USOO943985OB2 (12) United States Patent (10) Patent No.: US 9,439,850 B2 Kelliher et al. (45) Date of Patent: *Sep. 13, 2016 (54) USE OF PUFAS FOR TREATING SKIN (2013.01); A61 K3I/573 (2013.01); A61 K NFLAMMATION 45/06 (2013.01); C07C 59/42 (2013.01) (58) Field of Classification Search (71) Applicant: Dignity Sciences Limited, Dublin (IE) CPC ............. A61 K9/0014; A61K 31/002: A61 K (72) Inventors: Adam Kelliher, London (GB); Angus 31/573; A61K 45/06; C07C 51/42 Morrison, Isle of Lewis (GB); Phil USPC .......................................................... 514/560 Knowles, Cumbria (GB) See application file for complete search history. (73) Assignee: Dignity Sciences Limited, Dublin (IE) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this U.S. PATENT DOCUMENTS patent is extended or adjusted under 35 4,273,763. A 6, 1981 Horrobin U.S.C. 154(b) by 0 days. 4,309.415 A 1/1982 Horrobin This patent is Subject to a terminal dis (Continued) claimer. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 14/203,837 EP O1394.80 5, 1952 (22) Filed: Mar. 11, 2014 EP OO35856 9, 1981 (Continued) (65) Prior Publication Data OTHER PUBLICATIONS US 2014/O194399 A1 Jul. 10, 2014 Conrow et al., Org. Proc. Res. & Dev. 15:301-304 (2011). Related U.S. Application Data (Continued) (63) Continuation of application No. 13/461,472, filed on May 1, 2012, now Pat. No. 8,729.126, which is a Primary Examiner — Deborah D Carr continuation of application No. 13/318,290, filed as (74) Attorney, Agent, or Firm — Perkins Coie LLP application No. PCT/GB2010/000844 on Apr. 29, 2010, now Pat. No. 8,536,223. (57) ABSTRACT (60) Provisional application No. 61/177,811, filed on May The present invention provides a compound which is a 13, 2009. polyunsaturated fatty acid (PUFA) derivative of formula (I), (30) Foreign Application Priority Data Apr. 29, 2009 (GB) ................................... O9074 13.9 O (51) Int. Cl. RO --~~ A6 IK 9/00 (2006.01) A6 IK 3L/202 (2006.01) or a pharmaceutically acceptable salt, or Solvate thereof, for (Continued) use in treating various skin disorders. (52) U.S. Cl. CPC ........... A61K 9/0014 (2013.01); A61K 3 1/202 16 Claims, 5 Drawing Sheets US 9,439,850 B2 Page 2 (51) Int. Cl. EP 0309086 3, 1989 A 6LX 3/573 (2006.01) EP O409559 1991 A6 IK 45/06 (2006.01) E. 'S 28. C07C 59/42 (2006.01) EP 250818O 10, 2012 JP 2006219.454 8, 2006 (56) References Cited JP 2006.306812 11 2006 WO WO9816215 4f1998 U.S. PATENT DOCUMENTS WO WO9852556 11, 1998 WO WOO 103696 1, 2001 4,386,072 A 5, 1983 Horrobin et al. WO WOO2O1969 1, 2002 4,388,324 A 6, 1983 Horrobin WO WOO2O89791 11 2002 4,444,755 A 4, 1984 Horrobin WO WOO2092O71 11 2002 4,826,877 A 5, 1989 Stewart et al. WO WOO2O964.08 12/2002 4,888,326 A 12/1989 Horrobin WO WO2007079224 7/2007 4,898,885 A 2f1990 Horrobin WO WO2O08070129 6, 2008 4,965,075 A 10, 1990 Horrobin et al. WO WO 20080701.29 A2 * 6, 2008 ........ A61K 31,202 4,970,076 A 11/1990 Horrobin WO WO2008114141 9, 2008 4,996,233 A 2f1991 Horrobin WO WO2O10020603 2, 2010 4,997,657 A 3, 1991 Horrobin et al. WO WO2010.125330 11 2010 5,145,686 A 9, 1992 Horrobin et al. WO WO2010.125340 11 2010 5, 198,468 A 3, 1993 Horrobin WO WO2O13057284 4/2013 5,318,991 A 6, 1994 Horrobin et al. WO WO2O13057287 4/2013 5,324,748 A 6, 1994 Horrobin WO WO2013O82265 6, 2013 5,328,691 A 7, 1994 Horrobin et al. WO WO2O13112876 8, 2013 5,380,757 A 1/1995 Horrobin WO WO2O13124479 8, 2013 5,552,150 A 9, 1996 Horrobin et al. WO WO2O14022816 2, 2014 5,562.913 A 10, 1996 Horrobin 5,580,556 A 12/1996 Horrobin OTHER PUBLICATIONS 5,583,159 A 12/1996 Horrobin et al. 5,589,509 A 12/1996 Horrobin Desbois et al., “Antibacterial free fatty adds: activities, mechanisms 5,614,208 A 3/1997 Horrobin et al. of action and biotechnological potential.' Appl. Microbiol. 5,618,558 A 4, 1997 Horrobin et al. Biotechnol. (2010) 85:1629-1642. SE A 22 E. al Eishof et al. “Biocatalytic large-scale production of 12(S)- 5,709,885 A 1/1998 Hellen et al. hydroperoxy-9(Z), 116 octadecadienoic acid from hydrolysed saf 5,888,541 A 3, 1999 Horrobin et al. flower oil by a crude soybean-flour extract as lipoxygenase source.” 6,069,168 A 5, 2000 Horrobin et al. Rec. Trav. Chim Pays-Bas, 115, 11-12, p. 499-504 (1996). 6,177,470 B1 1/2001 Horrobin et al. Elshof et al., “Biocatalytic hydroxylation of linoleic acid in a 6.479,544 B1 1 1/2002 Horrobin double-fed batch system with lipoxygenase and cysteine,” 100:6. 6,630,157 B1 10/2003 Horrobin et al. pp. 246-251 (1999). 7:50 R: $39, Rani, et al. Erythema, Retrieved online Feb. 11, 2014). Retrieved from 8.293,790 B2 10/2012 Manku et al. Rhttp:/ummelu health medical aimed conditionery. 8,536,223 B2 9, 2013 Kelliher et al. 68 A ------- 2003/OO73930 A1 4/2003 Morrissey et al. Feldlaufer et al., Antimicrobial activity of fatty acids against 2003/0194446 A1 10, 2003 Akes et al. Bacillus larvae, the causative agent of American Foulbrood dis 2007/00 15438 A1 1/2007 Lange et al. ease.” Apidologie (1993). 24. pp. 95-99. 2008.01254.87 A1 5, 2008 Das et al. Huang et al., “Antimicrobial activity of n-6, n-7 and n-9 fatty acids 2008.0161275 A1 7/2008 Gorstrup and their esters for oral microorganisms,” Archives of Oral Biology, 2008/0213357 A1 9, 2008 Hebard et al. 55 (2010), pp. 555-560. 2009,0176284 A1 7/2009 Furihata et al. Kawashima et al., “Subchronic (13-week) oral toxicity study of 2010/O184727 A1 T/2010 Roach et al. dihomo-y-linolenic acid (DGLA) oil in rats.” Food and Chemical 2010/0278948 A1 11, 2010 Courtin Toxicology (2009). 2010/0317735 Al 12/2010 Hong et al. Kiistala et al., “In vivo Separation of Epidermis by Production of 2011 OO15415 A1 1/2011 Singh et al. Sucti ------ ? 2011/00 16585 A1 1/2011 Pereira et al. uction Blister," Lancet 1964: 1444-1445 (1964). 2011 OO39010 A1 2/2011 Rein et al. Kiistala, “Suction buster device for separation fo viable epidermis 2011/0059885 A1 3/2011 Lea et al. from dermis,” J. Invest. Dermatol. 50: 129-137 (1968). 2012/O142773 A1 6, 2012 Kelliher et al. Miller et al., “Dietary Supplementation with Ethyl Ester Concen 2012fO213824 A1 8, 2012 Kelliher et al. trates of Fish Oil (N-3) and Borage Oil (N-6) Polyunsaturated Fatty 2012fO232147 A1 9, 2012 Manku et al. Acids Induces Epidermal Generation of Local Putative Anti-Inflam 2012fO264705 A1 10, 2012 Manku et al. matory Metabolites.” The Journ. of Invest. Dermatol., vol. 96, No. 2013/0101533 A1 4/2013 Manku et al. 1, pp. 98-103 (1991). 2013/01O2575 A1 4/2013 Manku et al. Miller et al. "Guinea Pig Epidermins Generates Putative Anti 2013/0267,598 A1 10, 2013 Manku et al. Inflammatory Metabolites from Fish Oil Polyunsaturated Acids.” 2013/0274338 A1 10, 2013 Manku et al. Lipids, vol. 24, No. 12 (1989). 2013/0331448 A1 12/2013 Manku et al. Mosmann, J. Immunol.1. v. W Meth. vol. 65, pp. 55-63 (1983). Mundlein et al., "Comparison of Transepiderminal Water Losee FOREIGN PATENT DOCUMENTS (TEWL) Measurements with Two Novel Sensors Based on Different EP OO37175 10, 1981 Sensing Principles,” Sensors and Actuators A: Physical, 142(1):67 EP OO78434 5, 1983 72 (2008). EP O087863 9, 1983 Nijs et al., “Adult-onset asthma, is it really different?” Eur, Respir. EP O087864 9, 1983 Rev., vol. 22(127), pp. 44-52, Mar. 1, 2013. EP O087865 9, 1983 PCT/EP12/070809 International Search Report dated Jan. 22, 2013. EP O115419 8, 1984 PCT/EP12/070813 International Search Report dated Jan. 14, 2013. EP O 132089 1, 1985 PCT/EP2013/053677 International Search Report dated Jun. 19, EP O173478 3, 1986 2013. US 9,439,850 B2 Page 3 (56) References Cited Schreiner at al., “Transfer of Penicillin G and Ampicillin into Human Skin Blisters Induced by Suction.” Scand. Journ. Infect. Dis. OTHER PUBLICATIONS 14(Suppl.);233-237 (1978). Tope, “Multi-electrode radio frequency resurfacing of ex vivo PCT/GB2010/000844 International Search Report dated Jul. 19, hontan skin.” Dermatol. Surg., 25:348-52 (1999). Xue et al., “Optimization of Synthethic Conditions for the Prepa Fusoid too International Search Report dated Feb. 5, ration of Dihomo-gamma-Linolenic Acid from gamma-Linolenic Acid,” Journ Amer. Oil Chemists’ Soc., Jan. 2009, vol. 86, Issue 1, Fusososol International Search Report dated Mar. 29. pp. 77-82. Ziboh et al., “Dihomo-gama-linolenic acid 15 Fusos ossos International Search Report dated Feb. 4. hydroxyeicosatrienoic acid in skin inflammatory and proliferative processes,” pp. 198-206 (2001). s et al., “Microdialysis documents changes in the micromilieu Ziboh et al., Am. J. Clin. Nutr. 2000:71(suppl):361S-6S. of psoriatic plaques under continuous systemic therapy.” Experi mental Dermatology 20:130-133 (2011). * cited by examiner U.S. Patent Sep. 13, 2016 Sheet 1 of 5 US 9,439,850 B2 Figure 1 U.S. Patent Sep. 13, 2016 Sheet 2 of 5 US 9,439,850 B2 Figure 2 U.S. Patent Sep.