Methods for treating pulmonary fibrosis

Abstract

A method of treating or preventing pulmonary fibrosis in a patient in need thereof by administering to said patient a FAK inhibitor defined by Formula I, or a pharmaceutically acceptable derivative thereof. In a second embodiment, there is provided a FAK inhibitor defined by Formula I, or a pharmaceutically acceptable derivative thereof, for use in treating pulmonary fibrosis in a patient in need thereof. In a third embodiment, there is provided use of a FAK inhibitor defined by Formula I, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for treating or preventing pulmonary fibrosis in a patient in need thereof. TIFF2023527358000007.tif6071

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is directed to a method of treating or preventing pulmonary fibrosis (preferably, idiopathic pulmonary fibrosis or pulmonary fibrosis associated with coronavirus infection) in a patient in need thereof by administering to said patient a FAK inhibitor defined by the following Formula I, or a salt or prodrug thereof: [ka] . [Background technology]

[0002] Background of the Invention Patients with a wide range of lung disorders, including idiopathic pulmonary fibrosis (IPF), have a progressive, fibrotic clinical phenotype characterized by increasing degrees of fibrosis on high-resolution computed tomography (CT), declining lung function, worsening symptoms and quality of life, and premature death despite current treatments. Based on clinical and pathophysiological similarities among these diseases, it has been hypothesized that such disorders with progressive phenotypes, regardless of etiology, share common pathological mechanisms and, therefore, may all respond to similar treatments (1).

[0003] Idiopathic pulmonary fibrosis (IPF) is a rare, progressive disease occurring primarily in elderly people, characterized by chronic and progressive fibrosis of the pulmonary interstitium, leading to exertional shortness of breath, cough, dyspnea, and deterioration of pulmonary function (2).

[0004] As the name suggests, this disease has unknown causes and a variable clinical course, but the prognosis is exceptionally poor. An analysis of U.S. Medicare claims has shown that increasing age and male gender are associated with a higher incidence of IPF (3). Other risk factors include smoking history (4), occupational exposure (5), and certain viral infections (2). Without antifibrotic treatment, the median survival from diagnosis is nearly three years (6). Given the poor survival rate, novel treatments are needed, but IPF is notoriously resistant to pharmacological intervention.

[0005] The Genetics Home Reference estimates that approximately 30,000 to 40,000 new cases of IPF are diagnosed each year in the United States. (7) The incidence and prevalence of IPF increase significantly with age, and the population prevalence of IPF in the United States is estimated to be 130,000 cases. (1)

[0006] A decline in forced vital capacity (FVC) is a clinically prominent feature of IPF (8), and clinical studies have shown that the antifibrotic agents nintedanib and pirfenidone slow the deterioration of forced vital capacity (FVC) caused by IPF (9). Notably, nintedanib and pirfenidone are the only drugs that can slow the progression of IPF, reducing the rate of decline in lung function without reversing disease progression.

[0007] In patients with mild or moderate baseline FVC impairment, nintedanib and pirfenidone have been shown to reduce the rate of FVC decline by nearly 50% over one year of treatment (10, 11). Longer treatment with nintedanib for up to four years has also demonstrated a sustained decline in FVC deterioration (12). Despite these promising results, clinical uptake of nintedanib and pirfenidone has been slow, primarily due to their relatively modest impact on disease progression and the side effect profile of these drugs. In patients with IPF, side effects of pirfenidone include diarrhea, photosensitivity, and rash (13), while nausea and diarrhea are the most common adverse effects of nintedanib (14).

[0008] In addition to nintedanib and pirfenidone, clinical guidelines recommended comprehensive disease management (15), including pulmonary rehabilitation, symptom management, vaccinations, management of comorbidities, and supplemental oxygen (16).

[0009] Nintedanib and pirfenidone improve the management of IPF, but new treatments are needed.

[0010] Furthermore, such therapies may be useful in managing coronavirus infections, as data from previous coronavirus infections, such as severe acute respiratory syndrome and Middle East respiratory syndrome, and emerging data from the COVID-19 pandemic suggest that there may be a significant causal role for fibrosis after SARS-CoV-2 infection. Available or in developmental antifibrotic therapies may be of value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and may have a role in preventing fibrosis after SARS-CoV-2 infection (17). 1 Flaherty, K. R., ‘Nintedanib in Progressive Fibrosing Interstitial Lung Diseases’, N Engl J Med 2019;381:1718-27. 2 Martinez, F. J., et al., 'Idiopathic Pulmonary Fibrosis', Nat Rev Dis Primers, 3 (2017), 17074 3 Raghu, G., et al., 'Idiopathic Pulmonary Fibrosis in Us Medicare Beneficiaries Aged 65 Years and Older: Incidence, Prevalence, and Survival, 2001-11', Lancet Respir Med, 2 (2014), 566-72. 4 Karkkainen, M., et al., 'Effect of Smoking and Comorbidities on Survival in Idiopathic Pulmonary Fibrosis', Respir Res, 18 (2017), 160. 5 Taskar, V. S., and Coultas, D. B., 'Is Idiopathic Pulmonary Fibrosis an Environmental Disease?', Proc Am Thorac Soc, 3 (2006), 293-8. 6 Lancaster, L., et al., 'Safety and Survival Data in Patients with Idiopathic Pulmonary Fibrosis Treated with Nintedanib: Pooled Data from Six Clinical Trials', BMJ Open Respir Res, 6 (2019), e000397. 7 GeneticsHomeReference, 'Idiopathic Pulmonary Fibrosis', National Institutes of Health, (2020) <https: / / ghr.nlm.nih.gov / condition / idiopathic-pulmonary-fibrosis#statistics> [Accessed 13 Feb 2020 2020]. 8 Russell, A. M., et al., 'Daily Home Spirometry: An Effective Tool for Detecting Progression in Idiopathic Pulmonary Fibrosis', Am J Respir Crit Care Med, 194 (2016), 989-97. 9 Maher, T. M., and Strek, M. E., 'Antifibrotic Therapy for Idiopathic Pulmonary Fibrosis: Time to Treat', Respir Res, 20 (2019), 205. 10 King, T. E., Jr., et al., 'A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis', N Engl J Med, 370 (2014), 2083-92. 11 Richeldi, L., et al., 'Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis', N Engl J Med, 370 (2014), 2071-82. 12 Crestani, B., et al., 'Long-Term Safety and Tolerability of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis: Results from the Open-Label Extension Study, Inpulsis-On', Lancet Respir Med, 7 (2019), 60-68. 13 Lancaster, L. H., et al., 'Pirfenidone Safety and Adverse Event Management in Idiopathic Pulmonary Fibrosis', Eur Respir Rev, 26 (2017). 14 Kato, M., et al., 'Gastrointestinal Adverse Effects of Nintedanib and the Associated Risk Factors in Patients with Idiopathic Pulmonary Fibrosis', Sci Rep, 9 (2019), 12062. 15 van Manen, M. J., et al., 'Optimizing Quality of Life in Patients with Idiopathic Pulmonary Fibrosis', Ther Adv Respir Dis, 11 (2017), 157-69. 16 Visca, D., et al., 'Effect of Ambulatory Oxygen on Quality of Life for Patients with Fibrotic Lung Disease (Ambox): A Prospective, Open-Label, Mixed-Method, Crossover Randomised Controlled Trial', Lancet Respir Med, 6 (2018), 759-70. 17. George, P., et al., 'Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy', Lancet Respir Med (2020), https: / / doi.org / 10.1016 / S2213-2600(20)30225-3. 18. Mercer, PF, and Chambers, RC, 'Coagulation and Coagulation Signalling in Fibrosis', Biochim Biophys Acta, 1832 (2013), 1018-27. 19. Lagares, D., and Kapoor, M., 'Targeting Focal Adhesion Kinase in Fibrotic Diseases', BioDrugs, 27 (2013), 15-23.

Prior Technology Literature

Non-licensed literature

[0011] [Non-licensed document 1] 1 Flaherty, KR, 'Nintedanib in Progressive Fibrosing Interstitial Lung Diseases', N Engl J Med 2019;381:1718-27. [Non-licensed document 2] 2 Martinez, FJ, et al., 'Idiopathic Pulmonary Fibrosis', Nat Rev Dis Primers, 3 (2017), 17074 [Non-licensed document 3] 3 Raghu, G., et al., 'Idiopathic Pulmonary Fibrosis in Us Medicare Beneficiaries Aged 65 Years and Older: Incidence, Prevalence, and Survival, 2001-11', Lancet Respir Med, 2(2014), 566-72.

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[0012] Summary of the Invention The inventors have found that the FAK (focal adhesion kinase) inhibitor of formula I (which is the third example of 13 examples presented in WO2012110774) is surprisingly selective for FAK over other kinases (and therefore less likely to exhibit off-target effects associated with toxicity), and is effective in treating pulmonary fibrosis, particularly idiopathic pulmonary fibrosis.

[0013] The term "pulmonary fibrosis," as used herein, refers to any one of a wide range of lung disorders, including idiopathic pulmonary fibrosis (IPF), that have a progressive, fibrogenic clinical phenotype characterized by increasing degrees of fibrosis on high-resolution computed tomography (CT), declining lung function, worsening symptoms and quality of life, and premature death, despite current treatments.

[0014] The term "infection caused by coronavirus" includes, but is not limited to, infection caused by coronaviruses associated with Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19 (SARS-CoV-2).

[0015] Thus, in a first embodiment, there is provided a method of treating or preventing pulmonary fibrosis in a patient in need thereof by administering to said patient a FAK inhibitor defined by the following formula I, or a pharmaceutically acceptable derivative thereof: [ka] .

[0016] Preferably, the salt is a tartrate.

[0017] In a second embodiment, there is provided a FAK inhibitor as defined by Formula I, or a pharmaceutically acceptable derivative thereof, for use in the treatment of pulmonary fibrosis in a patient in need thereof.

[0018] In a third embodiment, there is provided the use of a FAK inhibitor as defined by Formula I, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for treating or preventing pulmonary fibrosis in a patient in need thereof.

[0019] In a preferred form, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0020] In another preferred form, the pulmonary fibrosis is associated with infection by a coronavirus, particularly the coronavirus associated with COVID-19 (SARS-CoV-2). [Brief explanation of the drawings]

[0021] [Figure 1]Protocol used to evaluate the ability of compounds of formula I to prevent or treat pulmonary fibrosis induced by intratracheal bleomycin (30 μl; 0.05 U / mouse) or PBS (30 μl; vehicle control).

[0022] [Figure 2] Pulmonary fibrosis assessed by Masson's trichrome staining (magnification x20). Upper panel: treatment protocol. Lower panel: prophylaxis protocol.

[0023] [Figure 3] Prevention protocol. a) Measurement of pulmonary fibrosis in mice (n=8 mice per group) on day 23 after treatment with PBS, bleomycin and vehicle, bleomycin and compound of formula I at 40 mg / kg or 80 mg / kg. (a) Semiquantitative analysis of fibrosis was obtained using the Ashcroft score (n=4 mice per group). (b) Acid-soluble collagen content in mouse lungs (n=8 mice per group). All bars represent the mean ± standard error of n=4-8 mice, as indicated. *p<0.05, **p≦0.01, and ***p≦0.001 by one-way ANOVA.

[0024] [Figure 4] Treatment protocol. a) Measurement of pulmonary fibrosis in mice (n=8 mice per group) obtained on day 22 after treatment with PBS, bleomycin and vehicle, bleomycin and compound of formula I at 40 mg / kg or 80 mg / kg. (a) Semiquantitative analysis of fibrosis was obtained using the Ashcroft score (n=4 mice per group). (b) Acid-soluble collagen content in mouse lungs (n=8 mice per group). All bars represent the mean ± standard error of n=4-8 mice, as indicated. *p<0.05 and **p≦0.01 by one-way ANOVA.

[0025] [Figure 5-1]Measurement of airway hyperresponsiveness (AHR) in mouse lungs after methacholine challenge. Panels (a)-(d) Day 23 of the prophylaxis protocol after a single intratracheal dose of PBS or bleomycin and oral administration of the indicated compound of Formula I. Panels (e)-(h) Day 22 of the treatment protocol after a single intratracheal dose of PBS or bleomycin and oral administration of the indicated compound of Formula I. Panels show (a, e) airway resistance, (b, f) transpulmonary resistance, (c, g) elastance, and (d, h) compliance after a 10 mg / ml methacholine challenge. All symbols and bars represent the mean ± standard error of the mean for n=8 mice per group. *p≦0.05, **p≦0.01, and ***p≦0.001 by one-way ANOVA. [Figure 5-2] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0026] Detailed Description of the Embodiments The compound of Formula I is a potent and selective small molecule inhibitor of focal adhesion kinase (FAK). Biochemical assays showed that the compound of Formula I had an IC50 of 2.2 nM against FAK, while a cellular assay using MDA-231 LNA cells determined an IC50 of 7 nM. Surprisingly, in a KINOMEScan™ assay, which assessed the relative inhibitory potency of the compound of Formula I compared to 467 other kinases, the compound of Formula I tested at a 1 micromolar concentration was found to have an S10 selectivity score of 0.02, making it a highly selective inhibitor of FAK compared to other kinases.

[0027] These studies indicate that the compounds of Formula I are the most potent and selective FAK inhibitors described, especially when compared to other known FAK inhibitors such as PF-562,271 or TAE226, both of which have significant off-target kinase activity (Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J, et al. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res 2008;68(6):1935-1944 (for PF-562,271), and Wang ZG, Fukazawa T, Nishikawa T, Watanabe N, Sakurama K, Motoki T, Takaoka M, Hatakeyama S, Omori O, Ohara T, et al. TAE226, a dual inhibitor for FAK and IGF-IR, has inhibitory effects on mTOR signaling in esophageal cancer cells. Oncol Rep 2008;20(6):1473-14770 (for TAE226).

[0028] The compound of Formula I has been shown to exhibit drug-like properties in that it exhibits dose-proportional exposure after oral administration in rats, mice, and dogs, has no detectable inhibition of common cytochrome P450s, and does not exhibit unique metabolites upon exposure to human, rat, dog, or primate hepatocytes. The L-tartrate salt of the compound of Formula I is one of the proposed drug substances, and this salt form has been found to be sufficiently soluble for use in preclinical studies without the need for the addition of novel excipients or solubilizers. Stability studies of the L-tartrate salt of the compound of Formula I have shown no significant degradation after 9 months under both long-term and accelerated conditions.

[0029] The compound has been shown to be effective in models of pulmonary fibrosis.

[0030] Without being bound by theory, the inventors believe that the following rationale explains the reasons for the effectiveness of compounds of formula I.

[0031] Deposition of collagen, fibrin, and other components of the extracellular matrix is ​​an integral part of wound healing and normal tissue repair. However, in the context of chronic inflammatory diseases, the persistent activity of myofibroblasts recruited to sites of inflammation or differentiated from mesenchymal precursors can result in excessive and persistent deposition of fibrous connective tissue, potentially leading to organ scarring, dysfunction, and death (18). In recent years, our understanding of the cellular and molecular mechanisms underlying fibrosis has improved, providing a rationale for therapeutic targeting of specific effector cells and signaling pathways in the fibrotic cascade.

[0032] Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in various cellular processes, particularly those related to adhesion and migration of most cell types. The structure of the FAK protein allows it to interact with several classes of cell surface receptors, such as integrins, G protein-coupled receptors (GPCRs), and receptor tyrosine kinases (RTKs), and with the actin cytoskeleton via adaptor proteins such as talin and paxillin (19). Consistent with these functions, FAK is important for the transduction of chemotactic and haptotactic stimuli from the extracellular environment and the integration of changes in cell adhesion and motility in response to these signals. In addition to these functions, FAK dimerization in response to integrin clustering on the cell surface allows autophosphorylation of Y397, docking of Src, and activation of cell signaling pathways, including the PI3K / Akt pathway.

[0033] FAK has been shown to contribute to multiple mechanisms underlying fibrosis ( 19 ), and collectively, this evidence provides a strong biological rationale for targeting FAK for the treatment and prevention of fibrotic diseases of the lung and other tissues.

[0034] The term "pharmaceutically acceptable derivative" can include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound that, when administered to a subject, can yield (directly or indirectly) a compound of Formula I, or an active metabolite or residue thereof.

[0035] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0036] General information regarding the types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and can be found in textbooks such as "Handbook of Pharmaceutical Salts" by PH Stahl and CG Wermuth, 1st edition, 2002, Wiley-VCH.

[0037] Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, methyl, ethyl, propyl, and butyl bromides, and methyl, ethyl, propyl, and butyl iodides; dialkyl sulfates, such as dimethyl sulfate and diethyl sulfate;

[0038] The term "treatment", as used herein generally, in the context of treating a condition, whether in humans or animals (e.g., in veterinary applications), relates to treatment and therapy, such that some desired therapeutic effect is achieved, e.g., inhibiting the progression of the condition, including slowing the rate of progression, halting the rate of progression, ameliorating the condition, and curing the condition.

[0039] The term "prevention" refers to the use of a compound of Formulation I as a preventative measure (ie, prophylaxis) in patients susceptible to pulmonary fibrosis.

[0040] A compound of Formula I or a pharmaceutical composition comprising a compound of Formula I may be administered to a subject by any convenient route of administration, whether systemic / peripheral or at the desired site of action, including, but not limited to, oral (e.g., by ingestion); topical (including, e.g., transdermal, intranasal, ocular, buccal and sublingual); pulmonary (e.g., by inhalation or breath therapy, e.g., using an aerosol, e.g., through the mouth or nose); rectal; vaginal; parenteral by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal; e.g., by implantation of a subcutaneous or transmuscular depot. The subject can be a eukaryote, an animal, a vertebrate, a mammal, a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a primate, a primate (e.g., a monkey or ape), a monkey (e.g., a marmoset, baboon), an ape (e.g., a gorilla, chimpanzee, orangutan, gibbon), or a human.

[0041] While it is possible for a compound of Formula I to be administered alone, it is preferable to supply the compound of Formula I as a pharmaceutical composition (e.g., a formulation) comprising at least a compound of Formula I, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other substances well known to those of skill in the art, and, optionally, other therapeutic or prophylactic agents.

[0042] Accordingly, the present invention further provides the use of the pharmaceutical composition in a method.

[0043] The term "pharmaceutically acceptable," as used herein, pertains to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0044] Suitable carriers, excipients, etc. can be found in standard pharmaceutical textbooks, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.

[0045] Preparation can be conveniently provided in unit dosage form, and can be prepared by any method known in the art of pharmacy.This method includes the step of mixing tartrate with carrier that constitutes one or more accessory ingredients.Generally, preparation is prepared by uniformly and intimately mixing tartrate with liquid carrier or finely divided solid carrier, or both, and then, if necessary, shaping product.

[0046] The formulation may be in the form of a liquid, solution, suspension, emulsion, elixir, syrup, tablet, lozenge, granule, powder, capsule, cachet, pill, ampoule, suppository, pessary, ointment, gel, paste, cream, spray, mist, foam, lotion, oil, bolus, electuary or aerosol.

[0047] Formulations suitable for oral administration (e.g., by ingestion) may be supplied as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of tartrate, as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, as an oil-in-water or water-in-oil liquid emulsion, as a bolus, as a electuary, or as a paste.

[0048] Preferably, the formulation is suitable for oral administration.

[0049] Tablets can be prepared by conventional means, such as compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing a free-flowing form of tartrate, such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid), in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may be coated or engraved as needed, and may be formulated to provide slow or controlled release of the tartrate salt using, for example, various percentages of hydroxypropyl methylcellulose to achieve the desired release profile. The tablets may be enteric coated as needed to provide release in parts of the digestive tract other than the stomach.

[0050] Formulations suitable for topical administration (e.g., transdermal, intranasal, ophthalmic, buccal, and sublingual) may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. Alternatively, the formulation may comprise a patch or dressing, such as a bandage or adhesive plaster, impregnated with the tartrate salt and, optionally, one or more excipients or diluents.

[0051] Formulations suitable for topical administration in the mouth include lozenges comprising the tartrate salt in a flavored base, usually sucrose and acacia or tragacanth; mouthwashes comprising the tartrate salt in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the tartrate salt in a suitable liquid carrier.

[0052] Formulations suitable for topical administration to the eye also include eye drops, wherein the tartrate salt is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the tartrate salt.

[0053] Formulations suitable for nasal administration wherein the carrier is a solid include coarse powders having a particle size in the range, for example, from about 20 to about 500 microns, administered by sniffing, i.e., rapid inhalation through the nasal passage from a container of the powder held close to the nose. Formulations suitable for administration wherein the carrier is a liquid, for example, as a nasal spray, nasal drops, or by aerosol administration by nebulizer, include aqueous or oily solutions of the tartrate salt.

[0054] Formulations suitable for administration by inhalation include those delivered as an aerosol spray from pressurized packs with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichorotetrafluoroethane, carbon dioxide or other suitable gas.

[0055] Formulations suitable for topical administration via the skin include ointments, creams, and emulsions. When formulated into an ointment, the tartrate may be used with either a paraffin-miscible or water-miscible ointment base, as needed. Alternatively, the tartrate may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably contain a compound that enhances the absorption or penetration of the tartrate through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0056] When formulated as topical emulsion, oily phase may simply contain emulsifier (otherwise known as emulsion) as needed, or may contain a mixture of at least one emulsifier and fat or oil, or both fat and oil.Preferably, a hydrophilic emulsifier is contained together with a lipophilic emulsifier, which acts as a stabilizer.It is also preferred that the hydrophilic emulsifier contains both oil and fat.

[0057] Together, the emulsifiers with or without stabilizers constitute the so-called emulsifying waxes, and the waxes together with oils and / or fats constitute the so-called emulsifying ointment bases, which form the oily dispersed phase of cream formulations.

[0058] Suitable emulsion and emulsifier stabilizers include Tween® 60, Span® 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Because the solubility of tartrate salts in most oils likely to be used in pharmaceutical emulsion formulations can be very low, the selection of an oil or fat suitable for the formulation is based on achieving the desired aesthetic properties. Therefore, creams should preferably be non-sticky, non-staining, and washable products with suitable consistency to avoid leakage from tubes or other containers. Linear or branched mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters (known as Crodamol CAP) may also be used, the latter three being preferred esters. These may be used alone or in combination depending on the properties required.

[0059] Alternatively, high melting point lipids such as white petrolatum and / or liquid paraffin or other mineral oils can be used.

[0060] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0061] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the tartrate, such carriers as are known in the art to be appropriate.

[0062] Suitable formulations for parenteral administration (e.g., via injection, including cutaneous, subcutaneous, intramuscular, intravenous, and intradermal) include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions (which may contain antioxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient), and aqueous and non-aqueous sterile suspensions (which may contain suspending agents and thickening agents, and liposomes or other microparticulate systems designed to target the compound to blood components or one or more organs). Examples of isotonic vehicles suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of tartrate in the solution is about 1 ng / ml to about 10 μg / ml, for example, about 10 ng / ml to about 1 pg / ml. The formulations may be supplied in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Ready-to-use injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. The formulations may be in the form of liposomes or other microparticulate systems, in which the tartrate salt is designed to target blood components or one or more organs.

[0063] It is understood that the appropriate dosage of tartrate and compositions containing tartrate may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects of the treatment of the present invention. The selected dosage level depends on various factors, including, but not limited to, the activity of the specific compound, the route of administration, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds and / or substances used in combination, and the patient's age, sex, weight, condition, general health and medical history. The amount of compound and the route of administration are ultimately at the discretion of the physician, but generally, the dosage will achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmful or adverse side effects.

[0064] Administration in vivo can be effected in one dose, continuously or intermittently (eg, in divided doses at appropriate intervals) throughout the course of treatment.

[0065] Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with dose levels and pattern selected by the treating physician.

[0066] In general, a suitable dose of a compound of formula I is in the range of about 100 pg to about 250 mg per kilogram of subject body weight per day.

[0067] In a preferred embodiment, the suitable dose of the compound of formula I is 40 mg / kg.

[0068] It will be understood that the invention disclosed and defined herein extends to all alternative combinations of two or more of the individual features described above or which are apparent from the text or drawings, all of which constitute various alternative aspects of the invention. [Example]

[0069] The invention will now be described by reference to the following non-limiting examples. Compounds of Formula I in Preclinical Disease Models:

[0070] The efficacy of compounds of formula I in both treating and preventing bleomycin-induced pulmonary fibrosis is demonstrated in studies designed by the present inventors. The study design for the treatment and prevention experiments is shown in FIG.

[0071] Pulmonary fibrosis in female C57BL / 6 mice (ARC, Perth, Australia) between 6 and 8 weeks of age was induced by a single intratracheal dose of bleomycin (0.05 U / mouse). Control mice received 30 μl of buffered saline.

[0072] Mice in the prophylactic study were administered 24 hours after bleomycin administration through day 22, once daily by oral gavage with 200 μl of vehicle (sterile water containing 0.5% (w / v) hydroxypropylmethylcellulose, 0.5% (v / v) benzyl alcohol, and 0.4% (v / v) Tween® 80) or a compound of Formula I at a dose of 40 mg / kg or 80 mg / kg.

[0073] Mice in the treatment study were administered 200 μl of vehicle (sterile water containing 0.5% (w / v) hydroxypropylmethylcellulose, 0.5% (v / v) benzyl alcohol, and 0.4% (v / v) Tween® 80) or a compound of Formula I at a dose of 40 mg / kg or 80 mg / kg once daily by oral gavage from day 7 to day 21 after bleomycin administration.

[0074] There were 8 mice per group for all experiments, and all mice were weighed daily during the administration of treatment. Prevention model:

[0075] Although intratracheal challenge with bleomycin did not result in a significant increase in lung weight compared with PBS challenge on day 23, histological analysis revealed a highly significant increase in lung injury as assessed by the Ashcroft score (Figure 2, lower panel, and Figure 3a). Compound of Formula I administered at 40 mg / kg, but not at 80 mg / kg, attenuated bleomycin-induced lung injury compared with vehicle (Figure 3a).

[0076] Intratracheal bleomycin caused an increase in soluble lung collagen on day 23 (Figure 3b). Oral administration of the FAK inhibitor of formula I inhibited soluble collagen levels to baseline (PBS) levels (Figure 3b).

[0077] Airway hyperresponsiveness (AHR), assessed by airway and transpulmonary resistance, elastance, and compliance, was significantly greater in magnitude in bleomycin-challenged mice at a dose of 10 mg / ml methacholine compared with PBS (Figures 5a-d). Treatment with either 40 mg / kg or 80 mg / kg of the compound of Formula I significantly reduced airway resistance compared with vehicle treatment. At 10 mg / ml methacholine, treatment with the FAK inhibitor did not significantly inhibit other measures of AHR. However, compared with vehicle treatment, the compound of Formula I tended to return AHR parameters to baseline (PBS challenge) levels. Treatment model:

[0078] Intratracheal challenge with bleomycin did not result in a significant increase in lung weight on day 22 compared to PBS challenge. Histological analysis of mouse lung sections revealed a significant increase in lung injury as assessed by the Ashcroft score (top panel of Figure 2 and Figure 4a). Administration of the compound of formula I, starting on day 7 after bleomycin exposure, did not significantly modify bleomycin-induced lung injury compared to vehicle (Figure 4a).

[0079] In the treatment model, intratracheal bleomycin caused an increase in soluble lung collagen on day 22 (FIG. 4b). Compound of Formula I at 80 mg / kg inhibited soluble collagen levels compared to vehicle treatment (FIG. 4b).

[0080] Airway hyperresponsiveness (AHR), as assessed by airway and transpulmonary resistance, elastance, and compliance, was significantly greater in magnitude in bleomycin-challenged mice at a dose of 10 mg / ml methacholine compared to PBS (Figure 5e-h). Treatment with the compound of Formula I had no effect on airway resistance compared to vehicle treatment (Figure 5e). For all other measures of AHR, administration of the compound of Formula I, beginning 7 days after bleomycin exposure, effectively reversed AHR up to 10 mg / ml methacholine compared to vehicle treatment.

[0081] Taken together, the efficacy in the bleomycin model of pulmonary fibrosis demonstrates that compounds of Formula I provide clinical benefit to patients with pulmonary fibrosis. The present invention provides, for example, the following items. (Item 1) 1. A method of treating or preventing pulmonary fibrosis in a patient in need thereof by administering to said patient a FAK inhibitor as defined by Formula I, or a pharmaceutically acceptable derivative thereof: [ka] 。 (Item 2) 1. A FAK inhibitor as defined by formula I, or a pharmaceutically acceptable derivative thereof, for use in the treatment of pulmonary fibrosis in a patient in need thereof: [ka] 。 (Item 3) 1. Use of a FAK inhibitor as defined by formula I, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for treating or preventing pulmonary fibrosis in a patient in need thereof: [ka] 。 (Item 4) 4. The method, compound or use according to any one of items 1 to 3, wherein the salt is a tartrate salt. (Item 5) 5. The method, compound or use according to any one of items 1 to 4, wherein said pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). (Item 6) 6. The method, compound or use according to any one of items 1 to 5, wherein said pulmonary fibrosis is associated with infection with a coronavirus.

Claims

1. A pharmaceutical composition for treating or preventing pulmonary fibrosis comprising a FAK inhibitor as defined by formula I, or a salt thereof: 【Chemistry 3】 。

2. Use of a FAK inhibitor as defined by formula I, or a salt thereof, in the manufacture of a medicament for treating or preventing pulmonary fibrosis: 【Chemistry 5】 。

3. 3. The pharmaceutical composition of claim 1 or the use of claim 2, wherein the salt is a tartrate salt.

4. 3. The pharmaceutical composition of claim 1 or the use of claim 2, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

5. 3. The pharmaceutical composition of claim 1 or the use of claim 2, wherein the pulmonary fibrosis is associated with infection with a coronavirus.

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