JPS596851B2 - piperidine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel therapeutically useful piperidine derivatives and methods for their preparation.

The novel piperidine derivatives of the present invention are compounds represented by the general formula, their pharmaceutically acceptable acid addition salts, and quaternary ammonium derivatives.

In the formula, R represents a lower alkoxy group (preferably a methoxy group or an ethoxy group) or an allyloxy group, and R1' is a hydrogen atom, an amino group, a lower alkylamino group (
(preferably a methylamino group), a di(lower)alkylamino group (preferably a dimethylamino group), or a lower acylamino group (preferably a lower alkanoylamino group, such as an acetamido group or a trifluoroacetamido group)
, R2'' represents a halogen atom (preferably a chlorine atom or a bromine atom), or an amino group, a sulfonamide group, or a lower alkylsulfonyl group (preferably a methylsulfonyl group), and R3'' represents a hydrogen atom or a lower alkyl group ( (preferably a methyl group), and R4' represents a cyclohexenyl or cyclohex-1,4-dienyl group which may be substituted with a methyl group. "Lower" as applied and limited herein to alkoxy, alkyl, acyl and alkanoyl groups means those groups containing up to 6 carbon atoms.

Of particular importance are the compounds of the general formula 1 in which R4' represents a cyclohex-1,4-dienyl group optionally substituted by a methyl group, in particular N-[1-cyclohex-
1ζ4'-dienylmethylpiperid-4-yl]-2-
Methoxy-4-amino-5-chlorobenzamide, N-
[1-Cyclohexa-1',4'-dienylmethylbiperid-4-yl]-2-methoxy-4-methylamino-
5-chlorobenzamide, N-[1-cyclohexa-1
'・4/-dienylmethylpiperido-4-yl]-2-methoxy-4-acetamido-5-chlorobenzamide and N-[1-(4-methylcyclohex-l・4-dienyl)methylpiperido-4 -yl]-2-methoxy-
4-amino-5-chlorobenzamide and pharmaceutically acceptable acid addition salts thereof.

According to one aspect of the invention, the piperidine derivative of general formula 1 has the general formula:

prepared by a process comprising reacting a reactive derivative of benzoic acid of the general formula [with the corresponding piperidine derivative of the general formula, in which the various symbols are as previously shown be done. The reactive derivatives of benzoic acid mentioned above may be halides (preferably chlorides), alkyl esters (preferably methyl esters), acid anhydrides or mixed acid anhydrides, N-imidazolamides or acid azides. The reaction is preferably carried out in the presence of an inert organic solvent such as benzene, toluene, chloroform, tetrahydrofuran or dioxane at a temperature of -5 to 120°C.

Benzoic acid halides of the general formula can be prepared by reacting the acid with thionyl chloride or phosphorus halide in the presence of an inert organic solvent such as benzene, toluene or a halogenated hydrocarbon.

The mixed acid anhydride of benzoic acid of the general formula It can be produced by reacting with an alkyl chloroformate. The esters and anhydrides of benzoic acid of the formula which may be used as starting materials in the process can be prepared from benzoic acid by methods known per se, as well as the N-imidazole amides or acid azides of these acids. It can also be manufactured. According to another aspect of the present invention, piperidine derivatives of general formula 1 are prepared by directly reacting benzoic acid of general formula with piperidine derivatives of general formula in the presence of a suitable dehydrating agent. be done.

Such agents include silicon tetrachloride, mono-, di-, trialkylsilyl chloride, titanium tetrachloride, N-N'-dicyclohexylcarbodiimide, thionyl chloride, sulfur trioxide in dimethyl sulfoxide, toluene-p-sulfonyl chloride, Acetone dimethyl acetal or a polymer dehydrating agent. The reaction is carried out in an inert organic solvent such as methylene chloride, acetone pyridine, ethyl acetate or dioxane.
It is carried out at a temperature of 0 to 110°C. In the production of a compound of general formula 1 in which the symbols R1'' and/or R2' represent an amino group, the amino group of the acid of the general formula or a derivative thereof is removed before the compound is reacted with the piperidine derivative of the general formula. protection is sometimes recommended.
In this case, N- of the amino-substituted benzoic acid represented by the general formula
An acyl derivative is first prepared, and the acyl protecting group is preferably an acetyl, chloroacetyl, trifluoroacetyl or phthalimido group. After the reaction between the N-acetylated compound of the general formula or its reactive derivative and the piperidine derivative of the general formula, the compound of the general formula 1
The corresponding N-acyl derivative of the compound represented by is obtained and the compound is then subjected to acid or alkaline hydrolysis to give the general formula 1 in which R1'' and/or R2'' represent an amino group.
yields the corresponding compound. Acidic hydrolysis of N-acylated compounds may be carried out by heating with dilute hydrochloric acid, preferably at the boiling point of the reaction mixture, whereas alkaline hydrolysis is preferably carried out using sodium hydroxide or potassium hydroxide in an aqueous alcoholic solution. The test is carried out at room temperature.
The piperidine derivatives of general formula 1 have as one of their main pharmacological properties the ability to antagonize the effects of endogenous or exogenous dopamine or dopaminergic agents.

They have shown activity that may be considered effective in the treatment of gastrointestinal and brain dysfunction in mammals, including humans. They have also been shown to be able to exhibit anorexic properties.
Their characteristic properties are dopaminergic agents, antagonism of the action of apomorphine, local anesthetic activity in animals and the ability to induce catatonia in rats and mice.
They may therefore be useful in the treatment of nausea and vomiting of various causes and also as neuroleptics or tranquilizers. These include gastrointestinal disorders, congestive heart failure, nausea and vomiting resulting from post-operative conditions, indigestion, flatulence, bile reflux, hiatal hernia, peptic ulcers, reflux, gastritis, enteritis and ChOlethiasis. for the treatment of various conditions affecting the central nervous system, such as other gastrointestinal disorders, as well as acute and chronic mental illness, chronic illness, schizophrenia, severe behavioral disorders and non-depressive depressive states, and hemicephaly. It would be useful. They may also be useful in the treatment of obesity and similar conditions where administration of appetite suppressants is warranted. For therapeutic purposes, piperidine derivatives of general formula 1 may be used as sulfates, hydrohalides, phosphates, lower alkanesulfonates, arylsulfonates, one or more double bonds, aryl nuclei or hydroxy 1 to 20 which may contain other functional groups such as amino groups, amino groups or keto groups.
salts of aliphatic monobasic acids, dibasic acids or royal basic acids of carbon atoms, aromatic nuclei optionally containing hydroxy groups, lower alkoxy groups, amino groups, mono- or di-(lower) alkylamino groups and sulfonamides. They may also be used in the form of addition salts of non-toxic pharmaceutically acceptable inorganic or organic acids, such as salts of aromatic acids which may be substituted with groups such as .

They may also be used in the form of pharmaceutically acceptable quaternary ammonium salts, such as the salts formed by the reaction of piperidine derivatives of general formula 1 with lower alkyl halides or sulfuric esters. Pharmaceutically acceptable acid addition salts of piperidine derivatives represented by general formula 1 and
Ammonium derivatives may be produced by methods known per se.

Contains as an active ingredient at least one piperidine derivative of the general formula 1 of the present invention, or a non-toxic pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof, together with a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition can be formed that Preferably, the compositions are formulated in a form suitable for oral, topical, transdermal or parenteral administration. The pharmaceutically acceptable carriers or diluents with which the active compounds, or compounds, are combined to form the above-mentioned compositions are well known per se, and the actual adjuvants used, inter alia, to administer those compositions. Depends on the method.

The above compositions are preferably adapted for oral administration. The compositions for oral administration in this case may take the form of tablets, capsules, pills or effervescent granules or liquid preparations such as combinations, elixirs, syrups or suspensions, all of which contain the compounds of the invention. such formulations may be prepared by methods well known to those skilled in the art. Diluents that may be used in preparing these compositions include liquid or solid diluents that are compatible with the active ingredient, along with colorants or flavoring agents, if desired.

Tablets or capsules may conveniently contain from 0.1 to 20 w of active ingredient or equivalents thereof of acid addition salts or quaternary ammonium derivatives. Liquid compositions adapted for oral use may be in the form of solutions or suspensions. The Σ solution may be an aqueous solution of a soluble salt or other derivative of the active compound, for example in association with sucrose to form a syrup.

Suspensions may contain the water-insoluble active compounds of the invention or their acid addition salts or quaternary ammonium derivatives in association with water together with suspending agents and flavoring agents. Parenteral injection compositions may be prepared from water-soluble salts, which may or may not be lyophilized.

It may also be dissolved in water or a suitable parenteral injection fluid. The compounds of the invention may be mixed with other active antacids and anti-ulcer agents (other than anticholinergic agents) for oral or, where appropriate, parenteral use.

The following Reference Example 1 and Examples 1 and 2 illustrate the production of the piperidine compound of the present invention. Reference example 1 Lithium (57,
A solution of 0.7 mol) in anhydrous diethyl ether (100 mol)
1-benzyl-4-aminopiperidine (507
, 0.264 mol) in portions.

After stirring for half an hour, absolute ethanol (180 ml) was added in portions, the solvent was removed in vacuo and the residue was dissolved in water.
The aqueous solution was extracted with diethyl ether, and the organic layer was dried and distilled in vacuo to yield 1-cyclohexa-1',4'-diethylmethyl-4-aminopiperidine (48y), boiling point 1.
17-118°C/0.5 mmHg1 was obtained. In the same manner, 1-(4-methylcyclohex-1,4-dienyl)methyl-4-aminopiperidine, boiling point 104-106℃/
0.07mmHg11-(1-cyclohexane-4'
-dienynoleyethyl)-4-aminopiperidine, bp 103-105°C/0.08m71LHg1 and 1-cyclohexen-3'-ylmethyl-4-aminopiperidine, bp 101-103°C/0.05m1LHg were also prepared. .

Example 1 Triethylamine (7.0 ml, .0.05 mol) and ethyl chloroformate (4.8T 11.0.05 mol) were sequentially mixed with 2-methoxy-4-amino-5-chlorobenzoic acid 10 in anhydrous tetrahydrofuran (300 ml). .17, 0
．． 05 mol) into a stirred suspension, while the temperature was kept between -5 and -5 mol.
It was kept at -10°C.

After stirring at this temperature for 0.5 h, 1-cyclohexa-1ζ4'-dienylmethyl-4-aminopiperidine (9.67,0.
05 mol) was added and the temperature was kept at -5 to -10°C for 1 hour, then the reaction mixture was left at room temperature overnight. The solvent was removed in vacuo, the residue was poured into water, extracted with chloroform and the organic layer was washed with water. The chloroform solution was dried (Na2SO4) and the solvent removed in vacuo to give a solid which was triturated with a mixture of methanol and diethyl ether. N-(1-cyclohexa-1',4'-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-
5-chlorobenzamide (12.2y) was obtained. The hydrochloride monohydrate was prepared by adding a saturated ethanolic solution of hydrogen chloride to a solution of the base in ethanol.

Recrystallization of the precipitate from ethanol yields a white solid, melting point 22.
6-227°C (decomposition) was obtained. In a similar manner, N-(1-cyclohexa-1ζl-dienylmethylpiperid-14-yl)-2-methoxy-5-methylsulfonylbenzamide hydrochloride, melting point 209-211°C (decomposition)
, N-(1-cyclohexa-1ζ4'-dienylmethylpiperid-4-yl)-2-methoxy-5-chlorobenzamide hydrochloride, melting point 231-233°C, N-(1-cyclohex-di-4' -dienylmethylpiperide-4-
yl)-2-methoxy-4-amino-5-bromobenzamide hydrochloride, melting point 215°C (decomposition), N-(1-cyclohexa-1',4'-dienylmethylpiperido-4-
yl)-2-methoxy-5-sulfonamide benzamide hydrochloride, melting point 230-231°C (decomposition), N-(1-
Cyclohexa-1ζ4'-dienylmethylpiperide-4
-yl)-2-methoxy-4-acetamido-5-chlorobenzamide hydrochloride monohydrate, melting point 193-195°C
, N-[1-(4-methylcyclohex-1,4-dienyl)methyl-piperid-14-yl]-2-methoxy-
4-Amino-5-chlorobenzamide hydrochloride, melting point 24
6-248°C (decomposition), N-[1-(1-cyclohex-1',4'-dienylethyl)piperid-4-yl]
-2-Methoxy-4-amino-5-chlorobenzamide hydrochloride, melting point 241-242°C (decomposed), N-[1-(
1-Cyclohexa-di-l-dienylethyl)biperid-4-yl]-2-ethoxy-4-acetamido-5-
Chlorobenzamide, its fumarate salt is 171-173
N-[1-(1-cyclohexa-1'.
4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide hydrochloride,
Melting point: 264-266°C, N-(1-cyclohexa-1'
・4'-dienylmethylpiperid-14-yl)-2-methoxy-4,5-diaminobenzamide dihydrochloride monohydrate, melting point 240-242°C, N-(1-cyclohexa-
D-4'-dienynolemethylpiperid-14-yl)-2
-methoxy-4-dimethylamino-5-chlorobenzamide, its fumarate salt melting at 182-184°C;
N-(1-Cyclohexa-1ζ4'-dienylmethylpiperid-14-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, its fumarate salt is 203-
N-(1-cyclohexate-4), which melts at 205°C.
'-dienylmethylpiperid-14-yl)-2-allyloxy-4-amino-5-chlorobenzamide hydrochloride,
Melting point: 180-182°C, N-(1-cyclohexa-1'
・4'-dienylmethylpiperid-14-yl)-2-ethoxy-4-amino-5-chlorobenzamide hydrochloride,
Melting point 247-249℃, N-(1-cyclohexane
4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-acetamido-5-chlorobenzamide, its fumarate salt melts at 173-175°C, and N-
(1-cyclohexen-3'-ylmethylpiperide-4
-yl)-2-methoxy-4-amino-5-chlorobenzamide, melting point 189-191°C, was also prepared.

Fumarate salts of piperidine derivatives as described above are prepared by adding fumaric acid to a hot ethanolic solution of piperidine base, the amount of added acid being substantially equimolar to the amount of piperidine base present, stirring the hot mixture until dissolved; The resulting solution was then cooled to crystallize the fumarate salt.

Example 2 N-(1-cyclohexene- in acetone (75ml)
3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide (3,57,0
．． A solution of methyl iodide (2.631, 0.0185 mol) in acetone (25 ml) was slowly added to a warm solution of 0.0093 mol).

The mixture was stirred at room temperature for 12 hours and then heated under reflux for a further 4 hours. The mixture was then concentrated in vacuo to a small volume and the residue was filtered through P-N-(1-cyclohexene-3
″-ylmethylpiperid-14-yl)-2-methoxy-
4-Amino-5-chlorobenzamide methyl iodide (
4y), melting point 231-233°C (decomposition), was obtained after recrystallization from a mixture of ethanol and water.The following Reference Examples 2-6 contain pharmaceutical compositions using the compounds of the present invention and their manufacturing procedures is exemplified.

Reference example 2N-(1-cyclohexa-1',4'-dienylmethylpiperid-14-yl)-2-methoxy-4-
100,000 tablets each containing amino-5-chlorobenzamide hydrochloride monohydrate 2η were prepared from the following formulation.

N-(1-cyclohexa-1'・4'- dienylmethylpiperid-4-yl) -2-methoxy-4-amino-5- chlorobenz Amide hydrochloride monohydrate 200r procedure All powder is 0.6m7! It was passed through an L sieve.

They were then all mixed for 20 minutes in a suitable mixer and compressed into 125 watt tablets using a 6 mm disc and flat beveled punch. The integration time of the tablet was approximately 60 seconds. Reference example 3N-(1
-Cyclohexa-1ζ4/-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate 1 mf7 each containing 100,000 capsules of the following formulation: Manufactured from.

N-(1-Cyclohexa-1ζ4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenz Procedure Pass the above ingredients through a 40 mesh sieve and then mix in a suitable mixer. and dispensed into 100,000 gelatin capsules (180η).

Reference example 4 N-(1-cyclohexa-1ζ4'-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-5-
10,000 suppositories, each containing 5 mf of chlorobenzamide hydrochloride monohydrate, were prepared as follows.

N-(1-Cyclohexa-1ζ4'-dienylmethylpiperid-14-yl) 12-methoxy-4-amino-5-chlorobenz procedure Melt theoproma oil and prepare N-(1-cyclohexa-1'
- 4'-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride monohydrate was suspended therein.

The mixture was then poured into a suitable suppository mold to produce 2.0 tons of suppositories. Reference example 5 N-(1-cyclohexa-1ζ4'-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-5-
50,000 ampoules each containing 2 volumes of chlorobenzamide hydrochloride monohydrate were prepared from the following formulation.

N-(1-cyclohexa-V-4'-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-5-chlorobenz Procedure N-(1-cyclohex-1ζ4'-dienylmethyl piperid-4-yl)-2-methoxy-4-amino-5-
Chlorobenzamide hydrochloride monohydrate and sodium chloride in water approximately 801? , and dissolved by heating gently.

The solution was diluted to 1001 with water and passed through a bacteria retention filter and filled into 2 ml glass ampoules in a known manner. The preparation of solutions for injection can be carried out under sterile conditions. It is also possible to work under normal conditions and then heat sterilize the filled ampoule. Reference example 6 N-(1-cyclohexa-1ζ4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
One thousand 150 ml bottles each containing 75 ml of chlorobenzamide hydrochloride monohydrate were prepared as follows.

N-(1-Cyclohex-di-4/-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenz Procedure N-(1-cyclohex-1'-4'-dienyl) Methylpiperid-4-yl)-2-methoxy-4-amino-5
-Chlorobenzamide hydrochloride monohydrate and zorpic acid were dissolved in 100 parts of water, then sorbitol, citric acid and seasonings were added and stirred until dissolved.

The mixture was diluted to 1501 and dispensed into bottles. A piperidine derivative represented by the general formula 1 other than N-(1-cyclohexa-1',4'-dienylmethylpiperid-14-yl)-2-methoxy-4-amino-5-chlorobenzamide as an active ingredient, For example, compositions similar to those described in Reference Examples 2 to 6 can be prepared with other products corresponding to the formula described in Example 1.

The piperidine derivatives of the general formula are novel derivatives and as such constitute another aspect of the invention.

Claims (1)

[Claims] 1 Piperidine derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) and their pharmaceutically acceptable acid addition salts (in the formula, R' is a lower alkoxy group or an allyloxy group) , R^1' represents a hydrogen atom, or an amino group, a lower alkylamino group, a di(lower) alkylamino group, or a lower acylamino group, and R^2' represents a halogen atom, or an amino group, a sulfonamide group, or (represents a lower alkylsulfonyl group, R^3' represents a hydrogen atom or a lower alkyl group, and R^4' represents a cyclohexenyl or cyclohex-1,4-dienyl group which may be substituted with a methyl group). 2 When R' is a lower alkoxy group, it represents a methoxy group or an ethoxy group, when R^1 is (i) a lower alkylamino group, it represents a methylamino group, and (ii) when it is a di(lower) alkylamino group, it represents a dimethylamino group. or (i
ii) When it is a lower acylamino group, it represents a lower alkanoylamino group, when R^2' is (i) a halogen atom, it represents a chlorine atom or a bromine atom, or (ii) when it is a lower alkylsulfonyl group, it represents a methylsulfonyl group, R^
When 3' is a lower alkyl group, it represents a methyl group, and R^4
Piperidine derivatives and pharmaceutically acceptable acid addition salts thereof according to claim 1, wherein ' represents a cyclohexenyl or cyclohex-1,4-dienyl group optionally substituted with a methyl group. 3. The piperidine derivative according to claim 1 or 2, wherein R^1' represents an acetamido group. 4. The piperidine derivative according to claim 1, 2 or 3, wherein R^4' represents a cyclohex-1,4-dienyl group optionally substituted with a methyl group. Claim 1, which is 5 N-[1-cyclohexa-1',4'-dienylmethylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide.
Piperidine derivatives described in Section 1. 6 The piperidine according to claim 1, which is N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide. derivative. 7 N-[1-(4-methylcyclohex-1,4-dienyl)methylpiperid-4-yl]-2-methoxy-
The piperidine derivative according to claim 1, which is 4-amino-5-chlorobenzamide. 8. The piperidine derivative according to claim 1, which is N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-methylsulfonylbenzamide. 9. The piperidine derivative according to claim 1, which is N-(1-cyclohexa-1'.4'-dienylmethylpiperid-4-yl)-2-methoxy-5-chlorobenzamide. 10 The piperidine according to claim 1, which is N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide. derivative. 11 The piperidine derivative according to claim 1, which is N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-sulfonamidobenzamide. 12 N-[1-(1-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-methoxy-
The piperidine derivative according to claim 1, which is 4-amino-5-chlorobenzamide. 13 N-[1-(1-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-
The piperidine derivative according to claim 1, which is 4-acetamido-5-chlorobenzamide. 14 N-[1-(1-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-
The piperidine derivative according to claim 1, which is 4-amino-5-chlorobenzamide. 15 The piperidine derivative according to claim 1, which is N-(1-cyclohexa-1', 4'-dienylmethylpiperid-4-yl-2-methoxy-4, 5-diaminobenzamide. 16 The piperidine according to claim 1, which is N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide. Derivative. Claim 1, which is 17 N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide. Piperidine derivatives as described.
The piperidine derivative according to claim 1, which is amino-5-chlorobenzamide. 19 N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, or the compound described in claim 1 Piperidine derivatives. 20 The piperidine according to claim 1, which is N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-acetamido-5-chlorobenzamide. derivative. 21 N-(1-cyclohexen-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
The piperidine derivative according to claim 1, which is chlorobenzamide. 22. A pharmaceutically acceptable acid addition salt of the compound according to any one of claims 5 to 21. 23. A pharmaceutically acceptable quaternary ammonium derivative of the compound according to any one of claims 5 to 21. 24 General formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼The reactive derivative of benzoic acid represented by (II) and the general formula, ▲There are mathematical formulas, chemical formulas, tables, etc.▼The piperidine derivative represented by (III) A method for producing piperidine derivatives represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I), which involves reacting. (In the formula, R' represents a lower alkoxy group or an allyloxy group, R^1' represents a hydrogen atom, an amino group, a lower alkylamino group, a di(lower) alkylamino group, or a lower acylamino group, and R^2' represents a halogen atom, or an amino group, a sulfonamide group, or a lower alkylsulfonyl group, R^3' represents a hydrogen atom or a lower alkyl group, and R^4' represents cyclohexenyl or cyclohexa- which may be substituted with a methyl group. 1,4-dienyl group) 25 Reactive derivatives of benzoic acid are halides, alkyl esters, acid anhydrides, mixed acid anhydrides, N
- The method according to claim 24, which is an imidazole amide or an acid amide. 26. The method according to claim 24 or 25, wherein the reaction is carried out in an inert organic solvent at a temperature of -5 to 120°C.