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(12) United States Patent (10) Patent No.: US 9,353,075 B2 Piomelli Et Al US009353075B2 (12) United States Patent (10) Patent No.: US 9,353,075 B2 Piomelli et al. (45) Date of Patent: May 31, 2016 (54) DISUBSTITUTED BETA-LACTONES AS (56) References Cited INHIBITORS OF N-ACYLETHANOLAMINE ACIDAMIDASE (NAAA) U.S. PATENT DOCUMENTS 5,260,310 A 11/1993 Derungs et al. (71) Applicants: The Regents of the University of 6,358,978 B1 3/2002 Ritzeler et al. California, Oakland, CA (US); 2005, 0131.032 A1 6/2005 Sit et al. Fondazione Istituto Italiano Di 2007/O155747 A1 7/2007 Dasse et al. Tecnologia, Genoa (IT): Universita 2008/0050336 A1 2/2008 Bachand et al. 2009.0054526 A1 2/2009 Hansen et al. Degli Studi Di Parma, Parma (IT): 2010.0311711 A1 12/2010 Piomelli et al. Universita Degli Studi Di Urbino 2014/0094.508 A1 4/2014 Piomelli et al. “Carlo Bo”, Urbino (IT) FOREIGN PATENT DOCUMENTS (72) Inventors: Daniele Piomelli, Irvine, CA (US); Tiziano Bandiera, Gambolo (IT): WO 2009/049238 A1 4/2009 Marco Mor, Ghedi (IT): Giorgio WO WO-2011/082285 A1 T 2011 Tarzia, Petriano (IT): Fabio Bertozzi, WO WO-2013,078430 A1 5, 2013 Genoa (IT); Stefano Ponzano, Florence (IT) OTHER PUBLICATIONS Armirotti et al., “B-Lactones Inhibit N-acylethanolamine Acid (73) Assignees: The Regents of the University of Amidase by S-Acylation of the Catalytic N-Terminal Cysteine.” ACS California, Oakland, CA (US); Medicinal Chemistry Letters (ACS), 2012, vol. 3, No. 5, pp. 422-426. Fondazione Istituto Italiano Di Astarita et al., “Pharmacological Characterization of Hydrolysis Technologia, Genoa (IT); Universita Resistant Analogs of Oleoylethanolamide with Potent Anorexiant Degli Studi Di Parma, Parma (IT): Properties.” The Journal of Pharmacology and Experimental Thera Universita Degli Studi Di Urbino peutics, vol. 318, No. 2, received Mar. 24, 2006, accepted May 12, “Carlo Bo”, Urbino (IT) 2006. Dias et al., “Antimicrobial properties of highly fluorinated silver (I) (*) Notice: Subject to any disclaimer, the term of this tis(pyrazoili)borates,” Journal of Inorganic Biochemistry, 2006, vol. patent is extended or adjusted under 35 100, No. 100, pp. 158-160. U.S.C. 154(b) by 0 days. Duranti et al., “N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Struc ture—Activity and Structure—Property Relationships,” Journal of (21) Appl. No.: 13/684,017 Medicinal Chemistry, May 2012, pp. A-M. dx.doi.org/10.1021/ jm3.00349. (22) Filed: Nov. 21, 2012 Higashibayashi et al "Synthetic studies on thiostrepton family of peptide antibiotics: synthesis of the pentapeptide segment containing (65) Prior Publication Data dihydroxyisoleucine, thiazoline and dehydroamino acid.” Tetrahe US 2013/0281490 A1 Oct. 24, 2013 dron Letters (Elsevier B.V.), 2004, vol. 45, No. 19, pp. 3707-3712. (Continued) Related U.S. Application Data (60) Provisional application No. 61/562,862, filed on Nov. Primary Examiner — Shobha Kantamneni 22, 2011. (74) Attorney, Agent, or Firm — Mintz Levin Cohn Ferris Glovsky and Popeo, P.C. (51) Int. Cl. C07D 305/12 (2006.01) (57) ABSTRACT A6 IK3I/585 (2006.01) A6 IK3I/38 (2006.01) The present invention provides compounds and pharmaceu CO7D 405/2 (2006.01) tical compositions for inhibiting N-acylethanolamine acid C07D 407/12 (2006.01) CO7D 409/2 (2006.01) amidase (NAAA). Inhibition of NAAA is contemplated as a A6 IK3I/365 (2006.01) method to sustain the levels of palmitoylethanolamide (PEA) (52) U.S. Cl. and oleylethanolamide (OEA), two substrates of NAAA, in CPC ............ C07D 305/12 (2013.01); A61K3I/365 conditions characterized by reduced concentrations of PEA (2013.01); A61 K3I/38 (2013.01); C07D and OEA. The invention also provides methods for treating 405/12 (2013.01); C07D407/12 (2013.01); inflammatory diseases and pain, and other disorders in which C07D409/12 (2013.01) decreased levels of PEA and OEA are associated with the (58) Field of Classification Search disorder. CPC ... A61K 31/135; A61K 31/337; A61K 31/38: CO7D 305/12 See application file for complete search history. 2 Claims, 26 Drawing Sheets US 9,353,075 B2 Page 2 (56) References Cited Spetzler et al., “Preparation and application of 0-amino-Serine, Ams, a new building block in chemoselective ligation chemistry,” Journal OTHER PUBLICATIONS of Peptide Science, 1999, vol. 5, Issue 12, pp. 582-592. Stigers et al., “Incorporation of chlorinated analogues of aliphatic Holt et al., “Inhibition offatty acid amide hydrolase, a key endocan amino acids during cell-free protein synthesis.” Chemical Commu nabinoid metabolizing enzyme, by analogues of ibuprofen and nications (Royal Soc. of Chemistry), 2011, vol. 47, No. 6, pp. 1839 indomethacin.” Eur J Pharmacol., Jun. 2007, 565(1-3)a;26-36, Epub 1841. Mar. 7, 2007 (abstract). Lall et al., “Serine and Threonine B-Lactones: A New Class of Hepa Tsuboi et al., Molecular Characterization of N-Acylethanolamine titis A Virus 3C Cysteine Proteinase Inhibitors,” Journal of Organic hydrolyzing Acid Amidase, a Novel Member of the Choloylglycine Chemistry (American Chemical Society), 2002, vol. 67, No. 5, pp. Hydrolase Family with Structural and Functional Similarity to Acid 1536-1547. Ceramidase, The Journal of Biological Chemistry, vol. 280, No. 12, Li et al., “Design and Synthesis of Potent N-Acylethanolamine Issue of Mar. 25, pp. 11082-11092, 2005. hydrolyzing Acid Amidase (NAAA) Inhibitor as Anti-Inflammatory Ueda et al., “A second N-acylethanolamine hydrolase in mammalian Compounds.” PLoS One, Aug. 2012;7(8):e43023. tissues.” Neuropharmacology, 2005, vol. 48, pp. 1079-1085. Lohse et al., “Incorporation of a phosphonic acid isostere of aspartic Valls et al., “Synthesis of beta-chloro alpha-amino acids: (2S,3R)- acid into peptides Using Fmoc-solid phase synthesis.” Tetrahedron and (2S,3S)-3-chloroleucine.” Tetrahedron Letters, vol. 47, pp. 3701 Letters, 1998, vol.39, Issue 15, pp. 2067-2070. 3705, available online Apr. 12, 2006. Mori et at “Total Synthesis of Siomycin A: Construction of Synthetic Wang et al., “f-Lactone probes identify a papain-like peptide ligase Segments.” Chemistry—An Asian Journal (Wiley VCH Verlag), in Arabidopsis thaliana,” Nature Chemical Biology (Nature Publish 2008, vol. 3, No. 6, pp.984-1012. ing Group), 2008, vol. 4. No. 9, pp. 557-563. Pu et al., “Synthesis, Stability, and Antimicrobial Activity of (+)- International Search Report and Written Opinion, Mail date Feb. 28. Obafluorin and Related B-Lactone Antibiotics,” Journal of Organic 2013, PCT application No. PCT/US2012/066421, pp. 11. Chemistry, 1994, vol. 59, No. 13, pp. 3642-3655. He, G. etal. (May 23, 2011, e-published Apr. 27, 2011). “A practical Saturnino et al., “Synthesis and biological evaluation of new potential strategy for the structural diversification of aliphatic scaffolds inhibitors of N-acylethanolamine hydrolyzing acid amidase.” through the palladium-catalyzed picolinamide-directed remote Bioorganic & Medicinal Chemistry Letters, 2010, vol. 20, Issue 3, functionalization of unactivated C(sp3)-H bonds.” Angewandte pp. 1210-1213. Chemie Int. Ed. 50(22):5192-5196. Solorzano et al., “Selective N-acylethanolamine-hydrolyzing acid International Search Report mailed on Dec. 17, 2008, for PCT Appli amidase inhibition reveals a key role for endogenous cation No. PCT/US2008/079621, 1 page. palmitoylethanolamide in inflammation.” PNAS, 2009, vol. 106, No. Pu, Y. etal. (1991). “Synthesis and Acylation of Salts of L-Threonine 49, pp. 20966-20971. B-Lactone: A Route to B-Lactone Antibiotics.” J Org Chem SolorZano et al., “Synthesis and structure-activity relationships of 56(3): 1280-1283. N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing Pu, Y. et al. (1994). “Synthesis, Stability, and Antimicrobial Activity acid amidase inhibitors,” J. Med. Chem., 2010, vol. 53, No. 15, pp. of (+)-Obafluorin and Related B-Lactone Antibiotics.”J Org Chem 577O-5781. 59(13):3642-3655. U.S. Patent May 31, 2016 Sheet 1 of 26 US 9,353,075 B2 Figure s S & Compound 6 U.S. Patent May 31, 2016 Sheet 2 of 26 US 9,353,075 B2 Figure 2 0.8 0. 2 0.0 Nave Vehicle 1 % 3% 10% 30 % Compound 6 DNFB U.S. Patent May 31, 2016 Sheet 3 of 26 US 9,353,075 B2 Figure 3 t - . - r ..& -- h 8 O 12 24 26 time (h) CARRA -6 Veh (petrolatum + 5% auric acid) -8. Compound 6 - 30% -- Compound 6 - 10% & Compound 6 - 3% ** P C 0.005 WS Veh & Compound 6 - 1% *** P <0.001 VS veh U.S. Patent May 31, 2016 Sheet 5 of 26 US 9,353,075 B2 Figure 5 Cutaneous hyperalgesia O20 0.15 30 E. st o 0.10 20 E g 0.05 10 s O 0.00 time time -er + i + veh +f-r veh -8- +1+ Compound 6 x +1+ Compound 6 *8 -f- veh 8 -j- veh - -f- Compound 6 I -f- Compound 6 * p-0.005vs +1+ veh; * p-0.001 vs -j- veh and -f- Compound 6; ### p<0.001 vs +14 veh and +/- Compound 6 U.S. Patent May 31, 2016 Sheet 6 of 26 US 9,353,075 B2 0.15 O. O. 0.05 OOO time (h) -Or Veh (petrolatum + 5% auric acid) x Compound 6 - 30% -8- AM 630 1 g/paw (CB2 antagonist) + Compound 6-30% -8- AM 251 1 g/paw (CB1 antagonist) + Compound 6 - 30% nor GW 6471 1 g/paw (PPARC. antagonist) + Compound 6-30% ## P < 0.001 vs compound 6 alone, ns = not significant vs veh; * P <0.001 vs veh U.S. Patent May 31, 2016 Sheet 7 of 26 US 9,353,075 B2 Figure 7 cutaneousCutaneous hyperalgesia 30 se E 20 es s c S. wn?E 10 O O 4. O 4. O 4. ?h ? ?h time (h) CARRA CARRA CARRA CARRA CARRA Mil Veh ( petrolatum + 5% lauric acid) x Compound 6 - 30% O AM 630 gll paw + Compound 6 - 30% AM251 1 g paw + Compound 6 - 30% x GW 647 1 ug? paw + Compound 6 - 30% fifth P < 0.001 vs Compound 6 alone; ns = not significant vs veh; * P<0.001 vs veh U.S.
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