WO2021260560A1 - Composition pour le traitement de la fibrose pulmonaire - Google Patents

Composition pour le traitement de la fibrose pulmonaire Download PDF

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Publication number
WO2021260560A1
WO2021260560A1 PCT/IB2021/055521 IB2021055521W WO2021260560A1 WO 2021260560 A1 WO2021260560 A1 WO 2021260560A1 IB 2021055521 W IB2021055521 W IB 2021055521W WO 2021260560 A1 WO2021260560 A1 WO 2021260560A1
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WO
WIPO (PCT)
Prior art keywords
pulmonary fibrosis
formula
group
compound
composition
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PCT/IB2021/055521
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English (en)
Korean (ko)
Inventor
윤치호
김민경
Original Assignee
제이더블유중외제약 주식회사
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Priority to KR1020237002576A priority Critical patent/KR20230031304A/ko
Publication of WO2021260560A1 publication Critical patent/WO2021260560A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to pulmonary fibrosis (Pulmonary Fibrosis), particularly for pulmonary fibrosis caused by Idiopathic Pulmonary Fibrosis (IPF) and/or coronavirus infection-19. It relates to a therapeutic composition comprising a compound having a high therapeutic effect. Background air pulmonary fibrosis proceeds from interstitial lung inflammation caused by various causes, and idiopathic pulmonary fibrosis (IPF) of unknown cause is the most frequent form, and the average survival period after diagnosis is within 2-3 years. It is an intractable lung disease with no effective treatment to such an extent that the 5-year survival rate is only 20%.
  • lung inflammatory response and unregulated immune mechanism abnormal signal transduction system in alveolar epithelial cells, suppression of fibrinolytic activity due to epithelial cell damage, activation of fibroblasts in lung interstitium, mesenchymal transformation of epithelial cells, endothelium Cell-derived fibroblast differentiation, influx of inactive blood fibroblasts into the lungs, and cell transformation such as differentiation into fibroblasts are important factors in lung fibrosis as a mechanism of myofibroblast differentiation and proliferation.
  • TGF-P As a factor related to lung fibrosis, TGF-P is best known, and it is known to induce fibrosis by activating AKT/mTOR, SMAD, ffnt/p-catenin, and YAP/TAZ signaling systems.
  • oxidative stress which increases simultaneously with the activation of the signal transduction system, plays an important role, and microRNAs that increase or inhibit post-transcriptional expression of fibrosis regulators or intermediate mediators, DNA methyl at ion, PDGF growth factor and IL -4 is known as a major factor involved in fibrosis.
  • SARS-Cov-2 severe acute respiratory syndrome coronavirus
  • An object of the present invention is to provide a composition for treating pulmonary fibrosis or a pharmaceutical formulation comprising the same.
  • Another object of the present invention is to provide a method for treating pulmonary fibrosis comprising administering the composition for treating pulmonary fibrosis or a pharmaceutical formulation comprising the same to an individual in need of pulmonary fibrosis treatment.
  • the present invention provides a pharmaceutical composition for treating pulmonary fibrosis comprising a compound having the structure of Formula I, a prodrug thereof, a salt thereof, or an isomer thereof.
  • 3 ⁇ 4 is an alkyl group of 6 or an alkenyl group of 0 2 6
  • prodrug of the compound of formula (I) according to the present invention has the structure of formula (III).
  • the prodrug of the compound of formula (I) according to the present invention, formula (III), may have the structure of formula (IV) to formula (VI), but is not limited thereto 2021/260560 ? €1/162021/055521 is not.
  • the compound having the structures of Formulas I to VI according to the present invention may be prepared by the method described in Korean Patent No. 1,692,921, but is not limited thereto.
  • the present invention also relates to pharmaceutically acceptable salts of compounds of formulas (I) to (VI).
  • Non-limiting examples of the pharmaceutically acceptable salts of the compounds of Formulas I to VI include hydrochloric acid, ]3-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, horse rate, 2021/260560 €1/162021/055521 di-!-toluyl salts of tartaric acid, ortinic acid, edicylic acid, hemi-edicylic acid and mandelic acid may be exemplified, but not limited thereto.
  • the therapeutic composition comprising the compounds of formulas (I) to (VI) according to the present invention may include one or more pharmaceutically acceptable carriers.
  • the therapeutic composition according to the present invention may be administered orally or parenterally, and parenteral administration is intranasal, intranasal, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous , It may be prepared in a formulation suitable for intraperitoneal, intestinal, topical, sublingual or rectal dosage forms and administered by the above route, but is not limited thereto. Accordingly, the present invention provides a pharmaceutical formulation for oral or parenteral administration comprising the therapeutic composition according to the present invention.
  • the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same may be administered orally, or may be administered intranasally or intranasally, especially in the form of a spray (large) or aerosol (large) when administered intranasally or intranasally administration of It is more preferable to be formulated and administered in a dosage form for administration, but is not limited thereto.
  • the pharmaceutical formulation for intranasal or intranasal administration may be prepared according to techniques well known in the art to which the present invention pertains, and benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, fluorocarbons and/or others It can be prepared as a solution in saline using solubilizing or dispersing agents known in the art.
  • the therapeutic composition according to the present invention may be formulated in a sterile injectable formulation as a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents.
  • Sterile injectable formulations are also non-toxic It may be a sterile injectable solution or suspension in a parenterally acceptable diluent or solvent (eg, a solution in 1,3-butanediol).
  • a parenterally acceptable diluent or solvent eg, a solution in 1,3-butanediol.
  • pharmaceutically acceptable vehicles and solvents include mannitol, water, Ringel's solution, and isotonic sodium chloride solution.
  • sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile oil with less irritation may be used, including synthetic mono or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are pharmaceutically acceptable natural oils (eg, olive oil or castor oil), especially polyoxyethylated ones thereof, and are useful in injection preparations.
  • the therapeutic composition according to the present invention is not limited thereto, but may be formulated in any orally acceptable pharmaceutical dosage form, including capsules, pellets, tablets, aqueous suspensions and solutions, and administered orally.
  • excipients When formulated for oral administration, it may be formulated to include one or more pharmaceutically acceptable excipients in the therapeutic composition according to the present invention, and such excipients include a filler (diluent), disintegrant, binder, lubricant (Lubricant), preservatives, antioxidants, buffers, chelating agents, solubilizers and at least one selected from the group consisting of a sweetener may be used.
  • the filler (diluent) is mannitol, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, Microcrystalline cellulose (microcrystal 1 ine cel lulose), microcrystalline silicified cellulose (microcrystal 1 ine si l ici fied cel lulose), powdered cellulose, dextrates, dextrose, fructose ( fructose), lactitol (lact itol), lactose anhydrous (lactose anhydrous) , lactose monohydrate ( lactose monohydrate) , lactose dihydrate ( lactose dihydrate) , lactose trihydrate , mannitol sorbitol , starch , pregelat inized starch , sucrose , talc , xylitol , maltose maltose Lin (maltose maltodextr in
  • the pharmaceutical formulation for oral administration according to the present invention is preferably a capsule, pellet or tablet, but is not limited thereto, and the tablet is more preferably a film-coated tablet including a film coating layer.
  • the film coating layer is selected from the group consisting of polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, methacrylic acid copolymer, polyethylene oxide and xanthan gum.
  • the film coating layer is polyvinyl alcohol, a copolymer of polyvinyl alcohol and polyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, meta It may include one or more film coating bases selected from the group consisting of acrylic acid copolymer, polyethylene oxide and xanthan gum, but is not limited thereto.
  • the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same can be used for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19.
  • the present invention uses the therapeutic composition according to the present invention or a pharmaceutical formulation comprising the same for the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19, and It relates to a method of treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis and/or pulmonary fibrosis caused by coronavirus infection-19, characterized in that the pharmaceutical formulation according to the present invention is administered to a patient in need of the treatment.
  • FIG. 1 is a view showing the overall experimental conditions according to the present invention.
  • FIG. 2 is a view showing changes in inflammatory cells in a mouse model of Bleomycin-induced pulmonary fibrosis following administration of a compound of Formula II according to the present invention and pirfenidone, a control drug.
  • FIG. 3 is a view showing changes in inflammation-related cytokines in a mouse model of Bleomycin-induced pulmonary fibrosis following administration of the compound of Formula II according to the present invention.
  • TGF Tissue Growth Factor
  • FIG. 4 is an ashcroe in a mouse model of Bleomycin-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention. It is a drawing showing the score (Ashcroft Score). 5 is a view showing changes in total collagen in the lungs of a mouse model of Bleomycin-induced pulmonary fibrosis according to administration of a compound of Formula II according to the present invention. 6 is a view showing changes in alveolar surface area, alveolar bronchus and perivascular wall thickness in a mouse model of bleomycin vs. 1601 ⁇ (: ⁇ )-induced pulmonary fibrosis according to the administration of the compound of Formula II according to the present invention. (A) Alveolar surface area
  • Lung fibrosis was induced in mice by intratracheal injection of 3 mg/kg bleomycin under isof lurane saw lip anesthesia (Matrix, Orchard Park, NY, USA).
  • pirfenidone 200 mg/kg/bid, po, 2% DMSO, 0.5% CMC
  • B291 in all the drawings means a compound of Formula II, and the numbers 0.1, 1.0 and 5.0 after B291 mean that the dosage of the compound of Formula II is 0.1 mg/kg, 1.0 mg/kg and 5.0 mg/kg, respectively. do.
  • BPFD is pirfenidone (pirfenidone)
  • pirfenidone is a normal control group (sa ine-inst i 1 led mice administered with drug vehicle, SAL + VEH) administered drug vehicle to the saline (saline) treated experimental animals
  • BV refers to the pulmonary fibrosis group administered with drug vehicle to bleomycin-treated animals (bleomycin-inst il led mice administered with drug vehicle, BLM+VEH).
  • the test group for the effect of the compound of formula II is a 6-species group, a normal control group (saline-inst i 1 led mice administered with drug vehicle, SAL+VEH), a lung fibrosis group (bleomycin) -inst il led mice administered with drug vehicle, BLM+VEH), 3 groups (0.1 mg/kg, 1.0 mg/kg and 5.0 mg/kg) administered with a compound of Formula II at 0.1 mg/kg in a mouse model of bleomycin-induced pulmonary fibrosis ), and a group administered with 200.0 mg/kg of pirfenidone as a drug control group in a mouse model of bleomycin-induced lung fibrosis (see Table 1).
  • Example 2 Inflammatory cell change After sacrificing the mouse according to Example 1, the chest cavity was opened so that the lungs could be sufficiently expanded, the trachea was incised, and 1 mi PBS was slowly injected into the lungs through a tube inserted into the airway, and this was recovered. to 4 (the bronchial lavage fluid..., and stored in the bronchoalveolar lavage fluid were used to using the (Chemometec, Gydevang, Denmark NucleoCounter) measuring the total number of inflammatory cells, in PBS the cells precipitated after centrifugation It was resuspended and spread on slides with cytospin (Thermo Electron, Waltham, MA, USA) and used for differentiation of inflammatory cells.
  • cytospin Thermo Electron, Waltham, MA, USA
  • the total number of inflammatory cells was significantly reduced, and the number of macrophages, lymphocytes and neutrophils also decreased.
  • the pirfenidone drug control group there was no change in the increase in the total number of inflammatory cells along with the increase in macrophages, and the number of lymphocytes and neutrophils showed a tendency to decrease.
  • a significant decrease in the total number of inflammatory cells was confirmed with a decrease in macrophages in a dose-related manner in the groups administered with the compound of Formula II at 0.1 mg/kg and 1.0 mg/kg.
  • Example 3 Inflammatory cytokine change After extracting and electrophoresis-separated proteins from mouse lung tissue, the expression of TGF-p, TNF-a, IL-lp and IL-17 was confirmed by Western blotting and quantitatively analyzed. The significantly increased expression of TGF-IL-17, TNF-a and IL-1 ⁇ proteins in the bleomycin-induced pulmonary fibrosis reaction was decreased in the group administered with the compound of Formula II.
  • IL-ip was significantly decreased in the group administered with the compound of formula II at 1.0 mg/kg and 5.0 mg/kg, and the expression of TGF- and IL-17 was maximally reduced in the group administered with the compound of formula II at 1.0 mg/kg.
  • TNF-a showed a significant decrease in the 5.0 mg/kg administration group, there is a difference in pro-inflammatory protein expression according to the administration dose.
  • the increase in IL-17 in the lungs tended to decrease in all drug administration groups, but there was no statistical significance.
  • the pirfenidone drug control group had no effect on increasing the expression of TGF-y ⁇ and IL-17, and showed a tendency to decrease the protein expression of TNF-a and IL-1 y ⁇ .
  • both TGF-/37 ⁇ were significantly reduced in the group administered with the compound of Formula II, and the reduction of IL-17 in the previous administration group, TNF-a reduction and 1.0 mg at the same level in the 5.0 mg/kg administration group
  • TNF-a reduction and 1.0 mg at the same level in the 5.0 mg/kg administration group There was a decrease in IL-1 in the /kg and 5.0 mg/kg administration groups.
  • Example 4 Example 4.
  • a mouse lung tissue slide was prepared and the degree of tissue change was observed by staining with Hemetoxylin & eosin (H&E), and the degree of inflammation was measured and quantified in the stained tissue.
  • H&E Hemetoxylin & eosin
  • the concentration of collagen extracted from mouse lung tissue was quantified by Sircol assay to analyze the deposited amount.
  • the Ashcroft Score a quantitative indicator for the severity of pulmonary fibrosis, was decreased by administration of the compound of Formula II (see FIG. 4 , the plot is the mean ⁇ standard error of 6 mouse groups, # is ⁇ C0.05, ## means ⁇ C0.01, and ⁇ means ⁇ C0.001) .
  • Collagen deposition amount was reduced to a level equivalent to that of the drug control group, or the statistical significance level of the decrease was high in the 5.0 mg/kg administration group (see FIG. 5 , the plot is the mean ⁇ standard error of 6 mouse groups, # is ⁇ C0.05, ## means three 01, and ⁇ means ⁇ C0.0()1) .
  • the decrease in the alveolar surface area, the thickening of the alveolar wall, the bronchial wall, and the blood vessel wall were alleviated (see FIGS. 6(A) to 6(D), the plot shows that of the six mouse groups 2021/260560 ? €1/162021/055521 mean ⁇ standard error, # means ⁇ 0.05, ## means ⁇ 0.01, and ⁇ means ⁇ 0.001).
  • the compounds of Formulas I to VI according to the present invention can achieve excellent effects in treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, or pulmonary fibrosis caused by coronavirus infection-19.
  • pulmonary fibrosis particularly idiopathic pulmonary fibrosis, or pulmonary fibrosis caused by coronavirus infection-19.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition thérapeutique, comprenant un composé présentant une excellente efficacité thérapeutique contre la fibrose pulmonaire, en particulier la fibrose pulmonaire idiopathique (IPF) ou la fibrose pulmonaire provoquée par une infection à coronavirus (covid-19).
PCT/IB2021/055521 2020-06-26 2021-06-23 Composition pour le traitement de la fibrose pulmonaire WO2021260560A1 (fr)

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KR1020237002576A KR20230031304A (ko) 2020-06-26 2021-06-23 폐섬유화증 치료용 조성물

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KR10-2020-0078130 2020-06-26
KR1020200078130A KR20220000460A (ko) 2020-06-26 2020-06-26 폐섬유화증 치료용 조성물

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010044485A1 (fr) * 2008-10-14 2010-04-22 Prism Biolab Corporation Mimétiques d'hélice alpha dans le traitement du cancer
WO2012050393A2 (fr) * 2010-10-14 2012-04-19 제이더블유중외제약 주식회사 Nouveau composé à mimétique inverse, procédé de production, et utilisation de ce composé
US20160166577A1 (en) * 2012-10-19 2016-06-16 Prism Pharma Co., Ltd. Treatment of pulmonary fibrosis using an inhibitor of cbp/catenin
US20160303137A1 (en) * 2015-04-20 2016-10-20 Indiana University Research And Technology Corporation Dual pi3k and wnt pathway inhibition as a treatment for cancer
WO2017184808A1 (fr) * 2016-04-20 2017-10-26 University Of Southern California Composés et procédés pour augmenter l'hématopoïèse

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102459271B (zh) 2009-04-15 2014-07-02 Jw制药公司 回折模拟物的新化合物及其制备方法和用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010044485A1 (fr) * 2008-10-14 2010-04-22 Prism Biolab Corporation Mimétiques d'hélice alpha dans le traitement du cancer
WO2012050393A2 (fr) * 2010-10-14 2012-04-19 제이더블유중외제약 주식회사 Nouveau composé à mimétique inverse, procédé de production, et utilisation de ce composé
US20160166577A1 (en) * 2012-10-19 2016-06-16 Prism Pharma Co., Ltd. Treatment of pulmonary fibrosis using an inhibitor of cbp/catenin
US20160303137A1 (en) * 2015-04-20 2016-10-20 Indiana University Research And Technology Corporation Dual pi3k and wnt pathway inhibition as a treatment for cancer
WO2017184808A1 (fr) * 2016-04-20 2017-10-26 University Of Southern California Composés et procédés pour augmenter l'hématopoïèse

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KR20230031304A (ko) 2023-03-07

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