WO2022022706A1 - Compositions et méthodes de traitement de maladies pulmonaires - Google Patents

Compositions et méthodes de traitement de maladies pulmonaires Download PDF

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Publication number
WO2022022706A1
WO2022022706A1 PCT/CN2021/109800 CN2021109800W WO2022022706A1 WO 2022022706 A1 WO2022022706 A1 WO 2022022706A1 CN 2021109800 W CN2021109800 W CN 2021109800W WO 2022022706 A1 WO2022022706 A1 WO 2022022706A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
administered
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English (en)
Inventor
Yifan Zhai
Dajun Yang
Dong Fang
Saijie Zhu
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Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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Ascentage Pharma Suzhou Co Ltd
Ascentage Pharma Group Co Ltd
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • IPF Idiopathic pulmonary fibrosis
  • UPF interstitial pneumonia
  • RIPF Radiation-induced pulmonary fibrosis
  • the present disclosure provides a method of treating or preventing a lung disease in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing a lung disease in a subject.
  • the present disclosure provides use of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a lung disease in a subject.
  • the present disclosure provides a pharmaceutical composition for treating or preventing a lung disease, comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical kit for treating or preventing a lung disease, comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • FIGS. 1A and 1B are a set of graphs showing that Compound No. 1 and Compound No. 2 significantly improved the body weight loss and survival of mice with idiopathic pulmonary fibrosis.
  • FIGS. 2A and 2B are a set of graphs showing that Compound No. 1 and Compound No. 2 significantly improved lung fibrosis and inflammatory score of mice with idiopathic pulmonary fibrosis.
  • FIG. 3 is a graph showing that Compound No. 1 significantly reduced collagen deposition in the lung of mice with idiopathic pulmonary fibrosis.
  • FIG. 4 is a graph showing that Compound No. 1 and Compound No. 2 significantly reduced the number of SA- ⁇ -galactosidase-positive cell in the lung of mice with idiopathic pulmonary fibrosis.
  • FIG. 5 is a graph showing that Compound No. 1 and Compound No. 2 significantly reduced the mRNA level of p16 gene in the lung of mice with idiopathic pulmonary fibrosis.
  • FIGS. 6A and 6B are a set of graphs showing that Bleomycin challenge significantly increased the mRNA level of BCL-xL gene in mouse lung.
  • FIGs. 7A-7F is a graph showing that Compound No. 1 and Compound No. 2 significantly reduced the mRNA level of SASP-related genes in the lung of mice with idiopathic pulmonary fibrosis.
  • FIGS. 8A and 8B are a set of graphs showing the expression level of BCL-xL protein was significantly increased in lung of mice after bleomycin challenge as compared with mice.
  • FIG. 9 is a graph showing Compound No. 1 and Compound No. 2 significantly improved the survival proportion of mice with radiation-induced pulmonary fibrosis.
  • FIG. 10 is a graph showing Compound No. 1 and Compound No. 2 significantly reduced the lung size of mice with radiation-induced pulmonary fibrosis.
  • FIG. 11 is a graph showing Compound No. 2 significantly reduced the number of senescent cells in the lung of mice with radiation-induced pulmonary fibrosis.
  • Compound No. 1 may be identified by the IUPAC name of (3R) -1- (3- (4- (4- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylaminosulfonyl) -2-trifluoromethylsulfonyl-anilino) -4-phenylthio-butyl) -piperidine-4-carboxylic acid 3-phosphonopropyl ester.
  • Compound No. 2 may be identified by the IUPAC name of (R) -1- (3- ( (4- (N- (4- (4- (3- (2- (4-chlorophenyl) -1-isopropyl-5-methyl-4- (methylsulfonyl) -1H-pyrrol-3-yl) -5-fluorophenyl) -piperazin-1-yl) phenyl) sulfamoyl) -2- ( (trifluoromethyl) sulfonyl) phenyl) amino) -4- (phenylthio) -butyl) piperidine-4-carboxylic acid.
  • the present disclosure provides a method of treating or preventing a lung disease in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a lung disease in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1 or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a lung disease in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 2 or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing a lung disease in a subject.
  • the present disclosure provides Compound No. 1, or a pharmaceutically acceptable salt thereof, for treating or preventing a lung disease in a subject.
  • the present disclosure provides Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing a lung disease in a subject.
  • the present disclosure provides use of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a lung disease in a subject.
  • the present disclosure provides use of Compound No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a lung disease in a subject.
  • the present disclosure provides use of Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a lung disease in a subject.
  • the present disclosure provides a method of treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides a method of treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1 or a pharmaceutically acceptable salt thereof.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides a method of treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 2 or a pharmaceutically acceptable salt thereof.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides Compound No. 1, or a pharmaceutically acceptable salt thereof, for treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides use of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides use of Compound No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides use of Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing idiopathic pulmonary fibrosis (IPF) in a subject.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides a method of treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • RIPF radiation-induced pulmonary fibrosis
  • the present disclosure provides a method of treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 1 or a pharmaceutically acceptable salt thereof.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides a method of treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of Compound No. 2 or a pharmaceutically acceptable salt thereof.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides Compound No. 1, or a pharmaceutically acceptable salt thereof, for treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides Compound No. 2, or a pharmaceutically acceptable salt thereof, for treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides use of Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides use of Compound No. 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
  • RPF radiation-induced pulmonary fibrosis
  • the present disclosure provides use of Compound No. 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
  • RPF radiation-induced pulmonary fibrosis
  • the subject is a mammal.
  • the subject is a mouse.
  • the subject is a human.
  • the lung disease is an interstitial lung disease.
  • the lung disease is a pulmonary fibrosis.
  • the lung disease is idiopathic pulmonary fibrosis (IPF) .
  • IPF idiopathic pulmonary fibrosis
  • the lung disease is a radiation-induced lung disease.
  • the lung disease is a radiation-induced interstitial lung disease.
  • the lung disease is a radiation-induced pulmonary fibrosis (RIPF) .
  • RIPF radiation-induced pulmonary fibrosis
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered by enternal administration.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered by oral administration.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered by parenteral administration.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered by intravenous administration.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered by intratracheal instillation.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered once daily.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered twice daily.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three or more times daily.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered once weekly.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered twice weekly.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered three or more times weekly.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered with one or more drug holidays.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered without any drug holiday.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered for about one week, about two weeks, or about three weeks.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered for about three weeks.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered twice (e.g., at day 1 and day 4) weekly for a bout three weeks.
  • Compound No. 1 or the pharmaceutically acceptable salt thereof is administered once daily for about three weeks.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered by enternal administration.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered by oral administration.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered by parenteral administration.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered by intravenous administration.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered by intratracheal instillation.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered once daily.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered twice daily.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered three or more times daily.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered once weekly.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered twice weekly.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered three or more times weekly.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered with one or more drug holidays.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered without any drug holiday.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered for about one week, about two weeks, or about three weeks.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered for about three weeks.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered twice (e.g., at day 1 and day 4) weekly for a bout three weeks.
  • Compound No. 2 or the pharmaceutically acceptable salt thereof is administered once daily for about three weeks.
  • the present disclosure provides a pharmaceutical composition for treating or preventing a lung disease, comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition for treating or preventing idiopathic pulmonary fibrosis (IPF) , comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides a pharmaceutical composition for treating or preventing radiation-induced pulmonary fibrosis (RIPF) , comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for treating or preventing radiation-induced pulmonary fibrosis comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises Compound No. 1 or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises Compound No. 2 or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical kit for treating or preventing a lung disease, comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical kit for treating or preventing idiopathic pulmonary fibrosis (IPF) , comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • IPF idiopathic pulmonary fibrosis
  • the present disclosure provides a pharmaceutical kit for treating or preventing radiation-induced pulmonary fibrosis (RIPF) , comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical kit for treating or preventing radiation-induced pulmonary fibrosis comprising Compound No. 1, Compound No. 2, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical kit comprises Compound No. 1 or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical kit comprises Compound No. 2 or a pharmaceutically acceptable salt thereof.
  • compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, N.J. ) or phosphate buffered saline (PBS) .
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) , and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease and also preferably causing complete regression of the disease.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the term “about” refers to a range covering any normal fluctuations appreciated by one of ordinary skill in the relevant art. In some embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100%of a possible value) .
  • the term “pharmaceutically acceptable salt” refers to a derivative of the compound of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1, 2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] -oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt can be 1: 1, or any ratio other than 1: 1, e.g., 3: 1, 2: 1, 1: 2, or 1: 3.
  • all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined here
  • a pharmaceutically acceptable salt for example, can be formed between an pharmaceutically acceptable anion and a positively charged group (e.g., amino) on a substituted benzene compound.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate) .
  • the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • the substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates and dihydrates.
  • Nonlimiting examples of solvates include ethanol solvates and acetone solvates.
  • the expressions “one or more of A, B, or C, ” “one or more A, B, or C, ” “one or more of A, B, and C, ” “one or more A, B, and C, ” “selected from the group consisting of A, B, and C” , “selected from A, B, and C” , and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and/or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • the term “subject” is interchangeable with the term “subject in need thereof” , both of which refer to a subject having a disease or having an increased risk of developing the disease.
  • a “subject” includes a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the mammal is a human.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • a compound of the present disclosure can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • preventing, ” “prevent, ” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof
  • the dosage will also depend on the route of administration.
  • routes of administration A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • the term “pharmaceutically effective amount” refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Pharmaceutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • the pharmaceutically acceptable salt of a compound is also a prodrug of the compound.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1, 2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] -oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt can be 1: 1, or any ration other than 1: 1, e.g., 3: 1, 2: 1, 1: 2, or 1: 3.
  • prodrug refers to any agent which, when administered to a mammal, is converted in whole or in part to a targeted compound.
  • the prodrug of a compound is also a pharmaceutically acceptable salt of the compound.
  • esters for example, pharmaceutically acceptable esters.
  • a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester.
  • an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester.
  • the compounds, or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • the compound is administered orally.
  • One skilled in the art will recognize the advantages of certain routes of administration.
  • the dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • the compounds described herein, and the pharmaceutically acceptable salts thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • Example 1 Study of Compound No. 1 and Compound No. 2 in Mouse Model of Idiopathic Pulmonary Fibrosis.
  • mice Male C57BL/6 mice (6-8 weeks, 18-20 g) were randomized into the following four groups: (1) group, (2) model + vehicle group, (3) Compound No. 1 group, and (4) Compound No. 2 group. Mice in the group were intratracheally instilled with 50 ⁇ L 0.9%saline and left untreated until sacrifice. Mice in the rest three groups were intratracheally instilled with 50 ⁇ L bleomycin at the dose of 1 unit/kg, and then treated with vehicle (Compound No. 1 vehicle, iv, biw_D1/4 ⁇ 3w) , Compound No.
  • vehicle Compound No. 1 vehicle, iv, biw_D1/4 ⁇ 3w
  • mice The body weight and survival proportion of mice were recorded daily. As seen in FIGS. 1A and 1B, intratracheal bleomycin instillation caused continuous weight loss and death of the mice. The average body weight of mice decreased from 23.3 ⁇ 0.3 g before bleomycin challenging to 18.8 ⁇ 1.4 g at the end of the study, and the survival proportion was 80%. On the other hand, no obvious body weight loss was observed in the mice treated with Compound No. 1 and Compound No. 2, with the survival proportions of 100%and 90%at the end of the study.
  • mice Histopathology.
  • the left lungs of mice were fixed with 10%neutral-buffered formalin for 48 hours at room temperature, then subjected to paraffin embedding and sliced into 4 ⁇ m sections. After dewaxing, the lung sections were subjected to hematoxylin and eosin (H&E) and Masson’s trichrome staining.
  • H&E staining were used to evaluate tissue inflammation based on the extent of inflammatory cell infiltration (0 for no visible lesion, 1 for minimal, 2 for mild, 3 for moderate, and 4 for marked) .
  • Specimen with Masson’s trichrome staining were used to evaluate fibrosis according to an eight-tier, modified Ashcroft scale. All the assessments were conducted in a blinded fashion.
  • Collagen assay A portion of the right lungs were used for collagen assay.
  • the harvested lung tissue were added with 6 M HCl at the ratio of 1 : 10 (mg tissue : ⁇ L 6 M HCl) , and incubated at 95 °C for 20 hours in a calibrated oven. After cooling back to room temperature, the samples were centrifuged at 13,000 g for 10 minutes. The obtained supernatants were diluted appropriately and subjected to collagen content assay using a total collagen assay kit (QuickZyme, Netherland) . The data were presented as micrograms of collagen per right lung.
  • the lung of mice challenged with bleomycin showed significantly higher collagen deposition than that of the mice (12.7 ⁇ 1.1 vs 3.0 ⁇ 0.1 ⁇ g/right lung, p ⁇ 0.0001) , suggesting the formation of fibrosis.
  • Treatment with 50 mg/kg Compound No. 1 significantly reduced the collagen content to 5.6 ⁇ 0.5 ⁇ g/right lung (p ⁇ 0.0001, vs model-vehicle) , which was in agreement with the reduced fibrosis score.
  • SA- ⁇ -Gal staining Frozen sections were prepared using half of the right lungs. SA ⁇ Gal staining was conducted using Senescence ⁇ Galactosidase Staining Kit (Solarbio Life Science, Beijing, China) following the manufacturer's protocol. Images were acquired using a Nikon Eclipse 90i microscope, and the number of SA- ⁇ -galactosidase-positive cells, i.e. senescent cells, was counted in six random microscopic fields per sample.
  • intratracheal bleomycin instillation resulted in a significant increase of the number of senescent cells in the lung of mice (p ⁇ 0.0001 vs ) , reaching 10.4 ⁇ 1.2 per field.
  • Treatment with 50 mg/kg Compound No. 1 and 10 mg/kg Compound No. 2 significantly reduced the number of senescent cells to 6.2 ⁇ 0.6 (p ⁇ 0.01, vs Model-vehicle) and 3.9 ⁇ 0.6 (p ⁇ 0.0001, vs Model-vehicle) per field respectively.
  • the mRNA level of senescence marker p16 was significantly increased in lung of mice after bleomycin challenge as compared with mice (p ⁇ 0.0001) , indicating the induction of cellular senescence in vivo. Consistent with the reduction of SA ⁇ Gal positive cell, the mRNA level of p16 gene was also significantly reduced after Compound No. 1 treatment (p ⁇ 0.0001, vs model-vehicle) .
  • FIG. 7 showed the change of the transcriptional level of SASP-related genes in the lung of mice with idiopathic pulmonary fibrosis after treatment with Compound No. 1 and Compound No. 2.
  • the mRNA levels of pro-inflammatory (Mcp1, Mmp10 and Il-6) and pro-fibrotic (Pai-1, Il-11 and Tgfb) SASP factors were significantly increased after bleomycin challenge, but was significantly reduced after treatment with Compound No. 1 and Compound No. 2.
  • mice were fixed with 10%neutral-buffered formalin for 48 hours at room remperature, then subjected to paraffin embedding and sliced into 4 ⁇ m sections. After dewaxing, the lung sections were subjected to IHC staining to detect the expression of BCL-2 and BCL-xL proteins in the lung of mice. Three representative regions were selected from each slide, and then analyzed by ImageJ software to obtain the percentage of positively stained area.
  • the BCL-2 protein expression was slightly increased in lung of mice after bleomycin challenge as compared with mice (p > 0.05, t-test) .
  • the expression level of BCL-xL protein was significantly increased in lung of mice after bleomycin challenge as compared with mice (p ⁇ 0.05, t-test) .
  • mice Male C57BL/6 mice (23-25 g) were randomized into the following four groups: (1) group, (2) model + vehicle group, (3) Compound No. 1 group, and (4) Compound No. 2 group. Mice in the group were untreated until sacrifice. Mice in the rest three groups were exposed to a single dose of 17 Gy of radiation on the right side of the thorax, and 16 weeks after irradiation, the mice were treated with with vehicle (Compound No. 1 vehicle, iv, biw_D1/4 ⁇ 3w) , Compound No. 1 (50 mg/kg, iv, biw_D1/4 ⁇ 3w) or Compound No. 2 (10 mg/kg, ip, qd ⁇ 3w) for another 6 weeks.
  • vehicle Compound No. 1 vehicle, iv, biw_D1/4 ⁇ 3w
  • Compound No. 1 50 mg/kg, iv, biw_D1/4 ⁇ 3w
  • Compound No. 2 10 mg/kg, ip, qd ⁇ 3w
  • mice Histopathology.
  • the left lungs of mice were fixed with 10%neutral-buffered formalin for 48 hours at room temperature, then subjected to paraffin embedding and sliced into 4 ⁇ m sections. After dewaxing, the lung sections were subjected to hematoxylin and eosin (H&E) and Masson’s trichrome staining.
  • H&E staining were used to evaluate tissue inflammation based on the extent of inflammatory cell infiltration (0 for no visible lesion, 1 for minimal, 2 for mild, 3 for moderate, and 4 for marked) .
  • Specimen with Masson’s trichrome staining were used to evaluate fibrosis according to an eight-tier, modified Ashcroft scale. All the assessments were conducted in a blinded fashion.
  • SA- ⁇ -Gal staining Frozen sections were prepared using half of the right lungs. SA ⁇ Gal staining was conducted using Senescence ⁇ Galactosidase Staining Kit (Solarbio Life Science, Beijing, China) following the manufacturer's protocol. Images were acquired using a Nikon Eclipse 90i microscope, and the number of SA- ⁇ -galactosidase-positive cells, i.e. senescent cells, was counted in six random microscopic fields per sample.

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Abstract

L'invention concerne des méthodes de traitement ou de prévention de maladies pulmonaires (par exemple la fibrose pulmonaire idiopathique (FPI) ou une fibrose pulmonaire causée par la radiothérapie (RIPF)) à l'aide du composé n° 1, du composé n° 2, ou de leur sel pharmaceutiquement acceptable, des compositions pharmaceutiques et des kits pharmaceutiques appropriés pour le traitement ou la prévention.
PCT/CN2021/109800 2020-07-31 2021-07-30 Compositions et méthodes de traitement de maladies pulmonaires Ceased WO2022022706A1 (fr)

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CN105246882A (zh) * 2013-01-16 2016-01-13 密执安大学评议会 BCL-2/Bcl-xL抑制剂和使用所述抑制剂的治疗方法
CN108025006A (zh) * 2015-02-06 2018-05-11 尤尼蒂生物技术公司 化合物及在治疗衰老相关病症中的用途
CN110960537A (zh) * 2018-07-31 2020-04-07 苏州亚盛药业有限公司 Bcl-2/Bcl-xL抑制剂与化疗药物的组合及其应用

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WO2019033122A1 (fr) * 2017-08-11 2019-02-14 Unity Biotechnology, Inc. Traitement de maladies pulmonaires à l'aide d'agents pharmaceutiques qui éliminent des cellules sénescentes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105246882A (zh) * 2013-01-16 2016-01-13 密执安大学评议会 BCL-2/Bcl-xL抑制剂和使用所述抑制剂的治疗方法
CN108025006A (zh) * 2015-02-06 2018-05-11 尤尼蒂生物技术公司 化合物及在治疗衰老相关病症中的用途
CN110960537A (zh) * 2018-07-31 2020-04-07 苏州亚盛药业有限公司 Bcl-2/Bcl-xL抑制剂与化疗药物的组合及其应用

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