Lufenuron

Structural formula
	Structural formula without stereochemistry
General
Non-proprietary name	Lufenuron
other names	N - {[2,5-dichloro-4- (1,1,2,3,3,3-hexafluoropropoxy) phenyl] carbamoyl} -2,6-difluorobenzamide ( IUPAC ) ; ( RS ) -1- [2,5-dichloro-4- (1,1,2,3,3,3-hexafluoropropoxy) phenyl] -3- (2,6-difluorobenzoyl) urea;
Molecular formula	C 17 H 8 Cl 2 F 8 N 2 O 3
External identifiers / databases
EC number	410-690-9
ECHA InfoCard	100.101.025
PubChem	71777
ChemSpider	64813
DrugBank	DB11424
Wikidata	Q412933
Drug information
ATC code	Q P53BC01
Drug class	Antiparasitic , antifungal
properties
Molar mass	511.15 g mol −1
density	1.68 g cm −3 (racemate, polymorph A); 1.69 g cm −3 (racemate, polymorph C);
Melting point	175 ° C ( racemate , polymorph A); 147 ° C (racemate, polymorph C); 165–166 ° C ( enantiomer , polymorph E);
solubility	insoluble in water.
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 317-410
	P: 273-280-501
Toxicological data	> 2000 mg kg −1 ( LD 50 , rat , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Lufenuron is a chitin inhibitor that is effective against larvae of insects (larval insecticide ) and against fungi ( antifungal agent ). In veterinary medicine it is mainly used against fleas in cats and dogs , as well as in combination with other active ingredients as a broad spectrum antiparasitic . It was found to be ineffective against dermatophytosis . In dogs, the active ingredient is also used for heartworm prophylaxis . The active ingredient belongs to the derivatives of benzoylphenyl urea.

chemistry

synthesis

In the first step, the starting material 2,5-dichloro-4- (1,1,2,3,3,3-hexafluoropropoxy) aniline is reacted with phosgene . After concentration by distillation, the reaction of the resulting isocyanate with 2,6-difluorobenzamide gives the target compound. The synthesis sequence gives the racemate . A separation of enantiomers may chromatography on a chiral done column.

Physical Properties

Lufenuron is a colorless, crystalline and highly lipophilic substance. The structure contains a stereocenter so that two enantiomers exist. However, only the racemate is used in pharmaceutical formulations. The racemate shows a pronounced polymorphic behavior. Four different polymorphic forms are known. The thermodynamically stable and commercially used form A melts at 175 ° C with a melting enthalpy of 33.3 kJ mol ⁻¹ . Form B is created through crystallization from the melt and converts exothermically between 66 ° C and 92 ° C into Form C, which suggests a monotropic ratio. Form C can be obtained by precipitation from ethanolic or dichloromethane solution or recrystallization from amorphous material. The melting point at 147 ° C and the enthalpy of fusion of 22.3 kJ mol ⁻¹ indicate a monotropic relationship to form A. An exothermic conversion was also observed between 91 ° C and 121 ° C, confirming the monotropic relationship. A form D can also be obtained from the melt and converts monotropically to form A above 94 ° C. The compound is insoluble in water, but very soluble in organic solvents such as methanol , dichloromethane, xylenes and toluene .

pharmacology

The drug is rapidly absorbed after oral or subcutaneous administration and accumulates in adipose tissue . From this it is gradually released into the blood so that long-lasting active ingredient levels (up to 6 months) are achieved. Lufenuron is hardly metabolized and is excreted in the liver and ultimately in the faeces.

Lufenuron is ingested by female fleas and other blood-sucking insects and enters the ovaries and eggs in them. By disrupting the biosynthesis of chitin , it prevents the larvae from developing so that further development does not occur. For effective control of ectoparasites, the drug is usually combined with an adult insecticide .

The oral LD ₅₀ in rats is over 2000 mg / kg.

Side effects

In addition to local swellings at the injection site, oral administration may result in vomiting, fatigue, reluctance to eat, diarrhea, shortness of breath, itching and other skin problems. The injection preparation must not be used in dogs because of severe skin reactions.

Trade names

Monopreparations : Program

Combination preparations : Program Plus (with milbemycin oxime ), Sentinel Spectrum (with milbemycin oxime and praziquantel )

Individual evidence

↑ ^a ^b ^c ^d ^e ^f ^g ^h M. Szelagiewicz, C. Marcolli, S. Cianferani, AP Hard, A. Vit, A. Burkhard, M. von Raumer, U. Ch. Hofmeier, A. Zilian, E. Francotte , R. Schenker: In situ Characterization of Polymorphic Forms - The Potential of Raman Techniques. In: J. Therm. Anal. Cal. 57, 1999, pp. 23-43.
↑ ^a ^b ^c ^d entry to lufenuron at Vetpharm, accessed on 23 November 2011th
↑ Entry on N- (2,5-dichloro-4- (1,1,2,3,3,3-hexafluoropropoxy) phenylaminocarbonyl) -2,6-difluorobenzamide in the GESTIS substance database of the IFA , accessed on February 1 2016(JavaScript required) .
↑ Entry on Lufenuron (ISO) in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on March 17, 2017. Manufacturers or distributors can expand the harmonized classification and labeling .
↑ ^a ^b ^c sheet lufenuron at Sigma-Aldrich , accessed on May 12, 2017 ( PDF ).
↑ Michael Cieslicki: Clinical and mycological effectiveness of Lufenuron in the dermatophytosis of the cat. In: Small Animal Practice. 9, 2005, pp. 575-580.

[Szelagiewicz-1] ↑ ^a ^b ^c ^d ^e ^f ^g ^h M. Szelagiewicz, C. Marcolli, S. Cianferani, AP Hard, A. Vit, A. Burkhard, M. von Raumer, U. Ch. Hofmeier, A. Zilian, E. Francotte , R. Schenker: In situ Characterization of Polymorphic Forms - The Potential of Raman Techniques. In: J. Therm. Anal. Cal. 57, 1999, pp. 23-43.

[Clinipharm-2] try to lufenuron at Vetpharm, accessed on 23 November 2011th

[GESTIS-3] Entry on N- (2,5-dichloro-4- (1,1,2,3,3,3-hexafluoropropoxy) phenylaminocarbonyl) -2,6-difluorobenzamide in the GESTIS substance database of the IFA , accessed on February 1 2016(JavaScript required) .

[CLP_100.101.025-4] Entry on Lufenuron (ISO) in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on March 17, 2017. Manufacturers or distributors can expand the harmonized classification and labeling .

[sigma-5] sheet lufenuron at Sigma-Aldrich , accessed on May 12, 2017 ( PDF ).

[6] Michael Cieslicki: Clinical and mycological effectiveness of Lufenuron in the dermatophytosis of the cat. In: Small Animal Practice. 9, 2005, pp. 575-580.