AU2006248657B2 - Pyrrole derivatives as positive allosteric modulators of metabotropic glutamate receptors - Google Patents

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Publication number

AU2006248657B2

AU2006248657B2 AU2006248657A AU2006248657A AU2006248657B2 AU 2006248657 B2 AU2006248657 B2 AU 2006248657B2 AU 2006248657 A AU2006248657 A AU 2006248657A AU 2006248657 A AU2006248657 A AU 2006248657A AU 2006248657 B2 AU2006248657 B2 AU 2006248657B2

Authority

AU

Australia

Prior art keywords

alkyl

oxadiazol

piperidin

methanone

fluoro

Prior art date

2005-05-18

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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• 230000003281 allosteric effect Effects 0.000 title claims description 18
• 102000016193 Metabotropic glutamate receptors Human genes 0.000 title claims description 14
• 108010010914 Metabotropic glutamate receptors Proteins 0.000 title claims description 14
• 150000003233 pyrroles Chemical class 0.000 title abstract 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 222
• 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims abstract description 50
• 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims abstract description 50
• 208000015114 central nervous system disease Diseases 0.000 claims abstract description 22
• 230000002265 prevention Effects 0.000 claims abstract description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
• 125000000217 alkyl group Chemical group 0.000 claims description 339
• 125000003118 aryl group Chemical group 0.000 claims description 158
• 125000001072 heteroaryl group Chemical group 0.000 claims description 143
• 239000000203 mixture Substances 0.000 claims description 122
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 88
• 229910052736 halogen Inorganic materials 0.000 claims description 64
• 150000002367 halogens Chemical class 0.000 claims description 64
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 239000001257 hydrogen Substances 0.000 claims description 61
• 125000001424 substituent group Chemical group 0.000 claims description 61
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 60
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
• -1 hydroxy, amino Chemical group 0.000 claims description 51
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 35
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 30
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 30
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 29
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 29
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 27
• 150000003839 salts Chemical class 0.000 claims description 23
• 229910052799 carbon Inorganic materials 0.000 claims description 21
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 18
• 239000012453 solvate Substances 0.000 claims description 18
• 150000001204 N-oxides Chemical class 0.000 claims description 17
• 150000004677 hydrates Chemical class 0.000 claims description 17
• 150000002431 hydrogen Chemical class 0.000 claims description 17
• 125000004429 atom Chemical group 0.000 claims description 16
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 15
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 15
• 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 15
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
• 125000005843 halogen group Chemical group 0.000 claims description 14
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
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• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
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• KIIWYGFIAGRWCK-NSHDSACASA-N (6-fluoropyridin-3-yl)-[(3S)-3-[3-(4-fluoro-1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical group FC1=CNC(C=2N=C(ON=2)[C@@H]2CN(CCC2)C(=O)C=2C=NC(F)=CC=2)=C1 KIIWYGFIAGRWCK-NSHDSACASA-N 0.000 claims description 4
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• CVXSESIHZWEERI-LBPRGKRZSA-N [(3S)-3-[3-(4-chloro-1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2NC=C(Cl)C=2)CCC1 CVXSESIHZWEERI-LBPRGKRZSA-N 0.000 claims description 4
• AWUZMJOSTMJVGT-NSHDSACASA-N [(3S)-3-[5-(4-bromo-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]-(6-fluoropyridin-3-yl)methanone Chemical compound C1=NC(F)=CC=C1C(=O)N1C[C@@H](C=2N=C(ON=2)C=2NC=C(Br)C=2)CCC1 AWUZMJOSTMJVGT-NSHDSACASA-N 0.000 claims description 4
• FUZQYPIJFKDVBA-LBPRGKRZSA-N [(3S)-3-[5-(4-chloro-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1C[C@@H](C=2N=C(ON=2)C=2NC=C(Cl)C=2)CCC1 FUZQYPIJFKDVBA-LBPRGKRZSA-N 0.000 claims description 4
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
• RANDMAUZUPLZBV-LBPRGKRZSA-N (3,4-difluorophenyl)-[(3S)-3-[3-(5-methyl-1H-imidazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CC1=CNC(C=2N=C(ON=2)[C@@H]2CN(CCC2)C(=O)C=2C=C(F)C(F)=CC=2)=N1 RANDMAUZUPLZBV-LBPRGKRZSA-N 0.000 claims description 3
• BWUIIXZUPYXCHA-UHFFFAOYSA-N (4-fluoro-2-methylphenyl)-[3-[5-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound CC1=CC(F)=CC=C1C(=O)N1CC(C=2N=C(ON=2)C=2NC=CC=2)CCC1 BWUIIXZUPYXCHA-UHFFFAOYSA-N 0.000 claims description 3
• BOYOGJRLPORQHQ-CYBMUJFWSA-N (4-fluorophenyl)-[(3R)-3-[3-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1C[C@H](C=2ON=C(N=2)C=2NC=CC=2)CCC1 BOYOGJRLPORQHQ-CYBMUJFWSA-N 0.000 claims description 3
• RIYADNUXTBLENX-LBPRGKRZSA-N (6-fluoropyridin-3-yl)-[(3S)-3-[3-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=NC(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2NC=CC=2)CCC1 RIYADNUXTBLENX-LBPRGKRZSA-N 0.000 claims description 3
• FVPNESLLQQDQBH-NSHDSACASA-N (6-fluoropyridin-3-yl)-[(3S)-3-[5-[4-(trifluoromethyl)-1H-pyrrol-2-yl]-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound C1=NC(F)=CC=C1C(=O)N1C[C@@H](C=2N=C(ON=2)C=2NC=C(C=2)C(F)(F)F)CCC1 FVPNESLLQQDQBH-NSHDSACASA-N 0.000 claims description 3
• KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 3
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• WHGRYTYIQIILBL-JTQLQIEISA-N [(3S)-3-[5-(4-bromo-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]-(3-fluoropyridin-4-yl)methanone Chemical compound FC1=CN=CC=C1C(=O)N1C[C@@H](C=2N=C(ON=2)C=2NC=C(Br)C=2)CCC1 WHGRYTYIQIILBL-JTQLQIEISA-N 0.000 claims description 3
• COMUOENAGNUWHL-NSHDSACASA-N [(3S)-3-[5-(4-chloro-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]-(2-fluoropyridin-4-yl)methanone Chemical compound C1=NC(F)=CC(C(=O)N2C[C@H](CCC2)C=2N=C(ON=2)C=2NC=C(Cl)C=2)=C1 COMUOENAGNUWHL-NSHDSACASA-N 0.000 claims description 3
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• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 2
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• NPBWXMYQFSITMF-NSHDSACASA-N (6-fluoropyridin-3-yl)-[(3S)-3-[3-[4-(trifluoromethyl)-1H-pyrrol-2-yl]-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=NC(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2NC=C(C=2)C(F)(F)F)CCC1 NPBWXMYQFSITMF-NSHDSACASA-N 0.000 claims description 2
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