the present invention provides tetrahydropyridines which can function as monoamine transporter inhibitors , and therefore have utility as selective serotonin transporter ( sert ) inhibitors . without intending to be bound by any particular structural classification , it is considered that the compounds are generally related to ritalin . these compounds may be administered orally , parenterally , intramuscularly , intravenously , mucosally or by other route . in one embodiment , the route of administration is oral . the dosage regimen of these compounds is well within the purview of those skilled in the art . by way of example , the dose levels may be from 4 micrograms per kilogram of body weight up to 50 milligrams / kg of body weight . by way of another example , the dose may be from 20 micrograms / kg up to 15 mg / kg . other ingredients may be added to the compounds as part of a pharmaceutical composition depending on the dosage form , particular needs of the patient , and method of manufacture , among other things . examples include but are not limited to binders , lubricants , fillers , flavorings , preservatives , colorings , diluents , etc . the selection of particular substances and their compatibilities with the compositions of the present invention can be readily ascertained by those of ordinary skill in the art . details are also provided in u . s . pat . no . 5 , 763 , 455 , which is incorporated herein by reference . threo - methylphenidate ( 1 ) in its racemic form is sold under the trade - name ritalin . this invention describes the potential use of erythro unsaturated structures ( 2 ) related to ritalin as therapeutic agents for neuropsychiatric diseases . we have found that compounds of formula 2 , above , can show favorable biological activity . accordingly , the compounds of the present invention have the following general structure : its enantiomer , threo - diastereomer ( where the structure is as shown except the dashed bond between the hydrogen and the pyridine ring is directed out of the page instead of into the page ) or racemic or diastereomeric mixtures thereof . r can be such that the r - bearing ring is mono -, di - or tri - substituted , and in which the substituents consist of hydrogen , alkyl , alkenyl , alkoxy , halo , nitro , cyano , keto , amino , carboxylate , or a combination thereof . preferably r represents one or more substituents selected from the group consisting of hydrogen , substituted or unsubstituted phenyls , halogens , and adjacent rings which share a side with the r - bearing phenyl group . preferred are substituents such as hydrogen , unsubstituted phenyls , one or more chlorines , bromine , and single adjacent aromatic rings which , together with the r - bearing ring , comprise a naphthyl group . more preferred are r - groups in the para - position of the r - bearing ring , such as an unsubstituted phenyl in the para position on the r - bearing ring ; chlorine substituents at either or both the meta and / or para positions , a bromine substituent at the para position ; and one adjacent ring such that , together with the r - bearing ring , it comprises a para - 2 - naphthyl group . in one embodiment , compound 2 has the structure : while the present invention is illustrated by way of the following examples , the examples are meant only to illustrate particular embodiments of the present invention and are not meant to be limiting in any way . this example describes the synthesis of compounds of the invention . in one embodiment , we synthesized n - boc - tetrahydropyridine ( 4a ) by a c — h activation step . this reaction preferentially forms the eyrthro product with reasonably high diastereo - and enantioselectivity . the synthesis of the tetrahydropyridines was achieved using the general procedure shown above . a variety of methyl aryldiazoacetates were reacted with n - boc - tetrahydropyridine . the diastereoselectivity of the products range from 57 - 82 % de , and the enantioselectivites were 65 - 95 % ee . reaction of methyl aryldiazoacetates with n - boc - tetrahydropyridine to obtain examples of compounds of the invention is shown in table 1 . methyl 4 - bromo - phenyldiazoacetate ( 418 mg , 1 . 6 mmol ) in 2 , 2 - dimethylbutane ( 10 ml ) and toluene ( 4 ml ) was added dropwise over 3 . 5 h using a syringe pump to a solution of rh 2 ( s - dosp ) 4 ( 31 mg , 0 . 016 mmol ) and tert - butyl 5 , 6 - dihydropyridine - 1 ( 2h )- carboxylate ( 150 mg , 0 . 82 mmol ) in 2 , 2 - dimethylbutane ( 10 ml ). after the addition was complete , the reaction was stirred for 1 h at 23 ° c . the solvent was removed under reduced pressure and the residue was redissolved in dcm ( 15 ml ). tfa ( 0 . 3 ml , 4 . 1 mmol ) was added and the reaction was stirred for 16 h . the solvent was removed under reduced pressure and the residue was dissolved in et 2 o ( 30 ml ), extracted with 10 % hcl ( 3 × 15 ml ). the combined aqueous layers were basified to ph 8 - 9 ( nahco 3 , 1m naoh ) and extracted with etoac ( 3 × 30 ml ). the combined etoac layers were washed with water ( 30 ml ) and brine ( 30 ml ), then dried over na 2 so 4 . the solvent was removed under reduced pressure and a diastereoselectivity of 82 % was obtained ( as determined by 1 h nmr of the crude reaction mixture ). the residue was purified by flash chromatography ( sio 2 , et 2 o / pentane / tea = 50 / 50 / 2 ) to give the free amine . the free amine was then dissolved in et 2 o ( 20 ml ) and hcl ( 1m in et 2 o , 5 eq ) was added . the reaction was stirred for 1 h then the solvent was removed under reduced pressure to give the title compound ( 2s , 2 ′ r )- 107 ( 398 mg , 1 . 15 mmol , 70 % yield ) as a white solid . mp = 185 - 186 ° c . ; [ α ]− 74 ° ( c 1 . 08 , chcl 3 ); ftir ( neat ): 2935 , 2728 , 2699 , 1732 , 1486 , 1434 , 1357 , 1254 , 1165 , 1068 , 1011 cm − 1 ; 1 h nmr ( 500 mhz , free amine , cdcl 3 ) 7 . 52 - 7 . 38 ( m , 4h ), 6 . 09 - 6 . 01 ( m , 1h ), 5 . 65 - 5 . 60 ( m , 1h ), 4 . 33 - 4 . 21 ( m , 1h ), 3 . 70 - 3 . 59 m , 4h ), 3 . 06 - 2 . 97 ( m , 1h ), 2 . 92 - 2 . 40 ( m , 1h ), 2 . 63 - 2 . 53 ( m , 1h ), 2 . 27 - 2 . 23 ( m , 1h ); 13 c nmr ( 75 mhz , cdcl 3 ) 170 . 6 ( c ), 132 . 4 ( ch ), 131 . 5 ( c ), 131 . 2 ( ch ), 128 . 2 ( ch ), 123 . 0 ( c ), 121 . 9 ( ch ), 54 . 5 ( ch ), 53 . 1 ( ch ), 52 . 8 ( ch 3 ), 41 . 5 ( ch 2 ), 21 . 6 ( ch 2 ), n — h proton not observed ; lrms ( esi ) m / z ( relative intensity ): 310 ( 100 ); hrms ( esi ) calcd for c 14 h 17 brno 2 ( mh + - hcl ): 310 . 0437 . found : 310 . 0431 . the above compound ( 2s , 2 ′ r )- 107 was converted to the trifluoroacetamide in order to measure the enantiomeric excess . pyridine ( 2 drops ) and tfaa ( 2 drops ) were added to a solution of the free amine ( 5 mg ) in dcm ( 1 ml ). the reaction mixture was stirred for 3 h . the solvent was removed under reduced pressure and the residue was purified by flash chromatography ( sio 2 , etoac / pentane = 1 : 9 ) to give the amide . hplc analysis ( trifluoroacetamide ): ee 95 % ( r , r - whelk column , 3 . 0 % i - proh in hexanes , 0 . 6 ml / min , λ = 254 nm , t r = 23 . 2 , minor ; 31 . 2 , major ). binding of at biogenic amine transporters was determined using striatum and frontal cortex dissected from frozen sprague - dawley rat brains ( pel - freez , rogers , ark .). affinities of analogs at dopamine transport sites were determined by displacement of [ 125 i ] rti - 55 binding in membranes from rat striatum , using 0 . 5 mg ( original wet weight ) of membranes and 10 pm [ 125 i ] rti - 55 . non - specific binding was determined in the presence of 1 μm wf - 23 ( analog 3a ). affinities of analogs at 5 - ht transport sites were determined by displacement of [ 3 h ] paroxetine binding in membranes from rat frontal cortex , using 50 mg ( original wet weight ) of membranes and 0 . 4 nm [ 3 h ] paroxetine . non - specific binding was determined in the presence of 10 μm fluoxetine . binding of analogs at norepinephrine transport sites was determined by displacement of [ 3 h ] nisoxetine binding in membranes from rat forebrain , using 0 . 7 nm [ 3 h ] nisoxetine . non - specific binding was determined in the presence of 1 μm desipramine . potencies were calculated from displacement curves using 7 - 10 concentrations of unlabeled analogs , as analyzed by non - linear curve fitting . because binding of tropanes at dopamine transporters is generally regarded as multiphasic , 3 potencies in inhibiting [ 125 i ] rti - 55 binding are reported as ic 50 values . for [ 3 h ] paroxetine and [ 3 h ] nisoxetine binding assays , k i values were calculated using the cheng - prusoff equation . 4 all data are mean values ± s . e . m . of at least three separate experiments , each of which was conducted in triplicate . the binding affinities to dopamine ( da ), serotonin ( 5 - ht ), and norepinephrine ( ne ) transporters for the series of compounds 4 were determined by standard methods ( fig1 ). the compounds 4 displayed promising biological activity , many having good binding affinities to dopamine and norepinephrine transporters . compounds binding to more than one monoamine transporter have been shown to be effective as antidepressants and so , the tetrahydropyridine derivatives 4 are expected to have similar activity . the foregoing description of the specific embodiments is for the purpose of illustration and is not to be construed as restrictive . from the teachings of the present invention , those skilled in the art will recognize that various modifications and changes may be made without departing from the spirit of the invention .
provided are novel tetrahydropyridine derivatives bearing substituents . these compounds can be used for alleviating the symptoms of cns disorders .