it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed . as used herein , the use of the singular includes the plural unless specifically stated otherwise . it will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers , such that the compounds may exist in enantiomeric as well as in diastereomeric forms . unless it is specifically noted otherwise , the scope of the present invention includes all enantiomers , diastereomers and racemic mixtures . some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases , and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention . the present invention includes all pharmaceutically acceptable isotopically enriched compounds . any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 h ( or d ) in place of protium 1 h ( or h ) or use of 13 c enriched material in place of 12 c and the like . similar substitutions can be employed for n , o and s . the use of isotopes may assist in analytical as well as therapeutic aspects of the invention . for example , use of deuterium may increase the in vivo half - life by altering the metabolism ( rate ) of the compounds of the invention . these compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents . the following examples are for illustrative purposes only and are not intended , nor should they be construed as limiting the invention in any manner . those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention . as will be evident to those skilled in the art , individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner . for example , in the case of diasteroisomeric isomers , chromatographic separation may be employed . compound names were generated with acd version 8 . in general , characterization of the compounds is performed according to the following methods : proton nuclear magnetic resonance ( 1 h nmr ) spectra were recorded on a varian 300 or 600 mhz spectrometer in deuterated solvent . chemical shifts were reported as δ ( delta ) values in parts per million ( ppm ) relative to tetramethylsilane ( tms ) as an internal standard ( 0 . 00 ppm ) and multiplicities were reported as s , singlet ; d , doublet ; t , triplet ; q , quartet ; m , multiplet ; br , broad . data were reported in the following format : chemical shift ( multiplicity , coupling constant ( s ) j in hertz ( hz ), integrated intensity ). all the reagents , solvents , catalysts for which the synthesis is not described are purchased from chemical vendors such as sigma aldrich , fluka , bio - blocks , combi - blocks , tci , vwr , lancaster , oakwood , trans world chemical , alfa , fisher , maybridge , frontier , matrix , ukrorgsynth , toronto , ryan scientific , silicycle , anaspec , syn chem , chem - impex , mic - scientific , ltd ; however some known intermediates , were prepared according to published procedures . usually the compounds of the invention were purified by column chromatography ( auto - column ) on an teledyne - isco combiflash with a silica column , unless noted otherwise . a solution of 100 mg of 4 -{ 5 -[( 3 - chlorophenyl )( 4 - ethylphenoxy ) methyl ]- 1 , 2 , 4 - oxadiazol - 3 - yl } benzaldehyde ), 3 - azetidinecarboxylic acid ( 24 . 0 mg , 1 . 0 eq ), and tea ( 0 . 1 ml , 0 . 7 mmol ) was mixed with meoh ( 10 ml ). then hoac ( 5 drops ) and nacnbh 3 ( 15 . 0 mg , 1 . 0 eq ) in meoh / ch 2 cl 2 were added and gave compound 1 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 17 ( t , j = 7 . 62 hz , 3h ) 2 . 56 ( q , j = 7 . 42 hz , 2h ) 3 . 36 ( br . s ., 1h ) 3 . 77 - 4 . 22 ( m , 6h ) 6 . 44 ( s , 1h ) 6 . 92 ( d , j = 8 . 79 hz , 2h ) 7 . 08 ( d , j = 8 . 50 hz , 2h ) 7 . 33 ( d , j = 4 . 98 hz , 2h ) 7 . 50 ( d , j = 7 . 62 hz , 3h ) 7 . 65 ( s , 1h ) 8 . 06 ( d , j = 8 . 20 hz , 2h ). compounds 2 through 6 were prepared in a similar manner to the method described in example 1 . the starting materials and the results are tabulated below in table 1 for each case . compounds were synthesized and tested for s1p1 activity using the gtp γ 35 s binding assay . these compounds may be assessed for their ability to activate or block activation of the human s1p1 receptor in cells stably expressing the s1p1 receptor . gtp γ 35 s binding was measured in the medium containing ( mm ) hepes 25 , ph 7 . 4 , mgcl 2 10 , nacl 100 , dithitothreitol 0 . 5 , digitonin 0 . 003 %, 0 . 2 nm gtp γ 35 s , and 5 μg membrane protein in a volume of 150 μl . test compounds were included in the concentration range from 0 . 08 to 5 , 000 nm unless indicated otherwise . membranes were incubated with 100 μm 5 ′- adenylylimmidodiphosphate for 30 min , and subsequently with 10 μm gdp for 10 min on ice . drug solutions and membrane were mixed , and then reactions were initiated by adding gtp γ 35 s and continued for 30 min at 25 ° c . reaction mixtures were filtered over whatman gf / b filters under vacuum , and washed three times with 3 ml of ice - cold buffer ( hepes 25 , ph7 . 4 , mgcl 2 10 and nacl - 100 ). filters were dried and mixed with scintillant , and counted for 35 s activity using a β - counter . agonist - induced gtp γ 35 s binding was obtained by subtracting that in the absence of agonist . binding data were analyzed using a non - linear regression method . in case of antagonist assay , the reaction mixture contained 10 nm s1p in the presence of test antagonist at concentrations ranging from 0 . 08 to 5000 nm . table 2 shows activity potency : s1p1 receptor from gtp γ 35 s : nm , ( ec 50 ). activity potency : s1p1 receptor from gtp γ 35 s : nm , ( ec 50 ),
the present invention relates to novel azetidine derivatives , processes for preparing them , pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine - 1 - phosphate receptors .