Substituted-aryl-2-phenylethyl-1h-imidazole compounds as subtype selective modulators of alpha 2b and/or alpha 2c adrenergic receptors

(54) Title: ARYL-2-PHENYLETHYL-1H-IMIDAZOL COMPOUND REPLACED AS A SUBTYPE OF SELECTIVE ADRENERGIC MODULATORS ALFA 2B AND / OR ALFA 2C (51) Int. Cl .: C07D 233/58; C07D 233/64; C07D 401/06; A61K 31/4164; A61K 31/4427; (...) (30) Unionist Priority: 09/01/2008 US 11 / 971.829 (73) Holder (s): ALLERGAN, INC.

(72) Inventor (s): SANTOSH C. SINHA; TOOD M. HEIDELBAUCH; SMITAS. BHAT; KEN CHOW; MICHAEL E. GARST (74) Attorney (s): DANNEMANN, SIEMSEN, BIGLER & IPANEMA MOREIRA (86) International Application: PCT US2009030074 of 05/01/2009 (87) International Publication: WO

2009/089132 of 07/16/2009

Invention Patent Specification Report for ARYL-2-PHENYLETHYL-1-H-IMIDAZOLE COMPOUNDS REPLACED AS SUBTYPE OF ALPHA 2B AND / OR ALPHA 2C ADRENERGIC SELECTIVE MODULATORS.

CROSS REFERENCE

This Patent Application claims priority for US Patent Application serial number 11 / 971,829 filed on January 9, 2008, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

Generally described here are subtypes of selective modulators of alpha 2B and / or alpha 2C receptors useful for preparing pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Alpha 2 adrenergic receptors have been characterized by molecular and pharmacological methods that include alpha 1A, alpha 1B, alpha 2A, alpha 2B and alpha 2C. Activation of these alpha receptors evokes physiological responses. The adrenergic modulators described in this invention activate one or both alpha 2B and / or alpha 2C receptors and have useful therapeutic actions.

Human adrenergic receptors are integral membrane proteins that have been classified into two broad classes, alpha and beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system under the binding of catecholamines, norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms a basis for the classification: alpha receptors tend to bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The preferred binding affinity of these hormones is reversed for beta receptors. In many tissues, functional responses, such as contraction of smooth muscle, induced by alpha receptor activation, are opposite to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and beta receptors was also highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors have also been subdivided into alpha 1, alpha 2, beta 1, and beta 2 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds that exhibit selective binding between these two subtypes have been developed. Thus, in Published International Patent Application WO 92/0073, the selective ability of the terazosin R (+) enantiomer to selectively bind to alpha 1 subtype adrenergic receptors has been reported. The alpha 1 / alpha 2 selectivity of this compound has been reported to be significant because alpha 2 receptor agonist stimulation has been reported to inhibit epinephrine and norepinephrine secretion, while alpha 2 receptor antagonism has been reported to increase secretion of these hormones. Thus, the use of non-selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, was reported to be limited by its alpha 2 adrenergic receptor-mediated induction of increased plasma catecholamine concentration and the accompanying physiological sequelae (increased heart rate and contraction smooth muscle). For another general basis on alpha adrenergic receptors, attention is directed to Robert R. Ruffolo, Jr., AlphaAdrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinicai Pharmacology series, Karger, 1991), in which the basis of the subclassification alpha 1 / alpha 2, molecular biology, signal transduction, agonist structure-activity, receptor functions, and therapeutic applications for compounds that exhibit adrenergic receptor affinity are explored.

The cloning, sequencing and expression of alpha receptor subtypes in animal tissues induced the subclassification of alpha 1 adrenoreceptors into alpha 1A, alpha 1B, and alpha 1D. Similarly, alpha 2 adrenoreceptors were also classified as alpha 2A, alpha 2B, and alpha 2C receptors. Each alpha 2 receptor subtype appears to exhibit its own pharmacological and tissue specificities. Compounds having a degree of specificity for one or more of these subtypes can be more specific therapeutic agents for a given indication than an alpha 2 receptor pan-agonist (such as the drug clonidine) or a pan-antagonist.

Among other indications, such as the treatment of glaucoma, hypertension, sexual dysfunction, and depression, certain compounds having alpha 2 adrenergic receptor agonist activity are known analgesics. However, many compounds having such activity do not provide the desired activity and specificity when treating disorders modulated by alpha 2 adrenoreceptors. For example, many compounds that have been found to be effective agents in the treatment of pain are often found to have undesirable side effects, such as causing hypotension and sedation at systemically effective doses. There is a need for new drugs that provide pain relief without causing these undesirable side effects. In addition, there is a need for agents that exhibit activity against pain, particularly chronic pain, such as chronic neuropathic pain and visceral pain.

British Patent 1,499,485, issued February 1, 1978 describes certain thiocarbamide derivatives; some of these derivatives are said to be useful in the treatment of conditions such as hypertension, depression or pain.

International Patent Applications W001 / 00586 published on January 4, 2002 and W099 / 28300 published on June 10, 1999 describe certain imidazole derivatives that act as alpha 2b and / or alpha 2c adrenergic receptor agonists. US Patent No. 6,313,172 describes phenylmethyl thiourea derivatives used for the treatment of pain.

SUMMARY OF THE INVENTION

Generally described here are substituted aryl-2-phenylethyl-1H-imidazole compounds as a subtype of selective alpha 2b and / or alpha 2c adrenergic receptor modulators that include compounds represented by formula 1:

<img file="BRPI0907613A2_D0001.tif" />

where n = 1-4;

XéCou N;

R¹-R⁶ can be the same or different and are independently selected from the group consisting of H, C1-6 alkyl, OCH3, OH, F, Cl, Br, CH2OH, CH2N (R⁷) 2, C (O) R⁸, CH₂CN, cf_3: where R⁷ is H or C1-6 alkyl; and

R⁸ is C 1-6 alkyl or aryl.

Also described here are pharmaceutical compositions that contain a pharmaceutical carrier and a therapeutically effective amount of substituted aryl-2-phenylethyl-1-H-imidazole compounds as a subtype of selective alpha 2b and / or alpha 2c adrenergic receptor modulators that includes a compound represented by formula 1.

Also described are methods of administering to a mammal the present substituted aryl-2-phenylethyl-1-H-imidazole compounds as a subtype of selective alpha 2b and / or alpha 2c adrenergic receptor modulators for the treatment of glaucoma, pressure elevated intraocular, ischemic neuropathies, optic neuropathy, pain, visceral pain, corneal pain, headache, migraine, cancer pain, back pain, irritable bowel syndrome pain, muscle pain and pain associated with diabetic neuropathy, treatment of diabetic retinopathy, other retinal degenerative conditions, stroke, cognitive deficits, neuropsychiatric conditions, drug addiction and dependence, withdrawal symptoms, obsessive-compulsive disorders, obesity, insulin resistance , conditions related to stress, diarrhea, diuresis, nasal congestion, spasticity5, attention deficit disorder, psychosis, anxiety, depression, autoimmune disease, Crohn's disease, gastritis, Alzheimer's, Parkinson's ALS, and other neurodegenerative diseases.

DETAILED DESCRIPTION OF THE INVENTION

The general structures of exemplary specific subtype modulators of alpha 2b and / or alpha 2c adrenergic receptors that are used in the present pharmaceutical compositions and treatment methods are provided by the general formulas, below.

In one aspect of the invention, a compound having selective modulation activity at alpha 2b and / or alpha 2c adrenergic receptors is represented

<img file="BRPI0907613A2_D0002.tif" />

where n = 1-4;

XéCouN;

R¹-R⁶ can be the same or different and are independently selected from the group consisting of H, C-i_6 alkyl, OCH3, OH, F, Cl, Br, CH2OH, CH2N (R⁷) 2, C (O) R⁸ch₂cn, cf_3; where R⁷ is H or 0 ^ 6 alkyl; and R⁸ is C1-6 alkyl or aryl.

In another aspect of the invention, in the compound of formula 1, none of R¹ to R⁶ is switched to the position for.

In the compound of formula 1, n can be 1 or 2 and the C1.6 alkyl can be methyl.

In another aspect of the invention, a compound is represented by formula 2:

<img file="BRPI0907613A2_D0003.tif" />

Formula 2 where R¹-R⁴ can be the same or different and are independently selected from the group consisting of H, C1-6 alkyl, OCH3, OH, F, Cl, Br, CH2OH, CH2N (R^s) 2, C (O) R⁶, CH₂CN, and CF₃;

where R⁵ is H or C4 alkyl; and R⁶ is C1-6 alkyl or aryl.

Alternatively, in the compound of formula 2, n may be 1 or 2, and the C1-6 alkyl may be methyl.

In another aspect of the invention, a compound is represented by formula 3:

<img file="BRPI0907613A2_D0004.tif" />

selected from the group consisting of H, CH₃, 0-6 alkyl, OCH₃, OH, F, Cl, Br, CH₂OH, CH₂N (R³) 2, C (O) R⁴, CH2CN, and CF₃; where R³ is H or 0-6 alkyl; and R⁴ is O_6 alkyl or aryl.

Alternatively, in the compound of formula 3, n can be 1 or 2, and 0-6 alkyl can be methyl.

The following represent exemplary compounds of the present

<img file="BRPI0907613A2_D0005.tif" />

Possible tautomers of the imidazole moieties described here include:

<img file="BRPI0907613A2_D0006.tif" />

For any structure described here, the scope of a compound 5 also includes any tautomer that can be formed.

Unless otherwise indicated, reference to a compound should be constructed broadly to include pharmaceutically acceptable salts, prodrugs, tautomers, alternating solid forms, non-covalent complexes, and combinations thereof, of a chemical entity of the described structure or chemical name .

A pharmaceutically acceptable salt is any salt of the parent compound that is suitable for administration to an animal or human. A pharmaceutically acceptable salt also refers to any salt that can be formed in vivo as a result of administering an acid, another salt, or a prodrug that is converted to an acid or salt. A salt comprises one or more ionic forms of the compound, such as a base or conjugated acid, associated with one or more corresponding counterions. Salts can be formed from or incorporate one or more deprotonated acidic groups (for example, carboxylic acids), one or more basic protonated groups (for example, amines), or both (for example, zwitterions).

A prodrug is a compound that is converted to a therapeutically active compound after administration. For example, conversion can occur by [adapting this part to the structure being claimed], or some other biologically labile group. Prodrug preparation is well known in the art. For example, Prodrugs and Drug Delivery Systems, which is a chapter in Richard B. Silverman, Organic Chemistry of Drug Design and Drug Action, 2^The Edition, Elsevier Academic Press: Amsterdam, 2004, pages 496 to 557, provides another detail on the subject.

Tautomers are isomers that are in rapid equilibrium with each other. For example, tautomers can be linked by transferring a proton, hydrogen atom, or hydride ion.

Unless stereochemistry is explicitly described, a structure is intended to include each possible stereoisomer, both pure and in any possible mixture.

Alternating solid forms are solid forms that differ from those that may result from the practice of the procedures described here. For example, alternating solid forms can be polymorphic, different species of amorphous solid forms, glass, and the like.

Non-covalent complexes are complexes that can form between the compound and one or more additional chemical species that do not involve a covalent bonding interaction between the compound and the additional chemical species. They may or may not have a specific relationship between the compound and additional chemical species. Examples can include solvates, hydrates, charge transfer complexes, and the like.

Aryl is an aromatic ring or ring system, including all carbon rings or ring systems such as phenyl, naphthyl, biphenyl, and the like, and heteroaryl. Heteroaryl is an aromatic ring or ring system containing one or more heteroatoms of O, N, or S. Both aryl and heteroaryl may be substituted or unsubstituted, and unless otherwise indicated, aryl and heteroaryl should be considered to mean substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

Subject to the restrictions described here (for example, limits on the number of atoms for a substituent), examples of substituents include, but are not limited to:

Hydrocarbyl, meaning a portion consisting of carbon and hydrogen only, including, but not limited to: alkyl, meaning hydrocarbyl having no double or triple bond, including, but not limited to:

linear alkyl, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, nhexyl, etc., branched alkyl, for example, Zso-propyl, i-butyl and other branched butyl isomers, pentyl isomers branched, etc., cycloalkyl, for example , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., combinations of linear, branched, and / or cycloalkyl;

alkenyl, for example, hydrocarbyl having 1 or more double bonds, including linear, branched, or cycloalkenyl alkynyl, for example, hydrocarbyl having 1 or more triple bonds, including linear, branched, or cycloalkenyl; combinations of alkyl, alkenyl, and / or alkynyl alkyl-CN, such as -CH2-CN, - (CH₂)₂-CN; - (CH₂) 3-CN, and the like; hydroxyalkyl, i.e., alkyl-OH, such as hydroxymethyl, hydroxyethyl, and the like;

ether substituents, including -O-alkyl, alkyl-O-alkyl, and the like; thioether substituents, including -S-alkyl, alkyl-S-alkyl, and the like; amine substituents, including -NH₂, -NH-alkyl, -N-alkyl¹alkyl² (ie, alkyl¹ and alkyl² are the same or different, and both are linked to N), alkylNH2, alkyl-NH-alkyl, alkyl-N-alkyl¹alkyl², and the like; aminoalkyl, meaning alkyl amine, such as aminomethyl (-CH2-amine), aminoethyl, and the like;

ester substituents, including -CO₂-alkyl, -CO₂.phenyl, etc .;

other carbonyl substituents, including aldehydes; ketones, such as

X as acyl (ie hydrocarbon _and similar; in particular, acetyl, propionyl, and benzoyl substituents are contemplated; phenyl or substituted phenyl;

fluorocarbons or hydroflourocarbons such as -CF_3i _CH₂CF₃, etc.; and CN;

combinations of the above are also possible, subject to the defined restrictions.

The compounds of the present invention have the structural formulas 15 described in table 1, which also include their potency of intrinsic activity (nM of effectiveness (EC50)) for alpha 2a, alpha 2B and alpha 2C receptors. The activity of the compounds is expressed as their relative efficacy compared to a standard total agonist.

Table 1: Biological Data: nM of Intrinsic Activity Power Effectiveness (EC50)

<td colspan="3"></td><td>Alpha 2A</td><td>Alpha 2B</td><td>Alpha 2C</td>

<td></td><td></td><td></td><td>Data No.</td><td> 2,09</td><td> 26</td>

<td></td><td>Me</td><td></td><td> (0,28)</td><td> (1,01)</td><td> (0,36)</td>

<td>Me.</td><td>ΙΙΊ</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>i! __ /</td><td></td><td></td><td></td>

<td colspan="2"></td><td>Alpha 2A</td><td>Alpha 2B</td><td>Alpha 2C</td>

<td></td><td>kk</td><td>Data No.</td><td> 8,4</td><td> 41</td>

<td>Cl ° Ύί</td><td>ksk 'K v&gt; - NH</td><td> (0,21)</td><td> (0,97)</td><td> (0,41)</td>

<td></td><td>kk</td><td>Data No.</td><td> 4,4</td><td>Data No.</td>

<td>F kk</td><td>r ^ Y .N M ~~ -NH</td><td> (0,04)</td><td> (0,53)</td><td> (0,17)</td>

<td></td><td>kk</td><td>Data No.</td><td> 101</td><td>Data No.</td>

<td>Me r kjj</td><td>x&gt; NH</td><td> (0,10)</td><td> (0,69)</td><td> (0,21)</td>

<td></td><td>kk</td><td>Data No.</td><td> 3,5</td><td>Data No.</td>

<td>F f</td><td>x&gt; NH</td><td> (0,04)</td><td> (0,43)</td><td> (0,18)</td>

<td></td><td>kk</td><td>Data No.</td><td> 2,8</td><td>Data No.</td>

<td>kk</td><td>Xxk T?&gt;</td><td> (0,05)</td><td> (0,69)</td><td> (0,10)</td>

<td></td><td>kk</td><td>Data No.</td><td> 66</td><td>Data No.</td>

<td>^N\ k</td><td>x&gt; ^ '-' NH</td><td> (0,02)</td><td> (0,74)</td><td> (0,09)</td>

<td></td><td>Alpha 2A</td><td>Alpha 2B</td><td>Alpha 2C</td>

<td></td><td>Data No.</td><td> 7,8</td><td>Data No.</td>

<td></td><td> (0,09)</td><td> (0,80)</td><td> (0,19)</td>

<td>^Cl\ TFO</td><td></td><td></td><td></td>

The compounds described here are alpha 2B / 2C adrenergic receptor agonists. The alpha 2 receptor activity of the compounds of the present invention is demonstrated in an assay called the Receptor Selection and Amplification Technology (RSAT) assay, which is described in the Publication by Messier et al., 1995, Pharmacol. Toxicol. 76, pages 308 to 311 (incorporated by reference) and is also described below. Another relevant reference to this essay is Conklin et al., (1993) Nature 363: 274-6, also incorporated by reference.

The RSAT assay assesses a receptor-mediated loss of contact inhibition that results in selective proliferation of receptor-containing cells in a mixed population of confluent cells. The increase in cell number is assessed with an appropriate transfected marker gene β-galactosidase, the activity of which can be easily assessed in a 96-well format. Receptors that activate the G, G protein_q, elicit this answer. Alpha 2 receptors, which normally attach to Gj, activate the RSAT response when coexpressed with a G protein_q hybrid that has a Gj receptor recognition domain, called G_q/ i5.

NIH-3T3 cells are seeded at a density of 2x10⁶cells in 15 cm plates and maintained in Dulbecco's modified Eagle's medium supplemented with 10% calf serum. One day later, cells are cotransfected by precipitation of calcium phosphate with mammalian expression plasmids encoding p-SV-8-galactosidase (5 to 10 pg), receptor (1 to 2 pg) and protein G (1 to 2 pg) . 40 pg of salmon sperm DNA can also be included in the transfection mix. Fresh media are added the next day and 1 to 2 days later, the cells were harvested and frozen in 50 assay aliquots. The cells are thawed and 100 µl added to 100 μΙ aliquots of various concentrations of drugs in triplicate in 96-well plates. Incubations continue 72 to 96 hours at 37 ° C. After washing with phosphate-buffered saline, the retrograde galactosidase enzyme activity is determined by adding 200 μrom of the chromogenic substrate (consisting of 3.5 mM onitrophenyl-beta-D-galactopyranoside and 0.5% nonidete P-40 in phosphate buffered saline), incubating overnight at 30 ° C and evaluating the optical density at 420 nm. Absorbance is an assessment of enzyme activity, which depends on the cell number and reflects receptor-mediated cell proliferation. Intrinsic efficacy or activity is calculated as a ratio of the maximum effect of the drug to the maximum effect of a standard total agonist for each receptor subtype. Brimonidine, also called UK14304, the chemical structure of which is shown below, is used as a standard agonist for the alpha 2A, alpha 2B and alpha 2C receptors.

Diseases and conditions that can be treated according to the compounds described here include, but are not limited to, the neurodegenerative aspects of the following:

Maculopathies / diseases and conditions of retinal degeneration include non-exudative age-related macular degeneration (ARMD), exudative age-related macular degeneration (ARMD), choroidal neovascularization, diabetic retinopathy, central serous chorioretinopathy, cystoid macular edema, macular diabetic macular edema and myopic retinal degeneration.

Uveitis / retinitis / choroiditis / other inflammatory diseases and conditions include multifocal placoid pigment epitheliopathy, Behcet's disease, hunting lead retinochoroidopathy, infections (syphilis, lime, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, syndrome syndrome multiple evanescent spot (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome, enhanced internal choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, acute retinal pigment epithelitis, and acute macular neuroretinopathy.

Vascular diseases / exudative diseases include diabetic retinopathy, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branched retinal vein occlusion, hypertensive background changes, ocular ischemic syndrome, retinal arterial microaneurisms, Coat's disease, parafoveal telangiectasia, hemirretinal vein occlusion, papillophlebitis, central retinal artery occlusion, branched retinal artery occlusion, carotid artery disease (CAD), frozen branching angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease.

Traumatic / surgical / environmental diseases and conditions include sympathetic ophthalmia, retinal uveitic disease, retinal displacement, trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy and bone marrow transplant retinopathy. Proliferative disorders include proliferative vitreal retinopathy and epiretinal membranes.

Infectious disorders include ocular histoplasmosis, ocular toxocariase, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV infection, viral retinitis, necrosis acute retinal, progressive external retinal necrosis, fungal retinal disease, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis.

Genetic disorders include retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, standard retinal pigmented epithelium dystrophy, X-linked retinoschisis, Sorsby fundus dystrophy , benign concentric maculopathy, crystalline Bietti dystrophy, and elastic pseudoxanthoma.

Conditions and diseases associated with retinal tears and orifices include retinal dislocation, macular orifice and giant retinal tear.

Conditions and diseases associated with tumors include retinal diseases associated with tumors, congenital RPE hypertrophy, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined retinal pigment epithelium and retinal hamartoma, retinoblastoma, vasoproliferative tumors of the ocular fundus, astrococcal retinal, and intraocular lymphoid tumors.

Generally speaking alpha 2 agonists can alleviate sympathetically sensitized conditions that are typically associated with periods of stress. These include the neurological conditions of 1) increased sensitivity to stimuli such as intracranial pressure, light and noise characteristic of migraines and other headaches; 2) increased sensitivity to stimuli characteristic of Irritable Bowel Syndrome and other gastrointestinal disorders such as functional dyspepsia; 3) the itching sensation associated with psoriasis and other dermatological conditions; 4) muscle tension and spasticity; 5) sensitivity to normally innocuous stimuli such as light touch and spontaneous pain characteristic of conditions such as fibromyalgia; 6) several cardiovascular disorders involving hypertension, tachycardia, cardiac ischemia and peripheral vasoconstriction; 7) metabolic disorders including obesity and insulin resistance; 8) behavioral disorders such as drug and alcohol dependence, obsessive-compulsive disorder, Tourette's syndrome, attention deficit disorder, anxiety and depression; 9) altered immune system function such as autoimmune diseases including lupus erythematosus and dry eye disorders; 10) chronic inflammatory disorders such as Crohn's disease and gastritis; 11) sweating (hyperhidrosis) and tremor; and 12) sexual dysfunction.

Alpha 2 agonists including alpha 2B / 2C agonists are also useful in the treatment of glaucoma, high intraocular pressure, neurodegenerative diseases including Alzheimer's, Parkinson's, ALS, schizophrenia, ischemic nerve damage such as stroke or spinal injury, and retinal injury as in glaucoma, macular degeneration, diabetic retinopathy, retinal dystrophies, Lebers optic neuropathy, other optic neuropathies, optic neuritis often associated with multiple sclerosis, retinal vein occlusions, and following procedures such as photodynamic therapy and LASIX. Also included are chronic pain conditions such as cancer pain, post-operative pain, allodynamic pain, neuropathic pain, CRPS or causalgia, and visceral pain.

The compounds are used according to the present invention as highly effective analgesics, particularly in chronic pain models, with minimal undesirable side effects, such as sedation and cardiovascular depression, commonly seen with other alpha 2 receptor agonists.

The present compounds can be administered in pharmaceutically effective dosages. Such dosages are usually the minimum dose necessary to obtain the desired therapeutic effect; in the treatment of chronic pain, this amount would be approximately that needed to reduce the discomfort caused by the pain to tolerable levels. The actual amount of the compound to be administered in any given case will be determined by a doctor taking into account the relevant circumstances, such as the severity of the pain, the age and weight of the patient, the general physical condition of the patient, the cause of the pain, and the route of administration.

The compounds are useful in treating pain in a mammal; particularly a human being. Preferably, the patient will be administered the compound orally in any pharmacologically acceptable form, such as a tablet, liquid, capsule, powder and the like. However, other routes may be desirable or necessary, particularly if the patient suffers from nausea. Other such routes may include transdermal, parenteral, subcutaneous, intranasal, intrathecal, intramuscular, intravenous, and intrarectal delivery modes. In addition, formulations can be designed to delay the release of the active compound for a certain period of time, or to carefully control the amount of drug released at a given time during the course of therapy.

Another aspect of the present invention relates to therapeutic compositions comprising the compounds currently described and a pharmaceutically acceptable carrier. The vehicle can be solid, semi-solid, or liquid material that acts as an excipient or vehicle for the active compound. The formulations can also include wetting agents, emulsifying agents, preserving agents, sweetening agents, and / or flavoring agents. If used in an ophthalmic or infusion format, the formulation may contain one or more salts to adjust the formulation's osmotic pressure.

Another aspect of the present invention relates to methods for treating alpha 2B receptor-mediated diseases or conditions by administering one or more compounds currently described.

Alpha 2B receptor-mediated diseases or conditions may include, but are not limited to, glaucoma, elevated intraocular pressure, ischemic neuropathies, optic neuropathy, pain, visceral pain, corneal pain, headache, migraine, cancer pain, headache back, irritable bowel syndrome pain, muscle pain and pain associated with diabetic neuropathy, treatment of diabetic retinopathy, other degenerative retinal conditions, stroke, cognitive deficits, neuropsychiatric conditions, drug addiction and dependence, withdrawal symptoms, obsessive-compulsive disorders, obesity, insulin resistance, stress-related conditions, diarrhea, diuresis, nasal congestion, spasticity, attention deficit disorder, psychosis, anxiety, depression, autoimmune disease, Crohn's disease, gastritis, Alzheimer's, and Parkinson's ALS.

Chronic pain (such as cancer pain, arthritis, and many neuropathic injuries) is known to be acute pain (such as pain produced by an immediate mechanical stimulus, such as cutting tissue, pinching, stinging, or crushing tissue ) are distinct neurological phenomena mediated to a great extent by different nerve fibers and neuroreceptors or by a redisposition or alteration of the function of these nerves under chronic stimulation. Acute pain sensation is transmitted very quickly, primarily by afferent nerve fibers called C fibers, which normally have a high threshold for mechanical, thermal, and chemical stimulation. While the mechanisms of chronic pain are not fully understood, acute tissue injury can originate within minutes or hours after initial stimulation for secondary symptoms, including a regional reduction in the magnitude of the stimuli needed to elicit a pain response. This phenomenon, which typically occurs in a region emanating from the (but larger than) site of the original stimulus, is called hyperalgesia. The secondary response can give rise to the profoundly enhanced sensitivity to mechanical or thermal stimuli.

Afferent A fibers can be stimulated at a lower threshold than C fibers, and appear to be involved in the sensation of chronic pain. For example, under normal conditions, low-threshold stimulation of these fibers (such as a light brush or tickle) is not painful. However, under certain conditions such as those following nerve damage or in the condition mediated by herpes virus, known as herpes zoster, the application of such a light touch or the tissue brush can still be very painful. This condition is called allodynia and appears to be mediated at least in part by afferent A nerves. C fibers may also be involved in the sensation of chronic pain, but in this case it seems clear that the persistent burning of neurons for some time makes some kind of change that currently results in the sensation of chronic pain.

Acute pain is understood to mean immediate pain, usually of a high threshold, produced by injury such as a cut, crush, burn, or by chemical stimulation such as that experienced under exposure to capsaicin, the active ingredient in peppers.

Chronic pain means pain other than acute pain, such as, without limitation, neuropathic pain, visceral pain (including that produced by Crohn's disease and irritable bowel syndrome (IBS)), and referred pain. Example A

Method A: Procedure for the preparation of 4- (1- (1 Himidazol-4-yl) -2 phenylethyl) pyridine:

<img file="BRPI0907613A2_D0007.tif" />

Intermediate 1

Intermediate 2

Intermediate 3

<img file="BRPI0907613A2_D0008.tif" />

<img file="BRPI0907613A2_D0009.tif" />

A solution of 4-iodo-1-tritylimidazole (commercially available, 6.1 g, 14.01 mmol) in dichloromethane (30 mL) at -10 ° C was treated with ethyl magnesium bromide (4.7 mL, 14 , 01 mmols, 3M in ether) and allowed to react for 45 min. A solution of pyridine-4-benzaldehyde, (Intermediate 1) (1.2 g, 11.2 mmols) in dichloromethane was added via syringe at -10 ° C and stirred for 16 hours at room temperature. The mixture was quenched with water (50 ml) and a saturated solution of ammonium chloride (50 ml). The residue was isolated in a typical aqueous preparation and purified by MPLC with 3% 5% MeOH: CH2 Cl2 to provide 2-phenyl-1 (pyridin-4-yl) -1- (1-trityl-IH-imidazole-5- il) ethanol, (Intermediate 2) as a solid, (3.1 g).

A mixture of 2-phenyl-1- (pyridin-4yl) -1- (1-trityl-IH-imidazol-5yl) ethanol, (Intermediate 2) (3.1 g, 7.4 mmols) in CH₂CI₂ (60 mL) was treated with activated manganese (IV) oxide (commercially available from Aldrich) MnO₂ (2.9 g, 37.8 mmols) at room temperature. The mixture was heated to 60 ° C for 2 hours. The mixture was then cooled to room temperature and filtered through Celite and the solvent was removed in vacuo. The residue was purified by MPLC with 3 to 5% MeOH: CH₂CI₂ to provide, pyridin-4-yl (1-trityl-1H-imidazol-5-yl) methanone, (Intermediate 3) (3.01 g).

A solution of pyridin-4-yl (1-trityl-1H-imidazol-5-yl) methanone (500 mg, 1.19 mmol) in dichloromethane (25 mL) at room temperature was treated with benzyl magnesium bromide (0.595 ml, 1.78 mmol, 3M in ether) and allowed to react at room temperature and the reaction mixture was then stirred at room temperature for 16 hours. The mixture was quenched with water (20 ml) and a saturated ammonium chloride solution (20 ml). The residue was isolated in a typical aqueous preparation to provide pyridin-4-yl (1-trityl-1H-imidazol-5-yl) methanol, (Intermediate 4) (526 mg, brown).

A mixture of pyridin-4-yl (1-trityl-1 H-imidazol-5-yl) methanol, (Intermediate 4) (526 g, 1.03 mmol) in 57% aqueous Hl (10 mL) and iPrOH ( 2 mL) red phosphorus (318 mg, 10.3 mmoles) was added to a resealable tube and heated to 160 ° C for 16 h. The mixture was then cooled to room temperature and poured into ice water, which was then basified with NaOH and diluted with CHCl3. The residue was isolated in a typical aqueous preparation using CHCl3 and purified by MPLC with 5 to 15% MeOH: CH2 Cl2 to provide 4- (1- (1 H-imidazol-5-yl) -2-phenylethyl) pyridine (AGN214418) as a solid, 36 mg. ¹HRMN (CD₃OD, 300 MHz) δ 6.98 (s, 1H), 7.20-7.11, (m, 9H), 7.61 (s, 1H), 4.38 (t, J = 9Hz, 1H) , 3.43 (dd, J = 6Hz, 12 Hz, 1H), 3.19 (dd, J = 9Hz, 15Hz, 1H).

Example B

Method B: Procedure for the preparation of 4- (1- (2,315 d imethylphenyl) -2-phenylethyl) -1 H-imidazole:

<img file="BRPI0907613A2_D0010.tif" />

A solution of 1-trityl-IH-imidazole-4-carbaldehyde (commercially available, 2.08 g, 6.15 mmol) in dichloromethane (40 mL) at 0 ° C was treated with 2,3-dimethyl magnesium bromide (18.4 mL, 9.2 mmols, 0.5 M in

THF) and allowed to stir for 16 hours at room temperature. The mixture was quenched with water (50 ml) and a saturated solution of ammonium chloride (50 ml). The residue was isolated in a typical aqueous preparation to provide (2,3-dimethylphenyl) (1-trityl-1H imidazol-5-yl) methanol, (Intermediate 6) as a solid, (2.8 g, crude).

A mixture of (2,3-dimethylphenyl) (1-trityl-IH-imidazol-5-yl) methanol, (Intermediate 6) (2.4 g, 7.4 mmols) in CH₂CI₂ (60 mL) was treated with activated manganese (IV) oxide (commercially available from Aldrich): MnO₂(2.8 g, 32.3 mmols) at room temperature. The mixture was heated to 60 ° C for 2 hours. The mixture was then cooled to room temperature and filtered through Celite and the solvent was removed in vacuo. The residue was purified by MPLC with 3 to 5% MeOH: CH₂CI₂ to provide (2,3dimethylphenyl) (1-trityl-IH-imidazol-5-yl) methanone, (Intermediate 7), 1.48 g, (62%).

A solution of (2,3-dimethylphenyl) (1-trityl-1H-imidazol-5-yl) methanone (450 mg, 1.01 mmol) in dichloromethane (25 mL) at room temperature was treated with benzyl magnesium bromide (1.51 mmol) and allowed to react at room temperature and the reaction mixture was then stirred at room temperature for 5 hours. The mixture was quenched with water (10 ml) and a saturated solution of ammonium chloride (10 ml). The residue was isolated in a typical aqueous preparation to provide crude 1- (2,3dimethylphenyl) -2-phenyl-1- (1-trityl-1H-imidazol-5-yl) ethanol (Intermediate 8), which was taken to the next step without any purification.

A solution of 1- (2,3-dimethylphenyl) -2-phenyl-1- (1-trityl-1H-imidazol5-yl) ethanol, (Intermediate 8) crude in dichloromethane (20 mL) was reacted with trifluoroacetic acid (2 ml) and triethylsilane (0.5 ml) at room temperature for 24 hours. The mixture was evaporated under reduced pressure and quenched with aqueous NaOH. This material was subjected to an aqueous preparation and the residue was purified by chromatography on silica gel with NH₃5% MeOH: CH₂C1₂ to produce a mixture of 5- (1- (2,3-dimethylphenyl) -2-phenylvinyl) 1H imidazole (intermediate 9) (322 mg).

A mixture of (Intermediates 9) (322 mg) in EtOH (10 mL) was reduced by the action of 10% Pd / C (53 mg) under an atmosphere of H₂ for 16 hours at room temperature. The mixture was filtered through Cellos and free of solvent under reduced pressure. The residue was purified by chromatography on silica gel with NH₃5% MeOH: CH₂CI₂ to provide 4- (1- (2,3dimethylphenyl) -2-phenylethyl) -1 H imidazole as a solid, (135 mg) AGN214303. ¹HRMN (CD₃OD, 300MHz) δ 7.55 (s, 1H), 7.14 - 6.96, (m, 8H), 6.75, (s, 1H), 4.58 (t, J = 9Hz, 1H) , 3.43 (dd, J = 6Hz, 12 Hz, 1H), 3.19 (dd, J = 9Hz, 15Hz, 1H), 2.19 (s, 3H), 2.02 (s, 3H).

Example C

Method C: Procedure for the preparation of 4- (1- (2-fluoroenyl) -2-phenylethyl) -1H-imidazole AGN-217125:

<img file="BRPI0907613A2_D0011.tif" />

<img file="BRPI0907613A2_D0012.tif" />

<img file="BRPI0907613A2_D0013.tif" />

Intermediate 12

<img file="BRPI0907613A2_D0014.tif" />

A solution of 2- (2-fluorophenyl) acetonitrile (2.1 g, 15.5 mmol) in tetrahydrofuran (50 ml) and hexane (20 ml) was treated with n-butyl lithium (6.2 ml, 15 , 5ols) at -78 ° C. The mixture was stirred at -78 ° C for one hour. A solution of benzyl magnesium bromide (2.02 ml, 17.05 mmols) in hexane (10 ml) was added at -78 ° C. The mixture was stirred at -78 ° C for two hours, then warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and extracted in ether. The combined organic layers were washed with brine, dried over magnesium sulfate, then filtered and evaporated. Purification by MPLC with 3 to 5% MeOH: CH₂CI₂ provided 2- (2fluorophenyl) -3-phenylpropanonitrile, (Intermediate 11), (3.4 g).

A solution of 2- (2-fluorophenyl) -3 phenylpropanonitrile (Intermediate 23) (2 g, 8.8 ml) in toluene (50 ml) was treated with diisobutylaluminum hydride (10.6 ml, 10.6 ml) at -78 ° C. The mixture was stirred at -78 ° C and gradually warmed to room temperature over six hours. The reaction was quenched slowly with aqueous saturated ammonium chloride.

Celite was added and stirred at room temperature for one hour.

The mixture was filtered and concentrated. The crude product was purified by MPLC using 0 to 20% EtOAc: Hexane to provide 2- (2dichlorophenyl) -3-phenylpropanal (Intermediate 12) (1.1 g).

A solution of 2- (2-fluorophenyl) -3-phenylpropanal (Intermediate

12) (707 mg, 3.1 ml) in Ethanol (20 ml) was treated with Tosmic (tosyl methyl isocyanide) (604 mg, 3.1 ml) at room temperature. The mixture was stirred at room temperature for one hour. The mixture was concentrated in vacuo. The residue was dissolved in methanol saturated with ammonia (50 ml) and heated in a sealed tube at 80 ° C overnight, cooled to room temperature and the solvent evaporated. Column purification using 0 to 10% methanol in dichloromethane gave 350 mg of the product, 4- (1- (2-fluorophenyl) -2-phenylethyl) -1H-imdazole AGN-21712S. ¹HRMN (CD₃OD, 300MHz) δ 7.57 (s, 1H), 7.33-6.93, (m, 9H), 6.82 (s, 1H), 4.60 (t, J = 9Hz, 1H), 3.43 (dd, J = 6Hz, 12 Hz, 1H), 3.19 (dd, J = 9Hz, 15Hz, 1H).

Example D

Method D: Procedure for the preparation of 4- (1,2-diphenylethyl) -1 H-imidazole AGN-217242:

<img file="BRPI0907613A2_D0015.tif" />

A solution of 2-phenylacetyl chloride (commercially available, 4.7 g, 30.5 mmols) in dichloromethane (100 ml) was treated with N, 0 dimethylhydroxylamine (3.25 g, 33.5 mmols), followed by by the addition of triethyl amine (8.5. G, 61 mmols) and diaminopyridine (305 mg). The mixture was stirred at room temperature overnight. The mixture was quenched with water (50 ml) and a saturated solution of ammonium chloride (50 ml). The residue was isolated in a typical aqueous preparation and purified by MPLC with 0 to 2% MeOH: CH₂CI₂ to provide N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (3.5 g 78.7%).

A solution of 4-iodo-1-tritylimidazole (commercially available, 5.08 g, 13.7 mmol) in dichloromethane (100 mL) at -10 ° C was treated with ethylmagnesium bromide (4.5 mL, 13.7 mmols, 3M in ether) and allowed to react for 45 minutes. A solution of N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (2.0 g, 11.2 mmols) in dichloromethane was added by syringe at -10 ° C and stirred for 16 hours at room temperature. environment. The mixture was quenched with water (50 ml) and a saturated solution of ammonium chloride (50 ml). The residue was isolated in a typical aqueous preparation and purified by MPLC with 3 to 5% MeOH: CH₂CI₂ to provide 2-phenyl-1- (1-trityl-1H-imidazol-4-yl) ethanone, (Intermediate 14) as a solid, (4.65 g).

A solution of 2-phenyl-1- (1-trityl-IH-imidazol-4-yl) ethanone, (Intermediate 14) (595 mg, 1.39 mmol) in dichloromethane (30 mL) at 0 ° C was treated with 3-chlorophenyl magnesium bromide (1 mL, 2.02 mmol, 2M in ether) and allowed to react at room temperature overnight. The mixture was quenched with water (20 ml) and a saturated ammonium chloride solution (20 ml). The residue was isolated in a typical aqueous preparation to provide 1 - (3-chlorophenyl) -2-phenyl-1 - (1-trityl-1 H-imidazol-4-yl) ethanol, (Intermediate 15), (469 mg, gross).

To a mixture of 1- (3-chlorophenyl) -2-phenyl-1- (1-trityl-1 H-imidazol-4yl) ethanol, (Intermediate 15) mg; 0.9 mmol) in 57% aqueous Hl (10 mL) and iPrOH (2 mL) red phosphorus (280 mg, 9.0 mmol) was added to a resealable tube and heated at 160 ° C for 16 hours. The mixture was then cooled to room temperature and poured into ice water, which was then basified with NaOH and diluted with CHCI₃. The residue was isolated in a typical aqueous preparation using CHCI₃ and purified by MPLC with 5 to 15% MeOH: CH₂CI₂ to provide 4- (1- (3-chlorophenyl) -2-phenylvinyl) 1 H-imidazole, as a solid, (86 rug), AGN-216677. ¹HRMN (CD₃OD, 300 MHz) δ IJA (s, 1H), 7.37-6.96 (m, 9H), 6.55 (s, 1H).

A mixture of 4- (1- (3-chlorophenyl) -2-phenylvinyl) -1 H-imidazole (AGN216677) (35 mg) in EtOH (10 mL) was reduced by the action of 10% Pd / C (20 mg ) under H atmosphere₂ for 16 hours at room temperature. The mixture was filtered through Celite and solvent-free under reduced pressure. The residue was purified by chromatography on silica gel with 5% NH₃MeOH: CH₂CI₂ to provide 4- (1,2-diphenylethyl) -1 H-imidazole as a solid, (31 mg), AGN217242. ¹H NMR (300 MHz, CD₃OD): δ 7.38 (s, 1H), 7.107.26 (m, 8H), 7.08 (s, 1H), 4.41 (t, J = 9 Hz, 3H), 3.43 (dd ; J = 9 Hz, 15 Hz, 1H), 3.27 (dd, J = 6 Hz, 9 Hz, 1H).

The following compounds were synthesized by one of the methods described above:

4- (1- (2,3-dichlorophenyl) -2-phenylethyl) -1 H-imidazole, AGN-217124:

(Method: A) ¹H NMR (300 MHz, CDCI₃): δ 7.56 (s, 1H), 7.10-7.19 (m, 8H), 6.75 (s, 1H), 4.87 (t, = 9 Hz, 3H), 3.46 (dd, J = 6 Hz, 15 Hz, 1H), 3.26 (dd, J = 6 Hz, 15 Hz, 1H).

4- (1- (2,3-difluorophenyl) -2-phenylethyl) -1 H-imidazole, AGN-217153:

(Method: C) ¹H NMR (300 MHz, CD₃OD): δ 6.88 (s, 1H), 7.02-7.17 (m, 8H), 7.59 (s, 1H), 4.62 (t, J = 9 Hz, 3H), 3 , 44 (dd, J = 6 Hz, 15 Hz, 1H), 3.18 (dd, J = 6 Hz, 15 Hz, 1H).

4- (2-phenyl-1-o-tolylvinyl) -1 H-imidazole, AGN-216678:

(Method: D) ¹H NMR (300 MHz, CDCI₃): δ 7.64 (s, 1H), 7.39-6.91 (m, 9H), 6.53 (s, 1H), 2.10 (s, 1H).

Unless otherwise indicated, all numbers expressing amounts of ingredients, properties such as molecular weight, reaction conditions, and so on used in the specification and claims must be modified in all cases by the term approximately. Consequently, unless otherwise indicated, the numerical parameters set out in the specification and appended claims are approximations that may vary depending on the desired properties sought to be obtained by the present invention. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter must at least be constructed taking into account the number of significant digits reported and applying ordinary rounding techniques. Although the ranges and numerical parameters that represent the broad scope of the present invention are approximations, the numerical values ​​established in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective test assessments.

The terms one, one (an) one, one (a), o, a and similar referents used in the context of the description of the invention (especially in the context of the following claims) must be constructed to encompass the singular and the plural, unless otherwise indicated here or clearly contradicted by the context. The recitation of ranges of values ​​is merely intended to serve as a shorthand method of referring individually to each separate value that is included in the range. Unless otherwise indicated here, each individual value is incorporated into the specification as if it were individually recited here. All methods described here can be performed in any suitable order unless otherwise indicated here or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (for example, as such) provided herein is intended merely to better illustrate the invention and not to propose a limitation on the scope of the invention otherwise claimed. No language in the specification should be constructed as an indication of any unclaimed element essential to the practice of the invention.

Groups of elements or alternative embodiments of the invention described herein should not be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other group members or other elements found in it. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is considered to contain the group as modified, thereby filling in the description described for all Markush groups used in the attached claims.

Certain embodiments of this invention are described here, including the best way known to the inventors for carrying out the invention. Certainly, variations in these described modalities will become evident to those skilled in the art in reading the previous description. The inventors expect technicians skilled in the use of variations as appropriate, and intend that the invention be practiced in a manner other than that specifically described here. Accordingly, this invention includes all of the modifications and equivalents of the subject matter listed in the claims attached to it as permitted by applicable law. In addition, any combination of the elements described above in all possible variations thereof is covered by the invention unless otherwise indicated herein or otherwise clearly contradicted by the context.

In addition, numerous references have been made to Patents and

Printed publications throughout this specification. Each of the references and printed publications mentioned above is individually incorporated by reference in its entirety.

In closing, it should be understood that the modalities of the invention described here are illustrative of the principles of the present invention. Other modifications that can be employed are within the scope of the invention. Thus, by way of example, but not limitation, alternative configurations of the present invention can be used in accordance with the teachings here. Consequently, the present invention is not limited to that precisely as shown and described.