NZ584519A - Aryl amides useful as inhibitors of voltage-gated sodium channels - Google Patents

Info

Publication number

NZ584519A

NZ584519A NZ584519A NZ58451908A NZ584519A NZ 584519 A NZ584519 A NZ 584519A NZ 584519 A NZ584519 A NZ 584519A NZ 58451908 A NZ58451908 A NZ 58451908A NZ 584519 A NZ584519 A NZ 584519A

Authority

NZ

New Zealand

Prior art keywords

ring

pain

benzamide

aliphatic

hydrogen

Prior art date

2007-10-11

Links

• Espacenet
• Global Dossier
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• -1 Aryl amides Chemical class 0.000 title claims abstract description 182
• 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 title abstract description 12
• 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 title abstract description 12
• 239000003112 inhibitor Substances 0.000 title abstract description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 252
• 208000002193 Pain Diseases 0.000 claims abstract description 118
• 230000036407 pain Effects 0.000 claims abstract description 89
• 208000004296 neuralgia Diseases 0.000 claims abstract description 38
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 34
• 208000021722 neuropathic pain Diseases 0.000 claims abstract description 27
• 230000001154 acute effect Effects 0.000 claims abstract description 24
• 206010015037 epilepsy Diseases 0.000 claims abstract description 19
• 208000035475 disorder Diseases 0.000 claims abstract description 17
• 230000001684 chronic effect Effects 0.000 claims abstract description 16
• 201000006417 multiple sclerosis Diseases 0.000 claims abstract description 13
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 11
• 206010027599 migraine Diseases 0.000 claims abstract description 11
• 208000009935 visceral pain Diseases 0.000 claims abstract description 11
• 208000008035 Back Pain Diseases 0.000 claims abstract description 10
• 206010019233 Headaches Diseases 0.000 claims abstract description 10
• 230000002981 neuropathic effect Effects 0.000 claims abstract description 10
• 206010065390 Inflammatory pain Diseases 0.000 claims abstract description 9
• 206010003119 arrhythmia Diseases 0.000 claims abstract description 9
• 208000006561 Cluster Headache Diseases 0.000 claims abstract description 8
• 208000016285 Movement disease Diseases 0.000 claims abstract description 8
• 206010061533 Myotonia Diseases 0.000 claims abstract description 8
• 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 8
• 206010044652 trigeminal neuralgia Diseases 0.000 claims abstract description 8
• 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 7
• 206010003591 Ataxia Diseases 0.000 claims abstract description 7
• 208000004404 Intractable Pain Diseases 0.000 claims abstract description 7
• 206010028836 Neck pain Diseases 0.000 claims abstract description 7
• 208000004550 Postoperative Pain Diseases 0.000 claims abstract description 7
• 208000019901 Anxiety disease Diseases 0.000 claims abstract description 6
• 208000000003 Breakthrough pain Diseases 0.000 claims abstract description 6
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims abstract description 6
• 206010036376 Postherpetic Neuralgia Diseases 0.000 claims abstract description 6
• 208000006011 Stroke Diseases 0.000 claims abstract description 6
• 230000036506 anxiety Effects 0.000 claims abstract description 6
• 230000006793 arrhythmia Effects 0.000 claims abstract description 6
• 208000015706 neuroendocrine disease Diseases 0.000 claims abstract description 6
• 201000008482 osteoarthritis Diseases 0.000 claims abstract description 6
• 206010058019 Cancer Pain Diseases 0.000 claims abstract description 5
• 206010021639 Incontinence Diseases 0.000 claims abstract description 5
• 206010059604 Radicular pain Diseases 0.000 claims abstract description 5
• 208000008765 Sciatica Diseases 0.000 claims abstract description 5
• 206010003246 arthritis Diseases 0.000 claims abstract description 5
• 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 5
• 208000020016 psychiatric disease Diseases 0.000 claims abstract description 5
• 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 4
• 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 4
• 206010020772 Hypertension Diseases 0.000 claims abstract description 4
• 208000001294 Nociceptive Pain Diseases 0.000 claims abstract description 4
• 206010033557 Palpitations Diseases 0.000 claims abstract description 4
• 208000030886 Traumatic Brain injury Diseases 0.000 claims abstract description 4
• 230000002159 abnormal effect Effects 0.000 claims abstract description 4
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 4
• 206010008118 cerebral infarction Diseases 0.000 claims abstract description 4
• 230000005176 gastrointestinal motility Effects 0.000 claims abstract description 4
• 230000009529 traumatic brain injury Effects 0.000 claims abstract description 4
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 154
• 125000001931 aliphatic group Chemical group 0.000 claims description 142
• 229910052739 hydrogen Inorganic materials 0.000 claims description 108
• 239000001257 hydrogen Substances 0.000 claims description 108
• 229910052736 halogen Inorganic materials 0.000 claims description 104
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 98
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 97
• 229910052760 oxygen Inorganic materials 0.000 claims description 79
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 77
• 229910052717 sulfur Inorganic materials 0.000 claims description 70
• 150000002367 halogens Chemical class 0.000 claims description 69
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 68
• 229910052757 nitrogen Inorganic materials 0.000 claims description 66
• 125000000623 heterocyclic group Chemical group 0.000 claims description 62
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
• 125000004429 atom Chemical group 0.000 claims description 57
• 125000003118 aryl group Chemical group 0.000 claims description 55
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 55
• 239000001301 oxygen Chemical group 0.000 claims description 55
• 125000001424 substituent group Chemical group 0.000 claims description 52
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 51
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 48
• 239000011593 sulfur Chemical group 0.000 claims description 48
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 46
• 125000005842 heteroatom Chemical group 0.000 claims description 46
• 125000001072 heteroaryl group Chemical group 0.000 claims description 43
• 125000000464 thioxo group Chemical group S=* 0.000 claims description 43
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 42
• 125000005843 halogen group Chemical group 0.000 claims description 41
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 41
• 125000002950 monocyclic group Chemical group 0.000 claims description 40
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 39
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 37
• 125000000217 alkyl group Chemical group 0.000 claims description 36
• 102000018674 Sodium Channels Human genes 0.000 claims description 34
• 108010052164 Sodium Channels Proteins 0.000 claims description 34
• 239000003814 drug Substances 0.000 claims description 33
• 229920006395 saturated elastomer Polymers 0.000 claims description 32
• 125000004043 oxo group Chemical group O=* 0.000 claims description 29
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 29
• 150000003839 salts Chemical class 0.000 claims description 29
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 25
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 21
• 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 18
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 18
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 16
• 125000003386 piperidinyl group Chemical group 0.000 claims description 16
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 16
• 125000004432 carbon atom Chemical group C* 0.000 claims description 15
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
• 125000004193 piperazinyl group Chemical group 0.000 claims description 14
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
• 125000006413 ring segment Chemical group 0.000 claims description 12
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 12
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 11
• 229910052794 bromium Inorganic materials 0.000 claims description 11
• 229910052731 fluorine Inorganic materials 0.000 claims description 11
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 9
• 125000006317 cyclopropyl amino group Chemical group 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 7
• 239000003981 vehicle Substances 0.000 claims description 7
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 5
• 239000002671 adjuvant Substances 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
• AVQKFIYCHKRMRS-UHFFFAOYSA-N 2-(4-methoxyphenoxy)-5-nitro-n-(3-sulfamoylphenyl)benzamide Chemical compound C1=CC(OC)=CC=C1OC1=CC=C([N+]([O-])=O)C=C1C(=O)NC1=CC=CC(S(N)(=O)=O)=C1 AVQKFIYCHKRMRS-UHFFFAOYSA-N 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 2
• 230000004048 modification Effects 0.000 claims 1
• 238000012986 modification Methods 0.000 claims 1
• ZSTQBEVUJOQXMA-UHFFFAOYSA-N n-[5-(diethylsulfamoyl)-2-methoxyphenyl]-2-phenoxybenzamide Chemical compound CCN(CC)S(=O)(=O)C1=CC=C(OC)C(NC(=O)C=2C(=CC=CC=2)OC=2C=CC=CC=2)=C1 ZSTQBEVUJOQXMA-UHFFFAOYSA-N 0.000 claims 1
• 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 84
• 208000000094 Chronic Pain Diseases 0.000 abstract description 11
• 208000005298 acute pain Diseases 0.000 abstract description 11
• 238000000034 method Methods 0.000 description 57
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 41
• 125000004093 cyano group Chemical group *C#N 0.000 description 37
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• 230000000694 effects Effects 0.000 description 30
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
• 239000011734 sodium Substances 0.000 description 25
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 23
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• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
• 125000003710 aryl alkyl group Chemical group 0.000 description 18
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
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• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
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• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 10
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• VJYNRXFXHKIGLT-UHFFFAOYSA-N 5-[3-(1,3-diethyl-4,6-dioxo-2-sulfanylidene-1,3-diazinan-5-yl)prop-2-enylidene]-1,3-diethyl-2-sulfanylidene-1,3-diazinane-4,6-dione Chemical compound O=C1N(CC)C(=S)N(CC)C(=O)C1C=CC=C1C(=O)N(CC)C(=S)N(CC)C1=O VJYNRXFXHKIGLT-UHFFFAOYSA-N 0.000 description 8
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