the compounds utilized in the present invention , having the formula ( i ) as defined above , are readily and generally prepared by the following reaction process . to an alcoholic solution of sodium methoxide is added an alcoholic solution of hydroxylamine hydrochloride and a compound of the formula ## str6 ## wherein x is an alkyl group and r 1 , r 2 , r 3 and r 5 are as defined for formula ( i ). the reaction mixture is stirred for about 12 to 24 hours , preferably 16 hours , at room temperature . the solvent is evaporated and the residue is worked - up according to methods well known to those skilled in the art . the intermediate ester compounds of the formula ## str7 ## are synthesized according to the following procedure . to a mixture of n - chlorosuccinimide and pyridine in an inert solvent , such as methylene chloride , is added an oxime of the formula ## str8 ## wherein r 1 and r 2 are as defined above for formula ( i ). the mixture is allowed to stir for about 2 to 5 hours , preferably about 2 hours . a compound of the formula ## str9 ## wherein r 3 and r 5 are as defined above for formula i and x is an alkyl group , is added followed by the addition of triethylamine to the mixture and the mixture is stirred for about 2 hours more at room temperature . the reaction is worked up according to methods well known to those skilled in the art . where possible , as ascertained by one skilled in the art enabled by this disclosure , pharmaceutically - acceptable acid addition salts of certain compounds of this invention can be prepared which include , but are not limited to , those formed with hcl , hbr , hno 3 , h 2 so 4 , h 3 po 4 , ch 3 so 3 h , p - ch 3 c 6 h 4 so 3 h , ch 3 co 2 h , gluconic acid , tartaric acid , maleic acid and succinic acid . the ability of the compounds or the pharmaceutically acceptable salts thereof to inhibit 5 - lo and , consequently , demonstrate their effectiveness for treating or alleviating inflammatory diseases or conditions , allergy and cardiovascular diseases in mammals is shown by the following in vitro assay . venous blood from healthy volunteers is collected in heparin ( 20 u / ml ). compounds are dissolved in dmso . each compound is tested at 4 concentrations . zileuton ( a 5 - lipoxygenase inhibitor available from abbott laboratories , this particular batch was synthesized in house , the synthetic procedure is well - known in the art ) and dmso alone are used as positive and negative controls , respectively . 10 μl of compound or dmso is added to glass borosilicate tubes ( 12 × 75 mm ) and warmed to 37 ° c . one milliliter of whole blood is added to each tube . following a 15 min . incubation period whole blood is stimulated with the calcium ionophore a23187 ( purchased from sigma chemical co ., st . louis , mo . 63178 ), at 50 μm for 1 hour . tubes are immediately placed in a 4c centrifuge and spun at 1500 × g to isolate plasma . a 50 μl volume of plasma is taken for measurement of leukotriene - b4 ( ltb4 ). samples are diluted 1 : 800 for assay by leukotriene b4 enzyme immunoassay kit ( eia ) ( cayman chemical co ., ann arbor , mich .) using the manufacturers instructions . a ltb - 4 standard curve from 250 to 7 . 8 pg / ml is run with each plate . 50 μl of diluted sample is added per well . 50 μl of ltb - 4 acetylcholinesterase tracer followed by 50 μl of ltb - 4 antiserum are then added . plates are covered with plastic film and incubated for 18 hours at room temperature . wells are emptied and rinsed 5 times with wash buffer prior to development with ellman &# 39 ; s reagent ( available from cayman chemical , ann arbor , mich .) in the dark for 1 hour at room temperature , or until the b0 ( total absorbance ) wells exhibit absorbance between 0 . 3 and 0 . 8 a . u . the plates are read at 405 nm using a thermomax microplate reader ( molecular devices , menlo park , cal .). the ltb - 4 standard curve is fitted to a semi - log equation . absorbance values for experimental wells are averaged and the pg / ml ltb - 4 concentration is determined by interpolating the average absorbance onto the standard curve . percent inhibition is determined by the following equation : (- ( pg / ml ) ltb - 4 experimental /( pg / ml ) ltb - 4 dmso control !- 1 )× 100 . ic 50 is determined by linear regression of drug concentration plotted against inhibition and interpolation of the x value at y = 50 . for administration to humans to inhibit 5 - lo and in the treatment of inflammatory diseases or conditions , allergy and cardiovascular diseases , oral dosages of the compounds of formula ( i ) or the pharmaceutically acceptable salts thereof , are generally in the range of from 0 . 1 - 500 mg daily for an average adult patient ( 70 kg ). thus for a typical adult patient , individual tablets or capsules contain from 0 . 1 to 50 mg of active compound , in a suitable pharmaceutically acceptable vehicle or carrier . multiple tablets or capsules may be required to meet the dosage requirements . dosages for intravenous administration are typically within the range of 0 . 1 to 10 mg per single dose as required . for intranasal or inhaler administration , the dosage is generally formulated as a 0 . 1 to 1 % ( w / v ) solution . in practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age , weight and response of the particular patient . the above dosages are exemplary of the average case but there can , of course , be individual instances where higher or lower dosage ranges are merited , and all such dosages are within the scope of this invention . for human use , the compounds of the formula ( i ) and the pharmaceutically acceptable salts thereof can be administered alone , but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended mute of administration and standard pharmaceutical practice . for example , they may be administered orally in the form of tablets containing such excipients as starch or lactose , or in capsules or ovales either alone or in admixture with excipients , or in the form of elixirs or suspensions containing flavoring or coloring agents . they may be injected parenterally ; for example , intravenously , intramuscularly or subcutaneously . for parenteral administration , they are best used in the form of a sterile aqueous solution which may contain other substances ; for example , enough salts or glucose to make the solution isotonic . for topical administration , they are best used in the form of solutions , lotions , ointments , salves and the like . the following example illustrates the synthesis of a compound used in the present invention . the following example combined with the synthetic methodologies described immediately above enables one skilled in the art to prepare the compounds used in the present invention . to a solution of sodium methoxide , prepared from 97 mg ( 4 . 2 mmol ) of sodium and 10 ml of methanol , was added 146 mg ( 2 . 1 mmol ) of hydroxylamine hydrochloride in a solution of 3 ml of methanol followed by 500 mg ( 1 . 5 mmol ) of 3 -( 3 - cyclopentyoxy - 4 - methoxy ) phenyl - 2 - isoxazoline - 5 - carboxylic acid ethyl ester . after stirring for about 16 h at rt , the solvent was evaporated and the residue was dissolved in 50 ml of water and washed with ether ( 2 × 50 ml ). the aqueous layer was acidified to ph 1 with aqueous hcl solution and the precipitate ( 231 mg ) was filtered and recrystallized twice from ch 2 cl 2 etoac to give 52 mg of the title compound , mp 167 °- 168 ° c . 1 h nmr ( dmso - d 6 ): δ1 . 54 - 1 . 92 ( 8h , m ), 3 . 48 - 3 . 67 ( 2h , m ), 3 . 78 ( 3h , s ), 4 . 79 - 4 . 85 ( 1h , m ), 4 . 95 ( 1h , t , j = 8 ), 6 . 99 ( 1h , d , j = 9 ), 7 . 17 ( 1h , d , j = 9 ), 7 . 23 ( 1h , s ), 9 . 03 ( 1h , s ); anal . calc &# 39 ; d . for c 16 h 20 n 2 o 5 : c , 59 . 99 ; h , 6 . 29 ; n , 8 . 74 . found : c , 59 . 82 ; h , 6 . 05 ; n , 8 . 65 .
this invention relates to a method of inhibiting 5 - lipoxygenase in a mammal in need thereof by administering compounds of the core of formula ## str1 ## the racemic , racemic - diastereomeric mixtures and optical isomers of said compounds and the pharmaceutically acceptable salts thereof .