HK1165728B - Use of pufas for treating skin inflammation - Google Patents

Description

Use of polyunsaturated fatty acids for treating skin inflammation

Technical Field

The present invention relates to a novel method of treating skin inflammation, particularly skin inflammation caused by atopic eczema, contact dermatitis, psoriasis or uremic pruritis (uremic pruritis).

Background

Most general skin disorders and discomforts include many different components. Thus, many skin disorders involve (a) hyperproliferation, (b) inflammation and/or (c) dehydration. Hyperproliferation involves an abnormally high state of cell division, which can lead to excessive exfoliation of the skin. Inflammation involves swelling and redness of the skin, as well as increased sensations of heat and pain in the skin. Dehydration involves loss of water from the skin and can be attributed to damage to the normally waterproof top layer (epidermis) of the skin, for example.

Inflammation of the skin (dermatitis) in mammals can result from a number of different etiologies. Dermatitis can be caused by eczema, especially atopic eczema (atopic dermatitis), disseminated neurodermatitis, flexo eczema, infantile eczema, prurigo (prurigo diathsique), contact dermatitis, (e.g. irritant contact dermatitis, allergic contact dermatitis and light contact dermatitis), xerotic eczema, seborrheic eczema, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis, neurodermatitis and self-eczematization. Dermatitis can also be caused by inflammation of the skin resulting from exposure to radiation, particularly to ultraviolet radiation. Other causes of dermatitis include uremic pruritus and autoimmune diseases, especially lupus and psoriasis.

Skin inflammation results in rash, redness, skin edema (swelling), itching, blistering, pain and/or heat and can be unsightly. Itching caused by inflammation can lead to scratching. Scratching of already somewhat damaged skin can easily lead to breakdown of the epidermal barrier, causing bleeding and subsequent infection by pathogens. The secondary infection can require treatment with an antibiotic.

It is well known that in the case of treating skin conditions having many different components, i.e. hyperproliferative, inflammatory and/or dehydrated components, many different therapies may be used. Thus, in the treatment of psoriasis, for example, anti-hyperproliferative drugs may be used to treat the hyperproliferative component of the disease, anti-inflammatory drugs may be used to treat the inflammatory component and emollients may be used to treat the dehydrated component.

The most common form of treatment for skin inflammation is oral and/or topical steroids (steroids). However, steroid therapy has drawbacks. Common side effects associated with steroids include growth retardation, thinning of the skin, muscle loss and osteoporosis.

The present invention relates to a novel method for the treatment of skin inflammation in mammals, in particular skin inflammation caused by atopic eczema, contact dermatitis, psoriasis or uremic pruritus.

eicosanoic-8Z, 11Z, 14Z-trienoic acid (dihomo-gamma-linolenic acid or DGLA) is a commercially available polyunsaturated fatty acid (PUFA). The DGLA has the following structure.

EP-A-0085579 describes the use of DGLA in combination with ｃA lithium antipruritic salt. EP-A-0173478 describes the use of DGLA in combination with anti-inflammatory glucocorticoids. In these applications, the reason for supplementation of lithium salts and glucocorticoids with DGLA is that it is believed that lithium salts and glucocorticoids block the release of DGLA from endogenous reservoirs in the body. Advantageously, it has now been found that DGLA can be effectively used as a monotherapy.

5-hydroxy-eicosa-6E, 8Z, 11Z-trienoic acid (5-HETrE) is a commercially available PUFA derivative derived from melittic acid (mead acid). The 5-HETrE has the structure shown below.

8-hydroxy-eicosa-9E, 11Z, 14Z-trienoic acid (8-HETrE) is a commercially available PUFA derivative derived from eicosa-8Z, 11Z, 14Z-trienoic acid (dihomo-gamma-linolenic acid or DGLA). The 8-HETrE has the structure shown below.

15-hydroxy-eicosa-8Z, 11Z, 13E-trienoic acid (15-HETrE) is a commercially available PUFA derivative derived from eicosa-8Z, 11Z, 14Z-trienoic acid (dihomo-gamma-linolenic acid or DGLA). The 15-HETrE has the structure shown below.

It is known that 15-HETrE has antiproliferative properties when applied directly to the skin (Xi, et al; prostagladins, Leukotrienes and Essential Fatty Acids (2000)62(1), 13 to 19).

13-hydroxy-octadeca-6Z, 9Z, 11E-gamma-trienoic acid (13-HOTrE (gamma)) is a commercially available PUFA derivative derived from gamma-linolenic acid (GLA). 13-HOTrE (. gamma.) has the structure shown below.

It has now surprisingly been found that DGLA, 5-HETrE, 8-HETrE, 15-HETrE, 13-HOTrE (gamma) and derivatives thereof can be used clinically by topical administration in mammals for the treatment of skin inflammation, particularly skin inflammation caused by atopic eczema, contact dermatitis, psoriasis or uremic pruritus. It is a particular discovery of the present invention that these compounds reduce COX-2 enzyme levels in the skin upon topical application. Enzymes of the COX-2 family have been strongly associated with inflammation and have been found to be present in increased amounts in inflamed tissues.

Disclosure of Invention

Accordingly, the present invention provides compounds which are polyunsaturated fatty acid (PUFA) derivatives of formula (I),

or a pharmaceutically acceptable salt or solvate thereof, wherein

-Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-，-(CH₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -or-CH₂- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂)-；

R₁Is a hydrogen atom; or

R₁Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl; or

R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently is a hydrogen atom or- (C ═ O) -R₆Wherein R is₆Is an aliphatic group having 3 to 29 carbon atoms; or

R₁Is of the formula- (CH)₂OCH₂)_mAn OH group, wherein m is an integer from 1 to 200;

R₂is a hydrogen atom; or

R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl, or R₅Is an aliphatic group having 3 to 29 carbon atoms; or

R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is an integer from 1 to 200;

and wherein

The alkyl, alkenyl, alkynyl and aliphatic groups are the same or different and are each unsubstituted or substituted with 1, 2 or 3 unsubstituted substituents which are the same or different and are selected from halogen atoms and C₁-C₄Alkoxy radical, C₂-C₄Alkenyloxy radical, C₁-C₄Haloalkyl, C₂-C₄Haloalkenyl group, C₁-C₄Halogenoalkoxy, C₂-C₄Haloalkenyloxy, hydroxy, -SR ', and-NR ' R ' groups, wherein R ' and R ' are the same or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group;

-said aryl, heteroaryl, carbocyclyl and heterocyclyl are identical or different and are each unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents,the substituents being identical or different and being selected from halogen atoms, and cyano, nitro, C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₂-C₄Alkenyl radical, C₂-C₄Alkenyloxy radical, C₁-C₄Haloalkyl, C₂-C₄Haloalkenyl group, C₁-C₄Halogenoalkoxy, C₂-C₄Haloalkenyloxy, hydroxy, C₁-C₄Hydroxyalkyl, -SR ' and-NR ' R ' groups, wherein each R ' and R ' are the same or different and represent hydrogen or unsubstituted C₁-C₄An alkyl group;

and wherein the PUFA derivatives are in the form of racemates, stereoisomers or mixtures of stereoisomers,

the compounds are useful for treating skin inflammation in mammals by topical administration.

Detailed Description

FIG. 1 shows the results of an immunohistochemical assay that determined the amount of COX-2 enzyme present in the skin of the excised pig ears at 0 and 6 hours after staining with diaminobenzidine.

Figure 2 shows the results of an immunohistochemical assay that determined the amount of COX-2 enzyme present in the skin of the excised pig ears that had been treated with ketoprofen in fish oil at 0 and 6 hours after staining with diaminobenzidine.

FIG. 3 shows the results of an immunohistochemical assay to determine the amount of COX-2 enzyme present in the skin of the excised pig ears which had been treated with DGLA, a representative compound of the invention, 0 and 6 hours after staining with diaminobenzidine.

FIG. 4 shows the results of an immunohistochemical assay to determine the amount of COX-2 enzyme present in the skin of the excised pig ears which had been treated with the representative compound of the invention 15-HETrE 0 and 6 hours after staining with diaminobenzidine.

FIG. 5 shows the results of a Western blot analysis that determined the effect of DGLA (second band) and 15-HETrE (third band) on COX-2 expression in porcine skin relative to water (first band). The level in the control was set as a value of 100%.

Preferably, the alkyl, alkenyl, alkynyl and aliphatic groups are unsubstituted or substituted with 1, 2 or 3, preferably 1 or 2, more preferably 1 unsubstituted substituents, which are identical or different and are selected from halogen atoms and C₁-C₄Alkoxy, hydroxy, C₁-C₄Haloalkyl, C₂-C₄Haloalkenyl group, C₁-C₄Haloalkoxy and-NR 'R ", wherein R' and R" are the same or different and represent hydrogen or C₁-C₂An alkyl group. More preferably, the substituents are halogen, C₁-C₄Alkoxy, hydroxy and a-NR 'R' group, wherein R 'and R' are identical or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group. Particularly preferred substituents include hydroxy and-NR 'R' groups, wherein R 'and R' are the same and represent hydrogen.

In the case where the above alkyl, alkenyl, alkynyl and aliphatic group are substituted with two or three substituents, preferably not more than two substituents are selected from hydroxyl. More preferably, no more than one substituent is selected from hydroxyl.

Most preferably, the above alkyl, alkenyl and alkynyl groups are unsubstituted.

As used herein, C₁-C₆Alkyl is a linear or branched alkyl group containing 1 to 6 carbon atoms, e.g. C containing 1 to 4 carbon atoms₁-C₄Alkyl, preferably C having 1 to 2 carbon atoms₁-C₂An alkyl group. C₁-C₄Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. For the avoidance of doubt, where two alkyl groups are present in a compound of the invention, the alkyl groups may be the same or different.

As used herein, C₂-C₆Alkenyl is having at least one optionally cisLinear or branched alkenyl radicals of formula (I) or (II) having a double bond in trans configuration and containing 2 to 6 carbon atoms, e.g. C containing 2 to 4 carbon atoms₂-C₄Alkenyl, such as-CH ═ CH₂or-CH₂-CH＝CH₂，-CH₂-CH₂-CH＝CH₂，-CH₂-CH＝CH-CH₃，-CH＝C(CH₃)-CH₃and-CH₂-C(CH₃)＝CH₂Preferably C having 2 carbon atoms₂An alkenyl group. For the avoidance of doubt, where two alkenyl groups are present in a compound of the invention, they may be the same or different.

As used herein, C₂-C₆Alkynyl is a linear or branched alkynyl group containing 2 to 6 carbon atoms, e.g. C containing 2 to 4 carbon atoms₂-C₄Alkynyl, preferably C containing 2 carbon atoms₂Alkynyl. Exemplary alkynyl groups include-C.ident.CH or-CH₂-C.ident.CH, and also 1-and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. For the avoidance of doubt, where two alkynyl groups are present in a compound of the invention, they may be the same or different.

Preferably, said C₁-C₆Alkyl is C₁-C₂Alkyl radical, said C₂-C₆Alkenyl is C₂Alkenyl and said C₂-C₆Alkynyl is C₂Alkynyl.

As used herein, a halogen atom is chlorine, fluorine, bromine or iodine.

As used herein, C₁-C₆Alkoxy or C₂-C₆Alkenyloxy is generally each said C attached to an oxygen atom₁-C₆Alkyl (e.g. C)₁-C₄Alkyl) group or said C₂-C₆Alkenyl (e.g. C)₂-C₄Alkenyl) groups.

The haloalkyl, haloalkenyl, haloalkoxy or haloalkenyloxy radicals are generally each independently substitutedSaid alkyl, alkenyl, alkoxy or alkenyloxy substituted with one or more of said halogen atoms. Typically, it is substituted with 1, 2 or 3 of said halogen atoms. Preferably, haloalkyl and haloalkoxy include perhaloalkyl and perhaloalkoxy, such as-CX₃and-OCX₃Wherein X is the halogen atom such as chlorine and fluorine.

As used herein, C₁-C₄Alkylthio or C₂-C₄Alkenylthio radicals are generally each the C mentioned attached to the sulfur atom₁-C₄Alkyl or C₂-C₄Alkenyl radicals, e.g. S-CH₃。

As used herein, C₁-C₄Hydroxyalkyl is C substituted by one or more hydroxy groups₁-C₄An alkyl group. Typically, it is substituted with one, two or three hydroxyl groups. Preferably, it is substituted by a single hydroxyl group.

As used herein, C₆-C₁₀Aryl is a monocyclic or polycyclic, preferably monocyclic, aromatic ring containing from 6 to 10 carbon atoms, e.g. C containing 6 carbon atoms₆And (4) an aryl group. Examples of the aryl group include phenyl, naphthalene and azulene. Phenyl is preferred.

As used herein, a 5-to 10-membered heteroaryl is a monocyclic or polycyclic, preferably monocyclic, 5-to 10-membered aromatic ring such as a 5-or 6-membered ring containing at least one heteroatom, for example 1, 2, 3 or 4 heteroatoms selected from O, S and N. In case the ring contains 4 heteroatoms, they are preferably all nitrogen atoms. Examples include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and tetrazolyl. Thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl are preferred, for example pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. More preferred groups are thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, for example pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl and triazinyl, most preferably pyridyl.

As used herein, a 5-to 10-membered heterocyclyl is non-aromatic, saturated or unsaturated, monocyclic or polycyclic, preferably monocyclic, C_5-10Carbocycle, in which one or more, e.g. 1, 2, 3 or 4, of the carbon atoms is substituted by a group selected from N, O, S (O) and S (O)₂And wherein one or more of the remaining carbon atoms is optionally replaced with a group-c (o) -or-c(s) -. In case one or more of the remaining carbon atoms are replaced with a group-c (o) -or-c(s) -it is preferred to replace only one or two (more preferably two) of said carbon atoms. Typically, the 5-to 10-membered heterocyclyl ring is a 5-to 6-membered ring.

Suitable heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiocyclopentyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, methylenedioxyphenyl, ethylenedioxyphenyl, thiomorpholinyl, S-oxo-thiomorpholinyl, S, S-dioxo-thiomorpholinyl, morpholinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, trioxypentyl, trithioheterocyclohexyl, imidazolinyl, pyranyl, pyrazolinyl, thiexocyclopentyl, thiexothiazolidinyl, 1H-pyrazolin-5- (4H) -onyl, 1, 3, 4-thiadiazole-2 (3H) -sulfinyl, oxopyrrolidinyl, oxothiazolidinyl, oxopyrazolyl, succinimidyl and maleimide. Preferred heterocyclyl groups are groups and moieties of pyrrolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiocyclopentyl, dioxolanyl, pyrazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, thiomorpholinyl and morpholine.

For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl indicate that an "N" moiety may be present in the ring if it is attached to each adjacent ring atom via a single bond, the skilled person will appreciate that the N atom is protonated (or carries a substituent as defined below).

As used herein, C₃-C₇The carbocyclic group is a non-aromatic saturated or unsaturated hydrocarbon ring having 3 to 7 carbon atoms. Preferably, it is a saturated or monounsaturated hydrocarbon ring (i.e., a cycloalkyl moiety or cycloalkenyl moiety) having from 3 to 7 carbon atoms, more preferably from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and monounsaturated variants thereof, more particularly cyclopentyl and cyclohexyl. C₃-C₇Carbocyclyl also includes C as described above₃-C₇Carbocyclyl, but wherein one or more ring carbon atoms are replaced by a group-C (O) -. More preferably, 0, 1 or 2 ring carbon atoms (most preferably 0) are replaced by-C (O) -. Most preferably, said C₃-C₇The carbocyclyl group is cyclohexyl.

In general, R₁And R₅The aryl, heteroaryl, heterocyclyl and carbocyclyl in (a) are unsubstituted or substituted with 1, 2, 3 or 4 unsubstituted substituents, for example 1, 2 or 3 unsubstituted substituents. Preferred substituents include halogen atoms and C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₁-C₄Alkoxy radical, C₂-C₄Alkenyloxy radical, C₁-C₄Haloalkyl, C₂-C₄Haloalkenyl group, C₁-C₄Halogenoalkoxy, C₂-C₄Haloalkenyloxy, hydroxy, mercapto, cyano, nitro, C₁-C₄Hydroxyalkyl radical, C₂-C₄Hydroxyalkenyl radical, C₁-C₄Alkylthio radical, C₂-C₄Alkenylthio and-NR 'R' groups, wherein each R 'and R' are the same or different and represent hydrogen or C₁-C₄An alkyl group. More preferred substituents include halogen atoms and unsubstituted C₁-C₄Alkyl radical, C₁-C₄Alkoxy, hydroxy, C₁-C₄Haloalkyl, C₁-C₄Halogenoalkoxy, C₁-C₄Hydroxyalkyl, cyano, nitro, -SR ' and-NR ' R ' groups, wherein R ' and R ' are identical or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group. More preferred substituents include halogen atom, hydroxy group and C₁-C₂Alkyl and C₁-C₂An alkoxy group.

Most preferably, the above aryl, heteroaryl, heterocyclyl and carbocyclyl groups are unsubstituted.

At R₁And R₅In the case where the aryl, heteroaryl, heterocyclyl and carbocyclyl in (a) are substituted with two, three or four substituents, preferably no more than two substituents are selected from hydroxy, cyano and nitro. More preferably, no more than one substituent is selected from the group consisting of hydroxy, cyano and nitro.

As used herein, a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid; and organic acids such as citric acid, fumaric acid, maleic acid, malic acid, ascorbic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal (e.g., sodium or potassium) and alkaline earth metal (e.g., calcium or magnesium) hydroxides; and organic bases such as alkylamines, aralkylamines and heterocyclic amines.

The term "solvate" refers to a complex or aggregate of a solute, i.e., one or more molecules of a compound of the present invention or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent. The solvate is typically a crystalline solid having a substantially fixed solute/solvent molar ratio. Representative solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid, and the like. In the case where the solvent is water, the solvate formed is a hydrate.

The compounds of the invention may contain chiral centers. Accordingly, they can be used in the form of a racemic mixture, an enantiomer or a mixture enriched in one or more stereoisomers. The scope of the invention as described and claimed encompasses the racemic forms as well as the individual enantiomers, and the stereoisomer-enriched mixtures of the compounds of the invention.

It will be appreciated that the term "or a pharmaceutically acceptable salt or solvate thereof" is intended to include all forms of salts and solvates, such as solvates of pharmaceutically acceptable salts of the compounds of the present invention.

R₅And R₆And may be an aliphatic group having 3 to 29 carbon atoms. Generally, aliphatic groups are not cyclic. The aliphatic groups are generally linear or branched, preferably linear. Typically, the aliphatic group has from 7 to 25 carbon atoms, more preferably from 11 to 25 carbon atoms. The aliphatic group is generally unsubstituted or substituted with one hydroxyl group. The aliphatic group is preferably unsubstituted.

The aliphatic groups may be saturated, monounsaturated or polyunsaturated. Saturated aliphatic groups are preferred.

Generally, saturated aliphatic groups have from 7 to 25 carbon atoms, preferably from 11 to 17 carbon atoms.

Monounsaturated aliphatic groups generally contain a single C ═ C double bond. The double bond has either the cis or trans configuration. A single double bond may be present at any position in the aliphatic group, but that position is typically at the 7 th or 9 th carbon atom at the end of the aliphatic group distal to the (C ═ O) group to which the aliphatic group is attached. Typically, the monounsaturated aliphatic group has from 7 to 25 carbon atoms, preferably from 15 to 23 carbon atoms.

Polyunsaturated aliphatic groups typically contain two or more C ═ C double bonds, for example 2, 3, 4, 5 or 6C ═ C double bonds. Each double bond may have a cis or trans configuration. The double bond may be present at any point in the aliphatic chain, but typically the C ═ C double bond furthest from the (C ═ O) group to which the aliphatic group is attached is located at the 3 rd, 6 th or 9 th carbon atom at the end of the aliphatic group distal to the (C ═ O) group to which the aliphatic group is attached. Typically, the polyunsaturated aliphatic group has from 7 to 25 carbon atoms, preferably from 15 to 23 carbon atoms.

Typically, the aliphatic group is a group R, wherein R-CO₂H is a fatty acid. Preferably, the fatty acid is lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, cis-vaccenic acid, oleic acid, eicosenoic acid, erucic acid, nervonic acid, α -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, linoleic acid, γ -linolenic acid, eicosadienoic acid, dihomo- γ -linolenic acid, arachidonic acid, docosadienoic acid, adrenic acid, docosapentaenoic acid, or mead acid (mead acid). More preferably, the fatty acid is lauric acid, myristic acid, palmitic acid, or stearic acid.

In one embodiment, the aliphatic group having 3 to 29 carbon atoms is an aliphatic group of a PUFA derivative of formula (I) as defined herein, i.e. wherein-Alk-is of formula- (CH) as defined herein₂)₃-Alk-(CH₂)₄CH₃An aliphatic group of (a).

In a preferred embodiment, the aliphatic group having 3 to 29 carbon atoms is that of dihomo-gamma-linolenic acid or 15-hydroxyeicosatrienoic acid, i.e., the aliphatic group is- (CH)₂)₆-CH＝CH-CH₂-CH＝CH-CH₂-CH＝CH-(CH₂)₄CH₃Wherein all of the C ═ C double bonds have the cis configuration, or- (CH)₂)₆- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OH)-(CH₂)₄CH₃. Preferably, the aliphatic group having 3 to 29 carbon atoms is the aliphatic group of 15-hydroxyeicosatrienoic acid, i.e. the aliphatic group is- (CH)₂)₆- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OH)-(CH₂)₄CH₃。

In a more preferred embodiment, the PUFA derivative of formula (I) is of formula R' (C ═ O) O — CH₂-CH(O(C＝O)R′)-CH₂-O (C ═ O) R ', wherein each R ' is an aliphatic group of 15-hydroxyeicosatrienoic acid, i.e. R ' is- (CH)₂)₆- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OH)-(CH₂)₄CH₃. Thus, the PUFA derivatives of the formula (I) are preferably

It will be understood that the left hand side of the-Alk-moiety is bonded to the moiety bearing the-COOR₁Part of the unsaturated carbon chain and the right hand side of the-Alk-group is bonded to the saturated carbon chain.

Typically, -Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH ═ CH-, or- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -. Preferably, -Alk-is- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH＝CH-。

In general, R₁Is a hydrogen atom; or R₁Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₆Aryl, 5-to 6-membered heteroaryl, C₃-C₆Carbocyclyl or 5-to 6-membered heterocyclyl; or R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄As defined herein; or R₁Is of the formula- (CH)₂OCH₂)_mAn OH group, wherein m is as defined herein, wherein the alkyl, alkenyl and alkynyl groups are the same or different and are each unsubstituted or substituted with 1 or 2 unsubstituted substituents which are the same or different and are selected from halogen atoms, C₁-C₄Alkoxy, hydroxy, and-NR 'R' groups, wherein R 'and R' are the same or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group; and said aryl, heteroaryl, carbocyclyl and heterocyclyl are identical or different and are each unsubstituted or substituted by 1, 2 or 3 unsubstituted substituents which are identical or different and are selected from halogen atoms, and cyano, nitro, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, and-NR 'R' groups, wherein each R 'and R' are the same or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group.

Preferably, R₁Is a hydrogen atom; or R₁Is unsubstituted C₁-C₄An alkyl group; or R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄As defined herein; or R₁Is of the formula- (CH)₂OCH₂)_mAn OH group, wherein m is as defined herein.

More preferably, R₁Is a hydrogen atom; or R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄As defined herein, and wherein R₃Or R₄At least one of which is- (C ═ O) -R₆Wherein R is₆As defined herein.

Most preferably, R₁Is a hydrogen atom.

m is generally an integer from 5 to 150, preferably from 10 to 50.

R₃In general, - (C ═ O) -R₆Wherein R is₆As defined herein.

R₄In general, - (C ═ O) -R₆Wherein R is₆As defined herein.

Preferably, R₃And R₄Are both- (C ═ O) -R₆Wherein each R₆May be the same or different and are as defined herein.

Generally, in R₃And R₄Are both- (C ═ O) -R₆In the case of (1), then R₅Is not an aliphatic group having 3 to 29 carbon atoms.

R₆Is an aliphatic group having from 3 to 29 carbon atoms, as defined herein. Typically, the aliphatic group is saturated. In general, R₆Is an aliphatic group having 7 to 25 carbon atoms, preferably 11 to 17 carbon atoms. Preferably, R₆Is a group R, wherein R-CO₂H is lauric acid (auric acid), myristic acid, palmitic acid, or stearic acid.

In general, R₂Is a hydrogen atom; or R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₆Aryl, 5-to 6-membered heteroaryl, C₃-C₆Carbocyclyl or 5-to 6-membered heterocyclyl, or R₅Is an aliphatic group having 3 to 29 carbon atoms; or R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is as defined herein, wherein the alkyl, alkenyl and alkynyl groups are the same or different and are each unsubstituted or substituted with 1 or 2 unsubstituted substituents which are the same or different and are selected from halogen atoms, C₁-C₄Alkoxy, hydroxy, and-NR 'R' groups, wherein R 'and R' are the same or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group; and said aryl, heteroaryl, carbocyclyl and heterocyclyl are identical or different and are each unsubstituted or substituted by 1, 2 or 3 unsubstituted substituentsThe substituents being identical or different and being selected from halogen atoms, and cyano, nitro, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, and-NR 'R' groups, wherein each R 'and R' are the same or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group.

Preferably, R₂Is a hydrogen atom; or R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is unsubstituted C₁-C₄An alkyl group; or R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is an aliphatic group having 3 to 29 carbon atoms; or R₂Is of the formula- (CH)₂OCH₂)_nThe radical of OH, wherein n is as defined herein.

More preferably, R₂Is a hydrogen atom; or R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is an aliphatic group having 3 to 29 carbon atoms; or R₂Is of the formula- (CH)₂OCH₂)_nThe radical of OH, wherein n is as defined herein.

Most preferably, R₂Is a hydrogen atom.

n is generally an integer from 5 to 150, preferably from 10 to 50.

At R₅In the case of an aliphatic group having 3 to 29 carbon atoms, the aliphatic group is as defined herein. Typically, the aliphatic group is saturated. In general, R₅Is an aliphatic group having 7 to 25 carbon atoms, preferably 11 to 17 carbon atoms. Preferably, R₅Is a group R, wherein R-CO₂H is lauric acid, myristic acid, palmitic acid, or stearic acid.

In one embodiment, the PUFA derivative of formula (I) is present as a racemic mixture of the R and S enantiomers.

In a further embodiment, the PUFA derivative of formula (I) is present as the R enantiomer.

In a further embodiment, the PUFA derivative of formula (I) is present as the S enantiomer.

Typically, the mammal is a human.

In a preferred embodiment, -Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH ═ CH-, or- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂)-；R₁Is a hydrogen atom, unsubstituted C₁-C₄Alkyl, or formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently is a hydrogen atom or- (C ═ O) -R₆Wherein R is₆Is a linear aliphatic radical having from 11 to 25 carbon atoms which is unsubstituted or substituted by a hydroxyl group, or R₁Is of the formula- (CH)₂OCH₂)_mA radical of OH, wherein m is an integer from 5 to 150; and R is₂Is a hydrogen atom, a radical- (C ═ O) -R₅Wherein R is₅Is unsubstituted C₁-C₄Alkyl, or a radical- (C ═ O) -R₅Wherein R is₅Is a linear aliphatic group having 11 to 25 carbon atoms, which aliphatic group is unsubstituted or substituted with one hydroxyl group; or R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is an integer from 5 to 150.

In a more preferred embodiment, -Alk-is- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂)-；R₁Is a hydrogen atom, unsubstituted C₁-C₄Alkyl, or formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently is a hydrogen atom or- (C ═ O) -R₆Wherein R is₆Is a linear aliphatic radical having 11 to 25 carbon atoms, which is unsubstituted or substituted by oneHydroxy substituted, or R₁Is of the formula- (CH)₂OCH₂)_mA radical of OH, wherein m is an integer from 5 to 150; and R is₂Is a hydrogen atom, a radical- (C ═ O) -R₅Wherein R is₅Is unsubstituted C₁-C₄Alkyl, or a radical- (C ═ O) -R₅Wherein R is₅Is a linear aliphatic group having 11 to 25 carbon atoms, which aliphatic group is unsubstituted or substituted with one hydroxyl group; or R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is an integer from 5 to 150.

In a most preferred embodiment, -Alk-is- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂)-；R₁Is a hydrogen atom of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Wherein R is₃And R₄Each independently is a hydrogen atom or- (C ═ O) -R₆Wherein R is₆Is an unsubstituted, linear, saturated aliphatic radical having from 11 to 17 carbon atoms, and where R is₃Or R₄At least one of which is- (C ═ O) -R₆(ii) a And R is₂Is a hydrogen atom, or a radical- (C ═ O) -R₅Wherein R is₅Is an unsubstituted, linear, saturated aliphatic radical having from 11 to 17 carbon atoms, or R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is an integer from 10 to 50.

Generally, in the compounds of the present invention including the preferred embodiments described above, (a) R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently represents a hydrogen atom or- (C ═ O) -R₆Wherein R is₆Is a saturated aliphatic radical having from 3 to 29 carbon atoms, where R₃Or R₄At least one of which is- (C ═ O) -R₆(ii) a Or

(b)R₁Is of the formula- (CH)₂OCH₂)_mAn OH group, wherein m is as defined herein; and/or

(c)R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is a saturated aliphatic group having 3 to 29 carbon atoms; or

(d)R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is as defined herein. The compounds are particularly lipophilic, which may be advantageous in some cases.

In this preferred embodiment, R (a) is preferably₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently is a hydrogen atom or- (C ═ O) -R₆Wherein R is₆Is a saturated aliphatic radical having from 3 to 29 carbon atoms, where R₃Or R₄At least one of which is- (C ═ O) -R₆(ii) a And/or (c) R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is a saturated aliphatic group having 3 to 29 carbon atoms.

In a more preferred embodiment, R₁And R₂Are all hydrogen atoms.

In a particularly preferred embodiment, -Alk-is- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -, and R₁And R₂Are all hydrogen atoms. In this embodiment, the PUFA derivative of formula (I) is 15-HETrE and is represented by the formula:

generally, the compounds of the invention are administered as one or more treatments per day, preferably 1 to 4 treatments per day, more preferably 1 to 2 treatments per day.

Typically, the compounds of the invention are present at 0.1mg/m²Day to 1kg/m²A day, preferably 1mg/m²Day to 100g/m²Better one day, betterSelecting 10mg/m²Day to 10g/m²A day, most preferably 100mg/m²Day to 1g/m²Daily doses per day.

Skin inflammation includes rash, urticaria, blisters and/or wheal and may be caused by eczema, exposure to radiation, autoimmune diseases and/or uremic pruritus.

In a preferred embodiment, the skin inflammation is caused by atopic eczema, contact dermatitis, psoriasis or uremic pruritus.

In yet another preferred embodiment, the skin inflammation is caused by exposure of the skin to electromagnetic radiation. This includes, for example, exposure to sunlight, heat, X-rays, or radioactive substances. Thus, in this embodiment, the compounds of the present invention are generally used to treat sunburn.

The term eczema applies to a wide range of skin conditions of various etiologies. Generally, eczema is classified by epidermal inflammation. Common symptoms associated with eczema include dryness, recurrent skin rash, redness, skin edema (swelling), itching, dryness, crusting, flaking, blistering, cracking, weeping, and bleeding. Eczema includes atopic eczema (atopic dermatitis), contact dermatitis, xerotic eczema, seborrheic dermatitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis (dermatitis herpetiformis), neurodermatitis, and self-eczematization. Eczema is typically atopic eczema or contact dermatitis.

Atopic eczema is exacerbated primarily by contact or ingestion of allergens, including animal hair and dander, food allergens such as nuts or shellfish, or drugs such as penicillin.

Contact dermatitis includes allergic contact dermatitis, irritant contact dermatitis and light contact dermatitis.

Electromagnetic radiation includes radio waves, microwaves, terahertz radiation, infrared radiation, visible light, ultraviolet radiation, X-rays and gamma rays. The electromagnetic radiation is preferably infrared radiation, visible light, ultraviolet radiation, X-rays and gamma rays, more preferably ultraviolet radiation, X-rays and gamma rays.

Autoimmune diseases can involve an autoimmune response to the skin. Examples of such autoimmune diseases are lupus and psoriasis.

Uremic pruritus is a skin disorder associated with chronic renal failure. It also frequently affects patients undergoing dialysis treatment.

Generally, the compounds of the invention are combined with corticosteroids.

Suitable corticosteroids for use in combination with the compounds of the invention are clobetasol dipropionate, betamethasone dipropionate, halbetasol propionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide, desoximetasone, triamcinolone acetonide, mometasone furoate, fluticasone propionate, fluocinolone acetonide, hydrocortisone valerate, hydrocortisone butyrate, triamcinolone acetonide, desonide, prednisolone, methylprednisolone, dexamethasone, naftifide, deflazacort, haloprednisolone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, clocotolone pivalate, methylprednisolone aceponate, dexamethasone palmitate, tiprednisolone, hydrocortisone acepone, alclomethasone dipropionate, halometasone, sulfoheptylprednisolone, rimexolone, prednisolone farnesyl salt, ciclesonide, delosone propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone sodium phosphate and hydrocortisone propionate.

Preferred corticosteroids for use in combination with the compounds of the invention are clobetasol dipropionate, betamethasone dipropionate, halbetasol propionate, diflorasone diacetate, fluocinonide acetate, halcinonide, amcinonide, desoximetasone, triamcinolone acetonide, mometasone furoate, fluticasone propionate, fluocinolone acetonide, hydrocortisone valerate, hydrocortisone butyrate, triamcinolone acetonide, desonide, and prednisone.

Within the scope of the present invention, any reference to a corticosteroid includes reference to a salt or derivative thereof which may be formed from the corticosteroid. Examples of possible salts or derivatives include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates, farnesyl salts, levulinic acid salts, sulphoheptates, bronicates, furoates or acetonates. In some cases, corticosteroids may also occur in their hydrate form.

The present invention specifically finds that combining a compound of the invention with a corticosteroid allows the amount of corticosteroid to be administered to be reduced without reducing the efficacy of the treatment. Thus, in a preferred embodiment, the compounds of the invention are used in combination with a corticosteroid wherein the corticosteroid is administered at a daily dosage that is 50% or less, preferably 25% or less, more preferably 10% or less, most preferably 5% or less of the recommended daily dosage of said corticosteroid in said mammal.

The recommended daily dosage of corticosteroids in mammals is well known to those skilled in the art. For example, the recommended daily dose of hydrocortisone in humans is about 0.35g/m²The day is. The recommended daily dose of clobetasol propionate in humans is 0.009 to 0.018g/m²The day is.

Thus, the compounds of the invention are generally used in combination with hydrocortisone, wherein the daily dose of hydrocortisone is 0.175g/m²A day or less, preferably 0.0875g/m²A day or less, more preferably 0.035g/m²A day, most preferably 0.0175g/m²A day or less. The compounds of the invention are typically used in combination with clobetasol propionate, wherein the daily dose of clobetasol propionate is 0.009g/m²A day or less, preferably 0.0045g/m²A day or less, more preferably 0.0018g/m²A day or less, most preferably 0.0009g/m²A day or less.

The compounds of the present invention are typically combined with other therapeutic agents that are not corticosteroids but are effective in treating skin conditions/diseases. Such therapeutic agents are well known to the skilled artisan and include, but are not limited to, immunomodulators, antibiotics, immunosuppressants and anti-itch drugs.

The compounds of the invention are generally commercially available or can be prepared analogously by known methods. For example, DGLA and 15-HETrE are both commercially available. These available fatty acids can be easily derivatized by known methods to obtain the PUFA derivatives of formula (I).

For example, a PUFA derivative of formula (I) as defined herein, wherein R₁Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl; or R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄As defined herein; or R₁Is of the formula- (CH)₂OCH₂)_mOH groups, wherein m is as defined herein, can be prepared by: with the formula R₁Esterification of' -OH alcohol with a compound of the formula

wherein-Alk-is as defined herein and X is a leaving group, such as a halogen atom, a tosylate or a mesylate group; wherein R is₁Is' a C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl; or R₁' is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄As defined herein; or R₁' is of the formula- (CH)₂OCH₂)_mOH group, wherein m is as defined herein, to obtain a PUFA derivative of formula (I) as defined herein. Alternatively, X may be hydroxyl. In this case, the reaction is preferably carried out under acidic conditions or in the presence of a suitable catalyst, for example pyridine. Formula R₁' -OH compounds are generally commercially available or can be prepared analogously by known methods.

In the case of-Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH ═ CH-, or- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -in the case of a PUFA derivative of formula (I) as defined herein, wherein R₂Is a radical- (C ═ O) -R₅Wherein R is₅Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl, or R₅Is an aliphatic group having 3 to 29 carbon atoms, and can be prepared by: from carboxylic acid derivative Y- (C ═ O) -R'₅Treating a compound of formula (I) as defined herein, wherein-Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH ═ CH-, or- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -, and R₂Is a hydrogen atom; wherein R'₅Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl, or R'₅Is provided with 3An aliphatic group of up to 29 carbon atoms, and Y is a leaving group, such as a halogen atom, a tosylate or mesylate group. Formula Y- (C ═ O) -R'₅The compounds are generally commercially available or can be prepared analogously by known methods.

In the case of-Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH ═ CH-, or- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -in the case of a PUFA derivative of formula (I) as defined herein, wherein R₂Is of the formula- (CH)₂OCH₂)_nOH groups, wherein n is as defined herein, can be prepared by: by the formula Z- (CH)₂OCH₂)_nOH Compound treatment A compound of formula (I) as defined herein, wherein-Alk-is-CH (OR)₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH＝CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH ═ CH- [ cis ] form]CH＝CH-CH₂- [ cis form ]]CH ═ CH-, or- (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH- [ trans form]CH＝CH-CH(OR₂) -, and R₂Is a hydrogen atom; wherein n is as defined herein and Z is a good leaving group, such as a halogen atom, a tosylate or a mesylate group. Formula Z- (CH)₂OCH₂)_nOH compounds are generally commercially available or can be prepared analogously by known methods.

The present invention also provides a pharmaceutical composition suitable for topical administration comprising a PUFA derivative as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent or carrier for use in the treatment of skin inflammation as defined herein in a mammal as defined herein.

Preferred pharmaceutical compositions are sterile and pyrogen free.

The pharmaceutical composition is typically in the form of a gel, ointment, cream or lotion.

Where the pharmaceutical composition is a gel, it typically comprises a hydrophilic polymer such as cross-linked polyethylene glycol, cross-linked starch or polyvinylpyrrolidone.

Ointments, creams or lotions generally contain a mixture of an aqueous phase and an oily phase.

The pharmaceutical composition may additionally contain one or more emollients, emulsifiers, thickeners and/or preservatives, especially if it is a cream or ointment.

Emollients suitable for inclusion into creams or ointments of the present invention are typically long chain alcohols, for example C8-C22 alcohols such as cetyl, stearyl and cetearyl alcohols, hydrocarbons such as petrolatum and light mineral oil, or acetylated lanolin. The total amount of emollients in the pharmaceutical composition is preferably from about 5% to about 30% by weight, and more preferably from about 5% to about 10% by weight, based on the total weight of the pharmaceutical composition.

Emulsifiers are typically nonionic surfactants, such as polysorbate 60 (from ici americas), sorbitan monostearate, polyglycerol-4 oleate and polyoxyethylene (4) lauryl ether. Generally, the total amount of emulsifier is from about 2% to about 14% by weight, and more preferably from about 2% to about 6% by weight, based on the total weight of the pharmaceutical composition.

Pharmaceutically acceptable thickeners such as veegum.tm.k (available from r.t. vanderbilt Company, Inc.), and long chain alcohols (i.e., C8-C22 alcohols such as cetyl, stearyl, and cetearyl alcohols) may be used. The total amount of thickening agent present is preferably from about 3% to about 12% by weight, based on the total weight of the pharmaceutical composition.

Preservatives such as methylparaben, propylparaben and benzyl alcohol can be present in the pharmaceutical composition. Suitable amounts of such preservatives are known to those skilled in the art. The pharmaceutical composition may also comprise fat-soluble antioxidants such as ascorbyl palmitate, vitamin E and/or vitamin C in the presence of lecithin.

Optionally, additional solubilizing agents such as benzyl alcohol, lactic acid, acetic acid, stearic acid, or hydrochloric acid may be included in the pharmaceutical composition. If an additional solubilizer is used, it is preferably present in an amount of about 1% to about 12% by weight, based on the total weight of the pharmaceutical composition.

Optionally, the pharmaceutical composition can contain a humectant such as glycerin and a skin penetration enhancer such as butyl stearate, urea, and DMSO.

It is known to the person skilled in the art that a single ingredient in a cream can exert more than one action, i.e. cetyl alcohol can act as an emollient and as a thickener.

In one embodiment, the pharmaceutical composition is in the form of a cream. Creams generally comprise an oil phase and an aqueous phase which are mixed together to form an emulsion. Preferably, the cream comprises an oil-in-water emulsion. Preferably, the amount of water present in the cream of the present invention is from about 45% to about 85% by weight, based on the total weight of the cream.

Where the pharmaceutical composition is in the form of an ointment, it will generally comprise a pharmaceutically acceptable ointment base such as petrolatum or a combination of polyethylene glycol 400 (from Union Carbide) and polyethylene glycol 3350 (from Union Carbide). The amount of ointment base present in the ointments of the invention is preferably from about 60% to about 95% by weight, based on the total weight of the ointment.

In the pharmaceutical composition of the present invention, the amount of the PUFA derivative of formula (I) is typically from 0.01% to 50% by weight, preferably from 0.5% to 25% by weight, more preferably from 1% to 10% by weight, for example about 5% by weight, based on the total weight of the pharmaceutical composition.

The compounds/compositions of the invention are formulated for topical administration and can be delivered in the range of 0.00001 to 10g, preferably 0.0001 to 1g, active ingredient/m²The amount of treatment area is administered to the patient.

The pharmaceutical compositions of the invention may additionally comprise one or more corticosteroids as defined herein. The amount of corticosteroid present in the pharmaceutical compositions of the present invention is generally 50% or less, preferably 25% or less, more preferably 10% or less, most preferably 5% or less of the recommended amount of said corticosteroid in commercially available formulations. The skilled person is familiar with the amount of corticosteroid present in various topical formulations. For example, hydrocortisone is typically present in most commercially available formulations in an amount of 1% w/w. The amount of clobetasol propionate present in most commercially available formulations is typically 0.0525% w/w.

Thus, the pharmaceutical composition of the invention typically comprises hydrocortisone in an amount of 0.5% w/w or less, preferably 0.025% w/w or less, more preferably 0.01% w/w or less, most preferably 0.005% w/w or less. The pharmaceutical compositions of the present invention generally comprise clobetasol propionate in an amount of 0.026% w/w or less, preferably 0.013% w/w or less, more preferably 0.0053% w/w or less, most preferably 0.0026% w/w or less.

The pharmaceutical compositions of the invention generally comprise one or more other therapeutic agents as defined herein which are not corticosteroids. The amount of one or more other therapeutic agents other than a corticosteroid present in the composition will be apparent to those skilled in the art.

The pharmaceutical composition of the present invention can be simply prepared by mixing the respective ingredients in a suitable manner.

The invention also provides the use of a compound which is a PUFA derivative of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use by topical administration in the treatment of skin inflammation as defined herein in a mammal.

The present invention also provides a method of treating inflammation of the skin as defined herein in a mammal as defined herein, which method comprises administering to the skin of said mammal a therapeutically effective amount of a compound which is a PUFA derivative of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides a pharmaceutical composition comprising a polyunsaturated fatty acid (PUFA) derivative of formula (II),

or a pharmaceutically acceptable salt or solvate thereof, wherein

- - -Alk- -is- - (CH)₂)₃- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH＝CH-CH₂- [ cis form ]]CH ═ CH —; and

R₁as defined herein;

the composition is used for treating skin inflammation in a mammal by topical administration and is substantially free of lithium salts and glucocorticoids.

The skilled person will appreciate that in this embodiment, the pharmaceutically acceptable salt of the PUFA derivative of formula (II) is not a lithium salt.

Generally, pharmaceutical compositions comprising polyunsaturated fatty acid (PUFA) derivatives of formula (II) contain a PUFA derivative of formula (II) as the only active ingredient.

Preferably, the pharmaceutical composition comprising a polyunsaturated fatty acid (PUFA) derivative of formula (II) comprises a PUFA derivative of formula (II) and a pharmaceutically acceptable diluent or carrier as defined herein.

Preferably, the PUFA derivative of formula (II) is of formula R "(C ═ O) O — CH₂-CH(O(C＝O)R″)-CH₂-O (C ═ O) R ", wherein each R" is the same and is an aliphatic group of dihomo-y-linolenic acid, i.e. R "is- (CH)₂)₆-CH＝CH-CH₂-CH＝CH-CH₂-CH＝CH-(CH₂)₄CH₃Wherein all C ═ C double bonds have the cis configuration. Thus, PUFA derivatives of formula (II) are preferred.

In a particularly preferred embodiment, R₁Is a hydrogen atom. In this embodiment, the PUFA derivative of formula (II) is DGLA and is represented by the formula:

the present invention also provides the use of a pharmaceutical composition comprising a polyunsaturated fatty acid (PUFA) derivative of formula (II) as defined herein, wherein the composition is substantially free of lithium salts and glucocorticoids, in the manufacture of a medicament for use by topical administration in the treatment of skin inflammation as defined herein in a mammal as defined herein.

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 said mammal a therapeutically effective amount of a pharmaceutical composition comprising a polyunsaturated fatty acid (PUFA) derivative of formula (II) as defined herein, wherein the composition is substantially free of lithium salts and glucocorticoids.

Detailed Description

Immunohistochemical analysis was performed to measure the extent of expression of COX-2 enzyme in the skin of the ears of ex vivo pigs. Enzymes of the COX-2 family are strongly associated with inflammation and have been found to be present in increased amounts in inflamed tissues. Thus, reduced COX-2 levels in the skin correspond to reduced skin inflammation.

Example 1

Freshly cut pig ears were immersed in ice-cold Hank buffer for transport from slaughterhouse to laboratory. After arrival, the pig ears were first washed with running tap water, the full skin was peeled from the underlying cartilage by blunt dissection with a scalpel, and the hair was removed with an electric razor. The skin was applied within 2 hours after sacrifice. The whole skin was cut into approximately 2cm by 2cm and placed in Hanks balanced salt to maintain skin viability.

A2 mm strip of skin was cut with a surgical scalpel, then fixed with 40% formaldehyde solution, dehydrated and placed in melted wax. Sections of 5 μm thickness were cut with a Shandon Finesse microtome (Thermoscientific, Waltham, Mass., USA) and placed on pre-cleaned microscope slides of 2.5 cmx7.5cmx1mm. Skin sections were stained with diaminobenzidine, which binds to COX-2 enzyme, and slides were visualized on an optical microscope with an image capture device.

The skin membrane was mounted in a Franz diffusion cell using Hanks buffer as the receptive phase. Water was used as the feed phase. After 6 hours, the skin was removed from the Franz cell apparatus, the oversupplied phase was removed, and the skin was wiped clean with a cleaning paper towel. The diffusion area was then cut into approximately 2mm strips with a surgical scalpel, and the skin strips were then fixed with 40% formaldehyde solution, dehydrated, and placed in melted wax. Sections of 5 μm thickness were cut with a Shandon Finesse microtome (Thermo Scientific, Waltham, MA, USA) and placed on pre-cleaned microscope slides of 2.5 cmx7.5cmx1mm. Skin sections were stained with diaminobenzidine, which binds to COX-2 enzyme, and slides were visualized on an optical microscope with an image capture device.

The results of this experiment are shown in figure 1. Dark staining appeared in the samples after both 0 and 6 hours, indicating a sustained presence of COX-2 in the skin. This indicates that water has no anti-inflammatory activity.

Example 2

An experiment was performed as described in example 1, but ketoprofen, a known COX-2 inhibitor, contained in fish oil was supplied.

The results of this experiment are shown in figure 2. After six hours, the amount of dark staining decreased, indicating that ketoprofen penetrated the viable epidermis and was active against COX-2 expression in the skin.

Example 3

The experiment was carried out as described in example 1, but the phase supplied was DGLA as a representative compound of the invention.

The results of this experiment are shown in figure 3. After six hours, the amount of dark staining decreased, indicating that DGLA penetrated into the viable epidermis and was active against COX-2 expression in the skin.

Example 4

An experiment was carried out as described in example 1, but the representative compound 15-HETrE of the present invention was supplied.

The results of this experiment are shown in fig. 4. After six hours, the amount of dark staining decreased, indicating that 15-HETrE penetrated into the viable epidermis and was active against COX-2 expression in the skin.

Example 5

Western blot experiments were performed to determine the effect of topical application of DGLA and 15-HETrE, representative compounds of the invention, on COX-2 expression in porcine skin. Water was used as a control.

Porcine skin membranes were gently cleaned with deionized water (as described in example 1) and subsequently lysed in (Silverson, Chesham, UK) RIPA lysis buffer [50mM Tris-HCl (pH7.4), 150mM NaCl, 1mM PMSF, 1mM EDTA, 5. mu.g mL^-1Aprotinin, 5. mu.g mL^-1Leupeptin, 1% Triton X-100, 1% sodium deoxycholate, 0.1% SDS]And (4) medium homogenizing. After incubation on ice for 15 minutes, the lysates were clarified by centrifugation at 14000Xg for 2X15 minutes and the supernatants were stored at-80 ℃ for subsequent protein analysis.

Aliquots of 30. mu.g total protein were separated by SDS-PAGE, transferred to nitrocellulose membrane using a Trans-Blot electrophoretic transfer cell, and briefly stained with Ponceau S to confirm efficient transfer. Immunoblots were incubated in blocking solution [ Tris-buffered saline (TBS) -Tween 20 containing 5% (w/v) commercial skim milk powder (Marvel) ] for 1 hour at room temperature. After washing, membranes were probed overnight at 4 ℃ with 1: 1000 COX-2 antibody, 1: 1000 5-LOX and 1: 500 iNOS in (1: 20 and 1: 100 protein blocking agent and sodium azide solution, respectively, made up to volume with TBS Tween). The membrane was then incubated with HRP-conjugated anti-rabbit at 1: 10000 for 1 hour. For β -actin, membranes were probed with anti-actin and anti-mouse (1: 10000 each) for 1h at room temperature. After washing 3 × 10 min in TBS tween, it was finally exposed to freshly prepared Dura substrate for chemiluminescence for the appropriate time, followed by autoradiography.

The results of this experiment are shown in fig. 5. It can be seen that a significant decrease in COX-2 expression was observed following administration of DGLA and 15-HETrE relative to controls.

Claims (16)

1. A compound which is a polyunsaturated fatty acid derivative of formula (I),

I

or a pharmaceutically acceptable salt thereof, wherein

- - -Alk- -is- -CH (OR)₂) - [ trans ] form]CH = CH- [ cis [ ]]CH=CH-CH₂- [ cis form ]]CH=CH-C₃H₆-，-(CH₂)₃-CH(OR₂) - [ trans ] form]CH = CH- [ cis [ ]]CH=CH-CH₂- [ cis form ]]CH=CH-，-(CH₂)₃- [ cis form ]]CH=CH-CH₂- [ cis form ]]CH = CH- [ trans ]]CH=CH-CH(OR₂) -or- (CH)₂)₃- [ cis form ]]CH=CH-CH₂- [ cis form ]]CH=CH-CH₂- [ cis form ]]CH=CH-；

-R₁Is a hydrogen atom; or

R₁Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl; or

R₁Is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently is a hydrogen atom or- (C = O) -R₆Wherein R is₆Is an aliphatic group having 3 to 29 carbon atoms; or

R₁Is of the formula- (CH)₂OCH₂)_mAn OH group, wherein m is an integer from 1 to 200;

-R₂is a hydrogen atom; or

R₂Is a group- (C = O) -R₅Wherein R is₅Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₃-C₇Carbocyclyl or 5-to 10-membered heterocyclyl, or R₅Is an aliphatic group having 3 to 29 carbon atoms; or

R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is an integer from 1 to 200;

and wherein

-said alkyl, alkenyl, alkynyl and aliphatic groups are identical or different and are each unsubstituted or substituted by 1, 2 or 3 unsubstituted substituents which are identical or different and are selected from halogen atoms and C_1-C₄Alkoxy radical, C_2-C₄Alkenyloxy radical，C_1-C₄Haloalkyl, C_2-C₄Haloalkenyl group, C_1-C₄Halogenoalkoxy, C_2-C₄Haloalkenyloxy, hydroxy, -SR ', and-NR ' R ' ' groups, wherein R ' and R ' ' are the same or different and represent hydrogen or unsubstituted C₁-C₂An alkyl group;

-said aryl, heteroaryl, carbocyclyl and heterocyclyl are identical or different and are each unsubstituted or substituted by 1, 2, 3 or 4 unsubstituted substituents which are identical or different and are selected from halogen atoms, and cyano, nitro, C_1-C₄Alkyl radical, C_1-C₄Alkoxy radical, C_2-C₄Alkenyl radical, C_2-C₄Alkenyloxy radical, C_1-C₄Haloalkyl, C_2-C₄Haloalkenyl group, C_1-C₄Halogenoalkoxy, C_2-C₄Haloalkenyloxy, hydroxy, C_1-C₄Hydroxyalkyl, -SR ' and-NR ' R ' ' groups, wherein each R ' and R ' ' are identical or different and represent hydrogen or unsubstituted C_1-C₄An alkyl group;

and wherein the polyunsaturated fatty acid derivatives are in the form of racemates, stereoisomers or mixtures of stereoisomers,

the compounds are useful for treating skin inflammation in mammals by topical administration.

2. A compound according to claim 1, wherein R₁Is a hydrogen atom.

3. A compound according to claim 1 or 2, wherein-Alk-is- (CH)₂)₃- [ cis form ]]CH=CH-CH₂- [ cis form ]]CH = CH- [ trans ]]CH=CH-CH(OR₂)-。

4. A compound according to claim 1 or 2, wherein R₂Is a hydrogen atom.

5. A compound according to claim 1 or 2, wherein the polyunsaturated fatty acid derivative is present as the R enantiomer.

6. A compound according to claim 1 or 2, wherein the polyunsaturated fatty acid derivative is present as the S enantiomer.

7. A compound according to claim 1 or 2, wherein the mammal is a human.

8. A compound according to claim 1 or 2, wherein the skin inflammation is caused by atopic eczema, contact dermatitis, psoriasis or uremic pruritus.

9. A compound according to claim 1 or 2, wherein:

(a)R₁is of the formula-CH₂-CH(OR₃)-CH₂-(OR₄) Group, wherein R₃And R₄Each independently represents a hydrogen atom or- (C = O) -R₆Wherein R is₆Is a saturated aliphatic radical having from 3 to 29 carbon atoms, where R₃Or R₄Is- (C = O) -R₆(ii) a Or

(b)R₁Is of the formula- (CH)₂OCH₂)_mAn OH group, wherein m is as defined in claim 1; and/or

(c)R₂Is a group- (C = O) -R₅Wherein R is₅Is a saturated aliphatic group having 3 to 29 carbon atoms; or

(d)R₂Is of the formula- (CH)₂OCH₂)_nAn OH group, wherein n is as defined in claim 1.

10. A compound according to claim 1 or 2 in combination with a corticosteroid.

11. A compound according to claim 1 or 2, wherein the skin inflammation is caused by exposure of the skin to electromagnetic radiation.

12. A pharmaceutical composition suitable for topical administration comprising a polyunsaturated fatty acid derivative as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier for use in the treatment of skin inflammation in a mammal.

13. The pharmaceutical composition according to claim 12, which is in the form of a gel, ointment, cream or lotion.

14. Use of a compound which is a polyunsaturated fatty acid derivative of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of skin inflammation in a mammal.

15. A pharmaceutical composition comprising a polyunsaturated fatty acid derivative of formula (II),

II

or a pharmaceutically acceptable salt thereof, wherein

- - -Alk- -is- - (CH)₂)₃- [ cis form ]]CH=CH-CH₂- [ cis form ]]CH=CH-CH₂- [ cis form ]]CH = CH-; and

R₁as defined in claim 1 or 2;

the composition is used for treating skin inflammation in mammals by topical administration and is free of lithium salts and glucocorticoids.

16. The pharmaceutical composition according to claim 15, which contains the polyunsaturated fatty acid derivative of formula (II) as the only active ingredient.