MXPA05000898A - Moduladores de receptor de estrogeno selectivos que contiene, un grupo fenilsulfonilo. - Google Patents

Info

Publication number

MXPA05000898A

MXPA05000898A MXPA05000898A MXPA05000898A MXPA05000898A MX PA05000898 A MXPA05000898 A MX PA05000898A MX PA05000898 A MXPA05000898 A MX PA05000898A MX PA05000898 A MXPA05000898 A MX PA05000898A MX PA05000898 A MXPA05000898 A MX PA05000898A

Authority

MX

Mexico

Prior art keywords

mmol

compound

add

phenyl

dry

Prior art date

2002-07-22

Links

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• 239000000333 selective estrogen receptor modulator Substances 0.000 title abstract description 9
• 229940095743 selective estrogen receptor modulator Drugs 0.000 title abstract description 5
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 title 1
• 239000002253 acid Substances 0.000 claims abstract description 43
• 150000003839 salts Chemical class 0.000 claims abstract description 43
• 201000009273 Endometriosis Diseases 0.000 claims abstract description 12
• 201000010260 leiomyoma Diseases 0.000 claims abstract description 12
• 206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 9
• 201000007954 uterine fibroid Diseases 0.000 claims abstract description 9
• 150000001875 compounds Chemical class 0.000 claims description 345
• -1 chloro, methyl Chemical group 0.000 claims description 126
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000000217 alkyl group Chemical group 0.000 claims description 18
• 238000000034 method Methods 0.000 claims description 17
• 238000011282 treatment Methods 0.000 claims description 17
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 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 claims description 7
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
• 125000001153 fluoro group Chemical group F* 0.000 claims description 6
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
• 101150047265 COR2 gene Proteins 0.000 claims description 5
• 101100467189 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) QCR2 gene Proteins 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
• 229910052739 hydrogen Inorganic materials 0.000 claims description 5
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 710
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 423
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 358
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 328
• 238000003756 stirring Methods 0.000 description 188
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 174
• 239000012141 concentrate Substances 0.000 description 149
• 235000008504 concentrate Nutrition 0.000 description 148
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 140
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 138
• 235000019439 ethyl acetate Nutrition 0.000 description 129
• 239000012044 organic layer Substances 0.000 description 118
• 239000000243 solution Substances 0.000 description 116
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 110
• 238000006243 chemical reaction Methods 0.000 description 103
• 229910001868 water Inorganic materials 0.000 description 103
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 101
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 96
• 239000000203 mixture Substances 0.000 description 96
• 229920006395 saturated elastomer Polymers 0.000 description 96
• 239000010410 layer Substances 0.000 description 90
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 89
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 89
• 239000012267 brine Substances 0.000 description 87
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 87
• 238000001819 mass spectrum Methods 0.000 description 82
• 150000002500 ions Chemical class 0.000 description 78
• 239000007921 spray Substances 0.000 description 78
• 239000000284 extract Substances 0.000 description 76
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 71
• 239000007787 solid Substances 0.000 description 71
• 238000002360 preparation method Methods 0.000 description 67
• 239000011541 reaction mixture Substances 0.000 description 67
• 239000000741 silica gel Substances 0.000 description 62
• 229910002027 silica gel Inorganic materials 0.000 description 62
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 58
• 229910052938 sodium sulfate Inorganic materials 0.000 description 56
• 235000011152 sodium sulphate Nutrition 0.000 description 56
• XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 54
• 239000000725 suspension Substances 0.000 description 54
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 51
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 50
• 229910052681 coesite Inorganic materials 0.000 description 50
• 229910052906 cristobalite Inorganic materials 0.000 description 50
• 235000017557 sodium bicarbonate Nutrition 0.000 description 50
• 229910052682 stishovite Inorganic materials 0.000 description 50
• 229910052905 tridymite Inorganic materials 0.000 description 50
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• 239000000047 product Substances 0.000 description 41
• 238000010992 reflux Methods 0.000 description 39
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
• 239000002904 solvent Substances 0.000 description 33
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• 239000012299 nitrogen atmosphere Substances 0.000 description 30
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 30
• 239000000460 chlorine Substances 0.000 description 29
• 239000011734 sodium Substances 0.000 description 29
• WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 28
• 239000012458 free base Substances 0.000 description 27
• 239000000463 material Substances 0.000 description 27
• 238000003818 flash chromatography Methods 0.000 description 26
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
• 235000019341 magnesium sulphate Nutrition 0.000 description 25
• LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 25
• 239000000706 filtrate Substances 0.000 description 24
• 241000700159 Rattus Species 0.000 description 22
• 239000002244 precipitate Substances 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 239000000843 powder Substances 0.000 description 20
• 239000012065 filter cake Substances 0.000 description 18
• 238000010438 heat treatment Methods 0.000 description 18
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 17
• 229910015845 BBr3 Inorganic materials 0.000 description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
• 229910052757 nitrogen Inorganic materials 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• 238000005192 partition Methods 0.000 description 17
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 16
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• 229940011871 estrogen Drugs 0.000 description 14
• 239000000262 estrogen Substances 0.000 description 14
• 238000012360 testing method Methods 0.000 description 14
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
• 239000000556 agonist Substances 0.000 description 13
• 239000003826 tablet Substances 0.000 description 13
• VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 12
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
• 239000007832 Na2SO4 Substances 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• 239000013058 crude material Substances 0.000 description 12
• 229960005309 estradiol Drugs 0.000 description 12
• 229960000583 acetic acid Drugs 0.000 description 11
• 239000005557 antagonist Substances 0.000 description 11
• 238000003556 assay Methods 0.000 description 11
• 239000003054 catalyst Substances 0.000 description 11
• 210000004291 uterus Anatomy 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
• 235000011114 ammonium hydroxide Nutrition 0.000 description 10
• 239000002609 medium Substances 0.000 description 10
• 239000012312 sodium hydride Substances 0.000 description 10
• 229910000104 sodium hydride Inorganic materials 0.000 description 10
• 235000019270 ammonium chloride Nutrition 0.000 description 9
• 239000007864 aqueous solution Substances 0.000 description 9
• 238000001914 filtration Methods 0.000 description 9
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 8
• 206010067269 Uterine fibrosis Diseases 0.000 description 8
• 239000004480 active ingredient Substances 0.000 description 8
• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 8
• 239000012911 assay medium Substances 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
• 229930182833 estradiol Natural products 0.000 description 8
• 239000012091 fetal bovine serum Substances 0.000 description 8
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
• 238000002953 preparative HPLC Methods 0.000 description 8
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
• 210000000988 bone and bone Anatomy 0.000 description 7
• 229910002092 carbon dioxide Inorganic materials 0.000 description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
• 230000000694 effects Effects 0.000 description 7
• 235000011056 potassium acetate Nutrition 0.000 description 7
• 238000010926 purge Methods 0.000 description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
• 230000004044 response Effects 0.000 description 7
• 239000000523 sample Substances 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
• 239000003981 vehicle Substances 0.000 description 7
• HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 6
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
• 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
• 239000000908 ammonium hydroxide Substances 0.000 description 6
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
• 239000002775 capsule Substances 0.000 description 6
• 238000001514 detection method Methods 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 238000011534 incubation Methods 0.000 description 6
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
• NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 6
• 239000008194 pharmaceutical composition Substances 0.000 description 6
• 239000000377 silicon dioxide Substances 0.000 description 6
• 230000000638 stimulation Effects 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
• 210000001519 tissue Anatomy 0.000 description 6
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 5
• BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 5
• 229910052794 bromium Inorganic materials 0.000 description 5
• 239000007884 disintegrant Substances 0.000 description 5
• 239000003814 drug Substances 0.000 description 5
• 238000001035 drying Methods 0.000 description 5
• 239000006260 foam Substances 0.000 description 5
• 239000012362 glacial acetic acid Substances 0.000 description 5
• 230000005764 inhibitory process Effects 0.000 description 5
• 238000002663 nebulization Methods 0.000 description 5
• 230000002611 ovarian Effects 0.000 description 5
• 239000012071 phase Substances 0.000 description 5
• 229960003531 phenolsulfonphthalein Drugs 0.000 description 5
• 229960005235 piperonyl butoxide Drugs 0.000 description 5
• 229910000027 potassium carbonate Inorganic materials 0.000 description 5
• 239000012047 saturated solution Substances 0.000 description 5
• 208000024891 symptom Diseases 0.000 description 5
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
• SERCRKYPSIZEAN-UHFFFAOYSA-N 1-[2-[4-[(2-bromo-6-phenylmethoxy-1-benzothiophen-3-yl)oxy]phenoxy]ethyl]piperidine Chemical compound C=1C=C2C(OC=3C=CC(OCCN4CCCCC4)=CC=3)=C(Br)SC2=CC=1OCC1=CC=CC=C1 SERCRKYPSIZEAN-UHFFFAOYSA-N 0.000 description 4
• BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 4
• OPBFFNZNNJKRCS-UHFFFAOYSA-N 2-hydroxy-4,4-dimethylpentanoic acid Chemical compound CC(C)(C)CC(O)C(O)=O OPBFFNZNNJKRCS-UHFFFAOYSA-N 0.000 description 4
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