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
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- Prior art keywords
- alkyl
- carbocyclyl
- substituted
- heteroaryl
- compound
- Prior art date
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- 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
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- 239000003814 drug Substances 0.000 claims description 23
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- 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
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- 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
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- 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
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- 241000588652 Neisseria gonorrhoeae Species 0.000 claims description 3
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 290
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- 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)
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|---|---|---|---|
| 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)
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| JP2020527597A JP2020527597A (ja) | 2020-09-10 |
| JP2020527597A5 JP2020527597A5 (https=) | 2021-07-26 |
| JP7281822B2 true JP7281822B2 (ja) | 2023-05-26 |
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| JP2022139960A Pending JP2022169800A (ja) | 2017-05-26 | 2022-09-02 | 細菌の排出ポンプ阻害剤 |
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| Country | Link |
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| US (1) | US11826357B2 (https=) |
| EP (1) | EP3630109A4 (https=) |
| JP (2) | JP7281822B2 (https=) |
| CN (1) | CN111163774A (https=) |
| WO (1) | WO2018218192A1 (https=) |
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| US10556854B2 (en) | 2016-02-24 | 2020-02-11 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| WO2017147335A1 (en) | 2016-02-24 | 2017-08-31 | Rutgers, The State University Of New Jersey | Bacterial efflux pump inhibitors |
| SG11201908351TA (en) | 2017-03-10 | 2019-10-30 | Edmond J Lavoie | Indole derivatives as 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 |
| WO2019099402A1 (en) | 2017-11-14 | 2019-05-23 | Rutgers, The State University Of New Jersey | Therapeutic compounds and methods to treat infection |
| JP7732999B2 (ja) | 2020-04-03 | 2025-09-02 | バーテックス ファーマシューティカルズ インコーポレイテッド | アルファ１－アンチトリプシンのモジュレーター |
| US20240239771A1 (en) * | 2020-05-29 | 2024-07-18 | Taxis Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors |
| WO2025043115A1 (en) * | 2023-08-23 | 2025-02-27 | 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 | |||
| US3996159A (en) * | 1972-12-13 | 1976-12-07 | Schering Corporation | Antimicrobial compositions |
| AR204240A1 (es) * | 1972-12-13 | 1975-12-10 | Scherico Ltd | La preparacion de 2-aminoalcohil-3-fenil-indoles |
| 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 |
| US6326391B1 (en) * | 1998-12-04 | 2001-12-04 | 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 |
| WO2011101710A1 (en) | 2010-02-16 | 2011-08-25 | Wockhardt Research Centre | Efflux pump inhibitors |
| WO2004062674A2 (en) | 2003-01-07 | 2004-07-29 | 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 |
| EP1758920A1 (en) | 2004-05-21 | 2007-03-07 | Mpex Pharmaceuticals, Inc. | Bacterial efflux pump inhibitors and methods of treating bacterial infections |
| WO2006058088A2 (en) | 2004-11-23 | 2006-06-01 | Ptc Therapeutics, Inc. | Carbazole, carboline and indole derivatives useful in the inhibition of 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 |
| CA2927045A1 (en) | 2006-10-03 | 2008-04-10 | Muthiah Manoharan | Lipid containing formulations |
| EA200901212A1 (ru) * | 2007-03-29 | 2010-04-30 | Новартис Аг | 3-имидазолилиндолы, предназначенные для лечения пролиферативных заболеваний |
| 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 |
| JP5608655B2 (ja) | 2008-09-18 | 2014-10-15 | エヴォテック アーゲー | Ｐ２ｘ３受容体活性のモジュレーター |
| WO2010115184A2 (en) | 2009-04-03 | 2010-10-07 | Achillion Pharmaceuticals, Inc. | Hydroxythienoquinolones and related compounds as anti-infective agents |
| 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 |
| WO2014078294A1 (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 |
| CN107709314A (zh) | 2015-06-11 | 2018-02-16 | 巴斯利尔药物国际股份公司 | 外排泵抑制剂及其治疗性用途 |
| WO2017147335A1 (en) | 2016-02-24 | 2017-08-31 | 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 WO PCT/US2018/034724 patent/WO2018218192A1/en not_active Ceased
- 2018-05-25 US US16/616,903 patent/US11826357B2/en active Active
- 2018-05-25 JP JP2020515831A patent/JP7281822B2/ja active Active
- 2018-05-25 CN CN201880045566.2A patent/CN111163774A/zh active Pending
-
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 |
|---|---|
| EP3630109A4 (en) | 2021-03-17 |
| US20200197382A1 (en) | 2020-06-25 |
| JP2020527597A (ja) | 2020-09-10 |
| WO2018218192A1 (en) | 2018-11-29 |
| EP3630109A1 (en) | 2020-04-08 |
| US11826357B2 (en) | 2023-11-28 |
| CN111163774A (zh) | 2020-05-15 |
| JP2022169800A (ja) | 2022-11-09 |
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