ZA200603680B - Morpholine derivatives as norepinephrine reuptake inhibitors - Google Patents

Info

Publication number

ZA200603680B

ZA200603680B ZA200603680A ZA200603680A ZA200603680B ZA 200603680 B ZA200603680 B ZA 200603680B ZA 200603680 A ZA200603680 A ZA 200603680A ZA 200603680 A ZA200603680 A ZA 200603680A ZA 200603680 B ZA200603680 B ZA 200603680B

Authority

ZA

South Africa

Prior art keywords

optionally substituted

halogen atoms

alkyl

compound

alkoxy

Prior art date

2003-11-10

Links

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• Global Dossier
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• 150000002780 morpholines Chemical class 0.000 title description 3
• 239000002767 noradrenalin uptake inhibitor Substances 0.000 title description 2
• 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 title 1
• 125000005843 halogen group Chemical group 0.000 claims description 165
• 238000000034 method Methods 0.000 claims description 149
• 150000001875 compounds Chemical class 0.000 claims description 144
• -1 -CONRR Chemical group 0.000 claims description 95
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 76
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 72
• 125000001424 substituent group Chemical group 0.000 claims description 67
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
• 150000003839 salts Chemical class 0.000 claims description 49
• 229910052799 carbon Inorganic materials 0.000 claims description 42
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 40
• 125000001153 fluoro group Chemical group F* 0.000 claims description 38
• 208000035475 disorder Diseases 0.000 claims description 36
• 125000004414 alkyl thio group Chemical group 0.000 claims description 32
• 238000002360 preparation method Methods 0.000 claims description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
• SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 22
• 229960002748 norepinephrine Drugs 0.000 claims description 22
• SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 22
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 17
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
• 125000000217 alkyl group Chemical group 0.000 claims description 15
• 241000124008 Mammalia Species 0.000 claims description 14
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• 229910052736 halogen Inorganic materials 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 13
• 238000006467 substitution reaction Methods 0.000 claims description 13
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
• 230000004064 dysfunction Effects 0.000 claims description 11
• 125000001544 thienyl group Chemical group 0.000 claims description 11
• 125000004076 pyridyl group Chemical group 0.000 claims description 9
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 8
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 8
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 7
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 7
• 239000003112 inhibitor Substances 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
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• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 19
• 230000001419 dependent effect Effects 0.000 claims 7
• 125000003545 alkoxy group Chemical group 0.000 claims 1
• 125000004429 atom Chemical group 0.000 claims 1
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• 239000000243 solution Substances 0.000 description 89
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• 239000002585 base Substances 0.000 description 27
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• 150000001408 amides Chemical group 0.000 description 19
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
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• 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
• 235000019341 magnesium sulphate Nutrition 0.000 description 14
• 230000002829 reductive effect Effects 0.000 description 14
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• 239000007818 Grignard reagent Substances 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
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• 150000004795 grignard reagents Chemical class 0.000 description 12
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• 239000002904 solvent Substances 0.000 description 11
• YWGQTZRPLDPUBG-UHFFFAOYSA-M COc1ccc(F)cc1C[Mg]Br Chemical compound COc1ccc(F)cc1C[Mg]Br YWGQTZRPLDPUBG-UHFFFAOYSA-M 0.000 description 10
• 208000028017 Psychotic disease Diseases 0.000 description 10
• 239000012074 organic phase Substances 0.000 description 10
• SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 description 9
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
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• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 9
• QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 9
• JDVADOGJQJZIOJ-UHFFFAOYSA-N ethyl 4-benzylmorpholine-2-carboxylate Chemical compound C1COC(C(=O)OCC)CN1CC1=CC=CC=C1 JDVADOGJQJZIOJ-UHFFFAOYSA-N 0.000 description 9
• 150000002576 ketones Chemical class 0.000 description 9
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