CA2744946A1

CA2744946A1 - Cyclic inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1

Cyclic inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1 Download PDF

Info

Publication number: CA2744946A1
Authority: CA; Canada
Prior art keywords: halo; alkyl; alkoxy; hydroxy; compound
Prior art date: 2009-02-04
Legal status : Abandoned

Application number

CA2744946A

Other languages

English (en)

French (fr)

Inventor

Frank Himmelsbach

Matthias Eckhardt

Current Assignee

Boehringer Ingelheim International GmbH

Original Assignee

Boehringer Ingelheim International GmbH

Priority date

2009-02-04

Filing date

2010-02-03

Publication date

2010-08-12

2010-02-03 Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH

2010-08-12 Publication of CA2744946A1 publication Critical patent/CA2744946A1/en

Status Abandoned legal-status Critical Current

Links

239000003112 inhibitor Substances 0.000 title description 30
101710088194 Dehydrogenase Proteins 0.000 title description 8
125000004122 cyclic group Chemical group 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims abstract description 262
150000003839 salts Chemical class 0.000 claims abstract description 79
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
238000011282 treatment Methods 0.000 claims abstract description 20
201000010099 disease Diseases 0.000 claims abstract description 19
238000000034 method Methods 0.000 claims abstract description 11
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
241000124008 Mammalia Species 0.000 claims abstract description 6
-1 heteroaryl oxo Chemical group 0.000 claims description 300
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 243
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 212
125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 151
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 102
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 95
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 94
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 93
125000003545 alkoxy group Chemical group 0.000 claims description 73
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 67
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 58
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 50
125000001424 substituent group Chemical group 0.000 claims description 50
125000004093 cyano group Chemical group *C#N 0.000 claims description 47
125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 43
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 42
125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 42
239000000460 chlorine Substances 0.000 claims description 42
125000000000 cycloalkoxy group Chemical group 0.000 claims description 42
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 42
125000005148 cycloalkylalkanesulfinyl group Chemical group 0.000 claims description 42
125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 42
125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 41
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 41
125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 40
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 40
125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 39
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 39
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
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
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 33
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 33
125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 30
QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 30
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 30
125000001072 heteroaryl group Chemical group 0.000 claims description 30
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 25
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
125000005167 cycloalkylaminocarbonyl group Chemical group 0.000 claims description 24
125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 23
229910052739 hydrogen Inorganic materials 0.000 claims description 23
230000000694 effects Effects 0.000 claims description 22
229910052736 halogen Inorganic materials 0.000 claims description 22
150000002367 halogens Chemical group 0.000 claims description 22
125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 21
125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 21
125000006517 heterocyclyl carbonyl group Chemical group 0.000 claims description 21
239000001257 hydrogen Substances 0.000 claims description 20
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 19
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 19
125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 18
125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 18
125000000217 alkyl group Chemical group 0.000 claims description 18
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 18
125000004043 oxo group Chemical group O=* 0.000 claims description 18
125000002541 furyl group Chemical group 0.000 claims description 17
125000002971 oxazolyl group Chemical group 0.000 claims description 17
125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 17
125000001544 thienyl group Chemical group 0.000 claims description 17
125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 16
125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 16
125000003368 amide group Chemical class 0.000 claims description 16
125000000842 isoxazolyl group Chemical group 0.000 claims description 16
125000001188 haloalkyl group Chemical group 0.000 claims description 15
229910052799 carbon Inorganic materials 0.000 claims description 14
125000005145 cycloalkylaminosulfonyl group Chemical group 0.000 claims description 12
230000002401 inhibitory effect Effects 0.000 claims description 11
125000004432 carbon atom Chemical group C* 0.000 claims description 10
125000000623 heterocyclic group Chemical group 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
125000004663 dialkyl amino group Chemical group 0.000 claims description 9
125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 8
125000004414 alkyl thio group Chemical group 0.000 claims description 8
230000014509 gene expression Effects 0.000 claims description 7
125000003118 aryl group Chemical group 0.000 claims description 6
125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 6
125000000753 cycloalkyl group Chemical group 0.000 claims description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
125000002947 alkylene group Chemical group 0.000 claims description 4
125000001769 aryl amino group Chemical group 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000005241 heteroarylamino group Chemical group 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
239000003085 diluting agent Substances 0.000 claims description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 claims description 2
239000001301 oxygen Substances 0.000 claims description 2
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150000002431 hydrogen Chemical group 0.000 claims 10
125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 1
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 112
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238000001819 mass spectrum Methods 0.000 description 68
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YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 46
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
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239000000543 intermediate Substances 0.000 description 39
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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 16
238000002868 homogeneous time resolved fluorescence Methods 0.000 description 15
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