Pharmaceutical compositions comprising (3-(1-(1h-imidazol-4-yl)ethyl)-2-methylphenyl)methanol

Abstract

The present invention relates to a method for lowering intraocular pressure in a subject requiring such treatment, comprising the step of administering a therapeutically effective amount of [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or its enantiomer, its tautomer, and a pharmaceutical composition containing these, and to the use of these as pharmaceuticals.

Description

Technology Field

[0001] Related applications

[0002] This application claims priority to U.S. provisional patent application No. 61 / 414,180 filed on November 16, 2010, the entirety of which is incorporated herein by reference.

[0003] Technical field of the present invention

[0004] The present invention relates to a method for lowering intraocular pressure in a subject requiring such treatment, comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol, its enantiomer, its tautomer, or a pharmaceutically acceptable salt thereof. Background Technology

[0005] The compound [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol is known as a selective modulator of alpha-2 adrenergic receptors. Three alpha-1 and three alpha-2 adrenergic receptors have been characterized by molecular and pharmaceutical methods. Activation of these alpha receptors elicits physiological responses along with useful therapeutic actions.

[0006] The compound 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole, commonly known as medetomidine, is an alpha 2 adrenergic agonist used for sedation in animals. The hydrochloride of (S) 4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole, the (S) enantiomer of medetomidine, commonly known as dexmedetomidine, has also been shown to be used as a sedative or analgesic in cats and dogs.

[0007]

[0008] The metabolite of dexmedetomidine is (S) [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol. Literature by Hui, Y.-H et al. [ Journal of Chromatography

[1997] (762, 281-291] describes the compound (S) [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol together with its racemic mixture.

[0009] [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol is [Synthesis of detomidine and medetomidine metabolites: 1,2,3-trisubstituted arenes with 4'(5')-imidazolylmethyl groups], Journal of Heterocyclic Chemistry It is recorded in (1993), 30(6), (1645-1651)].

[0010] Kavanagh et al., “Synthesis of Possible Metabolites of Medetomidine {1-(2,3-dimethylphenyl)-1-[imidazol-4(5)-yl]ethane”, Journal of Chemical Research, Synopses [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol is described in

[1993] , (4), 152-3].

[0011] [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol] is from the literature by Salonen et al. ["Biotransformation of Medetomidine in the Rat", Xenobiotica It is described in

[1990] , 20(5), 471-80.

[0012] International patent application WO 2010093930 A1 discloses [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol and its (S) and (R) enantiomers. The problem to be solved

[0013] Adrenergic alpha-2 agonists play a crucial role in regulating aqueous humor formation and facilitating aqueous humor outflow; as a result, these compounds lower intraocular pressure (IOP) in patients with glaucoma. Two drugs, apraclonidine (Iopidine) and brimonidine (Alphagan P, available from Allergan, Inc.), are currently prescribed for patients with glaucoma. While these drugs lower elevated intraocular pressure, Alphagan P is the only alpha-2 adrenergic approved for only three doses per day, whereas Iopidine is approved only for short-term IOP control. Considering the elderly population of glaucoma patients, a dosing frequency of three times per day is by no means optimal and can lead to poor patient compliance.

[0014] means of solving the problem

[0015] The present invention relates to a method for lowering intraocular pressure in a subject requiring such treatment, comprising the step of administering a pharmaceutical composition comprising a therapeutically effective amount of (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol, its enantiomer, its tautomer, or a pharmaceutically acceptable salt thereof. Brief explanation of the drawing

[0016] Fig. 1 silver compound (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol( Compound 1 A drawing illustrating that ) has similar efficacy to brimonidine (Alphagan P (registered trademark)) and has a longer duration of intraocular pressure than brimonidine. Specific details for implementing the invention

[0017] In a further aspect, the present invention relates to a method for lowering intraocular pressure in a subject requiring such treatment, comprising the step of administering a pharmaceutical composition comprising a therapeutically effective amount of (S) [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol, its enantiomer, its tautomer, or a pharmaceutically acceptable salt thereof.

[0018] In a further aspect, the present invention relates to a method for lowering intraocular pressure, comprising the step of administering a composition comprising the step of locally administering a therapeutically effective amount of a pharmaceutical composition comprising (S) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol, a salt thereof, to a patient’s diseased eye.

[0019] In a further aspect, the present invention relates to a method for lowering intraocular pressure in a subject requiring such treatment, comprising the step of administering a pharmaceutical composition comprising a therapeutically effective amount of (R) [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0020] In a further embodiment, the present invention provides a pharmaceutical composition containing (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol as an active ingredient or a pharmaceutical composition thereof for regulating alpha 2 adrenergic receptors.

[0021] In a further embodiment, the present invention provides a pharmaceutical composition containing (S) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol as an active ingredient for regulating alpha 2 adrenergic receptors.

[0022] In a further embodiment, the present invention provides a pharmaceutical composition containing (R) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol as an active ingredient for regulating alpha 2 adrenergic receptors.

[0023] Pharmaceutical compositions of [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol and its (S) and (R) enantiomers are used, but are not limited to, for the treatment of glaucoma, elevated intraocular pressure, ischemic neuropathy, optic neuropathy, pain, visceral pain, corneal pain, headache, migraine, cancer pain, back pain, irritable bowel syndrome pain, myalgia and pain associated with diabetic neuropathy, treatment of diabetic retinopathy, other retinal degenerative diseases, stroke, cognitive decline, neuropsychiatric diseases, drug dependence and addiction, withdrawal symptoms, obsessive-compulsive disorder, obesity, insulin resistance, stress-related diseases, diarrhea, diuresis, nasal congestion, rigidity, attention deficit disorder, psychosis, anxiety, depression, autoimmune diseases, Crohn's disease, gastritis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases, dermatological diseases, cutaneous erythema (redness) and It is useful for treating mammals, including humans, with a range of diseases and conditions alleviated by alpha 2A, 2B, and 2C activation for treating inflammation, rosacea, and acne.

[0024] The present invention relates to a pharmaceutical composition containing an active ingredient [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol for the treatment of and / or alleviation of diseases responsive to treatment by an agonist of alpha-adrenergic receptors, or containing an active ingredient (S) [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or containing an active ingredient (R) [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol.

[0025] These pharmaceutical compositions can be used to lower IOP in glaucoma and other ophthalmic diseases.

[0026] In a further aspect of the present invention, a method for lowering the intraocular pressure of a patient requiring treatment is provided, comprising the step of administering a therapeutically effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or a salt thereof as a single dose to the patient's diseased eye, wherein the diseased eye maintains an intraocular pressure below baseline intraocular pressure for at least eight (8) hours and preferably at least ten (10) hours and more preferably at least twelve (12) hours from the time of administration.

[0027] In a further aspect of the present invention, a method for lowering the intraocular pressure of a patient requiring treatment is provided, comprising the step of administering a therapeutically effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or a salt thereof as a single dose to the patient's diseased eye, wherein the diseased eye maintains an intraocular pressure below baseline for at least eight (8) hours.

[0028] In a further aspect of the present invention, a method for lowering the intraocular pressure of a patient requiring treatment is provided, comprising the step of administering a therapeutically effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or a salt thereof as a single dose to the patient's diseased eye, wherein the diseased eye maintains an intraocular pressure below baseline intraocular pressure for at least ten (10) hours.

[0029] In a further aspect of the present invention, a method for lowering the intraocular pressure of a patient requiring treatment is provided, comprising the step of administering a therapeutically effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or a salt thereof as a single dose to the patient's diseased eye, wherein the diseased eye maintains an intraocular pressure below baseline for at least twelve (12) hours.

[0030] As used in this specification, the term "baseline" refers to an intraocular pressure measurement taken of an untreated eye.

[0031] As used in this specification, the term "subject" refers to a human patient.

[0032] In a further aspect of the present invention, the invention relates to a method for lowering intraocular pressure in a patient requiring treatment, comprising the step of administering a therapeutically effective amount of [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or its enantiomer, its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0033] In a further aspect of the present invention, the invention relates to a method for lowering intraocular pressure in a patient requiring treatment, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition comprising, essentially comprising, or comprising, [S] [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0034] In a further aspect of the present invention, the invention relates to a method for lowering intraocular pressure in a patient requiring treatment, comprising the step of administering a therapeutically effective amount of a pharmaceutical composition comprising, essentially comprising, or comprising, [R] [3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0035] In a further aspect of the present invention, a method is provided for treating a patient with elevated intraocular pressure with an effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol to lower intraocular pressure, wherein the improvement comprises, essentially, or is achieved by administering a single dose of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol to the patient’s diseased eye to lower the elevated intraocular pressure for an extended period of at least eight (8) hours, preferably at least ten (10) hours, and more preferably at least twelve (12) hours.

[0036] In a further aspect of the present invention, a method is provided for treating a patient with elevated intraocular pressure with an effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol to lower intraocular pressure, wherein the improvement is achieved by lowering the elevated intraocular pressure for an extended period of eight (8) hours.

[0037] In a further aspect of the present invention, a method is provided for treating a patient with elevated intraocular pressure with an effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol to lower intraocular pressure, wherein the improvement is achieved by lowering the elevated intraocular pressure for an extended period of ten (10) hours.

[0038] In a further aspect of the present invention, a method is provided for treating a patient with elevated intraocular pressure with an effective amount of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol to lower intraocular pressure, wherein the improvement is achieved by lowering the elevated intraocular pressure for an extended period of twelve (12) hours.

[0039] In a further aspect of the present invention, a method for lowering the intraocular pressure of a patient requiring treatment is provided, comprising the step of administering a therapeutically effective amount of a composition containing (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol to the patient's diseased eye once or twice a day, preferably once a day, wherein the diseased eye maintains an intraocular pressure below baseline intraocular pressure for one day.

[0040] In a further method of the present invention, the intraocular pressure is lowered for at least eight (8) hours after administration.

[0041] In a further method of the present invention, the intraocular pressure is lowered for at least ten (10) hours after administration.

[0042] In a further method of the present invention, the intraocular pressure is lowered for at least twelve (12) hours after administration.

[0043] In a further method of the present invention, a composition used as a single dose to lower intraocular pressure for at least eight (8) hours and preferably at least ten (10) hours and more preferably at least twelve (12) hours may contain pharmaceutically acceptable (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol in a vehicle in an amount of about 0.01 to about 5 weight%, preferably about 0.01 to about 2 weight%, more preferably about 0.05 to about 1 weight%. The composition is preferably formulated as an eye drop suitable for topical administration.

[0044] In forming a composition for topical administration, the pharmaceutical composition is preferably formulated as a solution in water at a pH of about 5.5 to about 8.0, for example, about 6.9. Although the exact dosage remains at the discretion of the clinician, it is recommended that the solution be applied topically by putting one drop into each eye one or two times, preferably once a day. Other ingredients that may be preferred for use in the ophthalmic formulations used in the method of the present invention include preservatives, co-solvents, and viscosity building agents; sodium chloride, potassium chloride, calcium chloride dihydrate, magnesium chloride hexahydrate, boric acid, and sodium borate decahydrate (as a buffer), and purified water. (Clinical Ocular Pharmacology , Jimmy D. Bartlett, Siret D. Jaanus, 2008, p 266). Therefore, a preservative is required to prevent microbial contamination during use. Suitable preservatives include stabilized oxychloro complex (sold under the trademark Purite), stabilized chlorine dioxide, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, sodium edetate, sorbic acid, Onamer M, or other agents known to those skilled in the art ( Review of Ophthalmology , June 2001, Robert Noecker, MD). A common side effect of these preservatives is burning.

[0045] A further method of the present invention provides an improvement in that the patient is exposed to less of the preservative, because, unlike the alpha-2 adrenergic agonist of the prior art which requires administration three times a day to control elevated intraocular pressure, the (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol-containing composition is administered at most only once, twice a day. Typically, for the composition used in the method of the present invention, the effective concentration of the preservative will be in the range of about 0.001% by weight to about 1% by weight, preferably about 0.01% by weight to about 0.5% by weight. In particular, the stable oxychloro complex (Purite (trademark)) will be in the range of about 0.001% by weight to about 0.01% by weight.

[0046] The solubility of the components of the composition may be enhanced by a surfactant or other suitable co-solvents in the composition. Such co-solvents include polysorbates 20, 60, and 80, Pluronic (trademark) F-68, F-84, and P-103, cyclodextrin, Solutol, or other agents known to those skilled in the art. Typically, such co-solvents are used in amounts ranging from about 0.01 wt% to about 2 wt%.

[0047] Increasing the viscosity of an aqueous solution may be desirable for increasing ocular absorption of the active compound, reducing variability in formulation preparation, reducing physical separation of the suspension or emulsion components of the formulation, and / or otherwise improving the ophthalmic formulation. Such viscous components include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, or other agents known to those skilled in the art. Such agents are typically used in levels of about 0.01% by weight to about 2% by weight.

[0048] The following formulations are representative ophthalmic compositions of the present invention for topical use when indicated to treat elevated intraocular pressure associated with glaucoma. In one example, the free base of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol was distilled in sterile distilled water, hydrochloric acid was added, and the hydrochloride salt of the compound was formed in situ. The solution was titrated with sodium hydroxide until the pH of the solution reached about 8.0. The final concentration of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol is about 1 wt%. In another example, the free base of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol was dissolved in sterile distilled water together with boric acid, benzalkonium chloride, and glycerin.

[0049] The compounds of the present invention are formulated as pharmaceutical compositions. As used herein, the term "pharmaceutical composition" means a composition suitable for administration to human patients for the treatment of a disease. In additional embodiments, the compounds of the present invention are thus formulated as pharmaceutically acceptable salts and further comprise one or more pharmaceutically acceptable excipients.

[0050] "Pharmaceuticalally acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base and is obtained by reaction with inorganic acids, such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. The acid addition salt form of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol, which is produced in free form as a base, is an inorganic acid, such as hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, etc.; It can be obtained by treating a free base with a suitable acid, such as organic acids, e.g., acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvate, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, carbonic acid, parmoic acid, citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and formic acid (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- Zurich, 2002, 329-345).

[0051] The compound may also be administered as a pharmaceutically acceptable quaternary salt known to those skilled in the art, specifically, but not limited to, formula -NY + Z - It comprises a quaternary ammonium salt, wherein Y is hydrogen, alkyl, or benzyl, and Z is a counterion comprising, but not limited to, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., fumarate, benzoate, succinate, acetate, glycolate, malate, maleate, fumarate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzylloate, and diphenylacetate).

[0052] In a further embodiment of the present invention, a pharmaceutical composition is provided comprising at least one of the present invention within its pharmaceutically acceptable carrier. The phrase "pharmaceutically acceptable" means that the carrier, diluent, or excipient is compatible with other components of the formulation and is not harmful to its recipient.

[0053] The pharmaceutical composition of the present invention may be used in the form of a solid, solution, emulsion, dispersion, patch, micelle, liposome, etc., wherein the resulting composition contains one or more compounds of the present invention as active ingredients mixed with an organic or inorganic carrier or excipient suitable for enteric or parenteral use. The compounds of the present invention may be combined with, for example, ordinary non-toxic pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable use. Carriers that may be used include, but are not limited to, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium-chain length triglycerides, dextran, and other carriers suitable for use in the manufacture of formulations in solid, semi-solid, or liquid form. Additionally, adjuvants, stabilizers, thickeners, coloring agents, and flavoring agents may be used. The compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect in a treatment or disease condition.

[0054] Pharmaceutical compositions containing compounds of the present invention may be in forms suitable for oral use, e.g., tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may provide pharmaceutically excellent and palatable formulations by containing one or more agents selected from the group consisting of sweeteners such as sucrose, lactose, or saccharin, flavorings such as peppermint, wintergreen, or cherry, coloring agents, and preservatives. Tablets containing compounds of the present invention may also be prepared by known methods by mixing with non-toxic, pharmaceutically acceptable excipients. The excipients used are, for example, (1) inactive diluents such as calcium carbonate, lactose, calcium phosphate, or sodium phosphate; (2) granulosic agents and disintegrants such as corn starch, potato starch, or alginic acid; (3) binders such as tragacanth gum, corn starch, gelatin, or acacia; and (4) lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or may provide sustained release over a long period by coating them by known techniques to delay degradation and absorption in the gastrointestinal tract. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. In some cases, the oral formulation may be in the form of hard gelatin capsules, where the compound of the invention is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin. They may also be in the form of soft gelatin capsules, where the compound of the invention is mixed with water or an oily medium, for example, peanut oil, liquid paraffin, or oil-leaf oil.

[0055] The pharmaceutical composition may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using a dispersant or wetting agent and a suspending agent. The sterile injectable formulation may also be a sterile injectable solution or suspension as a non-toxic, parenterally acceptable diluent or solvent, for example, a solution of 1,3-butanediol. Sterile fixing oils are typically used as solutions or suspension media. For this purpose, any blended fixing oil may be used, comprising synthetic mono- or diglicerides, fatty acids (including oleic acid), naturally occurring vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fat vehicles such as ethyl oleate. If necessary, buffers, preservatives, antioxidants, etc. may be included.

[0056] The present invention also relates to the use of 3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol or its enantiomer or its tautomer or its pharmaceutically acceptable salt for the manufacture of a medicine for therapeutic use. The present invention relates to a method for the manufacture of a medicine intended for therapeutic use, wherein the compound used is 3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol or its enantiomer or its tautomer or its pharmaceutically active derivative or its salt.

[0057] The present invention relates to the use of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol or pharmaceutically acceptable salts thereof for the manufacture of medicines for therapeutic use. The present invention also relates to a method for the manufacture of medicines intended for therapeutic use, wherein the compound used is (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol or pharmaceutically active derivatives or salts thereof.

[0058] The present invention relates to the use of (R)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for therapeutic use. The present invention also relates to a method for the manufacture of a medicine intended for therapeutic use, wherein the compound used is (R)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol or a pharmaceutically active derivative or salt thereof.

[0059] Because individual subjects may vary significantly in severity and each drug may possess its own unique therapeutic characteristics, the precise method of administration and formulation used for each subject is left to the discretion of the attending physician. Patients will be administered orally in any acceptable form, such as tablets, liquids, capsules, or powders; or, particularly if the patient experiences nausea, other routes may be preferred or necessary. These other routes may include, without limitation, transdermal, parenteral, subcutaneous, intranasal, via implantable stents, intrathecal, intravitreal, topical to the eye, posterior to the eye, intramuscular, intravenous, and rectal delivery methods. In any given case, the actual amount of compound administered will be determined by the physician taking into account appropriate circumstances, such as the severity of the disease, the patient's age and weight, the patient's physical condition, the cause of the disease, and the route of administration. Accordingly, formulations may be designed to delay the release of the active compound over a given time period or to carefully control the amount of drug released at a given time during the course of treatment.

[0060] (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol and its pharmaceutically acceptable salts have alpha-2 adrenergic receptor agonist activity extended in lowering intraocular pressure and may be administered via different routes including, but not limited to, formulations such as topical eye drops, direct injection, application to the back of the eye, or sustained-release pellets, suspensions, gels, or any suitable drug delivery system (DDS) known in the art that can further enhance the long duration of action.

[0061] While topical administration is preferred, this compound may also be used as an endoscopic implant as described in U.S. Patent Publication No. 20050244463. Such biocompatible endoscopic implants include (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol and polymers related to (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol to facilitate its release into the eye over a long period of time.

[0062] The present invention is not limited to the scope of the exemplified embodiments, which are intended merely as examples of specific aspects of the invention. In addition to what is disclosed herein, various modifications of the invention will become apparent to those skilled in the art by carefully reading this specification, including the claims originally filed. All such modifications are intended to fall within the scope of the appended claims.

[0063] The following analyses and animal models are used to demonstrate the efficacy and selectivity of the compound according to the present invention.

[0064] Example 1

[0065] In vivo IOP compound screening

[0066] The experimental animals used were male Dutch-Belted rabbits (Myrtle's Rabbitry) aged 6 months or older with normal blood pressure (n=4 / compound / screened dose). One drop (50 µl) of the drug formulation was administered topically to the right eye (treated eye) by pipette at approximately 07:00 hours. The rabbits' IOP (treated and untreated eyes) was measured at 0 hours prior to administration and at 0.5, 1, 2, 3, 4, 6, and 8 hours after topical ophthalmic administration. The IOP at the time of ophthalmic administration (0 hours) was used as the baseline value. Prior to tonometric measurements, 0.05% proparacaine (50 µl) was administered to each eye. Tonometric IOP measurements were obtained using a Mentor Pneumontonmeter. Additionally, all studies were labeled. Each rabbit was washed for at least one week between administrations. All animals were tested for changes in pupil diameter, sedation, and ocular irritation throughout the entire experiment.

[0067] At a concentration of 0.15%, (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol (Compound 1) lowered IOP in the treated eyes of DB rabbits for at least 6 hours, whereas the effect of brimonidine (0.15%) was minimal at 6 hours. (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl]methanol showed very little effect in the contralateral eye, but brimonidine showed a strong contralateral effect. Data Fig. 1 It is represented in.

[0068] Example 2

[0069] FLIPR Ca +2 Inflow analysis

[0070] So α 1A Receptor, human alpha 2A receptor, and chimeric G protein G qi5HEK 293 cells stably expressing were placed in poly-D-lysine-coated 384-well plates at a density of 20,000 to 40,000 cells per well and grown overnight in DMEM supplemented with 10% fetal bovine serum. For FLIPR (fluorometric image plate reader), cells were washed with HBSS / HEPES buffer (1X Hanks Buffered Salt Solution, 20 mM HEPES, pH 7.4) prior to the addition of Fluo-4-AM (4 uM Fluo-4-AM, 0.04% fluronic acid in HBSS / HEPES buffer) and calcium-sensitive dye. Cells were loaded with the dye at 37°C for 40 minutes, followed by four washes with HBSS / HEPES buffer. For the analysis of both active and antagonistic substances, the test compounds were tested at concentrations ranging from 0.64 nM to 10,000 nM.

[0071] For the analysis of the active substance, the reaction is initiated by the addition of an appropriate dilution of the compound, and the transient calcium signal is captured. EC using ActivityBase. 50 The peak height of the calcium curve is determined and used to calculate efficiency. Norepinephrine is the standard total agonist used to evaluate alpha-1 and alpha-2 receptor activity.

[0072] In vitro pharmacokinetics of (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol inflow compound FLIPR analysis a1A a2A 1 Brimonidin 600-2400 (0.3) 5 (0.95) 2 (S)-[3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl] methanol (compound 1) 340-2400(0.7) 25 (0.9) EC50 units nM (efficacy)

Claims

Claim 1 A pharmaceutical composition comprising (S) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol or a salt thereof, which is useful for a method of treating glaucoma by lowering elevated intraocular pressure for an extended period of at least 8 hours, wherein the method comprises the step of administering a therapeutically effective amount of said composition to the diseased eye of a patient, and said composition is formulated for once-daily administration. Claim 2 A pharmaceutical composition according to claim 1, wherein the composition comprises 0.01% to 5% by weight of (S) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol or a salt thereof. Claim 3 A pharmaceutical composition according to claim 1, wherein the composition comprises 0.01% to 2% by weight of (S) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol or a salt thereof. Claim 4 A pharmaceutical composition according to claim 1, wherein the composition comprises 0.05% to 1% by weight of (S) (3-(1-(1H-imidazole-4-yl)ethyl)-2-methylphenyl)methanol or a salt thereof. Claim 5 A pharmaceutical composition according to claim 1, wherein the composition further comprises 0.001% to 1% by weight of a preservative. Claim 6 A pharmaceutical composition according to claim 1, wherein the composition further comprises 0.01% to 0.5% by weight of a preservative. Claim 7 A pharmaceutical composition according to claim 1, wherein the composition further comprises 0.001% by weight to 0.01% by weight of a preservative. Claim 8 A pharmaceutical composition according to claim 1, wherein the composition further comprises 0.01% to 2% by weight of a co-solvent. Claim 9 A pharmaceutical composition according to claim 1, wherein the composition further comprises 0.01% to 2% by weight of a viscosity building agent. Claim 10 delete Claim 11 In claim 1, the composition is a pharmaceutical composition administered topically to the eye. Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete

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