MX2014005935A - Tieno- y furo-pirimidinas y piridinas, utiles como inhibidores del canal de potasio. - Google Patents

Info

Publication number

MX2014005935A

MX2014005935A MX2014005935A MX2014005935A MX2014005935A MX 2014005935 A MX2014005935 A MX 2014005935A MX 2014005935 A MX2014005935 A MX 2014005935A MX 2014005935 A MX2014005935 A MX 2014005935A MX 2014005935 A MX2014005935 A MX 2014005935A

Authority

MX

Mexico

Prior art keywords

optionally substituted

6alkyl

thieno

pyrimidin

phenyl

Prior art date

2011-11-15

Links

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• 102000004257 Potassium Channel Human genes 0.000 title abstract description 20
• 239000003112 inhibitor Substances 0.000 title abstract description 20
• 108020001213 potassium channel Proteins 0.000 title abstract description 20
• 150000003222 pyridines Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 330
• 102100033063 G protein-activated inward rectifier potassium channel 1 Human genes 0.000 claims abstract description 61
• 101000944266 Homo sapiens G protein-activated inward rectifier potassium channel 1 Proteins 0.000 claims abstract description 61
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 59
• 101000614712 Homo sapiens G protein-activated inward rectifier potassium channel 4 Proteins 0.000 claims abstract description 55
• 102100021237 G protein-activated inward rectifier potassium channel 4 Human genes 0.000 claims abstract description 54
• 201000010099 disease Diseases 0.000 claims abstract description 48
• 230000005764 inhibitory process Effects 0.000 claims abstract description 31
• 230000001404 mediated effect Effects 0.000 claims abstract description 26
• 238000011282 treatment Methods 0.000 claims abstract description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
• 229910052720 vanadium Inorganic materials 0.000 claims abstract description 10
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 9
• -1 tetrahydro-1,3-oxazinyl Chemical group 0.000 claims description 431
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 154
• 238000000034 method Methods 0.000 claims description 139
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 122
• 239000000203 mixture Substances 0.000 claims description 94
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 85
• 229910052757 nitrogen Inorganic materials 0.000 claims description 68
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 65
• 125000001072 heteroaryl group Chemical group 0.000 claims description 63
• 206010003658 Atrial Fibrillation Diseases 0.000 claims description 56
• 229910003827 NRaRb Inorganic materials 0.000 claims description 56
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 56
• 125000003386 piperidinyl group Chemical group 0.000 claims description 53
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
• 239000003814 drug Substances 0.000 claims description 50
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 44
• 125000003107 substituted aryl group Chemical group 0.000 claims description 42
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 41
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 34
• 210000002837 heart atrium Anatomy 0.000 claims description 33
• 125000002757 morpholinyl group Chemical group 0.000 claims description 33
• 125000000217 alkyl group Chemical group 0.000 claims description 32
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 32
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
• 125000001424 substituent group Chemical group 0.000 claims description 26
• 229910052717 sulfur Inorganic materials 0.000 claims description 25
• 125000003118 aryl group Chemical group 0.000 claims description 24
• 230000004064 dysfunction Effects 0.000 claims description 22
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 19
• 206010003662 Atrial flutter Diseases 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 18
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 208000001435 Thromboembolism Diseases 0.000 claims description 15
• 125000003106 haloaryl group Chemical group 0.000 claims description 14
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
• 125000004953 trihalomethyl group Chemical group 0.000 claims description 14
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 13
• 125000005968 oxazolinyl group Chemical group 0.000 claims description 13
• 206010042600 Supraventricular arrhythmias Diseases 0.000 claims description 12
• 125000002393 azetidinyl group Chemical group 0.000 claims description 12
• 210000002216 heart Anatomy 0.000 claims description 12
• 125000006004 trihaloethyl group Chemical group 0.000 claims description 12
• 210000001992 atrioventricular node Anatomy 0.000 claims description 11
• 210000000481 breast Anatomy 0.000 claims description 11
• 208000035475 disorder Diseases 0.000 claims description 11
• 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 11
• 230000002441 reversible effect Effects 0.000 claims description 11
• 125000006008 trihaloethoxy group Chemical group 0.000 claims description 11
• 125000004951 trihalomethoxy group Chemical group 0.000 claims description 11
• 208000006011 Stroke Diseases 0.000 claims description 10
• 229910052739 hydrogen Inorganic materials 0.000 claims description 10
• 125000003725 azepanyl group Chemical group 0.000 claims description 9
• 239000001257 hydrogen Substances 0.000 claims description 9
• 208000005189 Embolism Diseases 0.000 claims description 8
• 206010028980 Neoplasm Diseases 0.000 claims description 8
• 208000002193 Pain Diseases 0.000 claims description 8
• 208000004301 Sinus Arrhythmia Diseases 0.000 claims description 8
• 208000007536 Thrombosis Diseases 0.000 claims description 8
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• 239000005556 hormone Substances 0.000 claims description 8
• 229940088597 hormone Drugs 0.000 claims description 8
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• 208000010125 myocardial infarction Diseases 0.000 claims description 7
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 7
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
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• 229910052705 radium Inorganic materials 0.000 claims description 6
• 229910052701 rubidium Inorganic materials 0.000 claims description 6
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 5
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 5
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 5
• 230000008602 contraction Effects 0.000 claims description 5
• 230000000955 neuroendocrine Effects 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• HIRSDTQHJHCMSL-UHFFFAOYSA-N 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine Chemical compound C1CC(N)CCN1C1=NC=NC2=C1C(C=1C=CC=CC=1)=CS2 HIRSDTQHJHCMSL-UHFFFAOYSA-N 0.000 claims description 2
• ZCGQJNHNULHCGN-UHFFFAOYSA-N 1-(6-methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-one Chemical compound C=12C(C=3C=CC=CC=3)=C(C)SC2=NC=NC=1N1CCC(=O)CC1 ZCGQJNHNULHCGN-UHFFFAOYSA-N 0.000 claims description 2
• WPZQFXGPJKULGO-UHFFFAOYSA-N 1-[5-(4-bromophenyl)thieno[2,3-d]pyrimidin-4-yl]piperidin-4-amine Chemical compound C1CC(N)CCN1C1=NC=NC2=C1C(C=1C=CC(Br)=CC=1)=CS2 WPZQFXGPJKULGO-UHFFFAOYSA-N 0.000 claims description 2
• MBSDVCRHBCVPOE-UHFFFAOYSA-N 1-[5-(4-bromophenyl)thieno[2,3-d]pyrimidin-4-yl]piperidin-4-one Chemical compound C1=CC(Br)=CC=C1C1=CSC2=NC=NC(N3CCC(=O)CC3)=C12 MBSDVCRHBCVPOE-UHFFFAOYSA-N 0.000 claims description 2
• JPDCBVOCAONAFB-UHFFFAOYSA-N 1-[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]piperidin-4-one Chemical compound C1=CC(C)=CC=C1C1=CSC2=NC=NC(N3CCC(=O)CC3)=C12 JPDCBVOCAONAFB-UHFFFAOYSA-N 0.000 claims description 2
• MJILZRSAPALVKX-UHFFFAOYSA-N 1-phenylmethoxy-3-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl]amino]propan-2-ol Chemical compound C=1C=CC=CC=1COCC(O)CNC(CC1)CCN1C(C1=2)=NC=NC=2SC=C1C1=CC=CC=C1 MJILZRSAPALVKX-UHFFFAOYSA-N 0.000 claims description 2
• KULJWIMKNZHLIB-UHFFFAOYSA-N 2-[[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl]amino]cyclohexan-1-ol Chemical compound OC1CCCCC1NC1CCN(C=2C=3C(C=4C=CC=CC=4)=CSC=3N=CN=2)CC1 KULJWIMKNZHLIB-UHFFFAOYSA-N 0.000 claims description 2
• 230000006735 deficit Effects 0.000 claims description 2
• XQHDQCRNRSAGPV-UHFFFAOYSA-N tert-butyl n-[1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl]carbamate Chemical compound C=12C(C)=CSC2=NC=NC=1N1CCC(NC(=O)OC(C)(C)C)CC1 XQHDQCRNRSAGPV-UHFFFAOYSA-N 0.000 claims description 2
• DENZKSMZADASCI-UHFFFAOYSA-N tert-butyl n-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl]carbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCN1C1=NC=NC2=C1C(C=1C=CC=CC=1)=CS2 DENZKSMZADASCI-UHFFFAOYSA-N 0.000 claims description 2
• NESAZZCPNCLODA-UHFFFAOYSA-N tert-butyl n-[1-(6-methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl]carbamate Chemical compound C=12C(C=3C=CC=CC=3)=C(C)SC2=NC=NC=1N1CCC(NC(=O)OC(C)(C)C)CC1 NESAZZCPNCLODA-UHFFFAOYSA-N 0.000 claims description 2
• FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 9
• JLOIWHWGPIRXBQ-UHFFFAOYSA-N 1-(5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine Chemical compound C=12C(C)=CSC2=NC=NC=1N1CCC(N)CC1 JLOIWHWGPIRXBQ-UHFFFAOYSA-N 0.000 claims 1
• VLCVHCJARZAQOT-UHFFFAOYSA-N 1-(6-methyl-5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine Chemical compound C=12C(C=3C=CC=CC=3)=C(C)SC2=NC=NC=1N1CCC(N)CC1 VLCVHCJARZAQOT-UHFFFAOYSA-N 0.000 claims 1
• 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
• DQRYKEHGQJTOES-UHFFFAOYSA-N 6-(1,3-benzodioxol-5-yloxymethyl)-4-[1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-yl]morpholin-3-one Chemical compound O=C1COC(COC=2C=C3OCOC3=CC=2)CN1C(CC1)CCN1C(C1=2)=NC=NC=2SC=C1C1=CC=CC=C1 DQRYKEHGQJTOES-UHFFFAOYSA-N 0.000 claims 1
• 208000021908 Myocardial disease Diseases 0.000 claims 1
• XLAROEYDJSPGTP-UHFFFAOYSA-N [Cl-].C(C1=CC=CC=C1)OCC(C[NH2+]C1CCN(CC1)C=1C2=C(N=CN1)SC=C2C2=CC=CC=C2)O Chemical compound [Cl-].C(C1=CC=CC=C1)OCC(C[NH2+]C1CCN(CC1)C=1C2=C(N=CN1)SC=C2C2=CC=CC=C2)O XLAROEYDJSPGTP-UHFFFAOYSA-N 0.000 claims 1
• 230000007211 cardiovascular event Effects 0.000 claims 1
• 208000013403 hyperactivity Diseases 0.000 claims 1
• 210000004165 myocardium Anatomy 0.000 claims 1
• XLJSUFGVURYUEV-UHFFFAOYSA-N tert-butyl n-[1-[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]piperidin-4-yl]carbamate Chemical compound C1=CC(C)=CC=C1C1=CSC2=NC=NC(N3CCC(CC3)NC(=O)OC(C)(C)C)=C12 XLJSUFGVURYUEV-UHFFFAOYSA-N 0.000 claims 1
• 229910052740 iodine Inorganic materials 0.000 abstract description 3
• 238000006243 chemical reaction Methods 0.000 description 208
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 198
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 155
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 141
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
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• 239000002904 solvent Substances 0.000 description 63
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 62
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• 125000005843 halogen group Chemical group 0.000 description 42
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• 229910052938 sodium sulfate Inorganic materials 0.000 description 31
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• 238000003786 synthesis reaction Methods 0.000 description 31
• 238000007796 conventional method Methods 0.000 description 29
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• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 27
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 25
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• 125000004429 atom Chemical group 0.000 description 15
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• 241000282472 Canis lupus familiaris Species 0.000 description 13
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