the invention will now be described in more detail by way of example only : the methods used for synthesis of the compounds of the invention are illustrated by the general schemes below . all compounds and intermediates were characterised by nuclear magnetic resonance ( nmr ). the starting materials and reagents used in preparing these compounds are available from commercial suppliers or can be prepared by methods obvious to those skilled in the art . these general schemes are merely illustrative of methods by which the compounds of this invention can be synthesised , and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure . room temperature in the following schemes means the temperature ranging from 20 ° c . to 25 ° c . a solution of phenyltrimethylammonium tribromide ( 50 . 1 g , 133 mmol ) in thf ( 200 ml ) was added dropwise to a stirred solution of 1 -( 3 - nitrophenyl ) ethanone ( 20 g , 121 mmol ) in thf ( 200 ml ) at room temperature . the reaction mixture was allowed to stir at room temperature for 1 h . the white suspension was filtered and the filter cake was washed with thf , the filtrate was evaporated in vacuum to give a yellow oil . the residue was then dissolved in etoac and was washed with water . the organic layer was dried ( mgso 4 ) and evaporated in vacuum to give a yellow oil that solidified into an yellow solid . solid recrystallised from propan - 2 - ol and final product was isolated as an off - white solid . 2 - bromo - 1 -( 3 - nitrophenyl ) ethanone ( 20 . 5 g , 70 % yield ). ( 1 h , 600 mhz , 20 ° c ., cdcl 3 ) δ : 8 . 83 ( 1h , t , j = 2 hz ), 8 . 49 ( 1h , ddd , j = 1 . 0 , 2 . 3 , 8 . 2 hz ), 8 . 34 ( 1h , ddd , j = 1 . 0 , 1 . 7 , 7 . 8 hz ), 7 . 75 ( 1h , t , j = 8 . 1 hz ), 4 . 49 ( 2h , s ). ( 13 c , 150 mhz , 20 ° c ., cdcl 3 ) δ : 189 . 3 , 148 . 5 , 135 . 1 , 134 . 4 , 130 . 2 , 128 . 1 , 123 . 8 , 29 . 9 melting point ( mp ): 90 - 91 ° c . to a solution of 3 - nitroacetophenone ( 1 wt , 1 eq ) in acetic acid ( 10 vol ) is charged over a period of not less than 2 hours , maintaining the temperature below 30 ° c ., a solution of bromine ( 0 . 34 vol , 1 . 08 eq ). after stirring for 1 hour at a temperature between 25 ° c . and 30 ° c ., the reaction is checked for completeness . after reaction completeness cold water ( 12 vol ) is charged , forming a white precipitate . the suspension is stirred for an additional hour at 15 ° c . and then filtered . the cake is washed with water ( 4 . 5 vol ). the product is dried under vacuum at a temperature not more than 45 ° c . until loss on drying & lt ; 1 . 0 %. the isolated yield of the brominated product was around 66 %. this alternative approach may lend itself better to scaling - up . water ( 8 ml ) was added to a stirred suspension of 2 - bromo - 1 -( 3 - nitrophenyl ) ethanone ( 57 . 1 g , 234 mmol ) and formamide ( 116 ml , 2 . 9 mol ). the mixture was allowed to stir at 140 ° c . for 5 h . the brown residue was poured into 300 ml of water and the resulting precipitate was separated by filtration and was washed with a 1m hcl solution . the filtrate was basified with 50 % naoh and the resulting yellow precipitate was separated by filtration and was washed with water . the solid was dried and then recrystallised from propan - 2 - ol . 4 -( 3 - nitrophenyl )- 1h - imidazole ( 7 . 05 g , 44 % yield ). ( 1 h , 600 mhz , 20 ° c ., dmso ) δ : 12 . 37 ( 1h , s , br ), 8 . 58 ( 1h , mt , j = 2 . 0 hz ), 8 . 21 ( 1h , ddd , j = 1 . 0 , 1 . 6 , 7 . 8 hz ), 8 . 02 ( 1h , ddd , j = 1 . 0 , 2 . 5 , 8 . 2 hz ), 7 . 88 ( 1h , dd , j = 1 . 2 hz ), 7 . 79 ( 1h , dd , j = 1 . 1 hz ), 7 . 64 ( 1h , t , j = 8 . 1 hz ) ( 13 c , 150 mhz , 20 ° c ., dmso ) δ : 148 . 4 , 137 . 9 , 136 . 8 , 136 . 6 , 130 . 5 , 130 . 0 , 120 . 5 , 118 . 3 , 114 . 6 in terms of enhancements to this step of the process , it has been found that the use of formamide alone ( i . e . without water ) as suspension medium leads to increased yield , as does increasing the temperature from 140 to 170 ° c . ( up to 80 %). an enhanced protocol is thus as follows : a solution of 2 - bromo - 1 -( 3 - nitrophenyl ) ethanone ( 1 wt , 1 eq ) in formamide ( 10 vol ) is heated to 170 ° c . and stirred over a period of not more than 4 hours . after stirring for 4 hours the reaction is checked for completeness . after reaction completeness the mixture is cooled to r . t ., and water ( 15 vol ) is charged . the suspension is filtered and the cake is washed with 3n hcl ( 2 vol ) and the mother liquor filtered again . adjust the solution ph to 14 by addition of 50 % naoh ( 2 vol ), maintaining the mixture temperature between 0 ° c . and 5 ° c . after stirring the suspension at 0 / 5 ° c . for nlt 30 minutes , filter and wash the cake with water ( 5 vol ). the product is dried under vacuum at a temperature not more than 45 ° c . until loss on drying & lt ; 1 . 0 %. a solution of n - methylcyclopentanamine ( 10 g , 101 mmol ) in thf ( 126 ml ) was added dropwise to phosgene solution ( 63 . 7 ml , 121 mmol , 20 % in toluene ) at 0 ° c . to give a white suspension . the reaction mixture was allowed to stir at room temperature for 1 h . the solution was poured into ice . the organic layer was diluted with etoac , was separated washed with 1m hcl , dried ( mgso 4 ) and evaporated in vacuum to give a clear mobile oil . cyclopentyl ( methyl ) carbamic chloride ( 13 . 1 g , 80 % yield ). ( 1 h , 600 mhz , 20 ° c ., cdcl 3 ) δ : 4 . 65 ( 1h , m ), 3 . 0 , 2 . 93 ( 3h , 2 singlets ), 1 . 92 ( 2h , m ), 1 . 73 ( 2h , m ), 1 . 59 ( 4h , m ) ( 13 c , 150 mhz , 20 ° c ., cdcl 3 ) δ : 149 . 7 , 149 . 3 , 61 . 1 , 59 . 5 , 33 . 1 , 31 . 1 , 28 . 8 , 28 . 5 , 24 . 0 the carbamoylation step can also be carried out using triphosgene / dcm and sodium carbonate , as follows : a solution of triphosgene ( 1 . 2 wt , 0 . 4 eq ) in dcm ( 10 vol ) is cooled to 0 / 5 ° c . and stirred over a period of not more than 10 minutes . a solution of n - methylcyclopentylamine ( 1 wt , 1 eq ) in dcm ( 5 vol ) is charged maintaining the reaction temperature below 10 ° c . after the amine solution addition charge na2co3 ( 2 . 14 wt , 2 eq ) and allow to warm to r . t . after stirring for 2 hours the reaction mixture is filtered and the cake is washed with dcm ( 1 vol ). after concentration to dryness yellow oil is obtained and used as - is without further treatment . sodium hydride ( 5 . 1 g , 127 mmol , 60 % dispersion in mineral oil ) was added portionwise to a stirred suspension of 4 -( 3 - nitrophenyl )- 1h - imidazole ( 20 g , 106 mmol ) in thf ( 500 ml ) at 0 ° c . the yellow suspension turned into a deep red suspension . the mixture was allowed to stir at room temperature for 30 minutes before adding a solution of cyclopentyl ( methyl ) carbamic chloride ( 25 . 6 g , 159 mmol ) in thf ( 26 ml ). the suspension was then allowed to stir at room temperature for 2 h . water was added at 0 ° c . and the thf was evaporated . the organic residue was extracted with dcm , the organic layer was separated , dried ( mgso 4 ) and evaporated in vacuum to give a beige solid . the solid was triturated with propan - 2 - ol . n - cyclopentyl - n - methyl - 4 -( 3 - nitrophenyl )- 1h - imidazole - 1 - carboxamide ( 25 . 18 g , 76 % yield ). ( 1 h , 600 mhz , 20 ° c ., cdcl3 ) δ : 8 . 63 ( 1h , mt , j = 2 . 0 hz ), 8 . 16 ( 1h , ddd , j = 1 . 0 , 1 . 6 , 7 . 8 hz ), 8 . 14 ( 1h , ddd , j = 1 . 0 , 2 . 3 , 8 . 2 hz ), 7 . 96 ( 1h , d , j = 1 . 3 hz ), 7 . 65 ( 1h , dd , j = 1 . 3 hz ), 7 . 58 ( 1h , t , j = 8 . 1 hz ), 4 . 45 ( 1h , m ), 3 . 03 ( 3h , s ), 1 . 98 ( 2h , m ), 1 . 80 ( 2h , m ), 1 . 73 ( 2h , m ), 1 . 66 ( 2h , m ) ( 13 c , 150 mhz , 20 ° c ., cdcl3 ) δ : 151 . 3 , 148 . 7 , 140 . 1 , 137 . 3 , 134 . 9 , 130 . 9 , 129 . 7 , 122 . 1 , 119 . 9 , 114 . 6 , 59 . 4 , 31 . 3 , 28 . 9 , 24 . 4 a mixture of ethyl acetate ( 160 ml ) and etoh ( 160 ml ) was added to wet pd / c ( 0 . 846 g , 0 . 795 mmol , 10 %) under an atmosphere of argon . to this was added n - cyclopentyl - n - methyl - 4 -( 3 - nitrophenyl )- 1h - imidazole - 1 - carboxamide ( 5 g , 15 . 91 mmol ) portionwise and the suspension was allowed to stir at room temperature overnight under an atmosphere of hydrogen . the mixture was flushed with argon and filtered through celite and the celite was washed with dcm . the filtrate was evaporated in vacuum to give a clear oil that solidified into a colourless solid . the solid was recrystallised from propan - 2 - ol . 4 -( 3 - aminophenyl )- n - cyclopentyl - n - methyl - 1h - imidazole - 1 - carboxamide ( 3 . 62 g , 80 % yield ). ( 1 h , 600 mhz , 20 ° c ., dmso ) δ : 8 . 06 ( 1h , d , j = 1 . 3 hz ), 7 . 77 ( 1h , d , j = 1 . 1 hz ), 7 . 08 ( 1h , t , j = 1 . 9 hz ), 7 . 0 ( 1h , t , j = 7 . 8 hz ), 6 . 98 ( 1h , md , j = 7 . 7 hz ), 6 . 45 ( 1h , ddd , j = 1 . 2 , 2 . 3 , 7 . 7 hz ), 5 . 07 ( 2h , s ), 4 . 37 ( 1h , m ), 2 . 92 ( 3h , s ), 1 . 87 ( 2h , m ), 1 . 68 ( 4h , m ), 1 . 53 ( 2h , m ) ( 13 c , 150 mhz , 20 ° c ., dmso ) δ : 151 . 2 , 148 . 8 , 141 . 4 , 137 . 3 , 133 . 8 , 129 . 0 , 113 . 7 , 112 . 9 , 112 . 8 , 110 . 4 , 58 . 4 , 31 . 2 , 28 . 2 , 24 . 0 in an alternative embodiment , the aniline derivative product of this step can be used in the subsequent step without purification , i . e . such that this and the subsequent step can be telescoped . potassium cyanate ( 0 . 445 g , 5 . 49 mmol ) was added portionwise to a stirred solution of 4 -( 3 - aminophenyl )- n - cyclopentyl - n - methyl - 1h - imidazole - 1 - carboxamide ( 1 . 3 g , 4 . 57 mmol ) in a mixture of 2n hydrogen chloride ( 2 . 286 ml , 4 . 57 mmol ) in water ( 4 ml ) at 0 ° c . the mixture was allowed to stir at room temperature for 24 h . potassium cyanate ( 0 . 220 g , 2 . 74 mmol ) was added and the mixture was allowed to stir at room temperature for another night . water was added and the organic layer was diluted with a mixture of dcm / propan - 2 - ol 7 : 3 . the organic layer was separated and was washed with a 1n hcl aqueous solution . the organic layer was separated , dried ( mgso 4 ) and evaporated in vacuum to give a colourless foam . the product was purified by column chromatography ( silica , dcm / meoh 5 %, 10 %) and was isolated as a colourless solid . the solid was recrystallised from etoh at 0 ° c . n - cyclopentyl - n - methyl - 4 -( 3 - ureidophenyl )- 1h - imidazole - 1 - carboxamide ( 0 . 403 g , 26 % yield ). the compounds of the invention above were characterised by melting point and nmr as detailed below . nmr spectra were recorded on a bruker 600 mhz avance iii spectrometer with solvent used as internal standard . 13c spectra were recorded at 150 mhz and 1h spectra were recorded at 600 mhz . data are reported in the following order : approximate chemical shift ( ppm ), number of protons , multiplicity ( br , broad ; d , doublet ; m , multiplet ; s , singlet , t ; triplet ) and coupling constant ( hz ). ( 13 c , 150 mhz , 20 ° c ., dmso ) δ : 156 , 151 . 1 , 140 . 9 , 140 . 8 , 137 . 5 , 133 . 7 , 128 . 9 , 117 . 9 , 116 . 6 , 114 . 2 , 114 . 2 , 58 . 4 , 31 . 2 , 28 . 2 , 24 . ( 1 h , 600 mhz , 20 ° c ., dmso ) δ : 8 . 55 ( 1h , s ), 8 . 09 ( 1h , d , j = 1 . 2 hz ), 7 . 86 ( 1h , d , j = 1 . 2 hz ), 7 . 85 ( 1h , t , j = 1 . 8 hz ), 7 . 35 ( 1h , md ), 7 . 34 ( 1h , md ), 7 . 22 ( 1h , t , j = 7 . 8 hz ), 5 . 84 ( 2h , s ), 4 . 36 ( 1h , m ), 2 . 93 ( 3h , s ), 1 . 87 ( 2h , m ), 1 . 69 ( 4h , m ), 1 . 54 ( 2h , m ). an enhancement to this final step ( urea formation on the phenyl ring ) consists of using acetic acid as solvent for the 4 -( 3 - aminophenyl )- n - cyclopentyl - n - methyl - 1h - imidazole - 1 - carboxamide instead of water . this leads to an improvement in yield ( around 78 %), and an improved isolation protocol . the enhanced step may be described as follows : 4 -( 3 - aminophenyl )- n - cyclopentyl - n - methyl - 1h - imidazole - 1 - carboxamide is dissolved in acoh ( 8 . 8 vol ) at room temperature . to the resulting solution at room temperature is added a solution of potassium cyanate ( 0 . 65 wt , 2 . 5 eq ) in water ( 0 . 9 vol ). the resulting solution is stirred at room temperature until reaction completion ( starting material & lt ; 0 . 1 %). within 1 h , the precipitation of the urea product occurred . to the resulting slurry is added water ( 5 vol ), and more solid crashes out . the beige suspension is then aged for 1 h at room temperature , and filtered . the beige solid is washed with water ( 10 vol ), dried under vacuum oven until loss on drying & lt ; 1 . 5 %. in case this enhanced step ( using acetic acid ) leads to an n - acetylated aniline impurity , a recrystallisation may be performed . this may be as follows : to a solution of the urea product ( 1 wt ) in acetic acid ( 5 vol ) at room temperature was added drop wise water ( 5 vol ) over 30 minutes . after having seeded , water ( 2 vol ) was added and the slurry was aged at room temperature for 1 h . the slurry is cooled to 10 ° c ., stirred at 10 ° c . for at least 1 h and filtered . the off white solid is washed with a 9 : 1 mixture of water / acetic acid ( 2 vol ), water ( 10 vol ), dried in a vacuum oven at 55 ° c . the off white solid ( 0 . 82 wt ) is then dissolved in acetic acid ( 3 . 96 vol ) at room temperature and water ( 4 . 1 vol ) was added drop wise over 30 minutes . to the solution was then added seed , followed by water ( 1 . 6 vol ). the resulting slurry was stirred at room temperature for at least 1 h and then cooled to 10 ° c . after aging the slurry at 10 ° c . for at least 1 h , the solid is filtered , washed with a 9 : 1 mixture of water / acetic acid ( 1 . 6 vol ), water ( 10 vol ), dried in a vacuum oven at 55 ° c . until loss on drying is & lt ; 1 . 5 %. in vivo testing was performed according to the protocol described below . brh ( brain homogenate ) indicates inhibition in central nervous tissue , in this case , brain , and lvh ( liver homogenate ) indicates inhibition in peripheral tissue , in this case , liver . the controls were the reaction mix minus the test compounds . therefore , a low value for the test compound indicates a strong inhibitor . a value of 100 indicates that no measurable inhibition took place . the animals used for experiments were male nmri mice ( weighing 27 - 44 g ) obtained from interfauna ibérica ( spain ). mice were kept 5 per cage , under controlled environmental conditions ( 12 hr light / dark cycle and room temperature 22 ± 1 ° c .). food and tap water were allowed ad libitum and the experiments were all carried out during daylight hours . animals were administered 30 mg / kg or 3 mg / kg compound of the invention or comparator compounds via oral route ( 8 ml / kg ; compound suspended in 0 . 5 % carboxymethylcellulose ( cmc ) or solubilized in water ) or vehicle ( controls ) using animal feeding stainless steel curve needles ( perfectum , u . s . a .). fifteen minutes before sacrifice animal were anesthetized with pentobarbital 60 mg / kg administered intraperitoneally . a fragment of liver , left lung lobe and brain without cerebellum were removed and put in plastic vials containing membrane buffer ( 3 mm mgcl 2 , 1 mm edta , 50 mm tris hcl ph 7 . 4 ). tissues were stored at − 30 ° c . until analysis . animals were always fasted overnight before administration of compounds except for time points of & gt ; 18 h , where food was removed on the morning of day of administration and the compound was administered in the afternoon of the same day . animals were then given water but nothing else . all animal procedures were conducted in strict adherence to the european directive for protection of vertebrate animals used for experimental and other scientific purposes ( 86 / 609cee ) and portuguese legislation ( decreto - lei 129 / 92 , portarias 1005 / 92 e 1131 / 97 ). the number of animals used was the minimum possible in compliance with current regulations and scientific integrity anandamide [ ethanolamine - 1 - 3 h -] ( 40 - 60 ci / mmol ) was obtained from american radiochemicals . all other reagents were obtained from sigma - aldrich . optiphase supermix was obtained from perkin elmer and activated charcoal were obtained from sigma - aldrich . tissues were thawed on ice and were homogenized in 10 volumes of membrane buffer ( 3 mm mgcl 2 , 1 mm edta , 50 mm tris hcl ph 7 . 4 ) with either potter - elvejhem ( brains − 8 strokes at 500 rpm ) or heidolph diax ( livers — 2 strokes at position 5 for 20 sec with 30 sec pauses ). total protein in tissues was determined with the biorad protein assay ( biorad ) using a standard curve of bsa ( 50 - 250 μg / ml ). reaction mix ( total volume of 200 μl ) contained : 2 μm aea ( 2 μm aea + 5 nm 3 h - aea ), 0 . 1 % fatty acid free bsa , 15 μg ( brain ), 5 μg ( liver ) or 50 μg ( lung ) protein , in 1 mm edta , 10 mm tris ph 7 . 6 . after a 15 min pre - incubation period at 37 ° c ., reaction was started by the addition of the substrate solution ( cold aea + radiolabelled aea + bsa ). reaction was carried out for 10 min ( brain and lung ) or 7 min ( liver ) before termination by the addition of 400 μl activated charcoal suspension ( 8 g charcoal in 32 ml 0 . 5 m hcl in continuous agitation ). after a 30 min incubation period at room temperature with agitation , charcoal was sedimented by centrifugation in microfuge ( 10 min at 13000 rpm ). 200 μl of the supernatant were added to 800 μl optiphase supermix scintillation cocktail previously distributed in 24 - well plates . counts per minute ( cpm ) were determined in a microbetatrilux scintillation counter . the percentage of remaining enzymatic activity was calculated with respect to controls and after blank subtraction . the test compounds were given in increasing doses ( 10 , 3 , 1 , 0 . 3 , 0 . 03 and 0 . 01 mg / kg ) to the animals and at 8 h post - administration faah activity was determined according to the aforementioned in - vivo protocol , then ed 50 values were calculated by “ prisma ” software with 95 % of confidence intervals . stability of the test compounds was performed in mlm ( mouse liver microsomes ) or hlm ( human liver microsomes ) in the presence and in the absence of nadph . the stability was measured using the incubation mixture ( 100 μl total volume ) contained lmg / ml total protein , mgcl 2 5 mm and 50 mm k - phosphate buffer . samples were incubated in the presence and in the absence of nadph 1 mm . reactions were pre - incubated 5 min and the reaction initiated with the compound under test ( 504 for hlm and 5004 for mlm ). samples were incubated for 60 min in a shaking water bath at 37 ° c . the reaction was stopped by adding 100 μl of acetonitrile . samples were then centrifuged , filtered and supernatant injected in hlpc - msd . test compounds were dissolved in dmso and the final concentration of dmso in the reaction was below 0 . 5 % ( v / v ). at to acetonitrile was added before adding the compound . all experiments were performed with samples in duplicate . compound 1 ( n - cyclopentyl - n - methyl - 4 -( 3 - ureidophenyl )- 1h - imidazole - 1 - carboxamide ; also referred to as the compound of formula a , above ) was tested . also , two comparator compounds were tested which are disclosed in wo 2010 / 074588 . these are as follows : comparator compound 1 is structurally similar to compound 1 , although there are clear differences between these compounds . comparator compound 2 is also structurally similar to compound 1 but , again , there are clear differences between these two compounds . as can be seen from the above table , compound 1 is the most potent compound in terms of faah inhibition in the liver . in particular , compound 1 is much more potent than comparator compound 1 . peripheral selectivity can be calculated by dividing the faah activity in the liver by the faah activity in the brain . when doing this , a lower number shows a compound is peripherally more selective . the results are given in the table below : these results show that compound 1 is the most peripherally selective compound by more than a factor of 2 . further , compound 1 is much more peripherally selective than comparator compound 1 . additional data relating to the activity of faah at various concentrations for compound 1 and comparator compound 2 are given in the table below : as can be seen , at all doses , the faah activity is much lower following administration of compound 1 compared to comparator compound 2 . in particular , at 0 . 1 mg / kg at 8 hours post - dose , the faah activity is significantly lower for compound 1 compared to comparator compound 2 . this shows that compound 1 is significantly more potent than comparator compound 2 . at 0 . 1 mg / kg , compound 1 is more than 10 - fold more potent than comparator compound 2 . this is a surprisingly big difference in potency . this data is also evidence that compound 1 is metabolically stable since , when conducting inhibition experiments in vivo , the metabolic stability of the compound will also play a role in the level of inhibition and the length of time over which inhibition takes place . the table below shows faah inhibition ed 50 data ( median effective dose , the dose of compound required to produce 50 % inhibition of faah in liver ) of the compounds after p . o . administration in mouse . confidence intervals ( 95 %) are included . the below table shows the metabolic stability of compound 1 and comparator compound 2 . the stability data are given as % of remaining compound after 1 h exposure to mlm or hlm . 100 % means no metabolic reaction at all and 0 % corresponds to full enzymatic degradation . “ cyp -” refers to the absence of cofactor ( nadph ) which is essential for cyp metabolic reactions . therefore “ cyp -” can be regarded as control value . “ cyp +” refers to the presence of cofactor and the enzymatic degradation may take place according to the stability of the test compound . as can be seen , compound 1 is more stable than comparator compound 2 in both mlm and hlm . anandamide [ ethanolamine - 1 - 3 h -] was obtained from american radiochemicals — with a specific activity of 60 ci / mmol . all other reagents were obtained from sigma - aldrich . optiphase supermix was obtained from perkin elmer and activated charcoal was obtained from sigma . frozen brains from 4 wistar rats were homogenized in 20 ml 1 mm mgcl 2 , 20 mm hepes ( 4 -( 2 - hydroxyethyl )- 1 - piperazineethanesulfonic acid ) ph 7 . 0 with potter - elvejhem ( 8 strokes at 500 rpm ). homogenates were centrifuged for 20 min at 36000 g at 4 ° c . ( beckman , 70ti rotor ). pellets were resuspended in 15 ml of the same buffer and centrifuged under the same conditions . pellets were resuspended in 15 ml of the same buffer and incubated for 15 min at 37 ° c . after which they were centrifuged for 20 min at 36000 g at 4 ° c . each pellet was then resuspended in 10 ml 3 mm mgcl 2 , 1 mm edta ( ethylenediaminetetraacetic acid ), 50 mm tris ( 2 - amino - 2 - hydroxymethyl - propane - 1 , 3 - diol ) ph 7 . 4 and protein determined with the biorad protein assay ( biorad ) using a standard curve of bsa ( bovine serum albumin ) ( 50 - 250 μg / ml ). reaction mix ( total volume of 200 μl ) contained : 2 μm aea ( 2 μm aea + 5 nm 3 h - aea ), 0 . 1 % fatty acid free bsa , 5 or 10 μg protein , in 1 mm edta , 10 mm tris ph 7 . 6 and compound 1 at various concentrations . stock solution ( 10 mm ) was prepared in 100 % dmso ( dimethyl sulfoxide ) and the dmso concentration in the assay will be 0 . 1 %. after a 15 min preincubation period at 37 ° c ., reaction was started by the addition of the substrate solution ( cold aea + radiolabelled aea + bsa ). reaction was carried out for 10 min before termination by the addition of 400 μl activated charcoal suspension ( 8 g charcoal in 32 ml 0 . 5 m hcl in continuous agitation ). after a 30 min incubation period at room temperature with agitation , charcoal is sedimented by centrifugation in microfuge ( 10 min at 15000 g ). 200 μl of the supernatant was added to 800 μl optiphase supermix scintillation cocktail previously distributed in 24 - well plates . counts per minute ( cpm ) or disintegrations per minute ( dpm ) were determined in a microbetatrilux scintillation counter . in each assay blanks ( no protein ) and controls ( no compound ) were present . raw data acquisition was performed with the software “ microbeta trilux windows workstation version 4 . 01 ”. data analysis was performed using prism 5 for windows software , version 5 . 02 ( graphpad software inc ., san diego , calif .). ic 50 value of compound 1 was determined by fitting experimental data to the log ( inhibitor ) vs normalized response — variable slope equation : using this protocol , compound 1 was determined to have an ic 50 of 27 nm . as can be seen from all the results above , compound 1 is significantly more potent , more peripherally selective and / or more metabolically stable than either of comparator compounds 1 and 2 . to a solution of cyclopentylamine ( 3 ml , 30 . 3 mmol ) in thf ( 20 ml ) at 0 ° c . were added respectively 3m sodium hydroxide ( 15 . 15 ml , 45 . 5 mmol ) and ethyl chloroformate ( 3 . 47 ml , 36 . 4 mmol ). the resulting biphasic mixture was stirred for 4 h at room temperature . the reaction mixture was diluted with mtbe ( 30 ml ) and ammonium hydroxide ( 5 ml ). the resulting mixture was stirred at room temperature for 10 minutes and then allowed to separate . the organic layer was washed with water , 0 . 5m hcl , dried over na 2 so 4 , filtered . the filtrate was concentrated under reduced pressure . ethyl cyclopentylcarbamate ( 4 . 35 g ) was obtained as colorless oil in 95 % yield and was used in the next step without further purification this reaction proceeds very well . the yield and the quality of the product were high . the reduction of carbamates to the corresponding methyl amine is well known in general . this reduction requires usually the use of an excess of lithium aluminum hydride ( lah ) in thf at reflux . however , the use of lithium aluminum hydride in large scale may require a more complex work up . therefore , the fieser work - up was used ( for x g of lah , use x ml of water , x ml of 15 to 25 % naoh then followed by 3x ml , of water ) which is safer and easier to handle . a first attempt was successfully performed on the t - butyl carbamate using lah , fieser work up followed by formation of the hydrochloride salt resulting from the addition of concentrated hcl . the n - methyl cyclopentylamine hydrochloride was obtained in 63 % after isolation . the quality and the yield resulting from this first attempt led to a repeat using the ethyl carbamate , which led to a molar yield of 83 %, and a quality range : & gt ; 98 % by nmr . to a suspension of lah ( 2 , 414 g , 63 . 6 mmol , 5 eq ) in thf ( 20 ml ) at room temperature under nitrogen was added a solution of ethyl cyclopentyl carbamate ( 2 g , 12 . 72 mmol ) in thf ( 8 ml ) over 20 minutes . note : gas evolution . the dropping funnel was rinsed with thf ( 2 ml ). the reaction mixture was heated to 65 ° c . ( internal temperature , reflux ) during 6 h . the suspension was cooled to 0 ° c . ( water - ice bath ). the suspension was diluted with mtbe ( 30 ml ). to the suspension were added dropwise 2 . 4 ml of water ( strong gas evolution and exothermic reaction was observed ), dropwise 3 . 6 ml of 10 % naoh ( good stirring is necessary ) and finally dropwise 7 . 2 ml of water . the resulting slurry was warmed to room temperature and stirred for 30 minutes at room temperature . to the white suspension was added mgso4 ( 10 g ). the resulting slurry was stirred for 10 minutes , then filtered . the solid was washed with mtbe ( 20 ml ). to the combined filtrates were added conc hcl ( 1 , 272 ml , 15 . 27 mmol , 1 . 2 eq ). the resulting mixture was stirred overnight at room temperature and then concentrated to dryness . the residue was dissolved in propan - 2 - ol ( 20 ml ) then concentrated to 2 vol ( 4 ml ). to the resulting solution was then added mtbe ( l2 ml ). a white crystalline solid crushed out . the slurry was stirred at room temperature for 1 h and then the solid was collected , washed with mtbe ( 4 ml ), dried in a vacuum oven at 50 ° c . for 4 h . a first crop of white needles ( 884 mg ) was obtained . the combined mother liquor and washes were concentrated to dryness . isopropyl acetate ( iproac ) was added to the residue , white crystals started to appear . more iproac was added but some solids were crusted on the flask wall . some dcm was added and clear solid was obtained . the dcm was removed and a white solid was crashed out , filtered and washed with iproac . the white crystalline solid was dried in a vacuum oven at 50 ° c . for 4 h . a second crop of white needles ( 547 mg ) was obtained . the n - methyl cyclopentylamine hydrochloride was obtained as white needles in 83 % molar yield . the use of cyclopentanone and n - methylamine hydrochloride in presence of a catalytic amount of triethylamine and pd / c under hydrogen pressure in methanol at 65 ° c . was found to give the best results . under these conditions , the n - methylcyclopentylamine hydrochloride was isolated as a white solid in 49 % yield . the source of palladium and reagent equivalents were tested to improve the yield and the quality of the product ( removal of methylamine hydrochloride ). using pd / c ( jm , 5r39 paste ) with a slight excess of methyl amine hydrochloride ( 1 . 1 eq ) it was possible to improve the yield up to 69 %. note that the removal of methyl amine hydrochloride is feasible by suspending the n - methylcyclopentylamine hydrochloride in dichloromethane in the presence of sodium carbonate followed by distillation . no methylamine is detected in the final product . to palladium 5 % on carbon , 5r 39 paste ( 0 . 75 g , 0 . 176 mmol , 0 . 001 eq ) were added successively meoh ( 105 ml ), methylamine hydrochloride ( 13 . 24 g , 196 mmol ), cyclopentanone ( 15 . 77 ml , 178 mmol ) and finally triethylamine ( 0 . 621 ml , 4 . 46 mmol ). the resulting slurry was placed into an autoclave and was charged with 5 bar hydrogen . the autoclave was heated at 65 ° c . and stirred overnight . the reaction mixture was cooled slowly and tlc ( eluent pe / ethyl acetate 8 : 2 , dip permanganate ) showed no starting material . the black slurry was filtered through celite and washed with meoh ( 10 ml ). the methanol was removed and replaced by isopropanol ( 60 ml ). the solution was concentrated to 2 vol and isopropyl ether ( 60 ml ) was added . the resulting mixture was stirred at room temperature . a white solid was observed and then the slurry was stirred at 0 ° c . for 1 h , then filtered . the solid was washed with isopropyl ether / propan - 2 - ol 9 : 1 ( 30 ml ), dried in a vacuum oven overnight . a white crystalline solid of n - methylcyclopentylamine hcl ( 16 . 9 g , 69 . 5 % yield ) was obtained .
a compound having the following structure : or a pharmaceutically acceptable salt or derivative thereof . the compound may be used in the treatment or prevention of a disorder selected from appetite regulation , obesity , metabolic disorders , cachexia , anorexia , pain , inflammation , neurotoxicity , neurotrauma , stroke , multiple sclerosis , spinal cord injury , parkinson &# 39 ; s disease , levodopa - induced dyskinesia , huntington &# 39 ; s disease , gilles de la tourette &# 39 ; s syndrome , tardive dyskinesia , dystonia , amyotrophic lateral sclerosis , alzheimer &# 39 ; s disease , epilepsy , schizophrenia , anxiety , depression , insomnia , nausea , emesis , alcohol disorders , drug addictions such as opiates , nicotine , cocaine , alcohol and psychostimulants , hypertension , circulatory shock , myocardial reperfusion injury , atherosclerosis , asthma , glaucoma , retinopathy , cancer , inflammatory bowel disease , acute and chronic liver disease such as hepatitis and liver cirrhosis , arthritis and osteoporosis .