WO2011028596A1 - Chemical compounds - Google Patents
Chemical compounds Download PDFInfo
- Publication number
- WO2011028596A1 WO2011028596A1 PCT/US2010/046782 US2010046782W WO2011028596A1 WO 2011028596 A1 WO2011028596 A1 WO 2011028596A1 US 2010046782 W US2010046782 W US 2010046782W WO 2011028596 A1 WO2011028596 A1 WO 2011028596A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- mmol
- imidazol
- carbonyl
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 156
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 27
- 208000015181 infectious disease Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 87
- 125000003003 spiro group Chemical group 0.000 claims description 16
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 14
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 208000036142 Viral infection Diseases 0.000 claims description 7
- 230000009385 viral infection Effects 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 239000001257 hydrogen Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000011737 fluorine Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims 1
- 229940126543 compound 14 Drugs 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 165
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 143
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 104
- 238000006243 chemical reaction Methods 0.000 description 103
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 102
- 239000000243 solution Substances 0.000 description 81
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 64
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 63
- 239000007787 solid Substances 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 61
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 51
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 51
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 50
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 34
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- 241000711549 Hepacivirus C Species 0.000 description 28
- 239000000203 mixture Substances 0.000 description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 25
- 239000003921 oil Substances 0.000 description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 239000007821 HATU Substances 0.000 description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 239000010410 layer Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000005695 Ammonium acetate Substances 0.000 description 15
- 229940043376 ammonium acetate Drugs 0.000 description 15
- 235000019257 ammonium acetate Nutrition 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 14
- 239000012267 brine Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- CEFVHPDFGLDQKU-YFKPBYRVSA-N (2s)-2-(methoxycarbonylamino)-3-methylbutanoic acid Chemical compound COC(=O)N[C@@H](C(C)C)C(O)=O CEFVHPDFGLDQKU-YFKPBYRVSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 229960000329 ribavirin Drugs 0.000 description 8
- UYTDNJCFAGYWSM-AWEZNQCLSA-N 6-o-benzyl 7-o-ethyl (7s)-2,2-difluoro-6-azaspiro[3.4]octane-6,7-dicarboxylate Chemical compound C([C@H](N(C1)C(=O)OCC=2C=CC=CC=2)C(=O)OCC)C21CC(F)(F)C2 UYTDNJCFAGYWSM-AWEZNQCLSA-N 0.000 description 7
- 102000006992 Interferon-alpha Human genes 0.000 description 7
- 108010047761 Interferon-alpha Proteins 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- -1 hexafluorophosphate Chemical compound 0.000 description 7
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- CNWMWGLCXVNBAS-GOSISDBHSA-N (2S)-2-[[2-(4-bromophenyl)-2-oxoethyl]carbamoyl]-2-tert-butylpyrrolidine-1-carboxylic acid Chemical compound C=1C=C(Br)C=CC=1C(=O)CNC(=O)[C@@]1(C(C)(C)C)CCCN1C(O)=O CNWMWGLCXVNBAS-GOSISDBHSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- NHGMMPUNSLXQHZ-WYBXAQPNSA-N Cl.Cl.COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C(=O)CN)=CN1 Chemical compound Cl.Cl.COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C=2C=CC(=CC=2)C(=O)CN)=CN1 NHGMMPUNSLXQHZ-WYBXAQPNSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 6
- 239000012458 free base Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- XRFKZAWVKVORNI-LBPRGKRZSA-N 1-o-benzyl 2-o-methyl (2s)-4-oxopyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1CC(=O)CN1C(=O)OCC1=CC=CC=C1 XRFKZAWVKVORNI-LBPRGKRZSA-N 0.000 description 5
- ZQFATRVLQKIVTH-UHFFFAOYSA-N 2-amino-1-(4-bromophenyl)ethanone Chemical compound NCC(=O)C1=CC=C(Br)C=C1 ZQFATRVLQKIVTH-UHFFFAOYSA-N 0.000 description 5
- RTSLQVZQORGDQQ-UHFFFAOYSA-N 2-bromo-1-[4-[4-(2-bromoacetyl)phenyl]phenyl]ethanone Chemical compound C1=CC(C(=O)CBr)=CC=C1C1=CC=C(C(=O)CBr)C=C1 RTSLQVZQORGDQQ-UHFFFAOYSA-N 0.000 description 5
- 0 CC(*)(C(*)(*)CC1c2ncc(-c(cc3)ccc3-c(cc3)ccc3-c3cnc(C(CC(*)(*)C4(C)*)N4C(C(*)NC(O*)=O)=O)[n]3)[n]2)N1C(C(*)NC(O*)=O)=O Chemical compound CC(*)(C(*)(*)CC1c2ncc(-c(cc3)ccc3-c(cc3)ccc3-c3cnc(C(CC(*)(*)C4(C)*)N4C(C(*)NC(O*)=O)=O)[n]3)[n]2)N1C(C(*)NC(O*)=O)=O 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DELCNAKCLRAMPX-DHLKQENFSA-N [2-[4-[4-(2-bromoacetyl)phenyl]phenyl]-2-oxoethyl] (2s)-1-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carboxylate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)OCC(=O)C1=CC=C(C=2C=CC(=CC=2)C(=O)CBr)C=C1 DELCNAKCLRAMPX-DHLKQENFSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- QXZSSQNYUNNRJG-UHFFFAOYSA-N ethyl 8-oxa-1-azaspiro[4.5]decane-2-carboxylate Chemical compound N1C(C(=O)OCC)CCC11CCOCC1 QXZSSQNYUNNRJG-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 108010076039 Polyproteins Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- PDSARLAMTJYZPL-YVYLOCOQSA-N [2-[4-[4-[2-[(2s)-1-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]oxyacetyl]phenyl]phenyl]-2-oxoethyl] (7s)-2,2-difluoro-6-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]-6-azaspiro[3.4]octane-7-carboxylate Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)OCC(=O)C1=CC=C(C=2C=CC(=CC=2)C(=O)COC(=O)[C@H]2N(CC3(CC(F)(F)C3)C2)C(=O)[C@@H](NC(=O)OC)C(C)C)C=C1 PDSARLAMTJYZPL-YVYLOCOQSA-N 0.000 description 4
- ZXOBITBSWLNEDL-UHFFFAOYSA-N ethyl 1-acetyl-8-oxa-1-azaspiro[4.5]decane-2-carboxylate Chemical compound CC(=O)N1C(C(=O)OCC)CCC11CCOCC1 ZXOBITBSWLNEDL-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- WVDLFOBBAVELAQ-ROZOJAHRSA-N methyl n-[(2s)-1-[(3s,7s,9s)-3-[5-[4-[4-[2-[(3s,7s,9s)-2-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]-7,9-dimethyl-6,10-dioxa-2-azaspiro[4.5]decan-3-yl]-1h-imidazol-5-yl]phenyl]phenyl]-1h-imidazol-2-yl]-7,9-dimethyl-6,10-dioxa-2-azaspiro[4.5]decan-2-y Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=CC(=CC=2)C=2C=CC(=CC=2)C=2NC(=NC=2)[C@H]2N(CC3(C2)O[C@@H](C)C[C@H](C)O3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21O[C@@H](C)C[C@H](C)O2 WVDLFOBBAVELAQ-ROZOJAHRSA-N 0.000 description 4
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- FLXDSCXAVOHNBG-ZDUSSCGKSA-N (3s)-2-phenylmethoxycarbonyl-6,10-dioxa-2-azaspiro[4.5]decane-3-carboxylic acid Chemical compound C([C@H](N(C1)C(=O)OCC=2C=CC=CC=2)C(=O)O)C21OCCCO2 FLXDSCXAVOHNBG-ZDUSSCGKSA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- CZJQHBDBZNUPBE-LOACHALJSA-N 2-[(2s)-2-(methoxycarbonylamino)-3-methylbutanoyl]-8-[(2-methylpropan-2-yl)oxycarbonyl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)[C@H](C(C)C)NC(=O)OC)CC21CCN(C(=O)OC(C)(C)C)CC2 CZJQHBDBZNUPBE-LOACHALJSA-N 0.000 description 3
- KOMVOYYLVLKMLS-INIZCTEOSA-N 2-o-benzyl 3-o-ethyl (3s)-8-oxa-2-azaspiro[4.5]decane-2,3-dicarboxylate Chemical compound C([C@H](N(C1)C(=O)OCC=2C=CC=CC=2)C(=O)OCC)C21CCOCC2 KOMVOYYLVLKMLS-INIZCTEOSA-N 0.000 description 3
- IHHSNQUDYNAHSC-AWEZNQCLSA-N 2-o-benzyl 3-o-methyl (3s)-6,10-dioxa-2-azaspiro[4.5]decane-2,3-dicarboxylate Chemical compound C([C@H](N(C1)C(=O)OCC=2C=CC=CC=2)C(=O)OC)C21OCCCO2 IHHSNQUDYNAHSC-AWEZNQCLSA-N 0.000 description 3
- SLXLDVSCBKHICP-UHFFFAOYSA-N 2-o-tert-butyl 6-o-ethyl 2,7-diazaspiro[3.4]octane-2,6-dicarboxylate Chemical compound C1NC(C(=O)OCC)CC11CN(C(=O)OC(C)(C)C)C1 SLXLDVSCBKHICP-UHFFFAOYSA-N 0.000 description 3
- QVBAWLJSUSKNHM-UHFFFAOYSA-N 6-o-benzyl 7-o-ethyl 2-hydroxy-6-azaspiro[3.4]octane-6,7-dicarboxylate Chemical compound C1N(C(=O)OCC=2C=CC=CC=2)C(C(=O)OCC)CC21CC(O)C2 QVBAWLJSUSKNHM-UHFFFAOYSA-N 0.000 description 3
- GJAGNTOMDAXWQH-UHFFFAOYSA-N 6-o-benzyl 7-o-ethyl 2-oxo-6-azaspiro[3.4]octane-6,7-dicarboxylate Chemical compound C1N(C(=O)OCC=2C=CC=CC=2)C(C(=O)OCC)CC21CC(=O)C2 GJAGNTOMDAXWQH-UHFFFAOYSA-N 0.000 description 3
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 3
- 206010019663 Hepatic failure Diseases 0.000 description 3
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- XAYBFASIKQZINL-UHFFFAOYSA-N ethyl 8-[tert-butyl(dimethyl)silyl]oxy-2-azaspiro[4.5]decane-3-carboxylate Chemical compound C1NC(C(=O)OCC)CC21CCC(O[Si](C)(C)C(C)(C)C)CC2 XAYBFASIKQZINL-UHFFFAOYSA-N 0.000 description 1
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- LFAGQMCIGQNPJG-UHFFFAOYSA-N silver cyanide Chemical compound [Ag+].N#[C-] LFAGQMCIGQNPJG-UHFFFAOYSA-N 0.000 description 1
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- JYUQEWCJWDGCRX-UHFFFAOYSA-N tert-butyl 4-formylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C=O)CC1 JYUQEWCJWDGCRX-UHFFFAOYSA-N 0.000 description 1
- ATQJBOSFTLBQHM-UHFFFAOYSA-N tert-butyl n-[2-oxo-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate Chemical compound C1=CC(C(=O)CNC(=O)OC(C)(C)C)=CC=C1B1OC(C)(C)C(C)(C)O1 ATQJBOSFTLBQHM-UHFFFAOYSA-N 0.000 description 1
- QAJMGOWQTHRWPL-UHFFFAOYSA-N tert-butyl-[2-oxo-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamic acid Chemical compound C1=CC(C(=O)CN(C(C)(C)C)C(O)=O)=CC=C1B1OC(C)(C)C(C)(C)O1 QAJMGOWQTHRWPL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present disclosure relates to antiviral compounds.
- the present disclosure relates to compounds useful for the treatment of hepatitis C virus (HCV) infection, crystalline salts of the compounds, pharmaceutical compositions comprising the compounds, and methods for treating HCV infection.
- HCV hepatitis C virus
- Chronic infection with HCV is a major health problem associated with liver cirrhosis, hepatocellular carcinoma and liver failure.
- An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al., Pat ol.Oncol.Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997 ' , 26:15S-20S.
- In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
- HCV Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. Liver cirrhosis can ultimately lead to liver failure. Liver failure resulting from chronic HCV infection is now recognized as a leading cause of liver transplantation.
- HCV is a member of the Flaviviridae family of RNA viruses that affect animals and humans.
- the genome is a single ⁇ 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
- the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
- the organization of structural and nonstructural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a- NS4b-NS5a-NS5b.
- HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes. See, for example, Thomson BJ and Finch RG, Clin Microbial Infect. 2005, 1 1 :86-94, and Moriishi K and Matsuura Y, Antivir.Chem.Chemother. 2003, 14:285-297.
- IFN- alpha interferon alpha
- ribavirin the standard treatment for chronic HCV.
- IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.
- IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control.
- a number of approaches are being pursued to combat the virus. They include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
- the viral targets the NS3/4A protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. See, for example, Ni, Z. J. and Wagman, A. S. Curr. Opin. Drug Discov. Devel. 2004, 7, 446-459, Beaulieu, P. L. and Tsantrizos, Y. S. Curr. Opin. Investig. Drugs 2004, 5, 838-850, and Griffith, et al. , Ann. Rep. Med. Chem 39, 223-237, 2004.
- antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication.
- host cell proteins that are necessary for viral replication.
- Watashi, et al, Molecular Cell, 19, 1 1 1 - 122, 2005 show how antiviral activity can be achieved by inhibiting host cell cyclophilins.
- a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans. See, Horsmans, et al, Hepatology, 42, 724-731 , 2005.
- each R is independently H or Ci each R 2 is independently Ci -3 alkyl;
- each X is independently CRR, O, or S;
- n 2 or 3;
- each R is independently methyl, hydrogen, or deuterium.
- the present invention discloses compounds of Formula II;
- each R 1 is independently H or Ci_ 3 alkyl
- each R 2 is independently Ci -3 alkyl
- each X is independently CRR, O, or S;
- each n is independently 2 or 3;
- each R is independently methyl, hydrogen, or deuterium.
- each R 1 is independently H or Ci_ 3 alkyl
- each R 2 is independently Ci -3 alkyl
- each saturated spiro formed from R 3 groups is independently cycloalkyl, or may contain 1 or 2 oxygen atoms, or 1 or 2 sulfur atoms, or 1 S0 2 , or 1 NR 4 ;
- each R 4 is independently H, C(0)OCi_ 4 alkyl, C(0)d_ 4 alkyl, C(0)NCi_ 4 alkyl, or S0 2 Ci.
- each spiro ring may optionally be substituted with deuterium, fluorine, or 1 or 2 methyl groups.
- the present invention discloses pharmaceutically acceptable salts of the compounds of Formula I, II, or III.
- the present invention discloses pharmaceutical compositions comprising a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof.
- the present invention discloses a method for treating a viral infection, for example infection with HCV, in a human, comprising administration of a pharmaceutical composition of the invention.
- the compounds can exist in various enantiomeric mixtures.
- the compounds of Formula I, II, or III, or pharmaceutically acceptable salts thereof are enantiomerically enriched with the enantiomer wherein all of the chiral carbons referred to in the previous paragraph are in the S configuration.
- reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
- An example of a compound with four chiral carbons in S configuration is illustrated below.
- each X is identical.
- D deuterium
- every CRR group in the spiro is CH 2 or every CRR group in the spiro is CD 2 .
- Deuterium is naturally present in very small amounts in hydrogen compounds. By designating a substituent as deuterium or D, applicants mean that the natural isotopic amount of deuterium has been increased so that more that half of that particular substituent is D as compared to H.
- no more than 2 Rs are methyl.
- each of said spiro groups is bonded to the same relative carbon atom in each saturated nitrogen containing ring.
- salts can be prepared by methods well known in the art. Suitable salts include those described, for example, in P. Heinrich Stahl, Camille G. Wermuth (eds.), handbook of Pharmaceutical Salts properties, selection, and Use; 2002. See also, WO 2009/020828 (Kimet. Al), which describes the preparation of crystalline salts of certain anti-viral compounds. Preferred salts include HCI salts, for example a di-HCI salt, and sulphate salts.
- the compounds and salts of the invention may be used alone or in combination with one or more other therapeutic agents.
- the further therapeutic agent is selected from Standard of Care therapies such as
- interferon/ribavarin, small molecule HCV replication inhibitors (more commonly referred to as direct acting antivirals.
- Suitable combination therapies are described, for example in WO 2008/064218 (Leivers et. al), WO 2008/244380 (Bachand et. al), and US 2009/0068140 (Bachand et. al). These references also contain significant disclosure regarding routes of administration, and other information regarding how to make, formulate, and use the compounds.
- Pd(dppf)CI 2 (2.6 g 3.18mmol) was added to a mixture of 1 ,1-dimethylethyl [2- (4-bromophenyl)-2-oxoethyl]carbamate (Intermediate 5) (20g , 63.7mmol), bis(pinacolato)diboron (19.4g, 76.4mmol) and KOAc (24.8g, 0.254mol) in dioxane (300ml_), the flask was purged with nitrogen (3x) and heated to 80 °C for 16 hrs under nitrogen atmosphere.
- Methyl N-[(methyloxy)carbonyl]-L-valyl-4-oxo-L-prolinate (Intermediate 13) (650mg, 2.164mmol), (2S,4S)-2,4-pentanediol (902mg, 8.66mmol) and TsOH (82mg, 0.43mmol) were heated to reflux in toluene (40ml_) with Dean Stark trap overnight. After cooled down to rt and diluted with ethyl acetate, the resulting solution was washed with NaHC0 3 (ss) and brine. The organic later was dried over MgS04, filtered and evaporated.
- Example 2 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(8S)-7-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-1 ,4-dioxa-7-azaspiro[4.4lnon-8-yll-1 /-/- imidazol-4-yl ⁇ -4-biphenylyl)-1 /-/-imidazol-2-yl]-1 -
- Example 3 dimethyl (4,4'-biphenyldiylbis ⁇ 1 /-/-imidazole-4,2-diyl[(3S,7S,9S)-7,9- dimethyl-6,10-dioxa-2-azaspiro[4.5ldecane-3,2-diyllf(2S)-3-methyl-1-oxo-1 ,2-
- Example 4 dimethyl (4,4'-biphenyldiylbis ⁇ 1 H-imidazole-4,2-diyl(8S)-1 ,4-dioxa-7- zaspiro[4.4lnonane-8,7-diyl[(2S)-3-methyl-1-oxo-1 ,2-butanediyll))biscarbamate
- Example 5 methyl ((1 S)-1-methyl-2-((3S)-3-[4-(4'-(2-[(2S)-1-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-2-pyrrolidinyll-1 /-/-imidazol-4-yl)-4-biphenylyl)- -/-imidazol-2-yll-6, 10-dioxa-2-azaspiro[4.51dec-2- -2-oxoethyl)carbamate
- Example 6 methyl [(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(3S)-2-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyl1amino ⁇ butanoyl)-6, 10-dioxa-2-azaspiro[4.51dec-3-yl1-1 H- imidazol-4-yl)-4-biphenylyl)-1 H-imidazol-2- ⁇ - ⁇ - rrolidinvDcarbonyDpropyllcarbamate
- Example 7 methyl [(1 S)-1 -(((2S)-2-[4-(4'-(2-[(3S)-8.8-dimethyl-2-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyl]amino ⁇ butanoyl)-6, 10-dioxa-2-azaspiro[4.5ldec-3-yl]-1 A7- imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1 -pyrrolidinyl)carbonyl)-2- methylpropyllcarbamate
- Example 8 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(3S)-2-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-6, 10-dioxa-2-azaspiro[4.5ldec-3-yll-1 H- imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1 - Pyrrolidinyl)carbonyl)propyllcarbamate-c
- Example 9 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(8S)-7-((2S)-3-methyl-2-
- Example 10 methyl f(1 S)-1 -(((2S)-2-[4-(4'-(2-[(2R.3R.8S)-2.3-dimethyl-7-((2S)-3- methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-1 ,4-dioxa-7-azaspiro[4.41non-8-yll- 1 /-/-imidazol-5-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1 -pyrrolidinyl)carbonyl)-2- methylpropyllcarbamate
- Example 1 1 methyl f(1 S)-1 -(((2S)-2-[4-(4'-(2-[(2S.3S.8S)-2.3-dimethyl-7-((2S)-3- methyl-2- ⁇ [(methyloxy)carbonyl]amino ⁇ butanoyl)-1 ,4-dioxa-7-azaspiro[4.4]non-8-yl1- 1 H-imidazol-5-yl)-4-biphenylyl)-1 H-imidazo
- Example 12 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(8S)-7-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-1 ,4-dithia-7-azaspiro[4.4lnon-8-yll-1 /-/- imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1 -
- Example 13 methyl[(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(8S)-7-((2S)-2-([(methyloxy) carbonyl1amino ⁇ butanoyl)-1 ,4-dithia-7-azaspiro[4.41non-8-yl1-1 H-imidazol-4-yl ⁇ -4-
- Example 14 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(8S)-7- ( ⁇ [(methyloxy)carbonyll amino)acetyl)-1 ,4-dithia-7-azaspiro[4.4lnon-8-yll-1 /-/-imidazol- 4-yl ⁇ -4-biphenylyl)-1 /-/-imidazol-2-yl1-1-pyrrolidinyl ⁇ carbonyl)propyl1carbamate
- Example 15 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[2-((2S)-3-methyl-2-
- Example 16 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[2-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-8,8-dioxido-8-thia-2-azaspiro[4.51dec-3-yll- 1 /-/-imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1-
- Example 17 methyl [(1 S)-1 -(((2S)-2-[4-(4'-(2-[8.8-difluoro-2-((2S)-3-methyl-2-
- Solvent volume was then reduced in vacuo to ⁇ 100ml_ and cooled to 20°C. 100ml_ of water was slowly added and resulting slight grey-yellow solid was filtered and washed with water (200ml_), hexane (200ml_) and dried under the vacuum (12h).
- the reaction was partitioned between EtOAc and water (250 mL) each, the organic layer was separated and washed with saturated NaHC0 3 (100 mL) and dried (MgS0 4 ) and concentrated in vacuo.
- the reaction was found to be incomplete by TLC.
- the residue was dissolved in dry THF (60 mL), cooled to 0 °C and treated with HF-pyridine (1.6 mL, 18.0 mmol), warmed to room temperature and stirred for 2 h under nitrogen.
- the reaction was poured into saturated NaHC0 3 (100 mL) and solid potassium carbonate was added until gas evolution ceased.
- Example 18 dimethyl (4,4'-biphenyldiylbis ⁇ 1 /-/-imidazole-4,2-diyl(3S)-8-oxa-2-
- Example 19 1 , 1 -dimethylethyl 2-(A/-[(methyloxy)carbonyll-L-valyl)-3-(4-(4'-[2-((2S)-1 -
- This compound was obtained as a racemate from 1 ,1-dimethylethyl 4-formyl- 1-piperidinecarboxylate following the procedure outlined in WO 98/08850 pp. 50.
- Example 20 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[2-((2S)-3-methyl-2-
- Example 22 methyl 2-(A/-[(methyloxy)carbonyll-L-valyl)-3-(4-(4'-[2-((2S)-1-(A/-
- Example 23 1 ,1-dimethylethyl 6-(A/-[(methyloxy)carbonyll-L-valyl)-7-(4-(4'-[2-((2S)-1-
- Example 24 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[6-((2S)-3-methyl-2-
- This compound was prepared in an analogous fashion to Example 20 from 1 ,1-dimethylethyl 6- ⁇ N-[(methyloxy)carbonyl]-L-valyl ⁇ -7-(4- ⁇ 4'-[2-((2S)-1- ⁇ N- [(methyloxy)carbonyl]-L-valyl ⁇ -2-pyrrolidinyl)-1 /-/-imidazol-4-yl]-4-biphenylyl ⁇ -1 /-/- imidazol-2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate (298 mg, 0.34 mmol) to afford the title compound as a yellow solid (203 mg, 77% yield).
- Example 25 methyl [(1 S)-1 -(((2S)-2-[4-(4'-(2-[2-acetyl-6-((2S)-3-methyl-2-
- Example 26 methyl 6-(A/-[(methyloxy)carbonyll-L-valyl)-7-(4-(4'-[2-((2S)-1-(A/-
- Example 27 methyl [(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[(methylamino)carbonyll-6- ((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-2,6-diazaspiro[3.41oct-7-yll- 1 /-/-imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1-
- Example 28 methyl f(1 S)-2-methyl-1 -(((2S)-2-[4-(4'-(2-[6-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyl1amino ⁇ butanoyl)-2-(methylsulfonyl)-2,6-diazaspiro[3.41oct-7-yl1- 1 /-/-imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1 - pyrrolidinvDcarbonvDpropyllcarbamate
- Example 29 methyl [(1 S)-1 -(((2S)-2-[4-(4'-(2-[(7S)-2.2-difluoro-6-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-6-azaspiro[3.4loct-7-yll-1 /-/-imidazol-4-yl)-4-
- Example 30 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[1-((2S)-3-methyl-2- ⁇ [(methyloxy)carbonyllamino)butanoyl)-8-oxa-1-azaspiro[4.5ldec-2-yll-1 /-/-imidazol-4- -4-biphenylyl)-1 /-/-imidazol-2-yll-1-pyrrolidinyl)carbonyl)propyll carbamate
- Intermedaite 163 ethyl 2-amino-4-(tetrahvdro-4/-/-pyran-4-ylidene)butanoate
- Example 31 methyl ((1 S)-1-([(2S)-2-(4-(4'-[2-(1-acetyl-8-oxa-1-azaspiro[4.5ldec-2- vD-1 /-/-imidazol-4-yll-4-biphenylyl)-1 /-/-imidazol-2-yl)-1 -pyrrolidinyllcarbonyl)-2-
- This compound was prepared in an analogous fashion to 169 from 1-acetyl-8- oxa-1-azaspiro[4.5]decane-2-carboxylic acid (171 ) (56 mg, 0.25 mmol) and methyl ⁇ (1 S)-1-[((2S)-2- ⁇ 4-[4'-(aminoacetyl)-4-biphenylyl]-1 H-imidazol-2-yl ⁇ -1- pyrrolidinyl)carbonyl]-2-methylpropyl ⁇ carbamate dihydrochloride (1 ) (142 mg, 0.25 mmol) to afford the title compound as an off-white solid (1 18 mg, 67% yield).
- Examples 32 to 37 were prepared, using the synthetic sequence similar to Examples 30 and 31.
- Example 32 methyl [(1 S)-1 -(((2S)-2-[4-(4'-(2-[8.8-difluoro-1 -((2S)-3-methyl-2- ⁇ [(methyloxy) carbonyllamino)butanoyl)-1-azaspiro[4.5ldec-2-yll-1 /-/-imidazol-4-yl)-4-
- Example 34 methyl ((1 S)-2-(8.8-difluoro-2-[4-(4'-(2-[(2S)-1-((2S)-3-methyl-2- ⁇ [(methyloxy) carbonyl1amino ⁇ butanoyl)-2-pyrrolidinyl1-1 /-/-imidazol-4-yl ⁇ -4- biphenylvD-1 /-/-imidazol-2-yll-1 -azaspiro[4.5ldec-1 -yl)-1 -methyl-2-
- Example 36 methyl «1 S I-ir ⁇ S ⁇ - ⁇ -n-acetyl-S.S-difluoro-l-
- Example 37 methyl f(1 S)-2-methyl-1-(((2S)-2-[4-(4'-(2-[1-((2S)-3-methyl-2- ⁇ [(methyloxy) carbonyllamino)butanoyl)-8,8-dioxido-8-thia-1-azaspiro[4.5ldec-2-yll- 1 /-/-imidazol-4-yl)-4-biphenylyl)-1 /-/-imidazol-2-yll-1- Pyrrolidinyl)carbonyl)propyllcarbamate
- the ET cell line is stably transfected with RNA transcripts harboring a l 389 luc-ubi-neo/NS3-37ET replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV- IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I; K1846T) ⁇ Krieger at al, 2001 and unpublished).
- the genotype 1 a replicon is a stable cell line licensed from Apath LLC, modified to contain the firefly luciferase gene.
- the cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM Glutamine, Penicillin (100 IU/mL)/Streptomycin (100 ⁇ g/mL), 1x nonessential amino acids, and 250-500 ⁇ g/mL G418 ("Geneticin"). They were all available through Life Technologies (Bethesda, Md.). The cells were plated at 5 x 10 3 cells/well in 384 well plates containing compounds. The final concentration of compounds ranged between 0.03 pM to 50 ⁇ and the final DMSO concentration of 0.5-1 %.
- Luciferase activity was measured 48 hours later by adding a Steady glo reagent (Promega, Madison, Wis.). Percent inhibition of replication data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell titer glo (Promega, Madison, Wis). EC50s were determined from an 1 1 point dose response curve using 3-4-fold serial dilution for each compound, which spans a concentration range > 1000 fold. The level of inhibition for each compound was determined with Activity Base or with BioAssay plus the Excel XC50 module.
- Percent inhibition was determined with the following equation where the cross-talk corrected value is the value from the test well, the compound positive control mean is the average value of the wells with no compound present, and the DMSO negative control mean is the average value of the wells with DMSO but no cells present.
- WO 2009/020828 discloses the crystalline di-HCI salt of a compound said to be useful for treating HCV infection.
- the title compound of WO 2009/020828 was prepared as described in that patent.
- Example 2 The compound of Example 2 was isolated and purified as the amorphous free- base. This amorphous free-base was dissolved in acetone (3.6 mL; 30 vol) at room temperature with stirring. Hydrochloric acid (316 uL of 1.0M in dioxane; 2.1 equivalents) was added and resulted in an amorphous precipitate. Methanol (480 uL; 4 vol) was added in aliquots until solids just dissolved. Crystalline seeds of the WO 2009/020828 di-HCI compound were added, and the mixture stirred over the weekend. The product was filtered with no wash, and the yield was 62.6% (84.0mg; 0.0946 mmol) of crystalline di-HCI salt of the compound of Example 2.
- the compound of Example 2 was isolated and purified as the amorphous free- base. This amorphous free-base (555mg; 0.696mmol) was dissolved in acetone (8.3ml_; 15vol) and methanol (2.2ml_; 4vol) at 50°C with stirring. Hydrochloric acid (1.46ml_ of 1.0M in dioxane; 2.1 equivalents) was added slowly followed by seed crystals of the di-HCI salt of the compound of Example 2. The slurry was maintained at 50°C for one hour, cooled to room temperature, and stirred over the weekend. The product was quickly filtered with no wash and dried at 50°C in a vacuum oven with nitrogen bleed. The yield was 54.0% (327mg; 0.376mmol) of crystalline di-HCI salt of the compound of Example 2.
- the amorphous sulfate salt of the compound of Example 2 was prepared by adding 1.0 eq of sulfuric acid to a solution of free-base and concentrating to dryness.
- the amorphous sulfate salt (-50 mg; 0.056 mmol) was taken up in acetone (750ul; 15 volumes), and the mixture was heated to 50°C.
- Methanol (21 Oul; 4.2 vol) was added 10uL at a time until the solids almost all dissolved, resulting in a cloudy solution. This cloudy solution was mixed at 50°C for 16 hours, then cooled to 23°C.
- the product was filtered, analyzed, and determined to be consistent with crystalline sulfate salt of the compound of Example 2.
- Crystalline sulfate salt of the compound of Example 2 :
- the amorphous free-base of the compound of Example 2 (250mg; 0.314mmol) was mixed with methanol (1.25ml_; 5vol) and heated to 50°C with stirring to accelerate dissolution. Sulfuric acid (0.105ml_ of 3.0M in water; 1.0 equivalent) was added slowly followed by seed crystals of the sulfate salt of the compound of Example 2. The slurry was maintained at 50°C for three hours to form a moderately thick, yellow slurry. The temperature was decreased to 15°C to increase the yield. The product was filtered with no wash and dried at 50°C in a vacuum oven with nitrogen bleed. The yield was 73.6% (21 1 mg; 0.231 mmol) of crystalline sulfate salt of GSK2336805.
- the crystalline di-HCI and sulfate salts of the compound of Example 2 were analyzed by ion chromatography, powder X-ray diffraction (PXRD), Raman, DSC, and TGA. All analyses were consistent with crystalline salts.
- the powder X-ray diffraction was performed with a PANalytical X'Pert-Pro MPD with
- Johansson Ka1 monochromator using X'Celerator detector.
- the key operating parameters were: Radiation: Cu (Ka1 ), 1.54060 angstroms (monochromatic);
- Detector X'Celerator; Tension: 45 kV; Current: 40 mA; Start angle: 2.0°20; End angle: 50.0°20; Step size: 0.02°; Time/step: 40.0 sec; Scan speed: 0.05 sec;
- Incident beam 2° fixed anti-scatter slit, and programmable divergence slit; Diffracted beam: 0.02 rad soller slit, and programmable anti-scatter slit. Samples were prepared on silicon zero background sample holder.
- the di-HCI salt of the compound of Example 2 had significant peaks in powder X-ray diffraction pattern at values of two theta in degrees and d-spacing in Angstrom in parenthesis of 5.3(16.55), 9.9 (8.94), 10.4 (8.54), 13.3(6.65), 18.9(4.70),
- the TGA trace of the di-HCI salt of the compound of Example 2 was consistent with an anhydrous form.
- the DSC trace of the di-HCI salt of the compound of Example 2 showed an onset of melting and/or decomposition at approximately 262°C.
- the sulfate salt of the compound of Example 2 had significant peaks in powder X-ray diffraction pattern at values of two theta in degrees and d-spacing in Angstrom of 5.6(15.87), 7.1 (12.39), 8.0(1 1.10), 10.5(8.41 ), 1 1.9(7.41 ), 12.6(7.02), 13.4(6.61 ), 14.3(6.18), 16.6(5.33), 17.5(5.07), 18.4(4.81 ), 20.0(4.43), 21.2(4.19), 23.8(3.73).
- the TGA trace of the sulfate salt of the compound of Example 2 was consistent with a variable hydrate form.
- the DSC trace of the sulfate salt of the compound of Example 2 showed an onset of melting and/or decomposition at approximately 241°C.
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Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
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EA201290089A EA201290089A1 (en) | 2009-09-04 | 2010-08-26 | CHEMICAL COMPOUNDS |
BR112012003578A BR112012003578A8 (en) | 2009-09-04 | 2010-08-26 | COMPOUND, PHARMACEUTICALLY ACCEPTABLE SALT, SULFATE SALT, PHARMACEUTICAL COMPOSITION, METHOD FOR TREATING A VIRAL INFECTION, AND, USE OF A COMPOUND OR SALT |
EP10814293A EP2473056A4 (en) | 2009-09-04 | 2010-08-26 | Chemical compounds |
JP2012527916A JP5795316B2 (en) | 2009-09-04 | 2010-08-26 | Compound |
SG2012014791A SG178952A1 (en) | 2009-09-04 | 2010-08-26 | Chemical compounds |
MX2012002759A MX2012002759A (en) | 2009-09-04 | 2010-08-26 | Chemical compounds. |
CA2771327A CA2771327A1 (en) | 2009-09-04 | 2010-08-26 | Chemical compounds |
NZ597982A NZ597982A (en) | 2009-09-04 | 2010-08-26 | CHEMICAL COMPOUNDS for treating Hepatitis C virus |
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