JPS60188369A - Novel phenylpropargylamine derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (An't r /l line 4q1) The present invention provides novel and useful phenylpropargylamine derivatives and acid addition salts thereof, methods for producing them, and methods for producing them that are orally ingested by warm-blooded harmful animals. (Means for solving the problem) The compound of the present invention has the following general formula I 3C [wherein R is a hydroxymethyl group, 2 to 6 a straight-chain or branched button alkoxymethyl group having carbon atoms, an optionally substituted phenoxymethyl group, a straight-chain or branched alkanoyloxymethyl group having 3 to 10 carbon atoms, an optionally substituted benzoyl group. Oxymethyl group, 2
Straight-chain or branched alkylsulfonyloxymethyl groups having ~9 carbon atoms, optionally substituted phenylsulfonyloxymethyl groups, formyl groups, which may be the same or different and each having 1 to 4 carbon atoms; have 1
represents an aminomethyl group or a hydroxyiminomethyl group optionally substituted with one or two straight-chain or branched-chain alkyl groups. ] phenylpropargylamine derivatives and their acid addition salts. Acid addition salts are formed with inorganic acids such as hydrochloric, sulfuric, phosphoric, nitric or sulfamino acids, or with organic acids such as acetic, octanoic, methanesulfonic, glutamic or 2-hydroxyethanesulfonic acids. be able to.

In the present specification, the appropriately substituted phenyl moiety is one or more selected from the group consisting of a halogen atom, a trifluoromethyl group, and a straight or branched alkyl and alkoxy group having 1 to 4 carbon atoms. It can be substituted with the above substituents.

Preferred compounds of general formula I are those in which R is a hydroxymethyl group, 2
Straight-chain or branched alkoxymethyl groups having ~6 carbon atoms, straight-chain or branched alkanoyloxymethyl groups having 3 to 7 carbon atoms, optionally substituted benzoyloxymethyl groups, 2 It represents a straight chain or branched alkylsulfonyloxymethyl group, formyl group or hydroxyiminomethyl group having ~6 carbon atoms.

(Effect) Compounds of general formula I and their acid addition salts are highly toxic to warm-blooded animals, especially Gera animals (e.g. rats and mice) by oral administration, and are harmful to warm-blooded pests (i.e. undesirable animals). It can be used to kill animals (bleeding animals) to control, for example, Gera fauna infestations. When herein the use of a compound of general formula (I), for example as a fungicidal animal agent, for killing warm-blooded pests is described, this description also includes acid addition salts of the compound of general formula I. intend to.

The following compound of the general formula ■ is of great interest for the killing of warm-blooded pests by oral administration: Compound Layer 1.1-(3,5-bistrifluoromethylphenyl)
-3-(4-(t,t-dimethyl-2-hydroxyethyl)piperidinocoprop-1-yne, 2, 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1, 1-dimethyl-2-methoxyethyl)piperidinocoprop-1-y16-, 3.1-(3,5-bistrifluoromethylphenyl)
-3-(4-(1,1-dimethyl-2-acetyloxyethyl)piperidinocoprop-1-yne, t1-(3,5-bistrifluoromethylphenyl)
-a-(4-(t,1-dimethyl-2-oxoethyl)
Piperidinocoprop-1-yne 15.1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1
-dimethyl-2-benzoyloxyethyl)piperidinoco-prop-1-yne, 6.1-(3,5-bistrifluoromethylphenyl)
-3-(4-(1,1-dimethyl-2-hydroxyiminoethyl)piperidinocoprop-1-yne.

7.1-(3,5-bistrifluoromethylphenyl)
-3-[4-(1,1-dimethyl-2-methylsulfonyloxyethyl)piperidinocoprobu-1-yne.

The following tests demonstrate the usefulness of the compound of the general formula (2) as a bactericidal animal agent. Various doses of the test compound in the form of an aqueous suspension were orally administered to one group of mice. The acute oral LD50 (i.e. 50
The dose per kg of animal body weight (immediate) required to cause % mortality was determined from the number of animals for each dose killed over the observation period with reference to published tables.

(Left below) Compound 16 Observation 1 (as free base) 78 5 to 68 years after administration,
There were no significant signs of death prior to death.

1, (as hydrochloride) 62 2 (as hydrochloride) 68 3, (as hydrochloride) 68 4, (as hydrochloride) 68 1, (as nitrate) 72 1, (as acetate) 95 1, (null (as a phenylpronocarpylamine salt) 72 The compound of general formula l can be prepared by applying or adapting a known method for producing phenylpronocargylamine derivatives.
For example, it can be prepared by one of the following methods: 19- [wherein X represents a halogen, preferably a bromine atom or a bromine atom]. ] and a compound of the general formula ■ shown below [wherein R' is a hydroxymethyl group, a linear or branched alkoxymethyl group having 2 to 6 carbon atoms,
an appropriately substituted phenoxymethyl group, a linear or branched alkanoyloxymethyl group having 3 to 10 carbon atoms, an appropriately substituted benzoyloxymethyl group,
It represents a straight-chain or branched alkylsulfonyloxymethyl group having 2 to 9 carbon atoms or an optionally substituted phenylsulfonyloxymethyl group. ] reaction with the compound ゛.

20- The reaction between the compound of general formula (■) and the compound of general formula (■) produces copper (
I) in the presence of a salt, preferably cuprous iodide and dichlorbis(triphenylphosphine)palladium (I) and optionally triarylphosphine, preferably tri-0-tolylphosphine or triphenylphosphine, or lblpalladium (IT ) compounds, preferably palladium acetate and triarylphosphines,
Preferably, the reaction can be carried out in the presence of tri0-tolylphosphine or triphenylphosphine. This reaction can be carried out at room temperature to the reflux temperature of the reaction mixture, optionally in the presence of an inert organic solvent such as acetonitrile, and in the presence of an organic base such as diethylamine. Organic bases may conveniently be used as solvents in the aforementioned steps.

(2) General formula shown below ■ F2O For example, sodium, potassium or lithium atom,
or an alkaline earth metal, such as a magnesium atom or a copper, silver or zinc atom. ] and a compound of the general formula V as shown herein, in which R" is a hydroxymethyl group, or one or two groups, which may be the same or different (and each having from 1 to 4 carbon atoms) represents an aminomethyl group suitably substituted with a straight or branched alkyl group, Y represents a hydrogen atom when the gero symbol M1 in the general formula (■) represents a hydrogen atom, or Y represents a hydrogen atom in the general formula (■). When the halftone symbol M1 represents a metal atom, it represents halogenomethylene, C-4 alkoxymethylene, chloromercuriomethylene or an alkyl- or aryl-sulfonyloxymethylene group, such as a tosyloxymethylene group. , and when the symbol M1 in the general formula (2) represents a hydrogen atom, that is, when the compound of the general formula (2) is a compound of the following formula (2), reaction with a formaldehyde source.

When the compound of general formula (■) is a compound of general formula (2), the reaction of the compound of general formula (V) with a formaldehyde source, such as paraformaldehyde or formalin, may be performed using copper(I).
an inert organic solvent in the presence of a salt, preferably cuprous chloride;
For example, the reaction can be carried out in a dioxane at room temperature to the reflux temperature of the reaction mixture, preferably 23-100°C.

When the compound of general formula (1) is not a compound of general formula (2), the reaction with the compound of general formula V can be carried out in the absence of a formaldehyde source in an inert organic solvent at room temperature to the reflux temperature of the reaction mixture.

(3) The following general formula (■) F, C F, C [wherein 2 represents a chlorine, bromine or iodine atom, or haalkylsulfonyloxy or arylsulfonyloxy, such as tosyloxy. ] and a compound of the following general formula ■ [wherein R'' is a hydroxymethyl group, a linear or branched alkoxymethyl group having 2 to 6 carbon atoms, or an appropriately substituted phenoxymethyl group and M2 represents an alkali metal, preferably a lithium atom, or when symbol 2 in the general formula (2) represents a chlorine, bromine or iodine atom, M2 may further represent a hydrogen atom. reaction.

This reaction can be carried out in an inert organic solvent, preferably diethyl ether or tetrahydrogen when the symbol M2 in the general formula (2) represents an alkali metal atom.

When the symbol M2 in the general formula (2) represents a hydrogen atom, the reaction can be carried out in the presence of an inorganic base such as potassium carbonate at room temperature to the reflux temperature of the reaction mixture.

(4) R is a straight chain or branched alkanoyloxymethyl group having 3 to 10 carbon atoms, an appropriately substituted benzoyloxymethyl group, a straight chain or branched chain having 2 to 9 carbon atoms; When representing an alkylsulfonyloxymethyl group or an appropriately substituted phenylsulfonyloxymethyl group, a compound of the general formula (1) (in the formula, R represents a hydroxymethyl group) and a suitable alkanoyl or benzoyl group, or by reaction with phenylsulfonyl (preferably chloride or bromide).
For example, it can be carried out in the presence of a vehicle such as dichloromethane or tetrahydrofuran at 0°C to the reflux temperature of the reaction mixture.

(5) When R represents a formyl group, general formula I (wherein,
R represents a hydroxymethyl group. ) is oxidized with a suitable oxidizing agent, such as pyridium chlorochromate, for example at the reflux temperature of the dichloromethane.

(6) R may be the same or different, and each is 1 to 4
, an aminomethyl group optionally substituted by 1 or 2 straight-chain or branched alkyl groups having 2 to 9 carbon atoms, the general formula I by reacting a straight-chain or branched alkylsulfonyloxymethyl group or an appropriately substituted phenylsulfonyloxymethyl group with ammonia or a suitable amine.

(7) When R represents a hydroxyiminomethyl group, the reaction is performed by reacting a compound of general formula I (wherein R represents a formyl group) with a hydroxylamine salt.

This reaction can be carried out at room temperature to the reflux temperature of the reaction mixture in the presence of an inert organic solvent such as ethanol and optionally an acid acceptor such as triethylamine. .

The compound of general formula (1) is a compound of general formula V (wherein, Y represents a hydrogen atom) [i.e.
2-Hydroxyethylnorpiperidine] and 1-bromoprop-2-yne, 1-chloroprop-2-yne, are combined with an inorganic or organic base, such as potassium carbonate, or a compound of the general formula V (where Y is a hydrogen atom). can be produced by reacting in the presence of an excess of a compound (showing).

This reaction can be carried out, if necessary, in the presence of an inert organic solvent such as methanol, acetone or acetonitrile.

Compounds of general formula
s)% Vol. 13, p. 159 (t9ft)*28- (1975), p. 255; and 2 is chlorine source (193
B), page 2662 can be applied or manufactured.

Acid addition salts are prepared from compounds of the general formula (1) by methods known per se, for example by adding stoichiometric amounts of the compound of the general formula (1) and a suitable acid, such as hydrochloric acid, sulfuric acid, phosphoric acid.

with an inorganic acid such as nitric acid or sulfamic acid, or an organic acid such as acetic acid, octanoic acid, methanesulfonic acid, glutamic acid or 2-hydroxyethanesulfonic acid in a suitable solvent such as diethyl ether, ethyl acetate or acetone. The @acid addition salts that can be prepared by the reaction can be purified by recrystallization from one or more suitable solvents.

The formation of acid addition salts provides a means to obtain compounds of general formula I in pure form.

Compounds of general formulas (1), m, (2), vg and (2) can be produced by methods known per se.

The term "methods known per se" as used herein means methods conventionally used or described in the chemical literature.

The present invention will be explained below with reference to Examples and Comparative Examples. When describing medium pressure liquid chromatography, the pressure used was 5 to 10 bonds per I In'' and the support was silica (Merck type 9385; 230-400 mesh).

Example 1 Compound 41 Triphenylphosphine (100■) Copper chloride (■) (5
■) and dichlorbis(triphenylphosphine) 5Q
(8,75 cm) was dissolved in triethylamine (5d) with mild heating. The solution thus obtained was cooled to laboratory temperature and dissolved in 3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidinocopropylene.
1-yne (o, 97 g) was added with stirring. The stirred mixture was heated under reflux and 3,5-bistrifluoromethylbromobenzene [which can be prepared as described by E.T. Matsusada] (1,47F
') was added. After heating under reflux for 15 minutes, the reaction mixture was filtered. The precipitate was diluted with cold triethylamine (5 in.
). Evaporation of solution f and washings gave a brown crystalline solid, which was mixed with n-hexane (50 IIL) for 3
Stirred for 0 minutes. The n-hexane solution was then decanted and the TA fraction was further diluted with n-hexane (tso
Washed with i7.

The n-hexane solutions were decanted and the n-hexane solutions were combined and evaporated to dryness to give a pale yellow crystalline solid (
1.92g), (melting point 71-76°C) 31- was obtained, which was subjected to medium pressure liquid chromatography [eluent dichloromethane; methanol (95:5 by volume)] to obtain a compound with a melting point of 85-87 @C. -(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidinocoprob-1-
Yin (1,56 fl) was obtained as beige crystals.

Example 2 Compound/162 triphenylphosphine (o, o7eg) and i%
Copper (0,033,1 it) and bistriphenylphosphine palladium dichloride (0,067 g) were added to triethylamine (38 ml) and stirred magnetically for 40 min.
Heated at ℃. Then 3-[4-(1,1-dimethyl-2-methoxyethyl)piperidinocoprop-1-yne (7,99) was added.

3.5-bistrifluoromethyl-bromobenzene (1
After adding 1,19), the solution was heated at 80° C. for 1 hour and left overnight at room temperature. The precipitated solid 32-vP was separated and washed with dichloromethane (som). The d5 solution and the washings were evaporated under reduced pressure to give a brown oil after evaporation of the added toluene. Petroleum ether (boiling point 60-8
0°C) After adding water and filtering to remove a small amount of tar,
The solution was brought to pH 1 by addition of hydrogen chloride ether solution. The precipitated pale yellow solid was separated, washed with petroleum ether (boiling point 60-80°C) and dried to give 1-(3,
5-bistrifluoromethylphenyl)-3-[4-(
1,1-dimethyl-2-methoxyethyl)piperidinocoprop-1-yne hydrochloride (10,3,9) with a melting point of 169
Obtained as a pale yellow solid at -170°C.

Example 3 Compound layer 3 Acetyl chloride (5aLJ)vt-(a,5-bistrifluoromethylphenyl)-3-[4-('+1-dimethyl-2-hydroxyethyl)piperidinocoprop-1-
In (1, 5 & ) was added while rotating. An exothermic reaction occurred to give the product, which solidified rapidly. After 1 hour, the solid was added to ice (30 Illl) and then extracted with diethyl ether (50 Illl). The extract was brought to basic pH with a saturated aqueous solution of sodium carbonate, and the ether layer was collected. aqueous phase with diethyl ether (sod)
and the combined ether solutions were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow oil (1.7 g). This oil was dissolved in diethyl ether (zom) and excess hydrogen chloride solution in ether was added. The precipitated colorless solid was separated from P and recrystallized from a mixture of isopropyl alcohol and diethyl ether to give 1-(3,5-bistrifluoromethylphenyl)-3-(4-(t,x-dimethyl- 2-
Acetyloxyethyl)piperidinocoprop-1-yne hydrochloride (1.1 g) was obtained as colorless crystals with a melting point of 182-184°C.

t-(a) in dichloromethane (zod).

5-bistrifluoromethylphenyl)-3-[4-(
A solution of 1,1-dimethyl-2-hydroxyethyl)piperidinocoprop-1-yne (3,0,li') was mixed with pyridium chlorochromate (1,75 g) and dichloromethane (
20rnl) under anhydrous conditions. 4
．． After stirring for 5 hours, the reaction was complete and dry diethyl ether (60 fnl) was added. After filtration twice, the solution was evaporated under reduced pressure to give a brown solid (2.7 g). This solid was dissolved in silica gel (Merck; 0.04~o, o6aam)
Chromatographing using medium pressure and eluting with a mixture of dichloromethane and ethyl acetate (1:1) gave the product as a yellow oil (0.9 g). A solution of hydrogen chloride in ether was added to an ether solution of this oil at pH 1.
and the precipitated white solid was diluted with petroleum ether (boiling point 60-80°C, 30 ml) and then separated to give 1-(3 , fi-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-oxoethyl)piperidinocoprop-1-ine hydrochloride (1,O,!i') was obtained.

(Left below) 36- (1) ]-(3,5-
bistrifluoromethylphenyl)-3-[4-(1,
A solution of 1-dimethyl-2-hydroxyethyl)piperidinocozolobu-1-yne (2,0,1) was dissolved in a solution of concentrated sulfuric acid in diethyl ether (concentrated sulfuric acid in diethyl ether 1:25 volume, 13-). The solvent was evaporated under reduced pressure and the i,1-(3,5-bistrifluoromethylphenyl)-3-(4-(1,1-dimethyl -2-hydroxyethyl)piperidinocoprop-1=ine sulfate (
2,4,1 was obtained as a pale yellow semi-solid.

(11) 1-(3゜5-bistrifluoromethylphenyl)-3-(4-(
A bath solution of 1,1-dimethyl-2-hydroxyethyl)piperidinocoprop-1-yne (2.0 g) was diluted with an aqueous solution of nitric acid.
f (0.25 mol, 19.6 mg) with magnetic stirring. The solvent was evaporated under reduced pressure and the residue was reduced to 0.
Dehydration with 314IIIHg gave 1-(3,5-bistrifluoromethylphenyl)-3-(4-(1,1-dimethyl-2-hydroxyethyl)piperidino]propylene 1-
The yne nitrate (2,281I) was obtained as a brown solid.

(iii) 1-(3,5-bistrifluoromethylphenyl)-3-44-(1,1-dimethyl-2-hydroxyethyl)piperidinoco in dry diethyl ether (20 min) containing a few drops of ethanol. Prop-1-
A solution of in(2,01i1) was brought to pH 1 with an ethereal solution of hydrogen chloride gas. The resulting solution was diluted to 4Qml with petroleum ether (boiling point 60-80°C), the pale yellow solid was separated by furnace, and diluted with diethyl ether and petroleum ether.
: Washed with a solution of 1 (25 ml) and dried,
1-(3,5-bistrifluoromethylphenyl)-37(4-(1,1-dimethyl-2-hydroxyethyl)piperidino) prop-1- with a melting point of 183-185°C
Inohydrochloride (2.1 g) was obtained as pale yellow crystals.

The following was produced by the same procedure as described in (11) above.

Aqueous solution of 6-sulfamino acid (0,0237% W/V;
2Q wL13 ) was used as the acid component, and 1-(3,
5-L”trifluoromethylphenyl)-3-(4-
(1,4-dimethyl-2-hydroxyethyl)piperidinocoprop-1-insulfamate (2,421) was obtained as a brown oil.

(■) An i solution of acetic acid in diethyl ether (0,0
14%W/V: 20m1. ) as the acid component, 1-(3,5-bistrifluoromethylphenyl)-
3-(4-(1,1-dimethyl-2-hydroxyethyl)piperidinocoprop-1-yne acetate (2,249)
was obtained as a red solid.

(VD:) A solution of orthophosphoric acid in ethyl ether (
0,027% W/v; 20Id) as the acid component, 1-(3,5-bistrifluoromethylphenyl)-
・3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidinocoprocy-1-yne phosphate (2,47g
) was obtained as an orange rubbery substance.

Triethylamine (1,27d) was dissolved in dichloromethane (
1-(3,5-bistrifluoromethylphenyl)-3-(4-(1,1-dimethyl-2-hydroxyethyl)hyperidino)frobu-1-yne (3,sg
) was added to the solution with mechanical stirring. Benzoyl chloride (
1,2,1 was slowly added over 15 minutes and then refluxed for 4 hours.

After cooling to room temperature, benzoyl chloride (1,29
) was added thereto, and the mixture was further refluxed for 1.5 hours. After cooling,′
The mixture was added to excess aqueous sodium bicarbonate and heated on a steam bath for 2 hours. After cooling, the mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate,
The mixture was evaporated under reduced pressure to obtain a red oil (4, ay). This oil was chromatographed on silica gel (Merck) and a mixture of dichloromethane and methanol (9
5:5) under medium pressure to give 1-(3,5-bistrifluoromethylphenyl)-3f(4-(x').

1-:)Methyl-2-benzoyloxyethyl)piperidinocoprop-1-yne (3.0 g) was obtained as a brown oil.

Triethylamine (0,4 η words) and then hydroxylamine hydrochloride (0; 18 g) were dissolved in ethanol (10
1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,17dimethyl-2-oxoethyl)piperidino]probu-1-yne (1,(1)) in The mixture was left overnight at room temperature and then heated under reflux conditions for 2 hours. After cooling and evaporation of the solvent, the dark orange solid was chromatographed on silica gel (Merck & Co.). Elution under medium pressure with a mixture (95:5) of 3-[4-(1,1-dimethyl-2-
Hydroxyiminoethyl)piperidino)-1-(3,5
-bistrifluoromethylphenyl)prop-1-yne, the pale yellow gum gradually solidified (0.9J
i+).

Triethylamine (0,75,!it) and then methylsulfonyl chloride (0,85 g) were dissolved in 1-(3,5-bistrifluoromethylphenyl)-3-(4-(1°1-dimethyl) in tetrahydrofuran (50 mg). -2-hydroxyethyl)piperidinocoprop-1-
was added to the solution of in(3,OF).

After stirring for 5 hours, the triethylamine hydrochloride precipitate was filtered off and the filtrate was evaporated under reduced pressure to give a brown gum. This gum was purified by medium pressure chromatography using a mixture of dichloromethane and ethyl acetate (85:15) as eluent to obtain 1-(3,5-bistrifluoromethylphenyl)-3-[4 -(1,1-dimethyl-2-methylsulfonyloxyethyl)piperidinocoflobu-1-yne (2.4 g) was obtained as a colorless gum.

Reference Example 1 3-(4-(1,1-dimethyl-2-hydroxyethyl)piperidino) Prop-1-yne (used as starting material in Example 1) was prepared as follows: 4-(1 , 1-dimethyl-2-hydroxyethyl)piperidine acetate (1.6 g) was added to the IOW/V without stirring.
% aqueous sodium hydroxide solution (6 rnl) and then prochloride Qlugyl (0.56 mg) was added with stirring using a laboratory temperature trowel. Stirring was continued for 6 hours at laboratory temperature and the reaction mixture was then filtered to give an oily solid which was then dissolved in diethyl ether (50ml).

The ethereal solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give a dark yellow oil (1 g), which was recrystallized from petroleum ether (boiling point 60-80°C) with a melting point of 78-82°C. 3-(4-(1,1-dimethyl-2
-hydroxyethyl)piperidinocoprop-1-yne (
0.82 g) was obtained as pale yellow crystals.

Reference Example 2 4-(1,1-dimethyl-2-hydroxyethyl)piperidine acetate (used as starting material in Reference Example 1)
was prepared as follows: 4-(1,1-:)methyl-
2-Hydroxyethyl, Volume 93, Page 7228. Hydrogenation was carried out under a pressure of 50 pounds per inch for 10 hours until 100% of the theoretical uptake of hydrogen occurred. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure (15 mHp) to give a light yellow color. An oil was obtained which was then distilled (boiling point 120°C 10.2 flHJ?
) to give a colorless oil which was recrystallized from a mixture of ethanol and diethyl ether, melting point 108-11.
4-(1,1-dimethyl-2-hydroxyethyl)piperidine acetate (1, sl) was obtained as colorless crystals at 0°C.

Reference example 3 10% W/V sodium hydroxide aqueous solution (22 hours)
was added to 4-(1,1-:)methyl-2-methoxyethyl)piperidine (9,6II) at room temperature with stirring.

Prono(lugil chloride (3,8 rnl) was added in one portion and the mixture was stirred mechanically overnight. After 2 days at room temperature, the solution was diluted with excess water and dichloromethane (3X50
m). The organic phase was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give a brown oil (10.2 g
) was obtained. A sample of this oil was mixed with silica gel (Merck & Co., Ltd.,
0.04-0.06311) under medium pressure, eluting with a mixture of ethyl acetate and dichloromethane (1:1) to give an almost colorless oil (2.6 g
) was obtained. A solution of this oil in dry diethyl ether was brought to pH 1 by addition of ethereal hydrogen chloride solution to give an oil which rapidly crystallized. After filtering and washing with dry diethyl ether, mp 152-154
3-(4-(1,,1-dimethyl-2-methoxyethyl)piperidinocoprop-1-yne (2,OF)) was obtained as white crystals.

A solution of 4-(1,1-dimethyl-2-methoxyethyl)-pyridine (10,OF) in acetic acid (120 rne) was diluted with platinum dioxide at 40 P, S, i from room temperature to 43 °C.
Catalytic hydrogenation was carried out for 41 hours at °C.

An additional amount of platinum dioxide was added 24 hours after the start of the reaction, and a final addition was made after a further 8 hours. After a total of 41 hours, the solution obtained after filtering the catalyst was evaporated under reduced pressure and more toluene was added and evaporated to remove acetic acid. The resulting yellow oil was dissolved in dichloromethane and brought to pH 12 with a dilute aqueous solution of sodium hydroxide. After saturation with IJ chloride, the organic phase was separated and the aqueous layer was re-extracted five times with dichloromethane. The organic solutions were combined, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 4-(
1,1-1 Methyl-2-methoxyethyl)-piperidine (9,7,9) was obtained as a sachet oil.

Reference example 5 4- in dry dimethylformamide (150m/)
(1,1-dimethyl-2-hydroxyethyl)pyridine (15,9) was dissolved in sodium hydride (80% chili oil dispersion,
3.3 g) in a nitrogen atmosphere with stirring under OC. After 15 minutes at OC, the mixture was cooled to -200 and treated with dry dimethylformamide (50 td
) of iodomethane (7.4 m) was added dropwise over 5 minutes.

The mixture, which turned from white to an orange precipitate, was slowly warmed to room temperature and stirred under 9 tubes overnight.

After pouring into excess water, the mixture was diluted with dichloromethane 3.
Extracted twice. The extract was washed twice with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a dark oil after evaporation of additional toluene. This oil was chromatographed under medium pressure on silica gel (Merck & Co., 0.04-0.063) using a mixture of dichloromethane and ethyl acetate (2:1) as the solvent.
,1-dimethyl-2-methoxyethyl)pyridine (11
,0g) was obtained as a brown oil.

According to a feature of the invention, there is provided a method for killing unwanted warm-blooded pests, in particular gerodonts, which method particularly comprises administering an effective lethal dose of at least one compound of general formula I or an acid addition salt thereof. Geralds [e.g. rats and mice, e.g. Rattus ra
Rattus n.
orvegicus) and Earth Z-Fist Musculus (M■
It consists of oral administration to animals for the purpose of suppressing or eradicating the infestation of S. musculus). Oral administration of an effective lethal dose of at least one compound of general formula I or an acid addition salt thereof to an undesirable animal can be achieved by administering a single bolus dose of a compound of general formula I or an acid addition salt thereof (
(acute administration) or preferably by several small doses (
(chronic administration).

When compounds of general formula I or their acid addition salts are used to kill undesirable warm-blooded pests (e.g. geratodonts), humans and domestic animals as well as wild animals whose control or eradication is undesirable may be used. Usual standard precautions should be taken to avoid incorrect administration.

A particularly valuable property of the compounds of general formula I and their acid addition salts is that when used as rodenticides there is generally a lag period of about 2 to 9 days between administration and the appearance of signs of toxicity and mortality. present, during which they can be ingested and killed by chronic administration, and during which the galetes can be removed from the area where the administration took place or from the vicinity of the area of infestation, thereby establishing a relationship between treated and untreated animals. The goal is to reduce the risk that people will suspect the source of intake and avoid it.

Another particularly valuable property of the compounds of general formula I and their acid addition salts is that sedation is the predominant symptom and that treated animals die quietly without showing any signs of distress. Although there is a lag period between ingestion and death, this period is shorter than that seen with anticoagulant rodenticides and is sufficient to prevent infestation of warm-blooded pests (particularly galetes). Advantageously, the period of treatment and observation required to ensure that suppression is achieved is reduced.

Anticoagulant rodenticides, such as those of the coumarin type (e.g., warfarin) and those of the indandione type (e.g., chlorophacinone), are widely used to control or eliminate infestations of galetes. However, the emergence of rodents in many areas, particularly rats and mice, that are resistant to anticoagulant rodenticides has shown that the efficacy of these anticoagulant rodenticides has increased. - Increasing restrictions on customers. Compounds of general formula I and acid addition salts thereof are equivalent to the anticoagulant rodenticides tζ resistant, as well as to the species ζ of galedonts that do not have this resistance. It has been found. Therefore, as a preferred feature of the invention, the present invention provides a method for treating galetes, in particular anticoagulant rodenticides norvegicus.
s ) and Musmus musculus ((Musmus-cu
A method is provided for killing rats and mice, such as IUS), which method comprises orally administering to these galetes an effective lethal dose of at least one compound of general formula I or an acid addition salt thereof. ing. An effective lethal dose of a compound of general formula (III) and its acid addition salts can be administered to a warm-blooded pest, such as a galela tooth, in undiluted form if desired, or more commonly in liquid or as a solid orally ingestible composition (e.g., a bait), which composition may contain a compound of general formula I or an acid addition salt thereof, for example, in a cereal such as oatmeal, a vegetable flour such as barley flour, wheat flour, or bean flour. Rokoshi soap powder, bread, cakes, grains, seeds, fruits, chocolate,
In a suitable ingestible carrier such as animal flour, animal or vegetable oils and fats, such as peanut oil and corn oil, and other known ingestible animal or vegetable substances, such as fish and prepared animal foods. , other ingestible additives such as attractant flavoring substances, binders, antioxidants, surfactants such as humectants,
Dispersants or emulsifiers and warning coloring substances may or may not be added. Chocolate can be used alone or together with other uptake carriers as a particularly suitable uptake carrier, and more preferably sugar can be used with other uptake carriers to facilitate administration.

The bait can be in the natural physical form of the ingestion carrier used, such as liquids and powders, or can be formulated as granules, pills, pellets, tablets or pastes as desired. Liquid, solid or pasty poison baits can, if desired, be placed in sachets that can be easily opened by pests (eg, geronts). A suitable physical form, Tatoe, is a solid intake carrier containing 2-20% sugar and/or vegetable or animal oil or chocolate (e.g. vegetable flour or barley flour). Small pieces of active substance can be coated or impregnated onto supports consisting of blocks or sheets, such as wax, wood, synthetic plastics, cardboard or paper; It is a particularly suitable material.

Particularly suitable rodenticide baits include o, ooi to 10% by weight of at least one compound of general formula I or an acid addition salt thereof, 85 to 98.999% by weight of a grain carrier;
~5% by weight of vegetable or animal oil and 0-0.5% by weight of warning coloring substances.

The orally ingestible composition according to the invention further comprises the general formula I
or an acid addition salt thereof in combination with a solid, ingestible carrier that is a powder (for example, powdered talc which can be used as a tracking powder). Tracking powders of this type are placed in various locations, particularly in frequently frequented and infested passages of galedonts, to be deposited on the fur and feet of the galedonts, and later ingested orally during play.

Liquid and solid orally ingestible compositions according to the invention preferably contain from 0.001 to 10% by weight, especially from 0.05 to 10% by weight.
0.2% by weight of at least one compound according to general formula I or an acid addition salt thereof, wherein the compound of general formula I or an acid addition salt thereof is incorporated undiluted into a liquid or solid uptake carrier or support. can be created by
Preferably, concentrates containing a compound of general formula I or an acid addition salt thereof are prepared by incorporating into a liquid or solid uptake carrier or support. Incorporating a compound of general formula ■, or an acid addition salt thereof, in an undiluted state or as a liquid or solid concentrate into an uptake carrier or support can be accomplished, for example, by mixing or incorporating a liquid and then removing a solvent, such as by evaporation. This can be done by conventional techniques such as removing.

A liquid or solid orally ingestible composition comprising a compound of general formula I or an acid addition salt thereof in a suitable orally ingestible carrier or support constitutes a further feature of the invention and is suitable for carrying out the method of the invention. During implementation, it can be distributed appropriately to areas infested with harmful animals.

In particular, the method of the invention can be used to improve crop growing areas, such as cereal growing areas and plantations, such as oil palm plantations, as well as domestic, agricultural, industrial, commercial and office buildings such as factories, hospitals, etc. Public facilities, warehouses, ships, kitchen facilities, dogs, and the areas near these structures and ships are protected from harmful animals, especially galeodonts (
For example, it can protect against damage caused by rats and mice.

[The term orally ingestible composition j refers to a composition that can be orally ingested by a warm-blooded pest, such as a galela tooth;
It means a composition which is not excluded from these harmful animals and which, after ingestion, releases a lethal dose of the compound of general formula I or its acid addition salt into the animal's body. Suitable orally consumable carriers and supports have properties suitable for making orally consumable compositions of this type and are chemically and physically compatible with the compound of general formula I or its acid addition salt. be.

(Blank below) Liquid or solid concentrates suitable for use in preparing liquid or solid orally ingestible compositions according to the present invention include compounds of general formula 1 or acid addition salts thereof. in combination with a liquid or solid diluent or carrier, e.g. in the form of a solution, emulsion, syrup, coating, granule, tablet, pellet or powder, and containing other ingestible additives e.g. as mentioned above. However, they may not be included and constitute other features of the invention.

Diluents suitable for use in the concentrates are compatible with the compound of general formula I and its acid addition salts and the uptake carrier or support, and which are compatible with the uptake carrier or support for the animal. A liquid or solid that has no adverse effects and, in the case of a liquid diluent, can be easily removed, for example by evaporation, after incorporating the liquid concentrate into the uptake carrier or support. Solid diluents suitable for use in the concentrates of the present invention include starch, sucrose, lactose and edible carriers as described above. Suitable liquid diluents for use in the concentrates according to the invention include water and animal or vegetable oils and organic solvents such as xylene, isophorone, dioxane or acetone. Compatible with the ingestion carrier or support in which the compound of general formula I and the concentrate are to be incorporated and having no adverse effect on the acceptability of the ingestion carrier or support in animals, e.g. not repellent to rodents. A liquid concentrate consisting of a compound of general formula I dissolved in a solvent such as H-J-T oil, corn oil, xylene, isophorone, dioxane and acetone can be used to prepare a solid orally ingestible concentrate. Particularly suitable.

The liquid concentrates can be aqueous or aqueous-organic solutions, suspensions or emulsions; the acid addition salts of the compounds of the general formula I are particularly suitable for this purpose.

It will be appreciated that the liquid or solid concentrates according to the invention are similar in composition to the liquid or solid orally ingestible compositions according to the invention, but do not contain compounds of general formula I or their acid additions. Higher concentrations of salt can be contained and diluted with an appropriate additional amount of an uptake carrier or support to yield a composition that can be easily administered to animals. Liquid and solid concentrates according to the invention suitable for formulation in an orally ingestible carrier or support preferably contain from 1 to 90 g, especially from 1 to 5 wt. It consists of salt.

In this specification, when referring to the weight of the compound of general formula I and its acid addition salt in the orally ingestible compositions and concentrates according to the invention, this refers to the weight of the compound of general formula I in the acid addition salt. means the content of

The liquid or solid rodenticidal concentrates and orally ingestible rodenticidal compositions according to the invention may further contain a compound of general formula (1) or an acid addition salt thereof, if necessary.
It may be included in combination with one or more rodenticidal anticoagulant compounds, such as those of the coumarin type (eg, warfarin) or of the indandione type (eg, chlorophacinone).

Examples 9 to 15 below illustrate the rodenticidal compositions of the present invention.

Example 9 Peanut oil (100 m/) R: 1-(3,5-his)lifluoromethylphenyl)-3-(4-(1,1-
A concentrate was prepared by dissolving dimethyl-2-hydroxyethyl)piperidinocozolobu-1-yne (22). This concentrate is added in an amount of 0.001 to 10% by weight based on the total weight of the feed.
It can be incorporated into edible feeds in an amount of preferably 0.05 to 0.2% by weight of the compound, mixed with grains, particles, flours, wrinkles, fruits, vegetables or meat. Orally ingestible compositions of this type are suitable for use in the control of undesirable galetes.

Example 10 1. in acetone (20 ml). -(3,5-bistrifluoromethylphenyl) -3-(4-(1,1-dimethyl-2-hydroxyethyl)piperidinocoprop-1-
By dissolving In(1,Of) and homogeneously impregnating laboratory rat food pellets) (1kl?) f'8, a rodenticidal composition is prepared and used for the control of undesirable galetes. I found a suitable poison bait.

Example 11 1-(3,5-bistrifluoromethylphenyl)-3
-(4-1,1-dimethyl-2-hydroxyethyl)piperidinocoprop-1-yne (5f) was added to sucrose (1009
), wheat flour (30g) and corn starch (70%
) was intimately mixed with the mixture.

This powder concentrate was used to coat pieces of shoulder meat, such as beef and pork, to create a bait for use in the control of undesirable galetes.

Example 12 1-(3,5-bistrifluoromethylphenyl)-3
-[4-(1,1-dimethyl-2-hydroxyethyl)
Piperidinocoprop-1-yne (1,0#), oatmeal (899,9), wholemeal flour (50J) and corn oil (50F) are mixed thoroughly and intimately in a blender until the entire mixture is mixed. By uniformly distributing the ingredients, a rodenticidal composition was created, which provided a bait suitable for use in controlling undesirable rodents.

If desired, 0.05% by weight of a suitable warning colorant, such as Florazole Sky Blue, can also be incorporated into the composition.

Example 13 1-(3,5-bistrifluoromethylphenyl)-a
-[4-(1,1-dimethyl-2-hydroxyethyl)
Piperidinocoprop-1-yne (1,011), moistened coarse oatmeal (949II) and sugar (50g) are thoroughly mixed in a blender to intimately distribute the ingredients throughout the mixture and remove unwanted gelatin. A rodenticidal composition was obtained as a bait that can be used to control odontids. If desired, 0.05 weight percent of a suitable warning colorant, such as Florazole Sky Blue, can be incorporated into the composition.

Example 14 1-(3,5-bistrifluoromethylphenyl)-3
-[4-(1,1-dimethyl-2-hydroxyethyl)
A rodenticidal tracing powder was prepared by intimately mixing piperidinocoprop-1-ine hydrochloride (1,0,9) and powdered Merck (99 g).

This powder is placed in a passageway frequented by rats, where it adheres to the rat's fur and paws, and then tampered with for 3 minutes.
: Sometimes ingested by rats to kill them.

Example 15 1-(3,5-bistrifluoromethylphenyl)-3
44-(1,1-:)methyl-2-hydroxyethyl)
Piperidinocoprop-1-yne hydrochloride (90 g) and whole meal flour (IOF) were intimately mixed in a blender;
A concentrate was made by evenly distributing it throughout the mixture.

The concentrate thus obtained (100,!iF) was then mixed with oatmeal (8900g) and whole meal powder (500,!iF).
1 iF) and corn oil (500,9') in a blender to create a bait suitable for controlling undesirable galetes, evenly distributing the ingredients throughout the bait.

1-(3,5-bistrifluoromethylphenyl)-3
-(4-(1,1-dimethyl-2-hydroxyethyl)
Preparing compositions in the same manner as in Examples 9 to 15 above, using other salts or other compounds according to general formula (1) or acid addition salts thereof in place of piperidinocoprocy-1-yne or its hydrochloride. I can do it.

-/2-

Claims (1)

[Claims] Formula (1): [In the formula, R is a hydroxymethyl group, a linear or branched alkoxymethyl group having 2 to 6 carbon atoms, an appropriately substituted phenoxymethyl group, 3 Straight-chain or branched alkanoyloxymethyl groups having ~10 carbon atoms, optionally substituted benzoyloxymethyl groups, 2
Straight-chain or molecular alkylsulfonyloxymethyl groups having ~9 carbon atoms, appropriately substituted phenylsulfonyloxymethyl groups, formyl groups, which may be the same or different and each having 1 to 4 carbon atoms 1
represents an aminomethyl group or a hydroxyiminomethyl group optionally substituted with one or two straight-chain or branched-chain alkyl groups. ] phenylpropargylamine derivatives, and acid addition salts thereof. (2) The appropriately substituted phenyl moiety defined by the symbol R is a halogen atom, a trifluoromethyl group, and 1 to 4
Compounds according to claim 1, which may be substituted by one or more substituents selected from straight-chain or branched alkyl and alkoxy groups having 5 carbon atoms. (3) R is a hydroxymethyl group, a linear or molecular chain alkoxymethyl group having 2 to 6 carbon atoms, 3 to
straight-chain or branched alkanoyloxymethyl groups having 7 carbon atoms, optionally substituted benzoyloxymethyl groups, straight-chain or branched alkylsulfonyloxymethyl groups having 2 to 6 carbon atoms, The compound according to claim 1, which exhibits a formyl group or a hydroxyiminomethyl group. +4) The compound according to claim 1, which is 1-(3,5-bistrifluoromethylphenyl)-3-(4-(1,1-dimethyl-2-hydroxyethyl)hypericino]furofu-1-yne) (5) Claim 1 which is 1-(3,5-bistrifluoromethylphenyl)-3-(4-(1,1-dimethyl-2-methoxyethyl)piperidinocoprop-1-yne) (6) A patent for 1-(3,5-bistrifluoromethylphenyl)-3-(4-(t,t-dimethyl-2-acetyloxyethyl)piperidinocoflobou-1-yne) Compound according to claim 1. (7) 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-oxoethyl)piperidinocoprop-1-yne (8) An acid addition salt of the compound according to any one of claims 1 to 7. (9) R represents R', This is the hydroxymethyl group,
Straight-chain or branched alkoxymethyl groups having 2 to 6 carbon atoms, optionally substituted phenoxymethyl groups,
Straight-chain or branched alkanoyloxymethyl radicals having 3 to 10 carbon atoms, optionally substituted benzoyloxymethyl radicals, straight-chain or branched alkylsulfonyl radicals having 2 to 9 carbon atoms. When producing the phenylpropargylamine derivative according to claim 1, which represents an oxymethyl group or an appropriately substituted phenylsulfonyloxymethyl group, a compound of the general formula 23C [wherein, X represents a halogen atom] is used. ] A compound of the general formula: [wherein R' has the above meaning. ] A method for producing a tosulfenylbrobargylamine derivative, comprising reacting with a compound. On R represents a group R#, which is a hydroxymethyl group,
or which may be the same or different and which 4- represents an aminomethyl group or a hydroxymethyl group optionally substituted by one or two straight-chain or branched alkyl groups each having 1 to 4 carbon atoms; When producing phenylpropargylamine derivatives, the general formula: [
In the formula, Ml represents a hydrogen atom, an alkali metal or alkaline earth metal atom, or a copper, silver or zinc atom. ] A compound of the formula: [In the formula, R″ has the above meaning, Y represents a hydrogen atom when the gero symbol M1 in the general formula (■) represents a hydrogen atom,
Or, when the symbol M1 in the general formula (■) represents a metal atom, halogenomethylene "Cl-4 alkoxymethylene,
Chlormercuriomethylene mataha represents an alkyl or aryl-sulfonyloxymethylene group. ], and further the symbol M1 in the general formula ■
2. The method for producing a phenylpropargylamine derivative according to claim 1, which comprises reacting with a formaldehyde source when represents a hydrogen atom. a R represents a group R'', which is a hydroxymethyl group,
When producing a phenylpropargylamine derivative having a linear or branched alkoxymethyl group or an appropriately substituted phenoxymethyl group having 2 to 6 carbon atoms, the general formula: [wherein 2 is chlorine or bromine] or represents an iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group. ] A compound of the general formula: [wherein R/11 has the above meaning, and M represents an alkali metal atom, or when symbol 2 in the general formula (■) represents a chlorine, bromine or iodine atom, M2 can further represent a hydrogen atom. ] A method for producing a phenylpropargylamine derivative according to claim 1, which comprises reacting with a compound. α2 R is a straight-chain or branched alkanoyloxymethyl group having 3 to 10 carbon atoms, an optionally substituted benzoyloxymethyl group, a straight-chain or branched lead having 2 to 9 carbon atoms, When producing a phenylpropargylamine derivative having an alkylsulfonyloxymethyl group or an appropriately substituted phenylsulfonyloxymethyl group, a compound of the general formula (3) in which R represents a hydroxymethyl group is converted to a suitable halokenated alkanoyl, benzoyl, or alkyl group. A method for producing a phenylpropargylamine derivative according to claim 1, which comprises reacting with sulfonyl or phenylsulfonyl. (IS A method for producing a propargylamine derivative. a4 R may be the same or different, and each is 1 to 4.
In preparing phenylpropargylamine derivatives representing an aminomethyl group optionally substituted by 1 or 28 straight-chain or branched alkyl groups having 1 or 28 carbon atoms, R has 2 to 9 carbon atoms. Claims characterized in that they involve reacting a compound of general formula I having a linear or branched alkylsulfonyloxymethyl group or an optionally substituted phenylsulfonyloxymethyl group with ammonia or an amine. 2. A method for producing a phenylpropargylamine derivative according to item 1. (Lω A claim characterized in that the production of a phenylpropalkylamine derivative in which R represents a hydroxyiminomethyl group involves reacting a compound of general formula I in which R represents a formyl group with a salt of hydroxylamine. A method for producing a phenylpropargylamine derivative according to claim 1. al19 Claims 9 to 15 include a step of converting the obtained phenylpropargylamine derivative into an acid addition salt thereof by a method known per se. The method according to any one of claims 9 to 16, which is substantially described in any of Examples 1 to 8 herein. The phenylpropargylamine derivative or acid addition salt thereof according to claim 1, produced by the method according to any one of claims 9 to 17. α9 Claim 1 A method for killing an undesirable warm-blooded harmful animal, the method comprising orally administering to the animal an effective lethal dose of a phenylpropargylamine derivative or an acid addition salt thereof. 19
The method described in section. 21. The method according to claim 20, wherein the animal is a rat or a mouse. Q4: The method according to claim 20 or 21, in which the Gera bacteria animal is resistant to an anticoagulant fungicidal animal agent (c) A patent claim substantially described in the present specification The method according to item 19. The phenylpropargylamine derivative or acid addition salt thereof according to claim 1 is blended with a carrier or support suitable for ingestion by harmful animals.
A composition for orally ingesting and killing undesirable bloodletting pests. (c) Claim 1 of 0.001 to 10% by weight
25. The liquid or solid composition according to claim 24, comprising the phenylpropargylamine derivative described in claim 24 or an acid addition salt thereof. CIo, 0fi to 0.2% by weight Claim 11
25. The liquid or solid composition according to claim 24, comprising the phenylpropargylamine derivative or acid addition salt thereof according to claim 1-. @1 to 90% by weight of the phenylpropargylamine derivative t according to claim 1 or its acid addition salt, suitable for blending into a carrier or support that can be orally ingested by warm-blooded harmful animals. Liquid or solid concentrate 0 (2) 1 to 5% by weight of the phenylpropargylamine derivative or acid addition salt thereof according to claim 1 in a carrier or support that can be orally ingested by warm-blooded harmful animals. A liquid or solid concentrate suitable for compounding. 12. A composition according to any of claims 24 to 28, further comprising one or more fungicidal anticoagulant compounds of the coumarin or indandione type. (to) The composition according to claim 24, which is substantially as described in any of Examples 9 to 15 herein.