TW201238947A - Oxadiazole inhibitors of leukotriene production - Google Patents

Info

Publication number

TW201238947A

TW201238947A TW100129127A TW100129127A TW201238947A TW 201238947 A TW201238947 A TW 201238947A TW 100129127 A TW100129127 A TW 100129127A TW 100129127 A TW100129127 A TW 100129127A TW 201238947 A TW201238947 A TW 201238947A

Authority

TW

Taiwan

Prior art keywords

doc

group

alkyl

phenyl

etoac

Prior art date

2010-08-16

Links

• Espacenet
• Global Dossier
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• 150000002617 leukotrienes Chemical class 0.000 title claims description 22
• 238000004519 manufacturing process Methods 0.000 title claims description 3
• 239000003112 inhibitor Substances 0.000 title description 9
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 162
• 150000003839 salts Chemical class 0.000 claims abstract description 53
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
• 125000000217 alkyl group Chemical group 0.000 claims description 97
• -1 cyano, benzyl Chemical group 0.000 claims description 92
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
• 229910052739 hydrogen Inorganic materials 0.000 claims description 39
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
• 239000001257 hydrogen Substances 0.000 claims description 38
• 125000003545 alkoxy group Chemical group 0.000 claims description 32
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 25
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 23
• 201000010099 disease Diseases 0.000 claims description 22
• 150000002431 hydrogen Chemical group 0.000 claims description 21
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 19
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 18
• 239000000460 chlorine Substances 0.000 claims description 18
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• 125000002837 carbocyclic group Chemical group 0.000 claims description 16
• 125000001072 heteroaryl group Chemical group 0.000 claims description 16
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 229910052736 halogen Inorganic materials 0.000 claims description 14
• 150000002367 halogens Chemical class 0.000 claims description 14
• 125000004076 pyridyl group Chemical group 0.000 claims description 14
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 12
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 11
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 11
• 125000004429 atom Chemical group 0.000 claims description 10
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
• 150000002825 nitriles Chemical class 0.000 claims description 10
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 9
• 125000002757 morpholinyl group Chemical group 0.000 claims description 9
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
• NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 8
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
• 125000003282 alkyl amino group Chemical group 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
• 208000017169 kidney disease Diseases 0.000 claims description 6
• 230000001404 mediated effect Effects 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 5
• XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 5
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 239000000463 material Substances 0.000 claims description 5
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 229910052717 sulfur Chemical group 0.000 claims description 5
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 5
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 208000026935 allergic disease Diseases 0.000 claims description 4
• 125000002393 azetidinyl group Chemical group 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
• 125000005265 dialkylamine group Chemical group 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 230000003176 fibrotic effect Effects 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 4
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 4
• 229910052760 oxygen Inorganic materials 0.000 claims description 4
• 239000001301 oxygen Chemical group 0.000 claims description 4
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
• 239000011593 sulfur Chemical group 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• 125000000335 thiazolyl group Chemical group 0.000 claims description 4
• 208000019693 Lung disease Diseases 0.000 claims description 3
• 125000003277 amino group Chemical group 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 125000001246 bromo group Chemical group Br* 0.000 claims description 3
• 201000011510 cancer Diseases 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
• 230000002757 inflammatory effect Effects 0.000 claims description 3
• 239000000126 substance Substances 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
• 206010038389 Renal cancer Diseases 0.000 claims description 2
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 239000011737 fluorine Chemical group 0.000 claims description 2
• 229910052731 fluorine Chemical group 0.000 claims description 2
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
• 201000010982 kidney cancer Diseases 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 229960005181 morphine Drugs 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 125000001424 substituent group Chemical group 0.000 claims description 2
• 238000006467 substitution reaction Methods 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
• XYNBEQAWBCGIMD-UHFFFAOYSA-N 1,4-dihydropyrazine Chemical group N1C=CNC=C1 XYNBEQAWBCGIMD-UHFFFAOYSA-N 0.000 claims 1
• AHEKENQPEQYCMG-UHFFFAOYSA-N 1-methyl-1,3-diazinane Chemical group CN1CCCNC1 AHEKENQPEQYCMG-UHFFFAOYSA-N 0.000 claims 1
• LUMNWCHHXDUKFI-UHFFFAOYSA-N 5-bicyclo[2.2.1]hept-2-enylmethanol Chemical group C1C2C(CO)CC1C=C2 LUMNWCHHXDUKFI-UHFFFAOYSA-N 0.000 claims 1
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 1
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 1
• 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
• DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims 1
• 125000004122 cyclic group Chemical group 0.000 claims 1
• 125000006612 decyloxy group Chemical group 0.000 claims 1
• 150000001993 dienes Chemical class 0.000 claims 1
• 125000005843 halogen group Chemical group 0.000 claims 1
• 239000004615 ingredient Substances 0.000 claims 1
• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 1
• 125000006085 pyrrolopyridyl group Chemical group 0.000 claims 1
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 1
• 229930192474 thiophene Natural products 0.000 claims 1
• 239000000543 intermediate Substances 0.000 abstract description 94
• 238000000034 method Methods 0.000 abstract description 92
• 230000008569 process Effects 0.000 abstract description 4
• 208000037765 diseases and disorders Diseases 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 338
• 235000019439 ethyl acetate Nutrition 0.000 description 174
• 239000000203 mixture Substances 0.000 description 121
• 238000006243 chemical reaction Methods 0.000 description 92
• 230000015572 biosynthetic process Effects 0.000 description 87
• 238000003786 synthesis reaction Methods 0.000 description 85
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 83
• 239000000243 solution Substances 0.000 description 79
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 69
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 67
• 239000011541 reaction mixture Substances 0.000 description 61
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
• 206010057190 Respiratory tract infections Diseases 0.000 description 53
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 48
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• 239000003153 chemical reaction reagent Substances 0.000 description 34
• 239000002585 base Substances 0.000 description 29
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 26
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 23
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
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• 239000000725 suspension Substances 0.000 description 19
• 239000012267 brine Substances 0.000 description 18
• 101710187011 Arachidonate 5-lipoxygenase-activating protein Proteins 0.000 description 16
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• 239000002904 solvent Substances 0.000 description 16
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• 239000012044 organic layer Substances 0.000 description 15
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• 239000002253 acid Substances 0.000 description 14
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• 239000000706 filtrate Substances 0.000 description 12
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