CA2708961C - (het)aryl-p-quinone derivatives for treatment of mitochondrial diseases - Google Patents
(het)aryl-p-quinone derivatives for treatment of mitochondrial diseases Download PDFInfo
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- CA2708961C CA2708961C CA2708961A CA2708961A CA2708961C CA 2708961 C CA2708961 C CA 2708961C CA 2708961 A CA2708961 A CA 2708961A CA 2708961 A CA2708961 A CA 2708961A CA 2708961 C CA2708961 C CA 2708961C
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- Prior art keywords
- compound
- hydroxy
- alkyl
- diene
- dione
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- 208000012268 mitochondrial disease Diseases 0.000 title claims abstract description 104
- 238000011282 treatment Methods 0.000 title abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 502
- 208000024412 Friedreich ataxia Diseases 0.000 claims abstract description 34
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 claims abstract description 28
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 claims abstract description 25
- 206010048804 Kearns-Sayre syndrome Diseases 0.000 claims abstract description 23
- 201000002169 Mitochondrial myopathy Diseases 0.000 claims abstract description 19
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 claims abstract description 15
- 208000014644 Brain disease Diseases 0.000 claims abstract description 10
- 208000032274 Encephalopathy Diseases 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims description 236
- 239000000203 mixture Substances 0.000 claims description 201
- 229910052736 halogen Inorganic materials 0.000 claims description 143
- 150000002367 halogens Chemical class 0.000 claims description 129
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 99
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 97
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 95
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 76
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 72
- 125000003118 aryl group Chemical group 0.000 claims description 68
- -1 -N((C1-C4)-alkyl)2 Chemical group 0.000 claims description 67
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 57
- 201000010099 disease Diseases 0.000 claims description 55
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 125000000623 heterocyclic group Chemical group 0.000 claims description 51
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 47
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 44
- 208000035475 disorder Diseases 0.000 claims description 39
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 39
- 230000007812 deficiency Effects 0.000 claims description 32
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 30
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 29
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 125000001153 fluoro group Chemical group F* 0.000 claims description 26
- 208000029560 autism spectrum disease Diseases 0.000 claims description 24
- 210000003470 mitochondria Anatomy 0.000 claims description 23
- 150000003573 thiols Chemical class 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000004043 oxo group Chemical group O=* 0.000 claims description 20
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- 230000002490 cerebral effect Effects 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000001624 naphthyl group Chemical group 0.000 claims description 15
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- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 11
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 claims description 10
- 201000000915 Chronic Progressive External Ophthalmoplegia Diseases 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 229910052717 sulfur Chemical group 0.000 claims description 9
- 239000011593 sulfur Chemical group 0.000 claims description 9
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- 125000003342 alkenyl group Chemical group 0.000 claims description 8
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- 108010024882 Electron Transport Complex III Proteins 0.000 claims description 7
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- 125000000304 alkynyl group Chemical group 0.000 claims description 7
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- 208000002155 Cytochrome-c Oxidase Deficiency Diseases 0.000 claims description 6
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- 108010007425 oligomycin sensitivity conferring protein Proteins 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 201000010384 renal tubular acidosis Diseases 0.000 claims description 6
- 230000002792 vascular Effects 0.000 claims description 6
- QVIPRTNEYGUELS-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C=CC(Cl)=CC=2)=C1CCC(C)(C)O QVIPRTNEYGUELS-UHFFFAOYSA-N 0.000 claims description 5
- SFNNDQVZSABNTF-UHFFFAOYSA-N 2-(4-chlorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(CCC(C)(C)O)C(=O)C(C=2C=CC(Cl)=CC=2)=C1C SFNNDQVZSABNTF-UHFFFAOYSA-N 0.000 claims description 5
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
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- PFCMMFVHMXNJOT-UHFFFAOYSA-N 2-(4-fluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C=CC(F)=CC=2)=C1CCC(C)(C)O PFCMMFVHMXNJOT-UHFFFAOYSA-N 0.000 claims description 4
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- DEDXEEVQIANDKC-UHFFFAOYSA-N 2-(2-fluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C(=CC=CC=2)F)=C1CCC(C)(C)O DEDXEEVQIANDKC-UHFFFAOYSA-N 0.000 claims description 3
- KSEDDPPMVSBWER-UHFFFAOYSA-N 2-(3,4-difluorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(CCC(C)(C)O)C(=O)C(C=2C=C(F)C(F)=CC=2)=C1C KSEDDPPMVSBWER-UHFFFAOYSA-N 0.000 claims description 3
- AWKZKODRAUUWJR-UHFFFAOYSA-N 2-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C=C(F)C=CC=2)=C1CCC(C)(C)O AWKZKODRAUUWJR-UHFFFAOYSA-N 0.000 claims description 3
- BWLZEUQOMIHJIN-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-3-(1-hydroxy-2-phenylethyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C(O)CC=2C=CC=CC=2)=C1CCC(C)(C)O BWLZEUQOMIHJIN-UHFFFAOYSA-N 0.000 claims description 3
- IAFSJZOBPHUUAJ-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-3-(4-methoxyphenyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound C1=CC(OC)=CC=C1C1=C(CCC(C)(C)O)C(=O)C(C)=C(C)C1=O IAFSJZOBPHUUAJ-UHFFFAOYSA-N 0.000 claims description 3
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- OFSOCAUHHVJKNS-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-3-[2-(1h-imidazol-5-yl)ethyl]-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(CCC(C)(C)O)=C1CCC1=CN=CN1 OFSOCAUHHVJKNS-UHFFFAOYSA-N 0.000 claims description 3
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- RMPBGNMYHDNLMV-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-(3-phenylpropyl)cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(CCC(C)(C)O)=C1CCCC1=CC=CC=C1 RMPBGNMYHDNLMV-UHFFFAOYSA-N 0.000 claims description 3
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- ZBYZQYBZMSOQQK-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C=CC=CC=2)=C1CCC(C)(C)O ZBYZQYBZMSOQQK-UHFFFAOYSA-N 0.000 claims description 3
- JHQIXMCFXKLVLD-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-6-(4-methoxyphenyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound C1=CC(OC)=CC=C1C1=C(C)C(=O)C(C)=C(CCC(C)(C)O)C1=O JHQIXMCFXKLVLD-UHFFFAOYSA-N 0.000 claims description 3
- IUDXSCGIQPHNGU-UHFFFAOYSA-N 2-(4-fluorophenyl)-6-(3-hydroxy-3-methylbutyl)-3,5-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(CCC(C)(C)O)C(=O)C(C=2C=CC(F)=CC=2)=C1C IUDXSCGIQPHNGU-UHFFFAOYSA-N 0.000 claims description 3
- RWGCFWBUCIJFOF-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C=CC(=CC=2)C(C)(C)C)=C1CCC(C)(C)O RWGCFWBUCIJFOF-UHFFFAOYSA-N 0.000 claims description 3
- JXVUFWRGFVHAJA-UHFFFAOYSA-N 2-(4-ethylphenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound C1=CC(CC)=CC=C1C1=C(CCC(C)(C)O)C(=O)C(C)=C(C)C1=O JXVUFWRGFVHAJA-UHFFFAOYSA-N 0.000 claims description 2
- LOWAFOSZWAXVPN-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-[4-(trifluoromethyl)phenyl]cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(CCC(C)(C)O)C(=O)C(C=2C=CC(=CC=2)C(F)(F)F)=C1C LOWAFOSZWAXVPN-UHFFFAOYSA-N 0.000 claims 4
- LZBJQFBCLCRSIF-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-5,6-dimethyl-3-[4-(trifluoromethyl)phenyl]cyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C=CC(=CC=2)C(F)(F)F)=C1CCC(C)(C)O LZBJQFBCLCRSIF-UHFFFAOYSA-N 0.000 claims 4
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- KIKSVHSICFHSIH-UHFFFAOYSA-N 2-(2,4-difluorophenyl)-3-(3-hydroxy-3-methylbutyl)-5,6-dimethylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(C)C(=O)C(C=2C(=CC(F)=CC=2)F)=C1CCC(C)(C)O KIKSVHSICFHSIH-UHFFFAOYSA-N 0.000 claims 2
- JURMPCPDCFUXPK-UHFFFAOYSA-N 2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-naphthalen-2-ylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(C)=C(CCC(C)(C)O)C(=O)C(C=2C=C3C=CC=CC3=CC=2)=C1C JURMPCPDCFUXPK-UHFFFAOYSA-N 0.000 claims 2
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- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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Applications Claiming Priority (5)
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| US1038708P | 2008-01-08 | 2008-01-08 | |
| US1040908P | 2008-01-08 | 2008-01-08 | |
| US61/010,387 | 2008-01-08 | ||
| US61/010,409 | 2008-01-08 | ||
| PCT/US2009/030229 WO2009089224A1 (en) | 2008-01-08 | 2009-01-06 | (HET) ARYL-p-QUINONE DERIVATIVES FOR TREATMENT OF MITOCHONDRIAL DISEASES |
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| CA2708961A1 CA2708961A1 (en) | 2009-07-16 |
| CA2708961C true CA2708961C (en) | 2017-03-28 |
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| CA2708961A Expired - Fee Related CA2708961C (en) | 2008-01-08 | 2009-01-06 | (het)aryl-p-quinone derivatives for treatment of mitochondrial diseases |
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| EP (1) | EP2237664A4 (enExample) |
| JP (3) | JP5649454B2 (enExample) |
| CA (1) | CA2708961C (enExample) |
| EA (1) | EA023618B1 (enExample) |
| WO (1) | WO2009089224A1 (enExample) |
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| EP2262508B1 (en) | 2008-03-05 | 2018-10-03 | BioElectron Technology Corporation | SUBSTITUTED-p-QUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISEASES |
| CA2717741C (en) * | 2008-03-05 | 2018-04-03 | Edison Pharmaceuticals, Inc. | Treatment of hearing and balance impairments with redox-active therapeutics |
| CA2729227C (en) | 2008-06-25 | 2018-05-22 | Andrew W. Hinman | 2-heterocyclylaminoalkyl-(p-quinone) derivatives for treatment of oxidative stress diseases |
| MX363223B (es) | 2008-09-10 | 2019-03-15 | Bioelectron Tech Corp | Tratamiento de trastornos generalizados del desarrollo con terapeuticos con actividad redox. |
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| EP2892516A1 (en) | 2012-09-07 | 2015-07-15 | Edison Pharmaceuticals, Inc. | Quinone derivatives for use in the modulation of redox status of individuals |
| EP2970158B1 (en) | 2013-03-15 | 2019-02-20 | BioElectron Technology Corporation | Alkyl-heteroaryl substituted quinone derivatives for treatment of oxidative stress disorders |
| US9296712B2 (en) | 2013-03-15 | 2016-03-29 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
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-
2009
- 2009-01-06 EP EP09700856.9A patent/EP2237664A4/en not_active Withdrawn
- 2009-01-06 US US12/811,694 patent/US8952071B2/en not_active Expired - Fee Related
- 2009-01-06 CA CA2708961A patent/CA2708961C/en not_active Expired - Fee Related
- 2009-01-06 EA EA201001119A patent/EA023618B1/ru not_active IP Right Cessation
- 2009-01-06 JP JP2010542313A patent/JP5649454B2/ja not_active Expired - Fee Related
- 2009-01-06 WO PCT/US2009/030229 patent/WO2009089224A1/en not_active Ceased
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2013
- 2013-12-26 JP JP2013268441A patent/JP2014058569A/ja not_active Withdrawn
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2014
- 2014-12-30 US US14/586,516 patent/US9486435B2/en not_active Expired - Fee Related
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2015
- 2015-12-03 JP JP2015236261A patent/JP2016034979A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JP2011509298A (ja) | 2011-03-24 |
| WO2009089224A1 (en) | 2009-07-16 |
| EA023618B1 (ru) | 2016-06-30 |
| JP5649454B2 (ja) | 2015-01-07 |
| EA201001119A1 (ru) | 2011-02-28 |
| US9486435B2 (en) | 2016-11-08 |
| US8952071B2 (en) | 2015-02-10 |
| JP2016034979A (ja) | 2016-03-17 |
| JP2014058569A (ja) | 2014-04-03 |
| CA2708961A1 (en) | 2009-07-16 |
| EP2237664A1 (en) | 2010-10-13 |
| US20150297551A1 (en) | 2015-10-22 |
| EP2237664A4 (en) | 2013-05-22 |
| US20110046219A1 (en) | 2011-02-24 |
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