Treatment

Abstract

The present disclosure provides a method for treating or preventing a thrombotic disorder, comprising administering to a subject in need thereof an effective amount of Compound (1), [Formula 1] The disclosure further relates to compositions for use in such methods.

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 150,301, filed February 17, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow to a part of the heart is reduced or stopped, causing damage to the heart muscle. Worldwide, approximately 15.9 million myocardial infarctions occurred in 2015, and more than 3 million people suffered ST-elevation MI (STEMI). Of those who die due to an MI, about half die within an hour of their first symptoms, before they can reach a hospital. There is a direct relationship between the time the heart arteries remain closed and the severity of the heart attack and chances of survival. Therefore, prehospital care is important. In the past 40 years, in-hospital STEMI mortality has dropped dramatically, but prehospital mortality has remained unchanged.

[0003] Oral P2Y12 antagonists are given with aspirin at the first point of medical care (e.g., in the ambulance) but are ineffective because these drugs require several hours to reach maximal efficacy in STEMI.Early intravenous administration of αIIbβ3 (GPIIb / IIIa) antagonists improves clinical outcomes but requires an initial bolus followed by a continuous infusion.

[0004] Because transport to a hospital or other care facility can take more than an hour, there is an urgent need for a fast-acting treatment that can be administered to achieve a high degree of inhibition of platelet function before patients with MI arrive at a care facility. Furthermore, to reduce the risk of bleeding, it would be desirable for the antiplatelet effect of fast-acting treatments to decrease as the effect of commonly co-administered oral P2Y12 antagonists, such as the current standard of care, reaches its maximal effect. Summary of the Invention

[0005] In one embodiment, provided herein is a method for treating or preventing a thrombotic disorder, comprising administering to a subject in need thereof an effective amount of Compound (1), [ka] or a pharmacokinetic or pharmacokinetically acceptable salt thereof, at a dose ranging from 0.01 to 0.3 mg / kg, inclusive. In one embodiment, the thrombotic disorder is ST-elevation myocardial infarction (STEMI). In one embodiment, compound (1) is administered in the form of a solution comprising acetic acid, hydrochloric acid, glycerin, and water. In one embodiment, compound (1) is administered in the form of a lyophilized solid formulation. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 shows inhibition of PAR1 / PAR4-induced platelet aggregation (BASE channel) measured by VerifyNow by Compound (1) (RUC-4) in STEMI patients treated with Compound (I). [Diagram 2] FIG. 1 shows the mean simulated response time relationship to Compound (I) by dose level for a 94.3 kg individual. [Diagram 3] FIG. 1 shows the equivalence of VerifyNow and Light Transmission Aggregometry for measuring Compound (1) (RUC-4). [Figure 4] FIG. 1 is a schematic diagram of platelet aggregation including the relevant receptor-ligand interactions. [Diagram 5] A and B show inhibition of ADP-induced platelet aggregation by compound (1) (RUC-4) as measured by light transmittance aggregometry in healthy subjects (5A) and subjects with aspirin-stabilized coronary artery disease (5B). [Figure 6] FIG. 1 shows the pharmacodynamics of compound (1) (RUC-4) and ticagerol (a P2Y12 inhibitor) and their complementary effects in the treatment of STEMI. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] RUC-4 is an inhibitor of the platelet αIIbβ3 receptor and is described in U.S. Patent No. 9,303,044, which is incorporated herein by reference. In this disclosure, RUC-4 is referred to as compound (1). Mechanistically, RUC-4 inhibits ligand binding to αIIbβ3 by binding to both the αIIb and β3 subunits and displacing Mg2+ metal from the ion-dependent adhesion site required for ligand binding (MIDAS). This locks the β3 subunit of the receptor in its inactive conformation. This may reduce the likelihood of thrombocytopenia, since data suggest that most of the thrombocytopenia caused by current αIIbβ3 antagonists is due to the presence of antibodies against the conformation of the receptor induced by the binding of the drug. Thrombocytopenia is one of the potentially dangerous side effects of all current drugs (~0.5-2%). RUC-4 may also exhibit increased efficacy compared to anticoagulants such as eptifibatide and tirofiban, which induce a high affinity binding conformation that can result in ligand binding and platelet aggregation when drug levels are reduced.

[0008] In one aspect, provided herein is a method for treating or preventing a thrombotic disorder, comprising administering to a subject in need thereof an effective amount of Compound (1), [ka] or a pharma- ceutically acceptable salt thereof at a dose in the range of 0.01 to 0.3 mg / kg, inclusive.

[0009] Thrombotic disorders In some embodiments, the thrombotic disorder is myocardial infarction (MI). In some embodiments, the thrombotic disorder is ST-segment elevation myocardial infarction (STEMI), also referred to as ST-segment elevation myocardial infarction. In some embodiments, the thrombotic disorder is non-ST-segment elevation myocardial infarction (NSTEMI). In some embodiments, the thrombotic disorder is acute coronary syndrome (ACS). In some embodiments, the thrombotic disorder is stroke. In some embodiments, the thrombotic disorder is unstable angina. In some embodiments, the thrombotic disorder is macrovascular or microvascular thrombosis caused by a diverse group of triggering events and affecting one or more organs or implanted or extracorporeal artificial materials (e.g., retina, kidney, heart valve, vascular shunt or fistula, left ventricular assist device, or intravascular coiled wire used to treat aneurysms).

[0010] Dosage In certain embodiments, the dose of Compound (1) or a pharma- ceutically acceptable salt thereof is defined in terms of the amount of Compound (1) in free (i.e., non-salt) form. In certain embodiments, the dose is in the range of 0.01 to 0.3 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.05 to 0.3 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.1 to 0.3 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.15 to 0.3 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.2 to 0.3 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.25 to 0.3 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.01 to 0.2 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.05 to 0.2 mg / kg, inclusive. In certain embodiments, the dose is in the range of 0.1 to 0.2 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.15 to 0.2 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.01 to 0.15 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.05 to 0.15 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.1 to 0.15 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.07 to 0.075 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.08 to 0.085 mg / kg, inclusive. In some embodiments, the dose is in the range of 0.09 to 0.095 mg / kg, inclusive. In some embodiments, the dose is 0.07 mg / kg. In some embodiments, the dose is 0.075 mg / kg. In some embodiments, the dose is 0.08 mg / kg. In some embodiments, the dose is 0.085 mg / kg. In some embodiments, the dose is 0.09 mg / kg. In some embodiments, the dose is 0.095 mg / kg. In some embodiments, the dose is 0.10 mg / kg. In some embodiments, the dose is 0.11 mg / kg. In some embodiments, the dose is 0.12 mg / kg. In some embodiments, the dose is 0.13 mg / kg. In some embodiments, the dose is 0.14 mg / kg. In some embodiments, the dose is 0.15 mg / kg.

[0011] In some embodiments, the method includes administering to a subject an acetate salt of Compound (1), designated Compound (1a). In some embodiments, the acetate salt is the monoacetate salt. In some embodiments, the acetate salt is the diacetate salt.

[0012] Dose Selection Several factors are considered in connection with dose selection. A high degree of inhibition of platelet aggregation (e.g., at least 80%) must be consistently achieved within 15 minutes of administration. The risk of bleeding must be minimized, especially in underweight individuals (e.g., elderly women) who are at highest risk of bleeding. It is also desirable that compound (1) persists, e.g., maintaining at least 50% inhibition of platelet function out to 120 minutes.

[0013] However, the determination of the antiplatelet effect due to compound (1) may be confounded by the presence of other antiplatelet agents, such as aspirin, ticagrelor, and αIIbβ3 antagonists other than compound (1). Therefore, an assay capable of distinguishing the effect of compound (1) from the effect of other antiplatelet agents is required.

[0014] Light transmission aggregometry (LTA) is considered the gold standard assay for evaluating the efficacy of antiplatelet drugs such as compound (I) due to its relevance to clinical outcomes. As illustrated in Figure 4, activators such as ADP, iso-TRAP, and arachidonic acid (AA) can be used to evaluate the differential effects of various platelet inhibitors. Compound (1) dramatically inhibits ADP and AA, while aspirin does not significantly inhibit ADP or iso-TRAP-induced LTA, and ticagrelor (and other P2Y12 inhibitors) inhibit ADP-induced LTA to various degrees and slightly inhibit iso-TRAP-induced LTA (depending on the dose administered). Addition of ADP + PAR-4 activating peptide completely inhibits the inhibition of platelet aggregation by P2Y12 inhibitors.

[0015] LTA can be difficult to perform during STEMI because the patient is transported by ambulance or treated with percutaneous coronary intervention (PCI) in a cardiac catheterization lab that is remote from the clinical laboratory. LTA requires significant manipulation of the blood sample and the addition of reagents. Alternatively, rapid platelet function assays such as VerifyNow can be used directly on blood samples without any manipulation. See, for example, Joseph A. Jakubowski et al., Platelets, December 2011;22(8):619-625.

[0016] VerifyNow (VN) assays (Instrumentation Laboratories, Bedford, MA) are whole blood, cartridge-based, automated, and provide results within 15 minutes of blood collection. They are based on the agglutination of fibrinogen-coated beads by platelets activated by various agonists. Commercially available VN assays are designed to study the antiplatelet effects of aspirin (VN Aspirin Cartridge, arachidonic acid activator) or P2Y12 antagonists (VN PRUTest Cartridge and VN P2Y12 Cartridge, ADP+PGE1 activator / inhibitor combinations). Modified thrombin receptor activating peptides (iso-TRAPs) are contained within separate reaction chambers (in addition to the ADP+PGE1 reaction chamber) in both the PRUTest and P2Y12 cartridges, and the P2Y12 cartridge additionally contains a "BASE channel" reaction chamber. In the "BASE channel" reaction chamber, a PAR-1 activating peptide (iso-TRAP) at higher concentrations is combined with a PAR-4 activating peptide (PAR-4AP) to achieve potent activation that can overcome the effects of P2Y12 antagonists.

[0017] Using the VerifyNow ADP+PGE1, iso-TRAP, and BASE channel assays, compound (1)-mediated inhibition can be reported in near real time. The VN assay can be used to help deconvolute the antiplatelet effects of αIIbβ3 antagonists versus P2Y12 antagonists. Compound (1) dramatically inhibits all three VN assays, while aspirin does not inhibit any assays, and ticagrelor dramatically inhibits the ADP+PGE1 assay, slightly inhibits the iso-TRAP assay, and does not inhibit the BASE channel assay. The BASE channel assay was used to monitor the pharmacodynamic effects of compound (1) independent of any P2Y12 inhibitors.

[0018] Compositions and Administration In some embodiments of the method, Compound (1), or a pharma- ceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition comprising one or more carriers, diluents, or excipients. In some embodiments, the pharmaceutical composition is a solution. In some embodiments, the pharmaceutical composition is a microemulsion. In some embodiments, the pharmaceutical composition is a suspension. In some embodiments, the pharmaceutical composition is an emulsion. In some embodiments, the pharmaceutical composition is a gel. In some embodiments, the pharmaceutical composition is a slurry.

[0019] In certain embodiments, the pharmaceutical composition comprises a pharma- ceutically acceptable salt of Compound 1. In certain embodiments, the pharma- ceutically acceptable salt is an acetate salt, e.g., the monoacetate or diacetate salt.

[0020] In one embodiment, the pharmaceutical composition comprising compound (1) or a pharma- ceutically acceptable salt thereof is a solution. In one embodiment, the concentration (in the solution) of compound (1) or a pharma- ceutically acceptable salt thereof is 0.01 to 100 mg / mL (inclusive). In one embodiment, the concentration is 0.05 to 100 mg / mL (inclusive). In one embodiment, the concentration is 0.1 to 100 mg / mL (inclusive). In one embodiment, the concentration is 1 to 100 mg / mL (inclusive). In one embodiment, the concentration is 10 to 100 mg / mL (inclusive). In one embodiment, the concentration is 15 to 100 mg / mL (inclusive). In one embodiment, the concentration is 20 to 100 mg / mL (inclusive). In one embodiment, the concentration is 30 to 100 mg / mL (inclusive). In one embodiment, the concentration is 40 to 100 mg / mL (inclusive). In one embodiment, the concentration is 50 to 100 mg / mL (inclusive). In some embodiments, the concentration is 0.05 to 50 mg / mL (inclusive). In some embodiments, the concentration is 0.1 to 50 mg / mL (inclusive). In some embodiments, the concentration is 1 to 50 mg / mL (inclusive). In some embodiments, the concentration is 10 to 50 mg / mL (inclusive). In some embodiments, the concentration is 15 to 50 mg / mL (inclusive). In some embodiments, the concentration is 20 to 50 mg / mL (inclusive). In some embodiments, the concentration is 30 to 50 mg / mL (inclusive). In some embodiments, the concentration is 40 to 50 mg / mL (inclusive). In some embodiments, the concentration is 0.05 to 25 mg / mL (inclusive). In some embodiments, the concentration is 0.1 to 25 mg / mL (inclusive). In some embodiments, the concentration is 1 to 25 mg / mL (inclusive). In some embodiments, the concentration is 10 to 25 mg / mL (inclusive). In some embodiments, the concentration is 15 to 25 mg / mL, inclusive. In some embodiments, the concentration is 20 to 25 mg / mL, inclusive. In some embodiments, the concentration is 0.05 to 10 mg / mL, inclusive. In some embodiments, the concentration is 0.1 to 10 mg / mL, inclusive. In some embodiments, the concentration is 1 to 10 mg / mL, inclusive.

[0021] In certain embodiments, the concentration of Compound (1) or a pharma- ceutically acceptable salt thereof in the solution is about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, or about 25 mg / mL.

[0022] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, is administered to a subject by injection. In certain embodiments, the injection is subcutaneous. In other particular embodiments, the site of injection includes the arm, leg, thigh, back, buttocks, and abdomen. In some embodiments, the injection administration is performed using a pre-filled syringe, pen, or auto-injector. In some embodiments, the administration is self-administered by auto-injector.

[0023] In some embodiments, the volume of the injection is 2 mL or less, hi some embodiments, the volume of the injection is 1 mL or less, for example, about 0.9 mL, about 0.8 mL, about 0.7 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL, about 0.3 mL, about 0.2 mL, or about 0.1 mL.

[0024] In certain embodiments, administration of Compound (1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, results in minimal injection site reactions (e.g., bruising, bleeding, swelling, and discomfort) in a subject at t=0, t=1 hour, t=1 day, t=3 days, or t=1 month after injection. In certain embodiments, administration results in an injection site reaction that resolves within 30 days, e.g., within 25, 20, 15, 10, or 5 days.

[0025] In some embodiments, the methods disclosed herein include a single administration (e.g., injection). In some embodiments, the methods disclosed herein include multiple administrations (e.g., injections). For example, some embodiments include administering a first dose of Compound (1), or a pharma- ceutically acceptable salt thereof, or a composition thereof, and, optionally, a second dose. The second dose is administered when such administration is desirable, advantageous, or necessary.

[0026] In some embodiments, the dosage of the subsequent (e.g., second) administration is the same dose as the dosage of the first administration. In some embodiments, the dosage of the subsequent (e.g., second) administration is different from the dosage of the first administration. Exemplary dosages, formulations, and concentrations are described herein.

[0027] combination In some embodiments, the methods described herein further comprise administering to the subject an additional therapeutic compound (e.g., one or more additional therapeutic compounds). In some embodiments, the additional therapeutic compound is an anticoagulant. In some embodiments, the additional therapeutic compound is heparin. In some embodiments, the additional therapeutic compound is a P2Y12 inhibitor, e.g., ticagelor, prasugrel, or clopidogrel. In some embodiments, the additional therapeutic compound is aspirin. In some embodiments, the additional therapeutic compound is selected from cangrelor, warfarin, enoxaparin, fondaparinux, dalteparin, bivalirudin, hirudin, rivaroxaban, dabigatran, apixaban, and edoxaban.

[0028] In some embodiments, the methods described herein further comprise administering to the subject a P2Y12 inhibitor and heparin. In some embodiments, the methods described herein further comprise administering to the subject an aspirin and heparin.

[0029] In certain embodiments, the additional therapeutic agent is administered to the subject prior to administration of Compound (1), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In certain embodiments, the additional therapeutic agent is administered to the subject after administration of Compound (1), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In certain embodiments, the additional therapeutic agent is administered to the subject simultaneously with administration of Compound (1), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0030] In some embodiments of the methods described herein, the subject is administered aspirin prior to the onset of symptoms, or after the onset of symptoms but prior to administration of Compound (1), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0031] In some embodiments of the methods described herein, the subject is administered a P2Y12 inhibitor prior to the onset of symptoms, or after the onset of symptoms but prior to administration of compound (1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments of the methods described herein, the subject is administered aspirin and a P2Y12 inhibitor prior to the onset of symptoms, or after the onset of symptoms but prior to administration of compound (1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments of the methods described herein, the subject is administered a P2Y12 inhibitor simultaneously with administration of compound (1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments of the methods described herein, the subject is administered a P2Y12 inhibitor after administration of compound (1) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0032] Administration In certain embodiments of the method, the subject is experiencing one or more symptoms of a thrombotic disorder and compound (1) or a pharma- ceutically acceptable salt thereof is administered within 6 hours of the onset of symptoms or the demonstration of a diagnosis of ECG findings of MI. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 5 hours of the onset of symptoms. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 4 hours of the onset of symptoms. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 3 hours of the onset of symptoms. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 2 hours of the onset of symptoms. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 1 hour of the onset of symptoms. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 30 minutes of the onset of symptoms. In certain embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is administered within 15 minutes of the onset of symptoms.

[0033] In some embodiments, the symptoms are selected from chest pain or discomfort, shortness of breath, dizziness or lightheadedness, nausea or vomiting, sweating, palpitations, and anxiety or fear. In some embodiments, the diagnosis of ST segment elevation is established by characteristic ECG findings.

[0034] clinical purpose In some embodiments of the methods described herein, treating includes restoring coronary blood flow. In some embodiments, treating includes at least partially restoring coronary blood flow. For example, coronary blood flow may be restored by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

[0035] In certain embodiments of the methods described herein, treating comprises restoring, at least partially restoring or maintaining coronary blood flow.

[0036] In some embodiments of the methods described herein, treating includes achieving an improvement in Thrombolysis in Myocardial Infarction (TIMI) frame count, TIMI flow grade, or TIMI myocardial perfusion grade in the subject. In some embodiments, the improvement is compared to a placebo. Placebo refers to the absence of any treatment or a comparison to a treatment with no biological effect. In some embodiments, the improvement is achieved within 1 to 5 hours after administration of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0037] In one embodiment, a reduction in TIMI frame count of at least 5 is achieved within 1 to 5 hours after administration of Compound (1), a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described herein.

[0038] In some embodiments of the methods described herein, treating comprises achieving and / or maintaining a stable platelet count in the subject, hi some embodiments, the platelet count does not vary by more than 10%, 20%, or 30%.

[0039] In some embodiments of the methods described herein, treating includes achieving ≥80% inhibition of platelet aggregation in the subject. In some embodiments, achieving ≥80% inhibition of platelet aggregation in the subject is achieved within 5-90, 5-60, or 10-30 minutes after administering Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, achieving ≥80% inhibition of platelet aggregation in the subject is achieved within about 15 minutes after administering Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0040] In some embodiments of the methods described herein, treating includes achieving ST deviation resolution in the subject. In some embodiments, the ST deviation resolution in the subject is ≧70% compared to baseline. In some embodiments, the ST deviation resolution is measured relative to a placebo. In some embodiments, the ST deviation resolution in the subject is ≧80% compared to baseline. In some embodiments, the ST deviation resolution in the subject is ≧90% compared to baseline. In some embodiments, the ST deviation resolution in the subject is achieved within about 1-5 hours after administering Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0041] In some embodiments of the methods described herein, treating includes achieving a reduction in residual ST deviation in the subject. In some embodiments, the reduction is measured relative to a placebo. In some embodiments, the reduction in residual ST deviation in the subject is achieved following a single administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the reduction in residual ST deviation in the subject is achieved within about 1-5 hours after administration of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0042] In certain embodiments of the methods described herein, treating comprises achieving a reduction in all-cause mortality and / or cardiovascular mortality relative to placebo at 12 months.

[0043] In some embodiments of the methods described herein, treating comprises achieving a composite improvement in all-cause mortality, recurrent myocardial infarction (MI), emergency target vessel revascularization (TVR), or blinded rescue use of an intravenous (IV) αIIbβ3 antagonist or IV P2Y12 antagonist in the subject up to one month after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the determination is made against placebo up to one month after PCI / angiography, compared to placebo.

[0044] In some embodiments of the methods described herein, treating comprises achieving a reduction in acute stent thrombosis in the subject up to 24 hours after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the reduction in stent thrombosis is measured relative to a placebo.

[0045] In some embodiments of the methods described herein, treating includes directly or indirectly achieving a reduction in heart failure for several years after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the reduction is measured against a placebo. This effect can be predicted by measuring B-type natriuretic protein (BNP), specifically by measuring N-terminal pro-B-type natriuretic protein, measured within about one day after administration of Compound (1), a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described herein.

[0046] In some embodiments of the methods described herein, treating comprises achieving no mortality in the subject within 30 days after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, no mortality is measured against a placebo.

[0047] In some embodiments of the methods described herein, treating comprises achieving freedom from stroke in the subject within 30 days after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, freedom from stroke is measured against a placebo.

[0048] In some embodiments of the methods described herein, treating comprises achieving freedom from recurrent myocardial infarction (MI) in the subject within 30 days after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, freedom from recurrent myocardial infarction is measured against a placebo.

[0049] In some embodiments of the methods described herein, treating comprises achieving no acute stent thrombosis in the subject up to 24 hours after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the no acute stent thrombosis is measured against a placebo.

[0050] In some embodiments of the methods described herein, treating comprises achieving no new onset of heart failure or no re-hospitalization for heart failure within 30 days after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the no new onset of heart failure or no re-hospitalization for heart failure is measured against a placebo.

[0051] In certain embodiments of the methods described herein, treating comprises achieving a peak high-sensitivity cardiac troponin T (hs-cTnT) of less than 10-fold the upper limit of normal 24 hours after administration (e.g., a single subcutaneous injection) of Compound (1), a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition described herein. In certain embodiments, peak hs-cTnT is measured relative to a placebo.

[0052] Patient population In some embodiments, the subject has a history of coronary artery disease. In some embodiments, the subject has stable coronary artery disease. In some embodiments, the subject does not have a history of coronary artery disease.

[0053] In certain embodiments, the subject is administered (or self-administers) other pharmacological therapy at the onset of symptoms of a thrombotic disorder, hi some embodiments, the other pharmacological therapy includes one or more of aspirin, warfarin, a statin, and a P2Y12 inhibitor.

[0054] Specific Embodiments In certain aspects, provided herein is a method for treating STEMI, comprising administering to a subject in need thereof a composition comprising 0.075 mg / kg of Compound (1) by subcutaneous injection. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, glycerin, and water. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, citric acid, glycerin, and water.

[0055] In another particular aspect, provided herein is a method for treating STEMI, comprising administering to a subject in need thereof a composition comprising 0.09 mg / kg of Compound (1) by subcutaneous injection. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, glycerin, and water. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, citric acid, glycerin, and water.

[0056] In certain aspects, provided herein is a method for treating STEMI, comprising administering to a subject in need thereof a composition comprising 0.11 mg / kg of Compound (1) by subcutaneous injection. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, glycerin, and water. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, citric acid, glycerin, and water.

[0057] In certain aspects, provided herein is a method for treating STEMI, comprising administering to a subject in need thereof a composition comprising 0.13 mg / kg of Compound (1) by subcutaneous injection. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, glycerin, and water. In certain embodiments, the composition further comprises acetic acid, hydrochloric acid, citric acid, glycerin, and water.

[0058] definition Unless otherwise indicated, the terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0059] The terms "condition," "disease," and "disorder" may be used interchangeably.

[0060] An "effective amount" of a compound described herein, or a pharma- ceutically acceptable salt thereof, refers to an amount sufficient to induce a desired biological response. The effective amount of a compound described herein may vary depending on factors such as the desired biological endpoint, side effects, severity of the disease or disorder, identity of the particular compound, pharmacokinetics, and pharmacodynamics, condition being treated, mode, route, and desired or required frequency of administration, species, age, and health or general condition of the subject. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactic treatment. In some embodiments, the effective amount is the amount of a compound in a single dose described herein. In some embodiments, the effective amount is the total amount of a compound in multiple doses described herein. In some embodiments, the desired dose is delivered three times a day, twice a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations).

[0061] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with human and non-human animal tissues without undue toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, and the like. Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1-4 Alkyl)4- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0062] A "subject" to which administration is intended refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, or an adolescent), or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus or rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird such as a chicken, a duck, a goose, or a turkey)). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic or genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0063] The terms "treatment," "treat," and "treating" refer to amelioration, alleviation, or inhibition of progression of a disease or condition described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a pathogen). Treatment may also be continued after symptoms have resolved, e.g., to delay or prevent recurrence.

[0064] The terms "prevent", "preventing", or "prevention" refer to the prophylactic treatment of a subject who does not have a disease and has not had the disease but is at risk of developing the disease, or a subject who has had the disease and does not have the disease but is at risk of relapse. In certain embodiments, the subject is at higher risk of developing the disease or at higher risk of relapse than the average healthy member of the population.

[0065] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent or prevent the recurrence of a condition or one or more symptoms associated with that condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic effect of other prophylactic agents.

[0066] composition In another aspect, provided herein are compositions comprising Compound (I) or a pharma- ceutically acceptable salt thereof, in the amounts and / or concentrations described herein, and one or more carriers, diluents, or excipients.

[0067] Working Example [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0068] [Table 2] Example 3. In vitro studies Whole blood anticoagulated with either sodium citrate (0.32%) or PPACK (100 μM) from healthy volunteers with or without daily aspirin was treated in vitro with compound (I) (RUC-4) to achieve final whole blood concentrations of 30-900 nM. Blood was incubated at room temperature for 10 min and then tested by either IIb / IIIa or PRU cartridges.

[0069] Example 4. Research results Results of in vitro studies Compound (I) (RUC-4) causes dose-dependent inhibition of the VN isoTRAP channel in both IIb / IIIa and PRU cartridges, as well as the ADP+PGE1 channel in the PRU cartridge. Both channels produce comparable results in the inhibition of 20 μM ADP-induced light transmission aggregation (LTA). Since P2Y12 antagonists inhibit the ADP+PGE1 channel but not the isoTRAP channel, the effect of RUC-4 on patients not treated with P2Y12 antagonists can be monitored by the PRU ADP+PGE1 channel or the isoTRAP channel in either the PRU or IIb / IIIa cartridges. The effect of RUC-4 in patients treated with P2Y12 antagonists can be monitored by the isoTRAP channel in either cartridge. The results are shown in Figure 3.

[0070] Example 5. In vivo studies in healthy volunteers and stable CAD patients taking aspirin Sequentially, healthy volunteers (HV) receiving aspirin, then patients with stable coronary artery disease (CAD), were given ascending doses of RUC-4 or placebo at a sentinel dose in a randomized, blinded fashion. Inhibition of platelet aggregation (IPA) to adenosine diphosphate (ADP; 20 μM), RUC-4 blood levels, laboratory assessments, and clinical assessments were performed over 24 hours and 7 days. Doses were increased to a dose that produced ≥80% IPA within 15 minutes, with a return toward baseline achieved within 4 hours. VerifyNow (VN) was also measured in a subset of stable CAD patients.

[0071] Example 6. Research results In vivo study results Fifteen minutes after SC injection, mean ± SD IPA was 6.9 ± 7.1% after placebo and 71.8 ± 15.0% after RUC-4 at 0.05 mg / kg (n = 6) and 84.7 ± 16.7% after RUC-4 at 0.075 mg / kg (n = 6). In all cases, IPA decreased over 90 to 120 minutes. CAD: Fifteen minutes after SC injection of placebo or 0.04 mg / kg (n = 2), 0.05 mg / kg (n = 6), and 0.075 mg / kg (n = 18) RUC-4, IPA was 14.6 ± 11.7%, 53.6 ± 17.0%, 76.9 ± 10.6%, and 88.9 ± 12.7%, respectively. RUC-4 blood concentrations correlated closely with IPA. Aspirin did not affect the blood concentrations of IPA or RUC-4. The results are shown in Figure 5.

[0072] Example 7. In vivo study in patients with ST-segment elevation myocardial infarction (STEMI) The open-label, dose-escalation, phase 2 CEL-02 study aimed to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), safety, and tolerability of RUC-4 in STEMI patients treated with aspirin and ticagrelor in the ambulance undergoing primary percutaneous coronary intervention (pPCI). STEMI patients undergoing pPCI at St. Antonius Hospital Nieuwegein, Netherlands, received a single weight-adjusted subcutaneous injection of RUC-4 before coronary angiography. After evaluation of each of the eight evaluable patients, the dose was increased until the optimal dose for platelet inhibition was reached. All patients were treated simultaneously with aspirin, ticagrelor, and unfractionated heparin (UFH) (5000 IU) in the ambulance. Additional UFH during PCI was administered only if ACT was <200 seconds (2500-5000 IU). Blood samples for (PD) and (PK) were taken before and 15, 45, 60, 90, 120, 180, and 240 min after RUC-4 administration. Platelet inhibition was measured using oral P2Y agonists with protease-activated receptor-1 (PAR-1) peptide (iso-TRAP) and PAR-4 activating peptide as agonists. 12 Reverse platelet inhibition by inhibitors, VerifyNow P2Y 12 Assay was measured by the BASE channel.

[0073] Example 8. Research results In vivo study results Twenty-seven patients received RUC-4 at doses of 0.075 mg / kg (n = 8), 0.090 mg / kg (n = 9), or 0.11 mg / kg (n = 10). RUC-4 demonstrated a dose-responsive maximal platelet inhibition 15 min after administration (mean [SD], 83.7% [9.9%], 89.6% [6.6%], and 92.5% [5.8%], respectively). At 120 min after administration, platelet inhibition was 17.9% (17%), 22.6% (32.9%), and 31.6% (15.7%), respectively. Results are also shown in Figure 1. In this study in patients with STEMI, a single subcutaneous administration of RUC-4 induced a dose-dependent response of maximal platelet function inhibition within 15 min and a dose-dependent recovery of platelet function within 120 min.

[0074] Embodiment 1. A method for treating or preventing a thrombotic disorder, comprising administering to a subject in need thereof an effective amount of compound (1); [ka] or a pharma- ceutically acceptable salt thereof at a dose in the range of 0.01 to 0.3 mg / kg (inclusive).

[0075] 2. The method of embodiment 1, wherein said dose is in the range of 0.05 to 0.25 mg / kg, inclusive.

[0076] 3. The method of any one of the preceding embodiments, wherein said dose is in the range of 0.075 to 0.15 mg / kg, inclusive.

[0077] 4. The method of any one of the preceding embodiments, wherein said dose is in the range of 0.09 to 0.15 mg / kg, inclusive.

[0078] 5. The method of any one of the preceding embodiments, wherein said dose is in the range of 0.1 to 0.15 mg / kg, inclusive.

[0079] 6. The method of any one of the preceding embodiments, wherein the thrombotic disorder is myocardial infarction.

[0080] 7. The method of any one of the preceding embodiments, wherein said thrombotic disorder is ST-elevation myocardial infarction (STEMI).

[0081] 8. The method of any one of the preceding embodiments, wherein the compound or a pharma- ceutically acceptable salt thereof is administered by injection.

[0082] 9. The method of embodiment 8, wherein the injection is an intramuscular injection.

[0083] 10. The method of embodiment 8, wherein the injection is a subcutaneous injection.

[0084] 11. The method according to any one of embodiments 8 to 10, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in the form of a solution, suspension, or emulsion.

[0085] 12. The method of embodiment 11, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in the form of a solution.

[0086] 13. The method of embodiment 12, wherein the concentration of the compound or a pharma- ceutically acceptable salt thereof in the solution is 0.01 to 100 mg / mL, inclusive.

[0087] 14. The method of embodiment 13, wherein the concentration is about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, or about 25 mg / mL.

[0088] 15. The method of any one of embodiments 11-12, wherein the solution further comprises one or more of acetic acid, hydrochloric acid, citric acid, glycerin, and water.

[0089] 16. The method of any one of embodiments 8-15, wherein administration of the compound or a pharma- ceutically acceptable salt thereof results in minimal injection site reactions in the subject at t=0, t=1 hour, t=1 day, t=3 days, or t=1 month after injection.

[0090] 17. The method of any one of the preceding embodiments, wherein the subject is experiencing one or more symptoms of the thrombotic disorder, and the compound, or a pharma- ceutically acceptable salt thereof, is administered within 30 minutes to 6 hours of onset of the symptoms.

[0091] 18. The method of embodiment 17, wherein the thrombotic disorder is STEMI and the symptoms are selected from chest pain or discomfort, shortness of breath, dizziness or lightheadedness, nausea or vomiting, sweating, palpitations, and anxiety or fear.

[0092] 19. The method of any one of the preceding embodiments, wherein treating comprises at least partially restoring or maintaining coronary blood flow.

[0093] 20. The method of any one of the preceding embodiments, wherein treating comprises achieving an improvement in Thrombolysis in Myocardial Infarction (TIMI) frame count or TIMI flow rate, preferably within 1 to 5 hours after administering the compound or a pharmacologic salt thereof.

[0094] 21. The method of embodiment 20, wherein treating comprises achieving an improvement in TIMI frame count or TIMI flow rate within at least 5 hours, preferably within 1 to 5 hours, after administering the compound or a pharma- ceutically acceptable salt thereof.

[0095] 22. The method of any one of the preceding embodiments, wherein treating comprises maintaining a stable platelet count, preferably within 1 to 5 hours after administering the compound or a pharma- ceutically acceptable salt thereof.

[0096] 23. The method of any one of the preceding embodiments, wherein treating comprises achieving ≧80% inhibition of platelet aggregation, preferably within 5 to 90 minutes (e.g., 15 minutes) after administering the compound or a pharma- ceutically acceptable salt thereof.

[0097] 24. The method of any one of the preceding embodiments, wherein treating comprises achieving an improvement in ST deviation resolution (≧70% compared to baseline), preferably within 1 to 5 hours after administering the compound or a pharma- ceutically acceptable salt thereof.

[0098] 25. The method of any one of the preceding embodiments, wherein treating comprises achieving a reduction in residual ST deviation following a single subcutaneous injection.

[0099] 26. The method of any one of the preceding embodiments, wherein treating comprises achieving a composite improvement in all-cause mortality, recurrent myocardial infarction (MI), urgent target vessel revascularization (TVR), or blinded rescue use of an intravenous (IV) αIIbβ3 antagonist or an IV P2Y12 antagonist after a single subcutaneous injection.

[0100] 27. The method of any one of the preceding embodiments, wherein treating comprises achieving a reduction in acute stent thrombosis following a single subcutaneous injection.

[0101] 28. The method of any one of the preceding embodiments, wherein treating comprises achieving no deaths in the subject within 30 days after administering the compound or a pharma- ceutically acceptable salt thereof.

[0102] 29. The method of any one of the preceding embodiments, wherein treating comprises achieving no stroke occurrence in the subject within 30 days after administering the compound or a pharmacologic salt thereof.

[0103] 30. The method of any one of the preceding embodiments, wherein treating comprises achieving no recurrent myocardial infarction (MI) in the subject within 30 days after administering the compound or a pharma- ceutically acceptable salt thereof.

[0104] 31. The method of any one of the preceding embodiments, wherein treating comprises achieving freedom from acute stent thrombosis in the subject for up to 24 hours after administering the compound or a pharma- ceutically acceptable salt thereof.

[0105] 32. The method of any one of the preceding embodiments, wherein treating comprises achieving no new onset of heart failure or no rehospitalization for heart failure in the subject within 30 days after administering the compound or a pharma- ceutically acceptable salt thereof.

[0106] 33. The method of any one of the preceding embodiments, wherein treating comprises achieving a peak high-sensitivity cardiac troponin T (hs-cTnT) of less than 10-fold the upper limit of normal 24 hours after administering the compound or a pharma- ceutically acceptable salt thereof.

[0107] 34. The method of any one of the preceding embodiments, further comprising administering a second dose of compound (1), or a pharma- ceutically acceptable salt thereof.

[0108] 35. The method of any one of the preceding embodiments, further comprising administering to said subject a P2Y12 inhibitor, for example, ticagelor, prasugrel, or clopidogrel.

[0109] 36. The method of embodiment 34, further comprising administering to the subject aspirin.

[0110] 37. The method of embodiment 35, comprising administering to the subject aspirin and a P2Y12 inhibitor.

[0111] 38. The method of embodiment 35, comprising administering to the subject aspirin, a P2Y12 inhibitor, and heparin.

[0112] 39. The method of any one of the preceding embodiments, wherein the subject has been administered aspirin, e.g., prior to the onset of symptoms, or after the onset of symptoms but prior to administration.

[0113] 40. The method of embodiment 34, further comprising administering heparin to the subject.

[0114] 41. The method of any one of the preceding embodiments, wherein the subject has a history of coronary artery disease.

[0115] 42. The method of any one of the preceding embodiments, wherein the subject has stable coronary artery disease.

Claims

1. A pharmaceutical for treating or preventing a thrombotic disorder, comprising compound (1), 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, The medicament comprising administering to a subject in need thereof the compound or a pharma- ceutically acceptable salt thereof at a dose ranging from 0.01 to 0.3 mg / kg, inclusive.

2. 2. The method of claim 1, wherein the dose is in the range of 0.05 to 0.25 mg / kg (inclusive), in the range of 0.075 to 0.15 mg / kg (inclusive), in the range of 0.09 to 0.15 mg / kg (inclusive), or in the range of 0.1 to 0.15 mg / kg (inclusive).

3. The method of claim 1, wherein the thrombotic disorder is myocardial infarction or ST-elevation myocardial infarction (STEMI).

4. 2. The method of claim 1, wherein the compound or a pharma- ceutically acceptable salt thereof is administered by injection, optionally wherein the injection is intramuscular or subcutaneous.

5. 5. The medicament of claim 4, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in the form of a solution, optionally wherein the concentration of the compound or a pharma- ceutically acceptable salt thereof in the solution is between 0.01 and 100 mg / mL, inclusive.

6. 6. The pharmaceutical composition of claim 5, wherein the concentration is about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, about 20 mg / mL, about 21 mg / mL, about 22 mg / mL, about 23 mg / mL, about 24 mg / mL, or about 25 mg / mL.

7. 6. The medicament of claim 5, wherein the solution further comprises one or more of acetic acid, hydrochloric acid, citric acid, glycerin, and water.

8. 5. The method of claim 4, wherein administration of the compound or a pharma- ceutically acceptable salt thereof results in minimal injection site reactions in the subject at t=0, t=1 hour, t=1 day, t=3 days, or t=1 month after injection.

9. The method of claim 1, wherein the subject is experiencing one or more symptoms of the thrombotic disorder, and the compound or a pharma- ceutically acceptable salt thereof is administered within 30 minutes to 6 hours of onset of the symptoms.

10. 10. The method of claim 9, wherein the thrombotic disorder is STEMI and the symptoms are selected from chest pain or discomfort, shortness of breath, dizziness or lightheadedness, nausea or vomiting, sweating, palpitations, and anxiety or fear.

11. The method of claim 1 , wherein treating comprises at least partially restoring or maintaining coronary blood flow.

12. Treating is achieving an improvement in Thrombolysis in Myocardial Infarction (TIMI) frame count or TIMI flow rate, preferably within 1 to 5 hours after administering the compound or a pharma- ceutically acceptable salt thereof; or achieving an improvement in TIMI frame count or TIMI flow rate within at least 5 hours, preferably within 1 to 5 hours, after administration of the compound or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition of claim 1 .

13. Treating comprises maintaining a stable platelet count, preferably within 1 to 5 hours after administering the compound or a pharma- ceutically acceptable salt thereof; or achieving ≧80% inhibition of platelet aggregation, preferably within 5 to 90 minutes after administration of the compound or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition of claim 1 .

14. Treating is achieving an improvement in ST deviation resolution (≧70% compared to baseline), preferably within 1 to 5 hours after administering the compound or a pharma- ceutically acceptable salt thereof; or Achieving a reduction in residual ST deviation following a single subcutaneous injection; The pharmaceutical composition of claim 1 .

15. The medicament of claim 1, wherein treating comprises achieving a composite improvement in all-cause mortality, recurrent myocardial infarction (MI), urgent target vessel revascularization (TVR), or blinded rescue use of an intravenous (IV) αIIbβ3 antagonist or an IV P2Y12 antagonist after a single subcutaneous injection.

16. treating achieves a reduction in acute stent thrombosis after a single subcutaneous injection; or achieving freedom from acute stent thrombosis in said subject for up to 24 hours after administration of said compound or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition of claim 1 .

17. treating achieves no deaths occurring in said subject within 30 days after administering said compound or a pharma- ceutically acceptable salt thereof; achieving no stroke occurrence in said subject within 30 days after administration of said compound or a pharmacologic acceptable salt thereof; achieving no recurrent myocardial infarction (MI) in said subject within 30 days after administration of said compound or a pharma- ceutical acceptable salt thereof; or achieving no new onset of heart failure or no rehospitalization for heart failure in said subject within 30 days after administration of said compound or a pharma- ceutically acceptable salt thereof; The pharmaceutical composition according to any one of claims 1 to 16, comprising:

18. The method of any one of claims 1 to 16, wherein treating comprises achieving a peak high-sensitivity cardiac troponin T (hs-cTnT) of less than 10 times the upper limit of normal 24 hours after administration of the compound or a pharma- ceutically acceptable salt thereof.

19. The method of claim 1, further comprising administering a second dose of compound (1) or a pharma- ceutically acceptable salt thereof.

20. The method of claim 1, further comprising administering to the subject one or more of a P2Y12 inhibitor, aspirin, and heparin.

21. 2. The method of claim 1, wherein the subject has been administered aspirin prior to the onset of symptoms, or after the onset of symptoms but prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

22. The method of claim 1 , wherein the subject has a history of coronary artery disease or stable coronary artery disease.

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