MX2015000746A - Terapia de combinacion de inhibidores para el receptor del factor de crecimiento insulinico tipo 1 (igf1r) y fosfatidilinositol 3-cinasa (pi3k). - Google Patents

Terapia de combinacion de inhibidores para el receptor del factor de crecimiento insulinico tipo 1 (igf1r) y fosfatidilinositol 3-cinasa (pi3k).

Info

Publication number
MX2015000746A
MX2015000746A MX2015000746A MX2015000746A MX2015000746A MX 2015000746 A MX2015000746 A MX 2015000746A MX 2015000746 A MX2015000746 A MX 2015000746A MX 2015000746 A MX2015000746 A MX 2015000746A MX 2015000746 A MX2015000746 A MX 2015000746A
Authority
MX
Mexico
Prior art keywords
inhibitors
combination
igf1
pi3k
amide
Prior art date
Application number
MX2015000746A
Other languages
English (en)
Inventor
Xizhong Huang
Malte Peters
Zhu Alexander Cao
Jennifer Lorraine Gansert
David Dong Eun Chang
Karl Maria Schumacher
Original Assignee
Novartis Ag
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Publication of MX2015000746A publication Critical patent/MX2015000746A/es

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/427Thiazoles not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Reproductive Health (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La presente invención se refiere a una combinación farmacéutica que comprende un compuesto inhibidor específico de isoforma alfa de fosfatidilinositol 3-cinasa, tal como 2-amida 1-({4-metil-5-[2-(2,2,2-trifluoro-1,1-dimetil-etil)-piridin-4-il] -tiazol-2-il}-amida) del ácido (S)- pirrolidin1,2-dicarboxílico, o una sal farmacéuticamente aceptable de este, y un inhibidor de IGF1R (por ejemplo, el ANTICUERPO A inhibidor de IGF1R, o una variante o derivado de este), una composición farmacéutica de dicha combinación, métodos para el tratamiento del cáncer que comprenden la administración de cantidades terapéuticamente eficaces de los inhibidores a un sujeto que lo necesita, y usos de dicha combinación para el tratamiento del cáncer.
MX2015000746A 2012-07-20 2013-07-19 Terapia de combinacion de inhibidores para el receptor del factor de crecimiento insulinico tipo 1 (igf1r) y fosfatidilinositol 3-cinasa (pi3k). MX2015000746A (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261673809P 2012-07-20 2012-07-20
US201361759490P 2013-02-01 2013-02-01
PCT/US2013/051345 WO2014015280A1 (en) 2012-07-20 2013-07-19 Combination therapy of inhibitors for igf1 r and pi3k

Publications (1)

Publication Number Publication Date
MX2015000746A true MX2015000746A (es) 2015-09-10

Family

ID=48875809

Family Applications (1)

Application Number Title Priority Date Filing Date
MX2015000746A MX2015000746A (es) 2012-07-20 2013-07-19 Terapia de combinacion de inhibidores para el receptor del factor de crecimiento insulinico tipo 1 (igf1r) y fosfatidilinositol 3-cinasa (pi3k).

Country Status (11)

Country Link
US (1) US8980259B2 (es)
EP (1) EP2875050A1 (es)
JP (1) JP2015524414A (es)
KR (1) KR20150041783A (es)
CN (1) CN104822703A (es)
AU (1) AU2013292298A1 (es)
BR (1) BR112015001212A2 (es)
CA (1) CA2879219A1 (es)
MX (1) MX2015000746A (es)
RU (1) RU2015105786A (es)
WO (1) WO2014015280A1 (es)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2013239624A1 (en) * 2012-03-30 2014-10-02 Novartis Ag Compounds for use in the treatment of neuroblastoma, Ewing's Sarcoma or rhabdomyosarcoma
US20170165246A1 (en) * 2014-02-11 2017-06-15 Novartis Ag Pharmaceutical combinations comprising a pi3k inhibitor for the treatment of cancer
CN112494653A (zh) * 2015-02-05 2021-03-16 特尔诺沃有限公司 用于治疗癌症的irs/stat3双重调节剂与抗癌剂的组合
WO2016182988A1 (en) 2015-05-08 2016-11-17 Memorial Sloan Kettering Cancer Center Compositions and methods for treatment of glioma
CN107573416A (zh) * 2016-06-30 2018-01-12 中国科学院深圳先进技术研究院 抗igf1r和cd3特异性双靶向抗体、含该双靶向抗体表达盒的微环dna及应用
TW201813963A (zh) 2016-09-23 2018-04-16 美商基利科學股份有限公司 磷脂醯肌醇3-激酶抑制劑
TW201825465A (zh) 2016-09-23 2018-07-16 美商基利科學股份有限公司 磷脂醯肌醇3-激酶抑制劑
TW201815787A (zh) 2016-09-23 2018-05-01 美商基利科學股份有限公司 磷脂醯肌醇3-激酶抑制劑
CN113512116B (zh) * 2020-04-10 2022-09-20 苏州普乐康医药科技有限公司 一种抗igf-1r抗体及其应用

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5595756A (en) * 1993-12-22 1997-01-21 Inex Pharmaceuticals Corporation Liposomal compositions for enhanced retention of bioactive agents
FR2714383B1 (fr) 1993-12-29 1996-02-09 Centre Nat Rech Scient Contrôle de l'expression de gènes.
DE69834828T2 (de) 1997-11-27 2007-01-04 Commonwealth Scientific And Industrial Research Organisation Verfahren zur konstruktion von agonisten und antagonisten des igf-rezeptors (1-462)
US6875741B2 (en) 1998-09-02 2005-04-05 Renuka Pillutla Insulin and IGF-1 receptor agonists and antagonists
US7173005B2 (en) 1998-09-02 2007-02-06 Antyra Inc. Insulin and IGF-1 receptor agonists and antagonists
US20030236190A1 (en) 1998-09-02 2003-12-25 Renuka Pillutla Isulin and IGF-1 receptor agonists and antagonists
EP1006184A1 (en) 1998-12-03 2000-06-07 F. Hoffmann-La Roche Ag IGF-1 receptor interacting proteins (IIPs) genes coding therefor and uses thereof
US6608108B2 (en) 1999-10-15 2003-08-19 Johns Hopkins University Method for treatment of tumors using nordihydroguaiaretic acid derivatives
DZ3494A1 (fr) 2001-01-05 2002-07-11 Pfizer Anticorps anti-recepteur du facteur de croissance i analogue a l'insuline
AU2002248609B2 (en) 2001-03-14 2007-03-01 Genentech, Inc. IGF antagonist peptides
SE0104140D0 (sv) 2001-12-07 2001-12-07 Astrazeneca Ab Novel Compounds
DK1461359T3 (da) 2002-01-18 2007-07-09 Pf Medicament Hidtil ukendte anti-IGF-IR-antistoffer og anvendelser deraf
US7241444B2 (en) 2002-01-18 2007-07-10 Pierre Fabre Medicament Anti-IGF-IR antibodies and uses thereof
EP1432724A4 (en) 2002-02-20 2006-02-01 Sirna Therapeutics Inc RNA inhibition mediated inhibition of MAP KINASE GENES
US7217796B2 (en) 2002-05-24 2007-05-15 Schering Corporation Neutralizing human anti-IGFR antibody
US8034904B2 (en) 2002-06-14 2011-10-11 Immunogen Inc. Anti-IGF-I receptor antibody
US7538195B2 (en) 2002-06-14 2009-05-26 Immunogen Inc. Anti-IGF-I receptor antibody
US7803781B2 (en) 2003-02-28 2010-09-28 Isis Pharmaceuticals, Inc. Modulation of growth hormone receptor expression and insulin-like growth factor expression
JP2007528201A (ja) 2003-03-14 2007-10-11 ファルマシア・コーポレーション 癌治療のためのigf−i受容体に対する抗体
WO2004087756A2 (en) 2003-04-02 2004-10-14 F. Hoffmann-La Roche Ag Antibodies against insulin-like growth factor i receptor and uses thereof
ES2527871T3 (es) 2003-05-01 2015-02-02 Imclone Llc Anticuerpos completamente humanos dirigidos contra el receptor del factor de crecimiento 1 similar a la insulina humana
US7579157B2 (en) 2003-07-10 2009-08-25 Hoffmann-La Roche Inc. Antibody selection method against IGF-IR
UA83509C2 (en) 2003-10-15 2008-07-25 Оси Фармасьютикалз, Инк. Imidazopyrazines as tyrosine kinase inhibitors
PE20050928A1 (es) 2003-11-21 2005-11-08 Schering Corp Combinaciones terapeuticas de anticuerpo anti-igfr1
WO2005058967A2 (en) 2003-12-16 2005-06-30 Pierre Fabre Medicament Novel anti-insulin/igf-i hybrid receptor or anti-insulin/igf-i hybrid receptor and igf-ir antibodies and uses thereof
US7781393B2 (en) 2004-02-25 2010-08-24 Dana-Farber Cancer Institute, Inc. Methods for inhibiting tumor cell growth
BRPI0418462A (pt) 2004-03-12 2007-06-05 Analytecon Sa derivados de tetrahidroisoquinolina e terahidrobenzazepina como inibidores igf-1r
CN102924458B (zh) 2004-04-02 2014-11-05 Osi制药有限责任公司 6,6-双环取代的杂双环蛋白激酶抑制剂
US8758994B2 (en) 2004-06-21 2014-06-24 Exelixis, Inc. CDK9 as modifier of the IGF pathway and methods of use
AR053090A1 (es) 2004-07-20 2007-04-25 Osi Pharm Inc Imidazotriazinas como inhibidores de proteina quinasas y su uso para la preparacion de medicamentos
FR2873699B1 (fr) 2004-07-29 2009-08-21 Pierre Fabre Medicament Sa Nouveaux anticorps anti igf ir rt leurs utilisations
TW200615268A (en) 2004-08-02 2006-05-16 Osi Pharm Inc Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds
GB0426154D0 (en) 2004-11-29 2004-12-29 European Molecular Biology Lab Embl IGF-1 novel peptides
MY146381A (en) 2004-12-22 2012-08-15 Amgen Inc Compositions and methods relating relating to anti-igf-1 receptor antibodies
AU2005322855B2 (en) 2004-12-30 2012-09-20 Exelixis, Inc. Pyrimidine derivatives as kinase modulators and method of use
JP2008542685A (ja) 2005-05-05 2008-11-27 ヴァロリザーシヨン・アッシュエスジ,ソシエテ・アン・コマンディット サイトカイン受容体修飾因子及びその使用
BRPI0611984A2 (pt) 2005-06-17 2009-07-07 Imclone Systems Inc uso de anticorpos igf-ir para fabricação de um medicamento para tratar um tumor ósseo
WO2007000328A1 (en) 2005-06-27 2007-01-04 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Antibodies that bind to an epitope on insulin-like growth factor 1 receptor and uses thereof
FR2888850B1 (fr) 2005-07-22 2013-01-11 Pf Medicament Nouveaux anticorps anti-igf-ir et leurs applications
WO2007029107A1 (en) 2005-09-09 2007-03-15 Analytecon Sa Isoquinolines derivatives as igf-1r inhibitors
KR20080042897A (ko) 2005-09-09 2008-05-15 아날리테콘에스.에이. Igf-1r 억제제로서 이소퀴놀린
WO2007031745A1 (en) 2005-09-16 2007-03-22 Astrazeneca Ab Pyrimidine derivatives for the inhibition of igf-ir tyrosine kinase activity
US7884078B2 (en) 2006-02-10 2011-02-08 Massachusetts Institute Of Technology CPG15 compounds as insulin receptor and insulin-like growth factor receptor agonists
ES2442491T3 (es) 2006-03-03 2014-02-11 Nerviano Medical Sciences S.R.L. Biciclopirazoles activos como inhibidores de cinasa
WO2007099166A1 (en) 2006-03-03 2007-09-07 Nerviano Medical Sciences S.R.L. Pyrazolo-pyridine derivatives active as kinase inhibitors
MX2008012146A (es) 2006-03-28 2008-10-03 Biogen Idec Inc Anticuerpos anti-receptor 1 de factor de crecimiento tipo insulina (igf-1r) y uso de los mismos.
TW200833711A (en) 2006-12-22 2008-08-16 Genentech Inc Antibodies to insulin-like growth factor receptor
EP2139484B9 (en) * 2007-04-10 2014-06-11 Exelixis, Inc. Methods of treating cancer using pyridopyrimidinone inhibitors of pi3k alpha
UA104147C2 (uk) 2008-09-10 2014-01-10 Новартис Аг Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань
AR082418A1 (es) 2010-08-02 2012-12-05 Novartis Ag Formas cristalinas de 1-(4-metil-5-[2-(2,2,2-trifluoro-1,1-dimetil-etil)-piridin-4-il]-tiazol-2-il)-amida de 2-amida del acido (s)-pirrolidin-1,2-dicarboxilico

Also Published As

Publication number Publication date
AU2013292298A1 (en) 2015-02-05
WO2014015280A1 (en) 2014-01-23
RU2015105786A (ru) 2016-09-10
JP2015524414A (ja) 2015-08-24
KR20150041783A (ko) 2015-04-17
CN104822703A (zh) 2015-08-05
EP2875050A1 (en) 2015-05-27
CA2879219A1 (en) 2014-01-23
BR112015001212A2 (pt) 2017-08-01
US8980259B2 (en) 2015-03-17
US20140023661A1 (en) 2014-01-23

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