AU2002312788B2 - Dihydro-benzo [b] [1, 4] diazepin-2-one derivatives as mGluR2 antagonists II - Google Patents

Info

Publication number

AU2002312788B2

AU2002312788B2 AU2002312788A AU2002312788A AU2002312788B2 AU 2002312788 B2 AU2002312788 B2 AU 2002312788B2 AU 2002312788 A AU2002312788 A AU 2002312788A AU 2002312788 A AU2002312788 A AU 2002312788A AU 2002312788 B2 AU2002312788 B2 AU 2002312788B2

Authority

AU

Australia

Prior art keywords

phenyl

methyl

acid tert

amino

butyl ester

Prior art date

2001-04-12

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.)

Ceased

Links

• Espacenet
• Global Dossier
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• 102100036837 Metabotropic glutamate receptor 2 Human genes 0.000 title description 7
• 108010038421 metabotropic glutamate receptor 2 Proteins 0.000 title description 3
• 239000005557 antagonist Substances 0.000 title description 2
• 238000000034 method Methods 0.000 claims description 678
• 150000001875 compounds Chemical class 0.000 claims description 601
• -1 3-oxo-piperazin-l-yl Chemical group 0.000 claims description 396
• 125000000217 alkyl group Chemical group 0.000 claims description 63
• 239000002253 acid Substances 0.000 claims description 55
• 125000003545 alkoxy group Chemical group 0.000 claims description 52
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
• 150000003839 salts Chemical class 0.000 claims description 23
• AZIZBYRGIGKTLW-UHFFFAOYSA-N 1,4-diazepin-2-one Chemical compound O=C1C=NC=CC=N1 AZIZBYRGIGKTLW-UHFFFAOYSA-N 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 17
• 150000002367 halogens Chemical class 0.000 claims description 14
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
• 239000003814 drug Substances 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• 125000001153 fluoro group Chemical group F* 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 208000028017 Psychotic disease Diseases 0.000 claims description 8
• 230000001154 acute effect Effects 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
• 230000001684 chronic effect Effects 0.000 claims description 8
• 208000024827 Alzheimer disease Diseases 0.000 claims description 7
• 208000026139 Memory disease Diseases 0.000 claims description 7
• 208000010877 cognitive disease Diseases 0.000 claims description 7
• 239000001257 hydrogen Substances 0.000 claims description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims description 7
• 201000000980 schizophrenia Diseases 0.000 claims description 7
• 208000012902 Nervous system disease Diseases 0.000 claims description 6
• 208000025966 Neurological disease Diseases 0.000 claims description 6
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 230000002265 prevention Effects 0.000 claims description 6
• 230000008569 process Effects 0.000 claims description 6
• 238000007363 ring formation reaction Methods 0.000 claims description 6
• 125000003277 amino group Chemical group 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 125000003282 alkyl amino group Chemical group 0.000 claims description 3
• 125000005605 benzo group Chemical group 0.000 claims description 3
• 238000010511 deprotection reaction Methods 0.000 claims description 3
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• OHWFEQKMVFNWLV-UHFFFAOYSA-N 7-(dimethylamino)-8-methyl-4-[3-(3-methyl-1,2-oxazol-5-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(C)C(N(C)C)=CC=2N=C1C(C=1)=CC=CC=1C1=CC(C)=NO1 OHWFEQKMVFNWLV-UHFFFAOYSA-N 0.000 claims description 2
• PUMGQYZLUWHXDO-UHFFFAOYSA-N 8-methyl-7-[methyl(2-methylpropyl)amino]-4-[3-[5-(pyrrolidin-1-ylmethyl)triazol-1-yl]phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(C)C(N(C)CC(C)C)=CC=2N=C1C(C=1)=CC=CC=1N1N=NC=C1CN1CCCC1 PUMGQYZLUWHXDO-UHFFFAOYSA-N 0.000 claims description 2
• 241000124008 Mammalia Species 0.000 claims description 2
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
• 125000002971 oxazolyl group Chemical group 0.000 claims description 2
• 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 2
• 125000000335 thiazolyl group Chemical group 0.000 claims description 2
• 125000005843 halogen group Chemical group 0.000 claims 3
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
• QDKZHQGXPVFLHU-UHFFFAOYSA-N 1,5-benzodiazepin-2-one Chemical compound O=C1C=CN=C2C=CC=CC2=N1 QDKZHQGXPVFLHU-UHFFFAOYSA-N 0.000 claims 2
• 150000002431 hydrogen Chemical group 0.000 claims 2
• ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical compound N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 claims 1
• DJMZLSQXQSZBAN-UHFFFAOYSA-N 4-[2-oxo-7-(2,2,2-trifluoroethoxy)-8-(trifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-4-yl]pyridine-2-carbonitrile Chemical compound C1C(=O)NC=2C=C(C(F)(F)F)C(OCC(F)(F)F)=CC=2N=C1C1=CC=NC(C#N)=C1 DJMZLSQXQSZBAN-UHFFFAOYSA-N 0.000 claims 1
• ASXHDONHHPHYRD-UHFFFAOYSA-N 4-[3-(3-methyl-1,2-oxazol-5-yl)phenyl]-2-oxo-7-piperidin-1-yl-1,3-dihydro-1,5-benzodiazepine-8-carbonitrile Chemical compound O1N=C(C)C=C1C1=CC=CC(C=2CC(=O)NC3=CC(=C(N4CCCCC4)C=C3N=2)C#N)=C1 ASXHDONHHPHYRD-UHFFFAOYSA-N 0.000 claims 1
• OWPXWLMWINGIJA-UHFFFAOYSA-N 4-[3-(3-methyl-1,2-oxazol-5-yl)phenyl]-7-[methyl(propyl)amino]-8-(trifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(C(F)(F)F)C(N(C)CCC)=CC=2N=C1C(C=1)=CC=CC=1C1=CC(C)=NO1 OWPXWLMWINGIJA-UHFFFAOYSA-N 0.000 claims 1
• MOZPRFSXXYUWQA-UHFFFAOYSA-N 4-[3-[5-(azetidin-1-ylmethyl)triazol-1-yl]phenyl]-8-chloro-7-[methyl(2-methylpropyl)amino]-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(Cl)C(N(C)CC(C)C)=CC=2N=C1C(C=1)=CC=CC=1N1N=NC=C1CN1CCC1 MOZPRFSXXYUWQA-UHFFFAOYSA-N 0.000 claims 1
• MMFHASXGTDQSPH-UHFFFAOYSA-N 4-[7-[methyl(propan-2-yl)amino]-2-oxo-8-(trifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-4-yl]pyridine-2-carbonitrile Chemical compound C1C(=O)NC=2C=C(C(F)(F)F)C(N(C)C(C)C)=CC=2N=C1C1=CC=NC(C#N)=C1 MMFHASXGTDQSPH-UHFFFAOYSA-N 0.000 claims 1
• VYNUPTPNOCSSBJ-UHFFFAOYSA-N 7-(diethylamino)-4-[3-(3-methyl-1,2-oxazol-5-yl)phenyl]-2-oxo-1,3-dihydro-1,5-benzodiazepine-8-carbonitrile Chemical compound C1C(=O)NC=2C=C(C#N)C(N(CC)CC)=CC=2N=C1C(C=1)=CC=CC=1C1=CC(C)=NO1 VYNUPTPNOCSSBJ-UHFFFAOYSA-N 0.000 claims 1
• DDDRVKGHRFVCSK-UHFFFAOYSA-N 7-(dimethylamino)-4-(3-imidazol-1-ylphenyl)-8-(trifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(C(F)(F)F)C(N(C)C)=CC=2N=C1C(C=1)=CC=CC=1N1C=CN=C1 DDDRVKGHRFVCSK-UHFFFAOYSA-N 0.000 claims 1
• GGCLCUPVAHZUHM-UHFFFAOYSA-N 7-[methyl(propan-2-yl)amino]-4-[3-[5-(pyrrolidin-1-ylmethyl)triazol-1-yl]phenyl]-8-(trifluoromethyl)-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(C(F)(F)F)C(N(C)C(C)C)=CC=2N=C1C(C=1)=CC=CC=1N1N=NC=C1CN1CCCC1 GGCLCUPVAHZUHM-UHFFFAOYSA-N 0.000 claims 1
• ADOSEGKIEQRXKL-UHFFFAOYSA-N 8-chloro-4-[3-[4-(hydroxymethyl)-1,3-thiazol-2-yl]phenyl]-7-[methyl(propyl)amino]-1,3-dihydro-1,5-benzodiazepin-2-one Chemical compound C1C(=O)NC=2C=C(Cl)C(N(C)CCC)=CC=2N=C1C(C=1)=CC=CC=1C1=NC(CO)=CS1 ADOSEGKIEQRXKL-UHFFFAOYSA-N 0.000 claims 1
• 230000006806 disease prevention Effects 0.000 claims 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
• 125000002883 imidazolyl group Chemical group 0.000 claims 1
• 230000000926 neurological effect Effects 0.000 claims 1
• 239000007787 solid Substances 0.000 description 378
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 323
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 107
• 239000000243 solution Substances 0.000 description 93
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 86
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• MEGIEGFVRNXYSU-UHFFFAOYSA-N tert-butyl n-[2-amino-5-(dimethylamino)-4-(trifluoromethyl)phenyl]carbamate Chemical compound CN(C)C1=CC(NC(=O)OC(C)(C)C)=C(N)C=C1C(F)(F)F MEGIEGFVRNXYSU-UHFFFAOYSA-N 0.000 description 60
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 44
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 43
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• NSUKZHPOWCPFRY-UHFFFAOYSA-N methyl 3-[2-methyl-5-(oxan-2-yloxymethyl)-1,3-thiazol-4-yl]benzoate Chemical compound COC(=O)C1=CC=CC(C2=C(SC(C)=N2)COC2OCCCC2)=C1 NSUKZHPOWCPFRY-UHFFFAOYSA-N 0.000 description 1
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• TZFTWLWSTINBGP-UHFFFAOYSA-N methyl 3-[4-(oxan-2-yloxymethyl)-1,3-oxazol-2-yl]benzoate Chemical compound COC(=O)C1=CC=CC(C=2OC=C(COC3OCCCC3)N=2)=C1 TZFTWLWSTINBGP-UHFFFAOYSA-N 0.000 description 1
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