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Resolvins: Biotemplates for Therapeutic Interventions

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Resolvins: Biotemplates for Therapeutic Interventions (19) & (11) EP 2 216 318 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 11.08.2010 Bulletin 2010/32 C07C 59/42 (2006.01) C07C 69/73 (2006.01) C07D 303/38 (2006.01) A61K 31/202 (2006.01) (2006.01) (2006.01) (21) Application number: 09009237.0 A61K 31/232 A61K 31/336 (22) Date of filing: 12.08.2003 (84) Designated Contracting States: (71) Applicant: BRIGHAM AND WOMEN’S HOSPITAL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Boston, HU IE IT LI LU MC NL PT RO SE SI SK TR Massachusetts 02115 (US) (30) Priority: 12.08.2002 US 402798 P (72) Inventor: Serhan, Charles, N. 12.08.2003 US 639714 Needham, MA 02492 (US) (62) Document number(s) of the earlier application(s) in (74) Representative: Strehl Schübel-Hopf & Partner accordance with Art. 76 EPC: Maximilianstrasse 54 03785253.0 / 1 537 067 80538 München (DE) (27) Previously filed application: Remarks: 12.08.2003 EP 03785253 This application was filed on 15-07-2009 as a divisional application to the application mentioned under INID code 62. (54) Resolvins: Biotemplates for therapeutic interventions (57) The present invention is generally drawn to nov- logical properties. The present invention therefore pro- el isolated therapeutic agents, termed resolvins, gener- vides for many new useful therapeutic di- or tri-hydroxy ated from the interaction between a dietary omega- 3 pol- derivatives of EPA or DHA (resolvins) that diminish, pre- yunsaturated fatty acid (PUFA) such as eicosapentae- vent, or eliminate inflammation or PMN migration, for ex- noic acid (EPA) or docosahexaenoic acid (DHA), cy- ample. The present invention also provides methods of clooxygenase-II (COX-2) and an analgesic, such as as- use, methods of preparation, and packaged pharmaceu- pirin (ASA). Surprisingly, careful isolation of compounds ticals for use as medicaments for the compounds dis- generated from the combination of components in an ap- closed throughout the specification. propriate environment provide di- and tri- hydroxy EPA or DHA compounds having unique structural and physio- EP 2 216 318 A2 Printed by Jouve, 75001 PARIS (FR) EP 2 216 318 A2 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to previously unknown therapeutic agents derived from novel signaling and biochemical pathways that use eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), both of which are polyunsaturated fatty acids (PUFAs) as precursors to the production of bioactive novel endogenous products that control physiologic events in inflammation and resolution in vascular endothelial reactions and neural systems (brain). More specifically, the present invention relates to di- and trihydroxy potent bioactive products termed "Resolvins," which are 10 derived from the biochemical interactions of a 5 lipoxygenases, such as cyclooxygenase and a polyunsaturated fatty acid. In addition, therapeutic stable analogs of resolvins that enhance their biologic properties are described that can be used to expedite resolution by inhibiting the pro-inflammatory amplification of leukocyte entry. BACKGROUND OF THE INVENTION 15 [0002] The roles of eicosanoids in diverse physiologic and pathologic scenarios provide clear examples of the impor- tance of fatty acid precursors such as arachidonic acid in cell communication, a sharp departure from their structural and storage assignments (3-5). Among the classes of bioactive eicosanoids, including prostaglandins, leukotrienes (LT), lipoxins (LX) and cis-epoxyeicosatrienoic acids or EETs (4, 6), it is now apparent that counterregulatory autacoids exist 20 within these classes of eicosanoids. Of the cyclooxygenase pathways, prostacyclin and thromboxane are important vascular counter-regulators (7). In inflammation, leukotriene products of the 5-lipoxygenase are pro-inflammatory me- diators (4, 8), and lipoxins generated via lipoxygenase interactions can counterregulate certain leukotriene-mediated events (for a recent review, see 9). The emergence of temporal and spacial separation in biosynthesis of eicosanoids during inflammation sheds lighton distinctfunctional settings for lipoxins as"stop" orpro- resolution signals (10). Moreover, 25 aspirin (ASA) treatment can pirate the lipoxin system, triggering formation of their 15-epimeric or their R-containing isoform (ASA-triggered LX) that serve as LX mimetics, to mount pro- resolution status (9, 11, 12), as well as enhancers in epithelial-based anti-microbial host defense (13). [0003] Leukocytes from several species of fish rich in omega- 3 fatty acids generate prostaglandins, leukotrienes and lipoxins from both arachidonic acid (C20:4) and eicosapentaenoic acid (C20:5). Their immune functions in marine or- 30 ganisms appear similar to those in humans; namely, as drivers of cell motility. Yet, fish cells generate quantitatively similar levels of both 4 and 5 series (EPA-derived) leukotrienes and lipoxins, which is sharply different than human tissues that use predominantly C20: 4-derived mediators (reviewed in 14). Omega- 3 fatty acids such as eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6) may be beneficial in several human diseases including atherosclerosis, asthma, cardiovascular, cancer (reviewed in 15), and, more recently, mental depression (16, 17) and 35 preventing sudden death after myocardial infarction (18, 19). Of interest are results from the GISSI-Prevenzione trial that evaluated omega-3 polyunsaturated fatty acid supplementation with more than 11,300 patients that provide evidence for a decrease of ∼ 45 % in cardiovascular death (20). [0004] It is noteworthy that both patient groups received aspirin in the GISSI trial while comparing tocopherol vs. omega-3 supplementation (20) as did a significant number of participants in the most recent Physician Health study 40 report (18). The impact of ASA to the results of these studies was not tested although firmly concluding the benefits of omega-3 fatty acids in risk reduction (18, 20, 21). Eating fish rich in omega-3’s is now recommended by the American Heart Association (see http://www.americanheart.org). However, what is evident from animal studies is that DHA is the bioactive cardiovascular protective component of fish oils (22). The mechanism(s) for omega-3 protective properties in heart disease and in prostate cancer remains unclear and the molecular bases are still sought to explain the clinical 45 phenomena associated with fish oil trials. [0005] The heightened awareness that unresolved inflammation is important in many chronic disorders including heart disease, atherosclerosis, asthma, and Alzheimer’s disease (23, 24) leads to question whether omega- 3 utilization during ASA therapy is converted to endogenous bioactive compounds relevant in human disease and health. Recently, data suggests that at sites of inflammation omega-3 PUFA eicosapentaenoic acid (EPA) is converted to potent bioactive 50 products that target neutrophil recruitment (2). Hence, COX-2, which has a larger substrate tunnel/channel than COX- 1 (25, 26), acts on C20: 4 as well as additional substrates that can be productively accommodated as exemplified by the ability to convert the omega- 3 polyene family of lipids (i.e., C18:3 and C20:5), possibly for tissue- specific COX-2 missions (2) such as those associated with ischemic preconditioning (19), resolution (10, 12, 27) and/or other disease processes. EPA and COX-2 (2) or DHA (28-32) raise the possibility that, in addition to arachidonic acid, omega-3 fatty acids in 55 certain biologic processes, e.g., ischemia-induced cardiac arrhythmias (22), may serve as substrates for conversion to potent bioactive products (2). However, the biological role and significance of products that could be derived from DHA in inflammation has remained to be established. [0006] A need therefore exists for an improved understanding of the function of these materials in physiology as well 2 EP 2 216 318 A2 as the isolation of bioactive agents that can serve to eliminate or diminish various disease states or conditions, such as those associated with inflammation. BRIEF SUMMARY OF THE INVENTION 5 [0007] The present invention, in one embodiment, is drawn to isolated therapeutic agents generated from the interaction between a dietary omega- 3 polyunsaturated fatty acid (PUFA) such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), cyclooxygenase-II (COX-2) and an analgesic, such as aspirin (ASA). Surprisingly, careful and challenging isolation of previously unknown and unappreciated compounds are generated from exudates by the combination of 10 components in an appropriate environment to provide di- and tri- hydroxy EPA or DHA compounds having unique structural and physiological properties. The present invention therefore provides for many new useful therapeutic di- or tri-hydroxy derivatives of EPA or DHA that diminish, prevent, or eliminate inflammation, for example. [0008] The di- and tri-hydroxy EPA and DHA therapeutic agents of the invention include, for example: 15 20 25 30 35 40 45 50 55 3 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 4 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 5 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 6 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 7 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 8 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 9 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 10 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 11 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 12 EP 2 216 318 A2 5 10 15 20 25 30 35 40 45 50 55 13 EP 2 216
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