NZ535517A - Anxiolytic agents with reduced sedative and ataxic effects - Google Patents
Anxiolytic agents with reduced sedative and ataxic effectsInfo
- Publication number
- NZ535517A NZ535517A NZ535517A NZ53551703A NZ535517A NZ 535517 A NZ535517 A NZ 535517A NZ 535517 A NZ535517 A NZ 535517A NZ 53551703 A NZ53551703 A NZ 53551703A NZ 535517 A NZ535517 A NZ 535517A
- Authority
- NZ
- New Zealand
- Prior art keywords
- substituted
- cyclopropyl
- substituent
- ring
- phenyl
- Prior art date
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
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 121
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 53
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 125000004432 carbon atom Chemical group C* 0.000 claims description 39
- -1 CH2CCH Chemical group 0.000 claims description 37
- 125000001544 thienyl group Chemical group 0.000 claims description 37
- 239000000651 prodrug Substances 0.000 claims description 36
- 229940002612 prodrug Drugs 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 125000004122 cyclic group Chemical group 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 23
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000006431 methyl cyclopropyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000006430 alkyl cyclopropyl group Chemical group 0.000 claims description 5
- ROWMQJJMCWDJDT-UHFFFAOYSA-N tribromomethane Chemical compound Br[C](Br)Br ROWMQJJMCWDJDT-UHFFFAOYSA-N 0.000 claims description 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 2
- IKNCGYCHMGNBCP-UHFFFAOYSA-N propan-1-olate Chemical compound CCC[O-] IKNCGYCHMGNBCP-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 25
- 230000000949 anxiolytic effect Effects 0.000 abstract description 17
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- 239000003158 myorelaxant agent Substances 0.000 abstract description 4
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- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 130
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- 238000005481 NMR spectroscopy Methods 0.000 description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 54
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 239000000556 agonist Substances 0.000 description 11
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 11
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Classifications
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- 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
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- 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
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
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- 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
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- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- 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
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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- 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
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- 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
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- C07D498/04—Ortho-condensed systems
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- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- 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)
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| NZ547480A NZ547480A (en) | 2002-03-28 | 2003-03-28 | Anxiolytic agents with reduced sedative and ataxic effects |
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| 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 |
| US7709522B2 (en) * | 2008-01-22 | 2010-05-04 | Eli Lilly And Company | Kappa selective opioid receptor antagonist |
| 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 |
| BR112018015386A2 (pt) | 2016-01-27 | 2019-03-19 | Universität Zürich | uso de moduladores de receptor gabaa para tratamento de prurido |
| EP4129297A1 (en) | 2016-03-18 | 2023-02-08 | UWM Research Foundation, Inc. | Treatment of cognitive and mood symptoms in neurodegenerative and neuropsychiatric disorders with alpha5-containing gabaa receptor agonists |
| AU2017313753B2 (en) | 2016-08-16 | 2022-01-27 | The Trustees Of Columbia University In The City Of New York | 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 |
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| TWI878507B (zh) | 2020-03-31 | 2025-04-01 | 瑞士商赫孚孟拉羅股份公司 | 作為 GABA A γ1 PAM 的新穎苯并二氮呯衍生物 |
| US12161622B2 (en) | 2021-05-04 | 2024-12-10 | Janssen Pharmaceuticals, Inc. | Compositions and methods for the treatment of depression |
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| JP2024537773A (ja) | 2021-09-29 | 2024-10-16 | エフ． ホフマン－ラ ロシュ アーゲー | ＧＡＢＡ Ａγ１ ＰＡＭとしての新規ベンゾジアゼピン誘導体 |
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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 |
| US4280957A (en) | 1974-09-11 | 1981-07-28 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
| US4440685A (en) * | 1974-09-11 | 1984-04-03 | 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. |
| 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 |
| MC1999A1 (fr) | 1987-12-18 | 1990-01-26 | Hoffmann La Roche | Composes tricycliques |
| US5968176A (en) * | 1997-05-29 | 1999-10-19 | 3Com Corporation | Multilayer firewall system |
| EP1379511B1 (en) * | 2001-04-12 | 2005-07-20 | F. Hoffmann-La Roche Ag | DIHYDRO-BENZO (b) (1, 4) DIAZEPIN-2-ONE DERIVATIVES AS MGLUR2 ANTAGONISTS II |
| US7161904B2 (en) * | 2002-06-04 | 2007-01-09 | Fortinet, Inc. | System and method for hierarchical metering in a virtual router based network switch |
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2003
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- 2003-03-28 CN CNA038073439A patent/CN1642924A/zh active Pending
- 2003-03-28 DK DK03723846T patent/DK1490344T3/da active
- 2003-03-28 KR KR1020087012062A patent/KR20080060286A/ko not_active Ceased
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- 2003-03-28 CA CA002480869A patent/CA2480869A1/en not_active Abandoned
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| US20070054881A1 (en) | 2007-03-08 |
| US7235656B2 (en) | 2007-06-26 |
| US20080108605A1 (en) | 2008-05-08 |
| WO2003082832A3 (en) | 2004-04-08 |
| WO2003082832A2 (en) | 2003-10-09 |
| CA2480869A1 (en) | 2003-10-09 |
| KR20040098029A (ko) | 2004-11-18 |
| CN1642924A (zh) | 2005-07-20 |
| US20070299058A1 (en) | 2007-12-27 |
| IL163958A0 (en) | 2005-12-18 |
| US7119196B2 (en) | 2006-10-10 |
| US20100130481A1 (en) | 2010-05-27 |
| DE60319812T2 (de) | 2009-04-23 |
| AU2003230754A1 (en) | 2003-10-13 |
| MXPA04009332A (es) | 2005-12-12 |
| ATE389640T1 (de) | 2008-04-15 |
| DK1490344T3 (da) | 2008-06-16 |
| EP1490344A2 (en) | 2004-12-29 |
| US20040082573A1 (en) | 2004-04-29 |
| DE60319812D1 (de) | 2008-04-30 |
| ES2300576T3 (es) | 2008-06-16 |
| US20070049580A1 (en) | 2007-03-01 |
| AU2003230754B2 (en) | 2007-10-25 |
| KR100865410B1 (ko) | 2008-10-24 |
| KR20080060286A (ko) | 2008-07-01 |
| JP2005525392A (ja) | 2005-08-25 |
| EP1490344B1 (en) | 2008-03-19 |
| BR0308918A (pt) | 2005-01-04 |
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