BRPI0716715B1 - Derivados de 4-(n-azacicloalquil) anilidas como moduladores de canal de potássio, seus usos, produto, composição, comprimido e cápsula - Google Patents
Derivados de 4-(n-azacicloalquil) anilidas como moduladores de canal de potássio, seus usos, produto, composição, comprimido e cápsula Download PDFInfo
- Publication number
- BRPI0716715B1 BRPI0716715B1 BRPI0716715-6A BRPI0716715A BRPI0716715B1 BR PI0716715 B1 BRPI0716715 B1 BR PI0716715B1 BR PI0716715 A BRPI0716715 A BR PI0716715A BR PI0716715 B1 BRPI0716715 B1 BR PI0716715B1
- Authority
- BR
- Brazil
- Prior art keywords
- alkyl
- isoquinolin
- dihydro
- chloro
- cycloalkyl
- Prior art date
Links
- 102000004257 Potassium Channel Human genes 0.000 title claims abstract description 14
- 108020001213 potassium channel Proteins 0.000 title claims abstract description 14
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- 150000001875 compounds Chemical class 0.000 claims abstract description 496
- 206010015037 epilepsy Diseases 0.000 claims abstract description 18
- 230000004913 activation Effects 0.000 claims abstract description 4
- 101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims description 277
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 222
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 159
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 124
- 229910052736 halogen Inorganic materials 0.000 claims description 119
- 150000002367 halogens Chemical class 0.000 claims description 119
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 106
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 100
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 99
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 229910052731 fluorine Inorganic materials 0.000 claims description 81
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 78
- 229910052801 chlorine Inorganic materials 0.000 claims description 70
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- -1 2-(N,N-dimethylamino)ethyl Chemical group 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 58
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 56
- 229910052786 argon Inorganic materials 0.000 claims description 51
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 46
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 32
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 29
- 229910052794 bromium Inorganic materials 0.000 claims description 28
- 229910052763 palladium Inorganic materials 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 27
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 26
- 125000004076 pyridyl group Chemical group 0.000 claims description 26
- 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 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 206010010904 Convulsion Diseases 0.000 claims description 16
- 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 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
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- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 7
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims description 7
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 7
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- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims description 7
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- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 4
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- 239000006188 syrup Substances 0.000 claims description 4
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- PXVUSPQWZDZSJK-UHFFFAOYSA-N n-[4-(3,4-dihydro-1h-isoquinolin-2-yl)-2,6-dimethoxyphenyl]-3,3-dimethylbutanamide Chemical compound COC1=C(NC(=O)CC(C)(C)C)C(OC)=CC(N2CC3=CC=CC=C3CC2)=C1 PXVUSPQWZDZSJK-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
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- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims 5
- 125000002541 furyl group Chemical group 0.000 claims 4
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- 206010001497 Agitation Diseases 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
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- 125000003944 tolyl group Chemical group 0.000 claims 1
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- 108090000013 Voltage-Gated Potassium Channels Proteins 0.000 abstract 1
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- 150000003931 anilides Chemical class 0.000 abstract 1
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- 239000011541 reaction mixture Substances 0.000 description 94
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 92
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 54
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
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- 239000002244 precipitate Substances 0.000 description 20
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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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- 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 8
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- 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
-
- 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
- A61P25/08—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
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
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| PCT/US2007/018571 WO2008024398A2 (en) | 2006-08-23 | 2007-08-22 | Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators |
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| WO2004082677A1 (en) | 2003-03-21 | 2004-09-30 | H. Lundbeck A/S | Substituted p-diaminobenzene derivatives |
| WO2004096767A1 (en) | 2003-04-25 | 2004-11-11 | H. Lundbeck A/S | Sustituted indoline and indole derivatives |
| WO2004105795A1 (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 |
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| US20050089559A1 (en) | 2003-10-23 | 2005-04-28 | Istvan Szelenyi | Combinations of potassium channel openers 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 |
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| TWI349666B (en) | 2004-03-12 | 2011-10-01 | Lundbeck & Co As H | Substituted morpholine and thiomorpholine derivatives |
| EP1737852A2 (en) | 2004-04-13 | 2007-01-03 | Icagen, Inc. | Polycyclic pyridines as potassium ion channel modulators |
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| 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 |
| AU2006220130B2 (en) | 2005-03-03 | 2011-07-28 | H. Lundbeck A/S | Substituted pyridine derivatives |
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| JP2010511052A (ja) | 2006-11-28 | 2010-04-08 | バレアント ファーマシューティカルズ インターナショナル | カリウムチャネル調節因子としての１，４ジアミノ二環式レチガビンアナログ |
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2007
- 2007-08-22 EP EP07837199.4A patent/EP2061465B1/en active Active
- 2007-08-22 CA CA2661462A patent/CA2661462C/en active Active
- 2007-08-22 US US11/894,877 patent/US8293911B2/en active Active
- 2007-08-22 BR BRPI0716715-6A patent/BRPI0716715B1/pt active IP Right Grant
- 2007-08-22 KR KR1020097005943A patent/KR20090079191A/ko not_active Withdrawn
- 2007-08-22 MX MX2009002002A patent/MX2009002002A/es active IP Right Grant
- 2007-08-22 AU AU2007288253A patent/AU2007288253B2/en active Active
- 2007-08-22 PT PT78371994T patent/PT2061465E/pt unknown
- 2007-08-22 NZ NZ575652A patent/NZ575652A/en unknown
- 2007-08-22 WO PCT/US2007/018571 patent/WO2008024398A2/en not_active Ceased
- 2007-08-22 SG SG2011060944A patent/SG174095A1/en unknown
- 2007-08-22 RU RU2009110172/15A patent/RU2009110172A/ru not_active Application Discontinuation
- 2007-08-22 DK DK07837199.4T patent/DK2061465T3/da active
- 2007-08-22 PL PL07837199T patent/PL2061465T3/pl unknown
- 2007-08-22 JP JP2009525618A patent/JP5419691B2/ja active Active
- 2007-08-22 ES ES07837199T patent/ES2420960T3/es active Active
- 2007-08-22 CN CNA2007800392650A patent/CN101563085A/zh active Pending
- 2007-08-23 TW TW096131287A patent/TW200827339A/zh unknown
- 2007-08-23 CL CL200702455A patent/CL2007002455A1/es unknown
- 2007-08-23 AR ARP070103756A patent/AR062508A1/es unknown
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2009
- 2009-02-22 IL IL197161A patent/IL197161A/en active IP Right Grant
- 2009-03-20 NO NO20091183A patent/NO343575B1/no unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0716715A2 (pt) | 2013-09-03 |
| ZA200901977B (en) | 2010-02-24 |
| PT2061465E (pt) | 2013-07-15 |
| EP2061465B1 (en) | 2013-04-10 |
| JP5419691B2 (ja) | 2014-02-19 |
| WO2008024398B1 (en) | 2008-08-14 |
| AU2007288253A1 (en) | 2008-02-28 |
| MX2009002002A (es) | 2009-07-22 |
| CA2661462A1 (en) | 2008-02-28 |
| ES2420960T3 (es) | 2013-08-28 |
| NZ575652A (en) | 2011-08-26 |
| JP2010501568A (ja) | 2010-01-21 |
| RU2009110172A (ru) | 2010-09-27 |
| SG174095A1 (en) | 2011-09-29 |
| DK2061465T3 (da) | 2013-07-08 |
| TW200827339A (en) | 2008-07-01 |
| CA2661462C (en) | 2015-09-29 |
| WO2008024398A3 (en) | 2008-06-26 |
| IL197161A (en) | 2015-07-30 |
| AU2007288253B2 (en) | 2013-05-02 |
| NO343575B1 (no) | 2019-04-08 |
| CN101563085A (zh) | 2009-10-21 |
| WO2008024398A2 (en) | 2008-02-28 |
| KR20090079191A (ko) | 2009-07-21 |
| AR062508A1 (es) | 2008-11-12 |
| IL197161A0 (en) | 2009-12-24 |
| EP2061465A2 (en) | 2009-05-27 |
| EP2061465A4 (en) | 2011-03-16 |
| PL2061465T3 (pl) | 2014-03-31 |
| CL2007002455A1 (es) | 2008-04-18 |
| US8293911B2 (en) | 2012-10-23 |
| US20080139610A1 (en) | 2008-06-12 |
| NO20091183L (no) | 2009-05-08 |
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