Compounds, formulations, and methods for treating or preventing inflammatory skin disorders

Abstract

In methods, compounds, and topical formulations for treatment of rosacea incorporating compounds represented by the formulas below: wherein each of R1, R2, and R3 is independently hydrogen, hologen, alkyl, or alkoxy; each of R4 and R5 is independently hydrogen, alkyl, or alkoxy; and each of R6 and R7 is independently hydrogen, nitro, alkyl, or alkoxy; wherein each of A1, A3, and A4 is independently hydrogen or alkyl; and A2 is independently hydrogen or hydroxy; and wherein each of B1, B2, and B3 is independently hydrogen, hydroxy, or alkoxy; and each of B4 and B5 is independently hydrogen or alkyl, applying such compounds topically as sprays, mists, aerosols, solutions, lotions, gels, creams, ointments, pastes, unguents, emulsions, and suspensions to treat rosacea and its symptoms.

Description

[0001] Cross References to Related Applications

[0002] This application claims priority to US Patent Application Serial No. 60 / 574,142, filed May 25, 2004, the contents of which are incorporated herein by reference. This application is also a division of U.S. Patent Application No. 10 / 853,585, filed May 25, 2004, which in turn claims priority from U.S. Patent Application No. 60 / 473,611, filed May 27, 2003, the contents of which are incorporated in Here for reference. technical field

[0003] The present invention relates to compounds and methods for the treatment or prevention of inflammatory skin diseases (inflammatory conditions of the skin). The compounds and methods provided herein are particularly useful for treating or preventing inflammatory skin diseases and symptoms associated therewith. Background technique

[0004] Many people are affected by inflammatory skin diseases that cause unsightly and painful rashes, acne, persistent red blood vessels, and acne-like r...

Examples

Embodiment 1

[0110] 1.7.1 Example 1: (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine Synthesis

[0111] To a stirred solution of 6-amino-5-bromoquinoxaline hydrogen bromide (10 g) in distilled water (150 mL) was added thiophosgene (3 mL). The solution was stirred at room temperature for 2 h, and the resulting precipitate was collected by filtration, rinsed with water, and dried to give 5-bromo-6-isothiocyanato-quinoxaline.

[0112] 5-Bromo-6-isothiocyanato-quinoxaline (3.5 g) was directly dissolved in benzene (400 mL), and added dropwise to well-stirred ethylenediamine (15 g ) in the solution. In about two hours, an oil layer separated as the lower layer. The upper benzene layer was discarded, and the oil layer was washed with diethyl ether, and then dissolved in methanol (500 mL). The methanol solution was refluxed until evolution of hydrogen sulfide ceased. The methanol solution was concentrated under vacuum to a volume of about 100 mL, a yellow solid precipitated....

Embodiment 2

[0114] Aqueous aqueous topical formulations of the present invention include (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate (brimonide tartrate) (0.15wt.%); as a preservative (0.005%) (stabilized chlorine dioxide); and inert components: boric acid, calcium chloride, magnesium chloride, potassium chloride, pure water, sodium borate, sodium carboxymethylcellulose, sodium chloride, and with hydrochloric acid and / or sodium hydroxide to adjust the pH value to 5.6-6.6. The osmolality is 250-350mOsmol / kg.

Embodiment 3

[0116] Aqueous aqueous topical formulations of the present invention include (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate (brimonide tartrate) (0.15wt%); benzylamine chloride as a preservative; and inert components: boric acid, calcium chloride, magnesium chloride, potassium chloride, purified water, sodium borate, sodium carboxymethylcellulose, Sodium chloride, and adjust the pH value to 5.6-6.6 with hydrochloric acid and / or sodium hydroxide. The osmolality is 250-350mOsmol / kg.

[0117] 1.7.4 Example 4

[0118] Possible cream topical formulations of the invention are described in the table below.

[0119] Possible Cream Topical Formulations of the Invention (Hydrophilic Ointment USP)

[0120] components weight percentage Brimonidine tartrate 0.15％ stearic acid 7％ stearyl alcohol 5％ cetyl alcohol 2％ glycerin 10％ sodium lauryl sulfate 1％ Propylparaben 0.05％ Methylparaben 0.25％ D...

[0001] Cross References to Related Applications

[0002] This application claims priority to US Patent Application Serial No. 60 / 574,142, filed May 25, 2004, the contents of which are incorporated herein by reference. This application is also a division of U.S. Patent Application No. 10 / 853,585, filed May 25, 2004, which in turn claims priority from U.S. Patent Application No. 60 / 473,611, filed May 27, 2003, the contents of which are incorporated in Here for reference. technical field

[0003] The present invention relates to compounds and methods for the treatment or prevention of inflammatory skin diseases (inflammatory conditions of the skin). The compounds and methods provided herein are particularly useful for treating or preventing inflammatory skin diseases and symptoms associated therewith. Background technique

[0004] Many people are affected by inflammatory skin diseases that cause unsightly and painful rashes, acne, persistent red blood vessels, and acne-like r...

Examples

Embodiment 1

[0110] 1.7.1 Example 1: (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine Synthesis

[0111] To a stirred solution of 6-amino-5-bromoquinoxaline hydrogen bromide (10 g) in distilled water (150 mL) was added thiophosgene (3 mL). The solution was stirred at room temperature for 2 h, and the resulting precipitate was collected by filtration, rinsed with water, and dried to give 5-bromo-6-isothiocyanato-quinoxaline.

[0112] 5-Bromo-6-isothiocyanato-quinoxaline (3.5 g) was directly dissolved in benzene (400 mL), and added dropwise to well-stirred ethylenediamine (15 g ) in the solution. In about two hours, an oil layer separated as the lower layer. The upper benzene layer was discarded, and the oil layer was washed with diethyl ether, and then dissolved in methanol (500 mL). The methanol solution was refluxed until evolution of hydrogen sulfide ceased. The methanol solution was concentrated under vacuum to a volume of about 100 mL, a yellow solid precipitated....

Embodiment 2

[0114] Aqueous aqueous topical formulations of the present invention include (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate (brimonide tartrate) (0.15wt.%); as a preservative (0.005%) (stabilized chlorine dioxide); and inert components: boric acid, calcium chloride, magnesium chloride, potassium chloride, pure water, sodium borate, sodium carboxymethylcellulose, sodium chloride, and with hydrochloric acid and / or sodium hydroxide to adjust the pH value to 5.6-6.6. The osmolality is 250-350mOsmol / kg.

Embodiment 3

[0116] Aqueous aqueous topical formulations of the present invention include (5-bromo-quinoxalin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine-L-tartrate (brimonide tartrate) (0.15wt%); benzylamine chloride as a preservative; and inert components: boric acid, calcium chloride, magnesium chloride, potassium chloride, purified water, sodium borate, sodium carboxymethylcellulose, Sodium chloride, and adjust the pH value to 5.6-6.6 with hydrochloric acid and / or sodium hydroxide. The osmolality is 250-350mOsmol / kg.

[0117] 1.7.4 Example 4

[0118] Possible cream topical formulations of the invention are described in the table below.

[0119] Possible Cream Topical Formulations of the Invention (Hydrophilic Ointment USP)

[0120] components weight percentage Brimonidine tartrate 0.15％ stearic acid 7％ stearyl alcohol 5％ cetyl alcohol 2％ glycerin 10％ sodium lauryl sulfate 1％ Propylparaben 0.05％ Methylparaben 0.25％ D...

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