Indian Patents. 268615:NEW INSECT REPELLENTS

Title of Invention	NEW INSECT REPELLENTS
Abstract	The invention comprises 2-phenylacetamide compounds of General Formula I having insect repellent properties which are effective and easy to prepare. These compounds can be used as an active ingredient to make any insect repellent formulations such as creams, sprays or any other forms and thus can be used safely for personal protection.

Full Text	Field of the invention This invention comprises aromatic amides derivatives which can be used as insect repellent. These compounds can be used as an active ingredient to make insect repellent formulations such as creams, sprays, aerosols or any other forms suitable for application of the repellent and that can be used safely for personal protection. Background of invention Insects like mosquitoes, biting flies, chiggers and ticks can be annoying and pose a serious risk to public health. Particularly female mosquitoes feed on human blood to help their egg develop into offspring. When it bites, it may cause allergic reactions such as rashes or lesions, itchy red bumps in addition to the painful bite. Not only they disturb normal activities, but may also transfer different insect borne diseases, such as malaria, yellow fever, filariasis, tularemia, encephalitis, typhus disease, which every year cause death of millions of person. Worldwide, however, mosquitoes transmits disease to more than 70 crore people annually and are responsible for the death of 1 of every 17 people currently alive. The only way to protect from such insect problems is to use personal protection products containing insect repellents. Insect repellents are chemical substances that protect people from insect attack by making the body unattractive or offensive to the insects. A repellent does not have to kill insects to be effective, although some are natural botanical products. The use of insect repellent compounds dates back to antiquity, when various plant oils, smokes, tars, etc. were used to displace or kill insects. Before the Second World War, there were only four principal repellents: oil of citronella, sometimes used as a hair dressing for head lice, dimethyl phthalate, discovered in 1929, Indalone R, which was patented in 1937 and rutgers 612, which became available in 1939. At the outbreak of World War II, the later three components were combined into a formulation for use by military known as 6-2-2; six parts dimethyl phthalate, two parts indalone and two parts rutgers 612. by 1956, more than 20,000 compounds were screened for the potential mosquito repellent activity in US. In 1953, the insect repellent properties of N,N-diethyl-m-toluamide were discovered and the first DEET product was introduced in 1956. DEET is still the most widely used mosquito repellent in US. Although DEET is very popular compound world wide, and has generally been regarded as safe, its toxic effects have been recorded,including encephalopathy in children, urticaria syndrome, anaphylaxia, hypotension and decreased heart rate. Toxicology studies in rats and dogs in which sublethal intraperitoneal injections were used revealed that DEET could induce dose dependent hypotension and bradycardia. Another compound, N,N-diethylphenyl acetamide (DEPA) was developed by the DRDO Gwalior, to use as a multi-insect repellent in India. It is also commercially available in various formulations in India. It has similar cosmetic properties to DEET, similar dermal absorption and excretion, plus symptoms of acute poisoning with DEPA are similar to DEET (S.S Rao et al, Toxicologic studies of an insect repellent N,N-diethy!phenylacetamide, Indian J Med Res, 1987, 85, 626). (Formula Removed) Bayer AG plans to market a mosquito repellent with the name BayrepelR, the active ingredients of which is 1-piperdinecarboxylic acid, 2-(2-hydroxyethyl)-l-methylpropylester (KBR 3023). (Formula Removed) Merck 3535 is an insect repellent for application to human skin and clothing in public health operations.to repel biting arthropods such as mosquitoes.flies and ticks. It was developed in 1975 by Merck and the efficacy of IR3535 was independently evaluated by Cilek et al. In comparative efficacy study of IR3535 and DEET as repellents against adult Aedes aegypti and Culex quinquefasciatus. J. Amer. Mosquito Control Assoc, 2004, 20 (3), page 299-304. Although it has low toxicity but it is irritating to eyes and sometime skin. Efficacy data present for IR 3535 is variable. (Formula Removed) sec-butyl 2-(2-hydroxyethyl)piperidine-1 -carboxy late (KBR3023orPicaridin) In addition to the above synthetic chemicals, plant-derived substances are also reported and available in various insect repellent formulations. Plant whose essential oils have been reported to have repellent activity include citronella. cedar, verbena, pennyroyal, geranium, lavender, pine, cajeput, cinnamon, rosemary, basil, thyme, allspice, garlic and peppermint. The main drawback of these natural oils is that unlike synthetic insect repellents, plant-derived repellents have been relatively poorly studied. When tested, most of these essential oils tended to give short- lasting protection, usually less than 2 hours. There is a need to develop new repellent molecules that can overcome the disadvantages or drawbacks of those known in the art. The new compounds should be effective and easy to prepare. Objects of the invention An aspect of the present invention is to provide 2-phenylacetarnide insect repellent compounds for the purpose of personal protection. Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds which are simple to prepare. Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds, which repel the insect effectively without side effects and are safe for human use. Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds, which are stable for atleast 2 years. Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds that can be used in the form of insect repellent formulations. Statement of the invention According to the present invention, there is provided an insect repellent 2-phenylacetamide compound represented by General Formula I: wherein Rb R2, R3, R4, R3 are independently -OCH3, -CH3 or H. Summary of the invention The present invention comprises 2-phenylacetamide compounds having insect repellent properties. These compounds are characterized by a combination of excellent repellent activity, long stability period, extended protection time and no toxicity and long stability. These compounds can be used as active ingredients in insect repellent formulation such as in form of spray, cream, solution or the kind of any formulation which is conveniently applicable as a mosquito repellent. Detailed description of the invention Effective insect repellents are an important tool to protect people from serious mosquito-and tick-borne disease. Each year, millions of people die from diseases transmitted by insects. The most familiar insect pest is the mosquito. These flying insects acting as major vectors have been responsible for much of the lethal diseases that are felt worldwide and are regarded as a global health problem, mosquitoes transmit disease to more than 70 crore people annually. The insect repellent compounds provided by this invention can be represented by the following general formula I: (Formula Removed) wherein R1 R2, R3, R4, R3 are independently -OCH3, -CH3 or H. In a preferred embodiment, the compound of formula II N,N-Diethyl-3-methoxy-2-phenyl acetamide is used as an insect repellent. (Formula Removed) In an another preferred embodiment the compound of formula (III) N,N-Diethyl-2-(4-methoxyphenyl) acetamide is used as an active ingredient for repelling insects. Yet in an another preferred embodiment compound of formula IV N,N-Diethyl-2-m-tolyl-acetamide or N,N-Diethyl-2-(3-methylphenyl) acetamide is used as an insect repellent. (Formula Removed) In an another preferred embodiment, compound of formula V N,N -Diethyl-2-p tolyl-acetamide or N,N-Diethyl-2-(4-methylphenyl) acetamide is used as an active ingredient for repelling insects. The compounds of the present invention can be used to prepare formulations. These compounds can be used as an active ingredients or in the combination with other known repellent compounds in the personal protection products in various forms such as aerosols, sprays, creams, and other suitable formulations which can be used for application as an insect repellent. The active ingredient contained in the mosquito repellent may be in the range of 5 to 30 % w/w of the final product. The formulations can be prepared with other suitable additives such as inert ingredients to form base for the formulation. The inert ingredients to be used for preparation of repellent may depend on the form of the final product. Mosquito repellents are prepared as aerosols, pumps, lotions, and oils or any other suitable form which can be used as a mosquito repellent. Mosquito repellents that are prepared as lotions or creams are essentially skin creams which have active ingredient added at a certain level. They are primarily composed of water, surfactants, fatty alcohol (such as cetyl alcohol, cetostearyl alcohol), fragrance, and other emollients (such as liquid paraffin). Other ingredients include higher fatty acids like stearic acid alongwith use of alkalies such as sodium hydroxide, potassium hydroxide, borax, triethanolamine (TEA), etc. Humectants such as glycerin, polyproylene glycol and sorbitol are used which prevent the evaporation of moisture from the skin surface. When applied to the skin, these products have the dual benefit of repelling mosquitoes and moisturizing skin. Aerosols are the most common form for mosquito repellents. They are made up of few different types of ingredients, including a solvent, a propellant and miscellaneous ingredients. The solvent is usually an organic alcohol such as ethanol or propanol which dilutes the active ingredient to an appropriate concentration. It also aids in keeping all of the raw materials mixed, ensuring that the product will remain effective even after long-storage. The propellant is a volatile compound which creates the pressure that causes the rest of the product will remain effective even after long-term storage. The propellant is a volatile compound which creates the pressure that causes the rest of the product to be forced out of the container. Common propellants include liquefied hydrocarbon gases like propane, butane or isobutane, hydrofluorocarbons, and dimethyl ether. Other ingredients such as fragrances and emollients are added to aerosol mosquito repellents to make them more cosmetically appealing. Still other compounds are added to prevent corrosion and other stability problems (i.e. preservatives such as methyl paraben, ethyl paraben, butyl paraben and propyl paraben). A solution of active ingredient can be prepared in oil of plant origin such as coconut oil, soyabean oil, cedar oil, chrysanthemum oil, clove oil, eucalyptus oil, fennel oil, lavender oil, lemongrass oil, neem oil, peppermint oil, soyabean oil and the kind, to provide protection from insects. It has been found that a combination of various repellent compounds of the present invention alongwith any conventional mosquito repellent provide greater effectiveness than any of the compound alone. Those skilled in the art will recognize that numerous applications, variations and modifications from these compounds of the invention are possible from the details herein. The following examples are given by the way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention. Examples: 1) Preparation of N,N-Diethyl-3-methoxy-2- phenyl acetamide 3-methoxy-2- phenylacetic acid (0.5 mole) was taken in a 1 liter two necked round bottom flask fitted with water condenser and a calcium chloride guard tube. This was placed over a magnetic stirrer cum hot plate. To this, freshly distilled thionyl chloride (0.7 mole) was added slowly using a pressure-equalizing funnel fitted in the side neck of the round bottom flask. After complete addition, the reaction mixture was stirred constantly and was heated at 100 degree C. so that thionyl chloride gets re-fluxed for 4 hours. After completion of the reaction, the flask was cooled; excess thionyl chloride was distilled off and then pure 3-methoxy-2-phenyl acetyl chloride was distilled under vacuum. This pure 3-methoxy-2-phenyl acetyl chloride was taken in a two necked round bottom flask fitted with a reflux condenser and calcium guard tube. To this diethyl amine (0.7mole) diluted with 50 ml of anhydrous dichloromethane was added dropwise using a pressure equalizing funnel with constant stirring of the reaction mixture. Though the reaction was exothermic, the temperature was maintained by the reflux of dichloromethane. After complete addition, the reaction mixture was stirred for 1 hour and then cooled. Pure N,N-Diethyl-3-methoxy-2- phenyl acetamide was obtained by distillation of the reaction mixture under the vacuum. The purity of the compound analyzed using GC was 99%. (Formula Removed) Similarly, other amides viz N,N Diethyl-4-methoxy-2-phenylacetamide, N,N-Diethyl-3-methyl-2-phenylacetamide, N,N-Diethyl-4-methyl-2-phenylacetamide were synthesized using 4-methoxy-2-phenylacetic acid, 3-methyl-2-phenylacetic acid, 4-methyl-2-phenylacetic acid respectively as starting materials respectively instead of 3-methoxy-2-phenylacetic acid. All these compounds were also checked for their purities and analysed by spectroscopy techniques. 2) Preparation of spray for personal protection A solution of N,N-Diethyl-4-methoxy-2-phenylacetamide (20% w/w) as an active ingredient, is mixed with isopropanol (Pharmacopeia grade) to prepare a spray solution for personal protection. 3) Preparation of cream for personal protection by using N,N-Diethyl-4-methyl-2-phenyacetamide: A solution of N,N-Diethyl-4-methyl-2-phenyacetamide (20% w/w) as an active ingredient, is mixed with stearic acid (13%), stearyl alcohol (1%), cetyl alcohol (1%), glycerine (5%), methyl paraben (0.05%), propyl paraben (0.05%), potassium hydroxide (0.9%), and pure water to make 100 % to prepare a cream for personal protection from insects. This cream can be applied on the exposed areas of skin to protect from mosquito bites. 4) Preparation of cream for personal protection by using N,N-Diethyl-4-methoxy-2-phenylacetamide: A solution of N,N-Diethyl-4-methoxy-2-phenylacetamide (20% w/w) as an active ingredient, is mixed with stearic acid (13%), stearyl alcohol (1%), cetyl alcohol (1%), glycerine (5%), methyl paraben (0.05%), propyl paraben (0.05%), potassium hydroxide (0.9%), and pure water to make 100 to prepare a cream for personal protection from insects. This cream can be applied on the exposed areas of skin to protect from mosquito bites. 5) Evaluation of bioefficacy of the insect repellent compounds: The insect repellent property of these compounds was evaluated against mosquitoes at Entomology Division, DRDO, Gwalior. Behavioral responses of Aedes aegypti mosquitoes to the chemically synthesized compounds, mentioned above,ware studied using Y-maze olfactometer. Mosquitoes showed better flight orientation towards the control than the above compounds application site in the behavioral study showing clearly the repellent property. The bioefficacy test for the determination of the protection time was performed on 20% concentration of the compounds in isopropanol, used as solvent. The protection time of the analogs are shown in the following table (Table Removed) 6) Evaluation of Toxicological effect of the insect repellent compounds for human use: The toxicological effect of the insect repellent compounds was carried out at Toxicology Division DRDO, Gwalior. The various test parameters included, Primary Skin Irritation Index (PSII), Dermal Toxicity Studies, Biochemical analysis such as WBC, RBC, HGB, and platelets in the blood, Cholesterol, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in the serum. The Primary Skin irritation Index (PSII) i.e the average sum of erythema and edema for all sites on all rabbits were computed and the following result were observed. The PSII value for all these compounds are shown in the following table. (Table Removed) The PSII value of N,N-Diethyl-2-(3-methylphenyl) acetamide was calculated to be 0.125. The scoring scale showed that the compound is negligibly irritant. The PSII value for N,N-Diethyl-2-(4-methylphenyl) acetamide was found to be zero. The scoring scale showed that the compound was non-irritant. The PSII value for N,N-Diethyl-3-methoxy 2- phenyl acetamide and N,N-Diethyl-2-(4-methoxyphenyl) acetamide was calculated to be zero. The scoring scale showed that both the compounds were not irritant. The dermal LD50 data shows that the above new compounds viz. N,N-Diethyl-2-(3-methylphenyl) acetamide, N,N-Diethyl-2-(4-methylphenyl) acetamide, N,N-Diethyl-3-methoxy 2-phenyl acetamide, N,N-Diethyl-2-(4-methoxyphenyl) acetamide was greater than 6400 mg/kg. The comparative toxicological evaluation data shows that these compounds are safer as compared to presently known insecticides and repellents revealing the safety profile of the compounds. Following the oral and dermal toxicological study data, there was no significant effect on the body weight of mice and rats, respectively, during fourteen days study. Thus the toxicological studies of the compounds clearly showed that these are safe for human use. We claim: 1. Insect repellent acetamide compounds represented by General Formula I(Formula Removed) wherein R1 R2, R3, R4, R5 are independently -OCH3, -CH3 or H. 2. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-3-methoxy 2- phenyl acetamide. (Formula Removed)3. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-2-(4-methylphenyl) acetamide.(Formula Removed) 4. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-3-methoxy 2- phenyl acetamide. (Formula Removed) 5. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-2-(4-methoxyphenyl) acetamide. 6. An insect repellent composition comprising 5 to 30 % w/w of the 2-phenylacetamide compound as claimed in claim 1. 6. The insect repellent composition as claimed in claim 6 wherein the composition is in the form of a spray, cream or an aerosol. 7. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is used as an active ingredient in insect repellent composition. 8. The Insect repellent acetamide compound such as herein described with respect to foregoing examples. 10. The insect repellent composition such as herein described with respect to the foregoing examples.

Full Text

Field of the invention
This invention comprises aromatic amides derivatives which can be used as insect repellent. These compounds can be used as an active ingredient to make insect repellent formulations such as creams, sprays, aerosols or any other forms suitable for application of the repellent and that can be used safely for personal protection.
Background of invention
Insects like mosquitoes, biting flies, chiggers and ticks can be annoying and pose a serious risk to public health. Particularly female mosquitoes feed on human blood to help their egg develop into offspring. When it bites, it may cause allergic reactions such as rashes or lesions, itchy red bumps in addition to the painful bite. Not only they disturb normal activities, but may also transfer different insect borne diseases, such as malaria, yellow fever, filariasis, tularemia, encephalitis, typhus disease, which every year cause death of millions of person. Worldwide, however, mosquitoes transmits disease to more than 70 crore people annually and are responsible for the death of 1 of every 17 people currently alive. The only way to protect from such insect problems is to use personal protection products containing insect repellents. Insect repellents are chemical substances that protect people from insect attack by making the body unattractive or offensive to the insects. A repellent does not have to kill insects to be effective, although some are natural botanical products.
The use of insect repellent compounds dates back to antiquity, when various plant oils, smokes, tars, etc. were used to displace or kill insects. Before the Second World War, there were only four principal repellents: oil of citronella, sometimes used as a hair dressing for head lice, dimethyl phthalate, discovered in 1929, Indalone R, which was patented in 1937 and rutgers 612, which became available in 1939. At the outbreak of World War II, the later three components were combined into a formulation for use by military known as 6-2-2; six parts dimethyl phthalate, two parts indalone and two parts rutgers 612. by 1956, more than 20,000 compounds were screened for the potential mosquito repellent activity in US. In 1953, the insect repellent properties of N,N-diethyl-m-toluamide were discovered and the first DEET product was introduced in 1956. DEET is still the most widely used mosquito repellent in US.
Although DEET is very popular compound world wide, and has generally been regarded as safe, its toxic effects have been recorded,including encephalopathy in children, urticaria syndrome, anaphylaxia, hypotension and decreased heart rate. Toxicology studies in rats and dogs in which sublethal intraperitoneal injections were used revealed that DEET could induce dose dependent hypotension and bradycardia.
Another compound, N,N-diethylphenyl acetamide (DEPA) was developed by the DRDO Gwalior, to use as a multi-insect repellent in India. It is also commercially available in various formulations in India. It has similar cosmetic properties to DEET, similar dermal absorption and excretion, plus symptoms of acute poisoning with DEPA are similar to DEET (S.S Rao et al, Toxicologic studies of an insect repellent N,N-diethy!phenylacetamide, Indian J Med Res, 1987, 85, 626).
(Formula Removed)
Bayer AG plans to market a mosquito repellent with the name BayrepelR, the active ingredients of which is 1-piperdinecarboxylic acid, 2-(2-hydroxyethyl)-l-methylpropylester (KBR 3023).

(Formula Removed)
Merck 3535 is an insect repellent for application to human skin and clothing in public health operations.to repel biting arthropods such as mosquitoes.flies and ticks. It was developed in 1975 by Merck and the efficacy of IR3535 was independently evaluated by Cilek et al. In comparative efficacy study of IR3535 and DEET as repellents against adult Aedes aegypti and Culex quinquefasciatus. J. Amer. Mosquito Control Assoc, 2004, 20 (3), page 299-304.
Although it has low toxicity but it is irritating to eyes and sometime skin. Efficacy data present for IR 3535 is variable.
(Formula Removed)
sec-butyl 2-(2-hydroxyethyl)piperidine-1 -carboxy late (KBR3023orPicaridin) In addition to the above synthetic chemicals, plant-derived substances are also reported and available in various insect repellent formulations. Plant whose essential oils have been reported to have repellent activity include citronella. cedar, verbena, pennyroyal, geranium, lavender, pine, cajeput, cinnamon, rosemary, basil, thyme, allspice, garlic and peppermint. The main drawback of these natural oils is that unlike synthetic insect repellents, plant-derived repellents have been relatively poorly studied. When tested, most of these essential oils tended to give short- lasting protection, usually less than 2 hours.
There is a need to develop new repellent molecules that can overcome the disadvantages or drawbacks of those known in the art. The new compounds should be effective and easy to prepare.
Objects of the invention
An aspect of the present invention is to provide 2-phenylacetarnide insect repellent compounds for the purpose of personal protection.
Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds which are simple to prepare.
Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds, which repel the insect effectively without side effects and are safe for human use.
Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds, which are stable for atleast 2 years.
Another aspect of the present invention is to provide 2-phenylacetamide insect repellent compounds that can be used in the form of insect repellent formulations.
Statement of the invention
According to the present invention, there is provided an insect repellent 2-phenylacetamide compound represented by General Formula I:
wherein Rb R2, R3, R4, R3 are independently -OCH3, -CH3 or H.
Summary of the invention
The present invention comprises 2-phenylacetamide compounds having insect repellent properties. These compounds are characterized by a combination of excellent repellent activity, long stability period, extended protection time and no toxicity and long stability. These compounds can be used as active ingredients in insect repellent formulation such as in form of spray, cream, solution or the kind of any formulation which is conveniently applicable as a mosquito repellent.
Detailed description of the invention
Effective insect repellents are an important tool to protect people from serious mosquito-and tick-borne disease. Each year, millions of people die from diseases transmitted by insects. The most familiar insect pest is the mosquito. These flying insects acting as major vectors have been responsible for much of the lethal diseases that are felt worldwide and are regarded as a global health problem, mosquitoes transmit disease to more than 70 crore people annually.
The insect repellent compounds provided by this invention can be represented by the following general formula I:
(Formula Removed)

wherein R1 R2, R3, R4, R3 are independently -OCH3, -CH3 or H.
In a preferred embodiment, the compound of formula II N,N-Diethyl-3-methoxy-2-phenyl acetamide is used as an insect repellent.
(Formula Removed)

In an another preferred embodiment the compound of formula (III) N,N-Diethyl-2-(4-methoxyphenyl) acetamide is used as an active ingredient for repelling insects.
Yet in an another preferred embodiment compound of formula IV N,N-Diethyl-2-m-tolyl-acetamide or N,N-Diethyl-2-(3-methylphenyl) acetamide is used as an insect repellent.
(Formula Removed)

In an another preferred embodiment, compound of formula V N,N -Diethyl-2-p tolyl-acetamide or N,N-Diethyl-2-(4-methylphenyl) acetamide is used as an active ingredient for repelling insects.
The compounds of the present invention can be used to prepare formulations. These compounds can be used as an active ingredients or in the combination with other known repellent compounds in the personal protection products in various forms such as aerosols, sprays, creams, and other suitable formulations which can be used for application as an insect repellent. The active ingredient contained in the mosquito repellent may be in the range of 5 to 30 % w/w of the final product. The formulations can be prepared with other suitable additives such as inert ingredients to form base for the formulation. The inert ingredients to be used for preparation of repellent may depend on the form of the final product. Mosquito repellents are prepared as aerosols, pumps, lotions, and oils or any other suitable form which can be used as a mosquito repellent. Mosquito repellents that are prepared as lotions or creams are essentially skin creams which have active ingredient added at a certain level. They are primarily composed of water, surfactants, fatty alcohol (such as cetyl alcohol, cetostearyl alcohol), fragrance, and other emollients (such as liquid paraffin). Other ingredients include higher fatty acids like stearic acid alongwith use of alkalies such as sodium hydroxide, potassium hydroxide, borax, triethanolamine (TEA), etc. Humectants such as glycerin, polyproylene glycol and sorbitol are used which prevent the evaporation of moisture from the skin surface. When applied to the skin, these products have the dual benefit of repelling mosquitoes and moisturizing skin. Aerosols are the most common form for mosquito repellents. They are made up of few different types of ingredients, including a solvent, a propellant and miscellaneous ingredients. The solvent is usually an organic alcohol such as ethanol or propanol which dilutes the active
ingredient to an appropriate concentration. It also aids in keeping all of the raw materials mixed, ensuring that the product will remain effective even after long-storage. The propellant is a volatile compound which creates the pressure that causes the rest of the product will remain effective even after long-term storage. The propellant is a volatile compound which creates the pressure that causes the rest of the product to be forced out of the container. Common propellants include liquefied hydrocarbon gases like propane, butane or isobutane, hydrofluorocarbons, and dimethyl ether. Other ingredients such as fragrances and emollients are added to aerosol mosquito repellents to make them more cosmetically appealing. Still other compounds are added to prevent corrosion and other stability problems (i.e. preservatives such as methyl paraben, ethyl paraben, butyl paraben and propyl paraben). A solution of active ingredient can be prepared in oil of plant origin such as coconut oil, soyabean oil, cedar oil, chrysanthemum oil, clove oil, eucalyptus oil, fennel oil, lavender oil, lemongrass oil, neem oil, peppermint oil, soyabean oil and the kind, to provide protection from insects. It has been found that a combination of various repellent compounds of the present invention alongwith any conventional mosquito repellent provide greater effectiveness than any of the compound alone. Those skilled in the art will recognize that numerous applications, variations and modifications from these compounds of the invention are possible from the details herein. The following examples are given by the way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention.
Examples:
1) Preparation of N,N-Diethyl-3-methoxy-2- phenyl acetamide
3-methoxy-2- phenylacetic acid (0.5 mole) was taken in a 1 liter two necked round bottom flask fitted with water condenser and a calcium chloride guard tube. This was placed over a magnetic stirrer cum hot plate. To this, freshly distilled thionyl chloride (0.7 mole) was added slowly using a pressure-equalizing funnel fitted in the side neck of the round bottom flask. After complete addition, the reaction mixture was stirred constantly and was heated at 100 degree C. so that thionyl chloride gets re-fluxed for 4 hours. After completion of the reaction, the flask was cooled; excess thionyl chloride was distilled off and then pure 3-methoxy-2-phenyl acetyl chloride was distilled under vacuum.
This pure 3-methoxy-2-phenyl acetyl chloride was taken in a two necked round bottom flask fitted with a reflux condenser and calcium guard tube. To this diethyl amine (0.7mole) diluted with 50 ml of anhydrous dichloromethane was added dropwise using a pressure equalizing
funnel with constant stirring of the reaction mixture. Though the reaction was exothermic, the temperature was maintained by the reflux of dichloromethane. After complete addition, the reaction mixture was stirred for 1 hour and then cooled. Pure N,N-Diethyl-3-methoxy-2- phenyl acetamide was obtained by distillation of the reaction mixture under the vacuum. The purity of the compound analyzed using GC was 99%.
(Formula Removed)
Similarly, other amides viz N,N Diethyl-4-methoxy-2-phenylacetamide, N,N-Diethyl-3-methyl-2-phenylacetamide, N,N-Diethyl-4-methyl-2-phenylacetamide were synthesized using 4-methoxy-2-phenylacetic acid, 3-methyl-2-phenylacetic acid, 4-methyl-2-phenylacetic acid respectively as starting materials respectively instead of 3-methoxy-2-phenylacetic acid. All these compounds were also checked for their purities and analysed by spectroscopy techniques.
2) Preparation of spray for personal protection
A solution of N,N-Diethyl-4-methoxy-2-phenylacetamide (20% w/w) as an active ingredient, is mixed with isopropanol (Pharmacopeia grade) to prepare a spray solution for personal protection.
3) Preparation of cream for personal protection by using N,N-Diethyl-4-methyl-2-phenyacetamide:
A solution of N,N-Diethyl-4-methyl-2-phenyacetamide (20% w/w) as an active ingredient, is mixed with stearic acid (13%), stearyl alcohol (1%), cetyl alcohol (1%), glycerine (5%), methyl paraben (0.05%), propyl paraben (0.05%), potassium hydroxide (0.9%), and pure water to make 100 % to prepare a cream for personal protection from insects. This cream can be applied on the exposed areas of skin to protect from mosquito bites.
4) Preparation of cream for personal protection by using N,N-Diethyl-4-methoxy-2-phenylacetamide:
A solution of N,N-Diethyl-4-methoxy-2-phenylacetamide (20% w/w) as an active ingredient, is mixed with stearic acid (13%), stearyl alcohol (1%), cetyl alcohol (1%), glycerine (5%), methyl paraben (0.05%), propyl paraben (0.05%), potassium hydroxide (0.9%), and pure water to make 100 to prepare a cream for personal protection from insects. This cream can be applied on the exposed areas of skin to protect from mosquito bites.
5) Evaluation of bioefficacy of the insect repellent compounds:
The insect repellent property of these compounds was evaluated against mosquitoes at Entomology Division, DRDO, Gwalior. Behavioral responses of Aedes aegypti mosquitoes to the chemically synthesized compounds, mentioned above,ware studied using Y-maze olfactometer. Mosquitoes showed better flight orientation towards the control than the above compounds application site in the behavioral study showing clearly the repellent property. The bioefficacy test for the determination of the protection time was performed on 20% concentration of the compounds in isopropanol, used as solvent. The protection time of the analogs are shown in the following table

(Table Removed)
6) Evaluation of Toxicological effect of the insect repellent compounds for human use:
The toxicological effect of the insect repellent compounds was carried out at Toxicology Division DRDO, Gwalior. The various test parameters included, Primary Skin Irritation Index (PSII), Dermal Toxicity Studies, Biochemical analysis such as WBC, RBC, HGB, and platelets in the blood, Cholesterol, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in the serum. The Primary Skin irritation Index (PSII) i.e the average sum of erythema and edema for all sites on all rabbits were computed and the following result were observed. The PSII value for all these compounds are shown in the following table.

(Table Removed)
The PSII value of N,N-Diethyl-2-(3-methylphenyl) acetamide was calculated to be 0.125. The scoring scale showed that the compound is negligibly irritant. The PSII value for N,N-Diethyl-2-(4-methylphenyl) acetamide was found to be zero. The scoring scale showed that the compound was non-irritant. The PSII value for N,N-Diethyl-3-methoxy 2- phenyl acetamide and N,N-Diethyl-2-(4-methoxyphenyl) acetamide was calculated to be zero. The scoring scale showed that both the compounds were not irritant.
The dermal LD50 data shows that the above new compounds viz. N,N-Diethyl-2-(3-methylphenyl) acetamide, N,N-Diethyl-2-(4-methylphenyl) acetamide, N,N-Diethyl-3-methoxy 2-phenyl acetamide, N,N-Diethyl-2-(4-methoxyphenyl) acetamide was greater than 6400 mg/kg. The comparative toxicological evaluation data shows that these compounds are safer as compared to presently known insecticides and repellents revealing the safety profile of the
compounds.
Following the oral and dermal toxicological study data, there was no significant effect on the body weight of mice and rats, respectively, during fourteen days study. Thus the toxicological studies of the compounds clearly showed that these are safe for human use.

We claim:
1. Insect repellent acetamide compounds represented by General Formula I(Formula Removed)
wherein R1 R2, R3, R4, R5 are independently -OCH3, -CH3 or H.
2. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-3-methoxy 2- phenyl acetamide.

(Formula Removed)3. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-2-(4-methylphenyl) acetamide.(Formula Removed)
4. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-3-methoxy 2- phenyl acetamide.
(Formula Removed)
5. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is N,N-Diethyl-2-(4-methoxyphenyl) acetamide.
6. An insect repellent composition comprising 5 to 30 % w/w of the 2-phenylacetamide compound as claimed in claim 1.
6. The insect repellent composition as claimed in claim 6 wherein the composition is in the form of a spray, cream or an aerosol.
7. The insect repellent acetamide compound as claimed in claim 1, wherein the compound is used as an active ingredient in insect repellent composition.
8. The Insect repellent acetamide compound such as herein described with respect to foregoing examples.
10. The insect repellent composition such as herein described with respect to the foregoing
examples.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=6FbVu8Cgkb6KO2DR1zqKAQ==&loc=+mN2fYxnTC4l0fUd8W4CAA==

« Previous Patent

Next Patent »

Patent Number

268615

Indian Patent Application Number

520/DEL/2010

PG Journal Number

37/2015

Publication Date

11-Sep-2015

Grant Date

08-Sep-2015

Date of Filing

08-Mar-2010

Name of Patentee

DIRECTOR GENERAL, DEFENCE RESEARCH & DEVELOPMENT ORGANISATION

Applicant Address

DRDO, MINISTRY OF DEFENCE, ROOM NO. 348, B-WING, DRDO BAHAVAN, RAJAJI MARG, NEW DELHI-110011 (INDIA);

Inventors:

#	Inventor's Name	Inventor's Address
1	GANESAN, KUMARAN	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002
2	PARASHAR, BRAHMA DUTT	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002
3	GAUTAM, ANSHOO	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002
4	GARUD, AKANKSHA	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002
5	KUMAR, PRAVIN	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002
6	PRAKASH, SHRI	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002
7	VIJAYARAGHAVAN, RAJAGOPALAN	DEFENCE R&D ESTABLISHMENT, JHANSI ROAD, GWALIOR - 474002

PCT International Classification Number

C07C255/45;

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA