180349A1 (zh) * | 2015-05-14 | 2016-11-17 | 四川海思科制药有限公司 | 具有β2受体激动及M受体拮抗活性的联苯衍生物及其在医药上的用途 |
CN107074833B (zh) * | 2015-07-21 | 2021-05-25 | 四川海思科制药有限公司 | 具有β2受体激动及M3受体拮抗活性的苯并环衍生物及其在医药上的用途 |
US20210205291A1 (en) * | 2016-01-22 | 2021-07-08 | Sichuan Haisco Pharmaceutical Co., Ltd. | Nitrogenous heterocyclic amide derivative, preparation method thereof, and pharmaceutical application |
WO2019015640A1 (zh) * | 2017-07-21 | 2019-01-24 | 四川海思科制药有限公司 | 一种氮杂环酰胺衍生物的盐、其晶型及其制备方法和用途 |
TW201907922A (zh) * | 2017-07-21 | 2019-03-01 | 大陸商四川海思科製藥有限公司 | 氮雜環醯胺衍生物之組合物及其製備方法 |
CN108794395B (zh) * | 2018-07-06 | 2021-04-20 | 大连理工大学 | 一种2-喹啉酮类化合物的制备方法 |
CN111423434A (zh) * | 2019-01-09 | 2020-07-17 | 四川海思科制药有限公司 | 一种碳酰胺衍生物及其制备方法 |
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US6541669B1 (en) * | 1998-06-08 | 2003-04-01 | Theravance, Inc. | β2-adrenergic receptor agonists |
UA73543C2 (uk) * | 1999-12-07 | 2005-08-15 | Тераванс, Інк. | Похідні сечовини, фармацевтична композиція та застосування похідного при приготуванні лікарського засобу для лікування захворювання, яке опосередковується мускариновим рецептором |
CA2392028C (en) * | 1999-12-07 | 2009-08-18 | Theravance, Inc. | Carbamate derivatives having muscarinic receptor antagonist activity |
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2004
- 2004-02-13 CN CN2008100741605A patent/CN101239971B/zh not_active Expired - Lifetime
- 2004-02-13 CN CN2008100741592A patent/CN101239970B/zh not_active Expired - Lifetime
- 2004-02-13 CN CN2008100741569A patent/CN101239968B/zh not_active Expired - Lifetime
- 2004-02-13 CN CN2008100741573A patent/CN101239969B/zh not_active Expired - Lifetime
- 2004-02-13 ES ES04711253T patent/ES2351392T3/es not_active Expired - Lifetime
- 2004-02-13 CN CNB2004800065284A patent/CN100378092C/zh not_active Expired - Lifetime
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2005
- 2005-08-03 ZA ZA200506215A patent/ZA200506215B/en unknown
-
2014
- 2014-12-17 AR ARP140104705A patent/AR098785A2/es not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CN101239968A (zh) | 2008-08-13 |
CN101239971A (zh) | 2008-08-13 |
CN100378092C (zh) | 2008-04-02 |
ZA200506215B (en) | 2006-06-28 |
CN101239968B (zh) | 2011-07-20 |
CN101239969A (zh) | 2008-08-13 |
AR098785A2 (es) | 2016-06-15 |
CN101239969B (zh) | 2011-07-20 |
ES2351392T3 (es) | 2011-02-03 |
CN101239971B (zh) | 2011-07-20 |
CN101239970A (zh) | 2008-08-13 |
CN1759108A (zh) | 2006-04-12 |
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