the lower alkyl group as defined for the substituent in the above - mentioned formula ( i ) means a straight or branched - chain alkyl group containing 1 - 4 carbon atoms . methyl , ethyl or propyl is preferred . the lower alkoxy group means a straight or branched alkoxyl group containing 1 - 4 carbon atoms . methoxy , ethoxy or propoxy is preferred . the amide derivatives represented by the above - mentioned formula ( i ) are produced by reacting a reactive derivative of a carboxylic acid represented by the formula ( ii ) ## str2 ## wherein r 3 and n have the same meanings as defined above and r 4 and r 5 which may be the same or different and represent hydroxy - protective groups or lower alkyl groups with an amine derivative represented by the formula ( iii ) ## str3 ## wherein x has the same meaning as defined above , and if required , removing the hydroxy - protective groups . as the above - mentioned reactive derivative of the carboxylic acid ( ii ) is preferably employed a halide , for example , chloride or bromide , or an anhydride of said carboxylic acid . as the hydroxy - protective group is preferably employed an aliphatic or aromatic acyl group such as acetyl , propionyl , benzoyl or toluoyl ; or benzyl group . the above - mentioned reaction is carried out by a method known per se . for example , the reactive derivative of the carboxylic acid ( ii ) is dissolved in an appropriate organic solvent such as , for example , chloroform , the amine derivative ( iii ) is added to the solution , and the mixture is reacted at room temperature for several hours . after completion of the reaction , the desired product ( i ) is isolated from the reaction mixture by a conventional method and purified by such a means as column chromatography . when r 4 and / or r 5 in the above formula ( ii ) is a hydroxy - protective group , the protective group is removed by a conventional method . for example , when the protective group is an acyl group , deacylation is effected by the treatment with a mineral acid such as hydrochloric acid . when the protective group is benzyl group , the removal is effected by a catalytic reduction . the amide derivatives of the invention are useful as a lypoxygenase inhibitor and are administered for the therapy and prevention of diseases such as allergic asthma and allergic rhinitis . the dose is variable depending upon patient &# 39 ; s conditions , but is generally 10 - 2000 mg , and preferably 20 - 600 mg per day for an adult . it may be administered in one to three divided doses in a day as needed depending upon patient &# 39 ; s conditions . route of administration may be in any suitable form , and oral administration is particularly desirable . intravenous administration is also feasible . the compound of the invention may be administered either alone or in admixture , as one of the active ingredients , with pharmaceutical carriers or excipients , by employing conventional procedures , in a variety of forms such as tablets , sugar - coated tablets , powders , capsules , granules , suspension , emulsion and injectable solution . examples of the carriers or excipients are calcium carbonate , calcium phosphate , starch , glucose , lactose , dextrin , alginic acid , mannitol , talc , and magnesium stearate . examples and a test example are given to illustrate the invention in more details , but the invention is not limited thereto in any way . to a suspension of 200 mg ( 0 . 703 mmol ) of 3 -( 3 - methoxy - 4 - benzyloxyphenyl )- 2 - propenic acid in dry chloroform ( 6 ml ) was added 178 . 5 mg ( 1 . 406 mmol ) of oxalyl chloride in the atmosphere of argon at room temperature . the mixture was stirred for one hour , and the reaction mixture was concentrated under reduced pressure . to the residue thus obtained was added dry chloroform ( 4 ml ) followed by addition of a solution of 264 mg ( 0 . 703 mmol ) of brmohexine in dry chloroform ( 2 ml ), and the solution was stirred for 3 hours . to the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate followed by extraction with chloroform . the organic layer was concentrated under reduced pressure , and the residue thus obtained was subjected to column chromatography on silica gel . from the benzene - ethyl acetate ( 10 : 1 ) eluate was obtained 275 . 8 mg ( 0 . 429 mmol ) of n - cyclohexyl - n - methyl -( 2 -( 3 -( 3 - methoxy - 4 - benzyloxy - phenyl )- 2 - propenoylamino )- 3 , 5 - dibromobenzyl ) amine . to a solution of 275 mg ( 0 . 428 mmol ) of the amine compound in acetic acid ( 3 ml ) was added concentrated hydrochloric acid ( 1 . 5 ml ), and the mixture was stirred at 100 ° c . for 2 hours and then at room temperature for 14 hours . to the reaction mixture were added ice water and 1n sodium hydroxide to adjust the ph to 8 , followed by extraction with ethyl acetate . the organic layer was concentrated under reduced pressure , and the residue was subjected to column chromatography on silica gel . from the benzene - ethyl acetate ( 5 : 1 ) eluate was obtained 134 . 5 mg ( 0 . 243 mmol ) of n - cyclohexyl - n - methyl -( 2 -( 3 -( 3 - methoxy - 4 - hydroxyphenyl )- 2 - propenoylamino )- 3 , 5 - dibromobenzyl ) amine . spectrophotometric data of the product support structure of the formula ( iv ) shown below . ## str4 ## 1 h - nmr ( cdcl 3 ). tbd . ( ppm ): 0 . 93 - 2 . 40 ( 11h , m ), 2 . 11 ( 3h , s ), 3 . 54 ( 2h , bs ), 3 . 88 ( 3h , s ), 6 . 36 ( 1h , d , j = 15 . 5 hz ), 6 . 73 - 7 . 45 ( 5h , m ), 7 , 62 ( 1h , d , j = 15 . 5 hz ), 7 . 68 ( 1h , d , j = 2 . 0 hz ). ir ( kbr ) ν max cm - 1 : 3250 , 2930 , 2850 , 1680 , 1620 , 1595 . to a solution of 103 . 5 mg ( 0 . 47 mmol ) of 5 -( 3 - methoxy - 4 - hydroxyphenyl )- 2 , 4 - pentadienoic acid in dry tetrahydrofuran ( 3 ml ) was added 119 . 3 mg ( 0 . 94 mmol ) of oxalyl chloride in the atmosphere of argon at room temperature . the mixture was stirred for 1 . 5 hours , and the reaction mixture was concentrated under reduced pressure . to the residue thus obtained was added dry tetrahydrofuran ( 2 ml ) followed by addition of 135 mg ( 0 . 36 mmol ) of brmohexine in dry tetrahydrofuran ( 2 ml ) at room temperature . the mixture was stirred with heating under reflux for 2 hours and at room temperature for 14 hours . to the reaction mixture was added saturated aqueous solution of sodium carbonate followed by extraction with ethyl acetate . the organic layer was concentrated under reduced pressure , and the residue thus obtained was subjected to column chromatography on silica gel . from the benzene - ethyl acetate ( 10 : 1 ) eluate was obtained 140 . 8 mg ( 0 . 24 mmol ) of n - cyclohexyl - n - methyl -( 2 -( 5 -( 3 - methoxy - 4 - hydroxyphenyl ) 2 , 4 - pentadienoylamino )- 3 , 5 - dibromobenzyl ) amine . spectrophotomethic data of the product support structure of the formula ( v ) shown below . ## str5 ## 1 h - nmr ( cdcl 3 ) δ ( ppm ): 1 . 06 - 2 . 35 ( 11h , m ), 2 . 10 ( 3h , s ), 3 . 51 ( 2h , bs ), 3 , 88 ( 3h , s ), 6 . 00 ( 1h , d , j = 15 . 0 hz ), 6 . 50 - 7 . 75 ( 8h , m ), 7 . 66 ( 1h , d , j = 2 . 0 hz ). ir ( kbr ) ν max cm - 1 : 3210 , 2920 , 2840 , 1650 , 1605 , 1580 . mouse mastocytoma cells , strain p815 were diluted in a medium containing 90 % of the eagle basal medium ( manufactured by gibco laboratories ) to a cencentration of 5 × 10 4 cells / ml . the diluted liquor was subjected to shake culture in air at 37 ° c . for 48 hours . the culture liquor was cooled with ice and centrifuged to collect the cells . the cells were re - suspended in a phosphate buffer solution at ph 7 . 4 to a concentration of 2 × 10 7 cells / ml . the suspension was treated in an ultrasonic cell fragmenting machine and then centrifuged at 10 , 000 ppm for 10 min . the supernatant was used as the 5 - lypoxygenase enzyme solution . to a test tube in which 20 μl of radiolabelled arachidonic acid ( 10 μ curies / ml ), indomethacine ( 2 × 10 8 mol ) and an amide derivative of the invention to be tested were placed 0 . 45 ml of phosphate buffer solution , 0 . 45 ml of the above - prepared enzyme solution and 0 . 1 ml of 8 mm cacl 2 ( calcium chloride ) solution . the mixture was reacted at 37 ° c . for 5 min . after cooled with ice , 60 μl of 1n -- hcl ( hydrochloric acid ) was added , and the resulting mixture was extracted with 8 ml of ethyl acetate . the extract was concentrated , and the concentrate was spotted and developed on a silica gel thin layer plate ( merck 60f 254 ). determination of the inhibitory activity was made by collecting the portion corresponding to 5 - hbte ( 5 -( s )- hydroxy - 6 , 8 , 11 , 14 - eicosatetraenic acid ) and ltb 4 ( leucotriene b 4 ), which were 5 - lypoxygenase products as detected with a radio - thin layer scanner ( dunnschicht - scanner ii lb 2723 manufactured by berthold ), and measuring the radioactivity by means of a scintillation counter . reduction in the 5 - lypoxygenase inhibitory activity is demonstrated by decrease in amount of the 5 - lypoxygenase products . as shown in table 1 below , results of the test indicate high 5 - lypoxygenase inhibitory activities . amide derivatives of the invention not shown in table i also demonstrated 5 - lypoxygenase inhibitory activities . table i__________________________________________________________________________5 - lypoxygenase inhibitory activity 50 % inhibitory concentrationstructural formula example ic . sub . 50 ( mol ) __________________________________________________________________________ ## str6 ## 1 4 × 10 . sup .- 6 ## str7 ## 2 3 × 10 . sup .- 7__________________________________________________________________________ the 50 % inhibitory concentration as shown in table i means concentration of the amide derivative which is required for inhibiting the formation of the abovementioned 5 - lypoxygenase products , 5 - hete and ltb 4 by 50 % of that in the absence of the amide derivative . an acute toxicity test by oral administration was conducted using icr male mice ( 5 weeks old ). the ld 50 value was 300 mg / kg or higher with any of the compounds of the invention thereby confirming higher safety than the effective dose .
novel amide derivatives are disclosed . as examples of said amide derivatives are mentioned n - cyclohexyl - n - methyl -- 2 -- 3 , 5 - dibromobenzyl ) amine and n - cyclohexyl - n - methyl -- 2 , 4 - pentadienoylamino )- 3 , 5 - dibromobenzyl ) amine . these amide derivatives have a 5 - lipoxygenase inhibitory activity and are useful as an antiallergic agent .