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
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 Download PDFInfo
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- 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
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- alkyl
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- alkoxy
- cycloalkyl
- hydroxy
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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
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- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 3
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- 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
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- 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
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- 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
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- 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
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 14
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
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-
2008
- 2008-11-06 AR ARP080104852A patent/AR069207A1/es unknown
- 2008-11-07 TW TW097143034A patent/TW200934495A/zh unknown
- 2008-11-07 CL CL2008003339A patent/CL2008003339A1/es unknown
- 2008-11-07 EP EP08846298.1A patent/EP2220052B1/en not_active Not-in-force
- 2008-11-07 CA CA2704222A patent/CA2704222A1/en not_active Abandoned
- 2008-11-07 US US12/745,663 patent/US9079861B2/en not_active Expired - Fee Related
- 2008-11-07 WO PCT/US2008/012618 patent/WO2009061498A1/en not_active Ceased
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|---|---|
| AR069207A1 (es) | 2010-01-06 |
| CL2008003339A1 (es) | 2009-10-16 |
| TW200934495A (en) | 2009-08-16 |
| EP2220052A1 (en) | 2010-08-25 |
| WO2009061498A1 (en) | 2009-05-14 |
| JP2011503068A (ja) | 2011-01-27 |
| US20100324045A1 (en) | 2010-12-23 |
| US9079861B2 (en) | 2015-07-14 |
| EP2220052B1 (en) | 2015-03-25 |
| CA2704222A1 (en) | 2009-05-14 |
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