CA2788783C - Heterocycles as potassium channel modulators - Google Patents

Info

Publication number

CA2788783C

CA2788783C CA2788783A CA2788783A CA2788783C CA 2788783 C CA2788783 C CA 2788783C CA 2788783 A CA2788783 A CA 2788783A CA 2788783 A CA2788783 A CA 2788783A CA 2788783 C CA2788783 C CA 2788783C

Authority

CA

Canada

Prior art keywords

pyridin

imidazo

fluoro

trifluoromethyl

pain

Prior art date

2010-02-16

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.)

Expired - Fee Related

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• 108020001213 potassium channel Proteins 0.000 title claims abstract description 74
• 102000004257 Potassium Channel Human genes 0.000 title claims abstract description 73
• 125000000623 heterocyclic group Chemical group 0.000 title abstract description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 384
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 46
• 238000011282 treatment Methods 0.000 claims abstract description 28
• 206010010904 Convulsion Diseases 0.000 claims abstract description 20
• 208000019901 Anxiety disease Diseases 0.000 claims abstract description 18
• 230000001419 dependent effect Effects 0.000 claims abstract description 18
• 206010015037 epilepsy Diseases 0.000 claims abstract description 17
• 230000036506 anxiety Effects 0.000 claims abstract description 16
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 12
• 208000015114 central nervous system disease Diseases 0.000 claims abstract description 12
• 206010027599 migraine Diseases 0.000 claims abstract description 12
• 208000027232 peripheral nervous system disease Diseases 0.000 claims abstract description 12
• 208000020925 Bipolar disease Diseases 0.000 claims abstract description 10
• 208000018737 Parkinson disease Diseases 0.000 claims abstract description 10
• 201000007737 Retinal degeneration Diseases 0.000 claims abstract description 9
• 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 9
• 230000004770 neurodegeneration Effects 0.000 claims abstract description 9
• 230000004258 retinal degeneration Effects 0.000 claims abstract description 9
• 206010044652 trigeminal neuralgia Diseases 0.000 claims abstract description 9
• 208000019022 Mood disease Diseases 0.000 claims abstract description 8
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 7
• 208000000044 Amnesia Diseases 0.000 claims abstract description 7
• 206010003591 Ataxia Diseases 0.000 claims abstract description 7
• 208000003174 Brain Neoplasms Diseases 0.000 claims abstract description 7
• 208000011897 Deaf-Blind disease Diseases 0.000 claims abstract description 7
• 208000026139 Memory disease Diseases 0.000 claims abstract description 7
• 208000008238 Muscle Spasticity Diseases 0.000 claims abstract description 7
• 206010028632 Myokymia Diseases 0.000 claims abstract description 7
• 208000028017 Psychotic disease Diseases 0.000 claims abstract description 7
• 208000032257 benign familial neonatal 1 seizures Diseases 0.000 claims abstract description 7
• 230000007812 deficiency Effects 0.000 claims abstract description 7
• 230000013016 learning Effects 0.000 claims abstract description 7
• 230000006984 memory degeneration Effects 0.000 claims abstract description 7
• 208000023060 memory loss Diseases 0.000 claims abstract description 7
• 208000005264 motor neuron disease Diseases 0.000 claims abstract description 7
• 208000018198 spasticity Diseases 0.000 claims abstract description 7
• 208000002193 Pain Diseases 0.000 claims description 94
• 230000036407 pain Effects 0.000 claims description 81
• 150000003839 salts Chemical class 0.000 claims description 57
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 50
• 210000004027 cell Anatomy 0.000 claims description 43
• 208000035475 disorder Diseases 0.000 claims description 28
• 230000000694 effects Effects 0.000 claims description 26
• DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 24
• 150000002500 ions Chemical class 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 13
• 208000004296 neuralgia Diseases 0.000 claims description 11
• 208000021722 neuropathic pain Diseases 0.000 claims description 11
• 208000009935 visceral pain Diseases 0.000 claims description 11
• 206010058019 Cancer Pain Diseases 0.000 claims description 10
• 206010065390 Inflammatory pain Diseases 0.000 claims description 9
• 208000012902 Nervous system disease Diseases 0.000 claims description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 7
• 208000001294 Nociceptive Pain Diseases 0.000 claims description 6
• 208000006011 Stroke Diseases 0.000 claims description 6
• 230000010370 hearing loss Effects 0.000 claims description 5
• 231100000888 hearing loss Toxicity 0.000 claims description 5
• 208000016354 hearing loss disease Diseases 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 206010011878 Deafness Diseases 0.000 claims description 3
• 206010028391 Musculoskeletal Pain Diseases 0.000 claims description 3
• 206010012601 diabetes mellitus Diseases 0.000 claims description 2
• JZVWEABTJQFGAO-UHFFFAOYSA-N n-(3-cyclobutyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3,3-dimethylbutanamide Chemical compound FC(F)(F)C(C)(C)CC(=O)NC=1N=C2C=CC(F)=CN2C=1C1CCC1 JZVWEABTJQFGAO-UHFFFAOYSA-N 0.000 claims 1
• CVZZPEUPCXZOTD-UHFFFAOYSA-N n-[3-(cyclohexylmethyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl]-4,4,4-trifluoro-3,3-dimethylbutanamide Chemical compound FC(F)(F)C(C)(C)CC(=O)NC=1N=C2C=CC(F)=CN2C=1CC1CCCCC1 CVZZPEUPCXZOTD-UHFFFAOYSA-N 0.000 claims 1
• BPMXKSZIVZAGJP-UHFFFAOYSA-N n-[3-cyclobutyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]-3,3,3-trifluoro-2,2-dimethylpropanamide Chemical compound FC(F)(F)C(C)(C)C(=O)NC=1N=C2C=CC(C(F)(F)F)=NN2C=1C1CCC1 BPMXKSZIVZAGJP-UHFFFAOYSA-N 0.000 claims 1
• XUNJIMLWMVGTSK-UHFFFAOYSA-N n-[3-cyclobutyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]-4,4,4-trifluoro-3,3-dimethylbutanamide Chemical compound FC(F)(F)C(C)(C)CC(=O)NC=1N=C2C=CC(C(F)(F)F)=NN2C=1C1CCC1 XUNJIMLWMVGTSK-UHFFFAOYSA-N 0.000 claims 1
• HAMPHMHYVVBIAN-UHFFFAOYSA-N n-[3-cyclopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-4,4,4-trifluoro-3,3-dimethylbutanamide Chemical compound FC(F)(F)C(C)(C)CC(=O)NC=1N=C2C=CC(C(F)(F)F)=CN2C=1C1CCCC1 HAMPHMHYVVBIAN-UHFFFAOYSA-N 0.000 claims 1
• YREYHQNMOUCMQS-UHFFFAOYSA-N n-[3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-4,4,4-trifluoro-3,3-dimethylbutanamide Chemical compound FC(F)(F)C(C)(C)CC(=O)NC=1N=C2C=CC(C(F)(F)F)=CN2C=1C1CC1 YREYHQNMOUCMQS-UHFFFAOYSA-N 0.000 claims 1
• WWDNCUUKKLRWDQ-UHFFFAOYSA-N n-[3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]-3,3,3-trifluoro-2,2-dimethylpropanamide Chemical compound FC(F)(F)C(C)(C)C(=O)NC=1N=C2C=CC(C(F)(F)F)=NN2C=1C1CC1 WWDNCUUKKLRWDQ-UHFFFAOYSA-N 0.000 claims 1
• HJHYTJIDVLJSPN-UHFFFAOYSA-N n-[3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-b]pyridazin-2-yl]-3,4-difluorobenzamide Chemical compound C1=C(F)C(F)=CC=C1C(=O)NC1=C(C2CC2)N2N=C(C(F)(F)F)C=CC2=N1 HJHYTJIDVLJSPN-UHFFFAOYSA-N 0.000 claims 1
• XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 83
• 239000000203 mixture Substances 0.000 abstract description 44
• 230000004907 flux Effects 0.000 abstract description 21
• 201000010099 disease Diseases 0.000 abstract description 18
• 229910001414 potassium ion Inorganic materials 0.000 abstract description 5
• NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 abstract description 3
• 239000004090 neuroprotective agent Substances 0.000 abstract description 3
• -1 hydrocarbon radical Chemical class 0.000 description 372
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 168
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 113
• 125000001424 substituent group Chemical group 0.000 description 100
• 125000003118 aryl group Chemical group 0.000 description 97
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 73
• 229910052736 halogen Inorganic materials 0.000 description 66
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 64
• 150000002367 halogens Chemical class 0.000 description 64
• 125000001072 heteroaryl group Chemical group 0.000 description 59
• 125000004093 cyano group Chemical group *C#N 0.000 description 49
• 125000000217 alkyl group Chemical group 0.000 description 48
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 45
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 40
• 230000015572 biosynthetic process Effects 0.000 description 38
• 229910052757 nitrogen Inorganic materials 0.000 description 38
• 238000003786 synthesis reaction Methods 0.000 description 37
• 108091006146 Channels Proteins 0.000 description 36
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 36
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 35
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 35
• 239000012453 solvate Substances 0.000 description 34
• 239000007787 solid Substances 0.000 description 33
• 238000006243 chemical reaction Methods 0.000 description 32
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 32
• 239000000243 solution Substances 0.000 description 29
• 239000002904 solvent Substances 0.000 description 25
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 24
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 23
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 23
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
• 238000003556 assay Methods 0.000 description 22
• 229910052799 carbon Inorganic materials 0.000 description 22
• 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 22
• 150000004677 hydrates Chemical class 0.000 description 22
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 21
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 21
• 238000002360 preparation method Methods 0.000 description 21
• 108010006746 KCNQ2 Potassium Channel Proteins 0.000 description 20
• 102000005453 KCNQ2 Potassium Channel Human genes 0.000 description 20
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 20
• 125000005842 heteroatom Chemical group 0.000 description 20
• 239000010410 layer Substances 0.000 description 20
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 20
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 19
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 19
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 18
• 241000700159 Rattus Species 0.000 description 18
• 125000001309 chloro group Chemical group Cl* 0.000 description 18
• 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 18
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 18
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
• 235000019341 magnesium sulphate Nutrition 0.000 description 18
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 17
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
• 229920006395 saturated elastomer Polymers 0.000 description 17
• 125000000753 cycloalkyl group Chemical group 0.000 description 16
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 16
• 239000012044 organic layer Substances 0.000 description 16
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
• 230000004044 response Effects 0.000 description 15
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 14
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 14
• 125000006648 (C1-C8) haloalkyl group Chemical group 0.000 description 13
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• 125000004429 atom Chemical group 0.000 description 13
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• 208000014674 injury Diseases 0.000 description 13
• 238000012360 testing method Methods 0.000 description 13
• 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• 125000004432 carbon atom Chemical group C* 0.000 description 12
• 125000002950 monocyclic group Chemical group 0.000 description 12
• 125000003367 polycyclic group Chemical group 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 208000027418 Wounds and injury Diseases 0.000 description 11
• 239000012043 crude product Substances 0.000 description 11
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
• 208000024891 symptom Diseases 0.000 description 11
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 11
• 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 10
• 206010020853 Hypertonic bladder Diseases 0.000 description 10
• 230000006378 damage Effects 0.000 description 10
• 210000002683 foot Anatomy 0.000 description 10
• 150000003254 radicals Chemical class 0.000 description 10
• 229910052701 rubidium Inorganic materials 0.000 description 10
• 239000004215 Carbon black (E152) Substances 0.000 description 9
• 108010038888 KCNQ3 Potassium Channel Proteins 0.000 description 9
• 102000015686 KCNQ3 Potassium Channel Human genes 0.000 description 9
• 241001465754 Metazoa Species 0.000 description 9
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 229930195733 hydrocarbon Natural products 0.000 description 9
• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 description 9
• 239000011591 potassium Substances 0.000 description 9
• 230000036515 potency Effects 0.000 description 9
• 239000000377 silicon dioxide Substances 0.000 description 9
• 125000004434 sulfur atom Chemical group 0.000 description 9
• 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 8
• 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 8
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 8
• 150000001602 bicycloalkyls Chemical group 0.000 description 8
• 125000001246 bromo group Chemical group Br* 0.000 description 8
• 239000011575 calcium Substances 0.000 description 8
• 125000004404 heteroalkyl group Chemical group 0.000 description 8
• 239000000543 intermediate Substances 0.000 description 8
• 239000007788 liquid Substances 0.000 description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 8
• 230000001473 noxious effect Effects 0.000 description 8
• 229910052700 potassium Inorganic materials 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 8
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• 239000007858 starting material Substances 0.000 description 8
• 208000011580 syndromic disease Diseases 0.000 description 8
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
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• 208000004454 Hyperalgesia Diseases 0.000 description 7
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• 230000004913 activation Effects 0.000 description 7
• 125000002947 alkylene group Chemical group 0.000 description 7
• 125000004104 aryloxy group Chemical group 0.000 description 7
• 239000000460 chlorine Substances 0.000 description 7
• 238000004440 column chromatography Methods 0.000 description 7
• RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 description 7
• 210000000929 nociceptor Anatomy 0.000 description 7
• 108091008700 nociceptors Proteins 0.000 description 7
• 125000004526 pyridazin-2-yl group Chemical group N1N(C=CC=C1)* 0.000 description 7
• 239000000126 substance Substances 0.000 description 7
• 125000006509 3,4-difluorobenzyl group Chemical group [H]C1=C(F)C(F)=C([H])C(=C1[H])C([H])([H])* 0.000 description 6
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 6
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• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
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• 229910052791 calcium Inorganic materials 0.000 description 6
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• 238000001727 in vivo Methods 0.000 description 6
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• 125000004001 thioalkyl group Chemical group 0.000 description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 6
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 5
• 125000001054 5 membered carbocyclic group Chemical group 0.000 description 5
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• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
• LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 5
• 125000003710 aryl alkyl group Chemical group 0.000 description 5
• 125000004190 benzothiazol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N=C(*)SC2=C1[H] 0.000 description 5
• 230000037396 body weight Effects 0.000 description 5
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• 229910052801 chlorine Inorganic materials 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• 125000004474 heteroalkylene group Chemical group 0.000 description 5
• 230000007062 hydrolysis Effects 0.000 description 5
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• 230000004054 inflammatory process Effects 0.000 description 5
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