CA2429709A1

CA2429709A1 - Composes de motilide

Composes de motilide Download PDF

Info

Publication number: CA2429709A1
Authority: CA; Canada
Prior art keywords: substituted; unsubstituted; alkyl; alkynyl; alkenyl
Prior art date: 2000-12-01
Legal status : Abandoned

Application number

CA002429709A

Other languages

English (en)

Inventor

Gary Ashley

Daniel Santi

Zong-Qiang Tian

Brian Metcalf

Current Assignee

Kosan Biosciences Inc

Original Assignee

Individual

Priority date

2000-12-01

Filing date

2001-11-21

Publication date

2002-07-04

2001-11-21 Application filed by Individual filed Critical Individual

2002-07-04 Publication of CA2429709A1 publication Critical patent/CA2429709A1/fr

Status Abandoned legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 97
125000002877 alkyl aryl group Chemical group 0.000 claims description 80
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 77
125000005024 alkenyl aryl group Chemical group 0.000 claims description 71
239000001257 hydrogen Substances 0.000 claims description 65
229910052739 hydrogen Inorganic materials 0.000 claims description 65
125000005025 alkynylaryl group Chemical group 0.000 claims description 64
239000000203 mixture Substances 0.000 claims description 57
-1 prop-2-enyl Chemical group 0.000 claims description 55
125000003118 aryl group Chemical group 0.000 claims description 50
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 49
125000000217 alkyl group Chemical group 0.000 claims description 45
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
125000000304 alkynyl group Chemical group 0.000 claims description 34
238000000034 method Methods 0.000 claims description 33
125000003107 substituted aryl group Chemical group 0.000 claims description 29
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 28
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 27
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical class O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 claims description 12
YHVUVJYEERGYNU-UHFFFAOYSA-N 4',8-Di-Me ether-5,7,8-Trihydroxy-3-(4-hydroxybenzyl)-4-chromanone Natural products COC1(C)CC(O)OC(C)C1O YHVUVJYEERGYNU-UHFFFAOYSA-N 0.000 claims description 11
125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 9
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 8
125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 8
206010021518 Impaired gastric emptying Diseases 0.000 claims description 8
208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 8
208000001288 gastroparesis Diseases 0.000 claims description 8
125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 7
125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 6
206010010774 Constipation Diseases 0.000 claims description 6
201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 claims description 6
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 6
125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
206010047700 Vomiting Diseases 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 5
150000004820 halides Chemical group 0.000 claims description 5
230000004899 motility Effects 0.000 claims description 5
230000001684 chronic effect Effects 0.000 claims description 4
210000000232 gallbladder Anatomy 0.000 claims description 4
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
208000007882 Gastritis Diseases 0.000 claims description 3
206010052105 Gastrointestinal hypomotility Diseases 0.000 claims description 3
206010021333 Ileus paralytic Diseases 0.000 claims description 3
206010039710 Scleroderma Diseases 0.000 claims description 3
208000022531 anorexia Diseases 0.000 claims description 3
VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical group C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 claims description 3
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
206010061428 decreased appetite Diseases 0.000 claims description 3
230000001771 impaired effect Effects 0.000 claims description 3
201000007620 paralytic ileus Diseases 0.000 claims description 3
230000002980 postoperative effect Effects 0.000 claims description 3
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
229920002554 vinyl polymer Chemical group 0.000 claims description 3
125000005017 substituted alkenyl group Chemical group 0.000 claims description 2
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 42
125000005865 C2-C10alkynyl group Chemical group 0.000 claims 42
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 39
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 14
125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims 3
125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims 3
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 2
238000011282 treatment Methods 0.000 abstract description 13
239000003120 macrolide antibiotic agent Substances 0.000 abstract description 9
208000017228 Gastrointestinal motility disease Diseases 0.000 abstract description 2
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound 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 102
229960003276 erythromycin Drugs 0.000 description 84
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
239000000243 solution Substances 0.000 description 69
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 66
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 55
239000000047 product Substances 0.000 description 54
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
125000003342 alkenyl group Chemical group 0.000 description 33
229910052943 magnesium sulfate Inorganic materials 0.000 description 32
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
239000007787 solid Substances 0.000 description 28
235000019439 ethyl acetate Nutrition 0.000 description 26
239000012043 crude product Substances 0.000 description 25
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
238000006243 chemical reaction Methods 0.000 description 24
HQZOLNNEQAKEHT-UHFFFAOYSA-N (3R,4S,5R,6S,7S,9R,11R,12S,13R,14R)-14-ethyl-4,6,12-trihydroxy-3,5,7,9,11,13-hexamethyloxacyclotetradecane-2,10-dione Natural products CCC1OC(=O)C(C)C(O)C(C)C(O)C(C)CC(C)C(=O)C(C)C(O)C1C HQZOLNNEQAKEHT-UHFFFAOYSA-N 0.000 description 20
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
229930006677 Erythromycin A Natural products 0.000 description 20
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 19
150000003951 lactams Chemical class 0.000 description 19
238000010898 silica gel chromatography Methods 0.000 description 19
150000002431 hydrogen Chemical class 0.000 description 18
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
150000002084 enol ethers Chemical group 0.000 description 16
239000000284 extract Substances 0.000 description 16
238000003818 flash chromatography Methods 0.000 description 16
239000011347 resin Substances 0.000 description 15
229920005989 resin Polymers 0.000 description 15
239000000741 silica gel Substances 0.000 description 15
229910002027 silica gel Inorganic materials 0.000 description 15
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
150000002924 oxiranes Chemical class 0.000 description 13
239000007858 starting material Substances 0.000 description 13
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
238000005481 NMR spectroscopy Methods 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
230000002829 reductive effect Effects 0.000 description 11
125000001424 substituent group Chemical group 0.000 description 11
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 9
239000012267 brine Substances 0.000 description 9
238000001914 filtration Methods 0.000 description 9
239000011630 iodine Substances 0.000 description 9
229910052740 iodine Inorganic materials 0.000 description 9
150000002923 oximes Chemical class 0.000 description 9
150000003839 salts Chemical class 0.000 description 9
QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 9
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
239000002253 acid Substances 0.000 description 8
238000000855 fermentation Methods 0.000 description 8
230000004151 fermentation Effects 0.000 description 8
125000002541 furyl group Chemical group 0.000 description 8
229910000027 potassium carbonate Inorganic materials 0.000 description 8
229920006395 saturated elastomer Polymers 0.000 description 8
238000004809 thin layer chromatography Methods 0.000 description 8
TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 7
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 7
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
239000000872 buffer Substances 0.000 description 7
208000035475 disorder Diseases 0.000 description 7
230000000694 effects Effects 0.000 description 7
101150086043 eryA gene Proteins 0.000 description 7
PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 7
125000004043 oxo group Chemical group O=* 0.000 description 7
229910052760 oxygen Inorganic materials 0.000 description 7
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
101150028073 rplD gene Proteins 0.000 description 7
HRNGDAQBEIFYGL-UHFFFAOYSA-N 3,4-dihydroxy-4-tetradeca-3,6-dienoyloxybutanoic acid Chemical compound CCCCCCCC=CCC=CCC(=O)OC(O)C(O)CC(O)=O HRNGDAQBEIFYGL-UHFFFAOYSA-N 0.000 description 6
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
101150041968 CDC13 gene Proteins 0.000 description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
229960000583 acetic acid Drugs 0.000 description 6
125000003710 aryl alkyl group Chemical group 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
IDRYSCOQVVUBIJ-PPGFLMPOSA-N erythromycin B Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@H]([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)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 IDRYSCOQVVUBIJ-PPGFLMPOSA-N 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
238000002360 preparation method Methods 0.000 description 6
125000006239 protecting group Chemical group 0.000 description 6
238000002390 rotary evaporation Methods 0.000 description 6
235000017281 sodium acetate Nutrition 0.000 description 6
229910000033 sodium borohydride Inorganic materials 0.000 description 6
239000012279 sodium borohydride Substances 0.000 description 6
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 6
LVRVABPNVHYXRT-BQWXUCBYSA-N 52906-92-0 Chemical compound C([C@H](N)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)C1=CC=CC=C1 LVRVABPNVHYXRT-BQWXUCBYSA-N 0.000 description 5
IDRYSCOQVVUBIJ-UHFFFAOYSA-N Erythromycin-B Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(C)C(CC)OC(=O)C(C)C1OC1CC(C)(OC)C(O)C(C)O1 IDRYSCOQVVUBIJ-UHFFFAOYSA-N 0.000 description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
102000002419 Motilin Human genes 0.000 description 5
101800002372 Motilin Proteins 0.000 description 5
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
235000011054 acetic acid Nutrition 0.000 description 5
239000000556 agonist Substances 0.000 description 5
150000001299 aldehydes Chemical class 0.000 description 5
125000003545 alkoxy group Chemical group 0.000 description 5
239000002024 ethyl acetate extract Substances 0.000 description 5
239000000543 intermediate Substances 0.000 description 5
150000002576 ketones Chemical class 0.000 description 5
230000035772 mutation Effects 0.000 description 5
239000003921 oil Substances 0.000 description 5
235000019198 oils Nutrition 0.000 description 5
239000012071 phase Substances 0.000 description 5
108090000623 proteins and genes Proteins 0.000 description 5
238000000746 purification Methods 0.000 description 5
210000002784 stomach Anatomy 0.000 description 5
OLPAVFVRSHWADO-KYEFFAPUSA-N 8,8a-Deoxyoleandolide Chemical compound C[C@H]1C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)[C@@H](C)OC(=O)[C@H](C)[C@@H](O)[C@H](C)[C@H]1O OLPAVFVRSHWADO-KYEFFAPUSA-N 0.000 description 4
OLPAVFVRSHWADO-UHFFFAOYSA-N 8,8a-deoxyoleandolide Natural products CC1CC(C)C(=O)C(C)C(O)C(C)C(C)OC(=O)C(C)C(O)C(C)C1O OLPAVFVRSHWADO-UHFFFAOYSA-N 0.000 description 4
101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 4
229920002261 Corn starch Polymers 0.000 description 4
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
108010030975 Polyketide Synthases Proteins 0.000 description 4
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
238000013019 agitation Methods 0.000 description 4
239000012298 atmosphere Substances 0.000 description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
125000001721 carboxyacetyl group Chemical group 0.000 description 4
230000008602 contraction Effects 0.000 description 4
239000008120 corn starch Substances 0.000 description 4
229940099112 cornstarch Drugs 0.000 description 4
RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 4
JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 4
201000010099 disease Diseases 0.000 description 4
238000010828 elution Methods 0.000 description 4
239000006260 foam Substances 0.000 description 4
125000001475 halogen functional group Chemical group 0.000 description 4
238000011068 loading method Methods 0.000 description 4
238000004519 manufacturing process Methods 0.000 description 4
239000000463 material Substances 0.000 description 4
239000002773 nucleotide Substances 0.000 description 4
125000003729 nucleotide group Chemical group 0.000 description 4
239000001301 oxygen Substances 0.000 description 4
239000000651 prodrug Substances 0.000 description 4
229940002612 prodrug Drugs 0.000 description 4
239000011541 reaction mixture Substances 0.000 description 4
208000024891 symptom Diseases 0.000 description 4
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125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
XQKBFQXWZCFNFF-UHFFFAOYSA-K triiodosamarium Chemical compound I[Sm](I)I XQKBFQXWZCFNFF-UHFFFAOYSA-K 0.000 description 1
125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 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
231100000397 ulcer Toxicity 0.000 description 1
238000001291 vacuum drying Methods 0.000 description 1
229940070710 valerate Drugs 0.000 description 1
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
239000013598 vector Substances 0.000 description 1
230000003612 virological effect Effects 0.000 description 1
239000003039 volatile agent Substances 0.000 description 1