Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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 is directed to methods of treating or preventing pulmonary fibrosis (preferably idiopathic pulmonary fibrosis or pulmonary fibrosis associated with a coronavirus infection) in a patient in need thereof by administering a FAK inhibitor defined by formula I below or a salt or prodrug thereof to said patient:
• IPF IPNF
• CT computed tomography
• Idiopathic pulmonary fibrosis is a rare progressive disease, mainly in older adults and is characterized by chronic and progressive fibrosing of the lung interstitium leading to exertion-related breathlessness, cough, dyspnea and worsening lung function (2). As the name suggests, the disease has no known cause and while the clinical course is variable, the prognosis is exceptionally poor.
• An analysis of US Medicare claims indicated that increased age and male gender were associated with increased incidence of IPF (3).
• Other risk factors include a history of smoking (4), occupational exposures (5) and certain viral infections (2). Without antifibrotic treatment there is a median survival time from diagnosis of approximately 3 years (6). Given the low survival rates, new therapies are needed but IPF is notoriously resistant to pharmacological intervention.
• FVC forced vital capacity
• nintedanib and pirfenidone have shown a reduction in the rate of decline in FVC by approximately 50% over 1 year of treatment (10, 11). Extended treatment with nintedanib for up to four years also demonstrated a sustained decline in deterioration of FVC (12).
• uptake in clinical prescription of nintedanib and pirfenidone has been slow, primarily due to their relatively marginal impact on the slowing of disease progression and these drugs’ side effect profiles.
• Side effects of pirfenidone include diarrhea, photosensitivity and rash (13), while nausea and diarrhea are the most common adverse effects of nintedanib in patients with IPF (14).
• nintedanib and pirfenidone have improved the management of IPF, new therapies are required. 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, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS- CoV-2 infection.
• Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection (17).
• the FAK (focal adhesion kinase) inhibitor of formula I (which is the third example of the thirteen examples presented in WO2012110774) is surprisingly selective for FAK when compared to other kinases (and therefore is less likely to show off-target effects associated with toxicity) and shows efficacy in the treatment of pulmonary fibrosis, particularly idiopathic pulmonary fibrosis.
• pulmonary fibrosis refers to any one of a spectrum of lung disorders, including idiopathic pulmonary fibrosis (IPF), having a progressive fibrosing clinical phenotype that is characterized by an increasing extent of fibrosis on high-resolution computed tomography (CT), decline in lung function, worsening of symptoms and quality of life, and early death despite current therapy.
• IPF idiopathic pulmonary fibrosis
• CT computed tomography
• infection with a coronavirus includes but is not limited to infection with a coronavirus associated with severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), as well as COVID-19 (SARS-CoV-2). Accordingly, in a first embodiment, there is provided a method of treating or preventing pulmonary fibrosis in a patient in need thereof by administering a FAK inhibitor defined by formula I below or a pharmaceutically acceptable derivative thereof to said patient:
• the salt is a tartrate salt.
• a FAK inhibitor defined by formula I or a pharmaceutically acceptable derivative thereof for use in the treatment of pulmonary fibrosis in a patient in need thereof.
• 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.
• the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).
• the pulmonary fibrosis is associated with infection by a coronavirus, particularly a coronavirus associated with COVID-19 (SARS-CoV-2).
• a coronavirus particularly a coronavirus associated with COVID-19 (SARS-CoV-2).
• Figure 1 Protocols used to assess the ability of the compound of Formula I to prevent or treat lung fibrosis induced by intratracheal bleomycin (30 pi; 0.05U/mouse) or PBS (30 mI; vehicle control).
• FIG. 1 Lung fibrosis assessed by Masson’s trichrome staining (magnification x 20). Top panels: Treatment protocol. Bottom Panels: Prevention Protocol.
• AHR airways hyper-responsiveness
• the compound of Formula I is a potent and selective small molecule inhibitor of focal adhesion kinase (FAK).
• FAK focal adhesion kinase
• the IC50 of the compound of formula I for FAK was shown to be 2.2 nM while in a cellular assay using MDA-231 LNA cells, the IC50 was determined to be 7 nM.
• the compound of formula I tested at a concentration of 1 micromolar was found to have a S10 selectivity score of 0.02, making it a highly selective inhibitor of FAK relative to other kinases.
• the compound of formula I has been shown to exhibit drug-like properties in that it shows dose-proportional exposures following oral dosing in rats, mice and dogs; possesses no detectable inhibition of common cytochrome P450s and displays no unique metabolites upon exposure to human, rat, dog or primate hepatocytes.
• the L-tartrate salt of the compound of Formula I is one proposed drug substance and this salt form has proven sufficiently soluble for use in preclinical studies without the need for addition of novel excipients or dissolution agents. 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.
• the compound has been shown to be effective in models of pulmonary fibrosis.
• FAM Focal adhesion kinase
• GPCRs G protein-coupled receptors
• RTKs receptor tyrosine kinases
• FAK is important in transducing chemotactic and haptotactic stimuli from the extracellular environment and orchestrating changes in cellular adhesion and motility in response to these signals.
• dimerization of FAK in response to integrin clustering at the cell surface permits autophosphorylation of Y397, docking of Srcand the activation of cell signaling pathways, including the PI3K/Akt pathway.
• the term “pharmaceutically acceptable derivative” may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an active metabolite or residue thereof.
• Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
• pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
• Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• treatment refers generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
• prevention means use of the compound of Formulation I as a prophylactic measure (i.e. prophylaxis) in a patient susceptible to pulmonary fibrosis.
• the compound of Formula I or pharmaceutical composition comprising the compound of Formula I may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or at the site of desired 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 insufflation therapy using, e.g. an aerosol, e.g.
• vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
• the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g.
• a mouse canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
• canine e.g. a dog
• feline e.g. a cat
• equine e.g. a horse
• a primate e.g. a monkey or ape
• a monkey e.g. marmoset, baboon
• an ape e.g. gorilla, chimpanzee, orang-utan, gibbon
• a human e.g. gorilla, chimpanzee, orang-utan, gibbon
• composition comprising at least the compound of formula I, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
• the present invention further provides use in the method of pharmaceutical compositions.
• pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• a subject e.g. human
• Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
• Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the tartrate salt with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the tartrate salt with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
• Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
• Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the tartrate salt; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
• the formulation is suitable for oral administration.
• a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the tartrate salt in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
• Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the tartrate salt therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
• Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
• Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
• a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with the tartrate salt and optionally one or more excipients or diluents.
• Formulations suitable for topical administration in the mouth include losenges comprising the tartrate salt in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the tartrate salt in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the tartrate salt in a suitable liquid carrier.
• 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.
• Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the tartrate salt.
• Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
• a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
• Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
• the tartrate salt When formulated in an ointment, the tartrate salt may optionally be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the tartrate salt may be formulated in a cream with an oil-in-water cream base.
• the aqueous phase of the cream base may include, 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.
• the topical formulations may desirably include a compound which enhances absorption or penetration of the tartrate salt through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
• the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
• an emulsifier otherwise known as an emulgent
• a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
• the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
• the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
• Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
• the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the tartrate salt in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
• the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
• Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required.
• mono-isoadipate such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the
• high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
• Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
• Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the tartrate salt, such carriers as are known in the art to be appropriate.
• Formulations suitable for parenteral administration e.g.
• injection by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal
• aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient
• aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
• Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
• concentration of the tartrate salt in the solution is from about 1 ng/ml to about 10 pg/ml, for example from about 10 ng/ml to about 1 pg/ml.
• the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
• Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the tartrate salt to blood components or one or more organs.
• appropriate dosages of the tartrate salt, and compositions comprising the tartrate salt can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
• the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
• the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
• Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. 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 the dose level and pattern being selected by the treating physician.
• a suitable dose of the compound of formula I is in the range of about 100 pg to about 250 mg per kilogram body weight of the subject per day.
• a suitable dose of the compound of Formula I is 40 mg/kg.
• Lung fibrosis in female C57BL/6 mice aged between 6-8 weeks was induced by a single intra-tracheal dose of bleomycin (0.05U/mouse).
• mice in the prevention study were dosed orally once daily from 24 hours post bleomycin administration until day 22 with either 200mI of vehicle (Sterile water containing 0.5 % (w/v) hydroxypropylmethylcellulose, 0.5% (v/v) benzyl alcohol and 0.4% (v/v) Tween 80), or the compound of Formula I at a dosage of 40 mg/kg or 80 mg/kg by oral gavage.
• vehicle Sterile water containing 0.5 % (w/v) hydroxypropylmethylcellulose, 0.5% (v/v) benzyl alcohol and 0.4% (v/v) Tween 80
• the compound of Formula I at a dosage of 40 mg/kg or 80 mg/kg by oral gavage.
• mice in the treatment study were dosed once daily from day 7 post bleomycin administration until day 21 with either 200mI of vehicle (Sterile water containing 0.5 % (w/v) hydroxypropylmethylcellulose, 0.5% (v/v) benzyl alcohol and 0.4% (v/v) Tween 80) or the compound of Formula I at a dosage of 40mg/kg or 80mg/kg by oral gavage.
• vehicle Sterile water containing 0.5 % (w/v) hydroxypropylmethylcellulose, 0.5% (v/v) benzyl alcohol and 0.4% (v/v) Tween 80
• the compound of Formula I at a dosage of 40mg/kg or 80mg/kg by oral gavage.
• mice There were eight mice per group for all experiments and all mice were weighed daily during administration of the treatments.
• Intratracheal challenge with bleomycin did not cause a significant increase in lung weight at day 23 compared to PBS challenge but histological analysis revealed a highly significant increase in lung damage as assessed by the Ashcroft score ( Figure 2, bottom panels and Figure 3a).
• the compound of Formula I dosed at 40 mg/kg but not at 80 mg/kg attenuated bleomycin-induced lung damage compared to vehicle ( Figure 3a).
• Intra-tracheal bleomycin caused an increase in soluble lung collagen at day 23 (Figure 3b).
• Oral administration of FAK inhibitor of Formula I inhibited soluble collagen levels to baseline (PBS) levels ( Figure 3b).
• Intratracheal challenge with bleomycin did not cause a significant increase in lung weight at day 22 compared to PBS challenge. Histological analysis of mouse lung sections revealed a significant increase in lung damage as assessed by the Ashcroft score ( Figure 2 top panels and Figure 4a). Administration of the compound of Formula I commencing 7 days following bleomycin exposure did not significantly alter bleomycin- induced lung damage compared to vehicle ( Figure 4a).

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