Subcutaneous administration of p2y12 receptor antagonist

Abstract

To provide a P2Y12 receptor antagonist or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of a disease selected from acute coronary syndrome, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke, and transient ischemic attack.SOLUTION: A P2Y12 receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester, and is administered to a patient via intradermal or subcutaneous administration.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester for use as a medicament by subcutaneous or intradermal administration. ester) (hereinafter also referred to as "Compound 1"), (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol) (hereinafter also referred to as "Compound 2") Hereinafter, also referred to as "Tikagrelor".) and (1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol ((1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol) (hereinafter, also referred to as "Tikagrelor-M"). 12The present invention relates to a receptor antagonist or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] When vascular integrity is compromised, circulating platelets adhere to the damaged vessel wall and aggregate to form a plug that seals the injury site and prevents blood loss. Autopsy studies have shown that rupture of atherosclerotic plaques can lead to loss of control of platelet thrombus formation and occlusion of blood vessels (Davies MJ et al., (1986) Circulation 73:418-427). Inhibition of platelet aggregation has been recognized as an effective strategy for the prevention of atherothrombotic events in patients with atherosclerotic disease of the coronary, peripheral and cerebrovascular circulation (Davi G et al., (2007) N Engl J Med 357:2482-2494).

[0003] ADP receptors P2Y1 and P2Y 12 P2Y plays an important role in platelet activation and aggregation (Andre P et al. (2003) J Clin Invest 112:398-406). 12 Receptor inhibition has been shown to be a valid concept for preventing major adverse cardiovascular events in patients with acute coronary syndrome (ACS) by the thienopyridines ticlopidine, clopidogrel and prasugrel (Franchi F et al. (2015) Nat Rev Cardiol 12:30-47). These drugs, following metabolic activation, inhibit P2Y 12 It irreversibly blocks receptor and platelet function (Antman EM et al., (2004) Circulation 110:588-636; Anderson JL et al., (2011) Circulation 123:e426-579), leading to increased efficacy and increased bleeding (Wiviot t SD et al. (2007) Circulation 116:2923-2932). P2Y 12In studies with knockout mice, clopidogrel and prasugrel were shown to cause more blood loss after tail amputation compared to vehicle, indicating that increased blood loss may be due to off-target effects of thienopyridines (Andre P et al., (2011) J Pharmacol Exp Ther 338:22-30).

[0004] Direct acting, reversible binding P2Y 12 Preclinical studies with the antagonist ticagrelor have demonstrated a wider therapeutic window than clopidogrel in rat and dog thrombosis models (van Giezen JJ et al., (2009) Thromb Res 124:565-571; Becker RC et al., (2010) Thromb Haemost 103:535-544). This difference is due to the fact that ticagrelor inhibits the P2Y 12 It has been argued that this could be explained by reversible binding to ticagrelor. Ticagrelor inhibits ADP-induced platelet aggregation in patients to a greater extent than clopidogrel (Husted S et al., (2006) Eur Heart J 27:1038-1047; Cannon CP et al., (2010) Lancet 375:283-293), and in a pivotal phase 3 study (PLATO) for patients with post acute coronary syndrome, ticagrelor showed superior efficacy to clopidogrel, with no significant difference in risk for major bleeding events. However, a significant increase in fatal intracranial bleeding and major or minor bleeding based on study criteria was reported for ticagrelor (Wallentin L et al., (2009) N Engl J Med 361:1045-1057).

[0005] Several studies have confirmed the effectiveness of early administration of platelet function inhibitors, such as glycoprotein IIb / IIIa inhibitors, to patients with ST-segment elevation myocardial infarction (STEMI), especially shortly after the onset of symptoms (Van't Hof AW et al., (2008) Lancet 372:537-546; Herrmann HC et al., (2009) JACC Cardiovasc Interv 2:917-924; ten Berg JM et al., (2010) J Am Coll Cardiol 55:2446-2455). Furthermore, various studies and meta-analyses have suggested that pretreating patients with STEMI with clopidogrel can reduce the rate of ischemic events without causing excessive bleeding (Sabatine MS et al., (2005) JAMA 294:1224-1232; Bellemain-Appaix A et al., (2012) JAMA 308:2507-2516; Zeymer U et al., (2012) Clin Res Cardiol 101:305-312). However, the efficacy of clopidogrel is limited by its slow onset of action and variable response (Oliphant CS et al., (2016) J Pharm Pract 29:26-34). Oral P2Y 12The receptor antagonists ticagrelor and prasugrel have been reported to inhibit platelet function for less than one hour (Storey RF et al., (2010) J Am Coll Cardiol 56:1456-1462; Wiviott SD et al., (2007) Circulation 116:2923-2932). However, contrary to this, some studies have suggested that it takes several hours for prasugrel or ticagrelor to fully exert their effects on platelet function in patients with STEMI (Alexopoulos D et al. (2012) Circ Cardiovasc Interv 5:797-804; Valgimigli M et al. (2012) JACC Cardiovasc Interv 5:268-277; Parodi G et al. (2013) J Am Coll Cardiol 61:1601-1606; Montalescot G et al. (2014) N Engl J Med 371:2339). Indeed, in the ATLANTIC clinical trial (Montalescot G et al. (2013) N Engl J Med 369:999-1010), oral ticagrelor was shown to be effective in patients with ongoing STEMI. We found that there were no significant differences in two coprimary endpoints between the groups receiving early prehospital treatment with a catheter (in the ambulance) and those receiving treatment later in the hospital (in the catheter laboratory). The two coprimary endpoints were (i) the proportion of patients who did not have a resolution of at least 70% of ST-segment elevation before percutaneous coronary intervention (PCI) and (ii) the proportion of patients with infarct-related vascular obstruction on initial angiography. In addition to the extremely short time to PCI in this study, Montalescot et al. noted that "another potential limitation is the efficacy of orally administered P2Y 12"This is associated with a delay in the absorption of the P2Y receptor antagonist," and "in half of the study population, the onset of action may have been further delayed by the coadministration of morphine." Therefore, there is a strong need for therapeutic options that provide rapid and high inhibition of platelet aggregation, for example in patients with acute coronary syndromes, and that allow inhibition of platelet aggregation to be achieved as early as possible after the onset of cardiac symptoms. Surprisingly, P2Y 12 Subcutaneous administration of the receptor antagonists (particularly Compound 1) to patients results in, among other things, an increase in the P2Y 12 It has been found that administering the P2Y receptor antagonist by the patient or a relative prior to the arrival of emergency medical providers will accomplish this need. 12 Receptor antagonists include most of the known and approved P2Y 12 In contrast to receptor antagonists, they must possess a specific combination of physicochemical and pharmacological properties, such as Compound 1. Compound 1 is a directly acting, reversible P2Y 12It is an antagonist (Caroff E et al., (2015) J Med Chem 58:9133-9153) and therefore does not require metabolic activation, which usually slows the onset of action and is highly dependent on the pharmacodynamics of the individual patient's metabolism. In phase 1 clinical trials, no bleeding events were observed after oral administration of compound 1 or its prodrug (Baldoni D et al., (2014) Clin Drug Investig 34(11):807-818); In the FeCl3 rat thrombosis model, compound 1 was shown to have a significantly wider therapeutic window than ticagrelor (Rey M et al., (2017) Pharma Res Per 5(5):e00338(doi:10.1002 / prp2.338)). Compound 1 has excellent efficacy and is highly soluble in aqueous media (75 mg / mL, pH=8.4, when reconstituted with water as lyophilized disodium salt of Compound 1), making it compatible with the limits of subcutaneous volume for conventional bolus-injection. The results of a Phase 1 clinical trial in healthy volunteers showed that the pharmacokinetic and pharmacodynamic properties of Compound 1 are suitable for subcutaneous administration. For example, at doses of Compound 1 8 mg and above, the %IPA peak (inhibition of platelet aggregation) exceeded 85% within 15 min. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 shows the time dependence of AF488-fibrinogen binding intensity after subcutaneous administration of the hydrochloride salt of Compound 1 (0.2 mg / kg) to male Balb / c mice. [Diagram 2] FIG. 2 shows the time dependence of AF488-fibrinogen binding intensity after subcutaneous administration of ticagrelor (1.0 mg / kg) to male Balb / c mice. [Diagram 3] FIG. 3 shows the time dependence of AF488-fibrinogen binding intensity after subcutaneous administration of Elinogrel (30 mg / kg) to male Balb / c mice. [Figure 4]FIG. 4 shows the time dependence of AF488-fibrinogen binding intensity following subcutaneous administration of Cangrelor (0.2 mg / kg) to male Balb / c mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Detailed Description of the Invention Various aspects of the invention are described below: 1) A first aspect of the present invention relates to a P2Y agonist for use in the prevention or treatment (preferably the treatment) of a disease. 12 a P2Y receptor antagonist or a pharma- ceutical acceptable salt thereof, wherein the disease is selected from acute arterial thromboses and acute venous thromboses; 12 The receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester (compound 1), (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (tikagrelor) and (1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol (tikagrelor-M); the above P2Y 12 The P2Y receptor antagonist is administered and / or is intended to be administered to a patient by intradermal or subcutaneous administration. 12 The present invention relates to a receptor antagonist or a pharma- ceutically acceptable salt thereof.

[0008] 2) A further embodiment of the invention relates to a P2Y 2+ receptor antagonist for use according to embodiment 1), in which the disease is selected from acute arterial thrombosis. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0009] 3) A further embodiment of the present invention relates to a P2Y agonist for use according to embodiment 1), wherein said disease is selected from acute coronary syndromes, myocardial infarction, peripheral ischaemia, amaurosis, sudden cardiac death, ischaemic stroke and transient ischaemic attack. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0010] 4) A further embodiment of the present invention relates to a P2Y agonist for use according to embodiment 1), in which the disease is selected from acute coronary syndromes, peripheral ischemia, amaurosis, ischemic stroke and transient ischemic attacks. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0011] 5) A further embodiment of the invention relates to a P2Y agonist for use according to embodiment 1), in which the disease is an acute coronary syndrome. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0012] 6) A further embodiment of the present invention relates to a P2Y agonist for use according to embodiment 1), in which the disease is myocardial infarction. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0013] 7) A further embodiment of the present invention relates to a P2Y agonist for use according to embodiment 1), in which the disease is peripheral ischemia. 12The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0014] 8) A further embodiment of the invention relates to a P2Y 2+ receptor antagonist for use according to embodiment 1), in which the disease is amaurosis. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0015] 9) A further embodiment of the invention relates to a P2Y agonist for use according to embodiment 1), in which the disease is sudden cardiac death. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0016] 10) A further embodiment of the invention relates to a P2Y agonist for use according to embodiment 1), in which the disease is selected from ischemic stroke and transient ischemic attack. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0017] 11) A further aspect of the present invention is the P2Y 12 P2Y receptor antagonist for use according to any one of the embodiments 1) to 10), in which the receptor antagonist is administered and / or is intended to be administered before hospitalization. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0018] 12) A further aspect of the present invention is the P2Y 12 P2Y receptor antagonists for use according to embodiment 11), in which the receptor antagonist is administered and / or is intended to be administered by self-administration by the patient. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0019] 13) A further aspect of the present invention is the P2Y 12 P2Y receptor antagonists for use according to embodiment 11), in which the receptor antagonist is administered and / or is intended to be administered by a medical professional.12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0020] 14) A further aspect of the invention is the use of P2Y 200 mg / kg / day for use in emergency care for suspected acute coronary syndrome (ACS), by self-administration by patients prior to hospital admission. 12 The P2Y receptor antagonist or a pharma- ceutically acceptable salt thereof 12 The receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester (compound 1), (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (tikagrelor) and (1S,2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol (tikagrelor-M); the above P2Y 12 The P2Y receptor antagonist is administered and / or is intended to be administered to a patient by intradermal or subcutaneous administration. 12 The present invention relates to a receptor antagonist or a pharma- ceutically acceptable salt thereof.

[0021] 15) A further aspect of the present invention is the P2Y 12 P2Y receptor antagonist for use according to any one of the embodiments 1) to 14), in which the receptor antagonist is administered and / or is intended to be administered to the patient by subcutaneous administration. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0022] 16) A further aspect of the present invention is the P2Y12 A P2Y receptor antagonist for use according to any one of the embodiments 1) to 15), in which the receptor antagonist is administered and / or is intended to be administered by use of an autoinjector device. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0023] 17) A further aspect of the present invention is the P2Y 12 A P2Y receptor antagonist for use according to any one of the embodiments 1) to 11), in which the receptor antagonist is administered and / or is intended to be administered to a patient by subcutaneous administration and by self-administration by the patient by use of an autoinjector device. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0024] 18) A further embodiment of the present invention relates to a P2Y 2+ -agonist for use according to any one of embodiments 1) to 17), in which the patient to be treated is a patient with atherosclerotic disease. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0025] 19) A further embodiment of the present invention relates to a method for treating a patient with P2Y 2+ in a patient with known coronary artery disease who has previously experienced symptoms of an acute coronary syndrome. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0026] 20) A further aspect of the present invention is the P2Y 12 A P2Y receptor antagonist for use according to any one of aspects 1) to 19), wherein the receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester (compound 1) or a pharma- ceutically acceptable salt thereof. 12 The present invention relates to a receptor antagonist or a pharma- ceutically acceptable salt thereof.

[0027] 21) A further aspect of the present invention is the P2Y 12 The receptor antagonist is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor) or a pharma- ceutical acceptable salt thereof or (1S, P2Y for use according to any one of the aspects 1) to 19), which is 2R,3S,4R)-4-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol (Ticagrelor-M) or a pharma- ceutical acceptable salt thereof. 12 The present invention relates to a P2Y receptor antagonist or a pharma- ceutically acceptable salt thereof. 12 The receptor antagonist is (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor) or a pharma- ceutical acceptable salt thereof.

[0028] 22) A further aspect of the invention relates to the P2Y 12 The P2Y receptor antagonist for use according to any one of the embodiments 1) to 21), wherein the amount of the receptor antagonist (particularly compound 1) is between 1 mg and 75 mg per administration. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0029] The P2Y 12The lower limits of the amount of the receptor antagonist (particularly compound 1) are 1 mg, 5 mg, 10 mg, and 20 mg. The upper limits are 35 mg, 40 mg, 50 mg, and 75 mg. It is understood that each lower limit may be combined with each upper limit. Thus, all combinations are specifically disclosed herein. 12 The preferred amount of the receptor antagonist (particularly compound 1) is 10 mg to 40 mg per administration.

[0030] In another preferred embodiment, the P2Y 12 The amount of the receptor antagonist (particularly compound 1) is 5 mg to 20 mg per administration.

[0031] 23) A further aspect of the present invention is the P2Y 12 A P2Y receptor antagonist (particularly compound 1), optionally together with one or more therapeutically inactive excipients, is dissolved in a pharma- ceutically acceptable liquid to give a solution, and the amount of said solution administered and / or intended to be administered is between 0.1 mL and 3.0 mL for each administration, for use according to any one of the embodiments 1) to 22). 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0032] The lower limit of the amount of the solution is 0.1mL, 0.2mL, 0.5mL and 0.8mL. The upper limit is 1.0mL, 1.4mL, 2.0mL and 3.0mL. Each lower limit may be combined with each upper limit. Thus, all combinations are specifically disclosed herein. The preferred amount of the solution is 0.5mL to 1.4mL.

[0033] 24) A further embodiment of the invention relates to a P2Y solution for use according to embodiment 23), in which the solution is administered and / or is intended to be administered within an administration time of between 1 second and 90 seconds. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0034] The lower limits of the administration time are 1 second, 3 seconds, 5 seconds, and 8 seconds. The upper limits are 15 seconds, 30 seconds, 60 seconds, and 90 seconds. Each lower limit can be combined with each upper limit. Therefore, all combinations are specifically disclosed in this specification. The preferred administration time is 5 seconds to 30 seconds.

[0035] 25) A further aspect of the present invention is the P2Y 12 P2Y receptor antagonist for use according to any one of the embodiments 1) to 24), in which the compound 1 is administered and / or is intended to be administered by bolus injection. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0036] 26) A further aspect of the present invention is the P2Y 12 A P2Y receptor antagonist for use according to any one of the embodiments 1) to 24), in which the receptor antagonist (particularly compound 1) is administered and / or is intended to be administered in a first subcutaneous injection that is a bolus injection and at least one further subcutaneous injection. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0037] 27) A further embodiment of the invention relates to a P2Y 2000 formulation for use according to embodiment 26), in which the further subcutaneous injection is a continuous injection lasting for a maximum of 5 hours. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0038] The continuous injection may last for up to 5 hours, up to 4 hours, up to 3 hours, up to 2 hours, up to 1 hour, up to 30 minutes or up to 15 minutes. Furthermore, the continuous injection is administered and / or is intended to be administered at a lower flow rate than the bolus injection. The flow rate of the continuous injection may be in the range of 0.01% to 10% of the flow rate of the bolus injection. The lower limits of the flow rate of the continuous injection are 0.01%, 0.05%, 0.1% and 0.5% of the flow rate of the bolus injection. The upper limits are 0.5%, 1%, 2%, 5% and 10%. Each lower limit may be combined with each upper limit. Thus, all combinations are specifically disclosed herein. The continuous injection may begin immediately after the end of the bolus injection or may begin up to 2 hours, up to 1 hour, ... It may start up to 30 minutes or up to 15 minutes late.

[0039] 28) A further embodiment of the invention relates to a P2Y 2+ agonist for use according to embodiment 26), in which the further subcutaneous injections are 1 to 10 further bolus injections. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0040] The lower limit of the number of further bolus injections is 1 and 2. The upper limit is 3, 5, 7 and 10. Each lower limit may be combined with each upper limit. Thus, all combinations are specifically disclosed herein. The time between two successive bolus injections may be in the range of 5 minutes to 120 minutes. The lower limit of the time between two successive bolus injections is 5 minutes, 10 minutes, 15 minutes and 30 minutes. The upper limit is 30 minutes, 60 minutes, 90 minutes and 120 minutes. Each lower limit may be combined with each upper limit. Thus, all combinations are specifically disclosed herein. The volume administered and / or intended to be administered in the further bolus injection is in the range of 5% to 100% of the volume of the first bolus injection. The lower limit of the volume of the further bolus injection is 5%, 10%, 20% and 30% of the volume of the first bolus injection. The upper limits are 30%, 50%, 70% and 100%. It is understood that each lower limit may be combined with each upper limit, and thus all combinations are specifically disclosed herein.

[0041] 29) A further aspect of the present invention relates to the P2Y 12 A method for use according to any one of aspects 1) to 28), in which inhibition of platelet aggregation is achieved by at least 75% in at least 80% of patients within 30 minutes after the start of administration of the P2Y receptor antagonist. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0042] 30) A further embodiment of the invention relates to a P2Y 2+ inhibitor for use according to embodiment 29), in which the inhibition of platelet aggregation reaches at least 80%. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0043] 31) A further embodiment of the invention relates to a P2Y 2+ inhibitor for use according to embodiment 29), in which the inhibition of platelet aggregation reaches at least 85%. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0044] 32) A further aspect of the present invention is the P2Y 12 A method for use according to any one of aspects 29) to 31), in which platelet aggregation is inhibited in at least 80% of patients within 25 minutes after the start of administration of the P2Y receptor antagonist. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0045] 33) A further aspect of the present invention is the P2Y 12 A method for use according to any one of aspects 29) to 31), in which platelet aggregation is inhibited in at least 80% of patients within 20 minutes after the start of administration of the P2Y receptor antagonist. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0046] 34) A further embodiment of the invention relates to a P2Y 2+ -agonist for use according to any one of embodiments 29) to 33), in which platelet aggregation is inhibited in at least 85% of patients. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0047] 35) A further embodiment of the invention relates to a P2Y 2+ -agonist for use according to any one of embodiments 29) to 33), in which platelet aggregation is inhibited in at least 90% of patients. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0048] 36) A further embodiment of the invention relates to a method for treating pulmonary hypertension, comprising administering to said patient a therapeutically effective amount of pulmonary hypertension, the method ... 12 The P2Y receptor antagonist for use according to any one of the embodiments 1) to 35) above, wherein the P2Y receptor antagonist is administered for at least 3 hours after the start of administration. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0049] 37) A further embodiment of the invention relates to a method for treating pulmonary hypertension, comprising administering to said patient a therapeutically effective amount of pulmonary hypertension, the method ... 12 The method according to any one of the embodiments 1) to 35), wherein the duration of inhibition is 3 to 12 hours, beginning after administration of the P2Y receptor antagonist. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0050] The lower limit of the inhibition time is 3 hours and 4 hours. The upper limit is 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours and 12 hours. Each lower limit can be combined with each upper limit. Therefore, all combinations are specifically disclosed in this specification. The preferred inhibition time is 4 hours to 8 hours.

[0051] 38) A further aspect of the present invention is the P2Y 12 A P2Y receptor antagonist for use according to any one of embodiments 1) to 37), wherein the receptor antagonist is administered to the patient by subcutaneous administration. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0052] 39) A further aspect of the present invention relates to the P2Y 12 P2Y receptor antagonist for use according to any one of embodiments 1) to 37), in which the receptor antagonist is intended to be administered to the patient by subcutaneous administration. 12 The present invention relates to a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof.

[0053] 40) A further aspect of the present invention relates to a P2Y compound selected from compound 1, ticagrelor and ticagrelor-M. 12The present invention relates to a pharmaceutical composition for use according to any one of the aspects 1) to 37) having as active ingredient a receptor antagonist (in particular compound 1) or a pharma- ceutically acceptable salt thereof, which is administered and / or is intended to be administered to a patient by subcutaneous administration, and which further comprises at least one therapeutically inactive excipient.

[0054] The preparation of a pharmaceutical composition for subcutaneous administration of compound 1 (or ticagrelor or ticagrelor-M) can be carried out by methods well known to any person skilled in the art (for example, as described in Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]. ), Compound 1 (or ticagrelor or ticagrelor-M) or a pharma- ceutically acceptable salt thereof can be formulated into a pharmaceutical dosage form together with a suitable non-toxic, inert, pharma- ceutically acceptable solid or liquid carrier material and, if necessary, a conventional pharmaceutical adjuvant / excipient.

[0055] P2Y 12 Whenever a receptor antagonist (compound 1 and / or ticagrelor and / or ticagrelor-M) or a pharma- ceutically acceptable salt thereof is described as being useful for the prevention or treatment (particularly the treatment) of a disease, the P2Y 12 It should be understood that the receptor antagonist (compound 1 and / or ticagrelor and / or ticagrelor-M) or a pharma- ceutically acceptable salt thereof is also useful for the manufacture of a medicament for the prevention or treatment (particularly treatment) of the disease. Thus, the present invention is particularly directed to the following further The present invention includes embodiments comprising: 41) A further aspect of the invention relates to a P2Y compound selected from compound 1, ticagrelor and ticagrelor-M for the manufacture of a medicament for use according to any one of aspects 1) to 39). 12The present invention relates to the use of a receptor antagonist or a pharma- ceutically acceptable salt thereof.

[0056] 42) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for use according to any one of aspects 1) to 20) or 22) to 39).

[0057] 43) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, said disease being selected from acute arterial thrombosis and acute venous thrombosis, and said medicament being administered and / or intended to be administered to a patient by subcutaneous administration.

[0058] 44) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, wherein said disease is selected from acute arterial thrombosis, and said medicament is administered and / or is intended to be administered to a patient by subcutaneous administration.

[0059] 45) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, said disease being selected from acute coronary syndrome, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke and transient ischemic attack, and said medicament is administered and / or is intended to be administered to a patient by subcutaneous administration.

[0060] 46) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, said disease being selected from acute coronary syndromes, peripheral ischemia, amaurosis, ischemic stroke and transient ischemic attack, and said medicament is administered and / or is intended to be administered to a patient by subcutaneous administration.

[0061] 47) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of acute coronary syndromes, said medicament being administered and / or intended to be administered to a patient by subcutaneous administration.

[0062] 48) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of myocardial infarction, said medicament being administered and / or intended to be administered to a patient by subcutaneous administration.

[0063] 49) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of peripheral ischemia, said medicament being administered and / or intended to be administered to a patient by subcutaneous administration.

[0064] 50) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of amaurosis, said medicament being administered and / or intended to be administered to a patient by subcutaneous administration.

[0065] 51) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of sudden cardiac death, said medicament being administered and / or intended to be administered to a patient by subcutaneous administration.

[0066] 52) A further aspect of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, wherein said disease is selected from ischemic stroke and transient ischemic attack, and wherein said medicament is administered and / or is intended to be administered to a patient by subcutaneous administration.

[0067] 53) A further embodiment of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof according to any one of embodiments 41) to 52), in which compound 1 or a pharma- ceutically acceptable salt thereof is administered to a patient by subcutaneous administration.

[0068] 54) A further embodiment of the invention relates to the use of compound 1 or a pharma- ceutically acceptable salt thereof according to any one of embodiments 41) to 52), in which compound 1 or a pharma- ceutically acceptable salt thereof is intended to be administered to a patient by subcutaneous administration.

[0069] 55) A further aspect of the present invention relates to a P2Y agonist selected from compound 1, ticagrelor and ticagrelor-M for the manufacture of a medicament for use by self-administration by a patient before admission to a hospital in emergency treatment of suspected acute coronary syndrome (ACS). 12 Use of a P2Y receptor antagonist (preferably compound 1) or a pharma- ceutically acceptable salt thereof, comprising: 12 The use relates to the receptor antagonist being administered to the patient by subcutaneous administration.

[0070] 56) A further aspect of the present invention relates to a P2Y agonist selected from compound 1, ticagrelor and ticagrelor-M for the manufacture of a medicament for use by self-administration by a patient before admission to a hospital in emergency treatment of suspected acute coronary syndrome (ACS). 12 Use of a P2Y receptor antagonist (preferably compound 1) or a pharma- ceutically acceptable salt thereof, comprising: 12 The use relates to a method for treating a patient's condition in which the receptor antagonist is intended to be administered to the patient by subcutaneous administration.

[0071] Thus, based on the dependencies of the various embodiments disclosed in the above sections, the following embodiments, among others, are possible, contemplated, and specifically disclosed herein as individual aspects:

[0072] 1、2+1、3+1、4+1、5+1、6+1、7+1、8+1、9+1、10+1、11+1、11+3+1、11+5+1、12+11+1、12+11+3+1、12+11+5+1、13+11+1、13+11+3+1、13+11+5+1、14、15+1、15+3+1、15+5+1、15+11+1、15+11+3+1、15+11+5+1、15+12+11+1、15+12+11+3+1、15+12+11+5+1、15+14、16+1、16+3+1、16+5+1、16+11+1、16+11+3+1、16+11+5+1、16+12+11+1、16+12+11+3+1、16+12+11+5+1、16+14、16+15+1、16+15+3+1、16+15+5+1、16+15+11+1、16+15+11+3+1、16+15+11+5+1、16+15+12+11+1、16+15+12+11+3+1、16+15+12+11+5+1、16+15+14、17+1、17+3+1、17+5+1、17+11+1、17+11+3+1、17+11+5+1、18+1、18+3+1、18+5+1、18+11+1、18+11+3+1、18+11+5+1、18+12+11+1、18+12+11+3+1、18+12+11+5+1、18+14、18+15+1、18+15+3+1、18+15+5+1、18+15+11+1、18+15+11+3+1、18+15+11+5+1、18+15+12+11+1、18+15+12+11+3+1、18+15+12+11+5+1、18+15+14、19+1、19+3+1、19+5+1、19+11+1、19+11+3+1、19+11+5+1、19+12+11+1、19+12+11+3+1、19+12+11+5+1、19+14、19+15+1、19+15+3+1、19+15+5+1、19+15+11+1、19+15+11+3+1、19+15+11+5+1、19+15+12+1 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39+22+20+19+16+15+11+3+1, 39+22+20+1 9+16+15+11+5+1, 39+22+20+19+16+15+12+11+1, 39+22+20+19+16+15+12+11+3+1, 39+22+20+19+16+15+12+11+5+1, 39+22+20+19+16+15+14, 40, 41.

[0073] In the above list, the numbers refer to the embodiments according to the above numbers, and "+" indicates a dependency from another embodiment. The various embodiments are individually separated by commas. In other words, for example, "11+3+1" means embodiment 11) which is dependent on embodiment 3) which is dependent on embodiment 1), i.e. embodiment "11+3+1" corresponds to embodiment 1) further limited by the features of embodiments 3) and 11).

[0074] P2Y agonists described as being useful in the treatment or prevention of a disease according to any one of aspects 1) to 38). 12 It is understood that the receptor antagonists, particularly compound 1, are also useful in methods for the treatment and / or prevention of the above-mentioned diseases, which methods comprise administering a pharma- ceutical effective amount of P2Y 12 The method comprises subcutaneously administering the receptor antagonist, or a pharma- ceutically acceptable salt thereof, to a human subject in need thereof.

[0075] The present invention relates to a method for emergency treatment of acute coronary syndrome (ACS) by self-administration by a patient prior to hospitalization of a pharmacologic effective amount of compound 1, ticagrelor or ticagrelor-M (particularly compound 1) or a pharmacologic acceptable salt thereof, comprising a step of subcutaneous administration to said patient in need thereof.

[0076] The present invention also relates to a method for treating a disease responsive to inhibition of platelet activation and / or platelet aggregation, comprising subcutaneously administering a pharma- tically effective amount of compound 1, ticagrelor or ticagrelor-M (particularly compound 1) or a pharma- tically acceptable salt thereof to a human subject in need thereof.

[0077] The present invention also relates to a method for treating P2Y deficiency, comprising subcutaneously administering a pharma- tically effective amount of compound 1, ticagrelor or ticagrelor-M (particularly compound 1) or a pharma- tically acceptable salt thereof to a human subject in need thereof. 12 Methods for treating diseases responsive to receptor antagonists are also disclosed.

[0078] P2Y 12 The pharmaceutical composition containing the receptor antagonist (compound 1, ticagrelor or ticagrelor-M) or a pharma- ceutical acceptable salt thereof may be in the form of an aqueous or oily solution, a suspension or an emulsion (preferably an aqueous solution), and may optionally further contain one or more excipients. The excipient may be, for example, a pharma- ceutical acceptable acid or base (to adjust the pH value of the pharmaceutical composition) or a pharma- ceutical acceptable salt such as sodium chloride (to adjust the tonicity of the pharmaceutical composition).

[0079] The pharmaceutical composition comprises a P2Y 12 It may be in the form of a ready-to-use solution, suspension or emulsion containing the receptor antagonist, or in the form of an injectable powder. The injectable powders must be reconstituted in a pharma- ceutically acceptable liquid prior to subcutaneous administration to give an aqueous or oily solution, suspension, or emulsion. The solids may be in crystalline or amorphous form, or any mixture thereof.

[0080] General terms and expressions used above and / or below in this specification preferably have the following meanings in the present disclosure:

[0081] The term "acute coronary syndrome" (ACS) refers to a syndrome resulting from a sudden reduction or blockage of blood flow in some coronary arteries. Acute coronary syndromes include ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) or unstable angina. P2Y is disclosed as being useful for the prevention or treatment of ACS. 12 It is understood that the receptor antagonists will likewise be useful in the prevention or treatment of STEMI, NSTEMI and / or unstable angina.

[0082] The term "emergency treatment for suspected acute coronary syndrome" refers to the treatment of a patient who exhibits symptoms of ACS such as sudden onset chest pain, chest discomfort (intermittent or not), persistent retrosternal pressure lasting at least 10 minutes or heaviness radiating to the left arm, neck, back or jaw, nausea / vomiting, shortness of breath, fatigue, palpitations, lightheadedness or fainting (particularly telltale symptoms of ACS such as sudden onset chest pain, chest discomfort (intermittent or not), persistent retrosternal pressure lasting at least 10 minutes or heaviness radiating to the left arm, neck, back or jaw); and who should and / or require treatment before an electrocardiogram, chest x-ray and / or blood tests can be performed. In one embodiment, the patient is one who is known to be at high risk of suffering from ACS before the onset of the symptoms of ACS (particularly telltale symptoms), e.g. a patient with known coronary artery disease who has previously experienced symptoms of acute coronary syndrome. In a further embodiment, the treatment is self-administered by the patient prior to hospital admission; preferably, said patient is trained by a medical professional prior to such self-administration to better recognize the symptoms of ACS.

[0083] The term "coronary artery disease" (CAD) refers to a group of diseases that includes myocardial infarction, unstable angina, stable angina, and sudden cardiac death.

[0084] The term "patients with a prior acute coronary syndrome episode" refers to patients who have had a myocardial infarction (STEMI or NSTEMI) or unstable angina.

[0085] The term "subcutaneous administration" refers to administration of a pharmaceutical composition into subcutaneous tissue by injection. Typical administration sites are the outer upper arm area, abdomen (avoiding the area close to the navel), anterior thighs, chest, neck, upper back and upper buttocks areas; preferably the abdomen and anterior thighs. Subcutaneous administration can be performed using any type of suitable injection device, such as, for example, a syringe or an autoinjector device.

[0086] The term "intradermal administration" refers to administration of a pharmaceutical composition into the dermis by injection. Typical administration sites are the inner surface of the forearm and the upper back below the shoulder blade.

[0087] The term "bolus injection" when used in reference to subcutaneous administration / injection refers to the administration of a discrete amount of P2Y 12 This means that the receptor antagonist is injected within a relatively short period of time (usually between 1 and 90 seconds).

[0088] The term "patient" refers to the P2Y 12 Receptor antagonists can be used to prevent or treat In a preferred embodiment, the patient is a mammal, particularly a human, having a disease or disorder that can be treated with P2Y 12 A human having a disease or disorder that can be prevented or treated (particularly treated) with a receptor antagonist, the human being being known in advance to have a statistically high risk of developing the disease or disorder.

[0089] The term "self-administration by the patient" means administration of a pharmaceutical composition to a patient by the patient himself or herself or by an acquaintance such as a relative, friend or neighbor who has minimal medical training, particularly by the patient himself.

[0090] The term "administration by a medical professional" means administration of a pharmaceutical composition to a patient by a person professionally trained to do so, such as a nurse or surgeon. Any such administration is preferably performed prior to admission of the patient to a hospital (e.g. in an ambulance or any other location before the patient arrives at the hospital).

[0091] The term "autoinjector device" refers to a medical device in which a pharmaceutical composition is automatically injected after pressing a trigger or activator, etc. The autoinjector device may be in the form of, for example, a pen device, a patch device, a patch pump.

[0092] P2Y 12 Any reference to a P2Y receptor antagonist is intended to include such 12 Pharmaceutically acceptable salts of the receptor antagonists are also referred to.

[0093] The term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects. Such salts include inorganic or organic acid and / or base addition salts, depending on the presence of basic and / or acidic groups in the subject compound. For reference, see, for example, "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and "Pharmaceutical Salts and Co-crystals", Johan Wouters and Luc See Quere (Eds.), RSC Publishing, 2012.

[0094] A preferred pharma- ceutically acceptable salt of Compound 1 is the hydrochloride salt of Compound 1. Another preferred pharma- ceutically acceptable salt of Compound 1 is the 2-amino-2-(hydroxymethyl)-1,3-propanediol or sodium salt of Compound 1.

[0095] The term "pharmaceutical acceptable liquid" refers to the P2Y 12 It means a liquid that, when mixed with a receptor antagonist (particularly compound 1) or a pharma- ceutically acceptable salt thereof, optionally with one or more therapeutically inactive excipients, gives an injectable solution, suspension or emulsion (particularly a solution) and exhibits minimal undesirable toxic effects. A preferred example of a pharma- ceutically acceptable liquid is water, particularly water for injection, especially distilled water for injection.

[0096] When not used in reference to temperature, the term "about" preceding a numerical value "X" in this application denotes between X-10%X and X+10%X, preferably between X-5%X and X+5%X. In the specific case of temperatures, the term "about" preceding a temperature "Y" in this application denotes a range spanning Y-10°C to Y+10°C, preferably a range spanning Y-5°C to Y+5°C.

[0097] Whenever the word "between" is used to describe a numerical range, it is understood that the endpoints of the stated range are expressly included in the range. For example, if a volume range is described as being between 0.1 mL and 3.0 mL, the endpoints 0.1 mL and 3.0 mL are included in the range. Alternatively, if the variable is defined to be an integer between 1 and 4, it means that the variable is the integer 1, 2, 3 or 4.

[0098] Experimental section Abbreviation: The following abbreviations are used throughout the specification and examples: ACS acute coronary syndrome aq. aqueous solution ET external temperature FACS Fluorescence-activated cell sorting h time IPC In-Process Control IT internal temperature min PBS Phosphate Buffered Saline PCI Percutaneous Coronary Intervention PEG400 Poly(ethylene glycol) RT room temperature sat. saturation sec second vol. Solvent (L) per kg of starting material

[0099] Preparation of Compound 1 and its HCl salt: Compound 1 may be prepared according to the procedures disclosed in WO2009 / 069100 (Example 2) or Caroff E et al., J. Med. Chem. (2015), 58, 9133-9153. Alternatively, compound 1 and its HCl salt may be prepared according to the following procedures:

[0100] A 15 L reactor was charged with sodium (S)-6-(3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxylate (584 g, 1.82 mol) and 1-hydroxy-benzotriazole monohydrate (HOBt) (274 g, 1.1 eq.). Water (1305 mL, 2.0 vol.) was added. The pH of the suspension was 5-6. Butyl (R)-4-(2-amino-3-(diethoxyphosphoryl)propanoyl)piperazine-1-carboxylate (665.7 g, 1.0 eq.) was dissolved in tetrahydrofuran (THF) (1960 mL, 3.0 vol.). The solution was added to the reaction at 20-30° C. over a period of 5-10 min. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl) (389 g, 1.2 eq.) dissolved in water (1305 mL, 2.0 vol.) was added to the reaction at 20-30° C. over 15-30 min. The pH of the reaction remained between 6-7. The reaction was stirred at 20-30° C. for 4 h. IPC showed 93% conversion. The reaction was diluted with dichloromethane (DCM) (3265 mL, 5.0 vol.) and ½ saturated aqueous sodium bicarbonate (3265 mL, 5.0 vol.). The layers were separated. The organic layer was washed again with ½ saturated aqueous sodium bicarbonate (3265 mL, 5.0 vol.). The layers were separated. IPC showed that the HOBt was completely removed. The organic layer was washed with 10% citric acid (3265 mL, 5.0 vol.). A total of 3.75 L of solvent was distilled off at a minimum of 800 mbar and ET=75-80° C. during 40 min. The remaining solution was cooled to 20-30° C. Aq. 32% HCl (3 L, 19 eq.) was added at 20-30° C. during 5-10 min. After 4 h of stirring, IPC showed hydrolysis was complete. Water (5.2 L, 8 vol.) was added at 20-30° C. The reaction was diluted with DCM (5.2 L, 8 vol.). The layers were separated. The aqueous layer was extracted twice again with DCM (5.2 L, 8 vol.). All DCM layers were combined and purified by HPLC. Filtered through an olycap 75HD filter. A total of 14 L of solvent was distilled off at atmospheric pressure and ET=75-80° C. for 2 h. Acetone (21.6 L, 33 vol.) was added to the refluxing reaction mixture at ET=70-75° C. To the fine suspension was added water (325 mL, 0.5 vol.) under reflux. The fine pale suspension was stirred under reflux for 1.5 h to give a thick white slurry. The slurry was cooled (gradually) to IT=25° C. for 1 h. The solid product was isolated by filtration. The filter cake was rinsed with acetone (4.5 L, 7 vol.) and dried by passing nitrogen through it to give 750 g (69%) of ((R)-3-(4-(butoxycarbonyl)piperazin-1-yl)-2-(6-((S)-3-methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carboxamido)-3-oxopropyl)phosphonic acid hydrochloride as a white solid. The purity by LC-MS was >99% a / a and the purity by 1H-NMR assay was 98% w / w.

[0101] Formulation of Compound 1 (low dose 1 mg / mL): An aqueous solution of 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris base, 21.6 mL, 1.0 M) was added to 4.80 L of water for injection (WFI) in a glass vessel. 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (6.00 g) and mannitol (210 g) were added successively and the mixture was stirred until completely dissolved. Further Tris base was added to obtain a pH of 7.4 ± 0.1. The solution was diluted with WFI to a final volume of 6.00 L, refilled into glass vials (1.1 mL per vial), dried by lyophilization, and reconstituted with 1.0 mL of WFI prior to administration to provide a solution of Compound 1 for subcutaneous administration.

[0102] Formulation of Compound 1 (higher dose of 20 mg / mL): An aqueous solution of 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris base, 21.6 mL, 1.0 M) was added to 4.80 L of water for injection (WFI) in a glass container. 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride (120 g) and mannitol (120 g) were added successively and the mixture was stirred until completely dissolved. Further Tris base was added to obtain a pH=7.4±0.1. The solution was diluted with WFI to a final volume of 6.00 L, refilled into glass vials (1.1 mL per vial), dried by lyophilization, and reconstituted with 1.0 mL of WFI before administration to obtain a solution of Compound 1 for subcutaneous administration.

[0103] P2Y 12 In vivo measurement of time-dependent platelet inhibition following subcutaneous administration of receptor antagonists: animal: Male Balb / c mice were purchased from Charles River laboratories (Sulzfeld, Germany). All animals were kept under identical conditions according to the guidelines of the Veterinary Office of the Canton of Basel-Landschaft. The animals were kept in a specialized animal housing facility that provided group cages, standardized food / water ad libitum and standardized lighting and environmental conditions. A technical assistant performed at least one observation per day. The animals were given sufficient time to acclimate to the experimental environment. Stress was also reduced by enriching the cage and allowing them to retreat to dark-colored housing (taking advantage of the fact that albino mice are color-blind in the red region of the light spectrum). In the red housing, the animals feel that they are in the dark, but this housing is visible to normal human vision.

[0104] Reagents: The hydrochloride salt of compound 1 was synthesized according to the procedure described above. Ticagrelor was extracted from commercially available tablets (Brilique).

[0105] Fibrinogen Human Plasma Alexa Fluor TM488 conjugate, catalog number F-13191, was purchased from Molecular Probes and handled as described on the supplier's data sheet.

[0106] Preparation of test compounds: Compound 1 hydrochloride (0.04 mg / mL), ticagrelor (0.2 mg / mL), elinogrel (6 mg / mL) or cangrelor (0.04 mg / mL) was dissolved in 25% PEG400 / water.

[0107] Experimental group: Compounds were administered by subcutaneous injection into the lower abdomen: Compound 1 hydrochloride, 0.2 mg / kg (5 mL / kg each) Ticagrelor, 1 mg / kg (5 mL / kg each) Elinogrel, 30 mg / kg (5 mL / kg each) Cangrelor, 0.2 mg / kg (5 mL / kg each) Animal treatment: After an acclimation period of at least 7 days, mice were anesthetized with isoflurane (2-5%). The animals were then placed on a temperature-controlled heating table to maintain body temperature at 36-38°C. A polyurethane catheter (BTPU-027) was inserted into the right jugular vein, and heparin was injected into the vena cava before blood collection. For accurate platelet testing, it is necessary to ensure that blood collection does not cause platelet activation. Therefore, heparin (4000U / kg / 2.5mL) was injected intravenously to prevent blood clotting.

[0108] Experimental procedure: 2 minutes after heparin injection, 60 μL of whole blood was collected via the caval catheter (baseline). After baseline blood collection, test compound was subcutaneously injected into the lower abdomen of the animals. 10, 20, 30, 40 and 60 minutes after subcutaneous injection of test compound, 60 μL of whole blood was collected via the caval catheter for fibrinogen binding test.

[0109] AF488-Fibrinogen Binding Assay: In particular, the study demonstrated the potency of P2Y 12 This test was adapted to reliably examine the effects of antagonists on mouse platelets. The test allows the measurement of ADP-induced AF488-fibrinogen binding to mouse platelets using only 6 μL of whole blood and without a washing step.

[0110] First, blood was incubated with 4 μL of vehicle or 4 μL of compound 1 hydrochloride (to give a final concentration of 2 μM in the diluted blood) for 15 min at RT. In previous experiments, this concentration of compound 1 hydrochloride was determined to 100% inhibit ADP-induced AF488-fibrinogen binding to platelets, indicating a non-specific signal. Next, 10 μL of AF488-fibrinogen was added (to give a final concentration of 0.5 mg / mL) and then incubated for 5 min. Platelets were then incubated with 10 μL of ADP (to give a final concentration of 20 μM) for 5 min to induce AF488-fibrinogen binding. In addition, platelet-specific allophycocyanin (APC) anti-mouse CD61 (integrin beta 3) antibody (clone 2C9.G2) was incubated for 10 min. Platelets were then fixed by adding 34 μL of cold paraformaldehyde solution (to a final concentration of 0.1%) and stored for approximately 20 min at 4° C. Finally, samples were diluted with 1.8 mL of cold PBS and left at 4° C. for at least 2 h (the time required to gently lyse red blood cells) before being measured by flow cytometry.

[0111] Get the data: Flow cytometry was performed using a FACSCanto II instrument (BD Bioscience). Since two different lasers were used, no fluorescence compensation settings were required.

[0112] First, platelets were detected using the platelet-specific fluorescent signal of APC-CD61 (APC settings for peak fluorescence emission at 660 nm). Platelet populations were then gated using forward scatter (FSC) and side scatter (SSC) and their FITC-labeled fibrinogen signals (FITC settings for peak fluorescence emission at 525 nm) were quantified as the mean fluorescence intensity (MFI) of 5000 platelets. For each sample, the MFI of the corresponding non-specific sample was subtracted.

[0113] [Table 1]

[0114] In vivo measurement of time-dependent inhibition of platelet aggregation (IPA) after subcutaneous administration of compound 1 to healthy volunteers: The time- and dose-dependence of plasma concentrations and inhibition of platelet aggregation (IPA) following subcutaneous administration of Compound 1 was investigated in healthy male subjects in a Phase 1 clinical trial.

[0115] Test Plan: In a randomized, double-blind, placebo-controlled study, 48 subjects received single subcutaneous doses ranging from 1 to 32 mg (1 mg, 2 mg, 4 mg, 8 mg, 16 mg, and 32 mg) under fasting conditions. Compound 1 exposure (n=6 for Compound 1 and n=2 for placebo per dose level).

[0116] Subcutaneous formulation of Compound 1: Compound 1 for sc administration was obtained in sealed glass vials of 20 mg strength. The vials contained lyophilized Compound 1, which was reconstituted with 1 mL of water for injection to give a stock solution of 20 mg / mL (see above: Compound 1 Formulation (Higher Dose of 20 mg / mL)). These stock solutions were further diluted with 0.9% sodium chloride to prepare 2, 4, 8, 16 and 20 mg / mL solutions. Injection volumes were 0.5 mL for dose levels 1, 2, 4 and 8 mg. For dose levels 16 and 32 mg, 0.8 mL of the 20 mg / mL solution was injected once or twice.

[0117] The injection solutions were prepared for administration in syringes suitable for sc injection. The solutions were administered by injection into the thigh.

[0118] Assessment of Pharmacokinetic (PK) Parameters: Plasma PK parameters of Compound 1 were derived by non-compartmental analysis of the plasma concentration-time profiles. The following parameters were obtained: Maximum plasma concentration (C max );C max Arrival time to (t max ); the area under the plasma concentration-time curve (AUC) from zero to time t of the last measured concentration above the limit of quantification (AUC 0-t ); and terminal elimination half-life (t 1 / 2 ).

[0119] 1) Blood collection Blood was collected by direct venipuncture or via an iv catheter placed in an antecubital vein in the arm into 4 mL Monovette® or equivalent tubes containing ethylenediaminetetraacetic acid. Immediately after collection of the required amount of blood, the Monovettes® were tilted slowly back and forth (without shaking) to mix the anticoagulant into the solution and immediately chilled on ice. Within 30 minutes of collection, the Monovettes® were centrifuged at approximately 1500 g for 10 minutes at 4°C. Plasma was transferred into one labeled polypropylene tube to avoid carry-over of red blood cells. All samples were stored upright at less than -70°C.

[0120] 2) Bioanalysis Compound 1 was analyzed in plasma using a validated liquid chromatography coupled to tandem mass spectrometry assay. The lower limit of quantification (LLOQ) was 1 ng / mL. Concentrations were calculated from a calibration curve. Quality control (QC) samples were analyzed throughout the study. Their measured concentrations were used to determine the between-run and overall accuracy and precision of the assay.

[0121] 3) Results [Table 2]

[0122] Assessment of Pharmacodynamic (PD) Parameters (Inhibition of Platelet Aggregation): 1) Blood collection PD blood samples were collected by direct venipuncture or via an iv catheter placed in an antecubital vein in the arm using an 18-21 gauge needle. The first 2 mL of blood was discarded, and then blood was gently introduced into two open-ended 3.5 mL collection tubes. The LTA (Light Transmission Platelet Transmittance Assay) test collection tubes contained phenylalanine-proline-arginine-chloromethylketone (PPACK) as the anticoagulant.

[0123] 2) Bioanalysis Adenosine diphosphate (ADP)-induced platelet aggregation was assessed by the LTA test, which measures platelet-induced aggregation as an increase in light transparency (Michelson AD, Methods for the measurement of platelet function (2009) Am J Cardiol 103(3):20A-26A).

[0124] LTA Test: Two 3.5 mL blood samples were centrifuged to prepare platelet-rich plasma (PRP) and platelet-poor plasma (PPP). If necessary, the final platelet count of the PRP was adjusted to 260 x 10 per liter by dilution with PPP from the same donor. 9Platelets were adjusted to 1000 μg / ml. The tests were performed using an 8-channel aggregometer and aggregation was recorded for 6 min after addition of 20 μM ADP as agonist. Results are expressed as the percentage change in light transmission at maximum (peak) platelet aggregation (MPA), calculated with a baseline signal of 0%. Measurements were performed in duplicate.

[0125] 3) Results [Table 3]

[0126] As can be seen in Table 3, at each dose level, peak %IPA was reached within approximately 15-30 minutes after dosing. At doses of 4 mg and above (within 15 minutes for doses of 8 mg and above), peak %IPA exceeded 85%. The length of the PD effect was dose-dependent. Mean %IPA above 85% persisted for approximately 5 h and 12 h after dosing with 16 mg and 32 mg of Compound 1, respectively.

Claims

1. P2Y for use in the prevention or treatment of disease １２ A P2Y receptor antagonist or a pharma- ceutically acceptable salt thereof, wherein the disease is selected from acute arterial thrombosis and acute venous thrombosis; １２ The P2Y receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester; １２ The P2Y receptor antagonist is administered and / or is intended to be administered to a patient by intradermal or subcutaneous administration. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the disease is selected from acute coronary syndrome, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke and transient ischemic attack. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

3. The P2Y １２ 3. A method for treating a patient with a P2Y receptor antagonist for use according to claim 1 or 2, wherein the receptor antagonist is administered and / or is intended to be administered before admission to hospital. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

4. The P2Y １２ 4. A method for treating a P2Y receptor antagonist for use according to claim 3, wherein the receptor antagonist is administered and / or is intended to be administered by self-administration by the patient. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

5. P2Y for self-administration by patients prior to hospital admission in emergency care for suspected acute coronary syndrome １２ A P2Y receptor antagonist or a pharma- ceutically acceptable salt thereof, １２ The P2Y receptor antagonist is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester; １２ The P2Y receptor antagonist is administered and / or is intended to be administered to a patient by intradermal or subcutaneous administration. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

6. The P2Y １２ A method for treating a P2Y receptor antagonist according to any one of claims 1 to 5, wherein the receptor antagonist is administered and / or is intended to be administered to a patient by subcutaneous administration. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

7. A P2Y compound for use according to any one of claims 1 to 6, wherein the amount of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester administered and / or intended to be administered is between 1 mg and 75 mg per each administration. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

8. The P2Y １２ A method for the treatment of a P2Y receptor antagonist according to any one of claims 1 to 7, wherein the receptor antagonist is administered and / or is intended to be administered by bolus injection. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

9. The P2Y １２ A method for the treatment of a patient with a P2Y receptor antagonist comprising administering to said patient a therapeutically effective amount of said P2Y receptor antagonist for use according to any one of claims 1 to 8, in which the inhibition of platelet aggregation reaches at least 75% in at least 80% of patients within 30 minutes after the start of administration of said receptor antagonist. １２ A receptor antagonist or a pharma- ceutically acceptable salt thereof.

10. P2Y １２ 10. A pharmaceutical composition for use according to any one of claims 1 to 9, comprising as active ingredient the receptor antagonist 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester or a pharma- ceutically acceptable salt thereof, which is administered and / or intended to be administered to a patient by subcutaneous administration, and further comprising at least one therapeutically inactive excipient.

11. 2. Use of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, said disease being selected from acute coronary syndrome, myocardial infarction, peripheral ischemia, amaurosis, sudden cardiac death, ischemic stroke and transient ischemic attack, and said medicament is administered and / or is intended to be administered to a patient by subcutaneous administration.

12. P2Y for the manufacture of a medicament for use by self-administration by patients prior to hospitalization in emergency treatment of suspected acute coronary syndrome. １２ 2. Use of the P2Y receptor antagonist 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester or a pharma- ceutical acceptable salt thereof, １２ The use wherein the receptor antagonist is intended to be administered to the patient by subcutaneous administration.

13. 2. A method for emergency treatment of acute coronary syndrome by self-administration by a patient prior to hospital admission of a pharma- ceutical effective amount of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester or a pharma- ceutical acceptable salt thereof, comprising the step of subcutaneous administration to a patient in need thereof.

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