ES2637288T3 - N-((1H-indol-3-il)-alquil)-4-bencil)benzamida y derivados de N-((1H-pirrolo[2,3-b]piridin-3-il)-alquil)-4-bencil)benzamida como inhibidores de la agregación de alfa-sinucleína para el tratamiento de trastornos neurodegenerativos - Google Patents
N-((1H-indol-3-il)-alquil)-4-bencil)benzamida y derivados de N-((1H-pirrolo[2,3-b]piridin-3-il)-alquil)-4-bencil)benzamida como inhibidores de la agregación de alfa-sinucleína para el tratamiento de trastornos neurodegenerativos Download PDFInfo
- Publication number
- ES2637288T3 ES2637288T3 ES11805450.1T ES11805450T ES2637288T3 ES 2637288 T3 ES2637288 T3 ES 2637288T3 ES 11805450 T ES11805450 T ES 11805450T ES 2637288 T3 ES2637288 T3 ES 2637288T3
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- Prior art keywords
- benzamide
- mmol
- heterocycle
- ethyl
- chloro
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- -1 1H-indole-3-yl Chemical group 0.000 title claims abstract description 178
- 238000011282 treatment Methods 0.000 title claims description 8
- 208000015122 neurodegenerative disease Diseases 0.000 title claims 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title description 20
- 102000003802 alpha-Synuclein Human genes 0.000 title description 14
- 108090000185 alpha-Synuclein Proteins 0.000 title description 14
- 230000002776 aggregation Effects 0.000 title description 8
- 238000004220 aggregation Methods 0.000 title description 8
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 44
- 239000001257 hydrogen Substances 0.000 claims abstract description 44
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 37
- 150000002367 halogens Chemical class 0.000 claims abstract description 35
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 10
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
- 208000011990 Corticobasal Degeneration Diseases 0.000 claims 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims 1
- 201000010374 Down Syndrome Diseases 0.000 claims 1
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- 208000014060 Niemann-Pick disease Diseases 0.000 claims 1
- 206010033799 Paralysis Diseases 0.000 claims 1
- 208000027089 Parkinsonian disease Diseases 0.000 claims 1
- 206010034010 Parkinsonism Diseases 0.000 claims 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims 1
- 208000030886 Traumatic Brain injury Diseases 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- 210000000349 chromosome Anatomy 0.000 claims 1
- 125000004438 haloalkoxy group Chemical group 0.000 claims 1
- LKPAAZZXRWGIGQ-UHFFFAOYSA-N n-[2-(5-hydroxy-1h-indol-3-yl)ethyl]pyridine-3-carboxamide Chemical compound C12=CC(O)=CC=C2NC=C1CCNC(=O)C1=CC=CN=C1 LKPAAZZXRWGIGQ-UHFFFAOYSA-N 0.000 claims 1
- 208000033510 neuroaxonal dystrophy Diseases 0.000 claims 1
- 208000002593 pantothenate kinase-associated neurodegeneration Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 230000000750 progressive effect Effects 0.000 claims 1
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 230000009529 traumatic brain injury Effects 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 abstract description 121
- 229910052760 oxygen Inorganic materials 0.000 abstract description 97
- 125000003342 alkenyl group Chemical group 0.000 abstract description 85
- 125000000304 alkynyl group Chemical group 0.000 abstract description 83
- 125000005842 heteroatom Chemical group 0.000 abstract description 82
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 71
- 125000000217 alkyl group Chemical group 0.000 abstract description 69
- 229910052799 carbon Inorganic materials 0.000 abstract description 59
- 125000003118 aryl group Chemical group 0.000 abstract description 58
- 125000006270 aryl alkenylene group Chemical group 0.000 abstract description 43
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 31
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 19
- 125000004429 atom Chemical group 0.000 abstract description 15
- 125000006588 heterocycloalkylene group Chemical group 0.000 abstract description 14
- 125000004419 alkynylene group Chemical group 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 129
- 238000002360 preparation method Methods 0.000 description 58
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
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- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 53
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 51
- 238000003818 flash chromatography Methods 0.000 description 50
- 238000000034 method Methods 0.000 description 50
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 48
- 239000003480 eluent Substances 0.000 description 46
- 239000000741 silica gel Substances 0.000 description 45
- 229910002027 silica gel Inorganic materials 0.000 description 45
- 239000007787 solid Substances 0.000 description 44
- 239000000203 mixture Substances 0.000 description 43
- 150000001721 carbon Chemical group 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 229910000029 sodium carbonate Inorganic materials 0.000 description 25
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- 239000013067 intermediate product Substances 0.000 description 19
- 235000009518 sodium iodide Nutrition 0.000 description 19
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
- 239000007821 HATU Substances 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 229930195733 hydrocarbon Natural products 0.000 description 16
- 239000013058 crude material Substances 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 14
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 description 12
- 125000006591 (C2-C6) alkynylene group Chemical group 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000004215 Carbon black (E152) Substances 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 101150070547 MAPT gene Proteins 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 9
- 125000002947 alkylene group Chemical group 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 125000002541 furyl group Chemical group 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 125000002757 morpholinyl group Chemical group 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000001544 thienyl group Chemical group 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 125000002883 imidazolyl group Chemical group 0.000 description 8
- 125000003226 pyrazolyl group Chemical group 0.000 description 8
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 8
- PBANXRNIXGEHPZ-UHFFFAOYSA-N 2-(5-chloro-1h-indol-3-yl)ethanamine;hydron;chloride Chemical compound Cl.C1=C(Cl)C=C2C(CCN)=CNC2=C1 PBANXRNIXGEHPZ-UHFFFAOYSA-N 0.000 description 7
- SJHWVLADKRXQQR-UHFFFAOYSA-N 4-[(3-fluorophenyl)methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CC1=CC=CC(F)=C1 SJHWVLADKRXQQR-UHFFFAOYSA-N 0.000 description 7
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
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- 125000005936 piperidyl group Chemical group 0.000 description 7
- 125000000168 pyrrolyl group Chemical group 0.000 description 7
- 125000000335 thiazolyl group Chemical group 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 6
- FIKAKWIAUPDISJ-UHFFFAOYSA-L paraquat dichloride Chemical compound [Cl-].[Cl-].C1=C[N+](C)=CC=C1C1=CC=[N+](C)C=C1 FIKAKWIAUPDISJ-UHFFFAOYSA-L 0.000 description 6
- 125000003373 pyrazinyl group Chemical group 0.000 description 6
- 125000002098 pyridazinyl group Chemical group 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 239000000377 silicon dioxide Substances 0.000 description 6
- 125000003831 tetrazolyl group Chemical group 0.000 description 6
- 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 6
- MYTGFBZJLDLWQG-UHFFFAOYSA-N 5-chloro-1h-indole Chemical compound ClC1=CC=C2NC=CC2=C1 MYTGFBZJLDLWQG-UHFFFAOYSA-N 0.000 description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 5
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 5
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 5
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 5
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- 238000000746 purification Methods 0.000 description 5
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 5
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 5
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
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- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 4
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- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 4
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 4
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
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- 125000005955 1H-indazolyl group Chemical group 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 125000004404 heteroalkyl group Chemical group 0.000 description 3
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- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000004926 indolenyl group Chemical group 0.000 description 3
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- OTVNTVPPKKNUEI-UHFFFAOYSA-N n-[2-(5-chloro-2-methyl-1h-indol-3-yl)ethyl]-4-[(3-fluorophenyl)methyl]benzamide Chemical compound CC=1NC2=CC=C(Cl)C=C2C=1CCNC(=O)C(C=C1)=CC=C1CC1=CC=CC(F)=C1 OTVNTVPPKKNUEI-UHFFFAOYSA-N 0.000 description 1
- FZHXBXLABVHVTC-UHFFFAOYSA-N n-[2-(5-cyano-2-triethylsilyl-1h-indol-3-yl)ethyl]-4-[(3-fluorophenyl)methyl]benzamide Chemical compound CC[Si](CC)(CC)C=1NC2=CC=C(C#N)C=C2C=1CCNC(=O)C(C=C1)=CC=C1CC1=CC=CC(F)=C1 FZHXBXLABVHVTC-UHFFFAOYSA-N 0.000 description 1
- PYUNPSUJSCJYCH-UHFFFAOYSA-N n-[2-(6-chloro-5-methyl-1h-indol-3-yl)ethyl]-4-[(3-fluorophenyl)methyl]benzamide Chemical compound C=1NC=2C=C(Cl)C(C)=CC=2C=1CCNC(=O)C(C=C1)=CC=C1CC1=CC=CC(F)=C1 PYUNPSUJSCJYCH-UHFFFAOYSA-N 0.000 description 1
- OWSGWODVDLLTQM-UHFFFAOYSA-N n-[3-(5-chloro-1h-indol-3-yl)propyl]-4-[(3-fluorophenyl)methyl]benzamide Chemical compound FC1=CC=CC(CC=2C=CC(=CC=2)C(=O)NCCCC=2C3=CC(Cl)=CC=C3NC=2)=C1 OWSGWODVDLLTQM-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 229950006327 napsilate Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 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
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 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
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000005032 thiofuranyl group Chemical group S1C(=CC=C1)* 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D409/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB1021103.5A GB201021103D0 (en) | 2010-12-13 | 2010-12-13 | New compounds for the treatment of neurodegenerative diseases |
| GB201021103 | 2010-12-13 | ||
| PCT/EP2011/072568 WO2012080221A1 (en) | 2010-12-13 | 2011-12-13 | New compounds for the treatment of neurodegenerative diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2637288T3 true ES2637288T3 (es) | 2017-10-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| ES11805450.1T Active ES2637288T3 (es) | 2010-12-13 | 2011-12-13 | N-((1H-indol-3-il)-alquil)-4-bencil)benzamida y derivados de N-((1H-pirrolo[2,3-b]piridin-3-il)-alquil)-4-bencil)benzamida como inhibidores de la agregación de alfa-sinucleína para el tratamiento de trastornos neurodegenerativos |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9266832B2 (enExample) |
| EP (1) | EP2651888B1 (enExample) |
| JP (1) | JP6050241B2 (enExample) |
| CN (1) | CN103261156B (enExample) |
| CA (1) | CA2819171C (enExample) |
| DK (1) | DK2651888T3 (enExample) |
| ES (1) | ES2637288T3 (enExample) |
| GB (1) | GB201021103D0 (enExample) |
| HR (1) | HRP20171186T1 (enExample) |
| HU (1) | HUE033277T2 (enExample) |
| SI (1) | SI2651888T1 (enExample) |
| WO (1) | WO2012080221A1 (enExample) |
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| GB201021104D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| GB201021103D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | New compounds for the treatment of neurodegenerative diseases |
| BR112016015449A8 (pt) * | 2013-12-30 | 2020-06-09 | Lifesci Pharmaceuticals Inc | compostos inibidores terapêuticos, composição farmacêutica os compreendendo e uso dos mesmos |
| HUE050964T2 (hu) * | 2014-01-29 | 2021-01-28 | UCB Biopharma SRL | Heteroaril amidok mint protein aggregáció inhibitorai |
| CN104744353B (zh) * | 2015-03-31 | 2017-11-24 | 山东友帮生化科技有限公司 | 2‑氨基‑3‑碘‑5‑氯吡啶的合成方法 |
| CN105130978B (zh) * | 2015-07-22 | 2017-11-21 | 中国人民解放军军事医学科学院基础医学研究所 | 一种化合物及其在帕金森疾病方面的应用 |
| US10975066B2 (en) | 2015-07-29 | 2021-04-13 | UCB Biopharma SRL | Bis-heteroaryl derivatives as modulators of protein aggregation |
| US11970486B2 (en) | 2016-10-24 | 2024-04-30 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
| CN110392833A (zh) | 2017-01-06 | 2019-10-29 | 优曼尼蒂治疗公司 | 治疗神经病症的方法 |
| RU2019126170A (ru) | 2017-01-26 | 2021-02-26 | Юсб Байофарма Спрл | Бисгетероарильные производные в качестве модуляторов агрегации белков |
| WO2018138088A1 (en) | 2017-01-26 | 2018-08-02 | Ucb Biopharma Sprl | Bicyclic bis-heteroaryl derivatives as modulators of protein aggregation |
| BR112019011931A2 (pt) | 2017-01-26 | 2019-10-29 | Ucb Biopharma Sprl | derivados de alcóxi bis-heteroarila como moduladores da agregação de proteína |
| EP3589616A1 (en) | 2017-02-28 | 2020-01-08 | Universitat Autònoma de Barcelona | (nitro-phenyl)-nitropyridine compounds for treating synucleinopathies |
| WO2019025424A1 (en) | 2017-08-04 | 2019-02-07 | Universitat Autonoma De Barcelona | COMPOUNDS FOR TREATING SYNUCLEINOPATHIES |
| WO2019084157A1 (en) | 2017-10-24 | 2019-05-02 | Yumanity Therapeutics, Inc. | COMPOUNDS AND USES THEREOF |
| WO2019161917A1 (en) | 2018-02-23 | 2019-08-29 | Universitat Autonoma De Barcelona | 4-substituted 1-ethenylsulfonyl-2-nitrobenzene compounds for treating synucleinopathies |
| AU2019238326B2 (en) | 2018-03-23 | 2025-03-06 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
| HUE066335T2 (hu) | 2018-10-05 | 2024-07-28 | Annapurna Bio Inc | Vegyületek és készítmények APJ receptor aktivitáshoz kapcsolódó állapotok kezelésére |
| MA54829A (fr) | 2019-01-24 | 2021-12-01 | Yumanity Therapeutics Inc | Composés et leurs utilisations |
| MA55385A (fr) * | 2019-03-22 | 2022-01-26 | Yumanity Therapeutics Inc | Composés et leurs utilisations |
| CA3148602A1 (en) * | 2019-08-02 | 2021-02-11 | Acelot, Inc. | Small molecule drugs and related methods for treatment of diseases related to tdp-43, alpha-synuclein, huntingtin's protein and tau protein oligomer formation |
| EA202192047A1 (ru) | 2019-11-13 | 2021-12-08 | Юманити Терапьютикс, Инк. | Соединения и их применение |
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| US3202669A (en) | 1963-11-06 | 1965-08-24 | Upjohn Co | 6-methoxy-1-(3, 4, 5-trimethoxy phenyl)-9h-pyrido [3, 4-b] indole and its acid addition salts |
| IL130169A (en) | 1999-05-27 | 2006-08-20 | Neurim Pharma 1991 | Indole derivatives, and pharmaceutical preparations, skin protection preparations, and cosmetics containing them |
| US6306890B1 (en) | 1999-08-30 | 2001-10-23 | Vanderbilt University | Esters derived from indolealkanols and novel amides derived from indolealkylamides that are selective COX-2 inhibitors |
| GB9922171D0 (en) * | 1999-09-21 | 1999-11-17 | Zeneca Ltd | Chemical compounds |
| EP1284266A4 (en) * | 2000-05-02 | 2005-11-16 | Meiji Seika Kaisha | NEW INDOIND DERIVATIVES WITH CHYME-INHIBITABLE ACTIVITIES AND METHOD FOR THEIR PREPARATION |
| DOP2002000332A (es) * | 2001-02-14 | 2002-08-30 | Warner Lambert Co | Inhibidores de piridina de metaloproteinasas de la matriz |
| CN103265477B (zh) | 2003-02-26 | 2017-01-11 | 苏根公司 | 作为蛋白激酶抑制剂的氨基杂芳基化合物 |
| WO2006007542A1 (en) | 2004-07-01 | 2006-01-19 | The Regents Of The University Of California | Small molecule inhibition of a pdz-domain interaction |
| EP1817025A2 (en) | 2004-11-23 | 2007-08-15 | PTC Therapeutics, Inc. | Tetrahydrocarbazoles as active agents for inhibiting vegf production by translational control |
| JP2009501709A (ja) * | 2005-07-12 | 2009-01-22 | バイエル・クロツプサイエンス・エス・アー | 新規ベンゾヘテロシクリルエチルベンズアミド誘導体 |
| EP2149552A1 (de) * | 2008-07-30 | 2010-02-03 | Bayer Schering Pharma AG | 5,6 substituierte Benzamid-Derivate als Modulatoren des EP2-Rezeptors |
| CA2751534A1 (en) * | 2009-03-03 | 2010-09-10 | Pfizer Inc. | Novel phenyl imidazoles and phenyl triazoles as gamma-secretase modulators |
| GB0910003D0 (en) * | 2009-06-11 | 2009-07-22 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| ES2360435B1 (es) * | 2009-10-30 | 2012-05-04 | Consejo Superior De Investigaciones Cientificas (Csic) (70%) | Derivados de biss (aralquil) amino y sistemas (6+5)-heteroaromaticos y su uso en el tratamiento de patologias neurodegenerativas, incluida la enfermedad de alzheimer |
| EP2622970A4 (en) * | 2010-09-29 | 2014-04-16 | Ajinomoto Kk | SALT TASTE AMPLIFIERS |
| JP6117104B2 (ja) | 2010-11-15 | 2017-04-19 | アッヴィ・インコーポレイテッド | Ｎａｍｐｔおよびｒｏｃｋ阻害薬 |
| GB201021104D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| GB201021103D0 (en) | 2010-12-13 | 2011-01-26 | Univ Leuven Kath | New compounds for the treatment of neurodegenerative diseases |
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2010
- 2010-12-13 GB GBGB1021103.5A patent/GB201021103D0/en not_active Ceased
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2011
- 2011-12-13 HR HRP20171186TT patent/HRP20171186T1/hr unknown
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- 2011-12-13 ES ES11805450.1T patent/ES2637288T3/es active Active
- 2011-12-13 HU HUE11805450A patent/HUE033277T2/en unknown
- 2011-12-13 CA CA2819171A patent/CA2819171C/en active Active
- 2011-12-13 US US13/993,723 patent/US9266832B2/en active Active
- 2011-12-13 EP EP11805450.1A patent/EP2651888B1/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2819171A1 (en) | 2012-06-21 |
| US20130274260A1 (en) | 2013-10-17 |
| HUE033277T2 (en) | 2017-11-28 |
| JP2013544872A (ja) | 2013-12-19 |
| CN103261156B (zh) | 2016-12-28 |
| WO2012080221A1 (en) | 2012-06-21 |
| SI2651888T1 (sl) | 2017-10-30 |
| EP2651888B1 (en) | 2017-05-17 |
| GB201021103D0 (en) | 2011-01-26 |
| EP2651888A1 (en) | 2013-10-23 |
| HRP20171186T1 (hr) | 2017-10-20 |
| JP6050241B2 (ja) | 2016-12-21 |
| CN103261156A (zh) | 2013-08-21 |
| DK2651888T3 (en) | 2017-08-28 |
| US9266832B2 (en) | 2016-02-23 |
| CA2819171C (en) | 2020-02-18 |
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