ES2671818T3 - Compuesto de benzotiofeno - Google Patents

Compuesto de benzotiofeno Download PDF

Info

Publication number: ES2671818T3
Authority: ES; Spain
Prior art keywords: compound; methyl; salt; benzothiophene; chloro
Prior art date: 2013-06-06
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

ES14807340.6T

Other languages

English (en)

Spanish (es)

Inventor

Tsukasa Ishihara

Kazuhiro Ikegai

Ikumi Kuriwaki

Hiroyuki Hisamichi

Nobuaki Takeshita

Ryuichi Takezawa

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Astellas Pharma Inc

Original Assignee

Astellas Pharma Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2013-06-06

Filing date

2014-06-06

Publication date

2018-06-08

2014-06-06 Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc

2018-06-08 Application granted granted Critical

2018-06-08 Publication of ES2671818T3 publication Critical patent/ES2671818T3/es

Status Active legal-status Critical Current

2034-06-06 Anticipated expiration legal-status Critical

Links

-1 Benzothiophene compound Chemical class 0.000 title description 44
FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims abstract description 130
150000003839 salts Chemical class 0.000 claims abstract description 67
229910052736 halogen Inorganic materials 0.000 claims abstract description 21
150000002367 halogens Chemical class 0.000 claims abstract description 18
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 14
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 10
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims abstract description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
125000000217 alkyl group Chemical group 0.000 claims description 29
201000008482 osteoarthritis Diseases 0.000 claims description 28
208000002193 Pain Diseases 0.000 claims description 26
230000036407 pain Effects 0.000 claims description 26
208000001640 Fibromyalgia Diseases 0.000 claims description 23
206010065390 Inflammatory pain Diseases 0.000 claims description 23
208000004296 neuralgia Diseases 0.000 claims description 22
208000021722 neuropathic pain Diseases 0.000 claims description 22
208000009935 visceral pain Diseases 0.000 claims description 14
125000002947 alkylene group Chemical group 0.000 claims description 11
239000008194 pharmaceutical composition Substances 0.000 claims description 11
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 9
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
239000000546 pharmaceutical excipient Substances 0.000 claims description 7
230000002265 prevention Effects 0.000 claims description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
201000010099 disease Diseases 0.000 claims description 5
125000005843 halogen group Chemical group 0.000 claims description 5
IOWRHVVSRLGDKK-LJQANCHMSA-N 5-(6-chloro-2-methyl-1-benzothiophen-3-yl)-2-[(2r)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound C([C@H]1OCCN(C1)C1=CC=C(C=C1C(O)=O)C=1C2=CC=C(Cl)C=C2SC=1C)NC1CCC1 IOWRHVVSRLGDKK-LJQANCHMSA-N 0.000 claims description 3
CGAJHTSRDXRFJT-MRXNPFEDSA-N 5-[5-chloro-6-(trifluoromethyl)-1-benzothiophen-3-yl]-2-[(2r)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound C([C@H]1OCCN(C1)C1=CC=C(C=C1C(=O)O)C=1C2=CC(Cl)=C(C=C2SC=1)C(F)(F)F)NC1CCC1 CGAJHTSRDXRFJT-MRXNPFEDSA-N 0.000 claims description 3
RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 3
125000006318 tert-butyl amino group Chemical group [H]N(*)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
WISAQICIQGLGBZ-UHFFFAOYSA-N 3-fluoro-2-methyl-1-benzothiophene Chemical compound C1=CC=C2C(F)=C(C)SC2=C1 WISAQICIQGLGBZ-UHFFFAOYSA-N 0.000 claims description 2
BIACSKOCQXVCTM-QGZVFWFLSA-N 5-(6-chloro-2-fluoro-1-benzothiophen-3-yl)-2-[(2r)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound C([C@H]1OCCN(C1)C1=CC=C(C=C1C(=O)O)C=1C2=CC=C(Cl)C=C2SC=1F)NC1CCC1 BIACSKOCQXVCTM-QGZVFWFLSA-N 0.000 claims description 2
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
AKAPRLWYPCCXRD-QGZVFWFLSA-N 5-(6-chloro-5-fluoro-2-methyl-1-benzothiophen-3-yl)-2-[(2R)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound Cc1sc2cc(Cl)c(F)cc2c1-c1ccc(N2CCO[C@H](CNC3CCC3)C2)c(c1)C(O)=O AKAPRLWYPCCXRD-QGZVFWFLSA-N 0.000 claims 1
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 73
235000002639 sodium chloride Nutrition 0.000 description 51
238000002360 preparation method Methods 0.000 description 47
239000000203 mixture Substances 0.000 description 43
239000011541 reaction mixture Substances 0.000 description 42
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
238000005481 NMR spectroscopy Methods 0.000 description 37
235000019439 ethyl acetate Nutrition 0.000 description 36
238000003756 stirring Methods 0.000 description 34
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
238000012360 testing method Methods 0.000 description 27
108091006146 Channels Proteins 0.000 description 26
239000012044 organic layer Substances 0.000 description 26
239000002904 solvent Substances 0.000 description 26
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
239000007864 aqueous solution Substances 0.000 description 22
239000012267 brine Substances 0.000 description 22
238000000605 extraction Methods 0.000 description 21
239000000741 silica gel Substances 0.000 description 21
229910002027 silica gel Inorganic materials 0.000 description 21
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
239000012738 dissolution medium Substances 0.000 description 20
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
238000006243 chemical reaction Methods 0.000 description 19
239000003795 chemical substances by application Substances 0.000 description 19
230000000694 effects Effects 0.000 description 19
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
239000007832 Na2SO4 Substances 0.000 description 18
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
229910052938 sodium sulfate Inorganic materials 0.000 description 18
235000011152 sodium sulphate Nutrition 0.000 description 18
239000000243 solution Substances 0.000 description 18
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
229910000041 hydrogen chloride Inorganic materials 0.000 description 16
238000000034 method Methods 0.000 description 16
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
229940000406 drug candidate Drugs 0.000 description 14
239000003777 experimental drug Substances 0.000 description 14
229910052739 hydrogen Inorganic materials 0.000 description 14
229920006395 saturated elastomer Polymers 0.000 description 14
101150064205 ESR1 gene Proteins 0.000 description 13
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
239000007858 starting material Substances 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
241000700159 Rattus Species 0.000 description 12
238000001816 cooling Methods 0.000 description 12
239000000126 substance Substances 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 10
239000012190 activator Substances 0.000 description 9
238000001914 filtration Methods 0.000 description 9
229940095102 methyl benzoate Drugs 0.000 description 9
235000017557 sodium bicarbonate Nutrition 0.000 description 9
229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
239000002253 acid Substances 0.000 description 8
210000004027 cell Anatomy 0.000 description 8
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 7
239000002585 base Substances 0.000 description 7
125000001188 haloalkyl group Chemical group 0.000 description 7
210000003141 lower extremity Anatomy 0.000 description 7
125000006239 protecting group Chemical group 0.000 description 7
230000035945 sensitivity Effects 0.000 description 7
235000017550 sodium carbonate Nutrition 0.000 description 7
229910000029 sodium carbonate Inorganic materials 0.000 description 7
WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
239000004480 active ingredient Substances 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
238000009826 distribution Methods 0.000 description 6
230000006872 improvement Effects 0.000 description 6
239000007788 liquid Substances 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
235000019341 magnesium sulphate Nutrition 0.000 description 6
239000012046 mixed solvent Substances 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
208000004998 Abdominal Pain Diseases 0.000 description 5
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
101100534514 Mus musculus Stmn1 gene Proteins 0.000 description 5
238000000692 Student's t-test Methods 0.000 description 5
229910052786 argon Inorganic materials 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
239000011575 calcium Substances 0.000 description 5
229910052791 calcium Inorganic materials 0.000 description 5
230000003287 optical effect Effects 0.000 description 5
238000002559 palpation Methods 0.000 description 5
239000000843 powder Substances 0.000 description 5
239000000047 product Substances 0.000 description 5
BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 5
239000000725 suspension Substances 0.000 description 5
DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 4
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
239000012359 Methanesulfonyl chloride Substances 0.000 description 4
XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 4
QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 4
235000011054 acetic acid Nutrition 0.000 description 4
239000012300 argon atmosphere Substances 0.000 description 4
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
125000000524 functional group Chemical group 0.000 description 4
230000002401 inhibitory effect Effects 0.000 description 4
239000007924 injection Substances 0.000 description 4
238000002347 injection Methods 0.000 description 4
JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 4
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
239000000651 prodrug Substances 0.000 description 4
229940002612 prodrug Drugs 0.000 description 4
238000010992 reflux Methods 0.000 description 4
229960003147 reserpine Drugs 0.000 description 4
MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 4
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
235000019345 sodium thiosulphate Nutrition 0.000 description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 4
NVSVCEJKKYMAKI-UHFFFAOYSA-N (6-chloro-2-methyl-1-benzothiophen-3-yl)boronic acid Chemical compound Cc1sc2cc(Cl)ccc2c1B(O)O NVSVCEJKKYMAKI-UHFFFAOYSA-N 0.000 description 3
KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
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 3
WCYJTARCKSXTLI-UHFFFAOYSA-N 6-chloro-2-methyl-1-benzothiophene Chemical compound C1=C(Cl)C=C2SC(C)=CC2=C1 WCYJTARCKSXTLI-UHFFFAOYSA-N 0.000 description 3
OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
108010045489 Calcium-Activated Potassium Channels Proteins 0.000 description 3
102000005702 Calcium-Activated Potassium Channels Human genes 0.000 description 3
239000012981 Hank's balanced salt solution Substances 0.000 description 3
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
230000009471 action Effects 0.000 description 3
230000002421 anti-septic effect Effects 0.000 description 3
230000037396 body weight Effects 0.000 description 3
229910052794 bromium Inorganic materials 0.000 description 3
239000013078 crystal Substances 0.000 description 3
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
238000006073 displacement reaction Methods 0.000 description 3
239000003814 drug Substances 0.000 description 3
239000000839 emulsion Substances 0.000 description 3
150000002170 ethers Chemical class 0.000 description 3
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
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239000002198 insoluble material Substances 0.000 description 3
208000002551 irritable bowel syndrome Diseases 0.000 description 3
239000002609 medium Substances 0.000 description 3
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239000002184 metal Substances 0.000 description 3
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239000008247 solid mixture Substances 0.000 description 3
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CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
BZHSQEBARZGORM-UHFFFAOYSA-N (6-chloro-5-fluoro-1-benzothiophen-2-yl)methanol Chemical compound OCc1cc2cc(F)c(Cl)cc2s1 BZHSQEBARZGORM-UHFFFAOYSA-N 0.000 description 2
PNZVZGQUBVFVQL-UHFFFAOYSA-N 1-(bromomethyl)-5-chloro-2-fluoro-4-(trifluoromethyl)benzene Chemical compound Fc1cc(c(Cl)cc1CBr)C(F)(F)F PNZVZGQUBVFVQL-UHFFFAOYSA-N 0.000 description 2
LXQMHOKEXZETKB-UHFFFAOYSA-N 1-amino-2-methylpropan-2-ol Chemical compound CC(C)(O)CN LXQMHOKEXZETKB-UHFFFAOYSA-N 0.000 description 2
VMZJDAVSEGGMCF-UHFFFAOYSA-N 1-chloro-4-fluoro-2-iodo-5-methylbenzene Chemical compound Cc1cc(Cl)c(I)cc1F VMZJDAVSEGGMCF-UHFFFAOYSA-N 0.000 description 2
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239000003002 pH adjusting agent Substances 0.000 description 1
208000027753 pain disease Diseases 0.000 description 1
LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
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239000011591 potassium Substances 0.000 description 1
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239000004036 potassium channel stimulating agent Substances 0.000 description 1
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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238000012827 research and development Methods 0.000 description 1
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PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
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LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
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Classifications

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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
- A—HUMAN NECESSITIES
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Neurology (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Pain & Pain Management (AREA)
Rheumatology (AREA)
Physical Education & Sports Medicine (AREA)
Orthopedic Medicine & Surgery (AREA)
Immunology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

ES14807340.6T 2013-06-06 2014-06-06 Compuesto de benzotiofeno Active ES2671818T3 (es)

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JP2013119416		2013-06-06
JP2013119416		2013-06-06
PCT/JP2014/065141 WO2014196644A1 (ja)	2013-06-06	2014-06-06	ベンゾチオフェン化合物

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EP (1)	EP3006443B1 (2)
JP (1)	JP6314978B2 (2)
KR (1)	KR102253721B1 (2)
CN (1)	CN105263926B (2)
AR (1)	AR096544A1 (2)
AU (1)	AU2014275768B2 (2)
BR (1)	BR112015030533B1 (2)
CA (1)	CA2914606C (2)
CY (1)	CY1120341T1 (2)
DK (1)	DK3006443T3 (2)
ES (1)	ES2671818T3 (2)
HR (1)	HRP20180722T1 (2)
HU (1)	HUE038920T2 (2)
IL (1)	IL242800B (2)
LT (1)	LT3006443T (2)
MX (1)	MX2015016743A (2)
MY (1)	MY199155A (2)
NO (1)	NO3006443T3 (2)
PH (1)	PH12015502637B1 (2)
PL (1)	PL3006443T3 (2)
PT (1)	PT3006443T (2)
RS (1)	RS57250B1 (2)
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SG (1)	SG11201509989VA (2)
SI (1)	SI3006443T1 (2)
SM (1)	SMT201800306T1 (2)
TR (1)	TR201808724T4 (2)
TW (1)	TWI624466B (2)
UA (1)	UA117484C2 (2)
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US5614639A (en) *	1995-03-31	1997-03-25	Eli Lilly And Company	Process for preparing 2-substituted benzo[b]thiophene compounds and intermediates thereof
US20040116405A1 (en)	2001-02-06	2004-06-17	Brian Cox	Use of bicyclic esters or amides for the treatment of diseases responsive to enhanced potassium channel activity
WO2003005025A1 (en) *	2001-07-03	2003-01-16	Biovitrum Ab	Methods for identifying compounds modulating the activity of ppar-gamma
JP2006522130A (ja)	2003-04-03	2006-09-28	メルク　エンド　カムパニー　インコーポレーテッド	ナトリウムチャンネル遮断薬としてのビアリール置換ピラゾール
CN1852906A (zh)	2003-07-15	2006-10-25	史密丝克莱恩比彻姆公司	新化合物
WO2008054435A2 (en) *	2006-01-09	2008-05-08	The Regents Of The University Of California	Use of sk channel activators to prevent relapse/reinstatement of drugs of abuse
WO2009035671A1 (en) *	2007-09-12	2009-03-19	Janssen Pharmaceutica N.V.	Substituted nitrogen-containing heteroaryl derivatives useful as modulators of the histamine h4 receptor
EP2358750B1 (en)	2008-11-10	2017-01-11	Boehringer Ingelheim International GmbH	Compositions and methods for modulating cell-cell fusion via intermediate-conductance calcium-activated potassium channels
AR090037A1 (es)	2011-11-15	2014-10-15	Xention Ltd	Derivados de tieno y/o furo-pirimidinas y piridinas inhibidores de los canales de potasio

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- 2014-06-06 NO NO14807340A patent/NO3006443T3/no unknown
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- 2014-06-06 PT PT148073406T patent/PT3006443T/pt unknown
- 2014-06-06 MX MX2015016743A patent/MX2015016743A/es active IP Right Grant
- 2014-06-06 WO PCT/JP2014/065141 patent/WO2014196644A1/ja not_active Ceased
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- 2014-06-06 JP JP2015521510A patent/JP6314978B2/ja not_active Expired - Fee Related
- 2014-06-06 RU RU2015152150A patent/RU2667507C2/ru active
- 2014-06-06 AU AU2014275768A patent/AU2014275768B2/en not_active Ceased
- 2014-06-06 UA UAA201512058A patent/UA117484C2/uk unknown
- 2014-06-06 US US14/298,208 patent/US8981119B2/en active Active
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- 2014-06-06 ES ES14807340.6T patent/ES2671818T3/es active Active
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- 2014-06-06 TR TR2018/08724T patent/TR201808724T4/tr unknown
- 2014-06-06 SI SI201430718T patent/SI3006443T1/en unknown
- 2014-06-06 DK DK14807340.6T patent/DK3006443T3/en active
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2015
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Also Published As

Publication number	Publication date
MX2015016743A (es)	2016-03-21
PL3006443T3 (pl)	2018-09-28
EP3006443A1 (en)	2016-04-13
NO3006443T3 (2)	2018-09-22
US8981119B2 (en)	2015-03-17
LT3006443T (lt)	2018-07-10
IL242800B (en)	2019-06-30
UA117484C2 (uk)	2018-08-10
MY199155A (en)	2023-10-18
AU2014275768A1 (en)	2015-12-17
AR096544A1 (es)	2016-01-13
TW201536775A (zh)	2015-10-01
BR112015030533B1 (pt)	2023-02-28
RU2667507C2 (ru)	2018-09-21
US20150133433A1 (en)	2015-05-14
WO2014196644A1 (ja)	2014-12-11
US9399038B2 (en)	2016-07-26
TR201808724T4 (tr)	2018-07-23
CA2914606A1 (en)	2014-12-11
US20140364421A1 (en)	2014-12-11
PH12015502637B1 (en)	2019-02-08
CN105263926B (zh)	2018-05-11
HUE038920T2 (hu)	2018-12-28
ZA201508866B (en)	2017-11-29
HK1215570A1 (zh)	2016-09-02
AU2014275768B2 (en)	2017-12-14
TWI624466B (zh)	2018-05-21
HRP20180722T1 (hr)	2018-06-15
KR102253721B1 (ko)	2021-05-18
IL242800A0 (en)	2016-02-01
PT3006443T (pt)	2018-06-07
CN105263926A (zh)	2016-01-20
RU2015152150A (ru)	2017-07-13
RS57250B1 (sr)	2018-07-31
DK3006443T3 (en)	2018-06-25
CA2914606C (en)	2021-03-23
SMT201800306T1 (it)	2018-07-17
CY1120341T1 (el)	2019-07-10
EP3006443A4 (en)	2016-12-21
PH12015502637A1 (en)	2016-03-07
EP3006443B1 (en)	2018-04-25
SG11201509989VA (en)	2016-01-28
KR20160015281A (ko)	2016-02-12
SI3006443T1 (en)	2018-08-31
JP6314978B2 (ja)	2018-04-25
BR112015030533A2 (pt)	2020-10-20
JPWO2014196644A1 (ja)	2017-02-23

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