CA2523541A1

CA2523541A1 - Novel ketolide derivatives

Novel ketolide derivatives Download PDF

Info

Publication number: CA2523541A1
Authority: CA; Canada
Prior art keywords: substituted; alkyl; hydrogen; compound; heteroaryl
Prior art date: 2003-04-25
Legal status : Abandoned

Application number

CA002523541A

Other languages

English (en)

French (fr)

Inventor

Matthew Burger

Daniel Chu

Current Assignee

Novartis Vaccines and Diagnostics Inc

Original Assignee

Individual

Priority date

2003-04-25

Filing date

2004-04-23

Publication date

2004-11-11

2004-04-23 Application filed by Individual filed Critical Individual

2004-11-11 Publication of CA2523541A1 publication Critical patent/CA2523541A1/en

Status Abandoned legal-status Critical Current

Links

239000003835 ketolide antibiotic agent Substances 0.000 title abstract description 34
150000001875 compounds Chemical class 0.000 claims abstract description 157
150000003839 salts Chemical class 0.000 claims abstract description 48
150000002148 esters Chemical class 0.000 claims abstract description 43
239000000651 prodrug Substances 0.000 claims abstract description 42
229940002612 prodrug Drugs 0.000 claims abstract description 42
238000000034 method Methods 0.000 claims abstract description 35
208000035143 Bacterial infection Diseases 0.000 claims abstract description 12
208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 12
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
-1 (i) -CN Chemical class 0.000 claims description 95
239000001257 hydrogen Substances 0.000 claims description 95
229910052739 hydrogen Inorganic materials 0.000 claims description 95
125000001072 heteroaryl group Chemical group 0.000 claims description 86
125000003118 aryl group Chemical group 0.000 claims description 53
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 50
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 34
125000003107 substituted aryl group Chemical group 0.000 claims description 32
229910052736 halogen Inorganic materials 0.000 claims description 30
150000002367 halogens Chemical class 0.000 claims description 30
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
239000003814 drug Substances 0.000 claims description 20
125000001424 substituent group Chemical group 0.000 claims description 19
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
125000004432 carbon atom Chemical group C* 0.000 claims description 12
125000004093 cyano group Chemical group *C#N 0.000 claims description 12
229910052757 nitrogen Inorganic materials 0.000 claims description 11
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
238000011282 treatment Methods 0.000 claims description 9
239000003937 drug carrier Substances 0.000 claims description 8
125000005842 heteroatom Chemical group 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
XKSVJEIDWNGLPU-UHFFFAOYSA-N 4-[4-(6-methoxypyridin-3-yl)-2-methyl-1h-imidazol-5-yl]butan-1-amine Chemical compound C1=NC(OC)=CC=C1C1=C(CCCCN)NC(C)=N1 XKSVJEIDWNGLPU-UHFFFAOYSA-N 0.000 claims description 7
PPRSDMPJYFFMPE-UHFFFAOYSA-N 4-[5-(2-chloropyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound N1C(CCCCN)=NC=C1C1=CC=CN=C1Cl PPRSDMPJYFFMPE-UHFFFAOYSA-N 0.000 claims description 7
229910052731 fluorine Inorganic materials 0.000 claims description 7
125000005843 halogen group Chemical group 0.000 claims description 7
XBPASXLWMTZZFC-UHFFFAOYSA-N 4-[4-(6-chloropyridin-3-yl)-2-methyl-1h-imidazol-5-yl]butan-1-amine Chemical compound N1C(C)=NC(C=2C=NC(Cl)=CC=2)=C1CCCCN XBPASXLWMTZZFC-UHFFFAOYSA-N 0.000 claims description 6
QQVBDZQUKYLIMS-UHFFFAOYSA-N 4-[4-(6-methoxypyridin-3-yl)-5-methyl-1h-imidazol-2-yl]butan-1-amine Chemical compound C1=NC(OC)=CC=C1C1=C(C)NC(CCCCN)=N1 QQVBDZQUKYLIMS-UHFFFAOYSA-N 0.000 claims description 6
LZPSNHQTMJQMHZ-UHFFFAOYSA-N 4-[5-(4-chloropyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound N1C(CCCCN)=NC=C1C1=CN=CC=C1Cl LZPSNHQTMJQMHZ-UHFFFAOYSA-N 0.000 claims description 6
QJUWCCQVNSGPBX-UHFFFAOYSA-N 4-[5-(6-chloro-5-methylpyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound N1=C(Cl)C(C)=CC(C=2NC(CCCCN)=NC=2)=C1 QJUWCCQVNSGPBX-UHFFFAOYSA-N 0.000 claims description 6
150000001412 amines Chemical class 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 6
125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 5
OIKYGVHOAKNOIT-UHFFFAOYSA-N 4-[4-(6-chloropyridin-3-yl)-5-methyl-1h-imidazol-2-yl]butan-1-amine Chemical compound N1C(CCCCN)=NC(C=2C=NC(Cl)=CC=2)=C1C OIKYGVHOAKNOIT-UHFFFAOYSA-N 0.000 claims description 5
UFDZCQISEHSRBP-UHFFFAOYSA-N 5-[1-(4-aminobutyl)imidazol-4-yl]-n,n-dimethylpyridin-2-amine Chemical compound C1=NC(N(C)C)=CC=C1C1=CN(CCCCN)C=N1 UFDZCQISEHSRBP-UHFFFAOYSA-N 0.000 claims description 5
125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
DFAGLOLGEMMVPT-UHFFFAOYSA-N 4-[5-(4-methoxypyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound COC1=CC=NC=C1C1=CN=C(CCCCN)N1 DFAGLOLGEMMVPT-UHFFFAOYSA-N 0.000 claims description 4
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
125000001153 fluoro group Chemical group F* 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
238000011321 prophylaxis Methods 0.000 claims description 4
SKSZYTFXIDNVRR-UHFFFAOYSA-N 4-[4-(6-chloropyridin-3-yl)imidazol-1-yl]butan-1-amine Chemical compound NCCCCN1C=NC(C=2C=NC(Cl)=CC=2)=C1 SKSZYTFXIDNVRR-UHFFFAOYSA-N 0.000 claims description 3
KQPJSTREOMVENQ-UHFFFAOYSA-N 4-[4-(6-ethoxypyridin-3-yl)imidazol-1-yl]butan-1-amine Chemical compound C1=NC(OCC)=CC=C1C1=CN(CCCCN)C=N1 KQPJSTREOMVENQ-UHFFFAOYSA-N 0.000 claims description 3
VYBHXZVSJYBFMA-UHFFFAOYSA-N 4-[4-(6-fluoropyridin-3-yl)imidazol-1-yl]butan-1-amine Chemical compound NCCCCN1C=NC(C=2C=NC(F)=CC=2)=C1 VYBHXZVSJYBFMA-UHFFFAOYSA-N 0.000 claims description 3
IYWJLGFXMICCGN-UHFFFAOYSA-N 4-[4-(6-methoxypyridin-3-yl)imidazol-1-yl]butan-1-amine Chemical compound C1=NC(OC)=CC=C1C1=CN(CCCCN)C=N1 IYWJLGFXMICCGN-UHFFFAOYSA-N 0.000 claims description 3
FMZZOIPURNVGLD-UHFFFAOYSA-N 4-[4-(6-methylpyridin-3-yl)imidazol-1-yl]butan-1-amine Chemical compound C1=NC(C)=CC=C1C1=CN(CCCCN)C=N1 FMZZOIPURNVGLD-UHFFFAOYSA-N 0.000 claims description 3
UGBFATORHKYKHA-UHFFFAOYSA-N 5-[1-(4-aminobutyl)imidazol-4-yl]pyridin-2-amine Chemical compound NCCCCN1C=NC(C=2C=NC(N)=CC=2)=C1 UGBFATORHKYKHA-UHFFFAOYSA-N 0.000 claims description 3
239000011737 fluorine Substances 0.000 claims description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 2
YKYIFUROKBDHCY-ONEGZZNKSA-N (e)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one Chemical group CCO\C=C\C(=O)C(F)(F)F YKYIFUROKBDHCY-ONEGZZNKSA-N 0.000 claims description 2
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
150000002431 hydrogen Chemical group 0.000 claims 34
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 6
125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims 3
125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims 2
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 2
125000001843 C4-C10 alkenyl group Chemical group 0.000 claims 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
LQOULELNWBAZQA-UHFFFAOYSA-N 4-[4-[6-(aminomethyl)pyridin-3-yl]imidazol-1-yl]butan-1-amine Chemical compound NCCCCN1C=NC(C=2C=NC(CN)=CC=2)=C1 LQOULELNWBAZQA-UHFFFAOYSA-N 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 5
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 200
239000000243 solution Substances 0.000 description 104
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
239000011541 reaction mixture Substances 0.000 description 56
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 49
239000000203 mixture Substances 0.000 description 47
239000003921 oil Substances 0.000 description 47
235000019198 oils Nutrition 0.000 description 47
238000003756 stirring Methods 0.000 description 37
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
238000006243 chemical reaction Methods 0.000 description 33
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
125000000217 alkyl group Chemical group 0.000 description 26
239000002904 solvent Substances 0.000 description 25
239000012043 crude product Substances 0.000 description 23
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 22
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 22
238000001816 cooling Methods 0.000 description 21
239000010410 layer Substances 0.000 description 20
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 20
235000019441 ethanol Nutrition 0.000 description 19
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
229940079593 drug Drugs 0.000 description 17
229910052938 sodium sulfate Inorganic materials 0.000 description 17
235000011152 sodium sulphate Nutrition 0.000 description 17
239000007787 solid Substances 0.000 description 17
229910001868 water Inorganic materials 0.000 description 17
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Natural products O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 14
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
238000010438 heat treatment Methods 0.000 description 13
229910052943 magnesium sulfate Inorganic materials 0.000 description 13
239000007864 aqueous solution Substances 0.000 description 12
238000001990 intravenous administration Methods 0.000 description 12
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 11
235000019439 ethyl acetate Nutrition 0.000 description 11
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
239000013058 crude material Substances 0.000 description 10
238000009472 formulation Methods 0.000 description 10
229910000027 potassium carbonate Inorganic materials 0.000 description 10
239000011592 zinc chloride Substances 0.000 description 10
235000005074 zinc chloride Nutrition 0.000 description 10
HIDHQZBPBJIEFC-UHFFFAOYSA-N 4-[5-(6-chloropyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound N1C(CCCCN)=NC=C1C1=CC=C(Cl)N=C1 HIDHQZBPBJIEFC-UHFFFAOYSA-N 0.000 description 9
DXJZJYPLPZEYBH-UHFFFAOYSA-N 4-iodo-1-tritylimidazole Chemical compound C1=NC(I)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 DXJZJYPLPZEYBH-UHFFFAOYSA-N 0.000 description 9
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 9
HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 9
239000000843 powder Substances 0.000 description 9
UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 description 8
125000004043 oxo group Chemical group O=* 0.000 description 8
239000000546 pharmaceutical excipient Substances 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
239000000443 aerosol Substances 0.000 description 7
230000000694 effects Effects 0.000 description 7
238000003818 flash chromatography Methods 0.000 description 7
125000000592 heterocycloalkyl group Chemical group 0.000 description 7
125000006239 protecting group Chemical group 0.000 description 7
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
239000002253 acid Substances 0.000 description 6
239000000872 buffer Substances 0.000 description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
239000008101 lactose Substances 0.000 description 6
210000004072 lung Anatomy 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
239000000463 material Substances 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
229920001223 polyethylene glycol Polymers 0.000 description 6
125000004076 pyridyl group Chemical group 0.000 description 6
239000012265 solid product Substances 0.000 description 6
239000000126 substance Substances 0.000 description 6
LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 6
229960003250 telithromycin Drugs 0.000 description 6
ZJRNIOIGQQTOHC-UHFFFAOYSA-N 4-[5-(6-fluoropyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound N1C(CCCCN)=NC=C1C1=CC=C(F)N=C1 ZJRNIOIGQQTOHC-UHFFFAOYSA-N 0.000 description 5
MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 description 5
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
241000700159 Rattus Species 0.000 description 5
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
229920002472 Starch Polymers 0.000 description 5
230000000844 anti-bacterial effect Effects 0.000 description 5
229910052794 bromium Inorganic materials 0.000 description 5
210000003123 bronchiole Anatomy 0.000 description 5
239000002775 capsule Substances 0.000 description 5
150000003857 carboxamides Chemical class 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
239000000460 chlorine Substances 0.000 description 5
229910052801 chlorine Inorganic materials 0.000 description 5
238000004587 chromatography analysis Methods 0.000 description 5
238000000576 coating method Methods 0.000 description 5
125000004663 dialkyl amino group Chemical group 0.000 description 5
239000002552 dosage form Substances 0.000 description 5
229960003276 erythromycin Drugs 0.000 description 5
239000000706 filtrate Substances 0.000 description 5
229910052740 iodine Inorganic materials 0.000 description 5
239000002609 medium Substances 0.000 description 5
231100000252 nontoxic Toxicity 0.000 description 5
230000003000 nontoxic effect Effects 0.000 description 5
239000006187 pill Substances 0.000 description 5
239000007909 solid dosage form Substances 0.000 description 5
235000019698 starch Nutrition 0.000 description 5
125000000547 substituted alkyl group Chemical group 0.000 description 5
229910052717 sulfur Inorganic materials 0.000 description 5
239000003826 tablet Substances 0.000 description 5
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
239000001993 wax Substances 0.000 description 5
PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
KFXHOMGKZRERDY-UHFFFAOYSA-N 2-[4-[4-(6-chloro-5-methylpyridin-3-yl)imidazol-1-yl]butyl]isoindole-1,3-dione Chemical compound N1=C(Cl)C(C)=CC(C=2N=CN(CCCCN3C(C4=CC=CC=C4C3=O)=O)C=2)=C1 KFXHOMGKZRERDY-UHFFFAOYSA-N 0.000 description 4
BVRZUWOMKGICDX-UHFFFAOYSA-N 2-[4-[5-(2-chloropyridin-3-yl)-1h-imidazol-2-yl]butyl]isoindole-1,3-dione Chemical compound ClC1=NC=CC=C1C(N1)=CN=C1CCCCN1C(=O)C2=CC=CC=C2C1=O BVRZUWOMKGICDX-UHFFFAOYSA-N 0.000 description 4
DIQVDBYJNJZQGO-UHFFFAOYSA-N 2-fluoro-5-(1h-imidazol-5-yl)pyridine Chemical compound C1=NC(F)=CC=C1C1=CNC=N1 DIQVDBYJNJZQGO-UHFFFAOYSA-N 0.000 description 4
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
IARPAMAHBYVKLN-UHFFFAOYSA-N 4-[5-(6-methoxypyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound C1=NC(OC)=CC=C1C1=CN=C(CCCCN)N1 IARPAMAHBYVKLN-UHFFFAOYSA-N 0.000 description 4
QCJCAQKAQQPBNU-UHFFFAOYSA-N 4-[5-(6-methylpyridin-3-yl)-1h-imidazol-2-yl]butan-1-amine Chemical compound C1=NC(C)=CC=C1C1=CN=C(CCCCN)N1 QCJCAQKAQQPBNU-UHFFFAOYSA-N 0.000 description 4
PEAOEIWYQVXZMB-UHFFFAOYSA-N 5-bromo-2-chloropyridine Chemical compound ClC1=CC=C(Br)C=N1 PEAOEIWYQVXZMB-UHFFFAOYSA-N 0.000 description 4
241000894006 Bacteria Species 0.000 description 4
241000282412 Homo Species 0.000 description 4
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
241000124008 Mammalia Species 0.000 description 4
241001465754 Metazoa Species 0.000 description 4
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
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239000011734 sodium Substances 0.000 description 1
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239000012312 sodium hydride Substances 0.000 description 1
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238000013222 sprague-dawley male rat Methods 0.000 description 1
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238000010254 subcutaneous injection Methods 0.000 description 1
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125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
231100001274 therapeutic index Toxicity 0.000 description 1
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AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
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VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
238000011269 treatment regimen Methods 0.000 description 1
125000005106 triarylsilyl group Chemical group 0.000 description 1
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
125000002948 undecyl group Chemical group [H]C([*])([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])[H] 0.000 description 1
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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