JP2012506848A

JP2012506848A - グルタミン酸受容体モジュレーターとしての三環式化合物

グルタミン酸受容体モジュレーターとしての三環式化合物 Download PDF

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Publication number: JP2012506848A
Authority: JP; Japan
Prior art keywords: methyl; carboxamide; dihydro; pyrazole; methylpyridin
Prior art date: 2008-10-27
Legal status : Withdrawn

Application number

JP2011532652A

Other languages

English (en)

Japanese (ja)

Other versions

JP2012506848A5 (enExample

Inventor

ピーター、バーティナト

メラフ、フィヒマン

ショミル、ゴーシュ

ジャン、リン

ダリア、シーガル

ツァオダ、ツァン

Current Assignee

Glaxo Group Ltd

Original Assignee

Glaxo Group Ltd

Priority date

2008-10-27

Filing date

2009-10-23

Publication date

2012-03-22

2009-10-23 Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd

2012-03-22 Publication of JP2012506848A publication Critical patent/JP2012506848A/ja

2012-11-29 Publication of JP2012506848A5 publication Critical patent/JP2012506848A5/ja

Status Withdrawn legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 263
102000018899 Glutamate Receptors Human genes 0.000 title description 6
108010027915 Glutamate Receptors Proteins 0.000 title description 6
238000000034 method Methods 0.000 claims abstract description 82
-1 cyano, hydroxy Chemical group 0.000 claims description 267
SYGSTRANUHFLOT-UHFFFAOYSA-N chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound C1=CC=C2C3=NN=C(C(=O)N)C3=COC2=C1 SYGSTRANUHFLOT-UHFFFAOYSA-N 0.000 claims description 158
125000000217 alkyl group Chemical group 0.000 claims description 144
229910052739 hydrogen Inorganic materials 0.000 claims description 115
239000001257 hydrogen Substances 0.000 claims description 115
125000000753 cycloalkyl group Chemical group 0.000 claims description 100
125000001188 haloalkyl group Chemical group 0.000 claims description 99
125000003118 aryl group Chemical group 0.000 claims description 97
125000001589 carboacyl group Chemical group 0.000 claims description 87
125000000623 heterocyclic group Chemical group 0.000 claims description 86
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 81
229910052736 halogen Inorganic materials 0.000 claims description 73
150000002367 halogens Chemical class 0.000 claims description 73
125000003545 alkoxy group Chemical group 0.000 claims description 70
125000001072 heteroaryl group Chemical group 0.000 claims description 64
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 63
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 60
125000004093 cyano group Chemical group *C#N 0.000 claims description 57
150000002431 hydrogen Chemical class 0.000 claims description 54
125000003342 alkenyl group Chemical group 0.000 claims description 45
125000000304 alkynyl group Chemical group 0.000 claims description 45
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 40
125000001424 substituent group Chemical group 0.000 claims description 37
150000003839 salts Chemical class 0.000 claims description 36
229910052757 nitrogen Inorganic materials 0.000 claims description 32
150000003857 carboxamides Chemical class 0.000 claims description 31
BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 claims description 30
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 29
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 29
ABDMQSFNJPYOLA-UHFFFAOYSA-N NS(=O)(=O)[N+]([O-])=O Chemical compound NS(=O)(=O)[N+]([O-])=O ABDMQSFNJPYOLA-UHFFFAOYSA-N 0.000 claims description 27
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 25
150000001204 N-oxides Chemical class 0.000 claims description 21
229910002091 carbon monoxide Inorganic materials 0.000 claims description 17
229910052760 oxygen Inorganic materials 0.000 claims description 17
229910052799 carbon Inorganic materials 0.000 claims description 16
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 15
239000005711 Benzoic acid Substances 0.000 claims description 14
235000010233 benzoic acid Nutrition 0.000 claims description 14
WWAFSLUZQOZZNF-UHFFFAOYSA-N cyclohepta[c]pyrazole-3-carboxamide Chemical compound C1=CC=CC=C2C(C(=O)N)=NN=C21 WWAFSLUZQOZZNF-UHFFFAOYSA-N 0.000 claims description 14
229910052727 yttrium Inorganic materials 0.000 claims description 14
125000002837 carbocyclic group Chemical group 0.000 claims description 12
239000003937 drug carrier Substances 0.000 claims description 12
150000004702 methyl esters Chemical class 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
229910005965 SO 2 Inorganic materials 0.000 claims description 10
BLTDCIWCFCUQCB-UHFFFAOYSA-N quinoline-3-carboxamide Chemical compound C1=CC=CC2=CC(C(=O)N)=CN=C21 BLTDCIWCFCUQCB-UHFFFAOYSA-N 0.000 claims description 10
229940124530 sulfonamide Drugs 0.000 claims description 10
BDJZCHPNVIUIIM-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-5-oxo-4h-pyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=NC=CC=C4C(=O)C3)N(C)N=2)=N1 BDJZCHPNVIUIIM-UHFFFAOYSA-N 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
150000003456 sulfonamides Chemical class 0.000 claims description 9
229910052717 sulfur Inorganic materials 0.000 claims description 9
GLWLBNURXMGXQU-UHFFFAOYSA-N n-(3-chlorophenyl)-1-methylpyrazolo[4,3-c]quinoline-3-carboxamide Chemical compound C12=CN=C3C=CC=CC3=C2N(C)N=C1C(=O)NC1=CC=CC(Cl)=C1 GLWLBNURXMGXQU-UHFFFAOYSA-N 0.000 claims description 8
IWGREDKROULLQB-UHFFFAOYSA-N 2,3-dihydro-1,4-benzoxazin-4-yl-(1-methyl-4h-chromeno[4,3-c]pyrazol-3-yl)methanone Chemical compound C1OC2=CC=CC=C2C2=C1C(C(=O)N1C3=CC=CC=C3OCC1)=NN2C IWGREDKROULLQB-UHFFFAOYSA-N 0.000 claims description 7
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
VNYHFICCURNDMT-UHFFFAOYSA-N 5-acetyl-n-(3-chlorophenyl)-1-methyl-4h-pyrazolo[4,3-c]quinoline-3-carboxamide Chemical compound N=1N(C)C=2C3=CC=CC=C3N(C(=O)C)CC=2C=1C(=O)NC1=CC=CC(Cl)=C1 VNYHFICCURNDMT-UHFFFAOYSA-N 0.000 claims description 7
208000002193 Pain Diseases 0.000 claims description 7
TVFIYRKPCACCNL-UHFFFAOYSA-N furan-2-carboxamide Chemical compound NC(=O)C1=CC=CO1 TVFIYRKPCACCNL-UHFFFAOYSA-N 0.000 claims description 7
YVQFXQUHGOALOJ-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-4,5-dihydropyrazolo[4,3-h]isoquinoline-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=CN=CC=C4CC3)N(C)N=2)=N1 YVQFXQUHGOALOJ-UHFFFAOYSA-N 0.000 claims description 6
SJWIAQHMFLXKRF-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-4,5-dihydropyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=NC=CC=C4CC3)N(C)N=2)=N1 SJWIAQHMFLXKRF-UHFFFAOYSA-N 0.000 claims description 6
ONBSDUFTCWELTF-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-4h-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide Chemical compound C=12COC3=CC=CC=C3N2C(C)=NC=1C(=O)NC1=CC=CC(C)=N1 ONBSDUFTCWELTF-UHFFFAOYSA-N 0.000 claims description 6
IXUINHVZQQJJBW-UHFFFAOYSA-N 3-chloro-n-[(1-methyl-4h-chromeno[4,3-c]pyrazol-3-yl)methyl]aniline Chemical compound C1=2COC3=CC=CC=C3C=2N(C)N=C1CNC1=CC=CC(Cl)=C1 IXUINHVZQQJJBW-UHFFFAOYSA-N 0.000 claims description 6
SXEYEWRZLARJEO-UHFFFAOYSA-N 8-chloro-n-(3-chlorophenyl)-1-methyl-4h-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound C1=2COC3=CC=C(Cl)C=C3C=2N(C)N=C1C(=O)NC1=CC=CC(Cl)=C1 SXEYEWRZLARJEO-UHFFFAOYSA-N 0.000 claims description 6
208000024827 Alzheimer disease Diseases 0.000 claims description 6
208000019901 Anxiety disease Diseases 0.000 claims description 6
208000012661 Dyskinesia Diseases 0.000 claims description 6
230000036506 anxiety Effects 0.000 claims description 6
125000004494 ethyl ester group Chemical group 0.000 claims description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 6
QTKXZSBVDXKGMT-UHFFFAOYSA-N n-(3-chlorophenyl)-1,4,4-trimethylchromeno[4,3-c]pyrazole-3-carboxamide Chemical compound C12=CC=CC=C2OC(C)(C)C2=C1N(C)N=C2C(=O)NC1=CC=CC(Cl)=C1 QTKXZSBVDXKGMT-UHFFFAOYSA-N 0.000 claims description 6
FUQSTBWDBRBORW-UHFFFAOYSA-N n-(3-chlorophenyl)-1-methyl-4,5-dihydrobenzo[g]indazole-3-carboxamide Chemical compound C1=2CCC3=CC=CC=C3C=2N(C)N=C1C(=O)NC1=CC=CC(Cl)=C1 FUQSTBWDBRBORW-UHFFFAOYSA-N 0.000 claims description 6
DPVPQVFQPCGHCY-UHFFFAOYSA-N n-(3-chlorophenyl)-8-fluoro-2-methyl-4h-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound CN1N=C(C2=CC(F)=CC=C2OC2)C2=C1C(=O)NC1=CC=CC(Cl)=C1 DPVPQVFQPCGHCY-UHFFFAOYSA-N 0.000 claims description 6
ZOSHECDTIIVUTC-UHFFFAOYSA-N n-(4-chloropyridin-2-yl)-1-methyl-4h-chromeno[4,3-c]pyrazole-3-carboxamide Chemical compound C1=2COC3=CC=CC=C3C=2N(C)N=C1C(=O)NC1=CC(Cl)=CC=N1 ZOSHECDTIIVUTC-UHFFFAOYSA-N 0.000 claims description 6
UYUYLOXPYHOKSI-UHFFFAOYSA-N n-(6-methylpyridin-2-yl)-2,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=CC=CC=C4OC3)NN=2)=N1 UYUYLOXPYHOKSI-UHFFFAOYSA-N 0.000 claims description 6
BMWWVNBXABDUCZ-UHFFFAOYSA-N 1,5,5-trimethyl-n-(6-methylpyridin-2-yl)-4h-pyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=NC=CC=C4C(C)(C)C3)N(C)N=2)=N1 BMWWVNBXABDUCZ-UHFFFAOYSA-N 0.000 claims description 5
QVMJSZASSYYWNQ-UHFFFAOYSA-N 1,5-dimethyl-n-(6-methylpyridin-2-yl)-4,6-dihydropyrazolo[4,3-d][2]benzazepine-3-carboxamide Chemical compound N=1N(C)C=2C3=CC=CC=C3CN(C)CC=2C=1C(=O)NC1=CC=CC(C)=N1 QVMJSZASSYYWNQ-UHFFFAOYSA-N 0.000 claims description 5
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NFHQWJXNGUPFHM-UHFFFAOYSA-N 1-ethyl-n-(6-methylpyridin-2-yl)-4,5-dihydropyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound C1=2CCC3=CC=CN=C3C=2N(CC)N=C1C(=O)NC1=CC=CC(C)=N1 NFHQWJXNGUPFHM-UHFFFAOYSA-N 0.000 claims description 5
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ANGKGBOGRLFDAQ-UHFFFAOYSA-N 1-methyl-n-(2-methylpyrimidin-4-yl)-4,5-dihydropyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound CC1=NC=CC(NC(=O)C=2C3=C(C4=NC=CC=C4CC3)N(C)N=2)=N1 ANGKGBOGRLFDAQ-UHFFFAOYSA-N 0.000 claims description 5
OYGFTMJUTVUDQJ-UHFFFAOYSA-N 1-methyl-n-(6-methylpyrazin-2-yl)-4,5-dihydropyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound CC1=CN=CC(NC(=O)C=2C3=C(C4=NC=CC=C4CC3)N(C)N=2)=N1 OYGFTMJUTVUDQJ-UHFFFAOYSA-N 0.000 claims description 5
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RQZMLVWSFNGCLE-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-4,5-dihydropyrazolo[3,4-f]quinoxaline-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=NC=CN=C4CC3)N(C)N=2)=N1 RQZMLVWSFNGCLE-UHFFFAOYSA-N 0.000 claims description 5
PPFQPJIMARWLRA-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-4,5-dihydropyrazolo[4,3-h]quinolin-3-amine Chemical compound CC1=CC=CC(NC=2C3=C(C4=NC=CC=C4CC3)N(C)N=2)=N1 PPFQPJIMARWLRA-UHFFFAOYSA-N 0.000 claims description 5
XHRNDTVWNKFFQE-UHFFFAOYSA-N 1-methyl-n-(6-methylpyridin-2-yl)-5,6-dihydro-4h-pyrazolo[4,3-d][2]benzazepine-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=CC=CC=C4CNC3)N(C)N=2)=N1 XHRNDTVWNKFFQE-UHFFFAOYSA-N 0.000 claims description 5
SUSYSDXOYROVQP-UHFFFAOYSA-N 1-methyl-n-[1-(6-methylpyridin-2-yl)ethyl]-4,5-dihydropyrazolo[4,3-h]quinolin-3-amine Chemical compound N=1N(C)C(C2=NC=CC=C2CC2)=C2C=1NC(C)C1=CC=CC(C)=N1 SUSYSDXOYROVQP-UHFFFAOYSA-N 0.000 claims description 5
CFSAZOCKLWHLCY-UHFFFAOYSA-N 1-methyl-n-[6-(trifluoromethyl)pyridin-2-yl]-4,5-dihydropyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound C1=2CCC3=CC=CN=C3C=2N(C)N=C1C(=O)NC1=CC=CC(C(F)(F)F)=N1 CFSAZOCKLWHLCY-UHFFFAOYSA-N 0.000 claims description 5
RRLMDJWUEMMKQJ-UHFFFAOYSA-N 5,5-difluoro-1-methyl-n-(6-methylpyridin-2-yl)-4h-benzo[g]indazole-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=CC=CC=C4C(F)(F)C3)N(C)N=2)=N1 RRLMDJWUEMMKQJ-UHFFFAOYSA-N 0.000 claims description 5
ZTFWZGDQXXWKJL-UHFFFAOYSA-N 5,5-difluoro-1-methyl-n-(6-methylpyridin-2-yl)-4h-pyrazolo[4,3-h]quinoline-3-carboxamide Chemical compound CC1=CC=CC(NC(=O)C=2C3=C(C4=NC=CC=C4C(F)(F)C3)N(C)N=2)=N1 ZTFWZGDQXXWKJL-UHFFFAOYSA-N 0.000 claims description 5
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208000011580 syndromic disease Diseases 0.000 claims description 5
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