KR810000424B1 - Preparation for isoindole derivatives - Google Patents

Abstract

Title compds.(I; A = C2-10 alkylene; R1,R2,R3 and R4 are independently H, halogen, alkyl, alkoxy, trifluoromethyl; Z = -OR, -N-R7R8; R5 and R6 are independently H, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl; R7 and R8 are independently H, alkyl, cycloalkyl, alkoxyalkyl, aralkyl; X = eliminated atom or group), useful as appetite suppressing agent, were prepd. by reaction of IV and V. Thus, 8.7 g 2-(4-bromobutyl)-5-chloro-3-phenylisoindol-1-carboxylic acid ethyl ester was treated with 3.0 g sodium iodide and 1.6 g diethylamine in 40 ml acetone, and stirred at room temp for 20 hr to give I.

Description

Method for preparing isoindole derivatives

The present invention relates to a process for the preparation of isoindole derivatives of the following formula (I) useful as appetite suppressant.

In the above structural formula, A is C ₂ ~ C ₁₀ Z is -OR or

R is a alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, allyl or aralkyl group

R ₁ , R ₂ , R ₃ and R ₄ are each hydrogen or halogen or halogen or alkyl, alkoxy or trifluoromethyl

R ₅ and R ₆ are each hydrogen or alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aryl or aralkyl, or R ₅ and R ₆ together form a-(CH ₂ ) n-group ( Wherein n represents an integer from 2 to 7) or R ₅ and R ₆ together with the nitrogen atom to which they are attached comprise a 5 or 6 membered compound containing another nitrogen atom which may be substituted with an oxygen atom or an alkyl or hydroxy alkyl group Form a summon and R ₇ and R ₈ are each a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl or aralkyl group with at least one of R ₇ and R ₈ not being a hydrogen atom.

In this specification, "alkyl" or "alkoxy" is a straight chain and branched chain saturated hydrocarbon containing 6 carbon atoms, such as methyl, ethylpropyl, isopropyl, butyl group, etc., and "alkylene" is a straight chain and branched chain alkylene group, ie ethylene, methyl Ethylene, trimethylene, tetramethylene group and the like and “cycloalkyl” represents a C ₃ to C ₆ cycloalkyl group, ie cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group. 5- or 6-membered heterocycles are derived from saturated heterocycles containing two nitrogen atoms or one nitrogen atom and one oxygen atom, ie morpholino, N-methyl-piperazino, piperazino group and the like. "Halogen" represents fluorine, chlorine, bromine and iodine. “Aryl” refers to a mononuclear or polynuclear aromatic group in which one or more hydrogen atoms can be replaced with alkyl, alkoxy or halogen, such as phenyl, halophenyl, methoxyphenyl. The "leaving atom" or "leaving group" refers to a halogen atom, an arylsulfonyloxy group, i.e., a tosyloxy group and an alkyl sulfonyloxy group, i.e., a mesyloxy group.

In the present invention, it is particularly preferable that R ₁ , R ₂ , R ₃ , and R ₄ in the compound are hydrogen or a halogen atom or a trifluoromethyl group, respectively. In particular, R ₄ is a hydrogen atom and R ₁ is a chlorine or fluorine atom or a trifluoromethyl group. It is also preferable that R ₂ and R ₃ are hydrogen, chlorine or fluorine atoms, and R ₅ and R ₆ in the compound of formula (I) are each an alkyl group, in particular an ethyl or isopropyl group. In addition, A is ethylene 2-'3- (cyclohexylamino) propyl'-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester, 5-chloro-2- [3- (N-methylanilino) propyl ] -3-phenylisoindole-1-carboxylic acid ethyl ester.

According to the present invention, the isoindole derivatives of the above-mentioned structural formula (I) and pharmaceutically useful acid addition salts thereof are prepared by the following method.

It is prepared by reacting a compound of formula (IV) with an amine of formula (V) and converting the compound of formula (I) obtained if necessary to its pharmaceutically useful acid addition salts.

A, Z, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ in the structural formulas are as described above.

The reaction of the compound of formula (IV) with the amine of formula (V) according to the process of the invention is carried out in the presence of an excess of formula (V) amine, according to known methods. The reaction is carried out in an inert organic solvent such as aromatic hydrocarbons (eg benzene or toluene), chlorinated hydrocarbons (eg methylene chloride), ethers (eg diethyl ether) and the like in the presence of an acid binder. Suitable bases for this are, for example, potassium carbonate, sodium carbonate and the like. The temperature and pressure are not limited but are particularly good between 0 ° C. and the reflux temperature of the reaction mixture. The reaction is carried out under pressure (eg 1 to 100 atm) when using gaseous amines of formula (V) and under atmospheric pressure when using liquid amines. When reacting under normal pressure, it is preferable to carry out under reflux conditions.

Structural formula (I) compounds can be converted to basic and pharmacologically useful acid addition salts. Such salts include, for example, those formed with organic acids such as oxalic acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, ascorbic acid, salicylic acid and tartaric acid, and those formed with inorganic acids such as hydrochloric acid, bromic acid, sulfonic acid and phosphoric acid. have.

Compounds of formula IV can be prepared by methods analogous to those described in US Pat. No. 3,993,374.

Isoindole derivatives (i.e., compounds of formula (I) and their pharmaceutically useful acid addition salts) prepared according to the invention are used as medicaments. They show, for example, significant appetite lowering and are suitable as appetite suppressants. They have no central nervous stimulation effect relative to other appetite suppressants. Appetite lowering was measured by oral administration of the compound to a group of six rats fed with livium feed in a 48-hour test at a dose of 300 μmol / kg with 5% ammonia rubber. 24 and 48 hours after the first dose, the feed container was weighed to compare the consumption of untreated control animals (100%) with that of treated animals. ED ₆₅ refers to the dose in mg / kg of the derivative which reduced feed consumption to 65% of the control consumption of the control group. Thus, for example, ED ₆₅ of 5-chloro-2- [2- (diethylamino) ethyl] -3-phenylisoin-1-carboxylic acid ethyl ester (derivative A) is 42 mg / kg and 5-chloro-2 ED ₁₅ of-[3- (diethylamino) propyl] -3-phenylisoindole-1-carboxylic acid ethyl ester (derivative c) is 27 mg / kg. Toxicity (LD ₅₀ ) is 1250 mg / kg for derivatives and 2500 mg / kg for derivative C when measured on mice according to standard methods.

Isoindole derivatives prepared according to the present invention can be mixed with pharmaceutically useful carrier materials to form a medicament. Organic or inorganic inert carrier materials suitable for oral or parenteral administration such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol, petroleum jelly and the like can be used. . The drug may be in solid form (ie tablets, dragees, suppositories or capsules) or in liquid form (ie solutions, suspensions or emulsions). This preparation can be sterilized or contain preservatives, stabilizers, wetting agents, emulsifiers, salts and the like.

The dosage of the compound of formula (I) is preferably about 1 to 300 g. Oral dosage is about 0.1 to 0.5mg / kg per day. However, the range can be increased or decreased depending on the needs of the individual and the doctor's prescription.

The present invention is explained in more detail by the following examples.

Example 1

A solution of 8.7 g (0.02 mol) of 2- (4-bromobutyl) -5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester with 40 ml of acetone was charged with 3.0 g of sodium iodide and 1.6 g (0.022). Mole), and stirred for 20 hours under shading at room temperature. After concentration under reduced pressure, the residue is reacted with 40 ml of 1-N sodium hydroxide solution at 0-2 [deg.] C. and extracted with ether. The ethereal extract is immediately shaken with 4. ml of 0.5-N hydrochloric acid and the acidic aqueous layer is alkalized with 1-N sodium hydroxide at 0-2 ° C. The mixture is immediately extracted with methylene chloride and the shaded organic layer is dehydrated with sodium sulfate. The oil produced after concentration is dissolved in ether and reacted with etheric hydrochloric acid. Crystallized hydrochloride is filtered off and washed with ether. 5-chloro-2- [4- (diethylamino) butyl] -3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 137 to 140 ° C is obtained. Recrystallization with methylene chloride ether does not lower the melting point.

Starting materials are prepared as follows.

A solution of 12.0 g (0.04 mol) of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester and 240 ml of dimethylformamide was added to 0.08 mol of sodium hydroxide (55% dispersion in mineral oil 3.5) at -10 ° C under nitrogen. and react for 30 minutes in an ice bath. 26.0 g (0.12 mol) of 1,4-dibromobutane are added thereto at -10 ° C, and the mixture is stirred at room temperature for 1 hour and then heated to 60 ° C for 18 hours. After cooling, the mixture is poured into 2 liters of ice water and 100 g of sodium chloride are added to extract the separated oily product immediately with methylene chloride. The organic layer was shaded, washed with sodium chloride solution, dehydrated with sodium sulfate and evaporated to dryness under reduced pressure. The resulting oil is taken up in chloroform and chromatographed on 500 g of silica gel using chloroform / n-heptane ethanol (10: 10: 1) as eluent, taking care that the eluate is shaded. The homogeneous aliquots are combined and evaporated. 2- (4-Bromobutyl) -5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in oil is obtained and used for the next step as soon as possible.

Example 2

5 ml of a solution of 0.84 g (2 mmol) of 5-chloro-2- ｛2-[(methylsulfonyl) oxy] ethyl｝ -3-phenylisoindole-1-carboxylic acid ethyl ester and 5 ml of dimethyl sulfoxide React with ethyl amine to reflux heating for 17 hours under shading. Excess dietylamine is evaporated under reduced pressure and the resulting solution is poured into 50 ml of ice water. After addition of 3 g sodium chloride, the separated oil is extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution, dehydrated with sodium sulfate and concentrated to dryness under reduced pressure. The oily residue is dissolved in 15 ml of acetone, treated with 10 ml of 0.5-N hydrochloric acid and the mixture is shaken thoroughly. After cooling in an ice bath, the crystallized hydrochloride is isolated and purified in a similar manner as in Example 1.

5-chloro-2- [2- (diethyl amino) ethyl] -3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 248 to 285 ° C. (decomposition) is obtained.

Starting materials can be prepared as follows.

A solution of 30.0 g (0.1 mole) of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester and 300 ml of dimethyl sulfoxide with 66.8 g (0.4 mole) of bromoacetic acid ethyl ester and 27.6 g (0.2 mole) React with finely ground dry potassium carbonate and stir at room temperature for 17 hours. The mixture is poured into 750 ml of ice water, 50 g of sodium chloride is added, the product to be separated is suction filtered, washed with water and dissolved in methylene chloride. The aqueous layer is separated, the organic layer is dehydrated with sodium sulfate, filtered and concentrated to dryness. The resulting oil is triturated with ether and pentane to crystallize. A ester is obtained in 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetinate having a melting point of 100 to 101 ° C. Recrystallization with ethanol raises the melting point to 103-104 占 폚.

A suspension of 19.5 g (0.05 mol) of 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid ethyl ester and 150 ml of ethanol was reacted with 60 ml of 1,0N sodium hydroxide to reflux for 30 minutes. Boil it. The mixture is left in an ice bath for 2 hours, the crystallized sodium salt is filtered under vacuum, washed with ethanol and dissolved in a mixture of 400 ml of ethanol and 250 ml of water. The resulting solution is acidified with 160 ml of 0.5-N hydrochloric acid with stirring at 40 to 45 ° C. and left in an ice bath for 2 hours. The separated acid is filtered in vacuo, washed with water and dissolved in 750 ml of methylene chloride. The aqueous layer is separated and the organic layer is dehydrated with sodium sulfate and concentrated to about 200 ml. The crystallized colorless acid is filtered off with suction and washed with a small amount of methylene chloride. 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid having a melting point of 217 to 220 ° C. (decomposition) is obtained.

10.8 g (0.03 mol) of 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid and a solution of 100 ml of tetrahydrofuran in boron 1M solution in tetrahydrofuran under argon at 15 to 20 ° C Add dropwise to 72 ml. After 60 hours of stirring at room temperature, the clear solution was evaporated to dryness under reduced pressure by reacting with 30 ml of ethanol at 15 to 20 ℃. The solution obtained by dissolving the solid residue in methylene chloride is washed with 5% sodium bicarbonate solution and then again with water. The solid crude product obtained by dehydration of this solution with sodium sulfate and evaporation was chromatographed on 700 g of silica gel using methyl ethyl acetate (4: 1) as eluent. From the homogeneous liquid separation, 5-chloro-2- (2-hydroxyethyl) -3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 114 to 116 占 폚 is obtained. Recrystallization with ether pentane does not raise the melting point.

A solution of 3.4 g (10 mmol) of 5-chloro-2- (2-hydroxyethyl) -3-phenylisoindole-1-carboxylic acid ethyl ester, 3.4 ml (24 mmol) of triethylamine and 60 ml of methylene chloride Is reacted with 1.6 ml (20 mmol) of methanesulfochloride at 15-20 ° C. The mixture is left at room temperature for 30 minutes and diluted with methylene chloride to triple the volume. This solution is washed successively with water, 0.5N hydrochloric acid, 5% sodium bicarbonate solution and then again with water. Dehydration with sodium sulfate and evaporation of the solution yielded 5-chloro-2- ｛2-[(methylsulfonyl) oxy] ethyl｝ -3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 125 to 127 占 폚. Recrystallization from methylene hexane chloride does not raise the melting point.

Example 3

4.36 g (10 mmol) of 5-chloro-2- ｛3-[(methylsulfonyl) oxy] propyl｝ -3-phenylisoindole-1-carboxylic acid ethyl ester with 40 ml of acetone was added to 10 ml of N-methyl. React with butyl amine and boil at reflux for 5 hours. The mixture is concentrated to dryness under reduced pressure to partition the residue between 50 ml of ether. The ether layer is treated with 30 ml of 0.5N hydrochloric acid to shake the mixture completely. After cooling in an ice bath, the crystallized hydrochloride was dried by filtration in vacuo and recrystallized with methylene chloride ether to give 2- [3- (butylmethylamino) propyl] -5-chloro-3-phenyl having a melting point of 98 to 101 ° C. Isoindole-1-carboxylic acid ethyl ester hydrochloride is obtained.

Starting materials can be prepared as follows.

15.0 g (0.05 mole) of 5-chloro-3-phenylisoindole-1-carboxylic acid ethylester is reacted with 22.3 g (0.1 mole) of 3-bromopropyltetra hydropyran-2-yl ether. Boil for 3 hours with 600 ml of ethanol, 40 ml of water and 10 ml of concentrated hydrochloric acid under reflux to obtain and hydrolyze the oily tetrahydropyranyl derivative. The mixture is evaporated to dryness under reduced pressure, the residue is taken up in methylene chloride, washed with water and dehydrated with sodium sulfate. The oil produced after concentration is chromatographed on 350 g silica gel using methylene chloride ethyl acetate (4: 1) as eluent. From the homogeneous liquid separation, 5-chloro-2- (3-hydroxypropyl) -3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 94 to 96 占 폚 is obtained. Recrystallization with ether hexane does not raise the melting point. A solution of 10.8 g (30 mmol) of 5-chloro-2- (3-hydroxypropyl) -3-phenylisoindole-1-carboxylic acid ethyl ester, 10.2 ml (72 mmol) of triethylamine and 150 ml of methylene chloride React with 48 ml (60 mmol) of methanesulfochloride dissolved in 30 ml of methylene chloride at 15 to 20 ° C. The mixture is left at room temperature for 30 minutes and diluted with methylene chloride to double the volume. The solution thus obtained is subsequently washed with water, 0.5N hydrochloric acid, 5% sodium bicarbonate solution and again with water. After drying and evaporating this solution, 5-chloro-2-'3-[(methylsulfonyl) oxy] propyl'-3-phenylisoindole-1-carboxylic acid ester having a melting point of 89 to 91 占 폚 is obtained. It is no longer purified and used in the next step. Analytical samples are obtained by crystallization with ether hexane. Melting Point 91-92 ° C

In a similar manner to the above, the following isoindole derivatives are obtained.

Amin isoindole derivative

Diethanolamine 2-X3- [bis (2-hydroxyethyl amino] propyl｝ -5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride: melting point 205-207 DEG C (decomposition)

Methylpiperidine 5-chloro-2- [3- (4-methyl-1-piperidinyl) -propyl] -3-phenylisoindole-1-carboxylic acid hydrochloride: Melting point: 260 to 265 ° C. (decomposition)

Ethylamine 2- [3- (ethylamino) propyl] -5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride: melting point 182 to 184 ° C (decomposition)

Example 4

A solution of 8.4 g (0.03 mole) of toluene-4-sulfonic acid silver and 80 ml of acetonitrile at 9.5 g (0.02 mole) of 2- (5-bromo-3,3-dimethylphenyl) -5-chloro- It is reacted with 3-phenylisoindole-1-carboxylic acid ethyl ester and heated by shading under reflux for 3 hours. The mixture is concentrated to dryness under reduced pressure and the residue is boiled with 200 ml of ethylene chloride for 2-3 minutes. After cooling the silver salt is filtered off and the filtrate is evaporated to dryness. The resulting oily tosylate is immediately dissolved in 80 ml of acetone, treated with 20 ml of N-butylmethylamine and shaded for 17 hours under reflux and heated. The solution is filtered and concentrated to dryness immediately. The residue is partitioned between 150 ml of ether and 100 ml of water and the separated ether solution is treated with 60 ml of 0.5-N hydrochloric acid to shake the mixture completely. After cooling in an ice bath, the crystallized hydrochloride is filtered off with suction, washed with water and ether and dissolved in 80 ml of bethylene chloride. The aqueous layer is separated and the organic layer is dehydrated with sodium sulphate, filtered and diluted with ether to give an optimal fourfold. 5- (2-butylethylamino-3,3-dimethylpentyl) -5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 197 to 199 ° C (decomposition) is precipitated. Recrystallization with methylene chloride ether gives colorless crystals having a melting point of 198 to 200 ° C. (decomposition).

Starting materials can be prepared as follows.

A solution of 24 g (0.08 mole) of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester and 480 ml of dimethylformamide was dissolved in argon at 0.16 moles of sodium hydride (mineral oil 55% dispersion 7.0 g) at -10 ° C. Reaction with and stirred for 15 minutes in an ice bath. 62 g (0.24 mole) of 1,5-dibromo-3,3-dimethylpentanol-5 ° C. is added and the mixture is stirred at room temperature for 1 hour and then heated at 60 ° C. for 18 hours. After cooling, the mixture is poured into 4 liters of ice water and 200 g of sodium chloride are added to extract the isolated product immediately with methylene chloride. The shaded organic layer was washed with saturated sodium chloride solution, dehydrated with sodium sulfate and concentrated to dryness under reduced pressure. The resulting oily residue is chromatographed on 1000 g of silica gel using methylene chloride as eluent, taking care to ensure that the eluate is shaded. The homogeneous aliquots are combined and the solid residue is recrystallized from ethanol. 2- (5-bromo-3,3-dimethylpentyl) -5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 87 to 88 占 폚 is obtained.

Example 5

4.36 g (10 mmol) of a solution of 4 ml of acetone of 5-chloro-2- ｛3-[(methylsulfonyl) oxy] -propyl 에스테르 -3-phenylisoindole-1-carboxylic acid ethyl ester was added with 10 ml of bis- Treated with (2-methoxyethyl) amine and boiled under reflux for 17 hours. The mixture is concentrated to dryness under reduced pressure and the residue is taken up in ether. After acidification with etheric hydrochloric acid the crystallized hydrochloride is dried under filtration and recrystallized from methylene chloride ether. 5-Chloro-2-'3- [bis (methoxyethyl) amino] -propyl'-3-pentylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 120 to 122 占 폚 is obtained.

4.36 g (10 mmol) of 5-chloro-2- ｛3-[(methylsulfonyl) oxy] -propyl｝ -3-phenylisoindole-1-carboxylic acid ethyl ester and 10 ml of cyclohexylamine in the same manner as described above Impure hydrochloride from and recrystallized with ethanol, 2- [3- (cyclohexylamino) -propyl] -5-chloro-3-phenylisoindole-1-carboxylic acid having a melting point of 212 to 214 캜 (decomposition) Ester hydrochloride is obtained.

Example 6

4.36 g (10 mmol) of 5-chloro-2- ｛3-[(methylsulfonyl) oxy] -propyl｝ -3-phenylisoindole-1-carboxylic acid ethyl ester with 25 ml of hexamethylphosphoric acid triamide The solution is treated with 25 ml of N-methylaniline and heated to 80 ° C. for 24 hours. The mixture is evaporated to dryness under reduced pressure and the residue is treated with 250 ml of ice water. The oily precipitate is taken up in methylene chloride and the extract is washed with a saturated solution of sodium chloride, dehydrated with sodium sulfate and concentrated to dryness. The resulting oil is purified by chromatography on 150 g aluminum oxide (neutral: Brockman activity). Elution with methylene chloride and evaporation of the solvent yielded 5-chloro-2- [3- (N-methylanilino) propyl] -3-phenylisoindole-1-carboxylic acid ethyl ester having a melting point of 108 to 110 ° C. Crystallization with ether / hexanes affords colorless crystals with the same melting point.

The following examples are intended to illustrate drugs containing isoindole derivatives prepared according to the present invention.

Example A

A tablet having the following composition is prepared. Per tablet

5-chloro-2- [2- (diethylamino) -ethyl] -3-phenylisoindole-1-

Carboxylic acid ethyl ester hydrochloride 5.46mg

Lactose 57.54mg

Corn Starch 54.00mg

Talc 2.70mg

Magnesium Stearate 0.30mg

120.00mg

Isoindole derivatives are mixed well with some of the lactose and corn starch. The paste is prepared from the remaining starch, granulated with the powder mixture and dried. After mixing with the remaining ingredients, it is compressed into tablets with a total weight of 120.0 mg.

Example B

A capsule having the following composition is prepared. Per capsule

5-chloro-2- [2- (diethylamino) -ethyl] -3-phenylosoindole-1-

Carboxylic acid ethyl ester hadrochloride 5.46 mg

Lactose 104.54mg

Corn Starch 20.00mg

Talc 9.00mg

Magnesium Stearate 1.00mg

Total weight 140.00mg

In a 10,000 capsule fill, the ingredients are prepared in 10,000-fold quantities. 54.6 g of isoindole derivatives are mixed uniformly with the same amount of lactose. The mixture is diluted with 109.2 g of lactose and mixed again uniformly. Continue dilution until lactose is used up. Corn starch, talc and magnesium stearate are added to distribute evenly in a suitable mixer. The processed mixture is filled into capsules of 140 mg each in a capsule filling machine.

Claims (1)

A process for preparing isoindole derivatives of formula (I) and pharmaceutically possible acid addition salts thereof, characterized by reacting a compound of formula (IV) with an amine of formula (V).

In the above structural formula A is an alkylene group having 2 to 10 carbon atoms, Z is -OR or

A group wherein R represents an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, allyl or aralkyl group, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen or a halogen atom or alkyl, alkoxy or Trifluoromethyl group and R ₅ and R ₆ each represent a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aryl or aralkyl group or R ₅ and R ₆ together-( CH ₂ ) n-group (n is an integer from 2 to 7) or R ₅ and R ₆ together with the nitrogen atom to which they are attached, an oxygen atom or other nitrogen atom which may be substituted with an alkyl or hydroxyalkyl group form a 5-or 6-membered heterocyclic ring and R ₇ and R ₈ each independently represent a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, or aralkyl group containing However, where R ₇ and R ₈ and at least one of which is not a hydrogen atom and X represents a leaving atom or a leaving group.