JP5564495B2 - チアゾリル−およびオキサゾリル−イソキノリノン、ならびにそれらの使用方法 - Google Patents
チアゾリル−およびオキサゾリル−イソキノリノン、ならびにそれらの使用方法 Download PDFInfo
- Publication number
- JP5564495B2 JP5564495B2 JP2011514801A JP2011514801A JP5564495B2 JP 5564495 B2 JP5564495 B2 JP 5564495B2 JP 2011514801 A JP2011514801 A JP 2011514801A JP 2011514801 A JP2011514801 A JP 2011514801A JP 5564495 B2 JP5564495 B2 JP 5564495B2
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- isoquinolin
- thiazolo
- hydroxy
- 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
Links
- 238000000034 method Methods 0.000 title description 51
- UYCKMHZYQJAMEH-UHFFFAOYSA-N 3-(1,3-oxazol-2-yl)-2h-isoquinolin-1-one Chemical class C=1C2=CC=CC=C2C(=O)NC=1C1=NC=CO1 UYCKMHZYQJAMEH-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 159
- 150000003839 salts Chemical group 0.000 claims description 62
- 239000000203 mixture Substances 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 43
- 238000011282 treatment Methods 0.000 claims description 37
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000002947 alkylene group Chemical group 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims description 26
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims description 24
- 125000004450 alkenylene group Chemical group 0.000 claims description 23
- 206010028980 Neoplasm Diseases 0.000 claims description 22
- 125000004419 alkynylene group Chemical group 0.000 claims description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- -1 C 1 -C 6 alkyl Chemical class 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000002950 monocyclic group Chemical group 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 17
- QFYOLODDTBRVSH-UHFFFAOYSA-N 2-[3-(dimethylamino)prop-1-ynyl]-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1=CC=C2C(N=C(S3)C#CCN(C)C)=C3NC(=O)C2=C1 QFYOLODDTBRVSH-UHFFFAOYSA-N 0.000 claims description 16
- 108091026813 Poly(ADPribose) Proteins 0.000 claims description 15
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 14
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- UFGKEUKYVUYZPF-UHFFFAOYSA-N 2-[2-(dimethylamino)ethyl]-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1=CC=C2C(N=C(S3)CCN(C)C)=C3NC(=O)C2=C1 UFGKEUKYVUYZPF-UHFFFAOYSA-N 0.000 claims description 12
- 208000028867 ischemia Diseases 0.000 claims description 12
- 125000006413 ring segment Chemical group 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 230000016273 neuron death Effects 0.000 claims description 7
- VTYYKKIMVNWVEB-PHIMTYICSA-N 2-[[(2r,6s)-2,6-dimethylpiperidin-1-yl]methyl]-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C[C@H]1CCC[C@@H](C)N1CC(S1)=NC2=C1NC(=O)C1=CC=CC(O)=C21 VTYYKKIMVNWVEB-PHIMTYICSA-N 0.000 claims description 6
- VKHNODUXUOMNKR-SNVBAGLBSA-N 2-[[(3r)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1[C@H](N(C)C)CCN1CC(S1)=NC2=C1NC(=O)C1=CC=CC(O)=C21 VKHNODUXUOMNKR-SNVBAGLBSA-N 0.000 claims description 6
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 6
- 206010063837 Reperfusion injury Diseases 0.000 claims description 6
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000010410 reperfusion Effects 0.000 claims description 6
- HDRITKBVBOESHB-UHFFFAOYSA-N 2-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-ylmethyl)-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1CCC2CCCCC2N1CC1=NC(C2=C(C(N3)=O)C=CC=C2O)=C3S1 HDRITKBVBOESHB-UHFFFAOYSA-N 0.000 claims description 5
- OKIORNRGRJGNDT-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1=CC(O)=C2C(N=C(S3)CN(C)C)=C3NC(=O)C2=C1 OKIORNRGRJGNDT-UHFFFAOYSA-N 0.000 claims description 5
- HGVOVHQTFMXKDZ-AOOOYVTPSA-N 2-[[(2s,6r)-2,6-dimethylmorpholin-4-yl]methyl]-9-hydroxy-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1[C@@H](C)O[C@@H](C)CN1CC(S1)=NC2=C1NC(=O)C1=CC=CC(O)=C21 HGVOVHQTFMXKDZ-AOOOYVTPSA-N 0.000 claims description 5
- HIALQSRLCAFPJR-UHFFFAOYSA-N 9-hydroxy-2-(morpholin-4-ylmethyl)-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound OC1=CC=CC(C(NC=2S3)=O)=C1C=2N=C3CN1CCOCC1 HIALQSRLCAFPJR-UHFFFAOYSA-N 0.000 claims description 5
- KXXIEYFYYLEDAM-UHFFFAOYSA-N 9-hydroxy-2-(piperidin-1-ylmethyl)-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound OC1=CC=CC(C(NC=2S3)=O)=C1C=2N=C3CN1CCCCC1 KXXIEYFYYLEDAM-UHFFFAOYSA-N 0.000 claims description 5
- VCOZPOCXDYPYDE-UHFFFAOYSA-N 9-hydroxy-2-(pyrrolidin-1-ylmethyl)-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound OC1=CC=CC(C(NC=2S3)=O)=C1C=2N=C3CN1CCCC1 VCOZPOCXDYPYDE-UHFFFAOYSA-N 0.000 claims description 5
- HNNWMLHDFNJBTE-UHFFFAOYSA-N 9-hydroxy-2-[(2-methylpyrrolidin-1-yl)methyl]-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound CC1CCCN1CC(S1)=NC2=C1NC(=O)C1=CC=CC(O)=C21 HNNWMLHDFNJBTE-UHFFFAOYSA-N 0.000 claims description 5
- KBEYEYKPUJXEOF-SNVBAGLBSA-N 9-hydroxy-2-[[(2r)-2-(trifluoromethyl)pyrrolidin-1-yl]methyl]-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound OC1=CC=CC(C(NC=2S3)=O)=C1C=2N=C3CN1CCC[C@@H]1C(F)(F)F KBEYEYKPUJXEOF-SNVBAGLBSA-N 0.000 claims description 5
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 6
- VYWQADLCKOEBTR-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-4h-[1,3]thiazolo[5,4-c]isoquinolin-5-one Chemical compound C1=CC=C2C(N=C(S3)CN(C)C)=C3NC(=O)C2=C1 VYWQADLCKOEBTR-UHFFFAOYSA-N 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 21
- 150000002431 hydrogen Chemical class 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
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- 239000004480 active ingredient Substances 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
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- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 7
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- 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
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Plural Heterocyclic Compounds (AREA)
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| US61/073,857 | 2008-06-19 | ||
| PCT/US2009/047767 WO2009155402A1 (en) | 2008-06-19 | 2009-06-18 | Thiazolyl- and oxazolyl-isoquinolinones and methods for using them |
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| JP2014067493A Withdrawn JP2014122242A (ja) | 2008-06-19 | 2014-03-28 | チアゾリル−およびオキサゾリル−イソキノリノン、ならびにそれらの使用方法 |
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| SA109300394B1 (ar) * | 2008-06-19 | 2013-01-22 | ويث | ثيازوليل- وأوكسازوليل- أيزوكوينولينونات وطرق لاستخدامها |
| JP5632368B2 (ja) * | 2008-06-19 | 2014-11-26 | ワイス・エルエルシー | チエニル−およびフラニル−イソキノリノン、ならびにそれらの使用方法 |
| BR112014000267A2 (pt) | 2011-07-04 | 2016-09-20 | Bayer Ip Gmbh | utilização de isoquinolinonas, isoquinolinedionas, isoquinolinetrionas e dihidroisoquinolinonas substituídas ou, em cada caso, sais das mesmas como agentes ativos contra o stress abiótico em plantas |
| ES2562903T3 (es) * | 2011-07-13 | 2016-03-09 | Santen Pharmaceutical Co., Ltd | Nuevo compuesto que tiene actividad inhibidora de PARP |
| WO2017013237A1 (en) | 2015-07-23 | 2017-01-26 | Institut Curie | Use of a combination of dbait molecule and parp inhibitors to treat cancer |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| WO2018162439A1 (en) | 2017-03-08 | 2018-09-13 | Onxeo | New predictive biomarker for the sensitivity to a treatment of cancer with a dbait molecule |
| WO2019175132A1 (en) | 2018-03-13 | 2019-09-19 | Onxeo | A dbait molecule against acquired resistance in the treatment of cancer |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| WO2024261243A1 (en) | 2023-06-21 | 2024-12-26 | Hemispherian As | Combination comprising a deoxycytidine derivative and a parp inhibitor for use in a method of treating hr proficient cancer |
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| EP0005745B1 (en) * | 1978-05-26 | 1982-07-14 | Gruppo Lepetit S.P.A. | Pyrazolo (3,4-c) and thiazolo (5,4-c) isoquinolines, methods for preparing them, these compounds for use as antiinflammatory, cns-depressant and anti-anxiety agents and pharmaceutical compositions thereof |
| ITMI20002358A1 (it) * | 2000-10-31 | 2002-05-01 | Flavio Moroni | Derivati di tieno ,2, 3-c|isochinolin-3-one come inibitori della poli(a dp-ribosio)polimerasi |
| AUPS137402A0 (en) * | 2002-03-26 | 2002-05-09 | Fujisawa Pharmaceutical Co., Ltd. | Novel tricyclic compounds |
| ATE540928T1 (de) | 2002-11-22 | 2012-01-15 | Mitsubishi Tanabe Pharma Corp | Isochinolinverbindungen und ihre medizinische verwendung |
| EP1913064B1 (en) | 2005-08-01 | 2011-11-16 | Wietek Holding GmbH | Process for the recycling of plastics |
| EP2069351B1 (en) * | 2006-06-20 | 2015-10-28 | AbbVie Inc. | Pyrazoloquinazolinones as parp inhibitors |
| SA109300394B1 (ar) * | 2008-06-19 | 2013-01-22 | ويث | ثيازوليل- وأوكسازوليل- أيزوكوينولينونات وطرق لاستخدامها |
| JP5632368B2 (ja) * | 2008-06-19 | 2014-11-26 | ワイス・エルエルシー | チエニル−およびフラニル−イソキノリノン、ならびにそれらの使用方法 |
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2009
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| US20150133443A1 (en) | 2015-05-14 |
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| JP2014122242A (ja) | 2014-07-03 |
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| US8906935B2 (en) | 2014-12-09 |
| AU2009260060B2 (en) | 2015-01-22 |
| EP2303895A1 (en) | 2011-04-06 |
| TWI471329B (zh) | 2015-02-01 |
| SA109300394B1 (ar) | 2013-01-22 |
| DK2303895T3 (en) | 2015-01-12 |
| ES2530815T3 (es) | 2015-03-05 |
| AR072265A1 (es) | 2010-08-18 |
| HK1212698A1 (en) | 2016-06-17 |
| HK1156310A1 (en) | 2012-06-08 |
| CA2728454A1 (en) | 2009-12-23 |
| EP2896626A1 (en) | 2015-07-22 |
| US20130059843A1 (en) | 2013-03-07 |
| WO2009155402A1 (en) | 2009-12-23 |
| EP2303895B1 (en) | 2014-09-24 |
| AU2009260060A1 (en) | 2009-12-23 |
| CA2728454C (en) | 2017-01-17 |
| US8299090B2 (en) | 2012-10-30 |
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