JP5679997B2 - １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状阻害剤 - Google Patents

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Publication number

JP5679997B2

JP5679997B2 JP2011548664A JP2011548664A JP5679997B2 JP 5679997 B2 JP5679997 B2 JP 5679997B2 JP 2011548664 A JP2011548664 A JP 2011548664A JP 2011548664 A JP2011548664 A JP 2011548664A JP 5679997 B2 JP5679997 B2 JP 5679997B2

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JP

Japan

Prior art keywords

halo

alkyl

alkoxy

cycloalkyl

hydroxy

Prior art date

2009-02-04

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.)

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• 239000003112 inhibitor Substances 0.000 title description 21
• 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 title description 4
• 125000004122 cyclic group Chemical group 0.000 title description 3
• 101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 title description 2
• 125000001475 halogen functional group Chemical group 0.000 claims description 219
• -1 Oki Chemical group 0.000 claims description 214
• 150000001875 compounds Chemical class 0.000 claims description 161
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 84
• 125000003545 alkoxy group Chemical group 0.000 claims description 77
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 72
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 61
• 150000003839 salts Chemical class 0.000 claims description 60
• 239000000460 chlorine Substances 0.000 claims description 54
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 52
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 50
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 48
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 43
• 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 42
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 42
• 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 37
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 34
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 34
• 229910052801 chlorine Inorganic materials 0.000 claims description 34
• 239000011737 fluorine Substances 0.000 claims description 34
• 229910052731 fluorine Inorganic materials 0.000 claims description 34
• 125000001072 heteroaryl group Chemical group 0.000 claims description 33
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
• 125000005366 cycloalkylthio group Chemical group 0.000 claims description 28
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 25
• 125000000217 alkyl group Chemical group 0.000 claims description 25
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 25
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 24
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 24
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 24
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 24
• 229910052794 bromium Inorganic materials 0.000 claims description 24
• 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 23
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 22
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 22
• 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 22
• 230000000694 effects Effects 0.000 claims description 22
• 229910052736 halogen Inorganic materials 0.000 claims description 22
• 150000002367 halogens Chemical class 0.000 claims description 22
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 21
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 21
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 21
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 21
• 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
• 125000005148 cycloalkylalkanesulfinyl group Chemical group 0.000 claims description 20
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 19
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 19
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 19
• 125000004043 oxo group Chemical group O=* 0.000 claims description 18
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 16
• 125000002541 furyl group Chemical group 0.000 claims description 16
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 16
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
• 125000002971 oxazolyl group Chemical group 0.000 claims description 16
• 125000001544 thienyl group Chemical group 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• 239000001257 hydrogen Substances 0.000 claims description 15
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 14
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 14
• 150000001408 amides Chemical class 0.000 claims description 14
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 13
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
• 125000001188 haloalkyl group Chemical group 0.000 claims description 11
• 230000002401 inhibitory effect Effects 0.000 claims description 11
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• 125000000623 heterocyclic group Chemical group 0.000 claims description 10
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
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• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 7
• 125000003118 aryl group Chemical group 0.000 claims description 7
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• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
• 125000002947 alkylene group Chemical group 0.000 claims description 4
• 125000001769 aryl amino group Chemical group 0.000 claims description 4
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• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 125000003368 amide group Chemical class 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
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• 239000003085 diluting agent Substances 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
• 125000003342 alkenyl group Chemical group 0.000 claims description 2
• 125000003282 alkyl amino group Chemical group 0.000 claims description 2
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 2
• 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 2
• VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
• 239000001301 oxygen Substances 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 5
• 241001024304 Mino Species 0.000 claims 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
• 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 109
• 239000000203 mixture Substances 0.000 description 97
• 238000001819 mass spectrum Methods 0.000 description 68
• 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 description 62
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• 239000000243 solution Substances 0.000 description 52
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
• 239000000543 intermediate Substances 0.000 description 39
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
• 125000001424 substituent group Chemical group 0.000 description 37
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
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• 239000003862 glucocorticoid Substances 0.000 description 31
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
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• 239000007819 coupling partner Substances 0.000 description 16
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