EA201792652A2 - Новые производные майтанзиноида с пептидным линкером и их конъюгаты - Google Patents

Новые производные майтанзиноида с пептидным линкером и их конъюгаты

Info

Publication number
EA201792652A2
EA201792652A2 EA201792652A EA201792652A EA201792652A2 EA 201792652 A2 EA201792652 A2 EA 201792652A2 EA 201792652 A EA201792652 A EA 201792652A EA 201792652 A EA201792652 A EA 201792652A EA 201792652 A2 EA201792652 A2 EA 201792652A2
Authority
EA
Eurasian Patent Office
Prior art keywords
conjugates
formula
present
maytanzinoids
compounds
Prior art date
Application number
EA201792652A
Other languages
English (en)
Other versions
EA201792652A3 (ru
Inventor
Уэйн К. Уиддисон
Original Assignee
Иммуноджен, Инк.
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 Иммуноджен, Инк. filed Critical Иммуноджен, Инк.
Publication of EA201792652A2 publication Critical patent/EA201792652A2/ru
Publication of EA201792652A3 publication Critical patent/EA201792652A3/ru

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones 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 other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Communicable Diseases (AREA)
  • Mycology (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Microbiology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Virology (AREA)
  • Transplantation (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Настоящее изобретение относится к новому конъюгату клеточносвязывающего агента и цитотоксического средства, имеющему пептидные линкеры, и, более конкретно, к конъюгатам формулы (I). В настоящем изобретении представлены также новые цитотоксические средства формулы (II), линкерные соединения, представленные формулой (III), и соединения лекарства и линкера, представленные формулой (IV). В настоящем изобретении дополнительно представлены композиции и способы, применимые для замедления патологического клеточного роста или лечения пролиферативного расстройства у млекопитающего с использованием соединений или конъюгатов настоящего изобретения.
EA201792652A 2011-06-21 2012-06-21 Новые производные майтанзиноида с пептидным линкером и их конъюгаты EA201792652A3 (ru)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US201161499548P 2011-06-21 2011-06-21

Publications (2)

Publication Number Publication Date
EA201792652A2 true EA201792652A2 (ru) 2018-05-31
EA201792652A3 EA201792652A3 (ru) 2018-09-28

Family

ID=46889411

Family Applications (2)

Application Number Title Priority Date Filing Date
EA201792652A EA201792652A3 (ru) 2011-06-21 2012-06-21 Новые производные майтанзиноида с пептидным линкером и их конъюгаты
EA201490095A EA029797B1 (ru) 2011-06-21 2012-06-21 Новые производные майтанзиноида с пептидным линкером и их конъюгаты

Family Applications After (1)

Application Number Title Priority Date Filing Date
EA201490095A EA029797B1 (ru) 2011-06-21 2012-06-21 Новые производные майтанзиноида с пептидным линкером и их конъюгаты

Country Status (14)

Country Link
US (2) US9289512B2 (ru)
EP (1) EP2723389A2 (ru)
JP (2) JP6209159B2 (ru)
KR (1) KR20140037208A (ru)
CN (1) CN103648532A (ru)
AU (1) AU2012272930B2 (ru)
BR (1) BR112013032928A2 (ru)
CA (1) CA2836927A1 (ru)
EA (2) EA201792652A3 (ru)
IL (2) IL230043A (ru)
MX (1) MX350954B (ru)
SG (2) SG195172A1 (ru)
WO (1) WO2012177837A2 (ru)
ZA (1) ZA201308703B (ru)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006012527A1 (en) 2004-07-23 2006-02-02 Endocyte, Inc. Bivalent linkers and conjugates thereof
EP2489372A3 (en) 2007-03-14 2013-01-02 Endocyte, Inc. Binding ligand linked drug delivery conjugates of tubulysins
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
CA2690943A1 (en) 2007-06-25 2008-12-31 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
CN103648532A (zh) 2011-06-21 2014-03-19 伊缪诺金公司 具有肽连接子的新型美登木素生物碱衍生物及其偶联物
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US20140080175A1 (en) 2012-03-29 2014-03-20 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
JP6239598B2 (ja) 2012-05-15 2017-11-29 ソレント・セラピューティクス・インコーポレイテッドＳｏｒｒｅｎｔｏ Ｔｈｅｒａｐｅｕｔｉｃｓ， Ｉｎｃ． 薬物複合体、複合体形成方法、およびその使用
WO2014062697A2 (en) 2012-10-16 2014-04-24 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
US9353150B2 (en) 2012-12-04 2016-05-31 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1 ,5]pyrrolo[2,3-b]-indole-1,4-diones for cancer treatment
KR20150119848A (ko) 2012-12-21 2015-10-26 바이오얼라이언스 씨.브이. 친수성 자기-희생 링커 및 그것의 포합체
JP6847388B2 (ja) * 2013-03-15 2021-03-31 レゲネロン ファーマシューティカルス，インコーポレーテッド 生物活性分子、そのコンジュゲート、及び治療用途
US10208125B2 (en) 2013-07-15 2019-02-19 University of Pittsburgh—of the Commonwealth System of Higher Education Anti-mucin 1 binding agents and uses thereof
BR112016004023A2 (pt) 2013-08-26 2022-11-16 Regeneron Pharma Composição, métodos para preparar uma composição e para tratar uma doença, e, composto
CA2934030A1 (en) 2013-10-15 2015-04-23 Sorrento Therapeutics Inc. Drug-conjugates with a targeting molecule and two different drugs
CN106661124A (zh) 2014-06-20 2017-05-10 荷商台医(有限合伙)公司 抗叶酸受体α(FRA)抗体‑药物缀合物及其使用方法
CN106573077B (zh) 2014-06-30 2019-07-30 塔弗达治疗有限公司 靶向缀合物及其颗粒和制剂
RU2741470C9 (ru) 2014-09-02 2021-04-27 Иммьюноджен, Инк. Способы составления композиций конъюгата антитело-лекарственное средство
EP3218009B1 (en) 2014-10-14 2021-04-07 Polytherics Limited Process for the conjugation of a peptide or protein with a reagent comprising a leaving group including a portion of peg
CN107849090A (zh) 2015-01-28 2018-03-27 索伦托医疗有限公司 抗体药物偶联物
CN107995912A (zh) * 2015-03-27 2018-05-04 里珍纳龙药品有限公司 美登素类衍生物、其偶联物和使用方法
CN106380508A (zh) * 2015-07-28 2017-02-08 上海皓元生物医药科技有限公司 一种抗体偶联药物连接子的工业化生产方法
CA3001712A1 (en) 2015-10-28 2017-05-04 Tarveda Therapeutics, Inc. Sstr-targeted conjugates and particles and formulations thereof
KR20180117102A (ko) 2016-01-08 2018-10-26 바이오얼라이언스 씨.브이. 사가 항-psgl-1 항체 및 이들의 용도
AU2017211120C1 (en) 2016-01-25 2021-10-07 Regeneron Pharmaceuticals, Inc. Maytansinoid derivatives, conjugates thereof, and methods of use
AU2017213858A1 (en) * 2016-02-05 2018-08-16 Immunogen, Inc. Efficient process for preparing cell-binding agent-cytotoxic agent conjugates
WO2017197045A1 (en) 2016-05-11 2017-11-16 Movassaghi Mohammad Convergent and enantioselective total synthesis of communesin analogs
EP3515945A1 (en) * 2016-09-23 2019-07-31 Regeneron Pharmaceuticals, Inc. Anti-steap2 antibodies, antibody-drug conjugates, and bispecific antigen-binding molecules that bind steap2 and cd3, and uses thereof
US20180140703A1 (en) * 2016-11-18 2018-05-24 The Regents Of The University California Tumor radiosensitization with antibody conjugates
RU2022101392A (ru) 2017-02-28 2022-03-02 Иммуноджен, Инк. Производные майтанзиноида с саморасщепляющимися пептидными линкерами и их конъюгаты
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
CA3095067A1 (en) * 2017-06-19 2018-12-27 Sichuan Baili Pharm Co. Ltd An antibody-drug conjugate having an acidic self-stabilization junction
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
KR20240015162A (ko) 2018-12-21 2024-02-02 어비디티 바이오사이언시스 인크. 항트랜스페린 수용체 항체 및 이의 용도
CA3127113A1 (en) 2019-01-30 2020-08-06 Dongxu Sun Anti-gal3 antibodies and uses thereof
CN109939242B (zh) * 2019-03-18 2020-10-09 北京大学 抗体前药偶联物及其制备和应用
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof
CN110501495A (zh) * 2019-08-27 2019-11-26 广东菲鹏生物有限公司 活化氨基固相颗粒与免疫氨基固相颗粒及其制备方法和应用及试剂盒
US11555190B2 (en) 2020-03-19 2023-01-17 Avidity Biosciences, Inc. Compositions and methods of treating Facioscapulohumeral muscular dystrophy
KR20220161378A (ko) 2020-03-27 2022-12-06 어비디티 바이오사이언시스 인크. 근이영양증의 치료용 조성물 및 방법
WO2022182415A1 (en) 2021-02-24 2022-09-01 Massachusetts Institute Of Technology Himastatin derivatives, and processes of preparation thereof, and uses thereof
BR112023018676A2 (pt) 2021-03-18 2023-10-10 Seagen Inc Conjugado anticorpo-fármaco, composição farmacêutica, métodos de tratamento de uma doença ou condição e de um câncer, e, composição de conjugado ligante-fármaco
WO2023288252A1 (en) 2021-07-13 2023-01-19 Truebinding, Inc. Methods of preventing protein aggregation
IL311452A (en) 2021-09-16 2024-05-01 Avidity Biosciences Inc Compositions and methods for the treatment of FSHD muscular dystrophy

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4307016A (en) 1978-03-24 1981-12-22 Takeda Chemical Industries, Ltd. Demethyl maytansinoids
US4256746A (en) 1978-11-14 1981-03-17 Takeda Chemical Industries Dechloromaytansinoids, their pharmaceutical compositions and method of use
JPS55102583A (en) 1979-01-31 1980-08-05 Takeda Chem Ind Ltd 20-acyloxy-20-demethylmaytansinoid compound
JPS55162791A (en) 1979-06-05 1980-12-18 Takeda Chem Ind Ltd Antibiotic c-15003pnd and its preparation
JPS5645483A (en) 1979-09-19 1981-04-25 Takeda Chem Ind Ltd C-15003phm and its preparation
EP0028683A1 (en) 1979-09-21 1981-05-20 Takeda Chemical Industries, Ltd. Antibiotic C-15003 PHO and production thereof
JPS5645485A (en) 1979-09-21 1981-04-25 Takeda Chem Ind Ltd Production of c-15003pnd
WO1982001188A1 (en) 1980-10-08 1982-04-15 Takeda Chemical Industries Ltd 4,5-deoxymaytansinoide compounds and process for preparing same
US4450254A (en) 1980-11-03 1984-05-22 Standard Oil Company Impact improvement of high nitrile resins
US4313946A (en) 1981-01-27 1982-02-02 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids from Trewia nudiflora
US4315929A (en) 1981-01-27 1982-02-16 The United States Of America As Represented By The Secretary Of Agriculture Method of controlling the European corn borer with trewiasine
JPS57192389A (en) 1981-05-20 1982-11-26 Takeda Chem Ind Ltd Novel maytansinoid
US4894348A (en) * 1987-07-01 1990-01-16 Ronald Robert C Fluorescein-conjugated proteins with enhanced fluorescence
GB8801646D0 (en) * 1988-01-26 1988-02-24 Nycomed As Chemical compounds
US5171666A (en) * 1988-04-22 1992-12-15 Eli Lilly And Company Monoclonal antibodies reactive with a cell-surface gylcoprotein expressed on human carcinomas
US5208020A (en) * 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
CA2026147C (en) * 1989-10-25 2006-02-07 Ravi J. Chari Cytotoxic agents comprising maytansinoids and their therapeutic use
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
ATE463573T1 (de) 1991-12-02 2010-04-15 Medimmune Ltd Herstellung von autoantikörpern auf phagenoberflächen ausgehend von antikörpersegmentbibliotheken
CA2076465C (en) 1992-03-25 2002-11-26 Ravi V. J. Chari Cell binding agent conjugates of analogues and derivatives of cc-1065
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
US6214345B1 (en) * 1993-05-14 2001-04-10 Bristol-Myers Squibb Co. Lysosomal enzyme-cleavable antitumor drug conjugates
US6355780B1 (en) 1995-02-22 2002-03-12 Yeda Research And Development Co. Ltd. Antibodies to the death domain motifs of regulatory proteins
CA2297070A1 (en) 1997-08-01 1999-02-11 Morphosys Ag Novel method and phage for the identification of nucleic acid sequences encoding members of a multimeric (poly)peptide complex
US7115396B2 (en) 1998-12-10 2006-10-03 Compound Therapeutics, Inc. Protein scaffolds for antibody mimics and other binding proteins
CA2385528C (en) * 1999-10-01 2013-12-10 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
JP2003514903A (ja) 1999-11-24 2003-04-22 イムノージェン インコーポレーテッド タキサンを含有する細胞傷害薬とその治療への利用
US7097840B2 (en) * 2000-03-16 2006-08-29 Genentech, Inc. Methods of treatment using anti-ErbB antibody-maytansinoid conjugates
US6333410B1 (en) 2000-08-18 2001-12-25 Immunogen, Inc. Process for the preparation and purification of thiol-containing maytansinoids
US7417130B2 (en) 2000-09-08 2008-08-26 University Of Zurich Collection of repeat proteins comprising repeat modules
WO2002042259A2 (en) * 2000-11-27 2002-05-30 University Of Maryland, Baltimore Methods of synthesizing and using derivatives of [2-(2-aminoethoxy)ethoxy] acetic acid
US6441163B1 (en) 2001-05-31 2002-08-27 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
US20050123536A1 (en) * 2001-11-20 2005-06-09 Che-Leung Law Treatment of immunological disorders using anti-dc30 antibodies
US6716821B2 (en) 2001-12-21 2004-04-06 Immunogen Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
WO2003062198A1 (en) * 2002-01-24 2003-07-31 Barnes Jewish Hospital Integrin targeted imaging agents
US6756397B2 (en) 2002-04-05 2004-06-29 Immunogen, Inc. Prodrugs of CC-1065 analogs
DK1545613T3 (da) 2002-07-31 2011-11-14 Seattle Genetics Inc Auristatinkonjugater og deres anvendelse til behandling af cancer, en autoimmun sygdom eller en infektiøs sygdom
CA2494074A1 (en) 2002-08-02 2004-02-12 Immunogen, Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
AU2003259163B2 (en) 2002-08-16 2008-07-03 Immunogen, Inc. Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs
JP5354835B2 (ja) 2002-11-07 2013-11-27 イミュノジェン・インコーポレーテッド 抗ｃｄ３３抗体、及びそれを用いた急性骨髄性白血病の治療方法
US8088387B2 (en) 2003-10-10 2012-01-03 Immunogen Inc. Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates
US7276497B2 (en) 2003-05-20 2007-10-02 Immunogen Inc. Cytotoxic agents comprising new maytansinoids
KR101520209B1 (ko) * 2003-11-06 2015-05-13 시애틀 지네틱스, 인크. 리간드에 접합될 수 있는 모노메틸발린 화합물
ES2549077T3 (es) * 2004-04-07 2015-10-22 Genentech, Inc. Espectrometría de masas de conjugados de anticuerpos
BRPI0510883B8 (pt) 2004-06-01 2021-05-25 Genentech Inc composto conjugado de droga e anticorpo, composição farmacêutica, método de fabricação de composto conjugado de droga e anticorpo e usos de uma formulação, de um conjugado de droga e anticorpo e um agente quimioterapêutico e de uma combinação
ES2579805T3 (es) 2004-09-23 2016-08-16 Genentech, Inc. Anticuerpos y conjugados modificados por ingeniería genética con cisteína
EP1817341A2 (en) 2004-11-29 2007-08-15 Seattle Genetics, Inc. Engineered antibodies and immunoconjugates
US7301019B2 (en) 2005-01-21 2007-11-27 Immunogen, Inc. Method for the preparation of maytansinoid esters
US7811572B2 (en) 2005-08-24 2010-10-12 Immunogen, Inc. Process for preparing purified drug conjugates
CA2597407C (en) 2005-02-11 2013-09-10 Immunogen, Inc. Process for preparing stable drug conjugates
BRPI0608175A2 (pt) * 2005-04-15 2009-11-10 Immunogen Inc método de eliminação de população de células heterogêneas ou mistas em tumores, assim como compostos maitansinóides
US8846577B2 (en) 2005-07-08 2014-09-30 University Of Zurich Phage display using cotranslational translocation of fusion polypeptides
CA2617953C (en) 2005-08-09 2013-12-17 Millennium Pharmaceuticals, Inc. Method of acylating maytansinol with chiral amino acids
JP5102772B2 (ja) 2005-11-29 2012-12-19 ザ・ユニバーシティ・オブ・シドニー デミボディ：二量体化活性化治療剤
WO2007098611A1 (en) 2006-03-03 2007-09-07 Queen's University At Kingston Compositions for treatment of cancer
WO2007147213A1 (en) 2006-06-22 2007-12-27 Walter And Eliza Hall Institute Of Medical Research Structure of the insulin receptor ectodomain
PE20090481A1 (es) * 2007-07-16 2009-05-18 Genentech Inc Anticuerpos anti-cd79b e inmunoconjugados humanizados y metodos de uso
CA2700391A1 (en) 2007-09-24 2009-04-02 University Of Zuerich Designed armadillo repeat proteins
CN104524590B (zh) * 2008-04-30 2019-06-21 伊缪诺金公司 交联剂和它们的用途
JP5873335B2 (ja) 2009-02-12 2016-03-01 ヤンセン バイオテツク，インコーポレーテツド フィブロネクチンｉｉｉ型ドメインに基づくスカフォールド組成物、方法及び使用
SI2437790T1 (sl) 2009-06-03 2019-07-31 Immunogen, Inc. Konjugacijske metode
AR080154A1 (es) 2010-02-10 2012-03-14 Immunogen Inc Anticuerpos cd20 y su utilizacion
KR102287474B1 (ko) 2010-02-24 2021-08-06 이뮤노젠 아이엔씨 엽산염 수용체 1 항체와 면역접합체 및 이들의 용도
JP5913307B2 (ja) * 2010-07-12 2016-04-27 コヴェックス・テクノロジーズ・アイルランド・リミテッド 多機能性抗体複合体
CN103648532A (zh) 2011-06-21 2014-03-19 伊缪诺金公司 具有肽连接子的新型美登木素生物碱衍生物及其偶联物

Also Published As

Publication number Publication date
EA201792652A3 (ru) 2018-09-28
NZ618262A (en) 2016-03-31
AU2012272930A1 (en) 2013-04-18
MX350954B (es) 2017-09-26
CN103648532A (zh) 2014-03-19
JP6209159B2 (ja) 2017-10-04
EP2723389A2 (en) 2014-04-30
JP2017197560A (ja) 2017-11-02
US20160263238A1 (en) 2016-09-15
AU2012272930B2 (en) 2015-06-11
MX2013015422A (es) 2014-09-22
US9289512B2 (en) 2016-03-22
US10494423B2 (en) 2019-12-03
WO2012177837A3 (en) 2013-07-11
EA029797B1 (ru) 2018-05-31
JP6598821B2 (ja) 2019-10-30
BR112013032928A2 (pt) 2017-01-24
US20130029900A1 (en) 2013-01-31
CA2836927A1 (en) 2012-12-27
JP2014520156A (ja) 2014-08-21
EA201490095A1 (ru) 2014-05-30
ZA201308703B (en) 2016-03-30
SG10201605041VA (en) 2016-08-30
IL230043A (en) 2017-11-30
WO2012177837A2 (en) 2012-12-27
KR20140037208A (ko) 2014-03-26
IL255475A (en) 2018-02-28
SG195172A1 (en) 2013-12-30

Similar Documents

Publication Publication Date Title
EA201792652A3 (ru) Новые производные майтанзиноида с пептидным линкером и их конъюгаты
AR125013A2 (es) Método para mejorar la solubilidad de una sustancia que es 9-etil-6,6-dimetil-8-(4-morfolin-4-il-piperidin-1-il)-11-oxo-6,11-dihidro-5h-benzo[b]carbazol-3-carbonitrilo o una sal del mismo
WO2012145112A3 (en) Novel maytansinoid derivatives with sulfoxide linker
CY1117340T1 (el) Κυτταροτοξικα παραγωγα βενζοδιαζεπινης
IN2014CN04961A (ru)
EA201390642A1 (ru) Цитотоксические агенты, содержащие новые производные анзамитоцина
MX368966B (es) Conjugados de proteina-polimero-farmaco.
EA201001724A1 (ru) Производные изоксазола и их применение в качестве потенциирующих средств для метаботропных глутаматных рецепторов
EA201391395A1 (ru) Терапевтические соединения
CO6470847A2 (es) Derivados amino-propiónicos sustituidos como inhibidores de neprilisina
EA201491607A1 (ru) Модуляторы толлподобных рецепторов
CY1112278T1 (el) Κυτταροτοξικοι παραγοντες που περιεχουν νεα παραγωγα τομαυμυciν και η θεραπευτικη χρηση τους
EA201590879A1 (ru) Арилконденсированные и гетероарилконденсированные лактамы
UY32660A (es) Derivados aminobutricos sustituidos como inhibidores de neprilisina
UY33731A (es) ?derivados de ácido amino-fenil-pentanoico sustituidos como inhibidores de nep?
UA109010C2 (en) MORPHOLINOPYRIMIDINES AND THEIR APPLICATIONS IN THERAPY
MX342709B (es) Tratamiento contra el cancer.
EA201291168A1 (ru) Фармацевтические композиции и способы их получения
EA201490471A1 (ru) Пиридазиноновые соединения и их применение в качестве ингибиторов daao
EA201591024A1 (ru) Димерные соединения
EA201491173A1 (ru) Применение n-гидроксисукцинимида для улучшения стабильности конъюгатов
TR201902057T4 (tr) Tetrasiklin bileşikleri.
DOP2012000078A (es) Derivados de espirolactama y usos de los mismos
WO2012159027A3 (en) Osw-1 analogs and conjugates, and uses thereof
BR112013025610A2 (pt) uso de um metapneumovírus aviário vivo, e, composição farmacêutica