described herein are n -( 2 and / or 3 - substituted benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine compounds as subtype selective α 2a and / or α 2c adrenergic modulators having the general structure wherein r 1 and r 2 are each independently selected from hydrogen , c 1 - 4 alkyl , c 1 - 4 alkoxy , oh , halogen , nr ′ 2 , cn , co 2 r ′, c ( o ) nr ′ r ″, alcohol , c 1 - 4 halogenated alkyl , c 1 - 4 halogenated alkoxy , and substituted or unsubstituted aryl or heteroaryl ; r ′ is selected from hydrogen , c 1 - 4 alkyl and c 1 - 4 halogenated alkyl , substituted or unsubstituted aryl or heteroaryl ; and r ″ is selected from hydrogen and c 1 - 4 alkyl , substituted or unsubstituted aryl or heteroaryl . in one embodiment , wherein r 1 and r 2 are each independently selected from hydrogen , c 1 - 10 alkyl , c 1 - 10 alkoxy , oh , halogen , nr ′ 2 , cn , co 2 r ′, c ( o ) nr ′ r ″, alcohol , c 1 - 10 halogenated alkyl , c 1 - 10 halogenated alkoxy , and substituted or unsubstituted aryl or heteroaryl ; r ′ is selected from hydrogen , c 1 - 10 alkyl and c 1 - 10 halogenated alkyl , substituted or unsubstituted aryl or heteroaryl ; and r ″ is selected from hydrogen and c 1 - 10 alkyl , substituted or unsubstituted aryl or heteroaryl . r 1 and r 2 can each independently be a c 1 - 10 alkyl , which includes c 3 - 10 cycloalkyls and c 3 - 10 branched alkyls . r 1 and r 2 can each also independently be a substituted or unsubstituted aryl or heteroaryl which can include aromatic , heteroaromatic , or multi - heteroaromatic groups . the substituted or unsubstituted aryl or heteroaryl can be selected from phenyl , pyridinyl , thienyl , furyl , naphthyl , quinolinyl , indanyl or benzofuryl . exemplary substituted or unsubstituted aryls or heteroaryls include , but are not limited to , benzenes , pyridines , thiophenes , furans , naphthalenes , quinolines , indans and benzofurans . the aryl groups may be substituted with any common organic fictional group . such aryl groups may be bonded to formula 1 at any available position on the aryl group . wherein at least one of r 4 - 9 must be formula 1 and wherein the remaining r 4 - 9 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be a pyridine as in formula 3 : wherein at least one of r 4 - 8 must be formula 1 and wherein the remaining r 4 - 8 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be a thiophene as in formula 4 : wherein at least one of r 4 - 7 must be formula 1 and wherein the remaining r 4 - 7 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be a furan as in formula 5 : wherein at least one of r 4 - 7 must be formula 1 and wherein the remaining r 4 - 7 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be a naphthalene as in formula 6 : wherein at least one of r 4 - 11 must be formula 1 and wherein the remaining r 4 - 11 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl . c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be a quinoline as in formula 7 : wherein at least one of r 4 - 10 must be formula 1 and wherein the remaining r 4 - 10 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be an indene as in formula 8 : wherein at least one of r 4 - 13 must be formula 1 and wherein the remaining r 4 - 13 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . another aryl group may be a benzofuran as in formula 9 : wherein at least one of r 4 - 9 must be formula 1 and wherein the remaining r 4 - 9 may be each independently substituted with a common organic functional group including , but not limited to , hydrogen , a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , thiol , or carboxy group substituted with a c 1 - 10 alkyl , c 1 - 10 alkenyl , c 1 - 10 alkynyl , aryl , halogen , hydroxyl , alkoxy , amino , cyano , nitro , or thiol group . α 2 adrenergic receptors have been characterized by molecular and pharmaceutical methods ; the methods including α 1a , α 1b , α 1d , α 2a , α 2b and α 2c subtypes . activation of these α - receptors can evoke physiological responses . adrenergic modulators described herein activate one or both of the α 2b and / or α 2c receptors and have useful therapeutic actions . the compounds described herein may be useful for the treatment of a wide range of conditions and diseases that are alleviated by α 2b and / or α 2c activation including , but not limited to , hypertension , congestive heart failure , asthma , depression , glaucoma , elevated intraocular pressure , ischemic neuropathies , optic neuropathy , pain , visceral pain , corneal pain , headache pain , migraine , cancer pain , back pain , irritable bowel syndrome pain , muscle pain , pain associated with diabetic neuropathy , the treatment of diabetic retinopathy , other retinal degenerative conditions , stroke , cognitive deficits , neuropsychiatric conditions , drug dependence , drug addiction , withdrawal symptoms , obsessive compulsive disorder , obesity , insulin resistance , stress related conditions , diarrhea , diuresis , nasal congestions , spasticity , attention deficit disorder , psychoses , anxiety , autoimmune disease , crohn &# 39 ; s disease , gastritis , alzheimer &# 39 ; s disease , parkinson &# 39 ; s disease , amyotrophic lateral sclerosis , and other neurodegenerative diseases . applicants have discovered that these compounds activate or modulate α 2b and α 2c receptors . additionally , these compounds act as a highly effective analgesic , particularly in chronic pain models , with minimal undesirable side effects , such as sedation and cardiovascular depression , commonly seen with agonists of α 2b and α 2c receptors . such compounds may be administered at pharmaceutically effective dosages . such dosages are normally the minimum dose necessary to achieve the desired therapeutic effect ; in the treatment of chronic pain , this amount would be roughly that necessary to reduce the discomfort caused by the pain to tolerable levels . generally , such doses will be in the range 1 - 1000 mg / day ; more preferably in the range 10 to 500 mg / day . however , 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 severity of the pain , the age and weight of the patient , the patient &# 39 ; s general physical condition , the cause of the pain , and the route of administration . the compounds may be useful in the treatment of pain in a mammal , particularly a human being . preferably , the patient will be given the compound orally in any 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 . such other routes may include , without limitation , transdermal , parenteral , subcutaneous , intranasal , intrathecal , intramuscular , intravenous , and intrarectal modes of delivery . additionally , the formulations may be designed to delay release of the active compound over a given period of time , or to carefully control the amount of drug released at a given time during the course of therapy . another embodiment is drawn to therapeutic compositions comprising the compounds of formula 1 , pharmaceutically acceptable derivatives , salts , prodrugs and / or combinations of these compounds and a pharmaceutically acceptable excipient . such an excipient may be a carrier or a diluent ; this is usually mixed with the active compound , or permitted to dilute or enclose the active compound . if a diluent , the carrier may be solid , semi - solid , or liquid material that acts as an excipient or vehicle for the active compound . the formulations may also include wetting agents , emulsifying agents , preserving agents , sweetening agents , and / or flavoring agents . if used as in an ophthalmic or infusion format , the formulation will usually contain one or more salt to influence the osmotic pressure of the formulation . another embodiment is directed to methods for the treatment of pain , particularly chronic pain , through the administration of a compound of formula 1 , and pharmaceutically acceptable salts , and derivatives thereof to a mammal in need thereof . as indicated above , the compound will usually be formulated in a form consistent with the desired mode of delivery . some embodiments provide methods that rely on administration of one or more pharmaceutical compositions to a subject . as used herein , the term “ subject ” means any animal capable of experiencing pain , for example , a human or other mammal such as a primate , horse , cow , dog or cat . the methods described herein are used to treat acute , neuropathic and chronic pain , and , as non - limiting examples , pain which is neuropathic , visceral or inflammatory in origin . in particular embodiments , the methods of the invention are used to treat neuropathic pain ; visceral pain ; post - operative pain ; pain resulting from cancer or cancer treatment ; and inflammatory pain . both acute and chronic pain can be treated by the methods described herein , and the term “ pain ” encompasses acute , neuropathic and chronic pain . as used herein , the term “ acute pain ” means immediate , generally high threshold , pain brought about by injury such as a cut , crush , burn , or by chemical stimulation such as that experienced upon exposure to capsaicin , the active ingredient in chili peppers . the term “ chronic pain ,” as used herein , means pain other than acute pain and includes , without limitation , neuropathic pain , visceral pain , inflammatory pain , headache pain , muscle pain and referred pain . it is understood that chronic pain is of relatively long duration , for example , several years and can be continuous or intermittent . unless otherwise indicated , reference to a compound should be construed broadly to include compounds , pharmaceutically acceptable salts , prodrugs , tautomers , alternate solid forms , non - covalent complexes , and combinations thereof , of a chemical entity of a depicted 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 which may form in vivo as a result of administration of an acid , another salt , or a prodrug which is converted into an acid or salt . a salt comprises one or more ionic forms of the compound , such as a conjugate acid or base , associated with one or more corresponding counter - ions . salts can form from or incorporate one or more deprotonated acidic groups ( e . g . carboxylic acid / carboxylate ), one or more protonated basic groups ( e . g . amine / ammonium ), or both ( e . g . zwitterions ). a prodrug is a compound which is converted to a therapeutically active compound after administration . for example , conversion may occur by hydrolysis of an ester group 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 , 2d ed ., elsevier academic press : amsterdam , 2004 , pp . 496 - 557 , provides further detail on the subject . tautomers are isomers that are in rapid equilibrium with one another . for example , tautomers may be related by transfer of a proton , hydrogen atom , or hydride ion . not intended to be limited by the above described compounds , various tautomers of the above compounds may be possible . for example , not intended as a limitation , tautomers are possible between the 4 , 5 - dihydrooxazole and the adjacent nitrogen as shown below . other tautomers are possible when the compound includes , for example but not limited to , enol , keto , lactamin , amide , imidic acid , amine , and imine groups . tautomers will generally reach an equilibrium state wherein the double bond is resonantly shared between the two bond lengths . unless stereochemistry is explicitly and unambiguously depicted , a structure is intended to include every possible stereoisomer , both pure or in any possible mixture . alternate solid forms are different solid forms than those that may result from practicing the procedures described herein . for example , alternate solid forms may be polymorphs , different kinds of amorphous solid forms , glasses , and the like . non - covalent complexes are complexes that may 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 ratio between the compound and the additional chemical species . examples might include solvates , hydrates , charge transfer complexes , and the like . the following examples provide synthesis methods for forming compounds described herein . one skilled in the art will appreciate that these examples can enable a skilled artisan to synthesize the compounds described herein . in scheme a above , formula 11 was either commercially available or synthesized by different reductive amination methods from formula 10 . one of those methods was published by david j . h . et al ( j . org . chem . 48 : 289 - 294 ( 1983 )). the key step was the coupling for formula 11 with imidazoline which had an appropriate leaving group on the second position to give formula 12 . the leaving group may be methylthiol ( r ═( o ) come ) or sulfuric acid ( r ═ h ). there are also other known coupling procedures known by those skilled in the art or by modifications of known procedures known by those skilled in the art . in scheme b , another method is depicted to synthesize formula 11 from substituted benzoic acid , substituted ester or substituted benzyl alcohol , all of which are commercially available . formula 13 was converted to an ester which can be reduced to formula 14 with lithium aluminum hydride ( lah ) or borane as reagents . conversion of the alcohol , formula 14 , to the azide , formula 15 , may be accomplished by methods such as mitsunobu reaction with diphenylphosphoryl azide in one step , or converting alcohol to a good leaving group which can be replaced with azide anion . denitrogenation of azide to amine was carried out with a phosphine such as triphenyl phosphine . subsequent basic hydrolysis liberated the intermediate to amine . the compounds described herein may also be synthesized by other methods known by those skilled in the art . to a 7 . 08 mmol solution of 2 - chloro - 3 - fluorobenzaldehyde 1 ( 1 . 00 g , commercially available from 3b medical systems , inc .) in 8 . 0 ml of tetrahydrofuran ( thf ) was added 8 . 50 ml of 1 . 0m lithium bis ( trimethylsilyl )- amide via syringe at 0 ° c . the resulting solution was stirred at 0 ° c . for 3 hours . 8 . 50 ml of 1 . 0m lah was added via syringe . three hours later , the reaction mixture was carefully poured onto crushed ice . ammonium chloride ( aq ) and rochelle &# 39 ; s salt ( aq ) were added to this mixture . the aqueous layer was extracted three times with 200 ml of chloroform / isopropanol ( 3 : 1 ). the pooled organic layer was dried over magnesium sulfate . the mixture was filtered , and the solvents were removed under vacuum to give ( 2 - chloro - 3 - fluorophenyl ) methanamine 2 . the weight of the product was 0 . 92 g . a mixture of 0 . 92 g of ( 2 - chloro - 3 - fluorophenyl ) methanamine 2 and 0 . 790 g of 4 , 5 - dihydro - 1h - imidazole - 2 - sulfonic acid ( commercially available from astatech ) in 10 . 0 ml of ethanol was heated in a sealed tube to 90 ° c . for 16 hours . then , the reaction mixture was cooled to room temperature . next , the ethanol was removed under vacuum . the remaining residue was basified with aqueous sodium bicarbonate solution and the ph was adjusted to about 10 with 2m sodium hydroxide . the aqueous layer was extracted three times with 100 ml of chloroform / isopropanol ( 3 : 1 ) the pooled organic layer was dried over magnesium sulfate and the mixture was then filtered . amino - modified silica gel was added to the filtrate and the solvents were removed under vacuum . purification by chromatography on amino - modified silica gel ( 3 . 5 % methanol in dichloromethane ) afforded 0 . 575 g of n -( 2 - chloro - 3 - fluoro - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine 3 as a yellow solid . 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 32 - 7 . 21 ( m , 2h ), 7 . 15 - 7 . 09 ( m , 1h ), 4 . 42 ( s , 2h ), 3 . 48 ( s , 4h ). the following compounds can also be prepared according to example 2 . n -( 2 - difluoromethoxy - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 43 - 7 . 32 ( m , 2h ), 7 . 24 - 7 . 16 ( m , 2h ), 6 . 90 ( t , j = 73 . 8 hz , 1h ), 4 . 43 ( s , 2h ), 3 . 62 ( s , 4h ). n -( 2 , 3 - dimethyl - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 11 - 7 . 04 ( m , 3h ), 4 . 33 ( s , 2h ), 3 . 56 ( s , 4h ). n -( trifluoromethyl - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 76 - 7 . 65 ( m , 2h ), 7 . 58 - 7 . 50 ( m , 2h ), 4 . 61 ( s , 2h ), 3 . 74 ( s , 4h ). n -( trifluoromethoxy - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 51 - 7 . 48 ( m , 1h ), 7 . 39 - 7 . 28 ( m , 3h ), 4 . 45 ( s , 2h ), 3 . 60 ( s , 4h ). n -( 2 - fluoro - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 40 ( t , j = 7 . 5 hz , 1h ), 7 . 28 ( q , j = 7 . 2 hz , 1h ), 7 . 11 - 7 . 03 ( m , 2h ), 4 . 41 ( s , 2h ), 3 . 56 ( s , 4h ). n -( 2 - fluoro - 3 - trifluoromethyl - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 66 ( t , j = 7 . 5 hz , 1h ), 7 . 57 ( q , j = 7 . 5 hz , 1h ), 7 . 30 ( t , j = 7 . 5 hz , 1h ), 4 . 42 ( s , 2h ), 3 . 50 ( s , 4h ). n -( 2 , 3 - dimethoxy - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 05 - 6 . 87 ( m , 3h ), 4 . 34 ( s , 2h ), 3 . 83 ( s , 6h ), 3 . 55 ( s , 4h ). 5 . 0 ml of sulfuric acid ( h 2 so 4 ) was slowly added to a solution of 5 . 0 g of 3 - bromo - 2 - methoxy - benzoic acid 4 in 100 ml of methanol ( meoh ). the resulting solution was heated to reflux overnight . the solution was cooled to room temperature and quenched with sodium bicarbonate to ph 7 . the aqueous layer was extracted several times with ethyl acetate . the combined organic extracts were washed with brine and dried over sodium sulphate . the resulting mixture was filtered . the solvents were evaporated under reduced pressure to afford 5 . 3 g of 3 - bromo - 2 - methoxy - benzoic acid methyl ester 5 . 2 . 4 g of lithium borohydride ( libh 4 ) was added to a solution of 5 . 3 g of 3 - bromo - 2 - methoxy - benzoic acid methyl ester 5 in 200 ml of ether ( et 2 o ) at 0 ° c . after stirring for 5 minutes , 5 ml of methanol was added . the reaction mixture was warmed to room temperature and kept there for 2 . 5 hours . thereafter , 2 . 4 g more of lithium borohydride was added . the reaction mixture was quenched with aluminum chloride . after standard aqueous work up , and silica gel column purification ( hexane / ethyl acetate 2 : 1 ), 4 . 0 g of 3 - bromo - 2 - methoxy - phenyl - methanol 6 was obtained . 6 . 00 g of diphenyl phosphorazidate and 4 . 1 g of 1 , 8 - diazabicyclo [ 5 . 4 . 0 ] undec - 7 - ene were added to 4 . 0 g of 3 - bromo - 2 - methoxy - phenyl - methanol 6 in 100 ml of toluene at 0 ° c . the mixture was stirred at room temperature overnight . the reaction mixture was quenched with aqueous ammonium chloride . the aqueous layer was extracted with ethyl acetate / thf . the pooled organic extracts were washed with brine and dried over magnesium sulfate . the mixture was filtered . the solvents were removed under vacuum . the residue was purified by chromatography on silica gel to give 1 - azidomethyl - 3 - bromo - 2 - methoxy - benzene 7 . 1 . 1 g of potassium hydroxide ( koh ) and 5 . 8 g of triphenyl phosphine ( ph 3 p ) were added to a solution of 1 - azidomethyl - 3 - bromo - 2 - methoxy - benzene 7 in 100 ml of thf and 10 ml of water . the mixture was stirred overnight at room temperature . the mixture was quenched with aqueous concentrated hydrochloride . after standard acid / base aqueous work up , 3 . 9 g of crude 3 - bromo - 2 - methoxy - benzylamine 8 was obtained ( after two steps ). 10 ml of acetic acid ( hoac ) was added to a solution of 3 . 9 g of 3 - bromo - 2 - methoxy - benzylamine 8 and 3 . 1 g of methyl 2 -( methylthio )- 4 , 5 - dihydro - 1h - imidazole - 1 - carboxylate in 100 ml of methanol . the resulting solution was heated to a gentle reflux and refluxed overnight . the solution was cooled to room temperature , quenched with sodium hydroxide and extracted with ethyl acetate . the combined organic extracts were washed with brine and dried over magnesium sulfate . the mixture was then filtered . the solvents were removed under vacuum . the remaining residue was purified by chromatography on silica gel ( 10 % saturated ammonia methanol in dichloromethane ) to give ( 3 - bromo - 2 - methoxy - benzyl - 4 , 5 - dihydro - 1h - imidazol - 2 - yl )- amine 9 . 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 51 ( d , j = 3 hz , 1h ), 7 . 25 - 7 . 29 ( m , 1h ), 6 . 80 ( d , j = 9 hz , 1h ), 4 . 46 ( s , 2h ), 3 . 84 ( s , 4h ), 3 . 63 ( s , 3h ). the following compounds can also be prepared according to example 3 . n -( 2 - chloro - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 51 - 7 . 53 ( m , 1h ), 7 . 28 - 7 . 29 ( m , 1h ), 7 . 14 - 7 . 21 ( m , 2h ), 4 . 59 ( s , 2h ), 3 . 58 ( s , 4h ). n -( 2 - methyl - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 08 - 7 . 12 ( m , 4h ), 4 . 45 ( d , j = 6 hz , 2h ), 3 . 54 ( s , 4h ), 2 . 28 ( s , 3h ). n -( 3 - chloro - 2 - fluoro - benzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine : 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 40 - 7 . 31 ( m , 2h ), 7 . 16 - 67 . 10 ( m , 1h ), 4 . 42 ( s , 2h ), 3 . 56 ( s , 4h ). a mixture of 5 . 32 g of ( 2 , 3 - dichlorophenyl ) methanamine 10 and 4 . 56 g of 4 , 5 - dihydro - 1h - imidazole - 2 - sulfonic acid are mixed in 40 . 0 ml ethanol ( etoh ) and heated in a sealed tube at 90 ° c . for 16 hours . then , the reaction mixture was cooled to room temperature . next , the ethanol was removed under vacuum . the remaining residue was basified with aqueous sodium bicarbonate solution and the ph was adjusted to about 10 with 2m sodium hydroxide . the aqueous layer was extracted three times with 400 ml of chloroform / isopropanol ( 3 : 1 ). the pooled organic layer was dried over magnesium sulfate and the mixture was then filtered . the filtrate was added to amino - modified silica gel ( 4 - 5 % methanol in dichloromethane ) and afforded 3 . 99 g of compound 11 as a yellow solid . 1 h nmr ( 300 mhz , cd 3 od ): δ = 7 . 43 ( dd , j = 7 . 8 , 1 . 8 hz , 1h , 7 . 37 - 7 . 33 m , 1h ), 7 . 26 ( t , j = 7 . 8 hz , 1h ), 4 . 43 ( s , 2h ), 3 . 51 ( s , 4h ). certain compounds described herein were tested for α - adrenergic activity using the receptor selection and amplification technology ( rsat ) assay ( messier et al ., 1995 , pharmacol . toxicol . 76 , pp . 308 - 311 ). cells expressing each of the α 2 adrenergic receptors alone were incubated with the various compounds and a receptor - mediated growth response was measured . the compound &# 39 ; s activity is expressed as its relative efficacy compared to standard full agonist ( see table 1 below ). the compounds described herein activate α 2b and / or α 2c receptors . various concentrations of n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine were administered orally to chung model rats . a model in accordance with kim and chung 1992 , pain 150 , pp 355 - 363 ( chung model ), for chronic pain ( in particular peripheral neuropathy ) involves the surgical ligation of the l5 ( and optionally the l6 ) spinal nerves on one side in experimental animals . rats recovering from the surgery gain weight and display a level of general activity similar to that of normal rats . however , these rats develop abnormalities of the foot , wherein the hindpaw is moderately everted and the toes are held together . more importantly , the hindpaw on the side affected by the surgery appears to become sensitive to pain from low - threshold mechanical stimuli , such as that producing a faint sensation of touch in a human , within about 1 week following surgery . this sensitivity to normally non - painful touch is called “ tactile allodynia ” and lasts for at least two months . the response includes lifting the affected hindpaw to escape from the stimulus , licking the paw and holding it in the air for many seconds . none of these responses is normally seen in the control group . rats are anesthetized before surgery . the surgical site is shaved and prepared either with betadine or novocain . incision is made from the thoracic vertebra xiii down toward the sacrum . muscle tissue is separated from the spinal vertebra ( left side ) at the l4 - s2 levels . the l6 vertebra is located and the transverse process is carefully removed with a small rongeur to expose the l4 - l6 spinal nerves . the l5 and l6 spinal nerves are isolated and tightly ligated with 6 - 0 silk thread . the same procedure is done on the right side as a control , except no ligation of the spinal nerves is performed . a complete hemostasis is confirmed , then the wounds are sutured . a small amount of antibiotic ointment is applied to the incised area , and the rat is transferred to the recovery plastic cage under a regulated heat - temperature lamp . on the day of the experiment , at least seven days after the surgery , typically six rats per test group are administered the test drugs by intraperitoneal ( i . p .) injection or oral gavage . for i . p . injection , the compounds are formulated in d h 2 o and given in a volume of 1 ml / kg body weight using an 18 - gauge , 3 inch gavage needle that is slowly inserted through the esophagus into the stomach . tactile allodynia is measured prior to and 30 minutes after drug administration using von frey hairs that are a series of fine hairs with incremental differences in stiffness . rats are placed in a plastic cage with a wire mesh bottom and allowed to acclimate for approximately 30 minutes . the von frey hairs are applied perpendicularly through the mesh to the mid - plantar region of the rats &# 39 ; hindpaw with sufficient force to cause slight buckling and held for 6 - 8 seconds . the applied force has been calculated to range from 0 . 41 to 15 . 1 grams . if the paw is sharply withdrawn , it is considered a positive response . a normal animal will not respond to stimuli in this range , but a surgically ligated paw will be withdrawn in response to a 1 - 2 gram hair . the 50 % paw withdrawal threshold is determined using the method of dixon , w . j ., ann . rev . pharmacol . toxicol . 20 : 441 - 462 ( 1980 ) hereby incorporated by reference . the post - drug threshold is compared to the pre - drug threshold and the percent reversal of tactile sensitivity is calculated based on a normal threshold of 15 . 1 grams . table 2 below shows the peak allodynia reversal at 30 μg / kg , 100 μg / kg or 300 μg / kg doses . as shown in table 2 , 30 μg / kg oral dosage resulted in 28 % allodynia reversal . the analgesic effect was seen quickly , in about 30 minutes . fig1 shows a peak percent allodynia reversal at 30 minutes followed by a steady decrease to baseline at about 120 minutes . data was acquired from wild type rats administered n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine intraperitoneally ( ip ). rats were split into groups of six and administered 1 mg / kg or 10 mg / kg doses of n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine to assess the sedative effects of the administration of the agent . as can be seen in both fig2 and table 3 , 10 mg / kg had a significant sedative effect on the dosed rats . the ddc model in the rat is a relatively new model of neuropathic pain discovered from clinical treatment of the aids virus . patients taking dideoxycytidine ( ddc ) for aids highly active antiretroviral therapy ( haart ) reported development of painful neuropathies . the experimental animal model in the rat for neuropathic pain by ddc injection manifests symptoms of human patients with causalgia . it is considered predictive of clinical activity against neuropathic pain ( joseph et al , 2004 ). compound n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine was tested in this ddc model of allodynic pain . the compound was administered intraperitoneally to male ddc treated rats . the animals are injected intraperitoneally ( ip ) with 25 mg / kg dideoxycytidine ( ddc ) using a sterile 30 gauge needle . approximately 3 weeks after the ddc injection a painful neuropathy develops causing sensitivity to light touch on the animals &# 39 ; extremities . this neuropathy can last for 2 - 3 months . the animals show no spontaneous pain , only a heightened response to mechanical stimuli ( von frey hair stimulation ). the allodynia is quantitated in the animals receiving ddc injections by stimulation with a series of 8 von frey hairs on the mid planter area of the hind paws in the up - down manner described by dixon ( dixon , 1980 ). male sprague - dawley rats ( charles river , wilmington , mass .) weighing approximately 150 - 300 grams were used for these studies . all experimental animals received n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine or vehicle in a single acute ip dose . in all studies , baseline measurements were taken prior to drug administration and then at 15 , 30 , 60 and 120 minutes post acute ip dosing ( vehicle or n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine ). the % allodynia reversal is calculated as : [( postdrug threshold — predrug threshold )/( 15 - predrug threshold )]× 100 . n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine was dissolved in 42 % dmso ( dimethyl sulfoxide ; sigma , st . louis , mo .) at a concentration of 3 mg / ml . this stock solution was kept frozen at − 20 ° c ., was thawed on the day of the study and diluted in dd - h 2 o to concentrations ranging from 0 . 01 - 0 . 1 mg / ml for ip dosing ( dosing volume = 1 ml / kg ). the vehicle is dd - h 2 o for these studies . data were compiled and analyzed using microsoft excel and / or kaleidagraph . data are expressed as mean ± standard error of the mean . comparisons between drug treated and vehicle groups were made using a two - tailed , 2 - sample , unpaired t - test . comparisons between baselines ( pre - drug ) and post - drug time points were made using a two - tailed , 2 - sample , paired t - test . the ddc model in male rats in a dose - related manner . a maximal effect of 86 % allodynia reversal was measured at 30 minutes post 0 . 1 mg / kg ip n -( 2 , 3 - dichlorobenzyl )- 4 , 5 - dihydro - 1h - imidazol - 2 - amine administration . the minimal statistically significant efficacious dose was 0 . 03 mg / kg , resulting in a 67 % allodynia reversal ( table 4 ). the no - effect dose was 0 . 01 mg / kg . unless otherwise indicated , all numbers expressing quantities of ingredients , properties such as molecular weight , reaction conditions , and so forth used in the specification and claims are to be understood as being modified in all instances by the term “ about .” accordingly , unless indicated to the contrary , the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention . at the very least , and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims , each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques . notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations , the numerical values set forth 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 testing measurements . the terms “ a ,” “ an ,” “ the ” and similar referents used in the context of describing the invention ( especially in the context of the following claims ) are to be construed to cover both the singular and the plural , unless otherwise indicated herein or clearly contradicted by context . recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range . unless otherwise indicated herein , each individual value is incorporated into the specification as if it were individually recited herein . all methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context . the use of any and all examples , or exemplary language ( e . g ., “ such as ”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed . no language in the specification should be construed as indicating any non - claimed element essential to the practice of the invention . groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations . each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein . 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 deemed to contain the group as modified thus fulfilling the written description of all markush groups used in the appended claims . certain embodiments of this invention are described herein , including the best mode known to the inventors for carrying out the invention . of course , variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description . the inventor expects skilled artisans to employ such variations as appropriate , and the inventors intend for the invention to be practiced otherwise than specifically described herein . accordingly , this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law . moreover , any combination of the above - described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context . furthermore , numerous references have been made to patents and printed publications throughout this specification . each of the above - cited references and printed publications are individually incorporated herein by reference in their entirety . in closing , it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention . other modifications that may be employed are within the scope of the invention . thus , by way of example , but not of limitation , alternative configurations of the present invention may be utilized in accordance with the teachings herein . accordingly , the present invention is not limited to that precisely as shown and described .
described herein are compounds for and methods of treating conditions or diseases in a subject by administering to the subject a pharmaceutical composition containing an effective amount of an α - adrenergic modulator . the compounds and methods are also useful for alleviating types of pain , acute , neuropathic and chronic .