CA2788712C - Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators - Google Patents
Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators Download PDFInfo
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- CA2788712C CA2788712C CA2788712A CA2788712A CA2788712C CA 2788712 C CA2788712 C CA 2788712C CA 2788712 A CA2788712 A CA 2788712A CA 2788712 A CA2788712 A CA 2788712A CA 2788712 C CA2788712 C CA 2788712C
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- 102000004257 Potassium Channel Human genes 0.000 title claims abstract description 20
- 108020001213 potassium channel Proteins 0.000 title claims abstract description 20
- 229940051881 anilide analgesics and antipyretics Drugs 0.000 title description 3
- 150000003931 anilides Chemical class 0.000 title description 2
- 238000000034 method Methods 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 229940126062 Compound A Drugs 0.000 claims description 19
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 19
- 108010006746 KCNQ2 Potassium Channel Proteins 0.000 claims description 16
- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 11
- 101000994656 Homo sapiens Potassium voltage-gated channel subfamily KQT member 5 Proteins 0.000 claims description 10
- 101000994648 Homo sapiens Potassium voltage-gated channel subfamily KQT member 4 Proteins 0.000 claims description 9
- 102100034363 Potassium voltage-gated channel subfamily KQT member 4 Human genes 0.000 claims description 9
- 102100034365 Potassium voltage-gated channel subfamily KQT member 5 Human genes 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 abstract description 470
- 206010015037 epilepsy Diseases 0.000 abstract description 18
- 230000004913 activation Effects 0.000 abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 abstract description 4
- 102000003734 Voltage-Gated Potassium Channels Human genes 0.000 abstract description 3
- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 abstract description 3
- 230000006806 disease prevention Effects 0.000 abstract description 2
- 208000037765 diseases and disorders Diseases 0.000 abstract description 2
- 101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 description 241
- 125000000753 cycloalkyl group Chemical group 0.000 description 154
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 127
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 102
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
- 239000011541 reaction mixture Substances 0.000 description 94
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 92
- 229910052736 halogen Inorganic materials 0.000 description 90
- 150000002367 halogens Chemical class 0.000 description 90
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 78
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 69
- 229910052739 hydrogen Inorganic materials 0.000 description 66
- 229910052731 fluorine Inorganic materials 0.000 description 60
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 59
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
- 229910052801 chlorine Inorganic materials 0.000 description 53
- 239000000243 solution Substances 0.000 description 53
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 50
- -1 isoquinolyl anilides Chemical class 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 229910052786 argon Inorganic materials 0.000 description 46
- 125000000392 cycloalkenyl group Chemical group 0.000 description 42
- 239000000203 mixture Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 239000007787 solid Substances 0.000 description 32
- 239000000843 powder Substances 0.000 description 29
- 125000000217 alkyl group Chemical group 0.000 description 28
- 229910052794 bromium Inorganic materials 0.000 description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 28
- 229910052763 palladium Inorganic materials 0.000 description 27
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 26
- BUTKIHRNYUEGKB-UHFFFAOYSA-N 3,3-dimethylbutanoyl chloride Chemical compound CC(C)(C)CC(Cl)=O BUTKIHRNYUEGKB-UHFFFAOYSA-N 0.000 description 25
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 238000012360 testing method Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 20
- 241000700159 Rattus Species 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 238000000746 purification Methods 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 description 16
- 125000001188 haloalkyl group Chemical group 0.000 description 16
- 125000004076 pyridyl group Chemical group 0.000 description 16
- 229960003312 retigabine Drugs 0.000 description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 206010010904 Convulsion Diseases 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- 108091006146 Channels Proteins 0.000 description 12
- 108010011185 KCNQ1 Potassium Channel Proteins 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- 102100037444 Potassium voltage-gated channel subfamily KQT member 1 Human genes 0.000 description 12
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 210000000287 oocyte Anatomy 0.000 description 11
- NCCSSGKUIKYAJD-UHFFFAOYSA-N rubidium(1+) Chemical compound [Rb+] NCCSSGKUIKYAJD-UHFFFAOYSA-N 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 10
- GAOGWONUOUYZFD-UHFFFAOYSA-N 4-bromo-2-chloro-6-(trifluoromethyl)aniline Chemical compound NC1=C(Cl)C=C(Br)C=C1C(F)(F)F GAOGWONUOUYZFD-UHFFFAOYSA-N 0.000 description 10
- 239000001961 anticonvulsive agent Substances 0.000 description 10
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- QGLAYJCJLHNIGJ-UHFFFAOYSA-N 4-bromo-2,6-dimethylaniline Chemical compound CC1=CC(Br)=CC(C)=C1N QGLAYJCJLHNIGJ-UHFFFAOYSA-N 0.000 description 9
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- 239000012044 organic layer Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 8
- 229960003965 antiepileptics Drugs 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- XEVJQEIJAXJBKV-UHFFFAOYSA-N n-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide Chemical compound CC1=CC(Br)=CC(C)=C1NC(=O)CC(C)(C)C XEVJQEIJAXJBKV-UHFFFAOYSA-N 0.000 description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 7
- OTRRSPQJZRCMDA-UHFFFAOYSA-N 2-chloro-6-(trifluoromethyl)aniline Chemical compound NC1=C(Cl)C=CC=C1C(F)(F)F OTRRSPQJZRCMDA-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
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- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 6
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 6
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 6
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- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 6
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- 238000002360 preparation method Methods 0.000 description 6
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- DIXGIKZIIZRFKE-UHFFFAOYSA-N 4-bromo-2-chloro-6-methylaniline Chemical compound CC1=CC(Br)=CC(Cl)=C1N DIXGIKZIIZRFKE-UHFFFAOYSA-N 0.000 description 5
- 108010038888 KCNQ3 Potassium Channel Proteins 0.000 description 5
- 229910006074 SO2NH2 Inorganic materials 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000000010 aprotic solvent Substances 0.000 description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
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- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 5
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- 125000000565 sulfonamide group Chemical group 0.000 description 5
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
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- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- 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
- A61K31/47—Quinolines; Isoquinolines
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
- A61K31/175—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine having the group, >N—C(O)—N=N— or, e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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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
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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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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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
- A61P25/08—Antiepileptics; Anticonvulsants
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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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
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| US12/698,070 US8993593B2 (en) | 2006-08-23 | 2010-02-01 | N-(4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide as potassium channel modulators |
| PCT/US2011/022345 WO2011094186A1 (en) | 2010-02-01 | 2011-01-25 | Derivatives of 4-(n-azacycloalkyl) aniilides as potassium channel modulators |
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| US20060063766A1 (en) | 2004-07-15 | 2006-03-23 | Molino Bruce F | Use of aryl- and heteroaryl-substituted tetrahydroisoquinolines to block reuptake of norepinephrine, dopamine, and serotonin |
| AR071997A1 (es) * | 2008-06-04 | 2010-07-28 | Bristol Myers Squibb Co | Forma cristalina de 6-((4s)-2-metil-4-(2-naftil)-1,2,3,4-tetrahidroisoquinolin-7-il)piridazin-3-amina |
| US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
| JP2012526823A (ja) | 2009-05-12 | 2012-11-01 | アルバニー モレキュラー リサーチ， インコーポレイテッド | アリール、ヘテロアリール、および複素環置換テトラヒドロイソキノリンならびにそれらの使用 |
| US20160058895A1 (en) | 2013-04-19 | 2016-03-03 | Oslo Universitetssykehus Hf | Radiolabeled gnrh antagonists as pet imaging agents |
| WO2017214539A1 (en) | 2016-06-10 | 2017-12-14 | Scifluor Life Sciences, Inc. | Fluorinated 2-amino-4-(substituted amino)phenyl carbamate derivatives |
| EP4279133A3 (en) * | 2018-05-11 | 2024-02-21 | Xenon Pharmaceuticals Inc. | Methods for enhancing the bioavailability and exposure of a voltage-gated potassium channel opener |
| CN110511220B (zh) | 2018-05-22 | 2022-04-01 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的对二氨基苯衍生物、其制备方法及其在医药上的应用 |
| TWI886158B (zh) | 2019-10-10 | 2025-06-11 | 加拿大商再諾製藥公司 | 選擇性鉀通道調節劑之固態晶型 |
| MA56607A1 (fr) * | 2019-11-08 | 2022-10-31 | Xenon Pharmaceuticals Inc | Méthodes de traitement de troubles dépressifs |
| PE20221169A1 (es) * | 2019-12-06 | 2022-07-25 | Xenon Pharmaceuticals Inc | Uso de un abridor de canal de potasio kv7 para tratar el dolor |
| US20210213009A1 (en) * | 2019-12-13 | 2021-07-15 | Xenon Pharmaceuticals Inc. | Methods of treating pain |
| JP2024508660A (ja) * | 2021-02-09 | 2024-02-28 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | 快感消失の治療に使用するための電位依存性カリウムチャネル開口薬 |
| AU2022218962A1 (en) | 2021-02-09 | 2023-09-14 | Xenon Pharmaceuticals Inc. | Conjoint therapy for treating seizure disorders |
| CN113698345B (zh) * | 2021-10-27 | 2022-02-01 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的化合物及其制备和应用 |
| JP7294734B2 (ja) * | 2021-10-27 | 2023-06-20 | シャンハイ ジムン バイオファーマ，インコーポレーテッド | カリウムチャネル調節剤としての化合物ならびにその調製および応用 |
| WO2023125935A1 (zh) * | 2021-12-31 | 2023-07-06 | 上海翰森生物医药科技有限公司 | 苯并哌啶衍生物调节剂、其制备方法和应用 |
| CN116535353A (zh) * | 2022-01-25 | 2023-08-04 | 上海挚盟医药科技有限公司 | 作为钾通道调节剂的酰胺类化合物及其制备和应用 |
| TW202404583A (zh) | 2022-06-08 | 2024-02-01 | 加拿大商再諾製藥公司 | 吡啶胺衍生物及其作為鉀通道調節劑之用途 |
| CN120441482A (zh) * | 2024-02-08 | 2025-08-08 | 上海挚盟医药科技有限公司 | 四氢异喹啉基化合物的晶型及其应用 |
| WO2025179128A1 (en) | 2024-02-22 | 2025-08-28 | Xenon Pharmaceuticals Inc. | Azetukalner for use in the treatment of depression, anhedonia or a seizure disorder such as epilepsy in pediatric subjects |
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| US725511A (en) * | 1902-10-07 | 1903-04-14 | John Thomson Press Company | Apparatus for securing ink-distributing cylinders to platen printing-press. |
| US3639385A (en) * | 1968-07-26 | 1972-02-01 | Eastman Kodak Co | Heterocyclic monoazo compounds from n n-diaralkyl anilines and polyester textile materials dyed therewith |
| US4181803A (en) * | 1973-12-14 | 1980-01-01 | Eisai Co., Ltd. | Propiophenone derivatives and preparation thereof |
| ATE25078T1 (de) * | 1982-10-27 | 1987-02-15 | Degussa | 2-amino-3-acylamino-6-benzylamino-pyridinderivate mit anti-epileptischer wirkung. |
| DE3337593A1 (de) | 1982-10-27 | 1984-05-03 | Degussa Ag, 6000 Frankfurt | 2-amino-3-acylamino-6-benzylamino-pyridin-derivate mit antiepileptischer wirkung |
| ATE46265T1 (de) | 1985-01-23 | 1989-09-15 | Asta Pharma Ag | Synergistische kombination von flupirtin und nicht-steroidalen antiphlogistika. |
| DE3604575A1 (de) | 1985-02-23 | 1986-08-28 | Degussa Ag, 6000 Frankfurt | Kombination von flupirtin und anticholinergisch wirkenden spasmolytika |
| EP0193056B1 (de) * | 1985-02-23 | 1989-06-07 | ASTA Pharma Aktiengesellschaft | Kombination von Flupirtin und anticholinergisch wirkenden Spasmolytika |
| JP2583067B2 (ja) * | 1987-08-04 | 1997-02-19 | 住友化学工業株式会社 | モノアゾ化合物およびそれを用いて疎水性繊維材料を染色または捺染する方法 |
| GB8800199D0 (en) * | 1988-01-06 | 1988-02-10 | Beecham Group Plc | Pharmaceutical preparation |
| MC2029A1 (fr) | 1988-05-16 | 1990-04-25 | Asta Pharma Ag | (n-heterocyclyl)-3 diamino-2,6 pyridines substituees et leurs n-oxydes,preparation de ces composes et leur application comme medicaments |
| US5629307A (en) * | 1989-10-20 | 1997-05-13 | Olney; John W. | Use of ibogaine in reducing excitotoxic brain damage |
| US6004945A (en) * | 1990-05-10 | 1999-12-21 | Fukunaga; Atsuo F. | Use of adenosine compounds to relieve pain |
| IN172468B (enExample) * | 1990-07-14 | 1993-08-14 | Asta Medica Ag | |
| US5643921A (en) * | 1990-09-26 | 1997-07-01 | E.R. Squibb & Sons, Inc. | Cardiopulmonary bypass and organ transplant using a potassium channel activator |
| US5234947A (en) * | 1991-11-07 | 1993-08-10 | New York University | Potassium channel activating compounds and methods of use thereof |
| DE4200259A1 (de) * | 1992-01-08 | 1993-07-15 | Asta Medica Ag | Neue 1,2,4-triaminobenzol-derivate und verfahren zu deren herstellung |
| US5262419A (en) * | 1992-06-11 | 1993-11-16 | E. R. Squibb & Sons, Inc. | Method for the prophylaxis and/or treatment of ulcerative gastrointestinal conditions using a potassium channel activator |
| CA2115792C (en) * | 1993-03-05 | 2005-11-01 | David J. Mayer | Method for the treatment of pain |
| US5428039A (en) * | 1994-02-20 | 1995-06-27 | The Center For Innovative Technology | Method for electively achieving reversible hyperpolarized cardiac arrest |
| WO1996009044A1 (en) * | 1994-09-22 | 1996-03-28 | Richard Alan Smith | Compositions useful for the preparation of medicines for treating a variety of intractable disorders |
| US5679706A (en) * | 1994-09-30 | 1997-10-21 | Bristol-Myers Squibb Company | Combination of a potassium channel activator and an antiarrhythmic agent |
| MX9703988A (es) * | 1994-12-12 | 1998-02-28 | Omeros Med Sys Inc | SOLUCIaN Y MÉTODO DE IRRIGACIaN PARA LA INHIBICIaN DEL DOLOR, LA INFLAMACIaN Y ES ESPASMO. |
| DE19539861A1 (de) * | 1995-10-26 | 1997-04-30 | Asta Medica Ag | Verwendung von 4-Amino-4-(4-fluorbenzylamino)-1-ethoxy-carbonylaminobenzen zur Prophylaxe und Behandlung der Folgen der akuten und chronischen zerebralen Minderdurchblutung sowie neurodegenerativer Erkrankungen |
| DE19701694A1 (de) * | 1997-01-20 | 1998-07-23 | Asta Medica Ag | Neue Modifikationen des 2-Amino-4-(4-fluorbenzylamino)-l-ethoxycarbonyl-aminobenzen sowie Verfahren zu ihrer Herstellung |
| US5760007A (en) * | 1997-07-16 | 1998-06-02 | Ortho Pharmaceutical Corporation | Anticonvulsant derivatives useful in treating neuropathic pain |
| ES2251095T3 (es) * | 1997-08-08 | 2006-04-16 | Chugai Seiyaku Kabushiki Kaisha | Agentes terapeuticos para complicaciones diabeticas. |
| US6265417B1 (en) * | 1997-12-18 | 2001-07-24 | Abbott Laboratories | Potassium channel openers |
| US6593335B1 (en) * | 1997-12-18 | 2003-07-15 | Abbott Laboratories | Potassium channel openers |
| US6211171B1 (en) * | 1998-05-19 | 2001-04-03 | Dalhousie University | Use of antidepressants for local analgesia |
| JP3441970B2 (ja) | 1998-06-30 | 2003-09-02 | 株式会社サミー | 豆腐の製造方法及び製造装置 |
| JP2000143510A (ja) | 1998-11-16 | 2000-05-23 | Taisho Pharmaceut Co Ltd | 外用組成物 |
| IL143726A0 (en) * | 1998-12-14 | 2002-04-21 | Cellegy Pharma Inc | A pharmaceutical composition containing a nitric oxide donor |
| US6281211B1 (en) * | 1999-02-04 | 2001-08-28 | Euro-Celtique S.A. | Substituted semicarbazides and the use thereof |
| GB9903476D0 (en) * | 1999-02-17 | 1999-04-07 | Zeneca Ltd | Therapeutic agents |
| CA2359485A1 (en) * | 1999-03-10 | 2000-09-14 | Warner-Lambert Company | Analgesic compositions comprising anti-epileptic compounds and methods of using same |
| WO2000055137A1 (en) | 1999-03-17 | 2000-09-21 | Signal Pharmaceuticals, Inc. | Compounds and methods for modulation of estrogen receptors |
| AT409083B (de) * | 1999-04-01 | 2002-05-27 | Sanochemia Pharmazeutika Ag | Pharmazeutische, tolperison enthaltende zubereitung zur oralen verabreichung |
| US6610324B2 (en) | 1999-04-07 | 2003-08-26 | The Mclean Hospital Corporation | Flupirtine in the treatment of fibromyalgia and related conditions |
| GB9915414D0 (en) | 1999-07-01 | 1999-09-01 | Glaxo Group Ltd | Medical use |
| MXPA01012726A (es) | 1999-07-06 | 2002-07-02 | Lilly Co Eli | Antagonistas selectivos del receptor de iglur5 para el tratamiento de la migrana. |
| US6472165B1 (en) | 1999-08-03 | 2002-10-29 | Arzneimittelwerk Dresden Gmbh | Modulatory binding site in potassium channels for screening and finding new active ingredients |
| DE60037321T4 (de) * | 1999-08-04 | 2010-01-07 | Icagen, Inc. | Benzanilide als öffner des kaliumkanals |
| US6495550B2 (en) * | 1999-08-04 | 2002-12-17 | Icagen, Inc. | Pyridine-substituted benzanilides as potassium ion channel openers |
| AU772075B2 (en) * | 1999-08-04 | 2004-04-08 | Icagen, Inc. | Methods for treating or preventing pain and anxiety |
| US6117900A (en) * | 1999-09-27 | 2000-09-12 | Asta Medica Aktiengesellschaft | Use of retigabine for the treatment of neuropathic pain |
| US6383511B1 (en) * | 1999-10-25 | 2002-05-07 | Epicept Corporation | Local prevention or amelioration of pain from surgically closed wounds |
| US6538004B2 (en) * | 2000-03-03 | 2003-03-25 | Abbott Laboratories | Tricyclic dihydropyrazolone and tricyclic dihydroisoxazolone potassium channel openers |
| US20020015730A1 (en) * | 2000-03-09 | 2002-02-07 | Torsten Hoffmann | Pharmaceutical formulations and method for making |
| US6348486B1 (en) * | 2000-10-17 | 2002-02-19 | American Home Products Corporation | Methods for modulating bladder function |
| US6589986B2 (en) * | 2000-12-20 | 2003-07-08 | Wyeth | Methods of treating anxiety disorders |
| US6469042B1 (en) * | 2001-02-20 | 2002-10-22 | Bristol-Myers Squibb Company | Fluoro oxindole derivatives as modulators if KCNQ potassium channels |
| AR033095A1 (es) * | 2001-04-04 | 2003-12-03 | Wyeth Corp | Metodos para el tratamiento de motilidad gastrica hiperactiva |
| GB0121214D0 (en) | 2001-08-31 | 2001-10-24 | Btg Int Ltd | Synthetic method |
| AU2003202115A1 (en) | 2002-02-12 | 2003-09-04 | Pfizer Inc. | Non-peptide compounds affecting the action of gonadotropin-releasing hormone (gnrh) |
| WO2003097586A1 (en) | 2002-05-17 | 2003-11-27 | Janssen Pharmaceutica N.V. | Aminotetralin-derived urea modulators of vanilloid vr1 receptor |
| WO2003106454A1 (en) | 2002-06-12 | 2003-12-24 | Orchid Chemicals & Pharmaceuticals Ltd | 1h-isoquinoline-oxazolidinone derivaties and their use as antibacterial agents |
| AUPS312602A0 (en) * | 2002-06-21 | 2002-07-18 | James Cook University | Organ arrest, protection, preservation and recovery |
| US7419981B2 (en) * | 2002-08-15 | 2008-09-02 | Pfizer Inc. | Synergistic combinations of an alpha-2-delta ligand and a cGMP phosphodieterse 5 inhibitor |
| AU2003294441A1 (en) * | 2002-11-22 | 2004-06-18 | Bristol-Myers Squibb Company | 1-aryl-2-hydroxyethyl amides as potassium channel openers |
| EP1585522B1 (en) * | 2002-12-23 | 2010-11-17 | Icagen, Inc. | Quinazolinones as potassium channel modulators |
| JP2006515300A (ja) | 2002-12-27 | 2006-05-25 | ハー・ルンドベック・アクチエゼルスカベット | 中枢神経系の疾患の治療に有用な１，２，４−トリアミノベンゼン誘導体 |
| EP1606247A1 (en) | 2003-03-14 | 2005-12-21 | H. Lundbeck A/S | Substituted aniline derivatives |
| BRPI0408437A (pt) | 2003-03-21 | 2006-04-04 | Lundbeck & Co As H | derivados de p-diaminobenzeno substituìdos, composição farmacêutica, e, uso da mesma |
| US20060264496A1 (en) | 2003-04-25 | 2006-11-23 | H. Lundbeck A/S | Substituted indoline and indole derivatives |
| AU2004243444A1 (en) | 2003-05-27 | 2004-12-09 | Altana Pharma Ag | Pharmaceutical combinations of a proton pump inhibitor and a compound which modifies gastrointestinal motility |
| US20050070570A1 (en) * | 2003-06-18 | 2005-03-31 | 4Sc Ag | Novel potassium channels modulators |
| EP1663239A4 (en) * | 2003-09-10 | 2008-07-23 | Cedars Sinai Medical Center | KALIUM CHANNEL-MEDIATED FEEDING OF MEDICINES BY THE BLOOD BRAIN BARRIER |
| US7799832B2 (en) * | 2003-10-23 | 2010-09-21 | Valeant Pharmaceuticals North America | Combinations of retigabine and sodium channel inhibitors or sodium channel-influencing active compounds for treating pains |
| DE10359335A1 (de) | 2003-10-23 | 2005-05-25 | Viatris Gmbh & Co. Kg | Kombinationen aus Kaliumkanalöffnern und Natriumkanalinhibitoren oder Natriumkanal beeinflussenden Wirkstoffen zur Behandlung von Schmerzzuständen |
| ES2235626B1 (es) | 2003-11-10 | 2006-11-01 | Almirall Prodesfarma, S.A. | Formas de administracion masticables, no comprimidas dosificadas individualmente. |
| TWI349666B (en) | 2004-03-12 | 2011-10-01 | Lundbeck & Co As H | Substituted morpholine and thiomorpholine derivatives |
| RU2006139933A (ru) | 2004-04-13 | 2008-05-20 | Икаген, Инк. (Us) | Полициклические пиридины как модуляторы калиевых ионных каналов |
| WO2005110405A1 (en) * | 2004-05-03 | 2005-11-24 | Duke University | Compositions for affecting weight loss |
| UA89503C2 (uk) | 2004-09-13 | 2010-02-10 | Х. Луннбек А/С | Заміщені похідні аніліну |
| EP1813285A4 (en) | 2004-11-19 | 2010-06-09 | Kissei Pharmaceutical | PROPHYLACTIC OR THERAPEUTIC AGENT AGAINST NEUROPATHIC PAIN |
| EP1688141A1 (en) * | 2005-01-31 | 2006-08-09 | elbion AG | The use of flupirtine for the treatment of overactive bladder and associated diseases, and for the treatment of irritable bowel syndrome |
| PL2298766T3 (pl) | 2005-03-03 | 2014-09-30 | H Lundbeck As | Preparaty farmaceutyczne zawierające podstawione pochodne pirydyny |
| US7683058B2 (en) * | 2005-09-09 | 2010-03-23 | H. Lundbeck A/S | Substituted pyrimidine derivatives |
| MX2009002002A (es) | 2006-08-23 | 2009-07-22 | Valeant Pharmaceuticals Int | Derivados de 4-(n-azacicloalquil) anilidas como moduladores de canal de potasio. |
| US8030518B2 (en) | 2006-11-28 | 2011-10-04 | Valeant Pharmaceuticals International | 1,4 diamino bicyclic retigabine analogues as potassium channel modulators |
-
2010
- 2010-02-01 US US12/698,070 patent/US8993593B2/en active Active
-
2011
- 2011-01-25 MX MX2012008969A patent/MX2012008969A/es unknown
- 2011-01-25 CA CA2788712A patent/CA2788712C/en active Active
- 2011-01-25 CN CN2011800161510A patent/CN102869250A/zh active Pending
- 2011-01-25 EA EA201290748A patent/EA201290748A1/ru unknown
- 2011-01-25 KR KR1020127022876A patent/KR101841989B1/ko active Active
- 2011-01-25 JP JP2012551221A patent/JP5844285B2/ja active Active
- 2011-01-25 AU AU2011209731A patent/AU2011209731A1/en not_active Abandoned
- 2011-01-25 WO PCT/US2011/022345 patent/WO2011094186A1/en not_active Ceased
- 2011-01-25 SG SG2012056438A patent/SG182799A1/en unknown
- 2011-01-25 BR BR112012019199A patent/BR112012019199A2/pt not_active Application Discontinuation
- 2011-01-25 EP EP11737504.8A patent/EP2531024A4/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| MX2012008969A (es) | 2012-09-07 |
| BR112012019199A2 (pt) | 2017-01-17 |
| JP2013518815A (ja) | 2013-05-23 |
| KR101841989B1 (ko) | 2018-03-26 |
| WO2011094186A1 (en) | 2011-08-04 |
| EP2531024A1 (en) | 2012-12-12 |
| EA201290748A1 (ru) | 2013-04-30 |
| US20110003850A1 (en) | 2011-01-06 |
| CN102869250A (zh) | 2013-01-09 |
| CA2788712A1 (en) | 2011-08-04 |
| KR20120123695A (ko) | 2012-11-09 |
| AU2011209731A1 (en) | 2012-08-23 |
| EP2531024A4 (en) | 2013-06-19 |
| US8993593B2 (en) | 2015-03-31 |
| JP5844285B2 (ja) | 2016-01-13 |
| SG182799A1 (en) | 2012-09-27 |
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