JP7012078B2 - 化合物 - Google Patents

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Publication number

JP7012078B2

JP7012078B2 JP2019520504A JP2019520504A JP7012078B2 JP 7012078 B2 JP7012078 B2 JP 7012078B2 JP 2019520504 A JP2019520504 A JP 2019520504A JP 2019520504 A JP2019520504 A JP 2019520504A JP 7012078 B2 JP7012078 B2 JP 7012078B2

Authority

JP

Japan

Prior art keywords

heterocyclyl

carbocyclyl

mmol

alkyl

methyl

Prior art date

2016-06-21

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.)

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• 150000001875 compounds Chemical class 0.000 title claims description 204
• -1 R 5 Chemical compound 0.000 claims description 104
• 125000000217 alkyl group Chemical group 0.000 claims description 70
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
• 125000000623 heterocyclic group Chemical group 0.000 claims description 42
• 125000001424 substituent group Chemical group 0.000 claims description 41
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 40
• 125000005843 halogen group Chemical group 0.000 claims description 40
• 125000003118 aryl group Chemical group 0.000 claims description 33
• 125000001072 heteroaryl group Chemical group 0.000 claims description 29
• 229910052757 nitrogen Inorganic materials 0.000 claims description 28
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 26
• 238000000034 method Methods 0.000 claims description 24
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 150000001450 anions Chemical class 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 17
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 17
• 125000004122 cyclic group Chemical group 0.000 claims description 17
• 125000002947 alkylene group Chemical group 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
• 208000023504 respiratory system disease Diseases 0.000 claims description 12
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
• 125000004450 alkenylene group Chemical group 0.000 claims description 11
• 125000004419 alkynylene group Chemical group 0.000 claims description 11
• YIBBMDDEXKBIAM-UHFFFAOYSA-M potassium;pentoxymethanedithioate Chemical compound [K+].CCCCCOC([S-])=S YIBBMDDEXKBIAM-UHFFFAOYSA-M 0.000 claims description 11
• 125000005647 linker group Chemical group 0.000 claims description 10
• 230000002265 prevention Effects 0.000 claims description 10
• 150000003839 salts Chemical class 0.000 claims description 10
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 9
• 125000003386 piperidinyl group Chemical group 0.000 claims description 8
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 7
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
• 230000001575 pathological effect Effects 0.000 claims description 7
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 6
• 239000003153 chemical reaction reagent Substances 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
• 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 4
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
• 230000008878 coupling Effects 0.000 claims description 4
• 238000010168 coupling process Methods 0.000 claims description 4
• 238000005859 coupling reaction Methods 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 4
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 3
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
• 230000000155 isotopic effect Effects 0.000 claims description 3
• 238000011200 topical administration Methods 0.000 claims description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
• 125000004014 thioethyl group Chemical group [H]SC([H])([H])C([H])([H])* 0.000 claims description 2
• 239000007787 solid Substances 0.000 description 185
• 239000000543 intermediate Substances 0.000 description 133
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 129
• 239000000047 product Substances 0.000 description 111
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
• 239000000243 solution Substances 0.000 description 95
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 86
• 238000006243 chemical reaction Methods 0.000 description 79
• 238000003786 synthesis reaction Methods 0.000 description 78
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 74
• 230000015572 biosynthetic process Effects 0.000 description 67
• 239000011541 reaction mixture Substances 0.000 description 66
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
• 235000019439 ethyl acetate Nutrition 0.000 description 54
• 239000000725 suspension Substances 0.000 description 54
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 48
• 239000000203 mixture Substances 0.000 description 48
• 238000003818 flash chromatography Methods 0.000 description 42
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 37
• 239000000460 chlorine Substances 0.000 description 37
• 235000019253 formic acid Nutrition 0.000 description 37
• 239000013058 crude material Substances 0.000 description 33
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
• 239000000706 filtrate Substances 0.000 description 24
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
• 239000003921 oil Substances 0.000 description 23
• 235000019198 oils Nutrition 0.000 description 22
• 239000011734 sodium Substances 0.000 description 22
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 18
• 239000007864 aqueous solution Substances 0.000 description 17
• 239000012267 brine Substances 0.000 description 17
• 229920006395 saturated elastomer Polymers 0.000 description 17
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
• 238000001914 filtration Methods 0.000 description 16
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 15
• 239000000377 silicon dioxide Substances 0.000 description 15
• 239000000126 substance Substances 0.000 description 15
• 0 CN*C(*C=C(*)*1)=C1C(*1C=*C=C1)=O Chemical compound CN*C(*C=C(*)*1)=C1C(*1C=*C=C1)=O 0.000 description 14
• 125000004432 carbon atom Chemical group C* 0.000 description 14
• 239000012074 organic phase Substances 0.000 description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 13
• 239000007788 liquid Substances 0.000 description 13
• 239000012071 phase Substances 0.000 description 13
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
• 239000013543 active substance Substances 0.000 description 12
• HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 12
• 210000003097 mucus Anatomy 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 239000002585 base Substances 0.000 description 11
• 239000002904 solvent Substances 0.000 description 11
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
• 239000002713 epithelial sodium channel blocking agent Substances 0.000 description 10
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 235000002639 sodium chloride Nutrition 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
• 239000007821 HATU Substances 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
• 239000003814 drug Substances 0.000 description 8
• ONADISBUDSWVGN-UHFFFAOYSA-M lithium 3-amino-6-bromopyrazine-2-carboxylate Chemical compound NC=1C(=NC(=CN=1)Br)C(=O)[O-].[Li+] ONADISBUDSWVGN-UHFFFAOYSA-M 0.000 description 8
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
• 239000003826 tablet Substances 0.000 description 8
• XABBIVBWOSMXQQ-UHFFFAOYSA-N (3-amino-6-bromopyrazin-2-yl)-imidazol-1-ylmethanone Chemical compound BrC=1N=C(C(=NC=1)N)C(=O)N1C=NC=C1 XABBIVBWOSMXQQ-UHFFFAOYSA-N 0.000 description 7
• 238000003556 assay Methods 0.000 description 7
• 239000012043 crude product Substances 0.000 description 7
• 230000000694 effects Effects 0.000 description 7
• VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 6
• 208000003556 Dry Eye Syndromes Diseases 0.000 description 6
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 6
• 239000008346 aqueous phase Substances 0.000 description 6
• 229940079593 drug Drugs 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 150000002430 hydrocarbons Chemical group 0.000 description 6
• 238000011534 incubation Methods 0.000 description 6
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
• 210000004072 lung Anatomy 0.000 description 6
• 239000002609 medium Substances 0.000 description 6
• 239000002244 precipitate Substances 0.000 description 6
• 238000002360 preparation method Methods 0.000 description 6
• 238000003756 stirring Methods 0.000 description 6
• FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 5
• 201000003883 Cystic fibrosis Diseases 0.000 description 5
• 238000010521 absorption reaction Methods 0.000 description 5
• 239000002253 acid Substances 0.000 description 5
• 230000000903 blocking effect Effects 0.000 description 5
• 125000002837 carbocyclic group Chemical group 0.000 description 5
• 239000003054 catalyst Substances 0.000 description 5
• 210000000981 epithelium Anatomy 0.000 description 5
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 5
• 210000003494 hepatocyte Anatomy 0.000 description 5
• 239000000463 material Substances 0.000 description 5
• 210000001589 microsome Anatomy 0.000 description 5
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
• 239000003960 organic solvent Substances 0.000 description 5
• 238000012360 testing method Methods 0.000 description 5
• YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
• 108091006146 Channels Proteins 0.000 description 4
• 206010012438 Dermatitis atopic Diseases 0.000 description 4
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
• 235000019502 Orange oil Nutrition 0.000 description 4
• 201000004681 Psoriasis Diseases 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
• 229930006000 Sucrose Natural products 0.000 description 4
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
• 239000012317 TBTU Substances 0.000 description 4
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
• XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 4
• 229960002576 amiloride Drugs 0.000 description 4
• 201000008937 atopic dermatitis Diseases 0.000 description 4
• 125000001246 bromo group Chemical group Br* 0.000 description 4
• 230000005587 bubbling Effects 0.000 description 4
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
• 150000001768 cations Chemical class 0.000 description 4
• 239000012530 fluid Substances 0.000 description 4
• 239000006260 foam Substances 0.000 description 4
• 230000007062 hydrolysis Effects 0.000 description 4
• 238000006460 hydrolysis reaction Methods 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
• CNXSIRHOIFRMOB-UHFFFAOYSA-N methyl 3-amino-6-bromopyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(Br)=CN=C1N CNXSIRHOIFRMOB-UHFFFAOYSA-N 0.000 description 4
• 238000002156 mixing Methods 0.000 description 4
• 239000010502 orange oil Substances 0.000 description 4
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
• 229920000728 polyester Polymers 0.000 description 4
• 239000000843 powder Substances 0.000 description 4
• 238000002953 preparative HPLC Methods 0.000 description 4
• 125000003373 pyrazinyl group Chemical group 0.000 description 4
• 239000000376 reactant Substances 0.000 description 4
• 230000000241 respiratory effect Effects 0.000 description 4
• 210000002345 respiratory system Anatomy 0.000 description 4
• 239000000523 sample Substances 0.000 description 4
• 239000011550 stock solution Substances 0.000 description 4
• 239000005720 sucrose Substances 0.000 description 4
• BSHYRRODPGNMMX-UHFFFAOYSA-N 3-amino-6-methylsulfanylpyrazine-2-carboxylic acid Chemical compound CSC1=CN=C(N)C(C(O)=O)=N1 BSHYRRODPGNMMX-UHFFFAOYSA-N 0.000 description 3
• 125000001054 5 membered carbocyclic group Chemical group 0.000 description 3
• 125000004008 6 membered carbocyclic group Chemical group 0.000 description 3
• 244000215068 Acacia senegal Species 0.000 description 3
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
• 206010013774 Dry eye Diseases 0.000 description 3
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
• 230000005526 G1 to G0 transition Effects 0.000 description 3
• 108010010803 Gelatin Proteins 0.000 description 3
• 229920000084 Gum arabic Polymers 0.000 description 3
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
• 235000010489 acacia gum Nutrition 0.000 description 3
• 239000000205 acacia gum Substances 0.000 description 3
• SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
• 239000012298 atmosphere Substances 0.000 description 3
• 125000004429 atom Chemical group 0.000 description 3
• 210000000424 bronchial epithelial cell Anatomy 0.000 description 3
• 239000000872 buffer Substances 0.000 description 3
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
• 239000000969 carrier Substances 0.000 description 3
• 239000003795 chemical substances by application Substances 0.000 description 3
• 239000008367 deionised water Substances 0.000 description 3
• 229910021641 deionized water Inorganic materials 0.000 description 3
• 238000001514 detection method Methods 0.000 description 3
• 238000010790 dilution Methods 0.000 description 3
• 239000012895 dilution Substances 0.000 description 3
• 238000001035 drying Methods 0.000 description 3
• 229920001971 elastomer Polymers 0.000 description 3
• PAVZHTXVORCEHP-UHFFFAOYSA-N ethylboronic acid Chemical compound CCB(O)O PAVZHTXVORCEHP-UHFFFAOYSA-N 0.000 description 3
• 238000001704 evaporation Methods 0.000 description 3
• 230000008020 evaporation Effects 0.000 description 3
• 238000002474 experimental method Methods 0.000 description 3
• 239000000284 extract Substances 0.000 description 3
• 239000000499 gel Substances 0.000 description 3
• 239000008273 gelatin Substances 0.000 description 3
• 229920000159 gelatin Polymers 0.000 description 3
• 235000019322 gelatine Nutrition 0.000 description 3
• 235000011852 gelatine desserts Nutrition 0.000 description 3
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
• 230000002401 inhibitory effect Effects 0.000 description 3
• 210000003734 kidney Anatomy 0.000 description 3
• 230000001404 mediated effect Effects 0.000 description 3
• VFKIJMHDBGWTIH-UHFFFAOYSA-N methyl 3-amino-6-methylpyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(C)=CN=C1N VFKIJMHDBGWTIH-UHFFFAOYSA-N 0.000 description 3
• 210000004877 mucosa Anatomy 0.000 description 3
• DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 3
• 229910052760 oxygen Inorganic materials 0.000 description 3
• 229910052763 palladium Inorganic materials 0.000 description 3
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
• 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
• 239000003380 propellant Substances 0.000 description 3
• 208000007750 pseudohypoaldosteronism Diseases 0.000 description 3
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