NZ577491A - 2-heteroaryl-3-hydroxy-4-oxo-pyrido[1,2-a]pyrimidines and uses thereof - Google Patents
2-heteroaryl-3-hydroxy-4-oxo-pyrido[1,2-a]pyrimidines and uses thereofInfo
- Publication number
- NZ577491A NZ577491A NZ577491A NZ57749107A NZ577491A NZ 577491 A NZ577491 A NZ 577491A NZ 577491 A NZ577491 A NZ 577491A NZ 57749107 A NZ57749107 A NZ 57749107A NZ 577491 A NZ577491 A NZ 577491A
- Authority
- NZ
- New Zealand
- Prior art keywords
- hydroxy
- oxo
- preparation
- carboxylic acid
- pyrimidine
- Prior art date
Links
- 150000003230 pyrimidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 30
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 29
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
- 125000001424 substituent group Chemical group 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 208000036142 Viral infection Diseases 0.000 claims abstract description 12
- 230000009385 viral infection Effects 0.000 claims abstract description 12
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims description 232
- -1 NR3R4 Chemical group 0.000 claims description 75
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 48
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000000651 prodrug Substances 0.000 claims description 21
- 229940002612 prodrug Drugs 0.000 claims description 21
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 9
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- 125000000539 amino acid group Chemical group 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 150000001408 amides Chemical group 0.000 claims description 5
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 238000011321 prophylaxis Methods 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
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- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical group [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 150000003536 tetrazoles Chemical class 0.000 claims description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
- 150000003852 triazoles Chemical class 0.000 claims description 2
- 125000006287 difluorobenzyl group Chemical group 0.000 claims 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims 1
- YNKQTHWULHZISA-UHFFFAOYSA-N 3-hydroxypyrido[1,2-a]pyrimidin-4-one Chemical class C1=CC=CN2C(=O)C(O)=CN=C21 YNKQTHWULHZISA-UHFFFAOYSA-N 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 180
- 238000000034 method Methods 0.000 description 168
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 151
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
- 239000000047 product Substances 0.000 description 131
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 239000000203 mixture Substances 0.000 description 73
- IXHNFOOSLAWRBQ-UHFFFAOYSA-N (3,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C(Cl)=C1 IXHNFOOSLAWRBQ-UHFFFAOYSA-N 0.000 description 69
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 68
- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 68
- 239000000243 solution Substances 0.000 description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 101150041968 CDC13 gene Proteins 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 39
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 36
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- 239000007787 solid Substances 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 239000002253 acid Substances 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 18
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 239000000872 buffer Substances 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 14
- IIVUJUOJERNGQX-UHFFFAOYSA-N pyrimidine-5-carboxylic acid Chemical compound OC(=O)C1=CN=CN=C1 IIVUJUOJERNGQX-UHFFFAOYSA-N 0.000 description 14
- 102100034343 Integrase Human genes 0.000 description 13
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- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
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- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- 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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
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- Virology (AREA)
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- Pulmonology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Applications Claiming Priority (5)
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| AU2006907283A AU2006907283A0 (en) | 2006-12-22 | Bicyclic pyrimidinones and uses thereof | |
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| AU2007903401A AU2007903401A0 (en) | 2007-06-25 | Bicyclic pyrimidinodes and uses thereof (3) | |
| AU2007904114A AU2007904114A0 (en) | 2007-07-31 | Bicyclic pyrimidinones and uses thereof (4) | |
| PCT/AU2007/001980 WO2008077188A1 (en) | 2006-12-22 | 2007-12-21 | Bicyclic pyrimidinones and uses thereof |
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| PL2247601T3 (pl) * | 2008-07-02 | 2013-09-30 | Avexa Ltd | Tiazopirymidynony i ich zastosowanie |
| EP2759544A1 (en) * | 2008-07-02 | 2014-07-30 | Avexa Limited | Compounds having antiviral properties |
| CA2729656A1 (en) * | 2008-07-02 | 2010-01-07 | Avexa Limited | Imidazopyrimidinones and uses thereof |
| CN102336751A (zh) * | 2010-07-16 | 2012-02-01 | 爱维艾珂瑟有限公司 | 新型抗病毒剂 |
| JP6448647B2 (ja) | 2013-09-12 | 2019-01-09 | アリオス バイオファーマ インク． | アザ−ピリドン化合物およびその用途 |
| US10195202B2 (en) | 2013-12-19 | 2019-02-05 | Ptc Therapeutics, Inc. | Methods for modulating the amount of RNA transcripts |
| EA036776B1 (ru) | 2015-03-11 | 2020-12-21 | Янссен Байофарма, Инк. | Соединения азапиридона и способы их применения |
| WO2016196386A1 (en) | 2015-05-30 | 2016-12-08 | Ptc Therapeutics, Inc. | Methods for modulating rna splicing |
| WO2017100726A1 (en) | 2015-12-10 | 2017-06-15 | Ptc Therapeutics, Inc. | Methods for treatng huntington's disease |
| EA201991309A1 (ru) | 2016-11-28 | 2019-11-29 | Способы модуляции сплайсинга рнк | |
| BR112019025740A2 (pt) | 2017-06-05 | 2020-06-23 | Ptc Therapeutics, Inc. | Compostos para tratar a doença de huntington |
| WO2018232039A1 (en) | 2017-06-14 | 2018-12-20 | Ptc Therapeutics, Inc. | Methods for modifying rna splicing |
| MX2019015580A (es) | 2017-06-28 | 2020-07-28 | Ptc Therapeutics Inc | Metodos para tratar la enfermedad de huntington. |
| US11382918B2 (en) | 2017-06-28 | 2022-07-12 | Ptc Therapeutics, Inc. | Methods for treating Huntington's Disease |
| SG11202009212WA (en) | 2018-03-27 | 2020-10-29 | Ptc Therapeutics Inc | Compounds for treating huntington's disease |
| JP7421507B2 (ja) | 2018-06-27 | 2024-01-24 | ピーティーシー セラピューティクス， インコーポレイテッド | ハンチントン病を処置するためのヘテロ環式およびヘテロアリール化合物 |
| EP3814360B8 (en) | 2018-06-27 | 2024-11-06 | PTC Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| BR112020026534A2 (pt) | 2018-06-27 | 2021-03-23 | Ptc Therapeutics, Inc. | Compostos de heteroarila para o tratamento da doença de huntington |
| BR112022010561A2 (pt) | 2019-12-02 | 2022-11-16 | Storm Therapeutics Ltd | Compostos poli-heterocíclicos como inibidores de mettl3 |
| US12070445B2 (en) * | 2021-08-27 | 2024-08-27 | Wisconsin Alumni Research Foundation | System and assay for monitoring production/release of membrane-lytic toxins in bacteria and compounds for modulating same |
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| ES2233708T3 (es) | 2000-09-20 | 2005-06-16 | Schering Corporation | Imidazoles sustituidos como agonistas o antagonistas duales de la histamina h1 y la h3. |
| NZ533641A (en) | 2002-11-20 | 2006-07-28 | Japan Tobacco Inc | 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors |
| RU2379302C2 (ru) | 2003-12-18 | 2010-01-20 | Тиботек Фармасьютикалз Лтд. | Аминобензимидазолы и бензимидазолы в качестве ингибиторов репликации респираторно-синцитиального вируса |
| TW200526635A (en) | 2003-12-22 | 2005-08-16 | Shionogi & Co | Hydroxypyrimidinone derivative having HIV integrase inhibitory activity |
| CA2581516C (en) | 2004-10-12 | 2013-06-11 | Astrazeneca Ab | Quinazoline derivatives |
| US7981879B2 (en) * | 2005-03-31 | 2011-07-19 | Instituto di Ricerchi di Biologia Molecolare P. Angeletti S.p.A. | HIV integrase inhibitors |
| JP5094725B2 (ja) * | 2005-10-04 | 2012-12-12 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・エルレ・エルレ | Ｈｉｖインテグラーゼ阻害剤 |
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2007
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2010
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2012
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