ES2548127T3 - Activadores y aplicaciones terapéuticas de los mismos - Google Patents

Activadores y aplicaciones terapéuticas de los mismos Download PDF

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ES2548127T3
ES2548127T3 ES08775506.2T ES08775506T ES2548127T3 ES 2548127 T3 ES2548127 T3 ES 2548127T3 ES 08775506 T ES08775506 T ES 08775506T ES 2548127 T3 ES2548127 T3 ES 2548127T3
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compounds
activators
therapeutic applications
cell
formula
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Marikki Laiho
Karita Peltonen
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Johns Hopkins University
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Johns Hopkins University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Una composición farmacéutica que comprende un compuesto que tiene la fórmula**Fórmula** o la fórmula**Fórmula** o una sal farmacéuticamente aceptable del mismo; y un vehículo farmacéuticamente aceptable.

Description

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E08775506
23-09-2015
Identificación del compuesto
Estructura Nombre (IUPAC) Fórmula
7
C20H21N5O
9
4-(3-dimetilaminopropilamino)-6,8dimetil-quinolina-3-carboxilato de etilo C19H27N3O2
15
C20H23N5OS
20
5-(4-etoxifenil)-7-(3,4,5-trimetoxifenil)4,7-dihidro-[1,2,4]triazolo[1,5α]pirimidina
21
C21H20N4O2
22
2,4,7,9-tetrametilbenzo[b]-1,8-naftiridin5-amina C16H17N3
23
2,4,9-trimetilbenzo[b]-1,8-naftiridin-5amina C15H15N3
Se reivindican los compuestos 7 y 21 y su uso en el tratamiento del cáncer. Los compuestos 1, 9, 15, 20, 22 y 23 son compuestos de referencia.
Además de los compuestos 7 y 21, también se incluyen en la invención los homólogos cercanos e isómeros
5 posicionales de los compuestos que tienen aplicabilidad terapéutica igual o más potente. Los homólogos cercanos son compuestos que difieren, por ejemplo, por la sustitución de un resto químico en el compuesto con un resto químico sucesivo, por ejemplo, la sustitución con un grupo metilo o un grupo etilo o viceversa. También se incluyen en la invención las sales farmacéuticamente aceptables, ésteres y profármacos de los compuestos.
La cantidad de molécula pequeña de la invención utilizada para aplicaciones terapéuticas varía con las 10 consideraciones estándar, tales como la naturaleza de la afección que se trata, y la edad y condición del paciente, y
5
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E08775506
23-09-2015
en el ratón utilizando inyecciones intraperitoneales de los compuestos 7, 9, 15, 21, y 22 (9 dosis/3 semanas) no mostraron ninguna toxicidad aparente en los animales como se indica mediante las curvas de peso (Figura 7), patologías macroscópicas, o tinción de hematoxilina-eosina de tejidos tales como el timo, bazo, intestino, hígado o riñón (no mostrados). Soporte para su utilidad potencial como agentes anti-tumorales se indica mediante un modelo de linfoma de células B ortotópico. Los ratones fueron inyectados con células de linfoma de derrame pleural BC-3 establemente integradas con un gen reportero de luciferasa (Keller et al., 2006). Una vez que se establecieron los tumores, según lo medido por el monitor de bioluminiscencia in vivo, los ratones se trataron con inyecciones intraperitoneales de los compuestos tres veces a la semana. El tratamiento de los animales con los compuestos 15 y 22 condujo a la inhibición visible del crecimiento de células tumorales mientras que el compuesto 21 no tuvo ningún efecto (Figura 8). Los resultados indican potenciales efectos anti-tumorigénicos de los compuestos.
Referencias
Cho Y, Gorina S, Jeffrey PD, la estructura Pavletich N P. Crystal structure of a p53 tumor suppresor DNA complex, understanding tumorigenic mutations. Science 1994 265: 346-55.
el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B. Definition of a consensus binding site for p53. Nat. Genet. 1992 1: 45-9.
Friedman PN, Chen X, Bargonetti J, Prives C. The p53 protein is an unusually shaped tetramer that binds directly to DNA. Proc Natl Acad Sci EE.UU. 1,993 90: 3319-23.
Haapajarvi T, Pitkanen K, Laiho M. Human melanoma cell line UV responses show independecy of p53 function. Cell Growth Differ 1,999 10: 163 a 71.
Keller S A, Hernandez-Hopkins D, Vider J, Ponomarev V, Hyjek E, Schattner E J, Cesarman E. NF-kappaB is essential for the progression of KSHV-and EBV-infected lymphomas in vivo. Blood. 2006 107:3295-302.
Kern S E, Kinzler K W, Bruskin A, Jarosz D, Friedman P, Prives C, Vogelstein B. Identification of p53 as a sequencespecific DNA-binding protein. Science. 1991 252:1708-11.
Kim E, Albrechtsen N, Deppert W. DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53. Oncogene. 1997 15:857-69.
Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang J Y, Melino G. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci. 2000 113:1661-70.
Martins C P, Brown-Swigart L, Evan G1. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 2006 127:1323-34.
Melino G, Lu X, Gasco M, Crook T, Knight R A. Functional regulation of p73 and p63: development and cancer. Trends Biochem Sci. 2003 28:663-70.
Murray-Zmijewski F, Lane D P, Bourdon J C. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ. 2006 13:962-72.
Sarek G, Kurki S, Enback J, Iotzova G, Haas J, Laakkonen P, Laiho M, Ojala P M. Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas. J Clin Invest. 2007 117:1019-28.
Vassilev L T, Vu B T, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu E A. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004 303:844-8.
Ventura A, Kirsch D G, McLaughlin M E, Tuveson D A, Grimm J, Lintault L, Newman J, Reczek E E, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature 2007 445:661-5.
Vousden K H, Lane D P. p53 in health and disease. Nat Rev Mol Cell Biol. 2007 8:275-83.
Wang L, Wu Q, Qiu P, Mirza A, McGuirk M, Kirschmeier P, Greene J R, Wang Y, Pickett C B, Liu S. Analyses of p53 target genes in the human genome by bioinformatic and microarray approaches. J Biol. Chem. 2001 276:43604-10.
Wei C L, Wu Q, Vega V B, Chiu K P, Ng P, Zhang T, Shahab A, Yong H C, Fu Y, Weng Z, Liu J, Zhao X D, Chew J L, Lee Y L, Kuznetsov V A, Sung W K, Miller L D, Lim B, Liu E T, Yu Q, Ng H H, Ruan Y. A global map of p53 transcription-factor binding sites in the human genome. Cell. 2006 124:207-19.
Xing J, Sheppard H M, Corneillie S I, Liu X. p53 Stimulates TFIID-TFIIA-promoter complex assembly, and p53-T antigen complex inhibits TATA binding protein-TATA interaction. Mol Cell Biol. 2001 21:3652-61.
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Claims (1)

  1. imagen1
    imagen2
ES08775506.2T 2007-06-20 2008-06-19 Activadores y aplicaciones terapéuticas de los mismos Active ES2548127T3 (es)

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WOPCT/FI2007/000175 2007-06-20
PCT/FI2007/000175 WO2008155441A1 (en) 2007-06-20 2007-06-20 Activators and therapeutic applications thereof
PCT/FI2008/050381 WO2008155468A1 (en) 2007-06-20 2008-06-19 Activators and therapeutic applications thereof

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US (2) US8680107B2 (es)
EP (3) EP2195316B1 (es)
CA (2) CA2912456C (es)
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WO (2) WO2008155441A1 (es)

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* Cited by examiner, † Cited by third party
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EP3119781B1 (en) * 2014-03-20 2020-09-16 The Johns Hopkins University Compounds which inhibit rna polymerase, compositions including such compounds, and their use
US10111876B2 (en) * 2016-08-17 2018-10-30 Macau University Of Science And Technology ALK Kinase Inhibitor and its use
JP2019532937A (ja) * 2016-09-23 2019-11-14 ザ・ジョンズ・ホプキンス・ユニバーシティ Ｒｎａポリメラーゼｉ阻害に基づく、がんの併用治療戦略
CN110128477B (zh) * 2018-02-09 2021-08-27 天津医科大学 基于核仁应激的铂类化合物
CN110305128B (zh) * 2019-07-31 2021-08-24 桂林医学院 5-氨基苯并[b][1,8]萘啶类化合物的制备方法和应用
WO2022060816A1 (en) * 2020-09-15 2022-03-24 The Johns Hopkins University Compounds which inhibit rna polymerase
WO2022093919A1 (en) * 2020-10-28 2022-05-05 Dana-Farber Cancer Institute, Inc. Inhibitors of exo1 in combination with other cancer drugs to inhibit cancer cells

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Publication number Priority date Publication date Assignee Title
US5908840A (en) * 1996-11-26 1999-06-01 American Cyanamid Company Hetero-biaryl-pyridoquinazolinone derivatives as anti-cancer agents
CN1329493A (zh) * 1998-12-02 2002-01-02 辉瑞产品公司 恢复p53家族蛋白质的构象稳定性的方法和组合物
WO2002014321A1 (en) * 2000-08-11 2002-02-21 The Regents Of The University Of California Use of stat-6 inhibitors as therapeutic agents
US7132421B2 (en) * 2003-06-17 2006-11-07 Hoffmann-La Roche Inc. CIS-imidazoles
CA2528774A1 (en) * 2003-06-20 2005-01-27 Coley Pharmaceutical Gmbh Small molecule toll-like receptor (tlr) antagonists
WO2006093518A2 (en) * 2004-06-25 2006-09-08 Apath, Llc Thienyl compounds for treating virus-related conditions
US20090221624A1 (en) * 2005-05-06 2009-09-03 Olivo Paul D 4-aminoquinoline compounds for treating virus-related conditions
CA2644643C (en) * 2006-03-22 2015-05-19 Janssen Pharmaceutica N.V. Inhibitors of the interaction between mdm2 and p53

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CA2912456A1 (en) 2008-12-24
CA2691227C (en) 2016-02-02
EP2195316B1 (en) 2015-08-12
EP3427736A1 (en) 2019-01-16
WO2008155468A1 (en) 2008-12-24
EP2195316A1 (en) 2010-06-16
US20100179155A1 (en) 2010-07-15
EP3427736B1 (en) 2024-06-19
US8680107B2 (en) 2014-03-25
EP2889297B1 (en) 2018-10-03
WO2008155441A1 (en) 2008-12-24
ES2699735T3 (es) 2019-02-12
EP2889297A3 (en) 2015-09-23
EP2195316A4 (en) 2012-02-01
EP2889297A2 (en) 2015-07-01
US20140155432A1 (en) 2014-06-05
CA2691227A1 (en) 2008-12-24
CA2912456C (en) 2018-08-21
US10214491B2 (en) 2019-02-26

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