CN114053288A - Compositions and methods for treatment of pulmonary diseases - Google Patents

Compositions and methods for treatment of pulmonary diseases Download PDF

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Publication number
CN114053288A
CN114053288A CN202110872658.1A CN202110872658A CN114053288A CN 114053288 A CN114053288 A CN 114053288A CN 202110872658 A CN202110872658 A CN 202110872658A CN 114053288 A CN114053288 A CN 114053288A
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compound
pharmaceutically acceptable
acceptable salt
kit
pharmaceutical composition
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翟一帆
杨大俊
方东
朱赛杰
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Yasheng Pharmaceutical Group Hong Kong Co ltd
Suzhou Yasheng Pharmaceutical Co ltd
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Yasheng Pharmaceutical Group Hong Kong Co ltd
Suzhou Yasheng Pharmaceutical 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
    • 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 System
    • 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

Abstract

The present invention relates to methods of treating or preventing pulmonary diseases, e.g., Idiopathic Pulmonary Fibrosis (IPF) or radiation-induced pulmonary fibrosis (RIPF), using compound 1, compound 2, or a pharmaceutically acceptable salt thereof. The invention also relates to pharmaceutical compositions and pharmaceutical kits suitable for use in therapy.

Description

Compositions and methods for treatment of pulmonary diseases
Background
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by progressive lung scarring and histological manifestations of common interstitial pneumonia (UIP). It is associated with cough and increased dyspnea and decreased quality of life. IPF affects about 300 million people worldwide, with a significant increase in incidence with age (nat. rev. dis. primers 3; 17074 (2017)).
Radiation Induced Pulmonary Fibrosis (RIPF) is a common complication in lung and breast cancer patients following chest radiotherapy. The average incidence of RIPF after radiation treatment was 16% -28%. RIPF comprises a group of heterogeneous lung diseases characterized by progressive and irreversible destruction of the lungs and disruption of gas exchange (relative Oncology 12; 162-169 (2019)). There is therefore a need for new methods of treating or preventing pulmonary diseases, such as Idiopathic Pulmonary Fibrosis (IPF) or radiation-induced pulmonary fibrosis (RIPF). The present invention addresses this need.
SUMMARY
In some aspects, the invention provides a method of treating or preventing a pulmonary disease in a subject, comprising administering to the subject a pharmaceutically effective amount of compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a method of treating or preventing a pulmonary disorder in a subject with compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides for the use of compound 1, compound 2, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a pulmonary disorder in a subject.
In some aspects, the present invention provides a pharmaceutical composition for treating or preventing a pulmonary disease, comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a pharmaceutical kit for treating or preventing a pulmonary disorder comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event that there is a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure controls.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
Drawings
Figures 1A and 1B are a set of graphs showing that compound 1 and compound 2 significantly improve weight loss and survival in mice with idiopathic pulmonary fibrosis.
Figures 2A and 2B are a set of graphs showing that compound 1 and compound 2 significantly improved the pulmonary fibrosis and inflammation scores in idiopathic pulmonary fibrosis mice.
Figure 3 shows that compound 1 significantly reduced collagen deposition in the lungs of idiopathic pulmonary fibrosis mice.
Figure 4 shows that compound 1 and compound 2 significantly reduced the number of SA- β -galactosidase positive cells in the lungs of idiopathic pulmonary fibrosis mice
Figure 5 shows that compound 1 and compound 2 significantly reduced the mRNA level of the p16 gene in the lung of idiopathic pulmonary fibrosis mice.
FIGS. 6A and 6B show that bleomycin challenge significantly increased the mRNA level of the BCL-xL gene in the lungs of mice.
FIGS. 7A-7F show that Compound 1 and Compound 2 significantly reduced the mRNA levels of the SASP-associated genes in the lungs of mice with idiopathic pulmonary fibrosis
FIGS. 8A and 8B are a set of graphs showing that the expression level of BCL-xL protein in the lungs of mice was significantly increased after bleomycin challenge compared to untreated mice.
Figure 9 shows that compound 1 and compound 2 significantly improved survival in radiation-induced pulmonary fibrosis mice.
Figure 10 shows that compound 1 and compound 2 significantly reduced lung size in mice with radiation-induced pulmonary fibrosis
Figure 11 shows that compound 2 significantly reduced the number of senescent cells in the lungs of radiation-induced pulmonary fibrosis mice
Detailed Description
It is to be understood that the term "compound 1" as used herein refers to a compound having the structure:
Figure BDA0003189683680000031
compound 1 can be named by IUPAC as (3R) -3-phosphonopropyl 1- (3- (4- (4- (3- (2- (4-chlorophenyl))) -1-isopropyl-4-methanesulfonyl-5-methyl-1H-pyrrol-3-yl) -5-fluorophenyl) piperazin-1-yl) -phenylaminosulfonyl) -2-trifluoromethylsulfonyl-anilino) -4-thiophenyl-butyl) -piperidine-4-carboxylate.
It is to be understood that the term "compound 2" as used herein refers to a compound having the structure:
Figure BDA0003189683680000041
compound 2 can be named by IUPAC as (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.
Methods and uses of the invention
In some aspects, the invention provides a method of treating or preventing a pulmonary disease in a subject, comprising administering to the subject a pharmaceutically effective amount of compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a method of treating or preventing a pulmonary disease in a subject, comprising administering to the subject a pharmaceutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a method of treating or preventing a pulmonary disease in a subject, comprising administering to the subject a therapeutically effective amount of compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides compound 1, compound 2, or a pharmaceutically acceptable salt thereof for use in treating or preventing a pulmonary disorder in a subject.
In some aspects, the invention provides compound 1, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a pulmonary disorder in a subject.
In some aspects, the invention provides compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a pulmonary disorder in a subject.
In some aspects, the invention provides for the use of compound 1, compound 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a pulmonary disorder in a subject.
In some aspects, the present invention provides a use of compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a pulmonary disease in a subject.
In some aspects, the present disclosure provides a use of compound 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a pulmonary disease in a subject.
Exemplary embodiments of methods and uses
In some aspects, the present invention 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 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention 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 1 or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention 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 2 or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides compound 1, compound 2, or a pharmaceutically acceptable salt thereof for use in treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
In some aspects, the present invention provides compound 1, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
In some aspects, the present invention provides compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
In some aspects, the present invention provides the use of compound 1, compound 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
In some aspects, the present invention provides the use of compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
In some aspects, the present invention provides the use of compound 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
In some aspects, the invention 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 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention 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 1, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention 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 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides compound 1, compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
In some aspects, the present disclosure provides compound 1, or a pharmaceutically acceptable salt thereof, for use in treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
In some aspects, the present disclosure provides compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
In some aspects, the invention provides the use of compound 1, compound 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.
In some aspects, the present invention provides the use of compound 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.
In some aspects, the present disclosure provides the use of compound 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.
Suitable subjects and diseases
In some embodiments, the subject is a mammal.
In some embodiments, the subject is a mouse.
In some embodiments, the subject is a human.
In some embodiments, the lung disease is an interstitial lung disease.
In some embodiments, the lung disease is pulmonary fibrosis.
In some embodiments, the lung disease is Idiopathic Pulmonary Fibrosis (IPF).
In some embodiments, the lung disease is a radiation-induced lung disease.
In some embodiments, the lung disease is radiation-induced interstitial lung disease.
In some embodiments, the lung disease is radiation-induced pulmonary fibrosis (RIPF).
Administration of Compound 1
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered by enteral administration.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered parenterally.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered intravenously.
In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered by tracheal instillation.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered three or more times per day.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once per week.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice weekly.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered three or more times per week.
In some embodiments, there are one or more drug holidays in the administration of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, there is no drug holiday during the administration of compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for about 1 week, about 2 weeks, or about 3 weeks.
In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for about 3 weeks.
In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered twice weekly (e.g., on days 1 and 4) for about three weeks.
In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily for about three weeks.
Administration of Compound 2
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered by enteral administration.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered orally.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered parenterally.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered intravenously.
In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered by tracheal instillation.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered once daily.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered three or more times per day.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered once per week.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice weekly.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered three or more times per week.
In some embodiments, there are one or more drug holidays in the administration of compound 2 or a pharmaceutically acceptable salt thereof.
In some embodiments, there is no drug holiday during the administration of compound 2 or a pharmaceutically acceptable salt thereof.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered for about 1 week, about 2 weeks, or about 3 weeks.
In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered for about 3 weeks.
In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered twice weekly (e.g., on days 1 and 4) for about three weeks
In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered once daily for about three weeks.
Pharmaceutical composition and kit
In some aspects, the present invention provides a pharmaceutical composition for treating or preventing a pulmonary disease, comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides a pharmaceutical composition comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof for the treatment or prevention of Idiopathic Pulmonary Fibrosis (IPF).
In some aspects, the present invention provides a pharmaceutical composition comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of radiation-induced pulmonary fibrosis (RIPF).
In some embodiments, the pharmaceutical composition comprises compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition comprises compound 2 or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a pharmaceutical kit for treating or preventing a pulmonary disorder comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the present invention provides a pharmaceutical kit for treating or preventing Idiopathic Pulmonary Fibrosis (IPF), comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a pharmaceutical kit for treating or preventing radiation-induced pulmonary fibrosis (RIPF), comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical kit comprises compound 1 or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical kit comprises compound 2 or a pharmaceutically acceptable salt thereof.
Pharmaceutical compositions containing the active compounds of the present disclosure may be manufactured in a well-known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Of course, the appropriate formulation will depend on the route of administration chosen.
Pharmaceutical 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 dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM(BASF, Parsippany, n.j.) or Phosphate Buffered Saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be resistant to contamination by 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. For example, 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. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol in the composition, and sodium chloride. 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 the appropriate solvent with one or more of the ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. For the preparation of sterile powders for injectable solutions, the methods of preparation are vacuum drying and freeze-drying, which are powders of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compounds can be mixed with excipients and used in the form of tablets, dragees or capsules. Oral compositions can also be prepared for use as mouthwashes using a fluid carrier, wherein the compound in the fluid carrier is administered orally and rinsed and expectorated or swallowed. Pharmaceutically compatible binding agents and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of similar properties: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; excipient such as starch or lactose, and disintegrating agent such as alginic acid, primary gel, and corn starch; lubricants, such as magnesium stearate or steroids; glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such 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. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as is well known in the art.
The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. These materials are also commercially available 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 the person skilled in the art, for example as described in patent US4,522,811.
It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms disclosed herein is dictated by and directly dependent upon the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
In therapeutic applications, the dosage of a pharmaceutical composition used in accordance with the present disclosure will depend on the agent, age, weight, and clinical condition of the patient to be treated, the experience and judgment of the clinician or practitioner administering the treatment, and other factors affecting the selected dosage. In general, the dose should be sufficient to result in a reduction in the symptoms of the disease, preferably a regression of the symptoms, and also preferably a complete regression of the disease.
It will be appreciated that the pharmaceutical composition may be contained in a container, package or dispenser together with instructions for administration of the drug.
Definition of
As used herein, the term "about" is meant to encompass a range of any normal fluctuation as understood by one of ordinary skill in the relevant art. In some embodiments, the term "about" refers to a range that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referenced value in either direction (greater or less) unless otherwise stated or apparent from the context (unless such number exceeds 100% of the possible value). 13338693199
As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the presently disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. 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. For example, such conventional non-toxic salts include, but are not limited to, those derived from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1, 2-ethanesulfonic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, glycolarylaniline, hexylresorcinol, carbamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isoethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthoic acid, nitric acid, oxalic acid, benzoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfuric acid, tannin, tartaric acid, and mixtures thereof, Toluene sulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, arginine, and the like. Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic 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] -dec-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The invention also includes salts formed when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. In salt forms, it is understood that the ratio of compound to cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1: 3. It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same salts as defined herein.
It will be understood that the compounds described herein include the compounds themselves, as well as their pharmaceutically acceptable salts and their solvates, if applicable. For example, a pharmaceutically acceptable salt may be formed between a pharmaceutically acceptable anion and a positively charged group (e.g., amino group) 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, naphthenate, phthalate, and acetate (e.g., trifluoroacetate).
As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, salts can also be formed between cations and negatively charged groups (e.g., carboxylate salts) on substituted benzene compounds. Suitable cations include sodium, potassium, magnesium, calcium and ammonium cations such as tetramethylammonium. Substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
It is to be understood that the presently disclosed compounds, e.g., salts of the compounds, may exist in either hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include the monohydrate and the dihydrate. Non-limiting examples of solvates include ethanol solvates and acetone solvates.
As used herein, the expressions "one or more of A, B or C", "one or more of A, B or C", "one or more of A, B and C", "one or more of A, B and C", "selected from A, B and C", "selected from A, B and C", and the like, are used interchangeably and refer to a group selected from A, B and/or C, i.e., one or more a, one or more B, one or more C, or any combination thereof, unless otherwise specified.
It is to be understood that throughout the specification, where a composition is described as having, including, or comprising a particular component, it is contemplated that the composition also consists essentially of, or consists of, that component. Similarly, where a method or process is described as having, including, or comprising specific process steps, the process also consists essentially of, or consists of, the recited process steps. Further, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the invention remains operable. Further, two or more steps or actions may be performed simultaneously.
It is to be understood that the compounds disclosed herein can be prepared in a variety of ways using standard synthetic methods and procedures known to those skilled in the art, using commercially available starting materials, compounds known in the literature, or intermediates readily prepared, or as would be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations are available from the relevant scientific literature or standard textbooks in the field. Although not limited to any one or several sources, classical texts such as Smith, M.B., March, J., March's Advanced Organic Chemistry: Reactions, mechanics, and Structure,5, incorporated herein by referenceth edition,John Wiley&Sons:New York,2001；Greene,T.W.,Wuts,P.G.M.,Protective Groups in Organic Synthesis,3rd edition,John Wiley&Sons:New York,1999；R.Larock,Comprehensive Organic Transformations,VCH Publishers(1989)；L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and Sons(1994)；and L.Patquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and recognized Organic synthetic reference texts known to those skilled in the art.
As used herein, the term "subject" is interchangeable with the term "subject in need thereof, both referring to a subject having a disease or having an increased risk of developing the disease. "subject" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In some embodiments, the mammal is a human.
As used herein, the term "treating" or "treatment" describes the management and care of a patient for the purpose of combating a disease, disorder or condition and includes the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate a symptom or complication of a disease, disorder or condition, or to eliminate a disease, disorder or disease disorder. The term "treatment" may also include treatment of cells or animal models in vitro.
It will be appreciated that the compounds disclosed herein, or pharmaceutically acceptable salts, polymorphs or solvates thereof, may or may also be useful in the prevention of related diseases, conditions or disease disorders, or in the identification of suitable candidates for such purposes.
As used herein, the terms "preventing", "preventing" or "prevention" describe reducing or eliminating the onset of symptoms or complications of such diseases, conditions or disease disorders.
As used herein, the term "pharmaceutical composition" is a formulation containing a compound of the present invention in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is in any of a variety of forms including, for example, capsules, iv bags, tablets, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is an effective amount and varies with the particular treatment involved. Those skilled in the art will appreciate that routine variations in dosage are sometimes required depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the disclosed compounds include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants which may be required.
As used herein, 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, other problem, or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and biologically or otherwise non-adverse, including excipients that are useful for veterinary and human use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes one or more than one such excipient.
As used herein, the term "pharmaceutically effective amount" refers to an amount of an agent that is useful for treating, ameliorating, or preventing an identified disease or disorder, or that exhibits a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount for a subject will depend upon the weight, size and health of the subject, the nature and extent of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The pharmaceutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.
It is to be understood that all such forms are also included within the scope of the claimed disclosure for the disclosed compounds to be capable of further forming salts.
As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present disclosure, wherein the parent compound is modified by making acid or base salts thereof. In some embodiments, a pharmaceutically acceptable salt of a compound is also a prodrug of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. 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. For example, such conventional non-toxic salts include, but are not limited to, those derived from a compound selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1, 2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolarylaniline, hexylresorcinol, carbamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isoethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthoic acid, nitric acid, oxalic acid, benzoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfuric acid, tannin, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, arginine, and the like.
Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic 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] -dec-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, muconic acid, and the like. The invention also includes salts formed when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. In salt forms, it is understood that the ratio of compound to cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1: 3.
It will be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same salt as defined herein.
As used herein, the term "prodrug" refers to any agent that is converted, in whole or in part, to a targeting compound when administered to a mammal. In some embodiments, a prodrug of a compound is also a pharmaceutically acceptable salt of the compound.
It is to be understood that the compounds disclosed herein may also be prepared as esters, e.g., pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, such as a methyl, ethyl, or other ester. In addition, the alcohol groups in the compounds can be converted to their corresponding esters, such as acetates, propionates or other esters.
The compound or pharmaceutically acceptable salt thereof is administered orally, nasally, transdermally, pulmonarily, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of a particular route of administration.
The dosage regimen for the compound is selected in accordance with a variety of factors, including the 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 formulation and administration techniques of the compounds disclosed in the present invention may be found in Remington, the Science and Practice of Pharmacy,19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in pharmaceutical formulations 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 compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.
All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will be apparent from the various examples. The examples provided illustrate the different components and methods that can be used to practice the present disclosure. The examples do not limit the scope of the claims. Based on the present disclosure, the skilled artisan can identify and employ other components and methods useful in practicing the present disclosure.
All publications and patent documents cited herein are incorporated by reference to the same extent as if each individual publication or document were specifically and individually indicated to be incorporated by reference. Citation of publications and patent documents is not intended as an admission that they are pertinent prior art, nor does it constitute any admission as to the contents or date thereof. The present invention has now been described by way of written description, those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and the following examples are intended to be illustrative and not limiting of the claims.
Examples
Example 1 study of compound 1 and compound 2 in a mouse model of idiopathic pulmonary fibrosis.
A mouse model of idiopathic pulmonary fibrosis. All animal experiments were obtained from shanghai wisdom chemical research limited (shanghai, china). Male C57BL/6 mice (6-8 weeks old, 18-20g) were randomized into the following 4 groups: (1) untreated group, (2) model + solvent group, (3) compound 1 group, and (4) compound 2 group. The mice in the initial treatment group were administered 50mL of 0.9% physiological saline by intratracheal instillation, and were not treated until sacrificed. The remaining 3 groups of mice were instilled intratracheally with 50 μ L of bleomycin at a dose of 1 unit/kg, and then solvent (model-solvent group, iv, biw _ D1/4 × 3w), compound 1(50mg/kg, iv, biw _ D1/4 × 3w) or compound 2(10mg/kg, ip, qd × 3w) was administered from the day of bleomycin challenge. The 22 nd Gastrodia elata was drunken to kill the mice.
The body weight and survival rate of the mice were recorded daily. As shown in fig. 1A and 1B, intratracheal bleomycin instillation resulted in sustained weight loss and death in mice. The average body weight of the mice decreased from 23.3 + -0.3 g before the bleomycin challenge to 18.8 + -1.4 g at the end of the study, and the survival rate was 80%. On the other hand, no significant weight loss was observed in mice treated with compound 1 and compound 2, with survival rates at the end of the study of 100% and 90%.
Histopathology. The left lung of mice was fixed with 10% neutral buffered formalin for 48 hours at room temperature, then paraffin embedded and cut into 4 μm sections. After deparaffinization, lung sections were stained with hematoxylin and eosin (H & E) and Masson trichrome. Tissue inflammation was assessed by the extent of inflammatory cell infiltration using H & E stained specimens (0 for no visible lesions, 1 for minimal, 2 for mild, 3 for moderate, 4 for significant). Masson trichrome stained specimens were evaluated for fibrosis according to the eight-layer, modified Ashcroft scale. All evaluations were performed blindly.
As shown in fig. 2A and 2B, intratracheal infusion of bleomycin caused severe pulmonary fibrosis and inflammation, as represented by pathological scores of 6.5 ± 0.1 and 3.7 ± 0.2, respectively. The non-dosed group C57BL/6 mice showed no signs of pulmonary fibrosis and inflammation. Compound 1 and compound 2 administration significantly reduced the pathological score for fibrosis and inflammation. 50mg/kg compound 1 reduced fibrosis and inflammation scores to 4.1 ± 0.2 and 1.5 ± 0.2, respectively (p <0.0001 compared to model-solvent group); compound 2 at 10mg/kg reduced the fibrosis and inflammation scores to 5.6 ± 0.2(p <0.01, compared to the model-solvent group) and 2.2 ± 0.1(p <0.0001, compared to the model-solvent group), respectively.
And (4) testing collagen. A portion of the right lung was used for collagen determination. Harvested lung tissue was added 6M HCl at a ratio of 1:10(mg tissue: μ L6M HCl) and incubated in a calibrated oven at 95 ℃ for 20 hours. After cooling back to room temperature, the sample was centrifuged at 13,000g for 10 minutes. The obtained supernatant was appropriately diluted and subjected to collagen content measurement using a total collagen measurement kit (QuickZyme, netherlands). Data are expressed as micrograms of collagen per right lung.
As shown in figure 3, lungs from bleomycin-challenged mice showed significantly higher collagen deposition than uninfected mice (12.7 ± 1.1vs 3.0 ± 0.1 μ g/right lung, p <0.0001), indicating the formation of fibrosis. Treatment with 50mg/kg compound 1 significantly reduced collagen content to 5.6 ± 0.5 g/right lung (p <0.0001 compared to model-solvent group), which is consistent with a reduction in fibrosis score.
Staining with galactosidase activity. Frozen sections were prepared using half of the right lung. SA- β -Gal staining was performed using the Senescence β -galactosidase staining kit (Beijing Soilebao Tech., Ltd., China) according to the manufacturer's protocol. Images were taken using a Nikon Eclipse90i microscope and the number of SA- β -galactosidase positive cells (i.e., senescent cells) was counted in six random microscopic fields per sample.
As shown in fig. 4, intratracheal instillation of bleomycin resulted in a significant increase in the number of senescent cells in the lungs of mice (p <0.0001 compared to the non-dosed group), reaching 10.4 ± 1.2 per field. The 50mg/kg compound 1 and 10mg/kg compound 2 administration groups significantly reduced the number of senescent cells, 6.2 ± 0.6(p <0.01, compared to the model-solvent group) and 3.9 ± 0.6(p <0.0001, compared to the model-solvent group)/visual field, respectively.
Gene expression analysis was performed by quantitative RT-PCR. Total RNA was extracted from the right lung fraction using RNeasy mini kit (Qiagen CA, USA) according to the manufacturer's instructions. After quantification by NanoDrop 2000, the extracted RNA was reverse transcribed using a large capacity cDNA reverse transcription kit (Applied Biosystems, CA, USA). ViiA was used according to the instructions of "ABI Taqman Gene expression Master mixture protocolTMThe 7 real-time PCR system (Applied Biosystems, Calif., USA) performed qPCR. Hprt mRNA was used as a housekeeping gene, and the amount was determined by the Δ Δ Ct method. Transcript levels of the SASP-associated genes were normalized to Hprt mRNA. All Taqman probes were purchased from Applied Biosystems (CA, USA). The transcript levels of BCL-2 and BCL-xL genes that may contribute to the survival of senescent cells were also determined using quantitative RT-PCR, where the GAPDH gene was used as a housekeeping agentA gene.
As shown in fig. 5, mRNA levels of the aging marker p16 in the mouse lungs were significantly increased after bleomycin challenge (p <0.0001) compared to the non-administered group of mice, indicating that cellular aging was induced in vivo. Consistent with the reduction of SA- β -Gal positive cells, mRNA levels of the p16 gene were also significantly reduced after compound 1 treatment (p <0.0001 compared to the model-solvent set).
As shown in fig. 6A and 6B, bleomycin stimulated the mRNA level of BCL-xL gene in the lung of mice 1.8-fold higher than that of the non-dosed group of mice, suggesting that survival of cells in the lung of idiopathic pulmonary fibrosis mice was dependent on BCL-xL, consistent with the therapeutic efficacy of BCL-xL inhibitors, e.g., compound 1 and compound 2 in this mouse model of idiopathic pulmonary fibrosis.
Figure 7 shows the changes in the transcriptional levels of SASP-associated genes in the lungs of idiopathic pulmonary fibrosis mice treated with compound 1 and compound 2. Proinflammatory (Mcp1, Mmp10 and Il-6) and profibrotic (Pai-1, Il-11 and Tgfb) SASP factors were significantly increased in mRNA levels after bleomycin challenge, but significantly decreased after treatment with Compound 1 and Compound 2. These results are consistent with a reduced level of lung senescence (reduced number of SA- β -galactosidase positive cells and reduced p16 gene mRNA levels) and overall efficacy of fibrosis (reduced collagen content in the lung and reduced fibrosis score).
And (4) immunohistochemistry. Lungs of mice were fixed with 10% neutral buffered formalin solution for 48 hours at room temperature, embedded in paraffin, and sectioned to 4 μm. Lung sections were deparaffinized and then IHC stained to detect BCL-2 and BCL-xL protein expression in mouse lungs. Three representative regions were selected from each slide and then analyzed by ImageJ software to obtain the percentage of positively stained regions.
As shown in fig. 8A and 8B, BCL-2 protein expression in the lungs of mice was slightly increased after bleomycin challenge compared to untreated mice (p >0.05, t-test). On the other hand, the expression level of BCL-xL protein in the lung of mice was significantly increased after bleomycin challenge compared to untreated mice (p <0.05, t-test).
Example 2 study of compound 1 and compound 2 in a mouse model of radiation-induced pulmonary fibrosis.
Radiation-induced pulmonary fibrosis mouse model. All animal experiments were approved by the institutional animal care and use committee of the Beijing cooperative medical college and the institute of radiology, the Chinese medical academy of sciences. Male C57BL/6 mice (23-25g) were randomly divided into the following four groups: (1) untreated group, (2) model + solvent group, (3) compound 1 group, and (4) compound 2 group. Untreated groups of mice were untreated prior to sacrifice. The remaining three groups of mice received a single dose of 17Gy radiation in the right chest for 16 weeks after irradiation, and the mice received solvent (model-solvent group, iv, biw _ D1/4 × 3w), compound 1(50mg/kg, iv, biw _ D1/4 × 3w) or compound 2(10mg/kg, ip, qd × 3w) for 6 weeks.
As shown in figure 9, all mice in the non-irradiated group survived, irradiation caused death of the animals during the experiment, and survival rate at the end of the study was 70%. Treatment with compound 1 and compound 2 increased survival of mice to 100% and 90%, indicating their efficacy in radiation-induced pulmonary fibrosis. Lung tissue was collected and imaged after sacrifice of the mice. As shown in figure 10, the lungs were significantly enlarged after irradiation, possibly due to inflammation and fibrosis, and treatment with compound 1 and compound 2 reduced the lungs to nearly normal levels, indicating improved inflammation and fibrosis.
Histopathology. The left lung of mice was fixed with 10% neutral buffered formalin for 48 hours at room temperature, then paraffin embedded and cut into 4 μm sections. After deparaffinization, lung sections were stained with hematoxylin and eosin (H & E) and Masson trichrome. Tissue inflammation was assessed by the extent of inflammatory cell infiltration using H & E stained specimens (0 for no visible lesions, 1 for minimal, 2 for mild, 3 for moderate, 4 for significant). Masson trichrome stained specimens were evaluated for fibrosis according to the eight-layer, modified Ashcroft scale. All evaluations were performed blindly.
Staining with galactosidase activity. Frozen sections were prepared using half of the right lung. SA- β -Gal staining was performed using the Senescence β -galactosidase staining kit (Beijing Soilebao Tech., Ltd., China) according to the manufacturer's protocol. Images were taken using a Nikon Eclipse90i microscope and the number of SA- β -galactosidase positive cells (i.e., senescent cells) was counted in six random microscopic fields per sample.
As shown in fig. 11, chest irradiation resulted in a significant increase in the number of senescent cells in the mouse lung compared to the untreated group (44.0 ± 4.7vs 8.7 ± 2.1, p < 0.0001). Treatment with 50mg/kg compound 1 and 10mg/kg compound 2 reduced the number of senescent cells to 42.9 + -2.5 and 32.4 + -2.6, respectively. Significant differences were observed for compound 2 group (p <0.05, vs model-solvent group), suggesting that clearance of senescent cells may be responsible for the efficacy of radiation-induced pulmonary fibrosis.
Equivalents of the same
It should be understood that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims (50)

1. A method of treating or preventing a pulmonary disease in a subject, comprising administering to the subject a pharmaceutically effective amount of compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
2. Compound 1, compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing a pulmonary disorder in a subject.
3. Use of compound 1, compound 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a pulmonary disease in a subject.
4. A method of treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject, comprising administering to the subject a pharmaceutically effective amount of compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
5. Compound 1, compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
6. Use of compound 1, compound 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing Idiopathic Pulmonary Fibrosis (IPF) in a subject.
7. 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 1, compound 2, or a pharmaceutically acceptable salt thereof.
8. Compound 1, compound 2, or a pharmaceutically acceptable salt thereof, for use in treating or preventing radiation-induced pulmonary fibrosis (RIPF) in a subject.
9. Use of compound 1, compound 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.
10. A pharmaceutical composition for treating or preventing a pulmonary disease, comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition for treating or preventing Idiopathic Pulmonary Fibrosis (IPF), comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition for treating or preventing radiation-induced pulmonary fibrosis (RIPF), comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical kit for treating or preventing a pulmonary disease, comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical kit for treating or preventing Idiopathic Pulmonary Fibrosis (IPF), comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical kit for treating or preventing radiation-induced pulmonary fibrosis (RIPF), comprising compound 1, compound 2, or a pharmaceutically acceptable salt thereof.
16. The method, compound, use, pharmaceutical composition or pharmaceutical kit of any one of the preceding claims, wherein the subject is a mammal.
17. The method, compound, use, pharmaceutical composition or pharmaceutical kit of any one of the preceding claims, wherein the subject is a human.
18. The method, compound, use, pharmaceutical composition or pharmaceutical kit of any one of the preceding claims, wherein the lung disease is Idiopathic Pulmonary Fibrosis (IPF).
19. The method, compound, use, pharmaceutical composition or pharmaceutical kit of any preceding claim, wherein the lung disease is radiation-induced pulmonary fibrosis (RIPF).
20. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered by enteral administration.
21. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally.
22. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered by parenteral administration.
23. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered by intravenous administration.
24. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered by intratracheal instillation.
25. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once daily.
26. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily.
27. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered 3 or more times per day.
28. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once weekly.
29. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered twice weekly.
30. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered 3 or more times per week.
31. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered for about 3 weeks.
32. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered twice weekly for about three weeks.
33. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once daily for about three weeks.
34. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered by enteral administration.
35. The method, compound, use, pharmaceutical composition or kit of any one of the preceding claims, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered orally.
36. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered by parenteral administration.
37. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered by intravenous administration.
38. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered by intratracheal instillation.
39. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered once daily.
40. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily.
41. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered 3 or more times per day.
42. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered once per week.
43. The method, compound, use, pharmaceutical composition or pharmaceutical kit of any one of the preceding claims, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered twice weekly.
44. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein Compound 2, or a pharmaceutically acceptable salt thereof, is administered 3 or more times per week.
45. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered within one or more drug holidays.
46. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered without any drug holiday.
47. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered for about 1 week, about 2 weeks, or about 3 weeks.
48. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered for about 3 weeks.
49. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered twice weekly for three weeks.
50. The method, compound, use, pharmaceutical composition or kit of any preceding claim, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered once daily for about 3 weeks.
CN202110872658.1A 2020-07-31 2021-07-30 Compositions and methods for treatment of pulmonary diseases Pending CN114053288A (en)

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Cited By (1)

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CN110960537A (en) * 2018-07-31 2020-04-07 苏州亚盛药业有限公司 Combination of Bcl-2/Bcl-xL inhibitor and chemotherapeutic drug and application thereof

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WO2019033122A1 (en) * 2017-08-11 2019-02-14 Unity Biotechnology, Inc. Treatment of lung diseases using pharmaceutical agents that eliminate senescent cells
CN110960537A (en) * 2018-07-31 2020-04-07 苏州亚盛药业有限公司 Combination of Bcl-2/Bcl-xL inhibitor and chemotherapeutic drug and application thereof

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