BRPI0621052A2 - use of an a3 adenosine receptor agonist (a3ar) - Google Patents

Abstract

USE OF A ~ 3 ~ (A ~ 3 ~ AR) ADENOSIN RECEPTOR AGONIST. The present invention relates to methods and compositions for treating dry eye. The method comprises providing an individual exhibiting ophthalmic clinical symptoms and signs of dry eye with an A ~ 3 ~ adenosine agonist (A ~ 3 ~ AR). The A ~ 3 ~ AR agonist is preferably administered to the patient topically or orally.

Description

"USING AN ADENOSINE A3 RECEIVER AGONIST (A3AR)"

FIELD OF INVENTION

The invention relates to compounds and methods useful in treating dry eye.

BACKGROUND OF THE INVENTION

Preocular tear film plays an important role in maintaining corneal integrity, protecting against infection and preserving visual acuity. These functions, in turn, are critically dependent on the stability, tonicity and / or composition of the tear film structure. Alteration, deficiency or absence of the tear film can lead to unwanted corneal epithelial dryness, corneal ulceration and perforation, an increased incidence of infectious disease, and basically severe visual damage and blindness.

The condition of dry eye is often referred to as a syndrome, or a disease; and it is likewise known by a variety of terms. Keratoconjunctivitis sicca (KCS), or more commonly dry keratitis, refers to any eye with some degree of dryness.

In dry eye the eye becomes dry because there is abnormally high rate of tear evaporation or because not enough tears are being produced.

Around the world, countless individuals suffer from dry eye syndrome. Abnormalities leading to tear film dysfunction can be subdivided into four general categories: (a) Water tear deficiencies, which are most often responsible for dry eye states, originate from disorders of the tear gland and include autoimmune disease, alachrima. congenital disease, paralytic hyposecretion or obstruction of the excretory duet; (b) mucin deficiency, which is observed under various conjunctival cynicitis conditions, such as Stevens-Johnson syndrome, trachoma, pemphigoid, thermal and chemical burns, as well as hypovitaminosis A; (c) lipid anomialities, which may occur during inflammation of 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 preservative free, 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 little to stop or reverse any damage conditions. A newly introduced artificial tear product is based on castor oil emulsion (Refresh Endura tears).

In addition, warm wet compresses applied to the closed eyelid skin are also used to reduce tear loss due to evaporation.

For more severe cases of dry eye, where the cornea is inflamed, anti-inflammatory agents such as topical steroids (eye drops) are sometimes prescribed. An example includes the combination of niainone corri cyclosponna oil (Restasis).

Orai dry eye medication is also available. For example, pilocarpine, the active ingredient in Salagen® or cevimelin, the active ingredient in Evoxac®, are known to stimulate specific receptors in the tear gland and cause increased tear secretion.

Other remedies include punal tampons and such punishing closure (which blocks tears from the iatric duet flowing in the nose), and dietary supplements such as the commercially available Flax Seed Oil Supplement (Omega-3 Supplement, TheraTears). SUMMARY OF INTENT

According to a first aspect, the invention provides a method for treating dry eye condition in an individual comprising administering to said individual an amount of A3 adenosine receptor agonist (A3AR), the amount being effective for ameliorating dry eye symptoms.

According to one embodiment, the invention provides a method for treating dry eye syndrome in an individual, comprising administering to said individual an A3 adenosine receptor agonist (A3AR).

According to a second aspect, the invention provides a pharmaceutical composition for treating dry eye syndrome comprising as active ingredient an amount of A3AR agonist and a physiologically acceptable carrier, the amount of said A3AR agonist being effective to ameliorate dry eye symptoms. .

According to a third aspect, the present invention provides the use of an A3AR agonist for the preparation of a pharmaceutical composition for treating dry eye condition.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

Dry eye syndromes encompass a constellation of diverse disease processes that produce objective clinical signs of keratoconjunctivitis sicca (KCS). The classic prototype of dry eye syndrome is Sjogren's syndrome, but there are many other causes of KCS including healing conjunctival diseases such as trachoma and penigigo, non-healing syndromes causing specific dry eye findings, and atypical syndromes such as keratomalacia where Eye is symptomatic and objectively dry but tear production is paradoxically normal.

The main symptom of dry eye is usually a scratchy or sandy sensation as if something is in the eye. Other symptoms may include burning or burning of the eye; episodes of excess watering following periods of very dry sensation; a fibrous discharge from the eye; and pain and redness of the eye. Sometimes individuals with dry eye experience eyelid weight or blurred, changeable, or diminished vision, although vision loss is uncommon.

Some individuals with dry eye 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, tears do not remain long enough for the parent to dampen him completely.

The present invention provides a method for treating dry eye condition, specifically dry eye syndrome, comprising providing an individual exhibiting one or more dry eye symptoms and signs with an amount of A3 adenosine receptor agonist (A3AR), the amount being effective for treating dry eye condition.

As assessed, while the invention is described in the following detailed description with reference to the above method, it should be understood that also encompassed within the present invention are compositions comprising the A3AR agonist for use in said treatment.

In the context of the present invention the term "dry eye condition" denotes any condition or syndrome that results in the manifestation of dry eye symptoms. It includes an existing condition as well as pseudo dry eye conditions, ie conditions of high predisposition to develop dry eye syndromes. Dry eye syndrome can be as a result of another underlying condition causing dry eye, for example, Sjogren'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. Yet dry eye may be a result of infection, or a side effect of medications, or exposure to toxins, chemicals, or other substances that may cause a dry eye symptom or condition.

The term "dry eye symptoms" which may be used interchangeably with the term "dry eye signs" is used herein to denote 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 can be perceived by a patient and indicative of a dry eye syndrome includes dry eye sensation, sandiness in the eye, scratchy eye sensation, burning eye, burning or itching eye, excessive tearing. , eye pain, redness of the eye, blurred vision, degraded vision.

The terms "treat" or "treatment", and the like are used herein to refer to obtaining a desired pharmacological and physiological effect. The effect may be prophylactic in terms of partially preventing or preventing a dry eye disease, symptom or condition and / or may be therapeutic in terms of a partial or complete cure of an eye syndrome disease, condition, symptom or adverse effect. dry. The term "treatment" as used herein covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing dry eye syndrome from occurring in an individual who may be predisposed to develop the syndrome. dry eye syndrome but not yet diagnosed as having, that is, causing the clinical symptoms of dry eye syndrome not to develop in a patient who may be predisposed to dry eye syndrome but have not experienced or experienced symptoms of dry eye syndrome. dry eye; (b) inhibit dry eye syndrome, that is, stop or reduce the development of dry eye syndrome or its clinical symptoms; or (c) alleviate dry eye syndrome, that is, cause regression of dry eye syndrome and / or its symptoms or conditions.

The term "A3 adenosine receptor agonist" (A3AR agonist) in the context of the present invention refers to any molecule capable of specifically binding to A3AR5 thereby fully or partially activating said receptor. The A3AR agonist is thus a molecule that exerts its primary effect by binding and activating A3AR. This means that at the doses it is being administered it essentially binds and activates only the A3AR. In a preferred embodiment, an A3AR agonist has a human A3AR binding affinity (Ki) in the range of less than 100 nM, typically less than 50 nM, preferably less than 20 nM, more preferably less than 10 nM and ideally less than 5 nM. Particularly preferred are A3AR agonists that have a human A3R Ki of less than 2 nM and desirably less than 1 nM.

It should be noted that some A3AR agonists may also interact with and activate other lower affinity receptors (ie, a higher Ki). A molecule will be considered an A3AR agonist in the context of the invention (i.e., a molecule that exerts its primary effect through A3AR binding and activation) if its affinity for A3AR is at least 3-fold (i.e. its K1 to A3AR is at least 3 times lower), preferably 10 times, desirably 20 times and more preferably at least 50 times greater than the affinity for any other adenosine receptors (i.e. A1, A2a and A2b).

The affinity of an A3AR agonist for human A3AR as well as its relative affinity for other human adenosine receptors can be determined by various assays, such as a binding assay. Examples of binding assays include providing membrane containing a receptor and measuring the ability of the A3AR agonist to replace a bound radioactive agonist; use cells displaying the respective human adenosine receptor and measure, in a functional assay, the ability of the A3AR agonist to activate or deactivate, as appropriate, downstream of events such as the effect on adenylate cyclase measured by increasing or decreased cAMP level; etc. Of course, if the administered level of an A3AR agonist is increased such that its blood level reaches a level approaching the adenosine A1, A2a ε A2b receptor Ki, activation of these receptors may occur following such administration, in addition to the administration of such adenosine receptors. A3AR activation. An A3AR agonist is thus preferably administered at such a dose that the blood level is such that essentially only A3AR will be activated.

The characteristic of some adenosine A3AR agonists and methods of their preparation are described in detail in, inter alia, US 5,6SS,774; US 5,773,423, US 5,573,772, US 5,443.S36, US 6.04S.S65, WO 95/02604, WO 99/20284, WO 99/06053, WO 97/27173 and co-pending patent application no. No. 09 / 700,751 (corresponding to WO 01/19360), all of which are incorporated herein by reference.

The following examples are specified in US 5,68,874 in column 4, lines 67-column 6, line 16; lane 5, lines 40 to 45; lane 6, lines 21 to 42; lane 7, lines 1 to 11; lane 7, lines 34 to 36; and column 7, lines 60 to 61:

N6- (3-iodobenzyl) -9-methyladenine;

N6- (3-iodobenzyl) -9-hydroxyethyladenine;

R-N6 (3-iodobenzyl) -9- (2,3-dihydroxypropyljadenine;

S-N6- (3-iodobenzyl) -9- (2,3-diidioxypepyl) adenine;

N6- (3-iodobenzyladenyl-9-yl) acetic acid;

N6- (3-iodobenzyl) -9- (3-cyanopropyl) adenine;

2-chloro-N6- (3-iodobenzyl) -9-methyladenine;

2-amino-6- (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-propylaminoadenine;

2-hexylaminu-N6- (3-iodobenzyl) -9-methyladenine;

N6- (3-iodobeiziz) -2-methoxy-9-methyladenyl;

N6- (3-iodobeiizyl) -C, methyl-2-methylthioaddin;

N6- (3-iodobeiizyl) -9-methyl-2- (4-pyridylthio) adenine;

(1S, 2R3S, 4R) -4HO-aniino-2-phenylethylamino-9H-purin-9-yl) cyclopentane-1,2,3-triol;

(1S, 2R, 3S, 4R) -4- (6-amino-2-chloro-9H-purin-9-yl) cyclopentane-1,2,3-triol;

(±) -9- [2a, 3α-dihydroxy-4- (N-methylcarbamoyl) cyclopent-1-yl)] N6- (3 -iodobenzyl) adenine;

2-chloro- [2- (2'-amino-2'3 ', dideoxy-Î ± -D-5, methyl arabinofuronamido) -NÎ ± (3-iodobeiizyl) adenine;

2-chloro-9- (2 ', 3'-dideoxy-2'-fluoro-α-D-5'-methyl-arabino-furonamido) -N' - (3-iodobenzyl)) adenine;

9- (2-acetyl-3-deoxy-β-D-5-] riethyl ribofuronamido) -2-cyclo-N6 (3-iodobenzyl) adenine;

2-chloro-9- (3-deoxy-2-methanesulfonyl-α-D-5-methyl ribofuronamido) -NN 3-iodobenzyl) adenine;

2-chloro-9- (3,5,1,1,,3,3-tetraisopropyldisoxyoxy-α-D-5-ribofuranosyl) -N6- (3-iodobenzyl) adenma;

2-cyclo-9- (2,3'-O-thiocarbonyl-α-D-5-methyl-ribofuronamido) -N6-iodobenzyl) adenine;

9- (2-phenoxythiocarbonyl-3-deoxy-α-D-5-methyl-ribofuronamido) -2-chloro-N6- (3-iodobeiizyl) adenine;

1- (6-benzylamino-9H-purin-9-yl) -1-deoxy-N, 4-dimethyl-α-D-ribofuranosiduronamide; 2-clolo-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-berizyldenine;

2-chloro-9- (α-D-erythrouranosido) -N6- (3 -iodobenzyl) adenine;

N6- (benzodioxanomethyl) adenosine;

1- (6-furfurylamino-9H-purin-9-yl) -1-deoxy-N-methyl-α-D-ribofuranosiduronamide;

Nt, - [3- (L-piylamino) benzyl] adenosmo-5'-N-methyluronamide;

Nb- [3- (α-allylamino) benzyl] adenosine-5'-N-methyluronamide;

N ° - [3- (N-T-Boc-α-alanylamino) benzyl] adenosine-5'-N-methyluronamide

6- (N'-phenylidmzim1) purine-9-α-ribophyllanoside-5'-N-methyluronamide;

6- (O-phenylidoxyoxyamino) punno-9-α-riboflanosanos-5'-N-methyluronamide;

9- (α-D-2 ', 3'-dideoxyetheritrofuranosir) -N5 - [(3-α-alanylamino) benzyl] adenosine;

9- (α-D-erithOfuranosido) -2-methylamino-N6- (3-iodobenzyl) adenine;

2-chloro-N- (3-iodobenzyl) -9- (2-tetraethylphenyl) -9H-purin-6-amine;

2-chloro- (2'-deoxy-6'-thio-1-arabinosyl) adenine; and

2-chloro- (6'-thio-1-arabinosyl) adenine.

In US 5,773,423 in column 6, line 39, of column 7, line 14, specifically disclosed are compounds that include the formula: <formula> formula see original document page 11 </formula>

on what

X1 is RaRbNQ = O), wherein Ra and Rb may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, amino, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C3-C10 cycloalkyl ;

R2 is selected from the group consisting of hydrogen, halo, C1-C10 alkoxy, amino, C2-C10 alkenyl, and C2-C10 alkynyl; and

R5 is selected from the group consisting of R- and SL-phenylethyl, an unsubstituted benzyl group, and a substituted benzyl group at one or more positions with a substituent selected from the group consisting of C1-C10 alkyl, amino, halo, haloalkyl C 1 -C 10, nitro, hydroxy, acetamido, C 1 -C 10 alkoxy, and sulfo.

More specific compounds include those of the above formula wherein Ra and Rb may be the same or different and are selected from the group consisting of hydrogen and C1-C10 alkyl, particularly when R2 is hydrogen or halo, especially hydrogen.

Additional specific compounds are those compounds wherein Ra is hydrogen and R2 is hydrogen, particularly when R5 is unsubstituted benzyl.

More specific compounds are such compounds wherein R 0 is a C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, particularly a C 1 -C 10 alkyl, and more particularly methyl. Especially specific are those compounds where Ra is hydrogen, Rb is C1-C10 alkyl or C3-C10 cycloalkyl, and R5 is R- or SI-phenylethyl or a benzyl substituted at one or more positions with a substituent selected from the group consisting of halo amino, acetamido, C1-C10 haloalkyl, and sulfo, where the sulium 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. Furthermore, these compounds wherein R2 is a C2 -C10 alkenylene of the formula wherein R1 is a C1-C8 alkyl are particularly noted in this publication. Also specific are those compounds wherein R2 is except hydrogen, particularly those wherein R2 is halo, C1-C10 alkylamino, or C1-C10 alkylthio, and more preferably, when additionally Ra is hydrogen, Rb is C1-C10 alkyl, and / or R5 is a substituted benzyl.

Such specifically disclosed compounds include 2-chloro-N6- (3-iodobenzyl) -9- [5- (methylamido) -Î ± -D-ribofuranosyl] adenine, N6- (3-iodobenzyl) -2-] netylamino-9 - [5- (methylamido) -Î ± -D-ribofuranosyl] adenine, and N6- (3-iodobenzyl) -2-methylthio-9- [5- (methylamido) -Î ± -D-ribofuranosyl] adenine.

In addition, US 5,773,423 discloses in column 7, line 60, to column 8, line 6, modified A3AR-like xanthine-7-riboside agonists having the formula:

<formula> formula see original document page 12 </formula>

where X is Ο;

R6 is RaRbNCC = O), wherein Ra and Rb may be the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, amino, C1-C10 haloalkyl, C1-C10 aminoalkyl, and C3-C10 cycloalkyl ;

R7 and R8 may be the same or different and are selected from the group consisting of C1-C10 alkyl, R- and Sl-phenylethyl, an unsubstituted benzyl group, and a substituted benzyl group at one or more positions with a substituent selected from the group. group consisting of C1-C10 alkyl, amino, halo, C1-C10 haloalkyl, nitro, hydroxy, acetamido, C1-C10 alkoxy, and sulfo; and

R 9 is selected from the group consisting of halo, benzyl, phenyl, and C 3 -C 10 cycloalkyl.

WO 99/06053 discloses in examples 19 to 33 compounds selected from:

N6, (4-biphenylcarbonylamino) adenosine-5, -N-ethyluronamide;

N6- (2,4-dichlorobenzylcarbonylaminoVadenosine-5'-N-ethyluronamide;

N6- (4-methoxyphenylcarbonylamino) adenosine-5'-N-ethyluronamide;

N6- (4-c] orophenylcarbonylamino) adenosine-5, -N-ethyluronamide;

N6- (phenylcarbonylamino) 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;

N 6 - ((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-bis-propoxy-phenylcarbamoyl) -adenosine-5'-N-ethyluronamide;

N6-bis- (4-nitiOphenyl] carbamoyl) 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 primary effect by binding and activating adenosine A3AR and is a purine derivative falling within the scope of general formula (I):

<formula> formula see original document page 14 </formula>

on what,

- R 11 represents an alkyl, hydroxyalkyl, carboxyalkyl or cyanoalkyl or a group of the following general formula (II):

<formula> formula see original document page 14 </formula>

on what:

Y represents oxygen, sulfur or CH 2;

X11 represents H, alkyl, ReRfNC (O) - or HORg-, 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 are joined together to form a heterocyclic ring containing two to five carbon atoms. ; and

Rg is selected from the group consisting of alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl;

X 12 is H, hydroxyl, alkylamino, alkylamido or hydroxyalkyl;

- X13 and X14 independently represent hydrogen, hydroxyl, amino, starch, azido, halo, alkyl, alkoxy, carboxy, nitrile, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether, -OCOPh, -OC (= S) OPh either X13 or X14 are oxygen attached to> C = S to form a 5-membered ring, or X12 and X13 form the ring of formula (III):

<formula> formula see original document page 15 </formula>

where R 'and R "independently represent an alkyl group;

R 12 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 -NR15R16 wherein

R15 is a hydrogen atom or a group selected from alkyl, substituted alkyl or aryl-NH-C (Z) -, with Z being O, S, or NRa with Re having the meanings above; where when R15 is hydrogen than

- R 16 is selected from the group consisting of R- and S-1-phenylethyl, benzyl, phenylethyl or unsubstituted or substituted anilide groups at one or more positions with a substituent selected from the group consisting of alkyl, amino, halo, haloalkyl, nitro, hydroxyl, acetoamido, alkoxy, and sulfonic acid or a salt thereof; benzodioxanomethyl, fururyl, L-propylalanyl-aminobenzyl, β-alanylamino-benzyl, T-BOC-β-alanylaminobenzyl, phenylamino, carbamoyl, phenoxy or cycloalkyl; or R16 is a group of the following formula:

<formula> formula see original document page 16 </formula>

or when R15 is an alkyl or aryl-NH-C (Z) -, then R16 is selected from the group consisting of Ietherylaryl-NRa-C (Z) -, heteroaryl-C (Z), alkaryl-NRa-C ( Z) -, alkan-C (Z) -, aryl-NR-C (Z) - and aryl-C (Z) -; Z represents an oxygen, sulfo or amine; or a physiologically acceptable salt of the above compound.

According to a preferred embodiment, the A3AR agonist is a nucleoside derivative of general formula (IV):

<formula> formula see original document page 16 </formula>

wherein X1, R2 'and R5 are as defined above, and physiologically acceptable salts of said compound.

Non-cyclic carbohydrate groups (e.g. alkyl, alkenyl, alkynyl, alkoxy, aralkyl, alkaryl, alkylamine, etc.) which form part of the substituent of the compounds of the present invention are branched or unbranched, preferably containing from one or two to twelve carbon atoms.

Referring to "physiologically acceptable salts" of the compounds used by the present invention is meant any non-toxic alkali metal, alkaline earth metal, and ammonium salt commonly used in the pharmaceutical industry, including sodium, potassium, lithium, calcium salts, magnesium, barium ammonium and protamine zinc, which are prepared by methods known in the art. 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. Acid addition salts are those which retain the biological effectiveness and qualitative properties of these free bases and are non-toxic or otherwise undesirable. Examples include, inter alia, acids derived from mineral, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric acids and the like. Organic acids include, inter alia, tartaric, acetic, propionic, citric, malic, malonic, lactic, ionic, benzoic, cinnamic, mandelic, glycolic, pyruvic, succinic, salicylic and arylsulfonic acids, for example p-toluenesulfonic acids.

Specific examples of A3AR agonists which may be used in accordance with general formula (IV) of the present invention include, but are not limited to, N6-2- (4-adiphenyl) ethyladenosine (APNEA), N6- (4-amino-amino). 3-iodobeiizyl) adenosine-5 '- (N-methyluronarylide) (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.

In another embodiment, the A3AR agonist may be an adenosine-derived oxide, such as N6-benzyladenosine-5'-N-alkyluronamide-N1-oxide or N6-benzyladenosine-5'-N-dialkyluronamide-N1. -oxide, wherein the 2-purine position may be substituted with an alkoxy, amino, alkenyl, alkynyl or halogen.

The terms "effective amount" or "effective amount to" in the context of the present invention refers to an amount of A3AR agonist that prevents or reduces symptoms of dry eye in patients. The "effective amount" can be readily determined according to the invention by administering to a plurality of patients tested various amounts of the A3AR agonist and then plotting the physiological response (e.g. an integrated "SS index" combining several of the effects). beneficial effects) as a function of quantity. Alternatively, the effective amount may also be determined, sometimes, by experiments performed on appropriate animal models and then extrapolating to humans using one of a plurality of conversion methods; or by measuring the plasma concentration or area under the curve (AUC) of the plasma concentration over time and calculating the effective dose to produce a comparable plasma concentration or AUC. As known, the effective amount may depend on a variety of factors such as the mode of administration (e.g. oral administration may require a higher dose to obtain a delivered plasma level or AUC than intravenous administration); the age, weight, body surface area, gender, health condition and genetic factors of the patient; other medicines administered; etc.

Hereinafter, unless otherwise indicated, dosages are given by weight / kg, meaning A3AR agonist weight administered (e.g. IB-MECA) per kilogram body weight of the patient treated with each administration. For example, mg / kg and microgram / kg denote, respectively, milligrams of agent administered and micrograms of agent administered per kilogram of body weight of the treated patient.

The effective amount is preferably less than about 1 mg / kg body weight, particularly less than about 500 μg / kg or even less than about 200 μg / kg body weight or sometimes less than about 100 μg / kg. body weight or less than about less than 50 μg / kg body weight. With respect to IB-MECA, the effective amount is preferably less than 5 mg of each dose for one day administration (ie a dose of less than about 70 μg / kg body weight, assuming a weight of 70 mg), and less than about 4 mg each dose (ie less than about 57 body weight) for two daily dosing. The IB-MECA close-up is more preferably less than about 2 mg each dose and typically between about 0.1 to 1 mg each dose for one or two administrations per day (the corresponding body weight dosages being about 29 μg / kg and about 1.5 to 15 μg / kg body weight respectively).

Administration of the A3AR agonist to an individual may be together with a pharmaceutically acceptable carrier. In the case where administration is oral, the canker is one that is acceptable for oral administration. In the case where administration is topical, the carrier is one which is acceptable for topical administration, an example being ocular administration.

By the term "pharmaceutically acceptable carrier" is meant any inert, non-toxic materials which do not react with the A3AR agonist and which may be added to formulations such 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, syrup, aromatic powder, and various other forms. The carrier is sometimes selected based on the desired formulation formulation. The carrier may also sometimes have the effect of improving the release or penetration of the active ingredient into the target tissue, to improve drug stability, to reduce release rates, to communicate slow release properties, to reduce unwanted side effects, etc. The carrier may also be a formulation stabilizing substance (e.g., a preservative), to provide the formulation with an edible taste, etc. The carriers may be any of those conventionally used and are limited only by chemical-physical considerations such as solubility and lack of reactivity with the A3AR agonist, and by the route of administration. The carrier may include pharmaceutically compatible additives, dyes, diluents, buffering agents, clinting agents, wetting agents, preservatives, flavoring agents, and carriers. In addition, the carrier may be an adjuvant, which by definition are substances that affect the action of the active ingredient in a predictable manner.

Typical examples of carriers suitable for oral administration include (a) liquid solutions, where an effective amount of the active substance is dissolved in diluents, such as water, saline, natural juices, alcohols, syrups, etc .; (b) capsules (for example, the usual type of hard or soft shell gelatin containing, for example, surfactants, lubricants, and inert fillers), tablets, expectorant tablets (wherein the active substance is in a flavor, such as sucrose). and acacia or tragacanth or the active substance is in an inert base (such as gelatin and glycerin), and lozenges, 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, a Mimic solution (e.g., eye drops), an ophthalmic gel or an ointment or oily lotion. Topical administration of the A3AR agonist also comprises the use of ophthalmic patches conducting the A3AR agonist in a suitable layer-containing medicament and to be placed on top of the eyelid as well as for Ocular supplements which are devices containing the A3AR agonist and placed in the pouches. lower or upper conjunctival muscles (see for example WOOO59420). Eye drops can be prepared by dissolving the A3AR agonist in a sterile aqueous solution such as saline, buffering solution etc., or by combining powder compositions to be dissolved prior to use. Other additives may be included in the eye drops such as isotonicizing agents (eg sodium chloride, etc.), buffering agent (eg boronic acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.), preservatives (eg , benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.), thickeners (e.g., saccharide such as lactose, mannitol, maltose, etc.; for example, hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate, e.g., mucopolysaccharide such as chondroitin sulfate, etc., e.g., sodium polyacrylate, carboxyvinyl polymer, cross-linked polyacrylate, etc.).

Eye ointments can be prepared by mixing A3AR agonist in a base. Examples of base for ointment include petrolatum, selenium 50, Plastibase, macrogol, etc., but not limited to these.

Some exemplary ophthalmic viscosity enhancers that may be used in the present formulation include: sodium carboxymethyl cellulose; methylcellulose: hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxyethyl cellulose: polyethylene glycol 300; polyethylene glycol 400; polyvinyl alcohol; and providona.

Some natural products, such as veegurn, alginates, xanthan gum, gelatin, acacia and tragacanth, can also be used to increase the viscosity of alkali solutions.

A tonicity is important because hypotonic eye drops cause edema of the cornea, and hypertonic eye drops cause corneal deformation. The ideal tonicity is approximately 300 mOsM. Tonicity can be obtained by methods described in Remington: The Science and Practice of Pharmacy, known to those skilled in the art.

As used herein, the forms "one", and "the" include references in the singular as well as the plural unless the context clearly elites otherwise. For example, the term "an A3AR agonist" includes one or more compounds that are capable of specifically binding to A3AR, thereby fully or partially activating said receptor.

Furthermore, as used herein, the term "comprising" is intended to mean that the composition includes the reported active agent, that is, 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 that include the reported elements but exclude other elements that may be of essential importance in the treatment of dry eye syndrome. "Consisting of" must therefore mean excluding more than trace elements from other elements. Embodiments defined by each of these transition terms are within the scope of this invention.

Furthermore, all numerical values, for example, when referring to the amounts or ranges of the elements constituting the composition comprising the A3AR agonist as an active ingredient, are approximations that are varied (+) or (-) by up to 20%. , sometimes up to 10% of the set values. It should be understood, even if not always explicitly stated, that all numerical designations are preceded by the term "about".

The invention will now be exemplified in the following description of experiments that were performed according to the invention. It should be understood that these examples are intended to be in nature by way of illustration rather than limitation. Obviously, many modifications and variations of these examples are possible in light of the above teaching. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced otherwise in a large number of possible ways than as specifically described herein below.

EXAMPLE:

IB-MECA Improves Dry Eye Symptoms in Rheumatoid Arthritis Patients

Medication:

The A3AR agonist used was a clinical grade compound known generically as 1-Deoxy-1- [6 - [[(3-iodophenyl) methyl] amino] 9H-purino-9-yl] -N-methyl-D- ribofuranuronamide or as N6- (3-iodobenzyl) adenosine-5'-N-methyluronamide (IB-MECA), which has been synthesized for Can-Fite BioPharma, under Good Clinical Practice (GMP) by Albany Molecular Research Inc, Albany, NY , USA.

IB-MECA was fomulated in oval soft gel capsules. The capsules contained IB-MECA solutions in Cremofor RH 40 and Migliol 812. The capsules contained a dose of 0.1, 1 or 4 mg IB-MECA, the exact composition of each capsule type is shown in Tables 1 to 3. following:

Table 1: Composition of 0.1 mg Soft Gel Capsules with IB-MECA

<table> table see original document page 23 </column> </row> <table>

Table 2: Composition of 1 mg Soft-Gel Capsules with IB-MECA

<table> table see original document page 23 </column> </row> <table>

Table 3: Composition of 4 mg IB-MECA Soft Gel Capsules

<table> table see original document page 23 </column> </row> <table> Methods:

IB-MECA capsules were given to the patients orally twice daily. All patients had rheumatoid arthritis (RA) and were provided with IB-MECA within the framework of a clinical study aimed at testing the effect of IB-MECA on modifying RA disease symptoms in these patients. Patients randomly received capsules from one of the three doses above. Patients received LB-MECA over a 12-week period.

4 of the treated patients also suffered from Dry Syndrome and the effect of IB-MECA on their dry eye symptoms was also examined.

Results

Table 1 summarizes the results of CF101 treatment of patients with RA. Specifically, four patients at the age of 58 ± 4 years who suffered RA during S ± 2 years were followed. At baseline, patients had high levels of rheumatoid factor, ie 313 ± 120 IU / ml (0 <normal <40) and suffered from dry eyes for 5 ± 1.6 years. In CF101 treatment for 6.25 ± 1.1 months, an improvement in the Schirmer test from 8.5 ± 1.4 mm to 15.6 ± 2.9 mm was observed. Table 1

<table> table see original document page 25 </column> </row> <table>

Claims (9)

Use of an adenosine A3 receptor agonist (A3AR), characterized in that it is for the preparation of a pharmaceutical composition for the treatment of a dry eye condition in an individual. 2. Use of an A3AR agonist, characterized in that it is for the treatment of a dry eye condition in an individual. Use according to claim 1 or 2, characterized in that it is for the treatment of dry eye syndrome. Use according to claim 1 or 3, characterized in that said composition is formulated in a form suitable for oral administration. Use according to claim 1 or 3, characterized in that said composition is formulated in a form suitable for topical administration. Use according to claim 5, characterized in that said composition is formulated in a form suitable for administration to the eye. Use according to any one of claims 1 to -6, characterized in that said A3AR agonist is selected from N6-2- (4-aminophenyl) ethyladenosine (APNEA), N6- (4-amino-amine). 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). Use according to claim 7, characterized in that the A3AR agonist is IB-MECA. Use according to any one of claims 1 to 8, characterized in that said dry eye condition is associated with one or more clinical ophthalmic symptoms selected from the group consisting of foreign body sensation, burning, itching, irritation, redness, eye pain, blurred vision, degraded vision and excessive tearing.