CA2480869A1 - Anxiolytic agents with reduced sedative and ataxic effects - Google Patents
Anxiolytic agents with reduced sedative and ataxic effects Download PDFInfo
- Publication number
- CA2480869A1 CA2480869A1 CA002480869A CA2480869A CA2480869A1 CA 2480869 A1 CA2480869 A1 CA 2480869A1 CA 002480869 A CA002480869 A CA 002480869A CA 2480869 A CA2480869 A CA 2480869A CA 2480869 A1 CA2480869 A1 CA 2480869A1
- Authority
- CA
- Canada
- Prior art keywords
- substituted
- cyclopropyl
- substituent
- thienyl
- phenyl
- 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.)
- Abandoned
Links
- 230000002829 reductive effect Effects 0.000 title abstract description 63
- 239000002249 anxiolytic agent Substances 0.000 title abstract description 15
- 230000001624 sedative effect Effects 0.000 title abstract description 10
- 230000001977 ataxic effect Effects 0.000 title abstract description 8
- 239000000932 sedative agent Substances 0.000 title abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 165
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 125000001424 substituent group Chemical group 0.000 claims abstract description 71
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 61
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 54
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 53
- -1 CH2CCH Chemical group 0.000 claims abstract description 49
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 47
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 41
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 39
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 37
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 30
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 30
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 29
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims abstract description 22
- 125000006430 alkyl cyclopropyl group Chemical group 0.000 claims abstract description 7
- 239000000651 prodrug Substances 0.000 claims description 39
- 229940002612 prodrug Drugs 0.000 claims description 39
- 229910007161 Si(CH3)3 Inorganic materials 0.000 claims description 31
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 14
- 125000006431 methyl cyclopropyl group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- ROWMQJJMCWDJDT-UHFFFAOYSA-N tribromomethane Chemical compound Br[C](Br)Br ROWMQJJMCWDJDT-UHFFFAOYSA-N 0.000 claims description 8
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 claims description 8
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
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- 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- 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
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- 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
- C07D487/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—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
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Organic Chemistry (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Otolaryngology (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
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| US36840802P | 2002-03-28 | 2002-03-28 | |
| US60/368,408 | 2002-03-28 | ||
| PCT/US2003/009587 WO2003082832A2 (en) | 2002-03-28 | 2003-03-28 | Anxiolytic agents with reduced sedative and ataxic effects |
Publications (1)
| Publication Number | Publication Date |
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| CA2480869A1 true CA2480869A1 (en) | 2003-10-09 |
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Family Applications (1)
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| CA002480869A Abandoned CA2480869A1 (en) | 2002-03-28 | 2003-03-28 | Anxiolytic agents with reduced sedative and ataxic effects |
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| JP (1) | JP2005525392A (enExample) |
| KR (2) | KR20080060286A (enExample) |
| CN (1) | CN1642924A (enExample) |
| AT (1) | ATE389640T1 (enExample) |
| AU (1) | AU2003230754B2 (enExample) |
| BR (1) | BR0308918A (enExample) |
| CA (1) | CA2480869A1 (enExample) |
| DE (1) | DE60319812T2 (enExample) |
| DK (1) | DK1490344T3 (enExample) |
| ES (1) | ES2300576T3 (enExample) |
| IL (1) | IL163958A0 (enExample) |
| MX (1) | MXPA04009332A (enExample) |
| NZ (1) | NZ535517A (enExample) |
| WO (1) | WO2003082832A2 (enExample) |
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| USRE47475E1 (en) * | 2002-03-28 | 2019-07-02 | Wisys Technology Foundation, Inc. | Selective agents for pain suppression |
| AU2005260650A1 (en) | 2004-06-30 | 2006-01-12 | Wisys Technology Foundation, Inc. | Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects |
| US8119629B2 (en) * | 2007-10-03 | 2012-02-21 | Bristol-Meyers Squibb Company | Carboxamide GABAA α2 modulators |
| TWI422369B (zh) * | 2008-01-22 | 2014-01-11 | Lilly Co Eli | κ選擇性類鴉片受體拮抗劑 |
| US20100261711A1 (en) * | 2009-03-20 | 2010-10-14 | Wisys Technology Foundation | Selective anticonvulsant agents and their uses |
| JP2013209292A (ja) * | 2010-07-23 | 2013-10-10 | Nippon Chemiphar Co Ltd | Ｐ２ｘ４受容体拮抗剤 |
| US9006233B2 (en) | 2011-04-28 | 2015-04-14 | Uwm Research Foundation, Inc. | Gabaergic receptor subtype selective ligands and their uses |
| US20150374705A1 (en) | 2012-02-14 | 2015-12-31 | Shanghai Institues for Biological Sciences | Substances for treatment or relief of pain |
| CA2885148A1 (en) | 2012-09-21 | 2014-03-27 | Uwm Research Foundation, Inc. | Novel gabaa agonists and methods of using to control airway hyperresponsiveness and inflammation in asthma |
| FR3010785B1 (fr) * | 2013-09-18 | 2015-08-21 | Snecma | Procede de controle de la densite d'energie d'un faisceau laser par analyse d'image et dispositif correspondant |
| CA3012791C (en) | 2016-01-27 | 2024-01-23 | Universitat Zurich | Use of gabaa receptor modulators for treatment of itch |
| SI3439665T1 (sl) | 2016-03-18 | 2023-05-31 | Uwm Research Foundation, Inc. | Zdravljenje kognitivnih simptomov in simptomov razpoloženja pri nevrodegenerativnih in nevropsihiatričnih motnjah z agonisti receptorja GABAA, ki vsebujejo ALFA5 |
| CA3033964A1 (en) | 2016-08-16 | 2018-02-22 | Uwm Research Foundation, Inc. | Gaba(a) receptor modulators and methods to control airway hyperresponsiveness and inflammation in asthma |
| JP7139323B2 (ja) * | 2016-11-01 | 2022-09-20 | エフ．ホフマン－ラ ロシュ アーゲー | Ｃｎｓ関連疾患を処置するための１，３－ジヒドロ－１，４－ベンゾジアゼピン－２－チオン |
| CN107056760A (zh) * | 2017-01-22 | 2017-08-18 | 苏州楚凯药业有限公司 | 5,7位取代的1H‑苯并[e][1,4]二氮杂‑2(3H)‑酮衍生物的制备方法 |
| CN107216332B (zh) * | 2017-06-29 | 2019-04-30 | 上海药明康德新药开发有限公司 | 叔丁基-7-羟甲基-7,8-二氢4h吡唑并二氮杂卓5(6h)甲酸基酯的合成方法 |
| CN107325101B (zh) * | 2017-06-29 | 2019-03-26 | 上海合全药物研发有限公司 | 6-羟甲基-6,7-二氢-5h,9h-咪唑并二氮杂卓-8-羧酸叔丁酯的合成方法 |
| US20200316087A1 (en) | 2017-10-03 | 2020-10-08 | Uwm Research Foundation, Inc. | Novel combination therapy for anxiety disorders, epilepsy, and pain |
| CN115380034A (zh) | 2020-03-31 | 2022-11-22 | 豪夫迈·罗氏有限公司 | 作为GABA Aγ1 PAM的苯并二氮杂䓬衍生物 |
| US12161622B2 (en) | 2021-05-04 | 2024-12-10 | Janssen Pharmaceuticals, Inc. | Compositions and methods for the treatment of depression |
| AR127127A1 (es) * | 2021-09-24 | 2023-12-20 | Hoffmann La Roche | NUEVOS DERIVADOS DE PIRIDODIAZEPINAS COMO PAM DE GABAA g1 |
| EP4408848B1 (en) | 2021-09-29 | 2025-11-05 | F. Hoffmann-La Roche AG | Benzodiazepine derivatives as gaba a gamma1 positive allosteric modulators |
| JP2024536393A (ja) | 2021-10-06 | 2024-10-04 | エフ． ホフマン－ラ ロシュ アーゲー | ＧＡＢＡ Ａ γ１受容体のポジティブアロステリックモジュレーターとしてのベンゾジアゼピン誘導体 |
| WO2023170550A1 (en) | 2022-03-07 | 2023-09-14 | Janssen Pharmaceuticals, Inc. | Polymorph forms of aticaprant for use in treating major depressive disorder |
| JP2025508069A (ja) | 2022-03-07 | 2025-03-21 | ヤンセン ファーマシューティカルズ，インコーポレーテッド | アチカプラントを含む組成物 |
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| US2893992A (en) | 1959-07-07 | I ii i i | ||
| US3886141A (en) * | 1971-10-07 | 1975-05-27 | Hoffmann La Roche | Preparation of 5-pyridyl benzodiazepine utilizing hexamethylenetetramine |
| US4440685A (en) * | 1974-09-11 | 1984-04-03 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
| US4280957A (en) | 1974-09-11 | 1981-07-28 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
| US4401597A (en) | 1978-05-15 | 1983-08-30 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
| DE3435973A1 (de) * | 1984-10-01 | 1986-04-10 | Boehringer Ingelheim KG, 6507 Ingelheim | Diazepine enthaltende pharmazeutische zusammensetzungen mit paf-antagonistischer wirkung |
| ES2037013T3 (es) * | 1986-01-21 | 1993-06-16 | Boehringer Ingelheim Kg | Procedimiento para preparar tieno-1,4-diazepinas. |
| MC1999A1 (fr) * | 1987-12-18 | 1990-01-26 | Hoffmann La Roche | Composes tricycliques |
| US4959361A (en) * | 1987-12-18 | 1990-09-25 | Hoffmann-La Roche Inc. | Triazolo(4,3-A)(1,4)benzodiazepines and thieno (3,2-F)(1,2,4)triazolo(4,3-A)(1,4)diazepine compounds which have useful activity as platelet activating factor (PAF) antagonists |
| US5968176A (en) * | 1997-05-29 | 1999-10-19 | 3Com Corporation | Multilayer firewall system |
| CZ20033003A3 (cs) | 2001-04-12 | 2004-05-12 | F@Áhoffmann@Laárocheáag | Dihydrobenzo [b][�Ź@]diazepin@onové deriváty jako MGLUR@ antagonisty II |
| US7161904B2 (en) * | 2002-06-04 | 2007-01-09 | Fortinet, Inc. | System and method for hierarchical metering in a virtual router based network switch |
| US7415723B2 (en) * | 2002-06-11 | 2008-08-19 | Pandya Ashish A | Distributed network security system and a hardware processor therefor |
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2003
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- 2003-03-28 NZ NZ535517A patent/NZ535517A/en not_active IP Right Cessation
- 2003-03-28 WO PCT/US2003/009587 patent/WO2003082832A2/en not_active Ceased
- 2003-03-28 KR KR1020087012062A patent/KR20080060286A/ko not_active Ceased
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- 2003-03-28 KR KR1020047015305A patent/KR100865410B1/ko not_active Expired - Fee Related
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- 2003-03-28 EP EP03723846A patent/EP1490344B1/en not_active Expired - Lifetime
- 2003-03-28 CA CA002480869A patent/CA2480869A1/en not_active Abandoned
- 2003-03-28 DE DE60319812T patent/DE60319812T2/de not_active Expired - Lifetime
- 2003-03-28 AU AU2003230754A patent/AU2003230754B2/en not_active Ceased
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2007
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2010
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| US20070049580A1 (en) | 2007-03-01 |
| EP1490344B1 (en) | 2008-03-19 |
| ATE389640T1 (de) | 2008-04-15 |
| DK1490344T3 (da) | 2008-06-16 |
| CN1642924A (zh) | 2005-07-20 |
| US20070054881A1 (en) | 2007-03-08 |
| US20070299058A1 (en) | 2007-12-27 |
| NZ535517A (en) | 2007-02-23 |
| BR0308918A (pt) | 2005-01-04 |
| DE60319812T2 (de) | 2009-04-23 |
| JP2005525392A (ja) | 2005-08-25 |
| US20100130481A1 (en) | 2010-05-27 |
| AU2003230754B2 (en) | 2007-10-25 |
| US20080108605A1 (en) | 2008-05-08 |
| KR100865410B1 (ko) | 2008-10-24 |
| IL163958A0 (en) | 2005-12-18 |
| ES2300576T3 (es) | 2008-06-16 |
| EP1490344A2 (en) | 2004-12-29 |
| KR20080060286A (ko) | 2008-07-01 |
| DE60319812D1 (de) | 2008-04-30 |
| US7119196B2 (en) | 2006-10-10 |
| KR20040098029A (ko) | 2004-11-18 |
| WO2003082832A2 (en) | 2003-10-09 |
| MXPA04009332A (es) | 2005-12-12 |
| AU2003230754A1 (en) | 2003-10-13 |
| WO2003082832A3 (en) | 2004-04-08 |
| US20040082573A1 (en) | 2004-04-29 |
| US7235656B2 (en) | 2007-06-26 |
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| EEER | Examination request | ||
| FZDE | Discontinued |