Abstract:
A number of alicyclic carboxamides of the formula ##STR1## wherein n, R 1 , R 2 , and R 3  are defined hereinbelow have been found to be useful insect repellents.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to insect repellents and more particularly to certain novel carboxamides containing an alicyclic moiety and their use as insect repellents. 
     2. Description of the Prior Art 
     There is a continuing need for insect repellents or formulations thereof that are significantly more effective or longer lasting than those now in use. All of the repellents now in use for application to the skin have disadvantages, that is, they are not effective for long enough periods of time and are subject to loss by abrasion, evaporation, absorption, and immersion in water. Moreover, all cause a stinging sensation when they contact the eyelids and lips, and are effective only when they are present on the skin or clothing in relatively large quantities. Mosquitoes, sand flies, black flies, stable flies, tsetse flies, gnats, and tabanids are among the many species of biting fly that cause annoyance and distress throughout the world. Many species of biting insects spread human and animal diseases. There are many areas throughout the world in both developed and developing nations where the use of protective clothing and repellents is the only means available to individuals for personal protection. Deet (N,N-diethyl-m-toluamide) has proved to be the most outstanding all-purpose individual repellent yet developed (Proceedings of a Symposium, University of Alberta, Edmonton, Canada, May 16-18, 1972, Defense Research Board, Ottawa, Canada, 1973.  DR-217: 109-113). Deet was reported as a promising repellent in 1954 (Journal of Organic Chemistry, 19, 493, 1954). Since that time, no repellent has been reported as being superior to deet as an all-purpose repellent despite a continuing search for such a chemical. 
     SUMMARY OF THE INVENTION 
     An object of this invention is to provide a class of compounds that are useful as insect repellents. 
     The above object is accomplished by a number of novel carboxamides having from about 11 to about 18 carbon atoms and containing an alicyclic moiety. Many of these compounds are more effective than presently available repellents and many are effective against a wide variety of insects. 
     DESCRIPTION OF THE INVENTION 
     The compounds of this invention are represented by the formula below ##STR2## wherein R 3  is one of the groups A, B, or C ##STR3## R is hydrogen or lower alkyl, n is zero or the positive integer one, two, or three, each of R 1  and R 2  is alkyl, or taken together represent an alkylene, an alkenylene, an alkyl substituted alkylene, an alkylene ether, and alkyl substituted alkylene ether, or an alkyl substituted alkylene amine ring structure. 
     The compounds of this invention are useful as insect repellents and are particularly effective against many Dipteran. 
     The novel compounds of this invention are especially effective in repelling a wide variety of insects such as ticks, chiggers, cockroaches, and biting diptera such as mosquitoes, stable flies, deer flies, black flies, and sand flies. Certain novel amides reported in this invention are about equally as effective as deet against mosquitoes and are significantly more repellent than deet against other biting flies when tested on skin. The skin test is the obvious critical test when one considers personal protection; however, clothing repellents are also very important especially in areas of heavy mosquito infestations (The Journal of the American Medical Association, 196, 253, 1966). Certain amides of this invention provide exceptional protection against mosquitoes when applied to cloth. 
     The amides were synthesized as follows: the appropriate acid chloride was slowly added with stirring to an anhydrous ether solution of the amine cooled in an ice bath (either the amine itself or pyridine was used as a hydrochloric acid scavenger). The reaction mixture was allowed to warm to room temperature and then allowed to stand for several hours, usually overnight. The amides were isolated by routine extraction procedures and purified by distillation under high vacuum. Purity was checked by gas chromatographic analysis. 
     A typical procedure is illustrated by the following description of the synthesis of 1-(3-cyclohexenecarbonyl) piperidine, compound 20 in Table 1: 3-cyclohexenecarbonyl chloride, 28.9 grams (0.2 mole), was added dropwise to an ice cold solution (0°-10° C.) of piperidine, 34 grams (0.4 mole) in 250 ml of anhydrous ether. The solution was stirred vigorously during the addition. The reaction mixture was allowed to warm to room temperature and to stand overnight. Water was added to dissolve the precipitated piperidine hydrochloride salt. The organic layer was then washed sequentially with 5% hydrochloric acid and sodium bicarbonate solutions and finally with a saturated salt solution until the wash was neutral to litmus paper and dried over anhydrous magnesium sulfate. After filtering, the solvent was removed under reduced pressure (water pump). The crude amide was distilled under high vacuum to give 31.4 grams of product-b.p. 114°-15° C./0.2 mm Hg), n D   25  1.5159. 
     The physical constants of the compounds are presented in Table 1. 
     The repellent activity of the amides of the present invention was demonstrated by practical laboratory and field tests against mosquitoes and a variety of other biting diptera. The effectiveness of the repellents was determined by directly comparing their repellency with that of deet in tests on skin and with dimethyl phthalate in tests on cloth. 
     In the following description of the testing procedures the first confirmed bite is defined as a bite followed by another within thirty minutes. 
     For the purposes of this invention, the compounds were tested as solutes in alcohol, acetone, or other volatile solvent. However, other compatible liquid or solid carriers may also be used. 
     TESTING PROCEDURES 
     STABLE FLIES. 
     The repellents were applied as 1-ml aliquots of a 25% ethanol solution and spread evenly over the forearm of a subject from wrist to elbow. Since the ethanol solution was formulated on a weight-volume basis, 250 mg of repellent was applied to the forearm in each test. The most promising compounds (those equal to or better than the deet standard at the 25% dosage) were then tested as 12.5% and 6.25% ethanol solutions. 
     The evaluations were carried out in an outdoor cage (103 cm square and 133 cm high) constructed of aluminum and having a solid top and bottom and screen wire on four sides. Four of the sides had port openings covered with 30.5-cm (12-in.) tubular cloth stockinettes. The centers of the ports were 30 cm from the bottom of the cage, which rested on a table 80 cm high. One arm each of up to four treated subjects at a time could be inserted through the ports into the cage. 
     Approximately 12,000 S. calcitrans pupae were placed in cups and allowed to emerge in the test cage over an 8-day period. The tests were started the 4th day, when approximately 8000 flies had emerged. The remaining 4000 that emerged over the next 4 days maintained a relatively stable population in respect to numbers and avidity. Citrated beef blood on a cotton pad was offered for 45 minutes each day after the repellent tests were completed. This short-term feeding period provided a small but adequate food intake, and avidity was not reduced as a result of complete engorgement. Results obtained when an untreated forearm was inserted into the test cage before and during the tests each day gave a measure of the avidity of the flies, though it was impossible to count the attacks on the untreated arm. 
     The effectiveness of each chemical was determined by the protection time; that is, the time between treatment and the first confirmed bite. Therefore, 30 minutes after the application of the test chemical and every 30 minutes thereafter, the treated arms were inserted into the test cage for 3 minutes unless bites occurred sooner. 
     Since test subjects differ in attractiveness and insects differ in avidity, the best measure of the effectiveness of a repellent is its ratio of protection time vs. that of a standard repellent used in similar conditions. Deet was the standard in all of the tests reported here. It was paired with each of the other candidate repellents in 10 different test series. 
     The experimental design used was a round-robin series in which each repellent was paired concurrently against another repellent on the arms of a subject. An adjusted average protection time that allowed for individual variation between test subjects and test conditions was then computed (Soap and Chemical Specialties, 33, 115-17 and 129-133, 1957). 
     BLACK FLIES. 
     The principal test site was in the vicinity of Kidney Pond, Baxter State Park, Maine. Meadows bordered by fast moving mountain streams and an abundance of wildlife provided optimum breeding conditions in this area. Several species of blackflies were represented in the population attacking four test subjects. Of these, the two most abundant were identified as Simulium venustum Say and Prosimulium mixtum Syme and Davis. Repellents were applied as 1-ml aliquots of a 12.5 or 25% ethanol solution and spread evenly over the forearm of a subject from wrist to elbow. The ethanol solution was formulated on a weight-volume basis, so either 125 or 250 mg of repellent was applied in each test. 
     Treated arms were continuously exposed to the natural populations of flies. Subjects intermittently moved about with arms raised or on hips, squatted, or sat down for brief periods of 5 to 10 minutes. These positions, coupled with slow walking and standing every few minutes, appeared to be attractive to black flies (Simulids and Prosimulids) and were used as standard procedure in all tests. Heat-nets and gloves were worn by the test subjects to prevent attack on exposed untreated parts of the body. 
     Two series of round-robin tests were conducted in the spring of 1977 using 12.5 or 25% solutions of repellent in ethanol; one series was conducted during June 1978 using a 25% solution of repellent in ethanol. The effectiveness of each chemical was determined by the protection time, i.e., the time between treatment and the first confirmed bite. Since test subjects differ in attractiveness and insects differ in avidity, the best measure of the effectiveness of a repellent is the ratio of its protection time to that of a standard repellent under similar conditions. Deet was the standard repellent in these tests. 
     In the round-robin test each repellent was paired with each other repellent on the arms of a subject (four or five replicates). An adjusted average protection time that allowed for individual variations between test subjects and test conditions was then computed. Black fly landing rates ranged from 14 to 40/minute during the test period. 
     DEER FLIES. 
     The compounds and the standard repellent, deet, were tested on the forearms of human subjects against natural populations of the deer fly, Chrysops atlanticus. The materials were formulated as 25% ethanol solutions and applied at the rate of 1 ml per forearm. The field tests were conducted along logging roads adjacent to the marshes of the Ogeechee River at Richmond Hill, Ga., where C. atlanticus populations occur in great numbers annually. Since the flies are attracted to motion, the test subjects continually walked while exposing their treated arms to the flies. The tests were terminated when a confirmed bite was received. The chemicals were evaluated in round-robin tests with five compounds and a deet standard in each series. During the 3-week test period the landing rate averaged 33 flies/man and ranged from 13 to 54/man. 
     SAND FLIES. 
     Two test sites were used, one at YankeeTown, Fla. on the Gulf coast and one at Parris Island, South Carolina. The repellents were applied as 25% solutions in ethanol on the forearms (wrist to elbow) of test subjects. Because of the limited period of insect activity (early morning or late afternoon to dusk) the subjects were pretreated 2 hours prior to the test period to effect aging of the repellents. The repellents were evaluated against the standard repellent, deet, in paired tests (3 replications). A test repellent was applied to one arm of a subject and deet to the other. Effectiveness was determined by the number of bites received during the test period. A control (no repellent treatment) was included in each test to ascertain the level of insect pressure. 
     MOSQUITOES. 
     Tests on skin. 
     For laboratory tests, 1 ml of a 25% ethanol solution of the repellent was spread evenly over the forearm of the subject. The treated forearms were exposed to about 1500 female laboratory reared Aedes aegypti or Anopheles quadrimaculatus mosquitoes in cages. Effectiveness was based on complete protection, that is, the time between treatment and the first confirmed bite. The effectiveness of the compounds was compared to that of the standard repellent, deet. The chemicals were tested in a round-robin series in a balanced incomplete block design in which each repellent in the series was paired against each other repellent in the series on opposite arms of a given number of subjects. 
     The field tests were conducted at sites adjacent to Mosquito Lagoon near New Smyrna Beach, Fla. The repellents were applied in the same manner as for the laboratory tests. The treated arms were exposed continuously to the natural population of mosquitoes until the first confirmed bite was received. Protective clothing and head nets were worn by the test subjects to protect against attack on exposed untreated parts of the body. The experimental design used was a balanced incomplete block as in the laboratory tests. 
     Tests on cloth. 
     Test materials were applied at the rate of 3.3 g of compound per 0.1 m 2  cloth to a measured portion (0.03 m 2 ) of a cotton stocking as 10% solutions in acetone or other volatile solvent. After 2 hours, the treated stocking was placed over an untreated nylon stocking on the arm of a human subject and exposed for 1 minute in a cage containing about 1500 five- to eight-day old A. aegypti or A. quadrimaculatus. The test exposure was repeated at 24 hours and then at weekly intervals until five bites were received in 1 minute. Days to the first bite and to five bites were recorded. Between tests, the treated stockings were placed on a rack at room temperature, and evaporation was allowed to continue. A standard repellent, dimethyl phthalate, was tested concurrently and was effective for 11 to 21 days against both mosquito species. 
     The merits of the present invention are illustrated in the results shown in the tables. 
     The data in Table 2 show compounds 2, 7, 20, 33, 34, 47, and 49 were more active against the stable fly than the deet standard at all concentrations tested. Compounds 20 and 34 were significantly more effective than deet at all three dosages (0.05% level of confidence). Compounds 21 and 35 were more active than deet at two concentrations and equal to it at the lowest concentration tested. The repellent effect of certain of these chemicals was as much as 4.5× that of deet and provided protection up to 9 hours; the protection time of deet ranged from 2 to 3 hours. Data for compounds 4, 6, 17, 18, 19, 31, and 45 are shown to illustrate the unpredictability of repellent activity of closely related chemicals. 
     The data in Table 3 show all eight compounds and deet are very good black fly repellents. Compound 21 is significantly more effective than deet at the 25% dosage providing about 10.5 hours protection. There is no significant difference between the remaining compounds and deet at the 25% dosage. Although not significantly more effective than deet, the adjusted mean for compound 20 was 0.5 and 1.5 hours greater than that of deet at the two test dosages. Compounds 7 and 35 provided about 7 hours protection; compounds 20 and 47 provided over 8 hours protection; compounds 6 and 33 provided about 9 hours protection. 
     The data in Table 4 show 10 compounds that exceeded deet in repellency against deer flies. Compound 20 was significantly more effective than deet with an adjusted mean protection time of 6.3 hours. 
     The data in Table 5 show compounds 2, 7, 20, and 35 greatly superior to deet in tests conducted in Florida against the sand fly Culicoides mississippiensis. Compounds 2 and 20 were also superior to deet in the Parris Island tests against Culicoides hollensis. Deet is considered a good repellent for sand flies (Meditsinskaya Parazitologiya i Parazitarnye Bolezni, 35 (5), 549, 1963). A biting rate of about 5/hour would make the presence of sand flies tolerable to most people (Journal of Economic Entomology, 64 (1), 264, 1971). The data show certain compounds of this invention equalling or exceeding this criteria in one test and equalling or closely approaching it in the second test. The number of bites experienced by the check, clearly shows very high insect pressure during these tests, emphasizing the effectiveness of the repellents. 
     The data in Table 6 show the relative repellency of compounds of this invention against mosquitoes when applied to skin in laboratory and field tests. Deet is an excellent mosquito repellent (The Journal of the American Medical Association, 196, 253, 1966). Repellents 33 and 34 were about equally as effective against Aedes aegypti as deet; repellents 19, 20, 21, and 34 were about equally as effective against Anopheles quadrimaculatus as deet. In field tests, repellents 2 and 20 were 1.5 and 1.4 times as effective as deet against Aedes taeniorhynchus and 4, 6, 7, 21, 33, and 47 were about equally as effective as deet. Because deet is such an effective mosquito repellent, chemicals having 0.5 ratios to deet are considered good mosquito repellents. 
     The data in Table 7 show 91 of the repellents were more effective than the standard against one species of mosquito and 9 other compounds were about equally as effective as the standard. Repellents 91, 100, 101, and 115 provided outstanding protection of over 200 days and 29 other repellents provided exceptional protection of over 100 days against one species or the other. All chemicals providing 11 or more days protection are considered promising repellents. 
    
    
     The foregoing examples of repellent action of these novel amides against specific insect pests is meant to be illustrative rather than limiting. For example, the compounds of the present invention can be mixed with inert ingredients or with other known insect repellents. The compounds may also be formulated or embodied into repellent compositions in the form of creams, lotions, emulsions, suspensions, solutions, dusts, and aerosol or other type of sprays. 
     Although insect repellents are usually applied to the skin, the compounds of this invention and formulations containing them are also useful when applied to clothing, netting, packaging, shipping containers, animals, and growing plants. 
     
                                           TABLE 1__________________________________________________________________________Physical constants of compounds synthesized in accordance with theprocedures of this invention No.    ##STR4##     or m.p. (°C.)B.p. (°C./mmHg)Physical           constants                     n.sub.D.sup.25                         No.                            ##STR5##      or m.p. (°C.)B.p.                                         (°C./mmHg)Physical                                         constants                                                   n.sub.D.sup.25__________________________________________________________________________ ##STR6##1  N,N-Dimethylamino           69-70/0.45                    1.4794                        9  4-Methyl-1-piperidyl                                         113-14/0.8                                                  1.49702  N,N-Dipropylamino           93-5/0.45                    1.4685                        10 2-Ethyl-1-piperidyl                                         131/1.5  1.49703  N,N-Dibutylamino           133/1.5  1.4675                        11 2,6-Dimethyl-1-piperidyl                                         109-11/0.5                                                  1.49504  1-Pyrrolidyl 67-8         12 1,2,3,6-Tetrahydro-1-                                         107-9/0.5                                                  1.5175                           pyridinyl5  1-Piperidyl  108/0.45 1.5030                        13 4-Methyl-1-piperazinyl                                         100-2/0.1                                                  1.50416  1-Hexahydro-1H-azepinyl           120/0.25 1.5038                        14 4-Morpholinyl 57-87  2-Methyl-1-piperidyl           110-13/0.7                    1.5001                        15 2.6-Dimethyl-4-morpholinyl                                         116-17/0.3                                                  1.49198  3-Methyl-1-piperidyl           114-16/0.45                    1.4974 ##STR7##16 N,N-Dimethylamino           75-6/0.4 1.4960                        24 4-Methyl-1-piperidyl                                         110-12/0.15                                                  1.508717 N,N-Dipropylamino           88/0.15  1.4804                        25 2-Ethyl-1-piperidyl                                         114-15/0.1                                                  1.506818 N,N-Dibutylamino           103/0.1  1.4775                        26 2.6-Dimethyl-1-piperidyl                                         112-13/0.1                                                  1.505519 1-Pyrrolidyl 44-5         27 1,2,3,6-Tetrahydro-1-                                         114-16/0.45                                                  1.5315                           pyridinyl20 1-Piperidyl  114-15/0.2                    1.5159                        28 4-Methyl-1-piperazinyl                                         112-14/0.1                                                  1.518121 1-Hexahydro-1H-azepinyl           105-6/0.15                    1.5151                        29 4-Morpholinyl 114-16/0.25                                                  1.519422 2-Methyl-1-piperidyl           110-12/0.1                    1.5106                        30 2,6-Dimethyl-4-morpholinyl                                         115-16/0.4                                                  1.504323 3-Methyl-1-piperidyl           108-10/0.1                    1.5087 ##STR8##31 N,N-Dipropylamino           100/0.7  1.4682                        38 4-Methyl-1-piperidyl                                         108/0.8  1.490832 N,N-Dibutylamino           126/0.9  1.4669                        39 2-Ethyl-1-piperidyl                                         175-8/18 1.493033 1-Pyrrolidyl 95/0.25  1.4941                        40 2.6-Dimethyl-1-piperidyl                                         108-10/0.5                                                  1.490534 1-Piperidyl  104-6/0.5                    1.4970                        41 1,2,3,6-Tetrahydro-1-                                         118-20/1.3                                                  1.5100                           pyridinyl35 1-Hexahydro-1H-azepinyl           115-18/0.9                    1.5000                        42 4-Methyl-1-piperazinyl                                         120-2/1.0                                                  1.499036 2-Methyl-1-piperidyl           141-3/0.25                    1.4930                        43 4-Morpholinyl 108-9/0.4                                                  1.497537 3-Methyl-1-piperidyl           168-70/18                    1.4909                        44 2,6-Dimethyl-4-morpholinyl                                         75-7 ##STR9##45 N,N-Dipropylamino           108/2.0  1.4794                        52 4-Methyl-1-piperidyl                                         122-4/1.0                                                  1.502046 N,N-Dibutylamino           120/0.45 1.4765                        53 2-Ethyl-1-piperidyl                                         116-18/0.5                                                  1.503647 1-Pyrrolidyl 133-6/0.2                    1.5082                        54 2.6-Dimethyl-1-piperidyl                                         115-17/0.5                                                  1.501748 1-Piperidyl  109/0.5  1.5090                        55 1,2,3,6-Tetrahydro-1-                                         113-15/0.7                                                  1.5234                           pyridinyl49 1-Hexahydro-1H-azepinyl           135/0.9  1.5116                        56 4-Methyl-1-piperazinyl                                         105-7/0.3                                                  1.510650 2-Methyl-1-piperidyl           120-2/1.1                    1.5049                        57 4-Morpholinyl 104-5/0.2                                                  1.511551 3-Methyl-1-piperidyl           120-2/1.3                    1.5035                        58 2,6-Dimethyl-4-morpholinyl                                         122-5/0.4                                                  1.4990 ##STR10##59 N,N-Dipropylamino           93-5/0.2 1.4900                        66 4-Methyl-1-piperidyl                                         98-100/0.1                                                  1.516360 N,N-Dibutylamino           100-2/0.1                    1.4862                        67 2-Ethyl-1-piperidyl                                         108-9/0.15                                                  1.516861 1-Pyrrolidyl 105-8/0.15                    1.5262                        68 2,6-Dimethyl-1-piperidyl                                         100-1/0.15                                                  1.516662 1-Piperidyl  111-13/0.2                    1.5244                        69 1,2,3,6-Tetrahydro-1-                                         110/0.1  1.5401                           pyridinyl63 1-Hexahydro-1H-azepinyl           121-2/0.4                    1.5262                        70 4-Methyl-1-piperazinyl                                         103-4/0.1                                                  1.525364 2-Methyl-1-piperidyl           108-9/0.2                    1.5197                        71 4-Morpholinyl 99-100/0.1                                                  1.525865 3-Methyl-1-piperidyl           110-12/0.3                    1.5169                        72 2,6-Dimethyl-1-morpholinyl                                         100-2/0.1                                                  1.5113 ##STR11##73 N,N-Dimethylamino           87-8/0.45                    1.4780                        81 4-Methyl-1-piperidyl                                         121/0.5  1.493574 N,N-Dipropylamino           108-9/0.45                    1.4708                        82 2-Ethyl-1-piperidyl                                         122-4/0.2                                                  1.494375 N,N-Dibutylamino           139/0.75 1.4698                        83 2,6-Dimethyl-1-piperidyl                                         121-3/0.3                                                  1.494276 1-Pyrrolidyl 110-12/0.25                    1.4977                        84 1,2,3,6-Tetrahydro-1-                                         122-4/0.15                                                  1.5114                           pyridinyl77 1-Piperidyl  109-11/0.2                    1.5000                        85 4-Methyl-1-piperazinyl                                         109/0.15 1.501678 1-Hexahydro-1H-azepinyl           114-16/0.2                    1.5019                        86 4-Morpholinyl 68-7079 2-Methyl-1-piperidyl           105-7/0.2                    1.4945                        87 2,6-Dimethyl-4-morpholinyl                                         125-7/0.5                                                  1.489280 3-Methyl-1-piperidyl           118/0.4  1.4942 ##STR12##88 N,N-Dimethylamino           100-2/0.4                    1.4782                        96 4-Methyl-1-piperidyl                                         136-7/0.5                                                  1.491989 N,N-Dipropylamino           117-18/0.45                    1.4715                        97 2-Ethyl-1-piperidyl                                         126-7/0.1                                                  1.493890 N,N-Dibutylamino           133-5/0.4                    1.4701                        98 2,6-Dimethyl-1-piperidyl                                         135/0.35 1.489591 1-Pyrrolidyl 126-7/0.2                    1.4928                        99 1,2,3,6-Tetrahydro-1-                                         134-5/0.5                                                  1.5070                           pyridinyl92 1-Piperidyl  129-31/0.2                    1.4950                        100                           4-Methyl-1-piperazinyl                                         139- 40/0.1                                                  1.496693 1-Hexahydro-1H-azepinyl           131-4/0.3                    1.4985                        101                           4-Morpholinyl 122-4/0.1                                                  1.496194 2-Methyl-1-piperidyl           128-30/0.35                    1.4933                        102                           2,6-Dimethyl-4-morpholinyl                                         123-5/0.1                                                  1.487695 3-Methyl-1-piperidyl           136-8/0.5                    1.4912 ##STR13##103   N,N-Dimethylamino           109-10/0.4                    1.4764                        111                           4-Methyl-1-piperidyl                                         145-7/0.45                                                  1.4875104   N,N-Dipropylamino           128-30/0.4                    1.4712                        112                           2-Ethyl-1-piperidyl                                         145/0.25 1.4910105   N,N-Dibutylamino           148/0.4  1.4705                        113                           2,6-Dimethyl-1-piperidyl                                         151-3/0.5                                                  1.4874106   1-Pyrrolidyl 137-9/0.4                    1.4905                        114                           1,2,3,6-Tetrahydro-1-                                         145-6/0.45                                                  1.5035                           pyridinyl107   1-Piperidyl  139-40/0.5                    1.4920                        115                           4-Methyl-1-piperazinyl                                         134-5/0.15                                                  1.4975108   1-Hexahydro-1H-azepinyl           153-4/0.5                    1.4940                        116                           4-Morpholinyl 149-51/0.45                                                  1.4932109   2-Methyl-1-piperidyl           142-3/0.45                    1.4909                        117                           2,6-Dimethyl-4-morpholinyl                                         145-7/0.45                                                  1.4828110   3-Methyl-1-piperidyl           143-5/0.5                    1.4882__________________________________________________________________________ 
    
     
                       TABLE 2______________________________________Repellency of compounds to the stable fly Stomoxyxcalcitrans when applied to the skin at various concentrationsin ethanol and compared to deet as a test standard   Protection time   (minutes)%                  Adjusted                           Ratio to                                   No. ofNo.  Conc.    Range     mean    deet.sup.a                                   tests______________________________________2    6.25     30-90     55      1.7     312.5     300-360   315     4.50.sup.b                                   525.0     210-463   321     2.02.sup.b                                   54    25.0      30-270   103     0.4     56    25.0      30-268   183     0.71    57    25.0     120-300   246     2.01.sup.b                                   417   25.0     180-360   225     0.85    518   25.0      30-189   122     0.46    519   25.0      90-420   237     1.0     520   6.25      30-120   103     2.5.sup.b                                   312.5      60-240   128     2.4.sup.b                                   425.0     360-390   387     2.39.sup.b                                   521   6.25     30-60     33      1.0     512.5     270-450   306     1.42    525.0     300-510   457     3.78.sup.b                                   431   25.0     30-60     36      0.2     533   6.25      60-180   80      1.6     312.5      90-210   150     3.3.sup.b                                   425.0     240-270   266     1.6     434   6.25      30-120   118     2.4.sup.b                                   312.5     270-330   320     4.57.sup.b                                   525.0     390-510   419     2.6.sup.b                                   435   6.25     30-30     30      1.0     512.5     210-375   326     3.27.sup.b                                   525.0     390-510   459     2.9.sup.b                                   436   25.0      30-120   101     1.43    545   25.0      30-180   78      0.44    547   6.25     30-90 63  1.9     312.5     120-270   230     3.29.sup.b                                   525.0     150-405   264     1.66    549   6.25     30-60     38      1.15    512.5     150-330   306     1.42    525.0     480-510   538     3.02.sup.b                                   550   25.0      60-150   125     1.41    5______________________________________ .sup.a Data compiled from a number of different tests, accounting for the fluctuation between protection time and ratio to deet among the members o the series. .sup.b Significantly different from deet at the 0.05% level of confidence 
    
     
                       TABLE 3______________________________________Repellency of compounds applied to the skin as 12.5 and/or25% ethanol solutions compared with deet againstblackflies in two series of field tests     Protection time (min)   %                Adjusted Ratio to                                    No. ofNo.     Conc.   Range    mean     deet   tests______________________________________Test I (1977)Deet (Std)   12.5    145-283  161      1.00   5   25.0    287-511  426      1.00   420      12.5    123-314  193      1.20.sup.a                                    5   25.0    413-565  505      1.19.sup.a                                    4 7      12.5     26-222  95       0.59   5   25.0    309-515  424      1.00.sup.a                                    435      12.5     24-126  93       0.58   5   25.0    342-542  412      0.97.sup.a                                    4 2      12.5     25-112  71       0.44   5   25.0    198-375  314      0.74.sup.a                                    4Test II (1978)Deet (Std)   25.0    399-623  520      1.00   5 6      25.0    411-628  537      1.03.sup.a                                    521      25.0    524-725  632      1.21.sup.b                                    533      25.0    498-603  554      1.07.sup.a                                    547      25.0    425-649  486      0.94.sup.a                                    5______________________________________ .sup.a Not significantly different from deet at the 0.05% level of confidence. .sup.b Significantly different from deet at the 0.05% level of confidence 
    
     
                       TABLE 4______________________________________Repellency of compounds applied to the skin as25% ethanol solutions and compared with deet againstdeerflies in field tests (Avg. of 5 tests)Protection time (min)    Ratio toNo.     Range      Adjusted mean deet.sup.a______________________________________2        10-178    133           3.004        4-77      23            0.516        10-173    75            1.6917       15-143    62            1.3918       6-36      40            0.8920      363-421    380           5.83.sup.b21       91-203    91            1.131      10-44      45            0.6234       20-408    141           1.835       42-182    119           1.536       5-17      15            0.9445       4-110     18            0.2447       40-160    138           1.8949       37-244    129           1.7650       8-138     27            1.11______________________________________ .sup.a Data compiled from a number of tests, accounting for the fluctuation between the protection time and ratio to deet among the members of the series. .sup.b Significantly different from deet at the 0.05% level of confidence 
    
     
                       TABLE 5______________________________________Repellency of compounds applied to the skinas 25% ethanol solutions and compared with deetagainst the sandflies Culicoides mississippiensisand Culicoides hollensis in field testsCompounds     Average     Averagepaired        bites/test  bites/hour______________________________________Tests at Yankee Town, Fla. (Avg. 3 tests)Deet          29.0        19.22             3.33        2.4Deet          31.67       21.020            5.0         3.6Deet          106.0       70.835            6.67        4.2Deet          45.0        30.07             10.0        6.6Check         1299        865.8Tests at Parris Island, S. C. (Avg. 3 tests)Deet          28.67       18.620            9.33        6.0Deet          85.0        54.62             16.33       10.8Deet          12.0        7.87             16.67       10.8Check         1566        1277.4______________________________________ 
    
     
                       TABLE 6______________________________________Repellency of compounds to mosquitoes when appliedto the skin as 25% ethanol solutionsRatio to deetLaboratory test         Field test  Aedes      Anopheles     AedesNo.    aegypti    quadrimaculatus                           taeniorhynchus______________________________________ 2     0.22       0.28          1.5 4     0.22       0.11          0.77 6     0.14       0.74          0.82 7     0.70       0.11          1.1517     0.24       0.33          0.5218     0.13       0.05          0.0719     0.20       0.73          0.4420     0.68       1.0           1.421     0.64       0.86          0.731     0.24       0.08          0.4533     1.12       0.86          0.6934     0.89       1.0           0.3445     0.23       0.11          0.1247     0.28       0.24          0.9949     0.55       0.09          0.65______________________________________ 
    
     
                       TABLE 7______________________________________Repellency of compounds to mosquitoes in tests on clothAedes aegypti     Anopheles quadrimaculatusDays to           Days toNo.   1st bite  5 bites   1st bite  5 bites______________________________________ 2    15        15        8         84     30        38        38        795     30        38        30        306     106       113       22        387     104       104       111       1118     104       104       22        229     52        104       0         2210    104       104       1         2211    104       104       1         3712    15        15        15        1513    7         15        7         11114    0         1         27        2715    15        28        35        3517    15        15        15        1518    0         30        0         119    28        28        70        9420    21        28        28        4821    64        87        70        7022    69        69        83        8323    36        36        36        5124    20        20        83        8325    83        83        83        8326    36        36        36        3627    36        36        63        6328    28        28        63        8329    0         0         35        3530    8         8         22        2231    15        15        1         133    21        28        28        2834    21        28        13        1335    28        28        6         636    23        43        0         037    23        51        0         038    36        36        21        2139    51        71        0         040    1         23        0         041    8         15        8         842    1         1         36        5043    36        77        64        7144    28        28        15        1545    27        27        1         147    27        27        1         148    33        41        1         149    27        47        1         150    23        51        0         2351    36        36        0         2152    36        36        8         3655    15        15        0         157    8         22        36        10558    1         28        22        2259    1         35        49        4961    34        55        28        2862    70        70        70        9163    70        128       0         11164    70        70        0         7665    35        70        0         4966    70        70        0         7767    21        34        47        4768    1         28        20        2069    28        28        20        2070    28        28        47        4771    0         0         47        4772    0         34        20        19074    0         0         28        2876    108       108       21        11977    28        108       28        2878    21        130       1         879    28        102       0         080    28        102       0         081    28        51        8         882    0         28        8         883    101       108       108       10884    8         28        28        2885    0         105       134       17586    0         1         1         1887    0         105       126       12688    21        21        24        2491    169       169       238       23892    29        29        7         18293    21        65        21        4494    7         21        1         195    7         21        1         12697    0         12        0         1298    0         21        126       12699    0         12        0         93100   7         7         21        268101   61        133       238       238102   61        93        133       133103   42        42        24        54106   61        160       160       160107   0         36        36        36108   22        22        36        134110   0         1         36        36111   0         0         52        94112   13        13        36        104113   0         1         134       134114   0         36        134       134115   0         51        310       318+116   77        134       134       134117   22        22        134       134______________________________________ +Compound still in test.