WO2000024715A1

WO2000024715A1 - Piperidine compounds and their use in the population control of rodents and other vertebrate pests

Info

Publication number: WO2000024715A1
Application number: PCT/EP1999/007946
Authority: WO
Inventors: Jose Manuel Prieto Soto; Armando Vega Noverola; Jose Jauregui Luqui
Original assignee: Almirall Prodesfarma, S.A.
Priority date: 1998-10-23
Filing date: 1999-10-20
Publication date: 2000-05-04
Also published as: ES2154570B1; AU6474799A; ES2154570A1

Abstract

A piperidine compound of formula (I), wherein R?1 and R2¿ are the same or different and each independently represents an alkyl or C¿3?-C5 cycloalkyl group; R?3¿ represents a hydrogen atom or an alkyl, C¿3?-C5 cycloalkyl, alkanoyl or C3-C5 cycloalkyl-carbonyl group; R?4¿ represents a hydroxy group and R5 represents a hydrogen atom or R?4 and R5¿ together form a covalent bond; X?1 and X2¿ are the same or different and each independently represents a hydrogen or halogen atom; Y?1 and Y2¿ each represents a hydrogen atom or together represent a methylene, ethylene or ethenylene group; except when R?1 and R2¿ are a methyl group, R3 is a hydrogen atom, R4 is a hydroxy group, X?1 and X2¿ are both fluorine atoms and Y?1 and Y2¿ are both hydrogen atoms; and salts thereof; processes for their preparation, compositions containing them and their use in the population control of rodents and other vertebrate pests.

Description

PIPERIDINE COMPOUNDS AND THEIR USE IN THE POPULAΗON CONTROL OF RODENTS AND OTHER VERTEBRATE PESTS

This invention relates to new piperidine compounds, to processes for their preparation and to their use in the population control of rodents and other vertebrate pests.

US 3,956,296 relates to l-substituted-4-benzene piperidines of general formula

wherein R represents acetyl, aryloxyloweralkyl, aroylloweralkylcarbamoyl, N-lower-alkylcarbamoyl, N,N-dilower- alkylcarbamoyl, N-arylcarbamoyl, N- (ω-nitrogen containing heterocycle) lower-alkylcarbamoyl, N-ω-aminolower- alkyl) carbamoyl, 2-hydroxy-3- (o-methoxy- phenoxy)propyloxycarbamoyl, 2-carbamoylethyl, or (4-(p- fluorobenzoyl) -piperidinoethyl; R¹ represents hydrogen or hydroxy; R² represents phenyl, p-fluorophenyl, m-trifluoro- methylphenyl or cyclohexyl; Y represents hydrogen or fluorine with the proviso that when Y is hydrogen and R² is phenyl, R is other than aroylloweralkyl; as antiinflam atories, sedatives and tranquillizers .

EP-A-0 235 463 relates to piperidine derivatives of general formula

wherein; m is one to six inclusive;

A is hydrogen, -O-R¹, -ON, -(OJNR¹^, -C(0)ORⁱ, -C^OR¹, -CH₂NR^XR², or -OC(0)Rⁱ;

Q is -CH-, -CH₂- or -CH(OH)- d and n are zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon;

B is 0, S, -S(O)-, -S(0)₂-, -NtR¹)-, and =N-C(0)0R¹; z is one or zero

Ar, D and R are selected from phenyl and substituted phenyl with certain limitations, pyridinyl, thienyl, furanyl or naphthyl and, in addition, R may have values: benzyl, substituted benzyl, cycloalkyl or loweralkyl, and D may additionally have values: 2H-l-benzopyran-2-one, 4-oxo-4H-l- benzopyran-2-carboxylic acid loweralkyl ester, 1,4- benzodioxanloweralkyl-2-yl or quinolinyl; as cardiovascular, anti-histaminic and antisecretory agents. Related European Application No. 0 228 893 concerns the use of a sub-group of piperidine compounds selected from the above formula as antiallergic agents.

Surprisingly we have found that a narrow group of N- ethylphenoxy piperidine derivatives having 2,6-dialkyl groups on the phenoxy ring are unexpectedly active as ion channel modulators, and more specifically as compounds capable of affecting the release of insulin. These activities are much higher than would have been expected from the prior art, and the effect on insulin secretion much more evident in vivo than has been found with analogous compounds. Moreover we have surprisingly found that these compounds have a particularly high activity in certain types of animals including rodents, thus making such compounds of formula (I) useful as agents effective in the population control of rodents and other vertebrate pests. As the pesticidal activity is mediated by affecting insulin secretion, the compounds have the further advantage that they are ethical in their action over existing vertebrate pesticides such as the anti-coagulant pesticides. We have further found that these compounds have the advantage that they are palatable to rodents and other vertebrate pests whose populations are to be controlled, even when present in food/bait in a lethal amount.

Accordingly, the present invention provides piperidine compounds of formula (I) :

wherein:

R¹ and R² are the same or different and each independently represents an alkyl or C₃-C₅ cycloalkyl group; R³ represents a hydrogen atom or an alkyl, C₃-C₅ cycloalkyl, alkanoyl or C₃-C₅ cycloalkyl-carbonyl group;

R⁴ represents a hydroxy group and R⁵ represents a hydrogen atom or R⁴ and R⁵ together form a covalent bond;

X¹ and X² are the same or different and each independently represents a hydrogen or halogen atom (preferably fluorine, chlorine or bromine, most preferably fluorine) ;

Y¹ and Y² each represents a hydrogen atom or together represent a methylene, ethylene or ethenylene group; except when R¹ and R² are both methyl groups, R³ is a hydrogen atom, R⁴ is a hydroxy group, X¹ and X² are both fluorine atoms, and Y¹ and Y² are both hydrogen atoms; and salts thereof.

The alkyl and alkanoyl groups mentioned in relation to R-R³ are usually "lower" alkyl and alkanoyl groups, that is containing from 1 to 6 and particularly from 1 to 4 carbon atoms, the hydrocarbon chain being branched or straight. Preferred alkyl groups include: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and t-butyl. The most preferred alkyl groups are methyl and t-butyl. Preferred alkanoyl groups include: acetyl, propanoyl, 2-methylpropanoyl, butanoyl and 2,2-^'" dimethylpropanoyl. The most preferred alkanoyl group is an acetyl group.

In preferred compounds of the invention R¹ and R² are identical, more preferably R¹ and R² are both non-cyclic alkyl groups, most preferably R¹ and R² are both methyl groups.

In preferred compounds of the invention R³ represents an alkyl, C₃~C₅ cycloalkyl, alkanoyl or C₃-C₅ cycloalkyl-carbonyl group. More preferably R³ is an alkanoyl group, most preferably acetyl, or an alkyl group, preferably a branched alkyl group most preferably a t-butyl group.

A preferred group of compounds of formula (I) are those wherein Y¹ and Y² together represent a bridging moiety such as a methylene, ethylene or ethenylene group, most preferably an ethenylene group.

Also preferred are compounds wherein R⁴ and R⁵ togther represent a covalent bond.

Another preferred group of compounds of formula (I) are those wherein Y¹ and Y² each represent a hydrogen atom, X¹ is identical to X², R⁴ represents a hydroxy group and R⁵ represents a hydrogen atom.

Compounds of the invention preferably have an LD₅₀ value in mice of less than 30 mg/kg, preferably less than 25 mg/kg when orally ingested. The LD₅₀ value in mice being preferably measured according to the protocol detailed hereinbelow.

It will be appreciated that certain piperidine compounds of formula (I) possess one or more chiral centres and may exhibit optical isomerism. The isomers of such compounds including enantiomers and diastereoisomers, are within the scope of the invention. Of outstanding interest are:

[1- [2- (4-t-butyl-2, 6-dimethylphenoxy) ethyl] piperidin-4-yl] - bis- (4-fluorophenyl)methanol,

1- [4- [2- (4-dibenzo [a, d] cyclohepten-5-ylidenepiperidin-l- yl) ethoxy-3, 5-dimethylphenyl] ethanone and l-[4-[2-[4-(10,ll-dihydro-dibenzo[a,d]cyclohepten-5- ylidene) piperidin-1-yl] ethoxy] -3, 5-dimethylphenyl] ethanone .

According to a feature of the present invention, the piperidine compounds of formula (I) in which X¹ and X² are the same and R⁴ is a hydroxy group, can be prepared by the process which involves reacting an ester of the general formula (II) :

wherein R¹, R² and R³ are as defined above and R⁶ represents a methyl or ethyl group, with at least two moles of a magnesium derivative of the general formula (III) :

MgX wherein X^: is as defined above and X represents a chlorine, bromine or iodine atom, and hydrolysing the magnesium complex so obtained. The reaction is preferably carried out in an inert solvent such as diethyl ether or diisopropyl ether, at a temperature between 20 °C and the boiling point of the solvent.^" Hydrolysis of the magnesium complex may be effected with, for example, an aqueous ammonium chloride solution.

The ester starting materials of general formula (II) can be obtained by condensation of a 4-piperidine carboxylic acid ester of general formula (IV) :

wherein R⁶ is as hereinbefore defined, with a reactive intermediate of general formula (V) :

wherein R¹, R² and R³ are as defined above and Z is a leaving group such as a chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group. The reaction is preferably carried out in an organic solvent such as toluene, dioxane or methyl isobutyl ketone, at a temperature between 80°C and 140°C and in the presence of an acid-binding agent such as an alkali metal carbonate or bicarbonate.

The piperidine compounds of formula (I) are also prepared, according to another aspect of the invention, by reaction of a substituted α,α-di-phenylmethyl-piperidine derivative of formula (VI) :

wherein R⁴, R⁵, X¹, X², Y¹ and Y² are as defined above, with a reactive intermediate of formula (V) . The reaction is generally carried out in an organic solvent such as toluene, dioxane or methyl isobutyl ketone at a temperature between 80°C and 140°C and in the presence of an acid-binding agent such as an alkali metal carbonate or bicarbonate. The compounds of formula (VI) are known compounds and have been described, for example, in European Patent Application No. 228,893 and US Patent 4032642. The piperidine compounds of formula (I) can also be prepared according to a further feature of the invention by condensation of a compound of general formula (VII) :

wherein R⁴, R⁵, X¹, X², Y¹ and Y² are as defined above and Z¹ is a leaving group such as a chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group, with a phenol of formula (VIII) :

wherein R^:, R² and R³ are as defined above. The reaction is preferably carried out in an organic solvent such as toluene, dioxane, N,N-dimethyl formamide or methyl isobutyl ketone, at a temperature between 80 °C and 140 °C and in the presence of an acid-binding agent such as an alkali metal carbonate, bicarbonate or hydroxide.

The compounds of formula (VII) can be prepared from compounds of formula (VI) by condensation with the ethylene derivative of formula Z¹-CH₂CH₂-Z wherein Z and Z¹ are as defined above .

The piperidine compounds of formula (I) in which R⁴ and R⁵ together form a covalent bond, viz. compounds of formula (IX):

wherein R¹, R², R³, X¹, X², Y¹ and Y² are as defined above, can also be prepared by dehydratation of the corresponding compounds of formula (I) in which R⁴ is a hydroxy group and R⁵ is a hydrogen atom, viz. compounds of formula (X) :

wherein R¹, R², R³, X¹, X², Y¹ and Y² are as defined above. The dehydration reaction is carried out in an inert organic solvent as dioxane or tetrahydrofuran, in the presence of a dehydrating acid as sulfuric acid, polyphosphoric acid or acetic anhydride and at a temperature from 20 °C to the boiling point of the solvent .

The compounds of formula (I) can be converted by known methods into salts, preferably acid addition salts, for example by reaction of the basic compound with acids in appropriate solvents, for example alcohols, dialkyl ketones or ether. Suitable acid addition salts are those derived from inorganic acids, for example the hydrochlorides, and sulfates, and organic acids, for example the fumarates, acetates, succinates and citrates.

The invention also provides a composition comprising as an active constituent a piperidine compound of the invention and an acceptable diluent or carrier. In a further aspect the invention provides a composition comprising as an active constituent a piperidine compound of the invention and a suitable food and/or attractant for example bait, such as a mixture of cereal and/or fat optionally with an attractant. Preferred compositions of the invention comprise up to 5%, more preferably up to 1%, still more preferably up to 0.5% and most preferably up to 0.3% of the active piperidine compounds.

The compounds and compositions of the invention find application as a poison for rodents and other vertebrate pests and may be used in population contol of such animals including rats, mice, squirrels, moles, rabbits, shrews, possums and avian pests such as pigeons. Most preferably the compounds find application as rodenticides and are used in the population control of rodents most preferably rats and mice.

The invention also provides a method of rodent and other vertebrate pest control, preferably rodent control, most preferably rat or mouse control, which method comprises providing a rodent or other vertebrate pest with a compound or composition of the invention.

While the mode of action of the compound and compositions of the invention as agents for the population control of rodents and other vertebrate pests does not form part of the invention it is believed that it is mediated by affecting the release of insulin in the animal. This mode of action is advantageously more ethical than conventional rodent pesticides such as the anti-coagulent pesticides, and leads to decreased gross major organ damage and hence suffering of the animal in death.

The invention is further described below in the following Examples which should not be construed as limiting the invention in any way.

EXAMPLE 1

[1- [2- ( 4-t-butyl-2 , 6-dimethylphenoxy) ethyl] piperidin-4-yl] - bis- ( 4-fluorophenyl) methanol , hydrogen f umarate .

A. 4-t-butyl-2 , 6-dimethylphenol .

A mixture of 2, 6-dimethylphenol (61.1 g, 0.5 mol) , t- butanol (46.3 g, 0.625 mol) and 85% phosphoric acid (200 g) was stirred at 80-90°C for 48 hours. After cooling, the reaction mixture was extracted once with petroleum ether (175 ml) and with diethyl ether (2 x 100 ml) . The mixed organic extracts were washed with water and sodium bicarbonate saturated solution, dried (Na₂S0₄) and the solvent removed in vacuo. The residual oil crystallizes from petroleum ether to give 67.3 g (75%).

B. Ethyl 2- [ (2, 6-dimethyl-4-t-butyl) phenoxy] acetate. Sodium (1.85 g, 0.08 mol) was dissolved in absolute ethanol

(125 ml) at room temperature with stirring and 4-t-butyl-2, 6- dimethylphenol (14.0 g, 0.0785 mol) was added. After stirring for 0.25 h, the solution was evaporated in vacuo; benzene (3 x

75 ml) was added and the evaporation repeated three times. The residue was suspended in benzene (150 ml) and ethyl bromoacetate

(8.9 ml, 0.08 mol) slowly added. The reaction was heated for 12 hours under reflux. The cooled reaction mixture was washed successively with water (150 ml) , 2N sodium hydroxide (150 ml) , water (150 ml) , then dried over sodium sulfate and evaporated in vacuo to give an oil (19 g, 90%) .

C. 2- [ (4-t-butyl-2, 6-dimethyl) phenoxy] ethanol. Lithium aluminium hydride (3.8 g, 0.1 mol) was added to a stirred solution of ethyl 2- [ (2, 6-dimethyl-4-t-butyl) phenoxy] acetate (19 g, 0.07 mol) at room temperature. Following the addition the mixture was heated under reflux for 1 hour, cooled and worked up to give an oil which slowly crystallised (13 g, 83%) .

D. 2- [ (4-t-butyl-2, 6-dimethyl) phenoxy] ethyl methane sulfonate.

Methane sulfonyl chloride (5 ml, 0.061 mol) was added slowly to a stirred solution of 2- [ (4-t-butyl-2, 6- dimethyl) phenoxy] ethanol (12.5 g, 0.056 mol) and triethylamine (8.6 ml, 0.061 mol) in dichloromethane (150 ml) at 0-5°C. After stirring for 1 hr at this temperature the mixture was allowed to warm to room temperature over 12 hrs and then the reaction mixture washed successively with water (150 ml) , 2N sodium hydroxide (150 ml) , water (150 ml) , dried (Na₂S0₄) and concetrated in vacuo to give an oil (16.1 g) which was triturated with petroleum ether to give a solid (12.3 g, 73%).

E. (l-benzylpiperidin-4-yl) -bis- (4-fluorophenyl)methanol. 4-fluoro-bromobenzene (27.5 ml, 0.25 mol) in diethyl ether

(100 ml) was slowly added to a stirred mixture of magnesium turnings (6.1 g, 0.25 mol) in diethyl ether (300 ml) at room temperature under nitrogen, and the reaction mixture was heated under reflux for 1 hr. After cooling to room temperature a solution of ethyl l-benzylpiperidine-4-carboxylate (24.7 g, 0.1 mol) in diethyl ether (50 ml) was added and stirring continued for 12 hrs at ambient temperature, followed by heating under reflux for 1.5 hr The reaction mixture was poured onto ice- ammonium chloride saturated aqueous solution, the organic phase separated, washed with water (250 ml) , dried (Na₂S0₄) and concentrated in vacuo to give an oil (39.3 g) . The product was purified via the formation of the fumarate salt in ethanol and crystallization from ethyl acetate to give a 40 g of a solid. The free base was liberated by partitioning between dichloromethane (250 ml) and IN sodium hydroxide (250 ml) . The organic phase was washed with water (150 ml) , and evaporated in vacuo to give an oil (31 g, 79%) .

F. 4- [bis- (4-fluorophenyl) hydroxymethyl] piperidine-1- carboxylic acid ethyl ester. A mixture of the above compound obtained in E (14.2 g,

0.036 mol) and benzene (100 ml) was heated at 60-70°C and^" treated over 20 minutes with a solution of ethyl chloroformate (5.27 g; 4.7 ml, 0.049 mol) in benzene (25 ml). Following the addition the reaction was stirred for 0.5 hr at 65-70 °C and then heated under reflux for 1 hr. The reaction mixture was cooled, filtered and the solid collected, washed with a little diethyl ether to obtain a solid (11.2 g) , m.p. 132-136°C.

G. Bis- (4-fluorophenyl) piperidin-4-ylmethanol .

A mixture of the above compound obtained in F (11.0 g, 0.0293 mol), potassium hydroxide pellets (85%, 20 g, 0.293 mol) and isopropanol (100 ml) was heated under reflux for 6 hrs and concentrated in vacuo. The residue was dissolved in water (100 ml) cooled with ice, acidified with concentrated hydrochloric acid, made just alkaline with sodium hydroxide, and the aqueous mixture extracted with ethyl acetate (3 x 100 ml) . The organic extracts were combined, dried (Na₂S0₄) and concentrated to dryness in vacuo giving a residue that was triturated with diethyl ether to produce a solid product (6.0 g, 68%), m.p. 147- 150°C. H. [1- [2- (4-t-butyl-2, 6-dimethylphenoxy) ethyl] piperidin- 4-yl] -bis- (4-fluorophenyl )methanol, hydrogen fumarate .

A mixture of bis- (4-fluorophenyl) -4-piperidin-4-ylmethanol

(4.5 g, 0.015 mol), 2- [ (4-t-butyl-2, 6-dimethyl) phenoxy] ethanol methane sulfonate (4.8 g, 0.016 mol), potassium carbonate (4.5 g, 0.032 mol) and acetonitrile (150 ml) was heated under nitrogen at reflux for 48 hrs. The reaction mixture was diluted with ethyl acetate (100 ml) and then concentrated in vacuo. The residue was partitioned between water (100 ml) and dichloromethane (3 x 75 ml), the organic layers combined and dried (Na₂S0₄) and evaporated to give an oil. Purification by column chromatography on silica, eluting with methanol : ammonia (S.G. 0.88) .98.5:1.5 gave an oil (5.8 g) . The oil was dissolved in ethanol and one equivalent of fumaric acid added, the mixture concentrated in vacuo and treated with acetone, to produce a solid (3.8 g, 40%). Recrystallization from isopropanol gave [1- [2- (4-t-butyl-2, 6-dimethylphenoxy) ethyl] piperidin-4-yl] -bis- (4- fluorophenyl) methanol, hydrogen fumarate salt as a white solid (2.2 g) , m.p. 145-147°C.

Calc for C₃₂H₃₉F₂N0₂.C₄H₄0₄. C:69.32%; H:6.95%; N:2.25%. Found C:69.22%; H:7.13%; N:2.02%.

EXAMPLE 2

1- [4- [2- (4-dibenzo [a,d] cyclohepten-5-ylidenepiperidin-l- yl) ethoxy] -3, 5-dimethylphenyl] ethanone.

A. Acetic acid 2, 6-dimethylphenyl ester.

A solution of 2, 6-dimethylphenol (50 g, 0.41 mol), triethylamine (45.5 g, 62.5 ml, 0.45 mol) and butanone (300 ml) at 0°C was treated with acetyl chloride (35.3 g, 32.0 ml, 0.45 mol) drop by drop such that the temperature always stayed below 10 °C. Stirring was continued for 0.5 hrs at this temperature followed by a further hour at ambient. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was mixed with diethyl ether (300 ml) and washed with water (500 ml) . The organic phase was dried (Na₂S0₄) , filtered and evaporated in vacuo to give an oil which was distilled at reduced pressure to give the product (62.7 g, 93%), b.p. 51- 53°C/0.2 m Hg.

B. 1- (4-hydroxy-3, 5-dimethylphenyl) ethanone. A mixture of acetic acid 2, 6-dimethylphenyl ester (37.8 g, 0.23 mol) and aluminium chloride (31.0 g, 0.23 mol) was heated at 100°C for 20 h. The reaction mixture was mixed with ice (500 g) and extracted with dichloromethane (2 x 250 ml) . The combined organic layers were washed with water (2 x 200 ml) , dried with Na₂S0₄ and concentrated in vacuo. Trituration with cold diethyl ether produced 19.9 g (52%) of solid product, m.p. 154-156°C (after recrystallisation from benzene) .

C. 1- [4- (2-chloroethoxy) -3, 5-dimethylphenyl] ethanone. Sodium (in small chunks) (2.5 g, 0.11 mol) was added to absolute ethanol (150 ml) and stirred until dissolution was complete. 1- (4-hydroxy-3, 5-dimethylphenyl) ethanone (16.4 g, O.l^" mol) was added, followed by a solution of l-bromo-2-chloroethane

(12.5 ml, 0.15 mol) in ethanol (50 ml) and the mixture heated under reflux for 48 hours. A further quantity of l-bromo-2- chloroethane (6 ml) was added and heating under reflux continued for a further 24 h. The reaction mixture was concentrated in vacuo, the residue suspended in water (150 ml) and extracted with dichloromethane (2 x 100 ml) . The combined organic extracts were washed with sodium hydroxide (0.5 M, 100 ml), dried (Na₂S0₄) and evaporated in vacuo to give an oil which solidified with time to a solid product (16.0 g, 71%).

D. 4-dibenzo[a,d] cyclohepten-5-ylidenepiperidine-l- carboxylic acid ethyl ester.

To a solution of 4-dibenzo [a,d] cyclohepten-5-ylidene-l- methylpiperidine (cyproheptadine, 28.7 g, 0.1 mol) in benzene

(100 ml) at 60-70°C was added over 0.5 hrs, a solution of ethyl chloroformate (12.5 ml), 0.13 mol) in benzene (50 ml). After the addition, the reaction mixture was heated at reflux for 12 hrs.

The formed precipitate was filtered and the filtrate evaporated in vacuo, giving a solid. Trituration with diethyl ether gave the product (28.0 g, 81%), m.p. 120-123°C.

E. 4-Dibenzo [a, d] cyclohepten-5-ylidene piperidine.

A mixture of the above compound obtained in D (28 g, 0.081 mol), potassium hydroxide pellets (85%, 53 g, 0.81 mol) and isopropanol (275 ml) was heated at reflux for 6 hrs. The mixture was evaporated in vacuo, the residue dissolved in water (300 ml) and acidified with concentrated hydrochloric acid. The mixture was made just alkaline with concentrated aqueous ammonia, and extracted with dichloromethane (2 x 250 ml) ; the organic extracts were combined and washed with water (200 ml) , dried (Na,S0₄) and evaporated m vacuo. The resulting solid was triturated with diethyl ether to give the product (20.0 g, 90%), m.p. 144-146°C.

F. 1- [4- [2- (4-dibenzo [a,d] cyclohepten-5-ylidenepiperidin- 1-yl) ethoxy] -3, 5-dimethylphenyl] ethanone, hydrogen fumarate salt .

A mixture of 4-dibenzo [a, d] cyclohepten-5-ylidenepiperidine (3.0 g, 0.011 mol), 1- [4- (2-chloroethoxy) -3, 5-dimethylphenyl] ethanone (2.8 g, 0.012 mol) and potassium carbonate (3.3 g, 0.024 mol) in acetonitrile (150 ml) was heated at reflux for 48 hours. The reaction mixture was evaporated in vacuo, suspended in water (200 ml) , extracted with methylene chloride (2 x 150 ml), dried (Na,SO_) and evaporated in vacuo to give an oil. Purification by column chromatography on silica eluting with dichloromethane/ammonia gave 4.0 grams of purified product. Treatment of an ethanol solution with fumaric acid (1 eq.) and concentration of this solution gave 2.4 g of a solid which was recrystallized from ethanol to give 1- [4- [2- (4-dibenzo [a, d] cyclohepten-5-ylidenepiperidin-l-yl) ethoxy] -3, 5- dimethylphenyl] ethanone, hydrogen fumarate salt (2.1 g, 38%), m.p. 180-182°C.

Calc for C₃₂H₃₃N0₂ . C₄H₄0₄ C:74.59%; H:6.43%; N:2.42%. Found C:75.00%; H:6.46%; N:2.48%

EXAMPLE 3 l-[4-[2-[4-(10, 11-dihydro-dibenzo [a, d] cyclohepten-5- ylidene)piperidin-l-yl] ethoxy] -3, 5-dimethylphenyl] ethanone

A. 4- (10, 11-dihydro-dibenzo [a, d] cyclohepten-5- yliden) piperidine.

To a solution of 4- (dibenzo [a, d] cyclohepten-5- ylidene) piperidine (5.0 g, 0.018 mol) in methanol (250 ml) was added HC1 in ethanol (sat) to acid. Pd0₂ (0.5 g, 0.0036 mol) was added to the solution and the mixture was treated with H, (45 psi) at room temperature over three days. The reaction mixture was concentrated in vacuo, the residue was basified wirh sodium hydroxide and extracted with dichloromethane, dried with Na₂S0₄ and evaporated in vacuo giving a solid, which was suspended in petroleum ether and filtered. 4.3 g of the compound was obtained, m.p. 110-112°C.

B. l-[4-[2-[4-(10, 11-dihydro-dibenzo [a,d] cyclohepten-5-^" ylidene) piperidin-1-yl] ethoxy] -3, 5-dimethylphenyl] ethanone, hydrogen fumarate salt.

A mixture of 4- (10, 11-dihydro-dibenzo [a, d] cyclohepten-5- ylidene) piperidine (2.4 g, 0.0085 mol), 1- [4- (2-chloroethoxy) - 3, 5-dimethylphenyl] ethanone (2.1 g, 0.0093 mol) and potassium carbonate (2.6 g, 0.0186 mol) in acetonitrile (125 ml) was heated at reflux for 72 hours. The reaction mixture was evaporated in vacuo, suspended in water, extracted with methylene chloride, dried and evaporated in vacuo. Purification by column chromatography on silica eluting with dichloromethane/ammonia. Treatment of an ethanol solution with fumaric acid (1 eq.) and concentration in vacuo. The residue was dissolved in acetone and crystallized from diethyl ether and filtered. 2.3 g of a solid was recrystallized from ethanol to give 1- [4- [2- [4- (10, 11-dihydro-dibenzo [a, d] cyclohepten-5- ylidene) piperidin-1-yl] ethoxy] -3, 5-dimethylphenyl] ethanone, hydrogen fumarate salt (1.9 g, 47 %), m.p. 153-155°C.

Calc for C₃₂H₃₅N0₂ . C₄H₄0₄ C:74.33%; H:6.76%; N:2.41% Found C:74.61%; H:6.89%; N:2.42%

Effect on plasma glucose concentration in conscious rats.

Female Sprague-Dawley rats (CERJ-France, 190-220 g) were allowed free access to food and water up to the time of dosing with the compounds (10 mg/kg, p.o.). One hour after dosing, the animals were administered glucose (3g/kg) in aqueous solution (30% w/v) orally. Blood samples were obtained from the retro-orbital sinus, under light ether anaesthesia at times of 30, 60 and 120 minutes after glucose administration. The blood was treated with fluorourea heparin to prevent coagulation and glucose concentrations were measured using a Kem-O-mat automatic analyser.

Glucose Tolerance in rats

Treatment 10 mg/kg p.o. (glucose mmol/L)

30 min 60 min 120 min

Vehicle 8.7 8.9 8.9

Example 1 24.4 36.8 43.4

Example 2 32.3 40.0 43.8

LD_C Determination in Mice

Male Swiss mice (Almirall, 25-30 g) fasted overnight were randomized in groups of 3 animals and treated orally with 0.5% methylcellulose + 0.1% Tween 80 (vehicle) or compound at the doses of 1, 3, 10, 30 and 100 mg/kg; 10 ml/kg. Animals were observed along the following 48 hours and those who died were counted. The dose required to produce lethality in 50% of treated mice was determined. Results are given below.

Determination of rodenticidal activity in mice.

Albino mice of both sexes were used. Animals were housed individually and acclimatised on standard laboratory diet (SDS RMl powdered diet) for 72 hours before being presented with test bait. The bait (initially a non toxic cereal/fat mix) to which examples 1 or 2 were added at a concentration of 0.25%.

Bait presentation was as follows-

5 males and 5 females were given a choice of bait containing 0.25% of example 1 vs laboratory diet.

5 males and 5 females were given a choice of bait containing 0.25% of example 2 vs laboratory diet.

The mice were observed regularly. After complete mortality was achieved, 10 of 20 tested mice were subject to a post mortem in order to discover any gross effects of the active ingredients on major internal organs.

The results are presented in Table. Mortality for example 2 was 100% within 3 hours. Example 1 produced 80% mortality in the same period and the remaining 2 died subsequently. The post mortem examinations failed to find any evidence of gross major organ damage.

It was concluded that examples 1 and 2 were effective rodenticides at the concentration tested (0.25%). Onset of death after initial consumption of rodenticide was rapid with little observation of symptoms beforehand. Symptomatic mice not already dead when observed were seen to be immobile, becoming progressively more comatose. A comparison of bait and laboratory diet consumptions indicated that the test agents at the concentrations tested were palatable.

Claims

CLAIMS 1. A piperidine compound of formula (I):

wherein:

R¹ and R² are the same or different and each independently represents an alkyl or C₃-C₅ cycloalkyl group;

R³ represents a hydrogen atom or an alkyl, C₃-C₅ cycloalkyl, alkanoyl or C₃-C₅ cycloalkyl-carbonyl group;

R⁴ represents a hydroxy group and R⁵ represents a hydrogen atom or R⁴ and R⁵ together form a covalent bond; X¹ and X² are the same or different and each independently represents a hydrogen or halogen atom;

2. A compound according to claim 1 wherein R³ is an alkyl, C₃-C₅ cycloalkyl, alkanoyl or C₃-C₅ cycloalkyl-carbonyl group.

3. A compound according to claim 1 or claim 2 wherein each alkyl group and/or alkanoyl group contains from 1 to 6 carbon atoms .

4. A compound according to claim 1 or claim 2 wherein R¹ and R² are both methyl groups .

5. A compound according to any one of the preceding claims wherein R³ is a t-butyl group or an acetyl group.

6. A compound according to any one of the preceding claims wherein Y¹ and Y² together represent a methylene, ethylene or ethenylene group.

7. A compound according to any one of the preceding claims wherein R⁴ and R⁵ together represent a covalent bond.

8. A compound according to any one of claims 1 to 5 wherein Y¹ and Y² each represents a hydrogen atom, X¹ is the same as X², R⁴ represents a hydroxy group and R⁵ represents a hydrogen atom.

9. A compound according to any one of the preceding claims which has an LD₅₀ value in mice of not more than 30 mg/kg when orally ingested.

10. [1- [2- (4-butyl-2, 6-dimethylphenoxy) ethyl] piperidin-4- yl] -bis- (4-fluorophenyl) methanol,

1- [4- [2- (4-dibenzo [a,d] cyclohepten-5-ylidenepiperidin- 1-yl) ethoxy-3, 5-dimethylphenyl] ethanone and

1- [4- [2- [4- (10, 11-dihydro-dibenzo [a, d] cyclohepten-5- ylidene)piperidin-l-yl] ethoxy-3, 5-dimethylphenyl] ethanone.

11. A process for producing a piperidine compound as defined in any one of the preceding claims, which process comprises either:

(A) reacting a substituted α, -di-phenylmethyl-piperidine derivative of formula (VI) :

wherein R⁴, R⁵, X¹, X², Y¹ and Y² are as defined in the preceding claims, with a reactive intermediate of formula (V) :

wherein R¹, R² and R³ are as defined in the preceding claims and Z represents a leaving group; or

(B) reacting a compound of general formula (VII) :

wherein R⁴, R⁵, X¹, X², Y¹ and Y² are as defined in the preceding claims and Z¹ represents a leaving group, with a phenol of formula (VIII) :

wherein R¹, R² and R³ are as defined in the preceding claims.

12. A process according to claim 11 wherein the leaving group Z or Z¹ is a chlorine or bromine atom, or a methane sulfonate, p-toluene sulfonate or benzene sulfonate group.

13. A process for producing a compound as defined in claim 8, which process comprises reacting an ester of formula (II) :

wherein R¹, R² and R³ are as defined in the preceding claims and R⁶ represents a methyl or ethyl group, with at least two moles of a magnesium derivative of formula (III) :

MgX

wherein X¹ is as defined in the preceding claims and X represents a chlorine, bromine or iodine atom, and hydrolysing the magnesium complex so obtained.

14. A composition comprising as an active constituent a piperidine compound according to anyone of claims 1 to 10 and an acceptable diluent or carrier.

15. A composition comprising as an active constituent a piperidine compound according to anyone of claims 1 to 10 and a suitable food or attractant.

16. Use of a compound according to any one of claims 1 to 10 or a composition according to claim 14 or claim 15 as an agent for the extermination and/or control of rodents and other vertebrate pests.

17. A method of controlling rodents and other vertebrate pests, which method comprises providing a rodent or other vertebrate pest with a compound according to any one of claims 1 to 10 or a composition according to claim 14 or claim 15.