METHODS OF TREATING SKIN DISORDERS WITH CAFFEIC ACID ANALOGS

Info

Publication number: 20130244986
Type: Application
Filed: Apr 26, 2013
Publication Date: Sep 19, 2013
Applicant: Moleculin LLC (Houston, TX)
Inventors: Waldemar Priebe (Houston, TX), Charles Conrad (Spring, TX), Timothy Madden (Sugar Land, TX)
Application Number: 13/871,686

Abstract

Embodiments of the invention generally relate to pharmaceutical compositions containing at least one caffeic acid compound and methods for the topical treatment of proliferative and inflammatory skin disorders such as plaque psoriasis, atopic dermatitis, and other disorders. In some embodiments, the topical treatment includes applications of the pharmaceutical composition containing at least one caffeic acid compound or a mixture of caffeic acid compounds such as caffeic acid ester compounds, caffeic acid amide compounds, analogues thereof, derivatives thereof, salts thereof, or mixtures thereof. The pharmaceutical composition or topical dosage may contain the caffeic acid compound at a concentration by weight within a range from about 0.01% to about 20%, preferably, from about 0.1% to about 15%, preferably, from about 1% to about 10%, more preferably, from about 3% to about 7%, and more preferably, from about 4% to about 6%.

Description

Description

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit of U.S. Ser. No. 61/101,589, filed Sep. 30, 2008, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Embodiments of the invention generally relate to treating proliferative and inflammatory skin disorders and to the compositions utilized during the treatment.

2. Description of the Related Art

Many different skin diseases or disorders relate to persistent inflammation and abnormal cell growth. For example, psoriasis affects an estimated two to three percent of the world's population of which, plaque psoriasis (psoriasis vulgaris) comprises about 80 percent of these cases. Plaque psoriasis is characterized by raised, red inflamed lesions covered by a silvery white scale comprised of dead skin cells. Other forms of psoriasis include inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and guttate psoriasis. The lesions from psoriasis make the disorder both a medical and a cosmetic problem.

However, current topical treatments for psoriasis fail to produce satisfactory results. Prior treatments often take away some inflammation but do not cure or eliminate the disorder. Further, patients on such treatment may achieve only some improvement in their condition over long periods of several months.

Therefore, there exists a need for an improved topical composition and method for treating proliferative and inflammatory skin disorders such as plaque psoriasis, atopic dermatitis and other disorders.

SUMMARY OF THE INVENTION

Embodiments of the invention generally relate to pharmaceutical compositions containing at least one caffeic acid compound and methods for the topical treatment of proliferative and inflammatory skin disorders such as cutaneous T-cell lymphoma, plaque psoriasis, atopic dermatitis, and other skim disorders. In some embodiments, the topical treatment includes applications of the pharmaceutical composition containing at least one caffeic acid compound or a mixture of caffeic acid compounds such as caffeic acid ester compounds, caffeic acid amide compounds, analogues thereof, derivatives thereof, salts thereof, or mixtures thereof. Exemplary caffeic acid ester compounds include caffeic acid phenethyl ester (CAPE), caffeic acid benzyl ester (CABE), analogues thereof, derivatives thereof, salts thereof, or mixtures thereof.

In some embodiments, the pharmaceutical composition or topical dosage may contain the caffeic acid ester compound at a concentration by weight within a range from about 0.01% to about 20%, preferably, from about 0.1% to about 15%, preferably, from about 1% to about 10%, more preferably, from about 3% to about 7%, and more preferably, from about 4% to about 6%. In some examples, the topical pharmaceutical composition contains the caffeic acid ester compound at a concentration of about 5% by weight. In one example, the topical pharmaceutical composition contains CAPE at a concentration of about 5% by weight. In another example, the topical pharmaceutical composition contains CABE at a concentration of about 5% by weight.

In one embodiment, a method for treating proliferative skin disorders is provided which includes applying a topical pharmaceutical composition to a lesion, wherein the topical pharmaceutical composition comprises a caffeic acid amide compound having the generic chemical structure of:

where X is a halogen and R is hydrogen, hydroxyl, alkyl, alkoxy, C₃-C₇-cycloalkyl, C₆-C₁₀-aryl, C₇-C₁₀-aralkyl, heteroatom-substituted or heteroatom-unsubstituted, isomers thereof, or derivatives thereof, and the topical pharmaceutical composition comprises the caffeic acid amide compound at a concentration by weight within a range from about 0.01% to about 20%.

In one example, the caffeic acid amide compound has the chemical structure of:

In another example, the caffeic acid amide compound has the chemical structure of:

In another embodiment, a method for treating proliferative skin disorders is provided which includes applying a topical pharmaceutical composition to a lesion, wherein the topical pharmaceutical composition comprises a caffeic acid amide compound having the chemical structure of:

and the topical pharmaceutical composition comprises the caffeic acid amide compound at a concentration by weight within a range from about 0.01% to about 20%.

In some embodiments, the topical pharmaceutical composition or topical dosage may contain the caffeic acid amide compound at a concentration by weight within a range from about 0.01% to about 20%, preferably, from about 0.1% to about 15%, preferably, from about 1% to about 10%, more preferably, from about 3% to about 7%, and more preferably, from about 4% to about 6%. In one example, the topical pharmaceutical composition contains the caffeic acid amide compound at a concentration of about 5% by weight.

The topical pharmaceutical composition containing the caffeic acid compound may further contain at least one mechanistic compound. Useful mechanistic compounds include cell differentiating agents, anti-proliferative agents, mitochondrial inhibitors, topical steroids, immunosuppressive compounds, JAK2 inhibitors, JAK3 inhibitors, parathyroid hormone-related protein (PTHrP) agonists, cell adhesion blockers, derivatives thereof, or combinations thereof. In some examples, the topical pharmaceutical composition may also contain retinoic acid, retinoic acid derivatives, vitamin D, or vitamin D analogs—which may be used as a cell differentiating agent.

In another embodiment, a method for treating a skin disorder provides applying the topical pharmaceutical composition on lesions multiple times daily until symptoms of the disorder disappear.

In another embodiment, a pharmaceutical composition for topical application to psoriatic lesions is provided which includes a carrier suitable for topical administration, and a caffeic acid amide compound having the generic chemical structure of:

where X is a halogen and R is hydrogen, hydroxyl, alkyl, alkoxy, C₃-C₇-cycloalkyl, C₆-C₁₀-aryl, C₇-C₁₀-aralkyl, heteroatom-substituted or heteroatom-unsubstituted, isomers thereof, or derivatives thereof, and the caffeic acid amide compound is at a concentration by weight within a range from about 0.01% to about 20% of the pharmaceutical composition.

In another embodiment, the pharmaceutical composition for topical application to psoriatic lesions is provided which includes a carrier suitable for topical administration, and a caffeic acid amide compound having the chemical structure of:

and the caffeic acid amide compound is at a concentration by weight within a range from about 0.01% to about 20% of the pharmaceutical composition.

In some embodiments, the pharmaceutical composition may further contain petroleum jelly or dimethyl sulfoxide. Also, the caffeic acid compound may be an analogue, a derivative, or a salt of a caffeic acid or a caffeic acid amide compound.

DETAILED DESCRIPTION

Embodiments of the invention generally relate to pharmaceutical compositions containing at least one caffeic acid compound and methods for the topical treatment of proliferative and inflammatory skin disorders such as cutaneous T-cell lymphoma, plaque psoriasis, atopic dermatitis, and other disorders with a topical application of the pharmaceutical composition. Caffeic acid compounds as an active agent may include caffeic acid ester compounds, caffeic acid amide compounds, analogues thereof, derivatives thereof, salts thereof, or mixtures thereof.

According to one embodiment, the pharmaceutical composition contains at least one caffeic acid ester compound or a mixture of caffeic acid ester compounds as an active agent. In one example, the caffeic acid ester compound is caffeic acid phenethyl ester (CAPE). In another example, the caffeic acid ester compound is caffeic acid benzyl ester (CABE). CAPE and CABE have the following chemical structures:

In other examples, the pharmaceutical composition may contain analogues, derivatives, salts, or mixtures of CAPE, CABE, or other caffeic acid ester compounds useful as the active agent.

In another embodiment, the pharmaceutical composition contains at least one caffeic acid amide compound or a mixture of caffeic acid amide compounds as an active agent. In one example, the caffeic acid amide compound has the chemical structure 1:

In another example, the caffeic acid amide compound has the chemical structure 2:

In another example, the caffeic acid amide compound has the chemical structure 3:

In another example, the caffeic acid amide compound has the chemical structure 4:

In other examples, the pharmaceutical composition may contain analogues, derivatives, salts, or mixtures of caffeic acid amide compounds having the chemical structures 1, 2, 3, or 4 and useful as the active agent during the treatments described herein.

In other embodiments, the pharmaceutical composition may contain other caffeic acid amide compounds which are useful as active agents. The caffeic acid amide compounds may have a generic chemical structure, such as the chemical structure 5:

where X is a halogen and R is hydrogen, hydroxyl, alkyl, alkoxy, C₃-C₇-cycloalkyl, C₆-C₁₀-aryl, C₇-C₁₀-aralkyl, heteroatom-substituted or heteroatom-unsubstituted, isomers thereof, or derivatives thereof. In some examples, R is an alkyl group of C₁-C₁₂, including methyl, ethyl, propyl, butyl, amyl, isomers thereof, or derivatives thereof. The chemical structure 5 has stereochemistry about the carbon atom which is bonded to the R group. In one embodiment, the S-enantiomer of chemical structure 5 may be used as the active agent. In other examples, the pharmaceutical composition may contain analogues, derivatives, salts, or mixtures of caffeic acid amide compounds having the chemical structure 5 and useful as the active agent.

In other embodiments, the pharmaceutical composition may have other caffeic acid compounds which are useful as active agents. The caffeic acid compounds may have a more generic chemical structure, such as the chemical structure 6:

and pharmaceutically acceptable salts thereof, where R₁, R₂, R₃, R₆, R₇, R₈, or R₉are independently selected from H, OH, NO₂, N₃, NH₂, alkyl, alkoxy, O-acyl, COOH, F, Cl, Br, I, or derivatives thereof; R₄is H, CN, or SO₂R; X₁is O, NH, or S; and R₅is H, alkyl, alkoxy, cycloakyl, O-acyl, N-alkyl, N-acyl, or alkylamine. Alkyl groups usually have from 1 to 12 carbon atoms and include methyl, ethyl, propyl, butyl, amyl, isomers thereof, or derivatives thereof. In some examples, the alkyl groups may have from 1 to 6 carbon atoms. In other examples, the alkyl groups may have from 1 to 4 carbon atoms. The alkyl group may be optionally substituted with 1-3 substituents such as hydroxyl, alkylamine, —O-alkyl, acyl, —O-acyl, —N(R)-acyl, —C(O)—O-alkyl, —C(O)—N(R)-alkyl, thiol, and halo, where R is hydrogen or alkyl. Suitable alkyl groups include methyl, isopropyl, —CH₂-cyclohexyl, and cyclopropyl.

The chemical structure 6 has stereochemistry about the carbon atom which is bonded to the R₅group. In one embodiment, the S-enantiomer of chemical structure 6 may be used as the active agent. In other examples, the pharmaceutical composition may contain analogues, derivatives, salts, or mixtures of caffeic acid amide compounds having the chemical structure 6 and useful as the active agent.

The term “SO₂R”, where R is an alkyl group, refers to the group —SO₂-alkyl.

The term “alkanol” refers to the group—alkyl substituted with 1-3 hydroxy groups.

The term “alkylamine” refers to the group—alkyl substituted with 1-3 —NR₂groups, wherein each R group may be independently H and/or alkyl.

The term “acyl” refers to —C(O)—R where R is alkyl.

The term “cyclic alkyl” or “cycloalkyl” refers to alkyl groups that are cyclic. Cycloalkyl groups may have 3 to 12 carbon atoms. In some embodiments, the cycloalkyl groups may have 3 to 6 carbon atoms. In some embodiments, the cycloalkyl groups may have 3 to 4 carbon atoms. The cycloalkyl group may be optionally substituted with 1-3 substituents include hydroxyl, alkylamine, —O-alkyl, acyl, —O-acyl, —N(R)-acyl, —C(O)—O-alkyl, —C(O)—N(R)-alkyl, thiol, and halo, where R is H or alkyl. Suitable cyclic groups include cyclohexyl, cyclopentyl, and cyclopropyl.

The term “pharmaceutically acceptable salt” includes salts of the aforementioned compounds and prodrugs derived from the combination of a compound as set forth herein and an organic acid, an inorganic acid, or a base. Suitable acids include hydrogen chloride (HCl).

The following reaction illustrates synthesis of CAPE:

As shown, the general synthetic approach to CAPE and its analogs involves formation of an ester bond of caffeic acid or its analogs with phenyl derivatives containing a hydroxy group. The caffeic acid ester compounds may be synthesized by utilizing various methods of ester formation which leads to formation of an ester bond between caffeic acid and its analogs and respective alcohols. For example, Fischer Esterification (Fischer-Speier Esterification) utilizes a Lewis or Brønstedt acid-catalyzed esterification of carboxylic acids with alcohols to give esters via a reaction in which the products and reactants are in equilibrium, as may be influenced by either removing one product from the reaction mixture (for example, removal of the water by azeotropic distillation or absorption by molecular sieves) or by employing an excess of one reactant. Alternative reactions employ coupling reagents such as dicyclohexylcarbodiimide (Steglich Esterification), preformed esters (transesterification), carboxylic acid chlorides or anhydrides. Esters may also be produced by oxidations, such as by the Baeyer-Villiger oxidation and oxidative esterifications. Similar procedures can be used to make the analogs.

The caffeic acid compounds as described in embodiments herein represent suitable active agents for topical application to treat skin disorders or diseases. Caffeic acid compounds may include caffeic acid ester compounds, caffeic acid amide compounds, analogues thereof, derivatives thereof, salts thereof, or mixtures thereof. While not limited to any particular mechanism, it is believed that these active agents may inactivate one or more of six Signal Transducers and Activators of Transcription (STAT) pathways. For example, STAT3 inhibitors may remedy psoriasis disease states with complete effectiveness. STAT5 or its pathway or any other of the STAT1 through STAT6 proteins and their pathways may also be blocked by the active agent to treat the skin. Further, interleukin 6 (IL-6) and interleukin 9 (IL-9) signaling may also be affected by the active agent during treatment.

The active agent, such as a caffeic acid compound or a mixture thereof, may further be combined with other mechanistic compounds which include cell differentiating agents, anti-proliferative agents, mitochondrial inhibitors, topical steroids, immunosuppressive compounds, JAK2 inhibitors, JAK3 inhibitors, parathyroid hormone-related protein (PTHrP) agonists, cell adhesion blockers, and combinations thereof. Examples of cell differentiating agents include a retinoid, such as retinoic acid, vitamin D, vitamin D analogs, or a phorbol ester. The term vitamin D collectively refers to a group of structurally similar chemicals and their metabolites which include alfacalcidol (1-hydroxycholecalciferol), calcitriol (1,25-dihydroxycholecalciferol), cholecalciferol (vitamin D3), dihydrotachysterol (DHT) and ergocalciferol (vitamin D2). The active metabolite of vitamin D, 1,25-(OH)₂D₃, has a wide range of nonclassical actions in the body, such as regulation of cell growth and differentiation modulation of the immune system. Vitamin D may be used in combination with caffeic acid compounds including STAT3 inhibitors such as caffeic acid ester compounds (e.g., CAPE or CABE) to be effective in the treatment of skin inflammatory and proliferation disorders such as psoriasis. The caffeic acid compounds may tend to stop an active lesion while the cell differentiating agent may lessen the likelihood of reactivation of the lesion to prevent recurrence.

In another embodiment, some exemplary topical agents that may be combined with the active agent, such as a caffeic acid compound or a mixture thereof, may include cell differentiating and anti-proliferative agents (e.g., retinoic acid, retinoids (tazarotene), vitamin D, or vitamin D analogs (calcipotriene)); mitochondrial inhibitors (e.g., anthraline (dithranol, chrysarobin, or coal tar)); topical steroids (e.g., clobetasol propionate, betamethasone, betamethasone dipropionate, halobetasol propionate, fluocinonide, diflorasone diacetate, mometasone furoate, halcinonide, desoximetasone, fluticasone propionate, flurandrenolide, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone, hydrocortisone valerate, prednicarbate, desonide, or alclometasone dipropionate); immunosuppressive compounds (e.g., tacrolimus (FK-506)); JAK2 inhibitors (e.g., INCB18424); JAK3 inhibitors (e.g., CP-690,550); parathyroid hormone-related protein (PTHrP) agonists (e.g., PTH(1-34)); and cell adhesion blockers (e.g., pan-selectin antagonist bimosiamose).

The pharmaceutical composition containing the caffeic acid compound may be applied as topical dosages and have the form of ointments, pastes, creams, lotions, gels, powders, solutions, sprays, and transdermal patches. The active agents described herein may be mixed with a carrier, which may include excipients, preservatives, or buffers. Exemplary carriers include petroleum jelly and dimethyl sulfoxide (DMSO). These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, water, or mixtures thereof. Other carriers known to those having skill in the art may also be used to advantage.

In some embodiments, a topical pharmaceutical composition contains the caffeic acid compound (e.g., caffeic acid ester compounds or caffeic acid amide compounds) at a concentration by weight within a range from about 0.01% to about 20%, preferably, from about 0.1% to about 15%, preferably, from about 1% to about 10%, more preferably, from about 3% to about 7%, and more preferably, from about 4% to about 6%. In one example, the topical pharmaceutical composition contains the caffeic acid compound at a concentration by weight of about 5%.

In other embodiments, the topical dosage forms may contain about 0.5% to about 20.0% by weight of the caffeic acid compounds described herein. The weight percent of the compounds described herein within the topical dosage forms may range from about 1.0% to about 15.0% or about 5.0% to about 11.0% by weight of the pharmaceutical composition. Treatment regimes with the topical dosage forms may occur daily, twice daily, three times daily, or four times daily for durations, for example, of three weeks or four weeks or until symptoms are no longer present. In some examples, the topical dosage contains the caffeic acid amide compound at a concentration of about 5% by weight of the pharmaceutical composition. In other examples, the topical dosage contains the caffeic acid ester compound at a concentration of about 5% by weight of the pharmaceutical composition.

Treatment regimes with the pharmaceutical composition or the topical dosage forms may occur daily, twice daily, three times daily or four times daily for durations, for example, of three weeks or four weeks or until symptoms or the lesion are no longer present.

In many embodiments, the pharmaceutical compositions containing the caffeic acid compounds (e.g., caffeic acid ester compounds or caffeic acid amide compounds) may be useful to treat various tumors which include solid tumors, such as breast cancer, head and neck cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer and prostate cancer, and blood tumors, such as multiple myeloma, leukemias (e.g., HTLV-l-dependent, acute myelogenous leukemia, or large granular lymphocyte leukemia), and lymphomas (e.g., EBV-related/Burkitt's, mycosis fungoides, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, and anaplastic large-cell lymphoma).

In alternative embodiments, the pharmaceutical compositions containing caffeic acid compounds (e.g., caffeic acid amide compounds and caffeic acid ester compounds), tyrphostin, tyrphostin analogues, and other active agent compounds useful for pharmaceutical compositions and methods for the topical treatment of proliferative and inflammatory skin disorders such as plaque psoriasis and atopic dermatitis and other disorders with a topical application of the pharmaceutical composition. Embodiments provide that the pharmaceutical composition may contain one or more active agent compounds having the generic chemical structure:

wherein R₀may be selected from R₁and R₁—Z₁—; and wherein Z₁is alkyl; and wherein R₁may be selected from:

where X₁, X₂, X₃, and X₄, are each independently selected from hydrogen, halogen, alkyl, alkoxy, OH, trihalomethyl, or NO₂; where Y₁may be selected from halogen or NO₂; and R₂may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, halogen, hydrogen, OH, NO₂, thioether, amine, SH, or NH₂;

R₃may be selected from:

wherein Z₃is alkyl; and wherein m₁=1, 2, 3, or 4; and where R₄may be selected from: CN, substituted amine, CH₂S-alkyl, alkyl, and CH₂N₃; where R₅and R₆are each independently chosen from:

monosaccharide (e.g., glucose, fructose, galactose, etc.), polysaccharide, monosaccharide derivative (e.g., an acetylated monosaccharide such as acetylated galactose, 1,2,3,4-diisopropylideno-D-g-alactose) substituted and unsubstituted aryl, and substituted and unsubstituted alkylaryl; where Z may be selected from NH, S, and O, and where X₅and X₆are each independently chosen from hydrogen and lower alkyl.

In certain embodiments, R₄is CN. In certain embodiments, R₁may be chosen from:

In more specific embodiments, R₁may be:

In certain embodiments, X₁may be a halogen such as Br. R₅may be chosen from an alkylaryl having the structure:

an aryl having the structure:

wherein m=0, 1, 2, 3, 4, 5, 6, or 7 and, where X₅and X₆are each independently chosen from hydrogen and alkyl, and where R₇, R₈, R₉, R₁₀, and R₁₁, are each independently selected from hydrogen, halogen, alkyl, alkoxy, OH, trihalomethyl, or NO₂.

In more specific embodiments R₅is an alkylaryl. X₁, X₂, X₃, and X₄may be hydrogen. Z₁may be a lower alkyl, and the lower alkyl may be —(CH₂)_m3—, wherein m3=0, 1, 2, 3, or 4. Z₃may be a lower alkyl, and the lower alkyl may be —(CH₂)_m4—, wherein m4=0, 1, 2, 3, or 4. Y₁may be NO₂or a halogen, such as Cl or Br.

In certain embodiments, R₅may be selected from:

R₂may be hydrogen. Y₁may be selected from NO₂and a halogen, such as Br or Cl.

In one example, the pharmaceutical compositions may contain an active agent or similar compound, such as the caffeic acid amide compound having the chemical structure of:

In another example, the pharmaceutical compositions may contain an active agent or similar compound, such as the caffeic acid amide compound having the chemical structure of:

In other embodiments, the pharmaceutical compositions may contain active agents, such as the caffeic acid amide compounds having the following chemical structures:

wherein R₁may be —H or cyano and R₂may be heteroatom-substituted or heteroatom-unsubstituted C₃-C₇-cycloalkyl;

X₁may be halo and R₃may be heteroatom-substituted or heteroatom-unsubstituted C₁-C₇-cycloalkyl, C₆-C₁₀-aryl, or C₇-C₁₀-aralkyl;

X₂may be halo and R₄may be hydroxy or heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-acyloxy;

X₃may be halo or heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy; R₅may be —H or cyano, and R₆may be heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl, C₁-C₁₀-acyloxy, C₆-C₁₀-aryl, or C₇-C₁₀-aralkyl;

X₄may be halo or heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy; R₇may be —H or cyano; R₈may be heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl, C₁-C₁₀-acyloxy, C₆-C₁₀-aryl, or C₇-C₁₀-aralkyl;

X₅may be heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy; R₉may be —H or cyano; R₁₀may be heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl, C₁-C₁₀-acyloxy, aryl, or C₇-C₁₀-aralkyl; A may be —C(O)— or —S(O₂)—;

X₆may be halo or heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy; R₁₁may be heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl, C₁-C₇-cycloalkyl, C₁-C₁₀-acyloxy, C₆-C₁₀-aryl, or C₇-C₁₀-aralkyl; R₁₂may be cyclododecyl, imidazoyl, or cyclohexenyl; R₁₃may be —H or heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl, C₁-C₇-cycloalkyl, C₁-C₁₀-acyloxy, C₆-C₁₀-aryl, or C₇-C₁₀-aralkyl;

X₇may be halo or heteroatom-substituted or heteroatom-unsubstituted C₁-C₁₀-alkyl or C₁-C₁₀-alkoxy; R₁₄may be:

Other aspects of the invention include pharmaceutically acceptable salts, hydrates, amine-N-oxides, imine-N-oxides, tautomers, and optical isomers of the compounds described above and throughout this application.

In certain embodiments R₂may cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In further embodiments R₃may be phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In yet further embodiments, X₁or X₂may be —F, —Cl, —Br or —I. In still further embodiments, R₄may be hydroxy, acetoxy or 2,2-dimethylpropionyloxy. In still yet further embodiments, X₃or X₄may be methoxy, —F, —Cl, —Br or —I. In some embodiments, R₆or R₈may be methyl or cyclopropyl. In certain aspects, X₅may be methyl or acetoxymethyl.

In other embodiments, the pharmaceutical compositions may contain active agents, such as the caffeic acid compounds having the following chemical structures:

Some of the aforementioned caffeic acid compounds are shown as single enantiomers or diastereomers. Embodiments provide for all possible stereoisomers of any of the caffeic acid compounds above, as well as those described throughout the application. In some embodiments, the caffeic acid compound may be a single enantiomer substantially free from other stereoisomers. In other embodiments, the caffeic acid compound may be a mixture of different stereo isomers, wherein each stereo isomer has the same molecular formula. Embodiments provide for a racemic mixture of a given molecular formula.

In other embodiments of the invention, the pharmaceutical compositions may contain active agents or similar compounds having the chemical formula:

wherein A is —C(O)— or —SO₂—. In certain embodiments R₁is cyclododecyl,

In some of these embodiments, X₁, X₂, X₃, and X₄, are each independently hydrogen, halo, alkyl, alkoxyl, acetoxyl, alkylacetoxyl, —OH, trihalomethyl, or —NO₂; Y₁is halo, —OH or —NO₂; and R₂may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, halo, hydrogen, —OH, —NO₂, thioether, amino, —SH, or —NH₂; R₃is:

wherein Z₃may be a divalent alkyl; and wherein m₁=1, 2, 3, or 4; and R₄may be hydrogen, —CN, substituted amine, —CH₂S-alkyl, alkyl, or —CH₂N₃. In some of these embodiments, R₅and R₆are each independently:

monosaccharide, monosaccharide derivative, polysaccharide, polysaccharide derivative, aryl or aralkyl; Z may be selected from —NH, —S—, or —O—, and X₅and X₆may independently be selected from hydrogen, upper alkyl, lower alkyl, cycloalkyl, cycloarylalkyl, aralkyl, aryl, alkoxyl, hydroxyl, hydroxylalkyl, alkylester, alkylesteralkyl, alkylacetoxyl, or aryloxyl; with the proviso that if R₄.dbd.-CN, substituted amine, —CH₂S-alkyl, alkyl, or —CH₂N₃, then R₁may be selected from cyclododecyl,

In other embodiments, R₃may be:

where X₅or X₆is upper alkyl, hydroxyl, aryl, alkoxyl, aryloxyl; cycloalkyl, cycloarylalkyl, aralkyl, alkylester, alkylesteralkyl, alkylacetoxy, or aryloxyl.

In specific embodiments, Z₃may be —C₂H₄—. In some examples, X₁, X₂, X₃, and X₄, are each independently —F, —Cl, —Br, —CH₃, methoxy or alkylacetoxyl. In further embodiments, X₅or X₆is independently hydrogen, cyclopropyl, cyclobutyl, —CH₃, —CH₂OH, cyclopentyl, —CH₂OAc, —CH₂OC(O)C(CH₃)₃, —CH₂C₆H₅, cyclohexyl or aryl.

In other embodiments, R₅is an aralkyl having the structure:

and an aryl having the structure:

wherein m=0, 1, 2, 3, 4, 5, 6, or 7 and where X₅and X₆may each independently be selected from hydrogen or alkyl, and where R₇, R₈, R₉, R₁₀, and R₁₁may each independently be selected from hydrogen, halo, alkyl, alkoxy, —OH, trihalomethyl, or —NO₂.

Embodiments heretofore relate to pharmaceutical compositions and methods for treating psoriasis and similar skin disorders. However, embodiments of the invention may be utilized for other skin disorders and may benefit from the caffeic acid compounds described herein that inhibit cell proliferation. While the foregoing is directed to embodiments of the invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.

Claims

1. A method for treating proliferative skin disorders, comprising applying a topical pharmaceutical composition to a lesion, wherein the topical pharmaceutical composition comprises a compound of Formula I: wherein:

X is a halogen;

R is selected from the group consisting of hydrogen, hydroxyl, alkyl, alkoxy, C3-C7-cycloalkyl, C6-C10-aryl, and

the topical pharmaceutical composition comprises the compound of Formula I at a concentration by weight within a range from about 0.01% to about 20%.

2. The method of claim 1, wherein the topical pharmaceutical composition comprises the compound of claim 1 at a concentration by weight within a range from about 1% to about 10%.

3. The method of claim 2, wherein the topical pharmaceutical composition comprises the compound of claim 1 at a concentration by weight within a range from about 3% to about 7%.

4. The method of claim 1, wherein the compound of claim 1 has the chemical structure of:

5. The method of claim 1, wherein the compound of claim 1 has the chemical structure of:

6. The method of claim 1, wherein the compound of claim 1 has the chemical structure of:

7. The method of claim 1, wherein the topical pharmaceutical composition further comprises at least one additional agent selected from the group consisting of cell differentiating agents, anti-proliferative agents, mitochondrial inhibitors, topical steroids, immunosuppressive compounds, JAK2 inhibitors, JAK3 inhibitors, parathyroid hormone-related protein (PTHrP) agonists, cell adhesion blockers, and combinations thereof.

8. The method of claim 1, wherein the topical pharmaceutical composition further comprises a cell differentiating agent selected from the group consisting of retinoic acid, retinoic acid derivative, vitamin D, and a vitamin D analog.

9. The method of claim 1, wherein the topical pharmaceutical composition is applied multiple times daily until symptoms of the disorder disappear.

10. A method for treating proliferative skin disorders, comprising applying a topical pharmaceutical composition to a lesion, wherein the topical pharmaceutical composition comprises a compound having the chemical structure: at a concentration by weight within a range from about 0.01% to about 20%.

11. The method of claim 10, wherein the topical pharmaceutical composition comprises the compound of claim 10 at a concentration by weight within a range from about 1% to about 10%.

12. The method of claim 11, wherein the topical pharmaceutical composition comprises the compound of claim 10 at a concentration by weight within a range from about 3% to about 7%.

13. The method of claim 10, wherein the topical pharmaceutical composition further comprises at least one additional agent selected from the group consisting of cell differentiating agents, anti-proliferative agents, mitochondrial inhibitors, topical steroids, immunosuppressive compounds, JAK2 inhibitors, JAK3 inhibitors, parathyroid hormone-related protein (PTHrP) agonists, cell adhesion blockers, and combinations thereof.

14. The method of claim 10, wherein the topical pharmaceutical composition further comprises a cell differentiating agent selected from the group consisting of retinoic acid, retinoic acid derivative, vitamin D, or and a vitamin D analog.

15. The method of claim 10, wherein the topical pharmaceutical composition is applied multiple times daily until symptoms of the disorder disappear.

16-26. (canceled)