7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-A]pyrimidin-5-ones for the treatment of thrombotic disorders
Inventors
Coller, Barry S. • Thomas, Craig • Filizola, Marta • Mccoy, Joshua • HUANG, Wenwei • Shen, Min • Jiang, Jian-Kang
Assignees
Rockefeller University • Icahn School of Medicine at Mount Sinai • US Department of Health and Human Services
Publication Number
US-9303044-B2
Publication Date
2016-04-05
Expiration Date
2033-01-16
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Abstract
The present invention relates to compounds and compositions of Formula P useful for inhibiting and/or reducing platelet deposition, adhesion and/or aggregation. The definitions of variables A, B, R2, R3, R4, Ra, Ra′, Rb, Rb′, Rc, Rd, Rd′, Re, and Re′ are provided in the disclosure. The present invention further relates to methods for the treatment or prophylaxis of thrombotic disorders, including stroke, myocardial infarction, unstable angina, peripheral vascular disease, abrupt closure following angioplasty or stent placement and thrombosis as a result of vascular surgery.
Core Innovation
The invention relates to compounds and compositions of Formula P useful for inhibiting and/or reducing platelet deposition, adhesion and/or aggregation. These compounds act as αIIbβ3 antagonists that inhibit fibrinogen binding and platelet aggregation without inducing the binding of integrin β3 ligand-induced binding sites (LIBS) monoclonal antibodies, thus avoiding conformational changes in the β3 subunit associated with increased risk of thrombocytopenia and adverse effects found in traditional αIIbβ3 inhibitors.
The problem being solved is the need for additional platelet adhesion and aggregation inhibitory agents that effectively treat and prevent thrombotic disorders without the disadvantages of existing treatments. Current platelet inhibitors have side effects such as delayed onset, thrombocytopenia, severe allergic reactions, or require parenteral administration. Traditional small-molecule αIIbβ3 inhibitors cause conformational changes in β3 leading to severe complications.
This invention also provides pharmaceutical compositions, drug-eluting stents comprising the new αIIbβ3 antagonists, and methods for inhibiting platelet aggregation and adhesion to treat or prevent thrombotic disorders such as stroke, myocardial infarction, unstable angina, peripheral vascular disease, abrupt closure after angioplasty or stent placement, and thrombosis resulting from vascular surgery, atrial fibrillation, or inflammation.
Claims Coverage
The patent contains multiple independent claims covering compounds of different formulas, their pharmaceutical compositions, methods of treatment using these compounds, and drug-eluting stents incorporating them. The inventive features focus on novel compounds capable of inhibiting platelet adhesion and aggregation with improved safety profiles, specific compositions, and therapeutic methods.
Compounds of Formula P
Compounds defined by Formula P with specified substituents (A, B, R2, R3, R4, and others) provided in free or salt form that inhibit platelet adhesion and aggregation without inducing β3 LIBS binding, avoiding adverse conformational changes in integrin αIIbβ3.
Compounds of Formula I and Formula P-II
Specific embodiments of Formula P, including compounds of Formula I and Formula P-II (and Formula II), characterized by particular substituent patterns and limited β3 LIBS exposure, exhibiting IC50 values less than 100 μM in platelet aggregation assays.
Pharmaceutical compositions comprising compounds of Formula P, I, and P-II
Pharmaceutical compositions containing the compounds of Formula P, I, or P-II in free or pharmaceutically acceptable salt form, combined with pharmaceutically acceptable carriers or diluents, for inhibiting or reducing platelet aggregation and/or adhesion.
Methods of inhibiting platelet aggregation and adhesion
Methods of administering effective amounts of compounds of Formula P, I, or P-II to subjects in need, to reduce platelet aggregation and/or adhesion, thereby treating or preventing thrombotic disorders.
Methods for treatment or prophylaxis of thrombotic disorders
Methods involving administering compounds of Formula P, I, or P-II to subjects at risk of or having thrombotic disorders such as stroke, myocardial infarction, unstable angina, thrombosis induced by peripheral vascular surgery or angioplasty/stent placement, with or without additional therapeutic agents (e.g., anticoagulants, antiplatelets, fibrinolytics).
Drug-eluting stents comprising compounds of Formula P, I, and P-II
Drug-eluting stents, including coronary or carotid artery stents of metal, plastic, biodegradable or bioabsorbable materials, incorporating compounds of Formula P, I, or P-II within a biocompatible polymer matrix to release the compounds and inhibit platelet adhesion/aggregation at the stent site.
The claims focus on the novel compounds of defined chemical formulas acting as αIIbβ3 antagonists that inhibit platelet function without inducing harmful β3 subunit conformational changes, pharmaceutical compositions comprising these compounds, therapeutic methods for thrombotic disorders, and medical devices such as drug-eluting stents incorporating these compounds.
Stated Advantages
The compounds inhibit fibrinogen binding and platelet aggregation without inducing the binding of integrin β3 LIBS-specific monoclonal antibodies, avoiding conformational changes linked to thrombocytopenia and increased mortality.
The compounds provide effective inhibition of platelet adhesion and aggregation with IC50 values less than 100 μM, preferably less than 25 μM, and greater than 30% inhibition at 100 μM or less in adhesion assays.
The compounds can be administered orally or parenterally and may be used in combination with known anticoagulants, antiplatelet agents, or thrombolytic agents to enhance therapeutic efficacy.
The compounds enable drug-eluting stents that locally inhibit platelet adhesion and aggregation, potentially reducing thrombotic complications after stent placement.
Documented Applications
Treatment and prophylaxis of thrombotic disorders, including stroke, myocardial infarction, unstable angina, abrupt closure following angioplasty or stent placement, thrombosis induced by peripheral vascular surgery, peripheral vascular disease, and thrombotic disorders resulting from atrial fibrillation or inflammation.
Use in drug-eluting stents, such as coronary or carotid artery stents, to locally inhibit platelet adhesion and aggregation to prevent thrombosis at stent sites.
Combination therapy with therapeutic agents such as anticoagulants, antiplatelet agents, and fibrinolytic/thrombolytic agents including heparin, warfarin, prasugrel, aspirin, ticlopidine, clopidogrel, ticagrelor, abciximab, eptifibatide and tirofiban for enhanced treatment of thrombotic disorders.
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