AU2011292285A1 - Oxadiazole inhibitors of leukotriene production - Google Patents

Info

Publication number

AU2011292285A1

AU2011292285A1 AU2011292285A AU2011292285A AU2011292285A1 AU 2011292285 A1 AU2011292285 A1 AU 2011292285A1 AU 2011292285 A AU2011292285 A AU 2011292285A AU 2011292285 A AU2011292285 A AU 2011292285A AU 2011292285 A1 AU2011292285 A1 AU 2011292285A1

Authority

AU

Australia

Prior art keywords

pct

alkyl

oxadiazol

phenyl

methyl

Prior art date

2010-08-16

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• 150000002617 leukotrienes Chemical class 0.000 title claims description 23
• 239000003112 inhibitor Substances 0.000 title description 12
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 title description 7
• 238000004519 manufacturing process Methods 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims abstract description 192
• 150000003839 salts Chemical class 0.000 claims abstract description 50
• -1 -O-benzyl Chemical group 0.000 claims description 247
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 131
• 125000000217 alkyl group Chemical group 0.000 claims description 107
• 238000000034 method Methods 0.000 claims description 91
• 229910052757 nitrogen Inorganic materials 0.000 claims description 76
• 229910052739 hydrogen Inorganic materials 0.000 claims description 50
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 47
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 239000001257 hydrogen Substances 0.000 claims description 39
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
• 125000003545 alkoxy group Chemical group 0.000 claims description 34
• 125000000623 heterocyclic group Chemical group 0.000 claims description 27
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
• 150000002431 hydrogen Chemical class 0.000 claims description 23
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 22
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
• 229910052736 halogen Inorganic materials 0.000 claims description 19
• 150000002367 halogens Chemical class 0.000 claims description 19
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 125000002757 morpholinyl group Chemical group 0.000 claims description 17
• 125000004193 piperazinyl group Chemical group 0.000 claims description 17
• 125000003386 piperidinyl group Chemical group 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• 125000004043 oxo group Chemical group O=* 0.000 claims description 16
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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 14
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 13
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 13
• 125000004076 pyridyl group Chemical group 0.000 claims description 13
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
• 201000010099 disease Diseases 0.000 claims description 10
• 125000005843 halogen group Chemical group 0.000 claims description 10
• 150000002825 nitriles Chemical class 0.000 claims description 10
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
• 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 9
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
• 125000002883 imidazolyl group Chemical group 0.000 claims description 9
• 230000001404 mediated effect Effects 0.000 claims description 9
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
• 125000000335 thiazolyl group Chemical group 0.000 claims description 9
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
• 229910052717 sulfur Chemical group 0.000 claims description 8
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
• 201000001320 Atherosclerosis Diseases 0.000 claims description 7
• 125000002393 azetidinyl group Chemical group 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 7
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
• 125000002971 oxazolyl group Chemical group 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
• 230000000172 allergic effect Effects 0.000 claims description 6
• 208000010668 atopic eczema Diseases 0.000 claims description 6
• 230000003176 fibrotic effect Effects 0.000 claims description 6
• 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 6
• 230000002757 inflammatory effect Effects 0.000 claims description 6
• 229910052740 iodine Inorganic materials 0.000 claims description 6
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
• 229910052760 oxygen Inorganic materials 0.000 claims description 6
• 239000001301 oxygen Chemical group 0.000 claims description 6
• 230000002685 pulmonary effect Effects 0.000 claims description 6
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
• 125000003282 alkyl amino group Chemical group 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 125000001246 bromo group Chemical group Br* 0.000 claims description 5
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
• 125000002541 furyl group Chemical group 0.000 claims description 5
• 208000017169 kidney disease Diseases 0.000 claims description 5
• 125000003566 oxetanyl group Chemical group 0.000 claims description 5
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
• 239000011593 sulfur Chemical group 0.000 claims description 5
• 125000001544 thienyl group Chemical group 0.000 claims description 5
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 5
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 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
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
• 206010038389 Renal cancer Diseases 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 201000010982 kidney cancer Diseases 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 125000001425 triazolyl group Chemical group 0.000 claims description 3
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
• 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 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
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• SSURCGGGQUWIHH-UHFFFAOYSA-N NNON Chemical compound NNON SSURCGGGQUWIHH-UHFFFAOYSA-N 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 208
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 164
• 239000000543 intermediate Substances 0.000 description 130
• 239000000203 mixture Substances 0.000 description 121
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 113
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 100
• 230000015572 biosynthetic process Effects 0.000 description 90
• 238000003786 synthesis reaction Methods 0.000 description 90
• 238000006243 chemical reaction Methods 0.000 description 87
• 239000000243 solution Substances 0.000 description 83
• 235000019439 ethyl acetate Nutrition 0.000 description 79
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 68
• 239000011541 reaction mixture Substances 0.000 description 64
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
• 238000003818 flash chromatography Methods 0.000 description 58
• 239000011734 sodium Substances 0.000 description 58
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
• 239000000460 chlorine Substances 0.000 description 55
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 52
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
• 239000003153 chemical reaction reagent Substances 0.000 description 40
• 229910004298 SiO 2 Inorganic materials 0.000 description 34
• 239000007787 solid Substances 0.000 description 34
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
• 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 30
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 25
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• 239000000741 silica gel Substances 0.000 description 24
• 229910002027 silica gel Inorganic materials 0.000 description 24
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• 101000755875 Homo sapiens Arachidonate 5-lipoxygenase-activating protein Proteins 0.000 description 21
• 229920006395 saturated elastomer Polymers 0.000 description 21
• 239000002904 solvent Substances 0.000 description 21
• 102100022278 Arachidonate 5-lipoxygenase-activating protein Human genes 0.000 description 20
• 125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 description 19
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
• 239000000706 filtrate Substances 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 16
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 16
• 239000000725 suspension Substances 0.000 description 16
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
• 239000002585 base Substances 0.000 description 14
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 14
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 13
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 13
• 239000002253 acid Substances 0.000 description 13
• 150000001412 amines Chemical class 0.000 description 13
• 239000000047 product Substances 0.000 description 13
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
• 239000003480 eluent Substances 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• BPQVMIDUTRJYSC-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN=C(N)N=C1 BPQVMIDUTRJYSC-UHFFFAOYSA-N 0.000 description 10
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 10
• 238000001914 filtration Methods 0.000 description 10
• 230000014759 maintenance of location Effects 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
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• 239000013543 active substance Substances 0.000 description 9
• 238000000746 purification Methods 0.000 description 9
• 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 8
• 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 8
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
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• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 8
• 238000002953 preparative HPLC Methods 0.000 description 8
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
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• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
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• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 5
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