PYRAZOLONE COMPOUNDS FOR USE IN RETINAL DEGENERATIVE DISEASES - Patent application

Abstract

The present invention relates to compounds belonging to the pyrazolone class for use in the prevention and / or treatment of retinal degenerative diseases, in particular in the prevention and / or treatment of macular degeneration. The present invention also relates to pharmaceutical compositions, preferably topical ophthalmic compositions, comprising at least one compound belonging to the pyrazolone class for use in the prevention and / or treatment of retinal degenerative diseases, preferably macular degeneration.

Description

Detailed Description of the Invention

[0001] The present invention relates to compounds belonging to the pyrazolone class for use in the prevention and / or treatment of retinal degenerative diseases, in particular in the prevention and / or treatment of macular degeneration.

[0002] The present invention also relates to pharmaceutical compositions, preferably topical ophthalmic compositions, comprising at least one compound belonging to the pyrazolone class for use in the prevention and / or treatment of retinal degenerative diseases, preferably macular degeneration.

[0003] [Current state of the technology] The retina is a transparent, light-sensitive structure located at the back of the eye. The central part of the retina, called the macula, contains many photoreceptors called cones, which are the light-sensitive cells responsible for central and color vision. The peripheral part of the retina, surrounding the macula, contains photoreceptors called rods, which respond to lower amounts of light but are not sensitive to color. Rods can actually see in low-light conditions, but cannot perceive color.

[0004] The retina can be affected by a variety of conditions that can severely affect vision depending on the area of ​​the retina affected.

[0005] Some diseases that affect the retina can be traced back to degenerative diseases and can severely impair vision and lead to blindness.

[0006] Macular degeneration is an age-related, multifactorial disease that affects the macula. It is a progressive disease and is the leading cause of irreversible blindness in adults over 50 years of age. Macular degeneration disease has a prevalence ranging from 8.5% to 11% in the 65-74 age group and 27% in those over 75 years of age. Macular degeneration is therefore an age-related, and therefore a disease that will eventually affect a wider range of the world population due to increased life expectancy.

[0007] Two different forms of age-related macular degeneration are known: dry (non-exudative or atrophic) and wet (exudative or neovascular).

[0008] All age-related macular degeneration begins as the dry form, and approximately 15% of dry age-related macular degeneration cases then progress to the wet form.

[0009] Dry age-related macular degeneration causes changes in the retinal pigment epithelium, which typically appear as scotomas. The retinal pigment epithelium plays an essential role in maintaining the health and full function of rods and cones. Accumulation of waste products from the cones and rods can lead to the formation of drusen, which appear as yellow spots that characterize early stages of age-related macular degeneration.

[0010] The dry form is characterized by progressive thinning of the central retina, which is inadequately nourished by capillaries and atrophies, leading to the formation of atrophic lesions in the macula. Chorioretinal atrophy (called geographic atrophy) occurs in more advanced cases of dry age-related macular degeneration. The long-term consequence of this slow degenerative process is impaired function of the macula, which can no longer adequately collect light impulses. The majority of patients retain sufficient vision to be able to read and drive. Central blindness (scotoma) usually occurs late in the disease and can sometimes be severe. Symptoms are generally bilateral.

[0011] Wet macular degeneration, on the other hand, is characterized by abnormal blood vessel growth from the choroid relative to the macula (choroidal neovascularization). Localized macular edema or hemorrhage can result in macular elevation or cause localized retinal pigment epithelial detachment. Ultimately, untreated neovascularization leads to submacular disciform scars.

[0012] Generally more aggressive than the dry form, wet macular degeneration can cause rapid and severe central vision loss due to scarring of blood vessels.

[0013] Patients with wet age-related macular degeneration usually show rapid loss of visual function within a few days or weeks. The initial symptoms are generally visual distortions characterized by the presence of a scotoma or metamorphopsia (curvature of straight lines), followed by the formation of new blood vessels near or at the center of the macula. These newly formed blood vessels originate almost exclusively from the choroid (choroidal neovascularization) and are responsible for the formation of fibrovascular scars that destroy the central retina. Wet macular degeneration usually affects one eye at a time, therefore the condition is often unilateral.

[0014] Peripheral vision and color vision are generally unaffected, but if age-related macular degeneration is left untreated, patients can become legally blind (visual acuity <20 / 200) in the affected eye.

[0015] Most available treatments aim to prevent or cure the wet form of neovascular macular degeneration.

[0016] However, to date there remains no established treatment for the dry form.

[0017] Patients with extensive drusen, pigmentation changes, and / or geographic atrophy can reduce their risk of developing advanced age-related macular degeneration by 25% by taking antioxidant and mineral vitamin supplements that generally contain at least lutein or other vitamins, and sometimes zinc or other nutrients. In recent years, omega-3 fatty acids have been prescribed to patients with dry age-related macular degeneration and are included in over-the-counter nutritional supplements along with antioxidants.

[0018] Patients with unilateral wet age-related macular degeneration should take daily nutritional supplements recommended for the dry form to reduce the risk of vision loss in one eye.

[0019] Other non-resolving or otherwise invasive treatments used for the wet form include, for example, laser-induced thermal photocoagulation, photodynamic therapy, transpupillary thermotherapy, subretinal surgery, and macular relocation surgery.

[0020] Pharmacological treatment options for wet maculopathy include periodic intravitreal injections of vascular endothelial growth factor antagonist drugs (anti-VEGF), such as ranibizumab, bevacizumab, or aflibercept. On average, six or seven intravitreal injections are administered during the first year of treatment.

[0021] Additionally, corticosteroids, such as triamcinolone, may also be administered together with the anti-VEGF agents, also by intraocular injection.

[0022] However, the intravitreal administration method adopted in most currently available treatments is accompanied by several side effects. In fact, intravitreal injection is an invasive administration route that can lead to increased intraocular pressure, headache, vitreous inflammation (eye inflammation), vitreous detachment, retinal hemorrhage (bleeding from the back of the eye), visual obstruction and eye pain. The most dangerous complication, which does not occur frequently (about 1 / 1000), is septic endophthalmitis, a severe intraocular inflammatory condition due to infection of the vitreous cavity that can lead not only to pain and redness but also to much more serious consequences, such as loss of vision to total blindness. It should also be remembered that risks can be cumulative when injections are repeated.

[0023] Therefore, there is a clear need to provide new, non-invasive therapeutic methods for the long-term treatment of age-related macular degeneration, which allow for prevention and / or long-term treatment without incurring side effects associated with the administration method.

[0024] [Summary of the Invention] The applicant has addressed the problem of providing new therapies for the prevention and / or long-term treatment of retinal degenerative conditions, in particular macular degeneration, that do not suffer from the drawbacks and side effects of current therapies, in particular those requiring intravitreal administration, and in some cases are equally or more effective.

[0025] Applicants have surprisingly found that new therapeutic approaches based on the administration of compounds belonging to the pyrazolone class may be useful in the prevention and treatment of retinal degenerative conditions, such as macular degeneration.

[0026] Thus, a first aspect of the present invention is a compound belonging to the pyrazolone class for use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters and myopic maculopathy.

[0027] Advantageously, applicants have found that of the compounds belonging to the pyrazolone class, dipyrone and propyphenazone are particularly effective in preventing and / or treating macular degeneration.

[0028] In particular, the Applicant has observed that compounds belonging to the pyrazolone class, preferably dipyrone and propyphenazone, make it possible to prevent and / or treat both forms of macular degeneration, namely dry age-related macular degeneration and wet age-related macular degeneration.

[0029] Another aspect of the present invention is a pharmaceutical composition comprising at least one compound belonging to the pyrazolone class and at least one pharma- ceutically acceptable excipient for use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floats) and myopic maculopathy, preferably macular degeneration.

[0030] Preferably, the pharmaceutical composition according to the invention is a topical ophthalmic composition.

[0031] A further aspect of the present invention is a kit comprising a topical ophthalmic composition, a container containing the topical ophthalmic composition and a dispenser, wherein the composition is for use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters and myopic maculopathy, preferably macular degeneration.

[0032] Preferably, the topical ophthalmic composition in the kit is an aqueous solution.

[0033] Another aspect of the present invention is a method for the prevention and / or treatment of a retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular holes, macular pucker, floaters and myopic maculopathy comprising the step of administering to a patient at least one compound belonging to the pyrazolone class and / or an ophthalmic composition comprising at least one compound belonging to the pyrazolone class for use according to the present invention.

[0034] A final aspect of the present invention is a combination of at least one compound belonging to the pyrazolone class with an anti-VEGF agent and / or a corticosteroid for simultaneous, separate or sequential use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floats) and myopic maculopathy, preferably both forms of macular degeneration.

[0035] [Detailed Description of the Invention] One aspect of the present invention is a compound belonging to the pyrazolone class for use in the prevention and / or treatment of at least one retinal degenerative disease.In particular, the compounds according to the present invention have been shown to be useful in the prevention and / or treatment of macular degeneration.

[0036] Pyrazolones for use according to the invention have the following general formula (I): [ka] (In the formula, R1 and R2 are independently selected from H, linear or branched C1-C6 alkyl, and aryl optionally substituted with OH, C1-C6 alkoxy, linear or branched C1-C6 alkyl, or halogen; R3 is selected from linear or branched C1-C6 alkyl and OH; R4 is H, linear or branched C1-C8 alkyl, linear or branched C2-C8 alkenyl, -(CH2)1-4 -CO- linear or branched C1-C6 alkyl group, linear or branched C1-C6 alkyl group or -(CH2) (1-3) an amino group, -NHCO-aryl or -NHCO-heteroaryl group, each of which is mono- or di-substituted with -SO3H groups and combinations thereof; and pharma- ceutically acceptable salts thereof.

[0037] In this description, the term alkylene denotes a hydrocarbon chain having at least one carbon-carbon double bond.

[0038] Preferred pyrazolones for use according to the invention are R1 and R2 are independently selected from H, linear or branched C1-C3 alkyl, phenyl optionally substituted with OH; R3 is selected from linear or branched C1-C3 alkyl and OH; R4 is H, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, -(CH2) (2-3) -CO-Linear or branched C1-C4 alkyl group, linear or branched C1-C3 alkyl group, -(CH2) (1-2) -NHCO-nitrogenated heteroaryl groups, -amino groups mono- or di-substituted with -SOH groups and combinations thereof The compounds of formula (I) and their pharma- ceutically acceptable salts.

[0039] In a preferred embodiment, the pyrazolone for use according to the invention is R1 and R2 are independently selected from H, linear or branched C1-C3 alkyl, phenyl optionally substituted with OH; R3 is a linear or branched C1-C3 alkyl; R4 is H, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, -(CH2) (2-3) -CO-Linear or branched C1-C4 alkyl group, linear or branched C1-C3 alkyl group, -(CH2) (1-3)-NHCO-nitrogenated heteroaryl groups, -amino groups mono- or di-substituted with -SOH groups and combinations thereof The compounds of formula (I) and their pharma- ceutically acceptable salts.

[0040] Examples of pharma- ceutically acceptable salts are those obtained by addition of an acid or a base to a pyrazolone of formula (I) capable of forming acid or base salts with basic groups, such as, for example, amines or sulfonic acids or ketoenolic acids.

[0041] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0042] Pharmaceutically acceptable base addition salts can be formed with inorganic bases, such as ammonium salts and pharma-ceutically acceptable salts of metals from columns I to XII of the periodic table, such as sodium, potassium, calcium, magnesium, iron, silver, zinc and copper, or with organic bases, such as primary, secondary and tertiary amines, naturally occurring substituted amines or substituted amines, including cyclic amines.

[0043] Examples of suitable organic amines include isopropylamine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0044] Even more preferred pyrazolones for use according to the invention are the compounds of formula (I) reported in Table 1 below: [Table 1] Drugs belonging to the pyrazolone class have been used since the 1950s in the treatment of ankylosing spondylitis, in acute gout and in various types of musculoskeletal pathologies due to the nonsteroidal anti-inflammatory (NSAID), antipyretic and analgesic properties of drugs belonging to the pyrazolone class.

[0045] The compounds according to the invention belonging to the pyrazolone class are preferably selected from aminophenazone, dipyrone, phenazone, propyphenazone, nifenazone, phenylbutazone, pyrasanone, oxyphenylbutazone, kebuzone, feprazone, mofebutazone, tribuzone and mixtures thereof. In a particularly preferred embodiment, the compounds belonging to the pyrazolone class are selected from dipyrone, propyphenazone and mixtures thereof.

[0046] In an even more preferred embodiment, the compound belonging to the pyrazolone class is selected from dipyrone, propyphenazone and mixtures thereof, and said retinal degenerative disease is macular degeneration.

[0047] In one embodiment, the macular degeneration is dry age-related macular degeneration.

[0048] In another embodiment, the macular degeneration is wet age-related macular degeneration.

[0049] Dipyrone, also known as metamizole (trade name Novalgina®), has the following chemical formula: [ka] It is a nonsteroidal analgesic that has the following properties.

[0050] Dipyrone is commonly used as an antipyretic and analgesic for headaches, fevers, toothaches, menstrual cramps, etc.

[0051] For example, propyphenazone, also known as isopropylantipyrine, which has long been marketed under the names Optalidon® or Saridon® in combination with other active ingredients, has similar analgesic and antipyretic properties and has the following chemical formula: [ka] It is a phenazone derivative having the formula:

[0052] Applicants have advantageously observed that pyrazolones, particularly dipyrone and propyphenazone, but not traditional cyclooxygenase (COX) inhibitors such as indomethacin, are able to reduce retinal degenerative disease (see Experimental Section).

[0053] The compounds according to the invention, preferably selected from dipyrone and / or propyphenazone, can prevent and / or treat at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters and myopic maculopathy. Particularly preferred compounds according to the invention, i.e. dipyrone and / or propyphenazone, can be effective in preventing and treating both forms of macular degeneration (dry age-related macular degeneration and wet age-related macular degeneration).

[0054] According to a preferred embodiment of the present invention, the compounds of the present invention, preferably dipyrone and / or propyphenazone, can prevent and / or treat a specific type of retinal degenerative disease: both forms of macular degeneration (dry age-related macular degeneration and wet age-related macular degeneration). Thus, in a particularly preferred embodiment, the retinal degenerative disease that the compounds according to the present invention can treat is both forms of macular degeneration. Macular degeneration falls into a large category of maculopathy. In the present invention, the term "macular degeneration" is used to indicate a specific type of degenerative maculopathy.

[0055] The term "maculopathy" refers to a condition that affects the central portion of the retina called the macula. Maculopathy can be classified as acquired, myopic and hereditary maculopathy.

[0056] According to another aspect of the invention, compounds belonging to the pyrazolone class, preferably selected from dipyrone and / or propyphenazone, can be used for the prevention and / or treatment of myopic maculopathy.

[0057] Myopic maculopathy occurs in people with degenerative or pathological myopia. In particular, in subjects with myopic maculopathy, the retina cannot accommodate the elongation of the eye and becomes damaged.

[0058] In pathologic myopia, macular hemorrhage can occur along with a sudden decrease in vision, sometimes accompanied by metamorphopsia.

[0059] The most common acquired maculopathy is age-related macular degeneration.

[0060] Macular degeneration is a disease characterized by deterioration of the macula, the central part of the retina responsible for central vision.

[0061] The condition is often referred to as age-related macular degeneration or senile macular degeneration because it occurs primarily in individuals over the age of 60. Indeed, many older adults develop the condition as part of the natural aging process.

[0062] In the present invention, the expressions "age-related macular degeneration" and "senile macular degeneration" both refer to the retinal degenerative maculopathy described above.

[0063] According to the present invention, compounds belonging to the pyrazolone class may be useful in the prevention and / or treatment of both forms of macular degeneration, namely dry age-related macular degeneration and / or wet age-related macular degeneration.

[0064] Indeed, the compounds of the invention, especially dipyrone and propyphenazone, have shown efficacy in reducing oxidative damage of the retinal epithelium caused by injection of sodium iodate (NaIO3) in representative mouse models of both forms of macular degeneration (see Example 3). The mouse model of macular degeneration in which experiments were carried out to test the compounds according to the invention was obtained by intravenous administration of NaIO3. NaIO3, a metabolite of Septojod (an old drug that is no longer used to treat sepsis), was identified as being responsible for the blindness observed in patients treated with the precursor drug. It was subsequently shown that sodium iodate selectively damages retinal pigment epithelial (RPE, from the retinal pigment epithelium) cells, a pigment cell layer that is located above the choroid and nourishes the visual cells of the retina, and promotes the phenomenon of necroptosis in retinal pigment epithelial cells that spreads from the center to the periphery of the retina (patchy RPE degeneration).

[0065] It was observed that the damage caused by NaIO3 can then extend to the photoreceptors, which degenerate and die by apoptotic mechanisms. Based on these data, NaIO3 is an important tool for the study of diseases, such as age-related macular degeneration (AMD). Indeed, it was observed that NaIO3 exerts specific toxic effects on retinal pigment epithelial cells and photoreceptors through the generation of oxidative stress, even when administered systemically.

[0066] The animal model of macular degeneration obtained by injection of NaIO3 has been validated for many years by a series of scientific publications, which made it possible to establish that in animals treated with NaIO3, damage is observed in the central pole of the retina and that at higher doses of NaIO3, the damage can also extend to the periphery (Kiuchi, Current Eye Research 2002; Machalinska, Neurochemical Res. 2010; Wang, Invest Ophthalmol Vis Sci 2014; Commentaries Neural Regeneration Research 2014; Hanus, Cell Death Disc 2016; Chowers, Invest Ophtalmol 2017 and Koh, Journal of Photochemistry & Photobiology, 2019).

[0067] It was also observed that the pathological phenomena occurring in mice treated with NaIO3 exhibited characteristics observed in patients with acquired degenerative disorders, such as age-related macular degeneration, and toxic retinopathy due to intoxication with drugs, such as chloroquine, thioridazine or chlorpromazine.

[0068] In particular, according to Hanus (Cell Death Disc 2016), retinal degeneration induced by NaIO3 in animal models shows at least two characteristics similar to age-related macular degeneration affecting humans. First, it was observed that low doses lead to an irregular loss of cells in the RPE layer. Second, it was observed that the loss of cells in the RPE layer affects not only the photoreceptors but also the underlying choriocapillaris layer. In detail, morphological examination of the retina after administration of 100 mg / kg NaIO3 in mice showed depigmentation, swelling and vacuolation, suggesting necrosis of the RPE layer. Furthermore, in the same study, it was observed that higher dosages of NaIO3 caused increasing damage to the RPE layer, which gradually thinned over time, and also damaged the photoreceptors, while dosages below 10 mg / kg proved to have little effect on the retina.

[0069] A more recent study (Koh, Journal of Photochemistry & Photobiology, 2019) confirmed that RPE-specific toxicity caused by NaIO3 in a model of macular degeneration recapitulates the delayed effects of human age-related macular degeneration and retinitis pigmentosa.

[0070] In summary, the histopathological changes caused by NaIO3 in experimental animals that are characteristic of macular degeneration are discontinuity of the RPE layer, photoreceptor damage, and infiltration of macrophages (tissue mononuclear cells capable of phagocytosing and destroying foreign or damaged cells or material).

[0071] The model exhibits all of the histopathological features observed in humans and is therefore a valid model of macular degeneration.

[0072] A further aspect of the present invention relates to a pharmaceutical composition, preferably an ophthalmic composition, more preferably a topical ophthalmic composition, comprising a therapeutically effective amount of at least one compound belonging to the pyrazolone class and at least one pharma- ceutically acceptable excipient for use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floats) and myopic maculopathy.

[0073] In the pharmaceutical composition for use according to the invention, the at least one compound belonging to the pyrazolone class of formula (I) is selected from aminophenazone, dipyrone, phenazone, propyphenazone, nifenazone, phenylbutazone, pyrasanone, oxyphenylbutazone, kebuzone, feprazone, mofebutazone, tribuzone and mixtures thereof.

[0074] In a preferred embodiment, the pharmaceutical composition, preferably the ophthalmic composition, according to the invention comprises dipyrone and / or propyphenazone as compounds belonging to the pyrazolone class.

[0075] In a particularly preferred embodiment, a pharmaceutical composition, preferably an ophthalmic composition, comprising dipyrone and / or propyphenazone as preferred compounds is used for the prevention and / or treatment of macular degeneration, in particular dry age-related macular degeneration or wet age-related macular degeneration.

[0076] According to an embodiment, the ophthalmic composition comprises a plurality of compounds, preferably at least two compounds, belonging to the pyrazolone class, said compounds belonging to the pyrazolone class being preferably selected from dipyrone and propyphenazone.

[0077] The pharmaceutical composition, preferably the ophthalmic composition, according to the present invention, preferably comprising dipyrone and / or propyphenazone as compounds belonging to the pyrazolone class, can be advantageously used for the prevention and / or treatment of retinal degenerative diseases selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular holes, macular pucker, floaters (floats) and myopic maculopathy.

[0078] Preferably, said retinal degenerative disease is macular degeneration, in particular dry age-related macular degeneration and wet age-related macular degeneration.

[0079] The pharmaceutical compositions according to the invention may be administered systemically or locally by any route of administration suitable for achieving a concentration at the retinal level effective for the prevention or treatment of the condition in question.

[0080] Preferably, the pharmaceutical composition according to the invention is an ophthalmic composition suitable for internal or external administration to the eye.

[0081] According to embodiments, the composition is suitable for administration to the posterior segment of the eye, for example by injection or surgical implant, in particular to the retina, sclera, posterior chamber, vitreous chamber, subretinal space or to the suprachoroidal portion of the eye.

[0082] According to another embodiment, the composition is suitable for administration to the anterior segment of the eye by injection or surgical implant.

[0083] In another more preferred embodiment, the composition according to the invention is a topical ophthalmic composition suitable for external administration to the eye, for example by application to the lower eyelid pouch or conjunctival cul-de-sac on the external surface of the cornea or sclera.

[0084] The topical ophthalmic composition according to the present invention can be formulated, for example, in the form of a solution, suspension, emulsion, gel, ointment, eye insert or therapeutic contact lens. The topical use of the composition of the present invention, for example in the form of drops or eye drops, advantageously allows the treatment of one or more retinal diseases, preferably macular degeneration, in a non-invasive manner, avoiding the inconvenience and side effects of intravitreal administration currently commonly used to treat macular degeneration.

[0085] Furthermore, since generally only a small portion of a topically administered drug dose is effectively absorbed, it follows that potential systemic side effects of compounds belonging to the pyrazolone class according to the present invention are expected to be minimal.

[0086] The ophthalmic compositions according to the present invention may contain one or more ophthalmologically acceptable additives and / or excipients selected from those commonly used in ophthalmic formulations.

[0087] An "ophthalmologically acceptable excipient" is an inert excipient that allows for administration of a medicament to the eye and / or eyelid to treat an ocular disease or condition without adversely affecting the eye. In general, an excipient is a substance that not only favors the preservation of a product over time, but also contributes to enhancing the efficacy and tolerability of the product in which it is contained.

[0088] Examples of such ophthalmically acceptable additives or excipients include viscosity enhancing agents, permeation enhancers, buffering agents, osmolality adjusting agents, antioxidants, preservatives and surfactants.

[0089] Viscosity enhancing agents, which function to increase the viscosity of the composition and, consequently, the contact time of the drug with the ocular surface, are preferably selected from cellulose derivatives, preferably hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose; polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol acetate, dextran, gelatin, glycerin, polysorbate 80 and other gelling agents.

[0090] Penetration enhancers, which function to increase the permeability of drugs across the ocular membrane, are preferably selected from cyclodextrins, chelating agents, corona ethers, bile acids and bile salts.

[0091] The buffering agent has the function of providing and maintaining the pH of the composition as close as possible to physiological pH, preferably between 6 and 8. This action is essential to allow good tolerability of the preparation and to maintain its effectiveness. The preferred buffer is a phosphate buffer, but other buffers capable of maintaining the pH within the desired range are also included, as long as they are suitable for ophthalmic use.

[0092] The osmolality adjusting agent is a salt capable of making the liquid composition isotonic with ocular fluid. The preferred salt is sodium chloride (NaCl), but other biologically acceptable salts such as potassium chloride (KCl), calcium chloride (CaCl2) and magnesium chloride (MgCl2) and mixtures thereof, or substances such as propylene glycol, glycerin, dextrose, dextran 40 and 70 or the buffer substances mentioned above can also be used.

[0093] Antioxidants prevent or retard the deterioration of products caused by the action of atmospheric oxygen. Among the antioxidant substances most commonly used are ethylenediaminetetraacetic acid (EDTA), thiourea, sodium thiosulfate, sodium metabisulfite and sodium bisulfite.

[0094] Preservatives are substances that inhibit bacterial growth that may occur after opening the product.Suitable preservatives include, for example, quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride, benzethonium hydrochloride, chlorobutanol, EDTA, mercurial preservatives (such as thimerosal), phenylethyl alcohol, sodium benzoate, sodium propionate and sorbic acid.Many of these agents are surface-active compounds that, in addition to inhibiting bacterial growth, favor the penetration of drugs through the cornea.

[0095] Surfactants have the function of stabilizing the composition and favoring the penetration of the active ingredient into the ocular structures. Examples of surfactants are polysorbates and poloxamers.

[0096] In one embodiment, the ophthalmic composition for use according to the invention is an aqueous ophthalmic composition, for example in the form of eye drops for topical administration to the anterior segment of the eye. The aqueous ophthalmic composition according to said embodiment comprises a sufficient amount of water to achieve appropriate concentrations of the components of the composition.

[0097] Preferably, in a liquid, preferably aqueous, ophthalmic composition, the compound belonging to the pyrazolone class may be present in a concentration ranging from about 0.0001% to about 5% w / v of the aqueous composition, more preferably from about 0.01% to about 1% w / v, even more preferably from about 0.1 to about 1% w / v.

[0098] Ophthalmic compositions for use according to the invention may, for example, comprise a therapeutically effective amount of at least one compound belonging to the pyrazolone class, sodium chloride, magnesium chloride, mono- and dibasic sodium phosphate, and water for ophthalmic use.

[0099] In one embodiment, a topical ophthalmic composition, preferably a liquid composition, for use according to the invention may be part of a kit comprising the composition, a container containing the composition, and a dispenser.

[0100] In particular, the kit comprises the topical ophthalmic composition as described above, a container and a dispenser containing the topical ophthalmic composition, wherein the composition is for use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters and myopic maculopathy, preferably macular degeneration (both dry and wet age-related macular degeneration).

[0101] Preferably, the topical ophthalmic composition in the kit is an aqueous solution.

[0102] In the case of eye drops, the dispenser is a drop dispenser.

[0103] In another embodiment, the pharmaceutical composition, preferably the ophthalmic composition, for use according to the invention may further comprise at least one other pharma- ceutical active compound.

[0104] In a preferred embodiment, the pharmaceutical composition, preferably the ophthalmic composition, for use according to the invention may further comprise one or more vascular endothelial growth factor antagonist drugs (anti-VEGF) and / or corticosteroid drugs.

[0105] A further aspect of the present description also relates to a method for the prevention and / or treatment of at least one retinal degenerative disease, preferably selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floats) and myopic maculopathy, comprising the step of administering to a subject at least one compound belonging to the pyrazolone class of formula (I) and / or a pharmaceutical composition, preferably an ophthalmic composition, comprising at least one compound belonging to the pyrazolone class and one or more pharma- ceutically acceptable excipients.

[0106] In a preferred embodiment, the retinal degenerative disease is macular degeneration and the compound belonging to the pyrazolone class is selected from dipyrone, propyphenazone and mixtures thereof.

[0107] The doses used in the eyes in the experiments carried out in a validated mouse model of macular degeneration (Examples 1-3) correspond to approximately 40 mg of dipyrone and approximately 28 mg of propyphenazone in a 70 kg individual.

[0108] Thus, the method according to the invention may include, by way of example, topical ocular administration of at least one compound belonging to the pyrazolone class, in a single dose of 1-80 mg, for example 1-5 total doses per day.

[0109] The actual dosage and regimen of administration of the compounds for use according to the invention in the treatment or prevention of the aforementioned diseases will depend on a number of factors, such as the route of administration or the degree of affliction of the individual being treated.

[0110] These doses may generally be much lower than those used for analgesic purposes for systemic administration in humans (500-1000 mg for dipyrone and 125-286 mg for propyphenazone), with the undoubted advantage of reducing systemic side effects.

[0111] In an alternative embodiment, the method comprises administering one or more drugs commonly used to treat retinal degenerative diseases, preferably macular degeneration, in combination with a compound belonging to the pyrazolone class or an ophthalmic composition for use according to the invention.

[0112] Said drugs commonly used to treat retinal degenerative diseases are selected from vascular endothelial growth factor antagonists (anti-VEGF) and / or corticosteroids.

[0113] In a particularly preferred embodiment, the method comprises administering dipyrone and / or propyphenazone as compounds belonging to the pyrazolone class, and / or a composition comprising dipyrone and / or propyphenazone, together with a drug commonly used to treat retinal degenerative diseases, preferably a vascular endothelial growth factor antagonist (anti-VEGF) and / or a corticosteroid.

[0114] In this embodiment, the drugs currently used to treat macular degeneration, preferably anti-VEGF drugs and / or corticosteroids, may be administered before, during or after administration of a compound belonging to the pyrazolone class and / or the above-described ophthalmic composition.

[0115] Examples of anti-VEGF drugs currently used to treat macular degeneration that can be administered in combination with an ophthalmic composition comprising at least one compound belonging to the pyrazolone class include ranibizumab, bevacizumab or aflibercept.

[0116] Examples of corticosteroids currently used to treat macular degeneration that may be administered in combination with an ophthalmic composition comprising at least one compound belonging to the pyrazolone class include cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, beclomethasone, triamcinolone, paramethasone, mometasone, budesonide, fluocinonide, halcinonide, flumethasone, flunisolide, fluticasone, betamethasone, dexamethasone, hydrocortisone, and fluocortolone.

[0117] The method for preventing and / or treating a retinal degenerative disease preferably comprises the administration of at least one of the above-listed corticosteroids when said retinal degenerative disease is selected from diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy.

[0118] In another embodiment, the method for the prevention and / or treatment of at least one retinal degenerative disease as defined above comprises administering to a subject a composition comprising at least one compound belonging to the pyrazolone class and at least one drug selected from anti-VEGF drugs and / or corticosteroids and / or other drugs with different mechanisms of action that are potentially effective in the prevention and treatment of degenerative maculopathy, such as GT005, an experimental drug based on gene therapy and capable of modulating the activity of the complement system.

[0119] In this embodiment, a drug currently used to treat retinal diseases, preferably macular degeneration, is included in the composition of the invention and is thus co-administered with a compound belonging to the pyrazolone class and / or a composition comprising said compound.

[0120] In a final embodiment, the method includes administering one or more vitamin supplements commonly used in the treatment of macular degeneration in combination with a compound belonging to the pyrazolone class or an ophthalmic composition for use according to the invention.

[0121] In particular, the supplements that can be administered according to the above method are antioxidant and mineral supplements that generally contain at least vitamin C and vitamin E, lutein and zeaxanthin (two carotenoids), as well as polyphenols, and sometimes zinc or other nutrients. Recently, omega-3 fatty acids, along with antioxidants, have been included in commercially available nutritional supplements prescribed to patients suffering from dry age-related macular degeneration.

[0122] A final aspect of the invention relates to a combination of at least one compound belonging to the pyrazolone class with an anti-VEGF agent and / or a corticosteroid for simultaneous, separate or sequential use in the prevention and / or treatment of at least one retinal degenerative disease selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters and myopic maculopathy, preferably both forms of macular degeneration.

[0123] Preferably, the combination for use according to the invention comprises dipyrone and / or propyphenazone as compounds belonging to the pyrazolone class.

[0124] In a preferred embodiment, the combination of at least one compound belonging to the pyrazolone class with an anti-VEGF drug and / or a corticosteroid is used for the prevention and / or treatment of macular degeneration, in particular dry age-related macular degeneration and wet age-related macular degeneration.

[0125] In such embodiments, the combination includes an anti-VEGF agent selected from ranibizumab, bevacizumab, or aflibercept.

[0126] In such embodiments, the combination comprises a corticosteroid selected from cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, beclomethasone, triamcinolone, paramethasone, mometasone, budesonide, fluocinonide, halcinonide, flumethasone, flunisolide, fluticasone, betamethasone, dexamethasone, hydrocortisone, and fluocortolone.

[0127] In a particularly preferred embodiment of the combination for use in the prevention and / or treatment of macular degeneration (both dry and wet age-related macular degeneration), the compound belonging to the pyrazolone class is dipyrone, propyphenazone or a mixture thereof. [Brief description of the drawings]

[0128] [Figure 1A]Immunofluorescence images of the RPE layer of retinas taken from mice of the NaIO3-induced macular degeneration model on day 4 after treatment with NaIO3 or vehicle of NaIO3 (V1), and treatment with dipyrone (FN-001), propyphenazone (FN-002), or indomethacin (Ind) or their vehicles (V2). RPE65 indicates the antibody used to stain the RPE layer. The letters shown in each panel of Fig. 1A indicate the following: V1 / V2: Mice were given NaIO3 vehicle (V1) before and after administration of the various drugs in vehicle (V2). The various drugs in vehicle V2 consisted of 4% dimethyl sulfoxide (DMSO), 4% Tween 80 in 0.9% NaCl and were used as controls. These mice constituted the controls. V2 / NaIO3: Mice were administered various drug-dissolved vehicles (V2) before and after administration of NaIO3 dissolved in a vehicle of NaIO3 (V1) to obtain mice with macular degeneration. FN-001 / NaIO3: Mice were treated with dipyrone (FN-001) before and after administration of NaIO3 dissolved in a vehicle of NaIO3. FN-002 / NaIO3: Mice were treated with propyphenazone (FN-002) before and after administration of NaIO3 dissolved in a vehicle of NaIO3. Ind / NaIO3: Mice were treated with indomethacin (Ind) before and after administration of NaIO3 dissolved in a vehicle of NaIO3. [Figure 1B] 1B is a histogram representing the cumulative data of the immunofluorescence experiment shown in FIG. 1A. [Figure 2A]Immunofluorescence images of 4-hydroxynonenal (4-HNE), an oxidative stress biomarker, in retinas taken on day 4 from mice in the NaIO3-induced macular degeneration model after treatment with NaIO3 or its vehicle (V1) and with dipyrone (FN-001), propyphenazone (FN-002) or indomethacin (Ind) or their vehicles (V2). In Figure 2A, "DAPI" (4',6-diamidin-2-phenylindole) denotes the organic dye used to label the nuclei of retinal epithelial cells, "4-HNE" denotes the reactive species for the primary antibody to which the secondary fluorophore-labeled antibody binds, and "MERGE" denotes the overlay of two stainings, namely the staining obtained with DAPI and the staining obtained with an antibody that recognizes 4-HNE. The letters shown in each panel of FIG. 2A indicate the following: V1 / V2: Mice were administered with the vehicle (V1) containing various drugs before and after they received the vehicle (V2) containing NaIO3. These mice constitute the control. V2 / NaIO3: Mice were administered with the vehicle (V2) containing various drugs before and after the administration of NaIO3 in a vehicle of NaIO3 to obtain mice with macular degeneration. FN-001 / NaIO3: Mice were treated with dipyrone (FN-001) before and after the administration of NaIO3 in a vehicle of NaIO3. FN-002 / NaIO3: Mice were treated with propyphenazone (FN-002) before and after the administration of NaIO3 in a vehicle of NaIO3. Ind / NaIO3: Mice were treated with indomethacin (Ind) before and after the administration of NaIO3 in a vehicle of NaIO3. [Figure 2B] 2B is a histogram representing the cumulative data of the immunofluorescence experiment shown in FIG. 2A. EXAMPLES

[0129] Example 1 - Mouse model of macular degeneration To test compounds for use according to the present invention, a mouse model of macular degeneration was obtained.

[0130] The in vivo experiments were carried out in compliance with the guidelines laid down in Italian legislation (Legislative Decree 26 / 2014) and European regulations (EU Directive 2010 / 63 / EU). The study was carried out after protocol approval by the Ministry of Health (protocol number 687 / 2020-PR).

[0131] To generate a valid macular degeneration model, systemic administration of NaIO3 (via retro-orbital vein) was performed in C57BL / 6J male mice, 5-8 weeks old and weighing 22-25 g, supplied by Charles River (Milan, Italy). A total of 30 mice were used to perform the following experiments. The animals were kept in a temperature- and humidity-controlled environment (12-h dark / light cycle, food and water available ad libitum). The experiments were performed between 8:00 and 20:00 in a temperature-controlled room (20-22°C). At the end of the experiment, the animals were euthanized by inhalation of a mixture of 50% O2 / 50% CO2 for 1 min. Unless otherwise specified, all compounds used in the study were purchased from Merck Life Science SRL (Milan, Italy).

[0132] As mentioned above, the mouse model obtained by systemic administration (via retro-orbital vein) of NaIO3 is a model of macular degeneration. Indeed, after 3 days of administration, NaIO3 induced persistent retinal damage in mice with characteristics similar to those observed in age-related macular degeneration in humans.

[0133] It was observed that administration of NaIO3 in mice caused damage to the RPE layer (Figure 1A) and increased oxidative stress at the retinal level (Figure 2A), as evidenced by increased staining for 4-hydroxynonenal (4-HNE), a reactive carbonyl species used as a final indicator of oxidative stress.

[0134] Example 2 - Administration of dipyrone, propyphenazone, indomethacin or vehicle To evaluate the efficacy of the preferred compounds of the pyrazolone class, dipyrone and propyphenazone, in reducing and treating retinal damage specific to macular degeneration, a model of macular degeneration was developed in five experimental groups of mice, which were administered topical eye drops containing dipyrone, propyphenazone, indomethacin or their vehicles.

[0135] Indomethacin, a cyclooxygenase (COX) inhibitor, was used as a comparison to the effects resulting from administration of dipyrone and propyphenazone.

[0136] The drug vehicle consisted of 4% dimethylsulfoxide (DMSO), 4% Tween 80 in 0.9% NaCl and was used as a control.

[0137] In particular, a group of six mice (used as controls) received vehicle (V1) (NaCl, 0.9%) of NaIO3 (1 ml / kg) 60 min prior to injection into the retro-orbital vein, followed by eye drops (5 μl) containing the drug's vehicle (V2) (4% DMSO, 4% Tween 80 in 0.9% NaCl) instilled three times a day. Another 24 mice, in each group of six mice, received NaIO3 (1%, 20 mg / kg) (1 ml / kg) 60 min prior to injection into the retro-orbital vein, followed by eye drops (5 μl) of dipyrone (16.65 μg), propyphenazone (11.5 μg), indomethacin (17.85 μg) or their vehicles (4% DMSO, 4% Tween 80 in 0.9% NaCl) instilled three times a day.

[0138] For each group of mice, the first dose (day 1) of dipyrone, propyphenazone, indomethacin or vehicle (V2) was given 60 min before injection of NaIO3 or NaIO3 vehicle (V1), and the second and third doses were given 6 and 12 h after injection of vehicle (V1) or NaIO3, respectively. On two days (days 2 and 3) after injection of vehicle (V1) or NaIO3, dipyrone, propyphenazone, indomethacin or vehicle (V2) were administered to the various groups of mice at 8:00, 14:00 and 20:00.

[0139] At 9:00 on the fourth day after treatment with vehicle (V1) or NaIO3, mice were sacrificed (as previously reported), eyes were removed, and the eyes were processed for subsequent injury analysis.

[0140] Example 3 - Assessment of retinal pigment epithelium damage Damage to the retinal pigment epithelium (RPE) was assessed by direct immunofluorescence, which represents the layer of pigmented cells immediately outside the neurosensory retina that nourishes the visual cells of the retina and is tightly attached to the underlying choroid and to the overlying visual retinal cells.

[0141] Staining intensity of the RPE layer was quantified using a primary antibody (RPE65, #ab13826, mouse monoclonal, 1:100, Abcam, Cambridge, UK) conjugated to a secondary antibody (fluorophore-labeled, Alexa Fluor 488, #A28175, Thermo Fisher Scientific) in five groups of mice treated with V2 / V1, V2 / NaIO3, dipyrone / NaIO3, propyphenazone / NaIO3 and indomethacin / NaIO3. Cell nuclei were visualized using DAPI organic dye (#ab228549, Abcam, Cambridge, UK).

[0142] Figure 1A shows representative images and cumulative data of immunofluorescence staining of the RPE layer performed with a primary antibody (RPE65) on retinas harvested on day 4 of five groups of mice treated with V2 / V1, V2 / NaIO3, dipyrone / NaIO3, propyphenazone / NaIO3 and indomethacin / NaIO3. Data are presented as mean ± SEM. *p<0.05 vs. veh; §p<0.05 vs. NaIO3. Statistical analysis using one-way analysis of variance (ANOVA) test and Bonferroni test.

[0143] In mice injected with NaIO3, a decrease in the staining intensity of the RPE layer of 48.0 ± 2.9% (P < 0.01 vs. V1 / V2) was observed. Treatment with dipyrone and propyphenazone eye drops statistically significantly reduced the damage induced by NaIO3 in the RPE layer by 87.8 ± 7.8% (P < 0.01) and 99.2 ± 23.0% (P < 0.01), respectively, compared to V2 (Figures 1A and 1B). In contrast, indomethacin induced a moderate, non-significant decrease in the staining intensity of the RPE layer of 5.7 ± 14.9% (Figures 1A and 1B).

[0144] The level of oxidative stress was also assessed throughout the retinal thickness by measuring the immunofluorescence intensity of 4-hydroxynonenal (4-HNE), a reactive carbonyl species that is an ultimate indicator of oxidative stress.

[0145] Example 4 - Evaluation of oxidative stress at the retinal level Levels of 4-HNE were quantified using a primary antibody (#ab48506, monoclonal mouse [HNEJ-2], 1:40, Abcam, Cambridge, UK) conjugated to a secondary antibody (fluorophore-labeled, Alexa Fluor 594, #A A32742, Thermo Fisher Scientific) in five groups of mice treated with V2 / V1, V2 / NaIO3, dipyrone / NaIO3, propyphenazone / NaIO3 and indomethacin / NaIO3.

[0146] Cell nuclei were visualized using DAPI organic dye (#ab228549, Abcam, Cambridge, UK).

[0147] Administration of NaIO3 induced an increase of 187.5 ± 12.8% (P < 0.001 vs. V1 / V2) in 4-HNE immunofluorescence throughout the retinal tissue (Figures 2A and 2B).

[0148] Treatment with dipyrone and propyphenazone significantly reduced retinal 4-HNE levels by 69.7 ± 11.8% (P < 0.001 vs. V2) and 81.3 ± 7.0% (P < 0.001 vs. V2), respectively, whereas treatment with indomethacin produced a modest, nonsignificant reduction in 4-HNE levels of 17.5 ± 10.5% (Figures 2A and 2B). Figure 2A shows representative images and cumulative immunofluorescence staining data for 4-hydroxynonenal (4-HNE), an oxidative stress biomarker, with primary antibody (#ab48506, monoclonal mouse [HNEJ-2], 1:40, Abcam, Cambridge, UK) conjugated with secondary antibody (fluorophore-labeled, Alexa Fluor 594, #A A32742, Thermo Fisher Scientific) in five groups of mice treated with V2 / V1, V2 / NaIO3, dipyrone / NaIO3, propyphenazone / NaIO3 and indomethacin / NaIO3. Data are presented as mean ± SEM. *p<0.05 vs. V1 / V2; §p<0.05 vs. V2 / NaIO3. Statistical analysis using one-way analysis of variance (ANOVA) test and Bonferroni test.

[0149] Therefore, it is possible to conclude from the experimental evidence that dipyrone and propyphenazone have a protective effect against NaIO3-induced damage to cells of the RPE layer, which is of fundamental importance for maintaining macular photoreceptor function.

[0150] Furthermore, it was observed that dipyrone and propyphenazone protected the retina from NaIO3-induced increases in 4-HNE. A COX inhibitor (indomethacin) was demonstrated to be unable to protect against RPE damage or NaIO3-induced increases in 4-HNE.

Claims

1. A pharmaceutical composition for use in the prevention and / or treatment of at least one retinal degenerative disease, comprising a compound belonging to the pyrazolone class of formula (I) 【Chemical 1】 wherein, R1 and R2 are independently selected from H, linear or branched C1-C6 alkyl, and aryl optionally substituted with OH, C1-C6 alkoxy, linear or branched C1-C6 alkyl or halogen, R3 is selected from linear or branched C1-C6 alkyl and OH, R4 is H, a linear or branched C1-C8 alkyl, a linear or branched C2-C8 alkenyl, —(CH ２ ), １－４ —CO— a linear or branched C1-C6 alkyl group, a linear or branched C1-C6 alkyl, —(CH ２ ), （１－３） —SO ３ H group, or an amino group mono- or disubstituted with a combination thereof, —NHCO—aryl, —NHCO—heteroaryl group and pharmaceutically acceptable salts thereof. and a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

2. R1 and R2 are independently selected from H, linear or branched C1-C3 alkyl, and phenyl optionally substituted with OH; R3 is selected from linear or branched C1-C3 alkyl and OH; R4 is H, a linear or branched C1-C6 alkyl, a linear or branched C2-C6 alkenyl, -(CH ２ ) （２－３） -CO-linear or branched C1-C4 alkyl group, linear or branched C1-C3 alkyl, -(CH ２ ) （１－２） -SO ３ H group, or an amino group mono- or di-substituted with a combination thereof, -NHCO-nitrogenated heteroaryl group and pharmaceutically acceptable salts thereof, selected from A compound belonging to the pyrazolone class of formula (I) and a pharmaceutically acceptable salt thereof for use according to Claim 1.

3. The pharmaceutical composition according to Claim 1, wherein the compound is selected from aminophenazone, dipyrone, phenazone, propiphenazone, nifenazone, phenylbutazone, pyrazanone, oxyphenylbutazone, ketobzone, feprazone, mofebutazone, tribuzone and mixtures thereof.

4. The pharmaceutical composition according to Claim 1, wherein the compound is selected from dipyrone, propiphenazone and mixtures thereof.

5. The pharmaceutical composition according to Claim 1, wherein the compound is dipyrone.

6. The pharmaceutical composition according to Claim 1, wherein the compound is propiphenazone.

7. The pharmaceutical composition according to any one of Claims 1 to 6, wherein the retinal degenerative disease is selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters and myopic maculopathy.

8. The pharmaceutical composition according to Claim 7, wherein the retinal degenerative disease is macular degeneration.

9. The pharmaceutical composition according to Claim 8, wherein the macular degeneration is dry age-related macular degeneration.

10. The pharmaceutical composition according to Claim 8, wherein the macular degeneration is wet age-related macular degeneration.

11. The pharmaceutical composition according to Claim 7, wherein the pharmaceutical composition is an ophthalmic composition comprising at least one compound belonging to the pyrazolone class and at least one ophthalmically acceptable excipient.

12. The pharmaceutical composition according to claim 11, wherein the ophthalmic composition is a topical ophthalmic composition.

13. The pharmaceutical composition according to claim 11, wherein the ophthalmic composition is an aqueous solution.

14. The pharmaceutical composition according to claim 11, wherein the compound belonging to the pyrazolone class can be present in the ophthalmic composition at a concentration in the range of about 0.0001% to about 5% w / v.

15. The pharmaceutical composition according to claim 11, wherein the compound belonging to the pyrazolone class can be present in the ophthalmic composition at a concentration in the range of about 0.01% to about 1% w / v.

16. The pharmaceutical composition according to claim 11, wherein the compound belonging to the pyrazolone class can be present in the ophthalmic composition at a concentration in the range of about 0.1 to about 1% w / v.

17. A combination of at least one compound belonging to the pyrazolone class of formula (I) with an anti-VEGF drug and / or a corticosteroid drug for simultaneous, separate or sequential use in the prevention and / or treatment of at least one retinal degenerative disease selected from age-related macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floaters) and myopic maculopathy. [Chemical Formula 2] (wherein, R1 and R2 are independently selected from H, linear or branched C1-C6 alkyl, and aryl optionally substituted with OH, C1-C6 alkoxy, linear or branched C1-C6 alkyl or halogen, R3 is selected from linear or branched C1-C6 alkyl and OH, R4 is H, linear or branched C1-C8 alkyl, linear or branched C2-C8 alkenyl, -(CH2)1-4-CO-linear or branched C1-C6 alkyl group, linear or branched C1-C6 alkyl, -(CH2)(1-3)-SO3H group, or an amino group mono- or disubstituted with a combination thereof, -NHCO-aryl, -NHCO-heteroaryl group and pharmaceutically acceptable salts thereof. )

18. The combination according to claim 17, wherein the retinal degenerative disease is age-related macular degeneration.

19. The combination according to claim 18, wherein the retinal degenerative disease is wet age-related macular degeneration and / or dry age-related macular degeneration.

20. The combination according to claim 17, wherein the anti-VEGF drug is selected from ranibizumab, bevacizumab or aflibercept.

21. The combination according to claim 17, wherein the corticosteroid drug is selected from cortisone, prednisone, prednisolone, methylprednisolone, meprednisolone, beclomethasone, triamcinolone, paramethasone, mometasone, budesonide, fluocinonide, halcinonide, flumethasone, flunisolide, fluticasone, betamethasone, dexamethasone, hydrocortisone and fludrocortisone.

22. The combination according to claim 17, wherein the at least one compound belonging to the pyrazolone class is selected from dipyrone, propiphenazone and mixtures thereof.

23. A kit comprising a topical ophthalmic composition, a container containing the topical ophthalmic composition, and a dispenser, wherein the topical ophthalmic composition comprises a compound belonging to the pyrazolone class of formula (I) and at least one pharmaceutically acceptable excipient, and is for use in the prevention and / or treatment of retinal degenerative diseases. [Chemical Formula 3] (In the formula, R1 and R2 are independently selected from H, linear or branched C1-C6 alkyl, and aryl optionally substituted with OH, C1-C6 alkoxy, linear or branched C1-C6 alkyl or halogen, R3 is selected from linear or branched C1-C6 alkyl and OH, R4 is H, linear or branched C1-C8 alkyl, linear or branched C2-C8 alkenyl, -(CH2)1-4-CO-linear or branched C1-C6 alkyl group, linear or branched C1-C6 alkyl, -(CH2)(1-3)-SO3H group, or an amino group mono- or disubstituted with these combinations, -NHCO-aryl, -NHCO-heteroaryl group and pharmaceutically acceptable salts thereof. )

24. The kit according to claim 23, wherein the retinal degenerative disease is selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floaters) and myopic maculopathy.

25. The kit according to claim 23, wherein the topical ophthalmic composition is an aqueous solution.

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