JP2010523540A

JP2010523540A - スルホンアミドおよびその医薬組成物

スルホンアミドおよびその医薬組成物 Download PDF

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Publication number: JP2010523540A
Authority: JP; Japan
Prior art keywords: alkyl; cycloalkyl; halogen; aryl; heteroaryl
Prior art date: 2007-04-03
Legal status : Withdrawn

Application number

JP2010501609A

Other languages

English (en)

Japanese (ja)

Other versions

JP2010523540A5 (enExample

Inventor

ゲイルエステップキムバリー

フランツジョセフフリリアントン

ジョンオドネルクリストファー

Original Assignee

ファイザー・インク

Priority date

2007-04-03

Filing date

2008-03-26

Publication date

2010-07-15

2008-03-26 Application filed by ファイザー・インク filed Critical ファイザー・インク

2010-07-15 Publication of JP2010523540A publication Critical patent/JP2010523540A/ja

2011-05-06 Publication of JP2010523540A5 publication Critical patent/JP2010523540A5/ja

Status Withdrawn legal-status Critical Current

Links

239000008194 pharmaceutical composition Substances 0.000 title claims description 11
229940124530 sulfonamide Drugs 0.000 title description 9
150000003456 sulfonamides Chemical class 0.000 title description 9
150000001875 compounds Chemical class 0.000 claims abstract description 212
150000003839 salts Chemical class 0.000 claims abstract description 45
239000000126 substance Substances 0.000 claims abstract description 11
-1 cycloalkyl R 55 Chemical compound 0.000 claims description 148
125000000217 alkyl group Chemical group 0.000 claims description 115
125000001424 substituent group Chemical group 0.000 claims description 82
238000000034 method Methods 0.000 claims description 79
125000003118 aryl group Chemical group 0.000 claims description 74
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 71
125000000753 cycloalkyl group Chemical group 0.000 claims description 66
125000001072 heteroaryl group Chemical group 0.000 claims description 65
229910052736 halogen Inorganic materials 0.000 claims description 61
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 54
150000002367 halogens Chemical group 0.000 claims description 53
229910052757 nitrogen Inorganic materials 0.000 claims description 42
229910052799 carbon Inorganic materials 0.000 claims description 41
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 41
125000003545 alkoxy group Chemical group 0.000 claims description 40
229910052739 hydrogen Inorganic materials 0.000 claims description 39
239000001257 hydrogen Substances 0.000 claims description 39
125000005842 heteroatom Chemical group 0.000 claims description 30
125000004432 carbon atom Chemical group C* 0.000 claims description 29
125000004093 cyano group Chemical group *C#N 0.000 claims description 23
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
125000003342 alkenyl group Chemical group 0.000 claims description 18
125000000623 heterocyclic group Chemical group 0.000 claims description 18
239000001301 oxygen Chemical group 0.000 claims description 17
229910052760 oxygen Chemical group 0.000 claims description 17
229910052717 sulfur Inorganic materials 0.000 claims description 17
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 16
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
239000011593 sulfur Chemical group 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
241000124008 Mammalia Species 0.000 claims description 15
208000002193 Pain Diseases 0.000 claims description 15
239000003814 drug Substances 0.000 claims description 15
125000003282 alkyl amino group Chemical group 0.000 claims description 11
125000004663 dialkyl amino group Chemical group 0.000 claims description 11
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
201000000980 schizophrenia Diseases 0.000 claims description 10
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
208000019695 Migraine disease Diseases 0.000 claims description 8
125000004104 aryloxy group Chemical group 0.000 claims description 8
125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
229940079593 drug Drugs 0.000 claims description 8
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
230000001154 acute effect Effects 0.000 claims description 7
206010027599 migraine Diseases 0.000 claims description 7
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238000006467 substitution reaction Methods 0.000 claims description 7
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208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 6
206010012289 Dementia Diseases 0.000 claims description 6
208000007101 Muscle Cramp Diseases 0.000 claims description 6
208000005392 Spasm Diseases 0.000 claims description 6
206010044565 Tremor Diseases 0.000 claims description 6
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
125000000304 alkynyl group Chemical group 0.000 claims description 6
208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 6
125000001188 haloalkyl group Chemical group 0.000 claims description 6
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
125000001544 thienyl group Chemical group 0.000 claims description 6
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
206010015037 epilepsy Diseases 0.000 claims description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
208000019116 sleep disease Diseases 0.000 claims description 5
208000024827 Alzheimer disease Diseases 0.000 claims description 4
201000006474 Brain Ischemia Diseases 0.000 claims description 4
206010048962 Brain oedema Diseases 0.000 claims description 4
206010008120 Cerebral ischaemia Diseases 0.000 claims description 4
208000028698 Cognitive impairment Diseases 0.000 claims description 4
206010010904 Convulsion Diseases 0.000 claims description 4
208000012661 Dyskinesia Diseases 0.000 claims description 4
206010019196 Head injury Diseases 0.000 claims description 4
208000010496 Heart Arrest Diseases 0.000 claims description 4
208000023105 Huntington disease Diseases 0.000 claims description 4
208000019022 Mood disease Diseases 0.000 claims description 4
208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 claims description 4
208000028389 Nerve injury Diseases 0.000 claims description 4
208000018737 Parkinson disease Diseases 0.000 claims description 4
208000028017 Psychotic disease Diseases 0.000 claims description 4
208000017442 Retinal disease Diseases 0.000 claims description 4
208000006011 Stroke Diseases 0.000 claims description 4
208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 4
208000009205 Tinnitus Diseases 0.000 claims description 4
206010046543 Urinary incontinence Diseases 0.000 claims description 4
206010047700 Vomiting Diseases 0.000 claims description 4
125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 4
230000036506 anxiety Effects 0.000 claims description 4
208000006752 brain edema Diseases 0.000 claims description 4
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
206010008118 cerebral infarction Diseases 0.000 claims description 4
208000010877 cognitive disease Diseases 0.000 claims description 4
230000036461 convulsion Effects 0.000 claims description 4
125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
208000035475 disorder Diseases 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
230000002218 hypoglycaemic effect Effects 0.000 claims description 4
208000002780 macular degeneration Diseases 0.000 claims description 4
230000008764 nerve damage Effects 0.000 claims description 4
208000033300 perinatal asphyxia Diseases 0.000 claims description 4
208000024891 symptom Diseases 0.000 claims description 4
RZRJACCZWZTYJY-UHFFFAOYSA-N tert-butylsulfanyl n,n-dimethylcarbamodithioate Chemical group CN(C)C(=S)SSC(C)(C)C RZRJACCZWZTYJY-UHFFFAOYSA-N 0.000 claims description 4
231100000886 tinnitus Toxicity 0.000 claims description 4
206010044652 trigeminal neuralgia Diseases 0.000 claims description 4
125000004385 trihaloalkyl group Chemical group 0.000 claims description 4
230000008673 vomiting Effects 0.000 claims description 4
206010011878 Deafness Diseases 0.000 claims description 3
208000029578 Muscle disease Diseases 0.000 claims description 3
208000021642 Muscular disease Diseases 0.000 claims description 3
230000010370 hearing loss Effects 0.000 claims description 3
231100000888 hearing loss Toxicity 0.000 claims description 3
208000016354 hearing loss disease Diseases 0.000 claims description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 2
230000005540 biological transmission Effects 0.000 claims description 2
231100000040 eye damage Toxicity 0.000 claims description 2
125000005059 halophenyl group Chemical group 0.000 claims description 2
208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 2
208000020685 sleep-wake disease Diseases 0.000 claims description 2
208000020431 spinal cord injury Diseases 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims 9
210000005036 nerve Anatomy 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 63
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 212
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 136
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
239000000047 product Substances 0.000 description 105
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 94
235000019439 ethyl acetate Nutrition 0.000 description 90
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
238000006243 chemical reaction Methods 0.000 description 81
238000002360 preparation method Methods 0.000 description 81
238000005160 1H NMR spectroscopy Methods 0.000 description 79
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
239000000243 solution Substances 0.000 description 67
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
239000011541 reaction mixture Substances 0.000 description 59
239000007787 solid Substances 0.000 description 56
239000002904 solvent Substances 0.000 description 56
239000012044 organic layer Substances 0.000 description 55
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 43
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VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 41
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
238000000746 purification Methods 0.000 description 36
239000003921 oil Substances 0.000 description 34
235000019198 oils Nutrition 0.000 description 34
239000002585 base Substances 0.000 description 32
239000010410 layer Substances 0.000 description 32
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 31
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 30
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 29
238000000105 evaporative light scattering detection Methods 0.000 description 29
238000001819 mass spectrum Methods 0.000 description 28
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
210000004027 cell Anatomy 0.000 description 26
150000001412 amines Chemical class 0.000 description 24
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 22
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
229910052763 palladium Inorganic materials 0.000 description 22
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
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238000003756 stirring Methods 0.000 description 21
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239000002253 acid Substances 0.000 description 20
150000001732 carboxylic acid derivatives Chemical class 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
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239000003054 catalyst Substances 0.000 description 19
238000004440 column chromatography Methods 0.000 description 19
125000005843 halogen group Chemical group 0.000 description 19
239000011734 sodium Substances 0.000 description 19
102000003678 AMPA Receptors Human genes 0.000 description 18
108090000078 AMPA Receptors Proteins 0.000 description 18
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PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
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229910052938 sodium sulfate Inorganic materials 0.000 description 14
235000011152 sodium sulphate Nutrition 0.000 description 14
238000005481 NMR spectroscopy Methods 0.000 description 13
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HNDXKIMMSFCCFW-UHFFFAOYSA-N propane-2-sulphonic acid Chemical compound CC(C)S(O)(=O)=O HNDXKIMMSFCCFW-UHFFFAOYSA-N 0.000 description 12
239000000556 agonist Substances 0.000 description 10
150000001543 aryl boronic acids Chemical class 0.000 description 10
239000000460 chlorine Substances 0.000 description 10
239000012043 crude product Substances 0.000 description 10
238000009472 formulation Methods 0.000 description 10
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WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
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QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
125000004429 atom Chemical group 0.000 description 9
MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 9
239000000543 intermediate Substances 0.000 description 9
239000000377 silicon dioxide Substances 0.000 description 9
239000007858 starting material Substances 0.000 description 9
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WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
208000012902 Nervous system disease Diseases 0.000 description 8
208000025966 Neurological disease Diseases 0.000 description 8
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150000001408 amides Chemical class 0.000 description 8
230000015572 biosynthetic process Effects 0.000 description 8
229930195712 glutamate Natural products 0.000 description 8
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DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 7
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VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
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DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 6
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210000004556 brain Anatomy 0.000 description 5
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UQIYZJCPYGLLNO-PMACEKPBSA-N n-[(3s,4s)-4-hydroxy-4-(4-phenylphenyl)oxan-3-yl]propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)N[C@H]1COCC[C@]1(O)C1=CC=C(C=2C=CC=CC=2)C=C1 UQIYZJCPYGLLNO-PMACEKPBSA-N 0.000 description 5
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