NO144108B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE N- (1-BENZYLPIPERID-4-YL) -BENZAMIDES - Google Patents

Description

The present invention relates to an analog method

in the preparation of therapeutically active N-(1-benzylpiperid-4-yl)-benzamides, as stated in the preamble of the claim.

The process compounds have as one of their essential pharmacological properties the ability to antagonize the action of dopamine or dopaminergic agents of endogenous or exogenous origin. They can be used in the treatment of nausea and vomiting caused by gastrointestinal disorders, congestive heart failure, post-operative conditions, other gastrointestinal

all disorders such as dyspepsia, flatulence, bile regurgitation,

hiatus hernia, peptic ulcer, reflux aerophagitis, gastritis,

duodenitis and cholethiasis, and a number of conditions that on-

central nervous system effects such as acute and chronic psychoses, manic psychosis, schizophrenia, severe disturbances and non-melancholic depressive state and migraine.

Preferred process compounds are those with it

general formula I where X is a chlorine atom, and more particularly those compounds where R^ is ethyl, or preferably methyl, and particularly those compounds where R2 is chlorine in the 4-position and R3 is hydrogen, or R~ and R^ are both hydrogen , and their pharmacist-

ically acceptable acid addition salts, especially maleates, hydrochlorides and methanesulfonates. These preferred compounds include N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, otherwise known as 4-amino-N-(1-benzylpiperid-4-yl)-5 -chloro-o-anisamide. The compound has been named "Clebopride" by the World Health Organization.

The compounds of formula I can be prepared by reacting

a 2-Alkoxy-4-amino-5-halobenzoic acid of the general formula:

where X and R^ are as indicated above, in which the amino group is optionally protected with an acyl group which is acetyl, trifluoroacetyl, chloroacetyl or phthaloyl, or an active derivative of such an acid, with a 1-benzyl-4-aminopiperidine with the gener-

or formula:

where R~ and R^ are as indicated above, and where the amino group of the benzoic acid reactant or active derivatives thereof is protected, and to remove the protecting acyl group from the product obtained by hydrolysis.

The active derivative of the benzoic acid reactant may be an ester, acid halide (preferably chloride), a mixed anhydride, N-imidazolide or azide, or the derivative formed from N-ethyl-5-phenylisoxazolinium-3-sulfonate (Woodward's reagent).

The reaction is generally carried out in an inert organic solvent such as a halogenated, preferably chlorinated, hydrocarbon, an aromatic hydrocarbon, a C^-C^ alkyl ester of a C^-Cg alkanoic acid, a ketone or ether with C^-Cg alkyl groups , or a cyclic ether, e.g. tetrahydrofuran or dioxane, at a temperature from -20° to 150°C, depending on the reactants used. When a 2-alkoxy-4-acylamino-5-halobenzoic acid is used, the desired compounds of the general formula I are released from the intermediates obtained by acid hydrolysis of the acyl protecting group in an aqueous or aqueous-alcoholic medium at a temperature between room temperature and 100°C. For example, 2-methoxy-4-acetamido-5-chlorobenzoyl chloride can be reacted with 1-benzyl-4-aminopiperidine in an inert organic solvent as mentioned above, in the presence of an organic tertiary base, e.g. pyridine or triethylamine, to obtain N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide which is then hydrolyzed in aqueous or aqueous-alcoholic acid solutions to obtain N-(1-benzylpiperid- 4-yl)-2-methoxy-4-amino-5-chlorobenzamide.

When a C 1 -C 8 -alkyl ester of a 2-methoxy-4-acylamino-5-chlorobenzoic acid is used as reactant with a 1-benzyl-4-amino-piperidine of formula III, the reaction can be carried out in an aromatic or chlorinated hydrocarbon in presence of a base, such as an alkali metal C₁-C₂ alkoxide or a trialkyl derivative of aluminium, with continuous removal of the C₁-C₂ alcohol formed in the reaction.

1 6

2-Alkoxy-4-amino-5-halo-benzoic acids with the general formula II used as starting material for the compounds with the general formula I can be prepared from 4-acetamido-salicylic acid by alkylation and esterification of the 2-hydroxy group and the carboxy group, respectively . by treatment with a C₁-Cg alkyl halide or sulfate in an inert organic solvent, such as a C₁-Cg alkyl ester of a C₁-C₂-alkanoic acid or an alkyl ketone with 1-6 alkyl groups, in the presence of an inorganic base such as potassium carbonate. The product formed is then halogenated in the 5-position of the benzene nucleus with chlorine or bromine, in an organic solvent, e.g. acetic acid, in the presence of the halide of a heavy metal, such as ferric chloride. Other halogenating agents such as iodobenzene dichloride can also be used. The corresponding acids can be prepared from the obtained esters by acid hydrolysis in an aqueous or aqueous-alcoholic solution. The 1-benzyl-4-aminopiperidines of formula III can be prepared by reduction of the corresponding 1-benzyl-piperid-4-one oximes with an alkali metal aluminum hydride or an alkali metal in an alcoholic solvent [Harper N.J. et al,

J. Med. Chem. 7, 729,732 (1964)]. The 1-benzyl-piperid-4-one oximes can be prepared by reacting the corresponding ketone with hydroxylamine hydrochloride in aqueous alcoholic solution. The 1-benzylpiperid-4-ones are prepared by known methods [e.g. Becket et al, J. Med. Pharm. Chem. 1, 37 (1959)] or from 4-piperidone hydrochloride. The latter compound is transferred to its ethylene ketal with ethylene glycol. The ketal is then reacted with a benzoyl halide to give a l-benzoylpiperid-4-one-ethylene ketal which can be reduced with lithium aluminum hydride to give the corresponding 1-benzylpiperid-4-one-ethylene ketal, which on acid hydrolysis gives 1-benzylpiperid-4- one.

A preferred method for obtaining the compounds of formula I is the mixed anhydride method, for example 2-methoxy-4-amino-5-chlorobenzoic acid can be transferred to a mixed anhydride in situ with an alkyl chloroformate in the presence of a tertiary base, such as triethylamine or pyridine, in an inert organic solvent such as a chlorinated hydrocarbon, a C 1 -C 8 alkyl ester of a C 1 -C 8 fatty acid, a ketone or ether with C 1 -C 8 alkyl groups, a cyclic ether, e.g. tetrahydrofuran or dioxane, at a temperature from -20°C to room temperature, and the mixed anhydride formed can then be reacted with 1-benzyl-4-aminopiperidine to obtain N-(1-benzylpiperid-4-yl)-2-methoxy- 4-amino-5-chlorobenzamide.

This compound and other compounds of the general formula I can also be prepared by condensing the same acid or another acid of the general formula II, or a 4-acylamino derivative thereof, with 1-benzyl-4-amino-piperidine in the presence of a dehydrating agent such as silicon tetrachloride, a mono-, di- or tri-alkylsilyl halide, titanium tetrachloride, N,N<1->dicyclohexylarbodiimide, thionyl chloride or sulfur trichloride in dimethylsulfoxide, benzenesulfonyl chloride, toluene-p-sulfonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reactions can be carried out in an anhydrous inert organic solvent such as halogenated or aromatic hydrocarbons, pyridine, C-^-Cg-alkyl esters of C-^-Cg-alkanoic acids, alkyl ketones or ethers with C1,-CD,-alkyl groups, or cyclic ethers at temperatures between room temperature and the boiling point of the solvent used. If an acyl-protecting group is present, the desired compound of formula I is obtained by hydrolysis of the intermediate product obtained.

The compounds of the general formula I prepared by

the methods described above can be transferred on i and

known per se to pharmaceutically acceptable salts.

The present invention also includes the preparation of the salts of compounds of formula I with known biologically and pharmacologically acceptable inorganic and organic acids, for example such salts are sulphates, hydrohalides, phosphates, C^-Cg-alkanesulfonates, arylsulfonates, salts of C-^-C^ q-aliphatic mono-, di- or tribasic acids which may contain one or more double bonds, an aryl ring or another functional group such as hydroxy, amino or keto, salts of aromatic acids in which the aromatic core is optionally substituted with groups which hydroxy, C₁-C₆-alkoxy, amino, mono- or di-(C₆-C₆)alkylamirio or sulfonamido. Also included in the invention is the production of pharmaceutically acceptable quaternary salts of the compounds of the general formula I in which the tertiary nitrogen atom in the piperidine ring is quaternized by reaction with C-1-C8 alkyl halide or sulfate. In the preparation of dosage preparations, a person skilled in the art will select the appropriate pharmaceutically acceptable salt.

The preparations containing the process compounds can be adapted for oral, topical, percutaneous or parenteral use, but the preferred route of administration is per os. In this case, the oral preparations can take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations such as mixtures, elixirs, syrups or suspensions, all of which contain one or more of the compounds according to the invention. Such preparations can be prepared by known methods.

The process compounds can also be used in admixture with other active anti-acid and anti-ulcer agents (except anticholinergic agents) for oral or, in appropriate cases, for parenteral use.

The compounds according to the invention have shown activities which can be considered beneficial in the treatment of gastro-intestinal and cerebral malfunction in mammals including animals and humans. The characteristic properties of these compounds are antagonism of the effects of the dopaminergic agent, apomorphine, in animals, local anesthetic activity and the ability to induce catatonia in rats and mice. Consequently, they may be useful in the treatment of nausea and vomiting of various origins and as neuroleptic or psychosedative agents.

Compounds provided by the present invention have been shown to have antiemetic and neuroleptic properties and to increase the rate of gastric emptying in humans. For example, the compounds of formula (1^ and especially salts of "clebopride" have shown such properties at single doses between 0.01 (10 µg) and 20 mg. They can be used in doses of from 0.1 to 1000 mg per day for treatment of nausea and vomiting due to gastrointestinal disorders, congestive heart failure, post-operative conditions, etc, other gastrointestinal tract disorders such as dyspepsin, flatulence, bile regurgitation, hiatus hernia, peptic ulcer, reflex oesophagitis, gastritis duodenitis and cholelithiasis, and as an aid in radiography of the gastrointestinal tract, or they may be used as neuroleptic or psychosedative agents. The compounds cause considerably less central nervous system disturbance than chlorpromazine or other phenothiazine antiemetic agents, presumably as a function of their more selective anti-dopaminergic effects. Experimental trials have shown, for example, that hydrochloride and malate salts of "Clebopride" are metabolized extensively in rats and rabbits. Only very little of the unchanged drug is excreted in the urine. N-debenzylation is an essential metabolic reaction. Cleavage of the amide bond does not appear to be a significant metabolic reaction. Conjugation with glucuronic acid and/or sulfate occurs to a large extent in rabbits.

The pharmacokinetics of the drug after intravenous administration follows a similar pattern in both types. The relatively low plasma concentrations observed after oral administration of high doses of the malate salt, despite the rapidly occurring peak indicating good absorption, and the rapid appearance of metabolites in blood, suggest that extensive first pass metabolism and/or uptake is taking place in the liver.

The recognition of this phenomenon is important for the assessment of the drug's pharmacology and toxicology, and for the selection of optimal therapeutic doses for oral and parenteral administration.

Standard pharmacological tests have been carried out using many of the compounds covered by the general structural formula (I). These tests have been carried out with rats, mice, dogs and humans. In many of these tests, the method compounds have been compared with metoclopramide and other known therapeutic compounds which have similar properties to the compounds produced according to the invention.

A number of the process compounds were investigated. in parallel with metoclopramide on potential anti-emetic effects against apomorphine-induced gnawing in rats, and as a local anesthetic on the rat sciatic nerve (Table I). The most active compounds were also tested for their ability to decrease gastric emptying time in rats. The first compound (the hydrochloride salt of "Clebopride") was shown to have a potency similar to that of metoclopramide in this test.

As will be seen from Table I, some of these compounds exhibit a similar activity profile to metoclopramide,

and especially the first compound ("Clebopride" HCl salt) and compounds no. 2, 3 and 5 are more active as antiemetics.

Some of the compounds do not show antiapomorphine activity in rats even at high doses, but are active in antagonizing the effects of apomorphine in dogs and in pigeons at doses of 10-100ug/kg and 10-50 mg/kg, respectively.

These compounds cause considerably less disturbance in the central nervous system than chlorpromazine and other pheno-thiazine antiemetic agents do. This is shown in Table III from which it appears that "Clebopride", like metoclopramide and unlike chlorpromazine, exhibits antiemetic activity (anti-apomorphine activity) at doses far from those causing catatonia. The dose for the active compounds in humans can vary between 0.1 and 100 mg per day of up-

divided doses.

The hydrochloride salt of "Clebopride" has shown high activity against apomorphine-induced vomiting in dogs. When used by the oral route, the hydrochloride salt is approximately 8 times stronger than metoclopramide as shown in Table II.

The properties of the process compounds are illustrated

by the following discussion of pharmacological studies.

Based on pharmacological studies with mice, "Clebopride"-HCl salt has been shown to be a local anesthetic with a potency somewhat greater than that of both metoclopramide and procaine.

Other studies have indicated that "Clebopride"-HCl affects the central nervous system. For example, it has anticonvulsant

Activity. "Clebopride" is somewhat stronger than metoclopramide in preventing electrically induced convulsions in mice. However, neither "Clebopride" nor metoclopramide appears to inhibit convulsions induced by strychnine in mice, or has anti-oxotremorine activity. Nevertheless, both compounds are able to induce salivation and tremors in mice that have been pre-treated with a sub-threshold dose of oxotremorine. "Clebopride"-HCl salt but not metoclopramide, inhibits tonic convulsion (antileptazole) in mice, but apparently not chronic seizures induced by leptazole.

Both "Clebopride"-HC1 and metoclopramide inhibit spontaneous motor activity and cause incoordination, as measured on an accelerating rotarod in mice. Catatonia attributed to "Clebopride" has been noted in rats and to a lesser extent in mice.

"Clebopride"-HCl salt has weak effects on the cardio-vascular and respiratory systems. For example, in cats anesthetized with α-chloralose, a slow intravenous infusion of "Clebopride" HCl salt at a rate of 1 mg/kg.min to a total dose of 10 mg/kg produces a slight fall in both blood pressure and heart rate and slower respiratory movements.

"Clebopride"-HC1 has no particular effect on the autonomic nervous system.

The "Clebopride" HCl salt does not have antipyretic and analgesic activity. For example, "Clebopride" in a dose of 300 mg/kg per os has similar activity to 200 mg/kg acetyl-salicylic acid against yeast-induced pyrexia in rats. "Clebopride", at a dose of 300 mg/kg per os, almost completely inhibited the writhing syndrome induced in mice by intraperitoneal injection of acetic acid.

The "clebopride" HCl salt has weak anti-inflammatory activity and no particular parasympatholytic activity.

A number of the compounds produced according to the invention, particularly the hydrogen chloride, malate and methanesulfonate salts of "Clebopride", have been tested extensively in humans to determine maximum doses and the therapeutic effects of the compounds. These compounds have been administered to humans orally and parenterally.

Useful doses of "Clebopride" salts appear to lie between 0.1 and 30 mg per day, depending on the length of treatment and the desired therapeutic effect. Such doses of hydrochloride salts have been shown to be practically free of side effects, and single doses of between 0.2 and 5 mg seem to be effective for e.g. to increase gastric emptying.

A study was done to test the effect of "Clebopride" on slowing gastric emptying time in humans, using a range of doses (0.2 mg, 1 mg, 2 mg and 5 mg) compared to 10 mg of metoclopramide.

All drugs were given in liquid suspension by mouth, and the patients used had a number of diagnoses, but had in common some kind of gastric disorder.

The assessment was based on the subjective opinions of the radiologist expressed in the time required for the appearance of peristaltic waves and their ability to empty the stomach, according to the following scheme:

From this and other experiments, it is concluded that 0.2 mg of "Clebopride" produces an equally rapid and powerful contraction of the stomach as 20 mg of metoclopramide. 2 mg "Clebopride" has a faster onset of action and produces a stronger contraction than 20 mg metoclopramide.

Another study has been conducted to investigate the acute tolerance of the malate salt of "Clebopride" after intramuscular and intravenous administration in humans.

The research subjects used were healthy, voluntary men between the ages of 20 and 24, and were divided into eight groups and given the test compound according to the following schedule: Group I 1 mg intramuscularly per day for 5 days Group II 1.5 mg intramuscularly per day for 5 days Group III. 2 mg intramuscularly per day for 5 days Group IV 0.25 mg intravenously per day for 5 days Group V 0.50 mg intravenously per day for 5 days Group VI 1 mg intravenously per day for 5 days

Group VII 1.5 mg intravenously per day for 5 days Group VIII 2 mg intravenously per day for 5 days

The evaluated parameters were subjective symptoms; mental disorders; neurological disorders; autonomic symptoms; digestive disorders; urogenital disorders; . skin and mucous membranes; pulse; blood pressure temperature; other side effects; blood analysis (leukocyte composition, hemoglobin content, erythrocyte sedimentation rate, glucose, cholesterol, urea, liver function tests, transaminases); and urinalysis (specific gravity, albumin, sediment).

Significant effects can be summarized as follows: 1. Of the four people in group I, one case of light sleepiness was noted from the second day of the treatment. 2. Fatigue, sleepiness and exhaustion in three of the four people in group II accompanied by mild depression. 3. Three of the four people in group*III showed sleepiness, exhaustion and depression followed by euphoria. 4. Somnolence, fatigue and depression of moderate intensity were seen in many patients in groups IV to VIII and do not appear to be dose dependent. Moreover, in groups "VII and VIII, some sweating, hypersalivation and dryness of the mouth were seen on different. 5. Blood and urine analysis performed in groups II and VII showed no significant variations.

The following examples illustrate the preparation of the various compounds according to the invention.

Example 1

N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride

50 ml of 8N sodium hydroxide was added to a solution of 15.0 g (0.032 mol) N-(1-benzylpiperid-4-yl)-2-methoxy-4-(α,α,o-trifluoroacetamido)-5- chlorobenzamide in 50 ml of ethanol, and the reaction mixture was stirred at room temperature for 3 hours, after which it was diluted with water and extracted with chloroform. The chloroform extracts were dried, de-coloured and evaporated at low temperature, whereby a residue was obtained which was dissolved in acetone. A saturated solution of hydrogen chloride in ethanol was added to the acetone solution until the solution was slightly acidic. The solid was collected and recrystallized from ethanol with 4% water to give 12.3 g of a white product which was N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide- hydrochloride > Ho0,

m.p. 216-219°C, the base melted at 193-195°C.

Example 2

N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide

A solution of 15.1 g (0.075 mol) of 2-methoxy-4-amino-5-chlorobenzoic acid (see Method 7, p. 20) in 150 ml of dry tetrahydrofuran was cooled to -15° to -10°C. 10.5 ml (0.075 mol) of triethylamine in 30 ml of dry tetrahydrofuran was slowly added followed by 7.05 ml (0.075 mol) of ethyl chloroformate, also dissolved in dry tetrahydrofuran.

Stirring was maintained for 1 hour at -15° to -10°C, and then 14.26 g (0.075 mol) of 1-benzyl-4-aminopiperidine in 30 ml of tetrahydrofuran was added. The temperature of the reaction mixture was allowed to reach room temperature with stirring and was then held at this temperature for 6 hours, at which time the precipitate was filtered off. The organic extracts were evaporated at low temperature, the residue was dissolved in chloroform, and the solution was washed several times with water.

The chloroform extracts were evaporated at low temperature, whereby a paste was obtained which was dissolved in hot diethyl ether and allowed to crystallize. 21.2 g of a white solid N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide with m.p. 193-195°C.

Example 3

N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide

(a) 16.5 g (0.081 mol) of 2-methcocy-4-amino-5-chlorobenzoic acid, dissolved in 450 ml of anhydrous tetrahydrofuran was introduced into a 1 liter flask fitted with a stirrer and addition funnel. 11.4 ml (0.081 mol) of triethylamine in 30 ml of tetrahydrofuran was slowly added to this solution while it was kept at room temperature. The mixture was then cooled to between 10°C and 0°C,

and 6.48 mL (0.089 mol) of ethyl chloroformate in 15 mL of tetrahydrorufan was added. After stirring for 1 hour at the same temperature, 15.39 g (0.081 mol) of 1-benzyl-4-amino-piperidine dissolved in 30 ml of tetrahydrofuran was added, while maintaining the same temperature. When the addition was complete, the mixture was held between

0° and 10°C for 1 hour and then for 8 hours at room temperature. The triethylamine hydrochloride was filtered off and the organic phase was evaporated to dryness to give a white solid which was recrystallized from methanol to give 25.5 g of the title compound, m.p. 193-195°C. Yield 84%. (b) 34.5 g (0.134 mol) methyl 2-methoxy-4-acetamido-5-chlorobenzpate, 67 ml xylene, 26.63 g (0.140 mol) 1-benzyl-4-aminopiperidine and 6.7 g aluminum isopropylate was placed in a 500 ml flask equipped with a stirrer and a Vigreux distillation column of approx. 30 cm height. The mixture was heated until the theoretical amount of methanol had distilled off. Excess xylene was removed and the residue was treated with a mixture of 160 ml of water and 40 ml of concentrated hydrochloric acid. The xylene layer was removed and the aqueous solution was made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform extracts were evaporated and the colorless solid which remained was collected and m.p. 134-135°C.

This solid was heated under reflux with

a solution of 134 ml of concentrated hydrochloric acid and 220 ml of water for 1 hour. The solution was then made alkaline with sodium hydroxide and then extracted with chloroform. The chloroform extract was evaporated to give 37.5 g (72%) of the title compound as a white solid with m.p. 193-195°C. (c) To a solution of 8.04 g of 2-methoxy-4-amino-5-chloro-benzoic acid and 7.6 g of 4-amino-1-benzylpiperidine in 100 ml of anhydrous pyridine was added 3.4 g of silicon tetrachloride at room - temperature. The mixture was then heated under reflux for 3 hours, and the pyridine was removed in vacuo. The residue was then treated with a mixture of water and chloroform and stirred vigorously whereupon an insoluble residue separated. The clear liquid was decanted, and the aqueous phase was separated and made alkaline with a solution of sodium carbonate and then extracted with chloroform. The chloroform solution was dried and distilled to give 12 g of the title compound with m.p. 193-195°C. (d) To a solution of 4.0 g of 2-methoxy-4-amino-5-chlorobenzoic acid in 100 ml of methylene chloride, 4.1 g of N,N'-dicyclohexylcarbodiimide was added at room temperature. After a few minutes, 3.8 g of 4-amino-1-benzylpiperidine were added with stirring, and

the mixture was stirred at room temperature overnight.

The insoluble N,N'-dicyclohexylurea formed was separated by filtration, and the filtrate was washed with water, dried and the solvent removed in vacuo. The residue was recrystallized from methanol whereby 6.0 g of the title compound with melting point 194-195°C was obtained. (e) To a solution of 4.90 g of 4-acetamido-5-chloro-2-methoxy-benzoic acid in 80 ml of pyridine was added 13 ml of benzenesulfonyl chloride followed by 1.9 g of 4-amino-1-benzylpiperidine, and the mixture was stirred at room temperature for 1 hour. It was then poured into a mixture of ice and water, and the product was extracted with chloroform. The chloroform layer was separated, washed with water, dried, and the solvent was removed in vacuo. The residue was recrystallized from methanol which gave 3.5 g of the 4-acetamido compound with m.p. 134-135°C.

This compound was then hydrolysed by the method in example 3(b), whereby the pure title compound with m.p. 194-195°C. (f) To a mixture of 2.5 g of N-ethyl-5-phenyl-isoxazolinium-3-sulfonate (Woodward's reagent) in 25 ml of anhydrous acetonitrile was added dropwise at a temperature of -5° to 0° C a solution of 2.5 g of 4-acetamido-5-chloro-2-methoxy-benzoic acid 1 40 ml of anhydrous tetrahydrofuran containing 0.75 ml of triethylamine. After the addition was complete, the mixture was stirred at 0° C. for 1 hour and at room temperature for a further 1 hour. It was then cooled to -5° to 0°C and a solution of 2 g of 4-amino-1-benzylpiperidine in 10 ml of anhydrous tetrahydrofuran was added. The resulting mixture was stirred at 0° C. for 1 hour and at room temperature for 3 hours and the solvent was removed in vacuo. To the residue was added 40 ml of water and the resulting solution was made alkaline with sodium hydroxide solution and then extracted with chloroform. The chloroform solutions were separated, dried and the solvent removed. The residue was crystallized from methanol, whereby the product with a melting point of 134 - 135° C was obtained. This product was hydrolysed. by the method in example 3(b) whereby the desired title compound, N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, was obtained, m.p. 193-195°C.

By a method similar to that described in Example 3, the following compounds were prepared: N-(1-p-methoxy-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 238-239°C; N-(1-m-chlorobenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 249-251°C; N-(1-piperonylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenz-araide hydrochloride, m.p. 264-266°C; N-(1-p-chlorobenzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride, m.p. 253-256°C.

Example 4

N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide fumarate (C__H_ .ClN-,0- .C.H.O.)

20 24 3 2 4 4 4

A hot solution of 3.75 g of N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide in 130 ml of methanol was added to a hot solution of 1.2 g of fumaric acid in 60 ml acetone and 20 ml of methanol. The resulting solution was filtered and allowed to cool, whereby the product crystallized in a yield of 2.7 g with a melting point of 209-210°C.

Following a similar procedure, the following salts of N-(1'-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide were prepared:

Example 5

N-(1-benzylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide methiodide

1.25 ml (0 .02 mol) methyl iodide. The mixture was stirred at room temperature overnight and then heated to 45-50°C for 3 hours. The insoluble product was recovered by filtration and washed with acetone, whereby 4.5 g of product with a melting point of 201-203°C were obtained.

By a similar procedure, the iodoethylate was obtained

with m.p. 205-207°C.

The starting materials were prepared as follows:

Method 1

2- methoxy- 4-( g, g, g- trifluoroacetamido) - 5- chloro- benzos. bladder

2.65 g (0.037 mol) chlorine dissolved in 50 ml acetic acid was slowly added to a suspension of 9 g (0.034 mol) 2-methoxy-4-(<g>,a,<g->trifluoroacetamido)-benzoic acid in 160 ml acetic acid, idet. the temperature was kept between 15 and 20°C.

After completion of the addition, the reaction mixture was kept at room temperature for 4 hours. The reaction mixture was then poured into ice water and a white solid precipitated, which was filtered off and dried. It was then crystallized from acetone-ether, whereby 9.1 g of crystals with a melting point of 178 - 180° C were obtained

in a yield of 90%.

Using the same method, but starting from 2-methoxy-4-acetamido-benzoic acid, the following acids were also obtained: 2-methoxy-4-acetamido-5-chloro-benzoic acid with m.p. 208-210°C.

Method 2

2- methoxy- 4-( a, a, a- trifluoroacetamido)- 5- chlorobenzoyl chloride

A mixture of 10 g (0.033 mol) of 2-methoxy-4-(<g>,<g>,<g->trifluoroacetamido)-5-chlorobenzoic acid, 6.6 ml of thionyl chloride and 15 ml of dry benzene was heated at 60 - 70° C for 4 hours. The resulting solution was poured into 50 ml of petroleum ether and the precipitated product was collected by filtration in the form of a colorless solid (9 g) with a melting point of 91 - 93°C.

Method 3

N-(1-benzylpiperid-4-yl)-2-methoxy-4-(α,α,α-trifluoroacetamido)-5-chlorobenzamide hydrochloride

A solution of 14.7 g (0.046 mol) of 2-methoxy-4-(α,α,α-trifluoroacetamido)-5-chlorophenzoyl chloride in 100 ml of methyl ethyl ketone was added slowly while maintaining the temperature at 0-5°C, to a solution of 7.99 g (0.042 mol) 1-benzyl-4-amino-piperidine in 75 ml of methyl ethyl ketone cooled to a temperature of 0 - 5° C. After the addition was completed, the reaction mixture was kept at the same temperature while stirring in 1 hour and then at room temperature for 5 hours.

The solid that had separated was filtered off, washed with methyl ethyl ketone and then crystallized from ethanol, whereby 20 g of a white solid with m.p. 227-228°C.

Method 4

4- acetamidosalicylic acid

30.6 g (0.2 mol) p-aminosalicylic acid and 100 ml

ethanol was introduced into a 250 ml flask and the mixture was heated to 40°C. 20.4 g (0.2 mol) of acetic anhydride was then added at such a rate that the temperature did not exceed 50°C. When the addition was complete, the mixture was stirred at 50°C for 3 hours. The product was filtered off. Weight: 36 g, m.p. 235°C. Yield 92%.

Method 5

Methyl- 2- methoxy- 4- acetamidobenzoate

34 g (0.17 mol) 4-acetamidosalicylic acid, 57.96 g

(0.42 mol) of potassium carbonate and 250 ml of acetone were introduced into a 500 ml flask and heated to 40°C. Then, while maintaining the same temperature, 51.40 g (0.408 mol) methyl sulfate was added during approx. 15 minutes, and the mixture was heated under reflux for 5 hours. The mixture was cooled, and the precipitated potassium sulfate was filtered off, and the acetone solution was evaporated to one third of its original volume. Dilution with ethyl ether gave a crystalline solid which

was filtered out. Weight 34 g, m.p. 130-132°C. Yield 89%.

Method 6

Methyl- 2- methoxy- 4- acetamido- 5- chlorobenzoate

34.8 g of methyl-2-methoxy-4-acetamidobenzoate, 180 ml of acetic acid and a trace of ferric chloride were introduced into a 500 ml flask fitted with a stirrer, thermometer and gas inlet. The solids were dissolved by heating, and the solution was cooled to 15° C. While maintaining this temperature, a stream of chlorine was passed through the solution, the reaction being regulated by cooling, until the weight had increased by 11.2 g. The obtained solution was poured into 2 liters of water, which precipitated a white solid which was filtered off and gave 33 g of product with melting point 149 - 152° C in a yield of 82%.

Method 7

2- methoxy- 4- amino- 5- chloro- benzoic acid

25.75 g (0.1 mol) of methyl 2-methoxy-4-acetamido-5-chlorobenzoate suspended in 100 ml of ethanol was introduced into a 500 ml flask. 40 g of sodium hydroxide dissolved in 150 ml of water was added and the mixture was heated under reflux for 2.5 hours. The mixture was diluted with water and acidified with concentrated hydrochloric acid. The white solid that precipitated was collected and recrystallized from methanol. Weight: 17 g, sm.p. 213 - 215° C,

yield 84%.

Method 8

1- Benzy1- 4-piperidone oxime

48 g of 1-benzyl-4-piperidone-oxime hydrochloride (1) was placed in a liquid-liquid extraction apparatus and dissolved in a solution of 8 g of sodium hydroxide in 100 ml of water. After 7 hours of extraction with ether, 38 g of white solid with melting point 129 - 131° C was obtained in a yield of 93%. (1) P. Brookers, R.J. Terry and Walker. J.Chem.Soc. 3172 (1957).

Method 9

1- benzyl 1- 4- amino- piperidine

7.6 g (0.2 mol) of lithium aluminum hydride and 300 ml of anhydrous ether were introduced into a 1 liter flask equipped with a mechanical stirrer and Sochlet extractor. 20 g (0.1 mol) of 1-benzyl-4-piperidone oxime was placed in the Sochlet sleeve, and the mixture was heated under reflux for 12 hours, after which excess lithium aluminum hydride was destroyed. The ether extracts were dried and evaporated to dryness, whereby an oil weighing 18 g was obtained.

Distillation in vacuum gave 17 g of pure product with a boiling point of 103-105°C at 0.07 mmHg.

By a similar procedure, the following compounds were prepared:

1-(p-methoxybenzyl)-4-aminopiperidine dihydrochloride,

m.p. 2 5 7-2 5 9°C,

1-(m-chlorobenzyl)-4-aminopiperidine dihydrochloride,

m.p. 275-276°C,

1-(p-chlorobenzyl)-4-aminopiperidine dihydrochloride,

m.p. 308-310°C.

Claims (1)

Analogous procedure in the preparation of therapeutically active compounds with the general formula: where: X is chlorine or bromine, is straight-chain or branched alkyl with 1-6 carbon atoms, R2 and R^ can be hydrogen atoms, or one of these symbols can denote a chlorine atom in the 3- or 4-position, or methyl or methoxy in the 4 -position and the second symbol denote hydrogen, or R0 and R^ can together be a methylenedioxy group bound to the 3- and 4-positions, or pharmaceutically acceptable salts thereof, characterized in that a 2-Alkoxy-4-amino-5-halobenzoic acid of the general formula: where X and R^ are as indicated above, whose amino group is optionally protected with an acyl group, or an active derivative of such an acid, is reacted with a l- benzyl-4-aminopiperidine of the general formula: where R_ and R., are as indicated above, and when the amino group on the benzoic acid reactant or its active derivative is protected, the protecting acyl group is removed by hydrolysis, and that a base thus obtained is optionally transferred to an acid addition salt thereof, or an acid addition salt obtained is transferred to the free base.