MX2008009506A - Adenosine a3 receptor agonists for the treatment of dry eye disorders - Google Patents

Abstract

The present invention concerns methods and compositions for treating dry eye. The method comprises providing an individual exhibiting ophthalmologic clinical symptoms and signs of dry eye with an A3adenosine receptor (A3AR) agonist. The A3AR agonist is preferably administered to the subject either topically or orally.

Description

ADENOSIN A3 RECEPTOR AGONISTS FOR THE TREATMENT OF DRY EYE DISORDERS FIELD OF THE INVENTION The invention relates to compounds and methods useful in the treatment of dry eye.

BACKGROUND OF THE INVENTION The preocular tear film plays an important role in the maintenance of corneal integrity, protection against infection and preservation of visual acuity. These functions, in turn, are critically dependent on the stability, tonicity and / or composition of the structure of the tear film. The alteration, deficiency or absence of the tear film can lead to undesired corneal epithelial dryness, corneal ulceration and perforation, an increased incidence of an infectious disease and finally, severe visual deterioration and blindness. The dry eye condition is often referred to as a syndrome or a disease; and in the same way it is known by a variety of terms. Dry keratoconjunctivitis (KCS) or more commonly dry keratitis refers to any eye with some degree of dryness. In the dry eye, the eye becomes dry either due REF. : 191342 because there is an abnormally high rate of tear evaporation or because there are not enough tears. Throughout the world, countless individuals suffer from dry eye syndrome. Abnormalities that lead to tear film dysfunction can be subdivided into four general categories: (a) watery tear deficiencies that are more often responsible for dry eye states, originate from disorders of the lacrimal glands and include an autoimmune disease, congenital alacrima, paralytic hyposecretion or obstruction of excretory ducts; (b) mucin deficiency, which is observed in various conditions of conjunctival scarring, such as Stevens-Johnson syndrome, trachoma, pemphigoid, thermal and chemical burns, as well as hypovitaminosis A; (c) lipid abnormalities, which may occur during inflammation of the eyelid (eg chronic blepharitis); and (d) decreased eyelid function [Holly, F.J., Tear film physiology. Internat. Ophthalmol. Clin. 27: 2-6 (1987)]. The first line of treatment is usually eye drops, preferably free of preservatives, which act as artificial tears. Most artificial tears are hydrogels that increase the moisture content on the surface of the eye and provide some temporary relief. These solutions and ointments provide some temporary relief, but they are ineffective in stopping or reversing any harmful condition. A recently introduced artificial tears product is based on an emulsion of castor oil (tears Refresh Enduram). In addition, warm wet compresses applied to the skin of closed eyelids are also used to reduce the loss of tears due to evaporation. For more severe cases of dry eye, in which the cornea becomes inflamed, anti-inflammatory agents such as topical steroids (in eye drops) are sometimes prescribed. An example includes the combination of castor oil with cyclosporin. { RestasisWR). Oral medicine for dry eye is also available. For example, it is known that pilocarpine, the active ingredient in Salagen ™ or cevimeline, the active ingredient in Evoxac ™, stimulates specific receptors in the lacrimal gland and causes an increased secretion of tears. Other remedies include stern plugs and strut closure (which prevent tears from flowing down to the tear duct inside the nose) and food supplements such as the commercially available flax seed oil supplement (the Omega-3 Supplement, TheraTears).

BRIEF DESCRIPTION OF THE INVENTION According to a first aspect, the invention provides a method for treating the condition of dry eye in an individual comprising administering to the individual an amount of adenosine A3 receptor agonist (A3AR), the amount is effective to improve the symptoms of dry eye. According to one embodiment, the invention provides a method for treating dry eye syndrome in an individual, comprising administering to the individual an adenosine A3 receptor agonist (A3AR). According to a second aspect, the invention provides a pharmaceutical composition for treating dry eye syndrome comprising as an active ingredient an amount of A3AR agonist and a physiologically acceptable carrier, the amount of the A3AR agonist is effective to improve the symptoms of the Dry Eye. According to a third aspect, the present invention provides the use of an A3AR agonist for the preparation of a pharmaceutical composition for the treatment of dry eye condition.

DETAILED DESCRIPTION OF THE INVENTION The dry eye syndromes include a large number of diverse disease processes that produce objective clinical signs of keratocontactitis dry (KCS). The classic prototype of dry eye syndrome is Sjogren's syndrome, but there are many other causes of KCS that include healing conjunctival diseases such as trachoma and pemphigoid, non-healing syndromes that cause specific findings of the dry eye and atypical syndromes such as keratomalacia. in which the eye is symptomatically and objectively dry but the production of tears is paradoxically normal. The main symptom of dry eye is usually an abrasive or gritty sensation as if something were in the eye. Other symptoms may include itching or burning of the eye; episodes of excessive lacrimation that follow periods of very dry sensation; a fibrous discharge from the eye; and pain and redness of the eye. Sometimes individuals with dry eyes experience heaviness of the eyelids or blurred vision, changing or diminished, although loss of vision is not common. Some individuals with dry eyes may have tears running down their cheeks. This is because the eye may be producing less of the lipid and mucin layers of the tear film, which help keep tears in the eye. When this happens, the tears do not remain in the eye long enough to moisten it completely. The present invention provides a method for treating the condition of dry eye, specifically dry eye syndrome, which comprises providing an individual exhibiting one or more of the symptoms and signs of dry eye with an amount of the adenosine A3 receptor agonist. (A3AR), the amount is effective to treat the dry eye condition. As appreciated, while the invention is described in the following detailed description with reference to the above method, it should be understood that compositions comprising the A3AR agonist for use in the treatment are also included within the present invention. In the context of the present invention, the term "dry eye condition" indicates any condition or syndrome that results in the manifestation of dry eye symptoms. It includes an existing condition as well as pseudo-conditions of dry eye, that is, conditions of high predisposition to develop dry eye syndromes. The dry eye syndrome can be a result of another fundamental condition that causes dry eye, for example, Sjögren's syndrome, menopause or rheumatoid arthritis. Dry eye can also be a complication of inflammation, for example Blepharitis or a foreign body in the eye. Still the dry eye can be a result of an infection, or a side effect of medications, or exposure to toxins, chemicals or other substances that can cause a symptom or dry eye condition. The term "dry eye symptoms" which can be used interchangeably with the term "dry eye signs" is used herein to indicate any sensation or change in the normal function or structure of the eye that is experienced by an individual. . A non-limiting list of signs that may be perceived by a subject and may be indicative of dry eye syndrome includes dry eye sensation, gritty eye feel, abrasive eye feel, burning eye, itchy or itchy eye, excessive tearing , eye pain, redness of the eye, blurred vision, degraded vision. The terms "treat" or "treatment" and the like are used in this document to refer to obtaining a desired pharmacological and physiological effect. The effect can be prophylactic in terms of preventing or partially preventing a disease, symptom or dry eye condition and / or it can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to dry eye syndrome. The term "treatment", as used herein, covers any treatment of a disease in a mammal, particularly a human, and includes: (a) prevention of the occurrence of dry eye syndrome in an individual which may be predisposed to develop dry eye syndrome but which has not yet been diagnosed as having it, that is, causing the clinical symptoms of dry eye syndrome not to develop in a subject who may be predisposed to dry eye syndrome but still does not experience or show symptoms of dry eye syndrome; (b) the inhibition of dry eye syndrome that is, stopping or reducing the development of dry eye syndrome or its clinical symptoms; or (c) relief of dry eye syndrome, that is, causing the regression of the dry eye syndrome and / or its symptoms or conditions. The term "adenosine 3 receptor agonist" (A3AR agonist) in the context of the present invention refers to any molecule that is capable of specifically binding to the A3AR, thereby fully or partially activating the receptor. In this way, the A3AR agonist is a molecule that exerts its primordial effect through the binding and activation of the A3AR. This means that in the doses that are being administered it is essentially linked to and activates only the A3AR. In a preferred embodiment, an A3AR agonist has a binding affinity (Ki) towards the human A3AR in the range less than 100 nM, typically less than 50 nM, preferably less than 20 nM, more preferably less than 10 nM and ideally less that 5 nM.

A3AR agonists having a Ki to the human A3R less than 2 nM are particularly preferred. and desirably less than 1 nM. It should be noted that some A3AR agonists can also interact with and activate other receptors with lower affinities (specifically a higher Ki). A molecule will be considered an A3AR agonist in the context of the invention (specifically a molecule that exerts its primordial effect through the binding and activation of the A3AR) if its affinity for the A3AR is at least 3 times (ie its Ki at A3AR is at least 3 times lower), preferably 10 times, desirably 20 times and much more preferably at least 50 times larger than the affinity towards any of the other adenosine receptors (ie ??, A2a and A2b) · The affinity of an A3AR agonist to the human A3AR as well as its relative affinity towards the other human adenosine receptors can be determined by a variety of assays, such as a binding assay. Examples of binding assays include the provision of membranes containing a receptor and the measurement of the ability of the A3AR agonist to displace a linked radioactive agonist; the use of cells exhibiting the respective human adenosine receptor and the measurement, in a functional assay, of the ability of the A3AR agonist to activate or deactivate, as the case may be, the downstream signaling events such as the effect on the adenylate cyclase measured by increasing or decreasing the level of cAMP; etc. Clearly, if the administered level of an A3AR agonist is increased in such a way that its level in the blood reaches a level approaching that of the Ki of adenosine receptors Ai, A2a and A2bf, the activation of these receptors may occur. after this administration, in addition to the activation of the A3AR. In this manner, an A3AR agonist is preferably administered in a dose such that the level in the blood is such that only the A3AR will be activated essentially. The characteristic of some A3A adenosine agonists and methods for their preparation are described in detail in, inter alia, US 5,688,774; US 5,773,423, US 5,573,772, US 5,443,836, US 6,048,865, WO 95/02604, WO 99/20284, WO 99/06053, WO 97/27173 and co-pending patent application of applicant No. 09 / 700,751 (corresponding to WO document). 01/19360), all of which are incorporated herein by reference. The following examples are specified in US 5,688,774 in column 4, lines 67-column 6, line 16; column 5, lines 40-45; column 6, lines 21-42; column 7, lines 1-11; column 7, lines 34-36; and column 7, lines 60-61: N6- (3-iodobenzyl) -9-methyladenine; N6- (3-iodobenzyl) -9-hydroxyethyladenine; R-N6- (3-iodobenzyl) -9- (2,3-dihydroxypropyl) -adenine; S-N6- (3-iodobenzyl) -9- (2,3-dihydroxypropyl) adenine; N6- (3-iodobenzyladenin-9-yl) acetic acid; N6- (3-iodobenzyl) -9- (3-cyanopropyl) adenine; 2-chloro-N6- (3-iodobenzyl) -9-methyladenine; 2-amino-N6- (3-iodobenzyl) -9-methyladenine; 2-hydrazido-N6- (3-iodobenzyl) -9-methyladenine; N6- (3-iodobenzyl) -2-methylamino-9-methyladenine; 2-dimethylamino-N6- (3-iodobenzyl) -9-methyladenine; N6- (3-iodobenzyl) -9-methyl-2-propylamino adenine; 2-Hexylamino-N6- (3-iodobenzyl) -9-methyladenine; N6- (3-iodobenzyl) -2-methoxy-9-methyladenine; N6- (3-iodobenzyl) -9-methyl-2-methylthioadenine; N6- (3-iodobenzyl) -9-methyl-2- (4-pyridylthio) adenine; (1S, 2R, 3S, 4R) -4- (6-amino-2-phenylethylamino-9H-purine-9-yl) cyclopentane-1,2,3-triol; (1S, 2R, 3S, 4R) -4- (6-amino-2-chloro-9H-purine-9-yl) cyclopentane-1,2,3-triol; (±) -9- [2α, 3α-Dihydroxy-4α- (N-methylcarbamoyl) -cyclopent-la-yl)] - N 6 - (3-iodobenzyl) -adenine; 2-chloro-9- (2'-amino-2 ', 3'-dideoxy-α-D-5' -methyl-arabino-furonamido) -N6- (3-iodobenzyl) adenine; 2-chloro-9- (2 ', 3' -dideoxy-2 '-fluoro-á-D-5' -methyl-arabino-furonamido) -N6- (3-iodobenzyl) adenine; 9- (2-acetyl-3-deoxy-α-D-5-methyl-ribofuronamido) -2-chloro-N6 (3-iodobenzyl) adenine; 2-chloro-9- (3-deoxy-2-methanesulfonyl-α-D-S-methyl-ribofuronamido) -N6- (3-iodobenzyl) adenine; 2-chloro-9- (3-deoxy-α-D-5-methyl-ribofuronamido) -N6- (3-iodobenzyl) adenine; 2-chloro-9- (3, 5-1, 1, 3, 3-tetraisopropyldisiloxil-á-D-5-ribofuranosyl) -N6- (3-iodobenzyl) adenine; 2-chloro-9- (2 ', 3'-O-thiocarbonyl-α-D-5-methyl-ribofuronamido) -N6- (3-iodobenzyl) adenine; 9- (2-phenoxythiocarbonyl-3-deoxy-α-D-5-methyl-ribofuronamido) -2-chloro-N6- (3-iodobenzyl) adenine; 1- (6-benzylamino-9H-purine-9-yl) -1-deoxy-N, 4-dimethyl-α-D-ribofuranosiduronamide; 2-chloro-9- (2,3-dideoxy-α-D-5-methyl-ribofuronamido) -N6-benzyladenine; 2-chloro-9- (2'-azido-2 ', 3'-dideoxy-α-D-5' -methyl-arabino-furonamido) -N6-benzyl adenine; 2-chloro-9- (α-D-eritrofuranoside) -N6- (3-iodobenzyl) adenine; N6- (benzodioxanomethyl) adenosine; 1- (6-furfurylamino-9H-purine-9-yl) -1-deoxy-N-methyl-a-D-ribofuranosiduronamide; N6- [3- (L-prolylamino) benzyl] adenosine-5 '-N-methyluronamide; N6- [3- (a-alanylamino) benzyl] adenosine-5'-N-methyluronamide; N6- [3- (N-T-Boc-α-alanylamino) benzyl] adenosine-5'-N-methyluronamide 6- (N '-phenylhydrazinyl) purine-9-α-ribofuranoside-5'-N-methyluronamide; 6- (O-phenylhydroxylamino) purine-9-α-ribofuranoside-5'-N-methyluronamide; 9- (α-D-2 ', 3'-dideoxytritruranosyl) -N 6 - [(3-a-alanylamino) benzyl] adenosine; 9- (α-D-eritrofuranoside) -2-methylamino-N 6 - (3-iodobenzyl) adenine; 2-chloro-N- (3-iodobenzyl) -9- (2-tetrahydrofuryl) -9H-purine-6-amine; 2-chloro- (2'-deoxy-6'-thio-L-arabinosyl) adenine; and 2-chloro- (6'-thio-L-arabinosyl) adenine. In US 5,773,423 in column 6, line 39, to column 7, line 14, compounds are specifically disclosed which include the formula: wherein Xi is RaRbNC (= 0), wherein Ra and Rb may be the same or different and are selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, amino, haloalkyl of 1 to 10 carbon atoms, aminoalkyl of 1 to 10 carbon atoms and cycloalkyl of 3 to 10 carbon atoms. carbon; R 2 is selected from the group consisting of hydrogen, halo, alkyloxy of 1 to 10 carbon atoms, amino, alkenyl of 2 to 10 carbon atoms and alkynyl of 2 to 10 carbon atoms; and R5 is selected from the group consisting of R- and S-1-phenylethyl, an unsubstituted benzyl group and a benzyl group substituted at one or more positions by a substituent selected from the group consisting of alkyl of 1 to 10 carbon atoms , amino, halo, haloalkyl of 1 to 10 carbon atoms, nitro, hydroxy, acetamido, alkoxy of 1 to 10 carbon atoms and sulfo. More specific compounds include those of the above formula wherein Ra and Rb may be the same 0 and are selected from the group consisting of hydrogen and alkyl of 1 to 10 carbon atoms, particularly when R2 is hydrogen or halo, especially hydrogen. Additional specific compounds are those compounds wherein Ra is hydrogen and R 2 is hydrogen, particularly when R 5 is unsubstituted benzyl. The most specific compounds are the compounds wherein Rb is alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 10 carbon atoms, particularly an alkyl of 1 to 10 carbon atoms and more particularly methyl. Especially specific compounds are those compounds where Ra is hydrogen, Rb is alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 10 carbon atoms and R5 is R- or S-phenylethyl or benzyl substituted at one or more positions by a substituent selected from the group consisting of halo, amino, acetamido, haloalkyl of 1 to 10 carbon atoms and sulfo, wherein the sulfo derivative is a salt, such as a triethylammonium salt. An example of an especially preferred compound disclosed in US 5,773,423 is IB-MECA.

In addition, those compounds in which R2 is alkenylene of 2 to 10 carbon atoms of the formula Rd-C = C- where Rd is alkyl of 1 to 8 carbon atoms are particularly mentioned in this publication. Also specific are those compounds wherein R 2 is different from hydrogen, particularly those wherein R 2 is halo, C 1 -C 10 alkylamino or C 1 -C 10 alkylthio and, more preferably, when Ra is also hydrogen, Rb is alkyl of 1 to 10 carbon atoms and / or R 5 is substituted benzyl. These compounds disclosed specifically include 2-chloro-N6- (3-iodobenzyl) -9- [5- (methylamido) -α-D-ribofuranosyl] -adenine, N6- (3-iodobenzyl) -2-methylamino-9 - [5- (methylamido) -α-D-ribofuranosyl] -adenine and N 6 - (3-iodobenzyl) -2-methylthio-9- [5- (methylamido) -α-D-ribofuranosyl] -adenine. In addition, US 5,773,423 discloses in column 7, line 60, up to column 8, line 6, the A3AR agonists such as modified xanthine-7-ribosides which X is O; R6 is RaRbNC (= 0), wherein Ra and Rb may be the same or different and are selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, amino, haloalkyl of 1 to 10 carbon atoms, aminoalkyl from 1 to 10 carbon atoms and cycloalkyl of 3 to 10 carbon atoms; R7 and R8 can be the same or different and are selected from the group consisting of alkyl of 1 to 10 carbon atoms, R- and S-phenylethyl, an unsubstituted benzyl group and a benzyl group substituted at one or more positions by a substituent selected from the group consisting of alkyl of 1 to 10 carbon atoms, amino, halo, haloalkyl of 1 to 10 carbon atoms, nitro, hydroxy, acetamido, alkoxy of 1 to 10 carbon atoms and sulfo; and Rg is selected from the group consisting of halo, benzyl, phenyl and cycloalkyl of 3 to 10 carbon atoms. The document O 99/06053 discloses in the examples 19-33 the selected compounds of: N6- (4-biphenyl-carbonylamino) -adenosine-5 '-N-ethyluronamide; N6- (2,4-dichlorobenzylcarbonylamino) -adenosine-5'-N-ethyluronamide; N6- (4-methoxyphenyl-carbonylamino) -adenosine-5 '-N-ethyluronamide; N6- (4-chlorophenyl-carbonylamino) -adenosine-5 '-N-ethyluronamide; N6- (phenyl-carbonylamino) -adenosine-5 '-N-ethyluronamide; N6- (benzylcarbamoylamino) -adenosine-5 '-N-ethyluronamide; N6- (4-sulfonamido-phenylcarbamoyl) -adenosine-5 '-N-ethyluronamide; N6- (4-acetyl-phenylcarbamoyl) -adenosine-5 '-N-ethyluronamide; N6- ((R) -α-phenylethylcarbamoyl) -adenosine-5 '-N-ethyluronamide; N6- ((S) -α-phenylethylcarbamoyl) -adenosine-5 '-N-ethyluronamide; N6- (5-methyl-isoxazol-3-yl-carbamoyl) -adenosine-5'-N-ethyluronamide; N6- (1, 3, 4-thiadiazol-2-yl-carbamoyl) -adenosine-5 '-N-ethyluronamide; N6- (4-n-propoxy-phenylcarbamoyl) -adenosine-5 '-N-ethyluronamide; N6-bis- (4-nitrophenylcarbamoyl) -adenosine-5 '-N-ethyluronamide; and N6-bis- (5-chloro-pyridin-2-yl-carbamoyl) -adenosine-5'-N-ethyluronamide. According to one embodiment of the invention, the A3AR agonist is a compound that exerts its primordial effect through the binding and activation of the A3AR of adenosine and is a purine derivative that is within the scope of the general formula (I ): wherein, Rn represents alkyl, hydroxyalkyl, carboxyalkyl or cyanoalkyl or a group of the following general formula (II): in which: - Y represents oxygen, sulfur or CH2; - Xn represents H, alkyl, ReRfNC (= 0) - or HOR9-, wherein - Re and Rf may be the same or different and are selected from the group consisting of hydrogen, alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl and cycloalkyl or join together to form a heterocyclic ring containing from two to five carbon atoms; and Rg is selected from the group consisting of alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl and cycloalkyl; - X12 is H, hydroxyl, alkylamino, alkylamido or hydroxyalkyl; Xi3 and Xi4 independently represent hydrogen, hydroxyl, amino, amido, azido, halo, alkyl, alkoxy, carboxy, nitrile, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether, -OCOPh, -OC (= S) OPh or both Xi3 and Xi4 are oxygen atoms connected to > C = S to form a 5-membered ring, or X12 and X13 form the ring of the formula (III): wherein R 'and R "independently represent an alkyl group; R12 is selected from the group consisting of hydrogen, halo, alkyl ether, amino, hydrazido, alkylamino, alkoxy, thioalkoxy, pyridylthio, alkenyl; alkynyl, thio and alkylthio; and - R13 is a group of the formula -NRi5Ri6 wherein Ri5 is a hydrogen atom or a group selected from alkyl, substituted alkyl or aryl-NH-C (Z) -, with Z being 0, S or NRa with Re which has the above meanings; wherein when Ri5 is hydrogen then Ri6 is selected from the group consisting of R- and Sl-phenylethyl, benzyl, phenylethyl or anilide groups unsubstituted or substituted at one or more positions by a substituent selected from the group consisting of alkyl, amino, halo, haloalkyl, nitro, hydroxyl, acetoamido, alkoxy and sulfonic acid or a salt of the same; benzodioxanomethyl, fururyl, L-propylalanyl-aminobenzyl, β-alanylamino-benzyl, T-BOC-p-alanylaminobenzyl, phenylamino, carbamoyl, phenoxy or cycloalkyl; o Ri6 is a group of the following formula: or when R15 is alkyl or aryl-NH-C (Z) -, then, Ri6 is selected from the group consisting of heteroaryl-NRa-C (Z) -, heteroaryl-C (Z) -, alkaryl-NRa-C ( Z) -, alkaryl-C (Z) -, aryl-NR-C (Z) - and aryl-C (Z) -; Z represents oxygen, sulfur or amine; or a physiologically acceptable salt of the above compound. According to a preferred embodiment, the A3AR agonist is a nucleoside derivative of the general formula (IV): wherein Xi, R2 'and R5 are as defined above and the physiologically acceptable salts of the compound. Non-cyclic carbohydrate groups (eg, alkyl, alkenyl, alkynyl, alkoxy, aralkyl, alkaryl, alkylamine, etc.) which form part of the substituent of the compounds of the present invention are either branched or unbranched, preferably containing from one or two to twelve carbon atoms. By referring to the "physiologically acceptable salts" of the compounds employed by the present invention, any non-toxic alkali metal, alkaline earth metal and ammonium salt commonly used in the pharmaceutical industry, including the sodium, potassium, lithium, calcium salts, is proposed. magnesium, barium, ammonium and zinc protamine, which are prepared by methods known in the field. The term also includes non-toxic acid addition salts, which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. The acid addition salts are those that retinue the biological effectiveness and qualitative properties of the free bases and which are not toxic or otherwise undesirable. Examples include, inter alia, acids derived from mineral acids, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric and the like. Organic acids include, inter alia, tartaric, acetic, propionic, citric, malic, malonic, lactic, fumaric, benzoic, cinnamic, mandelic, glycolic, gluconic, pyruvic, succinic, salicylic, and arylsulfonic, eg, p-toluenesulfonic. Specific examples of the A3AR agonist which may be employed according to the general formula (IV) of the present invention include, but are not limited to, N6-2- (4-aminophenyl) ethyladenosine (APNEA), N6- (- amino-3-iodobenzyl) adenosine-5 '- (N-methyluronamide) (AB-MECA), N6- (3-iodobenzyl) -adenosine-5' -N-methyluronamide (IB-MECA) and 2-chloro-N6- (3-iodobenzyl) -adenosine-5 '-N-methyluronamide (Cl-IB-MECA). IB-MECA is the most preferred compound according to the invention. According to another embodiment, the A3AR agonist can be an adenosine oxide derivative, such as N6-benzyladenosine-5 '-N-alkyl-nitronamide-N1-oxide or N6-benzyladenosine-5' -N-dialkyluronamide-N1-oxide , wherein the position of 2-purine can be replaced by alkoxy, amino, alkenyl, alkynyl or halogen. The terms "effective amount" or "effective amount for" in the context of the present invention refer to an amount of the A3AR agonist that prevents or reduces dry eye symptoms in patients. The "effective amount" can be easily determined, according to the invention, by administering to a plurality of subjects tested several amounts of the A3AR agonist and then plotting on a graph the physiological response (e.g., an integrated "SS index"). which combines several of the therapeutically beneficial effects) as a function of quantity. Alternatively, the effective amount can also be determined, sometimes, through experiments performed in appropriate animal models and then extrapolated to humans using one of a plurality of conversion methods; or by measuring the concentration in the plasma or the area under the curve (AUC) of the concentration in the plasma over time and calculate the effective dose to produce a comparable plasma concentration or AUC. As is known, the effective amount may depend on a variety of factors such as the mode of administration (eg, oral administration may require a higher dose to achieve a given plasma level or AUC than an intravenous administration); age, weight, body surface area, gender, health condition and genetic factors of the subject; other drugs administered; etc. In the following, unless otherwise indicated, the dosages are indicated by weight / Kg, average weight of the administered A3AR agonist (eg IB-MECA) per kilogram of body weight of the subject treated in each administration. For example, mg / Kg and microgram / Kg indicate, respectively, milligrams of the administered agent and micrograms of the administered agent per kilogram of body weight of the treated subject. The effective amount is preferably less than about 1 mg / kg of body weight, particularly less than about 500 g / kg or even less than about 200 g / kg of body weight or sometimes less than about 100 μg / kg of body weight or even less than about 50 g / kg of body weight. With respect to the IB-MECA, the effective amount is preferably less than 5 mg in each dose, for once-a-day administration (specifically, a dose of less than about 70 μg / kg of body weight, assuming an average individual weight of about 70 kg) and less than about 4 mg of each dose (ie less than about 57 μq / kg body weight), for administration twice a day. The dose of IB-MECA is more preferably less than about 2 mg of each dose and typically between about 0.1-1 mg in each dose, for administration either once or twice a day (the corresponding dosages in weight per body weight are approximately 29 μg / kg and approximately 1.5-15 μ? / > ^ body weight, respectively). Administration of the A3AR agonist to an individual may be in conjunction with a pharmaceutically acceptable carrier. In the case where the administration is oral, the carrier is one that is acceptable for oral administration. In the case where the administration is topical, the carrier is one that is acceptable for topical administration, an example is ocular administration. By the term "pharmaceutically acceptable carrier" is proposed any of the non-toxic, inert materials, which do not react with the A3AR agonist and which can be added to the formulations as diluents or carriers or to give shape or consistency to the formulation . An oral formulation may be in the form of a pill, capsule, in the form of a syrup, an aromatic powder and various other forms. Sometimes the carrier is selected based on the desired form of the formulation. Sometimes the carrier can also have the effect of improving the supply or penetration of the active ingredient to the target tissue, to improve the stability of the drug, to decrease the elimination rates to grant slow release properties, to reduce unwanted side effects, and so on. . The carrier can also be a substance that stabilizes the formulation (for example a preservative), to provide the formulation with an edible flavor, and so on. The carriers can be any of those conventionally used and are limited only by the chemical-physical considerations, such as solubility and lack of reactivity with the A3AR agonist and the route of administration. The carrier may include pharmacologically compatible additives, colorants, diluents, buffers, disintegrating agents, wetting agents, preservatives, flavoring agents and carriers. In addition, the carrier can be an adjuvant, which by definition is the substances that affect the action of the active ingredient in a predictable manner. Typical examples of carriers suitable for oral administration comprise (a) liquid solutions, wherein an effective amount of the active substance is dissolved in the diluents, such as water, saline, natural juices, alcohols, syrups, etc.; (b) capsules (e.g. the type of ordinary hard or soft shell gelatin containing, for example, surfactants, lubricants and inert fillers), tablets, rhombic pastilles (wherein the active substance is in a flavor, such as sucrose and gum arabic or tragacanth gum or the active substance is in an inert base, such as gelatin and glycerin) and troches, each containing a predetermined amount of tragacanth as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; (e) suitable emulsions; (f) liposome formulation; and others. A topical formulation may be in any form suitable for topical administration, including, but not limited to, an ophthalmic solution (e.g. eye drop), an ophthalmic gel or an ophthalmic ointment or oily lotion. Topical administration of the A3AR agonist also comprises the use of ophthalmic patches carrying the A3AR agonist in a suitable layer containing the drug and placed on the upper part of the eyelid as well as ocular inserts which are devices containing the agonist of the A3AR and placed in the lower or upper conjunctival sacs (see for example WO0059420). The eye drop can be prepared by dissolving the A3AR agonist in a sterile aqueous solution such as saline, buffer solution, etc. or by combining the powder compositions to be dissolved before use. Other additives may be included in the eye drop such as isotonizing agents (e.g., sodium chloride, etc.), buffering agent (e.g., boric acid, sodium monoacid phosphate, sodium diacid phosphate, etc.), preservatives (e.g. of benzalkonium, benzethonium chloride, chlorobutanol, etc.), thickening agents (for example, saccharides such as lactose, mannitol, maltose, etc., for example, hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate, etc .; for example, a mucopolysaccharide such as chondroitin sulfate, etc., for example, sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, etc.). Ointments for the eyes can be prepared by mixing the A3AR agonist in a base. Examples of the base for ointment for the eyes include petrolatum, seleno 50, Plastibase ™, macrogol, etc., but are not limited thereto. Some exemplary ophthalmic viscosity improvers that can be used in the present formulation include: sodium carboxymethylcellulose; methylcellulose; hydroxypropylcellulose; hydroxypropylmethylcellulose; hydroxyethylcellulose; polyethylene glycol 300; polyethylene glycol 400; polyvinyl alcohol; and providona. Some natural products, such as Veegum ™, alginates, xanthan gum, gelatin, gum arabic and tragacanth gum can also be used to increase the viscosity of ophthalmic solutions. Tonicity is important because hypotonic eye drops cause edema of the cornea, and hypertonic eye drops cause deformation of the cornea. The ideal tonicity is approximately 300 mOsM. Tonicity can be achieved by means of the methods described in Remington: The Science and Practice of Pharmacy, known to those skilled in the art. As used in this document, the forms "a", "an" and "the", "the", "the", "the" include singular as well as plural references unless the context clearly dictates otherwise. For example, the term "an A3AR agonist" includes one or more compounds which are capable of specifically binding to the A3AR, thereby fully or partially activating the receptor. In addition, as used herein, the term "comprising" is intended to mean that the composition includes the aforementioned active agent, ie the A3AR agonist, but not excluding other elements, such as physiologically acceptable carriers and excipients. as well as other active agents. The term "consisting essentially of" is used to define compositions which include the elements cited but exclude other elements that may have an essential meaning in the treatment of dry eye syndrome. In this way, "consisting of" will imply that it excludes more than the trace elements of other elements. The modalities defined for each of these transition terms are within the scope of this invention. In addition, all numerical values, for example when referring to the amounts or ranges of the elements that make up the composition comprising the A3AR agonist as an active ingredient, are approximations which are varied (+) or (-) by up to 20. %, sometimes up to 10% of the established values. It should be understood, even if it is not always explicitly stated that all numerical designations are preceded by the term "approximately". The invention will now be exemplified in the following description of the experiments that were carried out according to the invention. It should be understood that it is proposed that these examples are in the nature of illustration rather than limitation. Obviously, many modifications and variations of these examples are possible in view of the previous teaching. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced otherwise, in an endless number of possible ways, as specifically described below in this document.EXAMPLE: IB-MECA improves dry eye symptoms in patients with Rheumatoid Arthritis oide Drug: The A3AR agonist used was of a clinical grade of the compound known generically as 1-Deoxy-l- [6- [[(3- iodophenyl) methyl] amino] -9H-purine-9-yl] -N-methyl-D-ribofuranuronamide or as N6- (3-iodobenzyl) -adenosine-5 '-N-methyluronamide (IB-MECA), which was synthesized by Can-Fite BioPharma, under good clinical practice (GMP) by Albany Molecular Research Inc., Albany, NY, USA. The IB-MECA was formulated in soft gel oval capsules. The capsules contained IB-MECA solutions in Cremophor RH 40MR and Miglyol 812MR. The capsules contained a dose of 0.1, 1 or 4 mg of IB-MECA, the exact composition of each type of capsules is shown in the following Tables 1-3: Table 1: Composition of Soft Gel Capsules 0.1 mg of IB-MECA Table 2: Composition of Soft Gel Capsules of 1 mg of IB-MECA Table 3. Composition of Soft Gel Capsules of 4 mg of IB-MECA Methods: The capsules with the IB-MECA were given to patients by the oral route twice a day. All the patients had rheumatoid arthritis (RA) and were provided with the IB-MECA within the general framework of a clinical study aimed at testing the effect of IB-MECA in the modification of the symptoms of RA disease in these patients. . Patients randomly received capsules from one of the three previous doses. Patients received the IB-MECA for a period of 12 weeks. 4 of the treated patients also suffered from dry keratitis and the effect of IB-MECA on their dry eye symptoms was also examined. RESULTS Table 1 summarizes the results of treatment with CF101 of patients with RA. Specifically, four patients aged 58 ± 4 years were observed who suffered RA for 8 ± 2 years. In the baseline, patients had elevated levels of rheumatoid factor, ie, 313 ± 120 IU / ml (0 <normal <40) and had suffered from dry eyes for 5 + 1.6 years. In the treatment with CF101 for 6.25 ± 1.1 months, an improvement was observed in the Schirmer test from 8.5 ± 1.4 mm to 15.6 ± 2.9 mm.

Table 1 - Effect of treatment with CF101 in patients with RA Duration Schirmer's Test Period Virus Age Age of eye Hepatitis Treatment of RA Left eye Right eye dry C Line of _. . . End of Line of (years) (years) (years) (months) Reference Study Reference End of Study 1 65 14 5 positive 4 6 9 14 9 2 58 7 7 positive 5 10 32 15 23 3 54 6 5 7 5 16 5 17 Average 59.75 8.00 5 6.25 6.75 16.5 10.25 14.75 SE 2.4 0.51 0.82 1.11 1.11 5.4 2.5 3.28 fifteen It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (17)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A method for treating a dry eye condition in an individual, characterized in that it comprises administering to the individual an amount of the adenosine A3 receptor agonist ( A3AR), the amount is effective to improve the symptoms of dry eye in the individual.
2. 2. The method of compliance with the claim 1, characterized in that it is for the treatment of dry eye syndrome.
3. 3. The method according to claim 1, characterized in that the A3R agonist is administered by the oral route.
4. 4. The method according to claim 1, characterized in that the A3R agonist is administered by the topical route to the individual.
5. 5. The method according to claim 4, characterized in that the A3R agonist is administered to the eye.
6. 6. The method according to claim 1, characterized in that the A3RAg is selected from N6-2- (4-aminophenyl) ethyladenosine (APNEA), N6- (4-amino-3-iodobenzyl) -adenosine-5 '- ( N-methyluronamide) (AB-MECA), N6- (3-iodobenzyl) -adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N6- (3-iodobenzyl) -adenosine-5'-N - Methyluronamide (Cl-IB-ECA).
7. 7. The method according to claim 7, characterized in that the A3RAg is IB-MECA.
8. 8. The method of compliance with the claim 1, characterized in that the ophthalmological clinical symptoms are one selected from the group consisting of a foreign body sensation, burning, itching, irritation, redness, eye pain, blurred vision, degraded vision and excessive lacrimation.
9. 9. A pharmaceutical composition for treating a dry eye condition, characterized in that it comprises an amount of an adenosine A3 receptor agonist (A3AR) and a pharmaceutically acceptable carrier, the amount of the A3AR agonist is effective in improving the symptoms of the eye dry in the individual.
10. 10. The composition according to claim 9, characterized in that it is in a form suitable for oral administration.
11. 11. The composition according to claim 9, characterized in that it is in a form suitable for topical administration.
12. 12. The composition according to claim 11, characterized in that it is in a form suitable for topical administration to the eye.
13. 13. The use of an A3 adenosine receptor (A3AR) agonist for the preparation of a pharmaceutical composition for treating dry eye condition.
14. 14. The use according to claim 13 for treating dry eye syndrome.
15. 15. The use according to claim 13 for the preparation of a pharmaceutical composition for oral administration.
16. 16. The use according to claim 13 for the preparation of a pharmaceutical composition for topical administration.
17. 17. The use according to claim 16 for the preparation of a pharmaceutical composition for topical administration to the eye.