USOO921 6151B2
(12) United States Patent (10) Patent No.: US 9.216,151 B2 Kelliher et al. (45) Date of Patent: *Dec. 22, 2015
(54) USE OF PUFAS FOR TREATING SKIN (58) Field of Classification Search NFLAMMATION CPC ...... A61K 8/36; A61K 8/37; A61 K31/20; A61K 31/201: A61K 31/202 (71) Applicant: Dignity Sciences Limited, Dublin (IE) USPC ...... 514/560:554/224 See application file for complete search history. (72) Inventors: Adam Kelliher, London (GB); Angus Morrison, Isle of Lewis (GB); Phil Knowles, Cumbria (GB) (56) References Cited (73) Assignee: Dignity Sciences Limited. (IE) U.S. PATENT DOCUMENTS 4,273,763. A 6, 1981 Horrobin (*) Notice: Subject to any disclaimer, the term of this 4,309.415 A 1/1982 Horrobin patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (Continued) This patent is Subject to a terminal dis FOREIGN PATENT DOCUMENTS claimer. EP O1394.80 5, 1952 (21) Appl. No.: 14/316.375 EP OO35856 9, 1981 (Continued) (22) Filed: Jun. 26, 2014 OTHER PUBLICATIONS (65) Prior Publication Data US 2014/03093O4 A1 Oct. 16, 2014 Conrow et al., Org. Proc. Res. & Dev. 15:301-304 (2011). (Continued) Related U.S. Application Data (63) Continuation of application No. 14/203,837, filed on Primary Examiner — Deborah D Carr Mar. 11, 2014, which is a continuation of application (74) Attorney, Agent, or Firm — Perkins Coie LLP No. 13/461,472, filed on May 1, 2012, now Pat. No. 8.729.126, which is a continuation of application No. (57) ABSTRACT (Continued) The present invention provides a compound which is a poly (30) Foreign Application Priority Data unsaturated fatty acid (PUFA) derivative of formula (I), Apr. 29, 2009 (GB) ...... O9074 13.9 O (51) Int. Cl. AOIN37/00 (2006.01) A6 IK3I/20 (2006.01) RO --- "Su-1N1 (Continued) (52) U.S. Cl. or a pharmaceutically acceptable salt, or Solvate thereof, for CPC ...... A61 K9/0014 (2013.01); A61 K3I/202 use in treating various skin disorders. (2013.01); A61 K3I/573 (2013.01); A61 K 45/06 (2013.01); C07C59/42 (2013.01) 19 Claims, 5 Drawing Sheets
US 9.216,151 B2 Page 2
Related U.S. Application Data 2013/0267,598 A1 10/2013 Manku et al. 2013/0274338 A1 10/2013 Manku et al. 13/318,290, filed as application No. PCT/GB2010/ 2013/0331448 A1 12/2013 Manku et al. 000844 on Apr. 29, 2010, now Pat. No. 8,536,223. FOREIGN PATENT DOCUMENTS (60) Provisional application No. 61/177,811, filed on May 13, 2009. EP OO37175 10, 1981 EP OO78434 5, 1983 EP O087863 9, 1983 EP O087864 9, 1983 (51) Int. Cl. EP O087865 9, 1983 A23D 9/00 (2006.01) EP O 115419 8, 1984 A6 IK9/00 (2006.01) EP O 132089 1, 1985 A6 IK3I/202 EP O173478 3, 1986 (2006.01) EP 0309086 3, 1989 A 6LX3/573 (2006.01) EP O409559 1, 1991 A6 IK 45/06 EP O416855 3, 1991 (2006.01) EP 1852114 11, 2007 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 WO2O10020603 4/2000 4,386,072 5, 1983 Horrobin et al. WO WOO 103696 1, 2001 4,388,324 6, 1983 Horrobin WO WOO2O1969 1, 2002 4,444,755 4, 1984 Horrobin WO WOO2O89791 11, 2002 4,826,877 5, 1989 Stewart et al. WO WOO2092O71 11, 2002 4,888,326 12, 1989 Horrobin WO WOO2O964.08 12/2002 4,898,885 2, 1990 Horrobin WO WO2007079224 7/2007 4,965,075 10, 1990 Horrobin et al. WO WO2O08070129 6, 2008 4,970,076 11, 1990 Horrobin WO WO 20080701.29 A2 * 6, 2008 ...... A61K 31,202 4,996,233 2, 1991 Horrobin WO WO2008114141 9, 2008 4,997,657 3, 1991 Horrobin et al. WO WO2010.125330 11, 2010 5,145,686 9, 1992 Horrobin et al. WO WO2010.125340 11, 2010 5, 198468 3, 1993 Horrobin WO WO2O13057284 4/2013 5,318,991 6, 1994 Horrobin et al. WO WO2O13057287 4/2013 5,324,748 6, 1994 Horrobin WO WO2013O82265 6, 2013 5,328,691 T. 1994 Horrobin et al. WO WO2O13112876 8, 2013 5,380,757 1, 1995 Horrobin WO WO2O13124479 8, 2013 5,552,150 9, 1996 Horrobin et al. WO WO2O14022816 2, 2014 5,562.913 10, 1996 Horrobin 5,580,556 12, 1996 Horrobin OTHER PUBLICATIONS 5,583, 159 12, 1996 Horrobin et al. 5,589,509 12, 1996 Horrobin Desbois et al., “Antibacterial free fatty acids: activities, mechanisms 5,614,208 3, 1997 Horrobin et al. of action and biotechnological potential. Appl. Microbiol. 5,618,558 4, 1997 Horrobin et al. 5,620,701 4, 1997 Horrobin et al. Biotechnol. (2010) 85:1629-1642. 5,663,202 9, 1997 Horrobin et al. Elshof et al. “Biocatalytic large-scale production of 12(S)- 5,709,855 1, 1998 Bockow et al. hydroperoxy-9(Z), 117 octadecadienoic acid from hydrolysed saf 5,888,541 3, 1999 Horrobin et al. flower oil by a crude Soybean-flour extract as lipoxygenase source.” 6,069,168 5, 2000 Horrobin et al. Rec. Trav. Chim Pays-Bas, 115, 11-12, p. 499-504 (1996). 6,177,470 1, 2001 Horrobin et al. Elshofetal., “Biocatalytic hydroxylation of linoleic acid in a double 6.479,544 11, 2002 Horrobin fed batch system with lipoxygenase and cysteine.” 100:6. pp. 246 6,630,157 10, 2003 Horrobin et al. 7,202.276 4, 2007 Buchanan et al. 251 (1999). 7,888,393 2, 2011 Bettle, III Erythema, Retrieved online Feb. 11, 2014). Retrieved from 8,293,790 10, 2012 Manku et al. URL:
(56) References Cited PCT/US2012/67030 International Search Report dated Feb. 5, 2013. PCT/US2013/023201 International Search Report dated Mar. 29, OTHER PUBLICATIONS 2013. PCT/US2013/053498 International Search Report dated Feb. 4, Miller et al., “Guinea Pig Epidermins Generates Putative Anti-In 2014. flammatory Metabolites from Fish Oil Polyunsaturated Acids.” Salgo et al., “Microdialysis documents changes in the micromilieu of psoriatic plaques under continuous systemic therapy.” Experimental Lipids, vol. 24, No. 12 (1989). Dermatology 20:130-133 (2011). Mosmann, J. Immunol. Meth. vol. 65, pp.55-63 (1983). Schreiner et al., “Transfer of Penicillin G and Ampicillin into Human Mundlein et al., “Comparison of Transepiderminal Water Losee Skin Blisters Induced by Suction.” Scand. Journ. Infect. Dis. (TEWL) Measurements with Two Novel Sensors Based on Different 14(Suppl.);233-237 (1978). Sensing Principles.” Sensors and Actuators A: Physical, 142(1):67 Tope, "Multi-electrode radio frequency resurfacing of ex vivo homan 72 (2008). skin.” Dermatol. Surg., 25:348-52 (1999). Nijs et al., “Adult-onset asthma, is it really different?” Eur, Respir. Xue et al., “Optimization of Synthetic Conditions for the Preparation Rev., vol. 22(127), pp. 44-52, Mar. 1, 2013. of Dihomogamma-Linolenic Acid from gamma-Linolenic Acid.” Journ Amer. Oil Chemists' Soc., Jan. 2009, vol. 86, Issue 1. pp. 77-82. PCT/EP12/070809 International Search Report dated Jan. 22, 2013. Ziboh et al., "Dihomo-gamma-linolenic acid 15 PCT/EP12/070813 International Search Report dated Jan. 14, 2013. hydroxyeicosatrienoic acid in skin inflammatory and proliferative PCT/EP2013/053677 International Search Report dated Jun. 19, processes.” pp. 198-206 (2001). 2013. Ziboh et al., Am. J. Clin. Nutr. 2000; 71(suppl):361S-6S. PCT/GB2010/000844 International Search Report dated Jul. 19, 2010. * cited by examiner U.S. Patent Dec. 22, 2015 Sheet 1 of 5 US 9.216,151 B2
Figure 1 U.S. Patent Dec. 22, 2015 Sheet 2 of 5 US 9.216,151 B2
Figure 2 U.S. Patent Dec. 22, 2015 Sheet 3 of 5 US 9.216,151 B2
Figure 3 U.S. Patent Dec. 22, 2015 Sheet 4 of 5 US 9.216,151 B2
Figure 4 U.S. Patent US 9.216,151 B2
Figure 5 US 9,216,151 B2 1. 2 USE OF PUFAS FORTREATING SKN inflammatory and/or dehydrative components, a number of NFLAMMATION different treatments may be used. Thus, in the treatment of psoriasis, for example, an antihyperproliferative may be used CROSS REFERENCE TO RELATED to treat the hyperproliferative component of the disease, an APPLICATIONS anti-inflammatory may be used to treat the inflammatory component and an emollient may be used to treat the dehy This application is a continuation of U.S. patent applica drative component. tion Ser. No. 14/203,837 filed Mar. 11, 2014, entitled “USE The most common form of treatment for inflammation of OF PUFAS FOR TREATING SKIN INFLAMMATION, the skin is oral and/or topical steroids. There are, however, which is a continuation of U.S. patent application Ser. No. 10 drawbacks associated with steroid treatments. Common side 13/461,472 filed May 1, 2012 (now U.S. Pat. No. 8,729,126), effects associated with steroids include stunting of growth, entitled “USE OF PUFAS FOR TREATING SKIN thinning of the skin, muscle loss and osteoporosis. INFLAMMATION,” which is a continuation of U.S. patent The present invention relates to new methods for treating application Ser. No. 13/318,290 filed Feb. 24, 2012 (now U.S. skin inflammation, in particular skin inflammation caused by Pat. No. 8,536.223), entitled “USE OF PUFAS FORTREAT 15 ING SKIN INFLAMMATION, which is a 35 USC S371 atopic eczema, contact dermatitis, psoriasis or uremic pruri National Stage application of International Application No. tis, in mammals. PCT/GB2010/000844 filed Apr. 29, 2010, entitled “USE OF Eicosa-8Z., 11Z., 14Z-trienoic acid (Dilhomo-y-linolenic PUFAS FORTREATING SKIN INFLAMMATION” which acid or DGLA) is a commercially available polyunsaturated claims the benefit of priority to United Kingdom Patent fatty acid (PUFA). DGLA has the structure shown below. Application No. GB 0907413.9 filed Apr. 29, 2009 and U.S.
Provisional Application No. 61/177,811 filed May 13, 2009: the entirety of each of which is incorporated herein by refer CCC. 25 FIELD OF THE INVENTION The present invention relates to novel methods of treating skin inflammation, in particular skin inflammation caused by atopic eczema, contact dermatitis, psoriasis or uremic pruri 30 EP-A-0085579 describes the use of DGLA in combination tis. with antipruritic lithium salts. EP-A-0173478 describes the use of DGLA in combination with anti-inflammatory gluco BACKGROUND OF THE INVENTION corticoids. In these applications, treatment with lithium salts and glucocorticoids is Supplemented with DGLA, as both Most common skin disorders and complaints comprise a 35 lithium salts and glucocorticoids are believed to block release number of different components. Thus, many skin disorders of DGLA from endogenous structures in the body. involve (a) hyperproliferation, (b) inflammation and/or (c) Advantageously, it has now been discovered that DLGA dehydration. Hyperproliferation involves a state of abnor can be used effectively as a monotherapy. mally high cell division, which can lead to excess flaking 5-Hydroxy-eicosa-6E.8Z.11Z-trienoic acid (5-HETrE)) is skin. Inflammation involves Swelling and redness of the skin, 40 a commercially available PUFA derivative derived from as well as sensations of increased heat, and pain in the skin. mead acid. 5-HETrE has the structure shown below. Dehydration involves loss of water from the skin and may be due, for example, to damage to the normally waterprooftop layer of the skin (epidermis). Inflammation of the skin (dermatitis) in mammals can 45 result from a number of different etiologies. Dermatitis can be HO caused by eczema, in particular atopic eczema (atopic der matitis), disseminated neurodermatitis, flexural eczema, infantile eczema, prurigo diathisique, contact dermatitis, (eg irritant contact dermatitis, allergic contact dermatitis and 50 photocontact dermatitis), Xerotic eczema, Seborrheic eczema, dyshidrosis, discoid eczema, Venous eczema, dermatitis her petiformis, neurodermatitis and autoeczematisation. Derma 8-Hydroxy-eicosa-9E,11Z., 14Z-trienoic acid (8-HETrE) is titis can also be caused by skin inflammation resulting from a commercially available PUFA derivative derived from exposure to radiation, in particular exposure to ultraviolet 55 eicosa-8Z.11Z.14Z-trienoic acid (Dilhomo-y-linolenic acidor radiation. Other causes of dermatitis includes uremic pruritis DGLA). 8-HETrE has the structure shown below. and autoimmune diseases, in particular lupus and psoriasis. Inflammation of the skin causes rashes, redness, skin edema (Swelling), itching, blistering, sensations of pain and/ or heat and can be unsightly. The itchiness caused by inflam 60 mation can lead to scratching. Scratching of skin that is HO already damaged in some way can easily lead to the barrier of the epidermis being broken, resulting in bleeding, and sec OH ondary infection with pathogens. Such secondary infection can require treatment with antibiotics. 65 It is well known that when treating a skin condition that has a number of different components, i.e. hyperproliferative, US 9,216,151 B2 3 4 15-Hydroxy-eicosa-8Z.11Z,13E-trienoic acid (15-HE R is a group of formula —CH2—CH(OR)—CH2— TrE) is a commercially available PUFA derivative derived (OR), wherein RandR are each independently hydro from eicosa-8Z.11Z,14Z-trienoic acid (Dilhomo-y-linolenic gen atoms or—(C=O)—R, wherein R is an aliphatic acid or DGLA). 15-HETrE has the structure shown below. group having from 3 to 29 carbon atoms; or R is a group of formula—(CHOCH), OH, wherein mis an integer of from 1 to 200; R is a hydrogenatom; or R is a group —(C=O)—Rs, wherein Rs is a C-C alkyl, C-C alkenyl, C-C alkynyl, Co-Co aryl, 5- to 10 10-membered heteroaryl, C-C, carbocyclyl or 5- to 100-membered heterocyclyl group, or Rs is an aliphatic group having from 3 to 29 carbon atoms; or 15-HETrE is known to have antiproliferative properties R is a group of formula—(CHOCH), OH, wherein n is when applied directly to the skin (Xi, et al; Prostaglandins, 15 an integer of from 1 to 200; Leukotrienes and Essential Fatty Acids (2000) 62(1), 13 to and wherein 19). said alkyl, alkenyl, alkynyl and aliphatic groups are the 13-Hydroxy-octadeca-6Z.97,11E-Y-trienoic acid (13 same or different and are each unsubstituted or substi HOTrE(Y)) is a commercially available PUFA derivative tuted with 1, 2 or 3 unsubstituted substituents which are derived from gamma-linolenic acid (GLA). 13-HOTrE(Y) has the same or different and are selected from halogen the structure shown below. atoms and C-C alkoxy, C-C alkenyloxy, C-C, haloalkyl, C-Chaloalkenyl, C-C haloalkoxy, C-C, haloalkenyloxy, hydroxyl. —SR', and —NR'R" groups where R' and R" are the same or different and represent 25 hydrogen or unsubstituted C-C alkyl; said aryl, heteroaryl, carbocyclyl and heterocyclyl groups are the same or different and are each unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents which are the same or different and are selected from the 30 halogen atoms, and cyano, nitro, C-C alkyl, C-C, It has now been surprisingly found that DGLA, 5-HETrE, alkoxy, C-C alkenyl, C-C alkenyloxy, C-C, 8-HETrE, 15-HETrE, 13-HOTrE(Y) and their derivatives are haloalkyl, C-Chaloalkenyl, C-C haloalkoxy, C-C, clinically useful in treating skin inflammation, in particular haloalkenyloxy, hydroxyl, C-C hydroxyalkyl, - SR" skin inflammation caused by atopic eczema, contact derma and—NR'R" groups wherein each RandR" is the same titis, psoriasis or uremic pruritis, by topical administration in 35 or different and represents hydrogen or unsubstituted mammals. A particular finding of the present invention is that C-C alkyl; these compounds reduce the level of COX-2 enzymes in the and wherein the PUFA derivative is in the form of a racemate, skin when applied topically. The COX-2 family of enzymes a stereoisomer or a mixture of stereoisomers, have been strongly linked to inflammation and have been which compound is for use in treating skin inflammation in a found to be present in increased amounts in inflamed tissue. 40 mammal, by topical administration. SUMMARY OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION The present invention therefore provides a compound FIG. 1 shows the results of an immunohistochemistry 45 assay to determine the amount of COX-2 enzymes present in which is a polyunsaturated fatty acid (PUFA) derivative of ex vivo porcine ear skin 0 and 6 hours after staining with formula (I). diaminobenzidine. FIG. 2 shows the results of an immunohistochemistry assay to determine the amount of COX-2 enzymes present in O 50 ex vivo porcine ear skin, which has been treated with keto profen in fish oil, O and 6 hours after staining with diami --- "S-1-1N nobenzidine. RO FIG. 3 shows the results of an immunohistochemistry assay to determine the amount of COX-2 enzymes present in or a pharmaceutically acceptable salt, or Solvate thereof, 55 ex vivo porcine ear skin, which has been treated with a rep wherein resentative compound of the invention, DGLA.. O and 6 hours -Alk- is —CH(OR)-transCH=CH-cis CH=CH after staining with diaminobenzidine. CH-cis ICH=CH-CH , —(CH) CH(OR)- FIG. 4 shows the results of an immunohistochemistry transCH=CH-cis ICH=CH-CH-cis assay to determine the amount of COX-2 enzymes present in CH-CH , —(CH)-cis ICH=CH-CH-cis 60 ex vivo porcine ear skin, which has been treated with a rep CH=CH-transCH=CH-CH(OR)– or -CH resentative compound of the invention, 15-HETrE, 0 and 6 cis ICH=CH-CH-cis ICH=CH-transCH=CH hours after staining with diaminobenzidine. CH(OR)–: FIG. 5 shows the results of a Western Blotting analysis to R is a hydrogenatom; or determine the effect of DGLA (second bar) and 15-HETrE R is a C-C alkyl, C-C alkenyl, C-C alkynyl, Co-Co 65 (third bar) on COX-2 expression in porcine skin relative to aryl, 5- to 10-membered heteroaryl, C-C, carbocyclyl water (first) bar. Levels in control were assigned a value of or 5- to 10-membered heterocyclyl group; or 100%. US 9,216,151 B2 5 6 Preferably the alkyl, alkenyl, alkynyl and aliphatic groups As used herein, a C-C alkylthio or C-C alkenylthio are unsubstituted or substituted with 1, 2 or 3, preferably 1 or group is typically a said C-C alkyl group or a C-C alkenyl 2, more preferably 1, unsubstituted substituents which are the group respectively which is attached to a Sulphur atom, for same or different and are selected from halogen atoms and example —S—CH. C-C alkoxy, hydroxyl, C-Chaloalkyl, C-Chaloalkenyl, As used herein, a C-C hydroxyalkyl group is a C-C C-C haloalkoxy and —NR'R'" wherein R' and R" are the alkyl group Substituted by one or more hydroxy groups. Typi same or different and represent hydrogen or C-C alkyl. cally, it is substituted by one, two or three hydroxy groups. More preferred Substituents are halogen, C-C alkoxy, Preferably, it is substituted by a single hydroxy group. hydroxyl and —NR'R" groups where R' and R" are the same As used herein, a C-C aryl group is a monocyclic or or different and represent hydrogen or unsubstituted C-C, 10 polycyclic, preferably monocyclic, aromatic ring containing alkyl. Particularly preferred substituents include hydroxyl form 6 to 10 carbon atoms, for example a Caryl group and —NR'R" groups where R' and R" are the same and containing 6 carbon atoms. Examples of Such aryl groups represent hydrogen. include phenyl, naphthalene and azulene. Phenyl is preferred. When the alkyl, alkenyl, alkynyl and aliphatic groups As used herein, a 5- to 10-membered heteroaryl group is a above are substituted by two or three substituents, it is pre 15 monocyclic or polycyclic, preferably monocyclic, 5- to ferred that not more than two substituents are selected from 10-membered aromatic ring. Such as a 5- or 6-membered ring, hydroxyl. More preferably, not more than one substituent is containing at least one heteroatom, for example 1, 2, 3 or 4 selected from hydroxyl. heteroatoms, selected from O, S and N. When the ring con Most preferably, the alkyl, alkenyl and alkynyl groups have tains 4 heteroatoms these are preferably all nitrogen atoms. are unsubstituted. Examples include thienyl, furyl, pyrrolyl, imidazolyl, thiaz As used herein, a C-C alkyl group is a linear or branched olyl, isothiazolyl pyrazolyl, oxazolyl, isoxazolyl, trizolyl, alkyl group containing from 1 to 6 carbonatoms, for example thiadiazolyl, oxadiazolyl pyridinyl, pyridazinyl, pyrimidi a C-C alkyl group containing from 1 to 4 carbon atoms, nyl, pyrazinyl, triazinyl and tetrazolyl groups. Thienyl, pyr preferably a C-C alkyl group containing from 1 to 2 carbon rolyl, imidazolyl, thiazolyl, isothiazolyl pyrazolyl, oxazolyl, atoms. Examples of C-C alkyl groups include methyl, ethyl, 25 isoxazolyl, trizolyl pyridinyl, pyridaZinyl, pyrimidinyl and n-propyl, i-propyl. n-butyl, i-butyl and t-butyl. For the avoid pyrazinyl groups are preferred, e.g. pyrrolyl, imidazolyl, thia ance of doubt, where two alkyl groups are present in a com Zolyl, isothiazolyl pyrazolyl, oxazolyl, isoxazolyl, trizolyl, pound of the present invention, the alkyl groups may be the pyridinyl, pyridaZinyl, pyrimidinyl and pyrazinyl groups. same or different. More preferred groups are thienyl, pyridinyl, pyridazinyl, As used herein, a C-C alkenyl group is a linear or 30 pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, e.g. pyridinyl, branched alkenyl group having at least one double bond of pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, either cis or trans configuration where applicable and con most preferably pyridinyl. taining from 2 to 6 carbonatoms, for example a C-C alkenyl As used herein, a 5- to 10-membered heterocyclyl group is group containing from 2 to 4 carbon atoms. Such as a non-aromatic, Saturated or unsaturated monocyclic or poly —CH=CH or —CH-CH=CH, —CH CH 35 cyclic, preferably monocyclic, Cso carbocyclic ring in CH=CH, -CH-CH=CH-CH, -CH=C(CH)– which one or more, for example 1, 2, 3, or 4, of the carbon CH and —CH2—C(CH)—CH2 preferably a C alkenyl atoms are replaced with a moiety selected from N, O, S, S(O) group having 2 carbon atoms. For the avoidance of doubt, and (SO), and wherein one or more of the remaining carbon where two alkenyl groups are present in a compound of the atoms is optionally replaced by a group —C(O)— or present invention, they may be the same or different. 40 —C(S)-. When one or more of the remaining carbon atoms As used herein, a C-C alkynyl group is a linear or is replaced by a group —C(O)— or —C(S)—, preferably branched alkynyl group containing from 2 to 6 carbon atoms, only one or two (more preferably two) Such carbonatoms are for example a C-C alkynyl group containing from 2 to 4 replaced. Typically, the 5- to 10-membered heterocyclyl ring carbon atoms, preferably a C alkynyl group containing 2 is a 5- to 6-membered ring. carbon atoms. Exemplary alkynyl groups include —C=CH 45 Suitable heterocyclyl groups include aZetidinyl, oxetanyl, or —CH2—C=CH, as well as 1- and 2-butynyl, 2-methyl thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isox 2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, azolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. For the avoidance of tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl. doubt, where two alkynyl groups are present in a compound dithiolanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazi of the present invention, they may be the same or different. 50 nyl, hexahydropyrimidinyl, methylenedioxyphenyl, ethyl Preferably, said C-C alkyl group is a C-C alkyl group, enedioxyphenyl, thiomorpholinyl. S-oxo-thiomorpholinyl, said C-C alkenyl group is a Calkenyl group and said C-C, S.S.-dioxo-thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, alkynyl group is a C alkynyl group. 1,4-dioxolanyl, trioxolanyl, trithianyl, imidazolinyl, pyranyl. As used herein, a halogen atom is chlorine, fluorine, bro pyrazolinyl, thioxolanyl, thioxothiazolidinyl, 1H-pyrazol-5- mine or iodine. 55 (4H)-onyl, 1,3,4-thiadizol-2(3H)-thionyl, oxopyrrolidinyl, As used herein, a C-C alkoxy group or a C-C alkeny oXothiazolidinyl, oxopyrazolidinyl. Succinimido and male loxy group is typically a said C-C alkyl (e.g. a C-C alkyl) imido groups and moieties. Preferred heterocyclyl groups are group or a said C-C alkenyl (e.g. a C-C alkenyl) group pyrrolidinyl, imidZolidinyl, oxazolidinyl, isoxazolidinyl, respectively which is attached to an oxygen atom. thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahy A haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy 60 drothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithi group is typically a said alkyl, alkenyl, alkoxy or alkenyloxy olanyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, group respectively which is Substituted by one or more said hexahydropyrimidinyl, thiomorpholinyl and morpholinyl halogen atoms. Typically, it is Substituted by 1, 2 or 3 said groups and moieties. halogen atoms. Preferred haloalkyl and haloalkoxy groups For the avoidance of doubt, although the above definitions include perhaloalkyl and perhaloalkoxy groups, such as 65 of heteroaryland heterocyclyl groups refer to an “N' moiety —CX and —OCX, wherein X is a said halogen atom, for which can be present in the ring, as will be evident to a skilled example chlorine and fluorine. chemist the Natom will be protonated (or will carry a sub US 9,216,151 B2 7 8 stituent as defined below) if it is attached to each of the claimed encompasses the racemic forms of the compounds of adjacent ring atoms via a single bond. the invention as well as the individual enantiomers, and Ste As used herein, a C-C, carbocyclic group is anon-aro reoisomer-enriched mixtures. matic Saturated or unsaturated hydrocarbon ring having from It will be appreciated that the term "or a pharmaceutically 3 to 7 carbon atoms. Preferably it is a saturated or mono acceptable salt or solvate thereof is intended to include all unsaturated hydrocarbon ring (i.e. a cycloalkyl moiety or a permutations of salts and Solvates, such as Solvates of phar cycloalkenyl moiety) having from 3 to 7 carbon atoms, more maceutically-acceptable salts of compounds of the invention. preferably having from 3 to 6 carbon atoms. Examples Rs and R may be an aliphatic group having 3 to 29 carbon include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl atoms. Typically, the aliphatic group is not cyclic. The ali and their mono-unsaturated variants, more particularly cyclo 10 phatic group is typically linear or branched, preferably linear. pentyl and cyclohexyl. A C-C, carbocyclyl group also Typically, the aliphatic group has 7 to 25 carbonatoms, more includes C-C, carbocyclyl groups described above but preferably 11 to 25 carbon atoms. The aliphatic group is wherein one or more ring carbon atoms are replaced by a typically unsubstituted or substituted with one hydroxyl group—C(O)—. More preferably 0, 1 or 2 ring carbonatoms 15 group. The aliphatic group is preferably unsubstituted. (most preferably 0) are replaced by —C(O)—. Most prefer Aliphatic groups may be saturated, monounsaturated or ably, said C-C, carbocyclyl group is cyclohexyl. polyunsaturated. Saturated aliphatic groups are preferred. Typically the aryl, heteroaryl, heterocyclyl and carbocyclyl Typically, saturated aliphatic groups have from 7 to 25 groups in R and Rs are unsubstituted or Substituted by 1,2,3, carbon atoms, preferably 11 to 17 carbon atoms. or 4 unsubstituted substituents, for example by 1, 2 or 3 Monounsaturated aliphatic groups typically contain a unsubstituted substituents. Preferred substituents include single C=C double bond. The double bond has cis or trans halogenatoms and C-C alkyl, C-C alkenyl, C-C alkoxy, configuration. The single double bond may be present at any C-C alkenyloxy, C-C haloalkyl, C-C haloalkenyl, point in the aliphatic group, it is typically 7 or 9 carbonatoms C-C haloalkoxy, C-C haloalkenyloxy, hydroxyl, mer from the end of the aliphatic group distal to the (C=O) group capto, cyano, nitro, C-C hydroxyalkyl, C-C hydroxyalk 25 to which the aliphatic group is attached. Typically, monoun enyl, C-C alkylthio, C-C alkenylthio and —N'R" groups saturated aliphatic groups have from 7 to 25 carbon atoms, wherein each RandR" is the same or different and represents preferably 15 to 23 carbon atoms. hydrogen or C-C alkyl. More preferred substituents include Polyunsaturated aliphatic groups typically contain two or halogen atoms and unsubstituted C-C alkyl, C-C alkoxy, more C=C double bonds, for example 2, 3, 4, 5 or 6 C=C hydroxyl, C-C haloalkyl, C-C haloalkoxy, C-C, 30 double bonds. Each double bond may have cis or trans con hydroxyalkyl, cyano, nitro. —SR' and —NR'R" groups figuration. The double bonds may be present at any point in where R and R" are the same or different and represent the aliphatic chain, but typically, the C–C double bond fur hydrogen or unsubstituted C-C alkyl. More preferred sub thest from the (C=O) group to which the aliphatic group is stituents include halogen atoms, hydroxyl groups and C-C, attached is 3, 6 or 9 carbonatoms from the end of the aliphatic alkyl and C-C alkoxy groups. 35 group distal to the (C=O) group to which the aliphatic group Most preferably, the aryl, heteroaryl, heterocyclyl and car is attached. Typically, polyunsaturated aliphatic groups have bocyclyl groups above are unsubstituted. from 7 to 25 carbon atoms, preferably 15 to 23 carbonatoms. When the aryl, heteroaryl, heterocyclyl and carbocyclyl Typically, said aliphatic group is the group R, wherein groups in R and Rs are Substituted by two, three or four R—COH is a fatty acid. Preferably, said fatty acid is lauric substituents, it is preferred that not more than two substituents 40 acid, myristic acid, palmitic acid, Stearic acid palmitoleic are selected from hydroxyl, cyano and nitro. More preferably, acid, cis-vaccenic acid, oleic acid, eicosenoic acid, erucic not more than one substituent is selected from hydroxyl, acid, nervonic acid, alpha-linolenic acid, Stearidonic acid, cyano and nitro. eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic As used herein, a pharmaceutically salt is a salt with a acid, docosapentaenoic acid, docosahexaenoic acid, tetra pharmaceutically acceptable acid or base. Pharmaceutically 45 cosapentaenoic acid, tetracosahexaenoic acid, linoleic acid, acceptable acids include both inorganic acids such as hydro gamma-linolenic acid, eicosadienoic acid, dihommo chloric, Sulphuric, phosphoric, diphosphoric, hydrobromic or gamma-linolenic acid, arachidonic acid, docosadienoic acid, nitric acid and organic acids Such as citric, fumaric, maleic, adrenic acid, docosapentaenoic acid, or mead acid. More malic, ascorbic. Succinic, tartaric, benzoic, acetic, methane preferably, said fatty acid is lauric acid, myristic acid, palm Sulphonic, ethaneSulphonic, benzenesulphonic or p-toluene 50 itic acid, or Stearic acid. Sulphonic acid. Pharmaceutically acceptable bases include In one embodiment, the aliphatic group having 3 to 29 alkali metal (e.g. sodium or potassium) and alkali earth metal carbon atoms is the aliphatic group of a PUFA derivative of (e.g.: calcium or magnesium) hydroxides and organic bases formula (I) as defined herein, i.e. the aliphatic group is of Such as alkylamines, aralkylamines and heterocyclic amines. formula—(CH)-Alk-(CH2)CH, where-Alk-is as defined The term "solvate” refers to a complex or aggregate formed 55 herein. by one or more molecules of a solute, i.e. compounds of the In a preferred embodiment, the aliphatic group having 3 to invention or pharmaceutically-acceptable salts thereof, and 29 carbon atoms is the aliphatic group of dihommo-gamma one or more molecules of a solvent. Such Solvates are typi linolenic acid or 15-hydroxyeicosatrienoic acid, i.e. the ali cally crystalline solids having a Substantially fixed molar ratio phatic group is —(CH) CH=CH-CH CH=CH of solute and solvent. Representative solvents include by way 60 CH-CH=CH-(CH2)CH, wherein all of the C–C of example, water, methanol, ethanol, isopropanol, acetic double bonds have cis configuration, or —(CH)-cis acid, and the like. When the solvent is water, the solvate CH=CH-CH-cis ICH=CH-transCH=CH-CH formed is a hydrate. (OH)—(CH2)CH. Preferably, the aliphatic group having 3 The compounds of the invention may contain a chiral cen to 29 carbon atoms is the aliphatic group is 15-hydroxeico ter. Accordingly, they can be used in the form of a racemic 65 Satrienoic acid, i.e. the aliphatic group is —(CH2)-cis mixture, an enantiomer, or a mixture enriched in one or more CH=CH-CH-cis ICH=CH-transCH=CH-CH stereoisomer. The scope of the invention as described and (OH)—(CH2)CH. US 9,216,151 B2 9 10 In a more preferred embodiment, the PUFA derivative of R is typically —(C=O)—R, wherein R is as defined formula (I) is of formula R'(C=O)C CH-CH(O(C=O) herein. R")—CH2—O(C=O)R', wherein each R" is the aliphatic R is typically —(C=O)—R, wherein R is as defined group of 15-hydroxeicosatrienoic acid, i.e. R' is —(CH2)- herein. cisCH=CH-CH-cis ICH=CH-transCH=CH-CH Preferably, both R and Ra are —(C=O)—R, wherein (OH)–(CH2)CH. Thus, the PUFA derivative of formula (I) each R may be the same or different and is as defined is preferably herein.
It is to be understood that the left hand side of the -Alk Typically, when R and Ra are both —(C=O)—R, then moiety is bonded to the unsaturated carbon chain bearing the 25 Rs is not an aliphatic group having 3 to 29 carbon atoms. —COOR moiety and the right hand side of the -Alk-group R is an aliphatic group having from 3 to 29 carbon atoms, is bonded to the saturated carbon chain. as defined herein. Typically, said aliphatic group is Saturated. Typically, -Alk- is —CH(OR)-transCH=CH-cis Typically, R is an aliphatic group having 7 to 25 carbon CH=CH-CH-cis ICH=CH-CH , —(CH) CH atoms, preferably 11 to 17 carbon atoms. Preferably, R is a (OR)-transCH=CH-cis ICH=CH-CH-cis 30 group R, wherein R-COH is auric acid, myristic acid, CH=CH-, or —(CH)-cis ICH=CH-CH-cis palmitic acid, or Stearic acid. CH=CH-transCH=CH-CH(OR)-. Preferably, -Alk Typically, R is a hydrogen atom; or R is a group is —CH)-cisCH=CH-CH-cis ICH=CH-CH-cis —(C=O)—Rs, wherein Rs is a C-C alkyl, C-C alkenyl, CH -CH . C-C alkynyl, Caryl, 5- to 6-membered heteroaryl, C-C, Typically, R is a hydrogen atom; or R is a C-C alkyl, 35 carbocyclyl or 5 to 6-membered heterocyclyl group, or Rs is C-C alkenyl, C-C alkynyl, Cs aryl, 5- to 6-membered an aliphatic group having from 3 to 29 carbon atoms; or R is heteroaryl, C-C carbocyclyl or 5- to 6-membered heterocy a group of formula—(HOCH),OH, wherein n is as defined clyl group; or R is a group of formula —CH2—CH(OR)— herein, wherein said alkyl, alkenyl and alkynyl groups are the CH (OR), wherein R and Rare as defined herein; or R same or different and are each unsubstituted or substituted is a group of formula —(CHOCH2)(OH, wherein m is as 40 with 1, or 2 unsubstituted substituents which are the same or defined herein, wherein said alkyl, alkenyl and alkynyl different and are selected from halogen atoms, C-C alkoxy, groups are the same or different and are each unsubstituted or hydroxyl, and—NR'R" groups where R' and R" are the same substituted with 1, or 2 unsubstituted substituents which are or different and represent hydrogen or unsubstituted C-C, the same or different and are selected from halogen atoms, 45 alkyl; and said aryl, heteroaryl, carbocyclyl and heterocyclyl C-C alkoxy, hydroxyl, and NR'R" groups where R' and groups are the same or different and are each unsubstituted or R" are the same or different and represent hydrogen or unsub substituted by 1, 2 or 3 unsubstituted substituents which are stituted C-C alkyl, and said aryl, heteroaryl, carbocyclyl the same or different and are selected from halogen atoms, and heterocyclyl groups are the same or different and are each and cyano, nitro, C-C alkyl, C-C alkoxy, and —NR'R'" unsubstituted or substituted by 1, 2 or 3 unsubstituted sub 50 groups wherein each R' and R" is the same or different and stituents which are the same or different and are selected from represents hydrogen or unsubstituted C-C alkyl group. halogen atoms, and cyano, nitro, C-C alkyl, C-C alkoxy, Preferably, R is a hydrogen atom; or R is a group and —NR'R" groups wherein each R" and R" is the same or —(C=O)—Rs, wherein Rs is unsubstituted C-C alkyl, or different and represents hydrogen or unsubstituted C-C, R is a group —(C=O)—Rs, wherein Rs is an aliphatic group alkyl group. 55 having from 3 to 29 carbonatoms; or R2 is a group of formula Preferably, R is a hydrogenatom; or R is an unsubstituted —(CHOCH), OH, wherein n is as defined herein. C-C alkyl group; or R is a group of formula —CH2—CH More preferably, R is a hydrogen atom; or R is a group (OR))—CH2—(OR), where R and Ra are as defined —(C=O)—Rs, wherein Rs is an aliphatic group having from herein; or R is a group of formula —(CHOCH),OH, 3 to 29 carbon atoms; or R is a group of formula wherein m is as defined herein. 60 —(CHOCH), OH, wherein n is as defined herein. More preferably, R is a hydrogen atom; or R is a group of Most preferably, R is a hydrogen atom. formula —CH2—CH(OR)—CH2—(OR), wherein R and n is typically an integer of from 5 to 150, preferably from Ra are as defined herein, and wherein at least one R or R is 10 to 50. —(C=O)—R, wherein R is as defined herein. When Rs is an aliphatic group having 3 to 29 carbonatoms, Most preferably, R is a hydrogenatom. 65 said aliphatic group is as defined herein. Typically, said ali m is typically an integer of from 5 to 150, preferably from phatic group is saturated. Typically, Rs is an aliphatic group 10 to 50. having 7 to 25 carbon atoms, preferably 11 to 17 carbon US 9,216,151 B2 11 12 atoms. Preferably, Rs is a group R, wherein R COH is auric (d) R is a group of formula—(CHOCH), OH, whereinn acid, myristic acid, palmitic acid, or Stearic acid. is as defined herein. Such compounds will be particularly In one embodiment, the PUFA derivative of formula (I) is lipophilic, which is advantageous in Some instances. present as a racemic mixture of the Rand Senantiomers. In this preferred embodiment, preferably (a) R is a group In another embodiment, the PUFA derivative of formula (I) of formula —CH, CH(OR)—CH (OR), wherein R is present as the Renantiomer. and R are each independently hydrogen atoms or In another embodiment, the PUFA derivative of formula (I) —(C=O)—R, one of R or R is —(C=O)—Re; and/or (c) is present as the Senantiomer. R is a group —(C=O)—Rs, wherein Rs is a saturated ali Typically, the mammal is a human. phatic group having 3 to 29 carbon atoms. In a preferred embodiment, -Alk- is —CH(OR)-trans 10 CH=CH-cis ICH=CH-CH-cis ICH=CH-CH , In a more preferred embodiment, both RandR are hydro —(CH) CH(OR)-transCH=CH-cis CH=CH gen atoms. CH-cis CH=CH , or —(CH)-cis CH=CH-CH In a particularly preferred embodiment, -Alk is cisCH=CH-transCH=CH-CH(OR) : R is a hydro —(CH)-cis ICH=CH-CH-cis CH=CH-trans gen atom, an unsubstituted C-C alkyl group, or a group of 15 CH=CH-CH(OR)—, and R and R are both hydrogen formula —CH, CH(OR)—CH2—(OR), wherein R and atoms. In this embodiment, the PUFA derivative of formula Ra are each independently hydrogen atoms or —(C=O)— (I) is 15-HETrE and is represented by the formula R, wherein R is a linear aliphatic group having from 11 to 25 carbon atoms, which aliphatic group is unsubstituted or Sub stituted with one hydroxyl group, or R is a group of formula —(CHOCH), OH, wherein m is an integer of from 5 to 150; and R is a hydrogen atom, a group of —(C=O)—Rs. wherein Rs is unsubstituted C-C alkyl, or a group —(C=O)—Rs, wherein Rs is a linear aliphatic group having from 11 to 25 carbon atoms, which aliphatic group is unsub 25 stituted or Substituted with one hydroxyl group; or R2 is a group of formula—(CHOCH2), OH, wherein n is an integer Typically, compounds of the invention are administered as of from 5 to 150. one or more treatments per day, preferably from 1 to 4 treat In a more preferred embodiment, -Alk- is —(CH2)-cis ments per day, more preferably from 1 to 2 treatments per day. CH=CH-CH-cis ICH=CH-transCH=CH-CH 30 Typically, compounds of the invention are administered at (OR ; R is a hydrogenatom, an unsubstituted C-C alkyl a daily dosage of from 0.1 mg/m/day to 1 kg/m/day, pref group, or a group of formula —CH2—CH(OR)—CH2— erably from 1 mg/m/day to 100 g/m/day, more preferably (OR), wherein R and Ra are each independently hydrogen from 10 mg/m/day to 10 g/m/day, most preferably from 100 atoms or —(C=O)—R, wherein R is a linear aliphatic mg/m/day to 1 g/m/day. group having from 11 to 25 carbon atoms, which aliphatic 35 Skin inflammation includes rashes, hives, blisters and/or group is unsubstituted or substituted with one hydroxyl wheals and may be caused by eczema, exposure to radiation, group, or R is a group of formula —(CHOCH2)(OH, autoimmune diseases, and/or uremic pruritis. wherein m is an integer of from 5 to 150; and R is a hydrogen In a preferred embodiment, the skin inflammation is caused atom, a group —(C=O)—Rs, wherein Rs is unsubstituted by atopic eczema, contact dermatitis, psoriasis or uremic C-C alkyl, or a group —(C=O)—Rs, wherein Rs is a linear 40 pruritis. aliphatic group having from 11 to 25 carbon atoms, which Inafurther preferred embodiment, the skin inflammation is aliphatic group is unsubstituted or Substituted with one caused by exposure of the skin to electromagnetic radiation. hydroxyl group; or R2 is a group of formula —(CH2 This includes, for example, exposure to Sunlight, heat, X-rays OCH), OH, wherein n is an integer of from 5 to 150. or radioactive materials. Thus, in this embodiment, the com In a most preferred embodiment, -Alk- is —(CH2)-cis 45 pound of the present invention is typically used to treat Sun CH=CH-CH-cis ICH=CH-transCH=CH-CH burn. (OR)—: R is a hydrogenatom, a group of formula—CH2— The term eczema is applied to a wide range of skin condi CH(OR)—CH2—(OR), wherein R and Ra are each tions with a variety of aetiologies. In general, eczema is independently hydrogen atoms or —(C=O)—R, wherein categorised by inflammation of the epidermis. Common R is an unsubstituted linear, Saturated aliphatic group having 50 symptoms associated with eczema include dryness, recurring from 11 to 17 carbon atoms, and wherein at least one of R or skin rashes, redness, skin edema (Swelling), itching, dryness, R is —(C=O)—R, and R is a hydrogen atom, or a group crusting, flaking, blistering, cracking, oozing, and bleeding. —(C=O)—Rs, wherein Rs is an unsubstituted linear, Satu Eczema includes atopic eczema (atopic dermatitis), contact rated aliphatic group having from 11 to 17 carbon atoms, or dermatitis, Xerotic eczema, seborrhoeic dermatitis, dyshydro R is a group of formula—(CHOCH), OH, wherein n is an 55 sis, discoid eczema, venous eczema, dermatitis herpetifor integer of from 10 to 50. mus, neurodermatitis, and autoeczematisation. Eczema is Typically, in the compounds of the present invention, typically atopic eczema or contact dermatitis. including the preferred embodiments set out above, (a) R is Atopic eczema is primarily aggravated by contact with or a group of formula —CH2—CH(OR))—CH2—(OR), intake of allergens, which include animal hair and dander, wherein R and Reach independently represent a hydrogen 60 food allergens, for example nuts or shellfish, or drugs, for atom or —(C=O)—R, wherein R is a saturated aliphatic example penicillin. group having from 3 to 29 carbonatoms, wherein at least one Contact dermatitis includes allergic contact dermatitis, of R or R is —(C=O)—Re; or irritant contact dermatitis and photocontact dermatitis. (b) R is a group of formula—(CHOCH), OH, wherein Electromagnetic radiation includes radio waves, micro m is as defined herein; and/or 65 waves, terahertz radiation, infrared radiation, visible light, (c) R is a group —(C=O)—Rs, wherein Rs is a saturated ultraviolet radiation, X-rays and gamma rays. Electromag aliphatic group having from 3 to 29 carbon atoms; or netic radiation is preferably infrared radiation, visible light, US 9,216,151 B2 13 14 ultraviolet radiation, X-rays and gamma rays, more prefer 0.0875 g/m/day or less, more preferably 0.035 g/m/day, ably ultraviolet radiation, X-rays and gamma rays. most preferably 0.0175 g/m/day or less. Compounds of the Autoimmune diseases can involve an autoimmune present invention are typically coadministered with clobeta response against the skin. Examples of Such autoimmune Sol propionate, wherein the daily dosage of clobetasol prop diseases are lupus and psoriasis. rionate is 0.009 g/m/day or less, preferably 0.0045 g/m/day Uremic pruritis is a disorder of the skin associated with or less, more preferably 0.0018 g/m/day or less, most pref chronic renal failure. It also frequently affects patients under erably 0.0009 g/m/day or less. going dialysis treatment. The compounds of the present invention are typically coad Typically, the compound of the present invention is co ministered with a further therapeutic agent, which is not a administered with a corticosteroid. 10 corticosteroid, which is effective in treating skin conditions/ Suitable corticosteroids to be used for co-administration diseases. Such therapeutic agents are well known to the with compounds of the invention are clobetasol diproprion skilled person and include, but are not limited to, immuno ate, betamethasone diproprionate, halbetasol proprionate, modulators, antiobiotics, immunosuppressants and anti-itch diflorasone diacetate, fluocinonide, halcinoide, amcinonide, drugs. desoximetasone, trimcinolone acetonide, mometaSone 15 Compounds of the invention are typically commercially furoate, fluticasone propionate, fluocinolone acetonide, available, or may be prepared by analogy with known meth hydrocortisone Valerate, hydrocortisone butyrate, triamina ods. Thus, for example, both DGLA and 15-HETrE are com lone acetonide, desonide, prednicarbate, prednisolone, meth mercially available. These available fatty acids can easily be ylprednisolone, dexmethasone, naflocort, deflazacort, halo derivatised to obtain PUFA derivatives of formula (I) by predone acetate, budesonide, beclomethasone dipropionate, known methods. hydrocortisone, clocortolone pivalate, methylprednisolone For example, PUFA derivatives of formula (I) as defined aceponate, dexamethasone palmitoate, tipredane, hydrocor herein, wherein R is a C-C alkyl, C-C alkenyl, C-C, tisone aceponate, alclometaSone dipropionate, halometa alkynyl, Co-Co aryl, 5- to 10-membered heteroaryl, C-C, Sone, methylprednisolone Suleptanate, rimexolone, predniso carbocyclyl or 5- to 10-membered heterocyclyl group; or R lone farnesylate, ciclesonide, deprodone 25 is a group of formula —CH2—CH(OR)—CH2—(OR), propionateloteprednol etabonate, betamethasone butyrate wherein R and Ra are as defined herein; or R is a group of propionate, flunisolide, prednisone, dexamethasone sodium formula—(CHOCH), OH, wherein m is as defined herein, phosphate, triamcinolone, betamethasone 17-valerate, can be prepared by esterifying a compound of formula betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium Succinate, prednisolone 30 Sodium phosphate and hydrocortisone probutate. O Preferred corticosteroids corticosteriods to be used for co administration with compounds of the invention are clobeta Sol diproprionate, betamethasone diproprionate, halbetasol --~~~ proprionate, diflorasone diacetate, fluocinonide, halcinonide, 35 amcinonide, desoximetasone, triamcinolone acetonide, wherein-Alk- is as defined herein and X is a leaving group, mometasone furoate, fluticaSone propionate, fluocinolone for example a halogenatom, a tosylate or mesylate group with acetonide, hydrocortisone Valerate, hydrocortisone butyrate, an alcohol of formula R' OH, wherein R is a C-C alkyl, triamcinalone acetonide, desonide, and prednicarbate. C-C alkenyl, C-C alkynyl, Co-Co aryl, 5- to 10-mem Any reference to corticosteroids within the scope of the 40 bered heteroaryl, C-C, carbocyclyl or 5- to 10-membered present invention includes a reference to salts or derivatives heterocyclyl group; or R' is a group of formula —CH2—CH thereof which may be formed from the corticosteroids. (OR)—CH2—(OR), wherein R and Ra are as defined Examples of possible salts or derivatives include: sodium herein; or R' is a group of formula —(CHOCH),OH, salts, Sulphobenzoates, phosphates, isonicotinates, acetates, wherein m is as defined herein, to obtaina PUFA derivative of propionates, dihydrogen phosphates, palmitates, pivaiates, 45 formula (I) as defined herein. Alternatively, X may be a farnesylates, aceponates, Suleptanates, prednicarbates, hydroxyl group. In that case, the reaction is preferably carried furoates or acetonides. In some cases the corticosteroids may out under acidic conditions, or in the presence of a Suitable also occur in the form of their hydrates. catalyst, for example pyridine. Compounds of formula R It is a particular finding of the present invention that co OH are typically commercially available or may be prepared administration of a compound of the present invention with a 50 by analogy with known methods. corticosteroid enables the amount of corticosteroid adminis When - Alk- is —CH(OR)-transCH=CH-cis tered to be reduced, without reducing the efficacy of the CH=CH-CH-cis ICH=CH-CH —(CH))—CH treatment. Thus, in a preferred embodiment, the compound of (OR)-transCH=CH-cis CH=CH-CH-cis the present invention is co-administered with a corticosteroid, CH=CH-, or —(CH)-cisCH=CH-CH-cis wherein the corticosteroid is administered at a daily dosage of 55 CH=CH-transCH=CH-CH(OR)—, PUFA derivatives 50% or less, preferably 25% or less, more preferably 10% or of formula (I) as defined herein, wherein R is a group of less, most preferably 5% or less, of the recommended daily —(C=O)—Rs, wherein Rs is a C-C alkyl, C-C alkenyl, dosage of said corticosteroid in said mammal. C-C alkynyl, a C-Caryl, a 5- to 10-membered heteroaryl, The person skilled in the art is well aware of the recom a C-C, carbocyclyl or a 5- to 10-membered heterocyclyl mended daily dosages of corticosteroids in mammals. For 60 group, or Rs is an aliphatic group having from 3 to 29 carbon example, the recommended daily dosage of hydrocortisone in atoms, can be prepared by treating a compound of formula (I) humans is approximately 0.35 g/m/day. The recommended as defined herein, wherein -Alk- is —CH(OR)-trans daily dosage of clobetasol propionate in humans is 0.009 to CH=CH-cis ICH=CH-CH-cis ICH=CH-CHH , 0.018 g/m/day. —(CH) CH(OR)-transCH=CH-cis CH=CH Thus, compounds of the present invention are typically 65 CH-cis ICH=CH , or —(CH)-cis ICH=CH-CH coadministered with hydrocortisone, wherein the daily dos cis ICH=CH-transCH=CH-CH(OR)—, and R is a age of hydroxortisone is 0.175 g/m/day or less, preferably hydrogen atom, with a carboxylic acid derivative US 9,216,151 B2 15 16 Y—(C=O)—R's, wherein R's is a C-C alkyl, C-C alk Preservatives such as methylparaben, propylparaben and enyl, C-C alkynyl, a C-C aryl, a 5- to 10-membered benzyl alcohol can be present in the pharmaceutical compo heteroaryl, a C-C, carbocyclyl or a 5- to 10-membered het sition. The appropriate amount of Such preservative(s) is erocyclyl group, or R's is an aliphatic group having from 3 to known to those skilled in the art. The pharmaceutical com 29 carbon atoms, and Y is a leaving group, for example a 5 position may also comprise a fat-soluble antioxidant Such as halogen atom, a tosylate or mesylate group. Compounds of ascorbyl palmitate, tocopherol and/or ascorbic acid in the formula Y—(C=O)—R's are typically commercially avail presence of lecithin. able or may be prepared by analogy with known methods. Optionally, an additional solubilizing agent Such as benzyl When - Alk- is —CH(OR)-transCH=CH-cis alcohol, lactic acid, acetic acid, Stearic acid or hydrochloric 10 acid can be included in the pharmaceutical composition. Ifan CH=CH-CH-cis ICH=CH-CH , —(CH) CH additional Solubilizing agent is used, the amount present is (OR)-transCH=CH-cis ICH=CH-CH-cis preferably about 1 wt % to about 12 wt % based on the total CH-CH , O —CH)-cis ICH=CH-CH-cis weight of the pharmaceutical composition. CH=CH-transCH=CH-CH(OR)—, PUFA derivatives Optionally, the pharmaceutical composition can contain a of formula (I) as defined herein, wherein R is a group of 15 humectant such as glycerin and a skin penetration enhancer formula—(CHOCH), OH, wherein n is as defined herein, such as butyl stearate, urea and DMSO. It is known to those can be prepared by treating a compound of formula (I) as skilled in the art that a single ingredient can perform more defined herein, wherein -Alk- is —CH(OR)-trans than one function in a cream, i.e., cetyl alcohol can serve both CH=CH-cis ICH=CH-CH-cis ICH=CH-CH as an emollient and as a thickener. C.H. , —(CH) CH(OR)-transCH=CH-cis In one embodiment, the pharmaceutical composition is in CH=CH-CH-cis ICH=CH-, or —CH)-cis the form of a cream. The cream typically consists of an oil CH=CH-CH-cis ICH=CH-transCH=CH-CH phase and a water phase mixed together to form an emulsion. (OR)—, and R is a hydrogen atom, with a compound of Preferably, the cream comprises an oil-in-water emulsion. formula Z (CHOCH), OH are typically commercially Preferably, the amount of water present in a cream of the available or may be prepared by analogy with known meth 25 invention is about 45 wt.% to about 85 wt.% based on the total ods. weight of the cream. The present invention also provides a pharmaceutical com Where the pharmaceutical composition is in the form of an position Suitable for topical administration comprising a ointment, it is typically comprises a pharmaceutically accept PUFA derivative, as defined herein, or a pharmaceutically able ointment base Such as petrolatum, or polyethylene glycol acceptable salt, or a solvate thereof, and a pharmaceutically 30 400 (available from Union Carbide) in combination with acceptable diluent or carrier, for use in treating skin inflam polyethylene glycol 3350 (available from Union Carbide). mation, as defined herein, in a mammal, as defined herein. The amount of ointment base present in an ointment of the Preferred pharmaceutical compositions are sterile and invention is preferably about 660 wt % to about 95 wt % based pyrogen free. on the total weight of the ointment. The pharmaceutical composition is typically in the form of 35 In the pharmaceutical composition of the present inven a gel, ointment, cream or lotion. tion, the amount of the PUFA derivative of formula (I) is When said pharmaceutical composition is a gel it typically typically from 0.01 wt % to 50 wt %, preferably from 0.5 wt comprises a hydrophilic polymer Such as cross-linked poly % to 25 wt %, more preferably from 1 wt % to 10 wt %, for ethylene glycol, cross-linked starch or polyvinyl pyrrolidone. example about 5 wt %, based on the total weight of the Anointment, cream or lotion typically contains an aqueous 40 pharmaceutical composition. phase and an oleaginous phase in admixture. The compound/composition of the present invention is The pharmaceutical composition may additionally contain formulated for topical administration and it may be adminis one or more emollients, emulsifiers, thickeners and/or preser tered to a patient in an amount such that from 0.00001 to 10g, Vatives, particularly when it is a cream or ointment. preferably from 0.0001 to 1 g active ingredient is delivered Emollients suitable for inclusion increams or ointments of 45 perm of the area being treated. the present invention are typically long chain alcohols, for Pharmaceutical compositions of the present invention may example a C8-C22 alcohol such as cetyl alcohol, stearyl alco additionally comprise one or more corticosteroids as defined hol and cetearyl alcohol, hydrocarbons such as petrolatum herein. The amount of the corticosteroid present in the phar and light mineral oil, or acetylated lanolin. The total amount maceutical composition of the invention is typically 50% or of emollient in the pharmaceutical composition is preferably 50 less, preferably 25% of less, more preferably 10% or less, about 5 wt % to about 30 wt %, and more preferably about 5 most preferably 5% or less, of the recommended amount of wt % to about 10 wt % based on the total weight of the said corticosteroid in a commercially available formulation. pharmaceutical composition. The skilled person is well aware of the amount of corticos The emulsifier is typically a nonionic Surface active agent, teroids present in various topical formulations. For example, e.g., polysorbate 60 (available from ICI Americas), sorbitan 55 the amount of hydrocortisone present in most commercially monostearate, polyglyceryl-4 oleate and poloxyethylene(4) available formulations is typically 1% w/w. The amount of lauryl ether. Generally the total amount of emulsifier is about clobetasol proprionate present in most commercially avail 2 wt % to about 14 wt %, and more preferably about 2 wt % able formulations is typically 0.0525% w/w. to about 6 wt % by weight based on the total weight of the Thus, pharmaceutical compositions of the present inven pharmaceutical composition. 60 tion typically comprise hydrocortisone in an amount of 0.5% Pharmaceutically acceptable thickeners, such as Vee w/w or less, preferably 0.025% w/w or less, more preferably gumTM K (available from R. T. Vanderbilt Company, Inc.), 0.01% w/w or less, most preferably 0.005% w/w or less. and long chain alcohols (i.e. C8-C22 alcohols such as cetyl Pharmaceutical compositions of the present invention typi alcohol, stearyl alcohol and cetearyl alcohol) can be used. The cally comprise clobetasol proprionate in an amount of total amount of thickener present is preferably about 3 wt % 65 0.026% w/w or less, preferably 0.013% w/w or less, more to about 12 wt % based on the total weight of the pharmaceu preferably 0.0053% w/w or less, most preferably 0.0026% tical composition. wfw or less. US 9,216,151 B2 17 18 The pharmaceutical compositions of the present invention Preferably, the pharmaceutical composition comprising a typically comprise one or more further therapeutic agents, polyunsaturated fatty acid (PUFA) derivative of formula (II) which are not corticosteroids, as defined herein. The amount consists of the PUFA derivative of formula (II) and a phar of the one or more further therapeutic agents, which are not maceutically acceptable diluent or carrier, as defined herein. corticosteroids, present in the composition will be evident to Preferably, the PUFA derivative of formula (II) is of for the person skilled in the art. mula R"(C=O)O CH, CH(O(C=O)R") CH, O Pharmaceutical compositions of the present invention may (C=O)R", wherein each R" is the same and is the aliphatic be prepared simply by admixing the ingredients in a Suitable group of dihommo-gamma-linolenic acid, i.e. R" is a. 10 —(CH) CH=CH-CH CH=CH-CH The present invention also provides the use of a compound CH=CH-(CH2)CH, wherein all of the C–C double which is a PUFA derivative of formula (I) as defined herein or bonds have cis configuration. Thus, the PUFA derivative of a pharmaceutically acceptable salt, or Solvate thereof, in the formula (II) is preferably
manufacture of a medicament for use in treating skin inflam 30 In a particularly preferred embodiments, R is a hydrogen mation, as defined herein, in a mammal, as defined herein, by atom. In this embodiment, the PUFA derivative of formula topical administration. (II) is DGLA and is represented by the formula The present invention also provides a method of treating skin inflammation, as defined herein, in a mammal, as defined herein, which method comprises administering to the skin of 35 said mammal a therapeutically effective amount of a com pound which is a PUFA derivative of formula (I) as defined herein or a pharmaceutically acceptable salt, or Solvate thereof. 40 The present invention also provides a pharmaceutical com position comprising a polyunsaturated fatty acid (PUFA) derivative of formula (II), The present invention also provides the use of a pharma ceutical composition comprising a polyunsaturated fatty acid 45 (PUFA) derivative of formula (II) as define herein in the II O manufacture of a medicament for use in treating skin inflam mation, as defined herein, in a mammal, as defined herein, by topical administration, wherein the composition is Substan RO -----> tially free of lithium salts and glucocorticoids. 50 The present invention also provides a method of treating skin inflammation, as defined herein, in a mammal, as defined or a pharmaceutically acceptable salt, or Solvate thereof, herein, which method comprises administering to the skin of wherein said mammal atherapeutically effective amount of a pharma -Alk- is —(CH)-cis ICH=CH-CH-cis CH=CH ceutical composition comprising a polyunsaturated fatty acid CH-cis ICH=CH-; and 55 (PUFA) derivative of formula (II) as defined herein, wherein R is as defined herein; the composition is Substantially free of lithium salts and glu which composition is for use in treating skin inflammation in cocorticoids. a mammal, by topical administration, and is Substantially free of lithium salts and glucocorticoids. EXAMPLES 60 As the skilled person will appreciate, in this embodiment, Immunohistochemistry analyses were carried out to mea the pharmaceutically acceptable salt of the PUFA derivative sure the degree of expression of COX-2 enzymes in ex vivo of formula (II) is not a lithium salt. porcine ear skin. The COX-2 family of enzymes have been Typically, the pharmaceutical composition comprising a strongly linked to inflammation and have been found to be polyunsaturated fatty acid (PUFA) derivative of formula (II) 65 present in increased amounts in inflamed tissue. Thus, a contains the PUFA derivative of formula (II) as sole active decreased level of COX-2 in the skin corresponds with ingredient. reduced inflammation of the skin. US 9,216,151 B2 19 20 Example 1 penetration of 15-HETrE into the viable epidermis and activ ity against COX-2 expression in the skin. Freshly excised porcine ears were immersed in iced Hank’s buffer for transport from the abattoir to the laboratory. Example 5 Upon arrival, the porcine ears were first washed with running tap water, and the full thickness skin was liberated from A Western Blotting experiment was carried out to deter underlying cartilage by blunt dissection using a scalpel and mine the effective of topically applied representative com hairs were removed with an electrical razor. The skin was pounds of the invention DGLA and 15-HETrE on the expres used within 2 h of slaughter. The full thickness skin was cut sion of COX-2 in porcine skin. Water was used as a control. 10 The porcine skin membranes (as described in Example 1) into approximately 2 cmx2 cm and placed in Hanks balance were gently cleaned with de-ionised water before being salt to maintain skin viability. homogenized (Silverson, Chesham, UK) in a RIPA lysis A2 mm Strip of skin was obtained using a Surgical scalpel buffer 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM and the skin strip then fixed using a 40% formaldehyde solu PMSF, 1 mM EDTA, 5umL'aprotinin, 5ugmL' leupeptin, tion, dehydrated and set in molten wax. The sections were cut 15 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS). using a Shandon Finesse microtome (Thermo Scientific, After 15 min incubation on ice, the lysates were clarified by Waltham, Mass., USA) to a thickness of 5um and were placed centrifugation at 14000xg for 2x15 min and the supernatant onto 2.5 cmx7.5 cm x1 mm pre-cleaned microslides. The stored at -80°C. for subsequent protein analysis. section of skin was stained with diaminobenzidine, which Aliquots of 30 ug total protein were separated by SDS binds to COX-2 enzymes and the slides visualised on a light PAGE, transferred to nitrocellulose membranes using the microscope with image capture facility. Trans-Blot electrophoretic Transfer Cell and briefly stained Skin membranes were mounted in Franz diffusion cells with Ponceau S to verify effective transfer. Immunoblots using Hanks buffer as receptor phase. Water was used as the were incubated for 1 h in a blocking solution tris-buffered donor phase. After 6 hours the skin was removed from the saline (TBS)-Tween 20 containing 5% (w/v) commercial Franz cell apparatus, excess donor phase was removed and 25 skimmed milk powder (Marvel) at room temperature. After the skin wiped clean with a clean paper tissue. The diffusional washing, the membrane was probed overnight at 4°C. with area was then cut into approximately 2 mm strips using a COX-2 antibody at 1:1000, 5-LOX at 1:1000 and iNOS at Surgical scalpel and the skin Strips then using a 40% formal 1:500 in (1:20 and 1:100 western blocking reagent and dehyde Solution, dehydrated and set in molten mass. The Sodium azide solution respectively made up to Volume with sections were cut using a Shandon Finesse microtome 30 TBS tween). Membranes were then incubated for 1 h with (Thermo Scientific, Waltham, Mass., USA) to a thickness of HRP-conjugated anti-rabbit at 1:10000. For B-actin, mem 5um and were placed onto 2.5 cmx7.5 cmx1 mm pre-cleaned branes were probed with anti-actin and anti-mouse for 1 h microslides. The section of skin was stained with diami each at room temperature at 1:10000. After 3x10 min washes nobenzidine, which binds to COX-2 enzymes, and the slides in TBS Tween, they were finally exposed to freshly prepared visualised on a light microscope with image capture facility. 35 Dura Substrate for chemiluminescence for appropriate time The results of this experiment are shown as FIG.1. A dark before performing autoradiography. stain is present in the sample both after 0 hours and 6 hours, The results of this experiment are shown as FIG.5. It can be indicating the continuing presence of COX-2 in the skin. This seen that a significant reduction in COX-2 expression is seen indicates that water has no anti-inflammatory activity. following dosing with DGLA and 15-HETrE, relative to the 40 control. Example 2 What is claimed is: 1. A method of treating uremic pruritus in a subject in need An experiment was carried out as described in Example 1, thereof, the method comprising administering a therapeuti except that the donor phase comprised ketoprofen, a known cally effective amount of a composition comprising DGLA COX-2 inhibitor, in fish oil. 45 or-15-HETrE, or an ester or pharmaceutically acceptable salt The results of this experiment are shown in FIG.2. After six thereof, to skin of the subject. hours, the amount of dark stain has reduced, indicating pen 2. The method of claim 1, wherein the composition com etration of ketoprofen into the viable epidermis and activity prises about 0.01 wt % to about 50 wt % 15-HETrE. against COX-2 expression in the skin. 3. The method of claim 1, wherein the composition com 50 prises about 0.01 wt % to about 50 wt % DGLA. Example 3 4. The method of claim 1, wherein the composition com prises about 0.01 wt % to about 25 wt % 15-HETrE. An experiment was carried out as described in Example 1, 5. The method of claim 1, wherein the composition com except that the donor phase comprised a representative com prises about 0.01 wt % to about 25 wt % DGLA. pound of the invention, DGLA. 55 6. The method of claim 1, wherein the composition com The results of this experiment are shown in FIG.3. After six prises about 1 mg to about 1000 mg of DGLA. hours, the amount of dark stain has reduced, indicating pen 7. The method of claim 1, wherein the composition com etration of DGLA into the viable epidermis and activity prises about 1 mg to about 1000 mg of 15-HETrE. against COX-2 expression in the skin. 8. The method of claim 1, wherein the composition is 60 administered topically to the skin of the mammal. Example 4 9. The method of claim 1, wherein the composition further comprises a pharmaceutically acceptable diluent or carrier. An experiment was carried out as described in Example 1, 10. The method of claim 1, wherein the composition com except that the donor phase comprised a representative com prises about 1 mg to about 1,000 mg of 15-HETrE. pound of the invention, 15-HETrE. 65 11. The method of claim 8, wherein the composition is The results of this experiment are shown as FIG. 4. After administered in an amount sufficient to deliver 0.00001 g to six hours, the amount of dark stain has reduced, indicating 10 g of 15-HETrE per square meter of skin. US 9,216,151 B2 21 22 12. The method of claim 8, wherein the composition is to 10-membered heterocyclyl group; a group of formula administered in an amount sufficient to deliver 0.0001 g to 1 —CH-CH(OR)—CH-(OR) wherein RandR are g of 15-HETrE per square meter of skin. each independently hydrogenatoms or —(C=O)—R. 13. The method of claim 1, wherein the composition is wherein R is an aliphatic group having from 3 to 29 carbon atoms; and a group of formula —(CHOCH), co-administered with a corticosteroid selected from the group OH, wherein m is an integer from 1 to 200; consisting of clobetasol diproprionate, betamethasone R is selected from the group consisting of: diproprionate, halbetasol proprionate, diflorasone diacetate, a hydrogen atom; fluocinonide, halcinonide, amcinonide, desoximetasone, tri a group of formula—(C=O)—Rs, wherein Rs is a C-C, amcinolone acetonide, mometasone furoate, fluticaSone alkyl, C-C alkenyl, C-C alkynyl, C-C aryl, 5- to proprionate, fluocinolone acetonide, hydrocortisone Valerate, 10 10-membered heteroaryl, C-C, carbocyclyl or 5- to hydrocortisone butyrate, triamcinalone acetonide, desonide, 10-membered heterocyclyl group: prednicarbate, prednisolone, methylprednisolone, dexam an aliphatic group having from 3 to 29 carbon atoms; and ethasone, naflocort, deflazacort, halopredone acetate, budes a group of formula —(CHOCH)—OH, wherein n is an onide, beclomethasone dipropionate, hydrocortisone, clocor integer of from 1 to 200; and tolone pivalate, methylprednisolone aceponate, 15 wherein said alkyl, alkenyl, alkynyl and aliphatic groups dexamethasone palmitoate, tipredane, hydrocortisone ace are the same or different and are each unsubstituted or ponate, alclometasone dipropionate, halometaSone, methyl substituted with 1, 2 or 3 unsubstituted substituents prednisolone Suleptanate, rimexolone, prednisolone farnesy which are the same or different and are selected from late, ciclesonide, deprodone propionateloteprednol halogen atoms and C-C alkoxy, C-C alkenyloxy, etabonate, betamethasone butyrate propionate, flunisolide, C-C haloalkyl, C-C haloalkenyl, C-C, prednisone, dexamethasone sodium phosphate, triamcino haloalkoxy, C-C haloalkenyloxy, hydroxyl. —SR', lone, betamethasone 17-Valerate, betamethasone, betametha and—NR'R" groups where R' and R" are the same or Sone dipropionate, hydrocortisone acetate, hydrocortisone different and represent hydrogen or unsubstituted Sodium Succinate, prednisolone sodium phosphate, hydrocor C-C alkyl, said aryl, heteroaryl, carbocyclyl and tisone probutate, and combinations thereof. 25 heterocyclyl groups are the same or different and are 14. The method of claim 13, wherein the corticosteroid is each unsubstituted or substituted by 1, 2, 3 or 4 unsub co-administered in an amount sufficient to provide 50% or stituted substituents which are the same or different less of the recommended daily dosage of said corticosteroid and are selected from halogen atoms, and cyano, in said mammal. nitro, C-C alkyl, C-C alkoxy, C-C alkenyl, 15. The method of claim 14, wherein the corticosteroid is 30 C-C alkenyloxy, C-C haloalkyl, C-C haloalk hydrocortisone. enyl, C-C haloalkoxy, C-C haloalkenyloxy, 16. The method of claim 1, wherein the composition is hydroxyl, C-C hydroxyalkyl, - SR" and —NR'R'" co-administered with a further therapeutic agent selected groups wherein each RandR" is the same or different from the group consisting of immunomodulators, antibiotics, 35 and represents hydrogen or unsubstituted C-C alkyl. immunosuppressants, and anti-itch drugs. 18. The method of claim 17, wherein: 17. A method of treating itching of the skin in a mammal, R is hydrogen or C-C alkyl; and the method comprising administering to the mammal a com R is a hydrogen atom or an aliphatic group having from 3 position comprising a therapeutically effective amount of a to 29 carbon atoms. compound of Formula (I): 19. A method of treating itching of the skin in a mammal, 40 the method comprising administering to the mammal a com position comprising a therapeutically effective amount of a Formula (I) compound of formula: O
45 RO --~~
or a pharmaceutically acceptable salt thereof, wherein -Alk- is —(CH)-cis ICH=CH-CH-cis ICH=CH 50 transCH=CH-CH(OR)–: R is selected from the group consisting of hydrogen; C-C alkyl, C-C alkenyl: C-C alkynyl: C-C aryl; or a pharmaceutically acceptable salt thereof. 5- to 10-membered heteroaryl; C-C, carbocyclyl or 5 k k k k k