KR20100138886A - Β2 아드레날린 수용체의 효능제로서의 4-(2-아미노-1-히드록시에틸) 페놀의 유도체 - Google Patents

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Publication number

KR20100138886A

KR20100138886A KR1020107018606A KR20107018606A KR20100138886A KR 20100138886 A KR20100138886 A KR 20100138886A KR 1020107018606 A KR1020107018606 A KR 1020107018606A KR 20107018606 A KR20107018606 A KR 20107018606A KR 20100138886 A KR20100138886 A KR 20100138886A

Authority

KR

South Korea

Prior art keywords

hydroxy

ethyl

phenyl

amino

urea

Prior art date

2008-02-28

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.)

Withdrawn

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• 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 title claims description 22
• 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 title claims description 22
• 239000000556 agonist Substances 0.000 title description 6
• QHGUCRYDKWKLMG-UHFFFAOYSA-N octopamine Chemical class NCC(O)C1=CC=C(O)C=C1 QHGUCRYDKWKLMG-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 275
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 241
• 150000003839 salts Chemical class 0.000 claims abstract description 33
• 125000001424 substituent group Chemical group 0.000 claims abstract description 28
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 23
• 125000002950 monocyclic group Chemical group 0.000 claims abstract description 22
• 125000003118 aryl group Chemical group 0.000 claims abstract description 20
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 18
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
• 239000012453 solvate Substances 0.000 claims abstract description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
• 125000005843 halogen group Chemical group 0.000 claims abstract description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
• 125000004104 aryloxy group Chemical group 0.000 claims abstract description 7
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims abstract description 6
• 125000003367 polycyclic group Chemical group 0.000 claims abstract description 6
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
• -1 methoxy, phenyl Chemical group 0.000 claims description 161
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 160
• 238000000034 method Methods 0.000 claims description 151
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 140
• 239000004202 carbamide Substances 0.000 claims description 102
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 99
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
• 201000010099 disease Diseases 0.000 claims description 24
• 239000003814 drug Substances 0.000 claims description 22
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
• 238000011282 treatment Methods 0.000 claims description 21
• 230000000694 effects Effects 0.000 claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 17
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 16
• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 12
• 239000003246 corticosteroid Substances 0.000 claims description 12
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 12
• 229940124597 therapeutic agent Drugs 0.000 claims description 11
• 208000019693 Lung disease Diseases 0.000 claims description 9
• 208000006673 asthma Diseases 0.000 claims description 9
• 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 8
• 230000001575 pathological effect Effects 0.000 claims description 8
• 208000010412 Glaucoma Diseases 0.000 claims description 7
• 208000012902 Nervous system disease Diseases 0.000 claims description 7
• 208000019622 heart disease Diseases 0.000 claims description 7
• 206010061218 Inflammation Diseases 0.000 claims description 6
• 208000025966 Neurological disease Diseases 0.000 claims description 6
• 229910052731 fluorine Inorganic materials 0.000 claims description 6
• 230000004054 inflammatory process Effects 0.000 claims description 6
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
• 230000036592 analgesia Effects 0.000 claims description 5
• GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
• GTFGVBZBPGZHBO-LOGQOBJBSA-N 1-[3-[2-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]propyl]phenyl]-3-(2-phenylphenyl)urea Chemical compound C([C@H](O)C=1C=C(CO)C(O)=CC=1)NC(C)CC(C=1)=CC=CC=1NC(=O)NC1=CC=CC=C1C1=CC=CC=C1 GTFGVBZBPGZHBO-LOGQOBJBSA-N 0.000 claims description 4
• PYWNXSDTPRPTMD-LOGQOBJBSA-N 1-[3-[2-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]propyl]phenyl]-3-(2-phenylphenyl)urea Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NC(C)CC(C=1)=CC=CC=1NC(=O)NC1=CC=CC=C1C1=CC=CC=C1 PYWNXSDTPRPTMD-LOGQOBJBSA-N 0.000 claims description 3
• WIBVTGVCBBKVAE-SANMLTNESA-N 1-[4-[2-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]ethyl]phenyl]-3-(3-phenylpropyl)urea Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCC(C=C1)=CC=C1NC(=O)NCCCC1=CC=CC=C1 WIBVTGVCBBKVAE-SANMLTNESA-N 0.000 claims description 3
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 3
• 125000003352 4-tert-butyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• QIDPXZGFGQSPCI-GJRDDLGUSA-N 1-(1-adamantyl)-3-[3-[2-[[(2r)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino]propyl]phenyl]urea Chemical compound C1([C@@H](O)CNC(CC=2C=C(NC(=O)NC34CC5CC(CC(C5)C3)C4)C=CC=2)C)=CC=C(O)C(CO)=C1 QIDPXZGFGQSPCI-GJRDDLGUSA-N 0.000 claims description 2
• BAKAALSDMKQZHQ-LJAQVGFWSA-N 1-benzhydryl-3-[4-[2-[[(2r)-2-hydroxy-2-(8-hydroxy-2-oxo-1h-quinolin-5-yl)ethyl]amino]ethyl]phenyl]urea Chemical compound C([C@H](O)C=1C=2C=CC(=O)NC=2C(O)=CC=1)NCCC(C=C1)=CC=C1NC(=O)NC(C=1C=CC=CC=1)C1=CC=CC=C1 BAKAALSDMKQZHQ-LJAQVGFWSA-N 0.000 claims description 2
• 230000001078 anti-cholinergic effect Effects 0.000 claims description 2
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
• CRENOMPMIHKRCK-LJAQVGFWSA-N n-[2-hydroxy-5-[(1r)-1-hydroxy-2-[2-[3-[(2-phenylphenyl)carbamoylamino]phenyl]ethylamino]ethyl]phenyl]formamide Chemical compound C([C@H](O)C=1C=C(NC=O)C(O)=CC=1)NCCC(C=1)=CC=CC=1NC(=O)NC1=CC=CC=C1C1=CC=CC=C1 CRENOMPMIHKRCK-LJAQVGFWSA-N 0.000 claims description 2
• 230000004936 stimulating effect Effects 0.000 claims description 2
• 235000012054 meals Nutrition 0.000 claims 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 claims 1
• 230000015572 biosynthetic process Effects 0.000 abstract 1
• 239000000543 intermediate Substances 0.000 description 405
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 294
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
• 239000007787 solid Substances 0.000 description 103
• 239000000203 mixture Substances 0.000 description 92
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 78
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 74
• 238000010898 silica gel chromatography Methods 0.000 description 70
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 67
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
• 239000002904 solvent Substances 0.000 description 66
• 239000000243 solution Substances 0.000 description 61
• 230000002829 reductive effect Effects 0.000 description 55
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
• 238000000746 purification Methods 0.000 description 53
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 49
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
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• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 43
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
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• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 28
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 28
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 28
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• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
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• 239000003921 oil Substances 0.000 description 23
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
• 235000019198 oils Nutrition 0.000 description 22
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
• QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 21
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 21
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