Patent Abstract:
this invention relates to a group of compounds for repelling blood - feeding ectoparasitic arthropods , and a method of deterring their landing and feeding on animals including humans , by applying in one or more formulations compounds that incorporate one or more sulfide and one or more hydroxyl groups to the skin , clothing or environment of animals , including humans . a method of repelling and deterring landing and feeding by blood - feeding arthropods on an animal by applying in effective amount one or more compounds that incorporate alkyl sulfide and alcohol moieties , or alkyl sulfide and amide moieties , or alkyl sulfide and amide moieties to the skin , clothing or environment of an animal .

Detailed Description:
the inventors &# 39 ; own research ( gries et al . 2008 ) has shown that 9 - allylsulfanylnonan - 1 - ol , 8 - allylsulfanyloctan - 2 - ol , and 8 - allylsulfanyloctan - 1 - ol are repellent to mosquitoes . in this application , the inventors disclose the discovery of a new set of compounds , including 8 - methylsulfanyloctan - 1 - ol , 8 - ethylsulfanyloctan - 1 - ol , 8 - propylsulfanyloctan - 1 - ol , 8 - butylsulfanyloctan - 1 - ol , 8 - pentylsulfanyloctan - 1 - ol and ( n , n )- diethyl - 8 - allylsulfanyl - octanamide that among other insects are deterrent to mosquitoes . fig1 illustrates synthetic pathways to ( n , n )- diethyl - 8 - allylsulfanyl - octanamide ( scheme 1 ), 8 - methylsulfanyl - 1 - octanol ( scheme 2 ), and 8 - propylsufanyl - 1 - octanol ( scheme 3 ). a black - eyed liverpool strain of aedes . aegypti was obtained from dr . carl lowenberger , simon fraser university ( sfu ). insects were reared under standardized conditions ( 60 - 70 % relative humidity , 26 - 28 ° c ., 14 h light : 10 h dark photoperiod ) in sfu &# 39 ; s insectary . neonate larvae that hatched in glass dishes of sterilized hypoxic water were transferred to trays of distilled water provisioned with nutrafin ® basix staple food fish diet . pupae were collected daily and separated by sex , and 15 females and 10 males were placed in a paper cup ( 7 . 5 cm diameter , 8 . 5 cm high ) with a mesh lid . emergent adults were fed a 10 % ( w / v ) sucrose solution via braided cotton dental rolls . arm - fed gravid females were offered water - containing paper cups , lined with paper - towel as an oviposition substrate . candidate repellents and deterrents were bioassayed according to a modified protocol from the world health organization ( 1996 ). at least 1 hour prior to each bioassay , 75 host - seeking non blood - fed , nulliparous , 5 - to 8 - day - old female aedes aegypti were placed into a wood - framed cage ( 26 . 5 cm on each side and 42 . 5 cm high ) with a wooden floor , screened mesh sides and top , and a clear acrylic front fitted with a cotton stockinette sleeve ( 10 cm diameter ). the test subject &# 39 ; s arm was covered with an elbow - length polyethylene glove with an excised patch ( 16 . 6 cm long , 6 cm wide ) to expose the ventral forearm of the test subject . candidate deterrents were formulated in mineral ( paraffin ) oil and applied to the exposed forearm 5 min prior to inserting the arm into the cage . the inserted arm remained in the cage for 3 min every 30 min . prior to each 3 - min bioassay period , the hand of the untreated arm was inserted into the cage to ascertain that it received 10 bites within 30 sec as an indication of “ biting pressure ”. the bioassay was terminated when the treated arm received ≧ 2 bites in one 3 - min bioassay period or one bite in each of two consecutive bioassay periods . the time elapsed from experiment initiation to first bite was recorded as deterrent failure or complete protection time . a mixture of allylbromide ( 1 , 1 . 30 ml , 15 mmol ) and thiourea ( 1 . 45 g , 15 mmol ) was refluxed in 50 ml of anhydrous ethanol for 3 hours and cooled to 25 ° c . pellets of koh ( 1 . 62 g , 30 mmol ) were added together with water ( 0 . 30 ml ). the reaction mixture was then refluxed for 2 hours . 8 - bromooctanoic acid was alkylated with potassium allylmercaptade ( jie et al . 1989 ) by adding to the reaction mixture 8 - bromooctanoic acid ( 2 . 23 g , 10 mmol ) and koh ( 1 . 30 g ), and refluxing for 5 hours under argon . thereafter , water ( 50 ml ) was added and the reaction mixture was extracted with hexane ( 2 × 40 ml ). the aqueous solution was acidified with conc . hcl and extracted again with ether ( 2 × 40 ml ). ethereal extracts were washed with a saturated aq . nacl solution and were dried over anh . mgso 4 . evaporation of solvents gave 8 - allylsulfanyl - octanoic acid ( 2 ) ( 50 % pure by gc ); ms [ m / z ( rel . intensity )]: 216 ( m +, 100 ), 199 ( 26 ), 169 ( 20 ), 157 ( 37 ), 139 ( 18 ), 123 ( 19 ), 113 ( 49 ), 95 ( 26 ), 87 ( 34 ), 74 ( 69 ), 55 ( 52 ), 45 ( 62 ), 41 ( 69 ). without further purification , the crude acid was dissolved in dry benzene ( 50 ml ), and freshly distilled thionyl chloride ( 1 . 50 ml ) was added . the reaction mixture was warmed to 50 ° c . and stirred for 5 hours under argon . excess thionyl chloride and benzene were removed in vacuo . the residue in 20 ml of ether was stirred at 0 ° c ., and diethylamide ( 4 ml ) was added slowly . after 20 min , water ( 10 ml ) was added and the product was extracted ( 2 × 40 ml ) with a 1 : 1 ether / hexane mixture . extracts were washed with a saturated aq . nacl solution , dried over anh . mgso 4 , concentrated and purified by flash chromatography , using ether / hexane mixtures with increasing proportions of ether ( 40 , 50 and 70 %) as consecutive eluents . the yield of ( n , n )- diethyl - 8 - allylsulfanyl - octanamide ( 3 )( 75 % pure by gc ) was 0 . 87 g ( 24 % yield ); ms [ m / z ( rel . intensity )]: 272 ( m + 1 , 74 ), 230 ( 100 ), 198 ( 44 ), 157 ( 20 ), 126 ( 24 ), 115 ( 36 ), 100 ( 66 ), 74 ( 48 ), 58 ( 31 ), 44 ( 29 ). a 2 . 5 m buli solution ( 4 ml , 10 mmol ) in hexane was added at − 78 ° c . under stirring to 8 - mercapto - 1 - octanol ( 4 ) ( 0 . 84 g , 4 . 76 mmol ) ( narchem corp ., chicago ill .) dissolved in a 4 : 1 mixture of thf / hmpa . after 30 min , iodomethane ( 0 . 6 ml , 10 mmol ) was added in one portion . the reaction mixture was allowed to warm to room temperature , quenched with water , and extracted with ether ( 2 × 30 ml ). ethereal extracts were washed with a saturated aq . nacl solution , dried over anh . mgso 4 , and concentrated . purification by flash chromatography afforded 0 . 65 g of known 8 - methylsulfanyl - 1 - octanol ( 5 ) ( bennett & amp ; gudgeon 1938 ; kawabato et al . 1989 ) (& gt ; 99 % pure by gc , 78 % yield ). other 8 - alkylsulfanyl - 1 - octanols , including 8 - methylsulfanyloctan - 1 - ol , 8 - ethylsulfanyloctan - 1 - ol ( compound previously known ; hu & amp ; neckers , 1997 ), 8 - propylsulfanyloctan - 1 - ol , 8 - butylsulfanyloctan - 1 - ol and 8 - pentylsulfanyloctan - 1 - ol were furnished in similar ways . 8 - propylsulfanyl - 1 - octanol ( 7 ) was produced via hydrogenation of 8 - allylsulfanyl - 1 - octanol ( 6 ) ( gries et al . 2008 ) in hexanes with 5 % pd / c as a catalyst ( quantitative yield ). to determine the deterrence of 8 - allylsulfanyloctan - 1 - ols against aedes aegypti , a 10 % formulation of either 8 - methylsulfanyloctan - 1 - ol , 8 - ethylsulfanyloctan - 1 - ol , 8 - propylsulfanyloctan - 1 - ol , 8 - butylsulfanyloctan - 1 - ol , or 8 - pentylsulfanyloctan - 1 - ol in mineral oil was applied in experiments 1 - 5 at a dose of 1 . 5 mg ( total composition ) per cm 2 to the skin of the test person , and was bioassayed according to the protocol described under example 2 . in experiment 6 , a 10 % formulation of 8 - allylsulfanyl - 1 - octanol ( gries et al . 2008 ) in mineral oil was bioassayed for comparison . each of experiments 1 - 6 was replicated 3 - 4 times . in experiments 1 - 5 , 10 % formulations of the 8 - alkylsulfanyl - octan - 1 - ols in mineral oil provided protection from bites by aedes egypti for an average duration ranging between 11 - 154 minutes ( fig2 ). the duration of protection was inversely related to the length of the alkyl chain . in experiment 6 , a 10 % formulation of previously reported 8 - allylsulfanyl - 1 - octanol provided protection for an average duration of 123 minutes . fig2 shows the duration of protection of a 100 cm 2 area of an exposed human forearm from bites by aedes aegypti caused by 10 % formulations of either 8 - methylsulfanyloctan - 1 - ol ( experiment 1 ), 8 - ethylsulfanyloctan - 1 - ol ( experiment 2 ), 8 - propylsulfanyloctan - 1 - ol ( experiment 3 ), 8 - butylsulfanyloctan - 1 - ol ( experiment 4 ), 8 - pentylsulfanyloctan - 1 - ol ( experiment 5 ) or 8 - allylsulfanyloctan - 1 - ol ( experiment 6 ) in mineral oil applied to the skin at a dose of 1 . 5 mg per cm 2 , as opposed to no protection provided by mineral oil alone . to determine the deterrence of ( n , n )- diethyl - 8 - allylsulfanyl - octanamide against aedes aegypti , a 10 % formulation of ( n , n )- diethyl - 8 - allylsulfanyl - octanamide in mineral oil was applied in experiment 7 at a dose of 1 . 5 mg ( total composition ) per cm 2 to the skin of the test person , and was bioassayed according to the protocol described under example 2 . experiment 7 was replicated 4 times . in experiment 7 , a 10 % formulation of ( n , n )- diethyl - 8 - allylsulfanyl - octanamide in mineral oil provided protection from bites by aedes egypti for an average duration of 156 min , which was slightly longer than the average duration of protection provided by 8 - allylsulfanyl - 1 - octanol in experiment 6 . fig3 shows the duration of protection of a 100 cm 2 area of an exposed human forearm from bites by aedes aegypti caused by 10 % formulations of ( n , n )- diethyl - 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