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WO2022037594A1 - Utilisation d'un agent chélateur de fer dans la préparation d'un médicament pour le traitement ou la prévention d'une infection à polyiomavirus - Google Patents

Utilisation d'un agent chélateur de fer dans la préparation d'un médicament pour le traitement ou la prévention d'une infection à polyiomavirus Download PDF

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WO2022037594A1
WO2022037594A1 PCT/CN2021/113130 CN2021113130W WO2022037594A1 WO 2022037594 A1 WO2022037594 A1 WO 2022037594A1 CN 2021113130 W CN2021113130 W CN 2021113130W WO 2022037594 A1 WO2022037594 A1 WO 2022037594A1
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virus
polyoma virus
infection
iron
polyoma
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朱同玉
巫国谊
石业静
孙佳佳
侯玉敏
吴楠楠
胡春兰
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SHANGHAI PUBLIC HEALTH CLINICAL CENTER
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/41—Heterocyclic 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic 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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the field of biomedicine, in particular to the use of an iron chelator in the preparation of a medicament for treating or preventing polyoma virus infection or inhibiting polyoma virus.
  • Polyomaviruses are small, non-enveloped, double-stranded DNA viruses that display restricted species and cell type specificity. A variety of polyomaviruses have been identified in humans with oncogenic potential and can cause chronic infection.
  • JC virus also known as John Cunningham virus (JCV)
  • PML multifocal leukoencephalopathy
  • BK virus (BKV) is also a human-specific polyoma virus, which is associated with BK virus nephropathy. Infections with JC and BK viruses are predominantly progressive and are usually found in early childhood infected populations.
  • JC and BK viruses are mostly latent in the host's kidney cells until reactivation occurs in immunosuppressed individuals.
  • Cytomegalovirus is a common pathogen in humans, and it is often associated with an asymptomatic primary infection, followed by a viral persistence or incubation phase.
  • Primary cytomegalovirus infection and persistent cytomegalovirus reactivation are frequently associated with life-threatening invasive visceral disease in patients with congenital or acquired immunodeficiency and in patients undergoing solid organ or bone marrow transplantation.
  • Iron chelators are commonly used to treat thalassemia, sideroblastic anemia, autoimmune hemolytic anemia, and other anemias. There are no reports on the use of iron chelators for the treatment or prevention of polyoma virus-related diseases.
  • the present invention relates to the use of an iron chelator in the manufacture of a medicament for the treatment or prevention of polyoma virus infection.
  • the present invention relates to a method of treating or preventing polyomavirus infection comprising administering to an individual in need thereof a therapeutically effective amount of an iron chelator of the present invention.
  • the individual is preferably a mammal, especially a human individual.
  • the present invention relates to iron chelators for use in the treatment or prevention of polyoma virus infection.
  • the iron chelator is one or more selected from the group consisting of deferasirox, deferoxamine, deferiprone, pyridoxal isonicotinyl hydrazone, Dp44mT, CGP 65015, CN128, Difliximab, Divin, VLX600, SP-420, and destitazol.
  • the polyoma virus infection is selected from the group consisting of BK virus, JC virus, cytomegalovirus, SV40 virus, Merkel cell polyoma virus, acanthosis-associated polyoma virus, KI polyoma virus, WU polyoma virus , human polyoma virus 6, human polyoma virus 7, human polyoma virus 9 and human polyoma virus 12 infection.
  • Figure 1 shows the relative DNA load of BK virus in cells
  • Figure 2 shows protein SDS gel electrophoresis of LT and VP1 of intracellular BK virus
  • Figure 3 shows protein SDS gel electrophoresis of intracellular BK virus VP1
  • Figure 4 shows the relative DNA load of BK virus in cells
  • Figure 5 shows protein SDS gel electrophoresis of LT and VP1 of intracellular BK virus
  • Figure 6 shows protein SDS gel electrophoresis of intracellular human cytomegalovirus UL44 and pp28.
  • the terms “one or more” or “at least one” refer to one, two, three, four, five, six, seven, eight, nine or more.
  • the term “combination thereof” refers to multi-component mixtures of the elements in question, such as two, three, four and up to the maximum possible multi-component mixtures.
  • the terms "optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes the occurrence and non-occurrence of said event or circumstance.
  • iron chelator refers to a drug that binds to iron (eg, in the body) and effectively increases iron excretion, thereby reducing iron load or its abnormal deposition in various organs.
  • iron chelators include, but are not limited to, deferasirox, deferoxamine, deferiprone, pyridoxal isonicotinyl hydrazone, Dp44mT, CGP 65015, CN128, diflixin, Divin, VLX600, SP- 420. Deferozol and combinations thereof.
  • iron chelator as used herein also encompasses salts, solvates (especially hydrates), esters, prodrugs, metabolites, crystal forms, co-crystals, stereoisomers, tautomers, isotopes thereof compound. Preferably, these forms are pharmaceutically acceptable.
  • the iron chelators themselves and forms listed or not listed above are encompassed within the scope of this application.
  • polyomavirus refers to a double-stranded DNA virus that can induce sarcoma or cancer in multiple sites or organs.
  • examples of polyoma viruses include, but are not limited to, BK virus, JC virus, cytomegalovirus, SV40 virus, Merkel cell polyoma virus, acanthosis-associated polyoma virus, KI polyoma virus, WU polyoma virus, human polyoma virus 6 , Human Polyoma 7, Human Polyoma 9, Human Polyoma 12.
  • disease associated with polyoma virus infection or “disease associated with polyoma virus infection” refers to a disease or condition resulting from the invasion of cells of an organism by polyoma virus. These diseases or conditions may or may not have obvious symptoms. Examples of such diseases include, but are not limited to, BK virus nephropathy, CM virus infection, brain JC virus infection, progressive multifocal leukoencephalopathy, BK virus associated hemorrhagic cystitis, cytomegalovirus infection after hematopoietic stem cell transplantation, post liver transplantation cytomegalovirus infection.
  • crystalline form or “crystal” refers to any solid material exhibiting a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic X-ray powder diffraction pattern with well-defined peaks.
  • co-crystal refers to a crystalline entity comprising at least two molecules in a stoichiometric or non-stoichiometric ratio.
  • solvate refers to a complex of variable stoichiometry formed by a solute and a solvent.
  • hydrate refers to a solvate comprising a drug with stoichiometric or non-stoichiometric amounts of water.
  • stereoisomers refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space.
  • "tautomer&quot refers to compounds which have specific compound structures in interchangeable forms and which vary in hydrogen atom and electron shift.
  • isotopic compound refers to a compound that contains, in its structure, one or more isotopes of atoms in natural or unnatural abundance.
  • pharmaceutically acceptable refers to a substance that, within the scope of normal medical judgment, is suitable for use in contact with a patient's tissue without undue toxicity, irritation, allergic reaction, etc., with a reasonable benefit to harm ratio, and can be effectively used for its intended purpose.
  • salts of inorganic bases can be selected from, for example, aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium and zinc salts. Further, salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium and sodium salts.
  • salts of pharmaceutically acceptable inorganic bases may be selected from ammonium, calcium, magnesium, potassium and sodium salts.
  • crystal structures may exist in solid salts, and hydrated forms may also exist.
  • Pharmaceutically acceptable salts of organic non-toxic bases can be selected from, for example, primary, secondary and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, sugar beet Alkali, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N -Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hebamine, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine, Piperidine, Polyamine Resin, Procaine , purine, theobromine, triethylamine, trimethylamine, tripropylamine and tromethamine.
  • basic ion exchange resins such
  • salts thereof need to be prepared with at least one pharmaceutically acceptable non-toxic acid, which can be selected from inorganic and organic acids.
  • non-toxic acid can be selected from inorganic and organic acids.
  • these acids may be selected, such as: citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid.
  • an effective amount refers to a dose of a compound or a pharmaceutically acceptable salt thereof capable of eliciting a biological or medical response in a tissue, system, animal or human observable by a researcher, veterinarian, clinician or other clinician.
  • excipient refers to an inactive ingredient that contains an active ingredient to bulk up the formulation when a dosage form is produced.
  • General classes of excipients include, for example, anti-adherents, binders, coatings, disintegrants, fillers, flavors, colors, lubricants, glidants, adsorbents, preservatives, and sweeteners.
  • sequential administration also known as switching administration, refers to the initial use of parenteral administration, such as subcutaneous injection, when using drugs to treat diseases. .
  • iron chelator as used herein has the meaning commonly understood by those of ordinary skill in the art, and is a drug that can bind to iron and effectively increase iron excretion, thereby reducing iron load or its abnormal deposition in various organs.
  • Iron chelators that may be used include, but are not limited to, deferasirox, deferoxamine, deferiprone, pyridoxal isonicotinyl hydrazone, Dp44mT, CGP 65015, CN128, diflixin, Divin, VLX600, SP-420 , one or more of deferiprone.
  • the iron chelator used in the present invention is selected from deferasirox, deferoxamine, deferiprone, and combinations thereof.
  • Deferasirox is an iron chelator whose chemical name is 4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]benzoic acid, and its structural formula is as follows.
  • Deferasirox is commercially available, eg, from Solebo.
  • Deferoxamine is a bacterial siderophore produced by actinomycetes and streptococci, and has the following structural formula.
  • Deferoxamine is often co-existed with acid ions in the form of salts, such as deferoxamine mesylate.
  • Deferoxamine is commercially available, for example, from Soleborg.
  • Deferiprone also known as L1, CP20, Ferriprox, or Kelfer
  • L1 CP20, Ferriprox, or Kelfer
  • Deferiprone is commercially available, eg, from Solebao.
  • Dp44mT is an iron chelator with selective anticancer activity with the following structure.
  • Dp44mT is commercially available. For example, it can be purchased from MedChemExpress.
  • CGP 65015 is an orally available iron chelator that removes iron deposits.
  • CGP 65015 has the following structure.
  • CGP 65015 is commercially available. For example, it can be purchased from MedChemExpress.
  • CN128 is an orally active and selective iron chelator, which is often used in the study of ⁇ -thalassemia and has the following structure.
  • CN128 is commercially available. For example, it can be purchased from MedChemExpress.
  • Deferitrin a deferitrin analog
  • Defliximab is commonly used to relieve chronic iron overload caused by blood transfusions, and it can also be used to treat severe beta thalassemia.
  • Diflixin has the following structure.
  • Difliximab is commercially available. For example, it can be purchased from MedChemExpress.
  • Divin is a potent iron chelator and a potent inhibitor of bacterial cell division, with bacteriostatic effects on both Gram-negative and Gram-positive bacteria. Divin has the following structure.
  • Divin is commercially available. For example, it can be purchased from MedChemExpress.
  • Pyridoxal isonicotinoyl hydrazine is a lipophilic ferric chelator that exhibits high iron chelation.
  • Pyridoxal isonicotinyl hydrazone has the following structure.
  • Pyridoxal isonicotinyl hydrazone is commercially available. For example, it can be purchased from MedChemExpress.
  • VLX600 is an iron chelation inhibitor of oxidative phosphorylation (OXPHOS). VLX600 can cause mitochondrial dysfunction and lead to a strong switch to glycolysis. VLX600 has the following structure.
  • VLX600 is commercially available. For example, it can be purchased from MedChemExpress.
  • SP-420 is a deferoxine analog with the following structure.
  • SP-420 is commercially available. For example, it can be purchased from MedChemExpress.
  • Deferitazole also denoted as SPD-602 or FBS701
  • SPD-602 is a deferoxine analog with the following structure.
  • SPD-602 is commercially available.
  • the iron chelating agent is at least two selected from the group consisting of deferasirox, deferoxamine, deferiprone, pyridoxal isonicotinyl hydrazone, Dp44mT, CGP 65015, CN128, defiance Liqun, Divin, VLX600, SP-420, Deferostazol.
  • the iron chelator is deferasirox.
  • the iron chelator is deferoxamine.
  • the iron chelator is deferiprone.
  • the iron chelator is VLX600.
  • the iron chelator is SP-420.
  • the iron chelator is deferiprozol.
  • the iron chelator is a combination of deferasirox and deferoxamine.
  • the iron chelator is a combination of deferasirox and deferiprone.
  • the iron chelator is a combination of deferioxamine and deferiprone.
  • the iron chelator is a combination of deferasirox, deferoxamine and deferiprone.
  • the iron chelator is a combination of larosirox and VLX600.
  • the iron chelator is a combination of deferasirox and SP-420.
  • the iron chelator is a combination of deferasirox and deferiprox.
  • polyoma virus refers to a double-stranded DNA virus that can induce sarcoma or cancer in multiple sites or organs.
  • iron chelators can be used to inhibit a polyoma virus selected from the group consisting of BK virus, JC virus, cytomegalovirus, SV40 virus, Merkel cell polyoma virus, acanthosis-associated polyoma virus, KI polyoma virus , WU polyoma virus, human polyoma virus 6, human polyoma virus 7, human polyoma virus 9, human polyoma virus 12, especially BK virus, JC virus or cytomegalovirus.
  • a polyoma virus selected from the group consisting of BK virus, JC virus, cytomegalovirus, SV40 virus, Merkel cell polyoma virus, acanthosis-associated polyoma virus, KI polyoma virus , WU polyoma virus, human polyoma virus 6, human polyoma virus 7, human polyoma virus 9, human polyoma virus 12, especially BK virus, JC virus or cytomegalovirus.
  • the present invention also relates to the use of an iron chelator in the preparation of a medicament for inhibiting polyoma virus replication.
  • the iron chelators and polyoma viruses are as described herein.
  • the BK virus genome is a circular double-stranded DNA of about 5 kb in length, and contains three major partitions: early coding region, late coding region and non-coding control region.
  • the early coding region encodes three regulatory proteins (large tumor antigen [TAg], small tumor antigen [tAg], and truncated tumor antigen [truncTAg]), which are the first viral proteins expressed in newly infected cells, Responsible for facilitating viral DNA replication and establishing a favorable cellular environment.
  • the late coding region encodes three structural proteins (VP1, VP2, and VP3) that make up the viral capsid, as well as an agnoprotein whose role during viral replication is unclear.
  • the non-coding control regions contain origins of replication, as well as early and late promoters that drive expression of the viral gene product.
  • JC virus is a member of the polyoma virus family, its genome is composed of double-stranded circular DNA with a size of 5.1kb, which produces two types of proteins in the early gene and late gene in the early stage of virus infection, that is, before DNA replication and in the later stage of the infection cycle.
  • the bidirectional coding sequences in between are responsible for viral gene expression and contain the viral DNA origin of replication.
  • the early viral proteins, the large T-antigen (T-Ag) and small T-Ag protein families, are produced by alternative splicing and have a regulatory role in coordinating the virus during its replication cycle.
  • Cytomegalovirus is a member of the herpes virus family. In humans, cytomegalovirus (CMV), also known as human cytomegalovirus (HCMV), is designated human herpes virus 5 (HHV-5). Cytomegalovirus (CMV) is the largest member of the herpesvirus family, with a double-stranded DNA genome of over 240 kbp, capable of encoding over 200 possible protein products. Cytomegalovirus (CMV) is also known as the beta-herpesvirus subgenus because it is a herpes virus that infects monocytes as well as lymphocytes.
  • SV40 refers to simian vacuolar virus 40, short for simian virus 40 or simian virus 40, and belongs to the family Polyomaviridae, an oncogenic virus found in both humans and monkeys.
  • the genome of the SV40 virus is a circular double-stranded DNA.
  • Merkel cell carcinoma also known as primary neuroendocrine carcinoma of the skin, is a rare but aggressive skin tumor.
  • Merkel cell polyomavirus (merkel cell polyomavirus, MCPyV) infection, ultraviolet radiation and immunosuppression are the main factors in the pathogenesis of MCC.
  • Acanthosis-associated polyomavirus also known as human polyomavirus 8 is associated with acanthosis.
  • KI polyomavirus is a human polyomavirus named after the Karolinska Institutet.
  • WU polyomavirus is a human polyomavirus named after the discoverer unit (Washington University).
  • the iron chelator can inhibit polyoma virus replication by inhibiting polyoma virus, thereby treating or preventing polyoma virus-related diseases.
  • Polyoma virus (infection) can cause some related diseases, such as but not limited to BK virus nephropathy, CM virus infection, brain JC virus infection, progressive multifocal leukoencephalopathy, BK virus associated hemorrhagic cystitis, hematopoietic stem cell transplantation. Cytomegalovirus infection, cytomegalovirus infection after liver transplantation.
  • the medicament can be used to treat or prevent polyoma virus (infection) related diseases.
  • the present invention also relates to the use of iron chelators in the preparation of medicaments for the treatment or prevention of polyoma virus-related diseases. wherein iron chelators, polyoma viruses and related diseases are as described herein.
  • the present invention relates to the use of an iron chelator in the manufacture of a medicament for the treatment or prevention of BK virus nephropathy or hemorrhagic cystitis.
  • the dose level and frequency of administration of iron chelators varies according to the type of polyoma virus disease, status of iron chelator receptor sensitivity, age, and virus level, and is for individual patients.
  • the dosage level and frequency of administration can be determined by the physician according to the actual situation. Generally, satisfactory results are achieved at daily doses of 0.001 to 100 mg/kg body weight, in particular from about 0.03 to 2.5 mg/kg body weight.
  • the daily dose for larger mammals, such as humans may be from about 0.5 mg to about 2000 mg, or more specifically, from 0.5 mg to 1000 mg, administered in a convenient form, for example, in divided doses up to four times daily or in sustained release form.
  • Suitable unit dosage forms for oral administration contain from about 1 to 50 mg of active ingredient.
  • the iron chelator is administered at a dose of 10-200 mg/kg/d. In a preferred embodiment, the iron chelator is administered at a dose of 20-100 mg/kg/d. For example 20mg/kg/d, 30mg/kg/d, 40mg/kg/d, 50mg/kg/d, 60mg/kg/d, 70mg/kg/d, 80mg/kg/d, 90mg/kg/d, 100mg /kg/d.
  • the iron chelator is administered 1-3 times daily. In a preferred embodiment, the iron chelator is administered three times a day. In another preferred embodiment, the iron chelator is administered once daily.
  • the deferiprone iron chelator is administered at a dose of 50-100 mg/kg/d. In a more preferred embodiment, the deferiprone iron chelator is administered at a dose of 100 mg/kg/d.
  • the deferasirox iron chelator is administered at a dose of 20-30 mg/kg/d. In a more preferred embodiment, the deferasirox iron chelator is administered at a dose of 30 mg/kg/d.
  • the deferiprone iron chelator is administered at a dose of 50-100 mg/kg/d three times a day. In another specific embodiment, the deferasirox iron chelator is administered at a dose of 20-30 mg/kg/d once daily.
  • Iron chelators are generally suitable for administration to a variety of animals, including mammals.
  • subjects for administration include, but are not limited to, humans and any other primates, mammals, including commercially relevant mammals, such as non-human primates, cows, pigs, horses, sheep, cats, and dogs.
  • the iron chelators of the present invention can be administered in the form of pharmaceutical compositions by any conventional route; for example enterally, for example orally, for example in tablet or capsule form, parenterally, for example in injectable solutions or suspensions in liquid form; or topical, such as in lotions, gels, ointments or creams, or in nasal or suppository forms; or sequentially, such as parenterally (e.g., subcutaneously) prior to treatment , and changed to oral administration after the condition improved.
  • a particularly preferred mode is sequential administration.
  • the drugs administered sequentially may be the same or different.
  • the various iron chelators in the medicament of the present invention are administered simultaneously or sequentially.
  • deferasirox is administered first, followed by deferoxamine.
  • deferasirox is administered first, followed by deferiprone.
  • the administration form of the present invention is sequential administration, first by subcutaneous injection of deferoxamine followed by oral administration of deferasirox.
  • the various iron chelators When administered simultaneously, the various iron chelators may be present in separate pharmaceutical compositions, or may be present in a single pharmaceutical composition, such as any of the many pharmaceutical compositions described herein.
  • the iron chelators described herein can be administered in the form of pharmaceutical compositions. Accordingly, the present invention also relates to a pharmaceutical composition comprising an iron chelator as described herein and one or more pharmaceutically acceptable carriers or excipients, and related uses.
  • “Pharmaceutically acceptable carrier” as used herein means a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, complications or other problems and with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carriers that can be used include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, Mineral oil, sesame oil, etc.
  • an exemplary carrier can be water.
  • Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • the compositions may also contain minor amounts of wetting agents, emulsifiers, lubricants, stabilizers or pH buffers, and the like, as desired.
  • Oral formulations may contain standard carriers.
  • the pharmaceutical composition containing the iron chelating agent in the form of a free base or a pharmaceutically acceptable salt of the present invention and at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing, granulating, coating, dissolving or dissolving in a conventional manner. Freeze drying process to manufacture.
  • a pharmaceutical composition comprising a compound of the present invention in combination with at least one pharmaceutically acceptable carrier or diluent can be prepared in a conventional manner by admixture with a pharmaceutically acceptable carrier or diluent.
  • a unit dosage form for oral administration contains, for example, from about 0.1 mg to about 500 mg of active substance.
  • the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution.
  • a suspension or dispersion such as an isotonic aqueous solution.
  • dispersions or suspensions may be prepared before use.
  • the pharmaceutical compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts to adjust the osmotic pressure and/or buffers.
  • Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid.
  • the solution or suspension may also contain thickening agents including, but not limited to, sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin, or solubilizers, such as Tween 80 (polyoxyethylene). (20) Sorbitan monooleate).
  • Suspensions in oil may contain as the oily ingredient vegetable oils, synthetic or semi-synthetic oils, commonly used for injectable purposes.
  • vegetable oils synthetic or semi-synthetic oils, commonly used for injectable purposes.
  • liquid fatty acid esters containing, as the acid component, long chain fatty acids having 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms.
  • Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, arachidic acid, behenic acid, or the corresponding unsaturated Acids such as oleic acid, elaidic acid, erucic acid, basalic acid and linoleic acid, and if desired, antioxidants such as vitamin E, 3-carotene or 3,5-di-tert-butylhydroxytoluene.
  • the alcohol component of these fatty acid esters can have six carbon atoms and can be monovalent or polyvalent, such as mono-, di- or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or amyl alcohol or isomers thereof, ethylene glycol and glycerol.
  • Suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl palmitate, isopropyl myristate, (polyoxyethylene glycerin), CS (unsaturated pegylated glycerides prepared by alcoholysis of almond oil, containing glycerides and polyethylene glycol esters), LABRASOL TM (saturated pegylated glycerides prepared by alcoholysis of TCM, containing glycerides and polyethylene glycol esters; both available from GaKefosse, France), and/or (Saturated fatty acid triglycerides with chain lengths C8 to C12 from Hüls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.
  • compositions for oral administration can be prepared, for example, by admixing the active ingredient with one or more solid carriers, granulating, if desired, the resulting mixture and processing the mixture by adding additional excipients or Granules, in the form of tablets or tablet cores.
  • Suitable carriers include, but are not limited to, fillers such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and also binders such as Starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, Such as the above-mentioned starch, carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or its salt, such as sodium alginate.
  • fillers such as sugars such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and also binders such as Starches, such as corn, wheat, rice or potato star
  • Additional excipients include flow conditioners and lubricants, such as silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof .
  • flow conditioners and lubricants such as silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof .
  • Tablet cores may be provided with a suitable, optionally enteric coating, by using, in particular, concentrated sugar solutions, which may include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or dissolved in A coating solution in a suitable organic solvent or solvent mixture, or, for enteric coatings, a solution of a suitable cellulose formulation, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate solution.
  • Dyestuffs or pigments may be added to the tablets or tablet coatings, eg, for identification purposes or to indicate different doses of active ingredient.
  • compositions for oral administration can also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol.
  • Hard capsules may contain the active ingredient in the form of granules, for example, in admixture with filler such as corn starch, binders and/or glidants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active ingredient may be dissolved or suspended in suitable liquid excipients such as fatty oils, paraffin oil, or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, stabilizers and detergents thereto,
  • suitable liquid excipients such as fatty oils, paraffin oil, or liquid polyethylene glycols or fatty acid esters of ethylene or propylene glycol, stabilizers and detergents thereto,
  • fatty acid ester type of polyoxyethylene sorbitol can also be added.
  • compositions suitable for rectal administration contain the active ingredient in combination with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions suitable for parenteral administration may contain the active ingredient in water-soluble form, such as water-soluble salts or aqueous injection suspensions containing viscosity-increasing substances, such as sodium carboxymethyl cellulose, aqueous solutions of sorbitol, and /or dextran, if desired, and stabilizers.
  • the active ingredient optionally with excipients, may also be in a lyophilized form, and a solution may be prepared by adding a suitable solvent prior to parenteral administration. Solutions used, for example, for parenteral administration, can also be used as infusion solutions.
  • Injectable formulations are usually prepared under sterile conditions by filling, for example, ampoules or vials, and sealed containers.
  • iron chelating agent of the present invention can be used alone, or two or more chelating agents can be used. On this basis, iron chelators can also be used in combination with other antiviral therapeutics.
  • an adjuvant drug may reduce the therapeutic effect of a compound of the present invention (eg, the therapeutic benefit of an adjuvant drug alone is minimal, but in combination with another drug, the therapeutic benefit of the individual may be enhanced), or,
  • the combination of a compound of the present invention with another therapeutic agent that is also therapeutic can enhance the therapeutic benefit of an individual.
  • concomitant use of an immunomodulatory agent may enhance clinical benefit when a compound of the invention is used in the treatment of JC virus nephropathy.
  • an anti-nausea drug may be used in combination.
  • therapies that may be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy on the diseased area, rest, dietary modification, and the like. Regardless of the disease, disorder or condition being treated, the two therapies should have an additive or synergistic effect to benefit the individual's treatment.
  • the iron chelator is used in combination with other antiviral therapeutics.
  • the other antiviral therapeutic agent is selected from one or more of the following: 1-O-hexadecyloxypropyl cidofovir, cidofovir, leflunomide , interferon, iodine, trifluorothymidine, vidarabine, ribavirin, acyclovir, propoxyuridine, azidothymidine, amantadine, or morpholineguanidine, especially 1 One or more of -O-hexadecyloxypropyl cidofovir, cidofovir and leflunomide.
  • the route of administration of the pharmaceutical composition of the compound described herein may be the same as the other drug, or the route of administration may be different due to differences in physical and chemical properties.
  • oral administration of a compound described herein results in and maintains good blood levels, whereas another therapeutic agent may require intravenous administration.
  • a compound described herein and another therapeutic agent can be administered simultaneously, sequentially or separately.
  • the present invention provides the use of an iron chelator in the preparation of a medicament for treating or preventing polyoma virus infection, and the use of the iron chelator in the preparation of a medicament for inhibiting polyoma virus replication.
  • the inventors found that iron chelators can effectively inhibit the replication of polyoma virus, thereby effectively treating or preventing polyoma virus infection and related diseases, and providing new directions and options for treatment.
  • Micropipette purchased from EPPENDORF.
  • Microplate reader Biotek microplate reader, purchased from Applied Biosystems.
  • Incubator Carbon dioxide incubator, purchased from Thermo Fisher Scientific.
  • PCR instrument real-time fluorescence quantitative PCR instrument, purchased from BIO-RAD.
  • Inverted microscope purchased from ZEISS.
  • Immunoblotting apparatus purchased from BIO-RAD.
  • Biological safety cabinet purchased from ESCO.
  • Centrifuge 5702R low-temperature high-speed desktop centrifuge, purchased from EPPENDORF.
  • Human proximal renal tubular epithelial cells HRPTEpiC (#4100), were purchased from ScienCell, USA, and were cultured in EpiCM (#4101) medium.
  • Human foreskin fibroblasts HFF cells were purchased from the American Type Culture Collection (ATCC).
  • BK polyoma virus ( VR-837 TM ), purchased from the American Type Culture Collection (ATCC), uses Vero to amplify the virus.
  • Human cytomegalovirus (HCMV) purchased from ATCC.
  • Pancreatin (0.25% Trypsin-0.1% EDTA) was purchased from Gibco.
  • Fetal bovine serum was purchased from Lonsera, Brazil, South America.
  • MEM and DMEM basal medium were purchased from Corning Company, USA.
  • Deferasirox, deferoxamine and deferiprone were purchased from Solepro.
  • the present invention reflects the replication situation of the BK virus in the culture system by detecting the protein expression of VP1 protein and/or LT in the BK virus.
  • VP1 protein is a capsid protein in polyoma virus with a molecular weight of 40KD, which is essential for host cell receptor recognition and correct virion assembly.
  • LT is a large tumor antigen with a molecular weight of 100 KD, which is a key early protein necessary to drive viral replication and induce cellular transformation. Large tumor antigens play a role in viral genome replication by driving quiescent cells into the cell cycle and automatically regulating viral early mRNA synthesis. Therefore, these two proteins are often used to characterize viral levels.
  • Example 1 Study on the inhibitory effect of iron chelators on BK virus
  • the purpose of this example was to investigate the inhibitory effect of different iron chelators on BK virus (BKV) in cells.
  • DFS Dissolve deferasirox
  • DFA deferoxamine
  • DFP deferiprone
  • the supernatant was discarded and replaced with a drug-free medium and a medium containing 100 ⁇ M deferasirox, 100 ⁇ M deferoxamine, and 100 ⁇ M deferiprone, respectively, and then placed in a cell incubator for further culturing for 72 h.
  • the results show that after BK virus infection, the DNA expression level of BK virus in cells is relatively high.
  • the iron chelators deferasirox, deferoxamine or deferiprone were added to the culture system, a significant decrease in the DNA expression level of BK virus could be observed.
  • adding an iron chelator to the culture system can effectively inhibit virus replication and reduce the expression level of virus-related proteins.
  • the addition of iron chelators can also effectively reduce the viral DNA load in the supernatant.
  • the iron chelator can effectively inhibit the replication of polyoma virus and achieve the inhibitory effect on polyoma virus.
  • Example 2 Study on the anti-BK virus effect of iron chelators and the level of iron ions
  • the purpose of this example is to study the inhibitory effect of iron chelators on BK virus in the presence of iron ions.
  • HRPTEPIC and TCCSUP cells grown in log phase were digested with 0.25% Trypsin-0.1% EDTA, and seeded into 6-well plates at a cell number of 3 ⁇ 10 5 cells/well, 2 ml per well.
  • the above two cells were infected within 24h of the cell seed plate, and the cell supernatant in the 6-well plate was dried as much as possible, and replaced with the corresponding medium containing 0.5MOI BKV.
  • the results show that after BK virus infection, the VP1 of BK virus in cells showed a higher level of protein expression.
  • the iron chelator deferasirox after adding the iron chelator deferasirox to the culture system, a significant decrease in the expression level of VP1 protein of BK virus could be observed.
  • the expression level of VP1 protein of BK virus did not show a significant decrease.
  • the results show that after BK virus infection, the DNA expression level of BK virus in cells is relatively high. In contrast, when deferasirox was added to the culture system, a significant decrease in the DNA expression level of BK virus was observed. However, after adding ferrous citrate to the culture system, or adding deferasirox and ferrous citrate to the culture system at the same time, the DNA expression level of BK virus did not show a significant decrease.
  • adding an iron chelator to the culture system can reduce the concentration of iron ions in the culture system, thereby reducing the expression level of BK virus-related proteins in cells. No significant effect was observed on the expression levels of BK virus-related proteins in cells by increasing the concentration of iron ions in the culture system. In addition, the simultaneous addition of iron chelators and additional iron ions to the culture system did not observe significant effects on the expression levels of BK virus-related proteins in cells.
  • iron chelating agent can reduce the content of iron ions, effectively inhibit the replication of the virus, and achieve the inhibitory effect on the virus. If an iron chelator is used at the same time as a higher concentration of iron ions is added, the effect of the iron chelator may be saturated or inhibited, and the replication of the virus can be restored.
  • Example 3 Study of iron chelators in the treatment or prevention of BK virus-related diseases
  • the purpose of this example is to study the inhibitory effect of iron chelators on BK virus in BKV permissive cells by administering iron chelators before and after BK virus infection of cells.
  • the TCCSUP cells grown in log phase were digested with 0.25% Trypsin-0.1% EDTA, and seeded into 6-well plates at a cell number of 3 ⁇ 10 5 cells/well, and divided into 4 groups. Infect the above cells within 24h of the cell seeding plate, and try to dry the cell supernatant in the 6-well plate as much as possible. 25 ⁇ M deferasirox, complete medium with BK virus (0.5 MOI). After 2 hours of infection, the supernatant was discarded, and the above four groups were replaced with complete medium, medium containing 25 ⁇ M deferasirox, complete medium and medium containing 25 ⁇ M deferasirox, and then placed in a cell incubator. Continue to cultivate for 72h.
  • iron chelators can be used to treat and prevent polyoma virus infection.
  • Example 4 Effect of iron chelators on human cytomegalovirus infection
  • the purpose of this example is to study the inhibitory effect of iron chelators on human cytomegalovirus infection by administering iron chelators before and after infection of cells by human cytomegalovirus.
  • DFS deferiprone
  • DFP deferiprone

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Abstract

L'invention concerne l'utilisation d'un agent chélateur dans la préparation d'un médicament pour le traitement ou la prévention d'une infection à polyomavirus.
PCT/CN2021/113130 2020-08-18 2021-08-17 Utilisation d'un agent chélateur de fer dans la préparation d'un médicament pour le traitement ou la prévention d'une infection à polyiomavirus Ceased WO2022037594A1 (fr)

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CN115429881A (zh) * 2022-09-02 2022-12-06 中国医学科学院基础医学研究所 铁螯合剂治疗β-连环蛋白活化突变的肿瘤
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