US 200901 24574A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0124574 A1 LOckW00d et al. (43) Pub. Date: May 14, 2009 (54) CAROTENOIDANALOGS AND DERIVATIVES A63L/365 (2006.01) FOR THE PREVENTION OF PLATELET A6II 3/66 (2006.01) AGGREGATION A613/60 (2006.01) A 6LX 3L/727 (2006.01) (76) Inventors: Samuel F. Lockwood, Lake A63L/366 (2006.01) Linden, MI (US); R. Preston A63L/4365 (2006.01) Mason, Manchester, MA (US) (52) U.S. Cl. ........... 514/56; 514/547: 514/483; 514/479; Correspondence Address: 514/473; 514/136; 514/163; 514/460; 514/301 MEYERTONS, HOOD, KIVLIN, KOWERT & (57) ABSTRACT GOETZEL, P.C. P.O. BOX 398 The presently described embodiments are directed to compo AUSTIN, TX 78767-0398 (US) sitions that include one or more carotenoid analogs or deriva tives for use in the treatment of a disorder associated with (21) Appl. No.: 12/079,253 platelet aggregation. Certain embodiments provide for the use of said carotenoid analogs or derivatives in preparing (22) Filed: Mar. 24, 2008 compositions suitable for use in Such treatments. Further embodiments provide for pharmaceutical compositions that Related U.S. Application Data include one or more carotenoid analogs or derivatives in (60) Provisional application No. 60/919,637, filed on Mar. R with St. E. still Ein or 23, 2007, provisional application No. 60/948,787, medicaments suitable Ior une treatment of a disorder associ filed on Jul. 10, 2007. ated with platelet aggregation. Yet farther embodiments pro s vide for methods of treating a disorder associated with plate O O let aggregation that include administering to a Subiect who Publication Classification E. from Such treatment Nitti . (51) Int. Cl. tions suitable for inhibiting platelet aggregation in a subject A6 IK 3L/225 (2006.01) undergoing said treatments, and that include carotenoidana A6IP 7/02 (2006.01) logs or derivatives, optionally in combination with one or A6 IK3I/27 (2006.01) more additional antiplatelet agents. Patent Application Publication May 14, 2009 Sheet 1 of 21 US 2009/O124574 A1 FIG. 1A FIG. 1B FIG 1C Welston gold Wire 6pm nano Sensor (tip 200 um) Endothelial cell w w reserver - 7 - 8 um ruler mirror." Patent Application Publication May 14, 2009 Sheet 2 of 21 US 2009/0124574 A1 A 25 20 15 O Control Astaxanthin Clopidogrel AstaXanthin -- Clopidogrel 3 O O 2 5 O 2 O O 150 100 50 Astaxanthin Clopidogrel AStaxanthin -- Clopidogrel FIG. 3 Patent Application Publication May 14, 2009 Sheet 3 of 21 US 2009/O124574 A1 <!--------------------------?--> 009Z 09ZZ 000Z 09/,?. 009|| 097|| 000|| 09/ 009 09% uOle Juego UOO ON Patent Application Publication May 14, 2009 Sheet 4 of 21 US 2009/0124574 A1 7OO KXX& x: 8 COLO OO CDC 388 &K 400çOQN!<- |- . OCDOOOO Control Astaxanth n Clopidogrel Astaxanthin -- Clopidogrel FIG. 5 Control Astaxanth r Clopidogrel Astaxanthin r Clopidogrel FIG. 6 Patent Application Publication May 14, 2009 Sheet 5 of 21 US 2009/0124574 A1 CN LO Control Astaxanthin Clopidogrel Astaxanthin -- Clopidogrel FIG. 7 Patent Application Publication May 14, 2009 Sheet 8 of 21 US 2009/O124574 A1 2500 5 c 2OOO O. N w 1500 X O Zas 1 OOO 8 500 o d Control Astaxanthin Aspirin Simvastatin 500 400 200 1OO Control AStaxanthin Aspirin Simvastatin FIG. 12 Patent Application Publication May 14, 2009 Sheet 9 of 21 US 2009/0124574 A1 500 400 300 200 1OO Control Aspirin Aspirin Aspirin Aspirin Aspirin -- -- H H AstaX AstaX AS tax Astax 0.1 uM 1.0 uM 5.0 uM 10.0 uM FIG. 13 4500 4000 3500 3000 2500 2000 1500 1 OOO 500 Control Aspirin Aspirin Aspirin Aspirin Aspirin Ha H Astax Astax AstaX AStax 0.1 uM 1.0 uM 5.0 uM 10.0 M FIG. 14 Patent Application Publication May 14, 2009 Sheet 10 of 21 US 2009/O124574 A1 375 T 300 225 - - 150 - Control Simva Simva Simva Simva Sinva s -- -- -- Astax Astax As tax AstaX 0.1 puM 1.0 uM 5.0 puM 10.0 uV FIG. 15 3500 3OOO 2500 2000 1500 1000 500 Control Simva Simva Simva Simva Simva -- -- -- Astax AstaX Astax Astax 0.1 uM 1.0 uM 5.0 uM 10.0 uM FIG. 16 Patent Application Publication May 14, 2009 Sheet 11 of 21 US 2009/0124574 A1 14 1 2 1 O 6 Control Aspirin Aspirin Aspirin Aspirin Aspirin H -- -- -- Astax AStax AStax AStax 0.1 uv 1.0 uM 5.0 uM 10.0 uM FIG. 17 Control Simva Simva Simva Simva Simva -- -- -- AstaX AStax AStax Astax 0.1 uM 1.0 uM 5.0 uM 10.0 uM FIG. 18 Patent Application Publication May 14, 2009 Sheet 12 of 21 US 2009/O124574 A1 Control Astaxanthin Aspirin Simvastatin FIG. 19 Patent Application Publication May 14, 2009 Sheet 13 of 21 US 2009/0124574 A1 Oz'91-' Patent Application Publication May 14, 2009 Sheet 14 of 21 US 2009/0124574 A1 Astaxanthin in Rat Plasma. 4 Hours. After Ingestion of Astaxanthin 50 40 30 20 10 O -10 Astaxanthin in Rat Plasma: 4 Hours. After ingestion of ADS -a CC YwE Gy d CS d h C c O CC Astaxanthin in Rat Plasma. 4 Hours. After Ingestion of ADL FIG 21 Patent Application Publication May 14, 2009 Sheet 15 of 21 US 2009/0124574 A1 Astaxanthin in Rat Plasma: 8 Hours. After Ingestion of Astaxanthin 50 40 30 Astaxanthin in Rat Plasma. 8 Hours. After ingestion of ADS 50 40 an ag 30 Ye'8 d O - C O a. Astaxanthin in Rat Plasma. 8 Hours. After Ingestion of ADL 50 40 30 2O 10 O -10 FIG 21 (Continued) Patent Application Publication May 14, 2009 Sheet 16 of 21 US 2009/O124574 A1 ZOZZOy?dXO–Kpn?SXAd Patent Application Publication May 14, 2009 Sheet 17 of 21 US 2009/O124574 A1 Patent Application Publication May 14, 2009 Sheet 18 of 21 US 2009/0124574 A1 m Patent Application Publication May 14, 2009 Sheet 19 of 21 US 2009/O124574 A1 Patent Application Publication May 14, 2009 Sheet 20 of 21 US 2009/O124574 A1 90710yIdxo–Ápn?SXd Patent Application Publication May 14, 2009 Sheet 21 of 21 US 2009/O124574 A1 ZOGLOMdXO–Ápn}SXAd US 2009/O124574 A1 May 14, 2009 CAROTENOID ANALOGS AND DERVATIVES granular contents of platelets Supply additional adhesion mol FOR THE PREVENTION OF PLATELET ecules, growth factors, coagulation enzymes and other spe AGGREGATION cialized molecules instrumental in the process of thrombus formation and the initiation of the healing process. PRIORITY CLAIM 0008. In addition to coronary artery disease/myocardial 0001. This application claims the benefit of priority under infarction, cerebrovascular disease and peripheral vascular 35 U.S.C. 119 (d)(e) to Provisional Patent Application Ser. disease, diseases and disorders associated with inappropriate No. 60/919,637, entitled “CAROTENOIDANALOGS AND platelet activity and arterial thrombosis also include, for DERIVATIVES FOR THE INHIBITION OF AGGREGA example, stable and unstable angina, transient ischemic TION' filed Mar. 23, 2007 and to Provisional Patent Appli attacks, placental insufficiency, unwanted thromboses Subse cation Ser. No. 60/948,787, entitled “CAROTENOIDANA quent to Surgical procedures (e.g., aortocoronary bypass Sur LOGS AND DERIVATIVES FOR THE PREVENTION OF gery, angioplasty and stent placement, and heart Valve PLATELET AGGREGATION filed Jul. 10, 2007. The replacement), or thromboses Subsequent to atrial fibrillation. above-cited applications are commonly assigned with the Inhibitors of platelet activity can provide therapeutic and present invention, and the entire contents thereof are incor preventive benefits for each of these diseases or disorders. It porated by reference as though fully set forth herein. is also possible that inappropriate platelet activation plays a role in venous thrombosis, such that platelet inhibitors can be BACKGROUND OF THE INVENTION useful for the treatment or prevention of disorders associated with such thromboses. 0002 1. Field of the Invention 0009. A connection is emerging between platelet activa 0003. The present invention generally relates to the field of tion and inflammation, particularly allergic inflammation medicinal chemistry. More specifically, the present invention (e.g., in asthma) and inflammation at the sites of atheroscle relates to the use of synthetic carotenoid analogs, derivatives rotic damage. Therefore, compounds that inhibit platelet acti and compositions made using same for the treatment and vation can also be useful in the treatment or prevention of prevention of platelet aggregation and thrombus formation in disorders involving inflammation. a subject. 0010. There are a number of agents presently available 0004 2. Description of the Relevant Art that target platelet function. For example, aspirin is a rela 0005 Platelet accumulation at sites of vascular injury is a tively weak platelet inhibitor. However, aspirin can cause dynamic process that mediates formation of both the primary life-threatening allergic reactions in sensitive individuals. hemostatic plug and pathologic thrombus formation. The 0011. Another platelet inhibiting agent is ticlopidine mechanisms by which platelet surface proteins direct platelet (TICLIDTM, Roche Pharmaceuticals). Because it requires the recruitment to thrombi under flow conditions have been stud production of active metabolites to be effective, the effect of ied in detail. In addition to directing initial platelet adhesion, ticlopidine is delayed 24-48 hours. The drug can also cause cell-surface receptor interactions activate intracellular signal thrombotic thrombocytopenic purpura, a life-threatening ing. Intracellular signaling stimulates the release of thrombo condition, as well as nausea, abdominal pain, dyspepsia, diar genic Substances from platelet granules. Signaling also medi rhea and skin rash. ates activation of the platelet integrin CfB (gpIb-IIIa) that (0012 Clodiprogel (PLAVIXTM, Bristol-Meyers Squibb/ facilitates firm adhesion of platelets to thrombi. Sanofi Pharmaceuticals) is another platelet inhibitor that 0006 Arterial thrombosis mediates tissue infarction in requires the generation of active metabolites for its therapeu coronary artery disease, cerebrovascular disease, and periph tic efficacy.