CA2759047A1 - Inhibiteurs cycliques de la 11beta-hydroxysteroide deshydrogenase 1 - Google Patents

Inhibiteurs cycliques de la 11beta-hydroxysteroide deshydrogenase 1 Download PDF

Info

Publication number: CA2759047A1
Authority: CA; Canada
Prior art keywords: phenyl; ethyl; oxazinan; mmol; methyl
Prior art date: 2009-04-30
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.): Abandoned

Application number

CA2759047A

Other languages

English (en)

Inventor

Martin Renz

Martin Schuele

Zhenrong Xu

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Boehringer Ingelheim International GmbH

Vitae Pharmaceuticals LLC

Original Assignee

Boehringer Ingelheim International GmbH

Vitae Pharmaceuticals LLC

Priority date (The priority date 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 date listed.)

2009-04-30

Filing date

2010-04-30

Publication date

2010-11-04

2009-04-30 Priority claimed from PCT/US2009/002653 external-priority patent/WO2009134400A1/fr

2009-07-23 Priority claimed from PCT/US2009/004261 external-priority patent/WO2010011314A1/fr

2010-04-30 Application filed by Boehringer Ingelheim International GmbH, Vitae Pharmaceuticals LLC filed Critical Boehringer Ingelheim International GmbH

2010-04-30 Priority claimed from PCT/US2010/033157 external-priority patent/WO2010127237A2/fr

2010-11-04 Publication of CA2759047A1 publication Critical patent/CA2759047A1/fr

Status Abandoned legal-status Critical Current

Links

239000003112 inhibitor Substances 0.000 title description 17
125000004122 cyclic group Chemical group 0.000 title description 4
102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 title description 2
101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 title 1
238000000034 method Methods 0.000 claims abstract description 267
150000001875 compounds Chemical class 0.000 claims abstract description 206
150000003839 salts Chemical class 0.000 claims abstract description 41
238000011282 treatment Methods 0.000 claims abstract description 29
230000005764 inhibitory process Effects 0.000 claims abstract description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
201000010099 disease Diseases 0.000 claims abstract description 10
238000004519 manufacturing process Methods 0.000 claims abstract description 5
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
-1 2-hydroxy-2-methylpropyl Chemical group 0.000 claims description 208
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 71
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 58
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
125000004093 cyano group Chemical group *C#N 0.000 claims description 38
150000004682 monohydrates Chemical class 0.000 claims description 35
125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 34
125000001188 haloalkyl group Chemical group 0.000 claims description 32
230000000694 effects Effects 0.000 claims description 26
229910052739 hydrogen Inorganic materials 0.000 claims description 19
125000001207 fluorophenyl group Chemical group 0.000 claims description 15
125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 14
229910052736 halogen Inorganic materials 0.000 claims description 14
150000002367 halogens Chemical class 0.000 claims description 14
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
239000001257 hydrogen Substances 0.000 claims description 10
230000014509 gene expression Effects 0.000 claims description 9
239000003814 drug Substances 0.000 claims description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
206010012601 diabetes mellitus Diseases 0.000 claims description 5
230000002401 inhibitory effect Effects 0.000 claims description 4
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
239000003085 diluting agent Substances 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 1
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
101100451537 Caenorhabditis elegans hsd-1 gene Proteins 0.000 claims 1
150000002431 hydrogen Chemical group 0.000 claims 1
238000006243 chemical reaction Methods 0.000 abstract description 99
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 abstract description 28
229960000890 hydrocortisone Drugs 0.000 abstract description 14
FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 abstract description 5
MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 abstract description 5
MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 abstract description 5
241000124008 Mammalia Species 0.000 abstract description 5
229960004544 cortisone Drugs 0.000 abstract description 5
230000009467 reduction Effects 0.000 abstract description 5
230000001225 therapeutic effect Effects 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 292
239000000203 mixture Substances 0.000 description 279
239000000243 solution Substances 0.000 description 217
125000000217 alkyl group Chemical group 0.000 description 166
125000005843 halogen group Chemical group 0.000 description 151
229910001868 water Inorganic materials 0.000 description 138
235000019439 ethyl acetate Nutrition 0.000 description 137
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 132
238000005160 1H NMR spectroscopy Methods 0.000 description 124
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 112
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 95
229910052938 sodium sulfate Inorganic materials 0.000 description 92
235000011152 sodium sulphate Nutrition 0.000 description 92
239000007832 Na2SO4 Substances 0.000 description 91
101150041968 CDC13 gene Proteins 0.000 description 90
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 90
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 90
125000003545 alkoxy group Chemical group 0.000 description 82
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 71
239000012267 brine Substances 0.000 description 70
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
239000012043 crude product Substances 0.000 description 62
125000004169 (C1-C6) alkyl group Chemical group 0.000 description 59
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 57
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
239000012074 organic phase Substances 0.000 description 52
239000012044 organic layer Substances 0.000 description 51
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 49
125000004457 alkyl amino carbonyl group Chemical group 0.000 description 49
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 48
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 48
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
229910000024 caesium carbonate Inorganic materials 0.000 description 45
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 45
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
125000001424 substituent group Chemical group 0.000 description 44
239000007787 solid Substances 0.000 description 43
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
238000010992 reflux Methods 0.000 description 41
239000011541 reaction mixture Substances 0.000 description 40
239000002904 solvent Substances 0.000 description 40
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 39
125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 38
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 38
125000004356 hydroxy functional group Chemical group O* 0.000 description 36
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
238000002953 preparative HPLC Methods 0.000 description 34
125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 32
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 31
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 29
125000000882 C2-C6 alkenyl group Chemical group 0.000 description 29
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
239000003862 glucocorticoid Substances 0.000 description 29
239000000543 intermediate Substances 0.000 description 29
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 29
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 28
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 description 28
238000012746 preparative thin layer chromatography Methods 0.000 description 28
238000004587 chromatography analysis Methods 0.000 description 27
238000004440 column chromatography Methods 0.000 description 27
125000005479 oxodihydropyridyl group Chemical group 0.000 description 27
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 27
238000001819 mass spectrum Methods 0.000 description 26
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 26
BXQWRZYOOZPLBJ-MMTVBGGISA-N (6s)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(1s)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-1,3-oxazinan-2-one Chemical compound C1([C@@]2(CC(C)(C)O)CCN(C(O2)=O)[C@@H](C)C=2C=CC(=CC=2)B2OC(C)(C)C(C)(C)O2)=CC=CC=C1 BXQWRZYOOZPLBJ-MMTVBGGISA-N 0.000 description 25
239000010410 layer Substances 0.000 description 25
229910052757 nitrogen Inorganic materials 0.000 description 24
239000003921 oil Substances 0.000 description 24
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 24
229910000027 potassium carbonate Inorganic materials 0.000 description 24
238000000634 powder X-ray diffraction Methods 0.000 description 24
239000000741 silica gel Substances 0.000 description 24
229910002027 silica gel Inorganic materials 0.000 description 24
125000003282 alkyl amino group Chemical group 0.000 description 23
125000003806 alkyl carbonyl amino group Chemical group 0.000 description 22
238000000746 purification Methods 0.000 description 22
235000017557 sodium bicarbonate Nutrition 0.000 description 22
229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
229910000104 sodium hydride Inorganic materials 0.000 description 22
239000000460 chlorine Substances 0.000 description 21
239000000706 filtrate Substances 0.000 description 20
230000002829 reductive effect Effects 0.000 description 20
125000004390 alkyl sulfonyl group Chemical group 0.000 description 19
238000004809 thin layer chromatography Methods 0.000 description 19
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
239000011737 fluorine Substances 0.000 description 18
229910052731 fluorine Inorganic materials 0.000 description 18
235000015320 potassium carbonate Nutrition 0.000 description 18
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 17
238000001816 cooling Methods 0.000 description 17
125000001072 heteroaryl group Chemical group 0.000 description 17
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 16
239000003153 chemical reaction reagent Substances 0.000 description 16
229910052801 chlorine Inorganic materials 0.000 description 16
239000013078 crystal Substances 0.000 description 16
230000005855 radiation Effects 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
210000004027 cell Anatomy 0.000 description 15
125000004435 hydrogen atom Chemical group [H]* 0.000 description 15
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 15
229940011051 isopropyl acetate Drugs 0.000 description 15
GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 15
239000000725 suspension Substances 0.000 description 15
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 14
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
125000004453 alkoxycarbonyl group Chemical group 0.000 description 14
125000004644 alkyl sulfinyl group Chemical group 0.000 description 14
125000004656 alkyl sulfonylamino group Chemical group 0.000 description 14
125000000000 cycloalkoxy group Chemical group 0.000 description 14
125000001316 cycloalkyl alkyl group Chemical group 0.000 description 14
125000005148 cycloalkylalkanesulfinyl group Chemical group 0.000 description 14
125000005112 cycloalkylalkoxy group Chemical group 0.000 description 14
230000008569 process Effects 0.000 description 14
238000001953 recrystallisation Methods 0.000 description 14
235000017550 sodium carbonate Nutrition 0.000 description 14
229910000029 sodium carbonate Inorganic materials 0.000 description 14
238000003756 stirring Methods 0.000 description 14
229940037128 systemic glucocorticoids Drugs 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
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
229910052794 bromium Inorganic materials 0.000 description 13
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 13
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 13
125000004433 nitrogen atom Chemical group N* 0.000 description 13
125000004043 oxo group Chemical group O=* 0.000 description 13
YZJCNADFGXFEHX-UHFFFAOYSA-N 4-iodo-1-methylpyridin-2-one Chemical compound CN1C=CC(I)=CC1=O YZJCNADFGXFEHX-UHFFFAOYSA-N 0.000 description 12
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
125000004414 alkyl thio group Chemical group 0.000 description 12
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 12
125000005145 cycloalkylaminosulfonyl group Chemical group 0.000 description 12
NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 12
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 12
125000004438 haloalkoxy group Chemical group 0.000 description 12
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
JONIMGVUGJVFQD-UHFFFAOYSA-N (4-methylphenyl)sulfonylformonitrile Chemical compound CC1=CC=C(S(=O)(=O)C#N)C=C1 JONIMGVUGJVFQD-UHFFFAOYSA-N 0.000 description 11
DNGAQKDEHIEQAQ-AOMKIAJQSA-N (6s)-3-[(1s)-1-(4-bromophenyl)ethyl]-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one Chemical compound C1([C@@]2(CC(C)(C)O)CCN(C(O2)=O)[C@@H](C)C=2C=CC(Br)=CC=2)=CC=CC=C1 DNGAQKDEHIEQAQ-AOMKIAJQSA-N 0.000 description 11
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 11
POHJRJNCZQENQG-UHFFFAOYSA-N 4-iodo-1h-pyridin-2-one Chemical compound IC=1C=CNC(=O)C=1 POHJRJNCZQENQG-UHFFFAOYSA-N 0.000 description 11
HHVFVHIUOMMWRN-UHFFFAOYSA-N 5-bromo-1-methylpyridin-2-one Chemical compound CN1C=C(Br)C=CC1=O HHVFVHIUOMMWRN-UHFFFAOYSA-N 0.000 description 11
101500025412 Mus musculus Processed cyclic AMP-responsive element-binding protein 3-like protein 1 Proteins 0.000 description 11
125000004432 carbon atom Chemical group C* 0.000 description 11
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
229910052943 magnesium sulfate Inorganic materials 0.000 description 11
239000000463 material Substances 0.000 description 11
239000012299 nitrogen atmosphere Substances 0.000 description 11
SXAUUPNZZAAJOG-YCRPNKLZSA-N (6r)-3-[(1s)-1-(4-bromophenyl)ethyl]-6-(4-fluorophenyl)-6-prop-2-enyl-1,3-oxazinan-2-one Chemical compound C1([C@@]2(CC=C)CCN(C(O2)=O)[C@@H](C)C=2C=CC(Br)=CC=2)=CC=C(F)C=C1 SXAUUPNZZAAJOG-YCRPNKLZSA-N 0.000 description 10
QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
101710088194 Dehydrogenase Proteins 0.000 description 10
BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
239000002253 acid Substances 0.000 description 10
125000003368 amide group Chemical class 0.000 description 10
238000001914 filtration Methods 0.000 description 10
NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
239000007858 starting material Substances 0.000 description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 10
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 10
YFOQSLIPUHGGQE-UHFFFAOYSA-N 4-bromo-1-methylpyridin-2-one Chemical compound CN1C=CC(Br)=CC1=O YFOQSLIPUHGGQE-UHFFFAOYSA-N 0.000 description 9
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 9
125000003601 C2-C6 alkynyl group Chemical group 0.000 description 9
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
229910021120 PdC12 Inorganic materials 0.000 description 9
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 9
125000003118 aryl group Chemical group 0.000 description 9
239000000284 extract Substances 0.000 description 9
238000004128 high performance liquid chromatography Methods 0.000 description 9
239000012442 inert solvent Substances 0.000 description 9
235000011149 sulphuric acid Nutrition 0.000 description 9
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CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical group C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
DNGMYXZLJGHHOM-UHFFFAOYSA-N thiazinane 1,1-dioxide Chemical compound O=S1(=O)CCCCN1 DNGMYXZLJGHHOM-UHFFFAOYSA-N 0.000 description 1
150000003573 thiols Chemical class 0.000 description 1
BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
239000010936 titanium Substances 0.000 description 1
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VHKIEYIESYMHPT-UHFFFAOYSA-N triethyl(methoxycarbonylsulfamoyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC VHKIEYIESYMHPT-UHFFFAOYSA-N 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 description 1
201000008827 tuberculosis Diseases 0.000 description 1
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230000000007 visual effect Effects 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000003643 water by type Substances 0.000 description 1
229910052727 yttrium Inorganic materials 0.000 description 1

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Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA2759047A 2009-04-30 2010-04-30 Inhibiteurs cycliques de la 11beta-hydroxysteroide deshydrogenase 1 Abandoned CA2759047A1 (fr)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
PCT/US2009/002653 WO2009134400A1 (fr)	2008-05-01	2009-04-30	Inhibiteurs cycliques de la 11-bêta-hydroxystéroïde déhydrogénase 1
USPCT/US2009/002653		2009-04-30
PCT/US2009/004261 WO2010011314A1 (fr)	2008-07-25	2009-07-23	Inhibiteurs cycliques de la 11 bêta-hydroxystéroïde déshydrogénase 1
USPCT/US2009/004261		2009-07-23
PCT/US2010/033157 WO2010127237A2 (fr)	2009-04-30	2010-04-30	Inhibiteurs cycliques de la 11béta-hydroxysteroïde déshydrogénase 1

Publications (1)

Publication Number	Publication Date
CA2759047A1 true CA2759047A1 (fr)	2010-11-04

Family

ID=45218974

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2759047A Abandoned CA2759047A1 (fr)	2009-04-30	2010-04-30	Inhibiteurs cycliques de la 11beta-hydroxysteroide deshydrogenase 1

Country Status (2)

Country	Link
CA (1)	CA2759047A1 (fr)
SG (1)	SG174879A1 (fr)

2010
- 2010-04-30 SG SG2011067485A patent/SG174879A1/en unknown
- 2010-04-30 CA CA2759047A patent/CA2759047A1/fr not_active Abandoned

Also Published As

Publication number	Publication date
SG174879A1 (en)	2011-11-28

Publication	Publication Date	Title
AU2009274567B2 (en)	2013-04-04	Cyclic inhibitors of 11 beta-hydroxysteroid dehydrogenase 1
AU2009241727B2 (en)	2013-05-02	Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8680093B2 (en)	2014-03-25	Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US20100331320A1 (en)	2010-12-30	Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
CA2723034A1 (fr)	2009-11-05	Inhibiteurs cycliques de la 11-beta-hydroxysteroide dehydrogenase 1
EP2291371A1 (fr)	2011-03-09	Inhibiteurs cycliques de la 11-bêta-hydroxystéroïde déhydrogénase 1
AU2010242876B2 (en)	2015-06-18	Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
IL215249A (en)	2014-12-31	Cyclic inhibitors of 11 in the hydroxysteroid steroid dehydrogenase 1
CA2759047A1 (fr)	2010-11-04	Inhibiteurs cycliques de la 11beta-hydroxysteroide deshydrogenase 1
MX2011000816A (es)	2011-08-03	Inhibidores ciclicos de 11 beta-hidroxiesteroide deshidrogenasa 1.

Legal Events

Date	Code	Title	Description
2015-04-28	EEER	Examination request	Effective date: 20150330
2017-06-13	FZDE	Discontinued	Effective date: 20170502