WO2018189566A1 - Utilisation d'un composé chimique en tant qu'agent thérapeutique - Google Patents

Utilisation d'un composé chimique en tant qu'agent thérapeutique Download PDF

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Publication number
WO2018189566A1
WO2018189566A1 PCT/IB2017/000748 IB2017000748W WO2018189566A1 WO 2018189566 A1 WO2018189566 A1 WO 2018189566A1 IB 2017000748 W IB2017000748 W IB 2017000748W WO 2018189566 A1 WO2018189566 A1 WO 2018189566A1
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infection
bacterial
viral
acid
influenza
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PCT/IB2017/000748
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English (en)
Inventor
Dorian Bevec
Andreas Christian HOCKE
Stefan HIPPENSTIEL
Katja ZSCHEPPANG
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Dorian Bevec
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Priority to PCT/IB2017/000748 priority Critical patent/WO2018189566A1/fr
Publication of WO2018189566A1 publication Critical patent/WO2018189566A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the present invention is directed to the use of the compound 4-(Cyclopropylamino)- 2-((4-(4-(ethanesulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide as a therapeutic agent for the prophylaxis and/or treatment of an infection, viral- bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co- infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.
  • the identification of a therapeutic compound effective for the prophylaxis and/or treatment of a disease can be based on the activity of the compound in a biological assay.
  • a biological assay that mimics a disease causative mechanism can be used to test the therapeutic activity of a candidate chemical entity.
  • the causative mechanism of many diseases is the over activity of a biological pathway.
  • a chemical entity that can reduce the activity of the biological pathway can be effective in the prophylaxis and/or treatment of the disease caused by the over activity of the biological pathway.
  • the causative mechanism of many diseases is the over production of a biological molecule.
  • a chemical entity that can reduce the production of the biological molecule or block the activity of the over produced biological molecule can be effective in the prophylaxis and/or treatment of the disease caused by the over production of the biological molecule.
  • the causative mechanism of many diseases is the under activity of a biological pathway.
  • a chemical entity that can increase the activity of the biological pathway can be effective in the prophylaxis and/or treatment of the disease caused by the under activity of the biological pathway.
  • the causative mechanism of many diseases is the under production of a biological molecule.
  • a chemical entity that can increase the production of the biological molecule or mimic the biological activity of the under produced biological molecule can be effective in the prophylaxis and/or treatment of the disease caused by the under production of the biological molecule.
  • the immune system in higher vertebrates represents the first line of defense against various antigens that can enter the vertebrate body, including microorganisms such as bacteria, fungi and viruses that are the causative agents of a variety of diseases.
  • influenza A virus IAV
  • antiviral chemotherapy with compounds such as amantadine and rimantadine have been shown to reduce the duration of symptoms of clinical infections (i.e., IAV infection)
  • major side effects and the emergence of drug-resistant variants have been described.
  • New classes of antiviral agents designed to target particular viral proteins such as influenza neuraminidase are being developed.
  • the ability of viruses to mutate the target proteins represents an obstacle for effective treatment with molecules, which selectively inhibit the function of specific viral polychemical entitys.
  • influenza A virus IAV
  • Severe pneumonia causes high mortalities worldwide which has remained almost unchanged since the introduction of antibiotics.
  • IAV and Streptococcus pneumoniae (S. pneumoniae), especially in subsequent co-infections, account for a majority of the fatal outcome.
  • mice Previous studies with mice indicate that mechanisms accounting for increased severity of secondary bacterial co-infection include IAV induced alterations of phagocyte functions, epithelial damage increasing bacterial adherence, or alteration of immune system components.
  • IFN interferons
  • GM- CSF granulocyte macrophage-colony stimulating factor
  • Still another aspect of the present invention relates to the use of a chemical entity as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents for the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.
  • Such pharmaceutical compositions comprise a chemical entity as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient, binders, disintegrates, glidents, diluents, lubricants, coloring agents, sweetening agents, flavoring agents, preservatives or the like.
  • the pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
  • the chemical entity is suitable for intravenous administration or suitable for oral administration or suitable for administration by inhalation.
  • Administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits.
  • the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain a chemical entity according to the present invention.
  • the chemical entity of the invention forms pharmaceutically acceptable salts with organic and inorganic acids.
  • suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesul
  • the salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.
  • the pharmaceutical compositions according to the present invention will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, aerosol preparations consistent with conventional pharmaceutical practices.
  • suitable formulations are gels, elixirs, dispersible granules, syrups, suspensions, creams, lotions, solutions, emulsions, suspensions, dispersions, and the like.
  • Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • the pharmaceutical compositions may be comprised of 5 to 95% by weight of the chemical entitys.
  • excipient and/or diluents can be used lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules).
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl-cellulose, polyethylene glycol and waxes.
  • lubricants that may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.
  • Powders for constitution refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
  • suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, and most preferably from about 40 to 50% by weight.
  • disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 1 to about 40% by weight of the composition, preferably 2 to about 30% by weight of the composition, more preferably from about 3 to 20% by weight of the composition, and most preferably from about 5 to about 10% by weight.
  • Binders characterize substances that bind or "glue” powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluents or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropyl-methylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate.
  • sugars such as sucrose, starches derived from wheat, corn rice and potato
  • natural gums such as acacia, gelatin and tragacanth
  • derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate
  • the amount of binder in the composition can range from about 1 to 30% by weight of the composition, preferably from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
  • Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.05 to about 15% by weight of the composition, preferably 0.2 to about 5% by weight of the composition, more preferably from about 0.3 to about 3%, and most preferably from about 0.3 to about 1.5% by weight of the composition.
  • Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.01 to 10% by weight of the composition, preferably 0.1% to about 7% by weight of the total composition, more preferably from about 0.2 to 5% by weight, and most preferably from about 0.5 to about 2% by weight.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary from about 0.01 to 10% by weight of the composition, preferably from about 0.05 to 6% by weight, more preferably from about 0.1 to about 4% by weight of the composition, and most preferably from about 0.1 to about 1%.
  • buffer when used with reference to hydrogen-ion concentration or pH, refers to the ability of a system, particularly an aqueous solution, to resist a change of pH on adding acid or alkali, or on dilution with a solvent.
  • carboxylic acid buffers such as acetate and carboxylic diacid buffers such as fumarate, tartrate and phthalate and carboxylic triacid buffers such as citrate.
  • carboxylic acid buffers such as acetate and carboxylic diacid buffers such as fumarate, tartrate and phthalate and carboxylic triacid buffers such as citrate.
  • Another group of preferred buffers is represented by inorganic buffers such as sulfate, borate, carbonate, oxalate, calcium hydroxyde and phosphate buffers.
  • nitrogen containing buffers such as imidazole, diethylenediamine, and piperazine.
  • sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2- hydroxy-1 ,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2- hydroxyethyl)piperazine-1-propanesulfonic acid (EPPS), 4-
  • TES hydroxy-1 ,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid
  • EPPS 4-(2- hydroxyethyl)piperazine-1-propanesulfonic acid
  • MOPS Morpholinepropanesulfonic acid
  • BES N,N-bis(2-hydroxyethyl)-2- aminoethanesulfonic acid
  • glycine buffers such as glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis(2-hydroxyethyl)glycine and N-[2-hydroxy-1 , 1- bis(hydroxy-methyl)ethyl]glycine (Tricine).
  • amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophane, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, ⁇ , ⁇ , ⁇ -trimethyllysine, 3-methylhistidine, 5-hydroxylysine, O- phosphoserine, ⁇ -carboxyglutamate, ⁇ - ⁇ -acetyllysine, ⁇ - ⁇ -methylarginine, citrulline, ornithine and derivatives thereof.
  • amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophane, lysine, arginine, hist
  • buffers suitable for pharmaceutical use e.g. buffers suitable for administration to a patient such as acetate, carbonate, citrate, fumarate, glutamate, lactate, phosphate, phthalate, and succinate buffers.
  • Particularly preferred examples of commonly used pharmaceutical buffers are acetate buffer, citrate buffer, glutamate buffer and phosphate buffer.
  • the group of carboxylic acid buffers are also most preferred.
  • carboxylic acid buffers shall refer to carboxylic mono acid buffers and carboxylic diacid buffers as well as carboxylic triacid buffers. Of course also combinations of buffers, especially of the buffers mentioned herein are useful for the present invention.
  • Some suitable pharmaceutical buffers are a citrate buffer (preferably at a final formulation concentration of from about 20 to 200 mM, more preferably at a final concentration of from about 30 to 120 mM) or an acetate buffer (preferably at a final formulation concentration of about 20 to 200 mM) or a phosphate buffer (preferably at a final formulation concentration of about 20 to 200 mM).
  • the preferred dosage concentration for either intravenous, oral, or inhalation administration is between 1 to 100 pmole/ml, and more preferably is between 10 to 50 mole/ml.
  • Another aspect of the present invention relates to a method of prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury, comprising administering to a patient in need thereof a pharmaceutical composition comprising a chemical entity according to the present invention.
  • the terms “prophylaxis” or “treatment” includes the administration of the chemical entity of the present invention to prevent, inhibit, or arrest the symptoms of an infectious disease, an infection, viral-bacterial co-infection, pulmonary viral- bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.
  • treatment with the chemical entity of the present invention will be done in combination with other protective compounds to prevent, inhibit, or arrest the symptoms of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.
  • active agent or "therapeutic agent” as used herein refers to an agent that can prevent, inhibit, or arrest the symptoms and/or progression of an infection, viral- bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co- infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.
  • therapeutic effect refers to the effective provision of protection effects to prevent, inhibit, or arrest the symptoms and/or progression of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.
  • a therapeutically effective amount means a sufficient amount of one or more of the chemical entitys of the invention to produce a therapeutic effect, as defined above, in a subject or patient in need of treatment.
  • subject or “patient” are used herein mean any mammal, including but not limited to human beings, including a human patient or subject to which the compositions of the invention can be administered.
  • mammals include human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals.
  • the chemical entity of the present invention can be used for the prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury, in combination administration with another therapeutic compound.
  • the term "combination administration" of a compound, therapeutic agent or known drug with a chemical entity of the present invention means administration of the drug and the one or more compounds at such time that both the known drug and the chemical entity will have a therapeutic effect. In some cases this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e. at the same time), prior, or subsequent administration of the drug with respect to the administration of a chemical entity of the present invention. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and chemical entitys of the present invention.
  • a chemical entity is deemed to have therapeutic activity if it demonstrated any one of the following activities listed in a) to g).
  • the chemical entity could inhibit the activity of an over active biological pathway.
  • the chemical entity could inhibit the production of an over produced biological molecule.
  • the chemical entity could inhibit the activity of an over produced biological molecule.
  • the chemical entity could increase the activity of an under active biological pathway.
  • the chemical entity could increase the production of an under produced biological molecule.
  • the chemical entity could mimic the activity of an under produced biological molecule.
  • the chemical entity could prevent, inhibit, or arrest the symptoms and/or progression of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.
  • inhibition is defined as a reduction of the activity or production of a biological pathway or molecule activity of between 10 to 100%. More preferably the reduction of the activity or production of a biological pathway or molecule activity is between 25 to 100%. Even more preferably the reduction of the activity or production of a biological pathway or molecule activity is between 50 to 100%.
  • increase is defined as an increase of the activity or production of a biological pathway or molecule of between 10 to 100%. More preferably the increase of the activity or production of a biological pathway or molecule activity is between 25 to 100%. Even more preferably the increase of the activity or production of a biological pathway or molecule activity is between 50 to 100%.
  • the following chemical entity was tested for the activity as a therapeutic agent for the prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury: 4-(Cyclopropylamino)-2-((4-(4-(ethanesulfonyl)piperazin-1- yl)phenyl)amino)pyrimidine-5-carboxamide, also known as Cerdulatinib.
  • the present invention relates to the use of the above-mentioned chemical entity as pharmaceutically active agent in medicine, i.e. as medicament.
  • a prerequisite for the analysis and interpretation of cytokine regulation during coinfection in ex vivo cultivated human lung tissue is the establishment and characterization of the model.
  • Fresh lung explants were obtained from 78 patients suffering from bronchial carcinoma, who underwent lung resection at local thoracic surgeries. The study was approved by the ethics committee at the Charite clinic (projects EA2/050/08 and EA2/023/07) and written informed consent was obtained from all patients.
  • Tumor-free peripheral lung tissue was first dissected into smaller pieces by scalpel, afterwards stamped into small cylinders (3 x 8 x 8 mm) using a biopsy punch (diameter 8 mm).
  • the human seasonal influenza H3N2 virus A/Panama/2007/1999 (Pan/99[H3N2]) strain was provided by T. Wolff (RKI, Berlin, Germany) and propagated using MDCK cells. Virus stocks were aliquoted, stored at -80 °C and titrated on MDCK cells by a standard plaque assay.
  • Human lung tissue was inoculated with control medium or Pan/99(H3N2) for 24 h. Additional samples were subsequently challenged with S. pneumoniae strain D39 for further 16h. As expected, exclusively AEC II were infected by IAV as indicated by pro-SP-C co-localization. S. pneumoniae D39 was detected closely attached to the cell surface of AEC I and AEC II as well as AM independent of prior IAV infection. Viral growth was next measured after 1 , 16, 24, and 48h to determine the highest amount of viral load under the conditions used.
  • IAV induced type I, II, and III IFN show unchanged expression during co- infection with S. pneumoniae
  • IFN are assumed to play a major role towards susceptibility to secondary bacterial infection; however, this is still unexamined for human lung tissue.
  • Pan/99(H3N2) significantly induced the release of IFNa2 and IFNb (type I), IFNg (type II), and IFNI1 (type III) whereas S. pneumoniae D39 showed no IFN induction at all.
  • the secretion pattern of all IFN remained unchanged in viral and bacterial co- infection, demonstrating that S. pneumoniae has no effect on IFN regulation, which might pave the way for a compromised secondary host defense against the bacteria.
  • IAV and IFN interfere with S. pneumoniae induced IL-1 b - GM-CSF axis in human lungs
  • cytokines and chemokines plays an important role for the initiation of innate immune responses to control viral and bacterial infections, and studies in mice revealed that induction of type I and II IFN during primary non-lethal influenza virus infection complicates the defense against a range of bacterial pathogens.
  • IFN IFN in human lung tissue can mimic IAV induced suppression of IL-1 b and GM-CSF.
  • IAV was replaced by IFNb and IFNg treatment for the same time course and compared the liberated amount of IL-1 b and GM-CSF.
  • IFN significantly blocked S. pneumonia induced IL-1 b and GM-CSF synthesis to a similar amount.
  • GM-CSF The expression of GM-CSF is depended on IL-1 b instead of TNFa.
  • the induction of COX-2 in the same lungs served as a positive control for effective TNFa stimulation.
  • the time course of both factors in S. pneumoniae infected human lung tissue was determined.
  • AEC II derived IFN blocks IL-1 b of AM leading to suppression of AEC II expressed GM-CSF
  • IAV induced IFN blocked IL-1 ⁇ release, finally leading to loss of GM-CSF production in human lungs.
  • AM and AEC II were isolated from fresh human lung tissue. Phenotype characterization by immunofluorescence staining showed isolated AM positive for CD68, AEC II for pancytokeratin, and pro-SP-C.
  • the release of IFN by IAV infected AEC II and AM demonstrates that AEC II are a major cellular source of IFN in the human alveolar compartment. In contrast, AEC II are negative for release of IL-1 b after infection with S.
  • pneumoniae were used for stimulation of GM-CSF in AEC II in presence or absence of Anakinra to provide evidence for the dependence of epithelial GM-CSF on IL-1 b released by AM.
  • the inhibition of epithelial GMCSF expression seems not restricted to IL-1 b suppression in AM alone, instead IFN may also directly inhibit GMCSF after IL-1 b stimulation.
  • Tyk2 inhibition restores IAV induced type I and III IFN mediated suppression of IL-1 ⁇ - GM-CSF axis

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  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Otolaryngology (AREA)
  • Dermatology (AREA)

Abstract

La présente invention concerne une nouvelle utilisation médicale du composé 4-(cyclopropylamino)-2-((4-(4-(éthanesulfonyl))pipérazin-1-yl)phényl)amino)pyrimidine-5-carboxamide en tant qu'agent thérapeutique pour la prophylaxie et/ou le traitement d'une infection, une co-infection virale-bactérienne, une co-infection virale-bactérienne pulmonaire, une co-infection grippale-bactérienne, une co-infection par la grippe et Streptococcus pneumoniae, une infection virale, une infection bactérienne, une infection pulmonaire, une pneumonie acquise en communauté, un syndrome de détresse respiratoire de l'adulte, une lésion pulmonaire aiguë. Une infection IAV précédente de l'alvéole humaine conduit à une modulation dépendante d'IFN de type I et III des cytokines précoces IL-1b et GM-CSF, qui sont essentiels pour l'orchestration d'une réponse immunitaire innée adéquate contre S pneumoniae. Leur suppression peut entraîner une altération de de la clairance bactérienne et de la réparation alvéolaire. L'inhibition sélective de Tyk2 associée à IFNR I et III peut restaurer complètement l'activation immunitaire altérée. Une inhibition pharmacologique de Tyk2 est suffisante en tant que traitement d'une co-infection virale-bactérienne dans la pneumonie humaine.
PCT/IB2017/000748 2017-04-10 2017-04-10 Utilisation d'un composé chimique en tant qu'agent thérapeutique WO2018189566A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009031011A2 (fr) * 2007-09-05 2009-03-12 Pfizer Limited Forme de sel
US20110201608A1 (en) * 2008-08-05 2011-08-18 Boehringer Ingelheim International Gmbh Substituted naphthyridines and use thereof as medicines
WO2015164604A1 (fr) * 2014-04-23 2015-10-29 Dana-Farber Cancer Institute, Inc. Inhibiteurs de janus kinase marqués de manière hydrophobe et utilisations associées
WO2016196385A1 (fr) * 2015-05-29 2016-12-08 Portola Pharmaceuticals, Inc. Cerdulatinib pour le traitement des affections malignes à cellules b
US20170042896A1 (en) * 2015-08-12 2017-02-16 Portola Pharmaceuticals, Inc. Cerdulatinib for treating myeloma

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009031011A2 (fr) * 2007-09-05 2009-03-12 Pfizer Limited Forme de sel
US20110201608A1 (en) * 2008-08-05 2011-08-18 Boehringer Ingelheim International Gmbh Substituted naphthyridines and use thereof as medicines
WO2015164604A1 (fr) * 2014-04-23 2015-10-29 Dana-Farber Cancer Institute, Inc. Inhibiteurs de janus kinase marqués de manière hydrophobe et utilisations associées
WO2016196385A1 (fr) * 2015-05-29 2016-12-08 Portola Pharmaceuticals, Inc. Cerdulatinib pour le traitement des affections malignes à cellules b
US20170042896A1 (en) * 2015-08-12 2017-02-16 Portola Pharmaceuticals, Inc. Cerdulatinib for treating myeloma

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