BRPI0610059A2 - derivados de pirrol como moduladores alostéricos positivos de receptores de glutamato metabotrópicos, composição farmacêutica compreendendo os mesmos e seus usos na fabricação de medicamento - Google Patents

Info

Publication number

BRPI0610059A2

BRPI0610059A2 BRPI0610059-7A BRPI0610059A BRPI0610059A2 BR PI0610059 A2 BRPI0610059 A2 BR PI0610059A2 BR PI0610059 A BRPI0610059 A BR PI0610059A BR PI0610059 A2 BRPI0610059 A2 BR PI0610059A2

Authority

BR

Brazil

Prior art keywords

alkyl

oxadiazol

piperidin

fluoro

pyrrol

Prior art date

2005-05-18

Links

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• 238000004519 manufacturing process Methods 0.000 title claims description 92
• 230000003281 allosteric effect Effects 0.000 title claims description 23
• 102000016193 Metabotropic glutamate receptors Human genes 0.000 title claims description 10
• 108010010914 Metabotropic glutamate receptors Proteins 0.000 title claims description 10
• 239000003814 drug Substances 0.000 title claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 212
• 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims abstract description 43
• 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims abstract description 43
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
• 208000015114 central nervous system disease Diseases 0.000 claims abstract description 11
• 230000002265 prevention Effects 0.000 claims abstract description 10
• 238000000034 method Methods 0.000 claims description 266
• 125000000217 alkyl group Chemical group 0.000 claims description 204
• -1 hydroxy , amino Chemical group 0.000 claims description 181
• 125000003118 aryl group Chemical group 0.000 claims description 133
• 125000001072 heteroaryl group Chemical group 0.000 claims description 125
• 239000000203 mixture Substances 0.000 claims description 108
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 104
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 79
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 54
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 54
• 229910052739 hydrogen Inorganic materials 0.000 claims description 53
• 239000001257 hydrogen Substances 0.000 claims description 53
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 35
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 32
• 125000001424 substituent group Chemical group 0.000 claims description 31
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 28
• 125000005843 halogen group Chemical group 0.000 claims description 28
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 24
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
• 229910052736 halogen Inorganic materials 0.000 claims description 22
• 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 19
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 17
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 17
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 16
• 125000004429 atom Chemical group 0.000 claims description 15
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
• 150000001204 N-oxides Chemical class 0.000 claims description 14
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
• 239000012453 solvate Substances 0.000 claims description 14
• KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 13
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 13
• 229940025084 amphetamine Drugs 0.000 claims description 13
• 150000004677 hydrates Chemical class 0.000 claims description 13
• 201000000980 schizophrenia Diseases 0.000 claims description 13
• 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 12
• 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 9
• 208000035475 disorder Diseases 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 6
• ZVBWKKUICJBUMA-LBPRGKRZSA-N (4-fluorophenyl)-[(3S)-3-[3-(1H-imidazol-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=CN=2)CCC1 ZVBWKKUICJBUMA-LBPRGKRZSA-N 0.000 claims description 5
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• 125000002619 bicyclic group Chemical group 0.000 claims description 5
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
• 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 5
• 208000011117 substance-related disease Diseases 0.000 claims description 5
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 5
• MENUUDHIISNRIW-HNNXBMFYSA-N (3,4-difluorophenyl)-[(3S)-3-[3-(1H-indol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=C(F)C(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2NC3=CC=CC=C3C=2)CCC1 MENUUDHIISNRIW-HNNXBMFYSA-N 0.000 claims description 4
• NYWQJTBZFYWELR-UHFFFAOYSA-N (3,4-difluorophenyl)-[3-[5-(1H-imidazol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound C1=C(F)C(F)=CC=C1C(=O)N1CC(C=2N=C(ON=2)C=2NC=CN=2)CCC1 NYWQJTBZFYWELR-UHFFFAOYSA-N 0.000 claims description 4
• LUWWVGZLSXBKFM-UHFFFAOYSA-N (3,4-difluorophenyl)-[3-[5-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound C1=C(F)C(F)=CC=C1C(=O)N1CC(C=2N=C(ON=2)C=2NC=CC=2)CCC1 LUWWVGZLSXBKFM-UHFFFAOYSA-N 0.000 claims description 4
• 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 4
• SQMDCGNVPLTEKC-INIZCTEOSA-N (4-fluorophenyl)-[(3S)-3-[3-(1H-indol-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=2NC3=CC=CC=C3C=2)CCC1 SQMDCGNVPLTEKC-INIZCTEOSA-N 0.000 claims description 4
• PEJDLTDYANPRBU-AWEZNQCLSA-N (4-fluorophenyl)-[(3S)-3-[5-(1H-pyrrol-2-yl)tetrazol-2-yl]piperidin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1C[C@@H](N2N=C(N=N2)C=2NC=CC=2)CCC1 PEJDLTDYANPRBU-AWEZNQCLSA-N 0.000 claims description 4
• BOACXNJMYAYPHQ-UHFFFAOYSA-N (4-fluorophenyl)-[3-[3-(1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]pyrrolidin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1CC(C=2ON=C(N=2)C=2NC=CC=2)CC1 BOACXNJMYAYPHQ-UHFFFAOYSA-N 0.000 claims description 4
• PPRTYCFGRLGSJU-UHFFFAOYSA-N (4-fluorophenyl)-[3-[5-(1h-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1CC(C=2N=C(ON=2)C=2NN=CC=2)CCC1 PPRTYCFGRLGSJU-UHFFFAOYSA-N 0.000 claims description 4
• 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 4
• 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 compound 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
• JNQJYRKKMMRSEN-ZDUSSCGKSA-N (6-fluoropyridin-3-yl)-[(3S)-3-[5-(4-methyl-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound CC1=CNC(C=2ON=C(N=2)[C@@H]2CN(CCC2)C(=O)C=2C=NC(F)=CC=2)=C1 JNQJYRKKMMRSEN-ZDUSSCGKSA-N 0.000 claims description 4
• OJYIYJOUIBEIFY-AWEZNQCLSA-N (6-fluoropyridin-3-yl)-[(3S)-3-[5-(4-propan-2-yl-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound CC(C)C1=CNC(C=2ON=C(N=2)[C@@H]2CN(CCC2)C(=O)C=2C=NC(F)=CC=2)=C1 OJYIYJOUIBEIFY-AWEZNQCLSA-N 0.000 claims description 4
• 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 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
• KSXKNDXBIXELCD-NSHDSACASA-N (2-fluoropyridin-4-yl)-[(3S)-3-[3-(4-fluoro-1H-pyrrol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound FC1=CNC(C=2N=C(ON=2)[C@@H]2CN(CCC2)C(=O)C=2C=C(F)N=CC=2)=C1 KSXKNDXBIXELCD-NSHDSACASA-N 0.000 claims description 3
• AEFNJYKVPGWFAJ-ZDUSSCGKSA-N (2-fluoropyridin-4-yl)-[(3S)-3-[5-(4-methyl-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound CC1=CNC(C=2ON=C(N=2)[C@@H]2CN(CCC2)C(=O)C=2C=C(F)N=CC=2)=C1 AEFNJYKVPGWFAJ-ZDUSSCGKSA-N 0.000 claims description 3
• KIPDNXNSBZJSHW-UHFFFAOYSA-N (3,4-difluorophenyl)-[3-[5-(1h-pyrazol-5-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound C1=C(F)C(F)=CC=C1C(=O)N1CC(C=2N=C(ON=2)C=2NN=CC=2)CCC1 KIPDNXNSBZJSHW-UHFFFAOYSA-N 0.000 claims description 3
• BRCRDKHUCOPYIX-JTQLQIEISA-N (3-fluoropyridin-4-yl)-[(3S)-3-[5-(4-fluoro-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound FC1=CNC(C=2ON=C(N=2)[C@@H]2CN(CCC2)C(=O)C=2C(=CN=CC=2)F)=C1 BRCRDKHUCOPYIX-JTQLQIEISA-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-ZDUSSCGKSA-N (4-fluorophenyl)-[(3S)-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-ZDUSSCGKSA-N 0.000 claims description 3
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• UURXMBRSMGNNJJ-UHFFFAOYSA-N (4-fluorophenyl)-[3-[5-(1H-imidazol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1CC(C=2N=C(ON=2)C=2NC=CN=2)CCC1 UURXMBRSMGNNJJ-UHFFFAOYSA-N 0.000 claims description 3
• NWTFTNUHQJJMBM-LBPRGKRZSA-N (5-methyl-1,2-oxazol-4-yl)-[(3S)-3-[3-(4-methyl-1H-pyrrol-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)C2=C(ON=C2)C)=C1 NWTFTNUHQJJMBM-LBPRGKRZSA-N 0.000 claims description 3
• YNVMGWGHDVYXMI-LBPRGKRZSA-N (5-methyl-1,2-oxazol-4-yl)-[(3S)-3-[5-(4-methyl-1H-pyrrol-2-yl)-1,2,4-oxadiazol-3-yl]piperidin-1-yl]methanone Chemical compound CC1=CNC(C=2ON=C(N=2)[C@@H]2CN(CCC2)C(=O)C2=C(ON=C2)C)=C1 YNVMGWGHDVYXMI-LBPRGKRZSA-N 0.000 claims description 3
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