GB2439923A - 5-Methyl-6,7-dihydro-5H-cyclopentapyrazine for use in therapy, especially treating platelet-related diseases such as thrombosis, and as a male contraceptive - Google Patents
5-Methyl-6,7-dihydro-5H-cyclopentapyrazine for use in therapy, especially treating platelet-related diseases such as thrombosis, and as a male contraceptive Download PDFInfo
- Publication number
- GB2439923A GB2439923A GB0613584A GB0613584A GB2439923A GB 2439923 A GB2439923 A GB 2439923A GB 0613584 A GB0613584 A GB 0613584A GB 0613584 A GB0613584 A GB 0613584A GB 2439923 A GB2439923 A GB 2439923A
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- Prior art keywords
- solvate
- salt
- treatment
- prophylaxis
- mdp
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Classifications
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- 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention pertains to the use of 5-methyl-6,7-dihydro-5H-cyclopentapyrazine (MDP), and salts and solvates thereof in therapy. The present invention also pertains to pharmaceutical compositions and kits comprising such compounds and the use of such compounds and compositions, both in vitro and in vivo, to inhibit P2 receptors (e.g. P2X1, P2Y1, and P2Y12 as found on platelets), to inhibit platelet activation and/or aggregation and in the treatment of disease conditions that are ameliorated by the inhibition of P2 receptors (e.g. platelet-related disease conditions, thrombotic events, thrombosis, cardiovascular diseases, myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism and respiratory disease conditions such as cystic fibrosis, bronchial asthma and obstructive airway diseases. The compounds and compositions may also be useful as a male contraceptive.
Description
<p>WJWILP639I 262</p>
<p>THERAPEUTIC COMPOUNDS</p>
<p>TECHNICAL FIELD</p>
<p>The present invention pertains generally to the field of therapeutic compounds, and more specifically to the use of 5-methyl-6,7-dihydro-5H-cyclopentaPYraZifle (MOP), and salts and solvates thereof in therapy. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit P2 receptors, for example, P2X1, P2Y1, and P2Y12, for exanple, as found on platelets; to inhibit platelet activation and/or aggregation; and in the treatment of disease conditions that are ameliorated by the inhibition of P2 receptors, for example, P2X1, P2Y1, and P2V12, for example, as found on platelets; for example: platelet-related disease conditions; thrombotic events; thrombosis; cardiovascular diseases; myocardial infarction; stroke; deep vein thrombosis; pulmonary embolism; respiratory disease conditions, such as cystic fibrosis, bronchial asthma and obstructive airway diseases; and as a male contraceptive.</p>
<p>BACKGROUND</p>
<p>A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.</p>
<p>Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and ucomprisingN will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.</p>
<p>Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.</p>
<p>WJW/LP6391262 Anti-Platelet Therapies At present, cardiovascular disease is the third leading cause of death and the leading cause of death and disability worldwide. On the basis of current estimates, there are more than 60 million people in the USA who suffer from a form of cardiovascular disease, and a high proportion of these are at increased risk of arterial thrombosis. These cardiovascular diseases include myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. The development of these life-threatening cardiovascular diseases is linked to excessive coagulation and clot formation. In turn, this is linked to platelet activation events Anti-platelet therapies have proven beneficial to cardiovascular disease sufferers, particularly in reducing acute primary peripheral arterial disease and atrial fibrillation, and secondary events such as those resulting from end-stage renal disease, diabetes, and individuals with carotid stenosis, myocardial infarction, and stroke.</p>
<p>At present, anti-thrombotic therapies are the most rapidly growing sector of the cardiovascular market. Currently, sales are valued at US$9.1 billion (2001), and have been forecasted to grow to US$22 billion by 2007 (Birch). Such growth is a reflection of the expansion of the anti-thrombotic market as a result of: an aging population, and an associated increase in vascular diseases; increased recognition of anti-platelet therapies as important for the prevention and treatment of cardiovascular disease; an increase in the use of combination anti-platelet therapy in high risk patients; and increased numbers of patients requiring therapies to prevent the onset of a secondary cardiovascular attack.</p>
<p>Despite this growing market need, there are currently few anti-platelet drugs available.</p>
<p>Even though they provide therapeutic benefit, the adverse events induced by the currently used drugs, the need for regular monitoring of coagulation parameters, and an inconvenient route of administration for some drugs, all drive a strong societal need for new, effective, and safe therapies for these cardiovascular diseases.</p>
<p>At present, there are four main oral antagonists (aspirin, ClopidogreK, Ticlopidine , Dipyridamole ) and one intravenous antagonist (Abciximab ) available on the market.</p>
<p>Aspirin is a prostanoid based drug, and beneficially reduces the risk of acute vascular events. By irreversibly binding to the active site of COX-1, aspirin inhibits the synthesis of thromboxane A2, a molecule that promotes platelet aggregation. Clinical studies demonstrate that aspirin reduces the incidence of myocardial infarction and stroke by 34% and 25% respectively, but only reduces vascular death in 15% patients. However, this leaves a high residual risk in patients that do not respond to aspirin. More WJW1LP6391262 importantly, aspirin taken as a prophylactic therapy is associated with increased risks of gastrointestinal complaints, bleeding, hemorrhagic stroke, renal failure, and arterial hypertension.</p>
<p>Clopidogrel is a thienopyridine derivative and is a selective P2Y12 antagonist (see below) Because it blocks a receptor that is solely present on the platelet cell surface, it has a relatively favourable safety profile. Compared to aspirin, Clopidogrel reduces serious cardiovascular events by 9%. Nonetheless, Clopidogrel has serious drawbacks, and many of the clinical studies that showed beneficial amounts of Clopidogrel also inhibited ADP-induced aggregation by 40-50%. Because of the P2Y12's important role in aggregation, at higher levels, Clopidogrel is likely to increase bleeding time.</p>
<p>Ticlopidine is a thienopyridine derivative, and also inhibits ADP-induced activation of GPllbtllla, by blocking P2Y receptors in the expectation of preventing fibrinogen-mediated platelet aggregation Clinical studies have shown that Ticlopidine decreases the risk of ischaemic stroke and non-fatal myocardial infarctions, and reduces complications associated with stent implant. Because it requires metabolic activation, the drug only becomes effective 3-7 days after activation and disappears about three days after therapy ceases. Despite its potent anti-platelet effects, this drug is only recommended for patients that show aspirin resistance, because of adverse effects on gastric and duodeal mucosa, skin rash, thrombocytopenic purpura (formation of microaggregates within the circulation, which also leads to low platelet count), and neutropenia (low neutrophil count).</p>
<p>Dipyridamole is a pyrimido[5,4-djpyrimidine derivative that inhibits platelet aggregation and causes vasodilation. It inhibits the cellular reuptake of adenosine into platelets, red blood cells, and endothelial cells leading to increased extracellular concentrations of adenosine. It also inhibits the enzyme adenosine deaminase which normally breaks down adenosine into inosine. This inhibition leads to further increased levels of extracellular adenosine. Dipyridamole also inhibits the enzyme phosphodiesterase which normally breaks down cAMP. Adenosine interacts with the adenosine receptors to cause increased cAMP via adenylate cyclase. cAMP impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Dipyridamole is also used in nuclear cardiac stress testing as a coronary vasodilator. Modified release dipyridamole is used in conjunction with aspirin (under the trade name Aggrenox ) in the secondary prevention of stroke and transient ischemic attack.</p>
<p>The best known, and most commonly used, antibody-based anti-platelet agent is Abciximab . This intravenously administered drug blocks the GPllb/Illa receptor, inhibits fibrinogen binding to activated platelets, inhibits clot retraction, and attenuates platelet pro- coagulant activity This drug does not affect GPIIb-mediated primary adhesion under WJWILP639I 262 high shear. Abciximab has been of particular benefit to patients undergoing surgery, particularly coronary interventions. However, like the small molecule antagonists, Abciximab has proven to be problematic in that it elevates bleeding risk.</p>
<p>While these drugs have shown clear efficacy benefits, improved efficacy is at the expense of safety. while the risk of thrombus formation is reduced, the risk of bleeding is significantly elevated. Thus, there is a pressing need to identify new drugs with a wide therapeutic window that are also efficacious and safe.</p>
<p>Also, because most clot formation occurs under high-shear conditions, new anti-platelet therapies suitable for use in such conditions is also needed.</p>
<p>Platelets Platelets or thrombocytes are the blood cell fragments that are involved in the cellular mechanisms that lead to the formation of blood clots. Low levels or dysfunction predisposes for bleeding, while high levels, although usually asymptomatic, may increase the risk of thrombosis Like red blood cells, platelets are anuclear (i.e., they have no cell nucleus) and discoid (disc-shaped); they measure 1.5--3.0 pm in diameter. The body has a very limited reserve of platelets, and they can be rapidly depleted. They contain RNA, a canalicular system, and several different types of granules; lysosomes (containing acid hydrolases), dense bodies (containing ADP, ATP serotonin, and calcium) and alpha granules (containing fibrinogen, factor V, vitronectin, thrombospondin, and von Willebrand factor), the contents of which are released upon activation of the platelet. These granule contents play an important role in both hemostasis and in the inflammatory response.</p>
<p>Platelets are produced in the bone marrow; the progenitor cell for platelets is the megakaryocyte. This large, multinucleated cell sheds platelets into the circulation.</p>
<p>Thrombopoietin (c-mpl ligand) is a hormone, mainly produced by the liver, that stimulates platelet production. It is bound to circulating platelets; if platelet levels are adequate, serum levels remain low. If the platelet count is decreased, more thrombopoeitin circulates freely and increases marrow production.</p>
<p>The,,circulaiing life of a platelet is 9-10 days. After this period, it is sequestered in the spleen. Decreased function (or absence) of the spleen may increase platelet counts, while hypersplenism (overactivity of the spleen, e.g., in Gaucher's disease, leukaemia, and cirrhosis) may lead to increased elimination and hence low platelet counts.</p>
<p>WJW/LP6 391262 Platelets are activated when brought into contact with: collagen (which is exposed when the endothelial blood vessel lining is damaged), thrombin (primarily through PAR-i), ADP, and receptors expressed on white blood cells or the endothelial cells of the blood vessels, among other activators. Once activated, they release a number of different coagulation factors and platelet activating factors. Platelet activation further results in the scramblase mediated transport of negatively charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes. The platelets adhere to each other via adhesion receptors or integrins, and to the endothelial cells in the wall of the blood vessel forming a haemostatic plug in conjunction with fibrin.</p>
<p>The high concentration of myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. The most common platelet adhesion receptor is glycoprotein (GP) lIb/Illa; this is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin, and von Willebrand factor (vWF).</p>
<p>Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).</p>
<p>There are many known platelet activators. They include: Collagen, especially with von Willebrand factor which is exposed when endothelial blood vessel lining is damaged and binds to GPVI, integrin a232 (and von Willebrand factor, GPIbIIXN complex and GPUb/llla, which is also known as integrin 01ib133) on the platelet; Thrombin, primarily through cleavage of the extracellular domain of PAR1 and PAR4; Thromboxane A2 (TxA2), which binds to TPa and TPI3 following its de novo generation; ADP through P2Y1 and P2Y12; Human neutrophil elastase (HNE) cleaves the OIib3 integrin on the platelet surface; P-selectin, which binds to PSGL-1 on eridothelial cells and white blood cells; and Convulxin, a purified protein from snake venom which binds to GPVI.</p>
<p>There are several known platelet inhibitors They include: Prostacyclin, which opposes the actions of Thromboxane A2; Nitric oxide; Clotting factors II, IX, X, Xl, Xli; and Nucleotidases, by breaking down ADP.</p>
<p>There are about 1012 circulating platelets in a typical healthy person, and a normal platelet count is between 150,000 and 400,000 per mm3 of blood. 95% of healthy people will have platelet counts in this range Some will have statistically abnormal platelet counts while having no abnormality, although the likelihood increases if the platelet count is either very low or very high.</p>
<p>Both thrombocytopenia (or thrombopenia) and thrombocytosis may present with coagulation problems. Generally, low platelet counts increase bleeding risks (although there are exceptions, e.g., immune heparin-induced thrombocytopenia) and thrombocytosis (high counts) may lead to thrombosis (although this is mainly when the elevated count is due to myeloproliferative disorder).</p>
<p>WJW!LP6391262 Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x109/L; it is contraindicated in thrombotic thrombocopenic purpura (TTP), as it fuels the coagulopathy. In patients having surgery, a level below 50 x 109/L is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80-100 x109/L.</p>
<p>Normal platelet counts are not a guarantee of adequate function. In some states the platelets, while being adequate in number, are dysfunctional. For instance, aspirin irreversibly disrupts platelet function and hence normal hemostasis; normal platelet function may not return until the aspirin is removed and the affected platelets have been replaced by new ones, which may take over a week. Similarly, uremia (a consequence of renal failure) leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.</p>
<p>Disorders leading to a reduced platelet count include: Thrombocytopenia, including Idiopathic thrombocytopenic purpura, Thrombotic thrornbocytopenic purpura, and Drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT); Gaucher's disease; and Aplastic anemia.</p>
<p>Disorders leading to platelet dysfunction or reduced count include: HELLP syndrome; Hemolytic-uremic syndrome; and Chemotherapy.</p>
<p>Disorders featuring an elevated platelet count include: Thrombocytosis, including benign essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease); may feature dysfunctional platelets.</p>
<p>Disorders of platelet adhesion or aggregation include: Bernard-Soulier syndrome; Glanzmann's thrombasthenia; Scott's syndrome; and von Willebrand disease.</p>
<p>Disorders of platelet metabolism include: Decreased cyclooxygenase activity, which may be induced or congenital; Storage pool defects, which may be acquired or congenital.</p>
<p>Disorders in which platelets play a pathogenetic role include: Hepatitis B Virus infection.</p>
<p>Platelet Receptors There are many different types of receptors on platelets. Some bind small molecules, such as epinephrine or thromboxarie A2 (TxA2), which help activate the platelet. Other receptors on the surface of platelets help the platelet to adhere to the sites of vascular injury These include the receptors for collagen (GPlaIIIa, GPIIbIlIIa, and GPVI), WJWILP6391 262 fibronectin (GPlc/lla), fibrinogen (GPUb/llla), vitronectin (GPIIb/llla), and von Willebrand factor (GPlb/IX). Other receptors exposed on the platelet surface help platelets aggregate to form a clot at the site of vessel injury, which ultimately stops bleeding from the site. These mostly include fibrinogen and the GPllb/llla receptor.</p>
<p>Platelet dense granules contain both ADP and ATP (up to 0.5 M each), and upon platelet activation and release of the dense granule contents, these nucleotides act at purinogenic receptors on the platelet surface to further stimulate activation. The known platelet purinogenic receptors for ADP are P2Y1 and P2Y12, while the known platelet purinogenic receptor for ATP is P2X1. P2Y1 and P2Y12 are metabatropic receptors coupled to Gq anq G, respecttvely.</p>
<p>P2X receptors are ATP-gated (ligand-gated) ion channels that mediate fast excitatory neurotransmission in excitable tissues including neurons, glia, and smooth muscle cells.</p>
<p>ATP can elicit rapid responses ("10 ms) via these ion channels, resulting in selective permeability to Na4, K4, and Ca24 cations. (See, for example, Boeynaems, J.M., et al., 2005, "Overview of the P2 receptors," Semin. Thromb. Hemost., Vol. 31, pp. 139-149.) Known P2X receptors include P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7.</p>
<p>The human, rat, and mouse P2X1 subunits were originally cloned from vas deferens and urinary bladder. The functional P2X1 receptor can be rapidly activated by ATP and its analogues. The rank order potency for agonist activation of recombinant P2X1 receptors was Bz-ATP >> 2-MeSATP AlP > aj3-meATP >> ADP. Agonists at this receptor are potently and selectively blocked by 1p51 as well as by other antagonists including TNP-ATP, the suramin analogues, NF023, NF279, NF449, and the PPADS analogues, MRS2159, and PPNDS. (See, for example, Rettinger, J., et al., 2005, "Profiling at recombinant homomeric and heteromeric rat P2X receptors identifies the suramin analogue NF449 as a highly potent P2X1 receptor antagonist," Neuropharmacology, Vol. 48, PP. 461-468.) Messenger RNA for the P2X1 receptor subunit is expressed in platelets, megakaryocytes, urinary bladder, smooth muscle layers of small arteries and arterioles, vas deferens, lung and spleen, dorsal root, trigeminal and celiac ganglia, spinal cord, and brain.</p>
<p>P2? receptors are G-protein-coupled receptors (GPCRs) with a typical heptahelical transmembrane (7-TM) motif and are sensitive to activation by both purines (ATP, ADP) and pyrimidines (UTP, UDP). (See, for example, Jacobson, K.A., et al., 2005, "Molecular recognition at adenine nucleotide (P2) receptors in platelets," Semin. Thromb. Hemost., Vol. 31, pp 205-216.) Known P2Y receptors include P2Y1, P2?2, P2?4, P2Y6, P2?11, P2?12, P2?13, and P2?14.</p>
<p>WJWILP639I 262 The P2Y1 receptor was the first P2 receptor to be cloned. The rank order of agonist activation is MRS2365 > 2-MeSATP ATP >>ADP, with ci,f3-MeATP, 3,y-MeATP, and UTP being inactive. MRS2179 and MRS2500 are the most potent P2Y1 antagonists yet reported. (See, e.g., Cattaneo, M., et al., 2004, "Antiaggregatory activity in human platelets of potent antagonists of the P2Y1 receptor," Biochem. Pharmacol., Vol. 68, pp. 1995-2002.) Suramin and Reactive Blue 2 (RB-2) can also block the effects of agonists at this receptor at niicromolar concentrations. Activation of the P2Y1 receptor results in either activation of PLC via the Gq coupling protein Gil or inhibition of adenylate cyclase via G, subunits that act independently. P2Y1 receptor activation can also directly modulate ion channel function, a G-protein-mediated effect that is independent of other second messenger systems.</p>
<p>The P2Y12 receptor was cloned from rat and human cDNA libraries and represents the elusive ADP-sensitive P2 receptor on platelets previously termed P2T, P2YADP, and P2YT. ADP is a full agonist at the P2Y12 receptor with ATP with its bioisosteres, including AR-C67085MX and AR-C69931MX, being functional antagonists. (See, e.g., Ingall, A.H., et al., 1999, "Antagonists of the platelet P2T receptor: A novel approach to antithrombotic therapy," J. Med. Chem., Vol. 42, pp. 213-220.) Ap4A, a P2,P3-monochloromethylene analogue, AppCHCIppA, and various phosphorothioate analogues are competitive inhibitors of platelet aggregation. The P2Y12 receptor is present on platelets and megakaryoblastic cell lines and is coupled to a G2 protein that inhibits adenylate cyclase.</p>
<p>P2Y12 knockout mice in general have a normal phenotype but exhibit prolonged bleeding time and reduced sensitivity to ADP, thrombin, and collagen.</p>
<p>ATP and ADP are the natural agonists at P2X1 and P2Y respectively. Following activation by ATP, the receptor is rapidly desensitized because of ATP binding. ATP can also act as an antagonist at the P2Y receptors. Because AlP is rapidly broken down into ADP in vitro from added apyrase (to preserve P2X1 activity) and platelet-surface ectonucleotidases, the commercial ATP analogue aj3-rnethylene-ATP (a,-meATP) is typically used to selectively activate and/or desensitize P2X1 receptors.</p>
<p>The P2Y1 and P2Y12 receptors are essential for normal aggregation in response to ADP: the Gq-coupled P2Y1 receptor initiates platelet aggregation but is not sufficient for a full platelet response, whereas the G-coupled P2Y12 receptor is responsible for completion of the aggregation triggered by ADP and other aggregating agents and also potentiates platelet secretion. Due to its central role in the formation and stabilization of a thrombus, the P2Y12 receptor is a well established target of antithrombotic drugs such as Clopidogrel . Experimental thrombosis in P2Y1 knockout mice and mice treated with a selective P2Y1 antagonist has shown that this receptor could be a potential target for new antithrombotic drugs WJWILP639I 262 Study of the role of the P2X1 receptor in hemostasis and thrombosis has long been hindered by a lack of potent and selective P2X1 antagonists and by the rapid and long-lasting desensitization of the receptor. When P2X1 desensitization is prevented by addition of a high concentration of apyrase (ATP-diphosphohydrolase), this receptor triggers a transient platelet shape change in response to the poorly hydrolysable ATP analog a43-meATP. Despite the fact that activation of the P2X1 receptor alone cannot induce platelet aggregation, it contributes to aggregation in response to collagen. The role of P2X1 in platelet functions appears to be particularly relevant under flow conditions characterized by high shear stress (see, e.g., Hechier, B., et al., 2003, "A Role of the Fast ATP-Gated P2X1 Cation Channel in Thrombosis of Small Arteries in vivo," J. Exp Med., Vol. 198, No. 4, pp. 661-667). A study of P2X1-deficierit (P2X1 -I-) mice has further indicated that this receptor contributes to the thrombosis of small arteries. P2X1 -I-mice display resistance to the localized arterial thrombosis of mesenteric arterioles triggered by laser-induced vessel wall injury and to the acute systemic thromboembolism induced by infusion of a mixture of collagen and adrenaline. Conversely, increased systemic thrombosis has been reported in mice overexpressing the human P2X1 receptor (Oury, C., Kuijpers, M.J., Toth-Zsamboki, E., Bonnefoy, A., Danloy, S, Vreys, I, Feijge, M.A., De Vos, R., Vermylen, J., Heemskerk, J.W., Hoylaerts, M.F., 2003, Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype," Blood, Vol 101(10), pp. 3969-3976). Hence, the P2X1 receptor is also a target for new antithrombotic drugs.</p>
<p>It has been suggested that combined inhibition of these three P2 receptors (P2Y1, P2Y12, and P2X1) may lead to greater risk reduction of thrombosis. P2Y12 is well-established to have a central role in thrombus formation and stabilization, and recent evidence suggests that P2Y1 may be a promising target for anti-thrombotic drug development. More recently, a role for P2X1 in thrombosis is emerging. Importantly, the role of P2X1 is particularly relevant under high-shear flow conditions, as present in small arteries and arterioles. Additionally in mice overexpressing P2X1, systemic thrombosis has been reported to increase significantly The inventors have determined that P2X1 to plays an important role in thrombosis, but not haemostasis. Additionally, the inventors have shown that P2X1 has a mechanism of signalling that is independent of other cross-linked platelet activation pathways, this allows P2X1 to accelerate thrombosis without interfering with haemostasis. Such results indicate that P2X1 is an ideal drug target for maximizing the therapeutic window by reducing the risk of thrombus formation without affecting bleeding.</p>
<p>There is focus on the P2 receptors as potential anti-platelet drug candidates because of their role in early-stage platelet activation. At present, Clopidogrel and Ticlopidine are the only P2 receptor antagonist drugs and they are selective for P2Y There are no WJW/LP6391262 known P2X1 antagonist drugs. More recently, a series of suramin analogues have been developed for P2XI antagonism. In particular, NF449 has been shown to effectively reduce collagen-induced platelet aggregation. Although NF449 has been offered as a potential compound for anti-thrombotic drug development, this may be difficult because of its large molecular weight.</p>
<p>The inventors have identified another P2X1 antagonist that is an excellent candidate for drug development: 5-rnethyl-6,7-dihydro-5H-cyclopentapyrazine (MDP).</p>
<p>A different pyrazine compound, 2,3,5,6-tetramethylpyrazine (TMP), is an active ingredient of a Chinese herbal medicine, Ligusticum wallichii Franch. Its extraction, isolation, and structural identification were reported in 1977 (see, e.g., Odebiyi, 0.0., 1980, "Antibacterial property of tetramethylpyrazine from the stem of Jatropha podagrica," Planta Med., Vol. 38, pp. 332-338). Previous animal pharmacological studies have shown that TMP provides beneficial cardiovascular effects that include reduction of arterial resistance, blood pressure (see, e.g., Dai, X.Z., Bache, R.J., 1985, "Coronary and systemic hemodynamic effects of tetramethyipyrazine in the dog," J. Cardiovasc.</p>
<p>Pharmacol., Vol. 7, pp. 841-849; Zhou, X.B., Salganicoff, L., Sevy, R.,1985, "[rhe pharmacological effect of iigustrazine on human platelets]," Yao Xue Xue Bao., Vol. 20, pp. 334-339), hypoxia-induced pulmonary hypertension (see, e.g., Xue, Q.F., Dai, S.L., Yuan, S.Y., Zhu, L.X., Wu, Y.Q., Wang, S.S., Li, C.C., Liu, C.Y., Wang, Z.Y., 1989, "Effect of chuanxiongqin (tetrame-thyipyrazine) on microcirculatory perfusion in hamsters and capillary permeability in rats," Proc Chin. Acad. Med. Sci. Peking Union Med. Coil., Vol. 161, pp. 1319-1323), capillary permeability (see, e.g., Tuttle R.S., 1989. "In vitro uterine response to tetramethylpyrazine, the active constituent of chung chong (a traditional Chinese medicine)," Am. J. Obstet. Gynecol., Vol. 161: pp. 1319-1323); increases coronary (see, e.g., Yang, Y.Y, Zeng, X.R., Liu, Z.F., Cai, F., Li, M.L, Zhou, W., Pei, J., Yang, Y., 2006, "[Effects of tetramethylpyrazine on large-conductance Ca(2+)-activated potassium channels in porcine coronary artery smooth muscle cells]," Sheng Li Xue Bao, Vol. 53(1), pp. 83-89) and cerebral blood flow (Feng, MG., Feng, G.H., Zhou, Q.G., 1988, "[Effects of methylhesperidin on coronary, renal and cerebral circulation in dogs]," Zhongguo Yao Li Xue Bao., Vol. 9(548),p. 550); and improves microcirculation (see, e g., Dai, X.Z., Bache, R.J., 1985, "Coronary and systemic hemodynamic effects of tetramethylpyrazine in the dog," J. Cardiovasc. Pharmacol., Vol. 7, pp. 841-849). Clinical trials conducted on TMP in China, whilst poorly designed, showed 30 patients suffering from angina pectoris exhibited symptomatic relief (see, e.g., Odebiyi, 0.0., 1980, "Antibacterial property of tetramethylpyrazine from the stem of Jatropha podagrica," Planta Med., Vol. 38, pp. 332-338), suggesting that IMP also provided cardiovascular benefits in humans (Liu, S-Y., Sylvester, D.M., 1994, "Antiplatelet structure-activity relationship of tetramethypyrazine," Life Sciences, Vol 55(17), pp. 1317-1 326) WJWILP639I 262 Animal studies in the West have shown that TMP improves coronary blood flow, is short acting, and has a low toxicity (see, e.g., Tuttle R.S., 1989. "In vitro uterine response to tetramethylpyrazine, the active constituent of chung chong (a traditional Chinese medicine)," Am. J Obstet. Gynecol., Vol. 161: PP. 1319-1323). However, there are mixed reports on its mode of action. One study in human platelets suggests that TMP has inhibitory effects at the alpha 2 adrenergic receptors (a2) (see, e.g., Hui, K.K., Yu, J.L., Tse, E., Borst, S., 1987, "The effects of tetramethylpyrazine on the human platelet alpha 2 adrenergic receptor adenylate cyclase system," Res. Commun. Chem Pathol.</p>
<p>PharmacoL, Vol. 58, pp 3-14). The authors suggested that TMP is an a2 adrenergic receptor partial agonist because increasing concentrations of TMP blocked the inhibitory effect of L-epinephrine on PGE1-induced cyclic AMP (cAMP) rises. These effects may identify potential mechanisms for the cardiovascular actions of TMP. Another study focusing across a series of agonists (ADP, collagen, thrombin) suggests that IMP inhibits ADP-induced aggregation in a dose-dependent manner by interfering with extracellular and intracellular Ca2-mobilisation. The authors postulated that IMP could decrease cation binding to the platelet membrane and thus affect the surface negative charge density (see, e.g., Liu, S.-Y., Sylvester, D.M., 1990, "Antithrombotic/antiplatelet activity of tetramethylpyrazine," Thrombosis Research, Vol. 58(2), pp. 129-140).</p>
<p>BRIEF DESCRIPTION OF THE DRAWINGS</p>
<p>Figure 1 is a graph of intracellular [Ca2] (nM) versus time for control, 16 nM MOP, and 32 nM MOP, as described in Study 1 below Figure 2 is a graph of transmission (%) versus time for control, 16 nM MDP, and 32 nM MDP, as described in Study 1 below.</p>
<p>Figure 3 is a graph of calcium response (% of control) as a function of MDP concentration (nM), as described in Study 1 below.</p>
<p>Figure 4 is a graph of intracellular [Ca21 (nM) versus time for control, 16 nM MDP, and 32 nM MOP, as described in Study 2 below.</p>
<p>Figure 5 is a graph of transmission (%) versus time for control, 16 nM MDP, and 32 nM MDP, as described in Study 2 below.</p>
<p>Figure 6 is a graph of calcium response (% of control) as a function of MDP concentration (nM), as described in Study 2 below.</p>
<p>WJWflP6391262 Figure 7 is a graph of intracellular [Ca2] (nM) versus concentration of ATP (pM) for control (squares), 8 nM MDP (circles), and 16 nM MDP (triangles), as described in Study 3 below.</p>
<p>SUMMARY OF THE INVENTION</p>
<p>The present invention pertains generally to the use of 5-methyl-6,7-dihydro-5H-cycloperitapyrazine (MDP), and salts and solvates thereof, in therapy.</p>
<p>Thus, one aspect of the invention pertains to a pharmaceutical composition comprising MOP or a salt or solvate thereof, and a pharmaceutically acceptable carrier, diluerit, or excipient Other aspects of the present invention pertain to use of MDP or a salt or solvate thereof in: a method of inhibiting receptor P2 (e.g., P2X1, P2Y1, P2Y12); a method of antagonising receptor P2 (e.g., P2X1, P2Y1, P2Y12); a method of inhibiting or preventing platelet activation and/or aggregation; a method of inhibiting or preventing platelet activation; a method of inhibiting or preventing P2 receptor-evoked platelet activation (e.g., P2XI receptor-evoked platelet activation, P2Y1 receptor-evoked platelet activation, P2Y12 receptor-evoked platelet activation); and a method of inhibiting or preventing platelet aggregation.</p>
<p>In one embodiment, the receptor P2 is platelet purinogenic receptor P2, for example, platelet purinogenic receptor P2X1, platelet purinogenic receptor P2Y1, platelet purinogenic receptor P2Y12.</p>
<p>Another aspect of the present invention pertains to the use of MOP or a salt or solvate thereof as an anti-platelet agent.</p>
<p>Another aspect of the present invention pertains to the use of MDP or a salt or solvate thereof as an anti-thrombosis agent.</p>
<p>Another aspect of the present invention pertains to MDP or a salt or solvate thereof, for use in a method of treatment of the human or animal body by therapy.</p>
<p>Another aspect of the present invention pertains to MDP or a salt or solvate thereof, for use in a method of treatment, for example, in a method of treatment or prophylaxis of (including, e g., reducing the risk of) a disease condition as described herein.</p>
<p>WJWILP639I 262 Another aspect of the present invention pertains to use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis, for example, in a method of treatment or prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein.</p>
<p>Another aspect of the present invention pertains to a method of treatment or prophylaxis, for example, a method of treatment or prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MDP or a salt or solvate thereof, preferably in the form of a pharmaceutical composition.</p>
<p>In one embodiment, the disease condition is: a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet activation and/or aggregation.</p>
<p>In one embodiment, the disease condition is: a platelet related disease condition.</p>
<p>In one embodiment, the disease condition is: a thrombotic event.</p>
<p>In one embodiment, the disease condition is: thrombosis.</p>
<p>In one embodiment, the disease condition is: thrombosis characterised by onset at high shear.</p>
<p>In one embodiment, the disease condition is: thrombosis in a patient having an increased risk of thrombosis, for example, in a patient suffering from diabetes mellitus; coronary heart disease, thrombocytosis; hyperlipidemia; a peripheral vascular disease; deep vein thrombosis; cardiac arrhythmia such as atrial fibrillation; end-stage renal disease; etc. In one embodiment, the disease condition is: thrombosis in a patient undergoing surgery, for example, coronary intervention surgery.</p>
<p>In one embodiment, the disease condition is: a cardiovascular disease In one embodiment, the disease condition is: myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism.</p>
<p>In one embodiment, the disease condition is: myocardial infarction; stroke; stroke in patients with atrial fibrillation, diabetes mellitus, or a cerebral vascular disease; stroke arising from or associated with atherosclerosis of the vasculature supplying the central nervous system, for example, vertebral basilar arteries; ischemic stroke; deep vein thrombosis; embolism; pulmonary embolism; occlusion of coronary, pulmonary, or WJWILP639I 262 -14 -cerebral arteries; aneurysm; obliterative arterial disease; steriosis; carotid stenosis; renal arterial stenosis; arteritis; Takayasu arteritis; coronary heart disease; angina; hyperlipidemia; peripheral arterial disease; disseminated intravascular coagulation; haemorrhage; fissure of atherosclerotic plaques; ischemic vascular disease; cardiac arrhythmia, such as atrial fibrillation; congestive heart failure; diseases characterised by increased platelet count in blood when the risk of thrombosis is high, such as thrombocytosis, for example, thrombocytosis in myeloproliferative diseases, and thrombocytosis secondary to infections; or hypertension.</p>
<p>Another aspect of the invention pertains to use of MDP or a salt or solvate thereof as a substitute drug for aspirin, Ticlopidine , Clopidogrel , Abciximab , and/or Dipyridamole .</p>
<p>These and other aspects of the invention are described in more detail below.</p>
<p>As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.</p>
<p>DETAILED DESCRIPTION OF THE INVENTION</p>
<p>MDP</p>
<p>The present invention pertains generally to the use of 5-methyl-6,7-dihydro-5H-cyclopentapyrazine (MDP), and salts and solvates thereof (hereinafter collectively referred to as "the active compounds"), in therapy.</p>
<p>MDP (C8H10N2, MW 134.1784, CAS Registry No 23747-48-0), also known as maple lactone pyrazine, is commercially available and is known for use as a flavouring agent.</p>
<p>It has an odour describes as "earthy baked potato peanut roasted" and a taste described as "musty, nutty, roasted, and grainy with coffee notes." CH3 The carbon ring atom to which the methyl group is attached is a chiral centre.</p>
<p>Consequently, MDP is optically active, and two enantiomers, (R)-MDP and (S)-MDP, are known, Unless otherwise specified, a reference to MDP without indicating the stereoisomeric configuration is intended to be a reference to both enantiomeric forms, including racemic and other mixtures thereof.</p>
<p>WJWILP 6391262 CH3 CH3 (R)-MDP (S)-MDP Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g, fractional crystallisation and chromatographic means) of the enantiomeric forms are known in the art and/or may readily be obtained by adapting known methods in a known manner.</p>
<p>In one embodiment, the MDP is (R)-MDP.</p>
<p>In one embodiment, the MDP is (S)-MDP.</p>
<p>In one embodiment, the MDP is a mixture of (R)-MDP and (S)-MDP.</p>
<p>In one embodiment, the MDP is racemic MDP. Salts</p>
<p>It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of MDP, as described herein, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.</p>
<p>Examples of suitable salts include: those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous; those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric; those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.</p>
<p>Unless otherwise specified, a reference to MDP also includes salt forms thereof.</p>
<p>Solvates It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of MDP. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., MDP, salt of MDP) and solvent. If the solvent is water, the WJWILP 6391262 -16-solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tn-hydrate, etc. Unless otherwise specified, a reference to MDP also includes solvate forms thereof.</p>
<p>Pharmaceutical Compositions One aspect of the invention pertains to a pharmaceutical composition comprising MDP or a salt or solvate thereof.</p>
<p>One aspect of the invention pertains to a pharmaceutical composition comprising MDP or a salt or solvate thereof, and a pharmaceutically acceptable carrier, diluent, or excipient Examples of suitable pharmaceutically acceptable carriers, dluents, and excipients are described below.</p>
<p>Uses: Inhibiting Receptors etc. One aspect of the present invention pertains to use of MDP or a salt or solvate thereof in a method of inhibiting receptor P2 (e.g., P2X1, P2Y1, P2Y12).</p>
<p>One aspect of the present invention pertains to a method of inhibiting receptor P2 (e.g P2X1, P2Y1, P2Y12), comprising contacting a platelet bearing said receptor with an effective amount of MOP or a salt or solvate thereof.</p>
<p>One aspect of the present invention pertains to use of MOP or a salt or solvate thereof in a method of antagonising receptor P2 (e.g., P2X1, P2Y1, P2Y12).</p>
<p>One aspect of the present invention pertains to a method of antagonising receptor P2 (e.g., P2X1, P2Y1, P2Y12), comprising contacting a platelet bearing said receptor with an effective amount of MOP or a salt or solvate thereof.</p>
<p>In one embodiment, the receptor P2 is platelet purinogenic receptor P2, for example, platelet purinogenic receptor P2X, platelet purinogenic receptor P2Y1, platelet purinogenic receptor P2Y12.</p>
<p>One aspect of the present invention pertains to use of MDP or a salt or solvate thereof in a method of inhibiting or preventing platelet activation and/or aggregation.</p>
<p>WJW!LP6391262 One aspect of the present invention pertains to a method of inhibiting or preventing platelet activation andlor aggregation, comprising contacting a platelet with an effective amount of MDP or a salt or solvate thereof.</p>
<p>One aspect of the present invention pertains to use of MDP or a salt or solvate thereof in a method of inhibiting or preventing platelet activation.</p>
<p>One aspect of the present invention pertains to a method of inhibiting or preventing platelet activation, comprising contacting a platelet with an effective amount of MDP or a salt or solvate thereof One aspect of the present invention pertains to use of MDP or a salt or solvate thereof in a method of inhibiting or preventing P2 receptor- evoked platelet activation (e.g., P2X1 receptor-evoked platelet activation, P2YI receptor-evoked platelet activation, P2Y12 receptor-evoked platelet activation).</p>
<p>One aspect of the present invention pertains to a method of inhibiting or preventing P2 receptor-evoked platelet activation (e.g., P2X1 receptor-evoked platelet activation, P2V1 receptor-evoked platelet activation, P2Y12 receptor-evoked platelet activation), comprising contacting a platelet with an effective amount of MDP or a salt or solvate thereof.</p>
<p>One aspect of the present invention pertains to use of MDP or a salt or solvate thereof in a method of inhibiting or preventing platelet aggregation.</p>
<p>One aspect of the present invention pertains to a method of inhibiting or preventing platelet aggregation, comprising contacting a platelet with an effective amount of MOP or a salt or solvate thereof.</p>
<p>One aspect of the present invention pertains to the use of MDP or a salt or solvate thereof as an anti-platelet agent.</p>
<p>Such methods may be performed, for example, in vitro, as part of an assay.</p>
<p>Such methods may be performed, for example, in vivo, by administration of MDP or a salt or solvate thereof to a patient Such methods may be performed, for example, as part of a method of dialysis or transfusion practiced on a patient, for example, by the addition of MOP or a salt or solvate thereof to blood or a blood product that is destined for, or that is to be returned to, a patient.</p>
<p>WJWILP639I 262 Use in Methods of Therapy Another aspect of the present invention pertains to MDP or a salt or solvate thereof, for use in a method of treatment of the human or animal body by therapy.</p>
<p>Another aspect of the present invention pertains to MOP or a salt or solvate thereof, for use in a method of treatment, for example, in a method of treatment or prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein.</p>
<p>Another aspect of the present invention pertains to MDP or a salt or solvate thereof, for use in a method of treatment of a disease condition as described herein.</p>
<p>Another aspect of the present invention pertains to MDP or a salt or solvate thereof, for use in a method of prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein.</p>
<p>Use in the Manufacture of Medicaments Another aspect of the present invention pertains to use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis, for example, in a method of treatment or prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein.</p>
<p>Another aspect of the present invention pertains to use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment, for example, in a method of treatment of a disease condition as described herein.</p>
<p>Another aspect of the present invention pertains to use of MOP or a salt or solvate thereof in the manufacture of a medicament for use in a method of prophylaxis, for example, in a method of prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein.</p>
<p>Methods of Treatment Another aspect of the present invention pertains to a method of treatment or prophylaxis, for example, a method of treatment or prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MDP or a salt or solvate thereof, preferably in the form of a pharmaceutical composition.</p>
<p>WJW/LP6391 262 Another aspect of the present invention pertains to a method of treatment, for example, a method of treatment of a disease condition as described herein, comprising administering to a patient in need of said treatment a therapeutically-effective amount of MDP or a salt or solvate thereof, preferably in the form of a pharmaceutical composition.</p>
<p>Another aspect of the present invention pertains to a method of prophylaxis, for example, a method of prophylaxis of (including, e.g., reducing the risk of) a disease condition as described herein, comprising administering to a patient in need of said prophylaxis a prophylactically-effective amount of MDP or a salt or solvate thereof, preferably in the form of a pharmaceutical composition.</p>
<p>Disease Conditions -Conditions Mediated by P2 In one embodiment, the disease condition is a disease condition that is mediated by receptor P2 (e.g., P2X1, P2Y1, P2Y12).</p>
<p>In one embodiment, the disease condition is a disease condition that is characterized by cells that express receptor P2 (e.g., P2X1, P2Y1, P2Y12), e.g., vas deferans tissue.</p>
<p>In one embodiment, the disease condition is a disease condition that is treated and/or prevented by the inhibit ion of receptor P2 (e.g., P2X1, P2Y1, P2Y12) In one embodiment, the disease condition is a disease condition that is treated and/or prevented by antagonising receptor P2 (e g., P2X1, P2Y1, P2Y12).</p>
<p>In one embodiment, the receptor P2 is platelet purinogenic receptor P2, for example, platelet purinogenic receptor P2X1, platelet purinogenic receptor P2Y1, platelet purinogenic receptor P2Y12.</p>
<p>Disease Conditions -Conditions Characterised by Platelet Activation/Aggregation In one embodiment, the disease condition is a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet activation and/or aggregation.</p>
<p>In one embodiment, the disease condition is a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet activation.</p>
<p>In one embodiment, the disease condition is a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet aggregation.</p>
<p>WJWILP639I 262 -20-Disease Conditions -Platelet-Related Disease Conditions In one embodiment, the disease condition is: a platelet related disease condition.</p>
<p>In one embodiment, the disease condition is: a thrombotic event.</p>
<p>In one embodiment, the disease condition is. thrombosis.</p>
<p>In one embodiment, the disease condition is. venous thrombosis, cerebral venous thrombosis; arterial thrombosis; or thrombopheblitis.</p>
<p>Thus, one aspect of the present invention pertains to the use of MOP or a salt or solvate thereof as an anti-thrombosis agent.</p>
<p>In one embodiment, the disease condition is. thrombosis characterised by onset at high shear.</p>
<p>In one embodiment, the disease condition is: thrombosis in a patient having an increased risk of thrombosis, for example, in a patient suffering from: diabetes mellitus, coronary heart disease; thrombocytosis; hyperlipidemia; a peripheral vascular disease; deep vein thrombosis, cardiac arrhythmia such as atrial fibrillation; end-stage renal disease; etc. In one embodiment, the disease condition is thrombosis in a patient undergoing surgery, for example, coronary intervention surgery.</p>
<p>In one embodiment, the disease condition is: a cardiovascular disease.</p>
<p>In one embodiment, the disease condition is: myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism.</p>
<p>In one embodiment, the disease condition is myocardial infarction; stroke; stroke in patients with atrial fibrillation, diabetes mellitus, or a cerebral vascular disease; stroke arising from or associated with atherosclerosis of the vasculature supplying the central nervous system, for example, vertebral basilar arteries; ischemic stroke; deep vein thrombosis; embolism; pulmonary embolism, occlusion of coronary, pulmonary, or cerebral arteries, aneurysm; obliterative arterial disease; stenosis; carotid stenosis; renal arterial stenosis; arteritis; Takayasu arteritis; coronary heart disease; angina; hyperlipidemia; peripheral arterial disease; disseminated intravascular coagulation, haemorrhage; fissure of atherosclerotic plaques; ischemic vascular disease; cardiac arrhythmia, such as atrial fibrillation; congestive heart failure; diseases characterised by increased platelet count in blood when the risk of thrombosis is high, such as WJWILP639I 262 thrombocytosis, for example, thrombocytosis in myeloproliferative diseases, and thrombocytosis secondary to infections; or hypertension.</p>
<p>Disease Conditions -Respiratory Disease Conditions AlP may also have a direct role in asthma through its actions on bronchial innervation.</p>
<p>Nucleotides trigger a reflex broncho-constriction by activating a P2X receptor on vagal C fibres, and both ATP and UTP can potentiate IgE-mediated mast-cell histamine release, which involves P2Y receptors Therefore, it is likely that MDP will also be useful in the treatment of respiratory conditions.</p>
<p>In one embodiment, the disease condition is. a respiratory disease condition.</p>
<p>In one embodiment, the disease condition is: cystic fibrosis.</p>
<p>In one embodiment, the disease condition is: bronchial asthma.</p>
<p>In one embodiment, the disease condition is: an obstructive airway disease.</p>
<p>Disease Conditions -Other Conditions In one embodiment, the disease condition is: chronic inflammatory pain In one embodiment, the disease condition is: neuropathic pain.</p>
<p>In one embodiment, the disease condition is: an inflammatory disease.</p>
<p>In one embodiment, the disease condition is a disease condition identified herein.</p>
<p>Disease Conditions -as an Alternative/Substitute Drug Another aspect of the present invention pertains to the use of MDP or a salt or solvate thereof as a substitute drug for aspirin, Ticlopidine , Clopidogrel , Abciximab , and/or Dipyridamole , for example, for patients that are sensitive to aspirin, Ticlopidine , Clopidogrel , Abciximab , and/or Dipyridamole , as well as for patients whose therapeutic window of anti-coagulation is small (e.g., patients with a history of gastrointestinal or intracranial bleeding; patients being treated with non-steroidal anti-inflammatory drugs; patients with poor dosage control of warfarin).</p>
<p>Non-steroidal inflammatory drugs (NSAIDs) are known to interact, often negatively, with the anti-platelet drugs (e.g., Vioox , Celebrex ). MDP, being a specific P2 inhibitor, may be used as a safe anti-platelet drug for patients who are also being treated with, or who would also be treated with, an NSAID, for example: Diclofenac (e.g. Cataflam or Voltaren from Novartis), Celecoxib (Celebrex from Pfizer), Parecoxib (Dynastat from Pfizer), Piroxicam (Feldene from Pfizer), Indomethacin (lndocid from Merck WJW!LP6391262 -22 -Sharp & Dohme), Meloxicam (Mobic from Boehringer Ingeiheim), Naproxen (Naprosyn from Roche), or Tenoxicam (Tilcotil from Roche).</p>
<p>Treatment The term treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition.</p>
<p>Unless otherwise specified, treatment as a prophylactic measure (i.e., prophylaxis) is encompassed by the term "treatment". For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment" but is more specifically described by the term "prophylaxis". Both absolute prophylaxis and probabilistic prophylaxis are encompassed by the term "prophylaxis". Thus, "prophylaxis" of a disease condition encompasses "reducing the risk of' that disease condition.</p>
<p>The term "therapeutically-effective amount," as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.</p>
<p>Similarly, the term "prophylactically-effective amount," as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired prophylactic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.</p>
<p>Combination Therapies The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.</p>
<p>For example, MDP or a salt or solvate thereof may also be used in combination therapies, e.g., in conjunction with other agents, for example, other anti-thrombosis agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in WJW/LP6391262 -23-immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.</p>
<p>For example, it may be beneficial to combine treatment with a MOP or asalt or solvate thereof with one or more other (e.g., 1, 2, 3, 4) agents or therapies, for example, treatment with one or more of: aspirin, Ticlopidine , Clopidogrel , Abciximab , and Dipyridamole .</p>
<p>In one embodiment, MDP or a salt or solvate thereof is combined with one or more (e.g., 1, 2, 3,4) additional therapeutic agents.</p>
<p>One aspect of the present invention pertains to MOP or a salt or solvate thereof, in combination with one or more additional therapeutic agents.</p>
<p>The particular combination would be at the discretion of the physician who would select dosages using his or her common general knowledge and dosing regimens known to a skilled practitioner.</p>
<p>The agents (i.e., MDP or a salt or solvate thereof, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).</p>
<p>The agents (i.e., MDP or a salt or solvate thereof, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use, as described below.</p>
<p>Use in Male Contraception MDP or a salt or solvate thereof may also be used as a male contraceptive, for example, by acting as an antagonist of the vas deferens P2X receptor.</p>
<p>Another aspect of the present invention pertains to MDP or a salt or solvate thereof, for use in a method of male contraception Another aspect of the present invention pertains to use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of male contraception WJW1LP6391262 -24 -Another aspect of the present invention pertains to a method of male contraception, comprising administering to a male patient in need of said contraception, an effective amount of MDP or a salt or solvate thereof.</p>
<p>Other Uses MDP or a salt or solvate thereof may also be used as part of an assay, for example, an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound.</p>
<p>MDP or a salt or solvate thereof may also be used as a standard or comparator, for example, in an assay, in order to identify other active compounds, other anti-platelet agents, other anti-thrombosis agents, etc. Kits Another aspect of the present invention pertains to a kit comprising (a) MDP or a salt or solvate thereof, preferably provided in the formS of a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound.</p>
<p>The written instructions may also include a list of indications for which the MOP or a salt or solvate thereof is a suitable treatment.</p>
<p>Routes of Administration The MDP or salt or solvate thereof, or the pharmaceutical composition comprising MDP or a salt or a solvate thereof may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action) Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual, transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, WJWILP639I 262 intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.</p>
<p>The Subject/Patient The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a Iagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g, a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.</p>
<p>Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.</p>
<p>In one preferred embodiment, the subject/patient is a human.</p>
<p>Formulations While it is possible for the active compound (i.e, MOP or a salt or solvate thereof) to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.</p>
<p>Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the active compound.</p>
<p>The term "pharmaceutically acceptable" as used herein pertains to compounds, ingredients, materials, compositions, dosage forms, etc, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in WJWILP6 391262 -26 -question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.</p>
<p>Suitable carriers, diluents, excipients, etc can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994.</p>
<p>The formulations may be prepared by any methods welt known in the art of pharmacy.</p>
<p>Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.</p>
<p>The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.</p>
<p>Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.</p>
<p>Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more active compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.</p>
<p>The active compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The active compound may be presented in a liposome or other microparticulate which is designed to target the active compound, for example, to blood components or one or more organs.</p>
<p>Formulations suitable for oral administration (e g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions WJW/LP6391 262 -27 - (e.g., oil-in-water, water-in-oil), elixirs, syrups, etectuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.</p>
<p>Formulations suitable for buccal administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Lozenges typically comprise the active compound in a flavoured basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the active compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the active compound in a suitable liquid carrier.</p>
<p>Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.</p>
<p>Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.</p>
<p>Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.</p>
<p>Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, WJWILPS39I 262 -28 -hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.</p>
<p>Ointments are typically prepared from the active compound and a paraffinic or a water-miscible ointment base.</p>
<p>Creams are typically prepared from the active compound and an oil-in-water cream base.</p>
<p>f desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-i,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.</p>
<p>Emulsions are typically prepared from the active compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.</p>
<p>Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono-or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethyihexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.</p>
<p>WJWILP 6391262 -29 Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound.</p>
<p>Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.</p>
<p>Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichiorodifluoromethane, trichlorofluorornethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.</p>
<p>Formulations suitable for ocular administration include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.</p>
<p>Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.</p>
<p>Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.</p>
<p>Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e g., solutions, suspensions), in which the active compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection Typically, the concentration of the active compound in the liquid is from about 1 ng/mL to about 10 pg/mL, for example from about 10 ng/mL to about 1 igImL The formulations may be presented in unit-dose or multi-dose sealed containers, for example, WJW/LP6391 262 -30 -ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.</p>
<p>Dosage It will be appreciated by one of skill in the art that appropriate dosages of the active compound (i.e., MDP or a salt or solvate thereof), and compositions comprising the active compound, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.</p>
<p>Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.</p>
<p>In general, a suitable dose of the active compound is in the range of about 50 pg to about nig (more typically about 100 pg to about 25 mg) per kilogram body weight of the subject per day. Where the active compound is a salt or solvate, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.</p>
<p>WJWILP639I 262 31 -Biological Methods and Studies Materials Apyrase Type VII, ADP (sodium salt), aj3-methylene adenosine triphosphate (aj3-rneATP) (Lithium salt), Adenosine 5'-triphosphate (AlP), disodium salt hydrate, dirnethyl sulphoxide (DMSO), and methyl-6,7-dihydrocyclopentapyrazine (MDP) were obtained from Sigma-Aldrich Co. Ltd (Old Brick Yard, Gillingham, UK). Fura-2 acetoxymethyl ester (fura-2/AM) was from Invitrogen (Paisley, UK) ADP was purified as described previously (Mahaut-Smith, M.P, Ennion, S.J., Roif, M.G., Evans, R.J., 2000, UADP is not an agonist at P2X(1) receptors: evidence for separate receptors stimulated by ATP and ADP on human platelets," Br. J. Pharmacol., Vol. 131(1), pp. 108-114).</p>
<p>Preparation of Platelet Suspensions Fura-2-Ioaded washed suspensions of human platelets from donors giving their informed consent were prepared using acid citrate dextrose anticoagulant and treated with aspirin (100 pM) and apyrase (0.32 U m11) as described in detail elsewhere (Roff, M.G., Brearley, C.A., Mahaut-Smith, M.P., 2001, "Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha,beta-methylene AlP," Thromb. Haemost., Vol. 85(2), pp. 303-308). The study was approved by the University of Cambridge Human Biology Research Ethics Committee Platelets were initially re-suspended in nominally Ca2-free saline (in mM. 145 NaCI, 5 KCI, 1 MgCl2, 10 HEPES, 10 glucose, titrated to pH 7 35 with NaOH) with type VII apyrase (0.32 U mr').</p>
<p>(Ca2J1 Measurements Fura-2 ratiometric fluorescence measurements were conducted at 37 C in a Cairn spectrofluorimeter system (Cairn Research Limited, Faversham, Kent, UK) and converted to [Ca2] as described elsewhere using a dissociation constant for Ca2 of 224 nM (Qhlmann, P., Hechler, B, Cazenave, J.P., Gachet, C., 2004, "Measurement and manipulation of [Ca2+]i in suspensions of platelets and cell cultures," Methods Mol Biol., Vol. 273, pp. 229-250; RoIf, M.G., Brearley, C.A., Mahaut-Smith, M.P., 2001, "Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha,beta-methylene AlP," Thromb Haemost., Vol. 85(2), pp. 303-308).</p>
<p>Study 1: Studies of P2X1 Studies were performed in order to determine the inhibitory effect of MDP on the P2X1 receptor.</p>
<p>WJWI1P6391262 -32 -Platelets were loaded with 2 pM fura-2AM (37 C for 45 minutes) and then mixed with Ca2-free saline at a volume ratio of 1:1 in a stirred-platelet cuvette system. To this was added either MDP (enough to give a concentration of 2,4,8, 16, 32, 64, or 128 nM) or water-vehicle control. 60 seconds later, enough aqueous CaCI2 (a source of external Ca24) was added to give a concentration of 2 mM. 30 seconds later, enough a,J3-meATP (an agonist selective for P2X1) was added to give a concentration of 10 pM.</p>
<p>Intracellular Ca24 levels were measured as a function of time, and in particular for about seconds before addition of agonist (to give a baseline value) and for about 60 seconds after addition of agonist (this is well after the peak response). The peak height of the Ca24 maximum (typically observed a few seconds after addition of agonist) was taken as the Ca2-response. The % control response for each particular MDP concentration was calculated with respect to the Ca24-response for a paired control Transmission (%) was also recorded as a function of time, and in particular for about seconds before addition of agonist (to give a baseline value) and for about 60 seconds after addition of agonist A decrease in transmission indicated a shape change (as observed when a water-vehicle control is used instead of MDP), whereas a lack of change in transmission (as observed when MDP is used) indicates a lack of shape change. Note that 32 nM MDP completely abolished the a,-meATP-evoked shape change response.</p>
<p>Representative traces of intracellular Ca24 level ([Ca2]1 (nM)) and percent transmission (%T) as a function of time, for control, 16 nM MOP, and 32 nM MDP, are shown in Figure 1 and Figure 2, respectively. The addition of the P2X1 agonist a,3-meATP is shown by the arrow in each figure.</p>
<p>In Figure 1, the top curve (control) shows the effect of the P2X1 agonist (aj3-meATP) alone, as the control. The middle curve (16 nM MDP) shows that the agonist response is attenuated by the presence of 16 nM antagonist (MOP). The bottom curve (32 nM MOP) shows that the agonist response is further attenuated by the presence of 32 nM antagonist (MOP).</p>
<p>In Figure 2, the bottom curve (control) shows a decrease in transmission which indicates a shape change of platelets stimulated by the agonist alone (a,13-meATP) The middle curve (16 nM MDP) shows that the agonist-evoked shape.change is attenuated by the presence of 16 nM antagonist (MOP). The bottom curve (32 nM MOP) shows that the agonist-evoked shape change is completely abolished by the presence of 32 nM antagonist (MDP).</p>
<p>WJWILP639I 262 -33 -Replicates (n =4) for each concentration of MOP were used to calculate the calcium response for that concentration (specifically, as the calcium level after MDP addition, as a percent of the calcium level for the control). A plot of the calcium response (as % of control) versus the logarithm of MDP concentration is shown in Figure 3. The error bars are SEM.</p>
<p>The linear relationship between the calcium level and the logarithm of MDP concentration indicates that MDP is acting in a concentration dependent manner to inhibit the P2X1 receptor.</p>
<p>These data demonstrate that MOP has P2X1 antagonistic effects for both intracellular Ca24 levels and shape-change at the nanomolar level, and that MDP plays an inhibitory role against P2 receptor evoked platelet activation Study 2: Studies of P2Y1 and P2Y Parallel studies were performed to determine the inhibitory effect of MOP on the P2Y1 and P2Y12 receptors.</p>
<p>Platelets were loaded with 2 pM fura-2AM (37 C for 45 minutes) and then mixed with Ca24-free saline at a volume ratio of 1:1 in a stirred-platelet cuvette system. To this was added either MDP (enough to give a concentration of 2, 4, 8, 16, 32, 64, or 128 nM) or water-vehicle control. 60 seconds later, enough aqueous MgCI2 (to provide an osmotic substituted for Ca24) was added to give a concentration of 2 mM. 30 seconds later, enough ADP (an agonist selective for P2Y1 and P2Y12) (hexokinase purified to removed contaminating ATP) was added to give a concentration of 10 pM.</p>
<p>Intracellular Ca2 levels were measured as a function of time, and in particular for about seconds before addition of agonist (to give a baseline value) and for about 60 seconds after addition of agonist. The peak height of the Ca24 maximum (typically observed a few seconds after addition of agonist) was taken as the Ca2-response. The % control response for each particular MOP concentration was calculated with respect to the Ca24-response for the control.</p>
<p>Transmission (%) was also recorded as a function of time, and in particular for about seconds before addition of agonist (to give a baseline value) and for about 60 seconds after addition of agonist. A decrease in transmission indicated a shape change (as observed when a water-vehicle control is used instead of MDP), whereas a lack of change in transmission (as observed when MDP is used) indicates a lack of shape change. Note that 32 nM MDP completely abolished the ADP-evoked shape change response.</p>
<p>WJW1LP6391262 -34 -Representative traces of intracellular Ca2 level ([Ca2], (nM)) and percent transmission (%T) as a function of time, for control, 16 nM MDP, and 32 nM MDP, are shown in Figure 4 and Figure 5, respectively. The addition of the P2X1 agonist a,f3-meATP is shown by thearrow in each figure.</p>
<p>In Figure 4, the top curve (control) shows the effect of the P2Y1 and P2Y12 agonist (ADP) alone, as the control. The middle curve (16 nM MDP) shows that the agonist response is attenuated by the presence of 16 nM antagonist (MDP). The bottom curve (32 nM MOP) shows that the agonist response is further attenuated by the presence of 32 nM antagonist (MOP).</p>
<p>In Figure 5, the bottom curve (control) shows a decrease in transmission which indicates a shape change of platelets stimulated by the agonist alone (ADP). The middle curve (16 nM MDP) shows that the agonist-evoked shape change is attenuated by the presence of 16 nM antagonist (MOP). The bottom curve (32 nM MDP) shows that the agonist-evoked shape change is completely abolished by the presence of 32 nM antagonist (MDP).</p>
<p>Replicates (n =4) for each concentration of MDP were used to calculate the calcium response for that concentration (specifically, as the calcium level after MDP addition, as a percent of the calcium level for the control). A plot of the calcium response (as % of control) versus the logarithm of MDP concentration is shown in Figure 6. The error bars are SEM The linear relationship between the calcium level and the logarithm of MDP concentration indicates that MDP is acting in a concentration dependent manner to inhibit the P2Y1 and P2Y12 receptors.</p>
<p>These data demonstrate that MOP has P2Y1 and P2Y12 antagonistic effects for both intracellular Ca2 levels and shape-change at the nanomolar level, and that MOP plays an inhibitory role against P2 receptor evoked platelet activation.</p>
<p>Study 3: Studies of P2X1 as a Competitive Antagonist Studies were also performed to determine the inhibitory effect of MOP on ATP-evoked Ca2' responses.</p>
<p>Platelets were loaded with 2 pM fura-2AM (37 C for 45 minutes) and then mixed with Ca2-free saline at a volume ratio of 1:1 in a stirred-platelet cuvette system. To this was added either (i) MOP (enough to give a concentration of 8 or 16 nM), MRS2179 (enough to give a concentration of 30 pM), and PGI2 (enough to give a concentration of 60 pM), or WJW/LP6391 262 -35 - (ii) a water-vehicle control (The addition of MRS2179 and PGI2 will completely abolish any contribution by P2Y receptors to the Ca2 increase.) 60 seconds later, enough aqueous CaCl2 (a source of external Ca2) was added to give a concentration of 2 mM.</p>
<p>seconds later, AlP (the physiological agonist for P2X1) was added (enough to give a concentration of 0.0012 to 10 pM).</p>
<p>Intracellular Ca2 levels were measured as a function of time, and in particular for about seconds before addition of ATP (to give a baseline value) and for about 60 seconds after addition of ATP. The peak height of the Ca2 maximum (typically observed a few seconds after addition of agonist) was taken as the Ca2-response. The % control response for each particular MDP concentration was calculated with respect to the Ca2-response for a paired control.</p>
<p>Replicates (n =4) for each concentration of ATP were used to calculate the intracellular Ca2 level for that ATP concentration. A plot of the intracellular Ca2 level versus the logarithm of ATP concentration is shown in Figure 7. The data were fitted with a best-fit sigmoidal curve. The error bars are SEM.</p>
<p>The Ca2-response in the absence of MDP (control, squares) had an EC50 of 0.048 nM and a rate-of-rise of 1.40. Pre-incubation with 8 nM MDP (circles) gave an EC50 of 0.24 nM and a rate-of-rise of 1.64. Pre-incubation with 16 nM MDP (triangles) gave an EC50 of 0.24 nM and a rate-of-rise of 1.64.</p>
<p>The addition of MDP caused both a "right-shift" of the Ca2-response curve (the EC5O is shifted to higher concentrations of ATP) and an attenuation of the maximum response.</p>
<p>This "right-shift" and attenuation of the Ca2-response curve upon addition of MOP indicates that MDP is an insurmountable antagonist of the P2X1 receptor.</p>
<p>The foregoing has described (he principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.</p>
Claims (1)
- <p>WJWILP639I 262 -36 -</p><p>CLAIMS</p><p>1. A pharmaceutical composition comprising 5-methyl-6,7-ciihydro-5H-cyclopentapyrazine (MOP) or a salt or solvate thereof.</p><p>2. A pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.</p><p>3. Use of MDP or a salt or solvate thereof in a method of inhibiting receptor P2.</p><p>4. Use of MDP or a salt or solvate thereof in a method of antagonising receptor P2.</p><p>5. Use according to claim 3 or 4, wherein receptor P2 is P2X1.</p><p>6. Use according to claim 3 or 4, wherein receptor P2 is P2Y1 and/or P2Y12.</p><p>7. Use of MDP or a salt or solvate thereof in a method of inhibiting or preventing platelet activation and/or aggregation.</p><p>8. Use of MOP or a salt or solvate thereof in a method of inhibiting or preventing platelet activation.</p><p>9. Use of MOP or a salt or solvate thereof in a method of inhibiting or preventing P2 receptor-evoked platelet activation.</p><p>Use according to claim 9, wherein the P2 receptor-evoked platelet activation is P2X1 receptor-evoked platelet activation.</p><p>11. Use according to claim 9, wherein the P2 receptor-evoked platelet activation is P2Y1 receptor-evoked platelet activation and/or P2Y12 receptor-evoked platelet activation.</p><p>12. Use of MOP or a salt or solvate thereof in a method of inhibiting or preventing platelet aggregation. ***</p><p>13 Use of MOP or a salt or solvate thereof as an anti-platelet agent.</p><p>WJW1LP6391262 -37- 14. Use of MDP or a salt or solvate thereof as an anti-thrombosis agent ** * 15. A method of/nh/biting receptor P2, comprising contacting a platelet bearing said receptor with an effective amount of MOP or a salt or solvate thereof.</p><p>16. A method of antagonising receptor P2, comprising contacting a platelet bearing said receptor with an effective amount of MDP or a salt or solvate thereof.</p><p>17. A method according to claim 15 or 16, wherein receptor P2 is P2X1.</p><p>18. A method according to claim 15 or 16, wherein receptor P2 is P2Y1 and/or P2Y12.</p><p>19. A method of inhibiting or preventing platelet activation and/or aggregation, comprising contacting a platelet with an effective amount of MOP or a salt or solvate thereof.</p><p>20. A method of inhibiting or preventing platelet activation, comprising contacting a platelet with an effective amount of MOP or a salt or solvate thereof.</p><p>21. A method of inhibiting or preventing P2 receptor-evoked platelet activation comprising contacting a platelet with an effective amount of MOP or a salt or solvate thereof.</p><p>22. A method according to claim 21, wherein the P2 receptor-evoked platelet activation is P2X1 receptor-evoked platelet activation.</p><p>23. A method according to claim 21, wherein the P2 receptor-evoked platelet activation is P2Y1 receptor-evoked platelet activation and/or P2Y12 receptor-evoked platelet activation 24. A method of inhibiting or preventing platelet aggregation, comprising contacting a platelet with an effective amount of MOP or a salt or solvate thereof. ** *</p><p>MOP or a salt or solvate thereof, for use in a method of treatment of the human or animal body by therapy.</p><p>WJW/LP6391 262 26. MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a disease condition that is mediated by receptor P2.</p><p>27. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a disease condition that is characterized by cells that express receptor P2 28. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a disease condition that is treated and/or prevented by the inhibition of receptor P2 29. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a disease condition that is treated and/or prevented by antagonising receptor P2.</p><p>30. MDP or a salt or solvate thereof, according to any one of claims 26 to 29, wherein the receptor P2 is P2X1.</p><p>31 MOP or a salt or solvate thereof, according to any one of claims 26 to 29, wherein the receptor P2 is P2Y1 or P2Y12.</p><p>32 MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet activation and/or aggregation.</p><p>33. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a platelet related disease condition.</p><p>34. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a thrombotic event.</p><p>35. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of thrombosis.</p><p>36. MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of venous thrombosis; cerebral venous thrombosis; arterial thrombosis; or thrombopheblitis.</p><p>37. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of thrombosis characterised by onset at high shear.</p><p>WJW/LP6391 262 -39 - 38. MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of thrombosis in a patient having an increased risk of thrombosis.</p><p>39. MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of thrombosis in a patient suffering from: diabetes mellitus; coronary heart disease; thrombocytosis; hyperlipidemia; a peripheral vascular disease; deep vein thrombosis; cardiac arrhythmia such as atrial fibrillation; and/or end-stage renal disease.</p><p>40. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of thrombosis in a patient undergoing surgery, for example, coronary intervention surgery.</p><p>41. MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a cardiovascular disease.</p><p>42. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism.</p><p>43. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of: myocardial infarction; stroke; stroke in patients with atrial fibrillation, diabetes mellitus, or a cerebral vascular disease; stroke arising from or associated with atherosclerosis of the vasculature supplying the central nervous system, for example, vertebral basilar arteries; ischemic stroke; deep vein thrombosis; embolism; pulmonary embolism; occlusion of coronary, pulmonary, or cerebral arteries; aneurysm; obliterative arterial disease; stenosis; carotid stenosis; renal arterial stenosis; arteritis; Takayasu arteritis; coronary heart disease; angina; hyperlipidemia, peripheral arterial disease; disseminated intravascular coagulation; haemorrhage; fissure of atherosclerotic plaques; ischemic vascular disease; cardiac arrhythmia, such as atrial fibrillation; congestive heart failure; diseases characterised by increased platelet count in blood when the risk of thrombosis is high, such as thrombocytosis, for example, thrombocytosis in myeloproliferative diseases, and thrombocytosis secondary to infections; or hypertension.</p><p>44. MDP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of a respiratory disease condition.</p><p>45. MOP or a salt or solvate thereof, for use in a method of treatment or prophylaxis of: cystic fibrosis, bronchial asthma, or an obstructive airway disease.</p><p>WJWILP639I 262 46. MDP or a salt or solvate thereof, according to any one of claims 26 to 45, wherein the method of treatment or prophylaxis further comprises treatment with one or more of: aspirin, Ticlopidine, Clopidogrel , Abciximab, and Dipyridamole .</p><p>47. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a disease condition that is mediated by platelet P2.</p><p>48. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a disease condition that is characterized by cells that express receptor P2.</p><p>49. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a disease condition that is treated and/or prevented by the inhibition of receptor P2.</p><p>50. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a disease condition that is treated and/or prevented by antagonising receptor P2 51. Use according to any one of claims 47 to 50, wherein the receptor P2 is P2X1.</p><p>52. Use according to any one of claims 47 to 50, wherein the receptor P2 is P2Y1 or P2Y12.</p><p>53. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet activation and/or aggregation.</p><p>54. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a platelet related disease condition.</p><p>55. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a thrombotic event.</p><p>56. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of thrombosis.</p><p>WJW!LP6391 262 57. Use of MOP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of: venous thrombosis; cerebral venous thrombosis; arterial thrombosis; or thrombophebf it is.</p><p>58. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of thrombosis characterised by onset at high shear.</p><p>59. Use of MDP or a salt or solvate thereof in the manufacture of a medicamerit for use in a method of treatment or prophylaxis of thrombosis in a patient having an increased risk of thrombosis 60. Use of MDP or a salt or solvate thereof in the manufacture of a medicanient for use in a method of treatment or prophylaxis of thrombosis in a patient suffering from: diabetes mellitus; coronary heart disease; thrombocytosis; hyperlipidemia; a peripheral vascular disease; deep vein thrombosis; cardiac arrhythmia such as atrial fibrillation; andlor end-stage renal disease.</p><p>61 Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of thrombosis in a patient undergoing surgery, for example, coronary intervention surgery.</p><p>62. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of a cardiovascular disease.</p><p>63. Use of MOP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism.</p><p>64. Use of MOP or a salt or solvate thereof in the manufacture of a med icament for use in a method of treatment or prophylaxis of: myocardial infarction; stroke; stroke in patients with atrial fibrillation, diabetes mellitus, or a cerebral vascular disease; stroke arising from or associated with atherosclerosis of the vasculature supplying the central nervous system, for example, vertebral basilar arteries; ischemic stroke; deep vein thrombosis; embolism; pulmonary embolism; occlusion of coronary, pulmonary, or cerebral arteries; aneurysm; obliterative arterial disease; stenosis; carotid stenosis; renal arterial stenosis; arteritis; Takayasu arteritis; coronary heart disease; angina; hyperlipidemia; peripheral arterial disease, disseminated intravascular coagulation, haemorrhage; fissure of atherosclerotic plaques; ischemic vascular disease; cardiac arrhythmia, such as atrial fibrillation; congestive heart failure; diseases characterised by increased WJWILP$39j262 -42 -platelet count in blood when the risk of thrombosis is high, such as thrombocytosis, for example, thrombocytosis in myeloproliferative diseases, and thrombocytosis secondary to infections; or hypertension.</p><p>65. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of: a respiratory disease condition.</p><p>66. Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of treatment or prophylaxis of: cystic fibrosis, bronchial asthma, or an obstructive airway disease.</p><p>67. Use according to any one of claims 47 to 66, wherein the method of treatment or prophylaxis further comprises treatment with one or more of: aspirin, Ticlopidine , Clopidogrel , Abciximab , and Dipyridamole .</p><p>68. A method of treatment or prophylaxis of a disease condition that is mediated by receptor P2, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically, or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>69. A method of treatment or prophylaxis of a disease condition that is characterized by cells that express receptor P2, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>70. A method of treatment or prophylaxis of a disease condition that is treated and/or prevented by the inhibition of receptor P2, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>71. A method of treatment or prophylaxis of a disease condition that is treated and/or prevented by antagonising receptor P2, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>72. A method according to any one of claims 64 to 67, wherein the receptor P2 is P2X1.</p><p>WJW1LP6391262 73. A method according to any one of claims 64 to 67, wherein the receptor P2 is P2Y1 or P2Y12.</p><p>74. A method of treatment or prophylaxis of a disease condition that is characterised by inappropriate, excessive, and/or undesirable platelet activation and/or aggregation, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophytactically-effective amount of MDP or a salt or solvate thereof.</p><p>75. A method of treatment or prophylaxis of a platelet related disease condition, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>76. A method of treatment or prophylaxis of thrombosis, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>77. A method of treatment or prophylaxis of: venous thrombosis; cerebral venous thrombosis; arterial thrombosis; or thrombopheblitis, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MDP or a salt or solvate thereof.</p><p>78. A method of treatment or prophytaxis of thrombosis characterised by onset at high shear, comprising admrnistering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>79. A method of treatment or prophylaxis of thrombosis in a patient having an increased risk of thrombosis, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically- or prophylactically-effective amount of MDP or a salt or solvate thereof.</p><p>80. A method of treatment or prophylaxis of thrombosis in a patient suffering from: diabetes mellitus; coronary heart disease; thrombocytosis; hyperlipidemia; a peripheral vascular disease; deep vein thrombosis; cardiac arrhythmia such as atrial fibrillation; and/or end-stage renal disease, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>WJW/1P6391 262 -44 - 81. A method of treatment or prophylaxis of thrombosis in a patient undergoing surgery, for example, coronary intervention surgery, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MDP or a salt or solvate thereof.</p><p>82. A method of tretment or prophylaxis of a cardiovascular disease, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof 83. A method of treatment or prophylaxis of myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>84. A method of treatment or prophylaxis of: myocardial infarction; stroke; stroke in patients with atrial fibrillation, diabetes mellitus, or a cerebral vascular disease; stroke arising from or associated with atherosclerosis of the vasculature supplying the central nervous system, for example, vertebral basilar arteries; ischemic stroke; deep vein thrombosis; embolism; pulmonary embolism; occlusion of coronary, pulmonary, or cerebral arteries; aneurysm; obliterative arterial disease; stenosis; carotid stenosis; renal arterial stenosis, arteritis; Takayasu arteritis; coronary heart disease; angina; hyperlipidernia; peripheral arterial disease; disseminated intravascular coagulation; haemorrhage; fissure of atherosclerotic plaques; ischemic vascular disease; cardiac arrhythmia, such as atrial fibrillation; congestive heart failure; diseases characterised by increased platelet count in blood when the risk of thrombosis is high, such as thrombocytosis, for example, thrombocytosis in myeloproliferative diseases, and thrombocytosis secondary to infections; or hypertension, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>85. A method of treatment or prophylaxis of a respiratory disease condition, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>86. A method of treatment or prophylaxis of cystic fibrosis, bronchial asthma, or an obstructive airway disease, comprising administering to a patient in need of said treatment or prophylaxis a therapeutically-or prophylactically-effective amount of MOP or a salt or solvate thereof.</p><p>WJW/LP6391 262 -45 - 87. A method of treatment or prophylaxis according to any one of claims 68 to 86, wherein the method of treatment or prophylaxis further comprises treatment with one or more of: aspirin, Ticlopidine , Clopidogrel , Abciximab , and Dipyridamole .</p><p>88. A kit comprising: (a) MDP or a salt or solvate thereof, preferably provided in the form of a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the MDP or salt or solvate thereof.</p><p>89. A method of preparing a pharmaceutical composition comprising 5-methyl-6,7-dihydro5I-1cycIopentapyrazin (MDP) or a salt or solvate thereof, comprising admixing MDP or a salt or solvate thereof with a pharmaceutically acceptable carrier, diluent, or excipient.</p><p>90. MDP or a salt or solvate thereof, for use in a method of male contraception.</p><p>91 Use of MDP or a salt or solvate thereof in the manufacture of a medicament for use in a method of male contraception.</p><p>92 A method of male contraception, comprising administering to a male patient in need of said contraception, an effective amount of MDP or a salt or solvate thereof.</p>
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