TRPA1 CHANNEL ANTAGONIST COMPOUNDS FOR USE IN RETINAL DEGENERATIVE DISEASES - Patent application

Abstract

The present invention relates to a TRPA1 channel antagonist compound for use in the prevention and / or treatment of retinal diseases, in particular in the prevention and / or treatment of macular degeneration.The present invention also relates to an ophthalmic composition comprising at least one TRPA1 channel antagonist compound for topical ophthalmic use in the prevention and / or treatment of at least one retinal degenerative disease, preferably macular degeneration.

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present invention relates to transient receptor potential ankyrin 1 (TRPA1) channel antagonist compounds for use in the prevention and / or treatment of retinal diseases, in particular in the prevention and / or treatment of macular degeneration. The present invention also relates to ophthalmic compositions comprising at least one TRPA1 channel antagonist compound for topical ophthalmic use in the prevention and / or treatment of at least one retinal degenerative disease, preferably macular degeneration.

[0002] [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 light-sensitive cells responsible for central and color vision, while the photoreceptors surrounding the macula, rods, are responsive to lower light levels but are not color-sensitive.

[0003] The retina can be affected by a variety of conditions that can severely affect vision depending on the area of ​​the retina affected.

[0004] Retinal damage can be direct or indirect. A condition resulting from indirect retinal damage is glaucoma. Glaucoma is an eye disease caused by increased pressure inside the eye, specifically due to blockage of the outflow pathway of aqueous humor, the fluid that circulates within the eye and ensures nutrition for vital ocular structures. As a result, the ratio between aqueous humor produced and aqueous humor drained increases, raising intraocular pressure above the normal 14-16 mmHg. If this pressure increase is significant or persists for a long time, it can damage the optic nerve. In addition to optic nerve damage, the condition is also characterized by changes in the retinal nerve fiber layer, thus indirectly resulting in retinal damage.

[0005] Current medical therapy is essentially based on the use of eye drops that function to reduce aqueous humor production or increase aqueous humor output. The first drug used was pilocarpine, an alkaloid from the plant Pilocarpus jaborandi, but it is now rarely used due to several unpleasant side effects. Current drugs used to treat glaucoma are beta-blockers, carbonic anhydrase inhibitors (including acetazolamide and diclofenamide), alpha-agonists, and prostaglandins (latanoprost).

[0006] Macular degeneration is one of several conditions that directly damage the retina.

[0007] Macular degeneration is an age-related, multifactorial disease affecting the macula. It is a progressive disease and the leading cause of irreversible blindness in adults over the age of 50. Macular degeneration is actually age-related, and therefore, due to increasing life expectancy, it is a disease that will eventually affect the world population more widely than ever before. Two different forms of age-related macular degeneration are known: dry (non-exudative or atrophic) and wet (exudative or neovascular) forms. Dry age-related macular degeneration is caused by changes in the retinal pigment epithelium, which plays an essential role in maintaining the health and full function of rods and cones. The accumulation of waste products in the cones and rods can lead to the formation of drusen, visible as yellow spots that characterize the early stages of age-related macular degeneration. The dry form is characterized by progressive thinning of the central retina, which is inadequately nourished by capillaries and atrophies, resulting in the formation of atrophic lesions in the macula. Areas of retinal choroidal atrophy (called geographic atrophy) occur in more advanced cases of dry age-related macular degeneration.

[0008] Wet macular degeneration, on the other hand, is characterized by the growth of abnormal blood vessels from the choroid relative to the macula (choroidal neovascularization). Localized macular edema or hemorrhage can lead to macular elevation or localized retinal pigment epithelial detachment. Ultimately, untreated neovascularization leads to a submacular disciform scar. These newly formed blood vessels almost exclusively originate from the choroid (choroidal neovascularization) and contribute to the formation of a fibrovascular scar that destroys the central retina.

[0009] Wet macular degeneration, which is generally more aggressive than dry macular degeneration, can cause rapid and severe central vision loss due to scarring of blood vessels. Patients with wet age-related macular degeneration usually exhibit rapid loss of visual function within days or weeks. The initial symptom is generally visual distortion 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.

[0010] Most available treatments aim to prevent or cure wet neovascular macular degeneration. However, to date, there is still no established treatment for dry neovascular macular degeneration. Patients with extensive drusen, pigmentation changes, and / or geographic atrophy can reduce the risk of developing advanced age-related macular degeneration by 25% by taking antioxidant vitamin and mineral supplements, which 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 commercially available nutritional supplements along with antioxidants.

[0011] Such vitamin and antioxidant supplements can be used to reduce direct damage, particularly direct degenerative damage, to the retina, rather than indirect damage. Indeed, it has been observed that nutritional supplements that can significantly reduce the risk of advanced macular degeneration offer no benefit when used to treat glaucoma because they do not lower intraocular pressure. Thus, it is clear that the two pathologies of glaucoma and macular degeneration, both of which involve the retina, have distinct molecular mechanisms. Indeed, the damage caused by excessive intraocular pressure that characterizes glaucoma is localized at the level of the inner cells of the retina (ganglion, amacrine, horizontal, and bipolar cells), rather than the retinal pigment epithelium (i.e., from the RPE layer) and photoreceptors (rods and cones). To study these two pathologies, glaucoma and macular degeneration, two animal models are used that exhibit, at a molecular level, the typical pathologies identified in patients with glaucoma and macular degeneration. Animal models of glaucoma exhibit pathology localized to the inner retinal cells (ganglion, amacrine, horizontal, and bipolar cells) and spare the retinal pigment epithelium (Souza Monteiro de Araujo et al., 2020), whereas animal models of macular degeneration exhibit damage to the central pole of the retina, which can extend to the periphery (Kiuchi, Current Eye Research 2002; Machalinska, Neurochemical Res. 2010; Wang, Invest Ophthalmol Vis Sci 2014; Commentaries NEURAL REGENERATION RESEARCH December 2014; Hanu, Cell Death Disc 2016; Chower, Invest Ophthalmol 2017; and Koh, Journal of Photochemistry & Photobiology 2019). Furthermore, loss of retinal pigment epithelium cells in mouse models of macular degeneration has been observed to affect not only photoreceptors but also the underlying choriocapillaris. Damage to the choriocapillaris layer underlying the photoreceptors has not been observed in animal models of glaucoma.Due to the distinct differences between the two pathologies, glaucoma and macular degeneration, which directly or indirectly affect the retina, drugs currently used to treat glaucoma cannot be used to treat macular degeneration, particularly dry macular degeneration, and vice versa.

[0012] Furthermore, with regard to macular degeneration, most of the available treatments are aimed at preventing or treating the wet form of macular degeneration rather than the dry form, and to date there is still no established treatment.

[0013] Pharmacological treatment options for wet macular degeneration include periodic intravitreal injection of vascular endothelial growth factor antagonists (anti-VEGF drugs), such as ranibizumab, bevacizumab, or aflibercept. In addition, corticosteroids, such as triamcinolone, can be administered together with anti-VEGF drugs via intraocular injection. Intravitreal administration is an invasive route of administration that can cause increased intraocular pressure, headache, vitreous inflammation (eye inflammation), vitreous detachment, retinal hemorrhage (bleeding from the back of the eye), visual disturbance, and eye pain. Although intravitreal administration is infrequent (approximately 1 / 1000), in severe cases, it can also cause septic endophthalmitis, a serious intraocular inflammatory disease resulting from infection of the vitreous cavity that can lead to visual loss or total blindness.

[0014] Therefore, there is a clear need to provide new, non-invasive therapies for the long-term treatment of age-related macular degeneration that allow for prevention and / or long-term treatment without incurring side effects associated with the administration method.

[0015] [Summary of the Invention] Applicant has addressed the problem of providing new therapies for the prevention and / or long-term treatment of retinal degenerative diseases, particularly macular degeneration, that do not involve the inconveniences and side effects of current therapies, particularly those requiring intravitreal administration, and in some cases are as effective or more effective.

[0016] Applicants have surprisingly found that new therapeutic methods based on the administration of at least one TRPA1 channel antagonist compound may be useful in the prevention and treatment of retinal degenerative diseases, such as macular degeneration.

[0017] Accordingly, a first aspect of the present invention is a TRPA1 channel antagonist compound 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.

[0018] In particular, applicants have observed that compounds that act as TRPA1 channel antagonist compounds may be particularly effective in preventing and / or treating macular degeneration.

[0019] Therefore, the TRPA1 channel antagonist compounds described in the present patent application can be advantageously used in the prevention and / or treatment of macular degeneration, particularly dry and wet age-related macular degeneration.

[0020] A further aspect of the present invention is a pharmaceutical composition comprising at least one TRPA1 channel antagonist compound and at least one pharmaceutically 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, and myopic maculopathy.

[0021] Preferably, the pharmaceutical composition for use according to the present invention is a topical ophthalmic composition for use in the prevention and / or treatment of macular degeneration.

[0022] 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 topical ophthalmic composition is for use in the prevention and / or treatment of at least one retinal degenerative disease as described above.

[0023] A further aspect of the 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 hole, macular pucker, floaters and myopic maculopathy, preferably macular degeneration, comprising the step of administering to a patient at least one TRPA1 channel antagonist compound or an ophthalmic composition for use according to the invention.

[0024] A final aspect of the present invention is a combination of a TRPA1 channel antagonist compound and an anti-VEGF agent and / or a corticosteroid agent 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.

[0025] [Detailed Description of the Invention] A first aspect of the present invention is a TRPA1 channel antagonist compound for use in the prevention and / or treatment of at least one retinal degenerative disease.

[0026] Applicants believe that inhibiting the activity of the TRPA1 channel and the signaling pathways downstream of the TRPA1 channel can prevent and / or treat retinal degenerative diseases.

[0027] The expression "TRPA1 channel antagonist" is intended to denote a compound capable of exerting inhibitory activity on the TRPA1 channel and the signaling pathways downstream of the TRPA1 channel. The compounds for use according to the invention inhibit the activity of the TRPA1 channel and therefore act as TRPA1 channel antagonists.

[0028] The TRPA1 receptor antagonists of the present invention bind to the TRPA1 receptor with high affinity. In any case, the binding affinity of the TRPA1 antagonist is better than the binding affinity between the antagonist and another subtype of a receptor in the TRP superfamily. Preferably, the binding affinity of the TRPA1 antagonist is at least 100-fold higher than the binding affinity between the antagonist and another subtype of a receptor in the TRP superfamily. Tests for determining whether a compound is a TRPA1 receptor antagonist are described, inter alia, in Radresa et al., The Open Pain Journal 2013, 6, (Suppl1 M14) 137-153.

[0029] TRP channels are the transporters of monovalent and divalent cations, particularly sodium (Na), which are primarily involved in regulating the activation of sensory pathways. + ) and calcium (Ca 2+ TRPCs represent a large, heterogeneous family of ion-permeable membrane ion channels. In mammals, 28 receptor subtypes have been identified, divided into six subfamilies: canonical (TRPC1-7), vanilloid (TRPV1-6), ankyrin (TRPA), melastatin (TRPM1-8), polycystin (TRPP1-3), and mucolipin (TRPML1-3).

[0030] The TRPA1 channel is the only member of the ankyrin family.

[0031] In particular, TRPA1 channels are expressed in primary sensory neurons of the dorsal, trigeminal, nodose, and vagus root ganglia, which give rise to afferent nerve fibers that transmit various types of sensory signals (mechanical, chemical, and thermal).

[0032] TRPA1 channels act as chemical sensors of oxidative stress in inflammation-prone tissues and play a key role in signaling pain stimuli.

[0033] TRPA1 channel antagonist compounds for use according to the present invention can be selected from, for example, the compounds described in the articles Expert Opin. Ther. Patents 2012, 22, 663-95, Pharm. Pat. Anal. 2015, 4, 75-94 and Expert Opin. Ther. Patents 2020, 30, 643-657.

[0034] Examples of such compounds are described, inter alia, in the articles Fanger et al., "TRPA1 as an Analgesic Target," The Open Drug Discovery Journal, 2010, 2, 64-70, and Chen et al., "TRPA1 as a drug target—promise and challenge," Naunyn-Schmiedeberg's Arch Pharmacol, 2015, 388:451-463, as well as in the patent documents and relevant citations reported herein. TRPA1 channel antagonist compounds for use according to the present invention can be prepared, for example, as described in the documents cited herein.

[0035] TRPA1 channel antagonist compounds for use according to the present invention are of the following classes: 1) Purinone derivatives and bioisosteres; 2) sulfonamide derivatives; 3) oxime derivatives; 4) amide derivatives; 5) Polycyclic heterocyclic aromatic derivatives; 6) Indazole derivatives and bioisosteres; 7) Phenylcarbamate derivatives and bioisosteres; or 8) Decalin derivatives The compound can be selected from compounds belonging to one of the following groups: salts, optical isomers, solvates and prodrugs thereof.

[0036] Preferably, the TRPA1 channel antagonist compounds for use according to the present invention are from the following classes: 2) sulfonamide derivatives; 5) polycyclic heterocyclic aromatic derivatives; or 6) Indazole derivatives and bioisosteres, The compound can be selected from compounds belonging to one of the following groups: salts, optical isomers, solvates and prodrugs thereof.

[0037] The chemical classes of compounds referred to below are described below.

[0038] 1) Purinone derivatives and their bioisosteres , for example as shown inter alia in the following documents: general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2019152465 (Eli Lilly) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015164643 (Hydra Biosciences) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2016044792 (Hydra Biosciences) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015155306 (Almirall) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2017060488 (Almirall) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2017064068 (Almirall) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015056094 and WO 2016042501 (Glenmark) relating to the compound; The following formula [ka] J.Med.Chem. 2016, 59, 2794-2809 (Amgen) for compound AM-0902 (CAS number 1883711-97-4); general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2018096159 (Hoffmann La Roche, Genentech) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2018162607 (Hoffmann La Roche, Genentech) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2019182925 (Hoffmann La Roche, Genentech) relating to the compound; WO 2021074198 (Boheringer) relating to tetrazole derivatives selected from the list of nine compounds of claim 1 (list 1.13); general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2013023102 (Hydra Biosciences) relating to the compound.

[0039] Preferred compounds of this class are the following compounds: HC-030031 (Hydra Bioscience, CAS No. 349085-38-7) of the following formula and analogs shown in WO 2012050641; [ka] Chembridge-5861528 (Alomone Lab, CAS number: 332117-28-9) of the following formula: [ka] CB-189625 and HX-100 (Hydra Biosciences and Cubist Pharmaceuticals) of the formula: and analogs; [ka] GRC17536 (Glenmark Pharmaceutical, CAS number: 1649479-05-9) of the following formula: [ka]

[0040] 2) Sulfonamide Derivatives , for example as shown inter alia in the following documents: general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2014049047 (Hoffmann La Roche) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015052264 (Hoffmann La Roche, Genentech) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2016128529 (Hoffmann La Roche, Genentech) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2018015410 (Hoffmann La Roche, Genentech) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2018029288 (Hoffmann La Roche, Genentech) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015115507 (Ajinomoto) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2017018495 (EA Pharma) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2017135462 (EA Pharma) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2010141805 (Janssen) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2012152983 (Orion) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) European Patent No. 2805718 (International Publication No. 2013108857, Ajinomoto) relating to the compound.

[0041] According to a preferred embodiment, compounds of this class have the following general formula A1 [ka] wherein A and B are equal to or different from each other and can represent a CH group or a nitrogen atom; Ar is preferably selected from the group consisting of aryl, pyridine, pyrimidine, pyrazine, pyrrole, imidazole, furan, thiophene and thiazole and can represent a 5- or 6-membered aromatic ring optionally substituted with one or more halogen atoms, preferably one or more fluorine or chlorine atoms; R1, R2 and R3 are equal to or different from each other and can represent a hydrogen atom, a fluoromethyl group or a group represented by the following formula: [ka] (wherein X and Y are equal to or different from each other and can represent a CH group or a nitrogen atom.) can represent residues of is expressed by

[0042] Preferred compounds of this class are the following compounds: The following formula [ka] JNJ-41477670(Janssen) Janssen [ka] The following formula (IV) [ka] GDC-0334 (Genetech / Roche)

[0043] In a particularly preferred embodiment, the compound for use in the prevention and / or treatment of at least one retinal degenerative disease is a compound of formula (IV).

[0044] In particular, the compounds of formula (IV) are capable of preventing and / or treating macular degeneration, both dry and wet age-related macular degeneration.

[0045] Indeed, as shown in the experimental section, the compound of formula (IV) proved to be particularly effective in protecting the retina from NaIO3-induced damage to cells of the RPE layer, which is of fundamental importance in maintaining the function of macular photoreceptors.

[0046] 3) Oxime Derivatives , for example as shown inter alia in the following documents: general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2009089083 (Abbott) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2009089082 (Abbott) relating to the compound;

[0047] Preferred compounds of this class are the following compounds: The following formula described in Pain 2011, 152, 1165-1172 [ka] A967079(Abbott); AP-18 (CAS number 55224-94-7) of the following formula [ka]

[0048] 4) Amide derivatives , for example as shown inter alia in the following documents: general formula [ka] In particular, compounds of the formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2016067143 (Pfizer) relating to the compound; general formula [ka] In particular, compounds of the formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2014053694 (Orion Corporation) relating to pyridine-3-carboxamide; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015144976 (Orion Corporation) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015144977 (Orion Corporation) relating to the compound; Of particular interest is the Orion Pharma compound identified by the acronym ODM-108.

[0049] general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2012050512 (ASTRAZENECA) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2020244460 (HANGZHOU WESTAN PHARMACEUTICAL) relating to the compound; general formula [ka] (In the formula, R 3 is -NHCO- or -CONH-, other substituents have the meanings indicated in the document itself. WO 2018015411 (Hoffmann La Roche, Genentech) relating to the compound.

[0050] Preferred compounds of this class are the following compounds: The following formula [ka] AZ465 (ASTRAZENECA) The following formula [ka] Pfizer The following formula [ka] Orion

[0051] 5) Polycyclic heteroaromatic derivatives , for example as shown inter alia in the following documents: general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2015103060 and WO 2018009717 (Algomedix) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) Bioorg.Med.Chem.Lett.2014, 24, 3464-3468 (Amgen) on the compound general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2009147079 (Janssen) relating to the compound

[0052] According to a preferred embodiment, compounds of this class have the following general formula A2 [ka] (In the formula, A can represent an oxygen atom, an —NH— group, or a carbonyl group —(C═O)—, and B can represent a —CH— group or a nitrogen atom.) It is expressed as:

[0053] Preferred compounds of this class of polycyclic heteroaromatic derivatives are represented by formulae (I) and (II) reported below: [ka] is a compound of

[0054] The compound of formula (I) is a TRPA1 channel antagonist (compound 10, CAS number 1620518-03-7) developed by Amgen.

[0055] The compound of formula (II) is a TRPA1 channel antagonist (compound 43, CAS number 1198174-47-8) developed by Janssen.

[0056] In a particularly preferred embodiment, the compound for use according to the invention is a compound of formula (II).

[0057] In particular, the compound of formula (II) can prevent and / or treat macular degeneration, both dry and wet age-related macular degeneration. Indeed, as shown in the experimental section, the compound of formula (II) has proven particularly effective in protecting the retina from NaIO3-induced damage to cells of the RPE layer, which is fundamentally important for maintaining the function of the macular photoreceptors.

[0058] In a further particularly preferred embodiment, the compound for use according to the invention is a compound of formula (I).

[0059] In particular, the compounds of formula (I) are capable of preventing and / or treating macular degeneration, both dry and wet age-related macular degeneration.

[0060] Indeed, as shown in the experimental section, the compound of formula (I) has proven particularly effective in protecting the retina from NaIO3-induced damage to cells of the RPE layer, which is of fundamental importance in maintaining the function of macular photoreceptors.

[0061] 6) Indazole derivatives and bioisosteres , for example as shown inter alia in the following documents: general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) J.Med.Chem.2014, 57, 5129-5140 (Novartis) on the compound; ACS Med Chem Lett.2017;8, 666-671 (Pfizer, amino and aryl indazoles, Tables 1 and 2); According to a preferred embodiment, compounds of this class have the following general formula A3 [ka] (wherein R6, R7, and R8 are equal to or different from each other and may represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a trifluoromethyl group.) is expressed by

[0062] Preferred compounds of this class are shown below: [ka] The compound of formula (III) is a TRPA1 channel antagonist (CAS number 1613505-14-8) developed by Novartis.

[0063] In a particularly preferred embodiment, the compound for use according to the invention is a compound of formula (III).

[0064] In particular, the compounds of formula (III) are capable of preventing and / or treating macular degeneration, both dry and wet age-related macular degeneration.

[0065] Indeed, as shown in the experimental section, the compound of formula (III) proved to be particularly effective in protecting the retina from NaIO3-induced damage to cells of the RPE layer, which is of fundamental importance in maintaining the function of macular photoreceptors.

[0066] 7) Phenylcarbamate derivatives and bioisosteres, such as those disclosed in, inter alia, the following documents: general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2014056958 (Hofmann-La Roche) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2014060341 (Hofmann-La Roche) relating to the compound; general formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2014072325 (Hofmann-La Roche) relating to the compound

[0067] Preferred compounds of this class are the following compounds: Hofmann-La Roche [ka]

[0068] 8) Decalin derivatives , for example as shown inter alia in the following documents: general formula [ka] Compounds of In particular, the following formula [ka] (wherein the substituents have the meanings indicated in the document itself.) WO 2011043954 (Merck) relating to the compound

[0069] Preferred compounds of this class are the following compounds: [ka]

[0070] The TRPA1 channel antagonist compounds for use according to the present invention may be in the form of a salt, optical isomer in pure or mixed form, solvate or prodrug, provided that it is pharmaceutically acceptable.

[0071] The term "prodrug" refers to a biologically inactive molecule that, when introduced into the body, undergoes an enzymatic chemical transformation that activates the biologically inactive molecule. Thus, a prodrug is a precursor to an active ingredient.

[0072] Preferably, the compounds for use according to the invention are selected from the compounds belonging to the class of polycyclic derivatives or indazole derivatives, since these classes are characterized by good pharmacokinetic properties and a good profile of action.

[0073] The TRPA1 channel antagonist compounds, preferably belonging to the class of polycyclic derivatives or indazole derivatives, 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 (floats), and myopic maculopathy.

[0074] According to a preferred embodiment of the present invention, the compounds of the present invention, which preferably belong to the class of polycyclic derivatives or indazole derivatives, are capable of preventing and / or treating a specific type of retinal degenerative disease: macular degeneration, which falls into the broad category of maculopathies.

[0075] In the present invention, the term "macular degeneration" is used to refer to a specific type of degenerative maculopathy.

[0076] The term "maculopathy" refers to a pathological condition affecting the central part of the retina, called the macula. Maculopathy can be classified into acquired maculopathy, myopic maculopathy, and hereditary maculopathy. According to another aspect of the present invention, a TRPA1 channel antagonist compound can be used to prevent and / or treat myopic maculopathy. Myopic maculopathy occurs in people with degenerative or pathological myopia. In particular, in subjects with myopic maculopathy, the retina cannot adapt to the elongation of the eyeball and is damaged. In pathological myopia, macular hemorrhage can occur, accompanied by sudden vision loss, sometimes metamorphopsia.

[0077] The most common acquired maculopathy is age-related macular degeneration.

[0078] Macular degeneration is a disease characterized by deterioration of the macula, the central part of the retina responsible for central vision.

[0079] In the present invention, the terms "age-related macular degeneration" and "senile macular degeneration" both refer to the above-described retinal degenerative maculopathy. According to the present invention, the TRPA1 channel antagonist compounds defined above are useful for the prevention and / or treatment of both forms of macular degeneration, i.e., dry age-related macular degeneration and wet age-related macular degeneration.

[0080] 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 TRPA1 channel antagonist compound and at least one pharmaceutically 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 both forms of macular degeneration.

[0081] In the pharmaceutical composition for use according to the present invention, the at least one TRPA1 channel antagonist compound belongs to one of the above classes 1) to 8), preferably classes 2), 5) and 6), more preferably classes 5) and 6) of polycyclic heterocyclic aromatic derivatives or indazole derivatives and bioisosteres, respectively.

[0082] In a particularly preferred embodiment, the compound belonging to the class of sulfonamide derivatives has the above-mentioned general formula A1). More preferably, said compound belonging to the class of sulfonamide derivatives and having the general formula A1) is a compound of the above-mentioned formula (IV).

[0083] In a particularly preferred embodiment, the compound belonging to the class of polycyclic derivatives present in said pharmaceutical composition has the general formula A2), said compound preferably being selected from the compounds of formula (I) or (II) above.

[0084] In a particularly preferred embodiment, the compounds belonging to the class of indazole derivatives and bioisosteres present in said pharmaceutical composition have the general formula A3.

[0085] More preferably, said compound belonging to the class of indazole derivatives and bioisosteres and having general formula A3 is a compound of formula (III) as defined above.

[0086] According to one embodiment, the ophthalmic composition comprises a plurality of TRPA1 channel antagonist compounds, preferably at least two TRPA1 channel antagonist compounds, which preferably belong to the class of polycyclic derivatives and / or indazole derivatives and are preferably selected from the compounds of formula (I) or (II) and (III) above, and even more preferably from the compounds of formulas (I) to (III).

[0087] The pharmaceutical composition, preferably the ophthalmic composition, for use according to the present invention can be advantageously used for the prevention and / or treatment of retinal degenerative diseases, preferably selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters (floaters) and myopic maculopathy.

[0088] Preferably, the retinal degenerative condition is macular degeneration, in particular dry and wet age-related macular degeneration.

[0089] Pharmaceutical compositions for use according to the invention may be administered by any route of administration suitable for achieving a concentration at the retinal level effective for the prevention and / or treatment of the condition in question. Preferably, the pharmaceutical composition for use according to the invention is an ophthalmic composition suitable for internal or external administration to the eye.

[0090] According to one embodiment, 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 suprachoroidal portion of the eye.

[0091] According to another preferred embodiment, the composition is suitable for administration to the anterior segment of the eye 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.

[0092] In another more preferred embodiment, the composition for use according to the invention is a topical ophthalmic composition suitable for topical administration to the eye, for example by application to the external surface of the cornea, the lower eyelid capsule or conjunctival fornix.

[0093] Topical ophthalmic compositions for use according to the present invention can be formulated in the form of, for example, a solution, suspension, emulsion, gel, ointment, eye insert, or therapeutic contact lens. Topical use of the compositions of the present invention, for example, in the form of drops or eye drops, advantageously allows for the treatment of one or more retinal diseases, particularly macular degeneration, in a non-invasive manner, avoiding the inconvenience and side effects of intravitreal administration currently commonly used to treat macular degeneration.

[0094] Ophthalmic compositions for use according to the present invention may include one or more ophthalmologically acceptable additives and / or excipients selected from those commonly used in ophthalmic formulations.

[0095] An "ophthalmologically acceptable excipient" is an inert excipient that allows for the administration of a medication to the eye and / or eyelid to treat an ocular disease or condition without adversely affecting the eye. Generally, an excipient is a substance that not only favors the preservation of a product over time, but also contributes to the efficacy and tolerability of the product in which it is contained.

[0096] Examples of such ophthalmically acceptable additives or excipients include viscosity enhancing agents, permeation enhancers, buffering agents, osmolality adjusting agents, antioxidants, preservatives and surfactants.

[0097] Viscosity increasing 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 acetate alcohol, dextran, gelatin, glycerin, polysorbate 80 and other gelling agents.

[0098] 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.

[0099] The buffering agent functions to provide and maintain the pH of the composition as close as possible to physiological pH, preferably between 6 and 8. This function is essential to allow good tolerability of the preparation and to maintain its effectiveness. A 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.

[0100] The osmolality adjusting agent is a salt capable of making the liquid composition isotonic with ocular fluid. A preferred salt is sodium chloride (NaCl), but other biologically acceptable salts, such as potassium chloride (KCl), calcium chloride (CaCl), and magnesium chloride (MgCl), and mixtures thereof, or buffer substances such as propylene glycol, glycerin, dextrose, dextran 40 and 70, or the buffer substances described above, can also be used.

[0101] Antioxidants prevent or retard product deterioration 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.

[0102] Preservatives are substances that inhibit bacterial growth that may occur after the product is opened. 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 not only inhibit bacterial growth but also favor the penetration of drugs through the cornea.

[0103] 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.

[0104] In one embodiment, the ophthalmic composition for use according to the invention is an aqueous ophthalmic composition in the form of eye drops, for example for topical administration to the anterior segment of the eye.

[0105] Aqueous ophthalmic compositions of TRPA1 channel antagonists contain a sufficient amount of water to achieve appropriate concentrations of the components of the composition.

[0106] Preferably, in a liquid, preferably aqueous, ophthalmic composition, the TRPA1 channel antagonist is present at a concentration in the range of about 0.0001% to about 5% w / v of the aqueous composition, more preferably about 0.01% to about 1% w / v, and even more preferably about 0.5% w / v.

[0107] Ophthalmic compositions for use according to the present invention can include, for example, a therapeutically effective amount of at least one TRPA1 channel antagonist compound, sodium chloride, magnesium chloride, mono- and dibasic sodium phosphate, and about 100 ml of water for ophthalmic use.

[0108] In one embodiment, a topical ophthalmic composition for use according to the invention, preferably a liquid composition, may be part of a kit comprising the composition, a container containing the composition, and a dispenser. In the case of eye drops, the dispenser is a drop dispenser.

[0109] In another embodiment, the pharmaceutical composition, preferably the ophthalmic composition, for use according to the present invention may further comprise at least one other pharmaceutically active compound.

[0110] In a preferred embodiment, the pharmaceutical composition, preferably the ophthalmic composition, for use according to the present invention may further comprise one or more vascular endothelial growth factor antagonist drugs (anti-VEGF) and / or corticosteroid drugs.

[0111] A further aspect of the present description relates to a method for preventing and / or treating 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 and myopic maculopathy, comprising the step of administering to a subject at least one TRPA1 channel antagonist compound or a pharmaceutical composition, preferably an ophthalmic composition, comprising at least one TRPA1 channel antagonist compound.

[0112] In a preferred embodiment, the retinal degenerative disease is macular degeneration, and the TRPA1 channel antagonist compound is selected from a compound belonging to the class of polycyclic derivatives, wherein the compound belonging to the class of polycyclic derivatives is a compound of formula (I), and a compound belonging to the class of indazole derivatives, wherein the compound belonging to the class of indazole derivatives is a compound of formula (III).

[0113] As a guideline, methods according to the present invention may involve topical ocular administration of at least one TRPA1 channel antagonist at a dose of 1-100 mg per dose, for a total of 1-5 doses per day.

[0114] The exact dosage and regimen of administration of the TRPA1 antagonist in the treatment or prevention of the aforementioned diseases will depend on many factors, such as the route of administration or the degree of affliction of the individual being treated.

[0115] In an alternative embodiment, the method comprises administering one or more drugs commonly used in the treatment of macular degeneration, preferably an anti-VEGF drug and / or a corticosteroid, in combination with a TRPA1 channel antagonist compound or an ophthalmic composition for use according to the present invention.

[0116] In this embodiment, the drugs currently used to treat macular degeneration, preferably anti-VEGF drugs and / or corticosteroid drugs, can be administered before, during, or after administration of the TRPA1 channel antagonist compound and / or the above-described ophthalmic composition.

[0117] 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 TRPA1 channel antagonist compound include ranibizumab, bevacizumab, and / or aflibercept.

[0118] Examples of corticosteroids currently used to treat macular degeneration that can be administered in combination with an ophthalmic composition comprising at least one TRPA1 channel antagonist compound include cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, beclomethasone, triamcinolone, paramethasone, mometasone, budesonide, fluocinonide, halcinonide, flumethasone, flunisolide, fluticasone, betamethasone, dexamethasone, hydrocortisone, and / or fluocortolone.

[0119] In particular, the method for preventing and / or treating a retinal degenerative disease comprises administering at least one of the above-listed corticosteroids when the retinal degenerative disease is selected from diabetic retinopathy, retinal detachment, central serous chorioretinopathy, and hypertensive retinopathy.

[0120] According to the present invention, the administration of the anti-VEGF agent and / or the corticosteroid may be simultaneous, separate or sequential.

[0121] In another embodiment, the method for preventing and / or treating at least one retinal degenerative disease as defined above comprises administering to a subject a composition comprising at least one TRPA1 channel antagonist compound and at least one drug selected from an anti-VEGF drug and a corticosteroid drug.

[0122] In such embodiments, drugs currently used to treat retinal diseases, such as macular degeneration, are already included in the compositions of the invention and are therefore co-administered with the TRPA1 channel antagonist compound and / or compositions comprising said compounds.

[0123] A final aspect of the present invention relates to a combination of at least one TRPA1 channel antagonist compound and an anti-VEGF agent and / or a corticosteroid agent 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 (floaters) and myopic maculopathy, preferably both forms of macular degeneration.

[0124] Preferably, the combination for use according to the present invention comprises at least one compound belonging to classes 2), 5) and 6) as defined above, more preferably a compound of formula I to IV according to the present description, as a TRPA1 channel antagonist compound.

[0125] In a preferred embodiment, the combination is useful for the prevention and / or treatment of macular degeneration, particularly dry age-related macular degeneration and wet age-related macular degeneration.

[0126] In such embodiments, the combination includes an anti-VEGF agent selected from ranibizumab, bevacizumab, or aflibercept.

[0127] In such embodiments, the combination includes a corticosteroid selected from cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, beclomethasone, triamcinolone, paramethasone, mometasone, budesonide, fluocinonide, halcinonide, flumethasone, flunisolide, fluticasone, betamethasone, dexamethasone, hydrocortisone, and fluocortolone. [Brief explanation of the drawings]

[0128] [Figure 1A]1 shows immunofluorescence images of the RPE layer of retinas harvested from mice in a NaIO3-induced macular degeneration model on day 4 after treatment with NaIO3 or its vehicle (V1), and a compound of Formula (IV) (designated as FN-005)—Class 2) sulfonamide derivatives; or a compound of Formula (I) (designated as FN-006)—Class 5) polycyclic heteroaromatic derivatives; or a compound of Formula (II) (designated as FN-007)—Class 5) polycyclic heteroaromatic derivatives; or a compound of Formula (III) (designated as FN-008)—Class 6) indazole derivatives and bioisosteres; or their vehicle (V2). RPE65 indicates the antibody used to stain the RPE layer. The letters in each panel of Figure 1A indicate the following: V1 / V2: Mice were administered with NaIO3 in a vehicle (V1) before and after receiving various drugs in a vehicle (V2). Therefore, the mice did not receive any active treatment. The V2 vehicle containing various drugs consisted of 4% dimethyl sulfoxide (DMSO), 4% Tween 80 in 0.9% NaCl. V2 / NaIO3: Mice were administered with various drugs in a vehicle (V2) before and after receiving NaIO3 in a NaIO3 vehicle (V1) to obtain mice with macular degeneration. FN-005 / NaIO3: Mice were treated with the compound of formula (IV) before and after receiving NaIO3 in a NaIO3 vehicle. FN-006 / NaIO3: Mice were treated with the compound of formula (I) before and after receiving NaIO3 in a NaIO3 vehicle. FN-007 / NaIO3: Mice were treated with the compound of formula (II) before and after administration of NaIO3 in a vehicle of NaIO3. FN-008 / NaIO3: Mice were treated with the compound of formula (III) before and after administration of NaIO3 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]Figure 1 shows immunofluorescence images of 4-hydroxynonenal (4-HNE), an oxidative stress biomarker, in retinas taken on day 4 from mice in a NaIO3-induced macular degeneration model after treatment with NaIO3 or its vehicle (V1), and: a compound of formula (IV) (designated as FN-005) - Class 2) sulfonamide derivatives; or a compound of formula (I) (designated as FN-006) - Class 5) polycyclic heteroaromatic derivatives; or a compound of formula (II) (designated as FN-007) - Class 5) polycyclic heteroaromatic derivatives; or a compound of formula (III) (designated as FN-008) - Class 6) indazole derivatives and bioisosteres; or their vehicle (V2). The letters in each panel of Figure 2A indicate the following: V1 / V2: Mice were administered various drug-dissolved vehicles (V1) before and after receiving NaIO3 vehicle (V2). These mice constitute the control group. V2 / NaIO3: Mice were administered various drug-dissolved vehicles (V2) before and after receiving NaIO3 in a NaIO3 vehicle to obtain mice with macular degeneration. FN-005 / NaIO3: Mice were treated with the compound of formula (IV) before and after receiving NaIO3 in a NaIO3 vehicle. FN-006 / NaIO3: Mice were treated with the compound of formula (I) before and after receiving NaIO3 in a NaIO3 vehicle. FN-007 / NaIO3: Mice were treated with the compound of formula (II) before and after receiving NaIO3 in a NaIO3 vehicle. FN-008 / NaIO3: Mice were treated with the compound of formula (II) before and after administration of NaIO3 dissolved in a vehicle of NaIO3. [Figure 2B] 2B is a histogram representing the cumulative data of the immunofluorescence experiment shown in FIG. 2A. [Example]

[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 Italian legislation (Legislative Decree 26 / 2014) and the guidelines laid down in European regulations (EU Directive 2010 / 63 / EU). The study was carried out after protocol approval by the Ministry of Health (protocol number 135 / 2022-PR).

[0131] To create a valid macular degeneration model, systemic administration of NaIO3 (via the retroorbital vein) was performed in C57BL / 6J male mice, 5–8 weeks old and weighing 22–25 g, provided by Charles River (Milan, Italy). A total of 36 mice were used for the experiments described below. Animals were kept in a temperature- and humidity-controlled environment (12-h dark / light cycle, food and water available ad libitum). Experiments were performed in a temperature-controlled room (20–22°C) between 8:00 and 20:00. At the end of the experiment, animals were euthanized by 1 min of inhalation of a mixture of 50% O2 / 50% CO2. The NaIO3, DMSO, Tween 80, and NaCl 0.9% reagents used in the study were purchased from Merck Life Science SRL (Milan, Italy).

[0132] The compounds tested in Example 2 (a compound belonging to class 2) of sulfonamide derivatives and having formula (IV) (GDC-0334), hereinafter referred to as FN-005; a compound belonging to class 5) of polycyclic heteroaromatic derivatives and having formula (I) (compound 10, Amgen), hereinafter referred to as FN-006; a compound belonging to class 5) of polycyclic heteroaromatic derivatives and having formula (II) (compound 43, Janssen), hereinafter referred to as FN-007; and a compound belonging to class 6) of indazole derivatives and bioisosteres and having formula (III) (compound 31, Novartis), hereinafter referred to as FN-008) were synthesized according to methods known in the art.

[0133] A mouse model obtained by systemic administration (via the retro-orbital vein) of NaIO3 is a model of macular degeneration.

[0134] Indeed, after 3 days of administration, it was observed that NaIO3 induced persistent retinal damage in the experimental mice with characteristics similar to those observed in human age-related macular degeneration.

[0135] Example 2 - Administration of preferred compounds belonging to classes 2), 5) and 6) set forth herein To evaluate the effectiveness of the preferred compounds belonging to classes 2), 5) and 6) according to the present description in reducing and treating retinal damage specific to macular degeneration, experiments were set up on six groups of model mice obtained according to the procedure described in Example 1.

[0136] In particular, the following compounds were tested: A compound belonging to the class 2) of sulfonamide derivatives and having formula (IV) (GDC-0334), hereinafter referred to as FN-005; A compound belonging to the class 5) of polycyclic heteroaromatic derivatives and having formula (I) (Compound 10, Amgen), hereinafter referred to as FN-006; A compound belonging to the class 5) of polycyclic heteroaromatic derivatives and having the formula (II) (compound 43, Janssen), hereinafter referred to as FN-007; and A compound belonging to the class of indazole derivatives and bioisosteres 6) and having formula (III) (Compound 31, Novartis), hereafter referred to as FN-008.

[0137] Mice were administered topical eye drops of the compound or a vehicle of the compound consisting of 4% DMSO, 4% Tween 80 in 0.9% NaCl.

[0138] Specifically, a group of six mice (used as controls) received (1 ml / kg) NaIO3 vehicle (V1) (NaCl, 0.9%) by infusion 60 minutes before injection into the retro-orbital vein, followed by eye drops (5 μl) containing the drug vehicle (V2) (4% DMSO, 4% Tween 80 in 0.9% NaCl) three times daily.

[0139] Another 30 mice, in groups of 6 mice each, received (1 ml / kg) NaIO3 (1%, 20 mg / kg) 60 minutes before injection into the retro-orbital vein, followed by eye drops (5 μl) of a 10 mM solution of the aforementioned compounds FN-005, FN-006, FN-007, FN-008, or the vehicle (V2) of the aforementioned compounds (4% DMSO, 4% Tween 80 in 0.9% NaCl) instilled three times daily.

[0140] For each group of mice, the first administration (Day 1) of the compound of formula (IV), the compound of formula (I), the compound of formula (II), and the compound of formula (III) or vehicle (V2) was administered 60 minutes before the injection of NaIO3 or the NaIO3 vehicle (V1), and the second and third administrations were administered 6 and 12 hours after the injection of vehicle (V1) or NaIO3, respectively. On the two days (Days 2 and 3) after the injection of vehicle (V1) or NaIO3, the compounds of formula (IV), (I), (II), and (III) or vehicle (V2) were administered to the various groups of mice at 8:00, 14:00, and 20:00.

[0141] At 9:00 on the fourth day after treatment with vehicle (V1) or NaIO3, mice given the compounds listed above as FN-005, FN-006, FN-007, FN-008 or the vehicle of the compounds listed above (V2) were sacrificed (as previously reported), the eyes were removed, and the eyes were processed for subsequent injury analysis.

[0142] Example 3 - Immunofluorescence for assessing retinal pigment epithelium damage Direct immunofluorescence was used to assess damage to the retinal pigment epithelium (RPE), which corresponds to the pigment cell layer adjacent to the neurosensory retina that nourishes the visual cells of the retina and is tightly attached to the underlying choroid and the overlying visual retinal cells.

[0143] The 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 fluorophore-conjugated antibody (Alexa Flu or 488, #A28175, Thermo Fisher Scientific) in six groups of mice treated with V2 / V1, V2 / NaIO3, compound of Formula (IV) and NaIO3 (FN-005 / NaIO3), compound of Formula (I) and NaIO3 (FN-006 / NaIO3), compound of Formula (II) and NaIO3 (FN-007 / NaIO3), and compound of Formula (III) and NaIO3 (FN-008 / NaIO3). Cell nuclei were visualized using DAPI organic dye (#ab228549, Abcam, Cambridge, UK).

[0144] 1A and 1B show representative images and cumulative data of immunofluorescence staining of the RPE layer performed with a primary antibody (RPE65) on retinas harvested on day 4 from six groups of mice treated with V2 / V1, V2 / NaIO3, the compound of formula (IV) and NaIO3 (FN-005 / NaIO3), the compound of formula (I) and NaIO3 (FN-006 / NaIO3), the compound of formula (II) and NaIO3 (FN-007 / NaIO3), and the compound of formula (III) and NaIO3 (FN-008 / NaIO3).

[0145] The above treatments are shown in Figure 1A as V2 / V1, V2 / NaIO3, FN-005 / NaIO3, FN-006 / NaIO3, FN-007 / NaIO3, and FN-008 / NaIO3.

[0146] In mice injected with NaIO3, a 60.7 ± 5.00% (P < 0.01 vs. V1 / V2) decrease in staining intensity in the RPE layer was observed (Figures 1A and 1B). Treatment with eye drops containing the compound of formula (IV), the compound of formula (I), the compound of formula (II), and the compound of formula (III) statistically significantly reduced NaIO3-induced damage in the RPE layer by 84.5 ± 33% (P < 0.01 vs. V2 / NaIO3), 48.0 ± 9.1% (P < 0.01 vs. V2 / NaIO3), 60.0 ± 12.8% (P < 0.01 vs. V2 / NaIO3), and 96.8 ± 20.0% (P < 0.01 vs. V2 / NaIO3), respectively, compared with V2 (Figures 1A and 1B).

[0147] Data on fluorescence intensity values ​​are presented per treatment as mean ± SEM. * p<0.05 vs. V1 / V2; §p<0.05 vs. NaIO3. Statistical analysis was performed using one-way analysis of variance (ANOVA) and Bonferroni tests.

[0148] Example 4 - Evaluation of oxidative stress at the retinal level The level of oxidative stress was assessed throughout the thickness of the retina by measuring the immunofluorescence intensity of 4-hydroxynonenal (4-HNE), a reactive carbonyl species that is the ultimate indicator of oxidative stress.

[0149] Levels of 4-HNE were quantified in six groups of mice treated as described above using a primary antibody (#ab48506, mouse monoclonal [HNEJ-2], 1:40, Abcam, Cambridge, UK) conjugated to a secondary fluorophore-labeled antibody (Alexa Fluor 594, #A A32742, Thermo Fisher Scientific).

[0150] Cell nuclei were visualized using DAPI organic dye (#ab228549, Abcam, Cambridge, UK).

[0151] Figures 2A and 2B show representative images and cumulative data of immunofluorescence staining for 4-HNE, an oxidative stress biomarker, in six groups of mice treated with V2 / V1, V2 / NaIO3, compound of formula (IV) and NaIO3 (FN-005 / NaIO3), compound of formula (I) and NaIO3 (FN-006 / NaIO3), compound of formula (II) and NaIO3 (FN-007 / NaIO3), and compound of formula (III) and NaIO3 (FN-008 / NaIO3).

[0152] The above treatments are shown in Figure 2A as V2 / V1, V2 / NaIO3, FN-005 / NaIO3, FN-006 / NaIO3, FN-007 / NaIO3, and FN-008 / NaIO3.

[0153] Administration of NaIO3 induced a 62.89 ± 4.20% (P < 0.001 vs. V1 / V2) increase in 4-HNE immunofluorescence throughout the retinal tissue (Figures 2A and 2B).

[0154] Treatment with compound of formula (IV), compound of formula (I), compound of formula (II), and compound of formula (III) statistically significantly reduced 4-HNE at the retinal level by 64.16 ± 17.51% (P < 0.01 vs. V2 / NaIO3), 59.56 ± 6.31% (P < 0.01 vs. V2 / NaIO3), 50.32 ± 6.30% (P < 0.01 vs. V2 / NaIO3), and 62.10 ± 7.55% (P < 0.01 vs. V2 / NaIO3), respectively (Figures 2A and 2B).

[0155] Data on fluorescence intensity values ​​are presented per treatment as mean ± SEM. * p<0.05 vs. V1 / V2; §p<0.05 vs. NaIO3. Statistical analysis was performed using one-way analysis of variance (ANOVA) and Bonferroni tests.

[0156] Therefore, it can be concluded from the experimental evidence that the test compounds exert a protective effect against NaIO3-induced damage to cells of the RPE layer, which is of fundamental importance for maintaining macular photoreceptor function. Furthermore, it was observed that the test compounds having formulas (IV), (I), (II), and (III) protect the retina from 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 selected from macular degeneration, diabetic retinopathy, retinal detachment, central serous chorioretinopathy, hypertensive retinopathy, macular hole, macular pucker, floaters, and myopic maculopathy, comprising at least one TRPA1 channel antagonist compound and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, wherein the retinal degenerative disease is macular degeneration.

3. The pharmaceutical composition according to claim 1, wherein the macular degeneration is dry age-related macular degeneration.

4. The pharmaceutical composition according to claim 1, wherein the macular degeneration is wet age-related macular degeneration.

5. The pharmaceutical composition comprises the TRPA1 channel antagonist compound, its salt, optical isomer, solvate or prodrug, and the TRPA1 channel antagonist compound belongs to the following classes: 2) Sulfonamide derivatives; 5) Polycyclic heteroaromatic derivatives; or 6) Indazole derivatives and biological equivalents The pharmaceutical composition according to claim 1, belonging to one of them.

6. The TRPA1 channel antagonist compound belonging to class 2) sulfonamide derivatives has the general formula A1 【Chemical 1】 [wherein A and B can be the same as or different from each other and represent a CH group or a nitrogen atom, Ar is preferably selected from the group consisting of aryl, pyridine, pyrimidine, pyrazine, pyrrole, imidazole, furan, thiophene and thiazole, and can represent a 5- or 6-membered aromatic ring which may be substituted with one or more halogen atoms, preferably one or more fluorine or chlorine atoms, and R1, R2 and R3 can be the same as or different from each other, a hydrogen atom, a fluoromethyl group or the following formula [Chemical 2] (wherein X and Y can be the same as or different from each other and represent a CH group or a nitrogen atom.) of the residue. ] The pharmaceutical composition according to claim 5, having.

7. The TRPA1 channel antagonist compound belonging to class 2) sulfonamide derivatives and having the general formula A1 is a compound of formula (IV) 【Chemical 3】 The pharmaceutical composition according to claim 6.

8. The TRPA1 channel antagonist compound belonging to class 5) polycyclic heteroaromatic derivatives has the general formula A2 【Chemical Formula 4】 (In the formula, A can represent an oxygen atom, -NH- group or carbonyl group -(C=O)-, and B can represent a -CH- group or a nitrogen atom.) The pharmaceutical composition according to claim 5, which has the following formula.

9. Belonging to class 5) polycyclic heterocyclic aromatic derivatives, the TRPA1 channel antagonist compound having the general formula A2 is a compound of formula (I) or a compound of formula (II) [Chemical Formula 5] The pharmaceutical composition according to claim 8, which is as follows.

10. Belonging to class 6) indazole derivatives and biological equivalents, the TRPA1 channel antagonist compound having the general formula A3 【Chemical Formula 6】 (In the formula, R6, R7 and R8 may be the same as or different from each other, and can represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or a trifluoromethyl group.) The pharmaceutical composition according to claim 5, which has the following formula.

11. Belonging to class 6) indazole derivatives and biological equivalents, the TRPA1 channel antagonist compound having the general formula A3 is of formula (III) 【Chemical Formula 7】 The pharmaceutical composition according to claim 10, which is a compound of the following formula.

12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an ophthalmic composition containing at least one TRPA1 channel antagonist compound and at least one pharmaceutically acceptable excipient.

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

14. The pharmaceutical composition according to claim 12, wherein the ophthalmic composition is an aqueous solution.

15. The pharmaceutical composition according to claim 12, wherein the TRPA1 channel antagonist compound is present at a concentration in the range of about 0.0001% to about 5% w / v of the ophthalmic composition.

16. The pharmaceutical composition according to claim 12, wherein the TRPA1 channel antagonist compound is present at a concentration in the range of about 0.1% to about 1% w / v of the ophthalmic composition.

17. The pharmaceutical composition according to claim 12, wherein the TRPA1 channel antagonist compound is present at a concentration of about 0.5% w / v of the ophthalmic composition. Kit comprising a topical ophthalmic composition comprising at least one TRPA1 channel antagonist compound and at least one pharmaceutically acceptable excipient, a container containing the topical ophthalmic composition, and a dispenser, wherein the topical ophthalmic composition is for 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, vitreous floaters, and myopic maculopathy.

19. Combination of a TRPA1 channel antagonist compound 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, vitreous floaters, and myopic maculopathy.

20. The combination according to claim 19, wherein the retinal degenerative disease is age-related macular degeneration.

21. The combination according to claim 20, wherein the retinal degenerative disease is dry age-related macular degeneration or wet age-related macular degeneration.

22. The combination according to claim 19, wherein the anti-VEGF drug is selected from ranibizumab, bevacizumab, and aflibercept.

23. The combination according to claim 19, wherein the corticosteroid drug is selected from cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, beclomethasone, triamcinolone, paramethasone, mometasone, budesonide, fluocinonide, halcinonide, flumethasone, flunisolide, fluticasone, betamethasone, dexamethasone, hydrocortisone, and fludrocortisone.

Images