ES2300576T3 - Agentes ansioliticos con efectos secundarios sedantes y ataxicos reducidos. - Google Patents
Agentes ansioliticos con efectos secundarios sedantes y ataxicos reducidos. Download PDFInfo
- Publication number
- ES2300576T3 ES2300576T3 ES03723846T ES03723846T ES2300576T3 ES 2300576 T3 ES2300576 T3 ES 2300576T3 ES 03723846 T ES03723846 T ES 03723846T ES 03723846 T ES03723846 T ES 03723846T ES 2300576 T3 ES2300576 T3 ES 2300576T3
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- Prior art keywords
- compound
- mmol
- mixture
- nmr
- phenyl
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- Expired - Lifetime
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- 230000001977 ataxic effect Effects 0.000 title abstract description 7
- 230000000694 effects Effects 0.000 title description 30
- 206010003591 Ataxia Diseases 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
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- 229940079593 drug Drugs 0.000 claims description 33
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 229940002612 prodrug Drugs 0.000 claims description 24
- 239000000651 prodrug Substances 0.000 claims description 24
- 208000019901 Anxiety disease Diseases 0.000 claims description 22
- 125000001544 thienyl group Chemical group 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000004122 cyclic group Chemical group 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 13
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
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- 238000002360 preparation method Methods 0.000 claims description 6
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- 125000006431 methyl cyclopropyl group Chemical group 0.000 claims description 4
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- 238000000034 method Methods 0.000 abstract description 36
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
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- 239000012312 sodium hydride Substances 0.000 description 15
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 14
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- UVBXZOISXNZBLY-UHFFFAOYSA-L palladium(2+);triphenylphosphane;diacetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UVBXZOISXNZBLY-UHFFFAOYSA-L 0.000 description 13
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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 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 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 10
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- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 7
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- HZYHQJXUEKIREU-UHFFFAOYSA-N ethyl 8-ethynyl-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(C=C22)C#C)C=1CN=C2C1=CC=CC=C1 HZYHQJXUEKIREU-UHFFFAOYSA-N 0.000 description 7
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Classifications
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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
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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
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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
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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
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- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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- C07D243/20—Nitrogen atoms
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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
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- 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
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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
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- 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
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- 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
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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
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- Otolaryngology (AREA)
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- 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)
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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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- 2003-03-28 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
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| US20070049580A1 (en) | 2007-03-01 |
| EP1490344B1 (en) | 2008-03-19 |
| ATE389640T1 (de) | 2008-04-15 |
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| CN1642924A (zh) | 2005-07-20 |
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| BR0308918A (pt) | 2005-01-04 |
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| JP2005525392A (ja) | 2005-08-25 |
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| US20080108605A1 (en) | 2008-05-08 |
| KR100865410B1 (ko) | 2008-10-24 |
| IL163958A0 (en) | 2005-12-18 |
| 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 |
| CA2480869A1 (en) | 2003-10-09 |
| AU2003230754A1 (en) | 2003-10-13 |
| WO2003082832A3 (en) | 2004-04-08 |
| US20040082573A1 (en) | 2004-04-29 |
| US7235656B2 (en) | 2007-06-26 |
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