WO2012125400A1 - Compositions et procédés utilisant des antagonistes du récepteur de l'adénosine a3 pour traitement de maladies oculaires inflammatoires - Google Patents

Compositions et procédés utilisant des antagonistes du récepteur de l'adénosine a3 pour traitement de maladies oculaires inflammatoires Download PDF

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WO2012125400A1
WO2012125400A1 PCT/US2012/028247 US2012028247W WO2012125400A1 WO 2012125400 A1 WO2012125400 A1 WO 2012125400A1 US 2012028247 W US2012028247 W US 2012028247W WO 2012125400 A1 WO2012125400 A1 WO 2012125400A1
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group
adenosine
eye
alkyl
receptor antagonist
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PCT/US2012/028247
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Alan Jeffrey Jacobs
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Acorn Biomedical, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants

Definitions

  • the invention relates to compositions of adenosine A3 receptor antagonists and methods of their use for the treatment of inflammatory eye diseases.
  • Inflammatory eye diseases such as dry eye and uveitis, are serious conditions that can cause eye pain, redness, discomfort, or sensitivity to light.
  • the inflammatory eye disease can be unresponsive to treatment and may lead to blindness with glaucoma, cataract or retinopathy.
  • Treatment options for inflammatory eye disease are limited to steroids, non-steroid anti-inflammatory drugs (NSAIDs), immunosuppressive chemotherapy medications or immunomodulatory therapy (IMT).
  • NSAIDs non-steroid anti-inflammatory drugs
  • IMT immunomodulatory therapy
  • Conventional treatments may not reverse or stop progression of the eye disease.
  • inflammatory eye diseases can be difficult to treat and may recur after treatment.
  • Adenosine receptors belong to the G protein-coupled family of proteins and are characterized by seven transmembrane helical domains. Receptor activation leads to its internalization and the subsequent inhibition of: (i) adenylyl cyclase activity, (ii) cAMP formation and (iii) protein kinase A (PKA) expression, resulting in the initiation of various signaling pathways.
  • PKA protein kinase A
  • Adenosine A3 receptors are involved in a variety of important patho-physiological processes, including modulation of cerebral and cardiac ischemic damage, inflammation, modulation of intraocular pressure, regulation of normal and tumor cell growth, and immune suppression.
  • adenosine A3 receptor agonists and antagonists have been identified, such as adenosine derivatives, fiavonoids, and triazoloquinazolines, which specifically bind to the adenosine A3 receptor. See e.g., PCT/KR2007/001131; U.S. Patent No. 6,376,521; WO 2010/014921; U.S. Patent No. 6,199,127.
  • Agonists of the adenosine A3 receptor have been shown to desensitize the adenosine A3 receptor. Palmer and Stiles. (1999) Molecular Pharmacology; Palmer, T.M. et al. (1995) J. Biol. Chem.
  • CF101 adenosine A3 receptor agonist
  • the invention addresses these and other shortcomings of the prior art by providing methods for treating inflammatory eye disease using adenosine A3 receptor antagonist compositions.
  • Methods of the invention include treating an inflammatory eye disease by
  • the inflammatory eye disease is selected from the group consisting of: dry eye, uveitis, scleritis, blepharitis, keratitis, conjunctivitis, chorioretinital inflammation, choroiditis, retinitis, iridocyclitis, ulceris, posterior cyclitis, diabetic retinopathy, a post-surgery condition, allergies, eye trauma, eye bruises, foreign body, toxin exposure, chemical exposure, food allergies, hives, rheumatoid arthritis, sarcoidosis, juvenile idiopathic arthritis, lupus, Behcet's disease, viral infection, fungal infection, mycobacterial infection, parasite infection, bacterial infection, acanthamoeba infection, spirochete infection, Crohn's disease, arthritis, ulcerative colitis, lympho
  • the adenosine A3 receptor antagonist comprises any of the compositions described herein.
  • the adenosine A3 receptor antagonist is selected from the group consisting of: ACN-1052, LJ1251, MRS3820, MRS3771, LJ 979, MRS 3826, MRS 3827, MRS1191 or MRS 1292.
  • the inflammatory eye disease is uveitis
  • the adenosine A3 receptor antagonist is selected from the group consisting of: ACN-1052, LJ1251, or MRS3820.
  • the inflammatory eye disease is dry eye and the adenosine A3 receptor antagonist is selected from the group consisting of: ACN-1052, LJ1251, MRS3820, MRS 3771, LJ 979, MRS 3826, or MRS3827.
  • the adenosine A3 receptor antagonist is ACN-1052.
  • administering an effective amount of an adenosine A3 receptor antagonist reduces corneal inflammation. In one embodiment, administering an effective amount of an adenosine A3 receptor antagonist reduces inflammatory cytokine levels.
  • the mammalian subject is a human subject.
  • the adenosine A3 receptor antagonist is formulated for topical delivery to an eye of the mammalian subject. In other embodiments, the adenosine A3 receptor antagonist is formulated for topical delivery, intraocular injection, intravitreal injection, oral delivery, sublingual delivery, intranasal delivery, intravenous injection, intramuscular injection, intraperitoneal injection, or rectal delivery.
  • the method includes co-administering to the mammalian subject an effective amount of a steroid, a non-steroidal anti-inflammatory, or an
  • the immunosuppressant is cyclosporine A.
  • FIG. la shows a graph of tear reduction in mice after scopolamine patch application under dry environmental conditions.
  • FIG. lb shows histopathology scores 12 days after scopolamine administration in mice.
  • “a” indicates that the p-value is less than 0.05 relative to the vehicle control group
  • “b” indicates that the p-value was less than 0.05 reltaive to the no- treatment group.
  • N 10 female C57BL/6 mice per group.
  • FIG. 2 shows the effects of Dexamethasone (DEX) and cyclosporine (CSA, Restasis) in a Tear Break Up Test (TBUT) in concanavalin A (ConA)-induced dry eye in rabbits.
  • DEX Dexamethasone
  • CSA cyclosporine
  • ConA concanavalin A
  • FIG. 3a shows the effects of ConA injection on the Schirmer Tear Test (STT) in rabbits.
  • FIG. 3b shows the use of DEX and CSA in the Schirmer Tear Test (STT) in rabbits.
  • FIGs. 4a-4c shows representative photographs of the anterior area of the eye of a rat with a melanin-associated antigen (MAA) induced anterior uveitis.
  • MAA melanin-associated antigen
  • FIG. 5 shows histopathology scores 18 days after MAA injection in untreated rats and rats treated with vehicle, DEX, CSA, or Restasis.
  • FIGs. 6a-6c illustrates the photomicroscopy of histopathology findings in MAA- treated rats.
  • FIG. 7 shows inhibition of corneal injury by ACN-1052 in a mouse model of dry eye syndrome measured by corneal staining.
  • FIG. 8 shows the effect of ACN-1052 on dry eye syndrome in a mouse model measured by corneal staining.
  • Adenosine refers to a purine nucleoside and a metabolite of adenosine triphosphate (ATP).
  • Adenosine is a nucleoside composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a P-N9-glycosidic bond.
  • Adenosine plays an important role in biochemical processes, such as energy transfer, as adenosine triphosphate (ATP) and adenosine diphosphate (ADP), as well as in signal transduction as cyclic adenosine monophosphate, cAMP.
  • the IUPAC name is (2R,3R,4S,5R)-2-(6-amino-9H- purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol.
  • Adenosine mediates a wide variety of physiological functions by interacting with four cell surface receptors namely Al, A2a, A2b and A3.
  • Adenosine receptor refers to a class of purinergic receptors or G protein-coupled receptors that bind adenosine as an endogenous ligand.
  • Adenosine receptors include four types: Al, A2a, A2b, and A3.
  • Adenosine A3 receptor or "A3AR” or “A3 Adenosine Receptor” refers to a G protein-coupled receptor that is involved in a variety of intracellular signaling pathways and physiological functions.
  • Adenosine A3 receptors are ubiquitously expressed in a wide variety of tissues in human body, with high levels in peripheral organs and low levels in the brain.
  • Adenosine A3 receptors are involved in a variety of important patho-physiological processes, including modulation of cerebral and cardiac ischemic damage, inflammation, modulation of intraocular pressure, regulation of normal and tumor cell growth, and immunosuppression.
  • Adenosine A3 receptors are also involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, have been implicated in both neuroprotective and neurodegenerative effects, and may also mediate both cell proliferation and cell death.
  • the adenosine A3 receptor is encoded by the mR A with
  • GenBank Accession No. NM 000677 and has the protein sequence of GenBank Accession No. NP 000668.
  • the adenosine A3 receptor is encoded by the mRNA with
  • GenBank Accession No. NM 009631 Citations in this specification to GenBank Accession Numbers refer to those sequence versions current as of the filing date of this specification.
  • Adenosine A3 receptor antagonist or “A3AR Ag” refers to a ligand, molecule, composition, or drug that binds to an adenosine A3 receptor and inhibits or dampens agonist- mediated responses.
  • the A3AR Ag exerts its effect through binding and inactivation of the A3AR.
  • Adenosine A3 receptor antagonists can have affinity but no efficacy for their cognate receptors, and binding can disrupt the interaction and inhibit the function of an agonist or inverse agonist at the receptors.
  • Antagonists refer to receptor ligands, molecules, compositions or drugs that activate a cellular response by binding to a receptor.
  • Antagonists refer to receptor ligands, molecules, compositions or drugs that inhibit the receptor's agonist response, in some cases by blocking the receptor from the agonist.
  • Competitive antagonists or surmountable antagonists
  • the level of receptor inhibition is determined by the relative affinity of each molecule for the site and their relative concentrations.
  • Noncompetitive antagonists or non-surmountable antagonists are allosteric antagonists. These antagonists bind to a distinctly separate binding site from the agonist, exerting their action to that receptor via the other binding site.
  • Inflammatory eye disease refers to disorders, diseases, or conditions that affect the eye, including, but not limited to, dry eye, uveitis, scleritis, blepharitis, keratitis,
  • conjunctivitis chorioretinital inflammation, choroiditis, retinitis, iridocyclitis, ulceris, posterior cyclitis, diabetic retinopathy, post-surgery, allergy, trauma, bruises, foreign body, exposure to toxins or chemicals, food allergies, hives, autoimmune disorders (such as rheumatoid arthritis, sarcoidosis, juvenile idiopathic arthritis, lupus, Behcet's disease, etc.), infection (such as viral, fungal, mycobacteria, parasite, bacteria, acanthamoeba, spirochete, etc.), inflammatory conditions (such as Crohn's disease, arthritis and ulcerative colitis) and cancers (such as lymphoma, eye tumors, cancer of blood vessels, etc.), or an inflammatory retinal disease (such as neuroretinitis, Sarcoidosis-related retinitis, Behcet' s-related retinitis, or acute retinal
  • In vivo refers to processes that occur in a living organism.
  • Effective amount refers to a sufficient amount of an agent to provide the desired biological result.
  • the result can be a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an "effective amount” for therapeutic uses is the amount of the composition comprising an active composition herein required to provide a clinically significant decrease in inflammation in the eye, and thereby reducing symptoms of an eye disease, e.g. , uveitis, such as blurred vision or eye pain.
  • Treatment or “treatment” are used interchangeably and are meant to indicate
  • compositions in accordance with the methods of the invention further include ameliorating existing eye symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, and/or promoting resolution of the disease or condition.
  • “Ameliorating” refers to any therapeutically beneficial result in the treatment of a disease state, e.g., an eye disease, including prophylaxis, lessening in the severity or progression, remission, or cure thereof.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any substantial undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • a “subject” encompasses mammals.
  • a “mammal” includes any member of the Mammalia class: humans, non-human primates (chimpanzees, and other apes and monkey species), canines, felines, murines, bovines, equines, porcines, etc.
  • Other examples of mammals include cattle, horses, sheep, goats, swine, rabbits, dogs, cats, and rodents, such as rats, mice and guinea pigs, and the like.
  • the terms "subject” or “mammal” do not denote a particular age or gender.
  • Aryl refers to aromatic moieties such as phenyl, naphthyl, anthracenyl, and biphenyl.
  • Heterocyclyl refers to 3-7 membered rings which can be saturated or unsaturated or heteroaromatic, comprising carbon and one or more heteroatoms such as O, N, and S, and optionally hydrogen; optionally in combination with one or more aromatic rings.
  • heterocyclyl groups include pyridyl, piperidinyl, piperazinyl, pyrazinyl, pyrolyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, furyl, thiophenyl, tetrahydrothiophenyl, purinyl, pyrimidinyl, thiazolyl, thiazolidinyl, thiazolinyl, oxazolyl, tetrazolyl, tetrazinyl, benzoxazolyl, morpholinyl, thiomorpholinyl, quinolinyl, and isoquinolinyl.
  • heteroaryl alkyl include heteroaryl methyl such as 2- or 3- methyl substituted groups, e.g., thienylmethyl, pyridylmethyl,
  • Alkyl, alkoxy, and alkylamino groups can be linear or branched.
  • a substituent e.g., halo, amino, alkyl, hydroxyl, alkoxy, and others
  • the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g., 2, 3, 4, 5, and/or 6-position wherein the 1 -position is the point of attachment of the aryl group in the composition of the present invention.
  • Halo refers to fluorine, chlorine, bromine, and iodine.
  • compositions of the invention are provided.
  • compositions of the invention comprise adenosine A3 receptor antagonists.
  • compositions of the invention comprise adenosine derivatives, dihydropyridine derivatives, pyridine derivatives, or purine nucleosides.
  • composition of the invention comprises:
  • R is 3-iodobenzyl.
  • ACN-1052 also called LJ1251 or MRS3820
  • 2R,3R,4S is the chemical name (2R,3R,4S)-2-(6-(3-iodobenzylamino)-2- chloro-9H-purin-9-yl)-tetrahydrothiophene-3,4-diol. It is described in Jeong et al. (2007) Journal of Medicinal Chemistr .
  • ACN-1052 is also shown below:
  • ACN-1052 is freely soluble in DMSO and various mixtures of organic solvents such as DCM and DMSO. It is not appreciably soluble in water-based vehicles with low concentrations of organics such as DMSO or ethanol.
  • ACN-1052 can be synthesized by the following steps:
  • composition of the invention is selected from the group comprising:
  • a 3 ⁇ 4 antagonist prodrugs A antagonist ⁇ truncated ⁇
  • composition of the invention comprises:
  • MRS 1292 is derived from the agonist IB-MECA (N 6 -(3-iodobenzyl)-adenosine-5'-N- methyluronamide). MRS 1292 is described in Yang et al. (2005) Current Eye Research. 30:747-754. MRS 1292 can be synthesized by the following steps, described in Besada et al. (2006) Collect. Czech. Chem. Commun. 71(6):912-928.
  • composition of the invention comprises:
  • MRS 1191 has the IUPAC name 03-ethyl 05-(phenylmethyl) 2-methyl-6-phenyl-4- (2-phenylethynyl)-l ,4-dihydropyridine-3,5-dicarboxylate. MRS 1191 is described in Jacobson et al. (1997) Neuropharmacology. 36(9):1 157-1165. MRS 1191 can be synthesized by the following steps, wherein R 4 is phenylethynyl.
  • composition of the invention comprises:
  • R 1 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, Ci-C 6 alkoxy, hydroxyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl Ci-C 6 alkyl, C 3 -C 8 dicycloalkyl Ci-C 6 alkyl, C 7 -C 12 bicycloalkyl Ci-C 6 alkyl, C 7 -C 14 tricycloalkyl Ci-C 6 alkyl, C 6 -Ci 4 aryl, C 6 -Ci 4 aryl Ci- C 6 alkyl, C 6 -Ci 4 diaryl Ci-C 6 alkyl, C 6 -Ci 4 aryl Ci-C 6 alkoxy, Ci-C 6 alkyl carbonyl, sulfonyl, Ci-C 6 alkyl sulfonyl, C 6 -Cj 4 aryl sulfonyl, heterocyclyl Ci-C 6 alkyl carbony
  • R 2 is selected from the group consisting of hydrogen, halo, amino, hydrazido, mercapto, C1-C20 alkylamino, C 6 -Ci4 aryl amino, C 6 -Ci4 aryloxy, C1-C20 alkyl, C1-C20 alkoxy, C1-C20 thioalkoxy, pyridylthio, C7-C12 cycloalkyl C1-C20 alkyl, C7-C12 bicycloalkyl C1-C20 alkyl, C7-C2 bicycloalkenyl C1-C20 alkyl, C 6 -Ci4 aryl C1-C20 alkyl, C2-C20 alkenyl, C7- C12 cycloalkyl C 2 -C 2 o alkenyl, C7-C12 bicycloalkyl C 2 -C 2 o alkenyl, C7-C12 bicycloalkyl C 2
  • R 3 and R 4 are independently selected from the group consisting of hydroxyl, amino, thiol, ureido, Ci-C 6 alkyl carbonylamino, hydroxy Ci-C 6 alkyl, and hydrazinyl; and R 5 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heteroaryl, and Ci-C 6 aminoalkyl; or a pharmaceutically acceptable salt.
  • R 1 is selected from the group consisting of C 6 -Ci4 aryl Ci-C 6 alkyl and C 6 -Ci4 aryl C3-C8 cycloalkyl, wherein the aryl portion of R 1 is optionally substituted with one or more substituents selected from the group consisting of halo, amino, Ci-C 6 alkyl, Ci-C 6 alkoxy, C 6 -Ci4 aryloxy, hydroxy Ci-C 6 alkyl, hydroxy C 2 -C 6 alkenyl, hydroxy C 2 -C 6 alkynyl, aminocarbonyl Ci-C 6 alkoxy, and C 6 -Ci4 aryl Ci-C 6 alkoxy; and in one embodiment, R 1 is selected from the group consisting of benzyl, phenyl cyclopropyl, or 1-naphthyl methyl, wherein the phenyl or naphthyl portion of R 1 is optionally substituted with
  • R 1 is benzyl, phenyl cyclopropyl, or 1- naphthyl methyl, wherein the phenyl or naphthyl portion of R 1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, and alkoxy.
  • R 1 are benzyl and benzyl substituted with one or more substituents selected from the group consisting of halo and Ci-C 6 alkoxy.
  • R 1 is selected from the group consisting of 3-chlorobenzyl, 3-bromobenzyl, 3-iodobenzyl, 2-hydroxy-5-methoxy- benzyl, and 2,5-dimethoxybenzyl.
  • the phenyl cyclopropyl is traro-2- phenyl- 1 -cyclopropyl.
  • R 3 and R 4 are particularly hydroxyl.
  • R 5 is hydrogen.
  • adenosine A3 receptor antagonists include those described in WO 2010/014921 A2 (PCT/US2009/052439), which is incorporated by reference in its entirety.
  • the composition comprises:
  • R is a linear or branched Ci-C 5 alkyl which is non-substituted or is independently or selectively substituted with one or more C 6 -Cio aryl groups, a benzyl which is non-substituted or is independently or selectively substituted with halogen or one or more linear or branched C 1 -C4 alkoxy groups, or a hydroxycarbonyl-substituted benzyl; and
  • Y is H or a halogen atom.
  • A is O or S
  • R is methyl, ethyl, propyl, naphthylmethyl, benzyl, benzyl independently or selectively substituted with a substituent selected from a group consisting of F, CI, Br, I, C 1 -C3 alkoxy and combinations thereof, or toluic acid
  • Y is H or CI.
  • A is O or S
  • R is methyl, ethyl, 1- naphthylmethyl, benzyl, 2-chlorobenzyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3- iodobenzyl, 2-methoxy-5-chlorobenzyl, 2-methoxybenzyl, or 3-toluic acid
  • Y is H or CI.
  • compositions are described in U.S. Publication No. 2010/0137577.
  • the adenosine derivatives comprise: (2R,3R,4S)-2-(2-chloro-6-
  • adenosine derivatives for use as adenosine A3 receptor antagonists and synthesis are described in U.S. Publication No. 2010/0137577, which is incorporated by reference in its entirety.
  • the composition comprises:
  • Ri and R 3 are selected from the group consisting of hydrogen, hydroxy, Ci- C 6 alkyloxy, and Ci-C 6 alkylcarbonyloxy; R 2 is selected from the group consisting of:
  • the composition comprises:
  • Ri is selected from the group consisting of hydroxyl and Ci-C 6 alkoxy
  • M is a divalent radical selected from the group consisting of— CH(OH)— CH(R 2 )— and—
  • composition comprises:
  • R 2 is a Ci -C 6 alkyl
  • R ⁇ 5 is selected from the group consisting Ci-C 6 alkyl, Ci-C 6 haloalkyl, and phenyl which may be further substituted with Ci-C 6 alkyl, halo, nitro, furyl, or thienyl
  • R 3 is selected from the group consisting of Ci-C 6 alkyl, Ci-C 6 alkyloxycarbonyl, aryl Ci-C 6 alkyloxycarbonyl, Ci-C 6 alkylthiocarbonyl, Ci-C 6 alkylaminocarbonyl, and Ci-C 6 alkyloxy Ci-C 6 alkylcarbonyl, or R 3 together with R 2 forms a ring having 2-4 methylene groups, and Ci-C 6 alkenyloxycarbonyl;
  • R4 is selected from the group consisting of Ci-C 6 alkyl, aryl Ci-C 6 alkenyl, Ci-C 6 alkyl
  • the composition comprises:
  • R 2 is selected from the group consisting of hydrogen and Ci-C 6 alkyl
  • R 3 is selected from the group consisting of hydrogen and Ci-C 6 alkyloxycarbonyl
  • R4 is selected from the group consisting of Ci-C 6 alkyl, phenyl C 2 -C 6 alkenyl, phenyl C 2 -C 6 alkynyl, aryl, and aryl substituted with one or more substituents selected from the group consisting of nitro and Ci-C 6 alkyloxy
  • R 5 is selected from the group consisting of hydrogen, Ci-C 6 alkyloxycarbonyl, and aryl Ci-C 6 alkyloxy carbonyl
  • 5 is selected from the group consisting of hydrogen, aryl, and Ci-C 6 alkyl; with the proviso that when R4 is not alkyl.
  • the composition comprises:
  • Ri is selected from the group consisting of Ci-C 6 alkylcarbonyl, Ci-C 6 alkyloxycarbonyl, amino Ci-C 6 alkylcarbonyl, and arylcarbonyl wherein the aryl may be further substituted with halo, nitro, hydroxy, amino or cyano; and R 2 is hydrogen or halogen.
  • This composition is described in U.S. Patent No. 6,066,642.
  • Other embodiments of compositions including dihydronepyridine-, pyridine-, benzopyran-4-one- and
  • composition comprises:
  • R 2 is selected from the group consisting of Ci-C 6 alkyl, C3-C7 cycloalkyl, and Ci-C 6 alkoxy Ci-C 6 alkyl
  • R 3 is selected from the group consisting of Ci-C 6 alkoxy, Ci-C 6 alkylsulfanyl, hydroxy, Ci-C 6 alkoxy Ci-C 6 alkylsulfanyl, hydroxy Ci-C 6 alkylsulfanyl, and halo Ci-C 6 alkylsulfanyl, or R 3 together with R4 forms a 3-7 membered heterocyclic ring containing O, N, or S
  • R 4 is selected from the group consisting of Ci-C 6 alkyl, halo Ci-C 6 alkyl, hydroxy Ci-C 6 alkyl, Ci-C 6 alkoxy, Ci-C 6 alkylsulfanyl, Ci-C 6 alkylamino, Ci-C 6 alkylcarbonyl sulfanyl Ci-
  • the composition comprises:
  • R 2 is a Ci-C 6 alkyl
  • R 3 is selected from the group consisting of Ci -C 6 alkoxy, Ci-C 6 alkoxy Ci-C 6 alkylsulfanyl, and Ci -C 6 alkylsulfanyl
  • R 4 is selected from the group consisting of Ci -C 6 alkyl, acetal, formyl, aryl C 2 -C 6 alkenyl, and aryl C 2 -C 6 alkynyl
  • R 5 is selected from the group consisting of Ci-C 6 alkyl and aryl Ci-C 6 alkyl
  • 3 ⁇ 4 is selected from the group consisting of aryl and C 3 -C 6 cycloalkyl; wherein said aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
  • This composition is described in U.S. Patent No. 6,376,521. Other embodiments are described in U.S. Patent No. 6,376,521, which is described
  • composition comprises:
  • X is sulfur or oxygen
  • Ri is hydrogen, C 1 -C 5 alkyl, benzyl, halobenzyl, or phenyl C 1 -C 5 alkyl
  • R 2 is hydrogen, halogen, C 1 -C 5 alkoxy group, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 5 alkylthio, or thio
  • R 3 and R 3 ' may be the same or different and are hydrogen, hydroxy C 1 -C 5 alkyl, C 1 -C 5 alkoxycarbonyl, or C 1 -C 5 alkylaminocarbonyl
  • R 4 is hydrogen or C 1 -C 5 alkyl; or a pharmaceutically acceptable salt, or isomer.
  • R3 and R 3' are not the same.
  • X is sulfur.
  • Ri is 3-iodobenzyl
  • R 2 is chloride
  • R 3 is methylaminocarbonyl
  • R 3 > and R4 are hydrogen
  • X is sulfur.
  • composition comprises:
  • R ls R 2 and R 3 are as defined by the preceding formula.
  • the adenosine A3 receptor antagonist is (2R,3S,4R)-2-[2-chloro-6-(3-iodobenzylamino)purin- 9-yl]-3,4-dihydroxy-tet- rahydrothiophene-2-carboxylic acid methyl amide.
  • composition comprises:
  • R ls R 2 and R 3 are as defined above for the preceding formula, and specifically, Ri is hydrogen, methyl group, or 3-iodobenzyl group, R 2 is chloride, R 3 and R 4 are hydrogen, R 3 ' is methylaminocarbonyl group or hydroxymethyl group, and X is sulfur.
  • compositions include (2R,3R,4S,5R)-2-[2-chloro-6- (3iodobenzylamino)purin-9-yl]-5-hydroxymethyl- tetrahydrothiophene-3,4-diol,
  • the composition comprises:
  • R ls R 2 and R 3 are as defined by the preceding formula.
  • An example of the composition is (2S,3R,4S,5R)-2-[2-chloro-6-(3-iodobenzylamino)purin-9-yl]-5- hydroxymethy- ltetrahydrothiophene-3,4-diol.
  • This composition is described in U.S. Patent No. 7,199,127.
  • Other embodiments of compositions and their synthesis are described in U.S. Patent No. 7,199,127, which is incorporated by reference in its entirety.
  • composition of the invention comprises:
  • A is O or S
  • R is a linear or branched Ci-C 5 alkyl which is non-substituted or is independently or selectively substituted with one or more C 6 -Cio aryl groups, a benzyl which is non-substituted or is independently or selectively substituted with halogen or one or more linear or branched C1-C4 alkoxy groups, or a hydroxycarbonyl-substituted benzyl; and Y is H or a halogen atom.
  • A is O or S
  • R is methyl, ethyl, propyl, naphthylmethyl, benzyl, benzyl independently or selectively substituted with a substituent selected from a group consisting of F, CI, Br, I, C1-C3 alkoxy and combinations thereof, or toluic acid
  • Y is H or CI.
  • A is O or S
  • R is methyl, ethyl, 1- naphthylmethyl, benzyl, 2-chlorobenzyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3- iodobenzyl, 2-methoxy-5-chlorobenzyl, 2-methoxybenzyl, or 3-toluic acid
  • Y is H or CI.
  • adenosine derivatives include: (2R, 3R, 4S)-2-(2-chloro-6-(3- fluorobenzylamino)-9H-purin-9-yl) tetrahydrothiophen-3, 4-diol; (2R, 3R,4S)-2-(2-chloro-6- (3-chlorobenzylamino)-9H-purin-9-yl) tetrahydrothiophen-3, 4-diol; (2R, 3R,4S)-2-(6- (3- bromobenzylamino)-2-chloro-9H-purin-9-yl) tetrahydrothiophen-3, 4-diol; (2R, 3R, 4S)-2- (2-chloro-P-(3-iodobenzylamino)-9H-purin-9-yl) tetrahydrothiophen-3, 4-diol; (2R, 3R,4S)-2- (2-chlor
  • compositions of the invention comprise 2-(6-Cyano-l- yl)adenosine, 2-(6-cyano-l-hexyn-l-yl)adenosine 5 '-monophosphate, or salts thereof, as described in U.S. Patent No. 7,132,409 and U.S. Patent No. 6,936,596, which are incorporated by reference in their entireties.
  • composition of the invention comprises 2-(6-cyano-l-hexyn-
  • 1- yl)adenosine which can be produced by the following steps. Under argon, into a solution of 2-iodoadenosine (420 mg, 1.07 mmol) and bis(triphenylphosphine)palladium dichloride (75 mg, 10 mol %) dissolved in N,N-dimethylformamide (10 mL), diisopropylamine (0.18 mL, 1.28 mmol, 1.2 eq.) and 6-cyano-l-hexyne (137 mg, 1.28 mmol, 1.2 eq.) are added. Under ice-cooling conditions, cuprous iodide (10 mg, 5 mol %) is added, followed by stirring at 50°C for 24 hours.
  • reaction mixture is cooled to room temperature, and the solvent is removed under reduced pressure.
  • composition of the invention comprises triethylammonium
  • 2- (6-cyano-l-hexyn-l-yl)adenosine 5 '-monophosphate which can be produced by the following steps. Under argon, a 2-(6-cyano-l-hexyn-l-yl)adenosine (2.41 g) can be dissolved in triethyl phosphate (15 mL), and under ice-cooling conditions, phosphorous oxychloride (25.2 mL, 3.9 eq.) is added, followed by stirring at the same temperature for 5 hours. The reaction mixture is added drop-wise to a 10% sodium hydroxide solution (300 mL), and the resultant mixture is washed with ether.
  • IR(KBr)o max 3337, 3179, 2938, 2678, 2243, 1654, 1637, 1594, 1457, 1380, 1068, 919 cm "1 .
  • the composition of the invention comprises 2-(6-cyano-l- hexyn-l-yl)adenosine 5 '-monophosphate , which can be synthesized by the following steps.
  • a triethylammonium 2-(6-cyano-l-hexyn-l-yl)adenosine 5 '-monophosphate (1.1 g) is dissolved in water (20 mL), and, under ice-cooling conditions, IN HC1 solution (2 mL) was added thereto, followed by standing for 10 minutes. After having been diluted with water (20 mL), the resultant mixture is filtered.
  • the composition of the invention comprises monosodium 2-(6-cyano-l-hexyn-l-yl)adenosine 5 '-monophosphate or disodium 2-(6-cyano-l -hexyn- 1- yl)adenosine 5 ' -monophosphate.
  • a 2-(6-Cyano- 1 -hexyn- 1 -yl)adenosine 5 ' -monophosphate (800 mg) is dispersed in water (8 mL), and IN sodium hydroxide solution (1.8 mL) is added thereto, followed by stirring for 0.5 hours. After having been diluted with water (10 mL), the resultant mixture is purified by C 18 silica gel column chromatography
  • compositions of the invention include purine derivatives described in U.S. Patent No. 7,465,715, which is incorporated by reference in its entirety.
  • composition of the invention comprises the purine derivative of the formula:
  • Rl represents an alkyl, hydroxyalkyl, carboxyalkyl or cyanoalkyl or a group of the following general formula:
  • Y represents oxygen, sulfur or CH 2 ;
  • R a and R b 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 R c is selected from the group consisting of alkyl, amino, haloalkyl, aminoalkyl,
  • X 2 is H, hydroxyl, alkylamino, alkylamido or
  • X 3 and X 4 represent independently hydrogen, hydroxyl, amino, amido, azido, halo, alkyl, alkoxy, carboxy, nitrilo, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether,—
  • R and R" represent independently an alkyl group
  • R 2 is selected from the group consisting of hydrogen, halo, alkylether, amino, hydrazido, alkylamino, alkoxy, thioalkoxy, pyridylthio, alkenyl; alkynyl, thio, and alkylthio
  • R 3 is a group of the formula --NR 4 R 5 wherein R4 is a hydrogen atom or a group selected from alkyl, substituted alkyl or aryl-NH— C(Z) ⁇ , with Z being O, S, or NR a with R a having the above meanings; wherein when R4 is hydrogen, then R 5 is selected from the group consisting of R- and S-l-phenylethyl, benzyl, phenylethyl or anilide groups unsubstituted or substituted in one or more positions with a substituent selected from the group consisting of alkyl, amino, halo
  • R 5 is selected from the group consisting of heteroaryl-NR a -C(Z)-, heteroaryl-C(Z)-, alkaryl-NR a ⁇ C(Z)-, alkaryl-C(Z)--, aryl-NR--C(Z)-- and aryl-C(Z)— ; Z representing an oxygen, sulfur or imine; or a
  • composition of the invention comprises the nucleoside derivative, described in U.S. Patent No. 7,465,715:
  • the composition of the invention comprises N 6 -2- (4-aminophenyl)ethyladenosine (APNEA), N 6 -(4-amino-3-iodobenzyl) adenosine-5'-(N- methyluronanide) (AB-MECA), N 6 -(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB- MECA) and 2-chloro-N 6 -(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), which are described in U.S. Patent No. 7,465,715.
  • APIA N 6 -2- (4-aminophenyl)ethyladenosine
  • AB-MECA N 6 -(4-amino-3-iodobenzyl) adenosine-5'-(N- methyluronanide)
  • IB- MECA
  • compositions of the invention include adenosine A3 receptor antagonists described in U.S. Patent No. 7,064,112, which is incorporated by reference in its entirety.
  • composition of the invention comprises:
  • compositions of the invention include adenosine A3 receptor inhibitors described in U.S. Patent No. 6,673,802, which is incorporated by reference in its entirety.
  • composition of the invention comprises:
  • Ri and R 2 are each independently a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or together form a substituted or unsubstituted heterocyclic ring.
  • R 3 is a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety.
  • R 4 is a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety.
  • R5 and R 6 are each independently a halogen atom, e.g., chlorine, fluorine, or bromine, a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl moiety or R 4 and R 5 or R5 and R6 together form a substituted or unsubstituted heterocyclic or carbocyclic ring.
  • Ri and R 2 can each independently be a substituted or unsubstituted cycloalkyl or heteroarylalkyl moieties.
  • R 3 is a hydrogen atom or a substituted or unsubstituted heteroaryl moiety.
  • R 4 , R 5 and R 6 can each be independently a heteroaryl moieties.
  • Ri is a hydrogen atom
  • R 2 is a cyclohexanol, e.g., trans- cyclohexanol
  • R 3 is phenyl
  • R 4 is a hydrogen atom
  • R 5 is a methyl group
  • 5 is a methyl group.
  • Ri is a hydrogen atom
  • R 2 is:
  • R 3 is phenyl
  • R 4 is a hydrogen atom
  • R 5 and R 6 are methyl groups.
  • composition of the invention comprises:
  • Ri is hydrogen
  • R 2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkyl, or Ri and R 2 together form a substituted or unsubstituted heterocyclic ring
  • R 3 is unsubstituted or substituted aryl
  • R 4 is hydrogen
  • R 5 and R 6 are each independently hydrogen or alkyl, and pharmaceutically acceptable salts thereof.
  • composition of the invention comprises:
  • Ri and R 2 are each independently hydrogen, or substituted or unsubstituted alkoxy, aminoalkyl, alkyl, aryl, or alkylaryl, or together form a substituted or unsubstituted heterocyclic ring, provided that both Ri and R 2 are both not hydrogen;
  • R 3 is substituted or unsubstituted alkyl, arylalkyl, or aryl;
  • R4 is hydrogen or substituted or unsubstituted Ci-C 6 alkyl;
  • L is hydrogen, substituted or unsubstituted alkyl, or R 4 and L together form a substituted or unsubstituted heterocyclic or carbocyclic ring;
  • R 6 is hydrogen, substituted or unsubstituted alkyl, or halogen;
  • Q is CH 2 , O, S, or NRg, wherein R 8 is hydrogen or substituted or unsubstituted
  • composition of the invention comprises:
  • R 3 is a substituted or unsubstituted four to six membered ring, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1 ,2,4-triazole, pyridine, 2(lH)-pyridone, 4(lH)-pyridone, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, tetrazole, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, indole, 2,3-dihydroindole, lH-indole, indoline, benzopyrazole, 1 ,3-benzodioxole, benzoxazole, purine, coumarin, chromone, quinoline, tetrahydroquinoline, isoquinoline, benzo
  • compositions of the invention include nucleoside 5 '-pyrophosphate pyranosides and analogues described in U.S. Patent No. 6,897,201 , which is incorporated by reference in its entirety.
  • the composition of the invention comprises:
  • G 3 CH 2 , CHF, CF 2 , CH(OH) or CH(NHJ 7 );
  • G 4 CH 2 , CHF, CF 2 , CH(OH) or CH(NHJi 3 );
  • G 5 CH 2 , CHF, CF 2 , CH(OH) or CH(NHJi 7 );
  • G 6 CH 2 , CH(CH 2 OH); the number of hydrogen atoms bonded to the Gi-G 6 ring atoms is limited to a maximum of 8; also with the provision that the number of nitrogen atoms bonded to the Gi-G 6 ring atoms are limited to a maximum of 2;
  • J 7 , Ji 3 , and Ji 7 are independently H, C(0)H, or C(0)alkyl.
  • compositions of the invention include triazolopurine derivatives described in U.S. Patent Nos. 6,288,070 and 6,686,343, which are incorporated by reference in their entireties.
  • composition of the invention comprises:
  • Ri represents an alkyl group, or a phenyl group which is optionally substituted with a lower alkyl group
  • R 2 represents a pyridyl group, a furyl group, a thienyl group, a lower alkyl group, a phenyl lower alkyl group which optionally has 1 to 3 lower alkoxy groups as a substituent, a styryl group which optionally has 1 to 3 lower alkoxy groups as a substituent, a naphthyl group which optionally has a hydroxy groups as a substituent, or a phenyl group which optionally has 1 to 3 groups selected from lower alkyl group, lower alkoxy group, nitro group, hydroxyl group, amino group, N-lower alkylamino group, N,N-di lower alkylamino group, N-phenyl lower alkylamino group, N,N-bisphenyl lower alkylamino group, phenyl group, phen
  • alkylphosphorylmethyl group lower alkylthio group, lower alkoxy lower alkyl group, phenyl lower alkoxy lower alkyl group and halogen atom as a substituent; and
  • A represents a group:
  • R 3 represents a lower alkyl group or a phenyl lower alkyl group.
  • compositions of the invention include compositions described by Okamura et al. (2004) Bioorg. & Med. Chem. Lett. 14:2443-2446.
  • the composition of the invention is selected from the group consisting of: Monocyclic
  • Pyrazolo[4,3-e]-l,2,4-triazolo[l,5-c]pyrimidine and l ,2,4-triazolo[l,5- c]quinazoline rings can be synthesized bearing various substituents at the 2 and 5 positions of the ring to generate the A3 receptor antagonists of the invention.
  • the fused 1,2,4- triazolo[l,5-c]pyrimidine 9 can be synthesized by condensation of iminoester 8 and acylhydrazine based on the synthetic strategy, as shown in the Scheme below:
  • the iminoester 8 can be prepared by the reaction of primary amine analog 7 with a large excess of substituted orthoester. Iminoesterification of various aromatic or heterocyclic amines 7a-c were accomplished by condensation of trimethyl orthovalerate under the three different conditions, as shown in the table below.
  • 5-Amino-4- cyanoimidazole 7a can be converted to iminoester 8a in good yields (62-86%) at room temperature, at 90°C, or in the presence of a catalytic amount of dl-camphorsulfonic acid (CSA) at room temperature.
  • 3-Amino-4-cyanopyrazole 7b can be converted to 8b quantitatively by heating at 90°C or in the presence of a catalytic amount of CSA at room temperature, but there is no yield at room temperature without CSA.
  • 2-aminobenzonitrile 7c does not afford 8c at room temperature or by heating at 90°C.
  • the reaction can proceed in the presence of CSA at room temperature.
  • the reaction conditions using CSA can be chosen for the one-pot synthesis of fused l,2,4-triazolo[l,5-c]pyrimidine derivatives 9a-c.
  • Amines 7a-c can be transformed into the fused l,2,4-triazolo[l,5- c]pyrimidine derivatives 9a-c via intermediates 8a-c in situ by treatment with l . lmol equiv. of the corresponding orthoesters in the presence of 1% of CSA in DMF at room temperature.
  • compositions of the invention include compositions described by Okamura et al. (2004) Bioorg. & Med. Chem. Lett. 14:3775-3779. Okamura et al.
  • the composition of the invention comprises an adenosine A3 receptor antagonist selected from the group of:
  • R 1 and R 2 are selected from the table below
  • compositions of the invention include isoquinolines or quinazolines described by van Muijlwijk-Koezen, J.E. et al. (2000) J. Med. Chem. 43(11):2227-2238.
  • the composition of the invention comprises an adenosine A3 receptor antagonist selected from the group of:
  • compositions of isoquinolines or quinazolines described by van Muijlwijk- Koezen, J.E. et al. can be synthesized by the following steps.
  • the preparation of compounds 5a-k can be performed following the general synthetic strategy depicted the scheme shown above.
  • the intermediates 4a-k are synthesized initially based on a method described by Linschoten et al. with some modifications (Eur. J. Med. Chem.-Chim. Ther. 1984, 19, 137-142).
  • Treatment of 2-aminobenzonitrile (1) with strong base yielded a relatively stable anion as intermediate. This nucleophile reacts with nitriles 3a-k, and after hydrolysis the quinazoline derivatives 4a-k are obtained.
  • the yield of the derivatives is dependent on the bulkiness of substituents Rl of nitriles 3a-k due to steric hindrance in the nucleophilic attack of the anion.
  • the anion can react with the starting nitrile 1 which, after hydrolysis, yields the dimeric side product 2-(2-aminophenyl)- 4-quinazolineamine (2).
  • the course of the condensation reaction's dependence on the accessibility of the participating nitrile group to undergo nucleophilic attack is demonstrated by a mixture of 1 and trimethylacetonitrile (3c), which yields only dimer 2.
  • the derivatives 5a-k are prepared by reaction of phenyl isocyanate (7i) with 4-aminoquinazolines 4.
  • the substituted phenylurea derivatives 9a- h as well as compounds 8, 10, and 11 are prepared as depicted in the scheme shown below. Reaction of quinazolines 4 and isoquinolines 6 in dry acetonitrile at 30-50 °C with the appropriate isocyanate 7a-i affords the products 8-11 in good overall yields. The low solubility of the products in acetonitrile simplified the isolation and purification.
  • compositions of the invention include derivatives of triazoloquinazoline and pyrazolotriazolopyrimidine described in Canadian Patent Application No. 2437437.
  • the composition of the invention comprises:
  • Rl represents a lower alkyl group, a phenyl group, a lower alkoxy carbonyllower alkyl group, or a carboxy lower alkyl group
  • R2 represents a pyridyl group, a furyl group, a thienyl group, or a phenyl group which optionally has 1 to 3 groups selected from lower alkyl group, halogen atom, phenyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkoxy group, N,N-di lower alkylamino group, lower alkylthio group, lower alkanoyloxy group and nitro group as a substituent;
  • A represents a pyrazole ring which is optionally substituted with a group selected from lower alkyl group, phenyl lower alkyl group, lower alkoxycarbonyllower alkyl group, carboxy lower alkyl group and
  • composition of the invention comprises:
  • R 1 represents a lower alkyl group, a phenyl group, a lower alkoxycarbonyllower alkyl group, or a carboxy lower alkyl group
  • R 2 represents a pyridyl group, a furyl group, a thienyl group, or a phenyl group which optionally has 1 to 3 groups selected from lower alkyl group, halogen atom, phenyl group, halogen-substituted lower alkyl group, hydroxyl group, lower alkoxy group, N,N-di lower alkylamino group, lower alkylthio group, lower alkanoyloxy group and nitro group as a substituent.
  • compositions described in Canadian Patent Application No. 2437437 can be synthesized by the following steps:
  • R 2 is as defined above;
  • R la represents a lower alkyl group or a phenyl group;
  • Al represents a non-substituted pyrazole ring, or a benzene ring which is optionally substituted with 1 to 2 groups selected from halogen atom, lower alkyl group, nitro group and lower alkoxy group as a substituent; and
  • Z represents a lower alkyl group.
  • R 2 and Al are as defined above;
  • R la represents a lower alkyl group;
  • R 1 represents a lower alkyl group, a phenyl group or a lower alkoxy carbonyllower alkyl group,
  • R 2b represents a pyridyl group, a furyl group, a thienyl group, or a phenyl group which optionally have 1 to 3 groups selected from lower alkyl group, halogen atom, phenyl group, halogen-substituted lower alkyl group, hydroxy group, lower alkoxy group, N ,N-di lower alkylamino group, lower alkylthio group and nitro group as a substituent; and
  • R 2c represents a pyridyl group, a furyl group, a thienyl group, or a phenyl group which optionally have 1 to 3 groups selected from lower alkyl group, halogen atom, phenyl group, halogen
  • the compound (lc) of the present invention can be converted into compounds (ld-1) and (ld-2) wherein a substituent is introduced into the pyrazole ring by treating with a halide (9), as shown in the following reaction scheme.
  • R lb is as defined above;
  • R 2a represents a pyridyl group, a furyl group, a thienyl group, or a phenyl group which optionally has 1 to 3 groups selected from lower alkyl group, halogen atom, phenyl group, halogen-substituted lower alkyl group, lower alkoxy group, N,N-di lower alkylamino group, lower alkylthio group, lower alkanoyloxy group and nitro group as a substituent;
  • R 3 represents a lower alkyl group, a phenyl lower alkyl group, a lower alkoxycarbonyllower alkyl group, or a hydroxy lower alkyl group,
  • R 3a represents a lower alkyl group, a phenyl lower alkyl group, a lower alkoxy carbonyl lower alkyl group, or a trimethylsilyloxy-lower alkyl group;
  • X represents a
  • compositions of the invention include 2,6,9- trisubstituted purines.
  • 2,6,9-trisubstituted purines The synthesis of 2,6,9-trisubstituted purines is described by
  • compositions of the invention are provided.
  • compositions of the invention can be formulated in pharmaceutical compositions.
  • These compositions can comprise pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on the route of administration, e.g., topical or intraocular injection.
  • Administration is preferably in a "therapeutically effective amount" or
  • prophylaxis can be considered therapy
  • prophylaxis can be considered therapy
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the inflammatory eye disease being treated. Prescription of treatment, e.g. , decisions on dosage, etc. , is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington 's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack
  • compositions comprising the molecules described above, together with one or more pharmaceutically-acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • excipients include liquids such as water, saline, glycerol, polyethyleneglycol, hyaluronic acid, ethanol, cyclodextrins, modified cyclodextrins ⁇ i.e., sufobutyl ether cyclodextrins), etc.
  • Suitable excipients for non-liquid formulations are also known to those of skill in the art.
  • compositions of the present invention include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like
  • organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • auxiliary substances such as wetting or emulsifying agents, biological buffering substances, surfactants, and the like, may be present in such vehicles.
  • a biological buffer can be virtually any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically- acceptable range.
  • buffer solutions include saline, phosphate buffered saline (PBS), Tris buffered saline, Hank's buffered saline, and the like.
  • compositions of this invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sublingual), topical, intravitreal administration, intraocular injection, intravenous injection, intramuscular injection, rectal, intranasal administration, intraperitoneal administration, administration by inhalation or insufflation, or in other forms suitable for administration to an eye.
  • the preferred modes of administration are topical or intraocular administration, preferably using a convenient daily dosage regimen which can be adjusted according to the degree of the condition or disease.
  • the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single
  • compositions will include an effective amount of the selected compound in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
  • Formulations also include compositions of the invention administered as eye-drops, injectable liquids or solutions, or topical eye creams.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid,
  • micro crystalline cellulose acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a composition of the present invention including isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more
  • compositions can be presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the composition that is administered is in powder or particulate form.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g. , a buffered saline, before use.
  • Effective amounts of the compositions of the invention are administered to a subject in need of such treatment. Effective amounts are those amounts, which will result in a desired improvement in the condition, disease or disorder or symptoms of the condition, disease or disorder.
  • a suitable dose of a formulation of an adenosine A3 receptor antagonist will be in the range of 0.001 to 1000.0 milligrams per kilogram body weight of the recipient per day, in the range of 0.01 to 200.0 milligrams per kilogram body weight of the recipient per day, or in the range of 1 to 50 mg per kilogram body weight per day.
  • the formulation of an adenosine A3 receptor antagonist can be administered at 0.001 mg/kg, 0.01 mg.kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg per single dose.
  • the formulation of an adenosine A3 receptor antagonist can be administered at 0.001 mg/kg, 0.01 mg.kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg
  • the pharmaceutical composition may be administered once daily, or the adenosine A3 receptor antagonist may be administered as two, three, or more sub-doses at appropriate intervals throughout the day or even using continuous infusion or delivery through a controlled release formulation.
  • the adenosine A3 receptor antagonist contained in each sub-dose must be correspondingly smaller in order to achieve the total daily dosage.
  • the dosage unit can also be compounded for delivery over several days. The absolute amount will depend upon a variety of factors (including whether the administration is in conjunction with other methods of treatment, the number of doses and individual patient parameters including age, physical condition, size and weight) and can be determined with routine experimentation. In some embodiments, a maximum dose can be used, that is, the highest safe dose according to sound medical judgment.
  • the pharmaceutical composition is formulated for administration of a dosage regimen described herein, e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week.
  • a dosage regimen described herein e.g., not more than once every four weeks, not more than once every three weeks, not more than once every two weeks, or not more than once every week.
  • composition can be maintained for a month or longer, e.g., one, two, three, or six months, or one year or longer.
  • Methods for the use of adenosine A3 receptor antagonists and methods of treatment of various inflammatory eye diseases using adenosine A3 receptor antagonists are encompassed by the present invention.
  • Said methods of the invention include administering an effective amount of a composition comprising an adenosine A3 receptor antagonist to a subject that has an inflammatory eye disease.
  • Any of the adenosine A3 receptor antagonists described above may be used in the methods of use and methods of treatment of the invention.
  • Inflammatory eye diseases include, but are but not limited to, dry eye, uveitis, scleritis, blepharitis, keratitis, conjunctivitis, chorioretinital inflammation, choroiditis, retinitis, iridocyclitis, ulceris, posterior cyclitis, diabetic retinopathy, post-surgery, allergy, trauma, bruises, foreign body, exposure to toxins or chemicals, food allergies, hives, autoimmune disorders (such as rheumatoid arthritis, sarcoidosis, juvenile idiopathic arthritis, lupus, Behcet's disease, etc.), infection (such as viral, fungal, mycobacteria, parasite, bacteria, acanthamoeba, spirochete, etc), inflammatory conditions (such as Crohn's disease, arthritis and ulcerative colitis) and cancers (such as lymphoma, eye tumors, cancer of blood vessels, etc.), or an
  • animal models are used to induce inflammatory eye disease. See Barabino, S. et al. (2004) Investigative Opthalmo logy & Visual Science. 45(6): 1641-1646.
  • Dry eye syndrome is a prevalent inflammatory disorder of the lacrimal functional unit of multifactorial origin leading to chronic ocular surface disease, impaired quality of vision, and a wide range of complications, eventually causing a reduction in quality of life.
  • Some dry eye animal models have been developed in mice, rats, and rabbits, e.g., for lacrimal inflammation or human Sjogren's syndrome. Animal models for dry eye syndrome are discussed herein and in detail in Barabino, S. et al. (2004) Investig. Opthal. & Visual Sci.
  • a mouse model of botulinum (BTX)-induced dry eye was used to induce dry eye.
  • Botulinum toxin was injected into the lacrimal gland of mice. Dry eye developed and persisted over about 3-4 weeks with resultant decreases in tear production and
  • Dexamethasone was used as an appropriate positive control (cyclosporine is not as effective, but is still active).
  • a Phenol Red Thread Test for tear production was performed, and a fluorescein slit lamp examination was used to assess corneal damage.
  • a histopathology exam was performed on the eye and adenexal structures.
  • the Phenol Red Thread Test was used.
  • the Phenol Red Thread Test is a commercially available test (Zone-Quick, Showa Yakuhin Kako Co., Ltd). A cotton thread impregnated with phenol red dye was used. Phenol red is pH sensitive and changes from yellow to red when wetted by tears. The crimped end of a 70mm long thread was placed in the lower conjunctival fornix. Forceps were used to insert the folded portion of the thread into the palpebral conjunctiva of the eye 1/3 of the distance from the lateral canthus of the lower eye lid.
  • the length of the color change on the thread (which indicated the length of the thread wetted by the tears) was measured in millimeters. Wetting lengths should normally be between 9mm and 20mm. Patients with dry eyes have wetting values of less than 9 mm. A reading of less than 10 mm was used to indicate dry eyes, less than 20 mm indicates marginally dry eyes, and more than 20 mm indicated normal tear volume.
  • Botulinum injected and treatment started on Day 0 and for all groups. ANOVA followed by post hoc.
  • Botulinum injected and treatment started on Day 0 for all groups. ANOVA followed by post hoc Dunnett's: Statistically significant (**) p value less than 0.01 ; (*) p value less than 0.05. 50 ⁇ of 1% sodium fluorescein applied to corneal for slit lamp examination with cobalt light.
  • Botulinum injected and treatment started on Day 0 for all groups. ANOVA followed by post hoc Dunnett's: Statistically significant (**) p value less than 0.01 ; (*) p value less than 0.05.
  • stroma increased thickness of inflammatory cells in gland epithelium, inflammatory cell
  • a mouse model of Scopolamine -induced dry eye syndrome can be used.
  • Scopolamine patches were applied to the tails of mice, and the mice were maintained in an environment with blowing air and low humidity. Dry eye developed over about 2 weeks with resultant decreases in tear production and histopathologic damage to the cornea. The dry eye continued as long as the patches were applied.
  • the study design included experimental groups with at least 10 mice per group. A scopolamine patch was applied, and a dry environment was initiated. A topical
  • dexamethasone (DEX) was administered as an appropriate positive control (or cyclosporine (CSA) (Restasis) offers some protection as well).
  • CSA cyclosporine
  • Regular assessments of the Phenol Red Thread Test for tear production was performed.
  • a fluorescein slit lamp assessment was performed to determine corneal changes.
  • a histopathology was performed on eye and adenexal structures.
  • FIG. la shows a graph of typical tear reduction after scopolamine patch application and a dry environment.
  • FIG. lb also shows histopathology scores 12 days after scopolamine administration.
  • Four groups are shown for no-treatment, vehicle, DEX, and Restasis.
  • the p-value is less than 0.05 relative to the vehicle control group.
  • the p-value was less than 0.05 reltaive to the no-treatment group.
  • N 10 female C57BL/6 mice per group.
  • Scopolamine and air draft started on Day 0 for all groups. ANOVA followed by post hoc Dunnett's: Statistically significant (**) p value less than 0.01; (*) p value less than 0.05.
  • a corneal edema refers to the presence of edema in the corneal stroma as indicated by separation and spreading of the fibers.
  • Epithelial edema refers to the presence of intracellular or extracellular edema in the corneal epithelium.
  • Corneal thickness refers to the number of epithelial cell layers in the corneal epithelium, normally about 2-3 cell layers thick. In cases of injury to the corneal epithelium, the number of cell layers may be increased, and there may be other indications of epithelial proliferation, such as increased mitosis on the basal layer or cellular hypertrophy or hyperplasia.
  • Cyclosporine (CSA) produced a similar trend, but was generally not statistically significant.
  • a controlled adverse environment (CAE) model combines multiple
  • the CAE model is based on a clinical model, which has been widely used in human clinical dry eye studies and has been pivotal in determining treatment efficacy in various dry eye development programs.
  • mice were housed in polycarbonate cages with direct contact bedding.
  • the cages conformed to standards set forth in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences). Space recommendations for animals were in accordance with PHS policy and the Animal Welfare Act. Litter or bedding in animal cages was changed as often as necessary to keep animals dry and clean and to minimize offensive odors.
  • n ma s were ran om ze a ter uoresce n sta n ng on ay . os ng egan at least 1 hour after staining. [00181] ** Scopolamine injections began after staining evaluations.
  • mice were evaluated on the morning of day 5. Mice were assigned to treatment groups such that the average total staining between the groups was approximately equivalent ( ⁇ 2).
  • Topical treatment was administered according to the Guidance document: Topical Administration of Ocular Treatments in Preclinical Studies. On days 5 through 19, topical treatment with test article, positive control, or the control article (vehicle control) was administered as outlined in the table below. Group 1 received ocular treatment four times daily at approximately 7am, 1 lam, 2pm, and 6pm. All other groups were dosed twice daily at approximately 7am and 6pm. All times listed were ⁇ 1 hour, and the exact time of dosing was recorded in the datasheets. Mice were dosed topically to the central cornea using a calibrated micropipette, with a 3 drop of treatment (test or vehicle control article) in each eye. For example, the mice were dosed topically with either ACN- 1052 or a vehicle control.
  • test article tubes were masked throughout the experiment (labeled A-D) such that personnel dosing or performing the examinations did know the identity of the treatment groups.
  • Scopolamine Hydrobromide Injection Subcutaneous injection of scopolamine was administered according to the Technical Procedure: Injection of Scopolamine in a Murine Model of Dry Eye. Dursun D, Wang M, Monroy D, et al. "A mouse model of keratoconjunctivitis sicca.” Invest Ophthalmol Vis Sci. 2002/43. -632-638.
  • Corneal Fluorescein Staining Corneal staining was assessed according to the Guidance: Fluorescein Staining and Grading Procedure. 0.6 ⁇ ⁇ ⁇ ⁇ % sodium fluorescein was applied via a micro-pipette to the central cornea. Eight to ten minutes following application, corneal fluorescein staining was evaluated under magnification. The degree of fluorescein staining was assessed using a modified 0-4 grading scale (Ora Scale, modified from NEI), similar to that used in clinical dry eye studies, where five distinct areas of the cornea were graded individually. The sum of scores and the differences in the different regions of the cornea was assessed.
  • Guidance Fluorescein Staining and Grading Procedure. 0.6 ⁇ ⁇ ⁇ ⁇ % sodium fluorescein was applied via a micro-pipette to the central cornea. Eight to ten minutes following application, corneal fluorescein staining was evaluated under magnification. The degree of fluorescein staining was
  • Body weight was measured at baseline, at pre-scopolamine injection, and at sacrifice.
  • Eyes were monitored at baseline as well as during dosing for any abnormalities (e.g., conjunctival hyperemia, chemosis, discharge, lid edema and ulceration).
  • abnormalities e.g., conjunctival hyperemia, chemosis, discharge, lid edema and ulceration.
  • Unscheduled Deaths If an animal appears in poor condition or in extremis, it may be euthanized per the facility IACUC policy on humane care of animals. Depending on the timepoint of the experiment, animals were replaced if at all possible.
  • Tissue Collection and Preservation The right eye of each animal was immersed in 4% paraformaldeyhyde for 24-30 hours, after which they eye was transferred to a vial containing 70% ethanol and stored for potential histology and/or immunohistochemistry.
  • a model of concanavalin (ConA)-induced dry eye in rabbits can be used to induce dry eye syndrome.
  • the lacrimal gland was injected with ConA.
  • a self-limiting dry eye develops developed over about 2 weeks.
  • Injection of ConA into the lacrimal glands of rabbits produced a consistent and measureable decrease in both the Tear Break up Test (TBUT) and the Schirmer Tear Test (STT).
  • the Schirmer Tear Test included use of Schirmer tear test strips (Clement Clarke) according to the manufacturer's instructions. No topical anaesthetic was used. The rounded wick end of the test strip was folded at the indentation and then inserted into the lower fornix of the eye 1/3 of the distance from the lateral canthus of the lower eye lid. After 5 minutes, the strip was removed, and the wet part was measured up to the folded line. A reading of less than 5 mm can be judged to indicate dry eyes and less than 10 mm can indicate marginally dry eyes.
  • FIGs. 2, 3a and 3b present typical reduction and recovery of tear production in control and treated animals after ConA injection.
  • the study design included groups with at least 6 rabbits per group. Con A was injected into the lacrimal gland as a single dose on Day 0 and Day 3. Assessments included a Schirmer Tear Test (STT) and a Tear Break Up Test (TBUT) over a 2 week period.
  • STT Schirmer Tear Test
  • TBUT Tear Break Up Test
  • Histopathology was performed on the eye and adenexal structures.
  • a Schirmer Tear Test (STT) and a Tear Break Up Test (TBUT) can be performed.
  • STT Schirmer Tear Test
  • TBUT Tear Break Up Test
  • FIG. 2 the effects of DEX and CSA are shown in the TBUT test. Also, the effects of a test article (e.g., an adenosine A3 receptor antagonist) on the TBUT test are shown, demonstrating a statistically significant effect of both DEX and CSA on the TBUT Test. There was a clear dose related trend with a three doses of a test article, as well as with the high dose, demonstrating a statistically significant improvement in the TBUT.
  • a test article e.g., an adenosine A3 receptor antagonist
  • FIG. 3a the effects of ConA injection on the STT are presented. There was a decrease in the STT beginning about Day 2, continuing for about 3-4 days with recovery occurring between Days 8-10.
  • FIG. 3b DEX and CSA were used, and a trend towards improvement with DEX was seen, but it did not achieve statistical significance.
  • Uveitis is a swelling and irritation of the uvea, the middle layer of the eye.
  • Uveitis can be caused by autoimmune disorders such as rheumatoid arthritis or ankylosing spondylitis, infection or exposure to toxins.
  • autoimmune disorders such as rheumatoid arthritis or ankylosing spondylitis
  • the most common form of uveitis is anterior uveitis, which involves inflammation in the front part of the eye.
  • Symptoms of uveitis include, but are not limited to blurred vision, dark, floating spots in the vision, eye pain, redness of the eye, or sensitivity to light.
  • Acute anterior uveitis is a recurrent immune-mediated inflammatory condition involving the iris and ciliary region in man and occurs in about 4 out of 1000 individuals. Although it may be self-limiting, it may also be chronic and lead to irreversible eye damage including cataract and glaucoma. Photophobia and pain with hyperemia of the vessels, hypophyon, and iridiocyclitis is typical, and the condition is relatively responsive to steroids. However, in many instances, the disorder is unresponsive to treatment and may lead to blindness with glaucoma, cataract and retinopathy. In some cases, HLA B27 appears to be involved. Humans are usually treated with steroids; however, there are undesirable side effects. In the field of veterinary medicine, horses suffer from an analogous anterior recurrent uveitis which often leads to blindness as well and was known in the past as "Moon Blindness.”
  • a MAA-induced uveitis model in rats can be used.
  • a preparation of melanin- associated antigen (MAA) complexed with adjuvant was administered to Lewis Rats as an inoculation.
  • An acute to sub-acute recurrent immune-mediated iridiocyclitis developed and resolved over a 1-2 -month period. Both the ophthalmo logical presentation and the histologic features were analogous to the human condition.
  • the MAA antigen is an extract of bovine ocular melanin derived from the iris.
  • the MAA antigen induced uveitis by Day 15 in all treated rats, and the disease proceeded consistently between and among groups.
  • Both topical steroids and systemic cyclosporine markedly and consistently suppressed the inflammation.
  • Topical cyclosporine also suppressed inflammation, but not to the degree of steroid and systemic cyclosporine.
  • One study design included 10 Lewis rats per group, treated with a vehicle or test article (e.g., an adenosine A3 receptor antagonist) at 2-3 dose levels, and a positive control of topical dexamethasone (DEX) or systemic cyclosporine (CSA). Inflammation was induced with a MAA injection. Slit lamp scoring of inflammation was performed in the anterior segment of the eye thrice weekly for 4 weeks. The body weights of the animalswere measured weekly, and a necropsy with histopathologic examination was performed on the eye.
  • a vehicle or test article e.g., an adenosine A3 receptor antagonist
  • DEX topical dexamethasone
  • CSA systemic cyclosporine
  • a slit lamp examination was performed at least three times a week during the course of the study and the findings scored as per the scoring criteria.
  • Dexamethasone and to a lesser extent, CSA reduced the clinical ocular scoring in the anterior chamber as per direct slit lamp examination (topical Restasis has no effect). Ocular scoring results are presented below.
  • FIG. 4 shows representative photographs of the anterior area of the eye. Multiple hematoxylin-eosin stained sections of each eye were examined histopathologically and scored 0-4 for inflammation severity at Day 18 and Day 30. In MAA-treated eyes, there was a marked inflammation of the iris and ciliary areas. Both DEX and CSA significantly reduced the inflammation.
  • FIG. 4a shows a normal anterior chamber.
  • FIG. 4b shows the anterior chamber of a DEX and MAA treated rat, where there is hyperemia in the iris (Score 1).
  • FIG. 4c shows a photo of a MAA-treated rat, and the eye has an opaque anterior chamber and an obscured pupil (red reflex absent, proptosis and hypophyon; Score 4). Topical Restasis had no significant effect on inflammation.
  • FIG. 5 shows histopathology scores 18 days after MAA injection in untreated rats and rats treated with vehicle, DEX, CSA, or Restasis.
  • “a” indicates that the p- value was ⁇ 0.05 relative to the vehicle control group
  • “b” indicates that the p-value was ⁇ 0.05 relative to the no-treatment group.
  • FIGs. 6a-6c illustrate the photomicroscopy of histopathology findings in MAA treated rats.
  • Fig. 6a shows the normal ciliary process and sclera (HE lOOx; 0 score).
  • Fig. 6b shows a picture of a MAA-treated rat where there is marked inflammation of the ciliary process, iris, cornea, and uvea (200x; 4 score).
  • Fig. 6c shows a picture of a MAA-treated rat where there is there is marked inflammation of the ciliary process, iris, cornea, and uvea (400x; 4 score).
  • the MAA-induced model of anterior uveitis in Lewis Rats was characterized by a robust, uniform inflammation that peaks about Day 18 and underwent resolution by Day 30. The procedure was well tolerated, and there were marked inflammatory changes in the anterior segment that were visible via slit lamp examination clinically and were present histopathologically. Both DEX and CSA showed activity in inhibition of the inflammation, while topical Restasis is not particularly active.
  • neutrophils and/or mononuclear cells are neutrophils and/or mononuclear cells.
  • anterior chamber and posterior chamber anterior chamber and posterior chamber.
  • Inflammation may extend into cornea, anterior
  • Experimental autoimmune anterior uveitis can be induced by a self-antigen.
  • EAU Experimental autoimmune anterior uveitis
  • MA melanin-associated antigen isolated from bovine retinal pigment epithelium (RPE), iris, ciliary body, and choroid.
  • RPE retinal pigment epithelium
  • EAU can also be induced by adjuvant and a soluble protein fraction released by proteolytic digestion of bovine MAA with V8 protease.
  • MAA without the use of adjuvant. Bora, N.S. et al. 1997.
  • a murine model can be used to test the effects of compositions of the invention on experimental autoimmune uveitis (EAU).
  • EAU experimental autoimmune uveitis
  • C57BL/6 mice can be immunized with human interphotoreceptor retinoid-binding protein peptide (h-IRBP) to induce ocular inflammation.
  • h-IRBP human interphotoreceptor retinoid-binding protein peptide
  • the severity of EAU can be assessed clinically and histopatho logically, along with measures of T-cell activation and leukocyte adhesion in the retina.
  • Acute ocular inflammation can be induced using composition 48/80 (N-methyl-p- methoxyphenethylamine formaldehyde condensation product) in animal models.
  • Composition 48/80 can selectively degranulate mast cells to induce conjunctival eosinophilia in rabbits.
  • composition 48/80 topically on the eye in rabbits produced a brisk acute ocular inflammation that was responsive to dexamethasone treatment over a 1-3 day period.
  • the inflammation was characterized by an acute conjunctivitis
  • An allergic conjunctivitis can be induced by ovalbumin administration to guinea pigs and rabbits.
  • Guinea pigs are the preferred species due to the consistency of response. Animals were sensitized by ovalbumin and adjuvant injected intraperitoneally at two week intervals. One week later, one eye was challenged by topical administration of ovalbumin. In some embodiments, acute inflammation developed and persisted over about three days with a peak at about 24 hours.
  • a study design included groups with at least 6 guinea pigs or rabbits per group. Ovalbumin and adjuvant were injected intraperitoneally at two week intervals. One eye was challenged by topical application as a single dose of albumin in PBS to the eye. Topical dexamethasone was an appropriate positive control. Slit lamp and funduscopic examination was performed. A visual scoring of ocular clinical signs and/or a histopathology examination on the eye and adenexal structures was performed.
  • ovalbumin produced a brisk acute ophthalmitis that was responsive to dexamethasone treatment.
  • the inflammation was characterized clinically by redness, and inflammation of the eye.
  • the effects of Dexamethasone on cellularity of aqueous humor and ocular histopathology are shown in the tables below.
  • Example 1 Methods of Treatment of Dry Eye in Animal Models Using
  • Dry eye can be induced in animal models using one or more of the methods described above. As described in Sections LA through I.D, dry eye can be induced by botulinum toxin injections, administration of scopolamine, use of the CAE protocol, or injection of concanavalin A (Con A) into lacrimal glands. Suitable animal models include, but are not limited to, rodents, such as Sprague Dawley rats, or rabbits.
  • a composition or formulation comprising an adenosine A3 receptor antagonist described above is administered to the animal and is used to treat the dry eye condition.
  • Any of the compositions of the invention described above can be used for treatment of dry eye.
  • the adenosine A3 receptor antagonist used is ACN-1052, LJ1251, MRS 3820, MRS 3771, LJ 979, MRS 3826, or MRS 3827.
  • the adenosine A3 receptor antagonist used is MRS 1191 or MRS 1292.
  • the adenosine A3 receptor antagonist is ACN-1052.
  • the formulations of adenosine A3 receptor antagonist can be prepared for oral administration, injection, or non-invasive administration, such as topical administration.
  • the formulations can be prepared as (a) liquid solutions; (b) capsules, sachets, tablets, lozenges, and troches; (c) powders; (d) suspensions in an appropriate liquid; or (e) suitable emulsions. Examples include formulations administered as eye-drops, injectable liquids or solutions, or topical eye creams.
  • the dosage of the formulation can vary depending on the form of administration.
  • a suitable dose of a formulation of an adenosine A3 receptor antagonist will be in the range of 0.001 to 1000.0 milligrams per kilogram body weight of the animal per day, in the range of 0.01 to 200.0 milligrams per kilogram body weight of the animal per day, or in the range of 1 to 50 mg per kilogram body weight per day.
  • Optimal dosing schedules can be calculated by administering various doses of the adenosine A3 receptor antagonist to the animal and measuring efficacy of the different doses.
  • the optimized dose or formulation may be administered at various intervals of time: once a week, once every two days, once daily, BID (e.g., twice daily), TID, QID, or in multiple doses at appropriate intervals throughout the day, or even using continuous infusion or delivery through a controlled release formulation.
  • a dry eye study is performed using two experimental groups of mammals (e.g., a control group and a test group of 6 male NZW rabbits per group). The rabbits are assessed for inclusion in the study. Criteria include the entry criteria (scores of ⁇ 1 for conjunctival congestion and swelling; scores of 0 for all other observation variables) or exclusion criteria (no rabbits with gross signs of ocular irritation are used in this study).
  • ConA Prior to induction of dry eye (e.g., injection of Con A on day -4), one or more of the following assays can be performed: gross ocular observations; scoring of signs of irritation or discomfort; examination of corneal thickness by pachymetry; slit lamp ophthalmic examinations with fluorescein dye to examine the cornea surface; a Shirmer Tear Test; or a Tear Break Up Test.
  • ConA can be injected bilaterally into the lacrimal glands (on day -3 and day 0).
  • Each group is administered a vehicle or an adenosine A3 receptor antagonist (or a formulation of an adenosine A3 receptor antagonist).
  • Treatment can include administering a vehicle or an adenosine A3 receptor antagonist to both eyes three times daily (e.g., 9 am, 12 pm, 4 pm).
  • the following examinations are made (on days 1 to 14): daily gross ocular observations, signs of irritation or discomfort scored; daily corneal thickness measured by pachymetry; daily slit lamp ophthalmic examinations with fluorescein dye to examine cornea surface, scored according to McDonald Shadduck method; daily Shirmer Tear Test; or a daily Tear Break Up Test.
  • a terminal examination is performed based on a histopathology of the eye and adenexal structures.
  • the tear volume, tear function, and inflammatory cytokine levels in the lacrimal glands are assessed, along with a histological evaluation.
  • the density of mucus producing goblet cells, corneal inflammation, and corneal epithelial damage also are measured and compared to normal control animals. Evaluation of the results shows that treatment with a composition or formulation comprising an adenosine A3 receptor antagonist produces a significant improvement or amelioration in the symptoms and condition of dry eye syndrome in the animal compared to the control group.
  • Example 2 Methods of Treatment of Dry Eye Syndrome in Mice Using A
  • Dry eye syndrome was induced in mice using the CAE model and protocol described above in Section I.C.
  • the adenosine A3 receptor antagonist ACN- 1052 was selected and used for treatment of dry eye syndrome.
  • FIG. 7 shows an example of inhibition of corneal injury after treatment of ACN- 1052 in mice using the CAE model described above. Mice were exposed to 10 days of an adverse environment according to the CAE protocol and treated with ACN-1052, Restasis, or a vehicle control on the fifth day. The ACN-1052 antagonist resulted in approximately 30% reduction in corneal injury based on a measurement of corneal staining of the eye. Restasis produced a 20% change in corneal staining, whereas the vehicle control did not inhibit corneal injury.
  • FIG. 8 illustrates the effect of ACN- 1052 in a mouse model using the CAE protocol to induce dry eye syndrome.
  • Mice were exposed to 10 days of an adverse environment and treated with ACN-1052, Restasis or a vehicle control on the fifth day.
  • the percentage of eyes with an improvement in corneal staining was 88% in the group treated with ACN-1052, compared to 81% in the Restasis group and 63% in the vehicle control. .
  • Example 3 Methods of Treatment of Dry Eye Syndrome in Patients Using
  • compositions or formulations of adenosine A3 receptor antagonist can be used for treatment of patients with dry eye syndrome.
  • the composition or formulation can include a therapeutically effective amount of an adenosine A3 receptor antagonist and a
  • a subject e.g., a patient with dry eye syndrome or dry eye symptoms is suitable for treatment.
  • the symptoms of the patient Prior to treatment, the symptoms of the patient are assessed.
  • Symptoms can include, but are not limited to, a dry, gritty, scratchy, or filmy feeling in the eyes, a burning or itching in the eyes, redness of the eyes, intermittent excessive tearing, blurred vision, a sensation of having a foreign body in the eye, and light sensitivity.
  • a control group of patients without dry eye syndrome can be included in the study.
  • a composition or formulation comprising an adenosine A3 receptor antagonist described above is administered to the patient to treat the dry eye condition. Any of the compositions of the invention described above can be used for treatment of dry eye.
  • the adenosine A3 receptor antagonist used is ACN-1052, LJ1251, MRS 3820, MRS 3771, LJ 979, MRS 3826, or MRS 3827.
  • the adenosine A3 receptor antagonist used is MRS 1191 or MRS 1292.
  • the adenosine A3 receptor antagonist is ACN-1052.
  • the formulations can be suitable for oral administration, injection, or non-invasive administration, such as topical administration.
  • the formulations can be prepared as (a) liquid solutions; (b) capsules, sachets, tablets, lozenges, and troches; (c) powders; (d) suspensions in an appropriate liquid; or (e) suitable emulsions. Examples include formulations administered as eye-drops, injectable liquids or solutions, or topical eye creams.
  • Dosing is dependent on severity and responsiveness of the dry eye condition to be treated, with the course of treatment lasting hours, days, months, or until a cure is effected or an improvement of the dry eye is achieved. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Dosage will vary with the age, gender, weight and response of the particular patient, as well as the severity of the patient's symptoms. Optimum dosages may vary depending on the relative potency of individual compositions, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • a suitable dose of a formulation of an adenosine A3 receptor antagonist will be in the range of 0.001 to 1000.0 milligrams per kilogram body weight of the patient per day, in the range of 0.01 to 200.0 milligrams per kilogram body weight of the patient per day, or in the range of 1 to 50 mg per kilogram body weight per day.
  • the formulation may be administered at various intervals of time: once a week, once every two days, once daily, BID (e.g., twice daily), TID, QID, or in multiple doses at appropriate intervals throughout the day, or even using continuous infusion or delivery through a controlled release formulation.
  • BID e.g., twice daily
  • TID e.g., twice daily
  • QID e.g., QID
  • Improvement of symptoms can be determined by ocular examination and/or self-reporting of symptoms by the patient. For example, an improvement in redness of the eyes or a reduction in burning or itching in the eyes can be assessed. Tear volume, tear function, and corneal inflammation can also be analyzed. Treatment with a composition or formulation of an adenosine A3 receptor antagonist alleviates or improves the symptoms of dry eye syndrome in the patient.
  • Example 4 Methods of Treatment of Uveitis Using an Adenosine A3 Receptor Antagonist
  • Methods of the invention include treatment of uveitis using an adenosine A3 receptor antagonist.
  • Uveitis is induced by melanin-associated antigen, as described in methods above.
  • the compositions of the invention described above can be used in a formulation for treatment of uveitis.
  • the adenosine A3 receptor antagonist used for treatment of uveitis is ACN-1052, LJ1251 , or MRS3820.
  • the adenosine A3 receptor antagonist used is MRS 1 191 or MRS 1292.
  • the adenosine A3 receptor antagonist is ACN-1052.
  • a study is performed using two experimental groups (e.g., a control group and a test group of 6 male Lewis rats each).
  • uveitis is induced in all animals by an injection into the tail head of an emulsion containing melanin-associated antigen (MAA), Complete Freund's Adjuvant (CFA), and pertussis toxin.
  • MAA melanin-associated antigen
  • CFA Complete Freund's Adjuvant
  • pertussis toxin are used.
  • a vehicle and a composition comprising an adenosine A3 receptor antagonist is administered to both eyes in rats in Groups 1 and 2. Dosing occurs twice on day 0 and TID (three times per day) for the next 21 days.
  • the animals are housed in a well ventilated dry environment.
  • a treatment with a composition comprising an adenosine A3 receptor antagonist is shown to produce a significant improvement or amelioration in the symptoms and condition of uveitis in the animal subject, compared with the control group.
  • Example 5 Diabetic retinopathy and diabetic macular edema in the
  • Diabetic retinopathy refers to the damage to the eye's retina that occurs with long- term diabetes and that can cause blindness.
  • Diabetic macular edema is a swelling of the retina due to leaking of fluid from blood vessels within the macula, which is the central portion of the retina. Macular edema causes blurring in the middle of side of the central visual field, and visual loss can progress over time, making it impossible to focus clearly.
  • a streptozotocin-induced diabetic rat model is used to study the effects of administration of compositions of the invention.
  • Type I diabetes is induced in rats by administration of streptozotocin.
  • Retinopathy and diabetic macular edema in streptozotocin- induced diabetic rat model are described in Zheng et al. (2007) Diabetes. 56:337-345; Carmo, A. et al. (2000) Mediators of ' Inflammation. 9:243-248; Kusari, J. et al. (2007) Invest. Opthal. & Visual Sci. 48(11): 5152-5159.
  • the following assessments are performed: glycemia, angiography (HRA), electroretinography (ERG), histology and
  • the retinae are flat-mounted in a water-based fluorescence-anti-fading medium (Southern Biotechnology, Birmingham, Al) and imaged via fluorescence microscopy (Zeiss Axiovert FITC filter).
  • Leukocyte location is scored as either arteriolar, venular, or capillary and the total number of adherent leukocytes per retina are counted.
  • Blood-retinal barrier breakdown are counted by using Evans blue dye.
  • the retinae are carefully dissected and thoroughly dried in a Speed- Vac (Savant, St. Paul, MN) for 5 h. Evans blue is extracted by incubating each retina in 120 ⁇ formamide (Sigma) for 18 hours at 70°C. The supernatant is filtered through Ultrafree-MC tubes (30,000 NMWL, MiUipore, Bedford, MA) at 3,000 g, and the filtrate is used for triplicate spectrophotometric
  • the background- subtracted absorbance is determined by measuring each sample at both 620 nm, the absorbance maximum for Evans blue in formamide, and 740 nm, the absorbance minimum.
  • the concentration of dye in the extracts is calculated from a standard curve of Evans blue in formamide and is normalized for retina dry weight.
  • the blood-retinal barrier breakdown is calculated by using the following equation, with results expressed in microliters of plasma x g retina dry weight- 1 x hr-1 : [Evans blue ⁇ g)/ Retina dry weight (g)] / [Time-averaged Evans blue concentration ⁇ g /plasma ⁇ )/ circulation time (hr)].
  • a treatment using a composition comprising an adenosine A3 receptor antagonist is shown to produce a significant improvement or amelioration in the symptoms and condition of diabetic macular edema or diabetic retinopathy in the subject, compared with the control group.

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Abstract

L'invention concerne des compositions qui comportent des antagonistes du récepteur de l'adénosine A3 et des procédés pour leur utilisation dans le traitement de maladies oculaires inflammatoires, telles que l'uvéite et la kératoconjonctivite sèche.
PCT/US2012/028247 2011-03-14 2012-03-08 Compositions et procédés utilisant des antagonistes du récepteur de l'adénosine a3 pour traitement de maladies oculaires inflammatoires WO2012125400A1 (fr)

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CN109666053A (zh) * 2017-10-16 2019-04-23 张家口华健致远生物科技有限公司 一种a3腺苷受体激动剂及其用途
WO2019107964A1 (fr) * 2017-11-29 2019-06-06 퓨쳐메디신 주식회사 Composition pharmaceutique comprenant un dérivé de l'adénosine permettant la prévention et le traitement d'une maladie de la rétine ou d'une maladie du nerf optique
CN110003211A (zh) * 2019-05-06 2019-07-12 江苏联昇化学有限公司 一种抗癌药物cf-102的合成新工艺
WO2022124859A1 (fr) * 2020-12-11 2022-06-16 서울대학교산학협력단 Dérivé de 1'-homoadénosine et composition pharmaceutique pour prévenir ou traiter des maladies associées à l'hypoadiponectinémie ou le psoriasis le contenant en tant que principe actif
WO2023215261A1 (fr) * 2022-05-02 2023-11-09 Ocular Services On Demand, Llc Modèles mammifère avec pathologies oculaires

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WO2018174549A1 (fr) * 2017-03-21 2018-09-27 퓨쳐메디신 주식회사 Composition pharmaceutique pour la prévention et le traitement du glaucome, contenant un dérivé d'adénosine
US11185556B2 (en) 2017-03-21 2021-11-30 Future Medicine Co., Ltd. Pharmaceutical composition for preventing and treating glaucoma, containing adenosine derivative
AU2018238996B2 (en) * 2017-03-21 2021-01-28 Future Medicine Co., Ltd. Pharmaceutical composition for preventing and treating glaucoma, containing adenosine derivative
KR101805400B1 (ko) * 2017-03-21 2017-12-07 퓨쳐메디신 주식회사 아데노신 유도체를 포함하는 녹내장 예방 및 치료용 약학적 조성물
EP3603647A4 (fr) * 2017-03-21 2021-01-06 Future Medicine Co., Ltd. Composition pharmaceutique pour la prévention et le traitement du glaucome, contenant un dérivé d'adénosine
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CN109666053A (zh) * 2017-10-16 2019-04-23 张家口华健致远生物科技有限公司 一种a3腺苷受体激动剂及其用途
KR20190062894A (ko) * 2017-11-29 2019-06-07 퓨쳐메디신 주식회사 아데노신 유도체를 포함하는 망막 질환 또는 시신경 질환 예방 및 치료용 약학적 조성물
CN111432822A (zh) * 2017-11-29 2020-07-17 未来制药有限公司 包含腺苷衍生物的用于预防或治疗视网膜疾病或视神经疾病的药物组合物
KR102007640B1 (ko) * 2017-11-29 2019-08-07 퓨쳐메디신 주식회사 아데노신 유도체를 포함하는 망막 질환 또는 시신경 질환 예방 및 치료용 약학적 조성물
CN114886909A (zh) * 2017-11-29 2022-08-12 未来制药有限公司 包含腺苷衍生物的用于预防或治疗视网膜疾病或视神经疾病的药物组合物
JP2021504494A (ja) * 2017-11-29 2021-02-15 フューチャー・メディシン・カンパニー・リミテッドＦｕｔｕｒｅ Ｍｅｄｉｃｉｎｅ Ｃｏ．， Ｌｔｄ． アデノシン誘導体を含む網膜疾患または視神経疾患の予防及び治療用薬学的組成物
AU2018374675B2 (en) * 2017-11-29 2021-10-07 Future Medicine Co., Ltd. Pharmaceutical composition comprising adenosine derivative for prevention and treatment of retinal disease or optic nerve disease
WO2019107964A1 (fr) * 2017-11-29 2019-06-06 퓨쳐메디신 주식회사 Composition pharmaceutique comprenant un dérivé de l'adénosine permettant la prévention et le traitement d'une maladie de la rétine ou d'une maladie du nerf optique
JP7160384B2 (ja) 2017-11-29 2022-10-25 フューチャー・メディシン・カンパニー・リミテッド アデノシン誘導体を含む網膜疾患または視神経疾患の予防及び治療用薬学的組成物
CN111432822B (zh) * 2017-11-29 2022-07-01 未来制药有限公司 包含腺苷衍生物的用于预防或治疗视网膜疾病或视神经疾病的药物组合物
CN110003211A (zh) * 2019-05-06 2019-07-12 江苏联昇化学有限公司 一种抗癌药物cf-102的合成新工艺
WO2022124859A1 (fr) * 2020-12-11 2022-06-16 서울대학교산학협력단 Dérivé de 1'-homoadénosine et composition pharmaceutique pour prévenir ou traiter des maladies associées à l'hypoadiponectinémie ou le psoriasis le contenant en tant que principe actif
WO2023215261A1 (fr) * 2022-05-02 2023-11-09 Ocular Services On Demand, Llc Modèles mammifère avec pathologies oculaires

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