JP5695906B2 - １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状尿素阻害剤 - Google Patents

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Publication number

JP5695906B2

JP5695906B2 JP2010533113A JP2010533113A JP5695906B2 JP 5695906 B2 JP5695906 B2 JP 5695906B2 JP 2010533113 A JP2010533113 A JP 2010533113A JP 2010533113 A JP2010533113 A JP 2010533113A JP 5695906 B2 JP5695906 B2 JP 5695906B2

Authority

JP

Japan

Prior art keywords

alkyl

halo

alkoxy

cycloalkyl

hydroxy

Prior art date

2007-11-07

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.)

Expired - Fee Related

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• 239000003112 inhibitor Substances 0.000 title description 20
• 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 title description 3
• 101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 title 1
• ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical compound OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 title 1
• 125000005843 halogen group Chemical group 0.000 claims description 441
• -1 O Seo Chemical group 0.000 claims description 323
• 125000003545 alkoxy group Chemical group 0.000 claims description 249
• 125000000217 alkyl group Chemical group 0.000 claims description 248
• 150000001875 compounds Chemical class 0.000 claims description 155
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 137
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 111
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 104
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 92
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 87
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 81
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 79
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 75
• 125000001072 heteroaryl group Chemical group 0.000 claims description 74
• 125000004043 oxo group Chemical group O=* 0.000 claims description 72
• 150000003839 salts Chemical class 0.000 claims description 69
• 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 claims description 68
• 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 claims description 68
• 239000000460 chlorine Substances 0.000 claims description 63
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 62
• 125000003282 alkyl amino group Chemical group 0.000 claims description 61
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 60
• 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 60
• 125000005366 cycloalkylthio group Chemical group 0.000 claims description 60
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 58
• 239000011737 fluorine Substances 0.000 claims description 54
• 229910052731 fluorine Inorganic materials 0.000 claims description 54
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 52
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 50
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 48
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 48
• 150000001408 amides Chemical class 0.000 claims description 45
• 229910052757 nitrogen Inorganic materials 0.000 claims description 45
• 125000003342 alkenyl group Chemical group 0.000 claims description 44
• 125000004414 alkyl thio group Chemical group 0.000 claims description 44
• 229910052736 halogen Inorganic materials 0.000 claims description 44
• 150000002367 halogens Chemical class 0.000 claims description 44
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 41
• 229910052801 chlorine Inorganic materials 0.000 claims description 41
• 125000001188 haloalkyl group Chemical group 0.000 claims description 41
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 40
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 37
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 239000001257 hydrogen Substances 0.000 claims description 36
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
• 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 34
• 229910052794 bromium Inorganic materials 0.000 claims description 34
• 125000000623 heterocyclic group Chemical group 0.000 claims description 34
• 125000003118 aryl group Chemical group 0.000 claims description 33
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 33
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 32
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 32
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 31
• 125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 30
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 28
• 230000000694 effects Effects 0.000 claims description 27
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 24
• 125000005148 cycloalkylalkanesulfinyl group Chemical group 0.000 claims description 24
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 23
• 201000010099 disease Diseases 0.000 claims description 22
• 238000011282 treatment Methods 0.000 claims description 22
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 21
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
• 125000000304 alkynyl group Chemical group 0.000 claims description 21
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 20
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 20
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 19
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 19
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 19
• 125000002947 alkylene group Chemical group 0.000 claims description 18
• 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 17
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 17
• 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 15
• 125000001769 aryl amino group Chemical group 0.000 claims description 14
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 14
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims description 13
• 125000005145 cycloalkylaminosulfonyl group Chemical group 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
• 230000014509 gene expression Effects 0.000 claims description 8
• 229910052717 sulfur Inorganic materials 0.000 claims description 8
• 125000001544 thienyl group Chemical group 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 125000001153 fluoro group Chemical group F* 0.000 claims description 7
• 230000002401 inhibitory effect Effects 0.000 claims description 7
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
• 239000001301 oxygen Substances 0.000 claims description 5
• 125000004633 N-oxo-pyridyl group Chemical group 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• LLAPDLPYIYKTGQ-UHFFFAOYSA-N 1-aminoethyl Chemical group C[CH]N LLAPDLPYIYKTGQ-UHFFFAOYSA-N 0.000 claims description 3
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
• 229920002554 vinyl polymer Polymers 0.000 claims description 3
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
• 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
• 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• 125000006262 isopropyl amino sulfonyl group Chemical group 0.000 claims description 2
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
• 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 3
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
• 125000005549 heteroarylene group Chemical group 0.000 claims 1
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 1
• 238000000034 method Methods 0.000 description 94
• 125000001424 substituent group Chemical group 0.000 description 81
• 239000000203 mixture Substances 0.000 description 63
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
• 239000000243 solution Substances 0.000 description 53
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 46
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 43
• 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 35
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 32
• 239000003862 glucocorticoid Substances 0.000 description 30
• 238000006243 chemical reaction Methods 0.000 description 21
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 20
• 239000000543 intermediate Substances 0.000 description 20
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 19
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 19
• 125000001207 fluorophenyl group Chemical group 0.000 description 19
• 125000004433 nitrogen atom Chemical group N* 0.000 description 19
• 125000004432 carbon atom Chemical group C* 0.000 description 18
• 229960000890 hydrocortisone Drugs 0.000 description 18
• 125000005479 oxodihydropyridyl group Chemical group 0.000 description 17
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 16
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
• 235000019439 ethyl acetate Nutrition 0.000 description 15
• 229940037128 systemic glucocorticoids Drugs 0.000 description 15
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 14
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• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 12
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