JP2017516824A - アミノエステル誘導体 - Google Patents

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Publication number

JP2017516824A

JP2017516824A JP2016571037A JP2016571037A JP2017516824A JP 2017516824 A JP2017516824 A JP 2017516824A JP 2016571037 A JP2016571037 A JP 2016571037A JP 2016571037 A JP2016571037 A JP 2016571037A JP 2017516824 A JP2017516824 A JP 2017516824A

Authority

JP

Japan

Prior art keywords

methyl

ethyl

ium

dichloro

dimethoxyphenyl

Prior art date

2014-06-05

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.)

Withdrawn

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• -1 Amino ester Chemical class 0.000 title claims description 100
• 150000001875 compounds Chemical class 0.000 claims abstract description 247
• 239000000203 mixture Substances 0.000 claims abstract description 54
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 88
• 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 claims description 85
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 76
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 63
• QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 claims description 58
• 150000003839 salts Chemical class 0.000 claims description 30
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
• 229910052739 hydrogen Inorganic materials 0.000 claims description 25
• 239000001257 hydrogen Substances 0.000 claims description 25
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 23
• 239000012453 solvate Substances 0.000 claims description 22
• 125000000217 alkyl group Chemical group 0.000 claims description 17
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 16
• 238000011282 treatment Methods 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 125000002950 monocyclic group Chemical group 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 10
• 125000000732 arylene group Chemical group 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• XRMDCWJNPDVAFI-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium-4-ol Chemical compound CC1(C)CC(O)CC(C)(C)[N+]1=O XRMDCWJNPDVAFI-UHFFFAOYSA-N 0.000 claims description 8
• 125000003118 aryl group Chemical group 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 8
• 150000002367 halogens Chemical class 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• JBQMFBWTKWOSQX-UHFFFAOYSA-N 2,3-dihydro-1h-indene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)CCC2=C1 JBQMFBWTKWOSQX-UHFFFAOYSA-N 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 6
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
• 239000004480 active ingredient Substances 0.000 claims description 6
• 125000002619 bicyclic group Chemical group 0.000 claims description 6
• 150000001721 carbon Chemical group 0.000 claims description 6
• 125000005843 halogen group Chemical group 0.000 claims description 6
• 208000023504 respiratory system disease Diseases 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 4
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
• 208000006673 asthma Diseases 0.000 claims description 4
• 125000004429 atom Chemical group 0.000 claims description 4
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000001072 heteroaryl group Chemical group 0.000 claims description 4
• 125000005549 heteroarylene group Chemical group 0.000 claims description 4
• 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 3
• PKTJKKARCIJTJR-UHFFFAOYSA-N 2,2-difluoro-1,3-dioxolane Chemical group FC1(F)OCCO1 PKTJKKARCIJTJR-UHFFFAOYSA-N 0.000 claims description 2
• 208000000884 Airway Obstruction Diseases 0.000 claims description 2
• PGBFYLVIMDQYMS-UHFFFAOYSA-N Methyl thiophene-2-carboxylate Chemical compound COC(=O)C1=CC=CS1 PGBFYLVIMDQYMS-UHFFFAOYSA-N 0.000 claims description 2
• 241000283984 Rodentia Species 0.000 claims description 2
• 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 2
• 150000007942 carboxylates Chemical class 0.000 claims description 2
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
• 125000001424 substituent group Chemical group 0.000 claims description 2
• VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims description 2
• 208000018569 Respiratory Tract disease Diseases 0.000 claims 1
• 125000001145 hydrido group Chemical group *[H] 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 58
• 238000006243 chemical reaction Methods 0.000 abstract description 40
• 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 abstract description 27
• 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 abstract description 27
• MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 abstract description 25
• 239000000872 buffer Substances 0.000 abstract description 13
• 238000003556 assay Methods 0.000 abstract description 9
• 238000005119 centrifugation Methods 0.000 abstract description 8
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 abstract description 7
• 102000017925 CHRM3 Human genes 0.000 abstract description 6
• 101150060249 CHRM3 gene Proteins 0.000 abstract 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 abstract description 6
• 239000012528 membrane Substances 0.000 abstract description 6
• 230000027455 binding Effects 0.000 abstract description 5
• 229940122694 Muscarinic M3 receptor antagonist Drugs 0.000 abstract description 4
• DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 abstract description 4
• 238000002474 experimental method Methods 0.000 abstract description 4
• 239000003681 muscarinic M3 receptor antagonist Substances 0.000 abstract description 4
• 230000003551 muscarinic effect Effects 0.000 abstract description 4
• 239000008188 pellet Substances 0.000 abstract description 4
• 238000000159 protein binding assay Methods 0.000 abstract description 4
• 239000002287 radioligand Substances 0.000 abstract description 4
• 230000001225 therapeutic effect Effects 0.000 abstract 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 abstract description 3
• 229930006000 Sucrose Natural products 0.000 abstract description 3
• 229960001383 methylscopolamine Drugs 0.000 abstract description 3
• 230000009871 nonspecific binding Effects 0.000 abstract description 3
• 239000002953 phosphate buffered saline Substances 0.000 abstract description 3
• 239000005720 sucrose Substances 0.000 abstract description 3
• 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 abstract description 2
• 239000002532 enzyme inhibitor Substances 0.000 abstract description 2
• 238000001914 filtration Methods 0.000 abstract description 2
• LZCOQTDXKCNBEE-IKIFYQGPSA-N methscopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 LZCOQTDXKCNBEE-IKIFYQGPSA-N 0.000 abstract description 2
• 238000005406 washing Methods 0.000 abstract description 2
• TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 abstract 6
• 229910001629 magnesium chloride Inorganic materials 0.000 abstract 3
• LZCOQTDXKCNBEE-XJMZPCNVSA-N N-methylscopolamine Chemical compound C1([C@@H](CO)C(=O)OC2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 LZCOQTDXKCNBEE-XJMZPCNVSA-N 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
• 239000002904 solvent Substances 0.000 description 65
• 235000019439 ethyl acetate Nutrition 0.000 description 40
• 239000003643 water by type Substances 0.000 description 38
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 33
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 27
• 239000007787 solid Substances 0.000 description 25
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
• 238000005481 NMR spectroscopy Methods 0.000 description 20
• 238000000746 purification Methods 0.000 description 20
• 239000000243 solution Substances 0.000 description 20
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 18
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 17
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
• 239000000543 intermediate Substances 0.000 description 17
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
• 0 CCCCC(CCC[C@@](C)(*N(*)C(C*1)(C(O*)=O)c2c1cccc2)C=CCCC)*C(OC(Cc1cc*(*)cc1)c(cc1)cc(O*)c1O*1CCCC1)=O Chemical compound CCCCC(CCC[C@@](C)(*N(*)C(C*1)(C(O*)=O)c2c1cccc2)C=CCCC)*C(OC(Cc1cc*(*)cc1)c(cc1)cc(O*)c1O*1CCCC1)=O 0.000 description 15
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 14
• 230000000694 effects Effects 0.000 description 14
• 239000012071 phase Substances 0.000 description 14
• 238000002360 preparation method Methods 0.000 description 14
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 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
• 238000004128 high performance liquid chromatography Methods 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• 238000002953 preparative HPLC Methods 0.000 description 12
• 230000002829 reductive effect Effects 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• 239000008346 aqueous phase Substances 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• 230000005764 inhibitory process Effects 0.000 description 10
• 125000006413 ring segment Chemical group 0.000 description 10
• 238000004808 supercritical fluid chromatography Methods 0.000 description 10
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
• 239000002253 acid Substances 0.000 description 9
• 125000004432 carbon atom Chemical group C* 0.000 description 9
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 9
• 239000000284 extract Substances 0.000 description 9
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
• 239000000843 powder Substances 0.000 description 9
• 201000010099 disease Diseases 0.000 description 8
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
• 235000019441 ethanol Nutrition 0.000 description 8
• 239000003112 inhibitor Substances 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• 239000011541 reaction mixture Substances 0.000 description 8
• MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 8
• 229960002586 roflumilast Drugs 0.000 description 8
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 230000008485 antagonism Effects 0.000 description 7
• 229960004592 isopropanol Drugs 0.000 description 7
• 239000003607 modifier Substances 0.000 description 7
• 229910052760 oxygen Inorganic materials 0.000 description 7
• 239000000725 suspension Substances 0.000 description 7
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
• 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 6
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 6
• 229960004373 acetylcholine Drugs 0.000 description 6
• 239000012267 brine Substances 0.000 description 6
• 125000000753 cycloalkyl group Chemical group 0.000 description 6
• 235000019253 formic acid Nutrition 0.000 description 6
• 210000003097 mucus Anatomy 0.000 description 6
• 239000003149 muscarinic antagonist Substances 0.000 description 6
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 6
• 125000006239 protecting group Chemical group 0.000 description 6
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 6
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
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• 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 5
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
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• 230000005713 exacerbation Effects 0.000 description 5
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• 208000024891 symptom Diseases 0.000 description 5
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• 210000005091 airway smooth muscle Anatomy 0.000 description 4
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
• 229940124630 bronchodilator Drugs 0.000 description 4
• 239000003795 chemical substances by application Substances 0.000 description 4
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• 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 4
• 238000012360 testing method Methods 0.000 description 4
• 229910052720 vanadium Inorganic materials 0.000 description 4
• IVLICPVPXWEGCA-ZETCQYMHSA-N (3r)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@@H](O)CN1CC2 IVLICPVPXWEGCA-ZETCQYMHSA-N 0.000 description 3
• PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 3
• ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
• 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
• 102000017927 CHRM1 Human genes 0.000 description 3
• LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 3
• 101150073075 Chrm1 gene Proteins 0.000 description 3
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