CN105358151B - 用于治疗脊髓性肌萎缩的化合物 - Google Patents
用于治疗脊髓性肌萎缩的化合物 Download PDFInfo
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- CN105358151B CN105358151B CN201480035676.2A CN201480035676A CN105358151B CN 105358151 B CN105358151 B CN 105358151B CN 201480035676 A CN201480035676 A CN 201480035676A CN 105358151 B CN105358151 B CN 105358151B
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- fluoro
- pyridine
- methylimidazole
- niacinamide
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13173487.3 | 2013-06-25 | ||
| EP13173487 | 2013-06-25 | ||
| PCT/US2014/043577 WO2014209841A2 (en) | 2013-06-25 | 2014-06-23 | Compounds for treating spinal muscular atrophy |
Publications (2)
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| CN105358151A CN105358151A (zh) | 2016-02-24 |
| CN105358151B true CN105358151B (zh) | 2019-04-12 |
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| EP (1) | EP3013345B1 (enExample) |
| JP (1) | JP6492071B2 (enExample) |
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| RU (1) | RU2673542C2 (enExample) |
| TW (1) | TW201542543A (enExample) |
| WO (1) | WO2014209841A2 (enExample) |
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| MX372669B (es) | 2013-08-19 | 2020-04-23 | Hoffmann La Roche | Un compuesto que modifica el empalme del gen de foxm1 para usarse en la profilaxis o tratamiento de cáncer. |
| GB201410693D0 (en) | 2014-06-16 | 2014-07-30 | Univ Southampton | Splicing modulation |
| CA2952895C (en) * | 2014-06-25 | 2023-09-26 | F. Hoffmann-La Roche Ag | Imidazo[1,2-a]pyrazin-1yl-benzamide compounds for treating spinal muscular atrophy |
| EP3201339A4 (en) | 2014-10-03 | 2018-09-19 | Cold Spring Harbor Laboratory | Targeted augmentation of nuclear gene output |
| WO2016161572A1 (en) * | 2015-04-08 | 2016-10-13 | Merck Sharp & Dohme Corp. | TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF |
| EP3359685A1 (en) | 2015-10-09 | 2018-08-15 | University Of Southampton | Modulation of gene expression and screening for deregulated protein expression |
| KR102162062B1 (ko) | 2015-11-12 | 2020-10-07 | 에프. 호프만-라 로슈 아게 | 척수성 근위축증의 치료용 조성물 |
| CN108697709A (zh) | 2015-12-10 | 2018-10-23 | Ptc医疗公司 | 用于治疗亨廷顿病的方法 |
| JP6872550B2 (ja) | 2015-12-10 | 2021-05-19 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | 架橋されたピペリジン誘導体 |
| KR102604132B1 (ko) | 2015-12-14 | 2023-11-17 | 콜드스프링하버러보러토리 | 상염색체 우성 정신 지체 5 및 드라베 증후군의 치료를 위한 안티센스 올리고머 |
| US11096956B2 (en) | 2015-12-14 | 2021-08-24 | Stoke Therapeutics, Inc. | Antisense oligomers and uses thereof |
| AU2018282154B2 (en) | 2017-06-05 | 2022-04-07 | Ptc Therapeutics, Inc. | Compounds for treating huntington's disease |
| CN111182898B (zh) | 2017-06-28 | 2024-04-16 | Ptc医疗公司 | 用于治疗亨廷顿氏病的方法 |
| WO2019005993A1 (en) | 2017-06-28 | 2019-01-03 | Ptc Therapeutics, Inc. | METHODS OF TREATING HUNTINGTON'S DISEASE |
| MX2020001425A (es) | 2017-08-04 | 2020-08-06 | Skyhawk Therapeutics Inc | Metodos y composiciones para modular el empalme. |
| SI3673080T1 (sl) | 2017-08-25 | 2024-03-29 | Stoke Therapeutics, Inc. | Protismiselni oligomeri za zdravljenje bolezenskih stanj in bolezni |
| HRP20250322T1 (hr) | 2017-10-23 | 2025-06-06 | Stoke Therapeutics, Inc. | Protusmisleni oligomeri, namijenjeni liječenju stanja i bolesti uzrokovanih raspadanjem rna posredovanim besmislenim mutacijama |
| BR112020019373A2 (pt) | 2018-03-27 | 2020-12-29 | Ptc Therapeutics, Inc. | Compostos para o tratamento da doença de hutington |
| BR112020022512A2 (pt) | 2018-05-04 | 2021-05-04 | Stoke Therapeutics, Inc. | métodos e composições para tratamento de doença de armazenamento de éster de colesteril |
| EP3816160A4 (en) | 2018-06-27 | 2022-03-16 | Reborna Biosciences, Inc. | PROPHYLACTIC OR THERAPEUTIC AGENT FOR SPINAL MUSCULAR ATROPHY |
| WO2020005877A1 (en) | 2018-06-27 | 2020-01-02 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| IL279688B2 (en) | 2018-06-27 | 2025-01-01 | Ptc Therapeutics Inc | Heterocyclic and heteroaryl compounds for the treatment of Huntington's disease |
| EP3814360B8 (en) | 2018-06-27 | 2024-11-06 | PTC Therapeutics, Inc. | Heteroaryl compounds for treating huntington's disease |
| AU2019372057A1 (en) | 2018-11-02 | 2021-05-27 | Merck Sharp & Dohme Llc | 2-amino-N-heteroaryl-nicotinamides as NAV1.8 inhibitors |
| WO2020150626A1 (en) * | 2019-01-18 | 2020-07-23 | Biogen Ma Inc. | Imidazo[1,2-a]pyridinyl derivatives as irak4 inhibitors |
| CN114007613A (zh) | 2019-02-05 | 2022-02-01 | 斯基霍克疗法公司 | 用于调节剪接的方法和组合物 |
| JP7603595B2 (ja) | 2019-02-06 | 2024-12-20 | スカイホーク・セラピューティクス・インコーポレーテッド | スプライシングを調節するための方法および組成物 |
| EP3931182A4 (en) * | 2019-02-25 | 2023-01-25 | Beijing InnoCare Pharma Tech Co., Ltd. | PROCESS FOR THE PREPARATION OF 6-(1-ACRYLOYLPIPERIDINE-4-YL)-2-(4-PHENOXYPHENYL)NICOTINAMIDE |
| WO2021007378A1 (en) | 2019-07-11 | 2021-01-14 | Ptc Therapeutics, Inc. | Compounds for use in treating huntington's disease |
| US20240226098A1 (en) * | 2020-02-28 | 2024-07-11 | Remix Therapeutics Inc. | Compounds and methods for modulating splicing |
| AU2021270720A1 (en) | 2020-05-11 | 2022-12-08 | Stoke Therapeutics, Inc. | OPA1 antisense oligomers for treatment of conditions and diseases |
| AU2021272972A1 (en) | 2020-05-13 | 2022-12-08 | Chdi Foundation, Inc. | HTT modulators for treating Huntington's disease |
| WO2022169230A1 (ko) * | 2021-02-03 | 2022-08-11 | 단국대학교 천안캠퍼스 산학협력단 | 6-메톡시니코틴아미드를 유효성분으로 포함하는 근감소증의 예방 또는 치료용 조성물 |
| AU2022394333A1 (en) | 2021-11-17 | 2024-06-27 | Chdi Foundation, Inc. | HTT modulators for treating Huntington’s disease |
| US20250122192A1 (en) * | 2021-12-03 | 2025-04-17 | Rgenta Therapeutics, Inc. | 5-pyrimidinecarboxamide derivatives and methods of using the same |
| WO2023196972A1 (en) * | 2022-04-08 | 2023-10-12 | John Phillip Adams | Improving brain function |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128199A (zh) * | 2004-04-23 | 2008-02-20 | 布里斯托尔-迈尔斯斯奎布公司 | 作为激酶抑制剂的单环杂环 |
| CN101218238A (zh) * | 2005-03-21 | 2008-07-09 | S*Bio私人有限公司 | 咪唑并[1,2-a]吡啶衍生物：制备及药学应用 |
| WO2009042907A1 (en) * | 2007-09-27 | 2009-04-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| US20090105264A1 (en) * | 2005-11-03 | 2009-04-23 | Christopher Hamblett | Substituted Nicotinamide Compounds |
| WO2009147190A1 (en) * | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | Novel compounds |
| WO2009151546A2 (en) * | 2008-05-27 | 2009-12-17 | Ptc Therapeutics, Inc. | Methods for treating spinal muscular atrophy |
| WO2010019236A1 (en) * | 2008-08-13 | 2010-02-18 | Ptc Therapeutics, Inc | Methods for treating spinal muscular atrophy |
| WO2012142459A1 (en) * | 2011-04-14 | 2012-10-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9801526D0 (sv) * | 1998-04-29 | 1998-04-29 | Astra Ab | New compounds |
| US7666880B2 (en) * | 2005-03-21 | 2010-02-23 | S*Bio Pte Ltd. | Imidazo[1,2-A]pyridine derivatives: preparation and pharmaceutical applications |
| UY32138A (es) * | 2008-09-25 | 2010-04-30 | Boehringer Ingelheim Int | Amidas sustituidas del ácido 2-(2,6-dicloro-fenilamino)-6-fluoro-1-metil-1h-bencimidazol-5-carboxílico y sus sales farmacéuticamente aceptables |
-
2014
- 2014-06-23 MX MX2015017345A patent/MX363456B/es unknown
- 2014-06-23 WO PCT/US2014/043577 patent/WO2014209841A2/en not_active Ceased
- 2014-06-23 US US14/899,397 patent/US20160145270A1/en not_active Abandoned
- 2014-06-23 KR KR1020157036344A patent/KR102314290B1/ko active Active
- 2014-06-23 EP EP14816651.5A patent/EP3013345B1/en active Active
- 2014-06-23 CA CA2913785A patent/CA2913785C/en active Active
- 2014-06-23 RU RU2015154676A patent/RU2673542C2/ru active
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- 2014-06-23 BR BR112015030288-2A patent/BR112015030288B1/pt active IP Right Grant
- 2014-06-23 AR ARP140102349A patent/AR096684A1/es unknown
- 2014-06-24 TW TW103121679A patent/TW201542543A/zh unknown
-
2018
- 2018-04-09 US US15/948,444 patent/US10501482B2/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101128199A (zh) * | 2004-04-23 | 2008-02-20 | 布里斯托尔-迈尔斯斯奎布公司 | 作为激酶抑制剂的单环杂环 |
| CN101218238A (zh) * | 2005-03-21 | 2008-07-09 | S*Bio私人有限公司 | 咪唑并[1,2-a]吡啶衍生物：制备及药学应用 |
| US20090105264A1 (en) * | 2005-11-03 | 2009-04-23 | Christopher Hamblett | Substituted Nicotinamide Compounds |
| WO2009042907A1 (en) * | 2007-09-27 | 2009-04-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
| WO2009151546A2 (en) * | 2008-05-27 | 2009-12-17 | Ptc Therapeutics, Inc. | Methods for treating spinal muscular atrophy |
| WO2009147190A1 (en) * | 2008-06-05 | 2009-12-10 | Glaxo Group Limited | Novel compounds |
| WO2010019236A1 (en) * | 2008-08-13 | 2010-02-18 | Ptc Therapeutics, Inc | Methods for treating spinal muscular atrophy |
| WO2012142459A1 (en) * | 2011-04-14 | 2012-10-18 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Isoindoline compounds for the treatment of spinal muscular atrophy and other uses |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105358151A (zh) | 2016-02-24 |
| JP6492071B2 (ja) | 2019-03-27 |
| KR102314290B1 (ko) | 2021-10-21 |
| BR112015030288B1 (pt) | 2022-10-18 |
| TW201542543A (zh) | 2015-11-16 |
| WO2014209841A3 (en) | 2015-10-29 |
| BR112015030288A2 (enExample) | 2017-08-22 |
| CA2913785A1 (en) | 2014-12-31 |
| AR096684A1 (es) | 2016-01-27 |
| MX363456B (es) | 2019-03-25 |
| RU2015154676A3 (enExample) | 2018-03-15 |
| US10501482B2 (en) | 2019-12-10 |
| HK1215399A1 (zh) | 2016-08-26 |
| MX2015017345A (es) | 2016-08-03 |
| EP3013345B1 (en) | 2017-11-22 |
| CA2913785C (en) | 2021-08-31 |
| WO2014209841A2 (en) | 2014-12-31 |
| EP3013345A4 (en) | 2016-11-30 |
| US20180222925A1 (en) | 2018-08-09 |
| RU2673542C2 (ru) | 2018-11-28 |
| KR20160022312A (ko) | 2016-02-29 |
| EP3013345A2 (en) | 2016-05-04 |
| RU2015154676A (ru) | 2017-07-28 |
| JP2016530231A (ja) | 2016-09-29 |
| US20160145270A1 (en) | 2016-05-26 |
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