WO1992012707A1 - A benzoylurea-containing composition for parasite control in animals - Google Patents

A benzoylurea-containing composition for parasite control in animals Download PDF

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Publication number
WO1992012707A1
WO1992012707A1 PCT/US1992/000004 US9200004W WO9212707A1 WO 1992012707 A1 WO1992012707 A1 WO 1992012707A1 US 9200004 W US9200004 W US 9200004W WO 9212707 A1 WO9212707 A1 WO 9212707A1
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Prior art keywords
compound
milligrams
animals
animal
active ingredient
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Application number
PCT/US1992/000004
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French (fr)
Inventor
Clyde Allen Roberts
Original Assignee
E.I. Du Pont De Nemours And Company
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Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Publication of WO1992012707A1 publication Critical patent/WO1992012707A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine

Definitions

  • a composition comprising a particular benzoylurea and its use in controlling parasites in animals.
  • U.S. 4,973,589 discloses certain benzoylureas as flea control agents.
  • U.S. 4,666,942 and U.S. 4,698,365 disclose the compound of Formula I and its use as an insecticide.
  • EP 275,132 discloses the compound of Formula I for use against termites.
  • U.S. 4,005,223 discloses analogs of Formula I as insecticides.
  • WO 90/06680 discloses the compound of Formula I for control of cockroaches.
  • This invention concerns a method employing the following compound to control fleas and other chitin-producing parasites found in animals when orally administered or topically applied.
  • the compound is:
  • This compound has been found to possess a mode of action as a growth regulant and chitin growth inhibitor. When administered orally or topically, it can be employed to control fleas and mites of various species and any other chitin-producing parasites.
  • This invention also concerns a pharmacologically acceptable formulation of the described compound and a carrier therefor, said compound and carrier in an admixture of sufficient concentration (of active compound) to form an effective anti-parasitic dosage for control of internal or external parasites.
  • R represents, independently, NH 2 or NCO.
  • the reaction can be carried out in the presence of a solvent.
  • Suitable solvents are aromatic solvents such as benzene, toluene, xylene, or chlorobenzene, hydrocarbons such as petroleum fractions, chlorinated hydrocarbons such as chloroform, methylene chloride or dichloroethane, and ethers such as diethyl ether, dibutyl ether, or dioxan. Mixtures of solvents are also suitable.
  • the reaction is carried out at a temperature from 0°C to 100°C.
  • the molar ratio of isocyanate to amine is from about 1:1 to 2:1.
  • the reaction is carried out under anhydrous conditions.
  • Step B Preparation of N-(2,6-difl ⁇ .probenzgyl)-N , -(2- fluoro-4-r2-chloro-4-(trifluoromethyl phenoxy1- phenylurea (Compound of Formula I).
  • a solution of the compound of Step A (0.9 g) in dry toluene (5 ml) was treated with 2 f 6-difluorobenzoyl- isocyanate (0.56 g) and the mixture was stirred at room temperature overnight. The precipitated product was then separated, washed with cold methanol and dried in an oven at 60°C to give 1.15 g of the desired product, melting point 173 to 175°C.
  • the antiparasitic agent described herein can be administered by any means that effects its introduction into the blood of the animal. Alternatively, it can be applied topically directly to the infested area.
  • the compound can be administered by any conventional means available for oral and topical administration, either as an individual antiparasitic agent or in combination with other antiparasitic agents.
  • the compound can be administered alone, but is generally administered with a suitable carrier selected on the basis of the chosen route of administration and standard animal pharmaceutical practice.
  • compositions suitable for administration contain from about 2 milligrams to 2000 milligrams of active ingredient per unit dose.
  • the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.
  • an effective monthly dose of active ingredient will comprise, typically, about 10 to 500 milligrams per kilogram of body weight.
  • composition of the invention can be in a conventional form suitable for oral administration, for example a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, or suitable for topical application, for example a spray, cream, ointment or gel (hereafter referred to as "cream'') . It can also be administered to the food source of the recipient animal as a formulated powder or liquid.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of the agent over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of the agent over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere.
  • compositions which are ointments, creams and gels can, for example, contain the usual diluents, e.g., animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • diluents e.g., animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • Suitable carriers are described in Remington's
  • Unit capsules are prepared by filling standard two- piece hard gelatin capsules each with about 10 to 50 (or more) milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
  • a digestable oil such as soybean oil, cottonseed oil or olive oil
  • Tablets Tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • aqueous suspension is prepared for oral administration so that each 5 milliliters will contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
  • Cream is prepared for oral administration so that each 5 milliliters will contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
  • a cream for topical application is prepared by incorporating 100 milligrams of the finely pulverized active ingredient in 5 grams of a cream base which can comprise about 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% Span* 20, 0.3% Tween* 20 and 41.7% water.
  • Example 1 The compound described herein is formulated with any pharmacologically acceptable carrier suitable for fabricating unit doses of the compound for administration orally or topically to an animal suffering from, a parasite disease.
  • Unit doses will usually vary from as little as several milligrams to as many as 2 grams. Of course, smaller or larger doses can be employed depending on the weight of the animal and on the seriousness of the parasitic infestation. Typical formulations have been described hereinbefore.
  • treatment may begin.
  • Oral administration is typically made via food or drink.
  • Oral administration and/or topical application can be repeated as necessary employing a formulation of the correct dosage to treat the infected animal.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for controlling parasites in animals by treating them with an effective amount of a particular benzoylphenoxyphenylurea as the active ingredient and an antiparasitic composition comprising an effective amount of the active ingredient and a pharmacologically acceptable carrier therefor.

Description

TllLΣe A BENZOYLUREA-CONTAINING COMPOSITION FOR PARASITE CONTROL IN ANIMALS FIELD OF THE INVENTION
A composition comprising a particular benzoylurea and its use in controlling parasites in animals.
BACKGROUND OF THE INVENTION
U.S. 4,973,589 discloses certain benzoylureas as flea control agents. U.S. 4,666,942 and U.S. 4,698,365 disclose the compound of Formula I and its use as an insecticide. EP 275,132 discloses the compound of Formula I for use against termites. U.S. 4,005,223 discloses analogs of Formula I as insecticides. WO 90/06680 discloses the compound of Formula I for control of cockroaches.
No disclosure is known that teaches the compound of Formula I for parasite control in companion animals or its incorporation in a pharmacological formulation. SUMMARY OF THE INVENTION
This invention concerns a method employing the following compound to control fleas and other chitin-producing parasites found in animals when orally administered or topically applied. The compound is:
Figure imgf000003_0001
(I)
This compound has been found to possess a mode of action as a growth regulant and chitin growth inhibitor. When administered orally or topically, it can be employed to control fleas and mites of various species and any other chitin-producing parasites.
This invention also concerns a pharmacologically acceptable formulation of the described compound and a carrier therefor, said compound and carrier in an admixture of sufficient concentration (of active compound) to form an effective anti-parasitic dosage for control of internal or external parasites.
DETAILS QF THE INVENTION The compound can be prepared by reacting a compound of the formula
Figure imgf000004_0001
with a compound of the formula
Figure imgf000004_0002
in which R represents, independently, NH2 or NCO. The reaction can be carried out in the presence of a solvent. Suitable solvents are aromatic solvents such as benzene, toluene, xylene, or chlorobenzene, hydrocarbons such as petroleum fractions, chlorinated hydrocarbons such as chloroform, methylene chloride or dichloroethane, and ethers such as diethyl ether, dibutyl ether, or dioxan. Mixtures of solvents are also suitable.
Preferably, the reaction is carried out at a temperature from 0°C to 100°C. Preferably, the molar ratio of isocyanate to amine is from about 1:1 to 2:1. Preferably, the reaction is carried out under anhydrous conditions.
Compounds of Formula II can be prepared by reacting a compound of the formula
Figure imgf000005_0001
with a compound of the formula
Figure imgf000005_0002
to produce a compound of Formula II in which R is NH2.
For additional details pertaining to the preparation of compound, see U.S. Patent No. 4,698,365. The following details and Example illustrate the invention.
PREPARATION OF COMPOUND Step A; Preparation of 2-fluoro-4- ■2-chloro-4- rtrifluoromethyl.phenoxy. aniline
A solution of 2-fluoro-4-hydroxyaniline (7.1 g) and potassium hydroxide (3.7 g, 85% pure) in dimethyl- sulfoxide (25 ml) was heated to 80°C and treated with a solution of l,2-dichloro-4-(trifluoromethyl)benzene (10.9 g) in dimethylsulfoxide (10 ml). The mixture was stirred at 90 to 95°C for 20 hours, after which time it was diluted with a mixture of water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated down to give 3.6 g of the intermediate amine as a brown oil. Chromatography over silica gel using toluene/ petroleum ether (4:1 ratio) gave 1.1 g of the pure amine as a yellow oil.
Elemental Analysis:
Calculated: C; 51.1% H; 2.6% N; 4.6% Found: C; 50.3% H; 2.7% N; 4.3%
Step B: Preparation of N-(2,6-diflι.probenzgyl)-N,-(2- fluoro-4-r2-chloro-4-(trifluoromethyl phenoxy1- phenylurea (Compound of Formula I. A solution of the compound of Step A (0.9 g) in dry toluene (5 ml) was treated with 2f6-difluorobenzoyl- isocyanate (0.56 g) and the mixture was stirred at room temperature overnight. The precipitated product was then separated, washed with cold methanol and dried in an oven at 60°C to give 1.15 g of the desired product, melting point 173 to 175°C.
Elemental Analysis:
Calculated: C; 51.6% H; 2.3% N; 5.7% Found: C; 51.7% fi; 2.1% N; 5.7%
Formulation and use The antiparasitic agent described herein can be administered by any means that effects its introduction into the blood of the animal. Alternatively, it can be applied topically directly to the infested area.
The compound can be administered by any conventional means available for oral and topical administration, either as an individual antiparasitic agent or in combination with other antiparasitic agents. The compound can be administered alone, but is generally administered with a suitable carrier selected on the basis of the chosen route of administration and standard animal pharmaceutical practice.
The dosage administered will, of course, vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration: age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Dosage forms (compositions) suitable for administration contain from about 2 milligrams to 2000 milligrams of active ingredient per unit dose. In these compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition. For use in the treatment of companion-animal parasites, an effective monthly dose of active ingredient will comprise, typically, about 10 to 500 milligrams per kilogram of body weight. The composition of the invention can be in a conventional form suitable for oral administration, for example a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, or suitable for topical application, for example a spray, cream, ointment or gel (hereafter referred to as "cream'') . It can also be administered to the food source of the recipient animal as a formulated powder or liquid.
Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of the agent over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere.
The compositions which are ointments, creams and gels can, for example, contain the usual diluents, e.g., animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances. Suitable carriers are described in Remington's
Pharmaceutical Sciences,. A. Osol, a standard reference text in this field, useful dosage forms for administration of the compounds of this invention can be illustrated as follows: Capsules
Unit capsules are prepared by filling standard two- piece hard gelatin capsules each with about 10 to 50 (or more) milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
Tablets Tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Suspension An aqueous suspension is prepared for oral administration so that each 5 milliliters will contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin. Cream
A cream for topical application is prepared by incorporating 100 milligrams of the finely pulverized active ingredient in 5 grams of a cream base which can comprise about 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% Span* 20, 0.3% Tween* 20 and 41.7% water.
Example The compound described herein is formulated with any pharmacologically acceptable carrier suitable for fabricating unit doses of the compound for administration orally or topically to an animal suffering from, a parasite disease. Unit doses will usually vary from as little as several milligrams to as many as 2 grams. Of course, smaller or larger doses can be employed depending on the weight of the animal and on the seriousness of the parasitic infestation. Typical formulations have been described hereinbefore.
After determining the effective treatment for the patient animal, whether by oral administration or topical application of the anti-parasitic agent, treatment may begin. Oral administration is typically made via food or drink. Oral administration and/or topical application can be repeated as necessary employing a formulation of the correct dosage to treat the infected animal.

Claims

CLAIMSWhat is claimed:
1. An anti-parasitic composition comprising an effective amount of the compound:
Figure imgf000010_0001
and a pharmacologically acceptable carrier therefor.
2. A composition according to Claim 1 in an effective-dose formulation selected from the group: powder, tablet, capsule, aqueous suspension and topical cream.
3. A method for controlling parasites in an animal comprising treating the animal by oral administration or topically with an effective dosage of the active compound:
Figure imgf000010_0002
4. A method according to Claim 3 employing active compound in the form of a powder, tablet, capsule, aqueous suspension or topical cream.
PCT/US1992/000004 1991-01-22 1992-01-02 A benzoylurea-containing composition for parasite control in animals WO1992012707A1 (en)

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US643,974 1991-01-22

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709048A (en) * 2013-11-14 2014-04-09 江苏中旗作物保护股份有限公司 Flufenoxuron intermediate 2-fluoro-4-(2-chloro-4- trifluoromethyl phenoxyl) aniline synthesis method

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2300076A1 (en) * 1975-02-06 1976-09-03 Bayer Ag NEW
WO1986003941A1 (en) * 1984-12-28 1986-07-17 Union Carbide Corporation Use of acyl urea compounds for controlling endoparasites and ectoparasites of warm-blooded animals
EP0230400A2 (en) * 1986-01-21 1987-07-29 Ciba-Geigy Ag N-3-(5-Trifluoromethyl-pyridyl-2-oxy)phenyl-N'-benzoylureas for combating helminths in livestock
EP0255803A1 (en) * 1986-08-06 1988-02-10 Ciba-Geigy Ag Process for the prevention of re-infestation of dogs and cats by fleas
EP0161019B1 (en) * 1984-04-10 1989-01-25 Shell Internationale Researchmaatschappij B.V. Pesticidal benzoylurea compounds
WO1990006680A1 (en) * 1988-12-21 1990-06-28 E.I. Du Pont De Nemours And Company Insecticidal use of a benzoylurea

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2300076A1 (en) * 1975-02-06 1976-09-03 Bayer Ag NEW
EP0161019B1 (en) * 1984-04-10 1989-01-25 Shell Internationale Researchmaatschappij B.V. Pesticidal benzoylurea compounds
WO1986003941A1 (en) * 1984-12-28 1986-07-17 Union Carbide Corporation Use of acyl urea compounds for controlling endoparasites and ectoparasites of warm-blooded animals
EP0230400A2 (en) * 1986-01-21 1987-07-29 Ciba-Geigy Ag N-3-(5-Trifluoromethyl-pyridyl-2-oxy)phenyl-N'-benzoylureas for combating helminths in livestock
EP0255803A1 (en) * 1986-08-06 1988-02-10 Ciba-Geigy Ag Process for the prevention of re-infestation of dogs and cats by fleas
WO1990006680A1 (en) * 1988-12-21 1990-06-28 E.I. Du Pont De Nemours And Company Insecticidal use of a benzoylurea

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Medical Dictionary", 1985, 26th edition, pages 828-829,1352, W.B. Saunders Co., (Philadelphia, PA, US), see paragraph: "Mite"; paragraph: "Tetranychus" *
Pestic. Sci., vol. 28, no. 4, 1990, S.A. LEE et al.: "Cytochemical demonstration of the effects of the acylureas flufenoxuron and diflubenzuron on the incorporation of chitin into insect cuticle", pages 367-375, see the whole document *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103709048A (en) * 2013-11-14 2014-04-09 江苏中旗作物保护股份有限公司 Flufenoxuron intermediate 2-fluoro-4-(2-chloro-4- trifluoromethyl phenoxyl) aniline synthesis method
CN103709048B (en) * 2013-11-14 2017-11-24 江苏中旗作物保护股份有限公司 The synthetic method of flufenoxuron intermediate 2 fluorine 4 (4-trifluoromethylphenopendant of 2 chlorine 4) aniline

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