NZ624771B2 - Pharmaceutical compositions comprising 7-(1h-imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline for treating skin diseases and conditions - Google Patents

Abstract

Provided is the use of 7-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydro-quinoline or its enantiomers in the treatment of skin diseases and conditions in a patient in need thereof.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING 7-(1H-IMIDAZOLYLMETHYL)-5,6,7,8-TETRAHYDRO-QUINOLINE FOR TREATING SKIN DISEASES AND IONS By: Mohammed I. Dibas, Edward C. Hsia, John E. Donello and Daniel W. Gil D APPLICATION This application claims the benefit of U.S. Provisional Application Serial No. 61/558,104, filed November 10, 2011, the disclosure of which is hereby incorporated in its entirety herein by reference BACKGROUND OF THE INVENTION The present disclosure relates to a method for treating skin diseases and skin conditions in a patient in need thereof which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of 7-(1H- olylmethyl)-5,6,7,8-tetrahydro-quinoline or the enantiomers thereof, or the tautomers thereof, or pharmaceutically acceptable salts f.

SUMMARY OF THE RELATED ART Three alpha 1 and three alpha 2 adrenergic receptors have been characterized by molecular and pharmacological methods. Activation of these alpha ors evokes physiological responses having useful therapeutic actions. Alpha adrenergic ts act on the eral vasculature to cause vasoconstriction and thereby ameliorate the symptoms of inflammatory skin disorders, including erythema or redness. Alpha adrenergic agonists are useful for ocular l tissue to treat conjunctival redness (hyperemia), for nasal mucosa, as a decongestant for the treatment of allergic rhinitis, and for rectal mucosal administration suitable for treating and curing hemorrhoids.

H. E. Baldwin describes the diagnosis and the actual ents of rosacea and related skin es, in the Journal of Drugs in Dermatology 2012, Vol. 11(6) pages 725-730.

U.S. Patent No. 6,680,062 discloses topical ic and pharmaceutical compositions for the treatment of the skin.

U.S. Patent Application Publication No. 2012/0035123 describes combinations of compounds for treating skin diseases.

U.S. Patent No. 7,812,049 discloses a method for treating erythema resulting from rosacea comprising azoline. Oxymetazoline is a selective alpha-1 agonist and partial alpha-2 agonist topical decongestant.

Compound 7-(1H-imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline is known as a potent alpha 1 and alpha 2 adrenergic receptor pan agonist. The racemic mixture and the two enantiomers of 7-(1H-imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline are disclosed in U.S. Patent Number 477 B2. U.S. Patent Number 7,943,641 ses a composition comprising )(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline for the treatment of glaucoma or ocular hypertension.

BRIEF Y OF THE INVENTION It has now been discovered that the pharmaceutical itions of (S)-(+)(1HImidazolylmethyl )-5,6,7,8-tetrahydro-quinoline are useful for the treatment of skin diseases and skin conditions.

In a first aspect, the invention provides a use of 7-(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline, an enantiomer thereof, tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a skin condition in a patient suffering therefrom.

Also described is a kit, suitable for use in treating a skin condition, the kit comprising packaging material and a ceutical agent contained within said packaging material, wherein the ing material comprises a label which indicates the pharmaceutical agent can be used for treating a skin ion, and wherein said pharmaceutical agent comprises a therapeutically effective amount of 7-(1H- Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline or an enantiomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

In a second , the ion es a use of 7-(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline, an enantiomer f, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating ocular rosacea, pterygium, corneal neovascularization, ocular cicatricial goid, or conjunctival mia in a patient suffering thereof.

In a third aspect, the invention provides a use of (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline in the manufacture of a medicament to treat rosacea, psoriasis, rosacea fulminans, telangiectasia of the face, erythema of the skin, and sunburn.

Also described are pharmaceutical compositions containing as active ingredient 7- (1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline for treatment of skin diseases and skin conditions.

Also described are pharmaceutical itions containing as active ingredient (S)- (1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline for treatment of skin diseases and skin conditions.

Also described are pharmaceutical compositions containing as active ingredient (R)- (-)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline for treatment of skin diseases and skin conditions.

Also described is a method for treating skin diseases in a patient in need thereof which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydroquinoline or a ceutically acceptable salt thereof.

Also described is a method for treating skin diseases in a patient in need f which ses administering a pharmaceutical composition comprising a therapeutically effective amount of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- ydro-quinoline or a pharmaceutically acceptable salt thereof.

Also described is a method for treating skin diseases in a patient in need thereof which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of (R)-(-)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline or a pharmaceutically acceptable salt thereof.

Also described is a method for improving skin diseases in a patient in need thereof which ses administering a pharmaceutical composition comprising a therapeutically effective amount of 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydroquinoline or a pharmaceutically acceptable salt thereof.

Also bed is a method for improving skin diseases in a patient in need thereof which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline or a pharmaceutically acceptable salt thereof.

Also described is a method for improving skin diseases in a patient in need thereof which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of (R)-(-)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline or a pharmaceutically acceptable salt thereof.

The compound may be administered through different routes, ing but not d to, l dermatological application of an effective dose, direct injection, or formulations that may further enhance the long duration of action such as slow releasing pellets, suspensions, gels, solutions, creams, ointments, foams, emulsions, microemulsions, milks, patches, serums, ls, sprays, dispersions, microcapsules, es, microparticles, wet cloths, dry , facial cloths, or sustained delivery devices such as any suitable drug delivery system known in the art.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows topical (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro- quinoline inhibits 37°C-induced cutaneous vessel dilation in rat paws for at least 4 hrs post-treatment following a single application and for at least 6 hrs post-treatment following 4 daily applications.

Figure 2 shows the rate of percutaneous absorption as the flux of (S)-(+)(1H- Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline that appears in the receptor solution under the skin in an ex vivo human trunk skin preparation Figure 3 shows the distribution of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline following a 48 hour dose exposure to ex vivo human trunk skin as a mass recovered Figure 4 shows Inhibition of LLinduced mouse skin inflammation after topical treatment with (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline Figure 5 shows reduction of UVB-induced mouse skin ma (redness) for at least 48 hrs following treatment with(S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline.

Figure 6 shows reduction of UVB-induced cutaneous vessel on in mouse ears for at least 48 hrs following treatment with(S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline.

Figure 7 shows reduction of e hypersensitivity in UVB exposed mouse skin 4 hrs following ent with(S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydroquinoline.

DETAILED DESCRIPTION OF THE INVENTION In one aspect of the invention, there is provided a use of Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline, an enantiomer thereof, tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a skin condition in a patient suffering therefrom.

Also described is a kit, suitable for use in treating a skin condition, the kit comprising packaging al and a pharmaceutical agent contained within said ing material, wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for ng a skin ion, and wherein said pharmaceutical agent comprises a therapeutically effective amount of 7-(1HImidazolylmethyl 7,8-tetrahydro-quinoline or an enantiomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

In a second aspect of the invention, there is provided a use of 7-(1H-Imidazol ylmethyl)-5,6,7,8-tetrahydro-quinoline, an omer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a ment for treating ocular rosacea, pterygium or conjunctival hyperemia in a patient suffering thereof.

In a third aspect, the invention provides a use of (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline in the manufacture of a medicament to treat a, psoriasis, rosacea fulminans, telangiectasia of the face, erythema of the skin, and sunburn.

Also described is a method for ng skin diseases and skin conditions in a t in need thereof which comprises, consists essentially of or ts of administering a therapeutically effective amount of a pharmaceutical composition comprising, ting essentially of or consisting of a therapeutically ive amount of 7-(1HImidazolylmethyl )-5,6,7,8-tetrahydro-quinoline, or the enantiomers thereof, or the tautomers thereof, or pharmaceutically acceptable salts thereof.

Also described is a method for treating skin diseases and skin conditions in a patient in need thereof which comprises, consists essentially of or consists of administering a therapeutically effective amount of a pharmaceutical composition comprising, consisting ially of or consisting of a therapeutically effective amount of (S)-(+)- Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, or the tautomers thereof, or pharmaceutically acceptable salts thereof.

Also described is a method for treating skin diseases and skin conditions in a patient in need thereof which comprises, consists essentially of or consists of administering a therapeutically effective amount of a pharmaceutical composition comprising, consisting essentially of or ting of a therapeutically effective amount of (R)-(-)- 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, or the tautomers thereof, or pharmaceutically able salts thereof.

By “skin diseases” it should be understood any condition, int or affliction associated with the listed diseases.

Skin diseases and skin conditions which may be treated with ceutical compositions containing as active ingredient 7-(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline or its enantiomers either: (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline or (R)-(-)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydroquinoline e, but are not d to: rosacea, rosacea fulminans, sunburn, psoriasis, menopause-associated hot flashes, flushing and redness associated with hot s, ma associated with hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, treatment of redness and itch from insect bites, photoaging, seborrheic dermatitis, acne, allergic itis, telangiectasia (dilations of previously existing small blood vessels ) of the face, angioectasias, rhinophyma (hypertrophy of the nose with follicular dilation), acne-like skin eruptions (may ooze or crust), burning or stinging sensation, erythema of the skin, cutaneous hyperactivity with dilation of blood vessels of the skin, Lyell's syndrome, Stevens- Johnson syndrome, local g and discomfort ated with hemorrhoids, hemorrhoids, erythema multiforme minor, erythema multiforme major, erythema nodosum, eye puffiness, urticaria, pruritis, purpura, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, stasis dermatitis, lichen simplex cus, al itis, pseudofolliculitis barbae, granuloma annulare, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, eczema.

Skin conditions which result in rosacea can be induced by intake of spicy food, of alcohol, of chocolate, of hot or alcoholic , temperature variations, heat, exposure to ultraviolet or infrared radiation, exposure to low relative humidity, exposure of the skin to strong winds or currents of air, exposure of the skin to surfactants, irritants, irritant dermatological topical agents, and cosmetics or psychological stress.

The actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the ty of the condition, the age and weight of the patient, the patient’s general al condition, the cause of the condition, and the route of administration.

Also described is a method for treating skin es wherein the pharmaceutical composition comprising, ting essentially of or consisting of a eutically effective amount of 4-bromo-N-(imidazolidinylidene)-1H-benzimidazolamine, is selected from l skin application sing suspensions, gels, solutions, creams, lotions, ointments, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles, microparticles, wet cloths, dry cloths, facial cloths, applications and ations that may further enhance the long duration of actions such as a slow releasing pellets, direct injection, or sustained delivery devices such as any suitable drug delivery systems known in the art. ceutical compositions of the present invention can be used for the topical stration including solutions, gels, lotions creams, ointments, foams, mousses, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, patches, es, liposomes, microcapsules, vesicles and microparticles thereof.

Emulsions, such as creams and lotions that can be used as topical carriers and their preparation are disclosed in Remington: The Science and Practice of cy 282- 291 (Alfonso R. Gennaro Ed. 19th ed. 1995) hereby incorporated herein by reference.

Suitable gels for use herein are disclosed in Remington: The Science and Practice of Pharmacy 1517-1518 (Alfonso R. Gennaro Ed. 19th ed. 1995) hereby incorporated herein by reference. Other le gels for use within the invention are disclosed in U.S. Pat. No. 6,387,383, U.S. Pat. No. 6,517,847 and U.S. Pat. No. 6,468,989.

Also bed is a method for improving skin diseases, by administering to a patient in need thereof a pharmaceutical composition containing as active ingredient 7-(1HImidazolylmethyl )-5,6,7,8-tetrahydro-quinoline, including but not limited to: rosacea, rosacea fulminans, sunburn, psoriasis, menopause-associated hot flashes, flushing and redness associated with hot flashes, erythema associated with hot flashes, hot flashes resulting from orchiectomyatopic itis, treatment of redness and itch from insect bites, photoaging, seborrheic dermatitis, acne, allergic dermatitis, telangiectasia (dilations of usly existing small blood s ) of the face, angioectasias, rhinophyma (hypertrophy of the nose with follicular dilation), acne-like skin eruptions (may ooze or crust), burning or stinging sensation, erythema of the skin, cutaneous ctivity with dilation of blood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome, local itching and discomfort associated with hemorrhoids, hoids, erythema multiforme minor, ma multiforme major, ma nodosum, eye puffiness, urticaria, pruritis, purpura, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, stasis dermatitis, lichen simplex chronicus, perioral dermatitis, pseudofolliculitis barbae, granuloma re, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, eczema.

Also described is a method for improving skin diseases, by administering to a patient in need thereof a pharmaceutical composition containing as active ingredient (S)-(+)- 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, including but not limited to: rosacea, rosacea fulminans, sunburn, psoriasis, menopause-associated hot s, flushing and redness associated with hot flashes, erythema associated with hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, treatment of redness and itch from insect bites, photoaging, seborrheic dermatitis, acne, allergic dermatitis, telangiectasia (dilations of usly ng small blood s ) of the face, angioectasias, rhinophyma (hypertrophy of the nose with follicular dilation), acne-like skin eruptions (may ooze or crust), burning or stinging sensation, ma of the skin, cutaneous hyperactivity with dilation of blood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome, local itching and discomfort associated with hemorrhoids, hemorrhoids, ma orme minor, erythema multiforme major, ma nodosum, eye ess, urticaria, pruritis, purpura, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, stasis dermatitis, lichen x chronicus, perioral dermatitis, pseudofolliculitis barbae, granuloma annulare, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, eczema.

Also described is a method for ing skin diseases, by administering to a patient in need thereof a pharmaceutical ition containing as active ingredient (R)-(-)- 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, including but not limited to: rosacea, rosacea fulminans, sunburn, psoriasis, menopause-associated hot flashes, flushing and redness associated with hot s, erythema associated with hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, treatment of redness and itch from insect bites, photoaging, seborrheic dermatitis, acne, allergic dermatitis, telangiectasia ions of previously existing small blood vessels ) of the face, angioectasias, rhinophyma (hypertrophy of the nose with follicular dilation), acne-like skin eruptions (may ooze or , g or ng sensation, erythema of the skin, cutaneous hyperactivity with dilation of blood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome, local itching and discomfort associated with hemorrhoids, hemorrhoids, erythema multiforme minor, ma multiforme major, erythema nodosum, eye puffiness, urticaria, pruritis, purpura, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative itis, stasis dermatitis, lichen simplex cus, perioral dermatitis, pseudofolliculitis barbae, granuloma annulare, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, eczema.

Also described is a method of decreasing the irritation of skin associated with rosacea treatment regimen of topically applied a therapeutically ive amount of 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, the method of treating telangiectasia or angioectasias with a therapeutically ive amount of 7-(1HImidazolylmethyl )-5,6,7,8-tetrahydro-quinoline, and therefore, it also includes the method of reducing redness associated with the appearance of rosacea.

Also described is a method of sing the irritation of skin associated with rosacea treatment regimen of topically applied a therapeutically effective amount of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, the method of treating telangiectasia or angioectasias with a therapeutically effective amount of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, and therefore, it also es the method of reducing s associated with the appearance of rosacea.

Also described is a method of decreasing the irritation of skin associated with rosacea treatment regimen of topically d a therapeutically effective amount of (R)-(-)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, the method of treating telangiectasia or ctasias with a therapeutically effective amount of (R)-(-)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, and therefore, it also includes the method of reducing redness associated with the appearance of rosacea.

Also described is a method for treating skin es including but not limited to: rosacea induced by intake of spicy food, chocolate, alcohol, hot or alcoholic drinks, ature variations, heat, exposure to ultraviolet or infrared radiation, exposure to low relative humidity, exposure of the skin to strong winds or currents of air, exposure of the skin to surfactants, irritants, irritant dermatological topical agents, and cosmetics or psychological stress.

(S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline may be formulated with efficacy ing components as disclosed in U.S. Patent Number 383 Also described is an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for ng a skin disease and wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for treating a skin disease and wherein said ceutical agent comprises an ive amount of 7-(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline or a salt thereof.

Also described is an article of manufacture comprising packaging material and a pharmaceutical agent contained within said packaging material, wherein the pharmaceutical agent is therapeutically effective for treating a skin disease and wherein the packaging al comprises a label which tes the pharmaceutical agent can be used for treating a skin disease and wherein said pharmaceutical agent comprises an effective amount of (S)-(+)(1H-Imidazol ylmethyl)-5,6,7,8-tetrahydro-quinoline or a salt thereof.

Also described is an article of manufacture comprising packaging material and a pharmaceutical agent contained within said ing al, wherein the pharmaceutical agent is therapeutically effective for ng a skin disease and wherein the packaging material comprises a label which indicates the pharmaceutical agent can be used for treating a skin disease and wherein said pharmaceutical agent comprises an effective amount of (R)-(-)(1H-Imidazol ylmethyl)-5,6,7,8-tetrahydro-quinoline or a salt f.

Also described is a method for treating ocular diseases and conditions in a patient in need thereof which comprises, consists essentially of or consists of administering a eutically effective amount of a pharmaceutical composition comprising, consisting essentially of or consisting of a therapeutically effective amount of 7-(1HImidazolylmethyl )-5,6,7,8-tetrahydro-quinoline, or the enantiomers f, or the tautomers thereof, or pharmaceutically acceptable salts thereof.

Also bed is a method for treating ocular diseases and conditions in a patient in need thereof which comprises, consists essentially of or consists of administering a therapeutically effective amount of a pharmaceutical composition comprising, consisting essentially of or ting of a therapeutically effective amount of (S)-(+)- 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, or the tautomers thereof, or pharmaceutically acceptable salts thereof.

Also described is a method for treating ocular diseases and conditions in a t in need thereof which comprises, consists essentially of or consists of administering a therapeutically effective amount of a pharmaceutical composition comprising, consisting essentially of or ting of a therapeutically effective amount of (R)-(-)- Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, or the tautomers thereof, or pharmaceutically acceptable salts thereof.

By “ocular diseases” it should be understood any condition, complaint or affliction associated with the listed diseases.

Ocular diseases and conditions which may be treated with pharmaceutical compositions containing as active ingredient 7-(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline or its enantiomers either: (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline or (R)-(-)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydroquinoline e, but are not limited to: ocular rosacea, pterygium, redness, hyperemia, conjunctival hyperemia, corneal neovascularization, ocular cicatricial pemphygoid and Stevens-Johnson syndrome.

The (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline compound has physiochemical and pharmacokinetic properties that are beneficial for sustained ty, particularly when the drug is delivered continuously (e.g. to the skin by a dermal patch).

“Pharmaceutical composition,” as used here, means a composition that is suitable for administering to human patients for disease ent. In one embodiment the nd described herein is formulated as a pharmaceutically acceptable salt which further includes one or more organic or inorganic carriers or excipients suitable for dermatological applications. The pharmaceutically acceptable excipients may include one or more skin-penetrating agents, moisturizers, vatives, g , protective agents, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-inwater-in-silicon emulsions. The pharmaceutical composition may se excipients, binders, lubricants, solvents, disintegrants, or enhancers of cutenous penetration and will be administered preferably topically. The active ingredient is used in an amount of about 0.01% up to about 20% and preferably about 0.1% to about 10% by weight based on the total weight of the composition.

“Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free base and which are ed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or an organic acid such as for example, acetic acid, yacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric acid, sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, formic and, salicylic acid and the like (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zürich, 2002, 329-345).

Also described is a method for treating skin diseases and skin conditions wherein the pharmaceutical composition comprising, consisting essentially of, or consisting of a therapeutically effective amount of 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydroquinoline is ed from topical skin ation, direct injection, applications and formulations that may further enhance the long duration of actions such as a slow releasing pellet, suspension, gel, on, cream, ointment, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles, microparticles, wet cloths, dry cloths, facial cloths.

Also described is a method for treating skin diseases and skin conditions wherein the pharmaceutical composition comprising, ting ially of, or ting of a therapeutically effective amount of (R) -(-)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline is selected from l skin application, direct injection, applications and formulations that may further enhance the long duration of s such as a slow releasing pellet, suspension, gel, solution, cream, ointment, foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, vesicles, microparticles, wet cloths, dry cloths, facial cloths.

Also bed is a method for treating skin diseases and skin conditions wherein the pharmaceutical composition comprising, consisting essentially of, or consisting of a therapeutically effective amount of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline is selected from topical skin application, direct injection, applications and formulations that may r enhance the long duration of actions such as a slow releasing pellet, suspension, gel, solution, , cream, ointment, foams, emulsions, microemulsions, milks, serums, aerosols, , dispersions, microcapsules, vesicles, articles, wet cloths, soaps, cleansing bars, dry cloths, facial cloths.

The compositions described herein may be used in conjunction with rosacea treatments of topically applied agents such as yclic lactones of the avermectin family, macrolides known as milbemycins, other alpha 1 or alpha 2 receptor agonists, retinoids, phytosphingosine, green tea extract, azaleic acid.

The compositions described herein may also be used in conjunction with other classes of compounds such as: Antimicrobials (such as antiparasitic, cterial, antifungal, antiviral); Metronidazole, ivermectin, clindamycin, erythromycin, ycline, doxycycline, minocycline; Steroidal and eroidal anti-inflammatory agents (such as corticosteroids, tacrolimus, pimecrolimus, porine A); Antiangiogenesis agents; Antimycobacterial agents (such as dapsone); Sunscreensor sunblocks or anything that ons like a sunscreen/sunblock (such as titanium dioxide, zinc oxide, avobenzone); Antioxidants (such as Vitamins C, E, quercetin, resveratrol); Other alpha agonists (such as brimonidine, oxymetazoline, clonidine); Beta blockers (such as nadolol, propanolol, carvedilol); Antihistamines; Retinoids (such as tretinoin, adapalene, tazarotene, isotretinoin, retinaldehyde) Benzoyl peroxide; Menthol and other “cooling” agents; Sodium sulfacetamide and derivatives; Antifungal agents (such as imidazole derivatives, ployene compounds, allylamine compounds); Serine protease (kallikrein) inhibitors (such as aminocaproic acid); The term “comprising” as used in this ication means “consisting at least in part of”. When interpreting each statement in this ication that includes the term “comprising”, features other than that or those prefaced by the term may also be present. Related terms such as “comprise” and “comprises” are to be interpreted in the same manner.

The present invention is not to be limited in scope by the exemplified embodiments, which are only intended as illustrations of ic aspects of the invention. Various modifications of the invention, in addition to those disclosed herein, will be apparent to those d in the art by a careful reading of the ication, including the claims, as originally filed. It is intended that all such modifications will fall within the scope of the appended .

Example 1 Rat blood flow assay Background Rosacea can be triggered by heat exposure. The physiological sympathetic nervous system-mediated se to body cooling is cutaneous vasoconstriction and the response to body warming is cutaneous vasodilation. α-adrenergic agonists that act on the sympathetic nervous system outflow can regulate cutaneous blood flow in response to temperature changes.

Method A laser Doppler ascular perfusion monitor (laser Doppler flowmetry technique, LDP) was used to monitor red blood cell perfusion in the microvasculature of the hind foot pad. The laser doppler flowmetry (LDP) is an OxyFlo ascular Perfusion Monitor, from Oxford Optronix LTd. UK.

Briefly, 15 μL of test articles was applied topically once, or repeatedly (once daily for 4 consecutive days) to one hind foot pad of anaesthetized hairless CD rats and 15 μL of vehicle was d to the other footpad.

At various timepoints up to 8 hrs following the last test article administration, dynamic blood flow changes were ed and recorded every 15 seconds for 4 minutes per temperature interval for 5 als (22°C→37°C→4°C→37°C→22°C). Rats were placed on a 37°C heat pad to increase their temperature and on an ice pad to decrease their temperature to 4°C. The levels of blood flow in the two paws were compared.

Figure 1 shows topical )(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro- quinoline icantly inhibits 37°C induced vessel dilation for up to 4 hrs following single topical dosing to the skin at a concentration of 0.1%. Following 4 days of topical dosing (once per day), the duration of statistically significant inhibition is increased to at least 6 hrs. The % blood flow inhibition is calculated as the % difference in the AUC of peak 1 (first 8 min g and cooling interval) of the laser doppler recordings between the drug-treated and vehicle-treated paws. Data are the mean % inhibition values from 8-10 rats per group.

This data trates that l (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline can inhibit heat-induced cutaneous blood vessel dilation (or overall cutaneous blood flow) in rats, and the effect of one l application (15 μl of a 0.1% gel) lasts for at least 4 hours. There is an extended on of at least 6 hrs following 4-day repeat dosing.

Example 2 In vitro human skin permeability assay Human, ex vivo, trunk skin was cut into multiple smaller sections large enough to fit on nominal 2 cm2 static Franz diffusion cells. The dermal receptor compartment was filled to capacity with receptor solution consisting of 0.1 X phosphate buffered solution with 0.1% Oleth-20, and the epidermal chamber (chimney) is left open to ambient laboratory environment. The cells were placed in a ion apparatus in which the receptor solution in contact with the ide of the dermis was stirred magnetically at ~600 RPM and its temperature maintained to achieve a skin surface temperature of 32.0 ± 1.0 °C.

To assure the integrity of each skin section, its permeability to tritiated water was determined before application of the test products. Skin specimens in which absorption of 3H 2 were considered acceptable. 2O was less than 1.56 μL− equ/cm (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline was applied to three (3) replicate sections of the same donor skin for each donor, evaluating three (3) donors for the designated dose on. A dose of 5 mg formulation/cm2/skin section was evenly dispersed and rubbed into the skin surface using a glass rod.

At designated time points and at the end of the study dose duration, the receptor solution was removed in its entirety, and a predetermined volume t saved for subsequent analysis. After the last receptor sample was collected, the donor compartment (chimney) was removed, and the surface of the skin was cleansed twice to collect any un-absorbed formulation from the skin e. Following the surface cleanse, the skin was tape stripped to remove the stratum corneum. The tape strips were extracted ght in acetonitrile and ed for content of the compound of interest. The skin was then removed from the diffusion cell, split into epidermis and dermis, and each skin sample extracted ght in 50%:50% (v/v) ethanol/water or % (v/v) methanol water for epidermis and dermis, tively. The skin section samples were analyzed for content of (S)-(+)(1HImidazolylmethyl )-5,6,7,8-tetrahydro-quinoline. All samples were stored at ~ -20 °C (± 15 °C) g analysis. Quantitation of (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline was analyzed by liquid chromatography with tandem mass spectrometry (PLC/MS).

Replicates within donors were averaged and the standard deviation ated for each key parameter. Within donor averages were then collated and the across donor population mean with standard error of the mean calculated.

Figure 2 shows the rate of percutaneous absorption as the flux of (S)-(+)(1H- Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline that appears in the receptor solution under the skin after a 0.58% (w/w) dose.

Figure 3 shows the distribution of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline in each skin layer following a 48 hour dose exposure of a 0.58% (w/w) dose to ex vivo human trunk skin as a mass recovered.

The data indicate that (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline does penetrate into and through ex vivo human trunk skin using the in vitro Franz diffusion cell. The increased rate of flux at the 18 and 36 hr timepoints (Figure 2) and the higher concentration in the epidermis (Figure 3) suggests that the drug depots in the skin, which is consistent with a long duration of action and extended duration following repeated dosing.

Example 3 LLInduced Skin mation Mouse Model Background Rosacea skin is associated with increased levels of LL-37 icidin compared to normal skin. Intradermal injection of LL-37 into mice s skin inflammation that is similar to that seen in rosacea skin (Yamasaki 2007).

Method (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline gel or its corresponding vehicle was applied to the dorsal surface of the ears of BALB/c mice.

One hour following application, the left ear was intradermally injected with LL-37 peptide and the right ear was injected with phosphate-buffered saline (PBS). Ear thickness measurements were made with a digital caliper (Mitutoyo) at various timepoints up to 8 hrs post-injection with LL-37. Ear swelling is an indicator of inflammation.

Figure 4 shows statistically significant inhibition of LLinduced skin inflammation at 6 and 9 hrs after l treatment with )(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline. The data are the mean values from 9-10 mice per group.

The data indicates that topical administration of (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline has an anti-inflammatory effect that is relevant to the treatment of rosacea.

Example 4 iolet B-Induced Mouse n Model Background Rosacea can be triggered by exposure to ultraviolet (UV) light. Exposure of ss mice to UVB irradiation results in a sunburn-like response characterized by erythema, cutaneous blood vessel dilation, tactile hypersensitivity and inflammation that persists for at least 48 hrs.

Method SKH1 ss mice, lying on their stomachs with their left sides d, were exposed to UVB at an intensity of 120 mJ/cm2 for 91 sec. Approximately 30 min after irradiation, (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline gel or its corresponding vehicle was applied topically to a region of the back and the dorsal surface of the ears. At s timepoints up to 48 hrs post UVB-irradiation, the following assessments were made: 1. ature area in the exposed and unexposed ears by image analysis of digital photos using ImagePro Premier (Media Cybernetics) software. Images are converted to cale, expanded and thresholding, based on each ear’s baseline pixel values, is applied to the images. Thresholding differentiates the desired “object” features (i.e. vasculature network) from the background (i.e. skin tissue). The “object” pixels are then quantified and reported as the vasculature area. 2. Erythema on the exposed and unexposed back using a Chromameter (Konica Minolta). 3. Tactile hypersensitivity assessment using a paint brush test. The hypersensitivity is assessed by light stroking of the flank of the mice with a small paint brush every 5 min over 35 min. The behavioral response is scored as s: 0, no response; 1, mild squeaking with attempts to move away from the brush; 2, vigorous squeaking evoked by the brush, biting at the brush and strong efforts to escape. The scores at the eight time points are summed so the m hypersensitivity score for each mouse can be 16. The exposed (right) and unexposed (left) flanks were scored independently.

Figure 5 shows that l dosing of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline to the back 30 min following UVB exposure results in a statistically significant reduction of erythema (measured with a chromameter) to nearly baseline levels that lasts for at least 48 hrs. Data are the mean of values from 6 mice per group.

Figure 6 shows that topical dosing of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline to the ear 30 min following UVB exposure results in statistically significant cutaneous vasoconstriction (measured as a reduction of cutaneous vasculature area) to nearly baseline levels that lasts for at least 48 hrs. Data are the mean of values from 6 mice per group.

Figure 7 shows that topical dosing of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8- tetrahydro-quinoline to the back 30 min following UVB exposure results in a statistically significant reduction of e hypersensitivity (scored by the response to stroking with a paint brush) assessed 4 hrs following UVB irradiation. There was a reduction in hypersensitivity on both the UV-exposed and control sides. Data are the mean of values from 6 mice per group.

The data indicate that l administration of (S)-(+)(1H-Imidazolylmethyl)- ,6,7,8-tetrahydro-quinoline has a long-lasting beneficial effect on inflammation, erythema ss) and hypersensitivity, which are signs and symptoms of many skin diseases and conditions. The findings have particular relevance to the treatment of sunburn, rosacea and psoriasis.

In this specification where reference has been made to patent specifications, other al documents, or other sources of ation, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external nts is not to be construed as an ion that such documents, or such s of information, in any iction, are prior art, or form part of the common general knowledge in the art.

In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

Claims (22)

What is claimed is:

1. A use of 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, an enantiomer thereof, tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a skin condition in a patient suffering therefrom.

2. The use according to claim 1, wherein the medicament comprises )(1HImidazolylmethyl 7,8-tetrahydro-quinoline.

3. The use ing to claim 1, wherein the medicament comprises (S)-(+) (1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline.

4. The use according to any one of claims 1-3, wherein the treated condition is selected from: rosacea, rosacea fulminans, sunburn, psoriasis, menopauseassociated hot flashes, flushing and redness associated with hot flashes, erythema associated with hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, treatment of redness and itch from insect bites, photoaging, seborrheic dermatitis, acne, allergic itis, telangiectasia (dilations of previously ng small blood vessels ) of the face, angioectasias, rhinophyma (hypertrophy of the nose with follicular dilation), acne-like skin eruptions (may ooze or crust), burning or stinging ion, erythema of the skin, cutaneous hyperactivity with dilation of blood vessels of the skin, Lyell's syndrome, Stevens-Johnson syndrome, local itching and discomfort associated with hemorrhoids, hemorrhoids, erythema orme minor, erythema multiforme major, erythema nodosum, eye puffiness, urticaria, pruritis, purpura, varicose veins, contact dermatitis, atopic dermatitis, nummular dermatitis, generalized exfoliative dermatitis, stasis dermatitis, lichen simplex chronicus, al dermatitis, pseudofolliculitis barbae, granuloma re, actinic keratosis, basal cell oma, squamous cell carcinoma, and eczema.

5. The use according to any one of claims 1-4, wherein the ion is rosacea.

6. The use according to any one of claims 1-4, n the condition is psoriasis.

7. The use according to any one of claims 1-4, wherein the condition is rosacea fulminans.

8. The use according to any one of claims 1-4, wherein the condition is telangiectasia of the face.

9. The use according to any one of claims 1-4, wherein the condition is ma of the skin.

10. The use according to any one of claims 1-4, wherein the condition is sunburn.

11. The use of any one of claims 1-9, wherein said medicament is in a formulation suitable for topical dermatological administration or for direct injection.

12. The use of any one of claims 1-11 wherein said medicament is in the form of a suspension, gel, solution, cream, lotion, ointment, foam, emulsion, microemulsion, milk, serum, aerosol, spray, dispersion, microcapsule, vesicle, microparticle, wet cloth, dry cloth, or facial cloth.

13. A use of 7-(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline, an enantiomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in the cture of a medicament for treating ocular rosacea, ium, corneal neovascularization, ocular cicatricial pemphigoid or ctival hyperemia in a patient suffering thereof.

14. The use according to claim 13, wherein the medicament comprises ) (1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline.

15. The use according to claim 13, wherein the medicament comprises (S)-(+) (1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline.

16. A use of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline in the manufacture of a medicament for treating rosacea.

17. A use of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline in the manufacture of a medicament for treating psoriasis.

18. A use of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline in the cture of a medicament for treating rosacea fulminans.

19. A use of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline in the manufacture of a medicament for treating telangiectasia of the face.

20. A use of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline in the manufacture of a ment for treating erythema of the skin.

21. A use of (S)-(+)(1H-Imidazolylmethyl)-5,6,7,8-tetrahydro-quinoline in the manufacture of a medicament for treating sunburn.

22. A use as claimed in any one of claims 1, 13 and 16-21, substantially as herein described with reference to any e thereof and with or t reference to the accompanying drawings.