AU2007200923A1 - Composition Having Insect Repellent Characteristics - Google Patents

Description

Composition having insect repellent characteristics SThe present invention relates to a composition having insect repellent characteristics and to its use.

(Ni Many insects are known as a nuisance and some insect O 5 genera even represent a health hazard. Mosquitoes are (1 known to transmit diseases like yellow fever, dengue, encephalitis and malaria. The excrement of cockroaches as (1 well as their dead bodies have been identified as a significant allergen in house dust and cause asthma in children. Therefore, many efforts have been made to eradicate or at least to control these pests. Different effective insecticides have been produced until now, but various insects have developed resistance against them and others have been able to detect and avoid them. As many insecticides have undesirable effects on human and other animal life, their use has often been regulated or even forbidden. Furthermore, the public has become sensitive and tend to question the safety of many chemicals which were formerly taken granted. Further the public ask for products which can be applied at low concentrations.

Due to above mentioned concerns, there is a need for a product based on a different principle to get rid off the insects. As physical barriers to the insects are not always possible, e.g. in the open air, insect repellents have become important.

Certain compounds possessing insect repellent characteristics are known including materials such as citronella oil, tolu and Peru balsams, camphor, etc. Other natural sources have been investigated by researchers, A 13788 EP/Mz/Hz/20.12.02 2 e.g. the repellent effect of various eucalyptus against a selection of pests.

Diethyl-m-toluamide (DEET), which is commercially available as Delphone

T

has become a frequently used repellent and is considered to be a general or so called broad spectrum insect repellent. However, fears over possible allergenicity have led to the search for less hazardous insect repellents.

In US 5,182,305 N-aryl and N-cycloalkyl neoalkanamides are described to have insect repellent characteristics. Due to the good substantivity on surfaces they have been applied to, a long lasting repellency can be achieved. Similarly, in US 5'391'578 N-lower alkyl neoalkanamides are described to be superior to DEET in long lasting effectiveness of the insect repellency. In WO 00/16738 menthyl 2are described to be an effective insect repellent, comparable to DEET.

It was an object of the present invention to provide a composition having an outstanding repellent activity against insects.

It was further an object of the present invention to provide a composition having an outstanding repellent activity against German cockroaches.

It was further an object of the present invention to provide a composition, which is of low toxicity and therefore safe to be applied to the human body, pets and livestock.

Surprisingly, it has been found that compounds of formula I possess an insect repellency when applied to areas, A 13788 EP/Mz/Hz/20.12.02 3 locations, items, materials and structures, and to surfaces thereof to protect them against insect infestation and damage.

US Patent 4150052 discloses N-substituted p-methane carboxamides as having pronounced physiological cooling activity, which have little or no odor and which are substantially non-toxic. Said compounds may be readily prepared by methods known to those skilled in the art.

Such methods include e.g. the reaction of pmenthanecarbonyl chloride, obtained from menthane-3carboxylic acid with thionyl chloride, with the appropriate amine in presence of a proton scavenger like e.g. pyridine.

These compounds are 3-substituted-p-menthanes of the formula I:

H

3 R1 I (I) NR2

O

H

3 C CH 3 wherein

R

1 and R 2 represent H or a straight, branched, saturated or unsaturated, aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on the ring system and the number of carbon atoms of the ring system and the substituents to or on the ring system is smaller than and if R 1 is H, R 2 may also be a substituted or A 13788 EP/Mz/Hz/20.12.02 4 Sunsubstituted aryl or heteroaryl residue of with up to carbon atoms for example substituted phenyl, phenalkyl or Ssubstituted phenalkyl, naphtyl, pyridyl, or

SR

1 and R 2 may form together with the nitrogen atom to which they are attached, a cyclic or heterocyclic, saturated or unsaturated ring system having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on Sthe ring system and the number of carbon atoms of the ring system and the substituents to or on the ring system is smaller than 20. Said ring systems may be e.g. piperidino, morpholino etc.

In the above definition the expression "aliphatic or heteroaliphatic residue" embraces e.g. alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxyalkyl, aryloxyalkyl, alkylaminoalkyl, arylaminoalkyl and similar combinations.

The compounds of the invention have 3 stereogenic centers, giving rise to 8 stereoisomers. Thus, all possible stereoisomers are included in the scope of the present invention. In general, compounds of the formula (Ia)

CH

3 R 1 N'R2 l a) H3C OH 3 derived from the naturally occurring menthol menthanol] are much easier accessible and are therefore preferred.

The following compounds of formula I or Ia are preferred, wherein said formula A 13788 EP/Mz/Hz/20.12.02 5

R

1 represents H, and R 2 represents either a straight or branched, saturated or unsaturated, aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or cyclic residue having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on the ring system; or

R

1 represents methyl, and R 2 represents a straight, branched, saturated or unsaturated, aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on the ring system; or

R

1 represents ethyl, and R 2 represents a straight or branched, saturated or unsaturated aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or cyclic residue having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on the ring system or

R

1 represents propyl, and R 2 represents either a straight or branched, saturated or unsaturated aliphatic or heteroaliphatic residue having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on the ring system or

R

1 represents H or a straight or branched C 1 to C 6 aliphatic or heteroaliphatic residue and R 2 represents H or a straight or branched C 1 to C 6 aliphatic or heteroaliphatic residue; or

R

1 represents H and R 2 represents H or a straight or branched C 1 to C 8 aliphatic or heteroaliphatic residue; or A 13788 EP/Mz/Hz/20.12.02 -6- R1 represents H and R 2 represents represents a substituted or unsubstituted aryl or heteroaryl residue with up to carbon atoms; or

R

1 and R 2 form together with the nitrogen atom to which they are attached, a cyclic or heterocyclic, saturated or unsaturated ring system having 4 to 8 carbon atoms not counting carbon atoms of optional substiutents to or on the ring system.

Further preferred compounds are N-methyl-p-menthane-3-carboxamide, N-ethyl-p-menthane-3-carboxamide, N-propyl-p-menthane-3-carboxamide, N-isopropyl-p-menthane-3-carboxamide, N-butyl-p-menthane-3-carboxamide, N-sek-butyl-p-menthane-3-carboxamide, N-tert-butyl-p-menthane-3-carboxamide, N-pentyl-p-menthane-3-carboxamide, N-isopentyl-p-menthane-3-carboxamide, N-hexyl-p-menthane-3-carboxamide, N-octyl-p-menthane-3-carboxamide, N-ethylhexyl-p-menthane-3-carboxamide, N,N-dimethyl-p-menthane-3-carboxamide, N,N-diethyl-p-menthane-3-carboxamide, A 13788 EP/Mz/Hz/20.12.02 7 SN,N-dipropyl-p-menthane-3-carboxamide, CN, N,N-dibutyl-p-menthane-3-carboxamide, N,N-dihexyl-p-menthane-3-carboxamide, SN,N-ditridecylamin-p-menthane-3-carboxamide, CI 5 N-methyl-N-butyl-p-menthane-3-carboxamide, and O N-ethyl-N-butyl-p-menthane-3-carboxamide.

Compositions according to the present invention comprise at least one of the compounds of formula I in an amount effective to repel insects. The amounts in which compounds of formula I are incorporated in the various compositions described below vary within a wide range. The amounts depend on the nature and the intended use of the compositions to which they are added and from the presence or absence of other insect repellent agents. Typical concentrations of the compounds of the present invention are from 1 ppm in diluted use form in floor cleaner up to by weight in compositions which are introduced as a concentrate into the final product. Further variations are possible, due to the reason that the concentration range is considered as not critical.

Compositions comprising a compound of formula I or Ia are applied to objects, which are to be protected against insects, either directly, in liquid solution or dispersion, as aerosols or airsprays, or dispersed in a powdered carrier or in a suitable composition.

Products which are useful to repel insects are for example detergent compositions, cleaning compositions, paints, wallpaper, upholstery and/or rug shampoos, liquid soaps, A 13788 EP/Mz/Hz/20.12.02 8 c soap bars, floor polishes, floor waxes, furniture polishes, etc. Products which are useful to repel insects from the human body are also included in the scope of the present invention and include compositions such as fine S 5 fragrances, colognes, skin creams, sun cremes, skin Chlotions, deodorants, talcs, bath oils, soaps, shampoos, Shair conditioners and styling agents.

0 The compositions of the present invention may comprise C( compounds of formula I in combination with other known insect repellents, including, but not limited to, N,Ndiethyl-m-toluamide (DEET), N,N-diethyl-benzamide, menthyl N-aryl and N-cycloalkyl neoalkanamides, N-lower alkyl neoalkanamides and nepetalactone. The compositions of the present invention may also comprise natural oils known for their insect repellent characteristics. Examples for such oils include, without limiting, e.g. citronella oil, catnip oil, eucalyptus oil, cypress oil, galbanum oil, tolu and Peru balsams.

Compounds of formula I may also be used insecticides in order to repel insects from one area and toward the location, where the insecticide is applied to avoid the action of the insecticide in a special area, such as kitchen etc. Alternatively, compounds of formula I may be formulated with insecticides so that after loosing the repellent activity the treated area will still not be safe for insects.

Compounds of formula I may be added to a liquid composition either directly or, preferably, by admixing a compound of formula I with one or more fragrance compounds, fragrance compositions and the like and adding A 13788 EP/Mz/Hz/20.12.02 -9the resulting mixture to the composition. Such fragrance compounds may be of natural and/or synthetic origin, examples for such natural and synthetic fragrance ingredients can be found e.g. in ,Perfume and Flavor Materials of Natural Origin,,, S. Arctander, Ed., Elizabeth, 1960 and "Perfume and Flavor Chemicals", S. Arctander, Ed., Vol. I II, Allured Publishing Corporation, Carol Stream, USA, 1994. Compounds of formula I may also be added to the composition of the present invention in form of a solution. Solvents which may be used are known to those skilled in the art and include e.g. ethanol, ethylene glycol, propylene glycol, diethyl phthalate and dimethyl phthalate. As a preferred solvent dimethyl phthalate is used, which is known for its insect repellent characteristics.

The compositions of the present invention may comprise other ingredients normally used in the formulation of said compositions. Such ingredients are known to those skilled in the art and include e.g. antifoaming agents, antimicrobial agents, antioxidants, antiredeposition agents, bleaches, colorants, emulsifiers, enzymes, fats, fluorescers, fungicides, hydrotropes, moisturizers, optical brighteners, perfume carriers, perfume, preservatives, proteins, silicones, soil release agents, solubilizers, sugar derivatives, sun screens, surfactants, vitamins, waxes, etc.

Compounds of formula I have an outstanding effect both as contact and vapor repellent. They are superior to various commercial insect repellents in repelling action, especially against German cockroaches, which are considered to be the most difficult household pest to control. Due to their low vapor pressure the compounds of A 13788 EP/Mz/Hz/20.12.02 10 formula I are long-lasting on surfaces they have been applied to. The long-lasting insect repellency may last up to 2-3 weeks after topical application, depending on the concentration used. Furthermore, compounds of formula I are sufficiently stable in the compositions being object of the present invention to maintain their insect repellency.

Compositions of the present invention may also be incorporated in various materials during their manufacturing process. Methods for preparing a product comprising a composition according to the present invention by incorporating said composition into the product during extrusion are preferred.

Compounds of formula I also indicate that they are beside their effectiveness against German cockroaches also effective against other insects such as ants, bees, fleas, flies, hornets, mosquitoes, moths, silverfish, and wasps and against arachnids such as mites, spiders and ticks.

The effectiveness against mosquitoes is important also due to economic reasons, especially against the genera Anopheles (which is a known carrier of malaria and transmits also filariasis and encephalitis), Culex (which is a carrier of viral encephalitis and filariasis) and Aedes (which carries yellow fever, dengue and encephalitis). From the latter genus, the activity against Aedes aegypti is especially important.

The invention will be further described, by way of illustration, in the following examples.

A 13788 EP/Mz/Hz/20.12.02 11 Example 1: Compounds of formula I and Ia have been prepared according to the procedure described in US 4,150,052 (Watson et. al, May 16, 1977) from p-ienthane-3-carboxylic acid.

N-methyl-p-menthane-3-carboxamide I H-NMR (400 MHz, CDCl 3 0.77 3H, J CH 3 0.89 3H, J 6. 3, CH 3 0.-90 3H, J 0, CH 3 0.90- 1. 06 (in, 2H, CH 2 1. 25 (quint. 1H, J =12. 0, CH) 1.27- 1.38 (in, 1H, CH); 1. 53 (tt, 1H, J =11. 3, 2. 8, CH) 1.64- 1.80 (mn, 4H-, 2CH 2 1.-99 (td, 1H, J =11. 3, 3.4, CH) 2.81 3H, J 4. 8, CH 3 5. 56 (br. 1H-, NH) IR cm'1, ATR) :3275m, 2957m, 2928m, 1636s, 1558mn.

MS [in/z 197 1516) 154 (20) 86 (95) 73 (100) 58 (35) 55 (43).

N-ethyl-p-menthane-3-carboxahide 1 H-NMR (400 MHz, CDCl 3 0.78 3H, J CH 3 0.89 3 H, J 6. 4, CH 3 0.-9 0 3 H, J 9, CH- 3 0. 89 1.07 (mn, 2H, CH- 2 1.12 3H, J CH 3 1.27 (quint., 1H, J =12.0, CH); 1.22-1.40 (i,1H, CH); 1.44- 1. 60 (in, 1H, CH); 1. 62-1.82 (mn, 4H, 2CH 2 1. 98 (td, 1H, J 11.4, 3.3, CH); 3.20-3.40 (in, 2H, NCH 2 5.52 1H,

NH).

IR (Vmax, CM 1 ATR) 3270mn, 2957n, 2925n, 2869mn, 1637s, 1559mn.

A 13788 EP/Mz/Hz/20.12.02 12 MS [m/z 211 15%6) 168 (20) 100 (97) 87 (100) 83 (22) 72 (36) 55 (50) 44 (32).

N-propyl -p-menthane- 3-carboxamide 1 H-NMR (400 MHz, CDC1 3 0.78 3H, J CH 3 0.88- 0.94 (in, 9H, CH 2 3 CH 3 0.90-1.07 (in, 2H, CH 2 1.25 (quint., 1H, J 12.1, CH) 1.27-1.40 (i,1H, CH) 1.47- 1. 56 (i,3H, CH, CH 2 1. 65-1. 78 (mn, 4H-, 2CH 2 1. 98 (td, 1H, J =11. 4, 3. 3, CR) 3. 13 30 (mn, 2H, CR 2 5.56 (br., 1H, NH).

IR (Vmax, cm'1, ATR) 3286m, 2956m, 2920m, 1637s, 1553m.

MS [in/z (EIl]: 225 15%6), 182 (18) 114 (82) 101 (100) 86 (28) 55 (45) 43 (52).

N-phenyl-p-menthane-3-carboxamide 1 H-NMR (400 MHz, CDC1 3 0. 83 3H, J 6. 9, CH 3 0.-91 3H, J 6. 3, CH 3 0. 92 3H, J 6. 9, CRO); 0. 95 1.10 2H, CR 2 1.32 (quint., 1H, J 12. 0, CR) 1. 30 1.45 (mn, 1H, CR) 1. 59 92 (in, 5R, CR, 2CR 2 2. 16 (td, 1H, J 11.3, 3.5, CR); 7.09 1H, J 7.25 (br., 1H, NH); 7.31 (in, 2H); 7.53 (dd, 2H, J IR (vmax, cin', ATR) :3250mn, 2963mn, 1651s, 1597s, 1537s, 1442s, 753s.

MS [m/z 259 135 93 (100) 83 (44) (32).

A 13788 EP/MZ/HZ/20.12.02 13 N,N-dimethyl-p-menthane-3-carboxamide IH-NMR (4 00 MHz, CDC1 3 0. 73 Cd, 3H, J 6. 9, CH 3 0.8 9 3H, J 6. 4, CH 3 0.-9 0 Cd, 3H1, J 6. 9, CHA) 0. 92 1. 16 (i,2H, CH 2 1. 18 Ctt, 1H, J 12. 1, 12. 1, CH); 1. 30 1.42 C,1H, CH); 1.60-1.75 (mn, 5H, CH, 2CH 2 2.54 (td, 1H, J =10 3. 5, CH) 2. 95 CHA); 3. 07 Cs, CHA).

IR Cymax, cnf', ATR) :2951m, 2933m, 1639s, 1395m, 1119m.

MS [m/z (EIl]: 211 30%) 168 (22) 100 (100) 87 (92), 72 (86) SS (43).

N,N-diethyl-p-menthale-3-carboxalide 1 H-NMR (4 00 MHz, CDC1 3 0. 75 Cd, 3H, J 6. 9, CH 3 0.8 9 Cd, 31H, J 6. 4, CR 3 0.-9 0 Cd, 311, J 6 CHA); 0. 93 1. 08 (mn, 2H, CH 2 1.-10 3H, J 7. 1, CH 3 1.19 Ct, 311, J 7. 1, CR 3 1. 23 tt, 1H, J 11. 9, 12. 5, CH); 1. 30-1.42 Cm, 1H, CR) 1.6 0 77 Cm, 5H, CR, 2 CR 2 2. 43 Ctd, 1H1, J= 11.5, 3.5, CH); 3.28-3.43 Cm, 4H, 2NCH 2 IR CVmax, cflf 1 ATR) 2954m, 2871mn, 1633s, 1429m, 1121m.

MS [m/z 239 CM+, 32%6), 196 (51) 128 (100) 100 (73) 83 (60) 72 (56) 55 (54) 41 (38).

A 13788 EP/rMz/Hz/20.12.02 14 Example 2: The effectiveness of compounds of formula I as an insect repellent was determined using German cockroaches exposed to a formica surface partially treated/partially untreated with a test compound of formula I.

The study was conducted in an air conditioned laboratory at a temperature of 22 0 ±20C under a normal day/night cycle, using German cockroaches (Blatella Germanica) of mixed sex and age. The study was conducted over a 3 day period and the repellent effectiveness assessed 1, 2 and 3 days after cockroach introduction.

Test method: A. Treatment A rectangle of formica 40cm x 30cm was treated at mg/m 2 with a test compound of formula I. This was achieved by soaking a paper wipe (Rag on a Roll ca x 20cm) in a solution of the test compound in ethanol, squeezing out the excess liquid and wiping over the surface to give the required coverage. This was checked by weighing the cloth after application. The surface was allowed to dry. A similar rectangle was wiped with ethanol alone (untreated surface) B. Bioassays The treated formica rectangle was placed on the bench and a plastic container was placed on the rectangle.

This had been treated with fluon to prevent cockroach escape.

Two sheets of formica (10cm x 10cm) were placed on the A 13788 EP/Mz/Hz/20.12.02 15 formica, one on the treated surface and one on the untreated surface. This acted as a cockroach harbourage. The formica sheet to be used in the treated section was treated at the same rate as the treated formica. The formica was placed on two Icm high bottle tops to allow cockroaches access under the formica.

German cockroaches were added (5 adults and nymphs) to the centre of the formica. No food and water was supplied for these cockroaches.

At i, 2 and 3 days after cockroach introduction the number of cockroaches under each harbourage was counted. After each count the harbourage position was changed to avoid the possibility of habituation to one location, the harbourages were replaced and new cockroaches were added to replace any dead cockroaches.

The above was repeated 3 times to provide a total of 4 replicates.

C. Repellency results for compound 1 (example 1): Time After Replicate Number of Cockroaches present Cockroach Introduction (Days) Treated Untreated Dead Total Section Section 1 5 15 0 1 2 3 17 0 3 7 13 0 4 0 20 0 Total 15 65 0 A 13788 EP/Mz/Hz/20.12.02 16 1 5 15 0 2 2 3 17 0 3 5 14 1 4 0 20 0 Total 13 66 1 1 4 16 0 3 2 3 16 1 3 4 16 0 4 0 20 0 Total 11 68 1 D. In a similar way the repellency results for compound 2, 3, 4, 5 and 6 were determined. All results are summarized in the table below: Test Days After Percentage Present compound Treatment Treated Untreated Dead Section Section 1 18.7 81.3 0 1 2 16.3 82.5 1.2 3 13.8 85.0 1.2 Average 16.3 82.9 1 17.5 82.5 0 2 2 16.3 82.5 1.2 3 13.8 83.7 Average 15.9 82.9 1 16.3 83.7 0 3 2 6.3 92.5 1.2 3 6.3 93.7 0 Average 9.6 90.0 A 13788 EP/Mz/Hz/20.12.02 17 1 46.3 53.7 0 4 2 35.0 65.0 0 3 12.5 86.3 1.2 Average 31.3 68.3 1 15.0 85.0 0 2 10.0 88.8 1.2 3 15.0 83.8 1.2 Average 13.3 85.9 1 11.3 88.7 0 6 2 13.8 86.2 0 3 6.3 91.2 Average 10.5 88.7 All compounds showed good to very good cockroach repellency up to 3 days in this screening experiment.

Example 3: The effectiveness of compound 2 (example 1) as an insect repellent was determined using German cockroaches exposed to a formica surface partially treated/partially untreated, and was directly compared to the repellency of the well known insect repellents DEET (N,N-diethyl-metatoluamide) and N-methyl-neodecanamide.

The study was conducted in an air conditioned laboratory at a temperature of 22 0 ±2 0 C under a normal day/night cycle, using German cockroaches (Blatella Germanica) of mixed sex and age. The study was conducted over a 7 days period and the repellent effectiveness was assessed 1, 3, and 7 days after cockroach introduction. Each tray used in the study consisted of a melamine square tray of sides A 13788 EP/Mz/Hz/20.12.02 18 1.8m x 1.8m and 20cm high walls. The upper part of the wall was provided with electrical strip, which prevented cockroaches escaping.

Test method: A. Treatment A square of vinyl 90cm x 180cm was treated with the test compound at 20mg/m 2 This was achieved by soaking a paper wipe (Rag on a Roll, ca. 20cm x 20cm) in a solution of the test compound in ethanol, squeezing out the excess liquid and wiping over the surface to give the required coverage. This was checked by weighing the cloth after application. The surface was allowed to dry.

B. Bioassays The treated vinyl square was placed in one half of the tray. A similar untreated square was placed in the other half of the tray. This square was treated with ethanol alone.

Two sheets of formica (30cm x 30cm) were placed at one corner of each tray, one on the treated surface and one on the untreated surface. This acted as a cockroach harbourage. The formica sheet to be used in the treated section was treated at the same rate as the treated formica. The formica was placed on two Icm high bottle tops to allow cockroaches access under the formica.

German cockroaches were added (15 adults and nymphs) to the middle of the tray. No food and water was supplied for these cockroaches.

A 13788 EP/Mz/Hz/20.12.02 19 Cc, At 1, 2, 3 and 7 days after cockroach introduction the number of cockroaches under each harbourage was counted. After each count the harbourage position was changed to avoid the possibility of habituation to one 5 location, the harbourages were replaced and new cockroaches were added to replace any dead cockroaches.

The above was repeated 3 times to provide a total of 4 replicates.

C. Repellency results for compound 2 (example 1): Time After Replicate Number of Cockroaches Present Cockroach Introduction (Days) Treated Untreated Dead Total Section Section 1 0 50 0 1 2 0 49 1 3 3 47 0 4 0 50 0 Total 3 196 1 200 1 0 50 0 2 2 1 49 0 3 0 50 0 4 0 49 1 Total 1 198 1 200 1 6 44 0 3 2 3 47 0 A 13788 EP/Mz/Hz/20.12.02 20 3 0 50 0 4 0 49 1 Total 9 190 1 200 1 7 43 0 7 2 19 30 1 3 3 47 0 4 11 38 1 Total 40 158 2 200 D. In a similar way the repellency results for DEET and Nmethyl-neodecanamide were determined. All results are summarized in the table below: Treatment Days after Percentage Present Treatment Treated Untreated Dead Section Section 1 1.5 98.0 2 2 0.5 99.0 3 4.5 95.0 7 20.0 79.0 1 3.0 96.5 DEET 2 2.5 96.0 3 27.5 72.0 7 55.0 44.0 N-Methyl- 1 0.0 99.5 neodecan- 2 11.5 88.5 0.0 amide amide 3 36.5 62.5 7 45.0 54.0 Compound 2 provided excellent repellency with less than cockroaches present on the treated surface at 3 days and only 20% after 7 days. The results obtained are far better A 13788 EP/Mz/Hz/20.12.02 21 than for the benchmark repellents DEET and N-methylneodecanamide.

Example 4: The effectiveness of compound 2 (example 1) as an insect repellent was determined using ants exposed to a formica surface partially treated/partially untreated with compound 2, and was directly compared to the repellency of the well known insect repellents Farnesol and Dihydrofarnesal.

The study was conducted in an air conditioned laboratory at a temperature of 22 0 ±2°C under a normal day/night cycle, using Black Ants (Ochetellus sp) of mixed sex and age. The study ws conducted over a 3 day period and the repellent effectiveness assessed 1, 2 and 3 days after ant introduction.

Test method: A. Treatment One half of a rectangle of formica 40cm x 30cm was treated at 20mg/m 2 with the test compounds. This was achieved by soaking a paper wipe (Rag On A Roll approximately 20cm x 20cm) in a solution of the test compound in ethanol, squeezing out the excess liquid and wiping over the surface to give the required coverage. This was checked by weighing the cloth after application. The surface was allowed to dry. The other half was wiped with ethanol alone (untreated surface).

B. Bioassays A 13788 EP/Mz/Hz/20.12.02 22 The treated formica rectangle was placed on the bench and a glass ring (diameter 20cm) was placed on the rectangle. This had been treated with fluon to prevent ant escape.

A small plastic container 2cm in diameter was placed on the formica, one on the treated surface and one on the untreated surface. The plastic container placed on the treated surface had repellent applied in the same way as the treated formica. The plastic container on the untreated surface was wiped with ethanol.

24 hours after treatment (1 day) 20 ants were added to the centre of the formica. No food and water was supplied for these ants. 2 hours after this the number of ants on the treated and untreated surfaces was counted.

The above was repeated 3 times to provide a total of 4 replicates.

The above was repeated at 2 days and 3 days. New ants were used at each time period.

C. Ant Repellency results for compound 2 (example 1).

Time After Replicate The Number of Black Ants Present Ant Introduction (Days) Treated Untreated Dead Total Section Section 1 0 20 0 1 2 2 18 0 3 1 19 0 A 13788 EP/Mz/Hz/20.12.02 23 4 0 20 0 Total 3 77 0 1 1 19 0 2 2 3 17 0 3 2 18 0 4 3 17 0 Total 9 71 0 1 0 20 0 3 2 1 19 0 3 2 18 0 4 3 17 0 Total 6 74 0 D. In a similar way the ant repellency results for Farnesol and Dihydrofarnesal were determined. All results are summarized in the table below: Treatment Days After Percentage Present Treatment Treated Untreated Dead Section Section 1 20.0 80.0 0 Dihydro- 2 21.2 78.8 0 farnesal 3 12.5 87.5 0 Average 17.9 82.1 0 A 13788 EP/Mz/Hz/20.12.02 24 1 20.0 80.0 0 Farnesol 2 10.0 90.0 0 3 20.0 80.0 0 Average 16.7 83.3 0 1 3.7 96.3 0 2 2 11.2 88.8 0 3 7.5 92.5 0 Average 7.5 92.5 0 All 3 products gave repellency of ants at the three time periods 2 and 3 days) after treatment and there was no reduction in repellency at 3 days. The average percentage of ants on the treated section was approximately 17% for Dihydrofarnesol and Farnesol. The compound 2 of the present invention was superior to these two products and gave an average percentage of ants on the treated of Example The effectiveness of compound 2 (example 1) to reduce the presence of cloth moths on woolen cloth was determined and was directly compared to the repellency of the well known moth repellents Citronellol and Farnesol.

The study was conducted in an air conditioned laboratory at a temperature of 22 0 ±2 0 C under a normal day/night cycle, using Casemaking Clothes Moths (Tinea pellionella) of mixed sex and age. The study is conducted over a 5 days period and the repellent effectiveness was assessed as follows: Adults 2 days after insect introduction A 13788 EP/Mz/Hz/20.12.02 25 Test Method: A. Treatment Cc, A 10cm x 10cm square of black woolen fabric free of bactericide) was soaked in a solution of the candidate repellent in ethanol at 20g/L, squeezed and allowed to dry. The woollen square was placed in a small box x 10cm x 10cm) which was open at one end to allow entry of adult clothes moth.

A similar square of fabric treated with ethanol (control) was placed in another box of the same size.

B. Bioassays These two boxes were placed in an aquarium and 50 mixed sex adult moths were added. These were provided with food and water and left for 5 days.

At the end of 2 days the number of adult moths in each box was counted.

The above was repeated 3 times to provide 4 replicates.

C. Adult Moth Repellency results Compound Time After Replicate The Number of Moths Moth Present Introduction (Days) Treated Untreated Section Section 1 6 9 2 2 2 7 19 3 11 27 A 13788 EP/Mz/Hz/20.12.02 26 4 8 22 Total 32 77 (70.6%) 1 7 Citro- 2 nellol 2 0 12 3 5 26 4 14 Total 26 83 (76.1%) 1 9 18 Farnesol 2 2 4 19 3 5 21 4 9 19 Total 27 77 (74.0%) E. Results Adult repellency: Compound 2 of the present invention shows similar repellency activity as the benchmark repellents Citronellol and Farnesol and differences are small (range 23.9% to 29.4% of adults on treated surfaces).

Example 6: Cockroach repellency test in floor cleaner application The effectiveness of the compounds of formula I as an insect repellent was tested using German cockroaches (Blattella germanica) exposed to a surface partially treated/partially untreated with a test compound of formula I. The effectiveness was measured by counting in regular intervals the number of cockroaches in the two A 13788 EP/Mz/Hz/20.12.02 27 sectors of the test area and by observation of the behavior of the cockroaches.

A test room of 30 m 3 having a ground surface area of 12 m 2 was used for the tests, fulfilling the test norms AFNOR NF T 72-320 for efficiency tests of the aerosol type.

Test insects: German cockroaches (Blattella germanica), both sexes, 2 to 15 days old (origin standard INA).

The ground surface of the room was divided diagonally into two equal pieces by black adhesive tape. In the middle of the area a circle having 30 cm in diameter was marked.

One half of the surface, with the exception of the circle in the middle, was treated with 5 ml of a cleaning solution comprising the compound of formula I to be tested.

After the treated surface was dry again, 40 cockroaches were placed in the circle in the middle of the surface.

During a period of 1 hour the positions of the cockroaches were determined every 5 minutes.

For each time point the number of insects (in on the untreated side was determined.

Example 7: N-ethyl-p-menthane-3-carboxamide was added at 0.05% by weight to a regular all-purpose cleaner (APC), prepared according to example 10. This floor cleaner base was diluted at 2% into water and 5 ml of this solution A is applied to one half of the test surface (example 1) A 13788 EP/Mz/Hz/20.12.02 28 Similarly, a solution B, comprising nepetalactone (benchmark), was prepared and tested. The results are summarized in the table below: Compound insects on untreated side after 5 min after 1 h APC base, no additives 42% Solution B, 81% 77% nepetalactone Solution A, 86% 91% Compound 2, example 1 The APC containing compound 2 exhibited very good repellency, far better than the APC containing the benchmark repellent nepetalactone.

Example 8: The effectiveness of perfume compositions to repel ants was determined by analyzing data of counts of ants on the treated side of arenas half-treated with the test perfume compositions. Insects used for this study were pharaoh ants (Monomorium pharaonis), active workers from a wild colony. All ants were checked prior to the test to see whether their antennae are intact. Per replicate 20 ants were used.

Test method: A. Treatment One half of a 40cm x 70cm arena was treated at 10 g/m 2 r A 13788 EP/Mz/Hz/20.12.02 29 with the test solution. This was achieved by direct spraying ethanolic solutions containing 0.5% perfume A and B, respectively, to the floor of the arenas. The pump sprays were weighed before and after. The other half of the arena was treated with ethanol alone.

B. Bioassay The ants were introduced to the arena on the untreated side and their behavior monitored by recording whether the ants that approach the product boundary cross the boundary or turn away and avoid crossing. To ensure that there was no directional bias to the ants behavior, the arenas were rotated through 1800. Their behavior was monitored by recording whether the ants that approached the product boundary crossed or turned away. For each test 2 replicates were conducted.

C. Data Analysis The repellency results were calculated using the following equations: Repellency (number of ants turning away from the boundary number of ants approaching the boundary) x 100.

Example 9: The effectiveness of a perfume composition comprising compound 2 (example 1) to repel ants was determined according to the procedure described in example 8. The repellency of this perfume composition (perfume A) was compared to a composition without compound 2 (perfume B).

Composition of the tested perfumes A and B: A 13788 EP/Mz/Hz/20.12.02 30 Ingredients Parts per weight Perfume A Perfume B Bergamotte Essence Italie 100.0 100.0 Canelle Essence Chine 2.0 Farnesoll) 4.0 Galbanum Essence 2.0 Georgywood 2) 15.0 15.0 Ionone Beta 3 25.0 25.0 Lavandin Grosso Essence 50.0 50.0 Lina 1001 4 75.0 75.0 Litsea Cubeba Essence 75.0 75.0 Menthe Crepue Essence USA 2.0 Orange Essence Florida 200.0 200.0 Peonil1 e 5 50.0 50.0 Salicylate Benzyle 250.0 250.0 Dipropylene glycol 0.0 150.0 N-ethyl-p-menthane-3-carboxamide 150.0 0.0 Total 1000.0 1000.0 '~3,7,11-Trimethyl-2,6,1O-dodecatrien-l-o1 2) 1 (1,2,8,8-Tetramethyl-1,2,3,4,5,6,7,8-octahydro-naphthalen-2-yl)- (3E)-4-(2,6,6-Trimethyl-1-cyclohexen-1-yl)-3-buten-2-one 4 3,7-Dimethyl-1,6-octadien-3-ol 2-Cyclohexylidene-2-phenylacetonitrile Repellency Results: Time after No. of ants No. of ants Repellency ant intro- crossing the approaching the duction boundary boundary Perfume Perfume Perfume Perfume Perfume Perfume A B A B A B O h 45 36 47 52 95.7 69.2 24 h 32 28 39 43 82.0 65.1 48 h 45 31 51 48 88.2 64.6 72 h 36 26 49 41 73.5 r63.4 A 13788 EP/MZ/Hz/20.12.02 31 The perfume A gave very good repellency results against ants ranging from 96% (after application) to 74% (3 days after application) and had overall much better repellency properties than the corresponding perfume without compound 2 (perfume B).

Example Compositions suitable for use in the present invention include the following: A. All Purpose Cleaner (APC CLASSIC: FBA 001) INGREDIENTS CHEMICAL NAME %w/w PHASE A CITRIC ACID DEIONISED WATER PHASE B HOSTAPUR SAS 60 NEODOL 91/8 DOWANOL DPnB TEA (98%) NaOH(50%) 1.05 To 100 Na paraffin sulfonate Ethoxylated fatty alcohol C 9

C

11 8EO n-Butyl ether of propylene glycol Triethanolamine Sodium hydroxide 2.00 1.00 4.00 1.00 1.20 0.1 0.1 PHASE C PARMETOL DF 35 N-Ethyl-p-menthane-3-carboxamide

PROCESS:

While stirring, add one after the other parts A, B and C.

The pH value of the finished product is 9.3.

B. All purpose cleaner (APC disinfectant: FBA 005) A 13788 EP/Mz/Hz/20.12.02 32

INGREDIENTS

DEIONIZED WATER TRISODIUM CITRATE*2H 2 0 TRILON B TRILON A 92 ARQUAD 16/29 I NEODOL 45/7 CHEMICAL NAME Tetra sodium salt of EDTA Fri sodium salt of EDTA -exadecyl trimethyl ammonium chloride Ethoxylated fattyalcohol C14-C15 7EO

%W/W

To 100 0.8 0.4 0.2 0.1 0.1 BDGE Butyl dioxitol PARMETOL A 26 N-Ethyl-p-menthane-3-carboxamide (2)

PROCESS:

Mix at room temperature the different components in the order listed.

The pH value of the finished product is 8.10.

C. All purpose cleaner (APC SOAPY CLEANER FBA 006)

INGREDIENTS

DEIONISED WATER CHEMICAL NAME %w/w 50.00 1.00 COCONUT OIL TEA (98%) Triethanolamine Potassium hydroxide 1.50 0.40 KOH (50%) DEIONISED WATER 30.00

CARBITOL

NEODOL 91/8 Ethoxy diglycol Ethoxylated fatty alcohol 3.00 6.00 0.10

C

9

C

11 8EO N-Ethyl-p-menthane-3-carboxamide (2)

WATER

qs to 100.00 A 13788 EP/Mz/Hz/20.12.02 33

PROCESS:

Heat to 450C with stirring 50% of the deionised water. Add in order, KOH, TEA and the Coconut Oil. Stir for minutes. Add in order 30% of DI water with stirring, Carbitol, Neodol 91/8 and N-Ethyl-p-menthane-3carboxamide. Stir for 15 minutes. Add the remaining DI water and adjust the pH to 8.5 with KOH Stir for minutes.

D. Hydroalcoholic Cream (DED 002)

INGREDIENTS

PHASE A BRIJ 72 BRIJ 721 ARLAMOL E STEARYL ALCOHOL PARAFFIN OIL CETIOL OE PHASE B CARBOPOL 980 DEMINERALISED WATER CHEMICAL NAME Steareth-2 Steareth-21 PPG-15 Stearyl Ether Stearyl alcohol Mineral Oil Dicaprilyl ether Carbomer

%W/W

4.00 2.00 8.50 1.50 4.00 3.00 0.25 qsp 100 PHASE C NaOH (10%) Sodium Hydroxide qsp pH 6.0 to PHASE D ETHYL ALCOHOL 96 Alcohol N-Ethyl-p-menthane-3-carboxamide (2) 20.00 0.50 A 13788 EP/Mz/Hz/20.12.02 34

PROCESS:

Disperse Carbopol in water at 45 0 C, then heat Phase A and B to the same temperature (around 70 oC) under high stirring. When cooled add sodium hydroxide, alcohol and N- Ethyl-p-menthane-3-carboxamide.

E. AHA CREAM GEL:

INGREDIENTS

CRODAMOL MM SEPIGEL 305 DEIONISED WATER DED 004 CHEMICAL NAME %W/W Myristyl Myristate Polyacrylamide, C13-C14 Isoparaffin, Laureth 7 3.00 4.00 AHA CONCENTRATE Citric acid, tartaric acid, lactic acid, malic acid, ascorbic acid, glycolic acid, salycilic acid GERMABEN II Propylene glycol, Diazolidinyl urea, Methylparaben, Propylparaben N-Ethyl-p-menthane-3-carboxamide (2) qsp 100 5.00 1.00 0.50

PROCESS:

Heat CRODAMOL MM to 60 0 C. At 50 0 C add SEPIGEL under stirring. Then add water preheated to 50 0 C under stirring.

At 40 0 C add the rest of the constituents. Adjust the pH with sodium hydroxide to F. HYDROGEL (DED 005) A 13788 EP/Mz/Hz/20.12.02 35

INGREDIENT

CARBOPOL 980 PEMULEN TR1 LUBRAGEL CG CHEMICAL NAME Carbomer Acrylate/ C10-C30 Alkyl acrylate crosscopolymer Polyglycerylmethacrylate propylene glycol UCON 75H450 PEG/PPG-17/6 copolymer GLYCERIN Glycerol D PANTHENOL Panthenol HEXYLENE GLYCOL Hexylene Glycol DEIONISED WATER GERMALL 115 Imidazolidinyl Urea DEIONISED WATER NaOH Sodium Hydroxide qsp pH CREMOPHOR RH 40 PEG 40 Hydrogenated Castor oil N-Ethyl-p-menthane-3-carboxamide (2) %w/w 0.50 0.20 0.50 1.00 4.00 2.00 2.00 77.90 0.60 10.00 5.50 1.00 0.50

PROCESS:

Add D-Panthenol and glycerol to the water, then disperse Carbopol 980, then Pemulen TR 1, then add the rest of the constituents.

A 13788 EP/Mz/Hz/20.12.02

Claims (15)

1. The use of a compound of formula I as an insect repellent H 3 R1 N'R2 I) 0 H 3 C CH 3 wherein R 1 and R 2 represent independently H or a straight or branched, saturated or unsaturated aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue having 4 to 8 carbon atoms not counting optional substituents to or on the ring system; and if R 1 is H, R 2 may also be a substituted or unsubstituted aryl or heteroaryl residue with up to carbon atoms, or R I and R 2 may form together with the nitrogen atom to which they are attached, a cyclic or heterocyclic, saturated or unsaturated ring system having 4 to 8 carbon atoms not counting optional substituents to or on the ring system.

2. The use of a compound according to claim 1 wherein the compound is A 13788 WO/ 04.03.2002 37 NR2 (la) H 3 C CH 3 wherein R 1 and R 2 have the same meaning as in claim 1.

3. The use of a compound according to any of the preceding claims, wherein in said compound R 1 represents H, and R 2 represents a straight or branched, saturated or unsaturated aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue having 4 to 8 carbon atoms not counting the carbon atoms of optional substituents to or on the ring.

4. The use of a compound according to claim 1 or claim 2, wherein in said compound R 1 represents methyl, and R 2 represents a straight or branched, saturated or unsaturated aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue having 4 to 8 carbon atoms not counting the carbon atoms of optional substituents to or on the ring.

5. The use of a compound according to claim 1 or 2, wherein in said compound R 1 represents ethyl, and R 2 represents a straight or branched, saturated or A 13788 WO/ 04.03.2002 38 unsaturated aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue K having 4 to 8 carbon atoms not counting the carbon atoms of optional substituents to or on the ring. 5

6. The use of a compound according claim 1 or 2, wherein in said compound R R represents propyl, and R 2 represents a straight or branched, saturated or unsaturated aliphatic or heteroaliphatic residue having 1 to 20 carbon atoms, or a cyclic residue having 4 to 8 carbon atoms not counting the carbon atoms of optional substituents to or on the ring.

7. The use of a compound according claim 1 or 2, wherein in said compound R 1 represents H or a straight or branched Ci to C 6 alkyl residue and R 2 represents H or a straight or branched C 1 to C 6 aliphatic or heteroaliphatic residue.

8. The use of a compound according to claim 1 or 2, wherein in said compound R 1 represents H R 2 represents H or a straight or branched Ci to C 8 aliphatic or heteroaliphatic residue.

9. The use of a compound according claim 1 or 2, wherein in said compound R 1 represents H, and A 13788 WO/ 04.03.2002 39 R 2 represents a substituted or unsubstituted aryl or heteroaryl residue with up to 10 carbon atoms.

Ki The use of a compound according to claim 1 or 2, wherein in said compound Ki R I and R 2 form together with the nitrogen atom to which they are attached, a cyclic or heterocyclic, saturated or unsaturated ring system having 4 to 8 DDcarbon atoms not counting optional substituents to or on the ring system.

11. The use of a compound of formula I or Ia as defined in claim 1 or claim 2 as arachnid repellent.

12. The use of a compound of formula I or Ia as insect repellent in a composition comprising a compound selected from solvents, fragrance ingredients, insecticides, and insect repellents.

13. The use of a composition according to claim 12 in a product selected from the list of household products, industrial cleansing products, pet and livestock care products, fabrics, plastic materials, and covering materials.

14. Method for preparing a product comprising a composition according to claim 12 by incorporating said composition into a product during their manufacturing process.

15. A package containing a product comprising a compound of formula I as an insect repellent or arachnid repellent, together with instructions for the use of said product as an insect repellent and/or arachnid repellent. A 13788 WO/ 04.03.2002