SG182799A1 - Derivatives of 4-(n-azacycloalkyl) aniilides as potassium channel modulators - Google Patents
Derivatives of 4-(n-azacycloalkyl) aniilides as potassium channel modulators Download PDFInfo
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- SG182799A1 SG182799A1 SG2012056438A SG2012056438A SG182799A1 SG 182799 A1 SG182799 A1 SG 182799A1 SG 2012056438 A SG2012056438 A SG 2012056438A SG 2012056438 A SG2012056438 A SG 2012056438A SG 182799 A1 SG182799 A1 SG 182799A1
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- alkyl
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- 102000004257 Potassium Channel Human genes 0.000 title claims abstract description 21
- 108020001213 potassium channel Proteins 0.000 title claims abstract description 21
- 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 15
- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 11
- 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
- 150000001875 compounds Chemical class 0.000 abstract description 464
- 206010015037 epilepsy Diseases 0.000 abstract description 18
- 230000004913 activation Effects 0.000 abstract description 5
- 102000003734 Voltage-Gated Potassium Channels Human genes 0.000 abstract description 3
- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 abstract description 3
- 230000006806 disease prevention Effects 0.000 abstract description 2
- 208000037765 diseases and disorders Diseases 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 description 222
- 125000000753 cycloalkyl group Chemical group 0.000 description 215
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 124
- 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 70
- 229910052739 hydrogen Inorganic materials 0.000 description 62
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 58
- 229910052731 fluorine Inorganic materials 0.000 description 56
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 55
- 239000000243 solution Substances 0.000 description 53
- 229910052786 argon Inorganic materials 0.000 description 52
- 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
- 125000000392 cycloalkenyl group Chemical group 0.000 description 48
- 229910052801 chlorine Inorganic materials 0.000 description 44
- -1 isoquinolyl anilides Chemical class 0.000 description 44
- 239000000203 mixture Substances 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
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- 239000007787 solid Substances 0.000 description 32
- 239000000843 powder Substances 0.000 description 29
- 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
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- 125000003342 alkenyl group Chemical group 0.000 description 26
- 229910052794 bromium Inorganic materials 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 125000000304 alkynyl group Chemical group 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 238000012360 testing method Methods 0.000 description 22
- 229910052799 carbon Inorganic materials 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 20
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 description 19
- 241000700159 Rattus Species 0.000 description 19
- 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 18
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- 241001465754 Metazoa Species 0.000 description 16
- 125000001188 haloalkyl group Chemical group 0.000 description 16
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 16
- 125000004076 pyridyl group Chemical group 0.000 description 16
- 108091006146 Channels Proteins 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 239000011591 potassium Substances 0.000 description 13
- 229910052700 potassium Inorganic materials 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 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
- 150000003839 salts Chemical class 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 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
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- 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 10
- 229960005235 piperonyl butoxide Drugs 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- QGLAYJCJLHNIGJ-UHFFFAOYSA-N 4-bromo-2,6-dimethylaniline Chemical compound CC1=CC(Br)=CC(C)=C1N QGLAYJCJLHNIGJ-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000001961 anticonvulsive agent Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 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
- 239000002253 acid Substances 0.000 description 7
- 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
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- 238000003818 flash chromatography Methods 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- 108010011185 KCNQ1 Potassium Channel Proteins 0.000 description 6
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- 238000002360 preparation method Methods 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- DIXGIKZIIZRFKE-UHFFFAOYSA-N 4-bromo-2-chloro-6-methylaniline Chemical compound CC1=CC(Br)=CC(Cl)=C1N DIXGIKZIIZRFKE-UHFFFAOYSA-N 0.000 description 5
- YSICEHWFFMXFAP-UHFFFAOYSA-N 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline;hydrochloride Chemical compound Cl.C1NCCC2=CC(C(F)(F)F)=CC=C21 YSICEHWFFMXFAP-UHFFFAOYSA-N 0.000 description 5
- 108010038888 KCNQ3 Potassium Channel Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
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- 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
- 230000028161 membrane depolarization Effects 0.000 description 5
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- 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
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- 101000994656 Homo sapiens Potassium voltage-gated channel subfamily KQT member 5 Proteins 0.000 description 4
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Classifications
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- A—HUMAN NECESSITIES
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- 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
-
- 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
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- 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
-
- 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
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)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (1)
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|---|---|
| SG182799A1 true SG182799A1 (en) | 2012-09-27 |
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|---|---|---|---|
| SG2012056438A SG182799A1 (en) | 2010-02-01 | 2011-01-25 | Derivatives of 4-(n-azacycloalkyl) aniilides as potassium channel modulators |
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|---|---|
| US (1) | US8993593B2 (enExample) |
| EP (1) | EP2531024A4 (enExample) |
| JP (1) | JP5844285B2 (enExample) |
| KR (1) | KR101841989B1 (enExample) |
| CN (1) | CN102869250A (enExample) |
| AU (1) | AU2011209731A1 (enExample) |
| BR (1) | BR112012019199A2 (enExample) |
| CA (1) | CA2788712C (enExample) |
| EA (1) | EA201290748A1 (enExample) |
| MX (1) | MX2012008969A (enExample) |
| SG (1) | SG182799A1 (enExample) |
| WO (1) | WO2011094186A1 (enExample) |
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| CN101119969B (zh) | 2004-07-15 | 2014-04-09 | 阿尔巴尼分子研究公司 | 芳基和杂芳基取代的四氢异喹啉及其阻断去甲肾上腺素、多巴胺和血清素的重摄取的应用 |
| 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 |
| 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 |
| WO2010132437A1 (en) | 2009-05-12 | 2010-11-18 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
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2010
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2011
- 2011-01-25 KR KR1020127022876A patent/KR101841989B1/ko active Active
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- 2011-01-25 EP EP11737504.8A patent/EP2531024A4/en not_active Withdrawn
- 2011-01-25 EA EA201290748A patent/EA201290748A1/ru unknown
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- 2011-01-25 SG SG2012056438A patent/SG182799A1/en unknown
- 2011-01-25 MX MX2012008969A patent/MX2012008969A/es unknown
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| Publication number | Publication date |
|---|---|
| WO2011094186A1 (en) | 2011-08-04 |
| US20110003850A1 (en) | 2011-01-06 |
| JP5844285B2 (ja) | 2016-01-13 |
| AU2011209731A1 (en) | 2012-08-23 |
| US8993593B2 (en) | 2015-03-31 |
| CA2788712A1 (en) | 2011-08-04 |
| CA2788712C (en) | 2018-09-11 |
| JP2013518815A (ja) | 2013-05-23 |
| BR112012019199A2 (pt) | 2017-01-17 |
| EA201290748A1 (ru) | 2013-04-30 |
| CN102869250A (zh) | 2013-01-09 |
| KR20120123695A (ko) | 2012-11-09 |
| EP2531024A1 (en) | 2012-12-12 |
| EP2531024A4 (en) | 2013-06-19 |
| KR101841989B1 (ko) | 2018-03-26 |
| MX2012008969A (es) | 2012-09-07 |
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