Note: Descriptions are shown in the official language in which they were submitted.
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ADENOSINE 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, the protection against infection and the preservation of
visual
acuity. These functions, in turn, are critically dependent upon the stability,
tonicity and/or composition of the tear film structure. Alteration, deficiency
or
absence of the tear film may lead to undesired dryness of the corneal
epithelium,
ulceration and perforation of the cornea, an increased incidence of infectious
disease, and ultimately, severe visual impairment 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 keratitis sicca, refers to any eye with some degree of
dryness.
In dry eye the eye becomes dry either because there is abnormally high
rate of evaporation of tears or because there is not enough tears being
produced.
Throughout the world, countless individuals suffer from dry eye
syndrome. The abnormalities leading to tear film dysfunction may be subdivided
into four general categories: (a) aqueous tear deficiencies, which are most
frequently responsible for dry eye states, originate from lacrimal gland
disorders
and include autoimmune disease, congenital alacriina, paralytic hyposecretion
or
excretory duct obstruction; (b) inucin deficiency, which is observed in
various
conjunctival cicatrization conditions, such as Stevens-Johnson syndrome,
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trachoma, pemphigoid, thermal and chemical bums, as well as hypovitaminosis
A; (c) lipid abnormalities, which may occur during eyelid inflammation (e.g.
chronic blepharitis); and (d) diminished 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, that act as artificial tears. Most artificial tears are hydrogels that
increase the
moisture content on the eye surface and give some temporary relief. These
solutions and ointments give some temporary relief, but do little to arrest or
reverse any damaging conditions. A recently introduced artificial tear product
is
based on Castor oil emulsion (Refresh Endura tears).
In addition, warm moist compresses applied to the skin of the closed
eyelids are also used to reduce tear loss due to evaporation.
For more severe cases of dry eye, in which the cornea is inflamed, anti-
inflammatory agents, such as topical steroids (in eye drops) are sometimes
prescribed. One example includes the combination of castor oil with
cyclosporine
(Restasis).
Oral medicine for dry eye is also available. For example, pilocarpine, the
active ingredient in SalagenTM or cevilneline, the active ingredient in
EvoxacTM,
are known to stimulate specific receptors in lacrimal gland and cause
increased
secretion of tears.
Other remedies include punctal plugs and punctal closure (which block
the tears from flowing down the tear duct into the nose), and food
supplements,
such as the commercially available Flaxseed oil supplement (Omega-3
Supplement, TheraTears).
SUMMARY OF THE INVENTION
In accordance with a first aspect, the invention provides a method for
treating dry eye condition in an individual comprising administrating to said
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individual an amount of A3 adenosine receptor (A3AR) agonist, the amount being
effective to ameliorate dry eye symptoms.
According to one embodiment, the invention provides a method for
treating dry eye syndrome in an individual, comprising administrating to said
individual an A3 adenosine receptor (A3AR) agonist.
In accordance with 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.
In accordance with 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 EXEMPLARY EMBODIMENTS
Dry eye syndromes encompass a constellation of diverse disease processes
that produce objective clinical signs ofkeratoconjunctivitis sicca (KCS). The
classic
prototype of the dry eye syndrome is Sjogren's syndrome, but there are many
other
causes of KCS including cicatrising conjunctival d iseases such as trachoma
and
pemphigoid, non-cicatrising syndromes causing specific dry eye findings, and
atypical syndromes such as keratomalacia in which the eye is symptomatically
and
objectively dry but tear production is paradoxically normal.
The main symptom of dry eye is usually a scratchy or sandy feeling as if
something is in the eye. Other symptoms may include stinging or burning of the
eye; episodes of excess tearing that follow periods of very dry sensation; a
stringy
discharge from the eye; and pain and redness of the eye. Sometimes individuals
with dry eye experience heaviness of the eyelids or blurred, changing, or
decreased
vision, although loss of vision is uncommon.
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Some individuals with dry eye may have tears that run 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
stay in
the eye long enough to thoroughly moisten it.
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
(A3AR) agonist, the amount being 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 is to 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 syndromewhich results in the manifestation of dry eye
symptoms.
It includes an already existing condition as well as pseudo dry eye
conditions, i.e.
conditions high predisposition of developing dry eye syndromes. Dry eye
syndrome
may be as a result of another underlying condition causing dry eye, for
example,
Sjogren's syndrome, menopause or rheumatoid arthritis. Dry eye may also be a
complication of inflammation, e.g. Blepharitis or of 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 may cause a symptom or condition of dry
eye.
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
normal
function or structure of the eye that is experienced by an individual. A non-
limiting
list of signs which may be perceived by a subject and be indicative of an dry
eye
syndrome includes, dry eye feeling, sandy eye feeling, scratchy eye feeling,
burning
eye, stinging or itching eye, excessive tearing, eye pain, redness of the eye,
blurred
vision, degraded vision.
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The terms "treating" 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 preventing or partially preventing a disease, symptom
or
condition of dry eye and/or may 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) preventing dry eye
syndrome
from occurring in an individual which may be predisposed to develop dry eye
syndrome but has not yet been diagnosed as having it, i.e., causing the
clinical
symptoms of dry eye syndrome not to develop in a subject that may be
predisposed
to dry eye syndrome but does not yet experience or display symptoms of dry eye
syndrome; (b) inhibiting dry eye syndrome, i.e., arresting or reducing the
development of dry eye syndrome or its clinical symptoms; or (c) relieving dry
eye
syndrome, i.e., causing 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 the
A3AR, thereby fully or partially activating said receptor. The A3AR agonist is
thus a
molecule that exerts its prime effect through the binding and activation of
the
A3AR. This means that at the doses it is being administered it essentially
binds to
and activates only the A3AR. In a preferred embodiment, an A3AR agonist has a
binding affinity (K) to the human A3AR 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
K; to
the human A3R of less than 2 nM 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 (namely a higher Ki). A
molecule will
be considered an A3AR agonist in the context of the invention (namely a
molecule
that exerts its prime effect through the binding and activation A3AR) if its
affinity to
the A3AR is at least 3 times (i.e. its Ki to the A3AR is at least 3 times
lower),
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preferably 10 times, desirably 20 times and most preferably at least 50 times
larger
than the affinity to any other of the adenosine receptors (i.e. Al, Ala and
A2b).
The affinity of an A3AR agonist to the human A3AR as well as its relative
affinity to the other human adenosine receptors can be determined by a number
of
assays, such as a binding assay. Examples of binding assays include providing
membranes containing a receptor and measuring the ability of the A3AR agonist
to
displace a bound radioactive agonist; utilizing cells that display the
respective
human adenosine receptor and measuring, in a functional assay, the ability of
the
A3AR agonist to activate or deactivate, as the case may be, downstream
signaling
events such as the effect on adenylate cyclase measured through increase or
decrease of the cAMP level; etc. Clearly, if the administered level of an A3AR
agonist is increased such that its blood level reaches a level approaching
that of the
Ki of the Al, Aga and A2b adenosine receptors, activation of these receptors
may
occur following such administration, in addition to activation of the A3AR. An
A3AR agonist is thus preferably administered at a dose such that the blood
level is
such so that essentially only the A3AR will be activated.
The characteristic of some adenosine A3AR agonists and methods of their
preparation are described in detail in, inter alia, US 5,688,774; 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 applicant's co-pending patent application no.
09/700,751 (corresponding to WO 01/19360).
The following examples are specified in US 5,688,774 at 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;
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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-propylaminoadenine;
2-hexylamino-N6-(3-iodobenzyl)-9-methyladenine;
N6-(3 -iodobenzyl)-2-lnethoxy-9-methyladenine;
N6-(3 -iodobenzyl)-9-methyl-2-inethylthioadenine;
N6-(3 -iodobenzyl)-9-methyl-2-(4-pyridylthio)adenine;
(1 S,2R,3 S,4R)-4-(6-amino-2-phenylethylamino-9H-purin-9-
yl)cyclopentane-1,2 ,3-triol;
(1 S,2R,3S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl) cyclopentane-1,2,3-
triol;
( )-9-[2a,3 a-dihydroxy-4a-(N-methylcarbamoyl)cyclopent-1 a-yl)]-N6-(3-
iodobenzyl)-adenine;
2-chloro-9-(2'-amino-2',3'-dideoxy-a-D-5'-methyl-arabino-furonamido)-N6-
(3 -iodobenzyl)adenine;
2-chloro-9-(2',3'-dideoxy-2'-fluoro-a-D-5'-methyl-arabino furonamido)-N6-
(3-iodobenzyl)adenine;
9-(2-acetyl-3-deoxy-a-D-5-methyl-ribofuronamido)-2-chloro-N6(3-
iodobenzyl)adenine;
2-chloro-9-(3-deoxy-2-methanesulfonyl-a-D-5-methyl-ribofuronalnido)-N6-
(3 -iodobenzyl)adenine;
2-chloro-9-(3 -deoxy-a-D-5-methyl-ribofuronainido)-N6-(3 -
iodobenzyl)adenine;
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2-chloro-9-(3,5-1,1,3,3-tetraisopropyldisiloxyl-a-D-5-ribof iranosyl)-N6-(3-
iodobenzyl)adenine;
2-chloro-9-(2',3'-O-thiocarbonyl-a-D-5-methyl-ribofuronamido)-N6-(3-
iodobenzyl)adenine;
9-(2-phenoxythiocarbonyl-3-deoxy-a-D-5-methyl-ribofuronamido)-2-
chloro-N6-(3-iodobenzyl)adenine;
1-(6-benzylamino-9H-purin-9-yl)-1-deoxy-N,4-dimethyl-a-D-
ribofuranosiduronamide;
2-chloro-9-(2,3-dideoxy-a-D-5-methyl-ribofuronamido)-N6 benzyladenine;
2-chloro-9-(2'-azido-2',3'-dideoxy-a-D-5'-methyl-arabino-furonamido)- N6-
benzyladenine;
2-chloro-9-(a-D-erythrofuranoside)-N6-(3 -iodobenzyl)adenine;
N6-(benzodioxanemethyl)adenosine;
1-(6-furfurylamino-9H-purin-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-a-alanylamino)benzyl]adenosine-5'-N-methyluronamide
6-(N'-phenylhydrazinyl)purine-9-a-ribofuranoside-5'-N-methyluronamide;
6-(O-phenylhydroxylamino)purine-9-a-ribofuranoside-5'-N-
methyluronamide;
9-(a-D-2',3'-dideoxyerythrofuranosyl)-N6-[(3-a-
alanylamino)benzyl]adenosine;
9-(a-D-erythrofuranoside)-2-methylamino-N6-(3 -iodobenzyl)adenine;
2-chloro-N-(3-iodobenzyl)-9-(2-tetrahydrofuryl)-9H-purin-6-amine;
2-chloro-(2'-deoxy-6'-thio-L-arabinosyl)adenine; and
2-chloro-(6'-thio-L-arabinosyl)adenine.
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In US 5,773,423 at column 6, line 39, to column 7, line 14, specifically
disclosed are compounds which include the fonnula:
R5
NH
N 5 6-
~, I 1 N
8
9 4 3
5'X1 N N
R2
P'21'
OH OH
wherein
X1 is RaRbNC(=O), wherein R' and Rb may be the same or different and are
selected from the group consisting of hydrogen, C1-Clo alkyl, amino, C1-Clo
haloalkyl, C1-Clo aminoalkyl, and C3-C10 cycloalkyl;
R2 is selected from the group consisting of hydrogen, halo, C1-Clo alkyoxy,
amino, C2-C10 alkenyl, and C2-C10 alkenyl; and
R5 is selected from the group consisting of R- and S-1-phenylethyl, an
unsubstituted benzyl group, and a benzyl group substituted in one or more
positions
with a substituent selected from the group consisting of Cl-Clo alkyl, amino,
halo,
C1-Clo haloalkyl, nitro, hydroxy, acetamido, C1-Clo 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-Clo 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 Rb is a C1-Clo allcyl
or C3-C10 cycloalkyl, particularly a C1-Clo alkyl, and more particularly
methyl.
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Especially specific are those compounds where Ra is hydrogen, Rb is C1-Clo
alkyl or C3-C10 cycloalkyl, and R5 is R- or S-1-phenylethyl or a benzyl
substituted
in one or more positions with a substituent selected from the group consisting
of
halo, amino, acetamido, C1-Clo haloalkyl, and sulfo, where 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 a C2-C10 alkenylene of
the formula Rd C=C- where Rd is a C1-C8 alkyl are particularly noted in this
publication. Also specific are those compounds wherein R2 is other than
hydrogen,
particularly those wherein R2 is halo, Cl-Clo allcylamino, or C1-Clo
alkylthio, and,
more preferably, when additionally Ra is hydrogen, Rb is a C1-Clo alkyl,
and/or R5
is a substituted benzyl.
Such specifically disclosed compounds include 2-chloro-N6-(3-iodobenzyl)-
9- [5-(methylamido)-a-D-ribofuranosyl]-adenine, N6-(3-iodobenzyl)-2-
methylamino-9-[5-(methylamido)-a-D-ribofuranosyl]-adenine, and N6-(3-
iodobenzyl)-2-methylthio-9-[5-(methylamido)-a-D-ribofuranosyl]-adenine.
Further US 5,773,423 discloses at column 7, line 60, through column 8, line
6, A3AR agonists as modified xanthine-7-ribosides having the formula:
R3
N 4 3 X
9 2
Rg I 1
8 ~~ 5 4 N
5,R6 N
0 R7
1 0
3' 2'
OH OH
wherein
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X is 0;
R6 is RaRbNC(=O), wherein Ra and Rb may be the same or different and are
selected from the group consisting of hydrogen, Cl-C10 alkyl, amino, C1-C10
haloalkyl, C1-C10 aininoalkyl, and C3-C10 cycloalkyl;
R7 and R$ may be the same or different and are selected from the group
consisting of C1-C10 alkyl, R- and S-1-phenylethyl, an unsubstituted benzyl
group,
and a benzyl group substituted in one or more positions with a substituent
selected
from the group consisting of C1-C10 alkyl, amino, halo, C1-C10 haloallcyl,
nitro,
hydroxy, acetamido, C1-C10 alkoxy, and sulfo; and
R9 is selected from the group consisting of halo, benzyl, phenyl, and C3-C10
cycloalkyl.
WO 99/06053 discloses in examples 19-33 compounds selected from:
N6-(4-biphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide;
N6-(2,4-dichlorobenzyl-carbonylamino)-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)-a-phenylethylcarbamoyl)-adenosine-5'-N-ethyluronamide;
N6-((S)-a-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-phenylcarbainoyl)- 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.
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According to one embodiment of the invention, the A3AR agonist is a
compound that exerts its prime effect through the binding and activation of
the
adenosine A3AR and is a purine derivative falling within the scope of the
general
formula (I):
R13
N N
e (I)
N
I N R12
R11
wherein,
- R11 represents an allcyl, hydroxyalkyl, carboxyalkyl or cyanoalkyl or a
group of the following general formula (II):
X11 Y
X12 (II)
X13 X14
in which:
- Y represents oxygen, sulfur or CH2;
X11 represents H, alkyl, ReRfNC(=O)- or HORI-, wherein
- Re and Rf may be the same or different and are selected from the
group consisting of hydrogen, alkyl, amino, haloalkyl, aminoalkyl,
BOC-aminoallkyl, and cycloalkyl or are joined together to form a
heterocyclic ring containing two to five carbon atoms; and
- RI is selected from the group consisting of alkyl, amino, haloalkyl,
aminoalkyl, BOC-aminoalkyl, and cycloallcyl;
X12 is H, hydroxyl, alkylainino, alkylamido or hydroxyalkyl;
- X13 and X14 represent independently hydrogen, hydroxyl, amino,
amido, azido, halo, alkyl, alkoxy, carboxy, nitrilo, nitro, trifluoro, aryl,
alkaryl, thio, thioester, thioether, -OCOPh, -OC(=S)OPh or both X13 and
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X14 are oxygens connected to >C=S to form a 5-membered ring, or X12 and
X13 form the ring of formula (III):
O
R'Si
(III)
O\
R"Si O
where R' and R" represent independently an alkyl group;
- R12 is selected from the group consisting of hydrogen, halo, alkylether,
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 0, S, or NRa with R' having the above meanings;
wherein when R15 is hydrogen than
- R16 is selected from the group consisting of R- and S-1-phenylethyl,
benzyl, phenylethyl or anilide groups unsubstituted or substituted in one or
more
positions with a substituent selected from the group consisting of allcyl,
amino,
halo, haloalkyl, nitro, hydroxyl, acetoamido, alkoxy, and sulfonic acid or a
salt
thereof; benzodioxanemethyl, fururyl, L-propylalanyl- aminobenzyl, 13-
alanylamino- benzyl, T BOC-(3-alanylalninobenzyl, phenylamino, carbamoyl,
phenoxy or cycloalkyl; or R16 is a group of the following formula:
O O
NH2
H H
or when R15 is an alkyl or aryl-NH-C(Z)-, then, R16 is selected from the group
consisting of heteroaryl-NRa-C(Z)-, heteroaryl-C(Z)-, alkaryl-NRa-C(Z)-,
allearyl-
C(Z)-, aryl-NR-C(Z)- and aryl-C(Z)-; Z representing an oxygen, sulfor or
amine;
or a physiologically acceptable salt of the above compound.
According to one preferred embodiment, the A3AR agonist is a nucleoside
derivative of the general formula (IV):
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-5
I
NH
N N
(IV)
X1 N
N R2
O
0
OH OH
wherein X1, R2' and R5 are as defined above, and physiologically acceptable
salts of said compound.
The non-cyclic carbohydrate groups (e.g. alkyl, alkenyl, alkynyl, alkoxy,
aralkyl, alkaryl, alkylamine, etc) forming 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.
When referring to "physiologically acceptable salts" of the compounds
employed by the present invention it is meant any non-toxic alkali metal,
alkaline
earth metal, and ammonium salt commonly used in the pharmaceutical industry,
including the sodium, potassium, lithium, calcium, magnesium, barium ammonium
and protamine zinc salts, 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.
The acid addition salts are those which retain 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
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like. Organic acids include, inter alia, tartaric, acetic, propionic, citric,
malic,
malonic, lactic, fumaric, benzoic, cinnamic, mandelic, glycolic, gluconic,
pyruvic,
succinic salicylic and arylsulphonic, e.g. p-toluenesulphonic, acids.
Specific examples of A3AR agonist which may be employed according to
general formula (IV) of the present invention include, without being limited
thereto,
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 (CI-IB-MECA). IB-MECA is the most preferred compound in
accordance with the invention.
According to another embodiment, the A3AR agonist may be an oxide
derivative of adenosine, such as N6-benzyladenosine-5'-N-alkyluronamide-Nl-
oxide or N6-benzyladenosine-5'-N-dialkyluronamide-Nl-oxide, wherein the 2-
purine position may be substituted with an alkoxy, amino, alkenyl, alkynyl or
halogen.
The terms "effective amount" or "amount effective to" in the context of the
present invention refer to an amount of A3AR agonist which prevents or reduces
symptoms of dry eye in patients. The "effective amount" can be readily
determined,
in accordance with the invention, by administering to a plurality of tested
subjects
various amounts of the A3AR agonist and then plotting the physiological
response
(for example an integrated "SS index" combining several of the therapeutically
beneficial effects) as a function of the amount. Alternatively, the effective
amount
may also be determined, at times, through experiments perfonned in appropriate
animal models and then extrapolating to human beings using one of a plurality
of
conversion methods; or by measuring the plasma concentration or the area under
the curve (AUC) of the plasma concentration over time and calculating the
effective
dose so as to yield a comparable plasma concentration or AUC. As known, the
effective amount may depend on a variety of factors such as mode of
administration
(for example, oral administration may require a higher dose to achieve a given
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plasma level or AUC than an intravenous administration); the age, weight, body
surface area, gender, health condition and genetic factors of the subject;
other
administered drugs; etc.
In the following, unless otherwise indicated, dosages are indicated in
weight/Kg, meaning weight of administered A3AR agonist (e.g. IB-MECA) per
kilogram of body weight of the treated subject in each administration. For
example,
mg/Kg and microgram/Kg denote, respectively, milligrams of administered agent
and micrograms of administered agent per kilogram of body weight of the
treated
subject.
The effective amount is preferably less than about 1 mg/kg body weight,
particularly less than about 500 g/kg or even less than about 200 pg/kg body
weight or at times less than about 100 pg/lcg body weight or even less than
about
less than 50 g/kg body weight. With respect to IB-MECA, the effective amount
is
preferably less than 5 mg each dose, for once daily administration (namely a
dose
less than about 70 g/kg body weight, assuming an average individual weight of
about 70 kg), and less than about 4 mg each dose (i.e. less than about 57
pg/kg
body weight), for twice daily administration. The dose of IB-MECA is more
preferably less than about 2 mg each dose and typically between about 0.1-1 mg
each dose, for either once or twice daily administration (the corresponding
dosages
in weight per body weight being about 29 pg/kg and about 1.5-15 mg/kg body
weight, respectively).
The administration of the A3AR agonist to an individual may be together
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, one example being ocular administration.
By the term "pharmaceutically acceptable carrier" it is meant any one of
inert, non-toxic materials, which do not react with the A3AR agonist and which
can
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be added to formulations as diluents or carriers or to give form 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 other various forms. The carrier is selected at
times
based on the desired form of the formulation. The carrier may also at times
have the
effect of the improving the delivery or penetration of the active ingredient
to the
target tissue, for improving the stability of the drug, for slowing clearance
rates, for
imparting slow release properties, for reducing undesired side effects etc.
The
carrier may also be a substance that stabilizes the formulation (e.g. a
preservative),
for providing the formulation with an edible flavor, etc. The carriers may be
any of
those conventionally used and is 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 additives, colorants, diluents,
buffering
agents, disintegrating agents, moistening agents, preservatives, flavoring
agents,
and pharmacologically compatible carriers. In addition, the carrier may be an
adjuvant, which, by definition are substances affecting the action of the
active
ingredient in a predictable way.
Typical examples of carriers suitable for oral administration comprise (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
(e.g. the ordinary hard- or soft-shelled gelatin type containing, for example,
surfactants, lubricants, and inert fillers), tablets, lozenges (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 troches,
each
containing a predetermined amount of the tragacanth as solids or granules; (c)
powders; (d) suspensions in an appropriate liquid; (e) suitable emulsions; (f)
liposome fonnulation; and others.
A topical formulation may be in any form suitable for topical administration,
including, without being limited thereto, an ophthalmic solution (e.g. eye
drops), an
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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 drug containing layer and to be placed on top of the
eyelid as
well as to Ocular inserts which are devices containing the A3AR agonist and
placed
into the inferior or superior conjunctival sacs (see for example W00059420).
Eye drops may be prepared by dissolving A3AR agonist in a sterile aqueous
solution such as saline, buffering solution etc., or by combining powder
compositions to be dissolved before use. Other additives may be included in
the eye
drops such as isotonizing agents (e.g., sodium chloride, etc.), buffer agent
(e.g.,
boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.),
preservatives (e. g., benzalkonium chloride, benzethonium chloride,
chlorobutanol,
etc.), thickeners (e. g., saccharide such as lactose, mahnitol, maltose, etc.;
e.g.,
hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate,
etc.;
e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g., sodium
polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, etc.).
Eye ointments may be prepared by mixing A3AR agonist into a base.
Examples of the base for eye ointment include petrolatum, selen 50,
Plastibase,
macrogol, etc., but not limited thereto.
Some exemplary ophthalmic viscosity enhancers that can be used in the
present formulation include: carboxymethyl cellulose sodium; methylcellulose;
hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxyethyl
cellulose;
polyethylene glycol 300; polyethylene glycol 400; polyvinyl alcohol; and
providone.
Some natural products, such as veegum, alginates, xanthan gum, gelatin,
acacia and tragacanth, may also be used to increase the viscosity of
ophthalmic
solutions.
A tonicity is important because hypotonic eye drops cause an edema of the
cornea, and hypertonic eye drops cause deformation of the cornea. The ideal
tonicity is approximately 300 mOsM. The tonicity can be achieved by methods
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described in Remington: The Science and Practice of Pharmacy, known to those
versed in the art.
As used herein, the forms "a", "an" and "the" include singular as well as
plural references unless the context clearly dictates otherwise. For example,
the
term "an AAAR agonist" includes one or more compounds which are capable of
specifically binding to the A3AR, thereby fully or partially activating said
receptor.
Further, as used herein, the term "comprising" is intended to mean that the
composition include the recited active agent, i.e. A3AR agonist, but not
excluding
other elements, such as physiologically acceptable carriers and excipients as
well as
other active agents. The tern "consisting essentially of' is used to define
compositions which include the recited elements but exclude other elements
that
may have an essential significance on treatment of dry eye syndrome.
"Consisting
of' shall thus mean excluding more than trace elements of other elements.
Embodiments defined by each of these transition terms are within the scope of
this
invention.
Further, all numerical values, e.g. when referring the amounts or ranges of
the elements constituting the composition comprising the A3AR agonist as an
active
ingredient, are approximations which are varied (+) or (-) by up to 20%, at
times by
up to 10% of from the stated values. It is to be understood, even if not
always
explicitly stated that all numerical designations are preceded by the teen
"about".
The invention will now be exemplified in the following description of
experiments that were carried out in accordance with the invention. It is to
be
understood that these examples are intended to be in the nature of
illustration rather
than of limitation. Obviously, many modifications and variations of these
examples
are possible in light of the above teaching. It is therefore, to be understood
that
within the scope of the appended claims, the invention may be practiced
otherwise,
in a myriad of possible ways, than as specifically described hereinbelow.
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EXAMPLE:
IB-MECA improves dry eye symptoms in Rheumatoid Arthritis patients
Drug:
The A3AR agonist used was 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), that was synthesized for Can-Fite BioPharma,
under good clinical practice (GNIP) by Albany Molecular Research Inc, Albany,
NY, USA.
The IB-MECA was formulated in oval softgel capsules. The capsules
contained solutions of IB-MECA in CremophorTM RH 40 and MiglyolTM 812. The
capsules contained a dose of 0.1, 1 or 4 mg of IB-MECA, the exact composition
of each capsules' type is shown in the following Tabels 1-3:
Table 1: Composition of 0.1 mg IB-MECA Softgel Capsules
Ingredient Capsule %W/W
IB-MECA 0.105 mg 0.021
Polyoxyl 45 Castor Oil, 326.495 mg 65.299
USP (Cremo hor RH 40)
Mi lyol 812 173.400 mg 34.680
Table 2: Composition of 1 mg IB-MECA Softgel Capsules
Ingredient Capsule %W/W
IB-MECA 1.05 mg 0.210
Polyoxyl 45 Castor Oil, 325.975 mg 65.195
USP (Cremophor RH 40)
Mi 1 of 812 172.975 mg 1 34.595
Table 3: Composition of 4 mg IB-MECA Softgel Capsules
Ingredient Capsule %W/W
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IB-MECA 4.2 mg 0.84
Polyoxyl 45 Castor Oil, 324.4 mg 64.88
USP (Cremophor RH 40)
Miglyol 812 171.4 mg 34.28
Methods:
The capsules with IB-MECA were given to patients orally twice daily. All
patients had rheumatoid arthritis (RA) and were give IB-MECA within the
framework of a clinical study aimed at testing the effect of IB-MECA in
modifying RA disease symptoms in these patients. The patients received
randomly capsules of one of the above there doses. The patients received the
IB-
MECA for a period of 12 weeks.
4 out of the treated patients also suffered from Sicca and the effect of IB-
MECA on their dry eye symptoms was examined as well.
Results
Table 1 summarizes the results of CF 101 treatment of RA patients.
Specifically, four patients at the age 58 4 years who suffered from RA for 8 2
years were followed. At base line, the patients had elevated levels of
rheumatoid
factor, i.e., 313 120 IU/ml (0<normal<40) and had suffered from dry eyes for
1.6 years. Upon treatment with CF101 for 6.25 1.1 months, an improvement
in Schirmer's test from 8.5 1.4mm to 15.6 2.9mm was observed.
CA 02622975 2008-03-18
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