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WO 2008/118862 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 2 October 2008 (02.10.2008) PCT WO 2008/118862 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/01 (2006.01) A61P 9/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, (21) International Application Number: CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, PCT/US2008/058029 EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (22) International Filing Date: 24 March 2008 (24.03.2008) IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, (25) Filing Language: English MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, (26) Publication Language: English SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW 60/919,637 23 March 2007 (23.03.2007) US 60/948,787 10 July 2007 (10.07.2007) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): CAR- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, DAX PHARMACEUTICALS, INC. [US/US]; 99 193 ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Aiea Heights Dr., Suite 400, Aiea, Hawaii 96701 (US). European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, (72) Inventors; and NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, (75) Inventors/Applicants (for US only): LOCKWOOD, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Samuel, F [US/US]; 6709 Bar-K Ranch Road, Lago Vista, Texas 78645 (US). MASON, R. Preston [US/US]; Manchester, Massachusetts (US). Published: — with international search report (74) Agent: MEYERTONS, Eric B.; MEYERTONS, HOOD, — before the expiration of the time limit for amending the KIVLIN, KOWERT & GOETZEL, PC, P.O. Box 398, claims and to be republished in the event of receipt of Austin, Texas 78767-0398 (US). amendments (54) Title: CAROTENOID ANALOGS AND DERIVATIVESFOR THE PREVENTION OF PLATELET AGGREGATION (57) Abstract: The presently described embodiments are directed to compositions that include one or more carotenoid analogs or derivatives for use in the treatment of a disorder associated with platelet aggregation. Certain embodiments provide for the use of said carotenoid analogs or derivatives in preparing compositions suitable for use in such treatments. Further embodiments provide for pharmaceutical compositions that include one or more carotenoid analogs or derivatives in combination with one or more additional compositions or medicaments suitable for the treatment of a disorder associated with platelet aggregation. Yet further embodiments provide for methods of treating a disorder associated with platelet aggregation that include administering to a subject who would benefit from such treatment pharmaceutical compositions suitable for inhibiting platelet aggregation in a subject undergoing said treatments, and that include carotenoid analogs or derivatives, optionally in combination with one or more additional antiplatelet agents. CAROTENOID ANALOGS AND DERIVATIVES FOR THE PREVENTION OF PLATELET AGGREGATION BACKGROUND 1. Field of the Invention The present invention generally relates to the field of medicinal chemistry. More specifically, the present invention relates to the use of synthetic carotenoid analogs, derivatives and compositions made using same for the treatment and prevention of platelet aggregation and thrombus formation in a subject. 2. Description of the Relevant Art Platelet accumulation at sites of vascular injury is a dynamic process that mediates formation of both the primary hemostatic plug and pathologic thrombus formation. The mechanisms by which platelet surface proteins direct platelet recruitment to thrombi under flow conditions have been studied in detail. In addition to directing initial platelet adhesion, cell-surface receptor interactions activate intracellular signaling. Intracellular signaling stimulates the release of thrombogenic substances from platelet granules. α β Signaling also mediates activation of the platelet integrin irb 3 (gpIIb-IIIa) that facilitates firm adhesion of platelets to thrombi. Arterial thrombosis mediates tissue infarction in coronary artery disease, cerebrovascular disease, and peripheral vascular disease, and, thus, is the single most common cause of morbidity and mortality in the United States. Platelets are key mediators of arterial thrombosis. Thus, the identification of compounds that inhibit platelet function is of great importance to medicine. Platelets form the body's primary means of hemostasis and, as such, have developed an elaborate mechanism of surveying the vasculature for defects in endothelial integrity. This mechanism involves the ability to respond to subendothelial matrices, shear forces, neighboring platelets, the adrenal axis, as well as soluble proteinacious, nucleotide, and lipid signals. Despite this plethora of physiologic activators, the platelet has only a small repertoire of major functional outputs. Upon activation, platelets change shape, aggregate, and secrete their granular contents. The process of platelet activation involves the expression of activities not shared by functionally merit resting platelets, including, for example, ATP release, serotonin release, lysosomal release, alpha granule release, dense granule release, and cell surface expression of markers of activated platelets (including, but not limited to CD9, gplb, gpllb, gpllla, CDIa- Ha, P-selectin, PECAM-I, activated gpIIb/IIIa, and vitronectin receptor). In addition, platelet activation results in the aggregation of platelets with each other and with non-platelet surrounding cells. The granular contents of platelets supply additional adhesion molecules, growth factors, coagulation enzymes and other specialized molecules instrumental in the process of thrombus formation and the initiation of the healing process. In addition to coronary artery disease/myocardial infarction, cerebrovascular disease and peripheral vascular disease, diseases and disorders associated with inappropriate platelet activity and arterial thrombosis also include, for example, stable and unstable angina, transient ischemic attacks, placental insufficiency, unwanted thromboses subsequent to surgical procedures (e.g., aortocoronary bypass surgery, angioplasty and stent placement, and heart valve replacement), or thromboses subsequent to atrial fibrillation. Inhibitors of platelet activity can provide therapeutic and preventive benefits for each of these diseases or disorders. It is also possible that inappropriate platelet activation plays a role in venous thrombosis, such that platelet inhibitors can be useful for the treatment or prevention of disorders associated with such thromboses. A connection is emerging between platelet activation and inflammation, particularly allergic inflammation (e.g., in asthma) and inflammation at the sites of atherosclerotic damage. Therefore, compounds that inhibit platelet activation can also be useful in the treatment or prevention of disorders involving inflammation. There are a number of agents presently available that target platelet function. For example, aspirin is a relatively weak platelet inhibitor. However, aspirin can cause life-threatening allergic reactions in sensitive individuals. Another platelet inhibiting agent is ticlopidine (TICLID™, Roche Pharmaceuticals). Because it requires the production of active metabolites to be effective, the effect of ticlopidine is delayed 24-48 hours. The drug can also cause thrombotic thrombocytopenic purpura, a life-threatening condition, as well as nausea, abdominal pain, dyspepsia, diarrhea and skin rash. Clodiprogel (PLAVIX™, Bristol-Meyers Squibb/Sanofi Pharmaceuticals) is another platelet inhibitor that requires the generation of active metabolites for its therapeutic efficacy. Therefore, clodiprogel also has a delay of 24-48 hours for its effect. Clodiprogel can also cause thrombotic thrombocytopenia purpura as well as agranulocytopenia, both life-threatening conditions. The drug has also been associated with rash, edema, hypertension, hypercholesterolemia, nausea, abdominal pain, dyspepsia, diarrhea, urinary tract infections, liver enzyme elevations and arthralgia. The platelet inhibitory agents Abiximab and c7E3 Fab (REOPRO ABCIXIMAB™, manufacturer- -Centocor B.V., distributor-Eli Lilly and Co.) are only available in a parenteral form. The drugs can cause severe thrombocytopenia. Both have a very long half-life and, therefore, complicate surgery that is sometimes required in the setting of life-threatening arterial occlusion (e.g., emergent cardiac surgery in the setting of a myocardial infarction). Tirofiban (AGGRASTAT™, Merck and Co., Inc.) is another platelet inhibitory agent that is only available in a parenteral form. Tirofiban can cause thrombocytopenia, coronary artery dissection, bradycardia and edema, as well as dizziness and vasovagal reactions. Eptifibatide (INTEGRILIN™, COR Therapeutics, Inc., Key Pharmaceuticals Inc.) is another platelet inhibitory agent that is only available for parenteral administration. It can cause hypotension. There is only limited clinical experience with the oral
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