JP2013511556A - 肺高血圧症の処置のためのニトロキシル供与体 - Google Patents
肺高血圧症の処置のためのニトロキシル供与体 Download PDFInfo
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- JP2013511556A JP2013511556A JP2012540154A JP2012540154A JP2013511556A JP 2013511556 A JP2013511556 A JP 2013511556A JP 2012540154 A JP2012540154 A JP 2012540154A JP 2012540154 A JP2012540154 A JP 2012540154A JP 2013511556 A JP2013511556 A JP 2013511556A
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- JP
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- Prior art keywords
- alkyl
- hydroxybenzenesulfonamide
- halo
- substituted
- 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.)
- Pending
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- 208000002815 pulmonary hypertension Diseases 0.000 title claims abstract description 54
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 title claims description 40
- 238000011282 treatment Methods 0.000 title description 16
- 238000000034 method Methods 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 165
- -1 N-hydroxylsulfonamidyl Chemical group 0.000 claims description 116
- 150000001875 compounds Chemical class 0.000 claims description 101
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 42
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 16
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 15
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 11
- 125000005171 cycloalkylsulfanyl group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000005163 aryl sulfanyl group Chemical group 0.000 claims description 10
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 10
- 206010024119 Left ventricular failure Diseases 0.000 claims description 8
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 8
- 208000019622 heart disease Diseases 0.000 claims description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 5
- JTMRAKAVHPQVLR-UHFFFAOYSA-N 2-bromo-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC=C1Br JTMRAKAVHPQVLR-UHFFFAOYSA-N 0.000 claims description 4
- QVWABNGSRMHSSC-UHFFFAOYSA-N 2-fluoro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC=C1F QVWABNGSRMHSSC-UHFFFAOYSA-N 0.000 claims description 4
- UHLUYTLUWPLQIV-UHFFFAOYSA-N n-hydroxy-2-(trifluoromethyl)benzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC=C1C(F)(F)F UHLUYTLUWPLQIV-UHFFFAOYSA-N 0.000 claims description 4
- RPCWSYAQEVLTEE-UHFFFAOYSA-N n-hydroxy-2-iodobenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC=C1I RPCWSYAQEVLTEE-UHFFFAOYSA-N 0.000 claims description 4
- RZRWBKKAFHXNEQ-UHFFFAOYSA-N n-hydroxy-2-methylsulfonylbenzenesulfonamide Chemical compound CS(=O)(=O)C1=CC=CC=C1S(=O)(=O)NO RZRWBKKAFHXNEQ-UHFFFAOYSA-N 0.000 claims description 4
- ZRWVFIVDXWDXDB-UHFFFAOYSA-N 2,3-dichloro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC(Cl)=C1Cl ZRWVFIVDXWDXDB-UHFFFAOYSA-N 0.000 claims description 2
- PMCCDTRQTMOMDO-UHFFFAOYSA-N 2,4-dibromo-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(Br)C=C1Br PMCCDTRQTMOMDO-UHFFFAOYSA-N 0.000 claims description 2
- XZXRZAJTPROFFJ-UHFFFAOYSA-N 2,4-difluoro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(F)C=C1F XZXRZAJTPROFFJ-UHFFFAOYSA-N 0.000 claims description 2
- NQRQXMMHKBZSFH-UHFFFAOYSA-N 2,6-dichloro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=C(Cl)C=CC=C1Cl NQRQXMMHKBZSFH-UHFFFAOYSA-N 0.000 claims description 2
- KYAYUXVCXCRWGE-UHFFFAOYSA-N 2-bromo-4-fluoro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(F)C=C1Br KYAYUXVCXCRWGE-UHFFFAOYSA-N 0.000 claims description 2
- KDAUHUPSWREKDU-UHFFFAOYSA-N 2-chloro-4-fluoro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(F)C=C1Cl KDAUHUPSWREKDU-UHFFFAOYSA-N 0.000 claims description 2
- CRGRKPVYYZZUHX-UHFFFAOYSA-N 2-chloro-n-hydroxy-4-(trifluoromethyl)benzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1Cl CRGRKPVYYZZUHX-UHFFFAOYSA-N 0.000 claims description 2
- BASKBTQCHRZHSH-UHFFFAOYSA-N 2-chloro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC=C1Cl BASKBTQCHRZHSH-UHFFFAOYSA-N 0.000 claims description 2
- SNDSZUKNUDOLGZ-UHFFFAOYSA-N 4-bromo-2-chloro-n-hydroxybenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(Br)C=C1Cl SNDSZUKNUDOLGZ-UHFFFAOYSA-N 0.000 claims description 2
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 claims description 2
- 208000003037 Diastolic Heart Failure Diseases 0.000 claims description 2
- 208000008253 Systolic Heart Failure Diseases 0.000 claims description 2
- YWZWWGLSOOIVSN-UHFFFAOYSA-N n-hydroxy-2,4,6-tri(propan-2-yl)benzenesulfonamide Chemical compound CC(C)C1=CC(C(C)C)=C(S(=O)(=O)NO)C(C(C)C)=C1 YWZWWGLSOOIVSN-UHFFFAOYSA-N 0.000 claims description 2
- NBJISJHKYNUFIN-UHFFFAOYSA-N n-hydroxy-2,5-bis(trifluoromethyl)benzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC(C(F)(F)F)=CC=C1C(F)(F)F NBJISJHKYNUFIN-UHFFFAOYSA-N 0.000 claims description 2
- SEBLDBIKKKKJMQ-UHFFFAOYSA-N n-hydroxy-2-nitro-4-(trifluoromethyl)benzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O SEBLDBIKKKKJMQ-UHFFFAOYSA-N 0.000 claims description 2
- MGMDZPKSAJJKCS-UHFFFAOYSA-N n-hydroxy-2-phenylbenzenesulfonamide Chemical compound ONS(=O)(=O)C1=CC=CC=C1C1=CC=CC=C1 MGMDZPKSAJJKCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 13
- 230000004872 arterial blood pressure Effects 0.000 abstract description 32
- 210000001147 pulmonary artery Anatomy 0.000 abstract description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 86
- 125000005843 halogen group Chemical group 0.000 description 66
- 229910005965 SO 2 Inorganic materials 0.000 description 60
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 36
- 229910052757 nitrogen Inorganic materials 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 241001465754 Metazoa Species 0.000 description 27
- 125000001072 heteroaryl group Chemical group 0.000 description 27
- 125000000547 substituted alkyl group Chemical group 0.000 description 25
- 125000003342 alkenyl group Chemical group 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 19
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 229930192474 thiophene Natural products 0.000 description 18
- 125000002252 acyl group Chemical group 0.000 description 17
- 239000008194 pharmaceutical composition Substances 0.000 description 17
- 125000000304 alkynyl group Chemical group 0.000 description 16
- QPNKYNYIKKVVQB-UHFFFAOYSA-N crotaleschenine Natural products O1C(=O)C(C)C(C)C(C)(O)C(=O)OCC2=CCN3C2C1CC3 QPNKYNYIKKVVQB-UHFFFAOYSA-N 0.000 description 16
- 238000001802 infusion Methods 0.000 description 16
- QVCMHGGNRFRMAD-XFGHUUIASA-N monocrotaline Chemical compound C1OC(=O)[C@](C)(O)[C@@](O)(C)[C@@H](C)C(=O)O[C@@H]2CCN3[C@@H]2C1=CC3 QVCMHGGNRFRMAD-XFGHUUIASA-N 0.000 description 16
- QVCMHGGNRFRMAD-UHFFFAOYSA-N monocrotaline Natural products C1OC(=O)C(C)(O)C(O)(C)C(C)C(=O)OC2CCN3C2C1=CC3 QVCMHGGNRFRMAD-UHFFFAOYSA-N 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 125000003710 aryl alkyl group Chemical group 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 229910052794 bromium Inorganic materials 0.000 description 14
- 238000001990 intravenous administration Methods 0.000 description 14
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 14
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 14
- 229910052760 oxygen Inorganic materials 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 12
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- 125000004442 acylamino group Chemical group 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 229910052717 sulfur Inorganic materials 0.000 description 11
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- 125000005017 substituted alkenyl group Chemical group 0.000 description 10
- 125000004426 substituted alkynyl group Chemical group 0.000 description 10
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 9
- 125000006575 electron-withdrawing group Chemical group 0.000 description 9
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 8
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- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
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- 238000002474 experimental method Methods 0.000 description 8
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
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- 230000002829 reductive effect Effects 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 8
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- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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| US26412909P | 2009-11-24 | 2009-11-24 | |
| US61/264,129 | 2009-11-24 | ||
| PCT/US2010/057844 WO2011063400A1 (en) | 2009-11-23 | 2010-11-23 | Nitroxyl donors for the treatment of pulmonary hypertension |
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| JP2016015102A Pending JP2016128481A (ja) | 2009-11-23 | 2016-01-29 | 肺高血圧症の処置のためのニトロキシル供与体 |
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| JP2016015102A Pending JP2016128481A (ja) | 2009-11-23 | 2016-01-29 | 肺高血圧症の処置のためのニトロキシル供与体 |
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| EP (1) | EP2504003B1 (OSRAM) |
| JP (2) | JP2013511556A (OSRAM) |
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| SI (1) | SI2504003T1 (OSRAM) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5832447B2 (ja) | 2009-12-07 | 2015-12-16 | ザ ジョンズ ホプキンス ユニバーシティ | ビスアシル化ヒドロキシルアミン誘導体 |
| CA2782110A1 (en) * | 2009-12-07 | 2011-06-16 | Johns Hopkins University | N-acyloxysulfonamide and n-hydroxy-n-acylsulfonamide derivatives |
| HK1200168A1 (en) | 2011-10-17 | 2015-07-31 | The Johns Hopkins University | Meldrum 's acid, barbituric acid and pyrazolone derivatives substituted with hydroxylamine as hno donors |
| PT2945620T (pt) | 2013-01-18 | 2018-02-21 | Cardioxyl Pharmaceuticals Inc | Dadores de nitroxilo com índice terapêutico melhorado |
| ES2563902T3 (es) * | 2013-05-14 | 2016-03-16 | Active Biotech Ab | Derivados de N-(heteroaril)-sulfonamida útiles como inhibidores de S100 |
| ES2734060T3 (es) | 2014-01-17 | 2019-12-04 | Cardioxyl Pharmaceuticals Inc | Donadores de nitroxilo de N-hidroximetanosulfonamida |
| US9682938B2 (en) | 2014-05-27 | 2017-06-20 | Cardioxyl Pharmaceuticals, Inc. | Pyrazolone derivatives as nitroxyl donors |
| US9464061B2 (en) | 2014-05-27 | 2016-10-11 | The Johns Hopkins University | N-hydroxylamino-barbituric acid derivatives |
| JP6889704B2 (ja) | 2015-10-19 | 2021-06-18 | カルディオキシル ファーマシューティカルズ，インク． | ニトロキシルドナーとしてのピラゾロン誘導体 |
| KR20180070672A (ko) | 2015-10-19 | 2018-06-26 | 카르디옥실 파마슈티칼스 인코포레이티드 | 니트록실 공여자로서의 n-히드록실술폰아미드 유도체 |
| KR20190070912A (ko) | 2016-07-28 | 2019-06-21 | 더 존스 홉킨스 유니버시티 | O-치환된 히드록삼산 |
| US11083704B2 (en) | 2017-01-03 | 2021-08-10 | Bristol-Myers Squibb Company | Method of administering nitroxyl donating compounds |
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- 2010-11-23 HU HUE10784416A patent/HUE032253T2/en unknown
- 2010-11-23 SI SI201031332A patent/SI2504003T1/sl unknown
- 2010-11-23 EP EP10784416.9A patent/EP2504003B1/en active Active
- 2010-11-23 DK DK10784416.9T patent/DK2504003T3/en active
- 2010-11-23 SM SM20170090T patent/SMT201700090T1/it unknown
- 2010-11-23 PL PL10784416T patent/PL2504003T3/pl unknown
- 2010-11-23 PT PT107844169T patent/PT2504003T/pt unknown
- 2010-11-23 ES ES10784416.9T patent/ES2611852T3/es active Active
- 2010-11-23 LT LTEP10784416.9T patent/LT2504003T/lt unknown
- 2010-11-23 WO PCT/US2010/057844 patent/WO2011063400A1/en not_active Ceased
- 2010-11-23 RS RS20170138A patent/RS55697B1/sr unknown
- 2010-11-23 HR HRP20170183TT patent/HRP20170183T1/hr unknown
- 2010-11-23 JP JP2012540154A patent/JP2013511556A/ja active Pending
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2015
- 2015-04-24 US US14/696,319 patent/US20160081951A1/en not_active Abandoned
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2016
- 2016-01-29 JP JP2016015102A patent/JP2016128481A/ja active Pending
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2017
- 2017-02-07 CY CY20171100169T patent/CY1118603T1/el unknown
- 2017-02-09 SM SM201700090T patent/SMT201700090B/it unknown
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Also Published As
| Publication number | Publication date |
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| US20110160200A1 (en) | 2011-06-30 |
| PL2504003T3 (pl) | 2017-04-28 |
| WO2011063400A1 (en) | 2011-05-26 |
| WO2011063339A1 (en) | 2011-05-26 |
| HRP20170183T1 (hr) | 2017-03-24 |
| SI2504003T1 (sl) | 2017-01-31 |
| DK2504003T3 (en) | 2017-02-20 |
| EP2504003B1 (en) | 2016-11-09 |
| CY1118603T1 (el) | 2017-07-12 |
| ES2611852T3 (es) | 2017-05-10 |
| US20160081951A1 (en) | 2016-03-24 |
| HUE032253T2 (en) | 2017-09-28 |
| SMT201700090B (it) | 2017-03-08 |
| PT2504003T (pt) | 2017-01-31 |
| JP2016128481A (ja) | 2016-07-14 |
| LT2504003T (lt) | 2017-01-25 |
| RS55697B1 (sr) | 2017-07-31 |
| EP2504003A1 (en) | 2012-10-03 |
| SMT201700090T1 (it) | 2017-03-08 |
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