JP7281822B2 - 細菌の排出ポンプ阻害剤 - Google Patents
細菌の排出ポンプ阻害剤 Download PDFInfo
- Publication number
- JP7281822B2 JP7281822B2 JP2020515831A JP2020515831A JP7281822B2 JP 7281822 B2 JP7281822 B2 JP 7281822B2 JP 2020515831 A JP2020515831 A JP 2020515831A JP 2020515831 A JP2020515831 A JP 2020515831A JP 7281822 B2 JP7281822 B2 JP 7281822B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- carbocyclyl
- substituted
- heteroaryl
- compound
- Prior art date
- 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.)
- Active
Links
- 230000001580 bacterial effect Effects 0.000 title claims description 52
- 239000003112 inhibitor Substances 0.000 title description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 300
- 150000001875 compounds Chemical class 0.000 claims description 203
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 151
- -1 —CO 2 H Chemical group 0.000 claims description 135
- 150000003839 salts Chemical class 0.000 claims description 126
- 229910052739 hydrogen Inorganic materials 0.000 claims description 116
- 239000001257 hydrogen Substances 0.000 claims description 115
- 125000005843 halogen group Chemical group 0.000 claims description 111
- 125000003118 aryl group Chemical group 0.000 claims description 107
- 125000001072 heteroaryl group Chemical group 0.000 claims description 107
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 93
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 77
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 74
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 70
- 239000000203 mixture Substances 0.000 claims description 64
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 125000002950 monocyclic group Chemical group 0.000 claims description 55
- 239000003242 anti bacterial agent Substances 0.000 claims description 48
- 150000002431 hydrogen Chemical class 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 46
- 238000002360 preparation method Methods 0.000 claims description 45
- 241000894006 Bacteria Species 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 34
- 241001465754 Metazoa Species 0.000 claims description 32
- 230000002401 inhibitory effect Effects 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 208000035143 Bacterial infection Diseases 0.000 claims description 23
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 23
- 208000015181 infectious disease Diseases 0.000 claims description 18
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 16
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 16
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 13
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 10
- 239000004599 antimicrobial Substances 0.000 claims description 9
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 7
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000006373 (C2-C10) alkyl group Chemical group 0.000 claims description 6
- 241000606749 Aggregatibacter actinomycetemcomitans Species 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- 241000589602 Francisella tularensis Species 0.000 claims description 5
- 241000588655 Moraxella catarrhalis Species 0.000 claims description 5
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
- 241000588724 Escherichia coli Species 0.000 claims description 4
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 230000000069 prophylactic effect Effects 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 3
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 3
- 241000588624 Acinetobacter calcoaceticus Species 0.000 claims description 3
- 241001148231 Acinetobacter haemolyticus Species 0.000 claims description 3
- 241001135518 Acinetobacter lwoffii Species 0.000 claims description 3
- 241000186045 Actinomyces naeslundii Species 0.000 claims description 3
- 241000186044 Actinomyces viscosus Species 0.000 claims description 3
- 241000589155 Agrobacterium tumefaciens Species 0.000 claims description 3
- 241000193738 Bacillus anthracis Species 0.000 claims description 3
- 241000193755 Bacillus cereus Species 0.000 claims description 3
- 244000063299 Bacillus subtilis Species 0.000 claims description 3
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 3
- 241001135322 Bacteroides eggerthii Species 0.000 claims description 3
- 241000606124 Bacteroides fragilis Species 0.000 claims description 3
- 241000606123 Bacteroides thetaiotaomicron Species 0.000 claims description 3
- 241000606219 Bacteroides uniformis Species 0.000 claims description 3
- 241000606215 Bacteroides vulgatus Species 0.000 claims description 3
- 241000588779 Bordetella bronchiseptica Species 0.000 claims description 3
- 241000588780 Bordetella parapertussis Species 0.000 claims description 3
- 241000588832 Bordetella pertussis Species 0.000 claims description 3
- 241000589969 Borreliella burgdorferi Species 0.000 claims description 3
- 241000589513 Burkholderia cepacia Species 0.000 claims description 3
- 241000589877 Campylobacter coli Species 0.000 claims description 3
- 241000589874 Campylobacter fetus Species 0.000 claims description 3
- 241000589875 Campylobacter jejuni Species 0.000 claims description 3
- 241000010804 Caulobacter vibrioides Species 0.000 claims description 3
- 241000588919 Citrobacter freundii Species 0.000 claims description 3
- 241000588917 Citrobacter koseri Species 0.000 claims description 3
- 241000193163 Clostridioides difficile Species 0.000 claims description 3
- 241000918600 Corynebacterium ulcerans Species 0.000 claims description 3
- 241001135265 Cronobacter sakazakii Species 0.000 claims description 3
- 241000186427 Cutibacterium acnes Species 0.000 claims description 3
- 241001600125 Delftia acidovorans Species 0.000 claims description 3
- 241000881810 Enterobacter asburiae Species 0.000 claims description 3
- 241000588697 Enterobacter cloacae Species 0.000 claims description 3
- 241000194032 Enterococcus faecalis Species 0.000 claims description 3
- 241000194031 Enterococcus faecium Species 0.000 claims description 3
- 241000605986 Fusobacterium nucleatum Species 0.000 claims description 3
- 241000606788 Haemophilus haemolyticus Species 0.000 claims description 3
- 241000606768 Haemophilus influenzae Species 0.000 claims description 3
- 241000606822 Haemophilus parahaemolyticus Species 0.000 claims description 3
- 241000606766 Haemophilus parainfluenzae Species 0.000 claims description 3
- 241000590002 Helicobacter pylori Species 0.000 claims description 3
- 241000589015 Kingella denitrificans Species 0.000 claims description 3
- 241000589014 Kingella kingae Species 0.000 claims description 3
- 241000589012 Kingella oralis Species 0.000 claims description 3
- 241000588915 Klebsiella aerogenes Species 0.000 claims description 3
- 241000588749 Klebsiella oxytoca Species 0.000 claims description 3
- 241001534204 Klebsiella pneumoniae subsp. rhinoscleromatis Species 0.000 claims description 3
- 241000589242 Legionella pneumophila Species 0.000 claims description 3
- 241000186779 Listeria monocytogenes Species 0.000 claims description 3
- 241001293418 Mannheimia haemolytica Species 0.000 claims description 3
- 241000191938 Micrococcus luteus Species 0.000 claims description 3
- 241000588622 Moraxella bovis Species 0.000 claims description 3
- 241000588629 Moraxella lacunata Species 0.000 claims description 3
- 241000588772 Morganella morganii Species 0.000 claims description 3
- 241000186367 Mycobacterium avium Species 0.000 claims description 3
- 241000186364 Mycobacterium intracellulare Species 0.000 claims description 3
- 241000186362 Mycobacterium leprae Species 0.000 claims description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 3
- 241000588652 Neisseria gonorrhoeae Species 0.000 claims description 3
- 241000588650 Neisseria meningitidis Species 0.000 claims description 3
- 241001135232 Odoribacter splanchnicus Species 0.000 claims description 3
- 241000588912 Pantoea agglomerans Species 0.000 claims description 3
- 241000606210 Parabacteroides distasonis Species 0.000 claims description 3
- 241000606598 Pasteurella canis Species 0.000 claims description 3
- 241000606856 Pasteurella multocida Species 0.000 claims description 3
- 241000605862 Porphyromonas gingivalis Species 0.000 claims description 3
- 241000588770 Proteus mirabilis Species 0.000 claims description 3
- 241000588767 Proteus vulgaris Species 0.000 claims description 3
- 241000576783 Providencia alcalifaciens Species 0.000 claims description 3
- 241000588777 Providencia rettgeri Species 0.000 claims description 3
- 241000588778 Providencia stuartii Species 0.000 claims description 3
- 241000168225 Pseudomonas alcaligenes Species 0.000 claims description 3
- 241000589540 Pseudomonas fluorescens Species 0.000 claims description 3
- 241000589776 Pseudomonas putida Species 0.000 claims description 3
- 241001354013 Salmonella enterica subsp. enterica serovar Enteritidis Species 0.000 claims description 3
- 241000531795 Salmonella enterica subsp. enterica serovar Paratyphi A Species 0.000 claims description 3
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 claims description 3
- 241000607715 Serratia marcescens Species 0.000 claims description 3
- 241000607768 Shigella Species 0.000 claims description 3
- 241000607764 Shigella dysenteriae Species 0.000 claims description 3
- 241000607760 Shigella sonnei Species 0.000 claims description 3
- 241000191967 Staphylococcus aureus Species 0.000 claims description 3
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 3
- 241000191984 Staphylococcus haemolyticus Species 0.000 claims description 3
- 241000192087 Staphylococcus hominis Species 0.000 claims description 3
- 241000191980 Staphylococcus intermedius Species 0.000 claims description 3
- 241001464905 Staphylococcus saccharolyticus Species 0.000 claims description 3
- 241001147691 Staphylococcus saprophyticus Species 0.000 claims description 3
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 3
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 3
- 241000194024 Streptococcus salivarius Species 0.000 claims description 3
- 241000194023 Streptococcus sanguinis Species 0.000 claims description 3
- 241000722072 Suttonella indologenes Species 0.000 claims description 3
- 241001135235 Tannerella forsythia Species 0.000 claims description 3
- 241001148135 Veillonella parvula Species 0.000 claims description 3
- 241000607272 Vibrio parahaemolyticus Species 0.000 claims description 3
- 241000607481 Yersinia intermedia Species 0.000 claims description 3
- 241000607479 Yersinia pestis Species 0.000 claims description 3
- 241000607477 Yersinia pseudotuberculosis Species 0.000 claims description 3
- 241000606834 [Haemophilus] ducreyi Species 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 claims description 3
- 229940065181 bacillus anthracis Drugs 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229940092559 enterobacter aerogenes Drugs 0.000 claims description 3
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 3
- 229940047650 haemophilus influenzae Drugs 0.000 claims description 3
- 229940037467 helicobacter pylori Drugs 0.000 claims description 3
- 229940115932 legionella pneumophila Drugs 0.000 claims description 3
- 229940076266 morganella morganii Drugs 0.000 claims description 3
- 229940051027 pasteurella multocida Drugs 0.000 claims description 3
- 229940055019 propionibacterium acne Drugs 0.000 claims description 3
- 229940007042 proteus vulgaris Drugs 0.000 claims description 3
- 229940007046 shigella dysenteriae Drugs 0.000 claims description 3
- 229940115939 shigella sonnei Drugs 0.000 claims description 3
- 229940037649 staphylococcus haemolyticus Drugs 0.000 claims description 3
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 3
- 241000607534 Aeromonas Species 0.000 claims description 2
- 241000606125 Bacteroides Species 0.000 claims description 2
- 241000606161 Chlamydia Species 0.000 claims description 2
- 241000186227 Corynebacterium diphtheriae Species 0.000 claims description 2
- 241000207201 Gardnerella vaginalis Species 0.000 claims description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 claims description 2
- 241000191982 Staphylococcus hyicus Species 0.000 claims description 2
- 241000194017 Streptococcus Species 0.000 claims description 2
- 241000194019 Streptococcus mutans Species 0.000 claims description 2
- 241000607626 Vibrio cholerae Species 0.000 claims description 2
- 241000607447 Yersinia enterocolitica Species 0.000 claims description 2
- 238000002651 drug therapy Methods 0.000 claims description 2
- 229940118764 francisella tularensis Drugs 0.000 claims description 2
- 229940118696 vibrio cholerae Drugs 0.000 claims description 2
- 229940098232 yersinia enterocolitica Drugs 0.000 claims description 2
- 241000588621 Moraxella Species 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 290
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 171
- 235000019439 ethyl acetate Nutrition 0.000 description 126
- 230000002829 reductive effect Effects 0.000 description 111
- 239000000243 solution Substances 0.000 description 108
- 239000011541 reaction mixture Substances 0.000 description 102
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 100
- 239000000047 product Substances 0.000 description 84
- 238000005481 NMR spectroscopy Methods 0.000 description 75
- 239000000543 intermediate Substances 0.000 description 62
- 239000000843 powder Substances 0.000 description 62
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 54
- 230000003115 biocidal effect Effects 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 52
- 239000007787 solid Substances 0.000 description 52
- 239000012267 brine Substances 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 46
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 45
- 239000000706 filtrate Substances 0.000 description 44
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 238000010898 silica gel chromatography Methods 0.000 description 40
- 239000007858 starting material Substances 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 34
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 33
- 238000000034 method Methods 0.000 description 33
- 239000002244 precipitate Substances 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- 238000012360 testing method Methods 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 24
- 229940088710 antibiotic agent Drugs 0.000 description 22
- 238000003556 assay Methods 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 239000002904 solvent Substances 0.000 description 17
- 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 16
- 239000007788 liquid Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 230000008034 disappearance Effects 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229960003376 levofloxacin Drugs 0.000 description 9
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 229960002100 cefepime Drugs 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group 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
- 241000282412 Homo Species 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- PRDFBSVERLRRMY-UHFFFAOYSA-N 2'-(4-ethoxyphenyl)-5-(4-methylpiperazin-1-yl)-2,5'-bibenzimidazole Chemical compound C1=CC(OCC)=CC=C1C1=NC2=CC=C(C=3NC4=CC(=CC=C4N=3)N3CCN(C)CC3)C=C2N1 PRDFBSVERLRRMY-UHFFFAOYSA-N 0.000 description 5
- 206010040047 Sepsis Diseases 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000007429 general method Methods 0.000 description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 5
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 229940124597 therapeutic agent Drugs 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000008261 resistance mechanism Effects 0.000 description 4
- 229910052717 sulfur Chemical group 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- PRDQGRVCRWCISD-CVEARBPZSA-N tert-butyl N-[[(3R,5S)-5-(aminomethyl)-1-benzylpyrrolidin-3-yl]methyl]carbamate Chemical compound NC[C@@H]1C[C@@H](CN1CC1=CC=CC=C1)CNC(OC(C)(C)C)=O PRDQGRVCRWCISD-CVEARBPZSA-N 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- LBUNNMJLXWQQBY-UHFFFAOYSA-N 4-fluorophenylboronic acid Chemical compound OB(O)C1=CC=C(F)C=C1 LBUNNMJLXWQQBY-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 241000256215 Spongomorpha aeruginosa Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin 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)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 3
- 229960002626 clarithromycin Drugs 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- YEFQIZIMGDSXJE-LYKKTTPLSA-N tert-butyl N-[(2S)-1-(1,3-dioxoisoindol-2-yl)-5-[(2-methylpropan-2-yl)oxycarbonylamino]hexan-2-yl]carbamate Chemical compound O=C1N(C(C2=CC=CC=C12)=O)C[C@H](CCC(C)NC(OC(C)(C)C)=O)NC(OC(C)(C)C)=O YEFQIZIMGDSXJE-LYKKTTPLSA-N 0.000 description 3
- PRDQGRVCRWCISD-JKSUJKDBSA-N tert-butyl N-[[(3S,5R)-5-(aminomethyl)-1-benzylpyrrolidin-3-yl]methyl]carbamate Chemical compound NC[C@H]1C[C@H](CN1CC1=CC=CC=C1)CNC(OC(C)(C)C)=O PRDQGRVCRWCISD-JKSUJKDBSA-N 0.000 description 3
- PRDQGRVCRWCISD-HOTGVXAUSA-N tert-butyl N-[[(3S,5S)-5-(aminomethyl)-1-benzylpyrrolidin-3-yl]methyl]carbamate Chemical compound NC[C@@H]1C[C@H](CN1CC1=CC=CC=C1)CNC(OC(C)(C)C)=O PRDQGRVCRWCISD-HOTGVXAUSA-N 0.000 description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
- PUICHEUQJYHHDF-UHFFFAOYSA-N 1-O-tert-butyl 2-O-methyl 3-bromo-6-(4-fluorophenyl)indole-1,2-dicarboxylate Chemical compound BrC1=C(N(C2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)OC(C)(C)C)C(=O)OC PUICHEUQJYHHDF-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XKXLFDDJIZVRCL-FJSYBICCSA-N 3-(2-cyclopropylethynyl)-N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.C1(CC1)C#CC1=C(NC2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)NC[C@H](CCCN)N XKXLFDDJIZVRCL-FJSYBICCSA-N 0.000 description 2
- PBXTZNGFQWWAKQ-UHFFFAOYSA-N 3-(4-fluorophenyl)-7-hydroxy-1H-indole-2-carboxylic acid Chemical compound FC1=CC=C(C=C1)C1=C(NC2=C(C=CC=C12)O)C(=O)O PBXTZNGFQWWAKQ-UHFFFAOYSA-N 0.000 description 2
- OUXGJBKGTBDRIV-UHFFFAOYSA-N 3-(4-fluorophenyl)-7-methoxy-1H-indole-2-carboxylic acid Chemical compound COc1cccc2c(c([nH]c12)C(O)=O)-c1ccc(F)cc1 OUXGJBKGTBDRIV-UHFFFAOYSA-N 0.000 description 2
- KMMFEGRIEKLYRZ-IKXQUJFKSA-N 3-benzyl-N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC=C(C=C1)CC2=C(NC3=C2C=CC(=C3)C4=CC=C(C=C4)F)C(=O)NC[C@H](CCCN)N.Cl.Cl KMMFEGRIEKLYRZ-IKXQUJFKSA-N 0.000 description 2
- BHVLCFSMHRWSMO-NTEVMMBTSA-N 3-cyclopropyl-N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1CC1C2=C(NC3=C2C=CC(=C3)C4=CC=C(C=C4)F)C(=O)NC[C@H](CCCN)N.Cl.Cl BHVLCFSMHRWSMO-NTEVMMBTSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OABZCMVRLUSLOA-BOXHHOBZSA-N 4-[2-[[(2S)-2,5-diaminopentyl]carbamoyl]-6-(4-fluorophenyl)-1H-indol-3-yl]benzoic acid hydrochloride Chemical compound C1=CC(=CC=C1C2=C(NC3=C2C=CC(=C3)C4=CC=C(C=C4)F)C(=O)NC[C@H](CCCN)N)C(=O)O.Cl OABZCMVRLUSLOA-BOXHHOBZSA-N 0.000 description 2
- DCTDPNWURFTQTM-UHFFFAOYSA-N 5-(4-fluorophenyl)-3-(3-phenylmethoxyphenyl)-1H-indole-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC=1C=C(C=CC=1)C1=C(NC2=CC=C(C=C12)C1=CC=C(C=C1)F)C(=O)O DCTDPNWURFTQTM-UHFFFAOYSA-N 0.000 description 2
- TZPOAECCKTUZBT-UHFFFAOYSA-N 6-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1H-indole-2-carboxylic acid Chemical compound FC1=CC=C(C=C1)C1=CC=C2C(=C(NC2=C1)C(=O)O)C1=CC=C(C=C1)O TZPOAECCKTUZBT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241001232615 Acinetobacter baumannii ATCC 19606 = CIP 70.34 = JCM 6841 Species 0.000 description 2
- 241000352320 Amegilla aeruginosa Species 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- UGTJLJZQQFGTJD-UHFFFAOYSA-N Carbonylcyanide-3-chlorophenylhydrazone Chemical compound ClC1=CC=CC(NN=C(C#N)C#N)=C1 UGTJLJZQQFGTJD-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LEVXENQCQCZYIW-GHVWMZMZSA-N N-[(2R)-2,5-diaminopentyl]-3,6-bis(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.NCCC[C@@H](N)CNC(=O)c1[nH]c2cc(ccc2c1-c1ccc(F)cc1)-c1ccc(F)cc1 LEVXENQCQCZYIW-GHVWMZMZSA-N 0.000 description 2
- IRZZAGLTSNORGB-LXTUAOQPSA-N N-[(2S)-2,5-diamino-5-cyclopropylpentyl]-3,6-bis(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1CC1C(CC[C@@H](CNC(=O)C2=C(C3=C(N2)C=C(C=C3)C4=CC=C(C=C4)F)C5=CC=C(C=C5)F)N)N.Cl.Cl IRZZAGLTSNORGB-LXTUAOQPSA-N 0.000 description 2
- RYCTVTMKSIMJRX-YRAHNTHMSA-N N-[(2S)-2,5-diaminohexyl]-3,6-bis(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound CC(CC[C@@H](CNC(=O)C1=C(C2=C(N1)C=C(C=C2)C3=CC=C(C=C3)F)C4=CC=C(C=C4)F)N)N.Cl.Cl RYCTVTMKSIMJRX-YRAHNTHMSA-N 0.000 description 2
- IQCFDEJPRCFXOM-WLOLSGMKSA-N N-[(2S)-2,5-diaminopentyl]-3,5-bis(3,5-dimethylphenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound CC1=CC(=CC(=C1)C2=CC3=C(C=C2)NC(=C3C4=CC(=CC(=C4)C)C)C(=O)NC[C@H](CCCN)N)C.Cl.Cl IQCFDEJPRCFXOM-WLOLSGMKSA-N 0.000 description 2
- APLXSEVALFGCKF-FGJQBABTSA-N N-[(2S)-2,5-diaminopentyl]-3,5-bis(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC(=CC=C1C2=CC3=C(C=C2)NC(=C3C4=CC=C(C=C4)F)C(=O)NC[C@H](CCCN)N)F.Cl.Cl APLXSEVALFGCKF-FGJQBABTSA-N 0.000 description 2
- NAERNDCQPSVAHU-FGJQBABTSA-N N-[(2S)-2,5-diaminopentyl]-3,5-diphenyl-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC=C(C=C1)C2=CC3=C(C=C2)NC(=C3C4=CC=CC=C4)C(=O)NC[C@H](CCCN)N.Cl.Cl NAERNDCQPSVAHU-FGJQBABTSA-N 0.000 description 2
- AFDLELHYSKJANM-CKUXDGONSA-N N-[(2S)-2,5-diaminopentyl]-3-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC=C2C(=C1)C(=C(N2)C(=O)NC[C@H](CCCN)N)C3=CC=C(C=C3)F.Cl.Cl AFDLELHYSKJANM-CKUXDGONSA-N 0.000 description 2
- XEWQCRLALPNCOH-UTLKBRERSA-N N-[(2S)-2,5-diaminopentyl]-3-(4-fluorophenyl)-7-hydroxy-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC2=C(C(=C1)O)NC(=C2C3=CC=C(C=C3)F)C(=O)NC[C@H](CCCN)N.Cl.Cl XEWQCRLALPNCOH-UTLKBRERSA-N 0.000 description 2
- RPSBIRFSULGNRQ-CKUXDGONSA-N N-[(2S)-2,5-diaminopentyl]-3-(4-fluorophenyl)-7-methoxy-1H-indole-2-carboxamide dihydrochloride Chemical compound COC1=CC=CC2=C1NC(=C2C3=CC=C(C=C3)F)C(=O)NC[C@H](CCCN)N.Cl.Cl RPSBIRFSULGNRQ-CKUXDGONSA-N 0.000 description 2
- NIVGWGRFNVOGKX-LPCSYZHESA-N N-[(2S)-2,5-diaminopentyl]-5-(4-fluorophenyl)-3-(3-phenylmethoxyphenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.C(C1=CC=CC=C1)OC=1C=C(C=CC=1)C1=C(NC2=CC=C(C=C12)C1=CC=C(C=C1)F)C(=O)NC[C@H](CCCN)N NIVGWGRFNVOGKX-LPCSYZHESA-N 0.000 description 2
- QMRAVJWLPKBNLH-FJSYBICCSA-N N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-3-(4-hydroxyphenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC(=CC=C1C2=C(NC3=C2C=CC(=C3)C4=CC=C(C=C4)F)C(=O)NC[C@H](CCCN)N)O.Cl.Cl QMRAVJWLPKBNLH-FJSYBICCSA-N 0.000 description 2
- CHIMBZVSKOKLNA-UTLKBRERSA-N N-[(2S)-2,5-diaminopentyl]-7-fluoro-3-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC2=C(C(=C1)F)NC(=C2C3=CC=C(C=C3)F)C(=O)NC[C@H](CCCN)N.Cl.Cl CHIMBZVSKOKLNA-UTLKBRERSA-N 0.000 description 2
- LNSGBTVNCILTPO-MJPDGKJBSA-N N-[[(2S,4R)-4-(aminomethyl)pyrrolidin-2-yl]methyl]-3,6-bis(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1[C@@H](CN[C@@H]1CNC(=O)C2=C(C3=C(N2)C=C(C=C3)C4=CC=C(C=C4)F)C5=CC=C(C=C5)F)CN.Cl.Cl LNSGBTVNCILTPO-MJPDGKJBSA-N 0.000 description 2
- OCPJDORBTZYIIQ-QUHUPCLFSA-N N-[[(2S,4R)-4-(aminomethyl)pyrrolidin-2-yl]methyl]-3-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1[C@@H](CN[C@@H]1CNC(=O)C2=C(C3=CC=CC=C3N2)C4=CC=C(C=C4)F)CN.Cl.Cl OCPJDORBTZYIIQ-QUHUPCLFSA-N 0.000 description 2
- MVFOPAPDUORCBR-KJWOGLQMSA-N N-[[(2S,4R)-4-(aminomethyl)pyrrolidin-2-yl]methyl]-7-fluoro-3-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1[C@@H](CN[C@@H]1CNC(=O)C2=C(C3=C(N2)C(=CC=C3)F)C4=CC=C(C=C4)F)CN.Cl.Cl MVFOPAPDUORCBR-KJWOGLQMSA-N 0.000 description 2
- LNSGBTVNCILTPO-VXTQUWGESA-N N-[[(2S,4S)-4-(aminomethyl)pyrrolidin-2-yl]methyl]-3,6-bis(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound C1[C@H](CN[C@@H]1CNC(=O)C2=C(C3=C(N2)C=C(C=C3)C4=CC=C(C=C4)F)C5=CC=C(C=C5)F)CN.Cl.Cl LNSGBTVNCILTPO-VXTQUWGESA-N 0.000 description 2
- OCPJDORBTZYIIQ-SYQYBFJOSA-N N-[[(2S,4S)-4-(aminomethyl)pyrrolidin-2-yl]methyl]-3-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.NC[C@H]1CN[C@H](CNC(=O)c2[nH]c3ccccc3c2-c2ccc(F)cc2)C1 OCPJDORBTZYIIQ-SYQYBFJOSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000122971 Stenotrophomonas Species 0.000 description 2
- 241000193985 Streptococcus agalactiae Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940035674 anesthetics Drugs 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000000423 cell based assay Methods 0.000 description 2
- 239000007958 cherry flavor Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- BTJRKNUKPQBLAL-UHFFFAOYSA-N hydron;4-methylmorpholine;chloride Chemical compound Cl.CN1CCOCC1 BTJRKNUKPQBLAL-UHFFFAOYSA-N 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 229940041033 macrolides Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- DNHVXZDHGTWAQW-UHFFFAOYSA-N methyl 5-bromo-1h-indole-2-carboxylate Chemical compound BrC1=CC=C2NC(C(=O)OC)=CC2=C1 DNHVXZDHGTWAQW-UHFFFAOYSA-N 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 108010038379 sargramostim Proteins 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XBGHEPSASSWTPI-KIYNQFGBSA-N tert-butyl N-[(2S)-1-amino-5-[(2-methylpropan-2-yl)oxycarbonylamino]hexan-2-yl]carbamate Chemical compound NC[C@H](CCC(C)NC(OC(C)(C)C)=O)NC(OC(C)(C)C)=O XBGHEPSASSWTPI-KIYNQFGBSA-N 0.000 description 2
- QWHGJHWNCSTDMH-DICHSLLOSA-N tert-butyl N-[[(3R,5S)-1-benzyl-5-[[[3,6-bis(4-fluorophenyl)-1H-indole-2-carbonyl]amino]methyl]pyrrolidin-3-yl]methyl]carbamate Chemical compound C(C1=CC=CC=C1)N1C[C@H](C[C@H]1CNC(=O)C=1NC2=CC(=CC=C2C=1C1=CC=C(C=C1)F)C1=CC=C(C=C1)F)CNC(OC(C)(C)C)=O QWHGJHWNCSTDMH-DICHSLLOSA-N 0.000 description 2
- ONFKXXDEQJFUFQ-BVAGGSTKSA-N tert-butyl N-[[(3R,5S)-1-benzyl-5-[[[3-(4-fluorophenyl)-1H-indole-2-carbonyl]amino]methyl]pyrrolidin-3-yl]methyl]carbamate Chemical compound C(C1=CC=CC=C1)N1C[C@H](C[C@H]1CNC(=O)C=1NC2=CC=CC=C2C=1C1=CC=C(C=C1)F)CNC(OC(C)(C)C)=O ONFKXXDEQJFUFQ-BVAGGSTKSA-N 0.000 description 2
- VSLAHEVLDDWUFG-APWZRJJASA-N tert-butyl N-[[(3R,5S)-5-[[[3-(4-fluorophenyl)-1H-indole-2-carbonyl]amino]methyl]pyrrolidin-3-yl]methyl]carbamate Chemical compound C(C)(C)(C)OC(NC[C@H]1CN[C@@H](C1)CNC(=O)C=1NC2=CC=CC=C2C=1C1=CC=C(C=C1)F)=O VSLAHEVLDDWUFG-APWZRJJASA-N 0.000 description 2
- QWHGJHWNCSTDMH-IEWVHIKDSA-N tert-butyl N-[[(3S,5S)-1-benzyl-5-[[[3,6-bis(4-fluorophenyl)-1H-indole-2-carbonyl]amino]methyl]pyrrolidin-3-yl]methyl]carbamate Chemical compound CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](CNC(=O)C2=C(C3=CC=C(C=C3N2)C2=CC=C(F)C=C2)C2=CC=C(F)C=C2)N(CC2=CC=CC=C2)C1 QWHGJHWNCSTDMH-IEWVHIKDSA-N 0.000 description 2
- VSLAHEVLDDWUFG-LPHOPBHVSA-N tert-butyl N-[[(3S,5S)-5-[[[3-(4-fluorophenyl)-1H-indole-2-carbonyl]amino]methyl]pyrrolidin-3-yl]methyl]carbamate Chemical compound C(C)(C)(C)OC(NC[C@@H]1CN[C@@H](C1)CNC(=O)C=1NC2=CC=CC=C2C=1C1=CC=C(C=C1)F)=O VSLAHEVLDDWUFG-LPHOPBHVSA-N 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229940040944 tetracyclines Drugs 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- RJOJSMIZZYHNQG-SNVBAGLBSA-N (2r)-2,5-bis[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC(C)(C)OC(=O)NCCC[C@H](C(O)=O)NC(=O)OC(C)(C)C RJOJSMIZZYHNQG-SNVBAGLBSA-N 0.000 description 1
- RJOJSMIZZYHNQG-JTQLQIEISA-N (2s)-2,5-bis[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC(C)(C)OC(=O)NCCC[C@@H](C(O)=O)NC(=O)OC(C)(C)C RJOJSMIZZYHNQG-JTQLQIEISA-N 0.000 description 1
- WIJNYNBSPQMJGO-UHFFFAOYSA-N (3-phenylmethoxyphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(OCC=2C=CC=CC=2)=C1 WIJNYNBSPQMJGO-UHFFFAOYSA-N 0.000 description 1
- GNRHNKBJNUVWFZ-UHFFFAOYSA-N (4-carbamoylphenyl)boronic acid Chemical compound NC(=O)C1=CC=C(B(O)O)C=C1 GNRHNKBJNUVWFZ-UHFFFAOYSA-N 0.000 description 1
- COIQUVGFTILYGA-UHFFFAOYSA-N (4-hydroxyphenyl)boronic acid Chemical compound OB(O)C1=CC=C(O)C=C1 COIQUVGFTILYGA-UHFFFAOYSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- BLPQQYCWJRGQIW-UHFFFAOYSA-N 1-benzyl-4-cyanopyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CC(C#N)CN1CC1=CC=CC=C1 BLPQQYCWJRGQIW-UHFFFAOYSA-N 0.000 description 1
- MGBRGNWARSQECY-UHFFFAOYSA-N 1-methoxy-3-methyl-2-nitrobenzene Chemical compound COC1=CC=CC(C)=C1[N+]([O-])=O MGBRGNWARSQECY-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- VFHUJFBEFDVZPJ-UHFFFAOYSA-N 1h-indole-2-carboxamide Chemical class C1=CC=C2NC(C(=O)N)=CC2=C1 VFHUJFBEFDVZPJ-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- YCNQPAVKQPLZRS-UHFFFAOYSA-N 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1CC1=CC=CC=C1 YCNQPAVKQPLZRS-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 1
- WVZMEDOMPHPGKL-UHFFFAOYSA-N 3,5-diphenyl-1H-indole-2-carboxylic acid Chemical compound C1(=CC=CC=C1)C1=C(NC2=CC=C(C=C12)C1=CC=CC=C1)C(=O)O WVZMEDOMPHPGKL-UHFFFAOYSA-N 0.000 description 1
- DKOLFGTXGJVKKR-UHFFFAOYSA-N 3,6-bis(4-fluorophenyl)-1H-indole-2-carboxylic acid Chemical compound FC1=CC=C(C=C1)C1=C(NC2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)O DKOLFGTXGJVKKR-UHFFFAOYSA-N 0.000 description 1
- YVHUNOUOGSZZRM-FJSYBICCSA-N 3-(2-cyclopropylethyl)-N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.C1(CC1)CCC1=C(NC2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)NC[C@H](CCCN)N YVHUNOUOGSZZRM-FJSYBICCSA-N 0.000 description 1
- VIBLKUPWRSLVAT-UHFFFAOYSA-N 3-(2-cyclopropylethynyl)-6-(4-fluorophenyl)-1H-indole-2-carboxylic acid Chemical compound C1(CC1)C#CC1=C(NC2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)O VIBLKUPWRSLVAT-UHFFFAOYSA-N 0.000 description 1
- GLNGUZOSCNUAPP-UHFFFAOYSA-N 3-(4-carboxyphenyl)-6-(4-fluorophenyl)-1H-indole-2-carboxylic acid Chemical compound C(=O)(O)C1=CC=C(C=C1)C1=C(NC2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)O GLNGUZOSCNUAPP-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000004606 5,6,7,8-tetrahydroisoquinolinyl group Chemical group C1(=NC=CC=2CCCCC12)* 0.000 description 1
- YAULOOYNCJDPPU-UHFFFAOYSA-N 5-bromo-1h-indole-2-carboxylic acid Chemical compound BrC1=CC=C2NC(C(=O)O)=CC2=C1 YAULOOYNCJDPPU-UHFFFAOYSA-N 0.000 description 1
- VDZPQMMXNHXHCH-UHFFFAOYSA-N 6-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole-2-carboxylic acid Chemical compound FC1=CC=C(C=C1)C1=CC=C2C(=C(NC2=C1)C(=O)O)C1=CC=C(C=C1)C(F)(F)F VDZPQMMXNHXHCH-UHFFFAOYSA-N 0.000 description 1
- XCFLHJHZOCWZQO-UHFFFAOYSA-N 7-[2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethoxy]-3-(4-methoxyphenyl)chromen-4-one Chemical compound C1=CC(OC)=CC=C1C1=COC2=CC(OCC(=O)N3CCN(CC3)C=3C=CC(F)=CC=3)=CC=C2C1=O XCFLHJHZOCWZQO-UHFFFAOYSA-N 0.000 description 1
- RTAPDZBZLSXHQQ-UHFFFAOYSA-N 8-methyl-3,7-dihydropurine-2,6-dione Chemical class N1C(=O)NC(=O)C2=C1N=C(C)N2 RTAPDZBZLSXHQQ-UHFFFAOYSA-N 0.000 description 1
- 241000607528 Aeromonas hydrophila Species 0.000 description 1
- 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 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 241000511343 Chondrostoma nasus Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108010074604 Epoetin Alfa Proteins 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 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 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- POMQYPOXIGWJMD-FJSYBICCSA-N N-[(2S)-2,5-diaminopentyl]-5-(4-fluorophenyl)-3-(3-hydroxyphenyl)-1H-indole-2-carboxamide dihydrochloride Chemical compound Cl.Cl.N[C@H](CNC(=O)C=1NC2=CC=C(C=C2C=1C1=CC(=CC=C1)O)C1=CC=C(C=C1)F)CCCN POMQYPOXIGWJMD-FJSYBICCSA-N 0.000 description 1
- OQRRMNJLWDBZNE-FGJQBABTSA-N N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole-2-carboxamide dihydrochloride Chemical compound C1=CC(=CC=C1C2=C(NC3=C2C=CC(=C3)C4=CC=C(C=C4)F)C(=O)NC[C@H](CCCN)N)C(F)(F)F.Cl.Cl OQRRMNJLWDBZNE-FGJQBABTSA-N 0.000 description 1
- FHEXKWIHOJGFKS-MLQCRBJCSA-N N-[(2S)-2,5-diaminopentyl]-6-(4-fluorophenyl)-3-pyridin-4-yl-1H-indole-2-carboxamide trihydrochloride Chemical compound C1=CC(=CC=C1C2=CC3=C(C=C2)C(=C(N3)C(=O)NC[C@H](CCCN)N)C4=CC=NC=C4)F.Cl.Cl.Cl FHEXKWIHOJGFKS-MLQCRBJCSA-N 0.000 description 1
- JSJJHGZJDWVPEW-UHFFFAOYSA-N NC(C(C=C1)=CC=C1C1=C(C(O)=O)N(C(O)=O)C2=CC(C(C=C3)=CC=C3F)=CC=C12)=O Chemical compound NC(C(C=C1)=CC=C1C1=C(C(O)=O)N(C(O)=O)C2=CC(C(C=C3)=CC=C3F)=CC=C12)=O JSJJHGZJDWVPEW-UHFFFAOYSA-N 0.000 description 1
- ZCFPESQUYVDMRA-FQEVSTJZSA-N NCCC[C@H](N)CNC(=O)c1[nH]c2cc(ccc2c1-c1ccncc1)-c1ccc(F)cc1 Chemical compound NCCC[C@H](N)CNC(=O)c1[nH]c2cc(ccc2c1-c1ccncc1)-c1ccc(F)cc1 ZCFPESQUYVDMRA-FQEVSTJZSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- FSFMONSPYMQJLC-UHFFFAOYSA-N OC(C(N(C(O)=O)C1=CC(C(C=C2)=CC=C2F)=CC=C11)=C1C(C=C1)=CC=C1O)=O Chemical compound OC(C(N(C(O)=O)C1=CC(C(C=C2)=CC=C2F)=CC=C11)=C1C(C=C1)=CC=C1O)=O FSFMONSPYMQJLC-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- RDTKYDQESWASRY-QFIPXVFZSA-N [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OC[C@H](CCC(C)=O)NC(OC(C)(C)C)=O Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)OC[C@H](CCC(C)=O)NC(OC(C)(C)C)=O RDTKYDQESWASRY-QFIPXVFZSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 229940070021 anabolic steroids Drugs 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 229940125714 antidiarrheal agent Drugs 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000000228 antimanic agent Substances 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 238000011203 antimicrobial therapy Methods 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 229940030999 antipsoriatics Drugs 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229960004669 basiliximab Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229940125388 beta agonist Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940052491 bordetella pertussis Drugs 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 125000005050 dihydrooxazolyl group Chemical group O1C(NC=C1)* 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 206010013023 diphtheria Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000009144 enzymatic modification Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960003388 epoetin alfa Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002834 estrogen receptor modulator Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- QQXQAEWRSVZPJM-UHFFFAOYSA-N ethyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OCC)=CC2=C1 QQXQAEWRSVZPJM-UHFFFAOYSA-N 0.000 description 1
- FEJFNBAKUYAOCI-UHFFFAOYSA-N ethyl 3-(3-methoxy-2-nitrophenyl)-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CC1=CC=CC(OC)=C1[N+]([O-])=O FEJFNBAKUYAOCI-UHFFFAOYSA-N 0.000 description 1
- DRJWEOYWZOGNQU-UHFFFAOYSA-N ethyl 3-bromo-1h-indole-2-carboxylate Chemical compound C1=CC=C2C(Br)=C(C(=O)OCC)NC2=C1 DRJWEOYWZOGNQU-UHFFFAOYSA-N 0.000 description 1
- BRDVNJZQPSSLMK-UHFFFAOYSA-N ethyl 7-methoxy-1h-indole-2-carboxylate Chemical compound C1=CC(OC)=C2NC(C(=O)OCC)=CC2=C1 BRDVNJZQPSSLMK-UHFFFAOYSA-N 0.000 description 1
- HZAIHFIZXXSPFA-UHFFFAOYSA-N ethynylcyclopropane Chemical compound [C+]#CC1CC1 HZAIHFIZXXSPFA-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005908 glyceryl ester group Chemical group 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 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 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000003835 ketolide antibiotic agent Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 229940087875 leukine Drugs 0.000 description 1
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- NQPIEWBAWBFGOB-UHFFFAOYSA-N methyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC)=CC2=C1 NQPIEWBAWBFGOB-UHFFFAOYSA-N 0.000 description 1
- HTCRHKSPPBPEEH-UHFFFAOYSA-N methyl 3,5-dibromo-1h-indole-2-carboxylate Chemical compound C1=C(Br)C=C2C(Br)=C(C(=O)OC)NC2=C1 HTCRHKSPPBPEEH-UHFFFAOYSA-N 0.000 description 1
- MSYAPRAJUNTJSI-UHFFFAOYSA-N methyl 3-bromo-6-(4-fluorophenyl)-1H-indole-2-carboxylate Chemical compound BrC1=C(NC2=CC(=CC=C12)C1=CC=C(C=C1)F)C(=O)OC MSYAPRAJUNTJSI-UHFFFAOYSA-N 0.000 description 1
- YSZOSQUHTPONPI-UHFFFAOYSA-N methyl 6-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]-1H-indole-2-carboxylate Chemical compound FC1=CC=C(C=C1)C1=CC=C2C(=C(NC2=C1)C(=O)OC)C1=CC=C(C=C1)C(F)(F)F YSZOSQUHTPONPI-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940029345 neupogen Drugs 0.000 description 1
- 239000000842 neuromuscular blocking agent Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- BTVYFIMKUHNOBZ-QXMMDKDBSA-N rifamycin s Chemical class O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C\C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C(C)C(OC)\C=C/OC1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-QXMMDKDBSA-N 0.000 description 1
- 229940081192 rifamycins Drugs 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007892 solid unit dosage form Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- IYHKDSXSAAYBHX-WNWQKLGWSA-N tert-butyl N-[(2S)-1-[[3,6-bis(4-fluorophenyl)-1H-indole-2-carbonyl]amino]-5-[(2-methylpropan-2-yl)oxycarbonylamino]hexan-2-yl]carbamate Chemical compound C(C(NC(=O)OC(C)(C)C)C)C[C@@H](CNC(=O)C=1NC2=CC(C3=CC=C(F)C=C3)=CC=C2C=1C1=CC=C(F)C=C1)NC(=O)OC(C)(C)C IYHKDSXSAAYBHX-WNWQKLGWSA-N 0.000 description 1
- WQBLSZSUNPCJQM-QHSFNAQHSA-N tert-butyl N-[(2S)-1-[[3,6-bis(4-fluorophenyl)-1H-indole-2-carbonyl]amino]-5-cyclopropyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentan-2-yl]carbamate Chemical compound C1C(C(CC[C@@H](CNC(=O)C=2NC3=CC(C4=CC=C(C=C4)F)=CC=C3C=2C2=CC=C(F)C=C2)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1 WQBLSZSUNPCJQM-QHSFNAQHSA-N 0.000 description 1
- FDFPPZYOXICDON-LSLKUGRBSA-N tert-butyl N-[(2S)-1-amino-5-cyclopropyl-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentan-2-yl]carbamate Chemical compound NC[C@H](CCC(C1CC1)NC(OC(C)(C)C)=O)NC(OC(C)(C)C)=O FDFPPZYOXICDON-LSLKUGRBSA-N 0.000 description 1
- GMECAFGSQGIQDF-KIYNQFGBSA-N tert-butyl N-[(2S)-1-hydroxy-5-[(2-methylpropan-2-yl)oxycarbonylamino]hexan-2-yl]carbamate Chemical compound OC[C@H](CCC(C)NC(OC(C)(C)C)=O)NC(OC(C)(C)C)=O GMECAFGSQGIQDF-KIYNQFGBSA-N 0.000 description 1
- UAOSJSAZOSWUKU-RDGATRHJSA-N tert-butyl N-[[(3R,5S)-1-benzyl-5-[[[7-fluoro-3-(4-fluorophenyl)-1H-indole-2-carbonyl]amino]methyl]pyrrolidin-3-yl]methyl]carbamate Chemical compound N1(CC2=CC=CC=C2)C[C@H](C[C@H]1CNC(=O)C=1NC2=C(C=CC=C2C=1C1=CC=C(F)C=C1)F)CNC(=O)OC(C)(C)C UAOSJSAZOSWUKU-RDGATRHJSA-N 0.000 description 1
- AUQJFVQKNLQUDJ-LYKKTTPLSA-N tert-butyl N-[[(5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl]methyl]carbamate Chemical compound C(C1=CC=CC=C1)N1CC(C[C@H]1CO)CNC(OC(C)(C)C)=O AUQJFVQKNLQUDJ-LYKKTTPLSA-N 0.000 description 1
- KAVYWJSWKCWBQV-CPJSRVTESA-N tert-butyl n-[(2s)-1-[4-[[(2s)-1-[(4-fluorophenyl)methylamino]-1-oxopropan-2-yl]carbamoyl]piperidin-1-yl]-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N1CCC(CC1)C(=O)N[C@@H](C)C(=O)NCC=1C=CC(F)=CC=1)NC(=O)OC(C)(C)C)C1=CC=CC=C1 KAVYWJSWKCWBQV-CPJSRVTESA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005306 thianaphthenyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/403—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 carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2022139960A JP2022169800A (ja) | 2017-05-26 | 2022-09-02 | 細菌の排出ポンプ阻害剤 |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762511851P | 2017-05-26 | 2017-05-26 | |
| US62/511,851 | 2017-05-26 | ||
| US201762523156P | 2017-06-21 | 2017-06-21 | |
| US62/523,156 | 2017-06-21 | ||
| PCT/US2018/034724 WO2018218192A1 (en) | 2017-05-26 | 2018-05-25 | Bacterial efflux pump inhibitors |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022139960A Division JP2022169800A (ja) | 2017-05-26 | 2022-09-02 | 細菌の排出ポンプ阻害剤 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2020527597A JP2020527597A (ja) | 2020-09-10 |
| JP2020527597A5 JP2020527597A5 (https=) | 2021-07-26 |
| JP7281822B2 true JP7281822B2 (ja) | 2023-05-26 |
Family
ID=64395990
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020515831A Active JP7281822B2 (ja) | 2017-05-26 | 2018-05-25 | 細菌の排出ポンプ阻害剤 |
| JP2022139960A Pending JP2022169800A (ja) | 2017-05-26 | 2022-09-02 | 細菌の排出ポンプ阻害剤 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022139960A Pending JP2022169800A (ja) | 2017-05-26 | 2022-09-02 | 細菌の排出ポンプ阻害剤 |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US11826357B2 (https=) |
| EP (1) | EP3630109A4 (https=) |
| JP (2) | JP7281822B2 (https=) |
| CN (1) | CN111163774A (https=) |
| WO (1) | WO2018218192A1 (https=) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10836706B2 (en) | 2016-02-24 | 2020-11-17 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| US10556854B2 (en) | 2016-02-24 | 2020-02-11 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| US11938114B2 (en) | 2017-03-10 | 2024-03-26 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| WO2018165612A1 (en) | 2017-03-10 | 2018-09-13 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| CN110770224B (zh) | 2017-03-10 | 2022-11-18 | 罗格斯新泽西州立大学 | 作为外排泵抑制剂的吲哚衍生物 |
| EP3630109A4 (en) | 2017-05-26 | 2021-03-17 | Rutgers, the State University of New Jersey | BACTERIAL EFFLUX PUMP INHIBITORS |
| WO2019005841A1 (en) | 2017-06-26 | 2019-01-03 | Rutgers, The State University Of New Jersey | THERAPEUTIC COMPOUNDS AND METHODS FOR TREATING INFECTION |
| US11845742B2 (en) | 2017-11-14 | 2023-12-19 | Rutgers, The State University Of New Jersey | Therapeutic compounds and methods to treat infection |
| WO2021203014A1 (en) | 2020-04-03 | 2021-10-07 | Vertex Pharmaceuticals Incorporated | Pyrano[4,3-b]l ndole derivatives as alpha-1 -antitrypsin modulators for treating alpha-1 -antitrypsin deficiency (aatd) |
| US20240239771A1 (en) * | 2020-05-29 | 2024-07-18 | Taxis Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors |
| AU2024327693A1 (en) * | 2023-08-23 | 2026-04-02 | Taxis Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005508311A (ja) | 2001-08-07 | 2005-03-31 | エフ．ホフマン−ラ ロシュ アーゲー | ｏ−フェニレンジアミンのＮ−モノアシル化誘導体、その六員複素環式アナログ、及び薬剤としてのそれらの使用 |
| WO2009158375A1 (en) | 2008-06-25 | 2009-12-30 | Abbott Laboratories | Aza-cylic indole- 2 -carboxamides and methods of use thereof |
| WO2010119984A1 (en) | 2009-04-16 | 2010-10-21 | Banyu Pharmaceutical Co.,Ltd. | 3-aryl or heteroaryl-substituted indole derivative |
| JP2015527388A (ja) | 2012-09-07 | 2015-09-17 | ノバルティス アーゲー | インドールカルボキサミド誘導体およびその使用 |
| WO2015164482A1 (en) | 2014-04-22 | 2015-10-29 | The Johns Hopkins University | Inhibitors of drug-resistant mycobacterium tuberculosis |
| US20160271082A1 (en) | 2015-03-10 | 2016-09-22 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| JP2020510044A (ja) | 2017-03-10 | 2020-04-02 | ラトガーズ， ザ ステイト ユニバーシティ オブ ニュー ジャージー | 排出ポンプ阻害剤としてのインドール誘導体 |
Family Cites Families (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL133069C (https=) * | 1966-07-29 | |||
| AR204240A1 (es) | 1972-12-13 | 1975-12-10 | Scherico Ltd | La preparacion de 2-aminoalcohil-3-fenil-indoles |
| US3996159A (en) * | 1972-12-13 | 1976-12-07 | Schering Corporation | Antimicrobial compositions |
| US4014883A (en) * | 1973-09-10 | 1977-03-29 | Hoffmann-La Roche Inc. | Indoloquinolines, intermediates and processes |
| US3978224A (en) | 1975-07-01 | 1976-08-31 | Schering Corporation | Antimicrobial halo-substituted-2-cyanoethylaminoalkyl-3-phenyl-indoles |
| US4938949A (en) | 1988-09-12 | 1990-07-03 | University Of New York | Treatment of damaged bone marrow and dosage units therefor |
| WO1992004017A1 (en) | 1990-09-10 | 1992-03-19 | The Upjohn Company | Cis-n-(2-aminocyclohexyl)benzamide and their enantiomers as anticonvulsants |
| US5663152A (en) | 1995-01-19 | 1997-09-02 | Asahi Kasei Kogyo Kabushiki Kaisha | Potentiators for aminoglycosides |
| US6204279B1 (en) | 1998-06-03 | 2001-03-20 | Microcide Pharmaceuticals, Inc. | Peptidomimetic efflux pump inhibitors |
| CA2353557A1 (en) | 1998-12-04 | 2000-06-08 | Influx, Inc. | Inhibitors of multidrug transporters |
| US6730684B1 (en) | 1999-10-08 | 2004-05-04 | Affinium Pharmaceuticals, Inc. | Fab I inhibitors |
| US6555569B2 (en) | 2000-03-07 | 2003-04-29 | Pfizer Inc. | Use of heteroaryl substituted N-(indole-2-carbonyl-) amides for treatment of infection |
| US7829543B2 (en) | 2003-01-07 | 2010-11-09 | Paratek Pharmaceuticals, Inc. | Substituted polyamines as inhibitors of bacterial efflux pumps |
| US7994225B2 (en) | 2004-03-17 | 2011-08-09 | Rempex Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors for the treatment of ophthalmic and otic infections |
| WO2005113579A1 (en) * | 2004-05-21 | 2005-12-01 | Mpex Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors and methods of treating bacterial infections |
| US8143257B2 (en) | 2004-11-23 | 2012-03-27 | Ptc Therapeutics, Inc. | Substituted phenols as active agents inhibiting VEGF production |
| US7855228B2 (en) | 2005-02-10 | 2010-12-21 | The Board Of Trustees Of The Leland Stamford Junior University | Antibiotics targeting MreB |
| DE102006033109A1 (de) * | 2006-07-18 | 2008-01-31 | Grünenthal GmbH | Substituierte Heteroaryl-Derivate |
| EP3192788A1 (en) | 2006-10-03 | 2017-07-19 | Arbutus Biopharma Corporation | Lipid containing formulations |
| CA2682483A1 (en) * | 2007-03-29 | 2008-10-09 | Novartis Ag | 3-imidazolyl-indoles for the treatment of proliferative diseases |
| WO2009110002A1 (en) | 2008-03-05 | 2009-09-11 | Council Of Scientific & Industrial Research | Novel efflux pump inhibitors |
| EP2303852A4 (en) | 2008-06-26 | 2011-12-28 | Glaxosmithkline Llc | ACTIVITY INHIBITORS AKT |
| CA2737038A1 (en) | 2008-09-18 | 2010-03-25 | Evotec Ag | Amide compounds, compositions and uses thereof |
| EA201101451A1 (ru) | 2009-04-03 | 2012-03-30 | Ачиллион Фармасьютикалз, Инк. | Гидрокситиенохинолоны и родственные соединения как противоинфекционные средства |
| EP2536408A1 (en) | 2010-02-16 | 2012-12-26 | Wockhardt Research Centre | Efflux pump inhibitors |
| FR2969150B1 (fr) | 2010-12-20 | 2013-07-26 | Centre Nat Rech Scient | Nouvelles molecules indoliques demontrant des activites antibacteriennes dans une variete de bacteries a gram-negatif et positif dont des bacteries multidrogues-resistantes |
| CA2890748A1 (en) | 2012-11-13 | 2014-05-22 | Memorial Sloan-Kettering Cancer Center | Indole compounds and their use as antimicrobials |
| US9950993B2 (en) | 2015-03-13 | 2018-04-24 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| KR20180011843A (ko) | 2015-06-11 | 2018-02-02 | 바실리어 파마슈티카 인터내셔널 리미티드 | 유출-펌프 억제제 및 이의 치료적 용도 |
| US10836706B2 (en) | 2016-02-24 | 2020-11-17 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| US10556854B2 (en) | 2016-02-24 | 2020-02-11 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| US11938114B2 (en) | 2017-03-10 | 2024-03-26 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| WO2018165612A1 (en) | 2017-03-10 | 2018-09-13 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| EP3630109A4 (en) | 2017-05-26 | 2021-03-17 | Rutgers, the State University of New Jersey | BACTERIAL EFFLUX PUMP INHIBITORS |
| WO2019005841A1 (en) | 2017-06-26 | 2019-01-03 | Rutgers, The State University Of New Jersey | THERAPEUTIC COMPOUNDS AND METHODS FOR TREATING INFECTION |
| US20190031624A1 (en) | 2017-07-28 | 2019-01-31 | Rutgers, The State University Of New Jersey | Therapeutic compounds and methods to treat infection |
-
2018
- 2018-05-25 EP EP18806950.4A patent/EP3630109A4/en not_active Withdrawn
- 2018-05-25 CN CN201880045566.2A patent/CN111163774A/zh active Pending
- 2018-05-25 US US16/616,903 patent/US11826357B2/en active Active
- 2018-05-25 WO PCT/US2018/034724 patent/WO2018218192A1/en not_active Ceased
- 2018-05-25 JP JP2020515831A patent/JP7281822B2/ja active Active
-
2022
- 2022-09-02 JP JP2022139960A patent/JP2022169800A/ja active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005508311A (ja) | 2001-08-07 | 2005-03-31 | エフ．ホフマン−ラ ロシュ アーゲー | ｏ−フェニレンジアミンのＮ−モノアシル化誘導体、その六員複素環式アナログ、及び薬剤としてのそれらの使用 |
| WO2009158375A1 (en) | 2008-06-25 | 2009-12-30 | Abbott Laboratories | Aza-cylic indole- 2 -carboxamides and methods of use thereof |
| WO2010119984A1 (en) | 2009-04-16 | 2010-10-21 | Banyu Pharmaceutical Co.,Ltd. | 3-aryl or heteroaryl-substituted indole derivative |
| JP2015527388A (ja) | 2012-09-07 | 2015-09-17 | ノバルティス アーゲー | インドールカルボキサミド誘導体およびその使用 |
| WO2015164482A1 (en) | 2014-04-22 | 2015-10-29 | The Johns Hopkins University | Inhibitors of drug-resistant mycobacterium tuberculosis |
| US20160271082A1 (en) | 2015-03-10 | 2016-09-22 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| JP2020510044A (ja) | 2017-03-10 | 2020-04-02 | ラトガーズ， ザ ステイト ユニバーシティ オブ ニュー ジャージー | 排出ポンプ阻害剤としてのインドール誘導体 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2020527597A (ja) | 2020-09-10 |
| WO2018218192A1 (en) | 2018-11-29 |
| US20200197382A1 (en) | 2020-06-25 |
| JP2022169800A (ja) | 2022-11-09 |
| CN111163774A (zh) | 2020-05-15 |
| US11826357B2 (en) | 2023-11-28 |
| EP3630109A1 (en) | 2020-04-08 |
| EP3630109A4 (en) | 2021-03-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7281822B2 (ja) | 細菌の排出ポンプ阻害剤 | |
| JP7323179B2 (ja) | 排出ポンプ阻害剤としてのインドール誘導体 | |
| KR101475311B1 (ko) | 항암 활성을 갖는 화합물 | |
| US11938114B2 (en) | Bacterial efflux pump inhibitors | |
| US11180459B2 (en) | Bacterial efflux pump inhibitors | |
| US9926261B2 (en) | Bacterial efflux pump inhibitors | |
| WO2019099402A1 (en) | Therapeutic compounds and methods to treat infection | |
| WO2017147333A1 (en) | Bacterial efflux pump inhibitors | |
| WO2017147335A1 (en) | Bacterial efflux pump inhibitors | |
| WO2013106756A2 (en) | Antimicrobial agents | |
| WO2021243273A1 (en) | Bacterial efflux pump inhibitors | |
| HK40028701A (en) | Bacterial efflux pump inhibitors | |
| AU2024327693A1 (en) | Bacterial efflux pump inhibitors | |
| HK40083024A (en) | Quinoline compounds with anti-cancer activity | |
| HK40020543A (en) | Indole derivatives as efflux pump inhibitors | |
| HK1139143B (en) | Compounds with anti-cancer activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210511 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210511 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220526 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220602 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220902 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221228 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230324 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20230412 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20230509 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 7281822 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |