TWI718146B - 新穎的5-脂氧合酶啟動蛋白（ｆｌａｐ）抑制劑 - Google Patents

Info

Publication number

TWI718146B

TWI718146B TW105113757A TW105113757A TWI718146B TW I718146 B TWI718146 B TW I718146B TW 105113757 A TW105113757 A TW 105113757A TW 105113757 A TW105113757 A TW 105113757A TW I718146 B TWI718146 B TW I718146B

Authority

TW

Taiwan

Prior art keywords

methyl

pyrazol

reaction mixture

mmol

etoac

Prior art date

2015-05-04

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• 239000003112 inhibitor Substances 0.000 title description 6
• 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 title 1
• 108090000411 5-Lipoxygenase-Activating Proteins Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 367
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 113
• 150000003839 salts Chemical class 0.000 claims description 63
• 238000011282 treatment Methods 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 239000003814 drug Substances 0.000 claims description 12
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• 229940079593 drug Drugs 0.000 claims description 10
• 208000027866 inflammatory disease Diseases 0.000 claims description 9
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• 208000017169 kidney disease Diseases 0.000 claims description 7
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 6
• 238000002360 preparation method Methods 0.000 claims description 6
• 208000019553 vascular disease Diseases 0.000 claims description 5
• 230000002757 inflammatory effect Effects 0.000 claims description 4
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 4
• 230000009286 beneficial effect Effects 0.000 claims description 3
• 208000020832 chronic kidney disease Diseases 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
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• 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
• 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
• 206010037549 Purpura Diseases 0.000 claims description 2
• 241001672981 Purpura Species 0.000 claims description 2
• 206010065427 Reflux nephropathy Diseases 0.000 claims description 2
• 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
• 230000006806 disease prevention Effects 0.000 claims description 2
• 208000037765 diseases and disorders Diseases 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 201000005206 focal segmental glomerulosclerosis Diseases 0.000 claims description 2
• 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 claims description 2
• 231100000268 induced nephrotoxicity Toxicity 0.000 claims description 2
• 201000008383 nephritis Diseases 0.000 claims description 2
• 208000011580 syndromic disease Diseases 0.000 claims description 2
• 239000003053 toxin Substances 0.000 claims description 2
• 231100000765 toxin Toxicity 0.000 claims description 2
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• RHJVIGLEIFVHIJ-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1[CH]CCCC1 RHJVIGLEIFVHIJ-UHFFFAOYSA-N 0.000 claims 5
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• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 504
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• 235000019439 ethyl acetate Nutrition 0.000 description 252
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• PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 71
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 69
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 48
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• 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 44
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• 239000012044 organic layer Substances 0.000 description 43
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• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 34
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 32
• 239000002904 solvent Substances 0.000 description 31
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 29
• 238000000746 purification Methods 0.000 description 27
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• 239000003208 petroleum Substances 0.000 description 26
• 229910052757 nitrogen Inorganic materials 0.000 description 23
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• NEUWPDLMDVINSN-UHFFFAOYSA-N 1h-pyrazol-5-ylboronic acid Chemical compound OB(O)C=1C=CNN=1 NEUWPDLMDVINSN-UHFFFAOYSA-N 0.000 description 21
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
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• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
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• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
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