EA029518B1 - Бензоксазиноновые амиды в качестве модуляторов минералокортикоидного рецептора - Google Patents
Бензоксазиноновые амиды в качестве модуляторов минералокортикоидного рецептора Download PDFInfo
- Publication number
- EA029518B1 EA029518B1 EA201790046A EA201790046A EA029518B1 EA 029518 B1 EA029518 B1 EA 029518B1 EA 201790046 A EA201790046 A EA 201790046A EA 201790046 A EA201790046 A EA 201790046A EA 029518 B1 EA029518 B1 EA 029518B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- dihydro
- benzoxazin
- oxo
- carbonyl
- mmol
- Prior art date
Links
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 title abstract description 8
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 title abstract description 8
- 150000001408 amides Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 242
- -1 benzoxazinone amide Chemical class 0.000 claims abstract description 106
- 238000000034 method Methods 0.000 claims abstract description 86
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 93
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 37
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 241000124008 Mammalia Species 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 10
- 208000020832 chronic kidney disease Diseases 0.000 claims description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- 210000003038 endothelium Anatomy 0.000 abstract description 4
- 230000036542 oxidative stress Effects 0.000 abstract description 3
- 230000004218 vascular function Effects 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 134
- 239000000203 mixture Substances 0.000 description 120
- 239000000243 solution Substances 0.000 description 88
- 238000005481 NMR spectroscopy Methods 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 59
- 239000007787 solid Substances 0.000 description 54
- 239000011541 reaction mixture Substances 0.000 description 46
- 239000012071 phase Substances 0.000 description 44
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- 239000002904 solvent Substances 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 239000000047 product Substances 0.000 description 35
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 34
- 239000012267 brine Substances 0.000 description 34
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000012360 testing method Methods 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 25
- 239000005557 antagonist Substances 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 238000001228 spectrum Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 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 description 17
- 238000007792 addition Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 238000004458 analytical method Methods 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- CIYUDMUBYRVMLP-UHFFFAOYSA-N 3-oxo-4h-1,4-benzoxazine-6-carboxylic acid Chemical compound O1CC(=O)NC2=CC(C(=O)O)=CC=C21 CIYUDMUBYRVMLP-UHFFFAOYSA-N 0.000 description 12
- 206010020772 Hypertension Diseases 0.000 description 12
- 208000035475 disorder Diseases 0.000 description 12
- 230000003287 optical effect Effects 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 11
- 229960002478 aldosterone Drugs 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 208000033679 diabetic kidney disease Diseases 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 206010019280 Heart failures Diseases 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 9
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 9
- 241000282412 Homo Species 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 229910052738 indium Inorganic materials 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 229910052700 potassium Inorganic materials 0.000 description 9
- 238000002560 therapeutic procedure Methods 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 206010048554 Endothelial dysfunction Diseases 0.000 description 7
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229940043232 butyl acetate Drugs 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 230000008694 endothelial dysfunction Effects 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 230000002792 vascular Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002441 X-ray diffraction Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- 230000002526 effect on cardiovascular system Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 238000011068 loading method Methods 0.000 description 6
- 239000002395 mineralocorticoid Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 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 6
- 206010007558 Cardiac failure chronic Diseases 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- UDNBIQSFGWAEAW-UHFFFAOYSA-N [Rh].C1=CCCC=CCC1.CC Chemical compound [Rh].C1=CCCC=CCC1.CC UDNBIQSFGWAEAW-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000002374 hemiaminals Chemical class 0.000 description 5
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 5
- 208000017169 kidney disease Diseases 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- 208000002682 Hyperkalemia Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 101100293693 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) STO1 gene Proteins 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000008484 agonism Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 101150050497 cbc1 gene Proteins 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000132 electrospray ionisation Methods 0.000 description 3
- RFODVDZYIXMBMI-ONEGZZNKSA-N ethyl (e)-4-(5-fluoro-2-nitrophenoxy)but-2-enoate Chemical compound CCOC(=O)\C=C\COC1=CC(F)=CC=C1[N+]([O-])=O RFODVDZYIXMBMI-ONEGZZNKSA-N 0.000 description 3
- IESJFXUEPVHSBN-UHFFFAOYSA-N ethyl 2-(7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate Chemical compound BrC1=CC2=C(NC(CO2)CC(=O)OCC)C=C1 IESJFXUEPVHSBN-UHFFFAOYSA-N 0.000 description 3
- AOGJLQXRYVTQSH-UHFFFAOYSA-N ethyl 2-(7-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate Chemical compound ClC1=CC2=C(NC(CO2)CC(=O)OCC)C=C1 AOGJLQXRYVTQSH-UHFFFAOYSA-N 0.000 description 3
- OAABYIKOQIMZBY-UHFFFAOYSA-N ethyl 2-(7-fluoro-3,4-dihydro-2h-1,4-benzoxazin-3-yl)acetate Chemical compound FC1=CC=C2NC(CC(=O)OCC)COC2=C1 OAABYIKOQIMZBY-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000012256 powdered iron Substances 0.000 description 3
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QIVLKZPYVFXZTC-UHFFFAOYSA-N tert-butyl 7-fluoro-3-oxo-1,4-benzoxazine-4-carboxylate Chemical compound FC1=CC2=C(N(C(CO2)=O)C(=O)OC(C)(C)C)C=C1 QIVLKZPYVFXZTC-UHFFFAOYSA-N 0.000 description 3
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-N 0.000 description 2
- PFGRWCIVYGUJPQ-UHFFFAOYSA-N 2-[4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetic acid Chemical compound O=C1COC2=C(N1)C=C(C=C2)C(=O)N1C(COC2=C1C=CC=C2)CC(=O)O PFGRWCIVYGUJPQ-UHFFFAOYSA-N 0.000 description 2
- DDSAEVFEPNPYSM-UHFFFAOYSA-N 2-[7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetic acid Chemical compound BrC1=CC2=C(N(C(CO2)CC(=O)O)C(=O)C=2C=CC3=C(NC(CO3)=O)C=2)C=C1 DDSAEVFEPNPYSM-UHFFFAOYSA-N 0.000 description 2
- AESCUDVXIPQLFO-UHFFFAOYSA-N 2-[7-fluoro-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetic acid Chemical compound FC1=CC2=C(N(C(CO2)CC(=O)O)C(=O)C=2C=CC3=C(NC(CO3)=O)C=2)C=C1 AESCUDVXIPQLFO-UHFFFAOYSA-N 0.000 description 2
- IIDUNAVOCYMUFB-UHFFFAOYSA-N 2-amino-5-fluorophenol Chemical compound NC1=CC=C(F)C=C1O IIDUNAVOCYMUFB-UHFFFAOYSA-N 0.000 description 2
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 2
- QQURWFRNETXFTN-UHFFFAOYSA-N 5-fluoro-2-nitrophenol Chemical compound OC1=CC(F)=CC=C1[N+]([O-])=O QQURWFRNETXFTN-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 2
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 2
- 206010020571 Hyperaldosteronism Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000000342 Monte Carlo simulation Methods 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 229940127218 antiplatelet drug Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013058 crude material Substances 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229940030606 diuretics Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- PNSQMAZBBSMOTB-UHFFFAOYSA-N ethyl 2-[4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate Chemical compound O=C1COC2=C(N1)C=C(C=C2)C(=O)N1C(COC2=C1C=CC=C2)CC(=O)OCC PNSQMAZBBSMOTB-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 231100001231 less toxic Toxicity 0.000 description 2
- 239000002171 loop diuretic Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- JHWQFCKFDBQXGE-UHFFFAOYSA-N methyl 2-(3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate Chemical compound O1CC(NC2=C1C=CC=C2)CC(=O)OC JHWQFCKFDBQXGE-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000324 molecular mechanic Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 239000003579 shift reagent Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 2
- 229960002256 spironolactone Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- ZANHGRLCBARQNJ-UHFFFAOYSA-N tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound BrC1=CC2=C(N(C(CO2)CC(=O)OCC)C(=O)OC(C)(C)C)C=C1 ZANHGRLCBARQNJ-UHFFFAOYSA-N 0.000 description 2
- KPIODSCLHYGOHI-UHFFFAOYSA-N tert-butyl 7-bromo-3-oxo-1,4-benzoxazine-4-carboxylate Chemical compound BrC1=CC2=C(N(C(CO2)=O)C(=O)OC(C)(C)C)C=C1 KPIODSCLHYGOHI-UHFFFAOYSA-N 0.000 description 2
- ZAUCSTFIQFYJAJ-UHFFFAOYSA-N tert-butyl 7-chloro-3-(2-ethoxy-2-oxoethyl)-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound ClC1=CC2=C(N(C(CO2)CC(=O)OCC)C(=O)OC(C)(C)C)C=C1 ZAUCSTFIQFYJAJ-UHFFFAOYSA-N 0.000 description 2
- RNQGIJYCONUNCQ-UHFFFAOYSA-N tert-butyl 7-chloro-3-oxo-1,4-benzoxazine-4-carboxylate Chemical compound ClC1=CC2=C(N(C(CO2)=O)C(=O)OC(C)(C)C)C=C1 RNQGIJYCONUNCQ-UHFFFAOYSA-N 0.000 description 2
- 239000003451 thiazide diuretic agent Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 description 2
- ARLKVQYMFRECLV-JSGCOSHPSA-N (2s)-2-[[(2s)-2-amino-3-(1h-indol-3-yl)propanoyl]amino]-4-methylsulfanylbutanamide Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCSC)C(N)=O)=CNC2=C1 ARLKVQYMFRECLV-JSGCOSHPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- RULDHHMNJXAYGW-UHFFFAOYSA-N 2-[4-(2-aminoethyl)phenoxy]-n,n-diethylacetamide Chemical compound CCN(CC)C(=O)COC1=CC=C(CCN)C=C1 RULDHHMNJXAYGW-UHFFFAOYSA-N 0.000 description 1
- PGROELHINWWVFN-UHFFFAOYSA-N 2-[7-chloro-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetic acid Chemical compound ClC1=CC2=C(N(C(CO2)CC(=O)O)C(=O)C=2C=CC3=C(NC(CO3)=O)C=2)C=C1 PGROELHINWWVFN-UHFFFAOYSA-N 0.000 description 1
- DRQWUAAWZFIVTF-UHFFFAOYSA-N 2-amino-5-bromophenol Chemical compound NC1=CC=C(Br)C=C1O DRQWUAAWZFIVTF-UHFFFAOYSA-N 0.000 description 1
- FZCQMIRJCGWWCL-UHFFFAOYSA-N 2-amino-5-chlorophenol Chemical compound NC1=CC=C(Cl)C=C1O FZCQMIRJCGWWCL-UHFFFAOYSA-N 0.000 description 1
- BLJQGZXRECZHOS-UHFFFAOYSA-N 2-benzhydryl-1h-imidazole Chemical class C1=CNC(C(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 BLJQGZXRECZHOS-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- NNPDDCXJBSZKKM-UHFFFAOYSA-N 2h-1,4-oxazine-6-carboxylic acid Chemical compound OC(=O)C1=CN=CCO1 NNPDDCXJBSZKKM-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- UNBMPKNTYKDYCG-UHFFFAOYSA-N 4-methylpentan-2-amine Chemical compound CC(C)CC(C)N UNBMPKNTYKDYCG-UHFFFAOYSA-N 0.000 description 1
- DTWHNSNSUBKGTC-UHFFFAOYSA-N 5-bromo-2-nitrophenol Chemical compound OC1=CC(Br)=CC=C1[N+]([O-])=O DTWHNSNSUBKGTC-UHFFFAOYSA-N 0.000 description 1
- FPIWJQQRYHEICX-UHFFFAOYSA-N 6,11-dihydrobenzo[c][1]benzoxepine Chemical class C1OC2=CC=CC=C2CC2=CC=CC=C12 FPIWJQQRYHEICX-UHFFFAOYSA-N 0.000 description 1
- ZAXUQDMKVBOVCR-UHFFFAOYSA-N 7-bromo-4h-1,4-benzoxazin-3-one Chemical compound N1C(=O)COC2=CC(Br)=CC=C21 ZAXUQDMKVBOVCR-UHFFFAOYSA-N 0.000 description 1
- QGHYYLMIQSZWAX-UHFFFAOYSA-N 7-chloro-4h-1,4-benzoxazin-3-one Chemical compound N1C(=O)COC2=CC(Cl)=CC=C21 QGHYYLMIQSZWAX-UHFFFAOYSA-N 0.000 description 1
- TXRXHEOGQVPEBT-UHFFFAOYSA-N 7-fluoro-4h-1,4-benzoxazin-3-one Chemical compound N1C(=O)COC2=CC(F)=CC=C21 TXRXHEOGQVPEBT-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 101150103425 APR1 gene Proteins 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 108091005932 CCKBR Proteins 0.000 description 1
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 208000016998 Conn syndrome Diseases 0.000 description 1
- 235000019750 Crude protein Nutrition 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 102100029721 DnaJ homolog subfamily B member 1 Human genes 0.000 description 1
- 102000010180 Endothelin receptor Human genes 0.000 description 1
- 108050001739 Endothelin receptor Proteins 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000866018 Homo sapiens DnaJ homolog subfamily B member 1 Proteins 0.000 description 1
- 101001046529 Homo sapiens Mevalonate kinase Proteins 0.000 description 1
- 101000990990 Homo sapiens Midkine Proteins 0.000 description 1
- 101100202882 Homo sapiens SELENOO gene Proteins 0.000 description 1
- 101000587820 Homo sapiens Selenide, water dikinase 1 Proteins 0.000 description 1
- 101000701815 Homo sapiens Spermidine synthase Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 101100071331 Hypomyces subiculosus hpm8 gene Proteins 0.000 description 1
- 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 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 101710175625 Maltose/maltodextrin-binding periplasmic protein Proteins 0.000 description 1
- 241001346242 Morphnus guianensis Species 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 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 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100022022 Protein adenylyltransferase SelO, mitochondrial Human genes 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 206010039808 Secondary aldosteronism Diseases 0.000 description 1
- 102100031163 Selenide, water dikinase 1 Human genes 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 101100482220 Sulfurisphaera tokodaii (strain DSM 16993 / JCM 10545 / NBRC 100140 / 7) triC gene Proteins 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000037849 arterial hypertension Diseases 0.000 description 1
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 108091008698 baroreceptors Proteins 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 150000008371 chromenes Chemical class 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 238000002983 circular dichroism Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229910052593 corundum Inorganic materials 0.000 description 1
- 239000010431 corundum Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 229940082657 digitalis glycosides Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002519 electronic circular dichroism spectroscopy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 description 1
- 229960001208 eplerenone Drugs 0.000 description 1
- VUNDOQVRLOCGQL-ONEGZZNKSA-N ethyl (E)-4-(5-bromo-2-nitrophenoxy)but-2-enoate Chemical compound BrC=1C=CC(=C(OC/C=C/C(=O)OCC)C=1)[N+](=O)[O-] VUNDOQVRLOCGQL-ONEGZZNKSA-N 0.000 description 1
- LMUDHTHBENVWHS-UHFFFAOYSA-N ethyl 2-(3,4-dihydro-2h-1,4-benzoxazin-3-yl)acetate Chemical compound C1=CC=C2NC(CC(=O)OCC)COC2=C1 LMUDHTHBENVWHS-UHFFFAOYSA-N 0.000 description 1
- RFNFTHIKHVUSRK-UHFFFAOYSA-N ethyl 2-[7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate Chemical compound BrC1=CC2=C(N(C(CO2)CC(=O)OCC)C(=O)C=2C=CC3=C(NC(CO3)=O)C=2)C=C1 RFNFTHIKHVUSRK-UHFFFAOYSA-N 0.000 description 1
- LBGZQILXVPVXFC-UHFFFAOYSA-N ethyl 2-[7-chloro-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate Chemical compound ClC1=CC2=C(N(C(CO2)CC(=O)OCC)C(=O)C=2C=CC3=C(NC(CO3)=O)C=2)C=C1 LBGZQILXVPVXFC-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 102000053521 human MDK Human genes 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940030627 lipid modifying agent Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- TXPBVOLPRBZKTB-QPJJXVBHSA-N methyl (e)-4-(2-nitrophenoxy)but-2-enoate Chemical compound COC(=O)\C=C\COC1=CC=CC=C1[N+]([O-])=O TXPBVOLPRBZKTB-QPJJXVBHSA-N 0.000 description 1
- RWIKCBHOVNDESJ-NSCUHMNNSA-N methyl (e)-4-bromobut-2-enoate Chemical compound COC(=O)\C=C\CBr RWIKCBHOVNDESJ-NSCUHMNNSA-N 0.000 description 1
- FNZWYDHESSOBMD-UHFFFAOYSA-N methyl 2-[4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate Chemical compound O=C1COC2=C(N1)C=C(C=C2)C(=O)N1C(COC2=C1C=CC=C2)CC(=O)OC FNZWYDHESSOBMD-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910021421 monocrystalline silicon Inorganic materials 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- ATYVOGGOOLHXQV-UHFFFAOYSA-N n-(2,2-dimethyl-3-oxo-4-phenyl-1,4-benzoxazin-7-yl)methanesulfonamide Chemical compound O=C1C(C)(C)OC2=CC(NS(C)(=O)=O)=CC=C2N1C1=CC=CC=C1 ATYVOGGOOLHXQV-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- HKGOFWIZZIYCOS-UHFFFAOYSA-N naphthalene-2-sulfonic acid;hydrate Chemical compound O.C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 HKGOFWIZZIYCOS-UHFFFAOYSA-N 0.000 description 1
- 238000001783 near-resonance Rayleigh scattering spectroscopy Methods 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000673 poly(carbodihydridosilane) Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- VZOPRCCTKLAGPN-ZFJVMAEJSA-L potassium;sodium;(2r,3r)-2,3-dihydroxybutanedioate;tetrahydrate Chemical compound O.O.O.O.[Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VZOPRCCTKLAGPN-ZFJVMAEJSA-L 0.000 description 1
- 210000001774 pressoreceptor Anatomy 0.000 description 1
- 208000013846 primary aldosteronism Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- DGMKFQYCZXERLX-UHFFFAOYSA-N proglumide Chemical compound CCCN(CCC)C(=O)C(CCC(O)=O)NC(=O)C1=CC=CC=C1 DGMKFQYCZXERLX-UHFFFAOYSA-N 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000003345 scintillation counting Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- GMVHMNKRODAZBN-UHFFFAOYSA-N tert-butyl 3-(2-ethoxy-2-oxoethyl)-7-fluoro-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound C(C)OC(CC1COC2=C(N1C(=O)OC(C)(C)C)C=CC(=C2)F)=O GMVHMNKRODAZBN-UHFFFAOYSA-N 0.000 description 1
- ORFRTSZNGLZFPI-UHFFFAOYSA-N tert-butyl 7-chloro-3-hydroxy-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound ClC1=CC2=C(N(C(CO2)O)C(=O)OC(C)(C)C)C=C1 ORFRTSZNGLZFPI-UHFFFAOYSA-N 0.000 description 1
- RVMRKDNSYULXBH-UHFFFAOYSA-N tert-butyl 7-fluoro-3-hydroxy-2,3-dihydro-1,4-benzoxazine-4-carboxylate Chemical compound FC1=CC2=C(N(C(CO2)O)C(=O)OC(C)(C)C)C=C1 RVMRKDNSYULXBH-UHFFFAOYSA-N 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- PXFLCAQHOZXYED-UHFFFAOYSA-N tripyrrolidin-1-ylphosphane Chemical compound C1CCCN1P(N1CCCC1)N1CCCC1 PXFLCAQHOZXYED-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462018790P | 2014-06-30 | 2014-06-30 | |
| PCT/GB2015/051860 WO2016001631A1 (en) | 2014-06-30 | 2015-06-26 | Benzoxazinone amides as mineralocorticoid receptor modulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201790046A1 EA201790046A1 (ru) | 2017-08-31 |
| EA029518B1 true EA029518B1 (ru) | 2018-04-30 |
Family
ID=53539739
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201790046A EA029518B1 (ru) | 2014-06-30 | 2015-06-26 | Бензоксазиноновые амиды в качестве модуляторов минералокортикоидного рецептора |
Country Status (26)
| Country | Link |
|---|---|
| US (2) | US10017502B2 (enExample) |
| EP (1) | EP3160948B1 (enExample) |
| JP (1) | JP6368383B2 (enExample) |
| KR (1) | KR102012222B1 (enExample) |
| CN (1) | CN106536491B (enExample) |
| AR (1) | AR101036A1 (enExample) |
| AU (1) | AU2015282450C1 (enExample) |
| CA (1) | CA2953655C (enExample) |
| CY (1) | CY1121596T1 (enExample) |
| DK (1) | DK3160948T3 (enExample) |
| EA (1) | EA029518B1 (enExample) |
| ES (1) | ES2707726T3 (enExample) |
| HR (1) | HRP20190147T1 (enExample) |
| HU (1) | HUE042370T2 (enExample) |
| LT (1) | LT3160948T (enExample) |
| ME (1) | ME03316B (enExample) |
| MX (1) | MX367404B (enExample) |
| PL (1) | PL3160948T3 (enExample) |
| PT (1) | PT3160948T (enExample) |
| RS (1) | RS58274B1 (enExample) |
| SI (1) | SI3160948T1 (enExample) |
| SM (1) | SMT201900039T1 (enExample) |
| TR (1) | TR201900659T4 (enExample) |
| TW (1) | TWI677498B (enExample) |
| UY (1) | UY36195A (enExample) |
| WO (1) | WO2016001631A1 (enExample) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ME03316B (me) * | 2014-06-30 | 2019-10-20 | Astrazeneca Ab | Benzoksazinon amidi као modulatori mineralokorтikoidnog receptora |
| JOP20210009A1 (ar) | 2018-07-19 | 2021-01-12 | Astrazeneca Ab | طرق لعلاج HFpEF باستعمال داباجليفلوزين وتركيبات تشمله |
| CN112107568B (zh) * | 2019-06-19 | 2022-03-25 | 北京龙嘉博创医药科技有限公司 | 二芳基酰胺类化合物及其应用 |
| BR112020008705A2 (pt) * | 2019-08-30 | 2022-03-22 | Astrazeneca Ab | Métodos de tratamento da insuficiência cardíaca com fração de ejeção reduzida com dapagliflozina |
| JP2023536009A (ja) | 2020-07-27 | 2023-08-23 | アストラゼネカ・アクチエボラーグ | ダパグリフロジンによる慢性腎疾患の処置方法 |
| BR112023025793A2 (pt) * | 2021-06-15 | 2024-02-27 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Composto de fórmula (ii), um estereoisômero deste ou um sal farmaceuticamente aceitável deste, composição farmacêutica e uso do composto |
| TW202409023A (zh) | 2022-07-14 | 2024-03-01 | 美商富曼西公司 | 除草苯并𠯤 |
| US20250381145A1 (en) | 2022-09-01 | 2025-12-18 | Astrazeneca Ab | Combination of sglt2 inhibitors and mineralcorticoid receptor modulators for use in treatment of cardiorenal diseases |
| WO2024125591A1 (zh) * | 2022-12-15 | 2024-06-20 | 正大天晴药业集团股份有限公司 | 苯并恶嗪酮类化合物的结晶及其制备 |
| AU2024387082A1 (en) | 2023-11-21 | 2026-06-04 | Fmc Corporation | Substituted tetrahydroquinoline and tetrahydroquinoxaline herbicides |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015259A2 (en) * | 2004-07-28 | 2006-02-09 | Irm Llc | Compounds and compositions as modulators of steroid hormone nuclear receptors |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085868A1 (en) * | 2001-04-23 | 2002-10-31 | Astrazeneca Ab | Benzoxazinone derivatives for use in the treatment of angiogenesis |
| WO2004056820A1 (en) * | 2002-12-20 | 2004-07-08 | Warner-Lambert Company Llc | Benzoxazines and derivatives thereof as inhibitors of pi3ks |
| CN101018552A (zh) * | 2004-07-14 | 2007-08-15 | 利亘制药公司 | 细胞内受体调节剂化合物和方法 |
| TW200732331A (en) | 2005-12-28 | 2007-09-01 | Takeda Pharmaceuticals Co | Fused heterocyclic compound and use thereof |
| TWI385161B (zh) | 2006-02-02 | 2013-02-11 | Mitsubishi Tanabe Pharma Corp | 含氮雜雙環化合物 |
| ES2375877T3 (es) | 2006-10-31 | 2012-03-07 | Pfizer Products Inc. | Compuestos de pirazolina como antagonistas de receptores de mineralocorticoides. |
| DE102007009494A1 (de) | 2007-02-27 | 2008-08-28 | Bayer Healthcare Ag | Substituierte 4-Aryl-1, 4-dihydro-1,6-naphthyridinamide und ihre Verwendung |
| US8063090B2 (en) | 2007-03-23 | 2011-11-22 | Merck Sharp & Dohme Corp. | Mineralocorticoid receptor modulators |
| TWI444185B (zh) | 2007-04-09 | 2014-07-11 | Daiichi Sankyo Co Ltd | 吡咯衍生物之阻轉異構物 |
| US8258131B2 (en) | 2007-08-01 | 2012-09-04 | Mitsubishi Tanabe Pharma Corporation | Fused bicyclic compound |
| JP5173653B2 (ja) * | 2007-08-01 | 2013-04-03 | 田辺三菱製薬株式会社 | 医薬組成物 |
| TWI431010B (zh) | 2007-12-19 | 2014-03-21 | Lilly Co Eli | 礦皮質素受體拮抗劑及使用方法 |
| JP2011524896A (ja) * | 2008-06-18 | 2011-09-08 | アストラゼネカ・アクチエボラーグ | 呼吸器障害の処置用のベータ２−アドレナリン受容体アゴニストとして作用するベンズオキサジノン誘導体 |
| US20100094000A1 (en) | 2008-09-03 | 2010-04-15 | Takeda Pharmaceutical Company Limited | Pyrazole compounds |
| WO2010098286A1 (ja) | 2009-02-25 | 2010-09-02 | 第一三共株式会社 | ミネラルコルチコイド受容体拮抗薬を含有する医薬 |
| WO2010104721A1 (en) | 2009-03-12 | 2010-09-16 | Eli Lilly And Company | Mineralocorticoid receptor antagonist and methods of use |
| CA2756250A1 (en) | 2009-04-10 | 2010-10-14 | Pfizer Inc. | 4,5-dihydro-1h-pyrazole compounds and their pharmaceutical uses |
| WO2011141846A2 (en) | 2010-05-11 | 2011-11-17 | Koninklijke Philips Electronics N.V. | Lighting module |
| EP2569310A1 (en) | 2010-05-11 | 2013-03-20 | Pfizer Inc | Morpholine compounds as mineralocorticoid receptor antagonists |
| TW201216957A (en) | 2010-07-13 | 2012-05-01 | Dainippon Sumitomo Pharma Co | Biarylamide derivative or a pharmaceutically acceptable salt thereof |
| EP2638012A1 (en) | 2010-11-10 | 2013-09-18 | Boehringer Ingelheim International GmbH | Pyridyl ureas as mineralocorticoid receptor antagonists |
| ME03316B (me) * | 2014-06-30 | 2019-10-20 | Astrazeneca Ab | Benzoksazinon amidi као modulatori mineralokorтikoidnog receptora |
-
2015
- 2015-06-26 ME MEP-2019-19A patent/ME03316B/me unknown
- 2015-06-26 CN CN201580035032.8A patent/CN106536491B/zh active Active
- 2015-06-26 JP JP2016575499A patent/JP6368383B2/ja active Active
- 2015-06-26 EA EA201790046A patent/EA029518B1/ru not_active IP Right Cessation
- 2015-06-26 TR TR2019/00659T patent/TR201900659T4/tr unknown
- 2015-06-26 US US15/320,379 patent/US10017502B2/en active Active
- 2015-06-26 HU HUE15736015A patent/HUE042370T2/hu unknown
- 2015-06-26 UY UY0001036195A patent/UY36195A/es not_active Application Discontinuation
- 2015-06-26 RS RS20190085A patent/RS58274B1/sr unknown
- 2015-06-26 MX MX2017000183A patent/MX367404B/es active IP Right Grant
- 2015-06-26 HR HRP20190147TT patent/HRP20190147T1/hr unknown
- 2015-06-26 PL PL15736015T patent/PL3160948T3/pl unknown
- 2015-06-26 PT PT15736015T patent/PT3160948T/pt unknown
- 2015-06-26 DK DK15736015.7T patent/DK3160948T3/en active
- 2015-06-26 WO PCT/GB2015/051860 patent/WO2016001631A1/en not_active Ceased
- 2015-06-26 EP EP15736015.7A patent/EP3160948B1/en active Active
- 2015-06-26 CA CA2953655A patent/CA2953655C/en active Active
- 2015-06-26 LT LTEP15736015.7T patent/LT3160948T/lt unknown
- 2015-06-26 ES ES15736015T patent/ES2707726T3/es active Active
- 2015-06-26 AU AU2015282450A patent/AU2015282450C1/en active Active
- 2015-06-26 KR KR1020177002518A patent/KR102012222B1/ko active Active
- 2015-06-26 SI SI201530572T patent/SI3160948T1/sl unknown
- 2015-06-26 SM SM20190039T patent/SMT201900039T1/it unknown
- 2015-06-29 US US14/753,239 patent/US9394291B2/en active Active
- 2015-06-29 TW TW104120998A patent/TWI677498B/zh active
- 2015-06-30 AR ARP150102098A patent/AR101036A1/es active IP Right Grant
-
2019
- 2019-01-24 CY CY20191100097T patent/CY1121596T1/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015259A2 (en) * | 2004-07-28 | 2006-02-09 | Irm Llc | Compounds and compositions as modulators of steroid hormone nuclear receptors |
Non-Patent Citations (1)
| Title |
|---|
| HASUI TOMOAKI; OHRA TAIICHI; OHYABU NORIO; ASANO KOUHEI; MATSUI HIDEKI; MIZUKAMI ATSUSHI; HABUKA NORIYUKI; SOGABE SATOSHI; ENDO SA: "Design, synthesis, and structure–activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagon", BIOORGANIC & MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 21, no. 19, 1 January 1900 (1900-01-01), GB, pages 5983 - 5994, XP028706278, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2013.07.043 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102012222B1 (ko) | 무기질코르티코이드 수용체 조절제로서의 벤족사지논 아미드 | |
| JP5564036B2 (ja) | ヒストン脱アセチル化酵素阻害薬としてのスピロ環誘導体 | |
| KR101373902B1 (ko) | 신장 바깥 수질 포타슘 채널의 억제제 | |
| CA3133753A1 (en) | Novel small molecule inhibitors of tead transcription factors | |
| JP2025510705A (ja) | 縮合環化合物、それを含む医薬組成物及び応用 | |
| CA2908879C (en) | Crystal of pyrrole derivative and method for producing the same | |
| JP5315244B2 (ja) | アザビシクロヘキサン誘導体の使用 | |
| CA3196526A1 (en) | Malt-1 modulators | |
| CA3121289C (en) | Histone acetylase p300 inhibitor and use thereof | |
| HK1203943A1 (en) | Quinazolinedione derivative | |
| JP2025531844A (ja) | Ｅｎｌ／ａｆ９ ｙｅａｔｓ及びｆｌｔ３の阻害剤 | |
| ES2593057B1 (es) | Moduladores selectivos de la actividad del receptor GPR55: derivados de cromenopirazol | |
| HK1237338B (en) | Benzoxazinone amides as mineralocorticoid receptor modulators | |
| HK1237338A1 (en) | Benzoxazinone amides as mineralocorticoid receptor modulators | |
| OA21895A (en) | N-(HydroxyalkyI (Hetero) Aryl) Tetrahydrofuran carboxamides as modulators of sodium channels. | |
| Gao | Design, synthesis and evaluation of novel muscarinic ligands | |
| TW202604504A (zh) | 含氮並環化合物、含其的藥物組合物及其應用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KG TJ TM |