TWI431010B - 礦皮質素受體拮抗劑及使用方法 - Google Patents
礦皮質素受體拮抗劑及使用方法 Download PDFInfo
- Publication number
- TWI431010B TWI431010B TW097146779A TW97146779A TWI431010B TW I431010 B TWI431010 B TW I431010B TW 097146779 A TW097146779 A TW 097146779A TW 97146779 A TW97146779 A TW 97146779A TW I431010 B TWI431010 B TW I431010B
- Authority
- TW
- Taiwan
- Prior art keywords
- mol
- formula
- compound
- etoac
- bromo
- Prior art date
Links
- 238000000034 method Methods 0.000 title description 58
- 229940083712 aldosterone antagonist Drugs 0.000 title description 2
- 239000002394 mineralocorticoid antagonist Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 157
- 150000003839 salts Chemical class 0.000 claims description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 15
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 11
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 11
- 206010019280 Heart failures Diseases 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 208000020832 chronic kidney disease Diseases 0.000 claims description 11
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 11
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 8
- 230000002107 myocardial effect Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000011580 syndromic disease Diseases 0.000 claims description 8
- 239000004202 carbamide Substances 0.000 claims description 7
- 208000019025 Hypokalemia Diseases 0.000 claims description 6
- 229940079593 drug Drugs 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 6
- 208000024896 potassium deficiency disease Diseases 0.000 claims description 6
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000033764 rhythmic process Effects 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- 206010003119 arrhythmia Diseases 0.000 claims description 3
- 208000012904 Bartter disease Diseases 0.000 claims description 2
- 208000010062 Bartter syndrome Diseases 0.000 claims description 2
- 208000016998 Conn syndrome Diseases 0.000 claims description 2
- 208000013846 primary aldosteronism Diseases 0.000 claims description 2
- 230000001788 irregular Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 202
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 238000002360 preparation method Methods 0.000 description 101
- 235000019439 ethyl acetate Nutrition 0.000 description 91
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 65
- 239000000203 mixture Substances 0.000 description 64
- 239000000243 solution Substances 0.000 description 61
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 60
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- -1 N-methyl azetidinyl Chemical group 0.000 description 39
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 35
- 102100021316 Mineralocorticoid receptor Human genes 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 24
- 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 21
- 239000005557 antagonist Substances 0.000 description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- 239000001257 hydrogen Substances 0.000 description 20
- 229910052739 hydrogen Inorganic materials 0.000 description 20
- 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 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 19
- 229960002478 aldosterone Drugs 0.000 description 19
- 238000009739 binding Methods 0.000 description 19
- 239000000543 intermediate Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 19
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 17
- 230000027455 binding Effects 0.000 description 17
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 15
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 102100032187 Androgen receptor Human genes 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 108010080146 androgen receptors Proteins 0.000 description 14
- 239000013078 crystal Substances 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 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
- 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 11
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000003981 vehicle Substances 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 10
- 241001465754 Metazoa Species 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 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
- 150000002148 esters Chemical class 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 239000011737 fluorine Substances 0.000 description 9
- 239000012442 inert solvent Substances 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 229910052717 sulfur Inorganic materials 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
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 7
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 7
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 7
- 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 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 239000004305 biphenyl Substances 0.000 description 7
- 235000010290 biphenyl Nutrition 0.000 description 7
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 210000002700 urine Anatomy 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
- 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
- 239000002253 acid Substances 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
- 239000012267 brine Substances 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
- 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
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 6
- 230000003405 preventing effect Effects 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000002860 competitive effect Effects 0.000 description 5
- 239000003792 electrolyte Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 210000002706 plastid Anatomy 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
- 235000011056 potassium acetate Nutrition 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000000159 protein binding assay Methods 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- 102000005969 steroid hormone receptors Human genes 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101000615613 Homo sapiens Mineralocorticoid receptor Proteins 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 239000005089 Luciferase Substances 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
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 125000003277 amino group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-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
- 229940109239 creatinine Drugs 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
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 230000004962 physiological condition Effects 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- SBMSLRMNBSMKQC-UHFFFAOYSA-N pyrrolidin-1-amine Chemical compound NN1CCCC1 SBMSLRMNBSMKQC-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 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
- 230000003637 steroidlike Effects 0.000 description 4
- 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 4
- 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 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
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 3
- 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 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-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
- 208000002682 Hyperkalemia Diseases 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102000006601 Thymidine Kinase Human genes 0.000 description 3
- 108020004440 Thymidine kinase Proteins 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
- 150000001540 azides Chemical class 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
- 239000013058 crude material Substances 0.000 description 3
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 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
- RWMJRMPOKXSHHI-UHFFFAOYSA-N ethenylboron Chemical compound [B]C=C RWMJRMPOKXSHHI-UHFFFAOYSA-N 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 239000011976 maleic acid Substances 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
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical compound ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 description 3
- 238000003305 oral gavage Methods 0.000 description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 3
- 230000036961 partial effect Effects 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
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 210000002966 serum Anatomy 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
- 108020003113 steroid hormone receptors Proteins 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 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 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
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- 229920001567 vinyl ester resin Polymers 0.000 description 3
- 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
- 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 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
- QJVSUEWIZLSCAX-GNAZCLTHSA-N (3s,4s)-4-(4-bromo-2-nitroanilino)pyrrolidin-3-ol;hydrochloride Chemical compound Cl.O[C@H]1CNC[C@@H]1NC1=CC=C(Br)C=C1[N+]([O-])=O QJVSUEWIZLSCAX-GNAZCLTHSA-N 0.000 description 2
- PVPBBTJXIKFICP-UHFFFAOYSA-N (7-aminophenothiazin-3-ylidene)azanium;chloride Chemical compound [Cl-].C1=CC(=[NH2+])C=C2SC3=CC(N)=CC=C3N=C21 PVPBBTJXIKFICP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-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
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 2
- GQFITODJWOIYPF-UHFFFAOYSA-N 1-(bromomethyl)-2-iodobenzene Chemical compound BrCC1=CC=CC=C1I GQFITODJWOIYPF-UHFFFAOYSA-N 0.000 description 2
- 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 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-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
- SNJAKWDPQBWXFM-UHFFFAOYSA-N 2,3-dimethylhex-5-ene-2,3-diol Chemical compound CC(C)(O)C(C)(O)CC=C SNJAKWDPQBWXFM-UHFFFAOYSA-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
- PRKFHQWMICWPRU-UHFFFAOYSA-N 2-phenylpyrrolidin-1-amine Chemical compound NN1CCCC1C1=CC=CC=C1 PRKFHQWMICWPRU-UHFFFAOYSA-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 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 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 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
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-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
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- 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 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 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
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-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
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 108010085012 Steroid Receptors Proteins 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
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000000903 blocking effect 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
- 125000004744 butyloxycarbonyl group Chemical group 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
- 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
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 238000001035 drying Methods 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
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 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
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 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 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
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 2
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-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
- 239000012074 organic phase Substances 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 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
- 230000001737 promoting effect Effects 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
- 238000001525 receptor binding assay Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 2
- 229960002256 spironolactone Drugs 0.000 description 2
- 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 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
- 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
- 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 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
- 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
- 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 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
- 239000012096 transfection reagent Substances 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000001238 wet grinding Methods 0.000 description 2
- BJBUEDPLEOHJGE-UHFFFAOYSA-N (2R,3S)-3-Hydroxy-2-pyrolidinecarboxylic acid Natural products OC1CCNC1C(O)=O BJBUEDPLEOHJGE-UHFFFAOYSA-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-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
- WQBOWGPMMLEVOY-IMJSIDKUSA-N (2s,4s)-4-azidopyrrolidine-1,2-dicarboxylic acid Chemical compound OC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(O)=O WQBOWGPMMLEVOY-IMJSIDKUSA-N 0.000 description 1
- BYPLOVACRAMWKI-MWLCHTKSSA-N (3R,4R)-4-(4-bromo-2-nitroanilino)-3-hydroxypiperidine-1-carboxylic acid Chemical compound BrC1=CC(=C(C=C1)N[C@H]1[C@@H](CN(CC1)C(=O)O)O)[N+](=O)[O-] BYPLOVACRAMWKI-MWLCHTKSSA-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
- 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
- WLIADPFXSACYLS-UHFFFAOYSA-N 1,3-dichlorobut-2-ene Chemical compound CC(Cl)=CCCl WLIADPFXSACYLS-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
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WPDRTZQNLRNDMG-UHFFFAOYSA-N 1-bromopyrrolidine Chemical compound BrN1CCCC1 WPDRTZQNLRNDMG-UHFFFAOYSA-N 0.000 description 1
- LIMKKQOHDIMHEX-UHFFFAOYSA-N 1-hydroxypiperidin-2-amine Chemical compound NC1CCCCN1O LIMKKQOHDIMHEX-UHFFFAOYSA-N 0.000 description 1
- CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 1
- GMQPIGJXSZAXSJ-UHFFFAOYSA-N 1-methylsulfonylpyrrolidine Chemical compound CS(=O)(=O)N1CCCC1 GMQPIGJXSZAXSJ-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
- 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 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
- 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 1
- 238000005160 1H NMR spectroscopy Methods 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
- CIQOTANLSZEILP-UHFFFAOYSA-N 4-amino-1-methylpyrrolidin-3-ol Chemical compound CN1CC(N)C(O)C1 CIQOTANLSZEILP-UHFFFAOYSA-N 0.000 description 1
- UVBKPWNFXFUDOU-UHFFFAOYSA-N 4-aminopiperidin-3-ol Chemical compound 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
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical compound O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 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
- DHTUYLHSOFEBNX-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCCC(C1)(NCC2=CC=CC=C2)O Chemical compound CC(C)(C)OC(=O)N1CCCC(C1)(NCC2=CC=CC=C2)O DHTUYLHSOFEBNX-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 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
- 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 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
- 206010024870 Loss of libido Diseases 0.000 description 1
- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- 206010027339 Menstruation irregular 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
- OKLUZMUKXYWEGD-UHFFFAOYSA-N N-bromobutan-1-imine Chemical compound CCCC=NBr OKLUZMUKXYWEGD-UHFFFAOYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 102000007451 Steroid Receptors Human genes 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- IVHKZGYFKJRXBD-UHFFFAOYSA-N amino carbamate Chemical compound NOC(N)=O IVHKZGYFKJRXBD-UHFFFAOYSA-N 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
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 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
- 238000003339 best practice Methods 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
- 230000037396 body weight Effects 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical compound CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 1
- 239000002775 capsule Substances 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
- 238000012754 cardiac puncture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- CETPSERCERDGAM-UHFFFAOYSA-N ceric oxide Chemical compound O=[Ce]=O CETPSERCERDGAM-UHFFFAOYSA-N 0.000 description 1
- 229910000422 cerium(IV) oxide Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000005829 chemical entities Chemical class 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
- 238000004440 column chromatography Methods 0.000 description 1
- 108091008723 corticosteroid receptors Proteins 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
- 230000009260 cross reactivity Effects 0.000 description 1
- 238000006880 cross-coupling reaction Methods 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
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method 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
- 208000035475 disorder Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 238000005516 engineering process 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
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000036541 health Effects 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
- 102000046818 human AR Human genes 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- ATBKVKDEMSGMTQ-UHFFFAOYSA-N hydrazine triphenylphosphane Chemical compound NN.C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 ATBKVKDEMSGMTQ-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 108010046780 hydrocortisone receptor Proteins 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 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
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 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
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 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
- 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
- 239000007937 lozenge Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 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
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-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
- 239000006070 nanosuspension Substances 0.000 description 1
- 238000013059 nephrectomy Methods 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 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
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229940023569 palmate Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 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
- ONIBWKKTOPOVIA-UHFFFAOYSA-M prolinate Chemical compound [O-]C(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 229960001584 promegestone Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 210000005084 renal tissue Anatomy 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
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 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
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- MMPWHAJQEZIIEH-YUMQZZPRSA-N tert-butyl (1s,6s)-7-oxa-4-azabicyclo[4.1.0]heptane-4-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]2O[C@H]21 MMPWHAJQEZIIEH-YUMQZZPRSA-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
- 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 1
- 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 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
- 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
- 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
- DNVDJTZLMZISEU-VKGZEUJTSA-N tert-butyl (3s,4s)-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CCC1=CC=CC=C1 DNVDJTZLMZISEU-VKGZEUJTSA-N 0.000 description 1
- 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 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
- NUYWPLSBEHXOHO-UHFFFAOYSA-N tert-butyl 2-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1O NUYWPLSBEHXOHO-UHFFFAOYSA-N 0.000 description 1
- XTDXZSGSIMLARD-UHFFFAOYSA-N tert-butyl 2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC=CC=C1 XTDXZSGSIMLARD-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
- 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
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-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
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- LPQZERIRKRYGGM-UHFFFAOYSA-N tert-butyl pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1 LPQZERIRKRYGGM-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 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
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000017105 transposition Effects 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
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000010792 warming 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)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (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 (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1477607P | 2007-12-19 | 2007-12-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW200930721A TW200930721A (en) | 2009-07-16 |
| TWI431010B true TWI431010B (zh) | 2014-03-21 |
Family
ID=40430143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW097146779A TWI431010B (zh) | 2007-12-19 | 2008-12-02 | 礦皮質素受體拮抗劑及使用方法 |
Country Status (33)
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2188274A4 (en) | 2007-08-03 | 2011-05-25 | Boehringer Ingelheim Int | VIRAL POLYMERASE HEMMER |
| EA201000948A1 (ru) | 2007-12-19 | 2011-02-28 | Бёрингер Ингельхайм Интернациональ Гмбх | Ингибиторы вирусной полимеразы |
| WO2010104721A1 (en) * | 2009-03-12 | 2010-09-16 | Eli Lilly And Company | Mineralocorticoid receptor antagonist and methods of use |
| EP2977084B1 (en) | 2010-05-10 | 2017-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | 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 |
| NZ712949A (en) | 2013-05-02 | 2017-04-28 | Pfizer | Imidazo-triazine derivatives as pde10 inhibitors |
| AR099416A1 (es) | 2014-02-28 | 2016-07-20 | Lilly Co Eli | Terapia combinada para la hipertensión resistente |
| SI3160948T1 (sl) | 2014-06-30 | 2020-06-30 | Astrazeneca Ab | Amidi benzoksazinona, kot modulatorji receptorja mineralokortikoida |
| NZ730759A (en) * | 2014-11-21 | 2018-10-26 | Lilly Co Eli | 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 |
| ES2973248T3 (es) | 2016-07-26 | 2024-06-19 | Inst Nat Sante Rech Med | Antagonista del receptor mineralocorticoide para el tratamiento de la osteoartritis |
| MA45202B1 (fr) * | 2016-09-24 | 2022-04-29 | Kbp Biosciences Co Ltd | Composition pharmaceutique comprenant un antagoniste du récepteur minéralocorticoïde et son utilisation |
| WO2021180818A1 (en) | 2020-03-11 | 2021-09-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods of determining whether a subject has or is at risk of having a central serous chorioretinopathy |
| WO2023031277A1 (en) | 2021-08-31 | 2023-03-09 | INSERM (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 |
| US4999363A (en) * | 1988-06-09 | 1991-03-12 | 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 |
| AR014195A1 (es) | 1997-12-29 | 2001-02-07 | Ortho Mcneil Pharm Inc | Compuestos de trifenilpropanamida utiles para el tratamiento de procesos inflamatorios, composiciones anti-inflamatorias que los comprenden, ymetodos para prepararlos |
| JP2002541144A (ja) | 1999-01-26 | 2002-12-03 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | 医薬的に活性のある化合物及びその使用方法 |
| PL403800A1 (pl) * | 2001-11-21 | 2013-08-19 | Millennium Pharmaceuticals, Inc. | Kompozycja farmaceutyczna |
| TW200400816A (en) * | 2002-06-26 | 2004-01-16 | Lilly Co Eli | Tricyclic steroid hormone nuclear receptor modulators |
| WO2005066153A1 (en) | 2003-12-19 | 2005-07-21 | Eli Lilly And Company | Tricyclic steroid hormone nuclear receptor modulators |
| CN1918151A (zh) | 2003-12-19 | 2007-02-21 | 伊莱利利公司 | 三环甾类激素核受体调节剂 |
| 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 |
| TWI400239B (zh) | 2004-11-10 | 2013-07-01 | Incyte Corp | 內醯胺化合物及其作為醫藥品之用途 |
| HRP20120078T1 (hr) | 2006-10-31 | 2012-02-29 | Pfizer Products Inc. | Pirazolinski spojevi kao antagonisti mineralokortikoidnih receptora |
| US20100120736A1 (en) | 2007-03-29 | 2010-05-13 | N.V. Organon | Mineralocorticoid Receptor Antagonists |
| PE20091339A1 (es) | 2007-12-21 | 2009-09-26 | Glaxo Group Ltd | Derivados de oxadiazol con actividad sobre receptores s1p1 |
| GB0725102D0 (en) | 2007-12-21 | 2008-01-30 | Glaxo Group Ltd | Compounds |
| 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 |
| WO2010104721A1 (en) | 2009-03-12 | 2010-09-16 | 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 MX MX2010006911A patent/MX2010006911A/es active IP Right Grant
- 2008-12-09 UA UAA201007627A patent/UA100131C2/uk unknown
- 2008-12-09 SI SI200830852T patent/SI2235007T1/sl unknown
- 2008-12-09 US US12/330,539 patent/US7994164B2/en not_active Expired - Fee Related
- 2008-12-09 ES ES12185389.9T patent/ES2459318T3/es active Active
- 2008-12-09 AU AU2008343524A patent/AU2008343524B2/en not_active Ceased
- 2008-12-09 WO PCT/US2008/085997 patent/WO2009085584A1/en not_active Ceased
- 2008-12-09 ES ES08866835T patent/ES2396605T3/es active Active
- 2008-12-09 NZ NZ586300A patent/NZ586300A/en not_active IP Right Cessation
- 2008-12-09 EP EP12185389.9A patent/EP2537845B1/en active Active
- 2008-12-09 BR BRPI0820805-0A patent/BRPI0820805A2/pt not_active IP Right Cessation
- 2008-12-09 JP JP2010539618A patent/JP5562866B2/ja not_active Expired - Fee Related
- 2008-12-09 PT PT88668355T patent/PT2235007E/pt unknown
- 2008-12-09 EA EA201070762A patent/EA017668B1/ru not_active IP Right Cessation
- 2008-12-09 RS RS20120541A patent/RS52594B/sr unknown
- 2008-12-09 PL PL08866835T patent/PL2235007T3/pl unknown
- 2008-12-09 MY MYPI20102867 patent/MY150474A/en unknown
- 2008-12-09 CA CA2710409A patent/CA2710409C/en not_active Expired - Fee Related
- 2008-12-09 DK DK08866835.5T patent/DK2235007T3/da active
- 2008-12-09 KR KR1020107013601A patent/KR101254382B1/ko not_active Expired - Fee Related
- 2008-12-09 HR HRP20120916AT patent/HRP20120916T1/hr unknown
- 2008-12-09 EP EP08866835A patent/EP2235007B1/en active Active
- 2008-12-09 CN CN200880121527.2A patent/CN101903377B/zh not_active Expired - Fee Related
-
2010
- 2010-06-14 MA MA32909A patent/MA31910B1/fr unknown
- 2010-06-14 IL IL206353A patent/IL206353A/en not_active IP Right Cessation
- 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 EC EC2010010266A patent/ECSP10010266A/es unknown
- 2010-06-17 DO DO2010000185A patent/DOP2010000185A/es unknown
- 2010-06-17 GT GT201000179A patent/GT201000179A/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 |
|---|---|---|
| TWI431010B (zh) | 礦皮質素受體拮抗劑及使用方法 | |
| CN103827101B (zh) | 双环二氢喹啉-2-酮衍生物 | |
| DK3074400T3 (en) | Octahydro-cyclobuta [1,2-c; 3,4-c '] dipyrrole derivatives as autotaxin inhibitors | |
| CN107849017A (zh) | 作为magl抑制剂的1,1,1‑三氟‑3‑羟基丙‑2‑基氨基甲酸酯衍生物及1,1,1‑三氟‑4‑羟基丁‑2‑基氨基甲酸酯衍生物 | |
| KR20190112000A (ko) | Rho-키나아제 억제제로서 티로신 아마이드 유도체 | |
| US11976075B2 (en) | Inhibitors of the MYST family of lysine acetyl transferases | |
| CN101801194A (zh) | 具有5-ht6受体亲和力的3’取代的化合物 | |
| KR20100031578A (ko) | 5-ht6 수용체 친화성을 갖는 4'-치환된 화합물 | |
| CN112752757B (zh) | 作为rho-激酶抑制剂的酪氨酸酰胺衍生物 | |
| JP2021504334A (ja) | ピラゾロピリジノン化合物 | |
| CN113677673A (zh) | Trpc6的抑制剂 | |
| JP7295019B2 (ja) | 7-置換1-アリール-ナフチリジン-3-カルボン酸アミドおよびその使用 | |
| WO2017018475A1 (ja) | 新規リンカー部位を持つ縮合ピラゾール誘導体およびその医薬用途 | |
| WO2024261329A1 (en) | Heteroaryl-amine compounds and use thereof as hdac6 inhibitors | |
| WO2024246496A1 (en) | (hetero)aryl-carbonyl-heterobicyclic compounds as inhibitors of pms2 for cancer and degenerative illnesses | |
| WO2025245351A1 (en) | Substituted aryl sulfonamides and compositions and uses thereof | |
| Bhalay | Preparation of tyrosine amide derivatives as Rho- kinase inhibitors | |
| HK1144284B (en) | 6h-dibenz0 [b, e] oxepine derived nonsteroidal mineralocorticoid receptor antagonists | |
| HK40040371A (en) | Tyrosine amide derivatives as rho- kinase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |