JP2012519196A - スルホニル化されたテトラヒドロアゾロピラジンおよびその医薬としての使用 - Google Patents

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Publication number

JP2012519196A

JP2012519196A JP2011552360A JP2011552360A JP2012519196A JP 2012519196 A JP2012519196 A JP 2012519196A JP 2011552360 A JP2011552360 A JP 2011552360A JP 2011552360 A JP2011552360 A JP 2011552360A JP 2012519196 A JP2012519196 A JP 2012519196A

Authority

JP

Japan

Prior art keywords

alkyl

cycloalkyl

aryl

heteroaryl

phenyl

Prior art date

2009-03-04

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Withdrawn

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• WEXJJSPMIBHSKF-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-pyrrolo[2,3-b]pyrazine Chemical class N1CCNC2=C1C=CN2 WEXJJSPMIBHSKF-UHFFFAOYSA-N 0.000 title abstract description 18
• 150000001875 compounds Chemical class 0.000 claims abstract description 140
• -1 indole compound Chemical class 0.000 claims abstract description 127
• 239000003814 drug Substances 0.000 claims abstract description 18
• 125000000217 alkyl group Chemical group 0.000 claims description 258
• 125000003118 aryl group Chemical group 0.000 claims description 165
• 125000001424 substituent group Chemical group 0.000 claims description 159
• 125000001072 heteroaryl group Chemical group 0.000 claims description 153
• 229910052739 hydrogen Inorganic materials 0.000 claims description 110
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 104
• 239000000203 mixture Substances 0.000 claims description 99
• 125000002947 alkylene group Chemical group 0.000 claims description 94
• 229910052799 carbon Inorganic materials 0.000 claims description 94
• 125000004076 pyridyl group Chemical group 0.000 claims description 94
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 87
• 230000036961 partial effect Effects 0.000 claims description 62
• 125000001544 thienyl group Chemical group 0.000 claims description 60
• 229910052731 fluorine Inorganic materials 0.000 claims description 59
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 56
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 54
• 125000002883 imidazolyl group Chemical group 0.000 claims description 49
• 229910052801 chlorine Inorganic materials 0.000 claims description 47
• 125000001425 triazolyl group Chemical group 0.000 claims description 47
• 125000000335 thiazolyl group Chemical group 0.000 claims description 46
• 229920006395 saturated elastomer Polymers 0.000 claims description 42
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 40
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 31
• 125000000623 heterocyclic group Chemical group 0.000 claims description 29
• 229910052760 oxygen Inorganic materials 0.000 claims description 28
• 125000003386 piperidinyl group Chemical group 0.000 claims description 26
• 229910052794 bromium Inorganic materials 0.000 claims description 23
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 23
• 125000002393 azetidinyl group Chemical group 0.000 claims description 22
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 20
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
• 125000001624 naphthyl group Chemical group 0.000 claims description 18
• 229910052740 iodine Inorganic materials 0.000 claims description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• 125000004432 carbon atom Chemical group C* 0.000 claims description 15
• 229910052717 sulfur Inorganic materials 0.000 claims description 15
• 208000002193 Pain Diseases 0.000 claims description 14
• 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 13
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 13
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000002619 bicyclic group Chemical group 0.000 claims description 11
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 11
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 238000006467 substitution reaction Methods 0.000 claims description 11
• 125000002541 furyl group Chemical group 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 7
• 125000004450 alkenylene group Chemical group 0.000 claims description 6
• 125000005605 benzo group Chemical group 0.000 claims description 6
• 150000001923 cyclic compounds Chemical class 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 150000003839 salts Chemical class 0.000 claims description 6
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
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• 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 4
• 208000000094 Chronic Pain Diseases 0.000 claims description 4
• 206010065390 Inflammatory pain Diseases 0.000 claims description 4
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• 208000005298 acute pain Diseases 0.000 claims description 4
• 239000004037 angiogenesis inhibitor Substances 0.000 claims description 4
• NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 4
• 125000004122 cyclic group Chemical group 0.000 claims description 4
• 150000002391 heterocyclic compounds Chemical class 0.000 claims description 4
• 235000020824 obesity Nutrition 0.000 claims description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
• 230000010410 reperfusion Effects 0.000 claims description 4
• 208000011580 syndromic disease Diseases 0.000 claims description 4
• 208000009935 visceral pain Diseases 0.000 claims description 4
• 201000004624 Dermatitis Diseases 0.000 claims description 3
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• 208000025747 Rheumatic disease Diseases 0.000 claims description 3
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 3
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
• 206010012601 diabetes mellitus Diseases 0.000 claims description 3
• 125000004988 dibenzothienyl group Chemical group C1(=CC=CC=2SC3=C(C21)C=CC=C3)* 0.000 claims description 3
• 229910052736 halogen Inorganic materials 0.000 claims description 3
• 150000002367 halogens Chemical class 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 206010027599 migraine Diseases 0.000 claims description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 208000023504 respiratory system disease Diseases 0.000 claims description 3
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
• 125000005509 dibenzothiophenyl group Chemical group 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
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• 101000642536 Apis mellifera Venom serine protease 34 Proteins 0.000 claims 1
• 230000035479 physiological effects, processes and functions Effects 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 25
• 239000000126 substance Substances 0.000 abstract description 13
• 230000008569 process Effects 0.000 abstract description 5
• SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract 1
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract 1
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 425
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 230
• 239000000243 solution Substances 0.000 description 207
• 239000011541 reaction mixture Substances 0.000 description 188
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 142
• 239000011734 sodium Substances 0.000 description 99
• 230000002829 reductive effect Effects 0.000 description 95
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
• 239000012043 crude product Substances 0.000 description 86
• 238000004440 column chromatography Methods 0.000 description 84
• 235000019439 ethyl acetate Nutrition 0.000 description 82
• 239000002904 solvent Substances 0.000 description 79
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 77
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 70
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 70
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
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