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WO 2012/088402 Al 28 June 2012 (28.06.2012) W P O P C T

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WO 2012/088402 Al 28 June 2012 (28.06.2012) W P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/088402 Al 28 June 2012 (28.06.2012) W P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A01N 43/42 (2006.01) A61K 31/44 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/US201 1/066810 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 22 December 201 1 (22. 12.201 1) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/426,023 22 December 2010 (22. 12.2010) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (71) Applicant (for all designated States except US): THE TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, SCRIPPS RESEARCH INSTITUTE [US/US]; 10550 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, North Torrey Pines Road, La Jolla, CA 92037 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors; and GW, ML, MR, NE, SN, TD, TG). (75) Inventors/ Applicants (for US only): BOHN, Laura, M. [US/US]; 1965 1 Red Maple Lane, Jupiter, FL 33458 (US). Published: MICALIZIO, Glenn, C. [US/US]; 170 Isle Verde Way, — with international search report (Art. 21(3)) Palm Beach Gardens, FL 33418 (US). — before the expiration of the time limit for amending the (74) Agent: ZACHARIADES, Nicholas, A.; Duane Morris claims and to be republished in the event of receipt of LLP, 2700 North Military Trail, Suite 300, Boca Raton, FL amendments (Rule 48.2(h)) 3343 1 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: SYNTHESIS OF CONOLIDINE AND DISCOVERY OF A POTENT NON-OPIOID ANALGESIC FOR PAIN 00 3 n W n p ci ste ma r i FIGURE I - (57) Abstract: The first de novo synthetic pathway to the exceptionally rare C5-nor stemmadenine natural product, conolidine, and © the first asymmetric synthesis of any member of this natural product class arc described. C5-nor stemmadenine compositions are also described. These compounds, for example,(+/- )-,(+)- and (-)-conolidine are potent and efficacious non-opioid analgesics in tonic and persistent pain. SYNTHESIS OF CONOLIDINE AND DISCOVERY OF A POTENT NON-OPIOID ANALGESIC FOR PAIN CROSS REFERENCE TO RELATED APPLICATIONS [001] This application claims priority to U.S. Provisional Application No.: 61/426,023 filed December 22, 2010, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION [002] Embodiments of the invention comprise methods for synthesizing rare alkaloids, in particular C5-nor stemmadenine alkaloids. Further embodiments comprise novel synthetic alkaloids and uses in treatment of pain. BACKGROUND [003 ] The search for the next generation of therapeutics for the treatment of pain continues to define an active area of scientific pursuit. Among current pharmaceutical interventions, opioid analgesics represent among the most widely embraced. Unfortunately, these agents are clinically problematic as a result of their well-established adverse properties that include addiction, tolerance, hyperalgesia, depression of breathing, nausea, and chronic constipation. As a result, the identification of effective non-opioid analgesics to replace these therapeutics is widely held as an important area of investigation. SUMMARY [004] This Summary is provided to present a summary of the invention to briefly indicate the nature and substance of the invention. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. [005] The first total synthesis of the rare C5-nor stemmadenine alkaloid, conolidine, and the first asymmetric synthetic pathway to any C5-nor stemmadenine is described. With an efficient source of this alkaloid secured by synthetic means (9 steps, 18% overall yield), the production of sufficient quantities of the natural product (and related antipode) was followed by the first evaluation of this alkaloid in vivo. n addition, the results show that (+)-, (-)-,and (+/-)- conolidine (1) are potent non-opioid analgesics that are effective at alleviating chemically induced, inflammatory, and acute tonic pain. [006] Other aspects are described infra. [007] BRIEF DESCRIPTION OF THE DRAWINGS [008] Figure 1 shows the chemical structure of C5-nor-stemmadenine (1) and stemmadenine (2-3) alkaloids. [009] Figures 2A and 2B are a schematic representation showing the development of a synthesis strategy for conolidine. Figure 2A. shows the biomimetic synthesis of vallesamine (5). Figure 2B shows the retrosynthesis of conolidine. [010] Figure 3 is a schematic representation showing the execution of a biologically inspired synthesis pathway to ( +/-)-conolidine (1). a = Yield reported is for the preparation of the ½ H2SO4 salt (the compound employed in subsequent in vivo experiments). PMB = p - methoxybenzyl; DCE = 1, 2-dichloroethane, DCM = dichloromethane. ACE-C1 = a-chloroethyl chloroformate. [Oil] Figure 4 is a schematic representation showing an asymmetric synthesis of(+)- and (-)- conolidine. = After hydrolysis. [012] Figures 5A to 5F are graphs showing that conolidine is antinociceptive in visceral, tonic, and persistent pain models and is present at µΜ levels in the brain after systemic injection. Male adult C57BL/6 mice were treated with conolidine sulfate or vehicle ( 1 0% DMSO, i.p. 10 µΙ-Vg) at the times indicated. Figure 5A: conolidine sulfate (10 or 20 mg/kg, i.p. of the indicated enantiomer) was injected 15 minutes prior to acetic acid (0.75% in H20). Abdominal constrictions were recorded during the 30 minutes immediately following acetic acid injection. Drug effect versus vehicle: **/?<0.01, ***/?<0.001', Student's t test, n = 4-8 mice per treatment. Figure 5B: formalin (25 µL·, 5%, in saline) was injected into the hind paw pad (intraplantar) 1 minutes after conolidine sulfate (10 mg/kg, i.p.); paw licking was recorded 40 minutes following formalin injection. Phase 1 refers to the sum of time spent licking in the first 10 minutes of response and Phase 2 represents the 20-40 minute response period. Drug effect versus vehicle: V<0.05, **p < . \ , ***/?<0.001, Student's t test, n = 6-1 1 mice per treatment. Figure 5C: dose effect of(-)-conolidine sulfate in each phase of the formalin test. Drug effect by one-way 2 ANOVA: =0.0004 for Phase 1 and p<0.0001 for Phase 2; Bonferroni post-hoc analysis: vehicle vs. drug within each phase: **p<0.01.; ***p<0.00\, n= 7-12 mice per treatment. Figure 5D: dose effect of morphine sulfate in 10% DMSO compared to vehicle. Drug effect by one- way ANOVA: p=0.03 for Phase 1; p<0.0001 for Phase 2; Bonferroni post-hoc analysis: vehicle vs. drug within each phase: * <0.05; **p<0.0\ ***/?<0.001, n= 4-12 mice per treatment. Figure 5E: time effect of (-)-conolidine sulfate suppression of both phases of the formalin response. Conolidine (10 mg/kg, i.p.) or vehicle was administered at the times indicated prior to formalin challenge. Conolidine vs. vehicle: *p < . 5 **p<0.01; 60 vs. 15 minutes: #p<0.05, Student's t test, n= 6-1 mice per treatment. Figure 5F: Pharmacokinetic profile of conolidine in plasma and brain after 0 mg/kg, i.p. injection or 10 mg/kg per os (PO) of male C57BL/6 mice at the times indicated. [013] Figure 6 is a graph showing that conolidine's analgesic properties are not accompanied by central nervous system effects that impact locomotor activity. [014] Figure 7 shows that conolidine leads to phosphorylation of Akt in primary dorsal root ganglion (DRG) cultures from adult mouse. Densitometry graph shows normalization of the degree of phosphorylated Akt (p-Akt) over total Akt (t-Akt) detected by specific antibodies. N=4 individual preparations from 4 mice; *p<0.05, ***p < 0.0001, Student's t- test. DETAILED DESCRIPTION [015] Embodiments described herein are directed to methods for the synthesis of rare alkaloids and their use in the prevention or treatment of pain. In particular embodiments, novel C5-nor stemmadenine compounds are described. [016] Several aspects of the invention are described below with reference to example applications for illustration. t should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or with other methods. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention. Definitions [017] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
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