WO2007140181A2 - Polythérapie comprenant un inhibiteur de fixation de l'adénosine et un antagoniste des récepteurs de l'adénosine non sélectif - Google Patents

Polythérapie comprenant un inhibiteur de fixation de l'adénosine et un antagoniste des récepteurs de l'adénosine non sélectif Download PDF

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WO2007140181A2
WO2007140181A2 PCT/US2007/069440 US2007069440W WO2007140181A2 WO 2007140181 A2 WO2007140181 A2 WO 2007140181A2 US 2007069440 W US2007069440 W US 2007069440W WO 2007140181 A2 WO2007140181 A2 WO 2007140181A2
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adenosine
pharmaceutically acceptable
acceptable salt
selective
uptake inhibitor
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PCT/US2007/069440
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WO2007140181A3 (fr
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Edward Leung
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King Pharmaceuticals Research And Development, 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
    • A61K31/495—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
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

  • the present invention relates to a pharmaceutical combination comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a nonselective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, for the treatment of cancer diseases, and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome, through stimulation of the adenosine A 3 receptor.
  • Adenosine is known to be an endogenous modu ⁇ ator of a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor On the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects On the respiratory system, adenosine induces bronchoconstriction.
  • Adenosine acts as a ⁇ polysis inhibitor on fat cells and as an antiaggregant on platelets Increased adenosine levels could protect against excessive cellular damage and organ dysfunction
  • the protective effect of adenosine itself is insufficient because extracellular adenosine is rapidly taken up into adjacent cells and subsequently metabolized
  • Adenosine receptors Three major classes of adenosine receptors, classified as A 1 , A 2 , and A 3 , have been characterized pharmacologically
  • the A 1 receptors are coupled to the inhibition of adenylate cyclase through Gi proteins, and have also been shown to couple to other second messenger systems, including inhibition or stimulation of phosphoinosrtol turnover and activation of ion channels,
  • Adenosine A 2 receptors are further divided into two subtypes, A 2A and A 2B , at which adenosine and adenosine agonists activate adenylate cyclase with high and iow affinity, respectively.
  • the A 1 and A 3 receptors inhibit the activity of the same enzyme
  • the adenosine A 3 receptor sequence was first identified in a rat testes cDNA library, and this sequence, later cloned by homology to other G-protein coupled receptors from a rat brain cDNA library, was shown to correspond to a novel, functional adenosine receptor
  • a 3 receptor is implicated in processes of inflammation, hypotension, and mast cell degranulation, e g ⁇ the A 3 selective agonist, IB-MECA (CF101), is currently being developed for inflammatory disorders such as rheumatoid arthritis, dry eye syndrome and psoriasis (Can-Fite BioPharma Ltd .).
  • IB-MECA A 3 selective agonist
  • the A 3 receptor apparently also has a role in the central nervous system, e g, IB-MECA induces behavioral depression and upon chronic administration and protects against cerebral ischemia.
  • a 3 antagonists for the A 3 receptor are sought as potential anti-inflammatory or possibly anti-ischemic agents in the brain More recently, A 3 antagonists have been under development as antiasthmatic, antidepressant, antiarrhythmic, renal protective, antiparkinson and cognitive enhancing drugs
  • Inhibitors of adenosine uptake or transport have been used clinically for some time for the treatment of certain cardiovascular diseases, e.g., adenosine uptake inhibitors have been employed as vasodilators and platelet aggregation inhibitors More recently, the adenosine uptake inhibitor, KF24345, has been shown to significantly suppress iipopolysaccharide- induced tumor necrosis factor- ⁇ (TNF- ⁇ ) production and leukopenia in mice (Noji et at , Journal of Pharmacology and Experimental Therapeutics 2002, 300(1), 200-205)
  • TNF- ⁇ tumor necrosis factor- ⁇
  • Cancer diseases are characterized by abnormal and unregulated ceil growth Uncontrolled cell division and growth Seads to cell accumulation and tumor growth. Some areas of the body are more commonly involved, but essentially any area of the body can become cancerous Although cancer is often referred to as a single condition, it actually consists of more than 100 different diseases Most cancers are named for the type of cell or organ in which they start, if a cancer spreads (metastasizes), the new tumor bears the same name as the original (primary) tumor
  • Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of ca ⁇ cer- reiated deaths.
  • Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras, and tumor- suppressor genes like p53.
  • APC adenomatous polyposis coli
  • adenosine A 3 receptor modulators including A3 agonists
  • IB-MECA has been shown to inhibit HCT- 116 human colon carcinoma cell growth (Ohana et al., British Journal of Cancer 20QZ, 89(8), 1552 -1558), and the activation of the adenosine A 3 receptor has been implicated in the inhibition of melanoma ceil growth by deregulating protein kinase A and key components of the Wnt signaling pathway (Madi et al , Journal of Biological Chemistry 2003, 278(43), 42121-42130)
  • a 3 selective receptor agonists has also been found to induce apoptosis at high concentrations in HL-60 human leukemia cells (Kohno et a ⁇ ., Biochemical and Biophysical Research Communications 1996, 219(3), 904-910)
  • RA Rheumatoid arthritis
  • RA is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints it is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and Joint destruction.
  • RA is a systemic disease, often affecting extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles.
  • the symptoms that distinguish RA from other forms of arthritis are inflammation and soft-tissue swelling of many joints at the same time (polyarthritis).
  • the joints are usually affected initially asymmetrically and then in a symmetrical fashion as the disease progresses.
  • Osteoarthritis is a condition in which low-grade inflammation results in pain in the joints, caused by wearing of the cartilage that covers and acts as a cushion inside joints. As the bone surfaces become less well protected by cartilage, the patient experiences pain upon weight bearing, including walking and standing. Due to decreased movement because of the pain, regional muscles may atrophy, and ligaments may become more lax OA is the most common form of arthritis
  • the treatment for OA is relatively limited because there are currently no pharmacological agents capable of retarding or preventing the disease
  • the treatment of OA is predominantly focused on relief of pain, and maintenance of quality of jife and functional independence
  • Psoriasis is believed to be an immune-mediated disease which affects the skin and joints. It commonly causes red scaly plaques to appear on the skin.
  • the disorder is a chronic recurring condition which varies in severity from minor localized patches to complete body coverage Fingernails and toenails are frequently affected (psoriatic nail dystrophy).
  • Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Ten to fifteen percent of people with psoriasis have psoriatic arthritis. Currently, there is no cure for psoriasis. However, there are many treatment options that can clear psoriasis for a period of time Each treatment has advantages and disadvantages, and what works for one patient may not be effective for another
  • adenosine uptake inhibitors may be employed for the treatment of inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrom ⁇ when administered in combination with a non-selective adenosine receptor antagonist.
  • the present invention provides a pharmaceutical combination, including free and fixed combinations, comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, for the treatment of cancer diseases, and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome
  • the present invention provides a method for the treatment of cancer diseases through stimulation of the adenosine A 3 receptor, wherein the method comprises administering to a warm-blooded animal, including man, in need thereof, a therapeutically effective amount of a pharmaceutical combination comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist or a pharmaceutically acceptable salt thereof
  • the present invention provides a method for the treatment of inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome through stimulation of the adenosine A 3 receptor, wherein the method comprises administering to a warm-blooded animal, including man, in need thereof, a therapeutically effective amount of a pharmaceutical combination comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method to selectively stimulate the adenosine A 3 receptor by employing a combination of an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, in combination with a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical combination, including free and fixed combinations, comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, for the treatment of cancer diseases, and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome, through stimulation of the adenosine A 3 receptor
  • adenosine uptake inhibitor refers to any agent which is efficacious in blocking adenosine transport into ceils
  • non-selective adenosine receptor antagonist refers to all known compounds that will block all adenosine receptor subtypes except the adenosine A 3 subtype
  • treatment embraces alt the different forms or modes of treatment as known to those of the pertinent art and in particular includes preventive, curative, delay of progression and palliative treatment
  • combination or "pharmaceutical combination" of an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, means that the components can be administered together as a pharmaceutical composition or as part of the same, unitary dosage form, i e , a fixed combination,
  • a combination aiso includes administering an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, each separately but as part of the same therapeutic regimen, i e , a free combination.
  • a combination also refers, e g , administering an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, as separate dosages or dosage forms, but at the same time.
  • a combination also includes separate administration at different times and in any order
  • fixed combination means that the active compounds are all administered to a patient simultaneously in the form of a single entity or dosage As an example, a fixed combination would be one capsule containing two active compounds.
  • free combination means that the active compounds are ail administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits
  • terapéuticaally effective amount refers to an amount of a drug or a therapeutic agent that will elicit the desired biological or medical response of a tissue, system or an animal (including man) that is being sought by a researcher or clinician.
  • warm-blooded animal or patient are used interchangeably herein and include, but are not limited to, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, mice and laboratory animals.
  • the preferred mammals are humans.
  • pharmaceutically acceptable salt refers to a non-toxic salt commonly used in the pharmaceutical industry which may be prepared according to methods well-known in the art
  • Suitable adenosine uptake inhibitors include, but are not limited to, cilostazol, dilazep, dipyridamole, midazolam, nimodipine, nrtrobenzylthioinosine, propentofylline, KF24345 and R75231, the structures of which may be found, e g ., in Noji et ai ., Eur. J Pharmacol 2004, 495, 1-16.
  • Suitable adenosine uptake inhibitors also include those disclosed in EP 1698635, EP 582164, US 2005054637, US 6,649,616, US 5,624,926, US 5,382,584, the entire contents of which are incorporated herein by reference
  • adenosine uptake inhibitors to be employed in the methods and the pharmaceutical combinations of the present invention include cilostazol, dipyridamole or KF24345 or, in each case, a pharmaceutically acceptable salt thereof More preferably, the adenosine uptake inhibitor is cilostazol or dipyridamole Most preferably, the adenosine uptake inhibitor is dipyridamole
  • adenosine uptake inhibitors described herein above are known, and may be prepared and administered using methods well known in the art, e g , one skilled in art would be able to determine and optimize the dosages of the individual adenosine uptake inhibitors of the instant invention, e.g., by employing techniques described in Goodman and Gilman's "The Pharmacological Basis of Therapeutics, 10* Edition",. It should be noted that cilostazo! is a medication used in the alleviation of the symptoms of intermittent claudication in individuals with peripheral vascular disease, and is manufactured by Otsuka Pharmaceutical Co.
  • Dipyridamole is used on its own, or in combination with aspirin, to prevent stroke by reducing the ability of platelet to aggregate, and a modified release dipyridamole and the combination with aspirin are currently marketed as Persantine® and Aggrenox®, respectively ⁇ Boehringer lngelheim). Dipyridamole is also used in nuclear cardiac stress testing as a coronary vasodilator
  • Suitable non-selective adenosine receptor antagonist include, but are not limited to, methylxanthines which are widely known to be antagonists for the A 1 , A 2n , and A 2B receptors, but not for the adenosine A 3 receptor Among methylxanthines, caffeine, paraxanthine, theobromine, theophylline and aminophylline are preferred More preferably, the nonselective adenosine receptor antagonist is caffeine
  • the non-selective adenosine receptor antagonists are known, and may be administered using methods well known in the art, e.g., by employing techniques described in Goodman and Gilman's "The Pharmacological Basis of Therapeutics, 10 th Edition" [041]
  • caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs.
  • Caffeine stimulates the central nervous system resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts through several different mechanisms
  • Caffeine is metabolized in the liver by the cytochrome P 4 S 0 oxidase enzyme into three metabolic dimethylxanthines, which each have their own effects on the body:
  • Paraxanthine (84%) has the effect of increasing iipolysis, leading to elevated glycerol and free fatty acid plasma levels;
  • Theobromine (12%) dilates blood vessels and increases urine volume
  • Theobromine is also the principal alkaloid in cocoa, and therefore chocolate;
  • Theophylline (4%) relaxes smooth muscles of the bronchi, and is used to treat asthma
  • the therapeutic dose of theophylline is many times greater than the levels attained from caffeine metabolism .
  • Aminophylline is a drug that contains theophylline and ethylenediamine in 2:1 ratio It is more soluble in water than theophylline White or slightly yellowish granules or powder, having a slight ammoniaca) odor and a bitter taste Upon exposure to air, it gradually loses ethylenediamine and absorbs carbon dioxide with the liberation of free theophylline Aminophylline is fess potent and shorter-acting than theophylline Its most common use is in the treatment of bronchial asthma.
  • the pharmaceutical combination comprises the adenosine uptake inhibitor dipyridamole, or a pharmaceutically acceptable salt thereof, and the non-selective adenosine receptor antagonist caffeine
  • the compounds to be combined may be present as their pharmaceutically acceptable salts.
  • Compounds having, e.g., at least one basic group such as an amino group may form acid addition salts with acids such as mineral acids, organic carboxylic acids and organic sulfonic acids, e.g., hydrochloric acid, maleic acid and methanesulfonic acid, respectively.
  • compounds having at least one acidic group may form salts with bases such as alkati and alkafine earth metal salts, e g , sodium, lithium, potassium, calcium and magnesium, as well as ammonium salts, e g. r ammonium, trimethytammonium, diethylammonium and tris(hydroxymethyl)-methyl-ammonium salts and salts with amino acids
  • bases such as alkati and alkafine earth metal salts, e g , sodium, lithium, potassium, calcium and magnesium
  • ammonium salts e g. r ammonium, trimethytammonium, diethylammonium and tris(hydroxymethyl)-methyl-ammonium salts and salts with amino acids
  • the corresponding active ingredients, or a pharmaceutically acceptable salts may also be used in form of a solvate, such as a hydrate or including other solvents used, e g , in their crystallization.
  • the present invention also provides pharmaceutical compositions comprising an adenosine uptake inhibitor, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition according to the present invention may be employed for the treatment of cancer diseases, and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome.
  • an adenosine uptake inhibitor e.g., dipyridamole
  • a non-selective adenosine receptor antagonist e.g., caffeine
  • a pharmaceutically acceptable salt thereof e g,, caffeine
  • compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man
  • the pharmaceutical composition comprising an adenosine uptake inhibitor, in particular, dipyridamole, and a non-selective adenosine receptor antagonist, or a pharmaceutically acceptable salt thereof, e g , caffeine
  • adenosine uptake inhibitor in particular, dipyridamole
  • a non-selective adenosine receptor antagonist or a pharmaceutically acceptable salt thereof, e g , caffeine
  • Preferred are tablets and gelatin capsules comprising the active ingredient(s) together with: a) diluents, e g , lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e g , silica, talcum, stearic acid, its magnesium or calcium
  • Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-90%, preferably about 1-80%, of the active ingredient(s), conveniently from 30-95% for tablets and capsules, and 3-50% for liquid preparations.
  • the dosage of the active ingredients to be therapeutically effective in stimulating the adenosine A 3 receptor will, of course, depend on a variety of factors, such as mode of administration, horneothermic species, age and/or severity of individual condition, and the disease or disorder to be treated
  • Preferred dosages for the active ingredients of the pharmaceutical combinations according to the present invention are therapeutically effective dosages, especially those which are commercially available.
  • doses employed for adult human treatment will typically be in the range of 5-5000 mg/day, preferably 25-1000 mg/day, e g , for a patfent of approximately 75 kg in weight
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, e g .
  • the dosage or dosages which will result in optimal effects is achieved by coordinating the pharmacokinetic properties, e g , volume of distribution and time to maximum plasma concentration (T max ), of the therapeutic agents of the present invention so that the therapeutic windows of each agent overlap to the maximum extent possible.
  • T max time to maximum plasma concentration
  • the doses of dipyridamole to be administered to warm-blooded animals, including man, of approximately 75 kg body weight, especially the doses effective to block adenosine uptake to cells are from about 25 mg to about 1000 mg, preferably from about 100 mg to about 600 mg, e.g., from 200 to 400 mg/person/day, divided preferably into 1 to 4 si ⁇ gfe doses, which may, e g , be of the same size Usually, children receive about half of the adult dose. The dose necessary for each individual can be monitored and adjusted to an optimum level.
  • Single doses comprise, e g , 25 mg, 50 mg, 75 mg or 100 mg per adult patient.
  • the preferred doses of cifostazol range from about 20 to about 300 mg/person/day More preferably, 100 mg of cilostazof is administered twice a day Single doses comprise, e g , 50 mg or 100 mg per adult patient
  • the amount of a non -selective adenosine receptor antagonist, e g , caffeine, or a pharmaceutically acceptable salt thereof, administered in combination with an adenosine uptake inhibitor, e g , dipyridamole, or a pharmaceutically acceptable saft thereof, to a patient is a dose effective to treat cancer diseases or inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome in a patient.
  • a non-selective adenosine receptor antagonist e g,, caffeine, or a pharmaceutically acceptable salt thereof
  • an adenosine uptake inhibitor e g , dipyridamole, or a pharmaceutically acceptable sait thereof
  • the dose of a non-selective adenosine receptor antagonist is such that said adverse side effects are eliminated.
  • caffeine may be administered in combination with an adenosine uptake inhibitor, e.g., dipyridamole, to a patient of approximately 75 kg body weight at a dose between about 40 mg/day and about 400 rng/day
  • an adenosine uptake inhibitor e.g., dipyridamole
  • caffeine is administered at a dose between about 40 mg/day and about 400 mg/day
  • the doge of caffeine ranges from about 100 mg/day and about 200 mg/day
  • the preferred dose of theophylline ranges from about 400 mg to about 800 mg/day Likewise, the preferred dosage of aminophyiline ranges from about 400 mg to about 800 mg/day More preferably the doge of both theophylline and aminophylline ranges from about 400 mg to about 600 mg/day.
  • compositions according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination
  • adenosine uptake inhibitor is selected from the group consisting of cilostazol, dilazep, dipyridamole, midazolam, nimodipine, nitrobenzylthioinosine, propentofyltine, KF24345 and R75231, or in each case, a pharmaceutically acceptable salt thereof
  • adenosine uptake inhibitor is selected from the group consisting of cilostazol and dipyridamole, or in each case, a pharmaceutically acceptable salt thereof
  • adenosine uptake inhibitor is dipyridamole, or a pharmaceutically acceptable salt thereof.
  • Preferred are also combinations, such as a combined preparations or pharmaceutical compositions, respectively, wherein the non-selective adenosine receptor antagonist is selected from the group consisting of caffeine, paraxanthine, theobromine, theophylline and aminophylline, or in each case, a pharmaceutically acceptable salt thereof
  • adenosine uptake inhibitor is dipyridamole, or a pharmaceutically accepted salt thereof
  • the non-selective adenosine receptor antagonist is caffeine, or a pharmaceutically acceptable salt thereof
  • the present invention further relates to a method for the treatment of cancer diseases, and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome, through stimulation of the adenosine A 3 receptor, comprising administering to a warm-blooded animal, including man, in need thereof, a therapeutically effective amount of a combination comprising an adenosine uptake inhibitor, in particular dipyrimadole, or a pharmaceutically acceptable salt thereof, and a nonselective adenosine receptor antagonist, e.g., caffeine, or a pharmaceutically acceptable salt thereof
  • the present invention provides use of a combination of an adenosine uptake inhibitor in combination with a non-selective adenosine receptor antagonist to selectively stimulate the adenosine A 3 receptor
  • the present invention relates to the use of a combination comprising an adenosine uptake inhibitor, in particular, dipyrimadole, or a pharmaceutically acceptable salt thereof, and a non-selective adenosine receptor antagonist, e g , caffeine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of cancer diseases, and inflammatory disorders such as rheumatoid arthritis, osteoarthritis, psoriasis and dry eye syndrome [071]
  • the present invention also relates to combining separate pharmaceutical compositions in a kit form
  • the kit may comprise, e g , two separate pharmaceutical compositions: (1) a composition comprising an adenosine uptake inhibitor, in particular dipyridamole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent; and (2) a
  • the kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet, wherein each compartment contains a plurality of dosage forms (e g , tablets) comprising, e g , (1) or (2)
  • the kit may contain separate compartments each of which contains a whole dosage which in turn comprises separate dosage forms
  • An example of this type of kit is a blister pack wherein each individual blister contains two (or more) tablets, one (or more) tablet(s) comprising a pharmaceutical composition (1), and the second (or more) tablet(s) comprising a pharmaceuticai composition (2)
  • the kit comprises directions for the administration of the separate components
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e g , oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician
  • An adenosine uptake inhibitor e g , dipyridamole, or a pharmaceutical salt thereof, or the combination partners thereof, can be administered by various routes of administration
  • Each agent can be tested over a wide-range of dosages to determine the optima! drug level for each therapeutic agent alone, or in the specific combination thereof, to elicit the maximal response
  • ft fs preferred to use treatment groups consisting of at least 6 animals per group.
  • Example 10 illustrates the effect of a combination of an adenosine uptake inhibitor, e.g., dipyridamole, and a non-selective adenosine receptor antagonist, e g , caffeine, on cyclic AMP (cAMP) levels in hA 3 CHO cells.
  • an adenosine uptake inhibitor e.g., dipyridamole
  • a non-selective adenosine receptor antagonist e.g , caffeine
  • cAMP cyclic AMP
  • CHO cells transfected with A 3 receptors are pelleted by centrifugation at 250 g for 5 min, washed once in Dulbecco's Modified Eagle Medium (DMEM/F12) and re-suspended in the same buffer in a cell density of 1 10 6 celts/mL and used in the cyclic AMP (cAMP) assays CHO cells are kept under a humidified atmosphere of air/CO 2 at 37°C until the use in cAMP experiments
  • CHO cells expressing !1A 3 are suspended in 0 5 mL incubation mixture containing NaCI 150 mM, KCI 2 7 mM, NaH 2 PO 4 0.37 mM, MgSO 4 1 mM, CaCl 2 1 mM, glucose 5 mM, Hepes 5 mM, MgCI 2 10 mM, pH 74 at 37°C Then 0 5 mM Ro 20-1724 as phosphodiesterase inhibitor and caffeine (100 ⁇ M) are added and incubated for 5 min in a shaking bath at 37°C Dipyridamole (10 ⁇ M) and adenosine ⁇ 10 ⁇ M) are also incubated for 20 min in a shaking bath at 37°C Finally, forskolin ⁇ 1 ⁇ M) was incubated for 5 min at 37°C The reaction is terminated by the addition of cold 6% trichloroacetic acid (TCA) The final aqueous solution is tested for cycfic AMP

Abstract

La présente invention concerne une combinaison pharmaceutique comprenant un inhibiteur de fixation de l'adénosine ou un de ses sels de qualité pharmaceutique, ainsi qu'un antagoniste des récepteurs de l'adénosine non sélectif ou un de ses sels de qualité pharmaceutique, destinée au traitement de maladies cancéreuses, de troubles inflammatoires, tels que la polyarthrite rhumatoïde, l'ostéoarthrite, le psoriasis et le syndrome des yeux secs, par stimulation du récepteur de l'adénosine A3.
PCT/US2007/069440 2006-05-26 2007-05-22 Polythérapie comprenant un inhibiteur de fixation de l'adénosine et un antagoniste des récepteurs de l'adénosine non sélectif WO2007140181A2 (fr)

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Cited By (5)

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US9254289B2 (en) 2013-03-13 2016-02-09 Remedeye Inc. Methods for treating eye disorders using dipyridamole
WO2020065036A1 (fr) * 2018-09-27 2020-04-02 Iteos Therapeutics S.A. Utilisation d'un inhibiteur d'un transporteur de la famille des ent dans le traitement du cancer et de la combinaison de ceux-ci avec un antagoniste du récepteur de l'adénosine
BE1026612B1 (fr) * 2018-09-27 2020-07-02 Iteos Therapeutics S A Utilisation d’un inhibiteur d’un transporteur de la famille ent dans le traitement du cancer et combinaison de celui-ci avec un antagoniste de recepteur de l’adenosine
US10995101B2 (en) 2017-03-30 2021-05-04 Iteos Therapeutics Sa 2-oxo-thiazole derivatives as A2A inhibitors and compounds for use in the treatment of cancers
US11376255B2 (en) 2018-09-11 2022-07-05 iTeos Belgium SA Thiocarbamate derivatives as A2A inhibitors, pharmaceutical composition thereof and combinations with anticancer agents

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US9254289B2 (en) 2013-03-13 2016-02-09 Remedeye Inc. Methods for treating eye disorders using dipyridamole
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