CA2608012A1 - Novel oxadiazole derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors - Google Patents

Info

Publication number

CA2608012A1

CA2608012A1 CA002608012A CA2608012A CA2608012A1 CA 2608012 A1 CA2608012 A1 CA 2608012A1 CA 002608012 A CA002608012 A CA 002608012A CA 2608012 A CA2608012 A CA 2608012A CA 2608012 A1 CA2608012 A1 CA 2608012A1

Authority

CA

Canada

Prior art keywords

phenyl

fluoro

oxadiazol

piperidin

methanone

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 230000003281 allosteric effect Effects 0.000 title claims description 23
• 102000016193 Metabotropic glutamate receptors Human genes 0.000 title claims description 13
• 108010010914 Metabotropic glutamate receptors Proteins 0.000 title claims description 13
• 150000004866 oxadiazoles Chemical class 0.000 title abstract description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 228
• 108010065028 Metabotropic Glutamate 5 Receptor Proteins 0.000 claims abstract description 40
• 102000012777 Metabotropic Glutamate 5 Receptor Human genes 0.000 claims abstract description 40
• 208000015114 central nervous system disease Diseases 0.000 claims abstract description 14
• 230000002265 prevention Effects 0.000 claims abstract description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
• 238000000034 method Methods 0.000 claims description 263
• 125000000217 alkyl group Chemical group 0.000 claims description 81
• -1 hydroxy, amino Chemical group 0.000 claims description 66
• 125000003118 aryl group Chemical group 0.000 claims description 60
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 50
• 125000001072 heteroaryl group Chemical group 0.000 claims description 49
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 31
• 239000000203 mixture Substances 0.000 claims description 28
• 229910052736 halogen Inorganic materials 0.000 claims description 25
• 150000002367 halogens Chemical class 0.000 claims description 25
• 125000001424 substituent group Chemical group 0.000 claims description 24
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 22
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 21
• 229910052739 hydrogen Inorganic materials 0.000 claims description 20
• 239000001257 hydrogen Substances 0.000 claims description 20
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
• 201000000980 schizophrenia Diseases 0.000 claims description 14
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 12
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 12
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 12
• KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 11
• 150000003839 salts Chemical class 0.000 claims description 11
• 229940025084 amphetamine Drugs 0.000 claims description 10
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
• 208000028017 Psychotic disease Diseases 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
• 239000012453 solvate Substances 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 6
• 150000001204 N-oxides Chemical class 0.000 claims description 6
• 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 150000004677 hydrates Chemical class 0.000 claims description 6
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
• 208000019901 Anxiety disease Diseases 0.000 claims description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 208000010877 cognitive disease Diseases 0.000 claims description 5
• 208000035475 disorder Diseases 0.000 claims description 5
• LUQQNCFMWZZQLI-NSHDSACASA-N (2,4-difluorophenyl)-[(3s)-3-[3-(2-methyl-1,3-thiazol-5-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound S1C(C)=NC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C(=CC(F)=CC=2)F)=N1 LUQQNCFMWZZQLI-NSHDSACASA-N 0.000 claims description 4
• LUQDMFURIUHGRN-LBPRGKRZSA-N (3,4-difluorophenyl)-[(3s)-3-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound FC1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=C(F)C(F)=CC=2)=N1 LUQDMFURIUHGRN-LBPRGKRZSA-N 0.000 claims description 4
• PFGNSMGKXMEDJQ-LBPRGKRZSA-N (3,4-difluorophenyl)-[(3s)-3-[3-(2-methyl-1,3-thiazol-5-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound S1C(C)=NC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=C(F)C(F)=CC=2)=N1 PFGNSMGKXMEDJQ-LBPRGKRZSA-N 0.000 claims description 4
• JSVZRUOSIODDMU-AWEZNQCLSA-N (4-fluoro-2-methylphenyl)-[(3s)-3-[3-(2-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CC1=CC(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2C(=CC=CC=2)F)CCC1 JSVZRUOSIODDMU-AWEZNQCLSA-N 0.000 claims description 4
• VWVUSFXGPZGMPU-ZDUSSCGKSA-N (4-fluorophenyl)-[(3s)-3-[3-(2-methyl-1,3-thiazol-5-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound S1C(C)=NC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=CC(F)=CC=2)=N1 VWVUSFXGPZGMPU-ZDUSSCGKSA-N 0.000 claims description 4
• YKSCFSZDWWZLEF-HNNXBMFYSA-N (4-fluorophenyl)-[(3s)-3-[3-(3-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CC1=CC=CN=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=CC(F)=CC=2)=N1 YKSCFSZDWWZLEF-HNNXBMFYSA-N 0.000 claims description 4
• XDFWUDHCDXZYMV-LBPRGKRZSA-N (6-fluoropyridin-3-yl)-[(3s)-3-[3-(2-methyl-1,3-thiazol-5-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound S1C(C)=NC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=NC(F)=CC=2)=N1 XDFWUDHCDXZYMV-LBPRGKRZSA-N 0.000 claims description 4
• LLZNOXRRQQKZJD-HNNXBMFYSA-N 2-fluoro-5-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]benzonitrile Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=C(C(F)=CC=2)C#N)=N1 LLZNOXRRQQKZJD-HNNXBMFYSA-N 0.000 claims description 4
• QFMMOKDCOXWAJZ-AWEZNQCLSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(2-fluoropyridin-4-yl)methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=C(F)N=CC=2)=N1 QFMMOKDCOXWAJZ-AWEZNQCLSA-N 0.000 claims description 4
• IBWFEJNHMHBTBS-ZDUSSCGKSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(3-fluoropyridin-4-yl)methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C(=CN=CC=2)F)=N1 IBWFEJNHMHBTBS-ZDUSSCGKSA-N 0.000 claims description 4
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
• 238000003384 imaging method Methods 0.000 claims description 4
• 230000003227 neuromodulating effect Effects 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 208000011117 substance-related disease Diseases 0.000 claims description 4
• RWFCKJHNXMCJDE-HNNXBMFYSA-N (4-fluorophenyl)-[(3s)-3-[3-(6-methylpyridin-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CC1=CC=CC(C=2N=C(ON=2)[C@@H]2CN(CCC2)C(=O)C=2C=CC(F)=CC=2)=N1 RWFCKJHNXMCJDE-HNNXBMFYSA-N 0.000 claims description 3
• KFXKGPXJQLMBMW-ZDUSSCGKSA-N [(3s)-3-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(4-fluoro-2-methylphenyl)methanone Chemical compound CC1=CC(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2C(=CC(F)=CC=2)F)CCC1 KFXKGPXJQLMBMW-ZDUSSCGKSA-N 0.000 claims description 3
• QNFBKFBGEBITCP-LBPRGKRZSA-N [(3s)-3-[3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(6-fluoropyridin-3-yl)methanone Chemical compound FC1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=NC(F)=CC=2)=N1 QNFBKFBGEBITCP-LBPRGKRZSA-N 0.000 claims description 3
• QRRNOELOFVMJSB-INIZCTEOSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(1,2,5-trimethylpyrrol-3-yl)methanone Chemical compound CN1C(C)=CC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=C1C QRRNOELOFVMJSB-INIZCTEOSA-N 0.000 claims description 3
• FGSKISOVLNNQFO-AWEZNQCLSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(2-methylfuran-3-yl)methanone Chemical compound O1C=CC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=C1C FGSKISOVLNNQFO-AWEZNQCLSA-N 0.000 claims description 3
• YGNFIZHFAPPOIR-LBPRGKRZSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(4-methylthiadiazol-5-yl)methanone Chemical compound N1=NSC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=C1C YGNFIZHFAPPOIR-LBPRGKRZSA-N 0.000 claims description 3
• FKMGYJOXJPJOHR-ZDUSSCGKSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(5-methyl-1,2-oxazol-4-yl)methanone Chemical compound O1N=CC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=C1C FKMGYJOXJPJOHR-ZDUSSCGKSA-N 0.000 claims description 3
• IKHYAWIWACYCNL-HNNXBMFYSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-(thian-4-yl)methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C2CCSCC2)=N1 IKHYAWIWACYCNL-HNNXBMFYSA-N 0.000 claims description 3
• FNYQFUSDAGYVCH-QFIPXVFZSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-[3-(phenoxymethyl)phenyl]methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=C(COC=3C=CC=CC=3)C=CC=2)=N1 FNYQFUSDAGYVCH-QFIPXVFZSA-N 0.000 claims description 3
• XWLNRGMVWCNKGC-HNNXBMFYSA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-[4-(trifluoromethoxy)phenyl]methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=CC(OC(F)(F)F)=CC=2)=N1 XWLNRGMVWCNKGC-HNNXBMFYSA-N 0.000 claims description 3
• ZDDWOJJRUCFGAZ-NSHDSACASA-N [(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]-[5-(trifluoromethyl)-1h-pyrazol-4-yl]methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C(=NNC=2)C(F)(F)F)=N1 ZDDWOJJRUCFGAZ-NSHDSACASA-N 0.000 claims description 3
• 230000003287 optical effect Effects 0.000 claims description 3
• PSZICAUUIXXCES-AWEZNQCLSA-N (1,5-dimethylpyrazol-3-yl)-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CN1C(C)=CC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=N1 PSZICAUUIXXCES-AWEZNQCLSA-N 0.000 claims description 2
• LYOFRRCBNWEVBY-UHFFFAOYSA-N (3-fluorophenyl)-[3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone (4-fluorophenyl)-[3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound Fc1ccc(cc1)C(=O)N1CCCC(C1)c1nc(no1)-c1ccc(F)cc1.Fc1ccc(cc1)-c1noc(n1)C1CCCN(C1)C(=O)c1cccc(F)c1 LYOFRRCBNWEVBY-UHFFFAOYSA-N 0.000 claims description 2
• AONMKLWKMOJMQK-HNNXBMFYSA-N (4-fluoro-2-methylphenyl)-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound CC1=CC(F)=CC=C1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2C=CC(F)=CC=2)CCC1 AONMKLWKMOJMQK-HNNXBMFYSA-N 0.000 claims description 2
• HKDCESZSMXPUKC-HNNXBMFYSA-N (4-fluoro-3-methoxyphenyl)-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=C(F)C(OC)=CC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=C1 HKDCESZSMXPUKC-HNNXBMFYSA-N 0.000 claims description 2
• DTVMFUBCRPUKQW-INIZCTEOSA-N (4-fluoro-3-methylphenyl)-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=C(F)C(C)=CC(C(=O)N2C[C@H](CCC2)C=2ON=C(N=2)C=2C=CC(F)=CC=2)=C1 DTVMFUBCRPUKQW-INIZCTEOSA-N 0.000 claims description 2
• VXQCCZHCFBHTTD-OAHLLOKOSA-N (4-fluorophenyl)-[(3r)-3-[3-(4-fluorophenyl)-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=2C=CC(F)=CC=2)CCC1 VXQCCZHCFBHTTD-OAHLLOKOSA-N 0.000 claims description 2
• ZAMRYTAWPYUCCA-UHFFFAOYSA-N (4-fluorophenyl)-[3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-4-methylpiperazin-1-yl]methanone Chemical compound CN1CCN(C(=O)C=2C=CC(F)=CC=2)CC1C(ON=1)=NC=1C1=CC=C(F)C=C1 ZAMRYTAWPYUCCA-UHFFFAOYSA-N 0.000 claims description 2
• 125000006718 (C3-C7) heterocycloalkenyl group Chemical group 0.000 claims description 2
• 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 2
• ZQGZDOLILGHZKP-KRWDZBQOSA-N 1-[4-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidine-1-carbonyl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C(=O)N1C[C@@H](C=2ON=C(N=2)C=2C=CC(F)=CC=2)CCC1 ZQGZDOLILGHZKP-KRWDZBQOSA-N 0.000 claims description 2
• OMWQVSXCNLOTNT-HNNXBMFYSA-N 2,3-dihydro-1,4-benzodioxin-5-yl-[(3s)-3-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]methanone Chemical compound C1=CC(F)=CC=C1C1=NOC([C@@H]2CN(CCC2)C(=O)C=2C=3OCCOC=3C=CC=2)=N1 OMWQVSXCNLOTNT-HNNXBMFYSA-N 0.000 claims description 2
• 208000030814 Eating disease Diseases 0.000 claims description 2
• UUABGUYFQXGQQE-HQUXEWOTSA-N FC1=CC=C(C=C1)C(=O)N1C[C@H](CCC1)C1=NC(=NO1)C1=C(C=CC=C1)C.FC1=CC=C(C=C1)C1=NOC(=N1)[C@@H]1CN(CCC1)C(=O)C=1C=NOC1COC Chemical compound FC1=CC=C(C=C1)C(=O)N1C[C@H](CCC1)C1=NC(=NO1)C1=C(C=CC=C1)C.FC1=CC=C(C=C1)C1=NOC(=N1)[C@@H]1CN(CCC1)C(=O)C=1C=NOC1COC UUABGUYFQXGQQE-HQUXEWOTSA-N 0.000 claims description 2
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• GYPUEGHRXRONDP-HYDPEUQHSA-N FC=1C=C(C=CC1F)C(=O)N1C[C@H](CCC1)C1=NC(=NO1)C1=CC=CC=C1.FC1=CC=C(C=C1)C(=O)N1C[C@H](CCC1)C1=NC(=NO1)C1=CC=CC=C1 Chemical compound FC=1C=C(C=CC1F)C(=O)N1C[C@H](CCC1)C1=NC(=NO1)C1=CC=CC=C1.FC1=CC=C(C=C1)C(=O)N1C[C@H](CCC1)C1=NC(=NO1)C1=CC=CC=C1 GYPUEGHRXRONDP-HYDPEUQHSA-N 0.000 claims description 2
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