EA022358B1 - НОВЫЕ ПРОИЗВОДНЫЕ ЦИКЛОГЕКСИЛАМИНА, ОБЛАДАЮЩИЕ АГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ ПО ОТНОШЕНИЮ К β2 АДРЕНЕРГИЧЕСКОМУ РЕЦЕПТОРУ И АНТАГОНИСТИЧЕСКОЙ АКТИВНОСТЬЮ ПО ОТНОШЕНИЮ К M3 МУСКАРИНОВОМУ РЕЦЕПТОРУ - Google Patents

Info

Publication number

EA022358B1

EA022358B1 EA201201541A EA201201541A EA022358B1 EA 022358 B1 EA022358 B1 EA 022358B1 EA 201201541 A EA201201541 A EA 201201541A EA 201201541 A EA201201541 A EA 201201541A EA 022358 B1 EA022358 B1 EA 022358B1

Authority

EA

Eurasian Patent Office

Prior art keywords

amino

methyl

hydroxy

group

ethyl

Prior art date

2010-05-13

Links

• Espacenet
• Global Dossier
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• 229940121948 Muscarinic receptor antagonist Drugs 0.000 title claims abstract description 7
• 239000003149 muscarinic antagonist Substances 0.000 title claims abstract description 6
• 239000000048 adrenergic agonist Substances 0.000 title claims abstract description 5
• 230000000694 effects Effects 0.000 title claims description 28
• 150000003946 cyclohexylamines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 210
• 238000000034 method Methods 0.000 claims abstract description 44
• 238000002360 preparation method Methods 0.000 claims abstract description 29
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
• -1 8-hydroxy-2-oxo-1,2-dihydroquinolin-5yl Chemical group 0.000 claims description 524
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 382
• GUTQMBQKTSGBPQ-UHFFFAOYSA-N dithiophen-2-ylmethanone Chemical group C=1C=CSC=1C(=O)C1=CC=CS1 GUTQMBQKTSGBPQ-UHFFFAOYSA-N 0.000 claims description 283
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 226
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 204
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 192
• WIUHYQBOXHNHLG-UHFFFAOYSA-N acetic acid hydrofluoride Chemical compound F.C(C)(=O)O WIUHYQBOXHNHLG-UHFFFAOYSA-N 0.000 claims description 57
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 33
• 239000003814 drug Substances 0.000 claims description 32
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 27
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
• 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 claims description 23
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 23
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 125000001424 substituent group Chemical group 0.000 claims description 22
• 201000010099 disease Diseases 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 19
• 230000001575 pathological effect Effects 0.000 claims description 16
• 229910052801 chlorine Inorganic materials 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 14
• 125000001544 thienyl group Chemical group 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
• 229910052700 potassium Inorganic materials 0.000 claims description 13
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 12
• 208000006673 asthma Diseases 0.000 claims description 12
• 235000019253 formic acid Nutrition 0.000 claims description 12
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 11
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
• IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 10
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 10
• 229940049953 phenylacetate Drugs 0.000 claims description 10
• 239000012453 solvate Substances 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 9
• 239000000460 chlorine Substances 0.000 claims description 9
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 208000019693 Lung disease Diseases 0.000 claims description 8
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
• 208000010412 Glaucoma Diseases 0.000 claims description 7
• 206010061218 Inflammation Diseases 0.000 claims description 7
• 208000012902 Nervous system disease Diseases 0.000 claims description 7
• 230000004054 inflammatory process Effects 0.000 claims description 7
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
• 208000025966 Neurological disease Diseases 0.000 claims description 5
• 208000005107 Premature Birth Diseases 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• RWWDBINLIXRDCK-UHFFFAOYSA-N cyclohexyl 9-methylxanthene-9-carboxylate Chemical compound C1(CCCCC1)OC(=O)C1(C2=CC=CC=C2OC=2C=CC=CC1=2)C RWWDBINLIXRDCK-UHFFFAOYSA-N 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 229910052731 fluorine Inorganic materials 0.000 claims description 4
• 208000019622 heart disease Diseases 0.000 claims description 4
• 239000001301 oxygen Substances 0.000 claims description 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
• 206010036590 Premature baby Diseases 0.000 claims description 3
• 229940126157 adrenergic receptor agonist Drugs 0.000 claims description 3
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
• 230000000747 cardiac effect Effects 0.000 claims description 3
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
• 208000020446 Cardiac disease Diseases 0.000 claims description 2
• 230000005856 abnormality Effects 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 102100039705 Beta-2 adrenergic receptor Human genes 0.000 claims 2
• 125000004429 atom Chemical group 0.000 claims 2
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
• 241001122767 Theaceae Species 0.000 claims 1
• 125000003368 amide group Chemical group 0.000 claims 1
• 125000000753 cycloalkyl group Chemical group 0.000 claims 1
• 230000002496 gastric effect Effects 0.000 claims 1
• 230000009977 dual effect Effects 0.000 abstract description 5
• 230000008569 process Effects 0.000 abstract description 3
• 238000002644 respiratory therapy Methods 0.000 abstract 1
• 239000000543 intermediate Substances 0.000 description 490
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 177
• 239000000243 solution Substances 0.000 description 165
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 153
• PMDKYLLIOLFQPO-UHFFFAOYSA-N monocyclohexyl phthalate Chemical compound OC(=O)C1=CC=CC=C1C(=O)OC1CCCCC1 PMDKYLLIOLFQPO-UHFFFAOYSA-N 0.000 description 147
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 133
• 239000000203 mixture Substances 0.000 description 129
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 123
• 238000002474 experimental method Methods 0.000 description 110
• 239000007787 solid Substances 0.000 description 106
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 102
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 93
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
• 239000013058 crude material Substances 0.000 description 71
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 66
• 239000002904 solvent Substances 0.000 description 59
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 58
• 239000003921 oil Substances 0.000 description 55
• 235000019198 oils Nutrition 0.000 description 54
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
• 239000012267 brine Substances 0.000 description 40
• 238000000746 purification Methods 0.000 description 40
• 238000010898 silica gel chromatography Methods 0.000 description 40
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
• 230000002829 reductive effect Effects 0.000 description 39
• 238000005481 NMR spectroscopy Methods 0.000 description 37
• 230000015572 biosynthetic process Effects 0.000 description 36
• 238000004007 reversed phase HPLC Methods 0.000 description 35
• 238000003786 synthesis reaction Methods 0.000 description 34
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
• AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 29
• 239000012044 organic layer Substances 0.000 description 29
• 239000012230 colorless oil Substances 0.000 description 27
• 239000011541 reaction mixture Substances 0.000 description 26
• IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 25
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 24
• 239000000126 substance Substances 0.000 description 23
• 238000004440 column chromatography Methods 0.000 description 22
• 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 21
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• 229940079593 drug Drugs 0.000 description 21
• 238000003756 stirring Methods 0.000 description 21
• 239000000741 silica gel Substances 0.000 description 20
• 229910002027 silica gel Inorganic materials 0.000 description 20
• 235000017557 sodium bicarbonate Nutrition 0.000 description 20
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 19
• 239000000843 powder Substances 0.000 description 19
• 238000012360 testing method Methods 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 239000002775 capsule Substances 0.000 description 18
• 239000013067 intermediate product Substances 0.000 description 17
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 16
• 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 16
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
• 239000007858 starting material Substances 0.000 description 16
• 238000012545 processing Methods 0.000 description 15
• 239000004480 active ingredient Substances 0.000 description 14
• 230000001270 agonistic effect Effects 0.000 description 14
• 125000006239 protecting group Chemical group 0.000 description 14
• 229910052805 deuterium Inorganic materials 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 13
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 11
• AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 11
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 10
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 239000002253 acid Substances 0.000 description 10
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• OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 9
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• 239000001257 hydrogen Substances 0.000 description 9
• 239000008101 lactose Substances 0.000 description 9
• 229960001375 lactose Drugs 0.000 description 9
• 239000007788 liquid Substances 0.000 description 9
• 239000012280 lithium aluminium hydride Substances 0.000 description 9
• BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 8
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• 238000007792 addition Methods 0.000 description 8
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• 239000003246 corticosteroid Substances 0.000 description 8
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• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
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• 239000000047 product Substances 0.000 description 8
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• 229940124597 therapeutic agent Drugs 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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• MFIGJRRHGZYPDD-UHFFFAOYSA-N n,n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)NCCNC(C)C MFIGJRRHGZYPDD-UHFFFAOYSA-N 0.000 description 7
• 239000012299 nitrogen atmosphere Substances 0.000 description 7
• 210000003437 trachea Anatomy 0.000 description 7
• 206010006482 Bronchospasm Diseases 0.000 description 6
• 241000700198 Cavia Species 0.000 description 6
• 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 6
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• HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 6
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• 230000027455 binding Effects 0.000 description 6
• 239000000969 carrier Substances 0.000 description 6
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• CJCLKHXAGGPFKP-UHFFFAOYSA-N ethyl 4-amino-2,5-difluorobenzoate Chemical compound CCOC(=O)C1=CC(F)=C(N)C=C1F CJCLKHXAGGPFKP-UHFFFAOYSA-N 0.000 description 6
• 239000007903 gelatin capsule Substances 0.000 description 6
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• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
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• 230000002441 reversible effect Effects 0.000 description 6
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• 229910052708 sodium Inorganic materials 0.000 description 6
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 6
• JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 5
• 208000009079 Bronchial Spasm Diseases 0.000 description 5
• 208000014181 Bronchial disease Diseases 0.000 description 5
• VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 5
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
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• 235000019270 ammonium chloride Nutrition 0.000 description 5
• 239000012298 atmosphere Substances 0.000 description 5
• 229960004436 budesonide Drugs 0.000 description 5
• 239000003795 chemical substances by application Substances 0.000 description 5
• 238000004587 chromatography analysis Methods 0.000 description 5
• 229960001334 corticosteroids Drugs 0.000 description 5
• 125000004212 difluorophenyl group Chemical group 0.000 description 5
• 229960000289 fluticasone propionate Drugs 0.000 description 5
• WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 5
• 229960001340 histamine Drugs 0.000 description 5
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• 208000002551 irritable bowel syndrome Diseases 0.000 description 5
• 229960001317 isoprenaline Drugs 0.000 description 5
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