CA2494352C - Benzothiophene urea, benzofurane urea, and indole urea, and use of the same as alpha-7 achr agonists - Google Patents
Benzothiophene urea, benzofurane urea, and indole urea, and use of the same as alpha-7 achr agonists Download PDFInfo
- Publication number
- CA2494352C CA2494352C CA2494352A CA2494352A CA2494352C CA 2494352 C CA2494352 C CA 2494352C CA 2494352 A CA2494352 A CA 2494352A CA 2494352 A CA2494352 A CA 2494352A CA 2494352 C CA2494352 C CA 2494352C
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- Canada
- Prior art keywords
- alkyl
- optionally substituted
- hydrogen
- amino
- compound
- Prior art date
- 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.)
- Expired - Fee Related
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- 239000000556 agonist Substances 0.000 title description 4
- CLJSVCQVYHVIPO-UHFFFAOYSA-N 1-benzofuran;urea Chemical compound NC(N)=O.C1=CC=C2OC=CC2=C1 CLJSVCQVYHVIPO-UHFFFAOYSA-N 0.000 title description 2
- KTDUKICSGUVKLS-UHFFFAOYSA-N 1-benzothiophene;urea Chemical compound NC(N)=O.C1=CC=C2SC=CC2=C1 KTDUKICSGUVKLS-UHFFFAOYSA-N 0.000 title description 2
- FOPVBMRCPZYOMW-UHFFFAOYSA-N n-cyclohexyl-n-(cyclohexylcarbamoyl)-4-(1h-indol-3-yl)butanamide Chemical compound C=1NC2=CC=CC=C2C=1CCCC(=O)N(C(=O)NC1CCCCC1)C1CCCCC1 FOPVBMRCPZYOMW-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- -1 benzofuran- and indole ureas Chemical class 0.000 claims abstract description 116
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 239000012453 solvate Substances 0.000 claims abstract description 70
- 239000001257 hydrogen Substances 0.000 claims abstract description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 66
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 34
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 28
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 28
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 28
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000001301 oxygen Substances 0.000 claims abstract description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000011593 sulfur Substances 0.000 claims abstract description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 125000005605 benzo group Chemical group 0.000 claims abstract description 13
- 230000013016 learning Effects 0.000 claims abstract description 12
- 230000015654 memory Effects 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000008447 perception Effects 0.000 claims abstract description 7
- 238000011321 prophylaxis Methods 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 51
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical group 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- 241001465754 Metazoa Species 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004043 oxo group Chemical group O=* 0.000 claims description 11
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 11
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 10
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 10
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 5
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 5
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 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 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 230000006735 deficit Effects 0.000 claims description 4
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 235000013877 carbamide Nutrition 0.000 abstract description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 104
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 63
- 239000000047 product Substances 0.000 description 51
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
- 238000004128 high performance liquid chromatography Methods 0.000 description 40
- 239000000243 solution Substances 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 238000002953 preparative HPLC Methods 0.000 description 29
- 238000012360 testing method Methods 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 22
- 239000012458 free base Substances 0.000 description 22
- 150000003254 radicals Chemical class 0.000 description 22
- NLMFPPVQAZLCMR-GXKRWWSZSA-N 6-amino-n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-1-benzothiophene-2-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1N(CC2)CCC2[C@H]1NC(=O)C1=CC2=CC=C(N)C=C2S1 NLMFPPVQAZLCMR-GXKRWWSZSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 16
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 208000002193 Pain Diseases 0.000 description 11
- 238000007429 general method Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
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- 230000015572 biosynthetic process Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 7
- XLTANAWLDBYGFU-VTLKBQQISA-N methyllycaconitine Chemical compound C([C@]12CN([C@@H]3[C@@]4(O)[C@]5(O)[C@H]6[C@@H](OC)[C@@H]([C@H](C5)OC)C[C@H]6[C@@]3([C@@H]1[C@@H]4OC)[C@@H](OC)CC2)CC)OC(=O)C1=CC=CC=C1N1C(=O)C[C@H](C)C1=O XLTANAWLDBYGFU-VTLKBQQISA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
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- 238000011534 incubation Methods 0.000 description 5
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- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 4
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- 235000011152 sodium sulphate Nutrition 0.000 description 4
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- VCFFDCWMYDUMNP-FYZYNONXSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-6-[[3-(trifluoromethyl)phenyl]carbamoylamino]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(NC(=O)NC=2C=C3SC(=CC3=CC=2)C(=O)N[C@@H]2C3CCN(CC3)C2)=C1 VCFFDCWMYDUMNP-FYZYNONXSA-N 0.000 description 1
- MQWWHRLJZCJTPH-BOXHHOBZSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-6-[[4-(dimethylamino)phenyl]carbamoylamino]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(N(C)C)=CC=C1NC(=O)NC1=CC=C(C=C(S2)C(=O)N[C@@H]3C4CCN(CC4)C3)C2=C1 MQWWHRLJZCJTPH-BOXHHOBZSA-N 0.000 description 1
- AWNYWAUQNBMQPO-FYZYNONXSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-6-[[4-methoxy-3-(trifluoromethyl)phenyl]carbamoylamino]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.C1=C(C(F)(F)F)C(OC)=CC=C1NC(=O)NC1=CC=C(C=C(S2)C(=O)N[C@@H]3C4CCN(CC4)C3)C2=C1 AWNYWAUQNBMQPO-FYZYNONXSA-N 0.000 description 1
- VQLOWUHNXYIAKY-FYZYNONXSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-(phenylcarbamoylamino)-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound Cl.C=1C=CC=2C=C(C(=O)N[C@@H]3C4CCN(CC4)C3)SC=2C=1NC(=O)NC1=CC=CC=C1 VQLOWUHNXYIAKY-FYZYNONXSA-N 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005185 naphthylcarbonyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 229960001779 pargyline Drugs 0.000 description 1
- 125000004675 pentylcarbonyl group Chemical group C(CCCC)C(=O)* 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000024587 synaptic transmission, glutamatergic Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 230000000542 thalamic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- CMMXCVYESRODNH-UHFFFAOYSA-N trichloroepoxyethane Chemical class ClC1OC1(Cl)Cl CMMXCVYESRODNH-UHFFFAOYSA-N 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10234424A DE10234424A1 (de) | 2002-07-29 | 2002-07-29 | Benzothiophen-, Benzofuran- und Indolharnstoffe |
| DE10234424.8 | 2002-07-29 | ||
| PCT/EP2003/007588 WO2004013136A1 (de) | 2002-07-29 | 2003-07-14 | Benzothiophen-, benzofuran- und indolharnstoffe und deren verwendung als alpha7-achr agonisten |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2494352A1 CA2494352A1 (en) | 2004-02-12 |
| CA2494352C true CA2494352C (en) | 2011-11-08 |
Family
ID=30128473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2494352A Expired - Fee Related CA2494352C (en) | 2002-07-29 | 2003-07-14 | Benzothiophene urea, benzofurane urea, and indole urea, and use of the same as alpha-7 achr agonists |
Country Status (8)
| Country | Link |
|---|---|
| US (6) | US7795453B2 (https=) |
| EP (1) | EP1527073B1 (https=) |
| JP (1) | JP4601424B2 (https=) |
| AU (1) | AU2003254343A1 (https=) |
| CA (1) | CA2494352C (https=) |
| DE (2) | DE10234424A1 (https=) |
| ES (1) | ES2291694T3 (https=) |
| WO (1) | WO2004013136A1 (https=) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10164139A1 (de) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| MXPA04012439A (es) | 2002-06-10 | 2005-04-19 | Bayer Healthcare Ag | Amidas de acidos 2-heteroarilcarboxilicos. |
| DE10234424A1 (de) * | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
| GB0220581D0 (en) | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
| AR049401A1 (es) | 2004-06-18 | 2006-07-26 | Novartis Ag | Aza-biciclononanos |
| GB0415746D0 (en) | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
| GB0521508D0 (en) * | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
| GB0525672D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
| GB0525673D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
| LT2889033T (lt) | 2008-11-19 | 2018-07-10 | Forum Pharmaceuticals Inc. | Šizofrenijos negatyvių simptomų gydymas (r)-7-chlor-n-(chinuklidin-3-il)benzo[b]tiofen-2-karboksamidu ir jo farmaciniu požiūriu priimtinomis druskomis |
| JP5808319B2 (ja) * | 2009-05-11 | 2015-11-10 | フォルム ファーマシューティカルズ、インコーポレイテッド | アセチルコリンエステラーゼ阻害剤と組み合わせた特定のα７ニコチン酸受容体を用いた認知障害の治療 |
| JO3250B1 (ar) | 2009-09-22 | 2018-09-16 | Novartis Ag | إستعمال منشطات مستقبل نيكوتينيك أسيتيل كولين ألفا 7 |
| PE20170923A1 (es) | 2010-05-17 | 2017-07-12 | Forum Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin-3-il)benzo[b]tiofeno-2-carboxamida monohidratado |
| WO2012101060A1 (en) | 2011-01-27 | 2012-08-02 | Novartis Ag | Use of nicotinic acetylcholine receptor alpha 7 activators |
| AU2012232711B2 (en) | 2011-03-18 | 2016-04-28 | Novartis Ag | Combinations of alpha 7 nicotinic acetylcholine receptor activators and mGluR5 antagonists for use in dopamine induced dyskinesia in Parkinson's Disease |
| ES2776996T3 (es) | 2011-10-20 | 2020-08-03 | Novartis Ag | Biomarcadores predictivos de la sensibilidad al tratamiento por el activador del receptor de la acetilcolina nicotínico alfa 7 |
| EP3461481A1 (en) | 2012-05-08 | 2019-04-03 | Forum Pharmaceuticals Inc. | Methods of maintaining, treating or improving cognitive function |
| CN104837499B (zh) | 2012-12-11 | 2018-02-23 | 诺华有限公司 | 预测对α7烟碱型乙酰胆碱受体激活剂治疗响应性的生物标志物 |
| EP3623371A1 (en) | 2014-12-16 | 2020-03-18 | Axovant Sciences GmbH | Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors |
| CN107847494A (zh) | 2015-06-10 | 2018-03-27 | 阿考温特科学股份有限公司 | 作为α7‑烟碱乙酰胆碱受体激动剂的氨基苯并异噁唑化合物 |
| JP2018523707A (ja) | 2015-08-12 | 2018-08-23 | アクソバント サイエンシズ ゲーエムベーハー | α７−ニコチン性アセチルコリン受容体のアゴニストとしてのジェミナル置換アミノベンゾイソオキサゾール化合物 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4605652A (en) | 1985-02-04 | 1986-08-12 | A. H. Robins Company, Inc. | Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes |
| HU895334D0 (en) | 1986-07-30 | 1990-01-28 | Sandoz Ag | Process for the preparation of nasal pharmaceutical compositions |
| DE3841313A1 (de) | 1988-12-08 | 1990-06-13 | Bayer Ag | Schwarzes pigment, verfahren zu seiner herstellung sowie dessen verwendung |
| US5189041A (en) | 1990-11-16 | 1993-02-23 | Syntex (U.S.A.) Inc. | Tricyclic 5-ht3 receptor antagonists |
| GB9201749D0 (en) | 1992-01-28 | 1992-03-11 | Smithkline Beecham Plc | Medicaments |
| US6169759B1 (en) | 1999-03-22 | 2001-01-02 | Golden Bridge Technology | Common packet channel |
| SE9903997D0 (sv) * | 1999-11-03 | 1999-11-03 | Astra Ab | New compounds |
| GB0010955D0 (en) | 2000-05-05 | 2000-06-28 | Novartis Ag | Organic compounds |
| JP4616971B2 (ja) * | 2000-07-18 | 2011-01-19 | 田辺三菱製薬株式会社 | １−アザビシクロアルカン化合物およびその医薬用途 |
| US6492385B2 (en) | 2000-08-18 | 2002-12-10 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| WO2002016355A2 (en) * | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic) acetylcholine receptor ligands |
| US6599916B2 (en) | 2000-08-21 | 2003-07-29 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| DE10164139A1 (de) * | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-Heteroarylcarbonsäureamide |
| DE10234424A1 (de) * | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
| PE20170923A1 (es) * | 2010-05-17 | 2017-07-12 | Forum Pharmaceuticals Inc | Una forma cristalina de clorhidrato de (r)-7-cloro-n-(quinuclidin-3-il)benzo[b]tiofeno-2-carboxamida monohidratado |
-
2002
- 2002-07-29 DE DE10234424A patent/DE10234424A1/de not_active Withdrawn
-
2003
- 2003-07-14 JP JP2004525191A patent/JP4601424B2/ja not_active Expired - Fee Related
- 2003-07-14 US US10/522,611 patent/US7795453B2/en not_active Expired - Fee Related
- 2003-07-14 CA CA2494352A patent/CA2494352C/en not_active Expired - Fee Related
- 2003-07-14 DE DE50308015T patent/DE50308015D1/de not_active Expired - Lifetime
- 2003-07-14 EP EP03766162A patent/EP1527073B1/de not_active Expired - Lifetime
- 2003-07-14 AU AU2003254343A patent/AU2003254343A1/en not_active Abandoned
- 2003-07-14 ES ES03766162T patent/ES2291694T3/es not_active Expired - Lifetime
- 2003-07-14 WO PCT/EP2003/007588 patent/WO2004013136A1/de not_active Ceased
-
2010
- 2010-08-30 US US12/871,495 patent/US8153799B2/en not_active Expired - Fee Related
-
2012
- 2012-04-06 US US13/441,407 patent/US8772511B2/en not_active Expired - Fee Related
-
2014
- 2014-06-09 US US14/299,750 patent/US9714242B2/en not_active Expired - Fee Related
-
2017
- 2017-06-15 US US15/624,227 patent/US10196388B2/en not_active Expired - Fee Related
-
2018
- 2018-12-20 US US16/228,182 patent/US20190367504A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP1527073A1 (de) | 2005-05-04 |
| US8153799B2 (en) | 2012-04-10 |
| US20060106096A1 (en) | 2006-05-18 |
| DE50308015D1 (de) | 2007-10-04 |
| JP2005538111A (ja) | 2005-12-15 |
| AU2003254343A1 (en) | 2004-02-23 |
| US9714242B2 (en) | 2017-07-25 |
| EP1527073B1 (de) | 2007-08-22 |
| US20130060039A1 (en) | 2013-03-07 |
| US7795453B2 (en) | 2010-09-14 |
| CA2494352A1 (en) | 2004-02-12 |
| US20150065537A1 (en) | 2015-03-05 |
| DE10234424A1 (de) | 2004-02-12 |
| US20190367504A1 (en) | 2019-12-05 |
| WO2004013136A1 (de) | 2004-02-12 |
| ES2291694T3 (es) | 2008-03-01 |
| US8772511B2 (en) | 2014-07-08 |
| US10196388B2 (en) | 2019-02-05 |
| JP4601424B2 (ja) | 2010-12-22 |
| US20180127409A1 (en) | 2018-05-10 |
| US20100324085A1 (en) | 2010-12-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20210714 |