AU2008343524B2 - 6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists - Google Patents
6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists Download PDFInfo
- Publication number
- AU2008343524B2 AU2008343524B2 AU2008343524A AU2008343524A AU2008343524B2 AU 2008343524 B2 AU2008343524 B2 AU 2008343524B2 AU 2008343524 A AU2008343524 A AU 2008343524A AU 2008343524 A AU2008343524 A AU 2008343524A AU 2008343524 B2 AU2008343524 B2 AU 2008343524B2
- Authority
- AU
- Australia
- Prior art keywords
- mol
- formula
- compound
- methyl
- dibenzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 229940083712 aldosterone antagonist Drugs 0.000 title claims description 7
- 239000002394 mineralocorticoid antagonist Substances 0.000 title claims description 6
- FPIWJQQRYHEICX-UHFFFAOYSA-N 6,11-dihydrobenzo[c][1]benzoxepine Chemical compound C1OC2=CC=CC=C2CC2=CC=CC=C12 FPIWJQQRYHEICX-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 238000000034 method Methods 0.000 claims abstract description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 18
- 206010020772 Hypertension Diseases 0.000 claims abstract description 18
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 18
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 18
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 17
- 206010019280 Heart failures Diseases 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 34
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 20
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 206010003119 arrhythmia Diseases 0.000 claims description 11
- 208000016998 Conn syndrome Diseases 0.000 claims description 10
- 208000019025 Hypokalemia Diseases 0.000 claims description 10
- 230000006793 arrhythmia Effects 0.000 claims description 10
- 239000004202 carbamide Substances 0.000 claims description 10
- 230000002107 myocardial effect Effects 0.000 claims description 10
- 208000024896 potassium deficiency disease Diseases 0.000 claims description 10
- 208000013846 primary aldosteronism Diseases 0.000 claims description 10
- 208000012904 Bartter disease Diseases 0.000 claims description 9
- 208000010062 Bartter syndrome Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002464 receptor antagonist Substances 0.000 abstract 1
- 229940044551 receptor antagonist Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 140
- 238000002360 preparation method Methods 0.000 description 101
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 92
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 73
- 238000003756 stirring Methods 0.000 description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000012141 concentrate Substances 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 65
- 239000000203 mixture Substances 0.000 description 62
- 239000007787 solid Substances 0.000 description 58
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 48
- 235000019439 ethyl acetate Nutrition 0.000 description 47
- 239000012044 organic layer Substances 0.000 description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 39
- 102100021316 Mineralocorticoid receptor Human genes 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 34
- 239000002904 solvent Substances 0.000 description 34
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- -1 ethanol Chemical compound 0.000 description 31
- 239000000126 substance Substances 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 229910052757 nitrogen Inorganic materials 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 25
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 23
- 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 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 239000005557 antagonist Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 229940086542 triethylamine Drugs 0.000 description 22
- 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 21
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 229960002478 aldosterone Drugs 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 19
- 239000001257 hydrogen Substances 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000005909 Kieselgur Substances 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 18
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 238000009739 binding Methods 0.000 description 17
- 229910052717 sulfur Inorganic materials 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 16
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 15
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 15
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 15
- 230000027455 binding Effects 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- 208000035475 disorder Diseases 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 102100032187 Androgen receptor Human genes 0.000 description 14
- 108010080146 androgen receptors Proteins 0.000 description 14
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 102000003998 progesterone receptors Human genes 0.000 description 14
- 108090000468 progesterone receptors Proteins 0.000 description 14
- 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 14
- 125000001153 fluoro group Chemical group F* 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 239000002244 precipitate Substances 0.000 description 13
- 238000010791 quenching Methods 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- UQEANKGXXSENNF-UHFFFAOYSA-N 4-bromo-1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Br)=CC=C1F UQEANKGXXSENNF-UHFFFAOYSA-N 0.000 description 11
- 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 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000003446 ligand Substances 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- CCCIJQPRIXGQOE-XWSJACJDSA-N 17beta-hydroxy-17-methylestra-4,9,11-trien-3-one Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C=C2 CCCIJQPRIXGQOE-XWSJACJDSA-N 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 8
- SLIKWVTWIGHFJE-UHFFFAOYSA-N diphenoxymethylidenecyanamide Chemical compound C=1C=CC=CC=1OC(=NC#N)OC1=CC=CC=C1 SLIKWVTWIGHFJE-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 7
- 235000011056 potassium acetate Nutrition 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- RNNVXAMKKUKKFE-UHFFFAOYSA-N 3-ethenyldioxaborolane Chemical compound C=CB1CCOO1 RNNVXAMKKUKKFE-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-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
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 6
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 6
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 6
- 229940105329 carboxymethylcellulose Drugs 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 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
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- 101000615613 Homo sapiens Mineralocorticoid receptor Proteins 0.000 description 5
- 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 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003792 electrolyte Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 5
- 229920000053 polysorbate 80 Polymers 0.000 description 5
- 229940068968 polysorbate 80 Drugs 0.000 description 5
- 238000000159 protein binding assay Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 102000005969 steroid hormone receptors Human genes 0.000 description 5
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 4
- LIMKKQOHDIMHEX-UHFFFAOYSA-N 1-hydroxypiperidin-2-amine Chemical compound NC1CCCCN1O LIMKKQOHDIMHEX-UHFFFAOYSA-N 0.000 description 4
- KGVPNVYKWGRCHO-UHFFFAOYSA-N 1h-pyrrolo[2,1-c][1,4]oxazine Chemical compound C1OC=CN2C=CC=C12 KGVPNVYKWGRCHO-UHFFFAOYSA-N 0.000 description 4
- HUVAOAVBKOVPBZ-UHFFFAOYSA-N 2-bromo-5-fluorophenol Chemical compound OC1=CC(F)=CC=C1Br HUVAOAVBKOVPBZ-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000002682 Hyperkalemia Diseases 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 235000019502 Orange oil Nutrition 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 4
- INLLPKCGLOXCIV-UHFFFAOYSA-N bromoethene Chemical compound BrC=C INLLPKCGLOXCIV-UHFFFAOYSA-N 0.000 description 4
- 230000005587 bubbling Effects 0.000 description 4
- 230000002860 competitive effect Effects 0.000 description 4
- 229940109239 creatinine Drugs 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229960003957 dexamethasone Drugs 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 230000029142 excretion Effects 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000010502 orange oil Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 3
- QEYOGSASZSRTPT-LFIBNONCSA-N 2-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1\C=C/1C2=CC=C(F)C=C2OCC2=C(F)C=CC=C2\1 QEYOGSASZSRTPT-LFIBNONCSA-N 0.000 description 3
- PRKFHQWMICWPRU-UHFFFAOYSA-N 2-phenylpyrrolidin-1-amine Chemical compound NN1CCCC1C1=CC=CC=C1 PRKFHQWMICWPRU-UHFFFAOYSA-N 0.000 description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 3
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000001358 L(+)-tartaric acid Substances 0.000 description 3
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical group C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- ZKNXZJZQQIQXOD-UHFFFAOYSA-N diphenyl-(2-pyridin-4-ylcyclopropyl)methanol;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1CC1C1=CC=NC=C1 ZKNXZJZQQIQXOD-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 238000010494 dissociation reaction Methods 0.000 description 3
- 230000005593 dissociations Effects 0.000 description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 238000003305 oral gavage Methods 0.000 description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- QFFCYTLOTYIJMR-XMGTWHOFSA-N promegestone Chemical compound C1CC2=CC(=O)CCC2=C2[C@@H]1[C@@H]1CC[C@@](C(=O)CC)(C)[C@@]1(C)CC2 QFFCYTLOTYIJMR-XMGTWHOFSA-N 0.000 description 3
- 229960001584 promegestone Drugs 0.000 description 3
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 108020003113 steroid hormone receptors Proteins 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 150000003892 tartrate salts Chemical class 0.000 description 3
- GVYATPKTSSTHKN-ZIAGYGMSSA-N tert-butyl (3r,4r)-3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@@H](O)[C@@H]1NCC1=CC=CC=C1 GVYATPKTSSTHKN-ZIAGYGMSSA-N 0.000 description 3
- KREUZCYJWPQPJX-HTQZYQBOSA-N tert-butyl (3r,4r)-4-amino-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1 KREUZCYJWPQPJX-HTQZYQBOSA-N 0.000 description 3
- NNZWZNBXURWGSK-UHFFFAOYSA-N tert-butyl 3-(4-bromo-2-nitroanilino)azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1NC1=CC=C(Br)C=C1[N+]([O-])=O NNZWZNBXURWGSK-UHFFFAOYSA-N 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- JBWDAFURQPSESI-KPKJPENVSA-N (11e)-11-(bromomethylidene)-3,7-difluoro-6h-benzo[c][1]benzoxepine Chemical compound O1CC2=C(F)C=CC=C2\C(=C/Br)C2=CC=C(F)C=C12 JBWDAFURQPSESI-KPKJPENVSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- RCNXLEBXTHGOQC-OGFXRTJISA-N (2r)-1-morpholin-4-ylpropan-2-amine;hydrochloride Chemical compound Cl.C[C@@H](N)CN1CCOCC1 RCNXLEBXTHGOQC-OGFXRTJISA-N 0.000 description 2
- DKOPVVYGSCXKAM-ZYHUDNBSSA-N (3r,4r)-4-(4-bromo-2-nitroanilino)-1-methylpiperidin-3-ol Chemical compound O[C@@H]1CN(C)CC[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O DKOPVVYGSCXKAM-ZYHUDNBSSA-N 0.000 description 2
- LDSWIZQULAPCAB-FOKYBFFNSA-N (3r,4r)-4-(4-bromo-2-nitroanilino)piperidin-3-ol;hydrochloride Chemical compound Cl.O[C@@H]1CNCC[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O LDSWIZQULAPCAB-FOKYBFFNSA-N 0.000 description 2
- VPDLNNXVNJVJJH-ONGXEEELSA-N (3s,4s)-4-(4-bromo-2-nitroanilino)-1-methylpyrrolidin-3-ol Chemical compound C1N(C)C[C@H](O)[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O VPDLNNXVNJVJJH-ONGXEEELSA-N 0.000 description 2
- NUHDKCZXZRQHIN-ONGXEEELSA-N (3s,4s)-4-(4-bromo-2-nitroanilino)piperidin-3-ol Chemical compound O[C@H]1CNCC[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O NUHDKCZXZRQHIN-ONGXEEELSA-N 0.000 description 2
- QVNVXNCRVTXWOP-WPRPVWTQSA-N (3s,4s)-4-(4-bromo-2-nitroanilino)pyrrolidin-3-ol Chemical compound O[C@H]1CNC[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O QVNVXNCRVTXWOP-WPRPVWTQSA-N 0.000 description 2
- CWIMZRBTVQIIID-UWVGGRQHSA-N (7s,8as)-7-(4-bromo-2-nitroanilino)-6,7,8,8a-tetrahydro-1h-pyrrolo[2,1-c][1,4]oxazin-4-one Chemical compound [O-][N+](=O)C1=CC(Br)=CC=C1N[C@@H]1CN2C(=O)COC[C@@H]2C1 CWIMZRBTVQIIID-UWVGGRQHSA-N 0.000 description 2
- MRKAMURBGIFDAK-HOQWKFCYSA-N (7s,8as)-n-[4-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-2-nitrophenyl]-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[2,1-c][1,4]oxazin-7-amine Chemical compound C\12=CC=CC(F)=C2COC2=CC(F)=CC=C2C/1=C/C1=CC=C(N[C@@H]2CN3CCOC[C@@H]3C2)C([N+](=O)[O-])=C1 MRKAMURBGIFDAK-HOQWKFCYSA-N 0.000 description 2
- TUJFAJUEZKUVNX-IQVSESKRSA-N (z)-but-2-enedioic acid;[5-[(e)-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(3s,4s)-4-hydroxy-1-methylpyrrolidin-3-yl]benzimidazol-2-yl]cyanamide Chemical compound OC(=O)\C=C/C(O)=O.C1N(C)C[C@H](O)[C@H]1N1C(=N/C#N)/NC2=CC(\C=C/3C4=CC=C(F)C=C4OCC4=CC=CC=C4\3)=CC=C21 TUJFAJUEZKUVNX-IQVSESKRSA-N 0.000 description 2
- 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 2
- GQFITODJWOIYPF-UHFFFAOYSA-N 1-(bromomethyl)-2-iodobenzene Chemical group BrCC1=CC=CC=C1I GQFITODJWOIYPF-UHFFFAOYSA-N 0.000 description 2
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 2
- ACGCQQWDSLHRIT-UHFFFAOYSA-N 1-bromo-4-fluoro-2-[(2-iodophenyl)methoxy]benzene Chemical compound FC1=CC=C(Br)C(OCC=2C(=CC=CC=2)I)=C1 ACGCQQWDSLHRIT-UHFFFAOYSA-N 0.000 description 2
- NGFNZCVNNNEOTH-UHFFFAOYSA-N 1-bromo-5-fluorocyclohexa-2,4-diene-1-carbaldehyde Chemical compound FC1=CC=CC(Br)(C=O)C1 NGFNZCVNNNEOTH-UHFFFAOYSA-N 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 2
- MZMNEDXVUJLQAF-HTQZYQBOSA-N 1-o-tert-butyl 2-o-methyl (2r,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C MZMNEDXVUJLQAF-HTQZYQBOSA-N 0.000 description 2
- MZMNEDXVUJLQAF-SFYZADRCSA-N 1-o-tert-butyl 2-o-methyl (2s,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C MZMNEDXVUJLQAF-SFYZADRCSA-N 0.000 description 2
- QXGDJXLJHBZELB-BDAKNGLRSA-N 1-o-tert-butyl 2-o-methyl (2s,4r)-4-methylsulfonyloxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C QXGDJXLJHBZELB-BDAKNGLRSA-N 0.000 description 2
- BJQMWOSPZUZYNW-YUMQZZPRSA-N 1-o-tert-butyl 2-o-methyl (2s,4s)-4-azidopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C BJQMWOSPZUZYNW-YUMQZZPRSA-N 0.000 description 2
- ULKZECNDTHFDTC-LDADJPATSA-N 2-[(e)-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1\C=C/1C2=CC=C(F)C=C2OCC2=CC=CC=C2\1 ULKZECNDTHFDTC-LDADJPATSA-N 0.000 description 2
- XQDSIGDVDWFZPP-UHFFFAOYSA-N 2-phenylpiperidin-1-amine Chemical compound NN1CCCCC1C1=CC=CC=C1 XQDSIGDVDWFZPP-UHFFFAOYSA-N 0.000 description 2
- GLKHLBAXHLAQBJ-UHFFFAOYSA-N 3-bromo-2-nitroaniline Chemical compound NC1=CC=CC(Br)=C1[N+]([O-])=O GLKHLBAXHLAQBJ-UHFFFAOYSA-N 0.000 description 2
- JAQKCQVBCCMHJE-LLXCYVELSA-N 4-[(e)-(3,8-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-n-[(2r)-1-morpholin-4-ylpropan-2-yl]-2-nitroaniline Chemical compound C([C@@H](C)NC=1C(=CC(\C=C/2C3=CC=C(F)C=C3OCC3=CC(F)=CC=C3\2)=CC=1)[N+]([O-])=O)N1CCOCC1 JAQKCQVBCCMHJE-LLXCYVELSA-N 0.000 description 2
- NMKDWYNMMHMSHC-SNVBAGLBSA-N 4-bromo-n-[(2r)-1-morpholin-4-ylpropan-2-yl]-2-nitroaniline Chemical compound C([C@@H](C)NC=1C(=CC(Br)=CC=1)[N+]([O-])=O)N1CCOCC1 NMKDWYNMMHMSHC-SNVBAGLBSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- ISPMENGQGXFXSH-UHFFFAOYSA-N 5-bromo-5-(bromomethyl)-1-fluorocyclohexa-1,3-diene Chemical compound FC1=CC=CC(Br)(CBr)C1 ISPMENGQGXFXSH-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 2
- ATKZCKGPNZGDFU-UHFFFAOYSA-N B(O)O.C(=C)CC(O)(C)C(C)(C)O Chemical compound B(O)O.C(=C)CC(O)(C)C(C)(C)O ATKZCKGPNZGDFU-UHFFFAOYSA-N 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- MDFDJUGRFPKMLI-UHFFFAOYSA-N N-(4-bromo-2-nitrophenyl)azetidin-3-amine hydrochloride Chemical compound Cl.[O-][N+](=O)c1cc(Br)ccc1NC1CNC1 MDFDJUGRFPKMLI-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 108010085012 Steroid Receptors Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- NLKBUJQLMRHSKP-SSDOTTSWSA-N [(2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propyl] methanesulfonate Chemical compound CS(=O)(=O)OC[C@@H](C)NC(=O)OC(C)(C)C NLKBUJQLMRHSKP-SSDOTTSWSA-N 0.000 description 2
- HRXHRZIPVDLMAF-IUCAKERBSA-N [(2s,4s)-4-(4-bromo-2-nitroanilino)pyrrolidin-2-yl]methanol Chemical compound C1N[C@H](CO)C[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O HRXHRZIPVDLMAF-IUCAKERBSA-N 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- SXGBREZGMJVYRL-UHFFFAOYSA-N butan-1-amine;hydrobromide Chemical compound [Br-].CCCC[NH3+] SXGBREZGMJVYRL-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000003293 cardioprotective effect Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- YTNXKRLEBBVQPA-NTEUORMPSA-N ethyl (2e)-2-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)acetate Chemical compound O1CC2=C(F)C=CC=C2C(=C/C(=O)OCC)\C2=CC=C(F)C=C21 YTNXKRLEBBVQPA-NTEUORMPSA-N 0.000 description 2
- UNMCOTVGVGALHS-UHFFFAOYSA-N ethyl 3-[2-[(2-bromo-5-fluorophenoxy)methyl]phenyl]prop-2-enoate Chemical compound CCOC(=O)C=CC1=CC=CC=C1COC1=CC(F)=CC=C1Br UNMCOTVGVGALHS-UHFFFAOYSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 238000002825 functional assay Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- DBZUDAMQQMIYHP-UHFFFAOYSA-N n-(4-bromo-2-nitrophenyl)-4-methylpiperazin-1-amine Chemical compound C1CN(C)CCN1NC1=CC=C(Br)C=C1[N+]([O-])=O DBZUDAMQQMIYHP-UHFFFAOYSA-N 0.000 description 2
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical compound ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 description 2
- ZKONTOQLRAPWED-UHFFFAOYSA-N n-ethylmorpholin-4-amine Chemical class CCNN1CCOCC1 ZKONTOQLRAPWED-UHFFFAOYSA-N 0.000 description 2
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001525 receptor binding assay Methods 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 229960002256 spironolactone Drugs 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
- 230000000638 stimulation Effects 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- OCLZOKUGIXLYJZ-YUMQZZPRSA-N tert-butyl (2s,4s)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO OCLZOKUGIXLYJZ-YUMQZZPRSA-N 0.000 description 2
- TYVPMGGBXKDZAF-YUMQZZPRSA-N tert-butyl (2s,4s)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1CO TYVPMGGBXKDZAF-YUMQZZPRSA-N 0.000 description 2
- LWHRDKRVPKNHQP-DGCLKSJQSA-N tert-butyl (3r,4r)-3-(4-bromo-2-nitroanilino)-4-hydroxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@@H](O)[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O LWHRDKRVPKNHQP-DGCLKSJQSA-N 0.000 description 2
- JVRIILICSFSOJD-RNFRBKRXSA-N tert-butyl (3r,4r)-3-bromo-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Br)C1 JVRIILICSFSOJD-RNFRBKRXSA-N 0.000 description 2
- HRWKOZFJZUHZAK-TZMCWYRMSA-N tert-butyl (3r,4r)-4-(4-bromo-2-nitroanilino)-3-hydroxypiperidine-1-carboxylate Chemical compound O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O HRWKOZFJZUHZAK-TZMCWYRMSA-N 0.000 description 2
- KZKBBVVEKSUWIS-GXTWGEPZSA-N tert-butyl (3s,4r)-3-(4-bromo-2-nitroanilino)-4-(2-chloroacetyl)oxypyrrolidine-1-carboxylate Chemical compound ClCC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O KZKBBVVEKSUWIS-GXTWGEPZSA-N 0.000 description 2
- LWHRDKRVPKNHQP-AAEUAGOBSA-N tert-butyl (3s,4s)-3-(4-bromo-2-nitroanilino)-4-hydroxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O LWHRDKRVPKNHQP-AAEUAGOBSA-N 0.000 description 2
- GVYATPKTSSTHKN-KBPBESRZSA-N tert-butyl (3s,4s)-3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1NCC1=CC=CC=C1 GVYATPKTSSTHKN-KBPBESRZSA-N 0.000 description 2
- HRWKOZFJZUHZAK-JSGCOSHPSA-N tert-butyl (3s,4s)-4-(4-bromo-2-nitroanilino)-3-hydroxypiperidine-1-carboxylate Chemical compound O[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O HRWKOZFJZUHZAK-JSGCOSHPSA-N 0.000 description 2
- KREUZCYJWPQPJX-YUMQZZPRSA-N tert-butyl (3s,4s)-4-amino-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](O)C1 KREUZCYJWPQPJX-YUMQZZPRSA-N 0.000 description 2
- YEBDZDMYLQHGGZ-UHFFFAOYSA-N tert-butyl 2,5-dihydropyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC1 YEBDZDMYLQHGGZ-UHFFFAOYSA-N 0.000 description 2
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 2
- WOEQSXAIPTXOPY-UHFFFAOYSA-N tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1 WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 2
- LCEOLFDEIRVGNS-SNVBAGLBSA-N tert-butyl n-[(2r)-1-morpholin-4-ylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C)CN1CCOCC1 LCEOLFDEIRVGNS-SNVBAGLBSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 229920001567 vinyl ester resin Polymers 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- WZUVPPKBWHMQCE-XJKSGUPXSA-N (+)-haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 1
- BJBUEDPLEOHJGE-UHFFFAOYSA-N (2R,3S)-3-Hydroxy-2-pyrolidinecarboxylic acid Natural products OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-N 0.000 description 1
- OOGFPFWTORZYAN-RICNETNQSA-N (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound O[C@H]1CN[C@@H](C(O)=O)C1.O[C@H]1CN[C@@H](C(O)=O)C1 OOGFPFWTORZYAN-RICNETNQSA-N 0.000 description 1
- VQJGUUHKSTYEGE-GCYSTPHZSA-N (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound N1[C@H](C(=O)O)C[C@@H](O)C1.N1[C@H](C(=O)O)C[C@@H](O)C1.N1[C@H](C(=O)O)C[C@@H](O)C1 VQJGUUHKSTYEGE-GCYSTPHZSA-N 0.000 description 1
- BENKAPCDIOILGV-RNFRBKRXSA-N (2r,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(O)=O BENKAPCDIOILGV-RNFRBKRXSA-N 0.000 description 1
- YEJFFQAGTXBSTI-VKKIDBQXSA-N (2r,4r)-4-hydroxypyrrolidine-2-carboxylic acid;hydrochloride Chemical compound Cl.O[C@H]1CN[C@@H](C(O)=O)C1 YEJFFQAGTXBSTI-VKKIDBQXSA-N 0.000 description 1
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 description 1
- CVOAUOJFTYKHJC-RFZPGFLSSA-N (3R,4R)-4-azido-3-hydroxypiperidine-1-carboxylic acid Chemical compound N(=[N+]=[N-])[C@H]1[C@@H](CN(CC1)C(=O)O)O CVOAUOJFTYKHJC-RFZPGFLSSA-N 0.000 description 1
- DJVRJOHZJRXJNI-GHMZBOCLSA-N (3r,4r)-3-(benzylamino)-4-hydroxypyrrolidine-1-carboxylic acid Chemical compound O[C@@H]1CN(C(O)=O)C[C@H]1NCC1=CC=CC=C1 DJVRJOHZJRXJNI-GHMZBOCLSA-N 0.000 description 1
- XQINAWASZNRPFK-KKPGMBOPSA-N (3r,4r)-4-[4-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-2-nitroanilino]-1-methylpiperidin-3-ol Chemical compound O[C@@H]1CN(C)CC[C@H]1NC(C(=C1)[N+]([O-])=O)=CC=C1\C=C/1C2=CC=C(F)C=C2OCC2=C(F)C=CC=C2\1 XQINAWASZNRPFK-KKPGMBOPSA-N 0.000 description 1
- CIQOTANLSZEILP-RFZPGFLSSA-N (3r,4r)-4-amino-1-methylpyrrolidin-3-ol Chemical compound CN1C[C@@H](N)[C@H](O)C1 CIQOTANLSZEILP-RFZPGFLSSA-N 0.000 description 1
- AGDZQYSHSWJPKP-RFZPGFLSSA-N (3r,4r)-4-amino-3-hydroxypiperidine-1-carboxylic acid Chemical compound N[C@@H]1CCN(C(O)=O)C[C@H]1O AGDZQYSHSWJPKP-RFZPGFLSSA-N 0.000 description 1
- AKSFDQOICNFCSI-QWWZWVQMSA-N (3r,4r)-4-bromopyrrolidin-3-ol Chemical compound O[C@@H]1CNC[C@H]1Br AKSFDQOICNFCSI-QWWZWVQMSA-N 0.000 description 1
- DKOPVVYGSCXKAM-JQWIXIFHSA-N (3s,4s)-4-(4-bromo-2-nitroanilino)-1-methylpiperidin-3-ol Chemical compound O[C@H]1CN(C)CC[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O DKOPVVYGSCXKAM-JQWIXIFHSA-N 0.000 description 1
- HSJSQXHDZUUZOL-QWRGUYRKSA-N (7s,8as)-n-(4-bromo-2-nitrophenyl)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[2,1-c][1,4]oxazin-7-amine Chemical compound [O-][N+](=O)C1=CC(Br)=CC=C1N[C@@H]1CN2CCOC[C@@H]2C1 HSJSQXHDZUUZOL-QWRGUYRKSA-N 0.000 description 1
- WLIADPFXSACYLS-UHFFFAOYSA-N 1,3-dichlorobut-2-ene Chemical compound CC(Cl)=CCCl WLIADPFXSACYLS-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- RLLWVYYBXSBQJP-UHFFFAOYSA-N 1-azidopyrrolidine Chemical compound [N-]=[N+]=NN1CCCC1 RLLWVYYBXSBQJP-UHFFFAOYSA-N 0.000 description 1
- CZLWYKAZAVYQIK-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(Br)C(CBr)=C1 CZLWYKAZAVYQIK-UHFFFAOYSA-N 0.000 description 1
- LZSYGJNFCREHMD-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1Br LZSYGJNFCREHMD-UHFFFAOYSA-N 0.000 description 1
- NMRPEYWXKIHODK-UHFFFAOYSA-N 1-bromo-2-[(2-bromo-5-fluorophenoxy)methyl]-3-fluorobenzene Chemical compound FC1=CC=C(Br)C(OCC=2C(=CC=CC=2F)Br)=C1 NMRPEYWXKIHODK-UHFFFAOYSA-N 0.000 description 1
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 1
- FLVFPAIGVBQGET-UHFFFAOYSA-N 1-methylpyrrolidin-3-ol Chemical compound CN1CCC(O)C1 FLVFPAIGVBQGET-UHFFFAOYSA-N 0.000 description 1
- QXGDJXLJHBZELB-RKDXNWHRSA-N 1-o-tert-butyl 2-o-methyl (2r,4r)-4-methylsulfonyloxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C QXGDJXLJHBZELB-RKDXNWHRSA-N 0.000 description 1
- TXQUSDPQTQXELO-JGVFFNPUSA-N 1-o-tert-butyl 2-o-methyl (2r,4s)-4-bromopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C TXQUSDPQTQXELO-JGVFFNPUSA-N 0.000 description 1
- TXQUSDPQTQXELO-YUMQZZPRSA-N 1-o-tert-butyl 2-o-methyl (2s,4s)-4-bromopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C TXQUSDPQTQXELO-YUMQZZPRSA-N 0.000 description 1
- WVDGSSCWFMSRHN-UHFFFAOYSA-N 1-o-tert-butyl 2-o-methyl pyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)C1CCCN1C(=O)OC(C)(C)C WVDGSSCWFMSRHN-UHFFFAOYSA-N 0.000 description 1
- RDBQWOPXIYPGPA-WOJGMQOQSA-N 2-[(e)-(3,8-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1\C=C/1C2=CC=C(F)C=C2OCC2=CC(F)=CC=C2\1 RDBQWOPXIYPGPA-WOJGMQOQSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- FMRKYXVZQWHGDA-UHFFFAOYSA-N 2-bromo-5-chlorophenol Chemical compound OC1=CC(Cl)=CC=C1Br FMRKYXVZQWHGDA-UHFFFAOYSA-N 0.000 description 1
- KDBMEVYPXSYYDA-UHFFFAOYSA-N 3-(tert-butylamino)-2-hydroxypropanoic acid Chemical compound CC(C)(C)NCC(O)C(O)=O KDBMEVYPXSYYDA-UHFFFAOYSA-N 0.000 description 1
- XQINAWASZNRPFK-RGVLZGJSSA-N 4-[4-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-2-nitroanilino]-1-methylpiperidin-3-ol Chemical compound OC1CN(C)CCC1NC(C(=C1)[N+]([O-])=O)=CC=C1\C=C/1C2=CC=C(F)C=C2OCC2=C(F)C=CC=C2\1 XQINAWASZNRPFK-RGVLZGJSSA-N 0.000 description 1
- UVBKPWNFXFUDOU-UHFFFAOYSA-N 4-aminopiperidin-3-ol Chemical class NC1CCNCC1O UVBKPWNFXFUDOU-UHFFFAOYSA-N 0.000 description 1
- RJWLLQWLBMJCFD-UHFFFAOYSA-N 4-methylpiperazin-1-amine Chemical compound CN1CCN(N)CC1 RJWLLQWLBMJCFD-UHFFFAOYSA-N 0.000 description 1
- DQMVZJPBUAQCMA-UHFFFAOYSA-N 6,7,8,8a-tetrahydro-1h-pyrrolo[2,1-c][1,4]oxazin-4-one Chemical compound O=C1COCC2CCCN12 DQMVZJPBUAQCMA-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- SMWWNMQSZSZWSJ-IODNYQNNSA-N C(C(O)C1=CC=CC=C1)(=O)O.C(C)(C)(C)OC(=O)N1C[C@@H]([C@H](C1)O)NCC1=CC=CC=C1 Chemical compound C(C(O)C1=CC=CC=C1)(=O)O.C(C)(C)(C)OC(=O)N1C[C@@H]([C@H](C1)O)NCC1=CC=CC=C1 SMWWNMQSZSZWSJ-IODNYQNNSA-N 0.000 description 1
- SMWWNMQSZSZWSJ-DTPOWOMPSA-N C(C(O)C1=CC=CC=C1)(=O)O.C(C1=CC=CC=C1)N[C@@H]1CN(C[C@H]1O)C(=O)OC(C)(C)C Chemical compound C(C(O)C1=CC=CC=C1)(=O)O.C(C1=CC=CC=C1)N[C@@H]1CN(C[C@H]1O)C(=O)OC(C)(C)C SMWWNMQSZSZWSJ-DTPOWOMPSA-N 0.000 description 1
- TWOBOARBHJAQEP-UHFFFAOYSA-N C1C2=CC=CC=C2COC2=C1C(=CBr)CC(F)=C2 Chemical compound C1C2=CC=CC=C2COC2=C1C(=CBr)CC(F)=C2 TWOBOARBHJAQEP-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010065556 Drug Receptors Proteins 0.000 description 1
- 102000013138 Drug Receptors Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Natural products C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 1
- 101000775732 Homo sapiens Androgen receptor Proteins 0.000 description 1
- 101000926939 Homo sapiens Glucocorticoid receptor Proteins 0.000 description 1
- 101000928259 Homo sapiens NADPH:adrenodoxin oxidoreductase, mitochondrial Proteins 0.000 description 1
- 101000574060 Homo sapiens Progesterone receptor Proteins 0.000 description 1
- 229940127517 Hormone Receptor Modulators Drugs 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- SRHPFVKOJSFHKR-ORCGFQNDSA-N [1-[(7s,8ar)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[2,1-c][1,4]oxazin-7-yl]-5-[(e)-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]benzimidazol-2-yl]urea Chemical compound C\12=CC=CC=C2COC2=CC(F)=CC=C2C/1=C/C1=CC=C(N(C(=N/C(=O)N)/N2)[C@@H]3CN4CCOC[C@H]4C3)C2=C1 SRHPFVKOJSFHKR-ORCGFQNDSA-N 0.000 description 1
- FKIABHJHRFTRQF-QRQYZTNLSA-N [1-[(7s,8as)-3,4,6,7,8,8a-hexahydro-1h-pyrrolo[2,1-c][1,4]oxazin-7-yl]-5-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]benzimidazol-2-yl]cyanamide Chemical compound C=1C(F)=CC=C2C=1OCC1=C(F)C=CC=C1\C2=C/C1=CC=C(N([C@@H]2CN3CCOC[C@@H]3C2)\C(=N\C#N)N2)C2=C1 FKIABHJHRFTRQF-QRQYZTNLSA-N 0.000 description 1
- UGJBOQWJBNYSSP-NZYROCMPSA-N [5-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(2r)-1-morpholin-4-ylpropan-2-yl]benzimidazol-2-yl]cyanamide Chemical compound C([C@@H](C)N1C(/NC2=CC(\C=C\3C4=CC=CC(F)=C4COC4=CC(F)=CC=C4/3)=CC=C21)=N/C#N)N1CCOCC1 UGJBOQWJBNYSSP-NZYROCMPSA-N 0.000 description 1
- FWFIZMRVJAYDAF-ZMPUUUETSA-N [5-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(2r)-1-morpholin-4-ylpropan-2-yl]benzimidazol-2-yl]urea Chemical compound C([C@@H](C)N1C(/NC2=CC(\C=C\3C4=CC=CC(F)=C4COC4=CC(F)=CC=C4/3)=CC=C21)=N/C(N)=O)N1CCOCC1 FWFIZMRVJAYDAF-ZMPUUUETSA-N 0.000 description 1
- MLAMLYGQLCCLMJ-OZWXINDESA-N [5-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(3r,4r)-3-hydroxy-1-methylpiperidin-4-yl]benzimidazol-2-yl]cyanamide Chemical compound O[C@@H]1CN(C)CC[C@H]1N1C(=N/C#N)/NC2=CC(\C=C\3C4=CC=CC(F)=C4COC4=CC(F)=CC=C4/3)=CC=C21 MLAMLYGQLCCLMJ-OZWXINDESA-N 0.000 description 1
- MLAMLYGQLCCLMJ-HIJVIVJESA-N [5-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(3s,4s)-3-hydroxy-1-methylpiperidin-4-yl]benzimidazol-2-yl]cyanamide Chemical compound O[C@H]1CN(C)CC[C@@H]1N1C(=N/C#N)/NC2=CC(\C=C\3C4=CC=CC(F)=C4COC4=CC(F)=CC=C4/3)=CC=C21 MLAMLYGQLCCLMJ-HIJVIVJESA-N 0.000 description 1
- GTMPXIBYMDJRST-WYMPLXKRSA-N [5-[(e)-(3,8-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-(4-methylpiperazin-1-yl)benzimidazol-2-yl]cyanamide Chemical compound C1CN(C)CCN1N1C(=N/C#N)/NC2=CC(\C=C/3C4=CC=C(F)C=C4OCC4=CC(F)=CC=C4\3)=CC=C21 GTMPXIBYMDJRST-WYMPLXKRSA-N 0.000 description 1
- FTDSWTWTSHDKIA-MTYDYXEWSA-N [5-[(e)-(3,8-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(2r)-1-morpholin-4-ylpropan-2-yl]benzimidazol-2-yl]cyanamide Chemical compound C([C@@H](C)N1C(/NC2=CC(\C=C/3C4=CC=C(F)C=C4OCC4=CC(F)=CC=C4\3)=CC=C21)=N/C#N)N1CCOCC1 FTDSWTWTSHDKIA-MTYDYXEWSA-N 0.000 description 1
- YPCLDHGBEKZGEB-RUDKWAFVSA-N [5-[(e)-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(2r)-1-morpholin-4-ylpropan-2-yl]benzimidazol-2-yl]urea Chemical compound C([C@@H](C)N1C(/NC2=CC(\C=C/3C4=CC=C(F)C=C4OCC4=CC=CC=C4\3)=CC=C21)=N/C(N)=O)N1CCOCC1 YPCLDHGBEKZGEB-RUDKWAFVSA-N 0.000 description 1
- FMRCXWHCSOZFKE-WADMIHMQSA-N [5-[(e)-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(3s,4s)-4-hydroxy-1-methylpyrrolidin-3-yl]benzimidazol-2-yl]cyanamide Chemical compound C1N(C)C[C@H](O)[C@H]1N1C(=N/C#N)/NC2=CC(\C=C/3C4=CC=C(F)C=C4OCC4=CC=CC=C4\3)=CC=C21 FMRCXWHCSOZFKE-WADMIHMQSA-N 0.000 description 1
- YDFMYWUDVADGFG-SZNQACNXSA-N [5-[(e)-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-1-[(3s,4s)-4-hydroxy-1-methylpyrrolidin-3-yl]benzimidazol-2-yl]urea Chemical compound C1N(C)C[C@H](O)[C@H]1N1C(=N/C(N)=O)/NC2=CC(\C=C/3C4=CC=C(F)C=C4OCC4=CC=CC=C4\3)=CC=C21 YDFMYWUDVADGFG-SZNQACNXSA-N 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- PCJHDBHWLFUQLE-UHFFFAOYSA-N benzimidazol-2-ylidenecyanamide Chemical compound C1=CC=CC2=NC(=NC#N)N=C21 PCJHDBHWLFUQLE-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- AXSIIYFPGZWYLL-UHFFFAOYSA-N bis(propan-2-yloxycarbonyl)azaniumylideneazanide Chemical compound CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C AXSIIYFPGZWYLL-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000009956 central mechanism Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- BJBUEDPLEOHJGE-IUYQGCFVSA-N cis-3-hydroxy-D-proline zwitterion Chemical class O[C@H]1CCN[C@H]1C(O)=O BJBUEDPLEOHJGE-IUYQGCFVSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- BSHICDXRSZQYBP-UHFFFAOYSA-N dichloromethane;palladium(2+) Chemical compound [Pd+2].ClCCl BSHICDXRSZQYBP-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 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
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- LANYMOXIGNVBLO-MHWRWJLKSA-N ethyl (2e)-2-(3-fluoro-6h-benzo[c][1]benzoxepin-11-ylidene)acetate Chemical compound C1OC2=CC(F)=CC=C2C(=C/C(=O)OCC)/C2=CC=CC=C21 LANYMOXIGNVBLO-MHWRWJLKSA-N 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 201000000079 gynecomastia Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 102000046818 human AR Human genes 0.000 description 1
- 102000054091 human NR3C2 Human genes 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- JNODQFNWMXFMEV-UHFFFAOYSA-N latrepirdine Chemical compound C1N(C)CCC2=C1C1=CC(C)=CC=C1N2CCC1=CC=C(C)N=C1 JNODQFNWMXFMEV-UHFFFAOYSA-N 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical class [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- BLWYXBNNBYXPPL-UHFFFAOYSA-N methyl pyrrolidine-2-carboxylate Chemical compound COC(=O)C1CCCN1 BLWYXBNNBYXPPL-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002395 mineralocorticoid Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- SKPJYESITCGNPU-UHFFFAOYSA-N n-(4-bromo-2-nitrophenyl)-1-methylazetidin-3-amine Chemical compound C1N(C)CC1NC1=CC=C(Br)C=C1[N+]([O-])=O SKPJYESITCGNPU-UHFFFAOYSA-N 0.000 description 1
- JKCOOGPOMMWFSH-AWQFTUOYSA-N n-[4-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-2-nitrophenyl]-1-methylazetidin-3-amine Chemical compound C1N(C)CC1NC(C(=C1)[N+]([O-])=O)=CC=C1\C=C/1C2=CC=C(F)C=C2OCC2=C(F)C=CC=C2\1 JKCOOGPOMMWFSH-AWQFTUOYSA-N 0.000 description 1
- ORGSETPHZYIBNQ-FYJGNVAPSA-N n-[4-[(e)-(3,7-difluoro-6h-benzo[c][1]benzoxepin-11-ylidene)methyl]-2-nitrophenyl]-4-methylpiperazin-1-amine Chemical compound C1CN(C)CCN1NC(C(=C1)[N+]([O-])=O)=CC=C1\C=C/1C2=CC=C(F)C=C2OCC2=C(F)C=CC=C2\1 ORGSETPHZYIBNQ-FYJGNVAPSA-N 0.000 description 1
- QACOELYINOMVBY-UHFFFAOYSA-N n-benzylpiperidin-1-amine Chemical compound C=1C=CC=CC=1CNN1CCCCC1 QACOELYINOMVBY-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 108010042121 probasin Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 230000001084 renoprotective effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002398 sedimentation field-flow fractionation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000011684 sodium molybdate Substances 0.000 description 1
- 235000015393 sodium molybdate Nutrition 0.000 description 1
- TVXXNOYZHKPKGW-UHFFFAOYSA-N sodium molybdate (anhydrous) Chemical compound [Na+].[Na+].[O-][Mo]([O-])(=O)=O TVXXNOYZHKPKGW-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- TYVPMGGBXKDZAF-SFYZADRCSA-N tert-butyl (2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](C[C@H]1CO)N=[N+]=[N-] TYVPMGGBXKDZAF-SFYZADRCSA-N 0.000 description 1
- OCLZOKUGIXLYJZ-HTQZYQBOSA-N tert-butyl (2r,4r)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](N)C[C@@H]1CO OCLZOKUGIXLYJZ-HTQZYQBOSA-N 0.000 description 1
- TYVPMGGBXKDZAF-HTQZYQBOSA-N tert-butyl (2r,4r)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@@H]1CO TYVPMGGBXKDZAF-HTQZYQBOSA-N 0.000 description 1
- OCLZOKUGIXLYJZ-JGVFFNPUSA-N tert-butyl (2r,4s)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H]1CO OCLZOKUGIXLYJZ-JGVFFNPUSA-N 0.000 description 1
- OGLXDTLKKWBMPK-RYUDHWBXSA-N tert-butyl (2s,4s)-4-(4-bromo-2-nitroanilino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound C1[C@@H](CO)N(C(=O)OC(C)(C)C)C[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O OGLXDTLKKWBMPK-RYUDHWBXSA-N 0.000 description 1
- ITPHGVPTTDIMDB-CVEARBPZSA-N tert-butyl (3r,4r)-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate Chemical compound O[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CCC1=CC=CC=C1 ITPHGVPTTDIMDB-CVEARBPZSA-N 0.000 description 1
- ZDIVZXZUIPLHNP-HUUCEWRRSA-N tert-butyl (3r,4r)-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate Chemical compound O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NCC1=CC=CC=C1 ZDIVZXZUIPLHNP-HUUCEWRRSA-N 0.000 description 1
- FJCGXBAKIMNIDC-HTQZYQBOSA-N tert-butyl (3r,4r)-4-azido-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1 FJCGXBAKIMNIDC-HTQZYQBOSA-N 0.000 description 1
- DCYVVDAIMLJKKF-DHLKQENFSA-N tert-butyl (3r,4r)-4-benzyl-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate Chemical compound O[C@H]1CN(C(=O)OC(C)(C)C)CC[C@]1(CC=1C=CC=CC=1)CCC1=CC=CC=C1 DCYVVDAIMLJKKF-DHLKQENFSA-N 0.000 description 1
- LWHRDKRVPKNHQP-YPMHNXCESA-N tert-butyl (3r,4s)-3-(4-bromo-2-nitroanilino)-4-hydroxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@H](O)[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O LWHRDKRVPKNHQP-YPMHNXCESA-N 0.000 description 1
- LWHRDKRVPKNHQP-WCQYABFASA-N tert-butyl (3s,4r)-3-(4-bromo-2-nitroanilino)-4-hydroxypyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@@H](O)[C@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O LWHRDKRVPKNHQP-WCQYABFASA-N 0.000 description 1
- AHJZEZIYOBGVSK-JGVFFNPUSA-N tert-butyl (3s,4s)-3-(aminomethyl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](CN)C1 AHJZEZIYOBGVSK-JGVFFNPUSA-N 0.000 description 1
- MOZOQDNRVPHFOO-BQBZGAKWSA-N tert-butyl (3s,4s)-3-amino-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1 MOZOQDNRVPHFOO-BQBZGAKWSA-N 0.000 description 1
- ITPHGVPTTDIMDB-JKSUJKDBSA-N tert-butyl (3s,4s)-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate Chemical compound O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CCC1=CC=CC=C1 ITPHGVPTTDIMDB-JKSUJKDBSA-N 0.000 description 1
- OLMYDBBHYVEIME-DHLKQENFSA-N tert-butyl (3s,4s)-4-(benzylamino)-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate Chemical compound O[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@]1(NCC=1C=CC=CC=1)CCC1=CC=CC=C1 OLMYDBBHYVEIME-DHLKQENFSA-N 0.000 description 1
- SHHHRQFHCPINIB-UHFFFAOYSA-N tert-butyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=CC1 SHHHRQFHCPINIB-UHFFFAOYSA-N 0.000 description 1
- WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
- ZDIVZXZUIPLHNP-UHFFFAOYSA-N tert-butyl 4-(benzylamino)-3-hydroxypiperidine-1-carboxylate Chemical compound OC1CN(C(=O)OC(C)(C)C)CCC1NCC1=CC=CC=C1 ZDIVZXZUIPLHNP-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
- PDAFIZPRSXHMCO-ZCFIWIBFSA-N tert-butyl n-[(2r)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-ZCFIWIBFSA-N 0.000 description 1
- PDAFIZPRSXHMCO-LURJTMIESA-N tert-butyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-LURJTMIESA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- 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
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1477607P | 2007-12-19 | 2007-12-19 | |
| US61/014,776 | 2007-12-19 | ||
| PCT/US2008/085997 WO2009085584A1 (en) | 2007-12-19 | 2008-12-09 | 6h-dibenz0 [b, e] oxepine derived nonsteroidal mineralocorticoid receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2008343524A1 AU2008343524A1 (en) | 2009-07-09 |
| AU2008343524B2 true AU2008343524B2 (en) | 2012-03-08 |
Family
ID=40430143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2008343524A Ceased AU2008343524B2 (en) | 2007-12-19 | 2008-12-09 | 6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US7994164B2 (OSRAM) |
| EP (2) | EP2235007B1 (OSRAM) |
| JP (1) | JP5562866B2 (OSRAM) |
| KR (1) | KR101254382B1 (OSRAM) |
| CN (1) | CN101903377B (OSRAM) |
| AR (1) | AR069554A1 (OSRAM) |
| AU (1) | AU2008343524B2 (OSRAM) |
| BR (1) | BRPI0820805A2 (OSRAM) |
| CA (1) | CA2710409C (OSRAM) |
| CL (1) | CL2008003600A1 (OSRAM) |
| CO (1) | CO6300953A2 (OSRAM) |
| DK (1) | DK2235007T3 (OSRAM) |
| DO (1) | DOP2010000185A (OSRAM) |
| EA (1) | EA017668B1 (OSRAM) |
| EC (2) | ECSP10010266A (OSRAM) |
| ES (2) | ES2459318T3 (OSRAM) |
| GT (1) | GT201000179A (OSRAM) |
| HR (1) | HRP20120916T1 (OSRAM) |
| IL (1) | IL206353A (OSRAM) |
| MA (1) | MA31910B1 (OSRAM) |
| MX (1) | MX2010006911A (OSRAM) |
| MY (1) | MY150474A (OSRAM) |
| NZ (1) | NZ586300A (OSRAM) |
| PE (1) | PE20091057A1 (OSRAM) |
| PL (1) | PL2235007T3 (OSRAM) |
| PT (1) | PT2235007E (OSRAM) |
| RS (1) | RS52594B (OSRAM) |
| SI (1) | SI2235007T1 (OSRAM) |
| TN (1) | TN2010000292A1 (OSRAM) |
| TW (1) | TWI431010B (OSRAM) |
| UA (1) | UA100131C2 (OSRAM) |
| WO (1) | WO2009085584A1 (OSRAM) |
| ZA (1) | ZA201004257B (OSRAM) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8242140B2 (en) | 2007-08-03 | 2012-08-14 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| BRPI0821342A2 (pt) | 2007-12-19 | 2019-09-24 | Boehringer Ingelheim Int | inibidores da polimerase viral |
| AU2010222902B2 (en) * | 2009-03-12 | 2013-04-18 | Eli Lilly And Company | Mineralocorticoid receptor antagonist and methods of use |
| US8957052B2 (en) | 2010-05-10 | 2015-02-17 | Universite Paris Descartes | Methods and compositions for the treatment of fluid accumulation in and/or under the retina |
| WO2011157798A1 (en) | 2010-06-16 | 2011-12-22 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for stimulating reepithelialisation during wound healing |
| CN102060670A (zh) * | 2011-01-04 | 2011-05-18 | 常州大学 | 一种2-溴-6-氟苯甲醇的制备方法 |
| UA111696C2 (uk) | 2013-05-02 | 2016-05-25 | Пфайзер Інк. | Похідні імідазотриазину як інгібітори рde10 |
| AR099416A1 (es) | 2014-02-28 | 2016-07-20 | Lilly Co Eli | Terapia combinada para la hipertensión resistente |
| CA2953655C (en) | 2014-06-30 | 2020-05-12 | Astrazeneca Ab | Benzoxazinone amides as mineralocorticoid receptor modulators |
| US20170246166A1 (en) * | 2014-11-21 | 2017-08-31 | Eli Lilly And Company | 1,2-benzothiazole compounds for the treatment of kidney disorders |
| EP3362095B1 (en) | 2015-10-13 | 2020-11-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of choroidal neovascularisation |
| US20190262363A1 (en) | 2016-07-26 | 2019-08-29 | INSERM (Institut National de la Santé et de la Recherche Médicale | Antagonist of mineralocorticoid receptor for the treatment of osteoarthritis |
| UA123464C2 (uk) * | 2016-09-24 | 2021-04-07 | Кейбіпі Байосайєнсіз Ко., Лтд. | Фармацевтична композиція, яка містить антагоніст мінералокортикоїдних рецепторів, та її застосування |
| JP7697961B2 (ja) | 2020-03-11 | 2025-06-24 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 対象が中心性漿液性脈絡網膜症を有するか、または有する危険性があるかどうかを決定する方法。 |
| US20240366632A1 (en) | 2021-08-31 | 2024-11-07 | Institut National de la Santé et de la Recherche Médicale | Methods for the treatment of ocular rosacea |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072756A (en) | 1973-05-17 | 1978-02-07 | Sandoz Ltd. | Tricyclo piperidino ketones and soporific compositions thereof |
| SE426341C (sv) * | 1980-02-14 | 1985-09-23 | Fagersta Ab | Sett att forhindra korrosion i en forbrenningsanleggnings kylare och skorsten vid kylning av rokgaser |
| FR2603713B1 (fr) | 1986-09-10 | 1992-07-24 | Canon Kk | Derive nouveau de 5h-dibenzo(a,d)cycloheptane-(ene)ylidene, son procede de production et support electrophotographique photosensible le contenant |
| CA1338625C (en) * | 1988-06-09 | 1996-10-01 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds |
| GB8914061D0 (en) | 1989-06-19 | 1989-08-09 | Wellcome Found | Agents for potentiating the effects of antitumour agents and combating multiple drug resistance |
| US5378701A (en) | 1991-12-27 | 1995-01-03 | Kyowa Hakko Kogyo | Tricyclic compounds |
| ZA9811898B (en) | 1997-12-29 | 2000-06-28 | Ortho Mcneil Pharm Inc | Anti-Inflammatory Compounds. |
| EP1154997A4 (en) | 1999-01-26 | 2002-11-04 | Dana Farber Cancer Inst Inc | PHARMACEUTICALLY ACTIVE COMPOUNDS AND METHODS OF USE |
| ATE320431T1 (de) * | 2001-11-21 | 2006-04-15 | Millennium Pharm Inc | Chemokine rezeptor antagonisten und methoden zu deren anwendung |
| TW200400816A (en) * | 2002-06-26 | 2004-01-16 | Lilly Co Eli | Tricyclic steroid hormone nuclear receptor modulators |
| US7803814B2 (en) * | 2003-12-19 | 2010-09-28 | Eli Lilly And Company | Tricyclic steroid hormone nuclear receptor modulators |
| WO2005066153A1 (en) | 2003-12-19 | 2005-07-21 | Eli Lilly And Company | Tricyclic steroid hormone nuclear receptor modulators |
| TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
| JP2008508314A (ja) | 2004-07-28 | 2008-03-21 | アイアールエム・リミテッド・ライアビリティ・カンパニー | ステロイドホルモン核内受容体のモジュレーターとしての化合物および組成物 |
| US20060116382A1 (en) | 2004-11-10 | 2006-06-01 | Wenqing Yao | Lactam compounds and their use as pharmaceuticals |
| BRPI0717937A2 (pt) | 2006-10-31 | 2013-12-03 | Pfizer Prod Inc | Compostos de pirazona como antagonistas do receptor mineralocorticóide |
| JP2010522732A (ja) | 2007-03-29 | 2010-07-08 | ナームローゼ・フエンノートチヤツプ・オルガノン | 鉱質コルチコイド受容体アンタゴニスト |
| GB0725102D0 (en) | 2007-12-21 | 2008-01-30 | Glaxo Group Ltd | Compounds |
| PE20091339A1 (es) | 2007-12-21 | 2009-09-26 | Glaxo Group Ltd | Derivados de oxadiazol con actividad sobre receptores s1p1 |
| US20100292233A1 (en) | 2008-01-25 | 2010-11-18 | Arena Pharmaceuticals, Inc. | Dihydro-1h-pyrrolo[1,2-a]indol-1-yl carboxylic acid derivatives which act as s1p1 agonists |
| AU2010222902B2 (en) | 2009-03-12 | 2013-04-18 | Eli Lilly And Company | Mineralocorticoid receptor antagonist and methods of use |
-
2008
- 2008-12-02 TW TW097146779A patent/TWI431010B/zh not_active IP Right Cessation
- 2008-12-02 PE PE2008002008A patent/PE20091057A1/es not_active Application Discontinuation
- 2008-12-03 CL CL2008003600A patent/CL2008003600A1/es unknown
- 2008-12-03 AR ARP080105263A patent/AR069554A1/es unknown
- 2008-12-09 HR HRP20120916AT patent/HRP20120916T1/hr unknown
- 2008-12-09 WO PCT/US2008/085997 patent/WO2009085584A1/en not_active Ceased
- 2008-12-09 DK DK08866835.5T patent/DK2235007T3/da active
- 2008-12-09 CA CA2710409A patent/CA2710409C/en not_active Expired - Fee Related
- 2008-12-09 CN CN200880121527.2A patent/CN101903377B/zh not_active Expired - Fee Related
- 2008-12-09 EP EP08866835A patent/EP2235007B1/en active Active
- 2008-12-09 BR BRPI0820805-0A patent/BRPI0820805A2/pt not_active IP Right Cessation
- 2008-12-09 UA UAA201007627A patent/UA100131C2/uk unknown
- 2008-12-09 EP EP12185389.9A patent/EP2537845B1/en active Active
- 2008-12-09 MX MX2010006911A patent/MX2010006911A/es active IP Right Grant
- 2008-12-09 JP JP2010539618A patent/JP5562866B2/ja not_active Expired - Fee Related
- 2008-12-09 AU AU2008343524A patent/AU2008343524B2/en not_active Ceased
- 2008-12-09 KR KR1020107013601A patent/KR101254382B1/ko not_active Expired - Fee Related
- 2008-12-09 ES ES12185389.9T patent/ES2459318T3/es active Active
- 2008-12-09 ES ES08866835T patent/ES2396605T3/es active Active
- 2008-12-09 SI SI200830852T patent/SI2235007T1/sl unknown
- 2008-12-09 RS RS20120541A patent/RS52594B/sr unknown
- 2008-12-09 US US12/330,539 patent/US7994164B2/en not_active Expired - Fee Related
- 2008-12-09 PT PT88668355T patent/PT2235007E/pt unknown
- 2008-12-09 PL PL08866835T patent/PL2235007T3/pl unknown
- 2008-12-09 MY MYPI20102867 patent/MY150474A/en unknown
- 2008-12-09 NZ NZ586300A patent/NZ586300A/en not_active IP Right Cessation
- 2008-12-09 EA EA201070762A patent/EA017668B1/ru not_active IP Right Cessation
-
2010
- 2010-06-14 IL IL206353A patent/IL206353A/en not_active IP Right Cessation
- 2010-06-14 MA MA32909A patent/MA31910B1/fr unknown
- 2010-06-15 ZA ZA2010/04257A patent/ZA201004257B/en unknown
- 2010-06-16 CO CO10072532A patent/CO6300953A2/es not_active Application Discontinuation
- 2010-06-17 DO DO2010000185A patent/DOP2010000185A/es unknown
- 2010-06-17 GT GT201000179A patent/GT201000179A/es unknown
- 2010-06-17 EC EC2010010266A patent/ECSP10010266A/es unknown
- 2010-06-18 TN TN2010000292A patent/TN2010000292A1/fr unknown
-
2012
- 2012-07-17 EC ECSP12012048 patent/ECSP12012048A/es unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2008343524B2 (en) | 6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists | |
| EP1945222B1 (en) | Pyrrolo[2,1-f] [1,2,4]-triazin-4-ylamines as igf-1r kinase inhibitors for the treatment of cancer and other hyperproliferative diseases | |
| JP6908536B2 (ja) | ムスカリンｍ２受容体の正のアロステリックモジュレーター | |
| JP2008536927A (ja) | Ｎ−アルキル−アザシクロアルキルｎｍｄａ／ｎｒ２ｂ拮抗物質 | |
| EP4647433A1 (en) | Shp2 inhibitor and uses thereof | |
| JP2022545314A (ja) | プログラニュリンモジュレーターおよびその使用方法 | |
| CN108137543B (zh) | 选择性nr2b拮抗剂 | |
| AU2023209575A1 (en) | Compounds and their use in treating cancer | |
| WO2023017152A1 (en) | Specific small molecule inhibitors that block kmt9 methyltransferase activity and function | |
| HK1144284B (en) | 6h-dibenz0 [b, e] oxepine derived nonsteroidal mineralocorticoid receptor antagonists | |
| WO2025122809A1 (en) | M4 positive allosteric modulators | |
| WO2024220453A1 (en) | Pyrrolidinone urea fpr2 agonists | |
| US20190062305A1 (en) | Pyridyl or pyrazinyl compounds carrying a methyl-bound alpha-amino acid amide group | |
| WO2024257012A1 (en) | 3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octane derivatives as smarca2 degrading protacs for the treatment of cancer | |
| WO2024261329A1 (en) | Heteroaryl-amine compounds and use thereof as hdac6 inhibitors | |
| TW202540107A (zh) | Ｍ４陽性變構調節劑 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |